Background: Early detection of diabetic atherosclerosis (DAS) remains challenging, and the mechanisms underlying endothelial barrier dysfunction in this condition are not fully understood. Extracellular Hsp90α (eHsp90α) and the ER stress marker GRP78 have been implicated in vascular injury; however, their roles in DAS remain unclear. Therefore, this study aimed to investigate the association of eHsp90α and GRP78 with DAS and explore the underlying mechanisms. Methods: We recruited patients with diabetes mellitus (DM) and patients with DAS. We then compared the levels and potential efficacies of serum eHsp90α and the ER stress marker GRP78 between the two groups. We subsequently conducted cytological experiments and experiments with ApoE−/− mice to further explore the underlying mechanisms involved. Results: The serological analysis revealed that the levels of serum eHsp90α and the ER stress marker GRP78 were significantly higher in the DAS group than in the DM group and that the eHsp90α level was correlated with GRP78 level. The association and preliminary discriminative performance of the combination of eHsp90α and GRP78 levels were appeared higher than that of either marker alone. In addition, GRP78 plays a mediating role in the relationship between eHsp90α and DAS. Furthermore, the expression of GRP78 was higher in both diabetic ApoE−/− mice and DAS patients than in control ApoE−/− mice and AS patients. Cytological experiments revealed that eHsp90α induced endothelial barrier dysfunction mediated by ER stress via the LRP1 receptor. Conclusions: Our findings suggest that eHsp90α and GRP78 are associated with diabetic atherosclerosis and may be associated biomarkers with potential discriminative value, although further validation is required. The eHsp90α–LRP1–ER stress pathway may contribute to endothelial barrier dysfunction. However, further large-scale and longitudinal studies are required to validate these findings.

Decidualization deficiency is a hallmark pathology of unexplained recurrent spontaneous abortion (URSA), but the undefined molecular drivers hinder the development of effective therapies. Hyperoside, a bioactive flavonoid from Hypericum perforatum, exhibits therapeutic potential against URSA, yet its underlying mechanism of action remains unknown. In this study, we employed an integrated multi-omics approach coupled with a multi-dimensional validation framework that spanned URSA patient decidual tissues, in vivo mouse models, and in vitro telomerase-immortalized human endometrial stromal cell (T-hESC) decidualization system, to systematically investigate hyperoside's mechanism in URSA, with a focus on R-loop-driven endometrial stromal cell senescence. We found that hyperoside dose-dependently reduced embryo resorption and rescued decidualization deficiency by preventing stromal cell senescence. Mechanistically, hyperoside effectively alleviated aberrant intracellular R-loop accumulation, thereby suppressing excessive activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway which contributes to the initiation of the cellular senescence program. Further target identification and validation experiments confirmed that DExH-box helicase 9 (DHX9) was the functional molecular target of hyperoside, with the Thr419 residue serving as the critical binding site. Functional validation revealed that DHX9 knockdown or introduction of the T419A point mutation markedly attenuated the anti-senescence and pro-decidualization effects of hyperoside. In vivo experiments further confirmed that uterine-specific knockdown of DHX9 reduced hyperoside's protective effects against R-loop accumulation, cGAS-STING pathway activation, and embryo loss. Collectively, these findings demonstrate that hyperoside alleviates stromal cell senescence and decidualization deficiency in URSA through DHX9-dependent resolution of R-loops and subsequent suppression of cGAS-STING-associated senescence signaling. More broadly, this work identifies R-loop-mediated genomic stress as a previously underappreciated contributor to URSA-associated decidual dysfunction and provides a mechanistic basis for the protective effects of hyperoside through DHX9-dependent R-loop homeostasis.

Previous studies to date have demonstrated a significant relationship between spontaneous abortion (SA) and rheumatoid arthritis (RA). Moreover, positive links between gut microbiota and SA, RA have been discussed in observational studies. However, observational studies are prone to bias and result in the causality between gut microbiota and the comorbidity of SA and RA remaining unclear. We therefore aimed to investigate this using a two-sample Mendelian randomization study. A total gut microbiota-related sample size of 18,340 participants from genome-wide association studies was obtained. The summary statistics data for SA (98,453 subjects) and RA (1,53,457 subjects) were obtained from the MRC integrative epidemiology unit genome-wide association studies database as the outcome of gut microbiota. Inverse variance weighted, weighted median, weighted mode, MR-Egger and simple mode were used to assess the causal effects. Sensitivity analyses were applied using the Cochran's Q-statistic, MR-Egger, the leave-one-out analysis, and Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO). In addition, the statistical power was calculated to evaluate the cause-and-effect. We identified genus Alloprevotella as a shared protective factor for both SA (odds ratio [OR] = 0.903, 95% CI: 0.817-0.997, P = .043) and RA (OR = 0.826, 95% CI: 0.722-0.945, P = .005). In addition, increased abundance of genera Actinomyces (OR = 1.213, 95% CI: 1.025-1.435, P = .025), Subdoligranulum (OR = 1.208, 95% CI: 1.036-1.408, P = .016), and Veillonella (OR = 1.167, 95% CI: 1.003-1.358, P = .046) was causally associated with a higher risk of SA. For RA, decreased abundance of genera ChristensenellaceaeR (OR = 0.736, 95% CI: 0.570-0.950, P = .018), Enterorhabdus (OR = 0.806, 95% CI: 0.684-0.950, P = .010), Prevotella7 (OR = 0.895, 95% CI: 0.808-0.991, P = .032) and Hungatella (OR = 0.818, 95% CI: 0.691-0.970, P = .021), along with increased abundance of the Ruminococcus gauvreauii group (OR = 1.406, 95% CI: 1.112-1.777, P = .004), was linked to elevated disease risk. Sensitivity analyses, including MR-PRESSO, MR-Egger, and Cochran's Q-statistic, revealed no evidence of heterogeneity or pleiotropy. Furthermore, leave-one-out analysis confirmed the robustness of the causal estimates. Our study identified several gut microbiota genera with putative causal effects on SA (4 genera) and RA (6 genera). Notably, Alloprevotella emerged as a shared protective factor for both conditions. These findings suggest that gut microbiota, particularly Alloprevotella, may play a causal, protective role in the shared etiology of SA and RA, highlighting a potential common therapeutic target for future research and clinical management.

BACKGROUND:Type 2 diabetes mellitus (T2DM) and its complications, including diabetic lower extremity arterial disease (DLEAD) and diabetic foot (DF), impose significant health burdens worldwide. However, the differential expression of microRNAs (miRNAs) between T2DM and its complications and its causal effects remain poorly understood. METHODS:We conducted an exosome-wide association study (EWAS) comparing miRNA profiles between T2DM and its complications, including DLEAD and DF, without healthy controls. The significant miRNAs identified between DM and its complications were further validated by integrating cis-miRNA expression quantitative trait loci (cis-miR-eQTLs) and genome-wide association study (GWAS) summary data of T2DM and peripheral arterial disease (PAD) through two-sample Mendelian randomization (MR) analysis. RESULTS:We identified several differential expressions of miRNAs between T2DM, DLEAD, and DF, such as hsa-miR-409-3p between T2DM and DLEAD, hsa-miR-543 between T2DM and DF and hsa-miR-206 between DLEAD and DF. The two sample MR analysis revealed potential causal relationships between dysregulated miRNAs and T2DM and its complications, such as hsa-miR-30b-3p and hsa-miR-30b-5p showed causal associations with T2DM and PAD respectively. CONCLUSIONS:Our study elucidates the miRNA signatures associated with T2DM and its complications. These findings provide insights into the pathogenesis of T2DM and its complications and suggest potential therapeutic targets for intervention.

Chronic joint pain in rheumatoid arthritis (RA) represents a persistent therapeutic challenge, and although luteolin (LUT) exhibits established anti-inflammatory properties, its precise mechanism for alleviating RA-associated chronic pain remains undefined. Through systematic investigation in collagen-induced arthritis (CIA) mice, we demonstrated that LUT administration effectively attenuated chronic pain by modulating spinal cluster of differentiation 4 positive T (CD4+ T) cell dynamics and suppressing microglial activation. Integrated multi-omics profiling (cleavage under targets and tagmentation (CUT&Tag), RNA sequencing (RNA-seq), and metabolomics) coupled with functional validation revealed nuclear factor of activated T cells 2 (NFATC2) as the central transcriptional regulator governing T helper 17 (Th17) cell differentiation and spinal infiltration through protein kinase C epsilon (PRKCE)-signal transducer and activator of transcription 3 (STAT3) signaling transduction. Significantly, our mechanistic studies uncovered a previously unrecognized epigenetic cascade: LUT-mediated suppression of lactate dehydrogenase A (LDHA) activity disrupts glycolysis-fueled histone 3 lysine 9 lactylation (H3K9la), thereby epigenetically silencing NFATC2 transcription. Translational studies using RA patient-derived CD4+ T cells confirmed LUT's capacity to normalize pathological hyperactivity of the LDHA/H3K9la/NFATC2 axis, concomitantly regulating CD4+ T dynamics. Biophysical validation through molecular docking, surface plasmon resonance (SPR), and molecular dynamics (MD) simulations established LUT's direct binding to LDHA with high affinity. Collectively, these findings delineate a novel therapeutic paradigm wherein LUT alleviates RA-associated chronic pain by orchestrating Th17 differentiation and migratory capacity through coordinated blockade of the LDHA-H3K9la-NFATC2 signaling network, highlighting its potential as a disease-modifying agent for chronic pain management in RA.

Ferroptosis is regulated cell death due to the accumulation of iron-dependent lipid peroxidation in cells, providing a potential new strategy for anti-tumor therapy. In recent years, more and more studies have begun to explore the interaction between ferroptosis and the tumor microenvironment (TME), especially the relationship between immune cells in the TME and ferroptosis, revealing the role of ferroptosis in tumor immunotherapy. This article summarizes the main metabolic pathways and regulatory mechanisms of ferroptosis, and focuses on the new role of ferroptosis in immune cells in the TME, which may provide new diagnostic, prognostic or therapeutic opportunities for the cooperation of immunotherapy and ferroptosis treatment.

Ferroptosis is a programmed cell death characterized by iron-dependent lipid peroxidation, which is regulated by various cellular metabolic and signaling pathways. The main regulatory mechanisms of intracellular ferroptosis include the GSH-GPX4 pathway, the FSP1-CoQ10 pathway, the GCH1-BH4 pathway, and the DHODH-CoQH2 system. As the hub of iron metabolism and energy generation, mitochondria have been increasingly implicated in ferroptosis, underscoring their pivotal role in cellular processes. Ferroptosis is a significant mode of cell demise linked to cancer progression. It is expected to combat drug-resistant tumors by triggering iron-mediated cell death. This review delves into the intricate mechanisms governing intracellular ferroptosis, emphasizing the centrality of mitochondria in regulating this process within cancer cells. Furthermore, this review explores the potential and hurdles of targeting ferroptosis as a therapeutic avenue to overcome resistance to cancer treatment.

Spontaneous abortion (SA) is a challenging and frustrating obstetric complication. Immune dysregulation at the mother-fetal interface has long been recognized as a threat to pregnancy maintenance. Decidual macrophages are key gatekeepers for immune homeostasis at the mother-fetal interface, characterized by their heterogeneity and high plasticity. Abnormalities in their number, function, and phenotype are strongly associated with pregnancy loss. However, the specific regulation mechanisms remain elusive. Here, we outline the origin and identity of the endometrial macrophages and review their diverse changes in phenotypes and functions to pregnancy initiation. More importantly, we highlight the underlying mechanisms mediating aberrant changes in macrophage polarization and functions in the context of SA, involving epigenetic landscape dysregulation, metabolic reprogramming, and aberrant communication between macrophages and other component cells at the maternal-fetal interface. Altogether, these provide a clear framework for understanding the crucial roles and prospective therapeutic targets of macrophages in SA.

Ovarian cancer is a malignant tumor originating from the ovary, characterized by its high mortality rate and propensity for recurrence. In some patients, especially those with recurrent cancer, conventional treatments such as surgical resection or standard chemotherapy yield suboptimal results. Consequently, there is an urgent need for novel anti-cancer therapeutic strategies. Ferroptosis is a distinct form of cell death separate from apoptosis. Ferroptosis inducers have demonstrated promising potential in the treatment of ovarian cancer, with evidence indicating their ability to enhance ovarian cancer cell sensitivity to cisplatin. However, resistance of cancer cells to ferroptosis still remains an inevitable challenge. Here, we analyzed genome-scale CRISPR-Cas9 loss-of function screens and identified PAX8 as a ferroptosis resistance protein in ovarian cancer. We identified PAX8 as a susceptibility gene in GPX4-dependent ovarian cancer. Depletion of PAX8 rendered GPX4-dependent ovarian cancer cells significantly more sensitive to GPX4 inhibitors. Additionally, we found that PAX8 inhibited ferroptosis in ovarian cancer cells. Combined treatment with a PAX8 inhibitor and RSL3 suppressed ovarian cancer cell growth, induced ferroptosis, and was validated in a xenograft mouse model. Further exploration of the molecular mechanisms underlying PAX8 inhibition of ferroptosis mutations revealed upregulation of glutamate-cysteine ligase catalytic subunit (GCLC) expression. GCLC mediated the ferroptosis resistance induced by PAX8 in ovarian cancer. In conclusion, our study underscores the pivotal role of PAX8 as a therapeutic target in GPX4-dependent ovarian cancer. The combination of PAX8 inhibitors such as losartan and captopril with ferroptosis inducers represents a promising new approach for ovarian cancer therapy.

Tumor-associated macrophages (TAM) subtypes have been shown to impact cancer prognosis and resistance to immunotherapy. However, there is still a lack of systematic investigation into their molecular characteristics and clinical relevance in different cancer types. Single-cell RNA sequencing data from three different tumor types were used to cluster and type macrophages. Functional analysis and communication of TAM subpopulations were performed by Gene Ontology-Biological Process and CellChat respectively. Differential expression of characteristic genes in subpopulations was calculated using zscore as well as edgeR and Wilcoxon rank sum tests, and subsequently gene enrichment analysis of characteristic genes and anti-PD-1 resistance was performed by the REACTOME database. We revealed the heterogeneity of TAM, and identified eleven subtypes and their impact on prognosis. These subtypes expressed different molecular functions respectively, such as being involved in T cell activation, apoptosis and differentiation, or regulating viral bioprocesses or responses to viruses. The SPP1 pathway was identified as a critical mediator of communication between TAM subpopulations, as well as between TAM and epithelial cells. Macrophages with high expression of SPP1 resulted in poorer survival. By in vitro study, we showed SPP1 mediated the interactions between TAM clusters and between TAM and tumor cells. SPP1 promoted the tumor-promoting ability of TAM, and increased PDL1 expression and stemness of tumor cells. Inhibition of SPP1 attenuated N-cadherin and β-catenin expression and the activation of AKT and STAT3 pathway in tumor cells. Additionally, we found that several subpopulations could decrease the sensitivity of anti-PD-1 therapy in melanoma. SPP1 signal was a critical pathway of communication between macrophage subtypes. Some specific macrophage subtypes were associated with immunotherapy resistance and prognosis in some cancer types.

Background and aimsDiabetic atherosclerotic vascular disease is characterized by extensive vascular calcification. However, an elevated blood glucose level alone does not explain this pathogenesis. We investigated the metabolic markers underlying diabetic atherosclerosis and whether ehsp90α triggers vascular endothelial calcification in this particular metabolic environment.MethodsA parallel human/animal model metabolomics approach was used. We analyzed 40 serum samples collected from 24 patients with atherosclerosis and from the STZ-induced ApoE−/− mouse model. A multivariate statistical analysis of the data was performed, and mouse aortic tissue was collected for the assessment of plaque formation. In vitro, the effects of eHsp90α on endothelial cell calcification were analyzed by serum analysis, western blotting and immunoelectron microscopy.ResultsDiabetic ApoE−/− mice exhibited more severe plaque lesions and calcification damage. Stearamide, oleamide, l-thyroxine, l-homocitrulline and l-citrulline are biomarkers of diabetic ASVD; l-thyroxine was downregulated in both groups, and the thyroid sensitivity index was correlated with the serum Hsp90α concentration. In vitro studies showed that eHsp90α increased Runx2 expression in endothelial cells through the LRP1 receptor. l-thyroxine reduced the increase in Runx2 levels caused by eHsp90α and affected the distribution and expression of LRP1 through hydrogen bonding with glutamine at position 1054 in the extracellular segment of LRP1.ConclusionsThis study provides a mechanistic link between characteristic serum metabolites and diabetic atherosclerosis and thus offers new insight into the role of extracellular Hsp90α in promoting vascular calcification.

糖尿病皮肤病变是最常见但最容易被忽视的糖尿病并发症之一，严重影响患者的生存质量，甚至导致糖尿病足的发生。近年来研究提出，糖尿病皮肤病变可在一定程度上预测糖尿病并发症的进展、糖尿病足的发生，因此对于糖尿病皮肤病变的早期诊断及治疗具有重要意义。但目前关于糖尿病皮肤病变的发病机制仍未完全阐明，糖尿病皮肤病变的早期防治也未引起临床上的重视，因此不乏见到因皮肤病变导致严重糖尿病足并最终截肢的病例。该文结合国内外最新进展，从皮肤结构、慢性炎症损伤、皮肤微环境等方面，归纳总结糖尿病患者皮肤病变的病理生理改变，探讨糖尿病皮肤功能障碍潜在的发病机制，阐述皮肤微生态对于糖尿病皮肤病变的影响，为糖尿病皮肤病变的早期诊断和治疗提供理论依据。

Context Imbalance of the skin microbial community could impair skin immune homeostasis and thus trigger skin lesions. Dysbiosis of skin microbiome may be involved in the early pathogenesis of diabetic foot (DF). However, the potential mechanism remains unclear. Objective To investigate the dynamic composition and function of the foot skin microbiome with risk stratification for DF and assess whether dysbiosis of the skin microbiome induces diabetic skin lesions. Methods We enrolled 90 consecutive subjects who were divided into 5 groups based on DF risk stratification: very low, low, moderate, and high risk for ulcers and a healthy control group. Integrated analysis of 16S ribosomal RNA and metagenomic sequencing of cotton swab samples was applied to identify the foot skin microbiome composition and functions in subjects. Then a mouse model of microbiota transplantation was used to evaluate the effects of the skin microbiome on diabetic skin lesions. Results The results demonstrated that, with the progression of diabetic complications, the proportion of gram-negative bacteria in plantar skin increased. At the species level, metagenome sequencing analyses showed Moraxella osloensis to be a representative core strain in the high-risk group. The major microbial metabolites affecting diabetic skin lesions were increased amino acid metabolites, and antibiotic resistance genes in microorganisms were abundant. Skin microbiota from high-risk patients induced more inflammatory cell infiltration, similar to the lipopolysaccharide (LPS)-stimulated response, which was inhibited by Toll-like receptor 4 (TLR4) antagonists. Conclusions The skin microbiome in patients with diabetes undergoes dynamic changes at taxonomic and functional levels with the progression of diabetic complications. The increase in gram-negative bacteria on the skin surface through LPS-TLR4 signal transduction could induce inflammatory response in early diabetic skin lesions.

Diabetic foot ulcer (DFU) complications involve autophagy dysregulation. This study aimed to identify autophagy-related bioindicators in DFU. Differentially expressed genes (DEGs) between DFU and healthy samples were analysed from the Gene Expression Omnibus (GEO) datasets, GSE7014 and GSE29221. The roles of autophagy-related DEGs were investigated using protein-protein interaction (PPI) networks, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, Gene Ontology (GO) enrichment, and Gene Set Enrichment Analysis (GSEA). Immune cell infiltration's correlation with these DEGs was also assessed. From the Human Autophagy Database (HADB), 232 autophagy-related genes (ARGs) were identified, with an intersection of 17 key DEGs between GSE7014 and GSE29221. These genes are involved in pathways like autophagy-animal, NOD-like receptor signalling, and apoptosis. In the protein network, epidermal growth factor receptor (EGFR) and phosphatase and tensin homologue (PTEN) showed significant interactions with ARGs. Survival analysis indicated the prognostic importance of calpain 2 (CAPN2), integrin subunit beta 1 (ITGB1), and vesicle-associated membrane protein 3 (VAMP3). Lower immune scores were observed in the type 2 diabetes mellitus (DM2) group than in controls. Autophagy and ARGs significantly influence DFU pathophysiology.

Prenatal tobacco exposure (PTE) correlates significantly with a surge in adverse pregnancy outcomes, yet its pathological mechanisms remain partially unexplored. This study aims to meticulously examine the repercussions of PTE on placental immune landscapes, employing a coordinated research methodology encompassing bioinformatics, machine learning and animal studies. Concurrently, it aims to screen biomarkers and potential compounds that could sensitively indicate and mitigate placental immune disorders. In the course of this research, two gene expression omnibus (GEO) microarrays, namely GSE27272 and GSE7434, were included. Gene set enrichment analysis (GSEA) and immune enrichment investigations on differentially expressed genes (DEGs) indicated that PTE might perturb numerous innate or adaptive immune-related biological processes. A cohort of 52 immune-associated DEGs was acquired by cross-referencing the DEGs with gene sets derived from the ImmPort database. A protein-protein interaction (PPI) network was subsequently established, from which 10 hub genes were extracted using the maximal clique centrality (MCC) algorithm (JUN, NPY, SST, FLT4, FGF13, HBEGF, NR0B2, AREG, NR1I2, SEMA5B). Moreover, we substantiated the elevated affinity of tobacco reproductive toxicants, specifically nicotine and nitrosamine, with hub genes through molecular docking (JUN, FGF13 and NR1I2). This suggested that these genes could potentially serve as crucial loci for tobacco's influence on the placental immune microenvironment. To further elucidate the immune microenvironment landscape, consistent clustering analysis was conducted, yielding three subtypes, where the abundance of follicular helper T cells (p < 0.05) in subtype A, M2 macrophages (p < 0.01), neutrophils (p < 0.05) in subtype B and CD8+ T cells (p < 0.05), resting NK cells (p < 0.05), M2 macrophages (p < 0.05) in subtype C were significantly different from the control group. Additionally, three pivotal modules, designated as red, blue and green, were identified, each bearing a close association with differentially infiltrated immunocytes, as discerned by the weighted gene co-expression network analysis (WGCNA). Functional enrichment analysis was subsequently conducted on these modules. To further probe into the mechanisms by which immune-associated DEGs are implicated in intercellular communication, 20 genes serving as ligands or receptors and connected to differentially infiltrating immunocytes were isolated. Employing a variety of machine learning techniques, including one-way logistic regression, LASSO regression, random forest and artificial neural networks, we screened 11 signature genes from the intersection of immune-associated DEGs and secretory protein-encoding genes derived from the Human Protein Atlas. Notably, CCL18 and IFNA4 emerged as prospective peripheral blood markers capable of identifying PTE-induced immune disorders. These markers demonstrated impressive predictive power, as indicated by the area under the curve (AUC) of 0.713 (0.548-0.857) and 0.780 (0.618-0.914), respectively. Furthermore, we predicted 34 potential compounds, including cyclosporine, oestrogen and so on, which may engage with hub genes and attenuate immune disorders instigated by PTE. The diagnostic performance of these biomarkers, alongside the interventional effect of cyclosporine, was further corroborated in animal studies via ELISA, Western blot and immunofluorescence assays. In summary, this study identifies a disturbance in the placental immune landscape, a secondary effect of PTE, which may underlie multiple pregnancy complications. Importantly, our research contributes to the noninvasive and timely detection of PTE-induced placental immune disorders, while also offering innovative therapeutic strategies for their treatment.

Introduction Atherosclerosis is the main pathological change in diabetic angiopathy, and vascular inflammation plays an important role in early atherosclerosis. Extracellular heat shock protein 90 (eHsp90) is secreted into the serum and is involved in various physiological and pathophysiological processes. However, the specific mechanism of eHsp90 in early atherosclerosis remains unclear. This study explored the relationship between Hsp90 and diabetic lower extremity arterial disease and investigated the expression of eHsp90 in vascular endothelial cells under environmental stimulation and the function and mechanism of eHsp90α involved in diabetic atherosclerosis.Research design and methods One hundred and three selected patients were divided into three groups: the diabetes mellitus group (n=27), the diabetic lower extremity arterial disease group (n=46), and the diabetic critical limb ischemia group (n=30). The relationships among serum Hsp90, oxidative stress indexes, and patient outcomes and the correlations among the indexes were analyzed. H&E staining and immunohistochemistry were used to observe the vasculature of amputated feet from patients with diabetic foot. An oxidative stress endothelial injury model was established under high glucose in vitro to explore the role of eHsp90 release in atherosclerosis progression.Results The level of serum Hsp90 was upregulated with aggravation of diabetic vascular disease. Hsp90α was correlated with malondialdehyde to some extent and was an independent risk factor in the progression of diabetic vascular disease, with predictive ability. The expression area of Hsp90α was consistent with the area of inflammatory infiltration in the vessel lumen. Vascular endothelial cells were found to increase eHsp90α secretion under stress. Then inhibition of eHsp90α can reduce the degree of cellular inflammation and damage. Endothelial cell-conditioned medium and recombinant human Hsp90α increased monocyte migration via the low-denisity lipoprotein receptor-related protein 1 (LRP1) receptor to promote disease progression.Conclusions eHsp90α plays a critical role in the early inflammatory injury stage of atherosclerosis.Trial registration number NCT04787770.

Macrophages, the main immune cells in the skin, form an innate immune barrier. Under physiological conditions, skin maintains immune barrier function through macrophage phagocytosis and antigen presentation. Parenchymal and stromal cell regeneration plays an important role in skin injury repair and uses macrophage plasticity to influence and stabilize the skin microenvironment. Diabetic skin lesions are the most common diabetes complication and are involved in the early pathophysiology of diabetic foot. Therefore, studying the initial link in diabetic skin lesions is a research hot spot in the early pathogenesis of diabetic foot. Skin inflammation caused by hyperglycaemia, oxidative stress and other injuries is an important feature, but the specific mechanism is unknown. Recent studies have suggested that chronic inflammatory injury is widely involved in a variety of skin diseases, and whether it plays an important role in diabetic skin lesions is unclear. In this review, current research hotspots were combined with the pathogenesis of diabetic skin lesions and analysed from the perspectives of the physiological function of skin macrophages, the impairment of skin macrophages in diabetes, and the mechanism of chronic inflammatory injury in macrophages to provide a theoretical basis for early screening and evaluation of diabetic foot.

The microbiome is greatly significant for immune system development and homeostasis. Dysbiosis in gut microbial composition and function is linked to immune responses and the development of metabolic diseases, including diabetes mellitus (DM). However, skin microbiome changes in diabetic patients and their role in DM are poorly elucidated. In this review, we summarize recent findings about the association between the gut and skin microbiota and DM, highlighting their roles in the proinflammatory status of DM. Moreover, although there is evidence that the connection between the gut and skin causes the same activated innate immune response, additional studies are needed to explore the mechanism. These findings might inform future DM prevention, diagnosis and treatment.

Background: Atherosclerosis is the main pathological change in diabetic angiopathy, and vascular inflammation plays an important role in early atherosclerosis. Heat shock protein 90, a cellular molecular chaperone, was recently determined to be secreted extracellularly, but the specific mechanism remains unclear. This study explored the relationship between Hsp90 and diabetic peripheral artery disease through serological analyses of different groups of diabetic patients and investigated the relationship between extracellular Hsp90α and vascular inflammation at the cellular level. Methods: Seventy-seven selected patients were divided into three groups. The relationships among serum Hsp90, oxidative stress indexes and patient outcomes and the correlations among the indexes were analysed. An oxidative stress endothelial injury model was established under high glucose in vitro to explore the role of eHsp90 release in atherosclerosis progression. Results: Serum Hsp90 and MDA levels tended to increase in different groups with peripheral vascular disease aggravation. Hsp90α was correlated with MDA to some extent and was predictive. In vitro, high glucose and low H 2 O 2 treatment increased extracellular Hsp90 secretion, and endothelial cell conditioned medium and recombinant human Hsp90α increased monocyte migration (P<0.05). Conclusions: Extracellular Hsp90α participates in endothelial cell injury in diabetic vascular disease and initiates the inflammatory response by promoting monocyte migration. Trial registration: NCT04787770, ClinicalTrials.gov, Registered 9 March, 2021 - Prospective registered

Purpose Adrenocortical carcinoma (ACC) is a rare malignancy with poor prognosis, and researchers are interested in further studying its diagnosis and treatment. Our study aims to identify new potential therapeutic targets in ACC. Patients and Methods The core genes CDK1 and CCNB1 were previously screened using ACC data from The Cancer Genome Atlas (TCGA) as the most relevant to Bclaf1 and tumour prognosis. We used siRNA- or shRNA-based models to explore the role of Bcl-2-associated transcription factor 1 (Bclaf1) in SW-13 cell lines. Western blotting and qPCR were used to determine the effects of Bclaf1 on CDK1 and Cyclin B1. Results Based on biological information analysis, we found that Bcl-2-associated transcription factor 1 (Bclaf1) affected the progression of ACC and was associated with the cell cycle. Downregulated Bclaf1 expression inhibited the proliferation of SW-13 cells and affected the cell cycle process of SW-13 cells. BCLAF1 was correlated with CDK1 and CCNB1 and can regulate their mRNA and protein levels. Conclusion Bclaf1 might promote the development of ACC by regulating CDK1 and Cyclin B1 to drive mitosis.