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关键词： Agmatine   AhR   Anti-inflammation   Intestinal injury   Sepsis  

摘要： BACKGROUND:Sepsis-related intestinal injury is essential in multi-organ dysfunction induced by the systemic inflammatory response. Agmatine (AGM) has anti-inflammatory, antioxidative, and immunomodulatory properties. However, no reports of AGM alleviating sepsis-related intestinal injury have been found. Therefore, this study intends to investigate the protective effects of AGM on sepsis-related intestinal injury and its potential mechanism. METHODS:We first established a sepsis model by lipopolysaccharide (LPS) or cecum ligation perforation (CLP), and then used H&E staining, transmission electron microscopy (TEM), and TUNEL to examine the pathological changes in rat intestines after AGM treatment. ELISA was used to detect expression levels of inflammatory factors in ileal tissues and biochemical indexes of infectionin in serum. TNF-α induced Caco-2 cell inflammation model was established in vitro, and cell activity and proliferative capacity were detected by CCK8 and EdU after AGM treatment. The Caco-2 cell inflammation model with high or low expression of Aryl hydrocarbon receptor (AhR) was established, and whether AGM exerts anti-inflammatory effects via AhR/STAT3/IL-10 pathway was investigated using molecular docking, Co-IP, and Western Blot. RESULTS:The histopathological staining demonstrated that AGM significantly reduced intestinal injury and the content of inflammatory factors IL-1β, IL-6, and TNF-α, improved systemic infection and the survival rate of septic mice, and restored intestinal barrier function in CLP rats. In vitro, AGM improved cell viability and proliferative capacity of the Caco-2 cell inflammation model. AGM inhibits inflammatory factor expression by activating AhR, decreasing HIF-1 protein expression, and activating the STAT3/IL-10 signaling pathway. DISCUSSION AND CONCLUSION:AGM has the potential to ameliorate sepsis-related intestinal injury via the AhR-STAT3-IL-10 pathway, thereby offering theoretical basis for clinical treatment of sepsi

关键词： Allergic Contact Dermatitis   Biglycan   CD4(+)T cell   ECM   Fibroblastic Reticular Cells   Lumican   Lymph Node  

摘要： Allergic contact dermatitis (ACD) is a delayed-type IV hypersensitivity response driven by innate and adaptive immune cells. While specific immune regulations of these cell types are amply elucidated, their regulations by extracellular matrix (ECM) components and T cell mediated adaptive immunity in ACD remains unclear. Lumican and biglycan are ECM proteoglycans abundant in the dermis and lymph node, known to regulate innate immune myeloid cells, but have not been investigated in lymphoid cell regulations in ACD. By immunohistology we localized lumican and biglycan in skin biopsies of psoriatic patients. Using wild type (WT), lumican and biglycan knockout mice, we investigated CD4T cell infiltration, activation and proliferation in the skin and draining lymph node (dLN) of CHS-challenged mice by immunohistochemistry and flow cytometry. We used the OT-II adoptive transfer model to test antigen specific CD4T cell activation. We assessed interactions of the proteoglycans with LFA-1 on T cells by confocal microscopy. Compared to WTs, the knockouts showed severe ear inflammation, with increased CD4T cells infiltration in the dermis. CHS-challenged knockout mice dLN showed increased T-bet, STAT1 and -STAT4 signaling, indicating enhanced Th1 commitment and proliferation. We found that WT lymph node fibroblastic reticular cells (FRCs) secrete lumican, biglycan and decorin, a related proteoglycan, while none are expressed by naive or activated T cells. Lumican and biglycan interact with LFA-1 on T cell surfaces, and in vitro all three proteoglycans suppress CD4T cell activation. Secreted by dLN FRCs, lumican, biglycan, and possibly decorin interact with LFA-1 on CD4T cells to restrict its activation and reduce dermatitis severity.

摘要： Anemia of inflammation (AI) is the second most common form of anemia and is prevalent in patients with chronic inflammatory states, such as infection, autoimmunity, and cancer. Interleukin 6 (IL6) is well-known to induce the iron-sequestering hormone hepcidin, which results in iron-restricted anemia. The contributions of other pro-inflammatory cytokines such as tumor necrosis factor-α (TNFα) and interferon-γ (IFNγ) are less understood in the pathophysiology of AI. This study investigated the role of TNFα in a mouse model of AI by administering heat-killed Brucella Abortus (HKBA) to germline TNFα knockout (KO) mice. We hypothesized that TNFα possessed an important role in restoring steady-state erythropoiesis after inflammatory insult. TNFαKO injected with HKBA displayed a chronic anemia, with elevated pro-inflammatory IL12p40 and IFNγ cytokines that did not resolve. However, IFNγKO and TNFαKO/FNγKO double knock-out (DKO) mice showed reduced inflammation and anemia following HKBA administration. Since IFNγKO displayed normal serum TNFα and IL12p40 levels, we hypothesized that the persistent anemia was IFNγ-induced and TNFα was necessary for AI cessation. However, treatment with recombinant TNFα (rTNFα) accelerated death, while reducing IFNγ using an anti-IFNγ antibody (Ab) only briefly improved anemia. Only the combination of both the Ab and rTNFα together reversed the hyper-inflammatory phenotype, restored erythropoiesis, and prevented death of TNFαKO+HKBA mice. Our data provides compelling evidence for an anti-inflammatory role of TNFα that is necessary for the restoration of erythropoiesis and mitigation of pro-inflammatory IFNγ action in a mouse model of AI.

关键词： HLA   adverse effects   dapsone   dapsone hypersensitivity syndrome   leprosy   multidrug therapy  

摘要： BACKGROUND:The introduction of the World Health Organization's multidrug therapy (WHO-MDT) has significantly advanced leprosy treatment. Although dapsone is a fundamental component of MDT, it presents risks of adverse drug reactions (ADR), including the potentially fatal dapsone hypersensitivity syndrome (DHS). METHODS:Consequently, we conducted a retrospective observational study by reviewing the records of patients registered at the leprosy clinic within the department of dermatology at a tertiary care center from 2010 to 2022. We included all patients who experienced ADR due to dapsone that necessitated its discontinuation, with particular emphasis on those who developed DHS. RESULTS:Among 1598 leprosy patients treated with standard WHO-MDT, 45 patients developed ADR requiring cessation of dapsone (2.82% over 12 years). The most common ADR was abnormal liver function tests in 14 patients (0.87%) and anemia in 13 patients (0.81%), including one case each of hemolytic anemia and methemoglobinemia. Neuropsychiatric adverse effects were observed in five patients (0.31%). The incidence of DHS was 0.75% (12 patients), with maculopapular rash being the most frequent cutaneous manifestation. These patients were subsequently treated with MDT without dapsone, along with standard care for the ADR, resulting in no mortality or serious morbidity. CONCLUSION:While dapsone remains a cornerstone in the treatment of leprosy, the potential for clinically significant though infrequent adverse reactions highlights the need for vigilant monitoring and increased awareness among healthcare providers of the diverse manifestations of dapsone-related side effects.

关键词： IL-6   factor Xa   perivascular inflammation   proteinase-activated receptor   pulmonary arterial hypertension   pulmonary hypertension   vascular remodeling  

摘要： Activated factor X (FXa) induces inflammatory response and cell proliferation in various cell types via activation of proteinase-activated receptor-1 (PAR) and/or PAR. We thus aimed to investigate the impact of FXa on the development of pulmonary arterial hypertension (PAH) and the mechanisms involved. The effects of edoxaban, a selective FXa inhibitor, on hemodynamic, right ventricular (RV) hypertrophy, and vascular remodeling were evaluated in a monocrotaline (MCT)-exposed PH rat model. At 21 days after a single subcutaneous injection of MCT of 60 mg/kg, right ventricular systolic pressure (RVSP) and total pulmonary vascular resistance index (TPRI) were elevated concomitant with the increased plasma FXa and lung mRNA. Daily administration of edoxaban (10 mg/kg/day, by gavage) starting from the day of MCT injection for 21 days ameliorated RVSP, TPRI, RV hypertrophy, pulmonary vascular remodeling and macrophage accumulation. Edoxaban reduced NF-κB activity and mRNA level in the lungs of MCT-exposed rats. mRNA levels of , PAR and PAR in cultured pulmonary arterial smooth muscle cells (PASMCs) isolated from patients with PAH were higher than those seen in normal PASMCs. FXa stimulation increased cell proliferation and mRNA level of in normal PASMCs, both of which were blunted by edoxaban and PAR antagonist. Moreover, FXa stimulation activated extracellularly regulated kinases 1/2 in a PAR-dependent manner. Inhibition of FXa ameliorates NF-κB-IL-6‒mediated perivascular inflammation, pulmonary vascular remodeling and the development of PH in MCT-exposed rats, suggesting that FXa may be a potential target for the treatment of PAH.

关键词： Cancer   IL1 beta   molecular docking   MD simulation   therapeutics   ZINC08101049  

摘要： Cancer is a significant global health concern that has a major impact on morbidity and mortality worldwide. Research has demonstrated the involvement of Interleukin-1 beta (IL1 beta) in various aspects of cancer development and progression, including angiogenesis, tumor growth and metastasis. Consequently, targeting IL1 beta activity represents a promising approach for cancer therapeutics. In this study, we utilized molecular docking and MD simulations to discover potent IL1 beta inhibitors for the treatment of cancer. Five thousand compounds from ZINC15 database were screened against IL1 beta target, and the top ten small molecules were selected based on their binding energy. The small molecule named 'ZINC08101049' was prioritized based on binding energy (-9.1 kcal/Mol) and residual interaction specifically forming seven hydrogen bonds with amino acid residues namely GLN81, GLY136, LEU134, LYS138, SER84, THR137 and TYR24 of IL1 beta. Next, IL1 beta alone and in complex with ZINC08101049 was subjected to MD simulations to determine their behavior at atomic level. The results of molecular docking and MD simulation revealed ZINC08101049 as a potential inhibitor of IL1 beta, reflecting that ZINC08101049 can emerge as a promising small molecule paving for cancer therapeutics.

摘要： Regulatory T cell (T cell) therapy has been transformed through the use of chimeric antigen receptors (CARs). We previously found that human T cells minimally produce IL-10 and have a limited capacity to control innate immunity compared to type 1 regulatory T cells (T1 cells). To create "hybrid" CAR T cells with T1 cell-like properties, we examined whether the locus could be exploited to endow T cells with CAR-regulated IL-10 expression. CRISPR-mediated PD1 deletion increased CAR T cell activation, and knock-in of under control of the PD1 promoter resulted in CAR-induced IL-10 secretion. knock-in improved CAR T cell function, as determined by increased suppression of dendritic cells and alloantigen- and islet autoantigen-specific T cells. In vivo, knock-in CAR T cells were stable, safe, and suppressed dendritic cells and xenogeneic graft-versus-host disease. CRISPR-mediated engineering to simultaneously remove an inhibitory signal and enhance a suppressive mechanism is a previously unexplored approach to improve CAR T cell potency.

关键词： 光催化降解   离子液体硅铋光催化剂   氯吡苯脲   综合实验设计  

摘要： 围绕高效催化降解氯吡苯脲污染物设计了由硅烷化离子液体制备的离子液体硅铋光催化剂（BiSiOClI-IL），并开发了基于离子液体硅铋光催化剂吸附降解水中氯吡苯脲的综合实验，主要包括以硅烷化离子液体合成离子液体硅铋光催化剂、光催化剂的表征及其催化性能研究。通过优化条件，确定最优制备参数为反应温度80℃、碱式硝酸铋：硅烷化离子液体：碘化钾3∶3∶1（n/n/n）、pH 9。利用XRD、SEM、TEM、N2物理吸附等手段对一系列条件合成的BiSiOClI-IL进行表征，比表面积可达21.2 m2·g–1，在最优条件下去除率可达99%，进一步通过吸附动力学实验深入探究BiSiOClI-IL对吸附机理。该综合实验涉及物理化学、材料化学、仪器分析等课程知识，有助于锻炼学生的实验操作能力、培养学生创造性思维，同时为有机氯污染物去除方面提供一定的参考价值。