Cardioprotective Agent Research Articles

Design of a Randomized Placebo-Controlled Trial to Evaluate the Anti-inflammatory and Senolytic Effects of Quercetin in Patients Undergoing Coronary Artery Bypass Graft Surgery.

Background: Following an acute coronary syndrome, patients display an elevated inflammatory profile, promoted in part by cellular senescence. For patients requiring a coronary artery bypass (CABG) surgery, exposure to the surgical intervention and cardiopulmonary bypass further exacerbate their residual inflammation. Experimental evidence identified quercetin, a natural senolytic drug, as a cardioprotective agent against inflammatory injuries. The Q-CABG study aims to explore the efficacy of quercetin to reduce inflammation, myocardial injury and senescence in patients undergoing CABG following an acute coronary syndrome.Methods: Q-CABG is a phase II, prospectively registered, randomized, double-blind and placebo-controlled clinical trial. Recruited patients awaiting CABG surgery at the Montreal Heart Institute (n = 100) will be randomly assigned in a 1:1 ratio to receive either quercetin supplementation (500 mg twice daily) or placebo, starting 2 days before surgery and until the seventh postoperative day. The primary endpoint examines the effects of quercetin on blood inflammatory cytokines and markers of myocardial injury and senescence in this patient population. Blood samples will be taken at four time points: baseline, postoperative day 1, postoperative day 4 and at hospital discharge, or after a maximum of seven postoperative days. The secondary endpoint is the assessment of endothelial (dys) function by looking at ex vivo vascular reactivity and mRNA expression of endothelial cells from the wall of discarded segments of internal mammary artery.Discussion: The preventive intake of quercetin supplementation may help limit the vigorous inflammatory response triggered by CABG and subsequent postoperative complications in patients suffering from an acute coronary syndrome. In an exploratory way, quercetin supplementation could also improve endothelial function by eliminating senescent vascular endothelial cells. The results of this trial should provide valuable information regarding a novel approach to improve biological, and potentially clinical, outcomes post CABG.Clinical Trial Registration: ClinicalTrials.gov, Identifier NCT04907253.

Cordycepin Decreases Ischemia/Reperfusion Injury in Diabetic Hearts via Upregulating AMPK/Mfn2-dependent Mitochondrial Fusion.

Diabetes mellitus is considered to be a major risk factor for cardiovascular disease, the most common cause of death in diabetes. However, therapeutic strategies for myocardial protection in patients with diabetes are still limited. Cordycepin is a traditional Tibetan medicine with a long history of widespread use, and exerts a wide range of anti-tumor, anti-inflammatory, and anti-oxidative effects. In recent years, although the therapeutic potential of cordycepin has attracted the attention of researchers, it remains unknown whether cordycepin plays a protective role in myocardial ischemia/reperfusion (MI/R) injury in diabetic patients. Here, using a diabetic mouse model, we found that cordycepin protected diabetic hearts from MI/R injury by promoting mitochondrial fusion and Mfn2 expression. Our in vitro results showed that cordycepin enhanced Mfn2-medicated mitochondrial fusion, improved mitochondrial function, and reduced cardiomyocyte apoptosis in high-glucose/high-fat cultured simulated ischemia/reperfusion cardiomyocytes. Furthermore, we found that knockout of Mfn2 significantly blocked the cardioprotective effects of cordycepin in diabetic mice. Finally, an AMPK-dependent pathway was found to upregulate Mfn2 expression upon cordycepin treatment, indicating that cordycepin protected diabetic hearts via AMPK/Mfn2-dependent mitochondrial fusion. Collectively, our study firstly demonstrated that cordycepin could be a potential cardioprotective agent for MI/R injury, and we established a novel mechanism by which upregulated AMPK/Mfn2-dependent mitochondrial fusion contributes to the cardioprotective role of cordycepin.

Benzyl-para-di-[5-methyl-4-(n-octylamino) pyrimidin-2(1H)one] as an interferon beta (IFN-β) modulator.

IFN-β is a cytokine that plays a significant role in the immune system. Inhibition of IFN-β might be used as a therapeutic approach to treat septic shock. A peptidomimetic previously developed by our research team, 1-benzyl-5-methyl-4-(n-octylamino)pyrimidin-2(1H)-one (LT87), was used as an cardioprotective agent in a myocardial ischemia (MI) mouse model. We have developed new LT87 derivatives by synthetizing its dimers in an attempt to extend its structural variety and enhance its biological activity. A dimeric derivative, LT127, exhibited a dose-dependent inhibition of LPS-mediated IFN-β and subsequent CXCL10 mRNA transcription. The effect was selective and transduced through TLR4- and TRAM/TRIF-mediated signaling, with no significant effect on MyD88-dependent signaling. However, this effect was not specific to TLR4, since a similar effect was observed both on TLR8- and MDA5/RIG-I-stimulated IFN-β expression. Nevertheless, LT127 might serve as a drug candidate, specifically as an inhibitor for IFN-β production in order to develop a novel therapeutic approach to prevent septic shock.

Statin use can attenuate the decline in left ventricular ejection fraction during the cardiotoxic chemotherapy: a systemic review and meta-analysis

Abstract Background Antineoplastic medications such as anthracyclines and trastuzumab are effective in treating various hematologic and solid organ malignancies, however an increased risk of cardiotoxicity in patients has been reported. A decline in left ventricular ejection fraction (LVEF) is a common finding in chemotherapy-induced cardiomyopathy and is sometimes irreversible and lethal. Several agents such as beta blockers and angiotensin-converting enzyme (ACE) inhibitors have shown to reduce the chemotherapy-induced cardiotoxicity in cancer patients. The use of statins, however, to prevent chemotherapy-related cardiotoxicity is not as well studied as other cardioprotective agents. In this study, we aimed to investigate the difference in the degree of decline in the LVEF in patients who received concurrent statin during the chemotherapy compared to those who received chemotherapy alone. Methods A systematic search of MEDLINE and EMBASE databases was performed from inception to March 2021 for studies that reported the mean LVEF before and after chemotherapy in patients who received concurrent statin therapy and those who did not receive statin along with the chemotherapy. A random effects meta-analysis was performed to obtain the pooled WMD of LVEF between the intervention (statin with chemotherapy) and the control group (chemotherapy alone) before and after chemotherapy treatments using STATA 16. Results Four studies with a total of 297 patients were included in this meta-analysis. Of the 297 patients, 115 patients were in the intervention group and received statin with chemotherapy, while 182 patients were in the control group and received chemotherapy alone. Baseline mean LVEF had no statistically significant difference between the intervention (statin) and the control (no statin) group, and the WMD was −0.38% (95% CI: −1.27 to 0.51, p=0.342). Upon follow-up, the control group patients showed a significantly greater decline in LVEF, with WMD of −6.08% (95% CI: −8.55 to −3.61, p=0.013), compared to the intervention group. Conclusion Patients who did not receive statin during the chemotherapy period had a greater mean decline in LVEF from baseline compared to that of the control group after the chemotherapy treatments. Funding Acknowledgement Type of funding sources: None.

Only the NAD precursor nicotinamide riboside maintains cardioprotection under clinically relevant conditions, possibly through activation of glycolysis

Abstract Purpose Cardioprotective strategies against ischaemia-reperfusion injury (IRI) that remain effective in the clinical arena need to be developed. Here, we examined the efficacy of the cardioprotective compounds fingolimod (Fingo), empagliflozin (Empa), melatonin (Mela) and nicotinamide riboside (NR) in the presence of drugs routinely used clinically in IRI conditions such as cardiac by-pass surgery and PCI procedures (opiates, benzodiazepines, P2Y12 antagonist, propofol). Furthermore, we examine the mechanism of protection of effective compound(s). Methods Following pilot dose-response curves of each compound, cardioprotective efficacy of Fingo, Empa, Mela and NR in an in vivo rat model employing a clinically relevant anaesthetic background therapy (fentanyl-midazolam) were examined alone or in combination. Drugs were administered 30 min before 25 min left ascending coronary (LAD) ischaemia. Infarct size (IS) was determined following 2 h of reperfusion. Effective treatments were then tested in the presence of a P2Y12 antagonist (cangrelor) or propofol anaesthesia. Finally, the underlying metabolic mechanism of the efficient compound(s) was explored in an ex vivo Langendorff-perfused mouse heart model of cardiac IRI. Results We found that among these four compounds, only singular NR was able to reduce IS (30±14% vs 60±16%, P=0.009 vs control, Fig.1A) in vivo in the presence of clinically relevant background anaesthesia. NR still reduced IS in the presence of cangrelor (51±18% vs 71±4%, P=0.016 vs control, Fig.1B), but lost protection in the presence of propofol anaesthesia (62±16% vs 60±14%, P=0.839 vs control, Fig.1C). Furthermore, NR showed protection in the ex vivo model of IRI, where isolated hearts were perfused with glucose (G) and free fatty acid (FFA) palmitate (G+FFA): (IS%: 40±14% vs 64±12%, P=0.003 vs control; LDH release: 28.3±7.2 U/min/GWW vs 37.8±3.7 U/min/GWW, P=0.005 vs control; Rate-Pressure-Product (RPP) recovery (43±12% vs 31±8%, P=0.031 vs control, Fig.2A-C). However, NR's protection was lost when 1) glycolysis was by-passed, by replacing glucose in the perfusate with lactate (L) and pyruvate (P) (LP+FFA) or 2) glycolysis was overly activated by adding insulin to the perfusate (G+FFA+insulin) (Fig.2). Conclusion Our data suggests that NR is a promising cardioprotective agent to target cardiac ischaemia-reperfusion injury in clinical conditions employing opioid agonists, benzodiazepines and platelet P2Y12 inhibitors. This protection may, at least partly, be due to NR stimulation of cardiac glycolysis. Funding Acknowledgement Type of funding sources: None.

Insulin acts as an atypical KCNQ1/KCNE1‐current activator and reverses long QT in insulin‐resistant aged rats by accelerating the ventricular action potential repolarization through affecting the β3‐adrenergic receptor signaling pathway

Insufficient-heart function is associated with myocardial insulin resistance in the elderly, particularlyassociated with long-QT, in a dependency on dysfunctional KCNQ1/KCNE1-channels. So, we aimed to examine the contribution of alterations in KCNQ1/KCNE1-current (IKs ) to the aging-related remodeling of the heart as well as the role of insulin treatment on IKs in the aged rats. Prolonged late-phase action potential (AP) repolarization of ventricular cardiomyocytes from insulin-resistant 24-month-old rats was significantly reversed by in vitro treatment of insulin or PKG inhibitor (in vivo, as well) via recovery in depressed IKs . Although the protein level of either KCNQ1 or KCNE1 in cardiomyocytes was not affected with aging, PKG level was significantly increased in those cells. The inhibited IKs in β3 -ARs-stimulated cells could be reversed with a PKG inhibitor, indicating the correlation between PKG-activation and β3 -ARs activation. Furthermore, in vivo treatment of aged rats, characterized by β3 -ARs activation, with either insulin or a PKG inhibitor for 2 weeks provided significant recoveries in IKs , prolonged late phases of APs, prolonged QT-intervals, and low heart rates without no effect on insulin resistance. In vivo insulin treatment provided also significant recovery in increased PKG and decreased PIP2 level, without the insulin effect on the KCNQ1 level in β3 -ARs overexpressed cells. The inhibition of IKs in aged-rat cardiomyocytes seems to be associated with activated β3 -ARs dependent remodeling in the interaction between KCNQ1 and KCNE1. Significant recoveries in ventricular-repolarization of insulin-treated aged cardiomyocytes via recovery in IKs strongly emphasize two important issues: (1) IKs can be a novel target in aging-associated remodeling in the heart and insulin may be a cardioprotective agent in the maintenance of normal heart function during the aging process. (2) This study is one of the first to demonstrate insulin'sbenefits on long-QT in insulin-resistant aged rats by accelerating the ventricular AP repolarization through reversing the depressed IKs via affecting the β3 -ARs signaling pathway and particularly affecting activated PKG.

Randomized Evaluation of Beta Blocker and ACE-Inhibitor/Angiotensin Receptor Blocker Treatment for Post Infarct Angina in Patients With Myocardial Infarction With Non-obstructive Coronary Arteries: A MINOCA-BAT Sub Study Rationale and Design.

Introduction: Myocardial infarction with non-obstructive coronary arteries (MINOCA) occurs in ~10% of all patients with acute myocardial infarction (AMI), with an over-representation amongst women. Remarkably, it is estimated that as many as 1 in 4 patients with MINOCA experience ongoing angina at 12 months despite having no flow-restricting stenoses in their epicardial arteries. This manuscript presents the rationale behind Randomized Evaluation of Beta Blocker and Angiotensin-converting enzyme inhibitors/Angiotensin Receptor Blocker Treatment (ACEI/ARB) for Post Infarct Angina in MINOCA patients—The MINOCA BAT post infarct angina sub study.Methods: This trial is a registry-based, randomized, parallel, open-label, multicenter trial with 2 × 2 factorial design. The primary aim is to determine whether oral beta blockade compared with no oral beta blockade, and ACEI/ARB compared with no ACEI/ARB, reduce post infarct angina in patients discharged after MINOCA without clinical signs of heart failure and with left ventricular ejection fraction ≥40%. A total of 664 patients will be randomized into four groups; (i) ACEI/ARB with beta blocker, (ii) beta blocker only, (iii) ACEI/ARB only, or (iv) neither ACEI/ARB nor beta blocker and followed for 12 months.Results: The trial is currently recruiting in Australia and Sweden. Fifty six patients have been recruited thus far. Both sexes were equally distributed (52% women and 48% men) and the mean age was 56.3 ± 9.9 years.Conclusions: It remains unclear whether conventional secondary preventive therapies are beneficial to MINOCA patients in regard to post infarct angina. Existing registry-based literature suggest cardioprotective agents are less likely to be used in MINOCA patients. Thus, results from this trial will provide insights for future treatment strategies and guidelines specific to MINOCA patients.

An in vivo and in vitro model on the protective effect of corilagin on doxorubicin‐induced cardiotoxicity via regulation of apoptosis and PI3‐K/AKT signaling pathways

Globally, doxorubicin (DOX)-induced cardio dysfunction is a serious cause of morbidity and mortality in cancerous patients. An adverse event of cardiotoxicity is the main deem to restrict in the clinical application by oncologists. Corilagin (CN) is well known for its antioxidative, anti-fibrosis, and anticancer effects. Herein, we aimed to evaluate the action of CN on DOX-induced experimental animals and H9c2 cells. The myocardium-specific marker, CK-MB, and the influx of mitochondrial calcium levels were measured by using commercial kits. Biochemical indices reflecting oxidative stress and antioxidant attributes such as malondialdehyde, glutathione peroxidase, reduced glutathione, superoxide dismutase, and catalase were also analyzed in DOX-induced cardiotoxicanimals. In addition, mitochondrial ROS were measured by DCFH-DA in H9c2 cells under fluorescence microscopy. DOX induction significantly increased oxidative stress levels and also modulated apoptosis/survival protein expressions in myocardial tissues. Western blots were used to measure the expressional levels of Bax/Bcl-2, caspase-3, PI3-K/AKT, and PPARγ signaling pathways. Histological studies were executed to observe morphological changes in myocardial tissues. All of these DOX-induced effects were attenuated by CN (100 mg/kg bw). These in vitro and in vivo results point towards the fact that CN might be a novel cardioprotective agent against DOX-induced cardiotoxicity through modulating cardio apoptosis and oxidative stress.

Effects of pinealectomy and crocin treatment on rats with isoproterenol-induced myocardial infarction

The present study aimed to analyze the effects of pinealectomy and crocin treatment in isoproterenol-induced myocardial damage. Seventy rats were divided into seven groups: control, sham control, pinealectomy (PNX), isoproterenol (ISO; 85 mg/kg on the 29th and 30th days of the experiment, subcutaneous injection), PNX + ISO, PNX + crocin (50 mg/kg/day for 30 days, intragastric administration), and PNX + ISO + crocin. PNX procedure was performed on the first day of the study. A significant increase was observed in serum cardiac damage markers (CK-MB, Troponin I) after ISO administration. ISO administration led to a significant increase in cardiac oxidative stress parameters, such as malondialdehyde (MDA) and total oxidant status (TOS), while it led to a decrease in antioxidant defense system parameters, such as reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT) and total antioxidant status (TAS) when compared to control groups. Elevated MDA and TOS levels were observed, while reduced SOD and CAT activities, and decreased GSH and TAS levels were observed in the group that underwent PNX and ISO administration when compared to the PNX group. Furthermore, in the PNX + ISO + Crocin group, SOD and CAT activities, and GSH and TAS levels ameliorated and MDA and TOS levels were reduced with the crocin treatment when compared to the PNX + ISO group. Also, marked increases were observed in serum cardiac markers, histopathological and immunohistochemical findings after the crocin treatment. All findings demonstrated that crocin could be employed as a cardioprotective agent due to its antioxidant, anti-inflammatory, and anti-apoptotic properties.

The Role of Lisinopril and Bisoprolol to Prevent Anthracycline Induced Cardiotoxicity in Locally Advanced Breast Cancer Patients.

Background:Anthracyclines are a class of chemotherapeutic agents that are used to treat many different cancers, including breast cancer. Although anthracyclines remain an effective and commonly used therapy, their use is limited by cardiotoxicity. Heart failure and left ventricular (LV) dysfunction are the short and long-term complications of anthracyline exposure occurring in 5% to 23% of patients. Recent prospective studies have investigated the prophylactic role of ACE inhibitors and beta-blockers as cardioprotective agents. This study aimed to evaluate whether the addition of lisinopril and bisoprolol could prevent anthracycline induced cardiotoxicity. Methods:In this randomized, controlled trial, 74 subjects with locally advanced breast cancer were randomly assigned to a group receiving lisinopril and bisoprolol (n=37) or to a control group (n=37). Lisinopril and bisoprolol was started simultaneously 24 h before the first cycle of chemotherapy. The initial dose was 2.5 mg each, once daily, and was increased gradually under close supervision to 10 mg if SBP persistently remained >90 mmHg and HR >60 bpm. Echocardiographic studies were performed before and after the 6th cycle of neoadjuvant anthracycline-based chemotherapy (FAC). The primary endpoint was the change from baseline LVEF. Results:There was no difference in baseline LVEF between intervention and control group (65.77 ± 4.56 % v 65.64 ± 455 %, p = 0.92). There was also no difference in total anthracycline doses between 2 groups (579.48 ± 65.10 mg vs 557.50 ± 47.76 mg, p = 0.18). However, after 6 cycles of FAC, the rate of decline in LVEF was greater in control group (-5.52 ± 8,90 %) than in the intervention group (-0.27 ± 5.73 %) with p = 0.017. No severe adverse effects occurred in the intervention group related to the treatment with lisinopril and bisoprolol. Conclusion:Combined treatment with lisinopril and bisoprolol may prevent anthracycline-induced cardiotoxicity in patients with locally advanced breast cancer treated with anthracycline-based chemotherapy. The clinical relevance of this study should be confirmed in larger studies with longer follow up time.

Перспективи використання ресвератролу для лікування цукрового діабету та його ускладнень

Ресвератрол характеризується широким спектром фармакологічних ефектів і має множинну біологічну активність щодо хронічних захворювань, як протизапальний, протипухлинний, антидіабетичний, нейро- і кардіопротекторний засіб. Ресвератрол здійснює позитивний ефект при цукровому діабеті (ЦД) та діабетичних ускладненнях судин, що обумовлено його здатністю посилювати опосередковану оксидом азоту вазодилатацію. Продукти, багаті на ресвератрол, надають захисний ефект при таких вікових захворюваннях, як ЦД 2-го типу, атеросклероз, рак, артрит, катаракта, остеопороз, артеріальна гіпертензія і хвороба Альцгеймера. Ефекти ресвератролу свідчать про його перспективність як дієтичної добавки, що дозволяє поліпшити стан хворих на тяжкі хронічні захворювання, а також для профілактики цих захворювань у здорових людей і уповільнення процесів старіння.

Preconditioning the rat heart with 5-azacytidine attenuates myocardial ischemia/reperfusion injury via PI3K/GSK3β and mitochondrial KATP signaling axis.

5-Azacytidine is well known for its clinical usage in cancer treatments. The present study investigates the role of 5-azacytidine as a cardioprotective agent to ameliorate ischemia/reperfusion (I/R) injury. The cardioprotective effect of 5-azacytidine was evaluated in three experimental models: in vitro, ex vivo, and in vivo. The cardioprotective effect was evaluated via cell viability, hemodynamic indices, infarct size measurement, and assessment of histopathology, oxidative stress, and mitochondrial function. The experiments were repeated in the presence of PI3K/GSK3β and mitochondrial KATP (mtKATP ) cardioprotective signaling pathway inhibitors to understand the underlying mechanism. 5-Azacytidine improved the cell viability by 29% in I/R-challenged H9C2 cells. Both isolated rat heart and LAD ligation model confirmed the infarct sparing effect of 5-azacytidine against I/R. It also provided a beneficial effect by normalizing the altered hemodynamics, reducing the infarct size and cardiac injury markers, reversing the perturbation of mitochondria, reduced oxidative stress, and improved the pPI3K and pAKT protein expression from I/R. In addition, it also augmented the activation of PI3K/AKT and mtKATP signaling pathway, confirmed by using wortmannin (PI3K inhibitor), SB216763 (GSK3β inhibitor), and glibenclamide (mtKATP channel closer). The effectiveness of 5-azacytidine as a cardioprotective agent is attributed to its activation of the PI3K/GSK3β and mtKATP channel signaling axis, thereby preserving mitochondrial function and reducing oxidative stress.

Cardioprotecive Properties of Known Agents in Rat Ischemia-Reperfusion Model Under Clinically Relevant Conditions: Only the NAD Precursor Nicotinamide Riboside Reduces Infarct Size in Presence of Fentanyl, Midazolam and Cangrelor, but Not Propofol.

Background: Cardioprotective strategies against ischemia-reperfusion injury (IRI) that remain effective in the clinical arena need to be developed. Therefore, maintained efficacy of cardioprotective strategies in the presence of drugs routinely used clinically (e.g., opiates, benzodiazepines, P2Y12 antagonist, propofol) need to be identified in preclinical models.Methods: Here, we examined the efficacy of promising cardioprotective compounds [fingolimod (Fingo), empagliflozin (Empa), melatonin (Mela) and nicotinamide riboside (NR)] administered i.v. as bolus before start ischemia. Infarct size as percentage of the area of risk (IS%) was determined following 25 min of left ascending coronary (LAD) ischemia and 2 h of reperfusion in a fentanyl-midazolam anesthetized IRI rat model. Plasma lactate dehydrogenase (LDH) activity at 30 min reperfusion was determined as secondary outcome parameter. Following pilot dose-response experiments of each compound (3 dosages, n = 4–6 animals per dosage), potential cardioprotective drugs at the optimal observed dosage were subsequently tested alone or in combination (n = 6–8 animals per group). The effective treatment was subsequently tested in the presence of a P2Y12 antagonist (cangrelor; n = 6/7) or propofol aesthesia (n = 6 both groups).Results: Pilot studies suggested potential cardioprotective effects for 50 mg/kg NR (p = 0.005) and 500 μg/kg melatonin (p = 0.12), but not for Empa or Fingo. Protection was subsequently tested in a new series of experiments for solvents, NR, Mela and NR+Mela. Results demonstrated that only singular NR was able to reduce IS% (30 ± 14 vs. 60 ± 16%, P = 0.009 vs. control). Mela (63 ± 18%) and NR+Mela (47 ± 15%) were unable to significantly decrease IS%. NR still reduced IS in the presence of cangrelor (51 ± 18 vs. 71 ± 4%, P = 0.016 vs. control), but lost protection in the presence of propofol anesthesia (62 ± 16 vs. 60 ± 14%, P = 0.839 vs. control). LDH activity measurements supported all IS% results.Conclusion: This observational study suggests that NR is a promising cardioprotective agent to target cardiac ischemia-reperfusion injury in clinical conditions employing opioid agonists, benzodiazepines and platelet P2Y12 inhibitors, but not propofol.

Tetrahydrocurcumin Downregulates MAPKs/cPLA2 Signaling and Attenuates Platelet Thromboxane A2 Generation, Granule Secretion, and Thrombus Growth.

Platelet granule secretion plays a key role in atherothrombosis. Curcumin, a natural polyphenol compound derived from turmeric, exerts multiple biological activities. The current study sought to investigate the efficacy of tetrahydrocurcumin (THC, the major active metabolite of curcumin) on platelet granule secretion in vitro and thrombus formation in vivo. We found that THC significantly attenuated agonist-induced granule secretion in human gel-filtered platelets in vitro, including CD62P and CD63 expression and platelet factor 4, CCL5, and adenosine triphosphate release. These inhibitory effects of THC were partially mediated by the attenuation of cytosolic phospholipase A2 (cPLA2) phosphorylation, leading to a decrease in thromboxane A2 (TxA2) generation. Moreover, the MAPK (Erk1/2, JNK1/2, and p38 MAPK) signaling pathways were downregulated by THC treatment, resulting in reduced cPLA2 activation, TxA2 generation, and granule secretion. Additionally, THC and curcumin attenuated murine thrombus growth in a FeCl3-induced mesenteric arteriole thrombosis model in C57BL/6J mice without prolonging the tail bleeding time. THC exerted more potent inhibitory effects on thrombosis formation than curcumin. Through blocking cyclooxygenase-1 activity and thus inhibiting platelet TxA2 synthesis and granule secretion with aspirin, we found that THC did not further decrease the inhibitory effects of aspirin on thrombosis formation. Thus, through inhibiting MAPKs/cPLA2 signaling, and attenuating platelet TxA2 generation, granule secretion, and thrombus formation, THC may be a potent cardioprotective agent.

Pseudosterins A-C, Three 1-Ethyl-3-formyl-β-carbolines from Pseudostellaria heterophylla and Their Cardioprotective Effects.

Pseudostellaria heterophylla is used in China not only as a functional food but also as an herb to tonify the spleen, enhance immunity, and treat palpitation. Our previous investigation showed that a fraction enriched in glycosides obtained from the roots of P. heterophylla possessed pronounced protective effects on H9c2 cells against CoCl2-induced hypoxic injury. However, the active compounds responsible for the observed effects were still unknown. In the current investigation, pseudosterins A–C (1–3), three new alkaloids with a 1-ethyl-3-formyl-β-carboline skeleton, together with polydatin, have been isolated from the active fraction. Their structures were elucidated on the basis of spectroscopic analysis and quantum chemical calculations. The four compounds showed cardioprotective effects against sodium hydrosulfite-induced hypoxia-reoxygenation injury in H9c2 cells, with the three alkaloids being more potent. This is also the first report of alkaloids with a β-carboline skeleton isolated from P. heterophylla as cardioprotective agents.

Chlorogenic Acid Enhances Doxorubicin-Mediated Cytotoxic Effect in Osteosarcoma Cells.

Despite the recurring outbreak of resistance mechanisms and adverse reactions, doxorubicin (Doxo) still remains the standard-of-care for several cancers, including osteosarcoma (OS). As an appealing source of phytochemical compounds, naturally occurring molecules have extensively been reported to overcome Doxo limitations in preclinical models. Unlike other dietary polyphenols, only few studies recognize chlorogenic acid (CGA) as a potential partner in combination therapy, while, conversely, its anticancer evidence is steadily growing, ultimately in OS. On this basis, herein we examine the cooperating effects between CGA and Doxo in U2OS and MG-63 human OS cells. With respect to Doxo alone, the concomitant administration of CGA further decreased cell viability and growth, promoting cell death potentially via apoptosis induction. Furthermore, a longer-lasting reduction in clonogenic potential deeply supported the CGA ability to improve Doxo efficacy in those cells. Remarkably, CGA treatment ameliorated Doxo-induced cytotoxicity in H9c2 rat cardiomyocyte cells instead. Although inactivation of p44/42 MAPK was detected in response to CGA plus Doxo, PD98059-mediated p44/42 MAPK impairment enhanced the combination outcome in OS cells. These findings firstly propose CGA as a promising chemosensitizer and cardioprotective agent in OS therapy, suggesting the p44/42 MAPK pathway as relevantly involved in CGA-mediated Doxo susceptibility.

Cardioprotective effects of corilagin on doxorubicin induced cardiotoxicity via P13K/Akt and NF-κB signaling pathways in rats model

Even though doxorubicin (DOX) is a potential chemotherapeutic drug, its usage is restricted due to its ability to induce cardiac damage. In order to prevent this damage, a potent cardioprotective agent should be associated with DOX treatment. Corilagin is a natural polyphenol tannic acid which unveils enormous pharmacological activities predominantly as an antitumor agent. Hence, the current work is designed to study the precise mechanisms of corilagin upon administration in doxorubicin induced cardiotoxicity in experimental rats. DOX treated rats showed diminished level of blood pressures and heart rate, whereas corilagin along with DOX treatment improved the status. Cardiotoxicity enzymes and biomarkers were found to be increased in the serum of DOX induced rats. Upon treatment, corilagin could reduce the cardiotoxicity enzymes and biomarkers in serum. Histopathological examination of cardiac tissue also revealed the anti-toxic effects of corilagin in contrast to DOX. Injection of DOX in rats showed inflammatory cells infiltration, necrosis and fragmented myofibrils. Corilagin treatment reverted the cardiac histology to near normal. Inflammatory mediators and P13K, Akt, and NF-κB were upregulated in DOX administered rats. Corilagin repressed the levels of P13K, Akt, and NF-κB in DOX induced rats. In the present investigations, corilagin improved cardiac function via reducing injury, inflammation and promoting apoptosis thereby suggesting that corilagin would be recommended for DOX-induced cardiotoxicity.

Melissa officinalis tea favourably affects the frequency of premature ventricular beats and cardiometabolic profile among patients with premature ventricular contraction: A randomised open-label controlled trial.

Premature ventricular contraction (PVC) as one of the most common arrhythmias could worsen the morbidity of cardiovascular events, particularly concurrent with other risk factors. Considering the probable side effects of antiarrhythmic drugs chronic use, prescribing herbal medicines for such conditions is on the rise. Melissa officinalis (MO) is widely identified as an antiarrhythmic and cardioprotective agent but there is limited evidence for its clinical use. This research, thus, aimed to investigate the effects of MO tea among patients with PVCs. The present 12-week randomised controlled trial enrolled 60 patients with confirmed diagnosis of moderate to low-grade PVCs. The patients in intervention group received MO teabags (containing 2-g dried leaves/250mL in hot water) two times/day in addition to lifestyle modification recommendations, while control group only received lifestyle modification recommendations. After collecting the data, blood samples were gathered to explore serum concentrations of glucose and lipid markers. The number of premature ventricular beats and heart rates was determined by 24-hour rhythm Holter monitoring. On average, the patients aged 47years and approximately 67.8% (n=40) were women. The ANCOVA adjusted for baseline values and confounders revealed that patients in the MO tea group had significantly lower concentrations of triglyceride (adjusted mean (AM)=144.75mg/dL), total cholesterol (AM=155.35mg/dL), and fasting blood sugar (AM=90.85mg/dL), compared with the controls (AM=174.27, 171.99, 99.84mg/dL, respectively (P-value ≤.042). However, the intervention failed to affect LDL-C and HDL-C levels significantly. Significantly reduced frequency of 24-hour premature ventricular beats in the MO tea group (AM=2142.39) was also noted compared with the controls (AM=3126.05); (P-value=.017). The 24-hour heartbeats showed only a significant decrease within the intervention group (P-value<.01). Together, these results seem to support the higher cardioprotective effects of MO as a medicinal plant than lifestyle modifications alone. Nevertheless, further exploration of this hypothesis is warranted using large-scaled clinical trials.

Fat And Carbohydrate Oxidation During Cardiopulmonary Exercise Test In Childhood Acute Lymphoblastic Leukemia Survivors

PURPOSE: Analyses of indirect calorimetry during cardiopulmonary exercise tests (CPET) have the potential to bring new evidence about the metabolic health of childhood acute lymphoblastic leukemia (ALL) survivors. To propose a better knowledge of survivors’ metabolic health, we aimed to compare their carbohydrate and fat oxidation during a CPET. Moreover, we explored the long-term effects of doxorubicin and dexrazoxane on survivors’ metabolic health. METHODS: A total of 250 childhood ALL survivors were categorized into three groups depending on their prognostic risk (i.e., standard risk (SR), high risk with and without cardio-protective agent dexrazoxane (HR + DEX and HR)). They underwent a CPET on ergocycle to assess their oxygen consumption and their carbon dioxide production. Carbohydrate and fat oxidation rates were determined using the Peronnet and Massicotte’s equation. For each childhood ALL survivor, we produced a third-degree polynomial equation in order to obtain the best-fit curve for fat and carbohydrate oxidation rate (mg/min) against exercise intensity (%VO2peak). We also used them to compare carbohydrate and fat oxidation over a range of exercise intensities and to determine the maximal fat oxidation (MFO) rate and the peak fat oxidation (Fatmax) rate. MFO and Fatmax comparisons were made using one-way ANOVA. Multiple linear regression analysis was used to quantify each variable’s influence on the MFO and the Fatmax. RESULTS: We observed that MFO parameter was not different between the groups (p = 0.078) (SR = 273.7 ± 99.5 mg·min-1; HR + DEX = 247.3 ± 93.2 mg·min-1; and HR = 239.2 ± 86.0 mg·min-1). There was no difference between the groups for the Fatmax parameter (p = 0.865) (SR = 35.1 ± 7.4%; HR + DEX = 34.6 ± 7.5%; and HR = 35.7 ± 8.1%) and 14% of the variability was explained by the maximum oxygen uptake, sex and obesity. CONCLUSIONS: This study shows that although childhood ALL survivors have a reduced fat oxidation rates, that does not depend on the prognostic risk group. However, we observed a trend that suggests that the reduction of fat oxidation is doxorubicin dose-dependent and that the dexrazoxane treatment has the potential to limit these effects. Our study highlights that survivors’ metabolic health and substrate oxidation are compromised during a maximal cardiopulmonary exercise test.

Antioxidant, anti-inflammatory, and anti-apoptotic effects of crocin against doxorubicin-induced myocardial toxicity in rats.

Doxorubicin (DOX) is a well-known chemotherapeutic drug for most malignancies including breast cancer and leukemia whilst the usage of DOX is limited owing to its cardiotoxicity. In the present study, we aimed to investigate the effects of crocin on doxorubicin-induced cardiotoxicity in rats. Forty rats were randomly divided into four groups: (a) control [received normal saline as a dose of 1 ml/kg by intraperitoneal injection (ip) for 15 days], (b) crocin (received crocin as a dose of 40 mg/kg/24h by ip for 15 days), (c) DOX (received DOX as a dose of 2 mg/kg/48h by ip in six injection, cumulative dose 12 mg/kg), and (d) DOX+crocin (received DOX as a dose of 2 mg/kg/48h by ip in six injection, and crocin as a dose of 40 mg/kg/24h i.p for 15 days). As compared to the controls, the results showed that DOX administration caused significant increases in lipid indices [triglyseride (TG), low-dencity lipoproteins (LDL) (p<0.001), and very low-dencity lipoproteins (VLDL) (p<0.005)], oxidative stress parameters [malondialdehyde (MDA) and total oxidant status (TOS) (p<0.001)] and cardiac markers [creatine kinase-muscle/brain (CK-MB) and cardiac troponin I (cTnI) (p<0.001)]. Besides, significant decreases in antioxidant defense systems [glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), and total antioxidant status (TAS) (p<0.001)] were observed. The present study also demonstrated that co-administration of crocin with DOX significantly ameliorated the lipid profile (p<0.005), cardiac markers (p<0.005), and oxidative stress indices (p<0.001) as compared to DOX group. Histopathologically, significant increase in the mean histopathological damage score (MHDS) was found in the DOX group as compared to the controls (p<0.001). In contrast, the administration of crocin with DOX alleviated MHDS in myocardium (p<0.001). Taken together, our results reveal that crocin might be a cardioprotective agent in DOX-treated patients for cancer.