Serum Resistin Levels and Related Genetic Variants Are Associated With Bone Mineral Density in Postmenopausal Women

Background: Osteoporosis is a multifactorial disorder and a number of genetic variants or loci responsible for bone mineral density (BMD) have been identified. Resistin, a novel adipokine has diverse role in human body including its function in bone remodeling. The objective of this study was to see the association of serum resistin levels and related genetic variants (rs3931020, rs13144478) with BMD in postmenopausal females. Methods: This comparative analytical study was conducted on postmenopausal osteoporotic (n=101), osteopenic (n=77) and non-osteoporotic (n=74) females. For comparison and correlational analysis, Kruskal-Wallis test and Spearman’s rho correlation were used respectively. Hardy-Weinberg equilibrium (HWE) was calculated by using Chi-square test (χ2). Results: There was significant difference in the serum levels of resistin (p &lt;0.001), among the three groups. Significant negative correlation of resistin was observed with BMD at various sites. Serum resistin levels were significantly low in the rs3931020 AA homozygous genotype (p = 0.010), and significantly high in the rs13144478 AT heterozygous genotype (p = 0.020), BMD at all sites except left femoral neck was significantly high in rs3931020 AA genotype, while BMD at lumbar spine, left hip and total BMD were significantly low in the rs13144478 TT homozygotes. Conclusion: High serum resistin levels are associated with low BMD and single nucleotide variation in rs3931020 and rs13144478 may lead to high serum resistin levels and low bone mineral density. Resistin can serve as a new genetic marker, potential therapeutic target and predictor of osteoporosis.</p

Isonitrile-responsive and bioorthogonally removable tetrazine protecting groups.

In vivo compatible reactions have a broad range of possible applications in chemical biology and the pharmaceutical sciences. Here we report tetrazines that can be removed by exposure to isonitriles under very mild conditions. Tetrazylmethyl derivatives are easily accessible protecting groups for amines and phenols. The isonitrile-induced removal is rapid and near-quantitative. Intriguingly, the deprotection is especially effective with (trimethylsilyl)methyl isocyanide, and serum albumin can catalyze the elimination under physiological conditions. NMR and computational studies revealed that an imine-tautomerization step is often rate limiting, and the unexpected cleavage of the Si-C bond accelerates this step in the case with (trimethylsilyl)methyl isocyanide. Tetrazylmethyl-removal is compatible with use on biomacromolecules, in cellular environments, and in living organisms as demonstrated by cytotoxicity experiments and fluorophore-release studies on proteins and in zebrafish embryos. By combining tetrazylmethyl derivatives with previously reported tetrazine-responsive 3-isocyanopropyl groups, it was possible to liberate two fluorophores in vertebrates from a single bioorthogonal reaction. This chemistry will open new opportunities towards applications involving multiplexed release schemes and is a valuable asset to the growing toolbox of bioorthogonal dissociative reactions

DECODING THE SIGNAL: INTERROGATING ELECTROPHILE SIGNALING RESPONSES IN MAMMALIAN CELLS AND Danio rerio (ZEBRAFISH)

Redox homeostasis is crucial for the maintenance of organism fitness and survival. Redox imbalance is a marker of various pathologies including cancer and neurodegenerative diseases. At high levels, reactive electrophilic/oxygen/nitrogen species cause damage to cellular components such as proteins and DNA. More recently, it has come to light that at physiological concentrations the reactive species act as signaling molecules crucial for cellular communication. Given the chemical simplicity of these reactive messengers, it has been a challenge to understand how these reactive small molecules specifically perturb particular proteins—a prerequisite of redox signaling. Traditionally, redox signaling has been studied by swamping a model system (cells/whole organisms) with reactive signals leading to the generation of mixed responses from multiple simultaneous events. Such approaches mimic oxidative stress and are less amenable to the study of redox signaling. Here, I report the development and characterization of the targetable reactive electrophiles and oxidants (T-REX), a unique chemistry-based platform that (1) enables selective modification of redox-sensitive proteins with spatiotemporal precision in complex biological systems, (2) interrogates the consequences of this target-specific redox modification, and (3) allows unbiased screening for novel first-responding sensors capable of sensing reactive redox signals under signal-limited conditions. As proof-of-concept, I show that T-REX can selectively modify Keap1, an established electrophile-sensitive protein and an important regulator of the therapeutically-relevant Nrf2/antioxidant response (Nrf2/AR) signaling axis, with the model electrophile 4-hydroxynonenal (HNE). Additionally, my work for the first time shows that low stoichiometry HNE modification of Keap1 is sufficient to trigger AR in biological systems. This work also expands the applicability of T-REX to study redox signaling in zebrafish (Z-REX) and E. coli. I report here that selective modification of Keap1 in zebrafish suppresses innate and adaptive immune response. Finally, my collaborative work also shows that T-REX can be used to screen for novel first-responding redox sensors. I show that Akt3, an isoform of the Akt oncogenic kinase, senses electrophilic signals using a unique cysteine residue in the flexible linker region of the enzyme. HNE modification of Akt3 downregulates its kinase activity with functional signaling consequences in cells and zebrafish

Comparison of parameters of bone profile and homocysteine in physically active and non-active postmenopausal females

BACKGROUND AND OBJECTIVES: Optimal physical activity is important in attaining a peak bone mass. Physically active women have better bone mineral density and reduce fracture risk as compared to females living a sedentary life. The objective of this study was to compare parameters of bone profile and serum homocysteine levels in physically active and non-active postmenopausal females. METHODS: In this cross sectional study postmenopausal females between 50-70 years of age were recruited and divided into two groups: Physically inactive (n=133) performing light physical activity and Physically active (n=34) performing moderate physical activity. Physical activity (in metabolic equivalents), bone mineral density and serum homocysteine levels were assessed. Spearman’s rho correlation was applied to observe correlations. Two independent sample t test and Mann Whitney U test were applied to compare groups. P-value ≤ 0.05 was taken statistically significant. RESULTS: Parameters of bone profile were significantly higher and serum homocysteine levels were significantly lower in postmenopausal females performing moderate physical activity as compared to females performing light physical activity. Homocysteine was not significantly related to T-score and Z-score in both groups. CONCLUSION: Improving physical activity could be beneficial for improving the quality of bone, decreasing fracture risk and decreasing serum homocysteine levels