scholarly journals ATPase Inhibitory Factor 1 Is Critical for Regulating Sevoflurane-Induced Microglial Inflammatory Responses and Caspase-3 Activation

2021 ◽  
Vol 15 ◽  
Author(s):  
Yaru Xu ◽  
Ge Gao ◽  
Xiaoru Sun ◽  
Qidong Liu ◽  
Cheng Li
Keyword(s):  
Inflammatory Response ◽  
Caspase 3 ◽  
Inflammatory Responses ◽  
Animal Experiments ◽  
Atp Synthesis ◽  
Inhibitory Factor ◽  
Inflammatory Factors ◽  
General Anesthetics ◽  
General Anesthetic ◽  
Inhibitory Factor 1

Postoperative delirium (POD) is one of the most important complications after surgery with general anesthesia, for which the neurotoxicity of general anesthetics is a high-risk factor. However, the mechanism remains largely unknown, which also hinders the effective treatment of POD. Here, we confirmed that a clinical concentration of the general anesthetic sevoflurane increased the expression of inflammatory factors and activated the caspase-3 by upregulating ATPase inhibitory factor 1 (ATPIF1) expression in microglia. Upregulation of ATPIF1 decreased the synthesis of ATP which is an important signaling molecule secreted by microglia. Extracellular supplementation with ATP attenuated the microglial inflammatory response and caspase-3 activation caused by sevoflurane or overexpression of ATPIF1. Additionally, the microglial inflammatory response further upregulated ATPIF1 expression, resulting in a positive feedback loop. Animal experiments further indicated that intraperitoneal injection of ATP significantly alleviated sevoflurane anesthesia-induced POD-related anxiety behavior and memory damage in mice. This study reveals that ATPIF1, an important protein regulating ATP synthesis, mediates sevoflurane-induced neurotoxicity in microglia. ATP supplementation may be a potential clinical treatment to alleviate sevoflurane-induced POD.

Comparing the effect of intestinal bacteria from rabbit, pig, and chicken on inflammatory response in cultured rabbit crypt and villus

2019 ◽  
Vol 65 (1) ◽  
pp. 59-67 ◽  
Author(s):  
Hong Xiao Cui ◽  
Xiu Rong Xu
Keyword(s):  
Inflammatory Response ◽  
Inflammatory Responses ◽  
Intestinal Bacteria ◽  
Inflammatory Factors ◽  
Rabbit Ileum ◽  
Necrosis Factor Alpha ◽  
Heat Treated ◽  
Tnf Α ◽  
Factor Alpha ◽  
Anti Inflammatory

Rabbit is susceptible to intestinal infection, which often results in severe inflammatory response. To investigate whether the special community structure of rabbit intestinal bacteria contributes to this susceptibility, we compared the inflammatory responses of isolated rabbit crypt and villus to heat-treated total bacteria in pig, chicken, and rabbit ileal contents. The dominant phylum in pig and chicken ileum was Firmicutes, while Bacteroidetes was dominant in rabbit ileum. The intestinal bacteria from rabbit induced higher expression of toll-like receptor 4 (TLR4) in rabbit crypt and villus (P < 0.05). TLR2 and TLR3 expression was obviously stimulated by chicken and pig intestinal bacteria (P < 0.05) but not by those of rabbit. The ileal bacteria from those three animals all increased the expression of tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) in crypts and villus (P < 0.05). Chicken and pig ileal bacteria also stimulated the expression of anti-inflammatory factors interferon beta (IFN-β) and IL-10 (P < 0.05), while those of rabbit did not (P > 0.05). In conclusion, a higher abundance of Gram-negative bacteria in rabbit ileum did not lead to more expressive pro-inflammatory cytokines in isolated rabbit crypt and villus, but a higher percentage of Lactobacillus in chicken ileum might result in more expressive anti-inflammatory factors.

scholarly journals RhTrx-1 ameliorates miroglial neuroinflammation after cerebral ischemic stroke

2020 ◽  
Author(s):  
Yang Jiao ◽  
Jianjian Wang ◽  
Huixue Zhang ◽  
Yuze Cao ◽  
Yang Qu ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Inflammatory Response ◽  
Inflammatory Responses ◽  
Inflammatory Factors ◽  
Experimental Stroke ◽  
Inflammasome Activation ◽  
Cerebral Ischemic

Abstract Background Microglia are rapidly activated after ischemic stroke and participate in the occurrence of neuroinflammation, which exacerbates the injury of ischemic stroke. Receptor Interacting Serine Threonine Kinase 1 (RIPK1) is thought to be involved in the development of inflammatory responses, but its role in ischemic microglia remains unclear. Here, we applied recombinant human thioredoxin-1 (rhTrx-1), a potential neuroprotective agent, to explore the role of rhTrx-1 in inhibiting RIPK1-mediated neuroinflammatory responses in microglia. Method Middle cerebral artery occlusion (MCAO) and Oxygen and glucose deprivation (OGD) were conducted for in vivo and in vitro experimental stroke models. The expression of RIPK1 in microglia after ischemia was examined. The inflammatory response of microglia was analyzed after treatment with rhTrx-1 and Necrostatin-1 (Nec-1, inhibitors of RIPK1), and the mechanisms were explored. In addition, the effects of rhTrx-1 on neurobehavioral deficits and cerebral infarct volume were examined. Results RIPK1 expression was detected in microglia after ischemia. Molecular docking results showed that rhTrx-1 could directly bind to RIPK1. In vitro experiments found that rhTrx-1 reduced necroptosis, mitochondrial membrane potential damage, Reactive oxygen species (ROS) accumulation and NLR Family, pyrin domain-containing 3 protein (NLRP3) inflammasome activation by inhibiting RIPK-1 expression, and regulated microglial M1/M2 phenotypic changes, thereby reducing the release of inflammatory factors. Consistently, in vivo experiments found that rhTrx-1 treatment attenuated cerebral ischemic injury by inhibiting the inflammatory response. Conclusion Our study demonstrates the role of RIPK1 in microglia-arranged neuroinflammation after cerebral ischemia. Administration of rhTrx-1 provides neuroprotection in ischemic stroke-induced microglial neuroinflammation by inhibiting RIPK1 expression.

Cholinergic Modulation of General Anesthesia

2021 ◽  
Vol 19 ◽  
Author(s):  
L. Stan Leung ◽  
Tao Luo
Keyword(s):  
Inflammatory Response ◽  
General Anesthesia ◽  
Basal Forebrain ◽  
Animal Experiments ◽  
Cholinergic Neurons ◽  
Cognitive Disorder ◽  
General Anesthetic ◽  
Genetic Ablation ◽  
Behavioral Sensitivity ◽  
Anesthetic Exposure

: Acetylcholine in the brain serves arousal and cognitive functions. Cholinergic neurons in the mesopontine brainstem and basal forebrain are important for activation of the cerebral cortex, which is characterized by suppression of irregular slow waves and increase in gamma (30-100 Hz) activity in the electroencephalogram, and appearance of a hippocampal theta rhythm. During general anesthesia, decrease in acetylcholine release and cholinergic functions contribute to the desirable outcomes of general anesthesia such as amnesia, loss of awareness and consciousness, and immobility. Animal experiments indicate that inactivation, lesion or genetic ablation of cholinergic neurons in the basal forebrain potentiated the effects of inhalational and injectable anesthetics, including isoflurane, halothane, propofol, pentobarbital and in some cases, ketamine. Increased behavioral sensitivity to general anesthetic, faster induction time and delayed recovery of a loss of righting reflex have been shown in rodents with basal forebrain cholinergic deficits. Cholinergic stimulation in the prefrontal cortex, thalamus and basal forebrain hastens recovery from general anesthesia. Anticholinesterase accelerates emergence from general anesthesia, but with mixed success, in part depending on the anesthetic used. Cholinergic deficits may contribute to cognitive impairments after anesthesia and operations, which are severe in aged subjects. We propose a cholinergic hypothesis for postoperative cognitive disorder, in line with the cholinergic deficits and cognitive decline in aging and Alzheimer’s disease. The current animal literature suggests that brain cholinergic neurons can regulate the immune and inflammatory response after surgical operation and anesthetic exposure, and anticholinesterase and α7-nicotinic cholinergic agonists can alleviate postoperative inflammatory response and cognitive deficits.

Abstract 15465: Upregulation of Mitochondrial Atpase Inhibitory Factor 1 Mediates Increased Glycolysis in Pathological Cardiac Hypertrophy

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Bo Zhou ◽  
Arianne Caudal ◽  
Xiaoting Tang ◽  
Juan D Chavez ◽  
Andrew Keller ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Glucose Metabolism ◽  
Cardiac Hypertrophy ◽  
Fatty Acid Oxidation ◽  
Atp Synthase ◽  
Atp Synthesis ◽  
Inhibitory Factor ◽  
Acid Oxidation ◽  
Mitochondrial Atpase ◽  
Inhibitory Factor 1

Background: During the development of heart failure cardiac fuel metabolism switches from predominantly fatty acid oxidation (FAO) to increased reliance on glucose, especially glycolysis. Mechanisms responsible for the switch are poorly understood but appear to be coupled with impaired mitochondrial function. We recently demonstrated that increased glucose metabolism is required for cardiomyocytes growth during pathological remodeling. Hypothesis: Upregulation of mitochondrial ATPase inhibitory factor 1 (ATPIF1) in hypertrophied hearts suppresses ATP synthesis and shifts cardiac metabolism from fatty acid oxidation towards glucose metabolism. Methods and Results: We report that ATPIF1 expression is upregulated in cardiomyocytes and mouse hearts undergoing pathological hypertrophy. Using genetic models of ATPIF1 gain- and loss-of-function in cardiomyocytes and in mouse hearts,we find that upregulation of ATPIF1 in cardiac hypertrophy inhibits ATP synthesis. Furthermore, quantitative analysis of chemical crosslinking by mass spectrometry revealed that increased expression of ATPIF1 promoted the formation of F o F 1 -ATP synthase nonproductive tetramer. Impairment of F o F 1 -ATP synthase function in respiring mitochondria increasedROS generation resulting in transcriptional activation of glycolysis. Cardiac-specific deletion of ATPIF1 in mice prevented the switch to glycolysis in pressure overload induced cardiac hypertrophy. Conclusions: We show that upregulation of ATPIF1 drives glucose metabolism at the expense of energy supply during the pathological growth of cardiomyocytes. Our study proposes a central role of ATP synthase in toggling anabolic and catabolic metabolism during pathological remodeling, illustrating a new concept for metabolic reprogramming of the heart.

Physical exercise as a human model of limited inflammatory response

1998 ◽  
Vol 76 (5) ◽  
pp. 589-597 ◽  
Author(s):  
Pang N Shek ◽  
Roy J Shephard
Keyword(s):  
Physical Exercise ◽  
Inflammatory Response ◽  
Inflammatory Responses ◽  
Tissue Injury ◽  
Active Phase ◽  
Human Model ◽  
Inflammatory Factors ◽  
Trauma Patients ◽  
Inflammatory Reactions ◽  
Underlying Mechanisms

An inflammatory response represents a fundamental series of humoral and cellular reaction cascades in response to infection, tissue injury, and related insults. An excessive response is commonly seen under the pathological conditions of trauma, sepsis, and burns. It is becoming increasingly evident that most, if not all, of the distinguishing features of a classical inflammatory response are detectable in an exercising individual, namely mobilization and activation of granulocytes, lymphocytes, and monocytes; release of inflammatory factors and soluble mediators; involvement of active phase reactants; and activation of the complement and other reactive humoral cascade systems. While the manifestation of many exercise-induced immune and related changes has been reported and confirmed repeatedly, the underlying mechanisms triggering and modulating the elicited immune responses are, at best, poorly understood. Unlike the exaggerated and sometimes uncontrollable inflammatory response in septic and trauma patients resulting in morbidity and mortality, strenuous and severe exercise normally elicits an inflammatory response of a subclinical nature to facilitate the repairing process for site-specific tissue damage. Regardless of the inciting event, for example trauma, infection, or exercise, and given an appropriate triggering signal, a remarkably similar sequence of inflammatory reactions can be reproduced in the affected host. Therefore, physical exercise and training represent an acceptable and good model for the study of limited inflammatory responses in humans.Key words: trauma, infection, exercise, inflammatory response, cytokines.

scholarly journals Impact of Postprandial Lipemia and Glycemia on Inflammatory Factors in over 1000 Individuals in the US and UK: Insights from the PREDICT 1 and InterCardio Studies

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 1518-1518
Author(s):  
Sarah Berry ◽  
Mohsen Mazidi ◽  
Paul Franks ◽  
Ana Valdes ◽  
Naveed Sattar ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Microbial Diversity ◽  
Dietary Intervention ◽  
Inflammatory Responses ◽  
Metabolic Responses ◽  
Inflammatory Factors ◽  
Controlled Study ◽  
Low Grade ◽  
The Us ◽  
The Impact

Abstract Objectives Postprandial glycemia (PPG) and lipemia (PPL) initiate an acute inflammatory response, which may be relevant to future CVD. We characterised the impact of PPL and PPG on inflammatory responses using traditional (IL-6) and emerging (glycoprotein acetyls; GlycA) biomarkers of inflammation in a large scale, tightly controlled study (PREDICT 1; NCT03479866) and an independent validation study (InterCardio; NCT03438084). Methods The PREDICT 1 dietary intervention study of 1102 healthy individuals from the US and UK, assessed the postprandial (0–6 h) metabolic responses to sequential mixed-nutrient meals (50 g fat and 85 g carb at 0 h; 22 g fat and 71 g carb at 4 h). Baseline microbial diversity (16S Shannon diversity) and visceral fat mass (VFM; based on DXA) were also measured. Results were validated in an independent randomised crossover trial (n = 50). For both studies, glucose, triacylglycerol (TG), IL-6 and GlycA were measured at multiple intervals. Results In PREDICT 1, GlycA and IL-6 concentrations increased significantly after meals (by 4.5 and 169%; peak 6 h, respectively) but were not correlated. Peak postprandial TG and glucose concentrations were strongly associated with GlycA (r = 0.832 and r = 0.239, respectively) but not IL-6. Machine learning with cross-validation, revealed that PPL was the strongest predictor of postprandial GlycA. There was evidence of an interaction; individuals with higher microbial diversity and lower VFM had an attenuated inflammatory response. Individuals eliciting an enhanced response (30% rise at 6 h) had higher predicted CVD risk compared to the rest of the cohort. In the InterCardio study, the postprandial inflammatory increase in GlycA was also significantly correlated with PPL and varied within the four different types of fat tested. Conclusions In the first study to investigate postprandial inflammation at scale, we observed that PPL was a stronger determinant of systemic inflammation compared with PPG. The clinically significant and variable postprandial inflammatory response, and its association with lipemia and glycemia, highlights the potential for personalized dietary strategies to lower postprandial metabolic responses to reduce low grade inflammatory related diseases. Funding Sources NIHR, Wellcome Trust, Zoe Global Ltd, BBSRC DRINC.

scholarly journals Inflammatory Response and Oxidative Stress as Mechanism of Reducing Hyperuricemia of Gardenia jasminoides-Poria cocos with Network Pharmacology

2021 ◽  
Vol 2021 ◽  
pp. 1-18
Author(s):  
Lijun Liu ◽  
Shengjun Jiang ◽  
Xuqiang Liu ◽  
Qi Tang ◽  
Yan Chen ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Uric Acid ◽  
Inflammatory Response ◽  
Inflammatory Responses ◽  
Animal Experiments ◽  
Kidney Injury ◽  
Network Pharmacology ◽  
Poria Cocos ◽  
Gardenia Jasminoides ◽  
And Oxidative Stress

Hyperuricemia (HUA) is a metabolic disease, closely related to oxidative stress and inflammatory responses, caused by reduced excretion or increased production of uric acid. However, the existing therapeutic drugs have many side effects. It is imperative to find a drug or an alternative medicine to effectively control HUA. It was reported that Gardenia jasminoides and Poria cocos could reduce the level of uric acid in hyperuricemic rats through the inhibition of xanthine oxidase (XOD) activity. But there were few studies on its mechanism. Therefore, the effective ingredients in G. jasminoides and P. cocoa extracts (GPE), the active target sites, and the further potential mechanisms were studied by LC-/MS/MS, molecular docking, and network pharmacology, combined with the validation of animal experiments. These results proved that GPE could significantly improve HUA induced by potassium oxazine with the characteristics of multicomponent, multitarget, and multichannel overall regulation. In general, GPE could reduce the level of uric acid and alleviate liver and kidney injury caused by inflammatory response and oxidative stress. The mechanism might be related to the TNF-α and IL-7 signaling pathway.

scholarly journals Inflammatory response in postmenopausal osteoporotic fracture healing

2020 ◽  
Vol 9 (7) ◽  
pp. 368-385
Author(s):  
Simon K-H. Chow ◽  
Yu-Ning Chim ◽  
Jin-Yu Wang ◽  
Ronald M-Y. Wong ◽  
Victoria M-H. Choy ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Elderly Patients ◽  
Fracture Healing ◽  
Osteoporotic Fracture ◽  
Clinical Studies ◽  
Inflammatory Responses ◽  
Osteoporotic Fractures ◽  
Inflammatory Factors ◽  
Preclinical Studies ◽  
Local Inflammatory Response

A balanced inflammatory response is important for successful fracture healing. The response of osteoporotic fracture healing is deranged and an altered inflammatory response can be one underlying cause. The objectives of this review were to compare the inflammatory responses between normal and osteoporotic fractures and to examine the potential effects on different healing outcomes. A systematic literature search was conducted with relevant keywords in PubMed, Embase, and Web of Science independently. Original preclinical studies and clinical studies involving the investigation of inflammatory response in fracture healing in ovariectomized (OVX) animals or osteoporotic/elderly patients with available full text and written in English were included. In total, 14 articles were selected. Various inflammatory factors were reported; of those tumour necrosis factor-α (TNF-α) and interleukin (IL)-6 are two commonly studied markers. Preclinical studies showed that OVX animals generally demonstrated higher systemic inflammatory response and poorer healing outcomes compared to normal controls (SHAM). However, it is inconclusive if the local inflammatory response is higher or lower in OVX animals. As for clinical studies, they mainly examine the temporal changes of the inflammatory stage or perform comparison between osteoporotic/fragility fracture patients and normal subjects without fracture. Our review of these studies emphasizes the lack of understanding that inflammation plays in the altered fracture healing response of osteoporotic/elderly patients. Taken together, it is clear that additional studies, preclinical and clinical, are required to dissect the regulatory role of inflammatory response in osteoporotic fracture healing. Cite this article: Bone Joint Res 2020;9(7):368–385.

scholarly journals Complement protein C5a enhances the β-amyloid-induced neuro-inflammatory response in microglia in Alzheimer’s disease

2018 ◽  
Vol 34 ◽  
pp. 116-120 ◽  
Author(s):  
Xiao-qun An ◽  
Wei Xi ◽  
Chen-yun Gu ◽  
Xiao Huang
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Inflammatory Response ◽  
Inflammatory Responses ◽  
Inflammatory Factors ◽  
Complement Protein ◽  
Neuroinflammatory Response ◽  
Stat3 Signaling ◽  
Tnf Α ◽  
Neuro Inflammation

Objective: The dysregulation of neuro-inflammation is one of the attributes of the pathogenesis of Alzheimer’s disease (AD). Over-expression of complement proteins co-localizes with neurofibrillary tangles, thereby indicating that a complement system may be involved in neuro-inflammation. Here, we report the influence of complement activation on the neuro-inflammation using a microglial cell line. Methods: first, we performed a cytotoxic assay using the microglial cells BV-2. Second, after treatment of BV-2 cells with Aβ42 and/ or C5a, the anaphylatoxin derived from C5, we determined the expression levels of the pro-inflammatory factors TNF-α, IL-1β, and IL-6. Finally, we explored whether this neuroinflammatory response was mediated by JAK/ STAT3 signaling. Results: C5a had an enhanced effect on the neural cell viability of BV-2 cells treated with Aβ42. In addition, C5a also increased the Aβ-induced neuro-inflammatory response, and these effects were blocked by the C5aR antagonist, PMX205. Finally, we demonstrated that the neuro-inflammatory responses induced by Aβ and C5a were mediated through JAK/STAT3 signaling. By blocking this pathway with an antagonist, AG490, the expression of TNF-α, IL-1β, and IL-6 was alleviated. Conclusion: The complement protein C5a could exaggerate the Aβ-induced neuroinflammatory response in microglia, and C5aR may be a potential therapeutic tool for AD treatment.

scholarly journals Increased presence of nuclear DNAJA3 and upregulation of cytosolic STAT1 and of nucleic acid sensors trigger innate immunity in the ClpP-null mouse

Neurogenetics ◽  
2021 ◽  
Author(s):  
Antonia Maletzko ◽  
Jana Key ◽  
Ilka Wittig ◽  
Suzana Gispert ◽  
Gabriele Koepf ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Nucleic Acid ◽  
Inflammatory Responses ◽  
Subcellular Fractionation ◽  
Inflammatory Factors ◽  
Null Mouse ◽  
Loss Of Function ◽  
Response Factors ◽  
Perrault Syndrome ◽  
Acid Sensors

AbstractMitochondrial dysfunction may activate innate immunity, e.g. upon abnormal handling of mitochondrial DNA in TFAM mutants or in altered mitophagy. Recent reports showed that also deletion of mitochondrial matrix peptidase ClpP in mice triggers transcriptional upregulation of inflammatory factors. Here, we studied ClpP-null mouse brain at two ages and mouse embryonal fibroblasts, to identify which signaling pathways are responsible, employing mass spectrometry, subcellular fractionation, immunoblots, and reverse transcriptase polymerase chain reaction. Several mitochondrial unfolded protein response factors showed accumulation and altered migration in blue-native gels, prominently the co-chaperone DNAJA3. Its mitochondrial dysregulation increased also its extra-mitochondrial abundance in the nucleus, a relevant observation given that DNAJA3 modulates innate immunity. Similar observations were made for STAT1, a putative DNAJA3 interactor. Elevated expression was observed not only for the transcription factors Stat1/2, but also for two interferon-stimulated genes (Ifi44, Gbp3). Inflammatory responses were strongest for the RLR pattern recognition receptors (Ddx58, Ifih1, Oasl2, Trim25) and several cytosolic nucleic acid sensors (Ifit1, Ifit3, Oas1b, Ifi204, Mnda). The consistent dysregulation of these factors from an early age might influence also human Perrault syndrome, where ClpP loss-of-function leads to early infertility and deafness, with subsequent widespread neurodegeneration.

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