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Doxorubicin (DOX) is an important chemotherapeutic agent for the treatment of hematologic tumors and breast carcinoma. However, its clinical application is limited owing to severe cardiotoxicity. Pyroptosis is a form of programmed cell death linked to DOX-induced cardiotoxicity. Bone mesenchymal stem cell–derived exosomes (BMSC-Exos) and endothelial progenitor cells-derived exosomes(EPC-Exos) have a protective role in the myocardium. Here we found that BMSC-Exos could improve DOX-induced cardiotoxicity by inhibiting pyroptosis, but EPC-Exos couldn’t. Compared with EPCs-Exo, BMSC-Exo-overexpressing lncRNA GHET1 more effectively suppressed pyroptosis, protecting against DOX-induced cardiotoxicity. Further studies showed that lncRNA GHET1 effectively decreased the expression of Nod-like receptorprotein 3 (NLRP3), which plays a vital role in pyroptosis by binding to IGF2 mRNA-binding protein 1 (IGF2BP1), a non-catalytic posttranscriptional enhancer of NLRP3 mRNA. In summary, lncRNA GHET1 released by BMSC-Exo ameliorated DOX-induced pyroptosis by targeting IGF2BP1 to reduce posttranscriptional stabilization of NLRP3.

Objectives. We conducted a meta-analysis to quantitatively evaluate the effect of melatonin therapy on patients with myocardial ischemia-reperfusion injury (MIRI) and explore the influencing factors. Background. Although preclinical studies have shown that melatonin can alleviate MIRI, its protective effect on MIRI in patients remains controversial. Methods. We searched PubMed, the Cochrane Library, and Embase. The primary outcome was cardiac function (left ventricular ejection fraction [LVEF], left ventricular end-diastolic volume [LVEDV], and left ventricular end-systolic volume [LVESV]) and myocardial infarct parameters (total left ventricular mass and infarct size). Results. We included nine randomized controlled clinical trials with 631 subjects. Our results showed that melatonin had no significant effects on the primary outcome, but subgroup analyses indicated that when melatonin was administered by intravenous and intracoronary injection at the early stage of myocardial ischemia, LVEF was improved ( P = 0.03 ) and the infarct size was reduced ( P = 0.01 ), whereas when melatonin was injected at the late stage of myocardial ischemia (≥3.5 h or 2.5 h), the results were the opposite. Furthermore, melatonin intervention reduced the level of cardiac injury markers, inflammatory cytokines, oxidation factors, and increased the level of antioxidant factors ( P < 0.001 ). Conclusions. The results indicated that the cardioprotective function of melatonin for MIRI was influenced by the route and timing regimen of melatonin administration; the mechanism of which may be associated with the production of inflammatory cytokines, the balance of oxidation, and antioxidant factors.

Doxorubicin (DOX) has a wide antitumor spectrum, but its adverse cardiotoxicity may lead to heart failure. Urotensin II (UⅡ) is the most potent vasoconstrictor in mammals. It plays a role by activating the UII receptor (UT), the orphan G protein-coupled receptor (GPR14), collectively referred to as the UII/UT system. In the new version of "Chinese expert consensus on cardiac rehabilitation of chronic heart failure," it is pointed out that exercise rehabilitation is the cornerstone of cardiac rehabilitation. In this study, in vitro and in vivo assessments were performed using DOX-treated H9C2 cells and rats. It was found that the UT antagonist Urantide and exercise training improved DOX-induced cardiac insufficiency, reduced DOX-induced cardiomyocyte apoptosis, improved the structural disorder of myocardial fibers, and inhibited DOX-induced myocardial fibrosis. Further studies showed that Urantide alleviated DOX-induced cardiotoxicity by downregulating the expression levels of the p38 mitogen-activated protein kinase signaling pathway.

Background Increased Hcy level is an independent risk factor for coronary heart disease (CHD). It was proposed that yellow rice wine improves Hcy-induced EPCs dysfunction and inhibits the development of atherosclerotic plaques. In this study, we observed whether yellow rice wine and red wine improve the properties of homocysteine (Hcy)-induced endothelial progenitor cells (EPCs). Methods The bone marrow of rats was extracted to isolate EPCs from the bone marrow cell suspension using density-gradient centrifugation. The cells were inoculated on culture plates coated with human fibronectin (HFN), to induce mononuclear cell differentiation into EPCs. Samples were divided into 5 groups including a control group. Western blotting. and NO assays were used respectively to observe the generation of eNOS, p-eNOS and NO. MTT and transwell assays were conducted. Apoptosis and in vitro angiogenesis of EPCs were determined. Results Compared with the control group, the potential for proliferation, migration and in vitro angiogenesis of EPCs decreased significantly following Hcy intervention (P 0.05). No impact on apoptotic function of EPCs was observed (P > 0.05). Hcy significantly lowers the capacity of proliferation, migration and in vitro angiogenesis of EPCs and reduces the production of eNOS, p-eNOS and NO. Conclusion Our results showed Hcy significantly lowers the capacity of proliferation, migration and in vitro angiogenesis of EPCs and reduces the production of eNOS, p-eNOS and NO,which indicates that yellow rice wine and red wine in small doses improve the functions of EPCs.

Objectives: To evaluate the role and therapeutic value of homocysteine (hcy)-inducible endoplasmic reticulum stress (ERS) protein with ubiquitin like domain 1 (Herpud1) in hcy-induced calcific aortic valve disease (CAVD). Background: The morbidity and mortality rates of calcific aortic valve disease (CAVD) remain high while treatment options are limited.Methods: In vivo , we use the low-density lipoprotein receptor (LDLR) and Herpud1 double knockout (LDLR-/-/Herpud1-/-) mice assessment of aortic valve calcification lesions, ERS activation, autophagy, and osteogenic differentiation of aortic valve interstitial cells (AVICs). We used siRNA to knock down Herpud1 in cultured Primary AVICs were isolated from mice to further validate our findings. Results: Herpud1 was highly expressed in calcified human and mouse aortic valves as well as primary aortic valve interstitial cells (AVICs). Herpud1 deficiency inhibited hcy-induced CAVD in vitro and in vivo. Herpud1 silencing activated cell autophagy, which subsequently inhibited hcy-induced osteogenic differentiation of AVICs. Hcy increased Herpud1 expression through the ERS pathway and promoted CAVD progression. ERS inhibitor 4-phenyl butyric acid (4-PBA) significantly attenuated aortic valve calcification in high methionine diet–fed low-density lipoprotein receptor-/- (LDLR-/-) mice by suppressing ERS and subsequent Herpud1 biosynthesis. Conclusions: These findings identify a previously unknown mechanism of Herpud1 upregulation in CAVD progression, suggesting that Herpud1 silencing or inhibition is a viable therapeutic strategy for arresting CAVD progression.

Homocysteine (Hcy) is considered an independent risk factor for various cardiovascular diseases including atherosclerosis which is associated with lipid metabolism, inflammation, and oxidative stress. Results from our previous study suggested that Hcy-induced atherosclerosis could be reversed by Herpud1 knockout which inhibits vascular smooth muscle cell (VSMC) phenotype switching. Here, we aim to investigate more precise mechanisms behind the improvement in Hcy-induced atherosclerosis. Amyloid-β40 (Aβ40), a vital protein in Alzheimer disease (AD), has been regarded as an important component in the atherosclerosis program in recent years due to the biological similarity between AD and atherosclerosis. Thus, we determined to assess the value of Aβ40 in a Herpud1 knockout Hcy-induced atherosclerosis mouse model by measuring Aβ40 expression in tissue and biomarkers of lipid metabolism, inflammation, and oxidative stress in serum. Additionally, since endothelial dysfunction plays a prominent role in atherosclerosis, we tested human umbilical vein endothelial cell (HUVEC) function following Herpud1 silencing in vitro and evaluated JNK/AP1 signaling activation in our models because of its close relationship with Aβ40. As a result, our animal models showed that Herpud1 knockout reduced Aβ40 expression, inflammation, and oxidative stress levels other than lipid metabolism and alleviated atherosclerosis via JNK/AP1 signaling inhibition. Similarly, our cell experiments implied that Hcy-induced Aβ40 elevation and HUVEC dysfunction involving cell proliferation and apoptosis could be restored by Herpud1 silence through restraining JNK/AP1 pathway. Collectively, our study demonstrates that Herpud1 deficiency could reduce Aβ40 expression, thereby suppressing Hcy-induced atherosclerosis by blocking the JNK/AP1 pathway. This may provide novel potential targets for atherosclerosis prevention or treatment.

This newly inaugurated research database for 12-lead electrocardiogram signals was created under the auspices of Chapman University and Shaoxing People’s Hospital (Shaoxing Hospital Zhejiang University School of Medicine) and aims to enable the scientific community in conducting new studies on arrhythmia and other cardiovascular conditions. Certain types of arrhythmias, such as atrial fibrillation, have a pronounced negative impact on public health, quality of life, and medical expenditures. As a non-invasive test, long term ECG monitoring is a major and vital diagnostic tool for detecting these conditions. This practice, however, generates large amounts of data, the analysis of which requires considerable time and effort by human experts. Advancement of modern machine learning and statistical tools can be trained on high quality, large data to achieve exceptional levels of automated diagnostic accuracy. Thus, we collected and disseminated this novel database that contains 12-lead ECGs of 10,646 patients with a 500 Hz sampling rate that features 11 common rhythms and 67 additional cardiovascular conditions, all labeled by professional experts. The dataset consists of 10-second, 12-dimension ECGs and labels for rhythms and other conditions for each subject. The dataset can be used to design, compare, and fine-tune new and classical statistical and machine learning techniques in studies focused on arrhythmia and other cardiovascular conditions., Measurement(s)cardiac arrhythmiaTechnology Type(s)12 lead electrocardiography • digital curationFactor Type(s)sex • experimental condition • age groupSample Characteristic - OrganismHomo sapiens Machine-accessible metadata file describing the reported data: 10.6084/m9.figshare.11698521

Doxorubicin (DOX) is a highly effective and extensively used chemotherapeutic drug but is limited by its cardiotoxicity. In our previous study, we showed that DOX-induced cardiotoxicity (DIC) triggers autophagy and pyroptosis. Sirtuin 3(SIRT3) is an NAD + -dependent deacetylase of the mitochondria that regulates autophagy. However, it is unknown if the protective effects of SIRT3 on DOX-induced cardiotoxicity involve the inhibition of NLRP3 inflammasome activation. In this study, we constructed in vivo and in vitro DIC models to investigate the effects and potential mechanisms of SIRT3 on DIC. We found that the overexpression of SIRT3 remarkably attenuated DIC through inhibition of the NLRP3 inflammasome. Moreover, we found that the overexpression of SIRT3 restored the dynamic balance of autophagosome/autolysosomes by targeting the mTOR/ULK1 signaling pathway. Application of the mTOR agonist MHY1485 further demonstrated that SIRT3 inhibited NLRP3 inflammasome activation by regulating autophagy. Collectively, the results suggest that SIRT3 effectively attenuates the cardiotoxicity of DOX and provides a theoretical foundation for further exploration of DIC.

Background: Dietary polyphenols help to prevent cardiovascular diseases, and interactions between polyphenols and gut microbiota are known to exist. In this study, we speculated that gut microbiota-mediated metabolite regulation might contribute to the anticardiotoxic effects of yellow wine polyphenolic compound (YWPC) in doxorubicin (DOX)-treated rats. Methods: 16S-rDNA sequencing was performed to analyze the effects of YWPC on the gut microbiota in DOX-treated rats (n=6). Antibiotics were used to investigate the contribution of the altered microbiome to the role of YWPC (n=6). Plasma metabolomics were also analyzed by untargeted gas chromatography-mass spectrometry systems. Results: YWPC ameliorated DOX-mediated cardiotoxicity, as evidenced by increased cardiac and mitochondrial function and reduced levels of inflammation and myocardial apoptosis ( P Escherichia – Shigella , Dubosiella , and Allobaculum , along with enrichment of Muribaculaceae_unclassified , Ralstonia , and Rikenellaceae_RC9_gut_group in the gut, suggested that YWPC ameliorated DOX-induced microbial dysbiosis. YWPC also influenced the levels of metabolites altered by DOX, resulting in lower arachidonic acid and linoleic acid metabolism and higher tryptophan metabolite levels ( P Conclusions: YWPC protected against DOX-induced cardiotoxicity in a gut microbiota–dependent manner. This supports the use of dietary polyphenols as a therapeutic approach for the treatment of cardiovascular diseases via microbiota regulation.

Doxorubicin (DOX) is a potent anthracycline antineoplastic drug. However, its dose-dependent cardiotoxicity limits its clinical application. Ononin is a natural isoflavone glycoside that is crucial in modulating apoptosis-related signaling pathways. In this study, we assessed the possible cardioprotective effects of ononin in DOX-induced cardiotoxicity and elucidated the underlying molecular mechanisms. In vitro and in vivo assessments were performed using DOX-treated H9C2 cells and rats, respectively. First, DOX was injected into the tail veins of Wistar rats to induce cardiomyopathy. Next, rats in the DOX + Ononin30 and DOX + Ononin60 groups were intragastrically administered ononin two weeks before DOX treatment. H9C2 cells were treated with vehicle or DOX with or without ononin. Next, 3-TYP was used to determine the relationship between endoplasmic reticulum (ER) stress and sirtuin 3 (SIRT3) expression. Ononin treatment ameliorated DOX-induced myocardial injury as determined by echocardiography. Furthermore, ononin partially restored DOX-induced cardiac dysfunction; the left ventricular ejection fraction (LVEF) and left ventricular systolic fractional shortening (LVFS) increased after pre-treatment with ononin. Further, ononin suppressed DOX-induced ER stress and apoptosis in rat cardiomyocytes and H9C2 cells. The Bax/Bcl-2 ratio and 78-kD glucose-regulated protein (GRP78) and CCAAT enhancer-binding protein (CHOP) expression levels were higher in the DOX-treated group than in the control group but ononin treatment improved these parameters. These effects are associated with SIRT3 activity. Moreover, 3-TYP blocked the ononin-mediated protective effects. Hence, ononin positively affected DOX-induced cardiotoxicity by inhibiting ER stress and apoptosis, possibly mediated by stimulation of the SIRT3 pathway.

Introduction Doxorubicin (DOX) is a powerful anthracycline antineoplastic drug, but the clinical application of DOX is seriously limited by its dose-dependent cardiotoxicity. Ononin is a natural isoflavone glycoside and plays a key role in modulating apoptosis related signaling pathways. The aim of this study was to assess the possible cardioprotective effects of Ononin in DOX-induced cardiotoxicity and the underlying molecular mechanisms. Materials and methods Wistar rats were treated with normal saline, DOX with or without Ononin. After the last administration, cardiac function was evaluated by echocardiography. Rats were then sacrificed for histological and TUNEL analyses, with immunological detection for β-actinin, Bax, Bcl-2, GRP78, CHOP and SIRT3. An enzyme-linked immunosorbent assay was performed to assess the myocardial injury markers. H9C2 cells were treated with vehicle, DOX with or without Ononin. Then, 3-TYP was used to find out the relationship between ER stress and SIRT3. Results Ononin treatment ameliorated DOX-induced myocardial injury as demonstrated by echocardiography. Ononin partially restored DOX-induced cardiac dysfunction, both LVEF and LVFS were increased under the cotreatment of Ononin. Ononin also inhibited DOX-induced ER stress and apoptosis in rat cardiomyocytes and H9C2 cells. DOX group had a higher Bax/Bcl-2 ratio, GRP78 and CHOP expression then control group, but Ononin treatment improved these results. This effect was associated with SIRT3 activity, moreover, selective inhibition of SIRT3 blocked the protective effects of Ononin. Conclusion In the present study, we tested the hypothesis that Ononin may protect against DOX-induced cardiomyopathy through ER stress both in vitro and in vivo. Ononin is able to protect against DOX-induced cardiotoxicity by inhibiting ER stress and apoptosis, this effect may via stimulation of the SIRT3 pathway.

Background: Cardiac fibroblast (CF) activation is a hallmark feature of cardiac fibrosis in diabetic cardiomyopathy (DCM). Inhibition of the sodium-dependent glucose transporter 1 (SGLT1) attenuates cardiomyocyte apoptosis and delays the development of DCM. However, the role of SGLT1 in CF activation remains unclear.Methods: A rat model of DCM was established and treated with si‐SGLT1 to examine cardiac fibrosis. In addition, in vitro experiments were conducted to verify the regulatory role of SGLT1 in proliferation and collagen secretion in high-glucose– (HG–) treated CFs.Results: SGLT1 was found to be upregulated in diabetic cardiac tissues and HG-induced CFs. HG stimulation resulted in increased proliferation and migration, increased the expression of transforming growth factor-β1 and collagen I and collagen III, and increased phosphorylation of p38 mitogen-activated protein kinase and extracellular signal-regulated kinase (ERK) 1/2. These trends in HG-treated CFs were significantly reversed by si-SGLT1. Moreover, the overexpression of SGLT1 promoted CF proliferation and collagen synthesis and increased phosphorylation of p38 mitogen-activated protein kinase and ERK1/2. SGLT1 silencing significantly alleviated cardiac fibrosis, but had no effect on cardiac hypertrophy in diabetic hearts.Conclusion: These findings provide new information on the role of SGLT1 in CF activation, suggesting a novel therapeutic strategy for the treatment of DCM fibrosis.

Aims Doxorubicin (DOX), a widely used powerful chemotherapeutic component for cancer treatment, can give rise to severe cardiotoxicity that limits its clinical use. Pyroptosis is characterized by proinflammation and has been defined as a new type of programmed cell death in recent years. However, whether the DOX-induced cardiotoxicity is related to pyroptosis, and if so, which genes are involved in this process is largely unknown. In this study, we sought to identify the effect of DOX on cardiomyocyte pyroptosis and further reveal the underlying regulatory mechanism. Methods and results In vitro and in vivo experiments showed that DOX treatment induced cardiomyocyte pyroptosis as evidenced by increased cell death and upregulated expression levels of NLR family pyrin domain containing 3 (NLRP3), caspase-3, IL-1β, IL-18 and GMDSD-N. Inhibition of NLRP3 rescued the DOX-induced pyroptosis. qRT-PCR showed that TINCR lncRNA was upregulated by DOX treatment and knockdown of TINCR reversed the DOX-induced pyroptosis both in vitro and in vivo. Mechanistic investigations revealed that TINCR increased NLRP3 level via recruiting IGF2BP1 to enhance NLRP3 mRNA. And the effect of TINCR on cardiomyocyte pyroptosis was attenuated by the inhibition of NLRP3 or IGF2BP1. Finally, TINCR was not involved in DOX-induced pyroptosis in cancer cells. Conclusion TINCR mediates the DOX-induced cardiotoxicity and pyroptosis in an IGF2BP1-dependent manner. Therefore, TINCR may serve as a promising therapeutic target to overcome the cardiotoxicity of chemotherapy for cancer therapy.

Doxorubicin (DOX) is considered as the major culprit in chemotherapy‐induced cardiotoxicity. Yellow wine polyphenolic compounds (YWPC), which are full of polyphenols, have beneficial effects on cardiovascular disease. However, their role in DOX‐induced cardiotoxicity is poorly understood. Due to their antioxidant property, we have been suggested that YWPC could prevent DOX‐induced cardiotoxicity. In this study, we found that YWPC treatment (30 mg/kg/day) significantly improved DOX‐induced cardiac hypertrophy and cardiac dysfunction. YWPC alleviated DOX‐induced increase in oxidative stress levels, reduction in endogenous antioxidant enzyme activities and inflammatory response. Besides, administration of YWPC could prevent DOX‐induced mitochondria‐mediated cardiac apoptosis. Mechanistically, we found that YWPC attenuated DOX‐induced reactive oxygen species (ROS) and down‐regulation of transforming growth factor beta 1 (TGF‐β1)/smad3 pathway by promoting nuclear factor (erythroid‐derived 2)‐like 2 (Nrf2) nucleus translocation in cultured H9C2 cardiomyocytes. Additionally, YWPC against DOX‐induced TGF‐β1 up‐regulation were abolished by Nrf2 knockdown. Further studies revealed that YWPC could inhibit DOX‐induced cardiac fibrosis through inhibiting TGF‐β/smad3‐mediated ECM synthesis. Collectively, our results revealed that YWPC might be effective in mitigating DOX‐induced cardiotoxicity by Nrf2‐dependent down‐regulation of the TGF‐β/smad3 pathway.

Hyperhomocysteinemia (HHcy) is a highly-related risk factor in vascular smooth muscle cell (VSMC) phenotypic modulation and atherosclerosis. Growing evidence indicated that autophagy is involved in pathological arterial changes. However, the risk mechanisms by which homocysteine and VSMC autophagy interact with cardiovascular disease are poorly understood. This study verified the homocysteine-responsive endoplasmic reticulum protein promotion of VSMC phenotypic switching, and the formation of atherosclerotic plaque in vitro. We found that impaired autophagy, as evidenced by decreased levels of MAP1LC3B II/MAP1LC3B I, has a vital role in HHcy-induced human aortic (HA)-VSMC phenotypic switching, with a decrease in contractile proteins (SM α-actin and calponin) and an increase in osteopontin. Knockdown of the essential autophagy gene Atg7 by small interfering RNA promoted HA-VSMC phenotypic switching, indicating that impaired autophagy induces phenotypic switching in these cells. HHcy co-treatment with rapamycin triggered autophagy, which alleviated HA-VSMC phenotypic switching. Finally, we found that Krüppel-like factor 4 (KLF4), a zinc-finger transcription factor for maintaining genomic stability by resisting oxidative stress and restoring autophagy, is closely involved in this process. HHcy clearly decreased KLF4 expression. KLF4-specific siRNA aggravated defective autophagy and phenotypic switching. Mechanistically, KLF4 regulated the HHcy-induced decrease in HA-VSMC autophagy via the m-TOR signaling pathway. In conclusion, these results demonstrated that the KLF4-dependent rapamycin signaling pathway is a novel mechanism underlying HA-VSMC phenotypic switching and is crucial for HHcy-induced HA-VSMCs with defective autophagy to accelerate early atherosclerosis.

The role of endoplasmic reticulum (ER) stress in cardiovascular disease is now recognized. Tauroursodeoxycholic acid (TUDCA) is known to have cardiovascular protective effects by decreasing ER stress. This study aimed to assess the ability of TUDCA to decrease ER stress, inhibit dedifferentiation of vascular smooth muscle cells (VSMCs), and reduce in-stent restenosis. The effect of TUDCA on dedifferentiation of VSMCs and ER stress was investigated in vitro using wound-healing assays, MTT assays, and western blotting. For in vivo studies, 18 rabbits were fed an atherogenic diet to induce atheroma formation. Bare metal stents (BMS), BMS+TUDCA or Firebird stents were implanted in the left common carotid artery. Rabbits were euthanized after 28 days and processed for scanning electron microscope (SEM), histological examination (HE), and immunohistochemistry. In vitro TUDCA (10–1000 μmol/L) treatment significantly inhibited platelet-derived growth factor (PDGF)-BB-induced proliferation and migration in VSMCs in a concentration-dependent manner and decreased ER stress markers (IRE1, XBP1, KLF4, and GRP78). In vivo, we confirmed no significant difference in neointimal coverage on three stents surfaces; neointimal was significantly lower with BMS+TUDCA (1.6 ± 0.2 mm2) compared with Firebird (1.90 ± 0.1 mm2) and BMS (2.3 ± 0.1 mm2). Percent stenosis was lowest for BMS+TUDCA, then Firebird, and was significantly higher with BMS (28 ± 4%, 35 ± 7%, 40 ± 1%; respectively; P

Objective. To explore the effect of Musk Tongxin Dropping Pill (MTDP) on myocardial remodeling and microcirculation dysfunction in diabetic cardiomyopathy (DCM). Methods. Forty male SD rats were randomly divided into control group (control group, n = 10), DCM model group (DCM group, n = 10), DCM model + pioglitazone group (DCM + PLZ group, n = 10), and DCM model + MTDP group (DCM + MTDP group, n = 10). An intraperitoneal single injection of 65 mg/kg streptozotocin (STZ) was used to establish rat model of DCM and the rats in control group were treated with the same dose of sodium citrate buffer solution. DCM + PLZ group was treated with 3 mg/kg/d PLZ by ig after modeling, DCM + MTDP group was treated with 22 mg/kg/d MTDP by ig, and DCM group was treated with 2 ml/kg/d sodium carboxymethyl cellulose (CMC-Na) by ig. The general condition of rats was continuously observed. After intervening for 3 weeks, the random blood glucose of rats was detected by tail vein, and the echocardiography examination was performed. Blood specimens were collected from the abdominal aorta, serum nitric oxide (NO) and endothelin-1 (ET-1) were detected to estimate endothelial function, and tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), IL-1β, malondialdehyde (MDA), and superoxide dismutase (SOD) were detected to observe the changes of inflammation and oxidative stress indexes. The heart mass index (HMI) was calculated through the ratio of heart mass (HM) to the corresponding body mass (BM). Myocardial pathological tissue staining was performed. Results. Compared with control group, blood glucose in other three groups was higher. Left ventricular end systolic diameter (LVSD) and left ventricular end diastolic diameter (LVDD) in DCM group showed a significant increase, while left ventricular ejection fraction (LVEF) and heart rate (HR) in this group displayed an obvious decrease P < 0.01 . BM and HM in DCM group exhibited a reduction, and HM/BM × 103 revealed an apparent increase P < 0.01 . The levels of serum NO and SOD were distinctly downregulated P < 0.01 , and the levels of ET-1, MDA, TNF-α, IL-1β, and IL-6 were remarkably upregulated P < 0.01 . Compared with DCM group, a significant decrease was observed in LVSD and LVDD in DCM + MTDP group, while LVEF and HR obviously increased P < 0.05 . BM and HM indicated an apparent increase, but HM/BM ×103 reduced distinctly P < 0.01 . The levels of serum NO and SOD were markedly upregulated P < 0.05 , and the levels of ET-1, MDA, TNF-α, IL-1β, and IL-6 were significantly downregulated P < 0.05 . HE staining showed that myocardial cells arranged neatly in the control group but not in the DCM group. The intercellular space between myocardial cells in DCM group increased, accompanied by damage of myocardial fibers and infiltration of inflammatory cells. Masson staining displayed an increase in interstitial collagen fibers in DCM group. Carstairs staining showed that microembolization occurred in the myocardium in DCM group, while in DCM + MTDP and DCM + PLZ groups the corresponding myocardial pathological changes were significantly improved. Conclusions. MTDP might show a positive effect on myocardial remodeling and microcirculation dysfunction in DCM rats.

Background: Recent studies have revealed that a novel selective sodium-glucose cotransporter 1 (SGLT1) inhibiton has shown beneficial effects in cardiovascular diseases. However, the question of whether SGLT1 inhibition influences diabetic cardiomyopathy (DCM) remains unanswered. In this study, we investigated the influence and underlying mechanism of SGLTI inhibition on DCM.Methods: SGLT1 levels were measured in diabetic patients with similar conditions who visited our hospital from January to December 2019. Wistar male rats (n = 50) were divided into five groups: control, diabetes induced by streptozotocin infusion, and diabetes treated with 0.5, 1.0, or 1.5 mg/kg mizagliflozin via stomach gavage for 12 weeks. H9C2 cardiomyocytes were treated with mizagliflozin and then exposed to a high glucose concentration (30 mmol/L). TUNEL assays were performed, and bcl2, bax, p-p38, p-Erk, p-JNK and caspase-3 levels were measured. We used siRNA and an SGLT1 overexpression plasmid to detect the effects of SGLT1.Results: SGLT1 levels were significantly elevated in DCM patients, and receiver operating characteristic (ROC) curve analysis identified SGLT1 as influencing DCM. The area under the curve (AUC) was 0.705 (p < 0.05), with 65.8% sensitivity, and 62.2% specificity. SGLT1 inhibition appeared to attenuate apoptosis in DCM via the JNK and p38 pathway.Conclusion: SGLT1 can be used as a marker for the diagnosis of DCM, and SGLT1 inhibition can attenuate apoptosis, thereby suppressing DCM development via the JNK and p38 pathway.

Doxorubicin (DOX) is well-known for its potent antitumor activity but limited by its multiple and serious adverse effects. A major adverse effect is acute cardiotoxicity; yet, its mechanism has not been elucidated. Fucoidan is a multifunctional and nontoxic polysaccharide that is widely studied because of its favorable biological activities and safety. Hence, we proposed that fucoidan may play a protective role in DOX-induced acute cardiotoxicity without causing additional side effects. Sprague-Dawley rats were injected intraperitoneally with a single high dose of DOX to induce acute cardiac injury. Fucoidan was administered orally before DOX injection and AG490, a JAK2 inhibitor, was applied to verify the participation of the JAK2/STAT3 pathway. In vitro, H9C2 cells were treated with the same drugs at different concentrations and intervention times. in vivo and in vitro results demonstrated that DOX administration induced myocardial damage accompanied by acceleratory apoptosis and deficient autophagy in heart tissues or cells, which could be significantly improved by fucoidan supplement. AG490 partly abolished the cardioprotective effects of fucoidan, suggesting the involvement of JAK2 signaling. Additionally, western blotting revealed DOX-induced JAK2/STAT3 pathway activation, which was enhanced by fucoidan and weaken by AG490. Hence, fucoidan exerted a favorable effect on DOX-induced cardiotoxicity by enhancing autophagy and suppressing apoptosis in a JAK2/STAT3-dependent manner, which may provide a promising and novel therapeutic strategy against negative chemotherapy-induced effects.

An epidemic of Coronavirus Disease 2019 (COVID-19) began in December 2019 and triggered a Public Health Emergency of International Concern (PHEIC). We aimed to find risk factors for the progression of COVID-19 to help reducing the risk of critical illness and death for clinical help.The data of COVID-19 patients until March 20, 2020 were retrieved from four databases. We statistically analyzed the risk factors of critical/mortal and non-critical COVID-19 patients with meta-analysis.Thirteen studies were included in Meta-analysis, including a total number of 3027 patients with SARS-CoV-2 infection. Male, older than 65, and smoking were risk factors for disease progression in patients with COVID-19 (male: OR = 1.76, 95% CI (1.41, 2.18), P0.00001; age over 65 years old: OR =6.06, 95% CI(3.98, 9.22), P0.00001; current smoking: OR =2.51, 95% CI(1.39, 3.32), P = 0.0006). The proportion of underlying diseases such as hypertension, diabetes, cardiovascular disease, and respiratory disease were statistically significant higher in critical/mortal patients compared to the non-critical patients (diabetes: OR=3.68, 95% CI (2.68, 5.03), P0.00001; hypertension: OR = 2.72, 95% CI (1.60,4.64), P = 0.0002; cardiovascular disease: OR = 5.19, 95% CI(3.25, 8.29), P0.00001; respiratory disease: OR = 5.15, 95% CI(2.51, 10.57), P0.00001). Clinical manifestations such as fever, shortness of breath or dyspnea were associated with the progression of disease [fever: 0R = 0.56, 95% CI (0.38, 0.82), P = 0.003;shortness of breath or dyspnea: 0R=4.16, 95% CI (3.13, 5.53), P0.00001]. Laboratory examination such as aspartate amino transferase(AST)40U/L, creatinine(Cr) ≥ 133mol/L, hypersensitive cardiac troponin I(hs-cTnI)28pg/mL, procalcitonin(PCT)0.5ng/mL, lactatede hydrogenase(LDH)245U/L, and D-dimer0.5mg/L predicted the deterioration of disease while white blood cells(WBC)4 × 10Male, aged over 65, smoking patients might face a greater risk of developing into the critical or mortal condition and the comorbidities such as hypertension, diabetes, cardiovascular disease, and respiratory diseases could also greatly affect the prognosis of the COVID-19. Clinical manifestation such as fever, shortness of breath or dyspnea and laboratory examination such as WBC, AST, Cr, PCT, LDH, hs-cTnI and D-dimer could imply the progression of COVID-19.

The pro-aging miRNA, miR-34a, is hyperactivated in the cardiac myocardial tissues of patients and mice with diabetes, leading to diabetic cardiomyopathy (DCM). Increasing evidence suggests that dihydromyricetin (DHM) can be used to effectively treat cardiomyopathy. In this study, we investigated whether DHM affects the expression of miR-34a in DCM. The expression of miR-34a in high-glucose-induced cardiomyocytes and in the heart tissue of diabetic mice was determined by microRNA isolation and quantitative reverse transcription-polymerase chain reaction. Lipofectamine 3000 was used to transfect cardiomyocytes with miR-34a inhibitor, miR-34a mimics, and miR-control. These agents were intravenously injected into the tail vein of streptozotocin-induced diabetic mice. Autophagy and apoptosis were assessed in high-glucose-induced cardiomyocytes and cardiac tissue in diabetic mice by western blotting, immunofluorescence, Masson staining, hematoxylin and eosin staining (H&E), and electron microscopy. DHM clearly ameliorated the cardiac dysfunction in the diabetic mice. The expression of miR-34a was up-regulated in high-glucose-induced cardiomyocytes and in the hearts of diabetic mice, thus impairing autophagy. Treatment with DHM decreased the expression of miR-34a and rescued the impairment of autophagy in high-glucose-induced cardiomyocytes and in the heart tissue of diabetic mice, while the miR-34a mimic offset the effect of DHM with respect to the development of DCM by inhibiting autophagy. By decreasing the expression of miR-34a, DHM restores impaired autophagy, and thus ameliorates DCM. Therefore, DHM may potentially be used in the treatment of DCM.

To examine the clinical efficacy of Jiawei Shenfu decoction on tumor necrosis factor-al- pha (TNF-α) and nuclear factor-kappa B (NF-κB) levels in patients who have chronic heart failure with syndromes of deficiency of heart Yang.A total of 63 patients with syndromes of deficiency of heart Yang (chronic heart failure) were enrolled. Patients were randomly divided into the control group and Jiawei Shenfu group. All patients received standard medications for treatment of chronic heart failure. Patients in the Jiawei Shenfu group were additionally provided Jiawei Shenfu decoction one dose daily. Treatments continued for 4 consecutive weeks. The primary endpoint was the change in plasma B-type natriuretic peptide (BNP), NF-κB, and TNF-α levels during 4 weeks of treatment.At the 4-week follow-up, a significant reduction in BNP levels compared with baseline was observed in both groups, but the Jiawei Shenfu decoction group showed a significantly greater reduction than did the control group. The Jiawei Shenfu group also showed superior performance regarding the Minnesota Living with Heart Failure Questionnaire score, the Chinese medicine syndrome score, heart rate, left ventricular ejection fraction, and 6-min walking distance compared with the control group. The degree of changes in NF-κB and TNF-α levels in the Jiawei Shenfu group was more significant than that in the control group.Routine medicine combined with Jiawei Shenfu decoction for patients with heart Yang deficiency syndrome in chronic heart failure can improve the left ventricular ejection fraction and cardiac function, and reduce BNP levels. The mechanism may be related to inhibition of pro-inflamma- tory cytokines and the NF-κB-induced kinase pathway, leading to amelioration of the inflammatory response.

Myocardial contractile dysfunction in diabetic cardiomyocytes is a significant promoter of heart failure. Herein, we investigated the effect of icariin, a flavonoid monomer isolated from Epimedium, on diabetic cardiomyopathy (DCM) and explored the mechanisms underlying its unique pharmacological cardioprotective functions. High glucose (HG) conditions were simulated in vitro using cardiomyocytes isolated from neonatal C57 mice, while DCM was stimulated in vivo in db/db mice. Mice or cardiomyocytes were treated with icariin, with or without overexpression or silencing expression of Apelin and Sirt3 via transfection with adenoviral vectors (Ad-RNA) and specific small hairpin RNAs (Ad-sh-RNA), respectively. Icariin markedly improved mitochondrial function both in vivo and in vitro, as evidenced by increased level of mitochondrial-related proteins via western blot analysis (PGC-1α, Mfn2, and Cyt-b) and increased mitochondrial membrane potential, as observed via JC-1 staining. Further, icariin treatment decreased cardiac fibrogenesis (Masson staining), and inhibited apoptosis (TUNEL staining). Together, these changes improved cardiac function, according to multiple transthoracic echocardiography parameters, including LVEF, LVSF, LVESD, and LVEDD. Moreover, icariin significantly activated Apelin and Sirt3, which were inhibited by HG and DCM. Importantly, when Ad-sh-Apelin and Ad-sh-Sirt3 were transfected in cardiomyocytes or injected into the heart of db/db mice, the cardioprotective effects of icariin were abolished and mitochondrial homeostasis were disrupted. Further, it was postulated that since Ad-Apelin induced different results following increased Sirt3 expression, icariin may have attenuated DCM development by preventing mitochondrial dysfunction through the Apelin/Sirt3 pathway. Hence, protection against mitochondrial dysfunction using icariin may prove to be a promising therapeutic strategy against DCM in diabetes.

Arrhythmia constitutes a problem with the rate or rhythm of the heartbeat, and an early diagnosis is essential for the timely inception of successful treatment. We have jointly optimized the entire multi-stage arrhythmia classification scheme based on 12-lead surface ECGs that attains the accuracy performance level of professional cardiologists. The new approach is comprised of a three-step noise reduction stage, a novel feature extraction method and an optimal classification model with finely tuned hyperparameters. We carried out an exhaustive study comparing thousands of competing classification algorithms that were trained on our proprietary, large and expertly labeled dataset consisting of 12-lead ECGs from 40,258 patients with four arrhythmia classes: atrial fibrillation, general supraventricular tachycardia, sinus bradycardia and sinus rhythm including sinus irregularity rhythm. Our results show that the optimal approach consisted of Low Band Pass filter, Robust LOESS, Non Local Means smoothing, a proprietary feature extraction method based on percentiles of the empirical distribution of ratios of interval lengths and magnitudes of peaks and valleys, and Extreme Gradient Boosting Tree classifier, achieved an F1-Score of 0.988 on patients without additional cardiac conditions. The same noise reduction and feature extraction methods combined with Gradient Boosting Tree classifier achieved an F1-Score of 0.97 on patients with additional cardiac conditions. Our method achieved the highest classification accuracy (average 10-fold cross-validation F1-Score of 0.992) using an external validation data, MIT-BIH arrhythmia database. The proposed optimal multi-stage arrhythmia classification approach can dramatically benefit automatic ECG data analysis by providing cardiologist level accuracy and robust compatibility with various ECG data sources.

Doxorubicin (DOX) is a powerful anthracycline antineoplastic drug whose clinical application is limited by serious cardiotoxic side effects. Dihydromyricetin (DHM), a flavonoid compound extracted from the Japanese raisin tree (Hovenia dulcis), is cardioprotective in patients with heart failure; however, the underlying mechanisms are poorly understood. The aim of this study was to assess the possible anti-inflammatory properties of DHM in a rat model of DOX-induced cardiotoxicity and DOX-treated H9C2 cells, and gain insights into the molecular mechanisms that mediate these effects. The results showed that DHM treatment significantly improved the myocardial structure and function in DOX-exposed rats by alleviating NLRP3 inflammasome-mediated inflammation. DHM also inhibited DOX-induced activation of the NLRP3 inflammasome in H9C2 cells. This effect was mediated by inhibition of caspase-1 activity, suppression of IL-1β and IL-18 release, and upregulation of SIRT1 protein levels in vivo and in vitro. Moreover, selective inhibition of SIRT1 blocked the protective effects of DHM. Collectively, our findings indicate that DHM protects against DOX-induced cardiotoxicity by inhibiting NLRP3 inflammasome activation via stimulation of the SIRT1 pathway.

Background Phenotypic switching of vascular smooth muscle cells (VSMCs) plays a key role in atherosclerosis. We aimed to investigate whether Homocysteine-responsive endoplasmic reticulum protein (Herp) was involved in VSMC phenotypic switching and affected atheroprogression. Methods To assess the role of Herp in homocysteine (Hcy)-associated atherosclerosis, Herp −/− and LDLR −/− double knockout mice were generated and fed with a high methionine diet (HMD) to induce Hyperhomocysteinemia (HHcy). Atherosclerotic lesions, cholesterol homeostasis, endoplasmic reticulum (ER) stress activation, and the phenotype of VSMCs were assessed in vivo . We used siRNAs to knockdown Herp in cultured VSMCs to further validate our findings in vitro . Results HMD significantly activated the activating transcription factor 6 (ATF6)/Herp arm of ER stress in LDLR −/− mice, and induced the phenotypic switch of VSMCs, with the loss of contractile proteins (SMA and calponin) and an increase of OPN protein. Herp −/− /LDLR −/− mice developed reduced atherosclerotic lesions in the aortic sinus and the whole aorta when compared with LDLR −/− mice. However, Herp deficiency had no effect on diet-induced HHcy and hyperlipidemia. Inhibition of VSMC phenotypic switching, decreased proliferation and collagen accumulation were observed in Herp −/− /LDLR −/− mice when compared with LDLR −/− mice. In vitro experiments demonstrated that Hcy caused VSMC phenotypic switching, promoted cell proliferation and migration; this was reversed by Herp depletion. We achieved similar results via inhibition of ER stress using 4-phenylbutyric-acid (4-PBA) in Hcy-treated VSMCs. Conclusion Herp deficiency inhibits the phenotypic switch of VSMCs and the development of atherosclerosis, thus providing novel insights into the role of Herp in atherogenesis.

Many studies support the cardioprotective effects of folic acid (FA). We aimed to evaluate the utility of FA supplementation in preventing the development of atherosclerotic in low‐density lipoprotein receptor‐deficient (LDLR−/−) mice and to elucidate the molecular processes underlying this effect. LDLR−/− mice were randomly distributed into four groups: control group, HF group, HF + FA group and the HF + RAPA group. vascular smooth muscle cells (VSMCs) were divided into the following four groups: control group, PDGF group, PDGF + FA group and PDGF + FA + RAPA group. Blood lipid levels, oxidative stress and inflammatory cytokines were measured. Atherosclerosis severity was evaluated with oil red O staining. Haematoxylin and eosin (H&E) staining was used to assess atherosclerosis progression. Immunohistochemical staining was performed with antismooth muscle α‐actin (α‐SMA) antibodies and anti‐osteopontin (OPN) antibodies that demonstrate VSMC dedifferentiation. The protein expression of α‐SMA, OPN and mechanistic target of rapamycin (mTOR)/p70S6K signalling was detected by Western blot analysis. FA and rapamycin reduced serum levels of total cholesterol, triacylglycerol, LDL, inhibiting oxidative stress and the inflammatory response. Oil red O and H&E staining demonstrated that FA and rapamycin inhibited atherosclerosis. FA and rapamycin treatment inhibited VSMC dedifferentiation in vitro and in vivo, and FA and rapamycin attenuated the mTOR/p70S6K signalling pathway. Our findings suggest that FA attenuates atherosclerosis development and inhibits VSMC dedifferentiation in high‐fat‐fed LDLR−/− mice by reduced lipid levels and inhibiting oxidative stress and the inflammatory response through mTOR/p70S6K signalling pathway.