Glimepiride, a novel soluble epoxide hydrolase inhibitor, protects against heart failure via increasing epoxyeicosatrienoic acids.

BACKGROUND: Epoxyeicosatrienoic acids (EETs), which exert multiple endogenous protective effects, are hydrolyzed into less active dihydroxyeicosatrienoic acids (DHETs) by soluble epoxide hydrolase (sEH). However, commercial drugs related to EETs or sEH are not yet in clinical use. METHODS: Firstly, the plasma concentration of EETs and DHETs of 316 patients with heart failure (HF) were detected and quantitated by liquid chromatography-tandem mass spectrometry. Then, transverse aortic constriction (TAC)-induced HF was introduced in cardiomyocyte-specific Ephx2-/- mice. Moreover, Western blot, real-time PCR, luciferase reporter, ChIP assays were employed to explore the underlying mechanism. Finally, multiple sEH inhibitors were designed, synthesized, and validated in vitro and in vivo. RESULTS: The ratios of DHETs/EETs were increased in the plasma from patients with HF. Meanwhile, the expression of sEH was upregulated in the heart of patients and mice with HF, especially in cardiomyocytes. Cardiomyocyte-specific Ephx2-/- mice ameliorated cardiac dysfunction induced by TAC. Consistently, Ephx2 knockdown protected Angiotensin II (AngII)-treated cardiomyocytes via increasing EETs in vitro. Mechanistically, AngII could enhance the expression of transcript factor Krüppel-like factor 15 (KLF15), which in turn upregulated sEH. Importantly, glimepiride was identified as a novel sEH inhibitor, which benefited from the elevated EETs during HF. CONCLUSIONS: Glimepiride attenuates HF in mice in part by increasing EETs. CLINICAL TRIAL IDENTIFIER: NCT03461107 (https://clinicaltrials.gov).

Indoleamine 2,3-Dioxygenase 1 Deletion-Mediated Kynurenine Insufficiency Inhibits Pathological Cardiac Hypertrophy.

BACKGROUND: Aberrant amino acid metabolism is implicated in cardiac hypertrophy, while the involvement of tryptophan metabolism in pathological cardiac hypertrophy remains elusive. Herein, we aimed to investigate the effect and potential mechanism of IDO1 (indoleamine 2,3-dioxygenase) and its metabolite kynurenine (Kyn) on pathological cardiac hypertrophy. METHODS: Transverse aortic constriction was performed to induce cardiac hypertrophy in IDO1-knockout (KO) mice and AAV9-cTNT-shIDO1 mice. Liquid chromatography-mass spectrometry was used to detect the metabolites of tryptophan-Kyn pathway. Chromatin immunoprecipitation assay and dual luciferase assay were used to validate the binding of protein and DNA. RESULTS: IDO1 expression was upregulated in both human and murine hypertrophic myocardium, alongside with increased IDO1 activity and Kyn content in transverse aortic constriction-induced mice's hearts using liquid chromatography-mass spectrometry analysis. Myocardial remodeling and heart function were significantly improved in transverse aortic constriction-induced IDO1-KO mice, but were greatly exacerbated with subcutaneous Kyn administration. IDO1 inhibition or Kyn addition confirmed the alleviation or aggravation of hypertrophy in cardiomyocyte treated with isoprenaline, respectively. Mechanistically, IDO1 and metabolite Kyn contributed to pathological hypertrophy via the AhR (aryl hydrocarbon receptor)-GATA4 (GATA binding protein 4) axis. CONCLUSIONS: This study demonstrated that IDO1 deficiency and consequent Kyn insufficiency can protect against pathological cardiac hypertrophy by decreasing GATA4 expression in an AhR-dependent manner.

Genesis of Superlow Friction in Strengthening Si-DLC/PLC Nanostructured Multilayer Films for Robust Superlubricity at Ultrahigh Contact Stress.

Diamond-like carbon (DLC) films have significant potential to provide solutions for the friction reduction and the lubricity problem of mechanical moving friction pairs. However, the realization of excellent lubrication or even superlubricity and long lifetime under heavy loading conditions is still a great challenge, which is crucial for the applications of DLC in harsh environments. Here, we construct a group of property-strengthening Si-DLC/PLC multilayer films that could withstand ultrahigh contact stresses and achieve robust superlubricity. Under a peak Hertz contact stress of up to 2.37 GPa, the setup of a bilayer thickness of 324 nm enables the multilayered film (an overall film thickness of 1.53 µm) to achieve a superlow coefficient of friction toward 0.001 and an ultralow wear rate of 3.13 × 10-9 mm3/Nm. An alternating load reciprocating friction test emphasizes that this strengthening nanostructured Si-DLC/PLC multilayer possesses a kind of load self-adaptation because of its in situ nanoclustering transformation and local ordering of sp2-C phases at the sliding interface. The genesis of self-adaptation to the applied load is evaluated comprehensively to reveal its strengthening and toughening structural characteristics and robustness of the near-zero friction and wear features. The findings provide a significant design criterion for carbon-based solid lubricants applicable to harsh loading environments.

The correlation between paclitaxel chemotoxicity and the plasma albumin level in cancer patients.

WHAT IS KNOWN AND OBJECTIVE: The aim of this study was to evaluate the pharmacokinetics of paclitaxel in cancer patients with hypoalbuminemia following paclitaxel-containing chemotherapy and to provide a reference for the prevention of adverse events (AEs) after paclitaxel administration. METHODS: Peripheral blood was collected from cancer patients treated with paclitaxel. The plasma concentration of paclitaxel was determined by ultra-high performance liquid chromatography after 24 ± 8 h of chemotherapy, and individual paclitaxel time above a threshold concentration of 0.05 µmol/L (Tc>0.05 ) was calculated using the population pharmacokinetic model. Haematological and non-haematological toxicities were monitored after chemotherapy, and the correlation between different chemotherapy toxicities and Tc>0.05 was evaluated using the Prism software. RESULTS AND DISCUSSION: The enrolled patients were divided into the hypoalbuminemia group and normal albumin level group. The mean Tc>0.05 values in the normal albumin level and hypoalbuminemia groups were 36.89 and 24.93 h, respectively (P < 0.001). The risk of myelosuppression was positively correlated with Tc>0.05 . Due to the lower Tc>0.05 , the incidences of immediate AEs such as gastrointestinal reactions and rashes were higher in the hypoalbuminemia group than in the normal albumin level group, and the incidences of delayed AEs such as myelosuppression and neurotoxicity were lower in the hypoalbuminemia group. WHAT IS NEW AND CONCLUSIONS: Plasma albumin level has a conclusive effect on Tc>0.05 , which can predict the potential clinical toxicity of paclitaxel. The study provides a theoretical basis for administration of paclitaxel.

Mechanisms and Therapeutic Strategies of Viral Myocarditis Targeting Autophagy.

Viral myocarditis is caused by infection with viruses or bacteria, including coxsackievirus B3 (CVB3), and is characterized by acute or chronic inflammatory responses in the heart. The mortality associated with severe viral myocarditis is considerable. In some patients, viral myocarditis may develop into dilated cardiomyopathy or heart failure. Autophagy is involved in a wide range of physiological processes, including viral infection and replication. In the present review, we focus on the responses of cardiac tissues, cardiomyocytes, and cardiac fibroblasts to CVB3 infection. Subsequently, the effects of altered autophagy on the development of viral myocarditis are discussed. Finally, this review also examined and assessed the use of several popular autophagy modulating drugs, such as metformin, resveratrol, rapamycin, wortmannin, and 3-methyladenine, as alternative treatment strategies for viral myocarditis.

Follistatin Attenuates Myocardial Fibrosis in Diabetic Cardiomyopathy via the TGF-ß-Smad3 Pathway.

Follistatin (FST) is an endogenous protein that irreversibly inhibits TGF-ß superfamily members and plays an anti-fibrotic role in other diseases. However, the role of FST in diabetic cardiomyopathy remains unclear. In this study, we investigated the effects of FST on diabetic cardiomyopathy. The expression of FST was downregulated in the hearts of db/db mice. Remarkably, overexpressing FST efficiently protected against cardiac dysfunction. In addition, overexpression of FST promoted cardiac hypertrophy with an unchanged expression of atrial natriuretic peptide (ANP) and the ratio of myosin heavy chain-ß/myosin heavy chain-α (MYH7/MYH6). Furthermore, FST reduced cardiac fibrosis and the production of reactive oxygen species (ROS), and enhanced matrix metallopeptidase 9 (MMP9) activities in db/db mouse hearts. We also observed that overexpressing FST decreased the level of transforming growth factor beta (TGF-ß) superfamily members and the phosphorylation of Smad3; consistently, in vitro experiments also verified the above results. Our findings revealed the cardioprotective role of FST in attenuating diabetic cardiomyopathy through its anti-fibrotic effects through the TGF-ß-Smad3 pathway and provided a promising therapeutic strategy for diabetic cardiomyopathy.

miR-490-3p functions as a tumor suppressor in glioma by inhibiting high-mobility group AT-hook 2 expression.

Glioma is one of the most common types of malignant cancer and the significance of microRNAs (miRNAs) in cancer therapy has been demonstrated. In the current study, miR-490-3p expression was significantly downregulated in glioma tissue and cell lines. Overexpression of miR-490-3p inhibited glioma cell proliferation and migration in vitro. In addition, the high-mobility group AT-hook 2 (HMGA2) was identified as a candidate target gene of miR-490-3p. The current study demonstrated that miR-490-3p mimic could inhibit HMGA2 protein expression in glioma cells. In addition, correlation analysis demonstrated that miR-490-3p and HMGA2 expression was inversely correlated in glioma tissues. Furthermore, the inhibitory effect of miR-490-3p mimic on cell proliferation and migration was partially reversed by the overexpression of HMGA2. Taken together, these results suggest that miR-490-3p may have a tumor suppressive role in glioma and therefore miR-490-3p may be a new target for the treatment of glioma.

Correlation between serum interleukin-6 level and type 1 diabetes mellitus: A systematic review and meta-analysis.

OBJECTIVE: This report aimed to explore the association between the change of circulating interleukin-6 (IL-6) in patients and the development of type 1 diabetes mellitus (T1DM). METHODS: Four databases (PubMed, CNKI, WanFang and Civip) were used to search and list all clinical case-control studies about serum IL-6 level in T1DM patients between Jan 1, 2000 and Aug 31, 2016. RESULTS: A total of 20 case-control studies with 1238 T1DM patients and 742 healthy controls were included in this study. Compared to healthy controls, the serum content of IL-6 in patients with T1DM was significantly greater (overall: SMD, 1.49; 95% CI, 1.04 to 1.93; p<0.001), and notably increased in all subgroup with different age, ethnic and disease duration (all p<0.001). Furthermore, the analysis in subgroup exhibited that serum levels of IL-6 in the age greater than 20-year old (SMD, 1.64; 95% CI, 0.57-2.71; p<0.001), the diseased duration among 0-10years (SMD, 2.43; 95% CI, 1.42-3.44; p<0.001) and the sorted American group (SMD, 1.68; 95% CI, 0.85-2.51; p<0.001) were higher than those in control groups. CONCLUSIONS: Patients with T1DM were found to be linked to elevated level of serum IL-6, which the age, ethnic and disease durations in T1DM patients had no effect on the serum IL-6 levels for promoting diabetes mellitus.

[Study on effect of scutellarin in resisting liver fibrosis in rats].

Totally 80 rats were randomly divided into the control group, the model group, low, middle and high dose (25, 50, 100 mg x kg(-1)) scutellarin( SC) groups and the colchicine ( Col) group. Apart from the blank group, all of the remaining groups were intraperitoneally injected with 0.5 mL pig serum twice every week for consecutively 13 weeks and orally administered with the corresponding drugs since the 9th week. The blank group and the model group were orally given equal volume of normal saline once every for consecutively four weeks. After the experiment, efforts were made to detect the contents of alanine aminotransferase (ALT), aspertate aminotransferase (AST), albumin (ALB), total protein (TP), total bilirubin (TBIL), hyaluronic acid (HA), laminin (LN) and collagen type IV (CIV), collect liver tissues of fixed positions, observe the pathological changes through hematoxylin-eosin (HE) staining, conduct the pathological grading for liver fibrosis, determine the expressions of hepatic collagen type I and III (C I, C III) and calculate their color rendering index. Compared with the model group, low, middle and high dose (25, 50, 100 mg x kg(-1)) SC groups could decrease the contents of ALT, AST, TBIL, HA, LN, CIV, increase the contents of ALB, TP in serum and reduce the contents of C I, C III in liver tissues. In conclusion, scutellarin has a certain therapeutic effect on immune liver fibrosis in rats induced by pig serum.

Data processing and analysis in real-world traditional Chinese medicine clinical data: challenges and approaches.

Traditional Chinese medicine (TCM) is a clinical-based discipline in which real-world clinical practice plays a significant role for both the development of clinical therapy and theoretical research. The large-scale clinical data generated during the daily clinical operations of TCM provide a highly valuable knowledge source for clinical decision making. Secondary analysis of these data would be a vital task for TCM clinical studies before the randomised controlled trials are conducted. In this article, we discuss the challenges and issues, such as structured data curation, data preprocessing and quality, large-scale data management and complex data analysis requirements, in the data processing and analysis of real-world TCM clinical data. Furthermore, we also discuss related state-of-the-art research and solutions in China. We have shown that the clinical data warehouse based on the collection of structured electronic medical record data and clinical terminology would be a promising approach for generating clinical hypotheses and helping the discovery of clinical knowledge from large-scale real-world TCM clinical data.

CYP3A5*3 and MDR-1 C3435T single nucleotide polymorphisms in six Chinese ethnic groups.

The prevalent CYP3A5 *3 and the functional multi-drug resistance gene (MDR1) C3435T show marked interethnic variation among Orientals, Caucasians and Africans. This study aimed to investigate the distribution of CYP3A5*3 and MDR1 C3435T among Chinese ethnic groups. Genotypes of the CYP3A5*3 and MDR1 C3435T were determined in 839 unrelated healthy Chinese subjects by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assays. Frequencies (P < 0.05) of CYP3A5*3 variant alleles observed in Uygur Chinese, Kazakh Chinese and Tibetan Chinese (88.1%, 84.5% and 80.7%, respectively) were Significantly higher than those in Han Chinese, Wa Chinese and Bai Chinese (67.3%, 56.3% and 70.2%, respectively). Significantly higher 3435T variant frequencies (P < 0.05) were observed in Uygur Chinese (58.4%) and Kazakh Chinese (56.8%) compared with Han Chinese (44.2%), Tibetan Chinese (43.9%), Wa Chinese (45.8%) and Bai Chinese (44.2%). These results indicate that there were marked ethnic differences in the mutant frequencies of CYP3A5*3 and MDR1 C3435T among Chinese ethnic groups. Frequencies of those variants observed in Uygur Chinese, Kazakh Chinese, Tibetan Chinese, Wa Chinese and Bai Chinese wereintermediate between those seen in Han Chinese and African-American.

Distribution of polycyclic aromatic hydrocarbons in Datuo karst Tiankeng of South China.

Levels of polycyclic aromatic hydrocarbons (PAHs) were measured in surface soils of Datuo karst Tiankeng (large sinkholes) in South China with the use of a gas chromatography-mass spectroscopy (GC-MS) system. This paper provides data on the levels and distribution of PAHs from the top to the bottom of the Datuo karst Tiankeng. The results showed that the sum of the 16 EPA priority PAHs from the sampled locations from top to bottom had a relative increment in PAHs concentration. summation operatorPAHs ranged from 16.93 ng/g to 68.07 ng/g with a mean concentration of 42.15 ng/g. The correlated results showed the bottom of the large sinkhole, which accounts for the higher concentrations, probably acts like a trap for the PAHs. Thus, the low evaporation rate at the bottom may play a key role in controlling the high concentration of PAHs at the bottom.