Oenothein B,dimeric hydrolysable tannin inhibiting HCV invasion from Oenothera erythrosepala

The envelope proteins of the hepatitis C virus (HCV), E1 and E2, have been revealed to be essential for invasion of HCV. Thus, we were engaged in the search for the inhibitors against HCV invasion through the assay system using the model virus expressing recombinant HCV envelopes, E1 and E2. Now, we disclosed dimeric hydrolysable tannin oenothein B (1) from MeOH extract of Oenothera erythrosepala as an active principle for inhibition of HCV invasion and its potency was almost the same as that of monomeric hydrolysable tannin, tellimagrandin I (2). Furthermore, by use of stereoselectively prepared 1-β- and 1-α-O-methyl tellimagrandin Is (4 and 5), the introduction of methyl moiety into 1-hydroxy group of 2 was clarified to result in slightly reduction of activity and β-isomer was revealed to exhibit a little stronger activity than α-one.

     

CCAAT/enhancer-binding protein-d is induced in mesangial area during the early stages of anti-Thy1.1 glomerulonephritis and regulates cell proliferation and inflammatory gene expression in cultured rat mesangial cells

Background Interleukin (IL)-6, cyclooxygenase (COX)-2, and monocyte chemoattractant protein (MCP)-1 contribute to renal injury. The promoter regions of these genes contain CCAAT/enhancer-binding protein (C/EBP)-binding sites. In this study, we investigated the role of C/EBP-δ in mesangial cells (MCs). Methods In an in vivo study, anti-Thy 1.1 glomerulonephritis rats were generated and C/EBP-δ, IL-6, COX-2, and MCP-1 expressions were assessed by immunohistochemistry. In an in vitro study, cultured MCs were transfected with non-silencing (NS) short interfering RNA (siRNA) or C/EBP-δ siRNA. Subsequently, after stimulation with IL-1β, C/EBP-δ, IL-6, COX-2, and MCP-1 mRNA expression levels were evaluated using real-time polymerase chain reaction (PCR). IL-6 concentration in the culture medium was determined by enzyme-linked immunosorbent assay. In addition, cell proliferative activity against IL-1β or platelet-derived growth factor-BB was assessed by bromodeoxyuridine incorporation. Results In the in vivo study, C/EBP-δ, IL-6, COX-2, and MCP-1 were expressed in the mesangial region of anti-Thy 1.1 glomerulonephritis rats on day 1. In the in vitro study, IL-1β increased C/EBP-δ mRNA levels in NS siRNA-transfected MCs (7.3-fold), but no increase was evident in C/EBP-δ siRNA-transfected MCs. IL-6, COX-2, and MCP-1 mRNA levels in C/EBP-δ siRNA-transfected MCs were all lower than those in NS siRNA-transfected MCs (decreases of 57.7%, 85.7%, and 69.3%, respectively). The IL-6 concentration in the culture medium from C/EBP-δ siRNA transfected MCs (7.37 ± 4.3 pg/ml) was also lower than that in the culture medium from NS siRNA-transfected MCs (25.2 ± 3.4 pg/ml). Cell proliferative activity in C/EBP-δ siRNA-transfected MCs was lower than that in NS siRNA transfected MCs. Conclusions C/EBP-δ was induced in the mesangial region during the early stages of anti-Thy1.1 glomerulonephritis. C/EBP-δ contributes to inflammatory gene expression and MC proliferation.     

Serum cystatin C level is a marker of end-organ damage in patients with essential hypertension.

High urinary albumin excretion rate (AER) has been associated with the presence of atherosclerotic vascular damages and is an independent risk factor for all causes of death and cardiovascular morbidity and mortality in essential hypertensive patients. Serum cystatin C (s-CC) is a recently identified nonglycosylated 13-kD basic protein that has been suggested to be a useful marker of glomerular filtration rate. In the present study, we investigated the relationship between s-CC level and end-organ damages in the kidney, heart, and vessels of patients with essential hypertension. Sixty patients with essential hypertension participated in the present study. Patients with renal failure were excluded. Serum-CC level was measured by a particle-enhanced turbidimetric assay. Left ventricular mass index (LVMI) and intima media thickness (IMT) in the common carotid arteries were evaluated by ultrasound images. Twenty-four-hour blood pressure was measured by a cuff-oscillometric method. Serum-CC level was negatively correlated with creatinine clearance (r=-0.617, p<0.0001). It was also correlated with mean 24-h systolic blood pressure (24h-SBP) (r=0.308, p= 0.0167), LVMI (r=0.528, p<0.0001), and IMT (r=0.539, p<0.0001). Both AER and s-CC level were independently associated with mean 24h-SBP. AER but not s-CC level was associated with HDL-cholesterol. The present study was the first to demonstrate that s-CC level is a useful and convenient parameter of renal function, and may also prove to be an early marker of the severity of end-organ damage in patients with essential hypertension.     

Intrarenal and carotid hemodynamics in patients with essential hypertension

BACKGROUND: The pulsatility index (PI) and resistive index (RI) are used as markers of peripheral vascular resistance. Recently intrarenal PI and RI were introduced for the evaluation of the severity of acute and chronic renal failure, as well as for the diagnosis of renal artery stenosis and kidney graft rejection. In the present study, we evaluated intrarenal PI and RI in patients with essential hypertension. METHODS: Fifty-one patients with essential hypertension participated. The intima-media thickness (IMT) and mean diastolic (Vd) and systolic velocity (Vs) in the common carotid artery (CCA) were measured using ultrasound and Doppler flow methods. Relative diastolic flow velocity (Vd/Vs) was calculated as an assessment of CCA hemodynamics. Renal Doppler flow was obtained from the interlobar arteries in each of two kidneys. The mean PI ([peak systolic velocity--end-diastolic velocity]/mean velocity) and mean RI ([peak systolic velocity--end-diastolic velocity]/peak systolic velocity) were calculated. RESULTS: Intrarenal PI and RI were positively correlated with IMT and negatively correlated with Vd/Vs in CCA, indicating that renal vascular resistance is related to carotid stiffness. A stepwise regression analysis revealed that age and pulse pressure were independently associated with intrarenal PI and RI. CONCLUSIONS: These results suggest that the measurement of PI and RI is useful for the evaluation of arterial stiffness in patients with essential hypertension.     

A large degenerated subserous leiomyoma of the uterus: Uncommon scintigraphic and ultrasonographic findings

Bone imaging is commonly used as a sensitive indicator of metastatic bone diseases or other bone pathology. Furthermore, it is now generally known that technetium-99m (99mTc) phosphonates tend to concentrate in various tissues other than bones. Ultrasonography is also widely used for the evaluation of pelvic masses. Ultrasonography is especially useful for detecting a cystic mass. We present a case where the uptake of 99mTc phosphonate compounds occurred in the entire abdomen, and ultrasonography suggested a diagnosis of pseudomyxoma peritonei, but the condition was later proven to be degeneration of giant subserous leiomyoma of the uterus. We have found two interesting features in this case. One is the 99mTc phosphonate concentration in the large cystic and hyaline degeneration of subserous leiomyoma of the uterus without calcification, and the other is the sonographic finding of a large echogenic mass with innumerable small anechoic areas. To our knowledge, no cases of 99mTc phosphonate concentration in non-calcified leiomyoma of the uterus have been demonstrated.     

Coexistence of three distinct adrenal tumors in the same adrenal gland in a patient with primary aldosteronism and preclinical Cushing's syndrome

A 62-year-old woman was admitted to our hospital because of hypokalemia. Physical examination revealed no signs of excessive adrenocortical steroid production, as are found in Cushing's syndrome. Her plasma renin activity (PRA) was suppressed (0.10 ng/ml per h), and her serum aldosterone level was high (30.0 ng/dl). PRA was not increased after a renin-releasing test. Her plasma adrenocorticotropic hormone (ACTH) level was low (<5 pg/ml), but her serum cortisol level was normal (21.0 μg/dl). Administration of 8 mg dexamethasone did not suppress her plasma cortisol level. Finally, she was diagnosed with clinical primary aldosteronism associated with preclinical Cushing's syndrome. Magnetic resonance image revealed three sequential nodular masses (each 15 mm × 15 mm) in the right adrenal gland. A right adrenalectomy was performed by endoscopy. The three removed tumors appeared to have different characteristics. Microscopic examination revealed that the upper and lower tumors were adrenocortical adenomas, and the middle tumor was a black adenoma. Immunohistochemical staining for the enzymes involved in cortisol biosynthesis suggested that the upper tumor secreted aldosterone, whereas either or both of the two other tumors secreted cortisol. Surprisingly, at 33 years of age, she had been diagnosed with Cushing's syndrome, due to a cortisol-producing adrenocortical adenoma, and she had received a left adrenalectomy. Clinically and pathophysiologically, this was a very rare case.     

Valsartan reduces serum cystatin C and the renal vascular resistance in patients with essential hypertension

A high level of albuminuria and increased renal vascular resistance are associated with hypertensive renal damage. In this study, the authors investigated the effect of the angiotensin II receptor blocker, valsartan, on renal function and intrarenal hemodynamics in non-diabetic patients with essential hypertension. A prospective three-month study of the effects of valsartan, 40-80 mg/day, was performed in 30 hypertensive patients. As an assessment of renal function, serum creatinine, urine albumin/creatinine (Alb/Cr) ratio, and serum cystatin C levels were evaluated. Doppler ultrasonography of the kidney was performed for the evaluation of renal hemodynamics. Peak-systolic, end-diastolic, and mean velocities of interlobar arteries were evaluated, and the pulsatility index (PI) and resistive index (RI) were calculated. It was determined that patients with microalbuminuria had higher levels of serum cystatin C, PI, and RI compared to patients without microalbuminuria. Valsartan treatment significantly reduced systolic and diastolic blood pressure and decreased the Alb/Cr ratio. Serum creatinine was not changed, whereas serum cystatin C levels were significantly reduced. Valsartan treatment significantly decreased the PI in all patients and both PI and RI in patients with microalbuminuria. These results suggest that the angiotensin II receptor blocker, valsartan, is able to improve renal function by reducing renal vascular resistance in hypertensive patients, especially in patients with microalbuminuria, and may prevent future renal failure in patients with essential hypertension.     

Anticancer properties of artemisinin derivatives and their targeted delivery by transferrin conjugation

Artemisinin and its derivatives are well known antimalaria drugs and particularly useful for the treatment of infection of Plasmodium falciparum malaria parasites resistant to traditional antimalarials. Artemisinin has an endoperoxide bridge that is activated by intraparasitic heme-iron to form free radicals, which kill malaria parasites by alkylating biomolecules. In recent years, there are many reports of anticancer activities of artemisinins both in vitro and in vivo. Artemisinins have inhibitory effects on cancer cell growth, including many drug- and radiation-resistant cancer cell lines. The cytotoxic effect of artemisinin is specific to cancer cells because most cancer cells express a high concentration of transferrin receptors on cell surface and have higher iron ion influx than normal cells via transferrin mechanism. In addition, some artemisinin analogs have been shown to have antiangiogenesis activity. Artemisinin tagged to transferrin via carbohydrate chain has also been shown to have high potency and specificity against cancer cells. The conjugation enables targeted delivery of artemisinin into cancer cells. In this review, we discuss the anticancer activities and mechanisms of action of artemisinins and the transferrin-conjugate.     

Effect of renal impairment on the pharmacokinetics of memantine

The effect of renal impairment on the pharmacokinetics of a single oral dose of memantine (10 mg) was determined in Japanese subjects. Subjects were assigned to four groups based on baseline creatinine clearance (CL(CR)): normal renal function (> 80 mL/min, n = 6), and mild (50 to ≤ 80 mL/min, n = 6), moderate (30 to < 50 mL/min, n = 6), and severe renal impairment (5 to < 30 mL/min, n = 7). Mean memantine maximum plasma concentration (C(max)) was similar in the groups (12.66, 17.25, 15.75, and 15.83 ng/mL, respectively), as was mean time to C(max) (6.2, 5.2, 4.3, and 5.4 h, respectively). However, exposure to memantine determined from mean area under the plasma concentration-time curve was 1.62-, 1.97-, and 2.33-times higher in subjects with mild, moderate, and severe renal impairment, respectively, as compared to controls with normal renal function. Mean memantine plasma elimination half-life increased according to increasing renal impairment (61.15, 83.00, 100.13, and 124.31 h, respectively), while mean cumulative urinary recovery of unchanged memantine in 72 h after dosing decreased according to increasing renal impairment (33.68%, 33.47%, 23.60%, and 16.17%, respectively). These results are the same as those in the previous study on caucasian individuals, when compared per body weight. It is suggested that the dose of memantine should be halved in patients with renal impairment.