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The 78‐kDa glucose‐regulated protein (GRP78) has extracellular, anti‐inflammatory properties that can aid resolving inflammation. It has been established previously that GRP78 induced myeloid CD11c+ cell differentiation into distinct tolerogenic cells. This tolerance induction makes GRP78 a potential therapeutic agent for transplanted allogeneic grafts and autoimmune diseases, such as type 1 diabetes. In this research, it is revealed that rmGRP78‐treated NOD mice bone marrow‐derived CD11c+ cells (GRP78‐DCs) highly expressed B7‐H4 but down‐regulated CD86 and CD40, and retained a tolerogenic signature even after stimulation by LPS. In the assessment of in vivo therapeutic efficacy after the adoptive transfer of GRP78‐DCs into NOD mice, fluorescent imaging analyses revealed that the transfer specifically homed in inflamed pancreases, promoting β‐cell survival and alleviating insulitis in NOD mice. The adoptive transfer of GRP78‐DCs also helped reduce Th1, Th17, and CTL, suppressing inflammatory cytokine production in vivo. The findings suggest that adoptive GRP78‐DC transfer is critical to resolving inflammation in NOD mice and may have relevance in a clinical setting. [ABSTRACT FROM AUTHOR]

Objective. To reveal the molecular mechanism of the antagonistic effect of traditional Chinese medicine Tianma formula (TF) on dementia including vascular dementia (VaD) and Alzheimer's disease (AD) and to provide a scientific basis for the study of traditional Chinese medicine for prevention and treatment of dementia. Method. The TF was derived from the concerted application of traditional Chinese medicine. We detected the pharmacological effect of TF in VaD rats. The molecular mechanism of TF was examined by APP/PS1 mice in vivo, Caenorhabditis elegans (C. elegans) in vitro, ELISA, pathological assay via HE staining, and transcriptome. Based on RNA-seq analysis in VaD rats, the differentially expressed genes (DEGs) were identified and then verified by quantitative PCR (qPCR) and ELISA. The molecular mechanisms of TF on dementia were further confirmed by network pharmacology and molecular docking finally. Results. The Morris water maze showed that TF could improve the cognitive memory function of the VaD rats. The ELISA and histological analysis suggested that TF could protect the hippocampus via reducing tau and IL-6 levels and increasing SYN expression. Meanwhile, it could protect the neurological function by alleviating Aβ deposition in APP/PS1 mice and C. elegans. In the RNA-seq analysis, 3 sphingolipid metabolism pathway-related genes, ADORA3, FCER1G, and ACER2, and another 5 nerve-related genes in 45 key DEGs were identified, so it indicated that the protection mechanism of TF was mainly associated with the sphingolipid metabolism pathway. In the qPCR assay, compared with the model group, the mRNA expressions of the 8 genes mentioned above were upregulated, and these results were consistent with RNA-seq. The protein and mRNA levels of ACER2 were also upregulated. Also, the results of network pharmacology analysis and molecular docking were consistent with those of RNA-seq analysis. Conclusion. TF alleviates dementia by reducing Aβ deposition via the ACER2-mediated sphingolipid signaling pathway. [ABSTRACT FROM AUTHOR]

Berberine, a natural isoquinoline alkaloid isolated from the berberis species, has a wide array of biological properties such as anti-inflammatory, antibacterial, antifungal, and antihelminthic effects. We evaluated the antiviral effect of berberine against influenza A/FM1/1/47 (H1N1) in vivo and in vitro. The results showed that berberine strongly suppressed viral replication in A549 cells and in mouse lungs. Meanwhile, berberine relieved pulmonary inflammation and reduced necrosis, inflammatory cell infiltration, and pulmonary edema induced by viral infection in mice when compared with vehicle-treated mice. Berberine suppressed the viral infection-induced up-regulation of TLR7 signaling pathway, such as TLR7, MyD88, and NF-κB (p65), at both the mRNA and protein levels. Furthermore, berberine significantly inhibited the viral infection-induced increase in Th1/Th2 and Th17/Treg ratios as well as the production of inflammatory cytokines. Our data provide new insight into the potential of berberine as a therapeutic agent for viral infection via its antiviral activity. [ABSTRACT FROM AUTHOR]

Background: Systemic lupus erythematosus (SLE) is characterized by abnormal activated T cells, autoreactive B cells, and massive cytokines. The CD4+ T cells determined B-cells differentiation and cytokines production. The programmed death 1 (PD-1) is the checkpoint immunoinhibitory receptor of activated T cells, and its engagement could exhaust T cells. In this study, we investigated the role of PD-1 systemic engagement with PD-L1-Ig in lupus-like nephritis in SLE mice.Methods: The murine PD-L1-Ig was injected into SLE-prone mice. The proteinuria and survival ratio were monitored. The production of anti-dsDNA autoantibodies and cytokines in serum were measured by enzyme-linked immunosorbent assay. The cytokine-producing T cells (interferon-γ, IFN-γ and IL-17α) in kidney and spleen were detected with flowcytometry. The pathological evaluation of the Ig deposition in the glomeruliand was determined with immunofluorescence. Lymphocytes in 24-h urine were detected with flowcytometry.Results: The systemic administration of PD-L1-Ig activated PD-1-PD-L1 axis of CD4+ T lymphocytes, suppressed Th17 formation in many organs, including the spleen and the kidney, demolished abnormal production of cytokines (IFN-γ, IL-17, and IL-10) and anti-dsDNA autoantibodies in serum, inhibited immunoglobulin G deposition in the glomeruli with the decrease of proteinuria, and activated T cells in urine. Accordingly, the systemic conjugation of PD-L1-PD-1 impaired renal autoimmune injure and prolonged survival time.Conclusion: Our research demonstrated that the protective function of systemic activation of PD-1-PD-L1 axis with PD-L1-Ig attenuates the nephritis in SLE-prone mice, which facilitates us to understand the suppressive function of PD-1-PD-L1 axis in the pathogenesis and progress of the lupus nephritis, and to explore a possible effective therapeutic strategy to SLE. [ABSTRACT FROM AUTHOR]

Forsythiaside A, a phenylethanoid glycoside monomer extracted from Forsythia suspensa, shows anti-inflammatory, anti-infective, anti-oxidative, and antiviral pharmacological effects. The precise mechanism underlying the antiviral action of forsythiaside A is not completely clear. Therefore, in this study, we aimed to determine whether the anti-influenza action of forsythiaside A occurs via the retinoic acid-inducible gene-I–like receptors (RLRs) signaling pathway in the lung immune cells. Forsythiaside A was used to treat C57BL/6J mice and MAVS−/− mice infected with mouse-adapted influenza A virus FM1 (H1N1, A/FM1/1/47 strain), and the physical parameters (body weight and lung index) and the expression of key factors in the RLRs/NF-κB signaling pathway were evaluated. At the same time, the level of virus replication and the ratio of Th1/Th2 and Th17/Treg of T cell subsets were measured. Compared with the untreated group, the weight loss in the forsythiaside A group in the C57BL/6J mice decreased, and the histopathological sections showed less inflammatory damage after the infection with the influenza A virus FM1 strain. The gene and protein expression of retinoic acid-inducible gene-I (RIG-I), MAVS, and NF-κB were significantly decreased in the forsythiaside A group. Flow cytometry showed that Th1/Th2 and Th17/Treg differentiated into Th2 cells and Treg cells, respectively, after treatment with forsythiaside A. In conclusion, forsythiaside A reduces the inflammatory response caused by influenza A virus FM1 strain in mouse lungs by affecting the RLRs signaling pathway in the mouse lung immune cells. [ABSTRACT FROM AUTHOR]

Background: To investigate the effects and immunological mechanisms of the traditional Chinese medicine Xinjiaxiangruyin on controlling influenza virus (FM1 strain) infection in mice housed in a hygrothermal environment. Methods: Mice were housed in normal and hygrothermal environments, and intranasally infected with influenza virus (FM1). A high-performance liquid chromatography fingerprint of Xinjiaxiangruyin was used to provide an analytical method for quality control. Real-time quantitative polymerase chain reaction (RT-qPCR) was used to measure messenger RNA expression of Toll-like receptor 7 (TLR7), myeloid differentiation primary response 88 (MyD88), and nuclear factor-kappa B (NF-κB) p65 in the TLR7 signaling pathway and virus replication in the lungs. Western blotting was used to measure the expression levels of TLR7, MyD88, and NF-κB p65 proteins. Flow cytometry was used to detect the proportion of Th17/T-regulatory cells. Results: Xinjiaxiangruyin effectively alleviated lung inflammation in C57BL/6 mice in hot and humid environments. Guizhimahuanggebantang significantly reduced lung inflammation in C57BL/6 mice. The expression of TLR7, MyD88, and NF-κB p65 mRNA in lung tissue of WT mice in the normal environment, GZMHGBT group was significantly lower than that in the model group (P < 0.05). In WT mice exposed to the hot and humid environment, the expression levels of TLR7, MyD88, and NF-κB p65 mRNA in the XJXRY group were significantly different from those in the virus group. The expression levels of TLR7, MyD88, and NF-κB p65 protein in lung tissue of WT mice exposed to the normal environment, GZMHGBT group was significantly lower than those in the model group. In WT mice exposed to hot and humid environments, the expression levels of TLR7, MyD88, and NF-κB p65 protein in XJXRY group were significantly different from those in the virus group. Conclusion: Guizhimahuanggebantang demonstrated a satisfactory therapeutic effect on mice infected with the influenza A virus (FM1 strain) in a normal environment, and Xinjiaxiangruyin demonstrated a clear therapeutic effect in damp and hot environments and may play a protective role against influenza through downregulation of the TLR7 signal pathway. [ABSTRACT FROM AUTHOR]

Background: Influenza virus is a single-stranded RNA virus that causes influenza in humans and animals. About 600 million people around the world suffer from influenza every year. Upon recognizing viral RNA molecules, TLR7 (Toll-like receptor) initiates corresponding immune responses. Traditional Chinese Medicines (TCMs), including Yinqiao powder, Xinjiaxiangruyin and Guizhi-and-Mahuang decoction, have been extensively applied in clinical treatment of influenza. Although the therapeutic efficacy of TCMs against influenza virus in vivo was reported previously, its underlying mechanisms are not clearly understood. This study aimed to investigate the immunological mechanisms in the treatment of influenza virus infected mice with three Chinese herbal compounds as well as the effect on TLR7/NF-κB signaling pathway during recovery. Methods: Wild type and TLR7 KO C57BL/6 mice were infected with influenza virus FM1 and then treated with three TCMs. The physical parameters of mice (body weight and lung index) and the expression levels of components in TLR7/NF-κB signaling pathway were evaluated. Results: After viral infection, Guizhi-and-Mahuang decoction and Yinqiao powder showed better anti-viral effect under normal condition. Compared to the viral control group, expression levels of TLR7, MyD88, IRAK4 and NF-κB were significantly reduced in all treatment groups. Furthermore, the three TCM treatment groups showed poor therapeutic efficacy and no difference in viral load compared to the viral control group in TLR7 KO mice. Conclusion: Our study indicated that Guizhi-and-Mahuang decoction and Yinqiao powder might play a crucial role of anti-influenza virus by regulating TLR7/NF-κB signal pathway. [ABSTRACT FROM AUTHOR]

Objective. We wished to investigate the effects of the traditional Chinese medicine Gui Zhi Ma Huang Ge Ban Tang on controlling influenza A virus (IAV) infection and improving inflammation in mouse lungs. Method. Mice were maintained in normal and cold environments and infected with IAV by intranasal application, respectively. Real-time quantitative polymerase chain reaction was used to measure mRNA expression of TLR7, myeloid differentiation primary response 88 (MyD88), and nuclear factor-kappa B (NF-κB)p65 in the TLR7 signaling pathway and virus replication in lungs. Western blotting was used to measure expression levels of TLR7, MyD88, and NF-κB p65 proteins. Flow cytometry was used to detect the proportion of T-helper (Th)1/Th2 and Th17/T-regulatory (Treg) cells. Results. Application of Gui Zhi Ma Huang Ge Ban Tang in influenza-infected mice in a cold environment showed (i) downregulation of TLR7, MyD88, and NF-κBp65; (ii) inhibition of transcriptional activities of promoters coding for TLR7, MyD88, and NF-κBp65; (iii) reduction in the proportion of Th1/Th2 and Th17/Treg cells. Conclusions. Gui Zhi Ma Huang Ge Ban Tang had a good therapeutic effect on mice infected with IAV, especially in the cold environment. It could reduce lung inflammation in mice significantly and elicit an anti-influenza effect by downregulating expression of the key factors in TLR7 signaling pathway. [ABSTRACT FROM AUTHOR]