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Cardiac arrest (CA) can result in cerebral ischaemia–reperfusion injury and poor neurological outcomes. While bone marrow‐derived mesenchymal stem cells (BMSCs) have been shown to have protective effects in brain ischaemic disease, their efficacy can be reduced by the poor oxygen environment. In this study, we investigated the neuroprotective effects of hypoxic preconditioned BMSCs (HP‐BMSCs) and normoxic BMSCs (N‐BMSCs) in a cardiac arrest rat model by examining their ability to ameliorate cell pyroptosis. The mechanism underlying the process was also explored. Cardiac arrest was induced in rats for 8 min and surviving rats received 1 × 106 normoxic/hypoxic BMSCs or PBS via intracerebroventricular (ICV) transplantation. Neurological function of rats was evaluated using neurological deficit scores (NDSs) and examined for brain pathology. Serum S100B and neuron‐specific enolase (NSE) levels and cortical proinflammatory cytokines were measured to evaluate brain injury. Pyroptosis‐related proteins in the cortex after cardiopulmonary resuscitation (CPR) were measured using western blotting and immunofluorescent staining. Transplanted BMSCs were tracked using bioluminescence imaging. Results showed significantly better neurological function and neuropathological damage after transplantation with HP‐BMSCs. In addition, HP‐BMSCs reduced levels of pyroptosis‐related proteins in the rat cortex after CPR and significantly reduced levels of biomarkers for brain injury. Mechanistically, HP‐BMSCs alleviated brain injury by reducing the expressions of HMGB1, TLR4, NF‐κB p65, p38 MAPK and JNK in the cortex. Our study demonstrated that hypoxic preconditioning could enhance the efficacy of BMSCs in alleviating post‐resuscitation cortical pyroptosis. This effect may be related to the regulation of the HMGB1/TLR4/NF‐κB, MAPK signalling pathways. [ABSTRACT FROM AUTHOR]

Abstract Sleep deprivation (SD) can lead to cognitive impairment caused by neuroinflammation. MiR-181c-5p/HMGB1 axis plays a part in anti-inflammation effects. However, the mechanism that miR-181c-5p facilitates learning and memory in SD mice remains unclear. So we investigated the role of miR-181c-5p in learning and memory impairment induced by SD. We overexpressed miR-181c-5p in the mice hippocampus by injecting lentivirus vector-miR-181c-5p (LV-miR-181c-5p) particles. Mice were divided into four groups: control (Ctrl), SD, SD + miR-181c-5p and SD + vector. We found that mice in the third group showed ameliorated learning and memory compared with the fourth group. The content of ionized calcium binding adaptor molecule 1 (IBA-1) in the third group was decreased compared with the fourth group. Moreover, the expression levels of HMGB1, TLR4 and p-NF-κB in the hippocampus of overexpressed miR-181c-5p mice were reduced. In total, miR-181c-5p ameliorated learning and memory in SD mice via the HMGB1/TLR4/NF-κB pathway.

Raltegravir, an inhibitor of human immunodeficiency virus-1 (HIV-1) integrase, has been used to treat HIV/acquired immunodeficiency syndrome; however, its therapeutic effects on pulmonary fibrosis have not been investigated. In this study, the in vitro effects of raltegravir (RAV) on transforming growth factor beta 1 (TGF-β1)-induced pulmonary fibrosis on L929 mouse fibroblasts were investigated. In addition, the effects of RAV on an in vivo pulmonary fibrosis model induced by intratracheal instillation of bleomycin were investigated. The proliferation of L929 cells was inhibited after RAV treatment. Meanwhile, the in vitro and in vivo protein expression of nucleotide-binding oligomerization domain-like receptor 3 (NLRP3), high-mobility group box 1 (HMGB1), toll-like receptor 4 (TLR4), prolyl hydroxylase domain protein 2, phosphorylated nuclear factor-κB (p-NF-κB), hypoxia-inducible factor-1α (HIF-1α), collagens I and III was reduced relative to TGF-β1 or the bleomycin group. Raltegravir ameliorated pulmonary fibrosis by reducing the pathology score, collagen deposition, and expression of α-smooth muscle actin, NLRP3, HMGB1, TLR4, inhibitor of kappa B, p-NF-κB, HIF-1α, collagen I, and collagen III. The results of this study demonstrate that RAV attenuated experimental attenuates pulmonary fibrosis by inhibiting NLRP3 activation.

Raltegravir, an inhibitor of human immunodeficiency virus-1 (HIV-1) integrase, has been used to treat HIV/acquired immunodeficiency syndrome; however, its therapeutic effects on pulmonary fibrosis have not been investigated. In this study, the in vitro effects of raltegravir (RAV) on transforming growth factor beta 1 (TGF-β1)-induced pulmonary fibrosis on L929 mouse fibroblasts were investigated. In addition, the effects of RAV on an in vivo pulmonary fibrosis model induced by intratracheal instillation of bleomycin were investigated. The proliferation of L929 cells was inhibited after RAV treatment. Meanwhile, the in vitro and in vivo protein expression of nucleotide-binding oligomerization domain-like receptor 3 (NLRP3), high-mobility group box 1 (HMGB1), toll-like receptor 4 (TLR4), prolyl hydroxylase domain protein 2, phosphorylated nuclear factor-κB (p-NF-κB), hypoxia-inducible factor-1α (HIF-1α), collagens I and III was reduced relative to TGF-β1 or the bleomycin group. Raltegravir ameliorated pulmonary fibrosis by reducing the pathology score, collagen deposition, and expression of α-smooth muscle actin, NLRP3, HMGB1, TLR4, inhibitor of kappa B, p-NF-κB, HIF-1α, collagen I, and collagen III. The results of this study demonstrate that RAV attenuated experimental attenuates pulmonary fibrosis by inhibiting NLRP3 activation. [ABSTRACT FROM AUTHOR]

The current study was designed to investigate the hepatoprotective effects and possible mechanisms of Baicalein (BA) on the diabetic liver injury in vivo and in vitro . The results exhibited that BA significantly restored the blood glucose in oral glucose tolerance test (OGTT) and inhibited the levels of insulin, alanine aminotransferase (ALT), aspartate aminotransaminase (AST), total cholesterol (TC) and triglyceride (TG) in C57BL/KsJ-db/db mice. Moreover, BA strikingly attenuated the extent of steatosis in the liver tissues of diabetic mice. These results confirmed the hepatoprotective effects of BA on diabetic liver injury. Further in vivo investigations revealed that the hepatoprotective activities of BA was due to the effects on remarkably suppressing the inflammatory cascade, including attenuating the expressions of HMGB1, TLR4, Myd88, NF-κB and IκB proteins and inhibiting the production of interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α in diabetic mice. Finally, the hepatoprotective effects of BA were characterized in human hepatic HepG2 cells. With response to palmitic acid-challenge, increased amount of insulin, ALT, AST, TG, TC were observed, whereas BA pretreatment significantly restored these changes in HepG2 cells. Inflammation condition was also recovered with BA treatment as shown by the changes of HMGB1, TLR4, Myd88, NF-κB and IκB expressions and the levels of IL-1β, IL-6 and TNF-α. These findings elucidated that BA exhibited prominent hepatoprotective activities in diabetic live injury. [ABSTRACT FROM AUTHOR]

Baicalin (BA), a major polyphenol compound isolated from the extracts of Scutellaria radix, has been previously reported to ameliorate depressive-like behaviors in mice with chronic unpredictable mild stress (CUMS). However, its underlying antidepressant mechanisms remain unclear. This study was designed to confirm the antidepressant-like effects of BA on CUMS induced behavioral abnormalities in mice, and sought to explore the pharmacological mechanisms in vivo and in vitro. The CUMS procedure was carried out to induce depression in mice. Afterwards, the tail suspension test (TST), forced swim test (FST), and open field test (OFT) were performed within 24 h, then sucrose preference test (SPT) was conducted. Additionally, PC12 cells were pretreated with BA for 2 h, then further stimulated with corticosterone for 24 h. The levels of Interleukin-1β (IL-1β), IL-6 and Tumor Necrosis Factor-α (TNF-α) in serum, hippocampus homogenate and cell culture medium were determined using the enzyme-linked immunosorbent assay (ELISA) method. The protein expressions of inhibition of high mobility group box 1 protein (HMGB1)/Toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) pathways in hippocampus and PC12 cells were detected. Our results showed that CUMS-treated mice presented notable depressive-like symptoms, such as decreased sucrose consumption, increased FST and TST immobility time. While BA (25, 50 mg/kg) significantly attenuated these changes. Besides, BA treatment considerably inhibited inflammatory cytokinesl (IL-1β, IL-6, TNF-α) levels in serum, hippocampus homogenate and cell culture medium. Western blot analysis indicated that BA inhibited the expressions of HMGB1, TLR4, and p-NF-κBp65 both in vivo and in vitro. In conclusion, the present study confirmed that BA possessed efficient antidepressant effects on depression, which was possibly related to the inhibition of HMGB1/TLR4/NF-κB pathways.

Glycyrrhizin (Glyc) is a saponin triterpenoid that has signified its efficacy against Huntington's disease (HD). Nonetheless, its mechanism has not been fully clarified. Accordingly, this study was designed to evaluate the plausible mechanism of action of Glyc against 3-nitropropionic acid (3-NP)-induced HD. Rats were treated with Glyc (50 mg/kg, i.p.) for 3 weeks and 3-NP (10 mg/kg, i.p.) was administered at the latter 2 weeks alongside to induce HD. Animals exposed to 3-NP revealed a reduction in body weight, neurobehavioral abnormalities, and various deleterious effects related to overexpression of HMGB1 such as oxidative stress, apoptosis, and inflammation. Promisingly, Glyc administration provided valuable effects by reversing the decline in body weight with improved neurobehavioral deficits. Ameliorating oxidative stress via restoring GSH, SOD, and Nrf2 alongside with MDA suppression was evident. Furthermore, Glyc switched the HMGB1/TLR4/NF-κB p65 signaling off, reduced IL-6, IL-β, TNF-α, caspase-3, and increased Bcl-2 as well as BDNF. All these beneficial effects were mirrored by a better histopathological picture upon using Glyc that suppressed gliosis by reducing GFAP expression as observed in the immunohistochemistry results. Accordingly, the current study demonstrated a promising neuroprotective effect of Glyc against experimentally induced HD through alleviating deleterious events by diverse mechanisms. [ABSTRACT FROM AUTHOR]

Toxoplasma gondii (T. gondii) is an obligate intracellular parasite that can cause liver diseases in the host, including hepatitis and hepatomegaly. High mobility group box 1 (HMGB1) is the main inflammatory mediator causing cell injury or necrosis. HMGB1 binds to toll like receptor 4 (TLR4), then activates the nuclear factor-κB (NF-κB) signaling pathway, which promotes the release of inflammatory factors. Our previous studies showed that HMGB1 mediated TLR4/NF-κB signaling pathway plays an important role in liver injury induced by T. gondii infection. Resveratrol (RSV) is a small polyphenol, which has anti-inflammatory, anti-cancer, anti- T. gondii effect. However, the effect of RSV on liver injury caused by T. gondii infection is unclear. This study used the RH strain tachyzoites of T. gondii to infect murine liver line, NCTC-1469 cells to establish an in vitro model and acute infection of mice for the in vivo model to explore the protective effect of RSV on liver injury induced by T. gondii infection. The results showed that RSV inhibited the proliferation of T. gondii in the liver, reduced the alanine aminotransferase/aspartate aminotransferase levels and pathological liver damage. Additionally, RSV inhibited the production of tumor necrosis factor-α, inducible nitric oxide synthase and HMGB1 by interfering with the TLR4/NF-κB signaling pathway. These results indicate that RSV can protect liver injury caused by T. gondii infection by intervening in the HMGB1/TLR4/NF-κB signaling pathway. This study will provide a theoretical basis for RSV treatment of T. gondii infection induced liver injury. [Display omitted] • Resveratrol has a protective effect on liver injury induced by T. gondii infection. • Resveratrol inhibits the production of HMGB1induced by T. gondii infection. • Resveratrol reduces HMGB1 mediated TLR4/NF-κB signaling pathway in hepatocytes. [ABSTRACT FROM AUTHOR]

The inflammatory mediator high-mobility group box 1 (HMGB1)-induced signaling pathway has been shown to play an important role in the pathogenesis of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Matrine (MAT), a quinolizidine alkaloid component derived from the root of Sophorae flavescens , has the capacity to effectively suppress EAE. However, the impact of MAT treatment on HMGB1-induced signaling is not known. In the present study, we show that MAT treatment alleviated disease severity of ongoing EAE, reduced inflammatory infiltration and demyelination, and reduced the production of inflammatory factors including TNF-α, IL-6, and IL-1β in the CNS. Moreover, MAT administration significantly reduced the protein and RNA expression of HMGB1 and TLR4 in the spinal cord, particularly in astrocytes and microglia/infiltrating macrophages. The expression of MyD88 and TRAF6, and the phosphorylation of NF-κB p65, was also down-regulated after MAT treatment. In contrast, the level of IκB-α, an inhibitory molecule for NF-κB activation, was significantly increased. Furthermore, the direct inhibitory effect of MAT on HMGB1/TLR4/NF-κB signaling in macrophages was further confirmed in vitro. Taken together, these findings demonstrate that MAT treatment alleviated CNS inflammatory demyelination and activation of astrocytes and microglia/macrophages in EAE rats, and that the mechanism underlying these effects may be closely related to modulation of HMGB1/TLR4/NF-κB signaling pathway. Unlabelled Image • Matrine suppressed inflammation, demyelination and inflammatory cytokines in the CNS of EAE. • Matrine inhibited HMGB1, TLR4 expression in both astrocytes and microglia. • Matrine also inhibited MyD88, TRAF6 expression and NF-κB activation, with upregulated expression of IκB-α, an inhibitory molecule for NF-κB activation in the CNS. [ABSTRACT FROM AUTHOR]

Baicalin (BA), a major polyphenol compound isolated from the extracts of Scutellaria radix, has been previously reported to ameliorate depressive-like behaviors in mice with chronic unpredictable mild stress (CUMS). However, its underlying antidepressant mechanisms remain unclear. This study was designed to confirm the antidepressant-like effects of BA on CUMS induced behavioral abnormalities in mice, and sought to explore the pharmacological mechanisms in vivo and in vitro. The CUMS procedure was carried out to induce depression in mice. Afterwards, the tail suspension test (TST), forced swim test (FST), and open field test (OFT) were performed within 24 h, then sucrose preference test (SPT) was conducted. Additionally, PC12 cells were pretreated with BA for 2 h, then further stimulated with corticosterone for 24 h. The levels of Interleukin-1β (IL-1β), IL-6 and Tumor Necrosis Factor-α (TNF-α) in serum, hippocampus homogenate and cell culture medium were determined using the enzyme-linked immunosorbent assay (ELISA) method. The protein expressions of inhibition of high mobility group box 1 protein (HMGB1)/Toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) pathways in hippocampus and PC12 cells were detected. Our results showed that CUMS-treated mice presented notable depressive-like symptoms, such as decreased sucrose consumption, increased FST and TST immobility time. While BA (25, 50 mg/kg) significantly attenuated these changes. Besides, BA treatment considerably inhibited inflammatory cytokinesl (IL-1β, IL-6, TNF-α) levels in serum, hippocampus homogenate and cell culture medium. Western blot analysis indicated that BA inhibited the expressions of HMGB1, TLR4, and p-NF-κBp65 both in vivo and in vitro. In conclusion, the present study confirmed that BA possessed efficient antidepressant effects on depression, which was possibly related to the inhibition of HMGB1/TLR4/NF-κB pathways. [ABSTRACT FROM AUTHOR]

The current study was designed to investigate the protective effect and possible mechanisms of umbelliferone (Umb) on liver injury in diabetic C57BL/KsJ-db/db (dbdb) mice. Mice were divided into five groups: wild-type mice group (WY), dbdb mice group, dbdb mice + Metformin (100 mg/kg) group, dbdb mice + Umb (20, 40 mg/kg) group. Blood glucose regulation was assessed by an oral glucose tolerance test (OGTT). At 28 days after drug administration, blood samples were obtained for the analysis of lipids and enzymes related to hepatic function, including alanine aminotransferase (ALT), aspartate aminotransaminase (AST) and total cholesterol (TC) and triglyceride (TG). Expression levels of inflammatory cytokines (TNF-α, IL-1β, and IL-6) and oxidative stress indicators (SOD and MDA) were measured with ELISA kit. The expressions of high-mobility group box 1 (HMGB1), Toll-like receptor (TLR) 4 (TLR4), Myd88, NF-κB, IκB, Nrf2, and HO-1 proteins were also evaluated by Western blotting analysis. The results showed that Umb significantly restored the blood glucose in OGTT, and inhibited the levels of insulin, TG, TC, as well as activities of ALT and AST. Moreover, Umb inhibited diabetic inflammation through down-regulating the expression of HMGB1, TLR4, NF-κB, and IκB. In addition, Umb alleviated oxidative damage in the liver by activating Nrf2-mediated signal pathway. These findings demonstrated that Umb exhibited protective effect against diabetic live injury, which may be through inhibiting HMGB1-induced inflammatory response and activating Nrf2-mediated antioxidant., (© 2018 The Author(s).)