Scoparone chemical modification into semi-synthetic analogues featuring 3-substitution for their anti-inflammatory activity.

Natural products (NPs) continue to serve as a structural model for the development of new bioactive molecules and improve the process of identifying novel medicines. The biological effects of coumarins, one of the most researched compounds among NPs, are currently being thoroughly investigated. In the present investigation, we reported the synthesis of nineteen semi-synthetic 3-substituted scoparone analogues, followed by their characterization using analytical methods such as NMR, HPLC, and HRMS. All compounds screened for in vitro and in vivo study for their ability to reduce inflammation. The SAR study worked effectively for this particular scoparone 3-substitution, as compounds 3, 4, 9, 16, 18, and 20 displayed improved in vitro results for TNF-α than the parent molecule. Similarly, compounds 3, and 17 showed a higher percentage of IL-6 inhibition. Compounds 3, 4, and 12 have also been identified by in vivo studies as promising candidates with higher percent inhibition than the parent scoparone molecule. As evident from all in vitro and in vivo studies, compound 3 showed the most potent anti-inflammatory activity among all.

Antiarthritic activity of OA-DHZ; a gastroprotective NF-κB/MAPK/COX inhibitor.

Arthritis, a primary autoimmune disorder having a global incidence of 2.03% person/year, is presently being treated by many commercially available drugs that treat symptomatically or improve the disease's clinical state; however, all the therapies pose varying amount of side effects. Therefore, it has become a fundamental need to search for therapeutics that offer better efficacy and safety profile, and the natural or nature-derived products are known for their outstanding performance in this arena. OA-DHZ, known to possess anti-inflammatory and analgesic properties, when explored for its efficacy against arthritis in adjuvant-induced arthritis (AIA) model, was found to inhibit paw edema by 34% and TNF-α, IL-6, and IL-1ß by 67%, 39%, and 45% respectively when compared to diseased control. It was also able to reduce the inflamed spleen size by 45% and successfully normalized biochemical and hematological changes that followed arthritis. In vitro studies revealed that the underlying mechanism for inhibiting arthritis progression might be due to NF-κB /MAPK pathway modulation. OA-DHZ also showed selective inhibition of COX-2 in vitro while showing gastroprotective effects when evaluated for ulcerogenic and antiulcer potential in vivo. In contrast to the results obtained from in vivo experimentation, there is a disparity in the pharmacokinetic profile of OA-DHZ, where it showed low oral exposure and high clearance rate. OA-DHZ being antiarthritic acting via NF-κB /MAPK/ COX inhibition while showing gastroprotective effects, can be a suitable candidate to be in the drug pipeline and further exploration.

Phytochemical add-on therapy to DMARDs therapy in rheumatoid arthritis: In vitro and in vivo bases, clinical evidence and future trends.

The use of biologically active compounds derived from plants i.e. phytochemicals, have been known for ages for their pharmacological activities in the treatment of autoimmune disorders like rheumatoid arthritis (RA). Besides enormous scientific evidence, the therapeutic potential of phytochemicals is often undervalued. The treatment in RA involves the use of synthetic and biological disease modifying anti-rheumatic drugs (DMARDs). However, the long-term treatment in RA is associated with the risk of gastrointestinal, liver, pulmonary and renal toxicities and serious infections including latent tuberculosis, pneumococcus influenza, herpes zoster and hepatitis. These adverse effects sometimes lead to discontinuation of the therapy. A relatively new vision based on the combination of DMARDs with phytochemicals exhibiting anti-inflammatory, anti-arthritic, anti-oxidant, hepatoprotective and nephroprotective properties for the treatment of RA has achieved substantial importance in the last decade. From this perspective, the present review focuses on the combination of DMARDs (primarily MTX) with phytochemicals that have shown synergistic therapeutic effects while decreasing the toxic repercussions of current RA therapy. The review covers recent evidences of such combination studies that have shown promising results both in experimental arthritic models and clinical arthritis. Few of the combinations including resveratrol, sinomenine, coenzyme Q10 exhibited considerable interest because of their efficacy as an adjuvant to the MTX/standard DMARDs therapy in clinical trials. Besides giving an overview of such combination studies the review also critically discusses the limitations with the use of phytochemicals (e.g. solubility, permeability and bioavailability) compromising their clinical application. Additionally, it stresses upon the need of novel delivery systems and pharmaceutical technologies to increase the therapeutic efficacy of the combination therapy. Overall, the review unveils the potential of phytochemicals in combination with DMARDs with increased tolerability and superior efficacy in further refining the future of the RA therapy.

Molecular insights into the mechanisms of susceptibility of Labeo rohita against oomycete Aphanomyces invadans.

Aphanomyces invadans, the causative agent of epizootic ulcerative syndrome, is one of the most destructive pathogens of freshwater fishes. To date, the disease has been reported from over 160 fish species in 20 countries and notably, this is the first non-salmonid disease that has resulted in major impacts globally. In particular, Indian major carps (IMCs) are highly susceptible to this disease. To increase our knowledge particularly with regards to host immune response against A. invadans infection in a susceptible host, the gene expression profile in head kidney of A. invadans-infected and control rohu, Labeo rohita was investigated using RNA sequencing. Time course analysis of RNA-Seq data revealed 5608 differentially expressed genes, involved among others in Antigen processing and presentation, Leukocyte transendothelial migration, IL-17 signaling, Chemokine signaling, C-type lectin receptor signaling and Toll-like receptor signaling pathways. In the affected pathways, a number of immune genes were found to be downregulated, suggesting an immune evasion strategy of A. invadans in establishing the infection. The information generated in this study offers first systematic mechanistic understanding of the host-pathogen interaction that might underpin the development of new management strategies for this economically devastating fish-pathogenic oomycete A. invadans.

Advances in the possible treatment of COVID-19: A review.

The emergence of the global pandemic caused by novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has put a challenge to identify or derive the therapeutics for its prevention and treatment. Despite the unprecedented advances in the modern medicinal system, currently, there are no proven effective therapies. However, rapid research on SARS-CoV-2 epidemiology help unveiling some new targets for potential drug therapies. Many drugs have been screened, and even their clinical trials are going on at an exceptional pace. Amongst these RNA-dependent RNA polymerase inhibitors (favipiravir and remdesivir) and steroids especially dexamethasone showed promising effects. The biological agents like tocilizumab, interferons, and convalescent plasma prove to be beneficial in viral clearance. Moreover, many immunomodulatory and viral S protein targeting vaccines have their ongoing clinical trials. The establishment of various in vitro and in vivo models for preclinical studies can additionally help the current research. The volume and the pace of the clinical trials launched to evaluate the safety and efficacy of various agents against coronavirus disease 2019 (COVID-19) reflect the need for high-quality evidence for various therapies to be practiced by clinicians. This study aims to sum up all the current advances in the global medicinal system against the COVID-19.