Anti-inflammatory Response Research Articles

Insights into Adaption and Growth Evolution: Genome–Wide Copy Number Variation Analysis in Chinese Hainan Yellow Cattle Using Whole–Genome Re–Sequencing Data

Copy number variation (CNV) serves as a crucial source of genomic variation and significantly aids in the mining of genomic information in cattle. This study aims to analyze re–sequencing data from Chinese Hainan yellow cattle, to uncover breed CNV information, and to elucidate the resources of population genetic variation. We conducted whole–genome sequencing on 30 Chinese Hainan yellow cattle, thus generating 814.50 Gb of raw data. CNVs were called using CNVnator software, and subsequent filtering with Plink and HandyCNV yielded 197,434 high–quality CNVs and 5852 CNV regions (CNVRs). Notably, the proportion of deleted sequences (81.98%) exceeded that of duplicated sequences (18.02%), with the lengths of CNVs predominantly ranging between 20 and 500 Kb This distribution demonstrated a decrease in CNVR count with increasing fragment length. Furthermore, an analysis of the population genetic structure using CNVR databases from Chinese, Indian, and European commercial cattle breeds revealed differences between Chinese Bos indicus and Indian Bos indicus. Significant differences were also observed between Hainan yellow cattle and European commercial breeds. We conducted gene annotation for both Hainan yellow cattle and European commercial cattle, as well as for Chinese Bos indicus and Indian Bos indicus, identifying 206 genes that are expressed in both Chinese and Indian Bos indicus. These findings may provide valuable references for future research on Bos indicus. Additionally, selection signatures analysis based on Hainan yellow cattle and three European commercial cattle breeds identified putative pathways related to heat tolerance, disease resistance, fat metabolism, environmental adaptation, candidate genes associated with reproduction and the development of sperm and oocytes (CABS1, DLD, FSHR, HSD17B2, KDM2A), environmental adaptation (CNGB3, FAM161A, DIAPH3, EYA4, AAK1, ERBB4, ERC2), oxidative stress anti–inflammatory response (COMMD1, OXR1), disease resistance (CNTN5, HRH4, NAALADL2), and meat quality (EHHADH, RHOD, GFPT1, SULT1B1). This study provides a comprehensive exploration of CNVs at the molecular level in Chinese Hainan yellow cattle, offering theoretical support for future breeding and selection programs aimed at enhancing qualities of this breed.

Selective PPARδ Agonist GW501516 Protects Against LPS-Induced Macrophage Inflammation and Acute Liver Failure in Mice via Suppressing Inflammatory Mediators

Inflammation is critical in the development of acute liver failure (ALF). Peroxisome proliferator-activated receptor delta (PPARδ) regulates anti-inflammatory responses and is protective in several diseases such as obesity and cancer. However, the beneficial effects and underlying mechanisms of PPARδ agonist GW501516 in ALF remain unclear. This study investigated the molecular mechanisms underlying the anti-inflammatory effects of GW501516 in macrophages and assessed its protective potential against lipopolysaccharide (LPS)/galactosamine (GalN)-induced ALF. In vivo administration of GW501516 significantly reduced LPS/GalN-induced hepatotoxicity, as evidenced by lower mortality, decreased liver damage, and attenuated secretion of IL-1β, IL-6, and TNF-α. GW501516 treatment also decreased LPS-induced nitric oxide synthase 2 (NOS2) expression and nitric oxide (NO) production in RAW264.7 cells, an effect reversed by PPARδ siRNA. Additionally, GW501516 inhibited LPS-induced phosphorylation of p38 and c-Jun N-terminal kinase (JNK), suggesting that inactivation of these MAPKs contributes to its effects. The secretion of IL-6, TNF-α, and NF-κB DNA-binding activity were also suppressed by GW501516, while the nuclear translocation of the NF-κB p65 subunit was unaffected. In conclusion, our findings suggest that GW501516 exerts protective effects in ALF by inhibiting the production of inflammatory mediators. Therefore, GW501516 may act as a potential agent for developing anti-inflammatory therapies for ALF.

Alamandine, a protective component of the renin-angiotensin system, reduces cellular proliferation and interleukin-6 secretion in human macrophages through MasR–MrgDR heteromerization

Alamandine (ALA) exerts protective effects similar to angiotensin (Ang) (1–7) through Mas-related G protein-coupled receptor type D receptor (MrgDR) activation, distinct from Mas receptor (MasR). ALA induces anti-inflammatory effects in mice but its impact in human macrophages remains unclear. We aimed to investigate the anti-inflammatory effects of ALA in human macrophages. Interleukin (IL)-6 and IL-1β were measured by ELISA in human THP-1 macrophages and human monocyte-derived macrophages exposed to lipopolysaccharide (LPS). Consequences of MasR–MrgDR heteromerization were investigated in transfected HEK293T cells. ALA decreased IL-6 and IL-1β secretion in LPS-activated THP-1 macrophages. The ALA-induced decrease in IL-6 but not in IL-1β was prevented by MasR blockade and MasR downregulation, suggesting MasR–MrgDR interaction. In human monocyte-derived M1 macrophages, ALA decreased IL-1β secretion independently of MasR. MasR–MrgDR interaction was confirmed in THP-1 macrophages, human monocyte-derived macrophages, and transfected HEK293T cells. MasR and MrgDR formed a constitutive heteromer that was not influenced by ALA. ALA promoted Akt and ERK1/2 activation only in cells expressing MasR–MrgDR heteromers, and this effect was prevented by MasR blockade. While Ang-(1–7) reduced cellular proliferation in MasR −but not MrgDR- expressing cells, ALA antiproliferative effect was elicited in cells expressing MasR–MrgDR heteromers. ALA also induced an antiproliferative response in THP-1 cells and this effect was abolished by MasR blockade, reinforcing MasR–MrgDR interaction. MasR–MrgDR heteromerization is crucial for ALA-induced anti-inflammatory and antiproliferative responses in human macrophages. This study broaden our knowledge of the protective axis of the RAS, thus enabling novel therapeutic approaches in inflammatory-associated diseases

Au/Ag@ZnS yolk-shell photocatalysts enhanced with noble metals and hyaluronic acid for efficient hydrogen production in rheumatoid arthritis therapy

Rheumatoid arthritis, characterized by the abnormal proliferation of synovial cells and extensive macrophage infiltration, is a chronic inflammatory disease. Molecular hydrogen, known for its antioxidant properties, has shown promise in eliminating reactive oxygen species. However, the low solubility and bioavailability of hydrogen limit the effectiveness of this therapy. To overcome these issues, we developed a novel yolk-shell heterostructure, H-AAZS (Au/Ag@ZnS modified hyaluronic acid), utilizing a hydrothermal cation exchange process. Through ion doping, semiconductor hybridization, and Schottky barriers in H-AAZS, photocatalysis for hydrogen generation has been successfully implemented using 660 nm laser irradiation. Additionally, the H-AAZS demonstrate the capacity for mild photothermal therapy, inducing apoptosis in synovial cells with Au's hot electrons with 660 nm laser irradiation. This strategy not only improves the abnormal proliferation of synovial cells but also avoids the exacerbation of inflammation caused by thermal stimulation. Both in vitro and in vivo experiments validate the synergistic effects of hydrogen production mediated anti-inflammatory responses, macrophage polarization and photothermal therapy. Therefore, this work represents a significant advancement as it ingeniously harnesses photocatalysis to modulate the synovial microenvironment while mitigating the side effects associated with photothermal therapy. This nanocrystal provides new and valuable insights into the potential treatment of Rheumatoid arthritis.

Ononin delays the development of osteoarthritis by down-regulating MAPK and NF-κB pathways in rat models.

Osteoarthritis (OA) is featured as cartilage loss, joint pain and loss of labor, which the inflammatory reaction may play critical roles. Ononin is an isoflavone isolating from medicinal plants and has anti-inflammatory effects. Our study investigated the anti-inflammation response of ononin on OA. Anterior cruciate ligament transection (ACLT)-induced OA operation was used to establish research model, then treated with ononin for 8 weeks. The condition of joint injury was assessed using pathological staining. The concentration of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) in serum were measured by Elisa kit. The expression of collagen II and matrix metalloproteinase 13 (MMP-13) proteins to assess cartilage metabolism level by immunohistochemistry and Western blot. We detected the expression of proteins involved in the MAPK and NF-κB signaling pathways. Finally, we used molecular docking to assess the affinity of ononin for the target proteins ERK1/2, JNK1/2, p38 and p65. Our results confirmed that ononin ameliorated cartilage impairment through histopathological analysis by improving the morphological structures and cartilage tidal lines and decreasing Osteoarthritis Research Society International (OARSI) scores in OA rats. Moreover, ononin inhibited the secretion of above factors in OA rats. Furthermore, ononin has been shown to improve cartilage content levels in OA rats. In addition, ononin inhibited the reactivity of MAPK and NF-κB pathways in OA rats. And molecular docking indicated the ligand molecules could stably bind to the proteins of above receptors. Our results demonstrated that ononin may ameliorate cartilage damage and inflammatory response in OA rats by downgrading MAPK and NF-κB pathways, thus identifying ononin as a potential novel drug to treat OA.

Intestinal microflora and metabolites affect the progression of acute pancreatitis (AP)

Specific intestinal metabolites are closely associated with the classification, severity, and necrosis of acute pancreatitis (AP) and provide novel insights for in-depth clinical investigations. In this study, the gut microbiota and metabolites of 49 AP patients at different treatment stages and severities were analysed via 16S rDNA sequencing and untargeted metabolomics to investigate the trends in gut microbiota composition and metabolome profiles observed in patients with severe AP. These findings revealed an imbalance in intestinal flora homeostasis among AP patients characterized by a decrease in probiotics and an increase in opportunistic pathogens, which leads to damage to the intestinal mucosal barrier through reduced short-chain fatty acid (SCFA) secretion and disruption of the intestinal epithelium. This dysbiosis influences energy metabolism, anti-inflammatory responses, and immune regulation, and these results highlight significant differences in energy metabolism pathways. These findings suggest that the differential composition of intestinal flora, along with alterations in intestinal metabolites and metabolic pathways, contribute to the compromised integrity of the intestinal mucosal barrier and disturbances in energy metabolism in patients with severe AP.

The clinical praxis of bacteriocins as natural anti-microbial therapeutics.

In recent decades, the excessive use of antibiotics has resulted in a rise in antimicrobial drug resistance (ADR). Annually, a significant number of human lives are lost due to resistant infectious diseases, leading to around 700,000 deaths, and it is estimated that by 2050, there could be up to 10 million casualties. Apart from their possible application as preservatives in the food sector, bacteriocins are gaining acknowledgment as potential clinical treatments. Not only this, these antimicrobial peptides have revealed in modulating the host immune system producing anti-inflammatory and anti-modulatory responses. At the same time, due to the ever-increasing global threat of antibiotic resistance, bacteriocins have gained attraction among researchers due to their potential clinical applications. Bacteriocins as antimicrobial peptides, represent one of the most important natural defense mechanisms among bacterial species, particularly lactic acid bacteria (LAB), that can fight against infection-causing pathogens. In this review, we are highlighting the potential of bacteriocins as novel therapeutics for inhibiting a wide range of clinically relevant and multi-drug-resistant pathogens (MDR). We also highlight the effectiveness and potential applications of current bacteriocin treatments in combating antimicrobial resistance (AMR), thereby promoting human health.

Effect of Probiotics on Gastrointestinal Health Through the Aryl Hydrocarbon Receptor Pathway: A Systematic Review

Probiotics are living microorganisms recognized for conferring health benefits on the host by modulating the gut microbiota. They interact with various signaling pathways, including the aryl hydrocarbon receptor (AhR), which plays a crucial role in maintaining intestinal homeostasis and immune function. The activation of AhR by probiotics has been associated with benefits such as improved intestinal barrier function, reduced inflammation, and modulation of immune responses. This systematic review aims to summarize current knowledge on the signaling of AhR, mediated by probiotics in physiological conditions and gastrointestinal pathologies. We conducted a comprehensive search across databases, including PubMed and Embase, up until July 2024. Out of 163 studies screened, 18 met the inclusion criteria. Our findings revealed in healthy populations that probiotic consumption increases the production of AhR ligands promoting intestinal immune tolerance. Furthermore, in populations with gastrointestinal pathologies, probiotics ameliorated symptoms through AhR activation by Trp metabolites, leading to the upregulation of the anti-inflammatory response.

Evaluation of the Activity of Olibanum Oil as an Immune Booster in Rats

The applications of herbal medicine have recently acquired growing interest in range of the prophylaxis and treatment of diseases. Olibanum has been used since ancient eras and several reports studied the pharmacological characteristics of boswellic acid, particularly their effect on the inflammatory response, analgesic properties, and anti-arthritic activity mostly in cell lines, but new approaches include animal models to assess these natural derivatives effects taking into consideration of being safer than synthetic preparations. The impact of olibanum oil on several parameters was studied in rats during this study. These included white blood cell (WBC) count, lactate dehydrogenase (LDH), and C reactive protein (CRP), as well as other pro-inflammatory cytokines like tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6), and the cytokine interleukin -10 (IL-10) that is anti-inflammatory. Total WBCs in addition to IL-10 levels significantly increased in the oil-treated group in comparison with the control one, while the rats treated with olibanum oil revealed a significant reduced level of LDH, CRP, IL-6 and TNF- α compared with the controls (p < 0.05). These outcomes indicate that olibanum oil treatment are manifested by cytokine changes, it can improve the anti-inflammatory response and down-regulate the pro-inflammatory cytokines. So, the promising impact of olibanum oils as an immunomodulator could be used in alternative therapies.

Bioinformatics Analysis and Experimental Validation of Epigallocatechin-3-gallate Against Iopromide-induced Injury in HEK-293 Cells via Anti-oxidative and Anti-inflammation Pathways.

The administration of contrast agents can adversely affect kidney function. Nevertheless, the nephrotoxicity of iopromide in human renal cells, potential therapeutic agents, and the underlying molecular mechanisms have not been thoroughly investigated. The proliferation of HEK-293 kidney cells was assessed using the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazoliumbromide (MTT) assay. Apoptotic cell death was examined using the TUNEL assay and caspase-3 activity measurements. The impacts and potential pathways of epigallocatechin-3-gallate (EGCG) on iopromide-induced renal damage were analyzed through whole transcriptome sequencing. The redox state was assessed by measuring reactive oxygen species (ROS) production and 2,2-Diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity. Iopromide-induced inhibition of cell proliferation and apoptosis in HEK-293 cells was counteracted by EGCG co-treatment. Pathway analysis revealed that molecules related to antioxidant and anti-inflammatory responses, such as ERK1/2, STAT1, and NF-[Formula: see text]B, were pivotal in the action of EGCG. Iopromide-induced ROS production, decreased DPPH scavenging ability, DNA strand breaks, elevated caspase-3 activity, and reduced cell proliferation were all reversed by EGCG co-treatment in HEK-293 cells. The mechanisms likely involve the attenuation of oxidative stress, inflammatory responses, and apoptosis, with regulation through the ERK1/2, STAT1, and NF-[Formula: see text]B pathways. Further research is necessary to confirm the protective effects of EGCG on renal function, particularly against damage induced by contrast agents like iopromide.

Anti-inflammatory response controlled by gamma wave

Since recognized as an important factor in Alzheimer’s disease, microglia are often found to shift from a neuroprotective M2 phenotype to a pro-inflammatory M1 phenotype thus cause neuroinflammation. This research proposal aims to put forward a new therapy in treating Alzheimer’s disease, in specific, by modulating gamma wave frequency and thereby regulate the polarization state of microglia. If it changes from M1 to M2, it changes from pro-inflammatory to anti-inflammatory, which means this strategy is efficient in treating Alzheimer’s disease.

Anti-inflammatory response controlled by gamma wave

It is now believed that the cause of Alzheimer’s disease is the accumulation of amyloid-Bata, which is caused by a variety of factors, such as neuroinflammation. So in this study, the researchers will study the changes of microglia from M1 to M2 by changing the frequency of gamma wave. If microglia change from M1 to M2, that means it changes from pro-inflammatory to anti-inflammatory.

VSIG4 inhibits the anti-inflammatory reaction of immune cells after cardiogenic shock

Abstract Cardiogenic shock (CS) still has a mortality rate of approximately 50%. CS leads to a significant activation of the immune system. The aim of this study was to characterize the immune cell populations and the immune cell-specific changes in CS on admission to the clinic and after revascularization. We developed a web-based platform named 'IRCaS - Immune Cell Regulations in Cardiogenic Shock' to map the temporal course of immune cell-specific processes of CS after acute myocardial infarction (AMI) from admission to 3 days after revascularization. Our tool revealed an endogenous anti-inflammatory response after CS, which is inhibited by the cell-cell receptor VSIG4. The web platform contains newly acquired single-cell sequencing data from patients with CS after AMI on admission and 24, 48, and 72 hours after revascularisation, as well as controls. In total, 171,962 immune cells derived from peripheral blood mononuclear cells (PBMCs) were individually sequenced. Analysis of the immune cell populations revealed, that 24 hours after revascularisation, monocytes increased to 62.4% (vs. 30.4% in controls), while T cells decreased from 46.3% to 25.0%. On the immune cell expression level, we observed an inflammatory response indicated by IL1B which continuously increased from 24 h (1.6+fold), over 48h (3.1+fold) to 72 h (3.5+fold) after revascularization. Interestingly, there was a significant anti-inflammatory response shortly after revascularization, as evidenced by a transient increase in the anti-inflammatory CD16+ monocyte subpopulation from 12.1% to 26.7% at 24 hours and an increase in THBS1 after revascularization, which was only short-lived. We identified a negative feedback in the increasing anti-inflammatory CD16+ cells caused by a subsequent VSIG4 (+5.2-fold) increase. Indeed, overexpression of VSIG4 in monocytes resulted in a significant decrease of anti-inflammatory CD16+ monocytes by 33.9% and a decrease in anti-inflammatory transcripts. Our data show that in addition to the strong inflammatory response in CS, there is also an opposing anti-inflammatory response, which is however only short-lived, as it is attenuated by a negative feedback via an increase in VSIG4. In addition, our webplatform offers time-dynamic gene expression profiles of immune cells, allowing users to select and visualize specific genes during the course of CS after AMI.

Advancements in Research on Mesenchymal Stem-Cell-Derived Exosomal miRNAs: A Pivotal Insight into Aging and Age-Related Diseases

Mesenchymal stem cells (MSCs) are capable of differentiating into various cell types and play a crucial role in repairing aging tissues and diseased organs. Aging manifests as a gradual loss of cellular, tissue, and organ function, leading to the progression of pathologies. Exosomes (Exos) are extracellular vesicles secreted by cells, which maintain cellular homeostasis, clear cellular debris, and facilitate communication between cells and organs. This review provides a comprehensive summary of the mechanisms for the synthesis and sorting of MSC–Exo miRNAs and summarizes the current research status of MSCs–Exos in mitigating aging and age-related diseases. It delves into the underlying molecular mechanisms, which encompass antioxidative stress, anti-inflammatory response, and the promotion of angiogenesis. Additionally, this review also discusses potential challenges in and future strategies for advancing MSC–Exo miRNA-based therapies in the treatment of aging and age-related diseases.

Unveiling Stingless Bee Honey Anti-inflammatory Potential Through the Polarization of LPS-induced J774 Macrophages.

Macrophages play an important role during the inflammatory process. These cells can adopt either the pro- or anti-inflammatory phenotypes. While stingless bee honeys have demonstrated evidence of anti-inflammatory potential, their capacity to induce a shift from a pro-inflammatory state to an inflammation-resolution state has not been thoroughly investigated. In this study, the anti-inflammatory activity of two stingless bees (Scaptotrigona bicunctata-honey A and Melipona quadriasciata-honey G) honeys in J774 macrophages induced by LPS was evaluated. Both honeys exhibited non-cytotoxic effects and reduced nitrite and IL-4 levels. However, only honey G increased the levels of the anti-inflammatory cytokine IL-13, by 163.1 ± 14.8% (p < 0.05) and was further investigated for its immunomodulatory effect. This honey reduced the expression of TLR4 by 59.3 ± 3.5% (p < 0.001) and increased the mannose receptor levels by 67.3 ± 2.4% (p < 0.001). Moreover, it increased the phagocytic activity by 25.0 ± 7.7% (p < 0.01) and decreased the death of the macrophages by 32.1 ± 1.7% (p < 0.001). Collectively, these findings highlight stingless bee honey from Melipona quadriasciata bee has an important immunomodulatory effect, as it reduces the markers of the pro-inflammatory state of J774 cells and increases the markers of resolution or anti-inflammatory responses.

T lymphocyte-dependent IL-10 down-regulates a cytokine storm driven by Toxoplasma gondii GRA24.

As a model organism in the study of immunity to infection, Toxoplasma gondii has been instrumental in establishing key principles of host anti-microbial defense and its regulation. Here, we employed an attenuated uracil auxotroph strain of Type I Toxoplasma designated OMP to further untangle the early immune response to this parasitic pathogen. Experiments using αβ T cell-deficient Tcrb-/- mice unexpectedly revealed that an intact αβ T lymphocyte compartment was essential to survive infection with OMP. Subsequent antibody depletion and knockout mouse experiments demonstrated contributions from CD4+ T cells and most predominantly CD8+ T cells in resistance. Using transgenic knockout mice, we found only a partial requirement for IFN-γ and a lack of requirement for Toll-like receptor (TLR) adaptor MyD88 in resistance. In contrast to other studies on Toxoplasma, the ability to survive OMP infection did not require IL-12p40. Surprisingly, T cell-dependent IL-10 was found to be critical for survival, and deficiency of this cytokine triggered an abnormally high systemic inflammatory response. We also found that parasite molecule GRA24, a dense granule protein that triggers TLR-independent IL-12 production, acts as a virulence factor contributing to death of OMP-infected Tcrb-/- and IL-10-/- mice. Furthermore, resistance against OMP was restored in Tcrb-/- mice via monoclonal depletion of IL-12p40, suggesting that GRA24-induced IL-12 underlies the fatal immunopathology observed. Collectively, our studies provide insight into a novel and rapidly arising T lymphocyte-dependent anti-inflammatory response to T. gondii which operates independently of MyD88 and IL-12 and that depends on the function of parasite-dense granule protein GRA24.IMPORTANCEAs a model infectious microbe and an important human pathogen, the apicomplexan Toxoplasma gondii has provided many important insights into innate and adaptive immunity to infection. We show here that a low virulence uracil auxotrophic Toxoplasma strain emerges as a virulent parasite in the absence of an intact T cell compartment. Both CD4+ and CD8+ T lymphocytes are required for optimal protection, in line with previous findings in other models of Toxoplasma infection. Nevertheless, several novel aspects of the response were identified in our study. Protection occurs independently of IL-12 and MyD88 and only partially requires IFN-γ. This is noteworthy particularly because the cytokines IL-12 and IFN-γ have previously been regarded as essential for protective immunity to T. gondii. Instead, we identified the anti-inflammatory effects of T cell-dependent IL-10 as the critical factor enabling host survival. The parasite dense granule protein GRA24, a host-directed mitogen-activated protein kinase activator, was identified as a major virulence factor in T cell-deficient hosts. Collectively, our results provide new and unexpected insights into host resistance to Toxoplasma.

Protective Role of High-Density Lipoprotein in Multiple Sclerosis

Multiple sclerosis (MS) is a chronic, progressive demyelinating disease with a most likely autoimmune background and a neurodegenerative component. Besides the demyelinating process caused by autoreactive antibodies, an increased permeability in the blood–brain barrier (BBB) also plays a key role. Recently, there has been growing interest in assessing lipid profile alterations in patients with MS. As a result of myelin destruction, there is an increase in the level of cholesterol released from cells, which in turn causes disruptions in lipid metabolism homeostasis both in the central nervous system (CNS) and peripheral tissues. Currently, there is a growing body of evidence suggesting a protective role of HDL in MS through its effect on the BBB by decreasing its permeability. This follows from the impact of HDL on the endothelium and its anti-inflammatory effect, mostly by interacting with adhesion molecules like vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), and E-selectin. HDL, through its action via sphingosine-1-phosphate, exerts an inhibitory effect on leukocyte migration, and its antioxidant properties contribute to the improvement of the BBB function. In this review, we want to summarize these studies and focus on HDL as a mediator of the anti-inflammatory response in MS.

Immunological sub-phenotypes and response to convalescent plasma in COVID-19 induced ARDS: a secondary analysis of the CONFIDENT trial

BackgroundConvalescent plasma (CP) reduced the mortality in COVID-19 induced ARDS (C-ARDS) patients treated in the CONFIDENT trial. As patients are immunologically heterogeneous, we hypothesized that clusters may differ in their treatment responses to CP.MethodsWe measured 20 cytokines, chemokines and cell adhesion markers using a multiplex technique at the time of inclusion in the CONFIDENT trial in patients of centers having accepted to participate in this secondary study. We performed descriptive statistics, unsupervised hierarchical cluster analysis, and examined the association between the clusters and CP effect on day-28 mortality.ResultsOf the 475 patients included in CONFIDENT, 391 (82%) were sampled, and 196/391 (50.1%) had been assigned to CP. We identified four sub-phenotypes representing 89 (22.8%), 178 (45.5%), 38 (9.7%), and 86 (22.0%) patients. The most contributing biomarkers in the principal component analysis were IL-1β, IL-12p70, IL-6, IFN-α, IL-17A, IFN-γ, IL-13, TFN-α, total IgG, and CXCL10. Sub-phenotype-1 displayed a lower immune response, sub-phenotype-2 a higher adaptive response, sub-phenotype-3 the highest innate antiviral, pro and anti-inflammatory response, and adhesion molecule activation, and sub-phenotype-4 a higher pro and anti-inflammatory response, migration protein and adhesion molecule activation. Sub-phenotype-2 and sub-phenotype-4 had higher severity at the time of inclusion. The effect of CP treatment on mortality appeared higher than standard care in each sub-phenotype, without heterogeneity between sub-phenotypes (p = 0.97).ConclusionIn patients with C-ARDS, we identified 4 sub-phenotypes based on their immune response. These sub-phenotypes were associated with different clinical profiles. The response to CP was similar across the 4 sub-phenotypes.Trial registration: Ethics Committee of the University Hospital of Liège CE 2020/239. Clinicaltrials.gov NCT04558476. Registered 2020-09-11, https://www.clinicaltrials.gov/study/NCT04558476.

Integrative Human Genetic and Cellular Analysis of the Pathophysiological Roles of AnxA2 in Alzheimer's Disease.

Alzheimer's disease (AD) is an intractable and progressive neurodegenerative disease. Amyloid beta (Aβ) aggregation is the hallmark of AD. Aβ induces neurotoxicity through a variety of mechanisms, including interacting with membrane receptors to alter downstream signaling, damaging cellular or organelle membranes, interfering with protein degradation and synthesis, and inducing an excessive immune-inflammatory response, all of which lead to neuronal death and other pathological changes associated with AD. In this study, we extracted gene expression profiles from the GSE5281 and GSE97760 microarray datasets in the GEO (Gene Expression Omnibus) database, as well as from the Human Gene Database. We identified differentially expressed genes in the brain tissues of AD patients and healthy persons. Through GO, KEGG, and ROC analyses, annexin A2 (AnxA2) was identified as a putative target gene. Notably, accumulating evidence suggests that intracellular AnxA2 is a key regulator in various biological processes, including endocytosis, transmembrane transport, neuroinflammation, and apoptosis. Thus, we conducted a series of cell biology experiments to explore the biological function of AnxA2 in AD. The results indicate that AnxA2 gene knockdown primarily affects oxidative phosphorylation, cell cycle, AD, protein processing in the endoplasmic reticulum, SNARE interactions in vesicular transport, and autophagy. In SH-SY5Y cells secreting Aβ42, AnxA2 gene knockdown exacerbated Aβ42-induced cytotoxicity, including cell death, intracellular ROS levels, and neuronal senescence, altered cell cycle, and reduced ATP levels, suggesting its critical role in mitochondrial function maintenance. AnxA2 gene knockdown also exacerbated the inhibitory effect of Aβ42 on cell migration. AnxA2 overexpression reduced the inflammatory response induced by Aβ42, while its absence increased pro-inflammatory and decreased anti-inflammatory responses. Furthermore, AnxA2 gene knockdown facilitated apoptosis and decreased autophagy. These results indicated potential pathophysiological roles of AnxA2 in AD.

N-(4-methoxyphenyl) quinoline-8-sulfonamide reduces the inflammatory response of fibroblast-like synoviocytes by targeting receptor (calcitonin) activity modifying protein 1 in rheumatoid arthritis

BackgroundRheumatoid arthritis (RA) is characterized by chronic inflammation of the synovium of joints. Fibroblast-like synoviocytes (FLS) play an important role in RA pathogenesis. We aimed to investigate the effect of N-(4-methoxyphenyl) quinoline-8-sulfonamide (QS-3g) on the inflammatory response of FLS and explore the potential underlying mechanisms. MethodsWe screened and found that QS-3g exhibits the best anti-inflammatory response against FLS using the CCK8 assay. To investigate the therapeutic effects of QS-3g on K/BxN STA mice, we used H&E staining, immunofluorescence, immunohistochemistry, micro-CT, and other techniques. Additional investigations, including RNA-seq, molecular docking, and CETSA, revealed that QS-3g binds to RAMP1. ResultsAmong a series of 8-quinoline sulfonyl amide derivatives, QS-3g reduced the inflammatory response in TNF-α stimulated FLS, such as the release of interleukin (IL)-1β and IL-6. H&E staining and micro-CT showed that QS-3g inhibited synovial hypertrophy, inflammatory cell infiltration, and bone destruction. RNA-seq and CETSA analyses revealed the targeted inhibition of RAMP1 by QS-3g. Inhibition of RAMP1 expression could reduce IL-6 and IL-1β levels. Compared with RAMP1-si, combined administration of QS-3g and RAMP1-si reduced the TNF-α-induced inflammation in TNF-α stimulated FLS without statistically significant differences. Finally, the results of in vitro experiments showed that QS-3g could restore the balance of Gαi/Gαs by inhibiting Gαi and activating Gαs and up-regulate the expression of cAMP protein, thus inhibiting the RAMP1-mediated inflammatory response in FLS. ConclusionQS-3g could inhibit RAMP1 activity and mediate the Gαs/Gαi–cAMP pathway to reduce FLS inflammatory response. Therefore, QS-3g may serve as a novel anti-inflammatory compound for treating RA.