Paeoniflorin confers ferroptosis resistance by regulating the gut microbiota and its metabolites in diabetic cardiomyopathy.

Diabetic cardiomyopathy (DCM) is closely related to ferroptosis, a new type of cell death that mainly manifests as intracellular iron accumulation and lipid peroxidation. Paeoniflorin (PA) helps to improve impaired glucose tolerance, influences the distribution of the intestinal flora, and induces significant resistance to ferroptosis in several models. In this study, we found that PA improved cardiac dysfunction in mice with DCM by alleviating myocardial damage, resisting oxidative stress and ferroptosis, and changing the community composition and structure of the intestinal microbiota. Metabolomics analysis revealed that PA-treated fecal microbiota transplantation affected metabolites in DCM mice. Based on in vivo and in vitro experiments, 11,12-epoxyeicosatrienoic acid (11,12-EET) may serve as a key contributor that mediates the cardioprotective and antiferroptotic effects of PA-treated fecal microbiota transplantation (FMT) in DCM mice.NEW & NOTEWORTHY This study demonstrated for the first time that paeoniflorin (PA) exerts protective effects in diabetic cardiomyopathy mice by alleviating myocardial damage, resisting ferroptosis, and changing the community composition and structure of the intestinal microbiota, and 11,12-epoxyeicosatrienoic acid (11,12-EET) may serve as a key contributor in its therapeutic efficacy.

Dark chocolate intake and cardiovascular diseases: a Mendelian randomization study.

Previous intervention studies have shown some benefits of dark chocolate for the cardiovascular system, but it has not been established whether dark chocolate intake is associated with the risk of cardiovascular diseases (CVDs). To investigate the causality between dark chocolate intake and the risk of CVDs, a Mendelian randomization (MR) study was conducted. We obtained summary-level data on dark chocolate intake and CVDs from publicly available genome-wide association studies. In this MR study, the main approach was to use a fixed-effect model with inverse variance weighted (IVW) and evaluate the robustness of the results via sensitivity analysis. We found that dark chocolate intake was significantly associated with the reduction of the risk of essential hypertension (EH) (OR = 0.73; 95% CI 0.60-0.88; p = 1.06 × 10-3), as well as with the suggestive association to the reduced risk of venous thromboembolism (OR = 0.69; 95% CI 0.50-0.96; p = 2.81 × 10-2). However, no association was found between dark chocolate intake and the other ten CVDs. Our study provides evidence for a causality between dark chocolate intake and a reduced risk of EH, which has important implications for the prevention of EH in the population.

Emodin ameliorates doxorubicin-induced cardiotoxicity by inhibiting ferroptosis through the remodeling of gut microbiota composition.

The relationship between gut microbiota and doxorubicin-induced cardiotoxicity (DIC) is becoming increasingly clear. Emodin (EMO), a naturally occurring anthraquinone, exerts cardioprotective effects and plays a protective role by regulating gut microbiota composition. Therefore, the protective effect of EMO against DIC injury and its underlying mechanisms are worth investigating. In this study, we analyzed the differences in the gut microbiota in recipient mice transplanted with different flora using 16S-rDNA sequencing, analyzed the differences in serum metabolites among groups of mice using a nontargeted gas chromatography-mass spectrometry coupling system, and assessed cardiac function based on cardiac morphological staining, cardiac injury markers, and ferroptosis indicator assays. We found EMO ameliorated DIC and ferroptosis, as evidenced by decreased myocardial fibrosis, cardiomyocyte hypertrophy, and myocardial disorganization; improved ferroptosis indicators; and the maintenance of normal mitochondrial morphology. The protective effect of EMO was eliminated by the scavenging effect of antibiotics on the gut microbiota. Through fecal microbiota transplantation (FMT), we found that EMO restored the gut microbiota disrupted by doxorubicin (DOX) to near-normal levels. This was evidenced by an increased proportion of Bacteroidota and a decreased proportion of Verrucomicrobiota. FMT resulted in changes in the composition of serum metabolites. Mice transplanted with EMO-improved gut microbiota showed better cardiac function and ferroptosis indices; however, these beneficial effects were not observed in Nrf2 (Nfe2l2)-/- mice. Overall, EMO exerted a protective effect against DIC by attenuating ferroptosis, and the above effects occurred by remodeling the composition of gut microbiota perturbed by DOX and required Nrf2 mediation.NEW & NOTEWORTHY This study demonstrated for the first time the protective effect of emodin against DIC and verified by FMT that its cardioprotective effect was achieved by remodeling gut microbiota composition, resulting in attenuation of ferroptosis. Furthermore, we demonstrated that these effects were mediated by the redox-related gene Nrf2.

RTA 408 ameliorates diabetic cardiomyopathy by activating Nrf2 to regulate mitochondrial fission and fusion and inhibiting NF-κB-mediated inflammation.

Diabetic cardiomyopathy (dCM) is a major complication of diabetes; however, specific treatments for dCM are currently lacking. RTA 408, a semisynthetic triterpenoid, has shown therapeutic potential against various diseases by activating the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway. We established in vitro and in vivo models using high glucose toxicity and db/db mice, respectively, to simulate dCM. Our results demonstrated that RTA 408 activated Nrf2 and alleviated various dCM-related cardiac dysfunctions, both in vivo and in vitro. Additionally, it was found that silencing the Nrf2 gene eliminated the cardioprotective effect of RTA 408. RTA 408 ameliorated oxidative stress in dCM mice and high glucose-exposed H9C2 cells by activating Nrf2, inhibiting mitochondrial fission, exerting anti-inflammatory effects through the Nrf2/NF-κB axis, and ultimately suppressing apoptosis, thereby providing cardiac protection against dCM. These findings provide valuable insights for potential dCM treatments.NEW & NOTEWORTHY We demonstrated first that the nuclear factor erythroid 2-related factor 2 (Nrf2) activator RTA 408 has a protective effect against diabetic cardiomyopathy. We found that RTA 408 could stimulate the nuclear entry of Nrf2 protein, regulate the mitochondrial fission-fusion balance, and redistribute p65, which significantly alleviated the oxidative stress level in cardiomyocytes, thereby reducing apoptosis and inflammation, and protecting the systolic and diastolic functions of the heart.

The effect of ivabradine therapy on dilated cardiomyopathy patients with congestive heart failure: a systematic review and meta-analysis.

Background: Ivabradine improves cardiac function in patients with heart failure, but its effect on dilated cardiomyopathy (DCM) remains unclear. We performed a systematic review and meta-analysis to study the efficacy and potential mechanisms of ivabradine's effect on cardiac function and prognosis in patients with DCM. Methods: We searched PubMed, Cochrane Library, Embase, Web of Science, and four registers through September 28, 2022. All controlled trials of ivabradine for the treatment of DCM with congestive heart failure were included. Articles were limited to English, with the full text and necessary data available. We performed random- or fixed effects meta-analyses for all included outcome measures and compared the effect sizes for outcomes in patients treated with and without ivabradine. The quality of the studies was assessed using the Cochrane risk-of-bias tool for randomized trials (RoB2.0). Findings: Five trials with 357 participants were included. The pooled risk ratio was 0.48 [95% confidence interval (CI) (0.18, 1.25)] for all-cause mortality and 0.38 [95% CI (0.12, 1.23)] for cardiac mortality. The pooled mean difference was -15.95 [95% CI (-19.97, -11.92)] for resting heart rate, 3.96 [95% CI (0.99, 6.93)] for systolic blood pressure, 2.93 [95% CI (2.09, 3.77)] for left ventricular ejection fraction, -5.90 [95% CI (-9.36, -2.44)] for left ventricular end-systolic diameter, -3.41 [95% CI (-5.24, -1.58)] for left ventricular end-diastolic diameter, -0.81 [95% CI (-1.00, -0.62)] for left ventricular end-systolic volume, -0.67 [95% CI (-0.86, -0.48)] for left ventricular end-diastolic volume, -11.01 [95% CI (-19.66, -2.35)] for Minnesota Living with Heart Failure score, and -0.52 [95% CI (-0.73, -0.31)] for New York Heart Association class. Interpretation: Ivabradine reduces heart rate and ventricular volume, and improves cardiac function in patients with DCM, but showed no significant effect on the prognosis of patients.

Inhibiting mir-34a-5p regulates doxorubicin-induced autophagy disorder and alleviates myocardial pyroptosis by targeting Sirt3-AMPK pathway.

Doxorubicin (DOX) is a commonly used chemotherapy drug widely applied in various cancers such as breast cancer, leukemia, and sarcomas. However, its usage is limited by cardiotoxicity. Additionally, the cardiac toxicity of DOX accumulates with dose and duration, making it imperative to identify therapeutic targets for DOX-induced cardiomyopathy (DIC). It has been reported that miRNAs are involved in the progression of DIC. Mir-34a-5p has been identified as an early diagnostic marker for DIC. While studies have shown the involvement of mir-34a-5p in DIC apoptosis, it has not been validated in animal models, nor has the potential improvement of DIC by inhibiting mir-34a-5p been confirmed. Autophagy and pyroptosis are key factors in the development of DIC and can serve as therapeutic targets for its treatment. In this study, we found that mir-34a-5p was upregulated in the heart after DOX treatment and that the inhibition of mir-34-5p reduced autophagy and pyroptosis in DIC. We also found that the inhibition of mir-34a-5p inhibited pyroptosis by regulating autophagy and reducing mitochondrial reactive oxygen species. Moreover, we identified Sirtuin3 (Sirt3) as a target gene of mir-34a-5p using a double-luciferase reporter assay. overexpression Sirt3 reduced pyroptosis by alleviating autophagy. Our research findings suggest that inhibiting mir-34a-5p has a beneficial role in alleviating autophagy and pyroptosis in DIC. This provides therapeutic prospects for treating DIC.

Fecal Microbiota Transplantation in Mice Exerts a Protective Effect Against Doxorubicin-Induced Cardiac Toxicity by Regulating Nrf2-Mediated Cardiac Mitochondrial Fission and Fusion.

Aims: The relationship between the gut microbiota and cardiovascular system has been increasingly clarified. Fecal microbiota transplantation (FMT), used to improve gut microbiota, has been applied clinically for disease treatment and has great potential in combating doxorubicin (DOX)-induced cardiotoxicity. However, the application of FMT in the cardiovascular field and its molecular mechanisms are poorly understood. Results: During DOX-induced stress, FMT alters the gut microbiota and serum metabolites, leading to a reduction in cardiac injury. Correlation analysis indicated a close association between serum metabolite indole-3-propionic acid (IPA) and cardiac function. FMT and IPA achieve this by facilitating the translocation of Nfe2l2 (Nrf2) from the cytoplasm to the nucleus, thereby activating the expression of antioxidant molecules, reducing reactive oxygen species production, and inhibiting excessive mitochondrial fission. Consequently, mitochondrial function is preserved, leading to the mitigation of cardiac injury under DOX-induced stress. Innovation: FMT has the ability to modify the composition of the gut microbiota, providing not only protection to the intestinal mucosa but also influencing the generation of serum metabolites and regulating the Nrf2 gene to modulate the balance of cardiac mitochondrial fission and fusion. This study comprehensively demonstrates the efficacy of FMT in countering DOX-induced myocardial damage and elucidates the pathways linking the microbiota and the heart. Conclusion: FMT alters the gut microbiota and serum metabolites of recipient mice, promoting nuclear translocation of Nrf2 and subsequent activation of downstream antioxidant molecule expression, while inhibiting excessive mitochondrial fission to preserve cardiac integrity. Correlation analysis highlights IPA as a key contributor among differentially regulated metabolites.

Herpud1 deficiency alleviates homocysteine-induced aortic valve calcification.

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 and used high methionine diet (HMD) to assess of aortic valve calcification lesions, ERS activation, autophagy, and osteogenic differentiation of aortic valve interstitial cells (AVICs). In vitro, the role of Herpud1 in the Hcy-related osteogenic differentiation of AVICs was investigated by manipulating of Herpud1 expression. RESULTS: Herpud1 was highly expressed in calcified human and mouse aortic valves as well as primary aortic valve interstitial cells (AVICs). Hcy increased Herpud1 expression through the ERS pathway and promoted CAVD progression. 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. ERS inhibitor 4-phenyl butyric acid (4-PBA) significantly attenuated aortic valve calcification in HMD-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 Hcy-related CAVD, suggesting that Herpud1 silencing or inhibition is a viable therapeutic strategy for arresting CAVD progression. HIGHLIGHTS: • Herpud1 is upregulated in the leaflets of Hcy-treated mice and patients with CAVD. • In mice, global knockout of Herpud1 alleviates aortic valve calcification and Herpud1 silencing activates cell autophagy, inhibiting osteogenic differentiation of AVICs induced by Hcy. • 4-PBA suppressed Herpud1 expression to alleviate AVIC calcification in Hcy treated AVICs and to mitigate aortic valve calcification in mice.

Protective effect of urotensin II receptor antagonist urantide and exercise training on doxorubicin-induced cardiotoxicity.

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.

Repair effect of the poly (D,L-lactic acid) nanoparticle containing tauroursodeoxycholic acid-eluting stents on endothelial injury after stent implantation.

Background: Chronic endoplasmic reticulum stress (ERS) plays a crucial role in cardiovascular diseases. Thus, it can be considered a therapeutic target for these diseases. In this study, poly (D,L-lactic acid) (PDLLA) nanoparticle-eluting stents loaded with tauroursodeoxycholic acid (TUDCA), an ER stress inhibitor, was fabricated to assess their ability to reduce endothelial cell apoptosis and promote re-endothelialization after stent implantation. Materials and methods: PDLLA nanoparticles loaded with TUDCA were prepared via the emulsification-solvent evaporation method. The cumulative release rates of TUDCA were measured in vitro via high-performance liquid chromatography. The carotid arteries of rabbits were subsequently implanted with stents in vivo. The rabbits were then sacrificed after 4 weeks for scanning electron microscopy. Meanwhile, TUDCA concentration in the homogenate of the peripheral blood and distal vascular tissue after stent implantation was measured. The effect of TUDCA on ERS, apoptosis, and human umbilical vein endothelial cell (HUVEC) function was investigated in vitro by performing cell migration assay, wound healing assay, cell proliferation assays, endoplasmic reticulum (ER)-specific fluorescence staining, immunofluorescence, and western blotting. Results: TUDCA nanoparticles were released slowly over 28 days. In addition, TUDCA-eluting stents enhanced re-endothelialization and accelerated the recovery of endotheliocytes in vivo. ERS and apoptosis significantly increased in H2O2-treated HUVECs in vitro. Meanwhile, TUDCA reduced apoptosis and improved function by inhibiting ERS in H2O2-treated HUVECs. Decreased rates of apoptosis and ERS were observed after silencing XBP-1s in H2O2-treated HUVECs. Conclusion: TUDCA can inhibit apoptosis and promote re-endothelialization after stent implantation by inhibiting IRE/XBP1s-related ERS. These results indicate the potential therapeutic application of TUDCA as a drug-coated stent.

Functional components of Chinese rice wine can ameliorate diabetic cardiomyopathy through the modulation of autophagy, apoptosis, gut microbiota, and metabolites.

Background: Dietary polyphenols, polypeptides, and oligosaccharides modulate inflammation and immunity by altering the composition of gut microbiota. The polyphenols and polypeptides in Chinese rice wine have protective effects against cardiovascular disease. In this study, we hypothesized that the polyphenols, polypeptides, and oligosaccharides in Chinese rice wine can ameliorate diabetic cardiomyopathy (DCM) by altering gut microbiota and metabolites. Methods: Mice with DCM and high glucose cells were treated with rice wine polyphenols (RWPH), rice wine polypeptides (RWPE), and rice wine oligosaccharides. Cardiac function was evaluated by echocardiography and detection of myocardial injury markers. We observed the pathological structures using hematoxylin and eosin staining, Masson's trichrome staining, and transmission electron microscopy. The expression levels of autophagy-related proteins and stubRFP-sensGFP-LC3 fluorescence were measured to evaluate autophagy. We performed TUNEL staining and measured the levels of Bax, Bcl-2, and p53 to assess apoptosis. To analyze the effects of the rice wine functional components on the gut microbiota and metabolites of DCM mice, we performed fecal 16S-rDNA gene sequencing and serum untargeted metabolomics. Results: Our results showed an increase in cardiac and mitochondrial function, promotion of autophagy, and inhibition of cardiomyocyte apoptosis, which indicates that RWPH and RWPE can ameliorate DCM. The abundance of Akkermansia and Desulfovibrio were reduced by the presence of RWPH and RWPE. The growth of the Lachnospiraceae_NK4A136_group and Clostridiales-unclassified were promoted by the presence of RWPH. Tryptophan metabolism-associated metabolites were increased and phenylalanine levels were reduced by the presence of RWPH and RWPE. The biosynthesis of primary bile acids was enhanced by the presence of RWPH. Conclusion: Both RWPH and RWPE provided a protective effect against DCM by promoting autophagy, inhibiting apoptosis, and reversing both gut microbiota dysbiosis and metabolic dysregulation.

Machine learning algorithms identifying the risk of new-onset ACS in patients with type 2 diabetes mellitus: A retrospective cohort study.

Background: In recent years, the prevalence of type 2 diabetes mellitus (T2DM) has increased annually. The major complication of T2DM is cardiovascular disease (CVD). CVD is the main cause of death in T2DM patients, particularly those with comorbid acute coronary syndrome (ACS). Although risk prediction models using multivariate logistic regression are available to assess the probability of new-onset ACS development in T2DM patients, none have been established using machine learning (ML). Methods: Between January 2019 and January 2020, we enrolled 521 T2DM patients with new-onset ACS or no ACS from our institution's medical information recording system and divided them into a training dataset and a testing dataset. Seven ML algorithms were used to establish models to assess the probability of ACS coupled with 5-cross validation. Results: We established a nomogram to assess the probability of newly diagnosed ACS in T2DM patients with an area under the curve (AUC) of 0.80 in the testing dataset and identified some key features: family history of CVD, history of smoking and drinking, aspartate aminotransferase level, age, neutrophil count, and Killip grade, which accelerated the development of ACS in patients with T2DM. The AUC values of the seven ML models were 0.70-0.96, and random forest model had the best performance (accuracy, 0.89; AUC, 0.96; recall, 0.83; precision, 0.91; F1 score, 0.87). Conclusion: ML algorithms, especially random forest model (AUC, 0.961), had higher performance than conventional logistic regression (AUC, 0.801) for assessing new-onset ACS probability in T2DM patients with excellent clinical and diagnostic value.

Ononin alleviates endoplasmic reticulum stress in doxorubicin-induced cardiotoxicity by activating SIRT3.

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.

A Nomogram for Predicting Patent Foramen Ovale-Related Stroke Recurrence.

Background: The high prevalence of patent foramen ovale (PFO) in cryptogenic stroke suggested a stroke-causing role for PFO. As risk factors for recurrence of such stroke are not recognized, clinicians cannot sufficiently identify, treat, and follow-up high-risk patients. Therefore, this study aimed to establish a prediction model for PFO-related stroke recurrence. Methods: This study included 392 patients with PFO-related stroke in a training set and 164 patients with PFO-related stroke in an independent validation set. In the training set, independent risk factors for recurrence identified using forward stepwise Cox regression were included in nomogram 1, and those identified using least absolute shrinkage and selection operator(LASSO)regression were included in nomogram 2. Nomogram performance and discrimination were assessed using the concordance index (C-index), area under the curve (AUC), calibration curve, and decision curve analyses (DCA). The results were also validated in the validation set. Results: Nomogram 1 was based on homocysteine (Hcy), high-sensitivity C-reactive protein (hsCRP), and albumin (ALB), and nomogram 2 was based on age, diabetes, hypertension, right-to-left shunt, ALB, prealbumin, hsCRP, and Hcy. The C-index of nomogram 1 was 0.861, which was not significantly different from that of nomogram 2 (0.893). The 2- and 5-year AUCs of nomogram 1 were 0.863 and 0.777, respectively. In the validation set, nomogram 1 still had good discrimination (C-index, 0.862; 2-year AUC, 0.839; 5-year AUC, 0.990). The calibration curve showed good homogeneity between the prediction by nomogram 1 and the actual observation. DCA demonstrated that nomogram 1 was clinically useful. Moreover, patients were successfully divided into two distinct risk groups (low and high risk) for recurrence rate by nomogram 1. Conclusions: Nomogram 1, based on Hcy, hsCRP, and ALB levels, provided a more clinically realistic prognostic prediction for patients with PFO-related stroke. This model could help patients with PFO-related stroke to facilitate personalized prognostic evaluations.

Yellow Wine Polyphenolic Compound Protects Against Doxorubicin-Induced Cardiotoxicity by Modulating the Composition and Metabolic Function of the Gut Microbiota.

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<0.05 for all). The low abundance of 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<0.05 for all). Correlational studies indicated that YWPC alleviated DOX-induced inflammation and mitochondrial dysfunction by modulating the gut microbial community and its associated metabolites. Antibiotic treatment exacerbated cardiotoxicity in DOX-treated rats, and its effect on the gut microbiota partly abolished the anticardiotoxic effects of YWPC, suggesting that the microbiota is required for the cardioprotective role of YWPC. 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.

Fucoidan from Fucus vesiculosus attenuates doxorubicin-induced acute cardiotoxicity by regulating JAK2/STAT3-mediated apoptosis and autophagy.

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.

Herpud1 deficiency could reduce amyloid-ß40 expression and thereby suppress homocysteine-induced atherosclerosis by blocking the JNK/AP1 pathway.

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-ß40 (Aß40), 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 Aß40 in a Herpud1 knockout Hcy-induced atherosclerosis mouse model by measuring Aß40 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 Aß40. As a result, our animal models showed that Herpud1 knockout reduced Aß40 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 Aß40 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 Aß40 expression, thereby suppressing Hcy-induced atherosclerosis by blocking the JNK/AP1 pathway. This may provide novel potential targets for atherosclerosis prevention or treatment.

Icariin Ameliorates Diabetic Cardiomyopathy Through Apelin/Sirt3 Signalling to Improve Mitochondrial Dysfunction.

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 and cardiomyocytes were treated with icariin, with or without overexpression or silencing 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 an increased level of mitochondrial-related proteins via western blot analysis (PGC-1α, Mfn2, and Cyt-b) and an 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 was 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.