Targeted delivery of doxorubicin by Thermo/pH-responsive magnetic nanoparticles in a rat model of breast cancer.

The novel folate conjugated Thermo/pH-responsive magnetic nanoparticles (folate-poly-MNPs) have been developed as a potential nanocarrier for improving site-specific drug delivery, tumor drug accumulation, and therapeutic effects while reducing the adverse effects of conventional drug delivery systems. To evaluate the anticancer efficacy of developed tumor-targeted drug delivery system, forty rat models of breast cancer received saline as control, DOX, DOX-poly-MNPs, and DOX-folate-poly-MNPs at a dose of 2 mg/kg/48 h. The DOX-folate-poly-MNPs showed a significant increase in protein expression of BAX and C-caspase-3 with concomitant downregulation of Bcl-2 expression and ki67 proliferation index compared to the DOX group. The synergistic antitumor efficacy of passive and active drug targeting led to enhanced drug uptake, increased tumor cell apoptosis, decreased tumor volume, and a prolonged survival rate in animals, suggesting that DOX-folate-poly-MNPs may prove to be a promising nanomedicine for the smart treatment of breast cancer in the future.

Reducing the risk of death induced by aluminum phosphide poisoning: The new therapies.

Numerous people suffer from accidental or deliberate exposure to different pesticides when poisoning with aluminum phosphate (AlP) is increasing in the eastern countries. Aluminum phosphate is a conventional insecticide that quickly reacts with water or the moistures in the atmosphere and produces fatal phosphine gas, which absorbs quickly by the body. Oral consumption or inhalation of AlP leads to excessive reaction of the body such as fatigue, vomiting, fever, palpitation, vasodilatory shock, increasing blood pressure, cardiac dysfunction, pulmonary congestion, shortness of breath, and death. The garlic smell from the patient's mouth or exhale is one of the methods to recognize the positioning. Due to the lack of individual antidotes, several supportive treatments are required. The present study focused on the available and new therapies that help reduce the effect of AlP poisoning and the mortality rate. The therapies are divided into the antioxidant-related agent and the other agents. The impacts of each agent on the experimental cases are reported.

Sensing of oxidative stress biomarkers: The cardioprotective effect of taurine & grape seed extract against the poisoning induced by an agricultural pesticide aluminum phosphide.

Aluminum phosphide is a well-known hazardous agent used as an agricultural pesticide to protect stored grains from insect damage. However, accidental consumption of a trivial amount of it caused irreversible damage to the human body or even death in acute cases. The present study used taurine and grape seed extract as a natural cardioprotective medicine against aluminum phosphide poisoning by decreasing oxidative stress. The activity of oxidative stress biomarkers (Malondialdehyde, Catalase, Protein carbonyl, and Superoxide dismutase) were evaluated in the cell line model on Human Cardiac Myocyte cells. In the beginning, to clarify the pure impact of aluminum phosphide poison, taurine, and grape seed extract on the human heart cells, their effects on the biomarkers quantity in cell line were measured. Subsequently, the effect of taurine and grape seed extract with various concentrations as a treatment on the oxidative stress biomarkers of the poisoned heart cells were studied. Data analysis reveals that taurine and grape seed extract treatment can successfully diminish the poisoning effect by their antioxidant properties. The oxidative markers values of the poisoned cells were recovered by taurine and grape seed extracts treatment. Taurine (2 g/l) can recover Malondialdehyde, Catalase, Protein carbonyl, and Superoxide dismutase by 56%, 78%, 88%, 78%, when the recovering power of grape seed extract (100 g/l) for the aforementioned enzymes are 56%, 0.71%,74%, 51%, respectively. Therefore, it is clear that the performance of taurine in the recovery of the biomarkers' value is better than grape seed extract.

On the mechanisms of taurine in alleviating electrocardiographic, hemodynamic, and biochemical parameters following aluminum phosphide cardiotoxicity.

BACKGROUND: Aluminum phosphide (AlP) causes severe cardiotoxicity. Taurine has been chosen for the present study because of its positive known effects on cardiac injuries. METHOD: To evaluate AlP-induced cardiotoxicity, the animals were divided into seven groups, including the control group, the taurine group (500 mg/kg), AlP with LD50 dose, AlP + taurine 20, 50, 100, and 200 mg/kg group. To assess cardiac hemodynamic parameters, Wistar rats received taurine intraperitoneally 60 min after AlP gavage. Cardiac hemodynamic parameters were evaluated for 180 min. To study biochemical parameters, 24 h after AlP treatment, the animals were sacrificed, and heart tissues were collected. RESULT: ECG, BP, and HR abnormalities of AlP poisoning were improved by taurine treatment. AlP induced biochemical alterations including complexes I and IV activities, the ADP/ATP ratio, mitochondrial membrane potential, cytochrome C release, and oxidative stress biomarkers ameliorated by taurine. Moreover, taurine improved apoptosis, as well as lessened CK-MB and troponin I levels. Also, there were no significant changes between taurine 500 mg/kg and the control group in tests. CONCLUSION: The present findings showed that taurine could be a possible candidate for AlP cardiotoxicity treatment via the effect on mitochondrial electron transfer chain and maintaining intracellular ATP balance.

Study of the cardioprotective effects of crocin on Human Cardiac Myocyte cells and reduction of oxidative stress produced by aluminum phosphide poisoning.

OBJECTIVES: The effects of Crocin as a cardioprotective material against Aluminum phosphide poisoning by reducing the oxidative stress is investigated. METHODS: The level of biomarkers of oxidative stress (Catalase, Superoxide dismutase, Malondialdehyde and Protein carbonyl) were measured in the cell culture model on Human Cardiac Myocyte cells to detect the protective effect of crocin. Initially, to define the pure impact of aluminum phosphide poison and crocin on the heart cells, their effects on the biomarkers quantity in cell line were measured, separately, using the standard related kits. Later the effect of crocin with different concentration as a treatment on the oxidative stress biomarkers of the poisoned heart cells were monitored. Note that in pre-treatment case, the crocin was initially added to the cells before poisoning them. Data were analyzed using the analysis of variance method. KEY FINDINGS: Results showed that crocin treatment reduced the aluminum phosphide (AlP) poisoning effect significantly. The treatment resulted in substantial deviation in the biomarkers of oxidative stress at the pre- and post-treatment phases for all groups. The oxidative markers values of the poisoned cells were recovered by crocin treatment. CONCLUSIONS: Crocin is proposed as a potentially powerful antioxidant to treat the cardiotoxicity caused by aluminum phosphide poisoning.

Investigation of intestinal transportation of peptide-displaying bacteriophage particles using phage display method.

To investigate whether peptide sequences with specific translocation across the gastrointestinal barrier can be identified as drug delivery vehicles, in vivo phage display was conducted. For this purpose, a random library of 12-mer peptides displayed on M13 bacteriophage was orally administered to mice followed by recovery of the phage particles from the blood samples after three consecutive biopanning rounds. The obtained peptide sequences were analyzed using bioinformatics tools and software. The results demonstrated that M13 bacteriophage bearing peptides translocate nonspecifically across the mice intestinal mucosal barrier deduced from random distribution of amino acids in different positions of the identified peptide sequences. The most probable reason for entering the phage particles into systemic circulation after oral administration of the peptide library can be related to the nanoscale nature of their structures which provides a satisfying platform for the purpose of designing nanocarriers in pharmaceutical applications.

Cardioprotective Effect of Grape Seed Extract on Chronic Doxorubicin-Induced Cardiac Toxicity in Wistar Rats.

Purpose: The aim of the present study was to determine the ability of grape seed extract (GSE) as a powerful antioxidant in preventing adverse effect of doxorubicin (DOX) on heart function. Methods: Male rats were divided into three groups: control, DOX (2 mg/kg/48h, for 12 days) and GSE (100 mg/kg/24h, for 16 days) plus DOX. Left ventricular (LV) function and hemodynamic parameters were assessed using echocardiography, electrocardiography and a Millar pressure catheter. Histopathological analysis and in vitro antitumor activity were also evaluated. Results: DOX induced heart damage in rats through decreasing the left ventricular systolic and diastolic pressures, rate of rise/decrease of LV pressure, ejection fraction, fractional shortening and contractility index as demonstrated by echocardiography, electrocardiography and hemodynamic parameters relative to control group. Our data demonstrated that GSE treatment markedly attenuated DOX-induced toxicity, structural changes in myocardium and improved ventricular function. Additionally, GSE did not intervene with the antitumor effect of DOX. Conclusion: Collectively, the results suggest that GSE is potentially protective against DOX-induced toxicity in rat heart and maybe increase therapeutic index of DOX in human cancer treatment.

In vitro/vivo studies towards mechanisms of risperidone-induced oxidative stress and the protective role of coenzyme Q10 and N-acetylcysteine.

The hepatotoxic effects of the antipsychotic agent, risperidone (RIS) were investigated for better understanding the pathogenesis of RIS in liver toxicity in vivo and in in vitro. Isolated rat hepatocytes were obtained by collagenase perfusion technique and were then incubated with RIS, different antioxidants in particular coenzyme Q10 (CoQ10), N-acetyl cysteine (NAC). Our results showed that RIS could induce cytotoxicity via rising reactive oxygen species (ROS), mitochondrial potential collapse, lysosomal membrane leakiness, GSH depletion and lipid peroxidation. All of these effects were significantly (p < 0.05) inhibited by ROS scavengers, antioxidants, endocytosis inhibitors and adenosine triphosphate (ATP) generators. Similar outcomes were obtained from the in vivo experiments. Liver function enzyme test and histopathological evaluation confirmed RIS-(6 mg/kg) induced damage. Based on these results, it is suggested that RIS-induced liver toxicity is associated with mitochondrial/lysosomal cross-talk following the initiation of oxidative stress. Thus, the use of CoQ10 and/or NAC seems to be a safe therapeutic option in this context.

Crocin treatment prevents doxorubicin-induced cardiotoxicity in rats.

Doxorubicin (DOX)-induced cardiotoxicity is well-known as a serious complication of chemotherapy in patients with cancer. It is unknown whether crocin (CRO), main component of Crocus sativus L. (Saffron), could reduce the severity of DOX-induced cardiotoxicity. Therefore, this study was undertaken to assess the protective impact of CRO on DOX-induced cardiotoxicity in rats. The rats were divided into four groups: control, DOX (2mg/kg/48h, for 12days), and CRO groups that receiving DOX as in group 2 and CRO (20 and 40mg/kg/24h, for 20days) starting 4days prior to first DOX injection and throughout the study. Echocardiographic, electrocardiographic and hemodynamic studies, along with histopathological examination and MTT test were carried out. Our findings demonstrate that DOX resulted in cardiotoxicity manifested by decreased the left ventricular (LV) systolic and diastolic pressures, rate of rise/drop of LV pressure, ejection fraction, fractional shortening and contractility index, as compared to control group. In addition, histopathological analysis of heart confirmed adverse structural changes in myocardial cells following DOX administration. The results also showed that CRO treatment significantly improved DOX-induced heart damage, structural changes in the myocardium and ventricular function. In addition, CRO did not affect the in vitro antitumor activity of DOX. Taken together, our data confirm that CRO is protective against cardiovascular-related disorders produced by DOX, and clinical studies are needed to examine these findings in human.

Cardioprotective Effect of Phenytoin on Doxorubicin-induced Cardiac Toxicity in a Rat Model.

Doxorubicin (DOX) is an effective anticancer agent, but adverse cardiotoxic effects limit its use. Compounds reducing DOX cardiotoxicity could improve its therapeutic index. This study investigated the protective effects of phenytoin (Phen) for DOX-induced cardiomyopathy. Male Wistar rats were randomized into 5 groups to receive either saline, DOX (2 mg/kg per 48 hours, 6 doses, intraperitoneally) or DOX + Phen (5, 10, or 20 mg/kg/d, starting 4 days before DOX, intraperitoneally). The animals were assessed 24 hours after the last injection. Left ventricular (LV) function and hemodynamic parameters were assessed using transthoracic echocardiography, electrocardiography, and a Millar pressure catheter. Histopathological studies were performed, and the effect of Phen on the cytotoxicity of DOX was evaluated in vitro for the human breast adenocarcinoma cell line. DOX-impaired LV function significantly decreased the LV systolic and diastolic pressures, rate of rise/decrease of LV pressure, ejection fraction, fractional shortening, and contractility index. DOX caused structural changes in myocardial cells. Treatment with Phen decreased DOX-induced toxicity, significantly improved ventricular function, and ameliorated structural changes in the myocardium. Phen also did not interfere with the antitumor effect of DOX. The results confirm the cardioprotective effect of Phen against DOX-induced cardiomyopathy without removing antitumor effect of DOX.

Involvement of oxidative stress and mitochondrial/lysosomal cross-talk in olanzapine cytotoxicity in freshly isolated rat hepatocytes.

1. Olanzapine (OLZ) is a widely used atypical antipsychotic agent for the treatment of schizophrenia and other disorders. Serious hepatotoxicity and elevated liver enzymes have been reported in patients receiving OLZ. However, the cellular and molecular mechanisms of the OLZ hepatotoxicity are unknown. 2. In this study, the cytotoxic effect of OLZ on freshly isolated rat hepatocytes was assessed. Our results showed that the cytotoxicity of OLZ in hepatocytes is mediated by overproduction of reactive oxygen species (ROS), mitochondrial potential collapse, lysosomal membrane leakiness, GSH depletion and lipid peroxidation preceding cell lysis. All the aforementioned OLZ-induced cellular events were significantly (p < 0.05) prevented by ROS scavengers, antioxidants, endocytosis inhibitors and adenosine triphosphate generators. Also, the present results demonstrated that CYP450 is involved in OLZ-induced oxidative stress and cytotoxicity mechanism. 3. It is concluded that OLZ hepatotoxicity is associated with both mitochondrial/lysosomal involvement following the initiation of oxidative stress in hepatocytes.

Allopurinol prevents nitroglycerin-induced tolerance in rat thoracic aorta.

Xanthine oxidase is an important source of reactive oxygen species; so, it may play a role in the pathogenesis of endothelium dysfunction and its consequences. Allopurinol, a purine analog, is a famous xanthine oxidase inhibitor. This study aimed to investigate possible effects of allopurinol on nitroglycerin tolerance, vasoconstriction, and vasorelaxation in rat aortic ring. Using thoracic aortic rings obtained from male Wistar rats, the effect of allopurinol was examined on nitroglycerin-induced tolerance. In addition, changes of vasoconstriction (by using KCl and phenylephrine) and vasorelaxation (by using carbachol, sodium nitroprusside, and nitroglycerin) were also measured and compared between tissues treated with and without allopurinol. All 3 concentrations of allopurinol (50, 100, and 150 µM) significantly acted against the development of nitroglycerin-induced tolerance in comparison with controls. In terms of vasoconstriction and vasorelaxation, the effect of allopurinol was significant only on carbachol-induced (endothelium related) vasorelaxation in a dose-dependent manner. In conclusion, although allopurinol had no significant effect on the contractile response of the aorta, in accord with the previous data, it significantly intensified endothelium-dependent vasodilation. The inhibitory effect of allopurinol against the development of nitrate-induced tolerance may suggest its clinical benefit and is worth to be studied more extensively.

Mechanisms of the statins cytotoxicity in freshly isolated rat hepatocytes.

Statins are potent drugs, used as lipid-lowering agents in cardiovascular diseases. Hepatotoxicity is one of the serious adverse effects of statins, and the exact mechanism of hepatotoxicity is not yet clear. In this study, the cytotoxic effects of the most commonly used statins, that is, atorvastatin, lovastatin, and simvastatin toward isolated rat hepatocytes, were evaluated. Markers, such as cell death, reactive oxygen species (ROS) formation, lipid peroxidation, mitochondrial membrane potential, and the amount of reduced and oxidized glutathione in the statin-treated hepatocytes, were investigated. It was found that the statins caused cytotoxicity toward rat hepatocytes dose dependently. An elevation in ROS formation, accompanied by a significant amount of lipid peroxidation and mitochondrial depolarization, was observed. Cellular glutathione reservoirs were decreased, and a significant amount of oxidized glutathione was formed. This study suggests that the adverse effect of statins toward hepatocytes is mediated through oxidative stress and the hepatocytes mitochondria play an important role in the statin-induced toxicity.

17beta-estradiol inhibits calcium-dependent and -independent contractions in isolated human saphenous vein.

Studies suggest that estrogen modulate vascular reactivity but at present its exact mechanism of action has yet to be clarified. The aim of this study was to evaluate the effect of 17beta-estradiol (E2) on calcium-dependent and -independent contractions induced in the human saphenous veins (HSVs). HSVs were obtained from patients undergoing coronary artery bypass graft surgery. The ability of E2 to modulate Ca(2+) entry was assessed by obtaining concentration-response curve to CaCl(2) in the absence or presence of E2. In other experiments intracellular Ca(2+) was depleted by repeated application of phenylephrine in the presence of cyclopiazonic acid (CPA). Then, at the plateau of PGF(2alpha) contraction, E2 or nifedipine (NIF) was added. Involvement of protein kinase C (PKC) in relaxant effect of E2 was evaluated by application of phorbol-12,13-dibutyrate (PDBu) in normal or Ca(2+)-free Krebs' solution. When the contraction was obtained, E2 or NIF was added. In Ca(2+)-free hyperpolarizing solution, pretreatment with E2, concentration dependently reduced contractions induced by cumulative addition of calcium chloride. Furthermore, E2 elicited relaxant effects on the PGF(2alpha)-induced contractions in Ca(2+)-free solution in the presence or absence of CPA. Both E2 and NIF produced significant relaxation in HSV rings contracted by direct activation of PKC in Krebs' solution. However, in Ca(2+)-free solution, NIF failed to induce relaxant effect but E2 kept its effect on the PDBu-induced contraction. These results suggest that the relaxant effect of E2 on HSV is elicited by calcium-dependent and -independent pathways. The calcium-independent pathway may involve PKC inhibition.