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Most chemotherapeutic drugs for killing cancer cells are highly cytotoxic in normal cells, which limits their clinical applications. Therefore, a continuing challenge is identifying a drug that is hypersensitive to cancer cells but has minimal deleterious effects on healthy cells. The aims of this study were to evaluate the potential of 4β-hydroxywithanolide (4βHWE) for selectively killing cancer cells and to elucidate its related mechanisms. Changes in survival, oxidative stress, DNA damage, and apoptosis signaling were compared between 4βHWE-treated oral cancer (Ca9-22) and normal fibroblast (HGF-1) cells. At 24 h and 48 h, the numbers of Ca9-22 cells were substantially decreased, but the numbers of HGF-1 cells were only slightly decreased. Additionally, the IC50 values for 4βHWE in the Ca9-22 cells were 3.6 and 1.9 µg/ml at 24 and 48 h, respectively. Time-dependent abnormal increases in ROS and dose-responsive mitochondrial depolarization can be exploited by using 4βHWE in chemotherapies for selectively killing cancer cells. Dose-dependent DNA damage measured by comet-nuclear extract assay and flow cytometry-based γ-H2AX/propidium iodide (PI) analysis showed relatively severer damage in the Ca9-22 cells. At both low and high concentrations, 4βHWE preferably perturbed the cell cycle in Ca9-22 cells by increasing the subG1 population and arrest of G1 or G2/M. Selective induction of apoptosis in Ca9-22 cells was further confirmed by Annexin V/PI assay, by preferential expression of phosphorylated ataxia-telangiectasia- and Rad3-related protein (p-ATR), and by cleavage of caspase 9, caspase 3, and poly ADP-ribose polymerase (PARP). Together, the findings of this study, particularly the improved understanding of the selective killing mechanisms of 4βHWE, can be used to improve efficiency in killing oral cancer cells during chemoprevention and therapy.

BackgroundLong covid describes a syndrome of persistent symptoms following COVID-19 and is responsible for substantial healthcare and economic burden. Currently, no effective treatments have been established. Ashwagandha (Withania somnifera (L.) Dunal) is a medicinal herb traditionally used in India for its immune-strengthening and anti-inflammatory properties. Withanolides, a family of steroid-derived molecules unique to Ashwagandha, have been shown to modulate inflammatory pathways in animal models, and several small randomised trials in humans support its effectiveness for reducing symptoms that are also associated with long covid. Therefore, this study aims to assess whether Ashwagandha is effective and safe for improving functional status and reducing symptom burden in adults living with long covid.MethodsA randomised double-blind placebo-controlled trial will be performed at participating general practice (GP) surgeries and long covid clinics across the UK. Individuals diagnosed with long covid will be screened for eligibility and then randomised 1:1 to take 1000 mg daily of Ashwagandha root extract tablets (standardised to <0.9% withanolides) or matching placebo tablets for 3 months (target, n = 2500). Monthly online surveys will be performed to collect patient-reported outcomes, and monthly safety monitoring, including liver function tests, will be conducted by clinical site teams. The primary outcome of the Post-COVID Functional Status Scale score at 3 months will be assessed by baseline-adjusted ordinal logistic regression, according to a pre-published statistical analysis plan. The secondary outcomes included validated quality of life and long covid symptom scales, work status and productivity and adverse events. The trial has been approved as a Clinical Trial of an Investigational Medicinal Produce by the Medicines and Healthcare Regulatory Authority and by the NHS Research Ethics Committee and Health Research Authority.DiscussionTreatments for long covid are urgently needed. This trial will robustly evaluate the safety and efficacy of a candidate treatment with a promising efficacy and safety profile. If found to be effective, the findings will likely influence treatment guidelines and improve health outcomes in those living with long covid.Trial registration numberThis trial was pre-registered on 15/08/2022: ISRCTN12368131

Ashwagandha (Withania Somnifera, WS), belonging to the family Solanaceae, is an Ayurvedic herb known worldwide for its numerous beneficial health activities since ancient times. This medicinal plant provides benefits against many human illnesses such as epilepsy, depression, arthritis, diabetes, and palliative effects such as analgesic, rejuvenating, regenerating, and growth-promoting effects. Several clinical trials of the different parts of the herb have demonstrated safety in patients suffering from these diseases. In the last two decades, an active component of Withaferin A (WFA) has shown tremendous cytotoxic activity suggesting its potential as an anti-carcinogenic agent in treatment of several cancers. In spite of enormous progress, a thorough elaboration of the proposed mechanism and mode of action is absent. Herein, we provide a comprehensive review of the properties of WS extracts (WSE) containing complex mixtures of diverse components including WFA, which have shown inhibitory properties against many cancers, (breast, colon, prostate, colon, ovarian, lung, brain), along with their mechanism of actions and pathways involved.

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.

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 β-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.

Cancer, being the second leading cause of mortality, exists as a formidable health challenge. In spite of our enormous efforts, the emerging complexities in the molecular nature of disease progression limit the real success in finding an effective cancer cure. It is now conceivable that cancer is, in fact, a progressive illness, and the morbidity and mortality from cancer can be reduced by interfering with various oncogenic signaling pathways. A wide variety of structurally diverse classes of bioactive phytochemicals have been shown to exert anticancer effects in a large number of preclinical studies. Multiple lines of evidence suggest that withaferin-A can prevent the development of cancers of various histotypes. Accumulating data from different rodent models and cell culture experiments have revealed that withaferin-A suppresses experimentally induced carcinogenesis, largely by virtue of its potent anti-oxidative, anti-inflammatory, anti-proliferative and apoptosis-inducing properties. Moreover, withaferin-A sensitizes resistant cancer cells to existing chemotherapeutic agents. The purpose of this review is to highlight the mechanistic aspects underlying anticancer effects of withaferin-A.

Ayurveda is the traditional medical system of India and has been in use for more than 5000 years. The focus of Ayurveda is to maintain harmony and balance of the three Doshas (Vata, Pitta, Kapha), or life forces, that govern the physiology and health of each individual. Ashwagandha is considered one of the most useful plants in the Ayurvedic system for various illnesses, including cancer. Ethnopharmacological and phytochemical analyses have been elucidating the bioactive compounds in ashwagandha that mediate the anti-cancer effects. The most bioactive compounds appear to be the withanolides, including withaferin-A (WFA), withanone, and other withanolide derivatives. The focus of this review will be to discuss the pre-clinical and translational anti-cancer properties of WFA, withanone, and selected withanolides in terms of their ability to inhibit the growth of systemic forms of cancer and gliomas. The mechanisms of action of how these compounds affect tumor cell growth will also be discussed in detail, and include the induction of apoptosis, the inhibition of signal transduction pathways, the arrest of the cell cycle, and the inhibition of receptor tyrosine kinases. The final part will review how ashwagandha and its bioactive compounds could be applied to glioblastoma and gliomas.

The pathogenesis of Parkinson’s disease (PD) remains unclear, and there is no disease-modifying agent for PD. Withaferin A (WA), a naturally occurring compound, has emerged as a neuroprotective agent. However, the mechanisms by which WA is neuroprotective in PD are unknown. Here we show that WA protected against loss of dopaminergic neurons, neuroinflammation, and motor deficits in MPTP-induced PD mouse models. Whole-genome deep sequencing analysis combined with Meta-analysis of human PD studies reveal that DJ1, Nrf2, and STING in substantia nigra pars compacta (SNc) are linked to anti-PD effect of WA. We found that WA activated DJ1 and Nrf2, and suppressed STING within SNc; and overexpression of STING in SNc dampened the effect of WA. Using genetically modified mice (DJ1-KO, Nrf2-KO, STINGgt/gt and STING-KO) and immunolabeling technique, we identified that WA targeted DJ1-Nrf2-STING pathway in dopaminergic neurons; and we demonstrate that STING might be an important factor in PD pathogenesis. In addition, WA alleviated accumulation of phosphorylated α-synuclein (p-α-syn) and insoluble α-syn within SNc in adeno-associated virus (AAV)-mediated human α-syn overexpression PD model. Our comparative analysis on whole-genome transcriptome profiles suggests that STING might be a key target of WA and amantadine in PD treatment. This study highlights a multifaceted role for WA in neuroprotection, and suggests that WA can be a potential candidate for treatment of PD.

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.

Through years of evolutionary selection pressures, organisms have developed potent toxins that coincidentally have marked antineoplastic activity. These natural products have been vital for the development of multiagent treatment regimens currently employed in cancer chemotherapy, and are used in the treatment of a variety of malignancies. Therefore, this review catalogs recent advances in natural product-based drug discovery via the examination of mechanisms of action and available clinical data to highlight the utility of these novel compounds in the burgeoning age of precision medicine. The review also highlights the recent development of antibody-drug conjugates and other immunotoxins, which are capable of delivering highly cytotoxic agents previously deemed too toxic to elicit therapeutic benefit preferentially to neoplastic cells. Finally, the review examines natural products not currently used in the clinic that have novel mechanisms of action, and may serve to supplement current chemotherapeutic protocols.