Bidirectional two-sample mendelian randomization analysis identifies causal associations of MRI-based cortical thickness and surface area relation to NAFLD.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) patients have exhibited extra-hepatic neurological changes, but the causes and mechanisms remain unclear. This study investigates the causal effect of NAFLD on cortical structure through bidirectional two-sample Mendelian randomization analysis. METHODS: Genetic data from 778,614 European individuals across four NAFLD studies were used to determine genetically predicted NAFLD. Abdominal MRI scans from 32,860 UK Biobank participants were utilized to evaluate genetically predicted liver fat and volume. Data from the ENIGMA Consortium, comprising 51,665 patients, were used to evaluate the associations between genetic susceptibility, NAFLD risk, liver fat, liver volume, and alterations in cortical thickness (TH) and surface area (SA). Inverse-variance weighted (IVW) estimation, Cochran Q, and MR-Egger were employed to assess heterogeneity and pleiotropy. RESULTS: Overall, NAFLD did not significantly affect cortical SA or TH. However, potential associations were noted under global weighting, relating heightened NAFLD risk to reduced parahippocampal SA and decreased cortical TH in the caudal middle frontal, cuneus, lingual, and parstriangularis regions. Liver fat and volume also influenced the cortical structure of certain regions, although no Bonferroni-adjusted p-values reached significance. Two-step MR analysis revealed that liver fat, AST, and LDL levels mediated the impact of NAFLD on cortical structure. Multivariable MR analysis suggested that the impact of NAFLD on the cortical TH of lingual and parstriangularis was independent of BMI, obesity, hyperlipidemia, and diabetes. CONCLUSION: This study provides evidence that NAFLD causally influences the cortical structure of the brain, suggesting the existence of a liver-brain axis in the development of NAFLD.

[Chemical constituents from whole herb of Hedyotis scandens].

This study aimed to investigate the chemical constituents in the water extract of the whole herb of Hedyotis scandens by silica gel, ODS, and MCI column chromatographies together with preparative high-performance liquid chromatography(HPLC). The structures of isolated constituents were identified by NMR, HR-ESI-MS, etc. Thirteen compounds were isolated and identified as methyl 4-benzoyloxy-3-methoxybenzeneacetate(1), 4-benzoyloxy-3-methoxybenzeneacetic acid(2), 3-(4-hydroxy-3-methoxyphenyl)-propanoic acid(3), salicylic acid(4), 3-hydroxy-4-methoxypyridine(5), syringic acid(6), hydroxycinnamic acid(7),(R)-6-methyl-4,6-bis(4-methylpent-3-enyl)cyclohexa-1,3-dienecarbaldehyde(8), 1,2-bis(4-hydroxy-3-methoxyphenyl)-1,3-propanediol(9), 1H-indole-3-carboxaldehyde(10), isoscopoletin(11), syringaresinol(12), and pinoresinol(13). Among them, compounds 1 and 2 were new phenolic acid compounds, compounds 3-5, 8-11, and 13 were isolated from this genus for the first time, and compounds 6, 7, and 12 were obtained from H. scandens for the first time. The activity test showed that compounds 1 and 10 had a certain inhibitory effect on Mycobacterium smegmatis, with MIC_(50) values of 58.5 and 33.3 µg·mL~(-1), respectively.

[A new polyketide of endophytic fungi Aspergillus sp. ZJ-58 from Coptis chinensis].

A new polyketide, coptaspin A(1), along with two known compounds 4-acetyl-3,4-dihydro-6,8-dihydroxy-3-methoxy-5-methylisocoumarin(2), and cytochalasin Z_(12)(3), was isolated from the endophytic fungi Aspergillus sp. ZJ-58, which was isolated from the genuine medicinal plant Coptis chinensis in Chongqing after solid-state fermentation on rice and silica gel, MCI, and HPLC-based separation. Their structures were elucidated by MS, NMR, IR, UV, and ECD. The newly isolated compound 1 showed moderate inhibitory activities against LPS-induced NO production in RAW264.7 macrophages with the IC_(50) value of 58.7 µmol·L~(-1), suggesting its potential anti-inflammatory activity.

[Secondary metabolites of endophyte fungi Xylaria sp. from Coptis chinensis].

Two new polyketides, lasobutone A(1) and lasobutone B(2), along with three known compounds, guignardianone C(3), guignardic acid(4), and 4-hydroxy-17R-methylincisterol(5), were isolated from the endophytic fungi Xylaria sp. by silica gel, MCI, and preparative HPLC, which was separated from the Chinese medicinal material Coptis chinensis and cultivated through solid fermentation with rice. Their structures were elucidated on the basis of spectroscopic methods, such as MS, NMR, IR, UV, and ECD. Compounds 2 and 4 showed inhibitory activities against the nitric oxide(NO) production in the LPS-induced macrophage RAW264.7 with IC_(50) values of 58.7 and 42.5 µmol·L~(-1) respectively, while compound 5 exhibited cytotoxic activities against HT-29 with IC_(50) value of 14.3 µmol·L~(-1).

Penispidins A-C, Aromatic Sesquiterpenoids from Penicillium virgatum and Their Inhibitory Effects on Hepatic Lipid Accumulation.

Penispidins A-C (1-3), new aromatic sesquiterpenoids with two classes of rare carbon skeletons, were isolated from the endophytic fungus Penicillium virgatum HL-110. 1 represents the first example of a dunniane-type aromatic sesquiterpenoid, possessing a novel 4/6/6 tricyclic system, while (±)-2 and 3 have a 7,12-cyclized bisabolene skeleton, featuring a 3,4-benzo-fused 2-oxabicyclo[3.3.1]nonane central framework. Their structures were elucidated on the basis of spectroscopic methods, single-crystal X-ray diffraction, and ECD calculations. 1 inhibited hepatic lipid accumulation in HepG2 cells.

iNOS inhibitory activity of sesquiterpenoids and a monoterpenoid from the rhizomes of Curcuma wenyujin.

Eleven new sesquiterpenoids, wenyujinins A-K (1-11), and a new monoterpenoid, wenyujinin L (12), were isolated from the rhizomes of Curcuma wenyujin. Their structures and relative configurations were elucidated using 1D and 2D NMR, X-ray crystallographic analysis, and HRESIMS data. The absolute configurations of 1, 2, 3, 4, 6, 8, 9, and 10 were determined by comparison of the experimental and calculated ECD spectra. The absolute configuration of 5 was determined from the ECD data of the [Rh2(OCOCF3)4] complex, whereas those of 7 and 12 were determined from the ECD spectra of the compounds alone. Compounds 7 and 7a strongly inhibited the induction of NO production by LPS, with IC50 values of 7.6 and 8.5 µM, respectively. Compounds 6 and 10 moderately inhibited NO production with IC50 values of 47.7 and 48.6 µM, respectively.

Hedscandines A-C, three undescribed indole alkaloids from Hedyotis scandens with their anti-MRSA activity.

Hedscandines A-C (1-3), three undescribed indole alkaloids were isolated from Hedyotis scandens Roxb, a traditional Chinese medicine widely used in the treatment of respiratory ailments. Their structures were elucidated by extensive spectroscopic data and electronic circular dichroism calculation. Hedscandine A (1), possessed a unique carbon skeleton with a 1,4-oxazonin-2(3H)-one core system and displayed a rapid bactericidal activity against MRSA with a MIC value of 16 µg/mL. Mechanistic studies showed that compound 1 could disrupt the integrity of bacterial cell membranes and thus lead to bacterial death.

Three new guaiane sesquiterpene lactones from rhizomes of Curcuma wenyujin.

Three new guaiane sesquiterpene lactones (4S)-4-hydroxy-gweicurculactone (1), zedoalactone G (2), and (1R, 4R, 5S, 10S)-zedoalactone B (3), and three known guaiane sesquiterpene lactones, including zedoarolide B (4), zedoalactone B (5), and a new natural product (+)-zedoalactone A (6), were isolated from the rhizomes of Curcuma wenyujin Y.H. Chen et C. Ling. The structures were elucidated by spectroscopic methods including 1D and 2D NMR and HR-ESI-MS. The absolute configuration of 2 was determined via the calculated electronic circular dichroism (ECD), whereas the absolute configurations of 1 and 3 were determined via the ECD data of the [Rh2(OCOCF3)4] complex and [Mo2(OAc)4] complex, respectively. The inhibitory effects of compounds 1-6 on nitric oxide production in lipopolysaccharide-activated macrophages were evaluated. All of them exhibited weak anti-inflammatory activity.

Simultaneous determination of multiple sesquiterpenes in Curcuma wenyujin herbal medicines and related products with one single reference standard.

Some Curcuma species are widely used as herbal medicines. Sesquiterpenes are their important bioactive compounds and their quantitative analysis is generally accomplished by gas chromatography (GC) or high performance liquid chromatography (HPLC), but the instability and high cost of some sesquiterpene reference standards have limited their application. It is necessary to find a practicable means to control the quality of herbal medicines. Using one stable component contained in Curcuma species to determine multiple analogues should be a practical option. In this study, a simple HPLC method for determination of sesquiterpenes using relative response factors (RRFs) has been developed. The easily available and stable active component curdione was selected as the reference compound for calculating the RRFs of the other eight sesquiterpenes, including zedoarondiol (Zedo), isozedoarondiol (Isoz), aerugidiol (Aeru), (4S,5S)-(+)-germacrone-4,5-epoxide (Epox), curcumenone (Curc), neocurdione (Neoc), germacrone (Germ) and furanodiene (Fura). Their RRFs against curdione were between 0.131-1.301, with a good reproducibility. By using the RRFs, the quantification of sesquiterpenes in Curcuma wenyujin herbal medicines and related products was carried out. The method is especially useful for the determination of (4S,5S)-(+)-germacrone-4,5-epoxide, curcumenone, germacrone and furanodiene, which often are regarded as the principle components in Curcuma species, but unstable when were purified. It is an ideal means to analyze the components for which reference standards are not readily available.

Hand grip strength is inversely associated with total daily insulin dose requirement in patients with type 2 diabetes mellitus: a cross-sectional study.

Background: Short-term (2 weeks to 3 months) insulin intensive therapy using continuous subcutaneous insulin infusion (CSII) can improve islet beta cell function and prolong glycemic remission in patients with newly diagnosed type 2 diabetes mellitus (T2DM). However, the total daily insulin dose (TDD, IU/kg/d) required to achieve near-normoglycemic control with CSII still needs to be frequently adjusted based on blood glucose monitoring. Although real-time continuous glucose monitoring (rtCGM), which measures the interstitial fluid glucose concentration continuously without much difficulty, facilitates the adjustment of insulin dosage, its adoption in the T2DM population is strictly limited by insurance coverage and lack of awareness of rtCGM among clinicians. Thus, it is of clinical significance to identify easy-to-use parameters that may allow a more rapid and accurate prediction of TDD requirement. This study aimed to explore the association between hand grip strength (HGS) and TDD requirement in patients with T2DM receiving CSII therapy. Methods: A total of 180 eligible patients with T2DM were enrolled in the study and divided into three groups based on their HGS: low (L), medium (M), and high (H). The TDD requirement was calculated on day 7 or 8 of CSII treatment. Anthropometric parameters, including HGS, skeletal muscle mass, skeletal muscle index (SMI) and 6-m gait speed, and laboratory data, were collected on the morning of the second day after admission, within the first 24 h of CSII therapy. These parameters were used to identify significant predictors of TDD requirement using Pearson or Spearman correlation test, and stepwise multiple regression analysis. Results: There were no significant differences in age, duration of T2DM, waist-to-hip ratio (WHR), body mass index (BMI), blood pressure, liver function, estimated glomerular filtration rate, triglyceride, total cholesterol, glycosylated hemoglobin A1c (HbA1c), homeostatic model assessment of insulin resistance (HOMA-IR), and homeostasis model assessment of beta cell function (HOMA-ß) among the groups. The H group had higher body muscle mass-to-fat ratio (BMFR), skeletal muscle mass-to-fat ratio (SMFR), SMI, 6-m gait speed, and lower TDD requirement than the M and L groups. The HGS negatively correlated with TDD requirement (r = -0.33, p < 0.001) after adjusting for sex, age, BMI, WHR, HbA1c, Ln (HOMA-ß), Ln (HOMA-IR), Ln (BMFR), Ln (SMFR), SMI, and 6-m gait speed. Multivariate stepwise regression analysis indicated that HGS was an independent predictor of TDD requirement in patients with T2DM (ß = -0.45, p < 0 001). Conclusion: Lower HGS is associated with an increased TDD requirement in T2DM patients. HGS may facilitate the prediction of TDD requirement in T2DM patients receiving CSII therapy.

[Advance in chemical constituents and pharmacological activity of Curcuma wenyujin].

On the basis of a sysmatic survey on literatures, this essay summarized the studies on chemical constituents and pharmacological activity of Curcuma wenyujin. According to statistics, the reports for chemical constituents of the plant were mainly concentrated between 2007 and 2010. So far, totally 82 compounds were reported, including 57 sesquiterpenoids, 6 diterpenoids, 6 monoterpenes and 10 other components. Particularly, 23 compounds were new. Studies on its pharmacological activity covered antitumor, anti-inflammatory, analgesic, hepatoprotective, antioxidant, antithrombotic and antithrombosis. This essay summarized its chemical constituents and pharmacological activity, in order to facilitate its studies, development and utilization.

Heart rate-corrected QT interval: A novel diagnostic biomarker for diabetic peripheral neuropathy.

AIMS/INTRODUCTION: To explore the relationship between heart rate-corrected QT (QTc) interval and diabetic peripheral neuropathy (DPN), and whether QTc interval has diagnostic utility for DPN beyond nerve conduction velocity. MATERIALS AND METHODS: A total of 965 patients with diabetes, including 473 patients with DPN and 492 patients without DPN, underwent standard 12-lead electrocardiography and detailed assessments of peripheral neuropathy. RESULTS: Patients with DPN had longer QTc intervals than those without. Among participants, from the first to fourth quartile of QTc interval, the proportion of patients with DPN appreciably increased and the nerve conduction velocity obviously decreased (P for trend <0.001). The univariate and multivariate analyses showed that prolonged QTc interval was closely associated with increased risk of DPN (univariable odds ratio 1.112, 95% confidence interval 1.097-1.127, P < 0.001; multivariable odds ratio 1.118, 95% confidence interval 1.099-1.137, P < 0.001). Receiver operating characteristic analysis for the diagnosis of DPN showed a greater area under the curve for QTc interval of 0.894 than the median nerve motor conduction velocity of 0.691, median nerve sensory conduction velocity of 0.664 and peroneal nerve motor conduction velocity of 0.692. The optimal cut-off point of QTc interval for DPN was 428.5 ms with sensitivity of 0.715 and specificity of 0.920 (P < 0.001). The combination of QTc interval and nerve conduction testing increased the area under the curve for the diagnosis of DPN (from 0.736 to 0.916; P < 0.001). CONCLUSIONS: QTc interval with 428.5 ms has more reliable diagnostic utility for DPN than nerve conduction velocity, and prolonged QTc interval is closely associated with an increased risk of DPN.

14-Membered resorcylic acid lactone derivatives with their anti-inflammatory from the fungus Aspergillus sp. ZJ-65.

Two new 14-membered resorcylic acid lactone derivatives, ascarpins A (1) and B (2), together with three related known compounds (3-5) were isolated from the fungus Aspergillus sp. ZJ-65, obtaining from the intestine of grass carp. These structures were elucidated on the basis of extensive spectroscopic methods, chemical conversion, and comparison with literature. All isolates were tested for their inhibitory activity against LPS-induced NO production in RAW 264.7 macrophages. Among them, compounds 1-4 exhibited potential anti-inflammatory activity with IC50 values ranging from 7.6 to 48.3 µM.

MicroRNA-373-3p inhibits the growth of cervical cancer by targeting AKT1 both in vitro and in vivo.

OBJECTIVE: In this study, we aimed to investigate the function of microRNA-373-3p (miR-373-3p) in the pathogenesis of cervical cancer. METHODS: Human and mouse cervical cancer cell lines were transfected with miR-373-3p mimic and inhibitor. Cell proliferation and viability were evaluated with Cell Counting Kit-8 (CCK-8) assay and Lactate Dehydrogenase (LDH) assay, respectively. The AKT1-targeting role of miR-373-3p was analyzed by qPCR and Western blot. Finally, a mouse xenograft cervical tumor model was adopted to study the in vivo effect of miR-373-3p on tumor growth and the expression of AKT1. RESULTS: Over-expression of miR-373-3p significantly reduced the proliferation of cervical carcinoma cell line in vitro. In addition, miR-373-3p overexpression also inhibited cervical cancer growth in tumor-bearing mice. Mechanistically, we found that AKT1 gene can be targeted by miR-373-3p. MiR-373-3p mimic decreased the mRNA and protein expression of AKT1, while the miR-373-3p inhibitor increased the level of AKT1 in cervical cancer cells. AKT1 overexpression rescued the proliferation of cervical cancer cells transfected with miR-373-3p. CONCLUSION: MiR-373-3p can serve as a novel anti-tumor microRNA in cervical cancer by targeting AKT1.

Independent anti-inflammatory effect of insulin in newly diagnosed type 2 diabetes.

BACKGROUND: Although insulin has been reported to have an anti-inflammatory effect, whether this effect is independent of its property to reduce blood glucose with insulin treatment in type 2 diabetes has not been investigated in detail. The purpose of this study was to evaluate the independent anti-inflammatory effect of insulin in patients with newly diagnosed type 2 diabetes. RESEARCH DESIGN AND METHODS: An 8-week, randomized, parallel-group study that enrolled 90 patients with newly diagnosed type 2 diabetes, who were randomly assigned to receive either insulin or metformin, was carried out. The doses of insulin and metformin were titrated according to fasting plasma glucose (FPG) and postprandial plasma glucose (PPG) during the 4 weeks; the target of FPG was 126 mg/dL and that of PPG was 160 mg/dL. The blood glucose levels were kept stabilized till the end of the study. The serum concentrations of high-sensitive C-reactive protein (hsCRP) and interleukin (IL)-6 were measured before starting the study and 4 and 8 weeks after initiation of insulin or metformin therapy. RESULTS: After 4 weeks of dose titration, the levels of FPG were reduced in the two groups compared to baseline (p < 0.001), but there was no significant difference between the two groups (p > 0.05). During the next 4 weeks' treatment, the levels of FPG were stable, but the serum concentration of hsCRP and IL-6 was markedly reduced in the insulin-treated group compared with that in the metformin-treated group (p < 0.001). CONCLUSIONS: Our data suggest that insulin has an anti-inflammatory effect that is independent of the reduction it causes in blood glucose.

Asperfuranones A-C, 3(2H)-furanone derivatives from the fungus Aspergillus sp. and the configuration reassignment of their eighteen analogues.

Three undescribed 3(2H)-furanone derivatives, asperfuranones A-C (1-3), along with one known compound (4) were isolated from the Aspergillus sp. strain obtained from the intestines of centipede. Their structures were determined by NMR and MS spectroscopic analyses, and the absolute configurations were established by the Snatzke's sector rules, modified Mosher's method and electronic circular dichroism (ECD) calculation. Meanwhile, the application of the sector rules led to the reassignment of the absolute configurations of 4 and other seventeen previously reported analogues (5-21).

Aureochaeglobosins A-C, Three [4 + 2] Adducts of Chaetoglobosin and Aureonitol Derivatives from Chaetomium globosum.

Aureochaeglobosins A-C (1-3), three novel [4 + 2] cycloaddition heterodimers of chaetoglobosin and aureonitol derivatives, were obtained from the culture of endophytic fungus Chaetomium globosum, representing the first adduct examples of chaetoglobosins. Their structures were elucidated by extensive spectroscopic analyses, single-crystal X-ray diffraction, and a modified Mosher's method. Compounds 2 and 3 showed significant cytotoxicities against human MDA-MB-231 cancer cells with IC50 values of 7.6 and 10.8 µM, respectively.

Comparison of Efficacy and Safety of Lispro and Aspart Evaluated by Continuous Glucose Monitoring System in Patients with Newly Diagnosed Type 2 Diabetes.

OBJECTIVE: To compare the effect of the rapid-acting insulin analogues (RAIAs) aspart (NovoRapid) and lispro (Prandilin) on glycemic variations by continuous glucose monitoring system (CGMS) in patients within newly diagnosed type 2 diabetes mellitus (T2DM) receiving continuous subcutaneous insulin infusion (CSII) and metformin intensive therapy. METHODS: This is a single-blind randomized controlled trial. A total of 110 patients with newly diagnosed T2DM and with hemoglobin A1c (HbA1c%) above 9% was hospitalized and randomly divided into two groups: group Asp (NovoRapid group) and group Lis (Prandilin group). They all received CSII and metformin therapy. Treatments were maintained for 2-3 weeks after the glycaemic target was reached. C-peptide and insulin and fructosamine were determined. CGMS was continuously applied for 4 days after reaching the glycemic target. RESULTS: There were no significant differences in daily dosages of insulin, fasting plasma C-P and 2 h postprandial C-P and insulin, and fructosamine at the baseline and endpoint between the groups Asp and Lis. No significant differences were seen in the 24 h mean amplitude of glycemic excursions (MAGE), 24 h mean blood glucose (MBG), the standard deviation of the MBG (SDBG), fasting blood glucose, number of glycemic excursion (NGE), and the incidence of hypoglycemia between the two groups. Similarly, no significant differences were found in areas under the curve (AUC) of glucose above 10.0 mmol/L or the decremental area over the curve (AOC) of glucose below 3.9 mmol/L between the two groups. CONCLUSIONS: Lispro and aspart had the similar ability to control the glycemic variations in patients with newly diagnosed T2DM. This study was registered with ClinicalTrials.gov, number ChiCTR-IPR-17010338.

Metformin add-on continuous subcutaneous insulin infusion on precise insulin doses in patients with type 2 diabetes.

To investigate whether metformin add-on to the continuous subcutaneous insulin infusion (Met + CSII) therapy leads to a significant reduction in insulin doses required by type 2 diabetes (T2D) patients to maintain glycemic control, and an improvement in glycemic variation (GV) compared to CSII only therapy. We analyzed data from our two randomized, controlled open-label trials. Newly diagnoses T2D patients were randomized assigned to receive either CSII therapy or Met + CSII therapy for 4 weeks. Subjects were subjected to a 4-day continuous glucose monitoring (CGM) at the endpoint. Insulin doses and GV profiles were analyzed. The primary endpoint was differences in insulin doses and GV between the two groups. A total of 188 subjects were admitted as inpatients. Subjects in metformin add-on therapy required significantly lower total, basal and bolus insulin doses than those of control group. CGM data showed that patients in Met + CSII group exhibited significant reduction in the 24-hr mean amplitude of glycemic excursions (MAGE), the standard deviation, and the coefficient of variation compared to those of control group. Our data suggest that metformin add-on to CSII therapy leads to a significant reduction in insulin doses required by T2D patients to control glycemic variations.

Isocoumarin derivatives from the endophytic fungus, Pestalotiopsis sp.

Five new isocoumarin derivatives, pestalactone A-C (1-3) and pestapyrone D-E (4-5), together with two known compounds (6-7) were isolated from the solid cultures of the endophytic fungus Pestalotiopsis sp. obtained from Photinia frasery. Their structures were mainly determined by extensive spectroscopic analysis, Mo2(OCOCH3)4-induced electronic circular dichroism (ECD), and ECD calculation. Compounds 1 and 2 were rare isocoumarin derivatives and derived from distinctive polyketide pathways. Compound 3 exhibited potent antifungal activity against Candida glabrata (ATCC 90030) with an MIC50 value of 3.49±0.21µg/mL.