The inflammatory immunity and gut microbiota are associated with fear response differences in laying hens.

The fear response is a crucial adaptive mechanism for coping with environmental changes, and the individuals have different levels of fearfulness. The purpose of this study was to determine the status of the immune response and gut health in hens with different fear responses. A total of 80 healthy 75-wk-old native Lindian chickens were individually housed in conventional cages and categorized into high (TH) and low (TL) levels of fearfulness using the tonic immobility (TI) test. The immunological status and intestinal health of the laying hens were assessed, and the intestinal microbial community was sequenced using 16S rRNA testing. The results showed that the immune-related genes of interleukin (IL)-1ß, IL-4, IL-6, and IgG were significantly upregulated in the spleen of TH hens compared with hens in the TL group (P < 0.01). The inflammatory immune-related genes Toll-like receptor (TLR)2, TLR4, nuclear factor (NF)-κB, inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2, IL-10, and IgG were significantly increased in the intestinal tract, whereas IL-4, IgA, and the intestinal barrier gene claudin-4 were significantly decreased in TH hens (P < 0.05). In addition, serum concentrations of IL-1ß, IL-6, IL-10, interferon (IFN)-α and IgG were significantly higher in TH hens (P < 0.01). A high fear response also led to changes in gut microbial diversity, with a higher Simpson's index and lower ß-diversity similarity than hens with a low-fear response (P < 0.05). The TH group showed an increase in 8 genera, including Bacillaceae and Coprococcus, whereas the genus Anaerorhabdus decreased (P < 0.05). The gut microbiota has also been associated with gut barrier genes, and inflammatory cytokines. Bartonella stimulates IL-1ß and IgG secretion, whereas Lactobacillus inhibits IL-6 secretion, and Coprococcus and Subdoligranulum are associated with the maintenance of intestinal barrier function. The results of this study suggest that laying hens with high fear response levels have a more sensitive immune response and a more enriched gut microbiota, which may have positive effects on adapting to a complex environment.

Involvement of Embryo-Derived and Monocyte-Derived Intestinal Macrophages in the Pathogenesis of Inflammatory Bowel Disease and Their Prospects as Therapeutic Targets.

Inflammatory bowel disease (IBD) is a group of intestinal inflammatory diseases characterized by chronic, recurrent, remitting, or progressive inflammation, which causes the disturbance of the homeostasis between immune cells, such as macrophages, epithelial cells, and microorganisms. Intestinal macrophages (IMs) are the largest population of macrophages in the body, and the abnormal function of IMs is an important cause of IBD. Most IMs come from the replenishment of blood monocytes, while a small part come from embryos and can self-renew. Stimulated by the intestinal inflammatory microenvironment, monocyte-derived IMs can interact with intestinal epithelial cells, intestinal fibroblasts, and intestinal flora, resulting in the increased differentiation of proinflammatory phenotypes and the decreased differentiation of anti-inflammatory phenotypes, releasing a large number of proinflammatory factors and aggravating intestinal inflammation. Based on this mechanism, inhibiting the secretion of IMs' proinflammatory factors and enhancing the differentiation of anti-inflammatory phenotypes can help alleviate intestinal inflammation and promote tissue repair. At present, the clinical medication of IBD mainly includes 5-aminosalicylic acids (5-ASAs), glucocorticoid, immunosuppressants, and TNF-α inhibitors. The general principle of treatment is to control acute attacks, alleviate the condition, reduce recurrence, and prevent complications. Most classical IBD therapies affecting IMs function in a variety of ways, such as inhibiting the inflammatory signaling pathways and inducing IM2-type macrophage differentiation. This review explores the current understanding of the involvement of IMs in the pathogenesis of IBD and their prospects as therapeutic targets.

Research progress of Bruton's tyrosine kinase (BTK) inhibitors in the treatment of inflammatory and immune-mediated diseases / 中国药科大学学报

@#Abstract: Bruton’s tyrosine kinase (BTK), a cytoplasmic tyrosine kinase, plays a central role in the activation of B cells and granulocytes, operating downstream of B cell and Fcγ receptors, and is considered an attractive target for treating autoimmune diseases. Preclinical investigations have demonstrated that inhibition of BTK activity holds promise as a potential therapeutic strategy for inflammatory immune responses such as autoimmune diseases and allergies. This review provides an overview of the mechanisms by which BTK contributes to immune-related diseases and summarizes current research on the development of BTK inhibitors for treating these conditions, aiming to offer novel insights into non-oncology applications for BTK inhibitors.

Effect of Dunhuang medical prescription Dabupi Decoction combined with oxaliplatin on inflammatory immunity of gastric cancer-bearing mice based on IL-17/NF-κB signaling pathway / 中国免疫学杂志

Objective:To study anti-tumor effect of Dunhuang medical prescription Dabupi Decoction on gastric cancer-bearing mice and effect of Dabupi Decoction combined with oxaliplatin on inflammatory immunity of gastric cancer-bearing mice based on IL-17/NF-κB signaling pathway.Methods:Mouse model of MFC gastric cancer subcutaneously bearing tumor was established and ran-domly divided into model group,oxaliplatin group,high,medium and low doses of Dabupi Decoction combined with oxaliplatin groups[21.58,10.79,5.40 g/(kg·d)],with 10 mice in each group,male and female cage rearing.Administration began after 8 days of inoculation and continued for 14 days;next day after the last administration,eyeball blood was taken,mice were killed,tumor tissues were taken and weighed,and tumor inhibition rate was calculated.ELISA was used to detect contents of IL-17 and IL-6 in mice serum,immunohistochemistry(IHC),RT-qPCR and Western blot were used to detect IL-17,IL-6,NF-κB and p-NF-κB mRNA and protein expressions in mice tumor tissues,respectively.Results:Tumor inhibition rates of oxaliplatin group,high,medium and low doses of Dabupi decoction combined with oxaliplatin groups were 33.02%,52.92%,46.33%and 39.52%,respectively,and tumor quality of each treatment group was significantly lower than that of model group(P<0.01).High,medium and low doses of Dabupi Decoction combined with oxaliplatin groups were higher than that of oxaliplatin group.Compared with model group,contents of IL-17 and IL-6 in serum and expressions of IL-17,IL-6,NF-κB p65 and pNF-κB p65 mRNA and protein in tumor tissues in each treatment group were significantly reduced(P<0.01,P<0.05).Compared with oxaliplatin group,levels of IL-17 and IL-6 in serum and expres-sions of IL-17,IL-6,NF-κB p65 and pNF-κB p65 mRNA and protein in tumor tissues in high and medium doses of Dabupi Decoction combined with oxaliplatin groups were significantly reduced(P<0.01,P<0.05).Conclusion:Dunhuang medical prescription Dabupi Decoction has a certain anti-tumor effect on MFC gastric cancer-bearing mice,which can regulate inflammatory immunity and inhibit occurrence and development of gastric cancer by inhibiting IL-17/NF-κB signaling pathway.

Potential mechanistic roles of Interleukin-33 in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune disease that occurs mainly in synovial joints, causing synovial inflammation and joint injury. If diagnosed and treated in time, the disease can be well controlled. However, in clinical practice, patients often fail to get timely and effective treatment due to misdiagnosis, missed diagnosis, and other reasons, resulting in deterioration of the condition and poor prognosis, seriously affecting the patient's quality of life. So far, the pathogenesis of RA is still unclear. In recent years, it has been found that the imbalance of cytokines plays a vital role in the occurrence and development of RA. Most RA-related cytokines are produced by immune cells, which bind to the specific receptors of effector cells through paracrine and autocrine pathways. The effect of cytokines on inflammation can be divided into pro-inflammatory and anti-inflammatory factors. When the impact of pro-inflammatory factors is more significant than anti-inflammatory factors, the condition of RA will be aggravated, resulting in more inflammatory severe reactions and immune disorders. Interleukin-33 (IL-33) is a new member of the interleukin-1(IL-1) family, and its receptor is suppression of tumorigenicity 2 (ST2). IL-33 plays a vital role in immune diseases such as RA by promoting a series of biochemical reactions in macrophages, mast cells, granulocytes, and other cells. This article aims to summarize the research progress of IL-33 in the pathogenesis of RA in recent years, discuss its role in the pathogenesis of RA, and provide new ideas for the prevention and treatment of RA in the future.

Huanglian Jiedutang Regulates Inflammatory Immunity to Relieve Rheumatoid Arthritis / 中国实验方剂学杂志

ObjectiveTo observe the effects of Huanglian Jiedutang on pathological and immune damage in collagen-induced arthritis （CIA） model mice， and to explore the possible mechanism of Huanglian Jiedutang in relieving rheumatoid arthritis. MethodTwenty-four DBA/1 mice were randomly divided into normal group， model group， methotrexate group and Huanglian Jiedutang group， with six mice in each group. The CIA mice model were established using type Ⅱ collagen induction. The administration groups were respectively treated with Huanglian Jiedutang （5 g·kg-1） and methotrexate （0.5 mg·kg-1）. The joint swelling symptoms of the mice were observed， and the arthritis index was scored every 3 days. Flow cytometry was employed to detect granulocytes， monocytes， and T lymphocytes in peripheral blood. The expression of inflammatory cytokines in joint was determined by real-time polymerase chain reaction （Real-time PCR）. The ankle joint was scanned by micro-computed tomography （Micro-CT）， and the histopathological changes were observed through hematoxylin-eosin （HE） staining. ResultCompared with the normal group， the modeling led to joint swelling， elevated the joint index score （P<0.05）， increased the proportion of granulocytes （P<0.05） and decreased that of monocytes and T lymphocytes （P<0.01） in peripheral blood， and raised the neutrophil-to-lymphocyte ratio （NLR） （P<0.01）. Further， it up-regulated the expression of inflammatory cytokines such as tumor necrosis factor-α （TNF-α）， interleukin （IL）-1β， and IL-6 in joint （P<0.01）. Micro-CT showed obvious bone destruction in the ankle joint， and pathological examination revealed the infiltration of a large number of inflammatory cells and the synovial hyperplasia of joint tissue. Compared with the model group， Huanglian Jiedutang alleviated the symptoms of joint swelling， lowered the score of arthritis index （P<0.05）， increased the proportion of T lymphocytes and lowered NLR （P<0.01）. Moreover， it down-regulated the expression levels of TNF-α， IL-1β， and IL-6 in joint （P<0.01） and alleviated the bone destruction and pathological injury of joint tissue. ConclusionType Ⅱ collagen caused systemic and local inflammatory immune damage in CIA mice. Huanglian Jiedutang alleviates such injury， especially for that in local joint， thereby inhibiting joint injury and bone destruction in CIA mice.

The m6A epitranscriptome opens a new charter in immune system logic.

N6-methyladenosine (m6A), the most prevalent RNA internal modification, is present in most eukaryotic species and prokaryotes. Studies have highlighted an intricate network architecture by which m6A epitranscriptome impacts on immune response and function. However, it was only until recently that the mechanisms underlying the involvement of m6A modification in immune system were uncovered. Here, we systematically review the m6A involvement in the regulation of innate and adaptive immune cells. Further, the interplay between m6A modification and anti-inflammatory, anti-viral and anti-tumour immunity is also comprehensively summarized. Finally, we focus on the future prospects of m6A modification in immune modulation. A better understanding of the crosstalk between m6A modification and immune system is of great significance to reveal new pathogenic pathways and to develop promising therapeutic targets of diseases.

Effect of Celastrol on Neuropathic Pain Model Mice / 中国实验方剂学杂志

Objective:To investigate the effect of celastrol on painful and the emotional of anxiety and depression comorbidity on neuropathic pain model animal and to explore its possible mechanism．Method:Mice were randomly divided into sham group， model group， pregabalin group(25 mg·kg-1)， low， medium and high-dose celastrol groups (5，10，20 mg·kg-1). The mice model of neuropathic pain were established by the L5 spinal nerve ligation (SNL). After successful modeling， the treatment groups were given intragastric administration， the sham group and the model group were given the same volume of warm water.Mechanical pain were detected by Von Frey tests， anxiety and depression behaviors were separately detected by the open field and the tail tailing experiments， the pathological changes of microglial cells in hippocampus of mice in each group were observed by immunohistochemical staining (IHC). The inflammation of BV2 microglial cell made by 1 mg·L-1 lipopolysaccharide (LPS). Real-time quantitative polymerase chain reaction （Real-time PCR） was used to detect the mRNA expression levels of tumor necrosis factor-α (TNF-α). The expression levels of TNF-α protein were detected by immunofluorescence（IF） staining.Result:Compared with sham group， significant change of mechanical pain thresholds， anxiety and depression were detected in the SNL mice (P<0.05，P<0.01)， the significant decreases of the body size of hippocampal microglia (P<0.05). Compared with SNL model group， 20 mg·kg-1 celastrol significantly increased the 50% paw withdraw threshold and the time of the open feld tests (P<0.05，P<0.01)，and decreased the time of the tail tailing experiments in the SNL mice (P<0.05)， and the cell body area of hippocampal microglia in SNL mice was reduced (P<0.05). Experiment in vitro show， compared with control group， the expression of TNF-α mRNA and protein expression in LPS-induced BV2 microglia increased significantly from 2-4 h (P<0.05，P<0.01). Compared with the LPS group， after 100 nmol·L-1 celastrol administration， LPS-induced microglia inflammatory factor TNF-α mRNA and TNF-α protein expression were significantly decreased (P<0.01).Conclusion:Celastrol can relieve pain-emotion comorbidity on neuropathic pain model mice， and its mechanism may be related to the anti-inflammation in the central nerves system.

Immunomodulatory effects of intestinal lung axis microecology and other factors on the prognosis of advanced non-small cell lung cancer.

Overall survival (OS) of lung cancer varies greatly with individual patients in the global setting. Multiple factors may affect the prognosis. Different antibiotics have significant effects on the prognosis of lung cancer patients. The intestinal microbiome, nutritional status and inflammatory factors all have significant impact on OS of lung cancer patients.

Buyang Huanwu Decoction ameliorates ischemic stroke by modulating multiple targets with multiple components: In vitro evidences.

Buyang Huanwu Decoction (BYHWD) is a well-known traditional Chinese medicine prescription which is used to treat ischaemic stroke and stroke-induced disabilities. However, the exact mechanism underlying BYHWD's amelioration of ischaemic stroke and its effective constituents remain unclear. The present study aimed to identify the effective constituents of BYHWD and to further explore its action mechanisms in the amelioration of ischaemic stroke by testing the activities of 15 absorbable chemical constituents of BYHWD with the same methods under the same conditions. The following actions of these 15 compounds were revealed: 1) Ferulic acid, calycosin, formononetin, astrapterocarpan-3-O-ß-D-glucoside, paeonol, calycosin-7-O-ß-D-glucoside, astraisoflavan-7-O-ß-D-glucoside, ligustrazine, and propyl gallate significantly suppressed concanavalin A (Con A)-induced T lymphocyte proliferation; 2) Propyl gallate, calycosin-7-O-ß-D-glucoside, paeonol, and ferulic acid markedly inhibited LPS-induced apoptosis in RAW264.7 cells; 3) Propyl gallate and formononetin significantly inhibited LPS-induced NO release; 4) Hydroxysafflor yellow A and inosine protected PC12 cells against the injuries caused by glutamate; and 5) Formononetin, astragaloside IV, astraisoflavan-7-O-ß-D-glucoside, inosine, paeoniflorin, ononin, paeonol, propyl gallate, ligustrazine, and ferulic acid significantly suppressed the constriction of the thoracic aorta induced by KCl in rats. In conclusion, the results from the present study suggest that BYHWD exerts its ischaemic stroke ameliorating activities by modulating multiple targets with multiple components.

Buyang Huanwu Decoction ameliorates ischemic stroke by modulating multiple targets with multiple components: In vitro evidences / 中国天然药物

Buyang Huanwu Decoction (BYHWD) is a well-known traditional Chinese medicine prescription which is used to treat ischaemic stroke and stroke-induced disabilities. However, the exact mechanism underlying BYHWD's amelioration of ischaemic stroke and its effective constituents remain unclear. The present study aimed to identify the effective constituents of BYHWD and to further explore its action mechanisms in the amelioration of ischaemic stroke by testing the activities of 15 absorbable chemical constituents of BYHWD with the same methods under the same conditions. The following actions of these 15 compounds were revealed: 1) Ferulic acid, calycosin, formononetin, astrapterocarpan-3-O-β-D-glucoside, paeonol, calycosin-7-O-β-D-glucoside, astraisoflavan-7-O-β-D-glucoside, ligustrazine, and propyl gallate significantly suppressed concanavalin A (Con A)-induced T lymphocyte proliferation; 2) Propyl gallate, calycosin-7-O-β-D-glucoside, paeonol, and ferulic acid markedly inhibited LPS-induced apoptosis in RAW264.7 cells; 3) Propyl gallate and formononetin significantly inhibited LPS-induced NO release; 4) Hydroxysafflor yellow A and inosine protected PC12 cells against the injuries caused by glutamate; and 5) Formononetin, astragaloside IV, astraisoflavan-7-O-β-D-glucoside, inosine, paeoniflorin, ononin, paeonol, propyl gallate, ligustrazine, and ferulic acid significantly suppressed the constriction of the thoracic aorta induced by KCl in rats. In conclusion, the results from the present study suggest that BYHWD exerts its ischaemic stroke ameliorating activities by modulating multiple targets with multiple components.

Quantitative proteomic reveals the differences of peripheral blood mononuclear cells in the host immune response to sepsis / 中华急诊医学杂志

Objective To investigate the feasibility of differential expression proteins identification in peripheral blood mononuclear cells (PBMCs) of sepsis patients using Data Independent Acquisition liquid chromatography-mass spectrometry (DIA LC-MS). Methods Prospective studies were employed and targeted at 10 sepsis patients admitted to the Intensive Care Unit (ICU) of Shanghai Fifth People's Hospital Affiliated to Fudan University from April 2016 to July 2016. And 10 patients admitted to the ICU with similar age and sex that were not complicated with sepsis were served as the control group.The proteins from peripheral blood mononuclear cells in 10 sepsis patients and 10 control persons were analyzed using the latest DIA LC-MS technology and the skyline data extraction software; the model of data obtained from the above analysis was further discriminatorily analyzed with principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA) and orthogonal partial least squares discriminant analysis (OPLS-DA); then the differential proteins of peripheral blood mononuclear cells were analyzed by Pathway analysis and GO analysis. The possible markers were identified by preliminary screening according to variable importance in the projection (VIP). The top 3 proteins (VIP > 1, P< 0.05) were verified by ELISA and their ROC curves were analyzed. Results Totally 1062 fragment ions were identified and 119 proteins were obtained. Among them, 31 proteins were up-regulated and 88 proteins down-regulated. Pathway analysis showed that carbon metabolism, platelet activation, bacterial invasion of epithelium, and complement coagulation cascade activation were participated in the development of sepsis. ELISA showed that significant difference of HMGB-1, MMP-8, and LCN2 in the expression of peripheral blood mononuclear cells in the sepsis and control people (P<0.01). The area under the ROC curve is greater than 0.85, which has good sensitivity and specificity. Conclusions DIA-MS is a compelling way for detecting differential expression proteins. PCA, PLSDA and OPLSDA are suitable for pattern recognition. The high expression of HMGB-1, NGAL and MMP-8 in immune cells may be the potential biomarker of the disease, which lays the foundation for research of early diagnosis and treatment of sepsis.

Buyang Huanwu Decoction ameliorates ischemic stroke by modulating multiple targets with multiple components: In vitro evidences / 中国天然药物

Buyang Huanwu Decoction (BYHWD) is a well-known traditional Chinese medicine prescription which is used to treat ischaemic stroke and stroke-induced disabilities. However, the exact mechanism underlying BYHWD's amelioration of ischaemic stroke and its effective constituents remain unclear. The present study aimed to identify the effective constituents of BYHWD and to further explore its action mechanisms in the amelioration of ischaemic stroke by testing the activities of 15 absorbable chemical constituents of BYHWD with the same methods under the same conditions. The following actions of these 15 compounds were revealed: 1) Ferulic acid, calycosin, formononetin, astrapterocarpan-3-O-β-D-glucoside, paeonol, calycosin-7-O-β-D-glucoside, astraisoflavan-7-O-β-D-glucoside, ligustrazine, and propyl gallate significantly suppressed concanavalin A (Con A)-induced T lymphocyte proliferation; 2) Propyl gallate, calycosin-7-O-β-D-glucoside, paeonol, and ferulic acid markedly inhibited LPS-induced apoptosis in RAW264.7 cells; 3) Propyl gallate and formononetin significantly inhibited LPS-induced NO release; 4) Hydroxysafflor yellow A and inosine protected PC12 cells against the injuries caused by glutamate; and 5) Formononetin, astragaloside IV, astraisoflavan-7-O-β-D-glucoside, inosine, paeoniflorin, ononin, paeonol, propyl gallate, ligustrazine, and ferulic acid significantly suppressed the constriction of the thoracic aorta induced by KCl in rats. In conclusion, the results from the present study suggest that BYHWD exerts its ischaemic stroke ameliorating activities by modulating multiple targets with multiple components.

The emerging role of interleukin-37 in cardiovascular diseases.

INTRODUCTION: Interleukin (IL)-37 is a newly identified member of the IL-1 family, and shows a growing role in a variety of diseases. This review aims at summarizing and discussing the role of IL-37 in cardiovascular diseases. METHODS: Data for this review were identified by searches of MEDLINE, Embase, and PubMed using appropriate search terms. RESULTS: IL-37 is a newly identified cytokine belonging to the IL-1 family and is expressed in inflammatory immune cells and several parenchymal cells. It has potent anti-inflammatory and immunosuppressive properties, with two mechanisms underlying this function. IL-37 is produced as a precursor and then cleaved into mature form in the cytoplasm by caspase-1, translocating to nucleus and suppressing the transcription of several pro-inflammatory genes by binding SMAD-3. Besides, IL-37 can be secreted extracellularly, and binds to IL-18Ra chain and recruits Toll/IL-1R (TIR)-8 for transducing anti-inflammatory signaling. IL-37 is upregulated in an inducible manner and negatively regulates signaling mediated by TLR agonists and pro-inflammatory cytokines. The cytokine has been shown to inhibit both innate and adaptive immunological responses, exert antitumor effects, and act as a prognostic marker in a variety of autoimmune diseases. CONCLUSIONS: Recent studies have suggested that IL-37 plays a role in cardiovascular diseases. In this review, we provide an overview of the cytokine biology, discuss recent advances made in unraveling its cardio-protective effects, and suggest guidelines for future research.