Methyl Jasmonate-induced Increase in Intracellular Magnesium Promotes Apoptosis in Breast Cancer Cells.

BACKGROUND/AIM: Methyl jasmonate (MeJa) is a botanical stress hormone that serves as a defense mechanism to inhibit growth in stressed plants. It is well known that MeJa exhibits an anticancer effect by reducing intracellular ATP, activating reactive oxygen species (ROS) production, and promoting mitogen-activated protein kinase (MAPK) activity. Presently, no report has been published on MeJa-induced changes in intracellular Mg2+ concentration ([Mg2+]i), and TRPM7 as an Mg2+ transporter in cancer cells. Therefore, this study aimed to investigate the Mg2+ homeostatic changes and apoptotic effects following MeJa treatment using the MCF-7 human breast cancer cell line. MATERIALS AND METHODS: The MTT assay was used to assess the cell viability and half-inhibitory concentration, microscopic two-photon excitation wavelength spectrophotometry was used to measure the [Mg2+]i, a luminescent assay determined intracellular ATP levels, western blot assay measured TRPM7 levels, antioxidant capacities, endoplasmic reticulum (ER) stress, and MAPK signaling pathways, while the fluorescence assay evaluated ROS concentrations and the cell apoptotic index. RESULTS: This study provides evidence that MeJa has an antiapoptotic effect on MCF-7 cells. The increase in [Mg2+]i led to decreased TRPM7 expression, which is related to elevated ROS production, in addition to elevated ER stress and MAPK signaling pathway activity and decreased ATP content. CONCLUSION: The increase in [Mg2+]i leads to decreased TRPM7 expression and may be the epicenter of MeJa-induced apoptotic cell death in MCF-7 cells.

Application of Patient-Specific Instrumentation in a Dog Model with Antebrachial Growth Deformity Using a 3-D Phantom Bone Model.

One of the most frequent bone deformities in dogs is antebrachial growth deformity (AGD), which results from malunion of the distal growth plates. The objective of the present study was to re-align the limbs, which can correct the length mismatch and reset the coherence of the joint with the aid of a 3-D phantom model for surgical preplanning. A 14-month-old, intact female Golden Retriever with an angular deformity of the left radius and ulna was selected for the study. The diagnosis was confirmed by orthogonal radiographs. Moreover, computed tomography (CT) scans revealed a multiplane deformity with valgus, procurator, and external rotation of the left radius. The pre-surgical planning started with the quantification of the angular deformity, followed by a simulated virtual osteotomy, and concluded with an in vitro rehearsal surgery on 3-D printed phantom bone models. In the operating room, prefabricated patient-specific instrumentation (PSI) was attached at the planned site of the radial bone surface for a precise closing wedge osteotomy. Then two locking plates were fixed routinely. Post-operative radiographs showed accurate correction of the deformity as we had planned. At 12 weeks post-operatively, the follow-up surveys revealed improved gait, weight-bearing, and progression of bone healing. Our PSI design, based on novel surgical planning, was steady yet straightforward during the osteotomy. The osteotomy was performed without difficulty since the PSI that pre-determined the sites and angles let the surgeon perform the antebrachial malformation surgery. This method of operation reduces stress on the operator and helps to improve accuracy, repeatability, and surgery time.

An Easy and Economical Way to Produce a Three-Dimensional Bone Phantom in a Dog with Antebrachial Deformities.

3-D surgical planning for restorative osteotomy is costly and time-consuming because surgeons need to be helped from commercial companies to get 3-D printed bones. However, practitioners can save time and keep the cost to a minimum by utilizing free software and establishing their 3-D printers locally. Surgical planning for the corrective osteotomy of antebrachial growth deformities (AGD) is challenging for several reasons (the nature of the biapical or multiapical conformational abnormalities and lack of a reference value for the specific breed). Pre-operative planning challenges include: a definite description of the position of the center of rotation of angulation (CORA) and proper positioning of the osteotomies applicable to the CORA. In the present study, we demonstrated an accurate and reproducible bone-cutting technique using patient-specific instrumentations (PSI) 3-D technology. The results of the location precision showed that, by using PSIs, the surgeons were able to accurately replicate preoperative resection planning. PSI results also indicate that PSI technology provides a smaller standard deviation than the freehand method. PSI technology performed in the distal radial angular deformity may provide good cutting accuracy. In conclusion, the PSI technology may improve bone-cutting accuracy during corrective osteotomy by providing clinically acceptable margins.

Aralia continentalis kitagawa Extract Attenuates the Fatigue Induced by Exhaustive Exercise through Inhibition of Oxidative Stress.

The present study aimed to evaluate the anti-fatigue effects of Aralia continentalis kitagawa (AC) extract during exhaustive exercise of rats by forced swimming. Rats were subjected to forced swimming until exhausted after pre-treatment with AC extract for 21 days. Exhaustion time significantly increased in rats treated with AC extract. AC treatment also preserved blood homeostasis during fatigue due to exhaustive exercise. For fatigue-related serum biomarkers, AC extract significantly fail to decrease glucose and triglyceride (TG), but ameliorated increased lactate levels compared with levels in control rats. Metabolic acidosis, a major cause of fatigue, was effectively attenuated by AC extract, according to metabolic acidosis-related blood parameters. AC extract suppressed muscle injury and attenuated gastrocnemius muscle apoptotic responses due to exhaustive exercise. To investigate the mechanisms behind the AC extract anti-fatigue effect, we evaluated its effect on oxidative stress-related fatigue. We showed that pro-oxidants were inhibited, while antioxidants were preserved by AC extract treatment. Therefore, the anti-fatigue effect of AC extract was mediated by suppression of oxidative stress. Overall, the study demonstrated that AC extract effectively attenuates fatigue from exhaustive exercise through oxidative stress inhibition. AC extract, as an antioxidant, could be utilized as a therapeutic or preventive strategy against exhaustive exercise fatigue.

Red Ginseng Reduces Inflammatory Response via Suppression MAPK/P38 Signaling and p65 Nuclear Proteins Translocation in Rats and Raw 264.7 Macrophage.

Lipopolysaccharides (LPS) cause systemic inflammatory responses, which are characterized by high mortality and multiple signs, including metabolic disturbances, respiratory acidosis, hypotension, and vital organs disorder. Cytokines secretion and oxidative stress are the main features of the disease. Diagnosis and treatment of systemic inflammation (SI) remain a challenge. Korean Red Ginseng (RG) is one of medicinal herbs that showed a potent anti-oxidant effect. We aimed to study the protective effects of RG on systemic inflammatory response in rats and RAW 264.7 macrophage cells induced by LPS. The rats were treated with water and alcohol extracts of RG for four weeks to prevent the inflammatory response. The result showed that LPS toxin increased morbidity and mortality, and induced liver, kidney, and lung injuries manifested by deteriorated biomarkers. Hypotension, hypomagnesemia, acidosis, and oxidative stress were observed in septic rats. However, RG extracts attenuated liver, kidney, and lung enzymes and metabolites in treated groups via its anti-inflammatory and anti-oxidant properties. Furthermore, RG improved magnesium and blood pressure in the treated groups. RAW 264.7 macrophage cells exposed to LPS disturbance in translocation of p65 and MAPK/p38. Nevertheless, RG-pretreated cells did not significantly alter. In conclusion, RG reduced the rates of mortality and morbidity of treated rats - liver, kidney, and lung injuries were protected in the treated groups through the potentiation of anti-oxidant defense. RG was able to conserve mitochondrial function, inhibiting the activation of MAPK/p38 signaling and suppressing NF-κB p65 cytoplasm-nucleus transport. Further studies are needed to examine the effects on chronic conditions in animal models and human.

Long-term oral intake of Panax ginseng improves hypomagnesemia, hyperlactatemia, base deficit, and metabolic acidosis in an alloxan-induced rabbit model.

OBJECTIVES: Panax ginseng (PG) widely used for its various pharmacological activities, including effects on diabetes and its complications. This study aims to investigate the effect of PG on mortality-related hypomagnesemia, hyperlactatemia, metabolic acidosis, and other diabetes-induced abnormalities. MATERIALS AND METHODS: Type 1 diabetes was induced by IV injection of alloxan monohydrate 110 mg/kg into New Zealand white rabbits weighing 2-2.5 kg. PG was supplied in drinking water for 20 weeks. The effects of the PG treatment on diabetes were evaluated through hematological and biochemical analysis including ELISA assays for insulin and glycated haemoglobin A1c (HBA1c) before and after PG extract was supplied. RESULTS: The serum glucose, insulin, and HBA1c levels were significantly improved after the PG treatment compared to those found before PG treatment. In addition, Mg2+, lactate, and base deficit, and acidosis was significantly enhanced in treated rabbits. Moreover, PG showed hepato- and renoprotective effect. Likewise, electrolytes, lipid and protein profile were improved. CONCLUSION: The biochemical and hematological analysis data demonstrate that the PG is effective to alleviate the diabetes serious signs.

Cucurbitacin I Protects H9c2 Cardiomyoblasts against H2O2-Induced Oxidative Stress via Protection of Mitochondrial Dysfunction.

Cucurbitacin I, a triterpenoid natural compound, exhibits various pharmacological properties, including anticancer, anti-inflammatory, and hepatoprotective properties. However, antioxidant effects of cucurbitacin I in cardiac cells are currently unknown. In the present study, we assessed the preventive effects of cucurbitacin I against the oxidative stress in H9c2 cardiomyoblasts. To evaluate antioxidant effects of cucurbitacin I in H9c2 cardiomyoblasts, H2O2-treated H9c2 cells were pretreated with various concentrations of the cucurbitacin I. Cell viability, reactive oxygen species (ROS) production, and apoptosis were determined to elucidate the protective effects of cucurbitacin I against H2O2-induced oxidative stress in H9c2 cells. In addition, we assessed the mitochondrial functions and protein expression levels of mitogen-activated protein kinases (MAPKs). Cucurbitacin I prevented the cells against cell death and ROS production and elevated the antioxidant protein levels upon oxidative stress. Furthermore, cucurbitacin I preserved the mitochondrial functions and inhibited the apoptotic responses in H2O2-treated cells. Cucurbitacin I also suppressed the activation of MAPK proteins (extracellular signal-regulated kinase 1/2, c-Jun N-terminal kinase, and p38). Collectively, cucurbitacin I potentially protects the H9c2 cardiomyoblasts against oxidative stress and further suggests that it can be utilized as a therapeutic agent for the prevention of oxidative stress in cardiac injury.

Desipramine induces apoptosis in hepatocellular carcinoma cells.

Antitumor effects of antidepressants have been reported in many cancer cell lines. However, anti-proliferative effects of desipramine, a tricyclic antidepressant, in hepatocellular carcinoma are currently unknown. In this study, we examined the effects of desipramine in human hepatoma Hep3B cells. To evaluate anti-proliferative effects of desipramine in Hep3B cells, we determined cell viability, reactive oxygen species (ROS) production, mitochondrial membrane potential (MMP), mitogen-activated protein kinase (MAPK) activity, and intracellular Ca2+ levels after desipramine treatment. Desipramine reduced cell viability, increased ROS production, and decreased MMP activity in Hep3B cells. In addition, desipramine activated MAPKs (ERK 1/2, JNK, and p38) and increased intracellular Ca2+ levels. Pro-apoptotic effects of desipramine were abolished after MAPK inhibitors (PD98059, SB203580, and SP600125) or N-acetyl-L-cysteine (NAC), as a ROS scavenger, treatments. These findings suggest that desipramine shows anti-proliferative effects in Hep3B cells mediated by promotion of apoptosis, activation of MAPK signaling, and increase in intracellular Ca2+ levels.

Nigella sativa seed extract attenuates the fatigue induced by exhaustive swimming in rats.

In previous studies, Nigella sativa (NS) has been studied due to its various physiological and pharmacological activities. However, evidence on the effects of NS on physical fatigue following exhaustive swimming remains limited. In the present study, the authors evaluated the potential beneficial effects of NS against the fatigue activity following exhaustive swimming. Rats were orally administered with NS extract (2 g/kg/day) for 21 days, and the anti-fatigue effect was assessed by exhaustive swimming exercise. The presented results indicated that pre-treatment of NS extract significantly increased the time to exhaustion. In hemodynamic parameters, NS extract increased blood pO2 and O2sat, but decreased pCO2. For underlying mechanisms, NS extract protected depletion of energy, indicated by increased levels of blood pH, glucose and tissue glycogen contents, and decreased levels of blood lactate, tissue lactic dehydrogenase and creatine kinase, when the NS extract was pre-treated. In addition, the NS extract inhibited oxidative stress following exhaustive swimming, as reflected by the results of increased levels of superoxide dismutase and redox ratio, and decreased the level of malondialdehyde when the NS extract was pre-treated. Collectively, the present study demonstrated that NS extract has an anti-fatigue activity against exhaustive swimming by energy restoration and oxidative-stress defense.

Hypocholesterolemic Effects of Probiotic Mixture on Diet-Induced Hypercholesterolemic Rats.

Growing evidence has indicated that supplementation with probiotics improves lipid metabolism. We aimed to investigate the beneficial effects of a probiotics mixture (PM) of three strains belonging to the species Bifidobacterium (B. longum, B. lactis, and B. breve) and two strains belonging to the species Lactobacillus (L. reuteri and L. plantarum) on cholesterol-lowering efficacy in hypercholesterolemic rats. A hypercholesterolemic rat model was established by feeding a high-cholesterol diet for eight weeks. To test the effects of PM on hypercholesterolemia, hypercholesterolemic rats were assigned to four groups, which were treated daily with low (1.65 × 108 cfu/kg), medium (5.5 × 108 cfu/kg), or high (1.65 × 1010 cfu/kg) doses of probiotic mixture or simvastatin for eight weeks. Significant reductions of serum total cholesterol (TC), triacylglycerol (TG), and low-density lipoprotein (LDL)-cholesterol levels, but increases of high-density lipoprotein (HDL)-cholesterol were observed after supplementation of PM in hypercholesterolemic rats. In PM-supplemented hypercholesterolemic rats, hepatic tissue contents of TC and TG also significantly decreased. Notably, the histological evaluation of liver tissues demonstrated that PM dramatically decreased lipid accumulation. For their underlying mechanisms, we demonstrated that PM reduced expressions of cholesterol synthesis-related proteins such as sterol regulatory element-binding protein 1 (SREBP1), fatty acid synthase (FAS), and acetyl-CoA carboxylase (ACC) in the liver. Taken together, these findings suggest that PM has beneficial effects against hypercholesterolemia. Accordingly, our PM might be utilized as a novel therapeutic agent for the management of hypercholesterolemia.

Alterations of Mg2+ After Hemorrhagic Shock.

Hemorrhagic shock is generally characterized by hemodynamic instability with cellular hypoxia and diminishing cellular function, resulting from an imbalance between systemic oxygen delivery and consumption and redistribution of fluid and electrolytes. Magnesium (Mg) is the fourth most abundant cation overall and second most abundant intracellular cation in the body and an essential cofactor for the energy production and cellular metabolism. Data for blood total Mg (tMg; free-ionized, protein-bound, and anion-bound forms) and free Mg2+ levels after a traumatic injury are inconsistent and only limited information is available on hemorrhagic effects on free Mg2+ as the physiologically active form. The aim of this study was to determine changes in blood Mg2+ and tMg after hemorrhage in rats identifying mechanism and origin of the changes in blood Mg2+. Hemorrhagic shock produced significant increases in blood Mg2+, plasma tMg, Na+, K+, Cl-, anion gap, partial pressures of oxygen, glucose, and blood urea nitrogen but significant decreases in RBC tMg, blood Ca2+, HCO3-, pH, partial pressures of carbon dioxide, hematocrit, hemoglobin, total cholesterol, and plasma/RBC ATP. During hemorrhagic shock, K+, anion gap, and BUN showed significant positive correlations with changes in blood Mg2+ level, while Ca2+, pH, and T-CHO correlated to Mg2+ in a negative manner. In conclusion, hemorrhagic shock induced an increase in both blood-free Mg2+ and tMg, resulted from Mg2+ efflux from metabolic damaged cell with acidosis and ATP depletion.

Hepatoprotective effects of Nigella sativa seed extract against acetaminophen-induced oxidative stress.

OBJECTIVE: To investigate the protective effects of Nigella sativa seed extract (NSSE) against acetaminophen (APAP)-induced hepatotoxicity in TIB-73 cells and rats. METHODS: Toxicity in TIB-73 cells was induced with 10 µmol/L APAP and the protective effects of NSSE were evaluated at 25, 50, 75, 100 µg/mL. For in vivo examination, a total of 30 rats were equally divided into five experimental groups; normal control (vehicle), APAP (800 mg/kg body weight single IP injection) as a hepatotoxic control, and three APAP and NS pretreated (2 weeks) groups (APAP + NSSE 100 mg; APAP + NSSE 300 mg and APAP + NSSE 900 mg/kg). RESULTS: TIB-73 cell viability was drastically decreased by (49.0 ± 1.9)% after the 10 µmol/LAPAP treatment, which also increased reactive oxygen species production. Co-treatment with NSSE at 25, 50, 75, and 100 µg/mL significantly improved cell viability and suppressed reactive oxygen species generation. In vivo, the APAP induced alterations in blood lactate levels, pH, anionic gap, and ion levels (HCO3(-), Mg(2+) and K(+)), which tended to normalize with the NSSE pretreatment. The NSSE also significantly decreased elevated serum levels of alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, and alkaline phosphatase induced by APAP, which correlated with decreased levels of hepatic lipid peroxidation (malondialdehyde), increased superoxide dismutase levels, and reduced glutathione concentrations. Improved hepatic histology was also found in the treatment groups other than APAP group. CONCLUSIONS: The in vitro and in vivo findings of this study demonstrated that the NSSE has protective effects against APAP-induced hepatotoxicity and metabolic disturbances by improving antioxidant activities and suppressing both lipid peroxidation and ROS generation.

Cellular Hypertrophy and Increased Susceptibility to Spontaneous Calcium-Release of Rat Left Atrial Myocytes Due to Elevated Afterload.

Atrial remodeling due to elevated arterial pressure predisposes the heart to atrial fibrillation (AF). Although abnormal sarcoplasmic reticulum (SR) function has been associated with AF, there is little information on the effects of elevated afterload on atrial Ca2+-handling. We investigated the effects of ascending aortic banding (AoB) on Ca2+-handling in rat isolated atrial myocytes in comparison to age-matched sham-operated animals (Sham). Myocytes were either labelled for ryanodine receptor (RyR) or loaded with fluo-3-AM and imaged by confocal microscopy. AoB myocytes were hypertrophied in comparison to Sham controls (P<0.0001). RyR labeling was localized to the z-lines and to the cell edge. There were no differences between AoB and Sham in the intensity or pattern of RyR-staining. In both AoB and Sham, electrical stimulation evoked robust SR Ca2+-release at the cell edge whereas Ca2+ transients at the cell center were much smaller. Western blotting showed a decreased L-type Ca channel expression but no significant changes in RyR or RyR phosphorylation or in expression of Na+/Ca2+ exchanger, SR Ca2+ ATPase or phospholamban. Mathematical modeling indicated that [Ca2+]i transients at the cell center were accounted for by simple centripetal diffusion of Ca2+ released at the cell edge. In contrast, caffeine (10 mM) induced Ca2+ release was uniform across the cell. The caffeine-induced transient was smaller in AoB than in Sham, suggesting a reduced SR Ca2+-load in hypertrophied cells. There were no significant differences between AoB and Sham cells in the rate of Ca2+ extrusion during recovery of electrically-stimulated or caffeine-induced transients. The incidence and frequency of spontaneous Ca2+-transients following rapid-pacing (4 Hz) was greater in AoB than in Sham myocytes. In conclusion, elevated afterload causes cellular hypertrophy and remodeling of atrial SR Ca2+-release.

Antidiabetic Effects of Yam (Dioscorea batatas) and Its Active Constituent, Allantoin, in a Rat Model of Streptozotocin-Induced Diabetes.

The objective of this study was to investigate the therapeutic efficacies of crude yam (Dioscorea batatas) powder (PY), water extract of yam (EY), and allantoin (the active constituent of yam) in streptozotocin (STZ)-induced diabetic rats with respect to glucose, insulin, glucagon-like peptide-1 (GLP-1), C-peptide, glycated hemoglobin (HbAlc), lipid metabolism, and oxidative stress. For this purpose, 50 rats were divided into five groups: normal control (NC), diabetic control (STZ), and STZ plus treatment groups (STZ + PY, STZ + EY, and STZ + allantoin). After treatment for one-month, there was a decrease in blood glucose: 385 ± 7 in STZ, 231 ± 3 in STZ + PY, 214 ± 11 in STZ + EY, and 243 ± 6 mg/dL in STZ + allantoin, respectively. There were significant statistical differences (p < 0.001) compared to STZ (100%): 60% in STZ + PY, 55% in STZ + EY, and 63% in STZ + allantoin. With groups in the same order, there were significant decreases (p < 0.001) in HbAlc (100% as 24.4 ± 0.6 ng/mL, 78%, 75%, and 77%), total cholesterol (100% as 122 ± 3 mg/dL, 70%, 67%, and 69%), and low-density lipoprotein (100% as 29 ± 1 mg/dL, 45%, 48%, and 38%). There were also significant increases (p < 0.001) in insulin (100% as 0.22 ± 0.00 ng/mL, 173%, 209%, and 177%), GLP-1 (100% as 18.4 ± 0.7 pmol/mL, 160%, 166%, and 162%), and C-peptide (100% as 2.56 ± 0.10 ng/mL, 129%, 132%, and 130%). The treatment effectively ameliorated antioxidant stress as shown by a significant decrease (p < 0.001) in malondialdehyde (100% as 7.25 ± 0.11 nmol/mL, 87%, 86%, and 85%) together with increases (p < 0.01) in superoxide dismutase (100% as 167 ± 6 IU/mL, 147%, 159%, and 145%) and reduced glutathione (100% as 167 ± 6 nmol/mL, 123%, 141%, and 140%). The results indicate that yam and allantoin have antidiabetic effects by modulating antioxidant activities, lipid profiles and by promoting the release of GLP-1, thereby improving the function of ß-cells maintaining normal insulin and glucose levels.

Cucurbitacin I Attenuates Cardiomyocyte Hypertrophy via Inhibition of Connective Tissue Growth Factor (CCN2) and TGF- ß/Smads Signalings.

Cucurbitacin I is a naturally occurring triterpenoid derived from Cucurbitaceae family plants that exhibits a number of potentially useful pharmacological and biological activities. However, the therapeutic impact of cucurbitacin I on the heart has not heretofore been reported. To evaluate the functional role of cucurbitacin I in an in vitro model of cardiac hypertrophy, phenylephrine (PE)-stimulated cardiomyocytes were treated with a sub-cytotoxic concentration of the compound, and the effects on cell size and mRNA expression levels of ANF and ß-MHC were investigated. Consequently, PE-induced cell enlargement and upregulation of ANF and ß-MHC were significantly suppressed by pretreatment of the cardiomyocytes with cucurbitacin I. Notably, cucurbitacin I also impaired connective tissue growth factor (CTGF) and MAPK signaling, pro-hypertrophic factors, as well as TGF-ß/Smad signaling, the important contributing factors to fibrosis. The protective impact of cucurbitacin I was significantly blunted in CTGF-silenced or TGF-ß1-silenced hypertrophic cardiomyocytes, indicating that the compound exerts its beneficial actions through CTGF. Taken together, these findings signify that cucurbitacin I protects the heart against cardiac hypertrophy via inhibition of CTGF/MAPK, and TGF- ß/Smad-facilitated events. Accordingly, the present study provides new insights into the defensive capacity of cucurbitacin I against cardiac hypertrophy, and further suggesting cucurbitacin I's utility as a novel therapeutic agent for the management of heart diseases.

An accidental fatal attack on domestic pigeons by honey bees in Bangladesh.

Fatalities among avian species due to multiple bee stings are rare. Sixteen pigeons on a farm in Bangladesh each suffered multiple bee stings. Ten of the pigeons died before treatment, 5 (4-11 stings) died within 12 hr after treatment, and 1 pigeon (only 3 stings) survived. Body temperature, heart rate, respiratory rate, hematocrit, hemoglobin, erythrocytes, thrombocytes, MCV, MCH and MCHC decreased significantly after the incident, but leucocytes, heterophils, basophils, eosinophils, monocytes, ALT, AST, LDH, CK, creatinine, BUN and UA increased markedly. Overall, the hematological and biochemical changes in the bee-stung pigeons were similar to those of mammals; however, avian species may be more sensitive to bee stings than mammals.

Effects of candesartan, an angiotensin II receptor type I blocker, on atrial remodeling in spontaneously hypertensive rats.

Hypertension-induced structural remodeling of the left atrium (LA) has been suggested to involve the renin-angiotensin system. This study investigated whether treatment with an angiotensin receptor blocker, candesartan, regresses atrial remodeling in spontaneously hypertensive rats (SHR). Effects of treatment with candesartan were compared to treatment with a nonspecific vasodilatator, hydralazine. Thirty to 32-week-old adult male SHR were either untreated (n = 15) or received one of either candesartan cilexetil (n = 9; 3 mg/kg/day) or hydralazine (n = 10; 14 mg/kg/day) via their drinking water for 14 weeks prior to experiments. Untreated age- and sex-matched Wistar-Kyoto rats (WKY; n = 13) represented a normotensive control group. Untreated SHR were hypertensive, with left ventricular hypertrophy (LVH) compared to WKY, but there were no differences in systolic pressures in excised, perfused hearts. LA from SHR were hypertrophied and showed increased fibrosis compared to those from WKY, but there was no change in connexin-43 expression or phosphorylation. Treatment with candesartan reduced systolic tail artery pressures of conscious SHR below those of normotensive WKY and caused regression of both LVH and LA hypertrophy. Although hydralazine reduced SHR arterial pressures to those of WKY and led to regression of LA hypertrophy, it had no significant effect on LVH. Notably, LA fibrosis was unaffected by treatment with either agent. These data show that candesartan, at a dose sufficient to reduce blood pressure and LVH, did not cause regression of LA fibrosis in hypertensive rats. On the other hand, the data also suggest that normalization of arterial pressure can lead to the regression of LA hypertrophy.

Relationships between blood Mg2+ and energy metabolites/enzymes after acute exhaustive swimming exercise in rats.

Magnesium (Mg) plays a central role in neuronal activity, cardiac excitability, neuromuscular transmission, muscular contraction, vasomotor tone, and blood pressure, all of which are significantly related to physical performance. To date, the available data about detection of blood total Mg (tMg; free-ionized, protein-bound, and anion-complex forms) are inconsistent, and there is limited information on blood free-ionized Mg (Mg(2+)) in relation to physical exercise. The aim of this study was to determine the biochemical changes related to energy metabolism after acute exhaustive swimming exercise (AESE) in rats in an attempt to correlate the role of blood Mg(2+) with metabolites/enzymes related to energy production. After AESE, blood Mg(2+), tMg, K(+), partial pressure of carbon dioxide, lactate, total protein (T-PRO), high-density lipoprotein (HDL), creatinine (CRE), blood urea nitrogen (BUN), uric acid (UA), alanine aminotransferase (ALT), aspartate aminotransferase (AST), alanine phosphatase (ALP), lactate dehydrogenase (LDH), and creatinine kinase (CK) were significantly increased, whereas pH, partial pressure of oxygen, oxygen saturation, the Mg(2+)/tMg and Ca(2+)/Mg(2+) ratios, HCO3 (-), glucose, triglyceride (TG), and low-density lipoprotein (LDL) were significantly decreased. During AESE, lactate, T-PRO, albumin, AST, ALP, LDH, CK, CRE, BUN, and UA showed significant positive correlations with changes in blood Mg(2+), while glucose, TG, and LDL correlated to Mg(2+) in a negative manner. In conclusion, AESE induced increases in both blood Mg(2+) and tMg, accompanied by changes in blood metabolites and enzymes related to energy metabolism due to increased metabolic demands and mechanical damages.

Fluoxetine-induced apoptosis in hepatocellular carcinoma cells.

BACKGROUND: In addition to being used to treat mental disorders, a serious complication of cancer, antidepressants have been reported to improve cancer patient immunity, inhibit cell growth and have an antitumor effect on various cancer cell lines. We investigated the apoptotic effect of fluoxetine against the Hep3B human hepatocellular carcinoma cell line. MATERIALS AND METHODS: After treatments of Hep3B cells with fluoxetine, we measured cell viability, reactive oxygen species (ROS), mitochondrial membrane potential (MMP) and activation of mitogen-activated protein kinases (MAPK). RESULTS: Fluoxetine reduced the viability of cancer cells, induced loss of MMP and formation of ROS, reduced expression of extracellular signal-regulated kinase 1/2 and increased expression of c-JUN N-terminal kinase and p38 MAPK. N-Acetylcysteine, an oxidant-scavenger, and 1,2-bis (o-aminophenoxy) ethane-N,N,N',N'-tetraacetic acid (BAPTA-AM), an intracellular Ca(2+) chelator, prevented fluoxetine-induced modulation of MAPK. CONCLUSION: Fluoxetine appears to exhibit an apoptotic effect against Hep3B cells through the loss of MMP, formation of ROS and modulation of MAPK activities.

A study on hemodynamic characteristics at the stenosed blood vessel using computational fluid dynamics simulations.

In this study, we have used computational fluid dynamics to investigate the blood flow in the stenosed blood vessels. The numerical simulation using commercial software ADINA 8.6 were solved about the stenosed blood vessel according to the percent of stenosis and Reynolds number. The blood flow in the normal and stenosed blood vessel was grasped for the validity of the model. The characteristic of the pulsatile flow changed through the steady state flow and analysis of the pulsatile flow according to the time was grasped. The computational model with the characteristics of the fluid-structure interaction is introduced to investigate the wall shear stress, pressure distribution and axial flow velocity. The results show that axial flow velocity and wall shear stress in the region of stenosis was increased by increasing percent of stenosis and Reynolds number. Also, we can know that in the stenosed blood vessel the possibility of the generation of the aneurysm was increased by increasing Reynolds number and percent of stenosis.