Community screening for dementia among older adults in China: a machine learning-based strategy.

BACKGROUND: Dementia is a leading cause of disability in people older than 65 years worldwide. However, diagnosing dementia in its earliest symptomatic stages remains challenging. This study combined specific questions from the AD8 scale with comprehensive health-related characteristics, and used machine learning (ML) to construct diagnostic models of cognitive impairment (CI). METHODS: The study was based on the Shenzhen Healthy Ageing Research (SHARE) project, and we recruited 823 participants aged 65 years and older, who completed a comprehensive health assessment and cognitive function assessments. Permutation importance was used to select features. Five ML models using BalanceCascade were applied to predict CI: a support vector machine (SVM), multilayer perceptron (MLP), AdaBoost, gradient boosting decision tree (GBDT), and logistic regression (LR). An AD8 score ≥ 2 was used to define CI as a baseline. SHapley Additive exPlanations (SHAP) values were used to interpret the results of ML models. RESULTS: The first and sixth items of AD8, platelets, waist circumference, body mass index, carcinoembryonic antigens, age, serum uric acid, white blood cells, abnormal electrocardiogram, heart rate, and sex were selected as predictive features. Compared to the baseline (AUC = 0.65), the MLP showed the highest performance (AUC: 0.83 ± 0.04), followed by AdaBoost (AUC: 0.80 ± 0.04), SVM (AUC: 0.78 ± 0.04), GBDT (0.76 ± 0.04). Furthermore, the accuracy, sensitivity and specificity of four ML models were higher than the baseline. SHAP summary plots based on MLP showed the most influential feature on model decision for positive CI prediction was female sex, followed by older age and lower waist circumference. CONCLUSIONS: The diagnostic models of CI applying ML, especially the MLP, were substantially more effective than the traditional AD8 scale with a score of ≥ 2 points. Our findings may provide new ideas for community dementia screening and to promote such screening while minimizing medical and health resources.

RfxCas13d-mediated inhibition of Circ1647 alleviates renal fibrosis via PI3K/AKT signaling pathway.

BACKGROUND: Circular RNAs (CircRNAs) have been shown to be involved in the development of chronic kidney disease (CKD). This study aimed to investigate the role of Circ1647 in renal fibrosis, which is a hallmark of CKD. METHODS: In this study, we established a unilateral ureteral obstruction (UUO) model and delivered Circ1647 RfxCas13d knockdown plasmid into renal parenchymal cells via retrograde injection through the ureter followed by electroporation. After that, the pathological changes were determined by Hematoxylin and Eosin. Meanwhile, Immunohistochemistry, qRT-PCR and Western blot were conducted to assess the degree of fibrosis. In addition, overexpressing of Circ1647 in renal tubular epithelial cells (TCMK1) was performed to investigate the underlying mechanisms of Circ1647. RESULTS: Our results displayed that electroporation-mediated knockdown of Circ1647 by RfxCas13d knockdown plasmid significantly inhibited renal fibrosis in UUO mice as evidenced by reduced expression of fibronectin and α-SMA (alpha-smooth muscle actin). Conversely, overexpression of Circ1647 in TCMK1 cells promoted the fibrosis. In terms of mechanism, Circ1647 may mediate the PI3K/AKT Signaling Pathway as demonstrated by the balance of the phosphorylation of PI3K and AKT in vivo and the aggravated phosphorylation of PI3K and AKT in vitro. These observations were corroborated by the effects of the PI3K inhibitor LY294002, which mitigated fibrosis post Circ1647 overexpression. CONCLUSION: Our study suggests that Circ1647 plays a significant role in renal fibrosis by mediating the PI3K/AKT signaling pathway. RfxCas13d-mediated inhibition of Circ1647 may serve as a therapeutic target for renal fibrosis in CKD.

Associations of low-density lipoprotein cholesterol with all-cause and cause-specific mortality in older adults in China.

CONTEXT: Limited information was available on detailed associations of low-density lipoprotein cholesterol (LDL-C) with all-cause and cause-specific mortality in older adults. METHODS: This prospective cohort study included a representative sample of 211,290 adults aged 65 or older, who participated in Shenzhen Healthy Aging Research 2018-2019. The vital status of the participants by 31 December, 2021 was determined. We estimated the hazard ratios (HR) with 95% confidence intervals for all-cause or cause-specific mortality using multivariable Cox proportional hazards models and Cox models with restricted cubic spline(RCS) . RESULTS: The median follow-up time was 3.08 years. A total of 5,333 participants were confirmed to have died. Among them, 2,303 cardiovascular disease (CVD) deaths and 1,881 cancer deaths occurred. Compared to those with LDL-C of 100-129 mg/dL, the all-cause mortality risk was significantly higher for individuals with LDL-C level that was very low (< 70 mg/dL) or low (70-99 mg/dL). Compared with individuals with the reference LDL-C level, the multivariable-adjusted HR for CVD-specific mortality was 1.327 for those with very low LDL-C level (< 70 mg/dL), 1.437 for those with high LDL-C level (160 mg/dL ≦ LDL-C < 190mg/dL), 1.528 for those with very high LDL-C level (≥ 190 mg/dL). Low LDL-C level (70-99 mg/dL) and very low LDL-C level (< 70 mg/dL) were also associated with increased cancer mortality and other-cause mortality, respectively. The results from RCS curve showed similar results. CONCLUSION: Considering the risk of all-causes mortality and cause-specific mortality, we recommended 100-159 mg/dL as the optimal range of LDL-C among older adults in China.

Hairpin/DNA Ring Ternary Complex Initiated Rolling Circle Amplification for an Elevated Accuracy and Its Application in Analyzing Let-7a.

Rolling circle amplification (RCA) is an attractive isothermal nucleic acid amplification approach and has been widely applied in constructing a variety of biosensors. However, the inevitable drawbacks of lacking enough selectivity greatly hindered further applications of RCA-based approaches. Here, we develop a novel RCA-based approach by integrating the specific target recognition capability of the hairpin/DNA ring ternary complex and multiple signal amplification and successfully applied it for let-7a detection. In this method, let-7a specifically unfolds the hairpin probe (Hp probe) in the ternary complex to induce target recycle and RCA- and DNAzyme-based signal generation. Based on this, the established approach exhibits a high selectivity to let-7a, and the response of the approach to one base pair mismatched sequences was 24.9%, indicating a significantly improved specificity. Meanwhile, the limit of detection is as low as 342 aM, which can meet the high requirement for a trace amount of miRNA detection. In all, we believe that the established approach can offer a new avenue for miRNA detection and post-tumor care.

Sociodemographic and lifestyle determinants of multimorbidity among community-dwelling older adults: findings from 346,760 SHARE participants.

BACKGROUND: This study aimed to investigate the prevalence of multimorbidity and its associated factors among the older population in China to propose policy recommendations for the management of chronic diseases in older adults. METHODS: This study was conducted based on the 2021 Shenzhen Healthy Ageing Research (SHARE), and involved analysis of 346,760 participants aged 65 or older. Multimorbidity is defined as the presence of two or more clinically diagnosed or non self-reported chronic diseases among the eight chronic diseases surveyed in an individual. The Logistic analysis was adopted to explore the potential associated factors of multimorbidity. RESULTS: The prevalences of obesity, hypertension, diabetes, anemia, chronic kidney disease, hyperuricemia, dyslipidemia and fatty liver disease were 10.41%, 62.09%, 24.21%, 12.78%, 6.14%, 20.52%, 44.32%, and 33.25%, respectively. The prevalence of multimorbidity was 63.46%. The mean count of chronic diseases per participant was 2.14. Logistic regression indicated that gender, age, marriage status, lifestyle (smoking status, drinking status, and physical activity), and socioeconomic status (household registration, education level, payment method of medical expenses) were the common predictors of multimorbidity for older adults, among which, being women, married, or engaged in physical activity was found to be a relative determinant as a protective factor for multimorbidity after the other covariates were controlled. CONCLUSION: Multimorbidity is prevalent among older adults in Chinese. Guideline development, clinical management,and public intervention should target a group of diseases instead of a single condition.

Impact of central venous pressure during the first 24†h and its time-course on the lactate levels and clinical outcomes of patients who underwent coronary artery bypass grafting.

Purpose: Previous studies have revealed that elevated mean central venous pressure (CVP) was associated with poor prognosis in specific patient groups. But no study explored the impact of mean CVP on prognosis of patients who underwent coronary artery bypass grafting surgery (CABG). The purpose of this study was to investigate the impacts of elevated CVP and its time-course on clinical outcomes of patients who underwent CABG and potential mechanisms. Methods: A retrospective cohort study was performed based on the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. We first identified the CVP during specific period with the most predictive value. Patients were categorized into the low-CVP and high-CVP group on the basis of the cut-off value. A propensity score matching was used to adjust covariates. The primary outcome was a 28-day mortality. The secondary outcomes were 1-year mortality and in-hospital mortality, the length of intensive care unit (ICU) stay and hospitalization, acute kidney injury incidence, use of vasopressors, duration of ventilation and oxygen index, and lactate levels and clearance. Patients in the high-CVP group were categorized into the "second day CVP ≤ 13.46 mmHg" group and the "second day CVP > 13.46 mmHg" group, respectively, and the clinical outcomes were the same as before. Results: A total of 6,255 patients who underwent CABG were picked from the MIMIC-IV database, of which 5,641 CABG patients were monitored by CVP measurement during the first 2 days after ICU admission and 206,016 CVP records were extracted from the database. The mean CVP during the first 24 h was the most correlative and statistically significant for the 28-day mortality. The risk of the 28-day mortality was increased in the high-CVP group [OR 3.45 (95% CI: 1.77-6.70; p < 0.001)]. Patients with elevated CVP levels had worse secondary outcomes. The maximum of lactate levels and lactate clearance were also poor in the high-CVP group. For patients in the high-CVP group during the first 24 h, whose mean CVP during the second day lowered to less than the cut-off value, had better clinical outcomes. Conclusions: An elevated mean CVP during the first 24 h was correlated with poor outcomes in patients who underwent CABG. The potential mechanisms may be influencing the lactate levels and lactate clearance through the impact on afterload of tissue perfusion. Patients whose mean CVP during the second day dropped to less than the cut-off value had favorable prognosis.

Landscape analysis and overview of the literature on oxidative stress and pulmonary diseases.

Oxidative stress is caused by an imbalance in oxidant/antioxidant processes and is a critical process in pulmonary diseases. As no truly effective therapies exist for lung cancer, lung fibrosis and chronic obstructive pulmonary disease (COPD), at present, it is important to comprehensively study the relationship between oxidative stress and pulmonary diseases to identify truly effective therapeutics. Since there is no quantitative and qualitative bibliometric analysis of the literature in this area, this review provides an in-depth analysis of publications related to oxidative stress and pulmonary diseases over four periods, including from 1953 to 2007, 2008 to 2012, 2013 to 2017, and 2018 to 2022. Interest in many pulmonary diseases has increased, and the mechanisms and therapeutic drugs for pulmonary diseases have been well analyzed. Lung injury, lung cancer, asthma, COPD and pneumonia are the 5 most studied pulmonary diseases related to oxidative stress. Inflammation, apoptosis, nuclear factor erythroid 2 like 2 (NRF2), mitochondria, and nuclear factor-κB (NF-κB) are rapidly becoming the most commonly used top keywords. The top thirty medicines most studied for treating different pulmonary diseases were summarized. Antioxidants, especially those targeting reactive oxygen species (ROS) in specific organelles and certain diseases, may be a substantial and necessary choice in combined therapies rather than acting as a single "magic bullet" for the effective treatment of refractory pulmonary diseases.

Efficacy and safety of autologous platelet-rich plasma for diabetic foot ulcer healing: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: The occurrence of a diabetic foot ulcer (DFU) is a significant complication of diabetes that often precedes the need for amputation. Autologous platelet-rich plasma (Au-PRP), a substance abundant in various growth factors and cytokines, is increasingly being recognized as a promising method for promoting ulcer healing due to its potential similarities to the physiological wound healing process. METHODS: The databases Medline, EMBASE, PubMed, and the Cochrane Library were systematically accessed on January 26, 2023, without any consideration for the date of publication. The selection and assessment of research studies were conducted autonomously, based on predetermined criteria and methodological standards. Two researchers gathered data and evaluated the potential for bias separately. We utilize the Stata 17.0 software to conduct data analysis and generate relevant visual representations. RESULTS: The results of the meta-analysis indicate that autologous PRP has a significant positive effect on the healing rate (RR = 1.42, 95% CI 1.30-1.56, P < 0.001), reduces the healing time (MD = - 3.13, 95% CI - 5.86 to - 0.39, P < 0.001), accelerates the reduction of ulcer area (MD = 1.02, 95% CI 0.51-1.53, P < 0.001), decreases the rate of amputation (RR = 0.35, 95% CI 0.15-0.83, P < 0.001), and does not increase the incidence of adverse events (RR = 0.96, 95% CI 0.57-1.61, P > 0.05) when compared to conventional therapy. CONCLUSIONS: Au-PRP therapy has been shown to facilitate the process of wound healing and represents a viable and secure therapeutic alternative for individuals with DFU.

Andrographolide ameliorates hepatic steatosis by suppressing FATP2-mediated fatty acid uptake in mice with nonalcoholic fatty liver disease.

Excessive intrahepatocellular lipid accumulation or steatosis is caused by abnormal lipid metabolism and a common character of nonalcoholic fatty liver disease (NAFLD), which may progress into cirrhosis and hepatocellular cancer. Andrographolide (Andro) is the primary active ingredient extracted from Andrographis paniculata, showing a protective role against dietary steatosis with the mechanism not fully understood. In this study, we showed that administration of Andro (50, 100, and 200 mg/kg/day for 8 weeks, respectively) attenuated obesity and metabolic syndrome in high-fat diet (HFD)-fed mice with improved glucose tolerance, insulin sensitivity, and reduced hyperinsulinemia, hyperglycemia, and hyperlipidemia. HFD-fed mice presented hepatic steatosis, which was significantly prevented by Andro. In vitro, Andro decreased the intracellular lipid droplets in oleic acid-treated LO2 cells. The selected RT-PCR array revealed a robust expression suppression of the fatty acid transport proteins (FATPs) by Andro treatment. Most importantly, we found that Andro consistently reduced the expression of FATP2 in both the oleic acid-treated LO2 cells and liver tissues of HFD-fed mice. Overexpression of FATP2 abolished the lipid-lowering effect of Andro in oleic acid-treated LO2 cells. Andro treatment also reduced the fatty acid uptake in oleic acid-treated LO2 cells, which was blunted by FATP2 overexpression. Collectively, our findings reveal a novel mechanism underlying the anti-steatosis effect of Andro by suppressing FATP2-mediated fatty acid uptake, suggesting the potential therapeutic application of Andro in the treatment of NAFLD.

Elevated circulating GPHB5 levels in women with insulin resistance and polycystic ovary syndrome: A cross-sectional study and multiple intervention studies.

Objective: GPHB5 has been found to be associated with glucose and lipid metabolism in animal studies. However, the association of GPHB5 with IR and metabolic disorders remains unknown, and there is a lack of research in humans. Our aim in this study was to investigate the relationship between circulating GPHB5 and metabolic disorders in humans. Methods: Bioinformatics analysis was performed to understand the relationship between GPHB5 and metabolic disorders. GPHB5 mRNA expression in mice and rats was determined using RT-qPCR. Circulating GPHB5 concentrations were measured with an ELISA kit. EHC and OGTT were performed in humans. Results: Bioinformatics analysis shows that GPHB5 is associated with metabolic disorders and PCOS. GPHB5 mRNA expression levels in the metabolic-related tissues of HFD-fed mice, db/db and ob/ob mice, and PCOS rats were significantly higher than those of WT mice or rats. In human studies, we find that circulating GPHB5 levels were significantly higher in women with IR and PCOS. GPHB5 levels were positively correlated with age, BMI, WHR, BP, FBG, 2 h-BG, FIns, 2 h-Ins, TC, LDL-C, HbA1c, and FFA, but negatively correlated with adiponectin. Furthermore, GPHB5 was positively correlated with DHEAS and FAI, while negatively correlated with SHBG, FSH, SHBG and FSH. The increased GPHB5 concentration was related to IR and PCOS. After the treatment of metformin, GLP-1RA (Lira), and TZDs, circulating GPHB5 levels were decreased. Conclusions: Our results reveal that circulating GPHB5 could be a biomarker and potential therapeutic target for IR and PCOS in women.

The Prediction Value of D-Dimer on Prognosis in Intensive Care Unit among Old Patients ( ≥65 Years): A 9-Year Single-Center Retrospective Study of 9261 Cases.

Background: D-dimer (DD) has been indicated as a potential indicator due to its connection with the prognosis of the COVID-19 pandemic. Aging is linked to elevated DD levels in coagulation activation. However, few studies have investigated the correlation of DD with prognosis, especially in the old population. Therefore, this study aims at investigating the correlation of DD with prognosis in shock and perioperative populations over 65 years of age. Methods: We analyzed 9261 old patients admitted to intensive care units (ICUs) with either confirmed shock or in perioperative period of high-risk surgery, with 8813 of them had DD levels determined on admission. In-hospital mortality, length of ICU stay and ventilation time (VT) associated variables were assessed using generalized linear models. Results: Although DD levels had no positive correlations with in-hospital mortality (RR, 1.006; 95% CI, 0.998-1.014) and length of ICU stay (RR, 1.012; 95% CI, 0.997-1.028) in Model 3, they were strongly correlated with VT (RR, 1.577; 95% CI, 1.024-2.064). Higher DD levels in females (RR, 1.804; 95% CI, 1.116-2.602), those who used antibiotics (RR, 1.736; 95% CI, 1.092-2.453), those with surgery (RR, 1.640; 95% CI, 1.273-2.114), and those with shock (RR, 1.740; 95% CI, 1.001-2.687) had stronger correlation with longer VT than the counterparts. While patients who were between 65 and 74 years old (RR, 1.023; 95% CI, 1.003-1.043), with no use of antibiotics (RR, 1.007; 95% CI, 1.001-1.013) nor shock (RR, 1.011; 95% CI, 1.002-1.021), but had undergone surgical procedures (RR, 1.030; 95% CI, 1.012-1.048) were correlated with a longer ICU length of stay. Conclusion: DD levels at ICU admission are highly related to increased VT and length of ICU stay in the old population with either confirmed shock or after high-risk surgery, indicating the strong potential of DD as a marker with prognostic utility for all ICU patients in the future.

[Prevalence and factors of nonalcoholic fatty liver disease among elderly in Shenzhen City in 2018].

OBJECTIVE: To analyze the prevalence and influence factors of nonalcoholic fatty liver disease(NAFLD) among elderly in Shenzhen City. METHODS: From January to December in 2018, a convenient sampling method was used to select 121 042 survey subjects from Shenzhen community residents aged 65 years and above through questionnaire survey, physical examination, laboratory biochemical examination and b-ultrasound examination, demographic information, lifestyle, height, weight, waist circumference, blood pressure, fasting blood glucose, blood lipids, past history and liver B ultrasound result were collected. A total of 121 042 of the subjects were selected for the study with complete information. The logistic regression analysis were used to analyze the data. RESULTS: There were 33 179 NAFLD patients(27.41%). The variables adjusted by logistic regression analysis revealed that male(OR=0.633, 95%CI 0.612-0.654), illiteracy(OR=0.761, 95%CI 0.720-0.804), primary school education(OR=0.889, 95%CI 0.862-0.916), current smoking(OR=0.719, 95%CI 0.675-0.767), former smoking(OR=0.802, 95%CI 0.749-0.859), low-weight(OR=0.157, 95%CI 0.128-0.193) was negatively correlated with NAFLD(P<0.01).65-79 years old, obesity(OR=4.744, 95%CI 4.511-4.989), overweight(OR=2.421, 95%CI 2.341-2.504), central obesity(OR=1.823, 95%CI 1.764-1.883), hypertension(OR=1.101, 95%CI 1.069-1.134), diabetes(OR=1.578, 95%CI 1.528-1.630) and dyslipidemia(OR=1.685, 95%CI 1.639-1.734) was positive correlation with NAFLD(P<0.01). CONCLUSION: The prevalence of NAFLD among the elderly in Shenzhen City is relatively low compared with the national level, but its absolute value is higher. The prevalence of NAFLD is higher among the elderly who are female, highly educated, overweight, obese, central obese, suffering from hypertension, diabetes and dyslipidemia.

[Clinical value of pulse pressure/central venous pressure ratio in low cardiac output syndrome after cardiac surgery].

OBJECTIVE: To explore the relationship between the pulse pressure/central venous pressure (PP/CVP) ratio and the cardiac output (CO) of patients after cardiac surgery from the basic principles of hemodynamics, and to further evaluate the predictive value of PP/CVP ratio in patients with secondary low cardiac output syndrome (LCOS) after cardiac surgery. METHODS: A retrospective study was conducted, and patients who received pulse indicator continuous cardiac output (PiCCO) monitoring were enrolled at the department of critical care medicine of Peking Union Medical College Hospital from January 1, 2016, to September 1, 2021. Patients were divided into two groups: the LCOS group [cardiac index (CI) < 33.34 mL×s-1×m-2, 25 cases] and the non-LCOS group (CI ≥ 33.34 mL×s-1×m-2, 125 cases) according to the CI at 6 hours after surgery. The general clinical data and hemodynamic parameters were collected. Correlations between PP/CVP ratio and PiCCO monitoring indicators were performed with Pearson or Spearman correlation test. Receiver operator characteristic curve (ROC curve) analysis was carried out to evaluate the predictive value of the parameters in patients with LCOS after cardiac surgery. RESULTS: A total of 150 patients with PiCCO monitoring after cardiac surgery were included. There were no differences in baseline characteristics between the two groups, while PP in the LCOS group was lower than that in the non-LCOS group [mmHg (1 mmHg ≈ 0.133 kPa): 40 (37, 44) vs. 55 (46, 64)], CVP was higher than that in the non-LCOS group [mmHg: 12 (11, 14) vs. 10 (8, 12)], and PP/CVP ratio in the LCOS group was lower than that in the non-LCOS group [3.3 (2.9, 3.7) vs. 5.5 (4.6, 6.8)], with significant differences (all P < 0.05). Correlation analysis results showed that PP/CVP ratio was positively correlated with CI, CO, and stroke volume index (SVI), respectively (rs = 0.660, 0.592, 0.600, all P < 0.001). CI was negatively correlated with PP (rs = 0.509, P < 0.001) and positively correlated with CVP (rs = -0.297, P < 0.001). ROC curve analysis revealed that compared with PP, CVP, SVI and cardiac function index (CFI), PP/CVP ratio was the best predictor of LCOS after cardiac surgery [area under the ROC curve (AUC) was 0.94±0.02, P < 0.001], when the optimum cut-off value was 4.41, the sensitivity was 80.00%, and the specificity was 96.00%. CONCLUSIONS: PP/CVP ratio was moderately positively correlated with CO after cardiac surgery, and PP/CVP ratio could be used as a prognostic predictor for LCOS after cardiac surgery.

Hepatoprotective effect of curcumin against bisphenol A-induced hepatic steatosis via modulating gut microbiota dysbiosis and related gut-liver axis activation in CD-1 mice.

Chronic exposure to low-dose bisphenol A (BPA) has become a global problem of public health. Our previous work showed that low-dose BPA exposure caused gut microbial dysbiosis and hepatic steatosis. Curcumin, a polyphenol extracted from turmeric, has an inhibitory effect on liver lipid accumulation, whether curcumin can alleviate BPA-induced hepatic steatosis through improving intestinal flora and modulating gut-liver axis remains to be elucidated. Male CD-1 mice were fed with BPA-contaminated diet supplemented with or not with curcumin for 24 weeks. Curcumin supplementation markedly ameliorated liver fat accumulation and hepatic steatosis induced by BPA. Gut microbiota analysis via 16S rRNA sequencing revealed that the relative abundance of Proteobacteria and Firmicutes/Bacteroidetes ratio were increased in BPA-fed mice, and this alteration was reversed by curcumin treatment. Akkermansia, which was recognized as a potential probiotic, was significantly reduced after BPA exposure and was restored to the control level with curcumin addition. Furthermore, curcumin supplementation reversed the down-regulation of intestinal tight junction protein expressions (zona occludens-1 and occludin), improved increased gut permeability, reduced serum lipopolysaccharide level and suppressed the activation of hepatic toll-like receptor 4 / nuclear factor-κB (TLR4/NF-κB) pathway induced by BPA. These results indicated that the protective effect of curcumin against hepatic steatosis induced by BPA and further revealed that its mechanism might be its prebiotic effect on maintaining intestinal flora homeostasis and improving intestinal barrier function, consequently reducing serum lipopolysaccharide-triggered inflammatory response in the liver. Our work provides evidence for curcumin as a potential nutritional therapy for BPA-mediated hepatic steatosis.

The phosphorylation and dephosphorylation switch of VCP/p97 regulates the architecture of centrosome and spindle.

The proper orientation of centrosome and spindle is essential for genome stability; however, the mechanism that governs these processes remains elusive. Here, we demonstrated that polo-like kinase 1 (Plk1), a key mitotic kinase, phosphorylates residue Thr76 in VCP/p97 (an AAA-ATPase), at the centrosome from prophase to anaphase. This phosphorylation process recruits VCP to the centrosome and in this way, it regulates centrosome orientation. VCP exhibits strong co-localization with Eg5 (a mitotic kinesin motor), at the mitotic spindle, and the dephosphorylation of Thr76 in VCP is required for the enrichment of both VCP and Eg5 at the spindle, thus ensuring proper spindle architecture and chromosome segregation. We also showed that the phosphatase, PTEN, is responsible for the dephosphorylation of Thr76 in VCP; when PTEN was knocked down, the normal spread of VCP from the centrosome to the spindle was abolished. Cryo-EM structures of VCPT76A and VCPT76E, which represent dephosphorylated and phosphorylated states of VCP, respectively, revealed that the Thr76 phosphorylation modulates VCP by altering the inter-domain and inter-subunit interactions, and ultimately the nucleotide-binding pocket conformation. Interestingly, the tumor growth in nude mice implanted with VCPT76A-reconstituted cancer cells was significantly slower when compared with those implanted with VCPWT-reconstituted cancer cells. Collectively, our findings demonstrate that the phosphorylation and dephosphorylation switch of VCP regulates the architecture of centrosome and spindle for faithful chromosome segregation.

Iron overload and mitochondrial dysfunction orchestrate pulmonary fibrosis.

Pulmonary fibrosis (PF) is a chronic, progressive heterogeneous disease of lung tissues with poor lung function caused by scar tissue. Due to our limited understanding of its mechanism, there is currently no treatment strategy that can prevent the development of PF. In recent years, iron accumulation and mitochondrial damage have been reported to participate in PF, and drugs that reduce iron content and improve mitochondrial function have shown significant efficacy in animal experimental models. Excessive iron leads to mitochondrial impairment, which may be the key cause that results in the dysfunction of various kinds of pulmonary cells and further promotes PF. As an emerging research hotspot, there are few targeted effective therapeutic strategies at present due to limited mechanistic understanding. In this review, the roles of iron homeostasis imbalance and mitochondrial damage in PF are summarized and discussed, highlighting a promising direction for finding truly effective therapeutics for PF.

Permeant fluorescent probes visualize the activation of SARM1 and uncover an anti-neurodegenerative drug candidate.

SARM1 regulates axonal degeneration through its NAD-metabolizing activity and is a drug target for neurodegenerative disorders. We designed and synthesized fluorescent conjugates of styryl derivative with pyridine to serve as substrates of SARM1, which exhibited large red shifts after conversion. With the conjugates, SARM1 activation was visualized in live cells following elevation of endogenous NMN or treatment with a cell-permeant NMN-analog. In neurons, imaging documented mouse SARM1 activation preceded vincristine-induced axonal degeneration by hours. Library screening identified a derivative of nisoldipine (NSDP) as a covalent inhibitor of SARM1 that reacted with the cysteines, especially Cys311 in its ARM domain and blocked its NMN-activation, protecting axons from degeneration. The Cryo-EM structure showed that SARM1 was locked into an inactive conformation by the inhibitor, uncovering a potential neuroprotective mechanism of dihydropyridines.

Clioquinol Attenuates Pulmonary Fibrosis through Inactivation of Fibroblasts via Iron Chelation.

Strict control of iron homeostasis is critical for the maintenance of normal lung function. Iron accumulates in the lungs of patients with idiopathic pulmonary fibrosis (PF), but the characteristics of iron metabolism in the pathogenesis of PF and related targeting therapeutics are not well studied. In this study, we investigated the cellular and molecular characteristics of iron metabolism in fibrotic lungs and further explored the efficacy of clioquinol (CQ) for the treatment of PF as well as its functional mechanism. Iron aggregates accumulated in the lungs of patients with idiopathic PF, and FTL (ferritin light chain) transcripts were increased in their pulmonary fibroblasts. In the bleomycin (BLM)-induced PF (BLM-PF) mouse model, pulmonary iron accumulation is a very early and concomitant event of PF. Labile iron pool levels in both fibroblasts and macrophages from the BLM-PF model were elevated, and iron metabolism was dysregulated. CQ attenuated PF induced by BLM and FITC, and iron-saturated CQ did not alleviate BLM-PF. Furthermore, CQ inhibited the activation of fibroblasts, including proliferation, fibrotic differentiation, proinflammatory cytokine secretion, and migration. In conclusion, our study demonstrated that CQ, acting as an iron chelator, attenuates experimental PF through inactivation of fibroblasts, providing support for targeting iron metabolism as a basis for PF treatment.

Vacuolin-1 inhibits endosomal trafficking and metastasis via CapZß.

Metastasis is the fundamental cause of cancer mortality, but there are still very few anti-metastatic drugs available. Endosomal trafficking has been implicated in tumor metastasis, and we have previously found that small chemical vacuolin-1 (V1) potently inhibits autophagosome-lysosome fusion and general endosomal-lysosomal degradation. Here, we assessed the anti-metastatic activity of V1 both in vitro and in vivo. V1 significantly inhibits colony formation, migration, and invasion of various cancer cells in vitro. It also compromises the assembly-disassembly dynamics of focal adhesions (FAs) by inhibiting the recycling and degradation of integrins. In various experimental or transgenic mouse models, V1 significantly suppresses the metastasis and/or tumor growth of breast cancer or melanoma. We further identified capping protein Zß (CapZß) as a V1 binding protein and showed that it is required for the V1-mediated inhibition of migration and metastasis of cancer cells. Collectively, our results indicate that V1 targets CapZß to inhibit endosomal trafficking and metastasis.

DNMT3A inhibits E2F1-induced arterial marker expression and impairs angiogenesis in human umbilical artery endothelial cells.

Arterial marker genes EphrinB2 and HEY2 are essential for cardiovascular development and postnatal neovascularization. Our previous study confirmed that E2F1 could activate the transcription of EphrinB2 and HEY2 in human mesenchymal stem cells; however, the detailed mechanism has not been resolved yet. In this study, we focused on the interaction between E2F1 and DNMT3A, a de novo DNA methyltransferase, on regulating the expression of EphrinB2 and HEY2, and explored the potential mechanisms. Gain- and loss-of-function experiments implicated the positive effect of E2F1 on the expression of EphrinB2 and HEY2 and tube formation in human umbilical artery endothelial cells. Accumulation of DNMT3A decreased the levels of EphrinB2 and HEY2, and impaired tube formation induced by E2F1, while inhibiting DNMT3A by RNA interference augmented their expression and angiogenesis in E2F1-trasfected cells. We then asked whether the low expressions of EphrinB2 and HEY2 induced by DNMT3A are related to the methylation status of their promoters. Surprisingly, the methylation status of the CpG islands in the promoter region was not significantly affected by overexpression of exogenous DNMT3A. Furthermore, the interaction between E2F1 and DNMT3A was confirmed by co-immunoprecipitation. DNMT3A could inhibit the transcription of EphrinB2 and HEY2 promoters by affecting the binding of E2F1 to its recognition sequences as revealed by luciferase reporter assay and chromatin immunoprecipitation. These results identified a novel mechanism underlying the cooperation of DNMT3A with E2F1 on regulating target gene expression, and revealed their roles in the angiogenic process.