scholarly journals Anti-inflammatory and anti-apoptotic effects of N-acetylcysteine in diabetic rat corneal epithelium

2021 ◽  
Vol 14 (12) ◽  
pp. 1805-1812
Author(s):  
Sae-Byeok Hwang ◽  
◽  
Ji-Yun Park ◽  
Soon-Suk Kang ◽  
Ho Seok Chung ◽  
...  
Keyword(s):  
Corneal Epithelium ◽  
High Glucose ◽  
Annexin V ◽  
Diabetic Rats ◽  
Diabetic Rat ◽  
Apoptotic Cells ◽  
Glucose Medium ◽  
Tnf Α ◽  
Anti Inflammatory ◽  
Apoptotic Effects

AIM: To characterize the anti-inflammatory and anti-apoptotic effects of N-acetylcysteine (NAC) in streptozotocin (STZ)-induced diabetic rat corneal epithelium and human corneal epithelial cells (HCECs) exposed to a high-glucose environment. METHODS: HCECs were incubated in 0, 5, 50 mmol/L glucose medium, or 50 mmol/L glucose medium with NAC for 24h. Diabetes was induced in rats by intraperitoneal injection of 65 mg/kg STZ and some of these rats were topically administered NAC to corneas with 3 mice per group. We characterized receptor for advanced glycation end-products (RAGE) expression using immunofluorescence, and interleukin (IL)-1β and cleaved caspase-3 (CCAP-3) expression using immunohistochemistry. Circulating tumor necrosis factor (TNF)-α concentration was measured by ELISA and cleaved poly-ADP ribose polymerase (PARP) concentration was quantified by Western blotting. Apoptotic cells were detected using TUNEL assay and annexin V and propidium iodide staining. RESULTS: Diabetic rats had higher expression of RAGE (2.46±0.13 fold), IL-1β, and CCAP-3 in apoptotic cells of their corneas than control rats. The expression of RAGE (1.83±0.11 fold), IL-1β, and CCAP-3, and the number of apoptotic cells, were reduced by topical NAC treatment. HCECs incubated in 50 mmol/L glucose medium showed high concentrations of TNF-α (310±2.00 pg/mL) and cleaved PARP (7.43±0.56 fold), and more extensive apoptosis than cells in 50 mmol/L glucose medium. However, the addition of NAC reduced the concentrations of TNF-α (153.67±2.31 pg/mL) and cleaved PARP (5.55±0.31 fold) and the number of apoptotic cells. CONCLUSION: NAC inhibits inflammation and apoptosis in the corneas of diabetic rats and HCECs maintained in a high-glucose environment.

scholarly journals Inflammatory M1-like macrophages polarized by NK-4 undergo enhanced phenotypic switching to an anti-inflammatory M2-like phenotype upon co-culture with apoptotic cells

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Keizo Kohno ◽  
Satomi Koya-Miyata ◽  
Akira Harashima ◽  
Takahiko Tsukuda ◽  
Masataka Katakami ◽  
...  
Keyword(s):  
Wound Healing ◽  
Chronic Wounds ◽  
Macrophage Polarization ◽  
Phenotypic Switching ◽  
Apoptotic Cells ◽  
Phenotypic Switch ◽  
Inflammatory Phase ◽  
M1 Macrophage ◽  
Tnf Α ◽  
Anti Inflammatory

Abstract Background NK-4 has been used to promote wound healing since the early-1950s; however, the mechanism of action of NK-4 is unknown. In this study, we examined whether NK-4 exerts a regulatory effect on macrophages, which play multiple roles during wound healing from the initial inflammatory phase until the tissue regeneration phase. Results NK-4 treatment of THP-1 macrophages induced morphological features characteristic of classically-activated M1 macrophages, an inflammatory cytokine profile, and increased expression of the M1 macrophage-associated molecules CD38 and CD86. Interestingly, NK-4 augmented TNF-α production by THP-1 macrophages in combination with LPS, Pam3CSK4, or poly(I:C). Furthermore, NK-4 treatment enhanced THP-1 macrophage phagocytosis of latex beads. These results indicate that NK-4 drives macrophage polarization toward an inflammatory M1-like phenotype with increased phagocytic activity. Efferocytosis is a crucial event for resolution of the inflammatory phase in wound healing. NK-4-treated THP-1 macrophages co-cultured with apoptotic Jurkat E6.1 (Apo-J) cells switched from an M1-like phenotype to an M2-like phenotype, as seen in the inverted ratio of TNF-α to IL-10 produced in response to LPS. We identified two separate mechanisms that are involved in this phenotypic switch. First, recognition of phosphatidylserine molecules on Apo-J cells by THP-1 macrophages downregulates TNF-α production. Second, phagocytosis of Apo-J cells by THP-1 macrophages and activation of PI3K/Akt signaling pathway upregulates IL-10 production. Conclusion It is postulated that the phenotypic switch from a proinflammatory M1-like phenotype to an anti-inflammatory M2-like phenotype is dysregulated due to impaired efferocytosis of apoptotic neutrophils at the wound site. Our results demonstrate that NK-4 improves phagocytosis of apoptotic cells, suggesting its potential as a therapeutic strategy to resolve sustained inflammation in chronic wounds.

Anti-TNF-α Therapy Exerts Intestinal Anti-inflammatory and Anti-Apoptotic Effects After Massive Bowel Resection in a Rat

2020 ◽  
Vol Publish Ahead of Print ◽  
Author(s):  
Igor Sukhotnik ◽  
Yoav Ben-Shahar ◽  
Yulia Pollak ◽  
Shlomi Cohen ◽  
Anat Guz-Mark ◽  
...  
Keyword(s):  
Bowel Resection ◽  
Tnf Α ◽  
Anti Inflammatory ◽  
Apoptotic Effects ◽  
Massive Bowel Resection

scholarly journals Calcium Sensing Receptor Regulating Smooth Muscle Cells Proliferation Through Initiating Cystathionine-Gamma-Lyase/Hydrogen Sulfide Pathway in Diabetic Rat

2015 ◽  
Vol 35 (4) ◽  
pp. 1582-1598 ◽  
Author(s):  
Xin Zhong ◽  
Yuwen Wang ◽  
Jichao Wu ◽  
Aili Sun ◽  
Fan Yang ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Hydrogen Sulfide ◽  
Smooth Muscle Cells ◽  
Cyclin D1 ◽  
Western Blotting ◽  
High Glucose ◽  
Diabetic Rats ◽  
Diabetic Rat ◽  
Calcium Sensing Receptor ◽  
Calcium Sensing

Aims: Hydrogen sulfide (H2S) inhibits the proliferation of vascular smooth muscle cells (VSMCs). However, how cystathionine-gamma-lyase (CSE), a major enzyme that produces H2S, is regulated remains unknown. Whether calcium-sensing receptor (CaSR) inhibits the proliferation of VSMCs by regulating the endogenous CSE/H2S pathway in diabetic rat has not been previously investigated. Methods and Results: The morphological and ultrastructure alterations were tested by transmission electron microscopy, changes in the H2S concentration and the relaxation of the mesenteric secondary artery loop of diabetic rats were determined by Multiskan spectrum microplate spectrophotometer and isometric force transducer. Additionally, the expression levels of CaSR, CSE and Cyclin D1 in the mesenteric arteries of rats were examined by western blotting. The intracellular calcium concentration, the expression of p-CaMK II (phospho-calmodulin kinases II), CSE activity, the concentration of endogenous H2S and the proliferation of cultured VSMCs from rat thoracic aortas were measured by using confocal microscope, western blotting, microplate spectrophotometer, MTT and BrdU, respectively. The VSMC layer thickened, the H2S concentration dropped, the relaxation of the mesenteric secondary artery rings weakened, and the expression of CaSR and CSE decreased whereas the expression of Cyclin D1 increased in diabetic rats compared with the control group. The [Ca2+]i of VSMCs increased upon treatment with CaSR agonists (10 µM Calindol and 2.5 mM CaCl2), while it decreased upon administration of calhex231, U73122 and 2-APB. The expression of p-CaMK II and CSE increased upon treatment with CaSR agonists in VSMCs. CSE activity and the endogenous H2S concentration decreased in response to high glucose, while it increased with treatment of CaSR agonists. The proliferation rate increased in response to high glucose, and CaSR agonists or NaHS significantly reversed the proliferation of VSMCs caused by high glucose. Conclusions: Our results demonstrated that CaSR regulated the endogenous CSE/H2S pathway to inhibit the proliferation of VSMCs in both diabetic and high glucose models.

scholarly journals Mfn2 Regulates High Glucose-Induced MAMs Dysfunction and Apoptosis in Podocytes via PERK Pathway

2021 ◽  
Vol 9 ◽  
Author(s):  
Yun Cao ◽  
Zhaowei Chen ◽  
Jijia Hu ◽  
Jun Feng ◽  
Zijing Zhu ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
High Glucose ◽  
Diabetic Rats ◽  
Mitochondrial Morphology ◽  
Podocyte Injury ◽  
Unfolded Protein ◽  
Mitochondrial Functions ◽  
Protein Response ◽  
Apoptotic Effects

The endoplasmic reticulum (ER) stress and mitochondrial dysfunction in high glucose (HG)-induced podocyte injury have been demonstrated to the progression of diabetic kidney disease (DKD). However, the pathological mechanisms remain equivocal. Mitofusin2 (Mfn2) was initially identified as a dynamin-like protein involved in fusing the outer mitochondrial membrane (OMM). More recently, Mfn2 has been reported to be located at the ER membranes that contact OMM. Mitochondria-associated ER membranes (MAMs) is the intercellular membrane subdomain, which connects the mitochondria and ER through a proteinaceous tether. Here, we observed the suppression of Mfn2 expression in the glomeruli and glomerular podocytes of patients with DKD. Streptozotocin (STZ)-induced diabetic rats exhibited abnormal mitochondrial morphology and MAMs reduction in podocytes, accompanied by decreased expression of Mfn2 and activation of all three unfolded protein response (UPR) pathways (IRE1, ATF6, and PERK). The HG-induced mitochondrial dysfunction, MAMs reduction, and increased apoptosis in vitro were accompanied by the downregulation of Mfn2 and activation of the PERK pathway. Mfn2 physically interacts with PERK, and HG promotes a decrease in Mfn2-PERK interaction. In addition, Mfn2-silenced podocytes showed mitochondrial dysfunction, MAMs reduction, activation of PERK pathway, and increased apoptosis. Conversely, all these effects of HG stimulation were alleviated significantly by Mfn2 overexpression. Furthermore, the inhibition of PERK phosphorylation protected mitochondrial functions but did not affect the expression of Mfn2 in HG-treated podocytes. Therefore, this study confirmed that Mfn2 regulates the morphology and functions of MAMs and mitochondria, and exerts anti-apoptotic effects on podocytes by inhibiting the PERK pathway. Hence, the Mfn2-PERK signaling pathway may be a new therapeutic target for preventing podocyte injury in DKD.

scholarly journals IL-37 expression improves renal function after ischemia and reperfusion in mice model

2021 ◽  
Vol 9 (4) ◽  
pp. 207-224
Author(s):  
Paloma E Pinto ◽  
◽  
Aloisio M Requião-Moura
Keyword(s):  
Renal Failure ◽  
Inflammatory Response ◽  
Renal Ischemia ◽  
Mice Model ◽  
Leukocyte Accumulation ◽  
Tnf Α ◽  
Anti Inflammatory ◽  
Apoptotic Effects ◽  
Hematoxylin Eosin ◽  
Human Cytokine

Renal ischemia is a major problem in the world that lead to renal failure for which no effective treatment is available. Renal ischemia involves a robust inflammatory response, involving up-regulated chemokine expression and leukocyte accumulation, contributes to the mechanism of renal injury and renal failure. IL-37 is a new human cytokine and has an anti-inflammatory function. Currently, it is unknown whether IL-37 suppresses renal inflammatory response to ischemia. We tested the hypothesis that expression of human IL-37 in mouse protects the renal against ischemic injury through suppression of the renal inflammatory response. IL-37 Tg and WT mice were subjected to right renal nephrectomy to induce unilateral model of ischemia the microvascular clamp was positioned around the left renal pedicles. Serum sampling for measurements of TNF-α, IL-1β, Caspase3, MDA, HMGB1, urea and creatinine. Hematoxylin-eosin staining for histological analysis. The resulted data showed that IL-37 has anti-inflammatory effects in renal IRI as evidenced by significant reduction of the inflammatory markers levels TNF-α, IL-1β and HMGB1. IL-37 has potent antioxidant and anti-apoptotic effects with significant reduction in MDA and caspace-3 respectively

scholarly journals Antioxidant and Anti-Inflammatory Potential of Thymoquinone and Lycopene Mitigate the Chlorpyrifos-Induced Toxic Neuropathy

2021 ◽  
Vol 14 (9) ◽  
pp. 940
Author(s):  
Mohamed Aboubakr ◽  
Said M. Elshafae ◽  
Ehab Y. Abdelhiee ◽  
Sabreen E. Fadl ◽  
Ahmed Soliman ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Corn Oil ◽  
Organophosphate Pesticide ◽  
Toxic Neuropathy ◽  
Tnf Α ◽  
Anti Inflammatory ◽  
Factor Α ◽  
Apoptotic Effects ◽  
Oxidative State ◽  
Necrosis Factor

CPF (chlorpyrifos) is an organophosphate pesticide used in agricultural and veterinary applications. Our experiment aimed to explore the effects of thymoquinone (TQ) and/or lycopene (LP) against CPF-induced neurotoxicity. Wistar rats were categorized into seven groups: first group served as a control (corn oil only); second group, TQ (10 mg/kg); third group, LP (10 mg/kg); fourth group, CPF (10 mg/kg) and deemed as CPF toxic control; fifth group, TQ + CPF; sixth group, (LP + CPF); and seventh group, (TQ + LP + CPF). CPF intoxication inhibited acetylcholinesterase (AchE), decreased glutathione (GSH) content, and increased levels of malondialdehyde (MDA), an oxidative stress biomarker. Furthermore, CPF impaired the activity of antioxidant enzymes including superoxide dismutase (SOD) and catalase (CAT) along with enhancement of the level of inflammatory mediators such as tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-1β. CPF evoked apoptosis in brain tissue. TQ or LP treatment of CPF-intoxicated rats greatly improved AchE activity, oxidative state, inflammatory responses, and cell death. Co-administration of TQ and LP showed better restoration than their sole treatment. In conclusion, TQ or LP supplementation may alleviate CPF-induced neuronal injury, most likely due to TQ or LPs’ antioxidant, anti-inflammatory, and anti-apoptotic effects.

Cellular localisation of the kinin B1R in the pancreas of streptozotocin-treated rat and the anti-diabetic effect of the antagonist SSR240612

2016 ◽  
Vol 397 (4) ◽  
pp. 323-336 ◽  
Author(s):  
Nejla Tidjane ◽  
Louis Gaboury ◽  
Réjean Couture
Keyword(s):  
Immune Cells ◽  
Diabetic Rats ◽  
Diabetic Rat ◽  
Β Cells ◽  
Langerhans Islets ◽  
B1 Receptor ◽  
Cellular Localisation ◽  
Tnf Α ◽  
Kinin B1 Receptor ◽  
The Impact

Abstract The mechanism by which kinin B1 receptor (B1R) contributes to type 1 diabetes is addressed by determining the impact of its inhibition on diabetes and on its pancreatic expression and cellular localisation on immunocompetent cells and primary sensory C-fibres. Rats were made diabetic with streptozotocin (STZ). On day 4, they were treated daily for 7 days with a B1R antagonist (SSR240612, 10 mg/kg) or its vehicle. The surviving β-cells were measured by immunostaining. The expression of B1R, iNOS, TNF-α, macrophages, TCD4+, CGRP and TRPV1 was measured by Western blotting, qRT-PCR and immunofluorescence. Macrophages and TCD4+ lymphocytes were absent in control, but distributed abundantly in the pancreas of STZ-diabetic rats. B1R was upregulated on these immune cells infiltrating the diabetic rat pancreas while it was not expressed on primary sensory C-fibres even if the expression of TRPV1 and CGRP was enhanced. SSR240612 prevented the infiltration of macrophages and TCD4+ lymphocytes and the upregulation of B1R, iNOS, TNF-α and TRPV1. SSR240612 corrected hyperglycaemia and hypoinsulinaemia by improving the Langerhans islets survival or regeneration. It is concluded that kinin B1R antagonism exerts anti-diabetic action by preventing the infiltration of immune cells in the pancreas and by preserving the integrity of Langerhans islets β-cells.

scholarly journals Bitter Gourd Honey Ameliorates Hepatic and Renal Diabetic Complications on Type 2 Diabetes Rat Models by Antioxidant, Anti-Inflammatory, and Anti-Apoptotic Mechanisms

Foods ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 2872
Author(s):  
Chandra Sekhar Arigela ◽  
Giribabu Nelli ◽  
Siew Hua Gan ◽  
Kuttulebbai Nainamohamed Salam Sirajudeen ◽  
Kumarathevan Krishnan ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Diabetic Complications ◽  
Diabetic Rats ◽  
Male Rats ◽  
Bitter Gourd ◽  
Liver And Kidney ◽  
Streptozotocin Induced Diabetes ◽  
Treatment Of Diabetes ◽  
Anti Inflammatory ◽  
Apoptotic Effects

Honey has several pharmacological effects, including anti-diabetic activity. However, the effectiveness of bitter gourd honey (BGH) in the treatment of diabetes mellitus (DM) is unknown. The aim of this study was to determine the antioxidant, anti-inflammatory, and anti-apoptotic properties of BGH on the kidney and liver of a streptozotocin-induced diabetes rat model. Methods: A single dose (nicotinamide 110 mg/kg, streptozotocin (STZ) 55 mg/kg, intraperitoneal (i.p.)) was used to induce DM in male rats. For 28 days, normal or diabetic rats were administered 1 g/kg/day and 2 g/kg/day of BGH orally. After the treatment, blood, liver, and kidney samples were collected and analysed for biochemical, histological, and molecular parameters. In addition, liquid chromatography–mass spectrometry (LC-MS) was used to identify the major bioactive components in BGH. Results: The administration of BGH to diabetic rats resulted in significant reductions in alanine transaminase (ALT),aspartate aminotransferase (AST), creatinine, and urea levels. Diabetic rats treated with BGH showed lesser pathophysiological alterations in the liver and kidney as compared to non-treated control rats. BGH-treated diabetic rats exhibited reduced levels of oxidative stress (MDA levels), inflammatory (MYD88, NFKB, p-NFKB, IKKβ), and apoptotic (caspase-3) markers, as well as higher levels of antioxidant enzymes (SOD, CAT, and GPx) in the liver and kidney. BGH contains many bioactive compounds that may have antioxidative stress, anti-inflammatory, and anti-apoptotic effects. Conclusion: BGH protected the liver and kidney in diabetic rats by reducing oxidative stress, inflammation, and apoptosis-induced damage. As a result, BGH can be used as a potential therapy to ameliorate diabetic complications.

scholarly journals Adiponectin Modified BMSCs Alleviate Heart Fibrosis via Inhibition TGF-beta1/Smad in Diabetic Rats

2021 ◽  
Vol 9 ◽  
Author(s):  
Ke Meng ◽  
Huabo Cai ◽  
Simin Cai ◽  
Yucai Hong ◽  
Xiaoming Zhang
Keyword(s):  
Myocardial Fibrosis ◽  
High Glucose ◽  
Cardiac Fibrosis ◽  
Therapeutic Potential ◽  
Heart Diseases ◽  
Diabetic Rats ◽  
Diabetic Rat ◽  
H9c2 Cells

Background: Accumulating evidence suggested that bone marrow mesenchymal stem cells (BMSCs) have therapeutic potential for diabetes and heart diseases. However, the effects of BMSC on reducing myocardial fibrosis need to be optimized. This study aimed to investigate the mechanism of adiponectin (APN) modified BMSCs on myocardial fibrosis in diabetic model in vivo and in vitro.Methods: The high-fat diet combined with streptozotocin (STZ) injection were used to induced diabetic rat model. H9c2 cells were cultured under a high glucose medium as in vitro model. The BMSCs were modified by APN plasmid or APN small interfering RNA (siRNA), then transplanted to the diabetic rats by a single tail-vein injection, or co-cultured with H9c2 cells.Results: We demonstrated that diabetic rats showed typical diabetic symptoms, such as decreased cardiac function, accumulation of pathological lesions and collagen expression. However, these impairments were significantly prevented by the APN modified BMSCs treatment while no effects on APN siRNA modified BMSCs treated diabetic rats. Moreover, we confirmed that APN modified BMSCs could attenuate the expression of TGF-beta1/smad to suppress the myocardial fibrosis in the diabetic rats and high glucose induced H9c2 cells.Conclusion: The present results for the first time showed that APN modified BMSCs exerted protection on cardiac fibrosis via inhibiting TGF-beta1/smad signal pathway in diabetic rats. Our findings suggested that APN modified BMSCs might be a novel and optimal therapy for the diabetic cardiomyopathy in future.

Glucose stimulates O2 consumption, NOS, and Na/H exchange in diabetic rat proximal tubules

2002 ◽  
Vol 283 (2) ◽  
pp. F286-F293 ◽  
Author(s):  
Andrew Baines ◽  
Patrick Ho
Keyword(s):  
High Glucose ◽  
Glucose Concentration ◽  
Endothelial Nitric Oxide Synthase ◽  
Diabetic Rats ◽  
Proximal Tubules ◽  
Diabetic Rat ◽  
Uncontrolled Diabetes ◽  
Low Glucose ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

Endothelial nitric oxide synthase (NOS) and neuronal NOS protein increased in proximal tubules of acidotic diabetic rats 3–5 wk after streptozotocin injection. NOS activity (citrulline production) was similar in nondiabetic and diabetic tubules incubated with low glucose (5 mM glucose + 20 mM mannitol); but after 30 min with high glucose (25 mM), Ca-sensitive citrulline production had increased 23% in diabetic tubules. Glucose concentration did not influence citrulline production in nondiabetic tubules. High glucose increased carboxy-2-phenyl-4,4,5,5,-tetramethylimidazoline 1-oxyl-3-oxide (cpt10)-scavenged NO sevenfold in a suspension of diabetic tubules but did not alter NO in nondiabetic tubules. Diabetes increased ouabain-sensitive 86Rb uptake (141 ± 9 vs. 122 ± 6 nmol · min−1 · mg−1) and oligomycin-sensitive O2 consumption (Q˙o 2; 16.0 ± 1.7 vs. 11.3 ± 0.7 nmol · min−1 · mg−1). Ethylisopropyl amiloride-inhibitable Q˙o 2(6.5 ± 0.6 vs. 2.4 ± 0.3 nmol · min−1 · mg−1) accounted for increased oligomycin-sensitiveQ˙o 2 in diabetic tubules. N G-monomethyl-l-arginine methyl ester (l-NAME) inhibited most of the increase in86Rb uptake and Q˙o 2 in diabetic tubules. l-NAME had little effect on nondiabetic tubules. Inhibition of Q˙o 2 by ethylisopropyl amiloride and l-NAME was only 5–8% additive. Uncontrolled diabetes for 3–5 wk increases NOS protein in proximal tubules and makes NOS activity sensitive to glucose concentration. Under these conditions, NO stimulates Na-K-ATPase andQ˙o 2 in proximal tubules.

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