Targeting obesity with plant-derived pancreatic lipase inhibitors: A comprehensive review

Journal Pre-proof Targeting Obesity with plant-derived pancreatic lipase inhibitors: A comprehensive review Logesh Rajan, Dhanabal Palaniswamy, Suresh Kumar Mohankumar

PII:

S1043-6618(19)32788-4

DOI:

https://doi.org/10.1016/j.phrs.2020.104681

Reference:

YPHRS 104681

To appear in:

Pharmacological Research

Received Date:

6 December 2019

Revised Date:

3 February 2020

Accepted Date:

3 February 2020

Please cite this article as: Rajan L, Palaniswamy D, Mohankumar SK, Targeting Obesity with plant-derived pancreatic lipase inhibitors: A comprehensive review, Pharmacological Research (2020), doi: https://doi.org/10.1016/j.phrs.2020.104681

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Targeting Obesity with plant-derived pancreatic lipase inhibitors: A comprehensive review

Logesh Rajan 1, Dhanabal Palaniswamy 1 and Suresh Kumar Mohankumar 1* [email protected]

TIFAC CORE in Herbal Drugs, Department of Pharmacognosy, JSS College of Pharmacy, JSS

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Academy of Higher Education & Research, Rockland’s, Ooty – 643001, Tamil Nadu, India.

* Corresponding author: Prof. Suresh K. Mohankumar Director- Research, Coordinator- TIFAC CORE Herbal Drugs, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Rocklands, Ooty-643001, Nilgiris, Tamil Nadu,

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India.

Tel. No: +91-423-2443393 and +91-8903451179

______________________________________________________________________________________ GRAPHICAL ABSTRACT:

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______________________________________________________________________________________

Abstract

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The prevalence of obesity is alarmingly increasing in the last few decades and leading to many serious public health concerns worldwide. The dysregulated lipid homeostasis due to various genetic, environmental and lifestyle factors is considered one of the critical putative pathways mediating obesity. Nonetheless, the scientific advancements unleashing the molecular dynamics of lipid metabolism have provided deeper insights on the emerging roles of lipid hydrolysing enzymes, including pancreatic lipase. It is hypothesized that inhibiting pancreatic

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lipase would prevent the breakdown of triglyceride and delays the absorption of fatty acids

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into the systemic circulation and adipocytes. Whilst, orlistat is the only conventional

pancreatic lipase enzyme inhibitor available in clinics, identifying the safe clinical alternatives

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from plants to inhibit pancreatic lipase has been considered a significant advancement.

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Consequently, plants which have shown significant potential to combat obesity are now revisited for its abilities to inhibit pancreatic lipase. In this regard, our review surveyed the

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potential of medicinal plants and its phytoconstituents to inhibit pancreatic lipase and to elicit anti-obesity effects. Thus, the review collate and critically appraise the potential of medicinal

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plants and phyto-molecules inhibiting pancreatic lipase enzyme and consequently modulating triglyceride absorption in gut, and discuss its implications in the development of novel therapeutic strategies to combat obesity.

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Abbreviations:

Human Pancreatic Lipase – HPL Pancreatic lipase enzyme – PLE Diglycerides - DG

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Triglycerides - TG Dietary Triglycerides - DTG Free Fatty Acids - FFA Endoplasmic reticulum - ER

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Tetrahydrolipstatin - THL

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Triacylglycerols – TAGs

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Fatty Acids –FA

Total Cholesterol - TC

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Food intake – FI

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Epigallocatechin-3-Gallate - EGCG

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High fat Diet – HFD

Body weight – BW

Low density lipoprotein - LDL

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High density lipoprotein– HDL Phospholipids– PL Body Mass Index –BMI Body fat percentage – BF%

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Body fat mass - BFM Waist circumference– WC Relative risk _ RR

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Body weight gain - BWG

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Keywords: Obesity; Pancreatic lipase; Phytoconstituents; Enzyme inhibitors; Natural products; Orlistat.

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1.1.

Introduction

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Obesity is a chronic metabolic disease that significantly contributes towards morbidity and premature mortality in the world.. The prevalence of obesity is increasing alarmingly in developing

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countries, including India (Misra, 2008). The excessive accumulation of fats and its inappropriate storage in the body leads to a condition called obesity, which extensively affects human metabolic

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health (Sukhdev, 2013).

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Despite, the significant developments in medical fraternity in recent years, the effective treatment or management options available for obesity is very limited which warrants alternative

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strategies. Nonetheless, the strategies treating the complex pathogenesis like obesity needs simple drug approaches which are more easily available and acceptable to patients (Field, 2001).

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A large number of natural products i.e. plants, including extracts and phyto-molecules have shown beneficial to combat obesity. Thus, the current approaches are leaning towards the management of obesity with natural products, as it contains a large number of compounds that act synergistically to produce the anti-obesity effects (Sharma, 2018). The possible mechanisms by which plants elicit anti-

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obesity effects includes, lipid digestion and absorption, reduce food intake (FI), improved expenditure of energy, decreased lipogenesis, decreased differentiation of pre-adipocytes and increased breakdown of triglycerides (TG) (Moro, 2000; Howard, 1981; Abdollahi, 2003; Malloy, 2015; Seetalooa, 2019). Thus, identifying the potential plant-based molecules which have the abilities to combat weight gain

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is a timely task that could enable clinically safe affordable options for the management of obesity (Moreno, 2003; Birari, 2007; Sumantran, 2007). Lipolysis is the process by which the stored or circulating TG breaks down to release fatty acids, and is much enhanced in obesity due to the sympathetic state by excessive accumulation of fatty acids. Consequently, the circulating free fatty acids (FFA) levels rise higher than normal and lead to lipotoxicity. This in turn induces the oxidative stress to endoplasmic reticulum (ER) and triggers

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inflammatory pathways in both adipose and non-adipose tissues and result in dyslipidemia (Palatty,

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2012). The current therapeutic approaches are targeted to address either treating or preventing the lipotoxicity induced by excessive TG accumulation and lipolysis in obesity (Field, 2001; Eckel, 2004).

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Since, dietary triglycerides (DTG) are the main source of intake, an interesting approach towards

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reducing the lipid absorption is by inhibiting the lipases (Bray, 2007). In regards, Orlistat is a tetra hydrolipstatin from the bacterium Streptomyces toxytricini is the only conventional drug available in

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market that shows potential to inhibit pancreatic lipase enzyme (PLE) that helps in the breakdown of DTG in the small intestine (McClendon, 2009; Weibel, 1987). Viner et al., have reported that orlistat

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is capable of reducing blood pressure, increasing the oral glucose tolerance and also able to prevent the onset of diabetes (Viner, 2010). However, chronic administration of orlistat has been reported to elicit many adverse effects including cardiovascular and gastro-intestinal complications (Sharma, 2018; Cheung, 2013). Consequently, exploring the roles of medicinal plants and phyto-molecules on PLE

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and triglyceride absorption is gaining scientific momentum. 1.2. Pancreatic lipase inhibition in obesity management. Amongst the various putative targets studied in the management and control of obesity,

inhibiting fat accumulation by using PLE is an interesting approach towards developing newer and safer anti-obesity drugs. PLE is lipolytic in nature and is released from pancreatic acinar cells, which

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plays a pivotal role in the breakdown of TG (Mhatre, 2016). Thus, PLE plays a critical role in the intestine and does not directly involve with blood or brain avoiding other related side effects and complications. The PLE inhibition target offers search for a comparatively safer drugs in the management of obesity (Miled, 2000; Mu, 2004; De la Garza, 2011). 1.3. Role of Human Pancreatic Lipase (HPL). The crystallographic structure of HPL reveals that the inactive form of HPL is a single chain

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glycoprotein containing 449 amino acids folded into two domains. The larger N-terminal typically

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appears as α/β structure comprising 1-335 residues that holds the active catalytic site. The smaller Cterminal is sandwiched by the two layers of β sheet (Winkler, 1990). Normally, the active catalytic site

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is conserved and protected from the access of solvents and substrates. The HPL tend to lose its activity

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upon chemical modification of serine 152 which is located in the edge of N-terminal and C-terminal. Further, interfacial activation of the HPL enzyme at the surface of the lipid droplets occurs actively

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due to the complete exposure of hydrophobic region of the lipid directly to the active site of HPL (Gubenator, 1990; Packter, 1994). Conversely, binding of triglyceride substrate such as trilaurin to the

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active site required certain modification in the structure to accommodate the substrate access and binding at active site. The resulting model remained comparable with a fewer modification in the experimental structure with three main conformational changes in the structure. Firstly, as the disulfide bridge containing Cys237 and Cys261 loop at the active site has null interference or strained

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confirmation with substrate binding, the removal of Cys237 and Cys261 loop blocking the access of substrate to active binding site is considered a favorable confirmation. (Gubenator, 1993) Secondly, the side chain that contains three aromatic groups has to be modified with lower energy confirmation (x= 60" or 180") at the active site. Finally, since the Phe77 segment groups have no interaction with substrate binding processes, shifting the Phe77 from active catalytic Ser152 has also been considered

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as an acceptable confirmation. The above three steps are considered critical for the binding of substrate molecule, trilaurin to the active site. For instance, in the substrate, when the carbonyl group interacts with catalytic serine of the Oγ group; same group binds to oxy anion and forms a support to the Leu153 and Phe77 of NH groups; the present ester in trans form where FFA tails extend from the site. The sequential catalytic steps starting from Michaelis complex has been illustrated in in Figure 1 and 2. These illustrations explains in detail about the breakdown of TG upon HPL enzyme activation

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(Figure 1) and also inhibition by conventional PLE inhibitor, orlistat (Figure 2) (Gibon, 1984).

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A lot of alternative approaches and conformational model have been tried with trilaurin substrate which did not show promising results. Effective model named “Moloc” has been discussed, that

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carries a key character to minimize energy and further it also plays a part on collisions of non-bonded

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atoms based on the lengths and angles (Mueller, 1988; Gerber, 1988; Gerber, 1995).

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Figure 1. Schematic structural breakdown of triglyceride by PLE.

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Figure 2.PLE inhibition by Orlistat (THL) undergoes triglyceride breakdown (Gubernator, 1993; Weiner, 1981; Brooks, 1983).

1.4. Total pancreatic lipase secretion in humans. Total PLE secretions in response to regular meal cannot be used directly as a measure due to the interference of meal proteins and duodenal protein in the analysis. To overcome this difficulty,

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there were a number of alternative proposals, including using specific enzyme targeted approaches, including trypsin and lipase to quantify the total secretion of PLE. . The large number of studies estimated the total output of PLE by measuring the secretion of PLE in response to normal nutrition with energy levels of 300-600 kcal. For instance, when taking a normal diet for 4 weeks containing protein (10-25%), fat (40-25%), carbohydrates (50%), the interdigestive and postprandial level of PLE secretion output was 90 U/min*kg and 210–250 U/min*kg,

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respectively (Boivin, 1990). These studies and other literature provided the basis that the total PLE

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could be measured in both digestive and intraluminal levels also the activity of PLE could be

measured directly in intestinal chyme. data Likewise, the enzyme flow rates could also be obtained by

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multiplying the enzyme activities (U/min) at a given time and the amount of flow (U/ml) in

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intraduodenum. Parallelly, the effect of PLE on dietary fats could be assayed from the changes in total FFA’s in circulation and compared with the level of PLE obtained from earlier measurements

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(Carrière, 2000).

1.4.1. Pancreatic lipase enzyme flow rates in Intraduodenal and Duodenal

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In a broad-spectrum, there is a sustained increase in the enzyme output (3-4 folds) above pre-prandial values (DiMagno, 1977; Keller, 1997; Fried, 1991; Fried, 1988; Cantor, 1992; Beglinger, 1985; Bozkurt, 1988). Even by low caloric meal some studies reported a tenfold stimulation of enzyme secretion (Owyang, 1986; Katschinski, 1992). Overall, maximal and mean

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interdigestive secretion lipase in duodenum is shown in table 1 (Keller, 1997; Olsen, 1989; Carriere, 1993). A number of studies measured the inter luminal enzyme activities conducted either with or without markers, the inter-digestive lipase activity outcome ranges from 100-400 U/ml (Bozkurt, 1988; Braganza, 1978; Carriere, 1993) (DiMagno, 1977; Keller, 1997; Dukehart, 1989). Whilst the

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intraluminal lipase activity increases during postprandial state, the observed differences between preand post-prandial levels of PLE activity reported to be minimal.

Enzyme (U/min)

PLE in duodenum

Interdigestive

Late/mean

postprandial

Postprandial

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3000-6000

2000-4000

100-400

500-1500

400-1000

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PLE in duodenal juice

Early/maximal

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Table 1. The amount of PLE in duodenum and duodenal juice

In regards, Bozkurt et al., have estimated the PLE secretory rate in duodenal juice without

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using perfusion markers and reported that the flow of PLE was ranged between 2 ml/min during early (5-10 min after meal) and late postprandial state (after 2 hours of meal), however gradually

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peaked up to 5.3 ml/min (during 30-120 min after mean) and returned to baseline (Bozkurt, 1988).

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Consequently, the maximal postprandial activity ranges from 500-1500 U/ml, and the mean activity in postprandial period ranges from 400-500 U/ml (DiMagno, 1977; Bozkurt, 1988; Braganza, 1978)

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and 400-1000 U/ml (Keller, 1997; Carriere, 1993; Dukehart, 1989; Keller, 1996). 1.4.2. Role of diet on PLE secretions

The PLE secretion remains unchanged during food deprivation or fasting (Malagelada, 1973). However, upon the consumption of meal, dietary intake stimulates the secretion of PLE within the

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first hour and gradually returns to baseline and reaching its inter-digestive area (DiMagno, 1977; Fried, 1988; Cantor, 1992; Malagelada, 1979; Miller, 1979; Owyang, 1986; Wisen, 1993). In order to calculate the degree of enzyme response, mainly three factors are to be focused on the following, a) caloric content (Wisen, 1993; Brunner, 1974), b) nutrient intake and c) physical properties of the meal (O'Keefe, 2003). It was estimated that a mixed meal containing a minimum of 1 kcal/min loaded in intra-duodenum is required to trigger the PLE secretion, however, the individual nutrients 13

loaded either as protein, carbohydrate or lipids alone meals required only 0.36 kcal/min calorie (Katschinski, 1992). Previous studies report that prolonged consumption of HFD increases the PLE secretion output than a normal diet containing only carbohydrates. Boivin et al., reported that the dietary consumption of meal containing 10% carbohydrate and 40% dietary fats for four weeks have increased the inter digestive level of PLE secretion four times than the normal diet containing 80% carbohydrate and 10% fat. Of note, the PLE secretion induced by the HFD was twicer than the

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normal diet (Boivin, 1990). PLE secretion may also be affected by the physical properties of the

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meal, depending on the solid, liquid or homogenized state. The rate of PLE secretion is directly proportional to an increased gastric emptying time. Thus, the solid meals tend to prolong the

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secretion of PLE compared to homogenized meal (Malagelada, 1979). However, the overall pattern

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of PLE secretion in response to solid meals gradually declines at a very slow pace about 2-3 hours to reach a baseline at inter-digestive system, compared to slightly faster pace for homogenized meal

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(Keller, 1997; Dukehart, 1989; Miller, 1979; Beglinger, 1985; Vidon, 1988). 1.5. Pathophysiology of triglyceride breakdown

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Deeper understanding the mechanism involved in the triglyceride breakdown is critical and the process can be attained by lipase enzyme targets. Consumption of dietary fats is the key intake which constitutes a major source of mixed triglycerides, which undergoes absorption in the gastrointestinal tract by various biochemical reactions. Human lipase consists of a large number of a

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family which includes pancreatic, endothelial, hepatic and other lipoprotein lipases that possess structural resemblance. Pancreatic acinar cells secrete PLE, which shows its actions in the intestine and plays a key role in the breakdown of DTG into FFA’s and monoacylglycerol. The incomplete breakdown of dietary fats in stomach form larger fat globules that undergo hydrolysis to form small droplets of fat and together with bile salts it becomes small emulsion

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droplets, known as chylomicrons. The chylomicrons mainly contain diglycerides (DG) and TG in the middle and followed by a large number of mixtures of lipids, cholesterol, phospholipids, fatty acids, bile salts and denatured proteins that are present in the complex structure. The complete breakdown of dietary fats consequences into release of excessive amount of FFA’s into the system. The breakdown products including, monoacylglycerol (MAG) and diacylglycerol (DAG) completely adhere with fat globules and further absorbed by the intestinal cells. The enzyme colipase acts as the

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cofactor for PLE in facilitating the hydrolysis and breakdown of TG. Furthermore, colipase helps

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lipase to bind on the surface and reverses the phosphatidyl choline-mediated inhibition of enzymesubstrate complex (Shi, 2004; Mukherjee, 2003). The expression of PLE expression is abundant in

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all adult vertebrates (D’Agostino, 2002). PLE enzyme activity is optimal at the pH of 8.5, but found

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to be very active in pH 6.5 and least active in pH 4.0 (Holt, 1972).

The enzyme has highly potent activity against water-insoluble substrates, namely

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triacylglycerols (TAGs) (Verger, 1997). So, when the oil/water interface comes into effect, the enzyme gets activated and released and thus helps in the hydrolysis of TG (Wickham, 1998).

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Further, the enzyme adheres nonspecifically to the surface at a high affinity which consists of acylglycerol and non-polar compounds. It has a strong binding towards phospholipids and cholesterol (Verger, 1984; Andersson, 1996). Lipase precisely targets the acyl groups containing the 1(3)position of the glycerol moiety which presents lesser specificity (Brockerhoff, 1974; Schonheyder,

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1946; Laws, 1963; Sayari, 2000).

1.6. Conventional pancreatic lipase inhibitors Orlistat, a tetrahydrolipstatin (THL) obtained from S. toxytricini species, a strong inhibitor of

PLE (Weibel, 1987; Luthi-Peng, 1992). THL contains hydrophobic moieties, which contains two hydrocarbon chains that are bound with lactone ring and a side chain containing leucine and three

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fatty acids that are present on the sides of the fat droplets (McNeely, 1998). The mechanism by which orlistat breaks down the TG are discussed as per the previously reported substrate method, (Gubernator, 1993; Weiner, 1981; Brooks, 1983) in which the intermediate tetrahedral beta lactone falls, thus causing the ring to open. In the catalytic serine the formed hydroxy ester linkage group is limited towards the protein environment through a narrow cleft below the active site. Thus, the ester

water; therefore, it acylates the enzyme and causes it to be inactivated.

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1.7. Key role of pancreatic lipase in lipid digestion

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group is being protected from the hydroxy group and helps in the removal of the acyl group in the

The breaking down of fat globules in the duodenum into tiny droplets is an essential step in

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lipid digestion (Carey, 1983; Armand, 1994; Armand, 1996). The PLE catalyzes TAG by linking

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water-soluble and insoluble substrates and appear as a large emulsion particle (Entressangles, 1968; Brockman, 1984). As a result, the lipases work on emulsion droplets on the surface to completely

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change the physical properties by the process of hydrolysis (Prentki, 2008). The typical features suggest mainly is PLE’s specificity against the insoluble substrates (Verger, 1997). Once the

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hydrophilic head and hydrophobic tail interacts in the small intestine, it activates the enzyme; this takes place as soon as it comes across an oil/water interface to support hydrolysis. One interesting target in the management of obesity is by altering the metabolism of lipid by inhibiting PLE activity is an interesting approach and safer towards the development of an anti-obesity drug with lesser side

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effects (Chanoine, 2005).

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Figure 3. The mechanism of PLE inhibitors in TG breakdown. During hydrolysis, lipases

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present in GI tract breaks down fat (TG) into smaller molecules, which are absorbed through duodenal mucosa and in the step 5 lipase inhibitors bind to lipases and inactivate the enzyme,

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and thus leads to excretion of the undigested fat with faeces. The mechanism of PLE inhibitors in the digestion of TG is shown in figure 3. The inhibitor of lipase covalently binds at the active site to the hydroxyl group and forms many stable complexes (Medeiros-Neto, 2003; Al-Suwailem, 2006; Bray, 2007). Therefore, this confirms the structural

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modifications on the enzyme and exposes catalytic site. Once active site is visible, the serine residue containing hydroxyl groups are acylated and thus causing to irreversible inactivation of the enzyme. The inactivated enzyme does not play any role on hydrolyzing fats into fatty acids (FAs) and monoglycerides and thus the undigested TG’s are excreted through faeces (Al-Suwailem, 2006; Padwal, 2008; Gras, 2013) (Wilding, 2008).

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1.8. In-vitro reported Data 1.8.1. Pancreatic lipase inhibitors from the plant source The hidden potential of plant-based phyto-molecules inhibiting PLE and consequently eliciting anti-obesity properties strongly warrant the systematic approach to collate the scientific reports that establish the proof of concepts in experimental conditions both in-vitro and in-vivo. A wide range of phyto-molecules from medicinal plants were reported to poses anti-obesity effects (Birari, 2007;

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Mole, 1986; Griffiths, 1979; Haslam, 1989). However, the understanding whether or not these

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phyto-molecules elicit anti-obesity effects via inhibition of PLE is unknown. The following sections collate and critically appraise them in detail. The deeper understanding of molecules i.e. isolating,

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identifying and characterizing are indeed needed to find out potent PLE inhibitors and also the

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synergistic effects with the multiple nature of the compounds complicating the outcomes. The mechanism by which plants or phyto-molecules acts on PLE could be either reversible or

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irreversible inhibition, although a wide number of studies have reported to show that the secondary metabolites possess non-competitive type of PLE inhibition (Sergent, 2012). The binding phyto-

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molecules nonspecifically on the active sites of PLE might form soluble or insoluble complexes (Mole, 1986). Hence, the recent approaches start utilizing in-silico computational modeling approaches to find out the interaction of phyto-molecules with specific active binding site of PLE. Further, this review concentrate and systematically covers one of the major drug moieties in plants

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and also largely reported for its profound inhibitory effects on PLE, the phenolics including flavonoids, saponins, alkaloids and terpenoids. 1.8.2. Flavonoids. Flavonoids are a class of plant metabolites, which contains a large number

of polyphenolic grouping structure and are found abundant in plants (Spencer, 2008; Manach, 2004). They play a potential role in protecting the plants against environmental stressors, were a large

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proportion of flavonoidal molecules were found in leaves. The other plant parts that have rich flavonoids contents are fruits (orange juice and berries etc.) and vegetables (broccoli) (Assini, 2013). The ring structure of flavonoid contains two benzopyran rings (A and C) and a benzene ring (B) (Spencer, 2008). The flavonoids are subdivided into different subclass: flavanols, flavanones, flavones, dihydroflavonoles, anthocyanidins, bi-and isoflavonoids (Wollgast, 2000). This classification is based on the oxidation of the carbon ring in 3rd position and thus causing

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hydroxylation (Bhagwat, 2013). In regards to the specific role of flavonoids on PLE, the inhibitory

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potential of flavonoids (IC50) were listed in Table 2. The results indicate that plants rich in

flavonoids have demonstrated potential of inhibiting PL effectively. Selectively, Batubara et al.,

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screened Intsia palembanica and have isolated potential flavonoid from this plant includes (−)-

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robidanol, (+)-epirobidanol, 4′ dehydroxyrobidanol, fustin, naringenin, robinetin, myricetin, quercetin and 3,7,3′,5′-tetrahydroxyflavone. These compounds were screened for In-vitro PLE

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activity using 2, 3-dimercapto-1-propanoltributyrate as a substrate. The findings report that out of 10 compounds tested 7 showed PLE imbibition with IC50 ranges from 13.7- 835.0 µM. Of note, the

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following compounds namely (+)-epirobidanol, robinetin and naringenin exhibited potent inhibition of PLE (Batubara, 2014). Similarly, Assini et al., have reported that the flavonoids in citrus fruits such as naringenin, hesperidin and tangeretin elicit potent PLE inhibition (Assini, 2013). The inhibitory activities of catechin and rutin on PLE were well detected by using 4-nitrophenyl

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octanoate as substrate (Marrelli, 2014). The methanolic extract from Eremochloa ophiuroides contains C-glycoside flavones that showed a potential inhibitory effect using p-nitrophenyl-butyrate as substrate showing IC50 values 18.5-50.5 µM. Also, a number of studies reported that the flavones containing C-glycosyl group at the C6 position with two sugar moieties showed the highest PL inhibitory activity (Lee, 2010). The catechin, epicatechin, rutin, quercitrin, hesperidin and cyanidin-

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3-glucoside obtained from the aqueous extract of Litchi chinensis has shown PLE inhibition as well (Wu, 2013). Zhang et al., have shown flavonoids from Xanthoceras sorbifolium, which plays a role in reducing olein content of the substrate and decrease the lipase enzyme activities. The plant Capparis sicula have been reported to poses PLE inhibitory potential with IC50: 0.53±0.03mg/ml (Zhang, 2014). Kawaguchi and his colleagues reported that the hydroxy groups at the 3rd position along with the methoxy group in the 4th position of hesperidin and neohesperidin have showed

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potent PLE inhibition (Kawaguchi, 1997). PLE inhibition assay carried out using 4-MUO has

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demonstrated that among various extracts of Eryngium bornmuelleri, the extracts containing high phenolic compound, rutin showed potent activity. (Dalar, 2014) Likewise, Nakai et al., reported that

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Camellia sinensis is the rich source of polyphenols and the compounds including flavan-3-esters,

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epigallo-catechin-3,5-digallate has showed potent PLE inhibition with the IC50 of 0.098µM using 4MUO as substrate (Nakai, 2005). Conversely, the catechin and epicatechin a non-esterified flavan-3-

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ols exhibited less activity against PLE (IC50: >20µM) when compared to flavan-3-esters, suggesting the key role of galloyl moieties in accessing the active site of PLE and inhibition of PLE. Thomas

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et al., also report the inhibitory effect of fermented (0.28µg/mL) and unfermented (0.91µg/mL) activity on oolong tea (Thomas, 2014). Yuda et al., showed the activity on hot water extracts of C. sinensis, where it showed highest inhibition at 100°C to 140°C, however the hot extract prepared above 150°C has reduced activity. Gu et al. analyzed the proanthocyanins from the Theobroma

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cacao and reported that proanthocyanins is majorly responsible for the lipase activity (Yuda, 2012; Tsuchida, 2002; Gu, 2011). Shimura et al., studied the effect of luteolin from Chamaecrista nomame and reported that glycosylation mainly affect and modulate PLE activity showed with an IC50 of 7.1µM (Shimura, 1994). You et al., reported the activity in Vitis rotundifolia methanolic extracts that showed an IC50 of 11.15 and 16.90 mg/ml. The anthocyanins such as cyanidin, delphinidin,

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petunidin, peonidin and malvidin glycosides in grape extract were tested using various techniques and the result revealed that cyanidin and cyanidin-3,5-diglucoside showed stronger inhibition with an IC50 of 1.8µM and 1.38mM (You, 2011; Keller, 2001). Cha et al., reported the activity of Ligularia fischeri extracts that showed an IC50 of 1.38 µg/ml and identifying (−)Epigallocatechin3O-gallate that showed an IC50 of 1.8µM (Cha, 2012). Kato et al., reported the effect of flavonoids 3-O‑ b-xylopyranosyl (1→2)-O‑ b-galactopyranoside and 3-O-caffeoyl-4-O-

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galloyl-L-threonic acid that showed an IC50 of 300.00µM and 26 µM (Kato, 2012). Jeong et al.

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isolated a compound 5,7,4′-Trihydroxy-6,8diprenylisoflavone from Cudrania tricuspidata and a

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showed PLE inhibition with IC50 of 65.0µM (Jeong, 2014). Sakulnarmrat et al., reported that the methanolic extract of Santalum acuminatum containing compounds cyanidin-3 glucoside and

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quercetin that has an IC50 of 0.6mg/mL (Sakulnarmrat, 2014). The extracts of Alpinia galangal and

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Alpinia officinarum showed an IC50 of 48.20mg/ml and 3 mg/mL, respectively. It was proposed that the compounds galangin and 3-methylgalangin could be responsible for the PLE inhibition. (Kumar, 2013; Singh, 2015; Lunagariya, 2014). Lunagariya et al., have reported the PLE inhibitory activity

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for Nelumbo nucifera and showed an IC50 of 0.46 mg/mL. FurtherTao et al., identified three compounds from Nelumbo nucifera namely kaempferol-3-O-β-dglucuronide, quercetin-3-O-β-Darabinopyranosyl-(1→2)β-D-galactopyranoside and quercetin-3-O-β-D-glucuronide and reported

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with an IC50 of 66.86µM - 135.01µM (Tao, 2013; Lunagariya, 2014). Lunagariya et al., have studied its effects on Cassia sp and identified (2S)-3,4,7-Trihydroxyflavan-(4α-8)-Catechin, flavan (2S)3′,4′,7-trihydroxyflavan-(4α→8)-catechin and Bianthraquinone and reported with an IC50 of 5.5-41.8 µM (Lunagariya, 2014). Singh et al., have studied its effects on Glycyrrhiza sp. and identified Isoliquiritigenin, 3,3′,4,4′tetrahydroxy-2-methoxychalcone and Licochalcone A and reported with an IC50 ranges from 7.3-35.5 µM (Singh, 2015). Yoshikawa et al., reported on Salacia reticulata that 21

showed an IC50 of 264 mg/L on PL inhibition (Yoshikawa, 2002). Mukherjee et al., have studied on aqueous and methanolic extracts of Eugenia jambolana, Tinospora cordifolia, Azadirachta indica and Trigonell foenum graceum and reported with an IC50 of 285±15 and 230±20, 404±13 and 323±11, 543±15 and 476±14, 613±11 and 564±12, respectively (Mukherjee, 2013). Jaradat et al., reported that methanolic and aqueous extracts of Arum palaestinum, Crataegus azarolus, Malva parviflora, Taraxacum syriacum, Rhus coriaria, Rosmarinus officinalis, Psidium guajava, Brassica

of

nigra, Vitis vinifera and are reported with an IC50 of 147.9±2 and 107.2±2, 40.7±1.8 and 83.2±1.9,

ro

23.7±3 and 28.2±2.4, 74.1±2.2 and 39.8±1.8, 30.2±1.5 and 19.95±2.8, 65±2 and 51.3±2.4, 64.6±2 and 87.1±1.4, 66.1±2.1 and 47.9±2.4, 28.8±2.5 and 14.1±1.9 and compared with orlistat which

-p

showed an IC50 value of 12.38±2.3 µg/mL, respectively (Jaradat, 2017). Likewise, Long et al., have

re

studied the activity of methanolic and aqueous extracts of Origanum dayi and reported with an IC50 of 18.6±2.6 and 26.9±2 (Long, 2011). Singh et al., studied the activities of Erythrina abyssinica,

lP

Broussonetia kanzinoki, Aronia melanocarpa and Vigna sp. and identified the compounds eriodictyol and sigmoidin A, broussonone A and reported with an IC50 value of 134±19.39 and

ur na

4.5±0.87 µM, 28.4 µM, 1.17±0.05 mg/ml and 7.32 to 9.85 mg/ml, respectively (Singh, 2015). Marrelli et al., reported that the extracts obtained from the aerial parts of Leopoldia comosa using different solvent fractions such as hydro-alcoholic, n-hexane, chloroform and acetone, showed that n-hexane and acetone fractions has potent PLE inhibition with an IC50 value of 0.369 ± 0.020 and

Jo

0.336 ± 0.007, whereas the raw extract (3.819 ± 0.119) and chloroform (1.409 ± 0.033) showed less PLE inhibitory action, which was compared with orlistat (0.018 ± 0.001), respectively (Marrelli, 2019). Likewise, one of the recent study by Casacchia et al., report that the bulb extract of Leopoldia comosa showed significant inhibitory action on PLE with IC50 value of 70.5 ± 0.89

22

µg/mL, which was compared with orlistat and showed an IC50 value of 57.20 ± 0.19 µg/ mL respectively (Casacchia, 2019). Source

Phytocompounds

The IC50 value

The IC50 value

of the extract

of compound

Reference

and it’s scoring Flavonoids

(Pubchem CID:72276)

(water extract)

(+)Catechin

44.69:7mg/mL

(Pubchem CID:9064)

(water extract)

-

(Wu, 2013)

of

44.69:7mg/mL

ro

(−)-Epicatechin

(Wu, 2013)

-

(Wu, 2013)

-

(Wu, 2013)

-p

-

lP

re

Litchi chinensis

44.69:7mg/mL

(Pubchem CID:252359175)

(water extract)

Jo

ur na

Neohesperidin

Quercitrin

(Pubchem CID:5280459)

44.69:7mg/mL (water extract)

23

Rutin (Pubchem CID:5280805)

-

(Wu, 2013)

2.582µM

(Nakai,

44.69:7mg/mL

(−)-Epiafzelechin 3-Ogallate (Pubchem CID:467295)

(31)

2005)

re

(−)-Epicatechin 4β‑ 8) (−)-

-p

ro

Camellia Sinensis

1.38 µg/ml

of

(water extract)

1.38 µg/ml

0.147µM

1.38 µg/ml

0.680µM

lP

epigallocatechin3O-gallate(SNA) (−)-Epicatechin3-O-(3′Omethyl)gallate

(6)

(22)

(Nakai, 2005) (Nakai, 2005)

Jo

ur na

(Pubchem CID:11420256)

(−)-Epicatechin-3-Ogallate (Pubchem CID: 10790)

1.38 µg/ml

0.452µM (16),

(Nakai,

2.37µM (30)

2005; Yuda,

and

2012 ;

13µM (45)

Shimura, 1994)

24

(−)-Epicatechin3-

1.38 µg/ml

Ogallate(4β‑ 8)-(−)-

0.846µM (24)

(Nakai, 2005)

epigallocatechin3-O-gallate(SNA)

(−)-Epigallocatechin

1.38 µg/ml

(Yuda, 2012)

(72)

(−)-Epigallocatechin (4β‑ 8)-

1.38 µg/ml

(−)-epicatechin 3-O-gallate

ro

of

(Pubchem CID:72277)

128µM

0.913µM

2005)

-p

(26)

(Nakai,

lP

re

(Pubchem CID:46181828)

ur na

(−)-Epigallocatechin 3,5-di-Ogallate

1.38 µg/ml

0.098µM (2)

(Nakai, 2005)

Jo

(Pubchem CID:467299)

25

(−)-Epigallocatechin3O-gallate

1.38 µg/ml

(Pubchem CID:65064)

0.349µM (12),

(Nakai,

0.177µM (9)

2005; Yuda,

(−)-Epigallocatechin3Ogallate(4β-8)(−)-epicatechin3-

(20)

(Nakai, 2005)

lP

re

-p

Ogallate (Pubchem CID: 46181828)

0.612µM

ro

1.38 µg/ml

of

2012)

1.38 µg/ml

ur na

(−)-Epigallocatechin3O‑ pcoumaroate

0.885µM (25)

(Nakai, 2005)

Jo

(Pubchem CID:6474788)

(−)-Epigallocatechin3,5di-Ogallate

1.38 µg/ml

0.213µM (10)

(Nakai, 2005)

(Pubchem CID:467299)

26

(−)-Gallocatechin3-Ogallate

1.38 µg/ml

(14)

(Nakai, 2005)

(+)-Catechin(4R‑ 8)(−)-

1.38 µg/ml

7.912µM (42),

(Nakai,

0.174µM (8)

2005)

2.862µM

(Nakai,

-p

epigallocatechin

ro

of

(Pubchem CID:5276890)

0.437µM

lP

re

(Pubchem CID:72277)

(+)Gallocatechin (4R‑ 8)-(−)-

(32)

ur na

epicatechin

1.38 µg/ml

2005)

Jo

(Pubchem CID:14284599)

8-C-ascorbyl(−)epigallocatechin

1.38 µg/ml

0.646µM (21)

(Nakai, 2005)

(Pubchem CID:3001587)

27

8-C-ascorbyl(−)-

1.38 µg/ml

0.791µM

epigallocatechin3-O-gallate

(23)

2005)

-p

ro

of

(Pubchem CID:14520973)

(Nakai,

4.10µg/mL

(Pubchem CID:5281614)

(MeOH extract)

lP

ur na

Ampelopsin

re

3,7,3′,5′-Tetra hydroxyflavone

(Pubchem CID:161557)

4.10µg/mL (MeOH extract)

835.0µM (85)

36.0µM (60)

(Batubara, 2014)

(Batubara, 2014)

Jo

lip

ProcyanidinB-2 (Pubchem CID:122738)

1.38 µg/ml

7.958µM (43)

(Nakai, 2005)

28

ProcyanidinB-3

1.38 µg/ml

(33)

(Nakai, 2005)

ProdelphinidinA-23′O-gallate

0.171µM (7)

(Nakai, 2005)

ur na

lP

re

-p

(Pubchem CID:14521014)

1.38 µg/ml

ro

of

(Pubchem CID:146798)

2.941µM

ProdelphinidinB-2

1.38 µg/ml

(34)

(Nakai, 2005)

Jo

(Pubchem CID:5089687)

2.951µM

ProdelphinidinB-23,3′di-Ogallate

1.38 µg/ml

0.107µM (4)

(Nakai, 2005)

29

ProdelphinidinB-23′O-gallate

1.38 µg/ml

1.969µM (29)

(Nakai, 2005)

lP

re

-p

ro

(Pubchem CID:14521014)

of

(Pubchem CID:467306)

1.38 µg/ml

ur na

ProdelphinidinB-4

Jo

(Pubchem CID:14009028)

ProdelphinidinB-23′O-gallate (Pubchem CID: 14521014)

6.230µM (38)

1.38 µg/ml

0.223µM (11)

(Nakai, 2005)

(Nakai, 2005)

30

1.38 µg/ml

gallate

0.558µM (19)

2005)

lP

re

-p

ro

(Pubchem CID: 467306)

(Nakai,

of

ProdelphinidinB-23,3′di-O-

Jo

ophiuroides

Derhamnosylmaysin

ur na

Eremochloa

-

(Pubchem CID:44257945)

6-C-β‑ D-boivinopyranoside

(Lee, 2010)

(53)

-

(Pubchem CID:21629594)

Isoorientin

25.9µM

50.5µM

(Lee, 2010)

(64)

-

44.6µM

(Lee, 2010)

31

(Pubchem CID:114776)

(63)

Isoorientin2-O-α-Lrhamnoside

-

18.5µM (50)

-

31.6µM

(Lee, 2010)

-p

Orientin

ro

of

(Pubchem CID:44258057)

(Lee, 2010)

(56)

lP

re

(Pubchem CID:5281675)

Methyl chlorogenate

-

ur na

(Pubchem CID:6476139)

Jo

Licochalcone A

(57)

-

(Pubchem CID:5318998)

Chamaecrista

Luteolin

nomame

(Pubchem CID:5280445)

33.6±2.0 µM

35 µg/mL (106)

-

7.1µM (40)

(Lunagariya, 2014)

(Lunagariya, 2014)

(Shimura, 1994)

32

4.10µg/mL

337.5 µM

(Pubchem CID:5281672)

(MeOH extract)

Fustin

4.10µg/mL

(Pubchem CID:5317435)

(MeOH extract)

Quercetin

4.10µg/mL

(81)

2014)

ro

13.7µM

-p

(46)

(MeOH extract)

421.1µM (82)

(Batubara, 2014)

(Batubara, 2014)

ur na

lP

(Pubchem CID:5280343)

(Batubara,

of

Myricetin

re

Intsia palembanica

Citrus reticulata

Neohesperidin

-

(68)

(Kawaguchi, 1997)

Jo

(Pubchem CID:252359175)

75.3µM

Hesperidin (Pubchem CID:10621)

-

52.4µM (65)

(Kawaguchi, 1997)

33

Santalum

Quercetin

0.6mg/mL

acuminatum

(Pubchem CID:5280343)

[80% (v/v)

-

(Sakulnarmr at, 2014)

Quercetin-3-O-β-D-

-

66.86µM

ro

Nelumbo nucifera

of

MeOH extract]

arabinopyranosyl-(1→2)β-D-

(Tao, 2013)

(67)

-p

galactopyranoside

lP

re

(Pubchem CID:5484066)

ur na

Quercetin-3-O-β-D-

-

glucuronide

135.01µM

(Tao, 2013)

(75)

Jo

(Pubchem CID:5274585)

Kaempferol-3-O-βdglucuronide

-

94.00µM

(Tao, 2013)

(70)

34

(Pubchem CID:5318759)

-

0.46 mg/mL

-

(Lunagariya, 2014)

5.01mg/mL

bornmuelleri

(Pubchem CID: 5280805)

[80%(v/v)

-

(Tao, 2013)

of

Rutin

ro

Eryngium

Theaflavin

1.38 µg/ml

lP

Camellia sinensis

re

-p

acetone extract]

ur na

(Pubchem CID:114777)

Jo

Theaflavin3,3′-di-Ogallate (Pubchem CID:3589471)

0.106µM (3),

(Nakai,

1.203µM (27)

2005; Yuda, 2012)

1.38 µg/ml

0.092µM (1),

(Nakai,

0.364µM (13)

2005; Yuda, 2012)

35

Theaflavin3′-O-gallate

1.38 µg/ml

(Pubchem CID:3589471)

0.112µM (5),

(Nakai,

0.447µM (15)

2005; Yuda, 2012)

Theaflavin3-O-gallate

1.38 µg/ml

0.514µM (17)

3-O-caffeoyl-4-O-galloyl-L-

kamtschatica

threonic acid(SNA)

lP

Cassia mimosoides

-

re

Filipendula

flavan (2S)-3′,4′,7-

< 0.1 mg/mL

trihydroxyflavan-(4α→8)-

26 µM

(Lunagariya,

(54)

2014; Singh, 2015)

5.5 µM

(Lunagariya,

(36)

2014)

12.7±1.0 μM

(Lunagariya,

(44)

2014; Singh,

ur na

catechin

-p

ro

of

(Pubchem CID:3589471)

(Yuda, 2012)

Jo

(Pubchem CID:131752788)

Eisenia bicyclis

7-Phloroeckol (Pubchem CID:10480940)

-

2015)

36

Glycyrrhiza glabra

Isoliquiritigenin

-

7.3 μM

(Lunagariya,

(41)

2014; Singh,

(Pubchem CID:638278)

3,3′,4,4′tetrahydroxy-2-

of

2015)

35.5 μM

ro

-

methoxychalcone

(59)

re

Bianthraquinone

-

41.8 µM

lP

Cassia siamea

-p

(Pubchem CID:11742190)

ur na

(Pubchem CID:6737485)

Jo

Alpinia officinarum

Salacia reticulata

3-methylglangin

(62)

3 mg/mL

(Lunagariya, 2014; Singh, 2015)

(Lunagariya, 2014)

1.3 mg/mL

(Lunagariya,

(117)

2014; Singh,

(Pubchem CID:5281946)

2015)

-

264 mg/L

-

(Lunagariya, 2014;

37

Yoshikawa, 2002)

Eugenia jambolana

-

285±15

-

(Mukherjee,

(aqueous

2013)

extract),

(MeOH extract) -

404±13 (aqueous

(Mukherjee, 2013)

-p

extract),

-

ro

Tinospora cordifolia

of

230±20

re

323±11

(MeOH extract)

-

543±15

ur na

lP

Azadirachta indica

Trigonell foenum

Jo

graceum

-

Arum palaestinum

-

(aqueous

(Mukherjee, 2013)

extract), 476±14 (MeOH extract) 613±11

-

(aqueous

(Mukherjee, 2013)

extract), 564±12 (MeOH extract) -

147.9±2 (MeOH

-

(Jaradat, 2017)

38

extract), 107.2±2 (aqueous extract) Crataegus azarolus

-

40.7±1.8

-

(Jaradat,

(MeOH

2017)

of

extract),

(aqueous extract) -

23.7±3

-

-p

Malva parviflora

ro

83.2±1.9

2017)

re

(MeOH

(Jaradat,

extract),

Taraxacum

Jo

syriacum

ur na

lP

28.2±2.4

Rhus coriaria

-

(aqueous extract) 74.1±2.2

-

(MeOH

(Jaradat, 2017)

extract), 39.8±1.8 (aqueous extract)

-

30.2±1.5 (MeOH

-

(Jaradat, 2017)

extract),

39

19.95±2.8 (aqueous extract) Rosmarinus

-

65±2

officinalis

-

(Jaradat,

(MeOH

2017)

extract),

of

51.3±2.4

extract) Psidium guajava

-

64.6±2

-

-p

(MeOH

ro

(aqueous

(Jaradat, 2017)

re

extract),

87.1±1.4

-

Jo

ur na

Origanum dayi

lP

(aqueous

Brassica nigra

-

extract) 18.6±2.6

-

(Long, 2011)

-

(Jaradat,

(MeOH extract), 26.9±2 (aqueous extract) 66.1±2.1 (MeOH

2017)

extract), 47.9±2.4 (aqueous

40

extract) Vitis vinifera

-

28.8±2.5

6.7±0.7 µM

(Jaradat,

(MeOH

(39)

2017)

extract), 14.1±1.9 (aqueous

Hesperidin and neohesperidin

32 and

(Pubchem CID:10621 and

46 µg/ml

(Singh, 2015)

Glycyrrhiza

Jo

uralensis

ur na

lP

re

-p

252359175)

-

ro

Citrus unshiu

of

extract)

Licochalcone A

35 µg/ml

-

(Pubchem CID:5318998)

Eremochloa

Methyl chlorogenate

ophiuroides

(Pubchem CID:6476139)

(Singh, 2015)

-

33.6 µM

(Singh,

(58)

2015)

41

Cassia nomame

(2S)-3,4,7-Trihydroxyflavan-

-

(4α-8)-Catechin

5.5 µM

(Singh,

(37)

2015)

Erythrina abyssinica

of

(Pubchem CID: 131752788)

Eriodictyol and Sigmoidin A -

(Singh,

and 4.5±0.87

2015)

ro

(Pubchem CID:440735 and

134±19.39 (74)

µM (35)

Broussonetia

Jo

kanzinoki

-

ur na

Vigna sp.

lP

re

-p

73204)

Aronia melanocarpa

Broussonone A

7.32 to 9.85

-

mg/ml -

(Pubchem CID:57404243)

Cyanidin-3-glucosides

1.17±0.05

(Pubchem CID:44256718)

mg/ml

(Singh, 2015)

28.4 µM

(Singh,

(55)

2015)

-

(Singh, 2015)

42

Xanthoceras

-

0.27mg/mL

-

(Haslam,

sorbifolium

1989; Zhang,

Capparis sicula

-

0.53±0.03mg/m

-

-

3.819 ± 0.119

-

2019;

± 0.89 µg/mL

Casacchia,

(120)

2019)

re lP

*(SNA) – Structure Not Available

(Marrelli,

mg/ml and 70.5

-p

Leopoldia comosa

(Zhang, 2014)

ro

L

of

2014)

Table 2. PLE inhibitory activities of the medicinal plants and flavonoids with their IC50 values.

ur na

1.8.3. Alkaloids

Alkaloids are naturally occurring compounds that contains basic nitrogen atoms in the ring structure. The alkaloidal compounds that contain basic nitrogen atoms are reported to possess PLE inhibitory activity. The alkaloids consumed as a food component such as caffeine,

Jo

theophylline and theobromine has been shown to inhibit the tributyrin and tripalmitate which is catalyzed by PLE in a dose-dependent manner. The percentage of tripalmitate and tributyrin hydrolysis by lipase inhibition at 0.015-15mM concentrations was observed for caffeine (25.74% and 79.54%), theophylline (29.89% and 62.79%) and theobromine (21.08% and 67.74%) respectively (Wikiera, 2012; Lunagariya, 2014). Birari et al., have studied the effect of Murraya koenigii leaves extracts on PLE. The findings demonstrated that methanolic has showed PLE 43

inhibition with IC50 value of 92.2±0.6 mg/ml. Furthermore, the carbazole alkaloids isolated from the methanolic extract including mahanimbin, koenimbin, koenigicine and clausazoline-K has been reported with an IC50 value of 17.9 µM, 168.6 µM, 428.6 µM and <500 µM, respectively (Birari, 2009). Source

Phytocompounds

The IC50 value

The IC50 value

of the extract

of compound

Reference

Alkaloids Caffeine

-

-

ro

Theobroma cacao

of

and it’s scoring

-

-

lP

Theophylline

re

-p

(Pubchem CID:2519)

ur na

(Pubchem CID:2153)

Theobromine

Jo

al., 2012; Lunagariya, 2014)

(Wikiera et al., 2012; Lunagariya, 2014)

-

-

(Pubchem CID:5429)

Murraya koenigii

(Wikiera et

(Wikiera et al., 2012; Lunagariya, 2014)

Mahanimbine

92.2±0.6 mg.ml

17.9 µM

(Birari,

(Pubchem CID:167963)

in MeOH

(49)

2009)

extract

44

Murraya koenigii

Koenimbine

92.2±0.6 mg.ml

168.6 µM

(Birari,

(Pubchem CID:97487)

in MeOH

(78)

2009)

extract

Koenigicine

92.2±0.6 mg.ml

428.6 µM

(Birari,

(Pubchem CID:278055)

in MeOH

(83)

2009)

of

extract

92.2±0.6 mg.ml

<500 µM

(Birari,

(Pubchem CID:10537169)

in MeOH

(84)

2009)

re

-p

extract

ro

Clauszoline K

1.8.4. Saponins

lP

Table 3. PLE inhibitory activities of alkaloids with their IC50 values.

ur na

Another class of compounds targeting PLE is saponins. Yoshizumi et al., have studied the PLE inhibition activity of the leaves of Acanthopanax sessiliflorus and identified sessiloside and chiisanoside are reported with IC50 values of 0.36 and 0.75 mg/mL, respectively (Yoshizumi, 2006). Whereas, Li et al., reported in another species of Acanthopanax senticosus and identified

Jo

that triterpenoid saponins such as silphioside F, copteroside B, hederagenin 3-O-β-Dglucuronopyranoside 6′-Omethyl ester and gypsogenin 3-O-β-D-glucuronopyranoside also have reported to have potent PLE inhibition activity with IC50 value of 0.22, 0.25, 0.26 and 0.29 mM, respectively (Li, 2007). Kurihara et al., studied the effect of leaves of Cyclocarya paliurus on the PLE inhibition and reported that the dammarane type of triterpene saponins, cyclocarioside A, II, and III elicits triglyceride absorption by inhibiting PLE inhibition with an IC50 of 9.1 µg/mL 45

respectively (Kurihara, 2003). Various authors have studied the activity of Platycodin grandiflorum, and identified a saponin platycodin D that showed PLE inhibition and reported with an IC50 of 0.18±0.03 mM (Han, 2000 and 2002; Zhao, 2004; Xu, 2005; Zhao, 2005). Han et al., have studied the effects of Panax japonicas and identified chikusetsusaponin III and IV, 28 deglucosyl-chikusetsusaponins IV and V and reported that the saponins found to inhibit PLE effectively (Han, 2005). Liu et al., have studied the effects of PLE inhibition in another species of

of

Panax i.e. Panax quinquefolium which is reported with 78-98% inhibition (Liu, 2008). Kimura et

ro

al., have studied the effects of Aesculus turbinata and identified three major saponins such as

escins, deacetylescins and desacylescins and showed that Escins Ia and Ib and IIa and IIb showed

-p

effective PLE inhibition with an IC50 values ranging from 14-61 μg/mL (Kimura, 2006). Zheng et

re

al., studied the PLE inhibition activity of Scabiosa tschiliensis and showed with an IC50 of 0.12 mg/mL and identified scabiosaponins including scabiosaponin E-G, scabiosaponin I, hookeroside

lP

A and B and prosapogenin 1b, were prosapogenin 1b and believed that these compounds could possess the PLE inhibition that is to be evaluated in future (Zheng, 2004). Han and Yoshikawa

ur na

studied the effects on tea saponins in Camellia sinensis such as chakasaponins I, II, and III and reported to have a PLE inhibition with an IC50 value 0.17, 0.18 and 0.53 mM respectively (Han, 1999; Han, 2001; Yoshikawa, 2009). Kwon et al., studied the PLE inhibition activity on the roots of Dioscorea nipponica, showed that the saponins such as dioscin, diosgenin, prosapogenin A and

Jo

C and gracillin showed PLE inhibition and reported with an IC50 of 20, 28, 1.8, 42.2, and 28.9 µg/mL, respectively (Kwon et al., 2003). Similar studies have been carried out by Li and his colleagues on the same plant Dioscorea nipponica and showed the compounds dioscin, diosgenin, prosapogenin A and C and gracillin possessed PLE inhibition activity with an IC50 of 0.25, 0.26, 0.22 and 0.29 mM respectively (Li, 2007). Sugimoto et al., studied the effect from the leaves of

46

Ilex paraguariensis and identified matesaponin 1, nudicaucin C and 3-O-α-Lrhamnopyranosyl(1→2)-α-L-arabinopyranosyl oleanolic acid 28-O-β-D-glucopyranosyl(1→6)βD-glucopyranoside that showed potent PLE inhibitory activity with 94, 78, 77 and 83 % inhibition at 100 µM concentration respectively (Sugimoto, 2009). Zheng et al., studied the effects of Gypsophila oldhamiana and identified triterpenoidal saponins such as gypsosaponins A, B, and C and reported with a PLE inhibition of 58.2%, 99.2% and 50.3% respectively (Zheng, 2007). Karu

of

et al., studied the effects of Panax ginseng and isolated ginseng saponin that showed PLE

ro

inhibition activity with an IC50 of 500 µg/mL (Karu, 2007). Morikawa et al., have studied the

activity of Sapindus rarak and identified rarasaponins I and II, raraoside A and saponin E1 and

-p

showed PLE inhibition activity with an IC50 of 131 and 172 μM, 151 μM and 270 μM respectively

Phytocompounds

Saponins

lP

Source

re

(Morikawa, 2009).

Sessiloside

sessiliflorus

(Pubchem CID:11593218)

The IC50 value

of the extract

of compound

-

Reference

and it’s scoring

0.36 mg/ml

(Yoshizumi,

(113)

2006)

0.75 mg/ml

(Yoshizumi,

Jo

ur na

Acanthopanax

The IC50 value

Chiisanoside

-

47

(Pubchem CID:21626427)

Silphioside F

senticosus

(Pubchem CID:176079)

-

2006)

0.22 mM

(Li, 2007)

(89)

Copteroside B

-

0.25 mM

(Li, 2007)

(90)

lP

re

(Pubchem CID:158891)

-p

ro

of

Acanthopanax

(115)

hederagenin 3-O-β-D-

-

glucuronopyranoside 6′-

0.26 mM

(Li, 2007)

ur na

(91)

Omethyl ester

Jo

(Pubchem CID:13518139)

Gypsogenin 3-O-βDglucuronopyranoside

-

0.29 mM

(Li, 2007)

(92)

(Pubchem CID:21626375)

48

Cyclocarya paliurus

Cyclocarioside A

9.1 µg/mL

-

(Kurihara, 2003)

Cyclocarioside II(SNA)

Cyclocarioside III(SNA)

re

9.1 µg/mL

Platycodin D

-

grandiflorum

(Pubchem CID:162859)

lP

Platycodin

-

-p

9.1 µg/mL

ro

of

(Pubchem CID:3036134)

-

(Kurihara, 2003) (Kurihara, 2003)

0.18±0.03 mM

(Han, 2000

(88)

and 2002; Zhao, 2004;

ur na

Xu, 2005;

-

-

(Han, 2005)

Chikusetsusaponin IV

-

-

(Han, 2005)

Panax japonicas

Chikusetsusaponin III

Zhao, 2005).

Jo

(Pubchem CID:3036903)

(Pubchem CID:15602013)

49

28 deglucosyl-

-

-

(Han, 2005)

-

-

(Han, 2005)

-

-

-

Escins Ia and Ib and IIa and IIb

-

chikusetsusaponins IV 28 deglucosyl-

Panax

Aesculus turbinata

14-61 μg/mL

(100)

-p

(Pubchem CID: 6476030,

ro

quinquefolium

(Liu, 2008)

(Kimura, 2006)

re

6476031, 10079858 and

of

chikusetsusaponins V(SNA)

lP

10260627)

ur na

Deacetylescins(SNA)

Desacylescins

-

-

(Kimura, 2006)

-

-

2006)

Jo

(Pubchem CID:115866)

(Kimura,

Scabiosa tschiliensis

Scabiosaponin

0.12 mg/mL

-

Zheng, 2004)

(Pubchem CID: 21577271)

50

-

of

-

Zheng, 2004)

ro

Scabiosaponin I

ur na

lP

re

-p

(Pubchem CID: 21577271)

Hookeroside

-

-

Zheng, 2004)

-

0.12 mg/ml

Zheng, 2004)

Jo

(Pubchem CID:21577284)

Prosapogenin (Pubchem CID: 11061578)

(112)

51

Camellia sinensis

Chakasaponins I

-

(Pubchem CID:56672267)

0.17 mM

(Han, 1999;

(86)

Han, 2001; Yoshikawa,

-

0.18 mM

-p

Chakasaponins II

ro

of

2009)

(87)

lP

re

(Pubchem CID:56661893)

ur na

Chakasaponins III

-

Jo

(Pubchem CID:56675661)

Dioscorea nipponica Dioscin (Pubchem CID:119245)

(Han, 1999; Han, 2001; Yoshikawa, 2009)

0.53 mM

(Han, 1999;

(93)

Han, 2001; Yoshikawa, 2009)

-

20 µg/mL and

(Kwon,

0.25mM

2003; Li,

(101)

2007)

52

Diosgenin

-

Prosapogenin

(Kwon,

0.26 mM

2003; Li,

(103)

2007)

of

(Pubchem CID:99474)

28 µg/mL and

-

(Kwon,

µg/mL and 0.22

2003; Li,

mM

2007)

-p

ro

(Pubchem CID:11061578)

1.8 and 42.2

Gracillin

re

(97)

-

ur na

lP

(Pubchem CID:159861)

Ilex paraguariensis

Matesaponin 1

-

28.9 µg/mL and

(Kwon,

0.29 mM

2003; Li,

(104)

2007)

-

(Sugimoto, 2009)

Jo

(Pubchem CID:44575759)

Nudicaucin B (Pubchem CID:102316453)

-

-

(Sugimoto, 2009)

53

3-O-α-L-

-

-

(Sugimoto,

rhamnopyranosyl(1→2)-α-L-

2009)

arabinopyranosyl oleanolic acid

of

28-O-β-Dglucopyranosyl(1→6)β-D-

oldhamiana

(Pubchem CID:16655287)

Platycodin

Platycodin D

grandiflorum

(Pubchem CID:162859)

-

-

-p

Gypsosaponins A

(Zheng, 2007)

ur na

lP

re

Gypsophila

ro

glucopyranoside(SNA)

Jo

Panax ginseng

Senegasaponin A

(Pubchem CID:71627223)

-

-

(Zhao, 2004; Zhao, 2005)

-

500 µg/mL

(Karu, 2007)

(111)

54

Sapindus rarak

Rarasaponins I (SNA)

-

Raraoside A

-

(73)

2009)

151 μM

(Morikawa,

(76)

2009)

270 μM

-

ro

Arasaponin E1

(Morikawa,

of

(Pubchem CID:102479008)

131 and 172 μM

(79)

2009)

re

-p

(Pubchem CID:73148)

(Morikawa,

lP

*(SNA) – Structure Not Available

Table 4. PLE inhibitory activities of saponins with their IC50 values.

ur na

1.8.5. Terpenoids

Terpenoids are naturally occurring compounds that are majorly derived from group terpenes. Lee et al., studied the effects on aqueous extract of Gardenia jasminoides and identified terpenoidal compounds such as crocin and crocetin and showed PLE inhibition activity with an

Jo

IC50 of 2.1 and 2.6 mg/mL respectively (Lee, 2005). Jang et al., studied the activity of Actinidia arguta and isolated 3-O-trans-p-coumaroyl actinidic acid, ursolic acid, 23-hydroxyursolic acid, corosolic acid, asiatic acid and betulinic acid that are reported with PLE inhibitory activity with an IC50 of 14.95 ± 0.21, 15.83 ± 1.10, 41.67 ± 0.66, 20.42 ± 0.95, 76.45 ± 0.51 and 21.10 ± 0.55 µM respectively (Jang, 2008). Ninomiya et al., studied the effects of Salvia officinalis and identified compounds carnosic acid, carnosol, roylenoic acid, 7-methoxyrosmanol and oleanolic acid that are 55

reported with PLE inhibitory activity with an IC50 of 12, 4.4, 35, 32 and 83 µg/mL, respectively (Ninomiya, 2004). Bustanji et al., studied the effects of Ginkgo biloba and isolated trilactone terpenes such as ginkgolides A and B and bilobalide that showed PLE inhibition with an IC50 values of 22.9, 90.0 and 60.1 µg/ml respectively (Bustanji, 2011). Ahn et al., studied the effects of Fraxinus rhynchophylla and isolated Secoiridoids, ligstroside, oleuropein, 2-hydroxyoleuropein and hydroxyframoside B and showed PLE inhibitory activity (Ahn, 2013). Yamada et al., isolated

of

carvacrol from Monarda punctata and reported to have PLE inhibitory activity with an IC50 value

ro

of 4.07 mM (Yamada, 2010). Luyen et al., isolated sesquiterpene lactone such as 10α-hydroxy1α,4αendoperoxy-guaia-2-en-12,6α-olide from Chrysanthemum morifolium that showed PLE

Phytocompounds

The IC50 value

The IC50 value

of the extract

of compound

re

Source

-p

inhibition with an IC50 value of 161.0 µM (Luyen, 2013).

lP

Terpenoids Crocin

jasminoides

(Pubchem CID:5281233)

-

and it’s scoring

2.1 mg/mL

(Lee, 2005)

(118)

Jo

ur na

Gardenia

Reference

56

of ro Actinidia arguta

lP

(Pubchem CID:5281232)

3-O-trans-p-coumaroyl

-p

-

re

Crocetin

-

(Lee, 2005)

(119)

14.95 ± 0.21 µM (Jang, 2008) (47)

ur na

actinidic acid

2.6 mg/mL

Jo

(Pubchem CID:70680259)

Ursolic acid (Pubchem CID:649450

-

15.83 ± 1.10 µM (Jang, 2008) (48)

57

23-hydroxyursolic acid

-

41.67 ± 0.66 µM (Jang, 2008) (61)

-

20.42 ± 0.95 µM (Jang, 2008)

-p

Corosolic acid

ro

of

(Pubchem CID:14136881)

(51)

Asiatic acid

lP

re

(Pubchem CID:6918774)

-

Jo

ur na

(Pubchem CID:119034)

Betulinic acid

(Pubchem CID:64971)

76.45 ± 0.51 µM (Jang, 2008) (69)

-

21.10 ± 0.55 µM (Jang, 2008) (52)

58

Salvia officinalis

Carnosic acid

-

(Pubchem CID:65126)

Carnosol

-

(Ninomiya,

(99)

2004)

4.4 µg/mL

(Ninomiya,

(98)

2004)

-

35 µg/mL

(Ninomiya,

(107)

2004)

32 µg/mL

(Ninomiya,

(105)

2004)

83 µg/mL

(Ninomiya,

(109)

2004)

22.9 µg/ml

(Bustanji,

(102)

2011)

ur na

lP

(Pubchem CID:46883406)

re

7-methoxyrosmanol

-

-p

Roylenoic acid(SNA)

ro

of

(Pubchem CID:442009)

12 µg/mL

Oleanolic acid

-

Jo

(Pubchem CID:10494)

Ginkgo biloba

Ginkgolides A (Pubchem CID:9909368)

-

59

Ginkgolides B

-

(Bustanji,

(110)

2011)

Bilobalide

-

60.1 µg/ml

(Bustanji,

(108)

2011)

-

-

(Ahn, 2013)

-

-

(Ahn, 2013)

-

-

(Ahn, 2013)

re

-p

(Pubchem CID:73581)

Secoiridoids

rhynchophylla

(Pubchem CID:242083790)(SNA)

ur na

lP

Fraxinus

Ligstroside

ro

of

(Pubchem CID:65243)

90 µg/ml

Jo

(Pubchem CID:14136859)

Oleuropein (Pubchem CID:5281544)

60

2-hydroxyoleuropein

-

-

(Ahn, 2013)

-

(Ahn, 2013)

4.07 mM

(Yamada,

(95)

2010)

ur na

lP

re

(Pubchem CID:100926556)

-

-p

Hydroxyframoside B

ro

of

(Pubchem CID:102461562)

Monarda punctata

Carvacrol

Jo

(Pubchem CID:10364)

-

61

Chrysanthemum

10α-hydroxy-

morifolium

1α,4αendoperoxy-guaia-2-en-

-

161.0 µM

(Luyen,

(77)

2013)

12,6α-olide

*(SNA) – Structure Not Available Table 5. PLE inhibitory activities of the medicinal plants and terpenoids with their IC50 values.

of

Based on the previously reported active compounds from table 2,3,4 and 5, we have first time

ro

given a grading system using a cone diagram that establishes on representing the IC50 values (Figure 4).

-p

The Figure 4 showing the classification of IC50 values into six grades based on the previous reports. The Grade 1 (0.092-0.177 µM) molecules showing the highest inhibitory activity over PLE,

re

in continuation the molecules from the following: Grade 2 (0.213-7.958 µM), Grade 3 (12.7±1.0-

lP

835.0 µM), Grade 4 (0.17-178.4 mM), Grade 5 (1.8-500 µg/ml) showing lesser PLE inhibitory activity than that of Grade 1. Finally, the molecule represented in Grade 6 (0.12-3.819mg/ml) has

ur na

shown the least inhibitory activity towards the PLE. Thus, we conclude that this approach of grading system gives us a clear cut idea for selecting the natural molecule to combat obesity and based on the above grading system the phytoconstituents mainly flavonoids which showed the most potent results against PLE, whereas alkaloids, terpenoids and saponins showed less potent results when compared

Jo

to flavonoids.

62

of ro -p re

lP

Figure 4. Showing the grading of phytoconstituents based on its IC50 values, were pink color represents flavonoids, green color represents alkaloids, sky blue color represents terpenoids and

ur na

blue color represents saponins.

1.9. Triglyceride absorption reports in experimental animals 1.9.1. Orlistat

Porsgaard et al., studied the effect of orlistat on TG absorption in male wistar rats. The

Jo

study were divided into three groups: the first group was administered with orlistat (1mg) along with oil, the second group is the control which was administered with oil (270 mg/kg) and to both the groups i.e. malabsorbing and normal were treated with orlistat along with fish oil (450 mg/kg) and safflower oil (305 mg/kg) and finally the third group was administered with 2monopalmitoylglycerol (115mg/kg), oleic acid (195 mg/kg) and orlistat (25mg/kg) to understand the impact of drugs on lymph absorption. The author’s reported that the normal group showed 63

increased transport of TG to the lymph, whereas in the orlistat and malabsorption treated groups it did not show any changes in the transportation, but the color of lymph turned from clear to white. Therefore, the studies on the absorption of TG in the orlistat group, showed to significantly reduce the transportation in exogenous way when compared to other group. Thus, this showed to completely inhibit the PLE and thus leading to decreased hydrolysis of TG. Finally, the author’s concluded that the orlistat group possessed less TG transport and thus resulted in the PLE inhibition which may be

of

the cause for hydrolysis and also resulted that the absorbed TG was exhausted in the large intestine

ro

causing inhibition of TG absorption which contributes to inhibit PLE (Porsgaard, 2003). 1.9.2. Flavonoids

-p

Klaus et al., have studied the effect of flavonoids from Camellia sinensis such as,

re

epigallocatechin gallate, epicatechin gallate and gallocatechin gallate with HFD induced in C57BL/6J mice for a period of 11 months and resulted that there was a significant reduction in BW

lP

was observed (Klaus, 2005). Kishida et al., examined the estrogenic property of isoflavone, such as genistein and daidzein at a concentration of 100-300mg/kg, and the results showed a significant

ur na

reduction in the FI and BW in Sprague-Dawley (SD) rats. (Kishida, 2008). Revera et al., studied the effect of quercetin in obese zucker rats at a concentration of 2 or 10mg/kg for 10 weeks, and the results showed a significant decrease in the BW in both obese rats and their lean littermates (Rivera, 2008). Kobori et al., also studied the effects of quercetin in male C57/BL6J mice at a concentration

Jo

of 0.1 and 0.5 % for 2 weeks, which significantly reduced BW and visceral and hepatic fat in mice (Kobori, 2009). Another study carried out by Steward et al., showed the effect of quercetin (0.8 %) in HFD induced in C57BL/6J mice for 3 weeks and 8 weeks and the results showed that there was no significant differences in the BW was observed (Stewart, 2008). A recent study by Casuso et al., studied the effect of quercetin in exercised and sedentary rats, and administered with quercetin orally

64

(25 mg/kg on alternate days) for six weeks and the results showed that quercetin did not show any decrease in BWG which was compared to the control (Casuso, 2014). Choi et al., studied the antiadipogenic activity of rutin in HFD (64.4% of fat) on C57BL/6 mice and administered orally at a concentration of 25 and 50 mg/kg b.w./daily and the results showed decrease in the BWG and also showed significant reduction in the TC and TG, but did not show any difference in comparison with the HFD fed group (Choi, 2006). Kim et al., studied the activity of Aronia melanocarpa and

of

administered with a concentration of 100 and 200 mg/kg fed with HFD and was compared with the

ro

standard orlistat group. The results showed to increase in BWG of about 1.4 fold, which was

observed in the HFD + vehicle, whereas there was a significant decrease in BWG of about 30%

-p

found in A. melanocarpa treated HFD mice. Furthur, the A. melanocarpa (100 or 200 mg/kg) extract

re

group showed increase in both the perirenal and perigonadal fat mass and a decrease in the TG content in the HFD fed mice (Kim, 2018). You et al., studied the effect of cyanidin-3-glucoside in

lP

C57BL/6J mice for 15 weeks, and the result showed significant increase in BWG in the treatment groups. In addition, to the parallel studies showed a significant reduction in the epididymal and liver

ur na

fat weight (You, 2018). Bose et al., studied the activity of EGCG from green tea in HFD induced in C57BL/6J male mice and the results showed on long term treatment of EGCG significantly decreases the BW, FI and body fat parameters, in which the total visceral adipose tissue weight decreases up to 37% and also there was reduction in the fat liver mass in HFD mice (Bose, 2008).

Jo

Wu et al., studied the effect of Litchi chinenesis and identified flavonoids such as catechin, epicatechin, rutin, myricetin, hesperidin, quercitrin, neohesperidin, eriodictyol, quercetin and luteolin using hyper caloric diet for 10 weeks. The study were carried out using 2.5% and 5% litchi flower water extracts (LFWE), and the results showed to decrease in the FI and BW and also reduces the epididymal adipose tissue mass. Furthur, studying on the serum and fecal lipid contents, the LFWE

65

showed to decrease the TG levels in serum and increase the TG levels in fecal output (Wu, 2013). Kumar et al., studied the effect of galangin from Alpinia galangal in cafeteria diet fed in female rats for 6 weeks and the results showed decrease in BW in rats. The serum parameters showed significant decrease in the TC, LDL and TG, but an increased HDL-cholesterol level was observed. Therefore, the authors reported on the rhizomes of A. galangal for obesity management by showing decrease in the excess accumulation of fats (Kumar, 2013). Jung et al., reported the activity of Alpinia

of

officinarum ethanol extract (AOE) in HFD fed in C57BL/6J mice, and the results showed to

ro

decreases the BW, FI and brown adipose tissue mass in mice, whereas the fatty liver size increases (Jung, 2012). Mosqueda-Solís et al., studied the activity on hesperidin in diet-fed rats for 8 weeks,

-p

and the results showed significant reduction in the BW, energy expenditure and hepatic lipid content

re

in rats (Mosqueda-Solís, 2018). Im et al., studied the effect of isoorientin compound from Triticum aestivum and reported to inhibit the adipogenesis pathway (Im, 2015). Liou et al., studied the effect

lP

of licochalcone A in HFD induced in C57BL/6 mice and the results showed to significantly reduce the BW, epididymal and inguinal adipose weights, liver weight and liver lipid accumulation. Thus,

ur na

the authors reported that licochalcone A suppresses the lipogenesis and increases the lipolysis and fatty acid β-oxidation pathways (Liou, 2019). Kwon et al., studied the activity on luteolin in C57BL/6J diet-induced obese mice, and the results showed to decrease the BWG, epididymal, perirenal, retroperitoneal, mesenteric, subcutaneous and interscapular white adipose tissue (WAT),

Jo

compared with the HFD fed group (Kwon, 2018). Su et al., reported the effect of myricetin on HFD induced in C57BL/6 mice and results showed to significantly reduce the BW and visceral fat compared with HFD induced mice (Su, 2016). Lee et al., reported the effect on dietary anthocyanins such as cyanidin, delphinidin, peonidin, petunidin and malvidin in HFD induced in mice and the results showed to decrease the BWG, LDL, TAG and TC levels in HFD fed mice and also lowers the

66

fat accumulation in blood serum and liver (Lee, 2017). Varshney reported on quercetin, rutin and myricetin in HFD induced rats and the results showed to decrease the BW and serum lipid such as TC, TG, LDL levels against HFD treated groups (Varshney, 2019). Jin et al., reported on theaflavin 1, theaflavin-3-gallate, theaflavin-30-gallate and theaflavin-3,3-0digallate from tea in HFD induced rats and results showed that theaflavin 1 significantly decreases the BW by 10% when compared to control group. In terms of lipid profiles theaflavin 1 decreases the TC and TG levels for about 26.5%

of

(Jin, 2013). Gourineni et al., studied the activity of Vitis rotundifolia in grape extract and wine

ro

extract in HFD induced in C57BL/6J mice and the result showed that the which grape or wine

extract supplementation did not affect the FI and calorie intake in HFD animals, whereas the wine

-p

extract supplementation showed significant reduction in the plasma lipid levels in mice (Gourineni,

re

2012). Quesada et al., studied the activity of proanthocyanidins from grape seed in HFD induced in Wistar rats, and the results showed to significantly reduce the plasma triglyceride levels (Quesada,

lP

2009). Blade et al., studied the effect of proanthocyanidins reduce the plasma TG levels and LDL-C, and there was an increase in the HDL-C levels (Bladé, 2010). Casacchia et al., studied the activity of

ur na

Leopoldia comosa (Lc) on HFD (60% of fat) induced in Wistar rats, administered orally at 20 or 60 mg/day and orlistat was administered at 20 mg/day and after 12 weeks of treatment the results showed significant reduction on BW in HFD group, whereas the WC showed significantly higher and the abdominal, perirenal, epididymal and retroperitoneal fat deposition were significantly

Jo

increased in the HFD group. There was a significant decrease in the FI and increase in BMI was observed in the HFD group in both HFD + Lc (20 mg) and HFD + Lc (60 mg) group. The serum parameters showed significant decrease in the TC, LDL-C and TG on Lc 20 mg and 60 mg treatment respectively (Casacchia, 2019).

67

1.9.3. Alkaloids Gu et al., studied the effect of Theobroma cacao in HFD fed C57BL/6J male mice, and the results showed to reduce the BWG (16%) and retroperitoneal WAT weight (11%) compared to HFD fed controls (Gu, 2014). Eteng et al., reported the effect of theobromine from Theobroma cacao and studied the lipid profile in rats. The results showed significant reduction in serum TC, LDL and TG levels, whereas HDL level increases (Eteng, 2000). Jia et al., reported the effect of caffeine in HFD

of

induced C57BL6J mice and the results showed a significant decrease in the BW, liver weight,

ro

mesenteric, and epididymal fat weight in mice (Jia, 2014). Birari et al., reported the effect of

mahanimbine from Murraya koenigii (L.) extract for lipid lowering activity in HFD diet in male

-p

sprague drawly rats. The results of both the extract and mahanimbine showed decrease in the BWG

re

and moreover it also significant decreases the TC and TG levels. The authors have also identified koenimbine from the extract of Murraya koenigii, but they haven’t carried out the animal studies for

1.9.4. Saponins

lP

the same (Birari, 2010).

ur na

Kimura et al., reported the activities on proanthocyanidins from the seed of Aesculus turbinata in HFD diet induced in mice and the results showed to significantly decrease the FI and BW (Kimura, 2011). Xu et al., studied the effect of caffeine from green tea in HFD induced rat, which was compared with orlistat and the results showed to decrease the BW, FI and lee index,

Jo

where caffeine showed significant decrease in all the serum parameters such as TC, TG and LDL levels (Xu, 2005). Yoshizumi et al., studied the effects of chiisanoside from Acanthopanax sessiliflorus in oil gavage study in mice and the result showed that chiisanoside elevated the plasma TG level at 2 and 4h, followed by a decrease after 6h of administration. Therefore, on addition of 100 or 300mg/kg of chiisanoside significantly decreases the plasma TG level after 6h (Yoshizumi,

68

2008). Xu et al., reported the activity on aqueous extract of Cyclocarya paliurus (CPAE) in male wistar rats and the results showed to decrease in the BWG and the serum parameters such as TC, TG, and FFA levels in the CPAE group. Of note, the epididymal adipose tissue or the abdominal adipose tissue size significantly reduced on CPAE administration (Xu, 2017). Yao et al., studied the effect of Cyclocarya paliurus in HFD induced in SD rats and reported that the extract lowers the FI and BW in rats. Moreover, the extract also reduces the serum parameters such as TC, TG and LDL

of

levels (Yao, 2015). Kwon et al., studied the effect of Dioscorea nipponica (DN) and identified a

ro

compound dioscin in HFD using male SD rats and the results showed to significantly decrease the plasma TG levels on dioscin administration. On administration with the HFD+ 5% DN significantly

-p

decreases the BWG and also the subcutaneous, perirenal, and epididymal fat tissue size. The

re

excretion of fecal fat content with the administration of 2% and 5% DN showed significantly increase in TG levels (Kwon, 2003). Hu et al., studied the effect of escins isolated from the seeds of

lP

Aesculus turbinata in male wistar rats and the results showed to significantly decreased in the BW and FI in HFD+0.35%, 1% or 2% of escins treatment. The escins at a concentration of

ur na

250mg/kg/b.w. increases the plasma TG levels and at 1g/kg b.w. and the escins inhibits the plasma TG concentration that elevates the TG levels in the feces, whereas in HFD+2% escins administration significantly increases the TG level in the feces compared to the HFD group (Hu, 2008). Avci et al., studied the effect of escins from Aesculus hippocastanum in HFD fed in swiss

Jo

albino mice and reported to show that the escins significantly decrease the BW of up to 37.8% and also inhibit the leptin concentration of up to 31.6%. At a concentration of 100mg/kg the escins tend to decrease the serum TG, TC and LDL levels (Avci, 2010). Han et al., studied the activity of chikusetsusaponins and 28 deglucosyl-chikusetsusaponins IV and V from Panax japonicus in female strain mice and male wistar rats and reported that the mice fed with HFD+3% of chikusetsusaponins

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and orlistat at 0.025% concentration for 3 days significantly increase the TG levels. Furthur at the same concentration the results did not show any significant difference in the FI, whereas there was a significant decrease in the BW was observed. The plasma TG levels were significantly decreased on administration of chikusetsusaponins (Han, 2005). Park et al., studied the activity of Panax ginseng in various models such as SD rats, C57BL/6J mice, ICR mice, wistar rats, db/db mice and OLEFT rats and the results showed to significantly decrease the BW, TC, TG and LDL, whereas the HDL

of

significantly increases in all the treatment models (Park, 2018). Lee et al., studied the effect of

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platycodin D (PD) isolated from Platycodon grandiflorum roots in male C57BL/6 mice and the results showed slight decrease in the FI and BW on administration of PD. Moreover, the results

-p

showed decrease in the serum parameters such as TC, TG and LDL levels, whereas there was a

re

significant increase in HDL level was observed (Lee, 2012). Zhao et al., studied the effect of platycodin saponins (PS) in rats and reported that there was a significant decrease in the BW when

lP

compared to the control. Further the biochemical analysis on serum and hepatic parameters showed significant decrease in the TG and LDL levels, whereas TC and HDL were not significantly altered

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on PS treatment (Zhao, 2004; Zhao, 2005). Cha et al., studied the effect of Acanthopanax senticosus (ASE) in HFD induced in C57BL/6J mice and the results showed that there was significant difference observed on both Fi and BWG. Further, on administration of ASE showed to decrease the abdominal fat deposition in HFD group. The results on serum parameters showed that there were no

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significant changes in TG, TC, whereas a significant decrease in the HDL was observed (Cha, 2004). 1.9.5. Terpenoids

Kunkel et al., and his co-authors studied the effect of ursolic acid (UA) in mice and the

results showed significant reduction in the adiposity and leptin concentrations at 0.27% UA supplementation (Kunkel, 2011). Kunkel et al., studied the effect of UA in HFD induced in

70

C57BL/6 male mice and reported that UA increases the brown fat accumulation that spends its energy to generate heat and maintain the temperature of the body and the energy expenditure. Furthermore, UA enhances the signaling of skeletal muscle insulin/IGF-I which leads to Akt activation and muscle hypertrophy that reduces the adiposity in mice (Kunkel, 2012). Yan-xiang et al., studied the effect of UA at 10 mg/kg/day concentration in HFD induced mice and the results showed to significantly decrease the BW, blood glucose, insulin and leptin levels (Yan-xiang, 2013).

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Li et al., studied the effect UA supplement at 0.125%, 0.25% or 0.5% concentration for 6 weeks in

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HFD induced mice, and the results showed decrease in BW, hepatic steatosis and liver injury

parameters (Li, 2014). Rameshreddy et al., studied the activity of Asiatic acid (AA) in HFD induced

-p

SD rats and reported that AA significantly reduces the BW when compared with orlistat. The serum

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parameters showed decrease in the TC, TG, PL and FFA levels after administration of AA in HFD fed rats (Rameshreddy, 2018). Uddandrao et al., studied the effect of AA and reported that there was

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a decrease in the BW when compared to orlistat. The lipid parameters showed significant reduction in TC, TG and LDL, whereas the HDL and FFA level increases. The retroperitoneal, mesentric and

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epididymal fat pad significantly decreases on AA administration (Uddandrao, 2019). Kim et al., reported the activity of betulinic acid (BA) in HFD male C57BL/6 mice for 11 weeks and the results showed that there was decrease in the BW and no difference on FI was observed when compared to the control group. The results on fat pads such as inguinal, perigonadal and mesenteric showed

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significant decrease on BA treatment. There was a significant decrease observed in the serum TC and TG levels (Kim, 2019). Zhao et al., studied the effect of carnosic acid (CA) and carnosol from rosemary extract in HFD induced male C57BL/6J mice and the results showed to significantly decrease in the BWG, liver weight and fat mass. The plasma parameters showed significant decrease in the liver TG, TC and FFA levels. The CA administration inhibits the lipid absorption and

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significantly increases the fecal lipid excretion (Zhao, 2015). Cho et al., studied the effect of carvacrol in HFD induced in C57BL/6N mice and the results showed significant reduction in the BW and BWG. The FI did not show any significant difference on carvacrol supplement. The serum parameters showed significant decrease in TG and hepatic cholesterol levels on carvacrol supplementation (Cho, 2012). Yamada et al., studied the activity of dietary corosolic acid (CRA) in Male KK-Ay mice and the results showed a decrease in BW, whereas there was no differences in FI

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was observed. The serum parameters showed decrease in the liver weight, TG and hepatic TG levels

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(Yamada, 2008). Koh et al., reported the effect of Gardenia jasminoides (GK) in HFD induced C57bl/6J mice and the result showed that there was a slight decrease in the BW, whereas no

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significant difference in the FI was observed. The serum parameters showed significant decrease in

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the TC, TG and LDL, whereas the HDL levels is increased (Koh, 2019). Hazman et al., studied the effect of crocin from Gardenia jasminoides in male wistar rats fed with HFD and the results showed

lP

to significantly decrease the BW in rats (Hazman, 2016). Xiao and Lee et al., studied the effect of crocin and crocetin from Gardenia jasminoides and reported that crocin was found to exhibit anti-

ur na

hyperlipidemic effect. The serum parameters showed significant decrease in the TG and TC, whereas the HDL levels were significantly increased (Xiao, 2017; Lee, 2005). Hirata et al., studied the activity of Ginkgo biloba in male wistar rats and reported that the rats fed with HFD+GbE group showed significant decrease in the FI and BW (Hirata, 2019). Luo et al., studied the effect of

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Ginkgolide B (GB) in HFD induced in female C57BL/6 mice and the results showed that GB decreases the BWG, whereas there was no significant difference in FI was observed. The serum parameters showed significant decrease in the TG levels, but there was no difference observed in the TC, LDL and HDL levels (Luo, 2017). Khedher et al., studied the activity on the leaf extract of Salvia officinalis (SO) in C57Bl/6 male mice and reported that there was a significant reduction in

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the BW was observed. The results on fat mass showed decrease in size on SO treatment (Khedher, 2018). Djeziri et al., reported the activity of oleanolic acid (OLA) in HFD induced in C57BL/6J female mice and the result showed that there was an increase in the BWG initially, whereas after 5 weeks significant decrease in the BWG was observed (Djeziri, 2018). Kuem et al., studied the activity of oleuropein fed with HFD in C57BL/6N mice and the results showed to significantly decrease the BWG. There was a significant reduction in the total visceral fat pad weights was

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observed (Kuem, 2014).

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1.10. Triglyceride absorption reports in clinical studies 1.10.1. Flavonoids

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Jung kamel et al., reported the activity of Citrus reticulate peel water extract on obesity and

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fat reduction in adolescent, using 80 obese adolescents (40 females and 40 males) aged between 1218 years . The subjects were randomly divided into 2 groups: Group A: received 20 ml of the extract

lP

containing 800 mg of dry extract once a day, 30 minutes before breakfast or dinner, followed by a low caloric diet for 8 weeks. Group B: received 20 ml of placebo (the placebo syrup each containing

ur na

200 ml of excipient identical in appearance to the extract) once a day, 30 minutes before breakfast or dinner, followed by a low caloric diet for 8 weeks. The primary and secondary outcome in group A showed reduction in BMI, BF % and WC, as well as better lipid profile criteria. The isolated flavonoid molecules from the plant Citrus reticulate are hesperidin, naringin, acacetin, rutin and

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quercetin were found to be in higher amounts. The results showed significant reduction in BMI and WC after 4 & 8 weeks of supplementation of Citrus reticulate when compared with placebo group. Therefore, analysis of the obese adolescent for lipid profiles indicates that many of the therapeutic trial participants in both groups had high TC and TG. The results showed that there was significant decrease in the TC and TG levels. There was a satisfactory non-significant reduction in the LDL

73

levels after 2 months was observed in group A. There was a increased reduction in BF%, TC and TG was observed at the end of the study in group A. Further, BMR wasn't significantly increased (2.56%) which suggested the Citrus reticulate peel extract are to be well-tolerated and effective ingredient for weight management (Jung Kamel, 2019). Nagao et al., studied the effect of green tea (GT) i.e. Camellia sinensis and identified flavonoids such as catechin, epicatechin, epigallocatechin, epicatechin gallate and epigallocatechin-3-gallate. A wide number of clinical studies have been

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carried out on GT and green tea catechins (GTCs) in the management of obesity and it showed

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promising results (Wang, 2014; Huang, 2014; Miyoshi, 2015; Yang, 2016). A study on green tea for obesity activity was carried out by Nagao et al., who conducted a double-blind trial for 12 weeks,

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treated with a bottle of oolong tea consisting of GTCs of 690mg or 22mg/day. The results showed

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significant reduction in the BW, BMI, WC, BFM and subcutaneous fat (Nagao, 2005). In another study trial by Nagao and his colleagues, on administering with GTCs (582.8mg) group for 12 weeks

lP

and the result showed that there was a significant decrease in the WC in the GTCs group (Nagao, 2009). Maki et al., studied the role of GTCs in exercise-induced abdominal fat loss in adults. The

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participants were administered with GTCs (625mg) along with caffeine (39mg) and the control group receives only caffeine for 12 weeks and reported a significant reduction in the BW, whereas there was no difference in the BFM observed in both the groups, but it showed increased serum TG and abdominal fat area in the GTCs group (Maki, 2000). Similarly, Cardoso and his colleagues

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showed on consuming green tea and the results showed to significantly decrease the TG levels, body fat and WC on resistance training and increase the lean BFM (Cardoso, 2013). Chen et al., studied the effect of GTE in high dose and the result showed significant decrease in BW, WC and TC, TG and LDL levels (Chen, 2016). The Chinese subjects undergone randomized and placebo-controlled trial using 182 subjects and divided into 4 groups i.e. control, GT1, GT2 and GT3 groups. The

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control group receives 30 mg GTCs, 10 mg caffeine/day, GT1 subjects received 458 mg GTCs + 104 mg caffeine/day, the GT2 subjects received 468mg GTCs +126mg caffeine/day and GT3 subjects received 886 mg GTCs + 198 mg caffeine/day and all these treatment groups received extra highcatechin drink. The authors reported that the BW, abdominal fat and WC was significantly decreased. It was also observed in GT1 and GT2 groups, showed significant reduction in the BFM (Wang, 2010). In a study, using 35 obese participants are randomly assigned them into two groups.

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The control received four cups water/day and treatment group received GT four cups /day or green

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tea extract (GTE) two capsules with four cups water/day. It was observed that there was a

significantly reduction in both the treatment groups (Basu, 2010). In the parts of Kenya, a study trial

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have been carried out by Shimoda et al., on a green tea variety called purple tea which majorly

re

constitutes caffeine, theobromine, epigallocatechin, EGCG, and 1,2-di-O-galloyl-4,6-Ohexahydroxydiphenoylβ-D-glucose and have studied various parameters. The results showed

lP

increase in BW, BMI and BFM after administering the purple tea extract up to 100-200ml/day for 4 weeks (Shimoda, 2015). In another study the participants were subjected for randomized, placebo-

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controlled, double-blind, crossover study and were administered with black tea polyphenols (BTP) (55mg 3 times/day) for 10 days. They reported that there was an increase in the lipid excretion (from 5.51 g to 6.87 g/3 days) on intake in BTP (Ashigai, 2016). Another single-blind, randomized trial study carried out by taking 55 men and women who are obese were treated with GTE-enriched bread

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(280 and 360 g), caffeine (9123.2 and 158.4 mg) and EGCG (9188.3 and 242.1 mg), respectively. Therefore, the study resulted that GTE-enriched bread did not play a role in the waist loss or the HDL and TG levels (Bajerska, 2015). In a cross sectional study, Brown et al. administered decaffeinated GTCs and showed decrease in the BW, whereas there was a gain in the BW of placebo group (Brown, 2011). Dulloo et al., reported that GTE showed to cause oxidation of fats and also

75

possessed thermogenic properties (Dulloo, 1999). On a trial study on administration of catechincaffeine or caffeine supplementation reported to decrease the energy expenditure that contributes to the obesity effects (Hursel, 2011). In a trial study, Mielgo-Ayuso et al., reported on administration of EGCG (300mg/day) and resulted that it did not show any changes in the energy expenditure, adiposity reduction and also it did not improve weight loss in obese women (Mielgo-Ayuso, 2014). Dostal et al., reported in a study trial of randomized, double-blind, placebo-controlled using 937

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postmenopausal women and were administered decaffeinated GTE containing EGCG (843mg) and

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placebo group. In the same study few participants were conducted with BMI parameters. They reported that there was an increase in the BMI, whereas the percentage of tissue fat decreases

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(Dostal, 2016; Dostal, 2015).

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1.10.2. Alkaloids

Higdon et al., studied on healthy participants (4 male; 5 female), aged less than 27 years

lP

considered to have a normal BMI were taken for the study. The thermal reflective markers were placed on the skin for analyzing the data and the volunteers were acclimatized before the baseline

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imaging. Later on, the participants were treated with caffeinated beverage containing caffeine (65mg) in 200ml of water and control group received only water and allowed them to sit for 30 mins and again went for thermal imaging. The study was carried out under the standards of Nottingham University, in which 9 participants in each group gave 95% power for the detection of significant

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mean difference (Ilavenil, 2014). The thermal imaging was analyzed and the results showed that caffeine administration helps to enhance the BAT activity and also helps to improve the lipid and carbohydrate homeostasis which contributes to weight loss (Higdon, 2006). In another crosssectional, case-control, and cohort studies using coffee extract were carried out by observational study using randomized controlled trials and observed the relationship between intake of coffee and

76

adiposity and analyzed three parameters i.e. BW, BMI, or WC. The volunteers consuming the coffee extract were excluded and furthur the BMI and WC were identified based on the mean difference and standard deviation. Thus, for the studies using binary outcome indicated by BMI and WC parameters against RR, which showed 95% confidence interval (CI) were extracted on their study. Thus, the results showed that out of the three studies, the two Asian studies possessed the most promising outcomes on all parameters (Lee, 2017; Nordestgaard, 2015; Kim, 2017). The comparison

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of RR with the both the groups on intake of coffee showed 1.49 (95% CI = 0.97, 2.29), respectively.

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Lee and Kim et al., reported in South Korea that there was a very high heterogeneity (I2=94%)

observed showing a strong relation on values of RR = 1.71, 95% CI = 1.12, 2.61, I2=86% and other

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publication bias were not indicated (PEgger = 0.19). Other parameters were analyzed with the

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subgroups based on sex, which did not show any significant heterogeneity (Pheterogeneity = 0.13), whereas there was a significant increase in women with RR=2.01, 95% CI = 1.25, 3.21, I2 = 83%

lP

than in men RR=1.25, 95% CI = 0.95, 1.65, I2 = not relevant. Based on the comparison of four studies (Bouchard, 2010; Hino, 2007; Larsen, 2018; Balk, 2009), the results on the parameters of

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WC from WMD on comparing the highest vs. lowest amounts of intake of coffee showed 0.27 (95%) with a less heterogeneity (I2=45%) and eliminated the publication bias (PEgger = 0.98). Therefore, within each sex the results showed significant increase only on men with WMD =−0.21, 95% CI =−0.35,−0.08, I2=0%, whereas the heterogeneity by sex was found to be not significant

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(Pheterogeneity = 0.58). In a meta-analysis six studies were joined together (Grosso, 2015; Lee, 2017; Grosso, 2014; Takami, 2013; Kim, 2017; Shin, 2017), in which the WC≥90 cm for men (Takami, 2013) and WC≥80 cm women (Takami, 2013; Kim, 2017; Shin, 2017) were used. Thus, on comparing the RR results of highest vs. lowest based on the intake of coffee showed 1.07 (95% CI = 0.84, 1.36) and showed an higher heterogeneity of (I2=82%) (Lee, 2017; Takami, 2013; Kim, 2017;

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Shin, 2017), whereas the publication bias were not indicated (PEgger = 0.92). Therefore, the analysis in other subgroup with increased intake of coffee reported to reduce the BW in men with RR = 0.90, 95% CI = 0.66, 1.23, whereas in women it is increased with RR = 0.90, 95% CI = 0.66, 1.23, but however no significant difference in the heterogeneity by sex was observed (Pheterogeneity = 0.59). Another Child Cohort Study (MoBa) was carried out within Norwegian Mother by the Norwegian Institute of Public Health (Magnus, 2016), in which 40.6% of pregnant women were invited to

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participate. The study participants include 114500 children, 95200 mothers and 75200 fathers and

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the studies were conducted at 6, 18, 36 months and 5, 7 and 8 years. This study population contains about 62034 mother-child pairs constitutes to consume caffeine. After exclusion of all the

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parameters our final study population consist of about 50943 mother-child pairs given additional

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with their study gestational age (SGA) and other parameters such as weight or height were measured. At the end of five years 40% of the study population gave back their questionnaire and

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only had details on height and weight, whereas the caffeine intake did not effect on mothers during pregnancy. Therefore, estimation of caffeine intake in MoBa was carried out by Sengpiel et al., were

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parameters such as Food Frequency Questionnaire (FFQ) at the beginning stage (4-5 months) of the trial was carried out. The average intake of caffeine per day was calculated from all the sources, and intake for the included population (57 mg/day (23–120 mg/day)) and non-included population (964 mg/ day (25–129 mg/day) in 11091 mother’s populations. Therefore, the caffeine intake was

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categorized based on the median during pregnancy, and the intake levels observed are low (0–49 mg/day), average (50–199 mg/day), high (200-299 mg/day) or very high (≥300 mg/day). The results that the women reported to consume caffeine (200 and 300 mg/day) showed increased intake of 7.13% (n=3633) and 3.21% (n=1634), respectively, but showed low: 43%, average: 46%, high: 8% and very high: 3% and resulted that increase in intake of caffeine, higher the life of the mother. Also

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the study reports that the women having low education consume high amount of caffeine, with intake of 193 mg/ day (0–493 mg/day). The difference in the maternal and paternal caffeine intake was about 0.15, but there was a 45% increase in the paternal intake of caffeine in mothers (Papadopoulou, 2018). In other identified reports only 3 of the 20 published epidemiologic studies are associated with habitual of taking coffee. The analyzed report showed eleven prospective cohort studies (Van Dam, 2002; Tuomilehto, 2004; Salazar-Martinez, 2004; Rosengren, 2004; Van Dam,

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2004; Greenberg, 2005), out of which one was a meta-analysis and the remaining ten was cross-

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sectional studies (Van Dam, 2004), and seven studied showed dose related studies (Van Dam, 2002; Tuomilehto, 2004; Salazar-Martinez, 2004; Van Dam, 2004; Greenberg, 2005). Furthur, four studies

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were tested against decaffeinated coffee and found to have a protecting activity (Salazar-Martinez,

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2004; Greenberg, 2005), in which same results were found in two studies (Salazar-Martinez, 2004). Similarly, another four studies were carried out on constituents present in coffee (except caffeine),

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and showed to have a protective effect (Greenberg, 2005). In a prospective study on administering instant coffee did not show any protective effect (Greenberg, 2005), whereas in another study

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showed such effect (Van Dam, 2006). In a prospective study trial of consuming beverage which showed decrease in the BW in a dose-dependent manner (Greenberg, 2005). Furthur, this study was carried out by administering caffeinated and decaffeinated coffee, which showed significant decrease in the BW. A recent prospective epidemiological study trial resulted in increased intake of caffeine,

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coffee, and decaffeinated coffee showed significant decrease in the BWG (Lopez-Garcia, 2006). Ballagalle et al., studied on Murraya Koenigii in human experimental models using 38 subjects administered with curry leaves twice daily at a dose of 3 grams per meal for a period of 5 weeks (Balagalle, 1997). The results showed that there was a significant decrease in the TG and TC levels. Another very recent study trial was conducted by Molly et al., on 40 post-Menopausal women aged

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between age of 45-65 years who are characterized with hyperlipidemia, who are with or without hypolipidemic drugs and administered with curry leaf powder (5gms) for 45 days. The results showed that there was a significant decrease in TC, TG and LDL, whereas the HDL levels were increased (Molly, 2017). 1.10.3. Saponins Cho et al., have studied on healthy volunteers at Chung-Ang University Hospital, Seoul,

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Korea. The main criteria for inclusion were patients must have BMI ≥ 23kg/m2 aged between 18 and

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70 years of either sex. About 69 enrolled patients were randomized and divided into two groups, 39 patients put on target herbal ingredient (3times/day before meal HI) and 30 patients received placebo

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3 times/day before meal. The results showed that 9 subjects from THI-treated group and 6 subjects

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from placebo-treated group withdrew from the trial. Thus, there were 30 patients in the THI-treated group and 23 patients in the placebo-treated group at the time of the final study. The investigations

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on baseline values of both groups such as age, sex, weight, height, BMI, WC, hip circumference and laboratory investigations such as TC, TG, HDL, LDL levels were carried out. The results showed

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there was no significant difference, except the total bilirubin level between the two groups. In the THI-treated group, there was a decrease in the BW after 2 months treatment, which shows there was a statistical significance between two groups. But the results on TC, TG, HDL and LDL levels during the 2-month treatment in the THI-treated group did not show any significant difference.

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Therefore, the present study, reported that with the incidence of adverse drug reactions like nausea, indigestion, abdominal pain, loose stools, diarrhea, constipation, insomnia, itching, satiety, suppression of appetite leads to insignificant results in the both groups. Furthur reports on Platycodin D saponin a major component of Platycodi Radix, reported to inhibit the fat accumulation and adipogenesis (Cho, 2013).

80

S. No

Medicinal plants

Phytoconstituents

Estimation of

Compared

triglyceride

with orlistat

Reference

In-vivo studies Camellia sinensis

Epigallocatechin

The TG levels

gallate (EGCG),

in blood and

Bose, 2008; Jin,

theaflavin 1,

reduces the fatty

2013; Xu, 2005)

theaflavin-3-gallate,

liver content

and theaflavin-3,3-0-

-

Quercetin

The TG levels

N

re

2.

-p

digallate

in blood

Rutin

4.

Aronia melanocarpa -

(Rivera, 2008; Kobori, 2009; Stewart, 2008;

lP ur na

-

Jo

3.

(Klaus, 2005;

ro

theaflavin-3-0-gallate

Y

of

1.

Casuso, 2014; Wu, 2013; Varshney, 2019) No significant

N

difference

(Choi, 2006; Wu, 2013; Varshney, 2019)

The TG levels

Y

(Kim, 2018)

in blood

81

5.

-

Cyanidin-3-glucoside

The TG levels

Y

(You, 2018)

Catechin, epicatechin,

The TG levels in N

(Wu, 2013)

rutin, myricetin,

the serum and

hesperidin, quercitrin,

increase in the

neohesperidin,

fecal output

in blood 6.

Litchi chinenesis

of

eriodictyol, quercetin

7.

Alpinia galangal

Galangin

The TG levels in Y

9.

-

-

12.

13.

-

-

lP

Triticum aestivum

Jo

11.

Hesperidin

Isoorientin

ur na

10.

N

(Jung, 2012)

The TG levels

N

(Wu, 2013;

The fatty liver

re

Alpinia officinarum -

and fatty liver

Mosqueda-

lipids

Solís, 2018)

The TG levels

Y

(Im, 2015)

N

(Liou, 2019)

N

(Wu, 2013;

in blood

Licochalcone A

Luteolin

(Kumar, 2013)

-p

blood 8.

ro

and luteolin

The TG levels in serum and liver -

Kwon, 2018) Myricetin

No significant differences in

N

(Wu, 2013; Su, 2016; Varshney,

82

the TG levels 14.

-

Cyanidin,

The TG levels

delphinidin, peonidin,

in serum

2019) N

(Lee, 2017)

N

(Gourineni,

petunidin and malvidin Vitis rotundifolia

-

The TG levels in plasma

Caffeine and

The TG levels

N

theobromine

in serum and

Eteng, 2000;

fecal lipid

Jia, 2014)

ro

Theobroma cacao

-p

16.

2012)

of

15.

(Gu, 2014;

19.

Acanthopanax

21.

The TG levels

koenimbine

in serum

-

Chiisanoside

The plasma TG

Cyclocarya paliurus -

The serum TG

Dioscorea

Dioscin

Aesculus turbinata

Y

(Birari, 2010)

Y

(Kimura, 2011)

N

(Yoshizumi,

levels

levels

nipponica

22.

The plasma TG

sessiliflorus

Jo

20.

Aesculus turbinata

Mahanimbine and

lP

18.

Murraya koenigii

ur na

17.

re

content

2008) N

levels The plasma TG

(Xu, 2017; Yao, 2015)

N

(Kwon, 2003)

N

(Kwon, 2003)

levels Escins

Inhibits the plasma TG levels and

83

elevates the TG level in the feces 23.

Aesculus

Escins

The serum TG

hippocastanum 24.

Panax japonicus

Chikusetsusaponins

The plasma TG

and 28 deglucosyl-

levels

Y

(Han, 2005)

of

-

ro

IV and V Panax ginseng

(Avci, 2010)

levels

chikusetsusaponins

25.

N

The serum TG

(Park, 2018)

N

(Lee, 2012;

26.

Platycodon

Platycodin D

27.

Acanthopanax

-

Jo

28.

29.

-

serum TG levels

-

No significant

Zhao, 2005) N

(Cha, 2004)

N

(Kunkel, 2012;

changes in the

ur na

senticosus

The plasma and

lP

grandiflorum

re

-p

levels

N

Ursolic acid

serum triglycerides The hepatic TG content

Yan-xiang, 2013; Kunkel, 2011; Li, 2014)

Asiatic acid

The plasma and serum TG levels

Y

(Rameshreddy, 2018; Uddandrao,

84

2019) 30.

-

Betulinic acid

The serum TG

N

(Kim, 2019)

N

(Zhao, 2015)

N

(Cho, 2012)

31.

32.

Rosmarinus

Carnosic acid and

The plasma and

officinalis

carnosol

serum TG levels

-

Carvacrol

The hepatic TG content

-

Corosolic acid

The plasma and

N

(Yamada, 2008)

ro

33.

of

levels

hepatic TG

Gardenia

Crocin and crocetin

Ginkgolide B

ur na

Ginkgo biloba

Y

levels

lP

jasminoides

35.

The serum TG

re

34.

-p

levels

(Koh, 2019; Hazman, 2016; Xiao, 2017; Lee, 2005)

The serum TG

N

levels

(Hirata, 2019; Luo, 2017)

Salvia officinalis

-

-

N

(Khedher, 2018)

37.

-

Oleanolic acid

The serum TG

N

(Djeziri, 2018)

N

(Kuem, 2014)

Y

(Casacchia,

Jo

36.

38.

39.

-

Leopoldia comosa

Oleuropein

levels The plasma TG levels

-

The serum TG levels

2019)

85

Clinical studies 40.

Citrus reticulate

hesperidin, naringin,

The serum TG

acacetin, rutin and

levels

N

(Jung Kamel, 2019)

quercetin Camellia sinensis

catechin, epicatechin,

The serum and

epigallocatechin,

plasma TG

epicatechin gallate

levels

ro -p

re

Nagao, 2005; Maki, 2000; Cardoso, 2013; Wang, 2010;

galloyl-4,6-O-

Basu, 2010;

lP

EGCG and 1,2-di-O-

Shimoda, 2015;

diphenoylβ-D-

Ashigai, 2016;

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hexahydroxy

glucose

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Huang, 2014;

Yang, 2016;

3-gallate, caffeine,

epigallocatechin,

(Wang, 2014;

Miyoshi, 2015;

and epigallocatechin-

theobromine,

N

of

41.

Chen, 2016; Nagao, 2009; Bajerska, 2015; Brown, 2011; Dulloo, 1999; Hursel, 2011; Mielgo-Ayuso, 2014; Dostal,

86

2016; Dostal, 2015) 42.

Theobroma cacao

Caffeine

The serum TG

N

levels

(Higdon, 2006; Lee, 2017; Nordestgaard,

of

2015; Kim,

Jo

ur na

lP

re

-p

ro

2017; Bouchard, 2010; Hino, 2007; Larsen, 2018; Balk, 2009; Grosso, 2015; Lee, 2017; Grosso, 2014; Takami, 2013; Kim, 2017; Shin, 2017; Magnus, 2016; Sengpiel, 2013; Papadopoulou, 2018; Van

87

Dam, 2002; Tuomilehto, 2004; SalazarMartinez, 2004; Rosengren, 2004; Van

of

Dam, 2004;

-p

ro

Greenberg,

re Platycodi Radix

-

Platycodin D

Martinez, 2004; Greenberg, 2005; Van Dam, 2006;

lP Murraya Koenigii

Jo

44.

ur na

43.

2005; Salazar-

Lopez-Garcia, 2006) The serum TG

N

levels

(Balagalle, 1997; Molly, 2017)

No significant

Y

(Cho, 2013)

differences in the TG levels but reported to inhibit fat accumulation

88

re

-p

ro

of

Table 6. Triglyceride absorption reports in experimental animals and clinical studies.

Jo

ur na

lP

Fig5 a.

89

of ro -p re lP ur na Jo

Fig 5 b and 5 c.

Figure 5. In this figures 5a - represents the “correlation between in-vitro, in-vivo and clinical reported data”, figures 5b - represents the “networking of reported medicinal plants and its molecules from in-vitro studies” and figures 5c - represents the “networking of reported medicinal 90

plants and its molecules from in-vivo and clinical studies”. In this Figure 5b and c dark blue color represents pancreatic lipase, green color represents medicinal plants and purple color represents the phyto-molecules. 1.11. Others 1.11.1. Amino acids Apart from the plant origin and the phyto-molecules a wide number of amino acids are also

of

reported to inhibit PLE in-vitro and in-vivo. Lunder et al., reported on PLE inhibition on various

ro

peptides such as CLREQPQQC, CTALMSASC, D04-CPDANRINC, D10-CSQAPTPAC, D11CPPSYNGKC, D19-CPPSYNGKC, D21-CPPSYNGKC, D22-CTPTSPAMC, D23-CQPHPGQTC

-p

and E06-CSQLQTTKC. The results clearly indicated that the selected peptide D23 with amino acid

re

sequence CQPHPGQTC efficiently inhibits PLE (Lunder, 2005). Zhang et al., studied the effect of decapeptide from Chlorella pyenoidose for PLE inhibition and identified six peptides sequences

lP

such as SISISVAGGGR, LLVVYPWTQR, SDDPHTFGQGTK, SRQLTLYPGAER, KNGAPAEK, and KQTALVELVK using LC–MS/MS analysis. Based on the predicted score of six peptides by

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peptide ranker software, a short peptide LLVVYPWTQR (PP1- Leu-Leu-Val-Val-Try-Pro-Trp-ThrGln-Arg) was furthur selected for the study. The peptide sequence PP1 at a concentration of 200 µg/ml showed 47.95±2.3 % inhibition of PLE (Zhang, 2019). Stefanucci et al., reported the PLE activity on amide tripeptides and identified nine peptides namely H-Cys-Lys-Ala-NH2 (M1), H-Pro-

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Gln-Met-NH2 (M2), H-Tyr-Pro-Trp-NH2 (M3), H-Pro-Thr-Trp-NH2 (M4), H-Ile-Trp-Ser-NH2 (M5), H-Trp-Trp-Gln-NH2 (M6), H-Tyr-Phe-Ser-NH2 (M7), H-Ile-Asp-Met-NH2 (M8) and H-ProGln-His-NH2 (M9). The results showed that the in-vitro analysis of compounds from M1-9 (IC5044.34 ± 3.11 to 100.67 ± 3.75) inhibited the PLE which was compared with the orlistat, respectively,

91

in which the novel amide peptide sequences M5 and M7 were found to show the most potent activity (Stefanucci, 2019). 1.12. Limitations of this study The major study of this review explains clearly in detail about potential plants or molecules that target an enzyme pancreatic lipase in-vitro to combat obesity. But, the limitations of the study focusing on in-vivo and clinical reported data, there are no studies reported specifically on the

of

inhibition or the synthesis of PLE. Thus, they have focused on to correlate the triglyceride

ro

absorption in the systemic circulation and feces in order to see how the pancreatic lipase is

inhibited or not, could also be an acceptable approach to target pancreatic lipase inhibition.

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1.13. Conclusion and future perspectives

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Natural products have always been an inspirational target, to find out high therapeutic leads. Thus, there is a huge hope to find out novel compounds from the plant source which could be later

lP

developed as anti-obesity products. A large number of reported plants containing polyphenols has shown inhibitory properties against PLE, though, research is still ongoing on plants for the

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development of lipase inhibitors. In this scenario, lipase enzyme plays a crucial role in lipid biochemistry with a promising inhibitory effect shown by orlistat (Long and Cravatt, 2011). Orlistat is one of the clinically approved and only conventional drugs available in the market which is approved as PLE inhibitors. PLE inhibitors from plant source are an interesting approach, where

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studies reported that polyphenols mainly flavonoids have shown greater potential. The structural comparison studies concluded that the activity is mainly due to the presence, number and position of phenolic hydroxyl groups in the ring structure of flavonoids. Moreover, non-esterified flavan-3-ols such as catechin and epicatechin possess lesser inhibitory potentials than the esterified form. The enhancement of PLE inhibition was also attained by the presence of galloyl moieties in the ring

92

structure. After glycosylation group elimination in the ring structure, flavonoids and anthocyanin’s showed improved inhibitory activity. Likewise, the degree of polymerization of proanthocyanins is necessary for lipase activity. Studies reported that the presence of the methoxy group decreases activity and hydroxyl groups increase the activity. Besides, the inhibitory effect of lipase is mainly due to two factors, molecule size and position of the hydroxyl groups. Our critical analysis of invitro PLE data, depicted in a cone diagram has provided the detailed grading of flavonoid’s potential

of

in inhibiting PLE, although the experimental conditions would have influenced the outcomes.

ro

Therefore, to find out number of phyto-molecules from libraries present, there is a necessity that follows high throughput screening method to find out potential targets on PLE.

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In this review over more than 75 medicinal plants and 135 phyto-molecules have been

re

screened for PLE inhibition in-vitro. However, only 24 medicinal plants and 53 phyto-molecules have been screened for its in-vivo potential. Perhaps to confirm its in-vivo activity, many studies

lP

have reported to decrease TG absorption in the blood and increased TG in feces and together with decrease in BW and FI in experimental animals. Of note, only 5 medicinal plants and 16 phyto-

ur na

molecules have been studied in human and report the decrease BW, BMI with decreases in TG absorption in the systemic circulation. The observations in human validate and establish the proof of concept that the plants and phyto-molecules having potential to inhibit PLE and they could be developed as anti-obesity therapeutics.

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The network pharmacological approach showed that flavonoids among other class of phyto-

molecules, including saponins, terpenoids and others have stronger potentials in eliciting anti-obesity effects and the in-vitro and in-vivo data establish the possible links with PLE inhibition. This shows a wide number of medicinal plants and their phyto-molecules are yet to be translated from bench to clinics for the treatment of obesity. Thus, this review serves as a reference database to search for the

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medicinal plants and/or phyto-molecules that have showed potent activity for PLE inhibition in experimental and clinical conditions and the potential plants or phyto-molecule leads for clinical studies which could develop or give us newer anti-obesity drugs in near future. In contrast to the experimental and clinical reported data over medicinal plants and molecules, exploring the areas of amino acids is parallelly gaining scientific attention in the management of obesity by inhibiting PLE. The current advancements in the development of PLE inhibitors warrant better understanding

of

and application of modern tools like in-silico docking and metabolomics to characterize the

ro

structural activity relationship and network pharmacology. Experiments using computational modelling can identify new potential anti-obesity drugs with decreased adverse effects when

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compared to conventional drug-like orlistat. Nonetheless, complete understanding of phyto-

Conflict of Interest

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development of newer anti-obesity drugs.

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molecules against PLE with its additional documentation on its activity is essential towards

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The authors declare no competing financial interest.

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1.14. Acknowledgments

We highly acknowledge the TIFAC CORE in Herbal Drugs, JSS College of Pharmacy,

Ooty and JSS Academy of Higher Education and Research for providing us the infra-structure. This work was funded by the Indian Council of Medical Research (ICMR) as a senior research fellow with reference no. 45/43/2018/MP/BMS/dt. 05.12.2018. We would also like to thank Dr. Kannan

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Rengasamy and Dr. Mohamad Fawzi Mahomoodally for their constructive guidance for the manuscript. We acknowledge the help rendered by Mr. Deeparaj Paul for proof reading and

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ro

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suggestions for editing and formatting the manuscript.

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