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关键词： AMD   Sodium iodate   Cordyceps cicadae   Myriocin   TNF-RIPK1/3 pathway  

摘要： Ethnopharmacological relevance: Cordyceps cicadae (***), named "Chan Hua", an anamorph of Isaria cicadae Miquel, is an entomogenous complex formed by fungi parasitizing on the larvae of cicadas and belongs to the Claviciptaceae family and the genus Codyceps, which traditionally holds a significant place in Chinese ethnopharmacology, specifically for eye clarity and as a remedy for age-related ocular conditions. The underlying mechanisms contributing to its eyesight enhancement and potential effectiveness against Age-related macular degeneration (AMD) remain unexplored. Aim of the study: This study aims to elucidate the protective role of *** and its active ingredient, Myriocin (Myr), against AMD. Materials and methods: A chemical inducer was employed to make retinal pigment epithelium (RPE) damage in vitro and in vivo. The key ingredients of *** and their related mechanisms for anti-AMD were studied through bioinformatic analysis and molecular biological approaches. Results: Myr was identified through high-performance liquid chromatography (HPLC) as an active ingredient in ***, and demonstrated a protective effect on RPE cells, reducing the structural damage and cell death induced by sodium iodate (SI). Further, Myr reduced eyelid secretions in AMD mice and restored their retinal structure and function. The differentially expressed genes (DEGs) in Myr treatment are primarily associated with TNF and Necroptosis signaling pathways. Molecular docking indicated a strong affinity between TNF and Myr. Myr inhibited the TNF signaling pathway thereby reducing the expression of inflammatory factors in ARPE-19 cells. Additionally, Myr had consistent action with the necroptosis inhibitor Necrostatin-1 (Nec-1), inhibited the RIPK1/RIPK3/MLKL pathway thereby protecting ARPE-19 cells. Conclusion: The findings present Myr, as a potent protector against SI-induced AMD, predominantly through modulation of the TNF-RIPK1/RIPK3/MLKL signaling pathway, offering t

关键词： HLA   allogeneic   haplobank   histocompatibility   iPSC   registry  

摘要： BACKGROUND:Several countries have either developed or are developing national induced pluripotent stem cell (iPSC) banks of cell lines derived from donors with HLA homozygous genotypes (two identical haplotypes) prevalent in their local populations to provide immune matched tissues and cells to support regenerative medicine therapies. This 'haplobank' approach relies on knowledge of the HLA genotypes of the population to identify the most beneficial haplotypes for patient coverage, and ultimately identify donors or cord blood units carrying two copies of the target haplotype. AIMS:A potentially more efficient alternative to a national bank approach is to assess the haplotypes required to provide global patient coverage and to produce a single, global haplobank. Toward that end, we have developed an algorithm to prioritize HLA haplotypes that optimize coverage across the global population. METHODS:We analyzed data from eighteen countries participating in the Global Alliance for iPS Therapy (GAiT). A representative pool of HLA genotypes, reflecting the HLA of patients, was derived by sampling from each country's WMDA hematopoietic stem cell donor registry, or surrogate population. An algorithm was created based on HLA-A, -B and -DRB1 haplotype homozygous types with population HLA matching coverage defined by the absence of Host versus Graft (HvG) mismatches at these loci. HLA matching coverage was determined by iteratively selecting HLA haplotypes that provide the largest coverage against patient HLA genotypes sampled from the same population, excluding genotypes compatible with previous iterations. RESULTS:The top 10 haplotypes for each of the 18 countries were identified with patient coverage ranging from 19.5% in Brazil to 63.8% in Japan, with a mean coverage of 33.3%. In a 'global' model, utilizing the 180 most frequent haplotypes across all 18 populations (equivalent to 10 lines per country), the patient coverage ranged from 54.6% in India to 81.7% in Sweden, wit

关键词： Sarcoidosis   HLA   Single nucleotide polymorphism   Clinical phenotype   Extrapulmonary manifestation   Treatment requirement   Chest X-ray stage   Association  

关键词： Behcet's disease   IL-6   Polymorphism   Meta-analysis  

摘要： Objectives: This study aimed to investigate the association between circulating interleukin-6 (IL-6) levels and Beh & ccedil;et's disease (BD), and associations between polymorphisms in IL-6 gene and BD susceptibility. Method: A search of relevant articles was conducted in the Medline, Embase, and Web of Sciences databases. Subsequently, a meta-analysis was performed to assess circulating IL-6 levels in both the BD and control groups. Additionally, we investigated the association between the functional IL-6 promoter-174 G/C polymorphism and the risk of developing BD. Results: Nineteen studies involving 923 patients with BD and 910 controls were included in this meta-analysis. The results demonstrated a significant elevation in circulating IL-6 levels in the BD group than in the control group (standardized mean difference [SMD] = 1.600, 95 % confidence interval [CI] = 0.732-2.496, P<0.001). Furthermore, IL-6 levels were significantly higher in the active disease group than in the inactive disease group (SMD=1.292, 95 % CI=0.059-2.525, P<0.001). Intriguingly, the meta-analysis revealed an association between BD and the IL-6 CC+CG genotype in Arabs (odds ratio [OR] = 0.588, 95 % CI=0.393-0.881, P=0.010), whereas no such association was observed in European or Asian populations. Conclusions: Our meta-analysis revealed significantly higher circulating IL-6 levels in patients with BD and found evidence of association between IL and 6 promoter-174 G/C and BD susceptibility.

关键词： acute lung injury   NLRP3 inflammasome   macrophage polarization   placenta-derived mesenchymal stem cells   IL-10/STAT3 signaling  

摘要： Introduction Acute lung injury (ALI) is a clinically severe respiratory disorder that currently lacks specific and effective pharmacotherapy. The imbalance of M1/M2 macrophage polarization is pivotal in the initiation and progression of ALI. Shifting macrophage polarization from the proinflammatory M1 phenotype to the anti-inflammatory M2 phenotype could be a potential therapeutic strategy. The intratracheal administration of placental mesenchymal stem cells (pMSCs) has emerged as a novel and effective treatment for ALI. This study aimed to investigate the role and downstream mechanisms of pMSCs in reprogramming macrophage polarization to exert anti-inflammatory effects in *** The study used lipopolysaccharide (LPS) to induce inflammation in both cell and rat models of ALI. Intratracheal administration of pMSCs was tested as a therapeutic intervention. An expression dataset for MSCs cultured with LPS-treated macrophages was collected from the Gene Expression Omnibus database to predict downstream regulatory mechanisms. Experimental validation was conducted through in vitro and in vivo assays to assess pMSCs effects on macrophage polarization and *** Both in vitro and in vivo experiments validated that pMSCs promoted M2 macrophage polarization and reduced the release of inflammatory factors. Further analyses revealed that pMSCs activated the signal transducer and activator of transcription (STAT)3 signaling pathway by secreting interleukin (IL)-10, leading to increased STAT3 phosphorylation and nuclear translocation. This activation inhibited NLRP3 inflammasome activation, promoting M2 macrophage polarization and suppressing the inflammatory *** The study concluded that pMSCs alleviated lung injury in an LPS-induced ALI model by inhibiting M1 macrophage polarization and proinflammatory factor secretion, while promoting M2 macrophage polarization. This effect was mediated via the IL-10/STAT3/NLRP3 axis, presenting a novel thera

关键词： Dingxian pill   Epilepsy   Hippocampal neurons   Apoptosis   TNF-alpha/TNFR1 signaling pathway  

摘要： Ethnopharmacological relevance: Dingxian Pill (DXP), a famous traditional Chinese medicine prescription, and has been widely proven to have positive therapeutic effects on "Xianzheng" (the name of epilepsy in ancient China). However, the anti-epileptic molecular mechanisms of DXP are not yet fully understood and remain to be further investigated. Aim of the study: To elucidate the molecular mechanism of DXP's improvement in epileptic neuronal loss, damage and apoptosis by regulating TNF-alpha/TNFR1 signaling pathway. Materials and methods: Sixty Kunming mice were randomly divided in 6 groups: control group (equal volume of normal saline), model group (180 mg kg-1 pilocarpine hydrochloride - used to establish the epilepsy animal model), carbamazepine group (30 mg kg- 1), and low, medium, and high-dose Dingxian Pill groups (4.08, 8.16, and 16.32 g kg-1, respectively - oral administration once daily for 2 weeks). Successful establishment of the epileptic mouse model was monitored with electroencephalography. Pathological changes in hippocampal tissue were analyzed with hematoxylin-eosin staining. Hippocampal neuronal apoptosis was analyzed with TUNEL staining. TNF-alpha, TNFR1, TRADD, FADD, and caspase-8 mRNA and protein expression levels in hippocampal tissue were analyzed with real-time quantitative polymerase chain reaction, immunohistochemistry, and Western blot, respectively. Cleaved caspase-8 protein levels in hippocampal tissue were measured with immunohistochemistry and Western blot. Results: Compared to control, the model group showed an increase in continuous epileptic discharge waves on EEG, a damaged hippocampal neuron morphological structure, increased hippocampal neuronal apoptosis, and significantly increased TNF-alpha, TNFR1, TRADD, FADD, and caspase-8 mRNA and protein levels, and increased caspase-8 cleavage (P < 0.05). Compared to the model group, the carbamazepine group as well as the low-, medium-, and high-dose Dingxian Pill groups showed decreased

摘要： NK cells offer a promising alternative to T cell therapies in cancer. We evaluated IPH6501, a clinical-stage, tetraspecific NK cell engager (NKCE) armed with a non-alpha IL-2 variant (IL-2v), which targets CD20 and was developed for treating B cell non-Hodgkin lymphoma (B-NHL). CD20-NKCE-IL2v boosts NK cell proliferation and cytotoxicity, showing activity against a range of B-NHL cell lines, including those with low CD20 density. Whereas it presented reduced toxicities compared with those commonly associated with T cell therapies, CD20-NKCE-IL2v showed greater killing efficacy over a T cell engager targeting CD20 in in vitro preclinical models. CD20-NKCE-IL2v also increased the cell surface expression of NK cell-activating receptors, leading to activity against CD20-negative tumor cells. In vivo studies in nonhuman primates and tumor mouse models further validated its efficacy and revealed that CD20-NKCE-IL2v induces peripheral NK cell homing at the tumor site. CD20-NKCE-IL2v emerges as a potential alternative in the treatment landscape of B-NHL.

关键词： major histocompatibility complex (MHC)   MHC-IIA   positive selection   negative selection   macroevolution   Passeriformes  

摘要： The major histocompatibility complex (MHC) is central in adaptive immunity, with the highly polymorphic MHC genes encoding antigen-presenting molecules. Two MHC class II (MHC-II) loci, DA1 and DA2, predate the radiation of extant birds and persist throughout much of the avian phylogeny. Within each locus, the MHC-II molecules are encoded by A-genes (DAA) and B-genes (DAB), which are arranged in A-B dyads. However, in passerines (order Passeriformes), the DA2 locus has been lost, and the ancestral A-B dyad at the DA1 locus has been replaced by a putatively single A-gene (DAA1) and an array of highly polymorphic B-genes (DAB1). In this study, we genotyped the DAA1 gene of 15 passerine species and confirmed that passerines possess just one copy of DAA1. We then compared selection patterns in DAA1 between passerines and nonpasserines and found that exon 2, which encodes the antigen-presenting domain, has been subject to weaker positive selection and stronger negative selection in passerines compared with nonpasserines. Additional comparisons showed that the patterns of selection in the passerine DAA1 gene are unlikely to be related to the loss of the DA2 locus. Instead, our findings suggest that the expansion of DAB1 (MHC-IIB) has imposed an evolutionary constraint on the passerine DAA1 (MHC-IIA) gene. We speculate that this constraint may be the result of each DAA1 chain forming heterodimers with many different DAB1 chains.

关键词： 清心解瘀颗粒   血栓   内皮细胞   组织因子   蛋白激酶B/核转录因子-κB(Akt/NF-κB)信号通路  

摘要： 目的：观察清心解瘀颗粒对三氯化铁（FeCl3）诱导大鼠颈动脉血栓形成的作用及其对肿瘤坏死因子-α（TNF-α）诱导人脐静脉细胞融合细胞（***926）中血栓形成相关蛋白组织因子（TF）、组织因子途径抑制因子（TFPI）的表达及蛋白激酶B（Akt）/核转录因子-κB（NF-κB）信号通路的影响，初步探究清心解瘀颗粒抑制血栓形成的药效作用机制。方法：取36只SD大鼠，随机分为正常组、模型组、阿司匹林组、清心解瘀颗粒低、中、高剂量组，每组各6只。清心解瘀颗粒低、中、高组给药剂量分别为0.99、1.98、3.96 g·kg-1；阿司匹林组给药剂量为9 mg·kg-1，正常组与模型组给予等体积蒸馏水灌胃。连续预防性灌胃给药14 d后，采用45%的FeCl3溶液建立大鼠颈总动脉血栓模型，取下血管组织后称量大鼠血栓湿重；采用苏木素-伊红（HE）染色法观察各组大鼠颈总动脉血栓形成情况；采用酶联免疫吸附测定法（ELISA）检测各组大鼠血浆中血管性血友病因子（vWF）、血小板内皮细胞黏附分子-1（PECAM-1）、组织型纤溶酶原激活物（t-PA）及纤溶酶原激活物抑制剂-1（PAI-1）的含量；利用TNF-α诱导***926细胞建立内皮细胞损伤模型；采用细胞增殖与活性检测法（CCK-8）筛选清心解瘀颗粒干预浓度；采用蛋白免疫印迹法（Western blot）检测各组细胞中TF、TFPI、Akt、p-Akt、NF-κB p65、磷酸化（p）-NF-κB p65蛋白的表达。结果：动物实验结果显示，与正常组比较，模型组的颈动脉血栓质量明显增加（P<0.05），血管结构不清晰，管腔内有大量血栓形成；血浆中的vWF、PECAM-1、PAI-1含量明显升高，t-PA含量明显降低（P<0.05）。与模型组比较，各给药组均可降低FeCl3诱导的大鼠颈动脉血栓质量（P<0.05），明显减少管腔中的血栓形成；同时，明显降低血浆中PECAM-1、PAI-1含量，增加t-PA含量（P<0.05）；且清心解瘀颗粒各剂量给药组还可明显降低血浆中vWF的含量（P<0.05），但阿司匹林组则与模型组间差异无统计学意义。细胞实验结果显示，31.25、62.5、125、250、500 mg·L-1的清心解瘀颗粒对***926细胞活性无影响，因此后续采用250、500 mg·L-1的清心解瘀颗粒作为干预浓度；Western blot结果显示，与空白组比较，TNF-α刺激后***926细胞中TFPI的表达明显下调（P<0.05）,TF的表达及p-Akt/Akt、p-NF-κB p65/NF-κB p65的比值均明显升高（P<0.05）；清心解瘀颗粒干预后可上调TFPI的表达（P<0.05）并抑制TF的表达及下调p-Akt/Akt、p-NF-κB p65/NF-κB p65的比值（P<0.05）。结论：清心解瘀颗粒具有抑制血栓形成及调节TNF-α诱导内皮细胞中血栓形成相关因子TF、TFPI表达的作用，其机制可能与抑制Akt/NF-κB信号通路的异常活化有关。