scholarly journals Unique Subtype of Microglia in Degenerative Thalamus After Cortical Stroke

Stroke ◽  
2021 ◽  
Author(s):  
Zhijuan Cao ◽  
Sean S. Harvey ◽  
Terrance Chiang ◽  
Aulden G. Foltz ◽  
Alex G. Lee ◽  
...  
Keyword(s):  
Neurodegenerative Disease ◽  
Microglial Activation ◽  
Inflammatory Responses ◽  
Left Middle Cerebral Artery ◽  
Gene Expressions ◽  
Progressive Development ◽  
Permanent Occlusion ◽  
Cortical Stroke ◽  
Polymerase Chain ◽  
Neuronal Functions

Background and Purpose: Stroke disrupts neuronal functions in both local and remotely connected regions, leading to network-wide deficits that can hinder recovery. The thalamus is particularly affected, with progressive development of neurodegeneration accompanied by inflammatory responses. However, the complexity of the involved inflammatory responses is poorly understood. Herein we investigated the spatiotemporal changes in the secondary degenerative thalamus after cortical stroke, using targeted transcriptome approach in conjunction with histology and flow cytometry. Methods: Cortical ischemic stroke was generated by permanent occlusion of the left middle cerebral artery in male C57BL6J mice. Neurodegeneration, neuroinflammatory responses, and microglial activation were examined in naive and stroke mice at from poststroke days (PD) 1 to 84, in both ipsilesional somatosensory cortex and ipsilesional thalamus. NanoString neuropathology panel (780 genes) was used to examine transcriptome changes at PD7 and PD28. Fluorescence activated cell sorting was used to collect CD11c + microglia from ipsilesional thalamus, and gene expressions were validated by quantitative real-time polymerase chain reaction. Results: Neurodegeneration in the thalamus was detected at PD7 and progressively worsened by PD28. This was accompanied by rapid microglial activation detected as early as PD1, which preceded the neurodegenerative changes. Transcriptome analysis showed higher number of differentially expressed genes in ipsilesional thalamus at PD28. Notably, neuroinflammation was the top activated pathway, and microglia was the most enriched cell type. Itgax (CD11c) was the most significantly increased gene, and its expression was highly detected in microglia. Flow-sorted CD11c + microglia from degenerative thalamus indicated molecular signatures similar to neurodegenerative disease–associated microglia; these included downregulated Tmem119 and CX3CR1 and upregulated ApoE, Axl, LpL, CSF1, and Cst7. Conclusions: Our findings demonstrate the dynamic changes of microglia after stroke and highlight the importance of investigating stroke network-wide deficits. Importantly, we report the existence of a unique subtype of microglia (CD11c + ) with neurodegenerative disease–associated microglia features in the degenerative thalamus after stroke.

scholarly journals In Vitro Evaluation of the Anti-Inflammatory Effect of KMUP-1 and in Vivo Analysis of Its Therapeutic Potential in Osteoarthritis

Biomedicines ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 615
Author(s):  
Shang-En Huang ◽  
Erna Sulistyowati ◽  
Yu-Ying Chao ◽  
Bin-Nan Wu ◽  
Zen-Kong Dai ◽  
...  
Keyword(s):  
Articular Cartilage ◽  
Inflammatory Responses ◽  
Therapeutic Potential ◽  
Antioxidant Properties ◽  
Serum Levels ◽  
Gene Expressions ◽  
Tnf Α ◽  
Anti Inflammatory

Osteoarthritis is a degenerative arthropathy that is mainly characterized by dysregulation of inflammatory responses. KMUP-1, a derived chemical synthetic of xanthine, has been shown to have anti-inflammatory and antioxidant properties. Here, we aimed to investigate the in vitro anti-inflammatory and in vivo anti-osteoarthritis effects of KMUP-1. Protein and gene expressions of inflammation markers were determined by ELISA, Western blotting and microarray, respectively. RAW264.7 mouse macrophages were cultured and pretreated with KMUP-1 (1, 5, 10 μM). The productions of TNF-α, IL-6, MMP-2 and MMP- 9 were reduced by KMUP-1 pretreatment in LPS-induced inflammation of RAW264.7 cells. The expressions of iNOS, TNF-α, COX-2, MMP-2 and MMP-9 were also inhibited by KMUP-1 pretreatment. The gene expression levels of TNF and COX families were also downregulated. In addition, KMUP-1 suppressed the activations of ERK, JNK and p38 as well as phosphorylation of IκBα/NF-κB signaling pathways. Furthermore, SIRT1 inhibitor attenuated the inhibitory effect of KMUP-1 in LPS-induced NF-κB activation. In vivo study showed that KMUP-1 reduced mechanical hyperalgesia in monoiodoacetic acid (MIA)-induced rats OA. Additionally, KMUP-1 pretreatment reduced the serum levels of TNF-α and IL-6 in MIA-injected rats. Moreover, macroscopic and histological observation showed that KMUP-1 reduced articular cartilage erosion in rats. Our results demonstrated that KMUP-1 inhibited the inflammatory responses and restored SIRT1 in vitro, alleviated joint-related pain and cartilage destruction in vivo. Taken together, KMUP-1 has the potential to improve MIA-induced articular cartilage degradation by inhibiting the levels and expression of inflammatory mediators suggesting that KMUP-1 might be a potential therapeutic agent for OA.

Vibrio parahaemolyticus elevates interferon alpha production in intestinal-like epithelial Caco-2 cells

2007 ◽  
Vol 53 (9) ◽  
pp. 1084-1090
Author(s):  
Xin Lian ◽  
Akira Takahashi ◽  
Masayuki Nakano ◽  
Emiko Hori ◽  
Kazuaki Mawatari ◽  
...  
Keyword(s):  
Interferon Alpha ◽  
Vibrio Parahaemolyticus ◽  
Intestinal Loop ◽  
Gene Expressions ◽  
Tetratricopeptide Repeats ◽  
Mucosal Cells ◽  
Ifn Γ ◽  
Polymerase Chain ◽  
Inducible Protein ◽  
Gene Expression Levels

Vibrio parahaemolyticus is the leading cause of gastroenteritis from seafood consumption. We tried to determine how the gene expression levels of intestinal-like epithelial cells (Caco-2 cells) and mouse intestinal loop mucosal cells change upon infection with this bacterium. Since we found the robust production of interferon alpha (IFN-α) by the V. parahaemolyticus infection, we also assessed the upregulation of a number of IFN-stimulated genes (ISGs). The expressions of IFN protein were determined by Western blotting, and the gene expressions of Caco-2 cells after V. parahaemolyticus infection were determined by quantitative real-time reverse-transcription polymerase chain reaction. Three ISGs (i.e., IFN-α-inducible protein 15, IFN-α-inducible protein 6-16, and IFN-induced protein with tetratricopeptide repeats 1) were upregulated by V. parahaemolyticus infection. Infection induced the production of IFN-α, but not IFN-β or IFN-γ. The upregulation of the 3 ISGs was suppressed by treatment with a neutralizing IFN-α antibody. Moreover, the production of infection-induced IFN-α was found in the mouse intestinal loop mucosal cells. V. parahaemolyticus infection of Caco-2 cells results in IFN-α production and the expression of IFN-regulated genes.

scholarly journals Effects of Antioxidants in Reducing Accumulation of Fat in Hepatocyte

2018 ◽  
Vol 19 (9) ◽  
pp. 2563 ◽  
Author(s):  
Jung-Pyo Yang ◽  
Ji-Hun Shin ◽  
Seung-Hwan Seo ◽  
Sang-Gyun Kim ◽  
Sang Lee ◽  
...  
Keyword(s):  
Er Stress ◽  
Inflammatory Responses ◽  
Radical Scavenging ◽  
Gene Expressions ◽  
Fat Accumulation ◽  
Scavenging Effect ◽  
Radical Scavenging Effect ◽  
Vitro Model ◽  
Liver Hepatocellular Carcinoma

The progress of the hepatic steatosis (HS), a clinicopathological status, is influenced by cellular oxidative stress, lipogenesis, fatty acid (FA) oxidation, and inflammatory responses. Because antioxidants are gaining attention as potent preventive agents for HS, we aimed to investigate anti-lipogenic effects of the antioxidants vitamin C (VC), N-acetylcysteine (NAC), and astaxanthin (ATX) using hepatocytes. For this, we established an in vitro model using 1 mM oleic acid (OA) and human liver hepatocellular carcinoma (HepG2) cells; 10 μM antioxidants were evaluated for their ability to reduce fat accumulation in hepatocytes. Our results showed that all three antioxidants were effective to reduce fat accumulation for the molecular targets such as reduction in lipid droplets, triglyceride (TG) concentration, reactive oxygen species (ROS) production, and cell apoptosis, as well as in gene expressions of endoplasmic reticulum (ER) stress-related effectors, lipogenesis, and inflammatory cytokines. There were simultaneous increases in diphenyl-1-picrylhydrazyl (DPPH) radical scavenging effect, cell survival, AMPK phosphorylation, NRF2-related gene expression for cellular defense, and FA β-oxidation. However, among these, ATX more effectively inhibited ER stress and lipogenesis at the intracellular level than VC or NAC. Consequently, ATX was also more effective in inhibiting cell death, lipotoxicity, and inflammation. Our result emphasizes that ATX achieved greater lipotoxicity reduction than VC and NAC.

scholarly journals Linagliptin Ameliorates Hepatic Steatosis via Non-Canonical Mechanisms in Mice Treated with a Dual Inhibitor of Insulin Receptor and IGF-1 Receptor

2020 ◽  
Vol 21 (21) ◽  
pp. 7815
Author(s):  
Tomoko Okuyama ◽  
Jun Shirakawa ◽  
Kazuki Tajima ◽  
Yoko Ino ◽  
Heidrun Vethe ◽  
...  
Keyword(s):  
Insulin Receptor ◽  
Hepatic Steatosis ◽  
Insulin Signaling ◽  
Inflammatory Responses ◽  
Gene Expressions ◽  
Dual Inhibitor ◽  
Insulin Resistant ◽  
Glucose Levels ◽  
Hepatic Insulin Signaling ◽  
Igf1r Inhibitor

Abnormal hepatic insulin signaling is a cause or consequence of hepatic steatosis. DPP-4 inhibitors might be protective against fatty liver. We previously reported that the systemic inhibition of insulin receptor (IR) and IGF-1 receptor (IGF1R) by the administration of OSI-906 (linsitinib), a dual IR/IGF1R inhibitor, induced glucose intolerance, hepatic steatosis, and lipoatrophy in mice. In the present study, we investigated the effects of a DPP-4 inhibitor, linagliptin, on hepatic steatosis in OSI-906-treated mice. Unlike high-fat diet-induced hepatic steatosis, OSI-906-induced hepatic steatosis is not characterized by elevations in inflammatory responses or oxidative stress levels. Linagliptin improved OSI-906-induced hepatic steatosis via an insulin-signaling-independent pathway, without altering glucose levels, free fatty acid levels, gluconeogenic gene expressions in the liver, or visceral fat atrophy. Hepatic quantitative proteomic and phosphoproteomic analyses revealed that perilipin-2 (PLIN2), major urinary protein 20 (MUP20), cytochrome P450 2b10 (CYP2B10), and nicotinamide N-methyltransferase (NNMT) are possibly involved in the process of the amelioration of hepatic steatosis by linagliptin. Thus, linagliptin improved hepatic steatosis induced by IR and IGF1R inhibition via a previously unknown mechanism that did not involve gluconeogenesis, lipogenesis, or inflammation, suggesting the non-canonical actions of DPP-4 inhibitors in the treatment of hepatic steatosis under insulin-resistant conditions.

Gene expressions of TS and MDR-1 are predictive factors for chemosensitivity and survival in esophageal cancer with fluoropyrimidine-based chemotherapy

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 14120-14120
Author(s):  
K. Uchida ◽  
K. Hayashi ◽  
K. Kudo ◽  
H. Kuramochi ◽  
M. Yamamoto
Keyword(s):  
Esophageal Cancer ◽  
Mrna Expression ◽  
Overall Response Rate ◽  
Response Rate ◽  
Rt Pcr ◽  
Chain Reaction ◽  
Gene Expressions ◽  
Polymerase Chain ◽  
Relative Mrna Expression ◽  
Mdr 1

14120 Background: Fluoropyrimidines are widely used in chemotherapy regimens for esophageal cancer. To test the hypotheses of whether the relative mRNA expression of the enzyme TS, DPD and MDR-1 were associated with response to in esophageal cancer. We investigated the associations reported between intratumoral TS, DPD and MDR-1 gene expressions and the response with 5-FU based chemotherapy for patients with esophageal cancer. Methods: Twenty six pts with esophageal cancer were treated with 5-FU based chemotherapy (14 pts were treated with chemotherapy only, and 12 pts were chemoradiotherapy). mRNA was isolated from frozen tumor specimens, and relative expression levels of each gene/β-actin were measured using a quantitative reverse transcription polymerase chain reaction (RT-PCR) (Taqman®) system. Results: The overall response rate was 50.0%. Each mRNA expression was detectable in 26 patients. TS expressions were significantly lower in the responding tumors compared to the non-responders respectively (P=0.009). There were no significant associations between MDR-1 expression and the response. By setting up a cut-off level for TS and MDR-1 of Median, combining the two gene expression two-dimensionally revealed a relationship with the response (P=0.037). Additionally, MDR-1 expressions were statistically significant predictors of prolonged survival (P=0.0084). Conclusions: These results suggest that intratumoral TS and MDR-1 expressions are prognostic factors for survival after 5-FU based chemotherapy in esophageal cancer. No significant financial relationships to disclose.

scholarly journals Andrographolide Activates Keap1/Nrf2/ARE/HO-1 Pathway in HT22 Cells and Suppresses Microglial Activation by Aβ42through Nrf2-Related Inflammatory Response

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
Ji Yeon Seo ◽  
Euisun Pyo ◽  
Jin-Pyo An ◽  
Jinwoong Kim ◽  
Sang Hyun Sung ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Microglial Activation ◽  
Cell Activation ◽  
Inflammatory Responses ◽  
Antioxidant Response ◽  
Nuclear Factor ◽  
Antioxidant Response Element ◽  
Ht22 Cells ◽  
Oxide Synthase ◽  
Inducible Nitric Oxide

Therapeutic approach of Alzheimer’s disease (AD) has been gradually diversified. We examined the therapeutic and preventive potential of andrographolide, which is a lactone diterpenoid fromAndrographis paniculata, and focused on the Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-mediated heme oxygenase (HO)-1-inducing effects and the inhibitory activity of amyloid beta (Aβ)42-induced microglial activation related to Nrf2 and nuclear factorκB (NF-κB)-mediated inflammatory responses. Andrographolide induced the expression and translocation of Nrf2 from the cytoplasm to the nucleus, thereby activating antioxidant response element (ARE) gene transcription and HO-1 expression in murine hippocampal HT22 cells. Andrographolide eliminated intracellular Aβ42in BV-2 cells and decreased the production of interleukin (IL)-6, IL-1β, prostaglandin (PG)E2, and nitric oxide (NO) because of artificial phagocytic Aβ42. It decreased pNF-κB accumulation in the nucleus and the expression of inducible nitric oxide synthase (i-NOS) and cyclooxygenase II (COX-II) in the microglial BV-2 cell line. In summary, andrographolide activates Nrf2-mediated HO-1 expression and inhibits Aβ42-overexpressed microglial BV-2 cell activation. These results suggested that andrographolide might have the potential for further examination of the therapeutics of AD.

scholarly journals MiR-498 suppresses proliferation and inflammation in fibroblast-like synoviocytes in rheumatoid arthritis via targeting JAK1

2021 ◽  
Vol 18 (10) ◽  
pp. 2011-2017
Author(s):  
Lan Chai ◽  
Xian Zhen Zhang ◽  
Hai fang Ma ◽  
Fang Yuan
Keyword(s):  
Rheumatoid Arthritis ◽  
Cell Cycle ◽  
Polymerase Chain Reaction ◽  
Therapeutic Target ◽  
Cell Apoptosis ◽  
Inflammatory Responses ◽  
Chain Reaction ◽  
Polymerase Chain ◽  
Synovial Tissues ◽  
Fibroblast Like Synoviocytes

Purpose: To investigate the effect of microRNA 498 (miR-498) on proliferation and inflammation of rheumatoid arthritis (RA) fibroblast-like synoviocytes (RA-FLSs) in rheumatoid arthritis (RA). Methods: MiR-498 level was evaluated in both RA synovial tissues and RA-FLSs using real-time polymerase chain reaction (PCR). MicroRNA-498 overexpression or knockdown was performed in RAFLSs. Proliferation, apoptosis, cell cycle and inflammation induced by miR-498 mimics or inhibitor were used to explore the function of miR-498 in RA. Results: Expression level of miR-498 was downregulated in both RA synovial tissues and RA- FLSs. MicroRNA-498 mimics decreased proliferation and arrested cell cycle, whereas miR-498 inhibitor caused the opposite effects in RA-FLSs. In addition, miR-498 mimics suppressed inflammation and promoted cell apoptosis, while miR-498 inhibitor promoted inflammation and inhibited cell apoptosis in RA-FLSs. Furthermore, the effect of miR-498 on the proliferation, inflammation and apoptosis of RAFLSs was mediated by its ability to target and downregulate JAK1. Conclusion: These results indicate that miR-498 inhibits the proliferation and inflammatory responses of RA-FLSs by targeting JAK1, thus revealing a new therapeutic target for RA treatment.

scholarly journals 437. Longitudinal Plasma Cytokine Profiles Differentiating COVID-19 Severity Groups

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S320-S320
Author(s):  
Amanda M Green ◽  
Aisha Souquette ◽  
Mona Agrawal ◽  
Joshua Wolf ◽  
Joshua Wolf ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Clinical Severity ◽  
Cytokine Profiles ◽  
Severity Scores ◽  
Significant Difference ◽  
Cytokine Levels ◽  
Longitudinal Plasma ◽  
Prospective Cohorts ◽  
Polymerase Chain ◽  
Inflammatory Syndrome

Abstract Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), an infection with widely varying clinical severity. Severe COVID-19 was initially proposed to be secondary to cytokine storm syndrome (CSS). However, studies since showed that patients with severe COVID-19 rarely display CSS cytokine phenotypes, and may have more limited inflammatory responses instead. Methods Prospective cohorts, aged 0-90 years of age who tested positive by polymerase chain reaction (PCR) for SARS-CoV-2 were enrolled from inpatient hospitals and outpatient testing centers in Memphis, TN from May 2020-January 2021. Longitudinal blood samples were obtained including acute, sub-acute and convalescent timepoints. Severity scores of asymptomatic, mild, moderate, and severe COVID-19 were assigned at time of convalescent assessment. Plasma was analyzed with a quantitative human magnetic 38-plex cytokine assay. Results : 169 participants were enrolled, including 8 asymptomatic, 117 mild, 22 moderate and 17 severe cases, and 5 children with post-COVID-19 multisystem inflammatory syndrome in children (MIS-C). All moderate and severe patients were hospitalized and received treatment (39%). Clear distinctions were seen between asymptomatic-mild cases and moderate-severe cases at acute timepoints and during disease progression for GCSF, IL-8, IL-10, IL-15, IL-1Ra, IP-10, MIP-1a, MIP-1β, and TGFα. There was a significant difference between participants who did and did not require hospitalization for acute timepoint levels of IL-10, IL-15, MIP-1 β and TGFα (p< 0.01). Only 4 participants with active COVID-19 were found to meet criteria for CSS (2%), only 3 of which were severe. MIS-C participants showed nearly universally elevated cytokine levels compared to those with active COVID-19. Temporal and severity associations of IL-10 and IP-10 Figure 1. Temporal and severity associations of IL-10 and IP-10 Examples of differentiating cytokine profiles by severity and time. Among SARS-CoV-2 PCR positive participants, IL-10 and IP-10 displayed increased levels in their acute plasma samples as clinical severity increased [A,C]. IL-10 and IP-10 also showed distinct time-dependent responses (ln(Cytokine level (pg/mL)) that differentiated the more severe from the less severe groups [B,D]. Conclusion Moderate and severe acute COVID-19 has a distinct cytokine profile from asymptomatic and mild cases, as detected from acute, subacute and convalescent plasma. Disclosures Joshua Wolf, MBBS, PhD, FRACP, Karius Inc. (Research Grant or Support) Joshua Wolf, MBBS, PhD, FRACP, Nothing to disclose Paul Thomas, PhD, Cytoagents (Consultant)Immunoscape (Consultant)

scholarly journals Isorhynchophylline Ameliorates Cerebral Ischemia/Reperfusion Injury by Inhibiting CX3CR1-Mediated Microglial Activation and Neuroinflammation

2021 ◽  
Vol 12 ◽  
Author(s):  
Yuanyuan Deng ◽  
Ruirong Tan ◽  
Fei Li ◽  
Yuangui Liu ◽  
Jingshan Shi ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Microglial Activation ◽  
Inflammatory Responses ◽  
Ischemia Reperfusion Injury ◽  
Infarct Volume ◽  
Ischemia Reperfusion ◽  
Underlying Mechanism ◽  
Reperfusion Therapy ◽  
Artery Occlusion ◽  
Cerebral Ischemic

Reperfusion therapy is an effective way to rescue cerebral ischemic injury, but this therapy also shows the detrimental risk of devastating disorders and death due to the possible inflammatory responses involved in the pathologies. Hence, the therapy of ischemia/reperfusion (I/R) injury is a great challenge currently. Isorhynchophylline (IRN), a tetracyclic oxindole alkaloid extracted from Uncaria rhynchophylla, has previously shown neuroprotective and anti-inflammatory effects in microglial cells. This study systematically investigates the effect of IRN on I/R injury and its underlying mechanism. The effects of IRN on neuronal injury and microglia-mediated inflammatory response were assessed on a rat model with middle cerebral artery occlusion (MCAO) and reperfusion-induced injury. We found that IRN treatment attenuated the infarct volume and improved the neurological function in I/R injury rats. IRN treatment also reduced the neuronal death rate, brain water content, and aquaporin-4 expression in the ischemic penumbra of I/R injury rats’ brains. Besides, IRN treatment could inhibit the following process, including IκB-α degradation, NF-κB p65 activation, and CX3CR1 expression, as well as the microglial activation and inflammatory response. These findings suggest that IRN is a promising candidate to treat the cerebral I/R injury via inhibiting microglia activation and neuroinflammation.

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