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.

1G6-D7 Inhibits Homologous Recombination Repair by Targeting Extracellular HSP90α to Promote Apoptosis in Non-Small Cell Lung Cancer.

Despite recent advances in treatment, non-small cell lung cancer (NSCLC) continues to have a high mortality rate. Currently, NSCLC pathogenesis requires further investigation, and therapeutic drugs are still under development. Homologous recombination repair (HRR) repairs severe DNA double-strand breaks. Homologous recombination repair deficiency (HRD) occurs when HRR is impaired and causes irreparable double-strand DNA damage, leading to genomic instability and increasing the risk of cancer development. Poly(ADP-ribose) polymerase (PARP) inhibitors can effectively treat HRD-positive tumors. Extracellular heat shock protein 90α (eHSP90α) is highly expressed in hypoxic environments and inhibits apoptosis, thereby increasing cellular tolerance. Here, we investigated the relationship between eHSP90α and HRR in NSCLC. DNA damage models were established in NSCLC cell lines (A549 and H1299). The activation of DNA damage and HRR markers, apoptosis, proliferation, and migration were investigated. In vivo tumor models were established using BALB/c nude mice and A549 cells. We found that human recombinant HSP90α stimulation further activated HRR and reduced DNA damage extent; however, eHSP90α monoclonal antibody, 1G6-D7, effectively inhibited HRR. HRR inhibition and increased apoptosis were observed after LRP1 knockdown; this effect could not be reversed with hrHSP90α addition. The combined use of 1G6-D7 and olaparib caused significant apoptosis and HRR inhibition in vitro and demonstrated promising anti-tumor effects in vivo. Extracellular HSP90α may be involved in HRR in NSCLC through LRP1. The combined use of 1G6-D7 and PARP inhibitors may exert anti-tumor effects by inhibiting DNA repair and further inducing apoptosis of NSCLC cells.

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.

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.

[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.

Diabetes duration and glycaemic control as predictors of cardiovascular disease and mortality.

AIMS: To assess the associations of diabetes duration and glycaemic control (defined by plasma glycated haemoglobin [HbA1c] level) with the risks of cardiovascular disease (CVD) and all-cause mortality and to determine whether the addition of either or both to the established CVD risk factors can improve predictions. MATERIALS AND METHODS: A total of 435 679 participants from the UK Biobank without CVD at baseline were included. Cox models adjusting for classic risk factors (sociodemographic and anthropometric characteristics, lipid profiles and medication use) were used, and predictive utility was determined by the C-index and net reclassification improvement (NRI). RESULTS: Compared with participants without diabetes, participants with longer diabetes durations and poorer glycaemic control had a higher risk of fatal/nonfatal CVD. Among participants with diabetes, the fully-adjusted hazard ratios (HRs) for diabetes durations of 5 to <10 years, 10 to <15 years and ≥15 years were 1.15 (95% confidence interval [CI] 0.99, 1.34), 1.50 (95% CI 1.26, 1.79) and 2.22 (95% CI 1.90, 2.58; P-trend <0.01), respectively, compared with participants with diabetes durations <5 years. In addition, those with the longest disease duration (≥15 years) and poorer glycaemic control (HbA1c ≥64 mmol/mol [8%]) had the highest risk of fatal/nonfatal CVD (HR 3.12, 95% CI 2.52, 3.86). Among participants with diabetes, the addition of both diabetes duration and glycaemic control levels significantly improved both the C-index (change in C-index +0.0254; 95% CI 0.0111, 0.0398) and the overall NRI for fatal/nonfatal CVD (0.0992; 95% CI 0.0085, 0.1755) beyond the use of the classic risk factors. CONCLUSIONS: Both longer diabetes duration and poorer glycaemic control were associated with elevated risks of CVD and mortality. Clinicians should consider not only glycaemic control but also diabetes duration in CVD risk assessments for participants with diabetes.

Exenatide and Renal Outcomes in Patients with Type 2 Diabetes and Diabetic Kidney Disease.

BACKGROUND: Cardiovascular outcomes in clinical trials with type 2 diabetes mellitus (T2DM) patients have shown that glucagon-like peptide-1 receptor agonist can have a beneficial effect on the kidney. This trial aimed to assess the effects of exenatide on renal outcomes in patients with T2DM and diabetic kidney disease (DKD). METHODS: We performed a randomized parallel study encompassing 4 general hospitals. T2DM patients with an estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 and macroalbuminuria, defined as 24-h urinary albumin excretion rate (UAER) >0.3 g/24 h were randomized 1:1 to receive exenatide twice daily plus insulin glargine (intervention group) or insulin lispro plus glargine (control group) for 24 weeks. The primary outcome was the UAER percentage change from the baseline after 24 weeks of intervention. The rates of hypoglycemia, adverse events (AEs), and change in eGFR during the follow-up were measured as safety outcomes. RESULTS: Between March 2016 and April 2019, 92 patients were randomized and took at least 1 dose of the study drug. The mean age of the participants was 56 years. At baseline, the median UAER was 1,512.0 mg/24 h and mean eGFR was 70.4 mL/min/1.73 m2. After 24 weeks of treatment, the UAER percentage change was significantly lower in the intervention group than in the control group (p = 0.0255). Moreover, the body weight declined by 1.3 kg in the intervention group (the difference between the 2 groups was 2.7 kg, p = 0.0001). Compared to the control group, a lower frequency of hypoglycemia and more gastrointestinal AEs were observed in the intervention group. CONCLUSION: Exenatide plus insulin glargine treatment for 24 weeks resulted in a reduction of albuminuria in T2DM patients with DKD.

The role of secreted Hsp90α in HDM-induced asthmatic airway epithelial barrier dysfunction.

BACKGROUND: The dysfunction of airway epithelial barrier is closely related to the pathogenesis of asthma. Secreted Hsp90α participates in inflammation and Hsp90 inhibitor protects endothelial dysfunction. In the current study, we aimed to explore the role of secreted Hsp90α in asthmatic airway epithelial barrier function. METHODS: Male BALB/c mice were sensitized and challenged with HDM to generate asthma model. The 16HBE and Hsp90α-knockdown cells were cultured and treated according to the experiment requirements. Transepithelial Electric Resistance (TEER) and permeability of epithelial layer in vitro, distribution and expression of junction proteins both in vivo and in vitro were used to evaluate the epithelial barrier function. Western Blot was used to evaluate the expression of junction proteins and phosphorylated AKT in cells and lung tissues while ELISA were used to evaluate the Hsp90α expression and cytokines release in the lung homogenate. RESULTS: HDM resulted in a dysfunction of airway epithelial barrier both in vivo and in vitro, paralleled with the increased expression and release of Hsp90α. All of which were rescued in Hsp90α-knockdown cells or co-administration of 1G6-D7. Furthermore, either 1G6-D7 or PI3K inhibitor LY294002 suppressed the significant phosphorylation of AKT, which caused by secreted and recombinant Hsp90α, resulting in the restoration of epithelial barrier function. CONCLUSIONS: Secreted Hsp90α medicates HDM-induced asthmatic airway epithelial barrier dysfunction via PI3K/AKT pathway, indicating that anti-secreted Hsp90α therapy might be a potential treatment to asthma in future.

Blockade of extracellular heat shock protein 90α by 1G6-D7 attenuates pulmonary fibrosis through inhibiting ERK signaling.

Pulmonary fibrosis is characterized by lung fibroblast activation and ECM deposition and has a poor prognosis. Heat shock protein 90 (Hsp90) participates in organ fibrosis, and extracellular Hsp90α (eHsp90α) promotes fibroblast activation and migration. This study aimed to investigate whether a selective anti-Hsp90α monoclonal antibody, 1G6-D7, could attenuate lung fibrosis and whether 1G6-D7 presents a protective effect by inactivating the profibrotic pathway. Our results showed that eHsp90α was increased in mice with BLM-induced pulmonary fibrosis and that 1G6-D7 attenuated inflammation and collagen deposition in the lung. TGF-ß1 induced eHsp90α secretion, concomitantly promoting HFL-1 activation and ECM synthesis. 1G6-D7-mediated inhibition of eHsp90α significantly blocked these effects, meanwhile inhibiting downstream profibrotic pathways such as ERK, Akt, and P38. Human recombinant (hr)Hsp90α mimicked the effects of TGF-ß1, by activating profibrotic pathways and by upregulating LRP-1. Moreover, ERK inhibition effectively blocked the effect of (hr)Hsp90α. In conclusion, 1G6-D7 significantly protects against BLM-induced pulmonary fibrosis by ameliorating fibroblast activation and ECM production, which may be through blocking ERK signaling. Our results suggest a safer molecular therapy, 1G6-D7, in pulmonary fibrosis.

Hsp90α and Hsp90ß together operate a hypoxia and nutrient paucity stress-response mechanism during wound healing.

When tissues are injured and blood vessels clot, the local environment becomes ischemic, meaning that there is a lack of adequate supply of oxygen and glucose delivered to the surrounding cells. The heat shock protein-90 (Hsp90) family proteins protect tissues from various environmental insults and participate in the repair of damaged tissue. Here, we report discovery of a new ischemia-responsive mechanism in which the two Hsp90 isoforms Hsp90α and Hsp90ß (also known as HSP90AA1 and HSP90AB1, respectively) work together to promote cell motility in wounded skin and accelerate wound closure. We demonstrate that Hsp90α and Hsp90ß have distinct and non-exchangeable functions during wound healing. Under hypoxia and when there is a lack of serum factors, Hsp90ß binds to the cytoplasmic tail of the LDL receptor-related protein-1 (LRP-1) and stabilizes the receptor at the cell surface. Hsp90α, however, is secreted by the cell into extracellular space where it binds and signals through the LRP-1 receptor to promote cell motility, leading to wound closure. In addition to skin injury, we suggest that this repair mechanism applies broadly to other non-cutaneous injured tissues.

TSLP signaling blocking alleviates E-cadherin dysfunction of airway epithelium in a HDM-induced asthma model.

Recent studies have indicated that Thymic stromal lymphopoietin (TSLP) plays an important role in the prevention and treatment of asthma. However the role of TSLP in dysfunction of airway epithelial adherens junctions E-cadherin in house dust mite (HDM)-induced asthma has not been addressed. We hypothesized that TSLP contributed to HDM-induced E-cadherin dysfunction in asthmatic BALB/c mice and 16HBE cells. In vivo, a HDM-induced asthma mouse model was set up for 8weeks. Mice inhaled an anti-TSLP monoclonal antibody (mAb) before HDM. The mice treated with the anti-TSLP mAb ameliorated airway inflammation, the decreasing and aberrant distribution of E-cadherin and ß-catenin as well as phosphorylation(p)-AKT induced by HDM. In vitro, HDM increased the expression of TSLP and E-cadherin dysfunction by PI3K/Akt signaling pathway. The exposure of 16HBE to TSLP resulted in redistribution of E-cadherin. These results indicate that TSLP may be an important contributor in E-cadherin dysfunction of HDM-induced asthma. TSLP signaling blocking shows a protective effect in mice and that the PI3K/Akt pathway may play a role in this process.

Bevacizumab reduced auto-phosphorylation of VEGFR2 to protect HDM-induced asthma mice.

Vascular endothelial growth factor (VEFG) is a major angiogenic factor involved in both normal physiological processes, such as embryonic development and wound healing, and in diseases, like cancer. Recent studies have revealed the functions of VEGF in inflammation and immunoregulation. Asthma is a chronic inflammation of the airways characterized by airway epithelial barrier dysfunction and imbalance in T-helper (Th) 1/Th2 during immunoregulation. We hypothesized that VEGF plays an important role in asthma. Utilizing a house dust mite extract (HDM)-induced murine model of asthma, we investigated whether bevacizumab, a humanized anti-VEGF monoclonal antibody, could protect the epithelial barrier in murine airways. We found that bevacizumab reduced airway hyper-responsiveness (AHR) and airway inflammation induced by HDM. In addition, HDM exposure promoted expression of VEGF, and caused AHR, disruptions of the epithelial barrier, and airway inflammation. Bevacizumab ameliorated AHR and the release of Th2 cytokines, thereby protecting the epithelial barrier. Our data suggest that bevacizumab may be a new therapeutic strategy for asthma.

[Polarization of neutrophils from patients with asthma, chronic obstructive pulmonary disease and asthma-chronic obstructive pulmonary disease overlap syndrome].

OBJECTIVE: To explore the polarization of migration dynamics of neutrophils isolated from patients with asthma, chronic obstructive pulmonary disease (COPD) and asthma-COPD overlap syndrome (ACOS) compared with healthy smoking and non-smoking controls. METHODS: Recruited volunteers were classified as healthy controls, healthy smokers, asthma, COPD and ACOS at Nanfang Hospital from April 2013 to June 2014 according to the Global Strategy for the Diagnosis, Management and Prevention of COPD 2011, Global Strategy for Asthma Management and Prevention 2011 and Consensus on Overlap Phenotype COPD-asthma in COPD 2012. Neutrophils were freshly isolated from whole blood with density gradient technique. The proportion of polarized cells with gradient concentration of formyl-Met-Leu-Phe (fMLP) in Zigmond chamber and vital component of Store Operated Calcium Entry (SOCE) (stromal interaction molecule (STIM) 1, 2 and Orai1) in neutrophils was detected by Western blot. RESULTS: Asthma, COPD and ACOS neutrophils demonstrated a higher spontaneous polarization rate versus healthy controls and healthy smokers ((25.05 ± 4.06)%, (16.20 ± 4.46)%, (29.43 ± 5.53)% vs (7.27 ± 0.99)%, (7.06 ± 3.12)%, all P < 0.01), asthma and ACOS neutrophils showed a higher directed polarization rate ((14.62 ± 2.26)%, (8.00 ± 1.75)%, all P < 0.05), but COPD had a relatively lower rate of directional polarization rate than healthy controls and healthy smokers ((2.45 ± 0.54)% vs (5.12 ± 1.28)%, (5.24 ± 1.34)%, all P < 0.01). The vital component of SOCE in neutrophils from asthma, COPD and ACOS were all up-regulated versus healthy controls and healthy smokers (STIM1: 1.63 ± 0.14, 0.88 ± 0.41, 1.29 ± 0.22 vs 0.26 ± 0.14, 0.38 ± 0.12; STIM2: 0.52 ± 0.19, 0.22 ± 0.13, 0.24 ± 0.10 vs 0.05 ± 0.03, 0.10 ± 0.06; Orai1: 0.56 ± 0.04, 0.39 ± 0.05, 0.48 ± 0.05 vs 0.13 ± 0.04, 0.13 ± 0.03) (all P < 0.01). CONCLUSIONS: Asthma, COPD and ACOS neutrophils are intrinsically different than counterparts from healthy control subjects and healthy smokers. And vital components of SOCE from patient neutrophils are intrinsically up-regulated.

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.

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.

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.

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.

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.

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.