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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： Extracellular vesicles   Nanoparticles   Chlorophyll   Euglena gracilis   Anti-inflammation  

摘要： The development of materials from the photosynthetic microorganism Euglena (E. gracilis, as represented in this study) has gained attention as a new source of biofuel. In addition, Euglena is being marketed as a new food product, with the anti-inflammatory effects of the polysaccharide beta-1,3-glucan highlighted as one of its features. Recent advances in studies on extracellular vesicles (EVs), not only in mammals but also in plants and bacteria, have prompted us to explore Euglena extracellular vesicle-like nanoparticles (eEV-LNPs) as new anti-inflammatory agents. Although the amount of eEV-LNPs in the medium is low, it significantly increases after the heat denaturation of whole Euglena cultures at 120 degrees C for 20 min. This increase correlates with enhanced anti-inflammatory activity, as demonstrated by assays using RAW264.7 cells, particularly evident in the suppression of interleukin-6 (IL-6) expression to 10% of induced level by lipopolysaccharide. The administration of the water-soluble fraction from the heat-denatured Euglena culture to mice with a dextran sodium sulfate-induced colitis model ameliorates inflammatory symptoms by reducing IL-6 expression. Interestingly, the eEV-LNPs exhibited autofluorescence. Chloroform/methanol extraction of Euglena cells suggested that the amount of 7-hydroxymethyl pheophytin, a chlorophyll derivative with fluorescence, increases under 120 degrees C treatment and shows affinity for milk exosomes and anti-inflammatory activities with the suppression of IL-6 expression to 20% of induced level by lipopolysaccharide. These results suggest that heat-treated Euglena cells artificially produce autofluorescent eEV-LNPs encapsulating anti-inflammatory activity, which could serve as novel nanomaterials originated from Euglena.

关键词： Alzheimer's disease sequencing project (ADSP)   HLA-DQ alleles   Blood and brain sample exomes   AD and the adaptive immune system   Tau  

摘要： Although many studies have investigated the influence of HLA on the risk of Alzheimer's Disease (AD), there have been inconsistent results. Part of this problem has been attributed to limitations of a clinical assessment in the absence of histopathological confirmation or other quantitative assessments. This study employed a subset of the AD Sequencing Project, representing 2663 cases with histopathological confirmation of AD and confirmation of 881 cognitively normal cases. Two HLA allelic subtypes, DQB1*02:01 and DQB1*02:02, were associated with lower Braak staging, a measure of tauopathy in the brain. These HLA subtypes were also associated with a later age of onset. There was a lower occurrence of HLA-DQB1*02:01 and HLA-DQB1*02:02 in AD cases compared to cognitively normal cases. For all of the above results, replicative sets were confirmatory. The above results were also maintained for both HLA-DQB1*02:01 and HLA-DQB1*02:02 when removing the effect of APOE4 or APOE2. Interestingly, the HLA-DQB1*02 allele binds tau better than all other HLA-DQB1 alleles tested, per an in silico assessment, raising the question of whether deletion of tau binding, auto-reactive T-cells in the thymus could reduce the likelihood of the onset of AD?

关键词： MCP-1   PTMCs   Rats   Testis   Chemokine   IL-1 signaling  

摘要： Mono-(2-ethylhexyl) phthalate (MEHP) is a metabolite of the diester parent compound Di(2-ethylhexyl) phthalate (DEHP), a widespread environmental toxicant known for its harmful effects on Sertoli cells and the subsequent loss of germ cells through apoptosis in postnatal animals. Peritubular myoid cells (PTMCs) produce various signaling factors, including the chemokine monocyte chemotactic protein 1 (MCP-1);however, the MEHP exposure-induced BTB disruption followed by MCP-1 secretion by PTMCs, the recruitment, and activation of macrophages as well as molecular mechanisms that initiate the secretion in the testis has yet to be closely examined. In this study, we demonstrate for the first time that PTMCs generate MCP-1 via the interleukin-1 signaling pathway upon MEHP exposure. Primary PTMCs isolated from the testis of peripubertal rats were cultured and exposed to 100 mu M and 200 mu M MEHP. Total RNA was used for bulk RNA sequencing, qRT-PCR, and protein lysates for proteomic analysis. Testis and their interstitial fluid (IF) were obtained from MEHP-exposed animals to evaluate the levels of pro-inflammatory cytokines and chemokines in IF through a multiplex assay and in tissue sections through immunofluorescence studies. The RNA sequencing data show significant enrichment of the interleukin-1 signaling pathway after MEHP (200 mu M) exposure for 48 hours. This finding is further supported by the qRT-PCR results for select genes associated with the IL-1 signaling pathway, highlighting the crucial role of this pathway in the response of PTMCs to MEHP exposure. In summary, MEHP exposure stimulates MCP-1 production by PTMCs, and mechanistically, the IL-1 signal transduction pathway governs this response. Keywords: MCP-1, PTMCs, Rats, Testis, Chemokine, IL-1 signaling

关键词： Inflammatory bowel disease   Dihydroartemisinin   Disease activity   Oxidative stress   Anti-inflammatory   Necroptosis   Apoptosis  

摘要： Background: Ulcerative colitis (UC) is an inflammatory bowel disease characterized by the overproduction of reactive oxygen species (ROS) and the release of inflammatory mediators. Dihydroartemisinin (DHA) is a semisynthetic active metabolite of artemisinin that has anti-inflammatory, antioxidant, and anti-fibrotic properties. Objective: This study aimed to assess the therapeutic benefits of DHA on acetic acid(AA) -induced UC in rats, with particular emphasis on its anti-inflammatory effects and its influence on NF kappa B/TNF-alpha/RIPK1 necroptotic pathways. Methods: Eighteen rats were allocated into control, acetic acid-induced colitis (AA), and DHA-treated (AA+DHA) groups. Colitis was caused by rectal instillation of 5 % acetic acid. DHA was supplied via intraperitoneal injection. Histological, biochemical studies of oxidative stress, inflammatory and anti-inflammatory mediators, Western blotting for TNF-alpha, RIPK1, and caspase 3, and immunohistochemical assessment of NF kappa B, TNF-alpha, and RIPK1, were conducted. Results: DHA treatment markedly diminished macroscopic damage, disease activity index, histopathology scores, and malondialdehyde (MDA) levels, enhancing glutathione (GSH) levels. Additionally, DHA decreased serum TNF-alpha and IL-6 and increased IL-10. Western blotting and immunohistochemistry investigations validated the reduced expression of TNF-alpha, RIPK1, and caspase 3 in DHA-treated rats. Conclusion: DHA demonstrates protective properties against acetic acid-induced UC by decreasing oxidative stress and inflammation, modifying TNF-alpha activity to regulate apoptotic and necroptotic pathways. So, DHA may be a favorable therapeutic alternative for the management of ulcerative colitis.

关键词： Bladder cancer   Bioinformatic analysis   MiR-125b   Apoptosis   IL-6/IL-6R/STAT3 pathway  

摘要： Bladder cancer (BLCA) is an aggressive malignancy characterized by limited therapeutic options and a poor prognosis. Research has indicated that abnormally expressed miRNAs play a significant role in the pathogenesis of BLCA, although the specific mechanisms remain unclear. MiR-125b plays a tumor suppressor role in a variety of cancers and affects the biological processes of cancer cells such as proliferation, invasion, migration and apoptosis by regulating different signaling pathways. Elucidation of the molecular mechanisms underlying miR125b may provide clinical therapeutic strategies for bladder cancer. Here, miR-125b was downregulated whereas its targets IL-6R and STAT3 were upregulated in BLCA, as evidenced by bioinformatics analysis. Kaplan-Meier analysis confirmed that miR-125b serves as an independent prognostic factor linked to overall survival (OS) in patients with bladder cancer. Furthermore, overexpression of miR-125b significantly inhibited BLCA cell proliferation, migration, and invasion, while promoting apoptosis, as evidenced by an increased Bax/Bcl-2 ratio and activated cleaved caspase-3. Further investigations demonstrated that miR-125b directly targets and downregulates both IL-6R and STAT3. In a xenograft model, miR-125b overexpression effectively inhibited tumor growth in bladder cancer by blocking IL-6/IL-6R and STAT3 signaling pathways. Collectively, these findings broaden our understanding of the mechanism by which miR-125b acting as a BLCA suppressor in apoptotic regulation by targeting the IL-6/IL-6R/STAT3 signaling pathway, providing novel insights regarding the design of novel miRNA based therapeutic strategies against BLCA.

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： Cognitive dysfunction   Cytokines   Interleukin-1 beta   Interleukin-6   Methamphetamine   Tumor necrosis factor-alpha  

摘要： Objective:To investigate the cognitive impairment and peripheral inflammation induced by methamphetamine (METH) and their association in METH abusers. Methods:The cross-sectional study included 100 METH-dependent patients and 100 healthy controls. Cognitive screening was conducted using the Thai version of the Montreal Cognitive Assessment (MoCA-T). Thirty normal controls and 30 METH-dependent patients were randomly selected for blood collection to measure inflammatory markers, including tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6, using a quantitative enzyme-linked immunosorbent assay method. Results:METH-dependent patients had significantly poorer MoCA-T scores and higher levels of blood inflammatory markers compared to healthy controls. Demographic characteristics, METH use patterns, and proinflammatory cytokines were associated with cognitive impairment. The MoCA-T score was negatively associated with plasma TNF-α and IL-6 levels. Conclusion:METH-associated cognitive decline is correlated with elevated plasma levels of TNF-α and IL-6 cytokines, indicating the involvement of specific neuroinflammatory pathways in neurocognitive dysfunction. These insights could pave the way for novel therapeutic strategies aimed at mitigating neuroinflammation, potentially improving outcomes for individuals with METH addiction.

关键词： IL-33   ST2   Superoxide anion   Glial cells   Inflammation   And pain  

摘要： Reactive oxygen species such as superoxide anion have varied roles in inflammation and pain, which can be mimicked by potassium superoxide (KO2), the superoxide anion donor. Interleukin (IL)-33 has pleiotropic functions by activating its receptor suppression of tumorigenicity 2 (ST2). However, the role of IL-33/ST2 signaling in inflammatory pain initiated by reactive oxygen species (ROS) such as superoxide anion has not been investigated, which was the aim of the present study. IL-33 levels were assessed by enzyme-linked immunosorbent assay (ELISA). Mechanical and thermal hyperalgesia and overt pain were evaluated by electronic von Frey, hot plate, and abdominal writhing/paw flinching/licking, respectively. Edema and leukocyte recruitment (myeloperoxidase assay and total/differential cell count), antioxidant capacity, superoxide anion production and lipid peroxidation were assessed. Paw skin and spinal cord messenger ribonucleic acid (mRNA) expression of pro-inflammatory mediators and glial markers in the spinal cord were evaluated. Immunofluorescence was used to detect spinal glial and neuronal c-Fos activation. KO2 injection triggered IL-33 production in the paw skin and spinal cord of mice, induced hyperalgesia, edema, neutrophil recruitment to the paw tissue, overt pain-like behavior, and leukocyte recruitment to the peritoneum that were reduced in ST2 deficient mice. In the paw skin and spinal cord, KO2 triggered IL-33/ST2-dependent oxidative stress, and mRNA expression of inflammatory molecules, which were reduced by ST2 deficiency. KO2 induced spinal cord glial (at mRNA/protein levels) and neuronal activation in IL-33/ST2-dependent manner. IL-33/ST2 signaling mediates, at least in part, superoxide anion-induced inflammatory pain by modulating local and spinal inflammatory events.

关键词： IL-22   Intestinal injury   Predictive biomarker   Radiation   Radiosensitivity  

摘要： Considering the beneficial role played by IL-22 in alleviating radiation-induced intestinal injury through its promotion of epithelial regeneration, it was hypothesized that individuals with elevated IL-22 levels might display either minimal intestinal injury or increased resistance following ionizing irradiation exposure. To assess the impact of IL-22 on intestinal radiosensitivity, IL-22 expression levels was detected in serum of normal mice. Mice naturally with high or low levels of IL-22 or pretreated with IL-22 or anti-IL-22 were subjected to 10 Gy of total abdominal radiation (TAI). Daily observation, morphometric analysis, quantitative reverse transcriptase polymerase chain reaction, immunohistochemistry and western blot were employed to measure weight loss, survival rate, cell proliferation and death, and DNA damage. Furthermore, influence of IL-22 pretreatment on survival of intestinal organoid exposed to 6 Gy X-rays was evaluated. The results showed that IL-22 expression levels were varied between individuals. Surprisingly, mice with high IL-22 levels displayed exacerbated intestinal injury manifesting as increased weight loss, reduced regeneration capacity and more cell apoptosis. Notably, a strong positive correlation between weight loss and IL-22 expression level was observed. Additionally, pretreatment with IL-22 resulted in increased mortality accompanied by enhanced cell apoptosis and DNA damage in crypt of early exposure, as well as diminished survival of intestinal organoid, while pretreatment with anti-IL-22 antibody alleviated the intestinal injury. In this study, we established a direct link between IL-22 and radiosensitivity, suggesting IL-22 could be used as a potential biomarker for predicting individual intestinal radiosensitivity prior to radiation exposure. © 2025