Sirt5 improves cardiomyocytes fatty acid metabolism and ameliorates cardiac lipotoxicity in diabetic cardiomyopathy via CPT2 de-succinylation.

RATIONALE: The disruption of the balance between fatty acid (FA) uptake and oxidation (FAO) leads to cardiac lipotoxicity, serving as the driving force behind diabetic cardiomyopathy (DbCM). Sirtuin 5 (Sirt5), a lysine de-succinylase, could impact diverse metabolic pathways, including FA metabolism. Nevertheless, the precise roles of Sirt5 in cardiac lipotoxicity and DbCM remain unknown. OBJECTIVE: This study aims to elucidate the role and underlying mechanism of Sirt5 in the context of cardiac lipotoxicity and DbCM. METHODS AND RESULTS: The expression of myocardial Sirt5 was found to be modestly elevated in diabetic heart failure patients and mice. Cardiac dysfunction, hypertrophy and lipotoxicity were exacerbated by ablation of Sirt5 but improved by forced expression of Sirt5 in diabetic mice. Notably, Sirt5 deficiency impaired FAO without affecting the capacity of FA uptake in the diabetic heart, leading to accumulation of FA intermediate metabolites, which mainly included medium- and long-chain fatty acyl-carnitines. Mechanistically, succinylomics analyses identified carnitine palmitoyltransferase 2 (CPT2), a crucial enzyme involved in the reconversion of fatty acyl-carnitines to fatty acyl-CoA and facilitating FAO, as the functional succinylated substrate mediator of Sirt5. Succinylation of Lys424 in CPT2 was significantly increased by Sirt5 deficiency, leading to the inactivation of its enzymatic activity and the subsequent accumulation of fatty acyl-carnitines. CPT2 K424R mutation, which mitigated succinylation modification, counteracted the reduction of enzymatic activity in CPT2 mediated by Sirt5 deficiency, thereby attenuating Sirt5 knockout-induced FAO impairment and lipid deposition. CONCLUSIONS: Sirt5 deficiency impairs FAO, leading to cardiac lipotoxicity in the diabetic heart through the succinylation of Lys424 in CPT2. This underscores the potential roles of Sirt5 and CPT2 as therapeutic targets for addressing DbCM.

Arbidol attenuates liver fibrosis and activation of hepatic stellate cells by blocking TGF-ß1 signaling.

Chronic liver diseases (CLD) impact over 800 million people globally, causing about 2 million deaths annually. Arbidol (ARB), an indole-derivative used to treat influenza virus infection, was extensively used during COVID-19 pandemic in China. In recent years, studies have shown that ARB, compared to other antiviral drugs, exhibits greater liver-protective efficacy, indicating a potential hepatoprotective effect beyond its antiviral activity. However, the mechanism remains unclear. In this study, we investigated the impact of ARB on liver injury/fibrosis in bile duct ligated (BDL) mice and its effect on spontaneous and transforming growth factor ß1 (TGF-ß1)-induced activation of primary cultured hepatic stellate cells (HSCs). Oral administration of ARB significantly ameliorated BDL-induced liver injury/fibrosis as reflected by decreased serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), reduced collagen deposition, and diminished mRNA expression of fibrosis markers. ARB notably inhibited spontaneous and TGF-ß1-induced activation of primary cultured HSCs. Moreover, ARB also drastically attenuated mRNA expression levels of platelet-derived growth factor receptor (Pdgfr), transforming growth factor-beta receptor (Tgfbr) 1, Tgfbr2, matrix metalloproteinase (Mmp)-2, and Mmp-9 in activated HSCs. We further demonstrate that ARB mitigated Smad2/3 phosphorylation in both TGF-ß1 treated HSCs and BDL mice. These data together demonstrate that the therapeutic efficacy of ARB on liver fibrosis is independent of its antiviral activity and likely is achieved by blocking TGF-ß1 signaling-mediated HSC activation.

Performance of ChatGPT on the Chinese Postgraduate Examination for Clinical Medicine: Survey Study.

BACKGROUND: ChatGPT, an artificial intelligence (AI) based on large-scale language models, has sparked interest in the field of health care. Nonetheless, the capabilities of AI in text comprehension and generation are constrained by the quality and volume of available training data for a specific language, and the performance of AI across different languages requires further investigation. While AI harbors substantial potential in medicine, it is imperative to tackle challenges such as the formulation of clinical care standards; facilitating cultural transitions in medical education and practice; and managing ethical issues including data privacy, consent, and bias. OBJECTIVE: The study aimed to evaluate ChatGPT's performance in processing Chinese Postgraduate Examination for Clinical Medicine questions, assess its clinical reasoning ability, investigate potential limitations with the Chinese language, and explore its potential as a valuable tool for medical professionals in the Chinese context. METHODS: A data set of Chinese Postgraduate Examination for Clinical Medicine questions was used to assess the effectiveness of ChatGPT's (version 3.5) medical knowledge in the Chinese language, which has a data set of 165 medical questions that were divided into three categories: (1) common questions (n=90) assessing basic medical knowledge, (2) case analysis questions (n=45) focusing on clinical decision-making through patient case evaluations, and (3) multichoice questions (n=30) requiring the selection of multiple correct answers. First of all, we assessed whether ChatGPT could meet the stringent cutoff score defined by the government agency, which requires a performance within the top 20% of candidates. Additionally, in our evaluation of ChatGPT's performance on both original and encoded medical questions, 3 primary indicators were used: accuracy, concordance (which validates the answer), and the frequency of insights. RESULTS: Our evaluation revealed that ChatGPT scored 153.5 out of 300 for original questions in Chinese, which signifies the minimum score set to ensure that at least 20% more candidates pass than the enrollment quota. However, ChatGPT had low accuracy in answering open-ended medical questions, with only 31.5% total accuracy. The accuracy for common questions, multichoice questions, and case analysis questions was 42%, 37%, and 17%, respectively. ChatGPT achieved a 90% concordance across all questions. Among correct responses, the concordance was 100%, significantly exceeding that of incorrect responses (n=57, 50%; P<.001). ChatGPT provided innovative insights for 80% (n=132) of all questions, with an average of 2.95 insights per accurate response. CONCLUSIONS: Although ChatGPT surpassed the passing threshold for the Chinese Postgraduate Examination for Clinical Medicine, its performance in answering open-ended medical questions was suboptimal. Nonetheless, ChatGPT exhibited high internal concordance and the ability to generate multiple insights in the Chinese language. Future research should investigate the language-based discrepancies in ChatGPT's performance within the health care context.

The mediation effect of HDL-C: Non-HDL-C on the association between inflammatory score and recurrent coronary events.

Background: Inflammation and lipids are both involved in the pathogenesis of coronary heart disease (CHD). However, the mediation effect of lipoproteins on the association between inflammation and recurrent coronary events in CHD patients remains unclear. Methods: This was a retrospective study including CHD patients hospitalized in the Department of Cardiovascular Medicine in Sun Yat-sen Memorial Hospital between January 2011 and December 2012 with the endpoint of recurrent coronary events. The study calculated inflammatory score based on six serum inflammatory markers, including complement C3, complement C4, hyper-sensitive CRP, fibrinogen, D-dimer, and white blood cell count. Logistic regression analysis, subgroup analysis and mediation analysis were performed to assess the associations between inflammatory score and recurrent coronary events in different subpopulations and the identification of mediators. Inflammatory cytokine expression, cholesterol efflux capacity, and hepatic cholesterol influx were performed in additional CHD patients and healthy controls. Results: There were 191 CHD patients included in the analysis with a median inflammatory score of -0.78 (-2.17, 1.35) and 63 cases of recurrent coronary events. Subgroup logistic regression analysis demonstrated that inflammatory score was positively associated with recurrent coronary events only in the diabetic subgroup [OR: 1.241 (1.004, 1.534), P < 0.046]. HDL-cholesterol (HDL-C): non-HDL-C performed 46.74 % of negative mediation effect on this association. CHD patients had lower cholesterol efflux capacity than healthy controls, which was mediated by HDL: non-HDL ratio of 0.4. No difference was found in hepatic cholesterol influx between the two groups. Conclusion: Inflammatory score was associated with recurrent coronary events mediated by HDL-C: non-HDL-C ratio in diabetic CHD patients, indicating that lipoproteins might aggravate the inflammatory effect on atherosclerosis under hyperglycemia. Our findings suggested that anti-inflammatory and lipid-lowering therapies might be beneficial for this population.

DNA polymerase beta connects tumorigenicity with the circadian clock in liver cancer through the epigenetic demethylation of Per1.

The circadian-controlled DNA repair exhibits a strong diurnal rhythm. Disruption in circadian clock and DNA repair is closely linked with hepatocellular carcinoma (HCC) progression, but the mechanism remains unknown. Here, we show that polymerase beta (POLB), a critical enzyme in the DNA base excision repair pathway, is rhythmically expressed at the translational level in mouse livers. Hepatic POLB dysfunction dampens clock homeostasis, whereas retards HCC progression, by mediating the methylation of the 4th CpG island on the 5'UTR of clock gene Per1. Clinically, POLB is overexpressed in human HCC samples and positively associated with poor prognosis. Furthermore, the hepatic rhythmicity of POLB protein expression is orchestrated by Calreticulin (CALR). Our findings provide important insights into the molecular mechanism underlying the synergy between clock and food signals on the POLB-driven BER system and reveal new clock-dependent carcinogenetic effects of POLB. Therefore, chronobiological modulation of POLB may help to promote precise interventions for HCC.

Discovery of N-alkyl-N-benzyl thiazoles as novel TRPC antagonists for the treatment of glioblastoma multiforme.

Glioblastoma multiforme represents a substantial clinical challenge. Transient receptor potential channel (TRPC) antagonists might provide new therapeutic options for this aggressive cancer. In this study, a series of N-alkyl-N-benzoyl and N-alkyl-N-benzyl thiazoles were designed and prepared using a scaffold-hopping strategy and evaluated as TRPC6 antagonists. This resulted in the discovery of 15g, a potent TRPC antagonist that exhibited suitable inhibitory micromolar activities against TRPC3, TRPC4, TRPC5, TPRC6, and TRPC7 and displayed noteworthy anti-glioblastoma efficacy in vitro against U87 cell lines. In addition, 15g featured an acceptable pharmacokinetic profile and exhibited better in vivo potency (25 mg/kg/d) than the frontline therapeutic agent temozolomide (50 mg/kg/d) in xenograft models. Taken together, the TRPC antagonist 15g represents a promising lead compound for developing new anti-glioblastoma agents.

Four new alkaloids from the roots of Dactylicapnos scandens.

Four new alkaloids (1 - 4), together with five known ones (5 - 9), were isolated from the bulbs of Dactylicapnos scandens. The structures were determined by analysis of their spectroscopic data and quantum-chemical calculations. All the isolates were tested for their ability to modulate neuronal Ca2+ mobilization in primary cultured neocortical neurons. Compound 8 inhibited spontaneous Ca2+ oscillations at low micromolar concentrations.

Influence of bifenthrin exposure at different gestational stages on the neural development.

Perinatal exposure to bifenthrin (BF) alters neurodevelopment. However, the most susceptible time period to BF exposure and the possible mechanisms are not clear. In the current study, pregnant female mice were treated with BF (0.5 mg/kg/d) at three different stages [gestational day (GD) 0-5, 6-15 and 16-birth (B)] and neurologic deficits were evaluated in offspring mice. BF exposure at GD 16-B significantly altered the locomotor activity and caused learning and memory impairments in 6-week-old offspring. Gestational BF exposure also caused neuronal loss in the region of cornu ammonis of hippocampi of 6-week-old offspring. Interestingly, neurobehavioral impairments and neuronal loss were not observed in offspring at 10-week-old. BF exposure at GD 16-B also decreased protein levels of VGluT1, NR1 and NR2A while increased the protein levels of NR2B and VGAT1, as well as the gene levels of Il-1ß, Il-6 and Tnf-α in hippocampi of 6-week-old offspring. Collectively, these data demonstrate that gestational exposure to a low dose BF causes neurodevelopmental deficits that remit with the age and the late-stage of pregnancy is the most susceptible time window to BF exposure. Imbalance in excitatory/inhibitory neuronal transmission, altered expression levels of NMDA receptors and increased neural inflammation may be associated with BF prenatal exposure-triggered neurobehavioral impairments.

Association of Body Mass Index and Abdominal Obesity with Incidence of Atrial Fibrillation in Heart Failure with Preserved Ejection Fraction.

INTRODUCTION: The association between obesity and atrial fibrillation (AF) incidence in heart failure with preserved ejection fraction (HFpEF) patients is currently unclear. Our analyses and results are based on the whole Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial (placebo and spironolactone). METHOD: A total of 2138 subjects without baseline AF were included in the trial. Kaplan-Meier (K-M) curves and Cox regression with hazard ratios (HRs) and confidence intervals (CIs) were used to assess the incidence of AF with obesity. Of 2138 HFpEF patients without baseline AF, 1165 were obese (body mass index [BMI]≥30 kg/m2). RESULT: The K-M curve showed obese patients developed AF more than overweight (25≤ BMI ≤29.9 kg/m2) patients (p=0.013), confirmed by multivariable analysis, while there's no statistical difference between overweight and normal weight (18.5≤ BMI ≤24.9 kg/m2) patients. The occurrence of AF increased by 3% for every kg/m2 increase in BMI (adjusted HR, aHR: 1.03; 95% CI: 1.00-1.06), with a positive linear association (p for nonlinear: 0.145). Obesity was associated with AF incidence (aHR: 1.62; 95% CI: 1.05-2.50) compared with non-obesity (including overweight and normal-weight patients). CONCLUSION: Abdominal obesity was associated with increased AF incidence (aHR: 1.70; 95% CI: 1.04-2.77), and AF incidence rose by 18% per centimeter in circumference (aHR: 1.18; 95% CI: 1.04-1.34). Obesity and abdominal obesity increase the incidence of AF in HFpEF patients. Further studies need to determine whether there is a difference in AF in response to spironolactone across obese HFpEF pheno groups.

U-shaped association between the triglyceride-glucose index and atrial fibrillation incidence in a general population without known cardiovascular disease.

OBJECTIVE: The triglyceride-glucose (TyG) index has been shown to be a new alternative measure for insulin resistance. However, no study has attempted to investigate the association of the TyG index with incident atrial fibrillation (AF) in the general population without known cardiovascular diseases. METHODS: Individuals without known cardiovascular diseases (heart failure, coronary heart disease, or stroke) from the Atherosclerosis Risk in Communities (ARIC) cohort were recruited. The baseline TyG index was calculated as the Ln [fasting triglycerides (mg/dL) × fasting glucose (mg/dL)/2]. The association between the baseline TyG index and incident AF was examined using Cox regression. RESULTS: Of 11,851 participants, the mean age was 54.0 years; 6586 (55.6%) were female. During a median follow-up of 24.26 years, 1925 incidents of AF cases (0.78/per 100 person-years) occurred. An increased AF incidence with a graded TyG index was found by Kaplan‒Meier curves (P < 0.001). In multivariable-adjusted analysis, both < 8.80 (adjusted hazard ratio [aHR] = 1.15, 95% confidence interval [CI] 1.02, 1.29) and > 9.20 levels (aHR 1.18, 95% CI 1.03, 1.37) of the TyG index were associated with an increased risk of AF compared with the middle TyG index category (8.80-9.20). The exposure-effect analysis confirmed the U-shaped association between the TyG index and AF incidence (P = 0.041). Further sex-specific analysis showed that a U-shaped association between the TyG index and incident AF still existed in females but not in males. CONCLUSIONS: A U-shaped association between the TyG index and AF incidence is observed in Americans without known cardiovascular diseases. Female sex may be a modifier in the association between the TyG index and AF incidence.

Depressive symptoms, anxiety and social stress are associated with diminished cardiovascular reactivity in a psychological treatment-naive population.

BACKGROUND: There is now an increasing appreciation of how psychological health can contribute to cardiovascular disease, called the mind-heart connection. A blunted cardiovascular reactivity to depression and anxiety may be responsible for the potential mechanism, however, with inconsistent results. Anti-psychological drugs have an effect on the cardiovascular system and, thus, may disturb their relationship. However, in treatment-naive individuals with psychological symptoms, no research has specifically evaluated the relationship between psychological state and cardiovascular reactivity. METHODS: We included 883 treatment-naive individuals who came from a longitudinal cohort study of Midlife in the United States. Symptoms of depression, anxiety, and stress were assessed by the Center for Epidemiologic Studies Depression Scale (CES-D), Spielberger Trait Anxiety Inventory (STAI), the Liebowitz Social Anxiety scale (LSAS) and the Perceived Stress Scale (PSS), respectively. Cardiovascular reactivity was measured using standardized, laboratory-based stressful tasks. RESULTS: Treatment-naive individuals with depressive symptoms (CES-D ≥ 16), anxiety symptoms (STAI ≥ 54), and higher stress levels (PSS ≥ 27) had lower cardiovascular reactivity as assessed by systolic blood pressure (SBP) reactivity, diastolic blood pressure (DBP) reactivity and heart rate (HR) reactivity (P < 0.05). Pearson analyses showed that psychological symptoms were correlated with lower SBP reactivity, DBP reactivity, and heart rate reactivity (P < 0.05). Multivariate linear regression showed that depression and anxiety were negatively related to lower cardiovascular reactivity (SBP, DBP and HR reactivity) after full adjustments (P < 0.05). Stress was associated with reduced SBP and DBP reactivity but with a nonsignificant association with HR reactivity (P = 0.056). CONCLUSION: Depression, anxiety, and stress symptoms are associated with blunted cardiovascular reactivity in treatment-naive adult Americans. These findings suggest that blunted cardiovascular reactivity is an underlying mechanism linking psychological health and cardiovascular diseases.

Total flavone of flowers of Abelmoschus manihot (L.) Medic inhibits the expression of adhesion molecules in primary mesenteric arterial endothelial cells and ameliorates dextran sodium sulphate-induced ulcerative colitis in mice.

BACKGROUND: Flowers of Abelmoschus manihot (L.) medic (AM) is a traditional Chinese medicine used to treat chronic nephritis, nephrotic syndrome, diabetic nephropathy, and colonic inflammation. PURPOSE: This study aimed to explore the influence of the total flavone of AM flowers (TFA) on acute ulcerative colitis (UC) and the potential underlying mechanism. METHODS: Efficacy of TFA (30, 60, 120 mg/kg) on UC was evaluated in a dextran sodium sulphate (DSS)-induced colonic inflammatory mouse model by analyzing disease activity index (DAI), histopathological score, colon length, and cytokine expression. Expression levels of critical adhesion molecules and nuclear factor kappa B (NF-κB) were examined by qRT-PCR, Western blotting, or immunofluorescence labeling. Myeloperoxidase activity was examined using ELISA. In vitro THP-1 adhesion assay was used to evaluate monocyte adhesion. RESULTS: TFA significantly reduced DAI score, prevented colon shortening, and ameliorated histological injuries of colons in DSS-treated mice. TFA inhibited the expression of cytokines (IL-1ß and TNF-α) and adhesion molecules (ICAM-1, VCAM-1, and MAdCAM-1) in colon tissues of DSS mice. In vitro studies on mesenteric arterial endothelial cells (MAECs) showed that TFA attenuated TNF-α-induced upregulation of ICAM-1, VCAM-1, and MAdCAM-1, as well as THP-1 cell adhesion to MAECs. TFA also suppressed the phosphorylation and nuclear translocation of NF-κB in MAECs. CONCLUSION: TFA efficaciously ameliorates UC possibly by inhibiting monocyte adhesion through blocking TNF-α-induced NF-κB activation, which in turn suppresses the upregulation of adhesive molecules in colon endothelial cells. Inhibiting the expression of adhesion molecule in MAECs may represent a useful strategy for therapeutic development to treat UC, with TFA being a safe and efficacious therapeutic agent.

A Drimane Meroterpenoid Borate as a Synchronous Ca+ Oscillation Inhibitor from the Coral-Associated Fungus Alternaria sp. ZH-15.

Territrem F (1), a drimane meroterpenoid bearing a unique borate ring system, was isolated together with its diol precursor territrem B (2) from the fungus Alternaria sp. ZH-15 associated with the soft coral Lobophytum crassum collected in the South China Sea. The structure of the new compound was elucidated by spectroscopic analysis and an X-ray single-crystal diffraction study, representing a new type of boron-containing natural product. Both compounds significantly inhibited spontaneous synchronous Ca2+ oscillations (SCOs) and epileptic discharges induced by 4-aminopyridine, showing the potential for antiepileptic drug research. The 5,9-boronic ester derivative of 2 did not change its SCO inhibitory activity.

TRPM8 promotes hepatocellular carcinoma progression by inducing SNORA55 mediated nuclear-mitochondrial communication.

Transient receptor potential melastatin 8 (TRPM8) play crucial roles in solid tumors such as prostate and breast cancers. But the role of TRPM8 in hepatocellular carcinoma (HCC) and its underlying molecular mechanisms remain largely unknown. In this study, the functional roles of TRPM8 in HCC were systematically investigated for the first time. It was found that the expression level of TRPM8 was significantly upregulated in HCC, which was positively correlated with the worse clinicopathological characteristics. Functional studies revealed that pharmacological inhibition or genetic downregulation of TRPM8 ameliorated hepatocarcinogenesis in vitro and in vivo. Mechanistically, the oncogenic role of TRPM8 in HCC was at least partially achieved by affecting mitochondrial function. TRPM8 could modulate the expression of nucleolar relative molecule-small nucleolar RNA, H/ACA box 55 (SNORA55) by inducing transformation of chromatin structure and histone modification type. These data suggest that as a bridge molecule in TRPM8-triggered HCC, SNORA55 can migrate from nucleus to mitochondria and exert oncogenic role by affecting mitochondria function through targeting ATP5A1 and ATP5B. Herein, we uncovered the potent oncogenic role of TRPM8 in HCC by inducing nuclear and mitochondrial dysfunction in a SNORA55 dependent manner, and provided a potential therapeutic target for HCC.

Associations among carotid plaque progression, cerebrovascular/cardiovascular diseases and LDL-C/non-HDL-C goal achievement in diabetic patients: A retrospective cohort study.

BACKGROUND: Impaired glycolipid metabolism can induce vascular injury and plaque formation. It is important to investigate the associations between carotid plaque progression and lipid-lowering goal achievement and cardiovascular disease. METHODS: Diabetic patients who underwent at least 2 carotid ultrasound scans with intervals ≥0.5 years and were hospitalized in the Department of Endocrinology at Sun Yat-sen Memorial Hospital were included. Patients were divided into 3 groups based on carotid plaque progression: the persistent plaque absence, new-onset plaque and persistent plaque presence groups. The primary outcomes were CHD and stroke, while the secondary outcomes were low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (non-HDL-C) goal achievement. RESULTS: There were 304 diabetic patients included, with a median follow-up period of 2.15 years. In multivariable logistic regression analysis, persistent plaque presence was positively associated with a 2.285-fold increase in coronary heart disease (CHD) prevalence, while new-onset plaque was associated with a 3.225-fold increase in stroke prevalence compared to persistent plaque absence in patients with follow-up periods ≥ 0.5 years. The association remained significant in patients with a follow-up period ≥ 1 year and ≥2 years. The velocity of average plaque length change was independently associated with increased ΔLDL-C (last - goal) (ß = 0.073, P = 0.048). CONCLUSION: Carotid plaque progression had long-term association with CHD and stroke starting from 0.5 years, while the velocity of average plaque length associated with increased ΔLDL-C (last - goal) might reflect patient response to statins. Repeated carotid plaque measurements might guide lipid-lowering therapies.

Association of motor index scores with fall incidence among community-dwelling older people.

BACKGROUND: Several kinds of motor dysfunction have been studied for predicting future fall risk in community-dwelling older individuals. However, no study has tested the ability of the fine motor index (FINEA) and gross motor index (GROSSA) to predict the risk of falling, as well as the specific fall type. OBJECTIVE: We investigated the associations of FINEA/GROSSA scores with fall risk, explained falls, and unexplained falls. METHODS: A total of 6267 community-dwelling adults aged ≥ 50 years from the Irish Longitudinal Study on Aging (TILDA) cohort were included. First, the associations of FINEA and GROSSA scores with the history of total falls, explained falls and unexplained falls were assessed in a cross-sectional study and further verified in a prospective cohort after 2 years of follow-up by Poisson regression analysis. RESULTS: We found that high FINEA and GROSSA scores were positively associated with almost all fall histories (FINEA scores: total falls: adjusted prevalence ratio [aPR] = 1.28, P = 0.009; explained falls: aPR = 1.15, P = 0.231; unexplained falls: aPR = 1.88, P < 0.001; GROSSA scores: total falls: aPR = 1.39, P < 0.001; explained falls: aPR = 1.28, P = 0.012; unexplained falls: aPR = 2.18, P < 0.001) in a cross-sectional study. After 2 years of follow-up, high FINEA scores were associated with an increased incidence of total falls (adjusted rate ratio [aRR] = 1.42, P = 0.016) and explained falls (aRR = 1.51, P = 0.020) but not with unexplained falls (aRR = 1.41, P = 0.209). High GROSSA scores were associated with an increased incidence of unexplained falls (aRR = 1.57, P = 0.041) and were not associated with either total falls (aRR = 1.21, P = 0.129) or explained falls (aRR = 1.07, P = 0.656). Compared with individuals without limitations in either the FINEA or GROSSA, individuals with limitations in both indices had a higher risk of falls, including total falls (aRR = 1.35, P = 0.002), explained falls (aRR = 1.31, P = 0.033) and unexplained falls (aRR = 1.62, P = 0.004). CONCLUSION: FINEA scores were positively associated with accidental falls, while GROSSA scores were positively associated with unexplained falls. The group for whom both measures were impaired showed a significantly higher risk of both explained and unexplained falls. FINEA or GROSSA scores should be investigated further as possible tools to screen for and identify community-dwelling adults at high risk of falling.

Inhibition of TRPC6 suppressed TGFß-induced fibroblast-myofibroblast transdifferentiation in renal interstitial NRK-49F cells.

Renal fibrosis is a global health concern with limited curative treatment. Canonical transient receptor potential channel 6 (TRPC6), a nonselective cation channel, has been shown to regulate the renal fibrosis in murine models. However, the molecular mechanism is unclear. Fibroblast-myofibroblast transdifferentiation is one of the critical steps in the progression of renal fibrosis. In the present study, we demonstrate that transforming growth factor (TGF)-ß1 exposure significantly increases the TRPC6 expression in renal interstitial fibroblast NRK-49F cells. Pharmacological inhibition of TRPC6 and knockdown of Trpc6 by siRNA alleviate TGF-ß1-increased expression levels of α-smooth muscle actin (α-SMA) and collagen I, two key markers of myofibroblasts. Although direct activation of TRPC6 by 1-oleoyl-2-acetyl-sn-glycerol (OAG) does not affect the expression of α-SMA and collagen I, OAG potentiates TGF-ß1-induced fibroblast-myofibroblast transdifferentiation. Further study demonstrates that TGF-ß1 exposure increases the phosphorylation level of p38 and Yes-associated protein (YAP) translocation into the nuclei. Inhibition of p38 and YAP decreases TGF-ß1-enhanced TRPC6 and α-SMA expression. In conclusion, we demonstrate that TRPC6 is a key regulator of TGF-ß1-induced fibroblast-myofibroblast transdifferentiation and provides the mechanism of how TGF-ß1 exposure regulates TRPC6 expression in NRK-49F fibroblasts.

Liver fibrosis scores and atrial fibrillation incidence in heart failure with preserved ejection fraction.

AIM: Non-alcoholic fatty liver disease (NAFLD)-related advanced liver fibrosis (Stage 3 or 4) was reported to be linked to worse prognosis in patients with heart failure with preserved ejection fraction (HFpEF). This study aims to assess the relationship between liver fibrosis scores and new-onset atrial fibrillation (AF) incidence in patients with HFpEF in the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial. METHODS AND RESULTS: Baseline liver fibrosis levels, assessed by NAFLD fibrosis score (NFS) or Fibrosis-4 index (FIB-4), with AF incidence were expressed as hazard ratios (HRs) using the Cox proportional hazard model. The risk for advanced fibrosis was estimated to be 21.5% (447/2072) as assessed by FIB-4 (>3.25) and 4.2% (88/2072) as assessed by NFS (>0.676) in HFpEF patients without baseline AF. After a median follow-up of 3.11 years, 106 new-onset AF cases occurred. In multivariate analysis, elevated NFS [NFS = -1.455-0.676: HR 2.44, 95% confidence interval (CI) 1.27-4.68; NFS > 0.676: HR 3.36, 95% CI 1.27-6.80; per 1 unit increase: HR 1.15, 95% CI 1.01-1.32], not FIB-4 (FIB-4 = 1.45-3.25: HR 1.02, 95% CI 0.67-1.55; FIB-4 > 3.25: HR 1.69, 95% CI 0.76-3.79; per 1 unit increase: HR 1.13, 95% CI 0.93-1.37), was associated with increased AF incidence. The NFS (C-index 0.662), not FIB-4 (C-index 0.531), had a moderate predictive ability in predicting incident AF. CONCLUSIONS: Among patients with HFpEF, the risk of advanced liver fibrosis is associated with an increased incidence of new-onset AF and may be a novel predictor for new-onset AF. Additional studies are needed to confirm our results.

Usefulness of B-Type Natriuretic Peptide for Predicting the Risk of Stroke in Patients With Heart Failure With Preserved Ejection Fraction.

Background B-type natriuretic peptide (BNP) is a well-known biomarker for prognosis in heart failure with patients with preserved ejection fraction. However, the clinical predictive ability of BNP for the risk of stroke in HFpEF is not clear. Methods and Results A total of 799 patients with HFpEF from the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) trial were included. Association of baseline BNP with risk of stroke was assessed using the Cox proportional hazard model. The discriminatory ability of BNP was expressed using the C index. The improvement in 5-year stroke prediction was assessed by C statistic, categorical net reclassification improvement index, and relative integrated discrimination improvement. A total of 34 (4.3%) patients among the 799 patients with HFpEF experienced stroke events over a median of 2.85 years of follow-up. The stroke group showed a higher BNP level than the nonstroke group (375 pg/mL versus 241 pg/mL, respectively; P=0.006). Higher BNP levels were associated with increased risk of stroke after multivariable adjustment (hazard ratio, 3.29 [95% CI, 1.51-7.16]) and had a moderate performance for stroke prediction (C index, 0.67). Adding BNP to CHADS2/CHA2DS2-VASc/R2CHADS2 scores improved their predictive value for stroke (CHADS2: C index, 0.67; BNP+CHADS2: C index, 0.77; net reclassification improvement, 40.9%; integrated discrimination improvement, 3.0%; CHA2DS2-VASc: C index, 0.64; BNP+CHA2DS2-VASc: C index, 0.74; net reclassification improvement, 41.4%; integrated discrimination improvement, 2.2%; R2CHADS2: C index, 0.70; BNP+R2CHADS2: C index, 0.78; net reclassification improvement, 40.9%; integrated discrimination improvement, 3.2%). Conclusions BNP is associated with an increased risk of stroke in patients with HFpEF and may be a valuable biomarker for stroke prediction in HFpEF.

Synthesis of AC1903 analogs as potent transient receptor potential canonical channel 4/5 inhibitors and biological evaluation.

Transient receptor potential canonical (TRPC) channels are a class of non-selective cation channels expressed in a variety of tissues and organ systems where they functionally regulate physiological and pathological processes. TRPC5 has been shown to be a promising target for focal segmental glomerulosclerosis treatment. In this study, we report the synthesis and biological evaluation of a novel series of benzimidazole-based TRPC5 inhibitors. One compound, 8b, is 100-fold more potent than the parent compound, AC1903, in the suppression of TRPC5 channel activity. Interestingly, both AC1903 and 8b also suppressed TRPC4 channel activity with similar potency. Compound 8b also significantly blunts protamine sulfate-induced reorganization of podocyte cytoskeleton, interleukin (IL)-17-induced cell proliferation, and the expression of proinflammatory mediators in human keratinocyte HaCaT cells.