Simvastatin Protects Hepatocytes From Apoptosis by Suppressing the TNF-α/Caspase-3 Signaling Pathway in Mice With Burn Injury

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

Molecular Medicine Reports ◽

10.3892/mmr.2016.5250 ◽

2016 ◽

Vol 14 (1) ◽

pp. 551-559 ◽

Cited By ~ 15

Author(s):

MINGHAO ZHANG ◽

XIUYU WANG ◽

BIN BAI ◽

RUI ZHANG ◽

YUNHONG LI ◽

...

Keyword(s):

Signaling Pathway ◽

P38 Mapk ◽

Myocardial Injury ◽

Caspase 3 ◽

Tnf Α

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Glucocorticoid-induced, caspase-dependent organ apoptosis early after burn injury

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.2000.278.4.r1005 ◽

2000 ◽

Vol 278 (4) ◽

pp. R1005-R1018 ◽

Cited By ~ 57

Author(s):

Kunitaro Fukuzuka ◽

Carl K. Edwards ◽

Michael Clare-Salzler ◽

Edward M. Copeland ◽

Lyle L. Moldawer ◽

...

Keyword(s):

Caspase 3 ◽

Fas Ligand ◽

Burn Injury ◽

Terminal Deoxynucleotidyl Transferase ◽

Cell Populations ◽

Tnf Α ◽

Circulating Lymphocytes ◽

Underlying Mechanisms ◽

Factor Α ◽

Parenchymal Cells

Immune suppression and increased apoptotic loss of circulating lymphocytes have been reported after burn injury. However, little is known about the underlying mechanisms responsible for the increased apoptosis of lymphoid and parenchymal cells in solid organs and the role played by inflammatory mediators, such as tumor necrosis factor-α (TNF-α) and Fas ligand (FasL), as well as by glucocorticoids. To evaluate the role of endogenously produced glucocorticoids and FasL, mice subjected to a 20% steam burn were pretreated with a glucocorticoid receptor antagonist (mifepristone) or a neutralizing murine Fas fusion protein. Three and twenty-four hours after burn injury, histological analysis, caspase-3 activity, and in situ terminal deoxynucleotidyl transferase dUTP nick-end labeling staining and phenotyping of lymphocyte populations for apoptosis were evaluated. Burn injury increased the number of apoptotic cells and caspase-3 activity in thymus and spleen, but not in other solid organs. Increased apoptosis was seen in several T and B cell populations from both thymus and spleen. Mifepristone pretreatment significantly reduced the apoptosis and caspase-3 activity after burn injury, whereas blocking FasL activity had only minimal effects. We conclude that corticosteroids, and not FasL, are primarily responsible for the increased caspase-3 activity and apoptosis in thymus and spleen cell populations early after burn 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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Nano-Curcumin Protects Against Sodium Nitrite–Induced Lung Hypoxia Through Modulation of Mitogen-Activated Protein Kinases/c-Jun NH2-Terminal Kinase Signaling Pathway

Dose-Response ◽

10.1177/15593258211033148 ◽

2021 ◽

Vol 19 (3) ◽

pp. 155932582110331

Author(s):

Ahlam Alhusaini ◽

Sara Alhumaidan ◽

Renad Almogren ◽

Shaikha Alsaif ◽

Ebtesam Alsultan ◽

...

Keyword(s):

Signaling Pathway ◽

Protein Kinases ◽

Sodium Nitrite ◽

Caspase 3 ◽

Tissue Inhibitors Of Metalloproteinases ◽

Control Group ◽

Mitogen Activated Protein Kinases ◽

Tnf Α ◽

Mitogen Activated Protein ◽

Hypoxic Group

Background and objective This study was designed to compare the efficacy of curcumin (CRN) with that of nano-curcumin (N-CRN) in the mitigation of various biochemical indices in hypoxic lung induced by sodium nitrite (SN) in rats. Methods Twenty-four adult male albino rats were divided into 4 groups. Group 1: control group received carboxy methyl cellulose; Group 2: hypoxic group injected with single dose of SN (60 mg/kg, s.c.); Group 3: SN-intoxicated rats pre-injected with CRN (100 mg/kg, i.p.); and Group 4: SN-intoxicated rats pre-injected with N-CRN (100 mg/kg, i.p.). Curcumin and N-CRN were administered intraperitoneally 2 hour prior to SN intoxication. Hemoglobin concentration, serum tumor necrosis factor-alpha (TNF-α), and caspase-3 were analyzed. Gene expression of hypoxia inducible factor-1 (HIF-1α), matrix metallo-proteinases (MMP)-2, and tissue inhibitors of metalloproteinases (TIMPs)-2, as well as the protein expression of mitogen-activated protein kinases (MAPKs) and c-Jun NH2-terminal kinase (JNK) were examined in lung tissues. Results Hemoglobin level was markedly reduced, and serum TNF-α and caspase-3 were significantly elevated post SN intoxication. The lung MMP-2 and HIF-1α mRNA were overexpressed in the hypoxic group; while TIMP-2 mRNA was downregulated. Sodium nitrite administration increased proteins’ expressions of MAPK and JNK. Pretreatment with CRN or N-CRN markedly mitigated those alterations. These results were supported by histopathological examinations of lung tissue. Conclusion Interestingly, N-CRN exhibited a pronounced protective effect via suppression of inflammatory and apoptotic biomarkers and modulation of MAPK/JNK signaling pathway.

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Upregulation of microRNA-96 alleviates the neurological damage in acute seizure rats by down-regulating RAC1 and inhibiting the activation of RhoA/ROCK signaling pathway

10.21203/rs.2.19156/v1 ◽

2019 ◽

Author(s):

Zhihan Wang ◽

Wei Jiang ◽

Dabin Ren ◽

Wei Chen ◽

Ping Zheng

Keyword(s):

Signaling Pathway ◽

Caspase 3 ◽

Rat Hippocampus ◽

Luciferase Assay ◽

Neurological Damage ◽

Altered Expression ◽

Tnf Α ◽

Acute Seizure ◽

Related Proteins

Abstract Objective Today, the research about the involvement of non-coding RNAs on neurological disorders is still scarce. Hence, we aimed to investigate the effect of miR-96 targeted RAC1 to mediate RhoA/ROCK signaling pathway in neurological damage in acute seizure rats.MethodsThe acute seizure rat model was constructed by using classical chlorinated-pilocarpine injection, which was treated with miR-96 mimics, RAC1-siRNA or their controls. The number of BrdU positive cells, neuronal changes and apoptosis, expression of NGF, BDNF and GFAP were detected by different staining assays. At the same time, the activity of SOD, the content of MDA and the protein contents of TNF-α and IL-6 in rat hippocampus were detected as well. Next, the expression of NGF, BDNF, GFAP, Bax, Bcl-2, caspase-3, RAC1, RhoA and ROCK were determined by RT-qPCR and western blot analysis. Then, the binding site between miR-96 and RAC1 was analyzed by bioinformatics software and luciferase assay. Finally, the altered expression of miRNAs was investigated in exosomes released from excitotoxic neurons with a customized rat miRNA chipset.Results After upregulation of miR-96 or downregulation RAC1, BrdU-positive cells, TUNEL-positive cells, NGF, GFAP, MDA, TNF-α, IL-6, Bax, caspase-3, and pathway related proteins in rat hippocampus decreased while Bcl-2, BDNF, and the activity of SOD increased. Furthermore, RAC1 was found to be the target gene of miR-96 and their relationship was validated in in-vitro studies. Finally, the decreased expression of miR-96 in exosomes from kainic acid treated neurons was identified as well.Conclusion This study suggests that upregulation of miR-96 could downregulate RAC1 and inhibit the activation of RhoA/ROCK signaling pathway, thus alleviated the neurological damage in acute seizure rats.

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YQWY Decoction Improves Myocardial Remodeling via Activating the IL-10/Stat3 Signaling Pathway

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2020/7532892 ◽

2020 ◽

Vol 2020 ◽

pp. 1-10

Author(s):

He Li ◽

Zhi-Jun Gong ◽

Yun He ◽

Jing-Jing Huang ◽

Yu-Ning Jiang ◽

...

Keyword(s):

Left Ventricular Function ◽

Ventricular Function ◽

Signaling Pathway ◽

Myocardial Fibrosis ◽

Caspase 3 ◽

Left Ventricular ◽

Collagen I ◽

Stat3 Signaling ◽

Stat3 Signaling Pathway ◽

Tnf Α

Heart failure (HF) has been known as a global health problem, and cardiac remodeling plays an essential role in the development of HF. We hypothesized that YQWY decoction might exert a cardioprotective effect against myocardium inflammation, fibrosis, and apoptosis via activating the interleukin-10 (IL-10)/Stat3 signaling pathway. To test this hypothesis, the HF model in rats was established by pressure overload through the minimally invasive transverse aortic constriction (MTAC). Echocardiography was performed to assess the left ventricular function of rats. Myocardial fibrosis in rats was observed by Masson and Picrosirius red staining, and the degree of myocardial apoptosis was detected via TUNEL staining. In addition, expression levels of IL-10, tumor necrosis factor-α (TNF-α), Stat3 (P-Stat3), P65 (P-P65), CD68, collagen I, TGF-β, CTGF, Bax, Bcl-2, cleaved caspase-3, and PARP in rat serum and myocardium samples were examined by ELISA, western blot, and immunohistochemistry, respectively. YQWY decoction treatment significantly improved left ventricular function in HF rats, especially in those of the high-dose group (LVEF%: 51.29 ± 5.876 vs. 66.02 ± 1.264, P < 0.01 ;, LVFS%: 27.75 ± 3.757 vs. 37.76 ± 1.137, P < 0.01 ). Furthermore, YQWY decoction markedly inhibited MTAC-induced myocardial fibrosis as evidenced by downregulated collagen I, TGF-β, and CTGF in myocardium and alleviated apoptosis (downregulated caspase-3 and PARP and increased Bcl-2/Bax ratio in cardiomyocytes). In addition, YQWY decoction decreased the level of the proinflammatory cytokine TNF-α in both circulating blood and myocardium and attenuated infiltration of inflammatory cells in heart tissue from HF rats. Most importantly, YQWY decoction suppressed MTAC-induced NF-κB activation and phosphorylated Stat3 by upregulating IL-10 in rat heart tissues. Our study showed that YQWY decoction could attenuate MTAC-induced myocardial inflammation, fibrosis, apoptosis, and reverse the impairment of cardiac function in rats by activating the IL-10/Stat3 signaling pathway and improving myocardium remodeling. Our findings suggested a therapeutic potential of YQWY decoction in HF.

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Sulforaphane Attenuates Endometriosis in Rat Models Through Inhibiting PI3K/Akt Signaling Pathway

Dose-Response ◽

10.1177/1559325819855538 ◽

2019 ◽

Vol 17 (2) ◽

pp. 155932581985553 ◽

Cited By ~ 2

Author(s):

Aixiu Zhou ◽

Yiting Hong ◽

Yuchun Lv

Keyword(s):

Signaling Pathway ◽

Rat Model ◽

Caspase 3 ◽

B Cell Lymphoma ◽

Underlying Mechanism ◽

Akt Signaling ◽

Enzyme Linked Immunosorbent Assay ◽

Akt Signaling Pathway ◽

Tnf Α ◽

Ifn Γ

Sulforaphane exerts anti-inflammatory activity in inflammatory diseases. The endometriosis (EM) is accompanied by chronic inflammation. The present study aims to explore the therapeutic effects of sulforaphane on EM and its underlying mechanism. An EM rat model was established by transplantation of autologous fragments. The rats were intragastrically administered sulforaphane (5 mg/kg, 15 mg/kg, and 30 mg/kg) for 3 weeks. The volumes of endometriotic foci and adhesion score were calculated at the end of the experiment. Levels of interleukin (IL)-6, IL-10, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, and vascular endothelial growth factor (VEGF) were determined by enzyme-linked immunosorbent assay (ELISA). Expressions of VEGF, B-cell lymphoma/leukemia 2 (Bcl-2), Bax, cleaved caspase-3, PI3K, and Akt in endometrial tissue were determined by Western blotting. Relative expressions of PI3K and Akt were determined by quantitative polymerase chain reaction. Posttreatment of sulforaphane dose-dependently decreased the volumes of endometriotic foci and adhesion score in EM model. Additionally, posttreatment of sulforaphane inhibited levels of IL-6, IL-10, TNF-α, IFN-γ, and VEGF in peritoneal fluid and plasma. Posttreatment of sulforaphane regulated the expressions of VEGF, bcl-2, Bax, and cleaved Caspase-3 in EM model. The underlying mechanism revealed that sulforaphane attenuated EM in the rat model by inhibition of PI3K/Akt signaling pathway.

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Knockdown of TRIM52 alleviates LPS-induced inflammatory injury in human periodontal ligament cells through the TLR4/NF-κB pathway

Bioscience Reports ◽

10.1042/bsr20201223 ◽

2020 ◽

Vol 40 (8) ◽

Cited By ~ 1

Author(s):

Peng Liu ◽

Lijun Cui ◽

Lifang Shen

Keyword(s):

Signaling Pathway ◽

Periodontal Ligament ◽

Caspase 3 ◽

Quantitative Polymerase Chain Reaction ◽

Periodontal Ligament Cells ◽

Inflammatory Injury ◽

Human Periodontal Ligament Cells ◽

Diphenyltetrazolium Bromide ◽

Tnf Α ◽

Factor Α

Abstract Tripartite motif-containing (TRIM) 52 (TRIM52) is a vital regulator of inflammation. However, the function and mechanisms of TRIM52 in lipopolysaccharide (LPS)-induced inflammatory injury of human periodontal ligament cells (HPDLCs) in periodontitis remain undefined. In the present research, gene expression was determined using a quantitative polymerase chain reaction and Western blot. The effect of TRIM52 on LPS-induced inflammatory injury was evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, flow cytometry, and enyzme-linked immunosorbent assay (ELISA). We found that TRIM52 expression was up-regulated in LPS-treated HPDLCs. Knockdown of TRIM52 alleviated LPS-induced proliferative inhibition and apoptosis promotion in HPDLCs, as evidenced by a decrease in cleaved caspase-3 expression and caspase-3 activity. Silencing TRIM52 suppressed LPS-induced inflammatory response of HPDLCs, as indicated by the decrease in interleukin (IL)-6, IL-8, tumor necrosis factor-α (TNF-α) levels, and increase in IL-10 levels. TRIM52 knockdown inhibited LPS-induced activation of TLR4/nuclear factor-κ B (NF-κB) signaling pathway. Taken together, knockdown of TRIM52 mitigated LPS-induced inflammatory injury via the TLR4/NF-κB signaling pathway, providing an effective therapeutic target for periodontitis.

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