Association between Perceived Stress and Motoric Cognitive Risk Syndrome in an Elderly Population: Rugao Longevity and Aging Study.

INTRODUCTION: Previous studies have indicated a correlation between perceived stress and cognitive decline. However, it remains unknown whether high levels of perceived stress can result in motoric cognitive risk (MCR) syndrome. This study investigated the relationship between perceived stress and MCR in a community-based population. METHODS: The study cohort comprised 852 elderly individuals from the Rugao Longitudinal Aging Cohort. Perceived stress was assessed using the 10-item Perceived Stress Scale (PSS-10), while MCR was defined as the coexistence of subjective memory complaints (SMCs) and slow gait speed. RESULTS: The average age of the study participants is 79.84 ± 4.34 years. The mean score of PSS-10 among participants is 10.32 (range = 0-33; [SD] = 5.71), with a median score of 10.00 (6.00, 14.00). The prevalence of MCR is 9.3%. In the logistic regression analysis, for each 1-SD (5.71) increase in the global PSS-10 score, the risk of MCR increased by 40% (95% CI 1.09-1.80). Additionally, in the aspect of two components of MCR, with a 1-SD increase (5.71) in the global PSS-10 score, there was a 50% (95% CI 1.29-1.75) increase in the risk of SMCs and a 27% (95% CI 1.04-1.55) increase in the risk of slow gait speed. In terms of specific walking speed, there was a reverse correlation between the global PSS-10 score and walking speed (r = -0.14, p < 0.001). CONCLUSIONS: This study provided preliminary evidence that high levels of perceived stress were associated with the risk of MCR in a community-dwelling population.

CDKN2A promoter methylation enhances self-renewal of glioblastoma stem cells and confers resistance to carmustine.

BACKGROUND: Glioblastoma, a highly aggressive form of brain cancer, poses significant challenges due to its resistance to therapy and high recurrence rates. This study aimed to investigate the expression and functional implications of CDKN2A, a key tumor suppressor gene, in glioblastoma cells, building upon the existing background of knowledge in this field. METHOD: Quantitative reverse transcription PCR (qRT-PCR) analysis was performed to evaluate CDKN2A expression in U87 glioblastoma cells compared to normal human astrocytes (NHA). CDKN2A expression levels were manipulated using small interfering RNA (siRNA) and CDKN2A overexpression vector. Cell viability assays and carmustine sensitivity tests were conducted to assess the impact of CDKN2A modulation on glioblastoma cell viability and drug response. Sphere formation assays and western blot analysis were performed to investigate the role of CDKN2A in glioblastoma stem cell (GSC) self-renewal and pluripotency marker expression. Additionally, methylation-specific PCR (MSP) assays and demethylation treatment were employed to elucidate the mechanism of CDKN2A downregulation in U87 cells. RESULT: CDKN2A expression was significantly reduced in glioblastoma cells compared to NHA. CDKN2A overexpression resulted in decreased cell viability and enhanced sensitivity to carmustine treatment. CDKN2A inhibition promoted self-renewal capacity and increased pluripotency marker expression in U87 cells. CDKN2A upregulation led to elevated protein levels of p16INK4a, p14ARF, P53, and P21, which are involved in cell cycle regulation. CDKN2A downregulation in U87 cells was associated with high promoter methylation, which was reversed by treatment with a demethylating agent. CONCLUSION: Our findings demonstrate that CDKN2A downregulation in glioblastoma cells is associated with decreased cell viability, enhanced drug resistance, increased self-renewal capacity, and altered expression of pluripotency markers. The observed CDKN2A expression changes are mediated by promoter methylation. These results highlight the potential role of CDKN2A as a therapeutic target and prognostic marker in glioblastoma.

[Research progress in prevention and treatment of radiation-induced intestinal injury by traditional Chinese medicine active components].

Radiation-induced intestinal injury(RIII), a common complication of radiotherapy for pelvic malignancies, affects the quality of life and the radiotherapy efficacy for cancer. Currently, the main clinical approaches for the prevention and treatment of RIII include drug therapy, hyperbaric oxygen therapy, and surgical treatment. Among these methods, drug therapy is cost-effective. Traditional Chinese medicine(TCM) containing a variety of active components demonstrates mild side effects and good efficacy in preventing and treating RIII. Studies have proven that TCM active components, such as flavonoids, terpenoids, phenylpropanoids, and alkaloids, can protect the intestine against RIII by inhibiting oxidative stress, regulating the expression of inflammatory cytokines, modulating the mitochondrial apoptosis pathway, adjusting intestinal flora, and suppressing cell apoptosis. These mechanisms can help alleviate the symptoms of RIII. The paper aims to provide a theoretical reference for the discovery of new drugs for the prevention and treatment of RIII by reviewing the literature on TCM active components in the last 10 years.

Frailty index is associated with increased risk of elevated BNP in an elderly population: the Rugao Longevity and Ageing Study.

BACKGROUND AND AIMS: To explore whether frailty, defined by frailty index (FI), is associated with the risk of elevated B-type natriuretic peptide (BNP), a surrogate endpoint of cardiovascular events. METHODS: Data of 1382 community-dwelling elders who had no documented cardiovascular diseases aged 70-84 years from the ageing arm of the Rugao Longevity and Ageing Study was used. Traditional risk factor index (TI) was constructed using eight established cardiovascular-related risk factors. FI was constructed using 36 health deficits. Elevated BNP was defined as BNP ≥ 100pg/mL. Cardiovascular events include incident major cardiovascular events and cardiovascular death. RESULTS: During a 3-year follow-up period, 97 participants had cardiovascular events. TI was not associated with the risk of elevated BNP, but was associated with cardiovascular events (HR = 1.16, 95% CI 1.01-1.34). Frailty index was not only associated with cardiovascular events (HR = 1.32, 95% CI 1.06-1.64), but also associated with elevated BNP with an OR of 1.22 (95% CI 1.02-1.47) for each 0.1 increment. Further, both frailty (OR = 1.93, 95% CI 1.67-3.17) and pre-frailty (OR = 1.54, 95% CI 1.06-2.25) were associated with increased risk of elevated BNP. CONCLUSION: FI is associated with increased risks of both cardiovascular events and surrogated endpoint of cardiovascular disease-elevated BNP. Frailty may be a non-traditional risk factor of cardiovascular diseases and frailty index may be a measurement for early identifying high risk elderly individuals of cardiovascular abnormities.

Depressive symptoms are associated with incident frailty in a Chinese population: the Rugao Longevity and Aging Study.

BACKGROUND AND AIMS: This study aimed at investigating whether depression symptoms are associated with prevalent and incident physical frailty in Chinese older population. METHODS: We analyzed data of 1168 older Chinese adults aged 70 and above in the aging arm of the Rugao Longevity and Aging Study (RuLAS). Depressive symptoms (Geriatric Depression Scale ≥ 6) were assessed by the Geriatric Depression Scale. Frailty was defined using Fried phenotype criteria at baseline and 3-year survey. RESULTS: At baseline, 8.9% of the participants had depression symptoms. The prevalence of pre-frailty and frailty were 34.5% and 5.9%, respectively. The percentages of depressive symptoms increase from robust (5.3%) to pre-frail (11.2%), and then to frail (31.9%) groups. After adjustments of multiple covariates, depressive symptoms were associated with both prevalent pre-frailty (OR = 1.75, 95% CI 1.08-2.84) and prevalent frailty (OR = 5.64, 95% CI 2.85-11.14) at baseline. At 3-year survey, 9.3% participants reported the development of frailty. After multiple adjustments, depressive symptoms were associated with a 2.79-fold (95% CI 1.09-7.10) increased risk of 3-year incident frailty. CONCLUSION: Depressive symptoms are associated with prevalent and incident frailty in Chinese older population. Together with the observations of the European populations, depressive symptoms may be a candidate risk factor of frailty.

Frailty and incident depressive symptoms in a Chinese sample: the Rugao Longevity and Ageing Study.

BACKGROUND: To explore the cross-sectional and longitudinal associations between frailty and incident depressive symptoms in a Chinese elderly sample. METHODS: We analysed data of 1264 older Chinese elders aged 70-87 years in the Rugao Longevity and Ageing Study. The frailty phenotype was assessed using the Fried criteria and depression symptoms was measured by the Geriatric Depression Scale. RESULTS: At baseline, 10.6% of participants had depressive symptoms and 9.0% had frailty. In cross-sectional analysis, both pre-frailty (odds ratio (OR) = 2.18, 95% CI 1.35-3.51) and frailty (OR = 4.64, 95% CI 2.49-8.66) were associated with depressive symptoms. In longitudinal analyses, frailty (OR = 2.12, 95% CI 1.17-3.83), instead of pre-frailty, was associated with 1.5-year incident depressive symptoms in a full-adjusted model among participants free of baseline depressive symptoms. In the components of frailty, lower grip strength was associated with increased risk of depressive symptoms onset (OR = 1.56, 95% CI 1.06-2.29). CONCLUSIONS: Frailty and lower grip strength were associated with incident depressive symptoms in a Chinese elderly sample. Interventions designed to prevent depressive symptoms may be useful by utilising physical aspects of the elderly population.

Ischemic stroke prediction using machine learning in elderly Chinese population: The Rugao Longitudinal Ageing Study.

OBJECTIVE: Compared logistic regression (LR) with machine learning (ML) models, to predict the risk of ischemic stroke in an elderly population in China. METHODS: We applied 2208 records from the Rugao Longitudinal Ageing Study (RLAS) for ischemic stroke risk prediction assessment. Input variables included 103 phenotypes. For 3-year ischemic stroke risk prediction, we compared the discrimination and calibration of LR model and ML methods, where ML methods include Random Forest (RF), Gaussian kernel Support Vector Machines (SVM), Multilayer perceptron (MLP), K-Nearest Neighbors Algorithm (KNN), and Gradient Boosting Decision Tree (GBDT) to develop an ischemic stroke risk prediction model. RESULTS: Age, pulse, waist circumference, education level, ß2-microglobulin, homocysteine, cystatin C, folate, free triiodothyronine, platelet distribution width, QT interval, and QTc interval were significant induced predictors of ischemic stroke. For ischemic stroke prediction, the ML approach was able to tap more biochemical and ECG-related multidimensional phenotypic indicators compared to the LR model, which placed more importance on general demographic indicators. Compared to the LR model, SVM provided the best discrimination and calibration (C-index: 0.79 vs. 0.71, 11.27% improvement in model utility), with the best performance in both validation and test data. CONCLUSION: In a comparison of LR with five ML models, the accuracy of ischemic stroke prediction was higher by combining ML with multiple phenotypes. Combined with other studies based on elderly populations in China, ML techniques, especially SVM, have shown good long-term predictive performance, inspiring the potential value of ML use in clinical practice.

Berberine inhibits carcinogenesis through antagonizing the ATX-LPA-LPAR2-p38-leptin axis in a mouse hepatoma model.

Chemoprevention of hepatocellular carcinoma (HCC) is highly desirable in clinic. Berberine (BBR) is reported to play potential roles in cancer treatment and prevention. We studied the chemopreventive effect of BBR on hepatocellular carcinogenesis in an inflammation-driven mouse model, as it was enriched in liver after oral administration. Oral BBR significantly decreased the number and volume of visible nodular tumors, and prolonged the median overall survival by 9 and 8 weeks in the diethylnitrosamine (DEN)-injected male and female mice respectively. The nodular tumors were induced through activation of the lysophosphatidic acid (LPA) pathway in liver. LPA stimulated the abnormal leptin transcription through interacting with LPA receptor-2 (LPAR2) followed by p38 activation, and BBR inhibited carcinogenesis by suppressing the bioactivity of LPA. Specifically, BBR significantly reduced the expression of the LPA synthetase autotaxin (ATX) and LPAR2 in the nodular tumors of DEN-injected mice. Subsequently, BBR repressed the abnormal transcription of leptin stimulated by LPA-induced phosphorylation of p38 in hepatoma cells. In fact, BBR reduced the abnormal expression of leptin in livers of DEN-injected male mice throughout the course of an 8-month experiment. BBR might be a preventive agent for HCC, working at least partially through antagonizing the ATX-LPA-LPAR2-p38-leptin axis in liver.

Blastic plasmacytoid dendritic cell neoplasm with skin and bone marrow involvement: Report of three cases.

BACKGROUND: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and highly aggressive hematopoietic malignancy. BPDCN is difficult to diagnose because of the overlap in morphologic and immunophenotypic features with various cutaneous lymphatic hematopoietic tumors. CASE SUMMARY: We report on three BPDCN cases, all characterized by skin nodules and examined by histology, immunohistochemical detection, in situ hybridization for Epstein-Barr virus, and follow-up. We also review the relevant literature. All patients were positive for CD56 and negative for Epstein-Barr encoded small RNA. Two patients had bone marrow involvement. Chemotherapy is the main treatment for BPDCN, but case 1 showed bone marrow suppression and case 2 developed recurrence after chemotherapy. Case 1 survived for 7 mo, case 2 for 17 mo, and case 3 for 9 mo. CONCLUSION: An accurate pathological diagnosis is a precondition for treatment, and the diagnosis of BPDCN should be based on a combination of clinical symptoms, pathological characteristics, immunophenotype, and other auxiliary examinations. It is necessary to clarify the clinicopathological features and biological behavior of BPDCN to improve its understanding by both clinicians and pathologists. Case 2 survived significantly longer than the other two cases, suggesting that the treatment received by case 2 was more effective.

Secretory breast carcinoma in a female adult with liver metastsis: a case report and literature review.

BACKGROUND: Secretory breast carcinoma is an uncommon subset of breast cancer that usually has a favorable outcome. Although initially described in children, it also occurs in adults where it may metastasize, possibly resulting in death. To date, only 20 cases of secretory breast carcinoma with distant metastases have been described. CASE PRESENTATION: A 42-year-old female presented with liver metastasis after modified radical mastectomy of the left breast in 2008 at 34 years of age. The liver metastasis was morphologically similar to the primary tumor. Pan-TRK and Fluorescence in situ hybridization showed a rearrangement in the ETV6 gene. She subsequently underwent adjuvant chemotherapy with a fatal outcome. CONCLUSIONS: Although secretory breast carcinoma is usually associated with favorable outcomes, our study and reviews provide a novel insight into the genetic spectrum and treatment of secretory breast carcinoma showing reduced expression of hormone receptors, abnormal genomic profiles, and possible poor prognosis. Targeted therapy may curb clinically aggressive cases. Additional molecular investigations are needed to determine the links between specific mutations and poor prognosis.

Association Study of Mitochondrial DNA Haplogroup D and C5178A Polymorphisms with Chronic Kidney Disease.

Objective: To explore the associations of common mitochondrial DNA polymorphisms with chronic kidney disease (CKD). Methods: Data from 286 longevous individuals aged 95 years or older from the longevity arm from the Rugao Longevity and Ageing Study (RuLAS) were used. Twenty-eight common haplogroups defined by 33 single nucleotide polymorphisms were genotyped using SNaPshot minisequencing reaction assays. The creatinine-based estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Results: The prevalence of CKD was 23.6% among the longevous participants aged 95 years and older. The D haplogroup (67.37 ± 14.72 vs. 70.65 ± 11.07, p = 0.045), the D5 haplogroup (60.86 ± 18.36 vs. 70.34 ± 11.53, p = 0.002), and the 5178A allele (67.23 ± 14.48 vs. 70.75 ± 11.10, p = 0.029) were associated with lower eGFR levels compared with noncarriers. The D5 haplogroup (13.8% vs. 3.6%, p = 0.005) was significantly higher, while D haplogroup (35.4% vs. 24%, p = 0.067) and the 5178A allele (36.9% vs. 24.9%, p = 0.056) were borderline significantly higher in CKD individuals than those without CKD. Further, after adjusting for multiple covariates, the D haplogroup, the D5 haplogroup, and the 5178A allele were associated with increased odds of CKD with odds ratios of 1.93 (95% confidence interval [CI]: 1.00-3.72, p = 0.050), 4.76 (95% CI: 1.49-15.22, p = 0.009) and 2.04 (95% CI: 1.05-3.96, p = 0.035), respectively. Conclusions: The D and D5 haplogroups, as well as the 5178A allele are associated with decreased eGFR levels and an increased risk of CKD in a longevous population.

Berberine Improves Glucose and Lipid Metabolism in HepG2 Cells Through AMPKα1 Activation.

AIM: This study is designed to investigate whether or not AMP-activated protein kinase α1 (AMPKα1) is required for natural product berberine (BBR) to improve glucose and lipid metabolism in HepG2 cells. METHODS: AMPKα1 knocked-out (KO, AMPKα1-/- ) cells were obtained by co-transfection of the CRISPR/Cas9 KO and HDR (homology-directed repair) plasmid into HepG2 cells, as well as subsequent screen with puromycin. The expression levels of target proteins or mRNAs were determined by western blot or real-time RT-PCR, respectively. Cellular AMPK activity, glucose consumption, lactate release, glucose production, and lipid accumulation were determined by kits. RESULTS: The results showed that the AMPKα1 gene was successfully KO in HepG2 cells. In AMPKα1-/- cells, the protein expression of AMPKα1 and phosphorylated-AMPKα1 (p-AMPKα1) disappeared, the level of total AMPKα declined to about 45-50% of wild type (p < 0.01), while p-AMPKα level and AMPK activity were reduced to less than 10% of wild type (p < 0.001). BBR increased p-AMPKα1, p-AMPKα, AMPK activity, and stimulated glucose consumption, lactate release, inhibited glucose production in wild type HepG2 cells (p < 0.05 or p < 0.01). BBR also reduced intracellular lipid accumulation and suppressed the expression of lipogenic genes in oleic acid (OA) treated wild type HepG2 cells (p < 0.05 or p < 0.01). In AMPKα1-/- HepG2 cells, the stimulating effects of BBR on p-AMPKα1, p-AMPKα, AMPK activity, and its improving effects on glucose and lipid metabolism were completely abolished. CONCLUSION: Our study proves that AMPKα1 plays a critical role for BBR to improve glucose and lipid metabolism in HepG2 cells. Our results will provide new information to further understand the molecular mechanisms of BBR.

IL-33 promotes the progression of nonrheumatic aortic valve stenosis via inducing differential phenotypic transition in valvular interstitial cells.

OBJECTIVE: Interleukin (IL)-33 is a mediator in the pathogenesis of several inflammatory diseases. Its receptor, ST2, is overexpressed in nonrheumatic aortic valve stenosis (NR-AS). This study compared smooth muscle α-actin (α-SMA), osteopontin (OPN), and suppression of tumorigenicity 2 (ST2) expression between specimens from fibrotic and calcific stages of NR-AS and observed the effects and mechanisms of phenotypic transition of porcine valvular interstitial cells (VICs) in the presence of IL-33. METHODS: Peripheral blood IL-1 family mRNA and protein levels in NR-AS patients and healthy adults were quantified by real-time quantitative polymerase chain reaction (RT-qPCR) and enzyme-linked immunosorbent assay. Immunohistochemistry and immunofluorescence were used to detect the expression and coexpression of α-SMA, OPN, and ST2 in NR-AS specimens. Porcine VICs were stimulated with IL-33, IL-33+SB203580, or IL-33+SC75741. mRNA and protein expression levels of porcine VICs were detected by RT-qPCR and western blot. RESULTS: The mRNA and protein levels of IL-33 and sST2 in peripheral blood of NR-AS patients were higher than those in healthy adults. Immunohistochemistry and immunofluorescence showed higher expression of α-SMA, OPN, and ST2 in the calcific stage of NR-AS than in the fibrotic stage. Coexpression of ST2/α-SMA or ST2/OPN was found only in the calcific stage. Nuclear factor (NF)-κB and p38 mitogen-activated protein kinase (MAPK) phosphorylation levels were associated with IL-33-induced porcine VIC differentiation into myofibroblasts and osteoblasts, respectively. IL-33 stimulation also promoted the coexpression of ST2/OPN or α-SMA/OPN/ST2. CONCLUSION: IL-33 might be a potential biomarker for NR-AS. IL-33-induced porcine VIC differential phenotypic transition and differentiation into myofibroblasts and osteoblasts were dependent on the NF-κB and p38 MAPK signaling pathways, respectively.

Frailty phenotype, frailty index and risk of mortality in Chinese elderly population- Rugao longevity and ageing study.

BACKGROUND: To explore the associations of frailty phenotype and frailty index (FI) defined frailty and pre-frailty with mortality in a Chinese elderly population. METHODS: Data of 1788 community-dwelling elders aged 70-84 years from the ageing arm of Rugao Longevity and Ageing Study, a prospective cohort study, were used. Frailty phenotype was defined using modified Fried's phenotype (FP) criteria and FI was constructed using 45 health deficits. Mortality was ascertained using the Death Registry of Rugao's Civil Affairs Bureau. RESULTS: During 3-year follow-up, 149 (8.3%) of the 1788 elderly subjects died. For frailty phenotype, about 9.5% of the elderly were frail and 43% were pre-frail. For FI, frail (FI > 0.21) was approximately 27.5%, and pre-frail (FI: 0.1-0.21) was approximately 51.3%. Highest mortality was observed among frail participants defined by both FP and FI criteria (all Log Rank P < 0.05). Frailty defined by the frailty index was associated with a 2.31 fold (95% CI 1.16-4.6) risk of all-cause death compared with robust elderly. Compared with the robust elderly, not only frailty (HR 2.24, 95% CI 1.31-3.83) defined by frailty phenotype but also pre-frailty (HR 1.51, 95% CI 1.03-2.21) was associated with risk of all-cause mortality. CONCLUSIONS: Frailty, defined by either phenotype or index, is associated with increased risks of mortality in elderly Chinese community population.