👤 Ashwani K Dhingra

Alzheimer's Disease (AD) is a disabling neurodegenerative illness characterized by Amyloid-beta (Aβ) plaque deposition, tau tangles, and neuroinflammation. These pathological characteristics lead to progressive cognitive decline, and drug therapeutic approaches are bedeviled by extreme difficulty with the Blood-Brain Barrier (BBB) that prevents most drugs from effectively crossing into the brain. Extracellular vesicle-based nanomedicine is a prospective approach to overcome this hurdle. Extracellular vesicles are endogenously derived extracellular vesicles that can cross the BBB and deliver a variety of therapeutic cargos, including small interfering RNAs (siRNAs), microRNAs (miRNAs), proteins, and other small molecules. Since they can cross the BBB and exhibit low immunogenicity and toxicity, extracellular vesicles represent a promising strategy for drug delivery against AD. Recent studies have highlighted the potential of extracellular vesiclebased treatments to deliver anti-amyloid and anti-tau therapies, neuroprotectants (e.g., antioxidants), and immune-modulatory factors. Engineered extracellular vesicles containing siRNA against βsecretase eta-site app cleaving enzyme 1 (BACE1), anti-tau oligonucleotides, and anti-inflammatory cytokines have shown promising preclinical efficacy by reducing Aβ deposition, tau aggregation, and neuroinflammation. These changes have been associated with enhanced cognitive function. Besides, extracellular vesicle-based systems were investigated for gene-editing therapeutics with Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR-associated protein 9 (CRISPR/ Cas9) and Antisense Oligonucleotides (ASOs). Besides scalability concerns, cargo-loading efficiency, and long-term toxicity, extracellular vesicle-based nanomedicine is an innovative platform for targeted drug deli. Show less

Tuberculous pyomyositis is a rare and often under-recognized extrapulmonary manifestation of tuberculosis, presenting with non-specific symptoms such as fever and abscess, that may delay diagnosis. We report a unique case of disseminated tuberculous pyomyositis in a 56-year-old male with underlying chronic inflammatory arthritis. The diagnosis was confirmed using CBNAAT, line probe assay (LPA), and histopathology. Currently MRI is the standard imaging modality in use for imaging pyomyositis. Show less

Lipid processing in the retinal pigment epithelium (RPE) is important for maintaining the health and function of the neural retina and the RPE itself. One mode of en mass lipid transport from the RPE is apolipoprotein B-containing lipoproteins (Blps), the assembly of which is regulated by microsomal triglyceride transfer protein (MTP). To gain an initial understanding of how the loss of MTP and, thereby, Blp secretion alters other lipid processing pathways in the RPE, we measured the expression of proteins associated with β-oxidation and lipid droplets in mice lacking MTP expression in the RPE (RPEΔMttp) and age-matched controls. Expression of perilipin 2, a lipid droplet-associated protein, nearly doubled in the RPE of RPEΔMttp, and its localization with neutral lipids also increased. Meanwhile, expression of CPT1A, which mediates the transport of fatty acids into the mitochondria for β-oxidation, was unaffected. These results suggest that the loss of Blp assembly alters intracellular lipid storage patterns. Future studies will examine the effects of the loss of RPE-specific MTP expression and Blp secretion on additional lipid processing pathways. Show less

Nephropathy has become the most common reason for end-stage renal disease worldwide. The progression of end-stage renal disease occurs caused by decreased glomerular filtration rate, damage to capillaries in renal glomeruli or a higher risk of cardiovascular morbidity and mortality in diabetic patients. The involvement of mechanism in the development of nephropathy via generation of AGEs, the elevation of growth factors, altered hemodynamic and metabolic factors, inflammatory mediators, oxidative stress and dyslipidaemia. The prevalence of chronic kidney disease in India will rise from 3.7 million in 1990 to 7.63 million in 2020 becoming the main cause of mortality and morbidity. The pathogenesis of nephropathy mediates by various molecules that cause alterations in the structure and function of the kidney like growth factors, endothelins, transforming growth factor (TGF-β), and Angiotensin-converting enzymes (ACE), fibronectin and proinflammatory cytokines, mast cells and dyslipidemia. Growth factors like VEGF, IGFs, PDGF, EGFR and TGF-β contribute to excessive extracellular matrix accumulation, together with thickening of the glomerular and tubular basement membranes and an increase in the mesangial matrix, leading to glomerulosclerosis and tubulointerstitial fibrosis. Oxidative stress and inflammation factors like TNF-α, IL-1 and IL-6 are hypothesized to play a role in the development of pathological changes in nephropathy like renal hyperfiltration and hypertrophy, thickening of the glomerular basement membrane (GBM), glomerular lesion and tubulointerstitial fibrosis. Dyslipidemia is involved in the progression of nephropathy by impaired action of lipoprotein lipase, lecithincholesterol acyltransferase (LCAT) and cholesteryl ester transferase protein (CETP) resulting in the increased level of LDL-C, Triglyceride level and decrease HDL-C that enhance macrophage infiltration, excessive extracellular matrix production and accelerate inflammation with the development of proteinuria. Interruption in the RAS, oxidative stress and dyslipidemia have yielded much better results in terms of reno-protection and progression of nephropathy. In this review, we would focus on various factors that have been shown to contribute to renal injury in many experimental models of nephropathy. Show less