Oxidative stress in the insulin target tissues has been implicated in the pathophysiology of type 2 diabetes. The study has examined the oxidative stress parameters in the mitochondria of subcutaneous white adipose tissue from obese and non-obese subjects with or without type 2 diabetes. An accumulation of protein carbonyls, fluorescent lipid peroxidation products, and malondialdehyde occurs in the adipose tissue mitochondria of obese type 2 diabetic, non-diabetic obese, and non-obese diabetic subjects with the maximum increase noticed in the obese type 2 diabetes patients and the minimum in non-obese type 2 diabetics. The mitochondria from obese type 2 diabetics, non-diabetic obese, and non-obese type 2 diabetics also produce significantly more reactive oxygen species (ROS) in vitro compared to those of controls, and apparently the mitochondrial ROS production rate in each group is proportional to the respective load of oxidative damage markers. Likewise, the mitochondrial antioxidant enzymes like superoxide dismutase and glutathione peroxidase show decreased activities most markedly in obese type 2 diabetes subjects and to a lesser degree in non-obese type 2 diabetes or non-diabetic obese subjects in comparison to control. The results imply that mitochondrial dysfunction with enhanced ROS production may contribute to the metabolic abnormality of adipose tissue in obesity and diabetes.
Alzheimer's disease (AD), the major cause of dementia among the elderly world-wide, manifests in familial and sporadic forms, and the latter variety accounts for the majority of the patients affected by this disease. The etiopathogenesis of sporadic AD is complex and uncertain. The autopsy studies of AD brain have provided limited understanding of the antemortem pathogenesis of the disease. Experimental AD research with transgenic animal or various cell based models has so far failed to explain the complex and varied spectrum of AD dementia. The review, therefore, emphasizes the importance of AD related risk factors, especially those with metabolic implications, identified from various epidemiological studies, in providing clues to the pathogenesis of this complex disorder. Several metabolic risk factors of AD like hypercholesterolemia, hyperhomocysteinemia and type 2 diabetes have been studied extensively both in epidemiology and experimental research, while much less is known about the role of adipokines, proinflammatory cytokines and vitamin D in this context. Moreover, the results from many of these studies have shown a degree of variability which has hindered our understanding of the role of AD related risk factors in the disease progression. The review also encompasses the recent recommendations regarding clinical and neuropathological diagnosis of AD and brings out the inherent uncertainty and ambiguity in this area which may have a distinct impact on the outcome of various population-based studies on AD-related risk factors.
The pathophysiology of Helicobacter pylori-associated gastroduodenal diseases, ulcerogenesis, and carcinogenesis is intimately linked to activation of epidermal growth factor receptor (EGFR) and production of vascular endothelial growth factor (VEGF). Extracellular virulence factors, such as CagA and VacA, have been proposed to regulate EGFR activation and VEGF production in gastric epithelial cells. We demonstrate that the H. pylori secretory protein, HP0175, by virtue of its ability to bind TLR4, transactivates EGFR and stimulates EGFR-dependent VEGF production in the gastric cancer cell line AGS. Knock-out of the hp0175 gene attenuates the ability of the resultant H. pylori strain to activate EGFR or to induce VEGF production. HP0175-induced activation of EGFR is preceded by translocation of TLR4 into lipid rafts. In lipid rafts, the Src kinase family member Lyn interacts with TLR4, leading to tyrosine phosphorylation of TLR4. Knockdown of Lyn prevents HP0175-induced activation of EGFR and VEGF production. Tyrosine-phosphorylated TLR4 interacts with EGFR. This interaction is necessary for the activation of EGFR. Disruption of lipid rafts with methyl -cyclodextrin prevents HP0175-induced tyrosine phosphorylation of TLR4 and activation of EGFR. This mechanism of transactivation of EGFR is novel and distinct from that of metalloprotease-dependent shedding of EGF-like ligands, leading to autocrine activation of EGFR. It provides new insight into our understanding of the receptor cross-talk network.Receptor-tyrosine kinases are among key cell surface receptors that transduce external signals through the membrane to regulate biological processes, such as cell proliferation, differentiation, and survival. Within this group, the epidermal growth factor receptor (EGFR) 3 family is closely associated with the pathophysiology of cancer. EGFR is mutated or overexpressed in a wide variety of epithelial tumors (1-3). The classical pathway of activation of the EGFR occurs through binding of a ligand to its extracellular domain and subsequent autophosphorylation of two receptor molecules (4). Ligands such as epidermal growth factor (EGF) and heparin-binding EGF (HB-EGF) are synthesized as membrane-spanning molecules that are proteolytically cleaved to become active. Ligand binding initiates the formation of activated dimers/oligomers that undergo autophosphorylation of tyrosine residues in the cytoplasmic tail. This serves as the trigger for the recruitment of adaptor proteins and the initiation of signaling cascades within the cell. Mutations of EGFR, such as deletion of 801 bp encoded by exons 2-7 (5), result in a truncated receptor lacking 267 amino acid residues in the extracellular domain. This receptor shows ligand-independent, constitutive activity associated with increased tumorigenicity of tumors in vivo (6, 7). The paradigm for transactivation of EGFR has been the G protein-coupled receptor (GPCR)-mediated pathway (8). GPCR-dependent activation of matrix metalloproteases leads to cleavage of pro-HB-EGF and release...
Apoptosis is central to the interaction between pathogenic mycobacteria and host macrophages. Caspase-8-dependent apoptosis of infected macrophages, which requires activation of the mitogen-activated protein (MAP) kinase p38, lowers the spread of mycobacteria. Here we establish a link between the release of tumor necrosis factor (TNF) and mycobacteria-mediated macrophage apoptosis. TNF activated a pathway involving the kinases ASK1, p38 and c-Abl. This pathway led to phosphorylation of FLIP(S), which facilitated its interaction with the E3 ubiquitin ligase c-Cbl. This interaction triggered proteasomal degradation of FLIP(S), which promoted activation of caspase-8 and apoptosis. Our findings identify a previously unappreciated signaling pathway needed for Mycobacterium tuberculosis-triggered macrophage cell death.
The isoflavone, genistein, present in soybean is being actively investigated for its potential beneficial effect against Alzheimer's disease. Our data, however, show that in SHSY5Y cells genistein causes increased expression (mRNA and protein) of amyloid precursor protein (APP), increased mRNA expression and activity of β-secretase and diminished level of insulin degrading enzyme (IDE) which also degrades amyloid beta peptide. These effects of genistein lead to enhanced accumulation of amyloid beta peptide (Aβ42) in SHSY5Y cells. The results do not support the view that genistein could be a putative drug against AD and instead strengthen the epidemiological study which implies that genistein content of soybean food product (Tofu) leads to cognitive impairment.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.