Modulation of microglial phenotypes by dexmedetomidine through TREM2 reduces neuroinflammation in heatstroke

AbstractNo FDA approved pharmacological therapy is available to reduce neuroinflammation following heatstroke. Previous studies have indicated that dexmedetomidine (DEX) could protect against inflammation and brain injury in various inflammation-associated diseases. However, no one has tested whether DEX has neuro-protective effects in heatstroke. In this study, we focused on microglial phenotypic modulation to investigate the mechanisms underlying the anti-inflammatory effects of DEX in vivo and in vitro. We found that DEX treatment reduced the expression of CD68, iNOS, TNF-α, and IL-1β, and increased the expression of CD206, Arg1, IL-10 and TGF-β in microglia, ameliorating heatstroke induced neuroinflammation and brain injury in mice. TREM2, whose neuro-protective function has been validated by genetic studies in Alzheimer’s disease and Nasu-Hakola disease, was significantly promoted by DEX in the microglia. TREM2 esiRNA reversed the DEX-induced activation of PI3K/Akt signalling. Overall these findings indicated that DEX may serve, as a potential therapeutic approach to ameliorate heatstroke induced neuroinflammation and brain injury via TREM2 by activating PI3K/Akt signalling.

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α2-Adrenoceptor agonist dexmedetomidine protects septic acute kidney injury through increasing BMP-7 and inhibiting HDAC2 and HDAC5

AJP Renal Physiology ◽

10.1152/ajprenal.00143.2012 ◽

2012 ◽

Vol 303 (10) ◽

pp. F1443-F1453 ◽

Cited By ~ 46

Author(s):

Chung-Hsi Hsing ◽

Chiou-Feng Lin ◽

Edmund So ◽

Ding-Ping Sun ◽

Tai-Chi Chen ◽

...

Keyword(s):

Acute Kidney Injury ◽

Histone Deacetylases ◽

Trichostatin A ◽

Histone H3 ◽

Cecal Ligation ◽

Kidney Injury ◽

Protective Effects ◽

Tnf Α

Bone morphogenetic protein (BMP)-7 protects sepsis-induced acute kidney injury (AKI). Dexmedetomidine (DEX), an α2-adrenoceptor (α2-AR) agonist, has anti-inflammatory effects. We investigated the protective effects of DEX on sepsis-induced AKI and the expression of BMP-7 and histone deacetylases (HDACs). In vitro , the effects of DEX or trichostatin A (TSA, an HDAC inhibitor) on TNF-α, monocyte chemotactic protein (MCP-1), BMP-7, and HDAC mRNA expression in LPS-stimulated rat renal tubular epithelial NRK52E cells, was determined using real-time PCR. In vivo, mice were intraperitoneally injected with DEX (25 μg/kg) or saline immediately and 12 h after cecal ligation and puncture (CLP) surgery. Twenty-four hours after CLP, we examined kidney injury and renal TNF-α, MCP-1, BMP-7, and HDAC expression. Survival was monitored for 120 h. LPS increased HDAC2, HDAC5, TNF-α, and MCP-1 expression, but decreased BMP-7 expression in NRK52E cells. DEX treatment decreased the HDAC2, HDAC5, TNF-α, and MCP-1 expression, but increased BMP-7 and acetyl histone H3 expression, whose effects were blocked by yohimbine, an α2-AR antagonist. With DEX treatment, the LPS-induced TNF-α expression and cell death were attenuated in scRNAi-NRK52E but not BMP-7 RNAi-NRK52E cells. In CLP mice, DEX treatment increased survival and attenuated AKI. The expression of HDAC2, HDAC5, TNF-α, and MCP-1 mRNA in the kidneys of CLP mice was increased, but BMP-7 was decreased. However, DEX treatment reduced those changes. DEX reduces sepsis-induced AKI by decreasing TNF-α and MCP-1 and increasing BMP-7, which is associated with decreasing HDAC2 and HDAC5, as well as increasing acetyl histone H3.

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In Vivo and In Vitro Evaluation of the Protective Effects of Hesperidin in Lipopolysaccharide-Induced Inflammation and Cytotoxicity of Cell

Molecules ◽

10.3390/molecules25030478 ◽

2020 ◽

Vol 25 (3) ◽

pp. 478 ◽

Cited By ~ 6

Author(s):

Rasha Al-Rikabi ◽

Hanady Al-Shmgani ◽

Yaser Hassan Dewir ◽

Salah El-Hendawy

Keyword(s):

Breast Cancer ◽

Chromatin Condensation ◽

Control Group ◽

Potential Candidate ◽

Dependent Manner ◽

Protective Effects ◽

Mcf7 Cells ◽

Tnf Α

(1) Background: Plant flavonoids are efficient in preventing and treating various diseases. This study aimed to evaluate the ability of hesperidin, a flavonoid found in citrus fruits, in inhibiting lipopolysaccharide (LPS) induced inflammation, which induced lethal toxicity in vivo, and to evaluate its importance as an antitumor agent in breast cancer. The in vivo experiments revealed the protective effects of hesperidin against the negative LPS effects on the liver and spleen of male mice. (2) Methods: In the liver, the antioxidant activity was measured by estimating the concentration of glutathione (GSH) and catalase (CAT), whereas in spleen, the concentration of cytokines including IL-33 and TNF-α was measured. The in vitro experiments including MTT assay, clonogenity test, and sulforhodamine 101 stain with DAPI (4′, 6-diamidino-2-phenylindole) were used to assess the morphological apoptosis in breast cancer cells. (3) Results: The results of this study revealed a significant increase in the IL-33 and TNF-α cytokine levels in LPS challenged mice along with a considerable elevation in glutathione (GSH); moreover, the catalase (CAT) level was higher compared to that of the control group. Cytotoxicity of the MCF-7 cell line revealed significant differences among the groups treated with different concentrations when compared to the control groups, in a concentration-dependent manner. Hesperidin significantly inhibited the colony formation of MCF7 cells when compared to that of control. Clear changes were observed in the cell shape, including cell shrinkage and chromatin condensation, which were associated with a later apoptotic stage. (4) Conclusion: The results indicate that hesperidin might be a potential candidate in preventing diseases.

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FGF20 protected against BBB disruption after traumatic brain injury by activating the AKT/GSK3β pathway to upregulate junction protein expression and inhibiting JNK/NFκB-dependent neuroinflammation

10.21203/rs.2.19529/v1 ◽

2019 ◽

Author(s):

Jun Chen ◽

Xue Wang ◽

Jian Hu ◽

Wenting Huang ◽

Confidence Dordoe ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Inflammatory Response ◽

Brain Edema ◽

Microvascular Endothelial Cell ◽

Potential Candidate ◽

Protective Effects ◽

Tnf Α ◽

Junction Protein

Abstract Background ：Blood-brain barrier (BBB) disruption and the cerebral inflammatory response are two reciprocal mechanisms that work together to mediate the degree of brain edema, which is responsible for the majority of deaths after traumatic brain injury (TBI), and facilitate further brain damage, which leads to long-term TBI complications. Fibroblast growth factor 20 (FGF20), a neurotrophic factor, plays important roles in the development of dopaminergic neurons in Parkinson disease (PD). However, little is known about the role of FGF20 in TBI. The aim of the current study was to assess the protective effects of FGF20 in TBI through protecting the BBB. Methods: We explored the relationship between FGF20 and BBB function in controlled cortical impact (CCI)-induced TBI mice model and TNF-α-induced human brain microvascular endothelial cell (HBMEC) in vitro BBB disruption model. We also explored the mechanisms of these interactions and the signaling processes involved in BBB function and neuroinflammation. Results: In this study, we demonstrate that recombinant human FGF20 (rhFGF20) reduced neurofunctional deficits, brain edema and Evans Blue penetration in vivo after TBI. In an in vitro BBB disruption model of, rhFGF20 could reverse changes to TNF-α-induced HBMEC morphology, reduce Transwell permeability, and increase transendothelial electrical resistance (TEER). In both a TBI mouse model and in vitro , rhFGF20 upregulated the expression of BBB-associated tight junction (TJ) protein and adherens junction (AJ) protein via the AKT/GSK3β pathway. In addition, rhFGF20 inhibited the cerebral inflammatory response through regulating the JNK/NFκB pathway and further protected the function of the BBB. Conclusions : Our results contribute to a new treatment strategy in TBI research. FGF20 is a potential candidate to treat TBI as it protects the BBB via regulating the AKT/GSK3β and JNK/NFκB signaling pathways.

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In Silico, in Vitro and in Vivo Investigation of a Newly Synthesized Ionic Compound As Anti-Alzheimer Multi-Target Dual AChE/BuChE Inhibitor Possessing Neuro-Protective Effects Against Aβ Induced Neurotoxicity in PC12 Cells and Alzheimer Rat Model

10.21203/rs.3.rs-230581/v1 ◽

2021 ◽

Author(s):

Hosna Karami ◽

somaieh soltani ◽

Gerhard Wolber ◽

Saeed Sadigh-Eteghad ◽

Roghaye Nikbakht ◽

...

Keyword(s):

Pc12 Cells ◽

Quaternary Ammonium ◽

Aqueous Solubility ◽

In Vivo Studies ◽

Protective Effects ◽

Rat Models ◽

Tnf Α ◽

Neuro Inflammation

Abstract Multi-target anti Alzheimer’s disease (AD) compounds are promising leads for the development of AD modifying agents. Ionic compounds containing quaternary ammonium moiety were synthesized and their multi-targeted anti-AD effects were examined in the current study. Compound 5g possessed suitable aqueous solubility and cell toxicity. It also showed non-competitive dual hAChE/hBuChE inhibition activity. Compound 5g reversed the Aβ-treated PC12 cells’ morphology alteration and reduced PC12 cells’ death. Compound 5g possessed anti-oxidative stress activity through anti-oxidant, anti-ROS production and anti-lipid peroxidation mechanisms. It also reduced the expression of IL-1β and TNF-α genes. Furthermore, compound 5g LDH inhibition, reduction of neuro-inflammation and prevention of autophagy-apoptosis were approved by the results of in vitro studies. Compound 5g delivery to brain was confirmed by in vivo studies. Administration of compound 5g to Aβ-induced AD rat models improved their cognition function and spatial memory learning behavior. TNF-α and NFkB down-regulated in compound 5g treated AD rats’ hippocamp. Besides, compound 5g reversed the up-regulation of AChE in Aβ treated rats’ hippocamp. Molecular modeling studies confirmed the interaction of compound 5g with both steric and catalytic sites of ChE enzymes. The newly synthesized quaternary ammonium containing derivative (compound 5g) possessed multi-target anti-AD efficacy based on in vitro and in vivo studies and its efficacy in AD rat models were approved by behavioral and molecular investigations.

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Protective Effects of Lentinan Against Lipopolysaccharide-Induced Mastitis in Mice

Frontiers in Pharmacology ◽

10.3389/fphar.2021.755768 ◽

2021 ◽

Vol 12 ◽

Author(s):

Huifang Yin ◽

Guanhong Xue ◽

Ailing Dai ◽

Haichong Wu

Keyword(s):

Mammary Epithelial ◽

Economic Losses ◽

Dependent Manner ◽

Protective Effects ◽

Dairy Farmers ◽

Worldwide Production ◽

Tnf Α ◽

Anti Inflammatory

Mastitis is a worldwide production disease in dairy cows, which mainly affects milk yield, causing huge economic losses to dairy farmers. Lentinan is a kind of polysaccharide extracted from Lentinus edodes, which has no toxicity and possesses various pharmacological activities including antibacterial and immunomodulatory effects. Therefore, the anti-inflammatory function of lentinan on LPS-stimulated mastitis was carried out, and the mechanism involved was explored. In vivo, lentinan greatly reduced LPS-stimulated pathological injury, myeloperoxidase (MPO) activity, and the proinflammatory factor production (TNF-α and IL-1β) in mice. Further study was performed to determine the activation of the Wnt/β-catenin pathway during LPS stimulation. These results suggested that LPS-induced activation of the Wnt/β-catenin pathway was suppressed by lentinan administration. In vitro, we observed that the mouse mammary epithelial cell (mMEC) viability was not affected by lentinan treatment. As expected, LPS increased the TNF-α and IL-1β protein secretion and the activation of the Wnt/β-catenin pathway that was inhibited by lentinan administration in a dose-dependent manner in mMECs. Conclusively, lentinan exerts the anti-inflammatory function in LPS-stimulated mastitis via inhibiting the activation of the Wnt/β-catenin pathway. Thus, the results of our study also gave an insight that lentinan may serve as a potential treatment for mastitis.

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Abstract TMP26: Binding of KLF4 and HDAC2 to The Promoter Region of SM22alpha Mediates Phenotypic Modulation In vitro and In vivo: Implications in Cerebral Aneurysm Formation

Stroke ◽

10.1161/str.44.suppl_1.atmp26 ◽

2013 ◽

Vol 44 (suppl_1) ◽

Author(s):

Robert M Starke ◽

Muhammad S Ali ◽

Stavropoula I Tjoumakaris ◽

Pascal M Jabbour ◽

L. Fernando Gonzalez ◽

...

Keyword(s):

Cerebral Aneurysm ◽

Cigarette Smoke ◽

Promoter Region ◽

Molecular Mechanisms ◽

Phenotypic Modulation ◽

Necrosis Factor Alpha ◽

Aneurysm Formation ◽

Tnf Α

Cerebral Vascular Smooth Muscle Cell (VSMC) phenotypic modulation appears to play an important role in cerebral aneurysm formation and progression, yet the molecular mechanisms involved remain unknown. We investigated the role of inflammatory cytokine, Tumor Necrosis Factor-alpha (TNF-α) and cigarette smoke in directly mediating phenotypic modulation in VSMC. We hypothesize that this may, in part, occur through the binding of the transcription factor, KLF4, to the promoter region of SM22alpha, thereby downregulating VSMC differentiation and contractile genes. This may be critical in the pathogenesis of cerebral aneurysm formation. Methods: Cultured cerebral VSMC from rat Circle of Willis were treated with increasing doses of TNF-α (10ng/ml & 50ng/ml) and cigarette smoke extract (CSE; 10ug/ml & 40ug/ml) from 2 to 24hrs. VSMC were transfected with siRNA specific to KLF4. In vivo experiments included application of pluronic gel (containing TNF-α & CSE) to rat carotid artery adventitia. Expression of SM22alpha and KLF4 was measured with qPCR. Chromatin Immunoprecipitation (ChIP) was performed both in vitro and in vivo after treatment (TNF-α and CSE) and incubation with anti-KLF4, anti-HDAC2, anti-H4Ac and anti-H3K9Ac. Results: Both TNF-α and CSE independently suppress SM22alpha and increase expression of KLF4 in vitro and in vivo. siKLF4 inhibits the effects of TNF-α and CSE on KLF4 and SM22alpha. ChIP assays demonstrate that KLF4 binds directly to the promoter region of SM22alpha and further recruits HDAC2 to the promoter region. This complex leads to histone modifications leading to decreased acetylation of H4 and H3K9, resulting in decreased expression of SM22alpha. Conclusion: KLF4 is a key mediator of TNF-α and CSE induced phenotypic modulation of cerebral VSMC. Phenotypic modulation has been implicated in cerebral aneurysm formation in humans. KLF4 dependent regulation of cerebral VSMC phenotypic modulation may be an underlying molecular mechanism involved in the pathogenesis of cerebral aneurysm formation and a target for future therapies.

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Lactobacillus plantarum B7 attenuates Salmonella typhimurium infection in mice: preclinical study in vitro and in vivo

Asian Biomedicine ◽

10.1515/abm-2019-0022 ◽

2019 ◽

Vol 12 (5) ◽

pp. 211-218 ◽

Cited By ~ 1

Author(s):

Siwaporn Wongsen ◽

Duangporn Werawatganon ◽

Somying Tumwasorn

Keyword(s):

Salmonella Typhimurium ◽

Lactobacillus Plantarum ◽

Serum Levels ◽

Preclinical Study ◽

Control Group ◽

Protective Effects ◽

Tnf Α ◽

Factor Α

Abstract Background Salmonella typhimurium is a cause of gastroenteritis including diarrhea. Lactobacillus plantarum is a probiotic widely used to prevent and treat diarrhea. Objectives To determine the protective effects of L. plantarum B7 on diarrhea in mice induced by S. typhimurium. Methods Inhibition of S. typhimurium growth by L. plantarum B7 was determined using an agar spot method. Mice were divided into 3 groups (n = 8 each): a control group, an S group administered 3 × 109 CFU/mL S. typhimurium, and an S + LP group administered 1 × 109 CFU/mL L. plantarum B7 and 3 × 109 CFU/mL S. typhimurium daily for 3 days. Counts of S. typhimurium and percentage of fecal moisture content (%FMC) were determined from stool samples. Serum levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and CXCL1 were determined. Results L. plantarum B7 produced a clear zone on S. typhimurium. There were significantly less S. typhimurium in the feces from mice in the S+LP group than in the S group. Serum levels of TNF-α, IL-6, and CXCL1 in mice from the S group were significantly higher than levels in the S+LP and control groups. Feces from mice in the S group were soft and loose, whereas in the S+LP group they were hard and rod shaped. The %FMC in the S+LP group was significantly less than in the S group. Conclusions L. plantarum B7 can inhibit growth of S. typhimurium, decrease levels of proinflammatory cytokines, and attenuate symptoms of diarrhea induced in mice by S. typhimurium.

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Natural Compound Resveratrol Attenuates TNF-Alpha-Induced Vascular Dysfunction in Mice and Human Endothelial Cells: The Involvement of the NF-κB Signaling Pathway

International Journal of Molecular Sciences ◽

10.3390/ijms222212486 ◽

2021 ◽

Vol 22 (22) ◽

pp. 12486

Author(s):

Palanisamy Nallasamy ◽

Zi Yae Kang ◽

Xiaolun Sun ◽

Pon Velayutham Anandh Babu ◽

Dongmin Liu ◽

...

Keyword(s):

Endothelial Cells ◽

Adhesion Molecules ◽

Animal Study ◽

Natural Compound ◽

Nuclear Translocation ◽

Protective Effects ◽

Monocyte Adhesion ◽

Tnf Α

Resveratrol, a natural compound in grapes and red wine, has drawn attention due to potential cardiovascular-related health benefits. However, its effect on vascular inflammation at physiologically achievable concentrations is largely unknown. In this study, resveratrol in concentrations as low as 1 μm suppressed TNF-α-induced monocyte adhesion to human EA.hy926 endothelial cells (ECs), a key event in the initiation and development of atherosclerosis. Low concentrations of resveratrol (0.25–2 μm) also significantly attenuated TNF-α-stimulated mRNA expressions of MCP-1/CCL2 and ICAM-1, which are vital mediators of EC-monocyte adhesion molecules and cytokines for cardiovascular plaque formation. Additionally, resveratrol diminished TNF-α-induced IκB-α degradation and subsequent nuclear translocation of NF-κB p65 in ECs. In the animal study, resveratrol supplementation in diet significantly diminished TNF-α-induced increases in circulating levels of adhesion molecules and cytokines, monocyte adhesion to mouse aortic ECs, F4/80-positive macrophages and VCAM-1 expression in mice aortas and restored the disruption in aortic elastin fiber caused by TNF-α treatment. The animal study also confirmed that resveratrol blocks the activation of NF-κB In Vivo. In conclusion, resveratrol at physiologically achievable concentrations displayed protective effects against TNF-α-induced vascular endothelial inflammation in vitro and In Vivo. The ability of resveratrol in reducing inflammation may be associated with its role as a down-regulator of the NF-κB pathway.

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Contraceptive drugs mitigate experimental stroke-induced brain injury

Cardiovascular Research ◽

10.1093/cvr/cvy248 ◽

2018 ◽

Vol 115 (3) ◽

pp. 637-646 ◽

Cited By ~ 5

Author(s):

Mohamad El Amki ◽

Nadine Binder ◽

Riccardo Steffen ◽

Hannah Schneider ◽

Andreas R Luft ◽

...

Keyword(s):

Brain Injury ◽

Glucose Deprivation ◽

Artery Occlusion ◽

Experimental Models ◽

Experimental Stroke ◽

Protective Effects ◽

New Generation ◽

Cerebral Artery Occlusion

AbstractAimsEffective stroke treatments beyond reperfusion remain scant. The natural steroid hormone progesterone has shown protective effects in experimental models of brain injury and cardiovascular disease. However, unfavourable bioavailability limits its clinical use. Desogestrel and drospirenone are new generation progestins with progesterone-like properties, developed as oral contraceptives with excellent bioavailability and safety profile. We investigated the neuroprotective properties of these progestins in vivo using transient middle cerebral artery occlusion (MCAO) and in vitro using an oxygen-glucose deprivation and reoxygenation (OGD/R) model in primary neuronal cells.Methods and resultsMCAO was induced in female, female ovariectomized (modelling postmenopausal females) and male mice. Treatment with the progestins resulted in less severe strokes after MCAO and less neuronal death in OGD/R. Desogestrel and drospirenone induced higher expression levels of GABAAR α4 and delta subunits within the brain, suggesting changes in GABAAR configuration favouring tonic inhibition as potential mechanism of action. Treatment with the GABAAR blocker picrotoxin abolished the protection afforded by the progestins in vivo and in vitro.ConclusionFor the first time, here, we delineate a potential role of desogestrel and drospirenone, both clinically approved and safe drugs in mitigating the consequences of stroke. Contraception with desogestrel and drospirenone in progestin-only preparations may be particularly beneficial for women at risk of stroke.

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The protective effects of Fuzhengzhiyanghefuzhiyang decoction (FZHFZY) on imiquimod-induced psoriasis in mice through suppression of P38/Erk/NF-κB signaling

10.21203/rs.3.rs-342314/v1 ◽

2021 ◽

Author(s):

Haiming Chen ◽

Yue Lu ◽

Bin Tang ◽

Xiong Li ◽

Hongyu Zhang ◽

...

Keyword(s):

Mechanism Of Action ◽

Severity Index ◽

Raw264.7 Cells ◽

Mrna Levels ◽

Protective Effects ◽

Mice Model ◽

Raw264.7 Macrophages ◽

Tnf Α

Abstract Background Psoriasis is a chronic immune-mediated skin disease affecting approximately 2–3% of world's population. Fuzhenghefuzhiyang decoction (FZHFZY), a Chinese medicine formula created by Prof. Lu Chuanjian, has been shown to have remarkable anti-psoriasis effect in clinical practice. However, the mechanism of action of FZHFZY is unknown. The purpose of this study was to investigate the protective effects of FZHFZY in psoriasis-like skin inflammation both in vitro and in vivo and elucidate the mechanism of action of FZHFZY. Methods In vivo study, we evaluated the protective effect of FZHFZY in imiquimod-induced psoriasis-like mice model. Results indicated that FZHFZY can obviously decrease psoriasis area and severity index (PASI) scores. FZHFZY also suppressed the mRNA levels of IL-6, TNF-α, IL-23 and IL-8 in the skin and its anti-inflammatory activity may be related to its suppression of the P38/Erk/NF-κB signaling. In addition, immunohistochemistry (IHC) data showed that FZHFZY can suppress the expression of F4/80 which is the marker of macrophages in the psoriasis skin. Therefore, we designed to investigate the roles and underlying mechanisms of FZHFZY in LPS-stimulated RAW264.7 macrophages in vitro. Results Our results revealed FZHFZY treatment could significantly inhibit inflammation by modulating the expression of mediators, such as IL-6, TNF-α, IL-23 and IL-8, which expression was increased remarkably in the activated RAW264.7 cells. Our results also showed that FZHFZY inhibited the P38/Erk/NF-κB signaling pathways in RAW264.7 cells induced by LPS. Conclusions Taken together, our present study demonstrates that FZHFZY alleviated inflammatory response by suppressing the P38/Erk/NF-κB signaling in imiquimod-induced psoriasis-like mice model and LPS-stimulated RAW264.7.

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