Limonin Inhibits IL-1β-Induced Inflammation and Catabolism in Chondrocytes and Ameliorates Osteoarthritis by Activating Nrf2

Osteoarthritis (OA), a degenerative disorder, is considered to be one of the most common forms of arthritis. Limonin (Lim) is extracted from lemons and other citrus fruits. Limonin has been reported to have anti-inflammatory effects, while inflammation is a major cause of OA; thus, we propose that limonin may have a therapeutic effect on OA. In this study, the therapeutic effect of limonin on OA was assessed in chondrocytes in vitro in IL-1β induced OA and in the destabilization of the medial meniscus (DMM) mice in vivo. The Nrf2/HO-1/NF-κB signaling pathway was evaluated to illustrate the working mechanism of limonin on OA in chondrocytes. In this study, it was found that limonin can reduce the level of IL-1β induced proinflammatory cytokines such as INOS, COX-2, PGE2, NO, TNF-α, and IL-6. Limonin can also diminish the biosynthesis of IL-1β-stimulated chondrogenic catabolic enzymes such as MMP13 and ADAMTS5 in chondrocytes. The research on the mechanism study demonstrated that limonin exerts its protective effect on OA through the Nrf2/HO-1/NF-κB signaling pathway. Taken together, the present study shows that limonin may activate the Nrf2/HO-1/NF-κB pathway to alleviate OA, making it a candidate therapeutic agent for OA.

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The Combination Treatment of Curcumin and Probucol Protects Chondrocytes from TNF-α Induced Inflammation by Enhancing Autophagy and Reducing Apoptosis via the PI3K-Akt-mTOR Pathway

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/5558066 ◽

2021 ◽

Vol 2021 ◽

pp. 1-20

Author(s):

Guangtao Han ◽

Yubiao Zhang ◽

Haohuan Li

Keyword(s):

Signaling Pathway ◽

Combination Treatment ◽

Inflammatory Cytokine ◽

Combined Treatment ◽

Mtor Pathway ◽

Mtor Signaling ◽

Mtor Signaling Pathway ◽

Tnf Α

Osteoarthritis (OA) is a chronic joint disease characterized by cholesterol accumulation in chondrocytes, cartilage degeneration, as well as extracellular matrix (ECM) destruction, and joint dysfunction. Curcumin, a chemical that can reduce cholesterol levels in OA patients, also can inhibit the progression of OA. However, a high concentration of curcumin may also trigger apoptosis in normal chondrocytes. Besides curcumin, probucol that is found can also effectively decrease the cholesterol level in OA patients. Considering that high cholesterol is a risk factor of OA, it is speculated that the combination treatment of curcumin and probucol may be effective in the prevention of OA. To investigate the possible effects of such two chemicals on OA pathophysiology, chondrocyte apoptosis and autophagy behavior under inflammatory cytokine stress were studied, and specifically, the PI3K-Akt-mTOR signaling pathway was studied. Methods. Cell proliferation, colony formation, and EdU assay were performed to identify the cytotoxicity of curcumin and probucol on chondrocytes. Transwell assay was conducted to evaluate chondrocyte migration under TNF-α inflammation stress. Immunofluorescence, JC-1, flow cytometry, RT-PCR, and western blot were used to investigate the signal variations related to autophagy and apoptosis in chondrocytes and cartilage. A histological study was carried out on OA cartilage. Glycosaminoglycan (GAG) release was determined to evaluate the ECM degradation under stress. Results. Compared with a single intervention with curcumin or probucol, a combined treatment of these two chemicals is more effective in terms of protecting chondrocytes from stress injury induced by inflammatory cytokines. The promoted protection may be attributed to the inhibition of apoptosis and the blockage of the autophagy-related PI3K/Akt/mTOR pathway. Such results were also verified in vitro by immunofluorescence staining of OA chondrocytes and in vivo by immunohistochemistry staining of cartilage. Besides, in vivo studies also showed that when applied in combination, curcumin and probucol could block the PI3K-AKT-mTOR signaling pathway; promote COL-II expression; suppress P62, MMP-3, and MMP-13 expression; and inhibit TNF-α-stimulated cartilage degradation. Moreover, the combined medication could help reduce the release of ECM GAGs in OA cartilage and alleviate the severity of OA. Conclusion. A combined treatment of curcumin and probucol could be used to protect chondrocytes from inflammatory cytokine stress via inhibition of the autophagy-related PI3K/Akt/mTOR pathway both in vitro and in vivo, which might be of potential pharmaceutical value for OA prevention and therapy.

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Dangshen Erling Decoction Ameliorates Myocardial Hypertrophy via Inhibiting Myocardial Inflammation

Frontiers in Pharmacology ◽

10.3389/fphar.2021.725186 ◽

2022 ◽

Vol 12 ◽

Author(s):

Yigang Zhong ◽

Liuying Chen ◽

Miaofu Li ◽

Lian Chen ◽

Yufeng Qian ◽

...

Keyword(s):

Signaling Pathway ◽

Cardiac Tissue ◽

Myocardial Hypertrophy ◽

Cell Model ◽

H9c2 Cell ◽

Myocardial Inflammation ◽

Cross Sectional ◽

Tnf Α

Myocardial hypertrophy plays an essential role in the structural remodeling of the heart and the progression to heart failure (HF). There is an urgent need to understand the mechanisms underlying cardiac hypertrophy and to develop treatments for early intervention. Dangshen Erling decoction (DSELD) is a clinically used formula in Chinese medicine for treating coronary heart disease in patients with HF. However, the mechanism by which DSELD produces its cardioprotective effects remains largely unknown. This study explored the effects of DSELD on myocardial hypotrophy both in vitro and in vivo. In vitro studies indicated that DSELD significantly (p < 0.05) reduced the cross-sectional area of the myocardium and reduced elevated lactate dehydrogenase (LDH), tumor necrosis factor (TNF)-α, and interleukin (IL)-6 levels in the induced H9C2 cell model to study inflammation. In vivo experiments revealed that DSELD restores cardiac function and significantly reduces myocardial fibrosis in isoproterenol (ISO)-induced HF mouse model (p < 0.05). In addition, DSELD downregulated the expression of several inflammatory cytokines, such as granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte CSF (G-CSF), IL-1α, IL-1β, IL-3, IL-5, IL-7, IL-12, IL-13, and TNF-α in HF (p < 0.05). Further analysis of the cardiac tissue demonstrated that DSELD produces its anti-inflammatory effects via the Toll-like receptor (TLR)4 signaling pathway. The expression of TLR4 downstream proteins such as matrix metalloproteinase-9 (MMP9) and myeloid differentiation factor-88 (MyD88) was among the regulated targets. In conclusion, these observations suggest that DSELD exerts antihypertrophic effects by alleviating the inflammatory injury via the TLR4 signaling pathway in HF and thus holds promising therapeutic potentials.

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SDF-1/CXCR4 Augments the Therapeutic Effect of Bone Marrow Mesenchymal Stem Cells in the Treatment of Lipopolysaccharide-Induced Liver Injury by Promoting Their Migration Through PI3K/Akt Signaling Pathway

Cell Transplantation ◽

10.1177/0963689720929992 ◽

2020 ◽

Vol 29 ◽

pp. 096368972092999 ◽

Cited By ~ 1

Author(s):

Guanghui Xiu ◽

Xiuling Li ◽

Yunyu Yin ◽

Jintao Li ◽

Bingqin Li ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Liver Injury ◽

Signaling Pathway ◽

Therapeutic Effect ◽

Acute Liver Injury ◽

Akt Signaling ◽

Akt Signaling Pathway

Mesenchymal stem cells (MSCs) are thought to have great potential in the therapy of acute liver injury. It is possible that these cells may be regulated by the stromal cell-derived factor-1 (SDF-1)/CXC chemokine receptor-4 (CXCR4) signaling axis, which has been shown to promote stem cells migration in the inflammation-associated diseases. However, the effects of SDF-1/CXCR4 axis on the MSCs-transplantation-based treatment for acute liver injury and the underlying mechanisms are largely unknown. In this study, we sought to determine whether SDF-1/CXCR4 would augment the therapeutic effect of bone marrow mesenchymal stem cells (BMSCs) by promoting their migration, which may result from activating the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway, in a rat acute liver injury model induced by lipopolysaccharide (LPS). We found that BMSCs transplantation markedly attenuated liver injury and improved the survival of LPS-treated rats. Of interest, overexpression of CXCR4 in BMSCs could substantially promote their migration both in vitro and in vivo, and result in even better therapeutic effects. This might be attributed to the activation of PI3K/Akt signaling pathway in BMSCs that is downstream of CXCR4, as demonstrated by the use of the CXCR4 antagonist AMD3100 and PI3K pathway inhibitor LY294002 assays in vitro and in vivo. Together, our results unraveled a novel molecular mechanism for the therapeutic effect of BMSCs for the treatment of acute liver injury, which may shed a new light on the clinical application of BMSCs for acute liver failure.

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Activation of STING Pathway Contributed to Cisplatin-Induced Cardiac Dysfunction via Promoting the Activation of TNF-α-AP-1 Signal Pathway

Frontiers in Pharmacology ◽

10.3389/fphar.2021.711238 ◽

2021 ◽

Vol 12 ◽

Author(s):

Lintao Wang ◽

Suya Zhang ◽

Jibo Han ◽

Xiaoyan Nie ◽

Yajun Qi ◽

...

Keyword(s):

Signaling Pathway ◽

Cardiac Dysfunction ◽

Cardiovascular Complications ◽

Signal Pathway ◽

Cardiac Damage ◽

Potential Therapeutic Target ◽

Tnf Α ◽

Sting Pathway

Cardiovascular complications are a well-documented limitation of conventional cancer chemotherapy. As a notable side effect of cisplatin, cardiotoxicity represents a major obstacle to the treatment of cancer. Recently, it has been reported that cyclic GMP-AMP synthase (cGAS) stimulator of interferon genes (STING) signaling pathway was associated with the occurrence and development of cardiovascular diseases. However, the effect of STING on cardiac damage caused by cisplatin remains unclear. In this study, cisplatin was shown to activate the cGAS-STING signaling pathway, and deficiency of STING attenuated cisplatin-induced cardiotoxicity in vivo and in vitro. Mechanistically, the STING-TNF-α-AP-1 axis contributed to cisplatin-induced cardiotoxicity by triggering cardiomyocyte apoptosis. In conclusion, our results indicated that STING might be a critical regulator of cisplatin-induced cardiotoxicity and be considered as a potential therapeutic target for preventing the progression of chemotherapy-associated cardiovascular complications.

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Zanubrutinib Attenuated Bleomycin-Induced Pulmonary Fibrosis by Inhibiting the TGF-β1 Signaling Pathway

10.21203/rs.3.rs-720040/v1 ◽

2021 ◽

Author(s):

Xiaohe Li ◽

Yuli Wei ◽

Jinying Gu ◽

Jingjing Liang ◽

Shimeng Li ◽

...

Keyword(s):

Pulmonary Fibrosis ◽

Signaling Pathway ◽

Potential Effect ◽

Lymphocytic Leukemia ◽

Mechanism Study ◽

In Vivo Experiments ◽

Molecule Inhibitor ◽

Tgf Β1

Abstract Background: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and fatal interstitial lung disease with high mortality and limited treatment. So far, the only drugs approved for the treatment of IPF are Nintedanib and Pirfenidone. Zanubrutinib, a BTK small molecule inhibitor, is approved for the treatment of mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). In this study, we explored the potential effect and mechanisms of zanubrutinib on pulmonary fibrosis in vivo and in vitro. Methods: In the in vivo experiments, different doses of zanubrutinib were administered in a mouse model of bleomycin-induced pulmonary fibrosis, and pathological manifestations and lung function indexes were evaluated. The in vitro experiments were used a TGF-β1-treated fibroblast model to evaluate the effect of zanubrutinib on the activation and autophagy phenotype of fibroblasts and explored the underlying signaling pathways mechanism. Results: In vivo experiments proved that zanubrutinib effectively attenuated bleomycin (BLM)-induced pulmonary fibrosis in mice. In vitro mechanism study indicated that zanubrutinib could suppress collagen deposition, myofibroblast activation by inhibiting the TGF-β1/Smad pathway and induce autophagy through the TGF-β1/mTOR pathway. Conclusions: Zanubrutinib could alleviate bleomycin- induced lung fibrosis in mice by inhibiting the TGF-β1 signaling pathway.

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Tetrahydropalmatine has a therapeutic effect in a lipopolysaccharide-induced disseminated intravascular coagulation model

Journal of International Medical Research ◽

10.1177/0300060519889430 ◽

2019 ◽

Vol 48 (6) ◽

pp. 030006051988943

Author(s):

Lin Zhi ◽

Shangqi Yang ◽

Jiekun Chen ◽

Yuli Lu ◽

Jiahong Chen ◽

...

Keyword(s):

Signaling Pathway ◽

Therapeutic Effect ◽

Disseminated Intravascular Coagulation ◽

Kidney Injury ◽

Therapeutic Effects ◽

Intravascular Coagulation ◽

Pathway Activation ◽

Tnf Α ◽

Liver And Kidney

Objectives The aim of this study was to determine the therapeutic effects of tetrahydropalmatine (Tet) on disseminated intravascular coagulation (DIC) by exploring the role of Tet using a lipopolysaccharide (LPS)-induced DIC model. Methods/Materials: We established a mouse DIC model by injecting LPS. Hematoxylin-eosin (HE) staining was performed to detect liver and kidney damage. Blood samples were obtained to determine liver and kidney injury indexes, coagulation indexes, and inflammatory cytokines. An in vitro cell inflammation model was also established. Tumor necrosis factor-α (TNF-α) levels and nuclear factor kappa B (NF-κB) signaling pathway activation were determined by western blot. Result Tet ameliorated the damage to organ tissues, improved coagulation indexes, and reduced the inflammatory cytokine production in LPS-induced mouse DIC. Tet also inhibited TNF-α expression by suppressing NF-κB signaling pathway activation in an in vitro LPS model using RAW 264.7 macrophages. Conclusions Tet has a mitigating and therapeutic effect on the LPS-induced DIC model via anticoagulant and anti-inflammatory effects, showing its potential as an adjunct to DIC treatment.

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Activation of Nrf2/HO-1 by Peptide YD1 Attenuates Inflammatory Symptoms through Suppression of TLR4/MYyD88/NF-κB Signaling Cascade

International Journal of Molecular Sciences ◽

10.3390/ijms22105161 ◽

2021 ◽

Vol 22 (10) ◽

pp. 5161

Author(s):

Md Saifur Rahman ◽

Md Badrul Alam ◽

Young Kyun Kim ◽

Mst Hur Madina ◽

Ismail Fliss ◽

...

Keyword(s):

Therapeutic Agent ◽

Signaling Cascade ◽

Immunomodulatory Effects ◽

In Vivo Models ◽

Nrf2 Pathway ◽

Tnf Α ◽

Cox 2 ◽

Anti Inflammatory

In this study, we investigate the immunomodulatory effects of a novel antimicrobial peptide, YD1, isolated from Kimchi, in both in vitro and in vivo models. We establish that YD1 exerts its anti-inflammatory effects via up-regulation of the Nrf2 pathway, resulting in the production of HO-1, which suppresses activation of the NF-κB pathway, including the subsequent proinflammatory cytokines IL-1β, IL-6, and TNF-α. We also found that YD1 robustly suppresses nitric oxide (NO) and prostaglandin E2 (PGE2) production by down-regulating the expression of the upstream genes, iNOS and COX-2, acting as a strong antioxidant. Collectively, YD1 exhibits vigorous anti-inflammatory and antioxidant activity, presenting it as an interesting potential therapeutic agent.

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Garcinol Attenuates Lipoprotein(a)-Induced Oxidative Stress and Inflammatory Cytokine Production in Ventricular Cardiomyocyte through α7-Nicotinic Acetylcholine Receptor-Mediated Inhibition of the p38 MAPK and NF-κB Signaling Pathways

Antioxidants ◽

10.3390/antiox10030461 ◽

2021 ◽

Vol 10 (3) ◽

pp. 461

Author(s):

Nen-Chung Chang ◽

Chi-Tai Yeh ◽

Yen-Kuang Lin ◽

Kuang-Tai Kuo ◽

Iat-Hang Fong ◽

...

Keyword(s):

Oxidative Stress ◽

Signaling Pathway ◽

P38 Mapk ◽

Expression Patterns ◽

Nicotinic Acetylcholine ◽

Α7 Nachr ◽

Tnf Α ◽

Α7 Nachrs

Garcinol, a nicotinic acetylcholine receptor (nAChR) antagonist, has recently been established as an anti-inflammation agent. However, the molecular mechanism by which garcinol suppresses inflammation in the context of acute myocardial infarction (AMI) remains unclear. Hypothesis: We hypothesized that the administration of physiological doses of garcinol in mice with isoproterenol-induced AMI decreased the effect of lipoprotein(a) (Lp(a))-induced inflammation both in vivo and in vitro via the α7-nAChRs mediated p38 mitogen-activated protein kinase (MAPK)/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) signaling pathway. We analyzed altered reactive oxygen species (ROS) generation, the production of superoxide by mitochondria, cytokine expression patterns, and the role of the p38 MAPK/NF-κB signaling pathway after Lp(a)-stimulated human ventricular cardiomyocyte AC16 cells were treated with increasing doses of garcinol. C-reactive protein (CRP), interleukin (IL)-1β, IL-6, or tumor necrosis factor (TNF)-α production were detected by enzyme-linked immunosorbent assay. The Cell Counting Kit-8 assay was used to evaluate drug cytotoxicity. Western blots and confocal fluorescence microscopy were used to determine altered expression patterns of inflammatory biomarkers. We also examined whether the therapeutic effect of garcinol in AMI was mediated in part by α7-nAChR. Lp(a)-induced inflammatory cardiomyocytes had increased expression of membrane-bound α7-nAChRs in vitro and in vivo. Low-dose garcinol did not affect cardiomyocyte viability but significantly reduced mitochondrial ROS, CRP, IL-1β, IL-6, and TNF-α production in Lp(a)-stimulated cardiomyocytes (p < 0.05). The Lp(a)-induced phosphorylation of p38 MAPKs, CamKII, and NFκB, as well as NFκB-p65 nuclear translocation, was also suppressed (p < 0.05) by garcinol, while the inhibition of p38 MAPK by the inhibitor SB203580 decreased the phosphorylation of extracellular signal-regulated kinase (ERK) and p38 MAPK. Garcinol protected cardiomyocytes by inhibiting apoptosis and inflammation in mice with AMI. Furthermore, garcinol also enhanced the expression of microRNA-205 that suppressed the α7-nAChR-induced p38 MAPK/NF-κB signaling pathway. Garcinol suppresses Lp(a)-induced oxidative stress and inflammatory cytokines by α7-nAChR-mediated inhibition of p38 MAPK/NF-κB signaling in cardiomyocyte AC16 cells and isoproterenol-induced AMI mice.

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TNF-α-induced protein 8-like 2 negatively regulates the immune function of dendritic cells by suppressing autophagy via the TAK1/JNK pathway in septic mice

Cell Death and Disease ◽

10.1038/s41419-021-04327-x ◽

2021 ◽

Vol 12 (11) ◽

Author(s):

Shuang-Qing Liu ◽

Chao Ren ◽

Ren-Qi Yao ◽

Yao Wu ◽

Ying-Yi Luan ◽

...

Keyword(s):

Dendritic Cells ◽

Immune Function ◽

Signaling Pathway ◽

Transforming Growth Factor ◽

Jnk Pathway ◽

Septic Complications ◽

Tnf Α ◽

Autophagic Activity

AbstractTumor necrosis factor (TNF)-α-induced protein 8-like 2 (TIPE2) is a newly discovered negative immunoregulatory protein that is involved in various cellular immune responses to infections. However, the underlying mechanism by which TIPE2 affects the immune function of dendritic cells (DCs) is not yet understood. This study aimed to determine the correlations among DCs TIPE2 expression, autophagic activity and immune function in the context of sepsis. In addition, the signaling pathway by which TIPE2 regulates autophagy in DCs was investigated. We reported for the first time that TIPE2 overexpression (knock-in, KI) exerted an inhibitory effect on autophagy in DCs and markedly suppressed the immune function of DCs upon septic challenge both in vitro and in vivo. In addition, TIPE2 knockout (KO) in DCs significantly enhanced autophagy and improved the immune response of DCs in sepsis. Of note, we found that the transforming growth factor-β (TGF-β)-activated kinase-1 (TAK1)/c-Jun N-terminal kinase (JNK) pathway was inhibited by TIPE2 in DCs, resulting in downregulated autophagic activity. Collectively, these results suggest that TIPE2 can suppress the autophagic activity of DCs by inhibiting the TAK1/JNK signaling pathway and further negatively regulate the immune function of DCs in the development of septic complications.

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Piezo1 Promoted Hepatocellular Carcinoma Progression and EMT Through Activating TGF-β Signaling by Recruiting Rab5c

10.21203/rs.3.rs-1057169/v1 ◽

2021 ◽

Author(s):

Yiming Li ◽

Cong Xu ◽

Bo Sun ◽

Fangjing Zhong ◽

Momo Cao ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Signaling Pathway ◽

Cell Lines ◽

Epithelial Mesenchymal Transition ◽

Independent Study ◽

Gene Set Enrichment Analysis ◽

Mechanism Study ◽

Mesenchymal Transition

Abstract Background Piezo1 plays critical roles in vascular development during early embryogenesis. However, the function of Piezo1 in hepatocellular carcinoma (HCC) remain elusive. This study aimed to explore the function and mechanisms of Piezo1 in HCC. Methods qRT-PCR, western blot and immunohistochemistry analyses were used to determine Piezo1 expression in HCC samples and cell lines. The clinical significance of Piezo1 was assessed in two independent study cohorts containing 280 patients with HCC. Gene set enrichment analysis (GSEA) was performed to explore the signaling pathway of Piezo1. A series of in vitro and in vivo experiments were used to determine the role and molecular mechanism of Piezo1 in HCC progression. Results Piezo1 expression was significantly upregulated in HCC tissues and cell lines. High Piezo1 expression was closely correlated with aggressive clinicopathological features, poor clinical outcomes of HCC patients. Moreover, knockdown of Piezo1 in HCCLM3 and Hep3B cells significantly inhibited proliferation, migration, invasion and epithelial–mesenchymal transition (EMT) of HCC cells in vitro, and tumor growth, EMT and metastasis in vivo. Further mechanism study indicated that these phenotypic and function changes were mediated by TGF-β signaling pathway. Finally, we proved that Piezo1 exerted its tumor promotion effect by recruiting Rab5c to activating TGF-β signaling pathway. Conclusions We proved Piezo1 promotes progression of hepatocellular carcinoma via TGF-β signaling, which may serve as a novel prognostic predictor and the potential therapeutic target for HCC patients.

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