scholarly journals Melatonin Modulates Microglia Activation in Neuro-inflammation by Regulating the ER Stress/PPARd/SIRT1 Signaling Pathway

2021 ◽  
Author(s):  
Hung-Chuan Pan ◽  
Cheng-Ning Yang ◽  
Wen-Jane Lee ◽  
Jason Sheehan ◽  
Sheng-Mao Wu ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Er Stress ◽  
Peroxisome Proliferator ◽  
Primary Microglia ◽  
Activated Microglia ◽  
Biological Studies ◽  
Neuro Inflammation ◽  
Stress Dependent ◽  
M2 Phenotype

Abstract Background: Activated microglia-mediated neuro-inflammation plays a vital aspect in regulating the micromilieu of the central nervous system. Neuro-inflammation involves distinct alterations of microglial phenotypes, containing nocuous pro-inflammatory (M1) phenotype and neuroprotective anti-inflammatory (M2) phenotype. Currently, there is no effective treatment for modulating such alterations. Little evidence shows that melatonin prevents the detrimental cascade of activated microglia-mediated neuro-inflammation. Methods: The expression levels of M1/M2 marker of primary microglia influenced by Melatonin were detected via qPCR. Functional activities were explored by western blotting, luciferase activity, EMSA, and ChIP assay. Structure interaction was assessed by molecular docking and LIGPLOT analysis. ER stress detection was examined by ultrastructure TEM, calapin activity, and ERSE assay. The neurobehavioral evaluations and immunofluorescence staining in animals were used for investigation of Melatonin on the neuroinflammation in vivo. Results: Melatonin had targeted on Peroxisome Proliferator Activated Receptor Delta (PPARd) activity, boosted LPS-stimulated alterations in polarization from the M1 to the M2 phenotype, and thereby inhibited NFkB–IKKb activation in primary microglia. The PPARd agonist L-165041 or over-expression of PPARd plasmid (ov-PPARd) showed similar results. Molecular docking screening, dynamic simulation approaches, and biological studies of melatonin showed that the activated site was located at PPARd (phospho-Thr256-PPARd). Furthermore, we found that activated microglia had lowered PPARd activity as well as the downstream SIRT1 formation via enhancing ER stress. Melatonin, PPARd agonist and ov-PPARd all effectively reversed the above-mentioned effects. Melatonin blocked ER stress by regulating calapin activity and expression in LPS-activated microglia. Additionally, melatonin or L-165041 ameliorated the neurobehavioral deficits in LPS-aggravated neuroinflammatory mice through blocking microglia activities, and also promoted phenotype changes to M2-predominant microglia. Conclusions Melatonin suppressed neuro-inflammation in vitro and in vivo by tuning microglial activation through the ER stress-dependent PPARd/SIRT1 signaling cascade. We proposed that this treatment strategy is an encouraging pharmacological approach for the remedy of neuro-inflammation associated disorders.

scholarly journals Network pharmacology-based identification of major component of Angelica sinensis and its action mechanism for the treatment of acute myocardial infarction

2018 ◽  
Vol 38 (6) ◽  
Author(s):  
Xiaowei Niu ◽  
Jingjing Zhang ◽  
Jinrong Ni ◽  
Runqing Wang ◽  
Weiqiang Zhang ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Er Stress ◽  
Heart Function ◽  
Network Pharmacology ◽  
Angelica Sinensis ◽  
Peroxisome Proliferator ◽  
Multiple Targets

Background: To decipher the mechanisms of Angelica sinensis for the treatment of acute myocardial infarction (AMI) using network pharmacology analysis. Methods: Databases were searched for the information on constituents, targets, and diseases. Cytoscape software was used to construct the constituent–target–disease network and screen the major targets, which were annotated with the DAVID (Database for Annotation, Visualization and Integrated Discovery) tool. The cardioprotective effects of Angelica sinensis polysaccharide (ASP), a major component of A. sinensis, were validated both in H9c2 cells subjected to simulated ischemia by oxygen and glucose deprivation and in rats with AMI by ligation of the left anterior coronary artery. Results: We identified 228 major targets against AMI injury for A. sinensis, which regulated multiple pathways and hit multiple targets involved in several biological processes. ASP significantly decreased endoplasmic reticulum (ER) stress-induced cell death both in vitro and in vivo. In ischemia injury rats, ASP treatment reduced infarct size and preserved heart function. ASP enhanced activating transcription factor 6 (ATF6) activity, which improved ER-protein folding capacity. ASP activated the expression of p-AMP-activated protein kinase (p-AMPK) and peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α). Additionally, ASP attenuated levels of proinflammatory cytokines and maintained a balance in the oxidant/antioxidant levels after AMI. Conclusion:In silico analysis revealed the associations between A. sinensis and AMI through multiple targets and several key signaling pathways. Experimental data indicate that ASP protects the heart against ischemic injury by activating ATF6 to ameliorate the detrimental ER stress. ASP’s effects could be mediated via the activation of AMPK-PGC1α pathway.

scholarly journals Regulation of Adipsin Expression by Endoplasmic Reticulum Stress in Adipocytes

Biomolecules ◽  
2020 ◽  
Vol 10 (2) ◽  
pp. 314
Author(s):  
Ka-Young Ryu ◽  
Eon Ju Jeon ◽  
Jaechan Leem ◽  
Jae-Hyung Park ◽  
Hochan Cho
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Peroxisome Proliferator ◽  
Adipose Tissues ◽  
Peroxisome Proliferator Activated Receptor ◽  
Er Stress Response ◽  
Stress Markers ◽  
Transcriptional Reprogramming

Adpsin is an adipokine that stimulates insulin secretion from β-cells and improves glucose tolerance. Its expression has been found to be markedly reduced in obese animals. However, it remains unclear what factors lead to downregulation of adipsin in the context of obesity. Endoplasmic reticulum (ER) stress response is activated in various tissues under obesity-related conditions and can induce transcriptional reprogramming. Therefore, we aimed to investigate the relationship between adipsin expression and ER stress in adipose tissues during obesity. We observed that obese mice exhibited decreased levels of adipsin in adipose tissues and serum and increased ER stress markers in adipose tissues compared to lean mice. We also found that ER stress suppressed adipsin expression via adipocytes-intrinsic mechanisms. Moreover, the ER stress-mediated downregulation of adipsin was at least partially attributed to decreased expression of peroxisome proliferator-activated receptor γ (PPARγ), a key transcription factor in the regulation of adipocyte function. Finally, treatment with chemical chaperones recovered the ER stress-mediated downregulation of adipsin and PPARγ in vivo and in vitro. Our findings suggest that activated ER stress in adipose tissues is an important cause of the suppression of adipsin expression in the context of obesity.

scholarly journals In Silico Studies of Tumor Targeted Peptide-Conjugated Natural Products for Targeting Over-Expressed Receptors in Breast Cancer Cells Using Molecular Docking, Molecular Dynamics and MMGBSA Calculations

2022 ◽  
Vol 12 (1) ◽  
pp. 515
Author(s):  
Lucy R. Hart ◽  
Charlotta G. Lebedenko ◽  
Saige M. Mitchell ◽  
Rachel E. Daso ◽  
Ipsita A. Banerjee
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
In Silico ◽  
Point Mutations ◽  
Binding Energies ◽  
Peptide Sequence ◽  
Peroxisome Proliferator ◽  
Peptide Conjugates ◽  
Biological Studies ◽  
In Silico Studies

In this work, in silico studies were carried out for the design of diterpene and polyphenol-peptide conjugates to potentially target over-expressed breast tumor cell receptors. Four point mutations were induced into the known tumor-targeting peptide sequence YHWYGYTPQN at positions 1, 2, 8 and 10, resulting in four mutated peptides. Each peptide was separately conjugated with either chlorogenate, carnosate, gallate, or rosmarinate given their known anti-tumor activities, creating dual targeting compounds. Molecular docking studies were conducted with the epidermal growth factor receptor (EGFR), to which the original peptide sequence is known to bind, as well as the estrogen receptor (ERα) and peroxisome proliferator-activated receptor (PPARα) using both Autodock Vina and FireDock. Based on docking results, peptide conjugates and peptides were selected and subjected to molecular dynamics simulations. MMGBSA calculations were used to further probe the binding energies. ADME studies revealed that the compounds were not CYP substrates, though most were Pgp substrates. Additionally, most of the peptides and conjugates showed MDCK permeability. Our results indicated that several of the peptide conjugates enhanced binding interactions with the receptors and resulted in stable receptor-ligand complexes; Furthermore, they may successfully target ERα and PPARα in addition to EGFR and may be further explored for synthesis and biological studies for therapeutic applications.

scholarly journals Peroxisome Proliferator-Activated Receptor-Gamma Reduces ER Stress and Inflammation via Targeting NGBR Expression

2022 ◽  
Vol 12 ◽  
Author(s):  
Jialing Ma ◽  
Peng Zeng ◽  
Lipei Liu ◽  
Mengmeng Zhu ◽  
Juan Zheng ◽  
...  
Keyword(s):  
Er Stress ◽  
Promoter Region ◽  
Essential Role ◽  
Inhibitory Effect ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Hepatic Cells ◽  
Pparγ Expression

Increased Nogo-B receptor (NGBR) expression in the liver improves insulin sensitivity by reducing endoplasmic reticulum stress (ER stress) and activating the AMPK pathway, although it remains elusive the mechanisms by which NGBR is induced. In this study, we found that PPARγ ligands (rosiglitazone or pioglitazone) increased NGBR expression in hepatic cells and HUVECs. Furthermore, promoter analysis defined two PPREs (PPARγ-responsive elements) in the promoter region of NGBR, which was further confirmed by the ChIP assay. In vivo, using liver-specific PPARγ deficient (PPARγLKO) mice, we identified the key role of PPARγ expression in pioglitazone-induced NGBR expression. Meanwhile, the basal level of ER stress and inflammation was slightly increased by NGBR knockdown. However, the inhibitory effect of rosiglitazone on inflammation was abolished while rosiglitazone-inhibited ER stress was weakened by NGBR knockdown. Taken together, these findings show that NGBR is a previously unrecognized target of PPARγ activation and plays an essential role in PPARγ-reduced ER stress and inflammation.

Carbon monoxide-releasing molecules reverse leptin resistance induced by endoplasmic reticulum stress

2013 ◽  
Vol 304 (7) ◽  
pp. E780-E788 ◽  
Author(s):  
Min Zheng ◽  
Qinggao Zhang ◽  
Yeonsoo Joe ◽  
Seul-Ki Kim ◽  
Md. Jamal Uddin ◽  
...  
Keyword(s):  
Carbon Monoxide ◽  
Endoplasmic Reticulum ◽  
Body Weight ◽  
Er Stress ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Leptin Resistance ◽  
Stat3 Phosphorylation ◽  
Stress Dependent

Leptin, a circulating hormone, regulates food intake and body weight. While leptin resistance represents a major cause of obesity, the underlying mechanisms remain unclear. Endoplasmic reticulum (ER) stress can contribute to leptin resistance. Carbon monoxide (CO), a gaseous molecule, exerts antiapoptotic and anti-inflammatory effects in animal models of tissue injury. We hypothesized that CO could inhibit leptin resistance during ER stress. Thapsigargin or tunicamycin was used to induce ER stress in human cells expressing the leptin receptor. These agents markedly inhibited leptin-induced STAT3 phosphorylation, confirming that ER stress induces leptin resistance. The CO-releasing molecule CORM-2 blocked the ER stress-dependent inhibition of leptin-induced STAT3 phosphorylation. CORM-2 treatment induced the phosphorylation of protein kinase R-like endoplasmic reticulum kinase (PERK), and eukaryotic translation initiation factor-2α and enhanced PERK phosphorylation during ER stress. Furthermore, CORM-2 inhibited X-box binding protein-1 expression, activating transcription factor-6 cleavage, and inositol-requiring enzyme (IRE)1α phosphorylation induced by ER stress. IRE1α knockdown rescued leptin resistance, whereas PERK knockdown blocked CO-dependent regulation of IRE1α. In vivo, CO inhalation normalized body weight in animals fed high-fat diets. Furthermore, CO modulated ER stress pathways and rescued leptin resistance in vivo. In conclusion, the pathological mechanism of leptin resistance may be ameliorated by the pharmacological application of CO.

scholarly journals Microglia Polarization from M1 toward M2 Phenotype Is Promoted by Astragalus Polysaccharides Mediated through Inhibition of miR-155 in Experimental Autoimmune Encephalomyelitis

2021 ◽  
Vol 2021 ◽  
pp. 1-15
Author(s):  
Xiaojun Liu ◽  
Jinyun Ma ◽  
Guiqing Ding ◽  
Qianyi Gong ◽  
Yuanhua Wang ◽  
...  
Keyword(s):  
Experimental Autoimmune Encephalomyelitis ◽  
Autoimmune Encephalomyelitis ◽  
Activated Microglia ◽  
Tnf Α ◽  
Microglia Polarization ◽  
M1 Type ◽  
M2 Phenotype ◽  
Experimental Autoimmune

Activated microglia is considered to be major mediators of the neuroinflammatory environment in demyelinating diseases of the central nervous system (CNS). Activated microglia are mainly polarized into M1 type, which plays a role in promoting inflammation and demyelinating. However, the proportion of microglia polarized into M2 type is relatively low, which cannot fully play the role of anti-inflammatory and resistance to demyelinating. Our previous study found that Astragalus polysaccharides (APS) has an immunomodulatory effect and can inhibit neuroinflammation and demyelination in experimental autoimmune encephalomyelitis (EAE), which is a classic animal model of CNS demyelinating disease. In this study, we found that APS was effective in treating EAE mice. It restored microglia balance by inhibiting the polarization of microglia to M1-like phenotype and promoting the polarization of microglia to M2-like phenotype in vivo and in vitro. miR-155 is a key factor in regulating microglia polarization. We found that APS could inhibit the expression level of miR-155 in vivo and in vitro. Furthermore, we performed transfection overexpression and blocking experiments. The results showed that miR-155 mediated the polarization of microglia M1/M2 phenotype, while the selective inhibitor of miR-155 attenuated the inhibition of APS on microglia M1 phenotype and eliminated the promotion of APS on microglia M2 phenotype. Microglia can secrete IL-1α, TNF-α, and C1q after polarizing into M1 type and induce the activation of A1 neurotoxic astrocytes, further aggravating neuroinflammation and demyelination. APS reduced the secretion of IL-1α, TNF-α, and C1q by activated microglia, thus inhibited the formation of A1 neurotoxic astrocytes. In summary, our study suggests that APS regulates the polarization of microglia from M1 to M2 phenotype by inhibiting the miR-155, reduces the secretion of inflammatory factors, and inhibits the activation of neurotoxic astrocytes, thus effectively treating EAE.

scholarly journals PTP1B inhibitor alleviates deleterious microglial activation and neuronal injury after ischemic stroke by modulating ER stress-autophagy axis via PERK signaling in microglia

2019 ◽  
Author(s):  
Yu Zhu ◽  
Jianbo Yu ◽  
Jiangbiao Gong ◽  
Di Ye ◽  
Dexin Cheng ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Er Stress ◽  
Protein Interaction ◽  
Neuronal Apoptosis ◽  
Microglial Activation ◽  
Neuronal Injury ◽  
Primary Microglia ◽  
Cerebral Ir Injury

Abstract Background : Cerebral ischemia/reperfusion (IR) after ischemic stroke causes microglial activation which lead to neuronal injury. Protein tyrosine phosphatase 1B (PTP1B) emerges to be a positive regulator of neuroinflammation, yet the effect of its inhibition on microglial activation as well as cerebral IR injury is largely unknown. Here we explored whether PTP1B inhibitor sc-222227 attenuates microglial activation and mitigates neuronal injury after cerebral IR injury. Methods : Cerebral IR injury rat model was induced by transient middle cerebral artery occlusion (MCAO) and reperfusion. PTP1B inhibitor sc-222227 was administered intracerebroventricularly 0.5 h before IR injury. Neurological deficits, infarct volume and brain water content were examined. In vitro IR injury model were established by oxygen glucose deprivation/reoxygenation (OGD/R) in rat primary microglia. PTP1B protein level, microglial activation, neuroinflammation, endoplasmic reticulum (ER) stress, autophagy and neuronal apoptosis were detected in vivo and/or in vitro using western blot, immunohistochemistry, immunofluorescence, ELISA and real-time PCR assay. Protein interaction were assessed by proximity ligation assay. Results : PTP1B expression were significantly increased after cerebral IR injury in vivo, and the enhancement was most prominent in microglia. PTP1B inhibitor reduced IR-induced microglial activation both in vitro and in vivo, and further attenuated IR-induced microglial ER stress and autophagy in rat. In vitro experiment showed PTP1B inhibitor mitigated OGD/R-induced microglial activation through inhibiting ER stress-dependent autophagy, whose effect was partly abolished by PERK activator CCT020312. The protein interaction between PTP1B and phosphorylated PERK were significantly increase in response to OGD/R in primary microglia. Finally, PTP1B inhibitor reduced neuronal apoptosis and improved neurologic function after cerebral IR injury in rat. Conclusions : PTP1B inhibitor ameliorated neuronal injury and neurologic deficits following cerebral IR injury via attenuating deleterious microglial activation and subsequent neuroinflammation through modulating ER stress-autophagy axis in microglia. Treatment targeting microglial PTP1B might be a potential therapeutic strategy for ischemic stroke treatment.

scholarly journals A miR-494 dependent feedback loop regulates ER stress

2020 ◽  
Author(s):  
Namita Chatterjee ◽  
Cristina Espinosa-Diez ◽  
Sudarshan Anand
Keyword(s):  
Er Stress ◽  
Stress Responses ◽  
De Novo ◽  
Critical Role ◽  
Dependent Manner ◽  
Inflammatory Chemokines ◽  
Stress Dependent ◽  
And Control

AbstractDefects in stress responses are important contributors in many chronic conditions including cancer, cardiovascular disease, diabetes, and obesity-driven pathologies like non-alcoholic steatohepatitis (NASH). Specifically, endoplasmic reticulum (ER) stress is linked with these pathologies and control of ER stress can ameliorate tissue damage. MicroRNAs have a critical role in regulating diverse stress responses including ER stress. Here we show that miR-494 plays a functional role during ER stress. ER stress inducers (tunicamycin & thapsigargin) robustly increase the expression of miR-494 in vitro in an ATF6 dependent manner. Surprisingly, miR-494 pretreatment dampens the induction and magnitude of ER stress in response to tunicamycin in endothelial cells. Conversely, inhibition of miR-494 increases ER stress de novo and amplifies the effects of ER stress inducers. Using Mass Spectrometry (TMT-MS) we identified 23 proteins that are downregulated by both tunicamycin and miR-494. Among these, we found 6 transcripts which harbor a putative miR-494 binding site. We validated the anti-apoptotic gene BIRC5 (survivin) as one of the targets of miR-494 during ER stress. Finally, induction of ER stress in vivo increases miR-494 expression in the liver. Pretreatment of mice with a miR-494 plasmid via hydrodynamic injection decreased ER stress in response to tunicamycin in part by decreasing inflammatory chemokines and cytokines. In summary, our data indicates that ER stress driven miR-494 may act in a feedback inhibitory loop to dampen downstream ER stress signaling. We propose that RNA-based approaches targeting miR-494 or its targets may be attractive candidates for inhibiting ER stress dependent pathologies in human disease.

scholarly journals Unfolded protein-independent IRE1 activation contributes to multifaceted developmental processes in Arabidopsis

2019 ◽  
Author(s):  
Kei-ichiro Mishiba ◽  
Yuji Iwata ◽  
Tomofumi Mochizuki ◽  
Atsushi Matsumura ◽  
Nanami Nishioka ◽  
...  
Keyword(s):  
Er Stress ◽  
Male Gametophyte ◽  
Activation Mechanism ◽  
Alternative Activation ◽  
Developmental Defect ◽  
Mutant Form ◽  
Triple Mutant ◽  
Unfolded Protein ◽  
Stress Dependent

AbstractAs an initial step for the unfolded protein response (UPR) pathway, the luminal domain of inositol requiring enzyme 1 (IRE1) senses unfolded proteins in the endoplasmic reticulum (ER). Recent findings in yeast and metazoans suggest alternative IRE1 activation without the sensor domain, although its mechanism and physiological significance remain to be elucidated. In Arabidopsis, the IRE1A and IRE1B double mutant (ire1a/b) is unable to activate cytoplasmic splicing of bZIP60 mRNA and regulated IRE1-dependent decay (RIDD) under ER stress, while the mutant does not exhibit severe developmental defects and is fertile under non-stress conditions. In this study, we focused on a third Arabidopsis IRE1 gene, designated as IRE1C, whose product lacks a sensor domain. We found that even though ire1c and ire1a/c mutants did not exhibit defective bZIP60 splicing and RIDD under ER stress, the ire1a/b/c triple mutant is lethal. Heterozygous IRE1C (ire1c/+) mutation in the ire1a/b mutants resulted in growth defects and reduction of the number of pollen grains. Genetic analysis revealed that IRE1C is required for male gametophyte development in the ire1a/b mutant background. Expression of a mutant form of IRE1B that lacks the luminal sensor domain (ΔLD) in the ire1a/b mutant did not complement defects in ER stress-dependent bZIP60 splicing and RIDD. Nevertheless, expression of ΔLD complemented a developmental defect in the male gametophyte in ire1a/b/c haplotype. In vivo, the ΔLD protein was activated by glycerol treatment that increases the composition of saturated lipid and was able to activate RIDD but not bZIP60 splicing. Phenotypes of IRE1B mutants lacking the sensor domain produced by CRISPR/Cas9-mediated gene editing in the ire1a/c mutant background were essentially same as those of ΔLD-expressing ire1a/b mutant. These observations suggest that IRE1 contributes to plant development, especially male gametogenesis, using an alternative activation mechanism that bypasses the unfolded protein-sensing luminal domain.

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