Ac2-26 activated the AKT1/GSK3ß pathway to reduce cerebral neurons pyroptosis and improve cerebral function in rats after cardiopulmonary bypass.

BACKGROUND: Cardiopulmonary bypass (CPB) results in brain injury, which is primarily caused by inflammation. Ac2-26 protects against ischemic or hemorrhage brain injury. The present study was to explore the effect and mechanism of Ac2-26 on brain injury in CPB rats. METHODS: Forty-eight rats were randomized into sham, CPB, Ac, Ac/AKT1, Ac/GSK3ßi and Ac/AKT1/GSK3ßa groups. Rats in sham group only received anesthesia and in the other groups received standard CPB surgery. Rats in the sham and CPB groups received saline, and rats in the Ac, Ac/AKT1, Ac/GSK3ßi and Ac/AKT1/GSK3ßa groups received Ac2-26 immediately after CPB. Rats in the Ac/AKT1, Ac/GSK3ßi and Ac/AKT1/GSK3ßa groups were injected with shRNA, inhibitor and agonist of GSK3ß respectively. The neurological function score, brain edema and histological score were evaluated. The neuronal survival and hippocampal pyroptosis were assessed. The cytokines, activity of NF-κB, S100 calcium-binding protein ß(S100ß) and neuron-specific enolase (NSE), and oxidative were tested. The NLRP3, cleaved-caspase-1 and cleaved-gadermin D (GSDMD) in the brain were also detected. RESULTS: Compared to the sham group, all indicators were aggravated in rats that underwent CPB. Compared to the CPB group, Ac2-26 significantly improved neurological scores and brain edema and ameliorated pathological injury. Ac2-26 reduced the local and systemic inflammation, oxidative stress response and promoted neuronal survival. Ac2-26 reduced hippocampal pyroptosis and decreased pyroptotic proteins in brain tissue. The protection of Ac2-26 was notably lessened by shRNA and inhibitor of GSK3ß. The agonist of GSK3ß recovered the protection of Ac2-26 in presence of shRNA. CONCLUSIONS: Ac2-26 significantly improved neurological function, reduced brain injury via regulating inflammation, oxidative stress response and pyroptosis after CPB. The protective effect of Ac2-26 primarily depended on AKT1/ GSK3ß pathway.

Clinical value of BRE-AS1 in myocardial infarction and its role in myocardial infarction-induced cardiac muscle cell apoptosis.

Objectives. The aim of this study was to investigate the expression of long non-coding RNA (lncRNA) brain and reproductive organ-expressed protein (BRE) antisense RNA 1 (BRE-AS1) in patients with acute myocardial infarction (AMI) and its effect on ischemia/reperfusion (I/R)-induced oxidative stress and apoptosis of cardiomyocytes. Methods. Serum BRE-AS1 levels in patients with AMI was detected using quantitative real-time polymerase chain reaction (qRT-PCR). The diagnostic and prognostic values of BRE-AS1 were evaluated. H9c2 cells were treated with hypoxia/reoxygenation to establish an in vitro myocardial infarction cell model. The levels of inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and IL-6 were detected by enzyme-linked immunosorbent assay (ELISA). Levels of lactate dehydrogenase (LDH), malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) were determined by commercial kits. Cell counting kit-8 (CCK-8) and flow cytometry were used to evaluate the cell viability and cell apoptosis. Results. The expression of BRE-AS1 in serum of patients with AMI is upregulated, which shows the clinical diagnostic value for AMI. In the I/R injury cell model, the knockout of BRE-AS1 can significantly alleviate the increase in TNF-α, IL-1ß, and IL-6 levels, inhibit the production of LDH and MDA, increase the activities of SOD and GSH-Px, promote the cell viability and suppress cell apoptosis. Conclusions. Abnormally elevated BRE-AS1 has a high diagnostic value for AMI as well as a prognostic value for major adverse cardiovascular events (MACEs). The elevation of BRE-AS1 promoted oxidative stress injury and cell apoptosis in vitro.

Immune cell signatures and inflammatory mediators: unraveling their genetic impact on chronic kidney disease through Mendelian randomization.

Prior research has established associations between immune cells, inflammatory proteins, and chronic kidney disease (CKD). Our Mendelian randomization study aims to elucidate the genetic causal relationships among these factors and CKD. We applied Mendelian randomization using genetic variants associated with CKD from a large genome-wide association study (GWAS) and inflammatory markers from a comprehensive GWAS summary. The causal links between exposures (immune cell subtypes and inflammatory proteins) and CKD were primarily analyzed using the inverse variance-weighted, supplemented by sensitivity analyses, including MR-Egger, weighted median, weighted mode, and MR-PRESSO. Our analysis identified both absolute and relative counts of CD28 + CD45RA + CD8 + T cell (OR = 1.01; 95% CI = 1.01-1.02; p < 0.001, FDR = 0.018) (OR = 1.01; 95% CI = 1.00-1.01; p < 0.001, FDR = 0.002), CD28 on CD39 + CD8 + T cell(OR = 0.97; 95% CI = 0.96-0.99; p < 0.001, FDR = 0.006), CD16 on CD14-CD16 + monocyte (OR = 1.02; 95% CI = 1.01-1.03; p < 0.001, FDR = 0.004) and cytokines, such as IL-17A(OR = 1.11, 95% CI = 1.06-1.16, p < 0.001, FDR = 0.001), and LIF-R(OR = 1.06, 95% CI = 1.02-1.10, p = 0.005, FDR = 0.043) that are genetically predisposed to influence the risk of CKD. Moreover, the study discovered that CKD itself may causatively lead to alterations in certain proteins, including CST5(OR = 1.16, 95% CI = 1.09-1.24, p < 0.001, FDR = 0.001). No evidence of reverse causality was found for any single biomarker and CKD. This comprehensive MR investigation supports a genetic causal nexus between certain immune cell subtypes, inflammatory proteins, and CKD. These findings enhance the understanding of CKD's immunological underpinnings and open avenues for targeted treatments.

Exploring causal correlations between inflammatory cytokines and knee osteoarthritis: a two-sample Mendelian randomization.

Objectives: Knee osteoarthritis (KOA) and certain inflammatory cytokines (such as interleukin 1 [IL-1] and tumor necrosis factor alpha [TNF-a]) are related; however, the causal relationship remains unclear. Here, we aimed to assess the causal relationship between 41 inflammatory cytokines and KOA using Mendelian randomization (MR). Methods: Two-sample bidirectional MR was performed using genetic variation data for 41 inflammatory cytokines that were obtained from European Genome-Wide Association Study (GWAS) data (n=8293). KOA-related genetic association data were also obtained from European GWAS data (n=40,3124). Inverse variance weighting (IVW), MR, heterogeneity, sensitivity, and multiple validation analyses were performed. Results: Granulocyte colony-stimulating factor (G-CSF) or colony-stimulating factor 3 (CSF-3) levels were negatively associated with the risk of developing KOA (OR: 0.93, 95%CI:0.89-0.99, P=0.015). Additionally, macrophage inflammatory protein-1 alpha (MIP-1A/CCL3) was a consequence of KOA (OR: 0.72, 95%CI:0.54-0.97, P=0.032). No causal relationship was evident between other inflammatory cytokines and KOA development. Conclusion: This study suggests that certain inflammatory cytokines may be associated with KOA etiology. G-CSF exerts an upstream influence on KOA development, whereas MIP-1A (CCL-3) acts as a downstream factor.

Interactions between circulating inflammatory factors and autism spectrum disorder: a bidirectional Mendelian randomization study in European population.

Background: Extensive observational studies have reported an association between inflammatory factors and autism spectrum disorder (ASD), but their causal relationships remain unclear. This study aims to offer deeper insight into causal relationships between circulating inflammatory factors and ASD. Methods: Two-sample bidirectional Mendelian randomization (MR) analysis method was used in this study. The genetic variation of 91 circulating inflammatory factors was obtained from the genome-wide association study (GWAS) database of European ancestry. The germline GWAS summary data for ASD were also obtained (18,381 ASD cases and 27,969 controls). Single nucleotide polymorphisms robustly associated with the 91 inflammatory factors were used as instrumental variables. The random-effects inverse-variance weighted method was used as the primary analysis, and the Bonferroni correction for multiple comparisons was applied. Sensitivity tests were carried out to assess the validity of the causal relationship. Results: The forward MR analysis results suggest that levels of sulfotransferase 1A1, natural killer cell receptor 2B4, T-cell surface glycoprotein CD5, Fms-related tyrosine kinase 3 ligand, and tumor necrosis factor-related apoptosis-inducing ligand are positively associated with the occurrence of ASD, while levels of interleukin-7, interleukin-2 receptor subunit beta, and interleukin-2 are inversely associated with the occurrence of ASD. In addition, matrix metalloproteinase-10, caspase 8, tumor necrosis factor-related activation-induced cytokine, and C-C motif chemokine 19 were considered downstream consequences of ASD. Conclusion: This MR study identified additional inflammatory factors in patients with ASD relative to previous studies, and raised a possibility of ASD-caused immune abnormalities. These identified inflammatory factors may be potential biomarkers of immunologic dysfunction in ASD.

Single-cell transcriptomics reveals a role for pancreatic duct cells as potential mediators of inflammation in diabetes mellitus.

Introduction: Inflammation of the pancreas contributes to the development of diabetes mellitus. Although it is well-accepted that local inflammation leads to a progressive loss of functional beta cell mass that eventually causes the onset of the disease, the development of islet inflammation remains unclear. Methods: Here, we used single-cell RNA sequencing to explore the cell type-specific molecular response of primary human pancreatic cells exposed to an inflammatory environment. Results: We identified a duct subpopulation presenting a unique proinflammatory signature among all pancreatic cell types. Discussion: Overall, the findings of this study point towards a role for duct cells in the propagation of islet inflammation, and in immune cell recruitment and activation, which are key steps in the pathophysiology of diabetes mellitus.

Exploring causal correlations between inflammatory cytokines and Ménière's disease: a Mendelian randomization.

Objectives: Previous studies have highlighted associations between certain inflammatory cytokines and Ménière's Disease (MD), such as interleukin (IL) -13 and IL-1ß. This Mendelian randomization aims to comprehensively evaluate the causal relationships between 91 inflammatory cytokines and MD. Methods: A comprehensive two-sample Mendelian randomization (MR) analysis was conducted to determine the causal association between inflammatory cytokines and MD. Utilizing publicly accessible genetic datasets, we explored causal links between 91 inflammatory cytokines and MD risk. Comprehensive sensitivity analyses were employed to assess the robustness, heterogeneity, and presence of horizontal pleiotropy in our findings. Results: Our findings indicate that MD causally influences the levels of two cytokine types: IL-10 (P=0.048, OR=0.945, 95%CI =0.894~1.000) and Neurotrophin-3 (P=0.045, OR=0954, 95%CI =0.910~0.999). Furthermore, three cytokines exhibited significant causal effects on MD: CD40L receptor (P=0.008, OR=0.865, 95%CI =0.777-0.963), Delta and Notch-like epidermal growth factor-related receptor (DNER) (P=0.010, OR=1.216, 95%CI =1.048-1.412), and STAM binding protein (P=0.044, OR=0.776, 95%CI =0.606-0.993). Conclusion: This study suggests that the CD40L receptor, DNER, and STAM binding protein could potentially serve as upstream determinants of MD. Furthermore, our results imply that when MD is regarded as the exposure variable in MR analysis, it may causally correlate with elevated levels of IL-10 and Neurotrophin-3. Using these cytokines for MD diagnosis or as potential therapeutic targets holds great clinical significance.

New Mediators in the Crosstalk between Different Adipose Tissues.

Adipose tissue is a multifunctional organ that regulates many physiological processes such as energy homeostasis, nutrition, the regulation of insulin sensitivity, body temperature, and immune response. In this review, we highlight the relevance of the different mediators that control adipose tissue activity through a systematic review of the main players present in white and brown adipose tissues. Among them, inflammatory mediators secreted by the adipose tissue, such as classical adipokines and more recent ones, elements of the immune system infiltrated into the adipose tissue (certain cell types and interleukins), as well as the role of intestinal microbiota and derived metabolites, have been reviewed. Furthermore, anti-obesity mediators that promote the activation of beige adipose tissue, e.g., myokines, thyroid hormones, amino acids, and both long and micro RNAs, are exhaustively examined. Finally, we also analyze therapeutic strategies based on those mediators that have been described to date. In conclusion, novel regulators of obesity, such as microRNAs or microbiota, are being characterized and are promising tools to treat obesity in the future.

Betaine Protects Mice from Cardiotoxicity Triggered by Sodium Arsenite Through Antioxidative and Anti-inflammatory Pathways.

NaAsO2 is known as a harmful pollutant all over the world, and many chronic heart diseases can be attributed to its prolonged exposure in NaAsO2-contaminated water. Therefore, considering the anti-inflammatory and antioxidant effects of betaine (BET), in this study, our team investigated the cardioprotective effects of this phytochemical agent on sodium arsenite (NaAsO2)-induced cardiotoxicity. Forty male mice were randomly divided into 4 groups: (I) Control; (II) BET (500 mg/kg); (III) NaAsO2 (50 ppm); and (IV) NaAsO2 + BET. NaAsO2 was given to the animals for 8 weeks, but BET was given in the last two weeks. After decapitation, inflammatory factors and biochemical parameters were measured, and Western blot analyses were performed. BET decrease the activity level of alanine aspartate aminotransferase, creatine kinase MB, thiobarbituric acid reactive substances level, inflammatory factors (tumor necrosis factor-α) content, and nuclear factor kappa B expression. Furthermore, BET increased cardiac total thiol and activity levels of catalase, superoxide dismutase, and glutathione peroxidase and nuclear factor erythroid-2 expression. Hence, the administration of BET ameliorated the deleterious effects stemming from the imbalance of oxidative and antioxidant pathways and histopathological alterations observed in NaAsO2-intoxicated mice, thereby attenuating oxidative stress-induced damage and inflammation.

Therapeutic strategies targeting mechanisms of macrophages in diabetic heart disease.

Diabetic heart disease (DHD) is a serious complication in patients with diabetes. Despite numerous studies on the pathogenic mechanisms and therapeutic targets of DHD, effective means of prevention and treatment are still lacking. The pathogenic mechanisms of DHD include cardiac inflammation, insulin resistance, myocardial fibrosis, and oxidative stress. Macrophages, the primary cells of the human innate immune system, contribute significantly to these pathological processes, playing an important role in human disease and health. Therefore, drugs targeting macrophages hold great promise for the treatment of DHD. In this review, we examine how macrophages contribute to the development of DHD and which drugs could potentially be used to target macrophages in the treatment of DHD.

EphB1 causes retinal damage through inflammatory pathways in the retina and retinal Müller cells.

Purpose: To examine whether increased ephrin type-B receptor 1 (EphB1) leads to inflammatory mediators in retinal Müller cells. Methods: Diabetic human and mouse retinal samples were examined for EphB1 protein levels. Rat Müller cells (rMC-1) were grown in culture and treated with EphB1 siRNA or ephrin B1-Fc to explore inflammatory mediators in cells grown in high glucose. An EphB1 overexpression adeno-associated virus (AAV) was used to increase EphB1 in Müller cells in vivo. Ischemia/reperfusion (I/R) was performed on mice treated with the EphB1 overexpression AAV to explore the actions of EphB1 on retinal neuronal changes in vivo. Results: EphB1 protein levels were increased in diabetic human and mouse retinal samples. Knockdown of EphB1 reduced inflammatory mediator levels in Müller cells grown in high glucose. Ephrin B1-Fc increased inflammatory proteins in rMC-1 cells grown in normal and high glucose. Treatment of mice with I/R caused retinal thinning and loss of cell numbers in the ganglion cell layer. This was increased in mice exposed to I/R and treated with the EphB1 overexpressing AAVs. Conclusions: EphB1 is increased in the retinas of diabetic humans and mice and in high glucose-treated Müller cells. This increase leads to inflammatory proteins. EphB1 also enhanced retinal damage in response to I/R. Taken together, inhibition of EphB1 may offer a new therapeutic option for diabetic retinopathy.

Molecular and pathophysiological relationship between obesity and chronic inflammation in the manifestation of metabolic dysfunctions and their inflammation­mediating treatment options (Review).

Obesity reaches up to epidemic proportions globally and increases the risk for a wide spectrum of co­morbidities, including type­2 diabetes mellitus (T2DM), hypertension, dyslipidemia, cardiovascular diseases, non­alcoholic fatty liver disease, kidney diseases, respiratory disorders, sleep apnea, musculoskeletal disorders and osteoarthritis, subfertility, psychosocial problems and certain types of cancers. The underlying inflammatory mechanisms interconnecting obesity with metabolic dysfunction are not completely understood. Increased adiposity promotes pro­inflammatory polarization of macrophages toward the M1 phenotype, in adipose tissue (AT), with subsequent increased production of pro­inflammatory cytokines and adipokines, inducing therefore an overall, systemic, low­grade inflammation, which contributes to metabolic syndrome (MetS), insulin resistance (IR) and T2DM. Targeting inflammatory mediators could be alternative therapies to treat obesity, but their safety and efficacy remains to be studied further and confirmed in future clinical trials. The present review highlights the molecular and pathophysiological mechanisms by which the chronic low­grade inflammation in AT and the production of reactive oxygen species lead to MetS, IR and T2DM. In addition, focus is given on the role of anti­inflammatory agents, in the resolution of chronic inflammation, through the blockade of chemotactic factors, such as monocytes chemotractant protein­1, and/or the blockade of pro­inflammatory mediators, such as IL­1ß, TNF­α, visfatin, and plasminogen activator inhibitor­1, and/or the increased synthesis of adipokines, such as adiponectin and apelin, in obesity­associated metabolic dysfunction.

The roles of SFKs in the regulation of proinflammatory cytokines and NLRP3 in familial mediterranean fever patients.

Familial Mediterranean Fever (FMF) is caused by mutations in pyrin, a protein produced in innate immune cells that regulates the development of interleukin (IL)-1ß by interacting with caspase-1 and other components of inflammasomes. Although overexpression of proinflammatory cytokines have been observed in FMF patients, no studies have been conducted on the role of Src family kinases (SFKs). The purpose of this study was to examine the impact of SFKs on the modulation of IL-1ß, IL-6, IL-8, TNF-α, and NLRP3 inflammasome in patients with FMF. The study included 20 FMF patients and 20 controls. Peripheral blood mononuclear cells (PBMCs) were isolated by density gradient centrifugation. Protein expression levels of SFKs members were measured by western blot. The effect of lipopolysaccharide-induced (LPS) activation and PP2- induced inhibition of SFKs on NLRP3 and IL-1ß, IL 6, IL-8, TNF-α were examined by western blot and flow cytometry respectively. Patients with FMF have considerably greater levels of Lck expression. In addition, patients had a substantially greater basal level of NLRP3 than the control group (*p = 0.016). Most importantly, the levels of IL-1 ß were elevated with LPS stimulation and reduced with PP2 inhibition in FMF patients. These results suggest that SFKs are effective in regulation of IL-1 ß in FMF patients.

Pathogenesis of gout: Exploring more therapeutic target.

Gout is a chronic metabolic and immune disease, and its specific pathogenesis is still unclear. When the serum uric acid exceeds its saturation in the blood or tissue fluid, it is converted to monosodium urate crystals, which lead to acute arthritis of varying degrees, urinary stones, or irreversible peripheral joint damage, and in severe cases, impairment of vital organ function. Gout flare is a clinically significant state of acute inflammation in gout. The current treatment is mostly anti-inflammatory analgesics, which have numerous side effects with limited treatment methods. Gout pathogenesis involves many aspects. Therefore, exploring gout pathogenesis from multiple perspectives is conducive to identifying more therapeutic targets and providing safer and more effective alternative treatment options for patients with gout flare. Thus, this article is of great significance for further exploring the pathogenesis of gout. The author summarizes the pathogenesis of gout from four aspects: signaling pathways, inflammatory factors, intestinal flora, and programmed cell death, focusing on exploring more new therapeutic targets.

Prophylactic Administration of Gut Microbiome Metabolites Abrogated Microglial Activation and Subsequent Neuroinflammation in an Experimental Model of Japanese Encephalitis.

Short-chain fatty acids (SCFAs) are gut microbial metabolic derivatives produced during the fermentation of ingested complex carbohydrates. SCFAs have been widely regarded to have a potent anti-inflammatory and neuro-protective role and have implications in several disease conditions, such as, inflammatory bowel disease, type-2 diabetes, and neurodegenerative disorders. Japanese encephalitis virus (JEV), a neurotropic flavivirus, is associated with life threatening neuro-inflammation and neurological sequelae in infected hosts. In this study, we hypothesize that SCFAs have potential in mitigating JEV pathogenesis. Postnatal day 10 BALB/c mice were intraperitoneally injected with either a SCFA mixture (acetate, propionate, and butyrate) or PBS for a period of 7 days, followed by JEV infection. All mice were observed for onset and progression of symptoms. The brain tissue was collected upon reaching terminal illness for further analysis. SCFA-supplemented JEV-infected mice (SCFA + JEV) showed a delayed onset of symptoms, lower hindlimb clasping score, and decreased weight loss and increased survival by 3 days (p < 0.0001) upon infection as opposed to the PBS-treated JEV-infected animals (JEV). Significant downregulation of inflammatory cytokines TNF-α, MCP-1, IL-6, and IFN-Υ in the SCFA + JEV group relative to the JEV-infected control group was observed. Inflammatory mediators, phospho-NF-kB (P-NF-kB) and iba1, showed 2.08 ± 0.1 and 3.132 ± 0.43-fold upregulation in JEV versus 1.19 ± 0.11 and 1.31 ± 0.11-fold in the SCFA + JEV group, respectively. Tissue section analysis exhibited reduced glial activation (JEV group─42 ± 2.15 microglia/ROI; SCFA + JEV group─27.07 ± 1.8 microglia/ROI) in animals that received SCFA supplementation prior to infection as seen from the astrocytic and microglial morphometric analysis. Caspase-3 immunoblotting showed 4.08 ± 1.3-fold upregulation in JEV as compared to 1.03 ± 0.14-fold in the SCFA + JEV group and TUNEL assay showed a reduced cellular death post-JEV infection (JEV-6.4 ± 1.5 cells/ROI and SCFA + JEV-3.7 ± 0.73 cells/ROI). Our study critically contributes to the increasing evidence in support of SCFAs as an anti-inflammatory and neuro-protective agent, we further expand its scope as a potential supplementary intervention in JEV-mediated neuroinflammation.

Inflammatory cytokine profiles in erectile dysfunction: a bidirectional Mendelian randomization.

Objectives: Inflammatory cytokines (ICs) play an important role in erectile dysfunction (ED). Previous studies have demonstrated that most ED patients have high levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-8 (IL-8). The causality between 41 ICs and ED is investigated using the Mendelian randomization (MR) approach. Methods: Single nucleotide polymorphisms (SNPs) exposure data of 41 ICs came from a genome-wide association study (GWAS) of 8293 subjects. At the same time, the FINNGEN R9 database provided the ED outcome data containing 2205 ED patients and 164104 controls. MR-Egger (ME), inverse variance weighting (IVW), and weighted median (WM) were applied to conduct the MR study and IVW was taken as the main criterion. Results: From a genetic perspective, the increase of interferon-inducible protein-10 (IP-10) level significantly increased the risk of ED (P=0.043, odds ratio (OR)=1.269, 95% confidence interval (95%CI): 1.007-1.600), while the increase of interleukin-1 receptor antagonist (IL-1RA) markedly decreased the risk of ED (P=0.037, OR=0.768, 95%CI: 0.600-0.984). Meanwhile, IP-10 (p=0.099) and IL-1RA (p=0.135) failed to demonstrate causality in reverse MR analysis. Conclusions: Changes in ICs levels will significantly affect the risk of ED, especially IP-10 as a risk component for ED and IL-1RA as a protective component for ED. In the future, we can achieve targeted treatment and prevention of ED by intervening with specific inflammatory factors.

Establishment of a model of LPS-induced inflammatory injury in human aortic endothelial cells.

PURPOSE: We aim to establish an LPS-induced human aortic endothelial cells (HAECs) inflammatory injury model and explore the optimal conditions for inducing its injury. We expect to provide modeling references for the related experiments of vascular inflammatory diseases. METHODS: HAECs were cultured in vitro and treated with different concentrations of lipopolysaccharide (LPS) (0.1, 1, 10, 50, 100 µg/mL) for 6, 12, and 24 h to establish the HAECs inflammatory injury model. The cell viability was determined by CCK-8 assay; the expression levels of inflammatory cytokines in the cells were detected by RT-PCR；the apoptosis rate of the cells was detected by flow cytometry. RESULTS: ① Within 24 h of LPS treatment, the cell viability of the 0.1 and 1 µg/mL groups showed an overall increasing trend with time, while the cell viability of the 10, 50, and 100 µg/mL groups increased first and then decreased with time, and the cell viability of 50 and 100 µg/mL groups was significantly lower than the normal control group at 24 h (P<0.01). ② RT-PCR results showed that after 50 and 100 µg/mL LPS for 24 h, the inflammatory cytokines all showed an apparent upward trend compared with the normal control group (P<0.05), which was more significant in the 100 µg/mL group. ③ After 100 µg/mL LPS for 24 h, the apoptotic necrosis rate of HAECs was higher than the normal control group (P<0.01). CONCLUSIONS: This experiment successfully established a HAECs injury model, indicating that the optimal conditions for inducing injury are an LPS concentration of 100 µg/mL and a treatment time of 24 h.

Resolvin D2 prevents vascular remodeling, hypercontractility and endothelial dysfunction in obese hypertensive mice through modulation of vascular and proinflammatory factors.

During resolution of inflammation, specialized proresolving mediators (SPMs), including resolvins, are produced to restore tissue homeostasis. We hypothesized that there might be a dysregulation of SPMs pathways in pathological vascular remodeling and that resolvin D2 (RvD2) might prevent vascular remodeling and contractile and endothelial dysfunction in a model of obesity and hypertension. In aortic samples of patients with or without abdominal aortic aneurysms (AAA), we evaluated gene expression of enzymes involved in SPMs synthesis (ALOXs), SPMs receptors and pro-inflammatory genes. In an experimental model of aortic dilation induced by high fat diet (HFD, 60%, eighteen weeks) and angiotensin II (AngII) infusion (four weeks), we studied the effect of RvD2 administration in aorta and small mesenteric arteries structure and function and markers of inflammation. In human macrophages we evaluated the effects of AngII and RvD2 in macrophages function and SPMs profile. In patients, we found positive correlations between AAA and obesity, and between AAA and expression of ALOX15, RvD2 receptor GPR18, and pro-inflammatory genes. There was an inverse correlation between the expression of aortic ALOX15 and AAA growth rate. In the mice model, RvD2 partially prevented the HFD plus AngII-induced obesity and adipose tissue inflammation, hypertension, aortic and mesenteric arteries remodeling, hypercontratility and endothelial dysfunction, and the expression of vascular proinflammatory markers and cell apoptosis. In human macrophages, RvD2 prevented AngII-induced impaired efferocytosis and switched SPMs profile. RvD2 might represent a novel protective strategy in preventing vascular damage associated to hypertension and obesity likely through effects in vascular and immune cells.

The Role of JAK/STAT Signaling Pathway and Its Downstream Influencing Factors in the Treatment of Atherosclerosis.

Atherosclerosis is now widely considered to be a chronic inflammatory disease, with increasing evidence suggesting that lipid alone is not the main factor contributing to its development. Rather, atherosclerotic plaques contain a significant amount of inflammatory cells, characterized by the accumulation of monocytes and lymphocytes on the vessel wall. This suggests that inflammation may play a crucial role in the occurrence and progression of atherosclerosis. As research deepens, other pathological factors have also been found to influence the development of the disease. The Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway is a recently discovered target of inflammation that has gained attention in recent years. Numerous studies have provided evidence for the causal role of this pathway in atherosclerosis, and its downstream signaling factors play a significant role in this process. This brief review aims to explore the crucial role of the JAK/STAT pathway and its representative downstream signaling factors in the development of atherosclerosis. It provides a new theoretical basis for clinically affecting the development of atherosclerosis by interfering with the JAK/STAT signaling pathway.