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关键词： HLA‐G 14‐bp   meta‐analysis   polymorphism   recurrent spontaneous abortion  

摘要： We performed a meta-analysis to study the relationship between HLA-G 14-bp insertion/deletion polymorphism and recurrent spontaneous abortion (RSA). All literature was searched from PubMed, Web of Science, Embase and Wanfang databases. Statistical analyses were performed by the STATA software (Version 16.0). A total of 35 studies were analysed which included 3652 women with RSA and 3331 normal control subjects. The current meta-analysis revealed that 14-bp insertion/deletion polymorphism has a significant association with RSA (I vs. D: OR: 1.17; 95% CI (1.05-1.30); II + ID vs. DD: OR: 1.33; 95% CI (1.11-1.59); II vs. DD: OR: 1.34; 95% CI (1.07-1.66); ID vs. DD: OR: 1.30; 95% CI (1.08-1.58)). Subgroup analysis by the number of abortions indicated that there was no significant association between HLA-G 14-bp insertion/deletion polymorphism and RSA risk in women with two or more abortions. However, HLA-G 14-bp insertion/deletion polymorphism was associated with the risk of RSA in women with three or more abortions as well as the overall population (I vs. D: OR: 1.26; 95% CI (1.04-1.52); II + ID vs. DD: OR: 1.47; 95% CI (1.09-1.98); II vs. DD: OR: 1.52; 95% CI (1.08-2.13); ID vs. DD: OR: 1.45; 95% CI (1.06-1.99)). Subgroup analysis by ethnicity indicated that HLA-G 14-bp insertion/deletion polymorphism increased RSA risk in both Asian ancestry group (II + ID vs. DD: OR: 1.35; 95% CI (1.06-1.73); ID vs. DD: OR: 1.37; 95% CI (1.06-1.78)) and European ancestry group (I vs. D: OR: 1.25; 95% CI (1.08-1.45); II vs. ID + DD: OR: 1.48; 95% CI (1.14-1.91); II vs. DD: OR: 1.61; 95% CI (1.19-2.18)). A p value of < 0.05 was considered statistically significant for these analyses. Our current meta-analysis demonstrated that the HLA-G 14-bp insertion/deletion polymorphism increased the risk of RSA in Asian ancestry group and European ancestry group.

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： Alzheimer’s disease   Caspase-1   Long-term potentiation   Memory   Neuroinflammation   Synaptic failure   TNF   TNFR2  

摘要： Alzheimer's disease (AD) is a critical health problem with a projected increase in prevalence, demanding more efforts to find an effective treatment. AD is characterized by amyloid-β (Aβ) accumulation, which drives neuroinflammation. Aβ-mediated caspase-1-dependent neuroinflammation fuels memory loss through pro-inflammatory cytokines signaling. For instance, TNF promotes synaptic plasticity dysfunction impairing long-term potentiation (LTP), an early hallmark of AD. Thus, targeting TNF receptors (TNFR1 and TNFR2) with antagonists/agonists is a promising therapeutic strategy. Here, we found that intrahippocampal administration of a TNFR2-specific blocking antibody improved recognition memory, spatial memory, and synaptic potentiation in response to chemically induced LTP (cLTP) in 5xFAD mice. Additionally, we found that TNFR2 predominates over TNFR1 on the surface of hippocampal synaptosomes from wild-type mice and that TNFR2 levels increased on the synaptosomal surface of 5xFAD mice in a caspase-1-dependent manner. Notably, caspase-1 deletion and TNFR2 blocking improved synaptic potentiation of hippocampal synaptosomes from 5xFAD mice in response to cLTP. TNF signaling via TNFR2 also reduced cell viability and impaired BDNF-mediated neurite outgrowth in SN56 cholinergic cells. Thus, our data reveal that TNFR2 contributes to neuron- and synapse-specific deleterious effects, impacting the memory of 5xFAD mice, suggesting that TNFR2-dependent signaling at the synapsis should be considered for AD treatment.

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： Chimeric antigen receptor - CAR   Lymphoma   Mitochondria   Natural killer - NK  

摘要： BACKGROUND:Chimeric antigen receptor (CAR)-natural killer (NK) cell therapy has demonstrated safety and feasibility in clinical settings; however, limited efficacy due to intrinsic dysfunction and extrinsic suppression remains an unresolved issue. T cells provide multifaceted support to NK cell-mediated responses. Here, we aimed to design a novel CD19-targeted CAR-NK, engineered with secreted interleukin-15 and C-C motif chemokine ligand 21 (ie, 15×21 CAR-NK), capable of recruiting and cooperating with T cells. METHODS:We characterized 15×21 CAR-NK cells by performing experiments in vitro and in mouse models, and conducting RNA sequencing. RESULTS:15×21 CAR-NK cells exhibit strong capabilities in cytotoxicity, cytokine production, effector molecule expression, and T-cell recruitment in vitro. Cooperation with T cells promoted efficient tumor-cell elimination, alleviated mutual exhaustion phenotypes, and enhanced the expression of effector molecules/receptors. The recruitment and cooperative effects also result in effective tumor control in mouse models. In addition, 15×21 CAR-NK cells strongly enrich the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway - a key intracellular signaling cascade that is associated with enhanced downstream pro-survival signaling, anti-apoptotic ability, mitochondrial function, and cytotoxicity. CONCLUSIONS:Our study highlights the intrinsic advantages and extrinsic T-cell cooperative benefits of 15×21 CAR-NK cells, providing a promising strategy for NK-cell-based immunotherapy.

关键词： beta cells   butyrate   cytokine   inflammation   mitochondria   oxidative stress  

摘要： Butyrate, a gut microbiota-derived metabolite, supports cellular health. In pancreatic beta cells, inflammation and oxidative stress disrupt mitochondrial function, contributing to dysfunction. This study explores how butyrate influences mitochondrial function and redox balance to protect beta cells from interleukin-1beta (IL-1 beta)-induced stress. Pancreatic mouse islets were treated with IL-1 beta and/or butyrate for 10 days to model chronic inflammation in type 2 diabetes, and their effects on mitochondrial health and oxidative stress were studied. Butyrate protected against IL-1 beta-induced impairment of insulin secretion by enhancing mitochondrial function, as evidenced by an increased glucose-stimulated oxygen consumption rate and a higher mitochondrial membrane potential compared to IL-1 beta treatment alone. IL-1 beta increased mitochondrial mass, but the mitochondria appeared smaller and rounded, indicating fragmentation. In contrast, butyrate co-treatment promoted mitochondrial hyperfusion, as evidenced by elongated mitochondria, higher levels of fusion proteins Opa1 and Mfn2, and lower levels of fission protein Fis1 compared to IL-1 beta alone. Furthermore, butyrate reduced IL-1 beta-induced reactive oxygen species (ROS) production, antioxidant enzyme gene expression, and protein oxidation, indicating protection against oxidative stress. Butyrate co-treatment further enhanced redox balance by increasing reduced glutathione (GSH) levels and the ratio of GSH to oxidized glutathione (GSSG). These findings suggest that butyrate acts as a potent modulator of mitochondrial function and redox balance, counteracting IL-1 beta-induced dysfunction and providing a potential therapeutic strategy for improving insulin secretion in inflammatory conditions.

关键词： Pelvic organ prolapses   Adhesive   Exosomes   Immune response  

摘要： Pelvic organ prolapse (POP) is a prevalent condition among middle-aged women, resulting from weakened pelvic floor muscles and ligaments, which cause organ descent and associated dysfunctions. Surgical interventions utilizing polypropylene (PP) mesh are often limited by factors such as complex procedures and postoperative inflammation, leading to suboptimal outcomes. An innovative adhesive hydrogel (CAN-15) has been synthesized from carboxylated methacrylate polyvinyl alcohol (CMPVA), acrylic acid (AA), and acrylic acid N-hydroxysuccinimide ester (AA-NHS) through photopolymerization. This hydrogel exhibits a rapid photopolymerization rate (within 5 s) and robust adhesion (89.17 kPa), enabling the secure attachment of PP mesh to pelvic structures without sutures. Additionally, exosomes derived from interferon-gamma pre-treated adipose stem cells (IFN-gamma-Exos) demonstrate superior immunomodulatory capabilities compared to their non-pretreated counterparts (Exos). The integration of IFN-gamma-Exos with the CAN-15 hydrogel forms a functional adhesive (IFN-gamma-Exos@CAN-15) for POP surgeries. This adhesive facilitates a controlled release of exosomes, with IFN-gamma-Exos modulating the immune response by promoting macrophage polarization towards an anti-inflammatory M2 phenotype, thereby enhancing the local immunological microenvironment. In vivo, uterine prolapse mesh fixation experiments have shown secure mesh attachment and a markedly improved inflammatory response compared to suture methods. The IFN-gamma-Exos@CAN-15 adhesive represents a significant advancement in mesh-based pelvic floor repair surgeries.

关键词： aspartate   inflammation   malate-aspartate shuttle   noncommunicable diseases   sub-Saharan Africa   tumor necrosis factor-alpha   urbanization  

摘要： Urbanization in sub-Saharan Africa is characterized by a shift toward a proinflammatory state and rising rates of noncommunicable diseases. The biological mechanism(s) linking changes in environmental factors to health and disease are incompletely understood. We propose a TNF-hypersecreting phenotype described in rheumatoid arthritis patients also has a role in the inflammatory response differences observed between rural and urban populations living in Africa. The mechanism involves insufficient mitochondrial aspartate production, failed NAD+ regeneration, ER membrane expansion, and enhanced biogenesis of TNF-alpha. Supporting data show serum and stool aspartate levels decline with urbanization, and TNF-alpha production inversely correlates with stool aspartate levels across a spectrum of socioeconomic development. These findings suggest a new hypothesis for the inflammatory differences between rural and urban populations and their role in noncommunicable diseases like atherosclerosis.

关键词： Type-I interferon (IFN-I)   Periodontitis   Neutrophil   Interleukin-17 (IL-17)   Osteoclastogenesis   Monocytes   Single-cell analysis  

摘要： Type I interferons (IFNs-I), a group of pleiotropic cytokines, critically modulate host response in various inflammatory diseases. However, the role of the IFN-I pathway in periodontitis remains largely unknown. In this report, we describe that the IFN-(3 levels in the gingival crevicular fluid of human subjects were negatively associated with periodontitis and clinical gingival inflammation. Disruption of IFN-I signaling worsened alveolar bone resorption in a ligature-induced periodontitis murine model. Deficiency of the IFN-I pathway resulted in an exaggerated inflammatory response in myeloid cells and drastically increased the interleukin-17 (IL-17)-mediated neutrophil recruitment in the gingiva. We further identified that the myeloid lineage-specific IFN-I response was essential in safeguarding against periodontal inflammation by suppressing the IL-17-producing gamma S T cells in gingiva. IFN-I signaling also directly repressed osteoclastogenesis in monocytes, which are precursor cells for osteoclasts. Therefore, our findings demonstrate that an integral myeloid-specific IFN-I pathway protects against bone loss by keeping the IL-17-neutrophil axis in check and directly inhibiting osteoclast formation in periodontitis.