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Nerve and Retinal Changes in Experimental Diabetes
Published in John H. McNeill, Experimental Models of Diabetes, 2018
In hyperglycemia, as mentioned earlier, increased glycolysis in the tissues and an augmented polyol pathway activity cause an increase of the NADH/NAD+ ratio.141 This alteration has been termed pseudohypoxia, as it is similar to that seen in hypoxia. An increased NADH/NAD+ ratio may lead to alterations in lipid peroxidation, DAG synthesis, and defective DNA repair.141,187 Increased DAG synthesis further activates PKC in the retina.144,205 Redox imbalances have been demonstrated in the retina, which may favour increased free radical generation, increased prostaglandin synthesis, and decreased NO synthesis.141,187
Neuroendocrine tumors of the gastrointestinal tract
Published in Demetrius Pertsemlidis, William B. Inabnet III, Michel Gagner, Endocrine Surgery, 2017
Bernard Khoo, Tricia Tan, Stephen R. Bloom
The von Hippel–Lindau (VHL) syndrome is classically associated with renal cell carcinomas, central nervous system (CNS) hemangioblastomas, pheochromocytomas, and pancreatic tumors. The latter are typically cystic and most represent serous cystadenomas that are not NETs. Only the minority of these pancreatic lesions are NETs (≤20%). Nevertheless, this does suggest that the key pathogenic pathway activated by mutations in VHL is involved at some level in pancreatic NET pathogenesis. VHL mutations lead to reduced clearance of the hypoxia-induced transcription factor HIF-1alpha via ubiquitination and proteasomal degradation. As a result, there is activation, even under normoxic conditions, of the hypoxic response, which induces angiogenesis via vascular endothelial growth factor (VEGF), cellular growth via platelet-derived growth factor (PDGF) and TGF-alpha, metabolic changes promoting the transport of glucose, and cell survival. This so-called “pseudohypoxic” activation is classically associated with the pathogenesis of renal cell carcinomas, hemangioblastomas, pheochromocytomas, and paragangliomas. Although the exact pathogenetic link between activation of this pathway and the ultimate evolution of pancreatic NETs is yet to be clarified, it is of interest to note that sunitinib and other angiogenesis inhibitors are known to be effective against pancreatic NETs (see below).
Diabetic Nephropathy
Published in Emmanuel Opara, NUTRITION and DIABETES, 2005
Hyperglycemia causes in high cytosolic glucose concentrations in renal endothelial cells and pericytes that result in biochemical dysfunction: 1) activation of protein kinase C; 2) activation of hexosamine and polyol pathways; 3) metabolic pseudohypoxia from mitochondrial dysfunction with oxidative stress; and 4) accumulation of AGE (136, 155). Heilig et al. found a link between high cytosolic glucose concentrations and metabolic dysfunction by an overexpression of the GLUT1 glucose transporter in cultured rat renal mesangial cells. These normal cells acquired the characteristics of the diabetic phenotype, including increased extracellular matrix protein synthesis and activation of the polyol pathway (156).
A comparative study between the possible protective role of melatonin versus its combination with adipose derived-mesenchymal stem cells on experimentally induced diabetic retinopathy in adult male albino rats (Histological and immunohistochemical study)
Published in Ultrastructural Pathology, 2023
Samar Reda, Ghada A Elsammak, Tamer G Elsayed, Samar Abdelaziz Mostafa
In the diabetic group, H&E stained sections showed congested blood vessels appeared in between the retinal cells. The fundic examination of the same group showed neovascularization. In line with the findings of Abd El-Halim et al. in 2019 who discovered the same outcome. According to their findings, pseudohypoxia caused by disruption to the endothelial tight junction of the blood-retinal barrier causes hyperglycemia to increase the amount of VEGF.19 With the development of more leaky arteries, the damaged endothelial cells release more VEGF. The aberrant new blood vessels are more likely to bleed, which causes retinal edema and leukocyte aggregation, both of which drive the release of VEGF. This finding was supported by the diabetic group’s immune-stained VEGF sections, which displayed strongly positive VEGF immunoreactions.20
Prevalence of succinate dehydrogenase deficiency in paragangliomas and phaeochromocytomas at a tertiary hospital in Cape Town: a retrospective review
Published in Journal of Endocrinology, Metabolism and Diabetes of South Africa, 2021
Cassandra Bruce-Brand, Abraham C van Wyk
The SDH enzyme complex (mitochondrial complex II) catalyses the conversion of succinate to fumarate in the Krebs cycle.16 Loss of heterozygosity with inactivating germline mutations results in destabilisation of the SDH protein complex and abolishes its enzymatic activity leading to an accumulation of succinate.16,18–20 This results in reactive oxygen species causing free radical damage and activation of a pseudohypoxia pathway by increasing hypoxia-inducible factors.16,18–21 A third mechanism that has been proposed to explain how Krebs cycle dysfunction can lead to neoplasia is through a decrease in apoptosis.21 The SDH complex consists of four subunits, SDHA, SDHB, SDHC and SDHD. Hereditary PC/PGL syndrome can be caused by germline mutations in any of the SDH subunits as well as in SDHAF2, a mitochondrial protein that flavinates SDHA and promotes maturation of SDHB.16,21–24
Fumarate hydratase as a therapeutic target in renal cancer
Published in Expert Opinion on Therapeutic Targets, 2020
Priyanka Kancherla, Michael Daneshvar, Rebecca A. Sager, Mehdi Mollapour, Gennady Bratslavsky
Establishing HLRCC cell lines has allowed for confirmation and clarification of the proposed metabolic aberrations resulting from FH loss. Yang et al. established the first HLRCC tumor cell line model, UOK 262, a metastasis derived cell line [36]. This was followed by the UOK 268 cell line which was derived from a primary HLRCC-associated renal tumor [43]. Characterization of UOK262 cell line revealed overexpression of glycolytic enzymes including LDHA and GLUT1 via immunocytochemistry and mRNA expression as well as decreased mitochondrial oxygen consumption. A subsequent study characterizing the UOK 268 cell line confirmed absent FH catalytic activity via enzyme assay and revealed increased HIF1α expression in both UOK262 and UOK268 cell lines compared to control. This finding is consistent with the previously discussed pseudohypoxia model. These dedicated HLRCC cell line models confirm the role of the Warburg effect in this cancer.