Efficacy and safety of polyherbal formulation as an add-on to standard-of-care in mild-to-moderate COVID-19: A randomized, double-blind, placebo-controlled trial.

Background: Novel corona virus disease-2019 (COVID-19) pandemic is a significant contributor to morbidity and mortality in affected individuals. Modulating the immune response in COVID-19 is now an established treatment approach. Polyherbal formulations have long been assessed for their potential immune modulating effects and are expected to be beneficial on COVID-19. Methods: This study aims at assessing the efficacy and safety of polyherbal formulation (referred as IP) in comparison to placebo, as add on to the standard of care (SOC), in patients with mild to moderate COVID-19 patients. Hospitalized RT-PCR positive patients were randomized to either SOC + IP or SOC + Placebo arm. The viral load (VL) was assessed using quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Immunological parameters were also assessed. The clinical improvement was assessed using a numeric rating scale (NRS) and WHO ordinal scale, and follow-up period was 30 days. Results: Seventy-two patients were randomized to SOC + IP (n = 39) and SOC + Placebo (n = 33) arms. There was significant reduction in VL in SOC + IP arm from day 0-4 (p = 0.002), compared to SOC + Placebo arm (p = 0.106). Change in the NRS score and WHO score was significant in both arms, however, the difference between the two arms was statistically significant in favour of IP arm. The increase in Th1 response was significant in SOC + IP arm (p = 0.023), but not in SOC + Placebo arm. COVID-19 specific antibodies were numerically higher in the SOC + IP arm. Conclusion: The study finds that polyherbal formulation significantly reduces VL and contributes to immunomodulation and improvement in clinical conditions without side effects.

Prostate Apoptosis Response-4 (Par-4): A Novel Target in Pyronaridine-Induced Apoptosis in Glioblastoma (GBM) Cells.

Glioblastoma (GBM) is an aggressive form of brain tumor with a median survival of approximately 12 months. With no new drugs in the last few decades and limited success in clinics for known therapies, drug repurposing is an attractive choice for its treatment. Here, we examined the efficacy of pyronaridine (PYR), an anti-malarial drug in GBM cells. PYR induced anti-proliferative activity in GBM cells with IC50 ranging from 1.16 to 6.82 µM. Synergistic activity was observed when PYR was combined with Doxorubicin and Ritonavir. Mechanistically, PYR triggered mitochondrial membrane depolarization and enhanced the ROS levels causing caspase-3 mediated apoptosis. PYR significantly decreased markers associated with proliferation, EMT, hypoxia, and stemness and upregulated the expression of E-cadherin. Interestingly, PYR induced the expression of intracellular as well as secretory Par-4, a tumor suppressor in GBM cells, which was confirmed using siRNA. Notably, Par-4 levels in plasma samples of GBM patients were significantly lower than normal healthy volunteers. Thus, our study demonstrates for the first time that PYR can be repurposed against GBM with a novel mechanism of action involving Par-4. Herewith, we discuss the role of upregulated Par-4 in a highly interconnected signaling network thereby advocating its importance as a therapeutic target.

Exploring AyuGenomics approach for understanding COVID-19 predisposition and progression.

Recent reports on COVID-19 suggest that, the susceptibility to COVID-19 infection and its progression have a genetic predisposition. Majorly associated genetic variants are found in human leukocyte antigen (HLA), angiotensin convertase enzyme (ACE; rs1799752: ACE2; rs73635825), and transmembrane protease serine 2 (TMPRSS-2; rs12329760) genes. Identifying highly prone population having these variants is imperative for determining COVID-19 therapeutic strategies. Ayurveda (Indian traditional system of medicine) concept of Prakriti holds potential to predict genomic and phenotypic variations. Reported work on Prakriti correlates HLA-DR alleles with three broad phenotypes (Tridosha) described in Ayurveda (AyuGenomics). This is suggestive of differences in immune responses in individuals with specific constitutions. Therefore, the reported studies provide clues for clinically relevant hypotheses to be tested in systematic studies. The proposed approach of Ayurveda-based phenotype screening may offer a way ahead to design customized strategies for management of COVID-19 based on differences in Prakriti, immune response, and drug response. However, this needs clinical evaluation of the relation between Prakriti and genetic or phenotypic variants in COVID-19 prone and resistant populations.