KOtBu/DMF-Mediated Hydroalkylation of Alkenes via Benzylic C-H Bond Activation.

Catalytic hydroalkylation reaction of alkenes with benzylic hydrocarbons involving t-BuOK/DMF-mediated benzylic C-H bond activation is demonstrated. This direct and operational simple protocol affords a rapid and reliable access to a wide scope of benzylic compounds in good-to-excellent yields. The benzylic C-H's of either activated diarylmethanes (pKa ∼ 32.2) and benzyl thioethers (pKa ∼ 30.8) or inert alkylbenzenes could all act as useful synthetic platforms to be conveniently alkylated under mild reaction conditions.

Mechanical properties and electronic structure of Cu-doped tin: a first-principle study.

Metal doping is an effective method for improving the toughness of ceramic materials and reducing coating fractures. In this study, first-principle calculations based on density functional theory were performed to study the formation energy, elastic constant, and electronic structure of Cu-doped TiN. The results reveal that Cu tends to replace the Ti sites in TiN crystal cells; with an increase in Cu concentration, the formation energy of the Cu-doped TiN system decreases. This indicates that the structural stability of Cu-doped TiN decreases. From the calculated elastic constant and the Voigt-Reuss-Hill approximation, it is evident that the bulk modulus B and shear modulus G decrease as the Cu concentration increases. However, G decreases more rapidly, thus increasing the B/G ratio. According to Paugh's ratio, the increase in B/G indicates an increase in the ductility of TiN. The results of the band structure, density of states, charge density, and Mulliken bond population analysis reveal that Cu doping reduces the covalent bond strength of TiN, enhances metallicity, and reduces the structural stability of the system, enhancing the toughness of TiN. The results of this study will provide theoretical and experimental guidance for improving the toughness of TiN coatings.

Mitophagy receptor FUNDC1 is regulated by PGC-1α/NRF1 to fine tune mitochondrial homeostasis.

Mitophagy is an essential cellular autophagic process that selectively removes superfluous and damaged mitochondria, and it is coordinated with mitochondrial biogenesis to fine tune the quantity and quality of mitochondria. Coordination between these two opposing processes to maintain the functional mitochondrial network is of paramount importance for normal cellular and organismal metabolism. However, the underlying mechanism is not completely understood. Here we report that PGC-1α and nuclear respiratory factor 1 (NRF1), master regulators of mitochondrial biogenesis and metabolic adaptation, also transcriptionally upregulate the gene encoding FUNDC1, a previously characterized mitophagy receptor, in response to cold stress in brown fat tissue. NRF1 binds to the classic consensus site in the promoter of Fundc1 to upregulate its expression and to enhance mitophagy through its interaction with LC3. Specific knockout of Fundc1 in BAT results in reduced mitochondrial turnover and accumulation of functionally compromised mitochondria, leading to impaired adaptive thermogenesis. Our results demonstrate that FUNDC1-dependent mitophagy is directly coupled with mitochondrial biogenesis through the PGC-1α/NRF1 pathway, which dictates mitochondrial quantity, quality, and turnover and contributes to adaptive thermogenesis.

Comparative Analysis of 95 Patients with Different Severity in the Early Outbreak of COVID-19 in Wuhan, China.

OBJECTIVE: To explore the clinical characteristics of patients with different severity in the early outbreak of COVID-19, hoping to provide reference for clinical diagnosis and treatment. METHODS: We retrospectively analyzed the clinical data of 95 COVID-19 patients in Wuhan Red Cross Hospital of China from January 17 to February 13, 2020. All patients were investigated with epidemiological questionnaires. Outcomes were followed up until April 1, 2020. RESULTS: There were 53 males and 42 females, aged 22-84 years (mean 57.3 years). Clinical classification included 54 cases of common type, 27 cases of severe type, and 14 cases of critical type. Six patients had been exposed to the local Huanan seafood market. There were 38 clusters of COVID-19, including 27 family clusters and 11 work unit clusters. Common symptoms included fever (86 (90.5%) of 95), cough (73 (76.8%)), and fatigue (50 (52.6%)). Laboratory findings showed that the most common abnormalities were lymphopenia (75 (78.9%)), elevated D-dimer (60 (63.2%)), and elevated C-reactive protein (56 (58.9%)) on admission. All patients had abnormal chest computed tomography, showing patchy shadows or ground-glass opacities. Severe and critical cases were older, more likely to have shortness of breath, more likely to have underlying comorbidities, and more likely to have abnormal laboratory findings than common cases. The prognosis of patients with different degrees of severity was significantly different. All common and severe patients (100%) were cured and discharged from the hospital, while 10 (71.4%) of 14 critical patients died. CONCLUSIONS: COVID-19 has fast transmission speed and high pathogenicity. We must assess the severity of the disease and take corresponding treatment measures as early as possible.

Qiliqiangxin Improves Cardiac Function through Regulating Energy Metabolism via HIF-1α-Dependent and Independent Mechanisms in Heart Failure Rats after Acute Myocardial Infarction.

The present study is aimed at investigating whether Qiliqiangxin (QL) could regulate myocardial energy metabolism in heart failure rats after acute myocardial infarction (AMI) and further exploring the underlying mechanisms. AMI was established by ligating the left anterior descending coronary artery in adult male SD rats. AMI rats with ejection fraction (EF) < 50% at two weeks after the operation were chosen as heart failure rats for the main study. Rats were randomized into the sham, MI, MI+QL, and MI+QL+2-MeOE2 groups. The results showed that compared with the MI group, QL significantly improved cardiac function, reduced serum NT-proBNP level, and alleviated myocardial fibrosis. QL also increased myocardial capillary density by upregulated protein expressions of vascular endothelial growth factor (VEGF) and CD31 by regulating the HIF-1α/VEGF pathway. Moreover, QL promoted ATP production, glucose uptake, and glycolysis by upregulating HIF-1α and a series of glycolysis-relevant enzymes in a HIF-1α-dependent manner. QL also improved myocardial glucose oxidation enzyme expression and free fatty acid uptake by a HIF-1α-independent pathway. Our results indicate that QL treatment improves cardiac function through regulating glucose uptake, FFA uptake, and key enzymes of energy metabolism via HIF-1α-dependent and independent mechanisms.

Prognostic value of sST2 in patients with heart failure with reduced, mid-range and preserved ejection fraction.

BACKGROUNDS: Prognostic value of soluble suppression of tumorigenecity (sST2), a novel circulating biomarker for myocardial fibrosis, remains elusive in the heart failure patients with preserved ejection fraction (HFpEF). METHODS: 405 consecutive patients with heart failure (HF) were enrolled prospectively, and were grouped into HF with reduced ejection fraction (HFrEF, N = 215), HF with mid-range ejection fraction (HFmrEF, N = 80) and HFpEF (N = 110). The primary endpoint was the composite endpoint of all-cause death and HF rehospitalization. RESULTS: After a median of 12 months, 139 patients reached the primary endpoint, with 57 patients died and 82 patients rehospitalized. Multivariate analysis confirmed that sST2 was an independent risk factor of the primary endpoint for all HF patients [hazard ratio (HR) 2.35, 95% confidence interval (CI) 1.30-4.22, P = 0.004]. Predicting efficacy of sST2 on outcomes was higher for HFpEF (HR 6.48, 95%CI 1.89-22.21, P = 0.003) as compared to HFrEF (HR 3.21, 95% CI 1.67-6.19, P = 0.000). But the association between sST2 and outcomes in HFmrEF is not statistical (HR 3.38, 95%CI 0.82-13.86, P = 0.091). The combined use of sST2 and N terminal pro B type natriuretic peptide (NT-proBNP) could improve the prognostic value compared to using NT-proBNP alone in HFrEF (AUC = 0.794 vs. 0.752, P = 0.034). CONCLUSION: Higher baseline sST2 levels are associated with increased risk of all-cause death and HF rehospitalization in patients with HF independent of ejection fraction. The combined use of sST2 and NT-proBNP could improve the prognostic value than using these two values alone, especially for HFrEF patients.

Digoxin is associated with worse outcomes in patients with heart failure with reduced ejection fraction.

AIMS: The aim of this study was to investigate the impact of digoxin use on the outcomes of patients with heart failure with reduced ejection fraction (HFrEF) and its possible interaction with atrial fibrillation or use of currently guideline-recommended treatments in the real world in China. METHODS AND RESULTS: Patients hospitalized with HFrEF from 45 hospitals participating in the China National Heart Failure Registration Study (CN-HF) were enrolled to assess the all-cause mortality, HF mortality, all-cause re-hospitalization, and HF re-hospitalization associated with digoxin use. Eight hundred eighty-two eligible HFrEF patients in the CN-HF registry were included: 372 patients with digoxin and 510 patients without digoxin. Among them, 794 (90.0%) patients were followed up for the endpoint events, with a median follow-up of 28.6 months. Kaplan-Meier survival analysis showed that the all-cause mortality (P < 0.001) and all-cause re-hospitalization (P = 0.020) were significantly higher in digoxin group than non-digoxin group, while HF mortality (P = 0.232) and HF re-hospitalization (P = 0.098) were similar between the two groups. The adjusted Cox proportional-hazards regression analysis demonstrated that digoxin use remained as an independent risk factor for increased all-cause mortality [hazard ratio (HR) 1.76; 95% confidence interval (CI) 1.27-2.44; P = 0.001] and all-cause re-hospitalization (HR 1.27; 95% CI 1.03-1.57; P = 0.029) in HFrEF patients and the predictive value of digoxin for all-cause mortality irrespective of rhythm or in combination with other guideline-recommended therapies. CONCLUSIONS: Digoxin use is independently associated with increased risk of all-cause mortality and all-cause re-hospitalization in HFrEF patients.

Diffuse myocardial fibrosis and the prognosis of heart failure with reduced ejection fraction in Chinese patients: a cohort study.

Evidence regarding the relationship between diffuse myocardial fibrosis and the prognosis of heart failure with reduced ejection fraction (HFrEF) was limited. Therefore, this study set out to investigate whether diffuse myocardial fibrosis was independently related to the prognosis of failure with reduced ejection fraction in Chinese patients after adjusting for other covariates. The present study was a cohort study. A total of 45 consecutive HFrEF patients were involved in Zhongshan Hospital of Fudan University in China from 1/9/2015 to 31/12/2016. The target-independent variable was extracellular volume (ECV) quantified by cardiac magnetic resonance T1 mapping using the modified Look-Locker inversion recovery (MOLLI) sequence at baseline. To assess the prognostic impact of MOLLI-ECV, its association with hospitalization for heart failure/cardiac death was tested by multivariable Cox regression analysis. Covariates involved in this study included age, gender, body mass index, heart rate, systolic blood pressure diastolic blood pressure, smoking, hypertension, diabetes mellitus, etiology, NYHA functional class, blood urea nitrogen, creatinine, serum uric acid, total bilirubin, and growth stimulation-expressed gene 2. Ten age- and sex-matched healthy participants with no history of cardiovascular disease served as a control group. Mean MOLLI-ECV was significantly higher in HFrEF patients versus healthy controls (29.55 ± 1.46% vs. 23.17 ± 1.93%, P < 0.001). Patients were followed for 9 months, during which the primary outcome (cardiac death or first heart failure hospitalization) occurred in 15 patients. By Kaplan-Meier analysis, patients with high MOLLI-ECV ≥ 30.10% had shorter event-free survival than the middle (MOLLI-ECV between 30.10 and 28.60) and low (MOLLI-ECV < 28.60) MOLLI-ECV patients (log-rank, P = 0.0035). Result of fully-adjusted multivariable Cox regression analysis showed MOLLI-ECV was positively associated with the composite outcome of HFrEF patients after adjusting confounders hazard ratio (HR) 2.57, 95% CI (1.09, 6.04). By subgroup analysis, a stronger association was seen in patients who with NYHA functional class III-IV, hematocrit < 39.8%, left atrial diameter ≥ 53.5 mm, or without the medical history of MRA or diuretics other than MRA. The P for interaction was < 0.05. In HFrEF patients, the relationship between MOLLI-ECV determined by CMR and the composite outcome is linear. High MOLLI-ECV was associated with a higher rate of cardiac mortality and first HF hospitalization in the short term follow up.

Effects of Adiponectin on Diastolic Function in Mice Underwent Transverse Aorta Constriction.

Diastolic dysfunction is common in various cardiovascular diseases, which could be affected by adiponectin (APN). Nevertheless, the effects of APN on diastolic dysfunction in pressure overload model induced by transverse aorta constriction (TAC) remain to be further elucidated. Here, we demonstrated that treatment of APN attenuated diastolic dysfunction and cardiac hypertrophy in TAC mice. Notably, APN also improved active relaxation of adult cardiomyocytes, increased N2BA/N2B ratios of titin isoform, and reduced collagen type I to type III ratio and lysyl oxidase (Lox) expressions in the myocardial tissue. Moreover, APN supplementation suppressed TAC-induced oxidative stress. In vitro, inhibition of AMPK by compound C (Cpc) abrogated the effect of APN on modulation of titin isoform shift and the anti-hypertrophic effect of APN on cardiomyocytes induced by AngII. In summary, our findings indicate that APN could attenuate diastolic dysfunction in TAC mice, which are at least partially mediated by AMPK pathway.

Outcomes of patients with anemia and renal dysfunction in hospitalized heart failure with preserved ejection fraction (from the CN-HF registry).

BACKGROUND: Although a large number of studies on heart failure with reduced ejection fraction (HFrEF) have found that anemia and renal dysfunction (RD) independently predicted poor outcomes, there are still few reports on patients with heart failure with preserved ejection fraction (HFpEF). METHODS: Clinical data of HFpEF patients registered in the China National Heart Failure Registration Study (CN-HF) were evaluated and the clinical features of patients with or without anemia/RD were compared to explore the impact of anemia and RD on all-cause mortality and all-cause re-hospitalization. RESULTS: 1604 patients with HFpEF were enrolled, the prevalence of anemia was 51.0%. Although anemia was associated with increased risk of all-cause mortality and all-cause re-hospitalization in univariate COX regression (p < 0.05), multivariate COX model confirmed that anemia was not independently associated with all-cause mortality [hazard ratio (HR) 1.14, 95% confidence interval (CI) 0.85-1.52, p = 0.386] and all-cause re-hospitalization (HR 1.13, 95% CI 0.96-1.33, p = 0.152). Similarly, RD was not an independent predictor of all-cause mortality (HR 1.18, 95% CI 0.88-1.57, p = 0.269) and all-cause re-hospitalization (HR 0.94, 95% CI 0.79-1.12, p = 0.488) as assessed in the adjusted COX regression model. The interaction between RD and anemia on end-points events was also not statistically significant. However, anemia was associated with increased all-cause re-hospitalization in patients with New York Heart Association (NYHA) class III-IV. CONCLUSIONS: In patients with HFpEF from CN-HF registry, anemia was common, but was not an independent predictor of all-cause mortality and all-cause re-hospitalization, except for the all-cause re-hospitalization in patients with NYHA class III-IV.Clinical Trial Registration: http://www.clinicaltrials.gov/ct2/home; ID: NCT02079428.

Angiotensin II induces apoptosis of cardiac microvascular endothelial cells via regulating PTP1B/PI3K/Akt pathway.

Endothelial cell apoptosis and renin-angiotensin-aldosterone system (RAAS) activation are the major pathological mechanisms for cardiovascular disease and heart failure; however, the interaction and mechanism between them remain unclear. Investigating the role of PTP1B in angiotensin II (Ang II)-induced apoptosis of primary cardiac microvascular endothelial cells (CMECs) may provide direct evidence of the link between endothelial cell apoptosis and RAAS. Isolated rat CMECs were treated with different concentrations of Ang II to induce apoptosis, and an Ang II concentration of 4 nM was selected as the effective dose for the subsequent studies. The CMECs were cultured for 48 h with or without Ang II (4 nM) in the absence or presence of the PTP1B inhibitor TCS 401 (8 µM) and the PI3K inhibitor LY294002 (10 µM). The level of CMEC apoptosis was assessed by TUNEL staining and caspase-3 activity. The protein expressions of PTP1B, PI3K, Akt, p-Akt, Bcl-2, Bax, caspase-3, and cleaved caspase-3 were determined by Western blot (WB). The results showed that Ang II increased apoptosis of CMECs, upregulated PTP1B expression, and inhibited the PI3K/Akt pathway. Furthermore, cotreatment with PTP1B inhibitor significantly decreased the number of apoptotic CMECs induced by Ang II, along with increased PI3K expression, phosphorylation of Akt and the ratio of Bcl-2/Bax, decreased caspase-3 activity, and a cleaved caspase-3/caspase-3 ratio, while treatment with LY294002 partly inhibited the anti-apoptotic effect of the PTP1B inhibitor. Ang II induces apoptosis of primary rat CMECs via regulating the PTP1B/PI3K/Akt pathway.

FUN14 Domain-Containing 1-Mediated Mitophagy Suppresses Hepatocarcinogenesis by Inhibition of Inflammasome Activation in Mice.

Mitochondria lie at the heart of innate immunity, and aberrant mitochondrial activity contributes to immune activation and chronic inflammatory diseases, including liver cancers. Mitophagy is a selective process for removing dysfunctional mitochondria. The link between mitophagy and inflammation in tumorigenesis remains largely unexplored. We observed that FUN14 domain-containing 1 (FUNDC1), a previously characterized mitophagy receptor, accumulates in most human hepatocellular carcinomas (HCCs), and we thus explored the role of FUNDC1-mediated mitophagy in HCC initiation and progression in a mouse model in which HCC is induced by the chemical carcinogen, diethylnitrosamine (DEN). We showed that specific knockout of FUNDC1 in hepatocytes promotes the initiation and progression of DEN-induced HCC, whereas FUNDC1 transgenic hepatocytes protect against development of HCC. Hepatocyte-specific FUNDC1 ablation results in the accumulation of dysfunctional mitochondria and triggers a cascade of events involving inflammasome activation and hyperactivation of Janus kinase/signal transducer and activator of transcription signaling. Specifically, cytosolic mitochondrial DNA (mtDNA) release and caspase-1 activation are increased in FUNDC1-depleted hepatocytes. This subsequently results in the elevated release of proinflammatory cytokines, such as interleukin-1ß (IL1ß) and hyperproliferation of hepatocytes. Conclusion: Our results suggest that FUNDC1 suppresses HCC initiation by reducing inflammasome activation and inflammatory responses in hepatocytes, whereas up-regulation of FUNDC1 expression at the late stage of tumor development may benefit tumor growth. Our study thus describes a mechanistic link between mitophagic modulation of inflammatory response and tumorigenesis, and further implies that FUNDC1-mediated mitophagy and its related inflammatory response may represent a therapeutic target for liver cancer.