Bariatric arterial embolization slows gastric emptying and improves postprandial glycaemia in obese dogs with impaired glucose tolerance.

AIM: To evaluate the effects of bariatric arterial embolization (BAE) on gastric emptying of, and the glycaemic response to, an oral glucose load in an obese canine model with impaired glucose tolerance. METHODS: Eleven male dogs were fed a high-fat, high-fructose diet for 7 weeks before receiving BAE, which involved selective embolization of the left gastric artery (n = 5; 14.9 ± 0.8 kg), or the sham (n = 6; 12.6 ± 0.8 kg) procedure. Postprocedural body weight was measured weekly for 4 weeks. Prior to and at 4 weeks postprocedure, a glucose solution containing 13C-acetate was administered orally for evaluation of the gastric half-emptying time (T50) and the glycaemic response. The relationship between the changes in the blood glucose area under the curve over the first 60 minutes (AUC0-60min) and the T50 was also assessed. RESULTS: At 4 weeks postprocedure, BAE reduced body weight (BAE vs. the sham procedure: -5.7% ± 0.9% vs. 3.5% ± 0.9%, P < .001), slowed gastric emptying (T50 at baseline vs. postprocedure: 75.5 ± 2.0 vs. 82.5 ± 1.8 minutes, P = .021 in the BAE group; 73.8 ± 1.8 vs. 74.3 ± 1.9 minutes in the sham group) and lowered the glycaemic response to oral glucose (AUC0-60min at baseline vs. postprocedure: 99.2 ± 13.7 vs. 67.6 ± 9.8 mmol·min/L, P = .043 in the BAE group; 100.2 ± 13.4 vs. 103.9 ± 14.6 mmol·min/L in the sham group). The change in the glucose AUC0-60min correlated inversely with that of the T50 (r = -0.711; P = .014). CONCLUSIONS: In a canine model with impaired glucose tolerance, BAE, while reducing body weight, slowed gastric emptying and attenuated the glycaemic response to an oral glucose load.

Does information disclosure among public hospitals stimulate medical cost change efforts? A pilot study in Shanghai.

BACKGROUND: In 2013, the Shanghai Hospital Development Center issued a policy to advocate public hospitals to report their information about costs on diseases. The objective was to evaluate the impact of interhospital disclosure of costs on diseases on medical costs and compare costs per case following information disclosure between hospitals of different rankings. METHODS: The study uses the hospital-level performance report issued by Shanghai Hospital Development Center in the fourth quarter of 2013, which covers quarterly aggregated hospital-level discharge data from 14 tertiary public hospitals participating in thyroid malignant tumors and colorectal malignant tumors information disclosure from the first quarter of 2012 to the third quarter of 2020. An interrupted time series model with segmented regression analysis is employed to examine changes in quarterly trends with respect to costs per case and length of stay before and after information disclosure. We identified high- and low-cost hospitals by ranking them on a costs per case basis per disease group. RESULTS: This research identified significant differences in cost changes for thyroid malignant tumors and colorectal malignant tumors between hospitals after disclosing information. A hospital's discharge costs per case for thyroid malignant tumors increased significantly among top-cost hospitals (1629.251 RMB, P = 0.019), while decreased for thyroid and colorectal malignant tumors among low-cost hospitals (-1504.189 RMB, P = 0.003; -6511.650 RMB, P = 0.024, respectively). CONCLUSION: Our findings indicate that information disclosure of costs on diseases results in changes in discharge costs per case. And low-cost hospitals continued to maintain their leading edge, whereas the high-cost hospitals changed their position in the industry by reducing discharge costs per case after information disclosure.

How do inpatients' costs, length of stay, and quality of care vary across age groups after a new case-based payment reform in China? An interrupted time series analysis.

CONTEXT: A patient classification-based payment system called diagnosis-intervention packet (DIP) was piloted in a large city in southeast China in 2018. OBJECTIVE: This study evaluates the impact of DIP payment reform on total costs, out-of-pocket (OOP) payments, length of stay (LOS), and quality of care in hospitalised patients of different age. METHODS: An interrupted time series model was employed to examine the monthly trend changes of outcome variables before and after the DIP reform in adult patients, who were stratified into a younger (18-64 years) and an older group (≥ 65 years), further stratified into young-old (65-79 years) and oldest-old (≥ 80 years) groups. RESULTS: The adjusted monthly trend of costs per case significantly increased in the older adults (0.5%, P = 0.002) and oldest-old group (0.6%, P = 0.015). The adjusted monthly trend of average LOS decreased in the younger and young-old groups (monthly slope change: -0.058 days, P = 0.035; -0.025 days, P = 0.024, respectively), and increased in the oldest-old group (monthly slope change: 0.107 days, P = 0.030) significantly. The changes of adjusted monthly trends of in-hospital mortality rate were not significant in all age groups. CONCLUSION: Implementation of the DIP payment reform associated with increase in total costs per case in the older and oldest-old groups, and reduction in LOS in the younger and young-old groups without deteriorating quality of care.

Direct Excitation of Aldehyde to Activate the C(sp2 )-H Bond by Cobaloxime Catalysis toward Fluorenones Synthesis with Hydrogen Evolution.

A new way to form fluorenones via the direct excitation of substrates instead of photocatalyst to activate the C(sp2 )-H bond under redox-neutral condition is reported. Our design relies on the photoexcited aromatic aldehyde intermediates that can be intercepted by cobaloxime catalyst through single electron transfer for following ß-H elimination. The generation of acyl radical and successful interception by a metal catalyst cobaloxime avoid the use of a photocatalyst and stoichiometric external oxidants, affording a series of highly substituted fluorenones, including six-membered ketones, such as xanthone and thioxanthone derivatives in good to excellent yields, and with hydrogen as the only byproduct. This catalytic system features a readily available metal catalyst, mild reaction conditions and broad substrate scope, in which sunlight reaction and scale-up experiments by continuous-flow approach make the new methodology sustainable and amenable for potentially operational procedures.

Transition-Metal-Free, Site-Selective C-F Arylation of Polyfluoroarenes via Electrophotocatalysis.

Direct CAr-F arylation is effective and sustainable for synthesis of polyfluorobiaryls with different degrees of fluorination, which are important motifs in medical and material chemistry. However, with no aid of transition metals, the engagement of CAr-F bond activation has proved difficult. Herein, an unprecedented transition-metal-free strategy is reported for site-selective CAr-F arylation of polyfluoroarenes with simple (het)arenes. By merging N,N-bis(2,6-diisopropylphenyl)perylene-3,4,9,10-bis(dicarboximide)-catalyzed electrophotocatalytic reduction and anodic nitroxyl radical oxidation in an electrophotocatalytic cell, various polyfluoroaromatics (2F-6F and 8F), especially inactive partially fluorinated aromatics, undergo sacrificial-reagents-free C-F bond arylation with high regioselectivity, and the yields are comparable to those for reported transition-metal catalysis. This atom- and step-economic protocol features a paired electrocatalysis with organic mediators in both cathodic and anodic processes. The broad substrate scope and good functional-group compatibility highlight the merits of this operationally simple strategy. Moreover, the easy gram-scale synthesis and late-stage functionalization collectively advocate for the practical value, which would promote the vigorous development of fluorine chemistry.

TET2-mediated Cdkn2A DNA hydroxymethylation in midbrain dopaminergic neuron injury of Parkinson's disease.

It has been reported that abnormal epigenetic modification is associated with the occurrence of Parkinson's disease (PD). Here, we found that a ten-eleven translocation 2 (TET2), a staff of the DNA hydroxylases family, was increased in dopaminergic neurons in vitro and in vivo. Genome-wide mapping of DNA 5-hydroxymethylcytosine (5-hmC)-sequencing has revealed an aberrant epigenome 5-hmC landscape in 1-methyl-4-phenylpyridinium iodide (MPP+)-induced SH-SY5Y cells. The TET family of DNA hydroxylases could reverse DNA methylation by oxidization of 5-methylcytosine (5-mC) to 5-hmC. However, the relationship between modification of DNA hydroxymethylation and the pathogenesis of PD is not clear. According to the results of 5-hmC-sequencing studies, 5-hmC was associated with gene-rich regions in the genomes related to cell cycle, especially gene-cyclin-dependent kinase inhibitor 2A (Cdkn2A). Downregulation of TET2 expression could significantly rescue MPP+-stimulated SH-SY5Y cell damage and cell cycle arrest. Meanwhile, knockdown of Tet2 expression in the substantia nigra pars compacta of MPTP-induced PD mice resulted in attenuated MPTP-induced motor deficits and dopaminergic neuronal injury via p16 suppression. In this study, we demonstrated a critical function of TET2 in PD development via the CDKN2A activity-dependent epigenetic pathway, suggesting a potential new strategy for epigenetic therapy.

Discovery of cinnamamide-barbiturate hybrids as a novel class of Nrf2 activator against myocardial ischemia/reperfusion injury.

Myocardial ischemia/reperfusion (MI/R) has been a challenge for global public health. Activation of nuclear factor erythroid-2-related factor 2 (Nrf2) signaling could attenuate MI/R injury by maintaining cell redox balance and reducing oxidative damage. Cinnamamide derivatives have been proven to be a class of potential Nrf2 activators and cardioprotective agents. The development of novel cinnamamide derivatives to combat oxidative stress in cardiomyocytes is highly desirable. In this study, twenty-three cinnamamide-barbiturate hybrids were studied. Cell-based assays showed that most of the compounds exhibited excellent protective activity against H2O2-induced oxidative injury in H9c2 cells. Notably, compound 7w, which had the highest activity and low cytotoxicity, was demonstrated to remarkably reduce intracellular ROS accumulation by activating the mRNA expression of Nrf2 and its downstream antioxidant gene HO-1, indicating a novel promising antioxidant and Nrf2 activator. The probable binding mode between protein Keap1 and compound 7w was also studied via molecule docking. Furthermore, we found that the administration of compound 7w could significantly reduce the cardiac infarct size and improve the cardiac function against MI/R injury in rats, as well as decrease cardiac oxidative stress. Taken together, we report, for the first time, that cinnamamide-barbiturate hybrids are a novel class of potential cardioprotective agents. The excellent cardioprotective action of such compounds rely on enhancing the endogenous antioxidative system by upregulating the Nrf2 signaling pathway in vitro and in vivo against MI/R damage. These findings provide a new perspective for designing cinnamamide-barbiturate hybrids as a novel class of Nrf2 activator against cardiovascular diseases.

Synthesis of Five-Membered Cyclic Guanidines via Cascade [3 + 2] Cycloaddition of α-Haloamides with Organo-cyanamides.

The convenient preparation of N2-unprotected five-membered cyclic guanidines was achieved through a cascade [3 + 2] cycloaddition between organo-cyanamides and α-haloamides under mild conditions in good to excellent yields (up to 99%). The corresponding cyclic guanidines could be easily transformed into hydantoins via hydrolysis.

Hesperetin ameliorates diabetes-associated anxiety and depression-like behaviors in rats via activating Nrf2/ARE pathway.

Diabetes-associated affective disorders are of wide concern, and oxidative stress plays a vital role in the pathological process. This study was to investigate the cerebroprotective effects of hesperetin against anxious and depressive disorders caused by diabetes, exploring the potential mechanisms related to activation of Nrf2/ARE pathway. Streptozotocin-induced diabetic rats were intragastrically administrated with hesperetin (0, 50, and 150 mg/kg) for 10 weeks. Forced swimming test, open field test, and elevated plus maze were used to evaluate the anxiety and depression-like behaviors of rats. The brain was collected for assays of Nrf2/ARE pathway. Moreover, high glucose-cultured SH-SY5Y cells were used to further examine the neuroprotective effects of hesperetin and underlying mechanisms. Hesperetin showed anxiolytic and antidepressant effects in diabetic rats according to the behavior tests, and increased p-Nrf2 in cytoplasm and Nrf2 in nucleus followed by elevations in mRNA levels and protein expression of glyoxalase 1 (Glo-1) and γ-glutamylcysteine synthetase (γ-GCS) in brain, known target genes of Nrf2/ARE signaling. Moreover, hesperetin attenuated high glucose-induced neuronal damages through activation of the classical Nrf2/ARE pathway in SH-SY5Y cells. Further study indicated that PKC inhibition or GSK-3ß activation pretreatment attenuated even abolished the effect of hesperetin on the protein expression of Glo-1 and γ-GCS in high glucose-cultured SH-SY5Y cells. In summary, hesperetin ameliorated diabetes-associated anxiety and depression-like behaviors in rats, which was achieved through activation of the Nrf2/ARE pathway. Furthermore, an increase in nuclear Nrf2 phosphorylation from PKC activation and GSK-3ß inhibition contributed to the activation of Nrf2/ARE pathway by hesperetin.

Non-pharmacological interventions for older adults with depressive symptoms: a network meta-analysis of 35 randomized controlled trials.

Objective: To assess the effectiveness of non-pharmacological interventions for seniors with depressive symptoms.Methods: A comprehensive literature search was performed. We conducted network meta-analysis in two ways, intervention classes (psychosocial, psychotherapy, physical activity, combined, treatment as usual) and individual intervention (11 categories). Whenever included studies used different scales, the different instruments were converted to the units of the scale most frequently used (the Geriatric Depression Scale), such that the effect size was reported as a mean difference (MD) with 95% confidence interval (CI). The risk of bias of RCTs included in this review was assessed according to the Cochrane Handbook. Bayesian NMA was conducted using R-3.4.0 software.Results: A total of 35 RCTs with 3,797 enrolled patients were included. Compared to conventional treatment, physical activity and psychotherapy resulted in significant improvements in depressive symptoms (MD: 2.25, 95%CrI: 0.99-3.56; SUCRA = 86.07%; MD: 1.75, 95% CrI: 0.90-2.64; SUCRA = 66.44%, respectively). Similar results were obtained for music (MD: 2.6; 95% CrI: 0.84-4.35;SUCRA = 80.53%), life review (MD:1.92; 95% CrI:0.71-3.14; SUCRA = 65.62%), cognitive behavioral therapy (MD: 1.27; 95% CrI: 0.23-2.38; SUCRA = 45.4%), aerobic (MD: 1.84; 95% CrI: 0.39-3.36; SUCRA = 63%) and resistance training (MD: 1.72; 95% CrI: 0.06-3.42; SUCRA = 59.24%). Network meta-regression showed that there were no statistically significant subgroup effects.Conclusions: Physical activity and psychotherapy demonstrated statistically significant superiority over conventional treatment. Music and life review therapy proved the most promising individual interventions. However, conclusions are limited by the lack of sufficient sample size and consensus regarding intervention categories and so an adequately powered study is necessary to consolidate these findings.

Lnc-UCID Promotes G1/S Transition and Hepatoma Growth by Preventing DHX9-Mediated CDK6 Down-regulation.

Although thousands of long noncoding RNAs (lncRNAs) have been annotated, only a limited number of them have been functionally characterized. Here, we identified an oncogenic lncRNA, named lnc-UCID (lncRNA up-regulating CDK6 by interacting with DHX9). Lnc-UCID was up-regulated in hepatocellular carcinoma (HCC), and a higher lnc-UCID level was correlated with shorter recurrence-free survival of HCC patients. Both gain-of-function and loss-of function studies revealed that lnc-UCID enhanced cyclin-dependent kinase 6 (CDK6) expression and thereby promoted G1/S transition and cell proliferation. Studies from mouse xenograft models revealed that tumors derived from lnc-UCID-silenced HCC cells had a much smaller size than those from control cells, and intratumoral injection of lnc-UCID small interfering RNA suppressed xenograft growth. Mechanistically, the 850-1030-nt domain of lnc-UCID interacted physically with DEAH (Asp-Glu-Ala-His) box helicase 9 (DHX9), an RNA helicase. On the other hand, DHX9 post-transcriptionally suppressed CDK6 expression by binding to the 3'-untranslated region (3'UTR) of CDK6 mRNA. Further investigation disclosed that lnc-UCID enhanced CDK6 expression by competitively binding to DHX9 and sequestering DHX9 from CDK6-3'UTR. In an attempt to explore the mechanisms responsible for lnc-UCID up-regulation in HCC, we found that the lnc-UCID gene was frequently amplified in HCC. Furthermore, miR-148a, whose down-regulation was associated with an increase of lnc-UCID in HCC, could bind lnc-UCID and inhibit its expression. Conclusion: Up-regulation of lnc-UCID, which may result from amplification of its gene locus and down-regulation of miR-148a, can promote HCC growth by preventing the interaction of DHX9 with CDK6 and subsequently enhancing CDK6 expression. These findings provide insights into the biological functions of lncRNAs, the regulatory network of cell cycle control, and the mechanisms of HCC development, which may be exploited for anticancer therapy.

Recent advances in 1,4-functional group migration-mediated radical fluoroalkylation of alkenes and alkynes.

Recently, the combination of radical fluoroalkylation of alkenyl or alkynyl moieties and 1,4-functional group migration (1,4-FGM) has emerged as a powerful strategy for the synthesis of fluorine-containing compounds. In this article, some representative reactions of 1,4-FGM-mediated radical fluoroalkylation of N-(arylsulfonyl)acrylamides, tertiary alcohol-containing alkynes, tertiary alcohol-containing alkenes and intermolecular 1,4-FGM-type substrates have been discussed based on the types of substrates.

Regio- and Diastereoselective Access to 4-Imidazolidinones via an Aza-Mannich Initiated Cyclization of Sulfamate-Derived Cyclic Imines with α-Halo Hydroxamates.

An efficient regio- and diastereoselective cyclization of sulfamate-derived cyclic imines with unsubstituted or monosubstituted α-halo hydroxamates is developed under mild conditions. This reaction proceeds smoothly under transition-metal-free conditions via a domino aza-Mannich addition/intramolecular nucleophilic substitution sequence, providing a convenient route to access 2-monosubstituted and 2,5-disubstituted 4-imidazolidinones. Notably, the products were obtained with single trans-isomers in moderate to excellent yields.

Synthesis of spirobarbiturate-pyrrolidinones via a domino aza-Michael/SN2 cyclization of barbiturate-derived alkenes with N-alkoxy α-haloamides.

A highly efficient domino aza-MIRC (Michael Induced Ring Closure) reaction between barbiturate-derived alkenes and N-alkoxy α-haloamides has been achieved in moderate to excellent yields. This reaction proceeds smoothly under mild conditions via a domino aza-Michael addition/intramolecular SN2 sequence, providing a practical tool in the synthesis of bioactive molecules spirobarbiturate-3-pyrrolidinones.

Exercise training modalities in patients with type 2 diabetes mellitus: a systematic review and network meta-analysis.

INTRODUCTION: Current international guidelines recommend aerobic, resistance, and combined exercises for the management of type 2 diabetes mellitus (T2DM). In our study, we conducted a network meta-analysis to assess the comparative impact of different exercise training modalities on glycemic control, cardiovascular risk factors, and weight loss in patients with T2DM. METHODS: We searched five electronic databases to identify randomized controlled trials (RCTs) that compared the differences between different exercise training modalities for patients with T2DM. The risk of bias in the included RCTs was evaluated according to the Cochrane tool. Network meta-analysis was performed to calculate mean difference the ratio of the mean and absolute risk differences. Data were analyzed using R-3.4.0. RESULTS: A total of 37 studies with 2208 patients with T2DM were included in our study. Both supervised aerobic and supervised resistance exercises showed a significant reduction in HbA1c compared to no exercise (0.30% lower, 0.30% lower, respectively), however, there was a less reduction when compared to combined exercise (0.17% higher, 0.23% higher). Supervised aerobic also presented more significant improvement than no exercise in fasting plasma glucose (9.38 mg/dl lower), total cholesterol (20.24 mg/dl lower), triacylglycerol (19.34 mg/dl lower), and low-density lipoprotein cholesterol (11.88 mg/dl lower). Supervised resistance showed more benefit than no exercise in improving systolic blood pressure (3.90 mmHg lower]) and total cholesterol (22.08 mg/dl lower]. In addition, supervised aerobic exercise was more powerful in improving HbA1c and weight loss than unsupervised aerobic (HbA1c: 0.60% lower; weight loss: 5.02 kg lower) and unsupervised resistance (HbA1c: 0.53% lower) exercises. CONCLUSION: Compared with either supervised aerobic or supervised resistance exercise alone, combined exercise showed more pronounced improvement in HbA1c levels; however, there was a less marked improvement in some cardiovascular risk factors. In terms of weight loss, there were no significant differences among the combined, supervised aerobic, and supervised resistance exercises. TRIAL REGISTRATION: Our study protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO); registration number: CRD42017067518 .

Protective effects of sarsasapogenin against early stage of diabetic nephropathy in rats.

Rhizome of Anemarrhena asphodeloides Bunge (AA, family Liliaceae) has been widely used in China for thousands of years to treat febrile diseases and diabetes. Steroidal saponins from AA show good antidiabetes effects and ameliorate diabetic complications. This study was designed to investigate the effects of sarsasapogenin (Sar), a major sapogenin from AA, on diabetic nephropathy (DN) in rats, and to explore the possible mechanisms. Diabetic rats were divided into 3 groups treated orally with Sar (0, 20, or 60 mg/kg) and carboxymethylcellulose sodium, whereas normal rats for Sar (0 or 60 mg/kg) and carboxymethylcellulose sodium. We found that chronic treatment with Sar for 9 weeks significantly ameliorated renal dysfunction of diabetic rats, as evidenced by decreases in albuminuria, kidney weight index, serum uric acid, and morphologic changes such as extracellular matrix expansion and accumulation (fibronectin and collagen IV levels, etc.). Meanwhile, Sar treatment resulted in decreases in interleukin-18, NLRP3, and activated caspase 1 levels as well as advanced glycation endproducts (AGEs) and their receptor (RAGE) levels in the renal cortex of diabetic rats. However, Sar has no effects on the above indices in the normal rats. Therefore, Sar can markedly ameliorate diabetic nephropathy in rats via inhibition of NLRP3 inflammasome activation and AGEs-RAGE interaction.

The expression levels of transcription factors T-bet, GATA-3, RORγt and FOXP3 in peripheral blood lymphocyte (PBL) of patients with liver cancer and their significance.

OBJECTIVES: To investigate the expression of transcriptional factors (TFs) T-bet, GATA-3, RORγt and FOXP in peripheral blood mononuclear cells (PBMC) of patients with hepatocellular carcinoma (HCC) and to evaluate the correlation between the imbalances of Th1/Th2, Th17/Treg at the expression levels and liver cancer Methods: The peripheral venous blood was drawn from 20 HCC-patients (HCC-group) and 20 health participants (C-group). The expression levels of Th1, Th2 and Th17 and the major Treg-specific TFs T-bet, GATA-3, RORγt and FOXP3 in the PBMC were measured with quantitative real-time PCR(RT-qPCR). RESULTS: The mRNA level of Th1-specific TF T-bet in HCC-group was significantly lower than that of C-group (52.34±34.07 VS 104.01±56.00, P<0.01); the mRNA level of Th2-specifc TF, GATA-3, in HCC group was significantly higher than that in C-group (1.38±1.15 VS 0.58±0.65, P<0.05) and T-bet mRNA/GATA-3 mRNA ratio was significantly lower in HCC-group than in C-group (86.01±116.71 VS 461.88±708.81, P<0.05). The mRNA level of Th17-specific TF RORγt in HCC-group was significantly higher than that of C-group (72.32±32.82 VS 33.07±22.86, P<0.01). Treg-specific TF FOXP3 mRNA level was significant higher in HCC-group than in C-group (3.17±1.59 VS 1.39±1.13, P<0.01) CONCLUSION: T-bet mRNA level was reduced whereas GATA-3 mRNA level was increased and T-bet/GATA-3 ratio was significantly reduced in PBMC, indicating that Th1/Th2 ratio was of imbalance at TF levels in PBMC of HCC, displaying Th2 thrift phenomena. The mRNA levels of RORγt and FOXP3 in PBMC of HCC were significantly increased, indicating the existence of a predominant phenomenon of Th17- and Treg-expressing PBMC in HCC.