Vicious LQT induced by a combination of factors different from hERG inhibition.

Clinically, drug-induced torsades de pointes (TdP) are rare events, whereas the reduction of the human ether-à-go-go-related gene (hERG) current is common. In this study, we aimed to explore the specific factors that contribute to the deterioration of hERG inhibition into malignant ventricular arrhythmias. Cisapride, a drug removed from the market because it caused long QT (LQT) syndrome and torsade de pointes (TdP), was used to induce hERG inhibition. The effects of cisapride on the hERG current were evaluated using a whole-cell patch clamp. Based on the dose-response curve of cisapride, models of its effects at different doses (10, 100, and 1,000 nM) on guinea pig heart in vitro were established. The effects of cisapride on electrocardiogram (ECG) signals and QT interval changes in the guinea pigs were then comprehensively evaluated by multi-channel electrical mapping and high-resolution fluorescence mapping, and changes in the action potential were simultaneously detected. Cisapride dose-dependently inhibited the hERG current with a half inhibitory concentration (IC50) of 32.63 ± 3.71 nM. The complete hERG suppression by a high dose of cisapride (1,000 nM) prolonged the action potential duration (APD), but not early after depolarizations (EADs) and TdP occurred. With 1 µM cisapride and lower Mg2+/K+, the APD exhibited triangulation, dispersion, and instability. VT was induced in two of 12 guinea pig hearts. Furthermore, the combined administration of isoproterenol was not therapeutic and increased susceptibility to ventricular fibrillation (VF) development. hERG inhibition alone led to QT and ERP prolongation and exerted an anti-arrhythmic effect. However, after the combination with low concentrations of magnesium and potassium, the prolonged action potential became unstable, triangular, and dispersed, and VT was easy to induce. The combination of catecholamines shortened the APD, but triangulation and dispersion still existed. At this time, VF was easily induced and sustained.

RKIP-Mediated NF-κB Signaling is involved in ELF-MF-mediated improvement in AD rat.

In a previous study, we reported the positive effects of extremely low frequency electromagnetic field (ELF-MF) exposure on Alzheimer's disease (AD) rats; however, the underlying mechanism remains unclear. In addition, we found that Raf-1 kinase inhibitor protein (RKIP) was downregulated by microwave exposure in the rat hippocampus. Our hypothesis was that RKIP-mediated NF-κB pathway signaling is involved in the effect of ELF-MF on the AD rat. In this study, D-galactose intraperitoneal (50 mg/kg/d for 42 d) and Aß25-35 hippocampal (5 µL/unilateral, bilateral, single-dose) injection were implemented to establish an AD rat model. Animals were exposed to 50 Hz and 400 µT ELF-MF for 60 continuous days. The spatial memory ability of the rat was then tested using the Morris water maze. Protein expression and interaction were detected by western blotting and co-immunoprecipitation for RKIP-mediated NF-κB pathway factors. The results showed that ELF-MF exposure partially improved the cognitive disorder, upregulated the levels of RKIP, TAK1, and the RKIP/TAK1 interaction, but downregulated p-IKK levels in AD rats. These results indicated that RKIP-mediated NF-κB pathway signaling plays an important role in the ELF-MF exposure-mediated improvements in the AD rat. Our study suggested that ELF-MF exposure might have a potential therapeutic value for AD. Further in depth studies are required in the future.

Heijiangdan ointment relieves oxidative stress from radiation dermatitis induced by (60)Co γ-ray in mice.

OBJECTIVE: To investigate the effects of Heijiangdan Ointment ( HJD) on oxidative stress in (60)Co γ-ray radiation-induced dermatitis in mice. METHODS: Female Wistar mice with grade 4 radiation dermatitis induced by (60)Co γ-rays were randomly divided into four groups (n=12 per group); the HJD-treated, recombinant human epidermal growth factor (rhEGF)-treated, Trolox-treated, and untreated groups, along with a negative control group. On the 11th and 21st days after treatment, 6 mice in each group were chosen for evaluation. The levels of superoxide dismutase (SOD), malondialdehyde (MDA), and lactate dehydrogenase (LDH) were detected using spectrophotometric methods. The fibroblast mitochondria were observed by transmission electron microscopy (TEM). The expressions of fibroblast growth factor 2 (FGF-2) and transforming growth factor ß1 (TGF-ß1) were analyzed by western blot. RESULTS: Compared with the untreated group, the levels of SOD, MDA and LDH, on the 11th and 21st days after treatment showed significant difference (P<0.05). TEM analysis indicated that fibroblast mitochondria in the untreated group exhibited swelling and the cristae appeared fractured, while in the HJD group, the swelling of mitochondria was limited and the rough endoplasmic reticulum appeared more relaxed. The expressions of FGF-2 and TGF-ß1 increased in the untreated group compared with the negative control group (P<0.05). After treatment, the expression of FGF-2, rhEGF and Trolox in the HJD group were significantly increased compared with the untreated group (P<0.05), or compared with the negative control group (P<0.05). The expression of TGF-ß1 showed significant difference between untreated and negative control groups (P<0.05). HJD and Trolox increased the level of TGF-ß1 and the difference was marked as compared with the untreated and negative control groups (P<0.05). CONCLUSION: HJD relieves oxidative stress-induced injury, increases the antioxidant activity, mitigates the fibroblast mitochondrial damage, up-regulates the expression of growth factor, and promotes mitochondrial repair in mice.

Neuroprotective effects of dietary supplement Kang-fu-ling against high-power microwave through antioxidant action.

Kang-fu-ling (KFL) is a polybotanical dietary supplement with antioxidant properties. This study aimed to evaluate the potential protective effects of KFL on cognitive deficit induced by high-power microwave (HPM) and the underlying mechanism for this neuroprotection. The electron spin resonance technique was employed to evaluate the free radical scavenging activity of KFL in vitro and KFL exhibited scavenging hydroxyl radical activity. KFL at doses of 0.75, 1.5 and 3 g kg(-1) and vehicle were administered orally once daily for 14 days to male Wistar rats after being exposed to 30 mW cm(-2) HPM for 15 minutes. KFL reversed HPM-induced memory loss and the histopathological changes in hippocampus of rats. In addition, KFL displayed a protective effect against HPM-induced oxidative stress and activated the nuclear factor-E2-related factor 2 (Nrf2) and its target genes in the hippocampus of rats. The Nrf2-antioxidant response element (ARE) signaling pathway may be involved in the neuroprotective effects of KFL against HPM-induced oxidative stress. In summary, the dietary supplement KFL is a promising natural complex, which ameliorates oxidative stress, with neuroprotective effects against HPM.

The compound Chinese medicine "Kang Fu Ling" protects against high power microwave-induced myocardial injury.

BACKGROUND: The prevention and treatment of Microwave-caused cardiovascular injury remains elusive. This study investigated the cardiovascular protective effects of compound Chinese medicine "Kang Fu Ling" (KFL) against high power microwave (HPM)-induced myocardial injury and the role of the mitochondrial permeability transition pore (mPTP) opening in KFL protection. METHODS: Male Wistar rats (100) were divided into 5 equal groups: no treatment, radiation only, or radiation followed by treatment with KFL at 0.75, 1.5, or 3 g/kg/day. Electrocardiography was used to Electrophysiological examination. Histological and ultrastructural changes in heart tissue and isolated mitochondria were observed by light microscope and electron microscopy. mPTP opening and mitochondrial membrane potential were detected by confocal laser scanning microscopy and fluorescence analysis. Connexin-43 (Cx-43) and endothelial nitric oxide synthase (eNOS) were detected by immunohistochemistry. The expression of voltage-dependent anion channel (VDAC) was detected by western blotting. RESULTS: At 7 days after radiation, rats without KFL treatment showed a significantly lower heart rate (P<0.01) than untreated controls and a J point shift. Myocyte swelling and rearrangement were evident. Mitochondria exhibited rupture, and decreased fluorescence intensity, suggesting opening of mPTP and a consequent reduction in mitochondrial membrane potential. After treatment with 1.5 g/kg/day KFL for 7 d, the heart rate increased significantly (P<0.01), and the J point shift was reduced flavorfully (P<0.05) compared to untreated, irradiated rats; myocytes and mitochondria were of normal morphology. The fluorescence intensities of dye-treated mitochondria were also increased, suggesting inhibition of mPTP opening and preservation of the mitochondrial membrane potential. The microwave-induced decrease of Cx-43 and VDAC protein expression was significantly reversed. CONCLUSION: Microwave radiation can cause electrophysiological, histological and ultrastructural changes in the heart. KFL at 1.5 g/kg/day had the greatest protective effect on these cardiovascular events. mPTP plays an important role in the protective effects of KFL against microwave-radiation-induced myocardial injury.

Wushen, a food mixture containing 55 different natural ingredients, inhibits S180 tumor growth in vivo.

As cancer has become a worldwide threat to human life and health, developing a safe and effective tumor-inhibiting agent is presently a major scientific challenge. In this study, a food mixture produced from 55 different natural ingredients called wushen was fed to S180 tumor-bearing mice, and the antitumor effects were investigated in vivo. Kunming mice were implanted subcutaneously in the armpit with murine sarcoma S180 cells to construct the S180 tumor-bearing mouse model. The mice were randomly divided into three groups: control, wushen and 5-fluorouracil (5-Fu). 5-Fu was used as the positive drug treatment to confirm the reliability of the model. The food intake, antitumor rate, and spleen and thymus indices were recorded. Tumor histopathology was conducted using hematoxylin and eosin (H&E) staining. The catalase, glutathione peroxidase, and superoxide dismutase activities and the malondialdehyde concentration were measured to evaluate the antioxidative effects of the treatments. The antitumor rate of the mice fed wushen was 48.52%. Wushen-treated mice exhibited alterations in antioxidative enzyme activity and reduced liver lipid peroxidation. The results demonstrated that wushen has antitumor effects on S180 tumor-bearing mice in vivo, and the underlying mechanism is partially due to its antioxidant activity. Wushen, which contains various natural products, can be eaten directly and may be beneficial to human health.

[The protective effects of Aduola Fuzhenglin on the heart injury induced by microwave exposure in rats].

OBJECTIVE: To study the protective effects of AduoLa Fuzhenglin(ADL) on the heart injury induced by microwave exposure in rats. METHODS: One hundred forty male Wistar rats were divided randomly into 5 groups: control, microwave radiation, 0.75 g x kg(-1) d(-1) ADL, 1.50 g x kg(-1) d(-1) ADL and 3.00 g x kg(-1) d(-1) ADL pretreatment groups. Rats in three ADL pretreatment groups were administrated by ADL per day for 2w then exposed to 30 mW/cm2 microwaves for 15 min. The left ventricle blood of rats was obtained at 7 d and 14 d after exposure to microwaves, and the blood Ca2+, AST and CK were detected with Coulter automatic biochemical analyzer, then the histological changes and ultrastructure of heart were observed under light and electron microscopes. RESULTS: At 7 d and 14 d after exposure to microwaves, the blood Ca2+, AST and CK concentrations significantly increased (P<0.05 or P<0.01) as compared with controls; Heart muscle fibers showed wavilness, endotheliocyte karyopyknosis, anachromasis; The mitochondria swelling and cavitation, intercalary dies blurred in radiation groups. The changes in 0.75 g x kg(-1) d(-1) ADL pretreatment group were similar to the radiation group, but in 1.50 g x kg(-1)d(-1) and 3.00 g x kg(-1) d(-1) ADL pretreatment groups, above indexes of rats significantly reduced as compared with microwaves group (P<0.05); also the blood Ca2+, AST, CK contents were significantly lower than those in microwave group (P<0.05); The heart showed a tendency to improve. CONCLUSION: Microwave radiation (30 mW/cm2) can cause the blood Ca2+, AST and CK turbulence, and heart injury in the histology and ultrastructure; ADL at the dosages of 1.50 g x kg(-1) d(-1) and 3.00 g x kg(-1) d(-1) has a protective effects on the heart injury induced by microwave in rats.

[The construction and significance of the Chinese Museum of War Injuries].

The Chinese Museum of War Injuries is the only military medical museum in China which collects special weapons, conventional weapons, high-tech weapons and pathological specimens, materials and documents of human and animal injuries caused by military environments and military operations, amounting to 4,350 objects. The construction of the Chinese Museum of War Injuries played an important role in the aspects of military medical education and training, popularization of public health knowledge, preservation of military medical historical materials and opening up to the outside world etc, to which should priority attention should be paid to by the Chinese government and relevant military departments.

[Changes of apoptosis, mitochondrion membrane potential and Ca2+ of hypothalamic neurons induced by high power microwave].

OBJECTIVE: To explore the injury effect and mechanism of hypothalamic neurons after high power microwave (HPM) exposure. METHODS: Primarily cultured hypothalamic neurons were exposed to 10 and 30 mW/cm(2) HPM, and the inverted phase contrast microscope (IPCM) and flow cytometry (FCM) were employed to detect the injury of cells and change of mitochondrion membrane potential (MMP) and Ca(2+) in the cytoplasm of neurons. RESULTS: The ratio of apoptosis was significantly higher than that of the sham exposure (P < 0.05) induced by 10 and 30 mW/cm(2) HPM and necrosis increased significantly (P < 0.05) in the group of 30 mW/cm(2) at 6 h after exposure. The content of Ca(2+) in the cytoplasm of neuron cells increased (P < 0.01) while MMP decreased significantly (P < 0.01) after radiation of 30 mW/cm(2) HPM at 6 h after exposure. CONCLUSION: Apoptosis is one of the major death ways of hypothalamic neurons. The overloading of Ca(2+) and the decline of MMP are involved in the process.