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关键词： Cancer   Inflammatory Cytokines   Obesity, Body Mass Index   Venous Thromboembolism  

摘要： Background Obesity and cancer increase thrombosis risk. IL-6 and TNF-α, are key inflammatory cytokines, which may contribute to hypercoagulability in newly diagnosed, chemotherapy-naïve obese cancer patients, warranting further investigation. This study aimed to investigate the serum levels of these inflammatory biomarkers and risk of VTE in chemotherapy naïve obese cancer patients (CNOCPs).

关键词： aging   IL-33   Leydig cells   mesenchymal cells   steroidogenesis  

摘要： BackgroundSerum testosterone (T) concentration declines with aging in men, potentially affecting reproduction, mental and physical well-beings. A role of immune factors in Leydig cell (LC) function is well-known, but the specific factors involved, especially these playing roles in LC aging, are still unclear. This study investigated effects of interleukin 33 (IL-33) on LC function and its expression during testicular *** and Western blotting were used to determine IL-33 and its receptor IL1RL1 expressions in testes of young (3-month-old) and old (19-24-month-old) Wistar rats. In vitro, the effects of IL-33 on sex steroid hormone productions were evaluated in primary and MLTC-1 LCs over 2-24 h. Different steroidogenic stimulators or signaling molecules (luteinizing hormone [LH], 8-Br-cAMP, Forskolin, pertussis toxin, and MAPK activators) were compared with elucidate mechanisms. Steroidogenic pathway proteins and potential signaling molecules were explored by Western ***-33 is expressed by mesenchymal cells, with the number increasing significantly with aging. IL1RL1, its receptor, is expressed by LCs and remains unchanged. In vitro, IL-33 acutely inhibited LC steroidogenesis in a dose-dependent manner (1-100 ng/mL) within 2-24 h. The effect was LH-dependent;replacing LH with either 8-Br-cAMP or Forskolin abolished the inhibition. IL-33 mainly affected STAR in the steroidogenic pathway. Signaling molecules involving STAR regulation (AKT and MAPK) were down-regulated while PKA phosphorylation was increased. P38 MAPK involvement was confirmed as increased Tyr182 phosphorylation of P38 by SB203580 partly reversed the IL-33-induced steroidogenesis *** mesenchymal cells can synthesize IL-33, and LCs express the receptor IL1RL1. IL-33 inhibits LC steroidogenesis in vitro, partially via inhibiting P38 MAPK phosphorylation. As IL-33-expressing cell numbers rise significantly with aging, its role in age-r

关键词： biofilm-infected diabetic ulcers   core-shell microneedle   macrophage polarization   spatiotemporal immunomodulatory  

摘要： Macrophage phenotypic dysregulation, spatially by biofilm and dynamically in time, impedes the healing of diabetic ulcers (DUs). Effective treatment requires enabling spatiotemporal regulation of macrophage polarization, balancing the M1 pro-inflammatory antimicrobial response with the M2 anti-inflammatory tissue-regeneration response. Here, a core-shell microneedle system (LM-MG@MN) is proposed with spatiotemporal immunomodulation features, designed to spatially disrupt biofilm barriers and sequentially induce macrophage polarization from M0 to M1 and subsequently to M2 by regulating the NLRP3/IL-1 beta pathway. Glucose oxidase (GOX)-loaded 2D MXene nanosheets (MG) are encapsulated in a hyaluronic acid-beta-cyclodextrin (HA-beta-CD) matrix as the MN shell layer. The rapid dissolution of this shell triggers MG to induce pro-inflammatory polarization of macrophages from M0 to M1, aiding in clearing biofilm infections. Liposomes (LM) carrying the NLRP3 inflammasome inhibitor MCC950 are embedded within a methacrylate hyaluronic acid (HAMA) matrix in the MN core. In the later stages of wound healing, LM is released gradually from the core, promoting the anti-inflammatory polarization of macrophages from M1 to M2 and accelerating tissue regeneration by enhancing crosstalk with fibroblasts and endothelial cells. Additionally, RNA sequencing indicates that LM-MG@MN regulates macrophage metabolic reprogramming to enhance DUs healing. This spatiotemporal immunomodulation strategy offers a promising approach for clinical DUs treatment.

关键词： HLA-B27   uveitis   vitamin D  

摘要： In this study, we investigated the effects of HLA-DQB1*03:01 on the onset age of type-1 narcolepsy. We pooled data from 5,339 cases from China, Europe, Korea, Japan, and the United States to conduct the first transethnic study on age of onset (OA). GWAS was used to detect the associated genes. HLA alleles were imputed by HIBAG. Three datasets (DGN, CHINA, and CAUC) were used for TCR analyses. Chinese patients were found to have an earlier age of onset. Independently of this, only one strong GWAS significant effect was observed, summarized by the presence of DQB1*03:01 and centered around the coding region of this gene. In contrast, DQ0602 dosage did not strongly affect onset, and other known narcolepsy-associated genetic loci had minor effects. The DQB1*03:01 effect (mean -3.47 years, p=1.7 10-18) showed no heterogeneity across ethnic groups and was independent of common allelic variation at DQA1 in cis of DQB1*03:01 (DQA1*03:03; DQA1*0505; DQA1*06:01). This effect may be explained by presentation of peptide(s) across all DQ0301 heterodimers, or, considering genetic effects mapping on TCRA and TCRB, effects on TCR repertoire. Using bulk and single-cell RNA-seq data across two ethnic groups, we found that DQB1*03:01 alters TCR repertoire at specific positions, most significantly within the CDR2A, CDR2B and CDR3B loops. These results illustrate the remarkable conservation of narcolepsy genetic effects across ethnicity and suggest that specific TCRs regulate narcolepsy onset. This result will likely be illuminating of the pathophysiology once T cells causative of the disease have been identified.

关键词： Red nucleus   Neuropathic pain   Metabotropic glutamate receptors   Tumor necrosis factor-alpha   Interleukin-1 beta  

摘要： Metabotropic glutamate receptors (mGluR) participate in pain modulation and mediate different effects in nociceptive stimuli, relying on the receptor subtype activated and its anatomical location. Here, we addressed the functions of mGluR III group (mGluR4, mGluR6, mGluR7, and mGluR8) in the red nucleus (RN) in nociception and the development of neuropathic pain induced by spared nerve injury (SNI) using male rats. Our results showed that mGluR4, mGluR7, and mGluR8, except for mGluR6, were constitutively expressed in the RN of normal rats. At 2 weeks post-SNI, the expressions of mGluR4 and mGluR8 rather than mGluR7 were reduced in the RN contralateral to the nerve lesion. Unilateral administration of mGluR III antagonist MSOP to the RN of normal rats decreased the PWT of contralateral hindpaw and evoked pronounced mechanical allodynia, which was blocked by mGluR4 agonist VU0155041 or mGluR8 agonist AZ12216052 instead of mGluR7 agonist AMN082. Moreover, administration of VU0155041 or AZ12216052 to the RN contralateral to the nerve injury at 2 weeks post-SNI alleviated SNI-induced neuropathic pain. Further studies indicated that administration of MSOP to the RN of normal rats increased the expressions of nociceptive factors TNF-alpha and IL-1 beta, which were blocked by VU0155041 or AZ12216052 instead of AMN082. Additionally, administration of VU0155041 or AZ12216052 to the RN at 2 weeks post-SNI inhibited the overexpressions of TNF-alpha and IL-1 beta induced by SNI. These findings suggest that red nucleus mGluR4 and mGluR8 instead of mGluR7 inhibit nociception and the development of neuropathic pain by restraining the expressions of TNF-alpha and IL-1 beta.

关键词： IL-6   intestinal stem cells (ISCs)   IR-induced intestinal injury   STING   TLR2  

摘要： Ionizing radiation (IR) induced damages are common complications of radiotherapy for tumors, severely limiting the intensity and therapeutic efficacy of the radiotherapy program. Emerging data indicated that the cGAS-STING pathway has paradoxical effects on IR-induced damage. SR-717, as a non-nucleotide, small-molecule stimulator of interferon genes (STING) agonist, has been proven that it could activate the STING signaling pathway. In this work, we try to explore the radioprotection of the STING signaling pathway and figure out whether SR-717 could be a potential intestinal radioprotective agent. C57BL/6 mice were intraperitoneally treated with SR-717 or normal saline (NS). By analyzing the survival rate, body weight, and the number of peripheral blood cells after IR exposure, we found that SR-717 improved the survival rate and body weight of mice, protected the intestine from IR-induced damage as well as hematopoietic damage, and promoted the regeneration of intestinal stem cells (ISCs). Cell viability and apoptosis after irradiation were detected after stimulation of MODE-K cells with SR-717 or PBS. We found that SR-717 increased cell viability and inhibited apoptosis in vitro. The mechanism of SR-717 in intestinal radiation protection was investigated by RNA-seq. The results of RNA-seq and qRT-PCR suggested that SR-717 significantly activated the immune system via the STING-IL-6 signaling pathway. In addition, we discussed the role of TLR2 in SR-717-mediated anti-radiation activity, and TLR2 deletion significantly reversed the radioprotective effects of SR717. In conclusion, we proved STING signaling activation displayed anti-radiation activity and found SR-717 displayed anti-radiation activity via the STING-IL-6 signaling pathway, suggesting SR-717 could be a potential intestinal radioprotective agent.

关键词： NiO-NPs   Sodium houttuyfonate   Lung injury   TNF-alpha   JAK-STAT signaling pathway  

摘要： Nickel oxide nanomaterials (NiO-NPs), as engineered nanomaterials, are frequently implicated in the onset of various inflammatory disorders. However, no specific therapeutic agent is currently available for pneumonia induced by NiO-NPs exposure. In the present study, a cytotoxicity model was established using rat type II alveolar epithelial cells (ACE-II) to investigate the cellular effects of NiO-NPs, while a rat model of lung injury was developed in Wistar rats via a non-exposure tracheal instillation technique. To address this pathology, we formulated a sodium houttuyfonate (SH) nanoemulsion characterized by favorable fluidity and uniform dispersion, and evaluated its therapeutic efficacy and underlying mechanisms in NiO-NPs-induced acute lung injury through three distinct administration routes: Houttuynia cordata decoction, SH tablets and SH nano-emulsion. Concurrently, network pharmacology and transcriptomic analyses were conducted to identify key molecular targets and signaling pathways. The findings demonstrated that both Houttuynia cordata and SH significantly reduced TNF-alpha levels and inhibited the activation of the JAK-STAT signaling pathway both in vitro and in vivo, thereby mitigating NiO-NPs-induced pulmonary injury. Among the various formulations tested, the SH nanoemulsion exhibited the most pronounced therapeutic efficacy. This study offers a promising therapeutic strategy for NiO-NPs-induced lung injury and contributes to the advancement of pharmacological interventions for nanomaterial-related inflammatory diseases.

关键词： HIV   skin disorders   DQA1   DQB1   DRB1   cytokines  

摘要： Background and Objectives: This study explores the immunogenetic associations of human leukocyte antigens (HLAs) and cytokine levels in people living with HIV/AIDS (PLWH) who exhibit HIV-related skin disorders. HIV-related skin disorders, including inflammatory eruptions, atopic and seborrheic dermatitis, psoriasis, and pruritic papular eruption, are common among PLWH. These conditions may be influenced by genetic and immunological factors. This study aims to investigate the associations between HLA class II alleles, cytokine levels, and the presence of HIV-related dermatoses, providing insights into genetic susceptibility and immune mechanisms. Materials and Methods: This study included 115 PLWH with HIV-related skin disorders and a control group of 80 healthy individuals. HLA allele frequencies were analyzed, and cytokine levels (IL-1 beta, IL-10, IFN-y) were measured in blood samples. Statistical analyses were performed to identify significant differences in allele frequencies and cytokine responses between the groups. Results: Risk alleles (DQB1*0201:0301, OR = 19.4 and DQA1*0101:0501, OR = 4.2) and protective alleles (DRB1*07:13, OR = 0.19, DRB1*01:13, OR = 0.09, DRB1*04:11, OR = 0.07, and DQA1*0501:0501, OR = 0.24) showed statistically significant differences in frequency (p < 0.05) between PLWH and healthy controls. The protective DQA1*0501:0501 allele was associated with elevated levels of IL-1 beta (p < 0.001, r = 0.79) and IL-10 (p = 0.010, r = 0.63). Increased IL-1 beta levels may enhance immune responses, while higher IL-10 levels may exert anti-inflammatory effects, potentially reducing susceptibility to HIV-related dermatoses. Regression analysis revealed that IL-1 beta (Exp(B) = 0.76, p < 0.001) and IFN-gamma (Exp(B) = 1.06, p = 0.043) are significant predictors for the likelihood of developing HIV-related dermatoses. An increase in IL-1 beta levels reduced this likelihood by 24%, while an increase in IFN-gamma levels increased it by 6%. Conclusions: