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Zhao L
Wang C
Zhang Y
Nakao K
Lee SJ
Singh N
Zhang S
Wang Y
Li X
Cheng CY

Aristoforin, a novel stable derivative of hyperforin, is a potent anticancer agent.

Gartner M , Müller T , Simon JC , Giannis A , Sleeman JP

Chembiochem.2005 Jan ; 6(1):171-7.

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Institut für Organische Chemie, Universität Leipzig, Johannisallee 29, 04103 Leipzig, Germany.

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Hyperforin, a natural product of St. John's wort (Hypericum perforatum L.), has a number of pharmacological activities, including antidepressive and antibacterial properties. Furthermore, hyperforin has pronounced antitumor properties against different tumor cell lines, both in vitro and in vivo. Despite being a promising novel anticancer agent, the poor solubility and stability of hyperforin in aqueous solution limits its potential clinical application. In this study, we present the synthesis of hyperforin derivatives with improved pharmacological activity. The synthesized compounds were tested for their solubility and stability properties. They were also investigated for their antitumor properties, both in vitro and in vivo. One of these hyperforin derivatives, Aristoforin, is more soluble in aqueous solution than hyperforin and is additionally highly stable. Importantly, it retains the antitumor properties of the parental compound without inducing toxicity in experimental animals. These data strongly suggest that Aristoforin has potential as an anticancer drug.
PMID: 15593112 [PubMed - indexed for MEDLINE]

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Effects of bacterial toxins on endothelial tight junction in vitro: a mechanism-based investigation.

Singh Ashok K , Jiang Yin , Gupta Shveta
Toxicol Mech Methods.2007 ; 17(6):331-47.
PMID: 20020957[]

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ABSTRACT Lipopolysaccharide (LPS) and lipoteichoic acid (LTA), principal cell wall components of Gram-negative and Gram-positive bacteria, respectively, play a central role in altering the blood-brain barrier and facilitate bacterial infection of the host brain. Despite the significance of bacterial toxins in disease pathogenesis, mechanisms by which toxins impair the barrier are not yet known. This study, using an in vitro cell culture model, showed that LPS and LTA interacted with the endothelial cells and disrupted the tight junction between the cells that increased the barrier's permeability. Both toxins increased inducible nitric oxide synthase (iNOS) mRNA that is indicative of an increase in intracellular NO release, disrupted architecture of the tight junction proteins, suppressed zonula occludens-1 (ZO-1) and occludin (OCL) and junctional adhesive molecules (JAM) mRNA levels, and increased tumor necrosis factor alpha (TNFalpha) and interleukin-1 beta (IL-1beta) mRNA levels. Anti-CD14 antibodies blocked the increase in TNFalpha and IL-1beta mRNA levels but did not affect either changes in the tight junction or iNOS, ZO-1, OCL, and JAM mRNA levels in endothelial cells and astrocytes. Although both toxins did not cross the endothelial barrier, the abluminal neurons exhibited high inflammatory activity characterized by a sequential increase in TNFalpha, IL-1beta, external receptor kinase (ERK), and RelA-p50 that induced inflammation, followed by an increase in anti-inflammatory/apoptotic factors including IL-10 and cysteine-aspartic acid protease-8 (CASPASE-8), which resolve inflammation and induce apoptosis. Anti-CD14 antibodies in luminal buffer blocked the pro- and anti-inflammatory effects of the toxins in neurons. Thus, the CD14-TLR cascade that participates in the inflammatory effects of toxins may not participate in the toxin-induced barrier disruption in vitro. Since the toxins did not cross the endothelial barrier, induction of inflammation in neurons was due to a release of proinflammatory cytokines in the abluminal fluid.

Prognostic impact of metastatic lymph node ratio on gastric cancer after curative distal gastrectomy.

Huang Chang-Ming , Lin Jian-Xian , Zheng Chao-Hui , Li Ping , Xie Jian-Wei , Lin Bi-Juan , Wang Jia-Bin
World J Gastroenterol.2010 Apr 28 ; 16(16):2055-60.
PMID: 20419845[]

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AIM: To investigate the prognostic impact of metastatic lymph node ratio (rN) on gastric cancer after curative distal gastrectomy. METHODS: A total of 634 gastric cancer patients who underwent curative resection (R0) of lymph nodes at distal gastrectomy in 1995-2004. Correlations between positive nodes and retrieved nodes, between rN and retrieved nodes, and between rN and negative lymph node (LN) count were analyzed respectively. Prognostic factors were identified by univariate and multivariate analyses. Staging accuracy of the pN category (5th UICC/TNM system) and the rN category was compared according to the survival rates of patients. A linear regression model was used to identify the relation between rN and 5-year survival rate of the patients. RESULTS: The number of dissected LNs was related with metastatic LNs but not related with rN. Cox regression analysis showed that depth of invasion, pN and rN category were the independent predictors of survival (P < 0.05). There was a significant difference in survival between LN stages classified by the rN category or by the pN category (P < 0.05). However, no significant difference was found in survival rate between LN stages classified by the pN category or by the rN category (P > 0.05). Linear regression model showed a significant linear correlation between rN and the 5-year survival rate of gastric cancer patients (beta = 0.862, P < 0.001). Pearson's correlation test revealed that negative LN count was negatively correlated with rN (P < 0.001). CONCLUSION: rN category is a better prognostic tool than the 5th UICC pN category for gastric cancer patients after curative distal gastrectomy. Increased negative LN count can reduce rN and improve the survival rate of gastric cancer patients.

Effect of valsartan or olmesartan addition to amlodipine on ankle edema in hypertensive patients.

Fogari Roberto , Malamani Gian , Corradi Luca , Mugellini Amedeo , Preti Paola , Zoppi Annalisa , Derosa Giuseppe
Adv Ther.2010 Feb 19 ; ():.
PMID: 20174905[]

先週： 3位

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INTRODUCTION: The objective of this study was to compare the effect on ankle edema of adding valsartan (V) or olmesartan (O) to amlodipine (A) in the treatment of hypertension. METHODS: After a 4-week placebo period, 74 adult outpatients with essential hypertension (diastolic blood pressure [DBP] >90 and <110 mmHg, and systolic blood pressure [SBP] >140 mmHg) were treated with A 10 mg once daily for 4 weeks. Thereafter, nonresponder patients (DBP >90 mmHg and/or SBP >140 mmHg; n=51) were randomized to receive additional V 160 mg once daily or O 20 mg once daily for 8 weeks in two crossover periods, each separated by a 4-week placebo period. Clinic blood pressure (BP), heart rate, and ankle/foot volume (AFV) were evaluated and blood samples were drawn to evaluate plasma norepinephrine (NE) levels. RESULTS: Both V/A and O/A induced a greater SBP/DBP reduction than A monotherapy (-26.4/-20.8 mmHg and -24.4/-19.1 mmHg, respectively; all P<0.001 vs. baseline and P<0.01 vs. A). A monotherapy increased AFV by 24%, P<0.001 vs. baseline, while the addition of either V or A reduced such increases. However, with V/A the AFV increase (+9.7%, P<0.05 vs. baseline, P<0.01 vs. A) was lower than with O/A (+16.7%, P<0.01 vs. baseline, P<0.05 vs. A); the difference between the two combinations was significant. Plasma NE levels were significantly increased by A (+44.6%) and values did not change with the addition of V (+35.2%) or O (+33.7%). Plasma active renin (PAR) was unchanged by A but increased by V/A (+214.4%, P<0.05 vs. baseline) and further by O/A (+325.6%, P<0.01 vs. baseline; difference between the 2 combinations: P<0.05). An inverse correlation was found between the AFV decrease and PAR increase (r=-0.31, P<0.05). CONCLUSION: Adding V or O to A reduced ankle edema, but this effect was more pronounced with V. The greater degree of renin-angiotensin system activation observed with Ocould be related to such a difference.

[Effects of the flavonoids on cytochrome P-450 CYP1, 2E1, 3A4 and 19]

Zheng Jiao , Zhou Hong-Hao
Yao Xue Xue Bao.2007 Jan ; 42(1):8-12.
PMID: 17520800[]

先週： 9位

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Flavonoids are present in fruits, vegetables and beverages derived from plants, and in many dietary supplements or herbal remedies. A number of naturally occurring flavonoids have been shown to modulate the CYP450 system, including the induction or inhibition of these enzymes. This review focuses on the flavonoid effects on cytochrome P450 (CYP) enzyme CYP1, 2E1, 3A4 and 19. Flavonoids alter CYPs by various mechanisms, including the stimulation of gene expression via specific receptors and/or CYP protein, or mRNA stabilization and so on. But in vivo and in vitro, the effects of flavonoids are not always coincident as a result of concentrations of flavonoids, genetic and environmental factors. As well, flavonoids may interact with drugs through the induction or inhibition of their metabolism. Much attention should be paid to the metabolism interaction of the flavonoids when coadministered with other drugs.

Pulmonary hypertension as a risk factor for death in patients with sickle cell disease.

Gladwin Mark T , Sachdev Vandana , Jison Maria L , Shizukuda Yukitaka , Plehn Jonathan F , Minter Karin , Brown Bernice , Coles Wynona A , Nichols James S , Ernst Inez , Hunter Lori A , Blackwelder William C , Schechter Alan N , Rodgers Griffin P , Castro Oswaldo , Ognibene Frederick P
N Engl J Med.2004 Feb 26 ; 350(9):886-95.
PMID: 14985486[]

先週： 7位

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BACKGROUND: The prevalence of pulmonary hypertension in adults with sickle cell disease, the mechanism of its development, and its prospective prognostic significance are unknown. METHODS: We performed Doppler echocardiographic assessments of pulmonary-artery systolic pressure in 195 consecutive patients (82 men and 113 women; mean [+/-SD] age, 36+/-12 years). Pulmonary hypertension was prospectively defined as a tricuspid regurgitant jet velocity of at least 2.5 m per second. Patients were followed for a mean of 18 months, and data were censored at the time of death or loss to follow-up. RESULTS: Doppler-defined pulmonary hypertension occurred in 32 percent of patients. Multiple logistic-regression analysis, with the use of the dichotomous variable of a tricuspid regurgitant jet velocity of less than 2.5 m per second or 2.5 m per second or more, identified a self-reported history of cardiovascular or renal complications, increased systolic blood pressure, high lactate dehydrogenase levels (a marker of hemolysis), high levels of alkaline phosphatase, and low transferrin levels as significant independent correlates of pulmonary hypertension. The fetal hemoglobin level, white-cell count, and platelet count and the use of hydroxyurea therapy were unrelated to pulmonary hypertension. A tricuspid regurgitant jet velocity of at least 2.5 m per second, as compared with a velocity of less than 2.5 m per second, was strongly associated with an increased risk of death (rate ratio, 10.1; 95 percent confidence interval, 2.2 to 47.0; P<0.001) and remained so after adjustment for other possible risk factors in a proportional-hazards regression model. CONCLUSIONS: Pulmonary hypertension, diagnosed by Doppler echocardiography, is common in adults with sickle cell disease. It appears to be a complication of chronic hemolysis, is resistant to hydroxyurea therapy, and confers a high risk of death. Therapeutic trials targeting this population of patients are indicated.

Personality disorders and biosocial trait theories: The argument for radical legal reform.

Peters David C
Behav Sci Law.2010 Mar ; 28(2):289-302.
PMID: 20422651[]

先週： 6位

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This article reviews antisocial personality disorder, psychopathy, and violence and develops a three factor model of personality traits. Then a discussion of related personality disorders precedes the development of a categorical two factor model of impulsive versus remorseless violence. A paradigm of proactive, medical, and school based early intervention and prevention is advocated as a useful addition to the reactive detention of criminal justice. Integration of psychological tests, neuroimaging, and genomic data in early childhood and school based intervention strategies to prevent the development of conduct disorder and attenuate criminal propensity inform this approach.

Interferon-gamma: biologic functions and HCV therapy (type I/II) (1 of 2 parts).

Gattoni A , Parlato A , Vangieri B , Bresciani M , Derna R
Clin Ter.2006 Jul-Aug ; 157(4):377-86.
PMID: 17051976[]

先週： 8位

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PURPOSE: This review is aimed at exhaustively presenting and discussing the interferon-gamma (IFN-gamma), a cytokine that plays an important role in inducing and modulating an array of immune responses. DESIGN: A review of the most significant and recent clinical trials was performed. OVERVIEW: Although IFN-gamma has some antiviral activity, it is much less active in this regard than type I IFNs. IFN-gamma is involved in the regulation of nearly all phases of the immune and inflammatory responses, including the activation and differentiation of T cells, B cells, NK cells, macrophages, and others. It is therefore best regarded as a distint immunoregulatory cytokine. IFN-gamma secretion is a hallmark of Th1 lymphocytes. It is also secreted by nearly all CD8 T cells, by some Th0 cells, and by NK cells. Each of these cell types secretes IFN-gamma only when activated, usually as part of immune response and especially in response to IL-2 and IL-12. IFN-gamma production is inhibited by IL-4, IL-10, TGFbeta, glucocorticoids, cyclosporin A and FK506. Nearly all cell types express the heterodimeric receptor for IFN-beta and respond to this cytokine by increasing the surface expression of class I MHC proteins. As a result, virtually any cell in the vicinity of an IFN-beta-secreting cell becomes more efficient at presenting endogenous antigens and hence a better target for cytotoxic killing if it harbors an intracellular pathogen. Unlike the type I IFNs, IFN-gamma also increases the expression of class II MHC proteins on professional APCs, and so promotes antigen presentation to helper T cells as well. It also induces de novo expression of class II MHC proteins on venular endothelial cells and on some other epithelial and connective tissue cells that do not otherwise express them, thus enabling these cell types to function as temporary APCs at sites of intense immune reactions. The effector functions of NK cells are to lyse virus-infected cells and to secrete IFN-gamma, which activates macrofages to destroy phagocytosed microbes. The mechanism of NK cell-mediates cytolysis is essentially the same as that of cytolysis by CTLS. NK cells lyse virally infected cells before antigen specific CTLS came become fully active, that is, during the first few days after viral infection. NK cells are expanded and activated by cytokines of innate immunity, such as IL-12 and IL-15, and they kill infected cells, especially those that display reduced levels of class I molecoles. Some tumors, especially those of hematopoietic origin, are targets of NK cells, perlevels or types of class I MHC molecules. Therefore, IFN-gamma serves critical functions in innate immunity and in specific cell-mediated immunity (in addition, IFN activates neutrophilis and stimulates the cytolitic activity of NK cells). Many IFNs-gamma induced effects result in heigtened immune surveillance. CONCLUSIONS: IFN-gamma is a remarkable cytokine that orchestrates many distinct cellular programs through transcriptional control over large numbers of genes. Many IFNs-gamma-induced effects resulting in heightend immune surveillance and immune system function during infection have been discussed in this review. As the pathogens (microorganism with the potential to cause tissue injury or disease) augment local IFN-gamma production, and IFN-gamma augments the immune system response, an important function of IFN-gamma during in vivo infection is suggested. IFN-gamma is primarily secreted by activated T cells and natural killer cells, and can promote macrophage activation, mediate antiviral e antibacterial immunity, enhance antigen presentation, orchestrate activation of the innate immune system, coordinate lymphocyte-endothelium interaction, regulate Th1/Th2 balance, and control cellular proliferation and apoptosis.

The differentiation of rat adipose-derived stem cells into OEC-like cells on collagen scaffolds by co-culturing with OECs.

Wang Bin , Han Jin , Gao Yuan , Xiao Zhifeng , Chen Bing , Wang Xia , Zhao Wenxue , Dai Jianwu
Neurosci Lett.2007 Jun 29 ; 421(3):191-6.
PMID: 17574753[]

先週： 5位

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Olfactory ensheathing cells (OECs) transplantation is a promising or potential therapy for spinal cord injury (SCI). However, their clinical use is limited because of the availability. Adipose-derived stem cells (ADSCs) have been identified as an alternative source of adult stem cells in recent years. ADSCs could be differentiated into various mesenchymal tissues cells such as chondrocytes, adipocytes, osteoblasts, and myocytes and also could be differentiated into neural lineages. In this study, we examined the feasibility of using ADSCs as a source of stem cells for the differentiation of OECs by co-culture approach. When co-cultured with OECs, the ADSCs on three-dimensional collagen scaffolds were differentiated into OEC-like cells, with similar morphology and antigenic phenotypes (p75NTR+/Nestin+/GFAP-) of OECs. Co-cultured ADSCs were positive for several important functional markers of mature OECs such as neurotrophic factor GDNF, BDNF and myelin protein PLP and the conditioned medium of OEC-like cells could significantly promote DRG neuron growth and axon sprouting without NGF supporting in contrast to that of the ADSCs. Our results showed that ADSCs had the potential to differentiate into OEC-like cells on the three-dimensional collagen scaffolds in vitro.

Integration of the NF-kappaB and mitogen-activated protein kinase/AP-1 pathways at the collagenase-1 promoter: divergence of IL-1 and TNF-dependent signal transduction in rabbit primary synovial fibroblasts.

Barchowsky A , Frleta D , Vincenti M P
Cytokine.2000 Oct ; 12(10):1469-79.
PMID: 11023661[]

先週： 4位

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Collagenase-1 (MMP-1) is a protease that is expressed by stromal cells and that is involved in remodeling of the extracellular matrix. IL-1 and TNF-alpha enhance collagenase secretion by stromal cells, and chronic exposure of cells to these cytokines can contribute to connective tissue disease. In this study, we show that the NF-kappaB pathway is required for activation of collagenase-1 transcription in rabbit primary synovial fibroblasts (RSF). Although both IL-1 and TNF activate NF-kappaB in these cells, only IL-1 induces collagenase-1 transcription. We have reported previously that NF-kappaB and AP-1 cooperate to mediate IL-1-induced MMP-1 transcription. Here, we show that IL-1 is superior to TNF at inducing c-Jun synthesis, phosphorylation and binding activity in RSF. Similarly, IL-1 is more effective at activating the mitogen-activated protein kinases (MAPK), including the extracellular signal-regulated kinases (ERK), which are required for IL-1-induced MMP-1 transcription. Thus stimulation of the ERK and AP-1 pathways is an essential component of MMP-1 transcriptional activation, which is deficient in TNF-treated cells. These studies demonstrate cooperation between the MAPK and NF-kappaB signaling pathways for IL-1-dependent collagenase-1 transcription, and they define a dichotomy of IL-1- and TNF-elicited signaling that is relevant to cytokine-mediated connective tissue disease.

Effects of olmesartan, an angiotensin II receptor blocker, and amlodipine, a calcium channel blocker, on Cardio-Ankle Vascular Index (CAVI) in type 2 diabetic patients with hypertension.

Miyashita Yoh , Saiki Atsuhito , Endo Kei , Ban Noriko , Yamaguchi Takashi , Kawana Hidetoshi , Nagayama Daiji , Ohira Masahiro , Oyama Tomokazu , Shirai Kohji
J Atheroscler Thromb.2009 Oct ; 16(5):621-6.
PMID: 19907103[]

先週： 11位

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AIM: Recently, a novel device for measuring the cardio-ankle vascular index (CAVI) as an arterial stiffness parameter has been developed. In this study, we evaluated the effect of angiotensin II receptor blocker (ARB) and calcium channel (Ca) blocker on CAVI in type 2 diabetic patients with hypertension.METHODS: Seventy type 2 diabetes mellitus patients with hypertension were enrolled and randomly divided into two groups. One group was administered olmesartan medoxomil 10 mg/day for 12 months (ARB group), and the other group was administered amlodipine besilate 5 mg/day for 12 months (Ca blocker group).RESULTS: In the ARB group, a significant decrease in CAVI was observed after 12 months; however, no significant change in CAVI was observed in the Ca blocker group although changes in blood pressure were almost the same. By simple regression analyses, CAVI changes correlated positively with 8-OHdG changes.CONCLUSIONS: Olmesartan, an ARB, improved arterial stiffness more than amlodipine, and this effect might be due to not only the blood pressure-lowering effect but also to reducing the potential of oxidative stress recognized in olmesartan.

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A randomized, double-blind, four-arm parallel-group study of the efficacy and safety of azelnidipine and olmesartan medoxomil combination therapy compared with each monotherapy in Japanese patients with essential hypertension: the REZALT study.

Hypertens Res.2009 Oct 9 ; ():.
PMID: 19816505[]

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A 12-week randomized, double-blind, four-arm parallel-group, comparative study was conducted in patients with essential hypertension to evaluate the antihypertensive effect and safety of combination therapy with olmesartan medoxomil (OLM, an angiotensin-receptor blocker) 20 mg plus azelnidipine (AZL, a long-acting dihydropyridine calcium channel blocker) 16 mg, (O/A (20/16)), or OLM 10 mg/AZL 8 mg (O/A (10/8)) compared with those of monotherapy with OLM 20 mg (OLM (20)) or AZL 16 mg (AZL (16)). The change from baseline to week 12 in seated blood pressure (SeBP) was -23.6/-14.2 mm Hg (systolic/diastolic BP) in the O/A (20/16) group, and -20.3/-13.0 mm Hg in the O/A (10/8) group, which was a significantly greater reduction in SeBP than in the monotherapy groups (-15.7/-9.9 mm Hg in OLM (20); -15.0/-9.4 mm Hg in AZL (16)). The change from baseline in 24-h ambulatory BP was also significantly greater in the O/A (20/16) and O/A (10/8) combination groups (-22.1/-13.5 and -18.2/-10.6 mm Hg, respectively) than in the OLM (20) and AZL (16) monotherapy groups (-12.1/-6.9 and -12.0/-6.9 mm Hg). The proportion of patients achieving the SeBP goal (<130/85 mm Hg for normal BP or <140/90 mm Hg for high-normal BP) was significantly higher in the O/A (20/16) combination group than in the monotherapy groups. The incidence of adverse events was similar in the O/A combination groups and the monotherapy groups. These results showed that combination therapy with O/A was well tolerated and exerted a stronger antihypertensive effect compared with monotherapy with OLM or AZL in patients with essential hypertension.Hypertension Research advance online publication, 9 October 2009; doi:10.1038/hr.2009.163.

Risk Factors for Idiosyncratic Drug-Induced Liver Injury.

Chalasani Naga , Björnsson Einar
Gastroenterology.2010 Apr 12 ; ():.
PMID: 20394749[]

先週： 2位

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Idiosyncratic drug-induced liver injury (DILI) is a rare disorder that is not directly related to dosage and little is known about individuals who are at increased risk. There are no suitable preclinical models for the study of idiosyncratic DILI and its pathogenesis is poorly understood. It is likely to arise from complex interactions among genetic, non-genetic host susceptibility, and environmental factors. Non-genetic risk factors include age, gender, and other diseases (e.g. chronic liver disease or HIV infection). Compound-specific risk factors include daily dose, metabolism characteristics, and propensity for drug interactions. Alcohol consumption has been proposed as a risk factor for DILI from medications, but there is insufficient evidence to support this. Many studies have explored genetic defects that might be involved in pathogenesis and focused on genes involved in drug metabolism and the immune response. Multicenter databases of patients with DILI (the United States Drug Induced Liver Injury Network [DILIN], DILIGEN, and the Spanish DILI registry) are important tools for clinical and genetic research. A genome-wide association study of flucloxacillin hepatotoxicity has yielded ground-breaking results and many similar studies are underway. Nontheless, DILI is challenging to investigate because of its rarity, the lack of experimental models, the number of medications that might cause it, and challenges to diagnosis.

Effect of valsartan or olmesartan addition to amlodipine on ankle edema in hypertensive patients.

Fogari Roberto , Malamani Gian , Corradi Luca , Mugellini Amedeo , Preti Paola , Zoppi Annalisa , Derosa Giuseppe
Adv Ther.2010 Feb 19 ; ():.
PMID: 20174905[]

先週： 3位

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Involvement of Th17 and Th1 Effector Responses in Patients with Hepatitis B.

Ye Yufu , Xie Xiaojun , Yu Jiwei , Zhou Lin , Xie Haiyang , Jiang Guoping , Yu Xiaobo , Zhang Wenjin , Wu Jian , Zheng Shusen
J Clin Immunol.2010 Apr 15 ; ():.
PMID: 20393789[]

先週： 4位

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BACKGROUND: Local production of cytokines within the liver may play a pivotal role in the regulation of pathophysiological processes during inflammation. CD4+ T cells are regarded as the most prolific cytokine producers. The purpose of this study was to quantify intrahepatic expression of Th1, Th2, Th17, and Treg-associated cytokines or transcription factors in patients with acute hepatitis B or chronic hepatitis B (CHB) and to analyze their relative roles in the promotion and regulation of hepatitis B virus (HBV)-associated liver diseases. METHODS: Distribution and expression of IL-17, IFN-gamma, IL-4, Foxp3, and other cytokines in liver tissues were detected by immunohistochemistry and real-time quantitative PCR. Patients with hepatitis B were compared with patients with chronic hepatitis C, primary biliary cirrhosis, alcoholic liver cirrhosis, and healthy controls. RESULTS: The frequencies of intrahepatic IL-17 and IFN-gamma-producing cells in patients with HBV-associated liver dysfunction were much higher than that of IL-4 and Foxp3-positive cells. The level of the IL-17/IFN-gamma-positive cell ratio of patients with Child-Pugh class C (1.57 +/- 0.09) was much higher than that of patients with Child-Pugh class B (1.00 +/- 0.02) or A (0.93 +/- 0.05). There are more IL-17-producing cells than IFN-gamma-producing cells accumulating in the liver with severe hepatocellular damage. Liver IL-17-producing cell infiltration was positively associated with the grade of liver inflammation in CHB and positively correlated to intrahepatic IL-8 expression (r = 0.801, p < 0.01) or neutrophil infiltration (r = 0.917, p < 0.01). CONCLUSIONS: These results suggest that the balance of effector CD4+ Th responses (Th17 and Th1 responses) and regulatory response is an important element of immune regulation. Inappropriate, excessive, and non-specific Th17 and Th1 effector responses may be involved in the pathogenesis of HBV-associated liver inflammation and hepatocellular damage. Th17 response, especially, may exacerbate the inflammatory processes leading to liver failure. IL-17-mediating liver neutrophil recruitment via induction of IL-8 may be one potential mechanism of liver injury in patients with hepatitis B. An improved understanding of the factors that influence the differentiation and function of these cell types in vivo will be of great importance to the future development of immune therapies in HBV-associated liver disease.

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The Journal of biological chemistry

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Proceedings of the National Academy of Sciences of the United States of America

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3,522view , 141users

Journal of immunology (Baltimore, Md. : 1950)

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2,284view , 121users

Biochemistry

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Cancer research

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Blood

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Journal of virology

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Biochemical and biophysical research communications

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Science (New York, N.Y.)

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Giornale di psichiatria e di neuropatologia

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週間人気ジャーナルランキング - 保存数 (2010/09/04/ 09時更新)

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The Journal of biological chemistry

先週： 1位

5,876view , 210users

Proceedings of the National Academy of Sciences of the United States of America

先週： 2位

3,522view , 141users

Journal of immunology (Baltimore, Md. : 1950)

先週： 3位

2,284view , 121users

Developmental medicine and child neurology

先週： 4位

139view , 117users

PloS one

先週： 5位

1,309view , 108users

Journal of agricultural and food chemistry

先週： 6位

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Biochemical and biophysical research communications

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Giornale di psichiatria e di neuropatologia

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Protein synthesis is one of the major targets in the cell for antibiotics. This review endeavors to provide a comprehensive "post-ribosome structure" A-Z of the huge diversity of antibiotics that target the bacterial translation apparatus, with an emphasis on correlating the vast wealth of biochemical data with more recently available ribosome structures, in order to understand function. The binding site, mechanism of action, and modes of resistance for 26 different classes of protein synthesis inhibitors are presented, ranging from ABT-773 to Zyvox. In addition to improving our understanding of the process of translation, insight into the mechanism of action of antibiotics is essential to the development of novel and more effective antimicrobial agents to combat emerging bacterial resistance to many clinically-relevant drugs.

Branching Hormone is Busy Both Underground and Overground.

Yamaguchi Shinjiro , Kyozuka Junko
Plant Cell Physiol.2010 Jul ; 51(7):1091-4.
PMID: 20621958[]

2010/07/12

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Anxiety and depressive symptoms in Fibromyalgia are related to low health esteem but not to pain sensitivity or cerebral processing of pain.

Jensen Karin B , Petzke Frank , Carville Serena , Fransson Peter , Marcus Hanke , Williams Steven C R , Choy Ernest , Mainguy Yves , Gracely Richard , Ingvar Martin , Kosek Eva
Arthritis Rheum.2010 Jul 8 ; ():.
PMID: 20617526[]

2010/07/09

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OBJECTIVES:: Mood disturbance is common in patients with Fibromyalgia syndrome (FM) but the influence of psychological symptoms on pain processing in this disorder is unknown. We investigated the differential impact of depressive symptoms, anxiety and catastrophizing on; a) pain symptoms and subjective ratings of general health status; b) sensitivity to pain and cerebral processing of pressure pain. METHODS:: Female FM patients (n=83), mean age 44.2 (SD=8.2), fulfilling the ACR 1990 diagnostic criteria participated. Patients rated pain intensity (VAS), severity of FM (FIQ), general health status (SF-36), depressive symptoms (BDI), anxiety (STAI) and catastrophizing (CSQ). Experimental pain was induced to the thumb using a computer-controlled pressure stimulator. Event-related functional magnetic resonance imaging (fMRI) was performed during individually calibrated painful stimuli representing VAS 50 mm, as well as non-painful pressures. RESULTS:: A correlation analysis including all self-ratings showed that depressive symptoms, anxiety and catastrophizing scores were correlated (p<.001), but did not correlate with ratings of clinical pain, nor with sensitivity to pressure pain. However, the subjective rating of general health was correlated with depressive symptoms and anxiety (p<.001). Results from imaging analyses using self-rated psychological measures as co-variates, showed that brain activity during experimental pain was not modulated by depressive symptoms, anxiety, or catastrophizing. CONCLUSION:: Negative mood in FM patients can lead to a poor perception of one's physical health (and vice versa) but do not influence the performance in clinical and experimental pain assessments. Our data provide evidence for two partially segregated mechanisms involved in the neural processing of experimental pain and negative affect.

In or out stemness: comparing growth factor signalling in mouse embryonic stem cells and primordial germ cells.

De Felici Massimo , Farini Donatella , Dolci Susanna
Curr Stem Cell Res Ther.2009 May ; 4(2):87-97.
PMID: 19442193[]

2009/05/15

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Embryonic stem (ES) cells do not exist in nature but, usually produced from the inner cell mass (ICM) of the blastocyst, are considered equivalent to ICM cells captured during a short period of transient self-renewal and pluripotency capability. Although, artificial, ES cells represent a formidable model to investigate fundamental aspects of cell stemness and early embryo development. ES cells are indeed the only stem cell type able to indefinite self-renewal and to differentiate into cellular derivates of ectodermal, mesodermal and endodermal lineages. Recent extensive studies have revealed that ES cells maintain self-renewal and pluripotency because of a self-organizing network of transcription factors and intracellular pathways activated by extracellular signalling that together prevent their differentiation and promote their proliferation, and because of epigenetic processes that maintain the chromatin in a plastic differentiation status. Primordial germ cells (PGCs), the embryonic precursors of gametes, because of their unique ability to retain true developmental totipotency, are considered the mother of all stem cells. Despite several similarities with ES cells, they display only transient self-renewal capability and distinct lineage-specific characteristics. In fact, in normal condition PGCs are believed to differentiate into germ cells only, oogonia/oocytes in the female, and prospermatogonia in the male which ultimately produce eggs and sperm, respectively. It is not until the fertilization of the egg or parthenogenesis that the intrinsic germ cell totipotency program is revealed. Many aspects of the extrinsic factors and signalling required for ES cell self-renewal and pluripotency have been identified and dissected. On the other hand, several extrinsic factors controlling PGC development have been identified, but the underlying molecular signalling remains little defined. In the present review, by comparing the available information about signalling elicited by four growth factors such as leukaemia inhibitory factor (LIF), bone morphogenic protein 4 (BMP4), fibroblast growth factor 2 (FGF2) and kit ligand (KL) in mouse ES cells and PGCs, on which most of such studies have been performed, we aimed to give clues for the molecular understanding of the similarities and differences between these two unique cell types and to explain how apparent contradictory properties such as lineage-specific characteristics and pluripotency may coexist within PGCs. The first two growth factors have been demonstrated to control key aspects of the self-renewal and pluripotency of ES cells. BMP4 and KL are known for their crucial role in regulating various process of PGC development in the embryo from the formation of PGC precursors and PGC specification (BMP4) to their survival, proliferation and migration (KL). Moreover, the combined action of LIF, FGF2 and KL is necessary and sufficient for PGC transformation into ES-like cells termed embryonic germ (EG) cells.

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Low density lipoprotein receptor-related protein 5 (LRP5) mutations and osteoporosis, impaired glucose metabolism and hypercholesterolaemia.

Saarinen Anne , Saukkonen Tero , Kivelä Tero , Lahtinen Ulla , Laine Christine , Somer Mirja , Toiviainen-Salo Sanna , Cole William G , Lehesjoki Anna-Elina , Mäkitie Outi
Clin Endocrinol (Oxf).2010 Apr ; 72(4):481-8.
PMID: 19673927[]

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OBJECTIVE: Mutations in the low-density lipoprotein receptor-related protein 5 gene (LRP5) underlie osteoporosis-pseudoglioma syndrome. Animal models implicate a role for LRP5 in lipid and glucose homeostasis. The objective was to evaluate metabolic consequences of LRP5 mutations in humans. DESIGN AND PATIENTS: Thirteen Finnish individuals with homozygous or heterozygous LRP5 mutations were assessed for bone health, glucose and lipid metabolism, and for serum serotonin concentration. Results were compared with findings in family members without mutations. MEASUREMENTS: Bone mineral density (BMD), vertebral morphology, oral and intravenous glucose tolerance tests, lipid profile and serum serotonin concentrations. RESULTS: Two individuals were homozygous for R570W, one compound heterozygous for R570W and R1036Q, and 10 were heterozygous (six for R570W, three for R1036Q and one for R925C). Subjects with two LRP5 mutations had multiple spinal fractures and low BMD. Subjects with one mutation had significantly lower median lumbar spine (P = 0.004) and femoral neck (P = 0.005) BMD Z-scores, and more often vertebral fractures than the 18 individuals without mutations. Of the 12 subjects with LRP5 mutation six had diabetes and one had impaired glucose tolerance. Intravenous glucose tolerance tests suggested impaired beta-cell function; no insulin resistance was observed. Prevalence of hypercholesterolaemia was similar in mutation positive and negative subjects. Serum serotonin concentrations showed a trend towards higher concentrations in subjects with LRP5 mutation. CONCLUSIONS: We found high prevalence of osteoporosis and abnormal glucose metabolism in subjects with LRP5 mutation(s). Further studies are needed to establish the role of LRP5 in glucose and lipid metabolism.

Toll-like Receptor 2 Signaling in CD4(+) T Lymphocytes Promotes T Helper 17 Responses and Regulates the Pathogenesis of Autoimmune Disease.

Reynolds Joseph M , Pappu Bhanu P , Peng Juan , Martinez Gustavo J , Zhang Yongliang , Chung Yeonseok , Ma Li , Yang Xuexian O , Nurieva Roza I , Tian Qiang , Dong Chen
Immunity.2010 Apr 28 ; ():.
PMID: 20434372[]

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Toll-like receptors (TLRs) have previously been shown to play critical roles in the activation of innate immunity. Here, we describe that T cell expression of TLR2 regulates T helper 17 (Th17) cell responses. Stimulation with TLR2 agonists promoted Th17 differentiation in vitro and led to more robust proliferation and Th17 cytokine production. Using the experimental autoimmune encephalomyelitis (EAE) model, we found that TLR2 regulated Th17 cell-mediated autoimmunity in vivo and that loss of TLR2 in CD4(+) T cells dramatically ameliorated EAE. This study thus reveals a critical role of a TLR in the direct regulation of adaptive immune response and pathogenesis of autoimmune diseases.

Effects of bacterial toxins on endothelial tight junction in vitro: a mechanism-based investigation.

Singh Ashok K , Jiang Yin , Gupta Shveta
Toxicol Mech Methods.2007 ; 17(6):331-47.
PMID: 20020957[]

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Daniel Carolin , Wennhold Kerstin , Kim Hye-Jung , von Boehmer Harald
Proc Natl Acad Sci U S A.2010 Aug 30 ; ():.
PMID: 20805478[]

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2',5,7-Trihydroxy-4',5'-(2,2-dimethylchromeno)-8-(3-hydroxy-3-methylbutyl) flavanone purified from Cudrania tricuspidata induces apoptotic cell death of human leukemia U937 cells.

Rho Yoon-Hwa , Yoon Soo-Hyun , Kim Eun-Kyung , Kang Ji-Young , Lee Byong-Won , Park Ki-Hun , Bae Young-Seuk
Nat Prod Res.2007 Jun ; 21(7):616-24.
PMID: 17613819[]

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Cellular DNA topoisomerase I is an important target in cancer chemotherapy. A chloroform extract of the root barks of Cudrania tricuspidata showed an inhibitory effect on mammalian DNA topoisomerase I. The topoisomerase I inhibitory compound was purified and identified as 2',5,7-trihydroxy-4',5'-(2,2-dimethylchromeno)-8-(3-hydroxy-3-methylbutyl) flavanone. The compound, temporarily designated as PKH-3, was shown to inhibit the activity of topoisomerase I with IC50 about 1.0 mM. Concentration of 10 microM PKH-3 caused 50% growth inhibition of human cancer cell U937. PKH-3-induced cell death was characterized with the cleavage of poly(ADP-ribose) polymerase (PARP) and pro-caspase 3. Furthermore, PKH-3 induced the fragmentation of DNA into multiples of 180 b.p. (an apoptotic DNA ladder), indicating that the inhibitor triggered apoptosis. This induction of apoptosis by PKH-3 was also confirmed using flow cytometry analysis. Taken together, these results suggest that PKH-3 may function by inhibiting oncogenic disease, at least in part, through the inhibition of topoisomerase I activity.

Effects of branched-chain amino acid-enriched nutrient for patients with hepatocellular carcinoma following radiofrequency ablation: A one-year prospective trial.

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The type Ia supernova SNLS-03D3bb from a super-Chandrasekhar-mass white dwarf star.

Howell D Andrew , Sullivan Mark , Nugent Peter E , Ellis Richard S , Conley Alexander J , Le Borgne Damien , Carlberg Raymond G , Guy Julien , Balam David , Basa Stephane , Fouchez Dominique , Hook Isobel M , Hsiao Eric Y , Neill James D , Pain Reynald , Perrett Kathryn M , Pritchet Christopher J
Nature.2006 Sep 21 ; 443(7109):308-11.
PMID: 16988705[]

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Carlson Joe
Mod Healthc.2010 Aug 16 ; 40(33):24-9.
PMID: 20824927[]

2010/09/08

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Aristoforin, a novel stable derivative of hyperforin, is a potent anticancer agent.

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