OBJECTIVETo study the effects and mechanism of Buzhong Yiqi decoction on adriamycin-induced acute myocardial injury in rats.

METHOD50 rats were randomly divided to five groups: control group, heart failure group, low dose Buzhong Yiqi decoction, high dose Buzhong Yiqi decoction and captopril group. Adriamycin was injected into the latter four groups to built a model of heart failure. Then, the effects of different doses of Buzhong Yiqi decoction on hemodynamics, cardiac tissue histological changes, antioxidant capacity and apoptosis of the damaged hearts were studied.

RESULTAdriamycin led to myocardial fiber swelling and fracture, Buzhong Yiqi decoction could reduce myocardial lesions. Buzhong Yiqi decoction could also improve heart antioxidant capacity and inhibit adriamycin-induced cardiomyocyte apoptosis.

CONCLUSIONBuzhong Yiqi decoction could significantly ease adriamycin induced heart failure in rats, and the mechanism is related to anti-oxidation and inhibiting apoptosis.

Animals ; Antibiotics, Antineoplastic ; toxicity ; Doxorubicin ; toxicity ; Drugs, Chinese Herbal ; pharmacology ; Heart Failure ; chemically induced ; prevention & control ; Male ; Nitric Oxide ; biosynthesis ; Rats ; Rats, Sprague-Dawley ; Superoxide Dismutase ; blood ; Ventricular Function, Left ; drug effects

OBJECTIVEThe pathogenesis of minimal change nephrotic syndrome (MCNS) remains unclear. This study aimed to investigate the expression of interleukin-6 (IL-6) in rats with doxorubicin-induced nephropathy and its possible roles in the pathogenesis of MCNS.

METHODSEighty-three male Wistar rats were randomly assigned into a control group (n=32) and a nephropathy group (n=51). Nephropathy was induced by a single tail vein injection of doxorubicin (5 mg/kg). The control group was injected with normal saline. Twenty-four-hour urinary protein excretion was measured 7, 14, 28 and 42 days after doxorubicin injection. IL-6 expression in urine and renal tissues was determined using ELISA 7, 14, 28 and 42 days after doxorubicin injection.

RESULTSThe urinary protein excretion increased significantly in the nephropathy group 7, 14, 28 and 42 days after doxorubicin injection compared with that in the control group (P<0.01). IL-6 expression in urine and renal tissues increased significantly 7, 14, 28 and 42 days after doxorubicin injection compared with that in the control group (P<0.01). IL-6 expression in urine and renal tissues was positively correlated with 24-hour urinary protein excretion in the nephropathy group (r=0.794, P<0.01; r= 0.870, P<0.01). IL-6 expression in urine was positively correlated with that in renal tissues (r=0.739, P<0.01).

CONCLUSIONSIL-6 expression in the urine and renal tissues is increased in MCNS rats. IL-6 might play an important role in the pathogenesis of MCNS.

Animals ; Antibiotics, Antineoplastic ; toxicity ; Disease Models, Animal ; Doxorubicin ; toxicity ; Interleukin-6 ; analysis ; Kidney ; chemistry ; Male ; Nephrosis, Lipoid ; chemically induced ; immunology ; Rats ; Rats, Wistar

This study is to observe the protection of gross saponins of Tribulus terrestris (GSTT) on cardiocytes impaired by adriamycin (ADR) and approach its mechanism of action. Cardiocytes of neonate rat were cultivated for 72 hours and divided into normal control group, model (ADR 2 mg x L(-1)) group, and GSTT (100, 30, and 10 mg x L(-1)) groups. MTT colorimetric method was deployed to detect cardiocyte survival rate, activities of CK, LDH, AST, SOD, MDA and NO were detected, and apoptosis was detected with flow cytometry. Effect of GSTT on caspase-3 was detected with Western blotting. Compared with control group, contents of CK, LDH, AST, MDA and NO were increased, and activity of SOD was reduced (P < 0.05, P < 0.01, P < 0.001) by ADR. Numbers of survival cells were increased (P < 0.05, P < 0.001), contents of CK, LDH, AST, MDA and NO were decreased, and activity of SOD was increased (P < 0.05, P < 0.01, P < 0.001) by GSTT (100 and 30 mg x L(-1)). Apoptosis of cardiocytes and concentration of caspase-3 can be reduced by GSTT (100 and 30 mg x L(-1)). GSTT can protect cardiocytes impaired by ADR, which are possible involved with its effect of resisting oxygen free radical.
Animals ; Antibiotics, Antineoplastic ; toxicity ; Apoptosis ; drug effects ; Aspartate Aminotransferases ; metabolism ; Caspase 3 ; metabolism ; Cell Survival ; drug effects ; Cells, Cultured ; Creatine Kinase ; metabolism ; Doxorubicin ; toxicity ; L-Lactate Dehydrogenase ; metabolism ; Malondialdehyde ; metabolism ; Myocytes, Cardiac ; cytology ; metabolism ; Nitric Oxide ; metabolism ; Rats ; Rats, Wistar ; Saponins ; isolation & purification ; pharmacology ; Superoxide Dismutase ; metabolism ; Tribulus ; chemistry

PURPOSE: Matrix metalloproteinases (MMPs) have been implicated in the pathogenesis of pulmonary fibrosis. To understand the role of MMP-2 and MMP-9 in pulmonary fibrosis, we evaluated the sequential dynamic change and different cellular sources of the 2 MMPs along the time course and their differential expression in the bronchoalveolar lavage (BAL) fluid and in the lung parenchyma of the bleomycin-induced pulmonary fibrosis models in rats. MATERIALS AND METHODS: The level of MMPs in BAL fluid of 54 bleomycin-treated rats was assessed by zymography from 1 to 28 days after intratracheal bleomycin instillation. The level of MMPs in lung parenchyma was evaluated by immunohistochemistry. RESULTS: MMP-2 and MMP-9 were markedly increased in both the BAL fluid and in the lung parenchyma of the bleomycin-treated rats, especially in the early phase with the peak on the 4th day. The levels of both MMPs in the BAL fluid correlated generally well to those in lung parenchyma, although the level of MMP-9 in BAL fluid was higher than MMP-2. In the lung parenchyma, the 2 MMPs, in early stage, were predominantly expressed in the inflammatory cells. In late stage, type II pneumocytes and alveolar epithelial cells at the periphery of the fibrotic foci retained MMP expression, which was more prominent in the cells showing features of cellular injury and/or repair. CONCLUSION: In bleomycin-induced pulmonary fibrosis, MMP-2 and MMP-9 may play important roles, especially in the early phase. In the late stage, the MMP-2 and MMP-9 may play a role in the process of repair.
Animals ; Antibiotics, Antineoplastic/toxicity ; Bleomycin/toxicity ; Bronchioles/*enzymology/pathology ; Bronchoalveolar Lavage Fluid/cytology/immunology ; Disease Models, Animal ; Enzyme Activation ; Gelatin ; Immunohistochemistry ; Male ; Matrix Metalloproteinase 2/*metabolism ; Matrix Metalloproteinase 9/*metabolism ; Neutrophils/pathology ; Pulmonary Fibrosis/chemically induced/*metabolism/*pathology ; Rats ; Rats, Sprague-Dawley

OBJECTIVETo assess the cytotoxicity of carbon-coated iron nanoparticles (CCIN) and epirubicin-loaded CCIN on Hep-G2 cells in vitro and compare the acute toxicities of epirubicin and epirubicin-loaded CCIN in mice.

METHODSThe cytotoxicities of CCIN and epirubicin-loaded CCIN on HepG2 cells were assessed using MTT assay, and the uptake of CCIN by the tumor cells was observed by optical and electron microscopy. Different doses of epirubicin and equivalent doses of epirubicin-loaded CCIN were injected intravenously in mice to compare their acute toxicities.

RESULTSOptical and electron microscopy revealed cytoplasmic uptake of CCIN in the tumor cells without obvious destruction of the cell structural integrity. Incubation of the HepG-2 cells with different concentrations of CCIN suspension did not result in significant variation in the mean absorbance. MTT assay showed reduced cytotoxicity of epirubicin-loaded CCIN in HepG2 cells as compared with that of epirubicin alone. The cell growth inhibition rate was significantly higher with epirubicin-CCIN mixture that contained a lower proportion of CCIN. In acute toxicity experiment with mice, the median lethal dose (LD(50)) of epirubicin was 16.9 mg/kg, while that of epirubicin-CCIN mixture was 20.7 mg/kg.

CONCLUSIONCCIN uptake by HepG-2 cells does not cause obvious cytotoxicity in vitro within a certain concentration range, epirubicin-loaded CCIN has reduced cytotoxicity against HepG2 cells as compared with epirubicin, and the cytotoxicity of the mixture decreases with the increase in the CCIN content in the mixture. Epirubicin delivery in mixture with CCIN can reduce its acute toxicity in mice.

Animals ; Antibiotics, Antineoplastic ; pharmacology ; toxicity ; Carbon ; pharmacology ; toxicity ; Drug Carriers ; pharmacology ; toxicity ; Epirubicin ; pharmacology ; toxicity ; Ferric Compounds ; pharmacology ; toxicity ; Hep G2 Cells ; Humans ; Iron ; pharmacology ; toxicity ; Mice ; Nanoparticles ; toxicity ; Toxicity Tests, Acute

OBJECTIVETo determine the in vitro possible clastogenic and cytotoxic activities of Ulva rigida crude extracts (URE), and identify their antigenotoxic and protective effects on chemotherapeutic agent mitomycine-C (MMC).

METHODSAnti-clastogenic and anti-genotoxic activities of Ulva rigida crude extracts (URE) were studied using chromosome aberration (CA), sister chromatid exchange (SCE), and micronuclei (MN) tests in human lymphocytes cultured in vitro.

RESULTSThe chromosome aberration, sister chromatid exchange or micronuclei tests showed that URE at concentrations of 10, 20, and 40 microg/mL had no clastogenic activity in human lymphocyte cell culture. Three doses of URE significantly decreased the number of chromosomal aberrations and the frequencies of SCE and MN when compared with the culture treated with MMC (P < 0.0001).

CONCLUSIONAlthough URE itself is not a clastogenic or cytotoxic substance, it possesses strong antigenotoxic, anti-clastogenic, and protective effects on MMC in vitro.

Antibiotics, Antineoplastic ; pharmacology ; Antimutagenic Agents ; pharmacology ; Cells, Cultured ; Chlorophyta ; Chromosome Aberrations ; drug effects ; Dose-Response Relationship, Drug ; Humans ; Lymphocytes ; drug effects ; metabolism ; Micronucleus Tests ; Mitomycins ; pharmacology ; Mutagens ; toxicity ; Plant Extracts ; chemistry ; pharmacology ; Sister Chromatid Exchange ; drug effects

OBJECTIVEEarlier studies have confirmed that mesenchymal stem cells (MSCs) can transdifferentiate into myocytes and improve heart function in 2 weeks. But the mechanism is not clear. In this study, the mechanism of improvement of heart function after transplantation of MSCs was examined with suppression subtractive hybridization (SSH).

METHODSMSCs were isolated from thighone and tibia of Wistar rats, purified by adhesion-screening method, and expanded in vitro. Intraperitoneal injection of doxorubicin (at 2.5 mg/kg/time and total doses of 15 mg/kg) established cardiomyopathy models. MSCs were transplanted into cardiomyocytes. The differential genes between tester (rats with cardiomyopathy that were injected with MSCs) and driver (rats with cardiomyopathy that were injected with equivalent volume of culture medium) were screened with suppression subtractive hybridization.

RESULTSAfter 4 weeks of intraperitoneal injection of doxorubicin, left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) decreased by 26.48% and 40.61%, respectively (P < 0.01), as compared with those of normal group. Cardiomyopathy model was established successfully. And the heart function of the rats with cardiomyopathy was significantly improved after transplantation. Sixteen gene fragments were detected, and 12 of them were up-regulated in testers. They were rattus norvegicus mitochondrial BN/SsNHsdMCW, rattus norvegicus strain mitochondrial F344 X BN F1, rattus norvegicus mitochondrion H(+)-ATP synthase alphase subunit (Atp5al) mRNA, rattus norvegicus BHE/Cdb tRNA-Lys gene, rat mitochondrial H(+)-ATP synthase alpha subunit mRNA, rattus norvegic (wild-caught animal) complete mitochondrial genome, rattus norvegic clone BB.1.4.1 unknown Glu-Pro dipeptide repeat protein mRNA, Arabidopsis thaliana transgenic line C DNA, rat mitochondrial ATP synthase beta subunit mRNA, rattus norvegic mitochondrial genome, rat cardiac troponin T mRNA and rat mRNA for beta-globin. Four gene fragments were down-regulated in testers. They were rat mRNA for sarcomeric mitochondrial creatine kinase, rat mRNA for ribosomal phosphoprotein P2, rat alpha-crystallin B chain mRNA and rattus norvegicus NADH-ubiquinone oxidoreductase Fe-S protein 7 mRNA.

CONCLUSIONThe expression of the genes relating to mitochondrial synthesizing and contracting proteins synthesizing increased after MSC transplantation. The genes might enhance energy synthesis and promote MSC transdifferentiate into myocytes, and then improve heart function of rats with cardiomyopathy.

Animals ; Antibiotics, Antineoplastic ; toxicity ; Bone Marrow Transplantation ; methods ; Cardiomyopathies ; diagnostic imaging ; genetics ; surgery ; Cell Differentiation ; Cells, Cultured ; Disease Models, Animal ; Down-Regulation ; Doxorubicin ; toxicity ; Female ; Mesenchymal Stem Cell Transplantation ; methods ; Mitochondria ; genetics ; Myocytes, Cardiac ; RNA, Messenger ; Rats ; Rats, Wistar ; Treatment Outcome ; Ultrasonography ; Up-Regulation ; Ventricular Function, Left

Animals ; Antibiotics, Antineoplastic ; administration & dosage ; toxicity ; Apoptosis ; drug effects ; Daunorubicin ; administration & dosage ; toxicity ; Disease Models, Animal ; Female ; In Situ Nick-End Labeling ; Male ; Myocardium ; cytology ; metabolism ; pathology ; ultrastructure ; Neuregulins ; metabolism ; pharmacology ; RNA, Messenger ; metabolism ; Rats ; Rats, Wistar ; Receptor, ErbB-2 ; genetics ; metabolism ; Reverse Transcriptase Polymerase Chain Reaction

AIMMultidrug resistance ( MDR) as a major obstacle to successful clinical cancer chemotherapy, searching a novel effective antiresistant drug would be necessary.

METHODSA novel doxorubicin anti-resistant stealth liposomes (DARSLs) was prepared by co-encapsulating doxorubicin (DOX) and verapamil (VER) into stealth liposomes with ammonium sulfate gradient remote loading approach. In vitro cytotoxity of various DOX formulations and in vivo toxicity of DARSLs were evaluated using DOX-resistant rat prostate cancer cell line (MLLB2), human uterus sarcoma cell line (MES-SA/DX5) and normal SD rats, separately.

RESULTSThe DARSLs liposome suspensions mainly consisted of homogeneous large unilamellar vesicles (LUV) with average particle size of (118.1 +/- 22.3) nm. Encapsulation efficiencies of DOX and VER in DARSLs were more than 90% and about 70%, respectively, when the ratio of DOX/VER/Lipid was 1: 0.11 :10 (w/w/w). In vitro cytotoxicity tests of the DARSLs using rat prostate cancer cell line (MLLB2) and human uterus sarcoma cell line (MES-SA/DX5) showed that 5 micromol x L(-1) VER significantly reversed DOX-resistance of these 2 cell lines and DARSLs was the most effective on inhibition of DOX-resistant cell growth. Besides, compared to FDFV, much slower DOX distribution (confocal microscopy) to nuclei and cytoplasm in MLLB2 cells for DARSLs suggested that it might possess distinct mechanism of cytotoxicity. Systemic and cardiac toxicity evaluations in normal SD rats suggested that liposomal encapsulation could significantly improve the severe cardiotoxicity arising from simultanous administration of DOX and VER.

CONCLUSIONDARSLs is a novel anticancer liposome formulation with lower cardiotoxicity, effective drug-resistance reversal and intravenous injection.

Animals ; Antibiotics, Antineoplastic ; administration & dosage ; pharmacology ; toxicity ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Doxorubicin ; administration & dosage ; pharmacology ; toxicity ; Drug Carriers ; Drug Resistance, Multiple ; drug effects ; Drug Resistance, Neoplasm ; drug effects ; Female ; Heart Rate ; drug effects ; Humans ; Liposomes ; Male ; Myocytes, Cardiac ; drug effects ; ultrastructure ; Prostatic Neoplasms ; pathology ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Sarcoma ; pathology ; Uterine Neoplasms ; pathology

Although adriamycin (Doxorubicin) is one of the most effective and useful antineoplastic agents for the treatment of a variety of malignancies, its repeated administration can induce irreversible myocardial damage and resultant heart failure. Currently, no marker to detect early cardiac damage is available. The purpose of this study was to investigate whether an assessment of the acoustic properties of the myocardium could enable the earlier detection of myocardial damage after adriamycin chemotherapy. Forty Wistar rats were treated with adriamycin (2 mg/kg, i.v.) once a week for 2, 4, 6 or 8 weeks consecutively. Left ventricular ejection fraction (LVEF) was calculated using M-mode echocardiography data. The magnitude of cardiac cycle dependent variation of integrated backscatter (CVIB) of the myocardium was measured in the mid segment of the septum and in the posterior wall of the left ventricle, using a real time two dimensional integrated backscatter imaging system. LVEF was significantly lower in the adriamycin-treated 8-week group than in the controls (75 +/- 9 vs 57 +/- 8%, p < 0.05). Myocyte damage was only seen in the 8-week adriamycin-treated group. However, no significant changes of CVIB were observed between baseline or during follow-up in the ADR or control group. In conclusion, serial assessment of the acoustic properties of the myocardium may not be an optimal tool for the early detection of myocardial damage after doxorubicin chemotherapy in a rat model.
Animals ; Antibiotics, Antineoplastic/*toxicity ; Cardiomyopathies/*chemically induced/*ultrasonography ; Disease Models, Animal ; Doxorubicin/*toxicity ; *Echocardiography ; Male ; Rats ; Rats, Wistar ; Research Support, Non-U.S. Gov't