OBJECTIVETo explore the mitochondrial toxicities induced by zidovudine (AZT) and adefovir dipivoxil (ADV) antiviral drugs using a rat model system.

METHODSTwelve healthy Sprague-Dawley rats were randomly divided into three equal groups and treated by oral gavage with zidovudine (125 mg/kg/day), adefovir (40 mg/kg/day), or saline (equal volume) for 28 days. The rats' body weights were measured once a week, and blood was collected every two weeks for blood and biochemical tests. All animals were sacrificed at the end of treatment, and liver, kidney, skeletal muscle, and cardiac muscle were collected by necropsy. Mitochondria were isolated from the respective tissue samples, and the activities of respiratory chain complexes were measured. DNA was purified from each sample and the mitochondrial DNA (mtDNA) content was monitored by quantitative real time PCR. Mitochondrial morphology was analyzed under electron microscope.

RESULTSNo significant adverse effects, including body weight loss, abnormal blood or biochemistry, were observed in rats treated with AZT or ADV. The activities of mitochondrial cytochrome c oxidase in liver and cardiac muscle were slightly decreased in rats treated with AZT (liver: 9.44+/-3.09 vs. 17.8+/-12.38, P?=?0.21; cardiac muscle: 32.74+/-5.52 vs. 24.74+/-20.59, P?=?0.28; kidney: 4.42+/-1.53 vs. 14.45+/-13.75, P?=?0.18; skeletal muscle: 33.75+/-8.74 vs. 40.04+/-2.49, P?=?0.45). The mtDNA content was significantly decreased in cardiac muscle of AZT-treated rats (cardiac muscle: 0.15+/-0.13 vs. 0.32+/-0.42, P?=?0.85). The morphology of mitochondria in liver, kidney, skeletal muscle, and cardiac muscle was significantly altered in the AZT-treated rats and included disappearance of the outer membrane, severely damaged structure, and swollen or completely absent cristae. No obvious effects were noted in the ADV- or saline-treated rats.

CONCLUSIONSignificant adverse effects related to mitochondrial toxicity were observed in rats treated with AZT. The slightly decreased mtDNA content in ADV-treated rats may suggest that this antiviral drug can also cause mitochondrial toxic effects.

Adenine ; adverse effects ; analogs & derivatives ; Animals ; DNA, Mitochondrial ; drug effects ; Electron Transport Complex IV ; metabolism ; Female ; Kidney ; enzymology ; Liver ; enzymology ; Mitochondria ; drug effects ; metabolism ; Mitochondria, Heart ; drug effects ; Mitochondria, Liver ; drug effects ; Mitochondria, Muscle ; drug effects ; Muscle, Skeletal ; enzymology ; Myocardium ; enzymology ; Organophosphonates ; adverse effects ; Rats ; Rats, Sprague-Dawley ; Zidovudine ; adverse effects

No abstract available.
Mitochondria*

Heart Failure ; prevention & control ; Humans ; Mitochondria

OBJECTIVETo investigate the effects of seawater immersion on the function of myocardium and hepatocyte mitochondria in experimental hemorrhagic shock rats.

METHODSTwenty-four male Wistar rats were divided into three groups (n=8 in each group): control group, HSL group (hemorrhagic shock group on land) and HSS group (hemorrhagic shock group in seawater). The hemodynamic parameters, activities of H(+)-ATPase (adenosinetriphosphatase), succinate dehydrogenase (SDH) and Ca(2+)-Mg(2+)-ATPase, the calcium contents in myocardium and hepatocyte mitochondria were measured and the changes of proton translocation across the inner mitochondrial membrane were analyzed.

RESULTSThe hemodynamic indexes and the activities of H+-ATPase, SDH, Ca(2+)-Mg(2+)-ATPase in HSS group were significantly lower than those in control group and HSL group (P<0.05). In HSS group the calcium levels in tissue and mitochondria of myocardium and hepatocyte were elevated significantly compared with control group and HSL group (P<0.05). There was no significant difference in proton translocation among three groups.

CONCLUSIONSThis investigation demonstrates that seawater immersion can aggravate the conditions of hemorrhagic shock rats.

Animals ; Calcium ; metabolism ; Immersion ; Male ; Mitochondria, Heart ; enzymology ; Mitochondria, Liver ; enzymology ; Proton-Translocating ATPases ; metabolism ; Random Allocation ; Rats ; Rats, Wistar ; Seawater ; Shock, Hemorrhagic ; enzymology ; physiopathology

This study was performed to investigate the subcellular changes of rat atrial muscle cells by immobilization stress. Sprague -Dawley rats weighting 200 gm were immobilized in small round plastic tube for 2, 6, 12, and 24 hours respectively. The atrial tissue obtained from each animals were observed by transmission electron microscopes. In the heart of rat subjected 2 hours immobilization stress no significant morphological changes were found in electron microscopy, similarly as in control animal. After 6 and 12 hours immobilization stress, the following electron -microscopic changes of atrial myocytes were observed at the swelling of mitochondrial matrix with disturbance in cristea, focal loss of cytoplasmic matrix, vacuoles with myeline -like structure, apoptotic changes of myocytes, focal widening of intercalated disc interspace and lysis of myofibrils. After 24 hours immobilization stress, very small sized mitochondria, similarly as small sized secretory granules and various sized granules are observed in the perinuclear region of atrial myocytes. Atrial specific granules are moved centripetally toward the central region of the atrial myocytes after immobilization stress. Above results will be aid in understanding the structures of atrium with dual function of blood circulation and endocrine, and in research of modulation of secretory granules in atrial muscle cells.
Animals ; Blood Circulation ; Cytoplasm ; Heart ; Immobilization* ; Microscopy, Electron ; Mitochondria ; Muscle Cells* ; Myelin Sheath ; Myofibrils ; Plastics ; Rats* ; Secretory Vesicles ; Vacuoles

Insulin resistance in skeletal muscle, liver, beta-cells, fat cells, the gastrointestinal track, alpha-cells, kidneys, and brain represents the core defect in obesity or type 2 diabetes (T2D). Among them, skeletal muscle insulin resistance due to obesity or T2D is manifested by decreased glucose uptake because skeletal muscle comprises 40-50% of the total human body mass. Many previous reports indicate that T2D patients or obese insulin-resistant individuals have less mitochondria in their skeletal muscles than lean control subjects. Whether or not mitochondria in skeletal muscle play a causal role in insulin resistance has been debated. A large number of studies demonstrated that skeletal muscle insulin resistance is associated with mitochondrial deficiency including 1) reduced fatty acid oxidation and increased accumulation of lipid intermediates (e.g., FA-CoA, DAG, ceramide), 2) increased mitochondrial overload and incomplete fatty acid oxidation, and 3) increased mitochondrial oxidative stress (e.g., H2O2) in skeletal muscle. In contrast, some studies demonstrated that mitochondrial dysfunction in skeletal muscle is not responsible for insulin resistance, suggesting that 1) the development of insulin resistance in high-fat diet animals occurs with increased muscle mitochondria, and 2) fatty acid oxidation is higher in T2D patients and obese insulin-resistant individuals compared with lean control subjects. However, various types of exercises (acute vs chronic, aerobic vs resistance) are critical in the treatment and prevention of insulin resistance in obesity and T2D.
Adipocytes ; Animals ; Brain ; Diet, High-Fat ; Exercise ; Glucose ; Human Body ; Humans ; Insulin Resistance ; Kidney ; Liver ; Mitochondria ; Mitochondria, Muscle ; Muscle, Skeletal ; Obesity ; Oxidative Stress

OBJECTIVE: To observe ultra-structural pathological changes of materiality viscera of rats poisoned by different dose of tetramine and to study the toxic mechanism. METHODS: Acute and subacute tetramine toxicity models were made by oral administration with different dose of tetramine. Brain, heart, liver, spleen and kidney were extracted and observed by electromicroscopic examination. RESULTS: The injuries of brain cells, cardiocytes and liver cells were induced by different dose of tetramine. These were not obviously different of the injuries of the kindy cells and spleen cells of rats poisoned by different dose of tetramine. Ultra-structural pathological changes were abserved including mitochondria slight swelling and neurolemma's array turbulence in the brain cells, mitochondria swelling or abolish and rupture of muscle fiber in the heart cells, mitochondria swelling and the glycogen decreased in the liver cells. CONCLUSION The toxic target organs of tetramine are the heart, brain and liver.
Animals ; Brain/pathology* ; Bridged-Ring Compounds/poisoning* ; Dose-Response Relationship, Drug ; Female ; Liver/pathology* ; Male ; Microscopy, Electron, Transmission ; Mitochondria, Heart/pathology* ; Mitochondria, Liver/pathology* ; Myocardium/pathology* ; Poisoning/pathology* ; Rats ; Rats, Sprague-Dawley

OBJECTIVE: To find out the pathological change and the toxic mechanism of Chloranthus serratus Roem. et Schalt in mice. METHODS: Mice were intoxicated by oral administration with extracts of Chloranthus serratus Roem. et Schalt followed by pathological, serum biochemical, and coagulation mechanism examination. RESULTS: The LD50 in mice was 41.12 g/kg; All poisoned mice serum BUN and ALT increased markedly; Thrombocyte decreased and coagulation time increased; The organ index of liver, spleen and kidneys increased significantly; The cells of liver, kidney and heart were degeneration and necrosis, There were extensive hyperemia and hemorrhage in many organs. CONCLUSION The experiment suggests that the target organs were liver, kidney, heart and blood vessels; The toxic mechanism was the damage on the mitochondrional, endoplasmic reticulum and coagulation system.
Animals ; Biomarkers/blood* ; Dose-Response Relationship, Drug ; Endoplasmic Reticulum/drug effects* ; Female ; Forensic Pathology ; Kidney/pathology* ; Lethal Dose 50 ; Liver/pathology* ; Magnoliopsida/chemistry* ; Male ; Mice ; Mitochondria, Heart/drug effects* ; Mitochondria, Liver/drug effects* ; Myocardium/pathology* ; Plant Extracts/toxicity* ; Random Allocation

Liver, muscle, and adipose tissue are resistant to insulin action in type 2 diabetes. In spite of intensive studies, few diabetic genes have been identified. Recently, mitochondrial impairment has been observed in the muscle and adipose tissues of type 2 diabetes patients, implying that mitochondrial dysfunction could be a pivotal factor in type 2 diabetes. Here, we discuss mitochondrial malfunction leading to type 2 diabetes.
Adipose Tissue ; Humans ; Insulin ; Liver ; Mitochondria*

Liver, muscle, and adipose tissue are resistant to insulin action in type 2 diabetes. In spite of intensive studies, few diabetic genes have been identified. Recently, mitochondrial impairment has been observed in the muscle and adipose tissues of type 2 diabetes patients, implying that mitochondrial dysfunction could be a pivotal factor in type 2 diabetes. Here, we discuss mitochondrial malfunction leading to type 2 diabetes.
Adipose Tissue ; Humans ; Insulin ; Liver ; Mitochondria*