Oxymatrine protects against sepsis-induced myocardial injury via inhibition of the TNF-α/p38-MAPK/caspase-3 signaling pathway

Abstract 15-Lipoxygenase-2(15-LOX-2) is thought to regulate inflammation and immunological function however, its mechanisms of action are still unclear. Furthermore, it has been reported that salidroside has anti inflammatory properties , but its role in macrophage function has not been understood yet In this study, we aimed to determine how 15-LOX-2 expression level s affect the function of macrophages and the effect of salidroside on 15-LOX-2 deficient macrophages We used multiple functional genetic strategies to determine 15-LOX-2 function in macrophages. 15-LOX-2 deficiency promotes phagocytosis and proliferation of macrophages and impairs their apoptosis Mechanistically, t he expression levels of cyclophilinB (CypB) were upregulated in 15-LOX-2 deficient Ana 1 macrophages, whereas those of caspase 3 were down regulated. Furthermore, RNA-seq analysis showed that inflammation, complement, and TNF-α signaling pathway s were all activated in 15-LOX-2 deficient Ana 1 macrophages. Treatment of 15-LOX-2 deficient macrophages with salidroside, a natural product derived from Rhodiola species, effectively reversed the effects of 15-LOX-2 deficiency on caspase 3 and CypB levels, as well as on apoptosis and proliferation. In conclusion, our study shows that there is a newly identified link between 15-LOX-2 deficiency and salidroside in regulating macrophage survival, proliferation, and function. Salidroside may be a promising therapeutic strategy for treating inflammation related diseases resulting from 15-LOX-2 deficiency.

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Effects of Shugan-Jianpi Recipe on the Expression of the p38 MAPK/NF-κB Signaling Pathway in the Hepatocytes of NAFLD Rats

Medicines ◽

10.3390/medicines5030106 ◽

2018 ◽

Vol 5 (3) ◽

pp. 106 ◽

Cited By ~ 4

Author(s):

Yuanjun Deng ◽

Kairui Tang ◽

Runsen Chen ◽

Yajie Liu ◽

Huan Nie ◽

...

Keyword(s):

Signaling Pathway ◽

P38 Mapk ◽

Low Dose ◽

Serum Levels ◽

Inflammatory Factors ◽

Enzyme Linked Immunosorbent Assay ◽

High Dose ◽

Model Group ◽

Necrosis Factor Alpha ◽

Tnf Α

Background: In traditional Chinese medicine, the Shugan-Jianpi recipe is often used in the treatment of nonalcoholic fatty liver disease (NAFLD). This study aimed to explore the mechanism of the Shugan-Jianpi recipe in relation to rats with NAFLD induced by a high-fat diet. Methods: Rats were randomly divided into eight groups: normal group (NG), model group (MG), low-dose Chaihu–Shugan–San group (L-CG), high-dose Chaihu–Shugan–San group (H-CG), low-dose Shenling–Baizhu–San group (L-SG), high-dose Shenling–Baizhu–San group (H-SG), low dose of integrated-recipes group (L-IG), and high dose of integrated-recipes group (H-IG). After 26 weeks, a lipid profile, aspartate, and alanine aminotransferases in serum were detected. The serum levels of inflammatory factors including interleukin (IL)-1β, IL-6, and tumor necrosis factor-alpha (TNF-α) were analyzed using the enzyme linked immunosorbent assay (ELISA) method. Hepatic pathological changes were observed with hematoxylin-eosin (HE) and oil red O staining. The expression of the p38 mitogen-activated protein kinases (MAPK)/nuclear factor-κB (NF-κB) pathway was detected by quantitative real-time PCR and Western blotting. Results: A pathological section revealed that NAFLD rats have been successfully reproduced. Compared with the model group, each treatment group had different degrees of improvement. The Shugan-Jianpi recipe can inhibit the serum levels of IL-1β, IL-6, and TNF-α in NAFLD rats. The expression of mRNA and a protein related to the p38 MAPK/NF-κB signaling pathway were markedly decreased as a result of the Shugan-Jianpi recipe. Conclusions: The Shugan-Jianpi recipe could attenuate NAFLD progression, and its mechanism may be related to the suppression of the p38 MAPK/NF-κB signaling pathway in hepatocytes.

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Abstract 232: Role of Transient Receptor Potential Melastatin 2 in Cardiomyocyte Apoptosis Induced by TNF-α

Circulation Research ◽

10.1161/res.111.suppl_1.a232 ◽

2012 ◽

Vol 111 (suppl_1) ◽

Author(s):

Shuzhuang Li ◽

Xuan Liu ◽

Deqin Yu ◽

Chong Chen ◽

Xiaolong Chen

Keyword(s):

Myocardial Injury ◽

Caspase 3 ◽

Transient Receptor Potential ◽

Receptor Potential ◽

Cardiomyocyte Apoptosis ◽

Mechanical Trauma ◽

Causative Role ◽

Transient Receptor Potential Melastatin ◽

Tnf Α ◽

Transient Receptor

Mechanical trauma, such as that induced by motor vehicle crashes, represents a major medical and economic problem in the world. Identifying the mechanisms responsible for post-traumatic secondary myocardial injury is critical in order to reduce overall mortality and improve quality of life after trauma. We have previously demonstrated that mechanical trauma-induced overproduction of TNF-α plays a causative role in cardiomyocyte apoptosis via oxidative/nitrative stress. Transient receptor potential melastatin 2 (TRPM2) is a Ca 2+ permeable non-selective cation channel activated by oxidative stress, expressed in the cardiomyocytes. The present study attempted to identify whether TRPM2 is involved in TNF-α-induced cardiomyocyte apoptosis. Cardiomyocytes were isolated from adult male Sprague Dawley rats and cultured with TNF-α (10 ng/ml) for 12h. RT-PCR and semi-quantitative immunohistochemistry were used to quantify TRPM2 mRNA and protein levels respectively. Significant increases in TRPM2 mRNA and protein expression were observed in TNF-α-treated cardiomyocytes, suggesting that TRPM2 may contribute to TNF-α-induced cardiomyocyte apoptosis. To identify the effect of TRPM2 on TNF-α-induced cardiomyocyte apoptosis, cardiomyocytes were cultured with TNF-α or TNF-α + TRPM2 inhibitor (flufenamic acid (FFA) 100uM or clotrimazole 30uM), respectively. Exposure of cardiomyocytes to TNF-α for 12h induced significant apoptosis as determined by caspase-3 activation (1.7-fold increase vs. control, P < 0.01). In contrast, TNF-α-induced caspase-3 activity increases were significantly depressed by FFA and clotrimazole, respectively (P < 0.05). To further confirm the effect of TRPM2 on TNF-α-induced cardiomyocyte apoptosis, we tested the effects of TRPM2-specific small interfering RNA (siRNA). As a result, impressively, TNF-α-induced increases of caspase-3 activity and lysate nucleosomes were significantly reduced in TRPM2-specific siRNA-treated cardiomyocytes (P < 0.01). These results indicate that TRPM2 plays an important role in TNF-α-induced cardiomyocyte apoptosis. We propose functional inhibition of TRPM2 channels as a new therapeutic strategy for treating mechanical trauma-induced secondary myocardial injury.

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Role of endogenous testosterone in myocardial proinflammatory and proapoptotic signaling after acute ischemia-reperfusion

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00784.2004 ◽

2005 ◽

Vol 288 (1) ◽

pp. H221-H226 ◽

Cited By ~ 70

Author(s):

Meijing Wang ◽

Ben M. Tsai ◽

Ajay Kher ◽

Lauren B. Baker ◽

G. Mathenge Wairiuko ◽

...

Keyword(s):

P38 Mapk ◽

Functional Recovery ◽

Caspase 3 ◽

Diastolic Pressure ◽

Contractile Function ◽

Ischemia Reperfusion ◽

Left Ventricular ◽

Acute Ischemia ◽

Caspase 1 ◽

Tnf Α

Myocardial ischemia is the leading cause of death in both men and women; however, very little information exists regarding the effect of testosterone on the response of myocardium to acute ischemic injury. We hypothesized that testosterone may exert deleterious effects on myocardial inflammatory cytokine production, p38 MAPK activation, apoptotic signaling, and myocardial functional recovery after acute ischemia-reperfusion (I/R). To study this, isolated, perfused rat hearts (Langendorff) from adult males, castrated males, and males treated with a testosterone receptor blocker (flutamide) were subjected to 25 min of ischemia followed by 40 min of reperfusion. Myocardial contractile function (left ventricular developed pressure, left ventricular end-diastolic pressure, positive and negative first derivative of pressure) was continuously recorded. After reperfusion, hearts were analyzed for expression of tissue TNF-α, IL-1β, and IL-6 (ELISA) and activation of p38 MAPK, caspase-1, caspase-3, caspase-11, and Bcl-2 (Western blot). All indices of postischemic myocardial functional recovery were significantly higher in castrated males or flutamide-treated males compared with untreated males. After I/R, castrated male and flutamide-treated male hearts had decreased TNF-α, IL-1β, and IL-6; decreased activated p38 MAPK; decreased caspase-1, caspase-3, and caspase-11; and increased Bcl-2 expression compared with untreated males. These results show that blocking the testosterone receptor (flutamide) or depleting testosterone (castration) in normal males improves myocardial function after I/R. These effects may be attributed to the proinflammatory and/or the proapoptotic properties of endogenous testosterone. Further understanding may allow therapeutic manipulation of sex hormone signaling mechanisms in the treatment of acute I/R.

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The Role of Thymoquinone in Mitigating Carbon Tetrachloride-Induced Hepatocellular Carcinoma in Rats: Targeting the CHOP-1/JNK/P38 MAPK, NFκB/TNF-α/IL-10, and Bax/Bcl-2/Caspase-3 Signalling Pathways

Folia Biologica ◽

10.3409/fb_69-1.01 ◽

2021 ◽

Vol 69 (1) ◽

pp. 1-9

Author(s):

Rania Elsayed Hussein ◽

Laila Ahmed Rashed ◽

Basma Emad Aboulhoda ◽

Ghada Mahmoud Abdelaziz ◽

Ebtehal Gamal Abdelhady ◽

...

Keyword(s):

Gene Expression ◽

Hepatocellular Carcinoma ◽

P38 Mapk ◽

Caspase 3 ◽

B Cell Lymphoma ◽

Mitogen Activated Protein Kinase ◽

Lipid Peroxidation Product ◽

Tnf Α ◽

Anti Inflammatory ◽

Bax Gene

The present study was conducted to evaluate the effect of thymoquinone (TQ) on hepatocellular carcinoma (HCC) in rats. Our study has reported that TQ treatment of experimentally-induced HCC results in the up-regulation of the Jun-N-terminal kinase and p38 mitogen activated protein kinase pathway (JNK/p38 MAPK) and the enhancement of anti-inflammatory, anti-oxidant, and pro-apoptotic machineries. TQ resulted in a significant decrease in the levels of nuclear factor kappa-light-chain-enhancer of activated B-cells (NFκB), tumor necrosis factor-α (TNF-α), and a significant increase in the anti-inflammatory interleukin-10 (IL-10). The pro-apoptotic effect of TQ was demonstrated through stimulating the apoptotic Bcl-2-associated X (Bax) gene and inhibiting the anti-apoptotic B-cell lymphoma 2 (Bcl-2) gene together with increasing the level of caspase 3 and up-regulating the C/EBP homologous protein (CHOP-1) gene expression. TQ treatment also enhanced the activity of the ROS scavenger, superoxide dismutase (SOD), and decreased the level of the lipid peroxidation product malondialdehyde (MDA). TQ-dependent suppression of HCC was associated with the up-regulation of JNK/p38 MAPK, enhanced CHOP-1 expression, and subsequently increased Bax gene expression.

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Juglanin alleviates myocardial injury in rats with acute myocardial infarction through modulating MAPK signaling pathway

Quality Assurance and Safety of Crops & Foods ◽

10.15586/qas.v13i3.983 ◽

2021 ◽

Vol 13 (3) ◽

pp. 116-122

Author(s):

Jing Sun ◽

Lei Song

Keyword(s):

Myocardial Infarction ◽

Acute Myocardial Infarction ◽

Signaling Pathway ◽

Myocardial Injury ◽

Morphological Changes ◽

Mapk Signaling ◽

Protective Role ◽

Mitogen Activated Protein Kinase ◽

Enzyme Linked Immunosorbent Assay ◽

Tnf Α

The aim of this study was to investigate the protective role of Juglanin in rats suffering from acute myocardial infarction (AMI). Male Sprague–Dawley (SD) mice were used to construct the AMI model. Hematoxylin and Eosin staining was used to observe the morphological changes of cardiomyocytes. Changes in lactate dehydro-genase (LDH), caspase-3 and caspase-9 were measured using commercial kits. Enzyme-linked immunosorbent assay was used to measure the serum level of creatine kinase myocardial band (CK-MB), Interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), IL-10 and IL-1β. Protein expression and phosphorylation were determined by Western blotting test. The morphology of cardiomyocytes suffered great changes because of AMI, which included focal myocardial necrosis, severe inflammatory cell infiltration, and myocardial fiber dissolution, disorder, and partial rupture. The morphological changes in cardiomyocytes were significantly ameliorated through treatment with Juglanin (10 mg/kg and 30 mg/kg). Increment of serum CK-MB, LDH, IL-6, TNF-α, IL-10 and IL-1β was reduced in AMI rats treated with 10-mg/kg and 30-mg/kg Juglanin. Cell apoptosis was also inhibited by Juglanin treatment. AMI-induced phosphorylation of p38, extracellular signal-regulated kinase (p-ERK) and c-Jun N-terminal kinase (p-JNK) was suppressed through treatment with Juglanin. This study demonstrated that Juglanin alleviated myocardial injury in rats because of AMI through inactivation of mitogen-activated protein kinase signaling pathway, thus indicating a protective role in rat AMI model.

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Paricalcitol pretreatment attenuates renal ischemia/reperfusion injury by inhibiting p38 MAPK and activating PI3K/Akt signaling pathways

Turkish Journal of Biochemistry ◽

10.1515/tjb-2018-0155 ◽

2019 ◽

Vol 44 (4) ◽

pp. 452-461

Author(s):

Zahide Cavdar ◽

Cemre Ural ◽

Ayse Kocak ◽

Sevki Arslan ◽

Sibel Ersan ◽

...

Keyword(s):

Signaling Pathways ◽

P38 Mapk ◽

Caspase 3 ◽

Ischemia Reperfusion ◽

Akt Signaling ◽

Albino Rats ◽

Sod Activity ◽

Interstitial Inflammation ◽

Tnf Α ◽

Active Caspase

Abstract Objective This study aimed to investigate the renoprotective effects of paricalcitol, a synhetic vitamin D analog, through its possible roles on p38 MAPK and PI3K/Akt signaling pathways to prevent oxidative stress, inflammation and apoptosis during renal I/R. Materials and methods Total 20 kidney tissues of sham (n = 6), subjected to renal I/R bilaterally for 45 min ischemia followed by 24 h reperfusion (n = 7) and paricalcitol (0.3 μg/kg, ip) pretreated Wistar albino rats (n =7) were used in this study. Interstitial inflammation and active caspase-3 expression were evaluated histologically. TNF-α, IL-1β, kidney injury molecule-1 (KIM-1), MDA and SOD activity in kidneys were analysed biochemically. Furthermore, activation of p38 MAPK, PI3K/Akt signaling pathways and NFκB p65 were evaluated by western blot. Results Paricalcitol pretreatment significantly reduced interstitial inflammation during renal I/R, which was consistent with decreased tumor TNF-α, IL-1β, active caspase-3 and KIM-1 expression. Paricalcitol also reduced MDA level and attenuated the reduction of SOD activity in the kidney during I/R. Moreover, paricalcitol could suppress the p38 MAPK and NFκB p65, and also activate PI3K/Akt signaling pathway during renal I/R. Conclusion All these findings indicate that paricalcitol may be an effective practical strategy to prevent renal I/R injury.

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Electroacupuncture stimulation at Yanglingquan acupoint ameliorates hepatic ischemia-reperfusion injury by down-regulating ET-1 to inhibit TAK1-JNK/p38 pathway

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00012.2021 ◽

2021 ◽

Author(s):

Lai Wei ◽

Yinyin Su ◽

Siyou Tan ◽

Yi Zou ◽

Yixun Tang ◽

...

Keyword(s):

Reperfusion Injury ◽

Signaling Pathway ◽

Caspase 3 ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Expression Patterns ◽

Hepatic Ischemia ◽

Tnf Α ◽

Hepatic Ischemia Reperfusion ◽

Liver Tissues

The current study set out to investigate the molecular mechanism of electroacupuncture (EA) stimulation at Yanglingquan acupoint (GB34) in hepatic ischemia-reperfusion injury (HIRI) in rats via regulation of the endothelin-1 (ET-1) mediated transforming growth factor-β-activated kinase-1 (TAK1)-c-Jun NH2-terminal kinase (JNK)/p38 signaling pathway. First, EA stimulation was applied to the constructed rat model of HIRI at GB34. Subsequently, the activities of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and myeloperoxidase (MPO) in liver tissues were measured. Apoptotic changes in liver tissues in rats with HIRI were observed using TUNEL staining. Western blot assay was employed to determine the expression patterns of Bcl-2, Bax, c-caspase-3 and the activation of TAK1-JNK/p38 signaling pathway, and immunohistochemistry was conducted to determine the protein expression patterns of c-caspase-3 and ET-1. In addition, ELISA was performed to determine the levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-1β and IL-6 in serum. The results demonstrated a significant decline in the activities of AST and ALT and hepatocyte apoptosis in rats with HIRI following EA stimulation. Meanwhile, EA stimulation brought about decreases in the expression levels of Bcl-2, Bax and c-caspase-3, MPO activity, TNF-α, IL-1β and IL-6 in serum, and diminished those of ET-1 in liver tissues, in addition to inhibiting the TAK1-JNK/p38 signaling pathway. Over-expression of ET-1 could counter the inhibitory effects of EA stimulation of HIRI in rats. Together, our findings indicate that EA stimulation at GB34 down-regulates the expression of ET-1, which inhibits the TAK1-JNK/p38 signaling pathway, consequently alleviating HIRI in rats.

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Xenobiotic-induced TNF-α expression and apoptosis through the p38 MAPK signaling pathway

Toxicology Letters ◽

10.1016/j.toxlet.2004.09.008 ◽

2005 ◽

Vol 155 (2) ◽

pp. 227-238 ◽

Cited By ~ 29

Author(s):

Daniel E. Frigo ◽

Katinka A. Vigh ◽

Amanda P. Struckhoff ◽

Steven Elliott ◽

Barbara S. Beckman ◽

...

Keyword(s):

Signaling Pathway ◽

P38 Mapk ◽

Mapk Signaling ◽

Mapk Signaling Pathway ◽

Tnf Α

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Mechanism of attenuation of muscle protein degradation induced by tumor necrosis factor-α and angiotensin II by β-hydroxy-β-methylbutyrate

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.90567.2008 ◽

2008 ◽

Vol 295 (6) ◽

pp. E1417-E1426 ◽

Cited By ~ 61

Author(s):

Helen L. Eley ◽

Steven T. Russell ◽

Michael J. Tisdale

Keyword(s):

Protein Degradation ◽

P38 Mapk ◽

Total Protein ◽

Caspase 3 ◽

Muscle Protein ◽

Ang Ii ◽

Tnf Α ◽

Ros Formation ◽

Ifn Γ ◽

Factor Α

Both tumor necrosis factor-α (TNF-α)/interferon-γ (IFN-γ) and angiotensin II (ANG II) induced an increase in total protein degradation in murine myotubes, which was completely attenuated by treatment with β-hydroxy-β-methylbutyrate (HMB; 50 μM). There was an increase in formation of reactive oxygen species (ROS) within 30 min, as well as an increase in the activity of both caspase-3 and -8, and both effects were attenuated by HMB. Moreover, inhibitors of caspase-3 and -8 completely attenuated both ROS formation and total protein degradation induced by TNF-α/IFN-γ and ANG II. There was an increased autophosphorylation of double-stranded RNA-dependent protein kinase (PKR), which was attenuated by the specific caspase-3 and -8 inhibitors. Neither ROS formation or protein degradation occurred in myotubes expressing a catalytically inactive PKR variant, PKRΔ6, in response to TNF-α/IFN-γ, compared with myotubes expressing wild-type PKR, although there was still activation of caspase-3 and -8. HMB also attenuated activation of PKR, suggesting that it was important in protein degradation. Formation of ROS was attenuated by rotenone, an inhibitor of the mitochondrial electron transport chain, nitro-l-arginine methyl ester, an inhibitor of nitric oxide synthase, and SB 203580, a specific inhibitor of p38 mitogen-activated protein kinase (p38 MAPK), which also attenuated total protein degradation. Activation of p38 MAPK by PKR provides the link to ROS formation. These results suggest that TNF-α/IFN-γ and ANG II induce muscle protein degradation by a common signaling pathway, which is attenuated by HMB, and that this involves the initial activation of caspase-3 and -8, followed by autophosphorylation and activation of PKR, which then leads to increased ROS formation via activation of p38 MAPK. Increased ROS formation is known to induce protein degradation through the ubiquitin-proteasome pathway.

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