Dynamic and Assembly Characteristics of Deep-Cavity Basket Acting as a Host for Inclusion Complexation of Mitoxantrone in Biotic and Abiotic Systems.

We describe the preparation, dynamic, assembly characteristics of vase-shaped basket 13- along with its ability to form an inclusion complex with anticancer drug mitoxantrone in abiotic and biotic systems. This novel cavitand has a deep nonpolar pocket consisting of three naphthalimide sides fused to a bicyclic platform at the bottom while carrying polar glycines at the top. The results of 1 H Nuclear Magnetic Resonance (NMR), 1 H NMR Chemical Exchange Saturation Transfer (CEST), Calorimetry, Hybrid Replica Exchange Molecular Dynamics (REMD), and Microcrystal Electron Diffraction (MicroED) measurements are in line with 1 forming dimer [12 ]6- , to be in equilibrium with monomers 1(R) 3- (relaxed) and 1(S) 3- (squeezed). Through simultaneous line-shape analysis of 1 H NMR data, kinetic and thermodynamic parameters characterizing these equilibria were quantified. Basket 1(R) 3- includes anticancer drug mitoxantrone (MTO2+ ) in its pocket to give stable binary complex [MTO⊂1]- (Kd =2.1 µM) that can be precipitated in vitro with UV light or pH as stimuli. Both in vitro and in vivo studies showed that the basket is nontoxic, while at a higher proportion with respect to MTO it reduced its cytotoxicity in vitro. With well-characterized internal dynamics and dimerization, the ability to include mitoxantrone, and biocompatibility, the stage is set to develop sequestering agents from deep-cavity baskets.

Sacubitril/valsartan reverses cardiac structure and function in experimental model of hypertension-induced hypertrophic cardiomyopathy.

This study evaluated the effect of sacubtril/valsartan on cardiac remodeling, molecular and cellular adaptations in experimental (rat) model of hypertension-induced hypertrophic cardiomyopathy. Thirty Wistar Kyoto rats, 10 healthy (control) and 20 rats with confirmed hypertension-induced hypertrophic cardiomyopathy (HpCM), were used for this study. The HpCM group was further subdivided into untreated and sacubitril/valsartan-treated groups. Myocardial structure and function were assessed using echocardiography, Langendorff's isolated heart experiment, blood sampling and qualitative polymerase chain reaction. Echocardiographic examinations revealed protective effects of sacubitril/valsartan by improving left ventricular internal diameter in systole and diastole and fractional shortening. Additionally, sacubitril/valsartan treatment decreased systolic and diastolic blood pressures in comparison with untreated hypertensive rats. Moreover, sacubitril/valsartan treatment reduced oxidative stress and apoptosis (reduced expression of Bax and Cas9 genes) compared to untreated rats. There was a regular histomorphology of cardiomyocytes, interstitium, and blood vessels in treated rats compared to untreated HpCM rats which expressed hypertrophic cardiomyocytes, with polymorphic nuclei, prominent nucleoli and moderately dilated interstitium. In experimental model of hypertension-induced hypertrophic cardiomyopathy, sacubitril/valsartan treatment led to improved cardiac structure, haemodynamic performance, and reduced oxidative stress and apoptosis. Sacubitril/valsartan thus presents as a potential therapeutic strategy resulted in hypertension-induced hypertrophic cardiomyopathy.

Porphyromonas gingivalis induces cardiovascular dysfunction.

Porphyromonas gingivalis (P. gingivalis) is one of the most responsible periodontopathogenic bacteria in the development of periodontal disease (PD); however, its role in the development of other diseases still needs to be understood, specially its implications in the causation of cardiovascular pathogenesis. The aim of this study is to determine whether there is a direct association between P. gingivalis-induced PD with that of the development of cardiovascular disease, and whether a long-term administration of probiotic(s) could help improve the cardiovascular disease outcome. To test this hypothesis, we employed four different experimental groups of mice, designated as: Group I: Wild-type (WT) mice (C57BL/6J); Group II: Lactobacillus rhamnosus GG (LGG) (WT mice treated with a probiotic; LGG), Group III: PD (WT mice treated with P. gingivalis), and Group IV: PD + LGG (WT mice treated with P. gingivalis and LGG). PD was created by injecting 2 µL (i.e., 20 µg) of P. gingivalis lipopolysaccharide (LPS) intragingivally between the 1st and 2nd mandibular molars, two times a week for a total period of 6 weeks. The PD (LGG) intervention was done orally employing 2.5 × 105 CFU/day for a continuous period of 12 weeks. Immediately before the mice were sacrificed, echocardiography of the heart was performed, and after sacrifice, we collected serum samples, hearts, and the periodontal tissue. Histological assessment, cytokine analysis, and zymography of the cardiac tissue were performed. Results revealed inflammation of the heart muscle in the PD group that was marked by infiltration of neutrophils and monocytes, followed by fibrosis. Cytokine analysis of the mice sera revealed significantly elevated levels of tumor necrosis factor-α, IL-1ß, IL-6, and IL-17A in the PD group along with LPS-binding protein, and CD14. Most importantly, we observed elevated levels of P. gingivalis mRNAs in the heart tissues of PD mice. Zymographic analysis demonstrated matrix remodeling as revealed by increasing content of MMP-9 in the heart tissues of PD mice. Interestingly, LGG treatment was able to mitigate most of the pathological effects. The findings suggest that P. gingivalis could lead to cardiovascular system disorder and that probiotic intervention could alleviate, and most likely prevent bacteremia and its harmful effect(s) on the cardiovascular function.

Creatine phosphate administration in cardiac ischemia-reperfusion injury in rats: focus on differences between preconditioning, perconditioning, and postconditioning protocols.

The aim of this study was to examine and compare the influence of preconditioning, perconditioning, and postconditioning with creatine phosphate (PCr) on functional recovery and production of prooxidants in isolated rat hearts subjected to ex vivo ischemic-reperfusion (I-R) injury on a Langendorff apparatus. Wistar albino rats (male, n = 40) were divided into four groups: control and groups in which PCr (0.5 mmol/L, 5 min) was perfused before (Pre group), after (Post group), or during (Per group) ex vivo induced ischemia. PCr application was associated with the great benefits of preserving cardiac contractility (in Pre group 100.96% for +(dP/dt max) and 97.61% for -(dP/dt max), in Per group 96.72% for +(dP/dt max) and 95.60% for -(dP/dt max), and in Post group 143.84% for +(dP/dt max) and 104.36% for -(dP/dt max) in relation to the stabilization). In addition, PCr application prevented the increase in prooxidative markers during I-R injury in all therapeutic modalities. The most intensive benefits in the current investigation were observed when PCr was applied during the period of ischemia because the lowest fluctuations in the parameters of cardiac function and oxidative stress were observed. Overall, the results of this study highlight PCr-induced cardioprotection with promising prospects for future clinical use.

Dipeptidyl peptidase-4 inhibitors as new tools for cardioprotection.

Previous studies have demonstrated that individuals with type 2 diabetes mellitus (T2DM) have a two- to fourfold propensity to develop cardiovascular disease (CVD) than nondiabetic population, making CVD a major cause of death and disability among people with T2DM. The present treatment options for management of diabetes propose the earlier and more frequent use of new antidiabetic drugs that could control hyperglycaemia and reduce the risk of cardiovascular events. Findings from basic and clinical studies pointed out DPP-4 inhibitors as potentially novel pharmacological tools for cardioprotection. There is a growing body of evidence suggesting that these drugs have ability to protect the heart against acute ischaemia-reperfusion injury as well as reduce the size of infarction. Consequently, the prevention of degradation of the incretin hormones by the use of DPP-4 inhibitors represents a new strategy in the treatment of patients with T2DM and reduction of CV events in these patients. Here, we discuss the cardioprotective effects of DPP-4 inhibitors as well as proposed pathways that these hypoglycaemic agents target in the cardiovascular system.

Dipeptidyl peptidase 4 inhibitors attenuate cardiac ischaemia-reperfusion injury in rats with diabetes mellitus type 2.

The aim of our study was to assess and compare the effects of dipeptidyl peptidase 4 (DPP4) inhibitors, saxagliptin and sitagliptin, on metabolic control of disease and cardiac function in rats with diabetes mellitus type 2 (T2DM). This research would provide novel understanding into the potentially protective effects of DPP4 inhibitors in helping salvage of the heart exposed to ischaemia-reperfusion (I-R) injury. Forty-eight Wistar albino rats were randomly divided into four groups: CTRL, Control healthy group; T2DM, rats with T2DM; T2DM + Sit, rats with T2DM treated with 0.6 mg/kg of sitagliptin; T2DM + Sax, rats with T2DM treated with 0.45 mg/kg of saxagliptin for 3 weeks. At the end of the protocol, in vivo cardiac function was assessed by echocardiography, while in the blood samples glucose and insulin were determined. Additionally, ex vivo heart function was estimated on a model of I-R injury using Langendorff apparatus. Immunohistochemical analysis was used to determine the degree of myocardial apoptosis and necrosis, while DPP4 staining was performed to assess the cardiac DPP4 expression. Data were analyzed using a one-way analysis of variance (ANOVA) and the post hoc Bonferroni test for multiple comparisons. Improved glycoregulation was noticed in rats that received DPP4 inhibitors compared to untreated diabetic rats (P < .05). Moreover, better in vivo systolic function was observed in rats treated with both DPP4 inhibitors as evidenced by an increase in fractional shortening when compared to T2DM (P < .05). Most parameters of cardiac function in treated rats remained unaltered during reperfusion, thus suggesting that both drugs protected myocardium during flow restoration. Better effects on coronary circulation were achieved after sitagliptin application. Additionally, both DPP4 inhibitors showed similar potential to attenuate cardiac necrosis and apoptosis. Saxagliptin and sitagliptin might be efficient in preserving myocardial function and morphology in ex vivo induced I-R cardiac injury in rats with T2DM.

Neuroinflammation in Autism and Supplementation Based on Omega-3 Polyunsaturated Fatty Acids: A Narrative Review.

Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder characterized by persistent deficits in social communication and social interaction across multiple contexts and restricted, repetitive patterns of behavior, interests and activities. The maternal status of polyunsaturated fatty acids (PUFA) regulates microglial activity and neuroinflammatory pathways during a child's brain development. In children with ASD, the metabolism of PUFA is thought to be deficient or abnormal, leading to increased production of proinflammatory cytokines, increased oxidative stress and an imbalance in the formation and action of neurotransmitters. In addition, nutritional deficits in omega-3 PUFA may affect gut microbiota and contribute to ASD by the gut-brain axis. The aim of this study was to review the possible role of neuroinflammation in ASD development and the effect of omega-3 PUFA supplementation in children with ASD. Due to a wide heterogeneity across RCTs, no definitive conclusion about omega-3 PUFA effects in ASD can be drawn. Supplementation with PUFA could be considered as one of the aspects in regulating the biological status of the organism and could provide added value to standard medical and psychological interventions for reducing behavioral deficits.

Cardioprotective effects of high-intensity interval training are mediated through microRNA regulation of mitochondrial and oxidative stress pathways.

Human studies have shown high-intensity interval training (HIIT) has beneficial cardiovascular effects and is typically more time-efficient compared with traditional endurance exercise. The main goal of this study is to show the potential molecular and functional cardiovascular benefits of HIIT compared with endurance training (ET). Three groups of mice were used including sedentary-control, ET mice, and HIIT mice groups. Results indicated ejection fraction was increased in HIIT compared with ET while fractional shortening was increased in the HIIT group compared with both groups. Blood flow of the abdominal aorta was increased in both exercise groups compared with control. Increases in cross-sectional area and mitochondrial and antioxidative markers in HIIT compared with control were observed, along with several microRNAs. These findings indicate HIIT has specific cardiac-protective effects and may be a viable alternative to traditional ET as a cardiovascular preventative medicine intervention.

The impact of low mineral content water on cardiac function in diabetic rats: focus on oxidative stress.

The aim of this study was to estimate the effects of natural low mineral water from the source "Sneznik-1/79" in Serbia on glycemia as well as heart function in rats with diabetes mellitus type 2 (T2DM), with the special emphasis on the role of the oxidative stress. Twenty Wistar albino rats (males, 4 weeks old at the beginning of the study, body weight 180 ± 20 g) were included in the study. Rats were divided randomly into 2 groups (10 animals per group): T2DM: rats with diabetes mellitus type 2 with free access to tap water; T2DM + SW: rats with diabetes mellitus type with free access to natural mineral water from "Sneznik-1/79". Glucose level, ex vivo cardiac function as well as systemic and cardiac redox state were assessed. At the end of the study protocol, glucose level was lower in diabetic rats who consumed mineral water. Moreover cardiac function wasn't affected by mineral water intake, however, significant antioxidant effects were observed. Our study suggests that 4-week consumption of low mineral water from the spring "Sneznik-1/79" has important role in regulation of glycemia and altering redox state in favor of elevated antioxidant capacity without affecting heart function. Based on our findings we may assume that low mineral water from the spring "Sneznik-1/79" has the potential to be used either as preventive strategy or as additional therapeutic strategy in management of T2DM.

Garlic Derived Diallyl Trisulfide in Experimental Metabolic Syndrome: Metabolic Effects and Cardioprotective Role.

This study aimed to examine the effects of diallyl trisulfide (DATS), the most potent polysulfide derived from garlic, on metabolic syndrome and myocardial function in rats with metabolic syndrome (MetS). For that purpose, we used 36 male Wistar albino rats divided into control rats, rats with MetS and MetS rats treated with 40 mg/kg of DATS every second day for 3 weeks. In the first part, we studied the impact of DATS on MetS control and found that DATS significantly raised H2S, decreased homocysteine and glucose levels and enhanced lipid and antioxidative, while reducing prooxidative parameters. Additionally, this polysulfide improved cardiac function. In the second part, we investigated the impact of DATS on ex vivo induced ischemia/reperfusion (I/R) heart injury and found that DATS consumption significantly improved cardiodynamic parameters and prevented oxidative and histo-architectural variation in the heart. In addition, DATS significantly increased relative gene expression of eNOS, SOD-1 and -2, Bcl-2 and decreased relative gene expression of NF-κB, IL-17A, Bax, and caspases-3 and -9. Taken together, the data show that DATS can effectively mitigate MetS and have protective effects against ex vivo induced myocardial I/R injury in MetS rat.

TFAM overexpression diminishes skeletal muscle atrophy after hindlimb suspension in mice.

The present study aims to investigate if overexpressing the mitochondrial transcription factor A (TFAM) gene in a transgenic mouse model diminishes soleus and gastrocnemius atrophy occurring during hindlimb suspension (HLS). Additionally, we aim to observe if combining exercise training in TFAM transgenic mice prior to HLS has a synergistic effect in preventing skeletal muscle atrophy. Male C57BL/6J-based transgenic mice (12-14 weeks old) overexpressing TFAM were assigned to a control (T-Control), 7-day HLS (T-HLS), and 2-week exercise training prior to 7-day HLS (T-Ex + HLS) groups. These groups were compared to male C57BL/6J wild-type (WT) mice (12-14 weeks old) assigned to Control, 7-day HLS (HLS), 2-week exercise training prior to 7-day HLS (Ex + HLS), and 2-week exercise training (Ex). Overexpressing TFAM results in a decrease of 8.3% in soleus and 2.6% in gastrocnemius muscle weight to bodyweight ratio after only HLS compared to wild-type mice incurring a loss of 27.1% in soleus and 21.5% in gastrocnemius muscle after HLS. Our data indicates TFAM may play a critical role in protecting skeletal muscle from disuse atrophy and is correlated with increased expression of antioxidants (SOD-2) and potential redox balance. TFAM may be an attractive molecule of interest for potential, future therapeutic development. NEW AND NOTEWORTHY: To the best of our knowledge, this is the first time a TFAM overexpression transgenic mouse model is being used in the analysis of disuse-induced skeletal muscle atrophy. Here we provide evidence of a potential role for TFAM in diminishing skeletal muscle atrophy.

Exosomes: cell-created drug delivery systems.

Exosomes are 40- to 100- nm cell-originated vesicles derived from endocytic compartments that are released into almost all biological fluids. Exosomes are cell-created vesicles that inherit identical phospholipid membrane, explaining a wide application of electroporation as a technique for exosomes loading with exogenous cargoes. Another way of loading exosomes with therapeutic cargo is to overexpress a certain gene in exosome-donor cells or treat cell line with drug of interest that later will be gently enveloped into vesicles based on the process of EV biogenesis. Similarly, to visualize siRNA loading into exosomes as well as the exosomal product delivery to recipient cells, we have conducted an experiment where chemical-based exosome transfection was used. In this review, we discuss different ways of extracellular vesicle loading with exogenous cargoes and their advantages/limitations as well as novel alternative techniques of substance incorporation into nanoparticles.

The impact of aerobic and anaerobic training regimes on blood pressure in normotensive and hypertensive rats: focus on redox changes.

This study was aimed to assess the impact of aerobic and anaerobic type of exercise on blood pressure and redox status in normotensive and hypertensive rats. After 1 week of preconditioning feeding and 1 week of preconditioning running regimen, Wistar albino rats (n = 72; bw: 270 ± 50 g) were randomly assigned to three groups according to running protocol (high-intensity interval training (HIIT) or moderate-intensity training (MIT)): sedentary control, MIT, HIIT; spontaneous hypertensive sedentary control (SHR), SHR + MIT and SHR + HIIT. Blood pressure (BP) measurement was performed by a tail-cuff noninvasive method BP system. After 48 h of rest following the final training, the rats were fasted for 24 h and sacrificed under ketamine/xylazine anesthesia and blood samples were collected. The level of the next prooxidants were measured: superoxide anion radical (O2-); hydrogen peroxide (H2O2); nitrite level (NO2-) and index of lipid peroxidation (thiobarbituric acid reactive substances), and the activity of antioxidative enzymes: reduced glutathione (GSH) superoxide dismutase (SOD) and catalase (CAT) activity. After the last week of running, HIIT strongly affected SP, DP, and HR in SHR rats compared to other hypertensive rats, as well as after MIT in normotensive conditions. We have found that HIIT training protocol induced a higher increase of O2- and H2O2 as compared to MIT. Findings of the present study pointed out that contrary to normotensive conditions, in hypertensive conditions both training regimes reduced the BP levels, which was more prominent in case of HIIT. In addition, MIT seems to be connected with milder disturbance of pro-oxidant production and better antioxidant response.

Effects of different dietary regimes alone or in combination with standardized Aronia melanocarpa extract supplementation on lipid and fatty acids profiles in rats.

This study investigated different dietary strategies, high-fat (HFd), or standard diet (Sd) alone or in combination with standardized Aronia melanocarpa extract (SAE), as a polyphenol-rich diet, and their effects on lipids and fatty acids (FA) in rats with metabolic syndrome (MetS). Wistar albino rats were randomly divided into two groups: healthy and rats with MetS, and then depending on dietary patterns on six groups: healthy rats fed with Sd, healthy rats fed with Sd and SAE, rats with MetS fed with HFd, rats with MetS fed with HFd and SAE, rats with MetS fed with Sd, and rats with MetS fed with Sd and SAE. 4 weeks later, after an overnight fast (12-14 h), blood for determination of total cholesterol (TC), triglycerides (TG), high-density lipoprotein (HDL), low-density lipoprotein (LDL), index of lipid peroxidation (measured as TBARS), and FA was collected. Increased FA and lipid concentration found in MetS rats were reduced when changing dietary habits from HFd to Sd with or without SAE consumption. Consumption of SAE slightly affects the FA profiles, mostly palmitoleic acid in healthy rats and PUFA in MetS + HFd rats. Nevertheless, in a high-fat diet, SAE supplementation significantly decreases n-6/n-3 ratio, thereby decreasing systemic inflammation. Further researches are warranted to confirm these effects in humans.

The cardioprotective effects of diallyl trisulfide on diabetic rats with ex vivo induced ischemia/reperfusion injury.

Diallyl trisulfide (DATS) is distinguished as the most potent polysulfide isolated from garlic. The aim of our study was to investigate effects of oral administration of DATS on healthy and diabetic rats, with special attention on heart function. Rats were randomly divided into four groups: CTRL (healthy rats), DATS (healthy rats treated with DATS), DM (diabetic rats), DM + DATS (diabetic rats treated with DATS). DATS (40 mg/kg of body weight) was administered every other day for 3 weeks, at the end of which rats underwent echocardiography, glycemic measurement and redox status assessment. Isolated rat hearts were subjected to 30 min global ischemia and 60 min reperfusion, after which heart tissue was counterstain with hematoxylin and eosin and cardiac Troponin T staining (cTnT), while expression of Bax, B cell lymphoma 2 (Bcl-2), caspase-3, caspase-9 and superoxide dismutase-2 were examined in the left ventricle. DATS treatment significantly reduced blood glucose levels of diabetic rats, and improved cardiac function recovery, diminished oxidation status, attenuated cardiac remodeling and inhibited myocardial apoptosis in healthy and diabetic rats. DATS treatment causes promising cardioprotective effects on ex vivo-induced ischemia/reperfusion (I/R) injury in diabetic and healthy rat heart probably mediated by inhibited myocardial apoptosis. Moreover, appropriate DATS consumption may provide potential co-therapy or prevention of hyperglycemia and various cardiac complications in rats with DM.

The impact of high-intensity interval training and moderate-intensity continuous training regimes on cardiodynamic parameters in isolated heart of normotensive and hypertensive rats.

This study aimed to assess the impact of high-intensity interval training (HIIT) vs. moderate-intensity continuous training (MIT) on cardiodynamic parameters in isolated rat heart. Wistar albino rats were randomly assigned to groups according to running protocol: sedentary control, MIT, and HIIT; spontaneous hypertensive rat (SHR) sedentary control, SHR + MIT, and SHR + HIIT. HIIT groups performed the running in 5 sprints × 45-55 m/min for 30-90 s, with 2 min of rest after each sprint, while MIT groups performed the running of 10-15 m/min for 1 h with 3 min of rest every 100 m; both protocols were implemented 5 days/week over 4 weeks with 1 week of adaptation before protocols started. Isolated rat hearts were perfused according to Langendorff technique at gradually increased coronary perfusion pressures (40-120 cmH2O). Using a sensor placed in the left ventricle, we registered maximum and minimum rate of pressure development in the left ventricle, systolic and diastolic left ventricular pressure, and heart rate. Coronary flow was measured flowmetrically. MIT was connected with cardiac depression in normotensive conditions, while HIIT leads to cardiac depression in hypertensive rats. HIIT induced more significant increase of contractile and relaxation parameters of the isolated rat heart, especially in hypertensive animals.

Cisplatin and cisplatin analogues perfusion through isolated rat heart: the effects of acute application on oxidative stress biomarkers.

Drug-induced oxidative stress can occur in numerous tissues and organ systems (liver, kidney, ear, nervous system, and cardiovascular system). Cancer therapy with cisplatin is associated with side effects to which oxidative stress may contribute. We have compared the influences of cisplatin (reference compound) and its' analogues (dichloro(1,2-diaminocyclohexane)platinum(II) and chloro(2,2':6',2″-terpyridine)platinum(II)) in a model of isolated rat heart using the Langendorff technique. The production of oxidative stress biomarkers, antioxidant enzymes, myocardial damage, and expression of Bax, OH-1, and SODs were studied. Cisplatin and the analogues were perfused at concentration of 10-6 and 10-5 M during 30 min. The results of this study showed that examined platinum complexes had different ability to induce oxidative stress of isolated perfused rat heart. Varying the carrier ligands, such as 1,2-diaminocyclohexane and 2,2':6',2″-terpyridine, related to amino ligands (cisplatin) directly influenced the strength to induce production of oxidative stress biomarkers. Introducing 2,2':6',2″-terpyridine ligands provoked the smallest changes in antioxidant enzymes activity, lipid peroxidation, and expression of heme oxygenase-1, that undoubtedly indicated that this complex had the lowest impact on redox status in heart tissue. These findings may be useful in synthesis of novel platinum analogues with lower potential for oxidative stress induction. However, the fact that platinum complexes could induce toxic effects in the heart by other mechanisms should be taken into the consideration.

Efficiency of atorvastatin and simvastatin in improving cardiac function during the different degrees of hyperhomocysteinemia.

The aim of this study was to assess the impact of atorvastatin and simvastatin on myocardial contractility during the different degrees of hyperhomocysteinemia (HHcy) in rats. Study was conducted on adult male Wistar albino rats (n = 90; 4 weeks old; 100 ± 15 g body mass) in which HHcy was achieved by dietary manipulation. Animals were exposed to pharmacology treatment with atorvastatin in dose of 3 mg/kg per day i.p. or simvastatin in dose of 5 mg/kg per day i.p. at the same time every day, according to equivalent therapeutic doses of these statins (10 mg atorvastatin = 20 mg simvastatin). After the dietary manipulation and pharmacological treatment and confirmation of HHcy, all animals were sacrificed, hearts were isolated, and cardiac function was tested according to the Langendorff technique. Size of recovery of maximum rate of left ventricular development (dp/dtmax), minimum rate of left ventricular development (dp/dtmin), systolic left ventricular development, diastolic left ventricular development, heart rate, and coronary flow at the 40, 60, 80, 100, and 120 cmH2O coronary perfusion pressure were measured in state of physiological condition (homocysteine less than 15 µmol/L), mild HHcy, and moderate HHcy. Atorvastatin treatment significantly attenuated homocysteine-induced impairment of myocyte contractility and dominantly decreased dp/dtmax, dp/dtmin, and heart rate and induced greater changes in systolic left ventricular development compared with simvastatin. Treatment with atorvastatin seems able to revert systolic abnormalities and improve contractility during the different degrees of HHcy.

Vitamin B complex mitigates cardiac dysfunction in high-methionine diet-induced hyperhomocysteinemia.

This research is designed to test the hypothesis that elevated homocysteine (Hcy) levels in vivo, caused by a deficit in vitamin B complex, promote changes in cardiac function and redox status that lead to heart failure. In order to conduct the study, we used adult male Wistar albino rats (n = 30; 4 weeks old; 100 ± 15 g body weight). Hyperhomocysteinaemia (HHcy) in these animals was achieved by dietary manipulation. For 4 weeks, the animals were fed with a standard rodent chow (control, CF), a diet enriched in methionine with no deficiency in B vitamins (i.e., folic acid, B6 and B12) (HMNV) or a diet enriched in methionine and deficient in B vitamins (HMLV). After 28 days of dietary manipulation, all animals were killed. The rat hearts were isolated and retrogradely perfused according to the Langendorff technique at a gradually increasing perfusion pressure. We found a negative correlation between elevated serum Hcy and total body and heart weight. The maximum rate of left ventricular pressure development was significantly increased in the HMNV group compared with in the other groups. Systolic left ventricular pressure was significantly changed in all groups. HHcy induces remodelling of the cardiac tissues, as moderate HHcy is associated with more prominent interstitial and perivascular fibrosis. Our results suggest that a high methionine diet without vitamin B complex causes profound negative effects associated with HHcy.

The perfusion of cisplatin and cisplatin structural analogues through the isolated rat heart: The effects on coronary flow and cardiodynamic parameters.

The therapeutic use of cisplatin for the treatment of solid tumours is associated with organ toxicity. Amongst those, the cardiotoxicity is an occasional but very serious and severe side effect. To prevent or reduce these negative effects, many cisplatin analogues have been synthesized and evaluated in terms of being a less toxic and more effective agent. In present study, we examined the effects of cisplatin and its three analogues in the isolated rat heart to determine whether changes in the structure of the platinum complexes (changing of carrier ligands - ethylenediamine; 1,2-diaminocyclohexane; 2,2':6',2''-terpyridine) can influence their cardiotoxic effects. The results of our research indicate that the introduction of aromatic rings in the structure of the platinum complexes has a negative influence on the heart function. Conversely, the other two examined complexes had less negative effects on heart function compared to cisplatin. Our findings may be of interest for a possible synthetic strategy of introducing a carrier ligand that will exert a less cardiotoxic effect.