👤 M Shastri

Alzheimer's disease (AD) is a neurodegenerative disorder initiated by amyloid-beta (Aβ) accumulation, leading to impaired cognitive function. Several delivery approaches have been improved for AD management. Among them, human serum albumin (HSA) is broadly employed for drug delivery and targeting the Aβ in AD owing to its biocompatibility, Aβ inhibitory effect, and nanoform, which showed blood-brain barrier (BBB) crossing ability via glycoprotein 60 (gp60) receptor and secreted protein acidic and rich in cysteine (SPARC) protein to transfer the drug molecules in the brain. Thus far, there is no previous review focusing on HSA and its drug delivery system in AD. Hence, the reviewed article aimed to critically compile the HSA therapeutic as well as drug delivery role in AD management. It also delivers information on how HSA-incorporated nanoparticles with surfaced embedded ligands such as TAT, GM1, and so on, not only improve BBB permeability but also increase neuron cell targetability in AD brain. Additionally, Aβ and tau pathology, including various metabolic markers likely BACE1 and BACE2, etc., are discussed. Besides, the molecular interaction of HSA with Aβ and its distinctive forms are critically reviewed that HSA can segregate Zn(II) and Cu(II) metal ions from Aβ owing to high affinity. Furthermore, the BBB drug delivery challenges in AD are addressed. Finally, the clinical formulation of HSA for the management of AD is critically discussed on how the HSA inhibits Aβ oligomer and fibril, while glycated HSA participates in amyloid plaque formation, i.e., β-structure sheet formation. This review report provides theoretical background on HSA-based AD drug delivery and makes suggestions for future prospect-related work. Show less

Proliferative retinopathies are associated with formation of fibrous epiretinal membranes. At present, there is no pharmacological intervention for the treatment of retinopathies. Cytokines such as TGFβ are elevated in the vitreous humor of the patients with proliferative vitro-retinopathy, diabetic retinopathy and age-related macular degeneration. TGFβ isoforms lead to epithelial-mesenchymal transition (EMT) or trans-differentiation of the retinal pigment epithelial (RPE) cells. PI3K/Akt and MAPK/Erk pathways play important roles in the EMT of RPE cells. Therefore, inhibition of EMT by pharmacological agents is an important therapeutic strategy in retinopathy. Dichloroacetate (DCA) is shown to prevent proliferation and EMT of cancer cell lines but its effects are not explored on the prevention of EMT of RPE cells. In the present study, we have investigated the role of DCA in preventing TGFβ2 induced EMT of RPE cell line, ARPE-19. A wound-healing assay was utilized to detect the anti-EMT effect of DCA. The expressions of EMT and cell adhesion markers were carried out by immunofluorescence, western blotting, and quantitative real-time PCR. The expression of MAPK/Erk and PI3K/Akt pathway members was carried out using western blotting. We found that TGFβ2 exposure leads to an increase in the wound healing response, expression of EMT markers (Fibronectin, Collagen I, N-cadherin, MMP9, S100A4, α-SMA, Snai1, Slug) and a decrease in the expression of cell adhesion/epithelial markers (ZO-1, Connexin 43, E-cadherin). These changes were accompanied by the activation of PI3K/Akt and MAPK/Erk pathways. Simultaneous exposure of DCA along with TGFβ2 significantly inhibited wound healing response, expression of EMT markers and cell adhesion/epithelial markers. Furthermore, DCA and TGFβ2 effectively attenuated the activation of MAPK/Erk/JNK and PI3K/Akt/GSK3β pathways. Our results demonstrate that DCA has a strong anti-EMT effect on the ARPE-19 cells and hence can be utilized as a therapeutic agent in the prevention of proliferative retinopathies. Show less

Background The objective of this study was to investigate the association of polymorphisms in four genes, tumor necrosis factor-α (TNFA), patatin-like phospholipase domain containing 3 (PNPLA3), adiponectin (ADIPOQ) and apolipoprotein C3 (APOC3), with obesity and non-alcoholic fatty liver disease (NAFLD) in Asian Indian adolescents. Methods In this case-control study, 218 Asian Indian adolescents with overweight/obesity and 86 lean healthy adults without fatty liver were enrolled. Hepatic steatosis was assessed and graded by ultrasonography (USG). Serum insulin, lipids, alanine aminotransferase (ALT), aspartate aminotransferase (AST), TNF-α, adiponectin and apolipoprotein C3 were measured and genotyping was done. Frequencies of variant and wild genotypes in all adolescents and in the subgroups without steatosis, with grade 1 steatosis and with grade 2 or 3 steatosis were compared to those in the controls. The frequencies were also compared in the overweight adolescents with grade 2 or 3 steatosis and without steatosis. Results Variant genotypes of polymorphisms -863 C > A and -1031 T > C of the TNFA gene, 455 T > C of the APOC3 gene and the wild type of +276 G > T of the ADIPOQ gene were associated with obesity with odds ratios (OR, 95% confidence interval [CI]) of 2.5 (1.5-4.4), 2.5 (1.5-4.2), 2.0 (1.1-3.6) and 2.5 (1.4-5.0), respectively. Polymorphisms 455 T > C of APOC3 and rs738409 C > G of PNPLA3 were associated with NAFLD. Fasting insulin and triglycerides (TG) were higher in the adolescents with homozygous variant polymorphisms -1031 T > C of TNFA and 455 T > C of APOC3 genes, respectively. Conclusions Several polymorphisms were noted to have a significant association with obesity and NAFLD in Asian Indian adolescents. Show less

Bardet-Biedl syndrome (BBS, OMIM 209900) is a genetic disorder with the primary features of obesity, pigmentary retinopathy, polydactyly, renal malformations, mental retardation and hypogenitalism. Individuals with BBS are also at increased risk for diabetes mellitus, hypertension and congenital heart disease. What was once thought to be a homogeneous autosomal recessive disorder is now known to map to at least six loci: 11q13 (BBS1), 16q21 (BBS2), 3p13 p12 (BBS3), 15q22.3 q23 (BBS4), 2q31 (BBS5) and 20p12 (BBS6). There has been considerable interest in identifying the genes that underlie BBS, because some components of the phenotype are common. Cases of BBS mapping ro BBS6 are caused by mutations in MKKS; mutations in this gene also cause McKusick-Kaufman syndrome (hydrometrocolpos, post-axial polydactyly and congenital heart defects). In addition, we recently used positional cloning to identify the genes underlying BBS2 (ref. 16) and BBS4 (ref. 17). The BBS6 protein has similarity to a Thermoplasma acidophilum chaperonin, whereas BBS2 and BBS4 have no significant similarity to chaperonins. It has recently been suggested that three mutated alleles (two at one locus, and a third at a second locus) may be required for manifestation of BBS (triallelic inheritance). Here we report the identification of the gene BBS1 and show that a missense mutation of this gene is a frequent cause of BBS. In addition, we provide data showing that this common mutation is not involved in triallelic inheritance. Show less

Bardet-Biedl syndrome (BBS, MIM 209900) is a heterogeneous autosomal recessive disorder characterized by obesity, pigmentary retinopathy, polydactyly, renal malformations, mental retardation, and hypogenitalism. The disorder is also associated with diabetes mellitus, hypertension, and congenital heart disease. Six distinct BBS loci map to 11q13 (BBS1), 16q21 (BBS2), 3p13-p12 (BBS3), 15q22.3-q23 (BBS4), 2q31 (BBS5), and 20p12 (BBS6). Although BBS is rare in the general population (<1/100,000), there is considerable interest in identifying the genes causing BBS because components of the phenotype, such as obesity and diabetes, are common. We and others have demonstrated that BBS6 is caused by mutations in the gene MKKS (refs. 12,13), mutation of which also causes McKusick-Kaufman syndrome (hydrometrocolpos, post-axial polydactyly, and congenital heart defects). MKKS has sequence homology to the alpha subunit of a prokaryotic chaperonin in the thermosome Thermoplasma acidophilum. We recently identified a novel gene that causes BBS2. The BBS2 protein has no significant similarity to other chaperonins or known proteins. Here we report the positional cloning and identification of mutations in BBS patients in a novel gene designated BBS4. Show less