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关键词： Parkinson’s disease   GPR37   chronic pain   interleukin-6   oligodendrocyte   dopaminergic neuron  

摘要： Parkinson's disease (PD) is a common neurodegenerative disease and is difficult to treat due to its elusive mechanisms. Recent studies have identified a striking association between oligodendrocytes and PD progression, yet how oligodendrocytes regulate the pathogenesis of PD is still unknown. Here, we show that G-protein-coupled receptor 37 (GPR37) is upregulated in oligodendrocytes of the substantia nigra and that prosaposin (PSAP) secretion is increased in parkinsonian mice. The released PSAP can induce interleukin (IL)-6 upregulation and secretion from oligodendrocytes via a GPR37-dependent pathway, resulting in enhanced neuroinflammation, dopamine neuron degeneration, and behavioral deficits. GPR37 deficiency in oligodendrocytes prevents neurodegeneration in multiple PD models. Finally, the hallmarks of the PSAPGPR37-IL-6 axis are observed in patients with PD. Thus, our results reveal that dopaminergic neurons interact with oligodendrocytes via secreted PSAP, and our findings identify the PSAP-GPR37-IL-6 axis as a driver of PD pathogenesis and a potential therapeutic target that might alleviate PD progression in patients.

关键词： HLA homozygosity   graft rejection   post transplant cyclophosphamide  

摘要： Graft rejection is an important concern following haploidentical transplant with a reported incidence of 10-15%. The number of human leukocyte antigen (HLA) mismatches and the vector of mismatch have not been found to be associated with the risk of graft rejection in haploidentical transplants. Patients with HLA homozygosity at all loci (HLA-A, B, C, DRB1, and DQB1) undergoing haploidentical transplant is a rare scenario that results in zero mismatches in the graft-versus-host (GvH) direction and 2-5 mismatches in the host-versus-graft (HvG) direction depending on the donor haplotype. This results in a heavily skewed vector of HLA mismatch with unopposed allo-reactivity in the HvG direction. We reviewed our haploidentical transplant database for patients who were homozygous at all five loci and studied their outcomes. Seventy-one patients underwent haploidentical transplant at our center for malignant indications between July 1, 2010, and June 30, 2022. All but one patient received PTCy-based graft-versus-host disease (GvHD) prophylaxis. Of these 71 patients, two were homozygous at all five loci, and both patients developed graft rejection (100%). This was significantly higher than the risk of rejection in the remaining 69 patients where 5/69 (7.2%) had rejection (=0.0085). Herein, we describe these two cases and review the literature on the impact of patient HLA homozygosity on graft rejection in patients undergoing haploidentical transplant.

关键词： HLA molecular mismatch   major histocompatibility complex (MHC)   risk stratification   kidney transplantation   de novo DSA   Snow   PIRCHE-II   HLAMatchmaker  

摘要： Introduction The presence of de novo donor-specific antibody (dnDSA) has detrimental effect on allograft outcomes in kidney transplantation. As humoral responses in transplantation are elicited targeting non-self-epitopes on donor HLA proteins, assessing HLA mismatches at the molecular level provides a refined means for immunological risk *** In the present study, we utilized three HLA molecular mismatch assessment algorithms, Snow, HLAMatchmaker, and PIRCHE-II, to evaluate the independent and synergistic association of B cell and T cell epitope mismatches with dnDSA development in a cohort of 843 kidney transplant *** Our results demonstrated that B cell and T cell epitope mismatches at HLA Class I and DRB1/DQB1 loci are remarkably increased in dnDSA-positive recipients, even after normalization by allele mismatch numbers in individual study subjects. Furthermore, elevated Snow, verified eplet mismatches, and PIRCHE-II scores are significantly associated with dnDSA occurrence individually and in *** Our findings highlight the value of utilizing B cell and T cell epitope mismatch evaluation in living donor selection and immunological risk stratification to improve transplant outcomes.

关键词： Rheumatoid arthritis   Leptin   Anti-TNF-alpha   Treatment  

摘要： Background and objective Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by synovial inflammation, cartilage, and bone destruction. Several studies have shown that leptin plays an important role in the pathophysiology of RA disease. This study aimed to evaluate serum levels of leptin in RA patients receiving biologic drugs compared to RA patients managed by non-biologic drugs, and healthy individuals. Methods and material In this case-control study, three groups including RA patients receiving biological drugs (remission RA patients;n = 20), RA patients receiving DMARDs (active RA patients;n = 20), and healthy controls (n = 20) were included. Serum leptin levels and inflammatory markers, including C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), were measured in all participants. These measurements were subsequently compared across the three groups. Also, the correlation between leptin and inflammatory markers in each group was evaluated. Results In this study serum leptin levels in remission RA patients, active RA patients, and healthy individuals were 14.49 +/- 6.73, 16.94 +/- 7.72, and 7.59 +/- 5.94, respectively. Serum leptin level was significantly higher in patients with RA compared to healthy controls. No significant difference was observed in serum leptin levels between the two groups of RA patients (P < 0.001). There was a lost correlation between leptin and inflammatory markers in patients with active RA. However, a new correlation between leptin and inflammatory markers emerged in RA patients receiving biological drugs. Conclusion Our findings suggest that anti-TNF-alpha agents do not modulate serum leptin levels in RA patients. However, these agents may change a correlation between leptin and C-reactive protein (CRP) that is absent in patients with active RA.

关键词： Interleukin-22 receptor   Psoriasis   Alloferon   Keratinocytes  

摘要： Psoriasis is an immune-mediated inflammatory skin disease. IL-22, a proinflammatory cytokine, is implicated in psoriasis pathogenesis;however, there is currently no established biological treatment targeting IL-22 or its receptor, IL-22R alpha. Alloferon is a short peptide that has an antiinflammatory effect on skin disorders;however, little is known about its anti-inflammatory activity in psoriasis. We investigated the regulatory role of alloferon in the development of psoriasis in an imiquimod (IMQ)-induced psoriasis model through the regulation of IL-22R alpha expression. The expression of IL-22R alpha was analyzed by immunofluorescence staining in primary human keratinocytes. The effect of alloferon on the development of psoriasis was investigated in IMQ-induced wild-type and IL-22R alpha KO mice. We found that alloferon decreased the expression of IL-22R alpha in psoriasis-like keratinocytes treated with TNF-alpha, while epidermal hyperplasia was observed in IMQ-induced wild-type and IL-22R alpha KO mice. In addition, the expression of IL-1 beta, IL-19, and IL-33 was suppressed when IL-22R alpha KO mice were treated with alloferon. The findings of this study indicate that alloferon could be an effective potential drug for the treatment of psoriasis by interrupting IL-22 signaling and factors related to skin inflammation.

关键词： Beam propagation methods   Biosensors   Erbium fibers   Fiber lasers   Refractive index   Sensors  

摘要： Rapid detection of low concentrations of tumor necrosis factor-alpha (TNF-alpha) plays an important role in medical diagnostics. This study proposed a fast, label-free single mode-tapered no core-single mode (STNCS) microfiber structure for the ultra-low concentration of TNF-alpha detection. The experimental results show that the proposed microfiber biosensors have good spectral stability (0.0316 nm), fast detection (<20 min), good specificity and low limit of detection (LoD). When the STNCS biosensors (functionalized with 20 g/mL anti-TNF-alpha antibodies) are immersed in a TNF-alpha solution at a concentration of 1 pg/mL, the average wavelength shift can reach 0.951 nm, which is close to the theoretical LoD value (1.352 pg/mL). The proposed STNCS microfiber biosensors also demonstrated good specificity, showing limited cross-reactivity to other proteins, including C-reactive protein (CRP), interleukin-6 (IL-6) and bovine serum albumin (BSA). These results indicate that the proposed STNCS biosensors may possess potential uses in medical diagnosis, early detection, and intervention of diseases, etc. (c) 2025 Optica Publishing Group under the terms of the Optica Open Access Publishing Agreement

关键词： 尪痹胶囊   类风湿关节炎   湿热阻络型   临床疗效   免疫功能   炎症   作用机制  

摘要： 目的：观察尪痹胶囊治疗湿热阻络型类风湿关节炎临床疗效及对血清粒细胞-巨噬细胞集落刺激因子（Granulocyte-Macrophage Colony-Stimulating Factor， GM-CSF）、肿瘤坏死因子-α(Tumor Necrosis Factor-α， TNF-α)、CD4+T细胞亚群 (CD4+T-cell Subsets，CD4+ T-cell Subsets)的影响。方法：选择2020年6月至2023年6月于我院风湿免疫科治疗的98例类风湿关节炎患者作为研究对象，采用随机数字表法将上述患者分为对照组和观察组，每组49例，对照组患者予以来氟米特口服治疗，观察组在对照组基础上予以尪痹胶囊治疗。比较两组患者的临床疗效、中医证候积分和不良反应情况，以及治疗前后关节疼痛程度、血清炎症因子水平变化。结果：对照组患者的有效率为79.59%，观察组患者的有效率为93.88%，与对照组比较，观察组的有效率明显升高（P＜0.05）。治疗前两组患者的中医证候积分无明显差异（P＞0.05）；治疗后，观察组患者的晨僵、关节屈伸不利、发热、关节肿痛而热，水平相较于对照组均明显下降（P＜0.01）。干预前，两组患者的超声评分水平无明显差异（P＞0.05）。干预完成后，观察组患者超声评分水平相较于对照组均明显升高（P＜0.05）。干预前，两组患者的关节疼痛程度无明显差异（P＞0.05）。与对照组患者比较，观察组患者治疗后视觉模拟评分(Visual Analog Scale， VAS评分)、疾病活动评分28(Disease Activity Score 28， DAS28)评分均明显降低（P＜0.01）。干预前两组患者的血清炎症因子水平无明显差异（P＞0.05）。干预完成后，观察组患者的红细胞沉降率(Erythrocyte Sedimentation Rate， ESR)、C反应蛋白(C-Reactive Protein， CRP)、类风湿因子(Rheumatoid Factor， RF)、GM-CSF)、TNF-α水平相较于对照组均明显下降（P＜0.01）。干预过程中所有患者的主要不良反应有胃肠道不适、血细胞减少、转氨酶升高以及皮肤过敏等，两组患者的不良反应发生率无明显差异（P＞0.05）。结论：尪痹胶囊联合来氟米特治疗湿热阻络型类风湿关节炎具有良好的临床效果，减轻关节疼痛和功能障碍，改善关节超声状态，抑制炎症反应，且无不良反应增加。

关键词： African swine fever virus   C315R   RNA sequencing   interleukin-6   signal transducers and activators of transcription-3  

摘要： African swine fever (ASF) is an acute and highly contagious disease that has caused great losses in the past years. It is caused by African swine fever virus (ASFV), which is a large DNA virus encoding about 165 genes. It has been shown that the purified extracellular ASFV is internalized by both constitutive macropinocytosis and clathrin-mediated endocytosis, and the virus utilizes apoptotic bodies for infection and cell cell transmission. The ASFV-encoded RNA polymerase subunit C315R is thought to play an important role in ASFV replication and transcription. However, its involvement in ASFV infection, particularly in host response, remains only partially understood. In this study, the role of C315R in enhancing ASFV replication was investigated through RNA-Seq transcriptomic analysis, which was based on 3D4/21 cells transfected the plasmid expressing HA-tagged C315R or the empty vector. Our findings revealed that C315R significantly upregulates the expression of inflammatory mediators with a particular emphasis on IL-6. The most differentially expressed genes (DEGs) were predominantly associated with the TNF, IL-17, MAPK, and JAK STAT signaling pathways. RNA-seq results were validated through RT-PCR. Subsequently, we observed that ASFV infection increases IL-6 expression and STAT3 phosphorylation, which is regulated by the ASFV C315R protein. Notably, inhibiting STAT3 phosphorylation with specific inhibitors suppressed ASFV replication. In conclusion, our study demonstrates that the ASFV C315R protein actives STAT3 phosphorylation through promoting the transcription of IL-6 to facilitate virus replication. These findings highlight C315R as a positive regulator in the IL-6 STAT3 signaling axis during ASFV infection.