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While cumulative data indicate that indigenous commensal bacteria can facilitate enteric virus infection, little is known regarding whether intestinal microbes have a protective role in antagonizing enteric systemic infection by modulating host innate immunity. Although accumulating literature has pointed out that the microbiota has a fundamental impact on host systemic antiviral innate immune responses mediated by type I interferon (IFN), only a few specific commensal bacteria species have been revealed to be capable of regulating IFN-I and ISG expression, not to mention the underlying mechanisms. Intestinal microbiomes are of vital importance in antagonizing systemic viral infection. However, very little literature has shown whether commensal bacteria play a crucial role in protecting against enteric virus systemic infection from the aspect of modulating host innate immunity. In the present study, we utilized an enteric virus, encephalomyocarditis virus (EMCV), to inoculate mice treated with phosphate-buffered saline (PBS) or given an antibiotic cocktail (Abx) orally or intraperitoneally to examine the impact of microbiota depletion on virulence and viral replication in vivo . Microbiota depletion exacerbated the mortality, neuropathogenesis, viremia, and viral burden in brains following EMCV infection. Furthermore, Abx-treated mice exhibited severely diminished mononuclear phagocyte activation and impaired type I interferon (IFN) production and expression of IFN-stimulated genes (ISG) in peripheral blood mononuclear cells (PBMC), spleens, and brains. With the help of fecal bacterial 16S rRNA sequencing of PBS- and Abx-treated mice, we identified a single commensal bacterium, Blautia coccoides , that can restore mononuclear phagocyte- and IFNAR (IFN-α/β receptor)-dependent type I IFN responses to restrict systemic enteric virus infection. These findings may provide insight into the development of novel therapeutics for preventing enteric virus infection or possibly alleviating clinical diseases by activating host systemic innate immune responses via respective probiotic treatment using B. coccoides . IMPORTANCE While cumulative data indicate that indigenous commensal bacteria can facilitate enteric virus infection, little is known regarding whether intestinal microbes have a protective role in antagonizing enteric systemic infection by modulating host innate immunity. Although accumulating literature has pointed out that the microbiota has a fundamental impact on host systemic antiviral innate immune responses mediated by type I interferon (IFN), only a few specific commensal bacteria species have been revealed to be capable of regulating IFN-I and ISG expression, not to mention the underlying mechanisms. Thus, it is important to understand the cross talk between microbiota and host anti-enteric virus innate immune responses and characterize the specific bacterial species that possess protective functions. Our study demonstrates how fundamental innate immune mediators such as mononuclear phagocytes and type I IFN are regulated by commensal bacteria to antagonize enteric virus systemic infection. In particular, we have identified a novel commensal bacterium, Blautia coccoides , that can restrict enteric virus replication and neuropathogenesis by activating IFN-I and ISG responses in mononuclear phagocytes via an IFNAR- and STAT1-mediated signaling pathway.

Intestinal microbial metabolites have been increasingly recognized as important regulators of enteric viral infection. However, very little information is available about which specific microbiota-derived metabolites are crucial for swine enteric coronavirus (SECoV) infection in vivo . Using swine acute diarrhea syndrome (SADS)-CoV as a model, we were able to identify a greatly altered bile acid (BA) profile in the small intestine of infected piglets by untargeted metabolomic analysis. Using a newly established ex vivo model–the stem cell-derived porcine intestinal enteroid (PIE) culture–we demonstrated that certain BAs, cholic acid (CA) in particular, enhance SADS-CoV replication by acting on PIEs at the early phase of infection. We ruled out the possibility that CA exerts an augmenting effect on viral replication through classic farnesoid X receptor or Takeda G protein-coupled receptor 5 signaling, innate immune suppression or viral attachment. BA induced multiple cellular responses including rapid changes in caveolae-mediated endocytosis, endosomal acidification and dynamics of the endosomal/lysosomal system that are critical for SADS-CoV replication. Thus, our findings shed light on how SECoVs exploit microbiome-derived metabolite BAs to swiftly establish viral infection and accelerate replication within the intestinal microenvironment.

Introduction Severe acute pancreatitis (SAP) is a crucial gastrointestinal disease characterized by systemic inflammatory responses and persistent multiple organ failure. The role of bile acids (BAs) in diverse inflammatory diseases is increasingly recognized as crucial, but the underlying role of BA conjugation remains elusive. Objectives Our study aim to investigate the potential role of conjugated bile acids in SAP and reveal the molecular mechanisms underlying its regulatory effects. We hypothesized that taurochenodeoxycholic acid (TCDCA) and glycochenodeoxycholic acid (GCDCA) could protect SAP through inhibiting the activation of NLRP3 inflammasomes via the TGR5 pathway in macrophages. Methods To test our hypothesis, we used BA-CoA: amino acid N-acyltransferase knockout ( Baat −/− ) mice and established SAP mouse models using caerulein- and sodium taurocholate- induced. We utilized a range of methods, including pathology sections, qRT-PCR, immunofluorescence, Western blotting, and ELISA, to identify the mechanisms of regulation. Results BA-CoA: Amino acid N-acyltransferase knockout ( Baat −/− ) mice significantly exacerbated pancreatitis by increasing pancreatic and systemic inflammatory responses and pancreatic damage in SAP mouse models. Moreover, the serum TCDCA levels in Baat −/− mice were lower than those in wild-type (WT) mice with or without SAP, and GCDCA and TCDCA showed stronger anti-inflammatory effects than chenodeoxycholic acid (CDCA) in vitro. TCDCA treatment alleviated SAP in a Takeda G protein-coupled receptor 5 and NOD-like receptor family, pyrin domain containing 3 —dependent manner in vivo. Reinforcing our conclusions from the mouse study, clinical SAP patients exhibited decreased serum content of conjugated BAs, especially GCDCA, which was inversely correlated with the severity of systemic inflammatory responses. Conclusion Conjugated bile acids significantly inhibit NLRP3 inflammasome activation by activating TGR5 pathway, thereby alleviating pancreatic immunopathology. The results provide new insights into the variability of clinical outcomes and paves the way for developing more effective therapeutic interventions for AP.

The search for lead compounds with anti-neuroinflammatory activity from structurally ‘optimized’ natural products is a crucial and promising strategy in the quest to discover safe and efficacious agents for treating neurodegenerative diseases. A phytochemical investigation on the aerial portions of Hypericum elatoides led to the isolation of five nitrogenous polycyclic polyprenylated acylphloroglucinols (PPAPs), hyperelanitriles A–D ( 1 – 4 ) and hyperelamine A ( 5 ). Their structures were determined by spectroscopic analysis, ECD and NMR calculations, and X-ray crystallography. To the best of our knowledge, compounds 1 – 4 represent the first examples of acylphloroglucinols featuring an α-aminonitrile moiety, while 5 is a rare enamine-containing PPAP. Further, the synthesis of these naturally occurring PPAP-based nitriles or amines was accomplished. Compound 5 exhibited inhibitory activity against LPS-activated NO production in BV-2 cells, potentially through the suppression of TLR-4/NF-κB signaling. Here we show the isolation, structural elucidation, synthesis, and bioactive evaluation of compounds 1 – 5 . Natural products are a rich source of lead compounds in drug discovery. Here, the authors report the discovery and synthesis of five nitrogenous polycyclic polyprenylated acylphloroglucinols named hyperelanitriles A–D and hyperelamine A from the plant Hypericum elatoides with anti-inflammatory activity against lipopolysaccharides-activated nitric oxide production.

Although B cells play important roles in the humoral immune response and the regulation of adaptive immunity, B cell subpopulations with unique phenotypes, particularly those with non-classical immune functions, should be further investigated. By challenging mice with Listeria monocytogenes, Escherichia coli, vesicular stomatitis virus and Toll-like receptor ligands, we identified an inducible CDlla^hi FcγRIII^hi B cell subpopulation that is significantly expanded and produces high levels of IFN-γ during the early stage of the immune response. This subpopulation of B cells can promote macrophage activation via generating IFN-γ, thereby facilitating the innate immune response against intracellular bacterial infection. As this new subpopulation is of B cell origin and exhibits the phenotypic characteristics of B cells, we designated these cells as IFN-γ-producing innate B cells. Dendritic cells were essential for the inducible generation of these innate B cells from the follicular B cells via CD40L-CD40 ligation. Increased Bruton＇s tyrosine kinase activation was found to be responsible for the increased activation of non-canonical NF-κB pathway in these innate B cells after CD40 ligation, with the consequent induction of additional IFN-γ production. The identification of this new population of innate B cells may contribute to a better understanding of B cell functions in anti-infection immune responses and immune regulation.

Background： Prolonged gonadal hormone deficiency in patients with idiopathic hypogonadotropic hypogonadism （IHH） may produce adverse effects on the endocrine homeostasis and metabolism. This study aimed to compare basal serum adrenocorticotropic hormone （ACTH） and cortisol levels between male IHH patients and healthy controls. Moreover, this study compared the basal hypothalamic-pituitary-adrenal （HPA） axis in patients with and without nonalcoholic fatty liver disease （NAFLD）, and also evaluated the relationship between basal HPA axis and NAFLD in male IHH patients. Methods： This was a retrospective case-control study involving 75 Chinese male IHH patients （mean age 21.4 ± 3.8 years, range 17 30 years） and 135 healthy controls after matching tbr gender and age. All subjects underwent physical examination and blood testing for serum testosterone, luteinizing hormone, follicle-stimulating hormone. ACTH, and cortisol and biochemical tests. Results： Higher basal serum ACTH levels （8.25 ±3.78 pmol/L vs. 6.97 ±2.81 pmol/L） and lower cortisol levels （366.70 ±142.48 nmol/L vs. 452.82 ± 141.53 nmol/L） were observed ill male IHH patients than healthy subjects （all P 〈 0.05）. IHH patients also showed higher metabolism parameters and higher prevalence rate of NAFLD （34.9% vs. 4.4%） than the controls （all P 〈 0.05）. Basal serum ACTH （9.91 ±4.98 pmol/L vs. 7.60 ±2.96 pmol/L） and dehydroepiandrosterone sulfate （2123.7 ±925.8 μg/L vs. 1417.1 ±498.4 μg/L） levels were significantly higher in IHH patients with NAFLD than those without NAFLD （all P 〈 0.05）. We also found that basal serum ACTH levels were positively correlated with NAFLD （r = 0.289, P 〈 0.05） and triglyceride levels （r - 0.268, P 〈 0.05） in male IHH patients. Furthermore, NAFLD was independently associated with ACTH levels in male IHH patients by multiple linear regression analysis. Conclusions： The male IHH patients showed higher basal serum ACTH levels and lower cortisol levels than matched healthy controls. NAFLD was an independent associated factor for ACTH levels in male IHH patients. These preliminary findings provided evidence of the relationship between basal serum ACTH and NAFLD in male IHH patients.

Aim： We previously proven that carbocisteine, a conventional mucolytic drug, remarkably reduced the rate of acute exacerbations and improved the quality of life in the patients with chronic obstructive pulmonary disease. In this study we investigated the mechanisms underlying the anti-inflammatory effects of carbocisteine in human alveolar epithelial cells in vitro. Methods： Human lung adenocarcinoma cell line A549 was treated with TNF-α （10 ng/mL）. Carbocisteine was administered either 24 h prior to or after TNF-α exposure. The cytokine release and expression were measured using ELISA and qRT-PCR. Activation of NF-κB was analyzed with Western blotting, immunofluorescence assay and luciferase reporter gene assay. The expression of ERK1/2 MAPK signaling proteins was assessed with Western blotting. Results： Carbocisteine （10, 100, 1000 pmol/L）, administered either before or after TNF-α exposure, dose-dependently suppressed TNF-α-induced inflammation in A549 cells, as evidenced by diminished release of IL-6 and IL-8, and diminished mRNA expression of IL-6, IL-8, TNF-α, MCP-1 and MIP-1β. Furthermore, pretreatment with carbocisteine significantly decreased TNF-α-induced phosphorylation of NF-κB p65 and ERK1/2 MAPK, and inhibited the nuclear translocation of p65 subunit in A549 cells. In an NF-κB luciferase reporter system, pretreatment with carbocisteine dose-dependently inhibited TNF-α-induced transcriptional activity of NF-κB. Conclusion： Carbocisteine effectively suppresses TNF-α-induced inflammation in A549 cells via suppressing NF-KB and ERK1/2 MAPK signaling pathways.

A series of random copolymers (PCLAs) were synthesized by ring-opening polymerization of D,L-lactide (LA) and ε-caprolactone (CL) with different molar ratios. PCLA based polyurethanes (PCLAUs) were obtained by chain-extending of PCLA and polytetramethylene ether (PTMEG) with hexamethylene diisocyanate (HDI). All the PCLAUs exhibit good shape memory properties with high shape fixity ratios above 98% and shape recovery ratios above 82% in the first cycle and 91% in the second cycle. PCLAUs with less CL content show faster recovery speed and PCLAUs with more CL content show higher shape recovery ratio. The trigger temperature can be tuned or controlled around body temperature by adjusting the molar ratio of LA to CL. The PCLAUs have potential applications in implant biomedical devices, especially for minimally invasive deployable devices.

Zhu Chen, Sai-Juan Chen, Wei-Li Zhao and colleagues identify recurrent loss-of-function mutations in the RNA helicase gene DDX3X in 20% of subjects with natural killer/T-cell lymphoma (NKTCL) in their study. The results suggest that DDX3X acts as a tumor suppressor and that its inactivation leads to poor clinical outcome. Natural killer/T-cell lymphoma (NKTCL) is a malignant proliferation of CD56 + and cytoCD3 + lymphocytes with aggressive clinical course, which is prevalent in Asian and South American populations 1 . The molecular pathogenesis of NKTCL has largely remained elusive. We identified somatic gene mutations in 25 people with NKTCL by whole-exome sequencing and confirmed them in an extended validation group of 80 people by targeted sequencing. Recurrent mutations were most frequently located in the RNA helicase gene DDX3X (21/105 subjects, 20.0%), tumor suppressors ( TP53 and MGA ), JAK-STAT-pathway molecules ( STAT3 and STAT5B ) and epigenetic modifiers ( MLL2 , ARID1A , EP300 and ASXL3 ). As compared to wild-type protein, DDX3X mutants exhibited decreased RNA-unwinding activity, loss of suppressive effects on cell-cycle progression in NK cells and transcriptional activation of NF-κB and MAPK pathways. Clinically, patients with DDX3X mutations presented a poor prognosis. Our work thus contributes to the understanding of the disease mechanism of NKTCL.

Zika virus (ZIKV) has emerged as a rising concern in global health in recent years. The role of PD-1/PD-L1 immune checkpoint in acute ZIKV infection remains to be understood. In this study we demonstrated the activation of PD-1/PD-L1 immune checkpoint by ZIKV. mRNA and protein expression of PD-L1 was boosted by ZIKV not only in SF268 and JEG3 cell lines but also in human dendritic cells. PD-1 expression was more abundant on CD8 + T cells in ZIKV-infected mice. Elevated PD-L1 expression was also observed in the brain, testis and spleen of ZIKV-infected A129 mice. Blocking PD-L1 effectively inhibited ZIKV infection, reducing viral loads in all tissues. In addition, anti-PD-L1 antibody treatment further increased virus-specific CD8 + T cells, KLRG + CD8 + T cells, and effector memory CD8 + T cells. PD-L1 blockade also induced interferon γ, granzyme B, and interleukin 2 expression in antigen-specific CD8 + T cells, consistent with activation of these cells. Mechanistically, the induction of PD-L1 expression might be ascribed to viral NS4B protein and its interaction with GRP78. Our findings suggest that targeting the PD-1/PD-L1 pathway could have antiviral effect against ZIKV.