l-thyroxine attenuates extracellular Hsp90α-induced vascular endothelial calcification in diabetes mellitus, as revealed by parallel metabolic profiles.

BACKGROUND AND AIMS: Diabetic 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 extracellular Hsp90α (eHsp90α) triggers vascular endothelial calcification in this particular metabolic environment. METHODS: A 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 assessed by serum analysis, Western blotting and immunoelectron microscopy. RESULTS: Diabetic ApoE-/- mice showed 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 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. CONCLUSIONS: This 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.

Relationship between social isolation and glycaemic control of people previously diagnosed with diabetes: secondary analysis from the CHARLS.

OBJECTIVES: Social isolation may affect diabetes self-management. This study aimed to explore the relations between social isolation and glycaemic control in patients with diabetes and to explore lifestyle differences among individuals with different levels of social isolation. METHODS: The relevant data of 665 people previously diagnosed with diabetes included in the China Health and Retirement Longitudinal Study from 2011 to 2015 were extracted and analysed. The study included patient general information, blood glucose, lipids, glycosylated haemoglobin, social isolation index, health-related lifestyle factors and diabetes-related factors. Differences in metabolic abnormalities and modifiable lifestyles were compared among patients with varying levels of social isolation. RESULTS: Multiple linear regression analysis demonstrated that among men aged 45-64 years, the high social isolation group had significantly higher glycosylated haemoglobin levels compared with the low isolation group (7.29±1.81 vs 6.59±1.63, p=0.026). A positive correlation was observed between social isolation and blood glucose (ß=14.16; 95% CI 2.75 to 25.57; p=0.015) and glycosylated haemoglobin (ß=0.35; 95% CI 0.10 to 0.60; p=0.006), indicating that higher social isolation was associated with higher fasting blood glucose and glycosylated haemoglobin levels. However, no significant associations were observed in other age groups. Notably, men aged 45-65 years with high social isolation had higher depression rates (44.10% vs 24.60%, p=0.024), lower engagement in moderate exercise (5.70% vs 23.50%, p=0.019) and shorter 10-minute walks (17.10% vs 36.80%, p=0.027). Differences in other health-related and diabetes-related factors were not statistically significant. CONCLUSION: Middle-aged men with diabetes with higher social isolation tend to have higher blood glucose and glycosylated haemoglobin levels. This subset of patients requires targeted attention to provide social support from family and friends for improved glycaemic control. If necessary, education on diabetes should be made available to family members and friends.

Up-regulation of HSP90α in HDM-induced asthma causes pyroptosis of airway epithelial cells by activating the cGAS-STING-ER stress pathway.

Heat Shock protein 90 α (HSP90α), an main subtype of chaperone protein HSP90, involves important biological functions such as DNA damage repair, protein modification, innate immunity. However, the potential role of HSP90α in asthma occurrence and development is still unclear. This study aimed to elucidate the underlying mechanism of HSP90α in asthma by focusing on the cGAS-STING-Endoplasmic Reticulum stress pathway in inflammatory airway epithelial cell death (i.e., pyroptosis; inflammatory cell death). To accomplish that, we modeled allergen exposure in C57/6BL mice and bronchial epithelial cells with house dust mite. Protein technologies and immunofluorescence utilized to study the expression of HSP90α, activation of cGAS-STING pathway and pyroptosis. The effect of inhibitors on HDM-exposed mice detected by histological techniques and examination of bronchoalveolar lavage fluid. Results showed that HSP90α promotes asthma inflammation via pyroptosis and activation of the cGAS-STING-ER stress pathway. Treatment with the HSP90 inhibitor tanespimycin (17-AAG) significantly relieved airway inflammation and abrogated the effect of HSP90α on pyroptosis and cGAS-STING-ER stress in vitro and in vivo models of HDM. Further data indicated that up-regulation of HSP90α stabilized STING through interaction, which increased localization of STING on the ER. Activation of STING triggered ER stress and leaded to pyroptosis-related airway inflammation. The finding showed the potential role of pyroptosis caused by dysregulation of HSP90α on airway epithelial cells in allergic inflammation, suggested that targeting HSP90α in airway epithelial cells might prove to be a potential additional treatment strategy for asthma.

Tetrandrine alleviates pulmonary fibrosis by inhibiting alveolar epithelial cell senescence through PINK1/Parkin-mediated mitophagy.

Idiopathic pulmonary fibrosis (IPF) is a fatal and insidious interstitial lung disease. So far, there are no effective drugs for preventing the disease process. Cellular senescence plays a critical role in the development of IPF, with the senescence and insufficient mitophagy of alveolar epithelial cells being implicated in its pathogenesis. Tetrandrine is a natural alkaloid which is now produced synthetically. It was known that the tetrandrine has anti-fibrotic effects, but the efficacy and mechanisms are still not well evaluated. Here, we reveal the roles of tetrandrine on AECs senescence and the antifibrotic effects by using a bleomycin challenged mouse model of pulmonary fibrosis and a bleomycin-stimulated mouse alveolar epithelial cell line (MLE-12). We performed the ß-galactosidase staining, immunohistochemistry and fluorescence to assess senescence in MLE-12 cells. The mitophagy levels were detected by co-localization of LC3 and COVIX. Our findings indicate that tetrandrine suppressed bleomycin-induced fibroblast activation and ultimately blocked the increase of collagen deposition in mouse model lung tissue. It has significantly inhibited the bleomycin-induced senescence and senescence-associated secretory phenotype (SASP) in alveolar epithelial cells (AECs). Mechanistically, tetrandrine suppressed the decrease of mitochondrial autophagy-related protein expression to rescue the bleomycin-stimulated impaired mitophagy in MLE-12 cells. We revealed that knockdown the putative kinase 1 (PINK1) gene by a short interfering RNA (siRNA) could abolish the ability of tetrandrine and reverse the MLE-12 cells senescence, which indicated the mitophagy of MLE-12 cells is PINK1 dependent. Our data suggest the tetrandrine could be a novel and effective drug candidate for lung fibrosis and senescence-related fibrotic diseases.

Turmeric-Derived Nanoparticles Functionalized Aerogel Regulates Multicellular Networks to Promote Diabetic Wound Healing.

Regulation of excessive inflammation and impaired cell proliferation is crucial for healing diabetic wounds. Although plant-to-mammalian regulation offers effective approaches for chronic wound management, the development of a potent plant-based therapeutic presents challenges. This study aims to validate the efficacy of turmeric-derived nanoparticles (TDNPs) loaded with natural bioactive compounds. TDNPs can alleviate oxidative stress, promote fibroblast proliferation and migration, and reprogram macrophage polarization. Restoration of the fibroblast-macrophage communication network by TDNPs stimulates cellular regeneration, in turn enhancing diabetic wound healing. To address diabetic wound management, TDNPs are loaded in an ultralight-weight, high swelling ratio, breathable aerogel (AG) constructed with cellulose nanofibers and sodium alginate backbones to obtain TDNPs@AG (TAG). TAG features wound shape-customized accessibility, water-adaptable tissue adhesiveness, and capacity for sustained release of TDNPs, exhibiting outstanding performance in facilitating in vivo diabetic wound healing. This study highlights the potential of TDNPs in regenerative medicine and their applicability as a promising solution for wound healing in clinical settings.

Chinese expert consensus on the diagnosis, treatment, and management of asthma in women across life.

Background: The epidemiology and severity of asthma vary by sex and age. The diagnosis, treatment, and management of asthma in female patients are quite challenging. However, there is hitherto no comprehensive and standardized guidance for female patients with asthma. Methods: Corresponding search strategies were determined based on clinical concerns regarding female asthma. Search terms included "sex hormones and lung development", "sex hormone changes and asthma", "hormones and asthma immune response", "women, asthma", "children, asthma", "puberty, asthma", "menstruation, asthma", "pregnancy, asthma", "lactation, asthma", "menopause, asthma", "obesity, asthma", and "women, refractory, severe asthma". Literature was retrieved from PubMed/Medline, Embase, Cochrane Library, China Biology Medicine disc, China National Knowledge Infrastructure, Wanfang Data with the search date of July 30, 2022 as the last day. This consensus used the Grading of Recommendations Assessment, Development, and Evaluation to evaluate the strength of recommendation and quality of evidence. Results: We collected basic research results and clinical evidence-based medical data and reviewed the effects of sex hormones, classical genetics, and epigenetics on the clinical presentation and treatment response of female patients with asthma under different environmental effects. Based on that, we formulated this expert consensus on the management of female asthma throughout the life cycle. Conclusions: This expert consensus on the management of asthma in women throughout the life cycle provides diagnosis, treatment, and research reference for clinical and basic medical practitioners.

Association between red cell distribution width-and-albumin ratio and the risk of peripheral artery disease in patients with diabetes.

Aim: The aim of this study is to explore the association between red blood cell distribution width-to-albumin ratio (RAR) and the risk of peripheral artery disease (PAD) in patients with diabetes. Methods: This cross-sectional study extracted the data of 1,125 participants with diabetes from the National Health and Nutrition Examination Survey database. A weighted univariable logistic regression model was used to explore variables associated with PAD. With PAD as the outcome variable, a weighted logistic regression model was established. The odds ratio (OR) and 95% confidence interval (CI) were effect size. Results: After adjusting for covariates, the risk of PAD in patients with diabetes was observed in those with higher RAR (OR = 1.83; 95% CI: 1.06-3.15). In addition, RAR ≥3.25 was related to increased risk of PAD in patients with diabetes (OR = 2.04; 95% CI: 1.05-3.95). In people with diabetes aged ≥65, RAR was a risk factor for PAD with an OR value of 2.67 (95% CI: 1.30-5.46). RAR ≥3.25 was associated with increased risk of PAD (OR = 3.06; 95% CI: 1.15-8.11) relative to RAR <2.80. In people with diabetes who smoked, the risk of PAD was elevated in those with RAR ≥3.25 (OR = 2.85; 95% CI: 1.28-6.32). As for patients with cardiovascular disease, the risk of PAD was elevated as the increase of RAR (OR = 2.31; 95% CI: 1.05-5.10). RAR ≥3.25 was correlated with increased risk of PAD (OR = 3.75; 95% CI: 1.42-9.87). The area under the curve of RAR for the risk of PAD in patients with diabetes was 0.631 (95% CI: 0.588-0.675). Conclusion: A higher RAR was related to increased risk of PAD in patients with diabetes. The findings might offer a reference for the management of PAD in patients with diabetes.

Sex-specific associations of bisphenol A and its substitutes with body fat distribution among US adults: NHANES 2011-2016.

Bisphenol A (BPA) and its structural analogs (bisphenol S (BPS) and bisphenol F (BPF)) are widely consumed endocrine disrupting chemicals that may contribute to the etiology of obesity. To date, few studies have directly investigated the sex-related associations between bisphenols and body fat distribution in adults. In this study, we included 2669 participants from the National Health and Nutrition Examination Survey (NHANES) 2011-2016 to evaluate and compare sex-specific differences of the associations of BPA, BPS, and BPF with body fat distribution. We found that there were significant positive correlations between BPS and body fat indices (STFAT [adjustedß=1.94, 95% CI: (0.24, 3.64)], TAF [0.18 (0.04, 0.32)], SAT [0.15 (0.03, 0.27)], android fat mass [0.20 (0.004, 0.40)], BMI [1.63 (0.61, 2.65)], and WC [3.19 (0.64, 5.73)] in the highest quartiles of BPS), but not in BPA and BPF. Stratified analyses suggested that the significant associations of BPS with body fat indices were stronger in women than men (STFAT [adjustedß=3.75, 95% CI: (1.04, 6.45) vs. adjustedß=-0.06, 95% CI: (-2.23, 2.11), P for interaction < 0.001], TAF [ 0.32 (0.09, 0.54) vs. 0.01 (-0.17, 0.19), P for interaction < 0.001], SAT [0.27 (0.09, 0.45) vs. 0.01 (-0.14, 0.16), P for interaction < 0.001], android fat mass [0.41 (0.12, 0.71) vs. -0.02 (-0.28, 0.24), P for interaction < 0.001], gynoid fat mass [0.56 (0.11, 1.01) vs. -0.05 (-0.41, 0.31), P for interaction = 0.002], BMI [2.76 (1.08, 4.44) vs. 0.47 (-0.80, 1.74), P for interaction < 0.001], and WC [5.51 (1.44, 9.58) vs. 0.61 (-2.67, 3.88), P for interaction < 0.001]), and positive associations between BPS with fat distribution were also observed in non-smoking women. Our study indicated that in women, higher concentration of urinary BPS was associated with increased body fat accumulation, except for visceral adipose tissue mass. These findings emphasize the role of environmental BPS exposure in the increasing fat deposits, and confirm the need for more prospective cohort studies on a sex-specific manner.

Prevalence of S. aureus and/or MRSA in hospitalized patients with diabetic foot and establishment of LAMP methods for rapid detection of the SCCmec gene.

BACKGROUND: Patients with diabetic feet are prone to be infected due to the impaired immune system. However, the prognostic outcome of different microbial infections remains controversial. Identification and rapid screening of the pathogenic microorganisms that pose the greatest threat to the prognosis of patients with diabetic foot infections (DFIs) is critical. METHODS: Clinical data were statistically analyzed, which were obtained from 522 patients with DFIs, including pathogenic bacterial culture results and treatment outcomes at the last return visit. In addition, a loop-mediated isothermal amplification (LAMP) detection method was developed to identify the prevalent subtype of methicillin-resistant Staphylococcus aureus (MRSA) in DFIs patients. This study was approved by the Ethics Committee of Nanfang Hospital (NFEC-202012-K6) and registered on ClinicalTrials.gov (NCT04916457) on June 1, 2021. RESULTS: We found that the proportion of patients with infections of Staphylococcus aureus (S. aureus) and MRSA was 27.7% (145/522) and 33.7% (49/145), respectively. Additionally, the incidence of osteomyelitis was 46.9% (23/49) and amputation/disability was 40.8% (20/49) in patients with MRSA infection, which were significantly higher compared to patients with other types of bacterial infections such as methicillin-susceptible Staphylococcus aureus (MSSA). Notably, we demonstrated that the main prevalent subtype of MRSA in DFIs patients in our hospital was Staphylococcal chromosomal cassettes mec (SCCmec) type II. In addition, it only takes 1.5 h to complete the entire experimental procedure in this LAMP assay, providing high sensitivity (100%) and specificity (77.8%) in hospitalized patients with DFIs. CONCLUSIONS: We demonstrated there is a very high rate of MRSA isolation in patients with DFIs and revealed that patients infected with MRSA are at a higher risk of developing osteomyelitis, and amputation or disability. Importantly, we have developed a method for quickly screening newly admitted patients for MRSA.

Identification of autophagy-related genes in diabetic foot ulcer based on bioinformatic analysis.

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.

Associations of blood biomarkers with arterial stiffness in patients with diabetes mellitus: A population-based study.

BACKGROUND: Arterial stiffness contributes to additional cardiovascular risks in diabetic patients by triggering the loss of vascular and myocardial compliance and promoting endothelial dysfunction. Thus, prevention of arterial stiffness is a public health priority, and the identification of potential biomarkers may provide benefits for early prevention. This study investigates the relationships between serum laboratory tests and pulse wave velocity (PWV) tests. We also investigated the associations between PWV and all-cause mortality. METHODS: We examined a panel of 33 blood biomarkers among diabetic populations in the Atherosclerosis Risk in Communities Study. The carotid-femoral (cfPWV) and femoral-ankle PWV (faPWV) were measured using an automated cardiovascular screening device. The aortic-femoral arterial stiffness gradient (afSG) was calculated as faPWV divided by cfPWV. Biomarker levels were log-transformed and correlated with PWV. Cox proportional hazard models were employed for survival analysis. RESULTS: Among 1079 diabetic patients, biomarkers including high-density lipoprotein cholesterol, glycated hemoglobin, high-sensitivity troponin T, cystatin C, creatinine, and albuminuria were significantly correlated with afSG (R = 0.078, -0.193, -0.155, -0.153, -0.116, and -0.137, respectively) and cfPWV (R = -0.068, 0.175, 0.128, 0.066, 0.202, and 0.062, respectively). Compared with the lowest tertile of afSG, the risk of all-cause mortality was lower in the highest tertile (hazard ratio 0.543; 95% confidence interval 0.328-0.900). CONCLUSION: Certain biomarkers related to blood glucose monitoring, myocardial injury, and renal function significantly correlated with PWV, suggesting that these putative risk factors are likely to be important atherosclerosis mechanisms in diabetic patients. AfSG may be an independent predictor of mortality among diabetic populations.

Gram-Negative Bacteria and Lipopolysaccharides as Risk Factors for the Occurrence of Diabetic Foot.

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.

Long-Term Visit-To-Visit Blood Pressure Variability and Risk of Diabetes Mellitus in Chinese Population: A Retrospective Population-Based Study.

Objectives: To examine the association between visit-to-visit blood pressure variability (BPV) and incident diabetes mellitus (DM) risk in a Chinese population. Methods: Data comes from China Health and Nutrition Survey (n = 15,084). BPV was estimated as the average real variability (ARV) using at least three BP measurements from the year preceding the event and was divided into quartiles. Participants were also categorized into 9 groups on the basis of combinations of systolic BPV (SBPV) and diastolic BPV (DBPV) tertiles. Cox proportional hazards regression models were used. Results: During a median follow-up of 16.8 years, 1,030 (6.8%) participants developed diabetes (incidence rate: 4.65/1,000 person-years). The HRs (95% CIs) for the highest quartile (vs. the lowest quartile) of SBPV and DBPV were 1.60 (1.30-1.97) and 1.37 (1.13-1.67), respectively. Participants with both highest SBPV and DBPV tertile had an ≈89% higher risk of DM (HR, 1.89; 95% CI, 1.47-2.42) compared with those in the both SBPV and DBPV tertile 1 group. Conclusion: Higher SBP ARV and DBP ARV were independently associated with increased risk of incident DM, which was augmented when both presented together.

Association of Diabetes Mellitus Status and Hyperglycemia With Symptomatic Knee Osteoarthritis.

OBJECTIVE: Emerging evidence indicates that hyperglycemia has an adverse impact on the knee joint which, in turn, may increase the risk of knee osteoarthritis (OA), but evidence from the real-life settings of large-scale cohort studies remains unclear. We sought to evaluate the association of glycemic control and the risk of symptomatic knee OA in a community-based cohort of older adults. METHODS: We conducted a prospective analysis of 10,730 participants without knee OA. Comprehensive blood biomarker data were obtained. Diabetes mellitus (DM) was defined mainly using a glycosylated hemoglobin (HbA1c ) level of ≥6.5%; poor glycemic control in individuals with DM was defined as an HbA1c level of ≥7%. We fit Cox regression models, stratified according to DM status. We evaluated the hazards associated with HbA1c and fasting blood glucose levels using a spline model. RESULTS: During a median follow-up of 5 years, knee OA developed in 1,089 participants (108 with DM and 971 without). Knee OA was related to DM (hazard ratio [HR] 1.29 [95% confidence interval (95% CI) 1.02-1.78]), bad glycemic regulation in DM patients (HR 1.41 [95% CI 1.05-2.09]), and long-term DM (≥5 versus <5 years; HR 1.49 [95% CI 1.02-2.17]). High levels of HbA1c (>7.7% and 61 mmoles/mole) and fasting blood glucose (>186 mg/dl) were significantly associated with higher risk of incident knee OA. CONCLUSION: DM, bad glycemic management, and long-term DM are potential risk factors of symptomatic knee OA independent of age and body mass index. Targeting blood glucose, in addition to bodyweight, may be an important avenue for prevention of knee OA.

[Relationship Between Social Isolation and Health Behaviors and Ulcer Severity in Diabetic Foot Patients].

Objective: To explore the relationship between social isolation and health behaviors and ulcer severity in patients with diabetic foot. Methods: A cross-sectional study was conducted with 160 patients suffering from type 2 diabetes mellitus combined with diabetic foot. The patients received treatment at the Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University between September 2020 and December 2021. Patient information was collected, including the scores for Lubben Social Network Scale and the Wagner classification of foot ulcers. Analysis was conducted to study the characteristics of the patients' health behaviors, including whether they received information and education on diabetic foot, whether there were delays in their attempt to access medical service, the frequency of foot examinations, etc. In addition, patient demographic data were collected, including sex, age, education, and employment status. According to their scores for Lubben Social Network Scale, the patients were divided into a social isolation group ( n=60) and a non-social-isolation group ( n=100). The severity of the foot ulcers and the health behaviors of the two groups were compared to identify differences. Results: The findings suggest that, compared with the non-social-isolation group, the social isolation group had a higher proportion of diabetic foot patients with Wagner grade 3-5 diabetic foot ulcers ( P<0.05). Analysis of the health behaviors showed that the social isolation group had a higher proportion of diabetes foot patients who had never undergone examination of their feet and those who had delayed attempts to access medical service for their condition ( P<0.05). There were no significant differences between the two groups in terms of whether the patients had received information and education concerning diabetic foot, causes of foot injury, self-treatment of wounds, smoking, and drinking. Correlational analysis suggested that the scores of Lubben Social Network Scale were negatively correlated with the delayed attempts to access medical service ( r=-0.353, P=0.001), that is, the higher the degree of social isolation, the longer the delay in patients' attempt to access medical service for their diabetic foot. Conclusions: Social isolation is correlated to health behaviors and ulcer severity in patients with diabetic foot. Giving more attention to the problem of social isolation of diabetic foot patients and increasing their ties with the social environment and the members of their social network may have a positive effect on improving the delays in diabetic foot patients' attempt to access medical service, which is particularly important for follow-up treatment.

Rapid microbiological diagnosis based on 16S rRNA gene sequencing: A comparison of bacterial composition in diabetic foot infections and contralateral intact skin.

Diabetic foot infections (DFIs) represent a frequent complication of diabetes and a major cause of amputations. This study aimed to evaluate the utility of 16S rRNA gene sequencing for the rapid microbiological diagnosis of DFIs and to consistently characterize the microbiome of chronic diabetic foot ulcers (DFUs) and intact skin. Wound samples were collected by ulcer swabbing and tissue biopsy, and paired swabs of intact skin were collected from 10 patients with DFIs (five were moderately infected, and the other five were severely infected). Samples were analyzed by conventional culture and using Personal Genome Machine (PGM) 16S rRNA sequencing technology. The results showed that PGM technology detected significantly more bacterial genera (66.1 vs. 1.5 per wound sample, p < 0.001); more obligate anaerobes (52.5 vs. 0%, p < 0.001) and more polymicrobial infections (100.0 vs. 55.0%, p < 0.01) than conventional cultures. There was no statistically significant difference in bacterial richness, diversity or composition between the wound swabs and tissues (p > 0.05). The bacterial community on intact skin was significantly more diverse than that in DFUs (Chao1 value, p < 0.05; Shannon index value, p < 0.001). Gram-positive bacteria (67.6%) and aerobes (59.2%) were predominant in contralateral intact skin, while Gram-negative bacteria (63.3%) and obligate anaerobes (50.6%) were the most ubiquitous in DFUs. The most differentially abundant taxon in skin was Bacillales, while Bacteroidia was the bacterial taxon most representative of DFUs. Moreover, Fusobacterium (ρ = 0.80, p < 0.01) and Proteus (ρ = 0.78, p < 0.01) were significantly correlated with the duration of DFIs. In conclusion, PGM 16S rRNA sequencing technology could be a potentially useful technique for the rapid microbiological diagnosis of DFIs. Wound swabbing may be sufficient for sampling bacterial pathogens in DFIs compared with biopsy which is an invasive technique. The empirical use of broad-spectrum antibiotics covering Gram-negative obligate anaerobes should be considered for the treatment of moderate or severe DFIs.

Research progress on the mechanism by which skin macrophage dysfunction mediates chronic inflammatory injury in diabetic skin.

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.

Extracellular HSP90α promotes cellular senescence by modulating TGF-ß signaling in pulmonary fibrosis.

Recent findings suggest that extracellular heat shock protein 90α (eHSP90α) promotes pulmonary fibrosis, but the underlying mechanisms are not well understood. Aging, especially cellular senescence, is a critical risk factor for idiopathic pulmonary fibrosis (IPF). Here, we aim to investigate the role of eHSP90α on cellular senescence in IPF. Our results found that eHSP90α was upregulated in bleomycin (BLM)-induced mice, which correlated with the expression of senescence markers. This increase in eHSP90α mediated fibroblast senescence and facilitated mitochondrial dysfunction. eHSP90α activated TGF-ß signaling through the phosphorylation of the SMAD complex. The SMAD complex binding to p53 and p21 promoters triggered their transcription. In vivo, the blockade of eHSP90α with 1G6-D7, a specific eHSP90α antibody, in old mice attenuated the BLM-induced lung fibrosis. Our findings elucidate a crucial mechanism underlying eHSP90α-induced cellular senescence, providing a framework for aging-related fibrosis interventions.

Lipid variability and risk of microvascular complications in Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial: A post hoc analysis.

BACKGROUND: Greater lipid variability may cause adverse health events among diabetic patients. We aimed to examine the effect of lipid variability on the risk of diabetic microvascular outcomes among type 2 diabetes mellitus patients. METHODS: We assessed the association between visit-to-visit variability (measured by variability independent of mean) in high-density lipoprotein (HDL) cholesterol, low-density lipoprotein-cholesterol (LDL), triglyceride, and remnant cholesterol (RC) measurements among participants involved in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study and the risk of incident microvascular outcomes, including nephropathy, neuropathy, and retinopathy. Cox proportional hazards models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs), adjusted for potential confounders. RESULTS: There were 2400, 2470, and 2468 cases of nephropathy, neuropathy, and retinopathy during a follow-up period of 22 600, 21 542, and 26 701 person-years, respectively. Higher levels of HDL, triglyceride, and RC variability were associated with an increased risk of incident nephropathy and neuropathy. Compared with the lowest quartile, the fully adjusted HRs (95% CI) for the highest quartile of HDL, triglyceride, and RC variability for nephropathy risk were 1.57 (1.22, 2.01), 1.50 (1.18, 1.92), and 1.40 (1.09, 1.80), respectively; and for neuropathy, the corresponding risks were 1.36 (1.05, 1.75), 1.47 (1.14, 1.91), and 1.35 (1.04, 1.74), respectively. Null association was observed between LDL variability and all microvascular complications. Additionally, all associations of variability in the other lipids with retinopathy risk were null. CONCLUSION: Among individuals with type 2 diabetes mellitus, HDL, triglyceride, and RC variability were associated with increased risks of nephropathy and neuropathy but not retinopathy. TRIAL REGISTRATION: ClinicalTrials.gov., no. NCT00000620.

Extracellular Hsp90α, which participates in vascular inflammation, is a novel serum predictor of atherosclerosis in type 2 diabetes.

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.