Maternal and developmental toxicity of Bisphenol-A in SWR/J mice.

Bisphenol-A (BPA), an organic compound with two phenol functional groups, is a widely used industrial plasticizer with known estrogenic properties. It is used in the manufacture of epoxy resins and polycarbonate plastics. This study was designed to evaluate and assess the possible toxicity arising from the oral administration of BPA to pregnant mice. Pregnant SWR/J mice (15 mice/group) were administrated oral doses of BPA (125, 250 and 500 mg/kg/day) over the course of five-day intervals during gestation (D1-5, D6-10 and D11-15), while control groups received only corn oil. The results indicated that BPA was associated with a reduction in the body weight of the pregnant mice from around 2-3 days after administration until the end of gestation. The greatest effects were evident when the BPA was given during the later stages of pregnancy, and with higher doses. They also showed marked reduction in food intake and, to a lesser extent, in water intake. Furthermore, doses of BPA induced a reduction in implantation sites, lower foetal body weight and increased mortality rates. Abortion and foetal resorption rates were not affected by BPA administration, however. The above findings were concluded by discussing the possible mechanisms involved in producing these effects.

Identification of SARS-CoV-2 inhibitors from extracts of Houttuynia cordata Thunb.

Houttuynia cordata Thunb., a perennial herb belonging to the Saururaceae family is a well-known ingredient of Traditional Chinese medicine (TCM) with several therapeutic properties. During the severe acute respiratory syndrome (SARS) outbreak in China, it was one of the approved ingredients in SARS preventative formulations and therefore, the plant may contain novel bioactive chemicals that can be used to suppress the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a virus for which there are currently no effective drugs available. Like all RNA viruses, SARS-CoV-2 encode RNA-dependent RNA polymerase (RdRp) enzyme which aids viral gene transcription and replication. The present study is aimed at understanding the potential of bioactive compounds from H. cordata as inhibitors of the SARS-CoV-2 RdRp enzyme. We investigated the drug-likeness of the plant's active constituents, such as alkaloids, polyphenols, and flavonoids, as well as their binding affinity for the RdRp enzyme. Molecular docking experiments show that compounds 3 (1,2,3,4,5-pentamethoxy-dibenzo-quinolin-7-one), 14 (7-oxodehydroasimilobine), and 21 (1,2-dimethoxy-3-hydroxy-5-oxonoraporphine) have a high affinity for the drug target and that the complexes are maintained by hydrogen bonds with residues like Arg553, Cys622 and Asp623, as well as hydrophobic interactions with other residues. The lead compounds' complexes with the target enzyme remained stable throughout the molecular dynamics simulation. Analysis of molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) and molecular mechanics generalized Born surface area (MM-GBSA) revealed the key residues contributing considerably to binding free energy. Thus, the findings reveal the potential of H. cordata bioactive compounds as anti-SARS-CoV-2 drug candidate molecules against the target enzyme.

Structure-based virtual screening of phytochemicals and repurposing of FDA approved antiviral drugs unravels lead molecules as potential inhibitors of coronavirus 3C-like protease enzyme.

Coronaviruses are enveloped positive-strand RNA viruses belonging to family Coronaviridae and order Nidovirales which cause infections in birds and mammals. Among the human coronaviruses, highly pathogenic ones are Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) and the Middle East Respiratory Syndrome coronavirus (MERS-CoV) which have been implicated in severe respiratory syndrome in humans. There are no approved antiviral drugs or vaccines for the treatment of human CoV infection to date. The recent outbreak of new coronavirus pandemic, coronavirus disease 2019 (COVID-19) has caused a high mortality rate and infections around the world which necessitates the need for the discovery of novel anti-coronaviral drugs. Among the coronaviruses proteins, 3C-like protease (3CLpro) is an important drug target against coronaviral infection as the auto-cleavage process catalysed by the enzyme is crucial for viral maturation and replication. The present work is aimed at the identification of suitable lead molecules for the inhibition of 3CLpro enzyme via a computational screening of the Food and Drug Administration (FDA) approved antiviral drugs and phytochemicals. Based on binding energies and molecular interaction studies, we shortlisted five lead molecules (both FDA approved drugs and phytochemicals) for each enzyme targets (SARS-CoV-2 3CLpro, SARS-CoV 3CLpro and MERS-CoV 3CLpro). The lead molecules showed higher binding affinity compared to the standard inhibitors and exhibited favourable hydrophobic interactions and a good number of hydrogen bonds with their respective targets. A few promising leads with dual inhibition potential were identified among FDA approved antiviral drugs which include DB13879 (Glecaprevir), DB09102 (Daclatasvir), molecule DB09297 (Paritaprevir) and DB01072 (Atazanavir). Among the phytochemicals, 11,646,359 (Vincapusine), 120,716 (Alloyohimbine) and 10,308,017 (Gummadiol) showed triple inhibition potential against all the three targets and 102,004,710 (18-Hydroxy-3-epi-alpha-yohimbine) exhibited dual inhibition potential. Hence, the proposed lead molecules from our findings can be further investigated through in vitro and in vivo studies to develop into potential drug candidates against human coronaviral infections.

Evaluation of (ɳ6-p-cymene) ruthenium diclofenac complex as anticancer chemotherapeutic agent: interaction with biomolecules, cytotoxicity assays.

The designing of metal-based anticancer therapeutic agents can be optimized in a better and rapid way if the ligands utilized have standalone properties. Therefore, even when the organometallic/coordination complex (i.e., metallodrug) gets dissociated in extreme conditions, the ligand can endorse its biological properties. Herein, we have synthesized and characterized ɳ6-p-cymene ruthenium diclofenac complex. Furthermore, the ruthenium complex interactions with human serum albumin (HSA) and ct-DNA have been studied using various spectroscopic studies viz., UV, fluorescence, and circular dichroism and exhibited a significant binding propensity. Furthermore, in vitro cytotoxicity assays were carried out against human breast cancer "MCF-7" cell line. The ɳ6-p-cymene ruthenium diclofenac complex registered significant cytotoxicity with an IC50 value of ∼25.0 µM which is comparable to the standard drugs. The ɳ6-p-cymene ruthenium diclofenac complex was able to decrease the MCF-7 cell proliferation and induced significant levels of apoptosis with relatively low toxicity.