Efficacy and Safety of Ongericimab in Chinese Patients With Primary Hypercholesterolemia and Mixed Dyslipidemia.

BACKGROUND: A phase 3 trial was conducted to evaluate the efficacy and safety of ongericimab, a monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9, as an add-on treatment to optimized lipid-lowering therapy in Chinese patients with primary hypercholesterolemia and mixed dyslipidemia. METHODS AND RESULTS: A total of 806 patients who were receiving stable and optimized lipid-lowering therapy but did not achieve their low-density lipoprotein cholesterol (LDL-C) targets were enrolled and randomly assigned in a 2:1:2:1 ratio to receive either ongericimab 150 mg or matching placebo every 2 weeks, or ongericimab 300 mg or matching placebo every 4 weeks for 52 weeks. Efficacy and safety were evaluated in 802 patients who received at least 1 dose of ongericimab or placebo. The primary end point was the percentage change in LDL-C from baseline to week 24. Our findings demonstrated that the least-squares mean difference of percentage change in LDL-C from baseline to week 24 was -67.7% (95% CI, -72.5% to -63.0%; P<0.0001) in the ongericimab 150 mg every 2 weeks group compared with the placebo every 2 weeks group, and -61.2% (95% CI, -67.1% to -55.2%; P<0.0001) in the ongericimab 300 mg every 4 weeks group compared with the placebo every 4 weeks group. These reductions were sustained up to week 52. Furthermore, treatment with ongericimab favorably altered other lipid parameters. A similar incidence of adverse events was observed in the ongericimab and placebo groups. CONCLUSIONS: Ongericimab, as an add-on treatment to optimized lipid-lowering therapy, significantly reduced LDL-C and was well-tolerated in Chinese patients with primary hyperlipidemia and mixed dyslipidemia who did not achieve their LDL-C targets. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04781114.

Identification of diagnostic biomarkers for osteoarthritis through bioinformatics and machine learning.

Osteoarthritis (OA) is a prevalent degenerative joint disease characterized by cartilage degradation, inflammatory arthritis, and joint dysfunction. Currently, there is a lack of effective early diagnostic methods and treatment strategies for OA. Bioinformatics and biomarker research provide new possibilities for early detection and personalized therapy of OA. In this study, we investigated the molecular mechanisms of OA and important signaling pathways involved in disease progression through bioinformatics analysis. Firstly, using the limma package, we analyzed the differentially expressed genes (DEGs) between normal healthy samples and OA cartilage tissue samples. These DEGs were found to be primarily involved in biological processes such as extracellular matrix (ECM) binding, immune receptor activity, and cytokine activity, as well as signaling pathways including cytokine receptors, ECM-receptor interaction, and PI3K-Akt. Gene set enrichment analysis revealed that in the OA group, signaling pathways such as AMPK, B cell receptor, IL-17, and PPAR were downregulated, while calcium signaling pathway, cell adhesion molecules, ECM-receptor interaction, TGF-ß signaling pathway, and Wnt signaling pathway were upregulated. Additionally, we constructed a co-expression module network using WGCNA and identified key modules associated with OA, from which we selected 7 most predictive OA characteristic genes. Among them, ANTXR1, KCNS3, SGCD, and LIN7A were correlated with the level of immune cell infiltration. This study elucidates the mechanisms underlying the development of OA and identifies potential diagnostic markers and therapeutic targets, providing important insights for early diagnosis and treatment of OA.

Relationship between ultra-short heart rate variability and short-term mortality in hospitalized COVID-19 patients.

OBJECTIVE: To assess the association between ultra-short heart rate variability (US-HRV) and short-term mortality in patients with COVID-19 and develop prognostic prediction models to identify high-risk patients as early as possible. METHODS: A retrospective cohort study was performed on 488 patients diagnosed with COVID-19 and hospitalized in the First Affiliated Hospital of Fujian Medical University from December 2022 to January 2023. 10-s electrocardiogram (ECG) data were available for these patients. The US-HRV parameters including standard deviation of all normal-to-normal R-R intervals (SDNN) and root mean square of successive differences between normal-to-normal R-R intervals (rMSSD) were calculated using Nalong ECG software. The endpoint was short-term mortality, including in-hospital mortality or mortality within 1 week after discharge. RESULTS: Of the 488 patients, 76 (15.6%) died. The SDNN and rMSSD in the death group were significantly lower than those in the survival group (P < 0.001). The area under the receiver operating characteristic (ROC) curve (AUC) for SDNN and rMSSD to predict mortality was 0.761 and 0.715, respectively. The combined use of SDNN and rMSSD had an AUC of 0.774. The mortality rate in the group with SDNN ≤7.5 ms was higher than that of SDNN >7.5 ms group (P < 0.05). With the decrease of SDNN, the mortality of patients showed an upward trend, and the mortality of patients with SDNN ≤2 ms was the highest (66.7%). Multivariate logistic regression analysis identified SDNN as an independent predictor of prognosis (odds ratio (OR) = 5.791, 95% confidential interval (CI) 1.615-20.765, P = 0.007). The AUC of Model 1 (simple model) was 0.866 (95% CI 0.826-0.905). The AUC of Model 2 (comprehensive model) was 0.914 (95% CI 0.881-0.947). CONCLUSION: SDNN was associated with short-term mortality and provided the additional discriminatory power of the risk stratification model for hospitalized COVID-19 patients.

Efficacy and safety of 3D reconstruction and basket multi-electrode renal denervation (RDN) for refractory hypertensive patients with chronic kidney disease.

Renal Artery Sympathetic Denervation (RDN) can lower blood pressure. Different ablation catheters (single electrode, multi-electrode) have different scopes of ablation (renal artery main stem and branches). Few studies have compared the advantages and disadvantages of different ablation catheters and different procedures in terms of antihypertensive efficacy. To compare the efficacy and safety of 3D reconstruction radiofrequency ablation (3DRA) and basket multi-electrode radiofrequency ablation (BMRA) in Renal Artery Sympathetic Denervation. Fifty-three patients with Refractory hypertension (RHT) were divided into BMRA, (n = 28) and 3DRA(n = 25). BMRA group used a stereobasket multi-electrode ablation catheter with a controlled ablation temperature of 60°C and an ablation time of 120 s per site. 3DRA group used a NavStar pressure-monitored perfusion monopolar ablation catheter with a controlled ablation temperature of 40°C, an ablation time of 40 s per site, and an ablation energy of 12 W. Baseline and RDN parameters and complications were compared in both groups. Home and 24 h ambulatory blood pressure, type of anti-hypertensive medication taken, and serum creatinine were followed up at 1, 3, 6, 12, and 24 months after the RDN. There were no differences in baseline characteristics between the two groups. (23.14 ± 2.00)months of follow-up in the BMRA group resulted in a total of (25.86 ± 8.61) loci ablation. (19.28 ± 7.40)months of follow-up in the 3DRA group resulted in a total of (21.04 ± 6.47)loci ablation. Home SBP was significantly lower in both groups at 1 month after RDN treatment compared to baseline(H-SBP/mmHg: BMRA 149.9 ± 10.59 vs. baseline 168.36 ± 12.76; 3DRA 152.6 ± 14.91 vs. 164.89 ± 12.96, both p < .05). The proportion of people with 24 h ambulatory SBP attainment was significantly higher in both groups and was maintained for 24 months. At each follow-up time point, there were no differences in home and 24-h flow SBP, DBP, or Scr between the two groups. There were two cases of severe renal artery complications from implanted vascular stents and one case of femoral artery pseudoaneurysm in the 3DRA group. At follow-up, 1 (1.9%) patient in the 3DRA group died of unexplained death and 1 (1.9%) patient developed heart failure, and 1 (1.9%) patient in the BMRA group died of unexplained death. Basket multi-electrode radiofrequency ablation and 3D reconstruction radiofrequency ablation of the renal artery applied to RDN have comparable efficacy in reducing systolic blood pressure.

Honokiol ameliorates angiotensin II-induced cardiac hypertrophy by promoting dissociation of the Nur77-LKB1 complex and activating the AMPK pathway.

Pathological cardiac hypertrophy is a key contributor to heart failure, and the molecular mechanisms underlying honokiol (HNK)-mediated cardioprotection against this condition remain worth further exploring. This study aims to investigate the effect of HNK on angiotensin II (Ang II)-induced myocardial hypertrophy and elucidate the underlying mechanisms. Sprague-Dawley rats were exposed to Ang II infusion, followed by HNK or vehicle treatment for 4 weeks. Our results showed that HNK treatment protected against Ang II-induced myocardial hypertrophy, fibrosis and dysfunction in vivo and inhibited Ang II-induced hypertrophy in neonatal rat ventricular myocytes in vitro. Mechanistically, HNK suppressed the Ang II-induced Nur77 expression at the transcriptional level and promoted ubiquitination-mediated degradation of Nur77, leading to dissociation of the Nur77-LKB1 complex. This facilitated the translocation of LKB1 into the cytoplasm and activated the LKB1-AMPK pathway. Our findings suggest that HNK attenuates pathological remodelling and cardiac dysfunction induced by Ang II by promoting dissociation of the Nur77-LKB1 complex and subsequent activation of AMPK signalling. This study uncovers a novel role of HNK on the LKB1-AMPK pathway to protect against cardiac hypertrophy.

Management of nocturnal hypertension: An expert consensus document from Chinese Hypertension League.

Nocturnal hypertension is highly prevalent among Chinese and Asian populations, which is mainly attributed to high salt intake and high salt sensitivity. Nocturnal hypertension increases the risk of cardiovascular and all-cause mortality, independent of daytime blood pressure (BP). However, it can usually be detected by 24-h ambulatory BP monitoring, rather than routine office or home BP measurement, thus is often underdiagnosed in clinical practice. Currently, no specific guidance is available for the management of nocturnal hypertension in China or worldwide. Experts from the Chinese Hypertension League summarized the epidemiologic and pathophysiologic characteristics and clinical phenotype of nocturnal hypertension and provided consensus recommendations on optimal management of nocturnal hypertension, with the goal of maximally reducing the cardiovascular disease risks. In this consensus document, 24-h ABPM is recommended for screening and diagnosis of nocturnal hypertension, especially in the elderly, patients with diabetes, chronic kidney diseases, obstructive sleep apnea and other conditions prone to high nocturnal BP. Lifestyle modifications including salt intake restriction, exercise, weight loss, sleep improvement, and mental stress relief are recommended. Long-acting antihypertensive medications are preferred for nocturnal and 24-h BP control. Some newly developed agents, renal denervation, and other device-based therapy on nocturnal BP reduction are evaluated.

High serum lactate dehydrogenase as a predictor of cardiac insufficiency at follow-up in elderly patients with acute myocardial infarction.

BACKGROUND: Impairment of cardiac function progresses after acute myocardial infarction (AMI). Lactate dehydrogenase (LDH), a marker of cardiac injury and an enzyme in anaerobic glycolysis, is suggested as a risk factor for patient mortality in inflammatory diseases. METHODS: In this study, 448 older and 445 younger AMI patients were recruited and followed up. The effect of baseline serum LDH on post-infarction cardiac function was assessed at follow-up. RESULTS: Elderly patients in the high baseline LDH group had a high risk of being diagnosed with cardiac insufficiency during follow-up (adjusted hazard ratio: 3.643, P = 0.007), and the follow-up left ventricular ejection fraction of the quartile subgroup tended to decrease with increasing in baseline serum LDH (adjusted odds ratio: 1.301, P = 0.001) for each 100 U/L increase. The LVDd and LVVd of elderly patients in the high LDH group were not significantly different from those of patients in the normal LDH group at baseline but were further increased in the high LDH group at follow-up. In younger patients, the effect of LDH on post-infarction cardiac structure and function was similar to that in older patients, but unlike older patients, Cox regression analysis showed that LDH was not the predominant influence. CONCLUSION: Longitudinal changes in cardiac function were independently associated with high baseline serum LDH levels in patients with AMI. Baseline LDH levels are superior to other myocardial injury markers and may be a useful parameter in predicting future cardiac dysfunction after AMI, especially in the elderly.

LncRNA SNHG8 regulates the migration and angiogenesis of pHUVECs induced by high glucose via the TRPM7/ERK1/2 signaling axis.

This study aimed to evaluate the regulatory effect and molecular mechanism of long noncoding RNA small nucleolus RNA host gene 8 (LncRNA SNHG8) in the migration and angiogenesis of primary human umbilical vein endothelial cells (pHUVECs) under high-glucose (HG) conditions. The HG-induced endothelial injury model was established in vitro.The cell model of silencing SNHG8, overexpressing SNHG8, and silencing TRPM7 was established by transfecting SNHG8-siRNA, SNHG8 plasmid and TRPM7-siRNA into cells with liposomes.The SNHG8 level was determined through reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The expression levels of transient receptor potential melastatin 7 (TRPM7), endothelial nitric oxide synthase (eNOS), p-eNOS, extracellular signal-regulated kinase 1/2(ERK1/2), and p-ERK1/2 were assessed through western blot. Nitric oxide (NO) levels were measured with DAF-FM. pHUVEC migration was examined through wound healing and Transwell assay, and pHUVEC angiogenesis was observed through a tube formation assay. Results showed that HG promoted the expression of lncRNA SNHG8 and TRPM7 and decreased the ratio of p-eNOS/eNOS and p-ERK1/2/ERK1/2 in pHUVECs . NO production, migration , and angiogenesis were inhibited in pHUVECs under HG conditions. Silencing lncRNA SNHG8 and TRPM7 could significantly reverse the HG-induced decrease in eNOS activation, NO production , migration, and angiogenesis . SNHG8 and U0126 (ERK pathway inhibitor) overexpression enhanced the HG effects, whereas using U0126 did not affect the TRPM7 expression. In conclusion, lncRNA SNHG8 participates in HG-induced endothelial cell injury and likely regulates NO production, migration, and angiogenesis of pHUVECs via the TRPM7/ERK1/2 signaling axis.

Activation of AHR by ITE improves cardiac remodelling and function in rats after myocardial infarction.

AIMS: Left ventricular remodelling subsequent to myocardial infarction (MI) constitutes a pivotal underlying cause of heart failure. Intervention with the nontoxic endogenous aryl hydrocarbon receptor (AHR) agonist 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) in the acute phase of MI has been shown to ameliorate cardiac function, but its role in the chronic phase remains obscured. This study explores the beneficial role of ITE in delaying the progression of heart failure in the chronic phase of MI. METHODS AND RESULTS: MI rats established by ligating the left anterior descending coronary artery were treated with the indicated concentration of the AHR agonist ITE or vehicle alone. Echocardiography was performed to determine cardiac structure and function; myocardial morphology and fibrosis were observed by haematoxylin and eosin and Masson's trichrome staining; serum biochemical indices, BNP, and inflammatory cytokine levels were detected by enzyme-linked immunosorbent assay; F4/80+ iNOS+ M1 macrophages and F4/80+ CD206+ M2 macrophages were detected by immunofluorescence; the terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling assay was used to detect the apoptosis of cardiomyocytes; ultrastructural changes in myocardial tissue were observed by transmission electron microscopy; and Cyp1a1, Akt, P-Akt, p70S6K, P-p70S6K, Bcl-2, Bax, caspase-3, and cleaved caspase-3 protein levels were determined via Western blotting. We found that therapy with the AHR agonist ITE rescued cardiac remodelling and dysfunction in rats with MI and attenuated myocardial fibrosis, inflammation, and mitochondrial damage. Further studies confirmed that ITE dose-dependently improved myocardial cell apoptosis after MI, as demonstrated by reduced levels of the apoptosis-related proteins cleaved caspase-3 and Bax but increased expression levels of Bcl-2. These effects were attributed to ITE-induced activation of AHR receptors, leading to the down-regulation of Akt and p70S6K phosphorylation. CONCLUSIONS: The AHR agonist ITE alleviates cardiomyocyte apoptosis through the Akt/p70S6K signalling pathway, thereby rescuing left ventricular adverse remodelling and cardiac dysfunction after MI.

Retinoid X receptor agonists alleviate fibroblast activation and post-infarction cardiac remodeling via inhibition of TGF-ß1/Smad pathway.

Retinoid X receptor (RXR), particularly RXRα, has been implicated in cardiovascular diseases. However, the functional role of RXR activation in myocardial infarction (MI) remains unclear. This study aimed to determine the effects of RXR agonists on MI and to dissect the underlying mechanisms. Sprague-Dawley (SD) rats were subjected to MI and then treated (once daily for 4 weeks) with either RXR agonist bexarotene (10 or 30 mg/kg body weight) or vehicle. Heart function was determined using echocardiography and cardiac hemodynamic measurements. Four weeks post MI, myocardial tissues were collected to evaluate cardiac remodeling. Primary cardiac fibroblasts (CFs) were treated with or without RXR ligand 9-cis-RA followed by stimulation with TGF-ß1. Immunoblot, immunofluorescence, and co-immunoprecipitation were performed to elucidate the regulatory role of RXR agonists in TGF-ß1/Smad signaling. In vivo treatment with Bexarotene moderately affects systemic inflammation and apoptosis and ameliorated left ventricular dysfunction after MI in rat model. In contrast, bexarotene significantly inhibited post-MI myocardial fibrosis. Immunoblot analysis of heart tissue homogenates from MI rats revealed that bexarotene regulated the activation of the TGF-ß1/Smad signaling pathway. In vitro, 9-cis-RA inhibited the TGF-ß1-induced proliferation and collagen production of CFs. Importantly, upon activation by 9-cis-RA, RXRα interacted with p-Smad2 in cytoplasm, inhibiting the TGF-ß1-induced nuclear translocation of p-Smad2, thereby negatively regulating TGF-ß1/Smad signaling and attenuating the fibrotic response of CFs. These findings suggest that RXR agonists ameliorate post-infarction myocardial fibrosis, maladaptive remodeling, and heart dysfunction via attenuation of fibrotic response in CFs through inhibition of the TGF-ß1/Smad pathway activation.

Cardiovascular outcomes of ß-blocker-calcium channel blocker initial dual therapy vs. other initial dual therapies in Chinese patients with hypertension: A real-world retrospective study.

This retrospective study compared cardiovascular (CV) outcomes between initial ß-blocker (BB) + calcium channel blocker (CCB) dual therapy ("B + C") and other initial dual therapies in Chinese newly diagnosed hypertensive patients. In this study, all patients in a regional electronic database with newly diagnosed hypertension from January 01, 2012 to December 31, 2016 who received any initial optimal dual therapy recommended by the Chinese hypertension guideline were included. 1:2 propensity score matching (PSM) was used to balance baseline characteristics between patients receiving B + C and patients receiving other initial dual therapies ("Others"). The primary outcome was major adverse cardiovascular events (MACE) that occurred from January 01, 2012 to December 31, 2017, consisting of non-fatal stroke, non-fatal myocardial infarction (MI), non-fatal chronic heart failure (CHF), and all-cause death. Cox proportional hazard models were used to compare these CV outcomes in the 2 matched cohorts. After the PSM, 6227 patients receiving B + C and 12 454 patients receiving Others were included. Compared to patients receiving Others, patients receiving B + C had a significantly lower risk of MACE (hazard ratio [HR] 0.85; 95% confidential interval [CI] 0.78-0.92; p < .001), non-fatal stroke (HR 0.89; 95% CI 0.81-0.98; p = .018) and non-fatal CHF (HR 0.74; 95% CI 0.63-0.86; p < .0001). Additionally, differences in risks of non-fatal MI and all-cause death between the 2 treatment cohorts were not statistically significant. In conclusion, BB + CCB initial dual therapy was associated with a lower risk of MACE, stroke, and CHF than other optimal initial dual therapies recommended by the Chinese hypertension guideline in Chinese newly diagnosed hypertensive patients.

Blood pressure lowering effects of ß-blockers as add-on or combination therapy: A meta-analysis of randomized controlled trials.

The authors performed a meta-analysis to assess the efficacy of non-atenolol ß-blockers as add-on to monotherapy or as a component of combination antihypertensive therapy in patients with hypertension. The authors searched and identified relevant randomized controlled trials from PubMed until November 2021. Studies comparing blood pressure lowering effects of ß-blockers with diuretics, calcium channel blockers (CCBs), angiotensin-converting enzyme inhibitors (ACEIs), or angiotensin receptor blockers (ARBs) were included. The analysis included 20 studies with 5544 participants. ß-blockers add-on to monotherapy significantly reduced systolic and diastolic blood pressure as compared with non-ß-blocker monotherapy (weighted mean difference in mm Hg [95% confidence interval]: -4.1 [-6.0, -2.2] and -3.7 [-4.6, -2.8], respectively). These results were consistent across the comparisons with diuretics (systolic pressure, -10.2 [-14.2, -6.2]; diastolic pressure, -5.4 [-8.2, -2.6]), CCBs (systolic pressure, -4.1 [-7.1, -1.0]; diastolic pressure, -2.8 [-4.1, -1.5]), and ACEIs/ARBs (systolic pressure, -2.9 [-4.3, -1.5]; diastolic pressure, -4.2 [-5.0, -3.4]). There was no significant difference in blood pressure lowering effects between combinations with and without a ß-blocker (systolic pressure, -1.3 mm Hg [-5.8, 3.2]; diastolic pressure, -.3 mm Hg [-2.7, 2.1]). Metoprolol add-on or combination therapy had a significantly greater blood pressure reduction than non-ß-blocker therapy (systolic pressure, -3.6 mm Hg [-5.9, -1.3]; diastolic pressure, -2.1 mm Hg [-3.5, -.7]). In conclusion, non-atenolol ß-blockers are effective in lowering blood pressure as add-on to monotherapy or as a component of combination antihypertensive therapy. In line with the current hypertension guideline recommendations, ß-blockers can and should be used in combination with other antihypertensive drugs.

Prediction of presurgical metabolic syndrome for gastric cancer-specific mortality is more evident in smokers: The FIESTA study.

BACKGROUNDS: We aimed to test whether the prediction of presurgical metabolic syndrome for postsurgical survival outcomes of gastric cancer hinges upon cigarette smoking status. METHODS: This study is a part of the ongoing Fujian prospective investigation of cancer (FIESTA) study. Patients with gastric cancer received radical resection of primary gastric cancer between January 2000 and December 2010, with the latest follow-up ended in December 2015. The 1:1 propensity score matching analysis was adopted to balance confounders between smokers and never-smokers. Effect-size estimates are expressed as hazard ratio (HR) with 95% confidence interval (CI). Model performance was evaluated using the Hosmer and Lemeshow test and 10-fold cross-validated area under the receiver operating characteristic curve (AUROC). Statistical analyses were completed with SAS software (v9.4). RESULTS: Total 2779 patients with gastric cancer were analyzed, including 2223 smokers and 556 never-smokers. Median follow-up time was 45.6 months. Cigarette smoking was not associated with postsurgical survival differences. Presurgical metabolic syndrome complication was significantly associated with increased gastric cancer-specific mortality in smokers (HR [95% CI]: 2.73 [1.53-4.89], p < 0.001), but not in never-smokers. Relative excess risk due to interaction was estimated to be 2.43 (95% CI: 0.40-4.45). After constructing a risk assessment score, one unit increment was associated with 10% reduced risk of gastric cancer-specific mortality (HR [95% CI]: 0.90 [0.88-0.91], p < 0.001), with 10-fold cross-validated AUROC being 0.82 (95% CI: 0.74-0.92). CONCLUSIONS: Our findings showed that the prediction of presurgical metabolic syndrome for gastric cancer-specific mortality was more evident in smokers. Practically, this study provides evidence base for future personalized prediction and helped risk-stratify gastric cancer patients who might experience serious postsurgical consequences.

Prognostic value of long-term antidiabetic and antihypertensive therapy in postoperative gastric cancer patients: the FIESTA study.

BACKGROUND: Gastric cancer is often comorbid with hypertension and diabetes mellitus and increases the mortality risk. MATERIALS AND METHODS: We conducted this prospective cohort study to investigate antidiabetics and antihypertensives' impact on gastric cancer survival. 3012 patients with gastric carcinoma undergoing radical gastrectomy were enrolled since January 2000 and followed up until July 2020. RESULTS: Hypertension and diabetes patients had worse survival than patients without hypertension and diabetes [median survival time (MST): 48 versus 112.5 months, p < 0.001 for hypertension, MST: 32.7 versus 183+ months, p < 0.001 for diabetes]. Compared to untreated patients, treated patients had better survival (MST: 109.7 months versus 39.1 months, p < 0.001 for antihypertensives, MST: 120.9 months versus 22.3 months, p < 0.001 for antidiabetics). Antihypertensives and antidiabetics were related to 42% (HR 0.58, 95% CI 0.47-0.73, p < 0.001) and 70% (HR 0.30, 95% CI 0.24-0.38, p < 0.001) reduced mortality risk relative to those without medications. metformin and Calcium channel blockers can better-improved prognosis compared to others (p = 0.00029 and p = 0.015). CONCLUSION: Post-surgical gastric cancer patients could benefit substantially from anti-diabetes and antihypertensive therapy. Metformin and Calcium channel blockers may be superior to other medications.

Hyperglycemia induces gastric carcinoma proliferation and migration via the Pin1/BRD4 pathway.

Diabetes is a potential risk factor for gastric cancer (GC). Pin1, a peptidyl-prolyl cis/trans isomerase, promotes GC cell proliferation and migration. The role and underlying mechanism of the Pin1/BRD4 axis in hyperglycemia-induced proliferation and migration of GC cells were analyzed in vivo and in vitro. Proliferation and migration of GC cells were measured; Pin1 and BRD4 expression of the cell cycle were determined. Pin1 and BRD4 were downregulated by transfecting Pin1 shRNA lentivirus into GC cells and JQ1-intervention GC cells. Tumor formation and lung metastasis were assessed in vivo. Inhibition of Pin1 and BRD4 significantly suppressed high-glucose (HG)-induced GC cell proliferation and migration. HG enhanced G1/S cell-cycle transition, associated with increased Pin1 and BRD4 expression. Silencing Pin1 significantly downregulated the expression of BRD4 and NAP1L1 and upregulated that of P21 in GC cells. In vivo studies indicated that hyperglycemia promotes tumor growth and lung metastasis by inducing Pin1 and BRD4 expression. Thus, Pin1/BRD4 plays an important role in hyperglycemia-promoted tumor growth. The significance of these findings toward improved prognosis of diabetic patients with GC cannot be underestimated.

Effectiveness and safety of non-vitamin K antagonist oral anticoagulants in patients with hypertrophic cardiomyopathy with non-valvular atrial fibrillation.

Hypertrophic cardiomyopathy (HCM) patients with nonvalvular atrial fibrillation (AF) have an increased risk of suffering thromboembolic events. Vitamin K antagonists (VKA) are recommended as therapy but there is still limited data regarding the efficacy of prescribing non-vitamin K antagonist oral anticoagulants (NOACs). This retrospective study investigates the effectiveness and safety of NOAC administration in patients with HCM and AF. A total of 124 patients with HCM and AF on an oral anticoagulant therapy were recruited between January 2015 and December 2019; these patients were followed up until March 31, 2020. Kaplan-Meier analysis was used to compare the clinical outcomes in patients treated with NOACs versus warfarin. The Cox model was used to estimate the risk of clinically relevant bleeding. Our study included 124 patients, of which 48 (38.7%) received warfarin and 76 (61.3%) received NOACs. Survival analysis showed the patients undergoing NOACs had a lower risk of clinically relevant bleeding (log-rank P = 0.039) over a period of 53.6 months. The median time in therapeutic range (TTR) score was 50% (interquartile range: 40.43 to 57.08%). A total of nine patients (18.75%) had a good TTR with a median score of 66.35% (interquartile range: 64.58 to 77.75%). The incidence of death by all causes, cardiovascular death and thromboembolism were similar between NOAC and warfarin-treated patients (log-rank P = 0.239, log-rank P = 0.386, and log-rank P = 0.257, respectively). Patients treated with NOACs showed a significant reduction in the risk of clinical (P = 0.011) and gastrointestinal bleeding (P = 0.032). Cox multiple regression analysis showed age (HR 1.13, 95% CI 1.03-1.24; P = 0.013) and warfarin therapy (HR 7.37, 95% CI 1.63-33.36; P = 0.010) were independent predictors of clinically relevant bleeding. Compared to warfarin, NOACs were associated with a lower incidence of clinically relevant bleeding in HCM patients with AF, as demonstrated by the similar incidence of death by all causes, cardiovascular death and thromboembolic events.

Dapagliflozin: a sodium-glucose cotransporter 2 inhibitor, attenuates angiotensin II-induced cardiac fibrotic remodeling by regulating TGFß1/Smad signaling.

BACKGROUND: Cardiac remodeling is one of the major risk factors for heart failure. In patients with type 2 diabetes, sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of the first hospitalization for heart failure, possibly through glucose-independent mechanisms in part, but the underlying mechanisms remain largely unknown. This study aimed to shed light on the efficacy of dapagliflozin in reducing cardiac remodeling and potential mechanisms. METHODS: Sprague-Dawley (SD) rats, induced by chronic infusion of Angiotensin II (Ang II) at a dose of 520 ng/kg per minute for 4 weeks with ALZET® mini-osmotic pumps, were treated with either SGLT2 inhibitor dapagliflozin (DAPA) or vehicle alone. Echocardiography was performed to determine cardiac structure and function. Cardiac fibroblasts (CFs) were treated with Ang II (1 µM) with or without the indicated concentration (0.5, 1, 10 µM) of DAPA. The protein levels of collagen and TGF-ß1/Smad signaling were measured along with body weight, and blood biochemical indexes. RESULTS: DAPA pretreatment resulted in the amelioration of left ventricular dysfunction in Ang II-infused SD rats without affecting blood glucose and blood pressure. Myocardial hypertrophy, fibrosis and increased collagen synthesis caused by Ang II infusion were significantly inhibited by DAPA pretreatment. In vitro, DAPA inhibit the Ang II-induced collagen production of CFs. Immunoblot with heart tissue homogenates from chronic Ang II-infused rats revealed that DAPA inhibited the activation of TGF-ß1/Smads signaling. CONCLUSION: DAPA ameliorates Ang II-induced cardiac remodeling by regulating the TGF-ß1/Smad signaling in a non-glucose-lowering dependent manner.

Anti-Diabetic Atherosclerosis by Inhibiting High Glucose-Induced Vascular Smooth Muscle Cell Proliferation via Pin1/BRD4 Pathway.

METHODS: Diabetic Apoe-/- mice induced by streptozotocin were treated with vehicle, the Pin1 inhibitor juglone, or the BRD4 inhibitor JQ1 for 3 weeks. VSMCs were pretreated with juglone, JQ1, or vehicle for 45 min, and then exposed to high glucose for 48 h. Hematoxylin-eosin staining was performed to assess atherosclerotic plaques of the thoracic aorta. Western blotting was used to detect expression levels of Pin1, BRD4, cyclin D1, and matrix metalloproteinase-9 (MMP-9) in the thoracic aorta and VSMCs. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and transwell assay were used to measure proliferation and migration of VSMCs. RESULTS: Juglone and JQ1 significantly improved atherosclerosis of diabetic Apoe-/- mice and reduced high glucose-induced VSMC proliferation and migration. Cyclin D1 and MMP-9 levels in the thoracic aorta were lower in diabetic Apoe-/- mice treated with juglone and JQ1 compared with vehicle-treated diabetic Apoe-/- mice. Additionally, BRD4 protein expression in high glucose-induced VSMCs was inhibited by juglone and JQ1. Upregulation of Pin1 expression by transduction of the Pin1 plasmid vector promoted BRD4 expression induced by high glucose, and stimulated proliferation and migration of VSMCs. CONCLUSIONS: Inhibition of Pin1/BRD4 pathway may improve diabetic atherosclerosis by inhibiting proliferation and migration of VSMCs.

Retinoid X receptor agonists attenuates cardiomyopathy in streptozotocin-induced type 1 diabetes through LKB1-dependent anti-fibrosis effects.

Diabetic cardiac fibrosis increases ventricular stiffness and facilitates the occurrence of diastolic dysfunction. Retinoid X receptor (RXR) plays an important role in cardiac development and has been implicated in cardiovascular diseases. In the present study, we investigated the effects of RXR agonist treatment on streptozotocin (STZ)-induced diabetic cardiomyopathy (DCM) and the underlying mechanism. Sprague-Dawley (SD) rats induced by STZ injection were treated with either RXR agonist bexarotene (Bex) or vehicle alone. Echocardiography was performed to determine cardiac structure and function. Cardiac fibroblasts (CFs) were treated with high glucose (HG) with or without the indicated concentration of Bex or the RXR ligand 9-cis-retinoic acid (9-cis-RA). The protein abundance levels were measured along with collagen, body weight (BW), blood biochemical indexes and transforming growth factor-ß (TGF-ß) levels. The effects of RXRα down-regulation by RXRα small interfering RNA (siRNA) were examined. The results showed that bexarotene treatment resulted in amelioration of left ventricular dysfunction by inhibiting cardiomyocyte apoptosis and myocardial fibrosis. Immunoblot with heart tissue homogenates from diabetic rats revealed that bexarotene activated liver kinase B1 (LKB1) signaling and inhibited p70 ribosomal protein S6 kinase (p70S6K). The increased collagen levels in the heart tissues of DCM rats were reduced by bexarotene treatment. Treatment of CFs with HG resulted in significantly reduced LKB1 activity and increased p70S6K activity. RXRα mediated the antagonism of 9-cis-RA on HG-induced LKB1/p70S6K activation changes in vitro. Our findings suggest that RXR agonist ameliorates STZ-induced DCM by inhibiting myocardial fibrosis via modulation of the LKB1/p70S6K signaling pathway. RXR agonists may serve as novel therapeutic agents for the treatment of DCM.

Interaction between fasting blood glucose and tumor embolus in predicting the postoperative prognosis of 4330 Chinese patients with gastrointestinal tract cancer.

Objectives: We aimed to investigate the interaction between fasting blood glucose and tumor embolus, and the potential mediation effect of fasting blood glucose on tumor embolus in predicting gastrointestinal tract cancer-specific mortality risk postoperatively. Methods and Results: 4330 patients were consecutively recruited between January 2000 and December 2010, with annual follow-up ending in December 2015. The median follow-up time was 48.6 months. Two optimal cutoff points for fasting blood glucose (6.11 and 11.69 mmol/L) were identified. Patients with fasting blood glucose <6.11 mmol/L and negative tumor embolus had the best survival, and the worst survival was seen in patients with fasting blood glucose >11.69 mmol/L and positive tumor embolus. The risk was highest for patients with fasting blood glucose >11.69 mmol/L and positive tumor embolus (adjusted HR: 11.91, 95% CI: 9.13 to 15.52). Using the Sobel-Goodman mediation test, the proportion of total effect conferred by tumor embolus that was mediated by fasting blood glucose was estimated to be 45.3%. Conclusions: Our findings indicate a synergistic interaction between fasting blood glucose and tumor embolus in predicting the postoperative prognosis of gastrointestinal tract cancer.