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Revisiting the Multifaceted Therapeutic Potential of Withaferin A (WA), a Novel Steroidal Lactone, W-ferinAmax Ashwagandha, from Withania Somnifera (L) Dunal.
Kumar, P, Banik, SP, Goel, A, Chakraborty, S, Bagchi, M, Bagchi, D
Journal of the American Nutrition Association. 2024;(2):115-130
Abstract
Withania somnifera (L.) Dunal, abundant in the Indian subcontinent as Ashwagandha or winter cherry, is a herb of unprecedented therapeutic value. The number of ailments for which crude Ashwagandha extract can be used as a preventive or curative is practically limitless; and this explains why its use has been in vogue in ancient Ayurveda since at-least about four thousand years. The therapeutic potential of Ashwagandha mainly owes from its reservoir of alkaloids (isopelletierine, anaferine), steroidal lactones (withanolides) and saponins with an extra acyl group (sitoindoside VII and VIII). Withaferin A is an exceptionally potent withanolide which is found in high concentrations in W. somnifera plant extracts. The high reactivity of Withaferin A owes to the presence of a C-28 ergostane network with multiple sites of unsaturation and differential oxygenation. It interacts with the effectors of multiple signaling pathways involved in inflammatory response, oxidative stress response, cell cycle regulation and synaptic transmission and has been found to be significantly effective in inducing programmed cell death in cancer cells, restoring cognitive health, managing diabetes, alleviating metabolic disorders, and rejuvenating the overall body homeostasis. Additionally, recent studies suggest that Withaferin A (WA) has the potential to prevent viral endocytosis by sequestering TMPRSS2, the host transmembrane protease, without altering ACE-2 expression. The scope of performing subtle structural modifications in this multi-ring compound is believed to further expand its pharmacotherapeutic horizon. Very recently, a novel, heavy metal and pesticide free formulation of Ashwagandha whole herb extract, with a significant amount of WA, termed W-ferinAmax Ashwagandha, has been developed. The present review attempts to fathom the present and future of this wonder molecule with comprehensive discussion on its therapeutic potential, safety and toxicity.Key teaching pointsWithania somnifera (L.) Dunal is a medicinal plant with versatile therapeutic values.The therapeutic potential of the plant owes to the presence of withanolides such as Withaferin A.Withaferin A is a C-28 ergostane based triterpenoid with multiple reactive sites of therapeutic potential.It is effective against a broad spectrum of ailments including neurodegenerative disorders, cancer, inflammatory and oxidative stress disorders and it also promotes cardiovascular and sexual health.W-ferinAmax Ashwagandha, is a heavy metal and pesticide free Ashwagandha whole herb extract based formulation with significant amount of Withaferin A.
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Therapeutic potential of tocotrienols as chemosensitizers in cancer therapy.
Sailo, BL, Chauhan, S, Hegde, M, Girisa, S, Alqahtani, MS, Abbas, M, Goel, A, Sethi, G, Kunnumakkara, AB
Phytotherapy research : PTR. 2024
Abstract
Chemoresistance is the adaptation of cancer cells against therapeutic agents. When exhibited by cancer cells, chemoresistance helps them to avoid apoptosis, cause relapse, and metastasize, making it challenging for chemotherapeutic agents to treat cancer. Various strategies like dosage modification of drugs, nanoparticle-based delivery of chemotherapeutics, antibody-drug conjugates, and so on are being used to target and reverse chemoresistance, one among such is combination therapy. It uses the combination of two or more therapeutic agents to reverse multidrug resistance and improve the effects of chemotherapy. Phytochemicals are known to exhibit chemosensitizing properties and are found to be effective against various cancers. Tocotrienols (T3) and tocopherols (T) are natural bioactive analogs of vitamin E, which exhibit important medicinal value and potential curative properties apart from serving as an antioxidant and nutrient supplement. Notably, T3 exhibits a variety of pharmacological activities like anticancer, anti-inflammatory, antiproliferative, and so on. The chemosensitizing property of tocotrienol is exhibited by modulating several signaling pathways and molecular targets involved in cancer cell survival, proliferation, invasion, migration, and metastasis like NF-κB, STATs, Akt/mTOR, Bax/Bcl-2, Wnt/β-catenin, and many more. T3 sensitizes cancer cells to chemotherapeutic drugs including cisplatin, doxorubicin, and paclitaxel increasing drug concentration and cytotoxicity. Discussed herewith are the chemosensitizing properties of tocotrienols on various cancer cell types when combined with various drugs and biological molecules.
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Pathogenesis of rheumatoid arthritis and its treatment with anti-inflammatory natural products.
Sharma, A, Goel, A
Molecular biology reports. 2023;(5):4687-4706
Abstract
Introduction Rheumatoid arthritis (RA) is a common autoimmune disease across the globe that is chronic and systemic as well. The disease is linked with autoantibodies and is inflammatory, eventually targeting several molecules along with certain modified self-epitopes. The disease majorly affects the joints of an individual. Rheumatoid arthritis is manifested clinically by polyarthritis linked with the dysfunction of the joints. This chiefly affects the synovial joint lining and is linked with progressive dysfunction, premature death, along with socioeconomic implications. The macrophage activation, along with the activation of certain defense cells, results in a response to self-epitopes that helps in providing a better understanding of the disease pathogenesis. Material and methodology For this review article, papers have been retrieved and reviewed from database including PubMed, Scopus and Web of science. Relevant papers were taken fulfilling the criteria for writing this review article. Results This has resulted in the establishment of several new therapeutic techniques that serve as potential inhibitors of such cells. Researchers have gained an interest in understanding this disease to provide strategies for treatment in the last two decades. This also includes recognition followed by the treatment of the disease at its early stages. Various allopathic treatment approaches often have chronic and toxic teratogenic effects. However, to avoid this issue of toxicity followed by side effects, certain medicinal plants have been used in treating RA. Conclusion Medicinal plants possess active phytoconstituents that entail antioxidants as well as anti-inflammatory properties, making them a helpful alternative to allopathic drugs that are often linked with highly toxic effects. This review paper entails a thorough discussion of the epidemiology, pathophysiology, diagnosis, and management of RA. The paper will also focus on the use of herbal plants in the treatment of the disease to avoid the side effects that generally occur in allopathic treatment.
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SGLT2 inhibitors in hypertension: Role beyond diabetes and heart failure.
Gupta, R, Maitz, T, Egeler, D, Mehta, A, Nyaeme, M, Hajra, A, Goel, A, Sreenivasan, J, Patel, N, Aronow, WS
Trends in cardiovascular medicine. 2023;(8):479-486
Abstract
Type 2 Diabetes Mellitus (T2DM) is a pandemic that affects millions of patients worldwide. Diabetes affects multiple organ systems leading to comorbidities including hypertension. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) recently have been approved for the treatment of T2DM and heart failure with reduced and preserved ejection fraction. Retrospective analyses of clinical trials have noted SGLT2 inhibitors to have a promising effect on blood pressure. Moreover, the observed blood pressure reduction is not just an acute effect of treatment initiation but has been shown to have a long-term impact on both systolic and diastolic blood pressure. The mechanism of action leading to the blood pressure reduction is still unclear; however, proposed mechanisms are related to the natriuretic effect, modification of the renin-angiotensin-aldosterone system, and/or the reduction in the sympathetic nervous system, SGLT2i should be considered as second-line medication in those patients with diabetes or heart disease and concomitant hypertension. This article reviews the pharmacology, side effect profile, and clinical trials surrounding the use of SGLT2i for the treatment of hypertension.
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A critical assessment of the whole plant-based phytotherapeutics from Withania somnifera (L.) Dunal with respect to safety and efficacy vis-a-vis leaf or root extract-based formulation.
Kumar, P, Banik, SP, Goel, A, Chakraborty, S, Bagchi, M, Bagchi, D
Toxicology mechanisms and methods. 2023;(8):698-706
Abstract
Withania somnifera (L.) Dunal, popularly known as Ashwagandha or Indian ginseng, is well acclaimed for its health-enhancing effects, including its potent immunomodulatory, anti-inflammatory, neuroprotective, and anti-tumorigenic properties. The prime biological effectors of these attributes are a diverse group of ergostane-based steroidal lactones termed withanolides. Withanones and withanosides are distributed differentially across the plant body, whereas withanolides and withanones are known to be more abundant in leaves, while withanosides are found exclusively in the roots of the plants. Standardized W. somnifera extract is Generally Recognized as Safe (GRAS)-affirmed, however, moderate to severe toxic manifestations may occur at high dosages. Withaferin A, which also happens to be the primary bioactive ingredient for the effectiveness of this plant. There have been contrasting reports regarding the distribution of withaferin A in W. somnifera. While most reports state that the roots of the plant have the highest concentrations of this phytochemical, several others have indicated that leaves can accumulate withaferin A in proportionately higher amounts. A comprehensive survey of the available reports suggests that the biological effects of Ashwagandha are grossly synergistic in nature, with many withanolides together mediating the desired physiological effect. In addition, an assorted formulation of withanolides can also neutralize the toxic effects (if any) associated with withaferin A. This mini-review presents a fresh take on the recent developments regarding the safety and toxicity of the plant, along with a critical assessment of the use of roots against leaves as well as whole plants to develop therapeutic formulations. Going by the currently available scientific evidence, it is safe to infer that the use of whole plant formulations instead of exclusively root or leaf recipes may present the best possible option for further exploration of therapeutic benefits from this novel medicinal plant.HighlightsTherapeutic potential of withanolides owes to the presence of α,β unsaturated ketone which binds to amines, alcohols, and esters and 5β, 6β epoxy group which react with side chain thiols of proteins.At concentrations above NOAEL (no observed adverse effect level), the same mechanisms contribute towards toxicity of the molecule.Although withanosides are found exclusively in roots, whole plants have higher contents of withanones and withanolides.Whole plant-based formulations have other metabolites which can nullify the toxicity associated with roots.Extracts made from whole plants, therefore can holistically impart all therapeutic benefits as well as mitigate toxicity.
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Use of Psychedelics for Pain: A Scoping Review.
Goel, A, Rai, Y, Sivadas, S, Diep, C, Clarke, H, Shanthanna, H, Ladha, KS
Anesthesiology. 2023;(4):523-536
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Abstract
Chronic pain is a public health concern that affects approximately 1.5 billion people globally. Conventional therapeutic agents including opioid and non-opioid analgesics have been associated with adverse side effects, issues with addiction, and ineffective analgesia. Novel agents repurposed to treat pain via different mechanisms are needed to fill the therapeutic gap in chronic pain management. Psychedelics such as lysergic acid diethylamide and psilocybin (the active ingredient in psychedelic mushrooms) are thought to alter pain perception through direct serotonin receptor agonism, anti-inflammatory effects, and synaptic remodeling. This scoping review was conducted to identify human studies in which psychedelic agents were used for the treatment of pain. Twenty-one articles that assessed the effects of psychedelics in treating various pain states were included. The present scarcity of clinical trials and small sample sizes limit their application for clinical use. Overall, psychedelics appear to show promise for analgesia in patients with certain headache disorders and cancer pain diagnoses. Future studies must aim to examine the combined effects of psychotherapy and psychedelics on chronic pain.
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Flavonoids as promising anticancer therapeutics: Contemporary research, nanoantioxidant potential, and future scope.
Gupta, M, Ahmad, J, Ahamad, J, Kundu, S, Goel, A, Mishra, A
Phytotherapy research : PTR. 2023;(11):5159-5192
Abstract
Flavonoids are natural polyphenolic compounds considered safe, pleiotropic, and readily available molecules. It is widely distributed in various food products such as fruits and vegetables and beverages such as green tea, wine, and coca-based products. Many studies have reported the anticancer potential of flavonoids against different types of cancers, including solid tumors. The chemopreventive effect of flavonoids is attributed to various mechanisms, including modulation of autophagy, induction of cell cycle arrest, apoptosis, and antioxidant defense. Despite of significant anticancer activity of flavonoids, their clinical translation is limited due to their poor biopharmaceutical attributes (such as low aqueous solubility, limited permeability across the biological membranes (intestinal and blood-brain barrier), and stability issue in biological systems). A nanoparticulate system is an approach that is widely utilized to improve the biopharmaceutical performance and therapeutic efficacy of phytopharmaceuticals. The present review discusses the significant anticancer potential of promising flavonoids in different cancers and the utilization of nanoparticulate systems to improve their nanoantioxidant activity further to enhance the anticancer activity of loaded promising flavonoids. Although, various plant-derived secondary metabolites including flavonoids have been recommended for treating cancer, further vigilant research is warranted to prove their translational values.
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Caring for the Bone Health Among Liver Transplant Recipients.
Kumar, SE, Cherian, KE, Paul, TV, Goel, A
Journal of clinical and experimental hepatology. 2023;(6):1130-1139
Abstract
Liver transplant outcomes have improved over the years, and currently, the quality of life and long-term well-being of these patients needs to be improved. Improving bone health goes a long way toward achieving this objective. Poor bone health (osteopenia and osteoporosis) although prevalent, is often overlooked owing to its asymptomatic nature. It can be complicated by debilitating fracture affecting quality of life. It is recommended to assess and optimize bone health prior to liver transplant. Multiple factors contribute to poor bone health in a liver transplant recipient and it is vital to understand and ameliorate these. A careful and targeted approach with inputs from multidisciplinary team involving transplant physician, endocrinologist, occupational therapist, nutritionist, and nursing personnel may often be required. In this review, we aim to concisely discuss the various aspects related to prevalence, pathophysiology, evaluation, treatment, and follow-up of bone disease among liver transplant recipients.
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A comprehensive review on modulation of SIRT1 signaling pathways in the immune system of COVID-19 patients by phytotherapeutic melatonin and epigallocatechin-3-gallate.
Chattree, V, Singh, K, Singh, K, Goel, A, Maity, A, Lone, A
Journal of food biochemistry. 2022;(12):e14259
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SARS-CoV-2 infection has now become the world's most significant health hazard, with the World Health Organization declaring a pandemic on March 11, 2020. COVID-19 enters the lungs through angiotensin-converting enzyme 2 (ACE2) receptors, alters various signaling pathways, and causes immune cells to overproduce cytokines, resulting in mucosal inflammation, lung damage, and multiple organ failure in COVID-19 patients. Although several antiviral medications have been effective in managing the virus, they have not been effective in lowering the inflammation and symptoms of the illness. Several studies have found that epigallocatechin-3-gallate and melatonin upregulate sirtuins proteins, which leads to downregulation of pro-inflammatory gene transcription and NF-κB, protecting organisms from oxidative stress in autoimmune, respiratory, and cardiovascular illnesses. As a result, the purpose of this research is to understand more about the molecular pathways through which these phytochemicals affect COVID-19 patients' impaired immune systems, perhaps reducing hyperinflammation and symptom severity. PRACTICAL APPLICATIONS Polyphenols are natural secondary metabolites that are found to be present in plants. EGCG a polyphenol belonging to the flavonoid family in tea has potent anti-inflammatory and antioxidative properties that helps to counter the inflammation and oxidative stress associated with many neurodegenerative diseases. Melatonin, another strong antioxidant in plants, has been shown to possess antiviral function and alleviate oxidative stress in many inflammatory diseases. In this review, we propose an alternative therapy for COVID-19 patients by supplementing their diet with these nutraceuticals that perhaps by modulating sirtuin signaling pathways counteract cytokine storm and oxidative stress, the root causes of severe inflammation and symptoms in these patients.
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Finerenone: A New Era for Mineralocorticoid Receptor Antagonism and Cardiorenal Protection.
Parfianowicz, D, Shah, S, Nguyen, C, Maitz, TN, Hajra, A, Goel, A, Sreenivasan, J, Aronow, WS, Vyas, A, Gupta, R
Current problems in cardiology. 2022;(12):101386
Abstract
The renin-angiotensin-aldosterone system is a neurohormonal system responsible for maintaining homeostasis of fluid regulation, sodium balance, and blood pressure. The complexity of this pathway enables it to be a common target for blood pressure and volume-regulating medications. The mineralocorticoid receptor is one of these targets, and is found not only in the kidney, but also tissues making up the heart, blood vessels, and adipose. Mineralocorticoid receptor antagonists have been shown to slow progression of chronic kidney disease, treat refractory hypertension and primary aldosteronism, and improve morbidity and mortality in management of heart failure with reduced ejection fraction. The more well-studied medications were derived from steroid-based compounds, and thus come with a distinct side-effect profile. To avoid these adverse effects, developing a mineralocorticoid receptor antagonist (MRA) from a non-steroidal base compound has gained much interest. This review will focus on the novel non-steroidal MRA, Finerenone, to describe its unique mechanism of action while summarizing the available clinical trials supporting its use in patients with various etiologies of cardiorenal disease.