Transcriptional regulation of macrophages in heart failure.

Adverse cardiac remodeling after acute myocardial infarction is the most important pathological mechanism of heart failure and remains a major problem in clinical practice. Cardiac macrophages, derived from tissue resident macrophages and circulating monocyte, undergo significant phenotypic and functional changes following cardiac injury and play crucial roles in inflammatory response and tissue repair response. Currently, numerous studies indicate that epigenetic regulatory factors and transcription factors can regulate the transcription of inflammatory and reparative genes and timely conversion of inflammatory macrophages into reparative macrophages and then alleviate cardiac remodeling. Accordingly, targeting transcriptional regulation of macrophages may be a promising option for heart failure treatment. In this review, we not only summarize the origin and function of cardiac macrophages, but more importantly, describe the transcriptional regulation of macrophages in heart failure, aiming to provide a potential therapeutic target for heart failure.

Wave Propagation Characteristics and Compaction Status of Subgrade during Vibratory Compaction.

Vibratory compaction status has a significant influence on the construction quality of subgrade engineering. This study carried out field experiments to study the propagation characteristics of the vertical vibration wave in the soil field along the traveling direction of the vibratory roller. The propagation coefficients of the peak acceleration at different positions and compacting rounds are compared in both the time and frequency domains. The compaction status is estimated in the form of dynamic modulus of deformation (Evd) obtained by plate load tests. The experiment results show that the propagation coefficient of peak acceleration is affected by the traveling speed, excitation amplitude, and frequency of the vibratory roller, as well as the compacting rounds. An exponential relationship between the wave amplitudes of the fundamental mode and higher-order modes is revealed. The amplitude of the fundamental wave is maximum at the speed of 3 km/h, whereas the amplitudes of higher-order waves have a maximum of 1.5 km/h. The influences of compaction rounds on the average value of Evd are also investigated to provide a practical reference for engineering construction.

A Pharmacological Review of Tanshinones, Naturally Occurring Monomers from Salvia miltiorrhiza for the Treatment of Cardiovascular Diseases.

Cardiovascular diseases (CVDs) are a set of heart and blood vessel disorders that include coronary heart disease (CHD), rheumatic heart disease, and other conditions. Traditional Chinese Medicine (TCM) has definite effects on CVDs due to its multitarget and multicomponent properties, which are gradually gaining national attention. Tanshinones, the major active chemical compounds extracted from Salvia miltiorrhiza, exhibit beneficial improvement on multiple diseases, especially CVDs. At the level of biological activities, they play significant roles, including anti-inflammation, anti-oxidation, anti-apoptosis and anti-necroptosis, anti-hypertrophy, vasodilation, angiogenesis, combat against proliferation and migration of smooth muscle cells (SMCs), as well as anti-myocardial fibrosis and ventricular remodeling, which are all effective strategies in preventing and treating CVDs. Additionally, at the cellular level, Tanshinones produce marked effects on cardiomyocytes, macrophages, endothelia, SMCs, and fibroblasts in myocardia. In this review, we have summarized a brief overview of the chemical structures and pharmacological effects of Tanshinones as a CVD treatment to expound on different pharmacological properties in various cell types in myocardia.

Exploring the mechanism of Xingpi Capsule in diarrhea predominant-irritable bowel syndrome treatment based on multiomics technology.

BACKGROUND: Xingpi Capsule (XP), a commercially available over-the-counter herbal medicine in China, plays a prominent role in treating diarrhea-predominant irritable bowel syndrome (IBS-D). Nevertheless, the potential mechanisms remain unclear. PURPOSE: This study aimed to investigate XP efficacy in IBS-D and elucidate the underlying molecular mechanisms. METHODS: A rat IBS-D model was established by senna decoction gavage combined with restraint stress and swimming exhaustion. The changes in rat body weight and stool were recorded daily. Colon pathological changes and the number of colonic goblet cells of rats were observed by hematoxylin-eosin (HE) staining and Alcian blue plus periodic acid-Schiff (AB-PAS) staining, respectively. The expression of Occludin, a tight-junction-associated protein, was examined via immunohistochemistry. Images of colonic microvilli were obtained by TEM. Western blotting (WB) was used to analyze the protein expression of the ASK1/P38 MAPK pathway. The composition of the rat intestinal microbiota was detected by 16S rRNA sequencing. Changes in colonic metabolites were evaluated by liquid chromatography-mass spectrometry (LC-MS). Changes in colon RNA expression were assessed by RNA sequencing (RNA-Seq). The nontoxic range of hypoxanthine (HPX) was screened by Cell Counting Kit-8 (CCK8), the cell model of human colonic epithelial cells (NCM460) induced by lipopolysaccharide (LPS) was established, and the effective concentration of HPX was screened by CCK8. After transfection of pcDNA3.1-MAP3K5, Hoechst 33,342 staining, flow cytometry to detect cell apoptosis, and immunofluorescence to detect the fluorescence changes of ASK1 and ZO-1. WB detection of ASK1/P38 MAPK pathway protein expression changes. RESULTS: XP increased the body weight of IBS-D patients and reduced the loose stool rate, loose stool index, and Bristo score. In addition, XP mitigated colon lesions, increased the number of goblet cells and the expression of Occludin, and prevented severe distortion and effacement of the microvillous structure. Specifically, 16S rRNA gene sequence analysis showed that XP decreased the abundance of Desulfurium and Prevotella 9 at the phylum and genus levels while increasing the abundance of Bacteroides at the genus level. RNA-Seq combined with WB validation showed that XP exerted antidiarrheal effects by inhibiting the ASK1/P38 MAPK signaling pathway. Additionally, XP also increased the relative expression level of the metabolite HPX, as revealed by untargeted metabolomics analysis. Impressively, the correlation analysis between 16S rRNA sequencing and LC-MS suggested that HPX and Prevotella 9 are negatively correlated, which indicated that XP might increase the content of HPX by reducing the abundance of Prevotella 9. Meanwhile, a negative correlation between HPX and ASK1 was indicated through RNA-Seq and LC-MS, which suggested that the inhibition of ASK1 (Map3k5) may be ascribed to the increase in HPX after XP treatment. In vitro experiments have proven that HPX can alleviate LPS-induced NCM460 damage, specifically manifested as enhancing cell viability, reducing cell apoptosis, increasing ZO-1 expression, reducing the fluorescence intensity of MAP3K5 in the model group, and inhibiting the expression of ASK1/P38 MAPK pathway proteins. The protective effect of HPX was reversed after transfection with pcDNA 3.1-MAP3K5, which fully demonstrated that the protective mechanism of HPX was achieved by inhibiting MAP3K5 and its downstream pathways. CONCLUSION: XP displayed multifaceted protection against IBS-D in rats by regulating the intestinal microbiota, increasing the relative expression level of HPX, a metabolite of the microbiota, and inhibiting the ASK1/P38 MAPK signaling pathway.

Neocryptotanshinone protects against myocardial ischemia-reperfusion injury by promoting autolysosome degradation of protein aggregates via the ERK1/2-Nrf2-LAMP2 pathway.

BACKGROUND: Aggrephagy is a critical compensatory mechanism for the elimination of misfolded proteins resulting from stress and depends on the autolysosome degradation of protein aggregates. However, there have been few mechanism research related to aggrephagy in myocardial ischemia/reperfusion (I/R) injury. Neocryptotanshinone (NCTS) is a fat-soluble active compound extracted from Salvia miltiorrhiza, and may be cardioprotective against I/R. However, the efficacy and specific mechanism of NCTS on I/R have not been studied. PURPOSE: The current study aimed to investigate the molecular mechanism of NCTS involved in the therapeutic effect on I/R, with a special emphasis on the up-regulation of the ERK1/2-Nrf2-LAMP2 pathway to increase autolysosomal degradation during aggrephagy. METHODS: A rat model of myocardial I/R injury was constructed by left anterior descending (LAD) ligation-reperfusion. To verify cardiac protection, autolysosome clearance of protein aggregates, and their intracellular biological mechanism, an oxygen-glucose deprivation/recovery (OGD/R)-induced H9c2 cardiomyocyte model was created. RESULTS: NCTS was found to have a significant cardioprotective effect in I/R rats as evidenced by remarkably improved pathological anatomy, decreased myocardial damage indicators, and substantially enhanced cardiac performance. Mechanistically, NCTS might boost the levels of LAMP2 mRNA and protein, total and Ser40 phosphorylated Nrf2, and Thr202/Tyr204p-ERK1/2 protein. Simultaneously, the cytoplasmic Nrf2 level was reduced after NCTS administration, which was contrary to the total Nrf2 content. However, these beneficial changes were reversed by the co-administration with ERK1/2 inhibitor, PD98059. NCTS therapy up-regulated Rab7 protein content, Cathepsin B activity, and lysosomal acidity, while down-regulating autophagosome numbers, Ubiquitin (Ub), and autophagosome marker protein accumulations through the above signaling pathway. This might indicate that NCTS enhanced lysosomal fusion and hydrolytic capacity. It was also found that NCTS intervention limited oxidative stress and cellular apoptosis both in vivo and in vitro. CONCLUSIONS: We reported for the first time that NCTS promoted the autolysosome removal of protein aggregation both in vivo and in vitro, to exert the therapeutic advantages of myocardial I/R injury. This was reliant on the up-regulation of the ERK1/2-Nrf2-LAMP2 signaling pathway.

Shexiang Tongxin Dropping Pills Promote Macrophage Polarization-Induced Angiogenesis Against Coronary Microvascular Dysfunction via PI3K/Akt/mTORC1 Pathway.

Background: Accumulating evidence suggests that coronary microvascular dysfunction (CMD) is one of the important causes of coronary artery diseases. Angiogenesis can effectively improve CMD by increasing blood supply capacity, recovering cardiac function and poor hemodynamics. Clinical studies have approved Shexiang Tongxin dropping pill (STDP), which has exerted remarkable roles on ameliorating CMD, but the effects and mechanisms of STDPs on angiogenesis have not been clarified. Purpose: The purpose of this study was to elucidate the effects and potential mechanisms of STDPs on macrophage polarization-induced angiogenesis against CMD. Methods: Echocardiography, optical microangiography (OMAG), and histological examination were applied to evaluate cardioprotection and proangiogenic effects of STDPs on left anterior descending (LAD) ligation-induced CMD rats. In vitro, oxygen-glucose deprivation-reperfusion (OGD/R)-induced HUVEC model and LPS-stimulated bone marrow-derived macrophage (BMDM) model were established to observe the effects of STDPs on angiogenesis and M2 macrophage polarization. Results: STDPs improved cardiac function, increased microvascular density, and the number of M2 macrophages in the heart of CMD rats. In vitro, STDPs accelerated the proliferation, migration, and tube formation in OGD/R-induced HUVECs similar to the effects of VEGF-A. Furthermore, in LPS-stimulated BMDMs model, STDPs modulated M2 macrophage polarization and increased VEGF-A release via the PI3K/AKT/mTORC1 pathway. Conclusion: STDPs promoted macrophage polarization-induced angiogenesis against CMD via the PI3K/Akt/mTORC1 pathway. Our results demonstrated that the phenotype transformation of macrophages and stimulating the secretion of VEGF-A may be applied as novel cardioprotective targets for the treatment of CMD.

Ferruginol Restores SIRT1-PGC-1α-Mediated Mitochondrial Biogenesis and Fatty Acid Oxidation for the Treatment of DOX-Induced Cardiotoxicity.

Background: Doxorubicin (DOX), a broad-spectrum chemotherapy drug, has life-threatening cardiotoxicity. Therefore, searching cardioprotective drugs for DOX-induced cardiotoxicity (DIC) is urgently needed. Objectives: This study aimed to explore cardioprotective effect and specific mechanism by which Ferruginol (FGL) attenuated DIC in vivo and in vitro. Methods: We evaluated the cardioprotection of FGL and performed high-throughput RNA-Seq on a DIC mouse. Whereafter, multiple methods, including western blot, RT-qPCR, a transmission electron microscope, CO-IP, immunofluorescence, and other staining methods, and antagonist of SIRT1 and PGC-1α were utilized to confirm the cardioprotection and molecular mechanism of FGL. Results: FGL-exerted cardioprotection manifested as enhanced cardiac function and reduced structural damage and apoptosis. The transcriptome and other results revealed that FGL facilitated PGC-1α-mediated mitochondrial biogenesis and fatty acid oxidation (MB and FAO) by increasing the expression of PGC-1α and concurrently promoting the expression of SIRT1-enhancing deacetylase SIRT1 deacetylating and activating PGC-1α. Conclusions: These results documented that FGL exerted cardioprotective effects restoring MB&FAO via the SIRT1-PGC-1α axis.

[Safety evaluation and risk control measures for Aconiti Kusnezoffii Radix].

Through the comprehensive and systematic research of domestic and overseas literature and information, we studied ancient original records on Aconiti Kusnezoffii Radix and its toxicity, analyzed related adverse cases and the animal toxicity experiments in recent years, then systematically analyzed the safety of Aconitum and its preparations, and finally we summarized the clinical characteristics and potential risk factors related to the safety of Aconitum. A report on adverse events of Aconitum in 76 patients with myocardial damage and renal damage accounting for 53.9% and 42.1% respectively, indicated that the safety problems of Aconitum may be related to heart toxicity and liver-kidney toxicity. Aconitum had complex compositions, and based on the animal experiments, Aconitum decoction had the highest toxicity at 2 h, and it reduced significantly at 4 h, which showed that the toxic components mainly depend on the hydrolysis or the decomposition degree of diester diterpenoid alkaloids. According to the toxicity study, Aconitum toxicity might occur in cardiovascular system, nervous system, kidney, embryo, reproductive system, and it was contraindicated in pregnant women. So far, specific antidote for aconitine poisoning is still a blank. The key for treatment is to correct arrhythmia timely and effectively, maintain stable vital signs, and meanwhile, give gastric lavage, intravenous fluid infusion and other therapies. So we suggest that the basic study for Aconitum toxicology should be strengthened, and the pharmacology and mechanism of toxicity, as well as the mechanism of processing for raising efficiency and reducing toxicity, should be further clarified to determine the quantity-effect relationship and eliminate safety hazards in using Aconitum.

[Effects of total flavonoids in Astragali Complanati Semen on liver lipid level and ERα expression on liver in hyperlipidemia rats with kidney-Yang deficiency pattern].

Menopausal women appear lipid metabolism disorder with the ovarian function decline and the estrogen levels decreased. Modern clinical usually use estrogen replacement therapy and with long time application with lots of side effect appear. Traditional Chinese medicine has more secure and effective methords,using warming Yang drugs and methods. And the previous study proves the Chinese medicine Astragali Complanati Semen water extraction has a good role in regulation of blood lipids. Because of the liver is the most important organ on regulating metabolism, therefore this study aimed to evaluate the effects of total flavonoids in Astragali Complanati Semen(TFS)on liverlipid level and ERα expressionon liver in hyperlipidemia rats with kidney-Yang deficiency pattern to explore the substance basis and mechanism of Astragali Complanati Semen in regulate lipid effect and clarify traditional Chinese medicine advantages and features. This experiment uses hyperlipidemia rats with kidney-Yang deficiency pattern with bilateral ovariectomized and fed with high fat diet for 6 weeks. And rats of sham operation group and model group rats were intragastrilly(ig) with saline, estrogen group were intragastrilly with estrogen(0.2 mg·kg⁻¹). And three TFS group were intragastrilly with TFS at dose 28.5, 57, 114 mg·kg⁻¹ for 8 weeks. At the same time, TC, TG, LDL-C,HDL-C liver weight, liver index, uterine weight, uterine index, serum estrogen level, FSH levels and liver pathology, liver estrogen receptor expression were detected, weighting and calculating their organ index. The experimental results compared with the model group, TFS 114 mg·kg⁻¹ decreased the level of liver TG (P<0.05), TC (P<0.001) and LDL-C (P<0.001) and increased the level of HDL-C (P<0.05). Compared with the model group, estrogen group increased the level of blood serum (P<0.001) and decreased the level of FSH (P<0.001). In addition, compared with sham operation group,model group decreased the protein expression of ERα（P<0.01）. Compared with the model group, estrogen group increased the protein expression of ERα significantly（P<0.001）.TFS mid-dose group and TFS high-dose group is increased the protein expression of ERα（P<0.01, P<0.001）.In a conclusion,Flavonoids is the main active ingredient of Astragali Complanati Semen. The mechanism of it maybe is enhancing the estrogen receptor sensitivity or the number of estrogen receptors, amplifying the signal after the receptor conduction, which could result in lipid-lowering effect.

[Safety evaluation of Sophora tonkinensis and risk control].

The aim is to systemically review and evaluate the safety of Sophora tonkinensis from the literature on the herbal origin, toxicity record in modern literature and toxicological studies and publications in recent years. By systematic review and analysis, the results showed that its toxicity mainly involved the nervous system, the digestive system and the respiratory system, and respiratory failure may be the direct cause of death. The main symptoms included headache, dizziness, vomiting, nausea, abdominal pain, limbs weakness, palpitation, and chest distress; as well as pale complexion, limbs trembling, convulsions, chills, high heart rate, fall of blood pressure, shock, and respiratory failure to death in severe cases. High dose and long term medication may cause serious brain damage, especially in adolescents and children. The authors have proposed to use rationally under guidance of physician and strictly according to the dosage recommended by pharmacopoeia. The patients shall not be credulous about the folk prescriptions and test recipes to use it for,prevention of colds and treatment of sore throat at will. In addition, the researches on the conventional treatment methods for S. tonkinensis poisoning, the toxic substance basis, and toxicity mechanism shall be strengthened in further studies. These efforts will play important role in exerting the drug effect and avoiding side effect.