Total cholesterol to HDL cholesterol ratio (TC/HDL) is an important prognostic factor for CVD. This study used restricted cubic spline modeling to investigate the dose-response associations between ...TC/HDL and both CVD hospitalization and CVD rehospitalization in two independent prospective cohorts. The East Cambridgeshire and Fenland cohort includes 4,704 patients with T2D from 18 general practices in Cambridgeshire. The Randomized controlled trial of Peer Support In type 2 Diabetes cohort comprises 1,121 patients with T2D with posttrial follow-up data. TC/HDL and other demographic and clinical measurements were measured at baseline. Outcomes were CVD hospitalization over 2 years and CVD rehospitalization after 90 days of the prior CVD hospitalization. Modeling showed nonlinear relationships between TC/HDL and risks of CVD hospitalization and rehospitalization consistently in both cohorts (all P < 0.001 for linear tests). The lowest risks of CVD hospitalization and rehospitalization were consistently found for TC/HDL at 2.8 (95% CI: 2.6–3.0) in both cohorts and both overall and by gender. This is lower than the current lipid control target, 4.0 of TC/HDL. Reducing the TC/HDL target to 2.8 would include a further 33–44% patients with TC/HDL in the 2.8–4.0 range. Studies are required to assess the effectiveness and cost-effectiveness of the earlier introduction of, and more intensive, lipid-lowering treatment needed to achieve this new lower TC/HDL target.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract Background Studies have reported that pharmacologic interventions with candesartan or ramipril could reduce the risk of hypertension among prehypertensive subjects free of clinical ...cardiovascular disease (CVD), however, the cost-effectiveness and long-term cardiovascular risk of drug treatment among these population is unclear. Method A Markov state-transition model was developed to simulate a hypothetical cohort of Chinese adults with high-range prehypertension (130–139/85–89 mm Hg) but without CVD. Data on the incidence of CVD and hypertension was obtained from corresponding risk equations. Utility and disease-related costs were obtained from published literatures. Robustness and uncertainty was evaluated using deterministic and probabilistic sensitivity analyses. Results Compared with placebo, drug treatment resulted in delaying the development of hypertension by nearly 12 years and reducing the absolute incidence of hypertension by 32.01% over lifetime. The cumulative incidence of coronary heart disease, stroke and heart failure were reduced and survival was improved from 28.46 to 28.80 years. The average incremental cost effectiveness ratio for drug treatment was $12,994 per quality-adjusted life-year and the value was mostly sensitive to the effect size of treatment and age starting treatment. At a willingness-to-pay threshold of > 3 × China gross domestic product per capita in 2014, there was a 30.48% chance that drug treatment would remain cost-effective and a low chance of being cost-effective if relative risk of treatment on hypertension was larger than 0.64. Conclusion Drug treatment for prehypertension may help stem the current epidemic of hypertension among Chinese adults free of CVD, which may in turn reduce CVD complications and potentially be cost effective.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Background
Ginsenoside Rh2 (G‐Rh2) exerts anti‐tumor activity in non‐small cell lung cancer (NSCLC). microRNAs (miRNAs, miRs) play pivotal roles in NSCLC. We aimed to investigate whether G‐Rh2 ...inhibited NSCLC progression by targeting miRNA.
Methods
Cell viability, apoptosis and cycle were determined by Cell Counting Kit‐8, 6‐diamidino‐2‐phenylindole (DAPI) staining and flow cytometry. The potential target miRNAs of G‐Rh2 were screened by real‐time quantitative polymerase chain reaction (RT‐qPCR). The difference in miR‐28‐5p expression between lung adenocarcinoma (LUAD) tissues and normal tissues or lung squamous cell carcinoma (LUSC) tissues and normal tissues was retrieved from TCGA‐LUAD and TCGA‐LUSC, respectively. Kaplan–Meier Plotter was conducted to analyze the survival rate for different serine/threonine‐protein kinase 4 (STK4) expressions with different prognostic risks. immunohistochemistry of STK4 expression in non‐tumor and tumor tissues was analyzed from the HPA database. RT‐qPCR and Western blot were adopted for detecting mRNA and protein expression. TargetScan V7.2, miRanda and PITA were adopted for predicting targets of miR‐28‐5p, overlapped genes were subjected to GO analysis. The interactions of miR‐28‐5p‐Wnt and miR‐28‐5p‐STK4 were detected by TOP/FOP luciferase reporter assay and dual luciferase reporter assay, respectively.
Results
Current study observed that G‐Rh2 reduced miR‐28‐5p expression in NSCLC cells dose‐dependently. miR‐28‐5p was upregulated in NSCLC tissues and cells. The target genes of miR‐28‐5p were enriched in negative regulation of Wnt signaling. miR‐28‐5p inhibitor inactivated Wnt signaling, inhibited cell viability and cell cycle, while enhanced cell apoptosis of NSCLC cells by targeting STK4. G‐Rh2 exerted the similar effects with miR‐28‐5p inhibitor by reducing miR‐28‐5p. G‐Rh2 and miR‐28‐5p inhibitor exerted a synergistic effect on inhibiting NSCLC tumor growth.
Conclusion
In conclusion, G‐Rh2 attenuates NSCLC development by affecting miR‐28‐5p/STK4 axis and inactivating Wnt signaling. Taken together, we project out a novel therapeutic target for NSCLC.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Radiotherapy is the major form of treatment for head and neck carcinoma, a malignant tumour of epithelial origin. The identification of agents, which can be co-administered in order to sensitize ...these tumours to radiotherapy, has become a major focus of investigations. In the present study, a novel 20 nm nanocomposite, Ag/C225, was constructed, which consisted of silver nanoparticles (AgNPs) conjugated to an epidermal growth factor receptor-specific antibody (C225). Physical characterization demonstrated that the Ag/C225 nanoparticles were spherical and dispersed well in water. Enzyme-linked immunosorbent assays showed that the activity of C225 was preserved in the Ag/C225 nanoparticles. The results of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide analysis revealed that AgNPs and Ag/C225 inhibited the proliferation of nasopharyngeal carcinoma epithelial (CNE) cells in a dose- and time-dependent manner. Flow cytometry revealed that AgNPs and Ag/C225 induced the apoptosis of CNEs, and abrogated G2 arrest; the latter effect was more marked with Ag/C225 than with AgNPs. Clonogenic assays indicated that AgNPs and Ag/C225 increased the sensitivity of CNEs to irradiation. The sensitizer enhancement ratios were 1.610±0.012 and 1.405±0.033 Gy for AgNPs and Ag/C225, respectively. Western blot analysis revealed that combining X-ray irradiation with either AgNPs or Ag/C225 reduced the expression levels of DNA damage/repair proteins Ku-70, Ku-80 and Rad51; Ag/C225 was also more effective than AgNPs in this context. These results indicated that AgNPs and Ag/C225 effectively enhanced CNE cell radiosensitivity in vitro. Therefore, these potent agents may be considered for use as radiosensitizers during the treatment of human nasopharyngeal carcinoma.
Oral squamous cell carcinoma (OSCC) is one of the most common malignancy in the oral cancer threatening human health and the survival rate of OSCC has not been effectively improved in recent decades, ...so more effective biomarkers for the targeted therapy of OSCC are needed. Moreover, the role of CDH11 in OSCC has not been intensively investigated. We here show that the CDH11 protein and mRNA expression levels in the OSCC tissues were all significantly higher than in the non-cancerous tissues using RT-qPCR and western blot. This study also revealed that patients with higher CDH11 levels showed a higher incidence of perineural invasion and lymph node metastasis. By using data available from the Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and ArrayExpress databases, overexpressed CDH11 in OSCC that associated with patients'history of alcohol, negative Human Papilloma Virus (HPV) status, perineural invasion, infiltration of multiple immune cells, and Single-cell functional states including quiescence and angiogenesis, possessed an excellent discriminatory capability in the OSCC patients. Moreover, the majority of the biological processes or pathways were significantly clustered by co-expressed genes, including extracellular matrix organization, the epithelial to mesenchymal transition, carbon metabolism, and the PI3K-Akt signaling pathway, and the upstream transcriptional regulation mechanism of CDH11 in OSCC was showed on a transcription factor/miRNA-mRNA network with the online tool NetworkAnalyst. Finally, frequent mutation of CDH11 was observed on a mouse OSCC model through whole-genome sequencing. CDH11 might serve as a valuable biomarker in OSCC, as it was identified to be overexpressed in OSCC and related to its clinical progression.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
•EOP is linked to a high risk of complications, technique failure, and death in PD patients.•Although some risk factors have been examined, no risk score has previously been derived to predict EOP.•A ...well-discriminated and calibrated risk score for EOP has been derived and validated.•As a tool, the score could identify high-risk patients for further intervention.
Early onset peritonitis (EOP) increases the risk of clinical complications in patients initializing peritoneal dialysis (PD). This study aimed to develop and validate a risk prediction model for EOP among patients initializing PD.
3772 patients registered with the Henan Peritoneal Dialysis Registry (HPDR) between 2007 and 2015 were included. The main outcome, EOP, was defined as incident peritonitis occurring within 6 months of the initialization of PD. Multivariable logistic regression modeling was applied to derive the risk score. All accessible clinical measurements were screened as potential predictors. Assessment of the developed model in terms of model discrimination and calibration was performed using C statistics and a calibration slope, respectively, and validated internally through a bootstrapping (1000-fold) method to adjust for over-fitting.
The absolute risk of EOP was 14.5%. Age, cardiac function measurements, serum electrolyte test items, lipid profiles, liver function test items, blood urea nitrogen, and white cell count were significant predictors of EOP in the final risk score. Good model discrimination, with C statistics above 0.70, and calibration of agreed observed and predicted risks were identified in the model.
A prediction model that quantifies risks of EOP has been developed and validated. It is based on a small number of clinical metabolic measurements that are available for patients initializing PD in many developing countries, and could serve as a tool to screen the population at high risk of EOP.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background: Insulin resistance (IR) is increased among people with end-stage renal disease (ESRD). The Triglyceride glucose (TyG) index is a marker of IR and is also associated with the prognosis of ...cardiovascular disease among patients initiating peritoneal dialysis (PD). This study was aimed at examining the associations between TyG index and cardiovascular deaths in patients initiating PD. Methods and Results: Three thousand fifty-four patients initiating PD between 2007 and 2014 were included in a prospective cohort derived from Henan PD Registry, TyG index alongside other baseline characteristics were measured when ESRD patients initiated PD. Logistic regression adjusting for age, gender, and major cardiovascular risk factors estimated the association between TyG index and subsequent cardiovascular mortality within 2 years since the initiation of PD. Results: TyG index was positively associated with cardiovascular mortality: adjusted incidence rates ratio (95% CI) comparing the highest vs. lowest TyG index quartile was 2.32 (2.12–2.55) in all, 2.22 (2.01–2.46) in those with body mass index (BMI) <25 kg/m 2 , and 2.82 (2.24–3.54) in those with BMI ≥25 kg/m 2 , respectively. Linear dose-response relationships were revealed in all and by BMI. Conclusions: TyG index might be a prognostic factor in predicting cardiovascular mortality among patients initiating PD.
Physalis Calyx seu Fructus is the dry calyx or the calyx with fruit of the Solanaceae plant Physalis alkekengi L. var. franchetii (Mast.) Makino, with a long history of use in medicine and food. ...However, despite its many potential therapeutic and culinary applications, P. alkekengi is not being exploited for these applications on a large scale. This study analysed various research related to the different chemical components of P. alkekengi, including steroids, flavonoids, alkaloids, phenylpropanoids, sucrose esters, piperazines, volatile oils, polysaccharides, amino acids, and trace elements. In addition, research related to the pharmacological activities of P. alkekengi, including its anti-inflammatory, anti microbial, antioxidative, hypoglycaemic, analgesic, anti-tumour, and immunomodulatory effects were investigated. Research articles from 1974 to 2023 were obtained from websites such as Google Scholar, Baidu Scholar, and China National Knowledge Infrastructure, and journal databases such as Scopus and PubMed, with the keywords such as Physalis alkekengi, components, effects, and activities. This study aims to provide a comprehensive understanding of the progress of phytochemical and pharmacological research on the phytochemical and pharmacological aspects of P. alkekengi and a reference for the better exploitation of P. alkekengi in the food and pharmaceutical industries.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The human ether-a-go-go-related gene (hERG) potassium channel conducts rapid delayed rectifier potassium currents (IKr) and contributes to phase III cardiac action potential repolarization. Drugs ...inhibit hERG channels by binding to aromatic residues in hERG helixes. Berberine (BBR) has multiple actions, and its hydrogenated derivative dihydroberberine (DHB) is a potential candidate for developing new drugs. Previous studies have demonstrated that BBR blocks hERG channels and prolongs action potential duration (APD). Our present study aimed to investigate the effects and mechanism of DHB on hERG channels. Protein expression and the hERG current were analyzed using western blotting and patch-clamp, respectively. DHB inhibited the hERG current concentration-dependently after instantaneous perfusion, accelerated channel inactivation by directly binding tyrosine (Tyr652) and phenylalanine (Phe656), and decreased mature (155-kDa) and simultaneously increased immature (135-kDa) hERG expression, respectively. This suggests disruption of forward trafficking of hERG channels. Besides, DHB remarkably reduced heat shock protein 90 (Hsp90) expression and its interaction with hERG, indicating that DHB disrupted hERG trafficking by impairing channel folding. Meanwhie, DHB enhanced the expression of cleaved activating transcription factor-6 (ATF-6), a biomarker of unfolded protein response (UPR). Expression of calnexin and calreticulin, chaperones activated by ATF-6 to facilitate channel folding, were also increased, which indicating UPR activation. Additionally, the degradation rate of mature 155-kDa hERG increased following DHB exposure. In conclusion, we demonstrated that DHB acutely blocked hERG channels by binding the aromatic Tyr652 and Phe656. DHB may decrease hERG plasma membrane expression through two pathways involving disruption of forward trafficking of immature hERG channels and enhanced degradation of mature hERG channels. Furthermore, forward trafficking was disrupted by impaired channel folding associated with altered interactions between hERG proteins and chaperones. Finally, trafficking inhibition activated UPR, and mature hERG channel degradation was increased by DHB.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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