Cilostazol is a selective inhibitor of type 3 phosphodiesterase (PDE3) and has been widely used as an antiplatelet agent. Cilostazol mediates this activity through effects on the cyclic adenosine monophosphate (cAMP) signaling cascade. Recently, it has attracted attention as a neuroprotective agent. However, little is known about cilostazol's effect on excitotoxicity induced neuronal cell death. Therefore, this study evaluated the neuroprotective effect of cilostazol treatment against hippocampal neuronal damage in a mouse model of kainic acid (KA)-induced neuronal loss. Cilostazol pretreatment reduced KA-induced seizure scores and hippocampal neuron death. In addition, cilostazol pretreatment increased cAMP response element-binding protein (CREB) phosphorylation and decreased neuroinflammation. These observations suggest that cilostazol may have beneficial therapeutic effects on seizure activity and other neurological diseases associated with excitotoxicity.
Adenosine Monophosphate ; Animals ; Cell Death* ; Cyclic AMP Response Element-Binding Protein ; Hippocampus ; Kainic Acid ; Mice ; Neurons ; Neuroprotective Agents ; Phosphorylation ; Seizures ; Therapeutic Uses

A beneficial radioprotective agent has been used to treat the radiation-induced lung injury. This study was performed to investigate whether curcumin, which is known to have anti-inflammatory and antioxidant properties, could ameliorate radiation-induced pulmonary inflammation and fibrosis in irradiated lungs. Rats were given daily doses of intragastric curcumin (200 mg/kg) prior to a single irradiation and for 8 weeks after radiation. Histopathologic findings demonstrated that macrophage accumulation, interstitial edema, alveolar septal thickness, perivascular fibrosis, and collapse in radiation-treated lungs were inhibited by curcumin administration. Radiation-induced transforming growth factor-beta1 (TGF-beta1), connective tissue growth factor (CTGF) expression, and collagen accumulation were also inhibited by curcumin. Moreover, western blot analysis revealed that curcumin lowered radiation-induced increases of tumor necrosis factor-alpha (TNF-alpha), TNF receptor 1 (TNFR1), and cyclooxygenase-2 (COX-2). Curcumin also inhibited the nuclear translocation of nuclear factor-kappa B (NF-kappaB) p65 in radiation-treated lungs. These results indicate that long-term curcumin administration may reduce lung inflammation and fibrosis caused by radiation treatment.
Animals ; Blotting, Western ; Collagen ; Connective Tissue Growth Factor ; Curcumin ; Cyclooxygenase 2 ; Edema ; Fibrosis ; Inflammation ; Lung ; Lung Injury ; Macrophages ; Pneumonia ; Rats ; Receptors, Tumor Necrosis Factor ; Tumor Necrosis Factor-alpha

AMP-activated protein kinase (AMPK), an enzyme involved in energy homeostasis, regulates inflammatory responses, but its precise mechanisms are not fully understood. Recent evidence has shown that resveratrol (RES), an AMPK activator, reduces prostaglandin E2 production in lipopolysaccharide (LPS)-treated microglia. Here, we examined the effect of RES on nuclear factor kappa B (NF-kappaB) dependent cyclooxygenase (COX)-2 activation in LPS-treated RWA 264.7 macrophages. We found that treatment with RES increased AMPK activation. AMPK and acetyl CoA carboxylase phosphorylation were attenuated in cells treated with LPS+RES, compared to cells treated with LPS alone. RES inhibited tumor necrosis factor (TNF)-alpha and TNF receptor 1 in LPS-treated cells. Finally, RES inhibited LPS-induced NF-kappaB translocation into the nucleus and COX-2 expression. Moreover, the effects of 5-aminoimidazole-4-carboxamide ribose and compound C were consistent with the effects of RES in LPS-treated cells. Taken together, these results suggest that the anti-inflammatory action of RES in RAW 264.7 macrophages is dependent on AMPK activation and is associated with inhibition of the LPS-stimulated NF-kappaB-dependent COX-2 signaling pathway.
Acetyl-CoA Carboxylase ; AMP-Activated Protein Kinases ; Dinoprostone ; Homeostasis ; Macrophages ; Microglia ; NF-kappa B ; Phosphorylation ; Prostaglandin-Endoperoxide Synthases ; Receptors, Tumor Necrosis Factor ; Ribose ; Stilbenes ; Tumor Necrosis Factor-alpha

BACKGROUND AND OBJECTIVES: It is widely known that both bone loss and vascular calcification are age-related processes. The purpose of this study was to investigate the relationship between coronary artery calcium (CAC) score or bone mineral density (BMD) with age and whether there is a gender difference factoring in the two conditions among healthy subjects. SUBJECTS AND METHODS: Between March 2009 and August 2011, participants included 1727 subjects (mean age: 55+/-10 years, M : F=914 : 813) with routine health check-ups. After being categorized into three groups (normal, osteopenia, and osteoporosis) according to the World Health Organization (WHO) diagnostic classification, we estimated BMD by dual energy X-ray absorptiometry (DEXA) and CAC score by dual-source CT (DSCT). RESULTS: There was a significant gender difference among the risk factors, including total-lumbar spine (1.213+/-0.176 g/cm2 : 1.087+/-0.168 g/cm2, p<0.001) and femur (1.024+/-0.131 g/cm2 : 0.910+/-0.127 g/cm2, p<0.001) in BMD by DEXA, and CAC score (68+/-227 : 27+/-116, p<0.001) in coronary artery calcification by DSCT. Age in male [odds ratio (OR): 1.138 {95% confidence interval (CI): 1.088-1.190}, p<0.001] and menopause in female subjects {OR: 12.370 (95% CI: 3.120-49.047), p<0.001} were, respectively, independently associated with osteopenia. CONCLUSION: Although our results do not demonstrate a direct association between CAC score and BMD in both genders, there is a gender difference of CAC score in normal and osteopenia groups according to the WHO diagnostic classification. Additionally, we suggest that more specific therapeutic strategies be considered during any early bone loss period, especially in female subjects.
Absorptiometry, Photon ; Bone Density ; Bone Diseases, Metabolic ; Calcium ; Coronary Vessels ; Female ; Femur ; Humans ; Male ; Menopause ; Osteoporosis ; Risk Factors ; Spine ; Vascular Calcification ; World Health Organization

Sirtuin 1 (SIRT1) is a mammalian NAD+-dependent protein deacetylase that regulates cellular metabolism and inflammatory response. The organ-specific deletion of SIRT1 induces local inflammation and insulin resistance in dietary and genetic obesity. Macrophage-mediated inflammation contributes to insulin resistance and metabolic syndrome, however, the macrophage-specific SIRT1 function in the context of obesity is largely unknown. C57/BL6 wild type (WT) or myeloid-specific SIRT1 knockout (KO) mice were fed a high-fat diet (HFD) or normal diet (ND) for 12 weeks. Metabolic parameters and markers of hepatic steatosis and inflammation in liver were compared in WT and KO mice. SIRT1 deletion enhanced HFD-induced changes on body and liver weight gain, and increased glucose and insulin resistance. In liver, SIRT1 deletion increased the acetylation, and enhanced HFD-induced nuclear translocation of nuclear factor kappa B (NF-kappaB), hepatic inflammation and macrophage infiltration. HFD-fed KO mice showed severe hepatic steatosis by activating lipogenic pathway through sterol regulatory element-binding protein 1 (SREBP-1), and hepatic fibrogenesis, as indicated by induction of connective tissue growth factor (CTGF), alpha-smooth muscle actin (alpha-SMA), and collagen secretion. Myeloid-specific deletion of SIRT1 stimulates obesity-induced inflammation and increases the risk of hepatic fibrosis. Targeted induction of macrophage SIRT1 may be a good therapy for alleviating inflammation-associated metabolic syndrome.
Acetylation ; Actins ; Animals ; Collagen ; Connective Tissue Growth Factor ; Diet ; Diet, High-Fat ; Fibrosis ; Glucose ; Inflammation* ; Insulin Resistance ; Liver ; Macrophages ; Metabolism ; Mice* ; NF-kappa B ; Obesity ; Sirtuin 1 ; Sterol Regulatory Element Binding Protein 1 ; Weight Gain

Statins mediate vascular protection and reduce the prevalence of cardiovascular diseases. Recent work indicates that statins have anticonvulsive effects in the brain; however, little is known about the precise mechanism for its protective effect in kainic acid (KA)-induced seizures. Here, we investigated the protective effects of atorvastatin pretreatment on KA-induced neuroinflammation and hippocampal cell death. Mice were treated via intragastric administration of atorvastatin for 7 days, injected with KA, and then sacrificed after 24 h. We observed that atorvastatin pretreatment reduced KA-induced seizure activity, hippocampal cell death, and neuroinflammation. Atorvastatin pretreatment also inhibited KA-induced lipocalin-2 expression in the hippocampus and attenuated KA-induced hippocampal cyclooxygenase-2 expression and glial activation. Moreover, AKT phosphorylation in KA-treated hippocampus was inhibited by atorvastatin pretreatment. These findings suggest that atorvastatin pretreatment may protect hippocampal neurons during seizures by controlling lipocalin-2-associated neuroinflammation.
Animals ; Atorvastatin Calcium* ; Brain ; Cardiovascular Diseases ; Cell Death ; Cyclooxygenase 2 ; Hippocampus ; Hydroxymethylglutaryl-CoA Reductase Inhibitors ; Kainic Acid ; Mice ; Neurons* ; Phosphorylation ; Prevalence ; Seizures

Exendin-4 (Ex-4), a glucagon-like peptide-1 receptor (GLP-1R) agonist, has been known to reverse hepatic steatosis in ob/ob mice. Although many studies have evaluated molecular targets of Ex-4, its mechanism of action on hepatic steatosis and fibrosis has not fully been determined. In the liver, glucose transporter 4 (GLUT4) is mainly expressed in hepatocytes, endothelial cells and hepatic stellate cells (HSCs). In the present study, the effects of Ex-4 on GLUT4 expression were determined in the liver of ob/ob mice. Ob/ob mice were treated with Ex-4 for 10 weeks. Serum metabolic parameters, hepatic triglyceride levels, and liver tissues were evaluated for hepatic steatosis. The weights of the whole body and liver in ob/ob mice were reduced by long-term Ex-4 treatment. Serum metabolic parameters, hepatic steatosis, and hepatic fibrosis in ob/ob mice were reduced by Ex-4. Particularly, Ex-4 improved hepatic steatosis by enhancing GLUT4 via GLP-1R activation in ob/ob mice. Ex-4 treatment also inhibited hepatic fibrosis by decreasing expression of connective tissue growth factor in HSCs of ob/ob mice. Our data suggest that GLP-1 agonists exert a protective effect on hepatic steatosis and fibrosis in obesity and type 2 diabetes.
Animals ; Connective Tissue Growth Factor ; Endothelial Cells ; Fatty Liver* ; Fibrosis ; Glucagon-Like Peptide 1 ; Glucagon-Like Peptide-1 Receptor ; Glucose Transport Proteins, Facilitative* ; Hepatic Stellate Cells ; Hepatocytes ; Liver ; Mice* ; Obesity ; Triglycerides ; Weights and Measures

Adiponectin is an adipocyte-derived protein with anti-diabetic and anti-angiogenesis properties that improves both glucose metabolism and insulin resistance via the adenosine monophosphate-activated protein kinase (AMPK) cascade. Diabetic cognitive deficits are correlated with dysregulation of energy metabolism in the hippocampus. In the present study, we investigated the expression of adiponectin-mediated AMPK cascade proteins in the hippocampus of streptozotocin (STZ)-induced diabetic mice. Diabetes was induced by STZ (55 mg/kg) injection intraperitoneally. Twenty-four weeks after induction of diabetes, mice were sacrificed. Results showed that decreased serum adiponectin levels and increased expression of hippocampal adiponectin receptor 1 (AdipoR1) was expressed in diabetic mice. Phosphorylated AMPK, acetyl CoA carboxylase (ACC), and eNOS expression levels were increased in the hippocampus of diabetic mice. The immunoreactivity of glucose transporter 1 in the endothelium of hippocampal blood vessels was also increased. These results indicate that adiponectin-mediated AMPK cascade activation may play a role in catabolic process that is involved in diabetic neurodegeneration.
Acetyl-CoA Carboxylase ; Adenosine ; Adiponectin ; AMP-Activated Protein Kinases ; Animals ; Blood Vessels ; Endothelium ; Energy Metabolism ; Glucose ; Glucose Transport Proteins, Facilitative ; Hippocampus ; Insulin Resistance ; Mice ; Protein Kinases ; Proteins ; Receptors, Adiponectin ; Streptozocin

BACKGROUND: Since the bioavailability of itraconazole capsule is influenced by patients gastric acidity, it results in treatment failure due to its low dissolution and subsequent low absorption when administered in fasting. Itraconazole Melt-Extrusion tablet has been lately developed in order to improve its dissolution profile. It is the first clinical study to evaluate the efficacy and safety of itraconazole Melt-Extrusion tablet in Korea. OBJECTIVE: This study was conducted to evaluate the efficacy and safety of itraconazole melt-extrusion tablet 400mg daily for 1 week(pulse therapy) for hyperkeratotic type of tinea pedis and manus. METHODS: A clinical and mycological investigation was made of 812 outpatients with hyperkeratotic type of tinea pedis and/or tinea manus who had visited at 52 general hospitals under the lead of the Korean Dermatological Association from June to December, 1998. Patients confirmed by clinically and microscopically as hyperkeratotic type of tinea pedis and/or tinea manus were administered 2 tablets twice a day for one week and followed up for 8 weeks from the start of the medication. RESULTS: The results were summarized as follows; 1. Clinical symptoms of hyperkeratotic type of tinea pedis and/or tinea mauns were significantly improved at the end of study, week 8(p<0.001). 2. Clinical response rate, defined as more than 50% decrease of the sum of the clinical symptom scores, was 79.3%(512/646). 3. Mycological cure rate, dafined as both culture and KOH negative at week 8, was 78.2%(244 /312). 4. 40(5.5%) patients, of the 727 patients evaluable for drug safety evaluation, were reported to have adverse event. CONCLUSION: Itraconazole Melt-Extrusion tablet 400mg/day for 1 week (pulse therapy) is effective and safe in the treatment of hyperkeratotic type of tinea pedis and/or tinea manus.
Absorption ; Biological Availability ; Fasting ; Gastric Acid ; Hospitals, General ; Humans ; Itraconazole* ; Korea ; Outpatients ; Tablets ; Tinea Pedis* ; Tinea* ; Treatment Failure

Purinergic P2Y Receptor Antagonists ; Consensus ; Cardiovascular System ; Cardiology ; Asia