Investigating the mechanism of cornel iridoid glycosides on type 2 diabetes mellitus using serum and urine metabolites in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Cornel iridoid glycosides (CIG) are extracted from Corni fructus, a herbal medicine used in traditional Chinese medicine to treat diabetes. However, the antidiabetic effects of CIG and the underlying metabolic mechanisms require further exploration. AIM OF THE STUDY: This study aimed to assess the antidiabetic effects and metabolic mechanism of CIG by performing metabolomic analyses of serum and urine samples of rats. MATERIALS AND METHODS: A rat model of type 2 diabetes mellitus (T2DM) was established by administering a low dose of streptozotocin (30 mg/kg) intraperitoneally after 4 weeks of feeding a high-fat diet. The model was evaluated based on several parameters, including fasting blood glucose (FBG), random blood glucose (RBG), urine volume, liver index, body weight, histopathological sections, and serum biochemical parameters. Subsequently, serum and urine metabolomics were analyzed using ultra-high-pressure liquid chromatography coupled with linear ion trap-Orbitrap tandem mass spectrometry (UHPLC-LTQ-Orbitrap-MS). Data were analyzed using unsupervised principal component analysis (PCA) and supervised orthogonal partial least squares discriminant analysis (OPLS-DA). Differential metabolites were examined by the Kyoto Encyclopedia of Genes and Genomes (KEGG) metabolic pathways to explore the underlying mechanisms. RESULTS: After 4 weeks of treatment with different doses of CIG, varying degrees of antidiabetic effects were observed, along with reduced liver and pancreatic injury, and improved oxidative stress levels. Compared with the T2DM group, 19 and 23 differential metabolites were detected in the serum and urine of the CIG treatment group, respectively. The key metabolites involved in pathway regulation include taurine, chenodeoxycholic acid, glycocholic acid, and L-tyrosine in the serum and glycine, hippuric acid, phenylacetylglycine, citric acid, and D-glucuronic acid in the urine, which are related to lipid, amino acid, energy, and carbohydrate metabolism. CONCLUSIONS: This study confirmed the antidiabetic effects of CIG and revealed that CIG effectively controlled metabolic disorders in T2DM rats. This seems to be meaningful for the clinical application of CIG, and can benefit further studies on CIG mechanism.

Transcriptional Regulation of Selenoprotein F by Heat Shock Factor 1 during Selenium Supplementation and Stress Response.

Changes of Selenoprotein F (SELENOF) protein levels have been reported during selenium supplementation, stressful, and pathological conditions. However, the mechanisms of how these external factors regulate SELENOF gene expression are largely unknown. In this study, HEK293T cells were chosen as an in vitro model. The 5'-flanking regions of SELENOF were analyzed for promoter features. Dual-Glo Luciferase assays were used to detect promoter activities. Putative binding sites of Heat Shock Factor 1 (HSF1) were predicted in silico and the associations were further proved by chromatin immunoprecipitation (ChIP) assay. Selenate and tunicamycin (Tm) treatment were used to induce SELENOF up-regulation. The fold changes in SELENOF expression and other relative proteins were analyzed by Q-PCR and western blot. Our results showed that selenate and Tm treatment up-regulated SELENOF at mRNA and protein levels. SELENOF 5'-flanking regions from -818 to -248 were identified as core positive regulatory element regions. Four putative HSF1 binding sites were predicted in regions from -1430 to -248, and six out of seven primers detected positive results in ChIP assay. HSF1 over-expression and heat shock activation increased the promoter activities, and mRNA and protein levels of SELENOF. Over-expression and knockdown of HSF1 showed transcriptional regulation effects on SELENOF during selenate and Tm treatment. In conclusion, HSF1 was discovered as one of the transcription factors that were associated with SELENOF 5'-flanking regions and mediated the up-regulation of SELENOF during selenate and Tm treatment. Our work has provided experimental data for the molecular mechanism of SELENOF gene regulation, as well as uncovered the involvement of HSF1 in selenotranscriptomic for the first time.

Overexpression of NRK1 ameliorates diet- and age-induced hepatic steatosis and insulin resistance.

NAD+ is a co-enzyme in redox reactions and a substrate required for activity of various enzyme families, including sirtuins and poly(ADP-ribose) polymerases. Dietary supplementation of NAD+ precursors nicotinamide mononucleotide (NMN) or nicotinamide riboside (NR) protects against metabolic disease, neurodegenerative disorders and age-related physiological decline in mammals. Here we sought to identify the roles of nicotinamide riboside kinase 1 (NRK1) plays in regulating hepatic NAD+ biosynthesis and lipid metabolism. Using adenovirus mediated gene transduction to overexpress or knockdown NRK1 in mouse liver, we have demonstrated that NRK1 is critical for maintaining hepatic NAD+ levels and triglyceride content. We have further shown that the hepatic expression of Nmrk1 mRNA is significantly decreased either in mice treated with high-fat diet or in aged mice. However, adenoviral delivery of NRK1 in these diet- and age-induced mice elevates hepatic NAD+ levels, reduces hepatic steatosis, and improves glucose tolerance and insulin sensitivity. Our results provide important insights in targeting NRK1 for treating hepatic steatosis.

Characteristic patterns of normal meridian acupoint temperature.

BACKGROUND: Body temperature is an important indicator of health and illness. However, a single temperature measurement is not always reliable. Such measurements can be made using meridians, which are energy channels with acupoints being the nodes. To date, there is no published reference of meridian acupoint temperatures applicable to human health, and there is no clear digitalized indicator that could be utilized to evaluate human health by way of meridian acupoints up to now. METHODS: Our study recruited 100 healthy medical college students for the measurement of acupoint temperature. The temperatures of 135 acupoints of 14 main meridians were measured using infrared thermometers in order to provide a comprehensive body temperature reading of each study participant. RESULTS: The degree of the acupoint temperature consistently ranged from 34.88°C to 36.14°C. The gross thermograph was concentric, with high degree readings around the heart and low degree readings originating from the feet. The left and right body sides had significant correlation between the degrees of bilateral same name acupoint temperatures of 12 regular meridians (correlation coefficient, 0.367-0.985; p < 0.0001). There was also a significant correlation between the acupoint temperature for the governor vessel and the conception vessel (correlation coefficient, 0.083; p = 0.006). CONCLUSION: These findings indicate that meridian acupoint temperature is characterized by a consistently narrow range, as well as concentricity and symmetry in body temperature degree readings in college students. Meridian acupoint temperature may be a sensitive and valuable indicator to assist in the accurate evaluation of meridian and general human health, and the significance and changes of acupoint temperature in clinical conditions warrants future exploration.

Studies of DNA-binding properties of lafutidine as adjuvant anticancer agent to calf thymus DNA using multi-spectroscopic approaches, NMR relaxation data, molecular docking and dynamical simulation.

The interactions between lafutidine (LAF) and calf thymus DNA (ctDNA) have been investigated both experimentally and theoretically. UV-vis absorption studies confirmed that LAF binds to ctDNA through non-covalent interactions. Fluorescence quenching and time-resolved fluorescence spectroscopy studies showed that the binding of LAF with ctDNA occurred through static quenching mechanism, resulting in the formation of a LAF-ctDNA complex. The binding constants (K) of the complex were found to be around 103M-1 via NMR relaxation rates and fluorescence data, and the calculated thermodynamic parameters indicated that hydrogen bonds and van der Waals forces played major roles in the binding of LAF to ctDNA. The changes in CD spectra indicated that LAF induced a slight perturbation on the base stacking and helicity of B-DNA. A comparative study of the LAF-ctDNA complex with respect to potassium iodide quenching experiments and competition displacement assays with ethidium bromide, acridine orange, and Hoechst 33258 probes suggested that LAF interacted with ctDNA by minor groove mode. Molecular docking analysis further supported the minor groove binding. Molecular dynamics simulation indicated that LAF depart from the C-G region of DNA, but it can steadily bind with the middle part of DNA composed by A-T base pairs.

Interaction of lafutidine in binding to human serum albumin in gastric ulcer therapy: STD-NMR, WaterLOGSY-NMR, NMR relaxation times, Tr-NOESY, molecule docking, and spectroscopic studies.

In this study, lafutidine (LAF) was used as a model compound to investigate the binding mechanism between antiulcer drugs and human serum albumin (HSA) through various techniques, including STD-NMR, WaterLOGSY-NMR, (1)H NMR relaxation times, tr-NOESY, molecule docking calculation, FT-IR spectroscopy, and CD spectroscopy. The analyses of STD-NMR, which derived relative STD (%) intensities, and WaterLOGSY-NMR, determined that LAF bound to HSA. In particular, the pyridyl group of LAF was in close contact with HSA binding pocket, whereas furyl group had a secondary binding. Competitive STD-NMR and WaterLOGSY-NMR experiments, with warifarin and ibuprofen as site-selective probes, indicated that LAF preferentially bound to site II in the hydrophobic subdomains IIIA of HSA. The bound conformation of LAF at the HSA binding site was further elucidated by transferred NOE effect (tr-NOESY) experiment. Relaxation experiments provided quantitative information about the relationship between the affinity and structure of LAF. The molecule docking simulations conducted with AutoDock and the restraints derived from STD results led to three-dimensional models that were consistent with the NMR spectroscopic data. The presence of hydrophobic forces and hydrogen interactions was also determined. Additionally, FT-IR and CD spectroscopies showed that LAF induced secondary structure changes of HSA.

Consistent Efficacy of Wendan Decoction for the Treatment of Digestive Reflux Disorders.

Gastroesophageal reflux disease (GERD) and bile reflux gastritis (BRG) are common gastrointestinal (GI) disorders with unmet medical needs. Traditional Chinese medicine has long been used for the treatment of GERD and BRG whereas the ginger-containing formula Wendan decoction (WDD) targets homeostatic disturbances characterized by "reflux" and "gut-juice exposure" problems. Here we used WDD as a therapeutic tool to unravel the common pathogenesis of GI reflux disorders. Control clinical trials reporting the WDD-treated patients with GERD and BRG were included in this systematic review and meta-analysis. Outcome measurements were clinical efficacy defined by symptom relief with normal GI endoscopy, radiology, and pathology. Eventually, 33 studies involved 3253 participants (1351 vs. 1035 of the BRG in 20 publications, 449 vs. 418 of the GERD in 13 studies, and 194 vs. 159 of relapse rate in 6 trials). Pooled data showed a consistent therapeutic efficacy of WDD on BRG (OR = 6.00, 95%C = 4.68-7.69) and GERD (OR = 4.39, 95%CI = 2.72-7.07). The relapse rate was 12.4% for WDD, significantly lower than 44.0% for conventional therapies (OR = 0.14, 95%CI = 0.08-0.26). The consistent therapeutic efficacy of the single TCM formula on GERD and BRD indirectly indicates reflux as a common pathogenesis in reflux-associated GI disorders.

Efficacy of the wen dan decoction, a Chinese herbal formula, for metabolic syndrome.

CONTEXT: Metabolic syndrome (MS) refers to the clustering of metabolic derangements that include hyperglycemia, dyslipidemia, hypertension, and chronic kidney impairment. Those conditions are well known as being synergistically responsible for morbidity from cardiovascular disease as well as for driving the global epidemic of type 2 diabetes. It is still unknown whether an exact unifying pathogenesis of MS exists. OBJECTIVE: The meta-analysis intended to analyze the use of Chinese medicine (CM) as a therapeutic tool to explore indirectly the unifying pathogenesis of MS. METHODS: PubMed, the Chinese National Knowledge Infrastructure (CNKI), and the Wanfang databases were systematically searched from inception to November 2013 for randomized, controlled trials (RCTs) that compared treatment efficacy for MS patients using the Wen Dan decoction (WDD), a CM formula, versus Western conventional therapeutics. OUTCOME MEASURES: Measurements included tests of the overall therapeutic efficacy of WDD for hyperglycemia, hypertension, dyslipidemia, and renal functions, and the study also analyzed adverse events. Data were expressed as weighted mean differences (WMDs), with 95% confidence intervals (95% CIs) and the odds ratio (OR). RESULTS: A total of 31 RCTs were included for meta-analysis, involving 2512 patients and including 1282 participants in the intervention groups. The pooled data favored WDD over the control treatments as follows: (1) hyperglycemia, with a WMD of -0.95 mmol/L (95% CI: -1.19 to -0.71); (2) hypertension, with a WMD of -7.40 mm Hg (95% CI: -9.86 to -4.93); (3) dyslipidemia: (a) total cholesterol (TC), with a WMD of -0.62 mmol/L (95% CI: -0.90 to -0.33); (b) triglycerides (TGs), with a WMD of -0.32 mmol/L (95% CI: -0.52 to -0.13); (c) low-density lipoproteins (LDPs), with a WMD of -0.22 mmol/L (95% CI: -0.41 to -0.02); and (d) high-density lipoproteins (HDPs), with a WMD of 0.10 mmol/L (95% CI: 0.03 to 0.17); and (4) of renal functions: (a) urea, with a WMD of -3.41 mmol/L (95% CI: -5.50 to -1.32) and (b) creatinine, with a WMD of -68.81 µmol/L (95% CI: -132.63 to -4.98). No statistical significance was documented in creatinine clearance between the 2 treatments with a WMD of 15.47 mL/min (95% CI: -7.71 to 38.64). The overall efficacy rate was 91.4% for WDD and 66.9% for the control treatments (OR: 5.33; 95% CI: 4.06 to 6.99). Adverse events were rare and minor. CONCLUSIONS: The consistent improvements found in metabolic profiles by use of the single herbal formula may indirectly imply a common pathogenesis in MS.

Wen Dan Decoction for hemorrhagic stroke and ischemic stroke.

OBJECTIVE: The use of traditional Chinese medicine (TCM) in stroke is increasing worldwide. Here we report the existing clinical evidence of the Pinellia Ternata containing formula Wen Dan Decoction (WDD) for the treatment of ischemic stroke and hemorrhagic stroke. METHODS: PubMed, CNKI, Wan Fang database, Cochrane Library and online Clinical Trial Registry were searched up to 26 February 2013 for randomized, controlled clinical trials (RCTs) using WDD as intervention versus Western conventional medicine as control to treat stroke. Clinical outcomes were improvement of the Neurological Functional Deficit Scores (NFDS) and overall therapeutic efficacy rates including rate of cure. Meta-regression analysis using Hedges'g was performed for RCTs with significant heterogeneity. RESULTS: A total of 22 RCTs of ischemic stroke and 4 RCTs of hemorrhagic stroke, involving 2214 patients (1167 used WDD), met our inclusion criteria. Meta-analysis of the 13 RCTs reporting NFDS improvement favored WDD over the control (mean difference=-3.40, 95% confidence intervals [CI]=[-4.64, -2.15]). Rate of overall therapeutic efficacy (odds ratio [OR]=3.39, 95%CI=[1.81, 6.37]) for hemorrhagic stroke were significantly higher in WDD treated patients than the control subjects. In the 1898 patients with ischemic stroke, WDD medication also achieved higher rates of cure (OR=2.22, 95%CI=[1.66, 2.97]) and overall therapeutic efficacy (OR=3.31, 95%CI=[2.54, 4.31]) than the conventional treatment. CONCLUSIONS: WDD displays benefits on improvement of neurological function and overall therapeutic efficacy in post-stroke patients. TCM such as WDD may serve as a therapeutic tool of dual actions to explore the common mechanisms underlying cerebral hemorrhage and ischemia.