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Purpose: To investigate whether genetic variations in cytokine genes involved in the pathogenesis of peri-implantitis are associated with the occurrence of peri-implantitis, an issue that remains controversial and may vary according to the population evaluated. Materials and Methods: A cross-sectional analytical study was carried out on 102 Caucasian Portuguese individuals who were divided into two groups: (1) 43 individuals with peri-implantitis and (2) 59 individuals with good peri-implant health. Samples from the buccal mucosa were obtained, and genetic analysis was performed using the real-time polymerase chain reaction (PCR) technique for IL-1A and IL-1B and PCR for IL-1RN. Results: The IL-1A-889 C/T polymorphism presented with a higher prevalence of the less common allele (T allele) in patients with peri-implantitis (27.9%) than in healthy patients (16.9%), but without statistical significance (P = .060). For the IL-1B+3954 C/T and IL-1RN (variable number of tandem repeats [VNTR]) polymorphisms, analysis revealed that the allele and genotype frequencies did not differ significantly between groups. There was a significant association between a history of periodontitis and peri-implantitis (P = .020). Conclusions: The evaluated genetic polymorphisms had no influence on the occurrence of peri-implantitis in the study population. Further research into genetic variations in different populations is needed to elucidate the role of genetic factors in the onset and progression of peri-implant disease. [ABSTRACT FROM AUTHOR]

Objective: Polycystic ovary syndrome (PCOS) is a prevalent metabolic disorder with an increased risk for cardiovascular disease (CVD) that is enhanced by obesity. This study sought to determine whether a panel of cardiovascular risk proteins (CVRPs) would be dysregulated in overweight/obese PCOS patients, highlighting potential biomarkers for CVD in PCOS. Methods: In this exploratory cross-sectional study, plasma levels of 54 CVRPs were analyzed in women with PCOS (n = 147) and controls (n = 97). CVRPs were measured using the SOMAscan proteomic platform (version 3.1), with significant proteins identified through linear models, regression analysis, and receiver operating characteristic (ROC) analysis. Analysis on BMI-matched subsets of the cohort were undertaken. Functional enrichment and protein–protein interaction analyses elucidated the pathways involved. Results: Eleven CVRPs were dysregulated in PCOS (whole set, without matching for body mass index (BMI) or insulin resistance (IR)): leptin, Interleukin-1 receptor antagonist protein (IL-1Ra), polymeric immunoglobulin receptor (PIGR), interleukin-18 receptor (IL-18Ra), C-C motif chemokine 3 (MIP-1a), and angiopoietin-1 (ANGPT1) were upregulated whilst advanced glycosylation end product-specific receptor, soluble (sRAGE), bone morphogenetic protein 6 (BMP6); growth/differentiation factor 2 (GDF2), superoxide dismutase [Mn] mitochondrial (MnSOD), and SLAM family member 5 (SLAF5) were downregulated versus the controls. In BMI-matched (overweight/obese, BMI ≥ 26 kg/m2) subset analysis, six CVRPs were common to the whole set: ANGPT1 and IL-1Ra were upregulated; and sRAGE, BMP6, GDF2, and Mn-SOD were downregulated. In addition, lymphotactin (XCL1) was upregulated and placenta growth factor (PIGF), alpha-L-iduronidase (IDUA), angiopoietin-1 receptor, and soluble (sTie-2) and macrophage metalloelastase (MMP12) were downregulated. A subset analysis of BMI-matched plus insulin resistance (IR)-matched women revealed only upregulation of tissue factor (TF) and renin in PCOS, potentially serving as biomarkers for cardiovascular risk in overweight/obese women with PCOS. Conclusions: A combination of upregulated obesity-related CVRPs (ANGPT1/IL/1Ra/XCL1) and downregulated cardioprotective proteins (sRAGE/BMP6/Mn-SOD/GDF2) in overweight/obese PCOS women may contribute to the increased risk for CVD. TF and renin upregulation observed in the BMI- and IR-matched limited sample PCOS subgroup indicates their potential risk of CVD. [ABSTRACT FROM AUTHOR]

Background: Achalasia is a rare motility disorder of the esophagus often accompanied by immune dysregulation, yet specific underlying mechanisms remain poorly understood. Methods: We utilized Mendelian randomization (MR) to explore the causal effects of cytokine levels on achalasia, with cis-expression/protein quantitative trait loci (cis-eQTLs/pQTLs) for 47 cytokines selected from a genome-wide association study (GWAS) meta-analysis and GWAS data for achalasia obtained from FinnGen. For cytokines significantly linked to achalasia, we analyzed their plasma concentrations and expression differences in the lower esophageal sphincter (LES) using enzyme-linked immunosorbent assay and single-cell RNA sequencing (scRNA-seq) profiling, respectively. We further employed bioinformatics approaches to investigate underlying mechanisms. Results: We revealed positive associations of circulating Eotaxin, macrophage inflammatory protein-1b (MIP1b), soluble E-selectin (SeSelectin) and TNF-related apoptosis-inducing ligand (TRAIL) with achalasia. When combining MR findings with scRNA-seq data, we observed upregulation of TRAIL (OR = 2.70, 95% CI, 1.20–6.07), encoded by TNFSF10, in monocytes and downregulation of interleukin-1 receptor antagonist (IL-1ra) (OR = 0.70, 95% CI 0.59–0.84), encoded by IL1RN, in FOS_macrophages in achalasia. TNFSF10high monocytes in achalasia displayed activated type I interferon signaling, and IL1RNlow FOS_macrophages exhibited increased intercellular communications with various lymphocytes, together shaping the proinflammatory microenvironment of achalasia. Conclusions: We identified circulating Eotaxin, MIP1b, SeSelectin and TRAIL as potential drug targets for achalasia. TNFSF10high monocytes and IL1RNlow macrophages may play a role in the pathogenesis of achalasia. [ABSTRACT FROM AUTHOR]

Despite the potential benefits of cannabidiol as a skin-soothing ingredient, its regulatory status hampers its general use in cosmetic products in many countries. To develop an alternative to cannabidiol, fatty acid amide molecules mimicking the chemical structure of endocannabinoids were manufactured using a lipase-catalyzed process. A mixture of fatty acid amides from sunflower oil and 1-amino propan-3-ol was synthesized using an immobilized lipase reaction, and the activation of cannabinoid receptor 1 (CB1R) was measured using a cAMP assay. The anti-inflammatory activity of the endocannabimimetic ingredients was evaluated in cultured human monocytes and ex vivo human skin explant models. A clinical study was conducted to address the skin hydration, skin barrier function, and skin redness, and the ratio of the interleukin-1-receptor antagonist (IL1-RA) to IL-1α in corneocytes, as a marker for skin sensitivity, were also measured. As a result, the activation of CB1R by endocannabimimetic ingredients was observed in cAMP assays, and a reduction in inflammatory responses by human monocytes induced by lipopolysaccharide treatment were also observed. External stress-induced inflammatory responses were reduced in ex vivo human skin explants. Improvements in skin hydration and barrier function were observed in a clinical study. A significant decrease in skin redness and the IL-1RA to IL-1α ratio was also observed. Endocannabimimetic ingredients, as alternatives to cannabidiol, can be used in skin-soothing cosmetics to increase skin hydration, improve skin barrier function, and reduce skin sensitivity. [ABSTRACT FROM AUTHOR]

Background: Polymorphonuclear neutrophils (PMN) activation by monosodium urate crystals (MSU) is crucial to acute gouty arthritis and subsequent spontaneous remission within 7–10 days. Activated PMNs release neutrophil extracellular traps (NETs) that entrap MSU crystals, forming NET-MSU aggregates. Whether NET-MSU aggregates contribute to the resolution of acute inflammation remains to be elucidated. This study uses a cell-based approach to unveil their molecular bases. Methods: All-trans retinoic acid-differentiated HL-60 cells (dHL-60) served as surrogate PMNs. NET release from MSU-activated dHL-60 was confirmed by detecting DNA, neutrophil elastase, and citrullinated histone 3, forming large NET-MSU aggregates. NET area was measured with Fiji software after SYTOX Green staining. Released pro-inflammatory cytokines IL-8 and TNF-α, and the anti-inflammatory cytokine IL-1RA in culture supernatants were quantified to calculate the estimate inflammation score (EIS). Cellular redox state was determined by a FRET-based sensor. Expression of intracellular positive (ERK1/2) and negative (SHP-1 and SHIP-1) cytokine signaling regulators was detected by western blot. qPCR detected mRNA expressions of CISH and SOCS1–SOCS7. Flow cytometry measured neutrophil N1 (CD54) and N2 (CD182) surface markers after staining with fluorescent-conjugated antibodies. Results: Incubating dHL-60 with MSU for 4 h maximized NET-MSU aggregate formation and acute inflammation with an EIS of 11.6. Prolonging the incubation of dHL-60 + MSU to 22 h gradually raised the EIS to 19.40 without increasing NET area, due to reduced cellular redox capacity. Adding both new dHL-60 and new MSU crystals to the culture, mimicking the clinical scenario, increased NET area but conversely suppressed EIS to 1.53, indicating acute inflammation resolution. The resolution of acute inflammation following prolonged incubation was attributed to decreases in P-ERK and increases in P-SHP-1, SOCS2, SOCS3, and CISH gene expressions, which may suppress pro-inflammatory and enhance anti-inflammatory cytokine production. Moreover, the large NET-MSU aggregates facilitated N1 to N2 polarization, crucial for accelerating inflammation resolution. Conclusion: We explored the potential molecular basis for the spontaneous resolution of MSU induced acute inflammation using a cell-based model in that huge NET-MSU aggregates frustrate the transformation of newly entering PMNs to the N2 phenotype, enhancing the production of the anti-inflammatory cytokine IL-1RA. [ABSTRACT FROM AUTHOR]

Objective: Blood lipid levels play a critical role in the progression of atherosclerosis. However, even with adequate lipid reduction, significant residual cardiovascular risk remains. Therefore, it is necessary to seek novel therapeutic strategies for atherosclerosis that can not only lower lipid levels but also inhibit inflammation simultaneously. Methods: The fusion protein FD03-IL-1Ra was designed by linking the Angiopoietin-like 3 (ANGPTL3) nanobody and human interleukin-1 receptor antagonist (IL-1Ra) sequences to a mutated human immunoglobulin gamma 1 (IgG1) Fc. This construct was transfected into HEK293 cells for expression. The purity and thermal stability of the fusion protein were assessed using SDS-PAGE, SEC-HPLC, and differential scanning calorimetry. Binding affinities of the fusion protein to ANGPTL3 and IL-1 receptor were measured using Biacore T200. The biological activity of the fusion protein was validated through in vitro experiments. The therapeutic efficacy of the fusion protein was evaluated in an ApoE-/- mouse model of atherosclerosis, including serum lipid level determination, histological analysis of aorta and aortic sinus sections, and detection of inflammatory and oxidative stress markers. ImageJ software was utilized for quantitative image analysis. Statistical analysis was performed using one-way ANOVA followed by Bonferroni post hoc test. Results: The FD03-IL-1Ra fusion protein was successfully expressed, with no polymer formation detected, and it demonstrated good thermal and conformational stability. High affinity for both murine and human ANGPTL3 was exhibited by FD03-IL-1Ra, and it was able to antagonize hANGPTL3's inhibition of LPL activity. FD03-IL-1Ra also showed high affinity for both murine and human IL-1R, inhibiting IL-6 expression in A549 cells induced by IL-1β stimulation, as well as suppressing IL-1β-induced activity inhibition in A375.S2 cells. Our study revealed that the fusion protein effectively lowered serum lipid levels and alleviated inflammatory responses in mice. Furthermore, the fusion protein enhanced plaque stability by increasing collagen content within atherosclerotic plaques. Conclusions: These findings highlighted the potential of bifunctional interleukin-1 receptor antagonist and ANGPTL3 antibody fusion proteins for ameliorating the progression of atherosclerosis, presenting a promising novel therapeutic approach targeting both inflammation and lipid levels. [ABSTRACT FROM AUTHOR]

Objective Renal function and the skeleton are classic target organs in primary hyperparathyroidism (PHPT), affected by the chronic course of the disease. Most patients diagnosed today exhibit mild PHPT, characterized by slight hypercalcemia and no or unspecific symptoms. Concerns have been raised that PHPT could promote deteriorating kidney function and increase cardiovascular risk directly. To examine the effect of parathyroidectomy (PTX) on mild PHPT on renal function and markers for bone turnover, cardiovascular disease (CVD), and vascular inflammation. Design Prospective randomized controlled trial. ClinicalTrials.gov : NCT00522028. Setting Eight Scandinavian referral centers. Participants From 1998 to 2005, 191 patients with mild PHPT were included in Sweden, Norway, and Denmark. Of these 150 were included in the present analyses. Intervention Seventy patients were randomized to PTX and 80 to observation without intervention (OBS). Measures e-GFR was calculated based on creatinine and cystatin C. Markers of CVD and systemic inflammation: osteoprotegerin, vascular cell adhesion molecule 1, soluble CD40 ligand, interleukin-1 receptor antagonist, von Willebrand factor. Bone turnover markers: C-terminal telopeptide of type 1 collagen (CTX-1) and serum Procollagen type 1 N-terminal propeptide. Results No differences in the development of renal function or vascular and systemic inflammation were detected. CTX-1 was lower in PTX after 10 years. Limitations Secondary analyses of a randomized controlled trial. Conclusion PTX does not appear to affect renal function or markers of CVD and vascular inflammation in mild PHPT in a ten-year perspective. [ABSTRACT FROM AUTHOR]

Diabetic vascular disease is a major complication of diabetes mellitus (DM). Chemokine C-C motif ligand 7 (CCL7) attracts macrophages and monocytes, amplifying inflammatory processes in the vasculature. We hypothesized a causal role for CCL7 in diabetic vasculopathy. CCL7 concentrations were higher in the plasma of patients with type 2 DM, as well as in supernatants from their endothelial progenitor cells (EPCs). High-glucose stimulation increased the secretion of CCL7 from human dermal microvascular endothelial cells (HDMECs) through the c-Fos and c-Jun signaling pathways. CCL7 inhibition using knockdown or neutralization antibody treatment reversed the high glucose–induced impaired tube formation and migration abilities of EPCs, human aortic endothelial cells, human coronary artery endothelial cells, and HDMECs. Administration of recombinant human CCL7 protein impaired tube formation and migration abilities by down-regulating the AKT–endothelial nitric oxide synthase and AKT/nuclear factor erythroid 2–related factor 2/heme oxygenase–1/vascular endothelial growth factor/stromal cell–derived factor–1 pathways and by up-regulating ERK/phosphorylated p65/interleukin-1β/interleukin-6/tumor necrosis factor–α pathways through CC chemokine receptor 3 in endothelial cells. Ccl7 knockout in streptozotocin-treated mice showed improved neovasculogenesis in ischemic limbs and accelerated wound repair, with increased circulating EPCs and capillary density. CCL7 antibody treatment in db/db mice and high-fat diet–induced hyperglycemia mice showed improved neovasculogenesis in ischemic limbs and wound areas, accompanied by up-regulation of angiogenic proteins and down-regulation of inflammatory proteins. Endothelial cell–specific Ccl7-knockout mice showed ameliorated diabetic vasculopathy in streptozotocin-induced DM. This study highlights the potential of CCL7 as a therapeutic target for diabetic vasculopathy. Editor's summary: Diabetes can result in harmful vascular complications. It is not fully understood how inflammatory cells contribute to diabetic vasculopathy. Chang et al. showed that CCL7, an immune cell–recruiting factor, could be inhibited to improve vascular function in diabetes models. Inhibiting CCL7 in human cells promoted endothelial functions under high-glucose stress. In mouse models of diabetes including streptozotocin treatment, leptin receptor mutation, or high-fat diet feeding, CCL7 neutralization antibody treatment or genetic knockout improved blood flow recovery after experimental limb ischemia. Wound closure was also accelerated by CCL7 inhibition in each mouse model. Endothelial-specific CCL7 knockout had similar protective effects in streptozotocin-treated mice. These data suggest that CCL7 inhibition could be a therapeutic target for diabetic vasculopathy. —Brandon Berry [ABSTRACT FROM AUTHOR]

Aim: This study aimed to evaluate the effectiveness of combining Channa striata extract with calcium hydroxide (Ca(OH)2) in reducing lymphocyte counts and interleukin (IL)-1β levels in inflamed pulp teeth. Materials and Methods: A laboratory experimental setup with a posttest control group (CG) design was employed. Thirty-two rat incisor teeth were divided into four groups: a positive CG (100% Ca(OH)2), treatment 1 (25% C. striata extract + 75% Ca(OH)2), treatment 2 (50% C. striata extract + 50% Ca(OH)2), and treatment 3 (75% C. striata extract + 25% Ca(OH)2). These test materials were applied to Class 1 cavities extending to the pulp roof, with samples collected on days 1, 3, 5, and 7. Data were analyzed using analysis of variance and post hoc least significant difference tests. Results: In all the groups, the highest levels of lymphocytes and IL-1β were observed on day 3, followed by a decline on days 5 and 7. The combination of C. striata extract with Ca(OH)2 significantly reduced inflammatory markers, particularly lymphocyte and IL-1β levels. Conclusion: The extract of C. striata holds significant potential as an innovative therapeutic approach for managing inflamed dental pulp. [ABSTRACT FROM AUTHOR]

Background: The interleukin-1 receptor accessory protein (IL1RAP) is highly expressed on acute myeloid leukemia (AML) bulk blasts and leukemic stem cells (LSCs), but not on normal hematopoietic stem cells (HSCs), providing an opportunity to target and eliminate the disease, while sparing normal hematopoiesis. Herein, we report the activity of BIF002, a novel anti-IL1RAP/CD3 T cell engager (TCE) in AML. Methods: Antibodies to IL1RAP were isolated from CD138+ B cells collected from the immunized mice by optoelectric positioning and single cell sequencing. Individual mouse monoclonal antibodies (mAbs) were produced and characterized, from which we generated BIF002, an anti-human IL1RAP/CD3 TCE using Fab arm exchange. Mutations in human IgG1 Fc were introduced to reduce FcγR binding. The antileukemic activity of BIF002 was characterized in vitro and in vivo using multiple cell lines and patient derived AML samples. Results: IL1RAP was found to be highly expressed on most human AML cell lines and primary blasts, including CD34+ LSC-enriched subpopulation from patients with both de novo and relapsed/refractory (R/R) leukemia, but not on normal HSCs. In co-culture of T cells from healthy donors and IL1RAPhigh AML cell lines and primary blasts, BIF002 induced dose- and effector-to-target (E:T) ratio-dependent T cell activation and leukemic cell lysis at subnanomolar concentrations. BIF002 administered intravenously along with human T cells led to depletion of leukemic cells, and significantly prolonged survival of IL1RAPhigh MOLM13 or AML patient-derived xenografts with no off-target side effects, compared to controls. Of note, BiF002 effectively redirects T cells to eliminate LSCs, as evidenced by the absence of disease initiation in secondary recipients of bone marrow (BM) from BIF002+T cells-treated donors (median survival not reached; all survived > 200 days) compared with recipients of BM from vehicle- (median survival: 26 days; p = 0.0004) or isotype control antibody+T cells-treated donors (26 days; p = 0.0002). Conclusions: The novel anti-IL1RAP/CD3 TCE, BIF002, eradicates LSCs and significantly prolongs survival of AML xenografts, representing a promising, novel treatment for AML. [ABSTRACT FROM AUTHOR]

Objective Proteomics may discover pathophysiological changes related to hepatocellular carcinoma, an aggressive and lethal type of cancer with low sensitivity for early stage diagnosis. Design We measured 1305 prediagnostic (median = 12.7 years) SomaScan proteins from 54 pairs of healthy individuals who subsequently developed hepatocellular carcinoma and matched non–hepatocellular carcinoma control individuals from the Nurses' Health Study (NHS) and the Health Professionals Follow-up Study (HPFS). Candidate proteins were validated in the independent, prospective UK Biobank Pharma Proteomics Project (UKB-PPP). Results In NHS and HPFS, we identified 56 elevated proteins in hepatocellular carcinoma with an absolute fold change of more than 1.2 and a Wald test P value less than  .05 in conditional logistic regression analysis. Ingenuity pathway analysis identified enrichment of pathways associated with cell viability, adhesion, proteolysis, apoptosis, and inflammatory response. Four proteins—chitinase-3-like protein 1, growth differentiation factor 15, interleukin-1 receptor antagonist protein, and E-selectin—showed strong positive associations with hepatocellular carcinoma and were thus validated by enzyme-linked immunosorbent assay (odds ratio = 2.48-14.7, all P  <  .05) in the NHS and HPFS and by Olink platform (hazard ratio = 1.90-3.93, all P  <  .05) in the UKB-PPP. Adding these 4 proteins to a logistic regression model of traditional hepatocellular carcinoma risk factors increased the area under the curve from 0.67 to 0.87 in the NHS and HPFS. Consistently, model area under the curve was 0.88 for hepatocellular carcinoma risk prediction in the UKB-PPP. Conclusion However, the limited number of hepatocellular carcinoma patients in the cohorts necessitates caution in interpreting our findings, emphasizing the need for further validation in high-risk populations. [ABSTRACT FROM AUTHOR]

Vitamin D is proposed to have a protective effect against cardiovascular disease, though the mechanism is unclear. Vitamin D deficiency is common in polycystic ovary syndrome (PCOS), where it is strongly related to obesity, insulin resistance (IR) and risk of cardiovascular disease. To determine if the inherent pathophysiology of PCOS or vitamin D levels are linked to dysregulation of cardiovascular risk proteins (CVRPs), a study in non-obese women with PCOS and without IR was undertaken. Our hypothesis was that the levels of vitamin D3 and its active metabolite would be associated with CVRPs comparably in women with and without PCOS. In women with PCOS (n = 29) and controls (n = 29), 54 CVRPs were determined by Slow Off-rate Modified Aptamer (SOMA)-scan plasma protein measurement and correlated to 25-hydroxyvitamin D3 (25(OH)D3) and the active 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) measured by gold standard isotope-dilution liquid chromatography tandem mass spectrometry. Women with PCOS had comparable IR and systemic inflammation (normal C-reactive protein) to control women, though had higher free androgen index and anti-Mullerian hormone levels. 25(OH)D3 and 1,25(OH)2D3 levels did not differ between groups. Nine CVRPs were higher in PCOS (p < 0.05) (Galectin-9, Brother of CDO, C-motif chemokine 3, Interleukin-18 receptor-1, Thrombopoietin, Interleukin-1 receptor antagonist protein, Programmed cell death 1 ligand-2, Low-affinity immunoglobulin gamma Fc-region receptor II-b and human growth hormone), whilst 45 CVRPs did not differ. 25(OH)D3 correlated with five CVRPs in PCOS and one in controls (p < 0.05). Despite the women with PCOS not exhibiting overt systemic inflammation, 9 of 54 CVRPs were elevated, all relating to inflammation, and 5 of these correlated with 25(OH)D3, suggesting an ongoing underlying inflammatory process in PCOS even in the absence of obesity/IR. [ABSTRACT FROM AUTHOR]

Chronic inflammation is a constitutive component of many age-related diseases, including age-related macular degeneration (AMD). Here, we identified interleukin-1 receptor–associated kinase M (IRAK-M) as a key immunoregulator in retinal pigment epithelium (RPE) that declines during the aging process. Rare genetic variants of IRAK3, which encodes IRAK-M, were associated with an increased likelihood of developing AMD. In human samples and mouse models, IRAK-M abundance in the RPE declined with advancing age or exposure to oxidative stress and was further reduced in AMD. Irak3-knockout mice exhibited an increased incidence of outer retinal degeneration at earlier ages, which was further exacerbated by oxidative stressors. The absence of IRAK-M led to a disruption in RPE cell homeostasis, characterized by compromised mitochondrial function, cellular senescence, and aberrant cytokine production. IRAK-M overexpression protected RPE cells against oxidative or immune stressors. Subretinal delivery of adeno-associated virus (AAV)–expressing human IRAK3 rescued light-induced outer retinal degeneration in wild-type mice and attenuated age-related spontaneous retinal degeneration in Irak3-knockout mice. Our data show that replenishment of IRAK-M in the RPE may redress dysregulated pro-inflammatory processes in AMD, suggesting a potential treatment for retinal degeneration. Editor's summary: Age-related macular degeneration (AMD) progression is associated with chronic inflammation, but the role of the Myddosome complex, which is necessary for Toll-like receptor and IL-1R signaling, in AMD has not been fully elucidated. Here, Liu and colleagues identified rare variants in IRAK3, which encodes the inhibitory Myddosome component IRAK-M, as being associated with an increased risk of late AMD. Using human retinal samples and mouse models of aging and retinal injury, as well as Irak3-knockout mice, the authors showed that IRAK-M was present in retinal pigment epithelium (RPE) and decreased with age and injury. Overexpression of human IRAK3 in the RPE could attenuate outer retinal degeneration in these mouse models, suggesting a potential therapeutic strategy for AMD. —Melissa L. Norton [ABSTRACT FROM AUTHOR]

Objective: To explore the efficacy and potential mechanism of Fengshi Gutong capsule (FSGTC) in osteoarthritis (OA) inflammation. Methods: The impact of FSGTC on laboratory indicators of OA patients was explored using data mining technology and association rule analysis. Then, the OA cell model was constructed by inducing chondrocytes (CHs) with interleukin‐1β (IL‐1β). In the presence of FSGTC intervention, the regulatory mechanism of PACER/COX2/PGE2 in OA‐CH viability and inflammatory responses was evaluated. Results: Retrospective data mining showed that FSGTC effectively reduced inflammation indexes (ESR, HCRP) of OA patients. Cell experiments showed that LncRNA PACER (PACER) silencing inhibited the proliferation activity of OA‐CHs, increased the level of COX2 protein, elevated the levels of PGE2, TNF‐α, and IL‐1β, and decreased the levels of IL‐4 and IL‐10 (p <.01). On the contrary, FSGTC‐containing serum reversed the effect of PACER silencing on OA‐CHs (p <.01). After the addition of COX2 pathway inhibitor, the proliferation activity of OA‐CHs was enhanced; the levels of PGE2, TNF‐α, and IL‐1β were decreased while the levels of IL‐4 and IL‐10 were increased (p <.01). Conclusion: FSGTC inhibits IL‐1β‐induced inflammation in CHs and ameliorates OA by upregulating PACER and downregulating COX2/PGE2. [ABSTRACT FROM AUTHOR]

Endothelial‐to‐mesenchymal transition (EndMT) is a complex biological process of cellular transdifferentiation by which endothelial cells (ECs) lose their characteristics and acquire mesenchymal properties, leading to cardiovascular remodeling and complications in the adult cardiovascular diseases environment. Melatonin is involved in numerous physiological and pathological processes, including aging, and has anti‐inflammatory and antioxidant activities. This molecule is an effective therapeutic candidate for preventing oxidative stress, regulating endothelial function, and maintaining the EndMT balance to provide cardiovascular protection. Although recent studies have documented improved cardiac function by melatonin, the mechanism of action of melatonin on EndMT remains unclear. The present study investigated the effects of melatonin on induced EndMT by transforming growth factor‐β2/interleukin‐1β in both in vivo and in vitro models. The results revealed that melatonin reduced the migratory ability and reactive oxygen species levels of the cells and ameliorated mitochondrial dysfunction in vitro. Our findings indicate that melatonin prevents endothelial dysfunction and inhibits EndMT by activating related pathways, including nuclear factor kappa B and Smad. We also demonstrated that this molecule plays a crucial role in restoring cardiac function by regulating the EndMT process in the ischemic myocardial condition, both in vessel organoids and myocardial infarction (MI) animal models. In conclusion, melatonin is a promising agent that attenuates EC dysfunction and ameliorates cardiac damage compromising the EndMT process after MI. [ABSTRACT FROM AUTHOR]

Respiratory syncytial virus (RSV) infects neuronal cells in the central nervous system (CNS), resulting in neurological symptoms. In the present study, we intended to explore the mechanism of RSV infection‐induced neuroinflammatory injury from the perspective of the immune response and sought to identify effective protective measures against the injury. The findings showed that toll‐like receptor 4 (TLR4) was activated after RSV infection in human neuronal SY5Y cells. Furthermore, TLR4 activation induced autophagy and apoptosis in neuronal cells, promoted the formation of the NOD‐like receptor family pyrin domain containing 3 (NLRP3) inflammasome, and increased the secretion of downstream inflammatory cytokines such as interleukin‐1β (IL‐1β), interleukin‐18 (IL‐18) and tumour necrosis factor‐α (TNF‐α). Interestingly, blockade of TLR4 or treatment with exogenous melatonin significantly suppressed TLR4 activation as well as TLR4‐mediated apoptosis, autophagy and immune responses. Therefore, we infer that melatonin may act on the TLR4 to ameliorate RSV‐induced neuronal injury, which provides a new therapeutic target for RSV infection. [ABSTRACT FROM AUTHOR]

The article examines the relationship between adipose inflammation and insulin resistance. Topics covered include the association between obesity and diabetes, whether inflammation drive insulin resistance in humans and whether differences between humans and mice account for discrepancies in their metabolic response to immune perturbations. It also cites the role of proinflammatory immune cells in adipose tissue in obesity.

Our previous study using RNA sequencing and reverse transcription quantitative polymerase chain reaction (RT-qPCR) validation identified a long non-coding RNA (lnc), lnc-AL928768.3, correlating with risk and disease activity of rheumatoid arthritis (RA), then the present study was conducted to further investigate the interaction of lnc-AL928768.3 with lymphotoxin beta (LTB) and their impact on proliferation, migration, invasion, and inflammation in RA-fibroblast-like synoviocytes (RA-FLS). Human RA-FLS was obtained and transfected with lnc-AL928768.3 overexpression, negative control overexpression, lnc-AL928768.3 short hairpin RNA (shRNA) and negative control shRNA plasmids. Then cell functions and inflammatory cytokine expressions were detected. Afterward, rescue experiments were conducted via transfecting lnc-AL928768.3 shRNA with or without LTB overexpression plasmids in RA-FLS. Lnc-AL928768.3 enhanced proliferation and invasion, inhibited apoptosis, while had little impact on migration in RA-FLS. In addition, lnc-AL928768.3 positively modulated interleukin-1β (IL-1β), IL-6 and IL-8 expressions in RA-FLS supernatant; moreover, it also positively regulated LTB mRNA expression, LTB protein expression, p-NF-κB protein expression, and p-IKB-α protein expression in RA-FLS. Furthermore, following experiment showed that lnc-AL928768.3 positively regulated LTB expression while LTB did not impact on lnc-AL928768.3 expression in RA-FLS. Furthermore, in rescue experiments, LTB overexpression curtailed the effect of lnc-AL928768.3 knock-down on regulating proliferation, invasion, apoptosis and inflammatory cytokine expressions in RA-FLS. Lnc-AL928768.3 promotes proliferation, invasion, and inflammation while inhibits apoptosis of RA-FLS via activating LTB mediated NF-κB signaling. [ABSTRACT FROM AUTHOR]

Sustained liver injuries predominantly promote oxidative stress and inflammation that lead to the progression of chronic liver disease (CLD), including fibrosis, cirrhosis, and hepatocellular carcinoma. Boldine, an alkaloid isolated from Peumus boldus, has been shown to have antioxidant and anti-inflammatory effects. Currently, there is no definitive treatment option available for CLD. Therefore, we investigated the hepatoprotective effect of boldine against carbon tetrachloride (CCl4)-induced chronic liver injury in rats. CCl4 (2mL/kg., b.w., i.p.) was administered twice weekly for 5 weeks to induce chronic liver injury in rats. Separate groups of rats were given boldine (20mg/kg b.w., and 40mg/kg b.w.) and silymarin (100 mg/kg b.w.) orally, daily. Serum transaminases, lipid peroxidation, and antioxidant levels were measured, and nuclear factor-μB (NF-μB), tumor necrosis factor-α (TNF-α), cyclooxygenase-2 (cox-2), interleukin-1 β (IL-1β), and α-smooth muscle actin (α-SMA) gene and protein expressions were evaluated. CCl4 administration increased liver marker enzymes of hepatotoxicity in serum and oxidative stress markers, inflammatory genes and α-smooth muscle actin expression in liver tissue. Boldine concurrent treatment suppressed CCl4-induced elevation of transaminase levels in serum, restored enzymic and non-enzymic antioxidants, and downregulated NF-μB, TNF-α, Cox-2 and IL-1β expressions, thereby suppressing hepatic inflammation. Boldine administration also repressed α-SMA expression. The results of this study demonstrate the antioxidant, anti-inflammatory, and antifibrotic properties of boldine, and it can be a potential therapeutic candidate in the treatment of CLD. [ABSTRACT FROM AUTHOR]

Gremlin-1 is a bone morphogenetic protein (BMP) antagonist, by directly binding to the receptor and inhibiting BMP signaling and functioning, in which BMP is involved in the normal development of bone tissue and the process of maintaining homeostasis, according to studies, Gremlin-1 inhibition of BMP protein in osteoarthritis (OA) occurrence, development has great significance, nowadays, many scholars have found that Gremlin-1 and OA progression is closely related, Notably, Gremlin-1 is also involved in the process of interfering with the cell viability of mesenchymal stem cells and mediating osteoblast differentiation by related signaling pathways, leading to further deterioration of OA. Therefore, this article mainly starts from Gremlin-1 gene, discusses the relationship with OA and mediates related signaling pathways, inhibits the process of bone formation and affects the progress of OA. [ABSTRACT FROM AUTHOR]

Background: Patients with fibro-calcific aortic valve disease (FCAVD) have lipid depositions in their aortic valve that engender a proinflammatory impetus toward fibrosis and calcification and ultimately valve leaflet stenosis. Although the lipoprotein(a)-autotaxin (ATX)-lysophosphatidic acid axis has been suggested as a potential therapeutic target to prevent the development of FCAVD, supportive evidence using ATX inhibitors is lacking. We here evaluated the therapeutic potency of an ATX inhibitor to attenuate valvular calcification in the FCAVD animal models. Methods: ATX level and activity in healthy participants and patients with FCAVD were analyzed using a bioinformatics approach using the Gene Expression Omnibus datasets, enzyme-linked immunosorbent assay (ELISA), immunohistochemistry, and western blotting. To evaluate the efficacy of ATX inhibitor, interleukin-1 receptor antagonist-deficient (Il1rn-/-) mice and cholesterol-enriched diet-induced rabbits were used as the FCAVD models, and primary human valvular interstitial cells (VICs) from patients with calcification were employed. Results: The global gene expression profiles of the aortic valve tissue of patients with severe FCAVD demonstrated that ATX gene expression was significantly upregulated and correlated with lipid retention (r = 0.96) or fibro-calcific remodeling-related genes (r = 0.77) in comparison to age-matched non-FCAVD controls. Orally available ATX inhibitor, BBT-877, markedly ameliorated the osteogenic differentiation and further mineralization of primary human VICs in vitro. Additionally, ATX inhibition significantly attenuated fibrosis-related factors' production, with a detectable reduction of osteogenesis-related factors, in human VICs. Mechanistically, ATX inhibitor prohibited fibrotic changes in human VICs via both canonical and non-canonical TGF-β signaling, and subsequent induction of CTGF, a key factor in tissue fibrosis. In the in vivo FCAVD model system, ATX inhibitor exposure markedly reduced calcific lesion formation in interleukin-1 receptor antagonist-deficient mice (Il1rn-/-, P = 0.0210). This inhibition ameliorated the rate of change in the aortic valve area (P = 0.0287) and mean pressure gradient (P = 0.0249) in the FCAVD rabbit model. Moreover, transaortic maximal velocity (Vmax) was diminished with ATX inhibitor administration (mean Vmax = 1.082) compared to vehicle control (mean Vmax = 1.508, P = 0.0221). Importantly, ATX inhibitor administration suppressed the effects of a high-cholesterol diet and vitamin D2-driven fibrosis, in association with a reduction in macrophage infiltration and calcific deposition, in the aortic valves of this rabbit model. Conclusions: ATX inhibition attenuates the development of FCAVD while protecting against fibrosis and calcification in VICs, suggesting the potential of using ATX inhibitors to treat FCAVD. [ABSTRACT FROM AUTHOR]

Inhibiting pathological secretion of Interleukin-1β has shown beneficial effects in disease models and in the clinic and thus there is interest in finding inhibitors that can reduce its release from macrophages in response to their activation by foreign pathogens. We used an in vitro human macrophage model to investigate whether ICRF-193, a Topoisomerase II inhibitor could modulate IL1B mRNA expression and IL-1β secretion. These macrophage-like cells readily secrete IL-1β in response to Lipopolysaccharide (LPS). Upon exposure to a non-toxic dose of ICRF-193, IL-1β secretion was diminished by ~ 40%; however, level of transcription of IL1B was unaffected. We show that there was no Topoisomerase 2B (TOP2B) binding to several IL1B gene sites, which may explain why ICRF-193 does not alter IL1B mRNA levels. Hence, we show for the first time that ICRF-193 can reduce IL-1β secretion. Its low cost and the development of water-soluble prodrugs of ICRF-193 warrants its further investigation in the modulation of pathological secretion of this cytokine for the treatment of inflammatory disorders. (165 words). [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is a lifelong disease that markedly impairs quality of life. AD is considered a starting point of the “atopic march,” which begins at a young age and may progress to systemic allergic diseases. Moreover, it is strongly associated with comorbid allergic and inflammatory diseases including arthritis and inflammatory bowel disease. Understanding the pathogenesis of AD is essential for the development of targeted therapies. Epidermal barrier dysfunction, immune deviation toward a T helper 2 proinflammatory profile, and microbiome dysbiosis play important roles via complex interactions. The systemic involvement of type 2 inflammation, weather acute or chronic, and whether extrinsic or intrinsic, is evident in any type of AD. Studies on AD endotypes with unique biological mechanisms have been conducted according to clinical phenotypes, such as race or age, but the endotype for each phenotype, or endophenotype, has not yet been clearly identified. Therefore, AD is still being treated according to severity rather than endotype. Infancy-onset and severe AD are known risk factors leading to atopic march. In addition, up to 40% of adult AD are cases of infancy-onset AD that persist into adulthood, and these are often accompanied by other allergic diseases. Therefore, early intervention strategies to identify high-risk infants and young children, repair an impaired skin barrier, and control systemic inflammation may improve long-term outcomes in AD patients. However, to the best of our knowledge, no study has evaluated the effectiveness of early intervention on atopic march using systemic therapy in high-risk infants. This narrative review addresses the latest knowledge of systemic treatment, including Th2 cytokine receptor antagonists and Janus kinase inhibitors, for children with moderate to severe AD that is refractory to topical-treatment. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) represents the autoimmune disorder that shows aggressive arthritis as the main symptom. It is difficult to treat and can lead to joint deformation and function loss. At present, Trichinella spiralis (T. spiralis) antigen has attracted much attention because it plays a role in host immune regulatory mechanisms. Therefore, we selected T. spiralis recombinant protein 43 (Tsp43) to treat the bovine collagen type II (BCII)-induced mice RA model and explored its therapeutic mechanisms. This work first verified that Tsp43 could promote the expression of indoleamine 2, 3-dioxygenase (IDO) in dendritic cells (DCs) in vitro. Then, we randomized BALB/c mice (8 weeks old) into six groups, including control, phosphate buffer saline (PBS), BCII, BCII + heat inactivated Tsp43 (HiTsp43), BCII + Tsp43, and BCII + Tsp43 + 1-methyl-troptophan (1-MT) groups. To determine the therapeutic effect of Tsp43 on the BCII-induced mice RA model, relevant cytokines in each group and pathological changes in ankle joints were detected. To explore the mechanisms of Tsp43 on the BCII-induced mice RA model, we checked the expression of IDO in each group, CD4+T cell proliferation, and apoptosis. Collectively, Tsp43 decreased tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) expression in BCII-induced mice RA model and recovered the ankle injury to a certain extent. Tsp43 promoted high expression of IDO, caused expression of related apoptotic proteins in CD4+T cells, and caused apoptosis in CD4+T cells. In addition, Tsp43 reduced the proliferation of CD4+T cells. However, these effects can be inhibited by 1-MT (IDO inhibitor). These results suggested that Tsp43 played an important role in the treatment of arthritis by inhibiting the proliferation of CD4+T cells and inducing CD4+T cells apoptosis through the high expression of IDO. The purpose of this experiment was to provide a new idea for the treatment of RA and lay a foundation for the development of parasite-derived drugs for the treatment of RA. [ABSTRACT FROM AUTHOR]

The article discusses the role of complement factor D (Adipsin) in diabetic cardiomyopathy, a disorder of the cardiac muscle that affects patients with diabetes. The study found that high fat diet feeding in mice induced hyperglycemia and cardiac dysfunction, along with reduced serum levels of complement factor D. The researchers discovered that interleukin-1 receptor-associated kinase like 2 (Irak2) is a downstream regulator of complement factor D and plays a role in mitochondrial fitness. Increasing complement factor D inhibited the translocation of Irak2 to the mitochondria, improving mitochondrial integrity and cardiac function in diabetic cardiomyopathy. However, the study was limited to animal models and cardiomyocytes, and the effects in human cells were not verified. [Extracted from the article]

Background: The method of action of Bushen Formula (BSHXF) in the treatment of intervertebral disc degeneration (IVDD) was uncovered in this work using in vivo and in vitro tests. To clarify the mechanism of action of BSHXF, we validated the rat intervertebral disc degeneration model and the nucleus pulposus cell degeneration model.Methods: In an in vivo model of IVDD the study explores the impact of BSHXF on mitochondrial function, pro-inflammatory cytokines, pro-apoptotic factors, and matrix metalloproteinases. Additionally, it evaluates the induced degeneration of nucleus pulposus (NP) cells in an in vitro model stimulated by interleukin-1 β (IL-1β). The study measures the effects of BSHXF on both the inflammatory response and mitochondrial function.Results: The MRI results showed that BSHXF reduced intervertebral disc volume reduction and degradation of NP tissue. HE, SO-FG and immunofluorescence further confirmed the protective effect of BSHXF on degenerative intervertebral discs. BSHXF reduced the inflammatory levels of IL-6 IL-1β and TNF-α in degenerative intervertebral disc tissue. Meanwhile, JC-1, mPTP and ROS detection revealed that BSHXF can restore mitochondrial function by regulating the expression of antioxidant proteins, playing a protective role in NP cells. Finally, the WB results showed that BSHXF can alleviate IL-1β mediate the degeneration of NP cells. BSHXF can alleviate NP cell apoptosis by inhibiting the expression of bax, cleaved caspase-3, caspase-3, and cyt-c, and increasing the expression of Bcl-2.Conclusion: This study reveals that BSHXF inhibits the development of inflammatory factors, which may play a significant role in intervertebral disc degeneration. This implies that BSHXF is a suitable herbal medication for future research into inflammatory cytokine treatment. [ABSTRACT FROM AUTHOR]

Background: Diabetic cardiomyopathy (DCM) causes the myocardium to rely on fatty acid β-oxidation for energy. The accumulation of intracellular lipids and fatty acids in the myocardium usually results in lipotoxicity, which impairs myocardial function. Adipsin may play an important protective role in the pathogenesis of DCM. The aim of this study is to investigate the regulatory effect of Adipsin on DCM lipotoxicity and its molecular mechanism. Methods: A high-fat diet (HFD)-induced type 2 diabetes mellitus model was constructed in mice with adipose tissue-specific overexpression of Adipsin (Adipsin-Tg). Liquid chromatography-tandem mass spectrometry (LC–MS/MS), glutathione-S-transferase (GST) pull-down technique, Co-immunoprecipitation (Co-IP) and immunofluorescence colocalization analyses were used to investigate the molecules which can directly interact with Adipsin. The immunocolloidal gold method was also used to detect the interaction between Adipsin and its downstream modulator. Results: The expression of Adipsin was significantly downregulated in the HFD-induced DCM model (P < 0.05). Adipose tissue-specific overexpression of Adipsin significantly improved cardiac function and alleviated cardiac remodeling in DCM (P < 0.05). Adipsin overexpression also alleviated mitochondrial oxidative phosphorylation function in diabetic stress (P < 0.05). LC–MS/MS analysis, GST pull-down technique and Co-IP studies revealed that interleukin-1 receptor-associated kinase-like 2 (Irak2) was a downstream regulator of Adipsin. Immunofluorescence analysis also revealed that Adipsin was co-localized with Irak2 in cardiomyocytes. Immunocolloidal gold electron microscopy and Western blotting analysis indicated that Adipsin inhibited the mitochondrial translocation of Irak2 in DCM, thus dampening the interaction between Irak2 and prohibitin (Phb)-optic atrophy protein 1 (Opa1) on mitochondria and improving the structural integrity and function of mitochondria (P < 0.05). Interestingly, in the presence of Irak2 knockdown, Adipsin overexpression did not further alleviate myocardial mitochondrial destruction and cardiac dysfunction, suggesting a downstream role of Irak2 in Adipsin-induced responses (P < 0.05). Consistent with these findings, overexpression of Adipsin after Irak2 knockdown did not further reduce the accumulation of lipids and their metabolites in the cardiac myocardium, nor did it enhance the oxidation capacity of cardiomyocytes expose to palmitate (PA) (P < 0.05). These results indicated that Irak2 may be a downstream regulator of Adipsin. Conclusions: Adipsin improves fatty acid β-oxidation and alleviates mitochondrial injury in DCM. The mechanism is related to Irak2 interaction and inhibition of Irak2 mitochondrial translocation. [ABSTRACT FROM AUTHOR]

Sodium/water transport through Na+-K+-Cl- cotransporter-1 (NKCC1) and sodium/hydrogen exchanger-1 (NHE1) in both astrocytes and endothelial cells is critical to cytotoxic and ionic edema following spinal cord injury (SCI). High-mobility group box-1 (HMGB1) promotes spinal cord edema after SCI. Accordingly, we sought to identify both the role of HMGB1 and the mechanism of its effect on NKCC1 and NHE1 expression in astrocytes and endothelial cells as well as the role of the regulation of spinal cord edema after SCI. An SCI model was generated in adult female rats using a heavy falling object, and an in vitro oxygen-glucose deprivation/reoxygenation (OGD/R) model was generated in rat spinal cord astrocytes and microvascular endothelial cells. The inhibition of HMGB1 reduced NKCC1 and NHE1 expression in the spinal cord of SCI rats, in cultured spinal cord astrocytes, and in cultured microvascular endothelial cells. The effects of HMGB1 on NKCC1 and NHE1 expression were mediated—at least in part—by activation of the Toll-like receptor 4 (TLR4)–Toll/interleukin-1 receptor domain-containing adapter inducing interferon-β (TRIF)–nuclear factor-kappa B (NF-κB) signaling pathway. The inhibition of NKCC1 or NHE1 decreased the spinal cord water content in rats following SCI, increased the Na+ concentration in the medium of cultured astrocytes after OGD/R, and reduced the astrocytic cell volume and AQP4 expression. These results imply that HMGB1 inhibition results in a reduction in NKCC1 and NHE1 expression in both astrocytes and microvascular endothelial cells and thus decreases spinal cord edema after SCI in rats and that these effects occur through the HMGB1–TLR4–TRIF–NF-κB signaling pathway. [ABSTRACT FROM AUTHOR]

Prior evidence has linked inflammation with impulsivity, but most of this evidence is cross-sectional. In this study, we provoked an acute inflammatory cytokine response to see whether it lowered prepotent response inhibition on three cognitive tasks. This study features secondary analyses from a randomized crossover trial in which 171 postmenopausal breast cancer survivors (Stage I-IIIA) each received a typhoid capsular polysaccharide vaccination and a saline placebo injection in a random sequence at two separate visits at least one month apart. Participants completed the Stroop Color-Discrepant Task, the 2-back, and the Conners Continuous Performance Test (CPT) on the computer between 5 and 7 h after the injections. They had their blood drawn once before and repeatedly after the injection to measure interleukin-1 receptor antagonist and interleukin-6 responses. Women committed marginally fewer errors on the Stroop color-discrepant trials after the typhoid vaccine (M = 0.36, SE = 0.08), compared to placebo (M = 0.54, SE = 0.09, p =.076). Injection type did not predict 2-back accuracy (p =.80) or CPT commission errors (p =.47). Inflammatory cytokine responses were also unrelated to the outcomes of interest (p s>.16). We found no evidence that an acute inflammatory cytokine response provokes response disinhibition – an important facet of impulsivity. In fact, our only marginally non-significant result suggested that women were better able to inhibit their prepotent responses on the Stroop after receiving the typhoid vaccine, compared to placebo. Further experimental tests of the acute inflammatory cytokine response's effect on other aspects of impulsivity are warranted. The sample was female, primarily White, highly educated cancer survivors, and recruitment was not premised on impulsive traits or diagnosis with an impulsive-related disorder. Also, there are many facets of impulsivity, and this study only measured response inhibition. • Whether inflammation drives impulsivity or impulsive-related disorders is unclear. • We manipulated inflammation and measured response inhibition among 171 women. • They had a typhoid vaccine and placebo injection in a random order at two visits. • We found no evidence that acute inflammation provoked response disinhibition. • Further research should see if inflammation affects other aspects of impulsivity. [ABSTRACT FROM AUTHOR]

Interleukin-1-receptor-associated kinase 4 (IRAK4) possesses a crucial function in the toll-like receptor (TLR) signaling pathway, and the dysfunction of this molecule could lead to various infectious and immune-related diseases in addition to cancers. IRAK4 genetic variants have been linked to various types of diseases. Therefore, we conducted a comprehensive analysis to recognize the missense variants with the most damaging impacts on IRAK4 with the employment of diverse bioinformatics tools to study single-nucleotide polymorphisms' effects on function, stability, secondary structures, and 3D structure. The residues' location on the protein domain and their conservation status were investigated as well. Moreover, docking tools along with structural biology were engaged in analyzing the SNPs' effects on one of the developed IRAK4 inhibitors. By analyzing IRAK4 gene SNPs, the analysis distinguished ten variants as the most detrimental missense variants. All variants were situated in highly conserved positions on an important protein domain. L318S and L318F mutations were linked to changes in IRAK4 secondary structures. Eight SNPs were revealed to have a decreasing effect on the stability of IRAK4 via both I-Mutant 2.0 and Mu-Pro tools, while Mu-Pro tool identified a decreasing effect for the G198E SNP. In addition, detrimental effects on the 3D structure of IRAK4 were also discovered for the selected variants. Molecular modeling studies highlighted the detrimental impact of these identified SNP mutant residues on the druggability of the IRAK4 ATP-binding site towards the known target inhibitor, HG-12-6, as compared to the native protein. The loss of important ligand residue-wise contacts, altered protein global flexibility, increased steric clashes, and even electronic penalties at the ligand–binding site interfaces were all suggested to be associated with SNP models for hampering the HG-12-6 affinity towards IRAK4 target protein. This given model lays the foundation for the better prediction of various disorders relevant to IRAK4 malfunction and sheds light on the impact of deleterious IRAK4 variants on IRAK4 inhibitor efficacy. [ABSTRACT FROM AUTHOR]

The biogenic synthesis of nanoparticles has drawn significant attention. The spleen is the largest lymphatic organ that is adversely impacted during irradiation. The current study was designated to evaluate the possible anti‐inflammatory effect of matcha‐silver nanoparticles (M‐AgNPs) to reduce inflammation associated with γ‐radiation induced‐oxidative stress and inflammation in rats' spleen. Silver nanoparticles (AgNPs) were synthesized by biogenic synthesis using a green sonochemical method from matcha (M) green tea. The obtained M‐AgNPs were extensively characterized by dynamic light scattering, transmission electron microscopy, thermogravimetric analysis, and Fourier‐transform infrared spectroscopy. Using zetasizer analysis, the surface charge, particle size, and radical scavenging DPPH assay of M‐AgNPs were also examined. Biocompatibility and cytotoxicity were analyzed by MTT assay, and the IC50 was calculated. Four groups of 24 Wistar rats each had an equal number of animals. The next step involved measuring the levels of oxidative stress markers in the rat splenic tissue. Additionally, the amounts of inflammatory protein expression were evaluated using the ELISA analysis. The results indicated the formation of spherical nanoparticles of pure Ag° coated with matcha polyphenols at the nanoscale, as well as uniform monodisperse particles suited for cellular absorption. Results revealed that M‐AgNPs improved all biochemical parameters. Furthermore, M‐AgNPs relieve inflammation by reducing the expression of NOD‐like receptor family pyrin domain‐containing 3 (NLRP3), interleukin‐1β (IL‐1β), and enhancing the levels of ileSnt information regulator 1 (SIRT1). Histopathological examinations demonstrated the ability of M‐AgNPs to overcome the damage consequent to irradiation and recover the spleen's cellular structure. These results confirmed that matcha is a potential biomaterial for synthesizing AgNPs, which can be exploited for their anti‐inflammatory activity. Significance statement: This study is significant as it explores the biogenic synthesis of silver nanoparticles using matcha green tea and their potential anti‐inflammatory activity in reducing inflammation associated with irradiation‐induced oxidative stress. The study provides a detailed characterization of the synthesized nanoparticles using various techniques. The results of the study show that M‐AgNPs improved all biochemical parameters and reduced the expression of inflammatory markers while enhancing the levels of SIRT1. The study also demonstrated the ability of M‐AgNPs to recover the spleen's cellular structure after irradiation‐induced damage. These findings suggest that matcha could be a potential biomaterial for synthesizing AgNPs with anti‐inflammatory properties for treating inflammation‐associated disorders. [ABSTRACT FROM AUTHOR]

Critical-size defects (CSDs) are challenging oral clinical issues that need to be solved. Adipose-derived mesenchymal stem cells (ADSCs) and gene therapy offer a new target to solve these issues. Consequently, ADSCs attract more and more attention because of advantages such as easy obtainability and no ethical concerns. TNF receptor-associated factor 6 (TRAF6) is a significant binding protein both of tumour necrosis factor superfamily and of the toll/interleukin-1 receptor superfamily. Evidence is accumulating that TRAF6 inhibited osteoclast formation and promoted the proliferation of multiple myeloma cell lines and bone resorption. Here, we reported that overexpression of TRAF6 enhanced the proliferation, migration and osteogenesis of ADSCs through Raf-Erk-Merk-Hif1a pathway. Cell sheet of ADSCs combined with TRAF6 accelerated the healing of CSDs. In a word, TRAF6 enhanced osteogenesis, migration and proliferation through Raf-Erk-Merk-Hif1a pathway. [ABSTRACT FROM AUTHOR]

Nuclear receptor related-1 (Nurr1), a ligand-activated transcription factor, is considered a potential susceptibility gene for Parkinson's disease (PD), and has been demonstrated to possess protective effects against inflammation-induced neuronal damage. Despite the evidence showing decreased NURR1 level and increased pro-inflammatory cytokines in cell and animal models as well as in PD patients' peripheral blood mononuclear cells (PBMCs), the underlying mechanism remains elusive. In this study, we investigated the molecular mechanism of Nurr1 in PD-related inflammation. Through the miRNA-sequencing and verification in PBMCs from a cohort of 450 individuals, we identified a significant change of a Nurr1-dependent miRNA miR-30e-5p in PD patients compared to healthy controls (HC). Additionally, PD patients exhibited an elevated plasma interleukin-1β (IL-1β) level and increased nucleotide-binding domain-like receptor protein 3 (NLRP3) expression in PBMCs compared to HC. Statistical analyses revealed significant correlations among NURR1, miR-30e-5p, and NLRP3 levels in the PBMCs of PD patients. To further explore the involvement of Nurr1-miR-30e-5p-NLRP3 axis in the inflammation-mediated PD pathology, we developed a mouse model (Nurr1flox+/Cd11b−cre+, Nurr1cKO) conditionally knocking out Nurr1 in Cd11b-expressing cells. Our investigations in Nurr1cKO mice unveiled significant dopaminergic neurodegeneration following lipopolysaccharide-induced inflammation. Remarkably, Nurr1 deficiency triggered microglial activation and activated NLRP3 inflammasome, resulting in increased IL-1β secretion. Coincidently, we found that miR-30e-5p level was significantly decreased in the PBMCs and primary microglia of Nurr1cKO mice compared to the controls. Furthermore, our in vitro experiments demonstrated that miR-30e-5p specifically targeted NLRP3. In Nurr1-knockdown microglia, NLRP3 expression was upregulated via miR-30e-5p. In summary, our findings highlight the involvement of Nurr1-miR-30e-5p-NLRP3 axis in the inflammation-mediated neurodegeneration in PD, the results of which may offer promising prospects for developing PD biomarkers and targeted therapeutic interventions. [ABSTRACT FROM AUTHOR]

Background: Despite remarkable advancements in cancer immunotherapy, the overall response rate to anti-programmed cell death-1 (anti-PD-1) therapy in hepatocellular carcinoma (HCC) patients remains low. Our previous study has demonstrated the critical role of CacyBP/SIP (Calcyclin-Binding Protein and Siah-1 Interacting Protein) as a regulator of HCC development and progression. However, the possible impact of CacyBP on the tumor immune microenvironment has not yet been clarified. Methods: The expressions of CacyBP and Myd88 in HCC cell lines and tissues was detected by bioinformatics analysis, real-time quantitative PCR, western blotting and immunohistochemistry. The interaction between CacyBP and Myd88 was measured using co-immunoprecipitation and immunofluorescence. In vitro and in vivo assays were used to investigate the regulation of CacyBP on tumor-associated macrophages (TAMs). Results: We identified that CacyBP was positively correlated with Myd88, a master regulator of innate immunity, and Myd88 was a novel binding substrate downstream of CacyBP in HCC. Additionally, CacyBP protected Myd88 from Siah-1-mediated proteasome-dependent degradation by competitively binding to its Toll/interleukin-1 receptor (TIR) domain. Inhibition of CacyBP-Myd88 signaling subsequently diminished HDAC1-mediated H3K9ac and H3K27ac modifications on the CX3CL1 promoter and reduced its transcription and secretion in HCC cells. Moreover, by using in vitro and in vivo strategies, we demonstrated that depletion of CacyBP impaired the infiltration of TAMs and the immunosuppressive state of the tumor microenvironment, further sensitizing HCC-bearing anti-PD-1 therapy. Conclusions: Our findings suggest that targeting CacyBP may be a novel treatment strategy for improving the efficacy of anti-PD-1 immunotherapy in HCC. [ABSTRACT FROM AUTHOR]

Background: Myeloid differentiation factor-88 (MyD88) is a crucial adapter protein that coordinates the innate immune response and establishes an adaptive immune response. The interaction of the Toll/Interleukin-1 receptor (IL-1R) superfamily with MyD88 triggers the activation of various signalling pathways such as nuclear factor-κB (NF-κB) and activator protein-1 (AP-1), promoting the production of a variety of immune and inflammatory mediators and potentially driving the development of a variety of diseases. Objective: This article will explore the therapeutic potential and mechanism of the MyD88-specific inhibitor ST2825 and describe its use in the treatment of several diseases. We envision future research and clinical applications of ST2825 to provide new ideas for the development of anti-inflammatory drugs and disease-specific drugs to open new horizons for the prevention and treatment of related inflammatory diseases. Materials and methods: This review analysed relevant literature in PubMed and other databases. All relevant studies on MyD88 inhibitors and ST2825 that were published in the last 20 years were used as screening criteria. These studies looked at the development and improvement of MyD88 inhibitors and ST2825. Results: Recent evidence using the small-molecule inhibitor of ST2825 has suggested that blocking MyD88 activity can be used to treat diseases such as neuroinflammation, inflammatory diseases such as acute liver/kidney injury, or autoimmune diseases such as systemic lupus erythematosus and can affect transplantation immunity. In addition, ST2825 has potential therapeutic value in B-cell lymphoma with the MyD88 L265P mutation. Conclusion: Targeting MyD88 is a novel therapeutic strategy, and scientific research is presently focused on the development of MyD88 inhibitors. The peptidomimetic compound ST2825 is a widely studied small-molecule inhibitor of MyD88. Thus, ST2825 may be a potential therapeutic small-molecule agent for modulating host immune regulation in inflammatory diseases and inflammatory therapy. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate diacerein (interleukin-1β inhibitor) efficacy on ocular surface disease (OSD).Patients and Methods: This prospective observational study included patients who received diacerein for osteoarthritis and had dry eye (DE). The primary outcome was corneal staining score. Secondary outcomes were ocular surface disease index (OSDI) score, tear breakup time (TBUT), tear osmolarity (Osm), Schirmer's test results, interleukin-1α (IL-1α), interleukin-1β (IL-1β), and interleukin-1 receptor antagonist (IL-1Ra) levels in tears. All measurements were done at baseline and 2-month follow-up visits. Linear mixed models were used to examine the effect of all parameters, and log-transformed models were used for IL-1α, IL-1β, and IL-1Ra analyses.Results: Thirty-four patients (31 females and 3 males) were enrolled. The corneal staining score improved by 1.29 points (P=0.022, 95% confidence interval [95% CI] 0.19 to 2.40) after 2 months, and the OSDI score improved by 17.2 points (P< 0.001, 95% CI 10.82 to 23.58) but TUBT decreased by 0.66 seconds (P=0.021, 95% CI 0.10 to 1.22). No significant differences were observed in the tear Osm and Schirmer's test. IL-1Ra demonstrated no statistical difference, IL-1α was significantly increased by 80% (P=0.260), and IL-1β was significantly decreased by 99.21% (P< 0.001).Conclusion: Diacerein can improve corneal staining and decrease IL-1β levels in tears, which reflects better DE symptoms. Diacerein may be a promising alternative treatment for patients with OSD and osteoarthritis. [ABSTRACT FROM AUTHOR]

Objective: Tissue injury and inflammation are two potential outcomes of cerebral ischemia–reperfusion (I/R) injury. Salvianolic acid B (Sal B), isolated from the roots of Salvia miltiorrhiza, is one of the major water‐soluble compounds with a wide range of pharmacological effects including antioxidant, anti‐inflammatory, antiproliferative, and neuroprotective effects. In the present study, we explored the neuroprotective effects and potential mechanisms of Sal B after I/R injury. Methods: We induced cerebral ischemia in male CD‐1 mice through transient (60 min) middle cerebral artery occlusion (tMCAO), and then injected Sal B (30 mg/kg) intraperitoneally. Neurological deficits, infarct volumes, and brain edema were assessed at 24 and 72 h after tMCAO. We detected the expression of Toll‐like receptor 4 (TLR4), phosphorylated‐p38 mitogen‐activated protein kinase (P‐p38 MAPK), phosphorylated c‐Jun amino (N)‐terminal kinases (p‐JNK), nuclear factor‐κB (NF‐κB), and interleukin‐1β (IL‐1β) in the brain tissue. Results: Compared with the tMCAO group, Sal B significantly improved neurological deficits, reduced infarct size, attenuated cerebral edema, and downregulated the expression of pro‐inflammatory mediators TLR4, p‐p38MAPK, p‐JNK, nuclear NF‐κB, and IL‐1β in brain tissue after I/R injury. Conclusion: We found that Sal B protects brain tissues from I/R injury by activating its anti‐inflammatory properties. [ABSTRACT FROM AUTHOR]

[Display omitted] • ARAMIS is a national multicentre prospective randomized double blind study. • The study evaluates anakinra, an interleukin-1 receptor antagonist. • Anakinra is compared with placebo in 120 patients with acute myocarditis. • ARAMIS hypothesis: that anakinra is effective and safe in acute myocarditis. • Primary endpoint: number of days alive free from any myocarditis complications. • The endpoint is assessed from randomization to 28 days after hospital discharge. • A second randomization evaluates benefit and safety of ACE inhibitor continuation. • The evaluation is in patients with preserved LVEF 4 weeks after hospital discharge. Acute myocarditis is an inflammation of the myocardium that can cause life-threatening events. However, anti-inflammatory strategies did not reduce the risk of clinical outcomes in randomized trials. Recently, experimental studies have suggested that specific blockade of the interleukin-1β immune innate pathway could be effective in acute myocarditis. To test the hypothesis that inhibition of the interleukin-1β immune innate pathway can reduce the risk of clinical events in acute myocarditis. The "Anakinra versus placebo double blind Randomized controlled trial for the treatment of Acute MyocarditIS" (ARAMIS) trial (ClinicalTrials.gov identifier: NCT03018834) is a national multicentre randomized parallel-group double blind study among symptomatic patients with elevated cardiac troponin and cardiac magnetic resonance-proven acute myocarditis. Patients (n = 120) are randomized within 72 hours of hospital admission to receive a daily subcutaneous dose of anakinra 100 mg or placebo during the hospitalization, in addition to standard of care, including an angiotensin-converting enzyme inhibitor and a beta-blocker. The primary endpoint is the number of days alive free from any myocarditis complication, including ventricular arrhythmias, heart failure, recurrent chest pain requiring medication and ventricular dysfunction (defined as left ventricular ejection fraction < 50%), from randomization to 28 days after hospital discharge. At 28 days after discharge, patients with normal left ventricular ejection fraction are then randomized to angiotensin-converting enzyme inhibitor continuation or discontinuation and all patients are followed for 1 year, with regular left ventricular function evaluation. ARAMIS is the first trial evaluating inhibition of the interleukin-1β immune innate pathway in the setting of acute myocarditis. Although of small size, it will be the largest randomized trial in acute myocarditis, a serious and poorly studied cardiac condition. [ABSTRACT FROM AUTHOR]

Psoriasis is now considered to be the cutaneous phenotype of a systemic inflammatory condition, recognized under the term Psoriatic Disease (PsD). PsD has several extracutaneous manifestations, such as inflammatory articular and entheseal involvement, leading to psoriatic arthritis (PsA), and the less frequent intestinal and ocular manifestations with colitis/inflammatory bowel disease and uveitis, respectively. There have also been several reports of an increased frequency of comorbidities such as hypertension, diabetes, dyslipidemia, obesity, metabolic syndrome and cardiovascular manifestations during the course of PsD. The link between psoriasis and related comorbidities is considered a long-term disease sequela, often characterized by an unhealthy lifestyle and a consequence of systemic inflammation; hence, psoriasis requires adequate and prompt treatment, with the aim of controlling not only cutaneous manifestations but also extracutaneous manifestations and systemic inflammation. Pharmacological strategies for PsD have significantly increased over recent years. Recently, the targeted synthetic DMARDs, Janus kinase (JAK) inhibitors, tofacitinib and upadacitinib, were added to the therapeutic armamentarium for treating PsA, and deucravacitinib for psoriasis. These oral agents act directly on inflammatory mechanisms underlining the disease, as antagonists of the intracellular JAK signal pathway and, by STAT phosphorylation, inhibit gene proinflammatory cytokine transcription. JAK inhibitors represent a recent additional treatment strategy for PsD management and, among these, tofacitinib and upadacitinib have recently been approved for PsA, and deucravacitinib for psoriasis. In this review we describe ongoing and recent phase II and III randomized controlled trials (RCTs) evaluating the efficacy and safety of investigational JAK inhibitors in psoriasis and PsA. [ABSTRACT FROM AUTHOR]

Objective To investigate the effect of Xuebijing on rats with severe pneumonia （SP） and its possible mechanism. Methods Forty SP rats were randomly divided into model group, miRNA-155 agonist group （miRNA-155 agonist, 80 mg/kg）, Xuebijing low-dose group （Xuebijing injection, 4 mg/kg）, Xuebijing high-dose group （Xuebijing injection, 8 mg/kg）, miR-155 agonist + Xuebijing group （miR-155 agonist 80 mg/kg, Xuebijing injection 8 mg/kg）, with 8 rats in each. Eight healthy rats were included into control group. Control group and model group were injected with the same amount of normal saline through caudal vein. After 7 days of continuous administration, lung coefficient （LI）, interleukin-1β （IL-1β） level, receptor tyrosine kinase 2 （JAK2）, signal transduction and transcriptional activator 1 （STAT1） protein expression were detected in each group. Results Compared with those in the model group, the level of LI and IL-1β, p-JAK2/JAK2 and p-STAT1/STAT1 in lung tissue were increased in miR-155 agonist group （P < 0.05）. The level of LI and IL-1β, P-JAK2/JAK2 and P-Stat1/STAT1 in lung tissue were decreased in low and high dose Xuebijing group and miR-155 agonist + Xuebijing group （P < 0.05）. Compared with those in miR-155 agonist group, the level of LI and IL-1β, P-JAK2/JAK2 and P-Stat1/STAT1 in lung tissue were decreased in Xuebijing low and high dose group, and miR-155 agonist + Xuebijing group （P < 0.05）. Compared with those in Xuebijing low dose group, the level of LI, IL-1β, p-JAK2/JAK2 and p-STAT1/STAT1 in lung tissue were increased in Xuebijing high dose group （P < 0.05）. Compared with those in Xuebijing group, LI and IL-1β level, P-JAK2/JAK2 and P-Stat1/STAT1 in lung tissue were increased in miR-155 agonist + Xuebijing group （P < 0.05）. Conclusion Xuebijing can reduce lung injury in SP rats, possibly by inhibiting the expression of miR-155 and thereby reducing the JAK2/STAT1 signaling pathway. [ABSTRACT FROM AUTHOR]

Meniscus tears represent a common orthopedic injury that often requires surgery to restore pain‐free function. The need for surgical intervention is due, in part, to the inflammatory and catabolic environment that inhibits meniscus healing after injury. In other organ systems, healing is dependent on the migration of cells to the site of injury; however, in the meniscus, it is currently unknown how the microenvironment dictates cell migration in the postinjury inflamed setting. Here, we investigated how inflammatory cytokines alter meniscal fibrochondrocyte (MFC) migration and sensation of microenvironmental stiffness. We further tested whether an FDA approved interleukin‐1 receptor antagonist (IL‐1Ra; Anakinra) could rescue migratory deficits caused by inflammatory challenge. When cultured in the presence of inflammatory cytokines (tumor necrosis factor‐α [TNF‐α] or interleukin‐1β [IL‐1β]) for 1 day, MFC migration was inhibited for 3 days before returning to control levels at Day 7. This migratory deficit was clear in three‐dimensional as well, where fewer MFCs exposed to inflammatory cytokines migrated from a living meniscal explant compared with control. Notably, addition of IL‐1Ra to MFCs previously exposed to IL‐1β restored migration to baseline levels. This study demonstrates that joint inflammation can have negative impacts on meniscus cell migration and mechanosensation, affecting their potential for repair, and that resolution of this inflammation with concurrent anti‐inflammatories can reverse these deficits. Future work will apply these findings to mitigate the negative consequences of joint inflammation and promote repair in a clinically relevant meniscus injury model. [ABSTRACT FROM AUTHOR]

Background: The nucleotide-binding oligomeric domain (NOD)-like receptor protein 3 (NLRP3) inflammasome is believed to be a key mediator of neuroinflammation and subsequent secondary brain injury induced by ischemic stroke. However, the role and underlying mechanism of the NLRP3 inflammasome in neonates with hypoxic-ischemic encephalopathy (HIE) are still unclear. Methods: The protein expressions of the NLRP3 inflammasome including NLRP3, cysteinyl aspartate specific proteinase-1 (caspase-1) and interleukin-1β (IL-1β), the α-amino-3-hydroxy-5-methyl-4-isoxazole-propionicacid receptor (AMPAR) subunit, and the ATPase valosin-containing protein (VCP/p97), were determined by Western blotting. The interaction between p97 and AMPA glutamate receptor 1 (GluA1) was determined by co-immunoprecipitation. The histopathological level of hypoxic-ischemic brain damage (HIBD) was determined by triphenyltetrazolium chloride (TTC) staining. Polymerase chain reaction (PCR) and Western blotting were used to confirm the genotype of the knockout mice. Motor functions, including myodynamia and coordination, were evaluated by using grasping and rotarod tests. Hippocampus-dependent spatial cognitive function was measured by using the Morris-water maze (MWM). Results: We reported that the NLRP3 inflammasome signaling pathway, such as NLRP3, caspase-1 and IL-1β, was activated in rats with HIBD and oxygen-glucose deprivation (OGD)-treated cultured primary neurons. Further studies showed that the protein level of the AMPAR GluA1 subunit on the hippocampal postsynaptic membrane was significantly decreased in rats with HIBD, and it could be restored to control levels after treatment with the specific caspase-1 inhibitor AC-YVAD-CMK. Similarly, in vitro studies showed that OGD reduced GluA1 protein levels on the plasma membrane in cultured primary neurons, whereas AC-YVAD-CMK treatment restored this reduction. Importantly, we showed that OGD treatment obviously enhanced the interaction between p97 and GluA1, while AC-YVAD-CMK treatment promoted the dissociation of p97 from the GluA1 complex and consequently facilitated the localization of GluA1 on the plasma membrane of cultured primary neurons. Finally, we reported that the deficits in motor function, learning and memory in animals with HIBD, were ameliorated by pharmacological intervention or genetic ablation of caspase-1. Conclusion: Inhibiting the NLRP3 inflammasome signaling pathway promotes neurological recovery in animals with HIBD by increasing p97-mediated surface GluA1 expression, thereby providing new insight into HIE therapy. [ABSTRACT FROM AUTHOR]

Immunothrombosis—immune-mediated activation of coagulation—is protective against pathogens, but excessive immunothrombosis can result in pathological thrombosis and multiorgan damage, as in severe coronavirus disease 2019 (COVID-19). The NACHT-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome produces major proinflammatory cytokines of the interleukin (IL)-1 family, IL-1β and IL-18, and induces pyroptotic cell death. Activation of the NLRP3 inflammasome pathway also promotes immunothrombotic programs including release of neutrophil extracellular traps and tissue factor by leukocytes, and prothrombotic responses by platelets and the vascular endothelium. NLRP3 inflammasome activation occurs in patients with COVID-19 pneumonia. In preclinical models, NLRP3 inflammasome pathway blockade restrains COVID-19-like hyperinflammation and pathology. Anakinra, recombinant human IL-1 receptor antagonist, showed safety and efficacy and is approved for the treatment of hypoxaemic COVID-19 patients with early signs of hyperinflammation. The non-selective NLRP3 inhibitor colchicine reduced hospitalization and death in a subgroup of COVID-19 outpatients but is not approved for the treatment of COVID-19. Additional COVID-19 trials testing NLRP3 inflammasome pathway blockers are inconclusive or ongoing. We herein outline the contribution of immunothrombosis to COVID-19-associated coagulopathy, and review preclinical and clinical evidence suggesting an engagement of the NLRP3 inflammasome pathway in the immunothrombotic pathogenesis of COVID-19. We also summarize current efforts to target the NLRP3 inflammasome pathway in COVID-19, and discuss challenges, unmet gaps, and the therapeutic potential that inflammasome-targeted strategies may provide for inflammation-driven thrombotic disorders including COVID-19. [ABSTRACT FROM AUTHOR]

Background: Pancreatic ductal adenocarcinoma (PDA) is a pernicious disease characterized by an immunosuppressive milieu that is unresponsive to current immunotherapies. Interleukin-1 receptor antagonist (IL-1Ra) is a natural anti-inflammatory cytokine; however, its contribution to cancer pathogenesis and immunosuppression remains elusive. In this research, we investigated the role and mechanism of IL-1Ra in malignant progression of PDA. Results: Through analyzing clinical dataset and examining the pathological tumor tissues and serum samples, we have demonstrated that IL-1Ra expression is elevated in human PDA and positively associated with malignant progression of PDA. To study the biological function of IL-1Ra in tumors, we generated a set of mouse pancreatic cancer cell lines with a knockout (KO) of the Il1rn gene, encoding IL-1Ra, and compared the tumor growth rates in immune-competent and immune-deficient mice. We found that the Il1rn KO cells exhibited greater tumor inhibition in immune-competent mice, highlighting the crucial role of a functional immune system in Il1rn KO-mediated anti-tumor response. Consistently, we found an increase in CD8+ T cells and a decrease in CD11b+Ly6G− immunosuppressive mononuclear population in the tumor microenvironment of Il1rn KO-derived tumors. To monitor the inhibitory effects of IL-1Ra on immune cells, we utilized a luciferase-based reporter CD4+ T cell line and splenocytes, which were derived from transgenic mice expressing ovalbumin-specific T cell receptors in CD8+ T cells, and mice immunized with ovalbumin. We showed that IL-1Ra suppressed T cell receptor signaling and inhibited antigen-specific interferon-γ (IFN-γ) secretion and cytolytic activity in splenocytes. Conclusions: Our findings illustrate the immunosuppressive properties of the natural anti-inflammatory cytokine IL-1Ra, and provide a rationale for considering IL-1Ra-targeted therapies in the treatment of PDA. [ABSTRACT FROM AUTHOR]

A cold shock protein YB-1 is involved in the regulation of many fundamental biological processes. Previously, we demonstrated that YB-1 is also involved in the process of recognition of GMDP muramyl peptide by the NOD2 innate immunity system receptor and is able (upon preliminary administration) to protect mice from death in a model of septic shock induced by Escherichia coli bacteria. We hypothesized that the protective effect of YB-1 can be associated with the development of a state of tolerance ("nonresponse"). We tested the possibility of tolerance induction by the YB-1 protein in a model system on a J774 mouse macrophage cell line with the involvement of cell wall components of E. coli bacteria (GMDP (NOD2 receptor agonist) and LPS (TLR4 receptor agonist) immunostimulants). Changes in the cell response were estimated by the level of mRNA expression of the target molecules by a method of quantitative PCR analysis combined with reverse transcription. Upon pretreatment of cells with YB-1, there was a significant decrease in the level of mRNA expression of proinflammatory cytokines (IL-1β, TNF-α, and IL-6) in response to further stimulation with GMDP and LPS, as well as significant changes that were detected in the expression of mRNA of RIP2 and MyD88 adapter molecules and components of NF-κB transcription factor. Our data demonstrate that YB-1 is able to induce a tolerance to immunostimulants (such as GMDP and LPS) apparently due to an increase in the production of IL-1Ra anti-inflammatory cytokine and SOCS1 inhibitor. A more precise characterization of the peculiarities of YB-1-induced state of tolerance requires further studies. [ABSTRACT FROM AUTHOR]

Background: Osteoarthritis (OA) is a degenerative joint disease with lacking effective prevention targets. A disintegrin and metalloproteinase with thrombospondin motifs 12 (ADAMTS12) is a member of the ADAMTS family and is upregulated in OA pathologic tissues with no fully understood molecular mechanisms. Methods: The anterior cruciate ligament transection (ACL-T) method was used to establish rat OA models, and interleukin-1 beta (IL-1β) was administered to induce rat chondrocyte inflammation. Cartilage damage was analyzed via hematoxylin-eosin, Periodic Acid-Schiff, safranin O-fast green, Osteoarthritis Research Society International score, and micro-computed tomography assays. Chondrocyte apoptosis was detected by flow cytometry and TdT dUTP nick-end labeling. Signal transducer and activator of transcription 1 (STAT1), ADAMTS12, and methyltransferase-like 3 (METTL3) levels were detected by immunohistochemistry, quantitative polymerase chain reaction (qPCR), western blot, or immunofluorescence assay. The binding ability was confirmed by chromatin immunoprecipitation-qPCR, electromobility shift assay, dual-luciferase reporter, or RNA immunoprecipitation (RIP) assay. The methylation level of STAT1 was analyzed by MeRIP-qPCR assay. STAT1 stability was investigated by actinomycin D assay. Results: The STAT1 and ADAMTS12 expressions were significantly increased in the human and rat samples of cartilage injury, as well as in IL-1β-treated rat chondrocytes. STAT1 is bound to the promoter region of ADAMTS12 to activate its transcription. METTL3/ Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) mediated N6-methyladenosine modification of STAT1 promoted STAT1 mRNA stability, resulting in increased expression. ADAMTS12 expression was reduced and the IL-1β-induced inflammatory chondrocyte injury was attenuated by silencing METTL3. Additionally, knocking down METTL3 in ACL-T-produced OA rats reduced ADAMTS12 expression in their cartilage tissues, thereby alleviating cartilage damage. Conclusion: METTL3/IGF2BP2 axis increases STAT1 stability and expression to promote OA progression by up-regulating ADAMTS12 expression. [ABSTRACT FROM AUTHOR]

Chronic obstructive pulmonary disease (COPD) is a serious chronic lung disease. Schisandrin A (SchA) is one of the most important active ingredients in Schisandra chinensis and has been used to treat various lung diseases in several countries. Here, we studied the pharmacological effect of SchA on airway inflammation induced by cigarette smoke (CS) and explored the therapeutic mechanism of SchA in COPD model mice. Our results showed that SchA treatment significantly improved the lung function of CS-induced COPD model mice and reduced the recruitment of leukocytes and hypersecretion of interleukin-6 (IL-6), interleukin-1β (IL-1β) and tumor necrosis factor α (TNF-α) in bronchoalveolar lavage fluid (BALF). H&E staining showed that SchA treatment could effectively reduce emphysema, immune cell infiltration and airway wall destruction. In addition, we found that SchA treatment can stimulate the expression of heme oxygenase-1 (HO-1) through the nuclear factor-erythroid 2-related factor (Nrf2) pathway, significantly reduce oxidative stress, increase catalase (CAT) and superoxide dismutase (SOD) levels, and suppress the level of malondialdehyde (MDA) in COPD model mice. Moreover, SchA treatment suppressed the generation of the NLRP3/ASC/Caspase1 inflammasome complex to inhibit the inflammatory response caused by IL-1β and IL-18 and pyroptosis caused by GSDMD. In conclusion, our study shows that SchA treatment can inhibit the production of ROS and the activation of the NLRP3 inflammasome by upregulating Nrf-2, thereby producing anti-inflammatory effects and reducing lung injury in COPD model mice. More importantly, SchA exhibited similar anti-inflammatory effects to dexamethasone in COPD model mice, and we did not observe substantial side effects of SchA treatment. The high safety of SchA makes it a potential candidate drug for the treatment of COPD. [ABSTRACT FROM AUTHOR]

With the prolongation of life expectancy, the increase in the number of elderly individuals in societies and the high rates of disability, frailty and morbidity associated with this situation have led to the acceptance of old age as a prior social problem. And since the 2000s, many studies have been carried out in this field. Inflammation is a very important physiological function and a complex biological process that is initiated by the immune system in response to infection, injury or tissue damage. In connection with this process, inflammaging refers to the chronic, low-grade inflammation that occurs with aging. As one ages, the immune system undergoes changes including a descent in the production of new immune cells and a decrease in the ability of existing immune cells to function properly that can contribute to a state of chronic inflammation. Clinical trials suggest that modulating inflammation prevents many of the chronic diseases, frailty, and disability that increases at older age. In the light of existing information, one can predict that a possible reason for long life today is the capability of reaching an optimal balance between proinflammatory (C-Reactive Protein, Interleukin 6, Tumor necrosis factor-alpha) and anti-inflammatory (Interleukin-1 receptor antagonist protein, Cortisol, Interleukin-10) molecules. [ABSTRACT FROM AUTHOR]