Multi-targeting Andrographolide and its Natural Analogs as Potential Therapeutic Agents.

Andrographis paniculata (A. paniculata) is a medicinal plant used in the Indian and Chinese traditional medicinal systems for its various beneficial properties of therapeutics. This is due to the presence of a diterpene lactone called 'andrographolide'. Several biological activities like antiinflammatory, antitumour, anti-hyperglycaemic, anti-fertility, antiviral, cardio protective and hepatoprotective properties are attributed to andrographolide and its natural analogs. The studies have shown that not only this diterpene lactone (andrographolide), but also other related terpenoid analogs from A. paniculata could be exploited for disease prevention due to their structural similarity with diverse pharmacological activities. Several scientific groups are trying to unveil the underlying mechanisms involved in these biological actions brough aout by andrographolide and its analogs. This review aims at giving an overview on the therapeutical and/or pharmacological activities of andrographolide and its derivatives and also exemplify the underlying mechanisms involved.

The effect of a plant extract enriched in stigmasterol and ß-sitosterol on glycaemic status and glucose metabolism in alloxan-induced diabetic rats.

Banana is an extensively cultivated plant worldwide, mainly for its fruit, while its ancillary product, the banana pseudostem, is consumed as a vegetable and is highly recommended for diabetics in the traditional Indian medicine system. The present study was aimed at elucidating the mechanism of antihyperglycaemia exerted by the ethanol extract of banana pseudostem (EE) and its isolated compounds viz., stigmasterol (C1) and ß-sitosterol (C2), in an alloxan-induced diabetic rat model. Diabetic rats which were administered with C1, C2 and EE (100 and 200 mg per kg b. wt.) for 4 weeks showed reduced levels of fasting blood glucose and reversal of abnormalities in serum/urine protein, urea and creatinine in diabetic rats compared to the diabetic control group of rats. Diabetic symptoms such as polyphagia, polydipsia, polyuria, urine glucose and reduced body weight were ameliorated in the diabetic group of rats fed with EE, C1 and C2 (100 mg per kg b. wt., once daily) for 28 days. The levels of insulin and Hb were also increased, while the HbA1c level was reduced. The altered activities of hepatic marker enzymes viz., aspartate transaminase (AST), alanine transaminase (ALT) and alkaline phosphatase (ALP); glycolytic enzyme (hexokinase); shunt enzyme (glucose-6-phosphate dehydrogenase); gluconeogenic enzymes (glucose-6-phosphatase, fructose-1,6-bisphosphatase and lactate dehydrogenase) and pyruvate kinase were significantly reverted to normal levels by the administration of EE, C1 and C2. In addition, increased levels of hepatic glycogen and glycogen synthase and the corresponding decrease of glycogen phosphorylase activity in diabetic rats illustrated the antihyperglycaemic potential of EE and its components. The histological observations revealed a marked regeneration of the ß-cells in the drug treated diabetic rats. These findings suggest that EE might exert its antidiabetic potential in the presence of C1 and C2, attributable to the enhanced glycolytic activity, besides increasing the hepatic glucose utilization in diabetic rats by stimulating insulin secretion from the remnant ß-cells.

In vivo Toxicity Studies on Gall Extracts of Terminalia chebula (Gaertn.) Retz. (Combretaceae).

UNLABELLED: The galls of Terminala chebula (Gaertn.) Retz. (Combretaceae) are used for the treatment of various diseases in folk medicine and has been found to posses anti-inflammatory, anti-bacterial, anti-helmintic, anti-tyrosinase, and anti-aging activities. Considering the ethano-botanical and diverse pharmacological applications of galls of T. chebula, in this study, we investigate the possible toxic effects of different gall extracts of T. chebula by Brine shrimp (Artemia salina) toxicity assay. The cytotoxicity test of leaf gall extracts (petroleum ether, chloroform, ethanol, and aqueous) of T. chebula was evaluated by Brine shrimp (A. salina) toxicity assay, which is based on the ability to kill laboratory cultured Artemia nauplii (animals eggs) and also total content of polyphenols, flavonoids with other qualitative phytochemical analysis of the extract were determined. It was observed that the petroleum ether extract was virtually nontoxic on the shrimps, and exhibited very low toxicity with LC50 value of 4356.76 µg/ml. Furthermore, the chloroform extract exhibited very low toxicity, giving LC50 value of 1462.2 µg/ml. On the other hand, the ethanol extract was very toxic to brine shrimps with LC50 value of 68.64 µg/ml. The ethanol extract had the highest total phenolic and flavonoid content of 136 ± 1.5 mg of gallic acid equivalent/g d.w and 113 ± 1.6 mg of quercetin equivalent/g d.w, respectively. The higher toxicity effect was positively correlated to the high content of total polyphenols/flavonoids in the extract. This significant lethality of different extracts to brine shrimp is an indicative of the presence of potent cytotoxic components which warrants further investigation. SUMMARY: The present study investigates the toxicity effect of different extracts of galls of T. chebulla, which would serve as an index for formulation of drugs for treatment of various diseases. Presumably, these activities could be attributed in part to the polyphenolic features of the extract, as there was a strong correlation of higher toxic effect with that of high total phenolic and flavonoids content in the ethanolic leaf gall extracts of T. chebula.

Inhibition of Group IIA Secretory Phospholipase A2 and its Inflammatory Reactions in Mice by Ethanolic Extract of Andrographis paniculata, a Well-known Medicinal Food.

UNLABELLED: Andrographis paniculata Nees is an important medicinal plant found in the tropical regions of the world, which has been traditionally used in Indian and Chinese medicinal systems. It is also used as medicinal food. A. paniculata is found to exhibit anti-inflammatory activities; however, its inhibitory potential on inflammatory Group IIA phospholipases A2 (PLA2) and its associated inflammatory reactions are not clearly understood. The aim of the present study is to evaluate the inhibitory/neutralizing potential of ethanolic extract of A. paniculata on the isolated inflammatory PLA2 (VRV-PL-VIIIa) from Daboii rusellii pulchella (belonging to Group IIA inflammatory secretory PLA2 [sPLA2]) and its associated edema-induced activities in Swiss albino mice. A. paniculata extract dose dependently inhibited the Group IIA sPLA2 enzymatic activity with an IC50 value of 10.3 ± 0.5 µg/ml. Further, the extract dose dependently inhibited the edema formation, when co-injected with enzyme indicating that a strong correlation exists between lipolytic and pro-inflammatory activities of the enzyme. In conclusion, results of this study shows that the ethanolic extract of A. paniculata effectively inhibits Group IIA sPLA2 and its associated inflammatory activities, which substantiate its anti-inflammatory properties. The results of the present study warranted further studies to develop bioactive compound (s) in ethanolic extract of A. paniculata as potent therapeutic agent (s) for inflammatory diseases. SUMMARY: This study emphasis the anti-inflammatory effect of A. paniculata by inhibiting the inflammatory Group IIA sPLA2 and its associated inflammatory activities such as edema. It was found that there is a strong correlation between lipolytic activity and pro-inflammatory activity inhibition. Therefore, the study suggests that the extract processes potent anti-inflammatory agents, which could be developed as a potential therapeutic agent against inflammatory and related diseases.

Evaluating the Anticancer Potential of Ethanolic Gall Extract of Terminalia chebula (Gaertn.) Retz. (Combretaceae).

UNLABELLED: Plants have been an important source for discovery of anticancer compounds. With the current decline in the number of new molecular entities from the pharmaceutical industry, novel anticancer agents are being sought from traditional medicines; therefore the anticancer efficacy of many plants that are used in traditional medicine is yet to be verified. The objective of the study was to evaluate the cytotoxic potential of ethanolic leaf gall extract of Terminalia chebula are evaluated against buffalo rat liver 3A, MCF-7 (Human mammary gland adenocarcinoma) and A-549 (Human lung cancer) cell lines. The cytotoxic effect of the ethanolic extract was evaluated by MTT assay. The extract was potent and effective in inducing cytotoxic effects in all the cell lines with an IC50 value of 305.18 ± 1.7 µg/mL, 643.13 ± 4.2 µg/mL, and 208.16 ± 3.7 µ/mL, respectively. The extract was more effective against A549 cell lines when compared to others. The presences of phenolics, triterpenoids, and flavonoids were identified in the extract. The extract showed total phenolic and flavonoid content of 478 ± 2.2 mg of gallic acid equivalent/g d.w and 538 ± 1.4 mg of quercetinequivalent/g d.w, respectively. This higher content of total phenolics and flavonoids found in the ethanolic extract was directly associated to higher cytotoxicity activity. CONCLUSION: The ethanolic leaf gall extract of T. chebula showed effective cytotoxic activities; which might be attributed to the phenolics/flavonoids present in higher concentration. Future work will be interesting to know the chemical composition of the extract and also better understand the mechanism of action of the constituents present in the extract to develop it as drug for therapeutic application. SUMMARY: The present investigation establishes the anticancer activities of T. chebula leaf gall extracts on BRL3A, MCF-7, and A-549 cells. Presumably, these activities could be attributed in part to the phenolics/flavanoids features of the extract that has been demonstrated to act as cytotoxic agents. The experimental evidence obtained in the laboratory model could provide a rationale for the traditional use of plant as a source of easily available effective anticancer agents to the people, particularly in developing countries.

Therapeutic Potentials of Triterpenes in Diabetes and its Associated Complications.

Diabetes is a major chronic metabolic disorder globally and around of 285 million people are affected by the disease and the number is expected to double in the next two decades. The major focus of anti-diabetic therapies is to enhance insulin production, sensitivity and/or reduce the blood glucose level. Although several synthetic drugs have been developed as antidiabetic agents but their utility has been hampered due to their side effects and poor efficacy. In this scenario, research on natural products has been gained importance due their safety profile in toxicity studies. Terpenoids belong to an important class of natural products and several terpenoids have been reported as antidiabetic agents. Some of them are under various stages of pre-clinical and clinical evaluation to develop them as antidiabetic agents. These agents can inhibit enzymes responsible for the development of insulin resistance, normalization of plasma glucose and insulin levels and glucose metabolism. Triterpenes can act as promising agents in the treatment of diabetic retinopathy, neuropathy and nephropathy or in impaired wound healing by inhibiting several pathways involved in the diabetes and associated complications. However, efforts in understanding the biological actions and clinical studies involving the applications of triterpenes in treating diabetes are very limited. Hence, special attention is imperative to explore the therapeutic potential of these compounds and provide new information to the scientific community. This review aims to provide the recent advances in triterpenes chemistry, its derivatives, biological interventions and its therapeutic applications with special emphasis on diabetes and its associated disorders.

The anti-inflammatory activity of standard aqueous stem bark extract of Mangifera indica L. as evident in inhibition of Group IA sPLA2.

The standard aqueous stem bark extract is consumed as herbal drink and used in the pharmaceutical formulations to treat patients suffering from various disease conditions in Cuba. This study was carried out to evaluate the modulatory effect of standard aqueous bark extract of M. indica on Group IA sPLA2. M. indica extract, dose dependently inhibited the GIA sPLA2 (NN-XIa-PLA2) activity with an IC50 value 8.1 µg/ml. M. indica extract effectively inhibited the indirect hemolytic activity up to 98% at ~40 µg/ml concentration and at various concentrations (0-50 µg/ml), it dose dependently inhibited the edema formation. When examined as a function of increased substrate and calcium concentration, there was no relieve of inhibitory effect on the GIA sPLA2. Furthermore, the inhibition was irreversible as evidenced from binding studies. It is observed that the aqueous extract ofM. indica effectively inhibits sPLA2 and it is associated inflammatory activities, which substantiate their anti-inflammatory properties. The mode of inhibition could be due to direct interaction of components present in the extract, with sPLA2 enzyme. Further studies on understanding the principal constituents, responsible for the anti-inflammatory activity would be interesting to develop this into potent anti-inflammatory agent.

Anti-Lipoxygenase Activity of Leaf Gall Extracts of Terminalia chebula (Gaertn.) Retz. (Combretaceae).

UNLABELLED: Lipoxygenase (LOX) inhibitors are the promising therapeutic target for treating a wide spectrum of inflammatory-related diseases such as cancer, asthma, lymphoma, leukemia, and autoimmune disorders. In the present study, the photochemical constituents and the anti-LOX potential of leaf galls of Terminalia chebula are evaluated to exemplify its further potential development as medicine. Extracts of T. chebula galls were tested for anti-LOX activity using linoleic acid as substrate and lipoxidase as an enzyme and also the total content of polyphenols with phytochemical analysis of the extract were determined. The presence of highest total phenolic and flavonoid content of 141 ± 2.2 mg of gallic acid equivalent/g d.w and 125 ± 1.4 mg of quercetin equivalent/g d.w and maximal LOX inhibitory activity (52.67%) at 800 µg/mL concentrations were identified in the ethanolic extracts of leaf galls of T.chebula. The higher LOX inhibitory activity was positively correlated to the high content of total polyphenols/flavonoids. The results of this study confirm the folklore use of T. chebula leaves gall extracts as a natural anti-inflammatory agent and justify its ethnobotanical use. Therefore, the results encourage the use of T. chebula leave gall extracts for medicinal health, functional food, and nutraceuticals applications. SUMMARY: The present investigation demonstrated promising anti-LOX proper-ties of T. chebula leaves gall extracts. Presumably, these activities could be attributed in part to the polyphenolic features of the extract, as there was a strong correlation of higher LOX inhibiting activities with that of high total phenolic and flavonoid content in the methanolic leaf gall extracts of T. chebula. The results of this study confirm the folklore use of T. chebula leaves gall extracts as a natural anti-inflammatory agent and justify the ethnobotanical approach in the search for novel bioactive com-pounds.

Targeting arachidonic acid pathway by natural products for cancer prevention and therapy.

Arachidonic acid (AA) pathway, a metabolic process, plays a key role in carcinogenesis. Hence, AA pathway metabolic enzymes phospholipase A2s (PLA2s), cyclooxygenases (COXs) and lipoxygenases (LOXs) and their metabolic products, such as prostaglandins and leukotrienes, have been considered novel preventive and therapeutic targets in cancer. Bioactive natural products are a good source for development of novel cancer preventive and therapeutic drugs, which have been widely used in clinical practice due to their safety profiles. AA pathway inhibitory natural products have been developed as chemopreventive and therapeutic agents against several cancers. Curcumin, resveratrol, apigenin, anthocyans, berberine, ellagic acid, eugenol, fisetin, ursolic acid, [6]-gingerol, guggulsteone, lycopene and genistein are well known cancer chemopreventive agents which act by targeting multiple pathways, including COX-2. Nordihydroguaiaretic acid and baicalein can be chemopreventive molecules against various cancers by inhibiting LOXs. Several PLA2s inhibitory natural products have been identified with chemopreventive and therapeutic potentials against various cancers. In this review, we critically discuss the possible utility of natural products as preventive and therapeutic agents against various oncologic diseases, including prostate, pancreatic, lung, skin, gastric, oral, blood, head and neck, colorectal, liver, cervical and breast cancers, by targeting AA pathway. Further, the current status of clinical studies evaluating AA pathway inhibitory natural products in cancer is reviewed. In addition, various emerging issues, including bioavailability, toxicity and explorability of combination therapy, for the development of AA pathway inhibitory natural products as chemopreventive and therapeutic agents against human malignancy are also discussed.

Evaluating the inhibitory potential of Withania somnifera on platelet aggregation and inflammation enzymes: An in vitro and in silico study.

Context Withania somnifera (L.) Dunal is traditionally used for treating various ailments, but lacks scientific evaluation. Objective This study evaluates Withania somnifera (WS) for its effect on platelet activity and inflammatory enzymes. Materials and methods Aqueous and ethanolic (1:1) leaf extracts were subjected to in vitro indirect haemolytic activity using Naja naja venom, human platelet aggregation was quantified for lipid peroxidation using arachidonic acid (AA) as agonist and 5-lipoxygenase (5-LOX) levels were determined using standard spectrometric assays. Further, molecular docking was performed by the ligand fit method using molegro software package (Molegro ApS, Aarhus, Denmark). Results The study found that aqueous and ethanol extracts have very negligible effect (15%) with an IC50 value of 13.8 mg/mL on PLA2 from Naja naja venom. Further, extracts of WS also had very little effect (18%) with an IC50 value of 16.6 mg/mL on malondialdehyde (MDA) formation. However, a 65% inhibition of 5-LOX with an IC50 value of 0.92 mg/mL was observed in 1:1 ethanol extracts. The same was evident from SAR model with the active ingredient withaferin A binding predominantly on Phe 77, Tyr 98, Arg 99, Asp 164, Leu 168, Ser 382, Arg 395, Tyr 396 and Tyr 614 with an atomic contact energy value of -128.96 compared to standard phenidone (-103.61). Thus, the current study validates the application of WS for inflammatory diseases. Conclusion This study reveals the inhibitory potential of W. somnifera on inflammatory enzymes and platelet aggregation. Thus, WS can serve as a newer, safer and affordable medicine for inflammatory diseases.

Antioxidant activities of ficus glomerata (moraceae) leaf gall extracts.

An excess production or decreased scavenging of reactive oxygen species (ROS) has been implicated in the pathogenesis of diverse metabolic disorders such as diabetes, cancer, atherosclerosis and neurodegeneration. Hence the antioxidant therapy has gained an utmost importance in the treatment of such diseases linked to free radicals. The medicinal properties of plants have been investigated and explored for their potent antioxidant activities to counteract metabolic disorders. This research highlights the chemical composition and antioxidant potential of leaf gall extracts (aqueous and methanol) of Ficus glomerata (F. glomerata), which is extensively used in the preparation of traditional medications to treat various metabolic diseases. The presences of phenolics, flavonoids, phytosterols, terpenoids and reducing sugars were identified in both the extracts. In comparison to the aqueous extract, the methanol extract had the highest total phenolic and flavonoid content at 370 ± 3.2 mg of gallic acid equivalent per gram of dry weight (mg GAE/g dw) and 155 ± 3.2 mg of quercetin equivalent per gram of dry weight (mg QUE/g dw), respectively. The antioxidant activities of leaf gall extracts were examined using diphenylpicrylhydrazyl (DPPH), Nitric oxide scavenging, hydroxyl scavenging and ferric reducing power (FRAP) methods. In all the methods, the methanolic extract showed higher antioxidant potential than the aqueous extract. A higher content of both total phenolics and flavonoids were found in the methanolic extract and the significantly high antioxidant activity can be positively correlated to the high content of total polyphenols/flavonoids of the methanol extract. The results of this study confirm the folklore use of F. glomerata leaf gall extracts as a natural antioxidant and justify its ethnobotanical use. Further, the results of antioxidant properties encourage the use of F. glomerata leaf gall extracts for medicinal health, functional food and nutraceuticals applications. Future work will be interesting in knowing the chemical composition and better understand the mechanism of action of the antioxidants present for development as drug for its therapeutic application.

Antioxidant activities of leaf galls extracts of Terminalia chebula (Gaertn.) Retz. (Combretaceae).

BACKGROUND: Free radicals are implicated in several metabolic diseases and the antioxidant therapy has gained an utmost importance in the treatment. The medicinal properties of plants have been investigated and explored for their potent antioxidant activities to counteract metabolic disorders. In this study, the chemical composition and free radical scavenging potential of leaf gall extracts (ethanol, petroleum ether, chloroform and aqueous) of Terminelia chebula is evaluated, which is extensively used in the preparation of traditiona medications to treat various metabolic diseases. METHODS: The presences of phenolics, flavonoids, triterpens, saponins, glycosides, phytosterols, reducing sugars were identified in the extracts according to standard procedures. The free radical scavenging activities of the extract were also analysed by standard procedures. RESULTS: The methanol extract had the highest total phenolic and flavonoid content. The antioxidant activities of leaf gall extracts were examined using diphenylpicrylhydrazyl (DPPH), Super oxide radical scavenging, Hydroxyl scavenging and ferric reducing power (FRAP) methods. In all the methods, the ethanolic extract showed higher free radical scavenging potential than all the other extracts. CONCLUSIONS: As the higher content of both total phenolics and flavonoids were found in the ethanolic extract, so the significantly high antioxidant activity can be positively correlated to the high content of total polyphenols/flavonoids of the ethanol extract. The results of this study confirm the folklore use of T. chebula leaves gall extracts as a natural antioxidant and justify its ethnobotanical use. Further, the results of antioxidant properties encourage the use of T. chebula leave gall extracts for medicinal health, functional food and nutraceutical applications.

Antioxidant activity of insect gall extracts of Pistacia integerrima.

BACKGROUND: Pistacia integerrima (P. integerrina) insect galls are widely used in ayurveda and siddha system of medicine as karkatasringi. The use of leaf galls as a rejuvenator may be attributed to antioxidant property, however there is less scientific evidence. Therefore, the aim of this study was to evaluate the chemical composition and the antioxidant potential of leaf gall extracts (aqueous and ethanol) of P. integerrina, which is extensively used in the preparation of traditional medications. METHODS: The antioxidant activities of aqueous and ethanolic leaf gall extracts were examined using diphenylpicrylhydrazyl (DPPH), hydroxyl scavenging and ferric reducing power (FRAP) methods. RESULTS: The presences of phenolics, tannins, phytosterols, triterpenoids, saponins, flavonoids and reducing sugars were identified in both the extracts. In comparison to the aqueous extract, the ethanolic extract had the highest total phenolic and flavonoid content at 234 ±2.4 mg of GAE/g d.w. and 95.5 ±3.2 mg of QUE/g d.w., respectively. This higher content of total phenolics and flavonoids found in the ethanolic extract was directly associated with higher antioxidant activity. CONCLUSIONS: This study demonstrates the poetnet antioxidant activities of P. integerrima leaf gall extracts. Further, there was a strong association between the higher antioxidant activities with that of higher total phenolic and flavonoid content in the ethanolic leaf gall extracts of P. integerrima. The results encourage the use of P. integerrima leaf gall extracts for medicinal health, functional food and nutraceuticals applications, due to their antioxidant properties. Future work will be interesting to learn the chemical composition and better understand the mechanism of action of the antioxidants present in the extract for development as a drug for therapeutic application.

Antioxidant activity of Syzygium cumini leaf gall extracts.

INTRODUCTION: Free radicals are implicated in several metabolic diseases and the medicinal properties of plants have been explored for their potent antioxidant activities to counteract metabolic disorders. This research highlights the chemical composition and antioxidant potential of leaf gall extracts (aqueous and methanol) of Syzygium cumini (S. cumini), which have been extensively used in traditional medications to treat various metabolic diseases. METHODS: The antioxidant activities of leaf gall extracts were examined using diphenylpicrylhydrazyl (DPPH), nitric oxide scavenging, hydroxyl scavenging and ferric reducing power (FRAP) methods. RESULTS: In all the methods, the methanolic extract showed higher antioxidant potential than the standard ascorbic acid. The presence of phenolics, flavonoids, phytosterols, terpenoids, and reducing sugars was identified in both the extracts. When compared, the methanol extract had the highest total phenolic and flavonoid contents at 474±2.2 mg of GAE/g d.w and 668±1.4 mg of QUE/g d.w, respectively. The significant high antioxidant activity can be positively correlated to the high content of total polyphenols/flavonoids of the methanol extract. CONCLUSION: The present study confirms the folklore use of S. cumini leaves gall extracts as a natural antioxidant and justifies its ethnobotanical use. Further, the result of antioxidant properties encourages the use of S. cumini leaf gall extracts for medicinal health, functional food and nutraceuticals applications.