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关键词： Endometriosis   T(H)17 cells   IL-17   Endometrial tissue   PBMCs  

摘要： Endometriosis, an inflammatory disease, is characterized by the aberrant presence of endometrial tissues at ectopic locations. Accumulating evidence suggests that inflammatory cells, such as interleukin-17 (IL-17)-producing cells, may be involved in the pathogenesis of endometriosis. This investigation assessed the frequency of IL-17A (commonly known as IL-17)-producing cells in peripheral blood mononuclear cells (PBMCs), ectopic, and eutopic endometrial tissues in patients with endometriosis compared to non-endometriotic subjects. PBMCs, ectopic, and eutopic endometrial tissues were collected from 23 patients with endometriosis. PBMCs and endometrial tissues from 20 non-endometriotic women were used as the control group. The frequency of T helper 17 (T(H)17) lymphocytes in PBMCs was assessed using flow cytometry, and the expression level of IL-17 in eutopic and ectopic endometrial tissues was evaluated through immunohistochemistry. The percentage of T(H)17 and IL-17-producing lymphocytes was significantly higher in the PBMCs of patients with endometriosis compared to non-endometriotic subjects (P < 0.01 and P < 0.001, respectively). The expression of IL-17 protein in ectopic (P < 0.001) and eutopic (P < 0.05) endometrial tissues of patients with endometriosis increased compared to controls' endometrial tissue. Furthermore, the eutopic endometrium of patients with endometriosis showed a higher expression of IL-17 protein than the eutopic endometrial tissue of control subjects (P < 0.05). The findings suggest that the higher frequency of IL-17-producing cells in the PBMCs and endometrial tissues of patients with endometriosis contributes to the pathogenesis of endometriosis.

关键词： Peptides  

摘要： Recent advances in machine learning have revolutionized molecular design;however, a gap remains in integrating generative models with physics-based simulations to develop functional modulators, such as stable peptides, for challenging targets like the interleukin-23 receptor (IL23R) and its associated cytokine, interleukin-23 (IL23). The IL23R/IL23 axis plays a critical role in autoimmune diseases, and current therapies have largely been limited to antibody-based approaches. To address this gap, we employed a hybrid computational approach that combines Long Short-Term Memory (LSTM) networks for peptide generation, a Gated Recurrent Unit (GRU)-based classifier for anti-inflammatory property prediction, and molecular dynamics (MD) simulations to assess structural dynamics, binding interactions, as well as key properties such as binding affinity and stability. Using this hybrid framework, we identified novel inhibitory peptides, particularly P4, with an IC50 of 2 μM. Systematic experimental validation established its inhibitory activity, elucidated its binding mechanism, confirmed its specificity toward the IL23R, and demonstrated its ability to disrupt IL23R/IL23 interaction. This integrated approach highlights the significant potential of combining deep learning and simulations to accelerate the identification of peptide-based therapeutics targeting key protein targets. © 2025 Elsevier B.V.

关键词： Zinc   TNF-alpha   Immunology   Single-cell RNA sequencing   Transcriptomics   Metabolomics   Spinal cord injury  

摘要： Spinal cord injury (SCI) is a complex central nervous system (CNS) trauma that triggers multifaceted immune responses. In recent years, zinc has garnered considerable attention for its beneficial roles in anti-apoptosis and the attenuation of oxidative stress. However, the regulatory mechanisms by which zinc influence post-SCI immune-inflammatory responses remain insufficiently understood. In this study, we employed a multi-omics approach, combining transcriptomics, metabolomics, and single-cell RNA sequencing, to elucidate the mechanisms through which zinc ions modulate immune responses in injured spinal cord tissues. Our results demonstrate that zinc ions significantly regulate the expression of TNF-alpha signaling molecules. By inhibiting the TNF-alpha signaling pathway, zinc ions effectively mitigate apoptosis and reduce immune-inflammatory responses following SCI. Furthermore, through the integration of human and murine immune cell atlases, we performed a cluster analysis of key immune cell populations and constructed an immunological landscape of spinal cord tissues post-zinc ion treatment. Notably, we identified microglia, key CNS immune cells, as exerting a strong antiinflammatory effect by suppressing their TNF-alpha signaling activity. This study not only sheds light on the pivotal immune-inflammatory regulatory mechanisms of TNF-alpha signaling in zinc ion-mediated SCI therapy but also provides valuable theoretical and experimental insights for advancing preclinical research on SCI.

关键词： HLA   estimated glomerular filtration rate (eGFR)   genetic association study   kidney function   polymorphisms  

摘要： HLA allelic polymorphisms are associated with a variety of kidney-related traits in different populations. Although Taiwanese-specific genetic variants associated with kidney function have been reported, the role of HLA alleles is unclear. In this study, the association between eGFR and genetic variations in the HLA region was explored in a cohort of 59,448 Taiwanese subjects. A total of 448 genetic variations in the HLA region are significantly associated with eGFR. HLA-C*03 is associated with decreased eGFR, while HLA-DQA1*03, HLA-DQB1*03:03 and HLA-DQB1*03:03:02 demonstrated protective effects. Moreover, amino acid changes on HLA-C and HLA-DRB1 are significantly associated with eGFR. Finally, the eGFR-associated single nucleotide variations (SNVs) and insertions and deletions (indels) are enriched in the HLA-DQB1 gene. After conditional analysis, we identified two independent signals, including rs2853941, rs3830060. In summary, this study highlights the role of HLA-C, HLA-DQA1, HLA-DQB1 and HLA-DRB1 variations in kidney function in the Taiwan Han Chinese population.

关键词： Diabetes   Wound healing   Dermal matrix   Hydrogel   VEGF   IL-10   Microspheres  

摘要： Diabetic wounds are among the most common and costly complications in diabetic patients. As a result, numerous studies have been conducted to explore effective approaches for accelerating the wound healing process. Biological hydrogels are frequently used for wound healing due to their favorable properties compared to other materials. In this study, we evaluated the effect of a bioactive and degradable hydrogel based on dermal matrix (HDM) encapsulated with microspheres containing vascular endothelial growth factor (VEGF) and interleukin (IL)-10 on promoting wound healing in diabetic rats. Forty-five diabetic rats were randomly assigned to three groups (n = 15): control, HDM, and HDM encapsulated with microspheres containing VEGF and IL-10 (HDMM). In addition, non-diabetic untreated rats (healthy group) were considered as control (n = 15). Wound assessments were performed on days 7, 14, and 21. The results demonstrated significant improvements in wound closure rate, fibroblast and blood vessel counts, collagen density, concentration levels of TGF-b and VEGF cytokines, and biomechanical parameters in the treatment groups compared to the control group, with the most pronounced effects observed in the HDMM group. Additionally, the HDMM group exhibited a greater reduction in neutrophil and macrophage counts, as well as decreased levels of TNF-a and IL-1b cytokines compared to the other groups. In conclusion, the HDM loaded with microspheres containing VEGF and IL-10 showed a more significant effect in promoting the healing of diabetic wounds. (c) 2025 The Author(s). Published by Elsevier BV on behalf of The Japanese Society for Regenerative Medicine. This is an open access article under the CC BY-NC-ND license (http://***/ licenses/by-nc-nd/4.0/).

关键词： Bladder cancer   Cytoskeleton reorganization   TNF-alpha   METTL3   CLASP2   IQGAP1  

摘要： Background: Bladder cancer (BCa) metastasis is a multi-step process triggered by cytoskeleton reorganization. However, the regulation mechanism of cytoskeleton reorganization in BCa remains ambiguous. This study elucidated the influence of tumor necrosis factor-alpha (TNF-alpha) in cytoskeleton remodeling during BCa metastasis and its possible mechanisms. Methods: Colony formation, scratch, transwell, and the nude mouse model were adopted to evaluate the growth and metastasis. Molecular expression was assessed by immunohistochemical staining, quantitative real-time PCR (qRT-PCR), and Western blotting. The N6-methyladenosine (m6A) level was detected by methylated RNA immunoprecipitation (MeRIP). Protein interaction was validated by Co-immunoprecipitation (Co-IP). Immunofluorescence staining was used to identify rearrangement of actin filament fibers (F-actin) and protein colocalization. Results: TNF-alpha facilitated cytoplasmic linker associated protein 2 (CLASP2) and methyltransferase like 3 (METTL3) expression in a dose (10-50 ng/mL)-dependent manner in BCa. CLASP2 high expression suggested a shorter overall survival of BCa patients. CLASP2 deficiency suppressed BCa cell proliferation, migration, and invasion via disrupting F-actin cytoskeleton. Mechanistically, TNF-alpha promoted METTL3-mediated m6A modification of CLASP2 to enhance CLASP2 mRNA stability. Moreover, CLASP2 directly interplayed with IQ motif containing GTPase activating protein 1 (IQGAP1) to regulate F-actin cytoskeleton remodeling. In vivo data demonstrated that inhibition of METTL3/CLASP2 axis delayed lung metastasis in nude mice. Conclusion: TNF-alpha favors BCa cell metastasis, which involves METTL3-mediated m6A modification of CLASP2 that interacts with IQGAP1, thus leading to F-actin cytoskeleton remodeling. Our findings suggest targeting TNF alpha/METTL3/CLASP2/IQGAP1 axis as a potential avenue for promising treatment for BCa.

关键词： Anti-IL-23   Biologics   Psoriasis   Real-Life   Tildrakizumab  

摘要： IntroductionTildrakizumab is a monoclonal antibody targeting interleukin (IL)-23 approved for the treatment of moderate-to-severe plaque psoriasis across two different dosages (100 mg and 200 mg). The higher dosage is recommended for patients with a body weight >= 90 kg or a high disease burden (Psoriasis Area and Severity Index [PASI] >= 16 or the involvement of difficult-to-treat areas). We conducted a 52-week multicenter retrospective study to compare the effectiveness and safety of both dosages and assess their impact on specific patient *** enrolled a total of 540 patients with high disease burden or body weight >= 90 kg;177 and 363 were treated with tildrakizumab 200 mg and 100 mg, respectively. The effectiveness was evaluated in terms of PASI 90, PASI 100, and PASI <= 2 at weeks 16, 28, and 52. We also performed subanalyses according to the body weight (>= 90 kg), PASI >= 16, prior biologic exposure, involvement of difficult-to-treat areas, and the presence of at least one cardiometabolic *** 16 weeks of treatment, a higher proportion of patients in the 200-mg group achieved PASI 90 and PASI 100 compared to those in the 100-mg group (43.5% vs. 34.3% and 36.4% vs. 24.2%, respectively). These results were sustained at 1 year, with PASI 90 and PASI 100 reached by 68.6% and 52.9% of patients in the 200-mg group, respectively, versus 57.3% and 35% in the 100-mg group. All subgroup analyses consistently indicated a trend toward greater effectiveness with tildrakizumab 200 mg, particularly in terms of PASI 90 and PASI 100 achievement at weeks 16 and 52. No differences in the safety profile were observed throughout the study *** findings confirm the superior effectiveness of tildrakizumab 200 mg over 100 mg in specific subgroups of patients with a comparable safety profile across the study period.

关键词： DNA sequence analysis   HLA-A   new allele   next-generation sequencing   single nucleotide polymorphism  

摘要： The novel HLA-A*03:01:133 allele differs from A*03:01:01:01 by a change of C -> T in exon 4.

关键词： Thioacetamide   Ginkgo-biloba   dandelion   antioxidant   apoptosis  

摘要： Liver injuries, especially those induced by chemical toxins and pharmaceuticals, are increasingly prevalent. This study evaluated the hepatoprotective effects of Ginkgo biloba and dandelion extracts in a rat model of thioacetamide (TAA)-induced liver injury. Twenty-eight male albino rats were randomly assigned to four groups: control, TAA-treated, TAA plus G. biloba (100 mg/kg), and TAA plus dandelion (500 mg/kg). TAA administration over eight weeks significantly elevated serum liver enzymes (AST, ALT, ALP, and GGT), bilirubin, cholesterol, and triglycerides (P < 0.05) while significantly reducing total protein and albumin levels (P < 0.05). TAA also induced oxidative stress, evident by increased hepatic malondialdehyde and reduced glutathione levels (P < 0.05). Co-treatment with G. biloba or dandelion extracts significantly ameliorated these biochemical alterations (P < 0.05), with G. biloba demonstrating slightly stronger effects. Histopathological examination showed reduced necrosis, fibrosis, and inflammatory cell infiltration in treated groups. Immunohistochemical analysis confirmed decreased expression of TNF-alpha and P53 proteins (P < 0.05), indicating anti-inflammatory and anti-apoptotic properties. These findings suggest that G. biloba and dandelion extracts confer protective effects against TAA-induced liver damage through antioxidant, anti-inflammatory, and anti-apoptotic mechanisms.