Oligonol Ameliorates CCl4-Induced Liver Injury in Rats via the NF-Kappa B and MAPK Signaling Pathways

Oxidative stress is thought to be a key risk factor in the development of hepatic diseases. Blocking or retarding the reactions of oxidation and the inflammatory process by antioxidants could be a promising therapeutic intervention for prevention or treatment of liver injuries. Oligonol is a low molecular weight polyphenol containing catechin-type monomers and oligomers derived from lychee fruit. In this study, we investigated the anti-inflammatory effect of oligonol on carbon tetrachloride- (CCl4-) induced acute hepatic injury in rats. Oral administration of oligonol (10 or 50 mg/kg) reduced CCl4-induced abnormalities in liver histology and serum AST and serum ALT levels. Oligonol treatment attenuated the CCl4-induced production of inflammatory mediators, including TNF-α, IL-1β, cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS) mRNA levels. Western blot analysis showed that oligonol suppressed proinflammatory nuclear factor-kappa B (NF-κB) p65 activation, phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun NH2-terminal kinase (JNK), and p38 mitogen-activated protein kinases (MAPKs) as well as Akt. Oligonol exhibited strong antioxidative activityin vitroandin vivo, and hepatoprotective activity againstt-butyl hydroperoxide-induced HepG2 cells. Taken together, oligonol showed antioxidative and anti-inflammatory effects in CCl4-intoxicated rats by inhibiting oxidative stress and NF-κB activation via blockade of the activation of upstream kinases including MAPKs and Akt.

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Donepezil Regulates LPS and Aβ-Stimulated Neuroinflammation through MAPK/NLRP3 Inflammasome/STAT3 Signaling

International Journal of Molecular Sciences ◽

10.3390/ijms221910637 ◽

2021 ◽

Vol 22 (19) ◽

pp. 10637

Author(s):

Jieun Kim ◽

Hyun-ju Lee ◽

Seon Kyeong Park ◽

Jin-Hee Park ◽

Ha-Ram Jeong ◽

...

Keyword(s):

Nlrp3 Inflammasome ◽

Molecular Mechanisms ◽

Acetylcholinesterase Inhibitors ◽

Mapk Signaling ◽

Inos Mrna ◽

Mrna Levels ◽

Stat3 Phosphorylation ◽

5Xfad Mice

The acetylcholinesterase inhibitors donepezil and rivastigmine have been used as therapeutic drugs for Alzheimer’s disease (AD), but their effects on LPS- and Aβ-induced neuroinflammatory responses and the underlying molecular pathways have not been studied in detail in vitro and in vivo. In the present study, we found that 10 or 50 μM donepezil significantly decreased the LPS-induced increases in the mRNA levels of a number of proinflammatory cytokines in BV2 microglial cells, whereas 50 μM rivastigmine significantly diminished only LPS-stimulated IL-6 mRNA levels. In subsequent experiments in primary astrocytes, donepezil suppressed only LPS-stimulated iNOS mRNA levels. To identify the molecular mechanisms by which donepezil regulates LPS-induced neuroinflammation, we examined whether donepezil alters LPS-stimulated proinflammatory responses by modulating LPS-induced downstream signaling and the NLRP3 inflammasome. Importantly, we found that donepezil suppressed LPS-induced AKT/MAPK signaling, the NLRP3 inflammasome, and transcription factor NF-kB/STAT3 phosphorylation to reduce neuroinflammatory responses. In LPS-treated wild-type mice, a model of neuroinflammatory disease, donepezil significantly attenuated LPS-induced microglial activation, microglial density/morphology, and proinflammatory cytokine COX-2 and IL-6 levels. In a mouse model of AD (5xFAD mice), donepezil significantly reduced Aβ-induced microglial and astrocytic activation, density, and morphology. Taken together, our findings indicate that donepezil significantly downregulates LPS- and Aβ-evoked neuroinflammatory responses in vitro and in vivo and may be a therapeutic agent for neuroinflammation-associated diseases such as AD.

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Dipterocarpus tuberculatus Roxb. Ethanol Extract Has Anti-Inflammatory and Hepatoprotective Effects In Vitro and In Vivo by Targeting the IRAK1/AP-1 Pathway

Molecules ◽

10.3390/molecules26092529 ◽

2021 ◽

Vol 26 (9) ◽

pp. 2529

Author(s):

Haeyeop Kim ◽

Woo Seok Yang ◽

Khin Myo Htwe ◽

Mi-Nam Lee ◽

Young-Dong Kim ◽

...

Keyword(s):

Ethanol Extract ◽

Serum Levels ◽

Hepatoprotective Activity ◽

Tnf Α ◽

Anti Inflammatory ◽

Related Proteins ◽

Pro Inflammatory Cytokines ◽

Inflammatory Effect

Dipterocarpus tuberculatus Roxb. has been used traditionally as a remedy for many diseases, especially inflammation. Therefore, we analyzed and explored the mechanism of the anti-inflammatory effect of a Dipterocarpus tuberculatus Roxb. ethanol extract (Dt-EE). Dt-EE clearly and dose-dependently inhibited the expression of pro-inflammatory cytokines such as IL-6, TNF-α, and IL-1β in lipopolysaccharide (LPS)-treated RAW264.7 cells. Also, Dt-EE suppressed the activation of the MyD88/TRIF-mediated AP-1 pathway and the AP-1 pathway related proteins JNK2, MKK4/7, and TAK1, which occurred as a result of inhibiting the kinase activity of IRAK1 and IRAK4, the most upstream factors of the AP-1 pathway. Finally, Dt-EE displayed hepatoprotective activity in a mouse model of hepatitis induced with LPS/D-galactosamine (D-GalN) through decreasing the serum levels of alanine aminotransferase and suppressing the activation of JNK and IRAK1. Therefore, our results strongly suggest that Dt-EE could be a candidate anti-inflammatory herbal medicine with IRAK1/AP-1 inhibitory and hepatoprotective properties.

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Thymoquinone, a Dietary Bioactive Compound, Exerts Anti-Inflammatory Effects in Colitis by Stimulating Expression of the Colonic Epithelial PPAR-γ Transcription Factor

Nutrients ◽

10.3390/nu13041343 ◽

2021 ◽

Vol 13 (4) ◽

pp. 1343

Author(s):

Balaji Venkataraman ◽

Saeeda Almarzooqi ◽

Vishnu Raj ◽

Abdullah T. Alhassani ◽

Ahmad S. Alhassani ◽

...

Keyword(s):

Transcription Factor ◽

Activity Index ◽

Nigella Sativa ◽

Mapk Signaling ◽

Mitogen Activated Protein Kinase ◽

Ppar Γ ◽

Anti Inflammatory ◽

Ht 29

Inflammatory bowel diseases (IBD) are chronic inflammatory disorders with increasing incidence and prevalence worldwide. Here, we investigated thymoquinone (TQ), a naturally occurring phytochemical present in Nigella sativa, for anti-inflammatory effects in colonic inflammation. To address this, we used in vivo (mice) and in vitro (HT-29 cells) models in this investigation. Our results showed that TQ treatment significantly reduced the disease activity index (DAI), myeloperoxidase (MPO) activity, and protected colon microscopic architecture. In addition, TQ also reduced the expression of proinflammatory cytokines and mediators at both the mRNA and protein levels. Further, TQ decreased phosphorylation of the activated mitogen-activated protein kinase (MAPK) signaling pathway and nuclear factor kappa B (NF-κB) proteins and enhanced colon epithelial PPAR-γ transcription factor expression. TQ significantly decreased proinflammatory chemokines (CXCL-1 and IL-8), and mediator (COX-2) mRNA expression in HT-29 cells treated with TNF-α. TQ also increased HT-29 PPAR-γ mRNA, PPAR-γ protein expression, and PPAR-γ promoter activity. These results indicate that TQ inhibits MAPK and NF-κB signaling pathways and transcriptionally regulates PPAR-γ expression to induce potent anti-inflammatory activity in vivo and in vitro models of colon inflammation.

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Phytochemical Analysis of Anti-Inflammatory and Antioxidant Effects of Mahonia aquifolium Flower and Fruit Extracts

Oxidative Medicine and Cellular Longevity ◽

10.1155/2018/2879793 ◽

2018 ◽

Vol 2018 ◽

pp. 1-12 ◽

Cited By ~ 13

Author(s):

Andra-Diana Andreicut ◽

Alina Elena Pârvu ◽

Augustin Cătălin Mot ◽

Marcel Pârvu ◽

Eva Fischer Fodor ◽

...

Keyword(s):

Oxidative Stress ◽

Antioxidant Activity ◽

Stress Index ◽

Tnf Alpha ◽

Phytochemical Analysis ◽

Anti Inflammatory ◽

Mahonia Aquifolium ◽

Antioxidant Effects

Oxidative stress and inflammation are interlinked processes. The aim of the study was to perform a phytochemical analysis and to evaluate the antioxidant and anti-inflammatory activities of ethanolic Mahonia aquifolium flower (MF), green fruit (MGF), and ripe fruit (MRF) extracts. Plant extract chemical composition was evaluated by HLPC. A DPPH test was used for the in vitro antioxidant activity. The in vivo antioxidant effects and the anti-inflammatory potential were tested on a rat turpentine oil-induced inflammation, by measuring serum nitric oxide (NOx) and TNF-alpha, total oxidative status (TOS), total antioxidant reactivity (TAR), oxidative stress index (OSI), 3-nitrothyrosine (3NT), malondialdehyde (MDA), and total thiols (SH). Extracts were administrated orally in three dilutions (100%, 50%, and 25%) for seven days prior to inflammation. The effects were compared to diclofenac. The HPLC polyphenol and alkaloid analysis revealed chlorogenic acid as the most abundant compound. All extracts had a good in vitro antioxidant activity, decreased NOx, TOS, and 3NT, and increased SH. TNF-alpha was reduced, and TAR increased only by MF and MGF. MDA was not influenced. Our findings suggest that M. aquifolium has anti-inflammatory and antioxidant effects that support the use in primary prevention of the inflammatory processes.

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Modulatory effect of Syzygium aromaticum and Pelargonium graveolens on oxidative stress and inflammation

10.1101/362426 ◽

2018 ◽

Author(s):

Ilias Marmouzi ◽

El Mostafa Karym ◽

Rachid Alami ◽

Meryem El Jemli ◽

Mourad Kharbach ◽

...

Keyword(s):

Oxidative Stress ◽

Essential Oils ◽

Toxic Effect ◽

Tetrahymena Pyriformis ◽

Syzygium Aromaticum ◽

Minimal Risk ◽

Pelargonium Graveolens ◽

Anti Inflammatory

AbstractBackgroundTherapy combination is defined as disease treatment with two or more medication to acheive efficacy with lower doses or lower toxicity. Regarding its reported toxicities and efficacy, the Essential Oils (EOs) from Syzygium aromaticum (SA) and Pelargonium graveolens (PG) were combined for in vitro and in vivo assays and toxicities.MethodsThe Essential Oils and mixture were tested for in vivo/in vitro antioxidant and anti-inflammatory activities. The assays included the animal model of acute inflammation (carrageenan model), the protective effect on H2O2/Sodium nitroprissude induced stress in Tetrahymena pyriformis, and the in vitro antioxidant assays.ResultsThe chemical analysis of the investigated Oils has lead to the identification of Eugenol (74.06%), Caryophyllene (11.52%) and Carvacrol acetate (7.82%) as the major element in SA; while PG was much higher in Citronellol (30.77%), 10-epi-γ-Eudesmol (22.59%), and Geraniol (13.95%). In our pharmacological screening of samples, both Oils demonstrated good antioxidant effects. In vivo investigation of the antioxidant activity in the protozoa model (T. pyriformis) demonstrated a lesser toxic effect of EOs mixture with no significant differences when oxidative stress markers and antioxidant enzymes (MDA, SOD and CAT) were evaluated. On the other hand the in vivo model of inflammatory response to carrageenan demonstrated a good inhibitory potential of both EOs. The EOs Mixture demonstrated equivalent bioactivity with lower toxic effect and minimal risk for each compound.ConclusionsThe results from this study indicate that EOs mixture from SA and PG demonstrated promising modulatory antioxidant/anti-inflammatory effect, which suggest an efficient association for therapy.

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Hexarelin exerts neuroprotective and antioxidant effects against hydrogen peroxide-induced toxicity through the modulation of MAPK and PI3K/Akt patways in Neuro-2A cells

10.1101/2020.11.16.384321 ◽

2020 ◽

Author(s):

Ramona Meanti ◽

Laura Rizzi ◽

Elena Bresciani ◽

Laura Molteni ◽

Vittorio Locatelli ◽

...

Keyword(s):

Oxidative Stress ◽

Hydrogen Peroxide ◽

Apoptotic Cell ◽

Neuroblastoma Cell ◽

Neuroblastoma Cell Line ◽

Inhibitory Influence ◽

No Production ◽

Mrna Levels

AbstractHexarelin, a synthetic hexapeptide, protects cardiac and skeletal muscles by inhibiting apoptosis, both in vitro and in vivo. Moreover, evidence suggests that hexarelin could have important neuroprotective bioactivity.Oxidative stress and the generation of free radicals has been implicated in the etiologies of several neurodegenerative diseases, including amyotrophic lateral sclerosis, Parkinson’s disease, Alzheimer’s disease, Huntington’s disease and multiple sclerosis. In addition to direct oxidative stress, exogenous hydrogen peroxide (H2O2) can penetrate biological membranes and enhance the formation of other reactive oxygen species.The aim of this study was to examine the inhibitory influence of hexarelin on H2O2-induced apoptosis in Neuro-2A cells, a mouse neuroblastoma cell line. Our results indicate that H2O2 reduced the viability of Neuro-2A cells in a dose-related fashion. Furthermore, H2O2 induced significant changes in the morphology of Neuro-2A cells, reflected in the formation of apoptotic cell bodies, and an increase of nitric oxide (NO) production. Hexarelin effectively antagonized H2O2 oxidative damage to Neuro-2A cells as indicated by improved cell viability, normal morphology and reduced nitrite (NO2−) release. Hexarelin treatment of Neuro-2A cells also reduced mRNA levels of caspases−3 and −7 and those of the pro-apoptotic molecule Bax; by contrast, hexarelin treatment increased anti-apoptotic Bcl-2 mRNA levels. Hexarelin also reduced MAPKs phosphorylation induced by H2O2 and concurrently increased p-Akt protein expression.In conclusion, our results identify several neuroprotective and anti-apoptotic effects of hexarelin. These properties suggest that further investigation of hexarelin as a neuroprotective agent in an investigational and therapeutic context are merited.

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The 12-HHT/BLT2/NO Axis Is Associated to the Wound Healing and Skin Condition in Different Glycaemic States

Medical Sciences ◽

10.3390/medsci7040065 ◽

2019 ◽

Vol 7 (4) ◽

pp. 65

Author(s):

Leguina-Ruzzi ◽

Ortiz Diban ◽

Velarde

Keyword(s):

Nitric Oxide ◽

Wound Healing ◽

Tight Junction ◽

Skin Condition ◽

Inos Mrna ◽

Nitric Oxide Production ◽

Mrna Levels ◽

Oxide Production

Type 2 diabetes affects over 340 million people worldwide. This condition can go unnoticed and undiagnosed for years, leading to a late stage where high glycaemia produces complications such as delayed wound healing. Studies have shown that 12-HHT through BLT2, accelerates keratinocyte migration and wound healing. Additionally, evidence has shown the role of nitric oxide as a pro-regenerative mediator, which is decreased in diabetes. Our main goal was to study the association between the 12-HHT/BLT2 axis and the nitric oxide production in wound healing under different glycaemia conditions. For that purpose, we used in vivo and in vitro models. Our results show that the skin from diabetic mice showed reduced BLT2 and iNOS mRNA, TEER, 12-HHT, nitrites, and tight junction levels, accompanied by higher MMP9 mRNA levels. Furthermore, a positive correlation between BLT2 mRNA and nitrites was observed. In vitro, HaCaT-BLT2 cells showed higher nitric oxide and tight junction levels, and reduced MMP9 mRNA levels, compared to mock-keratinocytes under low and high glucose condition. The wound healing capacity was associated with higher nitric oxide production and was affected by the NOS inhibition. We suggest that the BLT2 expression improves the keratinocyte response to hyperglycaemia, associated with the production of nitric oxide.

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Nerolidol Mitigates Colonic Inflammation: An Experimental Study Using both In Vivo and In Vitro Models

Nutrients ◽

10.3390/nu12072032 ◽

2020 ◽

Vol 12 (7) ◽

pp. 2032

Author(s):

Vishnu Raj ◽

Balaji Venkataraman ◽

Saeeda Almarzooqi ◽

Sanjana Chandran ◽

Shreesh K. Ojha ◽

...

Keyword(s):

Nuclear Translocation ◽

In Vitro Models ◽

Mrna Levels ◽

Colonic Inflammation ◽

Tnf Α ◽

Cox 2 ◽

Anti Inflammatory ◽

Ht 29

Nerolidol (NED) is a naturally occurring sesquiterpene alcohol present in various plants with potent anti-inflammatory effects. In the current study, we investigated NED as a putative anti-inflammatory compound in an experimental model of colonic inflammation. C57BL/6J male black mice (C57BL/6J) were administered 3% dextran sodium sulfate (DSS) in drinking water for 7 days to induce colitis. Six groups received either vehicle alone or DSS alone or DSS with oral NED (50, 100, and 150 mg/kg body weight/day by oral gavage) or DSS with sulfasalazine. Disease activity index (DAI), colonic histology, and biochemical parameters were measured. TNF-α-treated HT-29 cells were used as in vitro model of colonic inflammation to study NED (25 µM and 50 µM). NED significantly decreased the DAI and reduced the inflammation-associated changes in colon length as well as macroscopic and microscopic architecture of the colon. Changes in tissue Myeloperoxidase (MPO) concentrations, neutrophil and macrophage mRNA expression (CXCL2 and CCL2), and proinflammatory cytokine content (IL-1β, IL-6, and TNF-α) both at the protein and mRNA level were significantly reduced by NED. The increase in content of the proinflammatory enzymes, COX-2 and iNOS induced by DSS were also significantly inhibited by NED along with tissue nitrate levels. NED promoted Nrf2 nuclear translocation dose dependently. NED significantly increased antioxidant enzymes activity (Superoxide dismutase (SOD) and Catalase (CAT)), Hemeoxygenase-1 (HO-1), and SOD3 mRNA levels. NED treatment in TNF-α-challenged HT-29 cells significantly decreased proinflammatory chemokines (CXCL1, IL-8, CCL2) and COX-2 mRNA levels. NED supplementation attenuates colon inflammation through its potent antioxidant and anti-inflammatory activity both in in vivo and in vitro models of colonic inflammation.

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Aloe Metabolites Prevent LPS-Induced Sepsis and Inflammatory Response by Inhibiting Mitogen-Activated Protein Kinase Activation

The American Journal of Chinese Medicine ◽

10.1142/s0192415x17500458 ◽

2017 ◽

Vol 45 (04) ◽

pp. 847-861 ◽

Cited By ~ 15

Author(s):

Chia-Yang Li ◽

Katsuhiko Suzuki ◽

Yung-Li Hung ◽

Meng-Syuan Yang ◽

Chung-Ping Yu ◽

...

Keyword(s):

Ex Vivo ◽

Aloe Vera ◽

Peritoneal Macrophages ◽

Mitogen Activated Protein Kinase ◽

Protective Effects ◽

Raw264.7 Macrophages ◽

Mitogen Activated Protein ◽

Anti Inflammatory

Aloe, a polyphenolic anthranoid-containing Aloe vera leaves, is a Chinese medicine and a popular dietary supplement worldwide. In in vivo situations, polyphenolic anthranoids are extensively broken down into glucuronides and sulfate metabolites by the gut and the liver. The anti-inflammatory potential of aloe metabolites has not been examined. The aim of this study was to investigate the anti-inflammatory effects of aloe metabolites from in vitro (lipopolysaccharides (LPS)-activated RAW264.7 macrophages) and ex vivo (LPS-activated peritoneal macrophages) to in vivo (LPS-induced septic mice). The production of proinflammatory cytokines (TNF-[Formula: see text] and IL-12) and NO was determined by ELISA and Griess reagents, respectively. The expression levels of iNOS and MAPKs were analyzed by Western blot. Our results showed that aloe metabolites inhibited the expression of iNOS, decreased the production of TNF-[Formula: see text], IL-12, and NO, and suppressed the phosphorylation of MAPKs by LPS-activated RAW264.7 macrophages. In addition, aloe metabolites reduced the production of NO, TNF-[Formula: see text] and IL-12 by murine peritoneal macrophages. Furthermore, aloe administration significantly reduced the NO level and exhibited protective effects against sepsis-related death in LPS-induced septic mice. These results suggest that aloe metabolites exerted anti-inflammatory effects in vivo, and that these effects were associated with the inhibition of inflammatory mediators. Therefore, aloe could be considered an effective therapeutic agent for the treatment of sepsis.

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Insulin acts via mitogen-activated protein kinase phosphorylation in rabbit blastocysts

Reproduction ◽

10.1530/rep.1.00204 ◽

2004 ◽

Vol 128 (5) ◽

pp. 517-526 ◽

Cited By ~ 37

Author(s):

Anne Navarrete Santos ◽

Sarah Tonack ◽

Michaela Kirstein ◽

Marie Pantaleon ◽

Peter Kaye ◽

...

Keyword(s):

Protein Kinase ◽

Glucose Transport ◽

Mapk Signaling ◽

Mitogen Activated Protein Kinase ◽

Preimplantation Embryos ◽

Mrna Levels ◽

Glut4 Translocation ◽

Mitogen Activated Protein ◽

Rabbit Embryos

The addition of insulin during in vitro culture has beneficial effects on rabbit preimplantation embryos leading to increased cell proliferation and reduced apoptosis. We have previously described the expression of the insulin receptor (IR) and the insulin-responsive glucose transporters (GLUT) 4 and 8 in rabbit preimplantation embryos. However, the effects of insulin on IR signaling and glucose metabolism have not been investigated in rabbit embryos. In the present study, the effects of 170 nM insulin on IR, GLUT4 and GLUT8 mRNA levels, Akt and Erk phosphorylation, GLUT4 translocation and methyl glucose transport were studied in cultured day 3 to day 6 rabbit embryos. Insulin stimulated phosphorylation of the mitogen-activated protein kinase (MAPK) Erk1/2 and levels of IR and GLUT4 mRNA, but not phosphorylation of the phosphatidylinositol 3-kinase-dependent protein kinase, Akt, GLUT8 mRNA levels, glucose uptake or GLUT4 translocation. Activation of the MAPK signaling pathway in the absence of GLUT4 translocation and of a glucose transport response suggest that in the rabbit preimplantation embryo insulin is acting as a growth factor rather than a component of glucose homeostatic control.

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