Oridonin enhances antitumor effects of doxorubicin in human osteosarcoma cells.

BACKGROUND: Doxorubicin is the chemotherapeutic drug of choice in osteosarcoma treatment, but its cumulative administration causes dilated cardiomyopathy. Combination therapy represents a potential strategy to reduce the therapeutic dosage of the chemotherapeutic agent and minimize its side effects. The aim of this study was to evaluate the potential of oridonin, a natural product from the medicinal herb Rabdosia rubescens, to act in combination with doxorubicin for osteosarcoma treatment. To date, there are no reports of the simultaneous administration of both drugs in osteosarcoma therapy. METHODS: The combined administration of different doses of oridonin and doxorubicin, as compared with the drugs alone, were tested in an in vitro model of osteosarcoma. The synergistic effect of the drugs on cell death was assessed by alamarBlue™ and by CompuSyn software. Early and late apoptosis markers (JC-1 fluorescence and Annexin V immunofluorescence), as well as the production of reactive oxygen species, were evaluated by flow cytometry. Western blot was used to assess the expression of anti-apoptotic proteins. RESULTS: Oridonin and doxorubicin presented a synergistic cytotoxic effect in osteosarcoma cells. In the presence of sub-cytotoxic concentrations of the natural product, there was an increased accumulation of intracellular doxorubicin, increased levels of reactive oxygen species (ROS), alteration of mitochondria membrane potential and a higher rate of apoptosis. CONCLUSION: The combined use of oridonin and doxorubicin could help to reduce the clinical dosage of doxorubicin and its dangerous side effects.

Complications of vitamin D deficiency from the foetus to the infant: One cause, one prevention, but who's responsibility?

Calcium and phosphorus represent building material for bones. The supplier of these bone minerals is the hormone calcitriol, which originates from vitamin D, itself made by sunshine in human skin. Requirement for bone minerals is highest during phases of rapid growth, and no one grows faster than the foetus and the infant, making them particularly vulnerable. Deprivation of calcium, whether through low calcium intake or low vitamin D, leads to serious health consequences throughout life, such as hypocalcaemic seizures, dilated cardiomyopathy, skeletal myopathy, congenital and infantile rickets, and osteomalacia. These 5 conditions are often summarised as 'symptomatic vitamin D deficiency', are fully reversible but also fully preventable. However, the increasing prevalence of rickets and osteomalacia, and the deaths from hypocalcaemic cardiomyopathy, demand action from global health care providers. Clarification of medical and parental responsibilities is a prerequisite to deliver successful prevention programmes. The foetus and infant have the human right to be protected against harm, and vitamin D supplementation has the same public health priority as vaccinations.

Cardiac electrophysiological alterations in heart/muscle-specific manganese-superoxide dismutase-deficient mice: prevention by a dietary antioxidant polyphenol.

Cardiac electrophysiological alterations induced by chronic exposure to reactive oxygen species and protective effects of dietary antioxidant have not been thoroughly examined. We recorded surface electrocardiograms (ECG) and evaluated cellular electrophysiological abnormalities in enzymatically-dissociated left ventricular (LV) myocytes in heart/muscle-specific manganese-superoxide dismutase-deficient (H/M-Sod2(-/-)) mice, which exhibit dilated cardiomyopathy due to increased oxidative stress. We also investigated the influences of intake of apple polyphenols (AP) containing mainly procyanidins with potent antioxidant activity. The QRS and QT intervals of ECG recorded in H/M-Sod2(-/-) mice were prolonged. The effective refractory period in the LV myocardium of H/M-Sod2(-/-) mice was prolonged, and susceptibility to ventricular tachycardia or fibrillation induced by rapid ventricular pacing was increased. Action potential duration in H/M-Sod2(-/-) LV myocytes was prolonged, and automaticity was enhanced. The density of the inwardly rectifier K(+) current (I K1) was decreased in the LV cells of H/M-Sod2(-/-) mice. The AP intake partially improved these electrophysiological alterations and extended the lifespan in H/M-Sod2(-/-) mice. Thus, chronic exposure of the heart to oxidative stress produces a variety of electrophysiological abnormalities, increased susceptibility to ventricular arrhythmias, and action potential changes associated with the reduced density of I K1. Dietary intake of antioxidant nutrients may prevent oxidative stress-induced electrophysiological disturbances.

Cardioprotective effect of grape-seed proanthocyanidins on doxorubicin-induced cardiac toxicity in rats.

CONTEXT: Doxorubicin (Dox) is an anthracycline antibiotic used as anticancer agent. However, its use is limited due to its cardiotoxicity which is mainly attributed to accumulation of reactive oxygen species. OBJECTIVE: This study was conducted to assess whether the antioxidant, proanthocyanidins (Pro) can ameliorate Dox-induced cardiotoxicity in rats. MATERIALS AND METHODS: Male Sprague-Dawely rats were divided into four groups. Group I was control. Group II received Pro (70 mg/kg, orally) once daily for 10 days. Group III received doxorubicin 15 mg/kg i.p. as a single dose on the 7th day and Group IV animals were treated with Pro once daily for 10 days and Dox on the 7th day. The parameters of study were serum biomarkers, cardiac tissue antioxidant status, ECG, and effect on aconitine-induced cardiotoxicity. RESULTS: Cardiac toxicity of doxorubicin was manifested as a significant increase in heart rate, elevation of the ST segment, prolongation of the QT interval and an increase in T wave amplitude. In addition, Dox enhanced aconitine-induced cardiotoxicity by a significant decrease in the aconitine dose producing ventricular tachycardia (VT). Administration of Pro significantly suppressed Dox-induced ECG changes and normalized the aconitine dose producing VT. The toxicity of Dox was also confirmed biochemically by significant elevation of serum CK-MB and LDH activities as well as myocardial MDA and GSH contents and decrease in serum catalase and myocardial SOD activities. Administration of Pro significantly suppressed these biochemical changes. DISCUSSION AND CONCLUSION: These results suggest that proanthocyanidins might be a potential cardioprotective agent against Dox-induced cardiotoxicity due to its antioxidant properties.

Protective effect of CardiPro against doxorubicin-induced cardiotoxicity in mice.

The effect of CardiPro, a polyherbal formulation, with an antioxidant property, has been studied on doxorubicin (DXR)-induced cardiotoxicity in mice. CardiPro (150 mg/kg b.w., twice daily was administered orally for 7 weeks along with four equal injections (each containing 4.0 mg/kg b.w., DXR) intraperitoneally, once weekly (cumulative dose 16 mg/kg). After a 3-week post DXR treatment period, cardiotoxicity was assessed by noting mortality, volume of ascites, liver congestion, changes in heart weight, myocardial lipid peroxidation, antioxidant enzymes and histology of heart. DXR-treated animals showed higher mortality (50%) and more ascites. Myocardial SOD and glutathione peroxidase activity were decreased and lipid peroxidation was increased. Histology of heart of DXR-treated animals showed loss of myofibrils and focal cytoplasmic vacuolization. CardiPro significantly protected the mice from DXR-induced cardiotoxic effects as evidenced by lower mortality (25%), less ascites, myocardial lipid peroxidation, normalization of antioxidant enzymes and minimal damage to the heart histologically. Our data confirm the earlier reports that DXR cardiotoxicity is associated with the free radical-induced tissue damage. Administration of CardiPro, with an antioxidant property, protected the DXR-induced cardiotoxicity in mice.

Panax ginseng reduces adriamycin-induced heart failure in rats.

The purpose of this study was to investigate the protective effects of Panax ginseng on adriamycin-induced heart failure. Wistar rats were divided into four groups: control, adriamycin, ginseng and adriamycin with ginseng. Adriamycin (cumulative dose, 15 mg/kg) was administered to rats in six equal intraperitoneal injections over a period of 2 weeks. Ginseng was administered via an oral feeding tube once a day for 30 days (cumulative dose, 150 g/kg). At the end of the 5 week post-treatment period, the hearts of the rats were used to study the synthesis rates of DNA, RNA and protein, myocardial antioxidants and lipid peroxidation. At the end of 3 weeks treatment, heart failure was characterized by ascites, congested liver and depressed cardiac function. Nucleic acid as well as protein synthesis was inhibited, lipid peroxidation was increased and myocardial glutathione peroxidase activity was decreased indicating adriamycin-induced heart failure. In contrast, the administration of ginseng, before and concurrent with adriamycin, significantly attenuated the myocardial effects, lowered the mortality as well as the amount of ascites, increased in myocardial glutathione peroxidase, macromolecular biosynthesis and superoxide dismutase activities, with a concomitant decrease in lipid peroxidation. These findings indicated that ginseng may be partially protective against adriamycin-induced heart failure.

Protective effect of Spirulina against doxorubicin-induced cardiotoxicity.

The generation of reactive oxygen species and mitochondrial dysfunction has been implicated in doxorubicin (DOX)-induced cardiotoxicity. The aim of the present study was to determine whether Spirulina, a blue-green algae, could serve as a cardioprotective agent during DOX treatment in a mouse model. Mice were treated with DOX (4 mg/kg bw, intraperitoneally), weekly, for 4 weeks. Spirulina was administered orally for 3 days twice daily, then for 7 weeks along with the four equal injections of DOX. Cardiotoxicity was assessed, at 3 weeks after the end of the DOX-treatment period, by mortality, volume of ascites, liver congestion, oxidative stress and ultrastructural changes of heart tissue. The DOX-treated animals showed higher mortality (53%) and more ascites. Myocardial damage, as assessed by ultrastructural changes, showed loss of myofibrils, cytoplasmic vacuolization and mitochondrial swelling. Myocardial superoxide dismutase and glutathione peroxidase activities were decreased and lipid peroxidation was increased. Pretreatment with Spirulina significantly protected the mice from DOX-induced cardiotoxic effects as evidenced from lower mortality (26%), less ascites, lower levels of lipid peroxidation, normalization of antioxidant enzymes and ultrastructural studies showing minimal damage to the heart. In vitro cytotoxic studies using ovarian cancer cells demonstrated that Spirulina did not compromise the anti-tumor activity of doxorubicin. These results suggest that Spirulina has a protective effect against cardiotoxicity induced by DOX and it may, therefore, improve the therapeutic index of DOX.

Isradipine prevents the development of spontaneously occurring cardiac necrosis in cardiomyopathic hamster.

Recent studies on the heart necrotizing process at the early stages of hamster polymyopathy have led us to believe that this hereditary disease derives from an anomalous transmembrane ion flux due to the presence of slow Na+ channels that contribute to intracellular Na+ accumulation which promote intracellular Ca2+ overload via the Ca2+ influx through the Na+-Ca2+ exchanger. In the present study, we investigated the potential beneficial effect of chronic treatment with a dual L-type Ca2+ and slow Na+ channel blockers isradipine, on the development of necrosis in myopathic hamster hearts. Young cardiomyopathic (CM) hamsters (CMH) were treated with isradipine (0.1 mg x kg(-1) x day(-1)) and nifedipine (1 mg x kg(-1) x day(-1)) for 4 consecutive weeks. Microscopic assessments were carried out in staged serial paraffin sections of heart ventricles from tissues freshly dissected at autopsy. In comparison with control nontreated hearts, which exhibited numerous necrotic calcific foci, myolytic lesions, and dilated right ventricle, isradipine treatment prevented, in a significant manner, all the above spontaneous pathological changes, while nifedipine had no effect. Our present observations provide evidence for the first time that in vivo treatment with a DHP Ca2+ channel blocker, isradipine, is cardioprotective against the development of necrosis in hereditary cardiomyopathy in the hamster. It is possible that the protective effect of isradipine in CMH could be largely due to the indirect blockade of Ca2+ influx through the Na+-Ca2+ exchanger as well as to possible direct blockade of Ca2+ influx through the T-type Ca2+ channel.

Studies on human dietary requirements and safe range of dietary intakes of selenium in China and their application in the prevention of related endemic diseases.

The human dietary selenium requirement in China has been estimated by various methods. The minimum dietary selenium requirement for the prevention of Keshan disease (KD) was found to be around 17 micrograms/d. On the other hand, an intake of 40 micrograms/d is required to maintain the plasma glutathione peroxidase (GPx) activity at plateau. Hence 40 micrograms/d is considered as the adequate dietary selenium requirement. Studies conducted in a chronic selenosis area indicate that the toxic dietary selenium intake (adverse effect level), which would maintain the characteristic fingernail changes, was approximately 1600 micrograms/d. The mean value of dietary selenium intakes, which enabled the five patients to recover from fingernail lesions, was found to be 819 +/- 126 micrograms/d. At a 95% confidence limit, the lower limit is around 600 micrograms/d. Therefore, 600 and 400 micrograms/d were suggested as the individual daily maximum safe selenium intake and the safe dietary selenium intake, respectively. The results were used in the prevention of Se-related endemic KD and Kashin-Beck disease (KBD).