This work was undertaken to investigate comparative effect of AT1 receptor blocker (ARB), 3-hydroxy-3-methylglutaryl (HMG) coenzymeA (CoA) reductase inhibitor (statin), and their combination on ...vascular injury of salt-sensitive hypertension.
Salt-loaded Dahl salt-sensitive hypertensive rats (DS rats) were treated with (1) vehicle, (2) hydralazine (5 mg/kg/d), (3) olmesartan (0.5 mg/kg/d), (4) pravastatin (100 mg/kg/d), and (5) combined olmesartan and pravastatin for 4 weeks. Olmesartan or pravastatin significantly and comparably improved vascular endothelium-dependent relaxation to acetylcholine, coronary arterial remodeling, and eNOS activity of DS rats. Olmesartan prevented vascular eNOS dimer disruption or the downregulation of dihydrofolate reductase (DHFR) more than pravastatin, whereas Akt phosphorylation was enhanced by pravastatin but not olmesartan, indicating differential pleiotropic effects between olmesartan and pravastatin. Add-on pravastatin significantly enhanced the improvement of vascular endothelial dysfunction and remodeling by olmesartan in DS rats. Moreover, pravastatin enhanced the increase in eNOS activity by olmesartan, being associated with additive effects of pravastatin on phosphorylation of Akt and eNOS.
Olmesartan and pravastatin exerted beneficial vascular effects in salt-sensitive hypertension, via differential pleiotropic effects. Pravastatin enhanced vascular protective effects of olmesartan. Thus, the combination of ARB with statin may be the potential therapeutic strategy for vascular diseases of salt-sensitive hypertension.
Objective The co-occurrence of kidney disease in patients with type 2 diabetes (T2D) is a major public health challenge. Although early detection and intervention can prevent or slow down the ...progression, the commonly used estimated glomerular filtration rate (eGFR) based on serum creatinine may be influenced by factors unrelated to kidney function. Therefore, there is a need to identify novel biomarkers that can more accurately assess renal function in T2D patients. In this study, we employed an interpretable machine-learning framework to identify plasma metabolomic features associated with GFR in T2D patients. Methods We retrieved 1626 patients with type 2 diabetes (T2D) in Liaoning Medical University First Affiliated Hospital (LMUFAH) as a development cohort and 716 T2D patients in Second Affiliated Hospital of Dalian Medical University (SAHDMU) as an external validation cohort. The metabolite features were screened by the orthogonal partial least squares discriminant analysis (OPLS-DA). We compared machine learning prediction methods, including logistic regression (LR), support vector machine (SVM), random forest (RF), and eXtreme Gradient Boosting (XGBoost). The Shapley Additive exPlanations (SHAP) were used to explain the optimal model. Results For T2D patients, compared with the normal or elevated eGFR group, glutarylcarnitine (C5DC) and decanoylcarnitine (C10) were significantly elevated in GFR mild reduction group, and citrulline and 9 acylcarnitines were also elevated significantly (FDR<0.05, FC > 1.2 and VIP > 1) in moderate or severe reduction group. The XGBoost model with metabolites had the best performance: in the internal validate dataset (AUROC=0.90, AUPRC=0.65, BS=0.064) and external validate cohort (AUROC=0.970, AUPRC=0.857, BS=0.046). Through the SHAP method, we found that C5DC higher than 0.1μmol/L, Cit higher than 26 μmol/L, triglyceride higher than 2 mmol/L, age greater than 65 years old, and duration of T2D more than 10 years were associated with reduced GFR. Conclusion Elevated plasma levels of citrulline and a panel of acylcarnitines were associated with reduced GFR in T2D patients, independent of other conventional risk factors.
Smoking is the biggest risk factor for lung cancer. Smokers have a much higher chance of developing lung tumors with a worse survival rate; however, non-smokers also develop lung tumors. A number of ...questions remain including the underlying difference between smoker and non-smoker lung cancer patients and the involvement of genetic and epigenetic processes in tumor development. The present study analyzed the mutation data of 100 non-small cell lung cancer (NSCLC) patients, 12 non-smokers, 48 ex-smokers and 40 smokers, from Tracking Non-Small Cell Lung Cancer Evolution through Therapy Consortium. A total of 68 genes exhibited different mutation patterns across non-smokers, ex-smokers and smokers. A number of these 68 genes encode membrane proteins with biological regulation, metabolic process, and response to stimulus functions. For each group of patients, the top 10 most frequently mutated genes were selected and their oncogenetic tree inferred, which reflected how the genes evolve during tumor genesis. By comparing the oncogenetic trees of non-smokers and smokers, it was identified that in non-smokers, the mutation of epidermal growth factor receptor (EGFR) was an early genetic alteration event and EGFR was the key driver, but in smokers, the mutation of titin (TTN) was more important. Based on network analysis, TTN can interact with spectrin a erythrocytic 1 through calmodulin 2 and troponin C1. These genetic differences during tumorigenesis of non-smoker and smoker lung cancer patients provided novel insights into the effects of smoking on the evolutionary trajectory of non-small cell lung cancer and may prove helpful for targeted therapy of different lung cancer subtypes. Key words: smoking, evolutionary trajectories, non-small cell lung cancer
This work is concerned with a mixed boundary value problem for a semilinear parabolic equation with a memory term. Under suitable conditions, we prove that the energy functional decays to zero as the ...time tends to infinity by the method of perturbation energy, in which the usual exponential and polynomial decay results are only special cases.
This paper is devoted to proving some new nonexistence theorems for a class of quasilinear parabolic differential inequalities with a singular potential term and nonlocal source term in the case of ...homogeneous and non-homogeneous by the test function method.
In order to obtain large-area titanium-steel cladding plate by vacuum rolling, the manufacturing process was discussed with the Hypermesh/LS-DYNA simulation software. The result showed that the ...reduction rates of each rolling pass were 20, 25 and 33%, respectively. And the total rate was 60%. Moreover, the vacuum rolling process mainly included the following steps: welding preparation, drilling vacuum holes, composite and assembly, vacuum extraction, accumulative seal welding, preheating and rolling. The final size of the cladding plate was 1650 × 12000 × (4 + 40) mm. It could be found that the vacuum rolling interface of the titanium-steel cladding plate was mainly divided into four parts: steel layer (I), decarburized layer (II), bonding layer (III) and titanium layer (IV). Acicular widmanstatten structure of β-titanium was formed in zone IV, which might reduce the impact toughness of joint. The microhardness test results showed that the hardness near the interface was relatively high. Macroscopically, the average shear strength (297 MPa) and the average tensile strength (590 MPa) were both much higher than the standard. However, the brittle fracture mode of shear specimens might decrease the joint property of vacuum rolling cladding plate.
Aim： TPN729MA is a novel selective PDE5 inhibitor currently under clinical development in China for the treatment of erectile dysfunction. In this study we characterized its preclinical ...pharmacokinetics （PK） and predict its human PK using a physiologically based pharmacokinetic （PBPK） model. Methods： The preclinical PK of TPN729MA was studied in rats and dogs. Human clearance （CL） values for TPN729MA were predicted from various allometric methods and from intrinsic CL determined in human liver microsomes. Human PK and plasma concentration versus time profiles of TPN729MA were predicted by using a PBPK model in GastroPlus. Considering the uncertainties in the prediction, a preliminary human study was conducted in 3 healthy male volunteers with an oral dose of 25 mg. Results： After a single intravenous administration of TPN729MA at a dose of i mg/kg in rats and 3 mg/kg in dogs, the plasma CL was 69.7 mL·min-1·kg-1 in rats and 26.3 mL·min-1·kg-1 in dogs, and the steady-state volumes of distribution （Vss） were 7.35 L/kg in rats and 6.48 L/kg in dogs. The oral bioavailability of TPN729MA was 10% in rats and above 34% in dogs. Profiles of predicted plasma concentration versus time were similar to those observed in humans at 25 rag, and the predicted Tmax, Cmax and AUC values were within 2-fold of the observed values. Conclusion： TPN729MA demonstrates good preclinical PK. This compound is a valuable candidate for further clinical development. This study shows the benefits of using a PBPK model to predict PK in humans.
We investigate the blow-up phenomena for a porous medium equation with weighted nonlocal source and inner absorption terms subject to null Dirichlet boundary condition. Based on a modified ...differential inequality technique, we establish some sufficient conditions to guarantee the existence of non-global solutions to the model and also derive the upper bounds for the blow-up time. Moreover, the lower bounds for the blow-up time are obtained under some appropriate measure in the whole-dimensional space (
N
≥
1
).
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