Luteolin-7-diglucuronide, a novel PTP1B inhibitor, ameliorates hepatic stellate cell activation and liver fibrosis in mice.

Liver fibrosis, one of the leading causes of morbidity and mortality worldwide, lacks effective therapy. The activation of hepatic stellate cells (HSCs) is the dominant event in hepatic fibrogenesis. Luteolin-7-diglucuronide (L7DG) is the major flavonoid extracted from Perilla frutescens and Verbena officinalis. Their beneficial effects in the treatment of liver diseases were well documented. In this study we investigated the anti-fibrotic activities of L7DG and the potential mechanisms. We established TGF-ß1-activated mouse primary hepatic stellate cells (pHSCs) and human HSC line LX-2 as in vitro liver fibrosis models. Co-treatment with L7DG (5, 20, 50 µM) dose-dependently decreased TGF-ß1-induced expression of fibrotic markers collagen 1, α-SMA and fibronectin. In liver fibrosis mouse models induced by CCl4 challenge alone or in combination with HFHC diet, administration of L7DG (40, 150 mg·kg-1·d-1, i.g., for 4 or 8 weeks) dose-dependently attenuated hepatic histopathological injury and collagen accumulation, decreased expression of fibrogenic genes. By conducting target prediction, molecular docking and enzyme activity detection, we identified L7DG as a potent inhibitor of protein tyrosine phosphatase 1B (PTP1B) with an IC50 value of 2.10 µM. Further studies revealed that L7DG inhibited PTP1B activity, up-regulated AMPK phosphorylation and subsequently inhibited HSC activation. This study demonstrates that the phytochemical L7DG may be a potential therapeutic candidate for the treatment of liver fibrosis.

[Establishment and content validity assessment of evaluation index system for development value of traditional Chinese medicine preparations in medical institutions].

The development of traditional Chinese medicine(TCM) preparations as an incubator for new drugs in medical institutions has flourished, while an evaluation index system remains to be established for comprehensively assessing the development value of these prescriptions. This study established an item pool through literature research, employed the Delphi method to determine the content of evaluation indexes, and adopted the superiority chart to determine the weight of each index. Two-level evaluation index system for the development value of TCM preparations in medical institutions was established, which included 7 first-level items and 36 se-cond-level items, demonstrating scientific validity. The first-level items(weight) were inheritance(10.61%), effectiveness(23.22%), safety(22.71%), innovation(13.21%), economy(10.00%), suitability(8.57%), and accessibility(11.68%). The top three second-level items in terms of weight distribution were adverse reaction monitoring(6.73%), evidence of therapeutic effect(5.71%), and clinical response rate(4.75%). The bottom three second-level items were production advantages(0.86%), medicinal dosage(0.48%), and medicinal smell or taste(0.18%). The content validity of the established system was assessed, which revealed that the index system was reliable, with the overall and average content validity indexes of 0.47 and 0.90, respectively. Furthermore, the established evaluation index system was used to evaluate six TCM preparations in a city-level hospital of TCM in Sichuan Province, which demonstrated that the system had operability. The results indicate that the evaluation index system is scientific, reliable, and operable, providing a reference for developers to selectively develop TCM preparations in medical institutions. In practical application, the system can be adjusted regarding the index weights according to actual conditions.

Predicting angiographic coronary artery disease using machine learning and high-frequency QRS.

AIM: Exercise stress ECG is a common diagnostic test for stable coronary artery disease, but its sensitivity and specificity need to be further improved. In this paper, we construct a machine learning model for the prediction of angiographic coronary artery disease by HFQRS analysis of cycling exercise ECG. METHODS AND RESULTS: This study prospectively included 140 inpatients and 59 healthy volunteers undergoing cycling exercise ECG. The CHD group (N=104) and non-CHD group (N=95) were determined by coronary angiography gold standard. Automated HF QRS analysis was performed by the blinded method. The coronary group was predominantly male, with a higher prevalence of age, BMI, hypertension, and diabetes than the non-coronary group ( P < 0.001 ), higher lipid levels in the coronary group ( P < 0.005 ), significantly longer QRS duration during exercise testing ( P < 0.005 ), more positive leads ( P < 0.001 ), and a greater proportion of significant changes in HFQRS ( P < 0.001 ). Age, Gender, Hypertension, Diabetes, and HF QRS Conclusions were screened by correlation analysis and multifactorial retrospective analysis to construct the machine learning models of the XGBoost Classifier, Logistic Regression, LightGBM Classifier, RandomForest Classifier, Artificial Neural Network and Support Vector Machine, respectively. CONCLUSION: Male, elderly, with hypertension, diabetes mellitus, and positive exercise stress test HFQRS conclusions suggested a high risk of CHD. The best performance of the Logistic Regression model was compared, and a column line graph for assessing the risk of CHD was further developed and validated.

[Research progress on curcumin improving chronic low-grade inflammation and related diseases].

Chronic low-grade inflammation(CLGI), a relatively new concept without a clear definition, refers to a nonspecific, chronic, continuous, and low-grade inflammation state, and it is closely associated with various chronic diseases, including obesity, inflammatory bowel disease, neurodegenerative diseases, and tumors. Improvement of CLGI can slow down disease progression. Anti-inflammatory treatment is an important strategy for prevention and treatment of CLGI. However, there is currently no definitive drug treatment method. Curcumin is a polyphenolic compound extracted from the rhizome of zingiberaceae, with significant anti-inflammatory activity. Research has shown that curcumin can play an anti-inflammatory role by regulating NF-κB, JAK/STAT, PI3K/Akt, MAPK, NLRP3 inflammasome, Nrf2/ARE, and other inflammation-related pathways. This paper summarized the anti-inflammatory mechanisms, pharmacological effect, and clinical application of curcumin in improving CLGI and other diseases, so as to provide a reference for in-depth research and clinical application of curcumin in improving CLGI.

Quercetin Ameliorates Myocardial Injury in Diabetic Rats by Regulating Autophagy and Apoptosis through AMPK/mTOR Signaling Pathway.

A high-glucose environment is involved in the progression of diabetes mellitus (DM). This study aims to explore the regulatory effects of quercetin (QUE) on autophagy and apoptosis after myocardial injury in rats with DM. The type 2 DM rat models were constructed using low-dose streptozotocin (STZ) treatment combined with a high-carbohydrate (HC) diet in vivo. Compared with the control group, the body weight was decreased, whereas blood pressure, blood glucose, and the LVW/BW ratio were increased in the diabetic group. The results showed that the myocardial fibers were disordered in the diabetic group. Moreover, we found that the myocardial collagen fibers, PAS-positive cells, and apoptosis were increased, whereas the mitochondrial structure was destroyed and autophagic vacuoles were significantly reduced in the diabetic group compared with the control group. The expression levels of autophagy-related proteins LC3 and Beclin1 were decreased, whereas the expression levels of P62, Caspae-3, and Bax/Bcl-2 were increased in the diabetic group in vitro and in vivo. Moreover, QUE treatment alleviated the cellular oxidative stress reaction under high-glucose environments. The results of immunoprecipitation (IP) showed that the autophagy protein Beclin1 was bound to Bcl-2, and the binding capacity increased in the HG group, whereas it decreased after QUE treatment, suggesting that QUE inhibited the binding capacity between Beclin1 and Bcl-2, thus leading to the preservation of Beclin1-induced autophagy. In addition, the blood pressure, blood glucose, and cardiac function of rats were improved following QUE treatment. In conclusion, QUE suppressed diabetic myocardial injury and ameliorated cardiac function by regulating myocardial autophagy and inhibition of apoptosis in diabetes through the AMPK/mTOR signaling pathway.

Resveratrol inhibits ferroptosis and decelerates heart failure progression via Sirt1/p53 pathway activation.

Resveratrol is an organic compound widely studied for its therapeutic uses. We investigated whether resveratrol exerts cardioprotective effects by inhibiting ferroptosis via the Sirt1/p53 pathway. A heart failure model was established by aortic coarctation in Sirt1 knockout mice. The superoxide dismutase (SOD), glutathione (GSH) levels and mitochondrial morphology in murine heart tissues were assessed at different time points to determine the role of ferroptosis in heart failure progression. The cardiac function of mice with heart failure was evaluated by determining the brain natriuretic peptide (BNP) and sST2 concentration and conducting echocardiography. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were transfected with the p53 K382R mutant and Sirt1 interference lentiviral vectors. Immunoprecipitation (IP) experiments were performed to investigate whether Sirt1 influences ferroptosis via p53 K382 acetylation and SLC7A11 expression modulation. Resveratrol improved cardiac function in mice and decelerated ferroptosis and fibrosis progression in heart failure. However, the ability of resveratrol to prevent ferroptosis and treat heart failure was lost after silencing Sirt1. Sirt1 reduced ferroptosis by diminishing the levels of p53 K382 acetylation, reducing the degradation of SLC7A11, and increasing the levels of GSH and glutathione peroxidase 4 (GPX4) in cells. In conclusion, by activating the Sirt1/p53 pathway in heart failure, resveratrol decreased the depletion of SLC7A11, inhibited ferroptosis, and improved cardiac function.

[Anatomic Abnormalities of Hippocampal Subfields in First-Episode Drug-Naïve Schizophrenia and Major Depressive Disorder: A Structural MRI Comparative Study].

Objective: To compare the structural changes along the longitudinal axis of hippocampus subfields between schizophrenia (SCZ) patients and major depressive disorder (MDD) patients in the early stage of their SCZ and MDD. Methods: Seventy-nine first-episode drug-naïve patients with SCZ, 48 first-episode drug-naïve patients with MDD, and 79 healthy controls (HC) were recruited and underwent assessment of clinical symptoms and magnetic resonance imaging (MRI) of the head. Following the calculation of hippocampal and subfield volumes with FreeSurfer, the volume of longitudinal subfields were summed up. Inter-group comparison of these indicators was made with the data of different groups and the correlation between clinical symptoms and the volumes of longitudinal subfields was analyzed. Results: Compared with HC, SCZ patients had smaller bilateral posterior hippocampus (left: t=－2.69, P=0.01; right: t=－2.90, P=0.004), while MDD patients exhibited no changes along the longitudinal axis of hippocampal subfields. In SCZ patients, the volume of bilateral posterior hippocampus was negatively correlated with the negative symptom scores of Positive and Negative Syndrome Scale (left: r=－0.29, P=0.01; right: r=－0.23, P=0.04). Conclusion: The smaller posterior hippocampus may be an imaging feature for distinguishing SCZ from MDD and may have contributed to the neuropathophysiological mechanism of SCZ in the early stage of the onset of the disease.

ALDH2 attenuates ischemia and reperfusion injury through regulation of mitochondrial fusion and fission by PI3K/AKT/mTOR pathway in diabetic cardiomyopathy.

The function of mitochondrial fusion and fission is one of the important factors causing ischemia-reperfusion (I/R) injury in diabetic myocardium. Aldehyde dehydrogenase 2 (ALDH2) is abundantly expressed in heart, which involved in the regulation of cellular energy metabolism and stress response. However, the mechanism of ALDH2 regulating mitochondrial fusion and fission in diabetic myocardial I/R injury has not been elucidated. In the present study, we found that the expression of ALDH2 was downregulated in rat diabetic myocardial I/R model. Functionally, the activation of ALDH2 resulted in the improvement of cardiac hemodynamic parameters and myocardial injury, which were abolished by the treatment of Daidzin, a specific inhibitor of ALDH2. In H9C2 cardiomyocyte hypoxia-reoxygenation model, ALDH2 regulated the dynamic balance of mitochondrial fusion and fission and maintained mitochondrial morphology stability. Meanwhile, ALDH2 reduced mitochondrial ROS levels, and apoptotic protein expression in cardiomyocytes, which was associated with the upregulation of phosphorylation (p-PI3KTyr458, p-AKTSer473, p-mTOR). Moreover, ALDH2 suppressed the mitoPTP opening through reducing 4-HNE. Therefore, our results demonstrated that ALDH2 alleviated the ischemia and reperfusion injury in diabetic cardiomyopathy through inhibition of mitoPTP opening and activation of PI3K/AKT/mTOR pathway.

Mechanisms of Quercetin against atrial fibrillation explored by network pharmacology combined with molecular docking and experimental validation.

Atrial fibrillation (AF) is a common atrial arrhythmia for which there is no specific therapeutic drug. Quercetin (Que) has been used to treat cardiovascular diseases such as arrhythmias. In this study, we explored the mechanism of action of Que in AF using network pharmacology and molecular docking. The chemical structure of Que was obtained from Pubchem. TCMSP, Swiss Target Prediction, Drugbank, STITCH, Pharmmapper, CTD, GeneCards, DISGENET and TTD were used to obtain drug component targets and AF-related genes, and extract AF and normal tissue by GEO database differentially expressed genes by GEO database. The top targets were IL6, VEGFA, JUN, MMP9 and EGFR, and Que for AF treatment might involve the role of AGE-RAGE signaling pathway in diabetic complications, MAPK signaling pathway and IL-17 signaling pathway. Molecular docking showed that Que binds strongly to key targets and is differentially expressed in AF. In vivo results showed that Que significantly reduced the duration of AF fibrillation and improved atrial remodeling, reduced p-MAPK protein expression, and inhibited the progression of AF. Combining network pharmacology and molecular docking approaches with in vivo studies advance our understanding of the intensive mechanisms of Quercetin, and provide the targeted basis for clinical Atrial fibrillation treatment.

Potassium Channels in the Transition from Fetal to the Neonatal Pulmonary Circulation.

The transition from the fetal to the neonatal circulation includes dilatation of the pulmonary arteries (PA) and closure of the Ductus Arteriosus Botalli (DAB). The resting membrane potential and various potassium channel activities in smooth muscle cells (SMC) from fetal and neonatal PA and DAB obtained from the same species has not been systematically analyzed. The key issue addressed in this paper is how the resting membrane potential and the whole-cell potassium current (IK) change when PASMC or DABSMC are transitioned from hypoxia, reflecting the fetal state, to normoxia, reflecting the post-partal state. Patch-clamp measurements were employed to characterize whole-cell K+ channel activity in fetal and post-partal (newborn) PASMC and DABSMC. The main finding of this paper is that the SMC from both tissues use a similar set of K+ channels (voltage-dependent (Kv), calcium-sensitive (KCa), TASK-1 and probably also TASK-2 channels); however, their activity level depends on the cell type and the oxygen level. Furthermore, we provide the first evidence for pH-sensitive non-inactivating K+ current in newborn DABSMC and PASMC, suggesting physiologically relevant TASK-1 and TASK-2 channel activity, the latter particularly in the Ductus Arteriosus Botalli.

Discovery of a novel DDRs kinase inhibitor XBLJ-13 for the treatment of idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic fatal lung disease characterized by destruction of lung parenchyma and deposition of extracellular matrix in interstitial and alveolar spaces. But known drugs for IPF are far from meeting clinical demands, validation of drug targets against pulmonary fibrosis is in urgent demand. Tyrosine kinase receptor DDRs has been considered as a potential therapeutic target for pulmonary fibrosis due to its pathological collagen binding property and the roles in regulating extracellular matrix remodeling. In this study we designed and synthesized a new indazole derivative XBLJ-13, and identified XBLJ-13 as a highly specific and potent DDRs inhibitor with anti-inflammation and anti-fibrosis activities. We first demonstrated that DDR1/2 was highly expressed in the lung tissues of IPF patients. Then we showed that XBLJ-13 potently inhibited DDR1 and DDR2 kinases with IC50 values of 17.18 nM and 15.13 nM, respectively. Among a panel of 34 kinases tested, XBLJ-13 displayed relatively high selectivity for DDRs with minimal inhibitory effect on PDGFR family and FGFR1, as well as Abl kinase that had high homology with DDRs. Extensive profiling of XBLJ-13 revealed that the new inhibitor had much lower toxicity than nintedanib and better pharmacokinetic properties in mice. Furthermore, pharmacodynamic evaluation conducted in bleomycin-induced pulmonary fibrosis mice showed that administration of XBLJ-13 (30, 60, 90 mg·kg-1·d-1, i.g.) for 12 days significantly and dose-dependently ameliorated lung inflammation and fibrosis. Together, this study confirms that DDRs kinase is a potential target for PF, Particularly, compound XBLJ-13 is a highly potent and specific DDRs inhibitor, along with good pharmacokinetics profiles, and preferable in vivo efficacy, suggesting that it is a potential candidate for the treatment of PF.

GSA-Human: Genome Sequence Archive for Human.

The Genome Sequence Archive for Human (GSA-Human) is a data repository specialized for human genetic related data derived from biomedical researches, and also supports the data collection and management of National Key Research and Development Projects. GSA-Human has a data security management strategy according to the national regulations of human genetic resources. It provides two different models of data access: Open-access and Controlled-access. Open-access data are universally and freely accessible for global researchers, while Controlled-access ensures that data are accessed only by authorized users with the permission of the Data Access Committee (DAC). Till July 2021, GSA-Human has housed more than 5.27 PB of data from 750 datasets.

Changes of Necroptosis in Irbesartan Medicated Cardioprotection in Diabetic Rats.

BACKGROUND: Diabetic cardiomyopathy (DCM) is strongly linked to microvascular disease, renin-angiotensin system (RAS) activation, cardiac inflammation and cell apoptosis. Irbesartan is an angiotensin II (Ang II) receptor antagonist in RAS system, which inhibited the conversion of Ang I into Ang II, while the specific mechanism is still obscure. OBJECTIVE: This study aims to investigate the expressions necroptosis RIP1-RIP3-MLKL pathway in myocardium of diabetic rats, and the protective action of irbesartan on myocardial damage. MATERIALS AND METHODS: In our study, 30 Sprague-Dawley rats were divided into 5 groups: CON4W, high glucose and high caloric (HC4W), diabetes mellitus 4 weeks (DM4W group), diabetes mellitus 8 weeks (DM8W group), and irbesartan diabetes 8 weeks (Ir DM8W group). RESULTS: We discovered that as diabetes progresses, the rats gradually lost weight, the HW/BW ratio were increased gradually, and the cardiac function became worse accompanied with the aggravation of inflammatory injury. Meanwhile, the myocardial fibers and cells were disordered, and the expression of positive substances, RIP1 and RIP3 increased significantly. The mRNA and protein levels of myocardial RIP1, RIP3 and MLKL were all increased with the progression of DM. After the intervention of irbesartan in diabetic rats, the cardiac function was improved, whereas inflammatory injury and HW/BW ratio were decreased. Also, the myocardial fibrosis injury was attenuated, and the PAS positive substances, RIP1 and RIP3 were significantly decreased. The curative effect of irbesartan was related to decreased myocardial RIP1, RIP3 and MLKL mRNA and protein levels. CONCLUSION: In conclusion, irbesartan has a cardioprotective effect on the diabetic rats, and its mechanism may be connected with inhibition of RIP1-RIP3-MLKL pathway.

Anatomy and Correlation of the Coracoid Process and Coracoclavicular Ligament Based on Three-Dimensional Computed Tomography Reconstruction and Magnetic Resonance Imaging.

BACKGROUND The anatomy of the coracoid process and coracoclavicular (CC) ligament have been described and the correlation between them has been assessed based on 3-dimensional computed tomography (CT) reconstruction and magnetic resonance imaging (MRI), which provide a guide for coracoclavicular ligament reconstruction. MATERIAL AND METHODS Data were collected from 300 patients who underwent both CT and MRI of the shoulder joint from January 2017 to January 2019 at the Jiang'an Hospital of Traditional Chinese Medicine. The coracoid process was observed and classified and parameters of the CC ligament were measured according to different corneal types. All of the statistics were collected and classified by 2 radiologists, and average values were determined.Measurements of segments were taken as follows: ab - In the coronal plane, the length of the CC ligament from the central point of the CC ligament at the clavicular attachment to the CC ligament at the center of the CC attachment); ac - The distance from the center point of the CC ligament at the supraclavicular attachment to the acromioclavicular joint; de - In the sagittal plane, the length of the CC ligament from the center of the clavicular attachment to the coracoid attachment point; fg - The maximum diameter of the CC ligament at the anterior and posterior margins of the clavicle attachment; hi - The largest diameter of the CC ligament at the anterior and posterior edge of the coracoid process attachment; dj - The distance of the coracoclavicular ligament from the center point of the coracoid process attachment to the coracoid process tip; kl - The distance in the supraclavicular plane from the coracoclavicular ligament to the subcoracoid process. RESULTS The analysis showed that there are 5 types of coracoid process: gourd (31%), short rod (20%), long rod (22.3%), wedge (10.3%), and water drop (6.3%). There were statistically significant differences between the lengths of the ac and hi segments in the among the wedge and gourd-type and the short rod and water drop-type coracoid processes. There were statistically significant differences between the lengths of the ab, de, and fg segments in the short rod, gourd, and long rod-type coracoid processes. There were statistically significant differences between the lengths of the ac, fg, hi, dj, and kl segments in the water drop, gourd, and long rod-type coracoid processes. CONCLUSIONS The present study indicated that measurement of the CC ligament and the different shapes of the coracoid process provide an anatomical basis for the diagnosis and treatment of shoulder diseases and the data can be used to improve the safety of CC ligament reconstruction.

Roxithromycin attenuates bleomycin-induced pulmonary fibrosis by targeting senescent cells.

Idiopathic pulmonary fibrosis (IPF) is an aging-associated disease with a poor prognosis. Emerging evidence has revealed that targeting senescent cells may be a potential treatment for IPF. In this study, we aimed to explore whether roxithromycin (RXM) can improve lung fibrosis by targeting senescent cells. First, we confirmed the ability of RXM to selectively kill senescent cells by inducing apoptosis and inhibiting the expression of senescence-associated secretory phenotype (SASP) factors, suggesting the potential role of RXM as a "senolytic" and "senomorphic" drug. Next, we observed that TGF-ß- and senescent cell-induced lung fibroblast activation was inhibited by RXM treatment, which prompted us to further investigate its effect in vivo. In a mouse model of bleomycin (BLM)-induced pulmonary fibrosis, RXM was shown to attenuate lung injury, inflammation, and fibrosis. Furthermore, the senescent phenotype of lung tissues induced by BLM was significantly diminished after RXM administration, indicating the potential of RXM as an antifibrotic and antisenescent agent. Interestingly, NADPH oxidase 4 (NOX4), implicated in lung fibrosis and cell senescence, was shown to be inhibited by RXM treatments. The antifibroblast activation and antisenescent effects of RXM were abolished in NOX4 knockdown cells, demonstrating that RXM may ameliorate BLM-induced pulmonary fibrosis by targeting senescent cells mediated by the NOX4 pathway. Collectively, these data demonstrated that RXM may be a potential clinical agent for IPF and further supported the notion that targeting cellular senescence is a promising treatment for progressive age-related disease.

Assessment of Prognostic Factors of Racial Disparities in Testicular Germ Cell Tumor Survival in the United States (1992-2015).

OBJECTIVE: Testicular germ cell tumors (TGCT) are the most common cancer among men aged 15 to 39 years. Previous studies have considered factors related to TGCT survival rate and race/ethnicity, but histological type of the diagnosed cancer has not yet been thoroughly assessed. METHODS: The data came from 42,854 eligible patients from 1992 to 2015 in the Surveillance Epidemiology and End Results 18. Frequencies and column percent by seminoma and nonseminoma subtypes were determined for each covariates. We used Cox proportional hazard regression to assess the impact of multiple factors on post-diagnostic mortality of TGCT. RESULTS: Black males were diagnosed at a later stage, more commonly with local or distant metastases. The incidence of TGCT in black non-seminoma tumors increased most significantly. The difference in survival rates between different ethnic and histological subtypes, overall survival (OS) in patients with non-seminoma was significantly worse than in patients with seminoma. The most important quantitative predictor of death was the stage at the time of diagnosis, and older diagnostic age is also important factor affecting mortality. CONCLUSION: Histological type of testicular germ cell tumor is an important factor in determining the prognosis of testicular cancer in males of different ethnic groups.

Simvastatin protects heart function and myocardial energy metabolism in pulmonary arterial hypertension induced right heart failure.

The favorable effect of simvastatin on pulmonary arterial hypertension (PAH) has been well defined despite the unknown etiology of PAH. However, whether simvastatin exerts similar effects on PAH induced right heart failure (RHF) remains to be determined. We aimed to investigate the function of simvastatin in PAH induced RHF. Rats in the RHF and simvastatin groups were injected intraperitoneally with monocrotaline to establish PAH-induced RHF model. The expression of miR-21-5p in rat myocardium was detected and miR-21-5p expression was inhibited using antagomiRNA. The effect of simvastatin on hemodynamic indexes, ventricular remodeling of myocardial tissues, myocardial energy metabolism, and calmodulin was explored. Dual-luciferase reporter system was used to verify the binding relationship between miR-21-5p and Smad7. In addition, the regulatory role of simvastatin in Smad7, TGFBR1 and Smad2/3 was investigated. Simvastatin treatment improved hemodynamic condition, myocardial tissue remodeling, and myocardial energy metabolism, as well as increasing calmodulin expression in rats with PAH-induced RHF. After simvastatin treatment, the expression of miR-21-5p in myocardium of rats was decreased significantly. miR-21-5p targeted Smad7 and inhibited the expression of Smad7. Compared with RHF rats, the expressions of TGFBR1 and Smad2/3 in myocardium of simvastatin-treated rats were decreased significantly. Collectively, we provided evidence that simvastatin can protect ATPase activity and maintain myocardial ATP energy reserve through the miR-21-5p/Smad/TGF-ß axis, thus ameliorating PAH induced RHF.

Efficacy of probiotics in the treatment of acute diarrhea in children: a systematic review and meta-analysis of clinical trials.

BACKGROUND: If acute diarrhea in children is not treated promptly and effectively, it can lead to severe dehydration and serious sequelae. Due to the imbalance of intestinal bacteria in children with acute diarrhea, the supplementation with probiotics is important, which can improve the intestinal microenvironment, promote immunity, and enhance resistance. This meta-analysis provides further evidence and discussion of the therapeutic effect of probiotics on acute diarrhea in children. METHODS: MEDLINE, EMBASE, PubMed, and the Cochrane Library databases were searched by rapid matching. The input keywords were as follows: (probiotics/synbiotics) and (child/children) and (acute diarrhea/acute gastroenteritis). Articles reporting on randomized controlled trials (RCTs) of probiotics in treating acute diarrhea in children were retrieved. The studies were published from 2010 to 2020. After screening and quality evaluation, Stata 16.0 software was used for the analysis. RESULTS: Twelve articles with 744 patients were included in the study, and the overall quality of the articles was excellent. Meta-analysis showed that the duration of diarrhea in the probiotics group was shorter than that in the control group [standard mean difference (SMD) =-0.74, 95% CI: -1.11 to -0.37, Z=-3.935, P=0.000], the 2-day treatment efficacy for diarrhea in the probiotics group was greater than that in the control group [odds ratio (OR) =2.12, 95% CI: 1.47-3.05, Z=3.998, P=0.000], and the length of hospital stay in the probiotics group was shorter than that of the control group (SMD =-0.60, 95% CI: -0.74 to -0.47, Z=-8.781, P=0.000). In the subgroup analysis, combined probiotics shortened the duration of diarrhea compared with single probiotic use, and Lactobacillus reuteri and Saccharomyces boulardii had a better therapeutic effect than Lactobacillus rhamnosus or Lactobacillus acidophilus. DISCUSSION: In the treatment of acute diarrhea in children, the addition of probiotics can shorten the duration of diarrhea, increase treatment efficacy after 2 days of treatment, and shorten the length of hospital stay. However, because of possible publication bias in the current study, further high-quality RCT studies in clinical settings are needed to verify the current results and continue the exploration of this topic.

MiR-324-3p Regulates Fibroblast Proliferation via Targeting TGF-ß1 in Atrial Fibrillation.

Atrial fibrillation (AF), one of the common clinical arrhythmias, lacks effective treatment manners. Cardiac fibroblasts play an essential role in myocardial fibrosis and cardiac remodeling, which are involved in AF progression. Reportedly, MicroRNAs (miRNAs) regulate the myocardial fibrosis in AF. However, whether miR-324-3p involves myocardial fibrosis in AF and the tentative molecular mechanisms of miR-324-3p regulating cardiac fibroblasts during AF remains unknown. In the present study, miR-324-3p was found to be decreased in patients with AF and AF rat model. Next, we investigated the effect of miR-324-3p on myocardial fibroblast proliferation through miR-324-3p overexpression and found that miR-324-3p inhibited fibroblast proliferation in vitro. Furthermore, we found that miR-324-3p directly targeted transforming growth factor ß1 in fibroblast, which may be involved in the development of myocardial fibrosis during AF. Meanwhile, miR-324-3p mimics treatment suppressed the PI3K/AKT signaling pathway in fibroblast. These results demonstrated a molecular mechanism of miR-324-3p regulating fibroblast proliferation in vitro, which might provide a novel potential treatment manner in AF in clinic.