Oxidative Stress In Cardiac Tissue Research Articles

Indole-3-acetic acid exposure leads to cardiovascular inflammation and fibrosis in chronic kidney disease rat model

Indole-3-acetic acid (IAA), a protein-bound uremic toxin, has been linked to cardiovascular morbidity and mortality in chronic kidney disease (CKD) patients. This study explores the influence of IAA (125 mg/kg) on cardiovascular changes in adenine sulfate-induced CKD rats. HPLC analysis revealed that IAA-exposed CKD rats had lower excretion and increased circulation of IAA compared to both CKD and IAA control groups. Moreover, echocardiography indicated that CKD rats exposed to IAA exhibited heart enlargement, thickening of the myocardium, and cardiac hypertrophy in contrast to CKD or IAA control group. Biochemical analyses supported the finding that IAA-induced CKD rats had elevated serum levels of c-Tn-I, CK-MB, and LDH; there was also evidence of oxidative stress in cardiac tissues, with a significant decrease in SOD and CAT levels, as well as an increase in MDA levels. The gene expression analysis found significant increases in ANP, BNP, β-MHC, TNF-α, IL-1β, and NF-κB levels in IAA-exposed CKD groups in contrast to the CKD or IAA control group. In addition, higher cardiac fibrosis markers, including Col-I and Col-III. The findings of this study indicate that IAA could trigger cardiovascular inflammation and fibrosis in CKD conditions.

Protective effects of mesenchymal stem cells-derived extracellular vesicles against ischemia-reperfusion injury of hearts donated after circulatory death: Preliminary study in a pig model

IntroductionInsufficient supply of cardiac grafts represents a severe obstacle in heart transplantation. Donation after Circulatory Death (DCD), in addition to conventional donation after brain death, is one promising option to overcome the organ shortage. However, DCD organs undergo an inevitable more extended period of warm unprotected ischemia between circulatory arrest and graft procurement. Mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) have shown remarkable protective effects against ischemia-reperfusion injury. Thus, we aimed to enhance grafts preservation from DCD donors, through treatment with MSC-EVs. MethodsFemale pigs were euthanized by barbiturate overdose and after 20 min of a flat EKG, the chest was opened, the heart harvested and subsequently connected to an extracorporeal perfusion machine. MSC-EVs, isolated by ion exchange chromatography, were added to the perfusion solution (1×1011 particles) and the heart was perfused for 2 h. Then, heart tissue biopsies were taken to assess histological changes, mitochondrial morphology, antioxidant enzyme activity and inflammation mediators’ expression. Biochemical parameters of myocardial viability were assessed in the perfusate. ResultsThe treatment with MSC-EVs significantly prevented mitochondria swelling, mitochondrial cristae loss and oxidative stress in cardiac tissue. The protective effect of MSC-EVs was confirmed by the delayed increase of the cardiac-specific enzymes CK and TnC in the perfusate and the reduction of caspase-3+ cells in tissue sections. ConclusionMSC-EVs improve graft quality by preserving the mitochondrial ultrastructure protecting the myocardium against oxidative stress, reducing apoptosis of cardiac cells and preventing the increase of pro-inflammatory cytokines.

DEPENDENCE OF OXIDATIVE BALANCE AND CHOLESTEROL METABOLISM IN MUSCLE TISSUE ON EXERCISE INTENSITY

Intriduction. Changes in oxidative balance and lipid metabolism have the leading role in performance limitation, adaptation and maladaptation to physical activity. It is especially important to analyse the direction of metabolic changes at the subcellular level. The aim of the study is to examine the state of oxidative balance and cholesterol metabolism in muscle tissue at moderate and maximal swim-ming load. Material and methods. A comprehensive study of indicators for free-radical oxidation (content of diene conjugates, TBA-active products, chemilu-minescence intensity), antioxidant defense (total antioxidant activity, antiradical activity) and cholesterol metabolism in tissues of heart muscle and thigh muscle of white male rats at moderate and maximum swimming load was carried out. Results. The patterns of metabolic changes in muscle tissue depending on the intensity of muscular work have been established: these are the forms of compensated oxidative stress at moderate and decompensated at maximum load, against the background of decreasing cholesterol content. In cardiac tissue oxidative stress phenomena were less expressed, and changes in cholesterol content were multidirectional: a tendency to decrease at moderate load and a significant increase at maximum load. Conclusion. The reduction of antioxidant defence resources and intensification of free-radical oxidation reactions constitute one of the leading mecha-nisms for metabolic disorders due to extreme physical load, which is confirmed by reliable changes in the studied parameters. The complex study of indicators characterizing the processes of free-radical oxidation, antioxidant protection and cholesterol content is an informative criterion for the influ-ence of physical exercise on the organism. The obtained data allow us to recommend the inclusion of antioxidants in the complex prevention and ther-apy of acute physical overstrain.

MiR-92b-3p Protects against Myocardial Ischemia-Reperfusion Injury by Inhibiting MAP3K2 in a Mouse Model.

MicroRNAs are well-known RNA regulators modulating biological functions in complex signaling networks. This work aims to explore the impact of microRNA-92b-3p (miR-92b-3p) on myocardial ischemia-reperfusion (I/R) injury. The I/R model was established by left anterior descending coronary artery ligation in mice. The hemodynamic parameters were detected through a multichannel physiological recorder. Myocardial injury markers: serum cardiac troponin I, myocardial kinase isoenzyme (creatine kinase-MB), and serum inflammatory factors (tumor necrosis factor-α, interleukin [IL]-1β, and IL-6) were evaluated by enzyme-linked immunosorbent assay. Cardiac tissue oxidative stress-related factors (malondialdehyde, glutathione peroxidase, total antioxidation capability, and superoxide dismutase) were assessed by colorimetry, myocardial pathology was observed by hematoxylin-eosin staining, and cardiomyocyte apoptosis was measured by triphosphate nick end-labeling staining, as well as the expression of miR-92b-3p and mitogen-activated protein kinase kinase kinase 2 (MAP3K2) in cardiac tissues were determined by reverse transcription quantitative polymerase chain reaction or western blot assay. The targeting relationship between miR-92b-3p and MAP3K2 was verified by bioinformatics, RNA immunoprecipitation, and luciferase reporter assays. miR-92b-3p was lowly expressed and MAP3K2 was highly expressed in myocardial I/R injury mice. Upregulation of miR-92b-3p improved hemodynamic indices, decreased serum levels of myocardial injury biomarkers, inhibited serum inflammatory response, alleviated cardiac tissue oxidative stress, relieved myocardial pathology, and reduced cardiomyocyte apoptosis during the myocardial I/R injury in mice. MAP3K2 was a direct target gene of miR-92b-3p. This research suggests that miR-92b-3p protects against myocardial I/R injury by inhibiting MAP3K2, which may provide novel candidates for treatment of myocardial I/R injury.

Role of L-, N- and T-type Calcium Channels in Achieving Maximum Analgesic and Minimum Toxic Effect of Tramadol

The aim of the study was to investigate the effects of lacidipine, amlodipine and benidipine on the analgesic activity and toxicity of tramadol. Rats (n=6/each group) were divided into five groups as control(CG), tramadol(TRD), lacidipine+tramadol(LTRD), amlodipine+tramadol(ATRD) and benidipine+tramadol(BTRD). Tramadol was administered once at a dose of 50 mg/kg and lacidipine, amlodipin, benidipin were administered at a dose of 4 mg/kg orally, once a day for 10 days. After the animals were sacrificed malondialdehyde(MDA) and total glutathione(tGSH) levels were measured in brain, heart, liver and kidney tissues. Troponin I(Tp I), alanine aminotransferase(ALT), aspartate aminotransferase(AST), blood urea nitrogen(BUN), and creatinine levels were determined in serum. Paw pain thresholds were measured 1 hour before and after drug administration. Analgesic effect of tramadol was increased the most by benidipine, while amlodipine and lacidipine increased it equally. Lacidipine failed to suppress MDA increase and tGSH decrease in brain tissue. Benidipine suppressed MDA increase and tGSH decrease in brain tissue better than amlodipine. All three drugs suppressed cardiac tissue oxidative stress and the release of TP I into the circulation. Lacidipine and amlodipine could not prevent tramadol-induced oxidative stress in liver and kidney tissues, whereas benidipine prevented excessive MDA increase and tGSH decrease. Benidipine significantly suppressed the increase of ALT, AST, BUN, and creatinine. Analgesic activity was 35.1% in TRD, 43.7% in LTRD 50.4% in ATRD and 67,5% in BTRD. Study results show that benidipine and tramadol co-treatment is better than co-treatment with lacidipine or amlodipine in achieving minimal toxic effects and maximum analgesia.

Δ(9)-tetrahydrocannabinol protects cardiac tissue against endoplasmic reticulum and oxidative stresses, apoptosis, and inflammation in rats with hyperinsulinemia.

In our study, we aimed to examine how δ(9)-tetrahydrocannabinol (THC) administration to hyperinsulinemia (HI) model rats would change endoplasmic reticulum stress (ERS), apoptosis, inflammation, and oxidative stress in cardiac tissue. Rats were divided into four groups (n = 32): Control (C), THC, HI, and Treatment (Tre). Fructose (10%) in the drinking water was given to HI and Tre rats for 12 weeks. 1.5 mg/kg/d THC was given intraperitoneally to THC and Tre rats in the last 4 weeks of the experiment. The mRNA expressions of ERS and apoptosis markers in the cardiac tissue were detected. TNF-α concentration and oxidative stress were also analyzed. THC treatment in rats with HI ameliorated the overexpression of GRP-78, IRE1α, ATF6, ATF4, CHOP, Cas-12, Cas-8, Cas-9, and Cas-3 mRNAs, markers of ERS and apoptosis (P < .0001 for all). In addition, THC has been shown to reduce inflammation in the Tre group by causing a decrease in increased cardiac TNF-α levels (P < .01). Moreover, THC prevented cardiac tissue damage by regulating the degraded oxidative stress marker levels and antioxidant enzyme activities in HI. Our findings suggest that THC treatment in rats with HI exhibited a significant effect in ameliorating cardiac tissue damage by improving the antioxidant defense system, inflammation, apoptosis, ERS, and oxidative stress.

Potential inhibitory effect of geraniol isolated from lemongrass (Cymbopogon commutatus Stapf) on tilmicosin-induced oxidative stress in cardiac tissue

An experimental study has been conducted to investigate the efficacy of geraniol (GNL) isolated from lemomgrass in protecting against cardiac toxicity induced by tilmicosin (TIL) in albino mice. Compared to TIL-treated mice, those supplemented with GNL had a thicker left ventricular wall and a smaller ventricular cavity. Studies of TIL animals treated with GNL showed that their cardiomyocytes had markedly changed in diameter and volume, along with a reduction in numerical density. After TIL induction, animals showed a significant increase in the protein expression of TGF-β1, TNF-α, nuclear factor kappa B (NF-kB), by 81.81, 73.75 and 66.67%, respectively, and hypertrophy marker proteins ANP, BNP, and calcineurin with respective percentages of 40, 33.34 and 42.34%. Interestingly, GNL significantly decreased the TGF-β1, TNF-α, NF-kB, ANP, BNP, and calcineurin levels by 60.94, 65.13, 52.37, 49.73, 44.18 and 36.84%, respectively. As observed from histopathology and Masson’s trichrome staining, supplementation with GNL could rescue TIL-induced cardiac hypertrophy. According to these results, GNL may protect the heart by reducing hypertrophy in mice and modulating biomarkers of fibrosis and apoptosis.

Gallic acid and sesame oil exert cardioprotection via mitochondrial protection and antioxidant properties on Ketamine-Induced cardiotoxicity model in rats

Ketamine is a cardiotoxic agent and can deplete ATP in cardiomyocytes through mitochondrial dysfunction. We investigated the effects of gallic acid and sesame oil in ketamine-induced cardiotoxicity in rats. Male Wistar rats were randomly divided into six groups including control; ketamine; ketamine + gallic acid; ketamine + sesame oil; gallic acid and sesame oil. Serum cardiac marker, cardiac tissue oxidative stress markers, histopathological analysis and mitochondrial toxicity parameters (succinate dehydrogenase activity, mitochondrial swelling, reactive oxygen species (ROS) production and collapse of mitochondria membrane potential) were measured on the fifteen days of the study. The results showed that ketamine administration increased serum cardiac markers, oxidative stress parameters, histopathological alterations and mitochondrial dysfunction in cardiac tissue. Gallic acid and sesame oil administration in presence of ketamine was observed to decrease serum cardiac markers, oxidative stress parameters, histopathological alterations and mitochondrial dysfunction in cardiac tissue. The results suggest that gallic acid and sesame oil exert cardioprotection via mitochondrial protection, antioxidant properties and ultimately improving mitochondrial function and cardiac function.

Chromium picolinate supplementation improves cardiac performance in hypoxic rats

Background Conditions associated with chronic hypoxia increase morbidity and mortality attributable to cardiovascular complications. Myocardial hypoxia is a common feature in several diseases including: stroke, infarction, anaemia, chronic lung diseases, obstructive sleep apnoea and cyanotic congenital heart defects. The present study was planned to investigate the cardiovascular effects of chronic intermittent hypoxia and its association with increased myocardial oxidative stress. In addition, to evaluate the protective effect of chromium supplementation, aiming at achieving an alternative that may enable to devise a therapy for hypoxic patients. Methods Male rats were allocated into three groups: control group (normoxic), untreated hypoxic group (exposed to hypoxia 8 h/day, 5 days/week for 6 weeks) and hypoxic group supplemented with chromium picolinate (90 µg/kg/day by gavage). Rats were subjected to measurement of body weight, haematocrit value, mean arterial blood pressure, heart rate and ECG recording. Cardiac activities of isolated hearts were studied on Langendorff preparation under basal conditions and in response to ischaemia/reperfusion. Thereafter, cardiac weights were determined and cardiac tissue catalase activity as well as malondialdhyde level were assessed. Results Significant results were obtained upon exposure to hypoxia including; low body weight, increased haematocrit, elevated blood pressure, left ventricular hypertrophy and impaired cardiac activities, basally and in response to ischaemia/reperfusion challenges, associated with increased oxidative stress in cardiac tissue. At the same time, chromium supplementation increased body weight, lowered blood pressure, reduced ventricular hypertrophy and significantly improved the cardiac performance. Conclusion Chromium supplementation confers protection against hypoxia-induced cardiovascular dysfunction by improvement of the antioxidant capacity.

Effects of four weeks lasting aerobic physical activity on cardiovascular biomarkers, oxidative stress and histomorphometric changes of heart and aorta in rats with experimentally induced hyperhomocysteinemia.

The aim of this study was to examine the effects of hyperhomocysteinemia and aerobic physical activity on changes of cardiovascular biomarkers in sera, oxidative stress in cardiac tissue, and histomorphometric parameters of heart and aorta in rats. Experiments were conducted on male Wistar albino rats organized into four groups (n = 10, per group): C (control group): 0.9% NaCl 0.2mL/day; H (homocysteine group): homocysteine 0.45µmol/g b.w./day; CPA (control + physical activity group): 0.9% NaCl 0.2mL/day and a program of physical activity on a treadmill; and HPA (homocysteine + physical activity group) homocysteine 0.45µmol/g b.w./day and a program of physical activity on a treadmill. Substances were applied subcutaneously twice a day. Lipid peroxidation and relative activity of Mn-superoxide dismutase isoform were significantly higher in active hyperhomocysteinemic rats in comparison to sedentary animals. Atherosclerotic plaques were detected in aorta samples of active hyperhomocysteinemic rats and also, they had increased left ventricle wall and interventricular septum, and transverse diameter of cardiomyocytes compared to sedentary groups. Aerobic physical activity in the condition of hyperhomocysteinemia can lead to increased oxidative stress in cardiac tissue and changes in histomorphometric parameters of the heart and aorta, as well increased lipid parameters and cardiac damage biomarkers in sera of rats.

Biochanin A Attenuates Cardiomyopathy in Type 2 Diabetic Rats by Increasing SIRT1 Expression and Reducing Oxidative Stress.

Diabetic cardiomyopathy is one of the major complications in type 2 diabetes associated with myocardial structure abnormality and major cause of morbidity in type 2 diabetic patients. Biochanin A is a methylated isoflavone present in flowering tops of Trifolium pratense reported for anti-inflammatory, anti-oxidant, anti-infective, anti-cancer and anti-diabetic activity. The study was designed to assess the efficacy of Biochanin A in type 2 diabetic cardiomyopathy. Type 2 diabetes was induced in rats feeding high fat diet for two weeks and administration of single low dose of streptozotocin. Biochanin A was administered for 16 weeks orally once in a day (10, 20 and 40 mg/kg of body weight). Various parameters such as blood glucose, cardiac markers, oxidative stress and hemodynamic parameters, immunohistochemical, histopathological investigation and SIRT1 expression were measured at the end of the study. Biochanin A treatment resulted into reduction in plasma concentration of cardiac markers along with reduction in hyperglycemia, hyperlipidemia and oxidative stress in cardiac tissue. Biochanin A treated animals also demonstrated improvement in hemodynamic parameters. Diabetic animals treated with different doses of Biochanin A shown increased SIRT1 expression in cardiac tissue, and also confirmed reduced cardiac hypertrophy and cardiac protection in histopathological study. Outcome of the study indicates that Biochanin A is the potential candidate to control hyperglycemia, oxidative stress and improve SIRT1 expression in cardiac tissue. Biochanin A might be considered as potential candidate to control progression of cardiomyopathy in type 2 diabetes mellitus.

Response of Cardiac Tissue Oxidative Stress After Aerobic Exercise and Capsaicin Administrations in Rats Fed High-Fat Diet

Background: Oxidative stress harms cells and impairs the balance between oxidative and antioxidative factors. Exercise and capsaicin have anti-inflammatory and antioxidant effects, as well as some benefits on the cardiovascular system. Objectives: The aim of the present study was to examine the effect of aerobic training with capsaicin on heart changes oxidative stress in rats fed a high-fat diet (HFD). Methods: In this experimental study, 40 male Wistar rats were fed a normal diet (ND, n = 8) or HFD (n = 32) for 8 weeks. After eight weeks, all rats were divided into five groups: ND, HFD, high-fat diet-training (HFDT), high-fat diet-capsaicin (HFDCap), high-fat diet-training-capsaicin (HFDTCap). Training groups performed a progressive aerobic running program (at 15 - 25 m/min, 30 - 60 min/day, and 5 days/week) on a motor-driven treadmill for eight weeks. Capsaicin (4 mg/kg/day) was administered orally, by gavage, once a day. Results: The results showed significant increase in cardiac SOD, GPx and CAT levels in HFDT (P &lt; 0.001), HFDCap (P &lt; 0.001) and HFDTCap (P &lt; 0.001) groups. Also, a significant increase in the amount of this index was observed in the HFDTCap compared to the HFDT and HFDCap groups (P &lt; 0.05). The level of malondialdehyde (MDA) in all experimental groups was significantly lower than the HFD group (P &lt; 0.001). Conclusions: Exercise and capsaicin improve HFD-induced oxidative stress. Therefore, exercise and capsaicin can be used as an appropriate alternative treatment for obesity and its associated inflammatory and oxidative effects.

Daidzein mitigates myocardial injury in streptozotocin-induced diabetes in rats

AimPresent study focuses on the effect of daidzein in an experimental model of diabetic cardiomyopathy in rats. Materials and methodsDiabetes was induced in male Sprague Dawley rats by a single intraperitoneal injection of STZ at dose 55 mg/kg. Daidzein treatment was started after six weeks of diabetes induction. Animals received daidzein at a dose of 25, 50, and 100 mg/kg orally for the next four weeks. Key findingsDiabetic control animals showed significant prolongation in QT interval, PR interval, and R wave amplitude as compared to normal control animals. Treatment with daidzein at dose 100 mg/kg significantly normalized the QT interval, PR interval, and R wave amplitude. A significant reduction in QRS duration was observed in diabetic animals. Treatment with daidzein significantly improved the QRS duration after treatment. Hemodynamic parameters like systolic pressure (SBP), diastolic pressure (DBP) and mean atrial pressure (MAP) were found to be significantly decreased in diabetic animals. Treatment with daidzein at dose 100 mg/kg significantly improved the SBP, DBP, and MAP. Daidzein treatment prevented the loss of cardiac marker enzyme from heart tissue and also increased the level of AMPK and SIRT1 in plasma. Protein expression of NOX-4 and RAC-1 was also found to be reduced in cardiac tissue of daidzein treated animals. Daidzein treatment improved oxidative defense mechanism and reduced cardiac tissue necrosis and fibrosis. SignificanceFrom the results, it can be concluded that daidzein mitigates the progression of diabetic cardiomyopathy by inhibiting NOX-4 induced oxidative stress in cardiac tissue.

Effect of Quercetin and Intermittent and Continuous Exercise on Catalase, Superoxide dismutase, and Malondialdehyde in the Heart of Rats with Colon Cancer

Background: Colorectal cancer is the fourth leading cause of death globally, and the second most common cancer in Europe. About 8% of all cancer-related deaths occur due to colorectal cancer, and the highest prevalence has been reported in Asia and Eastern Europe. Methods: In this experimental study, 80 rats were divided into two groups of cases (n=70) and controls (n=10). Colorectal cancer was induced weekly in rats by subcutaneous injection of 15 mg/kg Azoxymethane. The rats were then divided into 7 experimental subgroups of patients, saline, quercetin, intermittent exercise, continuous exercise, quercetin plus intermittent, and quercetin plus continuous exercise. Oxidative stress biomarkers, including superoxide dismutase (SOD), catalase (CAT), and malondialdehyde (MDA) were measured in the rats’ heart tissue by the ELISA method. Data were analyzed using ANOVA by SPSS software. Results: Oxidative stress in heart cells increased due to colorectal cancer. Quercetin alone or in combination with exercise significantly increased mean levels of CAT and SOD in the heart tissue of rats compared with patient and saline groups (P&lt;0.0001). In contrast, the MDA level was significantly decreased (P&lt;0.05). Conclusion: Colorectal cancer increased the oxidative stress in cardiac cells. Quercetin alone improved oxidative stress in cardiac tissue, and its combination with exercise was more effective.

Preconditioning with Short-term Dietary Restriction Attenuates Cardiac Oxidative Stress and Hypertrophy Induced by Chronic Pressure Overload.

Left ventricular (LV) hypertrophy and associated heart failure are becoming a more prevalent and critical public health issue with the aging of society, and are exacerbated by reactive oxygen species (ROS). Dietary restriction (DR) markedly inhibits senescent changes; however, prolonged DR is difficult. We herein investigated whether preconditioning with short-term DR attenuates chronic pressure overload-induced cardiac hypertrophy and associated oxidative stress. Male c57BL6 mice were randomly divided into an ad libitum (AL) diet or 40% restricted diet (DR preconditioning, DRPC) group for 2 weeks prior to ascending aortic constriction (AAC), and all mice were fed ad libitum after AAC surgery. Two weeks after surgery, pressure overload by AAC increased LV wall thickness in association with LV diastolic dysfunction and promoted myocyte hypertrophy and cardiac fibrosis in the AL+AAC group. Oxidative stress in cardiac tissue and mitochondria also increased in the AL+AAC group in association with increments in cardiac NADPH oxidase-derived and mitochondrial ROS production. LV hypertrophy and associated cardiac dysfunction and oxidative stress were significantly attenuated in the DRPC+AAC group. Moreover, less severe mitochondrial oxidative damage in the DRPC+AAC group was associated with the suppression of mitochondrial permeability transition and cardiac apoptosis. These results indicate that chronic pressure overload-induced cardiac hypertrophy in association with cardiac and mitochondrial oxidative damage were attenuated by preconditioning with short-term DR.

Irvingia gabonensis Seed Extract: An Effective Attenuator of Doxorubicin-Mediated Cardiotoxicity in Wistar Rats.

Cardiotoxicity as an off-target effect of doxorubicin therapy is a major limiting factor for its clinical use as a choice cytotoxic agent. Seeds of Irvingia gabonensis have been reported to possess both nutritional and medicinal values which include antidiabetic, weight losing, antihyperlipidemic, and antioxidative effects. Protective effects of Irvingia gabonensis ethanol seed extract (IGESE) was investigated in doxorubicin (DOX)-mediated cardiotoxicity induced with single intraperitoneal injection of 15 mg/kg of DOX following the oral pretreatments of Wistar rats with 100-400 mg/kg/day of IGESE for 10 days, using serum cardiac enzyme markers (cardiac troponin I (cTI) and lactate dehydrogenase (LDH)), cardiac tissue oxidative stress markers (catalase (CAT), malonyldialdehyde (MDA), superoxide dismutase (SOD), glutathione-S-transferase (GST), glutathione peroxidase (GSH-Px), and reduced glutathione (GSH)), and cardiac histopathology endpoints. In addition, both qualitative and quantitative analyses to determine IGESE's secondary metabolites profile and its in vitro antioxidant activities were also conducted. Results revealed that serum cTnI and LDH were significantly elevated by the DOX treatment. Similarly, activities of tissue SOD, CAT, GST, and GSH levels were profoundly reduced, while GPx activity and MDA levels were profoundly increased by DOX treatment. These biochemical changes were associated with microthrombi formation in the DOX-treated cardiac tissues on histological examination. However, oral pretreatments with 100-400 mg/kg/day of IGESE dissolved in 5% DMSO in distilled water significantly attenuated increases in the serum cTnI and LDH, prevented significant alterations in the serum lipid profile and the tissue activities and levels of oxidative stress markers while improving cardiovascular disease risk indices and DOX-induced histopathological lesions. The in vitro antioxidant studies showed IGESE to have good antioxidant profile and contained 56 major secondary metabolites prominent among which are γ-sitosterol, Phytol, neophytadiene, stigmasterol, vitamin E, hexadecanoic acid and its ethyl ester, Phytyl palmitate, campesterol, lupeol, and squalene. Overall, both the in vitro and in vivo findings indicate that IGESE may be a promising prophylactic cardioprotective agent against DOX-induced cardiotoxicity, at least in part mediated via IGESE's antioxidant and free radical scavenging and antithrombotic mechanisms.

African Vegetables (Clerodendrum volubile Leaf and Irvingia gabonensis Seed Extracts) Effectively Mitigate Trastuzumab-Induced Cardiotoxicity in Wistar Rats

Trastuzumab (TZM) is a humanized monoclonal antibody that has been approved for the clinical management of HER2-positive metastatic breast and gastric cancers but its use is limited by its cumulative dose and off-target cardiotoxicity. Unfortunately, till date, there is no approved antidote to this off-target toxicity. Therefore, an acute study was designed at investigating the protective potential and mechanism(s) of CVE and IGE in TZM-induced cardiotoxicity utilizing cardiac enzyme and oxidative stress markers and histopathological endpoints. 400 mg/kg/day CVE and IGE dissolved in 5% DMSO in sterile water were investigated in Wistar rats injected with 2.25 mg/kg/day/i.p. route of TZM for 7 days, using serum cTnI and LDH, complete lipid profile, cardiac tissue oxidative stress markers assays, and histopathological examination of TZM-intoxicated heart tissue. Results showed that 400 mg/kg/day CVE and IGE profoundly attenuated increases in the serum cTnI and LDH levels but caused no significant alterations in the serum lipids and weight gain pattern in the treated rats. CVE and IGE profoundly attenuated alterations in the cardiac tissue oxidative stress markers' activities while improving TZM-associated cardiac histological lesions. These results suggest that CVE and IGE could be mediating its cardioprotection via antioxidant, free radical scavenging, and antithrombotic mechanisms, thus, highlighting the therapeutic potentials of CVE and IGE in the management of TZM-mediated cardiotoxicity.

Clerodendrum volubile Ethanol Leaf Extract: A Potential Antidote to Doxorubicin-Induced Cardiotoxicity in Rats.

Doxorubicin is widely applied in hematological and solid tumor treatment but limited by its off-target cardiotoxicity. Thus, cardioprotective potential and mechanism(s) of CVE in DOX-induced cardiotoxicity were investigated using cardiac and oxidative stress markers and histopathological endpoints. 50–400 mg/kg/day CVE in 5% DMSO in distilled water were investigated in Wistar rats intraperitoneally injected with 2.5 mg/kg DOX on alternate days for 14 days, using serum troponin I and LDH, complete lipid profile, cardiac tissue oxidative stress marker assays, and histopathological examination of DOX-treated cardiac tissue. Preliminary qualitative and quantitative assays of CVE's secondary metabolites were also conducted. Phytochemical analyses revealed the presence of flavonoids (34.79 ± 0.37 mg/100 mg dry extract), alkaloids (36.73 ± 0.27 mg/100 mg dry extract), reducing sugars (07.78 ± 0.09 mg/100 mg dry extract), and cardiac glycosides (24.55 ± 0.12 mg/100 mg dry extract). 50–400 mg/kg/day CVE significantly attenuated increases in the serum LDH and troponin I levels. Similarly, the CVE dose unrelatedly decreased serum TG and VLDL-c levels without significant alterations in the serum TC, HDL-c, and LDL-c levels. Also, CVE profoundly attenuated alterations in the cardiac tissue oxidative stress markers' activities while improving DOX-associated cardiac histological lesions that were possibly mediated via free radical scavenging and/or antioxidant mechanisms. Overall, CVE may play a significant therapeutic role in the management of DOX-induced cardiotoxicity in humans.

Pandemic Influenza Infection Persists in Cardiac Tissue and Leads to MLKL-Dependent Proteome and Phosphoproteome Remodeling During Convalescence

Influenza-related cardiac complications have been increasingly defined in the clinical setting. Recent reports support a direct link between laboratory-confirmed influenza infection and adverse cardiac events. Here, we define candidate molecular mediators underlying influenza virus-induced cardiac pathogenesis after the resolution of pulmonary infection, as well as the potential role of necroptosis in this process using mice deficient in its effector molecule MLKL. Global proteome and phosphoproteome analyses using high resolution accurate mass-based LC-MS/MS and label-free quantitation was used. Both the global proteome and the phosphoproteome profiles were significantly altered in IAV-infected mouse hearts, with significantly altered expression of mitochondrial and muscle contraction protein levels and phosphorylation states. Intriguingly, necroptosis deficient mice showed partial protection from IAV-mediated proteomic changes. We confirmed changes in energy state and mitochondrial dysfunction in vitro and define molecular candidates for therapeutics targeting necroptosis and oxidative stress in cardiac tissue after influenza infection.

Role of nitric oxide in mediating the cardioprotective effect of agomelatine against isoproterenol-induced myocardial injury in rats.

Myocardial infarction (M/I) is a common cause of mortality worldwide. Agomelatine (AGO), a potent melatonin receptor agonist, proved to have ananti-inflammatory and antioxidant effect. The present study aimed to explore the cardioprotective effect of AGO on isoproterenol (ISO)-induced myocardial injury in a rat model and determine the role of nitric oxide (NO) in mediating this beneficial effect. Rats were randomly divided into 6 groups and treated for 12days. Group 1, control, received normal saline. Group 2, ISO group, received ISO (100mg/kg, i.p.) in 11th and 12th days. Group 3, positive control group, received atenolol (100mg/kg/day) + ISO. Group 4, AGO-treated group, received AGO (80mg/kg/day) + ISO. Group 5, L-NNA + ISO, received L-NG-nitro arginine (L-NNA) (25mg/kg, orally) + ISO. Group 6, AGO + L-NNA + ISO, co-treated with AGO + ISO + L-NNA. Serum cardiac enzymes and cardiac tissue oxidative stress parameters were assessed along with histopathological evaluation. Gene expression quantification of nuclear factor erythroid 2 (Nrf-2) and heme oxygenase-1 (HO-1) were assessed. Immunoexpression of inducible NO synthase (iNOS) and caspase-3 were evaluated. The outcomes proved that ISO significantly increased serum cardiac enzymes, with histopathological changes of myocardial tissue along with a major increase in oxidative, inflammatory, and nitrosative stress, besides a reduction in cardiac Nrf-2 and HO-1 gene expressions with marked myocardial cell apoptosis. However, pretreatment with AGO significantly reversed these profound ISO myocardial damaging effects. AGO protects against ISO-induced myocardial injury through its antioxidant, anti-inflammatory, and anti-apoptotic effects with modulation of NOS enzymes.