Non-enzymatic glycation and diabetic kidney disease.

Chronic diabetes leads to various complications including diabetic kidney disease (DKD). DKD is a major microvascular complication and the leading cause of morbidity and mortality in diabetic patients. Varying degrees of proteinuria and reduced glomerular filtration rate are the cardinal clinical manifestations of DKD that eventually progress into end-stage renal disease. Histopathologically, DKD is characterized by renal hypertrophy, mesangial expansion, podocyte injury, glomerulosclerosis, and tubulointerstitial fibrosis, ultimately leading to renal replacement therapy. Amongst the many mechanisms, hyperglycemia contributes to the pathogenesis of DKD via a mechanism known as non-enzymatic glycation (NEG). NEG is the irreversible conjugation of reducing sugars onto a free amino group of proteins by a series of events, resulting in the formation of initial Schiff's base and an Amadori product and to a variety of advanced glycation end products (AGEs). AGEs interact with cognate receptors and evoke aberrant signaling cascades that execute adverse events such as oxidative stress, inflammation, phenotypic switch, complement activation, and cell death in different kidney cells. Elevated levels of AGEs and their receptors were associated with clinical and morphological manifestations of DKD. In this chapter, we discussed the mechanism of AGEs accumulation, AGEs-induced cellular and molecular events in the kidney and their impact on the pathogenesis of DKD. We have also reflected upon the possible options to curtail the AGEs accumulation and approaches to prevent AGEs mediated adverse renal outcomes.

Epigenetically active chromatin in neonatal iWAT reveals GABPα as a potential regulator of beige adipogenesis.

Background: Thermogenic beige adipocytes, which dissipate energy as heat, are found in neonates and adults. Recent studies show that neonatal beige adipocytes are highly plastic and contribute to >50% of beige adipocytes in adults. Neonatal beige adipocytes are distinct from recruited beige adipocytes in that they develop independently of temperature and sympathetic innervation through poorly defined mechanisms. Methods: We characterized the neonatal beige adipocytes in the inguinal white adipose tissue (iWAT) of C57BL6 postnatal day 3 and 20 mice (P3 and P20) by imaging, genome-wide RNA-seq analysis, ChIP-seq analysis, qRT-PCR validation, and biochemical assays. Results: We found an increase in acetylated histone 3 lysine 27 (H3K27ac) on the promoter and enhancer regions of beige-specific gene UCP1 in iWAT of P20 mice. Furthermore, H3K27ac ChIP-seq analysis in the iWAT of P3 and P20 mice revealed strong H3K27ac signals at beige adipocyte-associated genes in the iWAT of P20 mice. The integration of H3K27ac ChIP-seq and RNA-seq analysis in the iWAT of P20 mice reveal epigenetically active signatures of beige adipocytes, including oxidative phosphorylation and mitochondrial metabolism. We identify the enrichment of GA-binding protein alpha (GABPα) binding regions in the epigenetically active chromatin regions of the P20 iWAT, particularly on beige genes, and demonstrate that GABPα is required for beige adipocyte differentiation. Moreover, transcriptomic analysis and glucose oxidation assays revealed increased glycolytic activity in the neonatal iWAT from P20. Conclusions: Our findings demonstrate that epigenetic mechanisms regulate the development of peri-weaning beige adipocytes via GABPα. Further studies to better understand the upstream mechanisms that regulate epigenetic activation of GABPα and characterization of the metabolic identity of neonatal beige adipocytes will help us harness their therapeutic potential in metabolic diseases.

Neuroblastoma: Emerging trends in pathogenesis, diagnosis, and therapeutic targets.

Neuroblastoma (NB) accounts for about 13% of all pediatric cancer mortality and is the leading cause of pediatric cancer death for children aged 1 to 5 years. NB, a developmental malignancy of neural ganglia, originates from neural crest-derived cells, which undergo a defective sympathetic neuronal differentiation due to genomic and epigenetic aberrations. NB is a complex disease with remarkable biological and genetic variation and clinical heterogeneity, such as spontaneous regression, treatment resistance, and poor survival rates. Depending on its severity, NB is categorized as high-risk, intermediate-risk, and low-risk., whereas high-risk NB accounts for a high infant mortality rate. Several studies revealed that NB cells suppress immune cell activity through diverse signaling pathways, including exosome-based signaling pathways. Exosome signaling has been shown to modulate gene expression in the target immune cells and attenuate the signaling events through non-coding RNAs. Since high-risk NB is characterized by a low survival rate and high clinical heterogeneity with current intensive therapies, it is crucial to unravel the molecular events of pathogenesis and develop novel therapeutic targets in high-risk, relapsed, or recurrent tumors in NB to improve patient survival. This article discusses etiology, pathophysiology, risk assessment, molecular cytogenetics, and the contribution of extracellular vesicles, non-coding RNAs, and cancer stem cells in the tumorigenesis of NB. We also detail the latest developments in NB immunotherapy and nanoparticle-mediated drug delivery treatment options.

Forskolin-loaded human serum albumin nanoparticles and its biological importance.

In this study, forskolin-loaded human serum albumin nanoparticles (FR-HSANPs) were successfully prepared by incorporation and affinity-binding methods. FR-HSANPs were characterized by transmission electron microscope that most of them are circular in shape and size is around 340 nm. The drug loading was more than 88% and further sustained release profiles were observed as it is 77.5% in 24 h time. Additionally, the cytotoxicity results with HepG2 cells indicated that FR-HSANPs showed significantly higher cytotoxicity and lower cell viability as compared to free forskolin (FR). Furthermore, to understand the binding mechanism of human serum albumin (HSA) with forskolin resulted from fluorescence quenching as a static mechanism and the binding constant is 6.26 ± 0.1 × 104 M-1, indicating a strong binding affinity. Further, association and dissociation kinetics of forskolin-HSA was calculated from surface plasmon resonance spectroscopy and the binding constant found to be Kforskolin = 3.4 ± 0.24 × 104 M-1 and also fast dissociation was observed. Further, we used circular dichroism and molecular dynamics simulations to elucidate the possible structural changes including local conformational changes and rigidity of the residues of both HSA and HSA-forskolin complexes.Communicated by Ramaswamy H. Sarma.

Exploration of binding studies of ß-oxalyldiamino propionic acid (ß-ODAP), a non-protein amino acid with human serum albumin-biophysical and computational approach.

Communicated by Ramaswamy H. Sarma.