Withaferin A as a Potential Therapeutic Target for the Treatment of Angiotensin II-Induced Cardiac Cachexia.

In our previous studies, we showed that the generation of ovarian tumors in NSG mice (immune-compromised) resulted in the induction of muscle and cardiac cachexia, and treatment with withaferin A (WFA; a steroidal lactone) attenuated both muscle and cardiac cachexia. However, our studies could not address if these restorations by WFA were mediated by its anti-tumorigenic properties that might, in turn, reduce the tumor burden or WFA's direct, inherent anti-cachectic properties. To address this important issue, in our present study, we used a cachectic model induced by the continuous infusion of Ang II by implanting osmotic pumps in immunocompetent C57BL/6 mice. The continuous infusion of Ang II resulted in the loss of the normal functions of the left ventricle (LV) (both systolic and diastolic), including a significant reduction in fractional shortening, an increase in heart weight and LV wall thickness, and the development of cardiac hypertrophy. The infusion of Ang II also resulted in the development of cardiac fibrosis, and significant increases in the expression levels of genes (ANP, BNP, and MHCß) associated with cardiac hypertrophy and the chemical staining of the collagen abundance as an indication of fibrosis. In addition, Ang II caused a significant increase in expression levels of inflammatory cytokines (IL-6, IL-17, MIP-2, and IFNγ), NLRP3 inflammasomes, AT1 receptor, and a decrease in AT2 receptor. Treatment with WFA rescued the LV functions and heart hypertrophy and fibrosis. Our results demonstrated, for the first time, that, while WFA has anti-tumorigenic properties, it also ameliorates the cardiac dysfunction induced by Ang II, suggesting that it could be an anticachectic agent that induces direct effects on cardiac muscles.

Withanolides from the active extract of Physalis angulate and their anti-hepatic fibrosis effects.

ETHNOPHARMACOLOGICAL RELEVANCE: Physalis angulata L., a traditional Chinese medicine called "Kuzhi" in China, was used traditionally to treat liver diseases (eg. icterus, hepatitis) as well as malaria, asthma, and rheumatism. AIM OF THE STUDY: Our study aimed to investigate the withanolides with anti-hepatic fibrosis effect from P. angulate. MATERIALS AND METHODS: Withanolides were obtained from the EtOH extract of P. angulate by bioassay-molecular networking analysis-guided isolation using column chromatography and normal/reversed-phase semipreparative HPLC. The structures of new withanolides were elucidated by combinations of spectroscopic techniques with NMR and ECD calculations. MTT cell viability assay, AO/EB staining method, cell wound healing assay, ELISA and Western blot experiments were employed to evaluate the anti-hepatic fibrosis activity and to uncover related mechanism. Molecular docking analysis and cellular thermal shift assay were used to evaluate and verify the interaction between the active withanolides and their potential targets. RESULTS: Eight unreported withanolides, withagulides A-H (1-8), along with twenty-eight known ones were obtained from P. angulate. Withanolides 6, 9, 10, 24, 27, and 29-32 showed marked anti-hepatic fibrosis effect with COL1A1 expression inhibition above 50 %. Physalin F (9), the main component in the active fraction, significantly decreased the TGF ß1-stimulated expressions of collagen I and α-SMA in LX-2 cells. Mechanism study revealed that physalin F exerted its anti-hepatic fibrosis effect via the PI3K/AKT/mTOR signaling pathway. CONCLUSION: This study suggested that withanolides were an important class of natural products with marked anti-hepatic fibrosis effect. The main withanolide physalin F might be a promising candidate for hepatic fibrosis treatment. The work provided experimental foundation for the use of P. angulate to treat hepatic fibrosis.

Withanolides: Promising candidates for cancer therapy.

Natural products have played a significant role throughout history in the prevention and treatment of numerous diseases, particularly cancers. As a natural product primarily derived from various medicinal plants in the Withania genus, withanolides have been shown in several studies to exhibit potential activities in cancer treatment. Consequently, understanding the molecular mechanism of withanolides could herald the discovery of new anticancer agents. Withanolides have been studied widely, especially in the last 20 years, and attracted the attention of numerous researchers. Currently, over 1200 withanolides have been classified, with approximately a quarter of them having been reported in the literature to be able to modulate the survival and death of cancer cells through multiple avenues. To what extent, though, has the anticancer effects of these compounds been studied? How far are they from being developed into clinical drugs? What are their potential, characteristic features, and challenges? In this review, we elaborate on the current knowledge of natural compounds belonging to this class and provide an overview of their natural sources, anticancer activity, mechanism of action, molecular targets, and implications for anticancer drug research. In addition, direct targets and clinical research to guide the design and implementation of future preclinical and clinical studies to accelerate the application of withanolides have been highlighted.

Withaferin-A attenuates diabetes mellitus induced male reproductive dysfunction mediated by ERα in brain and testes of Swiss albino mice.

Diabetes mellitus (DM) is a chronic metabolic disease, characterized by persistent hyperglycemia resulting from diminished insulin secretion or insulin resistance. The present study evaluated the ameliorative effects of Withaferin-A (WA) on DM-induced reproductive dysfunction in mice. For the same, mice were intraperitoneally injected with Streptozotocin (STZ), (40 mg/kg/day) for 5 consecutive days to induce DM. Mice were then treated with WA (8 mg/kg/day) in normal and diabetic conditions (STZ + WA). Next, blood glucose levels, oral glucose tolerance, intraperitoneal insulin tolerance, oxidative stress and reproductive parameters were estimated. For reproductive performance, immunofluorescent localization of gonadotropin-releasing hormone (GnRH-I) and estrogen receptor alpha (ERα) in the preoptic area and paraventricular nucleus region of hypothalamus and ERα in testes was performed. STZ-induced diabetes triggered reproductive dysfunctions as mediated by low GnRH-I and ERα in the brain and ERα in the testes along with declined testosterone and estradiol levels. Treatment with WA significantly reduced the blood glucose levels and enhanced glucose clearance accompanied by reduced oxidative stress in the brain, pancreas and testes as indicated by the low levels of H2O2 and MDA in diabetic mice treated with WA (STZ + WA). This study reports, for the first time, that WA can efficiently ameliorate DM-induced reproductive dysfunctions by enhancing endogenous testosterone, estrogen and increased GnRH-I and ERα in the brain and ERα in the testes of DM-induced male mice.

A standardized Ashwagandha root extract alleviates stress, anxiety, and improves quality of life in healthy adults by modulating stress hormones: Results from a randomized, double-blind, placebo-controlled study.

BACKGROUND: The coronavirus disease-2019 (COVID-19) pandemic has resulted in a surge in stress, anxiety, and depression worldwide. Ashwagandha, an ayurvedic adaptogen has been traditionally used to manage stress, anxiety, and general well-being. OBJECTIVE: We assessed the effect of Ashwagandha root extract (ARE-500 mg) standardized for 2.5% withanolides as per USP protocol with piperine (5 mg of 95% piperine) once daily for 60 days (12.5 mg withanolides/day) to alleviate stress and anxiety in healthy individuals with mild to moderate symptoms. METHODS: A randomized, double-blind, placebo-controlled study was conducted for 60 days using ARE (n = 27) and placebo (n = 27) once daily at night at Narayana Institute of Cardiac Sciences, Bangalore, and Vijaya Super Specialty Hospital, Nellore, in India. The objectives of this study were to assess an improvement in perceived stress scale (PSS), generalized anxiety disorder (GAD-7), quality of life (QOL), cognitive scores in the Cambridge Neuropsychological Test Automated Battery (CANTAB), changes in salivary cortisol, urinary serotonin, dopamine, serum levels of nitric oxide (NO), glutathione (GSH) and malondialdehyde (MDA) from baseline to end of the study. Safety was evaluated by laboratory parameters, and by monitoring any incidence of adverse events. RESULTS: 54 individuals were randomized and 50 of them completed the study. The PSS, GAD-7, and QOL scores improved significantly in all the participants taking ARE compared to the placebo. The CANTAB analysis revealed a significant improvement in multitasking, concentration, and decision taking time in ARE compared to placebo. ARE was also associated with a greater reduction in the morning salivary cortisol and an increase in urinary serotonin compared to placebo. Serum levels of NO, GSH, and MDA were not significantly different. Biochemical and hematological parameters remained in the normal range in all participants and ARE was well tolerated during the study. CONCLUSION: The results of the study suggest that ARE with 2.5% withanolides can effectively improve stress and anxiety by reducing cortisol and increasing serotonin in healthy individuals with mild to moderate symptoms.

Network Analysis of Anti-inflammatory Phytochemicals and Omics Data for Rheumatoid Arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is an inflammatory autoimmune disease that affects the synovial joints. Nearly 1.6 billion patients are affected by RA worldwide and the incidence of RA is about 0.5 to 1%. Recent studies reveal that immune cell responses and secretion of inflammatory factors are important for the control of RA. METHODS: In this study, a set of 402 phytochemicals with anti-inflammatory properties and 16 target proteins related to anti-inflammatory diseases were identified from the literature and they were subjected to network analysis. The protein-protein interaction (PPI) network was constructed using STRING (Search Tool for the Retrieval of Interacting Genes database) database. Visualization of the target gene-phytochemical network and its protein-protein interaction network was conducted using Cytoscape and further analyzed using MCODE (Molecular Complex Detection). The gene ontology and KEGG pathway analysis was performed using DAVID tool. RESULTS: Our results from the network approach indicate that the phytochemicals such as Withanolide, Diosgenin, and Butulin could act as potential substitute for anti-inflammatory drugs, including DMARDs. Genes such as Mitogen-activated protein kinase (MAPK) and Interleukin were found as hub genes and acted as best inhibitors for the target protein pathways. Curcumin, Catechin was also found to be involved in various signaling pathways such as NF-kappa B signaling pathway, ErbB signaling pathway and acted as the best inhibitor along with other candidate phytochemicals. CONCLUSION: In the current study, we were able to identify Withanolide, Diosgenin, and Butulin as potential anti-inflammatory phytochemicals and determine their association with key pathways involved in RA through network analysis. We hypothesized that natural compounds could significantly contribute to the reduction of dosage, improve the treatment and act as a therapeutic agent for more economical and safer treatment of RA.

Withaferin A Inhibits Fatty Acid Synthesis in Rat Mammary Tumors.

Withaferin A (WA), which is a small molecule derived from a medicinal plant (Withania somnifera), inhibits growth of human breast cancer xenografts and mammary tumor development in rodent models without any toxicity. However, the mechanism underlying inhibition of mammary cancer development by WA administration is not fully understood. Herein, we demonstrate that the fatty acid synthesis pathway is a novel target of WA in mammary tumors. Treatment of MCF-7 and MDA-MB-231 cells with WA resulted in suppression of fatty acid metabolizing enzymes, including ATP-citrate lyase (ACLY), acetyl-CoA carboxylase 1 (ACC1), fatty acid synthase (FASN), and carnitine palmitoyltransferase 1A (CPT1A). Expression of FASN and CPT1A was significantly higher in N-methyl-N-nitrosourea-induced mammary tumors in rats when compared with normal mammary tissues. WA-mediated inhibition of mammary tumor development in rats was associated with a statistically significant decrease in expression of ACC1 and FASN and suppression of plasma and/or mammary tumor levels of total free fatty acids and phospholipids. WA administration also resulted in a significant increase in percentage of natural killer cells in the spleen. The protein level of sterol regulatory element binding protein 1 (SREBP1) was decreased in MDA-MB-231 cells after WA treatment. Overexpression of SREBP1 in MDA-MB-231 cells conferred partial but significant protection against WA-mediated downregulation of ACLY and ACC1. In conclusion, circulating and/or mammary tumor levels of fatty acid synthesis enzymes and total free fatty acids may serve as biomarkers of WA efficacy in future clinical trials. PREVENTION RELEVANCE: The present study shows that breast cancer prevention by WA in rats is associated with suppression of fatty acid synthesis.

Adaptogenic activity of withaferin A on human cervical carcinoma cells using high-definition vibrational spectroscopic imaging.

Despite invaluable advances in cervical cancer therapy, treatment regimens for recurrent or persistent cancers and low-toxicity alternative treatment options are scarce. In recent years, substances classified as adaptogens have been identified as promising drug sources for preventing and treating cancer-based diseases on their ability to attack multiple molecular targets. This paper establishes the effectiveness of inhibition of the neoplastic process by a withaferin A (WFA), an adaptogenic substance, based on an in vitro model of cervical cancer. This study explores for the first time the potential of high-definition vibrational spectroscopy methods, i.e. Fourier-transform infrared (FT-IR) and Raman spectroscopic (RS) imaging at the single-cell level to evaluate the efficacy of the adaptogenic drug. HeLa cervical cancer cells were incubated with various concentrations of WFA at different incubation times. The multimodal spectroscopic approach combined with partial least squares (PLS) regression allowed the identification of molecular changes (e.g., lipids, protein secondary structures, or nucleic acids) induced by WFA at the cellular level. The results clearly illustrate the enormous potential of WFA in inhibiting the proliferation of cervical cancer cells. WFA inhibited the growth of the studied cancer cell line in a dose-dependent manner. Such studies provide comprehensive information on the sensitivity of cells to adaptogenic drugs. This is a fundamental step towards determining the rate and nature of adaptogen-induced changes in cancer cells.

Can Traditional Treatment Such as Ashwagandha Be Beneficial in Treating Depression?

Background: This study provides a path for many studies that may have been forgotten in the past to the use of modern-day knowledge supporting the use of traditional treatments, specifically Withania somnifera (ashwagandha). Primary Study Objective: The primary objective of this study was to bring back traditional therapy that could prove to be economically beneficial and possibly helpful to many clients with depression with few or no associated adverse events. Intervention: The key components of ashwagandha include 12 alkaloids and 35 withanolides, which have been proven in various studies to be beneficial in the treatment of anxiety and stress. While research supports that withanolides and alkaloides work as antidepressants and are the main reason ashwagandha is beneficial for depression, the mechanism of action in unknown. Studies also show that withanolides may bolster the immune system, increase stamina, fight inflammation and infection, combat tumors, reduce stress, revive the libido, protect the liver and soothe jangled nerves. Both of these molecules are steroidal and are similar in action and appearance. Ashwagandha stimulates the activation of immune system cells such as lymphocytes and has also been shown to inhibit inflammation and improve memory in animal experiments.

Withaferin A alleviates inflammation and joint injury in arthritic rats via elevating microRNA-1297 to target karyopherin alpha2.

Withaferin A (WFA) is a natural compound separated from the medicinal plant Withania somnifera. As reported, it has the potential to safely cure rheumatoid arthritis (RA) in animal models. Nevertheless, the action mechanism of WFA in treating RA has not been completely illuminated. The study was to explore the action and mechanism of WFA on arthritic rats. First, a collagen-induced arthritis rat model was established. WFA administration alleviated inflammation and injury in arthritic rats. Subsequently, fibroblast synovial cells (FLS) of arthritic rats were separated and cell proliferation and apoptosis abilities were tested. It was found that WFA was available to repress FLS cell proliferation and accelerate apoptosis. MicroRNA-1297 was downregulated in RA patients. Clinical correlation analysis suggested that miR-1297 in the serum of RA patients was negatively associated with pro-inflammatory factors interleukin (IL)-6, IL-17, tumor necrosis factor (TNF)-α, and RA diagnostic indexes (RF, DAS28). In the meantime, miR-1297 had superior diagnostic value in differentiating RA patients from healthy people. Karyopherin α2 (KPNA2) was the downstream target of miR-1297, while miR-1297 negatively modulated KPNA2 expression. Importantly, WFA further restrained KPNA2 expression via elevating miR-1297 in functional rescue experiments, thereby treating inflammation and injury in arthritic rats and repressing FLS cell proliferation and activation. In short, WFA alleviated inflammation and joint damage in arthritic rats via elevating miR-1297 to target KPNA2.

Withaferin A, a polyfunctional pharmacophore that includes covalent engagement of IPO5, is an inhibitor of influenza A replication.

Withaferin A, a natural steroidal lactone found in the extracts of Withania somnifera, is used extensively in traditional medicine and part of an ancient remedy in ayurvedic medicine. Prior investigations into its mode of action have shown withaferin to be a polyfunctional pharmacophore with the covalent engagement of a multitude of therapeutic targets. Herein, we report that withaferin A is also a covalent inhibitor of IPO5, an importin that translocates cargos from the cytosol to the nucleus. We show that withaferin inhibits influenza A replication in epithelial cells (A549). Using a panel of inhibitors that selectively recapitulate part of withaferin A's pharmacological profile (goyazensolide, withaferin A derivatives, FiVe1, and bardoxolone methyl), we show that IPO5 inhibition contributes to the influenza replication inhibition but is not essential for the observed activity of withaferin A. We show that bardoxolone methyl, a semisynthetic triterpenoid in clinical development to treat chronic kidney disease and that shares some of the pharmacological profile of withaferin, also inhibits influenza A replication effectively. The inhibitory activity against influenza A replication should stimulate further studies to repurpose this therapeutic.

Withanolide modulates the potential crosstalk between apoptosis and autophagy in different colorectal cancer cell lines.

Withaferin A (WFA), a withanolide, is isolated from plants of Withania somnifera (L.) Dual (Solanaceae), known as Indian ginseng, Indian winter cherry or Ashwagandha. It has been reported to exert multifaceted anti-neoplastic effects. Here, we analyzed the impact of WFA on apoptosis and autophagy activation in different human colorectal cancer cell lines. We observed that WFA exposure caused an increased aggregation of cells in the subG1 arrest in cell cycle, and increased the number of late apoptotic cells. WFA also induced the apoptosis via PARP and caspase-3 cleavage accompanied with suppression of levels of anti-apoptotic proteins like Bcl-2 and Bcl-xl. The influence of WFA on autophagy was validated by acridine orange, MDC staining, and immunocytochemistry of LC3. It was found that 24 h treatment of WFA increased the acridine and MDC stained autophagosome with induced the LC3 and other autophagy markers Atg7 and beclin-1 activation. We used Z-DEVD-FMK, a caspase-3 blocker, and 3-MA, an autophagy inhibitor, to confirm whether these effects were specific to apoptosis and autophagy, and observed the recovery of both these processes upon exposure to WFA. Moreover, the activation of ß-catenin protein was attenuated by WFA. Interestingly, small interfering RNA (siRNA)-promoted ß-catenin knockdown augmented the WFA-induced active form of p-GSK-3ß, and stimulated autophagy and apoptosis through PARP and LC3 activation. These findings suggested that WFA could stimulate activation of both apoptosis and autophagy process via modulating ß-catenin pathway.

Oxidative Stress and AKT-Associated Angiogenesis in a Zebrafish Model and Its Potential Application for Withanolides.

Oxidative stress and the AKT serine/threonine kinase (AKT) signaling pathway are essential regulators in cellular migration, metastasis, and angiogenesis. More than 300 withanolides were discovered from the plant family Solanaceae, exhibiting diverse functions. Notably, the relationship between oxidative stress, AKT signaling, and angiogenesis in withanolide treatments lacks comprehensive understanding. Here, we summarize connecting evidence related to oxidative stress, AKT signaling, and angiogenesis in the zebrafish model. A convenient vertebrate model monitored the in vivo effects of developmental and tumor xenograft angiogenesis using zebrafish embryos. The oxidative stress and AKT-signaling-modulating abilities of withanolides were highlighted in cancer treatments, which indicated that further assessments of their angiogenesis-modulating potential are necessary in the future. Moreover, targeting AKT for inhibiting AKT and its AKT signaling shows the potential for anti-migration and anti-angiogenesis purposes for future application to withanolides. This particularly holds for investigating the anti-angiogenetic effects mediated by the oxidative stress and AKT signaling pathways in withanolide-based cancer therapy in the future.

Recent Advances in the Chemistry and Therapeutic Evaluation of Naturally Occurring and Synthetic Withanolides.

Natural products are a major source of biologically active compounds that make promising lead molecules for developing efficacious drug-like molecules. Natural withanolides are found in many flora and fauna, including plants, algae, and corals, that traditionally have shown multiple health benefits and are known for their anti-cancer, anti-inflammatory, anti-bacterial, anti-leishmaniasis, and many other medicinal properties. Structures of these withanolides possess a few reactive sites that can be exploited to design and synthesize more potent and safe analogs. In this review, we discuss the literature evidence related to the medicinal implications, particularly anticancer properties of natural withanolides and their synthetic analogs, and provide perspectives on the translational potential of these promising compounds.

Total withanolides ameliorates imiquimod-induced psoriasis-like skin inflammation.

ETHNOPHARMACOLOGICAL RELEVANCE: Datura metel L. has been used as an anesthetic in clinic for more than 1800 years in China, and the main efficacy of D. metel L. flower is relieving asthma and cough, relieving spasm and relieving pain. From 1978 to 1980, Datura metel L. was used as an anesthetic agent and occasionally cured psoriasis patients during anesthesia clinically, and our group confirmed that the effective portion is total withanolides (YWS). Moreover, the new drug "Datura metel L. capsule" composed of YWS has since been approved and used for the treatment of more than 3,000 psoriasis patients, with efficacy and cure rates greater than 90% and 65%. However, the immunological mechanism has not been elucidated. AIM OF THE STUDY: Nowadays, although total withanolides from Datura metel L. have a better clinical efficacy in the treatment of psoriasis, there is a lack of overall understanding of the mechanism of their treatment, especially about some immune cells and proteins closely related to psoriasis and their relationship in executive function and biological significance. This study focused on investigating the mechanism of psoriasis treatment by YWS and determined the biochemical processes in the treatment of psoriasis based on Treg/Th17 axis cell-mediated bidirectional immunoregulatory functions, which provides an important scientific basis for understanding the mechanism underlying the treatment of psoriasis by YWS. MATERIALS AND METHODS: The effects of YWS on the lesion pathology of IMQ-induced psoriasis mice and the underlying molecular mechanism were assessed directly using HE staining, the PASI score and the animal body mass. We also investigated the effects of YWS on the Treg/Th17 axis and their critical functions in psoriasis pathogenesis via molecular biological methods. Finally, we performed differential proteomics analysis on skin in IMQ-induced psoriasis mice to clarify the effect of YWS by incorporates mass spectrometry-bioinformatics and annotated the functions and pathways associated with the differential proteins through GO enrichment, KEGG pathway analysis and PPI networks analysis, respectively. RESULTS: YWS regulated the imbalance of the Treg/Th17 axis. And proteomic analysis showed that YWS up-regulated 46 and down-regulated 37 proteins. According to the bioinformatics analysis, the improvement of Treg/Th17 imbalance may be the key immunological mechanism of YWS in the treatment of psoriasis by up-regulating the butyrate metabolism pathway, down-regulating leukocyte migration, inhibiting the phagocytic function of natural killer cells, suppressing osteoclast differentiation and interfering with chemokine activity, and the critical proteins involved are Lyn, HMGCS2, ABAT, ITGß2, PRKCß, MMP9, NCF1, JUNß, and Hck. CONCLUSION: This research clarified that the improvement of the imbalance of the Treg/Th17 axis may be the key immunological mechanism of YWS in the treatment of psoriasis through metabolic pathways and influencing key proteins. The results not only expand the therapeutic targets and approaches for the treatment of psoriasis, which is a challenging and complex disease, but also deepens the understanding of the mechanism of YWS in the treatment of psoriasis and other important conditions to open up a new way of thinking for research on YWS in the treatment of psoriasis.

Withaferin A in the Treatment of Liver Diseases: Progress and Pharmacokinetic Insights.

Withaferin A (WA) is a natural steroidal compound used in Ayurvedic medicine in India and elsewhere. Although WA was used as an anticancer reagent for decades, its role in the treatment of liver diseases has only recently been experimentally explored. Here, the effects of WA in the treatment of liver injury, systematic inflammation, and liver cancer are reviewed, and the toxicity and metabolism of WA as well as pharmacological potentials of other extracts from Withania somnifera (W. somnifera) discussed. The pharmacokinetic behaviors of WA are summarized and pharmacokinetic insights into current progress and future opportunities are highlighted. SIGNIFICANCE STATEMENT: This review outlines the current experimental progress of Withaferin A (WA) hepatoprotective activities and highlights gaps in the field. This work also discusses the pharmacokinetics of WA that can be used to guide future studies for the possible treatment of liver diseases with this compound.

Withaferin A: From Ancient Remedy to Potential Drug Candidate.

Withaferin A (WA) is a pivotal withanolide that has conquered a conspicuous place in research, owning to its multidimensional biological properties. It is an abundant constituent in Withania somnifera Dunal. (Ashwagandha, WS) that is one of the prehistoric pivotal remedies in Ayurveda. This article reviews the literature about the pharmacological profile of WA with special emphasis on its anticancer aspect. We reviewed research publications concerning WA through four databases and provided a descriptive analysis of literature without statistical or qualitative analysis. WA has been found as an effective remedy with multifaceted mechanisms and a broad spectrum of pharmacological profiles. It has anticancer, anti-inflammatory, antiherpetic, antifibrotic, antiplatelet, profibrinolytic, immunosuppressive, antipigmentation, antileishmanial, and healing potentials. Evidence for wide pharmacological actions of WA has been established by both in vivo and in vitro studies. Further, the scientific literature accentuates the role of WA harboring a variable therapeutic spectrum for integrative cancer chemoprevention and cure. WA is a modern drug from traditional medicine that is necessary to be advanced to clinical trials for advocating its utility as a commercial drug.

Ring A/B-Modified 17ß-Hydroxywithanolide Analogues as Antiproliferative Agents for Prostate Cancer and Potentiators of Immunotherapy for Renal Carcinoma and Melanoma.

Physachenolide C (1) is a 17ß-hydroxywithanolide natural product with a unique anticancer potential, as it exhibits potent and selective in vitro antiproliferative activity against prostate cancer (PC) cells and promotes TRAIL-induced apoptosis of renal carcinoma (RC) and poly I:C-induced apoptosis of melanoma cells. To explore the effect of ring A/B modifications of physachenolide C (1) on these biological activities, 23 of its natural and semisynthetic analogues were evaluated. Analogues 4-23 were prepared by chemical transformations of a readily accessible compound, physachenolide D (2). Compound 1 and its analogues 2-23 were evaluated for their antiproliferative activity against PC (LNCaP and 22Rv1), RC (ACHN), and melanoma (M14 and SK-MEL-28) cell lines and normal human foreskin fibroblast (HFF) cells. Most of the active analogues had selective and potent activity in reducing cell number for PC cell lines, some showing selectivity for androgen-independent and enzalutamide-resistant 22Rv1 cells compared to androgen-dependent LNCaP cells. Analogues with IC50s below 5.0 µM against ACHN cells, when tested in the presence of TRAIL, showed a significantly increased ability to reduce cell number, and those analogues active against the M14 and SK-MEL-28 cell lines exhibited enhanced activity when combined with poly I:C. These data provide additional structure-activity relationship information for 17ß-hydroxywithanolides and suggest that selective activities of some analogues may be exploited to develop natural products-based tumor-specific agents for cancer chemotherapy.

Phytochemistry, Food Application, and Therapeutic Potential of the Medicinal Plant (Withania coagulans): A Review.

Herbal plants have been utilized to treat and cure various health-related problems since ancient times. The use of Ayurvedic medicine is very significant because of its least reported side effects and host of advantages. Withania coagulans (Family; Solanaceae), a valuable medicinal plant, has been used to cure abnormal cell growth, wasting disorders, neural as well as physical problems, diabetes mellitus, insomnia, acute and chronic hepatic ailments. This review provides critical insight regarding the phytochemistry, biological activities, and pharmacognostic properties of W. coagulans. It has been known to possess diuretic, anti-inflammatory, anti-bacterial, anti-fungal, cardio-protective, hepato-protective, hypoglycemic, anti-oxidative, and anti-mutagenic properties owing to the existence of withanolides, an active compound present in it. Apart from withanolides, W. coagulans also contains many phytochemicals such as flavonoids, tannins, and ß-sterols. Several studies indicate that various parts of W. coagulans and their active constituents have numerous pharmacological and therapeutic properties and thus can be considered as a new drug therapy against multiple diseases.

A Perspective on Withania somnifera Modulating Antitumor Immunity in Targeting Prostate Cancer.

Medicinal plants serve as a lead source of bioactive compounds and have been an integral part of day-to-day life in treating various disease conditions since ancient times. Withaferin A (WFA), a bioactive ingredient of Withania somnifera, has been used for health and medicinal purposes for its adaptogenic, anti-inflammatory, and anticancer properties long before the published literature came into existence. Nearly 25% of pharmaceutical drugs are derived from medicinal plants, classified as dietary supplements. The bioactive compounds in these supplements may serve as chemotherapeutic substances competent to inhibit or reverse the process of carcinogenesis. The role of WFA is appreciated to polarize tumor-suppressive Th1-type immune response inducing natural killer cell activity and may provide an opportunity to manipulate the tumor microenvironment at an early stage to inhibit tumor progression. This article signifies the cumulative information about the role of WFA in modulating antitumor immunity and its potential in targeting prostate cancer.