Upstream Regulators and Downstream Effectors of NADPH Oxidases as Novel Therapeutic Targets for Diabetic Kidney Disease

Oxidative stress has been linked to the pathogenesis of diabetic nephropathy, the complication of diabetes in the kidney. NADPH oxidases of the Nox family, and in particular the homologue Nox4, are a major source of reactive oxygen species in the diabetic kidney and are critical mediators of redox signaling in glomerular and tubulointerstitial cells exposed to the diabetic milieu. Here, we present an overview of the current knowledge related to the understanding of the role of Nox enzymes in the processes that control mesangial cell, podocyte and tubulointerstitial cell injury induced by hyperglycemia and other predominant factors enhanced in the diabetic milieu, including the renin-angiotensin system and transforming growth factor-β. The nature of the upstream modulators of Nox enzymes as well as the downstream targets of the Nox NADPH oxidases implicated in the propagation of the redox processes that alter renal biology in diabetes will be highlighted.     

Beneficial effects of n-hexane bark extract of Onosma echioides L. on diabetic peripheral neuropathy

Onosma echioides Linn (Boraginaceae) is the most frequently used curative herb widely used for kidney obstruction, sciatic pain, and gout. The present study was designed to investigate the therapeutic effects of n-hexane bark extract of O. echioides (OE) L. root in vivo against Streptozotocin-induced diabetic neuropathy in SD rats. For in vivo activity, the experiment was categorized into five different groups (n = 5). Group-I was considered as nondiabetic/normal control (NC) treated with 0.5% carboxymethyl cellulose (CMC), Group II as diabetic control, Group-III, IV, and V served as diabetic treated with OE 50, OE 100, and pregabalin at a dose of 50, 100, and 10 mg/kg body weight, orally, respectively. Body weight, blood glucose, oral glucose tolerance test, behavioral studies (motor coordination test, thermal hyperalgesia, cold allodynia, locomotor activity, oxidative biomarkers (thio barbituric acid reactive substances [TBARS], superoxide dismutase [SOD], glutathione [GSH], and catalase), and histopathology of the sciatic nerve were performed. Treatment with OE showed a dose-dependent increase in neuroprotective activity by improving the myelination and decreasing the axonal swelling of nerve fibers. The verdicts of behavioral activities showed a remarkable effect on animals after the treatment of extract and standard drug pregabalin. In conclusion, our findings supported the traditional application of OE and explored its importance in the management of diabetic neuropathy. Additional clinical experiments may provide novel therapeutic drugs for diabetes and its complications.     

Effects of exercise training and diabetes on cardiac myosin heavy chain composition

This study determined whether the beneficial effects of exercise training on the diabetic heart previously observed are associated with alterations in ventricular myosin heavy chain (MHC) isoform composition. Diabetes was induced in rats by i.v. streptozotocin. Trained rats were run on a treadmill for 60 min/day, 27 m/min, 10% grade. After 10 wks, ventricular MHC isoenzyme protein composition was analyzed for MHC composition using gel electrophoresis. -MHC and -MHC mRNA were determined by Northern and slot blot hybridization techniques. Both protein and mRNA analyses indicated that sedentary control rats exhibited a predominance of -MHC. Sedentary diabetics exhibited a shift to -MHC. Exercise trained diabetic rats showed a predominance of -MHC. The results indicate that treadmill exercise training of diabetic rat does not prevent the diabetes-induced shift in MHC composition towards the -MHC isoform, thus it is unlikely that the beneficial effects of exercise training on the diabetic heart, previously shown, are due to a normalization of the myosin isoform composition.     

Decreased Incorporation of [3H]Inositol and [3H]Glycerol into Glycerolipids of Sciatic Nerve from the Streptozotocin Diabetic Rat

The incorporation of [3H]myo-inositol into individual phosphoinositides and of [3H]glycerol into glycerolipids was determined in sciatic nerve obtained from normal and streptozotocin diabetic rats and incubated in vitro. The uptake of inositol into lipid was approximately linear with time. More than 80% of the label was present in phosphatidylinositol with the remainder divided about equally between phosphatidylinositol phosphate and phosphatidylinositol-4,5-bisphosphate. Labeling was unchanged 2 weeks after induction of diabetes, but was reduced by 32% after 20 weeks of the disease. Glycerol incorporation occurred primarily into phosphatidylcholine and triacylglycerol and was depressed up to 45% into major phosphoglycerides in nerves from both 2- and 20-week diabetic animals. Triacylglycerol labeling was also substantially decreased, and the reduction was comparable in intact and epineurium free nerve, suggesting that a metabolically active pool of this compound, which is sensitive to hyperglycemia and/or insulin deficiency, is located in or immediately adjacent to the nerve fibers. The considerable decline in incorporation of these lipid precursors in diabetic nerve may be related to impaired inositol transport and to decrease overall energy utilization by the tissue.     

Effect of prolactin and glucocorticoids on P-enolpyruvate carboxykinase activity in liver and mammary gland from diabetic and lactating rats

Summary The administration of 2 bromo--ergocryptine, to reduce serum prolactin decreased the activity of cytosolic P-enolpyruvatc carboxykinase (GTP) (EC4.1.1.32) about 50% in both liver and mammary gland of lactating animals. Adrenalectomy had similar effects to those of bromo-a-ergocryptine. In contrast, there was a 50% increase in enzyme activity in the mammary gland of diabetic, lactating rats and a 10-fold increase in liver as compared with normal rats. P-enolpyruvate carboxykinase activity in mammary gland as liver is coordinately regulated by prolactin, glucocorticoids and insulin.     

P0 phosphorylation in nerves from normal and diabetic rats: Role of protein kinase C and turnover of phosphate groups

The effects of phorbol ester and forskolin on the net phosphorylation and turnover of P₀ phosphate groups was studied in normal and exprimentally diabetic rats. In sciatic nerve segments isolated from normal rats and incubated with [³²P]-inorganic phosphate, phosphorylation of the major peripheral myelin protein, P₀, was increased 2–5 fold in a time and dose-dependent manner by phorbol 12,13 dibutyrate (PDB). This increase was blocked by the protein kinase inhibitors, H-7 and staurosporine. Both the basal and PDB-stimulated phosphorylation of P₀ were significantly greater in segments of sciatic nerve from streptozotocin-induced diabetic rats. Prolonged exposure of nerve segments to PDB abolished the stimulated phosphorylation of P₀ and immunoblots of nerve proteins revealed a decrease in the content of the protein kinase C -isoform. The adenylate cyclase activator, forskolin, had no affect on the PDB-stimulated phosphorylation of P₀ in normal nerve but decreased phosphorylation in diabetic nerve. To measure turnover of P₀ phosphate groups, nerves were incubated with³²P and incorporated label was then chased in radioactivity-free medium for up to 4 hours. P₀ from normal nerve prelabeled under basal conditions lost 25% of its radioactivity during this time. In contrast, nearly all of the additional phosphate groups prelabeled in the presence of PDB disappeared after 2 hours of chase. P₀ phosphate groups from diabetic nerve displayed similar turnover kinetics. When forskolin was added to the chase medium, the turnover of P₀ phosphate moieties was accelerated in normal, but not in diabetic nerve. These findings clearly establish a prominent role for protein kinase C in P₀ phosphorylation, provide evidence for heterogeneous turnover of P₀ phosphate groups and suggest that cyclic AMP-mediated processes may modulate P₀ phosphorylation. Further, these results indicate that the metabolism of P₀ phosphate moieties is perturbed in nerve from diabetic animals.Special issue dedicated to Dr. Marjoris B. Lees.     

Effects of glycated albumin on mesangial cells: evidence for a role in diabetic nephropathy

Nonenzymatically glycated proteins are preferentially transported across the glomerular filtration barrier, and the glomerular mesangium in diabetes is bathed with serum containing increased concentrations of glycated albumin. We investigated effects of glycated albumin on mesangial cells, which are involved in diabetic nephropathy. [³H]-thymidine incorporation was significantly inhibited when murine mesangial cells were grown in culture media containing human serum that had been nonenzymatically glycated by incubation for 4 days with 28 mM glucose. This inhibition was reversed when monoclonal antibodies that selectively react with Amadori products of glycated albumin were added to the culture media. Purified glycated albumin containing Amadori adducts of the glycation reaction induced significant inhibition of thymidine incorporation and stimulation of Type IV collagen secretion compared with cells cultured in the presence of purified nonglycated albumin. These changes were prevented when monoclonal antibodies specifically reactive with fructosyl-lysine epitopes in glycated albumin were added to the cultures. The antibodies had no effect on growth or collagen production in the presence of nonglycated albumin. The results provide the first evidence directly implicating Amadori adducts in glycated albumin in the pathogenesis of diabetic nephropathy, which is characterized by decreased cellularity in association with expansion of the mesangial matrix.     

Utilidad y seguridad de los ingresos directos a una unidad hospitalaria de agudos de un servicio de geriatría valorados por atención geriátrica en residencias

Background and objectiveMore than half of institutionalized older people need a emergency department visit annually, with high resources consumption and higher risk of adverse events, due to high complexity. Direct admission to Acute Geriatric Unit (AGU), after geriatric consultant and nursing home medical team assessment, could be a safety and effective alternative to emergency department (ED) admission.MethodsRetrospective observational study of AGU patients admitted by Nursing Home Geriatric Team between January, 1st and December, 31st, 2021. Planned admissions and SARS-CoV-2 positive patients were excluded. Medical (sociodemographic, clinical, functional and cognitive) records and outcomes data (inpatient mortality, hospital and ED lenght of stay, transfer to ED and delirium within 48 h after admission, hospital discharge location) were collected.ResultsTwo hundred and six patients directly admitted, 101 through ED (N 307). 62.5% with Barthel index <40, 65% with dementia, 56.4% with Charlson index ≥3. Inpatient mortality was 14.6% in direct admission, 20.8% in ED referral group, p = 0.14. Hospital lenght of stay was 9.61 ± 6.01 days in direct admission, 11.22 ± 5.36 days in ED group, p = 0.02. 27.7% of patients with delirium in direct admission and 36.6% in ED group; only one patient was transferred to ED, within 48 h after admission.ConclusionsDirect admission is a safety and effective alternative to ED referral in institutionalized older people after geriatric assessment, due to no increased mortality, shorter length of stay and hospital cost reduction.     

Thioredoxin 1 overexpression attenuated diabetes-induced endoplasmic reticulum stress in Müller cells via apoptosis signal-regulating kinase 1

As one of the common and serious chronic complications of diabetes mellitus (DM), the related mechanism of diabetic retinopathy (DR) has not been fully understood. Müller cell reactive gliosis is one of the early pathophysiological features of DR. Therefore, exploring the manner to reduce diabetes-induced Müller cell damage is essential to delay DR. Thioredoxin 1 (Trx1), one of the ubiquitous redox enzymes, plays a vital role in redox homeostasis via protein–protein interactions, including apoptosis signal-regulating kinase 1 (ASK1). Previous studies have shown that upregulation of Trx by some drugs can attenuate endoplasmic reticulum stress (ERS) in DR, but the related mechanism was unclear. In this study, we used DM mouse and high glucose (HG)-cultured human Müller cells as models to clarify the effect of Trx1 on ERS and the underlying mechanism. The data showed that the diabetes-induced Müller cell damage was increased significantly. Moreover, the expression of ERS and reactive gliosis was also upregulated in diabetes in vivo and in vitro. However, it was reversed after Trx1 overexpression. Besides, ERS-related protein expression, reactive gliosis, and apoptosis were decreased after transfection with ASK1 small-interfering RNA in stable Trx1 overexpression Müller cells after HG treatment. Taken together, Trx1 could protect Müller cells from diabetes-induced damage, and the underlying mechanism was related to inhibited ERS via ASK1.     

八段锦联合抗阻运动对老年2型糖尿病患者糖脂代谢、氧化应激及生活质量的影响

摘要 目的：探讨八段锦联合抗阻运动对老年2型糖尿病（T2DM）患者糖脂代谢、氧化应激及生活质量的影响。方法：选取2021年4月~2022年5月期间在我院接受治疗的老年T2DM患者238例。按照随机数字表法分为对照组（在常规治疗的基础上,接受抗阻运动干预,119例）和联合组（在对照组的基础上,接受八段锦干预,119例）。观察两组糖脂代谢、氧化应激及生活质量的改善情况。结果：干预12周后,联合组体质量指数、腰臀比低于对照组（P<0.05）。干预12周后,联合组空腹血糖（FBG）、餐后2 h血糖（2hPG）、糖化血红蛋白（HbAlc）低于对照组（P<0.05）。干预12周后,联合组高密度脂蛋白胆固醇（HDL-C）高于对照组（P<0.05）,低密度脂蛋白胆固醇（LDL-C）、总胆固醇（TC）、甘油三酯（TG）低于对照组。干预12周后,联合组丙二醛（MDA）低于对照组,超氧化物歧化酶（SOD）、过氧化氢酶（CAT）高于对照组（P<0.05）。干预12周后,联合组的健康调查简表（SF-36）各维度评分均高于对照组（P<0.05）。结论：八段锦联合抗阻运动用于老年T2DM患者中,可有效改善患者的氧化应激、糖脂代谢,并提高患者的生活质量。