Umbelliferone Ameliorates Hepatic Steatosis and Lipid-Induced ER Stress in High-Fat Diet-Induced Obese Mice

Purpose@#Among the characteristics of non-alcoholic fatty liver disease (NAFLD), hepatic steatosis is due to excessive fat accumulation and causes liver damage and lipotoxicity, which are associated with insulin resistance, endoplasmic reticulum (ER) stress, and apoptosis. Umbelliferone (UMB) has various powerful pharmacological properties, such as antioxidant, anti-hyperglycemic, anti-viral, and anti-inflammatory effects. However, the mechanism of action in hepatic steatosis and lipid-induced ER stress is still unclear. Thus, the efficacy of UMB in hepatic steatosis and palmitate (PA)-induced hepatocellular lipotoxicity was evaluated in the present study. @*Materials and Methods@#Male C57BL/6J mice (n=40) were divided into four groups: regular diet (RD), UMB-supplemented RD, high-fat diet (HFD), and UMB-supplemented HFD. All mice were fed orally for 12 weeks. In addition, the effects of UMB on lipotoxicity were investigated in AML12 cells treated with PA (250 μM) for 24 h; Western blot analysis was used to evaluate the changes in ER stress and apoptotic-associated proteins. @*Results@#Administration with UMB in HFD-fed mice reduced lipid accumulation and hepatic triglyceride (TG) as well as serum insulin and glucose levels. In AML12 cells, UMB treatment reduced lipid accumulation as indicated by decreases in the levels of lipogenesis markers, such as SREBP1, FAS, PPAR-γ, and ADRP. Furthermore, UMB reduced both oxidative stress and ER stress-related cellular apoptosis. @*Conclusion@#UMB supplementation ameliorated hepatic steatosis and improved insulin resistance by inhibiting lipid accumulation and regulating ER stress. These findings strongly suggest that UMB may be a potential therapeutic compound against NAFLD.

A Simple and Nonenzymatic Method to Isolate Human Corpus Cavernosum Endothelial Cells and Pericytes for the Study of Erectile Dysfunction

Silencing Histone Deacetylase 7 Alleviates Transforming Growth Factor-β1-Induced Profibrotic Responses in Fibroblasts Derived from Peyronie's Plaque

PURPOSE: Epigenetic modifications, such as histone acetylation/deacetylation and DNA methylation, play a crucial role in the pathogenesis of inflammatory disorders and fibrotic diseases. The aim of this study was to study the differential gene expression of histone deacetylases (HDACs) in fibroblasts isolated from plaque tissue of Peyronie's disease (PD) or normal tunica albuginea (TA) and to examine the anti-fibrotic effect of small interfering RNA (siRNA)-mediated silencing of HDAC7 in fibroblasts derived from human PD plaque. MATERIALS AND METHODS: For differential gene expression study, we performed reverse-transcriptase polymerase chain reaction for HDAC isoforms (1–11) in fibroblasts isolated from PD plaque or normal TA. Fibroblasts isolated from PD plaque were pretreated with HDAC7 siRNA (100 pmol) and then stimulated with transforming growth factor-β1 (TGF-β1, 10 ng/mL). Protein was extracted from treated fibroblasts for Western blotting. We also performed immunocytochemistry to detect the expression of extracellular matrix proteins and to examine the effect of HDAC2 siRNA on the TGF-β1-induced nuclear translocation of Smad2/3 and myofibroblastic differentiation. RESULTS: The mRNA expression of HDAC2, 3, 4, 5, 7, 8, 10, and 11 was higher in fibroblasts isolated from PD plaque than in fibroblasts isolated from normal TA tissue. Knockdown of HDAC7 in PD fibroblasts inhibited TGF-β1-induced nuclear shuttle of Smad2 and Smad3, transdifferentiation of fibroblasts into myofibroblasts, and abrogated TGF-β1-induced production of extracellular matrix protein. CONCLUSIONS: These findings suggest that specific inhibition of HDAC7 with RNA interference may represent a promising epigenetic therapy for PD.

Systemic Lupus Erythematosus Presenting as Stevens-Johnson Syndrome: A Case Report / 대한피부과학회지

Acute cutaneous lupus erythematosus (ACLE) on the face is a usual pattern of presentation. However, it can rarely present with a generalized distribution. A hyperacute form of ACLE can mimic Stevens-Johnson syndrome (SJS) and toxic epidermal necrosis (TEN). A 33-year-old man presented with erythematous eroded papules and patches on his head, neck, and upper chest over 2 months. Moreover, he showed hemorrhagic crusted erosions on his lips, and buccal and nasal mucosa, in addition to conjunctival injection. A skin biopsy from his cheek showed a mild degree of vacuolar alteration, thickening of the basement membrane, perivascular and periadnexal lymphohistiocytic infiltration, and stromal mucin deposition. Direct immunofluorescence (DIF) demonstrated IgG and IgM deposits along the basement membrane zone. Laboratory investigations demonstrated pancytopenia, positive antinuclear antibody (ANA), anti-double stranded DNA (anti-dsDNA), and anti-Ro antibodies. The patient was diagnosed with systemic lupus erythematosus (SLE) based on clinical, histological, and laboratory markers of autoimmune disease. We report a rare case of SLE presenting as SJS.

Genetic Associations of Mitochondrial DNA Polymorphisms with Behcet's Disease in a Korean Population: A Pilot Study

OBJECTIVE: Pathogenesis of Behcet's disease (BD) is known to be multifactorial and accumulating data suggest genetic mechanisms. Variations in nuclear DNAs have been largely investigated, while studies on mitochondrial DNAs are limited. The purpose of the current study is to investigate associations of mitochondrial single nucleotide polymorphisms and haplotypes with BD. METHODS: Complete mitochondrial DNAs were sequenced using chip array with blood samples collected from 20 patients and 10 control subjects. Haplotypes were searched in hypervariable region 1 and 2. Chi square or Fisher's exact test was used to analyze associations of mitochondrial single nucleotide polymorphisms between two groups and associations between clinical characteristics and mitochondrial single nucleotide polymorphisms. RESULTS: From a total of 16,569 for each individual, 16,545 mitochondrial DNA nucleotides were sequenced. m.248A>G, m.709G>A, m.3970C>T, m.6392T>C, m.6962G>A, m.10310G>A, m.10609T>C, m.12406G>A, m.12882C>T, m.13928G>C, m.16129G>A, and m16304T>C were observed more frequently in the patient group, although without statistical significance, while m.304C>A, m.3010G>A, m.4883C>T, m.5178C>A, and m.14668C>T were more frequent in the control group (p=0.008, 0.026, 0.007, 0.007, and 0.026, respectively). m.16182A>C, m.16183A>C, and m.16189T>C were associated with uveitis (p=0.041, 0.022, and 0.014, respectively). None of the haplotypes we searched were statistically associated with BD risk, but B4a was observed more frequently in the patient group. CONCLUSION: We report the first association study between BD and mitochondrial single nucleotide polymorphisms in a Korean population. In the current study, m.248A>G, m.709G>A, m.3970C>T, m.6392T>C, m.6962G>A, m.10310G>A, m.10609T>C, m.12406G>A, m.12882C>T, m.13928G>C, m.16129G>A, and m16304 T>C could be candidate mitochondrial single nucleotide polymorphisms in BD.

A Case of Cryptococcal Meningoencephalitis Mimicking Lupus Psychosis

No abstract available.

Optimizing in vivo gene transfer into mouse corpus cavernosum by use of surface electroporation

PURPOSE: Electroporation is known to enhance the efficiency of gene transfer through a transient increase in cell membrane permeability. The aim of this study was to determine the optimal conditions for in vivo electroporation-mediated gene delivery into mouse corpus cavernosum. MATERIALS AND METHODS: Diabetes was induced in C57BL/6 mice by intraperitoneal injections of streptozotocin. After intracavernous injection of pCMV-Luc (100 microg/40 microL), different electroporation settings (5-50 V, 8-16 pulses with a duration of 40-100 ms) were applied to the penis to establish the optimal conditions for electroporation. Gene expression was evaluated by luciferase assay. We also assessed the undesired consequences of electroporation by visual inspection and hematoxylin-eosin staining of penile tissue. RESULTS: Electroporation profoundly induced gene expression in the corpus cavernosum tissue of normal mice in a voltage-dependent manner. We observed electrical burn scars in the penis of normal mice who received electroporation with eight 40-ms pulses at a voltage of 50 V and sixteen 40-ms pulses, eight 100-ms pulses, and sixteen 100-ms pulses at a voltage of 30 V. No detectable burn scars were noted in normal mice stimulated with eight 40-ms pulses at a voltage of 30 V. Electroporation also significantly induced gene expression in diabetic mice stimulated with 40-ms pulse at a voltage of 30 V without injury to the penis. CONCLUSIONS: We have established the optimal electroporation conditions for maximizing gene transfer into the corpus cavernosum of mice while avoiding damage to the erectile tissue. The electroporation-mediated gene delivery technique will be a valuable tool for gene therapy in the field of erectile dysfunction.

Adrenocortical Insufficiency due to Spontaneous Bilateral Adrenal Hemorrhage Presented as Acute Abdominal Pain / 이화의대지

Adrenocortical insufficiency is the clinical manifestation of deficient production or action of glucocorticoids. It is a life-threatening disorder that can result from primary adrenal failure or secondary adrenal failure due to impairment of the hypothalamic-pituitary axis. Primary adrenocortical insufficiency can be caused by autoimmune adrenalitis, infection (especially, tuberculosis), metastatic cancer, lymphoma, adrenal hemorrhage, infarction or drugs. Among these, adrenal hemorrhage may be caused by anticoagulant drug or heparin therapy, thromboembolic disease, hypercoagulable states such as antiphospholipid syndrome, physical trauma, postoperative state, sepsis and severe stress from any cause. However, even fewer reports exist of adrenocortical insufficiency due to spontaneous bilateral adrenal hemorrhage. We report a rare case of acute adrenocortical insufficiency due to spontaneous bilateral adrenal hemorrhage presenting as acute abdominal pain.

Multiple Gastric Ulcers as a Manifestation of Cytomegalovirus Infection in a Patient with Adult-onset Still's Disease

Cytomegalovirus (CMV) is a relatively common viral pathogen, and CMV infection is generally assumed asymptomatic in general hosts. In immunologically compromised patients, CMV infection can cause further serious diseases such as pneumonitis, retinitis, encephalitis, and enterocolitis. A 40-year-old man is being presented with acute fever, myalgia, and sore throat. Laboratory findings have revealed elevated ESR, CRP, and ferritin levels. The patient was being treated for adult-onset Still's disease (AOSD). Three weeks later, although AOSD activity was under control, the patient began to complain about oral soreness, epigastric pain, and diarrhea. Endoscopy revealed multiple round ulcers with white patches in the esophagus and the stomach, sparing the colon. Anti-fungal agent is being administered but failed to bring improvements after 2 weeks of therapy. CMV infection is confirmed with pathology, antiviral agents were initiated after the ulcers subsided. Currently, clinical associations between CMV infection and AOSD are suggested. CMV infection may be considered as a differential diagnosis when multiple upper gastrointestinal ulcerative lesions develop within patients whom have been treated AOSD with immunosuppressive agents.

Transforming Growth Factor-beta Type I Receptor Inhibitor Induces Functional and Morphologic Recovery in a Rat Model of Erectile Dysfunction and Cavernous Fibrosis / 대한남성과학회지

PURPOSE: To examine the effectiveness of small-molecule inhibitor of transforming growth factor-beta (TGF-beta) type I receptor, an activin receptor-like kinase 5 (ALK5), on erectile dysfunction (ED) in a rat model of cavernous fibrosis, in which fibrosis was induced by intracavernous injection of adenovirus expressing TGF-beta1 (Ad-TGF-beta1). MATERIALS AND METHODS: Four-month-old Sprague-Dawley rats were divided into four groups (n=10 per group): age-matched controls without treatment, age-matched controls receiving intracavernous injection of LacZ adenovirus, and cavernous fibrosis rats receiving an intracavernous injection of saline or ALK5 inhibitor (5 mg/kg). ALK5 inhibitor or saline was administered on day 5 after injection of Ad-TGF-beta1. On day 30, erectile function was assessed by electrical stimulation of the cavernous nerve and the penis was then harvested for histologic studies (n=6 per group) and for the measurement of the hydroxyproline level (n=4 per group). RESULTS: Ad-TGF-beta1-induced cavernous fibrosis rats treated with saline showed a significant decrease in cavernous smooth muscle and endothelial content, and an increase in collagen deposition, which resulted in profound deterioration of all erectile function parameters, such as the ratios of maximal intracavernous pressure (ICP), total ICP, and slope to mean arterial pressure. ALK5 inhibitor significantly restored erectile function in a rat model of cavernous fibrosis by increasing cavernous smooth muscle and endothelial content, and by blocking cavernous fibrosis. CONCLUSIONS: The results suggest that inhibition of the TGF-beta pathway is a promising therapeutic strategy for the treatment of ED related to cavernous fibrosis from various causes.

A Case of Behcet's Disease with Splenic Infarction / 대한내과학회지

Behcet's disease is a multisystem autoimmune disease with vasculitic features, and major vascular involvement occurs in 7.7-60% of patients. Venous lesions are more common than arterial lesions and arterial thrombotic events are relatively rare. We report a patient with Behcet's disease who developed a splenic infarct associated with splenic thrombotic arteritis. A 44-year-old man who had been diagnosed with Behcet's disease 5 years earlier presented with left flank pain lasting for 5 days. Laboratory tests revealed an elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). Computed tomography (CT) and three-dimensional CT showed a wedge-shaped splenic infarct and thrombus in the splenic artery. We treated him with low-molecular-weight heparin and prednisolone. The symptoms improved within 6 days of hospitalization, after which we stopped the heparin and added methotrexate and azathioprine. Splenic infarct should be ruled out if patients with Behcet's disease complain of new left-sided abdominal pain.

A Case of Behcet's Disease with Splenic Infarction / 대한내과학회지

Behcet's disease is a multisystem autoimmune disease with vasculitic features, and major vascular involvement occurs in 7.7-60% of patients. Venous lesions are more common than arterial lesions and arterial thrombotic events are relatively rare. We report a patient with Behcet's disease who developed a splenic infarct associated with splenic thrombotic arteritis. A 44-year-old man who had been diagnosed with Behcet's disease 5 years earlier presented with left flank pain lasting for 5 days. Laboratory tests revealed an elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). Computed tomography (CT) and three-dimensional CT showed a wedge-shaped splenic infarct and thrombus in the splenic artery. We treated him with low-molecular-weight heparin and prednisolone. The symptoms improved within 6 days of hospitalization, after which we stopped the heparin and added methotrexate and azathioprine. Splenic infarct should be ruled out if patients with Behcet's disease complain of new left-sided abdominal pain.

Synchronous Roentgenographically Occult Lung Carcinoma Treated with Argon Plasma Coagulation in a Patient with Resectable Primary Lung Cancer / 결핵및호흡기질환

We treated synchronous double primary lung cancers, where one site resulted from CIS disease, with lobectomy and argon plasma coagulation (APC) in a patient who couldn't tolerate pneumonectomy, which resulted in a reduction of the extent of surgery. APC could be a reasonable alternative for CIS disease of lung in inoperable patients.

Identification of DNA Methylation Markers for NSCLC Using Hpall-Mspl Methylation Microarray / 결핵및호흡기질환

BACKGROUND: Epigenetic alterations in certain genes are now known as at least important as genetic mutation in pathogenesis of cancer. Especially abnormal hypermethylation in or near promoter region of tumor suppressor genes (TSGs) are known to result in gene silencing and loss of gene function eventually. The authors tried to search for new lung cancer-specific TSGs which have CpG islands and HpaII sites, and are thought to be involved in carcinogenesis by epigenetic mechanism. METHODS: Tumor tissue and corresponding adjacent normal tissue were obtained from 10 patients who diagnosed with non small cell lung cancer (NSCLC) and underwent surgery in Konyang university hospital in 2005. Methylation profiles of promoter region of 21 genes in tumor tissue & non-tumor tissue were examined with HpaII-MspI methylation microarray (Methyl-Scan DNA chip(R), Genomic tree, Inc, South Korea). The rates of hypermethylation were compared in tumor and non-tumor group, and as a normal control, we obtained lung tissue from two young patients with pneumothorax during bullectomies, methylation profiles were examined in the same way. RESULTS: Among the 21 genes, 10 genes were commonly methylated in tumor, non-tumor, and control group. The 6 genes of APC, AR, RAR-b, HTR1B, EPHA3, and CFTR, among the rest of 11 genes were not methylated in control, and more frequently hypermethylated in tumor tissue than non-tumor tissue. CONCLUSION: In the present study, HTR1B, EPHA3, and CFTR are suggested as possible novel TSGs of NSCLC by epigenetic mechanism.

A Case of Pneumatosis Intestinalis Induced by Chemotherapy in a Patient with Lung Cancer

Pneumatosis intestinalis is an uncommon condition that is characterized by the presence of gas within the bowel wall. We experienced a case of pneumatosis intestinalis after cession of chemotherapy and we herein report on this case. A 58-year old man was admitted to our hospital for the evaluation of incidentally recognized pneumatosis intestinalis. He was diagnosed as having non small cell lung cancer in August 2006 and he received radiation therapy for concomitant brain metastasis and SVC syndrome in September 2006. He achieved a partial response after completing 6 cycles of chemotherapy with gemcitabine and cisplatin. Newly enlarged lymph nodes were observed on the follow-up CT, and chemotherapy with paclitaxel and carboplatin was started in July 2007. Due to the lack of a response, the therapeutic regimen was switched to oral erlotinib. After 1 month of treatment, the follow-up CT for response evaluation revealed pneumatosis intestinalis in the ascending colon without any subjective symptoms such as fever or abdominal pain. The laboratory results were within the normal range except for a slight increase of leukocytes. He underwent right hemicolectomy, but he didn't survive his postoperative acute renal failure and pneumonia

Efficacy and Safety of Weekly Low Dose Paclitaxel and Cisplatin as First Line Therapy in Advanced NSCLC of Elderly Patients

PURPOSE : Anti-cancer chemotherapeutic agents act by inhibiting tumor cell proliferation through cytotoxic action, therefore the generally tolerated maximum dose is administered to patients. However, this often results in the production of undesirable toxicities, such as bone marrow suppression, and a long interruption of treatment is necessary for recovery to occur before additional cycles of treatment are administered. Paclitaxel and cisplatin are well known effective chemotherapeutic agents used for the treatment of Non-Small Cell Lung Cancer (NCSLC), however, they have substantial toxicities. To evaluate efficacy and safety of a therapy consisting of a weekly low dose of paclitaxel and therapy in elderly patients with advanced NSCLC. MATERIALS AND METHODS : Thirteen treatment-naive, elderly patients over 65 years old who were diagnosed with stage IV NSCLC at Konyang University from April 2005 to October 2006 were enrolled in the present study. Paclitaxel at a dose of 55 mg/m2 in combination with cisplatin at a dose of 20 mg/m2 was administered intravenously on day 1, 8, and 15 with 1 week of interruption for a total of six cycles of chemotherapy. RESULTS : The mean age of the ten patients included in this study was 69.5 years. Following treatment, 50 % of the patients exhibited a partial response to treatment, whereas the disease remained stable in 40% of the patients, and progressed in 10% of the patients. The median survival time (Kaplan-Meier method) was 15 months (4~24 months), and the 6-month, 1-year, and 2-year survival rates were 80%, 50%, and 10%, respectively. The median progression survival time was 8 months (2~14 months) and the 6- and 12-month progression free survival rates were 60% and 10%, respectively. Grade 3 neutropenia occurred in only 1 case (10%). CONCLUSION : The results of this study indicated that chemotherapy consisting of a weekly low dose of paclitaxel and cisplatin could be more effective and have lesser toxicity when administered to elderly patients with advanced NSCLC. In addition, this treatment regimen showed a promising response rate

Diagnostic Accuracy and Safety of Medical Thoracoscopy / 결핵및호흡기질환

BACKGROUND: The causes of the pleural effusion are remained unclear in a the substantial number of patients with exudative effusions determined by an examination of the fluid obtained via thoracentesis. Among the various tools for diagnosing exudative pleural effusions, thoracoscopy has a high diagnostic yield for cancer and tuberculosis. Medical thoracoscopy can also be carried out under local anesthesia with mild sedation. The aim of this study was to determine diagnostic accuracy and safety of medical thoracoscopy. METHODS: Twenty-five patients with exudative pleural effusions of an unknown cause underwent medical thoracoscopy between October 2005 and September 2006 in Konyang University Hospital. The clinical data such as age, gender, preoperative pulmonary function, amounts of pleural effusion on lateral decubitus radiography were collected. The vital signs were recorded, and arterial blood gas analyses were performed five times during medical thoracoscopy in order to evaluate the cardiopulmonary status and acid-base changes. RESULTS: The mean age of the patients was 56.8 years (range 22-79). The mean depth of the effusion on lateral decubitus radiography (LDR) was 27.49 mm. The medical thoracoscopic pleural biopsy was diagnostic in 24 patients (96.0%), with a diagnosis of tuberculosis pleurisy in 9 patients (36%), malignant effusions in 8 patients (32%), and parapneumonic effusions in 7 patients (28%). Medical thoracoscopy failed to confirm the cause of the pleural effusion in one patient, who was diagnosed with tuberculosis by a pericardial biopsy. There were no significant changes in blood pressure, heart rate, acid-base and no major complications in all cases during medical thoracoscopy (p>0.05). CONCLUSIONS: Medical thoracoscopy is a safe method for patients with unknown pleural effusions with a relatively high diagnostic accuracy.