Zingerone produces antidiabetic effects and attenuates diabetic nephropathy by reducing oxidative stress and overexpression of NF-κB, TNF-α, and COX-2 proteins in rats

Patients with diabetic nephropathy have a high rate of cardiovascular events and mortality. Nontraditional cardiovascular risk factors such as oxidative stress and inflammation are thought to be particularly important in mediating these events. Studies suggest that thiazolidinediones (TZDs) can reduce the level of nontraditional cardiovascular risk in people with or without diabetes mellitus. Whether this benefit occurs in patients with diabetic nephropathy is unknown. I hypothesized that the TZD pioglitazone will mitigate oxidative stress and inflammation compared with glipizide in patients with overt diabetic nephropathy. Markers of oxidative stress (plasma and urine albumin carbonyl and total protein carbonyls and malondialdehyde), inflammation [white blood cell (WBC) count, C-reactive protein (CRP), plasma IL-6, TNF-α], and plaque stability [matrix metalloproteinase 9 (MMP-9)] were measured in frozen samples obtained from patients with overt diabetic nephropathy participating in a randomized, open-label, blinded end-point, 16-wk trial with glipizide ( n = 22) or pioglitazone ( n = 22). Pioglitazone therapy in men with advanced diabetic nephropathy reduced WBC count by 1,125/μl ( P < 0.001), CRP by 41% ( P = 0.042), IL-6 by 38% ( P = 0.009), and MMP-9 by 29% ( P = 0.016). Specific differential reductions in WBC count of 1,251/μl ( P = 0.009) and reduction in IL-6 of 58% with pioglitazone ( P = 0.001) were seen compared with glipizide. There were no statistically significant changes observed with plasma TNF-α concentrations or markers of oxidative stress with either hypoglycemic agent. In conclusion, pioglitazone reduces proinflammatory markers in patients with overt diabetic nephropathy, which indicates potentially beneficial effects on overall cardiovascular risk. This surrogate end point needs to be confirmed in trials designed to demonstrate cardiovascular protection.

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Targeting ROS/NF-κB sigaling pathway by the seedless black Vitis vinifera polyphenols in CCl4-intoxicated kidney, lung, brain, and spleen in rats

Scientific Reports ◽

10.1038/s41598-021-96008-0 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Noha H. Habashy ◽

Ahmad S. Kodous ◽

Marwa M. Abu-Serie

Keyword(s):

Oxidative Stress ◽

Gene Expression ◽

Vitis Vinifera ◽

Rat Kidney ◽

Environmental Pollutant ◽

Enhancing Effect ◽

Tnf Α ◽

Cox 2 ◽

Histopathological Studies ◽

And Oxidative Stress

AbstractCarbon tetrachloride (CCl4) is an abundant environmental pollutant that can generate free radicals and induce oxidative stress in different human and animal organs like the kidney, lung, brain, and spleen, causing toxicity. The present study evaluated the alleviative mechanism of the isolated polyphenolic fraction from seedless (pulp and skin) black Vitis vinifera (VVPF) on systemic oxidative and necroinflammatory stress in CCl4-intoxicated rats. Here, we found that the administration of VVPF to CCl4-intoxicated rats for ten days was obviously ameliorated the CCl4-induced systemic elevation in ROS, NO and TBARS levels, as well as MPO activity. Also, it upregulated the cellular activities of the enzymatic (SOD, and GPx) and non-enzymatic (TAC and GSH) antioxidants. Furthermore, the gene expression of the ROS-related necroinflammatory mediators (NF-κB, iNOS, COX-2, and TNF-α) in the kidney, brain, and spleen, as well as IL-1β, and IL-8 in the lung were greatly restored. The histopathological studies confirmed these biochemical results and showed a noticeable enhancing effect in the architecture of the studied organs after VVPF intake. Thus, this study indicated that VVPF had an alleviative effect on CCl4-induced necroinflammation and oxidative stress in rat kidney, lung, brain, and spleen via controlling the ROS/NF-κB pathway.

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Local anesthetic Ropivacaine protects rats from myocardial ischemia/reperfusion injury by inhibition of COX-2

Archives of Medical Science ◽

10.5114/aoms/132472 ◽

2021 ◽

Author(s):

Zhou Yu ◽

Sufang Sun ◽

Fang Hu

Keyword(s):

Oxidative Stress ◽

Creatine Kinase ◽

Ischemia Reperfusion ◽

Inos Expression ◽

Ischaemic Injury ◽

Cardiac Tissues ◽

Tnf Α ◽

Creatine Kinase Mb ◽

Cellular Apoptosis ◽

Cox 2

IntroductionMyocardial ischaemia/reperfusion (I/R) injury is the leading cause of morbidity and mortality worldwide. Despite novel advances in therapeutics, the management of myocardial I/R is still an unmet medical need. Therefore, in the present study, we have demonstrated the protective effect of ropivacaine (RPC) on the myocardial infarction in rats and its underlying mechanism.Material and methodsInitially, the effect of RPC was determined on the infarct size and histopathology of cardiac tissues. The effect of RPC was also determined on the levels of various cardiac biomarkers such as creatine kinase (CK), creatine kinase MB (CK-MB), alanine aminotransferase (ALT), asparganine aminotransferase (AST), and lactate dehydrogenase (LDH), and biomarkers of oxidative stress (MDA, SOD, and GSH) and inflammation (tumour necrosis factor-α (TNF-α), interleukin 1β (IL-1β), and IL-6). RPC effect was also quantified on cellular apoptosis and COX-2 and iNOS expression via western blot analysis. The RPC was further docked into the active site of COX-2.ResultsIt has been found that RPC reduces the improves haemodynamics of (LVSP and ± dp/dtmax, and LVEDP), infarct percentage and architecture of cardiac tissues of rats. It also reduces the level of studies cardiac injury biomarkers together with a reduction of oxidative stress (MDA, SOD, and GSH) and inflammation (TNF-α, IL-1β, and IL-6). Upon administration of RPC, the rate of cellular apoptosis was found to be greatly reduced, with a reduction in COX-2 and iNOS expression. In docking analysis, RPC creates van der Waals forces and pi-interactions with Tyr381, Arg106, Val102, Leu345, Val509, Ser339, Leu338, Val335, Ala513, His75, and Leu517 at the catalytic site of COX-2.ConclusionsCollectively, our results demonstrated that ropivacaine showed significant benefit against myocardial ischaemic injury.

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Honokiol ameliorates radiation-induced brain injury via the activation of SIRT3

Journal of International Medical Research ◽

10.1177/0300060520963993 ◽

2020 ◽

Vol 48 (10) ◽

pp. 030006052096399

Author(s):

Guixiang Liao ◽

Zhihong Zhao ◽

Hongli Yang ◽

Xiaming Li

Keyword(s):

Oxidative Stress ◽

Brain Injury ◽

Inflammatory Responses ◽

Tissue Injury ◽

Interleukin 1 ◽

Dependent Manner ◽

Ht22 Cells ◽

Tnf Α ◽

Radiation Induced ◽

Cox 2

Objective Sirtuin 3 (SIRT3) plays a vital role in regulating oxidative stress in tissue injury. The aim of this study was to evaluate the radioprotective effects of honokiol (HKL) in a zebrafish model of radiation-induced brain injury and in HT22 cells. Methods The levels of reactive oxygen species (ROS), tumor necrosis factor-alpha (TNF-α), and interleukin-1 beta (IL-1β) were evaluated in the zebrafish brain and HT22 cells. The expression levels of SIRT3 and cyclooxygenase-2 (COX-2) were measured using western blot assays and real-time polymerase chain reaction (RT-PCR). Results HKL treatment attenuated the levels of ROS, TNF-α, and IL-1β in both the in vivo and in vitro models of irradiation injury. Furthermore, HKL treatment increased the expression of SIRT3 and decreased the expression of COX-2. The radioprotective effects of HKL were achieved via SIRT3 activation. Conclusions HKL attenuated oxidative stress and pro-inflammatory responses in a SIRT3-dependent manner in radiation-induced brain injury.

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Apigenin ameliorates streptozotocin-induced diabetic nephropathy in rats via MAPK-NF-κB-TNF-α and TGF-β1-MAPK-fibronectin pathways

AJP Renal Physiology ◽

10.1152/ajprenal.00393.2016 ◽

2017 ◽

Vol 313 (2) ◽

pp. F414-F422 ◽

Cited By ~ 42

Author(s):

Salma Malik ◽

Kapil Suchal ◽

Sana Irfan Khan ◽

Jagriti Bhatia ◽

Kamal Kishore ◽

...

Keyword(s):

Oxidative Stress ◽

Diabetic Nephropathy ◽

Transforming Growth Factor ◽

Mapk Pathway ◽

Histopathological Examination ◽

Fasting Blood Glucose ◽

Transforming Growth Factor Β1 ◽

Diabetic Rats ◽

Tnf Α ◽

Per Se

Diabetic nephropathy (DN), a microvascular complication of diabetes, has emerged as an important health problem worldwide. There is strong evidence to suggest that oxidative stress, inflammation, and fibrosis play a pivotal role in the progression of DN. Apigenin has been shown to possess antioxidant, anti-inflammatory, antiapoptotic, antifibrotic, as well as antidiabetic properties. Hence, we evaluated whether apigenin halts the development and progression of DN in streptozotocin (STZ)-induced diabetic rats. Male albino Wistar rats were divided into control, diabetic control, and apigenin treatment groups (5–20 mg/kg po, respectively), apigenin per se (20 mg/kg po), and ramipril treatment group (2 mg/kg po). A single injection of STZ (55 mg/kg ip) was administered to all of the groups except control and per se groups to induce type 1 diabetes mellitus. Rats with fasting blood glucose >250 mg/dl were included in the study and randomized to different groups. Thereafter, the protocol was continued for 8 mo in all of the groups. Apigenin (20 mg/kg) treatment attenuated renal dysfunction, oxidative stress, and fibrosis (decreased transforming growth factor-β1, fibronectin, and type IV collagen) in the diabetic rats. It also significantly prevented MAPK activation, which inhibited inflammation (reduced TNF-α, IL-6, and NF-κB expression) and apoptosis (increased expression of Bcl-2 and decreased Bax and caspase-3). Furthermore, histopathological examination demonstrated reduced inflammation, collagen deposition, and glomerulosclerosis in the renal tissue. In addition, all of these changes were comparable with those produced by ramipril. Hence, apigenin ameliorated renal damage due to DN by suppressing oxidative stress and fibrosis and by inhibiting MAPK pathway.

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Angiotensin-(1–7) attenuates diabetic nephropathy in Zucker diabetic fatty rats

AJP Renal Physiology ◽

10.1152/ajprenal.00063.2012 ◽

2012 ◽

Vol 302 (12) ◽

pp. F1606-F1615 ◽

Cited By ~ 57

Author(s):

Jorge F. Giani ◽

Valeria Burghi ◽

Luciana C. Veiras ◽

Analía Tomat ◽

Marina C. Muñoz ◽

...

Keyword(s):

Oxidative Stress ◽

Type 2 Diabetes ◽

Diabetic Nephropathy ◽

Renal Fibrosis ◽

Hypoxia Inducible Factor ◽

Thiobarbituric Acid ◽

Zucker Rats ◽

Tnf Α ◽

Zucker Diabetic Fatty Rats

Angiotensin (ANG)-(1–7) is known to attenuate diabetic nephropathy; however, its role in the modulation of renal inflammation and oxidative stress in type 2 diabetes is poorly understood. Thus in the present study we evaluated the renal effects of a chronic ANG-(1–7) treatment in Zucker diabetic fatty rats (ZDF), an animal model of type 2 diabetes and nephropathy. Sixteen-week-old male ZDF and their respective controls [lean Zucker rats (LZR)] were used for this study. The protocol involved three groups: 1) LZR + saline, 2) ZDF + saline, and 3) ZDF + ANG-(1–7). For 2 wk, animals were implanted with subcutaneous osmotic pumps that delivered either saline or ANG-(1–7) (100 ng·kg−1·min−1) ( n = 4). Renal fibrosis and tissue parameters of oxidative stress were determined. Also, renal levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), ED-1, hypoxia-inducible factor-1α (HIF-1α), and neutrophil gelatinase-associated lipocalin (NGAL) were determined by immunohistochemistry and immunoblotting. ANG-(1–7) induced a reduction in triglyceridemia, proteinuria, and systolic blood pressure (SBP) together with a restoration of creatinine clearance in ZDF. Additionally, ANG-(1–7) reduced renal fibrosis, decreased thiobarbituric acid-reactive substances, and restored the activity of both renal superoxide dismutase and catalase in ZDF. This attenuation of renal oxidative stress proceeded with decreased renal immunostaining of IL-6, TNF-α, ED-1, HIF-1α, and NGAL to values similar to those displayed by LZR. Angiotensin-converting enzyme type 2 (ACE2) and ANG II levels remained unchanged after treatment with ANG-(1–7). Chronic ANG-(1–7) treatment exerts a renoprotective effect in ZDF associated with a reduction of SBP, oxidative stress, and inflammatory markers. Thus ANG-(1–7) emerges as a novel target for treatment of diabetic nephropathy.

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Si Miao San Attenuates Inflammation and Oxidative Stress in Rats with CIA via the Modulation of the Nrf2/ARE/PTEN Pathway

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2021/2843623 ◽

2021 ◽

Vol 2021 ◽

pp. 1-11

Author(s):

Pan Shen ◽

Yao Huang ◽

Xin Ba ◽

Weiji Lin ◽

Kai Qin ◽

...

Keyword(s):

Oxidative Stress ◽

High Dose ◽

Collagen Induced Arthritis ◽

Rat Serum ◽

Oxidative Stress Parameters ◽

Tnf Α ◽

Cox 2 ◽

Synovial Tissues ◽

Stress Damage ◽

And Oxidative Stress

Objective. Si Miao San (SMS) is a traditional Chinese formula used in China to treat rheumatic diseases. To date, its mechanism in rheumatoid arthritis (RA) treatment is uncertain. Our study aims to assess the antiarthritic effects of SMS in experimental arthritic rats. Materials and Methods. SMS (8.63, 4.31, and 2.16 g/kg/day) was orally administered after the first immunization from day 14 to day 53. The effects of SMS on rats with collagen-induced arthritis (CIA) were evaluated by arthritis score and histological assessment. The levels of cytokines and anti-CII antibodies in rat serum were measured by ELISAs. The expression of oxidative stress parameters was detected by biochemical assay kits. The levels of Nrf2, HO-1, NQO1, and PTEN were determined by western blotting. Results. Medium- and high-dose SMS treatment significantly decreased arthritis scores and alleviated ankle joint histopathology in the rats with CIA. It inhibited the production of IL-6, TNF-α, COX-2, and PGE2 in rat serum. SMS also suppressed the expression of anti-CII antibodies IgG1 and IgG2a. Moreover, SMS significantly suppressed the levels of MDA and MPO in the synovial tissues while increasing the levels of SOD and CAT in the rats with CIA. The levels of Nrf2, HO-1, NQO1, and PTEN were upregulated by SMS in rat synovial tissues. Conclusions. This study demonstrated that SMS effectively alleviated the disease progression of CIA by decreasing the levels of proinflammatory cytokines and reducing oxidative stress damage, as indicated by IL-6, TNF-α, COX-2, and PGE2 levels; inhibiting the overproduction of MDA and MPO; and enhancing antioxidant enzymes by upregulating the Nrf2/ARE/PTEN signalling pathway.

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Involvement of Rho-kinase/IκB-α/NF-κB activation in IL-1β-induced inflammatory response and oxidative stress in human chondrocytes

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2020-0305 ◽

2021 ◽

pp. 1-9

Author(s):

Rukiye Nalan Tiftik ◽

Meryem Temiz-Reşitoğlu ◽

Demet Sinem Güden ◽

Gülsen Bayrak ◽

İsmail Ün ◽

...

Keyword(s):

Oxidative Stress ◽

Inflammatory Response ◽

Nadph Oxidase ◽

Rho Kinase ◽

Human Chondrocytes ◽

Rock Inhibitor ◽

Pathway Activation ◽

Tnf Α ◽

Cox 2 ◽

And Oxidative Stress

It has been clearly indicated that osteoarthritis (OA) is an inflammatory and degenerative disease that could be promoted by Rho-kinase (ROCK); however, little is known about the role of ROCK/inhibitor κB alpha (IκB-α)/nuclear factor-κB (NF-κB) p65 pathway activation in interleukin-1β (IL-1β) induced inflammatory response and oxidative stress in primary human chondrocytes. To test this hypothesis, we focused on determining ROCK-II, IκB-α, p-IκB-α, NF-κB p65, p-NF-κB p65, IL-6, tumor necrosis factor alpha (TNF-α), cyclooxygenase-2 (COX-2), p22phox, and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subtype 4 (NOX4) protein expression, ROCK-II activity, NADPH oxidase levels, and total antioxidant capacity (TAC) in the presence and absence of ROCK-inhibitor fasudil. IL-1β (2 ng·mL–1, 24 h) increased the expression of ROCK-II, p-IκB-α, NF-κB p65, p-NF-κB p65, IL-6, TNF-α, COX-2, and p22phox proteins, and decreased the expression of IκB-α, and the NOX4 protein level did not alter. ROCK activity and NADPH oxidase levels were increased, whereas the TAC was decreased by IL-1β. Fasudil (10−5–10−7 M) reversed all these changes induced by IL-1β. These results demonstrate that ROCK/IκB-α/NF-κB p65 pathway activation contributes to the IL-1β-induced inflammatory response and oxidative stress, and thus, ROCK inhibition might be a beneficial treatment option for OA patients mainly based on its anti-inflammatory and antioxidant effects.

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Formononetin Upregulates Nrf2/HO-1 Signaling and Prevents Oxidative Stress, Inflammation, and Kidney Injury in Methotrexate-Induced Rats

Antioxidants ◽

10.3390/antiox8100430 ◽

2019 ◽

Vol 8 (10) ◽

pp. 430 ◽

Cited By ~ 9

Author(s):

Saleem H. Aladaileh ◽

Omnia E. Hussein ◽

Mohammad H. Abukhalil ◽

Sultan A. M. Saghir ◽

May Bin-Jumah ◽

...

Keyword(s):

Oxidative Stress ◽

Tissue Injury ◽

Kidney Injury ◽

Renal Tissue ◽

Antioxidant Defenses ◽

Heme Oxygenase 1 ◽

Caspase 9 ◽

Tnf Α ◽

Cox 2 ◽

Kidney Injury Molecule 1

Acute kidney injury (AKI) is a serious complication of methotrexate (MTX). This study explored the protective effect of the isoflavone formononetin (FN) against MTX nephrotoxicity with an emphasis on oxidative stress, inflammation, and nuclear factor (erythroid-derived 2)-like 2/heme oxygenase 1 (Nrf2/HO-1) signaling. Rats received FN (10, 20, and 40 mg/kg) for 10 days and a single dose of MTX on day 7. MTX induced kidney injury was characterized by increased serum creatinine and urea, kidney injury molecule-1 (Kim-1), and several histological alterations. FN ameliorated kidney function and inhibited the renal tissue injury induced by MTX. Reactive oxygen species (ROS), lipid peroxidation (LPO), nitric oxide, and 8-Oxo-2′-deoxyguanosine were increased, whereas antioxidant defenses were diminished in the kidney of MTX-administered rats. In addition, MTX upregulated renal iNOS, COX-2, TNF-α, IL-1β, Bax, caspase-9, and caspase-3, and decreased Bcl-2, Nrf2, and HO-1. FN suppressed oxidative stress, LPO, DNA damage, iNOS, COX-2, proinflammatory cytokines, and apoptosis, and boosted Bcl-2, antioxidants, and Nrf2/HO-1 signaling in MTX-administered rats. In conclusion, FN prevents MTX-induced AKI by activating Nrf2/HO-1 signaling and attenuates oxidative damage and inflammation. Thus, FN may represent an effective adjuvant that can prevent MTX nephrotoxicity, pending further mechanistic studies.

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