Adventitial macrophage accumulation impairs perivascular nerve function in mesenteric arteries with inflammatory bowel disease.

Introduction: Inflammatory bowel disease involves aberrant immune responses and is associated with both cardiovascular disease risk and altered intestinal blood flow. However, little is known about how inflammatory bowel disease affects regulation of perivascular nerves that mediate blood flow. Previous work found perivascular nerve function is impaired in mesenteric arteries with Inflammatory bowel disease. The purpose of this study was to determine the mechanism of impaired perivascular nerve function. Methods: RNA sequencing was performed on mesenteric arteries from IL10-/- mice treated with H. hepaticus to induce disease (inflammatory bowel disease) or left non-gavaged (Control). For all other studies, Control and Inflammatory bowel disease mice received either saline or clodronate liposome injections to study the effect of macrophage depletion. Perivascular nerve function was assessed using pressure myography and electrical field stimulation. Leukocyte populations, and perivascular nerves, and adventitial neurotransmitter receptors were labeled using fluorescent immunolabeling. Results: Inflammatory bowel disease was associated with increases in macrophage-associated gene expression, and immunolabeling showed accumulation of adventitial macrophages. Clodronate liposome injection eliminated adventitial macrophages, which reversed significant attenuation of sensory vasodilation, sympathetic vasoconstriction and sensory inhibition of sympathetic constriction in inflammatory bowel disease. Acetylcholine-mediated dilation was impaired in inflammatory bowel disease and restored after macrophage depletion, but sensory dilation remained nitric oxide independent regardless of disease and/or macrophage presence. Conclusion: Altered neuro-immune signaling between macrophages and perivascular nerves in the arterial adventitia contributes to impaired vasodilation, particularly via dilatory sensory nerves. Targeting the adventitial macrophage population may help preserve intestinal blood flow in Inflammatory bowel disease patients.

Is the new angel better than the old devil? Challenges and opportunities in CD47- SIRPα-based cancer therapy.

The efficacy of immunotherapies is limited due to the impenetrable nature of the tumor microenvironment (TME). The TME of many tumors is immune-privileged, thus allowing them to evade host immunosurveillance. One mechanism through which this occurs is via the overexpression of CD47, a 'don't eat me' protein that can interact with SIRPα on myeloid cells to suppress their phagocytic action. In recent times, many studies are focusing on CD47-SIRPα-dependent immunotherapies to incite a 'seek and eat' interaction between phagocytes and tumors. Thus, in this review, we highlight the basic molecular properties and mechanisms of CD47-SIRPα cascade. In addition, we discuss the major challenges and potential remedies associated with CD47-SIRPα-based immunotherapies.

Making Sense of "Nonsense" and More: Challenges and Opportunities in the Genetic Code Expansion, in the World of tRNA Modifications.

The evolutional development of the RNA translation process that leads to protein synthesis based on naturally occurring amino acids has its continuation via synthetic biology, the so-called rational bioengineering. Genetic code expansion (GCE) explores beyond the natural translational processes to further enhance the structural properties and augment the functionality of a wide range of proteins. Prokaryotic and eukaryotic ribosomal machinery have been proven to accept engineered tRNAs from orthogonal organisms to efficiently incorporate noncanonical amino acids (ncAAs) with rationally designed side chains. These side chains can be reactive or functional groups, which can be extensively utilized in biochemical, biophysical, and cellular studies. Genetic code extension offers the contingency of introducing more than one ncAA into protein through frameshift suppression, multi-site-specific incorporation of ncAAs, thereby increasing the vast number of possible applications. However, different mediating factors reduce the yield and efficiency of ncAA incorporation into synthetic proteins. In this review, we comment on the recent advancements in genetic code expansion to signify the relevance of systems biology in improving ncAA incorporation efficiency. We discuss the emerging impact of tRNA modifications and metabolism in protein design. We also provide examples of the latest successful accomplishments in synthetic protein therapeutics and show how codon expansion has been employed in various scientific and biotechnological applications.

Discovery of potential HER2 inhibitors from Mangifera indica for the treatment of HER2-Positive breast cancer: an integrated computational approach.

Human epidermal growth factor receptor 2 (HER2) is a member of epidermal growth factor receptors with tyrosine kinase functionality. The dimerization of HER2 leads to the autophosphorylation of tyrosine residues within its cytoplasmic domain, resulting in hyperactivation of several downstream signal transduction pathways that play an important role in tumorigenesis, cancer aggressiveness and cell proliferation. Amplification or overexpression of HER2 has been found in approximately 15-30% of breast cancers. Hence, HER2 serve as a therapeutic biomarker in breast cancer. Herein, we applied structural bioinformatics techniques via molecular docking, molecular dynamics simulations, Molecular mechanics/generalized Born surface area (MM/GBSA) calculations and pharmacokinetic models to identify putative HER2 inhibitors. Application of stringent molecular docking results in the identification of bioactive compounds from Mangifera indica as selective, potent inhibitors of HER2. However, only the top three compounds with the highest negative docking score (< -9kcal/mol) was considered in reference to neratinib (-8.601 kcal/mol) for computational analysis. The molecular dynamics simulations and post-simulation analysis of docked HER2-ligand complexes unveil the substantial stability for M. indica ligands over the 100 ns simulation period. Additionally, MM/GBSA binding free energy calculation supports the inhibitory potential for the docked ligands, which exclusively revealed the highest binding energy for selected M. indica ligands than the reference compound (neratinib). The pharmacokinetic model showed that M. indica ligands are promising therapeutic agents. Conclusively, bioactive compounds from M. indica may serve as lead molecules that could be developed into potent and effective HER2 inhibitors for breast cancer treatment.Communicated by Ramaswamy H. Sarma.

Sleep and Reproductive Health.

The reproductive function of humans is regulated by several sex hormones which are secreted in synergy with the circadian timing of the body. Sleep patterns produce generic signatures that physiologically drive the synthesis, secretion, and metabolism of hormones necessary for reproduction. Sleep deprivation among men and women is increasingly reported as one of the causes of infertility. In animal models, sleep disturbances impair the secretion of sexual hormones thereby leading to a decrease in testosterone level, reduced sperm motility and apoptosis of the Leydig cells in male rats. Sleep deprivation generates stressful stimuli intrinsically, due to circadian desynchrony and thereby increases the activation of the Hypothalamus-Pituitary Adrenal (HPA) axis, which, consequently, increases the production of corticosterone. The elevated level of corticosteroids results in a reduction in testosterone production. Sleep deprivation produces a commensurate effect on women by reducing the chances of fertility. Sleeplessness among female shift workers suppresses melatonin production as well as excessive HPA activation which results in early pregnancy loss, failed embryo implantation, anovulation and amenorrhea. Sleep deprivation in women has also be found to be associated with altered gonadotropin and sex steroid secretion which all together lead to female infertility. Poor quality of sleep is observed in middle-aged and older men and this also contributes to reduced testosterone concentrations. The influence of sleep disturbances post-menopausal is associated with irregular synthesis and secretion of female sex steroid hormones.