BACKGROUND AND OBJECTIVES

A mounting evidence links dysregulated immune response to cases of fatal pneumonia seen in COVID-19 infection. We aimed to validate the COVID-19-associated Hyperinflammatory Syndrome (cHIS) score, a novel clinical tool devised to identify those at risk for adverse outcomes, in a local population and investigate the relationship of cHIS score taken at admission and the risk of mortality and the need of mechanical ventilation.

This retrospective cohort study analyzed the sociodemographic, clinical, and laboratory data of 1,881 COVID-19 patients admitted at a tertiary hospital in Davao City, Philippines from January to December 2021. We calculated the cHIS score, composed of six clinical and laboratory criteria from admission, and used multivariate logistic regression to determine the risk of mortality and need of mechanical ventilation.

The cHIS score taken at admission, regardless of cut-off value, was a significant predictor of mortality (OR 0.979 [99% CI 0.894-1.064]) and need of mechanical ventilation (OR 0.586 [99% CI 0.4975-0.6745]). Using the Youden Index, a cut-off cHIS score of 3 or more was a better predictor of mortality (sensitivity, 88.59%; specificity, 71.72%), and a cut-off score of 2 or more was a better predictor of need of mechanical ventilation (sensitivity, 84.02%; specificity, 70.82%) than other cutoff cHIS scores.

Among COVID-19 patients, the cHIS score at admission correlated with the risk of mortality and the need of mechanical ventilation. Cutoff scores of 3 and 2 had the optimal sensitivities and specificities to predict the risk of mortality and the need of mechanical ventilation, respectively.

Cardioembolic stroke is a special type of ischemic stroke caused by cardiac diseases， and its development is closely associated with the structural and functional abnormalities of the heart. The pathophysiological mechanisms of this type of stroke are complex. It is often induced by thrombosis due to cardiac diseases， followed by thrombus detachment and entry into cerebral vessels， leading to ischemic injury and subsequent cascade reactions. Inflammatory response plays a crucial role in the development and progression of cardioembolic stroke， being involved in processes ranging from thrombosis to acute-phase brain injury after embolism， short-term neurological recovery， and long-term prognosis prediction， and can also be used as a biomarker and diagnostic factor. This article summarizes the mechanism by which inflammation contributes to the development and progression of cardioembolic stroke， as well as the current research advances in the etiology of cardioembolic stroke， the recovery of neurological function after stroke， and personalized treatment strategies.
Inflammation

OBJECTIVE: To investigate the effects and underlying mechanisms of VX765 on osteoarthritis (OA) and chondrocytes inflammation in rats. METHODS: Chondrocytes were isolated from the knee joints of 4-week-old Sprague Dawley (SD) rats. The third-generation cells were subjected to cell counting kit 8 (CCK-8) analysis to assess the impact of various concentrations (0, 1, 5, 10, 20, 50, 100 μmol/L) of VX765 on rat chondrocyte activity. An in vitro lipopolysaccharide (LPS) induced cell inflammation model was employed, dividing cells into control group, LPS group, VX765 concentration 1 group and VX765 concentration 2 group without obvious cytotoxicity. Western blot, real-time fluorescence quantitative PCR, and ELISA were conducted to measure the expression levels of inflammatory factors-transforming growth factor β ₁ (TGF-β ₁), interleukin 6 (IL-6), and tumor necrosis factor α (TNF-α). Additionally, Western blot and immunofluorescence staining were employed to assess the expressions of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase 1 (HO-1). Thirty-two SD rats were randomly assigned to sham surgery group (group A), OA group (group B), OA+VX765 (50 mg/kg) group (group C), and OA+VX765 (100 mg/kg) group (group D), with 8 rats in each group. Group A underwent a sham operation with a medial incision, while groups B to D underwent additional transverse incisions to the medial collateral ligament and anterior cruciate ligament, with removal of the medial meniscus. One week post-surgery, groups C and D were orally administered 50 mg/kg and 100 mg/kg VX765, respectively, while groups A and B received an equivalent volume of saline. Histopathological examination using HE and safranin-fast green staining was performed, and Mankin scoring was utilized for evaluation. Immunohistochemical staining technique was employed to analyze the expressions of matrix metalloproteinase 13 (MMP-13) and collagen type Ⅱ. RESULTS: The CCK-8 assay indicated a significant decrease in cell viability at VX765 concentrations exceeding 10 μmol/L ( P<0.05), so 4 μmol/L and 8 μmol/L VX765 without obvious cytotoxicity were selected for subsequent experiments. Following LPS induction, the expressions of TGF-β ₁, IL-6, and TNF-α in cells significantly increased when compared with the control group ( P<0.05). However, intervention with 4 μmol/L and 8 μmol/L VX765 led to a significant decrease in expression compared to the LPS group ( P<0.05). Western blot and immunofluorescence staining demonstrated a significant upregulation of Nrf2 pathway-related molecules Nrf2 and HO-1 protein expressions by VX765 ( P<0.05), indicating Nrf2 pathway activation. Histopathological examination of rat knee joint tissues and immunohistochemical staining revealed that, compared to group B, treatment with VX765 in groups C and D improved joint structural damage in rat OA, alleviated inflammatory reactions, downregulated MMP-13 expression, and increased collagen type Ⅱ expression. CONCLUSION VX765 can improve rat OA and reduce chondrocyte inflammation, possibly through the activation of the Nrf2 pathway.
Rats ; Animals ; Chondrocytes/metabolism* ; Matrix Metalloproteinase 13/metabolism* ; Rats, Sprague-Dawley ; Tumor Necrosis Factor-alpha/metabolism* ; Collagen Type II/metabolism* ; Interleukin-6 ; Lipopolysaccharides/pharmacology* ; NF-E2-Related Factor 2/pharmacology* ; Inflammation/drug therapy* ; Osteoarthritis/metabolism* ; Transforming Growth Factor beta1/metabolism* ; Dipeptides ; para-Aminobenzoates

OBJECTIVE: To summarize the research progress on the role of macrophage-mediated osteoimmune in osteonecrosis of the femoral head (ONFH) and its mechanisms. METHODS: Recent studies on the role and mechanism of macrophage-mediated osteoimmune in ONFH at home and abroad were extensively reviewed. The classification and function of macrophages were summarized, the osteoimmune regulation of macrophages on chronic inflammation in ONFH was summarized, and the pathophysiological mechanism of osteonecrosis was expounded from the perspective of osteoimmune, which provided new ideas for the treatment of ONFH. RESULTS: Macrophages are important immune cells involved in inflammatory response, which can differentiate into classically activated type (M1) and alternatively activated type (M2), and play specific functions to participate in and regulate the physiological and pathological processes of the body. Studies have shown that bone immune imbalance mediated by macrophages can cause local chronic inflammation and lead to the occurrence and development of ONFH. Therefore, regulating macrophage polarization is a potential ONFH treatment strategy. In chronic inflammatory microenvironment, inhibiting macrophage polarization to M1 can promote local inflammatory dissipation and effectively delay the progression of ONFH; regulating macrophage polarization to M2 can build a local osteoimmune microenvironment conducive to bone repair, which is helpful to necrotic tissue regeneration and repair to a certain extent. CONCLUSION At present, it has been confirmed that macrophage-mediated chronic inflammatory immune microenvironment is an important mechanism for the occurrence and development of ONFH. It is necessary to study the subtypes of immune cells in ONFH, the interaction between immune cells and macrophages, and the interaction between various immune cells and macrophages, which is beneficial to the development of potential therapeutic methods for ONFH.
Humans ; Femur Head/pathology* ; Osteonecrosis/therapy* ; Macrophages/pathology* ; Inflammation ; Femur Head Necrosis/pathology*

Objective To explore the significance of interleukin-17C(IL-17C)-mediated follicular helper T cell (Tfh) differentiation in atopic dermatitis (AD) model. Methods BALB/c mice were divided into control group, AD model group, low-dose MOR106 (anti-IL-17C huIgG1)(MDR106-L)treatment group and high-dose MOR106 (MOR106-H) treatment group, 8 mice in each group. Except for the control group, all the other groups were treated with 2, 4- dinitrochlorobenzene (DNCB) to establish AD models. The low-dose and high-dose MOR106 groups were treated with 5 mg/kg or 10 mg/kg MOR106 respectively. The differentiation of Tfh cell subsets in peripheral blood of mice was analyzed by flow cytometry, and the expression of Janus kinase 2/signal transducer and activator of transcription 3(JAK2/STAT3) signal pathway protein in skin tissue was detected by Western blot analysis. Results Compared with the control group, the dermatitis severity score, mass difference between two ears, spleen mass and spleen index of DNCB group increased significantly, while those of MOR106-L group and MOR106-H group decreased significantly. Compared with the control group, the Tfh subgroup of AD mice showed deregulated differentiation, resulting in a significant increase in the percentage of CD4⁺CXCR5⁺IFN-γ⁺Tfh1 cells, CD4⁺CXCR5⁺IL-17A⁺Tfh17 and CD4⁺CXCR5⁺IL-21⁺Tfh21 cells, and a significant decrease in the percentage of CD4⁺CXCR5⁺IL-10⁺Tfh10 cells and CD4⁺CXCR5⁺FOXP3⁺Tfr cells in peripheral blood. The protein levels of phosphorylated JAK2(p-JAK2) and p-STAT3 were significantly increased. MOR106 effectively reversed these changes of Tfh1, Tfh10, Tfh17, Tfh21 and Tfr cells in peripheral blood of AD mice. Compared with AD group, the levels of p-JAK2 and p-STAT3 protein in low-dose and high-dose MOR106 treatment groups decreased significantly. Conclusion MOR106 can reduce the inflammatory response of AD mice by blocking JAK2/STAT3 signaling pathway and inhibiting the differentiation of Tfh cells mediated by IL-17C.
Animals ; Mice ; Dermatitis, Atopic/drug therapy* ; Interleukin-17 ; T Follicular Helper Cells ; Janus Kinase 2 ; Dinitrochlorobenzene ; Inflammation ; Cell Differentiation ; Signal Transduction

OBJECTIVE: To examine the therapeutic effect of Fangji Fuling Decoction (FFD) on sepsis through network pharmacological analysis combined with in vitro and in vivo experiments. METHODS: A sepsis mouse model was constructed through intraperitoneal injection of 20 mg/kg lipopolysaccharide (LPS). RAW264.7 cells were stimulated by 250 ng/mL LPS to establish an in vitro cell model. Network pharmacology analysis identified the key molecular pathway associated with FFD in sepsis. Through ectopic expression and depletion experiments, the effect of FFD on multiple organ damage in septic mice, as well as on cell proliferation and apoptosis in relation to the mitogen-activated protein kinase 14/Forkhead Box O 3A (MAPK14/FOXO3A) signaling pathway, was analyzed. RESULTS: FFD reduced organ damage and inflammation in LPS-induced septic mice and suppressed LPS-induced macrophage apoptosis and inflammation in vitro (P<0.05). Network pharmacology analysis showed that FFD could regulate the MAPK14/FOXO signaling pathway during sepsis. As confirmed by in vitro cell experiments, FFD inhibited the MAPK14 signaling pathway or FOXO3A expression to relieve LPS-induced macrophage apoptosis and inflammation (P<0.05). Furthermore, FFD inhibited the MAPK14/FOXO3A signaling pathway to inhibit LPS-induced macrophage apoptosis in the lung tissue of septic mice (P<0.05). CONCLUSION FFD could ameliorate the LPS-induced inflammatory response in septic mice by inhibiting the MAPK14/FOXO3A signaling pathway.
Mice ; Animals ; Mitogen-Activated Protein Kinase 14/metabolism* ; Wolfiporia ; Lipopolysaccharides/pharmacology* ; Sepsis/complications* ; Signal Transduction ; Inflammation/drug therapy* ; Oxygen Radioisotopes

Background and Objectives: A mounting evidence links dysregulated immune response to cases of fatal pneumonia seen in COVID-19 infection. We aimed to validate the COVID-19-associated Hyperinflammatory Syndrome (cHIS) score, a novel clinical tool devised to identify those at risk for adverse outcomes, in a local population and investigate the relationship of cHIS score taken at admission and the risk of mortality and the need of mechanical ventilation Methods: This retrospective cohort study analyzed the sociodemographic, clinical, and laboratory data of 1,881 COVID-19 patients admitted at a tertiary hospital in Davao City, Philippines from January to December 2021. We calculated the cHIS score, composed of six clinical and laboratory criteria from admission, and used multivariate logistic regression to determine the risk of mortality and need of mechanical ventilation. Results: The cHIS score taken at admission, regardless of cut-off value, was a significant predictor of mortality (OR 0.979 [99% CI 0.894-1.064]) and need of mechanical ventilation (OR 0.586 [99% CI 0.4975-0.6745]). Using the Youden Index, a cut-off cHIS score of 3 or more was a better predictor of mortality (sensitivity, 88.59%; specificity, 71.72%), and a cut-off score of 2 or more was a better predictor of need of mechanical ventilation (sensitivity, 84.02%; specificity, 70.82%) than other cut-off cHIS scores. Conclusion Among COVID-19 patients, the cHIS score at admission correlated with the risk of mortality and the need of mechanical ventilation. Cutoff scores of 3 and 2 had the optimal sensitivities and specificities to predict the risk of mortality and the need of mechanical ventilation, respectively.
COVID-19 ; Inflammation ; Mortality ; Respiration, Artificial ; Cytokine Release Syndrome

Obesity ; Body Mass Index ; Leptin ; Inflammation ; Adipose Tissue

Sleep is an extremely important physiological state to maintain human life. Sleep disorders can not only cause anxiety and depression, but also induce multi-system diseases that seriously affect brain function and physical health. The neuroinflammation is a key pathological process after sleep disorders, which can induce a series of nervous system diseases. In recent years, the role of microglia activation in neuroinflammation has been paid more and more attention and become a research hotspot in this field. The imbalance of the central microenvironment after sleep disorders leads to changes in the activation and polarization of microglia, which triggers neuroinflammatory response. The activation and polarization of microglia in the sleep disorders are regulated by multiple signaling pathways and complex molecular mechanisms. This paper summarizes five signaling pathways of microglia activation in central inflammation induced by sleep disorders, including P2X7 receptor (P2X7R), p38MAPK, Toll-like receptor 4 (TLR4)/NF-κB, JAK/STAT, and α7 nicotinic acetylcholine receptor (α7-nAChR) pathways, in order to provide reference for further research and clinical treatment targets selection of sleep disorders.
Humans ; Neuroinflammatory Diseases ; Microglia/metabolism* ; Signal Transduction/physiology* ; NF-kappa B/metabolism* ; Inflammation/metabolism* ; Sleep Wake Disorders/metabolism*

Chronic inflammatory reaction has been established as an important sign of the occurrence and development of diabetes mellitus (DM), accompanied by the production of a large number of inflammatory factors, thus aggravating the disease progression. As an important non-invasive intervention measure to inhibit inflammation, exercise plays a very important role in the amelioration of DM. NOD-like receptor protein 3 (NLRP3) inflammasome, a regulatory factor of inflammatory response, can induce a variety of inflammatory cascades and cell death, which are closely related to glucose uptake and dyslipidemia regulation. The development of DM can be postponed with exercise. Previous studies have reported the effects of NLRP3 inflammasome on DM, but the crucial role of exercise in this process remains unclear. Therefore, this paper reviews the research progress on the improving effects of exercise intervention on the symptoms of DM by mediating NLRP3 inflammasome, providing a novel theoretical foundation for understanding the prevention and treatment of DM through exercise.
Humans ; Inflammasomes/metabolism* ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism* ; NLR Proteins ; Diabetes Mellitus ; Inflammation ; Exercise Therapy