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心力衰竭（简称心衰）是一种复杂的临床综合征,任何心室结构或功能受损所导致的充盈障碍或射血障碍均可引起心力衰竭。发达国家成年人群心力衰竭患病率达到1%~2%,而70岁以上的老年人群患病率升高到≥10%。随着人口的老龄化以及冠心病患病率的增加,心力衰竭患病率有上升趋势,并且已经成为人类致残、致死的重要疾病。心衰受到体内各种神经体液因素的调节,中枢神经激素如：肾素-血管紧张素系统（renin-angiotensin system,RAS）、炎性细胞因子（proinflammatory cytokines,PIC）、活性氧簇（reactive oxygen species,ROS）等的改变可能与心衰中枢活动增强密切相关,并可以明显改变外周交感神经的活动。持续的交感神经活动增强是心衰发生发展的重要原因,因此降低交感神经兴奋性成为心衰治疗研究的焦点之一。本文着重论述中枢神经激素对心衰的影响和可能的中枢调控机制。

摘要：高血压是我国人群脑卒中及冠心病发病的首位危险因素，严重危害人群健康。目前，我国高血压患者已超过2．7亿，并以每年l000万人的速度递增，如何提高对高血压的预防和治疗水平已成为迫切需要解决的重大医学和社会问题。以往对于高血压的研究主要集中于外周。近来研究表明，中枢调控在高血压的发生发展中具有重要作用。其中下丘脑室旁核（hypothalamicparaventricularnucleus，PVN）在维持心血管活动中起着关键作用，可直接支配交感神经节前神经元，参与外周交感神经活动的调节，并与高血压的发生发展密切相关。近年来研究表明，室旁核中炎性细胞因子（proinflammatorycytokines，PIC）、活性氧簇（reactiveoxygenspecies，R0s）、肾素血管紧张素系统（renin-angiotensinsystem，RAs）、神经递质（neurotransmitter，NT）及核因子KB（nuclearfactorKB，NF-~B）等神经激素参与高血压的病理生理过程，但室旁核中这些神经激素如何激活、相互间的作用以及对高血压的调控机制尚不清楚。因此，探明下丘脑室旁核神经激素兴奋对高血压的影响是本课题的研究重点。本研究将为高血压的中枢机制研究补充新内容。

Mesenchymal stem cells （MSCs） have great potential for treating various diseases, especially those related to tissue damage involving immune reactions. Various studies have demonstrated that MSCs are strongly immunosuppressive in vitro and in vivo. Our recent studies have shown that un-stimulated MSCs are indeed incapable of immunosuppression; they become potently immunosuppressive upon stimulation with the supernatant of activated lymphocytes, or with combinations of IFN-γ, with TNF-α, IL-1α or IL-1β. This observation revealed that under certain circumstances, inflammatory cytokines can actually become immunosuppressive. We showed that there is a species variation in the mechanisms of MSC-mediated immunosuppression： immunosuppression by cytokine-primed mouse MSCs is mediated by nitric oxide （NO）, whereas immunosuppression by cytokine-primed human MSCs is executed through indoleamine 2, 3-dioxygenase （IDO）. Additionally, upon stimulation with the inflammatory cytokines, both mouse and human MSCs secrete several leukocyte chemokines that apparently serve to attract immune cells into the proximity with MSCs, where NO or IDO is predicted to be most active. Therefore, immunosuppression by inflammatory cytokine-stimulated MSCs occurs via the concerted action of chemokines and immune-inhibitory NO or IDO produced by MSCs. Thus, our results provide novel information about the mechanisms of MSC-mediated immunosuppression and for better application of MSCs in treating tissue injuries induced by immune responses.

This chapter explores the possibility that capacitation and apoptosis are linked processes joined by their common dependence on the continued generation of reactive oxygen species （ROS）. According to this model capacitation is initiated in spematozoa following their release into the female reproductive tract as a consequence of intracellular ROS generation, which stimulates intracellular cAMP generation, inhibits tyrosine phosphatase activity and enhances the formation of oxysterols prior to their removal from the sperm surface by albumin. The continued generation of ROS by capacitating populations of spermatozoa eventually overwhelms the limited capacity of these cells to protect themselves from oxidative stress. As a result the over-capacitation of spermatozoa leads to a state of senescence and the activation of a truncated intrinsic apoptotic cascade characterized by enhanced mitochondrial RO$ generation, lipid peroxidation, motility loss, caspase activation and phosphatidylserine externalization. The latter may be particularly important in instructing phagocytic leukocytes that the removal of senescent, moribund spermatozoa should be a silent process unaccompanied by the generation of proinflammatory cytokines. These observations reveal the central role played by redox chemistry in defining the life and death of spermatozoa. A knowledge of these mechanisms may help us to engineer novel solutions to both support and preserve the functionality of these highly specialized cells.

The immunoresponsive gene 1 （IRG 1） protein has crucial functions in embryonic implantation and neurodegeneration. IRG1 promotes endotoxin tolerance by increasing A20 expression in macrophages through reactive oxygen species （ROS）. The cytoprotective protein heme oxygenase-1 （HO-1）, which generates endogenous carbon monoxide （CO）, is expressed in the lung during Lipopolysaccharide （LPS） tolerance and cross tolerance. However, the detailed molecular mechanisms and functional links between IRG1 and HO-1 in the innate immune system remain unknown. In the present study, we found that the CO releasing molecule-2 （CORM-2） and chemical inducers of HO- 1 increased I RG 1 expression in a time- and dose-dependent fashion in RAW264.7 cells. Furthermore, inhibition of HO-1 activity by zinc protoporphyrin IX （ZnPP） and HO-1 siRNA significantly reduced expression of IRG1 under these conditions. In addition, treatment with CO and HO-1 induction significantly increased A20 expression, which was reversed by ZnPP and HO-1 siRNA. LPS-stimulated TNF-a was significantly decreased, whereas IRG1 and A20 were increased by CORM-2 application and HO-1 induction, which in turn were abrogated by ZnPP. Interestingly, siRNA against IRG1 and A20 reversed the effects of CO and HO-1 on LPS-stimulated TNF-a production. Additionally, CO and HO-1 inducers significantly increased IRG1 and A20 expression and downregulated TNF-a production in a LPS-stimulated sepsis mice model. Furthermore, the effects of CO and HO-1 on TNF-α production were significantly reversed when ZnPP was administered. In conclusion, CO and HO-1 induction regulates IRG1 and A20 expression, leading to inhibition of inflammation in vitroand in an in vivomice model.

Decidual natural killer （dNK） cells actively participate in the establishment and maintenance of maternal-fetal immune tolerance and act as local guardians against infection. However, how dNK cells maintain the immune balance between tolerance and anti-infection immune responses during pregnancy remains unknown. Here, we demonstrated that the inhibitory molecule T-cell immunoglobulin domain and mucin domain-containing molecule-3 （Tim-3） are expressed on over 60% of dNK cells. Tim-3^＋ dNK cells display higher interleukin （IL）-4 and lower tumor necrosis factor （TNF）-α and perforin production. Human trophoblast cells can induce the transformation of peripheral NK cells into a dNK-like phenotype via the secretion of galectin-9 （Gal-9） and the interaction between Gal-9 and Tim-3. In addition, trophoblasts inhibit lipopolysaccharide （LPS）-induced pro-inflammatory cytokine and perforin production by dNK cells, which can be attenuated by Tim-3 neutralizing antibodies. Interestingly, a decreased percentage of Tim-3-expressing dNK cells were observed in human miscarriages and murine abortion-prone models. Moreover, T helper （Th）2-type cytokines were decreased and Thl-type cytokines were increased in Tim-3^＋ but not Tim-3- dNK cells from human and mouse miscarriages. Therefore, our results suggest that the Gal-9/Tim-3 signal is important for the regulation of dNK cell function, which is beneficial for the maintenance of a normal pregnancy.

Type I interferon （IFN） is an important component of antiviral innate immune signaling mediated by viral DNA and RNA recognition by the DNA sensor cGAS and RNA sensors RIG-I and MDA5. Activation of these DNA and RNA sensors leads to the recruitment of STING and MAVS, respectively, and converges on TANK-binding kinase 1 （TBK1） signaling for subsequent phosphorylation of IFN regulatory factor 3 （IRF3）. However, the mechanisms that control TBK1 activation are still poorly defined. Here, we identify tripartite motif 9 short isoform （TRIM9s） as a pos- itive regulator in type I IFN signaling. Upon viral infection, TRIM9s undergoes Lys-63-Unked auto-polyubiqultina- tion and serves as a platform to bridge GSK3β to TBK1, leading to the activation of IRF3 signaling. Interestingly, we found that TRIM9s selectively inhibits the production of pro-inflammatory cytokines, but enhances the expression of type ! IFNs as well as IFN-stimulated genes, in response to viral infection. Our findings reveal novel dual functions of TRIM9s in antiviral immunity, which serve to balance pro-inflammatory response and production of type I IFNs.

Chemerin is present in various inflammatory sites and is closely involved in tissue inflammation. Recent studies have demonstrated that chemerin treatment can cause either anti-inflammatory or pro-inflammatory effects according to the disease model being investigated. Elevated circulating chemerin was recently found in patients with inflammatory bowel disease （IBD）; however, the role of chemerin in intestinal inflammation remains unknown. In this study, we demonstrated that the administration of exogenous chemerin （aa 17-156） aggravated the severity of dextran sulfate sodium （DSS）-induced colitis, which was characterized by higher clinical scores, extensive mucosal damage and significantly increased local and systemic production of pro-inflammatory cytokines, including IL-6, TNF-a and interferon （IFN-7）. Interestingly, chemerin did not appear to influence the magnitudes of inflammatory infiltrates in the colons, but did result in significantly decreased colonic expression of M2 macrophage-associated genes, including Arginase 1 （Arg-1）, Yml, FIZZ1 and IL-IO, following DSS exposure, suggesting an impaired M2 macrophage skewing in vivo. Furthermore, an in vitro experiment showed that the addition of chemerin directly suppressed M2 macrophage-associated gene expression and STAT6 phosphorylation in IL-4-stimulated macrophages. Significantly elevated chemerin levels were found in colons from DSS-exposed mice and from ulcerative colitis （UC） patients and appeared to positively correlate with disease severity. Moreover, the in vivo administration of neutralizing anti-chemerin antibody significantly improved intestinal inflammation following DSS exposure. Taken together, our findings reveal a pro-inflammatory role for chemerin in DSS-induced colitis and the ability of chemerin to suppress the anti-inflammatory M2 macrophage response. Our study also suggests that upregulated chemerin in inflamed colons may contribute to the pathogenesis of IBD.

Background Diabetes mellitus was a chronic low‐grade inflammatory disease and had increased circulating inflammatory cytokines and acute phase proteins. We aimed to identify the changes of inflammatory cytokines in newly diagnosed type 2 diabetic patients after short‐term intensive insulin therapy using continuous subcutaneous insulin infusion (CSII). Methods Thirty‐three newly diagnosed type 2 diabetic patients were enrolled between September 2020 to December 2020. Expression of 40 inflammatory cytokines of the patients were tested with RayBiotech antibody array before and after 1 week of intensive insulin therapy of CSII. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was carried out to explore the signaling pathway involved in the therapy. Results Five inflammatory cytokines were downregulated significantly after 1 week of CSII therapy. They were interleukin‐6 receptor (IL‐6R), regulated upon activation normal T‐cell expressed and secreted (RANTES), intercellular adhesion molecule‐1 (ICAM‐1), tissue inhibitor of metalloproteinase‐1 (TIMP‐1), and platelet‐derived growth factor type BB (PDGF‐BB) (p < 0.05 and foldchange <0.83). Among patients with baseline glycated hemoglobin (HbA1c) < 10%, three proinflammatory cytokines were decreased significantly after therapy: IL‐6R, RANTES, and ICAM‐1. As for the patients with baseline HbA1c ≥ 10%, eight inflammatory cytokines were inhibited significantly after the treatment, including ICAM‐1, IL‐6R, RANTES, TIMP‐1, TIMP‐2, macrophage inflammatory protein‐1 beta (MIP‐1β), PDGF‐BB, and tumor necrosis factor receptor type II (TNF RII). No matter which subgroup of baseline HbA1c level was considered, the decreased cytokines after CSII therapy were significantly involved in TNF signaling pathway. Nuclear factor‐kappa B (NF‐κB) signaling pathway was mainly enriched in patients with baseline HbA1c ≥ 10%. Conclusions A panel of 40 inflammatory cytokines, measured by protein microarray, were evaluated for 1 week of CSII treatment in newly diagnosed type 2 diabetic patients. After treatment, many proinflammatory cytokines decreased. In the higher baseline HbA1c subgroup, more proinflammatory cytokines improved. No matter which subgroup of HbA1c level was considered, IL‐6R, RANTES, and ICAM‐1, which were involved in TNF signaling pathway, decreased significantly after CSII therapy. This was the first report showing that the cytokines of IL‐6R, TIMP‐2, PDGF‐BB, and TNF RII decreased after the CSII therapy. 摘要 背景 糖尿病是一种慢性低度炎症性疾病，循环中炎性细胞因子和急性期蛋白增多。我们旨在确定新诊断的2型糖尿病患者在使用持续皮下胰岛素输注(CSII)进行短期强化胰岛素治疗后炎性细胞因子的变化。 方法 纳入2020年9月至2020年12月新诊断的33例2型糖尿病患者。采用RayBiotech抗体阵列检测CSII强化胰岛素治疗1周前后患者40种炎性细胞因子的表达。并通过KEGG富集分析，以探索参与治疗的相关信号通路。 结果 CSII治疗1周后，5种炎性细胞因子表达明显下调。分别是IL‐6R, RANTES, ICAM‐1, TIMP‐1, PDGF‐BB(P<0.05，FoldChange<0.83)。治疗前HbA1c<10%的患者中，IL‐6R, RANTES, ICAM‐1三种促炎细胞因子治疗后均明显降低。基础糖化血红蛋白(HbA1c)≥10%的患者治疗后8种炎性细胞因子(ICAM‐1, IL‐6R, RANTES, TIMP‐1, TIMP‐2, 巨噬细胞炎性蛋白‐1β(MIP‐1β), PDGF‐BB以及肿瘤坏死因子受体II型(TNF‐RII))均受到明显抑制。无论基础HbA1c水平处于哪个亚组，CSII治疗后细胞因子的降低都与TNF信号通路密切相关。NF‐κB信号通路主要富集于基线HbA1c≥10%的患者。 结论 通过蛋白质芯片检测40种炎性细胞因子，对新诊断的2型糖尿病患者进行了为期一周的CSII治疗评估。治疗后，许多促炎细胞因子降低。在基线较高的HbA1c亚组中，有更多的促炎细胞因子改善。无论HbA1c水平处于哪个亚组，CSII治疗后参与TNF信号传导途径的IL‐6R, RANTES和ICAM‐1均显著降低。本研究首次报道了CSII治疗后IL‐6R, TIMP‐2, PDGF‐BB和TNF‐RII等细胞因子的降低。 Highlights Many proinflammatory cytokines could be decreased after 1 week of intensive insulin therapy using continuous subcutaneous insulin infusion (CSII). This was the first report showing that the cytokines of interleukin‐6 receptor (IL‐6R), tissue inhibitor of metalloproteinase‐2 (TIMP‐2), platelet‐derived growth factor type BB (PDGF‐BB), and tumor necrosis factor receptor type II (TNF RII) decreased after the CSII therapy. The circulating levels of IL‐6R, regulated upon activation normal T‐cell expressed and secreted (RANTES), and intercellular adhesion molecule‐1 (ICAM‐1) were decreased after 1 week of intensive insulin therapy using CSII no matter which subgroup of glycated hemoglobin was considered.

Background：Pyroptosis is the term for caspase-l-dependent cell death associated with pro-inflammatory cytokines.The role of alveolar macrophage （AM） pyroptosis in the pathogenesis of the acute lung injury and acute respiratory distress syndrome （ALI/ARDS） remains unclear.Methods：C57BL/6 wild-type mice were assigned to sham,lipopolysaccharide （LPS） ＋ vehicle,LPS ＋ acetyl-tyrosyl-valyl-alanyl-aspartyl-chloromethylketone （Ac-YVAD-CMK） and LPS ＋ Z-Asp-Glu-Val-Asp-fluoromethylketone groups.Mice were given intraperitoneal （IP） injections of LPS.Drugs were IP injected 1 h before LPS administration.Mice were sacrificed 16 h after LPS administration,and AMs were isolated.Western blot analysis for active caspase-1 and cleaved caspase-3,evaluation of lung injury and a cytokine release analysis were performed.AMs were treated with LPS and adenosine triphosphate （ATP）;caspase-l-dependent cell death was evaluated using flow cytometry;the apoptosis-associated speck-like protein containing a caspase recruitment domain （ASC） pyroptosomes were examined by immunofluorescence.Results：The expression of activated caspase-1 in AMs was enhanced following LPS challenge compared with the sham group.In the ex vivo study,the caspase-1/propidium iodide-positive cells,caspase-1 specks and ASC pyroptosomes were up-regulated in AMs following LPS/ATP stimulation.The specific caspase-1 inhibitor Ac-YVAD-CMK inhibited the activation of caspase-1 and pyroptotic cell death.Ac-YVAD-CMK also reduced the lung injury,pulmonary edema and total protein in bronchoalveolar lavage fluid （BALF）.In addition,Ac-YVAD-CMK significantly inhibited interleukin-β （IL-lβ） release both in serum and BALF and reduced the levels of IL-18,tumor necrosis factor-α （TNF-α）,High Mobility Group Box 1 （HMGB1） in BALF during LPS-induced ALI/ARDS.Conclusions：This study reported AM pyroptosis during LPS-induced ALI/ARDS in mice and has demonstrated that Ac-YVAD-CMK can prevent AM-induced pyroptosis and lung injury.These preliminary findings may form the basis for further studies to evaluate this pathway as a target for prevention or reduction of ALI/ARDS.