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关键词： ferroptosis   GBM   indole-3-pyruvic acid (I3P)   Nrf2   ubiquitination  

摘要： Glioblastoma multiforme (GBM) is the deadliest brain tumour with an extremely poor prognosis. Tryptophan catabolism could enhance an array of protumour-genic signals and promoted tumour progression in GBM. However, the mechanisms of oncogenic signalling under tryptophan catabolism and potential therapy targeting this pathway have not been completely understood. Interleukin 4-induced 1 (IL4I1) is newly defined as a tryptophan metabolic enzyme and the potential function in GBM cells still remains unclear. In our study, we found IL4I1 was upregulated in GBM patients and predicted poor prognosis. Upregulation of IL4I1 inhibited GBM ferroptosis in vitro and in vivo. Further, we found that indole-3-pyruvic acid (I3P) from tryptophan mediated by IL4I1 could scavenge free radical and had an impressive role in inhibiting ferroptosis. To clarify the potential mechanism of I3P in GBM ferroptosis, we performed transcriptomic analyses of GBM cells treated with I3P and found that Nrf2 related genes was upregulated. Further, we found that the ubiquitination of Nrf2 could be attenuate by I3P binding with Nrf2 directly. Knockdown of Nrf2 attenuated the induction of anti-ferroptosis by IL4I1, pointing to Nrf2 as a key mediator of this process. In vivo, overexpression of IL4I1 with ML385 in GBM xenografts promoted ferroptosis. Collectively, this study emphasises the crucial roles of IL4I1 in anti-ferroptosis through Nrf2 signalling pathway but not AHR pathway by catabolism tryptophan, suggesting IL4I1 and tryptophan reprogramming as potential therapeutic targets for GBM.

关键词： orthodontics   monocyte   macrophage activation   mechanotransduction   periodontal ligament  

摘要： Orthodontic root resorption (ORR) is a common yet significant complication of orthodontic treatment, largely driven by interactions between periodontal ligament cells (PDLCs) and M1 macrophages. Despite the clinical relevance of ORR, the role of mechanosensitive ion channels in PDLC-mediated ORR and the underlying mechanisms regulating inflammatory cell recruitment remain poorly understood. Here, we identified PIEZO1 as a critical mechanosensitive ion channel that modulates monocyte recruitment and ORR. Using in vivo models treated with the PIEZO1 activator Yoda1 and inhibitor AAV-shPiezo1, we demonstrated that PIEZO1 activation promoted the recruitment of Ly6Chi inflammatory monocytes and exacerbated ORR. In contrast, PIEZO1 inhibition attenuated ORR and the accumulation of M1 macrophages. Mechanistically, PIEZO1 positively regulated the C-X-C motif chemokine 12 (CXCL12) and its receptor, C-X-C chemokine receptor type 4 (CXCR4). Blocking the CXCL12/CXCR4 axis using the CXCR4 antagonist AMD3100 significantly alleviated ORR, reversed M1 macrophage accumulation, and mitigated the recruitment of CD11b+Ly6Chi monocytes. Transwell migration assays with application of the PIEZO1 activator Yoda1 and PIEZO1 inhibitor GsMTX4 consistently confirmed the PIEZO1/CXCL12/CXCR4 axis as a key driver of PDLC-monocyte interactions. Notably, PIEZO1 overactivation was linked to excessive IL-6 production, and IL-6 deficiency inhibited the activation of PIEZO1 induced by Yoda1, leading to attenuation of ORR, M1 macrophage accumulation, and CXCL12/CXCR4 axis activation. Collectively, these findings reveal PIEZO1 in PDLCs as a pivotal modulator of inflammatory monocyte recruitment via the CXCL12/CXCR4 axis in ORR, with IL-6 playing an essential role in PIEZO1 activation. This study provides new insights into the molecular crosstalk between PDLCs and macrophages, offering potential therapeutic targets for mitigating ORR in orthodontic patients.

摘要： Type 1 diabetes (T1D) is a chronic autoimmune disease that leads to the progressive loss of pancreatic beta cells. Interferons (IFNs) contribute to the initiation and amplification of beta cell autoimmunity. STAT1 is the main mediator of IFN signalling but little is known on its complex activation processes and role in the progression of beta cell failure. We presently show that two T1D candidate genes (i.e. and ) modulate STAT1 activation via two different pathways, namely the JAK/STAT, involved in the short-term phosphorylation of its tyrosine residue (Y701), and the MAPKs pathway, involved in the long-term phosphorylation of its serine residue (S727). Each STAT1 phosphorylation type can independently induce expression of the chemokine , but both residues are necessary for the expression of MHC class I molecules. IFN-α-induced STAT1 activation is dynamic and residue-dependent, being STAT1-Y701 fast (detectable after 4h) but transitory (back to basal by 24h) while STAT1-S727 increases slowly (peak at 48h) and is associated with the long-term effects of IFN-α exposure. These pathways can be chemically dissociated in human beta cells by the use of JAK1/2, TYK2 or JNK1 inhibitors. The present findings provide a novel understanding of the dynamics of STAT1 activation and will be useful to develop novel and hopefully targeted (i.e. favouring individuals with particular polymorphisms) therapies for T1D and other autoimmune diseases.

关键词： WIF1   Wnt5a/MAPK-JNK signaling   DNA methylation   Ankylosing spondylitis   Inflammatory injury  

摘要： The activity of Wnt inhibitory factor 1 (WIF1) is reduced upon promoter methylation and is involved in cartilage degradation in osteoarthritis. This study aims to investigate the mechanism by which WIF1 methylation is involved in chondrocyte damage in ankylosing spondylitis (AS). A model of chondrocyte inflammatory injury in AS was constructed by stimulation with interleukin (IL)-17. WIF1 level in injured chondrocytes was detected by western blot and RT-qPCR. ELISA kits were used to assess the levels of inflammatory cytokines. The expressions of MMP9, MMP13, collagen II, and ADAMTS-4 were tested by western blot and RT-qPCR. Wnt5a/mMAPK signaling and associated phosphorylated protein expressions were observed using western blot. After overexpression of Wnt5a, the same assays were used to evaluate the above indexes. The methylation level of the WIF1 promoter was measured by MSP-PCR assay. WIF1 expression declined in IL-17-induced chondrocytes. Overexpression of WIF1 decreased the levels of inflammatory factors TNF alpha, IL-1 beta, and IL-6, as well as downregulated the expressions of MMP9, MMP13, collagen II, and ADAMTS-4. Likewise, elevated WIF1 inhibited the Wnt5a/MAPK signaling and phosphorylation of JNK. However, upregulation of Wnt5a in IL-17-treated chondrocytes attenuated these responses. Besides, in damaged chondrocytes, WIF1 expression was reduced due to promoter methylation, while it was upregulated after demethylation. In summary, WIF1 exhibits high methylation levels in AS and is involved in inflammatory injury and matrix degradation in chondrocytes by regulating the Wnt5a/MAPK-JNK pathway.

关键词： severe obesity   RNA-seq   transcriptome   proteome   multi-omics   understudied population   obesity   adiposity  

摘要： Polygenic severe obesity (body mass index [BMI] >= 40 kg/m(2)) has increased, especially in Hispanic/Latino populations, yet we know little about the underlying mechanistic pathways. We analyzed whole-blood multiomics data to identify genes differentially regulated in severe obesity in Mexican Americans from the Cameron County Hispanic Cohort. Our RNA sequencing analysis identified 124 genes significantly differentially expressed between severe obesity cases (BMI >= 40 kg/m(2)) and controls (BMI <25 kg/m(2));33% replicated in an independent sample from the same population. Our integrative approach identified inflammatory genes, including IL4R, ZNF438, and LILRA5. Several genes displayed transcriptomic effects on severe obesity in subcutaneous adipose tissue. We further showed that the genetic regulation of these genes is associated with several traits in a large biobank, including bone fractures, obstructive sleep apnea, and hyperaldosteronism, illuminating potential risk mechanisms. Our findings furnish a molecular architecture of the severe obesity phenotype across multiple molecular domains.

摘要： Ineffective erythropoiesis (IE) commonly underlies anemia in congenital disorders. However, the causes of IE remain largely unknown. Recently, attention has been drawn to the involvement of nucleated erythrocytes in immune responses, providing a new perspective for exploring the etiology of IE. In this study, we found that the kdm4b-/- mutant zebrafish developed an IE-like defect, including impaired terminal maturation and apoptosis of erythroblasts, as confirmed by observations in Kdm4b-/- mutant mice. Thus, the Kdm4b mutant serves as an appropriate model for studying IE. Mechanistically, kdm4b primarily targets interleukin 6 (il6) to regulate the previously underrated immune activity of embryonic erythroblasts. The erythroblast-secreted Il6, in the absence of kdm4b, increased pro-inflammatory activities of myeloid cells and elevated T cell counts. Meanwhile, the activated Il6-pStat3 signaling elevated mitochondrial oxidative stress, leading to the maturation arrest of erythroblasts. Collectively, we demonstrate an important role for kdm4b in coordinating terminal maturation and immune function in erythroblasts. These findings might shed light on our understanding of the etiology of IE and the discovery of new effective compounds.

关键词： HLA-DR+ regulatory T cells   immune tolerance   systemic lupus erythematosus  

摘要： Background Systemic lupus erythematosus (SLE) is a complex autoimmune disease that affects multiple organ systems. A key element in maintaining immune tolerance and preventing autoimmunity is the role of regulatory T cells (Treg cells). Among these, HLA-DR+ Treg cells represent a distinct subset, and their altered expression and functionality in SLE are closely associated with the progression of the disease. This review explores the biological characteristics of HLA-DR+ Treg cells, their mechanisms of action in SLE, as well as their potential and the challenges they pose as therapeutic targets. Methods and results This review offers a comprehensive analysis of the mechanisms by which HLA-DR+ Treg cells regulate immune responses. It highlights their direct interactions with autoreactive T cells and antigen-presenting cells, which contribute to the suppression of autoimmunity. Additionally, the review explores the critical role of these cells in maintaining immune tolerance and their promising potential in the context of antigen-specific immunotherapy. Discussion The potential of HLA-DR+ Treg cells in the treatment of systemic lupus erythematosus (SLE) is considerable, particularly due to their capacity to generate antigen-specific Tregs. The development of Treg-based therapies, including the expansion of both polyclonal and antigen-specific Tregs, is an area of active investigation. Nonetheless, several challenges persist, such as the need to optimize protocols for Treg generation and expansion, ensure the stability of the Treg phenotype, and address potential safety concerns associated with cellular *** research is essential to fully harness the potential of HLA-DR+ Treg cells in the treatment of SLE and other autoimmune diseases.

摘要： Metastatic progression depends upon the ability of disseminated tumor cells to evade immune surveillance. MHC molecule expression facilitates T cell recognition and activation to permit the eradication of metastatic tumor cells. We identified nuclear corepressor 2 (NCOR2) as a key epigenetic regulator of MHC class I molecule expression on breast tumor cells. Patients with triple negative breast cancers (TNBC) that expressed high levels of NCOR2 also exhibited reduced metastasis free survival and decreased MHC class I expression, and the metastatic lesions in patients with TNBC had high nuclear NCOR2 and reduced CD8 T cell levels and activity. Genetically and experimentally reducing NCOR2 expression in tumor cells permitted interferon gamma upregulation of MHC class I, and potentiated CD8 T cell activity and induction of apoptosis to repress metastatic progression of disseminated breast cancer cells. These studies provide evidence to support NCOR2 as a targetable epigenetic regulator of metastasis towards which therapies could be developed to reduce patient mortality.

关键词： erlotinib   familial adenomatous polyposis (FAP)   MHC   sulindac   tumor immunomodulation  

摘要： A previously reported clinical trial in familial adenomatous polyposis (FAP) patients treated with erlotinib plus sulindac (ERL + SUL) highlighted immune response/interferon-gamma signaling as a key pathway. In this study, we combine intermittent low-dose ERL +/- SUL treatment in the polyposis in rat colon (Pirc) model with mechanistic studies on tumor-associated immune modulation. At clinically relevant doses, short-term (16 weeks) and long-term (46 weeks) ERL +/- SUL administration results in near-complete tumor suppression in Pirc colon and duodenum (p < 0.0001). We identify a low-dose threshold for significant antitumor activity in Pirc rats given SUL at 125 ppm in the diet plus ERL at 5 mg/kg body weight via twice-weekly oral gavage (SUL125 + ERL5 x 2). Longitudinal analyses show diminished expression of MHC class I and II genes in polyps larger than Grade 5, a novel finding in the Pirc model. Treatment with ERL +/- SUL upregulates the corresponding MHC and immune-associated factors in a subset of Pirc colon polyps, Pirc tumor cell lines, murine colon carcinoma cells, and FAP patient-derived organoids, with Nlrc5 playing a critical role in this effect. Imaging mass cytometry reveals that SUL125 + ERL5 x 2 increases tumor-associated Cd4(+) T cells by similar to 2.6-fold (p < 0.05), with no apparent effect on Cd8(+) T cells. The treatment also increases tumor-associated Cd68(+) cells (p < 0.05) and decreases Foxp3(+) (p < 0.01) and Arg1(+) (p < 0.05) cells. Thus, intermittent low-dose ERL + SUL treatment enhances tumor-associated MHC expression and remodels the immune cell niche toward a more permissive "helper" immune microenvironment. We conclude that early immune-interception strategies targeting interferon-gamma signaling may benefit FAP patients at drug doses below the clinical standard of care.

关键词： Arthritis   Polymorphism, Genetic   Spondyloarthritis   Sulfasalazine   Tumor Necrosis Factor Inhibitors  

摘要： Objectives Factors associated with peripheral arthritis and enthesitis, especially Achilles tendonitis and plantar fasciitis, were examined in a longitudinal cohort of 1075 patients with ankylosing spondylitis (AS) (also known as radiographic axial spondyloarthritis). Methods Patients were derived from the Prospective Study of Outcomes in Ankylosing Spondylitis cohort. Disease activity and functional indices, as well as physical examination and medications used, were measured at every study visit. Univariable and multivariable analyses of the association of peripheral arthritis and enthesitis with clinical, sociodemographic factors were performed. Human leucocyte antigen (HLA)-B alleles were analysed by single-stranded conformational polymorphism analysis. Results Those with peripheral arthritis on examination were more likely to have psoriasis (p=0.001, OR=1.68;CI, 1.11, 2.54), greater functional impairment (p<0.001 OR=1.72;CI, 1.31, 2.27), higher erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels (p<0.001), greater tumour necrosis factor (TNF) inhibitor (p<0.001, OR=1.50;CI, 1.14, 1.97) and use methotrexate/ sulfasalazine (p<0.001, OR=2.25, CI [1.57, 3.23]). Patients with enthesitis were less likely to be male (p<0.001, OR=0.57;CI, 0.43, 0.75) and have peripheral arthritis (p<0.001, OR=2.35;CI, 1.47, 3.75), greater functional impairment (p<0.001, OR=1.91;CI, 1.43, 2.55) and higher ESR/CRP levels (p<0.001). Patients with plantar fasciitis and/or Achilles’ tendonitis on examination were less likely to male (p<0.001 OR=0.57;CI, 0.43, 0.75), to have significant functional impairment (p<0.001), to be using TNF inhibitors (p<0.001, OR=1.48;CI 1.13, 1.93) and to be using either sulfasalazine or methotrexate (p<0.001, OR=1.86, CI, 1.30, 2.67). HLA-B*15 (p=0.03, OR=1.84;CI, 1.05, 3.21) and HLA-B*37 (p=0.04, OR=3.00;CI, 1.03, 8.74) were marginally increased in frequency in those with peripheral arthritis on examination compared with those without. Conc