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Medical Sciences	83%

Selected Abstracts

Syringetin, a flavonoid derivative in grape and wine, induces human osteoblast differentiation through bone morphogenetic protein-2/extracellular signal-regulated kinase 1/2 pathway

MOLECULAR NUTRITION & FOOD RESEARCH (FORMERLY NAHRUNG/FOOD), Issue 11 2009
Ya-Ling Hsu
Abstract Syringetin (3,5,7,4,-tetrahydroxy-3,,5,dimethoxyflavone), a flavonoid derivative, is present in grape and wine. By means of alkaline phosphatase (ALP) activity, osteocalcin, and type I collagen ELISA, we have shown that syringetin exhibits a significant induction of differentiation in MC3T3-E1 mouse calvaria osteoblasts and human fetal osteoblastic 1.19 cell line human osteoblasts. ALP and osteocalcin are phenotypic markers for early-stage differentiated osteoblasts and terminally differentiated osteoblasts, respectively. Our results indicate that syringetin stimulates osteoblast differentiation at various stages, from maturation to terminally differentiated osteoblasts. Induction of differentiation by syringetin is associated with increased bone morphogenetic protein-2 (BMP-2) production. The BMP-2 antagonist noggin blocked syringetin-mediated ALP activity and osteocalcin secretion enhancement, indicating that BMP-2 production is required in syringetin-mediated osteoblast maturation and differentiation. Induction of differentiation by syringetin is associated with increased activation of SMAD1/5/8 and extracellular signal-regulated kinase 1/2 (ERK1/2). Cotreatment of ERK1/2 inhibitor 2,-amino-3,-methoxyflavone inhibited syringetin-mediated ALP upregulation and osteocalcin production. In conclusion, syringetin increased BMP-2 synthesis, and subsequently activated SMAD1/5/8 and ERK1/2, and this effect may contribute to its action on the induction of osteoblast maturation and differentiation, followed by an increase of bone mass. [source]

Urinary proteins from patients with nephrotic syndrome alters the signalling proteins regulating epithelial,mesenchymal transition

NEPHROLOGY, Issue 1 2010
QIONG WEN
ABSTRACT: Aim: Proteinuria plays an important role in the progression of tubulointerstitial fibrosis, but the mechanism for the differential renal damage induced by proteinuria is unknown. This study examined the effects of urinary proteins from patients with idiopathic minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) on several epithelial,mesenchymal transition (EMT)-related marker proteins in cultured proximal tubular HK-2 cells. Methods: Urinary proteins from MCD and FSGS patients were extracted by ultrafiltration and incubated with HK-2 cells; the expression of the cytokeratin-18, ,-smooth muscle actin (,-SMA) and vimentin were assessed. p38 and extracellular regulated kinase (ERK) activation were measured by western blotting, and SB203580 (a p38 inhibitor) and PD98059 (an ERK1/2 inhibitor) were used to inhibit their activation. Results: It was observed that urinary proteins from FSGS patients more significantly induced the expression of ,-SMA and vimentin and reduced cytokeratin-18 expression than those from MCD patients in HK-2 cells. Both ERK1/2 and p38 were activated by urinary proteins from MCD or FSGS patients. Pretreatment of the cells with SB203580 or PD98059 abolished the effect of urinary proteins from FSGS patients on the expression of ,-SMA, vimentin and cytokeratin-18, while only SB203580 elicited this effect when cells were treated with urinary proteins from MCD patients. Conclusion: The urinary proteins from MCD and FSGS patients induced significant changes of EMT-related proteins through activation of distinct mitogen-activated protein kinase-related signalling pathways. Quality of proteinuria may play an important role in determining the severity and progression of tubular injury associated with different kidney diseases. [source]

Deceleration of Regenerative Response Improves the Outcome of Rat with Massive Hepatectomy

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 7 2010
M. Ninomiya
Small residual liver volume after massive hepatectomy or partial liver transplantation is a major cause of subsequent liver dysfunction. We hypothesize that the abrupt regenerative response of small remnant liver is responsible for subsequent deleterious outcome. To slow down the regenerative speed, NS-398 (ERK1/2 inhibitor) or PD98059 (selective MEK inhibitor) was administered after 70% or 90% partial hepatectomy (PH). The effects of regenerative speed on liver morphology, portal pressure and survival were assessed. In the 70% PH model, NS-398 treatment suppressed the abrupt replicative response of hepatocytes during the early phase of regeneration, although liver volume on day 7 was not significantly different from that of the control group. Immunohistochemical analysis for CD31 (for sinusoids) and AGp110 (for bile canaliculi) revealed that lobular architectural disturbance was alleviated by NS-398 treatment. In the 90% PH model, administration of NS-398 or PD98059, but not hepatocyte growth factor, significantly enhanced survival. The abrupt regenerative response of small remnant liver is suggested to be responsible for intensive lobular derangement and subsequent liver dysfunction. The suppression of MEK/ERK signaling pathway during the early phase after hepatectomy makes the regenerative response linear, and improves the prognosis for animals bearing a small remnant liver. [source]

Contribution of BCR,ABL-independent activation of ERK1/2 to acquired imatinib resistance in K562 chronic myeloid leukemia cells

CANCER SCIENCE, Issue 1 2010
Takeru Nambu
BCR,ABL tyrosine kinase, generated from the reciprocal chromosomal translocation t(9;22), causes chronic myeloid leukemia (CML). BCR,ABL is inhibited by imatinib; however, several mechanisms of imatinib resistance have been proposed that account for loss of imatinib efficacy in patients with CML. Previously, we showed that overexpression of the efflux drug transporter P-glycoprotein partially contributed to imatinib resistance in imatinib-resistant K562 CML cells having no BCR,ABL mutations. To explain an additional mechanism of drug resistance, we established a subclone (K562/R) of the cells and examined the BCR,ABL signaling pathway in these and wild-type K562 (K562/W) cells. We found the K562/R cells were 15 times more resistant to imatinib than their wild-type counterparts. In both cell lines, BCR,ABL and its downstream signaling molecules, such as ERK1/2, ERK5, STAT5, and AKT, were phosphorylated in the absence of imatinib. In both cell lines, imatinib effectively reduced the phosphorylation of all the above, except ERK1/2, whose phosphorylation was, interestingly, only inhibited in the wild-type cells. We then observed that phospho-ERK1/2 levels decreased in the presence of siRNA targeting BCR,ABL, again, only in the K562/W cells. However, using an ERK1/2 inhibitor, U0126, we found that we could reduce phospho-ERK1/2 levels in K562/R cells and restore their sensitivity to imatinib. Taken together, we conclude that the BCR,ABL-independent activation of ERK1/2 contributes to imatinib resistance in K562/R cells, and that ERK1/2 could be a target for the treatment of CML patients whose imatinib resistance is due to this mechanism. (Cancer Sci 2009) [source]

Leishmania donovani infection down-regulates TLR2-stimulated IL-12p40 and activates IL-10 in cells of macrophage/monocytic lineage by modulating MAPK pathways through a contact-dependent mechanism

CLINICAL & EXPERIMENTAL IMMUNOLOGY, Issue 2 2008
Dinesh Chandra
Summary The failure of Leishmania, an intracellular pathogen, to stimulate a pro-inflammatory response following entry into macrophages has been well reported. This occurs in spite of the fact that ligands for the toll-like receptors (TLR) have been recently shown on the parasite surface and their role in disease protection well documented. The outcome of infection in leishmaniasis is determined by the Th1 versus Th2 nature of the effector response and the generation of IL-12 and IL-10 by the infected macrophages is important for this decision. We evaluated the effect of L. donovani infection of monocytes (cell line THP-1, and monocytes derived from human peripheral blood) on Pam3cys (TLR2 ligand) and lipopolysaccharide (TLR4 ligand) stimulated production of IL-12p40 and IL-10. L. donovani infection caused suppression of TLR2 and TLR4-stimulated IL-12p40, with an increase in IL-10 production. Parasites also modulated the TLR2-stimulated mitogen-activated protein kinase (MAPK) pathway by suppressing MAPK P38 phosphorylation and activating extracellular regulated kinase (ERK)1/2 phosphorylation. These effects could be reversed either by using a MAPK P38 activator, anisomycin, or ERK1/2 inhibitor, U0126. L. donovani caused modulation of TLR2-stimulated MAPK pathways in a contact-dependent mechanism. In addition parasite structural integrity but not viability was required for suppression of TLR2-stimulated IL-12p40 and activation of IL-10. These observations suggest that L. donovani has evolved survival strategies that subvert the pro-inflammatory response generated through TLRs. [source]

Cathelicidin LL-37 induces the generation of reactive oxygen species and release of human ,-defensins from neutrophils

BRITISH JOURNAL OF DERMATOLOGY, Issue 6 2007
Y. Zheng
Summary Background, Psoriasis is characterized by epidermal infiltration of neutrophils that destroy invading microorganisms via a potent antimicrobial arsenal of oxidants and antimicrobial agents. In contrast to atopic dermatitis, psoriasis exhibits low levels of skin infections due to the presence of antimicrobial agents, including cathelicidin LL-37. LL-37 kills a broad spectrum of microbes, and activates neutrophil chemotaxis. Objective, To determine whether or not LL-37 could regulate additional neutrophil functions such as production of cytokines/chemokines, reactive oxygen species and release of neutrophil antimicrobial peptides. Methods, Human peripheral blood neutrophils were used in this study. The production of interleukin (IL)-8 and release of ,-defensins were analysed by enzyme-linked immunosorbent assay, and real-time polymerase chain reaction (PCR) was used to quantify ,-defensin gene expression. Phosphorylation of mitogen-activated protein kinase (MAPK) was determined by Western blotting. The generation of reactive oxygen species was examined using flow cytometry, and intracellular Ca2+ mobilization was measured using a calcium assay kit. Results, LL-37 enhanced the production of IL-8 under the control of MAPK p38 and extracellular signal regulated kinase (ERK), as evidenced by the inhibitory effects of p38 and ERK1/2 inhibitors on LL-37-mediated IL-8 production. Furthermore, LL-37 induced phosphorylation of p38 and ERK. We also revealed that LL-37 stimulated the generation of reactive oxygen species dose- and time-dependently, most probably via NADPH oxidase activation and intracellular Ca2+ mobilization. Finally, LL-37 induced both mRNA expression and protein release of ,-defensins, known as human neutrophil peptide 1,3. Conclusion, Taken together, we suggest that in addition to its microbicidal properties, LL-37 may contribute to innate immunity by enhancing neutrophil host defence functions at inflammation and/or infection sites. [source]