Protective Effects of Lithospermate B on Diabetic Nephropathy in OLETF Rat

Background: Magnesium lithospermate B(LAB), an active component isolated from Salvia milltiorrhizae, has been reported to have renoprotective effects in type 1 diabetic animal model. The purpose of this study was to examine the effects of LAB on the prevention of diabetic nephropathy in Otsuka Long-Evans Tokushima Fatty(OLETF) rat which is regarded as an animal model of type 2 diabetes. Methods: Ten microgram of LAB/kg or Vehicle(PBS) was given orally once daily to 10-week-old male OLETF rats and LETO rats for 40 weeks. Intra-peritoneal glucose tolerance test was performed at 50 weeks. 24 hr urinary protein excretion amounts were measured. Lipid peroxidation, TGF-beta1 and ED-1 of renal cortex were measured. Results: The mean body weight of LAB+OLETF was not significantly different from that of OLETF rats. LAB treatment decreased proteinuria, lipid peroxidation, and free fatty acid in OLETF rats without decrease in the plasma glucose concentration. Also, LAB inhibited the progression of glomerular hypertrophy and mesangial expansion. LAB effectively decreased ED-1 positive cells, ECM expansion, and TGF-beta1 level in the renal cortex of OLETF rats. Conclusion: These results suggest that the beneficial effects of LAB on the diabetic renal damage in the OLETF rats may depend on a mechanism of decreasing oxidative stress. LAB might be a new therapeutic agent for the prevention of nephropathy in type 2 diabetes as well as type 1 diabetes.ope

A Case of Primary Peripheral T-cell Lymphoma of the Stomach with Cytotoxic Phenotype

Primary gastric lymphoma is the most common form of extralymphatic non-Hodgkin's lymphoma (NHL). Most cases are of B-cell origin and few cases of lymphoma of T-cell origin have been reported. Peripheral T cell lymphoma is a lymphoma of extrathymic origin. Expression of T-cell intracellular antigen (TIA)-1 can be detected in all cytotoxic cells, and the expression of this cytotoxic protein is associated with extranodal presentation. We report a case of primary peripheral T cell lymphoma of the stomach with cytotoxic T-cell phenotype in a 70-year-old male presenting with upper gastrointestinal bleeding.ope

Visceral fat thickness measured by ultrasonography can estimate not only visceral obesity but also risks of cardiovascular and metabolic diseases

BACKGROUND: Visceral obesity is closely associated with cardiovascular disease and the metabolic syndrome. Estimating the amount of visceral fat is important and requires a straightforward, reliable, and practical method. OBJECTIVE: We investigated whether visceral fat thickness (VFT) measured by ultrasonography can adequately assess visceral fat accumulation and predict cardiovascular or metabolic diseases. DESIGN: Diabetic patients (240 men and 106 women) underwent ultrasonography to estimate visceral fat accumulation. RESULTS: The visceral adipose tissue area had the best correlation with VFT (r = 0.799, P < 0.001). VFT correlated with HDL-cholesterol, triacylglycerol, and high-sensitivity C-reactive protein concentrations, the homeostasis model assessment for insulin resistance, and the intima-media thickness at the common carotid artery (r = -0.30, 0.39, 0.34, 0.31, and 0.33, respectively; P < 0.05) in men and with triacylglycerol and high-sensitivity C-reactive protein concentrations and the homeostasis model assessment for insulin resistance (r = 0.33, 0.44, and 0.30, respectively; P < 0.05) in women. Men in the middle and high VFT tertiles had a higher odds ratio (OR) of coronary artery disease [ORs: 4.48 (95% CI: 1.29, 5.51) and 2.04 (1.06, 3.94), respectively; P = 0.016], hypertriacylglycerolemia [ORs: 2.87 (1.41, 5.86) and 1.91 (1.24, 2.95), respectively; P = 0.003], and the metabolic syndrome [ORs: 3.38 (1.61, 7.10) and 1.95 (1.16, 3.27), respectively; P = 0.003] than did those in the low tertile, after adjustment for age, waist circumference, and body mass index. CONCLUSION: VFT might be a reliable index for assessing the amount of visceral fat and for identifying diabetic patients, particularly men, who are at high risk of cardiovascular disease.ope

Hypercalcemia in hepatic tuberculosis: A case report in Korea

Although primary hyperparathyroidism and malignant diseases account for approximately 90% of the causes of hypercalcemia, they could occur in association with granulomatous diseases such as tuberculosis or sarcoidosis, especially in developing countries. Hepatic tuberculosis is difficult to diagnosis without suspicion in cases with normal findings on chest radiographs. We report a 70-year-old woman who presented with hypercalcemia due to hepatic tuberculosis. The diagnosis was made by a computed tomography scan and laparoscopic evaluation. After treatment with anti-tuberculosis medication, her hypercalcemia resolved. Increased vitamin D synthesis by activated macrophages in the granuloma tissue is the major mechanism of hypercalcemia in tuberculosis.ope

Protective Effects of Lithospermic Acid B on Diabetic Nephropathy in OLETF Rats Comparing with Amlodipine and Losartan

BACKGROUND: Lithospermic acid B (LAB), an active component isolated from Salvia miltiorrhizae, has been reported to have renoprotective effects in type 1 and type 2 diabetic animal models. We examined the effects of LAB on the prevention of diabetic nephropathy compared with amlodipine, a calcium channel blocker, and losartan, an angiotensin receptor blocker, in Otsuka Long-Evans-Tokushima Fatty (OLETF) rats, an animal model of type 2 diabetes. METHODS: LAB (20 mg/kg), amlodipine (10 mg/kg), or losartan (10 mg/kg) was given orally once daily to 10-week-old male OLETF rats for 28 weeks. RESULTS: None of LAB, losartan, and amlodipine exhibited effects on blood glucose levels. Treatment with amlodipine or losartan resulted in similar reductions in blood pressure; however, LAB was less effective in lowering blood pressure. Albuminuria was markedly suppressed by losartan and LAB, but not by amlodipine. LAB treatment decreased levels of renal lipid peroxidation, monocyte chemoattractant protein-1 (MCP-1), and transforming growth factor-beta1 (TGF-beta1). CONCLUSION: These results suggest that LAB has beneficial effects on the diabetic nephropathy in OLETF rats by decreasing oxidative stress and inflammation as potent as losartanope

Adiponectin Gene Polymorphism and Carotid Artery Intima-Media thickness in Type 2 Diabetes

Background: The aim of this study was to examine the association between the common polymorphisms of the adiponectin gene(ACDC) and the intima-media thickness(IMT) of the common carotid arteries in type 2 diabetic patients. Methods: The B mode ultrasound examination of carotid artery was performed on 133 type 2 diabetic patients. The carotid IMT was calculated using the Intimascope computer program. The SNP45 and SNP276 of the ACDC were examined. Results: There was no significant difference in the carotid IMT among the SNP45 genotypes(0.66+/-0.18mm for TT, 0.71+/-0.12mm for TG and 0.64+/-0.15mm for GG, P=NS). Subjects carrying the SNP276 GG genotype had a markedly lower serum adiponectin concentration than those carrying the TT genotype(3.35+/-2.00microgram/mL vs. 4.98+/-2.24microgram/mL, P=0.029) The carotid IMT was significantly higher in patients with the SNP276 GG genotype than those with the TT genotype (0.70+/-0.17mm vs. 0.59+/-0.13mm, P=0.032). Patients with the +45GG/+276GG genotype combination showed significantly higher mean carotid IMT than the other genotype combinations(0.78+/-0.09mm vs. 0.71+/-0.15mm, P=0.013) Conclusions: These results suggest that the adiponectin gene, SNP276 is associated with the carotid IMT in type 2 diabetic patients. Further studies are will be needed to confirm these genotypephenotype associations.ope

A polymorphism in the zinc transporter gene SLC30A8 confers resistance against posttransplantation diabetes mellitus in renal allograft recipients.

OBJECTIVE: Posttransplantation diabetes mellitus (PTDM) is a major metabolic complication in renal transplant recipients, and insulin secretory defects play an important role in the pathogenesis of PTDM. The R325W (rs13266634) nonsynonymous polymorphism in the islet-specific zinc transporter protein gene, SLC30A8, has been reported to be associated with type 2 diabetes and possibly with a defect in insulin secretion. This study investigated the association between genetic variations in the SLC30A8 gene and PTDM in renal allograft recipients. RESEARCH DESIGN AND METHODS: A total of 624 unrelated renal allograft recipients without previously diagnosed diabetes were enrolled. Rs13266634 was genotyped in the cohort, which consisted of 174 posttransplantation diabetic patients and 450 non-posttransplantation diabetic subjects. The genotyping of the SLC30A8 polymorphism was performed using real-time PCR. RESULTS: The prevalence of PTDM was 33.8% in patients carrying the R/R genotype, 26.8% in patients with the R/W genotype, and 19.8% in patients with the W/W genotype. There was a strong association between the number of W-alleles and PTDM risk reduction (P for trend = 0.007). Patients with at least one T-allele showed a decreased risk of PTDM compared with those with the R/R genotype (R/W, risk ratio [RR] 0.78, P = 0.126; W/W, RR 0.52, P = 0.007). The effect of the SLC30A8 genotype remained significant after adjustments for age, sex, body weight gain, and type of immunosuppressant (R/W, hazard ratio [HR] 0.77, P = 0.114; W/W, HR 0.58, P = 0.026). CONCLUSIONS: These data provide evidence that the SLC30A8 rs13266634 gene variation is associated with protection from the development of PTDM in renal allograft recipients.ope

Relation between the changes in abdominal fat distribution and the efficacy of rosiglitazone

의학과/석사[한글] Rosiglitazone은 thiazolidinedione(TZD)계 약물로, peroxisome proliferator-activated receptor-g(PPAR-g) 핵수용체에 작용하여 인슐린 저항성과 관련된 여러 가지 대사장애를 개선시킬 수 있는 약물로 알려져 있다. 본 연구의 목적은 제 2형 당뇨병 환자들을 대상으로 rosiglitazone의 혈당강하 효과와 복부지방 분포의 변화 간에 어떠한 관계가 있는지 알아보고자 함이다. 기존에 rosiglitazone등 TZD계열의 약물을 제외한 다른 경구 혈당 강하제나 인슐린으로 비교적 안정적으로 혈당 조절을 하고 있었던 제 2형 당뇨병 환자 173명(남자 111명, 여자 62명)에게 rosiglitazone(4 mg/day)을 추가로 복용하게 하였다. Rosiglitazone은 12주간 투여하였고, 투여 전후에 초음파로 복부지방 분포를 측정하였다. 초음파 정지 영상에서 피하지방 두께 (subcutaneous fat thickness, SFT)와 내장지방 두께(visceral fat thickness, VFT)를 측정하였다. Rosiglitazone 12주 치료 후 혈당과 인슐린 저항성은 개선되었고, 체중은 증가하였다. 복부 초음파 측정 결과, rosiglitazone 투여 후 피하지방 두께는 9.6% 증가하였고 내장지방 두께 피하지방 두께 비율은 감소하였으나, 내장지방 두께는 변화가 없었다. Rosiglitazone 투여 후 공복혈당의 변화량(%)과 당화 혈색소의 변화량(%)은 피하지방 두께 증가 (r=-0.327, p<0.001; r=-0.353, p<0.001, respectively) 혹은 체중 증가 (r=-0.316, p<0.001; r=-0.327, p<0.001, respectively)와 반비례 관계가 있었다. 다중 회귀분석결과, 피하지방 두께의 변화가 공복혈당(p=0.019)이나 당화 혈색소(p=0.010)의 개선과 관련이 있었다. 또, 다중 로지스틱 회귀분석 결과, rosiglitazone 투여 전 공복 혈당(p=0.007) 및 당화 혈색소(p=0.018), 초기 내장지방 두께(p=0.002), 피하지방 두께의 변화량(p=0.005) 그리고 내장지방 두께의 변화량(p=0.008) 등이 rosiglitazone의 치료 효과에 영향을 주는 요인, 또는 반응도를 예측할 수 있는 인자임을 알 수 있었다. 결론적으로, 피하지방 두께나 체중이 더 많이 증가한 군에서 rosiglitazone 투여로 인한 혈당 개선 효과가 더 좋음을 알 수 있었다. [영문]We investigated the inter-relation between the hypoglycemic effects of peroxisome proliferator-activated receptor (PPAR)-g ligand and the changes of regional adiposity in type 2 diabetic patients. We added rosiglitazone (4 mg/day) to 173 diabetic patients (111 males and 62 females) already taking a stable dose of conventional antidiabetic medication except PPAR-g lignads. Distribution of body fat was assessed by ultrasonography at baseline and repeated after 12 weeks. On ultrasonographic images, subcutaneous fat and visceral fat thickness (SFT and VFT, respectively) were measured. Rosiglitazone treatment significantly improved glycemic control and insulin sensitivity, and resulted in weight gain. In ultrasonographic findings, rosiglitazone treatment increased SFT by 9.6% and decreased VFT/SFT ratio, but did not alter VFT. The percent changes in fasting plasma glucose (FPG) and HbA1c concentrations after treatment were inversely correlated with the increase in SFT(r=-0.327 and r=-0.353, p<0.001, respectively) and/or body weight(r=-0.316, p<0.001 and r=-0.327, p<0.001). The group with the greater increase in SFT or body weight showed better glycemic control after treatment. By multiple regression analysis, the change in SFT was related with improvements of fasting plasma glucose (p=0.019) and HbA1c(p=0.010). Multiple logistic regression analysis revealed that baseline fasting plasma glucose(p=0.007) and HbA1c(p=0.018), baseline VFT(p=0.002), and the changes of SFT (p=0.005) andVFT (p=0.008) were independent predictors of response to rosiglitazone treatment. The present findings suggest that PPAR-g agonist significantly increased subcutaneous fat mass, but did not alter visceral fat mass, and that the hypoglycemic effect of PPAR-g agonist was closely correlated with the increase in body weight, especially subcutaneous fat mass. In contrast, the reduction in the visceral fat mass may be the prime determinant to improve dyslipidemiaope

항산화 효과 및 aldose reductase 억제 효과를 가진 magnesium lithospermate B의 당뇨병성 혈관 합병증 예방 효과

Dept. of Medicine/박사[한글]Magnesium lithospermate B (LAB)는 Salvia miltiorrhiza의 추출물이며 항산화 효과가 있다고 알려져 있다. 본 연구의 목적은 LAB가 당뇨병성 혈관 합병증을 예방하는 효과 및 그 기전에 대해 알아보고자 하였다.백서 대동맥의 혈관 평활근을 분리하여 사용하였다. 활성 산소족은 형광 물질인 CM-H2DCF-DA와 lucigenin을 사용하여 측정하였다. Aldose reductase (AR), protein kinase C (PKC), 그리고 Nuclear Factor-&#61547;B (NF-&#61547;B) activity를 측정하였다. 고혈당 (30mM glucose) 상태에서 백서 평활근 세포의 증식, 이동, 그리고 세포 주기 등을 측정하였다. 10주령의 Sprague-Dawley rat에게 목동맥 혈관에 풍선 확장술을 시행하고 28일후에 신생혈관의 증식정도를 관찰하였다. LAB (10 mg/kg/day)를 혈관에 풍선 확장술을 시행하기 1일전부터 투여하기 시작하여 총 29일간 복강내로 주입하였다.LAB는 화학적으로 생성된 활성 산소족을 직접적으로 감소시켰고 또한 고혈당으로 인해 세포 내에서 생성된 활성 산소족도 의미있게 감소시켰다. LAB는 recombinant AR 단백질을 직접적으로 감소시키는 효과가 있었고, 고혈당으로 인해 세포 내에서 활성이 증가된 AR을 유의하게 감소시켰다. LAB는 고혈당으로 인해 활성이 증가되는 protein kinase C와 NF-&#61547;B 역시 의미있게 감소시켰다. 고혈당은 PDGF-BB에 의한 평활근의 증식 및 이동을 정상혈당일 때 보다 유의하게 증가시키는데 LAB는 이를 억제하는 효과가 있었다. 또한 LAB를 투여한 백서에서, 목동맥에 풍선 확장술을 시행한 후 신생 혈관이 증식하는 것이 의미 있게 억제되었다 (31.2% vs. 83.7%, P<0.001).본 연구에서 LAB는 항산화제이자 AR 억제제로서 당뇨병성 혈관 합병증을 예방하는 효과가 있음을 알 수 있었다. LAB는 상기의 두 가지 기전을 통하여 당뇨병성 혈관 합병증을 예방하는 새로운 약제가 될 것으로 기대한다. [영문]Magnesium lithospermate B (LAB) is an extract of Salvia miltiorrhizae and has been characterized as an antioxidant. The aim of this study was to investigate the effect of LAB on the prevention of diabetic vascular complications and the mechanism(s) which are involved.Rat aortic vascular smooth muscle cells (VSMCs) were isolated and cultured. ROS were measured using the fluorescent probe CM-H2DCF-DA in the isolated VSMCs and lucigein in the cell free assay system. Aldose reductase (AR), protein kinase C (PKC), and nuclear factor (NF)-kB activity were measured. Hyperglycemia (HG, 30mM, 48h)-induced VSMC proliferation, cell cycle change, and migration were also analyzed. LAB (10mg/kg/day) was injected intraperitoneally once daily to 10-week old male Spraque-Dawley (SD) rats for 4 weeks. Neointimal hyperplasia was assessed after carotid balloon injury at 4 week by computerized morphometry.We found that LAB (50 mM) directly inhibited both exogenous ROS and HG-induced endogenous ROS. LAB directly inhibited AR in a dose dependent manner and inhibited HG-induced PKC membrane translocation and NF-kB nuclear translocation. LAB significantly inhibited VSMCs proliferation and migration under HG conditions. Neointimal hyperplasia after balloon injury in rat carotid artery was significantly reduced in LAB-treated group compared with the control group (31.2 % vs. 83.7 %, respectively, P<0.001).Together, these findings suggest that LAB may prevent diabetic vascular complications via direct suppression of intracellular ROS and AR. LAB may be a new therapeutic drug capable of preventing diabetic vascular complications via these dual mechanisms.prohibitio

Design, synthesis, and discovery of stilbene derivatives based on lithospermic acid B as potent protein tyrosine phosphatase 1B inhibitors

Dihydroxy stilbene derivatives were designed based on lithospermic acid B and were prepared from 4-(chloromethyl)benzoic acid. The inhibitory activities of the novel compounds against protein tyrosine phosphatase 1B (PTP1B) were evaluated. 3,4-Dihydroxy stilbene carbonyl compounds (7, 11b, 27b) inhibited PTP1B with IC50 values comparable to molybdate, while the conjugation-extended compound (15b) showed inhibition 3-fold better than preclinical RK682. The introduction of electron withdrawing groups or amides into the second phenyl ring, or extension of the conjugation into the stilbene molecule may increase stability of the generated radicals.ope