Ginsenoside Rg3 Attenuates TNF-α-Induced Damage in Chondrocytes through Regulating SIRT1-Mediated Anti-Apoptotic and Anti-Inflammatory Mechanisms

The upregulation of tumor necrosis factor-alpha (TNF-α) is a common event in arthritis, and the subsequent signaling cascade that leads to tissue damage has become the research focus. To explore a potential therapeutic strategy to prevent cartilage degradation, we tested the effect of ginsenoside Rg3, a bioactive component of Panax ginseng, on TNF-α-stimulated chondrocytes.TC28a2 Human Chondrocytes were treated with TNF-α to induce damage of chondrocytes. SIRT1 and PGC-1a expression levels were investigated by Western blotting assay. Mitochondrial SIRT3 and acetylated Cyclophilin D (CypD) were investigated using mitochondrial isolation. The mitochondrial mass number and mitochondrial DNA copy were studied for mitochondrial biogenesis. MitoSOX and JC-1 were used for the investigation of mitochondrial ROS and membrane potential. Apoptotic markers, pro-inflammatory events were also tested to prove the protective effects of Rg3. We showed Rg3 reversed the TNF-α-inhibited SIRT1 expression. Moreover, the activation of the SIRT1/PGC-1α/SIRT3 pathway by Rg3 suppressed the TNF-α-induced acetylation of CypD, resulting in less mitochondrial dysfunction and accumulation of reactive oxygen species (ROS). Additionally, we demonstrated that the reduction of ROS ameliorated the TNF-α-elicited apoptosis. Furthermore, the Rg3-reverted SIRT1/PGC-1α/SIRT3 activation mediated the repression of p38 MAPK, which downregulated the NF-κB translocation in the TNF-α-treated cells. Our results revealed that administration of Rg3 diminished the production of interleukin 8 (IL-8) and matrix metallopeptidase 9 (MMP-9) in chondrocytes via SIRT1/PGC-1α/SIRT3/p38 MAPK/NF-κB signaling in response to TNF-α stimulation. Taken together, we showed that Rg3 may serve as an adjunct therapy for patients with arthritis.

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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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Guaiane-Type Sesquiterpenoids From Dendranthema morifolium (Ramat.) S. Kitam Flowers Protect H9c2 Cardiomyocyte From LPS-Induced Injury

Natural Product Communications ◽

10.1177/1934578x19864179 ◽

2019 ◽

Vol 14 (7) ◽

pp. 1934578X1986417

Author(s):

Beibei Zhang ◽

Mengnan Zeng ◽

Meng Li ◽

Wenjing Chen ◽

Benke Li ◽

...

Keyword(s):

Caspase 3 ◽

Creatine Phosphate ◽

Cardiomyocyte Apoptosis ◽

Exocyclic Double Bond ◽

Enzyme Linked Immunosorbent Assay ◽

Protective Effects ◽

Caspase 9 ◽

Necrosis Factor Alpha ◽

Thiazolyl Blue Tetrazolium Bromide ◽

Tnf Α

This study investigated the protective effects of guaiane-type sesquiterpenoids isolated from Dendranthema morifolium (Ramat.) S. Kitam ﬂowers on lipopolysaccharide (LPS)-induced injury in H9c2 cardiomyocyte. Cell viability was determined by thiazolyl blue tetrazolium bromide (MTT). The content of released tumor necrosis factor alpha (TNF- α) and interleukin 6 (IL-6) was evaluated by enzyme-linked immunosorbent assay. The levels of lactate dehydrogenase (LDH) and creatine phosphate kinase (CK) were measured by using commercial available kits. The protein expression levels of pelF2 α, GRP78, Bax, caspase-3, caspase-9, Bcl-2, LC3-II, and p62 were measured by in-cell Western. Flow cytometry was used to detect H9c2 cardiomyocyte apoptosis. Compounds 5, 7, 1, 8, and 2 exhibited the effects of cardioprotection and activity sequence enhancement. The levels of IL-6, TNF- α, LDH, CK, pelF2 α, GRP78, Bax, caspase-3, caspase-9, p62, and H9c2 cardiomyocyte apoptosis were increased in LPS-treated H9c2 cardiomyocyte, while those of Bcl-2 and LC3-II were decreased. These effects could be effectively reversed by compounds 5, 7, 1, 8, and 2. Results demonstrated that the guaiane-type sesquiterpenoids could prevent LPS-induced injury in cardiomyocyte by decreasing endoplasmic reticulum (ER) stress, apoptosis, and autophagy as well as downregulating the inflammatory mediators. In addition, the active groups of guaiane-type sesquiterpenoids might be the angelate at C-8 and the exocyclic double bond at C-11.

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Protective effects of bisoprolol against cadmium-induced myocardial toxicity through inhibition of oxidative stress and NF-κΒ signalling in rats

Journal of Veterinary Research ◽

10.2478/jvetres-2021-0054 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Jinhua Liu ◽

Ying Xie ◽

Zhujun Han ◽

Hailong Wang ◽

Wenhu Xu

Keyword(s):

Oxidative Stress ◽

Cardiac Injury ◽

Therapeutic Drug ◽

Control Group ◽

Protective Effects ◽

Necrosis Factor Alpha ◽

Tissue Samples ◽

Gum Acacia ◽

Tnf Α ◽

Creatine Kinase Mb

Abstract Introduction The aim of the study was to investigate the mitigative effects of bisoprolol (BIS) in cadmium-induced myocardial toxicity on oxidative stress and its inhibitive effect on nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) signalling in rats. Material and Methods Male albino Wistar rats were assigned to control, Cd, BIS 2 (2 mg/kg b.w.) and BIS 8 (8 mg/kg b.w.) groups with nine rats in each. Over four weeks, the control group was administered 1% gum acacia, all other groups received 3mg/kg b.w. CdCl2 dissolved in distilled water, and the BIS groups were additionally given bisoprolol in gum acacia. Blood samples were collected for biochemical estimations. Blood pressure and serum biomarker (lactate dehydrogenase, aspirate transaminase, alanine transferase and creatine kinase-MB, enzyme (superoxide dismutase, lipid hydroxy peroxidase, catalase and malondialdehyde), and tumour necrosis factor alpha (TNF-α) concentrations were measured. Western blot analysis was conducted for NF-κB and glutathione S-transferase (GST). After sacrificing the rats, cardiac tissue samples were examined histopathologically. Results Our findings pointed to a significant decrease (P < 0.05) in the studied serum biomarkers and levels of the relevant enzymes in the BIS 8 group compared to the Cd group. A significant decrease (P < 0.05) in NF-kB p65 expression and TNF-α levels was noted in the BIS 8 group relative to the BIS 2 and Cd groups, indicating a reduction at a higher dose. In microscopy, histopathological changes in the cardiac muscles of the BIS 8 group were evident compared to those of the Cd group. Conclusion BIS seemed to have protective effects against cardiac injury induced by cadmium and could be considered a novel therapeutic drug and prognostic biomarker in the pathology of the many cardiovascular diseases caused by heavy metal intake.

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Mitogen-Activated Protein Kinase Phosphatase 1 Disrupts Proinflammatory Protein Synthesis in Endotoxin-Adapted Monocytes

Clinical and Vaccine Immunology ◽

10.1128/cvi.00264-13 ◽

2013 ◽

Vol 20 (9) ◽

pp. 1396-1404 ◽

Cited By ~ 8

Author(s):

Laura Brudecki ◽

Donald A. Ferguson ◽

Charles E. McCall ◽

Mohamed El Gazzar

Keyword(s):

Protein Kinase ◽

P38 Mapk ◽

Rna Binding ◽

Multiorgan Failure ◽

Mitogen Activated Protein Kinase ◽

Necrosis Factor Alpha ◽

Translational Repressor ◽

Proinflammatory Mediators ◽

Tnf Α ◽

Mitogen Activated Protein

ABSTRACTAutotoxic production of proinflammatory mediators during early sepsis induces excessive inflammation, and their later suppression may limit the immune response. We previously reported that sepsis differentially represses transcription and translation of tumor necrosis factor alpha (TNF-α) and interleukin 1β (IL-1β) to reprogram sepsis inflammation. This switch is gene specific and plays a crucial role in the clinically relevant syndrome of endotoxin adaptation/tolerance, multiorgan failure, and poor sepsis outcome. To further define the mechanisms responsible for translation disruption that follows inflammation induction, we used THP-1 human promonocytes as a model of Toll-like receptor 4 (TLR4) responses found in sepsis. We showed that phosphorylation-dependent activation of p38 mitogen-activated protein kinase (MAPK) and translation disruption of TNF-α and IL-6 follow increased MAPK phosphatase 1 (MKP-1) expression and that MKP-1 knockdown rephosphorylates p38 and restores the capacity to translate TNF-α and IL-6 mRNAs. We also observed that the RNA-binding protein motif 4 (RBM4), a p38 MAPK target, accumulates in an unphosphorylated form in the cytosol in endotoxin-adapted cells, suggesting that dephosphorylated RBM4 may function as a translational repressor. Moreover, MKP-1 knockdown promotes RBM4 phosphorylation, blocks its transfer from the nucleus to the cytosol, and reverses translation repression. We also found that microRNA 146a (miR-146a) knockdown prevents and miR-146a transfection induces MKP-1 expression, which lead to increases or decreases in TNF-α and IL-6 translation, respectively. We conclude that a TLR4-, miR-146a-, p38 MAPK-, and MKP-1-dependent autoregulatory pathway regulates the translation of proinflammatory genes during the acute inflammatory response by spatially and temporally modifying the phosphorylation state of RBM4 translational repressor protein.

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p38 Mitogen-Activated Protein Kinase-Dependent Hyperinduction of Tumor Necrosis Factor Alpha Expression in Response to Avian Influenza Virus H5N1

Journal of Virology ◽

10.1128/jvi.79.16.10147-10154.2005 ◽

2005 ◽

Vol 79 (16) ◽

pp. 10147-10154 ◽

Cited By ~ 97

Author(s):

Davy C. W. Lee ◽

Chung-Yan Cheung ◽

Anna H. Y. Law ◽

Chris K. P. Mok ◽

Malik Peiris ◽

...

Keyword(s):

P38 Mapk ◽

Influenza A ◽

Tumor Necrosis ◽

Mitogen Activated Protein Kinase ◽

Necrosis Factor Alpha ◽

Virus H5n1 ◽

Tnf Α ◽

Mitogen Activated Protein ◽

Factor Alpha ◽

Necrosis Factor

ABSTRACT Avian influenza A virus subtype H5N1 can infect humans to cause a severe viral pneumonia with mortality rates of more than 30%. The biological basis for this unusual disease severity is not fully understood. We previously demonstrated that in contrast to human influenza A virus subtypes including H1N1 or H3N2, the H5N1 virus associated with the “bird flu” outbreak in Hong Kong in 1997 (H5N1/97) hyperinduces proinflammatory cytokines, including tumor necrosis factor alpha (TNF-α), in primary human macrophages in vitro. To delineate the molecular mechanisms involved, we analyzed the role of transcription factor NF-κB and cellular kinases in TNF-α dysregulation. H5N1 and H1N1 viruses did not differ in the activation of NF-κB or degradation of IκB-α in human macrophages. However, we demonstrated that unlike H1N1 virus, H5N1/97 strongly activates mitogen-activated protein kinase (MAPK), including p38 MAPK and extracellular signal-regulated kinases 1 and 2. Specific inhibitors of p38 MAPK significantly reduced the H5N1/97-induced TNF-α expression in macrophages. Taken together, our findings suggest that H5N1/97-mediated hyperinduction of cytokines involves the p38 MAPK signaling pathway. These results may provide insights into the pathogenesis of H5N1 disease and rationales for the development of novel therapeutic strategies.

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Antcin K Inhibits TNF-α, IL-1β and IL-8 Expression in Synovial Fibroblasts and Ameliorates Cartilage Degradation: Implications for the Treatment of Rheumatoid Arthritis

Frontiers in Immunology ◽

10.3389/fimmu.2021.790925 ◽

2021 ◽

Vol 12 ◽

Author(s):

David Achudhan ◽

Shan-Chi Liu ◽

Yen-You Lin ◽

Chien-Chung Huang ◽

Chun-Hao Tsai ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Cytokine Production ◽

Bone Erosion ◽

Interleukin 1 ◽

Synovial Fibroblasts ◽

Nuclear Factor Κb ◽

Cartilage Degradation ◽

Signaling Cascades ◽

Necrosis Factor Alpha ◽

Tnf Α

Extracts from Taiwan’s traditional medicinal mushroom, Antrodia cinnamomea, exhibit anti-inflammatory activities in cellular and preclinical studies. However, this paper is the first to report that Antcin K, a triterpenoid isolated from A. cinnamomea, inhibits proinflammatory cytokine production in human rheumatoid synovial fibroblasts (RASFs), which are major players in rheumatoid arthritis (RA) disease. In our analysis of the mechanism of action, Antcin K inhibited the expression of three cytokines (tumor necrosis factor alpha [TNF-α], interleukin 1 beta [IL-1β] and IL-8) in human RASFs; cytokines that are crucial to RA synovial inflammation. Notably, incubation of RASFs with Antcin K reduced the phosphorylation of the focal adhesion kinase (FAK), phosphoinositide 3-kinase (PI3K), protein kinase B (AKT) and nuclear factor-κB (NF-κB) signaling cascades, all of which promote cytokine production in RA. Intraperitoneal injections of Antcin K (10 mg/kg or 30 mg/kg) attenuated paw swelling, cartilage degradation and bone erosion, and decreased serum levels of TNF-α, IL-1β, IL-8 in collagen-induced arthritis (CIA) mice; in further experiments, IL-6 levels were similarly reduced. The inhibitory effects of Antcin K upon TNF-α, IL-1β and IL-8 expression in human RASFs was achieved through the downregulation of the FAK, PI3K, AKT and NF-κB signaling cascades. Our data support clinical investigations using Antcin K in RA disease.

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Anti-Oxidant and Anti-Inflammatory Effects of Lipopolysaccharide from Rhodobacter sphaeroides against Ethanol-Induced Liver and Kidney Toxicity in Experimental Rats

Molecules ◽

10.3390/molecules26247437 ◽

2021 ◽

Vol 26 (24) ◽

pp. 7437

Author(s):

Eman T. Mehanna ◽

Al-Shimaa A. Ali ◽

Fatma El-Shaarawy ◽

Noha M. Mesbah ◽

Dina M. Abo-Elmatty ◽

...

Keyword(s):

Rhodobacter Sphaeroides ◽

Iron Homeostasis ◽

Kidney Injury ◽

Control Group ◽

Protective Effects ◽

Necrosis Factor Alpha ◽

Hepcidin Expression ◽

Tnf Α ◽

Anti Oxidant ◽

Anti Inflammatory

This study aimed to investigate the protective effects of lipopolysaccharide from Rhodobacter sphaeroides (LPS-RS) against ethanol-induced hepatotoxicity and nephrotoxicity in experimental rats. The study involved an intact control group, LPS-RS group, two groups were given ethanol (3 and 5 g/kg/day) for 28 days, and two other groups (LPS-RS + 3 g/kg ethanol) and (LPS-RS + 5 g/kg ethanol) received a daily dose of LPS-RS (800 μg/kg) before ethanol. Ethanol significantly increased the expression of nuclear factor kappa B (NF-κB) and levels of malondialdehyde (MDA), tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) in the liver tissue and decreased anti-oxidant enzymes. Hepcidin expression was downregulated in the liver, with increased serum levels of ferritin and iron. Prior-administration of LPS-RS alleviated the increase in oxidative stress and inflammatory markers, and preserved iron homeostasis markers. In the kidney, administration of ethanol caused significant increase in the expression of NF-κB and the levels of TNF-α and kidney injury markers; whereas LPS-RS + ethanol groups had significantly lower levels of those parameters. In conclusion; this study reports anti-oxidant, anti-inflammatory and iron homeostasis regulatory effects of the toll-like receptor 4 (TLR4) antagonist LPS-RS against ethanol induced toxicity in both the liver and the kidney of experimental rats.

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Protective Effects of the Third Generation Vasodilatory Βeta - Blocker Nebivolol against D-Galactosamine - Induced Hepatorenal Syndrome in Rats

Open Access Macedonian Journal of Medical Sciences ◽

10.3889/oamjms.2017.173 ◽

2017 ◽

Vol 5 (7) ◽

pp. 880-892 ◽

Cited By ~ 1

Author(s):

Ahmed Atwa ◽

Rehab Hegazy ◽

Rania Mohsen ◽

Neamat Yassin ◽

Sanaa Kenawy

Keyword(s):

Hepatorenal Syndrome ◽

Histopathological Examination ◽

Serum Levels ◽

Heme Oxygenase 1 ◽

Protective Effects ◽

Necrosis Factor Alpha ◽

Tnf Α ◽

Advanced Liver Cirrhosis ◽

Factor Alpha

BACKGROUND: Renal dysfunction is very common in patients with advanced liver cirrhosis and portal hypertension. The development of renal failure in the absence of clinical, anatomical or pathological causes renal of failure is termed hepatorenal syndrome (HRS).AIM: The present study was constructed to investigate the possible protective effects of nebivolol (Nebi) against D-galactosamine (Gal)-induced HRS in rats.MATERIAL AND METHODS: Rats were treated with Nebi for ten successive days. On the 8th day of the experiment, they received a single dose of Gal. Serum levels of Cr, BUN, Na+ and K+ as well as AST, ALT, total bilirubin (TB), NH3 and endothelin-1 (ET-1) were determined following Gal administration. Moreover, renal and liver contents of MDA, GSH, F2-isoprostanes (F2-IPs), tumor necrosis factor-alpha (TNF-α), nuclear factor kappa-B (NF-кB), total nitric oxide (NO), in addition to activities of caspase-3 (Cas-3), heme oxygenase-1 (HO-1), inducible and endothelial NO synthase (iNOS and eNOS) enzymes were also assessed. Finally, histopathological examination was performed.RESULTS: Nebi attenuated Gal-induced renal and hepatic dysfunction. It also decreased the Gal-induced oxidative stress and inflammatory recruitment.CONCLUSION: Results demonstrated both nephroprotective and hepatoprotective effects of Nebi against HRS and suggested a role of its antioxidant, anti-inflammatory, anti-apoptotic and NO-releasing properties.

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Tangeretin Inhibits Oxidative Stress and Inflammation via Upregulating Nrf-2 Signaling Pathway in Collagen-Induced Arthritic Rats

Pharmacology ◽

10.1159/000501163 ◽

2019 ◽

Vol 104 (3-4) ◽

pp. 187-195 ◽

Cited By ~ 7

Author(s):

Xing Li ◽

Peigen Xie ◽

Yu Hou ◽

Shudong Chen ◽

Peiheng He ◽

...

Keyword(s):

Oxidative Stress ◽

Signaling Pathway ◽

Chinese Herb ◽

Biological Properties ◽

Therapeutic Effects ◽

Protective Effects ◽

Necrosis Factor Alpha ◽

Tnf Α ◽

Ifn Γ ◽

Anti Inflammatory

Background/Aims: Tangeretin (TAN), a major phytochemical in tangerine peels and an important Chinese herb, has multiple biological properties, especially antioxidative and anti-inflammatory effects. However, the mechanisms remain unclear. Based on these findings, the aim of the present study was to assess the antioxidant and anti-inflammatory properties of TAN in bovine type II collagen-induced arthritis rats. Methods: TAN (50 mg/kg) was given orally once daily for 14 days. The effects of treatment were evaluated by biochemical assay (articular elastase, myeloperoxidase, end products of lipid peroxidation [MDA], antioxidant enzyme, such as superoxide dismutase, catalase, glutathione), nitric oxide, and inflammatory cytokines (interleukin-1β [IL-1β], IL-10, tumor necrosis factor-alpha [TNF-α], interferon-γ [IFN-γ], and prostaglandin E2 [PGE2]). The protective effects of TAN against rheumatoid arthritis (RA) were evident from the decrease in arthritis scoring. Furthermore, the Nrf-2 signaling pathway was assessed to illustrate the molecular mechanism. Results: TAN had therapeutic effects on RA by decreasing the oxidative stress damage and regulating inflammatory cytokine expression, including suppression of the accumulation of MDA products, decreasing the IL-1β, TNF-α, IFN-γ, and PGE2 levels, enhancing the IL-10 and the activity of antioxidant enzymes, which was through upregulating Nrf-2 signaling pathway. Conclusion: TAN might have potential as a therapeutic agent for the treatment of RA.

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