Effects of plant extracts and bioactive compounds on attenuation of bleomycin-induced pulmonary fibrosis

Biomedicine & Pharmacotherapy 107 (2018) 1454–1465

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Review

Effects of plant extracts and bioactive compounds on attenuation of bleomycin-induced pulmonary fibrosis Sarasadat Hosseinia, Mohsen Imenshahidib,c, Hossein Hosseinzadehb,c, Gholamreza Karimib,c,

T ⁎

a

Faculty of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran c Department of Pharmacodynamics and Toxicology, School of pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran b

A R T I C LE I N FO

A B S T R A C T

Keywords: Bleomycin Pulmonary fibrosis Plant extract Bioactive compound Herbal preparation

Introduction: Bleomycin (BLM) is a chemotherapeutic agent that is used in the management of some human cancers such as lymphomas and squamous cell carcinomas. The major limitation of BLM therapy is pulmonary toxicity. Combining medicinal herbs and chemotherapy drugs are proposed to attenuate this side effect of BLM. Methods: We conducted a search of some databases such as PubMed for articles and reviews published between 1998 and 2018, with different keywords including “bleomycin”, “pulmonary fibrosis”, “plant extract”, “bioactive compound”, “herbal preparation”. Results: Studies revealed that these natural products have several mechanisms of action to ameliorate pulmonary fibrosis such as inhibitory effects against the elevation of inflammatory markers such as NF-κB and preventing an increase in fibrotic markers like MMP-9 and HYP. Among the plant extracts that were evaluated, Chrysanthemum indicum enhanced the anti-cancer activity of BLM and showed a synergistic effect with BLM besides, substantial potential in improving BLM induced pulmonary fibrosis. Conclusion: In conclusion, the present review demonstrates that the herbs and their active ingredients are a promising source of compounds that can play pivotal roles in the alternative adjuvant chemotherapy in reducing the pulmonary fibrosis of BLM.

1. Introduction

signs with BLM lung toxicity are dyspnea, fever, cough, sputum, thoracic pain, tachypnea, cyanosis, pleuritic pain and pleural rubbing. A number of risk factors have been identified in several clinical studies including cumulative dose above 400 IU, tobacco smoking and patients older than 70 years which have an increased susceptibility to develop BLM-induced lung injury [6]. Cytokines and free radicals are key effectors of BLM-induced lung injury. BLM stimulates alveolar macrophages to secrete inflammatory cytokines such as tumor necrosis factor (TNF), interleukin (IL)-1, IL-18, IL-22 and IL-17a and endothelial cells to secrete IL-6. Fibroblasts are activated early in BLM-induced lung injury through stimulation of fibronectin which is produced by damaged endothelial cells or stimulation by cytokines such as TNF, platelet derived growth factor (PDGF) and transforming growth factor β (TGF_β). Continued exposure of lung

Bleomycin (BLM), is a key component of chemotherapy commonly employed in the treatment of Hodgkin lymphoma and testicular germcell tumors, the most highly curable cancers [1]. The mechanism of action and cytotoxic activity of BLM is exerted through inhibition of DNA and protein synthesis [2]. The toxic effects of BLM are generally attributed to formation of free radicals and organ specificity is driven by catalysing hydrolase which is poorly expressed in lung and skin tissue, rendering these organs vulnerable to toxicity [3]. Clinically, treatment with BLM is very limited due to the development of dosedependent pneumonitis that can progress to interstitial pulmonary fibrosis [4]. BLM induced pulmonary fibrosis may occur in up to 10 percent of the patients receiving the drug [5]. Patient’s symptoms and

Abbreviations: AMPK, AMP-activated protein kinase; BLM, bleomycin; COX 2, cycloxigenase-2; EMT, epithelial mesenchymal transition; GPx, glutathione peroxidase; GST, gluthatione S transferase; HYP, hydroxyproline; IFN-α, interferon alpha; IL, interleukin; JAK-STAT, the Janus kinase/signal transducers and activators of transcription; LOX2, lysyl oxidase 2; LPO, lipid peroxide; MAPK, mitogen-activated protein kinases; MDA, malondialdehyde; MMP, metalloproteinases; MPO, myeloperoxidase; NF-κB, nuclear factor-kappa B; Nrf 2, nuclear factor (erythroid-derived 2)-like 2; PDGF, platelet-derived growth factor; ROS, reactive oxygen species; SOD, superoxide dismutase; TGF-b, transforming growth factor-beta; TIMP, tissue inhibitors of metalloproteinases; TNF-α, tumor necrosis factor – α; α-SMA, α -smooth muscle actin ⁎ Corresponding author at: Pharmaceutical Research Center, Institute of Pharmaceutical Technology, Mashhad University of Medical Sciences, Mashhad, Iran. E-mail address: [email protected] (G. Karimi). https://doi.org/10.1016/j.biopha.2018.08.111 Received 5 July 2018; Received in revised form 15 August 2018; Accepted 23 August 2018 0753-3322/ © 2018 Elsevier Masson SAS. All rights reserved.

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Table 1 Summary of findings on plant extracts effects against pulmonary fibrosis. Plant

Type of extract

Ginkgo biloba

Vitis vinifera

Aqueous

Trigonellafoenum graceum

Hydroalcoholic

Rosmarinus offivinalis

Ethanolic

Chrysanthemum indicum

Paenial lactiflora

Aqueous

Rhodiola rosea

Ethanolic

Houttuynia cordata

Aqueous

Eclipta prostrate

Ethanolic

Radix astragalus

Passiflora edulis Citrus reticulata Nigella sativa Juglans regia Silybum marianum

Methanolic Aqueous

Tests

Dose (mg/kg) Animal/Route

Active ingredients

References

TNF-α Lung collagen content LPO TGF-β1 MMP-9 Cytokines (IL-1, IL-6) Profibroticmarkers (COL1A1, FN1) Nrf2 Fibrotic molecules (TNF-α, IL-1, IL-6, IL-8, HO1) GST Catalase MDA IL-6 TNF-α TGF-β1 MPO MDA HYP α-SMA Type1collagen GSH MMP-9 TGF-β SOD MDA INF-γ TNF-α HYP TGF-β1 MMP-9 -SMAα TGF-β1 Jagged1/Notch1expression Neutrophil accumulation MPO activity SOD HYP TGF-β1 FS Urinary secretion TGF-β1 HYP LPO NO MPO NF-κB MPO MDA LPO GSH Catalase, GST IL-10, IL-12

100 mg/kg Rat /Oral

Flavonoids Ginkgolide B Ginkgolide C Proanthocyanidins

[3]

200 mg/kg Rat/Oral

Glycosides (vicenin-1, trigoneoside)

[14]

75 mg/kg Rat/Intraperitoneal

Polyphenol

[17]

240 and 360 and 480 mg/kg Mice/Oral

Glycosides Flavonoids

[19]

50 mg/kg Mice/Oral

Paeoniflorin

[22]

125 and 250 and 500 mg/kg Rat/Oral

Flavonoids Polyphenols

[25]

1 g/kg Rat/Oral

Aristolactam Indoles

[28]

2.5 and 1.25 and 0.625 mg/kg Mice/Oral

Saponins Triterpenes

[31]

8 mg/kg Rat/ Intraperitoneal

Astragaloside

[33]

100 mg/kg Mice/Oral 5 and 10 and 20 mg/kg Rat/Oral 1mg/kg Rat/Oral 100 mg/kg Rat /Oral 50 and 100 mg/kg Mice/ Intraperitoneal

Anthocyanins Flavonoids Flavonoids Alkaloids Anthocyanins Thymoquinone Ellagic acid Flavonoid

[36] [38] [40] [41] [47]

100 mg/kg Mice/Oral

[8]

2. Results

to BLM can lead to increasing collagen synthesis and deposition of various matrix proteins including collagen, elastin, and proteoglycan. Moreover, BLM-activated alveolar macrophages stimulate the synthesis of hyaluronan, a connective tissue molecule that is seen in fibrotic lungs [7]. Interventions designed to limit the consequences of the inflammatory response. Due to few patients respond to the anti-inflammatory therapies and the prognosis remains poor [2], there is an urgent need for developing new drugs for the treatment of pulmonary fibrosis (PF) (Tables 1–4). In this review, we conducted a search of some databases such as PubMed, Scopus and Science direct for articles and reviews published between 1998 and 2018, with different keywords including “bleomycin”, “pulmonary fibrosis”, “plant extract”, “bioactive compound”, “herbal preparation” and the connectors AND or OR (Fig. 1). The results are categorized into three groups including plant extracts, herbal preparations and bioactive compounds.

2.1. Plant extracts 2.1.1. Ginkgo biloba Ginkgo biloba, a member of the Ginkgoaceae family is native to China. It is assumed that the antioxidant effect of Ginkgo biloba extract is based on flavonoids, ginkgolides B, C and bilobalide [8]. Bilobalide has shown anti-inflammatory properties and neuroprotection in preclinical models of stroke and Alzheimer’s disease [9]. The effects of Ginkgo biloba extract on BLM induced lung fibrosis in rats were investigated. The extract has been shown to regulate the ionic balance in the damaged cells and exert a specific and potent plateletactivating factor antagonistic activity. Furthermore, this study showed that administration of this extract could exhibit an inhibitory effect against the elevation of serum TNF-α and lipid peroxide (LPO) level 1455

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Table 2 Summary of findings on herbal preparations effects against pulmonary fibrosis. Herbal preparation

Tests

Feitai

LPO TGF-β Cell proliferation

Feining

HYP MDA SOD,GSH TNF-α HMGB1 -SMAα Vimentin E-cadherin

Yupingfeng

Renshen pingfei

DangguiBuxueTang

HYP TGF-β NFκB SOD MDA SMAD3 TNF-α TGF-β Type1collagen

Modified kushen Gancao

IL-6,IL-17 HYP TGF-β

Rikunshito

NFκB Neutrophil alveolar infiltration

Dose (mg/ kg)/ Animal/ Route

Major Plants

0.75 and 1.5 and 3 g/ kg Rat/Oral 1and 2and 4 mg/kg Rat/Gavage

Scutellaria baicalensis

[7]

Panax notoginseng Gentiana flowers

[45]

Astragalus membranaceus Saposhnikovia divaricate Astractylodis macrocephalae Panax ginseng Morus alba Asparagus cochinchinensis

[47]

Astragalus membranaceus Angelica sinensis

[51]

Sophora flavescens Glycyrrhiza uralensis

[53]

Atractyloids anceae rhizome Ginseng radix Pinelliae tuber Hoelen Bupleuri radix Zizyphi fructus Aurantii.nobilis pericarpium Pinellia Tuber Cinnamon Bark Schisandra Fruit Paeony Root Forsythia suspensa Lonicerae Japonicae

[56]

5 and 10 mg/kg Rat/ Gavage

0.65 mg/kg Rat/ Gavage

16 and 32 and 64 mg/ kg Rat/Oral 0.41 and 1.64 and 6.56 g/kg Mice/ Gavage 1000 mg/kg Mice/Oral

Hochu-ekki

Expression of the IL-5/INF-γ mRNA HYP

1 g/kg Mice/Oral

Sho-SeiryuTo (TJ19)

HYP MDA Lung/body weight ratio Lung index MDA HYP TNF-α

1.5 g/kg Rat/Oral

Yin-Chiaosan

1000 mg/kg Rat/Gavage

Table 3 Summary of findings on bioactive compounds effects against pulmonary fibrosis.

References

Compound

Type of fraction

Tests

Dose (mg/kg) Animal/Route

References

Gallic acid

Polyphenolic

50 and 100 and 200 mg/kg Rat/Oral

[1]

Lycopene

Carotenoid Secoiridoide glycoside

Celastrol Tanshinone II A

Triterpenoid Diterpene

5 mg/kg Rat/ Gavage 2.5 and 10 mg/ kg Mice/ Intraperitoneal 5 mg/kg Rat/Oral 15 mg/kg Rat/ Intraperitoneal

[67]

Gentiopicroside

Isoliensinine Loquat

Alkaloid triterpene

Glucoside

10 and 20 and 40 mg/kg Mice/Oral 50 and 150 and 450 mg/kg Rat/ Intratracheally 25 and 50 and 100 mg/kg Mice/Oral

[77] [79]

Rhapontin

Matrine

Alkaloid

25 mg/kg Mice/ Gavage

[84]

Triptolide HSYA Gambogic acid Resveratrol Apocynin Salvianolic acid

Diterpen Stilbene Catechol phenolic

IL1-β TNFα MDA GPx TNF-α NO TNF-α IL1β HYP TGF-β1 EMT HSP90 TNF-α, IL1, IL-6 PGE2 COX-2 NO HYP SOD MDA TNF-α TGF-β1 TNF-α TGF-β1 LOX-2 AMPK -SMAα HIF-1α JAKSTAT1 Severity of alveolitis TGF-β TGF-β Collagen 1 Smad3 -SMAα TGF-β PDGF VASH-2 VASH-1 SMA-α MPO, MDA HYP, GSH GSH, GPx MDA, Catalase TGF-β, Smad signaling Collagen

0.25 mg/kg Mice/Oral 26.7 and 40 and 60 mg/kg Mice/ Intraperitoneal 1 and 0.5 mg/kg Rat/Oral 10 mg/kg Rat/Oral 20 mg/kg Rat / Intraperitoneal 10 mg/kg Mouse / Intraperitoneal

[86] [88] [90] [99] [101] [103]

[49]

[58]

[60]

[62]

produced by BLM administration. Moreover, it significantly reduced the elevated levels of collagen induced by BLM. The results revealed the potent antifibrotic activity of Ginkgo biloba against BLM-induced lung fibrosis [3].

[70]

[72] [75]

[81]

as a concomitant therapy for patients with lung fibrosis, including that produced during BLM treatment, especially with regard to timing its administration. [8].

2.1.2. Vitis vinifera Vitis vinifera belongs to the Vitaceae family. Grape seed extract enriched in proanthocyanidins (oligomeric polyphenols) has been suggested to have multiple health benefits [10] such as cholesterol lowering, antioxidant, anti-tumor, cardioprotective and protection against ultraviolet rays [5]. Intragastric administration of Grape seed extract in BLM induced pulmonary fibrosis in mice decreased the lung inflammation by attenuating inflammatory cytokines such as IL-1 and IL-6. It also decreased the activation of TGF-β1 and matrix metalloproteinases 9 (MMP-9), prevented an increase in pro-fibrotic markers such as collagen type I alpha 1 and fibronectin 1 and attenuated a decrease in antifibrotic markers such as E-cadherin. Additional investigations are necessary to elucidate the full anti-fibrotic potentials of Grape seed extract

2.1.3. Trigonellafoenum graceum Fenugreek (Trigonellafoenum graceum) is a member of the Fabaceae family. Its seeds contain wide range of phytochemicals such as alkaloids, flavonoid glycosides, furostanol glycosides, saponins and mucilage [11]. Various properties have reported for Fenugreek such as antidiabetic, antihyperlipidemic, wound healing, anti-inflammation and anti-ulcer [12]. The effect of standardized fenugreek seed extract on BLM-induced pulmonary fibrosis was evaluated in rats. This study demonstrated that the this extract exerts its anti-fibrotic efficacy in biphasic manner where initially it causes induction of nuclear factor E2 (Nrf2) via its anti1456

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2.1.4. Rosmarinus officinalis Rosmarinus officinalis L. belongs to the Lamiaceae family [14]. It has been described to have antioxidant, anti-inflammatory and anticancer activities. Most of these observed effects are related to carnosic and rosmarinic acids [15]. The prophylactic and curative effect of rosmary leaves extract on rat model of BLM- induced pulmonary fibrosis has been assessed. The results demonstrated that this extract remarkably attenuated the malondialdehyde (MDA) levels. The activities of catalase and glutathioneS-transferase in the lung tissues were significantly restored. Moreover, notable decrease in collagen deposition is observed. The results suggested that the rosmary leaves extract could modulate cellular dynamics during fibrosis progression. Further studies need to be done to elucidate the molecular mechanisms of action of this whole plant extract as well as of which of its phenol compounds, both in vivo and in vitro [16].

Table 4 Summary of findings on medicinal mashrooms effects against pulmonary fibrosis. Mashrooms

Type of extract

Tests

Dose (mg/kg) Animal/Route

References

Hirsutella sinesis

Ethanolic

SMA, SOD, ROS-α NLRP3, P2 × 7R

1.5 mg/kg Mice/ Oral

[98]

Cordyceps sinensis

Aqueous

ROS, EMT MMP-9/ TIMP-1

0.54 g/kg 1.35 g/kg Rat/ Gavage

[101]

Ganoderma lucidum

Aqueous

SOD, MDA, HYP GPx, Catalase

100-300 mg/kg Rat/ Gavage

[103]

oxidant potential and eventually it showed anti-inflammatory through modulation of pro fibrogenic molecules such as TNF-α, IL-6, IL-8 and HO-1, thus inhibiting the fibrogenic molecules. results demonstrated that standardized fenugreek seed extract significantly reduce BLM induced pulmonary fibrosis [13].

2.1.5. Chrysanthemum indicum Chrysanthemum indicum belongs to the Sapotaceae family. The supercritical-carbon dioxide fluid extract from flowers and buds of C. indicum (CISCFE) has strong anti-inflammatory, anti-oxidant, and lung protective effects. The active molecules in C. indicum are glycosides and flavonoids [17]. In one research, it was illustrated that CISCFE enhanced BLM anti-

effect IL-1β, These could

Fig. 1. BLM induces a redox imbalance and oxidative stress in lung cells. The inflammatory cytokines and fibrotic biomarkers secreted by the injured epithelial cells recruit fibroblasts that differentiate into myofibroblasts. Myofibroblasts secrete collagen which accumulates due to imbalance between interstitial collagenases and their tissue inhibitors. The pattern of these changes results in the progressive remodeling and pulmonary fibrosis. 1457

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A number of compounds, including thiophene derivatives, steroids, triterpenes, flavonoids, polyacetylenes, polypeptides and coumestans have been isolated from its extract [29]. Orally administration of Eclipta prostrate extract to mice ameliorated BLM-induced increase in HYP content and lung oxidative stress. Moreover, it decreased BLM-induced TGF-β1 signaling in lung tissue. Also, it obviously down-regulated the high expression of MMP-2 and the ratio of MMP-9/TIMP-1 at a dose-dependent manner. In conclusion, the research demonstrated Eclipta prostrate extract could prevent the development of collagen deposition and fibrosis in BLM-induced mice pulmonary interstitial fibrosis [30].

tumor effect and reduced toxicity of BLM in tumor-bearing mice. The results showed that CISCFE combined with BLM could distinctly decrease the levels of inflammatory cytokines [TNF-α and IL-6]. It also attenuated oxidant enzymes [myeloperoxidase (MPO) and MDA]. The expression of TGF-β1 was evidently decreased in the CISCFE combined BLM group. These findings indicated that CISCFE could serve as a putative adjuvant drug with chemotherapy [18]. 2.1.6. Paeonia lactiflora Paeonia lactiflora Pall, a traditional Chinese herbal medicine, is a member of Paeoniaceae family which exhibits protective effect against liver diseases through antioxidation and free radicals scavenging mechanisms [19].The chemical components in the aqueous extract of this plant root include paeoniflorin, albiflorin, oxypaeoniflorin and benzoylpaeoniflorin [20]. In mice treated with BLM, paeoniflorin, the main active constituent of Paeonia lactiflora Pall roots significantly prolonged the survival periods, attenuated infiltration of inflammatory cells, interstitial fibrosis and deposition of extra cellular matrix in lung tissues. It also decreased the contents of hydroxyproline (HYP)-a marker of collagens-, type I collagen and α-Smooth muscle actin (α-SMA) -an indicator of myofibroblasts- in lung tissues of mice. The results of this study showed Paeoniflorin has a therapeutic potential for the treatment of pulmonary fibrosis [21].

2.1.10. Radix astragalus Radix astragalus is the dried root of Astragalus membranaceus; belongs to the Fabaceae family. Astragalus has been widely used by clinicians as a treatment for patients with diabetes and diabetic nephropathy. Polysaccharoses, astragaloside, isoflavones and saponin glycosides are the primary constituents of astragalus extracts [31]. The antifibrosis effects of Astragalus injection on BLM-induced pulmonary fibrosis in rats were considered. Astragalus injection significantly reduced the degree of alveolitis, lung fibrosis and markedly inhibited BLM-induced upregulation of α-SMA in the lungs. Jagged1/ Notch1signalling pathway has been shown to be involved in several kinds of tissue fibrosis. It can influence the switching of fibroblasts into myofibroblasts. In pulmonary fibrosis, Jagged1/ Notch1signaling can be activated in crosstalk with other signaling pathways, such as TGF-β to induce myofibroblast differentiation through the activation of SMA gene transcription. This administration also, suppressed the mRNA and protein expression of Jagged1/ Notch1and TGF-β1 expression in lung tissues of rat. The study demonstrated that Astragalus injection has significant inhibitory effects on BLM-induced pulmonary fibrosis [32].

2.1.7. Rhodiola rosea Rhodiola rosea (also known as golden root, rose root and Arctic root) is in the Crassulaceae family [22]. Polyphenolic bioactive compounds from the plant, such as rosavin, salidroside, syringin, triandrin and tyrosol have been reported to exert beneficial effects against several pathogens. Flavonoids isolated from the roots have been shown to inhibit the activity of neuraminidases from Clostridium perfringens and influenza virus [23]. The lung-protective activity of Rhodiola rosea in a BLM induced pulmonary fibrosis rat model has been investigated. Administration of ethanolic extract of this plant alleviated the loss of body weight induced by BLM and increased serum levels of glutathione (GSH). Expression levels of MMP decreased significantly in a dose-dependent manner. Moreover, the levels of TGF-β in lung tissues decreased. The results revealed that the protective effects of Rhodiola rosea against fibrotic lung injury in rats are correlated with its antioxidative and anti-inflammatory properties [24].

2.1.11. Passiflora edulis Passiflora edulis belongs to the Passifloraceae family. Recent studies demonstrate the effectiveness of Passion fruit peel extract against chloroform-induced liver toxicity, asthma, joint pain and hypertension in rodent and in human [33]. The extract of the passion fruit peel contains flavonoids, alkaloids, anthocyanins, glycosides, minerals and terpenoid compounds [34]. In one study, Passion fruit peel extract was purified to concentrate the organic constituents with anthocyanins and flavonoids as principal compounds. Administration of this extract in mouse model of BLM induced pulmonary fibrosis resulted in a marked decrease in neutrophil accumulation in BALF and reduced MPO activity in lung tissue and noticeably restored the decrease in superoxide dismutase (SOD). The protective effect of Passion fruit peel extract on BLM induced PF could be due to reduction of inflammatory cell migration into inflamed region, thereby minimizing lung damage [35].

2.1.8. Houttuynia cordata Houttuynia cordata belongs to the Saururaceae family, possesses a number of medicinally important activities such as antiviral, anti-oxidant and inhibitory effects on anaphylactic reaction [25]. Various types of chemical constituents such as aristolactams, oxoaporphines, amides, indoles, ionones, flavonoids, benzenoids, steroids and different volatile oils have been isolated from its extract [26]. In one study, the protective effects of this plant on BLM-induced pulmonary fibrosis in rats were evaluated. Administration of aqueous extract of Houttuynia cordata significantly decreased the levels of MDA, HYP, INF-γ and TNF-α. However, an increase in the concentration of catalase was noted in the BALF. It also remarkably improved the morphological appearance of the lung of BLM-treated rats. Further studies on its bioactive components and mechanism(s) of action may provide a scientific basis for the possible application of Houttuynia cordata in preventing the BLM-induced lung fibrosis [27].

2.1.12. Citrus reticulate Citrus reticulata belongs to the Rutaceae family. It has been used for the treatment of lung-related diseases for a long time. Various types of phytochemicals, such as flavonoids, alkaloids, anthocyanins, phenolic acids, carotenoids and tannins have been isolated from Citrus reticulata [36]. In one study, inhibitory effects of amines from Citrus reticulata on BLM-induced pulmonary fibrosis in rats were investigated. The amines from the pericarp of Citrus reticulata were isolated and their hydrochlorides were prepared. The results of screening using cultured human embryonic lung fibroblasts revealed that, of the amines, 4-methoxyphenethylamine hydrochloride (designated as amine hydrochloride 1) possessed the most potent inhibitory effect on pulmonary fibrosis. Further in vivo experiments using a rat model of BLM-induced pulmonary fibrosis demonstrated that the oral administration of amine hydrochloride significantly lowered the HYP content in both serum and lung tissue, (TGF)-β1 protein expression and alleviated pulmonary

2.1.9. Eclipta prostrate Eclipta prostrata is a member of the Asteraceae family. The extracts of this plant has been used in Brazilian traditional medicine to treat asthma and other respiratory illnesses. In addition, Eclipta prostrata exhibits immunomodulatory, antidiabetic, antitumor, anti-inflammatory, anti-hepatitis C virus and hepatoprotective activities [28]. 1458

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alveolitis and fibrosis. So, the amines from the pericarp of Citrus reticulata have therapeutic potential for use in the treatment of PF [37].

restored the depleted levels of GSH and antioxidant enzymes including catalase and GST which was initially suppressed by BLM. Moreover, it has been demonstrated that silymarin modulates the inflammatory reactions through up-regulation of anti-inflammatory cytokines, like IL10, IL-12. In conclusion, the present study demonstrates that silymarin attenuated BLM-induced pulmonary injury [45].

2.1.13. Nigella sativa Nigella sativa L. (black seed) is a member of Ranunculaceae family. Pharmacological studies have shown that the extract of seeds have antiinflammatory and anti-ischemic effects. Also, Karimi [38] obtained results that confirmed protective effects of aqueous and ethanolic extracts of Nigella sativa L. and Portulaca oleracea L. on free radical induced hemolysis of red blood cells [38]. This is also revealed that thymoquinone is the major bioactive component of the essential oil [39]. The effects of Nigella sativa oil on BLM-induced lung fibrosis in rats were investigated. The BLM group showed a significant increase in inflammatory index, fibrosis score and TGF-β1 distribution in the lung inflammatory infiltrate, accompanied by a decreased urinary secretion of Krebs cycle intermediates. However, administration of Nigella sativa oil resulted in a reduced inflammatory index and fibrosis score, and had an increased urinary secretion of histidine, fumarate, allantoin and malate. Furthermore, this treatment attenuated the effects of BLM-induced PF, by supporting lung, liver and kidney activity in resisting PF. In another study the pulmonary inflammation and fibrosis that had been induced by BLM, were significantly decreased in groups treated with Nigella sativa extract. Also, the HYP concentration and LPO activity in pulmonary tissue was significantly decreased. The findings provided an insight into the preventive and therapeutic potential of Nigella sativa oil in the treatment of BLM-induced PF. The active components of Nigella sativa, particularly omegas 3 and 6 and thymoquinones, should be investigated in future studies to prevent any unwanted toxicity of Nigella sativa treatment [40].

2.2. Herbal preparation 2.2.1. Feitai Feitai, a prescription formulation, is a mixture of the extracts of five medicinal herbs including Scutellaria baicalensis, Glehnia littoralis, Trichosanthes kirilowii, Stemona sessilifolia and Eriobotrya japonica. The ingredients of Feitai have some therapeutic effects such as anti-inflammatory, antibacterial, antitussive, and antipyretic effects [46]. To investigate the effects of Feitai on pulmonary fibrosis, Feitai was administered orally to BLM (BLM)-treated rats. Feitai showed beneficial effects by inhibiting inflammatory response and LPO in lung induced by BLM in vivo and reducing the cell proliferation and TGF-β stimulated type I collagen synthesis in vitro. The average scores of alveolitis and fibrosis in the lung sections of BLM–Feitai groups were significantly decreased compared with those of the BLM–water group. These results strongly demonstrated that Feitai could be useful in the treatment of pulmonary fibrosis [7]. 2.2.2. Feining Feining, a Chinese herbal formula, composed of Gentiana flowers and Panax notoginseng saponins. The flowers of Gentiana veitchiorum were used in decoction form in the traditional medicine of Tibet against tussis, tracheitis, smallpox and angina [47]. The effect of Feining on BLM-induced pulmonary injuries was investigated in rats. According to this study, Feining significantly reduced the HYP content of lungs. Moreover, Feining played a role against the oxidative damages by decreasing the MDA level, whereas increasing SOD and GSH activity which correlated with oxidation resistance and scavenging of free radicals. In addition, Feining alleviated inflammatory lung injury by decreasing TNF-α expression. The alveolitis scores in the lung sections of the Feining groups were significantly decreased. Thus, administration of Feining could be an effective therapy approach to cure pulmonary fibrosis [48].

2.1.14. Juglans regia Juglans regia (walnut) belongs to Juglandaceae family. Ellagic acid is a principal active dietary polyphenolic constituent present in walnut extract. It is pharmacologically active as an anti-inflammatory, antioxidant and antitumor agent [41]. The effect of walnut (Juglans regia) extract in a rat model of BLMinduced pulmonary toxicopathy was studied. There was a marked increase in the HYP level, LPO, NO production and in the activities of xanthine oxidase and MPO in the lung tissue in BLM-treated animals when compared to control animals. BLM also decreased the activities of antioxidant enzymes such as glutathione reductase and catalase and increased the lung inflammation and apoptosis by upregulating the NFκB signaling pathway. Treatment with walnut extract attenuated these changes in a significant manner. Histological findings supported the protective effects of walnut extract against BLM-induced lung injury. Overall, walnut extract decreases BLM-induced oxidative stress and lung inflammation by modulating the alveolar macrophage inflammatory response in rats [42].

2.2.3. Yupingfeng Yupingfeng a Chinese herbal prescription includes root of Astragalus membranaceus, rhizome of Atractylodis macrocephalae and root of Saposhnikovia divaricate. Total glucosides of Yupingfeng have been proven effective in anti-inflammation and immunoregulation [49]. Potential effects of Yupingfeng on BLM-induced PF in rats have been evaluated. The increased protein expression of high mobility group box1 (HMGB1) that is one of the mediators of inflammation, the mesenchymal markers including vimentin and α-SMA and the decreased protein expression of epithelial marker E-cadherin were dramatically inhibited after Yupingfeng treatment. The results demonstrated that herbal prescription could ameliorate BLM-induced PF by reducing HMGB1 activation and reversing epithelial-mesenchymal transition (EMT). Certainly, further elucidation of the interplay between HMGB1 and TGF-β1 may provide new mind for PF treatment [50].

2.1.15. Silybum marianum Silybum marianum belongs to Asteraceae family. Silymarin, a mixture of bioactive flavonolignans from the milk thistle (Silybum marianum), has been investigated for use as a cytoprotectant, an anti-carcinogen and a supportive treatment for liver damage [43]. Also, it was indicated by Karimi [44] that silymarin has a broad spectrum of cardiac protective activity against toxicity induced by some chemicals including metals, environmental pollutants, oxidative agents and anticancer drugs. In one study, the effect of silymarin on oxidative and inflammatory parameters in the lungs of mice exposed to BLM was evaluated. The results showed that silymarin treatment resulted in decrease in lung MDA and MPO activity. Free radical generation via cell membrane damage can leads to LPO product elevation; silymarin can modulate LPO by regulating membrane permeability and increasing the stability of membrane integrity. Besides, silymarin administration efficiently

2.2.4. Renshen Pingfei Renshen Pingfei decoction consists of Panax ginseng, Asparagus cochinchinensis, Morus alba, Lycium chinense, Glycyrrhiza uralensis, Anemarrhena asphodeloides and Citrus reticulate. It was normally used to treat feibi, an ancient disease in traditional Chinese medicine which is characterized by dry cough, progressive dyspnea, tarsalgia, unfavorable prognosis and shares similar symptoms with IPF [51]. In one study, the protective role of Renshen Pingfei decoction in rat model of BLM-induced PF was evaluated and explored. Administration 1459

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pericarpium, Glycyrrhizae radix, Cimicifugae rhizome and Zingiberis rhizome. It was used as a remedy for chronic diseases or weakness suffered after illness [60]. Preventive effects of Hochu-ekki-to on BLM-induced lung injury have been considered in mice. Mortality was significantly decreased in mice after Hochu-ekki-to administration. Moreover, the HYP content and fluid content in the lung was significantly attenuated. Histologically, the number of infiltrating cells was reduced. Also, the destruction of the lung architecture was ameliorated. Hochu-ekki-to inhibited the expression of the IL-5/INF-γ mRNA ratio in the lung. In Conclusions, treatment with this herbal formula partially prevented experimental lung fibrosis [61].

of this decoction exerted significant improvement in lung function by decreasing HYP content of lung tissue, reducing the level of TGFβ- 1 and NFκB in BALF, decreasing MDA level in serum, as well as downregulating the expressions of TGFβ- 1 and Smad3 of lung tissue. Thus, the Renshen Pingfei decoction could reduce the lung injury and improve lung function in BLM-induced PF. Also, the role of the chemical components identified in Renshen Pingfei is worthy of further study in PF treatment [52]. 2.2.5. Danggui–Buxue–Tang Danggui–Buxue–Tang is a traditional Chinese herbal formula which is a simple combination of two herbs including root of Astragalus membranaceus and root of Angelica sinensis. Pharmacological results indicated that this herbal formula has the abilities to promote hematopoietic functions, stimulate cardiovascular circulation, prevent osteoporosis, increase anti-oxidation activity and stimulate the immune system [53]. In a research, administration of total glucosides of Danggui–Buxue–Tang in rats reduced BLM-induced weight loss and decreased the lung index [lung index = lung weight/body weight× 100%]. Histological evidence supported the ability of Danggui–Buxue–Tang to attenuate BLM-induced lung fibrosis and consolidation. It could dose-dependently decrease TNF-α and TGF-β1 activity, as well as it could decrease type I collagen expression in lung tissues. However, more detailed work is required to completely clarify detailed mechanisms of the antifibrosis effects of Danggui–Buxue–Tang [54].

2.2.9. Sho-Seiryu-To (TJ-19) Sho-seiryu-to (a Chinese/Japanese traditional medicine) is a mixture of eight herbal components including Pinellia Tuber, Glycyrrhiza Root, Cinnamon Bark, Schisandra Fruit, Asiasarum Root, Paeony Root, Ephedra Herb and Ginger Rhizome. It has been used in the treatment of pulmonary diseases such as asthma, bronchitis and allergic diseases in Japan [62]. In one study, the effects of Sho-seiryu-to on BLM-induced pulmonary fibrosis in rats were examined. The results demonstrated that BLM induced the loss in body weight, increase in lung/body weight ratio and concentration of HYP and MDA in the lung tissues but, oral administration of Sho-seiryu-to attenuated these changes. Moreover, it prevented BLM-induced fibrotic damages in the lung histology. The results suggested that Sho-seiryu-to has prophylactic potential against BLM induced pulmonary fibrosis. Therefore, it may be a promising drug candidate and medicinal resource for preventing BLM-induced and idiopathic pulmonary fibrosis [63].

2.2.6. Modified Kushen Gancao Modified Kushen Gancao is a famous traditional Chinese medicinal formula, which consists of the root of Angelica sinensis, the root of Sophora flavescens and the rhizome of Glycyrrhiza uralensis. Kushen Gancao Formula has been used in the clinic to treat hepatitis and immune system diseases. In addition, it is reported to have anti-fibrotic activity in liver [55]. The inhibitory effects of Kushen Gancao on BLM-induced pulmonary fibrosis in mice have been investigated. This formula significantly decreased pulmonary alveolitis, fibrosis scores, IL-6, IL-17, TGF-β and HYP levels in lung tissue of mice. Furthermore, the expression of α-SMA was obviously decreased. In conclusion, Kushen Gancao has an anti-fibrotic effect and might be employed as a therapeutic candidate agent for attenuating pulmonary fibrosis [56].

2.2.10. Yin-Chiao-san Yin-Chiao-San is a traditional Chinese medicinal prescription clinically used for patients with lung diseases. There are ten crude drugs in this prescription including Forsythia suspensa, Lonicerae Japonicae, Lophatherum gracile, Platycodon grandiflorum, Menthae Haplocalycis, Arctium Lappa,Glycyrrhiza uralensis, Glycine max, Schizonepeta tenuifolia and Phragmites communis [64]. The effects of Yin-Chiao-San on BLM-induced Pulmonary Injury were investigated in rats. The results indicated that this treatment significantly reduced the lung index, MDA, HYP and TNF-α. Also, it enhanced antioxidant enzyme (catalase), anti-inflammatory activities and inhibited collagen formation. Thus, Yin-Chiao-San exhibited a preventive effect in BLM-induced PF and it is suggested that it may be applied to attenuate the side effects of BLM in chemotherapy [65].

2.2.7. Rikunshito Rikkunshito, a traditional Japanese herbal formula which is made from a hot-water extract of a mixture of eight varieties of plants [Atractyloids lanceae rhizome, Ginseng radix, Pinelliae tuber, Hoelen, Zizyphi fructus, Aurantii nobilis pericarpium, Glycyrrhizae radix and Zingiberis rhizome]. It was widely prescribed to patients with various gastrointestinal symptoms, such as abdominal fullness, nausea, and postprandial early satiety [57]. Previous studies showed that RKT ameliorated cisplatin-induced anorexia [58]. Rikkunshito was given to mice daily, starting 12 h after BLM administration. This treatment resulted in a definitively higher survival rate, smaller reductions in body weight and food intake. The amelioration of neutrophil alveolar infiltration, pulmonary vascular permeability, induction of proinflammatory cytokines, activation of the NF-κB pathway, apoptosis of alveolar epithelial cells and subsequent lung fibrosis were notable in the Rikkunshito-treated mice. The results highlight Rikkunshito as a promising therapeutic agent for the management of this intractable disease [59].

2.3. Bioactive compounds 2.3.1. Gallic acid Gallic acid and its derivatives are considered the main polyphenolic compounds in some of the fruits like grapes, mango and different berries [66]. Preclinical studies have shown that it possesses different pharmacological effects include antioxidant, anticancer, antimicrobial, anti-inflammatory and neuroprotective activities [67]. In one study, the effect of gallic acid against BLM-induced pulmonary fibrosis in rats was investigated. The results showed that intratracheal BLM administration significantly increased the inflammatory or fibrotic changes, collagen content, level of MDA and proinflammatory cytokines such as TNF-α and IL1β in lung. Moreover, it significantly decreased non-enzymatic (total thiol) and enzymatic [glutathione peroxidase (GPx)] antioxidant contents in rats’ lung tissue. However, oral administration of Galic acid reversed all of these biochemical indices as well as histopathological alterations induced by BLM. Thus, an effective supplement with Galic acid as an adjuvant therapy may be a promising compound in reducing the side effects of BLM [1].

2.2.8. Hochu-ekki-to Hochu-ekki-to is composed of 10 species of medicinal plants including Astragali radix, Atractylodis lanceae rhizome, Ginseng radix, Angelicae radix, Bupleuri radix, Zizyphi fructus, Aurantii nobilis 1460

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suggests therapeutic potential of this lipophilic diterpene for BLM- induced pulmonary fibrosis [79].

2.3.2. Lycopene Lycopene is a bioactive carotenoid presented in many fruits and vegetables such as tomatoes, watermelons and grapefruits [68]. It is one of the most potent antioxidants among dietary carotenoids. Dietary intake of tomatoes and tomato products containing lycopene has been shown to be associated with a decreased risk of chronic diseases, such as cancer and cardiovascular disease [69]. Also, it was indicated by Karimi [70] that tomato extract and lycopene treatment protected against acute Doxorubicin toxicity. The effects of lycopene on BLM induced pulmonary fibrosis in rats were evaluated. The MDA plasma concentration and pulmonary fibrosis grades in the lung sections of the lycopene treated groups were significantly decreased. Suppression of oxidative stress, the reduction of plasma TNF-α and NO levels and the down-regulation of TNF-α in lung contribute to the alleviation of PF in rats administered lycopene. Further studies on the role of lycopene in alleviating PF are necessary to better understand a mechanism [71].

2.3.6. Isoliensinine Isoliensinine, a bisbenzylisoquinoline alkaloid extracted from the Chinese traditional medicinal seed embryo of Nelumbo nucifera Gaertn, has antiarrhythmic effect [80]. The effects of Isoliensinine on BLM-induced pulmonary fibrosis were studied in mice. Isoliensinine administration remarkably enhanced the SOD activity and decreased the MDA level in a concentration-dependent manner and abated the lung histological injury induced by BLM. Also, it significantly inhibited the overexpression of TNF-α and TGF-β1 induced by BLM. These results indicated that Isoliensinine possessed a significant inhibitory effect on BLM induced pulmonary fibrosis [81]. 2.3.7. Triterpene acids of loquat Eriobotrya japonica (loquat) has a long history of medicinal use in South-East Asia. The triterpene acids of loquat have been proven to be effective components that have anti-inflammatory and antioxidative effects on chronic bronchitis in rats [82]. Antifibrosis effect of triterpene acids of loquat on rat model of BLMinduced pulmonary fibrosis was evaluated. It was reported that triterpene acids of loquat could ameliorate the structure of the lung and alleviate fibrogenesis. At the same time, it could reduce the expression of TNF-α and TGF-β1 in alveolar macrophage of rats with pulmonary fibrosis at either the protein or TNF-α mRNA expression. In conclusion, triterpene acids of loquat had a positive prophylactic effect on BLM induced lung fibrosis [83].

2.3.3. Gentiopicroside Gentiopicroside is a natural secoiridoid glycoside from gentian species of medicinal plants [72]. It has exhibited a variety of pharmacological activities including hepatoprotective, anti-inflammatory, antinociceptive and smooth muscle relaxing activities [73]. In one study, the effects of Gentiopicroside on BLM-induced pulmonary fibrosis were investigated in mice. The results demonstrated that administration of Gentiopicroside significantly decreased the contents of TNF-α and IL-1β in BALF of mice. HYP and TGF-β1 in lung tissues also decreased after Gentiopicroside treatment. The alveolar epithelial cells and TGF-β1 could be the main target cells and molecules of Gentiopicroside on BLM-induced PF. Gentiopicroside may also has the potential in combination with nintedanib or pirfenidone in treatment of PF to synergize the therapeutic effects and minimize the adverse effects, but this needs further investigation. [74].

2.3.8. Rhapontin Rhapontin is a stibene-type compound distributed widely in medicinal plants in the Rheum genus (Polygonaceae). Rhapontin has shown a variety of potentially beneficial effects; including anti-allergic, antidiabetic and anti-inflammatory activities [84]. In one study, protective role of Rhapontin against BLM-induced pulmonary fibrosis was investigated. Rhapontin obviously suppressed collagen accumulation via regulating TGF-β/Smad2/3 signaling pathway in BLM-damaged mice. There were higher expressions of lysyl oxidase 2 (Lox2) protein in lung tissues of BLM-treated mice, while Rhapontin significantly suppressed Lox2 expressions. Another possible mechanism for the anti-fibrotic activity of Rhapontin is activation in adenosine 5′-monophosphate-activated protein kinase (AMPK). AMPK activation attenuates the effects of BLM, thus counteracting the fibrotic trigger. Moreover, Rhapontin reduced α-SMA and hypoxia inducible factor-1α (HIF-1α) expressions in lung tissues and significantly decreased the levels of TNF-α of BALF. In summary, Rhapontin treatment effectively reversed BLM induced pulmonary fibrosis in mice [85].

2.3.4. Celastrol Celastrol, a triterpenoid derived from the Chinese medicinal plant Tripterygium wilfordii has antioxidant, anti-inflammatory and anticancer effects; it can also exert protective effect on myocardial ischemia–reperfusion injury [75]. In one study, celastrol was given to rats (5 mg/kg) orally twice a week after BLM administration. The expressions of epithelial marker proteins, E-cadherin and claudin were found to be reduced in the BLMinduced group of rats. Expression of mesenchymal markers N-cadherin, snail, slug, vimentin and β-catenin were enhanced in BLM-induced rat lungs. Celastrol reverted these cellular changes in rat lungs and it was found that celastrol could regulate EMT through the inhibition of heat shock protein 90 (HSP 90) that is directly associated with the downregulation of E-cadherin. The results indicated that EMT is a crucial phenomenon for the progression of fibrosis and celastrol provides protection against PF through the regulation of EMT [76].

2.3.9. Matrine Matrine is the major active component of the alkaloids of Sophora flavescens [86]. Matrine has a definite anti-liver fibrosis action and thus has been extensively applied in the treatments of chronic hepatitis [87]. According to a research, pulmonary fibrosis is associated with JAKSTAT signaling transduction pathways. Matrine can relieve the severity of alveolitis and pulmonary fibrosis and inhibit the growth of pulmonary fibrocytes by downregulating the abnormal expression of JAK STAT1 and STAT3. Therefore, Matrine exerted a remarkable effect against BLM induced pulmonary fibrosis [88].

2.3.5. Tanshinone ⅡA Tanshinone ⅡA is an important lipophilic diterpene extracted from the root of a Chinese herb termed Salvia miltiorrhiza Bunge [77]. Tanshinone ⅡA exerts antitumoral effects during tumorigenesis of numerous types of cancers; including prostate cancer, colon carcinoma and breast cancer [78]. The effects of Tanshinone ⅡA on BLM-induced pulmonary fibrosis were investigated in rats. BLM induced increased expression of TNF-α, IL-1β, IL-6, cyclooxygenase-2 (COX2), prostaglandin E2, MDA and NO synthase in rats, all of these changes were suppressed by Tanshinone ⅡA injection. In addition, severe pulmonary edema, inflammation and fibrosis were observed in the BLMtreated rats and the counts of total cells, neutrophils and lymphocytes were significantly increased in the BALF of those rats. These pathological changes were markedly attenuated by subsequent treatment with Tanshinone ⅡA. The study

2.3.10. Triptolide (PG490-88) PG490-88 is a water-soluble derivative of triptolide. Triptolide is a diterpene triepoxide from the Chinese herb, Tripterygium Wilfordii hook. It has potent antiproliferative and immunosuppressive properties. It has been used in traditional Chinese medicine in the treatment of rheumatoid arthritis [89]. 1461

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2.3.14. Apocynin Apocynin (4-hydroxy-3-methoxy-acetophenone), a natural occurring methoxy-substituted catechol, is extracted from the roots of Apocynum cannabinum and Picrorhiza kurroa. Several researches have demonstrated that apocynin can diminish neutrophil oxidative burst, neutrophil chemotaxis, and thus reduce neutrophil-mediated cell injury [98]. In a study, the preventive and therapeutic effect of apocynin on BLM -induced lung injury in rats was evaluated. According to the results, BLM caused a significant decrease in GSH, catalase, and GPX which were accompanied with significantly the increased MDA and total oxidant status levels in the lung tissue concomitant with increased levels of the cellular account and proinflammatory cytokines (IL-1β, IL-6, and IL-8) in the BALF. Otherwise, apocynin administration, both before and after BLM, reversed all biochemical markers and cytokine as well as histopathological changes induced by BLM. Interestingly, apocynin treatment reversed MPO activity in serum increased by BLM [99].

In one study, the antifibrotic properties of Triptolide on BLM induced pulmonary fibrosis in mice were evaluated. An enzyme-linked immunosorbent assay of TGF-β in the BALF showed a significant decrease in TGF-β in the Triptolide treated mice. Additionally, Triptolide blocked BLM-induced increase in TGF-β mRNA in cultured normal human lung fibroblasts. It is also observed that Triptolide is a potent antitumor agent in vivo. Moreover, it markedly reduced the number of myofibroblasts. Therefore this finding suggests a potential role of Triptolide in the treatment of BLM- induced pulmonary fibrosis [90]. 2.3.11. Hydroxysafflor yellow A Hydroxysafflor yellow A is an active component of Carthamus tinctorius. Studies have demonstrated that it possesses many pharmacological activities including anti-platelet aggregation and cardioprotective effects through its antioxidant and anti-inflammatory actions [91]. In one study, protective role of Hydroxysafflor yellow A against BLM-induced pulmonary fibrosis was investigated. Hydroxysafflor yellow A decreased the lung consolidation area and collagen deposition in mice with pulmonary fibrosis. The blood gas changes due to BLM were attenuated by Hydroxysafflor yellow A. Hydroxysafflor yellow A also alleviated the BLM-induced increase of TGF-β1, connective tissue growth factor, α-SMA, and collagen I mRNA levels. Moreover, it inhibits Smad3 phosphorylation and elevated expression of collagen I mRNA in EMT induced by TGF-β1. Therefore, this treatment could be useful to ameliorate pulmonary fibrosis [92].

2.3.15. Salvianolic acid Salvianolic acid B is a major ingredient of Salvia miltiorrhiza, and is the only commercially available monomer component extracted from Salvia miltiorrhiza. Salvianolic acid B contains seven phenolic hydroxyls. It has been reported that salvianolic acid B can effectively reverse liver fibrosis in patients suffering from chronic hepatitis B [100]. The effects of salvianolic acid B on BLM-Induced pulmonary fibrosis in mouse were investigated. The results showed that Salvianolic acid B had strong anti-inflammatory and anti-fibrotic effects through its inhibition of inflammatory cell infiltration, alveolar structure disruption, and collagen deposition. Furthermore, salvianolic acid B suppressed TGF-β-induced myofibroblastic differentiation of fibroblasts and TGF-βmediated epithelial-to-mesenchymal transition cells by inhibiting both Smad-dependent signaling and the Smad-independent MAPK pathway [101].

2.3.12. Gambogic acid Gamboge is a dry resin secreted by Garcinia hanburyi Hook and gambogic acid is the main active compound of gamboge. Gambogic acid has various bioactivities including anti-inflammatory, anti-tumor and anti- proliferation [93]. Protective role of gambogic acid in BLM induced pulmonary fibrosis was studied. Treatment with gambogic acid resulted in an amelioration of the BLM-induced pulmonary fibrosis in rats with a lower Vasohibin-2 (VASH-2); an endogenous and vascular endothelial growth factor. Instead, it was observed a higher VASH-1; a unique endogenous angiogenesis inhibitor with reductions of the pathological score, collagen deposition, α-SMA, PDGF and fibroblast growth factor -2 expressions. In summary, gambogic acid reversed EMT and prevented pulmonary fibrosis by modulating VASH-2/VASH-1 and suppressing the TGF- β1/ Smad3 pathway [94].

2.4. Medicinal mashrooms 2.4.1. Hirsutella sinesis Hirsutella sinensis mycelium, the anamorphic stage of natural Cordyceps sinensis, has emerged as an attractive substitute for the preparation of health supplements. Previous studies have showed that an ethanol extract of Hirsutella sinensis mycelium suppresses IL-1β and IL18 secretion by inhibiting both canonical and non-canonical inflammasomes in human macrophages [102]. In one study the effect of Hirsutella sinesis mycelium on BLM induced pulmonary fibrosis in mice was investigated. The results showed that pretreatment with Hirsutella sinesis inhibits TGF-β1–induced expression of fibronectin and α-SMA in lung fibroblasts. Hirsutella sinesis also restores SOD expression in lung fibroblasts and inhibits reactive oxygen species production in lung epithelial cells. Moreover, the purinergic receptor P2 × 7R is activated by ATP, which is released by injured lung cells following BLM treatment, leading to activation of the NLRP3 inflammasome, secretion of IL-1β, and development of lung fibrosis. Hirsutella sinesis reduces expression of the NLRP3 inflammasome and P2 × 7R in lung tissues. These findings suggest that Hirsutella sinesis may be used for the treatment of pulmonary inflammation and fibrosis [103].

2.3.13. Resveratrol Resveratrol is extracted from the several vegetal sources particularly grape skin, cranberry, mulberry, lingberry, bilberry, jackfruit, peanut and the butterfly orchid tree [95]. Effects of resveratrol on treatment of BLM-Induced pulmonary fibrosis in rats were investigated. This study primarily demonstrated that BLM induced lung fibrosis which was assessed by an increase in lung tissue HYP content and fibrosis score was partially reversed by oral administration of resveratrol. Furthermore, resveratrol was observed to reduce the increase of MDA levels in lung tissue and serum. Also, resveratrol treatment reversed an increase in the total cell count and number of neutrophils in BALF [96]. In another study, it was demonstrated that resveratrol treatment reversed all the biochemical indices induced by BLM such as a significant decrease in lung GSH and a remarkable increase in MPO activity. The results indicated the role of resveratrol to ameliorate oxidative injury and fibrosis due to BLM. Thus, an effective supplement with resveratrol as an adjuvant therapy may be a very promising agent in alleviating the side effects of BLM, an effective chemotherapeutic agent [97].

2.4.2. Cordyceps sinensis Cordyceps sinensis is an entomogenous fungus. It has been shown to relieve fibrosis in the liver and lung through an inhibition of TGF-b1 expression [104,105]. Protective role of Cordyceps on rat models of BLM induced lung fibrosis was studied. Reduction of infiltration of inflammatory cells, deposition of fibroblastic loci and collagen, formation of reactive oxygen species, and production of cytokines, as well as recovery from imbalance of MMP-9/TIMP-1 were observed in fibrotic rats after 1462

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treated by Gallic acid, Lycopene, Gentiopicroside, TanshinoneⅡA, Isoliensinine and Loquat was significantly decreased. AMP-activated protein kinase (AMPK) signaling plays a crucial role in the cellular energy balance which regulates not only intracellular energy balance via lipid and glucose but also a wide array of cell function. AMPK activation has been demonstrated to attenuate acute lung injury and regulate TGF-β-induced collagen production. Furthermore, AMPK activation inhibits the stimulatory effects of TGF-β on Smad2/3 activity, cell migration, and epithelial-to-mesenchymal transition in cancer cells. The protection of Rhapontin against lung inflammation or fibrosis is related to AMPK activation. Therefore, it is assumed that AMPK activation could be a key regulator in anti-inflammatory and anti-fibrotic processes for the treatment of BLM-induced lung fibrosis. Also, it is observed that Triptolide (PG490-88) is a potent antitumor agent in addition to its remarkable effect on improvement of BLM induced pulmonary fibrosis. BLM treatment has been shown to increase the production of ROS and induce the development of lung fibrosis. In addition, ROS have been shown in many cases to trigger NLRP3 inflammasome, a cytosolic protein complex, activation. According to the results ethanol extract of Hirsutella sinensis mycelium, a medicinal mushroom, suppresses IL-1β and IL-18 secretion by inhibiting both canonical and non-canonical inflammasomes in human macrophages. In this way inhibition of inflammasomes could be a promising target for attenuation of BLM-induced pulmonary fibrosis. In one study, the results indicated that ANXA2 (annexin A2) is a specific BLM target, and BLM binding with ANXA2 impedes transcription factor EB, a master regulator of macroautophagy/autophagy that is resulting in substantial acceleration of autophagic flux, leading to induction of pulmonary fibrosis. These findings provide insight into the mechanisms of BLM-induced fibrosis and may facilitate development of optimized BLM therapeutics devoid of lung toxicity [109]. AMPK is a critical sensor of cellular bioenergetics and controls the switch from anabolic to catabolic metabolism. According to a study, it was demonstrated that in humans with idiopathic pulmonary fibrosis and in an experimental mouse model of lung fibrosis, AMPK activity is lower in fibrotic regions associated with metabolically active and apoptosis-resistant myofibroblasts. So, the activation of AMPK by pharmacological agents may be a useful therapeutic strategy for progressive fibrotic disorders [110]. Low oral bioavailability but high bioactivity is a conundrum not yet solved for some herbs. Since most of herbal products are orally administered, the herbs' constituents are inevitably exposed to the intestinal microbiota and the interplays between herbal constituents and gut microbiota are expected. Emerging explorations of herb-microbiota interactions have an opportunity to revolutionize the way to view herbal therapeutics [111]. Most polyphenols are poorly absorbed in the small intestine and pass into the colon. Studies in germ-free and human microbiota-associated animals and in vitro faecal incubations provide evidence that parent polyphenols are extensively metabolized by the colonic microbiota, which can affect their bioactivity [112]. Further study of these types of interactions is essential to understand how the gut microbiota influences bioavailability of herbs. Plants and mushrooms are used for medicinal purposes and the screening of molecules possessing biological activities. In a study, it was indicated that water extracts of plants and mushrooms usually activate immune cells, whereas ethanol extracts inhibit immune cells. The opposite effects produced by water and ethanol extracts of plants and mushrooms on the immune system provide essential information for the preparation of extracts that may be used for the prevention and treatment of human disease. Another study showed that water and ethanol extracts of cultured mycelium from various species such as Ganoderma lucidum and Hirsutella sinensis produce opposite effects on the human NK cell lines that were initially derived from a case of non-Hodgkin’s lymphoma. Water extracts enhance NK cell cytotoxic activity against

treatment with Cordyceps in preventive (from the day of BLM administration) and therapeutic (from 14 days after BLM) regimens. The epithelial–mesenchymal transition could be partially reverted by cordycepin, a major component of Cordyceps. The findings provide an insight in to the preventive and therapeutic potentials of Cordyceps for the treatment of lung fibrosis [106]. 2.4.3. Ganoderma lucidum Ganoderma lucidum, rich in polysaccharides, has many therapeutic benefits on human diseases. Recently, polysaccharides from Ganoderma lucidum have been successfully obtained excellent antioxidant activities [107]. Protective roles of polysaccharides from Ganoderma lucidum on BLM-induced pulmonary fibrosis in rats were evaluated. The study demonstrated that treatment with polysaccharides from Ganoderma lucidum led to significant reduction in the pulmonary index, inflammatory cell infiltration and collagen deposition in rats with BLMinduced pulmonary fibrosis which was associated with increased levels of glutathione, glutathione peroxidase, catalase and SOD and decreased contents of MDA and HYP in the lung. These results indicated that polysaccharides from Ganoderma lucidum played a positive protective role in the pulmonary fibrosis and its possible mechanism was to improve lung antioxidant ability [108]. 3. Discussion Current evidence revealed that multiple molecules and signaling pathways such as oxidative stress, fibrotic biomarkers and inflammation are associated with BLM-induced pulmonary fibrosis. Based on this knowledge, various strategies were proposed. A number of natural products and herbal extracts demonstrated potency in limiting BLM pulmonary toxicity through experimental animal models. In accordance with the aforementioned literature, among the plant extracts that were evaluated, Chrysanthemum indicum enhanced the anti-cancer activity of BLM and have shown synergistic effect with BLM, besides substantial potential in improving BLM induced pulmonary fibrosis. This specific point indicated CISCFE as a potential adjuvant drug with chemotherapy after further investigations and clinical trials in the future. Among the herbal preparations although Feitai has beneficial effects on lung, additional studies are require to specify further the main mechanism of the protective role against BLM induced pulmonary fibrosis. Protein Smad3 is related to the signal transduction of TGF; that is why the TGF- β1/Smad3 signaling pathway is considered to have close relation with deposits of extracellular matrix and tissue fibrosis. According to aforementioned literature, protein and genetic expressions of Smad3 and TGF- β1 after interfered by RPFS were obviously decreased, however the role of the chemical components identified in RPFS is worthy of further study in pulmonary fibrosis treatment. Among the herbal preparations, Hochu-ekki (TJ-41), Sho-Seiryu-To (TJ-19) and Yin-Chiao-San demonstrated more beneficial effects in the prevention of pulmonary fibrosis induced by BLM. Therefore, these formulations could be attractive candidates and sources of prophylaxis against pulmonary toxicity induced by BLM. TNF-α is a pro-inflammatory cytokine with many biological properties and is thought to be important in the development of pulmonary fibrosis. Accumulating evidence suggests that alveolar macrophages secrete TNF-α in pulmonary fibrosis process. TNF-α could increase fibroblast proliferation, differentiation and collagen transcription indirectly via TGF-β or PDGF induction pathways. Furthermore, TNF-α activity promotes induction of matrix-degrading gelatinases that can enhance basement membrane disruption. TNF-α exerts its effects through activation of TNF receptor 1 and 2 (TNFR1/2), which could lead to a rapid activation of the JAK/STAT pathway. Among the bioactive compounds, the concentration of TNF-α in alveolar macrophages in animal models of pulmonary fibrosis that were 1463

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cancer cells, whereas ethanol extracts inhibit cytotoxicity. Regarding herbal medicine, new regulatory guidelines will be needed to assure the quality, efficacy, and safety of extracts derived from plants and mushrooms [113,114].

[12]

4. Conclusion

[14]

[13]

[15]

Various herbal compounds have been used for many years in different diseases. In this review article, the effects of plant extracts, herbal preparations and bioactive compounds on improving BLM-induced pulmonary fibrosis in animal trials were described. These natural products have several mechanisms of action to ameliorate PF such as inhibitory effects against the elevation of serum TNF-α, TGF-β and interleukins also, preventing an increase in fibrotic markers like MMP-9, NF-κB and HYP. Moreover, they can relieve the severity of alveolitis and inhibit the growth of pulmonary fibrocytes by downregulating the abnormal expression of JAK-STAT signaling transduction pathways and downregulating Jagged1/Notch1 signaling. Furthermore, they could restore the activities of catalase and glutathione-S-transferase in the lung tissues which were reduced by BLM. The results demonstrated that these plant extracts could attenuate BLM-induced PF by normalizing pro-oxidant parameters and by enhancing the activities of antioxidant enzymes. Thus, the herbs are a promising source of treatment agents for BLM-induced pulmonary fibrosis. Whereas the amelioration of the pulmonary fibrosis-the most important side effect of BLM- is a considerable point, the effects of the herbs on antitumor activity of BLM and their synergistic or additive impact on BLM pharmacodynamic are not obvious and need more studies. According to the results of these studies and their affirmative influences on alleviation of BLM induced pulmonary fibrosis in animals models, clinical trials are required to verify the safety and efficacy of them in human and their antifibrotic effects should be investigated in further detail. As regards, the questions about the most reasonable dosage of each compound for maximizing its effectiveness, the main effective ingredients and the interaction with other medicines are not clear and require more studies.

[16] [17]

[18]

[19] [20]

[21]

[22] [23] [24] [25] [26] [27] [28]

[29]

[30]

[31]

Conflict of interest [32]

The authors declare no conflict of interest. [33]

Acknowledgments [34]

The authors are thankful to the Vice Chancellor of Research, Mashhad University of Medical Sciences, for financial support.

[35] [36]

References

[37]

[1] S.D. Williams, et al., Treatment of disseminated germ-cell tumors with cisplatin, bleomycin, and either vinblastine or etoposide, N. Engl. J. Med. 316 (23) (1987) 1435–1440. [2] P.R. Twentyman, Bleomycin—mode of action with particular reference to the cell cycle, Pharmacol. Ther. 23 (3) (1983) 417–441. [3] R.T. Dorr, Bleomycin pharmacology: mechanism of action and resistance, and clinical pharmacokinetics, Seminars in Oncology, (1992) Elsevier. [4] D. Chandler, Possible mechanisms of bleomycin-induced fibrosis, Clin. Chest Med. 11 (1) (1990) 21–30. [5] P. Camus, Interstitial Lung Disease From Drugs, Biologics, and Radiation. Interstitial Lung Disease, 5th ed., People’s Medical Publishing House, Shelton, CT, 2011 637.. [6] S. Sleijfer, Bleomycin-induced pneumonitis, Chest 120 (2) (2001) 617–624. [7] M. Froudarakis, et al., Revisiting bleomycin from pathophysiology to safe clinical use, Crit. Rev. Oncol. Hematol. 87 (1) (2013) 90–100. [8] M. Iraz, et al., Ginkgo biloba inhibits bleomycin-induced lung fibrosis in rats, Pharmacol. Res. 53 (3) (2006) 310–316. [9] K.M. Nash, Z.A. Shah, Current perspectives on the beneficial role of Ginkgo biloba in neurological and cerebrovascular disorders, Integr. Med. Insights 10 (2015) p. IMI. S25054.. [10] A. Sarkaki, Z. Eidypour, F. Motamedi, Motor disturbances and thalamic electrical power of frequency bands’ improve by grape seed extract in animal model of Parkinson’s disease, Avicenna J. Phytomed. 2 (4) (2012) 222. [11] W.G. Taylor, et al., Variation in diosgenin levels among 10 accessions of fenugreek

[38]

[39] [40]

[41] [42] [43]

[44] [45] [46] [47]

1464

seeds produced in western Canada, J. Agric. Food Chem. 50 (21) (2002) 5994–5997. S.P. Patil, P.V. Niphadkar, M.M. Bapat, Allergy to fenugreek (Trigonella foenum graecum), Ann. Allergy Asthma Immunol. 78 (3) (1997) 297–300. A.D. Kandhare, et al., Effect of glycosides based standardized fenugreek seed extract in bleomycin-induced pulmonary fibrosis in rats: decisive role of Bax, Nrf2, NF-κB, Muc5ac, TNF-α and IL-1β, Chem. Biol. Interact. 237 (2015) 151–165. S. Habtemariam, The therapeutic potential of rosemary (Rosmarinus officinalis) diterpenes for Alzheimer’s disease, Evid. Complement. Altern. Med. 2016 (2016). M. Da Silva Afonso, L. SanT’Ana, Effects of pretreatment with rosemary (Rosmarinus officinalis L.) in the prevention of lipid oxidation in salted tilapia fillets, J. Food Qual. 31 (5) (2008) 586–595. S. Bahri, et al., Prophylactic and curative effect of rosemary leaves extract in a bleomycin model of pulmonary fibrosis, Pharm. Biol. 55 (1) (2017) 462–471. S. Arokiyaraj, et al., Rapid green synthesis of silver nanoparticles from Chrysanthemum indicum L. and its antibacterial and cytotoxic effects: an in vitro study, Int. J. Nanomedicine 9 (2014) 379. H.-M. Yang, et al., Supercritical-carbon dioxide fluid extract from Chrysanthemum indicum enhances anti-tumor effect and reduces toxicity of bleomycin in tumorbearing mice, Int. J. Mol. Sci. 18 (3) (2017) 465. R. Li, et al., Hepatoprotective action of Radix paeoniae Rubra aqueous extract against CCl4-induced hepatic damage, Molecules 16 (10) (2011) 8684–8693. X. Ma, et al., Paeonia lactiflora Pall. Protects against ANIT-induced cholestasis by activating Nrf2 via PI3K/Akt signaling pathway, Drug Des. Devel. Ther. 9 (2015) 5061. Y. Ji, et al., Paeoniflorin, the main active constituent of Paeonia lactiflora roots, attenuates bleomycin-induced pulmonary fibrosis in mice by suppressing the synthesis of type I collagen, J. Ethnopharmacol. 149 (3) (2013) 825–832. P.A. Rosenroot, Traditional use, chemical composition, pharmacology and clinical efficacy/А. Panossian, Phytomedicine 6 (17) (2010) 481–493. M. Ahmed, et al., Rhodiola rosea exerts antiviral activity in athletes following a competitive marathon race, Front. Nutr. 2 (2015) 24. K. Zhang, et al., Preventive effects of Rhodiola rosea L. on bleomycin-induced pulmonary fibrosis in rats, Int. J. Mol. Sci. 17 (6) (2016) 879. M. Kumar, S.K. Prasad, S. Hemalatha, A current update on the phytopharmacological aspects of Houttuynia cordata Thunb, Pharmacogn. Rev. 8 (15) (2014) 22. S.-C. Chou, et al., The constituents and their bioactivities of Houttuynia cordata, Chem. Pharm. Bull. 57 (11) (2009) 1227–1230. L.-T. Ng, et al., Protective effect of Houttuynia cordata extract on bleomycin-induced pulmonary fibrosis in rats, Am. J. Chin. Med. 35 (03) (2007) 465–475. L.J. de Freitas Morel, et al., A standardized methanol extract of Eclipta prostrata (L.) L.(Asteraceae) reduces bronchial hyperresponsiveness and production of Th2 cytokines in a murine model of asthma, J. Ethnopharmacol. 198 (2017) 226–234. I.-M. Chung, et al., Ethnopharmacological uses, phytochemistry, biological activities, and biotechnological applications of Eclipta prostrata, Appl. Microbiol. Biotechnol. 101 (13) (2017) 5247–5257. X.-Y. You, et al., Preventive effects of Ecliptae Herba extract and its component, ecliptasaponin A, on bleomycin-induced pulmonary fibrosis in mice, J. Ethnopharmacol. 175 (2015) 172–180. Y.-e. Yi, et al., Effect of astragalus injection on renal tubular epithelial transdifferentiation in type 2 diabetic mice, BMC Complement. Altern. Med. 16 (1) (2016) 222. Y. Zhou, et al., Astragalus injection attenuates bleomycin‐induced pulmonary fibrosis via down‐regulating Jagged1/Notch1 in lungs, J. Pharm. Pharmacol. 68 (3) (2016) 389–396. B.J. Lewis, et al., Antihypertensive effect of passion fruit peel extract and its major bioactive components following acute supplementation in spontaneously hypertensive rats, J. Nutr. Biochem. 24 (7) (2013) 1359–1366. S. Zibadi, et al., Oral administration of purple passion fruit peel extract attenuates blood pressure in female spontaneously hypertensive rats and humans, Nutr. Res. 27 (7) (2007) 408–416. S.R. Chilakapati, et al., Passion fruit peel extract attenuates bleomycin-induced pulmonary fibrosis in mice, Can. J. Physiol. Pharmacol. 92 (8) (2014) 631–639. Lh. Zhao, et al., Simultaneous quantification of seven bioactive flavonoids in citri reticulatae pericarpium by ultra‐fast liquid chromatography coupled with tandem mass spectrometry, Phytochem. Anal. 27 (3-4) (2016) 168–173. X.-M. Zhou, et al., Inhibitory effects of amines from Citrus reticulata on bleomycininduced pulmonary fibrosis in rats, Int. J. Mol. Med. 37 (2) (2016) 339–346. G. Karimi, et al., Protective effects of aqueous and ethanolic extracts of Nigella sativa L. and Portulaca oleracea L. on free radical induced hemolysis of RBCs, DARU: J. Faculty Pharm. Tehran Univ. Med. Sci. 19 (4) (2011) 295. A. Ahmad, et al., A review on therapeutic potential of Nigella sativa: a miracle herb, Asian Pac. J. Trop. Biomed. 3 (5) (2013) 337–352. A. Abidi, et al., Nigella sativa, a traditional Tunisian herbal medicine, attenuates bleomycin-induced pulmonary fibrosis in a rat model, Biomed. Pharmacother. 90 (2017) 626–637. S. Khan, et al., Ellagic acid attenuates bleomycin and cyclophosphamide-induced pulmonary toxicity in Wistar rats, Food Chem. Toxicol. 58 (2013) 210–219. S. Beigh, et al., Bleomycin-induced pulmonary toxicopathological changes in rats and its prevention by walnut extract, Biomed. Pharmacother. 94 (2017) 418–429. R. Jia, et al., The protective effect of silymarin on the carbon tetrachloride (CCl 4)induced liver injury in common carp (Cyprinus carpio), In Vitro Cell. Dev. Biol.Anim. 49 (3) (2013) 155–161. B.M. Razavi, G. Karimi, Protective effect of silymarin against chemical-induced cardiotoxicity, Iran. J. Basic Med. Sci. 19 (9) (2016) 916. K. Razavi-Azarkhiavi, et al., Silymarin alleviates bleomycin-induced pulmonary toxicity and lipid peroxidation in mice, Pharm. Biol. 52 (10) (2014) 1267–1271. L.-K. Gong, et al., Feitai attenuates bleomycin-induced pulmonary fibrosis in rats, Biol. Pharm. Bull. 27 (5) (2004) 634–640. Y.-X. ZHANG, D.-Z. LI, History of and recent advances in plant taxonomy, Plants of

Biomedicine & Pharmacotherapy 107 (2018) 1454–1465

S. Hosseini et al.

pulmonary fibrosis in mice, Planta Med. 71 (03) (2005) 225–230. [82] G.-l. JIANG, et al., Effect of MAPK signal transduction pathway on the expression of TNF-α in alveolar macrophage of chronic bronchitis rats and the target of TAL, Chin. Pharmacol. Bull. 5 (2009) 011. [83] Y. Yang, et al., Antifibrosis effects of triterpene acids of Eriobotrya japonica (Thunb.) Lindl. Leaf in a rat model of bleomycin‐induced pulmonary fibrosis, J. Pharm. Pharmacol. 64 (12) (2012) 1751–1760. [84] J. Chen, et al., Rhaponticin from rhubarb rhizomes alleviates liver steatosis and improves blood glucose and lipid profiles in KK/Ay diabetic mice, Planta Med. 75 (05) (2009) 472–477. [85] L. Tao, et al., Protective role of rhapontin in experimental pulmonary fibrosis in vitro and in vivo, Int. Immunopharmacol. 47 (2017) 38–46. [86] C. Yong‐gang, et al., Antiarrhythmic effects and ionic mechanisms of oxymatrine from Sophora flavescens, Phytother. Res. 24 (12) (2010) 1844–1849. [87] G. Gao, F.C. Law, Physiologically-based pharmacokinetics of Matrine in the rat after oral administration of pure chemical and ACAPHA®, Drug Metab. Dispos. (2009). [88] X. Ma, et al., Effects of matrine on JAK-STAT signaling transduction pathways in bleomycin-induced pulmonary fibrosis, Afr. J. Tradit. Complement. Altern. Med. 10 (3) (2013) 442–448. [89] X. Tao, et al., A prospective, controlled, double-blind, cross-over study of tripterygium wilfodii hook F in treatment of rheumatoid arthritis, Chin. Med. J. 102 (5) (1989) 327–332. [90] G. Krishna, et al., PG490-88, a derivative of triptolide, blocks bleomycin-induced lung fibrosis, Am. J. Pathol. 158 (3) (2001) 997–1004. [91] N. Hu, et al., Hydroxysafflor yellow A ameliorates renal fibrosis by suppressing TGF-β1-induced epithelial-to-mesenchymal transition, PLoS ONE 11 (4) (2016) p. e0153409. [92] M. Jin, et al., Hydroxysafflor yellow a attenuates bleomycin‐induced pulmonary fibrosis in mice, Phytother. Res. 30 (4) (2016) 577–587. [93] Z.-Q. Wu, et al., Gambogic acid inhibits proliferation of human lung carcinoma SPC-A1 cells in vivo and in vitro and represses telomerase activity and telomerase reverse transcriptase mRNA expression in the cells, Biol. Pharm. Bull. 27 (11) (2004) 1769–1774. [94] Y. Qu, et al., Protective role of gambogic acid in experimental pulmonary fibrosis in vitro and in vivo, Phytomedicine 23 (4) (2016) 350–358. [95] Y. Li, Z. Cao, H. Zhu, Upregulation of endogenous antioxidants and phase 2 enzymes by the red wine polyphenol, resveratrol in cultured aortic smooth muscle cells leads to cytoprotection against oxidative and electrophilic stress, Pharmacol. Res. 53 (1) (2006) 6–15. [96] R. Akgedik, et al., Effect of resveratrol on treatment of bleomycin-induced pulmonary fibrosis in rats, Inflammation 35 (5) (2012) 1732–1741. [97] G. Şener, et al., Resveratrol alleviates bleomycin-induced lung injury in rats, Pulm. Pharmacol. Ther. 20 (6) (2007) 642–649. [98] D. Impellizzeri, et al., Effect of apocynin, a NADPH oxidase inhibitor, on acute lung inflammation, Biochem. Pharmacol. 81 (5) (2011) 636–648. [99] T. Kilic, et al., Protective and therapeutic effect of apocynin on bleomycin-induced lung fibrosis in rats, Inflammation 38 (3) (2015) 1166–1180. [100] P. Liu, et al., Clinical observation of salvianolic acid B in treatment of liver fibrosis in chronic hepatitis B, World J. Gastroenterol. 8 (4) (2002) 679. [101] Q. Liu, et al., Salvianolic acid B attenuates experimental pulmonary fibrosis through inhibition of the TGF-β signaling pathway, Sci. Rep. 6 (2016) 27610. [102] T.-T. Huang, et al., Hirsutella sinensis mycelium suppresses interleukin-1β and interleukin-18 secretion by inhibiting both canonical and non-canonical inflammasomes, Sci. Rep. 3 (2013) 1374. [103] T.-T. Huang, et al., Hirsutella sinensis mycelium attenuates bleomycin-induced pulmonary inflammation and fibrosis in vivo, Sci. Rep. 5 (2015) 15282. [104] S.K. Das, et al., Medicinal uses of the mushroom Cordyceps militaris: current state and prospects, Fitoterapia 81 (8) (2010) 961–968. [105] S. Wang, et al., Effects of cordyceps sinensi on bleomycin-induced pulmonary fibrosis in mice, Zhongguo Zhong yao za zhi= Zhongguo zhongyao zazhi= China J. Chin. materia medica 32 (24) (2007) 2623–2627. [106] M. Chen, et al., Protective roles of Cordyceps on lung fibrosis in cellular and rat models, J. Ethnopharmacol. 143 (2) (2012) 448–454. [107] Y. Kan, et al., Antioxidant activity of polysaccharide extracted from Ganoderma lucidum using response surface methodology, Int. J. Biol. Macromol. 72 (2015) 151–157. [108] J. Chen, et al., Protective roles of polysaccharides from Ganoderma lucidum on bleomycin-induced pulmonary fibrosis in rats, Int. J. Biol. Macromol. 92 (2016) 278–281. [109] K. Wang, et al., Identification of ANXA2 (annexin A2) as a specific bleomycin target to induce pulmonary fibrosis by impeding TFEB-mediated autophagic flux, Autophagy 14 (2) (2018) 269–282. [110] S. Rangarajan, et al., Metformin reverses established lung fibrosis in a bleomycin model, Nat. Med. (2018) 1. [111] F. Chen, et al., Could the gut microbiota reconcile the oral bioavailability conundrum of traditional herbs? J. Ethnopharmacol. 179 (2016) 253–264. [112] I. Rowland, et al., Gut microbiota functions: metabolism of nutrients and other food components, Eur. J. Nutr. (2017) 1–24. [113] J. Martel, et al., Immunomodulatory properties of plants and mushrooms, Trends Pharmacol. Sci. (2017). [114] C.-C. Lu, et al., Immunomodulatory properties of medicinal mushrooms: differential effects of water and ethanol extracts on NK cell-mediated cytotoxicity, Innate Immun. 22 (7) (2016) 522–533.

China: A Companion to the Flora of China, (2015), p. 256. [48] X. Liang, et al., Effect of Feining on bleomycin-induced pulmonary injuries in rats, J. Ethnopharmacol. 134 (3) (2011) 971–976. [49] L. Li, et al., Total extract of Yupingfeng attenuates bleomycin-induced pulmonary fibrosis in rats, Phytomedicine 22 (1) (2015) 111–119. [50] W. Cui, et al., Total glycosides of Yupingfeng protects against bleomycin-induced pulmonary fibrosis in rats associated with reduced high mobility group box 1 activation and epithelial–mesenchymal transition, Inflamm. Res. 64 (12) (2015) 953–961. [51] J.-L. Tang, B.-Y. Liu, K.-W. Ma, Traditional chinese medicine, Lancet 372 (9654) (2008) 1938–1940. [52] F. Chen, et al., Effect of Renshen Pingfei Decoction, a traditional Chinese prescription, on IPF induced by Bleomycin in rats and regulation of TGF-β1/Smad3, J. Ethnopharmacol. 186 (2016) 289–297. [53] S. Huang, et al., Experiment on antiatherosis effect of Daguibuxue Decoction in rabbits, Beijing Zhong Yi Yao Da Xue Xue Bao 28 (2005) 140–144. [54] J. Gao, et al., Antifibrosis effects of total glucosides of Danggui–Buxue–Tang in a rat model of bleomycin-induced pulmonary fibrosis, J. Ethnopharmacol. 136 (1) (2011) 21–26. [55] L. Huang, et al., Optimization of a compound prescription for treating liver fibrosis, Nan fang yi ke da xue xue bao= J. South. Med. Univ. 32 (1) (2012) 106–108. [56] Y. Gao, et al., The Chinese herbal medicine formula mKG suppresses pulmonary fibrosis of mice induced by bleomycin, Int. J. Mol. Sci. 17 (2) (2016) 238. [57] H. Kusunoki, et al., Efficacy of Rikkunshito, a traditional Japanese medicine (Kampo), in treating functional dyspepsia, Intern. Med. 49 (20) (2010) 2195–2202. [58] H. Takeda, et al., Rikkunshito, an herbal medicine, suppresses cisplatin-induced anorexia in rats via 5-HT2 receptor antagonism, Gastroenterology 134 (7) (2008) 2004–2013. [59] H. Tsubouchi, et al., Rikkunshito ameliorates bleomycin-induced acute lung injury in a ghrelin-independent manner, Am. J. Physiol.-Lung Cell. Mol. Physiol. 306 (3) (2013) L233–L245. [60] S. Tajima, et al., Preventive effect of Hochu-ekki-to on lipopolysaccharide-induced acute lung injury in BALB/c mice, Lung 184 (6) (2006) 318–323. [61] S. Tajima, et al., Preventive effect of hochu‐ekki‐to, a Japanese herbal medicine, on bleomycin‐induced lung injury in mice, Respirology 12 (6) (2007) 814–822. [62] T. Miyamoto, et al., Effect of TSUMURA Sho-seiryu-to (TJ-19) on bronchitis in a double-blind placebo-controlled Study, J. Clin. Ther. Med. 17 (2001) 1189–1214. [63] C.-q. Yang, et al., The ethical Kampo formulation Sho-seiryu-to (TJ-19) prevents bleomycin-induced pulmonary fibrosis in rats, Biol. Pharm. Bull. 33 (8) (2010) 1438–1442. [64] G.G. Zhang, et al., A new compound from Forsythia suspensa (Thunb.) Vahl with antiviral effect on RSV, J. Herb. Pharmacother. 2 (3) (2002) 35–40. [65] F.L. Yen, et al., A kampo medicine, Yin‐Chiao‐san, prevents bleomycin‐induced pulmonary injury in rats, Phytother. Res. 21 (3) (2007) 251–258. [66] M.T. Mansouri, et al., Neuroprotective effects of oral gallic acid against oxidative stress induced by 6-hydroxydopamine in rats, Food Chem. 138 (2-3) (2013) 1028–1033. [67] M.T. Mansouri, et al., Gallic acid prevents memory deficits and oxidative stress induced by intracerebroventricular injection of streptozotocin in rats, Pharmacol. Biochem. Behav. 111 (2013) 90–96. [68] M.L. Nguyen, S.J. Schwartz, Lycopene: chemical and biological properties. (1999). [69] S. Agarwal, A.V. Rao, Tomato lycopene and its role in human health and chronic diseases, Can. Med. Assoc. J. 163 (6) (2000) 739–744. [70] G. Karimi, M. Ramezani, A. Abdi, Protective effects of lycopene and tomato extract against doxorubicin‐induced cardiotoxicity, Phytother. Res. 19 (10) (2005) 912–914. [71] C. Zhou, et al., Lycopene from tomatoes partially alleviates the bleomycin-induced experimental pulmonary fibrosis in rats, Nutr. Res. 28 (2) (2008) 122–130. [72] R.X. Tan, L.D. Kong, Secoiridoids from Gentiana siphonantha, Phytochemistry 46 (6) (1997) 1035–1038. [73] X. Tang, et al., Target profiling analyses of bile acids in the evaluation of hepatoprotective effect of gentiopicroside on ANIT-induced cholestatic liver injury in mice, J. Ethnopharmacol. 194 (2016) 63–71. [74] C. Chen, et al., Gentiopicroside ameliorates bleomycin-induced pulmonary fibrosis in mice via inhibiting inflammatory and fibrotic process, Biochem. Biophys. Res. Commun. (2017). [75] X. Li, et al., Protective effect of celastrol on myocardial ischemia-reperfusion injury, Anat. J. Cardiol./Anadolu Kardiyoloji Dergisi 18 (6) (2017). [76] T. Divya, B. Velavan, G. Sudhandiran, Regulation of TGF‐β/Smad mediated epithelial‐mesenchymal transition by celastrol provides protection against bleomycin‐induced pulmonary fibrosis, Basic Clin. Pharmacol. Toxicol. (2018). [77] L. Zhou, Z. Zuo, M.S.S. Chow, Danshen: an overview of its chemistry, pharmacology, pharmacokinetics, and clinical use, J. Clin. Pharmacol. 45 (12) (2005) 1345–1359. [78] T. Yu, et al., A novel anti-cancer agent, acetyltanshinone IIA, inhibits oestrogen receptor positive breast cancer cell growth by down-regulating the oestrogen receptor, Cancer Lett. 346 (1) (2014) 94–103. [79] H. He, et al., Tanshinone ⅡA attenuates bleomycin-induced pulmonary fibrosis in rats, Mol. Med. Rep. 11 (6) (2015) 4190–4196. [80] Z. Fan, W. Jialing, Q. Jiaqing, Effects of isoliensinine on experimental arrhythmia and myocardium action potential of guinea pig, Chin. Trad. Herbal Drugs 31 (10) (2000) 753–755. [81] J.-H. Xiao, et al., Inhibitory effects of isoliensinine on bleomycin-induced

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