It is appreciated far and wide that increased and regular consumption of fruits and vegetables is linked with noteworthy anticancer benefits. Extensively consumed as a spice in foods and beverages worldwide, ginger (Zingiber officinale Roscoe) is an excellent source of several bioactive phenolics, including non-volatile pungent compounds such as gingerols, paradols, shogaols and gingerones. Ginger has been known to display anti-inflammatory, antioxidant and antiproliferative activities, indicating its promising role as a chemopreventive agent. Here, we show that whole ginger extract (GE) exerts significant growth-inhibitory and death-inductory effects in a spectrum of prostate cancer cells. Comprehensive studies have confirmed that GE perturbed cell-cycle progression, impaired reproductive capacity, modulated cell-cycle and apoptosis regulatory molecules and induced a caspase-driven, mitochondrially mediated apoptosis in human prostate cancer cells. Remarkably, daily oral feeding of 100 mg/kg body weight of GE inhibited growth and progression of PC-3 xenografts by approximately 56 % in nude mice, as shown by measurements of tumour volume. Tumour tissue from GE-treated mice showed reduced proliferation index and widespread apoptosis compared with controls, as determined by immunoblotting and immunohistochemical methods. Most importantly, GE did not exert any detectable toxicity in normal, rapidly dividing tissues such as gut and bone marrow. To the best of our knowledge, this is the first report to demonstrate the in vitro and in vivo anticancer activity of whole GE for the management of prostate cancer.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), initially originated in China in year 2019 and spread rapidly across the globe within 5 months, causing over 96 million cases of infection and over 2 million deaths. Huge efforts were undertaken to bring the COVID-19 vaccines in clinical development, so that it can be made available at the earliest, if found to be efficacious in the trials. We developed a candidate vaccine ZyCoV-D comprising of a DNA plasmid vector carrying the gene encoding the spike protein (S) of the SARS-CoV-2 virus. The S protein of the virus includes the receptor binding domain (RBD), responsible for binding to the human angiotensin converting enzyme (ACE-2) receptor. The DNA plasmid construct was transformed into E. coli cells for large scale production. The immunogenicity potential of the plasmid DNA has been evaluated in mice, guinea pig, and rabbit models by intradermal route at 25, 100 and 500µg dose. Based on the animal studies proof-of-concept has been established and preclinical toxicology (PCT) studies were conducted in rat and rabbit model. Preliminary animal study demonstrates that the candidate DNA vaccine induces antibody response including neutralizing antibodies against SARS-CoV-2 and also provided Th-1 response as evidenced by elevated IFN-γ levels.

SUMMARYAim: Cardiac hypertrophy and myocardial fibrosis significantly contribute to the pathogenesis of diabetic cardiomyopathy (DCM). Altered expression of several genes and their regulation by microRNAs has been reported in hypertrophied failing hearts. This study aims to examine the role of Cdc42, Pak1, and miR-30c in the pathogenesis of cardiac hypertrophy in DCM. Methods: DCM was induced in Wistar rats by low-dose streptozotocin-high-fat diet for 12 weeks. Cardiac expression of Cdc42, Pak1 and miR-30c, and hypertrophy markers (ANP and b-MHC) was studied in DCM vs control rats and in high-glucose (HG)-treated H9c2 cardiomyocytes. Results: Diabetic rats showed cardiomyocyte hypertrophy, increased heart-to-body weight ratio, and an increased expression of ANP and b-MHC. Cardiac expression of Cdc42 and Pak1 genes was increased in diabetic hearts and in HG-treated cardiomyocytes. miR-30c was identified to target Cdc42 and Pak1 genes, and cardiac miR-30c expression was found to be decreased in DCM rats, patients with DCM, and in HG-treated cardiomyocytes. miR-30c overexpression decreased Cdc42 and Pak1 genes and attenuated HG-induced cardiomyocyte hypertrophy, whereas miR-30c inhibition increased Cdc42 and Pak1 gene expression and myocyte hypertrophy in HG-treated cardiomyocytes. Conclusion: Downregulation of miR-30c mediates prohypertrophic effects of hyperglycemia in DCM by upregulation of Cdc42 and Pak1 genes.

Noscapine, an opium-derived ‘kinder-gentler’ microtubule-modulating drug is in Phase I/II clinical trials for cancer chemotherapy. However, its limited water solubility encumbers its development into an oral anticancer drug with clinical promise. Here we report the synthesis of 9 third-generation, water-soluble noscapine analogs with negatively charged sulfonato and positively charged quaternary ammonium groups using noscapine, 9-bromonoscapine and 9-aminonoscapine as scaffolds. The predictive free energy of solvation was found to be lower for sulfonates (6a–c;8a–c) compared to the quaternary ammonium-substituted counterparts, explaining their higher water solubility. In addition, sulfonates showed higher charge dispersability, which may effectively shield the hydrophobicity of isoquinoline nucleus as indicated by hydrophobicity mapping methods. These in silico data underscore efficient net charge balancing, which may explain higher water solubility and thus enhanced antiproliferative efficacy and improved bioavailability. We observed that 6b, 8b and 8c strongly inhibited tubulin polymerization and demonstrated significant antiproliferative activity against four cancer cell lines compared to noscapine. Molecular simulation and docking studies of tubulin-drug complexes revealed that the brominated compound with a four-carbon chain (4b, 6b, 8b) showed optimal binding with tubulin heterodimers. Interestingly, 6b, 8b and 8c treated PC-3 cells resulted in preponderance of mitotic cells with multipolar spindle morphology, suggesting that they stall the cell cycle. Furthermore, in vivo pharmacokinetic evaluation of 6b, 8b and 8c revealed at least 1–2 fold improvement in their bioavailability compared to noscapine. To our knowledge, this is the first report to demonstrate novel water-soluble noscapine analogs that may pave the way for future pre-clinical drug development.

The etiology of cardiac fibrogenesis is quite diverse, but a common feature is the presence of activated fibroblasts. Experimental evidence suggests that a subset of cardiac fibroblasts is derived via transition of vascular endothelial cells into fibroblasts by endothelial-to-mesenchymal transition (EndMT). During EndMT, endothelial cells lose their endothelial characteristics and acquire a mesenchymal phenotype. Molecular mechanisms and the transcriptional mediators controlling EndMT in heart during development or disease remain relatively undefined. Myocardin-related transcription factor A facilitates the transcription of cytoskeletal genes by serum response factor during fibrosis; therefore, its specific role in cardiac EndMT might be of importance. Activation of activating transcription factor 3 (ATF-3) during cardiac EndMT is speculative, since ATF-3 responds to a transforming growth factor β (TGF-β) stimulus and controls the expression of the primary epithelial-to-mesenchymal transition markers Snail, Slug, and Twist. Although the role of TGF-β in EndMT-mediated cardiac fibrosis has been established, targeting of the TGF-β ligand has not proven to be a viable anti-fibrotic strategy owing to the broad functional importance of this ligand. Thus, targeting of downstream transcriptional mediators may be a useful therapeutic approach in attenuating cardiac fibrosis. Here, we discuss some of the transcription factors that may regulate EndMT-mediated cardiac fibrosis and their involvement in type 2 diabetes.