MicroRNA-24-3p alleviates cardiac fibrosis by suppressing cardiac fibroblasts mitophagy via downregulating PHB2.

Cardiac fibrosis is a pathological process of multiple cardiovascular diseases, which may lead to heart failure. Studies have shown that microRNAs (miRNAs) play critical roles in regulating mitophagy and cardiac fibrosis. We found that miR-24-3p expression was significantly downregulated in transverse aortic constriction (TAC) mice and cardiac fibroblasts (CFs) treated with Ang Ⅱ. We also found that, apart from improving cardiac structure and function, forced expression of miR-24-3p not only reduced the levels of collagen and α-SMA but also inhibited proliferation and migration of CFs. Next, our research proved that miR-24-3p suppressed the progression of mitophagy, autophagic flux, and the levels of mitophagy-related proteins in cardiac fibrosis models. Further analysis showed that PHB2 was a direct target of miR-24-3p. Finally, experiments showed that the knockdown of PHB2 reversed Ang Ⅱ-induced fibrosis in CFs. The results of our study suggests that increased expression of miR-24-3p contributes to the reduction of cardiac fibrosis and that it might be targeted therapeutically to alleviate cardiac fibrosis.

Innovative pharmacotherapy for hepatic metabolic and chronic inflammatory diseases in China.

Liver disease constitutes a significant global health concern, particularly in China where it has distinctive characteristics. China grapples with a staggering 300 million cases, predominantly due to hepatitis B and metabolic non-alcoholic fatty liver disease. Additionally, hepatocellular carcinoma has become a prevalent which is a lethal type of cancer. Despite the scarcity of innovative treatment options, Chinese hepatologists and researchers have achieved notable breakthroughs in the prevention, diagnosis, management and treatment of liver diseases. Traditional Chinese medicines have found widespread application in the treatment of various liver ailments owing to their commendable pharmacological efficacy and minimal side effects. Furthermore, there is a growing body of research in extracellular vesicles, cell therapy and gene therapy, offering new hope in the fight against liver diseases. This paper provides a comprehensive overview of the epidemiological characteristics of liver diseases and the diverse array of treatments that Chinese scholars and scientists have pursued in critical field.

Fufang Zhenzhu Tiaozhi (FTZ) suppression of macrophage pyroptosis: Key to stabilizing rupture-prone plaques.

BACKGROUND: Research on the Chinese herbal formula Fufang Zhenzhu Tiaozhi (FTZ) has demonstrated its effectiveness in treating hyperlipidemia and glycolipid metabolic disorders. Additionally, FTZ has shown inhibitory effects on oxidative stress, regulation of lipid metabolism, and reduction of inflammation in these conditions. However, the precise mechanisms through which FTZ modulates macrophage function in atherosclerosis remain incompletely understood. Therefore, this study aims to investigate whether FTZ can effectively stabilize rupture-prone plaques by suppressing macrophage pyroptosis and impeding the development of M1 macrophage polarization in ApoE-/- mice. METHODS: To assess the impact of FTZ on macrophage function and atherosclerosis in ApoE-/- mice, we orally administered FTZ at a dosage of 1.2 g/kg body weight daily for 14 weeks. Levels of interleukin-18 and interleukin-1ß were quantified using ELISA kits to gauge FTZ's influence on inflammation. Total cholesterol content was measured with a Cholesterol Assay Kit to evaluate FTZ's effect on lipid metabolism. Aortic tissues were stained with Oil Red O, and immunohistochemistry techniques were applied to assess atherosclerotic lesions and plaque stability. To evaluate the effects of FTZ on macrophage pyroptosis and oxidative damage, immunofluorescence staining was utilized. Additionally, we conducted an analysis of protein and mRNA expression levels of NLRP3 inflammasome-related genes and macrophage polarization-related genes using RT-PCR and western blotting techniques. RESULTS: This study illustrates the potential therapeutic effectiveness of FTZ in mitigating the severity of atherosclerosis and improving serum lipid profiles by inhibiting inflammation. The observed enhancements in atherosclerosis severity and inflammation can be attributed to the suppression of NLRP3 inflammasome activity and M1 polarization by FTZ. CONCLUSION: The current findings indicate that FTZ provides protection against atherosclerosis, positioning it as a promising candidate for novel therapies targeting atherosclerosis and related cardiovascular diseases.

m6A reader YTHDF1 promotes cardiac fibrosis by enhancing AXL translation.

Cardiac fibrosis caused by ventricular remodeling and dysfunction such as post-myocardial infarction (MI) can lead to heart failure. RNA N6-methyladenosine (m6A) methylation has been shown to play a pivotal role in the occurrence and development of many illnesses. In investigating the biological function of the m6A reader YTHDF1 in cardiac fibrosis, adeno-associated virus 9 was used to knock down or overexpress the YTHDF1 gene in mouse hearts, and MI surgery in vivo and transforming growth factor-ß (TGF-ß)-activated cardiac fibroblasts in vitro were performed to establish fibrosis models. Our results demonstrated that silencing YTHDF1 in mouse hearts can significantly restore impaired cardiac function and attenuate myocardial fibrosis, whereas YTHDF1 overexpression could further enhance cardiac dysfunction and aggravate the occurrence of ventricular pathological remodeling and fibrotic development. Mechanistically, zinc finger BED-type containing 6 mediated the transcriptional function of the YTHDF1 gene promoter. YTHDF1 augmented AXL translation and activated the TGF-ß-Smad2/3 signaling pathway, thereby aggravating the occurrence and development of cardiac dysfunction and myocardial fibrosis. Consistently, our data indicated that YTHDF1 was involved in activation, proliferation, and migration to participate in cardiac fibrosis in vitro. Our results revealed that YTHDF1 could serve as a potential therapeutic target for myocardial fibrosis.

The m6A Reader YTHDF1 Promotes Lung Carcinoma Progression via Regulating Ferritin Mediate Ferroptosis in an m6A-Dependent Manner.

N6-methyladenosine (m6A) plays a significant role as an epigenetic mechanism, which is involved in various cancers' progress via regulating mRNA modification. As a crucial m6A "reader", YTHDF1 is able to alter m6A-modified mRNA and promote the protein translation process in multiple cancers. However, the role of YTHDF1 in lung cancer has not been fully investigated. This study focuses on elucidating the function of YTHDF1 in the development of lung cancer and its underlying mechanism. We demonstrated that YTHDF1 was highly expressed in lung carcinoma progression; then, the loss of function experiments in lung cell lines confirmed that knockdown of YTHDF1 suppressed cell proliferation, migration and invasion and induced ferroptosis of lung cancer cells. Further functional assays showed that ferritin (FTH) was identified as the key target of YTHDF1 in lung cancer cells. Furthermore, the overexpression of ferritin in YTHDF1-depleted cells partially restored lung cancer cell suppression. Collectively, our data suggested that the upregulation of YTHDF1 promotes lung cancer carcinogenesis by accelerating ferritin translation in an m6A-dependent manner. We hope that our findings may provide a new target for lung cancer diagnosis and treatment.

Fufang Zhenzhu Tiaozhi (FTZ) capsule ameliorates diabetes-accelerated atherosclerosis via suppressing YTHDF2-mediated m6A modification of SIRT3 mRNA.

ETHNOPHARMACOLOGICAL RELEVANCE: Fufang Zhenzhu TiaoZhi (FTZ), a Chinese medicinal decoction, has continuously been used to treat metabolic syndrome. Atherosclerosis is the main pathological basis of cardiovascular disease. The N6 methyladenosine (m6A) modification is a highly dynamic and reversible process involving a variety of important biological processes. AIM OF THE STUDY: Here, we investigated the therapeutic effects and mechanism of FTZ in diabetes-accelerated atherosclerosis. MATERIALS AND METHODS: Doppler ultrasonography was used to examine the carotid intima-media thickness and plaque area in diabetic atherosclerosis patients. HFD mice were injected with streptozotocin to induce diabetes. HE and Oil red O staining were used to assess the effect of FTZ on lipid deposition. HUVECs were induced with HG/ox-LDL as a model of diabetic atherosclerosis. Furthermore, application of m6A methylation level kit, qRT-PCR, Western blot, tunel staining, reactive oxygen species staining and mPTP staining were performed to analyze the detailed mechanism. RESULTS: Clinical trials of FTZ have shown obvious effect of lowering blood glucose and blood lipids. These effects were reversed after FTZ intervention. Compared with the control, lipid deposition decreased significantly after FTZ administration. FTZ reduced endothelial cell apoptosis. At the same time, we found that FTZ reversed the increase of methylation reader YTHDF2 caused by ox-LDL treatment. Subsequently, we discovered that YTHDF2 degraded SIRT3 mRNA, leading to endothelial cell apoptosis and oxidative stress. CONCLUSION: FTZ attenuated diabetes-accelerated atherosclerosis by decreasing blood glucose and serum lipids levels, and increased endothelial cell antioxidant capacity, inhibited endothelial cell apoptosis via inhibiting YTHDF2-mediated m6A modification of SIRT3 mRNA, which reduced mRNA degradation.

The Chinese herbal medicine Fufang Zhenzhu Tiaozhi ameliorates diabetic cardiomyopathy by regulating cardiac abnormal lipid metabolism and mitochondrial dynamics in diabetic mice.

Diabetic cardiomyopathy (DCM) is an important complication leading to the death of patients with diabetes, but there is no effective strategy for clinical treatments. Fufang Zhenzhu Tiaozhi (FTZ) is a patent medicine that is a traditional Chinese medicine compound preparation with comprehensive effects for the prevention and treatment of glycolipid metabolic diseases under the guidance of "modulating liver, starting pivot and cleaning turbidity". FTZ was proposed by Professor Guo Jiao and is used for the clinical treatment of hyperlipidemia. This study was designed to explore the regulatory mechanisms of FTZ on heart lipid metabolism dysfunction and mitochondrial dynamics disorder in mice with DCM, and it provides a theoretical basis for the myocardial protective effect of FTZ in diabetes. In this study, we demonstrated that FTZ protected heart function in DCM mice and downregulated the overexpression of free fatty acids (FFAs) uptake-related proteins cluster of differentiation 36 (CD36), fatty acid binding protein 3 (FABP3) and carnitine palmitoyl transferase 1 (CPT1). Moreover, FTZ treatment showed a regulatory effect on mitochondrial dynamics by inhibiting mitochondrial fission and promoting mitochondrial fusion. We also identified in vitro that FTZ could restore lipid metabolism-related proteins, mitochondrial dynamics-related proteins and mitochondrial energy metabolism in PA-treated cardiomyocytes. Our study indicated that FTZ improves the cardiac function of diabetic mice by attenuating the increase in fasting blood glucose levels, inhibiting the decrease in body weight, alleviating disordered lipid metabolism, and restoring mitochondrial dynamics and myocardial apoptosis in diabetic mouse hearts.

YTHDF2 Promotes Cardiac Ferroptosis via Degradation of SLC7A11 in Cardiac Ischemia-Reperfusion Injury.

Aims: Myocardial ischemia-reperfusion (I/R) injury facilitates cardiomyocyte death and endangers human health. N6-methyladenosine (m6A) methylation plays a critical role in cardiovascular diseases. The m6A reader YTHDF2 identifies m6A-modified RNA and promotes target RNA degradation. Hence, we hypothesized that YTHDF2 affects I/R injury by regulating RNA stability. Results: Both messenger RNA (mRNA) and protein levels of YTHDF2 were upregulated in I/R mice and hypoxia-reoxygenation (H/R)-induced cardiomyocytes. Silencing endogenous YTHDF2 abrogated cardiac dysfunction and lowered the infarct size in I/R mice, and the forced expression of YTHDF2 aggravated these adverse pathological processes. Consistently, the protective effect of silencing YTHDF2 occurred in cardiomyocytes exposed to H/R and erastin. Further, RNA-Seq and RNA-binding protein immunoprecipitation (RIP) revealed that YTHDF2 recognized the m6A modification sites of the ferroptosis-related gene solute carrier family 7 member 11 (SLC7A11) mRNA to promote its degradation both in vivo and in vitro. Inhibition of SLC7A11 impaired cardiac function, increased infarct size, and the release of lactate dehydrogenase (LDH) in I/R mice after silencing YTHDF2. The beneficial effects of si-YTHDF2 on H/R injury were reversed by co-transfection with SLC7A11-specific siRNA (si-SLC7A11), which substantially exacerbated ferroptosis and the production of reactive oxygen species. Innovation and Conclusion: The cardioprotective effects of silencing YTHDF2 are accomplished by increasing SLC7A11 stability and expression, reducing ferroptosis, and providing novel potential therapeutic targets for treating ischemic cardiac diseases.

Mitochondrial damage and activation of the cytosolic DNA sensor cGAS-STING pathway lead to cardiac pyroptosis and hypertrophy in diabetic cardiomyopathy mice.

Diabetic cardiomyopathy (DCM) is a serious cardiac complication of diabetes that currently lacks specific treatment. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway has been suggested to contribute to the pathogenesis of cardiovascular diseases. However, whether cGAS-STING is involved in the development of DCM has not been established. Our study aimed to determine the role of cGAS-STING in the initiation of nucleotide-binding oligomerization domain-like receptor pyrin domain containing 3 (NLRP3) inflammasome-induced cardiac pyroptosis and chronic inflammation during the pathogenesis of DCM. C57BL/6J mice were preinjected with adeno-associated virus 9 (AAV9) intravenously via the tail vein to specifically knock down myocardial STING. After four weeks, mice with myocardium-specific knockdown of STING received injections of streptozotocin (STZ; 50 mg/kg) and a high-fat diet to induce diabetes. Measurements included echocardiography, immunohistochemical analyses, wheat germ agglutinin (WGA) staining, and western blotting. Here, we showed that the cGAS-STING signaling pathway was activated in diabetic hearts, which was indicated by the increased phosphorylation of TANK-binding kinase 1 (TBK1) and interferon (IFN) regulatory factor 3 (IRF3), leading to the activation of the NLRP3 inflammasome in the hearts of diabetic mice and proinflammatory cytokine release into serum. Moreover, STING knockdown via adeno-associated virus-9 (AAV9) in diabetic mouse heart alleviated cardiac pyroptosis and the inflammatory response, prevented diabetes-induced hypertrophy, and restored cardiac function. Mechanistically, we showed that palmitic acid (PA)-induced lipotoxicity impairs mitochondrial homeostasis, producing excessive mitochondrial reactive oxygen species (mtROS), which results in oxidative damage to mitochondrial DNA (mtDNA) and its release into the cytoplasm while switching on cGAS-STING-mediated pyroptosis in cardiomyocytes, thereby worsening the progression of diabetic cardiomyopathy. Our study demonstrated that activation of the cGAS-STING pathway caused by mitochondrial oxidative damage and mtDNA escape induced by free fatty acids promoted pyroptosis and proinflammatory responses in cardiomyocytes in a NLRP3 inflammasome-dependent manner, thus promoting myocardial hypertrophy during the progression of DCM.

The Chinese medicine Fufang Zhenzhu Tiaozhi capsule protects against atherosclerosis by suppressing EndMT via modulating Akt1/ß-catenin signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Fufang Zhenzhu Tiaozhi (FTZ) is a traditional Chinese herbal prescription that has been used to treat dyslipidemia, nonalcoholic fatty liver disease, atherosclerosis, diabetes and its complications in the clinic for almost ten years. Endothelial-mesenchymal transition (EndMT) is the key driver of atherosclerosis. However, the effects of FTZ on endothelial dysfunction and EndMT remain unknown. AIM OF THE STUDY: To evaluate the therapeutic effects of FTZ against EndMT and the underlying mechanisms. MATERIALS AND METHODS: An in vivo model of atherosclerosis was established by feeding ApoE-/- mice with a high-fat diet (HFD). The body weight, lipid levels, plaque area, lipid deposition and EndMT were evaluated using standard assays 12 weeks after intragastric administration of FTZ and simvastatin. Human umbilical vein endothelial cells (HUVECs) were treated with oxidized low-density lipoprotein (ox-LDL) to simulate EndMT in vitro. The degree of EndMT was assessed after treating the cells with FTZ or transfection with si-Akt1. The expression levels of genes involved in EndMT were quantified by real-time PCR or western blotting. RESULTS: FTZ ameliorated dyslipidemia and endothelial dysfunction in the atherosclerotic mice. In addition, FTZ reduced body weight and the total cholesterol, triglycerides and low-density lipoprotein levels, and increased that of high-density lipoproteins. FTZ also upregulated the expression of endothelial markers (CD31 and VE-cadherin) and decreased that of mesenchymal markers (ɑ-SMA and FSP1), indicating that it inhibits EndMT. Knocking down Akt1 exacerbated EndMT and reversed the therapeutic effect of FTZ. CONCLUSION: FTZ delayed atherosclerosis by inhibiting EndMT via the Akt1/ß-catenin pathway.

The Traditional Chinese Medicine Formula FTZ Protects against Cardiac Fibrosis by Suppressing the TGFß1-Smad2/3 Pathway.

Background: Fu fang Zhen Zhu Tiao Zhi (FTZ) is a patented preparation of Chinese herbal medicine that has been used as a natural medicine to treat several chronic diseases including cardiovascular disease. However, its effects on cardiac fibrosis remain unclear. Therefore, this study was designed to investigate the effects and potential mechanisms of FTZ in treating cardiac fibrosis. Methods: FTZ was administered to mice by oral gavage daily at a dosage of 1.2 g/kg or 2.4 g/kg of body weight for 7 weeks after a transverse aorta constriction (TAC) surgery. Doppler echocardiography, hematoxylin and eosin staining, and Masson's trichrome staining were used to assess the effect of FTZ on the cardiac structure and function of mice that had undergone TAC. EdU and wound-healing assays were performed to measure the proliferative and migratory abilities of cardiac fibroblasts. Western blotting and qRT-PCR were used to determine the expression of TGFß1, Col1A2, Col3, and α-SMA proteins and mRNA levels. Results: FTZ treatment reduced collagen synthesis, attenuated cardiac fibrosis, and improved cardiac function in mice subjected to TAC. Moreover, FTZ treatment prevented the proliferation and migration of cardiac fibroblasts and reduced Ang-II-induced collagen synthesis. Furthermore, FTZ downregulated the expression of TGFß1, p-smad2, and p-smad3 and inhibited the TGFß1-Smad2/3 pathway in the setting of cardiac fibrosis. Conclusion: FTZ alleviated the proliferation and migration of cardiac fibroblasts and suppressed collagen synthesis via the TGFß1-Smad2/3 pathway during the progression of cardiac fibrosis. These findings indicated the therapeutic potential of FTZ in treating cardiac fibrosis.

BAG3 Alleviates Atherosclerosis by Inhibiting Endothelial-to-Mesenchymal Transition via Autophagy Activation.

Atherosclerosis is a chronic systemic inflammatory disease that causes severe cardiovascular events. B cell lymphoma 2-associated athanogene (BAG3) was proven to participate in the regulation of tumor angiogenesis, neurodegenerative diseases, and cardiac diseases, but its role in atherosclerosis remains unclear. Here, we aim to investigate the role of BAG3 in atherosclerosis and elucidate the potential molecular mechanism. In this study, ApoE-/- mice were given a tail-vein injection of BAG3-overexpressing lentivirus and fed a 12-week high-fat diet (HFD) to investigate the role of BAG3 in atherosclerosis. The overexpression of BAG3 reduced plaque areas and improved atherosclerosis in ApoE-/- mice. Our research proves that BAG3 promotes autophagy in vitro, contributing to the suppression of EndMT in human umbilical vein endothelial cells (HUVECs). Mechanically, autophagy activation is mediated by BAG3 via the interaction between BAG3 and its chaperones HSP70 and HSPB8. In conclusion, BAG3 facilitates autophagy activation via the formation of the chaperone-assisted selective autophagy (CASA) complex interacting with HSP70 and HSPB8, leading to the inhibition of EndMT during the progression of atherosclerosis and indicating that BAG3 is a potential therapeutic target for atherosclerosis.

FTZ protects against cardiac hypertrophy and oxidative injury via microRNA-214 / SIRT3 signaling pathway.

BACKGROUND: Despite the fact that the initial hypertrophic response to ventricular pressure overload is thought to be compensatory, prolonged stress often leads to heart failure. Previous studies have shown that the Fufang-Zhenzhu-Tiaozhi (FTZ) formula is beneficial for the treatment of dyslipidemia and hyperglycemia. However, the effects of FTZ on cardiac hypertrophy remain unclear. OBJECTIVE: The aim of this study is to evaluate the protective effects of FTZ on cardiac hypertrophy and determine the underlying mechanisms. METHODS: TAC was utilized to establish a cardiac hypertrophy animal model, and FTZ was given via gavage for four weeks. Next, echocardiographic measurements were made. The morphology of mouse cardiomyocytes was examined using H&E and WGA staining. In vitro, the neonatal cardiomyocytes were stimulated with angiotensin Ⅱ (Ang Ⅱ). In addition to measuring the size of cardiomyocytes, qRT-PCR and western blotting were conducted to measure cardiac stress markers and pathway. RESULTS: According to our findings, FTZ alleviated cardiac hypertrophy in mice and cell models. Furthermore, expression of miR-214 was down-regulated following FTZ, whereas the effect of FTZ therapy was reversed using miR-214 transfection. Furthermore, the expression of Sirtuin 3 (SIRT3) was decreased in Ang Ⅱ-induced oxidative damage, which was associated with a reduction in SOD-1, GPX1, and HO-1 and an increase in MDA, while SIRT3 expression was restored following FTZ treatment. CONCLUSIONS: Collectively, these findings indicate that FTZ is a protective factor for cardiac hypertrophy due to its regulation of the miR-214-SIRT3 axis, which suggests that FTZ may be a therapeutic target for cardiac hypertrophy.

The Chinese herbal medicine Fufang Zhenzhu Tiaozhi protects against diabetic cardiomyopathy by alleviating cardiac lipotoxicity-induced oxidative stress and NLRP3-dependent inflammasome activation.

BACKGROUND: Fufang Zhenzhu Tiao Zhi (FTZ) formula is a Chinese herbal preparation used in the clinical treatment of disorders of glucolipid metabolism. Given its effective actions on the regulation of lipid dysfunction and its anti-inflammatory and antioxidative effects, we designed this study to investigate the cardioprotective effect and possible mechanism of FTZ in diabetic cardiomyopathy (DCM) mice. METHODS: FTZ was administered to diabetic mice by oral gavage daily at a dose of 1.2 g/kg or 2.4 g/kg bodyweight for 8 weeks. Doppler echocardiography, H&E, and WGA staining were used to evaluate cardiac function and structure in the mice. The levels of proinflammatory cytokines and lipids in serum were detected with corresponding commercial kits. Immunofluorescence staining and flow cytometry were used to detect oxidation damage and pyroptosis in myocardial cells. RT-PCR and western blotting were used to analyze the protein and mRNA expression levels of NLRP3 inflammasome-related genes. RESULTS: Our study indicated that FTZ improved cardiac function, attenuated heart hypertrophy, improved serum lipid and proinflammatory cytokine levels, and restrained oxidative stress and NLRP3 inflammasome-induced inflammatory activities in diabetic mouse hearts. The in vitro data suggested that FTZ suppressed intercellular lipid accumulation as well as palmitic acid (PA)-induced oxidative stress and NLRP3 inflammasome-dependent pyroptosis in cardiomyocytes. CONCLUSION: Our present findings indicate that FTZ inhibits DCM by inhibiting both oxidative stress and NLRP3 inflammasome activation induced by cardiac lipotoxicity.

Fu Fang Zhen Zhu Tiao Zhi Capsules Protect against Myocardial Ischemia by Inhibiting Cardiomyocyte Pyroptosis.

Background: Fu Fang Zhen Zhu Tiao Zhi (FTZ) is a traditional Chinese herbal prescription widely used to treat dyslipidemia, metabolic diseases, and diabetic coronary disorders. Cardiomyocyte death and loss of regenerative ability cause cardiac dysfunction and heart failure. FTZ can effectively treat diabetic cardiomyopathy and macrovascular diseases; however, the mechanism behind the phenomenon is still unclear. Here, we determined the mechanism of action of FTZ in treating myocardial infarction. Methods: Male C57BL/6 mice were treated with 2.4 or 1.2 g/kg FTZ, or administered saline by oral gavage daily for four weeks, and a 24-hour ligation was administered to the artery. Echocardiography was used to evaluate cardiac function. Hematoxylin and eosin and Evans blue/triphenyltetrazolium chloride staining were carried out by staining the cardiac tissue, used to evaluate cardiac function and infarct size. Using western blotting and reverse transcriptase-polymerase chain reaction, we determined the relative levels of NOD-like receptor protein (NLRP) 3, ASC, cleaved caspase-l (C-Caspase-1), GSDMD, and GSDMD-N. TUNEL, immunohistochemical, and immunofluorescence staining were used to determine cell death and NLRP3 expression. An enzyme-linked immunosorbent assay (ELISA) was used to detect the levels of interleukin (IL)-1ß and IL-18. Results: FTZ reduced ischemia-induced cardiomyocyte cell death in vivo and H2O2-induced cell death in vitro by maintaining cardiac architecture and restoring cardiac function. FTZ decreased the NLRP3 expression and inhibited pyroptosis-correlated genes, including NLRP3, ASC, GSDMD, C-Caspase-1, and GSDMD-N. NLRP3 overexpression impaired the efficacy of FTZ by inducing pyroptosis. Conclusion: FTZ could preserve cardiac function resulting from ischemic insult by inhibiting pyroptosis, which was partially reversed by NLRP3 overexpression, indicating that NLRP3 could be a potential target of FTZ in treating myocardial infarction.

Emodin alleviates cardiac fibrosis by suppressing activation of cardiac fibroblasts via upregulating metastasis associated protein 3.

Excess activation of cardiac fibroblasts inevitably induces cardiac fibrosis. Emodin has been used as a natural medicine against several chronic diseases. The objective of this study is to determine the effects of emodin on cardiac fibrosis and the underlying molecular mechanisms. Intragastric administration of emodin markedly decreased left ventricular wall thickness in a mouse model of pathological cardiac hypertrophy with excess fibrosis induced by transaortic constriction (TAC) and suppressed activation of cardiac fibroblasts induced by angiotensin II (AngII). Emodin upregulated expression of metastasis associated protein 3 (MTA3) and restored the MTA3 expression in the setting of cardiac fibrosis. Moreover, overexpression of MTA3 promoted cardiac fibrosis; in contrast, silence of MTA3 abrogated the inhibitory effect of emodin on fibroblast activation. Our findings unraveled the potential of emodin to alleviate cardiac fibrosis via upregulating MTA3 and highlight the regulatory role of MTA3 in the development of cardiac fibrosis.

MicroRNA­1 downregulation induced by carvedilol protects cardiomyocytes against apoptosis by targeting heat shock protein 60.

Myocardial infarction (MI) is the most common event in cardiovascular disease. Carvedilol, a ß­blocker with multiple pleiotropic actions, is widely used for the treatment cardiovascular diseases. However, the underlying mechanisms of carvedilol on alleviating MI are not fully understood. The aim of the present study was to investigate whether the beneficial effects of carvedilol were associated with regulation of microRNA­1 (miR­1). It was demonstrated that carvedilol ameliorated impaired cardiac function and decreased infarct size in a rat model of MI induced by coronary artery occlusion. Similarly, carvedilol reversed the H2O2­induced decrease in cardiomyocyte viability in a dose­dependent manner. The in vivo and in vitro models demonstrated the downregulation of miR­1 following treatment with carvedilol. Overexpression of miR­1, a known pro­apoptotic miRNA, decreased cell viability and induced cell apoptosis. Transfection of miR­1 abolished the beneficial effects of carvedilol. The expression of heat shock protein 60 (HSP60), a direct target of miR­1, was identified to be decreased in MI and H2O2­induced apoptosis, which was associated with a decrease in Bcl­2 and an increase in Bax; expression was restored following treatment with carvedilol. It was concluded that carvedilol partially exhibited its beneficial effects by downregulating miR­1 and increasing HSP60 expression. miR­1 has become a member of the group of carvedilol­responsive miRNAs. Future studies are required to fully elucidate the potential overlapping or compensatory effects of known carvedilol­responsive miRNAs and their underlying mechanisms of action in the pathophysiology of cardiovascular diseases.