Distinct roles of telomerase activity in age-related chronic diseases: An update literature review.

Although telomerase has low activity in somatic quiescent cells, it plays an significant roles in regenerative cells such as endothelial cells, hepatocytes, epithelial cells, and hemocytes. Telomerase activity and telomere length are critical factors in age-related chronic diseases as they are closely related to cell senescence. However, whether telomerase activity plays a key role in disease progression or whether the role of telomerase is unified among different diseases are unresolved. Considering that aging is the most important risk factor for neurodegenerative and metabolic diseases, this article will analyze the evidence, mechanism, and therapeutic potential of telomerase activity in several chronic disease, including type 2 diabetes, neurodegenerative diseases, atherosclerosis, heart failure and non-alcoholic fatty liver disease, in order to provide clues for the use of telomerase activity to target the treatment of age-related chronic diseases.

The origin, progress, and application of cell-based cardiac regeneration therapy.

Cardiovascular disease (CVD) has become a severe threat to human health, with morbidity and mortality increasing yearly and gradually becoming younger. When the disease progresses to the middle and late stages, the loss of a large number of cardiomyocytes is irreparable to the body itself, and clinical drug therapy and mechanical support therapy cannot reverse the development of the disease. To explore the source of regenerated myocardium in model animals with the ability of heart regeneration through lineage tracing and other methods, and develop a new alternative therapy for CVDs, namely cell therapy. It directly compensates for cardiomyocyte proliferation through adult stem cell differentiation or cell reprogramming, which indirectly promotes cardiomyocyte proliferation through non-cardiomyocyte paracrine, to play a role in heart repair and regeneration. This review comprehensively summarizes the origin of newly generated cardiomyocytes, the research progress of cardiac regeneration based on cell therapy, the opportunity and development of cardiac regeneration in the context of bioengineering, and the clinical application of cell therapy in ischemic diseases.

Guanxinning injection ameliorates cardiac remodeling in HF mouse and 3D heart spheroid models via p38/FOS/MMP1-mediated inhibition of myocardial hypertrophy and fibrosis.

BACKGROUND: Heart failure (HF) is a cardiovascular disease with high morbidity and mortality. Guanxinning injection (GXNI) is clinically used for the treatment of coronary heart disease, but its therapeutic efficacy and potential mechanism for HF are poorly understood. This study aimed to evaluate the therapeutic potential of GXNI on HF, with a special focus on its role in myocardial remodeling. METHODS: 3D cardiac organoids and transverse aortic constriction (TAC) mouse models were established and utilized. Heart function and pathology were evaluated by echocardiography, hemodynamic examination, tail-cuff blood pressure and histopathology. Key targets and pathways regulated by GXNI in HF mouse heart were revealed via RNA-seq and network pharmacology analysis, and were verified by RT-PCR, Western blot, immunohistochemistry and immunofluorescence. RESULTS: GXNI significantly inhibited cardiac hypertrophy and cells death. It protected mitochondrial function in cardiac hypertrophic organoids and markedly improved cardiac function in HF mice. Analysis of GXNI-regulated genes in HF mouse hearts revealed that IL-17A signaling in fibroblasts and the corresponding p38/c-Fos/Mmp1 pathway prominently mediated cardiac. Altered expressions of c-Fos, p38 and Mmp1 by GXNI in heart tissues and in cardiac organoids were validated by RT-PCR, WB, IHC, and IF. H&E and Masson staining confirmed that GXNI substantially ameliorated myocardial hypertrophy and fibrosis in HF mice and in 3D organoids. CONCLUSION: GXNI inhibited cardiac fibrosis and hypertrophy mainly via down-regulating p38/c-Fos/Mmp1 pathway, thereby ameliorating cardiac remodeling in HF mice. Findings in this study provide a new strategy for the clinical application of GXNI in the treatment of heart failure.

SUMO1 regulates post-infarct cardiac repair based on cellular heterogeneity.

Small ubiquitin-related modifier (SUMOylation) is a dynamic post-translational modification that maintains cardiac function and can protect against a hypertrophic response to cardiac pressure overload. However, the function of SUMOylation after myocardial infarction (MI) and the molecular details of heart cell responses to SUMO1 deficiency have not been determined. In this study, we demonstrated that SUMO1 protein was inconsistently abundant in different cell types and heart regions after MI. However, SUMO1 knockout significantly exacerbated systolic dysfunction and infarct size after myocardial injury. Single-nucleus RNA sequencing revealed the differential role of SUMO1 in regulating heart cells. Among cardiomyocytes, SUMO1 deletion increased the Nppa + Nppb + Ankrd1 + cardiomyocyte subcluster proportion after MI. In addition, the conversion of fibroblasts to myofibroblasts subclusters was inhibited in SUMO1 knockout mice. Importantly, SUMO1 loss promoted proliferation of endothelial cell subsets with the ability to reconstitute neovascularization and expressed angiogenesis-related genes. Computational analysis of ligand/receptor interactions suggested putative pathways that mediate cardiomyocytes to endothelial cell communication in the myocardium. Mice preinjected with cardiomyocyte-specific AAV-SUMO1, but not the endothelial cell-specific form, and exhibited ameliorated cardiac remodeling following MI. Collectively, our results identified the role of SUMO1 in cardiomyocytes, fibroblasts, and endothelial cells after MI. These findings provide new insights into SUMO1 involvement in the pathogenesis of MI and reveal novel therapeutic targets.

M2 Macrophage-Derived sEV Regulate Pro-Inflammatory CCR2+ Macrophage Subpopulations to Favor Post-AMI Cardiac Repair.

Tissue-resident cardiac macrophage subsets mediate cardiac tissue inflammation and repair after acute myocardial infarction (AMI). CC chemokine receptor 2 (CCR2)-expressing macrophages have phenotypical similarities to M1-polarized macrophages, are pro-inflammatory, and recruit CCR2+ circulating monocytes to infarcted myocardium. Small extracellular vesicles (sEV) from CCR2̶ macrophages, which phenotypically resemble M2-polarized macrophages, promote anti-inflammatory activity and cardiac repair. Here, the authors harvested M2 macrophage-derived sEV (M2EV ) from M2-polarized bone-marrow-derived macrophages for intramyocardial injection and recapitulation of sEV-mediated anti-inflammatory activity in ischemic-reperfusion (I/R) injured hearts. Rats and pigs received sham surgery; I/R without treatment; or I/R with autologous M2EV treatment. M2EV rescued cardiac function and attenuated injury markers, infarct size, and scar size. M2EV inhibited CCR2+ macrophage numbers, reduced monocyte-derived CCR2+ macrophage recruitment to infarct sites, induced M1-to-M2 macrophage switching and promoted neovascularization. Analysis of M2EV microRNA content revealed abundant miR-181b-5p, which regulated macrophage glucose uptake, glycolysis, and mitigated mitochondrial reactive oxygen species generation. Functional blockade of miR-181b-5p is detrimental to beneficial M2EV actions and resulted in failure to inhibit CCR2+ macrophage numbers and infarct size. Taken together, this investigation showed that M2EV rescued myocardial function, improved myocardial repair, and regulated CCR2+ macrophages via miR-181b-5p-dependent mechanisms, indicating an option for cell-free therapy for AMI.

Changes of energy metabolism in failing heart and its regulation by SIRT3.

Heart failure (HF) is the leading cause of hospitalization in elderly patients and a disease with extremely high morbidity and mortality rate worldwide. Although there are some existing treatment methods for heart failure, due to its complex pathogenesis and often accompanied by various comorbidities, there is still a lack of specific drugs to treat HF. The mortality rate of patients with HF is still high, highlighting an urgent need to elucidate the pathophysiological mechanisms of HF and seek new therapeutic approaches. The heart is an organ with a very high metabolic intensity, mainly using fatty acids, glucose, ketone bodies, and branched-chain amino acids as energy substrates to supply energy for the heart. Loss of metabolic flexibility and metabolic remodeling occurs with HF. Sirtuin3 (SIRT3) is a member of the NAD+-dependent Sirtuin family located in mitochondria, and can participate in mitochondrial physiological functions through the deacetylation of metabolic and respiratory enzymes in mitochondria. As the center of energy metabolism, mitochondria are involved in many physiological processes. Maintaining stable metabolic and physiological functions of the heart depends on normal mitochondrial function. The damage or loss of SIRT3 can lead to various cardiovascular diseases. Therefore, we summarize the recent progress of SIRT3 in cardiac mitochondrial protection and metabolic remodeling.

Rg3 regulates myocardial pyruvate metabolism via P300-mediated dihydrolipoamide dehydrogenase 2-hydroxyisobutyrylation in TAC-induced cardiac hypertrophy.

The failing heart is characterized by an increase in glucose uptake and glycolytic rates that is not accompanied by a concomitant increase in glucose oxidation. Lower coupling of glucose oxidation to glycolysis possibly owes to unchanged or reduced pyruvate oxidation in mitochondria. Therefore, increasing pyruvate oxidation may lead to new therapies for heart disease. Dihydrolipoamide dehydrogenase (DLD) is a component of the pyruvate dehydrogenase complex (PDH). DLD mutations or defects are closely associated with metabolic diseases. However, few studies explore the effects of DLD mutants or acylation status on PDH activity and pyruvate metabolism. P300 is protein 2-hydroxyisobutyryltransferases in cells, and P300-dependent lysine 2-hydroxyisobutyrylation of glycolytic enzymes affects glucose metabolism. However, there are no relevant reports on the effect of 2-hydroxyisobutyrylation on the energy metabolism of heart failure, and it is worth further in-depth study. In this study, we showed that 2-hydroxyisobutyrylation is an essential protein translational modification (PTM) that regulates the activity of pyruvate dehydrogenase complex (PDHc). In a mouse model of transverse aortic constriction (TAC)-induced cardiac hypertrophy, the 2-hydroxyisobutylation of DLD was significantly increased, related to the decrease in PDH activity. In addition, our data provide clear evidence that DLD is a direct substrate of P300. As one of the main active ingredients of ginseng, ginsenoside Rg3 (Rg3) can reduce the 2-hydroxyisobutylation levels of DLD and restore the PDH activity by inhibiting the acyltransferase activity of P300, thereby producing beneficial effects whenever the heart is injured. Therefore, this study suggests a novel strategy for reversing myocardial hypertrophy.

Impact of caregiver burden on caregiver mental health in patients with esophageal cancer: chain mediating effects of benefit finding and rumination, a cross-sectional study.

Background: Cancer caregivers are the main supporter for the tumor patients, they not only need to provide daily nursing to the patients, but also suffering the pressure from economy, emotion and even family members. The mental health of tumor patient is mostly noticed, while not caregivers. The mental health of caregiver greatly affected the nursing quality and even the treatment outcomes. In the current study, the mechanisms underlying the links between caregiver burden, benefit finding, mental health, and rumination in those caring for people with esophageal cancer were examined. Methods: The study was using a convenience sampling, 166 esophageal cancer patients in 2 general hospitals in Jiangsu Province, China, and caregivers of patients were included after excluded the non-conforming patients. Data were collected using investigator-developed questionnaires, the Benefit Finding Scale (BFS), the Event-Related Rumination Inventory (ERRI), the Zarit Burden Interview (ZBI), and the Hospital Anxiety and Depression Scale (HADS) during May 2020 to December 2020. The results were analyzed by SPSS, and the chain mediating effect was analyzed by the the SPSS PROCESS Macro Model. Results: The study comprised 166 caregivers with an average age of (59.96±11.48) years, most of them were female (85.5%). The ZBI was positive correlated with HADS (r=0.882, P<0.01), and negative correlated with BFS (r=-0.873, P<0.01). Intrusive rumination and deliberate rumination in caregivers were negatively correlated (r=-0.901, P<0.01) and positive correlated (r=0.904, P<0.01) with BFS scores, respectively. Furthermore, research have discovered a chain mediation impact of benefit finding and rumination between caregiver burden and psychological well-being among carers of esophageal cancer patients. Conclusions: The findings of this study imply that benefit finding and rumination are crucial components of the coping strategy used to buffer against negative emotion (such as anxiety and depression). Therefore, the mental health of caregivers should also be noticed, and health care professionals should provide targeted interventions to increase the caregiver's level of benefit finding and promote deliberate ruminative thinking.

Role of the CCL2-CCR2 axis in cardiovascular disease: Pathogenesis and clinical implications.

The CCL2-CCR2 axis is one of the major chemokine signaling pathways that has received special attention because of its function in the development and progression of cardiovascular disease. Numerous investigations have been performed over the past decades to explore the function of the CCL2-CCR2 signaling axis in cardiovascular disease. Laboratory data on the CCL2-CCR2 axis for cardiovascular disease have shown satisfactory outcomes, yet its clinical translation remains challenging. In this article, we describe the mechanisms of action of the CCL2-CCR2 axis in the development and evolution of cardiovascular diseases including heart failure, atherosclerosis and coronary atherosclerotic heart disease, hypertension and myocardial disease. Laboratory and clinical data on the use of the CCL2-CCR2 pathway as a targeted therapy for cardiovascular diseases are summarized. The potential of the CCL2-CCR2 axis in the treatment of cardiovascular diseases is explored.

Ginsenoside Rg3 ameliorates myocardial glucose metabolism and insulin resistance via activating the AMPK signaling pathway.

Background: Ginsenoside Rg3 is one of the main active ingredients in ginseng. Here, we aimed to confirm its protective effect on the heart function in transverse aortic coarctation (TAC)-induced heart failure mice and explore the potential molecular mechanisms involved. Methods: The effects of ginsenoside Rg3 on heart and mitochondrial function were investigated by treating TAC-induced heart failure in mice. The mechanism of ginsenoside Rg3 for improving heart and mitochondrial function in mice with heart failure was predicted through integrative analysis of the proteome and plasma metabolome. Glucose uptake and myocardial insulin sensitivity were evaluated using micro-positron emission tomography. The effect of ginsenoside Rg3 on myocardial insulin sensitivity was clarified by combining in vivo animal experiments and in vitro cell experiments. Results: Treatment of TAC-induced mouse models with ginsenoside Rg3 significantly improved heart function and protected mitochondrial structure and function. Fusion of metabolomics, proteomics, and targeted metabolomics data showed that Rg3 regulated the glycolysis process, and Rg3 not only regulated glucose uptake but also improve myocardial insulin resistance. The molecular mechanism of ginsenoside Rg3 regulation of glucose metabolism was determined by exploring the interaction pathways of AMPK, insulin resistance, and glucose metabolism. The effect of ginsenoside Rg3 on the promotion of glucose uptake in IR-H9c2 cells by AMPK activation was dependent on the insulin signaling pathway. Conclusions: Ginsenoside Rg3 modulates glucose metabolism and significantly ameliorates insulin resistance through activation of the AMPK pathway.

SGLT2 inhibitors break the vicious circle between heart failure and insulin resistance: targeting energy metabolism.

Heart failure (HF) often coexists with insulin resistance (IR), and the incidence of HF in type 2 diabetes mellitus (T2DM) patients is significantly higher. The reciprocal relationship between HF and IR has long been recognized, and the integration complicates the therapy of both. A number of mechanisms ascribe to the progression of cardiac IR, in which the main factors are the shift of myocardial substrate metabolism. Studies have found that SGLT2 inhibitors, an anti-diabetic drug, can improve the cardiac prognosis of patients with T2DM, which may be at least partially due to the relief of cardiac IR. Basic and clinical studies have revealed the important role of cardiac IR in the pathogenesis and progression of HF, and studies suggest that energy metabolism plays an important role in the pathogenesis of cardiac IR and HF. SGLT2 inhibitors mediated cardiovascular benefits through various mechanisms such as improving substrate utilization and improving myocardial energy. The regulation of SGLT2 inhibitors on cardiac energy status including carbohydrates, fatty acids (FA), amino acids and ketones, ATP transfer to the cytoplasm, and mitochondrial functional status have received extensive attention in HF, but its specific mechanism of action is still unclear. Therefore, this article reviews the relationship between IR and HF from the perspective of energy metabolism; subsequently, targeting energy metabolism discusses the pivotal role of SGLT2 inhibitors in improving cardiac IR and HF based on basic and clinical research evidences, and sought to clarify the molecular mechanism involved. (Fig. 1).

Tianma Gouteng Decoction regulates oxidative stress and inflammation in AngII-induced hypertensive mice via transcription factor EB to exert anti-hypertension effect.

Hypertension is one of the important causes of cardiovascular diseases, and the imbalance of vascular homeostasis caused by oxidative stress and endothelial inflammation occurs throughout hypertension pathogenesis. Therefore, inhibiting oxidative stress and endothelial inflammation is important for treating hypertension. Tianma Gouteng Decoction (TGD) is a Chinese herbal medicine that is commonly used to treat hypertension in China, and demonstrates clinically effective antihypertensive effects. However, its blood pressure reduction mechanism remains unclear. In this study, we further determined the antihypertensive effects of TGD and revealed its underlying mechanism. We established an AngII-induced hypertension mice model, which was treated with TGD for six weeks. We monitored blood pressure, heart rate, and body weight every week. After six weeks, we detected changes in the structure and function of the heart, the structure of blood vessels, and vasomotor factors. We also detected the expression of oxidative stress and inflammation-related genes. We found that TGD can significantly reduce blood pressure, improve cardiac structure and function, and reverse vascular remodeling, which could be due to the inhibition of oxidative stress and inflammation. We also found that the effect of inhibiting oxidative stress and inflammation could be related to the up-regulation of transcription factor EB (TFEB) expression by TGD. Therefore, we used AAV9 to knock down TFEB and observe the role of TFEB in TGD's antihypertensive and cardiovascular protection properties. We found that after TFEB knockdown, the protective effect of TGD on blood pressure and cardiovascular remodeling in AngII-induced hypertensive mice was inhibited, and that it was unable to inhibit oxidative stress and inflammation. Therefore, our study demonstrated for the first time that TGD could exert anti-oxidative stress and anti-inflammatory effects through TFEB and reverse the cardiovascular remodeling caused by hypertension.

Contradictory regulation of macrophages on atherosclerosis based on polarization, death and autophagy.

The main pathological feature of atherosclerosis is lipid metabolism disorder and inflammation. Macrophages, as the most important immune cells in the body, run through the beginning and end of disease development. After macrophages overtake the atherosclerosis-susceptible area apolipoprotein low-density lipoprotein ox-LDL, they transform into foam cells that adhere to blood vessels and recruit a large number of pro-inflammatory factors to initiate the disease. Promoting the outflow of lipids in foam cells and alleviating inflammation have become the basic ideas for the study of atherosclerosis treatment strategies. The polarization of macrophages refers to the estimation of the activation of macrophages at a specific point in space and time. Determining the proportion of different macrophage phenotypes in the plaque can help identify delay or prevent disease development. However, the abnormal polarization of macrophages and the accumulation of lipid also affect the growth state of cells to some extent, thus aggravate the influence on plaque area and stability. Besides, overactive or deficient autophagy of macrophages may also lead to cell death and participate in lipid metabolism and inflammation regression. In this paper, the role of macrophages in atherosclerosis was discussed from three aspects: polarization, death, and autophagy.

Regulation of energy metabolism by combination therapy attenuates cardiac metabolic remodeling in heart failure.

Cardiac metabolic remodeling is recognized as an important hallmark of heart failure (HF), while strategies that target energy metabolism have therapeutic potential in treating HF. Shen-Fu formula (S-F) is a standardized herbal preparation frequently used in clinical practice and is a promising combinatorial therapy for HF-related metabolic remodeling. Herein, we performed an untargeted multi-omics analysis using transcriptomics, proteomics, and metabolomics on HF mice induced by transverse aortic constriction (TAC). Integrated and pathway-driven analyses were used to reveal the therapeutic targets associated with S-F treatment. The cardioprotective effect and potential mechanism of S-F were verified by the results from echocardiography, hemodynamics, histopathology, and biochemical assays. As a result, S-F significantly alleviated myocardial fibrosis and hypertrophy, thus reducing the loss of heart function during adverse cardiac remodeling in TAC mice. Integrated omics analysis showed that S-F synergistically mediated the metabolic flexibility of fatty acids and glucose in cardiac energy metabolism. These effects of S-F were confirmed by the activation of AMP-activated protein kinase (AMPK) and its downstream targets in the failing heart. Collectively, our results demonstrated that S-F suppressed cardiac metabolic remodeling through activating AMPK-related pathways via energy-dependent mechanisms.

Qi Dan Li Xin pill improves chronic heart failure by regulating mTOR/p70S6k-mediated autophagy and inhibiting apoptosis.

Myocardial remodeling represents a key factor in chronic heart failure (CHF) development, and is characterized by chronic death of cardiomyocytes. Cardiac function changes may be attributed to inflammation, apoptosis and autophagy. This study assessed the effects of Qi Dan Li Xin Pill (QD) on heart function, inflammatory factors, autophagy and apoptosis in cardiac remodeling in CHF rats upon myocardial infarction (MI) induction. Male SD rats underwent a sham procedure or left anterior descending coronary artery (LADCA) ligation, causing MI. Twenty-eight days after modeling, the animals were treated daily with QD, valsartan and saline for 4 weeks. Echocardiography after 4 weeks of drug intervention revealed substantially improved left ventricular remodeling and cardiac function following QD treatment. As demonstrated by decreased IL-1ß, IL-6 and TNF-α amounts, this treatment also inhibited the apoptotic process and protected the viability of the myocardium. These outcomes may be attributed to enhanced autophagy in cardiomyocytes, which further reduced pro-inflammatory and pro apoptotic effects. This process may be achieved by QD regulation of the mTOR/P70S6K signaling pathway, suggesting that the traditional Chinese medicine Qi Dan Li Xin pill is effective in heart protective treatment, and is worth further investigation.

Toddalolactone Protects Lipopolysaccharide-Induced Sepsis and Attenuates Lipopolysaccharide-Induced Inflammatory Response by Modulating HMGB1-NF-κB Translocation.

Toddalolactone (TA-8) is a main compound isolated from Toddalia asiatica (L.) Lam., and its anti-inflammatory activity and anti-inflammatory mechanism are less studied. In the present study, we investigated the anti-inflammatory effects of TA-8. Our experimental results showed that TA-8 inhibited the production of pro-inflammatory cytokines by both lipopolysaccharide (LPS)-activated RAW 264.7 cells and septic mice. Moreover, TA-8 suppressed the NF-κB transcriptional activity, reduced the nuclear translocation and phosphorylation of NF-κB, blocked the translocation of HMGB1 from the nucleus to cytosol, and decreased LPS-induced up-regulation of TLR4 and IKBKB expression, and decreased IκBα phosphorylation. In addition, the administration of TA-8 decreased LPS-induced liver damage markers (AST and ALT), attenuated infiltration of inflammatory cells and tissue damage of lung, liver, and kidney, and improved survival in septic mice. Taken together, these results suggested that toddalolactone protects LPS-induced sepsis and attenuates LPS-induced inflammatory response by modulating HMGB1-NF-κB translocation. TA-8 could potentially be a novel anti-inflammatory and immunosuppressive drug candidate in the treatment of sepsis and septic shock.

Ginsenoside Rg3-loaded, reactive oxygen species-responsive polymeric nanoparticles for alleviating myocardial ischemia-reperfusion injury.

Myocardial ischemia-reperfusion injury (MIRI) is a serious threat to the health and lives of patients without any effective therapy. Excessive production of reactive oxygen species (ROS) is considered a principal cause of MIRI. Some natural products, including ginsenoside Rg3 (Rg3), exhibit robust antioxidant activity. However, the lack of an effective delivery strategy for this hydrophobic compound hinders its clinical application. In addition, therapeutic targets and molecular mechanisms of Rg3 require further elucidation to establish its mode of action. This study aimed to generate ROS-responsive nanoparticles (PEG-b-PPS) via the self-assembly of diblock copolymers of poly (ethylene glycol) (PEG) and poly (propylene sulfide) (PPS) and use them for Rg3 encapsulation and delivery. We identified FoxO3a as the therapeutic target of Rg3 using molecular docking and gene silencing. In rat ischemia-reperfusion model, an intramyocardial injection of Rg3-loaded PEG-b-PPS nanoparticles improved the cardiac function and reduced the infarct size. The mechanism of action was established as Rg3 targeting of FoxO3a, which inhibited the promotion of oxidative stress, inflammation, and fibrosis via downstream signaling pathways. In conclusion, this approach, involving ROS-responsive drug release, together with the identification of the target and mechanism of action of Rg3, provided an effective strategy for treating ischemic diseases and oxidative stress and could accelerate the implementation of hydrophobic natural products in clinical applications.

Effects of the combination of tanshinone IIA and puerarin on cardiac function and inflammatory response in myocardial ischemia mice.

BACKGROUND: Ventricular remodeling is a major pathological process of normal heart failure. With the aging of society, poor diet control, social, psychological and other risk factors in our country, the incidence of myocardial infarction and hypertension is reported to increase yearly. Many treatment methods have effectively delayed the occurrence of ventricular remodeling. However, in order to prevent and delay the occurrence and development of ventricular remodeling, the new treatment strategy cannot be ignored. METHODS: In this study, we used male C57BL/6 mice (8 weeks old), weight 23 g-27 g, SPF grade. According to the established methods of the research group, the left anterior descending branch of the coronary artery (LAD) was used to make the model of myocardial ischemia, and which was evaluated by the change of EF value in mice. The experiment included seven groups: sham operation group, model group, metoprolol group, puerarin group, tanshinone IIA group, tanshinone IIA: puerarin =1:1 group, tanshinone IIA: puerarin =1:2 group. The changes of cardiac function in each group were observed by echocardiography and hemodynamics after the drug delivery cycle was 3d, 7d, 14d and 28d. Detection of 3d serum enzyme indexes LDH, CK and CK-MB by automatic biochemical analyzer. The expression of CD11b, F4/80, Ly6C in cardiac tissues were detected by flow cytometry at 3d and 7d. The expression of IL-1ß and TNF- α in serum were detected by ELISA. IL-1ß, IL-6, IL-10, iNOS and other related genes were detected by RT-PCR method. HE, Masson staining and immunohistochemical staining were used to observe the changes of myocardial histomorphology in mice. We also examined the effects of different drug treatments on the proliferation and function of Raw264.7 cells, H9C2 cells and HUVECs. Western blot examined the effects of different drug treatments on the expression of inflammatory pathway related proteins TLR4 and C/EBP-ß. RESULTS: 1. Echocardiographic results showed that with the prolongation of ischemic time, the ejection fraction of the model group, the shortening rate of the short axis of the left ventricle, the flow rate of the outflow tract were significantly decreased, and the structure of the ventricle was significantly changed. Hemodynamic tests showed that the maximum and maximum rate of decline in the post-ischemia model group were significantly reduced, with increased systolic and diastolic volume, and a decrease in pressure difference. After treatment with drugs, all groups improved, but tanshinone IIA: puerarin = 1:1 group can significantly improve the above indicators after 28d of administration, which can effectively relieve the deterioration of cardiac function caused by acute myocardial infarction. 2. After administration for 3 and 7 days, the inflammatory cell CD11b monocytes and the F4/80 phenotype macrophages in heart tissue were detected by flow cytometry, and it was found that tanshinone IIA: puerarin = 1:1 can inhibit the release of inflammatory cells. The results of RT-PCR showed that the tanshinone IIA: puerarin = 1:1 group significantly improved the expression of inflammatory cytokines such as IL-1ß, IL-6, IL-10, and iNOS. In the immunohistochemical analysis of iNOS and Arg-1, the tanshinone IIA and puerarin 1:1 treatment group was able to inhibit the expression of M1 macrophages in the early stage of inflammation and promote the expression of M2 macrophages. 3. The cardiac index increased significantly and the serum TGF-ß increased after 28d. The combination of tanshinone IIA and puerarin could significantly reduce these indexes. HE, Masson, Sirius red and immunohistochemical staining were found in the combination of tanshinone IIA and puerarin can significantly reduce the structure of acute ischemic myocardial cell damage and interstitial edema, reduce collagen synthesis, and fibroblasts release, thereby inhibiting myocardial fibrosis and heart remodeling. 4. MTT assay showed a significantly greater proliferation of above two cells types treated with tanshinone IIA: puerarin =1:1 and more nodes and meshes were found in tanshinone IIA: puerarin =1:1 group compared with other groups. 5. The combination of tanshinone IIA and puerarin could regulate inflammation through inhibiting the expression of TLR4 protein, but up-regulating the expression of C/EBP-ß protein. CONCLUSION: The combination of tanshinone IIA and puerarin inhibits the immersion of inflammatory cells. Improving hemodynamics by improving cardiac function, reducing the destruction of cardiac myocytes, reducing collagen synthesis, inhibiting myocardial fibrosis and ventricular remodeling. Through the whole experiment, tanshinone IIA: puerarin = 1:1 is the best.

Prevalence of cardiovascular risk factors in non-menopausal and postmenopausal inpatients with type 2 diabetes mellitus in China.

BACKGROUND: To investigate the prevalence of cardiovascular disease (CVD) risk factors and assess the 10-year risk of CVD in non-menopausal and postmenopausal women with type 2 diabetes mellitus (T2DM). METHODS: A total of 569 patients with T2DM at a Chinese tertiary hospital were investigated using the Framingham Risk Score (FRS). We evaluated the 10-year risk of CVD, clinical and menopause characteristics in all subjects. RESULTS: Among the 569 diabetic patients, the incidence of smoking, dyslipidemia, hypertension, overweight or obesity, and nonalcoholic fatty liver disease (NAFLD) was 0.7, 36.2, 38.1 56.6 and 58.2%, respectively. The usage rate of hypoglycemic agents, antihypertensive agents, lipid modulators and antithrombotic drugs was 88.6, 78.3, 50.0 and 27.1%, respectively. However, only 1.2% of inpatients achieved the three target goals for the control of blood glucose (HbA1c < 7%), blood pressure (systolic blood pressure < 130 mmHg, diastolic blood pressure < 80 mmHg), and blood lipids (total cholesterol < 174 mg/dL). The 10-year risk of CVD was (1.6 ± 1.5%) and tended to increase along with age (F = 27.726, P <  0.001). For all subjects (n = 569), multiple linear regression analysis showed that menopause (ß = 0.275, P <  0.001), low-density lipoprotein cholesterol (LDL-C) (ß = 0.212, P <  0.001), fasting plasma glucose (FPG) (ß = 0.093, P = 0.018) and waist-to-hip-ratio (ß = - 0.078, P = 0.047) were risk factors of 10-year risk of CVD, which may explain the variance of 14.3%. In the postmenopausal group (n = 397), LDL-C (ß = 0.227, P <  0.001), FPG (ß = 0.139, P = 0.003) and time since menopause (ß = 0.230, P <  0.001) were found to be associated with CVD, which may explain the variance of 14.6%. CONCLUSION: The incidence of dyslipidmia, hypertension, overweight or obesity and NAFLD is high. The level of control of blood glucose, blood pressure, and blood lipids was found to be extremely low and the treatment status was not ideal. Besides menopause, LDL-C, FPG and time since menopause were found to be independent risk factors for the 10-year risk of CVD. Therefore, it is necessary to focus on comprehensive control of multiple risk factors, such as plasma glucose, blood pressure and serum lipid.

Cardioprotective Effect of Danhong Injection against Myocardial Infarction in Rats Is Critically Contributed by MicroRNAs.

BACKGROUND: Danhong injection (DHI) has been mainly used for the treatment of myocardial infarction, atherosclerosis, and coronary heart disease in clinical practice. Our previous studies have shown that DHI improves ventricular remodeling and preserves cardiac function in rats with myocardial infarction (MI). In this study, we focused on the potential mechanism of DHI in protecting cardiac function in MI rats. METHODS: Sprague-Dawley rats were subjected to ligation of the left anterior descending coronary artery (LAD) to prepare a myocardial infarction (MI) model. After 14 day DHI intervention, cardiac function was measured by echocardiography and myocardial fibrosis was assessed by Masson staining. Differentiated miRNAs were screened using rat immunopathology miScript miRNA PCR arrays, and their results were verified by RT-PCR, immunofluorescence, and immunoblotting. RESULTS: DHI treatment significantly reduced infarct size and improved cardiac function and hemodynamics in MI rats by echocardiography and morphology. miRNA PCR array results showed that DHI reversed 25 miRNAs known to be associated with inflammation and apoptosis. Moreover, the expression of inflammatory factors TNF-α, IL-1ß, and IL-6 was significantly reduced in the treated DHI group. Mechanistically, DHI downregulated the inflammatory transcription factor NF-κB (as reflected by inhibition of NF-κB p65 nuclear translocation and phosphorylation of the IκBα). CONCLUSIONS: DHI is effective in mitigating inflammation associated with MI by preventing NF-κB nuclear translocation and regulating miRNAs, thereby improving cardiac function in myocardial infarction rats.