scholarly journals The protective effect of trimetazidine against cisplatin-induced nephrotoxicity in rats

2016 ◽  
Vol 94 (7) ◽  
pp. 745-751 ◽  
Author(s):  
Nagla A. El-Sherbeeny ◽  
Ghalia M. Attia
Keyword(s):  
Oxidative Stress ◽  
Dna Binding ◽  
Protective Effect ◽  
Kidney Function ◽  
Structural Changes ◽  
Binding Activity ◽  
Significant Deterioration ◽  
Necrosis Factor Alpha ◽  
Dna Binding Activity ◽  
Tnf Α

Nephrotoxicity is a dose-limiting side effect of cisplatin (CSP). The study investigated the possible protective role of trimetazidine (TMZ) against CSP-induced nephrotoxicity in rats. Rats were divided into four groups; control, TMZ, CSP, and CSP + TMZ. The CSP group showed significant deterioration in kidney function with structural changes in the form of interstitial hemorrhage, glomeruli shrinkage and peritublar capillary congestion, tubular cells vacuolation, pyknosis, shedding and necrosis, and inflammatory cell infiltrates, all indicating renal damage. CSP also caused a significant increase in the lipid peroxidation marker malondialdehyde (MDA) levels, renal nuclear factor kappa B (NF-κB) DNA-binding activity and protein expression, and tumor necrosis factor alpha (TNF-α) and IL-6 levels. Treatment with TMZ before and after CSP injection produced significant improvement of kidney function and histopathology. TMZ treatment also significantly attenuated CSP-induced oxidative stress and suppressed elevated levels of TNF-α and IL-6 and NF-κB expression and its DNA-binding activity caused by CSP administration. TMZ has a protective effect against CSP-induced nephrotoxicity mediated by reduction of oxidative stress and attenuation of CSP-induced inflammation.

Dapagliflozin protects H9c2 cells against injury induced by lipopolysaccharide via suppression of CX3CL1/CX3CR1 axis and NF-κB activity

2021 ◽  
Vol 14 ◽  
Author(s):  
Yousef Faridvand ◽  
Maryam Nemati ◽  
Elham Zamani-Gharehchamani ◽  
Hamid Reza Nejabati ◽  
Arezoo Rezaie Nezhad Zamani ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Viability ◽  
Sglt2 Inhibitor ◽  
Binding Activity ◽  
Control Group ◽  
H9c2 Cell ◽  
H9c2 Cells ◽  
Dna Binding Activity ◽  
Inflammatory Conditions ◽  
Tnf Α

Background: Dapagliflozin, a selective Sodium-glucose cotransporter-2 (SGLT2) inhibitor, has been shown to play a key role in the control and management of the metabolic and cardiac disease. Objective: The current study aims to address the effects of dapagliflozin on the expression of fractalkine (FKN), known as CX3CL1, and its receptors CX3CR1, Nuclear factor-kappa B(NF-κB) p65 activity, Reactive oxygen species (ROS), and inflammation in LPS-treated H9c2 cell line. Methods: H9c2 cells were cultured with lipopolysaccharide (LPS) to establish a model of LPS-induced damage and then subsequently were treated with dapagliflozin for 72 h. Our work included measurement of cell viability (MTT), Malondialdehyde (MDA), intracellular ROS, tumor necrosis factor-α (TNF-α), NF-κB activity, and expression CX3CL1/CX3CR1. Results: The results showed that LPS-induced reduction of cell viability was successfully rescued by dapagliflozin treatment. The cellular levels of MDA, ROS, and TNF-α, as an indication of cellular oxidative stress and inflammation, were significantly elevated in H9c2 cells compared to the control group. Furthermore, dapagliflozin ameliorated inflammation and oxidative stress through the modulation of the levels of MDA, TNF-α, and ROS. Correspondingly, dapagliflozin reduced the expression of CX3CL1/CX3CR1, NF-κB p65 DNA binding activity and it also attenuated nuclear acetylated NF-κB p65 in LPS-induced injury in H9c2 cells compared to untreated cells. Conclusion: These findings shed light on the novel pharmacological potential of dapagliflozin in the alleviation of LPS-induced CX3CL1/CX3CR1-mediated injury in inflammatory conditions such as sepsis-induced cardiomyopathy.

Repressor Activity of SqrR, a Master Regulator of Persulfide-Responsive Genes, Is Regulated by Heme Coordination

2020 ◽  
Author(s):  
Takayuki Shimizu ◽  
Yuuki Hayashi ◽  
Munehito Arai ◽  
Shawn E McGlynn ◽  
Tatsuru Masuda ◽  
...  
Keyword(s):  
Dna Binding ◽  
Transcriptional Repression ◽  
Structural Changes ◽  
Gene Promoter ◽  
Binding Activity ◽  
Heme Binding ◽  
Master Regulator ◽  
Incremental Change ◽  
Dna Binding Activity

Abstract Reactive sulfur species (RSS) are involved in bioactive regulation via persulfidation of proteins. However, how cells regulate RSS-based signaling and RSS metabolism is poorly understood, despite the importance of universal regulation systems in biology. We previously showed that the persulfide-responsive transcriptional factor SqrR acts as a master regulator of sulfide-dependent photosynthesis in proteobacteria. Here, we demonstrated that SqrR also binds heme at a near one-to-one ratio with a binding constant similar to other heme-binding proteins. Heme does not change the DNA-binding pattern of SqrR to the target gene promoter region; however, DNA-binding affinity of SqrR is reduced by the binding of heme, altering its regulatory activity. Circular dichroism spectroscopy clearly showed secondary structural changes in SqrR by the heme binding. Incremental change in the intracellular heme concentration is associated with small, but significant reduction in the transcriptional repression by SqrR. Overall, these results indicate that SqrR has an ability to bind heme to modulate its DNA-binding activity, which may be important for the precise regulation of RSS metabolism in vivo.

Calorie restriction attenuates inflammatory responses to myocardial ischemia-reperfusion injury

2001 ◽  
Vol 280 (5) ◽  
pp. H2094-H2102 ◽  
Author(s):  
B. Chandrasekar ◽  
J. F. Nelson ◽  
J. T. Colston ◽  
G. L. Freeman
Keyword(s):  
Oxidative Stress ◽  
Dna Binding ◽  
Antioxidant Enzyme ◽  
Calorie Restriction ◽  
Inflammatory Responses ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Binding Activity ◽  
Dna Binding Activity ◽  
Myocardial Oxidative Stress

The life-prolonging effects of calorie restriction (CR) may be due to reduced damage from cumulative oxidative stress. Our goal was to determine the long-term effects of moderate dietary CR on the myocardial response to reperfusion after a single episode of sublethal ischemia. Male Fisher 344 rats were fed either an ad libitum (AL) or CR (40% less calories) diet. At age 12 mo the animals were anaesthetized and subjected to thoracotomy and a 15-min left-anterior descending coronary artery occlusion. The hearts were reperfused for various periods. GSH and GSSG levels, nuclear factor-κB (NF-κB) DNA binding activity, cytokine, and antioxidant enzyme expression were assessed in the ischemic zones. Sham-operated animals served as controls. Compared with the AL diet, chronic CR limited oxidative stress as seen by rapid recovery in GSH levels in previously ischemic myocardium. CR reduced DNA binding activity of NF-κB. The κB-responsive cytokines interleukin-1β and tumor necrosis factor-α were transiently expressed in the CR group but persisted longer in the AL group. Furthermore, expression of manganese superoxide dismutase, a key antioxidant enzyme, was significantly delayed in the AL group. Collectively these data indicate that CR significantly attenuates myocardial oxidative stress and the postischemic inflammatory response.

Effects of chronic ethanol consumption on cytokine regulation of liver regeneration

1998 ◽  
Vol 275 (4) ◽  
pp. G696-G704 ◽  
Author(s):  
Shi Qi Yang ◽  
Hui Zhi Lin ◽  
Ming Yin ◽  
Jeffrey H. Albrecht ◽  
Anna Mae Diehl
Keyword(s):  
Dna Binding ◽  
Liver Regeneration ◽  
Binding Activity ◽  
Chronic Ethanol ◽  
Cyclin D3 ◽  
Hepatocyte Proliferation ◽  
Ethanol Ingestion ◽  
Dna Binding Activity ◽  
Chronic Ethanol Consumption ◽  
Tnf Α

Ethanol ingestion may interrupt the proregenerative signal transduction that is initiated by injury-related cytokines such as tumor necrosis factor (TNF)-α and TNF-α- inducible cytokines including interleukin (IL)-6. To test this theory, liver regeneration, TNF-α and IL-6 expression, and cytokine-regulated prereplicative events were compared in ethanol-fed rats and isocalorically fed controls after 70% partial hepatectomy (PH). Ethanol feeding inhibits hepatocyte replication and recovery of liver mass after PH but generally promotes induction of both cytokines in the liver and extrahepatic tissues (i.e., white adipose tissue). Cytokine-regulated events that occur early in the prereplicative period are influenced differentially. TNF-α-dependent increases in hepatic nuclear factor-κB (NF-κB) p50 and p65 expression and DNA binding activity are prevented, whereas IL-6-dependent inductions of hepatic Stat-3 phosphorylation and DNA binding activity occur normally. In contrast, events (e.g., induction of cyclin D1, cdk-1, cyclin D3, and p53 mRNA) that occur at the end of the prereplicative period are uniformly inhibited. These findings indicate that chronic ethanol ingestion arrests the regenerative process during the prereplicative period and demonstrate that increased TNF-α, IL-6 and Stat-3 are not sufficient to assure hepatocyte proliferation after PH.

scholarly journals Accumulation of manganese superoxide dismutase under metal-depleted conditions: proposed role for zinc ions in cellular redox balance

2004 ◽  
Vol 377 (1) ◽  
pp. 241-248 ◽  
Author(s):  
Kaoru OTSU ◽  
Yoshitaka IKEDA ◽  
Junichi FUJII
Keyword(s):  
Oxidative Stress ◽  
Superoxide Dismutase ◽  
Dna Binding ◽  
Manganese Superoxide Dismutase ◽  
Binding Activity ◽  
Rat Liver Mitochondria ◽  
Zinc Ions ◽  
Dna Binding Activity ◽  
Manganese Superoxide ◽  
In Cells

A diet low in copper results in increased levels of MnSOD (manganese superoxide dismutase), a critical antioxidative enzyme conferring protection against oxidative stress, in rat liver mitochondria. The mechanism for this was investigated using cultured HepG2 cells, a human hepatocellular carcinoma-derived line. MnSOD activity increased 5–7-fold during incubation in a medium supplemented with metal-depleted fetal bovine serum, with a corresponding elevation of its mRNA levels. Metal depletion also decreased CuZnSOD and glutathione peroxidase levels to approx. 70–80% of baseline. When zinc ions were added to the medium at micromolar levels, MnSOD accumulation was suppressed; however, copper ions had essentially no effect on MnSOD expression. Since the intracellular redox status was shifted to a more oxidized state by metal depletion, we examined the DNA-binding activity of NF-κB (nuclear factor-κB), an oxidative stress-sensitive transactivating factor that plays a primary role in MnSOD induction. A gel shift assay indicated that the DNA-binding activity of NF-κB was increased in cells maintained in metal-depleted culture, suggesting the involvement of the transactivating function of NF-κB in this induction. This was further supported by the observation that curcumin suppressed both the DNA-binding activity of NF-κB and the induction of MnSOD mRNA in cells cultivated under metal-depleted conditions. These results suggest that the level of zinc, rather than copper, is a critical regulatory factor in MnSOD expression. It is possible that a deficiency of zinc in the low-copper diet may be primarily involved in MnSOD induction.

scholarly journals Lanthanum Chloride Inhibits LPS Mediated Expressions of Pro-Inflammatory Cytokines and Adhesion Molecules in HUVECs: Involvement of NF-κB-Jmjd3 Signaling

2017 ◽  
Vol 42 (5) ◽  
pp. 1713-1724 ◽  
Author(s):  
Xia Chen ◽  
Min Xiu ◽  
Juanjuan Xing ◽  
Shaoqing Yu ◽  
Dinghong Min ◽  
...  
Keyword(s):  
Dna Binding ◽  
Inflammatory Cytokines ◽  
Adhesion Molecule ◽  
Inflammatory Cytokine ◽  
Nuclear Translocation ◽  
Binding Activity ◽  
Promoter Regions ◽  
Dna Binding Activity ◽  
Tnf Α ◽  
Pro Inflammatory Cytokines

Background/Aims: To investigate the regulation of LaCl3 on lipopolysaccharides (LPS)-induced pro-inflammatory cytokines and adhesion molecules in human umbilical vein endothelial cells (HUVECs). Methods: Primary cultured HUVECs were pretreated with 2.5 µM LaCl3 for 30 min followed by 1 µg/ml LPS for 2 h. Pro-inflammatory cytokine and adhesion molecule expressions were determined by real-time RT-PCR and ELISA. NF-κB/p65 nuclear translocation was examined by immunofluorescence and immuno-blot, and its DNA-binding activity was measured by chemiluminescence. Recruitment of NF-κB/p65, Jmjd3, and H3K27me3 to gene promoter regions was determined by ChIP-qPCR. Results: LaCl3 exhibited no cytotoxic effects to primary HUVECs at concentrations ≤ 50 µM. LPS-mediated TNF-α, IL-1β, IL-6, MMP-9, and ICAM-1 production, nuclear translocation, and DNA-binding activity of NF-κB/p65, as well as Jmjd3 expression, were all reduced significantly by LaCl3. Furthermore, LaCl3 treatment significantly impaired LPS-induced enrichment of NF-κB/p65 to the promoter regions of TNF-α, MMP-9, IL-1β, ICAM-1, and IL-6; and of Jmjd3 to the promoter regions of TNF-α, MMP-9, IL-1β, and IL-6. H3K27me3 abundance in the promoter regions of TNF-α and ICAM-1 increased significantly in following LaCl3 treatment. Conclusion: LaCl3 inhibits pro-inflammatory cytokine and adhesion molecule expressions induced by LPS in HUVECs. NF-κB and histone demethylase Jmjd3 are involved in this effect.

Fas-associated death-domain protein inhibits TNF-α mediated NF-κB activation in cardiomyocytes

2005 ◽  
Vol 289 (5) ◽  
pp. H2073-H2080 ◽  
Author(s):  
Wei Chao ◽  
Yan Shen ◽  
Ling Li ◽  
Huailong Zhao ◽  
Steffen E. Meiler ◽  
...  
Keyword(s):  
Gene Transfer ◽  
Dna Binding ◽  
Nuclear Translocation ◽  
Binding Activity ◽  
Death Domain ◽  
Dna Binding Activity ◽  
Iκb Kinase ◽  
Tnf Α ◽  
Domain Protein

Fas-associated death-domain protein (FADD) is an adaptor molecule that links death receptors to caspase-8 in many cell types including cardiomyocytes (CMs). Although FADD has previously been reported to play an important role in CM apoptosis, the effect of FADD on CM NF-κB signaling, which is a proinflammatory pathway, has not been delineated. To investigate the role of FADD in CM NF-κB activation, we utilized adenoviral gene transfer of wild-type FADD and a truncation mutant that lacks the death-effector domain (FADD-DED) in rat CMs in vitro TNF-α activated NF-κB in CMs as demonstrated by phosphorylation and degradation of inhibitory-κB (IκB)-α-enhanced nuclear p65 and NF-κB DNA-binding activity as well as increased mRNA for the NF-κB-dependent adhesion molecule VCAM-1 (19 ± 4.1-fold) as measured by quantitative RT-PCR. Gene transfer of FADD inhibited TNF-α-induced IκB-α phosphorylation, decreased p65 nuclear translocation and NF-κB DNA-binding activity, and reduced VCAM-1 transcript levels by 53–65%. Interestingly, FADD-DED exhibited a similar but weaker inhibitory effect on NF-κB activation. The effects of FADD on NF-κB were cell-type specific. FADD expression also inhibited TNF-α-mediated NF-κB activation in human endothelial cells but not in rat pulmonary artery smooth muscle cells. In contrast, FADD expression actually activated NF-κB in human embryonic kidney (HEK)-293 cells. In CMs, FADD inhibited NF-κB activation as well as phosphorylation of IκB-α and IκB kinase (IKK)-β in response to cytokine stimulation or expression of the upstream kinases NF-κB-inducing kinase and IKK-β. These data demonstrate that FADD inhibits NF-κB activation in CMs, and this inhibition likely occurs at the level of phosphorylation and activation of IKK-β.

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