Histopathological Examination Of Cardiac Tissues Research Articles

Primary Protection of Diosmin Against Doxorubicin Cardiotoxicity via Inhibiting Oxido-Inflammatory Stress and Apoptosis in Rats.

Doxorubicin (DOX) is the cornerstone of chemotherapy. However, it has dose-dependent cardiotoxic events that limit its clinical use. This study was intended to investigate the efficiency of DOX as an anti-cancer against the MCF-7 cell line in the presence of diosmin (DIO) and to appraise the protective impact of DIO against DOX cardiotoxicity in vivo. In vitro study was carried out to establish the conservation of DOX cytotoxicity in the presence of DIO. In vivo study was conducted on 42 adult female Wistar rats that were equally allocated into 6 groups; control, DIO (100 mg/kg), DIO (200 mg/kg), DOX (20 mg/kg, single dose i.p.), DIO (100 mg/kg) + DOX, received DIO orally (100 mg/kg) for 30 days, then administrated with a single dose of DOX and DIO (200 mg/kg) + DOX, received DIO orally (200 mg/kg) for 30 days, then administrated with DOX. In vitro study showed preservation of cytotoxic activity of DOX on MCF-7 in the presence of DIO. In vivo study indicated that DOX altered electrocardiograph (ECG) parameters. Also, it yielded a significant rise in CK-MB, cTnT and LDH serum levels and cardiac contents of MDA, IL-1β; paralleled by a significant drop in cardiac IL-10 and SOD. Moreover, significant upregulation of Bax, TNF-α, and HIF-1α, in concomitant with significant downregulation of Bcl-2 mRNA in cardiac tissue have been recorded in the DOX group. Furthermore, histopathological description of cardiac tissues showed that DOX alters normal cardiac histoarchitecture. On the opposite side, DIO pretreatment could ameliorate ECG parameters, suppress IL-1β and enhanceIL-10, promote activity of SOD and repress MDA. Additionally, downregulation of Bax, TNF-α, HIF-1α and upregulation of Bcl-2 have been demonstrated in DIO-pretreated rats. Furthermore, the histopathological examination of cardiac tissues illustrated that DIO had a favorable impact on the protection of heart histoarchitecture. DIO is suggested for protection against acute cardiotoxicity caused by DOX without affecting antitumor activity.

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.

Can rutin ameliorate aluminum phosphide-induced acute cardiac toxicity in adult albino rats?

Current management of rice tablet or aluminium phosphide (AlP) poisoning has remained mostly supportive despite of its fatal outcome and unfortunately no antidote is found yet, therefore, there is a need to search for a treatment that can adequately protect against its toxicity. To the best of our knowledge, there are no studies until now concerning the cardioprotective effect of rutin against AlP cardiac toxicity in rats. For this purpose, this study was carried out to investigate the possible protective effect of rutin against AlP induced cardiotoxicity in rats. Forty male albino rats were randomly divided into four groups. Group I: normal control group was served as untreated rats and received distilled water orally through a gastric tube. Group II: Rutin treated group received a dose of 100 mg/kg rutin dissolved in distilled water and given orally through a gastric tube. Group III: AlP intoxicated rats received AlP oral single sub-lethal dose (2 mg/Kg body weight) dissolved in distilled water and given through a gastric tube. Group IV: AlP intoxicated rats + Rutin treated one hour after receiving AlP in doses as mentioned above. After that we tested the following parameters: ECG changes including HR and ST-segment elevation, serum level of TNF-α, IL-6 and H-FABP (pg/ml), antioxidant and Oxidant parameters in cardiac tissue as GSH, SOD, and MDA, apoptotic factor caspase-3 and histopathological examination of cardiac tissue was also included. The results showed that treatment with rutin caused a significant decrease in heart rate and ST segment elevation, a significant decrease in activity of TNF-α and IL-6 and levels of H-FABP also a significant decrease in the activity of SOD with decreased levels of MDA and caspase-3 level and a significant increase in the level of GSH compared to (AlP) intoxicated group, also histopathological changes induced by AlP improved after treatment with rutin. It is concluded that AlP intoxication caused ECG, biochemical and histopathological changes which were potentially improved with rutin. Â

The ameliorating effect of carotenoid rich fraction extracted from Dunaliella salina microalga against inflammation- associated cardiac dysfunction in obese rats

The carotenoid rich fraction of microalgae Dunaliella salina (crf-DS) have been receiving great attention, due to they abilities to protect and improve various disorders. The objective of this study is to explore the therapeutic efficiency of crf-DS on obesity-assciated cardiac dysfunction in the high-fat diet (HFD) treated rats. These rats were orally administered with crf-DS (150 mg /kg body weight), for six consecutive weeks in comparison with reference drug(orlistat). Specific cardiac biomarkers were examined including; adiponectin, plasminogen activator inhibitor (PAI-1), glucagon, troponin-I (cTnI). The cell adhesion molecules (VCAM and ICAM), C-reactive protein (CRP), collagen type II (Col II), collagen alpha-1 (III) chain (Col3A1), lipoxygenase activity (LOX), as well as histopathological examination of cardiac tissue were investigated. Results indicated a significant reduction(P ≤ 0.05) in adiponectin and glucagon levels in serum of obese rats. However, cTnI, PAI-1, cell adhesion molecules, CRP, Col II, and Col3A1 and LOX levels declared marked increase. Histopathological examination of cardiac tissue showed fibrosis with severe congestion in the myocardial blood vessels. On the other hand, rats medicated with a crf-DS demonstrated noticeable ameliorating effect in all the measured parameters. Beside, myocardial tissue of obese rats showed no alteration. Hence, It could be concluded that, oral supplementation with crf-DS is able to attenuate cardiac dysfunction in obese rats. Further extended work is needed to exploit, the possible application of D. salina as nutraceuticals and food additives.

Cichorium intybus attenuates streptozotocin induced diabetic cardiomyopathy via inhibition of oxidative stress and inflammatory response in rats.

The aim of the present study was to investigate the effects of Cichorium intybus on lipid peroxidation activities of both enzymatic and non-enzymatic antioxidants, inflammatory mediators, myocardial enzymes and histopathology of cardiac tissues in experimental diabetic cardiomyopathy (DCM). DCM was induced by single intraperitoneal injection of streptozotocin (STZ) (40 mg/kg) combined with high energy intake in rats. Seed extract of Cichorium intybus (CIE) (250 mg/kg & 500 mg/kg) was administered orally once a day for 3 weeks. Phytochemical investigations of seed extract revealed presence of some active ingredients such as alkaloids, tannins, saponin, phenols, glycosides, steroids, terpenoids and flavonoids. Seed extract of Cichorium intybus confirmed a significant potency towards restoring the blood glucose, an elevation of the levels of aspartate aminotransferase (AST), lactate dehydrogenase (LDH), superoxide dismutase (SOD), thiobarbituric acid reactive substances (TBARS), blood glutathione (GSH), TNF-α and IL-6 and a reduction in the levels of catalase (CAT) was observed following the STZ treatment. Oxidative stress was accompanied by myocardial degeneration as evidenced by histopathological examination of cardiac tissues. Administration of CIE reduced the lipid peroxides level in heart. Serum levels of AST, GSH, LDH and SOD were brought down to physiological levels by CIE in STZ induced DCM rats. CIE also markedly down-regulated serum TNF-α and IL-6 levels. Catalase that was reduced in serum was brought back to near normal level. The extensive necrotic changes of cardiac tissue by STZ was minimized to normal morphology upon CIE administration. The study demonstrates the cardioprotective effect of CIE via inhibition of oxidative stress and pro-inflammatory cytokines.

Aspernolide F, as a new cardioprotective butyrolactone against doxorubicin-induced cardiotoxicity

Endophytic fungi have known as a promising source of secondary metabolites. γ-Butyrolactones are a class of metabolites reported from Aspergillus genus, which attracted much attention for their bioactivities. This study aimed to assess the potential cardioprotective effects of aspernolide F (AF) separated from the endophytic fungus A. terreus against doxorubicin (DOX)-induced cardiotoxic effects in rats. Animals were treated with two different doses of AF for 10 days prior to DOX injection. Electrocardiographic (ECG), biochemical, histopathological and immunohistochemical analyses were performed. Results have shown that AF effectively protected against DOX-induced cardiac damage as AF counteracted DOX-induced ECG abnormalities and attenuated serum markers of cardiotoxicity (creatine kinase-MB, lactate dehydrogenase, troponin I, and troponin T). Histopathological examination of cardiac tissue revealed a remarkable improvement in DOX-induced lesions. In addition, AF ameliorated DOX-induced oxidative damage and increased the levels of antioxidants in cardiac tissues. AF treatment inhibited the activation of nuclear factor-κB (NF-κB) and decreased the immuno-expression of NF-κB in cardiac tissue. Furthermore, AF caused a marked lowering in the level of inflammatory cytokines (nitric oxide, tumor necrosis factor-α, and interleukin-6) in the cardiac tissue. Collectively, this study demonstrates the cardioprotective activity of AF against DOX-induced cardiac damage which may be due to its antioxidant and anti-inflammatory activities.

Effects of Abscisic Acid on the Diabetic Changes in Rat Myocardium

The present study aims to find out the possible protective effect of abscisic acid (ABA) on the development of diabetic cardiomyopathy (DCM) in type 2 diabetic rats. Materials and methods: Fifty male rats divided into: normal control group, diabetic group and three diabetic treated groups with either pioglitazone, or ABA, or both pioglitazone and ABA for 16 weeks. At the end of experiment, ECG was recorded, biochemical measurement of serum glucose, insulin, lipid profile, troponin I, creatine kinase MB (CK-MB), Lactate dehydrogenase (LDH), interleukin-1 beta (IL-1β) and tumor necrosis factor- alpha (TNF-α) was done, caspase 3 and 9 activity in heart, RT- PCR for connexin-43(Cx43) and histopathological examination of cardiac tissue. Results: Treatment with ABA exerted positive effects on blood glucose and insulin levels that found to be reflected on heart weight/body weight ratio in diabetic rats. Also, it exerted significant improvement in cardiac markers and pro-inflammatory cytokines. DCM is associated with increased myocyte cell death that indicated by increasing caspase 3 and 9 that improved significantly by ABA. Also, results indicated that myocardial Cx43 mRNA levels were lesser in diabetic versus non-diabetic rats. Cx43 deterioration in diabetics may be behind the prolongation of the QRS and QTc, that improved by ABA. The histopathological findings showed that ABA improved diabetic cardiomyocyte necrosis and fibrosis. Conclusion: The diabetic rats benefit from ABA intake due to its hypoglycemic, anti-inflammatory and anti-apoptotic effects. So, intake of ABA in combination with anti-diabetic drugs may be beneficial for the management of type 2 diabetes mellitus.

Cardioprotective effect of Pycnogenol in ischemic-reperfusion injury (IRI) in rats.

Oxidative stress plays a critical task in the biochemical and pathological alteration linked with myocardial ischemic-reperfusion injury (IRI). This warrants identifying agents with a potential for preventing such damage in an effective way. A novel plant based product, Pycnogenol, obtained from the French maritime pine (Pinus pinaster ssp. atlantica) bark extract was known for its tremendous antioxidant potential (both in vivo, in vitro). It was able to attenuate the symptoms of immune dysfunction through restoring a cellular antioxidant status in low micronutrient-induced immune deficient mice. Consequently, the present study was deals with the determination of protective effect of Pycnogenol in ischemic-reperfusion injury (IRI) in rats via Non-recirculating Langendorff's technique. The effect of Pycnogenol on the level of various key biomarkers in the rat heart homogenate was determined, such as, myocardial thiobarbituric acid reactive substances (TBARS, a marker of lipid peroxidation), lactic dehydrogenase (LDH) (a marker of tissue injury) and effect on endogenous antioxidants, e.g., superoxide dismutase (SOD), catalase (CAT), glutathione (GSH) and glutathione peroxidase (GPx). The activity of these biomarkers appreciably improved in Pycnogenol-treated group than IRI group (P < 0.05). The effect of Pycnogenol was further confirmed via histopathological examination of cardiac tissues, which suggests that, it considerably improved the injury related to tissue damage through suppression of edema and infiltration of neutrophil compared to IRI group. It also showed modulation of the expression of apoptotic factors, e.g. Bcl-2, bax and caspase-9 as confirmed by western blot analysis.

Gene expression analysis during recovery process indicates the mechanism for innate immune injury and repair from Coxsackievirus B3-induced myocarditis

To investigate the innate immune injury and repair mechanism during recovery from Coxsackievirus B3 (CVB3) induced myocarditis, we established an acute viral myocarditis recovery model by infecting BALB/c mice with CVB3. Histopathological examination of cardiac tissues after infection showed a gradual increase of myocardial injury to the maximum degree at 8dpi (days post infection), followed by a recovery process with reduced viral replication. We also measured expression changes of innate immune genes in heart after 4, 8 and 12 days of infection using innate immune real-time PCR array. The results showed expression alterations in many Pattern Recognition Receptors (PRRs) genes upon CVB3 infection, which activated multiple important signaling pathways during recovery process. The expression of TLRs, RLRs, PKR and cytokines were strongly induced and reached the peak at 4dpi in early myocarditis stage, followed by a gradual reduction in recovery stage, during which the levels were even lower than normal at 12dpi. The strong correlation between cardiac histopathology score and chemokine expression level suggested that the chemokines might play a role in pathological changes during early myocarditis stage. In addition, we also found that both cell survival signaling pathways (AKT1, p38MAPK) and antiviral signaling pathways (IKKα/β/ε) were activated and promoted the recovery during late myocarditis stage. Altogether, our observations improved the understanding of formation and progression of the pathological lesions, as well as the repair mechanism for acute viral myocarditis.

Transcriptome profiling of immune responses to cardiomyopathy syndrome (CMS) in Atlantic salmon

BackgroundCardiomyopathy syndrome (CMS) is a disease associated with severe myocarditis primarily in adult farmed Atlantic salmon (Salmo salar L.), caused by a double-stranded RNA virus named piscine myocarditis virus (PMCV) with structural similarities to the Totiviridae family. Here we present the first characterisation of host immune responses to CMS assessed by microarray transcriptome profiling.ResultsUnvaccinated farmed Atlantic salmon post-smolts were infected by intraperitoneal injection of PMCV and developed cardiac pathology consistent with CMS. From analysis of heart samples at several time points and different tissues at early and clinical stages by oligonucleotide microarrays (SIQ2.0 chip), six gene sets representing a broad range of immune responses were identified, showing significant temporal and spatial regulation. Histopathological examination of cardiac tissue showed myocardial lesions from 6 weeks post infection (wpi) that peaked at 8-9 wpi and was followed by a recovery. Viral RNA was detected in all organs from 4 wpi suggesting a broad tissue tropism. High correlation between viral load and cardiac histopathology score suggested that cytopathic effect of infection was a major determinant of the myocardial changes. Strong and systemic induction of antiviral and IFN-dependent genes from 2 wpi that levelled off during infection, was followed by a biphasic activation of pathways for B cells and MHC antigen presentation, both peaking at clinical pathology. This was preceded by a distinct cardiac activation of complement at 6 wpi, suggesting a complement-dependent activation of humoral Ab-responses. Peak of cardiac pathology and viral load coincided with cardiac-specific upregulation of T cell response genes and splenic induction of complement genes. Preceding the reduction in viral load and pathology, these responses were probably important for viral clearance and recovery.ConclusionsBy comparative analysis of gene expression, histology and viral load, the temporal and spatial regulation of immune responses were characterised and novel immune genes identified, ultimately leading to a more complete understanding of host-virus responses and pathology and protection in Atlantic salmon during CMS.

Cardiotoxic effects of arsenic trioxide/imatinib mesilate combination in rats

Cardiotoxicity is an important consideration in the evaluation of cancer chemotherapy, because chemotherapy-induced myocardial damage might be irreversible and lethal. This in-vivo study investigated the cardiotoxicity of either arsenic trioxide or imatinib mesilate, or a combination of both drugs, following repeated administration in male Wistar rats. Both arsenic trioxide and imatinib mesilate were administered daily at a dose of 5 mg kg(-1) intraperitoneally and 30 mg kg(-1) orally for 10 days, respectively. Cardiotoxicity was evaluated by biochemical and histopathological examination 48 h after the last dose. Treatment with either arsenic or imatinib, or both, resulted in significant increases in serum creatine kinase isoenzyme (CK-MB), glutathione peroxidase (GPx), lactate dehydrogenase (LDH) and aspartate aminotransferase (AST) activity levels. Cardiac tissue of rats treated with arsenic showed significant increases in levels of reduced glutathione (GSH) content, GPx activity, malondialdehyde (MDA) and total nitrate/nitrite (NOx), whereas imatinib treatment significantly increased cardiac GSH content and MDA production level and decreased GPx activity level and NOx content. A combination of arsenic and imatinib produced significant increases in cardiac GSH content, GPx activity and MDA production levels, in addition to a reduction in NOx content. Combination arsenic/imatinib treatment extensively increased GPx activity and MDA production levels compared with imatinib treatment alone. Moreover, rats treated with arsenic or imatinib, or both, showed a significant increase in serum bilirubin, creatinine and urea levels. Histopathological examination of cardiac tissue of the combination-treated group revealed fibroblastic proliferation, myocardial disorganization and myocardial necrosis. Liver peroxidative alterations revealed that treatment with either arsenic or imatinib, or the two combined, increased levels of reduced-GSH and MDA production levels. However, imatinib treatment depleted liver GPx activity level contrary to treatment with the combination. Rats treated with arsenic alone or arsenic/imatinib combination showed significant elevation in liver NOx. In conclusion, both arsenic trioxide and imatinib mesilate might have significant cardiotoxicity and cardiac function should be monitored during treatment with them alone or in combination, as well as in the presence of pre-existing cardiac dysfunction.

Propionyl- l-carnitine prevents the progression of cisplatin-induced cardiomyopathy in a carnitine-depleted rat model

This study has been initiated to investigate whether endogenous carnitine depletion and/or carnitine deficiency is a risk factor during development of cisplatin (CDDP)-induced cardiomyopathy and if so, whether carnitine supplementation by propionyl- l-carnitine (PLC) could offer protection against this toxicity. To achieve the ultimate goal of this study, a total of 60 adult male Wistar albino rats were divided into six groups. The first three groups were injected intraperitoneally with normal saline, PLC (500 mg kg −1), and d-carnitine (500 mg kg −1) respectively, for 10 successive days. The 4th, 5th, and 6th groups were injected intraperitoneally with the same doses of normal saline, PLC and d-carnitine, respectively, for 5 successive days before and after a single dose of CDDP (7 mg kg −1). On day 6 after CDDP treatment, animals were sacrificed, serum as well as hearts were isolated and analyzed. CDDP resulted in a significant increase in serum creatine phosphokinase isoenzyme (CK-MB) and lactate dehydrogenase (LDH), thiobarbituric acid reactive substances (TBARS) and total nitrate/nitrite (NO( x)) and a significant decrease in reduced glutathione (GSH), total carnitine, and adenosine triphosphate (ATP) content in cardiac tissues. In the carnitine-depleted rat model, CDDP induced dramatic increase in serum cardiomyopathy enzymatic indices, CK-MB and LDH, as well as progressive reduction in total carnitine and ATP content in cardiac tissue. Interestingly, PLC supplementation resulted in a complete reversal of the increase in cardiac enzymes, TBARS and NO x , and the decrease in total carnitine, GSH and ATP, induced by CDDP, to the control values. Moreover, histopathological examination of cardiac tissues confirmed the biochemical data, where PLC prevents CDDP-induced cardiac degenerative changes while d-carnitine aggravated CDDP-induced cardiac tissue damage. In conclusion, data from this study suggest for the first time that carnitine deficiency and oxidative stress are risk factors and should be viewed as mechanisms during development of CDDP-related cardiomyopathy and that carnitine supplementation, using PLC, prevents the progression of CDDP-induced cardiotoxicity.