Medicinal plant molecules against hepatitis C virus: Current status and future prospect.

Hepatitis C virus (HCV), a global malady, causes acute and chronic hepatitis leading to permanent liver damage, hepatocellular carcinoma, and death. Modern anti-HCV therapies are efficient, but mostly inaccessible for residents of underdeveloped regions. To innovate more effective treatments at affordable cost, medicinal plant-based products need to be explored. The aim of this article is to review plant constituents in the light of putative anti-HCV mechanisms of action, and discuss existing problems, challenges, and future directions for their potential application in therapeutic settings. One hundred sixty literatures were collected by using appropriate search strings via scientific search engines: Google Scholar, PubMed, ScienceDirect, and Scopus. Bibliography was prepared using Mendeley desktop software. We found a substantial number of plants that were reported to inhibit different stages of HCV life cycle. Traditional medicinal plants such as Phyllanthus amarus Schumach. and Thonn., Eclipta alba (L.) Hassk., and Acacia nilotica (L.) Delile exhibited strong anti-HCV activities. Again, several phytochemicals such as epigallocatechin-3-gallate, honokilol, punicalagin, and quercetin have shown broad-spectrum anti-HCV effect. We have presented promising phytochemicals like silymarin, curcumin, glycyrrhizin, and camptothecin for nanoparticle-based hepatocyte-targeted drug delivery. Nevertheless, only a few animal studies have been performed to validate the anti-HCV effect of these plant products. Again, insufficient clinical evaluation of the safety and effectiveness of herbal medications remain a problem. Selected plants products could be developed as novel therapeutics for HCV patients only after scrupulous evaluation of their safety and efficacy in a clinical set-up.

Plant Products as Inhibitors of Coronavirus 3CL Protease.

Background: The ongoing COVID-19 pandemic has created an alarming situation due to extensive loss of human lives and economy, posing enormous threat to global health security. Till date, no antiviral drug or vaccine against SARS-CoV-2 has reached the market, although a number of clinical trials are under way. The viral 3-chymotrypsin-like cysteine protease (3CLpro), playing pivotal roles in coronavirus replication and polyprotein processing, is essential for its life cycle. In fact, 3CLpro is already a proven drug discovery target for SARS- and MERS-CoVs. This underlines the importance of 3CL protease in the design of potent drugs against COVID-19. Methods: We have collected one hundred twenty-seven relevant literatures to prepare the review article. PubMed, Google Scholar and other scientific search engines were used to collect the literature based on keywords, like "SARS-CoVs-3CL protease," "medicinal plant and anti-SARS-CoVs-3CL protease" published during 2003-2020. However, earlier publications related to this topic are also cited for necessary illustration and discussion. Repetitive articles and non-English studies were excluded. Results: From the literature search, we have enlisted medicinal plants reported to inhibit coronavirus 3CL protease. Some of the plants like Isatis tinctoria L. (syn. Isatis indigotica Fort.), Torreya nucifera (L.) Siebold and Zucc., Psoralea corylifolia L., and Rheum palmatum L. have exhibited strong anti-3CLpro activity. We have also discussed about the phytochemicals with encouraging antiviral activity, such as, bavachinin, psoralidin, betulinic acid, curcumin and hinokinin, isolated from traditional medicinal plants. Conclusion: Currently, searching for a plant-derived novel drug with better therapeutic index is highly desirable due to lack of specific treatment for SARS-CoV-2. It is expected that in-depth evaluation of medicinally important plants would reveal new molecules with significant potential to inhibit coronavirus 3CL protease for development into approved antiviral drug against COVID-19 in future.

Anti-infective activities of 11 plants species used in traditional medicine in Malaysia.

Treatment of drug resistant protozoa, bacteria, and viruses requires new drugs with alternative chemotypes. Such compounds could be found from Southeast Asian medicinal plants. The present study examines the cytotoxic, antileishmanial, and antiplasmodial effects of 11 ethnopharmacologically important plant species in Malaysia. Chloroform extracts were tested for their toxicity against MRC-5 cells and Leishmania donovani by MTT, and chloroquine-resistant Plasmodium falciparum K1 strain by Histidine-Rich Protein II ELISA assays. None of the extract tested was cytotoxic to MRC-5 cells. Extracts of Uvaria grandiflora, Chilocarpus costatus, Tabernaemontana peduncularis, and Leuconotis eugenifolius had good activities against L. donovani with IC50 < 50 µg/mL. Extracts of U. grandiflora, C. costatus, T. peduncularis, L. eugenifolius, A. subulatum, and C. aeruginosa had good activities against P. falciparum K1 with IC50 < 10 µg/mL. Pinoresinol isolated from C. costatus was inactive against L. donovani and P. falciparum. C. costatus extract and pinoresinol increased the sensitivity of Staphylococcus epidermidis to cefotaxime. Pinoresinol demonstrated moderate activity against influenza virus (IC50 = 30.4 ±â€¯11 µg/mL) and was active against Coxsackie virus B3 (IC50 = 7.1 ±â€¯3.0 µg/mL). ß-Amyrin from L. eugenifolius inhibited L. donovani with IC50 value of 15.4 ±â€¯0.01 µM. Furanodienone from C. aeruginosa inhibited L. donovani and P. falciparum K1 with IC50 value of 39.5 ±â€¯0.2 and 17.0 ±â€¯0.05 µM, respectively. Furanodienone also inhibited the replication of influenza and Coxsackie virus B3 with IC50 value of 4.0 ±â€¯0.5 and 7.2 ±â€¯1.4 µg/mL (Ribavirin: IC50: 15.6 ±â€¯2.0 µg/mL), respectively. Our study provides evidence that medicinal plants in Malaysia have potentials as a source of chemotypes for the development of anti-infective leads.

Anti-HCV Activity from Semi-purified Methanolic Root Extracts of Valeriana wallichii.

Hepatitis C virus (HCV) is a serious global health problem affecting approximately 130-150 million individuals. Presently available direct-acting anti-HCV drugs have higher barriers to resistance and also improved success rate; however, cost concerns limit their utilization, especially in developing countries like India. Therefore, development of additional agents to combat HCV infection is needed. In the present study, we have evaluated anti-HCV potential of water, chloroform, and methanol extracts from roots of Valeriana wallichii, a traditional Indian medicinal plant. Huh-7.5 cells infected with J6/JFH chimeric HCV strain were treated with water, chloroform, and methanol extracts at different concentrations. Semi-quantitative reverse transcription polymerase chain reaction result demonstrated that methanolic extract showed reduction in HCV replication. The methanolic extract was fractionated by thin layer chromatography, and the purified fractions (F1, F2, F3, and F4) were checked for anti-HCV activity. Significant viral inhibition was noted only in F4 fraction. Further, intrinsic fluorescence assay of purified HCV RNA-dependent RNA polymerase NS5B in the presence of F4 resulted in sharp quenching of intrinsic fluorescence with increasing amount of plant extract. Our results indicated that methanolic extract of V. wallichii and its fraction (F4) inhibited HCV by binding with HCV NS5B protein. The findings would be further investigated to identify the active principle/lead molecule towards development of complementary and alternative therapeutics against HCV. Copyright © 2017 John Wiley & Sons, Ltd.

Polyphenolic Secondary Metabolites Synergize the Activity of Commercial Antibiotics against Clinical Isolates of ß-Lactamase-producing Klebsiella pneumoniae.

Emergence of worldwide antimicrobial resistance prompted us to study the resistance modifying potential of plant-derived dietary polyphenols, mainly caffeic acid, ellagic acid, epigallocatechin-3-gallate (EGCG) and quercetin. These compounds were studied in logical combination with clinically significant antibiotics (ciprofloxacin/gentamicin/tetracycline) against Klebsiella pneumoniae, after conducting phenotypic screening of a large number of clinical isolates and selecting the relevant strains possessing extended-spectrum ß-lactamase (ESBL) and K. pneumoniae carbapenemase (KPC)-type carbapenemase enzymes only. The study demonstrated that EGCG and caffeic acid could synergize the activity of tested antibiotics within a major population of ß-lactamase-producing K. pneumoniae. In spectrofluorimetric assay, ~17-fold greater ciprofloxacin accumulation was observed within K. pneumoniae cells pre-treated with EGCG in comparison with the untreated control, indicating its ability to synergize ciprofloxacin to restrain active drug-efflux. Further, electron micrograph of ESBL-producing K. pneumoniae clearly demonstrated the prospective efficacy of EGCG towards biofilm degradation.

Cinnamic Acid Bornyl Ester Derivatives from Valeriana wallichii Exhibit Antileishmanial In Vivo Activity in Leishmania major-Infected BALB/c Mice.

Human leishmaniasis covers a broad spectrum of clinical manifestations ranging from self-healing cutaneous leishmaniasis to severe and lethal visceral leishmaniasis caused among other species by Leishmania major or Leishmania donovani, respectively. Some drug candidates are in clinical trials to substitute current therapies, which are facing emerging drug-resistance accompanied with serious side effects. Here, two cinnamic acid bornyl ester derivatives (1 and 2) were assessed for their antileishmanial activity. Good selectivity and antileishmanial activity of bornyl 3-phenylpropanoate (2) in vitro prompted the antileishmanial assessment in vivo. For this purpose, BALB/c mice were infected with Leishmania major promastigotes and treated with three doses of 50 mg/kg/day of compound 2. The treatment prevented the characteristic swelling at the site of infection and correlated with reduced parasite burden. Transmitted light microscopy and transmission electron microscopy of Leishmania major promastigotes revealed that compounds 1 and 2 induce mitochondrial swelling. Subsequent studies on Leishmania major promastigotes showed the loss of mitochondrial transmembrane potential (ΔΨm) as a putative mode of action. As the cinnamic acid bornyl ester derivatives 1 and 2 had exhibited antileishmanial activity in vitro, and compound 2 in Leishmania major-infected BALB/c mice in vivo, they can be regarded as possible lead structures for the development of new antileishmanial therapeutic approaches.

Antimicrobial activity of pomegranate fruit constituents against drug-resistant Mycobacterium tuberculosis and ß-lactamase producing Klebsiella pneumoniae.

CONTEXT: The global surge in multi-drug resistant bacteria and the imminence of tuberculosis pandemic necessitate alternative therapeutic approaches to augment the existing medications. Pomegranate, the fruit of Punica granatum Linn. (Punicaceae), widely recognized for potency against a broad spectrum of bacterial pathogens, deserves further investigation in this respect. OBJECTIVE: This study determines the therapeutic potential of pomegranate juice, extracts of non-edible peel prepared with methanol/water, and its four polyphenolic constituents, namely caffeic acid, ellagic acid, epigallocatechin-3-gallate (EGCG) and quercetin, against drug-resistant clinical isolates. MATERIALS AND METHODS: Phenotypic characterisation of Mycobacterium tuberculosis, extended-spectrum ß-lactamase (ESBL) and KPC-type carbapenemase producing Klebsiella pneumoniae was performed by biochemical and molecular methods. Resistance profiles of M. tuberculosis and K. pneumoniae were determined using LJ proportion and Kirby-Bauer methods, respectively. Pomegranate fruit extracts, and the compounds, were evaluated at a dose range of 1024-0.5 µg/mL, and 512-0.25 µg/mL, respectively, to determine minimum inhibitory (MIC) and bactericidal concentrations (MBC) against the drug-resistant isolates by the broth micro-dilution method. RESULTS: The peel extracts exhibited greater antimycobacterial activity (MIC 64-1024 µg/mL) than the potable juice (MIC 256 - > 1024 µg/mL). EGCG and quercetin exhibited higher antitubercular (MIC 32-256 µg/mL) and antibacterial (MIC 64-56 µg/mL) potencies than caffeic acid and ellagic acid (MIC 64-512 µg/mL). DISCUSSION AND CONCLUSION: The pomegranate fruit peel and pure constituents were active against a broad panel of M. tuberculosis and ß-lactamase producing K. pneumoniae isolates. EGCG and quercetin need further investigation for prospective application against respiratory infections.

Antileishmanial and cytotoxic compounds from Valeriana wallichii and identification of a novel nepetolactone derivative.

The chloroform extract of Valeriana wallichii (V. wallichii) rhizomes was investigated to elucidate the structures responsible for reported antileishmanial activity. Besides bornyl caffeate (1, already been reported by us previously), bioassay-guided fractionation resulted in two additional cinnamic acid derivatives 2-3 with moderate leishmanicidal activity. The structure of a novel nepetolactone derivative 4 having a cinnamic acid moiety was elucidated by means of spectral analysis. To the best of our knowledge villoside aglycone (5) was isolated from this plant for the first time. The bioassay-guided fractionation yielded two new (compounds 6-7) and two known valtrates (compounds 8-9) with leishmanicidal potential against Leishmania major (L. major) promastigotes. In addition, ß-bisabolol (10), α-kessyl alcohol (11), valeranone (12), bornyl isovalerate (13) and linarin-2-O-methylbutyrate (14) were identified. This is the first report on the isolation of 4'-demethylpodophyllotoxin (15), podophyllotoxin (16) and pinoresinol (17) in V. wallichii. In total thirteen known and four new compounds were identified from the extract and their cytotoxic and antileishmanial properties were evaluated.

Acetylamine derivative of diospyrin, a plant-derived binaphthylquinonoid, inhibits human colon cancer growth in Nod-Scid mice.

Anticancer activity of diospyrin and its derivatives (1-5) was evaluated against thirteen human cell lines. Compared to diospyrin (1), the acetylamine derivative (4) exhibited increase in cytotoxicity, particularly in HT-29 colon cancer cells, showing GI50 values of 33.90 and 1.96 µM, respectively. Also, enhanced toxicity was observed when cells, pre-treated with compound 4, were exposed to radiation. In vivo assessment of 4 was undertaken on tumour-bearing Nod-Scid mice treated at 4 mg/kg/day. Significant reduction in relative tumour volume (~86-91 %) was observed during the 12th-37th days after drug treatment. Increased caspase-3 activity and DNA ladder formation was observed in HT-29 cells after treatment with 4, suggesting induction of apoptotic death after drug treatment. Moreover, flow cytometric determination of Annexin V- FITC positive and PI negative cells demonstrated 17.4, 26.4, and 27.9 % of early apoptosis, respectively, upon treatment with 5, 10 and 25 µM of 4. HT-29 cells after treatment with 4 (1-25 µM) revealed ~2.5- 3- folds generation of ROS. Furthermore, concentration dependent decrease of mitochondrial trans-membrane potential (∆ψm), and expression of Bcl-2/Bax and other marker proteins suggested involvement of mitochondrial pathway of cell death. Overall, our results demonstrated the underlying cell-death mechanism of the plant-derived naphthoquinonoid (4), and established it as a prospective chemotherapeutic 'lead' molecule against colon cancer.

Antileishmanial lead structures from nature: analysis of structure-activity relationships of a compound library derived from caffeic Acid bornyl ester.

Bioassay-guided fractionation of a chloroform extract of Valeriana wallichii (V. wallichii) rhizomes lead to the isolation and identification of caffeic acid bornyl ester (1) as the active component against Leishmania major (L. major) promastigotes (IC50 = 48.8 µM). To investigate the structure-activity relationship (SAR), a library of compounds based on 1 was synthesized and tested in vitro against L. major and L. donovani promastigotes, and L. major amastigotes. Cytotoxicity was determined using a murine J774.1 cell line and bone marrow derived macrophages (BMDM). Some compounds showed antileishmanial activity in the concentration range of pentamidine and miltefosine which are the standard drugs in use. In the L. major amastigote assay compounds 15, 19 and 20 showed good activity with relatively low cytotoxicity against BMDM, resulting in acceptable selectivity indices. Molecules with adjacent phenolic hydroxyl groups exhibited elevated cytotoxicity against murine cell lines J774.1 and BMDM. The Michael system seems not to be essential for antileishmanial activity. Based on the results compound 27 can be regarded as new lead structure for further structure optimization.

Antitubercular and antibacterial activity of quinonoid natural products against multi-drug resistant clinical isolates.

Multi-drug resistant Mycobacterium tuberculosis and other bacterial pathogens represent a major threat to human health. In view of the critical need to augment the current drug regime, we have investigated therapeutic potential of five quinonoids, viz. emodin, diospyrin, plumbagin, menadione and thymoquinone, derived from natural products. The antimicrobial activity of quinonoids was evaluated against a broad panel of multi-drug and extensively drug-resistant tuberculosis (M/XDR-TB) strains, rapid growing mycobacteria and other bacterial isolates, some of which were producers of ß-lactamase, Extended-spectrum ß-lactamase (ESBL), AmpC ß-lactamase, metallo-beta-lactamase (MBL) enzymes, as well as their drug-sensitive ATCC counterparts. All the tested quinones exhibited antimycobacterial and broad spectrum antibacterial activity, particularly against M. tuberculosis (lowest MIC 0.25 µg/mL) and Gram-positive bacteria (lowest MIC <4 µg/mL) of clinical origin. The order of antitubercular activity of the tested quinonoids was plumbagin > emodin ~ menadione ~ thymoquinone > diospyrin, whereas their antibacterial efficacy was plumbagin > menadione ~ thymoquinone > diospyrin > emodin. Furthermore, this is the first evaluation performed on these quinonoids against a broad panel of drug-resistant and drug-sensitive clinical isolates, to the best of our knowledge.

Evaluation of a diospyrin derivative as antileishmanial agent and potential modulator of ornithine decarboxylase of Leishmania donovani.

World health organization has called for academic research and development of new chemotherapeutic strategies to overcome the emerging resistance and side effects exhibited by the drugs currently used against leishmaniasis. Diospyrin, a bis-naphthoquinone isolated from Diospyros montana Roxb., and its semi-synthetic derivatives, were reported for inhibitory activity against protozoan parasites including Leishmania. Presently, we have investigated the antileishmanial effect of a di-epoxide derivative of diospyrin (D17), both in vitro and in vivo. Further, the safety profile of D17 was established by testing its toxicity against normal macrophage cells (IC50∼20.7 µM), and also against normal BALB/c mice in vivo. The compound showed enhanced activity (IC50∼7.2 µM) as compared to diospyrin (IC50∼12.6 µM) against Leishmania donovani promastigotes. Again, D17 was tested on L. donovani BHU1216 isolated from a sodium stibogluconate-unresponsive patient, and exhibited selective inhibition of the intracellular amastigotes (IC50∼0.18 µM). Also, treatment of infected BALB/c mice with D17 at 2mg/kg/day reduced the hepatic parasite load by about 38%. Subsequently, computational docking studies were undertaken on selected enzymes of trypanothione metabolism, viz. trypanothione reductase (TryR) and ornithine decarboxylase (ODC), followed by the enzyme kinetics, where D17 demonstrated non-competitive inhibition of the L. donovani ODC, but could not inhibit TryR.

Inhibitory effect of Nymphaea pubescens Willd. flower extract on carrageenan-induced inflammation and CCl4-induced hepatotoxicity in rats.

Nymphaea pubescens Willd. is used as ingredient of ethnic diet and folk medicine in South-East Asia. The water (NPW), methanol (NPM) and chloroform (NPC) extracts of N. pubescens flowers were investigated for NO·, O2·â» and DPPH radical scavenging and iron chelating activities in vitro. NPW was found to be the most potent free radical scavenger (EC50<100 µg/mL) whereas NPC did not show EC50 at 500 µg/mL. Therefore, NPW was selected for further studies on anti-inflammatory and hepatoprotective activities, using standard in vitro and in vivo models. NPW exhibited inhibition of nitrogen radical generation in LPS-activated macrophages (IC50=75.5 µg/mL) through suppression of iNOS protein, with no associated toxicity in the cells. Further, 500 mg/kg of NPW reduced rat paw edema by ~50% after 6h of carrageenan administration. Hepatoprotective activity of NPW was also evaluated in vivo on CCl4-induced hepatotoxicity model in rats. NPW treatment (500 mg/kg/day for ten days) attenuated CCl4-induced increase in serum enzymes, viz. alanine and aspartate aminotransferases (ALT and AST) and bilirubin. Also, glutathione and superoxide dismutase (SOD)-levels were restored towards normalcy in the liver of CCl4-treated rats, indicating the hepatoprotective role of NPW, which was found to contain a fair amount of flavonoids, phenolics, and saponin constituents.

Pomegranate pericarp extract enhances the antibacterial activity of ciprofloxacin against extended-spectrum ß-lactamase (ESBL) and metallo-ß-lactamase (MBL) producing Gram-negative bacilli.

A methanolic extract of Punica granatum (pomegranate) fruit pericarp (PGME) was tested in combination with ciprofloxacin against extended-spectrum ß-lactamase (ESBL) producing Escherichia coli, Klebsiella pneumoniae, and metallo-ß-lactamase (MBL) producing Pseudomonas aeruginosa, which were screened for their resistance profile against fluoroquinolone antibiotics. The minimum inhibitory concentrations (MIC) of ciprofloxacin and PGME, alone, were determined, and synergy of ciprofloxacin-PGME combinations evaluated by checkerboard assay and fractional inhibitory concentration (FIC). Nineteen out of forty-nine strains exhibited synergy with ciprofloxacin (FIC of 0.125-0.5 for ciprofloxacin) further verified by agar-well assay. This could be due to the bacterial efflux pump inhibitor (EPI) activity of the polyphenolic constituents of PGME. However, the isolates exhibiting a high level of ciprofloxacin resistance did not respond to ciprofloxacin-PGME combinations, which could be due to target site modification not influenced further by EPI activity of PGME. Again, some strains were sensitive or weakly resistant to ciprofloxacin, which exhibited 'indifference' to the combination, probably due to a lack of over-expressed efflux mechanism. Thus, a synergy of a ciprofloxacin-PGME combination was demonstrated for the first time against ESBL- and MBL-producing Gram-negative bacilli, and the efficacy of an existing drug improved with the help of an inexpensive alternative therapy.

Antileishmanial activity of cryptolepine analogues and apoptotic effects of 2,7-dibromocryptolepine against Leishmania donovani promastigotes.

Cryptolepine (5-methyl-10H-indolo [3, 2-b] quinoline), an indoloquinoline alkaloid (1) isolated from a medicinal plant traditionally used in Western Africa for treatment of malaria, has been shown to possess broad spectrum biological activity in addition to its antiplasmodial effect. Here, the antileishmanial properties of 11 synthetic derivatives of cryptolepine against Leishmania donovani parasites have been evaluated for the first time. 2,7-Dibromocryptolepine (8; IC50 0.5 ± 0.1 µM) was found to be the most active analogue against the promastigote form of a classical L. donovani strain (AG83) in comparison to the natural alkaloid, cryptolepine (1; IC50 1.6 ± 0.1 µM). Further, 8 was found to substantially inhibit the intracellular amastigote forms of two clinical isolates, one of them being an SbV-resistant strain of L. donovani. Moreover, the toxicity of 8 against normal mouse peritoneal macrophage cells was markedly lower than that of 1 (IC50 values: 9.0 ± 1.2 and 1.1 ± 0.3 µM, respectively), indicating 8 to be a prospective "lead" towards novel antileishmanial therapy. This was supported by studies on the mechanism of cytotoxicity induced by 8 in L. donovani promastigotes (AG83), which revealed the cytoplasmic and nuclear features of metazoan apoptosis. Light microscopic observation demonstrated a gradual decline in the motility, cell volume, and survival of the treated parasites with increasing incubation time. Flow cytometric analysis of phosphatidylserine externalization and distribution of cells in different phases of cell cycle confirmed the presence of a substantial percentage of cells in early apoptotic stage. Disruption of mitochondrial membrane integrity in terms of depolarization of membrane potential, and finally degradation of chromosomal DNA into oligonucleosomal fragments - the hallmark event of apoptosis - characterized the mode of cell death in L. donovani promastigotes.

Diospyrin derivative, an anticancer quinonoid, regulates apoptosis at endoplasmic reticulum as well as mitochondria by modulating cytosolic calcium in human breast carcinoma cells.

Diospyrin diethylether (D7), a bisnaphthoquinonoid derivative, exhibited an oxidative stress-dependent apoptosis in several human cancer cells and tumor models. The present study was aimed at evaluation of the increase in cytosolic calcium [Ca(2+)](c) leading to the apoptotic cell death triggered by D7 in MCF7 human breast carcinoma cells. A phosphotidylcholine-specific phospholipase C (PC-PLC) inhibitor, viz. U73122, and an antioxidant, viz. N-acetylcysteine, could significantly prevent the D7-induced rise in [Ca(2+)](c) and PC-PLC activity. Using an endoplasmic reticulum (ER)-Ca(2+) mobilizer (thapsigargin) and an ER-IP3R antagonist (heparin), results revealed ER as a major source of [Ca(2+)](c) which led to the activation of calpain and caspase12, and cleavage of fodrin. These effects including apoptosis were significantly inhibited by the pretreatment of Bapta-AM (a cell permeable Ca(2+)-specific chelator), or calpeptin (a calpain inhibitor). Furthermore, D7-induced [Ca(2+)](c) was found to alter mitochondrial membrane potential and induce cytochrome c release, which was inhibited by either Bapta-AM or ruthenium red (an inhibitor of mitochondrial Ca(2+) uniporter). Thus, these results provided a deeper insight into the D7-induced redox signaling which eventually integrated the calcium-dependent calpain/caspase12 activation and mitochondrial alterations to accentuate the induction of apoptotic cell death.

Valeriana wallichii root extracts and fractions with activity against Leishmania spp.

Leishmanial diseases, posing a public health problem worldwide, are caused by Leishmania parasites with a dimorphic life cycle alternating between the promastigote and amastigote forms. Promastigotes transmitted by the vector are transformed into amastigotes residing in the host tissue macrophages. Presently, new antiparasitic agents are needed against Leishmania donovani and Leishmania major, the respective organisms causing visceral and cutaneous leishmaniasis, since the available treatments are unsatisfactory due to toxicity, high cost, and emerging drug resistance. Over the years, traditional medicinal flora throughout the world enriched the modern pharmacopeia. Hence, roots of 'Indian Valerian' (Valeriana wallichii DC) were studied for its antileishmanial activity for the first time. The methanol and chloroform extracts showed activity against L. donovani promastigotes and both promastigotes and amastigotes of L. major. The most active fraction, F3, obtained from the chloroform extract, showed IC(50) at ∼ 3-7 µg/ml against both the promastigotes and 0.3 µg/ml against L. major amastigotes. On investigation of the mechanism of cytotoxicity in L. donovani promastigotes, the 'hall-mark' events of morphological degeneration, DNA fragmentation, externalization of phosphatidyl serine, and mitochondrial membrane depolarization indicated that F3 could induce apoptotic death in leishmanial cells. Therefore, the present study revealed a novel and unconventional property of V. wallichii root as a prospective source of effective antileishmanial agents.

The prospective role of plant products in radiotherapy of cancer: a current overview.

Treatment of cancer often requires exposure to radiation, which has several limitations involving non-specific toxicity toward normal cells, reducing the efficacy of treatment. Efforts are going on to find chemical compounds which would effectively offer protection to the normal tissues after radiation exposure during radiotherapy of cancer. In this regard, plant-derived compounds might serve as "leads" to design ideal radioprotectors/radiosensitizers. This article reviews some of the recent findings on prospective medicinal plants, phytochemicals, and their analogs, based on both in vitro and in vivo tumor models especially focused with relevance to cancer radiotherapy. Also, pertinent discussion has been presented on the molecular mechanism of apoptotic death in relation to the oxidative stress in cancer cells induced by some of these plant samples and their active constituents.

Anti-inflammatory and anticancer compounds isolated from Ventilago madraspatana Gaertn., Rubia cordifolia Linn. and Lantana camara Linn.

OBJECTIVES: The aim was to search for anti-inflammatory and anticancer compounds from three medicinal plants, viz. Ventilago madraspatana Gaertn., Rubia cordifolia Linn. and Lantana camara Linn. METHODS: The NO* scavenging potential of selected plant extracts was determined on LPS/IFN-gamma activated murine peritoneal macrophage cultures, and iNOS and COX-2 expression was evaluated by Western blot analysis. Bio-assay guided fractionation yielded four compounds: physcion and emodin from V. madraspatana, 1-hydroxytectoquinone from R. cordifolia, and oleanonic acid from L. camara. The anti-inflammatory activity of these compounds was tested through the carrageenan-induced rat-paw oedema model. They were then tested against a murine tumour (Ehrlich ascites carcinoma), and three human cancer cell lines, namely A375 (malignant skin melanoma), Hep2 (epidermoid laryngeal carcinoma) and U937 (lymphoma). KEY FINDINGS: All four compounds dose dependently inhibited NO* through suppression of iNOS protein without affecting macrophage viability. Physcion and emodin caused 65-68% reduction of oedema volume at 40 mg/kg, which validated their in-vivo anti-inflammatory effect. 1-Hydroxytectoquinone and oleanonic acid exhibited promising cytotoxicity against A375 cells. CONCLUSIONS: Ethnomedical reports on these traditional medicinal plants have been rationalised through an insight into the anti-inflammatory as well as anticancer potential of four constituents, characterised to be prospective candidates for designing novel therapeutic agents.