Ursolic acid protects chondrocytes, exhibits anti-inflammatory properties via regulation of the NF-κB/NLRP3 inflammasome pathway and ameliorates osteoarthritis

: In vivo and in vitro studies reveal that ursolic acid (UA) is able to counteract endogenous and exogenous inflammatory stimuli, and has favorable anti-inflammatory effects. The anti-inflammatory mechanisms mainly include decreasing the release of histamine in mast cells, suppressing the activities of lipoxygenase, cyclooxygenase and phospholipase, and reducing the production of nitric oxide and reactive oxygen species, blocking the activation of signal pathway, down-regulating the expression of inflammatory factors, and inhibiting the activities of elastase and complement. These mechanisms can open up new avenues for the scientific community to develop or improve novel therapeutic approaches to tackle inflammatory diseases such as arthritis, atherosclerosis, neuroinflammation, liver diseases, kidney diseases, diabetes, dermatitis, bowel diseases, cancer. The anti-inflammatory activity, the anti-inflammatory mechanism of ursolic acid and its therapeutic applications are reviewed in this paper.

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Clozapine Prevents Poly (I:C) Induced Inflammation by Modulating NLRP3 Pathway in Microglial Cells

Cells ◽

10.3390/cells9030577 ◽

2020 ◽

Vol 9 (3) ◽

pp. 577

Author(s):

Vijayasree V. Giridharan ◽

Giselli Scaini ◽

Gabriela D. Colpo ◽

Tejaswini Doifode ◽

Omar F. Pinjari ◽

...

Keyword(s):

Cell Cultures ◽

Nlrp3 Inflammasome ◽

Antipsychotic Drugs ◽

Poly I:C ◽

Tnf Α ◽

Cytokine Levels ◽

Primary Microglial Cell ◽

Anti Inflammatory ◽

The Brain ◽

Nlrp3 Expression

Schizophrenia is a complex psychiatric disorder that exhibits an interconnection between the immune system and the brain. Experimental and clinical studies have suggested the presence of neuroinflammation in schizophrenia. In the present study, the effect of antipsychotic drugs, including clozapine, risperidone, and haloperidol (10, 20 and 20 μM, respectively), on the production of IL-1α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-17, IL-18, INF-γ, and TNF-α was investigated in the unstimulated and polyriboinosinic-polyribocytidilic acid [poly (I:C)]-stimulated primary microglial cell cultures. In the unstimulated cultures, clozapine, risperidone, and haloperidol did not influence the cytokine levels. Nevertheless, in cell cultures under strong inflammatory activation by poly (I:C), clozapine reduced the levels of IL-1α, IL-1β, IL-2, and IL-17. Risperidone and haloperidol both reduced the levels of IL-1α, IL-1β, IL-2, and IL-17, and increased the levels of IL-6, IL-10, INF-γ, and TNF-α. Based on the results that were obtained with the antipsychotic drugs and observing that clozapine presented with a more significant anti-inflammatory effect, clozapine was selected for the subsequent experiments. We compared the profile of cytokine suppression obtained with the use of NLRP3 inflammasome inhibitor, CRID3 to that obtained with clozapine, to test our hypothesis that clozapine inhibits the NLRP3 inflammasome. Clozapine and CRID3 both reduced the IL-1α, IL-1β, IL-2, and IL-17 levels. Clozapine reduced the level of poly (I:C)-activated NLRP3 expression by 57%, which was higher than the reduction thay was seen with CRID3 treatment (45%). These results suggest that clozapine might exhibit anti-inflammatory effects by inhibiting NLRP3 inflammasome and this activity is not typical with the use of other antipsychotic drugs under the conditions of strong microglial activation.

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Eplerenone prevented obesity-induced inflammasome activation and glucose intolerance

Journal of Endocrinology ◽

10.1530/joe-17-0351 ◽

2017 ◽

Vol 235 (3) ◽

pp. 179-191 ◽

Cited By ~ 28

Author(s):

Tsutomu Wada ◽

Akari Ishikawa ◽

Eri Watanabe ◽

Yuto Nakamura ◽

Yusuke Aruga ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Glucose Intolerance ◽

Nlrp3 Inflammasome ◽

Inflammasome Activation ◽

M2 Macrophage ◽

Expression Levels ◽

Nlrp3 Inflammasome Activation ◽

M1 Macrophage ◽

Anti Inflammatory

Obesity-associated activation of the renin-angiotensin-aldosterone system is implicated in the pathogenesis of insulin resistance; however, influences of mineralocorticoid receptor (MR) inhibition remain unclear. Therefore, we aimed to clarify the anti-inflammatory mechanisms of MR inhibition using eplerenone, a selective MR antagonist, in C57BL/6 mice fed a high-fat diet (HFD) for 12 weeks. Eplerenone prevented excessive body weight gain and fat accumulation, ameliorated glucose intolerance and insulin resistance and enhanced energy metabolism. In the epididymal white adipose tissue (eWAT), eplerenone prevented obesity-induced accumulation of F4/80+CD11c+CD206−-M1-adipose tissue macrophage (ATM) and reduction of F4/80+CD11c−CD206+-M2-ATM. Interestingly, M1-macrophage exhibited lower expression levels of MR, compared with M2-macrophage, in the ATM of eWAT and in vitro-polarized bone marrow-derived macrophages (BMDM). Importantly, eplerenone and MR knockdown attenuated the increase in the expression levels of proIl1b, Il6 and Tnfa, in the eWAT and liver of HFD-fed mice and LPS-stimulated BMDM. Moreover, eplerenone suppressed IL1b secretion from eWAT of HFD-fed mice. To reveal the anti-inflammatory mechanism, we investigated the involvement of NLRP3-inflammasome activation, a key process of IL1b overproduction. Eplerenone suppressed the expression of the inflammasome components, Nlrp3 and Caspase1, in the eWAT and liver. Concerning the second triggering factors, ROS production and ATP- and nigericin-induced IL1b secretion were suppressed by eplerenone in the LPS-primed BMDM. These results indicate that eplerenone inhibited both the priming and triggering signals that promote NLRP3-inflammasome activation. Therefore, we consider MR to be a crucial target to prevent metabolic disorders by suppressing inflammasome-mediated chronic inflammation in the adipose tissue and liver under obese conditions.

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Coenzyme Q0 Inhibits NLRP3 Inflammasome Activation through Mitophagy Induction in LPS/ATP-Stimulated Macrophages

Oxidative Medicine and Cellular Longevity ◽

10.1155/2022/4266214 ◽

2022 ◽

Vol 2022 ◽

pp. 1-15

Author(s):

You-Cheng Hseu ◽

Yu-Fang Tseng ◽

Sudhir Pandey ◽

Sirjana Shrestha ◽

Kai-Yuan Lin ◽

...

Keyword(s):

Nlrp3 Inflammasome ◽

Coenzyme Q ◽

Antioxidant Properties ◽

Variable Number ◽

Ros Generation ◽

Inflammasome Activation ◽

Raw264.7 Macrophages ◽

Mitochondrial Ros ◽

Nlrp3 Inflammasome Activation ◽

Anti Inflammatory

Coenzyme Q (CoQ) analogs with a variable number of isoprenoid units have exhibited as anti-inflammatory as well as antioxidant molecules. Using novel quinone derivative CoQ0 (2,3-dimethoxy-5-methyl-1,4-benzoquinone, zero side chain isoprenoid), we studied its molecular activities against LPS/ATP-induced inflammation and redox imbalance in murine RAW264.7 macrophages. CoQ0’s non- or subcytotoxic concentration suppressed the NLRP3 inflammasome and procaspase-1 activation, followed by downregulation of IL1β expression in LPS/ATP-stimulated RAW264.7 macrophages. Similarly, treatment of CoQ0 led to LC3-I/II accumulation and p62/SQSTM1 activation. An increase in the Beclin-1/Bcl-2 ratio and a decrease in the expression of phosphorylated PI3K/AKT, p70 S6 kinase, and mTOR showed that autophagy was activated. Besides, CoQ0 increased Parkin protein to recruit damaged mitochondria and induced mitophagy in LPS/ATP-stimulated RAW264.7 macrophages. CoQ0 inhibited LPS/ATP-stimulated ROS generation in RAW264.7 macrophages. Notably, when LPS/ATP-stimulated RAW264.7 macrophages were treated with CoQ0, Mito-TEMPO (a mitochondrial ROS inhibitor), or N-acetylcysteine (NAC, a ROS inhibitor), there was a significant reduction of LPS/ATP-stimulated NLRP3 inflammasome activation and IL1β expression. Interestingly, treatment with CoQ0 or Mito-TEMPO, but not NAC, significantly increased LPS/ATP-induced LC3-II accumulation indicating that mitophagy plays a key role in the regulation of CoQ0-inhibited NLRP3 inflammasome activation. Nrf2 knockdown significantly decreased IL1β expression in LPS/ATP-stimulated RAW264.7 macrophages suggesting that CoQ0 inhibited ROS-mediated NLRP3 inflammasome activation and IL1β expression was suppressed due to the Nrf2 activation. Hence, this study showed that CoQ0 might be a promising candidate for the therapeutics of inflammatory disorders due to its effective anti-inflammatory as well as antioxidant properties.

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The anti-inflammatory effects of baicalin through suppression of NLRP3 inflammasome pathway in LPS-challenged piglet mononuclear phagocytes

Innate Immunity ◽

10.1177/1753425916631032 ◽

2016 ◽

Vol 22 (3) ◽

pp. 196-204 ◽

Cited By ~ 18

Author(s):

Chun Ye ◽

Sali Li ◽

Wenxu Yao ◽

Lei Xu ◽

Yinsheng Qiu ◽

...

Keyword(s):

Nlrp3 Inflammasome ◽

Mononuclear Phagocytes ◽

Anti Inflammatory

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Abstract 14045: Reperfusion Therapy With Recombinant Human Relaxin (Serelaxin) Attenuates Myocardial Inflammasome Formation and Ischemic Injury in Mice via eNOS-dependent Mechanism

Circulation ◽

10.1161/circ.132.suppl_3.14045 ◽

2015 ◽

Vol 132 (suppl_3) ◽

Author(s):

Juan Valle Raleigh ◽

Adolfo G Mauro ◽

Carlo Marchetti ◽

Jun He ◽

Stefano Toldo ◽

...

Keyword(s):

Infarct Size ◽

Nlrp3 Inflammasome ◽

Ischemia Reperfusion ◽

Ischemic Injury ◽

Reperfusion Therapy ◽

Coronary Artery Ligation ◽

Myocardial Infarct Size ◽

Caspase 1 ◽

Anti Inflammatory ◽

Dependent Mechanism

Background: The preconditioning-like infarct-sparing and anti-inflammatory effects of the peptide hormone relaxin following ischemic injury have been studied in the heart. Whether reperfusion therapy with recombinant human relaxin (serelaxin, SRLX) reduces myocardial infarct size and attenuates NLRP3 inflammasome formation/caspase-1 activation and subsequent loss of functional myocardium following ischemia/reperfusion (I/R) injury is unknown. Methods and Results: After baseline echocardiography, adult male C57BL (WT) or eNOS knockout (KO) mice underwent myocardial infarction (MI) by coronary artery ligation for 30 minutes followed by 24 h reperfusion. Mice were treated with either SRLX (10 μg/Kg; sc) or saline 5 minutes before reperfusion. SRLX improved survival at 24 h post MI in WT mice (79%) as compared with controls (42%), whereas there was no difference in survival between SRLX- and saline-treated eNOS KO mice. Moreover, SRLX significantly reduced infarct size, measured with TTC staining, and preserved LV fractional shortening (FS) and end-systolic diameter (LVESD) in WT mice as compared with controls. Interestingly, cardiac caspase-1 activity was markedly reduced in SRLX-treated mice compared with controls at 24 h post MI (Figure A-D). Genetic deletion of eNOS abolished the infarct-sparing and anti-inflammatory effects of SRLX as well as functional preservation. SRLX plasma levels were assessed 5 min. after treatment using ELISA and the results demonstrate therapeutic levels comparable to plasma relaxin during the first trimester of pregnancy (Figure E). Conclusion: Reperfusion therapy with SRLX attenuates myocardial I/R injury and NLRP3 inflammasome formation via eNOS-dependent mechanism. We propose that SRLX possesses an anti-inflammatory effect preventing caspase-1 activation and inflammatory complications following MI, which may shed some light on the mechanism behind the survival benefit observed in the RELAX-AHF trial.

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SPASMOLYTIC, ANTI-INFLAMMATORY, AND ANTIOXIDANT ACTIVITY OF SALVIA GESNERIFLORA LINDLEY

African Journal of Traditional Complementary and Alternative Medicines ◽

10.21010/ajtcam.v15i4.10 ◽

2018 ◽

Vol 15 (4) ◽

pp. 72

Author(s):

Abraham Gómez-Rivera ◽

Manasés González-Cortazar ◽

Ammy Joana Gallegos-García ◽

Armando Escobar-Ramos ◽

Gabriel Flores-Franco ◽

...

Keyword(s):

Antioxidant Activity ◽

Guinea Pig ◽

Ursolic Acid ◽

Antioxidant Potential ◽

Guinea Pig Ileum ◽

Chromatographic Profile ◽

Mouse Ear ◽

Inflammatory Edema ◽

Anti Inflammatory

Background: Salvia gesneriflora Lindley is employed in traditional Mexican medicine for the treatment of several diseases. Materials and Methods: The chromatographic profile of three extracts (SgH, SgD and SgM) of this plant allowed the identification of 11 components in SgH, the presence of rosmarinic (1), chlorogenic (2) and caffeic (3) acids and quercetin glucoside (4) in SgM and of ursolic acid (5) in SgD. The spasmolytic (electrically induced contractions of guinea-pig ileum), anti-inflammatory (edema in mouse ear) and antioxidant potential (DPPH, ABTS and FRAP assays) of the extracts were evaluated. Results: SgM showed the highest percentage of relaxation (80.67 ± 1.633%) with no significant difference (p

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Astragaloside IV Suppresses High Glucose-Induced NLRP3 Inflammasome Activation by Inhibiting TLR4/NF-κB and CaSR

Mediators of Inflammation ◽

10.1155/2019/1082497 ◽

2019 ◽

Vol 2019 ◽

pp. 1-16 ◽

Cited By ~ 10

Author(s):

Bin Leng ◽

Yingjie Zhang ◽

Xinran Liu ◽

Zhen Zhang ◽

Yang Liu ◽

...

Keyword(s):

Nlrp3 Inflammasome ◽

High Glucose ◽

Inflammasome Activation ◽

Astragaloside Iv ◽

Caspase 1 ◽

Endothelial Inflammation ◽

Nlrp3 Inflammasome Activation ◽

Anti Inflammatory

Long-term exposure to high glucose induces vascular endothelial inflammation that can result in cardiovascular disease. Astragaloside IV (As-IV) is widely used for anti-inflammatory treatment of cardiovascular diseases. However, its mechanism of action is still not fully understood. In this study, we investigated the effect of As-IV on high glucose-induced endothelial inflammation and explored its possible mechanisms. In vivo, As-IV (40 and 80 mg/kg/d) was orally administered to rats for 8 weeks after a single intraperitoneal injection of streptozotocin (STZ, 65 mg/kg). In vitro, human umbilical vein endothelial cells (HUVECs) were treated with high glucose (33 mM glucose) in the presence or absence of As-IV, NPS2143 (CaSR inhibitor), BAY 11-7082 (NF-κB p65 inhibitor), and INF39 (NLRP3 inhibitor), and overexpression of CaSR was induced by infection of CaSR-overexpressing lentiviral vectors to further discuss the anti-inflammatory property of As-IV. The results showed that high glucose increased the expression of interleukin-18 (IL-18), interleukin-1β (IL-1β), NLRP3, caspase-1, and ASC, as well as the protein level of TLR4, nucleus p65, and CaSR. As-IV can reverse these changes in vivo and in vitro. Meanwhile, NPS2143, BAY 11-7082, and INF39 could significantly abolish the high glucose-enhanced NLRP3, ASC, caspase-1, IL-18, and IL-1β expression in vitro. In addition, both NPS2143 and BAY 11-7082 attenuated high glucose-induced upregulation of NLRP3, ASC, caspase-1, IL-18, and IL-1β expression. In conclusion, this study suggested that As-IV could inhibit high glucose-induced NLRP3 inflammasome activation and subsequent secretion of proinflammatory cytokines via inhibiting TLR4/NF-κB signaling pathway and CaSR, which provides new insights into the anti-inflammatory activity of As-IV.

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