Stilbenes: a journey from folklore to pharmaceutical innovation.

In modern times, medicine is predominantly based on evidence-based practices, whereas in ancient times, indigenous people relied on plant-based medicines with factual evidence documented in ancient books or folklore that demonstrated their effectiveness against specific infections. Plants and microbes account for 70% of drugs approved by the USFDA (U.S. Food and Drug Administration). Stilbenes, polyphenolic compounds synthesized by plants under stress conditions, have garnered significant attention for their therapeutic potential, bridging ancient wisdom with modern healthcare. Resveratrol, the most studied stilbene, initially discovered in grapes, red wine, peanuts, and blueberries, exhibits diverse pharmacological properties, including cardiovascular protection, antioxidant effects, anticancer activity, and neuroprotection. Traditional remedies, documented in ancient texts like the Ayurvedic Charak Samhita, foreshadowed the medicinal properties of stilbenes long before their modern scientific validation. Today, stilbenes are integral to the booming wellness and health supplement market, with resveratrol alone projected to reach a market value of 90 million US$ by 2025. However, challenges in stilbene production persist due to limited natural sources and costly extraction methods. Bioprospecting efforts reveal promising candidates for stilbene production, particularly endophytic fungi, which demonstrate high-yield capabilities and genetic modifiability. However, the identification of optimal strains and fermentation processes remains a critical consideration. The current review emphasizes the knowledge of the medicinal properties of Stilbenes (i.e., cardiovascular, antioxidant, anticancer, anti-inflammatory, etc.) isolated from plant and microbial sources, while also discussing strategies for their commercial production and future research directions. This also includes examples of novel stilbenes compounds reported from plant and endophytic fungi.

Therapeutic Implications of Dietary Polyphenols-Loaded Nanoemulsions in Cancer Therapy.

Cancer is one of the major causes of death worldwide, even the second foremost cause related to non-communicable diseases. Cancer cells typically possess several cellular and biological processes including, persistence, propagation, differentiation, cellular death, and expression of cellular-type specific functions. The molecular picture of carcinogenesis and progression is unwinding, and it appears to be a tangled combination of processes occurring within and between cancer cells and their surrounding tissue matrix. Polyphenols are plant secondary metabolites abundant in fruits, vegetables, cereals, and other natural plant sources. Natural polyphenols have implicated potential anticancer activity by various mechanisms involved in their antitumor action, including modulation of signaling pathways majorly related to cellular proliferation, differentiation, relocation, angiogenesis, metastatic processes, and cell death. The applications of polyphenols have been limited due to the hydrophobic nature and lower oral bioavailability that could be possibly overcome through encapsulating them into nanocarrier-mediated delivery systems, leading to improved anticancer activity. Nanoemulsions (NEs) possess diverse feasible properties, including greater surface area, modifiable surficial charge, higher half-life, site-specific targeting, and formulation imaging capability necessary to create a practical therapeutic impact, and have drawn increased attention in cancer therapy research. This review has summarized and discussed the basic concepts, classification, delivery approaches, and anticancer mechanism of various polyphenols and polyphenols-encapsulated nanoemulsions with improved cancer therapy.

Functional implications and therapeutic targeting of androgen response elements in prostate cancer.

The androgen receptor (AR) plays an essential role in the growth and progression of prostate cancer (CaP). Ligand-activated AR inside the nucleus binds to the androgen response element (ARE) of the target genes in dimeric form and recruits transcriptional machinery to facilitate gene transcription. Pharmacological compounds that inhibit the AR action either bind to the ligand binding domain (LBD) or interfere with the interactions of AR with other co-regulatory proteins, slowing the progression of the disease. However, the emergence of resistance to conventional treatment makes clinical management of CaP difficult. Resistance has been associated with activation of androgen/AR axis that restores AR transcriptional activity. Activated AR signaling in resistance cases can be mediated by several mechanisms including AR amplification, gain-of-function AR mutations, androgen receptor variant (ARVs), intracrine androgen production, and overexpression of AR coactivators. Importantly, in castration resistant prostate cancer, ARVs lacking the LBD become constitutively active and promote hormone-independent development, underlining the need to concentrate on the other domain or the AR-DNA interface for the identification of novel actionable targets. In this review, we highlight the plasticity of AR-DNA binding and explain how fine-tuning AR's cooperative interactions with DNA translate into developing an alternative strategy to antagonize AR activity.

Hypoxia induced lactate acidosis modulates tumor microenvironment and lipid reprogramming to sustain the cancer cell survival.

It is well known that solid hypoxic tumour cells oxidise glucose through glycolysis, and the end product of this pathway is fermented into lactate which accumulates in the tumour microenvironment (TME). Initially, it was proclaimed that cancer cells cannot use lactate; therefore, they dump it into the TME and subsequently augment the acidity of the tumour milieu. Furthermore, the TME acts as a lactate sink with stope variable amount of lactate in different pathophysiological condition. Regardless of the amount of lactate pumped out within TME, it disappears immediately which still remains an unresolved puzzle. Recent findings have paved pathway in exploring the main role of lactate acidosis in TME. Cancer cells utilise lactate in the de novo fatty acid synthesis pathway to initiate angiogenesis and invasiveness, and lactate also plays a crucial role in the suppression of immunity. Furthermore, lactate re-programme the lipid biosynthetic pathway to develop a metabolic symbiosis in normoxic, moderately hypoxic and severely hypoxic cancer cells. For instance: severely hypoxic cancer cells enable to synthesizing poly unsaturated fatty acids (PUFA) in oxygen scarcity secretes excess of lactate in TME. Lactate from TME is taken up by the normoxic cancer cells whereas it is converted back to PUFAs after a sequence of reactions and then liberated in the TME to be utilized in the severely hypoxic cancer cells. Although much is known about the role of lactate in these biological processes, the exact molecular pathways that are involved remain unclear. This review attempts to understand the molecular pathways exploited by lactate to initiate angiogenesis, invasiveness, suppression of immunity and cause re-programming of lipid synthesis. This review will help the researchers to develop proper understanding of lactate associated bimodal regulations of TME.

Key insights into secondary metabolites from various Chaetomium species.

Endophytic fungi have proved to be a major source of secondary metabolites, wherein the genus Chaetomium has emerged as a source of multifarious bioactive natural compounds belonging to diverse classes such as chaetoglobosins, epipolythiodioxopiperazines, azaphilones, xanthones, anthraquinone, chromones, depsidones, terpenoids, and steroids. The objective of this review is to encapsulate recent findings on various Chaetomium strains, such as C. globosum, C. cupreum, C. elatum, C. subspirale, C. olivaceum, C. indicum, and C. nigricolor known for production of beneficial secondary metabolites, with an insight into their origin and function. A thorough literature survey was conducted for obtaining Chaetomium-derived secondary metabolites, with a scope of future application into drug development efforts. More than 100 secondary metabolites, with various beneficial properties such as antitumor, cytotoxic, antimalarial, and enzyme inhibitory activities, were enlisted. We believe this review will enhance the understanding of beneficial effects conferred by various Chaetomium-derived secondary metabolites and emphasize their potential in serving novel drug development efforts. KEY POINTS: • Identified Chaetomium-derived metabolites with potential for drug development. • More than 100 beneficial metabolites are enlisted. • Benefits include anti-cancerous, antimalarial, and anti-enzymatic properties.

Capsicum annuum L. and its bioactive constituents: A critical review of a traditional culinary spice in terms of its modern pharmacological potentials with toxicological issues.

Capsicum annuum L., commonly known as chili pepper, is used as an important spice globally and as a crude drug in many traditional medicine systems. The fruits of C. annuum have been used as a tonic, antiseptic, and stimulating agent, to treat dyspepsia, appetites, and flatulence, and to improve digestion and circulation. The article aims to critically review the phytochemical and pharmacological properties of C. annuum and its major compounds. Capsaicin, dihydrocapsaicin, and some carotenoids are reported as the major active compounds with several pharmacological potentials especially as anticancer and cardioprotectant. The anticancer effect of capsaicinoids is mainly mediated through mechanisms involving the interaction of Ca2+ -dependent activation of the MAPK pathway, suppression of NOX-dependent reactive oxygen species generation, and p53-mediated activation of mitochondrial apoptosis in cancer cells. Similarly, the cardioprotective effects of capsaicinoids are mediated through their interaction with cellular transient receptor potential vanilloid 1 channel, and restoration of calcitonin gene-related peptide via Ca2+ -dependent release of neuropeptides and suppression of bradykinin. In conclusion, this comprehensive review presents detailed information about the traditional uses, phytochemistry, and pharmacology of major bioactive principles of C. annuum with special emphasis on anticancer, cardioprotective effects, and plausible toxic adversities along with food safety.

Inhibitory activities of grape bioactive compounds against enzymes linked with human diseases.

A quest for identification of novel, safe and efficient natural compounds, as additives in the modern food and cosmetic industries, has been prompted by concerns about toxicity and side effects of synthetic products. Plant phenolic compounds are one of the most documented natural products due to their multifarious biological applications. Grape (Vitis vinifera) is an important source of phenolic compounds such as phenolic acids, tannins, quinones, coumarins and, most importantly, flavonoids/flavones. This review crisply encapsulates enzyme inhibitory activities of various grape polyphenols towards different key human-ailment-associated enzymes: xanthine oxidase (gout), tyrosinase (hyperpigmentation), α-amylase and α-glucosidase (diabetes mellitus), pancreatic lipase (obesity), cholinesterase (Alzheimer's disease), angiotensin i-converting enzymes (hypertension), α-synuclein (Parkinson's disease) and histone deacetylase (various diseases). The review also depicts the enzyme inhibitory mechanism of various grape polyphenols and briefly discusses their stature as potential therapeutic and drug development candidates. KEY POINTS: • Nineteen major bioactive polyphenols from the grape/grape products and their disease targets are presented • Sixty-two important polyphenols as enzyme inhibitors from grape/grape products are presented • A thorough description and graphical presentation of biological significance of polyphenols against various diseases.