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Intervertebral disk (IVD) degeneration (IVDD) can cause various spinal degenerative diseases. Cumulative evidence has indicated that IVDD can result from inflammation, apoptosis, autophagy, biomechanical changes and other factors. Currently, lack of conservative treatment for degenerative spinal diseases leads to an urgent demand for clinically applicable medication to ameliorate the progression of IVDD. Resveratrol (3,5,4'-trihydroxy-trans-stilbene), a polyphenol compound extracted from red wine or grapes, has shown protective effects on IVD, alleviating the progression of IVDD. Resveratrol has been demonstrated as a scavenger of free radicals both in vivo and in vitro. The antioxidant effects of resveratrol are likely attributed to its regulation on mitochondrial dysfunction or the elimination of reactive oxygen species. This review will summarize the mechanisms of the reactive oxygen species production and elaborate the mechanisms of resveratrol in retarding IVDD progression, providing a comprehensive understanding of the antioxidant effects of resveratrol in IVD.

Inflammation plays a pivotal role in promoting the pathophysiology of ischemic stroke (IS). Microglia is the major immunocompetent cells involved in different neuropathologies. The activation of cyclic GMP-AMP synthase (cGAS) and its downstream signaling protein-stimulator of interferon genes (STING) is increasingly recognized as a crucial determinant of neuropathophysiology. However, the mechanisms underlying cGAS-STING signaling regulating inflammatory response during IS remains to be elucidated. In this study, HT22 cells was used to establish an oxygen-glucose deprivation (OGD) cell model in vitro, and then this cell culture supernatant containing OGD-induced DAMPs (OIDs) was employed to stimulate BV2 microglia. Furthermore, a middle cerebral artery occlusion (MCAO) mouse model was established. Cells and MCAO mice were treated with si-cGAS or si-NC lentivirus. The expression levels of STING, cGAS and p-IRF3 in BV2 cells or MCAO mouse brain; the microglial M1/M2 polarization of BV2 microglia or isolated microglial cells from MCAO mouse brain; the contents of iNOS, TNF-α, TGF-β and IL-10 in the culture medium of BV2 cells or in murine brain homogenates, were all detected. In addition, the severity of cerebral infarction with or without the knockdown of cGAS in a MCAO mouse model was also determined by TTC staining. Results showed that OGD-induced DAMPs strongly activated cGAS-STING pathway and triggered microglia polarization in BV2 cells, reflecting as the accumulation of a plethora of pro-inflammatory factors in activated microglia. However, these effects could be inhibited by cGAS knockdown. In the MCAO mouse model, the inhibition of cGAS-STING pathway resulted from cGAS knockdown could effectively diminish cell apoptosis in mouse brain stimulated by MIDs (MCAO-induced DAMPs), reduced the area ratio of cerebral infarction and ultimately improved the injured nerve function during IS. Taken together, our elucidation of underlying mechanisms involved in the microglial inflammatory response, triggered by cGAS-STING signaling, highlights this pathway as a potential therapeutic target in IS.

Mei-Xiang Zhan,1,2,* Li Tang,3,* Yun-Fei Lu,4,* Huang-Hui Wu,1,* Zhi-Bin Guo,1 Zhong-Mou Shi,1 Chen-Long Yang,1 Yi-Qing Zou,1,2 Fei Yang,1,2,5 Guo-Zhong Chen1,2 1Department of Anesthesiology and Perioperative Medicine, Clinical Medical College, (900 Hospital of the Joint Logistic Support Force), Fujian Medical University, Fuzhou, Fujian, 350025, People’s Republic of China; 2Department of Anesthesiology and Perioperative Medicine, Dongfang Hospital, Xiamen University, Fuzhou, Fujian, 350025, People’s Republic of China; 3Department of Stomatology, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, People’s Republic of China; 4Department of Anesthesiology, Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, People’s Republic of China; 5Laboratory of Pain Research, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian, 350122, People’s Republic of China*These authors contributed equally to this workCorrespondence: Guo-Zhong Chen; Fei YangDepartment of Anesthesiology and Perioperative Medicine, 900 Hospital of the Joint Logistic Support Force, Fujian Medical University, #156 West 2 nd Ring Road North, Gulou District, Fuzhou, 350025, People’s Republic of ChinaEmail cgzssq2000@sina.com; yangfeimedbrain@outlook.comIntroduction: Ulinastatin, a broad-spectrum serine protease inhibitor, has been widely used to treat various diseases clinically. However, so far, the antinociceptive effect of ulinastatin remains less studied experimentally and the underlying mechanisms of ulinastatin for pain relief remain unclear. This study aimed to find evidence of the analgesic effect of ulinastatin on acute somatic and visceral pain.Methods: The analgesic effect of ulinastatin on acute somatic and visceral pain was evaluated by using formalin and acetic acid-induced writhing test. The analgesic mechanism of ulinastatin was verified by detecting the peripheral inflammatory cell infiltration and spinal glial activation with hematoxylin-eosin (H&E) and immunohistochemistry staining.Results: We found that both of intraperitoneal (i.p.) pre-administration and post-administration of ulinastatin could reduce the total number of flinching and the licking duration following intraplantar formalin injection in a dose-related manner. However, the inhibitory effect of ulinastatin existed only in the second phase (Phase 2) of formalin-induced spontaneous pain response, with no effect in the first phase (Phase 1). The formalin-induced edema and ulcer were also improved by i.p. administration of ulinastatin. Moreover, i.p. administration of ulinastatin was also able to delay the occurrence of acetic acid-induced writhing and reduced the total number of writhes dose-dependently. We further demonstrated that ulinastatin significantly decreased the local inflammatory cell infiltration in injured paw and peritoneum tissue under formalin and acetic acid test separately. The microglial and astrocytic activation in the spinal dorsal horn induced by intraplantar formalin and i.p. acetic acid injection were also dramatically inhibited by i.p. administration of ulinastatin.Conclusion: Our results for the first time provided a new line of evidence showing that ulinastatin could attenuate acute somatic and visceral pain by inhibiting the peripheral and spinal inflammatory reaction.Keywords: Ulinastatin, formalin, somatic pain, visceral pain, inflammation, antinociception

Neonatal pneumonia is a common illness in the neonatal period with a high fatality rate. Accumulating proofs have attested to the crucial role of circular RNAs (circRNAs) in pneumonia. This study was intended to expound on the function of circ_0038467 and the underlying mechanism in lipopolysaccharide (LPS)-stimulated 16HBE cell injury in neonatal pneumonia.16HBE cells were exposed to LPS to establish an in vitro neonatal pneumonia cell model. Quantitative real-time polymerase chain reaction (qRT-PCR) was implemented for detecting the levels of circ_0038467, microRNA-545-3p (miR-545-3p), and tumor necrosis factor receptor-associated factor 1 (TRAF1) in neonatal pneumonia serums and LPS-treated 16HBE cells. Cell Counting Kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EdU) incorporation, and flow cytometry assays were used to examine cell viability, proliferation, and apoptosis, respectively. The protein abundances of proliferation/apoptosis/inflammation-correlated makers and TRAF1 were tested by Western blot. RNase R and Actinomycin D assays were implemented to determine the features of circ_0038467. The mutual effect between miR-545-3p and circ_0038467 or TRAF1 was affirmed by a dual-luciferase reporter and RNA pull-down assay assays.Circ_0038467 was upregulated in neonatal pneumonia serum specimens and LPS-triggered 16HBE cells. LPS administration restrained 16HBE cell proliferation and promoted apoptosis and inflammation, whereas circ_0038467 silence recovered these influences. Meanwhile, miR-545-3p was targeted by circ_0038467, and circ_0038467 could modulate LPS-treated 16HBE cell injury through absorbing miR-545-3p. Furthermore, circ_0038467 controlled TRAF1 level via segregating miR-545-3p. Moreover, TRAF1 overexpression relieved the suppressive impact of circ_0038467 silence in LPS-triggered 16HBE cell detriment.Circ_0038467 knockdown mitigated LPS-exposed 16HBE cell damage through regulating miR-545-3p/PPARA axis.

Toxoplasma gondii is a widespread parasitic protozoan causing toxoplasmosis including pulmonary toxoplasmosis. As the first line of host defense, airway epithelial cells play critical roles in orchestrating pulmonary innate immunity. However, the mechanism underlying the airway inflammation induced by the T. gondii infection remains largely unclear. This study demonstrated that after infection with T. gondii, the major anion channel located in the apical membranes of airway epithelial cells, cystic fibrosis transmembrane conductance regulator (CFTR), was degraded by the parasite-secreted cysteine proteases. The intracellular Cl

Purpose. Jiaweishaoyao decoction (JWSYD) is a traditional prescription of Chinese medicine that is initially used for the treatment of diarrhea. This study is aimed at investigating the effects of JWSYD on DSS-induced ulcerative colitis (UC). Methods. DSS-induced UC mice and LPS-induced RAW264.7 cells were used as the UC model in vivo and in vitro. UC was assessed by body weight, disease activity index (DAI), colon length, spleen weight, and histopathological score (HE staining). The levels of TNF-α, IL-1β, and IL-6 were analyzed by ELISA and qRT-PCR. The levels of NLRP3 inflammasome- and NF-κB pathway-associated proteins were measured by western blot. Results. JWSYD alleviated DSS-induced UC in respect to body weight, DAI, colon length, spleen weight, and histopathological score. JWSYD reduced the levels of TNF-α, IL-1β, and IL-6 in DSS-induced UC mice and the supernatants of LPS-induced RAW264.7 cells. JWSYD suppressed the protein levels of inflammasome-associated proteins, including NLRP3, ASC1, Procaspase-1, Cleaved caspase-1, and Cleaved IL-1β in DSS-induced UC mice and LPS-induced RAW264.7 cells. In addition, JWSYD suppressed the NF-κB pathway in vitro and in vivo. Conclusion. JWSYD alleviated DSS-induced UC via inhibiting the NLRP3 inflammasome and NF-κB pathway.

Introduction Ischemia-reperfusion injury (IRI) is a serious complication of hepatectomy and liver transplantation. The aim of this study was to evaluate the protective effects of salvianolic acid-A (Sal-A) against IRI-induced hepatocellular injury. Material and methods Forty rats were randomly divided into the following four groups: (1) sham group, (2) IR group, (3) Sal-A(10) group and (4) Sal-A(20) group. After 90 min of ischemia and 6 h of reperfusion, serum alanine aminotransferease (ALT) and apartate aminotransferase (AST) levels were measured; the amounts of malondialdehyde (MDA) and superoxide dismutase (SOD) in the liver tissue were determined; the expression of Bcl-2 and caspase-3 was detected and the severity of apoptosis, inflammation and pathological alterations were evaluated. Also apoptosis and mRNA and protein levels of TLR4 (toll-like receptor 4) were tested. Results The serum aminotransferases, hepatic MDA concentration, and apoptotic cells in the IR group were significantly higher than in the sham group (p < 0.01), whereas the Sal-A group values were lower than in the IR group (p < 0.05). Compared with the IR group, the Sal-A groups had significantly higher Bcl-2 expression and downregulated cleaved caspase-3 expression in liver tissue. Moreover, increased mRNA and protein levels of TLR4 in IR rats and Sal-A could improve the increased mRNA and protein levels of TLR4. Conclusions Sal-A had a synergistically protective effect on the liver tissue against IRI that might be due to decreased oxidative stress, inflammation, hepatocellular apoptosis and include, at least in part, the regulation of TLR4.

Microglial inflammation plays an important part in the progression of multiple neurological diseases, including neurodegenerative diseases, stroke, depression, and traumatic encephalopathy. Here, we aimed to explore the role of pterostilbene (PTE) in the microglial inflammatory response and subsequent damage of cocultured neural cells and partially explain the underlying mechanisms. In the coculture system of lipopolysaccharide-activated BV-2 microglia and SH-SY5Y neuroblastoma, PTE (only given to BV-2) exhibited protection on SH-SY5Y cells, evidenced by improved SH-SY5Y morphology and viability and LDH release. It also attenuated SH-SY5Y apoptosis and oxidative stress, evidenced by TUNEL and DCFH-DA staining, as well as MDA, SOD, and GSH levels. Moreover, PTE upregulated SIRT-1 expression and suppressed acetylation of NF-κB p65 subunit in BV-2 microglia, thus decreasing the inflammatory factors, including TNF-α and IL-6. Furthermore, the effects above were reversed by SIRT-1 inhibitor EX527. These results suggest that PTE reduces the microglia-mediated inflammatory response and alleviates subsequent neuronal apoptosis and oxidative injury via increasing SIRT-1 expression and inhibiting the NF-κB signalling pathway.

Inflammation and oxidative stress play a key role in mediating the pathophysiology of hypoxic-ischemic (HI) brain injury. Nrf2 is a transcriptional factor that contributes to the innate defense of the body against oxidative stress and inflammation. The current study investigated the effect of Nrf2 in neonatal HI brain injury using Nrf2-/- mice. Nrf2-/- and wild-type Nrf2+/+ mice on a C57BL/6J background at postnatal day 9 underwent unilateral common carotid artery ligation, followed by hypoxia. Brain damage was determined by infarct size measurement. Apoptosis was evaluated by measuring the expression of Bax and Bcl-2. The levels of inflammatory cytokines and mediators involved in oxidative stress were measured. Nrf2 knockout exacerbated HI injury-induced brain infarct and cell apoptosis in the brain. Nrf2-/- mice showed increased inflammatory cytokines and MDA, and reduced activities of antioxidant enzymes including CAT, GSH-Px, and SOD. Nrf2-/- mice showed reduced HO-1 expression after HI injury compared with wild-type mice. This study supported a protective effect of Nrf2 in neonatal HI brain injury.

Rheumatoid arthritis (RA) is an autoimmune disease characterised by systemic and chronic synovitis that lead to joint destruction, pain, and many complications. Treatments only relieve certain symptoms, but do not cure RA completely. Prostaglandins (PGs) are lipid signalling molecules and released in the early phase of RA. Increasing evidences have shown five main contribution of PGs to the different stages and symptoms of RA. First, PGs maintain the autoimmune response and immune-system inflammation by modulating the differentiation, maturation, and cytokine production of immune cells. Second, PGs are beneficial for leukocyte infiltration, synovial hyperplasia, and angiogenesis to promote synovitis. Third, PGs are involved in cartilage degradation and bone resorption. Fourth, PGs are important mediators of joint-pain regulation. Finally, in the late stage of RA inflammation, PGs play a part in joint protection. Those findings suggest that PGs are potential therapy targets for RA. This review highlights recent advances in the RA development caused by PGs, and provides recommendations for future research directions.

Objective To explore the effect of hydrogen sulfide on inflammatory factors and energy metabolism of mitochondria after limbs reperfusion injury in rats. Methods Sixty rats were divided into three groups:sham operation group,control group(ischemia-reperfusion injury + saline group),and experimental group(ischemia-reperfusion injury + H

Accumulatig evidence demonstrated that inflammation is associated with the development of gestational diabetes mellitus (GDM). Fatty acid-binding protein 4 (FABP4) was reported to be involved in immune response. However, the effect of FABP4 in GDM remians unclear. This study focused on the effect of FABP4 in GDM. C57BL/KsJdb/+ (db/+) mice were used for GDM mouse model . BMS-309403 (BMS) was used to inhibit FABP4 levels in GDM mouse model. IL-6 and TNF-α concentrations in serum were determined via ELISA. Serum glucose and insulin concentrations were tested using commercial glucometer and mouse insulin ELISA kit, respectively. IL-6 and TNF-α mRNA and protein levels were detected using RT-PCR and western blot, respectively. FABP4 levels were upregulated in GDM group compared with control group and were positively associated with serum IL-6 and TNF-α levels. FABP4 inhibition by BMS significantly decreased body weight and serum glucose concentrations, increasd serum insulin concentration, suppressed IL-6 and TNF-α expression both in the serum and the pancreas, enhanced little size and inhibited birth weight in GDM mouse model. Inhibition of FABP4 attenuates GDM in genetic mice.

The traditional Chinese medicinal herb Notopterygium incisum Ting ex H.T. Chang has anti-rheumatism activity, and a mass spectrometry assay of patients' serum after administration of the herb revealed that notopterol is the most abundant component enriched. However, the functions of notopterol and its molecular target in rheumatoid arthritis (RA) treatment remain unknown. Here, we show in different RA mouse strains that both oral and intraperitoneal administration of notopterol result in significant therapeutic effects. Mechanistically, notopterol directly binds Janus kinase (JAK)2 and JAK3 kinase domains to inhibit JAK/signal transducers and activators of transcription (JAK-STAT) activation, leading to reduced production of inflammatory cytokines and chemokines. Critically, combination therapy using both notopterol and tumor necrosis factor (TNF) blocker results in enhanced therapeutic effects compared to using TNF blocker alone. We demonstrate that notopterol ameliorates RA pathology by targeting JAK-STAT signaling, raising the possibility that notopterol could be effective in treating other diseases characterized by aberrant JAK-STAT signaling pathway.

Left ventricular remodeling is an essential risk factor contributing to the pathogenesis of chronic heart failure (CHF). Basigin (BSG) promotes cardiovascular inflammation and myocardial remodeling processes by induction of extracellular matrix metalloproteinases and inflammatory cytokines. BSG rs8259 polymorphism was associated with BSG expression and risk of acute coronary syndrome. Therefore, we investigated whether rs8259 polymorphism contributes to risk and prognosis of CHF in Chinese patients. In total 922 adult patients with CHF and 1107 matched healthy controls were enrolled. BSG rs8259 polymorphism was genotyped using PCR-restriction fragment length polymorphism. Whole blood BSG mRNA expression data from Genotype-Tissue Expression project was accessed. Evaluation of follow-up data was performed in only 15.2% (140) of the patients with CHF. BSG rs8259 TT genotype was associated with a decreased risk of CHF (OR = 0.83, 95% CI = 0.72–0.96, p = 0.010), especially in patients with hypertension (OR = 0.80, 95% CI = 0.68–0.95, p = 0.011) and coronary heart disease (OR = 0.81, 95% CI = 0.69–0.96, p = 0.013) after adjustment for multiple cardiovascular risk factors. Rs8259 T allele was associated with decreased BSG mRNA in whole blood from 338 healthy normal donors (p = 1.31 × 10−6). However, rs8259 polymorphism failed to exhibit an association with cardiovascular mortality (p = 0.283). BSG rs8259 polymorphism may contribute to decreased risk of CHF in a Chinese Han population.

Hemophagocytic lymphohistiocytosis (HLH) is a potentially fatal disease characterized by overwhelming inflammation response and multiple organ damage. Most of the clinical and laboratory manifestations of HLH are thought to be related to hypercytokinemia and organ infiltration with lymphocytes and histiocytes. The aim of this study was to investigate the associations between cytokines and various manifestations of HLH. A total of 105 patients diagnosed with HLH were enrolled in this retrospective study. The information including the patients' demographic characteristics, clinical and laboratory findings at presentation and cytokine data were collected. The median age at diagnosis was 2.8years, with 74 patients (70.4%) documented Epstein-Barr virus infection. Hepatomegaly (88.6%), splenomegaly (81.9%), cytopenia (68.6%), elevated ferritin level (93.3%), hypofibrinogenemia (61.9%) and hemophagocytosis (77.3%) were found in more than half of the patients. Interleukin (IL)-6, IL-10 and interferon (IFN)-γ were found to be moderately or significantly elevated in most patients. In the correlation analysis, IFN-γ was closely related to the concentration of alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, lactate dehydrase (LDH), triglyceride and fibrinogen, while IL-10 was associated with platelet count. When split the patients into two groups according to the cytokine levels, patients with high IFN-γ presented higher level of ALT, AST, bilirubin, LDH, triglyceride, and fibrinogen, while patients with high IL-10 presented much lower hemoglobin and platelet count. In conclusion, the present study put forward clinical evidence that hypercytokinemia is related to organ damage in HLH. IFN-γ may contribute to liver impairment and coagulation disease, while IL-10 is a cytokine related to cytopenias.

Perfluorooctanoic acid (PFOA) is widely present in the environment and has been reported to induce hepatic toxicity in animals and humans. In this study, mice were orally administered different concentrations of PFOA (2.5, 5, or 10 mg/kg/day). Histological examination showed that the exposure to PFOA for 14 consecutive days led to serious hepatocellular injury and obvious inflammatory cell infiltration. In addition, malondialdehyde formation and hydrogen peroxide generation, indicators of oxidative stress, were significantly induced by PFOA treatment in the liver of mice. Furthermore, hepatic levels of interleukin-6, cyclooxygenase-2, and C-reactive protein, markers of inflammatory response, were markedly increased by exposure to PFOA in mice. These results demonstrated that PFOA-induced hepatic toxicity may be involved in oxidative stress and inflammatory response in mice.