Gentianella acuta improves TAC-induced cardiac remodelling by regulating the Notch and PI3K/Akt/FOXO1/3 pathways.

Cardiac remodelling mainly manifests as excessive myocardial hypertrophy and fibrosis, which are associated with heart failure. Gentianella acuta (G. acuta) is reportedly effective in cardiac protection; however, the mechanism by which it protects against cardiac remodelling is not fully understood. Here, we discuss the effects and mechanisms of G. acuta in transverse aortic constriction (TAC)-induced cardiac remodelling in rats. Cardiac function was analysed using echocardiography and electrocardiography. Haematoxylin and eosin, Masson's trichrome, and wheat germ agglutinin staining were used to observe pathophysiological changes. Additionally, real-time quantitative reverse transcription polymerase chain reaction and western blotting were used to measure protein levels and mRNA levels of genes related to myocardial hypertrophy and fibrosis. Immunofluorescence double staining was used to investigate the co-expression of endothelial and interstitial markers. Western blotting was used to estimate the expression and phosphorylation levels of the regulatory proteins involved in autophagy and endothelial-mesenchymal transition (EndMT). The results showed that G. acuta alleviated cardiac dysfunction and remodelling. The elevated levels of myocardial hypertrophy and fibrosis markers, induced by TAC, decreased significantly after G. acuta intervention. G. acuta decreased the expression of LC3 II and Beclin1, and increased p62 expression. G. acuta upregulated the expression of CD31 and vascular endothelial-cadherin, and prevented the expression of α-smooth muscle actin and vimentin. Furthermore, G. acuta inhibited the PI3K/Akt/FOXO1/3a pathway and activated the Notch signalling. These findings demonstrated that G. acuta has cardioprotective effects, such as alleviating myocardial fibrosis, inhibiting hypertrophy, reducing autophagy, and blocking EndMT by regulating the PI3K/Akt/FOXO1/3a and Notch signalling pathways.

Evaluation and validation of the prognostic value of anti-MDA5 IgG subclasses in dermatomyositis-associated interstitial lung disease.

OBJECTIVE: To investigate the association between the anti-melanoma differentiation associated gene 5 (MDA5) IgG subclasses and prognosis of patients with dermatomyositis (DM)-associated interstitial lung disease (ILD). METHODS: This retrospective study included 122 anti-MDA5 positive DM-ILD patients admitted from October 2017 to October 2020 as training cohort, and additional 68 patients from August 2014 to September 2017 as validation cohort. The levels of anti-MDA5 total IgG and IgG subclasses were measured using in-house enzyme-linked immunosorbent assays, and analysed in association with the patient prognosis. RESULTS: In the training cohort, the concentrations of anti-MDA5 IgG1 and IgG3 in non-survivors were significantly higher than in survivors (P < 0.05), whereas there were no significant differences in the IgG2 and IgG4 levels. Kaplan-Meier survival analysis revealed that the levels of anti-MDA5 total IgG, IgG1 and IgG3 were associated with mortality (P < 0.05). Multivariate analysis revealed anti-MDA5 IgG1 >13 U/ml and anti-MDA5 IgG3 >11 U/ml were independent risk factors for death of DM-ILD patients (P < 0.05). Anti-MDA5 IgG1 was confirmed as an independent risk factor in the validation cohort, while anti-MDA5 IgG3 was not. Anti-MDA5 IgG1 showed greater discriminable power for patient prognosis (Youden index 0.494) than anti-MDA5 total IgG, IgG3, or the combination of IgG1 and IgG3 (Youden index 0.356, 0.32 and 0.447, respectively). CONCLUSION: Anti-MDA5 IgG1 and IgG3 are significantly associated with poor prognosis in DM-ILD patients, and anti-MDA5 IgG1 is more efficient as a prognostic biomarker in DM-ILD patients.

Contribution of Necroptosis to Myofiber Death in Idiopathic Inflammatory Myopathies.

OBJECTIVE: Myofiber necrosis is a significant pathologic characteristic of idiopathic inflammatory myopathies (IIMs), and its molecular mechanism is largely unknown. Necroptosis is a recently identified form of regulated necrotic cell death, and its activation might have crucial biologic consequences. The aim of the present study was to investigate the role of necroptosis in IIM muscle damage. METHODS: Western blot and immunohistochemistry analyses were performed to examine the expression of receptor-interacting protein 3 (RIP-3) and mixed-lineage kinase domain-like (MLKL) proteins in 26 IIM patients and 4 healthy controls, as well as necroptosis-related damage-associated molecular pattern molecules. Tumor necrosis factor (TNF) was used to stimulate cultured C2C12 myoblasts, and the involvement of necroptosis in cell death of C2C12 cells was studied in vitro. RESULTS: The expression of RIP-3 and MLKL proteins and their phosphorylated forms was significantly increased in the muscle tissue of IIM patients compared to that of healthy controls. The expression levels of RIP-3 and MLKL proteins were associated with the severity of muscle damage in patients with IIM. Significant colocalization of MLKL with high mobility group box chromosomal protein 1 in necrotizing myofibers was observed in muscle biopsy tissue from patients with IIM. Stimulation of C2C12 myoblasts with TNF and a pan-caspase inhibitor, Z-VAD, resulted in the overactivation of necroptosis and significantly increased necrotic cell death. Strategies involving either inhibition of necroptosis with necrostatin-1 or knockdown of MLKL expression successfully prevented necroptosis-induced cell death of C2C12 cells. CONCLUSION: These findings demonstrate that overactivated necroptosis contributes to muscle damage in IIMs and suggest that necroptosis inhibitors could represent a new therapeutic target in the treatment of IIMs.

Trends in conventional cardiovascular risk factors and myocardial infarction subtypes among young Chinese men with a first acute myocardial infarction.

BACKGROUND: There is limited data on the characteristics of conventional risk factors (RFs) in young Chinese men hospitalized with a first acute myocardial infarction (AMI). HYPOTHESIS: We analyzed the trends in and prevalence of cardiovascular RFs and subtypes of MI during the first AMI in young Chinese men. METHODS: A total of 2739 men aged 18-44 years hospitalized for a first AMI were identified from 2007 to 2017. The overall prevalence of RFs and their respective temporal trends and subtypes of AMI were evaluated. RESULTS: The most prevalent conditions were smoking, followed by hypertension and then obesity. Patients aged <35 years had a much higher prevalence of hypercholesterolemia and obesity. Compared with a similar reference population in the United States, young Chinese men had a higher prevalence of smoking and dyslipidemia, but a lower prevalence of obesity, hypertension, and diabetes. The prevalence of hypertension increased from 2007 through 2017 (p trend <.001), whereas smoking decreased gradually. AMI frequently presented as ST-segment elevation MI (STEMI) (77.5%). Cluster of conventional RFs (3 RFs, odds ratio [OR]: 1.69, 95% confidence interval [CI]: 1.11-2.57; ≥4 RFs, OR: 2.50, 95% CI: 1.55-4.03] and multivessel disease (OR = 1.32, 95% CI: 1.08-1.60) increased the risk of non-STEMI (NSTEMI). CONCLUSIONS: Conventional RFs were highly prevalent in young Chinese men who were hospitalized for first AMI events, and the temporal trends varied different between China and US populations. Multivessel disease and cluster of conventional RFs are closely related to NSTEMI. Optimized preventive strategies among young adults are warranted.

Trends in low-density lipoprotein cholesterol level among Chinese young adults hospitalized with first acute myocardial infarction.

BACKGROUND: Representative data has shown a linear increase in mean low-density lipoprotein cholesterol (LDL-C) levels among Chinese adults, contributing to the burden of atherosclerotic cardiovascular disease (ASCVD). This study aimed to assess the trends in LDL-C levels and their association with coronary artery stenosis during the first acute myocardial infarction (AMI) in young Chinese adults. METHODS: A retrospective study including 2,781 adults, aged 18-44 years, hospitalized for their first AMI in Beijing Anzhen hospital between 2007 and 2017 was performed. RESULTS: Mean LDL-C level was 2.82±0.97 mmol/L with the prevalence of elevated LDL-C being 21.6% (601/2,781). Of the study, only 4.2% were aware of their elevated LDL-C status. Neither mean LDL-C concentration nor prevalence of elevated LDL-C showed a downward trend between 2007 and 2017 (P>0.05). Patients aged <35 years had the highest LDL-C level and frequency of elevated LDL-C among the three age groups (aged <35, 35-39, and 40-44 years; P<0.01). Patients with LDL-C ≥3.4 mmol/L evinced a more than 50% increased risk of coronary artery stenosis compared with those with LDL-C <1.4 mmol/L [adjusted odds ratio (OR) 3.19; 95% confidence interval (CI): 1.62 to 6.29]. Of the study, 62.0% had at least two conventional risk factors (RFs), and smoking, accompanied by hypertension, obesity, or elevated LDL-C were the most common combinations. CONCLUSIONS: The current study provides an overview of trends in LDL-C level and elevated LDL-C among young adults at the time of first AMI. Patients had a high prevalence of elevated LDL-C but low awareness of this status. Coronary artery stenosis was positively correlated with LDL-C level. Preventive strategies, including public education regarding cholesterol levels and benefits of maintaining LDL-C below 3.4 mmol/L should be considered for young adults as a primary preventive strategy.

[Study on effect of gypenosides on insulin sensitivity of rats with diabetes mellitus via regulating NF-κB signaling pathway].

This study focused on the ameliorative effects of gypenosides(GPS) on insulin sensitivity and inflammatory factors in rats with type 2 diabetes mellitus(T2 DM) and explored their possible molecular mechanisms. After the successful establishment of T2 DM model, diabetic rats were randomly divided into four groups, including model group, GPS groups(200, 100 mg·kg~(-1)) and metformin group(100 mg·kg~(-1)), with healthy rats serving as the control. After 6-week intragastric administration, fasting blood glucose(FBG) and oral glucose tolerance were examined. The levels of insulin, C-peptide, tumor necrosis factor-α(TNF-α), interleukin-1ß(IL-1ß), interleukin-6(IL-6) and C-reactive protein(CRP) in serum were examined. Then the homeostasis model assessment of insulin resistance(HOMA-IR) and insulin sensitivity index(ISI) were calculated. The protein expression levels of phosphorylated insulin receptor substrate-1(p-IRS-1) and phosphorylated protein kinase B(p-Akt) in skeletal muscle were measured by Western blot, as well as those of phosphorylated inhibitor of nuclear factor-κB(NF-κB) kinase ß(p-IKKß), phosphorylated alpha inhibitor of NF-κB(p-IκBα) and phosphorylated p65 subunit of NF-κB(p-p65) in adipose tissue. The relative expression levels of glucose transporter 4(GLUT4) mRNA in skeletal muscle and NF-κB mRNA in adipose tissue were measured by qRT-PCR, and the morphological changes of pancreatic tissue were observed. Compared with the model group, the GPS groups witnessed significant decrease in FBG, marked amelioration of impaired oral glucose tolerance and significant increase in ISI. Further, the high-dose GPS group saw significantly reduced HOMA-IR, TNF-α, IL-1ß and CRP, significantly increased expression levels of p-IRS-1(Tyr), p-Akt and GLUT4, and markedly inhibited p-IRS-1(Ser), p-IKKß, p-IκBα, p-p65 and NF-κB. The concentration of CRP and the expression levels of p-IRS-1(Ser), p-IKKß, p-IκBα and NF-κB were remarkably reduced in the low-dose GPS group. However, GPS was found less effective in the regulation of serum insulin, C-peptide and IL-6 levels and the alleviation of pancreatic islet injury. The results indicated that GPS can reduce FBG and improve insulin sensitivity in diabetic rats possibly by regulating the NF-κB signaling pathway, inhibiting inflammation, and thereby regulating the expression of key proteins in the insulin signaling pathway.

Impact of Conventional Cardiovascular Risk Factors on Left Internal Mammary Artery Graft Disease.

BACKGROUND: The development of atherosclerosis was considered as the common cause of the stenosis of coronary artery grafts. Left internal mammary artery (LIMA) was the best artery graft for further effectiveness of coronary artery bypass grafting (CABG). We sought to assess the impact of known conventional cardiovascular risk factors (RFs) on LIMA graft stenosis. METHODS: A retrospective study including 618 participants, who had recurrence of chest pain after CABG, aged ≥18 years, hospitalized for coronary angiography in Beijing Anzhen hospital between 2010 and 2017 was performed. All the participants were confirmed to have LIMA graft. Multivariate analysis was conducted to determine the relationship between conventional RFs and LIMA graft stenosis. RESULTS: Of the study, 220 (35.6%) participants continued to smoke, 504 (81.6%) were overweight or obese, and 411 (66.5%) and 242 (39.2%) reported concomitant hypertension and diabetes, respectively. LIMA graft stenosis occurred in 161 participants (26.1%). Postoperative smoking, a CABG duration of ≥10 years and hyperglycemia without diabetes had an increased risk of LIMA graft stenosis, the odds ratio (OR) was 1.86 [95% confidence interval (CI): 1.26-2.78], 2.24 (95%CI:1.33-3.478), and 2.44(95% CI:1.39-4.32), respectively. Statin use (OR, 0.28; 95% CI: 0.25-0.5) and low-density lipoprotein cholesterol (LDL-C) < 1.8 mmol/L (OR, 0.27; 95% CI: 0.14-0.53) had a significantly decreased risk of LIMA graft stenosis. While, only 15.4% (95/618) achieved the target LDL-C level. CONCLUSIONS: Postoperative smoking and hyperglycemia without diabetes had an increased risk of LIMA graft stenosis. Statin use and LDL-C <1.8 mmol/L decreased the risk.

Pleosporalins H and I, two new heptaketides from the endophytic fungus Pleosporales sp. F46 by using OSMAC strategy.

Two new heptaketides, pleosporalins H and I (1 and 2), as well as seven biosynthetically related known polyketides (3-9) were isolated from the endophytic fungus, Pleosporales sp. F46 by employing the one strain-many compounds (OSMAC) approach. The planar, relative and absolute structures of these compounds were identified by extensive spectroscopic analysis including HRMS, NMR, optical rotations and ECD calculations. The cytotoxic efficiencies of all isolated compounds 1-9 were evaluated against four cancer cell lines A549, CT-26, MCF-7 and MDA-MB-231.

Gentianella acuta prevents acute myocardial infarction induced by isoproterenol in rats via inhibition of galectin-3/TLR4/MyD88/NF-кB inflammatory signalling.

Gentianella acuta (G. acuta), as a folk medicine, was used to treat heart disease by the Ewenki people in Inner Mongolia. However, the effect of G. acuta on acute myocardial infarction (AMI) is not clear. To explore the mechanisms of G. acuta on isoproterenol (ISO)-induced AMI, rats were administered G. acuta for 28 days, then injected intraperitoneally with ISO (85 mg/kg) on days 29 and 30. An electrocardiogram helped to evaluate the myocardial injury. Serum lactate dehydrogenase (LDH), creatinine kinase (CK) and aspartate aminotransferase (AST) levels were evaluated, and haematoxylin eosin, Masson's trichrome staining and terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) staining were used to detect myocardial histological changes. Radioimmunoassay was used to measure serum tumour necrosis factor alpha (TNFα) and interleukin (IL)-6. An enzyme-linked immunosorbent assay kit was used to analyse serum galectin-3 (Gal-3) levels. Immunohistochemistry, Western blotting and reverse transcription polymerase chain reaction were used to examine relevant molecular events. The results revealed that pre-treatment with G. acuta decreased the elevation in the ST segment; reduced serum LDH, CK and AST levels; alleviated cardiac structure disorder; and reduced inflammatory infiltration, abnormal collagen deposition and cardiomyocyte apoptosis that were induced by ISO. Furthermore, pre-treatment with G. acuta inhibited serum Gal-3 levels and Gal-3 expression in heart tissue, and also impeded TLR4/MyD88/NF-кB signalling activation, which ultimately prevented the expression of inflammatory cytokines. The study indicated that pre-treatment with G. acuta protects against ISO-induced AMI, and the protective role may be related to inhibiting Gal-3/TLR4/MyD88/NF-кB inflammatory signalling.

Effects of perfluorocarbon liquids in macular hole retinal detachment treatment.

OBJECTIVE: This study aims to evaluate the clinical efficacy and visual function prognosis of macular hole retinal detachment treatment for high myopia by inverting the internal limiting membrane to overlay the macular hole with the assistance of perfluorocarbon liquids. METHODS: A total of 55 high myopia patients, who received macular hole retinal detachment treatment from 2013 to 2016, were included in this study. Among these patients, 38 patients were assigned to the first group and 17 patients (perfluorocarbon liquids) were assigned to the second group. The second group was further divided into two subgroups, according to the overlaying layer number of the internal limiting membrane valve: A group (multiple layers) and B group (single layer). RESULTS: The success rate of the internal limiting membrane inversion and overlaying on the macular hole was 23.68% and 100% in the first and second group, respectively. The differences in macular hole closing rate and postoperative best-corrected visual acuity between these two groups were statistically significant (p < 0.05). Furthermore, the differences in macular morphology recovery between the A and B groups were also statistically significant (p = 0.004 < 0.05). CONCLUSION: Perfluorocarbon liquids play a positive role in the operation process of the internal limiting membrane.

Modified citrus pectin ameliorates myocardial fibrosis and inflammation via suppressing galectin-3 and TLR4/MyD88/NF-κB signaling pathway.

Myocardial fibrosis (MF) plays a key role in the development and progression of heart failure (HF) with limited effective therapies. Galectin-3 (Gal-3) is a biomarker associated with fibrosis and inflammation in patients with HF. The Gal-3 inhibitor modified citrus pectin (MCP) protects against cardiac dysfunction, though the underlying mechanism remains unclear. The aim of this study was to investigate the effect and mechanism of MCP on MF using an isoproterenol (ISO)-induced rat model of HF. Cardiac function was analyzed by echocardiography and electrocardiography. Histopathological changes in the heart tissue were assessed by hematoxylin-eosin and Masson trichrome staining. The mRNA and protein expression levels of signaling molecules and pro-inflammatory cytokines were monitored by immunohistochemistry, western blot, qRT-PCR and ELISA analyses. The results demonstrated that MCP ameliorated cardiac dysfunction, decreased myocardial injury and reduced collagen deposition. Furthermore, MCP downregulated the expression of Gal-3, TLR4 and MyD88, thereby inhibiting NF-κB-p65 activation. MCP also decreased the expression of IL-1ß, IL-18 and TNF-α, which have been implicated in the pathogenesis of HF. These inhibitory effects were observed on day 15 and continued until day 22. Taken together, these results suggest that MCP ameliorates cardiac dysfunction through inhibiting inflammation and MF. These effects may be through downregulating Gal-3 expression and suppressing activation of the TLR4/MyD88/NF-κB signaling pathway. The present study supports the use of Gal-3 as a therapeutic target for the treatment of MF after myocardial infarction.

[Metallic Elemental Analysis of Tibetan Herbal Medicines and Tibetan Medicine Preparations by Synchrotron Radiation X-Ray Fluorescence].

To discuss the relationship between metallic element and disease through determine the elementals in Tibetan Herbal Medicines and Tibetan Medicine Preparations that have obvious effect on hepatobiliary diseases by Synchrotron Radiation X-ray Source, then to reveal the substance foundation of pharmacological action. The results show that all the Tibetan Herbal Medicines used in the experiment have the 9 kinds of metallic elements of potassium(K), calcium(Ca), titanium(Ti), vanadium(V), chromium(Cr), manganese(Mn), ferrum(Fe), zinc(Zn) and lead(Pb), the content of the elements are in the ppb or ppm level though the element constitute and the content have obvious difference. Tibetan Medicine Preparations have another 6 kinds of metallic elements of nickel(Ni), copper(Cu), rubidium(Rb), mercury(Hg), cobalt(Co), gallium(Ga) and 1 kind of nonmetallic elements of arsenic(As) when compare with Herbal Medicines, and the element constitute and the content also have obvious difference. Take advantage of SR-XRF, the test gets the basic data of elements of Tibetan Herbal Medicines and Preparations, supply the scientific support to discuss the interaction of pharmacological mechanism and the metallic elements, and find the suitability of the technique for the metallic elements detection in Tibetan Medicines.

Comparison of glycemic variability and glycated hemoglobin as risk factors of coronary artery disease in patients with undiagnosed diabetes.

BACKGROUND: The role of chronic hyperglycaemia as a coronary artery disease (CAD) risk factor is well-known, and the glycemic variability is still a matter of debate. The aim of this study was to investigate the association of admission glycemic excursion and hemoglobin A(1c) (HbA(1c)) with the presence and severity of CAD in patients with undiagnosed diabetes mellitus (DM). METHODS: We studied 286 newly diagnosed DM patients without prior revascularization undergoing coronary angiography for suspected ischaemic chest pain. Patients were grouped into those with CAD and without CAD according to angiographic results. The severity of CAD was assessed using the Gensini score. Glycemic variability, indicated as the mean amplitude of glycemic excursions (MAGE), was determined by a continuous glucose monitoring system. Serum levels of HbA(1c) and high-sensitive C-reactive protein (hs-CRP) as well as plasma concentrations of fasting glucose, lipids and creatinine were measured in all patients. Predictors of CAD were determined using multivariate Logistic regression model and receiver-operating characteristic (ROC) curves. RESULTS: The newly diagnosed DM patients with CAD were older, and more were male and current cigarette smokers compared with the patients without CAD. The CAD group had significantly higher levels of MAGE and HbA(1c). Individuals with high levels of HbA(1c) (≥ 7%) or MAGE (≥ 3.4 mmol/L) had also significantly higher CAD prevalence. Logistic regression analysis revealed that high MAGE level and high HbA(1c) level were independent predictors for CAD. The area under the receiver-operating characteristic curve for MAGE (0.606, P = 0.005) was superior to that for HbA(1c) (0.582, P = 0.028). Gensini score closely correlated with age, MAGE, HbA(1c), hs-CRP, creatinine and total cholesterol. Multivariate analysis indicated that age (P < 0.001), MAGE (P < 0.001), HbA(1c) (P = 0.022) and hs-CRP (P = 0.005) were independent determinants for Gensini score. CONCLUSIONS: Both admission glycemic excursion and chronic hyperglycaemia are associated with the severity of CAD in newly diagnosed DM patients. MAGE displays a significant value in predicting CAD in patients with undiagnosed diabetes even more than HbA(1c).