The protective effect of Macrostemonoside T from Allium macrostemon Bunge against Isoproterenol-Induced myocardial injury via the PI3K/Akt/mTOR signaling pathway.

Myocardial injury (MI) signifies a pathological aspect of cardiovascular diseases (CVDs) such as coronary artery disease, diabetic cardiomyopathy, and myocarditis. Macrostemonoside T (MST) has been isolated from Allium macrostemon Bunge (AMB), a key traditional Chinese medicine (TCM) used for treating chest stuffiness and pains. Although MST has demonstrated considerable antioxidant activity in vitro, its protective effect against MI remains unexplored. To investigate MST's effects in both in vivo and in vitro models of isoproterenol (ISO)-induced MI and elucidate its underlying molecular mechanisms. This study established an ISO-induced MI model in rats and assessed H9c2 cytotoxicity to examine MST's impact on MI. Various assays, including histopathological staining, TUNEL staining, immunohistochemical staining, DCFH-DA staining, JC-1 staining, ELISA technique, and Western blot (WB), were utilized to explore the potential molecular mechanisms of MI protection. In vivo experiments demonstrated that ISO caused myocardial fiber disorders, elevated cardiac enzyme levels, and apoptosis. However, pretreatment with MST significantly mitigated these detrimental changes. In vitro experiments revealed that MST boosted antioxidant enzyme levels and suppressed malondialdehyde (MDA) production in H9c2 cells. Concurrently, MST inhibited ISO-induced reactive oxygen species (ROS) production and mitigated the decline in mitochondrial membrane potential, thereby reducing the apoptosis rate. Moreover, pretreatment with MST elevated the expression levels of p-PI3K, p-Akt, and p-mTOR, indicating activation of the PI3K/Akt/mTOR signaling pathway and consequent protection against MI. MST attenuated ISO-induced MI in rats by impeding apoptosis through activation of the PI3K/Akt/mTOR signaling pathway. This study presents potential avenues for the development of precursor drugs for CVDs.

Effect of six month's treatment with omega-3 acid ethyl esters on long-term outcomes after acute myocardial infarction: The OMEGA-REMODEL randomized clinical trial.

BACKGROUND: Omega-3 polyunsaturated fatty acids (O3-FA) have been shown to reduce inflammation and adverse cardiac remodeling after acute myocardial infarction (AMI). However, the impact of O3-FA on long-term clinical outcomes remains uncertain. AIMS: To investigate the impact of O3-FA on adverse cardiac events in long-term follow up post AMI in a pilot-study. METHODS: Consecutive patients with AMI were randomized 1:1 to receive 6 months of O3-FA (4 g/daily) or placebo in the prospective, multicenter OMEGA-REMODEL trial. Primary endpoint was a composite of major adverse cardiovascular events (MACE) encompassing all-cause death, heart failure hospitalizations, recurrent acute coronary syndrome, and late coronary artery bypass graft (CABG). RESULTS: A total of 358 patients (62.8% male; 48.1 ± 16.1 years) were followed for a median of 6.6 (IQR: 5.0-9.1) years. Among those receiving O3-FA (n = 180), MACE occurred in 65 (36.1%) compared to 62 (34.8%) of 178 assigned to placebo. By intention-to-treat analysis, O3-FA treatment assignment did not reduce MACE (HR = 1.014; 95%CI = 0.716-1.436; p = 0.938), or its individual components. However, patients with a positive response to O3-FA treatment (n = 43), defined as an increase in the red blood cell omega-3 index (O3I) ≥5% after 6 months of treatment, had lower annualized MACE rates compared to those without (2.9% (95%CI = 1.2-5.1) vs 7.1% (95%CI = 5.7-8.9); p = 0.001). This treatment benefit persisted after adjustment for baseline characteristics (HRadjusted = 0.460; 95%CI = 0.218-0.970; p = 0.041). CONCLUSION: In long-term follow-up of the OMEGA-REMODEL randomized trial, O3-FA did not reduce MACE after AMI by intention to treat principle, however, patients who achieved a ≥ 5% increase of O3I subsequent to treatment had favorable outcomes.

Curdione inhibits ferroptosis in isoprenaline-induced myocardial infarction via regulating Keap1/Trx1/GPX4 signaling pathway.

Myocardial infarction (MI) is a common disease with high morbidity and mortality. Curdione is a sesquiterpenoid from Radix Curcumae. The current study is aimed to investigate the protective effect and mechanism of curdione on ferroptosis in MI. Isoproterenol (ISO) was used to induce MI injury in mice and H9c2 cells. Curdione was orally given to mice once daily for 7 days. Echocardiography, biochemical kits, and western blotting were performed on the markers of cardiac ferroptosis. Curdione at 50 and 100 mg/kg significantly alleviated ISO-induced myocardial injury. Curdione and ferrostatin-1 significantly attenuated ISO-induced H9c2 cell injury. Curdione effectively suppressed cardiac ferroptosis, evidenced by decreasing malondialdehyde and iron contents, and increasing glutathione (GSH) level, GSH peroxidase 4 (GPX4), and ferritin heavy chain 1 expression. Importantly, drug affinity responsive target stability, molecular docking, and surface plasmon resonance technologies elucidated the direct target Keap1 of curdione. Curdione disrupted the interaction between Keap1 and thioredoxin1 (Trx1) but enhanced the Trx1/GPX4 complex. In addition, curdione-derived protection against ISO-induced myocardial ferroptosis was blocked after overexpression of Keap1, while enhanced after Keap1 silence in H9c2 cells. These findings demonstrate that curdione inhibited ferroptosis in ISO-induced MI via regulating Keap1/Trx1/GPX4 signaling pathway.

Association of Long-term Exposure to Particulate Air Pollution With Cardiovascular Events in California.

Importance: Long-term exposure to fine particulate air pollution (PM2.5) is a known risk factor for cardiovascular events, but controversy remains as to whether the current National Ambient Air Quality Standard (12 µg/m3 for 1-year mean PM2.5) is sufficiently protective. Objective: To evaluate the associations between long-term fine particulate air pollution and cardiovascular events using electronic health record and geocoded address data. Design, Setting, and Participants: This retrospective cohort study included adults in the Kaiser Permanente Northern California integrated health care system during 2007 to 2016 and followed for up to 10 years. Study participants had no prior stroke or acute myocardial infarction (AMI), and lived in Northern California for at least 1 year. Analyses were conducted January 2020 to December 2022. Exposure: Long-term exposure to PM2.5. Individual-level time-varying 1-year mean PM2.5 exposures for every study participant were updated monthly from baseline through the end of follow-up, accounting for address changes. Main Outcomes and Measures: Incident AMI, ischemic heart disease (IHD) mortality, and cardiovascular disease (CVD) mortality. Cox proportional hazards models were fit with age as time scale, adjusted for sex, race and ethnicity, socioeconomic status, smoking, body mass index, baseline comorbidities, and baseline medication use. Associations below the current regulation limit were also examined. Results: The study cohort included 3.7 million adults (mean [SD] age: 41.1 [17.2] years; 1 992 058 [52.5%] female, 20 205 [0.5%] American Indian or Alaskan Native, 714 043 [18.8%] Asian, 287 980 [7.6%] Black, 696 796 [18.4%] Hispanic, 174 261 [4.6%] multiracial, 1 904 793 [50.2%] White). There was a 12% (95% CI, 7%-18%) increased risk of incident AMI, a 21% (95% CI, 13%-30%) increased risk of IHD mortality, and an 8% (95% CI, 3%-13%) increased risk of CVD mortality associated with a 10 µg/m3 increase in 1-year mean PM2.5. PM2.5 exposure at moderate concentrations (10.0 to 11.9 µg/m3) was associated with increased risks of incident AMI (6% [95% CI, 3%-10%]) and IHD mortality (7% [95% CI, 2%-12%]) compared with low concentrations (less than 8 µg/m3). Conclusions and Relevance: In this study, long-term PM2.5 exposure at moderate concentrations was associated with increased risks of incident AMI, IHD mortality, and CVD mortality. This study's findings add to the evidence that the current regulatory standard is not sufficiently protective.

Evidence of the Cardioprotective Effects of Aloysia polystachya in Isoproterenol-Induced Myocardial Infarction in Rats.

Aloysia polystachya is a plant species that is widely used in Brazilian folk medicine for the treatment of different disorders that affect the cardiovascular system. The aim of the study was to investigate the cardioprotective effects of an ethanol-soluble fraction of A. polystachya (ESAP) on isoproterenol-induced myocardial infarction in rats. Different groups of rats (n = 8) were orally treated with ESAP (30, 100, and 300 mg/kg), carvedilol (10 mg/kg), or vehicle (filtered water; 1 mL/100 g) for 7 days. Naive rats received no treatment. On the morning of day 6, acute myocardial infarction was induced by the acute oral administration of isoproterenol (100 mg/kg). On the morning of day 8, all rats underwent electrocardiography and transthoracic echocardiography. Blood samples were then collected, and serum levels of creatine kinase-MB fraction (CK-MB) and cardiac troponin T (cTNT) were quantified. ESAP significantly reduced electrocardiographic changes, improved the ventricular ejection fraction, and reduced serum levels of CK-MB and cTNT in infarcted rats. The cardioprotective effects of ESAP could be exploited as an effective tool against isoproterenol-induced myocardial infarction in rats.

Bergapten mediated inflammatory and apoptosis through AMPK/eNOS/AKT signaling pathway of isoproterenol-induced myocardial infarction in Wistar rats.

Bergapten (BeG) is explored for its anti-inflammatory and antioxidant properties. Myocardial infarction (MI) is reported to be one of the leading cardiovascular diseases characterized by mitochondrial dysfunction and apoptosis. The main purpose of this study is to assess the cardiopreventive effects of BeG (50 mg/kg) in isoproterenol (ISO)-induced MI in Wistar rats. The increased infarct size after ISO induction was reduced simultaneously on treatment with BeG. Similarly, augmented levels of cardiac biomarkers, namely cardiac troponin T, creatine kinase (CK), cardiac troponin I, and CK-MB were also suppressed by BeG. The increased rate of lipid hydroperoxides and thiobarbituric acid reactive substances owing to the oxidative stress caused by free radical generation in ISO-induced rats were also inhibited by BeG. Antioxidants reduce oxidative stress by scavenging free radicals. ISO induction reduces these antioxidant enzymes glutathione peroxidase, catalase, superoxide dismutase, and glutathione, and levels causing oxidative cardiac damage to the heart tissue. BeG supplementation improved these enzymes synthesis preventing potential damage to the myocardium. Inflammation caused by ISO pretreatment increased the secretion of proinflammatory cytokines in ISO-induced rats. Pretreatment with BeG suppressed these inflammatory cytokines to a normal level in ISO + BeG-treated rats. The histopathological examination of the morphological characteristics showed that the intensity of cardiac damage caused by ISO induction was less in BeG pretreated rats with less inflammatory cells and no necrosis. BeG also showed promising results in the molecular alteration of AMP-activated protein kinase/endothelial nitric oxide synthase/protein kinase B signaling molecules. These observations emphasize the cardioprotective effects of BeG and its potential use as a drug in the near future.

In vivo evaluation and molecular docking studies of Schinus molle L. fruit extract protective effect against isoproterenol-induced infarction in rats.

The aim of the current study was to assess the potential cardiopreventive effect of the methanolic extract of S. molle L. (MESM) on isoproterenol-induced infarction in rats. The biomolecules content was evaluated using HPLC-DAD-ESI-QTOF-MS/MS analysis. On the 29th and 30th days, two successive injections of isoproterenol (ISO) were given to Wistar rats to provoke myocardial infarction following pretreatment with either MESM (60 mg/kg b.w) or Pidogrel (Pid; 2 mg/kg b.w.). A total of sixteen phenolics were identified with masazino-flavanone as the most prevalent compound (1726.12 µg/g dm). Results showed that MESM offered cardioprevention by normalizing the ST segment and reducing the elevated cardiac risk parameters. The altered lipid biomarkers together with the plasma ionic levels were improved. Additionally, MESM inhibited the cardiac oxidative stress generated by ISO injection though enhancing antioxidant enzymes (GSH, CAT, SOD and GPX) which reduced lipid peroxidation and protein oxidation. MESM reduced myocardial apoptosis by significantly repressing mRNA expressions of Caspase-3 and Bax, with an upregulated Bcl-2 expression. Moreover, MESM reduced DNA fragmentation as well as the infarct size observed by TTC staining. In addition, MESM exhibited an antifibrotic effect by downregulating TGF-1ß expression and reducing collagen deposition in myocardial tissue, as confirmed by Trichrom Masson analysis. The histopathological findings revealed less muscle separation and fewer inflammatory cells in the ISO + MESM-treated rats. Results of the docking simulation indicated that catechin in MESM was inhibitory mainly due to hydrogen bonding interactions with PDI, ACE and TGF-ß1 proteins which could highlight the antithrombotic and antifibrotic capacity of MESM.

Metabolomics based mechanistic insights to vasorelaxant and cardioprotective effect of ethanolic extract of Citrullus lanatus (Thunb.) Matsum. & Nakai. seeds in isoproterenol induced myocardial infraction.

BACKGROUND: Cardiovascular diseases (CVDs) are a significant cause of morbidity and death in the current world, posing a challenge to both developing and industrialized nation's health systems. Citrullus lanatus (Thunb.) Matsum. & Nakai. seeds have long been utilized to supplement and enhance health and treat cardiovascular illnesses. However, its treatments for CVDs are still unknown. More research is required to fully comprehend the impact of C. lanatus seeds on vasorelaxation and myocardial infractions. PURPOSE: Therefore, an integrated metabolomics profiling technique was used to investigate possible pathways of C. lanatus in isoproterenol (ISO)-induced myocardial infarction (MI). Isoproterenol causes long-term cardiac hypertrophy by causing cardiomyocyte compensatory loss, eventually leading to heart failure. METHODS: In vitro models of vasoconstriction, atrium, and in vivo models of invasive blood pressure measurement and isoproterenol (ISO) induced cardiac hypertrophy in rats were used to understand underlying mechanistic by LC-MS/MS based dynamic metabolomics analysis of the serum and heart samples to be investigated the effect of ethanolic extract of C. lanatus (Cl.EtOH). RESULTS: Cl.EtOH exhibited vasorelaxant, negative chronotropic, and inotropic effects in in-vitro models whereas, a potent hypotensive effect was observed in normotensive rats. The Cl.EtOH protected the animals from ISO-induced myocardial infarction (MI) with therapeutic interventions in left ventricular thickness, cardiomyocyte hypertrophy, mRNA gene expression, biochemical assays, and metabolomic profiling of serum and heart tissues. CONCLUSIONS: For the first time, our study confirmed that C. lanatus seeds (Cl.EtOH) possess significant antihypertensive and prevent ISO-induced myocardial infarction. These findings comprehensively demonstrated mechanistic insights of Cl.EtOH in vasorelaxation and myocardial infarction. The current study provides evidence for further mechanistic studies and the development of C. lanatus seeds as a potential therapeutic intervention for patients with cardiovascular disorders.

Valencene post-treatment exhibits cardioprotection via inhibiting cardiac hypertrophy, oxidative stress, nuclear factor- κB inflammatory pathway, and myocardial infarct size in isoproterenol-induced myocardial infarcted rats; A molecular study.

The growing burden of myocardial infarction (MI) becomes a major global health issue that is accountable for considerable mortality worldwide. Hence, it is obligatory to develop a new treatment for MI having lesser side effects. Cardiac hypertrophy, oxidative stress, and inflammatory pathways play crucial roles in the pathogenesis of MI. This investigation established the anti-cardiac hypertrophic, antioxidant, anti-inflammatory, and myocardial infarct size limiting effects of valencene. Rats were induced MI by isoproterenol (100 mg/kg body weight) and then treated with valencene and cardiac sensitive markers, cardiac hypertrophy, oxidative stress, markers of inflammation, nuclear factor- κB inflammatory pathway, and myocardial infarct size was estimated/determined. The serum cardiac diagnostic markers, cardiac hypertrophy, conjugated dienes, markers of inflammation, pro-inflammatory cytokines, and myocardial infarct size were significantly (P < 0.05) increased by isoproterenol. Further, antioxidant enzymes and anti-inflammatory cytokine gene were significantly (P < 0.05) decreased in the heart. The 2, 3, 5-triphenyl tetrazolium chloride dye staining revealed a larger infarct size. Moreover, histological results of myocardial infarcted rat's cardiac tissue revealed separation of cardiac muscle fibers, necrosis, and inflammatory cells. Post-treatment with valencene (12 mg/kg body weight) orally, daily, for two weeks to isoproterenol-induced myocardial infarcted rats reversed all above said structural, biochemical, molecular, and histological parameters investigated, by its anti-cardiac hypertrophic, antioxidant, anti-inflammatory, and myocardial infarct size limiting effects. Thus, valencene is a potential candidate for inhibiting cardiac hypertrophy, oxidative stress, nuclear factor- κB inflammatory pathway, and myocardial infarct size and exhibited cardioprotection in MI.

Association Between 2-Dose vs 3-Dose Hepatitis B Vaccine and Acute Myocardial Infarction.

Importance: The 2-dose hepatitis B vaccine with a cytosine phosphoguanine adjuvant (HepB-CpG vaccine; Heplisav-B) generated higher seroprotection in prelicensure trials than did a 3-dose hepatitis B vaccine with an aluminum hydroxide adjuvant (HepB-alum vaccine; Engerix-B). However, in 1 trial, a higher number of acute myocardial infarction (MI) events were observed among those who received the HepB-CpG vaccine than among those who received the HepB-alum vaccine, an outcome requiring further study. Objective: To compare the rate of acute MI between recipients of HepB-CpG vaccine and HepB-alum vaccine. Design, Setting, and Participants: This prospective cohort noninferiority study was conducted at Kaiser Permanente Southern California (KPSC), an integrated health care system with 15 medical centers and approximately 4.7 million members. The study included 69 625 adults not undergoing dialysis who received at least 1 dose of a hepatitis B vaccine in either family medicine or internal medicine departments at KPSC from August 7, 2018, to October 31, 2019 (November 30, 2020, final follow-up). Exposures: Receipt of HepB-CpG vaccine vs HepB-alum vaccine. The first dose during the study period was the index dose. Main Outcomes and Measures: Individuals were followed up for 13 months after the index dose for occurrence of type 1 acute MI. Potential events were identified using diagnosis codes and adjudicated by cardiologists. The adjusted hazard ratio (HR) of acute MI was estimated comparing recipients of HepB-CpG vaccine with recipients of HepB-alum vaccine, with inverse probability of treatment weighting (IPTW) to adjust for demographic and clinical characteristics. The upper limit of the 1-sided 97.5% CI was compared with a noninferiority margin of 2. Results: Of the 31 183 recipients of HepB-CpG vaccine (median age, 49 years; IQR, 38-56 years), 51.2% (n = 15 965) were men, and 52.7% (n = 16 423) were Hispanic. Of the 38 442 recipients of HepB-alum (median age, 49 years; IQR, 39-56 years), 50.8% (19 533) were men, and 47.1% (n = 18 125) were Hispanic. Characteristics were well-balanced between vaccine groups after IPTW. Fifty-two type 1 acute MI events were confirmed among recipients of HepB-CpG vaccine for a rate of 1.67 per 1000-person-years, and 71 type 1 acute MI events were confirmed among recipients of HepB-alum vaccine for a rate of 1.86 per 1000 person-years (absolute rate difference, -0.19 [95% CI, -0.82 to 0.44]; adjusted HR, 0.92 [1-sided 97.5% CI, ∞ to 1.32], which was below the noninferiority margin; P < .001 for noninferiority). Conclusions and Relevance: In this cohort study, receipt of HepB-CpG vaccine compared with HepB-alum vaccine did not meet the statistical criterion for increased risk of acute myocardial infarction.

Metabolomics analysis delineates the therapeutic effects of hydroethanolic extract of Cucumis sativus L. seeds on hypertension and isoproterenol-induced myocardial infarction.

Cucumis sativus L., widely cultivated as an edible vegetable. Its seeds are well reputed for cardiovascular preventive properties. However, the mechanisms underlying for cardiovascular protection of C. sativus are still unidentified. Therefore, this study utilized a metabolomics approach to investigate putative mechanisms of C. sativus seeds in myocardial infarction (MI) and in vitro models of vasoconstriction, atrium, and invasive blood pressure measurement. Results showed that Cu.EtOH extract showed a vasorelaxant response with potent hypotensive effect in normotensive rats and L-NAME induced hypertension. Cu.EtOH caused a negative inotropic and positive chronotropic effect on the atrium. Cu.EtOH protected the animals from ISO-induced myocardial infarction (MI) interventions in left ventricular thickness, cardiomyocyte hypertrophy, mRNA gene expression, and biochemical assays. The metabolomics data suggested that Cu.EtOH mainly affected amino acid metabolism, BCAA degradation, ketone bodies degradation, and oxidative stress. Our study showed that Cu.EtOH suppressed inflammation with a strong anti-myocardial infarction impact. Additionally, our findings indicated Cu.EtOH reverted the amino acid metabolism, BCAA, and ketone bodies degradation. The findings show the antihypertensive mechanism of Cu.EtOH may include the modulation of endothelium-derived relaxing factor (EDRF) produced from nitric oxide (NO) and is connected with vascular endothelial function. C. sativus seeds, in particular, played a pivotal role in the treatment of myocardial and vascular disorders by enhancing the EDRF mechanism, energy generation, and antioxidant capacity. In summary, our findings showed the mechanistic insights on the therapeutic potential of C. sativus seeds for cardiovascular disorders.

Cardioprotective Effects of Aconite in Isoproterenol-Induced Myocardial Infarction in Rats.

Background: Myocardial infarction (MI) is a severe clinical condition caused by decreased or complete cessation of blood flow to a portion of the myocardium. Aconite, the lateral roots of Aconitum carmichaelii Debx., is a well-known Chinese medicine for treatment of heart failure and related cardiac diseases. The present study is aimed at investigating the cardioprotective effect of aconite on isoproterenol- (ISO)- induced MI. Methods: The qualitative analysis of aqueous extracts from brained aconite (AEBA) was conducted by HPLC. A rat model of MI induced by ISO was established to examine the effects of AEBA. The cardiac function was assessed by echocardiography. The serum levels of SOD, CK-MB, cTnT, and cTnI were detected to estimate myocardial injury. The pathological changes of heart tissue were evaluated by 2,3,5-triphenyltetrazolium chloride (TTC) staining, hematoxylin-eosin (HE) staining, and Masson's trichrome staining. The expressions of abnormal vascular remodeling and hypoxia-related components and the levels of inflammation-associated genes and proteins were detected by RT-qPCR, western blotting, and immunofluorescence. Results: The contents of benzoylaconine, benzoylmesaconine, benzoylhypacoitine, and hypaconitine in AEBA were 1.35 µg/g, 37.35 µg/g, 57.10 µg/g, and 2.46 µg/g, respectively. AEBA obviously improved heart function through promoting echocardiographic parameters, radial strain, and circumferential strain. The data of TTC staining, HE staining, and Masson's trichrome staining disclosed that AEBA could significantly reduce infarct size, inhibit inflammatory cell infiltration, and decrease the myocardial fibrosis. Moreover, AEBA distinctly suppressed the serum levels of SOD, MDA, CK-MB, cTnT, and cTnI in ISO-induced rats. The results of RT-qPCR indicated that AEBA inhibited the expressions of hypoxia- and inflammation-related genes, including VEGF, PKM2, GLUT-1, LDHA, TNF-α, IL-1ß, IL-6, and COX2. In addition, the western blotting and immunofluorescence analyses further confirmed the results of RT-qPCR. Conclusion: In summary, our results indicate that the AEBA could improve ISO-induced myocardial infarction by promoting cardiac function, alleviating myocardial hypoxia, and inhibiting inflammatory response and fibrosis in heart tissue.

Proton Pump Inhibitors, Associated Complications, and Alternative Therapies: A Shifting Risk Benefit Ratio.

OBJECTIVE: Our goal was to compile the most recent and accurate data on the side effects of proton pump inhibitors (PPI). We also compared the efficacy of PPI to the efficacy of different surgical options for acid reflux control. BACKGROUND: Proton pump inhibitors are the primary therapy for chronic control of gastroesophageal reflux disease (GERD), but newer studies demonstrate deleterious side effects. Collating this information and contrasting it with surgical therapy for GERD provides evidence for possible practice changes in treatment. METHODS: A literature search utilizing PubMed was performed evaluating for PPI and anti-reflux surgery (ARS), focusing on articles that reflected information regarding the usage and efficacy of symptom control of both PPI and ARS. Search terms included "ARS, fundoplication, MSA, acute interstitial nephritis, acute kidney injury, chronic kidney disease, meta-analysis, PPI, H2 blocker, cardiovascular risk, and gut dysbiosis." We evaluated 271 articles by title, abstract, and data for relevance and included 70. RESULTS: Long-term control of GERD with PPI may have a greater than expected side effect profile than initially thought. Surgical options may provide greater symptom control than PPI without the side effects of long-term medical therapy. CONCLUSIONS: Anti-reflux control can be safely achieved with either PPI or surgical options; however, the long-term side effects noted in the review such as increased risk of cardiovascular events, renal disease, and gut dysbiosis may suggest surgical anti-reflux control as a better long-term option.

Nuciferine from Nelumbo nucifera Gaertn. attenuates isoproterenol-induced myocardial infarction in Wistar rats.

The study explored the cardioprotective role of the methanolic leaf extract of Nelumbo nucifera and nuciferine against isoproterenol-induced myocardial infarction (MI) in Wistar rats. Pretreatment with leaf extract and nuciferine (200 and 20 mg/kg body weight, respectively) against MI induced by isoproterenol (85 mg/kg body weight) significantly decreased heart weight; levels of cardiac markers such as lactate dehydrogenase and creatine kinase-MB were similar to those in controls. The treatment significantly increased the content of endogenous antioxidants and decreased lipid peroxidation in all treated groups. Treated groups showed a significant reduction in heartbeats per minute as compared with the MI-induced positive control. The MI-induced group showed pathological implications such as tachycardia, left atrial enlargement, and anterolateral ST-elevated MI, which were absent in treated groups. Histology confirmed that the leaf extract and nuciferine prevented structural abnormality and inflammation in heart and liver tissues of treated groups. On in silico analysis, nuciferine showed stronger binding interaction with both ß1 and ß2 adrenergic receptors than isoproterenol. Hence, the leaf extract of N. nucifera and nuciferine could be used as plant-based cardioprotective agents.

Pharmacological evaluation of Vitis vinifera and Zingiber zerumbet on electrocardiographic, biochemical alterations and antioxidant status in isoproterenol-induced myocardial infarction in rats.

The Vitis vinifera (VV) and Zingiber zerumbet (ZZ) are popular functional foods which are used for the treatment of cardiovascular ailments. These possess antiproliferative, antiplatelet and antioxidant effects. The current study has been designed to ascertain their effectiveness against Isoproterenol (ISO)-induced myocardial infarction (MI). Chronic administration of VV and ZZ was accessed for its cardio-protective effect in ISO-induced MI rats. Male albino rats were treated with VV (250 mg/kg, p.o.), ZZ (200 mg/kg, p.o.) and its combination (Vitis vinifera + Zingiber zerumbet) VZ for 30 days prior to ISO administration (85 mg/kg, S/C). Electrocardiography (ECG) and Blood Pressure (BP) were measured using PowerLab data acquisition system. Biochemical serum markers, tissue histopathology and HPLC finger printing were performed. The VV, ZZ and its combination VZ showed significant protective effects on ST segment elevation, cardiac biomarkers; Troponin I (Trop I), creatine kinase-MB (CK-MB), alanine transaminase (ALT), aspartate amino transferase (AST), lactate dehydrogenase (LDH), enhanced the cardiac antioxidant defense system, restored the hematological (WBCs, RBCs, Platelets) & coagulation parameters and improved the lipid profile and histopathological alterations such as tissue necrosis, infiltration and edema which were observed only in ISO administered rats. These results indicate that V. vinifera and Z. zerumbet possess cardio protective effects possibly mediated through maintenance of endogenous antioxidant levels, cardiac biomarkers and lipid parameters.

Lipoxygenase inhibitor ML351 dysregulated an innate inflammatory response leading to impaired cardiac repair in acute heart failure.

The presistent increase of 12/15 lipoxygenase enzyme activity is correlated with uncontrolled inflammation, leading to organ dysfunction. ML351, a potent 12/15 lipoxygenase (12/15LOX) inhibitor, was reported to reduce infarct size and inflammation in a murine ischemic stroke model. In the presented work, we have applied three complementary experimental approaches, in-vitro, ex-vivo, and in-vivo, to determine whether pharmacological inhibition of 12/15LOX could dampen the inflammatory response in adult mice after Kdo2-Lipid A (KLA) as an endotoxin stimulator or post myocardial infarction (MI). Male C57BL/6 (8-12 weeks) mice were subjected to permanent coronary ligation thereby inducing acute heart failure (MI-d1 and MI-d5) for in-vivo studies. 12/15LOX antagonist ML351 (50 mg/kg) was subcutaneously injected 2 h post-MI, while MI-controls received saline. For ex-vivo experiments, ML351 (25 mg/kg) was injected as bolus after 5 min of inflammatory stimulus (KLA 1 µg/g) injection. Peritoneal macrophages (PMɸ) were harvested after 4 h post KLA. For in-vitro studies, PMɸ were treated with KLA (100 ng/mL), ML351 (10 µM), or KLA + ML351 for 4 h, and inflammatory response was evaluated. In-vivo, 5LOX expression was reduced after ML351 administration, inducing a compensatory increase of 12LOX that sensitized PMɸ toward a proinflammatory state. This was marked by higher inflammatory cytokines and dysregulation of the splenocardiac axis post-MI. ML351 treatment increased CD11b+ and Ly6Chigh populations in spleen and Ly6G+ population in heart, with a decrease in F4/80+ macrophage population at MI-d1. In-vitro results indicated that ML351 suppressed initiation of inflammation while ex-vivo results suggested ML351 overactivated inflammation consequently delaying the resolution process. Collectively, in-vitro, ex-vivo, and in-vivo results indicated that pharmacological blockade of lipoxygenases using ML351 impaired initiation of inflammation thereby dysregulated acute immune response in cardiac repair.

Passiflora edulis (var. Flavicarpa) Juice Supplementation Mitigates Isoproterenol-induced Myocardial Infarction in Rats.

The common reason for mortality globally is myocardial infarction. The study aimed to evaluate Passiflora edulis (PE) fruit juice potential in the experimental isoproterenol (ISO) treated rat model to manage myocardial injury. ISO (20 mg/100 g body weight) treated rats showed a significant increment in serum marker enzymes lactate dehydrogenase (LDH) and creatinine kinase (CK), serum glutamate pyruvate transaminase (SGPT), serum glutamate oxaloacetate transaminase (SGOT), serum alkaline phosphatase (ALP) and serum acid phosphatase (ACP) activity. Besides, phosphorus and calcium, serum cholesterol, and triglyceride levels (TG) were high in ISO groups. A significant decline in antioxidant activity and histopathological alteration was observed in ISO treated groups. PE juice pre-treatment (2 ml/kg) for 28 days and ISO treatment on the 29th and 30th days showed a protective effect on distorted biochemical and histopathologic parameters compared with reference drug metoprolol. These findings indicate the cardioprotective effect of PE juice on ISO-induced myocardial infracted rats.

Nootkatone attenuates myocardial oxidative damage, inflammation, and apoptosis in isoproterenol-induced myocardial infarction in rats.

BACKGROUND: Myocardial infarction (MI) is a lethal manifestation of cardiovascular diseases. Oxidative stress, inflammation, and subsequent cell death are known to play crucial roles in the pathogenesis of MI. Despite tremendous developments in interventional cardiology, there is need for novel drugs for the prevention and treatment of MI. For the development of novel drugs, usage of natural products has gained attention as a therapeutic approach for ischemic myocardial injury. Among many popular plant-derived compounds, Nootkatone (NKT), a natural bioactive sesquiterpene, abundantly found in grapefruit, has attracted attention for its plausible health benefits and pharmacological properties. PURPOSE: The present study investigated the cardioprotective effects of NKT in rats against MI induced by isoproterenol (ISO), a synthetic catecholamine and ß-adrenergic agonist that produces MI in a physiologically relevant manner. METHODS: MI was induced in male Wistar albino rats by subcutaneous injection of ISO (85 mg/kg body weight) on 9th and 10th day. Rats were pre- and co-treated with NKT (10 mg/kg) through daily oral administration for eleven days. RESULTS: ISO-induced MI was characterized by a significant decline in cardiac function, increased serum levels of cardiomyocyte injury markers, enhanced oxidative stress, and altered PI3K/Akt and NrF2/Keap1/HO-1 signaling pathways. ISO also elevated the levels of myocardial pro-inflammatory cytokines, promoted lysosomal dysfunction, altered TLR4-NFκB/MAPK signaling, and triggered intrinsic apoptotic pathway in heart tissues. However, NKT administration significantly restored or modulated majority of the altered biochemical and molecular parameters in ISO-treated rats. Furthermore, histopathological observations confirmed the myocardial restoring effect of NKT. CONCLUSION: The present study concludes the cardioprotective effects and underlying mechanisms of NKT against ISO-induced MI in rats, and suggests that NKT or plants containing NKT could be an alternative to cardioprotective agents in ischemic heart diseases.

Protective effects of myrrh essential oil on isoproterenol-induced myocardial infarction in rats through antioxidant, anti-inflammatory, Nrf2/HO-1 and apoptotic pathways.

ETHNOPHARMACOLOGICAL RELEVANCE: Myrrh, a traditional remedy, is the stem resinous exudate of Commiphora molmol Engler (Burseraceae). The aromatic yellowish-brown oleoresin has a long history in folk and traditional medicine, in Saudi Arabia and the Arab world. Severe universal concern attributable to the high mortality is Myocardial Infarction (MI). Acute administration of Isoproterenol (ISO) is an established animal model to induce myocardial injury. OBJECTIVE: The existing animal study was outlined to inspect the actions of Myrrh essential oil on cardiac functional, antioxidant status, apoptotic and inflammatory deviations in isoproterenol induced MI. MATERIALS AND METHODS: Normal and Myrrh control animals were administered normal saline and Myrrh essential oil for thirty days orally, respectively. On the 29th and 30th day, the animals were injected by saline (s.c.). In the ISO control, the animals were administered saline orally for 30 days and then confronted with ISO (85 mg/kg s.c.) on 29th and 30th days. In the Myrrh Groups (IV and V), the animals were treated with Myrrh essential oil (50 and 100 mg/k) respectively for 30 days and injected with ISO (85 mg/kg, s.c.) on 29th and 30th days. RESULTS: Animals experienced MI displayed functional blood pressure deviations, intensification in the heart to body weight ratio, myocytes indicative markers (CK-MB, CPK, LDH, cTnT, cTnI), lipid peroxidation (MDA), protein expression of Nrf2 and HO-1, apoptotic markers (Caspase 3,9), and inflammatory indicators. Conversely, animals pre-treated with Myrrh revealed obliteration of those elevations triggered by ISO induction, diminished elevated biochemical values and improved heart function. CONCLUSION: Myrrh abstain effective cardio-protective action in MI model through improving the oxidative condition with myocytes and abolishing apoptotic as well as inflammatory responses.

Ameliorative effect of ferruginol on isoprenaline hydrochloride-induced myocardial infarction in rats.

Cardiovascular-related diseases continue to be a leading cause of death globally. Among ischemic-induced cardiac diseases, myocardial infarction (MI) is reported to be of an alarming value. Despite numerous improvements in the medical intrusions, still this armamentarium fails to be effective in managing the illness without setbacks. Ferruginol (FGL) is a major polyphenols and terpenoids with numerous pharmacological activities including antioxidant and anti-inflammatory. Following, this work was aimed to explore the cardio protective effect of FGL (50 mg/kg) in isoprenaline hydrochloride (ISO)-induced MI in experimental rats. After treatment with FGL in ISO-induced MI in rats, noticeable changes were observed in the experimental rats. Injection of ISO to rats resulted in the augmented cardiac weight, serum cardiac markers (creatine kinase, creatine kinase-MB, cardiac troponin T, and Cardiac troponin I), lipid peroxidation end products (thiobarbituric acid-reactive substance and lipid hydroperoxides), reduced endogenous antioxidants (superoxide dismutase, catalase, glutathione peroxidase, and glutathione), reduced ATPase activity, and escalated pro-inflammatory cytokines (interleukin-6, tumor necrosis factor-α, and nuclear factor-κB) levels. Interestingly, the FGL supplementation to the ISO-treated rats revealed the diminished heart weight, reduced cardiac markers, and lipid peroxidation. FGL also possessed the improved antioxidants status and diminished pro-inflammatory mediator levels. The outcomes of histological analysis also evidenced the cardio protective role of FGL. Treatment with FGL reduced the cardiac damage biomarkers maintained to near normal levels in ISO-induced rats. These study findings disclose the prospective capability of FGL in the treatment of MI in the future.