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关键词： alendronate sodium bisphosphonate   bone mineral density   insulin-like growth factor   interleukin   osteoporosis  

摘要： Objective: To assess the effects of bisphosphonates (zoledronic acid injection) plus alendronate sodium on bone mineral density (BMD) and levels of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and insulin-like growth factor I (IGF-I) in patients with osteoporosis. Materials and methods: A total of 94 patients recruited from osteoporosis patients hospitalized in the period October 2021 to December 2022 were assigned to either a control group or an observation group using a random number table. The control group was treated with alendronate sodium alone, whereas the observation group received zoledronic acid injection in combination with alendronate sodium administered orally. Results: Pre-treatment values for BMD, serum levels of IL-6, TNF-alpha, and IGF-I did not differ between the two groups (p > 0.05). However, post-treatment BMD measured at the femoral neck, in lumbar vertebrae, and Ward's triangle were increased, as was serum IGF-I level (p < 0.05). In contrast, in comparison with the control group, reductions were observed in serum IL-6 and TNF-alpha (p < 0.05). The incidence of adverse reactions such as nausea and vomiting, diarrhea, musculoskeletal pain, and hypocalcemia was significantly lower in the observation group (p < 0.05). Conclusion: Zoledronic acid injection in combination with alendronate sodium increases the expression of IL-6, TNF-alpha, and IGF-I, suppresses bone resorption and promotes bone recovery in patients with osteoporosis.

关键词： cartilage degradation   condylar chondrocytes   DDX5   temporomandibular joint osteoarthritis   tumor necrosis factor signaling  

摘要： Background: Temporomandibular joint osteoarthritis (TMJOA) is a prevalent musculoskeletal condition characterized by pain, cartilage degeneration, and subchondral bone loss. Objective: This study sought to identify specific targets for the treatment of TMJOA. Method: Through high-throughput RNA-seq analysis in condylar chondrocytes (NC vs. MS), we discovered that DDX5 was downregulated and closely negatively related to the progression of TMJOA. Similarly, we found that DDX5 was downregulated in injured condylar cartilage of patients as well as the condyles of UAC-induced TMJOA mice. The chondrocyte-specific deletion of Ddx5 aggravated tissue destruction in TMJOA modeling by inducing degradation of extracellular matrix (ECM). Results: The loss of DDX5 facilitated chondrocyte degradation and the occurrence of joint inflammation in condylar chondrocytes. In addition, the local injection of AAV overexpressing DDX5 significantly alleviated inflammation, cartilage degradation, and subchondral bone loss in TMJOA mice. RNA-seq analysis revealed that the DDX5 deficiency mostly activated the TNF-induced nuclear factor-kappa B (NF-kappa B) signaling pathway causing the occurrence of TMJOA. Conclusion: Mechanistically, the inhibition of DDX5 accelerated cartilage degeneration by activating TNF-induced NF-kappa B signaling. Thus, DDX5 emerges as a potential effective drug target for future therapeutic approaches in TMJOA.

关键词： Chimeric antigen receptor  

关键词： hypertension   interleukin 17A   immunity   T helper 17 cells   inflammation  

摘要： Background The immune system is closely related to hypertension. Hypertension is an immune disorder to a certain extent, and inflammation is the basis of abnormally elevated blood pressure (BP). The accumulation of T cells and their cytokines can increase BP and end organ damage. T cells are activated by antigen-presenting cells of the innate immune system or by the influence of a high-sodium diet, the self-environment, or the gut microbiota. These cells produce inflammatory factors and cytokines, such as interleukin-17A (IL-17A) in T helper 17 cells, causing vascular inflammation, hypertension, and target organ damageMethods In this article, we provide an insightful review of the research progress regarding the role of IL-17A in the pathogenesis of hypertension and its effects on different organs while emphasizing the role of IL-17A and its mediated functions in the kidneys, brain, intestines, and vascular system in the development and progression of *** At the organ level, IL-17A is involved in the development and progression of hypertension in the kidneys, brain, intestines, and blood vessels, interacting with multiple signal *** These findings have significant implications for developing future immunomodulatory therapies, which may lead to the development of potential treatments for hypertension.

摘要： Accurate prediction of interleukin-13 (IL-13)-inducing epitopes is crucial for advancing targeted therapies against allergic inflammation, the cytokine storm associated with severe COVID-19, and related disorders. Current epitope prediction methods, however, often exhibit limitations in efficiency and accuracy. To address this, we introduce DeepEpilL13, a novel deep learning framework that uniquely synergizes pretrained language models with multiwindow convolutional neural networks (CNNs) for the rapid and accurate identification of IL-13-inducing epitopes from protein sequences. DeepEpilL13 leverages high-dimensional embeddings generated by the pretrained language model, which capture rich contextual information from protein sequences. These embeddings are then processed by a multiwindow CNN architecture, enabling the effective exploration of both local and global sequence patterns pertinent to IL-13 induction. The proposed DeepEpilL13 approach underwent rigorous evaluation using both benchmark data sets and an independent SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) data set. Results demonstrate that DeepEpilL13 achieves superior performance compared with traditional methods. On the benchmark data set, DeepEpilL13 attained a Matthews correlation coefficient (MCC) of 0.52 and an area under the receiver operating characteristic curve (AUC) of 0.86. Notably, when assessed on the independent SARS-CoV-2 data set, DeepEpilL13 exhibited remarkable robustness, achieving an MCC of 0.63 and an AUC of 0.92. These metrics underscore the enhanced predictive capability and robust applicability of DeepEpilL13, particularly within the context of the COVID-19 research and related viral infections. This study presents DeepEpilL13 as a powerful and efficient deep learning framework for accurate epitope prediction. By offering significant improvement in performance and robustness, DeepEpilL13 provides new and promising avenues for the development of epitope-based vacc

摘要： Enteroinvasive bacterial pathogens are responsible for an enormous worldwide disease burden that critically affects the young and immunocompromised. is a Gram-negative enteric pathogen, closely related to the plague agent , that colonizes intestinal tissues, induces the formation of pyogranulomas along the intestinal tract, and disseminates to systemic organs following oral infection of experimental rodents. Prior studies proposed that systemic tissues were colonized by a pool of intestinal replicating bacteria distinct from populations within Peyer's patches and mesenteric lymph nodes. Whether bacteria within intestinal pyogranulomas serve as the source for systemic dissemination, and the relationship between bacterial populations within different tissue sites is poorly defined. Moreover, the factors that regulate colonization and dissemination are not well understood. Here, we demonstrate, using Sequence Tag-based Analysis of Microbial Populations in R (STAMPR), that remarkably small founder populations independently colonize intestinal and systemic tissues. Notably, intestinal pyogranulomas contain clonal populations of bacteria that are restricted and do not spread to other tissues. However, populations of are shared among systemic organs and the blood, suggesting that systemic dissemination occurs via hematogenous spread. Finally, we demonstrate that TNF signaling is a key contributor to the bottlenecks limiting both tissue colonization and lymphatic dissemination of intestinal bacterial populations. Altogether, this study reveals previously undescribed aspects of infection dynamics of enteric bacterial pathogens.

关键词： IL-6   Trans-signaling   sgp130   Stroke   Sex-difference  

摘要： Introduction Elevated circulating IL-6 levels are associated with poorer outcomes after stroke, and increased serum IL-6 levels are linked to a higher risk of stroke. IL-6 binds to soluble IL-6 receptors (sIL-6R) and subsequently to ubiquitously expressed gp130, initiating proinflammatory trans-signaling. This study tested the hypothesis that inhibiting IL-6 trans-signaling by administering soluble (s) gp130 improves long-term functional outcomes in young mice after stroke. Methods Recombinant mouse gp130Fc chimera (sgp130) was administered one hour after middle cerebral artery occlusion (MCAO) followed by twice-weekly administration for 2 weeks in mice (8-15 weeks old). Behavioral assessments were done on days 7 and 28 post-MCAO for chronic studies. Flow cytometry was performed on days 3 (blood) and 7 (spleen and brain) to assess IL-6, mIL-6R, and phosphorylated STAT3 expression. Results Improved long-term functional outcomes were observed in male, but not female mice. To investigate the differential response in females, ELISA analyses revealed that plasma IL-6 levels increased in both sexes after MCAO, with a more pronounced induction in females. Additionally, circulating sIL-6R levels were significantly higher in females compared to males (p < 0.05) at 24 h post-MCAO. Administering a higher dose of sgp130 (1 mg/kg) to females improved long-term functional outcomes, suggesting that a higher dose is needed to inhibit IL-6 trans-signaling in females effectively. Mechanistically, sgp130 treatment reduced phosphorylated STAT3 expression in brain F4/80 macrophages and increased the expression of mIL-6R on splenic immune cells at day 7 post-MCAO in both sexes. Conclusion These findings demonstrate that inhibition of IL-6 trans-signaling with gp130Fc improves long-term functional outcomes in both male and female mice, albeit in a dose-dependent manner. This study provides novel insights into potential therapeutic strategies targeting IL-6 signaling pathways following str

摘要： Tumor necrosis factor-alpha (TNFα) induces vascular permeability and plays an important role in inflammation. In addition, TNFα-induced vascular leakage is involved in the increased extravasation of nanoparticle-formulated chemotherapeutic drugs, improving drug delivery and subsequent tumor response. Here, we uncovered a positive correlation between the presence of pericytes in the tumor-associated vasculature and TNFα-induced leakage and drug delivery, especially when drugs were encapsulated in nanoparticles. RNA-sequencing and pathway analysis identified high expression of CXCL10 in TNFα-stimulated pericytes. In addition, TNFα increased CXCL10 protein production by pericytes in vitro. In animal studies, tumor types with vessels with high pericyte coverage showed enhanced permeability and extravasation of drugs encapsulated in nanoparticles following treatment with TNFα, which could be blocked with a CXCL10 neutralizing antibody. In contrast, tumors harboring vessels with low pericyte numbers did not display increased drug extravasation in response to TNFα. Lack of pericyte coverage could be compensated by co-administration of CXCL10. These findings reveal a mechanism by which TNFα induces CXCL10 release from pericytes, resulting in increased endothelial permeability, vascular leakage, and drug delivery.