Histone Demethylase Modulation: Epigenetic Strategy to Combat Cancer Progression.

Epigenetic modifications are heritable, reversible changes in histones or the DNA that control gene functions, being exogenous to the genomic sequence itself. Human diseases, particularly cancer, are frequently connected to epigenetic dysregulations. One of them is histone methylation, which is a dynamically reversible and synchronously regulated process that orchestrates the three-dimensional epigenome, nuclear processes of transcription, DNA repair, cell cycle, and epigenetic functions, by adding or removing methylation groups to histones. Over the past few years, reversible histone methylation has become recognized as a crucial regulatory mechanism for the epigenome. With the development of numerous medications that target epigenetic regulators, epigenome-targeted therapy has been used in the treatment of malignancies and has shown meaningful therapeutic potential in preclinical and clinical trials. The present review focuses on the recent advances in our knowledge on the role of histone demethylases in tumor development and modulation, in emphasizing molecular mechanisms that control cancer cell progression. Finally, we emphasize current developments in the advent of new molecular inhibitors that target histone demethylases to regulate cancer progression.

SARS-CoV-2: Understanding the Transcriptional Regulation of ACE2 and TMPRSS2 and the Role of Single Nucleotide Polymorphism (SNP) at Codon 72 of p53 in the Innate Immune Response against Virus Infection.

Human ACE2 and the serine protease TMPRSS2 of novel SARS-CoV-2 are primary entry receptors in host cells. Expression of these genes at the transcriptional level has not been much discussed in detail. The ISRE elements of the ACE2 promoter are a binding site for the ISGF3 complex of the JAK/STAT signaling pathway. TMPRSS2, including IFNß, STAT1, and STAT2, has the PARP1 binding site near to TSS either up or downstream promoter region. It is well documented that PARP1 regulates gene expression at the transcription level. Therefore, to curb virus infection, both promoting type I IFN signaling to boost innate immunity and prevention of virus entry by inhibiting PARP1, ACE2 or TMPRSS2 are safe options. Most importantly, our aim is to attract the attention of the global scientific community towards the codon 72 Single Nucleotide Polymorphism (SNP) of p53 and its underneath role in the innate immune response against SARS-CoV-2. Here, we discuss codon 72 SNP of human p53's role in the different innate immune response to restrict virus-mediated mortality rate only in specific parts of the world. In addition, we discuss potential targets and emerging therapies using bioengineered bacteriophage, anti-sense, or CRISPR strategies.

NAD+ loss, a new player in AhR biology: prevention of thymus atrophy and hepatosteatosis by NAD+ repletion.

Dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin, TCDD) is a carcinogenic and highly toxic industrial byproduct that persists in the environment and produces a pleiotropic toxicity syndrome across vertebrate species that includes wasting, hepatosteatosis, and thymus atrophy. Dioxin toxicities require binding and activation of the aryl hydrocarbon receptor (AhR), a ligand activated transcription factor. However, after nearly 50 years of study, it remains unknown how AhR activation by dioxin produces toxic effects. Here, using the chick embryo close to hatching, a well-accepted model for dioxin toxicity, we identify NAD+ loss through PARP activation as a novel unifying mechanism for diverse effects of dioxin in vivo. We show that NAD+ loss is attributable to increased PARP activity in thymus and liver, as cotreatment with dioxin and the PARP inhibitor PJ34 increased NAD+ levels and prevented both thymus atrophy and hepatosteatosis. Our findings additionally support a role for decreased NAD+ dependent Sirt6 activity in mediating dioxin toxicity following PARP activation. Strikingly, treatment in vivo with the NAD+ repleting agent nicotinamide, a form of vitamin B3, prevented thymus atrophy and hepatosteatosis by dioxin and increased sirtuin activity, providing a therapeutic approach for preventing dioxin toxicities in vivo.

Comparative efficacy of different in vitro cultivation media for Trypanosoma evansi isolated from different mammalian hosts inhabiting different geographical areas of India.

The present study was undertaken to establish an optimal medium for primary culture initiation and maintenance of T. evansi isolated from different mammalian hosts of diverse geographical regions of India viz. donkey/1 (Hardoi, Uttar Pradesh), donkey/2 (Junagarh, Gujarat), pony/1 (Hisar, Haryana), camel/1 (Bikaner, Rajasthan) which represented isolates 1, 2, 3 and 4, respectively. Primary cultures were initiated with all four isolates in five different in vitro cultivation media with seeding density of 1 × 10(6) trypanosomes/ml. The parasites of all four isolates could remain viable only for 48 h in medium E (Alsever's solution) and for 72 h in medium A, C and D. Parasites reached to a maximum density (2.5-3.75 × 10(6)/ml) within 24 h and thereafter, a sharp decline (0.5-0.75 × 10(6)/ml) in the next 72 h was observed in 1, 2 and 3 isolates cultured in medium B. In isolate 4, parasite counts got more than doubled in 24 h and then decreased gradually up to sixth day post initiation of cultivation which thereafter increased gradually up to 34 days and a constant parasite number of 10(5)/ml could be achieved for 90 days in medium B. During this prolonged culture the trypanosomes retained their long slender morphology and infectivity to mice.