Defense potential of secondary metabolites in medicinal plants under UV-B stress

Journal of Photochemistry & Photobiology, B: Biology 193 (2019) 51–88

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Defense potential of secondary metabolites in medicinal plants under UV-B stress Swabha Takshak, S.B. Agrawal

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Laboratory of Air Pollution and Global Climate Change, Department of Botany, Banaras Hindu University, Varanasi 221 005, India

ARTICLE INFO

ABSTRACT

Keywords: Defense potential Medicinal plants Secondary metabolites UV-B radiation

Ultraviolet-B (UV-B) radiation has, for many decades now, been widely studied with respect to its consequences on plant and animal health. Though according to NASA, the ozone hole is on its way to recovery, it will still be a considerable time before UV-B levels reach pre-industrial limits. Thus, for the present, excessive UV-B reaching the Earth is a cause for concern, and UV-B related human ailments are on the rise. Plants produce various secondary metabolites as one of the defense strategies under UV-B. They provide photoprotection via their UV-B screening effects and by quenching the reactive oxygen- and nitrogen species produced under UV-B influence. These properties of plant secondary metabolites (PSMs) are being increasingly recognized and made use of in sunscreens and cosmetics, and pharma- and nutraceuticals are gradually becoming a part of the regular diet. Secondary metabolites derived from medicinal plants (alkaloids, terpenoids, and phenolics) are a source of pharmaceuticals, nutraceuticals, as well as more rigorously tested and regulated drugs. These metabolites have been implicated in providing protection not only to plants under the influence of UV-B, but also to animals/ animal cell lines, when the innate defenses in the latter are not adequate under UV-B-induced damage. The present review focuses on the defense potential of secondary metabolites derived from medicinal plants in both plants and animals. In plants, the concentrations of the alkaloids, terpenes/terpenoids, and phenolics have been discussed under UV-B irradiation as well as the fate of the genes and enzymes involved in their biosynthetic pathways. Their role in providing protection to animal models subjected to UV-B has been subsequently elucidated. Finally, we discuss the possible futuristic scenarios and implications for plant, animal, and human health pertaining to the defense potential of these secondary metabolites under UV-B radiation-mediated damages.

1. Ultraviolet-B radiation: historical aspects, current scenario, and future perspectives Since the advent of the industrial era and consequent anthropogenic causes of stratospheric ozone depletion, UV-B radiation (280–315 nm) has been reaching the Earth’s surface in increased amounts [1]. Since UV-B portion of the solar spectrum comprises approximately 0.7% of the total, and is not a major factor in influencing climatic conditions such as heating the Earth and affecting air movements, meteorologists considered it to be an inconsequential feature of weather and climate. Hence, it was measured only as a part of research efforts based on medical or environmental grounds, or as an offshoot of ozone measurements. Over the years, UV measurement programs were initiated and terminated round the globe (though not necessarily during the same duration) as per the demands and/or urgencies of the then situation. The initial measurements of UV were initiated by a group of

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physicians in the 1920s [2]. Later, the Dobson spectrophotometer [3] and later still, the more precise Brewer spectrophotometer [4] enabled easy and accurate measurements of UV. Ground-based measurements were made in Switzerland to enhance an understanding of the factors affecting UV radiation during the late 1950s and early 1960s [2]. Apprehensions about UV-B causing skin cancer revived the need and urgency regarding its measurements. UV-B measurement networks were established in Australia and USA in the 1970s, which ceased during the years 1981 and 1985, respectively [2]. In the latter year, however, the Antarctic ozone hole was discovered which jolted the meteorologists and scientists into conducting exhaustive and intense researches into explaining the ozone losses, its probable causes, its consequences (primarily increased UV-B radiation reaching the Earth’s surface), and advising the policy makers as to the probable measures to halt its continuing decline. One of the first consequences of these efforts was the Montreal Protocol on Substances that Deplete Ozone Layer,

Corresponding author. E-mail address: [email protected] (S.B. Agrawal).

https://doi.org/10.1016/j.jphotobiol.2019.02.002 Received 16 December 2018; Received in revised form 9 February 2019; Accepted 11 February 2019 Available online 13 February 2019 1011-1344/ © 2019 Elsevier B.V. All rights reserved.

Journal of Photochemistry & Photobiology, B: Biology 193 (2019) 51–88

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signed in 1987 to contain and limit the emission of ozone depleting substances (ODSs). Measurement of UV radiation implicates ozone column measurements, which in turn, are dependent upon the amount of ODSs in the atmosphere and our current status of knowledge regarding ozone depletion processes. Today, a number of ozone models are available which predict the current and future ozone column and consequent UVB scenarios, though the predictions and generalizations made by them are highly diverse depending upon the parameters included in devising the model [5]. Montreal Protocol, according to the studies up to 2013 by Chipperfield et al. [6], has been quite effective in controlling ODSs emissions. Antarctic ozone hole was initially expected to recover by ~2050, obliterating UV-B as a potent stress factor influencing life on Earth. However, some studies prior to 2013 as well as some later ones depict a not-so-simple scenario. For instance, in 2012, Anderson et al. [7] found a link between changing climatic conditions and increased incidence of UV-B reaching the Earth due to increase in the frequency and intensity of thunderstorms. These thunderstorms are capable of thrusting water molecules into the air up to the stratosphere whence the sulfate aerosols attract these molecules and chemical reactions occur that destroy ozone. Moreover, Laube et al. [8] have detected and quantified three CFCs and one HCFC with unknown emission sources; total emissions before 2012 amounted to more than 74,000 tons. These compounds are contributing to the destruction of ozone, leading to increased levels of UV-B reaching the Earth. Already, in 2006, predictions have been made that full ozone hole recovery is expected to occur by 2068 (as against 2050 as previously expected), and a significant decrease in the ozone-hole area is not expected to start to occur until about 2024 [9]. More recently, NASA scientists have predicted the ozone-hole size to return to pre-1980 levels by about 2075 [10]. Updates by the UNEP Environmental Assessment Panel [11] indicate that though the ozone levels over Antarctica have started to recover, the loss of stratospheric ozone over the Arctic observed in the winter of 20152016 and injection of water vapor into the lower stratosphere during severe storms are still causes of concern. They also report that the resulting UV-B on the Earth’s surface, due to these factors and due to variations in aerosols (amount and optical properties) and cloud cover, is responsible for still increasing incidences of melanomas and modulations in the immune system. The studies mentioned above are the reason that measurements of ozone columns and resulting UV-B intensities and/or the direct measurements of solar UV irradiances are still being carried out zealously all over the globe. Some of the latest studies in the area include those over Denmark [12], USA [13], Cape Point, South Africa [14], Greece [15], and Reunion Island in the southern tropics [16]. These focus on either the current solar UV irradiances and UV-B scenarios, or past trends in ozone and UV-B levels to simulate future trends. Researches are also under way to design and test new instruments and algorithms to measure various radiation levels in the troposphere, including UV. For instance, TROPOspheric Monitoring Instrument (TROPOMI, a spectrometer) measuring ultraviolet-, visible-, near infrared-, and shortwave infrared radiations has also been programmed to calculate the UV radiation reaching the Earth’s surface. Its aim is to monitor and provide information on the prevailing UV conditions over the globe; the preliminary results indicate successful implementation of the algorithm [17].

changes in plant architecture (altered morphological traits), physiological characteristics [20,21], and biochemical and genetic level changes [22,23]. The responses of plants to UV-B radiation vary widely depending upon the variability and intensity of UV-B radiation, which in turn depends upon its fluence rate, duration, and wavelength. Different crop species and different cultivars within the same species, differences in plant adaptation levels, and/or acclimation levels due to prior exposure to UV-B also cause variable plant responses [24–26]. Plants respond towards excessive UV-B damage via development of protective structures and mechanisms. The former include hairs, waxes, and other cellular modifications to provide optical protection, while the latter involve the induction of antioxidative enzymes and enhanced concentrations of protective molecules [27,28]. 3. Production of secondary metabolites (SMs) in plants in response to UV-B Secondary metabolites (SMs) were initially considered as by-products of various plant primary metabolic processes and consequently, not significant. However, later they were recognized to be as important (if not more so) as primary metabolites. They are responsible for plant adaptation and survival, especially under non-favorable conditions. Their functions include the following: attraction of insects as pollinators and seed dispersal agents; protection against herbivory, insect attacks and pathogens; acting as phytoalexins, UV-B screening compounds, growth hormones, and signaling compounds; and stimulation of root nodule formation. They are also commercially important, being exploited for the production of dyes, drugs, artificial flavoring compounds, nutraceuticals, and perfumes, amongst others [29,30]. SMs provide both active and passive resistance to plants. Constitutive metabolites provide passive resistance, while induced metabolites (that is, those that are newly synthesized, or those inherently present but synthesized in higher concentrations upon stress exposure) are responsible for active plant resistance [31]. Production of SMs in higher concentrations is an adaptive mechanism in response to enhanced UV-B exposure (studies on various agronomic crops have reported increases ranging from 10 to 300%) [27]. SMs accumulated in epidermal plant layers act as sunscreens, protecting underlying sensitive tissues from the damaging effects of UVB. However, prolonged exposure to UV-B might lower their protective potential probably by reducing overall photosynthate production [32]. As of early 2013, more than 200,000 SMs were identified from various living organisms while the total number of such compounds was estimated to be much higher [32]. 4. Protective mechanisms of plant secondary metabolites (PSMs) 4.1. In plants 4.1.1. Via direct screening The synthesis and accumulation of certain SMs in various cellular compartments in response to UV-B stress is the foundation of this particular protective mechanism. This mechanism has been termed “passive” and adheres to the proverb “Prevention is better than cure”. Screening prevents photodamage by alleviating its cause, that is, via absorption of excessive UV-B (and also visible light, in some instances) by photosensitive cellular components [33,34]. To successfully act as photoprotective UV-B screening pigments, the compounds should possess the following properties [35,36]:

2. Plant responses to UV-B UV-B has long been regarded as a potential factor causing stress to living organisms [18,19]. Plants, being sessile, are inevitably exposed to UV-B radiation and hence, adapt themselves as per the altered environmental conditions. Exposure to mild UV-B can induce acclimation responses, while severe stress conditions have been known to cause metabolic disorders. These adaptations manifest themselves in terms of

(i) They should absorb radiation in the UV-B range. (ii) They should be induced in the cells upon UV-B irradiation (both in vitro as well as in vivo). (iii) They should be highly photostable (so that the photoprotective screen, once formed, is able to provide a reliable long-term 52

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protection). (iv) They should enable the plants to offer enhanced resistance to UV-B radiation.

disadvantage) and was found to be more effective in preventing UV-B induced DNA damage than commercial sunscreen [47]. Many natural compounds such as anthocyanins, carotenoids, flavonoids, tannins, and even some vitamins and volatile oils from crops as well as medicinal plants are being increasingly used in cosmetics as photoprotecting agents. These compounds, besides possessing UV-Bblocking properties, have the additional advantages of acting as antioxidant-, anti-inflammatory-, anti-ageing-, and wound-healing agents reviewed in [46,48]. For instance, extracts from medicinal plants Helichrysum arenarium, Cratageus monogyna, and Sambucus nigra were found to meet the criteria of sunscreen products due to their high photostability and antioxidative properties [49].

4.1.2. Via their innate antioxidative potential This property of PSMs is evident when they scavenge reactive oxygen species (ROS) generated under UV-B stress. Of all the PSMs reported till date, the antioxidative potential of the compounds of the phenylpropanoid pathway, the phenolics, has been the most widely recorded and reported [37], since this pathway is ubiquitous in plants, unlike the alkaloid and terpenoid biosynthetic pathways. Various categories of phenylpropanoid pathway compounds such as flavonoids and their glycosides, phenolic acids (e.g., hydroxycinnamic acids) and their derivatives, stilbenes, and anthocyanins, amongst others, act as antioxidants [38]. These antioxidative properties are a function of not only the compound concentrations, but also their structures. For instance, monohydroxylated B-ring flavonoids (with a single –OH group) are better absorbers of UV-B as opposed to dihydroxy B-ring flavonoids, which contain two –OH groups and are better candidates for antioxidative function [38]. Similarly, flavonoids with a catechol group in their B ring are better antioxidants than those that lack this group [39]. The effectiveness of various phenylpropanoids in successfully scavenging ROS is also dependent upon their location, that is, the cellular compartment(s) in which they are biosynthesized and/or accumulated (such as cell walls and vacuoles of epidermal cells, trichomes, vacuoles of mesophyll cells, chloroplasts, or sometimes even the nucleus) reviewed in [38] and the dose and duration of UV-B irradiance. Under prolonged UV-B exposure, the ratio of flavonoids to hydroxycinnamates steeply increases [40] while the latter compounds are more prevalent in tissues experiencing lower doses of UV-B [41].

4.2.2. Via oral consumption (through foods and food supplements) PSMs have been reported to possess a number of medicinal properties including antioxidant, anti-inflammatory, anti-cancer, and antimicrobial, amongst others, and they are expected to play the same role in the human body, once consumed [31]. However, the evidence from an evolutionary standpoint suggests a majority of PSMs to act as feeding deterrents. Consequently, their consumption should ideally cause adverse effects on the human body. Now, this statement is both true and false at the same time because, as has been demonstrated by Son et al. [50], ingestion of relatively small amounts of PSMs does not prove to be toxic but only induces mild stress responses. Moreover, consumption of high quantities of PSMs is no guarantee of their protective and healthpromoting effects; in fact, they may prove to be detrimental. This clearly suggests that the beneficial effects of PSMs via oral consumption are dose-dependent [51]. Moreover, the dose consumed is not always the dose that is functional. Since PSMs are primarily consumed as a part of the diet (whole of the edible plant/plant part, instead of just a single particular PSM), their efficacy is also affected by plant-based factors such as the presence of dietary fibers and other vitamins and nutrients, which in turn affects their digestibility, bioavailability, and bioactivity [52,53]. To make it even more challenging, the nutritional value of PSMs (whether individually or in mixtures) once consumed, are difficult to determine because ‘they act through weak negative biological feedback mechanisms, undetectable in vitro’ [54].

4.2. In animals 4.2.1. Via topical application (sunscreens) As the name suggests, sunscreens when applied on skin, prevent UV rays from coming into contact with it, thus providing photoprotection. Initially, Lowe and co-workers [42] classified sunscreens into two broad categories: physical sunscreens (now more aptly termed sunblocks) and chemical sunscreens, based on their mechanism of action. Sunblocks, containing inert particles such as zinc oxide and titanium dioxide, act by reflecting photons of both UV-B and UV-A, and sometimes even those of visible radiation. Chemical sunscreens (or simply sunscreens) on the other hand, are generally aromatic organic compounds conjugated with a carbonyl group (e.g. benzophenone, and sulisobenzone). The chromophore moiety of these molecules allows them to absorb UV rays and release rays of lower energy. The molecule itself may or may not be destroyed in the process [43]. Sunblocks have various advantages over sunscreens in that they are opaque, and block a higher percentage of light compared to the latter. Moreover, as their mechanism of action is physical in nature, they do not cause any harm to the skin. Sunscreens, however, are translucent and require frequent re-application in order to achieve optimum efficiency. More importantly, absorption of UV rays might cause the activation of its molecules, which in turn, may cause adverse skin reactions [43,44]. Erythema is a visible sign of UV-B-induced damage on human skin. The efficacy of a sunscreen is demonstrated by its ability to delay the sun-induced skin erythema and is determined by its sun protection factor (SPF). SPF can be defined as the level of solar exposure needed to produce minimal erythema divided by the amount of solar radiation required to produce the same level of erythema on unprotected skin [45]. The only disadvantage of sunblocks is that they reflect visible radiation as well; consequently, they are visually obvious when applied on the skin, making them less appealing to the users [43]. Hence, the use of naturally occurring plant products is on the rise as effective photoprotection agents [46], though recently, a bioadhesive nanoparticle-based sunblock was developed (counteracting the visibility

5. Secondary metabolites (SMs) in medicinal plants and their responses to UV-B radiation SMs have been conventionally divided into three broad categories: alkaloids, terpenes and terpenoids, and phenolics (or phenylpropanoids, as these are derived via the phenylpropanoid biosynthetic pathway). From a generalized viewpoint, the concentrations of these compounds usually increase upon UV-exposure; as detailed in the following sections, their increased concentrations are instrumental in providing protection under UV-B stress by acting as sunscreens as well as through their antioxidant properties. 5.1. Alkaloids From a biological point of view, alkaloids, in their broadest sense, are biologically active heterocyclic chemical compounds containing nitrogen, possessing pharmacological properties, and having significant ecological functions [55]. The nitrogen atom present in their structure is responsible for their alkaline nature. The nitrogen atom may be primary, secondary, tertiary, or quaternary, which affects the properties of the alkaloid itself, as well as its derivatives [56]. There is no generalized pathway for the synthesis of all types of alkaloids. Based on their origin, alkaloids may be divided into three main categories [56,57]: a) True alkaloids: derived from amino acids and sharing a heterocyclic ring with nitrogen. These may occur in plants in free state, as salts, and/or as N-oxides. 53

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Fig. 1. Biosynthesis pathway of alkaloids (brachycerine, vindoline, vinblastine, and camptothecin derived from tryptophan and berberine derived from tyrosine). AS: Anthranilate synthase; TDC: Tryptophan decarboxylase; G10H: Geraniol 10-hydroxylase; CPR: Cytochrome P450 reductase; SLS: Secologanin synthase; STR: Strictosidine synthase; SGD: Strictosidine β-d-glucosidase; T16H: Tabersonine 16-hydroxylase; D4H: Desacetoxyvindoline −4-hydroxylase; DAT: Deacetylvindoline 4-O-acetyltransferase; TYDC: Tyrosine/Dopa decarboxylase; NCS: Norcoclaurine synthase; 6-OMT: 6-O-Methyltransferase; CNMT: (S)- coclaurine N-methyltransferase; NMCH: (S)-N-methylcoclaurine 3′-hydroxylase; 4’-OMT: 3′-hydroxy-N-methylcoclaurine 4′-O- methyltransferase; BBE: berberine bridge enzyme; SOMT: (S)-9-O-methyltransferase; SCO: (S)-canadine oxidase; THB: (S)-tetrahydroberberine oxidase [59–62]; berberine biosynthetic pathway: modified from [63].

b) Protoalkaloids: nitrogen atom derived from the amino acid does not form a part of the heterocyclic ring. These are relatively simple in their structure. c) Pseudoalkaloids: the basic carbon skeleton is not derived from amino acids directly, albeit from their pre- or post-cursors and the related amination and transamination reactions. The incorporation of nitrogen occurs at a relatively later stage in their biosynthetic pathway.

roseus. The enzymes TDC and strictosidine synthase (STR) were known to be up-regulated under UV-B radiation, as well as the concentrations of the alkaloids in their respective pathways. Two nuclear factors, GT-1 and 3AF1 were identified in tobacco and C. roseus cell cultures that interact with multiple TDC promoter regions. Mutagenesis of the GT-1 binding sites reduced the TDC promoter activation under UV light, which demonstrates a functional role for GT-1 in induction of TDC expression under UV [65]. Later, Ouwerkerk et al. [59] demonstrated that induction of TDC gene expression is regulated by a UV-B specific receptor and the corresponding signal transduction pathway(s) since any other wavelengths of light failed to induce TDC expression. They also identified several functional regions (UV-B responsive elements between -99 and +198) and redundant regions in the TDC promoter by loss-of-function and gain-of-function analyses. Peebles [66] showed that 20 minutes of UV-B light exposure caused an increase in TIA metabolite accumulation and an increase in G10H (Geraniol-10-hydroxylase), TDC, and STR transcripts in C. roseus hairy roots. Liu et al. [67] also studied the effects of UV light on the expression of TIA biosynthetic pathway genes and its metabolites in leaves of C. roseus seedlings. They found that the contents of vindoline and catharanthine increased initially but reduced upon prolonged exposure while vinblastine (generated by its precursors: vindoline and catharanthine) increased steadily up to 15 days of treatment. At the transcriptional level, vindoline levels

Alkaloids may be present in all the plant parts, or confined to specific tissues such as roots and seeds. Their ecologically important functions include protection of plants against pests and herbivores and attracting insects for pollination. They are also important from a pharmacological standpoint [56,58]. The studies on the effects of UV-B radiation on the alkaloid content in plants are very limited. Fig. 1 outlines the biosynthesis of some alkaloids with the entities confirmed to be influenced under UV-B highlighted. Probably the most widely studied group of alkaloids under UV-B stress is the terpenoid indole alkaloids (TIAs) in Catharanthus roseus cell cultures in vitro. TIAs of C. roseus provide protection against abiotic stresses including UV. Initially, Hirata et al. [64] demonstrated that near-UV light is responsible for the synthesis of dimeric TIAs in C. 54

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were found to be significantly correlated with deacetoxyvindoline-4hydroxylase (D4H) and deacetylvindoline-4-O-acetyltransferase (DAT) while catharanthine concentrations correlated with strictosidine synthase (STR) gene expression. Light induction of D4H and DAT genes is also phytochrome-mediated [68] suggesting that the expression of these genes is not UV-B specific. Zhu et al. [69] exposed C. roseus to binary stress (enhanced UV-B followed by dark incubation). Proteomic analysis revealed an increment in proteins pertaining to secondary metabolism. Moreover, genes and enzymes involved in the alkaloid biosynthetic pathway also showed various levels of upregulation; 10hydroxygeranioloxidoreductase (10-HGO) increased 2 fold compared to the control group, mRNA expression levels of 6-17-O-deacetylvindoline O-acetyltransferase (dat), tabersonine 16-hydroxylase (t16h), deacetoxyvindoline 4- hydroxylase (d4h), Octadecaniod-derivative Responsive Catharanthus AP2-domain Protein 3 (ORCA3), strictosidine synthase (str), geraniol-10-hydroxylase (g10h), and 10-hydroxygeraniol oxidoreductase (10-hgo) were up-regulated with t16h ORCA3 and str being increased approximately 4 fold. mRNA levels of strictosidine β-glucosidase (sgd), secologanin synthase (sls), and tryptophan decarboxylase (tdc) were upregulated upon 30 minutes of UV-B irradiation, but prolonged exposure of up to 60 minutes caused their decline. RT-PCR analysis revealed that the genes related to brachycerine biosynthesis (TDC, ACC oxidase (aminocyclopropanecarboxylate oxidase), UDP-glucose glucosyltransferase, lipase, and serine/threonine kinase) were all up-regulated under UV-B exposure [62,70] suggesting that the accumulation of this alkaloid is regulated at the transcriptional level by UV-B. Tropane alkaloid biosynthetic pathway genes in hairy root cultures of Anisodus luridus (commonly known as Himalayan Scopolia, an important source of alkaloids scopolamine and hyoscyamine), putrescine-N-methyl transferase (PMT), tropinone reductase 1 (TR1), cytochrome P450 (CYP80F1), and hyoscyamine 6β-hydroxylase (H6H) were found to be increased upon UV-B exposure of 9000 μW cm-2 for 24 hours [71]. More recent study on Clematis terniflora by Gao and coworkers [72] also revealed an increment in the proteins of secondary metabolism as well as increase in the expression levels of shikimate pathway genes such as shikimate kinase (CtSK), 5-enolpyruvylshikimate-3phosphate synthase (CtEPSPS), chorismate synthase (CtCS), L-tryptophan synthase (L-CtTS), and L-serine deaminase (L-CtSD) under UV-B dose of 120.8 μW cm-2 followed by 36 hours of dark incubation. Other genes involved in the biosynthesis of the indole nuclei like anthranilate synthase (CtAS), phosphoribosylanthranilate transferase (CtPAT), phosphoribosylanthranilate isomerase (CtPAI), and indole-3-glycerol phosphate synthase (CtIGPS) were also found to be upregulated.

pharmacological compounds, increased under supplemental UV-B in Ocimum basilicum [82–84], Cymbopogon citratus [85], and Mentha piperata [79,86]. Germacrene D and artemisinin are sesquiterpenes whose concentrations were found to be increased under supplementary UV-B conditions, the former being increased by 11.6% [87] and the latter by 10.5% [88]. Glycyrrhizin concentrations were found to be increased by 1.5-fold under 0.43 Wm−2 UV-B dose provided for 15 days to Glycyrrhiza uralensis [89], while no changes were observed in the total saponin levels, total centelloside concentrations, and two individual saponins, asiaticoside and madecassoside of Centella asiatica [90]. Carnosic acid is a diterpene and one of the major compounds of pharmacological importance found in Rosmarinus officinalis (rosemary, Lamiaceae). It is an antioxidant and prevents lipid peroxidation and consequent disruption of biological membranes [91]. Its concentration was found to be increased under both low (5.4 kJ m−2 day-1) and high (31 kJm−2 day-1) doses of UV-B [92]. Carotenoids are a group of about 700 lipophilic pigments. They are tetraterpenoids (C40) with eight C5 isoprene units linked in a regular head-to-tail manner except in the center of the molecule where the order is tail-to-head so that the molecule is symmetrical. Carotenoids can be classified into carotenes and xanthophyll depending upon the absence or presence of additional O-containing groups. Carotenoid concentrations have been known to increase under UV-B radiation [51]. Due to the presence of the conjugated double bond system, they are capable of absorbing light in the range of 350–500 nm [93]. Xanthophylls are functional in the light harvesting complex of the chloroplasts. They quench triplet excited states in chlorophyll by dissipating excess excitation energy via non-photochemical quenching. Carotenoid concentrations have been tested primarily in fruits and vegetables. Amongst the medicinal plants, its concentration under increased UV-B dose was found to be increased in Picea asperata [94], reduced in Withania somnifera [95], and remained unaffected in Turnera diffusa [96]. Other similar studies are presented in Table 1. Carotenoids act as accessory photosynthetic pigments, quench ROS (such as 1O2 and Chl*), and provide structural stability to light-harvesting complex proteins and thylakoid membranes. They also react with lipid peroxidation products and terminate free radical chain reactions [97]. Carotenoids may be enhanced upon UV-B exposure in plants in an attempt to protect the photosynthetic apparatus. However, prolonged exposure may cause the breakdown of these pigments and/ or inhibit their synthesis [98]. Resins are lipid-soluble complexes comprising of volatile fraction (diand triterpenoid compounds) as well as non-volatile fraction (monoand sesquiterpenoids) [99]. These do not attenuate UV-B radiation, but resin droplets may cause scattering or reflection of UV-B radiation from the stem surface [100]. Studies on the effects of UV-B on the components of the terpenoid biosynthetic pathway in medicinal plants are not abundant. Terpene synthases (TPS, responsible for the cyclisation of linear terpenes, hence also called terpene cyclases) have been known to be augmented in crop plants such as sugarcane [101] and grapes [80]. A more recent similar study has been conducted on peach (Prunus persica L. Batsch cv. Hujingmilu) [102]. It reported a decrease in the transcript levels of PpTPS1 by 86% and an increase of 80 fold in transcript levels of PpTPS2 after supplementary UV-B exposure. UV-B also caused a significant increase in PpJAZ1, PpJAZ5, and PpJAZ10 which are negative regulators of linalool biosynthesis. In Mentha piperata grown under field- as well as growth chamber conditions, and supplied with UV-B dose of 7.1 kJm-2day-1, genes encoding geranyl diphosphate synthase (Gpps), (-)-menthone reductase (Mr), (+)-menthofuran synthase (Mfs), and farnesyl diphosphate synthase (Fpps) were up-regulated. Isopentenyl diphosphate isomerase (Ippi), (-)-limonene synthase (Ls), (-)-limonene 3-hydroxylase (L3oh), and putative sesquiterpene synthase (S-TPS) were down-regulated under field conditions. Under growth chamber conditions, up-regulation was observed for 1-deoxy-D-xylulose-5-phosphate synthase (Dxs), Ippi, Gpps, Mr, and Fpps and down-regulation in case of L3oh, and S-TPS

5.2. Terpenes/Terpenoids These are lipid-soluble compounds with the inter-convertible isomers isopentenyl pyrophosphate (IPP) and dimethylallylpyrophosphate (DMAPP) forming their building blocks. These 5-carbon compounds give rise to terpene precursors such as geranyl, farnesyl, squalene, phytoene, etc. via condensation reactions involving prenyltransferases. Further physical (cyclization, and rearrangement of the skeletal framework) and chemical (e.g. oxidation) modifications result in the biosynthesis of several isoprenoids [73]. Localized predominantly in the glandular trichomes, and bud and bark exudates, they are vital for plant survival (e.g. chlorophyll, plant hormones) besides being an integral part of essential oils [74,75]. Their aromatic and pharmacological properties enable them to be exploited for various medicinal purposes [76]. Mono-, sesqui-, and diterpenes together form the majority of essential oils. Many members of these terpenoid groups have been studied under UV-B radiation. The biosynthetic pathway of some terpenoids is shown in Fig. 2. UV-B-influenced entities are highlighted. Monoterpenes such as limonene, linalool, camphor, borneol, myrcene, sabinene, 1,8-cineole (eucalyptol), nerol, geraniol, and z-citral, which are important 55

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S. Takshak and S.B. Agrawal

Fig. 2. Biosynthesis pathway of terpenoids (artemisinin, brassinosteroids, and withanolides). HMG-CoA: 3-hydroxy-3-methylglutaryl-coenzyme A; HMGR: HMG-CoA reductase; DXS: 1-Deoxy-D-xylulose-5-phosphate synthase; DXR: 1-Deoxy-D-xylulose-5-phosphate reducto-isomerase; IPPi: Isopentenyl pyrophosphate isomerase; FPS: Farnesyl pyrophosphate synthase; SQC: Sesquiterpene cyclase; SQS: Squalene synthase; CPR: Cytochrome P450 reductase; SQE: Squalene epoxidase; CAS: Cycloartenol synthase; GGPRS: Geranyl geranyl pyrophosphate synthase; ECS: 8-Epicedrol synthase; BFS: β-farnesene synthase; QHS: β-Caryophyllene synthase; ADS: Amorpha-4,11-diene synthase; CYP71AV1: Cytochrome P450-dependent monooxygenase/hydroxylase; DBR2: Double bond reductase; RED1: Dihydroartemisinic aldehyde reductase [77–81].

[79]. Rai et al. [88] subjected Artemisia annua (an antimalarial plant) to short-term UV-B radiation (4.2 kJ m−2 day−1) and assessed the concentration of artemisinin as well as expression of its biosynthetic pathway genes via RT-PCR analysis. Their observations showed that artemisinin concentration increased in plants exposed to UV-B while genes like 3-Hydroxyl-3-methyglutaryl CoA reductase (HMGR), cytochrome P450 oxidoreductase (CPR) and amorpha-4,11-diene synthase (ADS) were significantly up-regulated. Similar studies made on in vitro propagated A. annua plantlets revealed that under low dose of UV-B (2.8 Wm−2) genes like HMGR, 1-Deoxy-D-xylulose-5-phosphate reductoisomerase (DXR), Isopentenyl pyrophosphate isomerase (IPPi), Fernasyl diphosphate synthase (FPS), ADS, Cytochrome P450 dependent monooxygenase/hydroxylase (CYP71AV1) and Dihydroartemisinic aldehyde reductase (RED1) were up-regulated leading to enhanced artemisinin accumulation [103].

antioxidant properties providing protection against oxidative damage to membranes. Besides these, they are involved in plant pollination (colored compounds act as pollinator attractants), plant growth and reproduction (involved in plant growth hormones’ localization and transport, stimulation of root nodule formation), and plant protection (against pathogens and predators) [53,104]. Flavonoids form the largest sub-category of phenolic compounds. These are further sub-divided into six major classes: flavones, isoflavones, flavonols, flavonols, flavanols or catechins, flavonones, and anthocyanidins [105]. They provide protection by acting as UV-B filters and/or scavenging reactive oxygen species: flavonols [39,106], anthocyanins [107,108], and flavones [58]. Phenolic acids and their derivatives, especially hydroxycinnamic acids and their esters, are also involved in plant protection under UV-B-induced stress [109,110]. Other phenolic compounds involved in the phenomenon include coumarins and furanocoumaris [111,112], tannins [113,114], and lignin [115]. Fig. 3 provides a simplified view of the phenylpropanoid pathway, leading to the biosynthesis of various phenolics. In accordance with the studies on phenolic compounds, the genes and enzymes involved in their biosynthetic pathways have also been primarily studied in Arabidopsis and crop plants [119,120]. Amongst medicinal plants, the activities of phenylalanine ammonia lyase (PAL), cinnamyl alcohol dehydrogenase (CAD), 4-coumarate Co-A ligase (4CL), chalcone isomerase (CHI), and dihydroflavonol reductase (DFR)

5.3. Phenolics Phenolic compounds, products of the phenylpropanoid pathway, are omnipresent in plants, and as such, have been the most widely studied group of compounds under UV-B influence, with the focus initially being on the model plant Arabidopsis, and later mostly on crop plants. Phenolics have an absorption range of 280-350 nm, and consequently provide protection by direct absorption of UV-B. They also possess 56

Journal of Photochemistry & Photobiology, B: Biology 193 (2019) 51–88

S. Takshak and S.B. Agrawal

Table 1 Effects of UV-B radiation on pharmaceutically important components of some medicinal plants (2009–2018); ↑: increase, ↓: decrease. Plant Heteropogon contortus BL-1 Psychotria brachyceras Catharanthus roseus

UV-B dose −2

−1

A+7.2 kJm day (3 h, 40, 75, 110 DAG, April-November 2016) −2 −1 68.89 kJm day (24 h) 9000 μW cm−2 (20 min)

Mentha piperata

1345 μW cm−2 (1, 2, 3 h followed by 72 h of dark incubation) 9000 μW cm−2 (24 h) 120.8 μW cm−2 (5 h, followed by 36 h dark incubation) 7.1 kJm−2 day−1 (1 h/day for 1 day)

Ocimum basilicum

222.6 μWm−2

Cymbopogon citratus

A+1.8 kJm−2 day−1 (3 h/day for 80 days)

Ocimum sanctum

A+1.8 kJm-2 day-1; (3h/day for 60 days)

Artemisia annua Picea asperata Withania somnifera Turnera diffusa Willd

4.2 kJ m−2day−1 (30 min for 14 days) 16.41 kJ m−2 day−1 20% above ambient 0.5 ± 0.1 mW cm-2 (2 h), 1.0 ± 0.1 mW cm−2 (2h), 1.0 ± 0.1 mWcm−2 (4h) 2.8 Wm−2 (for 1, 2, 3, and 4 h)

Catharanthus roseus Anisodus luridus Clematis terniflora

Artemisia annua Populus tremula Withania somnifera

Simulating 20% decrease in stratospheric ozone A+3.6 kJm−2 day-1 (3 h, 100 days)

Coleus forskohlii

A+3.6 kJm-2 day-1 (3h, at 30, 60, and 90 DAT) −2

Glycyrrhiza uralensis

0.024 W cm

Catharanthus roseus

9000 μW cm−2 (20 min; harvested at 168 h)

Isatis indigotica Ginkgo biloba Phyllanthus amarus Acorus calamus

10.8 kJ m−2 (8 h/day for 8 days) 25.3 kJ m−2 (7 days) NA (2 h/day for 8 days) A+1.8 kJm−2 day-1 (3 h/day for 80 days)

Acorus calamus

A+1.8 kJ m−2 day-1; A+3.6 kJ m−2 day-1 (3 h/day for 80 days) 14.33 kJ m−2 day-1 (mid-April – October, 2007) 0.075 Wh m−2 0.15 W h m−2 14.33 kJ m−2 day−1 (8 h daily) 0.6 W m−2

Zanthoxylum bungeanum Tropaeolum majus Abies faxoniana Mentha piperata

(12, 24, 48, and 96 h)

UV-B induced changes in medicinal compounds studied

Reference

Tannins, phenolics ↑; carotenoids ↓ (40, 75 DAG), ↑ (110 DAG)

[28]

Brachycerine ↑ Terpenoid indole alkaloids ↑; serpentine, catharanthine, ajmalicene, lochnericine, tabersonine ↑; hörhammericine: no change Strictosidine, vindoline, catharanthine, ajmalicine ↑(1h)

[62] [66]

Scopolamine ↑ (1.6×); hyoscyamine ↓ Indole alkaloid (6-hydroxyl-1H-indol-3-yl) carboxylic acid methyl ester ↑ (7×) Essential oil content↑; (−)-Limonene, 1,8-cineole, E-(β)-ocimene, sabinene hydrate, linalool, (+)-menthofuran, (+)-pulegone, E-(β)-caryophyllene, germacrene-D↑; (−)-menthol, (+)-Cis-isopulegone, menthyl acetate, piperitinone↓; (−)-menthone, piperitone ↓ (growth chamber), ↑ (field) Volatile oil content ↑; α-pinene, sabinene, β-pinene, 1,8-cineole, linalool, βocimene, camphor, nerol, trans- α-bergamotene ↑; thujene, camphene, βmyrcene, α-phellandrene, δ-3-carene, α-terpinene, cis-ocimene, αterpinolene, eugenol, germacrene D, germacrene B, γ-cadinene ↓; camphene: no change Essential oil content ↑; 6-Methyl-5-hepten-2-one, β-myrcene, trans-ocimene, nerol, z-citral ↑; cis-Ocimene, geraniol formate↓; linalyl formate, βbisabolene, pulegol, bicyclo [3.1.1]hept-2-ene-2-methanol,6,6-dimethyl, 1H-3A,7 Methanoloazulene, octahydro-1,4,9,9-tetramet (detected); 1,3,6Octatriene,3,7-dimethyl, trans-d-Dehydrocarveol, 10,12-Octadecadiynoic acid, 2,6-Dimethyl-1,3,5,7-octatetraene (not detected) Essential oil content ↑; β-elemene, germacrene-D, camphenol, βcaryophyllene, ethyl linoleate, α-humulene, α-selinene, Elema-1,3,11(13)triene-ol, δ-cadinene↑; eugenol, β-bourbonene, β-selinene↓; 1-deoxy capsidol (not detected) Carotenoids, flavonoids, artemisinin content ↑ Carotenoids, UV-B absorbing compounds ↑ Carotenoids ↓; anthocyanins ↑; withaferin A ↑ Carotenoids: no change; phenolics ↓

[71] [72]

Carotenoids↓; total phenolics, flavonoids, anthocyanins ↑; artemisinin content↑ Salicylates: no change; phenolic acids, flavonoids, total phenolic glycosides, soluble-, non-soluble-, total condensed tannins ↑ Withanolide A ↓ (41.2% in leaves, not detected in roots); withaferin A ↑ (12.4% in leaves, 11.9% in roots); total alkaloids, anthocyanins, carotenoids, flavonoids, ↑ (both leaves and roots); phytosterols ↓ (leaves), ↑ (roots) Alkaloids, anthocyanins, carotenoids, lycopene, β-carotene, flavonoids, lignin, phenolics, phytosterols, saponins, tannins ↑ (in both leaves and roots) Apigenin, naringenin, O-malonylhexosides of tricetin, quercetin, and naringenin ↑; O-malonylhexosides of tricin, eriodictyol, and luteolin, Cpentosyl-apigenin O-hexoside, C-pentosyl-chrysoeriol O-hexoside ↓ Chrysoeriol 5-O-hexoside, chrysoeriol 7-O-hexoside, resokaempferol 7-Ohexoside ↑ (96h only); eriodictyol C-hexoside, luteolin 6-C-glucoside: no change (12, 24, 48h), ↓ (96h); C-pentosyl-apigenin O-p-coumaroylhexoside, C-pentosyl-apigenin O-feruloylhexoside, C-hexosyl-chrysoeriol Oferuloylhexoside, C-hexosyl-luteolin O-feruloylhexoside, C-pentosylchrysoeriol O- feruloylhexoside ↓ (12h), ↑ (24, 48, 96h) Terpenoid indole alkaloids ↑; lochnericine, serpentine, ajmalicine, tabersonine ↑; hörhammericine, rhammericine ↓; catharanthine: no change UV-B absorbing compounds ↑ Flavonoids ↑ Anthocyanins, flavonoids ↑ Essential oil yield ↑; phenolics ↑; 1-H-cyclopropa[a] naphthalene octahydro compound, aristolene, caryophyllene oxide, 4,4-Dimethyl-2,5-octadiyne, caryophyllene oxide, Carvacrol, ↑; β-asarone, euasarone, (1R,5S,E)-2 methyl-4-[2,2,3-trimethyl-6-methylidenecyclohex-2-, trans-methyl isoeugenol, elema-1,3,11(13)-trien-12-ol, iso-velleral, 1,8-Cineole ↓; carvacrol, p-cymene, 3-Cyclohexene-1-methanol (detected); linalool, germacrene-D (not detected) Carotenoids, flavonoids ↑

[103]

Phenolics ↑ (5–20%); alkaloids (benzophenanthridine, benzylisoquinoline, aporphine, protoberberine, berberine) ↑ Glucotropaeolin, phenolics ↑ (upto 6×) at 0.075 W h m−2; ↑ at 0.15 W h m−2 Carotenoids ↓ Menthol, limonene, menthyl acetate, 1,8-cineole ↑; menthone, isomenthone, menthofuran ↓ Flavonoids, tannins, hypericin ↑

[69]

[79]

[84]

[85]

[87]

[88] [94] [95] [96]

[110] [121] [122] [124]

[125] [126] [127] [128] [129]

[130] [131] [132] [133] [134] [135]

(continued on next page) 57

Journal of Photochemistry & Photobiology, B: Biology 193 (2019) 51–88

S. Takshak and S.B. Agrawal

Table 1 (continued) Plant

UV-B dose

UV-B induced changes in medicinal compounds studied

Reference

Hypericum perforatum L. Cymbopogon citratus

Simulating 17% ozone depletion above ambient A+1.8 kJ m−2 day-1; A+3.6 kJ m−2 day-1 (3 h/day for 80 days) UV-B exclusion

Carotenoids, phenolics, flavonoids, essential oil content ↑

[136]

Epidermal flavonoids ↓; individual flavonoids: myricetin-3-galactoside, quercetin-3-galactoside, quercetin-3-glucuronide, quercetin-3arabinopyranoside, quercetin-3-rhamnoside and kaempferol-3-rhamnoside ↓ ; chlorogenic acids, tannins, total flavonoids, total phenolics (no change) Glucosinolates (glucoibervirin, glucobrassicin, 1-methoxyglucobrassicin, gluconasturtiin, 4-methoxyglucobrassicin, neoglucobrassicin) ↑ (3-6x) Camptothecin ↑; 10-hydroxycamptothecin: no change Anthocyanins, flavonoids ↑ Total flavonoids, quercetin, kaempferol, isorhamnetin, ↑; Gb1 compound ↑ Carotenoids ↓; flavonoids, taxol ↑ Flavonoids, anthocyanins, catechins ↑ Polysaccharides, triterpenes, flavonoids ↑; saponins ↓ Epidermal flavonoids ↑ Flavonoids ↑(O. sanctum), ↓(O. basilicum, O. grattissimum at 60 min)

[137]

Isoflavones: genistin, daidzein, genistein, biochanin-A ↑ Base section: quercetin-3,4'-O-diglucoside ↑(low, 22h; medium, 2h, 22h); quercetin-4'-O-monoglucoside, quercetin: no chnage; Apical section: quercetin-3,4'-O-diglucoside ↑(low, 2h, 22h; medium, 2h, 22h); quercetin-4'O-monoglucoside, quercetin: no change Carotenoids, flavonoids, anthocyanins ↑ Iridoids ↑; 3,5-di-O-caffeoylquinic acid, secologanic acid ↑ Anthocyanins, flavonoids, phenolics ↑

[147] [148]

Phenolics ↓ (at 49.6 kJm−2 for 4 h/day); phenolics ↑ (at 6.2 kJ m−2 for 0.5 h at 6 h intervals) Total phenolics, gallic acid, cinnamic acid, ferulic acid, tannic acid, benzoic acid, catechin ↑; delphinidin, apigenin ↓; malvidin ↑; anthocyanins, flavonoids ↑ Quercetin ↑; cinnamic acids, non-soluble tannins↓; myrecetin, kaempferol, other flavonoids, chlorogenic acids, soluble tannins: no change Polyphenol content, caffeic acid, rosmarinic acid↑; p-coumaric acid ↓ (INT), ↑ (FGC) in Nepeta cataria f. citriodora; ↑(INT, FGC) in Melissa officinalis and Salvia officinalis Oil content ↑(INT)↓FGC: Nepeta cataria f. citriodora; ↓(INT, FGC): Melissa officinalis; no change (INT, FGC): Salvia officinalis Oil yield ↑(INT, FGC): Nepeta cataria f. citriodora; ↑(INT), no change (FGC): Melissa officinalis; ↑(INT, FGC): Salvia officinalis Nepeta cataria f. citriodora (INT, FGC): cis-ocimen↑↑; cis-3-hexenal ↓↓; trans-ocimen: no change; cis-3-hexenyl acetate: no change ↑; 6-methyl-5hepten-2-one ↑↑; trans-3-hexen-1-ol ↓no change; cis-3-hexen-1-ol ↓↑; trans2-hexen-1-ol ↓↓; Citronellal: no change; linalool ↓↓; β- caryophyllene ↑no change; citronellyl acetate: no change; α-humulene↑↑; neral↓ no change; neryl acetate↓ no change; geranial ↓ no change; geranyl acetate ↓↓; citronellol no change ↓; nerol no change ↓; geraniol: no change; β-ionone: no change; phytol ↑↑ Melissa officinalis (INT, FGC): β-myrcene ↓↓; cis-ocimen ↓↓; cis-3-hexenal no change ↑; trans-ocimen ↑↓; 6-methyl-5-hepten-2-one ↑ no change; trans3-hexen-1-ol ↑↑; trans-2-hexen-1-ol no change ↑; 1-octen-3-ol ↓↓; Citronellal ↓↓; Linalool no change ↑; β-caryophyllene ↑ no change; α-humulene ↑ no change; neral ↑no change; neryl acetate ↑↑; geranial ↑ no change; geranyl acetate: no change; citronellol ↓↓; nerol ↓ no change; geraniol ↓ no change; cis-9-octadecenoic acid methyl ester ↑↑ Salvia officinalis (INT, FGC): α-pinene: no change ↑; camphene ↑↑; βpinene ↓ no change; sabinene ↓↓; β-myrcene: no change; α-terpinene ↑ no change; limonene no change ↑; 1,8-cineole ↑↑; cis-ocimene ↓↓; cis-3-hexenal ↓↓; γ-terpinene no change ↓; p-cymol: no change; erpinolene ↓ no change; trans-3-hexen-1-ol: no change ↑; trans-2-hexen-1-ol ↓↓; α-thujone: no change; β-thujone: no change; camphor ↑↑; bornyl acetate ↑ no change; βcaryophyllene ↓↓;α-humulene ↓ no change; borneol ↑ no change; myrtenol ↑ ↑; viridiflorol ↓↓; manool ↓↓ Aerial part: essential oil yield↑; Composition after 60 min UV-B: geranial, trans-verbenol, linalool, 6-methyl-5-hepten-2-one, α-pinene oxide↑; z-citral, caryophyllene oxide, trans-caryophyllene, geranyl acetate, cis-verbenol, nerol↓; trans-carveol: no change; cis-carveol (detected); limonene oxide, αcaryophyllene, γ-cadinene, 4-nonanone, neryl acetate (not detected) Sub-aerial part: essential oil yield ↓;Composition after 60 min UV-B: E-citral, ς-elemene, α-eudesmol↓; germacrene-B, α-cadinol, α-bisabolene, αhumulene, azulene, nerol, limonene, germacrene-C, caryophyllene, transcaryophyllene, farnesol (detected); Z-citral, ς-cadinene, junipene, juniper camphor (not detected)

[152]

Betula pendula

Thellungiella halophila/salsuginea Camptotheca acuminata Indigofera tinctoria Ginkgo biloba Taxus chinensis var. mairei Malva neglecta Bupleurum scorzonerifolium Willd Betula pendula Ocimum sanctum, Ocimum basilicum, Ocimum gratissimum Genista tinctoria L. Asparagus officinalis

Caryopteris mongolica Lonicera japonica Artemisia lercheana, Ocimum basilicum, Nigella sativa Deschampsia antarctica

UVλ max 368 nm, 315–400 nm (13 W lamp), UVλ max 254 nm (30 W lamp); 60 min, 6 days 5 μmol m−2s−1 (3 days) NA (2 h/day for 8 days) 82.90 μWcm−2 (120, 240, 360 min) 10.8 μWcm−2 (3 months) 144–1728 Jm-2 (for 10–120 min) 380 mW cm−2 (for 0–300 s) 2.814 kJ m−2 day−1 0.4 Wm−2 (20, 40, 60 min) 254 nm, 366 nm Low: 0.54 kJ m−2 (2 h, 22 h); Medium: 1.08 kJ m−2 (2 h, 22 h) 30 Js−1 (for 1, 4, 24 h) 120 W (at 306 nm) 12.3 kJm−2 (for 5, 10, 20, 30 min)

Malva neglecta

49.6 kJm−2 (4 h/day); 6.2 kJ m−2 (0.5 h at 6 h intervals) 0–1296 Jm−2 (for 0–90 min)

Betula pendula

7.95 kJm−2day−1 −2

-1

Nepeta cataria f. citriodora, Melissa officinalis, Salvia officinalis

INT (intensive UV-B): 2.5 kJ m day (10 h); FGC (field-grown conditions): 1.0 kJ m−2 day1 (4 h)

Cymbopogon flexosus

NA (15 min, 30 min, 60 min; for 3 days)

[138] [139] [140] [141] [142] [143] [144] [145] [146]

[149] [150] [151]

[153] [154] [155]

[156]

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Journal of Photochemistry & Photobiology, B: Biology 193 (2019) 51–88

S. Takshak and S.B. Agrawal

Table 1 (continued) Plant

UV-B dose −2

Catharanthus roseus Coleus aromaticus

10.8 μW cm NA (UV1 for 2 h, UV2 for 3 h)

Artemisia annua

2.8 Wm−2 (for 1, 2, 3, 4 h)

Camptotheca acuminata Conocarpus lancifolius Scutellaria baicalensis

5 μmol m−2 s−1 (1 h, 9 days) 1.8, 3.6, 7.2 kJ m−2 (6 h/day) 12.1 μW cm−2 (8 h/day from 19th April to 3rd September, 2010): TL; 34.5 μW cm−2: TH NA (15, 30 min, 1, 1.5, 2, 2.5, 3, 3.5, 4 h)

Cymbopogon flexosus

Laurus nobilis

0.525–4.976 kJm−2 day-1 (2.5 h to 3.5 h) depending on the month (June 2009 to January 2010)

Kalanchoe pinnata Salix myrsinifolia

4.86–18.36 kJm−2 day−1 (for 1, 5, 10 days) A+30% above A

Withania somnifera

A+3.6 kJm−2 day−1 (3 h, 100 days)

Chrysanthemum morifolium Chrysanthemum morifolium

A+0.82 kJm−2 day-1 (8 h) 0, 50, 200, 400, 600, and 800 μW cm−2 (120 min)

UV-B induced changes in medicinal compounds studied

Reference

UV-B absorbing compounds ↑; Vinblastine, vindoline, catharanthine↑ Total phenolics, alkaloids, saponins, tannins, carotenoids↑; total triterpenes ↑(UV1), ↓(UV2) Essential oil composition: 2-Butanone, 4-hydroxy-, L-citrulline, ethanamine, 2-bromo-, α-pinene, α-thujene, α-cymene, ç-Terpinen, thymol, carvacrol, 2,4,6,8-Tetramethyl-1-undecene, 5,7-Dodecadiyn-1,12-diol, 3,5Heptadienal, 2-ethylidene-6-methyl, α-ocimene, Naphthalene, 1,2,3,5,6,8 ahexahydro-4,7-dimethyl-1-(1- methylethyl)-, 1-Butanamine, 4 methoxy, silane ↑; α-myrcene, linalool, carvomenthenol, caryophyllene, trans-αbergamotene, d-glucitol, α-phellandrene ↓; α-terpinene, p-Mentha-1,4(8)diene, 3,4- Xylenol (detected) Carotenoids↓; total phenolics, flavonoids, anthocyanins ↑; % monoterpenes↑ ; % sesquiterpenes, diterpenes, other compounds↓; carvone, T-carveol, sabinene hydrate, β-phellandral, 4-thujanol, borneol, camphor, α-pinene, camphene, steviol, duvatriendiol, β-cubebene, qinghaosu C, germacrene A, epicedrol↑; 1,8-cineole, 4-terpineol, p-cymene, thymol, phytol, germacrene B, caryophyllene, β-farnesene, amorphene, γ-elemene, amorphadendrene, longifolenaldehyde, intermedeol↓ Camptothecin (3.3×) ↑ (after 6 days) Total flavonoids ↑ TL, TH: Scutellarin ↓, no change; tectoridin↑↓; biacalin: no change; chrysin ↑↑ ; wogonoside, wogonin: no change Essential oil yield↑(up to 2 h)↓(2.5 h to 4 h); citral content↑ (up to 2 h, and 3 h)↓(2.5, 3.5, 4 h); geranial (up to 2 h, and 3 h)↓(2.5, 3.5, 4 h); neral ↑(30 min, 1.5, 3 h)↓(15 min, 1, 2, 2.5, 3.5, 4 h); nerol ↑(15 min)↓(30 min up to 3 h), not detected (3.5, 4 h); β-caryophyllene, geranyl acetate ↓(all times); linalool ↓(up to 30 min, 3.5 h)↑(1, 1.5 h), not detected (2, 2.5, 3, 4 h) Neoxanthin, β-carotene ↑; α-carotene: no change; violaxanthin: no change (pre-dawn), ↑(mid-day); antheraxanthin: no change; zeaxanthin↑(predawn), ↓(mid-day); VAZ (violaxanthin + antheraxanthin + zeaxanthin) pool: no change; AZ/VAZ: no change (pre-dawn), ↓(mid-day); lutein: no change; lutein-5,6-epoxide: no change (pre-dawn), ↑(mid-day); lutein+ lutein-5,6-epoxide: no change (pre-dawn), ↓(mid-day); total phenols, UV-B absorbing compounds: no change; quercetins, kaempferols ↓ Phenolics, flavonoids, quercetin ↑ Salicylates, cinnamoyl salicortin derivatives, chlorogenic acid derivatives, other flavonoids (except hypericin), phenolic glucosides: no change; chlorogenic acid, hypericin ↑(females) no change: males Methanolic leaf extracts: Perhydrofarnesyl acetone, isophytol, methyl linoleate, methyl stearate, ethyl stearate, nonacosane, trans-squalene, β-stigmasterol, withaferin A ↑ Neophytadiene, 3-Eicosyne, methyl palmitate, palmitic acid, linolenic acid, stearic acid, crenosterol, cholesterol, campeterol ↓ Eugenol, myristic acid, oleyl alcohol, dibutyl phthalate, ethyl palmitate, ethyl linoleate, geranyl geraniol, solanesol, stigmasterol acetate, β-carotene, brassicasterol, vitamin E, lycopene: detected d-tocopherol: not detected Methanolic root extracts: Neophytadiene, dibutyl phthalate ↑ 2,4-Ditert-butyl phenol, phytol, methyl palmitate, ethyl palmitate, methyl stearate, methyl behenate, ethyl behenate, phthalic acid ↓ Ledol, tridecanal, 1-Nonadecene, 2,6,10,15-Tetramethyl-heptadecane, palmitic acid, ethyl docosanoate, hexatriacontane, tetratetracontane, dotriacontane, stigmasterol acetate, retinol, sitosteryl oleate, podocarpa8,11,13-trien-3-ol, campesterol: detected α-Selinene, methyl oleate, ethyl (9Z,12Z)-9,12-octadecadienoate, ethyl oleate, ethyl stearate, podocarpic acid: not detected Total flavone concentration: no change; chlorogenic acid, free amino acids ↑ UV-B absorbing compounds ↑(400 to 800 μW cm−2); chlorogenic acid ↑(50 to 600 μW cm-2, no change at 800 μW cm−2); total flavones: no change (50, 800 μW cm−2), ↑(200 to 600 μW cm−2)

[157] [158]

[159]

[160] [161] [162] [163]

[164]

[165] [166] [167]

[168] [169]

(continued on next page)

59

Journal of Photochemistry & Photobiology, B: Biology 193 (2019) 51–88

S. Takshak and S.B. Agrawal

Table 1 (continued) Plant

UV-B dose −2

-1

-1

Populus alba, Populus russkii Coleus forskohlii

8.5 kJm day (8 h day , 15 days) A+3.6 kJm−2 day-1 (3 h, 90 days)

Prunella vulgaris L. Spica Trigonella foenum-graecum L.

120 μW cm−2 nm−1 (120 min) 3.0 kJ s−1 (4 h, 8 h)

UV-B induced changes in medicinal compounds studied

Reference

Flavonols: myrecetin, quercetin, kaempferol, rutin ↑; total anthocyanins ↑ Essential oil content ↓ (~7%) Methanolic leaf extracts: Trimethl citrate, methyl stearate, behenic alcohol ↑ Lauric acid, myristic acid, stearic acid, methyl palmitate, palmitic acid, hydromorphone TMS derivative, 1-Heptacosanol ↓ 1-Nonadecene, 1-Octadecene, 9-Eicosene, cembrane, trimethyl transaconitate, oleic acid, predinosone, dehydroabietic acid, cyclotetracosane: detcted Phthalic acid, 1-Triacontanol, β-Sitosterol acetate, podocarpa-8,11,13-trien3-ol, : not detected Methanolic root extracts: Dianhydromannitol, cadina-1,4-diene, δ-Cadinene, β-Cadinene, calacorene, behenic alcohol, dehydroabietic acid, di-N-octyl phthalate, 9-Tricosene, (Z)↑ Calamene, τ-Cadinol, cadalene, methyl palmitate, methyl stearate ↓ α-Amorphene, (+)-Ledene, squalene, phloroglucinol, calarene epoxide, neophytadiene, dehydroabietylamine, lilial, camazulene, calcitriol, methyl oleate, prednisone, lupenone, ferruginol: detected Cubenol, α-Cubebene, myristaldehyde, 7-Hydroxydiacetoxyscirpenol, selina-6-en-4-ol, 1-Nonadecene, 1-Octadecene, β-Carotene, cholesteryl myristate, tetrahydroedulan B, 1-Heptacosanol, 9-Hexacosene, 1-Eicosanol, lignoceric alcohol, 1,54-Dibromo-tetrapentacontane, methyl behenate: not detected Essential oil composition: Tricyclene, α-Pinene, d-Camphene, borneol, decanal, N-decyl acetate, selina-3,7 (11)-diene, 1,5,9,9-Tetramethyl-spiro[3.5]nonan-5-ol, ferruginol, hexacosane, sclareol ↑ β-Pinene, myrcene, γ-Terpinene, nonanal, terpinen-4-ol, bornyl acetate, cubebene, cyclosativene, copaene, guaia-1-10, (11)-diene, γ-Gurjunene, γMaaliene, α-Cis-bergamotene, β-Trans-bergamotene, sesquisabinene, αHumulene, β-Farnesene, cubenene, β-Bisabolene, β-Maaliene, +/− Transnerolidol, epicubenol, α-Muurolol, intermedeol, juniper camphor, 10,12,14Nonacosatriyonic acid, manoyl oxide, dehydroabietane, E,E,Z-1,3,12Nonadecatriene-5,14-diol, pentacosane, triacontane, camphor ↓ Sabinene, eucalyptol, 1-Decanol, cycloartenol, α-Bulnesene, cis-ocimene, selina-4,11-diene, cedran-8-ol, copaborneol, 9,10-Dehydro cycloisolongifolene, n-Tricosane: detected Limonene, cubebol, germacrene B, β-Sesquiphellandrene, β-Guaiene, (Z)Valerenyl acetate, 8-Propoxycedrane, zingiberenol, τ-cadinol, dibutyl phthalate, phytol, (11E,13Z) 11813-Labdadien-8-ol, retinol, cholesta-5,7,22trien-3-β-ol: not detected Rosmarinic acid, caffeic acid, flavonoids, salviaflaside, hyperoside ↑ Carotenoids ↓; anthocyanins, flavonoids ↑; phenolics ↑ (4 h), ↓ (8 h) Aromatic oil composition (leaves): 2-methyl-2-Dodecanol, 6,10,14-trimethyl-2- pentadecanone, pentadecanoic acid,14-methyl-methylester, 11-methyldodecanol, 2-methyl octadecane, nTetracosanol-1, 2-methyl eicosane ↑ Phytol, 2-methyl nonadecane, nonacos-1-ene ↓

[170] [171]

were increased upon UV-B exposure in the leaves and roots of Withania somnifera [121] and Coleus forskohlii [122]. Chalcone synthase (CHS) mRNA levels were found to be increased in Betula pendula upon incidence of UV-B [123]. A recent and relatively more detailed study on Glycyrrhiza uralensis [124] showed the following genes to be upregulated under UV-B: five genes encoding PAL, four genes encoding cinnamate-4-hydroxylase (C4H), seven CHS genes, one CHI gene, one flavonol synthase encoding gene, and five UDP-glucosyltransferases (UGTs). The studies pertaining to the alterations in alkaloids, terpenoids, and phenolics in medicinal plants subjected to UV-B for the past ten years (2009–2018) have been summarized in Table 1. For further similar studies, dating 2008 and prior, refer to Supplementary Table 1.

[172] [173]

were adverse. Moreover, the reproductive- and subsequent immediatesurvival stages were more susceptible to UV-B influence as compared to the later growth and developmental stages [175]. Laboratory studies on Poecilia reticulata (rainbow fish) have also revealed that UV-B-exposed parents produce offspring that are less susceptible to the unfavorable influences of this radiation, but become more vulnerable to infectious diseases [176]. Besides the animal taxa mentioned in the above cited research (zooplankton, cnidarians, crustaceans, echinoderms, mollusks, tunicates, fishes, and amphibians), UV-B studies have also covered reptiles [177,178], aves [179–181], and mammals, the latter including usually those animals which can be reared as pets or in captivity for commercial purposes [182,183]. A detailed discussion of the effects of UV-B on these organisms is beyond the scope of this manuscript. Here, we confine ourselves to the studies pertaining to the molecular level changes primarily in human and murine models under UV-B influence. We further discuss the defense potential of secondary metabolites, primarily derived from medicinal plants, on UV-B affected animal models.

6. Effects of UV-B on animals As is true for plants, the effects of UV-B on animals (both aquatic as well as terrestrial) too, are highly diverse and usually antagonistic. Meta-analysis studies on marine biota [174] and fresh water biota [175] have revealed that the overall effects of UV-B on the organisms 60

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Fig. 3. Phenylpropanoid pathway (Biosynthesis of different categories of phenolic compounds). PAL: Phenylalanine ammonia lyase; TAL: Tyrosine ammonia lyase; C4H: cinnamate-4-hydroxylase; 4Cl: 4-coumarate CoA ligase; CHS: Chalcone synthase; CHGT: Chalcone 2’-glucosyltransferase; CHI: Chalcone isomerase; FNS: Flavone synthase; UFGT: UDP-glucose:flavonoid 3-O-glucosyl transferase; F3H: Flavanone-3-hydroxylase; DFR: Dihydroflavanol reductase; FLS: Flavonol synthase; LAR: Leucoanthocyanidin reductase; ANR: Anthocyanidin reductase; ANS/LDOX: Anthocyanidin synthase/leucoanthocyanidin dioxygenase; 3RT: Anthocyanidin-3glucoside rhamnosyl transferase; CCR: Cinnamoyl CoA reductase; CAD: Cinnamoyl alcohol dehydrogenase; COMT: Caffeic acid-O-methyl transferase; F5H: Ferulate5-hydroxylase [116–118].

resistance against leishmaniasis in mice at 25 mJ cm−2 [190] and to upregulate the levels of antimicrobial peptides and cure atopic dermatitis at 40 mJ cm−2 [191], when used judicially in appropriate doses. Zhu et al. [192] have demonstrated that UV-B at 50 mJ cm−2 is capable of enhancing the levels of urocanic acid in the blood and brain tissue of mice (male, C57BL/6J) implicated in intraneuronal glutamate biosynthetic pathway leading to improved memory and learning capacity. However, such studies are few, and merit further inveatigations. Our knowledge of the impacts of UV-B at the molecular level in animals has been derived from the studies primarily involving model organisms (for example, murine models) in vivo and cellular model systems (for example, human cell lines) in vitro. Mice have served as excellent subjects to study and understand human biology and functionality because of the physiological and phylogenetic similarities between the two [193]. As far as cellular/molecular elements are concerned, the effects of UV-B have been largely studied on DNA and proteins, reactive oxygen species and antioxidant status, inflammatory changes, immunosuppression, on the extracellular matrix (ECM) and on molecules involved in cell signaling and cell cycle processes. These concepts have been briefly discussed below. An overview of some important effects of UV-B in animal models has been outlined in Fig. 4. DNA can be damaged by UV-B radiation either directly, resulting in the formation of entities such as cyclobutane pyrimidine dimers (CPDs)

6.1. Effects of UV-B on Human and Murine Subjects For long, UV-B radiation has been known to cause adverse effects in humans, especially on the skin (basal cell carcinomas, squamous cell carcinomas, cutaneous malignant melanomas) and the eyes (cataract, ptrygia, eye cancer- both carcinomas as well as melanoma) [184]. Other photosensitivity disorders attributed to UV-B have been reviewed by Kiss and Anstey [185]; these include both congenital- (e.g. xeroderma pigmentosum, trichothiodystrophy) and acquired syndromes (e.g. chronic actinic dermatitis, lupus erythematosus). However, lately, UV-B has been implicated in having beneficial effects as well. The most widely acknowledged beneficial effect of UV-B radiation is the improved vitamin D status in exposed individuals [128] which in turn plays important roles in preventing several diseases such as rickets, internal cancers (such as breast, colon, ovarian, and prostate), and in relieving hypertension and immunosuppression [186]. It has also been used in phototherapy for treating atopic dermatitis, psoriasis, and vitilago [187,188]. More recently, Wu et al. [189] have reviewed the technique and significance of ultraviolet blood irradiation (UBI), which has been used to treat diseases such as arthritis, asthma, pneumonia, poliomyelitis, tuberculosis, and others. They have also recommended further investigations into this technique to cure infections and to stimulate the immune system. UV-B has also been known to provide 61

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Fig. 4. An overview of some important UV-B mediated molecular-level changes in animals. ROS: reactive active species; C: cytosine; T: thymine; 8-OHdG: 8hydroxydeoxyguanosine; COX-2: cyclooxygenase-2; PGE2: prostaglandin E2; IL-10: interleukin-10; MAPK: Mitogen activated protein kinase; ERK: extracellular signal-regulated kinase; JNK: c-Jun-N-terminal kinase; NF-κB: nuclear factor-kappa B; Nrf2: nuclear erythroid 2-related factor 2; MMPs: matrix metalloproteinases.

and 6-4 photoproducts (6-4P), or indirectly via ROS. Mutations are likely to occur, and persist during successive cell divisions, when the repair machinery is overwhelmed and the DNA integrity is compromised. One such mutation occurs via C→T and CC→TT base substitution; these are termed as ‘UV-B fingerprint’ or ‘UV-B signature’ mutations [194]. These mutations have been known to occur in p53 and PTCH tumor suppressor genes; p53 mutations have been known to cause approximately 90% of squamous cell carcinomas (SCCs) and nearly 50% of basal cell carcinomas (BCCs) [195]. Other DNA disfigurements include single and double strand breaks, DNA crosslinks, and pyrimidine-purine adducts [186,196]. Enhanced ROS production due to UV-B not only causes damage to DNA but also to lipids and proteins of cellular and organellar membranes [197]. It is usually detected in terms of increased concentrations of thiobarbituric acid reactive substances (TBARS). The extent of oxidative DNA damage is usually inferred via the formation of 8-hydroxydeoxyguanosine (8-OHdG) formed as a result of singlet oxygen attacking the DNA base guanine [198]. Depending upon the extent of damage to the lipids and proteins, ROS may cause loss of membrane structure, compromising its function; severely destabilized membranes might lead to mutagenesis and cell death [186]. Moreover, the end products of protein and lipid peroxidation have been implicated in forming adducts with DNA [199,200]. Proteins, once oxidized, not only lose their original function, but also proceed to form crosslinks with the

DNA, blocking the latter from performing normal replication and transcription [200,201]. ROS production also influences the signal transduction pathways involved in inflammatory and immuno-modulatory responses to UV-B [202]. While ROS concentrations increase, the antioxidant levels decline upon UV-B exposure (Tables 2 and 3). However, the phenomenon is subjective to the dose and duration of the given radiation. Misra et al. [203] studied the rate of photoheamolysis in human erythrocytes (RBCs) under various UV-B intensities (0–2.0 mW/cm2) for the duration of 0–240 min. They reported that lower UV-B doses caused the glutathione content in RBC membranes to decline, while higher doses resulted in its increase. Induction of pro-inflammatory genes is another aspect of UV-B radiation exposure leading to photoageing and photocarcinogenesis. The inflammatory mediators include plasma-derived molecules such as bradykinin and plasmin, lipid-derived molecules such as prostaglandins and platelet activating factor (PAF), and a number of cytokines, such as interleukin-1 (IL-1), IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-13, IL-1β, tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ), some of which are inflammatory [202,204]. The interleukins, TNF-α, and lipid inflammatory mediators such as cyclooxygenase 2 (COX-2) and prostaglandin E2 (PGE2), increase under UV-B stimulus at both transcriptional and translational levels (See Tables 2 and 3). UV-B affects the immune system at both local and systemic levels. 62

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Table 2 Effects of medicinal plants-derived compounds (alkaloids/ terpenoids/ phenolics) on animal models (2009–2018). Animal model

Effects of UV-B

Medicinal compound

Compound description

Effects on UV-B treated animal model

Reference

Normal human dermal fibroblasts

- increased MMP-1 mRNA and protein levels - decreased type-I procollagen and its mRNA expression - increased IL-6 levels - reduced levels of TGF-1β - increased phosphorylation and overexpression of ERK, JNK, and p38 levels - elevated levels of phosphorylated c-fos and c-jun

Salvianolic acid B (polyphenol)

Phenolics

[218]

HaCaT human keratinocytes

- reduced cell viability - increase in intracellular ROS - increase in MMP-1 gene expression and activity - induction of phosphorylation of ERK1/2, JNK1/2, (MEK)1/2, (SEK) 1 - activation of c-Fos and c-Jun

3-bromo-4,5dihydroxybenzaldehyde (BDB): bromophenol

Phenolics

SKH-1 hairless mice, B16F10 melanoma cells

SKH-1 hairless mice: - induction of skin carcinogenesis - enhanced activity of p38/JNK and p13K/AKT - induction of inflammation - enhanced expression of cyclin D1, CDK1, and PCNA - downregulation of p53, p27, and p21 protein expression - suppression of caspase-3 activation and PARP-1 cleavage B16F10 melanoma cells: - induced cell mortality - downregulation of phosphorylation levels of p38 and JNK

Juglanin (flavonol)

Phenolics

Mouse epithelial cell line JB6, Female SKH-1 hairless mice

JB6 cells: - induction of apoptosis (increased PARP cleavage and caspase 3 activation) - increased number of CPDs - decreased levels of IL-12 SKH-1 hairless mice: - lowered levels of IL-12 - increased number of apoptotic cells and enhanced CPD formation

Silibinin (flavanolignan)

Phenolics

Human HaCaT keratinocytes

- increased intracellular ROS - HaCaT cell death

Quercitrin

Flavonoid (Phenolics)

Female albino hairless mice (Skh: hr-1)

- erythema, edema, increased thickness of stratum corneum, Malpighian layer, dermal and hypodermal layers - increased expression of heat shock protein 70 (Hsp-70) in epidermal layer; de novo synthesis in dermal and hypodermal layers - reduced activities of SOD and CAT

Porphyra-334 (P-334) and shinorine (P-334 + SH)

mycosporine-like aminoacids (MAAs)

- inhibition of MMP-1 secretion and its mRNA levels - increased mRNA expression and protein levels of type-I procollagen - decreased IL-6 levels - enhanced levels of TGF-1β - reduced phosphorylation and overexpression of ERK, JNK, and p38 levels - reduction in the levels of phosphorylated c-fos and c-jun - improvement in cell viability - scavenging of intracellular ROS - reduction of MMP-1 gene expression and activity - suppression of phosphorylation of ERK1/2, JNK1/2, (MEK)1/2, (SEK)1 - suppressed activation of cFos and c-Jun SKH-1 hairless mice: - amelioration of skin carcinogenesis - suppression of p38/JNK and p13K/AKT activity - inhibition of inflammation - reduced expression levels of cyclin D1, CDK1, and PCNA - promotion of p53, p27, and p21 expression - enhanced caspase-3 levels and PARP-1 cleavage B16F10 melanoma cells: - further increase in cell death percentage - further inactivation of p38 and JNK phosphorylated forms JB6 cells: - reduced PARP cleavage and caspase 3 activation indicating decreased apoptosis - accelerated removal of CPDs - enhanced production and secretion of IL-12 SKH-1 hairless mice: - amelioration of IL-12 reduction - decreased cell apoptosis, decreased CPD formation, and reduced number of CPD positive cells - reduction in ROS concentrations - restoration of HaCaT cell viability - prevention of erythema, edema, and thickening of cell layers - reduced levels of Hsp-70 proteins - prevention of antioxidative enzyme activity loss

[219]

[220]

[228]

[243]

[244]

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Table 2 (continued) Animal model

Effects of UV-B

Medicinal compound

Compound description

Effects on UV-B treated animal model

Reference

Female ICR mice, JB6P+ cells

- enhanced COX-2 expression, PEG2 production - enhanced COX-2 promoter activity - AP-1 and NF-κB transactivation - phosphorylation of JNK, p38 and ERK - increased Fyn kinase activity

Caffeic acid

Phenolics

[245]

JB6 P+ mouse epidermal cells

- increased COX-2 protein expression and PGE2 production - f transactivation of NF-κB and AP1 - increased phosphorylation of JNKs, p38 and Akt - induction of MAPKK4 and PI-SK activity

Delphinidin (anthocyanidin)

Phenolics

Human blood lymphocytes

- decreased cell viability - increased cytotoxicity - increased lipid peroxidation (enhanced levels of TBARS, LPH (lipid hydroperoxide), and CD (conjugated diene) - decreased activities of SOD, CAT, and GPx - reduced levels of vitamin C, vitamin E, and GSH - increased DNA damage - higher number of apoptotic cells JB6 P+ mouse epidermal cell line: - induction of COX-2 expression and AP-1 and NF-κB activation - enhanced phosphorylation of ERKs, p38, JNKs, and Akt - increase in PKCε and c-Src kinase activity SKH-1 hairless mice: - induction of skin tumorigenesis - enhanced COX-2 and TNF-α expression and cellular proliferation - increased of PKCε and c-Src kinase activity

Caffeic acid

Phenolics

- reduced COX-2 expression, PEG2 production - reduced COX-2 promoter activity - inhibition of AP-1 and NF-κB transactivation - inhibition of phosphorylation of JNK, p38 and ERK - inhibition of Fyn kinase activity - inhibition of COX-2 protein expression and PGE2 production - suppression of transactivation of NF-κB and AP-1 - suppression of phosphorylation of JNKs, p38 and Akt - inhibition of MAPKK4 and PI-SK activity - enhanced cell viability - reduced cytotoxicity - reduced lipid peroxidation - increased activities of SOD, CAT, and GPx - restoration of vitamin C, vitamin E, and GSH levels - reduced DNA damage - reduced number of apoptotic cells

Luteolin (flavonoid)

Phenolics

JB6 P+ mouse epidermal cell line, Female SKH-1 hairless mice

Female SKH-1 hairless mice

- tumor development and increased tumor multiplicity

Honokiol (biphenol)

Phenolics

JB6 P+ mouse epidermal cells

- induction of DNA damage - activation of NF-κB and AP-1 - enhanced phosphorylation of MAPKs (p38, ERK, and JNK)

Quercitrin (flavonoid)

Phenolics

JB6 P+ mouse epidermal cells

- increased COX-2 expression - transactivation of NF-κB and AP-1 - induction of MKK4-JNK1/2-c-Jun and Raf-1-MEK1/2-ERK1/2 signalling - induction of kinase activities of MKK4, Raf-1, and MEK1

Cyanidin (anthicyanidin)

Phenolics

JB6 P+ mouse epidermal cell line: - inhibition of COX-2 expression and AP-1 and NFκB activation - repression of phosphorylation of ERKs, p38, JNKs, and Akt - attenuation of PKCε and c-Src kinase activity SKH-1 hairless mice: - suppression of skin tumorigenesis - reduced COX-2 and TNF-α expression and cellular proliferation - inhibition of PKCε and c-Src kinase activity - prevention against tumor development and reduced tumor multiplicity - prevention of DNA damage - prevention of NF-κB and AP1 activation - suppression of p38, ERK, and JNK phosphorylation - reduced COX-2 expression - attenuation of transactivation of NF-κB and AP-1 - inhibition of induction of MKK4-JNK1/2-c-Jun and Raf1-MEK1/2-ERK1/2 signalling - inhibition of induction of kinase activities of MKK4, Raf1, and MEK1

[246]

[247]

[248]

[249] [250]

[251]

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Table 2 (continued) Animal model

Effects of UV-B

Medicinal compound

Compound description

Effects on UV-B treated animal model

Reference

Human HaCaT keratinocytes, male hairless mice (SKH-1/hr+/+)

HaCaT cells: - reduced cell viability - increased cytotoxicity - increased ROS production - increased mRNA expression of IL6, IL-8, and TNF-α - increased COX-2 production - phosphorylation of ERK1/2 - activation of NF-κB p65 (enhanced nuclear translocation) - enhanced expression of VEGF - increased expression of MMP-2 and MMP-9 - increased phosphorylation of EGFR - activation of Src, Lak, and Lyn Mouse skin: - enhanced in epidermal hyperplasia - increased VEGF production - number and area of subcutaneous blood vessels enhanced - increased expression of PECAM-1 and ICAM-1 - increased mRNA levels of MMP-1 and MMP-9 - enhanced COX-2 expression - increased phosphorylation of ERK1/2 - increased expression of IL-6 and TNF-α

Capsiate (capsaicinoids)

Alkaloid

[252]

JB6 P+ mouse epidermal cells, Female ICR mice

JB6 P+ mouse epidermal cells: - enhanced COX-2 protein expression - enhanced COX-2 promoter activity - transactivation of AP-1 - phosphorylation of Src, ERKs, p38, and JNKs - enhanced Src kinase activity Female ICR mice: - enhanced COX-2 protein expression and Src kinase activity

Kaempferol (flavonoid)

Phenolics

Human HaCaT keratinocytes

- enhancement in luciferase expression - induction of c-fos promoter HaCaT human keratinocytes: - decreased cell viability - increased production of IL-6 - enhanced COX-2 expression and PGE2 levels - activation of p38, ERK, and SAPK/ JNK HR-1 hairless mice: - increased skin thickness - increased COX-2 protein expression - severe hyperplasia

Quercetin (flavonoid)

Phenolics

Sulforaphane (isothiocyanate)

Phenolics

Human HaCaT keratinocytes: - increased cell viability - reduced cytotoxicity - decrease in ROS production - suppressed mRNA expression of IL-6, IL-8, and TNF-α - reduced COX-2 production - decreased phosphorylation of ERK1/2 - suppressed nuclear translocation of NF-κB p65 - suppression of VEGF production - reduced expression of MMP-2 and MMP-9 - inhibition of phosphorylation of EGFR - inhibition of Src, Lak, and Lyn activation Mouse skin: - reduction in epidermal hyperplasia - decreased VEGF production - number and area of subcutaneous blood vessels decreased - reduced expression of PECAM-1 and ICAM-1 - reduced mRNA levels of MMP-1 and MMP-9 - suppressed COX-2 expression - reduced phosphorylation of ERK1/2 - reduced expression of IL-6 and TNF-α JB6 P+ mouse epidermal cells: - reduced COX-2 protein expression - reduced COX-2 promoter activity - inhibition of transactivation of AP-1 - reduced phosphorylation of ERKs, JNKs, and p38; no effect on Src phosphorylation - attenuation of Src kinase activity Female ICR mice: - reduction in COX-2 protein expression and Src kinase activity - reduced luciferase expression - partial blockage of c-fos promoter induction Human HaCaT keratinocytes: - improved cell viability - reduced production of IL-6 - reduced COX-2 expression and PGE2 levels - inhibition of p38, ERK, and SAPK/JNK activation HR-1 hairless mice: - reduced skin thickness - decreased COX-2 protein expression - reduced severity of hyperplasia

Human HaCaT keratinocytes, female HR-1 hairless mice

[253]

[254] [255]

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Table 2 (continued) Animal model

Effects of UV-B

Medicinal compound

Compound description

Effects on UV-B treated animal model

Reference

Female SKH-1 hairless mice

- induction of skin carcinogenesis - induction of malignant progression of pappilomas to carcinomas - enahnced COX-2 expression and PGE2 production - increased levels of proinflammatory cytokines (TNF-α, IL1β, and IL-6) - enhanced levels of biomarkers of inflammation in skin tumors (PCNA, iNOS) - increased levels of cyclins (D1, D2, and E) and cyclin-dependent kinases (CDK2, -4, and -6) - upregulation of both regulatory and catalytic subunits of P13K (a cell survival kinase) in tumors - reduced cell survival - early onset of apoptotic response (caspase-3 activation and PARP cleavage) - induction of CPDs - enhanced levels of ROS - increased COX-2 expression and PGE2 levels

Honokiol (biphenol)

Phenolics

[256]

Luteolin (flavone)

Phenolics

Human HaCaT keratinocytes

- increased amount of lactate dehydrogenase released into the medium - reduced cell viability - increased number and extent of DNA breakage - increased caspase-3 and -9 activity - increased ROS production - increased concentration of IL-6

rosmarinic acid (phenolic acid)

Phenolics

Human dermal fibroblasts

- induction of senescence-like state - increased apoptosis and cell cycle arrest - increased MDA levels; reduced SOD levels - increased mt-DNA mutations

Genistein (isoflavone)

Phenolics

Female SKH-1 hairless mice

- tumor induction - induction of cellular apoptosis and sunburn - formation of thymine dimers indicating DNA damage - increased number of p53-positive and p21/Cip1-positive cells - increased number of PCNApositive cells (enhanced cellular proliferation) - increased activities of NF-κB, COX-2, NO, and PGE2

Glycyrrhizic acid (triterpenoid saponin glycoside)

Terpenoids

- inhibition of skin carcinogenesis - inhibition of malignant progression of pappilomas to carcinomas - inhibition of COX-2 expression and PGE2 production - reduction in the levels of proinflammatory cytokines - inhibition of biomarkers of inflammation in skin tumors - inhibition of expression levels of cyclins and cyclindependent - downregulation of both subunits of P13K (a cell survival kinase) in tumors - improved cell survival - delayed apoptotic response (reduction in caspase-3 activation and PARP cleavage) - reduction in CPD induction - reduced ROS levels - no effect on COX-2 expression and reduced PGE2 levels - reduction of lactate dehydrogenase released into the medium - improved cell viability - protection of DNA against single strand breaks - reduced caspase-3 and -9 activity - decrease in ROS production - attenuation of IL-6 release - suppression of senescencelike state - inhibition of apoptosis and cell cycle arrest - reversal of MDA and SOD levels - downregulation of mt-DNA mutations - reduced number of tumors as well as reduced tumor volume - reduced number of apoptotic cells and sunburn cells - reduction in the number of thymine dimer-positive cells - further enhancement in the number of p53-positive and p21/Cip1-positive cells - decreased number of PCNApositive cells - decreased activities of NF-κB, COX-2, NO, and PGE2

Normal human keratinocytes (NHKs)

[257]

[258]

[259]

[260]

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Table 2 (continued) Animal model

Effects of UV-B

Medicinal compound

Compound description

Effects on UV-B treated animal model

Reference

Female C3H/HeN mice (wild type), Xeroderma pigmentosum complementation group A (XPA)deficient mice, XPA-proficient and XPA-deficient human fibroblasts, normal human epidermal keratinocytes

Mice: - increase in the number of sunburn cells Human fibroblasts: - cell death induction Normal human epidermal keratinocytes: - induction of apoptosis - increased DNA damage - slight enhancement in the levels of NER genes (XPA, XPC, RPA1, and DDB2)

Silymarin (flavonoid)

Phenolics

[261]

Female SKH-1 hairless mice

- erythema, peeling, thickening of the skin and edema - hyperplasia - reduced CAT and SOD activities - increased lipid peroxidation - enhanced expression of COX-2 protein (inflammation) - enhanced ornithine decarboxylase (ODC) expression (cell proliferation) - increased expression of GADD45 and OGG1/2 (markers of DNA damage) - CPD formation (indicative of DNA damage) - increased ROS production - Increased nitration of tyrosine residues via enhanced expression of 3-nitrotyrosinase (3-NT) (marker of oxidative stress) - phosphorylation of ERK and p38 MAPK - increased COX-2 and PEG2 expression - induction of skin erythema - reduced cell viability - increased ROS production - increased COX-2 expression - phosphorylation of ERK1/2, JNK, and p38 - downregulation of AQP-3 expression - loss of cell viability - condensed nuclei, increased apoptotic bodies, and cellular debris - decrease in procollagen I levels - increase in pro-MMP-1 levels - increased cell cycle arrest - increase in caspase 3 and intracellular ROS levels - increase in the levels of NF-κB and cytochrome C

Hesperidin, and mangiferin

Phenolics

Mice: - reduction in the number of sunburn cells in XPAproficient mice, but not in XPA-deficient mice Human fibroblasts: - significant reduction in cell death in XPA-proficient fibroblasts compared to XPAdeficient fibroblasts Normal human epidermal keratinocytes: - protection against apoptosis - reduction and repair of DNA damage - significant enhancement in the levels of NER genes - reduction in sunburn effects - reduction in hyperplasia - prevention of loss of CAT and SOD activities - protection against lipid peroxidation - reduced COX-2 expression - prevention of cell proliferation - reduced expression of GADD45 and OGG1/2

Luteolin (flavonoid)

Phenolics

- prevention of CPD formation - scavenging of ROS - reduced nitrotyrosine production - prevention of ERK and p38 MAPK phosphorylation - inhibition of COX-2 and PEG2 expression - prevention of skin erythema

[263]

Chrysin (flavonoid)

Phenolics

[264]

Glycyrrhizic acid (triterpenoid saponin glycoside)

Terpenoids

- increased ROS production - decrease in JNK1 - decrease in c-Jun - reduced cell viability - increased ROS - oxidative damage to lipids, proteins, and DNA - cellular apoptosis (increased DNA fragmentation)

Epigallocatechingallate (EGCG)

- increased cell viability - reduced ROS production - reduced COX-2 expression - inhibition of ERK1/2, JNK, and p38 phosphorylation - upregulation of AQP-3 expression - restoration of cell viability loss - prevention of condensed nuclei-, apoptotic bodies-, and cellular debris formation - reversal in procollagen I and pro-MMP-1 levels - amelioration of cell cycle arrest - reduced caspase 3 and ROS levels - reduction in NF-κB and cytochrome C levels - inhibition of ROS production - inhibition of JNK1 decrease - inhibition of c-Jun decrease - improved cell viability - enhanced ROS scavenging - protection of biomolecules against oxidative damage - protection against cellular apoptosis

Human HaCaT keratinocytes

Human HaCaT keratinocytes

Human foreskin fibroblasts (Hs68)

Human RPE cells (ARPE19 cell line) Human HaCaT keratinocytes

3-bromo-4, 5dihydroxybenzaldehyde

(natural antioxidant mainly isolated from red algae)

[262]

[265]

[266] [267]

(continued on next page)

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Table 2 (continued) Animal model

Effects of UV-B

Medicinal compound

Compound description

Effects on UV-B treated animal model

Reference

Female BALB/cAnN.Cg-Foxn1nu/CrNarl nude mice

- induction of MMP-2 and -9 protein expression - increased phosphorylation of protein translation components (Akt, mTOR, 4E-BP1, p70S6K, eIF4E and S6) - enhanced expression of Raptor protein - decreased collagen fibres in the dermis - accumulation of elastic fibres in skin - enlarged sebaceous glands, dermal cyst proliferation and increased number of vacuoles Normal human keratinocytes: - reduced GSH levels - increase in ROS levels Normal human fibroblasts: - enhanced MMP-1 activity

Ferulic acid

Phenolics

- inhibition of expression of both MMP-2 and -9 proteins - phosphorylation inhibition of translational proteins - reduced expression of Raptor protein - reduced degradation of collagen fibres - reduced deposition of elastic fibres - prevention of enlargement of sebaceous glands and dermal cyst formation; reduction in number of vacuoles

[268]

Piceatannol (stilbenoid)

Phenolics

[269]

Human skin fibroblasts Hs68 cells

- increased expression of MMP-1, MMP-3 and MMP-9 - phosphorylation of MEK and ERK - induced c-Fos expression - increased phosphorylation of EGFR - increased ROS generation - increased mRNA levels of GADD45

Carnosic acid (phenolic diterpene)

Phenolics/ terpenoids

Human keratinocyte cell line (CCD 1102 KERTr), primary human keratinocytes JB6 cells, mouse skin tissue

- induction of cellular damage - increased apoptosis

Lutein (carotenoids)

Terpenoids

Normal human keratinocytes: - improved GSH levels - reduced ROS levels Normal human fibroblasts: - reduction in MMP-1 activity - reduced expression of MMP1, MMP-3 and MMP-9 - reduced phosphorylation of MEK and ERK - decreased c-Fos expression - inhibition of phosphorylation of EGFR - decreased ROS generation - reduced mRNA levels of GADD45 - reduction of cellular damage - decreased apoptosis

- dose-dependent increase of cleaved PARP1, C-caspase-3 - NF-κB transcription factor increased in muclei - mouse skin: acute epidermal necrosis with inflammatory infiltrates in the dermis - 7 days post UV-B in mouse skin: hyperkeratosis, actinic keratosis - dose-dependent DNA damage - increased 8-OHdG production - dose-dependent increase of γH2AX expression - decreased expression of XPA gene - increase in ROS (%O2-, H2O2, %OH) - JB6 cells: decreased expressions of catalase and SOD2, GSH levels Normal human dermal fibroblasts: - stimulation of ROS generation - increased MMP-1 expression and IL-6 production - decreased procollagen type-I production - increased phosphorylation of c-fos and c-jun SKH:HR-1 mice: - deep and wide wrinkles - decreased stratum corneum hydration levels - increased transepidermal water loss and erythema index - increased epidermal thickness - reduced levels of collagen fibres, elastin, procollagen type-I and TGFβ1 - increased MMP-1 levels and IL-6 expression

Quercitrin

Flavonoid (Phenolics)

[272]

Gallic acid

Phenolics

- decreased activation of CPARP1, C-caspase-3 - NF-κB transcription factor decreased in nuclei - mouse skin: no reduction in epidermal necrosis, reduction in inflammatory response - prevention of hyperkeratosis - reduction in DNA damage - reduced 8-OHdG production - reduced γH2AX expression - restoration of reduced XPA gene expression - decreased ROS production - JB6 cells: restored expressions of catalase and SOD2, GSH Normal human dermal fibroblasts: - decreased in ROS generation - lowered production of MMP1 and IL-6 - upregulation of procollagen type-I production - lowered activation of c-fos and c-jun SKH:HR-1 mice: - superficial and thinner wrinkles - improved stratum corneum hydration levels - reduced transepidermal water loss and erythema index - decreased epidermal thickness - enahnced levels of collagen fibres, elastin, procollagen type-I and TGF-β1 - reduced MMP-1 levels and IL-6 expression

Normal human keratinocytes, normal human fibroblasts

Normal human dermal fibroblasts, male hairless mice (SKH:HR-1)

[270]

[271]

[273]

(continued on next page) 68

Journal of Photochemistry & Photobiology, B: Biology 193 (2019) 51–88

S. Takshak and S.B. Agrawal

Table 2 (continued) Animal model

Effects of UV-B

Medicinal compound

Compound description

Effects on UV-B treated animal model

Reference

Human HaCaT keratinocytes

- decreased cell viability - increased DNA damage/ increased number of CPDs - depletion of GSH levels - enhanced COX-2 expression

Phloretin (dihydroxychalcone)

Phenolics

[274]

Female C57BL/6 mice, normal human dermal fibroblasts

Female C57BL/6 mice: - induction of epidermal thickening - dermal collagen fiber loss - decrease in type I and III collagen in dorsal mice skin - induction of MMP-1 and MMP-3 Normal human dermal fibroblasts: - reduced cell viability - increased number of SA-β-gal positive cells - increase G1 phase in cell cycle proportion - increased levels of p53, p21, and p16 proteins - increase in γH2AX protein levels

Baicalin (flavonoid)

Phenolics

Human HaCaT keratinocytes

- intracellular ROS generation - increased DNA fragmentation - increased levels of 8-OHdG and phospho H2A.X (biomarkers of DNA damage) - increased levels of protein carbonyls - increased lipid peroxidation (indicated by increased levels of 8isoprostane) - reduced cell viability and increased nuclear fragmentation - loss of mitochondrial membrane potential - reduced levels of Bcl-2 (an antiapoptotic protein) and increased levels of Bax (a pro-apoptotic protein) - elevated expression of cleaved caspase-9 and caspase-3 - development of skin tumor - mice skin showed squamous cell carcinoma, hyperplasia and dysplastic formation - lipid peroxidation and depletion of antioxidants (SOD, CAT, GPX, GSH, Vitamins C and E) - enhanced expression of VEGF, iNOS, mutated p53, Bcl-2 expressions and decreased Bax expression - increased expression of TNF-α and IL-6

Americanin B (a lignin compound)

Phenolics

- improved cell viability - reduced amount of DNA damage/ reduced number of CPDs - inhibition of GSH depletion - reduction in COX-2 expression Female C57BL/6 mice: - reduction in epidermal thickening - prevention of collagen fiber loss - prevention of collagen type I and III decrease - prevention of MMP-1 and MMP-3 induction Normal human dermal fibroblasts: - improved cell viability - decrease in the number of SA-β-gal positive cells - reduced proportion of the G1 phase of the cell cycle - decreased levels of p53, p21, and p16 proteins - reduction in γH2AX protein levels - scavenging activity on ROS - decreased DNA fragmentation - reduced levels of 8-OHdG and phospho H2A.X - reduced levels of protein carbonyls - reduced lipid peroxidation - enhanced cell viability and reduced cellular fragmentation - prevention of loss of mitochondrial membrane potential - reversal in the expression levels of Bcl-2 and Bax proteins - partial reversal of caspase-9 and caspase-3 expressions

Ferulic acid

Phenolics

- prevention of skin tumor formation - prevented the development of squamous cell carcinoma, hyperplasia and dysplastic formation - reduced lipid peroxidation, prevention of antioxidant depletion - reversal in the expression status of VEGF, iNOS, mutated p53, Bcl-2, and Bax - decreased expression of TNFα and IL-6

[277]

Swiss albino mice

[275]

[276]

(continued on next page)

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Table 2 (continued) Animal model

Effects of UV-B

Medicinal compound

Compound description

Effects on UV-B treated animal model

Reference

Male Swiss albino mice

Short term study (10 days): - induction of skin edema (increase in bifold skin thickness, ear thickness, and ear punch weight) - increased epidermal layer thickness, acanthosis formation, hyperplasia, and epidermal damages - increased lipid peroxidation (increased TBARS levels) - decreased activities of SOD, CAT, GPx, and GSH levels - overexpression of TNF-α, IL-6, COX-2, and NF-κB - downregulation of PPARγ protein expression Long term study (30 weeks): - development of skin tumors - induction of squamous cell carcinoma, keratinous pearls, hyperplasia, and dysplastic features in the dermis - enhanced expression of iNOS, TGF-β, and VEGF - decreased expression of p53 protein - increased ROS - increased cytoplasmic Ca2+ levels/ increased leakage of Ca2+ from endoplasmic reticulum (ER) - increased ER stress (via increased expression of glucose regulated protein 78 (GRP78), increased phosphorylation of eukaryotic initiation factor (p-eIF2a), increased expression of downstream effectors of p-eIF2a like activating transcription factor 4 (ATF4), C/EBP homologous (CHOP, also called as GADD 153) and growth arrest and DNA damage 34 (GADD34)) - activation of MAPK pathway (increased phosphorylation of p38, JNK, MEK; non-significant phosphorylation of ERK (pERK)) - loss of mitochondrial membrane potential - increased cellular apoptosis - increased PARP1 cleavage - increased expression of Bim (a pro-apoptic protein) - reduced cell viability - increased activity of senescenceassociated β-galactosidase - predominant G1/G0 phase distribution and minimal S phase distribution in the cell cycle - upregulated expressions of p53, p21, and p16 - decreased intracellular SOD activity and increased levels of MDA - elevated levels of MMP-1 - increase in IL-6 and TNF-α

Caffeic acid (hydroxycinnamic acid)

Phenolics

Short term study (10 days): - inhibition of skin edema - prevention of increased epidermal layer thickness, acanthosis formation, hyperplasia, and epidermal damages - decreased levels of TBARS - restored activities of SOD, CAT, GPx, and GSH levels - downregulation of TNF-α, IL6, COX-2, and NF-κB expression - prevention of PPARγ protein expression loss Long term study (30 weeks): - prevention of tumor formation - inhibition of formation of photocarcinogenic features - suppression of iNOS, TGF-β, and VEGF expression - enhanced expression of p53 protein

[278]

Glycyrrhizic acid

Triterpene (Terpenoids)

- reduction in ROS - restoration of Ca2+ imbalance - reduced expression of GRP78, reduced phosphorylation of eIF2a, reduced expression of CHOP, ATF4 and GADD34 - blockage of MAPK pathway activation (reduced phosphorylation of p38, JNK, MEK and ERK) - restoration of mitochondrial membrane potential - reduction in apoptosis - reduced PARP1 cleavege - reduced expression of Bim protein

[279]

- reversal of cell viability decline - reduced activity of βgalactosidase - decreased G1/G0 and increased S phase distribution in the cell cycle - decreased expressions of p53, p21, and p16 - no significant increase in SOD activity and reduced MDA levels - prevention of MMP-1 elevation - reduced expressions of IL-6 and TNF-α

[280]

Human skin fibroblasts (Hs68)

Primary human dermal fibroblasts

Salidroside (tyrosol glucoside)

(continued on next page)

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Table 2 (continued) Animal model

Effects of UV-B

Medicinal compound

Compound description

Effects on UV-B treated animal model

Reference

hairless mice (HRS/J)

- skin edema - increased myeloperoxidase activity - induction of MMP-9 activity - depletion of antioxidants (reduced glutathione, catalase) - lipid peroxidation, increased superoxide radical production - induction of gp91phox expression - induction of skin inflammation due to increased cytokine production

Hesperidin methyl chalcone (flavonoid)

Phenolics

[281]

Female SKH-1 hairless mice

- increase in skin fold, thickness, and redness - skin wrinkling and hyperplasia - development of skin carcinoma - oxidative damage to DNA, proteins, and lipids - reduced levels of GSH, SOD, CAT, and GPx

Pterostilbene

Phenolics

Hairless HRS/J mice

- increased lipid peroxidation - increased NO levels - increased number of apoptotic cells - increased cell proliferation/ tumor formation - upregulated expressions of IL-10, JAK -1, and nuclear STAT-3 - increased levels of cell cycle regulatory protein cyclin-D1 and cell proliferation marker PCNA - decreased protein levels of TSP-1, an antiproliferative marker - decreased expressions of proapoptotic proteins like Bax, cytochrome-c, caspase-9 and -3 - increased Bcl-2 expression - increased loss of cell viability - apoptosis - increased ROS - decreased cell viability - increased DNA strand breaks - induction of caspase-3-cleavage - induction of PARP1 cleavage

Genistein (isoflavone)

Phenolics

Caffeic acid (hydroxycinnamic acid)

Phenolics

- prevention of skin edema - reduced myeloperoxidase activity - reduction in MMP-9 activity - prevention of antioxidant depletion - inhibition of lipid peroxidation and superoxide radical production - inhibition of gp91phox expression - inhibition of increase in cytokine levels, preventing skin inflammation - reduction in skin inflammation responses - prevention of skin wrinkling and hyperplasia - prevention of skin carcinogenesis - reduction in oxidative damage to biomolecules - prevention of loss of antioxidant concentrations and activities - reduced lipid peroxidation - decreased NO levels - reduced number of apoptotic cells - reduced cell proliferation/ tumor formation - suppressed expressions of IL10, JAK-1, and nuclear STAT-3 - reduction in cyclin-D1 and PCNA expressions - increased expression of TSP-1 protein - increased expressions of proapoptotic marker proteins - suppressed expression of Bcl2

Baicalin (flavone)

Phenolics

[285]

Capsanthin, capsorubin (carotenoids)

Phenolics

- reduced cell viability loss - reduced cellular apoptosis - suppressed ROS production - improved cell viability - decrease in DNA strand breaks - reduction in caspase-3cleavage - no effect on PARP1 cleavage

Male Swiss albino mice

Human HaCaT keratinocytes Human dermal fibroblasts CCD-1064SK

[282]

[283]

[284]

[286]

(continued on next page)

71

Journal of Photochemistry & Photobiology, B: Biology 193 (2019) 51–88

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Table 2 (continued) Animal model

Effects of UV-B

Medicinal compound

Compound description

Effects on UV-B treated animal model

Reference

Swiss albino mice

Short term study (7 days): - induction of cutaneous edema (increased bifold skin thickness, ear thickness, and ear punch weight) - increased epidermal thickness, hyperplasia, acanthosis, and epidermal damage - overexpression of COX-2 and ODC - increased lipid peroxidation - decreased activities of SOD, CAT, and GPx Long term study (30 weeks): - increased number of tumors - development of SCC, keratinous pearls, hyperplasia, and dysplastic features in the dermis - NF-κB, TNF-α, and COX-2 upregulation - overexpression of VEGF, TGF-β1, and mutated p53 in the epidermis and dermis - increased Bcl2 expression and decreased Bax expression

Linalool (monoterpene)

Terpenoids

[287]

Human HaCaT keratinocytes

- inhibition of cell survival - increased ROS generation - induction of apoptosis - induction of DNA damage (as indicated by upregulation of phosphorylation levels of ATM, ATR and p53) - Attenuation of Bcl-2 antiapoptotic protein, increased expressions of pro-apoptotic Bax protein and cleaved caspase 3 - cytotoxic effects on skin cells - increased intracellular ROS generation - oxidative DNA damage - increase in fragmented nucleoids - increased lipid peroxidation (increased TBARS levels) - reduced concentrations of cellular antioxidants (GSH, SOD, CAT, GPx) - increased levels of NF-κB, COX-2, TNF-α, and IL-6 - downregulation of mRNA expression of HOGG1, XRCC1 - increased mRNA expression of MMP-1 and MMP-9

Cyanidin-3-O-glucoside (anthocyanin)

Phenolics

- inhibition of cutaneous edema - prevention of increased epidermal thickness, hyperplasia, acanthosis, and epidermal damage - prevention of of COX-2 and ODC overexpression - reduction in lipid peroxidation - enhanced activities of SOD, CAT, and GPx Long term study (30 weeks): - reduction in the number of tumors - inhibition of the development photocarcinogenic histological features - prevention of NF-κB, TNF-α, and COX-2 overexpression - suppressed expression of of VEGF, TGF-β1, and mutated p53 - reduced expression of Bcl2 and increased expression of Bax - elevated cell survival rate - increased ROS scavenging - reduction of apoptosis - decrease in phosphorylation levels of ATM, ATR and p53 indicating reduction in DNA damage - reversal in the expressions of Bcl-2, Bax, and cleaved caspase 3 proteins

7-hydroxycoumarin

Phenolics

- prevention of cytotoxicity - reduced intracellular ROS generation - prevention of DNA oxidative damage - prevention of fragmented nucleoid formation - reduced lipid peroxidation (reduced TBARS levels) - prevention of antioxidant loss - decreased levels of NF-κB, COX-2, TNF-α, and IL-6 - upregulation of mRNA expression of HOGG1, XRCC1 - reduced mRNA expression of MMP-1 and MMP-9

[289]

Human dermal fibroblasts (HDFa)

[288]

(continued on next page)

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Journal of Photochemistry & Photobiology, B: Biology 193 (2019) 51–88

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Table 2 (continued) Animal model

Effects of UV-B

Medicinal compound

Compound description

Effects on UV-B treated animal model

Reference

Human HaCaT keratinocytes, female BALB/c nude mice

HaCaT cells: - reduced cell viability - increased apoptosis (increased caspase-3 cleavage) - increased levels of Bax mRNA and reduced levels of Bcl2 mRNA - enhanced ROS generation - increased expression of proinflammatory cytokines (IL-1β, IL6, and IL-8) - increased COX-2 mRNA and protein levels BALB/c nude mice: - increased epidermal thickness and skin damage - increased expression of Bax and IL-6 - increased COX-2 protein levels - activation of p38 MAPK signaling pathway

Naringin (flavonoid)

Phenolics

[290]

Human HaCaT keratinocytes

- decreased cellular elasticity - induction of oxidative stress and DNA damage - disappearance of cell repair marker 53BP1 - reduced cell viability - increased intracellular ROS production - increased lipid peroxidation - decreased activities of SOD, CAT, GPx, and GSH levels - increased mutagenesis - increased DNA damage - reduction in mitochondrial membrane potential - increased nuclear fragmentation and apoptosis - enhanced expressions of XRCC1, GADD45α, HOGG1

Delphinidin (anthocyanidin)

Phenolics

Ferulic acid

Phenolics

- increase in caspase-3 activity (indicative of apoptosis) HaCaT human keratinocytes: - decreased cell viability - reduced translocation of Nrf2 to the nucleus - reduced transcription and translocation of Nrf2 and its target genes NQO1 and HO-1 - intracellular increase in ROS Guinea pigs: - increased sunburn - increased number of apoptotic cells and increased cellular DNA damage

Curcumin (polyphenol)

Phenolics

- reduced cell viability - increased expression of hyaluronidase genes

Epigallocatechin gallate (catechin) (polyphenol)

HaCaT cells: - improved cell viability - reduced caspase-3 cleavage, suggesting reduced apoptosis - reversal in the increase of Bax mRNA levels; normal levels of Bcl2 mRNA - inhibition of ROS production - reduced expression of proinflammatory cytokines, IL-1β, IL-6, and IL-8 - reduction in COX-2 mRNA and protein levels BALB/c nude mice: - reduced epidermal thickness and skin damage - reduced Bax and IL-6 expression - reduced levels of COX-2 - inhibition of activation of p38 MAPK signaling pathway - inhibition of loss of elasticity - reduction of oxidative stress and DNA damage - prevention of loss of cell repair marker 53BP1 - restoration of cell viability - reduced levels of intracellular ROS - decreased lipid peroxidation - restoration of antioxidant levels - reduced mutagenesis - reduction in DNA damage - Prevention of loss of mitochondrial membrane potential - reduced nuclear fragmentation and apoptosis - downregulation of expressions of XRCC1, GADD45α, HOGG1 - reduction in caspase-3 activity Human HaCaT keratinocytes: - increased cell viability - increased Nrf2 translocation to the nucleus - significantly enhanced protein levels and expression of Nrf2 as well as NQO1 and HO-1 - prevention of ROS increase Guinea pigs: - reduced sunburn - inhibition of formation of apoptotic cells and DNA damage reduction - increased cell viability - reduced expression of hyaluronidase genes

Human dermal fibroblasts (HDFa)

Human HaCaT keratinocytes Human HaCaT keratinocytes, skin of guinea pigs

Human HaCaT keratinocytes

Salidroside (tyrosol glucoside)

The number and activity of Langerhans cells (the antigen-presenting immune cells) of the epidermis are impaired by UV-B. Immunosuppression also involves IL-10 and urocanic acid; IL-12, on the other hand, has been known to prevent immunosuppression [195,205]. Human peripheral blood-derived dendritic cells and splenic dendritic cells are other antigen-presenting cells (APCs) whose ability to stimulate T cells is compromised upon UV-B exposure leading to immunomodulatory/immunosuppressive effects [206,207]. ROS are also responsible for impairing the normal functioning of APCs [208]. The

Phenolics

[291]

[292]

[293] [294]

[295]

extracellular matrix (ECM) is the non-cellular component of all tissues and organs comprised of glycoproteins (e.g. fibronectin), glycans, and structural proteins such as collagen, elastin, and laminin [209]. The remodeling of ECM is achieved by the action of zinc-containing extracellular proteolytic enzymes, the matrix metalloproteinases (MMPs) or elastases [210]. Secretion of MMPs by keratinocytes and fibroblasts under UV-B has been reported [211]. Primarily, MMP-1, -3, and -9 have been more widely investigated as to the effects of UV-B in various model cell lines and murine models (Tables 2 and 3). 73

74 -

Female SKH-1 hairless mice

Black raspberry extract

Green tea extract, white tea extract

- CD1a+ cell depletion and 8-OHdG formation - decreased number of Langerhans cells

90 human subjects (18-60 y) induction of carcinogenesis induction of tumor formation induction of acute edema increased neutrophil activation and infiltration enhanced p53 expression increased 8-OHdG levels

Anthocyanins

Punica granatum (pomegranate) juice, extract, and oil

Honeybush extracts

Prunella vulgaris extract

Plant whole extracts/ group of compounds

- reduced cell viability - increased ROS concentration - DNA damage - activation of ATR (ataxia telangiectasia and rad3-related kinase) 1 - phosphorylation of transcription factor p53 - elevated phosphorylation of proapoptotic Bad gene protein - reduced procollagen levels - increased secretion of MMP-1, MMP-8, and MMP-13 - enhanced production of proinflammatory cytokines IL-1β, IL-6, IL-8, and TNF-α - phosphorylation of IκB - enhanced nuclear translocation of NF-κB p65 - increased phosphorylation of JNK and p38 MAPK

- increased amount of lactate dehydrogenase released into the medium - reduced cell viability - increased number and extent of DNA breakage - increased caspase-3 and -9 activity - increased ROS production - increased concentration of IL-6 - erythema, peeling, thickening of the skin and edema - hyperplasia - reduced CAT and SOD activities - increased lipid peroxidation - enhanced expression of COX-2 protein (inflammation) - enhanced ornithine decarboxylase (ODC) expression (cell proliferation) - increased expression of GADD45 and OGG1/2 (markers of DNA damage) - induction of CPD and 8-OHdG formation - increase in the number of protein carbonyl groups - enhanced cellular proliferation - reduced tropoelastin levels - increase in protein levels and activity of MMPs 1, -2, -3, -7, -9, -11, and -12 - induction of c-jun phosphorylation and c-fos expression

Effects of UV-B Radiation

Human dermal fibroblasts

Human reconstituted skin (EpiDermTM FT-200)

SKH-1 mice

Human HaCaT keratinocytes

Animal Model

Table 3 Effects of whole plant/ plant part extracts on animal models (2009-2018)

[299]

[298]

[297]

[296]

[262]

[258]

Reference

(continued on next page)

- inhibition of CPD and 8-OHdG formation - inhibition of increase in protein carbonyl groups - inhibition of cellular proliferation - increase in tropoelastin levels - inhibition of protein levels and activity of MMPs 1, -2, -3, -7, -9, -11, and -12 - inhibition of c-jun phosphorylation and c-fos expression - increased cell viability - reduced ROS concentration - reduced DNA damage - decline in the activation of ATR1 and p53 transcription - blockage of phosphorylation of transcription factor p53 - increased procollagen levels - reduced secretion of MMP-1, MMP-8, and MMP-13 - reduced production of proinflammatory cytokines IL-1β, IL-6, IL-8, and TNF-α - reduced phosphorylation of IκB - reduced nuclear translocation of NF-κB p65 - reduced phosphorylation of JNK and p38 MAPK - prevention of CD1a+ cell depletion and 8OHdG formation - no reduction in the number of Langerhans cells - reduction of carcinogenesis - reduction in tumor size and inhibition of tumor progression - reduction of edema - reduced neutrophil activation; no effect on neutrophil infiltration - suppression of p53 expression - reduced 8-OHdG levels

- reduction of lactate dehydrogenase released into the medium - improved cell viability - protection of DNA against single strand breaks - reduced caspase-3 and -9 activity - decrease in ROS production - attenuation of IL-6 release - reduction in sunburn effects - reduction in hyperplasia - prevention of loss of CAT and SOD activities - protection against lipid peroxidation - reduced COX-2 expression - prevention of cell proliferation - reduced expression of GADD45 and OGG1/2

Effects on UV-B Treated Animal Models

S. Takshak and S.B. Agrawal

Journal of Photochemistry & Photobiology, B: Biology 193 (2019) 51–88

75 Human HaCaT keratinocytes: - reduced cell viability - enhanced production of cytokines and chemokines (IL-1β, TNFα, IL-6, and IL-8) Male C57BL/6 mice: - induction of edema, erythema, and thickening of epidermis - increased infiltration of leukocytes and dilation of blood vessels in the dermis - increased production of IL-1β and IL-6

Human HaCaT keratinocytes, male C57BL/6 mice

Female SKH-1 hairless mice

Human skin fibroblasts

-reduced cell viability - reduced cell viability - shedding of microvilli, degeneration of nucleus, nucleolus, and mitochondria - decreased cell viability - reduction in pro-collagen 1 levels - increased pro-matrix metalloproteinase 1 (pro-MMP-1) levels - increased number of apoptotic cells - induction of cutaneous edema, hyperplasia, and infiltration of leukocytes - enhanced lipid peroxidation and H2O2 generation - increase in epidermal ODC activity and protein expression - increased COX-2 and PCNA protein expression - formation of CPD and 8-oxodG - enhancement in p53 and p21 protein expression - activation of IKKα and NF-κB - enahnced phosphorylation and degradation of IκBα

Murine skin fibroblasts human HaCaT keratinocytes

decreased cell viability enhanced keratinocyte proliferation enhanced number of DNA single strand breaks increased activities of caspase-3 and -9 increased production of reactive oxygen and nitrogen species increased expressions of IL-1β and IL-6

-

- induction of erythema - increased melanin index - increase in the thickness of stratum corneum as well as total epidermal thickness - increased expression of CK5/6 and CK16 indicative of enhanced photoageing - increased MMP-2 and MMP-9 expression - depletion of CD1a+ Langerhans cells - induction of skin tumorogenesis - enhanced COX-2 expression and PGE2 production - increased levels of PCNA and cyclin D1 - increased levels of TNF-α, IL-1β, and IL-6 - increased levels of DNA damage - increased skin inflammation

Effects of UV-B Radiation

HaCaT keratinocytes

Female C3H/HeN mice

20 female volunteers

Animal Model

Table 3 (continued)

Water extract of Zingiber officinale (ginger)

Punica granatum (pomegranate) fruit extract

Emblica officinalis extract

Tea polysaccharides, tea polyphenols Green tea polyphenols

Lonicera caerulea and Vaccinium myrtillus fruit polyphenols

Green tea polyphenols

Green tea extracts (2-3% concentration)

Plant whole extracts/ group of compounds

[307]

[306]

[305]

[303] [304]

[302]

[301]

[300]

Reference

(continued on next page)

- delayed onset of erythema - prevention of melanin index increase - reduced thickness of stratum corneum and epidermis - attenuation of CK5/6 and CK16 overexpression - reduction in MMP-2 and MMP-9 expression - prevention of CD1a+ Langerhans cells depletion - inhibition of skin tumorogenesis - reduced COX-2 expression and PGE2 production - decreased levels of PCNA and cyclin D1 - reduced levels of TNF-α, IL-1β, and IL-6 - prevention of DNA damage - reduced skin inflammation - improved cell viability - prevention of keratinocyte proliferation - prevention of DNA single strand break formation - reduced activities of caspase-3 and -9 - reduced levels of reactive oxygen and nitrogen species - reduced IL-1β and IL-6 expressions - improved cell viability - improved cell viability - alleviation of negative morphological changes to cells - prevention of loss of cell viability - restoration of pro-collagen 1 levels - decreased levels of pro-MMP-1 - reduction in the number of apoptotic cells - inhibition of cutaneous edema, hyperplasia, and infiltration of leukocytes - inhibition of lipid peroxidation and H2O2 generation - inhibition of epidermal ODC activity and protein expression - inhibition of COX-2 and PCNA protein expression - inhibition of CPD and 8-oxodG formation - further enhancement in p53 and p21 protein expression - inhibition of IKKα and NF-κB activation - reduced phosphorylation and degradation of IκBα Human HaCaT keratinocytes: - improved cell viability - reduced production of cytokines and chemokines Male C57BL/6 mice: - reduction in edema, erythema, and thickening of epidermis - reduced infiltration of leukocytes and dilation of blood vessels in the dermis - reduced production of IL-1β and IL-6

Effects on UV-B Treated Animal Models

S. Takshak and S.B. Agrawal

Journal of Photochemistry & Photobiology, B: Biology 193 (2019) 51–88

- decreased cell viability - abnormalities in cell microstructure (microvilli shedding, nucleolus degeneration, mitochondria deformity, formation of vesicular structures) - DNA fragmentation - increase in ROS (H2O2, %OH) - increased lipid peroxidation - reduced protein expression and antioxidant enzyme activities (superoxide dismutase, catalase) - enhanced DNA fragmentation and number of apoptotic bodies - suppression of contact hypersensitivity response - early onset of wrinkling and enhanced wrinkle formation - reduced GSH levels, increased H2O2 and lipid peroxidation - induction of hyperplasia, infiltration of leukocytes, protein oxidation and lipid peroxidation - increased phosphorylation of MAPKs (ERK1/2, JNK1/2, and p38) - activation of NF-κB pathway - increased COX-2 and iNOS protein expression - increase in cyclin D1 and PCNA protein expression - induction of c-Jun phosphorylation and protein expression of MMP-2, -3, and -9 - deeper and wider wrinkle formation - increased epidermal thickness - decreased abundance and density of collagen fibres - increased erythema index - decreased stratum corneum hydration - decreased abundance of procollagen type-I and TGF-β1 - increased MMP-1 protein expression - decreased expression of profilaggrin and filaggrin in both epidermis and dermis

Human retinal pigment epithelial cells

Male hairless mice (HRS/J)

Female SKH-1 hairless mice

Male albino hairless mice (SKH: HR-1)

Female C3H/HeN mice

HaCaT keratinocytes

SKH-1 hairless mice

- reduced cell viability - enhanced transepidermal water loss - erythema - wrinkles and desquamation of skin - increased epidermal thickness of dorsal skin - reduced catalase activity - increased COX-2 expression - increased PCNA (proliferating cell nuclear antigen) - skin tumor development - infiltration of inflammatory leukocytes in the skin - enhanced COX-2 expression and PGE2 production - enhanced levels of PCNA and cyclin D1 (mRNA and protein levels) - induction of proinflammatory cytokines TNF-α, IL-1β, and IL-6

Effects of UV-B Radiation

Male ICR-Foxn/nu mice

Animal Model

Table 3 (continued)

76

Enzyme-processed Korean red ginseng extracts

Punica granatum (pomegranate) fruit extract

Formulation containing tannase-converted green tea extract

Grape seed proanthocyanidins

Ethyl acetate fraction of Sargassum muticum (a brown alga)

Green tea polyphenols

Grape seed proanthocyanidins

Soy isoflavone extract

Plant whole extracts/ group of compounds

[315]

[314]

[313]

[312]

[311]

[310]

[309]

[308]

Reference

(continued on next page)

- scavenging activity towards ROS - reduced lipid peroxidation - restoration of protein expression and activities of antioxidant enzymes - reduced cellular apoptosis - prevention of suppression of contact hypersensitivity response - delayed onset of wrinkling and decreased wrinkle development due to photoageing - improved GSH levels, reduced H2O2 and lipid peroxidation - inhibition of hyperplasia, infiltration of leukocytes, protein oxidation and lipid peroxidation - inhibition of phosphorylation of MAPKs - inhibition of NF-κB pathway - inhibition of COX-2 and iNOS protein expression - inhibition of cyclin D1 and PCNA protein expression - inhibition of c-Jun phosphorylation and protein expression of MMP-2, -3, and -9 - reduce wrinkle formation - prevention of epidermal thickening - restoration of collagen fibre density and abundance - reduced erythema index - improved hydration of stratum corneum - improved levels of procollagen type-I and TGFβ1 - reduced MMP-1 protein expression - enhanced expression of profilaggrin and filaggrin in both epidermis and dermis

- enhanced cell viability - reduced transepidermal water loss - reduced erythema - decreased wrinkles and desquamation - diminished epidermal thickness - enhanced catalase activity - decreased COX-2 expression - decreased PCNA expression - inhibition of skin tumor development - inhibition of infiltration of inflammatory leukocytes in the skin - redcued COX-2 expression and PGE2 production - reduced levels of PCNA and cyclin D1 (mRNA and protein levels) - inhibition of proinflammatory cytokine levels (TNF-α, IL-1β, and IL-6) - improved cell viability at lower concentrations - prevention of abnormalities of cellular microstructures - inhibition of DNA fragmentation

Effects on UV-B Treated Animal Models

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Journal of Photochemistry & Photobiology, B: Biology 193 (2019) 51–88

77 -

- skin erythema and inflammation - enhanced iNOS and COX-2 expression - increased phosphorylation of p38, JNK, ERK, and c-Jun -

Female SKH-1 hairless mice

Norman human dermal fibroblasts, HaCaT keratinocytes, albino hairless male mice (SKH:HR-1)

Female SKH-1 hairless mice

enhanced wrinkle formation increased epidermal thickness decreased collagen fiber density reduced SOD, catalase, and GPx activities increased expression of MMP-1, -3, and -9 reduced expression of TIMP-1 and type-I collagen

increased transepidermal water loss increased wrinkle area thickened epidermis and dermis infiltration of inflammatory cells in the dermis broken collagen fibres with reduced structural density denatured and tangled elastic fibres increased number of mast cells and prominent degranulation enhanced MMP-3 expression

NHDFs: - elevated mRNA levels of MMP-1 - reduced mRNA expression of procollagen type-I - decreased cell viability - reduced epidermal hydration Male Hos:HR-1 hairless mice: - thicker epidermal layers - reduced density of collagen fibres - higher protein levels of MMP-1 - reduced levels of procollagen type-I, TGF-β1, and elastin

- decreased cell viability - enhanced expression and protein levels of COX-2 and TNF-??, increased PEG2 production - increased expression of iNOS protein and NO production - increased intracellular ROS levels - reduced mRNA levels of antioxidant enzymes (Cu/Zn SOD, CAT) - BALB/c mice: hard, thick, uneven skin texture, hyperkeratosis - BALB/c mice: photodamage to the skin (increased epidermal hyperplasia, degeneration of elastic fibres, high expression of IL8) - BALB/c mice: phosphorylation of ERK, JNK, and p38 MAPK - Fibroblasts: phosphorylation of ERK, JNK, and p38 MAPK - Fibroblasts: enhanced expression of MMP-1 - Fibroblasts: enhanced expression of proinflammatory cytokines IL-1α, IL-1β, IL-6, and TNF-α

Effects of UV-B Radiation

Male Hos:HR-1 hairless mice, normal human dermal fibroblasts (NHDFs)

Human dermal fibroblasts and BALB/c mice

HaCaT keratinocytes, BALB/c mice

Animal Model

Table 3 (continued)

Green tea seed extract

Fermented soybean isoflavones

Water extracts of tea (Camellia sinensis)

Enzyme-modified Panax ginseng extratcs

EGb-761 (standardised extract of Ginkgo biloba)

ethylacetate fraction of ethanol extract of Sargassum fulvellum (a brown alga)

Plant whole extracts/ group of compounds

[321]

[320]

[319]

[318]

[317]

[316]

Reference

(continued on next page)

- amelioration of UVB-induced cytotoxicity - reduced expression and protein levels of COX-2 and TNF-??, reduced PEG2 production - inhibition of iNOS protein levels as well as NO production - reduction in intracellular ROS - upregulated antioxidant enzyme levels - BALB/c mice: reduction in coarse wrinkle formation in skin - BALB/c mice: reversal of the symptoms of photodamage to the skin - BALB/c mice: suppression of phosphorylation of MAPKs - Fibroblasts: inhibition of phosphorylation of ERK, JNK, and p38 MAPK - Fibroblasts: reduction in MMP-1 expression - Fibroblasts: reduced expression of proinflammatory cytokines NHDFs: - reduced mRNA levels of MMP-1 - elevated mRNA expression of procollagen type-I - increased cell viability - improved epidermal hydration Male Hos:HR-1 hairless mice: - reduced epidermal thickness - improved density of collagen fibres - decreased protein levels of MMP-1 - improved protein levels of procollagen type-I, TGF-β1, and elastin - reduced transepidermal water loss - reduce wrinkle area - reduced thickness of epidermis and dermis - reduced infiltration of inflammatory cells in the dermis - intact collagen fibres with a regular arrangement - less denaturation of elastic fibres - reduced number of mast cells and degree of degranulation - reduced MMP-3 expression - reduced erythema and skin inflammation - inhibition of iNOS and COX-2 expression - inhibition of phosphorylation of p38, JNK, ERK, and c-Jun - attenuation of wrinkle formation - reduced epidermal thickness - improved collagen fiber density - enhanced activities of SOD, catalase, and GPx - decreased expression of MMP-1, -3, and -9 - enahnced expression of TIMP-1 and type-I collagen

Effects on UV-B Treated Animal Models

S. Takshak and S.B. Agrawal

Journal of Photochemistry & Photobiology, B: Biology 193 (2019) 51–88

- increased ROS production - reduction in proliferative activity - increased cytotoxicity - increased apoptosis HaCaT human keratinocytes: - reduced cell viability - increased ROS generation SKH-1 hairless mice: - formation of thick, fixed wrinkles in the dorsal skin - increased epidermal thickness - increased transepidermal water loss - induction of erythema - increased expression of MMP-2 and MMP-9 - reduction in collagen levels - increased mRNA and protein levels of granulocyte macrophage colony stimulating factor (GM-CSF) - enhanced phosphorylation of ERK - phosphorylation of epidermal growth factor receptor (EGFR) - enhanced MMP-1 transcription and translation - increased AP-1 (activator protein-1) transactivation - increased binding affinity of AP-1 residues - enhanced kinase activity of P13K isoforms - increased collagen degradation - reduced cell viability - enhanced mRNA expression of IL-1b - reduction in telomerase activity NHDFs: - stimulation of ROS generation - increased MMP-1 and IL-6 levels NHDFs and HaCaT cells: - induction of MMP-1 mRNA expression SKH: HR-1 mice: - deeper and wider wrinkle formation - increased epidermal thickness - increased MMP-1 and reduction in elastin, procollagen type-I, and TGF-β1 HaCaT human keratinocytes: - decreased cell viability - increased intracellular ROS production - induced expression of MMP-2 and MMP-9 SKH-1 hairless mice: - induction of wrinkle formation and increased wrinkle area - induction of hyperplasia with increased epidermal thickness - reduced water holding capacity - increased erythema formation - upregulation of MMP-2, -9, and -13 gene expression - high levels of MMP-2 protein - reduced levels of collagen

Human skin fibroblasts

78

HaCaT human keratinocytes, SKH-1 hairless mice

Normal human dermal fibroblasts (NHDFs), HaCaT cells, Male albino hairless mice (SKH: HR-1)

Human HaCaT keratinocytes

HaCaT cells, human skin equivalent

Murine SP-1 keratinocytes

HaCaT human keratinocytes, Male SKH-1 hairless mice

HaCaT keratinocytes

reduced cell viability ROS generation increased number of DNA breaks induction of COX-2 expression and PGE2 production

-

Effects of UV-B Radiation

Human HaCaT keratinocytes

Animal Model

Table 3 (continued)

Spent coffee ground extracts

Galla chinensis extracts

Citrus bergamia (bergamot) fruit polyphenolic fraction

Brown pine leaf extract

Ginsenosides from Panax ginseng

Spent coffee ground ethanol extract

Galinsoga parviflora and Galinsoga quadriradiata aqueous and ethanolic extracts

Orange peel extract

Combination of rosemary extract (rich in polyphenols and diterpenes) and citrus extract (rich in flavonoids)

Plant whole extracts/ group of compounds

[330]

[329]

[328]

[327]

[326]

[325]

[324]

[323]

[322]

Reference

(continued on next page)

- prevention of cell viability loss - Attenuation of ROS generation - reduced number of DNA breaks - suppression of COX-2 expression and PGE2 production - ROS scavenging - further inhibition of cell proliferation - reduction in cytotoxic effects - prevention of apoptosis HaCaT human keratinocytes: - no significant effects on cell viability - inhibition of ROS generation SKH-1 hairless mice: - reduction of wrinkle formation - reduced epidermal thickness - reduced transepidermal water loss - inhibition of erythema formation - reduction in MMP-2 and MMP-9 expression - inhibition of collagen reduction - reduced mRNA and protein levels of GM-CSF - reduction in ERK phosphorylation - reduced phosphorylation of epidermal growth factor receptor - reduced MMP-1 transcription and translation - reduced AP-1 transactivation - suppression of binding affinity of AP-1 residues - inhibition of kinase activity of P13K isoforms - protection of collagen degradation - restoration of cell viability - reduced mRNA expression of IL-1b - preservation of telomerase activity NHDFs: - reduced ROS generation - inhibition of MMP-1 and IL-6 levels NHDFs and HaCaT cells: - reduced levels of of MMP-1 mRNA SKH: HR-1 mice: - amelioration of wrinkle formation - reduced epidermal thickness - reduced MMP-1 and improvement in elastin, procollagen type-I, and TGF-β1 HaCaT human keratinocytes: - enhanced cell viability - reduced intracellular ROS production - reduced expression of MMP-2 and MMP-9 SKH-1 hairless mice: - decreased wrinkle formation and wrinkle area - decreased epidermal thickness and hyperplasia - improved water holding capacity - reduced erythema formation - suppressed expression of MMP-2, -9, and -13 genes - reduced MMP-2 protein levels - suppression of collagen loss

Effects on UV-B Treated Animal Models

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Journal of Photochemistry & Photobiology, B: Biology 193 (2019) 51–88

79 -

C657BL mice

reduced levels of gluthathione increased lipid peroxidation infiltration of mast cells and neutrophils in skin enhanced expression of COX-2 loss of collagen increased MMP1 proteins increased melanin and pigments in skin erythema and epidermal hyperplasia increased expression of Nrf2 transcription factor and HO-1

- reduced cell viability - increased ROS production - increase in oxidative protein damage (increased protein carbonyl levels) - increased lipid peroxidation (higher levels of TBARS) - increased expressions of COX-2, IL-1β, iNOS, and HO-1 - enhanced expressions of SOD-2 and GSS

- increase in ROS production - induction of cellular apoptosis - increase in pro-apoptotic Bax-α protein levels - increase in NF-κB levels - reduced cell viability - cell proliferation - icTL1-α (intracellular interleukein 1-α) accumulation - reduced cell viability - increased intracellular ROS production - DNA damage and increased DNA damage response (increased strand breaks and histone H2AX activation) - reduced cell viability - increased ROS generation - increased levels of MMP-1 and MMP-3 - damaged procollagen type-I - increased IL-6 and TGF-β1 secretion - Activation of ERK, JNK, and p38 leading to their high phosphorylation levels - increased levels of phosphorylated forms of c-fos and c-jun Male albino hairless mice (HR-1): - increased wrinkle formation and collagen digestion - enhanced MMP-1 production - reduced production of procollagen type-I, elastin, and TGF-β1 NHDFs: - increased ROS generation - elevated release of LDH - depletion of intracellular GSH - increased MMP-1 and MMP-3 secretion - increased IL-6 production - enhanced collagen and TGF-β1 breakdown - enhanced MMP-1 mRNA levels - reduced levels of procollagen type-I mRNAs - induced phosphorylation of ERK, and p38

Effects of UV-B Radiation

Human corneal epithelial cells (HCEC-12)

Norman human dermal fibroblasts (NHDFs), male albino hairless mice (HR-1)

Human dermal fibroblasts

Human keratinocytes (HaCaT cells)

HaCaT keratinocytes

Human HaCaT keratinocytes

Animal Model

Table 3 (continued)

Grape stem extract

Matricaria chamomilla and Euphrasia officinalis extracts present in eye drops

Foeniculum vulgare Mill extract from seeds

Angelica archangelia extracts

Lemon balm extract

Rooibos (Aspalathus linearis) and honeybush (Cyclopia) herbal teas

Grape seed extract

Plant whole extracts/ group of compounds

Male albino hairless mice (HR-1): - inhibition of wrinkle formation and collagen digestion - suppression of MMP-1 production - increased production of procollagen type-I, elastin, and TGF-β1 NHDFs: - reduced ROS generation - reduced release of LDH - restoration of intracellular GSH - suppression of MMP-1 and MMP-3 production - reduced activation of IL-6 - inhibition of collagen and TGF-β1 breakdown - reduced MMP-1 mRNA levels - improved levels of procollagen type-I mRNAs - quenching of ERK and p38 phosphorylation - protection of cell viability - reduction in ROS production - reduced protein oxidative damage (reduced levels of protein carbonyls) - prevention of lipid peroxidation - reduction in the expressions of COX-2, IL-1β, iNOS, and HO-1 - restoration of SOD-2 and GSS expressions - recovered glutathione levels - reduced lipid peroxidation - prevention of skin infiltration of mast cells and neutrophils - prevention of COX-2 expression - prevention of collagen loss - reduced MMP1 expression - reduced contents of melanin and pigments - reduction in erythema and epidermal hyperplasia - downregulation of Nrf2 and HO-1 expression

- decreased ROS production - reduction of cellular apoptosis - reduction in Bax-α protein levels - decreased NF-κB levels - enhanced cell viability - inhibition of cell proliferation - inhibition of icTL1-α accumulation - increased cell viability - reduced ROS generation - prevention of DNA damage and reduction of DNA damage response - restoration of cell viability - reduced ROS generation - inhibition of MMP-1 and MMP-3 production - promotion of procollagen type-I levels - attenuation of IL-6 and TGF-β1 secretion - reduced phosphorylation of ERK, JNK, and p38 - inhibition of phosphorylation of c-fos and c-jun

Effects on UV-B Treated Animal Models

[337]

[336]

[335]

[334]

[333]

[332]

[331]

Reference

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Journal of Photochemistry & Photobiology, B: Biology 193 (2019) 51–88

Journal of Photochemistry & Photobiology, B: Biology 193 (2019) 51–88

S. Takshak and S.B. Agrawal

Mitogen activated protein kinase (MAPK), the nuclear factor-kappa B (NF-κB), nuclear erythroid 2-related factor 2 (Nrf2), and p53 signaling pathways are the major ones studied under UV-B influence [212,213]. The MAPK pathway components include extracellular signal-regulated kinase (ERK), c-Jun-N-terminal kinase (JNK) and p38 proteins. Proinflammatory cytokines along with various oxygen and nitrogen species activate MAPK pathway [214,215] implicated in mediating cell differentiation, regulation of gene expression, cellular proliferation, metabolism, and apoptosis [197,216]. UV-B-induced ROS production activates this pathway in a dose-dependent manner [217]. Activation (phosphorylation) of ERK, JNK, and p38 pathways have been reported in human dermal fibroblasts [218] and HaCaT human keratinocytes [219], amongst others, under UV-B influence. Conversely, UV-B reduced the phosphorylation levels of p38 and JNK in B16F10 murine melanoma cells [220]. NF-κB is an important transcription factor usually associated with suppression of cellular apoptosis and its various sub-units have been known to be differentially regulated under UV-B [221]. NF-κB pathway activation is mediated through the cytoplasmic I- κB kinase (IKK). I- κB, the inhibitor of NF-κB transcription factor, is degraded by IKK leaving the NF-κB free to translocate to the nucleus and activate the expression of its target genes [222]. The Nrf2 is a transcription factor that mediates the induction of detoxifying enzymes by binding to the antioxidant response element (ARE). Mild oxidative stress activates Nrf2 while the downregulation of Nrf2-dependent genes has been directly linked to increased oxidative stress [223]. p53 tumor suppressor pathway, along with its various downstream targets (for example p21, a cell cycle inhibitor) regulates DNA repair, cell cycle arrest, cell senescence, and death [224] protecting the cells against the accumulation of mutated/ damaged DNA which may lead to tumor induction [225]. The above mentioned pathways do not function in isolation but are interlinked, and are influenced by each other. Consequently, the ultimate cellular response to UV-B and UV-B mediated ROS generation is the result of the confluent action of these intermingling pathways. For instance, the activation protein-1 (AP-1) activates the MMPs expression and JNK and p38 pathways are implicated in increased AP-1 and COX-2 expression [202]. AP-1 also inhibits type-I collagen gene transcription [226]. Activation of degradative enzymes and inhibition of collagen synthesis leads to the structural deterioration of the matrix. Also, UV-B induced MAPK activation inhibits Transforming Growth Factor-β (TGFβ) causing further collagen degradation reviewed in [186]. Pittayapruek et al. [227] have demonstrated that the degradation of elastic fibers resulting in photoaged and wrinkled skin is mediated by MAPK pathway, NF-κB pathway, as well as enhanced activation of MMPs, specifically MMP-12. IL-12 levels have been found to be reduced upon UV-B exposure in mouse epithelial cell line JB6 and female SKH-1 hairless mice [228]. IL12 possesses anti-tumor activity and repairs CPD formation; its deficiency results in enhanced levels of UV-B induced damage such as enhanced phosphorylation of MAPK proteins, increase in COX-2 expression, PGE2 production, and inflammatory cytokines (IL-1β, IL-6, and TNF-α), while reducing NF-κB activation [229,230]. As stated above, increased levels of cytokines such as IL-10 and prostaglandins are responsible for increased immunosuppression reviewed [186]. Some other molecular entities affected by UV-B include cadherins (involved in cell to cell adhesion), integrins (responsible for adhesion of cells to extracellular matrix), basic fibroblast growth factor (bFGF; regulating cell proliferation, differentiation, migration, and survival), hepatocyte growth factor (HGF; stimulates DNA synthesis in epidermal melanocytes), endothelin1 (involved in melanin synthesis), and vascular endothelial growth factor (VEGF; implicated in regulating endothelial cell proliferation) [202,231].

6.2. Protective Role of medicinal secondary metabolites (MSMs) in human and murine models To prevent/ overcome the adverse effects encountered upon UV-B exposure, the animal bodies are equipped with various innate defenses. These defense-imparting molecules and mechanisms include the following:

• Melanin prevents direct penetration of UV radiation into the skin as •

• •

•

•

80

well as scavenges ROS, reducing the likelihood of oxidative damage to lipids, proteins, and DNA [194]. Though vitamin D has been proved to be beneficial in treating and preventing a number of diseases [186], the studies on its direct role in providing protection under UV-B are relatively scarce. Lee and Youn [232] showed that the active form of vitamin D [1,25(OH)2D3], upon topical application, was successful in reducing the formation of sunburn cells and improving cell viability in UV-Bexposed ICR mice as well as in human epidermal keratinocytes. In 2008, Ellison et al. [233] suggested a plausible role of 1,25(OH)2D3 and its vitamin D receptor (VDR) in UV-radiation-induced carcinoma, though it was found that 1,25(OH)2D3 may or may not be required in VDR’s cancer preventive/suppressive mechanisms. Also, Dixon et al. [234] demonstrated that in Skh:hr1 mice, 1,25(OH)2D3 reduced UV (both UV-A and UV-B) radiation-induced CPD formation and apoptotic cells and also mitigated immunosuppression. The development of skin tumors (papillomas and squamous cell carcinomas) was also prohibited in active vitamin D3-treated mice, establishing its photoprotective role. Base excision repair (BER) and nucleotide excision repair (NER) are the two major processes to repair the damage to DNA due to UVB. CPDs and 6-4Ps are targeted by NER while base changes (such as 8-OHdG formation) are acted upon by BER reviewed in [202]. To protect excessive ROS generation due to UV-B radiation, cell biosynthesize various enzymatic and non-enzymatic antioxidants of which superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and reduced glutathione (GSH) levels have been widely studied in animal models under UV-B exposure (Tables 2 and 3). However, as observed in the majority of studies (Tables 2 and 3), the levels of these antioxidants are adversely affected upon UV-B exposure. To counteract the phenomenon, the most pragmatic approach would be to complement the innate antioxidants with more of these compounds transdermally [235,236] or topically [237,238]. Innate polysaccharides have not been reported to play a role in photoprotection or ameliorate UV-B-induced damage. Recent studies, however, have shown that polysaccharides derived from the plant kingdom possess anti-ageing properties and protect against photodamage. For example, Lycium barbarum (wolfberry) polysaccharides led to reduced ROS production and DNA damage, as well as increased expression of Nrf-2-dependent ARE target genes in human HaCaT keratinocytes exposed to UV-B [239]. The photoprotective effects of low molecular weight fucoidan (LMF, a sulfated polysaccharide found in marine brown algae) were demonstrated by Kim and co-workers [240] in female SKH-1 hairless mice exposed to UV-B. Treated mice showed inhibition of wrinkle formation, skin edema, and neutrophil infiltration. LMF also caused reduction in ILβ release and inhibited oxidative stress while enhancing glutathione levels. MMP-1, -9, and -13 mRNA levels that were enhanced upon UV-B exposure, were reduced by LMF. Omega-3-fatty acids have also been implicated in photoprotection and in reducing UV-B-induced inflammation [241].

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S. Takshak and S.B. Agrawal

As indicated above, the innate defenses under UV-B stress do not always guarantee photoprotection, and extraneous molecules are required to mitigate this radiation’s effects. These can either be applied topically, or consumed orally [either as foods (crop plants) or as food supplements (derived from medicinal plants)]. Here we focus on plantderived secondary metabolites, more specifically those obtained from medicinal plants, as they affect UV-B treated animal models and model cell lines. Though a few studies have been performed on sea urchins [242] and zebrafish [243], here we confine ourselves to murine models, murine and human cell lines, and a few occasional studies conducted on human volunteers and guinea pigs (Tables 2 and 3). The tables summarize a number of studies on medicinal plant-derived secondary metabolites (alkaloids, terpenoids, and phenolics), more specifically, their various roles in ameliorating UV-B-induced stress in animal models. The literature cited here is for the past 10 years (2009–2018). For similar studies dating back further (2008 and prior), refer to Supplementary Tables 2 and 3.

The mode of administration is also influential in determining the efficacy of a given medicinal PSM. The three administration modes include topical application (e.g., quercitrin) [272], oral administration (e.g., green tea) [338], and intraperitonial application (e.g., genistein) [283]. In some studies, both oral as well as topical administration methods have been adopted (e.g., Galla chinensis extracts) [329]. In order to achieve a more accurate conception of the efficacy of any particular PSM, both pre- and post-UV-B treatment studies as well as via all modes of administration under same UV-B conditions need to be performed. Differences in animal responses to PSMs are only to be expected when plant/plant tissue extracts are administered as a whole versus when an individual compound is purified and administered. In the latter category too, differences might arise due to laboratory level isolation and purification of the compound against the industrial levelpurified compound. As reviewed by Jansen et al. [51], to ascertain the effects of a compound in a cocktail of PSMs is difficult. A comparative assessment of these three levels of PSMs on UV-B treated animal models might be a plausible field to explore, with the whole extracts being the most naturally relevant, but not necessarily being the most effective. There are numerous studies on the effects of UV-B on medicinal plants, and also on the effects of medicinal compounds on UV-B treated animal models. However, there is a dearth of studies on the effects of compounds obtained from UV-B treated medicinal plants on UV-B exposed animal models. UV-B exposure not only alters the concentration of the metabolite of interest in medicinal plants, but their relative concentrations as well [171]. Under UV-B, the altered metabolite profile might also alter the efficacy of the extracts in terms of providing adequate protection. The direct effects of UV-B on animals are mostly harmful. However, UV-B mediated alterations in medicinal plants might be beneficial from a nutraceutical/pharmacological perspective, as well as economically. According to the UV-B researchers, plants under this stress have a potency to enhance the levels of their secondary metabolites, making them more favorable pharmacologically. Moreover, the increased concentrations of these compounds, whether during the life cycle of the plant or in the fresh product after harvest, will reduce the amount of plant tissue being consumed for the production of the same amount of medicinal compound. Or rather, more of the PSM would be available for the unit amount of plant tissue harvested, changing the economic status of the herbal drugs for the better. This would be a positive step towards the conservation of medicinal plants and reduce their overexploitation (which might even lead to their extinction) [339]. Techniques such as cell and tissue culture and technological advances in genetic engineering aimed at producing and enhancing the concentrations of medicinal compounds can also be delved into, to improve the pharmaceutical and nutraceutical scenarios. However, the complexity of the metabolic pathways makes the entire procedure (from isolation of the desired compounds to its drug-testing stage) extremely tedious and tortuous [340]. Clearly, the use of UV-B radiation to improve the quantity(ies) of the desired medicinal compound(s) enhancing their protective status, still requires studies in the fields of UV-B dose optimization, metabolite accumulation dynamics (in plants), bioavailability and biopartitioning dynamics (in animal models) [54], as well as other regulatory mechanisms influencing these phenomena. Supplementary data to this article can be found online at https:// doi.org/10.1016/j.jphotobiol.2019.02.002.

7. Summary and future perspectives UV-B impacts are global, and affect plant and animal communities alike. Consequently, as is inevitable, organisms across both kingdoms have developed protection strategies to counter this stress. Plants rely only on their innate defense potential (biosynthesis of various secondary metabolites and antioxidants) to counter UV-B effects, while animals have the benefits of innate defenses as well as added advantages of mobility (finding shelter against sunlight) and deriving protective metabolites from plants. In both plants and animals, PSMs function via same two basic mechanisms: direct screening and through their antioxidative potential. As implied and reviewed by Korkina [31], PSMs are expected to play the same role in animals upon consumption as in plants. Most studies on animal models target crop plants, as they are consumed directly and have relatively more tangible benefits compared to the medicinal plants. The products from the latter are not a part of the regular diet and are only consumed as nutraceuticals, food supplements, or drugs (for treating certain ailments). The present review highlights the defense potential of SMs derived from medicinal plants. Majority of the phenolic compounds are in common in both medicinal as well as crop plants, the phenylpropanoid pathway being ubiquitous in nature. The concentrations of medicinal compounds (usually) increase upon UV-B exposure, protecting their photosynthetic machinery and primary metabolism mechanics. However, their levels and effectiveness are largely dependent upon the dose and duration of the radiation exposure as well as the developmental stage of the tissue [53]. Adverse effects of UV-B on animals include malignant and/ or nonmalignant tumors of the skin and eyes, cataracts, ptrygia, and various other photosensitivity disorders. The beneficial effects include vitamin D synthesis and phytotherapy. As of today, however, the adverse effects far outweigh the beneficial ones. UV-B may cause direct damage to DNA and increase ROS concentrations in the exposed tissue. The latter entities, depending upon their concentrations, further modulate various inflammatory and immune responses as well as affect cell-signaling cascades. The innate molecules in animals implicated in protection under UVB include melanin, vitamin D and its receptor, enzymatic and non-enzymatic antioxidants, omega-3 fatty acids, and polysaccharides. However, their protective efficacy is not always adequate; consequently, UV-B induced ailments become inevitable. PSMs, administered judicially, have proven beneficial in ameliorating the UV-B-induced damaging effects. The protective effects of PSMs on animals are a function of the compound concentration, dose and duration of UV-B exposure (defining the extent of the damage) and whether the compound was administered pre-UV-B (as a preventative measure, e.g., genistein) [283] or post-UV-B (as a curative measure, e.g., ferulic acid) [268] exposure.

Acknowledgements The authors are thankful to the Head, and to the Coordinator, Centre of Advanced Study, Department of Botany, Banaras Hindu University, for providing laboratory facilities for the part of our research related to this review and to University Grants Commission (UGC), New Delhi, for financial assistance in the form of Junior- and Senior Research Fellowships. 81

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Declaration of interest [26]

None.

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