Is bone mineral density a prognostic factor in postmenopausal women with luminal A breast cancer?

Purpose@#Several studies are concerned about the association between bone mineral density (BMD) and the risk of breast cancer in postmenopausal women, but it is controversial. Therefore, we evaluated whether BMD might be a risk factor for recurrences, or metastases in menopausal luminal A breast cancer patients. @*Methods@#In this retrospective study, data of 348 patients with luminal A breast cancer who received treatment at Pusan National University Yangsan Hospital between 2012 and 2016 were analyzed. Patients were divided into two groups: normal BMD and low BMD including osteopenia or osteoporosis in preoperative examination. Patients were also divided into three groups according to BMD changes: no change in BMD; improvement in BMD, and deterioration in BMD. Events were defined as recurrence, occurrence of contralateral breast cancer, and metastasis to any other organ. @*Results@#Preoperative examination revealed normal BMD in 129 of 348 patients and low BMD in 219 patients. During a median follow-up period of 78 months, only 14 patients (4.0%) experienced recurrences, distant metastases, or occurrences of contralateral breast cancer. Five-year disease-free survival rate was 98.2% for 219 patients with low BMD and 95.0% for 129 patients with normal BMD (P=0.33). Disease-free survival at 5 years was 97.0% for the no change in the BMD group, 94.6% for the BMD improvement group, and 98.4% for the BMD deterioration group (P=0.79). @*Conclusion@#In this study, BMD had no statistically significant associations on recurrences, metastases, or incidences of contralateral breast cancer in postmenopausal patients with luminal A breast cancer.

Explanatory Power and Prognostic Implications of Factors Associated with Troponin Elevation in Acute Ischemic Stroke / 대한뇌졸중학회지

Background@#and Purpose We investigated the impact of comorbidity burden on troponin elevation, with separate consideration of neurological conditions, in patients with acute ischemic stroke (AIS). @*Methods@#This prospective, observational cohort study consecutively enrolled patients with AIS for 2 years. Serum cardiac troponin I was repeatedly measured, and disease-related biomarkers were collected for diagnosis of preassigned comorbidities, including atrial fibrillation (AF), ischemic heart disease (IHD), myocardial hypertrophy (MH), heart failure (HF), renal insufficiency (RI), and active cancer. The severity of neurological deficits and insular cortical ischemic lesions were assessed as neurological conditions. Adjusted associations between these factors and troponin elevation were determined using a multivariate ordinal logistic regression model and area under the receiver operating characteristic curve (AUC). Cox proportional hazards model was used to determine the prognostic significance of comorbidity beyond neurological conditions. @*Results@#Among 1,092 patients (66.5±12.4 years, 63.3% male), 145 (13.3%) and 335 (30.7%) had elevated (≥0.040 ng/mL) and minimally-elevated (0.040–0.010 ng/mL) troponin, respectively. In the adjusted analysis, AF, MH, HF, RI, active cancer, and neurological deficits were associated with troponin elevation. The multivariate model with six comorbidities and two neurological conditions exhibited an AUC of 0.729 (95% confidence interval [CI], 0.698–0.759). In Cox regression, AF, IHD, and HF were associated with adverse cardio-cerebrovascular events, whereas HF and active cancer were associated with mortality. @*Conclusion@#Troponin elevation in patients with AIS can be explained by the burden of comorbidities in combination with neurological status, which explains the prognostic significance of troponin assay.

Clinical and endoscopic characteristics of sessile serrated lesions with dysplasia/carcinoma

Background/Aims@#Some sessile serrated lesions (SSLs) progress into dysplasia and colorectal cancer, however, the clinical and endoscopic characteristics of SSLs with dysplasia remain to be determined. In this study, we elucidated these characteristics in SSLs with dysplasia/carcinoma, compared with those of SSLs without dysplasia. @*Methods@#We retrospectively collected the clinical, endoscopic, and pathological data of 254 SSLs from 216 patients endoscopically resected between January 2009 and December 2020. @*Results@#All SSLs included 179 without dysplasia and 75 with dysplasia/carcinoma, including 55 with low-grade dysplasia, 10 with high-grade dysplasia, and 10 with submucosal cancer. In clinical characteristics, SSLs with dysplasia/carcinoma were significantly associated with advanced age, metabolic diseases, and high-risk adenomas. In endoscopic characteristics, SSLs with dysplasia/carcinoma were significantly associated with the distal colon, large size, polypoid morphology, surface-changes, no mucus cap, and narrow-band imaging international colorectal endoscopic classification (NICE) type 2/3. In the multivariate analysis, high-risk adenomas (odds ratio [OR], 2.98; p = 0.01), large size (OR, 1.18; p < 0.01), depression (OR, 11.74; p = 0.03), and NICE type 2/3 (OR, 14.97; p < 0.01) were significantly associated with SSLs with dysplasia/carcinoma. @*Conclusions@#SSLs had a higher risk of dysplasia in the distal colon than in the proximal colon. SSLs with large size, depression, and adenomatous surface-patterns, as well as those in patients with high-risk adenomas, increased the risk of dysplasia/ carcinoma. This suggests that the clinical and endoscopic characteristics can aid in the diagnosis and management of SSLs with dysplasia/carcinoma.

Volumetric change of the latissimus dorsi muscle after postoperative chemotherapy and radiotherapy in immediate breast reconstruction with an extended latissimus dorsi musculocutaneous flap: final results from serial studies

Background@#Breast reconstruction using an extended latissimus dorsi (eLD) flap can supplement more volume than reconstruction using various local flaps after partial mastectomy, and it is a valuable surgical method since the reconstruction area is not limited. However, when performing reconstruction, the surgeon should consider latissimus dorsi (LD) volume reduction due to postoperative chemotherapy (POCTx) and postoperative radiotherapy (PORTx). To evaluate the effect of POCTx and PORTx on LD volume reduction, the effects of each therapy—both separately and jointly—need to be demonstrated. The present study quantified LD volume reduction in patients who underwent POCTx and PORTx after receiving breast-conserving surgery (BCS) with an eLD flap. @*Methods@#This study included 48 patients who received immediate breast reconstruction using an eLD flap from January 2013 to March 2017, had chest computed tomography (CT) 7–10 days after surgery and 10–14 months after radiotherapy completion, and were observed for more than 3 years postoperatively. One surgeon performed the breast reconstruction procedures, and measurements of breast volume were obtained from axial CT views, using a picture archiving and communication system. A P-value <0.05 was the threshold for statistical significance. @*Results@#The average volume reduction of LD at 10–14 months after completing POCTx and PORTx was 64.5% (range, 42.8%–81.4%) in comparison to the volume measured 7–10 days after surgery. This change was statistically significant (P<0.05). @*Conclusions@#Based on the findings of this study, when harvesting an eLD flap, surgeons should anticipate an average LD volume reduction of 64.5% if chemotherapy and radiotherapy are scheduled after BCS with an eLD flap.

A Comparison of Salty Taste Assessment, Dietary Attitude and Dietary Behavior among Adult and Senior Women by Region and by Age in Korea / 대한지역사회영양학회지

OBJECTIVES: The purpose of this study was to compare and analyze the results of salty taste assessment, dietary attitudes, and dietary behaviors among adult and senior women by region and by age. The results generated from this was expected to provide fundamental data for implementing a nationwide salt reduction education program. METHODS: The salty taste assessment tool was applied to 4,064 subjects from 15 areas in Korea. Also, a survey of dietary attitude and dietary behavior related to salt intake was conducted for all subjects participated in this study. RESULTS: The salty taste assessment scores by region and by age were the lowest in capital (p < 0.01) and was highest among the 70+ year age group (p < 0.01). The dietary attitude scores and dietary behavior scores showed that Gyeongsang was the highest (p < 0.001) and the capital was the lowest. The dietary attitude scores were highest at 20&30's followed by 40's and 70's group (p < 0.001). Dietary behavior scores showed that 20's~30's and 40's groups were higher than the other age groups (p < 0.001). The score of 'I like kimchi' was 3.46 +/- 0.88, which was the highest among 10 dietary behavior questions. The score of 'I eat a lot of kimchi' was 3.30 +/- 0.90, which was the highest among 10 dietary behavior questions related to salt intake. The scores of salty taste assessment had significant positive correlations between the scores of dietary attitude (p < 0.001), dietary behavior (p < 0.001) and self-awareness (p < 0.001). CONCLUSIONS: Based on the results of salty taste assessment, we observed a tendency that older people and regions except the capital had higher preference for salty taste. Our results suggested the necessity for a nationwide salty reduction education program tailored for regions and for different age groups.

Stigma in Parents of a Child with Mental Illness / 정신간호학회지

PURPOSE: This study was done to explore the meaning of stigma in parents of a child with mental illness. METHODS: The participants were 6 mothers who had children with mental illness. Data were gathered using in-depth interviews. The interviews were recorded and transcribed verbatim. Data were analyzed using Colaizzi method. RESULTS: The significant results from analysis of the interviews can be grouped into 10 concept descriptions, 5 theme clusters. The essential theme clusters for the experiences of parents were 'Guilt as a parent towards an disabled child', 'Humiliation from loss of self-esteem', 'Loneliness from prejudice and discrimination', 'Frustration due to endless treatment', and 'Desire of normal happiness'. CONCLUSION: The finding of this study offer profound information on stigma experience of parents of children with mental illness and provide basic raw material for developing nursing intervention strategies for these parents.

Ginsan Enhances Humoral Antibody Response to Orally Delivered Antigen

BACKGROUND: There have been several reports describing the capability of ginseng extracts as an adjuvant. In this study, we tested if ginsan, a polysaccharide extracted from Panax ginseng, was effective in enhancing antibody response to orally delivered Salmonella antigen. METHODS: Ginsan was treated before oral salmonella antigen administration. Salmonella specific antibody was determined by ELISA. mRNA expression was determined by RT-PCR. Cell migration was determined by confocal microscopy and flow cytometry. COX expression was detected by western blot. RESULTS: Ginsan treatment before oral Salmonella antigen delivery significantly increased both secretory and serum antibody production. Ginsan increased the expression of COX in the Peyer's patches. Various genes were screened and we found that CCL3 mRNA expression was increased in the Peyer's patch. Ginsan increased dendritic cells in the Peyer's patch and newly migrated dendritic cells were mostly found in the subepithelial dome region. When COX inhibitors were treated, the expression of CCL3 was reduced. COX inhibitor also antagonized both the migration of dendritic cells and the humoral immune response against oral Salmonella antigen. CONCLUSION: Ginsan effectively enhances the humoral immune response to orally delivered antigen, mediated by CCL3 via COX. Ginsan may serve as a potent vaccine suppliment for oral immunization.

Protective Effect of Ginsan Against Vibrio vulnificus Infection

Ginsan, a botanic polysaccharide extracted from Panax ginseng, has recently been reported to modulate mucosal immune response. In this study, we investigated the protective effect of Ginsan against fatal Vibrio vulnificus mucosal infection. A lethal dose of V. vulnificus (1.0 x 106 CFU/mouse) was nasally inoculated to mice. The bacterial count in the nasal associated lymphoid tissue (NALT) of the mouse was significantly reduced in the Ginsan-treated group. The Ginsan-treated group showed improved survival compared to the control group (100% vs 18%). To elucidate the effect of Ginsan on modulating host immune response, cytokine mRNA expressions involved in mediating inflammation were determined by semiquantitative RT-PCR in the NALTs of the infected mice. Most of the cytokine mRNAs were similarly expressed as the control group. However, COX-1 mRNA expression level was higher in Ginsan-treated group compared to the control group. The protective effect of Ginsan was antagonized by treating with a specific COX-1 inhibitor, SC-560. Thus, these data suggest that the protective effect of Ginsan against V. vulnificus infection is partly mediated by modulating COX-1 expression.

Immunomodulatory Activity of Ginsan, a Polysaccharide of Panax Ginseng, on Dendritic Cells

Ginsan, a Panax ginseng polysaccharide that contains glucopyranoside and fructofuranoside, has immunomodulatory effects. Although several biologic studies of ginsan have been performed, its effects on dendritic cells (DCs), which are antigen-presenting cells of the immune system, have not been studied. We investigated the immunomodulatory effects of ginsan on DCs. Ginsan had little effect on DC viability, even when used at high concentrations. Ginsan markedly increased the levels of production by DCs of IL-12 and TNF-alpha, as measured by ELISA. To examine the maturation-inducing activity of ginsan, we measured the surface expression levels of the maturation markers MHC class II and CD86 (B7.2) on DCs. It is interesting that ginsan profoundly enhanced the expression of CD86 on DC surfaces, whereas it increased that of MHC class II only marginally. In 3H-thymidine incorporation assays, ginsan-treated DCs stimulated significantly higher proliferation of allogeneic CD4+ T lymphocytes than did medium-treated DCs. Taken together, our data demonstrate that ginsan stimulates DCs by inducing maturation. Because DCs are critical antigen-presenting cells in immune responses, this study provides valuable information on the activities of ginsan.

The Relationship of P2Y1 ADP Receptor Polymorphisms and Ischemic Vascular Disease

BACKGROUND: The platelet ADP receptor P2Y1 plays a key role in platelet aggregation. METHODS: We tested eight sites of P2Y1 and studied the possible link between the presence of P2Y1 polymorphisms and the risk of is chemic vascular disease in a case-control study. The polymorphisms A1622G, C647G and C2259G were selected according to linkage disequilibrium. We evaluated 275 patients with is chemic cerebrovascular disease and 275 control subjects. We also evaluated 171 patients with acute myocardial infarction (AMI), 166 patients with unstable angina (UA), 173 patients with stable angina (SA) and 188 control subjects. RESULTS: For the cerebrovascular disease patients, A1622G AA, AG [odds ratio (OR), 1.170; 95% confidence interval (CI), 0.784 to 1.748] and GG (OR, 1.031; 95% CI, 0.554 to 1.918) did not show any difference between the case and control subjects. C647G CC, CG (OR, 0.995; 95% CI, 0.639 to 1.550) and GG (OR, 1.012; 95% CI, 0.450 to 2.277) did not show any difference between the case and control subjects. C2259G CC, CG (OR, 0.619; 95% CI, 0.354 to 1.082) and GG did not show any difference between the case and control subjects. For coronary artery disease patients, C2259G GG, CG (for AMI patients OR, 0.880, 95% CI, 0.384 to 2.016; for UA patients, OR, 0.885, 95% CI, 0.410 to 1.911; for SA patients, OR, 1.156, 95% CI, 0.534 to 2.501) and CC did not show any difference between AMI, UA and SA patients and each control subject. C647G GG, CG (for AMI patients OR, 1.351, 95% CI, 0.731 to 2.497; for UA patients OR, 1.292, 95% CI, 0.723 to 2.309; for SA patients OR, 0.977, 95% CI, 0.530 to 1.803) and CC (for AMI patients OR, 0.355, 95% CI, 0.093 to 1.358; for UA patients OR, 0.645, 95% CI, 0.205 to 2.028; for SA patients OR, 0.385, 95% CI, 0.113 to 1.311) did not show any difference between AMI, UA and SA patients and each control subject. A1622G AA, AG (for AMI patients OR, 1.416, 95% CI, 0.786 to 2.549; for UA patients OR, 1.079, 95% CI, 0.611 to 1.904; for SA patients OR, 0.958, 95% CI, 0.529 to 1.732) and GG (for AMI patients OR, 0.525, 95% CI, 0.195 to 1.411; for UA patients OR, 0.568, 95% CI, 0.231 to 1.401; for SA patients OR, 0.441, 95% CI, 0.169 to 1.154) did not show any difference between AMI, UA and, SA patients and the control subjects. CONCLUSION: The distribution of P2Y1 polymorphisms did not show any association with ischemic vascular disease.

Comparative Study on the Sleep Patterns, Satisfaction of Sleep, and Sleep Enhancement Behaviors between Hospitalized and Non-hospitalized Elderly

PURPOSE: This study was to compare and analyze sleep patterns, satisfaction of sleep, and sleep enhancement behaviors between hospitalized and non-hospitalized elderly. METHODS: Subjects were 201 older adults, who were hospitalized patients or living in U-city, Gyung-gi province. Data was collected from June 10 to August 25, 2007, and was analyzed by the SAS program. RESULTS: 1) Non-hospitalized elderly had better sleep patterns than hospitalized elderly patients. 2) There was a strong positive correlation between sleep patterns and satisfaction of sleep in both groups. 3) In hospitalized elderly, there were significant differences in sleep patterns and satisfaction of sleep by month. 4) In non-hospitalized elderly, there was a significant difference in sleep patterns by presence or absence of spouses. There was a significant difference in satisfaction of sleep by those living with others. There were significant differences in sleep enhancement behaviors by age, religion, length of time, and sponsors. CONCLUSION: To relieve sleep disturbances of elderly, comprehension of sleep of the aged by nursing care givers should be obtained. Also, improving environments and elder's selfesteem with religious consideration and preparation of financial conditions are needed to promote the sleep of hospitalized and non-hospitalized elderly.

Overexpression of alpha-protease Inhibitor and Galectin-1 in Radiation-induced Early Phase of Pulmonary Fibrosis / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Radiation-induced pulmonary fibrosis (RIF) is a significant complication of radiotherapy for lung cancer. Despite the large number of studies, the molecular mechanisms of RIF are poorly understood. Therefore, the complex protein expression pattern in RIF was characterized by identifying the proteins with an altered expression level after thorax irradiation using two-dimensional electrophoresis (2-DE) and mass spectrometry. MATERIALS AND METHODS: A mouse model of RIF was used to examine the alteration of the lung proteome because of availability of murine data related to human cases and the abundance of murine fibrotic lung samples. A mouse model of RIF was induced in radiosensitive C57BL/6 mice. Twenty-one weeks after 25 Gy irradiation, hematoxylin-eosin staining and hydroxyproline assay confirmed the early-phase pulmonary fibrosis. RESULTS: Lung samples from the irradiated and age-matched control mice were used to generate 16 high quality 2-DE gels containing approximately 1,000 spots. Of the 31 significantly up- or down-regulated protein spots, 17 were identified by MALDI-TOF/MS. CONCLUSIONS: Two important upregulated proteins were found, the alpha-protease inhibitor and galectin-1, which might be used as potential markers for the early phase of RIF.

Mammographic Breast Density and Risk Factors of Breast Cancer in Korean Women Using Multicenter Study

BACKGROUND: Density patterns on mammography have been related to the risk factors for breast cancer in the western countries. High mammographic density appears to confer a 4-fold risk of breast cancer. While the proportion of high-density mammography is higher in Korean women than in Caucasian women, the incidence of breast cancer in Korean women is considerably lower. Therefore, we examined if the mammographic breast density pattern correlates with the risk factors for breast cancer in Korean women. METHODS: In a cross-sectional design, we recruited 1,758 pre- and post-menopause women without prior history of breast cancer and breast surgery who underwent screening mammogram and completed a self-administered questionnaire in 6 general hospitals. On the basis of ACR BI RADS breast composition, four density patterns were classified in caudocranial and mediolateral mammography by a designated radiologist in each hospital. Multiple linear logistic regression was used for statistical analyses. RESULTS: Inter-rater reliability between the initial report and the report made by another blinded radiologist was high (Pearson's co-efficient=0.81). Overall, the age, body mass index, family history of breast cancer, and duration of hormone replacement therapy correlated with the mammographic density patterns. In pre-menopausal women, the high body mass index and parity (=2) were associated with low mammographic density. In post- menopausal women, older age, high body mass index, negative family history of breast cancer, and duration of hormone replacement therapy were associated with low mammographic density. CONCLUSION: Our data showed that the mammographic breast density patterns correlated with risk factors for breast cancer in Korean women. While the proportion of high-density mammography is higher in Korean women, the incidence of breast cancer is lower than in the western population. This maybe dependent on other unknown factors. (J Korean Acad Fam Med 2006;27: 33-41)

Mohs Micrographic Surgery for the Treatment of Cutaneous Malignant Tumors and Evaluation of Patients' Satisfaction / 대한피부과학회지

BACKGROUND: Mohs micrographic surgery (MMS) is a specialized type of minimal marginal surgery that offers cure rates superior to other options in the treatment of skin cancers. OBJECTIVE: The purpose of this study was to report our experience of MMS for the treatment of cutaneous malignant tumors and to estimate patients' satisfaction. METHOD: We analyzed 60 cases of cutaneous malignant tumors treated by MMS at the Department of Dermatology, Chonnam University Hospital in Gwangju between March 2003 and May 2005. RESULTS: The mean duration of cancer was 3.6 years and the mean size was 17.2 mm. The most common cancer was basal cell carcinoma (71.7%), followed by squamous cell carcinoma (15.0%), and malignant melanoma (6.7%). The most common site was the face (75.0%). On the face, the nose (53.3 %) was the most common site, followed by the eyelid (15.6%), cheek (8.9%), the lip (8.9 %). The local flap was the most common method to repair surgical defects (53.3%), followed by primary closure (25.0%), and skin graft (21.7%). None of the cases was recurrent during 14-months (range, 0.6-27 months) follow up. Forty seven patients answered the questionnaire for satisfaction at doctor's explanation and cosmetic results. Of them, 42 patients (89.4%) were satisfied with the cosmetic result. CONCLUSION: MMS may be a safe and satisfactory method for the treatment of cutaneous malignant tumors.

Differential Effect of gamma-radiation-induced Heme Oxygenase-1 Activity in Female and Male C57BL/6 Mice

Ionizing radiation produces reactive oxygen species, which exert diverse biological effects on cells and animals. We investigated alterations of heme oxygenase (HO) and non-protein thiols (NPSH), which are known as two major anti-oxidant enzymes, in female and male C57BL/6 mice in the lung, liver, and brain after whole-body gamma-irradiation with 10 Gy (1-7 days) as well as in the lung after whole-thorax gamma-irradiation (WTI) with 12.5 Gy (1-26 weeks). Most significant alteration of HO activity was observed in the liver, which elevated 250% in males. NPSH level in female liver was increased on the 5th-7th days but decreased in males on the 3rd day. In the lung, the elevation of HO activity in both sexes and the pattern of NPSH change were similar to that of the liver. On the other hand, the increase of HO activity on the 16th week and the decrease of NPSH level on the 2nd week were observed only in male lung after WTI. This study shows that the liver is the most sensitive tissue to gamma-irradiation-induced alterations of HO activity in both female and male mice. In addition, there exists significant differential effect of gamma-irradiation on anti-oxidant system in female and male mice.

Comparison of Cefepime Monotherapy with Piperacillin-Tazobactam, Gentamicin Combination Therapy in Pediatric Cancer Patients with Febrile Neutropenia / 대한소아혈액종양학회지

PURPOSE: Cefepime is a new broad-spectrum antibiotics and is available as initial monotherapy in the management of pediatric cancer patients with febrile neutropenia. The aim of this study is to evaluate the efficacy of Cefepime monotherapy and piperacillin-tazobactam plus gentamicin combination therapy as an initial empirical antibiotics treatment in pediatric cancer patients with febrile neutropenia. METHODS: From January 2003 to July 2004, a total of 55 episodes of febrile neutropenia were analyzed retrospectively for this study. They were treated intravenous Cefepime (50 mg/kg every 8 hour) or piperacillin-tazobactam (90 mg/kg every 8hour) plus gentamicin (2.5 mg/kg every 8hour). Modification of antibiotics was done at 72~96 hour if fever persisted. Clinical responses were evaluated at the completion of therapy. RESULTS: Twenty-eight patients in the cefepime monotherapy and twenty-seven patients in the piperacillin-tazobactam plus gentamicin combination therapy were evaluable for efficacy. Modification of the empirical initial antibiotics therapy was done for 53% in the cefepime monotherapy group compared with 33.3% in the piperacillin-tazobactam plus gentamicin combination therapy group. The modification rate was not statistically significance between the treatment groups (P=0.130). And the overall success rate was 92.9% in cefepime monotherapy and 96.3% in piperacillin-tazobactam plus gentamicin combination therapy. So, there was no significant difference in success rate between two groups (P=0.514). A drug-related adverse event was reported in 1 case of piperacillin-tazobactam plus gentamicin combination therapy. There was no major adverse event. CONCLUSION: The empirical regimen of cefepime monotherapy is at least as effective as the regimen of piperacillin-tazobactam plus gentamicin combination therapy in pediatric malignancy patient with febrile neutropenia.

Episodic Ataxia Type 2 with Downbeating Nystagmus Caused by Mutation in the CACNA1A: A Case Report

Episodic ataxia type 2 (EA 2) is a rare disorder characterized by intermittent episodes of ataxia with interictal nystagmus. The authors report a patient with EA 2, who presented with recurrent episodes of vertigo, gait ataxia and interictal downbeat nystagmus, which had developed about 16 years before. The chromosomal analysis revealed a translocation between chromosome 7 and chromosome 19 (t(7;19)). The break point in chromosome 19 was the P13 locus of the CACNA1A gene.

YS 49, a Synthetic Isoquinoline Alkaloid, Protects Sheep Pulmonary Artery Endothelial Cells from tert-butylhydroperoxide-mediated Cytotoxicity

Endothelium, particularly pulmonary endothelium, is predisposed to injury by reactive oxygen species (ROS) and their derivatives. Heme oxygenase (HO) has been demonstrated to provide cytoprotective effects in models of oxidant-induced cellular and tissue injuries. In the present study, we investigated the effects of YS 49 against oxidant [tert-butylhydroperoxide (TBH) ]-induced injury using cultured sheep pulmonary artery endothelial cells (SPAECs). The viability of SPAECs was determined by quantifying reduction of a fluorogenic indicator Alamar blue. We found that TBH decreased cell viability in a time- and concentration-dependent manner. YS 49 concentration- and time-dependently increased HO-1 induction on SPAECs. As expected, YS 49 significantly decreased the TBH-induced cellular injury. In the presence of zinc protophorphyrin, HO-1 inhibitor, effect of YS 49 was significantly inhibited, indicating that HO-1 plays a protective role for YS 49. Furthermore, YS 49 showed free radical scavenging activity as evidenced by 1, 1-diphenyl-2-picrylhydrazyl (DPPH) and inhibition of lipid peroxidation. However, YS 49 did not inhibit apoptosis induced by lipopolysaccharide (LPS) in SPAECs. Taken together, HO-1 induction along with strong antioxidant action of YS 49 may be responsible for inhibition of TBH-induced injury in SPAECs.

Inhibition of Inducible Nitric Oxide Synthase Expression by YS 49, a Synthetic Isoquinoline Alkaloid, in ROS 17/2.8 Cells Activated with TNF-alpha, IFN-gamma and LPS

Nitric oxide (NO) has been suggested to act as a mediator of cytokine-induced effects of turn over of bone. Activation of the inducible nitric oxide synthase (iNOS) by inflammation has been related with apoptotic cell death in osteoblast. YS 49, a synthetic isoquinoline alkaloid, inhibits NO production in macrophages activated with cytokines. In the present study, we investigated the molecular mechanism of YS 49 to inhibit iNOS expression in ROS 17/2.8 cells, which were activated with combined treatment of inflammatory cytokines (TNF-alpha, IFN-gamma) and lipopolysaccharide (LPS). Results indicated that YS 49 concentration-dependently reduced iNOS mRNA and protein expression, as evidenced by Northern and Western blot analysis, respectively. The underlying mechanism by which YS 49 suppressed iNOS expression was not to affect iNOS mRNA stability but to inhibit activation and translocation of NF-kappaB by preventing the degradation of its inhibitory protein IkappaBalpha. As expected, YS 49 prevented NO-induced apoptotic cell death by sodium nitroprusside. Taken together, it is concluded that YS 49 inhibits iNOS expression by interfering with degradation of phosphorylated inhibitory kappaBalpha (p-IkappaBalpha). These actions may be beneficial for the treatment of inflammation of the joint, such as rheumatoid arthritis.

Enhancement of radiosensitivity by combined ceramide and dimethylsphingosine treatment in lung cancer cells

Ceramide generated from sphingomyelin in response to ionizing radiation has been implicated as a second messenger to induce cellular proapoptotic signals. Both ceramide and its metabolic inhibitor, N, N-dimethyl-D-erythro-sphingosine (DMS), might lead to sustained ceramide accumulation in cells more efficiently, thereby sensitizing them to gamma-radiation-induced cell death. To delineate this problem, the clonogenic survival of Lewis lung carcinoma (LLC) cells was evaluated following exposure to radiation together with or without C2-ceramide, DMS, or both. The treatment of ceramide/DMS synergistically decreased the survival of the irradiated cells compared with treatment with ceramide or DMS alone. Ceramide/DMS-treated cells displayed several apoptotic features after gamma-irradiation, including increased sub G1 population, TUNEL-positive fraction, and poly-(ADP-ribose) polymerase (PARP) cleavage. We also observed ceramide/ DMS induced disruption of mitochondrial membrane potential (MMP) and activation of caspase- 9 and -3 in a radiation-dose-dependent manner. Furthermore, pretreatment of LLC cells with ceramide/DMS not only increased the protein expression level of Bax, but also decreased Bcl-2 after gamma-irradiation. Taken together, the present study indicates that the radiosensitizing activity of ceramide/DMS on LLC cells most likely reflects the dominance of pro-apoptotic signals related to the mitochondria-dependent pathway.