The Hepatoprotection by Oleanolic Acid Preconditioning: Focusing on PPARαActivation

Objective. Previous studies have characterized the hepatoprotective and anti-inflammatory properties of oleanolic acid (OA). This study aimed to investigate the molecular mechanisms of OA hepatoprotection in concanavalin A- (ConA-) induced acute liver injury.Materials and Methods. ConA (20 mg/kg) was intravenously injected to induce acute liver injury in Balb/C mice. OA pretreatment (20, 40, and 80 mg/kg) was administered subcutaneously once daily for 3 consecutive days prior to treatment with ConA; 2, 8, and 24 h after ConA injection, the levels of serum liver enzymes and the histopathology of major factors and inflammatory cytokines were determined.Results. OA reduced the release of serum liver enzymes and inflammatory factors and prevented ConA mediated damage to the liver. OA elevated the expression levels of peroxisome proliferator-activated receptor alpha (PPARα) and decreased the phosphorylation of c-Jun NH2-terminal kinase (JNK).Conclusion. OA exhibits anti-inflammatory properties during ConA-induced acute liver injury by attenuating apoptosis and autophagy through activation of PPARαand downregulation of JNK signaling.

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Anti-Inflammatory Effects of Fucoxanthinol in LPS-Induced RAW264.7 Cells through the NAAA-PEA Pathway

Marine Drugs ◽

10.3390/md18040222 ◽

2020 ◽

Vol 18 (4) ◽

pp. 222 ◽

Cited By ~ 1

Author(s):

Wenhui Jin ◽

Longhe Yang ◽

Zhiwei Yi ◽

Hua Fang ◽

Weizhu Chen ◽

...

Keyword(s):

Nitric Oxide ◽

Inhibitory Effect ◽

Inflammatory Factors ◽

Lipid Mediator ◽

Peroxisome Proliferator ◽

Necrosis Factor Alpha ◽

Peroxisome Proliferator Activated Receptor ◽

Tnf Α ◽

Anti Inflammatory

Palmitoylethanolamide (PEA) is an endogenous lipid mediator with powerful anti-inflammatory and analgesic functions. PEA can be hydrolyzed by a lysosomal enzyme N-acylethanolamine acid amidase (NAAA), which is highly expressed in macrophages and other immune cells. The pharmacological inhibition of NAAA activity is a potential therapeutic strategy for inflammation-related diseases. Fucoxanthinol (FXOH) is a marine carotenoid from brown seaweeds with various beneficial effects. However, the anti-inflammatory effects and mechanism of action of FXOH in lipopolysaccharide (LPS)-stimulated macrophages remain unclear. This study aimed to explore the role of FXOH in the NAAA–PEA pathway and the anti-inflammatory effects based on this mechanism. In vitro results showed that FXOH can directly bind to the active site of NAAA protein and specifically inhibit the activity of NAAA enzyme. In an LPS-induced inflammatory model in macrophages, FXOH pretreatment significantly reversed the LPS-induced downregulation of PEA levels. FXOH also substantially attenuated the mRNA expression of inflammatory factors, including inducible nitric oxide synthase (iNOS), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), and markedly reduced the production of TNF-α, IL-6, IL-1β, and nitric oxide (NO). Moreover, the inhibitory effect of FXOH on NO induction was significantly abolished by the peroxisome proliferator-activated receptor α (PPAR-α) inhibitor GW6471. All these findings demonstrated that FXOH can prevent LPS-induced inflammation in macrophages, and its mechanisms may be associated with the regulation of the NAAA-PEA-PPAR-α pathway.

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Anti-Inflammatory and Hepatoprotective Effects of Ganoderma lucidum Polysaccharides against Carbon Tetrachloride-Induced Liver Injury in Kunming Mice

Pharmacology ◽

10.1159/000493896 ◽

2019 ◽

Vol 103 (3-4) ◽

pp. 143-150 ◽

Cited By ~ 8

Author(s):

Yu-Sheng Chen ◽

Quan-Zhan Chen ◽

Zhen-Jiong Wang ◽

Chun Hua

Keyword(s):

Carbon Tetrachloride ◽

Liver Injury ◽

Liver Tissue ◽

Ganoderma Lucidum ◽

Acute Liver Injury ◽

Liver Weight ◽

Inflammatory Factors ◽

Ganoderma Lucidum Polysaccharides ◽

Hepatoprotective Effects ◽

Anti Inflammatory

Background: Ganoderma lucidum Polysaccharides (GLPS) were found to possess various pharmacological properties including anti-inflammatory and hepatoprotective activities. However, the effect and possible mechanism of GLPS treatment on liver injury have not yet been reported. Therefore, this study aimed to explore the potential anti-inflammatory and hepatoprotective effects and possible mechanism of GLPS in carbon tetrachloride (CCl4)-induced acute liver injury mice. Summary: GLPS significantly reduced the activation of NLRP3 inflammasome and improved liver function in liver injury mice. It significantly inhibited CCl4-induced changes of alanine aminotransferase and aspartate aminotransferase activities in serum, as well as nitric oxide synthase (NOS) and cytochrome P450 2E1 (CYP2E1) activities in liver tissue; it also remarkably decreased levels of liver weight and index, total bilirubin, interleukin (IL)-1β, IL-18, IL-6 and tumor necrosis factor-α in serum, as well as malondialdehyde and IL-1β in liver tissue. Protein expression levels of liver NLRP3, ASC, and Caspase-1 were also downregulated, while the glutathione level in liver tissue was remarkably enhanced in GLPS groups compared to that of the model group. Key Message: These results suggested that GLPS may be a potential for the prevention and treatment of acute liver injury with liver inflammation. The possible mechanism may be related to the inhibition of free radical lipid peroxidation, NOS, and CYP2E1 activities and activation of liver inflammatory factors.

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δ-Tocotrienol, Isolated from Rice Bran, Exerts an Anti-Inflammatory Effect via MAPKs and PPARs Signaling Pathways in Lipopolysaccharide-Stimulated Macrophages

International Journal of Molecular Sciences ◽

10.3390/ijms19103022 ◽

2018 ◽

Vol 19 (10) ◽

pp. 3022 ◽

Cited By ~ 5

Author(s):

Junjun Shen ◽

Tao Yang ◽

Youzhi Xu ◽

Yi Luo ◽

Xinyue Zhong ◽

...

Keyword(s):

Rice Bran ◽

Molecular Mechanisms ◽

Mitogen Activated Protein Kinase ◽

Peroxisome Proliferator ◽

Activator Protein 1 ◽

Peroxisome Proliferator Activated Receptor ◽

Tnf Α ◽

Mitogen Activated Protein ◽

Anti Inflammatory ◽

Inflammatory Effect

δ-Tocotrienol, an important component of vitamin E, has been reported to possess some physiological functions, such as anticancer and anti-inflammation, however their molecular mechanisms are not clear. In this study, δ-tocotrienol was isolated and purified from rice bran. The anti-inflammatory effect and mechanism of δ-tocotrienol against lipopolysaccharides (LPS) activated pro-inflammatory mediator expressions in RAW264.7 cells were investigated. Results showed that δ-tocotrienol significantly inhibited LPS-stimulated nitric oxide (NO) and proinflammatory cytokine (TNF-α, IFN-γ, IL-1β and IL-6) production and blocked the phosphorylation of c-Jun N-terminal kinase (JNK) and extracellular regulated protein kinases 1/2 (ERK1/2). δ-Tocotrienol repressed the transcriptional activations and translocations of nuclear factor-kappa B (NF-κB) and activator protein-1 (AP-1), which were closely related with downregulated cytokine expressions. Meanwhile, δ-tocotrienol also affected the PPAR signal pathway and exerted an anti-inflammatory effect. Taken together, our data showed that δ-tocotrienol inhibited inflammation via mitogen-activated protein kinase (MAPK) and peroxisome proliferator-activated receptor (PPAR) signalings in LPS-stimulated macrophages.

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Liver apoptosis is age dependent and is reduced by activation of peroxisome proliferator-activated receptor-γ in hemorrhagic shock

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00262.2009 ◽

2010 ◽

Vol 298 (1) ◽

pp. G133-G141 ◽

Cited By ~ 7

Author(s):

Basilia Zingarelli ◽

Ranjit Chima ◽

Michael O'Connor ◽

Giovanna Piraino ◽

Alvin Denenberg ◽

...

Keyword(s):

Liver Injury ◽

Hemorrhagic Shock ◽

Molecular Mechanisms ◽

Pediatric Trauma ◽

Experimental Studies ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Young Rats ◽

Arterial Blood ◽

Age Dependent

A clinical observation in pediatric and adult intensive care units is that the incidence of multiple organ failure in pediatric trauma victims is lower than in adult patients. However, the molecular mechanisms are not yet defined. Recent experimental studies have shown that the nuclear peroxisome proliferator-activated receptor-γ (PPARγ) modulates the inflammatory process. In this study, we hypothesized that severity of liver injury may be age dependent and PPARγ activation may provide beneficial effects. Hemorrhagic shock was induced in anesthetized young (3–5 mo old) and mature male Wistar rats (11–13 mo old) by withdrawing blood to a mean arterial blood pressure of 50 mmHg. After 3 h, rats were rapidly resuscitated with shed blood. Animals were euthanized 3 h after resuscitation. In mature rats, liver injury appeared more pronounced compared with young rats and was characterized by marked hepatocyte apoptosis, extravasation of erythrocytes, and accumulation of neutrophils. The ratio between the antiapoptotic protein Bcl-2 and the proapoptotic protein BAX was lower, whereas activity of caspase-3, the executioner of apoptosis, was higher in liver of mature rats compared with young rats. Plasma alanine aminotransferase levels were not different between the two age groups. This heightened liver apoptosis was associated with a significant downregulation of PPARγ DNA binding in mature rats compared with young rats. Treatment with the PPARγ ligand ciglitazone significantly reduced liver apoptosis in mature rats. Our data suggest that liver injury after severe hemorrhage is age dependent and PPARγ activation is a novel hepatoprotective mechanism.

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An Integrative Pharmacology Based Analysis of Refined Liuweiwuling Against Liver Injury: A Novel Component Combination and Hepaprotective Mechanism

Frontiers in Pharmacology ◽

10.3389/fphar.2021.747010 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yuan Gao ◽

Wei Shi ◽

Hongyu Yao ◽

Yongqiang Ai ◽

Ruisheng Li ◽

...

Keyword(s):

Liver Disease ◽

Liver Injury ◽

Cell Apoptosis ◽

Liver Diseases ◽

Molecular Mechanisms ◽

Acute Liver Injury ◽

Network Pharmacology ◽

Active Ingredients ◽

Anti Inflammatory

Liver disease is a major cause of illness and death worldwide. In China, liver diseases, primarily alcoholic and nonalcoholic fatty liver disease, and viral hepatitis, affect approximately 300 million people, resulting in a major impact on the global burden of liver diseases. The use of Liuweiwuling (LWWL), a traditional Chinese medicine formula, approved by the Chinese Food and Drug Administration for decreasing aminotransferase levels induced by different liver diseases. Our previous study indicated a part of the material basis and mechanisms of LWWL in the treatment of hepatic fibrosis. However, knowledge of the materials and molecular mechanisms of LWWL in the treatment of liver diseases remains limited. Using pharmacokinetic and network pharmacology methods, this study demonstrated that the active components of LWWL were involved in the treatment mechanism against liver diseases and exerted anti-apoptosis and anti-inflammatory effects. Furthermore, esculetin, luteolin, schisandrin A and schisandrin B may play an important role by exerting anti-inflammatory and hepatoprotective effects in vitro. Esculeti and luteolin dose-dependently inhibited H2O2-induced cell apoptosis, and luteolin also inhibited the NF-κB signaling pathway in bone marrow-derived macrophages. schisandrin A and B inhibited the release of ROS in acetaminophen (APAP)-induced acute liver injury in vitro. Moreover, LWWL active ingredients protect against APAP-induced acute liver injury in mice. The four active ingredients may inhibit oxidative stress or inflammation to exert hepatoprotective effect. In conclusion, our results showed that the novel component combination of LWWL can protect against APAP-induced acute liver injury by inhibiting cell apoptosis and exerting anti-inflammatory effects.

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PPAR-γ Promotes the Polarization of Rat Retinal Microglia To M2 Phenotype By Regulating the Expression of CD200-CD200R1 Under Hypoxia

10.21203/rs.3.rs-1174536/v1 ◽

2022 ◽

Author(s):

Yiyi Hong ◽

Li Jiang ◽

Wei Huang ◽

Wen Deng ◽

Fen Tang ◽

...

Keyword(s):

Molecular Mechanisms ◽

Microglial Cells ◽

Peroxisome Proliferator ◽

Rt Pcr ◽

Peroxisome Proliferator Activated Receptor ◽

Knock Down ◽

Ppar Γ ◽

Tnf Α ◽

Anti Inflammatory ◽

M2 Phenotype

Abstract Objective Based on recent reports, peroxisome proliferator-activated receptor-γ (PPAR-γ) could promote microglial M2 polarization to inhibit inflammation. However, the specific molecular mechanisms instigate the anti-inflammatory ability of PPAR-γ in microglia have not been expounded. In the present study, we explored the molecular mechanisms of the anti-inflammatory effects of PPAR-γ in hypoxia-stimulated rat microglial cells. Methods shRNA expressing lentivirus was used to knock down PPAR-γ and CD200 genes. The hypoxia-induced polarization markers release (M1: iNOS, IL-1β, IL-6 and TNF-α; M2: Arg-1, YM1, IL-4 and IL-10) was assessed by RT-PCR, while PPAR-γ-related signals (PPAR-γ, PPAR-γ in cytoplasm or nucleus, CD200 and CD200Rs) were monitored by western blot and RT-PCR. Results Hypoxia enhanced PPAR-γ and CD200 expressions in microglial cells. In addition, PPAR-γ agonist 15d-PGJ2 elevated CD200 and CD200R1 expressions, while sh-PPAR-γ (PPAR-γ knock-down) had just the opposite effect. Following hypoxia, expressions of M1 markers increased significantly, while those of M2 markers decreased, and the above effects were attenuated by 15d-PGJ2. Conversely, knocking down PPAR-γ or CD200 inhibited the polarization of microglial cells to M2 phenotype. Conclusion Results demonstrated that PPAR-γ performed an anti-inflammatory function in hypoxia-stimulated microglial cells by promoting their polarization to M2 phenotype via CD200-CD200R1 pathway.

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Rhein attenuates lipopolysaccharide-primed inflammation through NF-κB inhibition in RAW264.7 cells: targeting the PPAR-γ signal pathway

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2019-0389 ◽

2020 ◽

Vol 98 (6) ◽

pp. 357-365 ◽

Cited By ~ 3

Author(s):

Quan Wen ◽

Jifei Miao ◽

Ngaikeung Lau ◽

Chaoying Zhang ◽

Peng Ye ◽

...

Keyword(s):

Inflammatory Process ◽

Raw264.7 Cells ◽

Inflammatory Factors ◽

Peroxisome Proliferator ◽

Inflammatory Factor ◽

Necrosis Factor Alpha ◽

Peroxisome Proliferator Activated Receptor ◽

Histone Deacetylase 3 ◽

Ppar Γ ◽

Anti Inflammatory

Inflammation is a common inducer of numerous severe diseases such as sepsis. The NF-κB signaling pathway plays a key role in the inflammatory process. Its activation promotes the release of pro-inflammatory mediators like inducible nitric oxide synthase and tumor necrosis factor alpha. Peroxisome proliferator-activated receptor gamma (PPAR-γ) inactivates nuclear factor kappa B (NF-κB) and subsequently attenuates inflammation. Rhein, an agent isolated from rhubarb, has been known to have anti-inflammatory effects. However, its influence on PPAR-γ remains largely unknown. In this study, an inflammation model was constructed by stimulating RAW264.7 cells with lipopolysaccharide. Rhein was used as a therapeutic agent, while rosiglitazone (PPAR-γ activator) and GW9662 (PPAR-γ inhibitor) were used as disrupters for in depth studies. The results demonstrated that rhein inhibits NF-κB activation and inflammatory factor release. However, GW9662 significantly reduced this effect, indicating that PPAR-γ is a critical mediator in the rhein-mediated anti-inflammatory process. Additionally, positive modulation of PPAR-γ expression and activity by rosiglitazone correspondingly influenced the effects of rhein on inflammatory factors and NF-κB expression. We also found that rhein could enhance PPAR-γ, NF-κB, and histone deacetylase 3 (HDAC3) binding. These results indicate that rhein exerts its anti-inflammation function by regulating the PPAR-γ–NF-κB–HDAC3 axis.

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Modelling the effects of PPARβδ of innate inflammatory responses in lung tissues

10.1101/2020.06.07.138867 ◽

2020 ◽

Author(s):

Noelia Perez Diaz ◽

Lisa A Lione ◽

Victoria Hutter ◽

Louise S. Mackenzie

Keyword(s):

Pulmonary Artery ◽

Mode Of Action ◽

Molecular Mechanisms ◽

Inflammatory Responses ◽

Binding Pocket ◽

Binding Energies ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Polar Interactions ◽

Anti Inflammatory

AbstractPeroxisome proliferator activated receptor beta/delta (PPARβ/δ) is a nuclear receptor ubiquitously expressed in cells whose signaling controls inflammation and metabolism. However, there are great discrepancies in understanding the role of PPARβ/δ, having both anti- and pro-effects on inflammation. Understanding the PPARβ/δ mechanism of action may provide new molecular mechanisms for treating a variety of inflammatory-related diseases.We studied the PPARβ/δ-regulation of LPS-induced inflammation of pulmonary artery, bronchi and parenchyma from rat, using different combinations of agonists (GW0742 or L-165402) and antagonists (GSK3787 or GSK0660). LPS-induced inflammation is largely regulated by PPARβ/δ in the pulmonary artery, but it is a minor factor in bronchi or parenchyma. Agonists do not significantly inhibit inflammation, but activates the PPARβ/δ induction mode of action. Surprisingly, co-incubation of the tissue with agonist plus antagonist shows anti-inflammatory effects and switches the PPARβ/δ mode of action from induction to trans-repression, indicating that the PPARβ/δ induction mode of action is pro-inflammatory and the trans-repression anti-inflammatory. Us of Computational chemistry methods indicates that PPARβ/δ agonists are predicted to form polar interactions with the residues His287, His413 and Tyr437 whilst PPARβ/δ antagonists form polar interactions with the residues Thr252 and Asn307. Further, our modelling indicates favorable binding energies and the feasibility of simultaneous binding of two ligands in the PPARβ/δ binding pocket. In summary, this study provides novel insight into the complex relationship between ligand binding profiles and functional outcomes in a rat lung inflammation model, which will help inform the design of novel therapies for inflammatory lung diseases.

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Radioprotective effect of pioglitazone against genotoxicity induced by ionizing radiation in human healthy lymphocytes

Cardiovascular & Hematological Agents in Medicinal Chemistry ◽

10.2174/1871525718666200525005231 ◽

2020 ◽

Vol 18 ◽

Author(s):

Roya Kazemi ◽

Seyed Jalal Hosseinimehr

Keyword(s):

Ionizing Radiation ◽

Human Lymphocytes ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

The Mean ◽

Anti Inflammatory ◽

Sensitizing Effect ◽

Binucleated Lymphocytes ◽

Inflammatory Effect

Objective: Pioglitazone (PG) is used to control high blood sugar in patients with type 2 diabetes mellitus. PG acts as a peroxisome proliferator-activated receptor γ agonist. In addition to the insulin-sensitizing effect, PG possesses anti-inflammatory effect. In this study, the protective effect of PG was evaluated against DNA damage induced by ionizing radiation in human healthy lymphocytes. Methods: The microtubes containing human whole blood were treated with PG at various concentrations (1-50 μM) for three hours. Then, the blood samples were irradiated with X-ray. Lymphocytes were cultured for determining the frequency of micronuclei as a genotoxicity biomarker in binucleated lymphocytes. Results: The mean percentage of micronuclei was significantly increased in human lymphocytes when were exposed to IR, while it was decreased in lymphocytes pre-treated with PG. The maximum reduction in the frequency of micronuclei in irradiated lymphocytes was observed at 5 μM of PG treatment (48% decrease). Conclusion: The anti-inflammatory property is suggested the mechanism action of PG for protection human lymphocytes against genotoxicity induced by ionizing radiation.

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