Molecular mechanisms of Asparagus racemosus willd. and Withania somnifera (L.) Dunal as chemotherapeutic adjuvants for breast cancer treatment.

ETHNOPHARMACOLOGICAL RELEVANCE: Despite various treatment modalities, the progression and metastasis of breast cancer (BC) are grave concerns due to the alarming disease-free survival rate (DFS) and overall survival rate (OS) of affected patients. Over the years, many antibiotics, synthetic compounds, medicinal plant isolates and polyherbal combinations have been used as adjuvants in therapy for the management of primary and secondary tumors. Paclitaxel (PTX)-based chemotherapy for breast cancer causes multiple adverse side effects in patients. Withania somnifera (L.) Dunal (WS) and Asparagus racemosus Willd. (AR) as Ayurveda-inspired plant-based adjuvants were investigated for their anticancer effects on MDA-MB-231 and 4T1 cells in mouse model systems. AIM OF THE STUDY: This study focused on evaluating the adjuvant properties of WS and AR plant extracts with PTX and their effectiveness over PTX alone in terms of tumor inhibition. MATERIALS AND METHODS: The effects of WS and AR on DNA double-strand breaks (DSBs), senescence induction and mitochondrial functions were evaluated in BC cells in vitro. The potential for cancer stem cell (CSC) inhibition was evaluated via mammosphere formation assays and CD44/CD24 immunostaining. In vivo tumor growth studies were conducted in athymic BALB/c mice for MDA-MB-231 cells and in BALB/c mice for 4T1 cells. RESULTS: Induction of senescence was evident due to DSBs induced by the WS and AR extracts. Mammosphere formation and CD44/CD24 CSC markers were reduced after treatment with WS, AR or the combination of both in MCF-7 cells. WS or AR inhibited epithelial-to-mesenchymal transition (EMT). In vivo studies demonstrated that tumor growth inhibition was more pronounced in the treated group than in the PTX alone group and the untreated control group. CONCLUSION: Our study showed that the use of WS or AR plant hydroalcoholic extracts in combination with paclitaxel (PTX) has better effects on sensitivity and efficacy than PTX alone, as demonstrated in in vitro BC cells and mouse models with BC cell grafts. Hence, scheduling adjuvant therapy with WS or AR alone or combined with PTX can be advantageous for the management of triple-negative BC (TNBC). Further studies are warranted in human clinical conditions to ascertain the efficacy of these treatments.

Co-administration of AYUSH 64 as an adjunct to standard of care in mild and moderate COVID-19: A randomized, controlled, multicentric clinical trial.

OBJECTIVE: Evaluate the efficacy of AYUSH 64, a standard polyherbal Ayurvedic drug in COVID-19. METHODS: During the first pandemic wave, 140 consenting and eligible hospitalized adult participants with mild-moderate symptomatic disease (specific standard RT-PCR assay positive) were selected as per a convenience sample, and randomized (1:1 ratio) to an open-label (assessor blind) two-arm multicentric drug trial; standard of care (SOC as per Indian guidelines) versus AYUSH 64 combined with SOC (AYUSH plus). Participants were assessed daily and discharged once clinical recovery (CR, primary efficacy) was achieved which was based on a predetermined set of criteria (resolution of symptoms, normal peripheral oximetry, and negative specific RT-PCR assay). Each participant was followed using an indigenous software program(mobile phone) and completed a 12-week study period. The dose of AYUSH 64 was 2 tablets oral, 500 mg each, bid for 12 weeks (AYUSH plus only). Significant P was <0.05 (two-sided). On randomization, the groups were found well matched. RESULTS: The mean interval time from randomization to CR was significantly superior in the AYUSH plus group [mean 6.45 days versus 8.26 days, 95% Confidence Interval of the difference -3.02 to -0.59 (P = 0.003, Student's 't test] as per-protocol analysis (134 participants); significant (P = 0.002) on an intention to treat analysis. 70% of the participants in AYUSH plus recovered during the first week (P = 0.046, Chi-square) and showed a significantly better change in physical health, fatigue, and quality of life measures. 48 adverse events, mostly mild and gut related, were reported by each group. There were 20 patient withdrawals (8 in AYUSH plus) but none due to an AE. There were no deaths. Daily assessment (hospitalization) and supervised drug intake ensured robust efficacy data. The open-label design was a concern (study outcome). CONCLUSIONS: AYUSH 64 in combination with SOC hastened recovery, reduced hospitalization, and improved health in COVID-19. It was considered safe and well-tolerated. Further clinical validation (Phase III) is required. TRIAL REGISTRATION: CTRI/2020/06/025557.

India and its pluralistic health system - a new philosophy for Universal Health Coverage.

In this article we attempt to put forth insights into using traditional medicine (TM) systems to achieve Universal Health Coverage (UHC). We discuss the need for reimagining India's health system and the importance of an inclusive approach for UHC. We comprehend the challenges with appropriate use of TM systems and the lessons from international experience of integrating TM systems. We highlight the pathways for better utilization of TM systems for UHC in India.

A narrative review on yoga: a potential intervention for augmenting immunomodulation and mental health in COVID-19.

BACKGROUND: The ongoing novel coronavirus disease 2019 (COVID-19) pandemic has a significant mortality rate of 3-5%. The principal causes of multiorgan failure and death are cytokine release syndrome and immune dysfunction. Stress, anxiety, and depression has been aggravated by the pandemic and its resultant restrictions in day-to-day life which may contribute to immune dysregulation. Thus, immunity strengthening and the prevention of cytokine release syndrome are important for preventing and minimizing mortality in COVID-19 patients. However, despite a few specific remedies that now exist for the SARS-CoV-2virus, the principal modes of prevention include vaccination, masking, and holistic healing methods, such as yoga. Currently, extensive research is being conducted to better understand the neuroendocrinoimmunological mechanisms by which yoga alleviates stress and inflammation. This review article explores the anti-inflammatory and immune-modulating potentials of yoga, along with its role in reducing risk for immune dysfunction and impaired mental health. METHODS: We conducted this narrative review from published literature in MEDLINE, EMBASE, COCHRANE databases. Screening was performed for titles and abstracts by two independent review authors; potentially eligible citations were retrieved for full-text review. References of included articles and articles of major non-indexed peer reviewed journals were searched for relevance by two independent review authors. A third review author checked the excluded records. All disagreements were resolved through discussion amongst review authors or through adjudication by a fourth review author. Abstracts, editorials, conference proceedings and clinical trial registrations were excluded. OBSERVATIONS: Yoga is a nonpharmacological, cost-effective, and safe intervention associated with several health benefits. Originating in ancient India, this vast discipline consists of postures (asanas), breathing techniques (pranayama), meditation (dhyana/dharana), and relaxation. Studies have demonstrated yoga's ability to bolster innate immunity and to inhibit cytokine release syndrome. As an intervention, yoga has been shown to improve mental health, as it alleviates anxiety, depression, and stress and enhances mindfulness, self-control, and self-regulation. Yoga has been correlated with numerous cardioprotective effects, which also may play a role in COVID-19 by preventing lung and cardiac injury. CONCLUSION AND RELEVANCE: This review paves the path for further research on yoga as a potential intervention for enhancing innate immunity and mental health and thus its role in prevention and adjunctive treatment in COVID-19.

Corrigendum: Randomized, Double Blind, Placebo Controlled, Clinical Trial to Study Ashwagandha Administration in Participants Vaccinated Against COVID-19 on Safety, Immunogenicity, and Protection With COVID-19 Vaccine-A Study Protocol.

[This corrects the article DOI: 10.3389/fmed.2022.761655.].

Randomized, Double Blind, Placebo Controlled, Clinical Trial to Study Ashwagandha Administration in Participants Vaccinated Against COVID-19 on Safety, Immunogenicity, and Protection With COVID-19 Vaccine-A Study Protocol.

INTRODUCTION: Vaccines have emerged as the most effective tool in the fight against COVID-19. Governments all over the world have rolled out the COVID-19 vaccine program for their populations. Oxford-AstraZeneca COVID-19 vaccine (COVISHIELD™) is widely used in India. A large number of Indian people have been consuming various traditional medicines in the hope of better protection against COVID-19 infection. Several studies have reported immunological benefits of Withania somnifera (Ashwagandha) and its potential as a vaccine adjuvant. We propose to study the safety, immunogenicity and clinical protection offered by a 6-month regimen of Ashwagandha in participants who volunteer to be vaccinated against COVID-19 (COVISHIELDTM) in the ongoing national program of vaccination. METHODS AND ANALYSIS: We designed a prospective, randomized, double-blind, parallel-group, placebo-controlled, two-arm, exploratory study on healthy volunteers receiving the COVISHIELDTM vaccine. The administration of Ashwagandha will begin within 7 days of the first or second dose of COVISHIELDTM. Primary outcome measure is immunogenicity as measured by SARS-CoV-2 spike (S1) and RBD-specific IgG antibody titres. Secondary outcome measures are safety, protective immune response and quality of life measures. All adverse events will be monitored at each time throughout the study. Participants will be tracked on a daily basis with a user-friendly mobile phone application. Following power calculation 600 participants will be recruited per arm to demonstrate superiority by a margin of 7% with 80% power. Study duration is 28 weeks with interim analysis at the end of 12 weeks. ETHICS AND DISSEMINATION: Ethics approval was obtained through the Central and Institutional Ethics Committees. Participant recruitment commenced in December 2021. Results will be presented in conferences and published in preprints followed by peer-reviewed medical journals. CLINICAL TRIAL REGISTRATION: [www.ClinicalTrials.gov], identifier [CTRI/2021/06/034496].

Ayurveda-based Botanicals as Therapeutic Adjuvants in Paclitaxel-induced Myelosuppression.

Chemotherapy-induced myelosuppression is one of the major challenges in cancer treatment. Ayurveda-based immunomodulatory botanicals Asparagus racemosus Willd (AR/Shatavari) and Withania somnifera (L.). Dunal (WS/Ashwagandha) have potential role to manage myelosuppression. We have developed a method to study the effects of AR and WS as therapeutic adjuvants to counter paclitaxel (PTX)-induced myelosuppression. Sixty female BALB/c mice were divided into six groups-vehicle control (VC), PTX alone, PTX with aqueous and hydroalcoholic extracts of AR (ARA, ARH) and WS (WSA, WSH). The myelosuppression was induced in mice by intraperitoneal administration of PTX at 25 mg/kg dose for three consecutive days. The extracts were orally administered with a dose of 100 mg/kg for 15 days prior to the induction with PTX administration. The mice were observed daily for morbidity parameters and were bled from retro-orbital plexus after 2 days of PTX dosing. The morbidity parameters simulate clinical adverse effects of PTX that include activity (extreme tiredness due to fatigue), behavior (numbness and weakness due to peripheral neuropathy), body posture (pain in muscles and joints), fur aspect and huddling (hair loss). The collected samples were used for blood cell count analysis and cytokine profiling using Bio-Plex assay. The PTX alone group showed a reduction in total leukocyte and neutrophil counts (4,800 ± 606; 893 ± 82) when compared with a VC group (9,183 ± 1,043; 1,612 ± 100) respectively. Pre-administration of ARA, ARH, WSA, and WSH extracts normalized leukocyte counts (10,000 ± 707; 9,166 ± 1,076; 10,333 ± 1,189; 9,066 ± 697) and neutrophil counts (1,482 ± 61; 1,251 ± 71; 1,467 ± 121; 1,219 ± 134) respectively. Additionally, higher morbidity score in PTX group (7.4 ± 0.7) was significantly restricted by ARA (4.8 ± 1.1), ARH (5.1 ± 0.6), WSA (4.5 ± 0.7), and WSH (5 ± 0.8). (Data represented in mean ± SD). The extracts also significantly modulated 20 cytokines to evade PTX-induced leukopenia, neutropenia, and morbidity. The AR and WS extracts significantly prevented PTX-induced myelosuppression (p < 0.0001) and morbidity signs (p < 0.05) by modulating associated cytokines. The results indicate AR and WS as therapeutic adjuvants in cancer management.

Research, biomedicine and Ayurveda: From evidence-based medicine to evidence-informed healthcare.

As the search for effective treatment for Covid-19 intensifies, traditional medicine systems are receiving increasing attention from researchers as well as the public. While scientific rigour is non-negotiable, there remain fundamental issues to be addressed when bringing evidence from traditional systems. Here we examine some of these issues pertaining to Ayurveda and the underlying philosophical underpinnings, and suggest potential ways to move forward. We find an ability to emerge from the cage of "biomedicalism" and its foundational reductionism essential for appropriate research in Ayurveda. We caution against pursuing research in Ayurveda by just mimicking modern medicine and highlight the need for appropriate use of modern science tools and methods to understand Ayurveda and explore its potential for healthcare. We emphasise the need and potential for transdisciplinary research in Ayurveda. A balance between evidence-based medicine and evidence-informed healthcare is required.

Withania somnifera as a safer option to hydroxychloroquine in the chemoprophylaxis of COVID-19: Results of interim analysis.

OBJECTIVES: To study the efficacy and safety of Withania somnifera (WS, Ashwagandha) in the prophylaxis against COVID-19 in high risk health care workers (HCW) in comparison to hydroxychloroquine (HCQ). To evaluate the general physical and mental health benefits of Ashwagandha. METHODS: A 16 week randomized prospective, open-label, parallel efficacy, two arm, multi-centre study. The primary efficacy measure was 'failure of prophylaxis' as confirmed COVID-19 by quantitative Reverse Transcription Polymerase Chain Reaction (RT-PCR) at any time during the study period. This study on 400 participants from three centres was designed to establish non-inferiority for WS to HCQ for prophylaxis against COVID-19 at 80 % power and significance p < 0.025, one-sided. The interim analysis was carried out on 160 participants after completion of 8 weeks. RESULTS: Participants in both the arms were well-matched at the baseline characteristics. Forty participants in the HCQ group and 26 participants in the WS group reported mild AE. The symptoms of confirmed COVID-19 were found to be 3.7 % (95 % CI 1.3-10.5 %) in the HCQ and 1.3 % (95 % CI 0.02-6.7 %) in the WS arm amongst the first 160 participants completing 8 weeks. CONCLUSION: Our intent was to explore a safer option to HCQ. We report that WS was not found inferior to HCQ and its efficacy was within the 15 % non-inferiority margin set a priori. WS as an immunomodulator has other clinical benefits including reducing mental stress. The final report of this study is expected by end of August 2021.