Astragaloside IV for Heart Failure: Preclinical Evidence and Possible Mechanisms, A Systematic Review and Meta-Analysis.

OBJECTIVE: To explore the cardioprotective effects of astragaloside IV (AS-IV) in heart failure (HF). METHODS: PubMed, Excerpta Medica Database (EMBASE), Cochrane Library, Web of Science, Wanfang Database, Chinese Bio-medical Literature and Retrieval System (SinoMed), China Science and Technology Journal Database (VIP), and China National Knowledge Infrastructure (CNKI) were searched from inception to November 1, 2021 for animal experiments to explore AS-IV in treating HF in rats or mice. The left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS), left ventricular end-diastolic dimension (LVEDD), left ventricular end-systolic dimension (LVESD), left ventricular weight-to-body weight (LVW/BW) and B-type brain natriuretic peptide (BNP) were recorded. The qualities of included studies were assessed by the risk of bias according to the Cochrane handbook. Meta-analysis was performed using Stata 13.0. RESULTS: Twenty-one articles involving 558 animals were considered. Compared with the control group, AS-IV improved cardiac function, specifically by increasing LVEF (mean difference (MD)=6.97, 95% confidence interval (CI)=5.92 to 8.03, P<0.05; fixed effects model) and LVFS (MD=7.01, 95% CI=5.84 to 8.81, P<0.05; fixed effects model), and decreasing LVEDD (MD=-4.24, 95% CI=-4.74 to -3.76, P<0.05; random effects model) and LVESD (MD=-4.18, 95% CI=-5.26 to -3.10, P<0.05; fixed effects model). In addition, the BNP and LVW/BW levels were decreased in the AS-IV treatment group (MD=-9.18, 95% CI=-14.13 to -4.22, P<0.05; random effects model; MD=-1.91, 95% CI=-2.42 to -1.39, P<0.05; random effects model). CONCLUSIONS: AS-IV is a promising therapeutic agent for HF. However, this conclusion needs to be clinically validated in the future.

Anti-inflammatory Therapy Progress in Major Adverse Cardiac Events after PCI: Chinese and Western Medicine.

Acute coronary syndrome (ACS) is one of the leading causes of death in cardiovascular disease. Percutaneous coronary intervention (PCI) is an important method for the treatment of coronary heart disease (CHD), and it has greatly reduced the mortality of ACS patients since its application. However, a series of new problems may occur after PCI, such as in-stent restenosis, no-reflow phenomenon, in-stent neoatherosclerosis, late stent thrombosis, myocardial ischemia-reperfusion injury, and malignant ventricular arrhythmias, which result in the occurrence of major adverse cardiac events (MACE) that seriously reduce the postoperative benefit for patients. The inflammatory response is a key mechanism of MACE after PCI. Therefore, examining effective anti-inflammatory therapies after PCI in patients with ACS is a current research focus to reduce the incidence of MACE. The pharmacological mechanism and clinical efficacy of routine Western medicine treatment for the anti-inflammatory treatment of CHD have been verified. Many Chinese medicine (CM) preparations have been widely used in the treatment of CHD. Basic and clinical studies showed that effectiveness of the combination of CM and Western medicine treatments in reducing incidence of MACE after PCI was better than Western medicine treatment alone. The current paper reviewed the potential mechanism of the inflammatory response and occurrence of MACE after PCI in patients with ACS and the research progress of combined Chinese and Western medicine treatments in reducing incidence of MACE. The results provide a theoretical basis for further research and clinical treatment.

Oral magnesium sulphate administration in rats with minimal hepatic encephalopathy: NMR-based metabolic characterization of the brain

Objective: To investigate the metabolic changes in rats with minimal hepatic encephalopathy (MHE) treated with oral magnesium sulphate administration. Materials and Methods: A total of 30 Sprague-Dawley rats were divided into a control group and MHE group (further divided into an MHE group and an MHE-Mg group treated with oral administration of 124 mg/kg/day magnesium sulphate). Morris water maze (MWM), Y maze and narrow beam walking (NBW) were used to evaluate cognitive and motor functions. Brain manganese and magnesium content were measured. The metabolic changes in rats with MHE were investigated using hydrogen-nuclear magnetic resonance. Metabolomic signatures were identified with enrichment and pathway analysis. Results: A significantly decreased number of entries into the MWM within the range of interest, longer latency and total time during NBW, and higher brain manganese content were found in rats with MHE. After magnesium sulphate treatment, the rats with MHE had better behavioural performance and lower brain manganese content. The 25 and 26 metabolomic signatures were identified in the cortex and striatum of rats with MHE. The pathway analysis revealed alanine, aspartate and glutamate metabolism as the major abnormal metabolic pathways associated with these metabolomic signatures. Conclusion: Alanine, aspartate and glutamate metabolism are major abnormal metabolic pathways in rats with MHE, which could be restored by magnesium sulphate treatment.

Pre-clinical Evidence: Berberine as a Promising Cardioprotective Candidate for Myocardial Ischemia/Reperfusion Injury, a Systematic Review, and Meta-Analysis.

Objective: Myocardial ischemia/reperfusion (I/R) injury is one of the causes of most cardiomyocyte injuries and deaths. Berberine (BBR) has been suggested a potential to exert protective effects against myocardial I/R injury. This systematic review aims to determine the intrinsic mechanisms of BBR's protective effects in myocardial I/R injury. Methods: Seven databases were searched for studies performed from inception to July 2020. Methodological quality was assessed by SYRCLE's-RoB tool. Results: Ten studies including a total of 270 animals were included in this study. The methodology quality scores of the included studies ranged from 5 to 7 points. The meta-analysis we conducted demonstrated that BBR significantly reduced myocardial infarct size and the incidence of ventricular arrhythmia, compared to control groups (P < 0.00001). Cardiac function of animals in the BBR treatment group was also markedly increased (P < 0.00001). The index of myocardial apoptosis and the levels of biomarkers of myocardial infarction (LDH and CK) were also decreased in the BBR treatment groups compared to the control groups (P < 0.00001). Conclusions: The pre-clinical evidence, according to our study, showed that BBR is a promising therapeutic agent for myocardial I/R injury. However, this conclusion should be further investigated in clinical studies.

Latent pseudorabies virus infection in medulla oblongata from quarantined pigs.

Pseudorabies virus (PRV) is a major pathogen in pig husbandry and is also a risk to human well-being. Pigs with latent PRV infection carry the virus lifelong, and it can be activated under conducive conditions. This poses a very important challenge to the control of the virus and may even prevent its elimination. To investigate latent infection with wild-type (wt) PRV, and also infection due to the use of live attenuated vaccines on farms, 80 pigs from two large-scale swine operations were traced. At 6 months old, the quarantined pigs were slaughtered and brain samples were collected. A PCR assay targeting the gB and gE genes was developed to detect PRV DNA fragments in medulla oblongata. Five of the samples (6.3%) were gB and gE gene fragment double-positive, 60 of the samples (75%) were gB single-positive, and 15 samples (18.7%) showed double-negative. A portion of latency-associated transcripts (LATs), EP0 mRNA, were found to be present in the gB gene fragment positive samples. Furthermore, the five double-positive samples were transmitted blindly, and apparent cytopathic effects were found in three of the five samples in the fourth generation. By means of Western blotting, PCR and sequencing, two of the isolated viruses were found to be related to vaccine strain Bartha-K61. Another was closely related to domestic epidemic strains HN1201 and LA and relatively unrelated to other Asian isolates. These results suggest that the live vaccines are latently present in brains, in a manner similar to wt PRV, and this poses potential safety issues in the pig husbandry industry. Wt PRV and live vaccine viruses were found to co-exist in pigs, demonstrating that the live vaccines were unable to confer complete sterilizing immunity, which may explain outbreaks of pseudorabies on vaccinated farms.

Promising Therapeutic Candidate for Myocardial Ischemia/Reperfusion Injury: What Are the Possible Mechanisms and Roles of Phytochemicals?

Percutaneous coronary intervention (PCI) is one of the most effective reperfusion strategies for acute myocardial infarction (AMI) despite myocardial ischemia/reperfusion (I/R) injury, causing one of the causes of most cardiomyocyte injuries and deaths. The pathological processes of myocardial I/R injury include apoptosis, autophagy, and irreversible cell death caused by calcium overload, oxidative stress, and inflammation. Eventually, myocardial I/R injury causes a spike of further cardiomyocyte injury that contributes to final infarct size (IS) and bound with hospitalization of heart failure as well as all-cause mortality within the following 12 months. Therefore, the addition of adjuvant intervention to improve myocardial salvage and cardiac function calls for further investigation. Phytochemicals are non-nutritive bioactive secondary compounds abundantly found in Chinese herbal medicine. Great effort has been put into phytochemicals because they are often in line with the expectations to improve myocardial I/R injury without compromising the clinical efficacy or to even produce synergy. We summarized the previous efforts, briefly outlined the mechanism of myocardial I/R injury, and focused on exploring the cardioprotective effects and potential mechanisms of all phytochemical types that have been investigated under myocardial I/R injury. Phytochemicals deserve to be utilized as promising therapeutic candidates for further development and research on combating myocardial I/R injury. Nevertheless, more studies are needed to provide a better understanding of the mechanism of myocardial I/R injury treatment using phytochemicals and possible side effects associated with this approach.

[Roles of autophagy onself-renewal and differentiation of mesenchymal stem cells].

Mesenchymal stem cells (MSCs), which have the potential of self-replication and differentiation, are a very valuable cell source for stem cell-based medical therapy. Their application has opened up a new way for disease research. Although MSCs can maintain cell stemness through self-renewal, with the prolongation of cell passage and culture time, the stemness of MSCs gradually decays, and the cell aging and differentiation potential decreases gradually. Autophagy is a highly conserved cytological process that degrades the modified, excess, and deleterious cytoplasmic components in autophagosomes, which are then degraded by fusion with lysosomes. As the main intracellular degradation and recycling pathway, autophagy plays an active role in maintaining cell homeostasis, self-renewal and pluripotency. In this paper, the role of autophagy in self-renewal and maintenance of multidirectional differentiation potential of MSCs was reviewed, which laid a theoretical foundation and practical basis for the research and application of MSCs.

Efficacy and Safety of Bushenjiangya-Optimized Granule for Left Ventricular Diastolic Dysfunction in Hypertensive Patients: A Double-Blind, Randomized, Placebo-Controlled Trial.

OBJECTIVE: The study aimed to evaluate the efficacy and safety of Bushenjiangya-optimized (BSJYO) granule on left ventricular diastolic dysfunction (LVDD) in hypertensive (HTN) patients. METHODS: 120 patients diagnosed with HTN plus LVDD were randomly assigned to the BSJYO granule group and placebo group, and all patients received basal western medicine (WM) treatment. After eight weeks of treatment, we evaluated echocardiography, traditional Chinese medicine (TCM) syndromes, 24-hour ambulatory blood pressure, liver and kidney functions, and adverse events. Major adverse cardiovascular events (MACEs) were collected at 6-month follow-up. RESULTS: Compared with pretreatment, E/Ea (Doppler-derived index of filling pressure and worsening LVDD) significantly decreased significantly after 8 weeks of treatment in the BSJYO granule plus basal WM group (10.52 ± 1.87 vs. 9.49 ± 1.49, P < 0.01), alongside reductions in significantly effective response (SER), effective response (ER), and total effective response (TER = SER + ER) in TCM symptom scores (21.59% vs. 71.70%, P < 0.01). There were no differences between treatment groups in kidney and liver function, early adverse events, or MACE. CONCLUSION: BSJYO granule plus basal WM is an effective and safe therapy for HTN patients with LVDD.

Tunneling Nanotubes Mediated microRNA-155 Intercellular Transportation Promotes Bladder Cancer Cells' Invasive and Proliferative Capacity.

OBJECTIVE: To investigate differential microRNAs' expression in heterogeneous bladder cancer cells, as well as to investigate the mechanism of changes in invasive and proliferative capacity induced by tunneling nanotubes (TNTs) mediated transport of microRNA between bladder cancer cells of varying histological grade. MATERIALS AND METHODS: Differences in microRNA expression between bladder cancer cells of different grade were identified from a literature review. The identified heterogeneous microRNAs were analyzed by qPCR in T24 (high grade) and RT4 (low grade) bladder cancer cells. Scanning electron microscopy (SEM) and laser confocal fluorescence microscopy (LCM) were used to observe tunneling nanotubes (TNTs) between RT4 and T24 cells. Differentially expressed microRNA was labeled and traced by Fluorescent In Situ Hybridization (FISH) following co-culture of T24 and RT4 cells. MicroRNA mimic and inhibition technologies were applied to investigate how TNTs-mediated intercellular transport of microRNA affects the invasive and proliferative behavior of bladder cancer cells. RESULTS: MicroRNA-155 (miR-155) levels were highly expressed in T24 cells, whereas the same was not true in RT4 cells. MiR-155 was confirmed to be a crucial factor sustaining T24 bladder cancer cell proliferation, migration and cell cycle progression by CCK8, Matrigel test and cell cycle analysis, respectively. After T24 and RT4 co-culture, TNTs were assessed by SEM and LCM between T24 and RT4 cells. In addition, we observed TNTs mediated transport of miR-155 from T24 cells to RT4 cells, which thereby acquired a higher proliferative rate, an increased frequency of cells in the S phase, and increased invasive ability in Matrigel test. At the same time, Deptor, the target protein of miR-155 in RT4 cells, was downregulated, followed by mTOR/4EBP1/p70S6K- eIF4e/S6RP signaling activation. CONCLUSION: MiR-155 was differentially expressed between RT4 and T24 bladder cancer cells. Intercellular transport of miR-155 via TNTs can promote bladder cancer cell reprogramming by Deptor-mTOR signal pathway activation.

Effects of human bone morphogenetic protein 2 (hBMP2) on tertiary dentin formation.

Formation of tertiary dentin to maintain pulp vitality is a major odontoblastic response to dental pulp injury. Human bone morphogenetic protein 2 (hBMP2) can promote proliferation and differentiation of odontoblasts. Current study is interested in evaluating if the hBMP2 can promote the regeneration of tertiary dentin and cure dental pulp injury using the adenoviral vector to deliver hBMP2 cDNA into the pulp. Primary culture of dental pulp cells of exfoliated deciduous teeth (hDPCs) was established. Human serotype 5 adenoviral vector, AdCMV-hBMP2, was created. AdCMV-hBMP2 was used to transduce hDPCs in vitro and dental pulp cells in animal model in vivo. Data clearly demonstrated that hBMP2 increased ALP and mineralization. Reverse transcription-real time quantitative PCR (RT-QPCR) data showed that hBMP2 dramatically increased gene expressions of Runx2 (Runt-related transcription factor 2), ALP, Col Iα (Collagen 1a1), SP7 (Osterix), DMP1 (dentin matrix acidic phosphoprotein 1), DSPP (dentin sialophosphoprotein), and BSP (bonesialoprotein), which are normally involved in osteogenesis/odontogenesis. Data from in vivo assays demonstrated that hBMP2 promoted pulp cell proliferation and increased formation of tertiary dentin in dental pulp. Our in vitro and in vivo data suggest that hBMP2 gene can efficiently be delivered into the dental pulp cells by adenovirus, and show potential clinical application for the treatment of dental pulp damage.

Comparison of the efficacy and acceptability of Chinese herbal medicine in adult patients with heart failure and reduced ejection fraction: study protocol for a systematic review and network meta-analysis.

INTRODUCTION: Heart failure with reduced ejection fraction (HFrEF) is defined as the clinical diagnosis of heart failure (HF) and ejection fraction (EF) ≤40%, which is a severe public healthcare issue and brings a heavy social and economic burden for patients with HFrEF. Chinese herbal medicine (CHM) has a long history in treating HF. Questions concerning the efficacy and acceptability of CHM-related interventions in adult patients with HFrEF led us to use the method of systematic review and network meta-analysis to integrate direct and indirect evidence to create hierarchies for all CHM. METHODS AND ANALYSIS: Nine medical databases, including PubMed, EMBASE (OVID), the Cochrane Library, Google Scholar, Web of Science, CNKI, VIP, Wanfang Database and CBM will be searched from the date of database inception to June 2015 (updated to March 2017) without language and publication status restriction. Completely randomised controlled trials (RCTs) comparing CHM or CHM plus routine treatment with CHM, CHM plus routine treatment, routine treatment, no treatment or placebo for adults with HFrEF will be examined. Our primary outcomes will include all-cause mortality, HF-related death, all-cause rehospitalisation, HF-related rehospitalisation and acceptability (discontinuation due to any adverse events during treatment). Secondary outcomes will include response rate, mean value or mean difference from baseline of surrogate indexes. We will perform the Bayesian network meta-analyses (NMA) for the most frequently reported primary or secondary outcome and the acceptability outcome, if available. Meta-regression, subgroup analyses and sensitivity analyses will be conducted based on prespecified effect modifiers to assess the robustness of the findings. DISSEMINATION: The results of this NMA will provide useful information about the effectiveness and acceptability of CHM in adults with HFrEF, which will also have implications for clinical practice and further research. Findings will be disseminated through peer-reviewed journal publication and conference presentations. PROSPERO REGISTRATION NUMBER: CRD42016053854.

Conventional Acupuncture for Cardiac Arrhythmia: A Systematic Review of Randomized Controlled Trials.

OBJECTIVE: To exam the effect and safety of conventional acupuncture (CA) on cardiac arrhythmia. METHODS: Nine medical databases were searched until February 2016 for randomized controlled trials. Heterogeneity was measured by Cochran Q test. Meta-analysis was conducted if I2 was less than 85% and the characteristics of included trials were similar. RESULTS: Nine qualified studies involving 638 patients were included. Only 1 study had definitely low risk of bias, while 7 trials were rated as unclear and 1 as high. Meta-analysis of CA alone did not have a significant benefit on response rate compared to amiodarone in patients with atrial fibrillation (Af) and atrial flutter (AF) [relative risk (RR): 1.09; 95% confidence interval (CI): 0.79-1.49; P=0.61; I2=61%, P=0.11]. However, 1 study with higher methodological quality detected a lower recurrence rate of Af in CA alone as compared with sham acupuncture plus no treatment, and benefits on ventricular rate and time of conversion to normal sinus rhythm were found in CA alone group by 1 study, as well as the response rate in CA plus deslanoside group by another study. Meta-analysis of CA plus anti-arrhythmia drug (AAD) was associated with a significant benefit on the response rate when compared with AAD alone in ventricular premature beat (VPB) patients (RR, 1.19, 95% CI: 1.05-1.34; P=0.005; I2=13%, P=0.32), and an improvement in quality-of-life score (QOLS) of VPB also showed in 1 individual study. Besides, a lower heart rate was detected in the CA alone group by 1 individual study when compared with no treatment in sinus tachycardia patients (MD-21.84 [-27.21,-16.47]) and lower adverse events of CA alone were reported than amiodarone. CONCLUSIONS: CA may be a useful and safe alternative or additive approach to AADs for cardiac arrhythmia, especially in VPB and Af patients, which mainly based on a pooled estimate and result from 1 study with higher methodological quality. However, we could not reach a robust conclusion due to low quality of overall evidence.

Global identification of chemical constituents and rat metabolites of Si-Miao-Wan by liquid chromatography-electrospray ionization/quadrupole time-of-flight mass spectrometry.

Si-Miao-Wan (SMW), a tradiational Chinese medicinal formula consisting of Atractylodis Rhizoma, Phellodendri Chinensis Cortex, Coicis Semen, and Achyranthis Bidentatae Radix, has been used for the treatment of gout and gouty arthritis for many years. In the present study, a liquid chromatography quadrupole-time-of-flight mass spectrometry (LC-Q-TOF/MS) method was established to identify the multiple constituents of SMW and its metabolites in rat biological samples after oral administration. A total of 48 compounds in SMW, including 21 alkaloids, 12 organic acids, 2 terpenes, 3 lactones, 2 phytosterols, and 8 other compounds, were tentatively characterized with the diagnostic-ion filtering strategy. Based on the diagnostic ions applied to identify compounds in SMW, 28 prototype compounds and 10 metabolic compounds were detected in the biological samples. This was the first comprehensive drug metabolism investigation of SMW in rats. The developed method could be a useful means for identifying the multi-components in SMW and the metabolic components. The results may help explore the possible metabolic processes and mechanism of action for SMW in vivo.

Ultra-high performance liquid chromatography with ultraviolet and tandem mass spectrometry for simultaneous determination of metabolites in purine pathway of rat plasma.

It has been proved that the purine metabolic pathway has been implicated in various biological disorders including gout, diabetes, coronary heart diseases, and neurodegenerative diseases. The analysis of the purine metabolic pathway in organisms reveals important alterations under different physiological and pathological conditions, which contributes to the pathological study, diagnosis, and therapy of related diseases. In the present study, an ultra-high performance liquid chromatography with ultraviolet and tandem mass spectrometry (UHPLC-UV-MS/MS) method was developed for conducting the comprehensive analysis of the metabolite profiles of the purine pathway in rat plasma through a single analysis. The purine metabolites including adenosine-5'-monophosphate, guanosine-5'-monophosphate, adenosine, inosine, guanosine, inosine-5'-monophosphate, deoxyadenosine, deoxyguanosine, deoxyinosine, xanthine, hypoxanthine, and uric acid, were separated and quantified in the short running time of 10min. After rapid chromatographic separation achieved by an Agilent Zorbax SB-Aq column, high concentration of uric acid and the remaining purine metabolites at lower levels were respectively detected by ultraviolet detector and triple quadruple mass spectrometry within a single analysis. The proposed method was validated by applying charcoal-stripped plasma as a matrix and it was proved to be linear (R2>0.982), accurate (with a relative error for accuracy <±15% and the relative standard deviation for intra- and inter-run precision <11%) and reproducible (with a matrix effect ranging between 86.49% and 111.44% with a maximum RSD of 8.69%). As a result, the method was successfully applied to the quantification of the endogenous purine metabolites in rat plasma. It was found that the concentration levels of the purine metabolites may keep a physiological balance as an integrated system in normal individuals and the concentration level of uric acid in rat plasma was 64µM which was more than 200 times greater than the other purine metabolites. The established method and the measurement of the concentration of these purines in normal rat plasma may help the investigation of the action mechanisms between purine disorders and related diseases.

[Studies on corrosion property of the anodic coating on the Mg alloy by micro-FTIR mapping].

Micro-FTIR mapping technology was used to monitor the amount and distribution of Mg(OH)2 on the anodic coating of magnesium alloy which was immersed in the 7.3 Wt% Na2SO4 solution for different time. In the solution, part of the MgO on the surface of the Mg alloy could gradually transform into Mg(OH)2 which could be detached from the Mg alloy surface and dis- solved into the solution. With immersion time of 2 h in 7.3 Wt% Na2SO4 solution 2h, FTIR mapping results showed that FTIR absorption signal of Mg(OH)2 was strongest and Mg(OH)2 was most on the surface of the anodic coating. After 4 hours, the content of Mg(OH)2 began to decrease, and the Mg alloy was etched gradually. The FTIR mapping results of another component Al2O3 with immersion time were almost similar to those of Mg(OH)2. The impedance of the oxide film was also analyzed using electrochemical impedance spectroscopy. It showed that the impedance changed with the immersion time and conformed to the corrosion law of the oxide coating. This research has a good guidance and application value for characterization of the anodic coating on magnesium alloy.