5 research outputs found
Citrus species – a golden treasure box of metabolites that is beneficial against disorders
No full textInhibition of Bungarus caeruleus snake venom toxicity by Citrus reticulata methanolic extract and in-silico analysis of possible binding modes
No full text67-76Snakebite envenomation has been one of the major causes of morbidity and mortality around the world. Though intravenous administration of commercial anti-venom systemically neutralizes the toxicity, adverse effects are commonly seen in the post-treatment period. Plant metabolites and their derivatives have been shown to exhibit a wide range of anti-ophidian properties. In this study, we have investigated the Bungaruscaeruleus venom neutralization potential of Citrus aurantium and Citrus reticulata Blanco peels in terms of phospholipase and hemolytic inhibition. Methanolic extract of C. reticulata exhibited the highest inhibition (93%) of PLA2 activity. However, the extracts of both these Citrus species significantly inhibited the hemolytic activity of the venom (54–82%). Molecular docking indicated the binding of the citrus metabolites to catalytic site residues (TRP19, GLY30, TYR31, GLY32, and HIS48) of PLA2. In vivo studies using Swiss Albino mice confirmed the neutralising capacity of the citrus peel extract, as reflected by the increase in survival time. Therefore, the study reveals that these metabolites in the methanolic extract of the citrus peel can be used as supplements for the management of snake bites
Molecular regulation of VEGFR-2 expression and activation in endothelial cells
No full textThesis (Ph.D.)--Boston University
PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at [email protected]. Thank you.Angiogenesis, a hallmark step in tumor growth and metastasis, is primarily driven by the action of vascular endothelial growth factor (VEGF) on its receptor, VEGFR-2. Central to its regulation, the abundance of VEGFR-2 on the surface of endothelial cells determines VEGF's ability to stimulate vasculogenesis and pathological angiogenesis. By using a yeast two-hybrid system we have identified PDCL3 (Phosducin like 3) as a novel VEGFR-2 interacting protein that serves as a chaperone protein. PDCL3 expression is highly up-regulated in pathological neovascularization in a mouse model of oxygen-induced proliferative retinopathy and its expression correlates with VEGFR-2 expression. Knockdown of PDCL3 in endothelial cells significantly reduced hypoxia-induced expression of VEGFR-2. Further studies showed that PDCL3 binds to both nascent and mature VEGFR-2 through recognition of its juxtamembrane (JM) domain. Preventing binding of PDCL3 to the JM domain, and manipulating expression of PDCL3 by over-expression and siRNA in endothelial cells, showed that PDCL3 controls the abundance of VEGFR-2 through inhibition of its ubiquitination and degradation. Various in vivo and in vitro angiogenesis assays showed that PDCL3 activity is required for VEGF-mediated endothelial cell proliferation, capillary tube formation, and angiogenesis in developing zebrafish embryos. Further investigation of the molecular mechanisms of VEGFR-2 protein homeostasis revealed that its PEST domain controls degradation and ubiquitination of mature VEGFR-2. The data demonstrate that β-Trcp1 ubiquitin E3 ligase is recruited to the PEST domain and mediates ubiquitination and degradation of VEGFR-2. The PEST domain via phospho-Y1173 also contributes to activation of p38 mitogen-activated protein kinase (p38 MAPK), which results in the stabilization of VEGFR-2. The work demonstrates that VEGFR-2 protein homeostasis in endothelial cells is controlled at multiple levels involving co-chaperone functions of PDCL3, βTrcp1 ubiquitin E3 ligase and p38 MAPK pathway
High Glucose-induced transcriptomic changes in human trabecular meshwork cells
No full textGlaucoma is a leading cause of irreversible blindness, often associated with elevated intraocular pressure (IOP) due to trabecular meshwork (TM) dysfunction. Diabetes mellitus (DM) is recognized as a significant risk factor for glaucoma; however, the molecular mechanisms through which hyperglycemia affects TM function remain unclear. This study investigated the impact of high glucose on gene expression in human TM (HTM) cells to uncover pathways that contribute to TM dysfunction and glaucoma pathogenesis under diabetic conditions. Primary HTM cells were cultured under normoglycemic (5.5 mM) and hyperglycemic (30 mM) conditions for seven days, followed by mRNA sequencing (mRNA-seq) to identify differentially expressed genes, with quantitative PCR (qPCR) used for confirmatory analysis. STRING network analysis was performed to predict potential interactions among upregulated and downregulated genes. mRNA-seq analysis revealed 25 significantly differentially expressed genes in high glucose conditions, including upregulated genes associated with oxidative stress, apoptosis, autophagy, immune response, and fibrosis. Notably, TXNIP gene was significantly upregulated, indicating increased oxidative stress and apoptosis in TM cells, while downregulation of autophagy-related genes, such as HSPA6 and LAMP3, suggests compromised protein quality control. Immune response genes, including CCL7 and CHI3L1, were upregulated, suggesting an inflammatory response to oxidative stress. Increased expression of fibrosis-related genes, such as SNAI1, FGF7, and KRT19, and an increase in ECM proteins like Collagen 1 and FN accumulation and fibril formation suggest increased fibrosis of TM in diabetic conditions, potentially elevating IOP. Metabolic changes in diabetic patients could therefore lead to TM dysfunction, impair aqueous humor outflow, and elevate IOP, thereby increasing glaucoma risk. Targeting oxidative stress and fibrosis pathways offers therapeutic strategies to mitigate glaucoma progression in diabetic populations
Inhibition of Bungarus caeruleus snake venom toxicity by Citrus reticulata methanolic extract and in silico analysis of possible binding modes
Full text linkSnakebite envenomation has been one of the major causes of morbidity and mortality around the world. Though intravenous administration of commercial anti-venom systemically neutralizes the toxicity, adverse effects are commonly seen in the post-treatment period. Plant metabolites and their derivatives have been shown to exhibit a wide range of antiophidian properties. In this study, we have investigated the Bungaruscaeruleus venom neutralization potential of Citrus aurantium and Citrus reticulata Blanco peels in terms of phospholipase and hemolytic inhibition. Methanolic extract of C. reticulata exhibited the highest inhibition (93%) of PLA2 activity. However, the extracts of both these Citrus species significantly inhibited the hemolytic activity of the venom (54–82%). Molecular docking indicated the binding of the citrus metabolites to catalytic site residues (TRP19, GLY30, TYR31, GLY32, and HIS48) of PLA2 . In vivo studies using Swiss Albino mice confirmed the neutralising capacity of the citrus peel extract, as reflected by the increase in survival time. Therefore, the study reveals that these metabolites in the methanolic extract of the citrus peel can be used as supplements for the management of snake bites
