Advances in targeted therapy for pulmonary arterial hypertension in children.

Pulmonary arterial hypertension (PAH) is a rare and devastating disease of the pulmonary vasculature with a high morbidity and mortality rate in infants and children. Currently, treatment approaches are mostly based on adult guidelines and pediatrician clinical experience, focusing on specific pulmonary antihypertensive therapy and conventional supportive care. The advent of targeted drugs has led to significant advances in the treatment of PAH in children, including endothelin receptor antagonists, phosphodiesterase type 5 inhibitors, and prostacyclins, which have been studied and proven to improve hemodynamics and functional class in children PAH. A new targeted drug, riociguat, is assessing its safety and efficacy in clinical trials. However, more randomized controlled studies are needed to evaluate the combination of drugs, treatment strategies, and clinical endpoints of targeted therapy in children PAH. In this review, we summarize the research advances of PAH-targeted therapy in children over the last decade in order to provide a theoretical basis for future studies. CONCLUSION: Pulmonary arterial hypertension (PAH) is a rare and devastating pulmonary vascular disease that is associated with a variety of diseases of any age in childhood onset. WHAT IS KNOWN: • Therapeutic strategies for targeted drugs for PAH in children are based almost exclusively on data from adult studies and clinical experience of pediatric specialists. • Due to the complex etiology of PAH in children and the relative lack of clinical trial data, the selection of appropriate targeted drug therapy remains difficult. WHAT IS NEW: • We redefine the definition of pulmonary arterial hypertension in children and summarize the progress of targeted therapy of pulmonary arterial hypertension in children in the past ten years. • The dosage and adverse reactions were summarized, and the mechanism of action was drawn according to the available targeted drugs. It can provide theoretical support for the development of guidelines and treatment strategies for the diagnosis and treatment of pulmonary arterial hypertension in children.

The Mechanism of the Photostability Enhancement of Thin-Film Transistors Based on Solution-Processed Oxide Semiconductors Doped with Tetravalent Lanthanides.

The applications of thin-film transistors (TFTs) based on oxide semiconductors are limited due to instability under negative bias illumination stress (NBIS). Here, we report TFTs based on solution-processed In2O3 semiconductors doped with Pr4+ or Tb4+, which can effectively improve the NBIS stability. The differences between the Pr4+-doped In2O3 (Pr:In2O3) and Tb4+-doped In2O3 (Tb:In2O3) are investigated in detail. The undoped In2O3 TFTs with different annealing temperatures exhibit poor NBIS stability with serious turn-on voltage shift (ΔVon). After doping with Pr4+/Tb4+, the TFTs show greatly improved NBIS stability. As the annealing temperature increases, the Pr:In2O3 TFTs have poorer NBIS stability (ΔVon are -3.2, -4.8, and -4.8 V for annealing temperature of 300, 350, and 400 °C, respectively), while the Tb:In2O3 TFTs have better NBIS stability (ΔVon are -3.6, -3.6, and -1.2 V for annealing temperature of 300, 350, and 400 ℃, respectively). Further studies reveal that the improvement of the NBIS stability of the Pr4+/Tb4+:In2O3 TFTs is attributed to the absorption of the illuminated light by the Pr/Tb4fn-O2p6 to Pr/Tb 4fn+1-O2p5 charge transfer (CT) transition and downconversion of the light to nonradiative transition with a relatively short relaxation time compared to the ionization process of the oxygen vacancies. The higher NBIS stability of Tb:In2O3 TFTs compared to Pr:In2O3 TFTs is ascribed to the smaller ion radius of Tb4+ and the lower energy level of Tb 4f7 with a isotropic half-full configuration compared to that of Pr 4f1, which would make it easier for the Tb4+ to absorb the visible light than the Pr4+.

An update on the economic burden of type 2 diabetes mellitus in China.

OBJECTIVES: This study aims to update the statistics on the economic burden of T2DM and to identify the factors affecting the economic costs of T2DM in China. METHODS: This study conducts a systematic review of the existing literature that has reported on the direct economic costs (mainly the direct medical resource consumption) and indirect economic costs (mainly non-medical costs and intangible costs) of T2DM as of 31 May 2019. RESULTS: The total expenditure on diabetes in China's western region is still relatively low. Additionally, the mean direct costs of T2DM are high in China's northern urban areas. However, compared to urban areas, in rural areas, the largest proportion of the total economic costs of T2DM is the mean indirect costs. Furthermore, age, sex, type and number of complications, type of medical insurance, diabetes duration, level of education, and income are the primary factors that influence the economic burden of T2DM. CONCLUSION: There is a considerable economic burden associated with T2DM in China. Therefore, to address the economic burden of T2DM, it is vital to take measures to reduce the prevalence rate of diabetes.

Impact on decision making framework for medicine purchasing in Chinese public hospital decision-making: determining the value of five dipeptidyl peptidase 4 (DPP-4) inhibitors.

BACKGROUND: Medicine purchasing in Chinese public hospitals is decided by the hospital Pharmacy Management Committee (PMC), that is complex, subjective and requires efficient approaches to ensure transparency and consistency for the factors being considered. This study aimed to use the Evidence and Value: Impact on Decision Making (EVIDEM) framework to assess medicine in these hospitals. In this study anti-diabetic drugs DPP-4 inhibitors, which work by inhibiting the activation of the Dipeptidyl Peptidase 4 (DPP-4) inhibitors, were appraised. METHODS: Following EVIDEM methodology (EVIDEM-10th), we convened an appraisal group and asked each individual to express their perspectives by assigning weights to each criterion. A systematic literature search for information of each criterion of five DPP-4 inhibitors was completed. Then the appraisal group scored for each criterion of the five DPP-4 inhibitors. The estimated value of the five DPP-4 inhibitors was obtained by Multi-Criteria Decision Analysis (MCDA) which combined individual weighting of each criterion with individual scoring for each intervention in each criterion. RESULTS: By assigning weights, the most important criterion was the quality of evidence (4.01±0.52), and that the comparative cost consequences-non-medical cost was the least important criterion (2.87±1.03). Criteria included disease severity, size of the affected population, comparative effectiveness, type of therapeutic/preventive benefit and cost of intervention, all of which were assigned the same weight of 3.58. After MCDA, the overall value orders for each DPP-4 inhibitor included Sitagliptin (0.45), Linagliptin (0.44), Vildagliptin (0.43), Alogliptin (0.42) and Saxagliptin (0.40). CONCLUSIONS: Based on EVIDEM framework and MCDA, we found that overall value of five DPP-4 inhibitors was similar. It is feasible to use the EVIDEM framework and MCDA in purchasing medicine for Chinese public hospitals.

Salvianolic acid A alleviates chronic ethanol-induced liver injury via promotion of ß-catenin nuclear accumulation by restoring SIRT1 in rats.

In recent years, alcoholic liver disease (ALD) has emerged as a growing public health problem worldwide. ß-catenin plays an important role in the growth, development, regeneration and metabolic activity of the liver. Salvianolic acid A (SalA) is a water-soluble component from the root extract of Salvia miltiorrhiza Bunge, and its effect on ALD has not yet been investigated. This study aimed to investigate the effect of SalA on chronic alcohol-induced liver injury and to explore the role of SIRT1-mediated ß-catenin deacetylation in such an effect. In this study, SalA treatment significantly alleviated the accumulation of lipid droplets and reduced the plasma alanine aminotransferase (ALT), aspartate aminotransferase (AST), total cholesterol (TC), triglyceride (TG), alcohol and ammonia levels in rats. SalA enhanced ethanol and ammonia metabolism and maintained mitochondrial homeostasis. Moreover, SalA restored the activity of the major ethanol-metabolizing enzymes and oxidative stress functions in the liver. Importantly, we found that SalA treatment effectively inhibited the ethanol-mediated decrease in nuclear ß-catenin by upregulating SIRT1 in the liver. SIRT1 then deacetylated ß-catenin to promote its accumulation in the nucleus, thereby preventing alcohol-induced liver injury. The results demonstrate that the SIRT1/ß-catenin pathway is a key therapeutic target in liver injury caused by chronic alcohol exposure and that SalA protects against alcohol-induced liver injury via the SIRT1-mediated deacetylation of ß-catenin.

Carnosic acid prevents COL1A2 transcription through the reduction of Smad3 acetylation via the AMPKα1/SIRT1 pathway.

Carnosic acid (CA), a major bioactive component in rosemary extract, has many biological and pharmaceutical activities. Smad3 acetylation can regulate the transcription of type I α2 collagen (COL1A2), which is the major component of the extracellular matrix (ECM). The aim of the current study was to evaluate whether CA inhibits COL1A2 transcription via the reduction of Smad3 acetylation against liver fibrosis. The results showed that CA treatment significantly suppressed COL1A2 transcription and markedly decreased the deposition of ECM induced by dimethylamine (DMN) in rats. Importantly, the suppression of COL1A2 transcription following CA treatment depended on the reduction of Smad3 acetylation via the activation of Sirtuin 1 (SIRT1), a nicotinamide adenine dinucleotide+ (NAD+)-dependent deacetylase. SIRT1 siRNA increased the acetylation of Smad3 and blocked CA-down-regulated Smad3 deacetylation. Notably, CA-mediated AMP-activated protein kinase-α1 (AMPKα1) activation not only increased AMPKα1 phosphorylation but also increased SIRT1 expression, thus leading to a significant reduction in Smad3 acetylation. Furthermore, CA-mediated SIRT1 activation was inhibited by AMPKα1 siRNA. Collectively, CA can inhibit the transcription of COL1A2 through SIRT1-mediated Smad3 deacetylation, and the activation of SIRT1 by CA involves the AMPKα1/SIRT1 pathway in liver fibrosis.

Carnosic acid protects non-alcoholic fatty liver-induced dopaminergic neuron injury in rats.

Non-alcoholic fatty liver disease (NAFLD) has been reported to induce cognitive impairments of hippocampus and may influence central nervous system. In the present study, we investigated whether carnosic acid (CA) ameliorates dopaminergic neuron injury in a rat model of NAFLD. In order to induce NAFLD, rats were fed with high-fat diet (HFD) for 10 weeks. We found that continued CA administration reduced lipid accumulation marked by decreases in alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride (TG), total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels, and an increase in high-density lipoprotein cholesterol (HDL-C) level in the serum. H&E staining revealed that feeding CA reduced lipid droplets accumulation, and alleviated oxidative stress by increasing in superoxide dismutase (SOD) level and decreasing in malondialdehyde (MDA) level in the liver. In addition, by measuring several parameters of gait analysis, we demonstrated that CA treatment ameliorated behavioral impairments, as evidenced by decreased duration and maximum variation, accompanied by increased average speed and cadence. Furthermore, CA treated-animals displayed an increase in the contents of dopamine (DA) and its metabolites 3,4-dihydroxyphenylacelic acid (DOPAC) and elevated the expressions of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra (SN) as well as the TH protein in the striatum. Together, these findings suggest that CA may be an effective agent in protecting rats from NAFLD-induced dopaminergic neuron injury.

Salvianolic acid B protects against chronic alcoholic liver injury via SIRT1-mediated inhibition of CRP and ChREBP in rats.

Salvianolic acid B (SalB), a water-soluble polyphenol extracted from Radix Salvia miltiorrhiza, has been reported to possess many pharmacological activities. This study investigated the hepatoprotective effects of SalB in chronic alcoholic liver disease (ALD) and explored the related signaling mechanisms. In vivo, SalB treatment significantly attenuated ethanol-induced liver injury by blocking the elevation of serum aminotransferase activities and markedly decreased hepatic lipid accumulation by reducing serum and liver triglyceride (TG) and total cholesterol (TC) levels. Moreover, SalB treatment ameliorated ethanol-induced hepatic inflammation by decreasing the levels of hepatotoxic cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). Importantly, SalB pretreatment significantly increased the expression of SIRT1 and downregulated the expression of inflammatory mediator C-reactive protein (CRP) and lipoprotein carbohydrate response element-binding protein (ChREBP). In vitro, SalB significantly reversed ethanol-induced down-regulation of SIRT1 and increased CRP and ChREBP expression. Interestingly, the effects of SalB on SIRT1, CRP and ChREBP were mostly abolished by treatment with either SIRT1 siRNA or EX527, a specific inhibitor of SIRT1, indicating that SalB decreased CRP and ChREBP expression by activating SIRT1. SalB exerted anti-steatotic and anti-inflammatory effects against alcoholic liver injury by inducing SIRT1-mediated inhibition of CRP and ChREBP expression.

New insights into salvianolic acid A action: Regulation of the TXNIP/NLRP3 and TXNIP/ChREBP pathways ameliorates HFD-induced NAFLD in rats.

Salvianolic acid A (SalA), one of the most efficacious polyphenol compounds extracted from Radix Salvia miltiorrhiza (Danshen), has been shown to possess many potential pharmacological activities. This study aimed to investigate whether SalA has hepatoprotective effects against high-fat diet (HFD)-induced non-alcoholic fatty liver disease (NAFLD) and to further explore the mechanism underlying this process. SalA treatment significantly attenuated HFD-induced obesity and liver injury, and markedly decreased lipid accumulation in HFD-fed rat livers. Moreover, SalA treatment ameliorated HFD-induced hepatic inflammation and oxidative stress by decreasing hepatotoxic levels of cytokines, suppressing the overproduction of reactive oxygen species (ROS) and methane dicarboxylic aldehyde (MDA) and preventing the decreased expression of superoxide dismutase (SOD). Importantly, SalA reversed the HFD- or palmitic acid (PA)-induced activation of the NLRP3 inflammasome, the nuclear translocation of ChREBP and the up-regulation of FAS, and these effects were accompanied by TXNIP down-regulation. However, TXNIP siRNA treatment partially abrogated the above-mentioned effects of SalA in PA-treated HepG2 cells. Together, our results demonstrated, for the first time, that SalA protects against HFD-induced NAFLD by ameliorating hepatic lipid accumulation and inflammation, and these protective effects may partially due to regulation of the TXNIP/NLRP3 and TXNIP/ChREBP pathways.

Carnosic acid alleviates chronic alcoholic liver injury by regulating the SIRT1/ChREBP and SIRT1/p66shc pathways in rats.

SCOPE: Carnosic acid (CA), which is extracted from rosemary, displays multiple pharmacological activities. This study aimed to investigate the effects of CA on chronic alcoholic liver injury and to elucidate the related mechanisms. METHODS AND RESULTS: An in vivo rat model was established by feeding rats a liquid diet containing ethanol, and an in vitro model was created by treating HepG2 cells with 100 mM ethanol for 48 h. In the rat model of alcohol-induced liver injury, CA significantly decreased serum aminotransferase, triglyceride and total cholesterol levels. Additionally, CA inhibited oxidative stress, inflammation, and cell death. Interestingly, CA activated SIRT1, which was associated with the downregulation of lipoprotein carbohydrate response element-binding protein (ChREBP) and growth factor adapter protein (p66shc). In HepG2 cells, ethanol-induced cell injury was associated with decreased SIRT1 and increased ChREBP and p66shc protein expression. These changes were reversed by CA but enhanced by a specific SIRT1 inhibitor, EX527. Moreover, the effects of CA on SIRT1, ChREBP, and p66shc were abolished by SIRT1 siRNA or EX527, indicating that CA decreased ChREBP and p66shc expression via SIRT1 activation. CONCLUSION: CA exerted protective effects against alcoholic liver injury by activating the SIRT1/ChREBP and SIRT1/p66shc pathways, which are related to the anti-steatosis, anti-oxidant, and anti-apoptosis effects.