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关键词： Interferon-gamma   Tumor necrosis factor-alpha   Endothelial barrier   Synergism   Proinflammatory cytokine  

摘要： Crosstalk and synergy between interferon-gamma (IFN-Y) and tumor necrosis factor-alpha (TNF-alpha) in endothelial cells have previously been documented, however, there is an absence of articles reviewing the synergistic effect of IFN-Y and TNF-alpha in regulating the endothelial barrier function. This review discusses the regulatory mechanisms and recent evidence of the synergism of IFN-gamma and TNF-alpha in causing destabilization of endothelial junctions in various clinical studies and preclinical models. Articles were retrieved from electronic databases such as Web of Science, PubMed, Google Scholar, and Scopus. The search terms used were "interferon", "interferon-gamma", "tumor necrosis factor-alpha", "vascular inflammation", "endothelial barrier", "endothelial permeability" and "synergism". We selected articles published between 2004 and 2024. Through the Rho-associated protein kinase (ROCK) and p38 mitogen-activated protein (MAP) kinase pathways, our results showed that IFN-gamma controls the remodeling of actin and the stability of junctions. In comparison to IFN-gamma, the signaling cascades triggered by TNF-alpha involve a variety of pathways such as nuclear factor-kappa B (NF-kappa B), small GTPases, tyrosine kinases, integrin receptors, and barrier-stabilizing molecules such as Ras-related proteins 1A (Rap1A) and Rac family small GTPase 1 (Rac1). In the context of IFN-gamma and TNF-alpha synergism, combined IFN-gamma and TNF-alpha alter adherens and tight junctions. It is deduced that c-Jun N-terminal kinase (JNK), signal transducers and activators of transcription (STAT1), and caspase signaling pathways regulate endothelial barrier disruption caused by IFN-gamma and TNF-alpha. Collectively, the mechanism underlying the synergistic action of IFN-gamma and TNF-alpha is still lacking. Future work is needed to explore the crosstalk pathways of IFN-gamma and TNF-alpha involved in the regulation of endothelial barrier function such as modulation of extracellu

关键词： Paclitaxel   H1.0   HDAC5   NF-kappa B   IL-6   Ovarian cancer  

摘要： Chemoresistance is a significant challenge and major obstacle to achieving cancer remission during chemotherapy, primarily due to the risk of recurrence and metastasis. This study reveals that linker histone H1.0 plays a crucial role in paclitaxel resistance (TXR) in ovarian cancer cells by regulating Histone deacetylase 5 (HDAC5), which deacetylates core histones and represses gene transactivation. Transcriptomic profile analysis revealed that cytokine signaling networks are enriched pathways that correlate with H1.0 expression. Advanced clustering analysis identified interleukin 6 (IL-6) as a key molecule connecting these enriched H1.0-related pathways. Furthermore, gain- and loss-of-H1.0 expression experiments showed that H1.0 controls IL-6 mRNA and protein expression in ovarian cancer cells. Additionally, our findings indicate that HDAC5 expression is downregulated in SKOV3/Txr cells compared with parental cells. H1.0 silencing in TXR cells increases HDAC5 levels, suggesting an antagonistic effect between H1.0 and HDAC5. Cell viability assays showed that HDAC5 overexpression markedly inhibited cell survival. Furthermore, ectopic HDAC5 overexpression reduced IL-6 mRNA and protein expression, which was increased by H1.0. This effect was associated with reduced H3K9Ac core histone acetylation and decreased NF-kappa B binding on the IL-6 promoter, as demonstrated by chromatin immunoprecipitation assays. Further analysis revealed that HDAC5 is downregulated in several tumor types. Furthermore, high H1.0 and IL-6 expression, coupled with low HDAC5 levels, was exclusively observed in ovarian carcinoma. Together, our results demonstrate an interplay between H1.0, HDAC5, and IL-6 in modulating paclitaxel resistance in ovarian cancer cells, highlighting new therapeutic targets to overcome chemoresistance.

关键词： dibutyltin   human immune cells   IL-1 beta   IL-6   inflammation   pentachlorophenol   TLR  

摘要： Pentachlorophenol (PCP) and dibutyltin dichloride (DBT) contaminate the environment due to their diverse applications. PCP has been found from 0.26 to 5 mu M in the serum of exposed individuals and at an average of 0.15 mu M in the unexposed. DBT has been detected in human blood at levels up to 0.3 mu M. Exposure to these contaminants is linked to pathological conditions including cancer. Interleukin-1 beta (IL-1 beta) and IL-6 are pro-inflammatory cytokines that when produced inappropriately can cause chronic inflammation, which is linked to pathologies including autoimmune diseases and cancer. PCP and DBT have been shown to increase the production of IL-1 beta and IL-6 by immune cells in a MAP kinase (MAPK) dependent process. Toll-like receptors (TLRs) activate the signaling pathways linked to MAPK that lead to production of these cytokines. This study demonstrates that PCP-induced production of IL-1 beta and IL-6 is dependent on TLR4 and TLR8, and independent of TLR1/2, TLR2, and TLR3. Additionally, DBT-induced IL-6 production depends on TLR1/2, whereas IL-1 beta production does not. Blocking the TLR-linked adapter protein, MyD88, lead to a loss of both PCP and DBT stimulation of IL-1 beta and IL-6. These findings indicate that both PCP and DBT interact with selected TLRs as part of their mechanisms of elevating the levels of critical pro-inflammatory cytokines, which may contribute to chronic inflammation and its related pathologies.

摘要： Novel alleles HLA-A*68:326 and -C*02:254N carry exonic mutations causing amino acid change or truncation.

关键词： COVID-19   Long COVID   HLA   KIR   Vaccination  

摘要： Background: The COVID-19 pandemic has led to widespread infection, with a significant subset of patients developing persistent symptoms known as Long COVID. Understanding the genetic factors influencing Long COVID susceptibility and severity is crucial for development of targeted interventions. Objective: This study aimed to evaluate the impact of HLA alleles, KIR receptors, and their interactions on the development of Long COVID in patients from southeastern Spain having contracted COVID-19 during the early 2020 pandemic wave. Methods: A cross-sectional prospective study enrolled 153 COVID-19 patients. Three months post-infection, HLAA, -B, -C, KIR genotyping and immunological variables were analyzed using serum and blood samples. Long COVID was diagnosed three years post- infection based on persistent symptoms. Results: Among the participants, 71 developed Long COVID. HLA-A*03 was less frequent in Long COVID compared to non-Long COVID patients (10.7 % vs. 30.5 %, p = 0.001). Patients with HLA-A*03 had a higher percentage of CD8+ T cells than patients with other allotypes (33.6 f 13.4 % vs 28.7 f 10.8 %, p = 0.033) and showed lower expression of KIR2DL1(1265 f 547 vs 1465 f 414 MFI, p = 0.031) and KIR3DL1 (300.6 f 125.0 vs 398.9 f 131.0 MFI, p = 0.047). Moreover, NK cells in HLA-A*03 patients showed lower expression of the TIGIT inhibitory receptor (73.7 f 12.2 % vs 78.2 f 10.8 %, p = 0.046). Conclusion: HLA-A*03 may play a protective role against Long COVID, potentially through enhanced immune responses involving CD8+ T cells and NK cells. Further research in larger, diverse cohorts is needed to validate these findings and to refine personalized medicine strategies for managing COVID-19 sequelae.

关键词： Fluorouracil   Oleuropein   Inflammation   Heart   Lung   Oxidative stress  

摘要： The cardiac and lung damage are considered a serious risk associated with the administration of chemotherapy agents like 5-fluorouracil (5-FU). Oleuropein (OLE) is valuable medicinal plant that has diverse pharmacological properties with remarkable antioxidant activities. This research aimed to evaluate the impact of OLE on cardiac and pulmonary toxicity induced by 5-FU. 24 adult rats were randomly assigned to four groups (N = 6), which included a control group, a group receiving 5-FU at a dosage of 100 mg/kg, a group administered OLE at 200 mg/kg, and a group treated with both 5-FU and OLE (5-FU + OLE). Following the treatment, blood samples were obtained for the assessment of biochemical parameters, and the cardiac and pulmonary tissues were removed for the measurement of oxidative stress and inflammatory cytokines and histological alterations. 5-FU elevated lipid profiles (triglyceride, low-density lipoprotein (LDL), and cholesterol), glucose serum levels, and myocardial injury markers (CK-MB and LDH), malondialdehyde (MDA), interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) expression. Additionally, the histopathological analysis of 5-FU revealed dystrophic calcification (DC) in the cardiac tissues and neutrophil infiltration in the lung tissues. However, the administration of OLE reduced lipid profiles, glucose, lactate dehydrogenase (LDH), creatine kinase-myocardial band (CK-MB) levels and inflammation, improved antioxidant capacity, and pathological alterations. It seems that OLE exerts cardio-pulmonary protective effects against 5-FU toxicity through the decrease of oxidative stress and inflammatory cytokines.

关键词： HLA   immune checkpoint inhibitor   lymphocyte   oral cancer   PD-L1  

摘要： Oral squamous cell carcinoma (OSCC) is one of the most common head and neck cancers, and immunotherapy targeting programmed cell death 1 (PD-1) has become a treatment option for recurrent OSCC after surgery and radiation therapy. However, few studies have identified definitive biomarkers for predicting patient response to anti-PD1 therapy in OSCC. In the present study, biopsy specimens were obtained from 23 patients with recurrent OSCC who were subsequently treated with anti-PD1 therapy. Immunohistochemical examinations of CD3, CD8, FOXP3, CD103, CD163, programmed cell death ligand 1 (PD-L1), HLA-A/B/C, HLA-DR, and beta 2 microglobulin were performed, and their correlation with clinical response was statistically analyzed. We found that an increased density of CD8-positive lymphocytes and increased PD-L1 expression predicted a favorable response to anti-PD1 therapy in recurrent OSCC. In contrast, clinical factors such as age and sex, and immune-related factors such as HLA-Classes I and II, were not associated with the response to anti-PD1 therapy. Taken together, our results suggest that immunohistochemical analysis of CD8 and PD-L1 may be useful for predicting the efficacy of anti-PD1 therapy in recurrent OSCC.

关键词： Autoimmunity   Enterovirus   HLA-I molecules   Immunofluorescence   Immunohistochemistry   Pancreas   Type 1 diabetes  

摘要： Aims/hypothesis Earlier studies of pancreases from donors with type 1 diabetes demonstrated enteroviral capsid protein VP1 in beta cells. In the context of a multidisciplinary approach undertaken by the nPOD-Virus group, we assessed VP1 positivity in pancreas and other tissues (spleen, duodenum and pancreatic lymph nodes) from 188 organ donors, including donors with type 1 diabetes and donors expressing autoantibody risk markers. We also investigated whether VP1 positivity is linked to the hyperexpression of HLA class I (HLA-I) molecules in islet cells. Methods Organ donor tissues were collected by the Network for Pancreatic Organ Donors with Diabetes (nPOD) from donors without diabetes (ND, n=76), donors expressing a single or multiple diabetes-associated autoantibodies (AAb(+), n=20;AAb(++), n=9) and donors with type 1 diabetes with residual insulin-containing islets (T1D-ICIs, n=41) or only insulin-deficient islets (T1D-IDIs, n=42). VP1 was assessed using immunohistochemistry (IHC) and HLA-I using IHC and immunofluorescence, in two independent laboratories. We determined assay concordance across laboratories and overall occurrence of positive assays, on a case-by-case basis and between donor groups. Results Islet cell VP1 positivity was detected in most T1D-ICI donors (77.5%) vs only 38.2% of ND donors (p<0.001). VP1 positivity was associated with HLA-I hyperexpression. Of those donors assessed for HLA-I and VP1, 73.7% had both VP1 immunopositivity and HLA-I hyperexpression (p<0.001 vs ND). Moreover, VP1(+) cells were detected at higher frequency in donors with HLA-I hyperexpression (p<0.001 vs normal HLA-I). Among VP1(+) donors, the proportion with HLA-I hyperexpression was significantly higher in the AAb(++) and T1D-ICI groups (94.9%, p<0.001 vs ND);this was not restricted to individuals with recent-onset diabetes. Critically, for all donor groups combined, HLA-I hyperexpression occurred more frequently in VP1(+) compared with VP1(-) donors (45.8% vs 16%, p<0.0