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Schematic illustration shows the main cascade of molecules in myocardial ischemia/reperfusion injury. Myocardial ischemia/reperfusion (oxidative stress) triggers ROS production and inflammation response (release of pro-inflammatory cytokines TLR-4, IL-6, TNF? , which induce ventricular arrhythmias) and decreases the endogenous anti-oxidants SOD and thioredoxin (Trx). Over-production of ROS and inflammation cytokines would initiate cardiomyocyte apoptosis cell death and cause myocardial infarct. Intravenous application of acacetin prodrug (bioconversion to acacetin) prevents the ischemia/reperfusioninduced reduction of the endogenous anti-oxidants and also reduces inflammation response, and thereby inhibits ventricular arrhythmias and myocardial apoptosis and significantly reduces infarct size.
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The morbidity and mortality of patients with ischemic cardiomyopathy resulted from ischemia/reperfusion injury are very high. The present study investigates whether our previously synthesized water-soluble phosphate prodrug of acacetin was cardioprotective against ischemia/reperfusion injury in an in vivo rat model. We found that intravenous admini...
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Context 1
... increased by ischemia/reperfusion injury. It is interesting to note that acace- tin treatment remarkably prevented the ischemia/reperfusion-induced reduction of SOD-2 and Bcl-2, preserved their activities, and thereby inhibited inflammation mediators (TLR-4, IL-6, and TNFα ) and cardiomyocyte apoptosis and decreased the myocardial infarct size (Fig. 8). The preservation of the anti-oxidant systems (SOD and thioredoxin) may be the key effect of acacetin for cardioprotection against ischemia/reperfusion ...
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... Acacetin has been recognized for its pharmacological properties, including antioxidant and anti-inflammatory effects, and has demonstrated therapeutic potential against various diseases in cellular or animal studies. Multiple studies have found that acacetin can exert protective effects on cardiovascular diseases by regulating pathways such as TGF-β/Smad3, MAPK, and PI3K/Akt, inhibiting the expression of inflammatory cytokines, and promoting the secretion of anti-inflammatory factors (Liu et al., 2016;Wu W.-Y. et al., 2018;Li Z.-Y. et al., 2023). ...
Objective: Our preliminary research indicates that acacetin modulates the nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain containing 3 (NLRP3) inflammasome, providing protection against Alzheimer’s Disease (AD) and cerebral ischemic reperfusion injury. The mechanisms of acacetin to inhibit the activation of the NLRP3 inflammasome remain fully elucidated. This study aims to investigate the effects and potential mechanisms of acacetin on various agonists induced NLRP3 inflammasome activation.
Methods: A model for the NLRP3 inflammasome activation was established in mouse bone marrow-derived macrophages (BMDMs) using Monosodium Urate (MSU), Nigericin, Adenosine Triphosphate (ATP), and Pam3CSK4, separately. Western blot analysis (WB) was employed to detect Pro-caspase-1, Pro-Interleukin-1β (Pro-IL-1β) in cell lysates, and caspase-1, IL-1β in supernatants. Enzyme-Linked Immunosorbent Assay (ELISA) was used to measured the release of IL-1β, IL-18, and Tumor Necrosis Factor-alpha (TNF-α) in cell supernatants to assess the impact of acacetin on NLRP3 inflammasome activation. The lactate dehydrogenase (LDH) release was also assessed. The Nuclear Factor Kappa B (NF-κB) and Mitogen-Activated Protein Kinase (MAPK) signaling pathways related proteins were evaluated by WB, and NF-κB nuclear translocation was observed via laser scanning confocal microscopy (LSCM). Disuccinimidyl Suberate (DSS) cross-linking was employed to detect oligomerization of Apoptosis-associated Speck-like protein containing a Caspase Recruitment Domain (ASC), and LSCM was also used to observe Reactive Oxygen Species (ROS) production. Inductively Coupled Plasma (ICP) and N-(6-methoxyquinolyl) acetoethyl ester (MQAE) assays were utilized to determined the effects of acacetin on the efflux of potassium (K+) and chloride (Cl-) ions.
Results: Acacetin inhibited NLRP3 inflammasome activation induced by various agonists, reducing the release of TNF-α, IL-1β, IL-18, and LDH. It suppressed the expression of Lipopolysaccharides (LPS)-activated Phosphorylated ERK (p-ERK), p-JNK, and p-p38, inhibited NF-κB p65 phosphorylation and nuclear translocation. Acacetin also reduced ROS production and inhibited ASC aggregation, thus suppressing NLRP3 inflammasome activation. Notably, acacetin did not affect K+ and Cl-ions efflux during the activation process.
Conclusion: Acacetin shows inhibitory effects on both the priming and assembly processes of the NLRP3 inflammasome, positioning it as a promising new candidate for the treatment of NLRP3 inflammasome-related diseases.
... The biological activities of acacetin in anti-cancer, anti-obesity, anti-diabetic, anti-inflammatory, anti-oxidant, and anti-microbial roles were well reviewed recently [22]. Considering the poor water solubility of acacetin, our previous group synthesized a watersoluble phosphate prodrug which could be converted into acacetin in vivo and prevent the induction of experimental atrial fibrillation in dogs and exhibit cardioprotective efficacy against ischemia/reperfusion injury in rats [23,24]. It has been reported that acacetin protects against D-galactosamine (D-GaIN)/LPS-induced liver injury by suppressing TLR4 signaling and enhancing autophagic flux [25]. ...
... Both acacetin and the water-soluble acacetin prodrug were kindly provided by Dr. Gui-Rong Li from Nanjing Amazigh Pharma Ltd. (Nanjing, China). The synthesis process and in vivo conversion of the acacetin prodrug were reported previously [23,24]. APAP, dimethyl sulfoxide (DMSO), MTT, rosiglitazone (RSG), and GW9662 were purchased from Sigma-Aldrich Chemicals (St. Louis, MO, USA). ...
A water-soluble acacetin prodrug has been synthesized and reported by our group previously. Acetaminophen (APAP) overdose is a leading cause of acute liver injury. We found that subcutaneous injection of acacetin prodrug (5, 10, 20 mg/kg) decreased serum ALT, AST, and ALP, corrected the abnormal MDA and GSH in liver, and improved intrahepatic hemorrhage and destruction of liver structures in APAP (300 mg/kg)-treated mice. Molecular mechanism analysis revealed that the expressions of endoplasmic reticulum (ER) stress markers ATF6, CHOP, and p-PERK, apoptosis-related protein BAX, and cleaved caspase 3 were decreased by acacetin in a dose-dependent manner in vivo and in vitro. Moreover, via the acacetin-upregulated peroxisome-proliferator-activated receptor gamma (PPARγ) of HepG2 cells and liver, the suppressive effect of acacetin on ER stress and apoptosis was abolished by PPARγ inhibitor (GW9662) or PPARγ-siRNA. Molecular docking revealed that acacetin can bind to three active pockets of PPARγ, mainly by hydrogen bond. Our results provide novel evidence that acacetin prodrug exhibits significant protective effect against APAP-induced liver injury by targeting PPARγ, thereby suppressing ER stress and hepatocyte apoptosis. Acacetin prodrug is likely a promising new drug candidate for treating patients with acute liver injury induced by APAP.
... For instance, pretreatment with acacetin significantly improved mitochondrial membrane potential dysfunction [10]. In addition, acacetin inhibits myocardial cell apoptosis by inhibiting the reduction of endogenous antioxidants, and has a significant therapeutic effect on myocardial injury caused by ischemia/reperfusion [11]. A large amount of literature has shown that the insulin pathway and mitochondrial damage affect each other, but it is not clear whether acacetin is still effective for myocardial damage caused by hypertension with insulin resistance [12]. ...
To explore the effect of acacetin on myocardial mitochondrial dysfunction in spontaneously hypertensive rats (SHR) with insulin resistance (IR), and the possible mechanism. Rapid IR was first induced in fructose-fed SHR, and they were then treated with acacetin (25, 50 mg/kg). After 7 weeks, the rats were tested for hypertension, IR, cardiac function, and mitochondrial damage status. Potential mechanisms of action were explored in terms of oxidative stress, mitochondrial fission and division, apoptosis, and the insulin signaling pathway. Subsequently, the PI3K gene was silenced, after intervention with acacetin (5 μM) for 24 h, and H2O2 was used to stimulate H9c2 for 4 h, it was evaluated whether silencing PI3K would affect the therapeutic effect of acacetin. In SHR fed with fructose, acacetin can improve hypertension, IR, cardiac function (LVEF, LVFS), and mitochondrial damage (mitochondria number, ATP); inhibit oxidative stress (ROS, SOD, Nrf2, Keap1), mitochondrial fission (MFF, Drp1), and myocardial cell apoptosis (apoptosis rate, Bax, Bcl-2, cytochrome c); promote mitochondrial fusion (Mfn2) and activate insulin signaling pathways (PI3K/AKT). However, silencing PI3K inhibited the abovementioned effects of acacetin. In conclusion, acacetin improved myocardial mitochondrial dysfunction through regulating oxidative stress, mitochondrial fission and fusion, and mitochondrial pathway apoptosis mediated by PI3K/AKT signaling pathway in hypertensive rats with IR.
... These strategies can not only lessen the myocardial infarction size and arrhythmia but also improve the myocardial systolic function after ischemia-reperfusion [68][69][70]. Moreover, some substances, such as lycopene, can be used as adjuvant therapy to mitigate myocardial I/R injury through their antioxidant abilities [71][72][73][74][75]. However, if antioxidants are used indiscriminately to quench reactive species (ROS/RNS) during I/R injury, they may interfere with normal physiological redox signals and damage cellular function [76]. ...
Tissue and organ ischemia can lead to cell trauma, tissue necrosis, irreversible damage, and death. While intended to reverse ischemia, reperfusion can further aggravate an ischemic injury (ischemia-reperfusion injury, I/R injury) through a range of pathologic processes. An I/R injury to one organ can also harm other organs, leading to systemic multiorgan failure. A type of carotenoid, lycopene, has been shown to treat and prevent many diseases (e.g., rheumatoid arthritis, cancer, diabetes, osteoporosis, male infertility, neurodegenerative diseases, and cardiovascular disease), making it a hot research topic in health care. Some recent researches have suggested that lycopene can evidently ameliorate ischemic and I/R injuries to many organs, but few clinical studies are available. Therefore, it is essential to review the effects of lycopene on ischemic and I/R injuries to different organs, which may help further research into its potential clinical applications.
... These strategies can not only lessen the myocardial infarction size and arrhythmia but also improve the myocardial systolic function after ischemia-reperfusion [68][69][70]. Moreover, some substances, such as lycopene, can be used as adjuvant therapy to mitigate myocardial I/R injury through their antioxidant abilities [71][72][73][74][75]. However, if antioxidants are used indiscriminately to quench reactive species (ROS/RNS) during I/R injury, they may interfere with normal physiological redox signals and damage cellular function [76]. ...
Tissue and organ ischemia can lead to cell trauma, tissue necrosis, irreversible damage, and death. While intended to reverse ischemia, reperfusion can further aggravate an ischemic injury (ischemia-reperfusion injury, I/R injury) through a range of pathologic processes. An I/R injury to one organ can also harm other organs, leading to systemic multiorgan failure. A type of carotenoid, lycopene, has been shown to treat and prevent many diseases (e.g., rheumatoid arthritis, cancer, diabetes, osteoporosis, male infertility, neurodegenerative diseases, and cardiovascular disease), making it a hot research topic in health care. Some recent researches have suggested that lycopene can evidently ameliorate ischemic and I/R injuries to many organs, but few clinical studies are available. Therefore, it is essential to review the effects of lycopene on ischemic and I/R injuries to different organs, which may help further research into its potential clinical applications.
... Stevioside, a common sweetener [192], contains polyphenol, can increase intracellular reduced GSH, upregulates SOD and Cat and decreases lipid peroxidation [193] (Figure 4A). Acacetin is a natural flavone of plant pigments [194] and can increase SOD2 [195], and Trx activity [196] (Figure 4A). N-3 polyunsaturated fatty acids (n3-PUFAs), such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), seem to have different effects: in mitochondria, DHA reduces the cytochrome complex IV activity and increases SOD [197]. ...
Oxidative stress is generated by the imbalance between reactive oxygen species (ROS) formation and antioxidant scavenger system’s activity. Increased ROS, such as superoxide anion, hydrogen peroxide, hydroxyl radical and peroxynitrite, likely contribute to the development and complications of atherosclerotic cardiovascular diseases (ASCVD). In genetically modified mouse models of atherosclerosis, the overexpression of ROS-generating enzymes and uncontrolled ROS formation appear to be associated with accelerated atherosclerosis. Conversely, the overexpression of ROS scavenger systems reduces or stabilizes atherosclerotic lesions, depending on the genetic background of the mouse model. In humans, higher levels of circulating biomarkers derived from the oxidation of lipids (8-epi-prostaglandin F2α, and malondialdehyde), as well as proteins (oxidized low-density lipoprotein, nitrotyrosine, protein carbonyls, advanced glycation end-products), are increased in conditions of high cardiovascular risk or overt ASCVD, and some oxidation biomarkers have been reported as independent predictors of ASCVD in large observational cohorts. In animal models, antioxidant supplementation with melatonin, resveratrol, Vitamin E, stevioside, acacetin and n-polyunsaturated fatty acids reduced ROS and attenuated atherosclerotic lesions. However, in humans, evidence from large, placebo-controlled, randomized trials or prospective studies failed to show any athero-protective effect of antioxidant supplementation with different compounds in different CV settings. However, the chronic consumption of diets known to be rich in antioxidant compounds (e.g., Mediterranean and high-fish diet), has shown to reduce ASCVD over decades. Future studies are needed to fill the gap between the data and targets derived from studies in animals and their pathogenetic and therapeutic significance in human ASCVD.
... Studies have shown that Saussurea involucrata contains a variety of active ingredients with different chemical structures, such as flavonoids, lignans, phenolics, phenylpropanoids, and sesquiterpenes. Many of these components have been reported to have pharmacologic activity against myocardial ischemia [11,13,14], which are often affected by the interaction between the body and the drug. ...
Saussurea involucrata has been reported to have potential therapeutic effects against myocardial ischemia. The pharmacological effects of oral natural medicines may be influenced by the participation of gut microbiota. In this study, we aimed to investigate the bidirectional regulation of gut microbiota and the main components of Saussurea involucrata. We first established a quantitative method for the four main components (chlorogenic acid, syringin, acanthoside B, rutin) which were chosen by fingerprint using liquid chromatography tandem mass spectrometry (LC-MS/MS), and found that gut microbiota has a strong metabolic effect on them. Meanwhile, we identified five major rat gut microbiota metabolites (M1–M5) using liquid chromatography tandem time-of-flight mass spectrometry (LC/MSn-IT-TOF). The metabolic properties of metabolites in vitro were preliminarily elucidated by LC-MS/MS for the first time. These five metabolites of Saussurea involucrata may all have potential contributions to the treatment of myocardial ischemia. Furthermore, the four main components (10 μg/mL) can significantly stimulate intestinal bacteria to produce short chain fatty acids in vitro, respectively, which can further contribute to the effect in myocardial ischemia. In this study, the therapeutic effect against myocardial ischemia of Saussurea involucrata was first reported to be related to the intestinal flora, which can be useful in understanding the effective substances of Saussurea involucrata.
... Rat I/R model and drug administration As previously described, the rat I/R injury was introduced (Zhang et al. 2010;Wei et al. 2018). A total of 36 rats were divided into 4 groups: sham group (n ¼ 10), sham rats treated with acacetin group (n ¼ 6), vehicle group (I/R rats injected with saline; n ¼ 9), and I/R rats treated with acacetin group (n ¼ 11; subcutaneously injected with 10 mg/kg acacetin on the neck of rats 15 min before the I/R injury conducted; Liu H et al. 2016;Tian et al. 2019;Liu et al. 2021). After 35 min of ischaemia, rats were reperfused. ...
Context
Acacetin is a natural source of flavonoids with anti-inflammatory and antioxidant effects.
Objective
This study determines acacetin’s protective effect and mechanism on myocardial ischaemia/reperfusion (I/R) injury.
Materials and methods
Sprague-Dawley rats were divided into sham and I/R injury and treatment with acacetin. Acacetin (10 mg/kg) was subcutaneously injected for 7 days. ECG and echocardiography were conducted to determine arrhythmia and heart function. The pathological characters of the heart were determined with triphenyl tetrazolium chloride staining, Haematoxylin & Eosin staining, and Masson staining. Expression of proteins in infarct tissues was examined with western blots.
Results
Administrated with acacetin in I/R rats significantly reduced the arrhythmia score from 4.90 to 2.50 and the reperfusion arrhythmia score from 3.79 to 1.82 in the vehicle or the acacetin group, respectively. LVEF was improved from 33.5% in the I/R group to 43.7% in the acacetin group, LVFS was increased from 16.4% to 24.5%, LVIDs was decreased from 6.5 to 5.3 mm. The inflammatory cell infiltration, myocardial fibrosis, and collagen 1 and 3 were reduced by acacetin. Acacetin promoted SOD and decreased MDA. In myocardial tissues, the expression level of TLR4 and IL-6 were restrained, and IL-10 was promoted. Apoptotic protein Bax was suppressed, and anti-apoptotic protein Bcl-2 was promoted in the acacetin group. Interestingly, the transcription factor Nrf-2/HO-1 pathway was also reversed by acacetin.
Discussion and conclusion
Our findings indicated that acacetin has a potential therapeutic effect in clinical application on treating I/R-induced heart injury.
... In this study, acacetin can significantly reduce the content of malondialdehyde (MDA), which is usually used to evaluate the oxidative damage of cells in the medium during hypoxia/ reoxygenation injury. Subsequently, an acacetin phosphate prodrug was applied to the in vivo experiments of ischemia/ reperfusion injury, and the studies showed that acacetin inhibited the apoptosis of myocardial cells by preventing the reduction of antioxidants such as SOD-2 and thioredoxin and reducing the release of inflammatory cytokines such as TLR4, IL-6, and TNFα, thus playing a protective role on the myocardium after myocardial infarction (MI) [34]. Further studies have confirmed that the antioxidant, anti-inflammatory, and antiapoptotic effects of acacetin on cells are mediated by AMPK-mediated Nrf2 activation [35]. ...
Acacetin (5,7-dihydroxy-4′-methoxyflavone) is the major bioactive component of the traditional Chinese medicine “Snow lotus”. As a natural flavonoid compound, it has been shown to have good pharmacological effects such as anti-inflammatory, anticancer, and anti-obesity. Among them, its prominent role in cardiovascular diseases (CVD) has received extensive attention from scholars in recent years. In this review, the protective effects of acacetin on a variety of cardiovascular diseases, as well as the existing problems and prospects, are discussed and summarized. This review also highlights the great potential of acacetin, a natural-derived Chinese medicine, as a cardiovascular agent candidate.
... Therefore, better therapeutic approaches are urgently required for targeting multiple molecules involved in left ventricular remodeling, e. g. cardiac myocyte growth and death, vascular rarefaction, fibrosis, inflammation, and electrophysiological remodeling . Our recent studies demonstrated that the natural flavone acacetin, which was initially isolated from the Chinese Medicinal herb Snow Lotus (Saussurea involucrata), provides cardioprotection against ischemia/reperfusion injury (Liu et al., 2016b;Wu et al., 2018) and doxorubicin cardiomyopathy (Wu et al., 2020) by increasing SOD, Bcl-2 and/or AMPK, Sirt1 and decreasing TNF-α, IL6, TLR-4, Bax, etc. The present study investigates whether acacetin could improve the Ang II-induced cellular hypertrophy in rat neonatal cardiomyocytes and pressure overload-induced hypertrophy by abdominal aorta constriction (AAC) in Sprague Dawley (SD) rats. ...
... Acacetin and water-soluble acacetin prodrug ( Fig. 1) used in the present study were synthesized with 99% purity as described previously (Li et al., 2008;Liu et al., 2016a) and the prodrug could be converted in vivo into acacetin which exhibits effective cardioprotection and anti-atrial fibrillation effects (Liu et al., 2016a(Liu et al., , 2016b. The concentration range of acacetin used in in vitro experiments and the dose of acacetin prodrug used in animal experiment were referenced in previous studies Liu et al., 2016b). ...
... Acacetin and water-soluble acacetin prodrug ( Fig. 1) used in the present study were synthesized with 99% purity as described previously (Li et al., 2008;Liu et al., 2016a) and the prodrug could be converted in vivo into acacetin which exhibits effective cardioprotection and anti-atrial fibrillation effects (Liu et al., 2016a(Liu et al., , 2016b. The concentration range of acacetin used in in vitro experiments and the dose of acacetin prodrug used in animal experiment were referenced in previous studies Liu et al., 2016b). ...
Diabetic cardiomyopathy seriously affects the life quality of diabetic patients and can lead to heart failure and death in severe cases. Acacetin was reported to be an anti-oxidant and anti-inflammatory agent in several cardiovascular diseases. However, the effect of acacetin on diabetic cardiomyopathy was not understood. This study was designed to explore the therapeutic effect of acacetin on diabetic cardiomyopathy and the potential mechanism with in vitro and in vivo experimental techniques. In cultured neonatal rat cardiomyocytes and H9C2 cardiac cells, acacetin (0.3, 1, 3 μM) showed effective protection against high glucose-induced injury in a concentration-dependent manner. Acacetin countered high glucose-induced increase of Bax and decrease of Bcl-2, SOD1, and SOD2. In streptozotocin-induced rat diabetic cardiomyopathy model, treatment with acacetin prodrug (10 mg/kg, s.c., b.i.d.) significantly improved the cardiac function and reduced myocardial injury, and reversed the increase of serum MDA, Ang Ⅱ, and IL-6 levels and myocardial Bax and IL-6, and the decrease of serum SOD, indicating that acacetin plays a cardioprotective effect by inhibiting oxidative stress, inflammation, and apoptosis. In addition, both in vitro and in vivo experimental results showed that acacetin increased the expression of PPAR-α and pAMPK, indicating that PPAR-α and pAMPK are potential targets of acacetin for the protection against diabetic cardiomyopathy. This study demonstrates the new application of acacetin for treating diabetic cardiomyopathy.
