Reversible cardiac function and left ventricular hypertrophy in a Chinese man with mitochondrial myopathy: a case report.

BACKGROUND: Mitochondrial myopathies (MMs) are a group of multi-system diseases caused by abnormalities in mitochondrial DNA (mtDNA) or mutations of nuclear DNA (nDNA). The diagnosis of mitochondrial myopathy (MM) is reliant on the combination of history and physical examination, muscle biopsy, histochemical studies, and next-generation sequencing. Patients with MMs have diverse clinical manifestations. In the contemporary literature, there is a paucity of reports on cardiac structure and function in this rare disease. We report a Chinese man with MM accompanied with both acute right heart failure and left ventricular hypertrophy. CASE PRESENTATION: A 49-year-old man presented with clinical features suggestive of MM, i.e., ophthalmoparesis, weakness of the pharyngeal and extremity muscles, and respiratory muscles which gradually progressed to respiratory insufficiency. He had a family history of mitochondrial myopathy. He had increased levels of serum creatine kinase and lactate. Muscle biopsy of left lateral thigh revealed 8% ragged red fibers (RRF) and 42% COX-negative fibers. Gene sequencing revealed a novel heterozygote TK2 variant (NM_001172644: c.584T>C, p.Leu195Pro) and another heterozygous variant (NM_004614.4:c.156+958G>A; rs1965661603) in the intron of TK2 gene. Based on these findings, we diagnosed the patient as a case of MM. Echocardiography revealed right heart enlargement, pulmonary hypertension, left ventricular hypertrophy, and thickening of the main pulmonary artery and its branches. The patient received non-invasive ventilation and coenzyme Q10 (CoQ10). The cardiac structure and function were restored at 1-month follow-up. CONCLUSIONS: This is the first report of reversible cardiac function impairment and left ventricular hypertrophy in a case of adult-onset MM, nocturnal hypoxia is a potential mechanism for left ventricular hypertrophy in patients with MM.

A Multifactorial Risk Score System for the Prediction of Diabetic Kidney Disease in Patients with Type 2 Diabetes Mellitus.

Purpose: In-depth investigations of risk factors for the identification of diabetic kidney disease (DKD) in type 2 diabetes mellitus (T2DM) are rare. We aimed to investigate the risk factors for developing DKD from multiple types of clinical data and conduct a comprehensive risk assessment for individuals with diabetes. Methods: We carried out a case-control study, enrolling 958 patients to identify the risk factors for developing DKD in T2DM patients from a database established from inpatient electronic medical records. Multivariable logistic regression was applied to develop a prediction model and the performance of the model was evaluated using the area under the curve (AUC) and calibration curve. A multifactorial risk score system was established according to the Framingham Study risk score. Results: DKD accounted for 34.03% of eligible patients in total. Twelve risk factors were selected in the final prediction model, including age, duration of diabetes, duration of hypertension, fasting blood glucose, fasting C-peptide, insulin use, systolic blood pressure, low-density lipoprotein, γ-glutamyl transpeptidase, platelet, uric acid, and thyroid stimulating hormone; and one protective factor, serum albumin. The prediction model showed an AUC of 0.862 (95% Confidence Interval (CI) 0.834-0.890) with an accuracy of 81.5% in the derivation dataset and an AUC of 0.876 (95% CI 0.825-0.928) in the validation dataset. The calibration curves were excellent and the estimated probability of DKD was more than 80% when the cumulative score for risk factors reached 17 points. Conclusion: Newly recognized risk factors were applied to assess the development of DKD in T2DM patients and the established risk score system was a reliable and feasible tool for assisting clinicians to identify patients at high risk of DKD.

Effect of ANKK1 Polymorphisms on Serum Valproic Acid Concentration in Chinese Han Adult Patients in the Early Postoperative Period.

INTRODUCTION: This study aimed to investigate the relationship between gene polymorphisms and clinical factors with the concentrations of valproic acid (VPA) in adult patients who underwent neurosurgery in China. METHODS: A total of 531 serum concentration samples at steady state were collected from 313 patients to develop a population pharmacokinetic (PPK) model. Data analysis was performed using nonlinear mixed effects modeling. Covariates included demographic parameters, biological characteristics, and genetic polymorphism. Bootstrap evaluation showed that the final model was stable. Sensitive analysis was performed to verify the relationship between gene polymorphisms and concentrations of VPA. Linear regression was used to analyze the relationship between VPA concentration, ANKK1, and daily dosage. RESULTS: In the recruited patients, 17 of 25 single-nucleotide polymorphism distributions were consistent with the Hardy-Weinberg equilibrium. A one-compartment model with first-order absorption and elimination was developed for VPA injections. VPA clearance was significantly influenced by three variables: sex (17.41% higher in male than female patients), body weight, and the ANKK1 gene. Typical values for the elimination clearance and the volume of central compartment were 0.614 L/min and 23.5 L, respectively. The model evaluation indicated the stable and precise performance of the final model. After sensitive analysis using Kruskal-Wallis and Mann-Whitney U tests, we found that patients with AA alleles had higher VPA concentrations than those with GG and AG alleles. Linear regression models showed that gene polymorphisms of ANKK1 had little effects on VPA concentration. CONCLUSION: A PPK model of VPA in Chinese Han patients was successfully established; this can be helpful for model-informed precision-dosing approaches in clinical patient care, and for exploring the mechanism of VPA-induced weight gain.

Blockage of TIM-3 relieves lupus nephritis by expanding Treg cells and promoting their suppressive capacity in MRL/lpr mice.

T Cell Immunoglobulin and Mucin Containing Protein-3 (TIM-3) is an important immune checkpoint protein that is expressed in Tregs and affects their function. However, the expression and role of TIM-3 in modulating regulatory T cells (Tregs) in lupus nephritis (LN) are still unknown. In this study, we found that the percentage of TIM-3+ cells among spleen lymphocytes, CD4+ T cells and Tregs was higher in MRL/lpr mice than in MpJ mice. TIM-3high CD4+ T cells and TIM-3high Tregs were mainly responsible for the increase. The percentage of Tregs in TIM-3high CD4+ T cells was lower than that in TIM-3low CD4+ T cells, and the expression of CTLA-4 and IL-10 was lower in TIM-3high Tregs than in the TIM-3low Tregs in MRL/lpr mice. Blockade of TIM-3 in vivo significantly increased the Treg population and the expression of CTLA-4 and IL-10 in Tregs, thus relieving the LN symptoms and pathology in MRL/lpr mice. Additionally, bioinformatics analysis indicated that TIM-3 regulates Treg cells in LN mainly through cytokine-cytokine receptor interactions, the PI3K-Akt signaling pathway, the T cell receptor signaling pathway, Th17 cell differentiation and the FoxO signaling pathway. Together, our study has demonstrated that TIM-3 regulates Tregs in LN and that overexpression of TIM-3 in CD4+ T cells and Tregs leads to Treg quantity and quality deficiency in MRL/lpr mice. Blockade of TIM-3 protects against LN by expanding Tregs and enhancing their suppressive capacity. Finally, TIM-3 might be a potential therapeutic target for the treatment of LN.

Anemone chinensis Bunge aqueous enema alleviates dextran sulfate sodium-induced colitis via inhibition of inflammation and regulation of the colonic mucosal microbiota.

ETHNOPHARMACOLOGICAL RELEVANCE: Although the incidence of ulcerative colitis (UC) increases every year, there is still a lack of satisfactory treatment options. Anemone chinensis Bunge (AB), a traditional Chinese herb, is a potent compound that can be prepared as a decoction, and then administered as an enema to relieve UC symptoms. However, the therapeutic effect and mechanisms of aqueous AB on UC are still unknown. AIM OF THE STUDY: This study investigates the potential therapeutic value and mechanism of AB aqueous enema for UC. MATERIALS AND METHODS: First, the practical components in aqueous AB were extracted and identified by UPLC-MS/MS. Second, the potential active targets and target genes related to UC were predicted, mapped, and analyzed by network pharmacology. Then, the effects of AB aqueous enema on UC were assessed using the dextran sulfate sodium (DSS)-induced colitis model with mice. Finally, the level of inflammation, the expression level of proteins associated with the colonic mucosal barrier, and the microbiota associated with the intestinal mucosal were investigated. RESULTS: Fourteen active ingredients in AB were identified. The network pharmacology-based analysis demonstrated that the active ingredients possibly affected ten key targets, such as IL-6, TNF, and PTGS2. They are also related to the tight junction proteins ZO-1, occludin, and claudin-1. Furthermore, mice treated with DSS developed severe mucosal colitis. AB aqueous enema decreased the disease activity index (DAI), significantly inhibited colonic damage, and greatly decreased colon length shortening (p < 0.05). AB also significantly restored tight junction proteins and the associated mucin proteins mucin-2 (MUC2) and mucin-3A (MUC3A). In addition, the diversity of the gut microbiota after administration of DSS was significantly decreased. However, the diversity was entirely restored after AB treatment. Recovery of the abundance of colonic mucosal bacteria, especially Lactobacillus reuteri and Lactobacillus gasseri, occurred at the species level after AB treatment. In vitro, AB can be utilized by the two bacteria, especially under glucose deficiency. CONCLUSIONS: Our study demonstrated that the AB aqueous enema alleviated colitis by restoring intestinal barrier proteins and regulating the gut microbiota.

Rapamycin relieves lupus nephritis by regulating TIM-3 and CD4+CD25+Foxp3+ Treg cells in an MRL/lpr mouse model.

Lupus nephritis (LN) is a severe consequence of systemic lupus erythematosus (SLE) and is an important driver of morbidity and mortality in SLE. Treg cells and TIM-3 play an important role in the pathogenesis of LN. The beneficial effect of rapamycin on LN has been confirmed in both mouse models and patients, but the effect of rapamycin on Treg cells and TIM-3 is not yet completely understood. In this study, rapamycin treatment attenuated proteinuria, histological damage, and renal deposition of C3, and improved renal function. Spleen and renal draining lymph node weight and serum levels of anti-dsDNA antibodies were also improved by rapamycin. Furthermore, the frequency of Treg cells and Treg functional molecules, such as cytotoxic T cell antigen 4 (CTLA-4), interleukin 10 (IL-10), and transforming growth factor ß1 (TGF-ß1), increased significantly after treatment with rapamycin in MRL/lpr mice. We also found that expression of TIM-3 was significantly decreased in CD4+ T cells and Treg cells in mice treated with rapamycin. In summary, the study demonstrated that rapamycin treatment induced preferential expansion of CD4+CD25+Foxp3+ Tregs with increased expression of CTLA-4, IL-10, and TGF-ß1, and decreased TIM-3 expression, thereby ameliorating lupus nephritis in the MRL/lpr mouse model.

EWASdb: epigenome-wide association study database.

DNA methylation, the most intensively studied epigenetic modification, plays an important role in understanding the molecular basis of diseases. Furthermore, epigenome-wide association study (EWAS) provides a systematic approach to identify epigenetic variants underlying common diseases/phenotypes. However, there is no comprehensive database to archive the results of EWASs. To fill this gap, we developed the EWASdb, which is a part of 'The EWAS Project', to store the epigenetic association results of DNA methylation from EWASs. In its current version (v 1.0, up to July 2018), the EWASdb has curated 1319 EWASs associated with 302 diseases/phenotypes. There are three types of EWAS results curated in this database: (i) EWAS for single marker; (ii) EWAS for KEGG pathway and (iii) EWAS for GO (Gene Ontology) category. As the first comprehensive EWAS database, EWASdb has been searched or downloaded by researchers from 43 countries to date. We believe that EWASdb will become a valuable resource and significantly contribute to the epigenetic research of diseases/phenotypes and have potential clinical applications. EWASdb is freely available at http://www.ewas.org.cn/ewasdb or http://www.bioapp.org/ewasdb.