Imbalanced oxidative stress and pro-inflammatory markers differentiate the development of diabetic neuropathy variants in streptozotocin-induced diabetic rats

Diabetes mellitus (DM) is a multifaceted metabolic disorder that results in dysfunction and failure of various organs. The present study aimed to evaluate the role of Thymoquinone (TQ), on antidiabetic, oxidative stress, and anti-inflammatory activities in streptozotocin (STZ)-induced (55 mg/kg b.w) diabetic rats. TQ was orally given for 8 consecutive weeks at dose of 150 mg/kg b.w. The blood glucose, insulin, total cholesterol, triglycerides, liver function enzymes, high density lipoprotein (HDL)-cholesterol, and low-density lipoprotein (LDL)-cholesterol levels were measured accordingly in control, diabetes control (DC), and TQ-treatment groups. These experiments confirmed that TQ conserves the insulin level (0.4 ng/mL vs. 0.23 ng/mL), fasting blood glucose (146 ± 7 mg/dL vs. 225 ± 5 mg/dL), and HbA1c (7.5% vs. 10.6%) quite considerably as compared to DC animals. Our results also confirmed that TQ treatment conserves the body weight and lipid profile significantly in STZ-treated animals as compared to the DC group. Moreover, the antioxidant enzymes (GSH, SOD, GST, and CAT) levels decreased, liver function enzymes (ALT, AST, and ALP), lipid peroxidation and inflammatory markers (TNF-α, CRP, IL-1β, IL-6) increased by STZ treatment, that is significantly restored after TQ treatment. As compared to untreated animals, TQ restored the hepatocytes architectural changes and collagen fibers and cox-2 protein expression in liver tissues as evaluated by hematoxylin and eosin, Masson’s trichrome, and immunohistochemistry staining. Taken together, all these findings indicated that TQ ameliorates glucose level and lipid metabolism. It restores liver function, antioxidant enzymes, anti-inflammatory markers, and maintains hepatocytes architecture in STZ-induced diabetes mellitus rats. Here, in this study, we have demonstrated for the first time the role of TQ in the reduction of the expression of cyclooxygenase-2 and fibrosis formation in diabetic rats. Based on the findings, the study suggests that TQ is a novel natural drug with a wide range of clinical applications including the management of diabetes mellitus.

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LCZ696 mitigates diabetic-induced nephropathy through inhibiting oxidative stress, NF-κB mediated inflammation and glomerulosclerosis in rats

PeerJ ◽

10.7717/peerj.9196 ◽

2020 ◽

Vol 8 ◽

pp. e9196 ◽

Cited By ~ 3

Author(s):

Mohamed Mohany ◽

Ahmed Z. Alanazi ◽

Faleh Alqahtani ◽

Osamah M. Belali ◽

Mohammed M. Ahmed ◽

...

Keyword(s):

Oxidative Stress ◽

Inflammatory Markers ◽

Time Course ◽

Therapeutic Potential ◽

Microvascular Complications ◽

Substantial Reduction ◽

Diabetic Rats ◽

Tissue Homogenate ◽

Oxidative Stress Biomarkers ◽

Tnf Α

Background Diabetic nephropathy (DN) is among the most common microvascular complications of diabetes resulting in end-stage renal disease and therefore search for candidates which can ameliorate the kidney function is needed simultaneously with standard diabetic pharmacotherapy. The current study was aimed to investigate the effect of long term sacubitril/valsartan therapy (LCZ696) in diabetic rats to assess its ameliorative impact against various pathological parameters such as oxidative stress, inflammation and glomerulosclerosis associated with chronic DN. Methods A single dose (60 mg/kg/day) of STZ was used to induce type 1 diabetes in adult male wistar rats. 2 weeks after diabetes induction, these rats were treated orally with valsartan (31 mg/kg) or LCZ696 (68 mg/kg) for 6 weeks. At end of the treatment period, serum and kidney samples were collected and analyzed. The serum levels of glucose, insulin, urea, creatinine, TNF-α, IL-1β, IL-6 and IL-10 levels were estimated. In renal tissue homogenate, the levels of inflammatory markers such as TNF-α, IL-1β, IL-6, NF-kB along with oxidative stress biomarkers including thiobarbituric acid-reacting substances (TBARs), glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione S-transferase (GST) were assessed. Histological changes were observed in kidney. Results Time course therapy withLCZ696 and valsartan in diabetic rats resulted in significant reduction of serum glucose, urea and creatinine levels (P < 0.05). Additionally, serum of treated diabetic rats showed a diminution in inflammatory (TNF-α, IL-1β, IL-6) and increment in anti-inflammatory (IL-10) cytokines levels (P < 0.05). Tissue homogenate of the kidney extracted from LCZ696 and valsartan treated diabetic rats revealed a substantial reduction in the levels of inflammatory markers such as TNF-α, IL-1β, IL-6, NF-kB and sufficient restoration of anti-oxidant enzyme levels (P < 0.05). Finally, in the histological sections of the kidney, prevention of renal injury was observed with limited necrosis and inflammatory cells infiltration. Conclusion Present data suggest that LCZ696 has sufficient therapeutic potential to restrict DN progression through inhibiting inflammation, oxidative stress and glomerulosclerosis.

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ApoE-Derived Peptides Attenuated Diabetes-Induced Oxidative Stress and Inflammation

Protein and Peptide Letters ◽

10.2174/0929866526666191002112655 ◽

2020 ◽

Vol 27 (3) ◽

pp. 193-200

Author(s):

Sunil A. Nankar ◽

Yogesh Bulani ◽

Shyam S. Sharma ◽

Abhay H. Pande

Keyword(s):

Oxidative Stress ◽

Inflammatory Markers ◽

Total Body Weight ◽

Diabetic Rats ◽

Potential Candidate ◽

Human Apolipoprotein ◽

Cellular Assays ◽

Inflammatory Conditions ◽

Oxidative Effects ◽

And Oxidative Stress

Background: Peptides derived from the apolipoproteins (apo-mimetic peptides) have emerged as a potential candidate for the treatment of various inflammatory conditions. Our previous results have shown that peptides derived from human apolipoprotein-E interact with various pro-inflammatory lipids and inhibit their inflammatory functions in cellular assays. Objective: In this study, two apoE-derived peptides were selected to investigate their antiinflammatory and anti-oxidative effects in streptozotocin-induced diabetic model of inflammation and oxidative stress. Methods: The peptides were injected intraperitoneally into the streptozotocin-induced diabetic rats and their anti-inflammatory and anti-oxidative effects were evaluated by monitoring various oxidative and inflammatory markers. Results: Administration of 4F, E5 and E8 peptides decreased the oxidative and inflammatory markers in STZ-induced diabetic rats to different extent, while had no significant effect on the other diabetic parameters (viz. total body weight of animals and increased blood glucose level). E5 peptide was found to be relatively more effective than 4F and E8 peptides in decreasing inflammation and oxidative stress. Conclusion: E5 peptide can be developed as a potential candidate for inflammatory conditions.

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Huayu Tongluo Recipe Attenuates Renal Oxidative Stress and Inflammation through the Activation of AMPK/Nrf2 Signaling Pathway in Streptozotocin- (STZ-) Induced Diabetic Rats

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2021/5873007 ◽

2021 ◽

Vol 2021 ◽

pp. 1-12

Author(s):

Yachun Li ◽

Shuai Guo ◽

Fan Yang ◽

Lifei Liu ◽

Zhiqiang Chen

Keyword(s):

Oxidative Stress ◽

Signaling Pathway ◽

Total Protein ◽

Inflammatory Markers ◽

Underlying Mechanism ◽

Renal Tissue ◽

Diabetic Rats ◽

Sprague Dawley ◽

Sod Activity ◽

Nrf2 Signaling Pathway

Diabetic nephropathy (DN), a severe microvascular complication of diabetes, is one of the leading causes of end-stage renal disease. Huayu Tongluo Recipe (HTR) has been widely used in the clinical treatment of DN in China, and its efficacy is reliable. This study aimed to explore the renoprotective effect of HTR and the underlying mechanism. Male Sprague-Dawley rats were fed with high sugar and fat diet combined with an intraperitoneal injection of STZ to establish the diabetic model. Rats in each group were respectively given drinking water, HTR, and irbesartan by gavage for 16 weeks. 24-hour urine samples were collected every 4 weeks to detect the content of total protein and 8-OHdG. Blood samples were taken to detect biochemical indicators and inflammatory markers at the end of 16th week. Renal tissue was collected to investigate pathological changes and to detect oxidative stress and inflammatory markers. AMPK/Nrf2 signaling pathway and fibrosis-related proteins were detected by immunohistochemistry, immunofluorescence, real-time PCR, and western blot. 24h urine total protein (24h UTP), serum creatinine (Scr), blood urea nitrogen (BUN), total cholesterol (TC), and triglyceride (TG) were decreased in the rats treated with HTR, while there was no noticeable change of blood glucose. HTR administration decreased malondialdehyde (MDA) content and increased superoxide dismutase (SOD) activity in kidneys, complying with reduced 8-OHdG in the urine. The levels of TNF-α, IL-1β, and MCP1 and the expression of nuclear NFκB were also lower after HTR treatment. Furthermore, HTR alleviated pathological renal injury and reduced the accumulation of extracellular matrix (ECM). Besides, HTR enhanced the AMPK/Nrf2 signaling and increased the expression of HO-1 while it inhibited the Nox4/TGF-β1 signaling in the kidneys of STZ-induced diabetic rats. HTR can inhibit renal oxidative stress and inflammation to reduce ECM accumulation and protect the kidney through activating the AMPK/Nrf2 signaling pathway in DN.

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Na+/H+ exchanger 1 inhibition reverses manifestation of peripheral diabetic neuropathy in type 1 diabetic rats

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00186.2013 ◽

2013 ◽

Vol 305 (3) ◽

pp. E396-E404 ◽

Cited By ~ 12

Author(s):

Sergey Lupachyk ◽

Pierre Watcho ◽

Hanna Shevalye ◽

Igor Vareniuk ◽

Alexander Obrosov ◽

...

Keyword(s):

Oxidative Stress ◽

Blood Flow ◽

Diabetic Neuropathy ◽

Vascular Reactivity ◽

Sensory Nerve ◽

Diabetic Rats ◽

Tactile Allodynia ◽

Advanced Glycation ◽

Peripheral Diabetic Neuropathy ◽

Intraepidermal Nerve Fiber

Evidence for an important role for Na+/H+ exchangers in diabetic complications is emerging. The aim of this study was to evaluate whether Na+/H+ exchanger 1 inhibition reverses experimental peripheral diabetic neuropathy. Control and streptozotocin-diabetic rats were treated with the specific Na+/H+ exchanger 1 inhibitor cariporide for 4 wk after 12 wk without treatment. Neuropathy end points included sciatic motor and sensory nerve conduction velocities, endoneurial nutritive blood flow, vascular reactivity of epineurial arterioles, thermal nociception, tactile allodynia, and intraepidermal nerve fiber density. Advanced glycation end product and markers of oxidative stress, including nitrated protein levels in sciatic nerve, were evaluated by Western blot. Rats with 12-wk duration of diabetes developed motor and sensory nerve conduction deficits, thermal hypoalgesia, tactile allodynia, and intraepidermal nerve fiber loss. All these changes, including impairment of nerve blood flow and vascular reactivity of epineurial arterioles, were partially reversed by 4 wk of cariporide treatment. Na+/H+ exchanger 1 inhibition was also associated with reduction of diabetes-induced accumulation of advanced glycation endproduct, oxidative stress, and nitrated proteins in sciatic nerve. In conclusion, these findings support an important role for Na+/H+ exchanger 1 in functional, structural, and biochemical manifestations of peripheral diabetic neuropathy and provide the rationale for development of Na+/H+ exchanger 1 inhibitors for treatment of diabetic vascular and neural complications.

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Attenuation of oxidative stress in hepatic and pancreatic tissues of STZ-induced diabetic rats treated with aqueous extract of Vochysia rufa

Planta Medica ◽

10.1055/s-0034-1394539 ◽

2014 ◽

Vol 80 (16) ◽

Cited By ~ 2

Author(s):

NM De Gouveia ◽

IB Moraes ◽

RMF Sousa ◽

MB Neto ◽

AV Mundim ◽

...

Keyword(s):

Oxidative Stress ◽

Aqueous Extract ◽

Diabetic Rats

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Effect of prostaglandin E1 analogue TFC 612 on diabetic neuropathy in streptozocin-induced diabetic rats. Comparison with aldose reductase inhibitor ONO 2235

Diabetes ◽

10.2337/diabetes.38.7.832 ◽

1989 ◽

Vol 38 (7) ◽

pp. 832-838 ◽

Cited By ~ 47

Author(s):

H. Yasuda ◽

M. Sonobe ◽

M. Yamashita ◽

M. Terada ◽

I. Hatanaka ◽

...

Keyword(s):

Diabetic Neuropathy ◽

Aldose Reductase ◽

Prostaglandin E1 ◽

Reductase Inhibitor ◽

Diabetic Rats ◽

Aldose Reductase Inhibitor

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Testicular Injury Attenuated by Rapamycin Through Induction of Autophagy and Inhibition of Endoplasmic Reticulum Stress in Streptozotocin- Induced Diabetic Rats

Endocrine Metabolic & Immune Disorders - Drug Targets ◽

10.2174/1871530319666190102112844 ◽

2019 ◽

Vol 19 (5) ◽

pp. 665-675 ◽

Cited By ~ 4

Author(s):

Wenjiao Shi ◽

Zhixin Guo ◽

Ruixia Yuan

Keyword(s):

Oxidative Stress ◽

Endoplasmic Reticulum ◽

Endoplasmic Reticulum Stress ◽

Protective Effect ◽

Er Stress ◽

B Cell Lymphoma ◽

Diabetic Rats ◽

Pathological Changes ◽

Rapamycin Treatment ◽

Related Proteins

Background and Objective: This study investigated whether rapamycin has a protective effect on the testis of diabetic rats by regulating autophagy, endoplasmic reticulum stress, and oxidative stress. Methods: Thirty male Sprague-Dawley rats were randomly divided into three groups: control, diabetic, and diabetic treated with rapamycin, which received gavage of rapamycin (2mg.kg-1.d-1) after induction of diabetes. Diabetic rats were induced by intraperitoneal injection of streptozotocin (STZ, 65mg.Kg-1). All rats were sacrificed at the termination after 8 weeks of rapamycin treatment. The testicular pathological changes were determined by hematoxylin and eosin staining. The protein or mRNA expression of autophagy-related proteins (Beclin1, microtubule-associated protein light chain 3 (LC3), p62), ER stress marked proteins (CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP), caspase-12), oxidative stress-related proteins (p22phox, nuclear factor erythroid2-related factor 2 (Nrf2)) and apoptosis-related proteins (Bax, B cell lymphoma-2 (Bcl-2)) were assayed by western blot or real-time fluorescence quantitative PCR. Results: There were significant pathological changes in the testes of diabetic rats. The expression of Beclin1, LC3, Nrf2, Bcl-2 were significantly decreased and p62, CHOP, caspase12, p22phox, and Bax were notably increased in the testis of diabetic rats (P <0.05). However, rapamycin treatment for 8 weeks significantly reversed the above changes in the testis of diabetic rats (P <0.05). Conclusion: Rapamycin appears to produce a protective effect on the testes of diabetic rats by inducing the expression of autophagy and inhibiting the expression of ER-stress, oxidative stress, and apoptosis.

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