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Objective: Galuteolin (Galu) is a substance extracted and purified from honeysuckle. The purpose of this study was to explore the effects of Galu on the TNF-α-induced RA-FLS cells (synoviocytes) and reveal its potential molecular mechanism from the perspectives of anti-apoptosis and anti-inflammation., Methods: After TNF-α stimulation, cell proliferation of RA-FLS was assessed by CCK-8 assay. TUNEL staining was used to detect the apoptosis. Western blot was used to detect the expressions of Iκκβ, p-p65, p65, p-IκB, IκB, Cleaved-caspase3, Caspase-3, Bcl-2, and Bax. HO-1 were determined by RT-PCR. The contents of pro-inflammatory cytokines IL-1β, IL-6, IL-8, and MMP-1 were determined by ELISA., Results: Galu significantly suppressed cell proliferation in a dose-dependent manner. Additionally, Galu obviously promotes cell apoptosis rate of RA-FLS cells and elevated the expression levels of HO-1, caspase-3, and Bax, while reducing the expression level of Bcl-2. Furthermore, Galu apparently inhibited the levels of Iκκβ, p-p65, and p-IκB. Moreover, Galu also significantly reduced the levels of pro-inflammatory factors IL-1β, IL-6, IL-8, and MMP-1 in RA-FLS cells., Conclusion: Galuteolin exerts protective effects against TNF-α-induced RA-FLS cells by inhibiting apoptosis and inflammation, which can guide the clinical use of rheumatoid arthritis.

Chronic inflammation is a common feature of obesity, with elevated cytokines such as interleukin-1 (IL-1) in the circulation and tissues. Here, we report an unconventional IL-1R-MyD88-IRAK2-PHB/OPA1 signaling axis that reprograms mitochondrial metabolism in adipocytes to exacerbate obesity. IL-1 induced recruitment of IRAK2 Myddosome to mitochondria outer membranes via recognition by TOM20, followed by TIMM50-guided translocation of IRAK2 into mitochondria inner membranes, to suppress oxidative phosphorylation and fatty acid oxidation, thereby attenuating energy expenditure. Adipocyte-specific MyD88 or IRAK2 deficiency reduced high-fat-diet-induced weight gain, increased energy expenditure and ameliorated insulin resistance, associated with a smaller adipocyte size and increased cristae formation. IRAK2 kinase inactivation also reduced high-fat diet-induced metabolic diseases. Mechanistically, IRAK2 suppressed respiratory super-complex formation via interaction with PHB1 and OPA1 upon stimulation of IL-1. Taken together, our results suggest that the IRAK2 Myddosome functions as a critical link between inflammation and metabolism, representing a novel therapeutic target for patients with obesity.

Apoptosis in murine dermal cells is retarded by ultraviolet B (UVB) irradiation-induced autophagic intervention while simultaneously epidermal cells commit apoptosis, during which inflammatory cytokines released from the lost epidermal cells promote immune responses of dermal inflammatory cells, forming morphological symptoms of acute cutaneous diseases. Autophagy is involved in prevention or provocation of apoptosis of dermal or epidermal cells of UVB-irradiated mice via modulation of intracellular metabolism, intervening the balance between cell death and survival in dermis and epidermis. p53 expressed in immune system affects autophagy function through activating or inactivating genes encoding apoptotic factors and inflammatory cytokines. Silibinin protects dermal and epidermal cells of UVB irradiated skin against abnormally autophagy-mediated apoptosis adjustments. In this study, how UVB irradiation intervenes autophagy in dermal and epidermal cells as well as how silibinin protects UVB irradiated skin through physiological recovering of autophagy function in dermis and epidermis are focused and elucidated preliminarily. Silibinin treatment (50 mg/kg/day for 4 days) reversed dermal and epidermal autophagy levels from UVB irradiation-induced improper autophagy intervention, repaired the balance between cell survival and death in dermis and epidermis, and protected skin against damage through mediation of p53 activation in dermal and epidermal cells.

NLRP3 inflammasome plays a critical spatiotemporal role in the pathogenesis of experimental autoimmune encephalomyelitis (EAE). This study reports a mechanistic insight into noncanonical NLRP3 inflammasome activation in microglia for the effector stage of EAE. Microglia-specific deficiency of ASC (apoptosis-associated speck-like protein containing a C-terminal caspase-activation and recruitment [CARD] domain) attenuated T cell expansion and neutrophil recruitment during EAE pathogenesis. Mechanistically, TLR stimulation led to IRAKM-caspase-8-ASC complex formation, resulting in the activation of caspase-8 and IL-1[beta] release in microglia. Noncanonical inflammasome-derived IL- 1[beta] produced by microglia in the CNS helped to expand the microglia population in an autocrine manner and amplified the production of inflammatory cytokines/chemokines. Furthermore, active caspase-8 was markedly increased in the microglia in the brain tissue from patients with multiple sclerosis. Taken together, our study suggests that microglia-derived IL-1[beta] via noncanonical caspase-8-dependent inflammasome is necessary for microglia to exert their pathogenic role during CNS inflammation., IntroductionNumerous studies indicate that the inflammatory process in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) is initiated by T cells that are reactive against myelin (1-6). Importantly, a growing [...]

[Display omitted] To test the hypothesis that a prediction rule including levels of interleukin-6 in pericardial drainage (pdIL-6) would improve the discrimination in classifying patients undergoing coronary artery bypass grafting (CABG) into different postoperative atrial fibrillation (POAF) risk levels. Prospective cohort study. A university-affiliated tertiary hospital. Patients undergoing CABG. None. We prospectively recruited patients who underwent CABG into derivation and validation cohorts. The independent predictors were identified in the derivation cohort using multiple logistic regression and tested in the validation cohort. The performance of the predictive model was tested using area under the receiver operating characteristic curve (AUC) in both cohorts. A prediction rule was created by assigning points to each predictor. Patients were classified in various risk levels according to their total risk scores. We enrolled 302 and 207 patients in the derivation and validation cohorts, respectively. Multiple logistic regression analysis identified six predictors: age ≥61 y, left atrial diameter ≥49 mm, right atrial diameter ≥45 mm, number of grafts ≥3, and serum uric acid ≥226 µmol/L and pdIL-6 levels ≥166 ng/mL at postoperative 12 h. The AUC of the model was 0.78 and 0.77 for the derivation and validation cohort, respectively, which was greatly increased by adding pdIL-6. Patients were stratified into low-risk, moderate-risk and high-risk groups. A POAF prediction rule including pdIL-6 had good performance for stratifying CABG patients into various risk groups for POAF. The inclusion of pdIL-6 resulted in clinically meaningful improvement in risk prediction. [ABSTRACT FROM AUTHOR]

The C-type lectin receptor Mincle is known for its important role in innate immune cells in recognizing pathogen and damage associated molecular patterns. Here we report a T cell–intrinsic role for Mincle in the pathogenesis of experimental autoimmune encephalomyelitis (EAE). Genomic deletion of Mincle in T cells impairs TH17, but not TH1 cell-mediated EAE, in alignment with significantly higher expression of Mincle in TH17 cells than in TH1 cells. Mechanistically, dying cells release β-glucosylceramide during inflammation, which serves as natural ligand for Mincle. Ligand engagement induces activation of the ASC-NLRP3 inflammasome, which leads to Caspase8-dependent IL-1β production and consequentially TH17 cell proliferation via an autocrine regulatory loop. Chemical inhibition of β-glucosylceramide synthesis greatly reduces inflammatory CD4+ T cells in the central nervous system and inhibits EAE progression in mice. Taken together, this study indicates that sensing of danger signals by Mincle on TH17 cells plays a critical role in promoting CNS inflammation. Mincle is a pattern recognition receptor that senses danger signals in innate immune cells. Here authors show in an experimental autoimmune encephalomyelitis mouse model that tissue damage triggers Mincle signaling on inflammatory helper T cells, leading to inflammasome-mediated IL-1β production and reinforced inflammation. [ABSTRACT FROM AUTHOR]

• UVB or cisplatin induces nuclear and mitochondrial DNA damages. • UVB or cisplatin activates cGAS-STING pathway. • STING knockdown inhibits apoptosis caused by UVB or cisplatin. • cGAS-STING activates NF-κB and IRF3-IFNβ pathway leading to apoptosis. Exposure to ultraviolet B (UVB) from sunlight causes DNA damage, serious cellular inflammation and aging, and even cell death in the skin, commonly known as sunburn, leading to cutaneous tissue disorders. DNA damage can be sensed as a danger-associated molecular pattern (DAMP) by the innate immune system. It has not been studied, however, whether cGAS-STING activation is involved in the apoptosis induced by UVB irradiation or by cisplatin treatment. Here we report the findings that within hours of DNA damages keratinocytes show an innate immune response, which involves the activation of cGAS-STING; a cytosolic DNA receptor, cGAS (cyclic guanosine monophosphate-adenosine monophosphate synthase), cyclic GMP-AMP (cGAMP) synthase, and DNA sensing adaptor, STING (protein stimulator of interferon genes). Either UVB irradiation or cisplatin treatment can cause DNA damages, releasing fragmented DNA from nucleus and/or mitochondria. Roles of cGAS-STING were examined in the HaCaT cells with DNA damages caused by UVB irradiation or cisplatin treatment. Silencing STING by siRNA rescued HaCaT cells from UVB or cisplatin-induced apoptosis. NF-κB, one of the major downstream components of STING pathway, which usually regulates the classical STING apoptotic pathway, was translocated to nucleus in the HaCaT cells irradiated with UVB. This translocation was attenuated by STING silencing. Treatment with BAY, an inhibitor of NF-κB pathway, blocked UVB-induced apoptosis. cGAS-STING-mediated production of IFNβ was induced by nuclear translocation of interferon regulatory factor 3 (IRF3). UVB irradiation inceased the nuclear translocation of IRF3, accompanied by enhanced expression level of IFNβ mRNA. The nuclear translocation of IRF3 and expression of IFNβ mRNA were attenuated by STING silencing. Treatment with MRT67307, an inhibitor of TBK1-IRF3-IFNβ pathway, blocked UVB-induced apoptosis. Therefore, we conclude that NF-κB pathway and IFNβ pathway residing in the downstream of STING are resposible for apoptosis of UVB-irradiated or cisplatin-treated HaCaT cells. [ABSTRACT FROM AUTHOR]

Abstract: Interleukin-10 (IL-10) may have therapeutic potential in various inflammatory diseases, including atherosclerosis, as it can inhibit oxLDL-induced foam cell formation and apoptosis in macrophages. This study investigated the effect of IL-10 on mitogen-activated protein kinase (MAPK) activation, and apoptosis induced by oxidized low-density lipoprotein (oxLDL) in cultured human umbilical vein endothelial cells (HUVEC). The results demonstrated that IL-10 significantly blocked the phosphorylation of p38 MAPK and c-Jun N-terminal kinase (JNK) and apoptosis induced by oxLDL. The inhibitory effect of IL-10 on oxLDL-induced apoptosis was partially dependent on reduced p38, but not JNK, phosphorylation. This study also discovered a linkage between IL-10 and p38 MAPK signaling in oxLDL-induced endothelial cell apoptosis. Interestingly, this study found that lectin-like oxidized LDL receptor-1 (LOX-1) was the only scavenger receptor, on the surface of HUVEC, that was upregulated by oxLDL and the increase in LOX-1 was not suppressed by IL-10. This study confirmed that IL-10 significantly upregulated the expression of suppressor of cytokine signaling-3 (SOCS3), whereas SOCS3 knockdown by siRNA effectively blocked the inhibitory effect of IL-10 on p38 MAPK-dependent apoptosis induced by oxLDL. These results showed for the first time, that IL-10 modulated oxLDL-induced apoptosis by upregulating SOCS3, which then interrupted p38 MAPK activation in endothelial cells. These findings support the essential role of p38 MAPK in the interplay of oxLDL and IL-10 in endothelial apoptosis. [Copyright &y& Elsevier]

Skin inflammation induced by ultraviolet B (UVB) radiation is characterized by migration and chemotaxis of inflammatory cells, epidermic thickening and erythema. Apoptosis and autophagy of epidermal and dermal cells are involved in its development through the adjustment of balance between cell survival and death. In this study, the role of balance between cell survival and apoptosis in dermis and epidermis in UVB-induced skin inflammation and the effect of autophagy on the balance were elucidated, and the protective mechanism of silibinin was investigated through the examination of the influence of autophagy activation or inhibition on erythema, migration, and chemotaxis of inflammatory cells as well as apoptosis adjustments. In UVB-irradiated controls, dermal apoptosis was retarded and the survival of inflammatory cells was promoted through the up-regulation of dermal autophagic level; epidermal apoptosis was increased through the down-regulation of epidermal autophagic level, causing migration and chemotaxis of neutrophils and mast cells as well as skin erythema. In silibinin-treated group (50 mg/kg/day for 4 days), dermal apoptosis was increased through inhibiting dermal autophagy; improper adjustment of epidermal apoptosis was attenuated through promoting epidermal autophagy, presenting dual effects on the balance between autophagy and apoptosis of epidermal and dermal cells and the protection. [ABSTRACT FROM PUBLISHER]

Ultraviolet B (UVB) irradiation causes skin inflammation and apoptosis. Mitochondria are highly dynamic and undergo constant fusion and fission that are essential for maintaining physiological functions of cells. Although dysfunction of mitochondria has been implicated in skin damages, little is known about the roles of mitochondrial dynamics in these processes. UVB irradiation increases abnormal mitochondrial content but decreases mitochondrial volume in immortalized human keratinocyte HaCaT cells. UVB irradiation resulted in marked upregulation of mitochondrial fission protein dynamin-related protein 1 (DRP1) and downregulation of mitochondrial outer membrane fusion proteins 1 and 2 (MFN1 and MFN2) in HaCaT cells. Mitochondrial dynamics was discovered to be crucial for NLRP3 inflammasome and cGAS-STING pathway activation, as well as the induction of apoptosis. Inhibition of mitochondrial fission by treatments with a DRP1 inhibitor, mdivi-1, or with DRP1-targeted siRNA, efficiently prevented UVB-induced NLRP3/cGAS-STING mediated pro-inflammatory pathways or apoptosis in the HaCaT cells, whereas inhibition of mitochondrial fusion with MFN1and 2 siRNA increased these pro-inflammatory pathways or apoptosis. The enhanced mitochondrial fission and reduced fusion caused the up-regulation of reactive oxygen species (ROS). Application of an antioxidant, N -acetyl- l -cysteine (NAC), which scavenges excessive ROS, attenuated inflammatory responses through suppressing NLRP3 inflammasome and cGAS-STING pathway activation, and rescued cells from apoptosis caused by UVB-irradiation. Together, our findings revealed the regulation of NLRP3/cGAS-STING inflammatory pathways and apoptosis by mitochondrial fission/fusion dynamics in UVB-irradiated HaCaT cells, providing a new strategy for the therapy of UVB skin injury. [Display omitted] • UVB perturbs mitochondrial fission/fusion dynamics in HaCaT cells. • Disturbed mitochondrial dynamics control the amount of mitochondria. • Disturbed mitochondrial dynamics regulate NLRP3/cGAS-STING mediated pro-inflammatory pathways and apoptosis. • ROS are responsible for pro-inflammatory pathways and apoptosis initiated by the dysregulated mitochondrial dynamics. [ABSTRACT FROM AUTHOR]