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The melanocortin 1 receptor (MC1R), a key regulator of melanogenesis, is known to control inflammation, acting in concert with the MC1R ligand α-melanocyte-stimulating hormone. Although cell migration is a key event in inflammation, few studies have addressed the function of MC1R in this context. Using highly motile melanoma cells, we found that the expression level of MC1R was associated with the extent of migration of mouse melanoma cells, suggesting that MC1R plays a functional role in controlling this migration. Overexpression of MC1R enhanced melanoma cell migration, whereas the opposite was true when MC1R levels were knocked down using small inhibitory RNAs. Interestingly, MC1R expression enhanced the synthesis of syndecan-2, a cell surface heparan sulfate proteoglycan known to be involved in melanoma cell migration. Knockdown of syndecan-2 expression decreased MC1R-mediated cell migration. Further, MC1R inhibited the activation of p38 MAPK, subsequently enhancing expression of sydnecan-2, in parallel with an increase in the extent of cell migration. Consistently, activation of p38 by H(2)O(2) inhibited syndecan-2 expression and cell migration, whereas inhibition of p38 activation enhanced syndecan-2 expression and cell migration. Finally, we found that α-melanocyte-stimulating hormone inhibited MC1R-mediated cell migration via activation of p38 and inhibition of syndecan-2 expression. Together, the data strongly suggest that MC1R regulates melanoma cell migration via inhibition of syndecan-2 expression.

Lactobacillus plantarum CJLP133 was isolated from Kimchi, a Korean fermented food, and its potential to improve mouse atopic dermatitis after onset was studied. Dermatitis was developed through house dust-mite extract application onto NC/Nga mice, and then CJLP133 feeding was started. CJLP133 suppressed dermatitis-like skin lesions and decreased high serum IgE levels through balancing between IL-4 and IFN-γ in serum. CJLP133 diminished skin thickening, mast cell accumulation into inflamed site, and lymph node enlargement. In lymph node cells, CJLP133 repressed secretion of T cell cytokines such as IFN-γ, IL-4, IL-5, and IL-10. However, CJLP133 decreased ratios of IFN-γ and IL-5 to IL-10 in lymph node cells, while it did not decrease ratios of IL-4 and IL-5 to IFN-γ. Conclusively, CJLP133 exhibited therapeutic potential for atopic dermatitis in mice through orderly increment of type 1 helper T cell activation and regulatory T cell activation. These results suggest that CJLP133 could treat human atopic dermatitis., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Nano-sized Cu-Sn and Cu oxide particles supported on ball-milled graphite were synthesized, and their electrochemical characteristics for use as anode active materials in lithium-ion batteries were investigated. The samples were also characterized via FE-SEM, XRD, and TGA. Most of the Cu oxides on BMG were monoclinic CuO crystals, whereas the Cu-Sn particles were composed of hexagonal Cu3Sn and tetragonal SnO2 crystals. These particles may contribute to an increase in the reversible capacity of lithium ion batteries.

The investigators quantified the relationship between the genetic polymorphism of HMGCR (3-hydroxy-3-methylglutaryl coenzyme A reductase) and the low-density lipoprotein cholesterol (LDL-C)-lowering effects of atorvastatin in a prospective clinical study. Twenty-four healthy participants were grouped into HMGCR rs3846662 GG (n = 13) and AA (n = 11) genotypes and given atorvastatin (20 mg/d) for 14 days. Serum levels of LDL-C, high-density lipoprotein cholesterol, total cholesterol, triglycerides, and creatinine kinase (CK) were measured before (day 1) and 7, 13, 14, 15, 16, 21, and 28 days after dosing initiation. Blood samples for pharmacokinetics were taken on days 14 through 16. The levels of LDL-C in the GG group were significantly higher than in the AA group at all observation times, with mean differences of 18% to 33% (P < .05). The area under the LDL-C-time curve and the minimum value of LDL-C in the GG group were 24% and 23% higher than in the AA group, respectively (P < .01). There was no significant difference in other lipids, CK, and pharmacokinetic parameters. The HMGCR rs3846662 GG genotype was quantitatively documented to be a significant determinant for higher LDL-C level in basal state and possibly in response to atorvastatin.

Objective: To investigate anatomical changes in the substantia nigra (SN) of Parkinson disease (PD) patients with age-matched controls by using ultra-high field magnetic resonance imaging (MRI)., Methods: We performed 7T MRI in 10 PD and 10 age-matched control subjects. Magnetic resonance images of the SN were obtained from a 3-dimensional (3D) T(2)*-weighted gradient echo sequence. Region of interest-based 3D shape analysis was performed to quantitatively compare images from the 2 groups., Results: The boundary between the SN and crus cerebri was not smooth in PD subjects. Undulation in the lateral surface of the SN appeared more intense in the side contralateral to that with the more severe symptoms, and more prominent at the rostral level of the SN than at the intermediate or caudal levels. In addition to the lateral surface, there was a striking difference in the dorsomedial aspects of the SN between PD and control subjects. In control subjects, a brighter signal region was observed along the dorsomedial surface of the lateral portion of SN, whereas in PD subjects, this region was observed as a dark region containing a hypointense signal in T(2)*-weighted images. The measurement of SN volumes, normalized to the intracranial volumes, showed higher values in PD subjects than in control subjects., Interpretation: This study demonstrates that 3D 7T MRI can definitively visualize anatomical alterations occurring in the SN of PD subjects. Further pathological studies are required to elucidate the nature of these anatomical alterations., (Copyright © 2012 American Neurological Association.)

The cell surface heparan sulfate proteoglycan syndecan-2 regulates the activation of matrix metalloproteinase-7 (MMP-7) as a docking receptor. Here, we demonstrate the role of MMP-7 on syndecan-2 shedding in colon cancer cells. Western blot analysis showed that shed syndecan-2 was found in the culture media from various colon cancer cells. Overexpression of MMP-7 enhanced syndecan-2 shedding, whereas the opposite was true when MMP-7 levels were knocked-down using small inhibitory RNAs. Consistently, HT29 cells treated with MMP-7, but neither MMP-2 nor MMP-9, showed increased shed syndecan-2 in a time- and concentration-dependent manner. Furthermore, MALDI-TOF MS analysis and N-terminal amino acid sequencing revealed that MMP-7 cleaved both recombinant syndecan-2 and an endogenously glycosylated syndecan-2 ectodomain in the N-terminus at Leu(149) residue in vitro. Taken together, the data suggest that MMP-7 directly mediates shedding of syndecan-2 from colon cancer cells., (Copyright © 2011 Elsevier Inc. All rights reserved.)

It is believed that the inherent differentiation program of melanocytes during embryogenesis predisposes melanoma cells to high frequency of metastasis. Sox10, a transcription factor expressed in neural crest stem cells and a subset of progeny lineages, plays a key role in the development of melanocytes. We show that B16F10 melanoma cells transfected with siRNAs specific for Sox10 display reduced migratory activity which in turn indicated that a subset of transcriptional regulatory target genes of Sox10 is likely to be involved in migration and metastasis of melanoma cells. We carried out a microarray-based gene expression profiling using a Sox10-specific siRNA to identify relevant regulatory targets and found that multiple genes including melanocortin-1 receptor (Mc1r) partake in the regulation of migration. We provide evidences that the effect of Sox10 on migration is mediated in large part by Mitf, a transcription factor downstream to Sox10. Among the mouse melanoma cell lines examined, however, only B16F10 showed robust down-regulation of Sox10 and inhibition of cell migration indicating that further dissection of dosage effects and/or cell line-specific regulatory networks is necessary. The involvement of Mc1r in migration was studied in detail in vivo using a murine metastasis model. Specifically, B16F10 melanoma cells treated with a specific siRNA showed reduced tendency in metastasizing to and colonizing the lung after being injected in the tail vein. These data reveal a cadre of novel regulators and mediators involved in migration and metastasis of melanoma cells that represents potential targets of therapeutic intervention.

Carcinoma-associated fibroblasts (CAFs) promote tumor invasion by secreting soluble factors. A tagged triazine library was screened in our novel transwell coculture model of CAF and oral squamous cell carcinoma (OSCC). We discovered compound S06, which reduced OSCC invasion by inhibiting secretion of CAF-derived proinvasive chemokines. The N-terminus of Hsp90 was found to be the cellular target of S06. Importantly, S06 did not induce hepatic toxicity, a side effect associated with well-known Hsp90 inhibitors. Moreover, S06 inhibited tumor cell migration in a zebrafish xenograft model. Our results demonstrate that Hsp90 is a novel target for stromal-based therapy to modulate proinvasive molecular crosstalk within the tumor microenvironment. Furthermore, S06 represents a new class of Hsp90 inhibitor and is an attractive candidate for anticancer drug development., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Pathophysiological aspects of dementia and its rate of cognitive deterioration could be dependent on disease subtype, Alzheimer's dementia (AD), vascular dementia (VaD), and Parkinson's disease with dementia (PDD). 150 patients diagnosed at the Chungnam National University Hospital (87 women and 63 men) memory clinic. The participants consisted of 68 patients with AD, 23 patients with VaD, and 59 patients with PDD, who were diagnosed by the individual criteria, respectively. Cognitive screening was evaluated using the Korean version of the mini-mental state examination (MMSE). Repeated evaluations were conducted at 6-month, 1 year, and 2 years after initial baseline assessment. Rates of cognitive decline were calculated by dividing MMSE score differences by the number of months lapsed. No difference was found between the three dementia subtypes with respect to baseline MMSE scores. Cognitive decline was not obvious up to 6-month of the follow-up, but by 12-month of follow-ups was significant regardless of the dementia subtype. Furthermore, the rate of cognitive decline in the AD group was significantly faster than in the PDD or VaD groups. This study suggests that rate of cognitive deterioration in dementia is not linear over time and that dementia subtypes have different rates of cognitive deterioration., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Among lithium alloy metals, silicon is an attractive candidate to replace commercial graphite anode because silicon possesses about ten times higher theoretical energy density than graphite. However, electrically nonconducting silicon undergoes a large volume changes during lithiation/delithiation reactions, which causes fast loss of storage capacity upon cycling due to electrode pulverization. To alleviate these problems, electrodes comprising Si nanoparticles (20 nm) and graphene platelets, denoted as SiGP-1 (Si = 35.5 wt%) and SiGP-2 (Si = 57.6 wt%), have been prepared with low cost materials and using easily scalable solution-dispersion methods. X-ray diffraction (XRD), scanning electron microscopy (SEM) and high-resolution transmission electron microscopy (HR-TEM) analyses indicated that Si nanoparticles were highly dispersed and encapsulated between graphene sheets that stacked into platelets in which portions of graphite phases were reconstituted. From the galvanostatic cycling test, SiGP-1 exhibited a reversible lithiation capacity of approximately 802 mAh/g with excellent capacity retention up to 30 cycles at 100 mA/g. Further cycling with a step-increase of current density (100-1,000 mA/g) up to 120 cycles revealed that it has an appreciable power capability as well, showing 520 mAh/g at 1,000 mA/g with capacity loss of 0.2-0.3% per cycle. The improved electrochemical performance is attributed to the robust electrical integrity provided by flexible graphene sheets that encapsulated dispersed Si nanopraticles and stacked into platelets with portions of reconstituted graphite phases in their structure.

Unlabelled: The CDT requires a patient to draw the face of a clock, insert all the numbers and set the hands for a specified time. This task engages a number of cognitive abilities including verbal understanding, memory, spatially coded knowledge, planning, concentration and visuoconstructive skills. Although CDT has been regarded as a simple and useful screening tool in dementia, little is known about the longitudinal changes in CDT performance and error types, according to dementia subtypes and their severity., Materials and Methods: Two hundred thirty-five consecutive patients with dementia (Alzheimer disease = AD, n=94, Parkinson's disease with dementia (PDD), n = 119, Vascular dementia = VaD, n = 22) were recruited from the memory clinic at Chungnam University hospital from January 2005 to July 2009. The Korean version of the mini-mental state examination (MMSE-K) and CDT were performed by all participants every 6 months. Scoring of the CDT performance was in accordance with the method of Mano and Wu. Error types of CDT were classified as follows: stimulus-bound response (SBR), conceptual deficit (CD), spatial and/or planning deficit (SPD) and perseveration error (PE). We divided patients into 3 groups by their initial MMSE-K score (severe, MMSE-K ≤ 17; moderate, 18 ≤ MMSE-K < 24; mild, 24 ≤ MMSE-K). Comparisons of CDT scores and error types in the three dementia subtypes and three cognitive groups were conducted., Results: Longitudinal changes on CDT and MMSE-K scores were not different between the three dementia subtypes. From the analysis of CDT error type, the most common error type was SPD in patients with mild to moderate dementia. In contrast, CD error was the most frequent in severe dementia group. The order of error frequency in all subjects from baseline to the last follow-up was as follows: SPD, CD, SBR and PE except CD was the most frequent error type in AD patients after 18 months from baseline., Conclusion: Longitudinal analysis of error on CDT may reflect different characteristics of cognitive deterioration according to dementia subtypes and dementia stages., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Four Lactobacillus strains - Lactobacillus plantarum CJLP133, L. plantarum CJLP243, L. plantarum CJNR26, and Lactobacillus gasseri CJMF3 - were isolated from Korean fermented food or healthy infant feces, and their capacity to modulate cellular and humoral immune responses was studied. Feeding of the tested lactobacilli for 8 weeks did not alter the weight of and cell numbers in the spleen of mice. However, CJLP133 and CJLP243 strains increased the T lymphocyte population in the spleen of mice, while CJNR26 and CJMF3 increased the B lymphocyte population. In splenocytes treated with concanavalin A, ingestion of CJLP133 and CJLP243 promoted T lymphocyte proliferation and secretion of T cell cytokines, whereas feeding of the CJNR26 and CJMF3 strains enhanced B lymphocyte proliferation in splenocytes treated with lipopolysaccharide and plaque formation. These results suggest that CJLP133 and CJLP243 have immunostimulating activity through the enhancement of T cell activation, while CJNR26 and CJMF3 exhibit immunopotentiation through the increment of B cell activation.

The cell surface heparan sulfate proteoglycan, syndecan-2, is crucial for the tumorigenic activity of colon cancer cells. However, the role played by the cytoplasmic domain of the protein remains unclear. Using colon cancer cells transfected with various syndecan-2-encoding genes with deletions in the cytoplasmic domain, it was shown that syndecan-2-induced migration activity requires the EFYA sequence of the C-terminal region; deletion of these residues abolished the rise in cell migration seen when the wild-type gene was transfected and syndecan-2 interaction with syntenin-1, suggesting that syntenin-1 functioned as a cytosolic signal effector downstream from syndecan-2. Colon cancer cells transfected with the syntenin-1 gene showed increased migratory activity, whereas migration was decreased in cells in which syntenin-1 was knock-down using small inhibitory RNA. In addition, syntenin-1 expression potentiated colon cancer cell migration induced by syndecan-2, and syndecan-2-mediated cell migration was reduced when syntenin-1 expression diminished. However, syntenin-1-mediated migration enhancement was not noted in colon cancer cells transfected with a gene encoding a syndecan-2 mutant lacking the cytoplasmic domain. Furthermore, in line with the increase in cell migration, syntenin-1 mediated Rac activation stimulated by syndecan-2. Together, the data suggest that the cytoplasmic domain of syndecan-2 regulates colon cancer cell migration via interaction with syntenin-1., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Melanocytes are highly motile cells that play an integral role in basic skin physiological processes such as wound healing and proper skin pigmentation. It has been postulated that surrounding keratinocytes contribute to melanocyte migration, but underlying mechanisms remain rather vague so far. In this study, we set out to analyze the specific potential contribution of keratinocyte components to melanocytes and melanoma cell migration-related processes. Our studies revealed that A375 human melanoma cell attachment, spreading, and migration are interestingly better supported by HaCaT keratinocyte extracellular matrix (ECM) than by self-derived A375 ECM. Moreover, HaCaT ECM caused increased integrin α6 expression, adhesion-mediated focal adhesion kinase phosphorylation, and focal adhesion formations. Similar effects were confirmed in human melanocytes. Furthermore, we found that keratinocyte-derived soluble factors did not appear to significantly contribute to these processes. Specific extrinsic factors that promoted melanoma migration were attributed to keratinocyte-derived laminin-332, whereas alternative ECM component such as laminin-111 and fibronectin functions appeared to have insignificant contributions. Taken together, these studies implicate extrinsic laminin-332 in promoting the high mobility property and perhaps invasiveness inherently characteristic of, and that are the menace of, melanocytes and melanomas, respectively.

Expression of carbonic anhydrase IX (CA9) was shown to be strongly involved in high incidences of metastasis and poor prognosis in various human tumors. In this study, we investigated the possible role for CA9 in tumor metastases in vitro, using a gene transfection tool in the human cervical carcinoma cell line C33A. Gene expression profiling of CA9-transfected cells (C33A/CA9) and vector-transfected cells (C33A/Mock) was investigated by DNA microarray. The biological functions of differentially expressed genes between the C33A/CA9 and C33A/Mock cells included cell growth, regulation of cell-cell and cell-extracellular matrix adhesion and cytoskeletal organization. Immunofluorescent stain and Matrigel culture showed cytoskeletal remodeling, disassembled focal adhesion, weakened cell-cell adhesion and increased motility in C33A/CA9 cells. These invasive and metastatic phenotypes were associated with Rho-GTPase-related epithelial-mesenchymal transition. Inhibition of the Rho/Rho kinase pathway by a ROCK inhibitor (Y27632) and si-Rho (short interference RNA against RhoA) showed that Rho-GTPase signaling was involved in cellular morphologic and migratory changes. The effect of CA9 on Rho-GTPase signaling was also confirmed by silencing CA9 expression. Our results suggest that CA9 overexpression induces weakening of cell adhesions and augmented cell motility by aberrant Rho-GTPase signal transduction. Our study shows an underlying mechanism of CA9-related enhanced metastatic potential of tumor cells.

Juvenile myoclonic epilepsy (JME) is an idiopathic, age-related generalized epileptic syndrome. Status epilepticus (SE) in JME is very rare, and little is known about its etiology. We report 2 cases of adult patients, retrospectively diagnosed as JME by non convulsive status epilepticus which occurred for the first time. One patient was a 52-year-old woman who was presented with confusion and brief generalized tonic-clonic seizure (GTCS) for the first time. The other patient, a 39 year-old woman, visited the ER with transient LOC following confused mental state. Electroencephalograms of both patients repetitively showed generalized polyspikes and slow waves which were disappeared after IV injection of lorazepam. With careful history taking, both of them the patients were diagnosed as JME, and the seizures stopped just after sodium valproate medication. NCSE in patients with JME is rare but detailed history taking and suspicion of the disorder is helpful for diagnosis.

Status epilepticus (SE) in pregnancy is very rare, and there are only a few case reports of refractory SE (RSE) during pregnancy. The patient was a 27-year-old primigravida woman with a 21-year history of seizures from cortical dysplasia. At 23 weeks of pregnancy, the patient's seizure frequency progressively increased, and the patient came to the ER in a confused mental state and with intermittent convulsive movements of her left arm. Electroencephalography (EEG) revealed repeated seizures. She was admitted to the ICU, and continuous EEG monitoring was done. Treatment was immediately started with various anti-SE medications, but her SE was not controlled. A cesarean section was done, and SE spontaneously stopped two weeks after the parturition. Parturition may be beneficial and the best treatment option in pregnant patients with RSE.

Orthognathic surgery is one of the most commonly performed cosmetic surgical procedures. Hemorrhage, infection, and facial palsy have been reported as complications of the surgery, but the occurrence is low. Our patient presented with facial palsy, postoperative bleeding, wound dehiscence, and descending necrotizing mediastinitis in a sequence. This is the first report of descending necrotizing mediastinitis after orthognathic surgery. Although these are very rare complications, awareness of the clinical presentation and the management of these conditions are important.

An increasing number of functions for syndecan cell surface heparan sulfate proteoglycans have been proposed over the last decade. Moreover, aberrant syndecan regulation has been found to play a critical role in multiple pathologies, including cancers, as well as wound healing and inflammation. As receptors, they have much in common with other molecules on the cell surface. Syndecans are type I transmembrane molecules with cytoplasmic domains that link to the actin cytoskeleton and can interact with a number of regulators. However, they are also highly complex by virtue of their external glycosaminoglycan chains, especially heparan sulfate. This heterodisperse polysaccharide has the potential to interact with many ligands from diverse protein families. Here, we relate the structural features of syndecans to some of their known functions., (Copyright © 2010 International Society of Matrix Biology. Published by Elsevier B.V. All rights reserved.)

Unlabelled: Lactobacilli isolated from Kimchi, a Korean traditional food, were tested for their capacity to modulate the T helper (Th) 1/Th2 balance. Ovalbumin (OVA)-sensitized mouse splenocytes were cultured with 26 strains of lactobacilli; the highest IL-12 induction and lowest IL-4 production were then observed in 4 strains, including Lactobacillus plantarum CJLP55, CJLP56, CJLP133, and CJLP136. These strains produced a larger amount of IL-12, which enhances differentiation and activation of Th1 cells, in macrophage cell-lines more than positive control strains L. casei KCTC 3109(T) and L. rhamnosus GG, although they also induced production of IL-10, which is a suppressor of IL-12. Indeed, CJLP133-stimulated macrophages induced production of more Th1 cytokine IFN-γ and less Th2 cytokine IL-4 than KCTC 3109(T) and GG in co-cultivation with T cells. These findings suggest that lactobacilli from Kimchi may modulate the Th1/Th2 balance via macrophage activation in the hypersensitive reaction caused by Th2 cells., Practical Application: Allergic reactions including asthma and atopy are caused by predominance of Th2 response over Th1 response. Lactobacilli isolated from fermented foods such as yogurt, cheese, and Kimchi showed health-promoting activities. The present study indicated that several lactobacilli strains from Kimchi may reduce allergic reactions through macrophage-mediated induction of Th1 response.

Increased expression and/or activation of H-Ras are often associated with tumor aggressiveness in breast cancer. Previously, we showed that H-Ras, but not N-Ras, induces MCF10A human breast epithelial cell invasion and migration, whereas both H-Ras and N-Ras induce cell proliferation and phenotypic transformation. In an attempt to determine the sequence requirement directing the divergent phenotype induced by H-Ras and N-Ras with a focus on the induction of human breast cell invasion, we investigated the structural and functional relationships between H-Ras and N-Ras using domain-swap and site-directed mutagenesis approaches. Here, we report that the hypervariable region (HVR), consisting of amino acids 166 to 189 in H-Ras, determines the invasive/migratory signaling program as shown by the exchange of invasive phenotype by swapping HVR sequences between H-Ras and N-Ras. We also demonstrate that the H-Ras-specific additional palmitoylation site at Cys184 is not responsible for the signaling events that distinguish between H-Ras and N-Ras. Importantly, this work identifies the C-terminal HVR, especially the flexible linker domain with two consecutive proline residues Pro173 and Pro174, as a critical domain that contributes to activation of H-Ras and its invasive potential in human breast epithelial cells. The present study sheds light on the structural basis for the Ras isoform-specific invasive program of breast epithelial cells, providing information for the development of agents that specifically target invasion-related H-Ras pathways in human cancer.

Aims: Although low and high intensity sub-sonic vibrations (SSV) have been shown to facilitate wound healing, very few studies have investigated the effects of SSV on 3T3-L1 preadipocytes. Therefore, the present study was undertaken to investigate the influence of SSV on the proliferation and maturation of 3T3-L1 preadipocytes., Main Methods: To evaluate the effect of SSV on 3T3-L1 cell proliferation, the cells were maintained in an apparatus that administered SSV (0.5 V) for 3 days at a frequency of 10, 20, 30, or 40 Hz. In addition, to study the effect of SSV on 3T3-L1 cell maturation, the cells were stimulated with SSV for 6 days at a frequency of 10, 20, 30, or 45 Hz., Key Findings: Sub-sonic vibrations inhibited the proliferation of 3T3-L1 preadipocytes at frequencies of 20 and 30 Hz. Triglyceride levels in cells subjected to SSV at frequencies ranging from 10 to 30 Hz increased compared with those measured in control cells. The expression of adipogenic genes, such as PPAR-γ and C/EBP-α, markedly increased in response to SSV at 20 Hz and 30 Hz during maturation., Significance: These results suggest that SSV affected adipogenic gene expression at 20 and 30 Hz., (Copyright © 2010 Elsevier Inc. All rights reserved.)

We performed this study to evaluate the relationship between the stages of PD and autonomic dysfunction, and to find an association between the autonomic dysfunction and cognitive impairment in PD. Sixty-three patients who met the criteria of the United Kingdom PD Society Brain Bank were enrolled prospectively. Clinical stages were using the Hoehn and Yahr (H&Y) staging and unified PD rating scale motor scores. Cognitive functions were evaluated using the mini-mental state examination (MMSE) and the modified MMSE (3MS) test. The scale for outcome in PD-autonomic (SCOPA-AUT) was used to evaluate autonomic symptoms. Severities of autonomic dysfunction were classified using the composite autonomic scoring scale (CASS). Fifty-four of the 63 patients (86%) had shown abnormalities on CASS. H&Y stages correlated with SCOPA-AUT (p<0.05) and 3MS and MMSE scores (p<0.05). H&Y stages were positively related with autonomic dysfunction, heart rate ratios during deep breathing and the quantitative sudomotor axon reflex test (QSART) scores. Autonomic dysfunction may be present from disease onset, whereas the rate of cognitive decline increases with disease progression. We recommend that both qualitative and quantitative autonomic evaluation from the early stage of disease and regular cognitive screening with disease progression might be useful to facilitate optimal management in PD., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

The role of amyloid-β (Aβ in the neurodegeneration of Alzheimer's disease remains controversial, to a large extent because of the lack of robust neurodegeneration in mouse models of AD. To address this question, we examined the effects of Aβ antibodies in the recently described monoaminergic (MAergic) axonal degeneration in AβPPswe/PS1dE9 mice. To determine if Aβ accumulation is directly involved in degeneration of MAergic axons, we examined the effects of passive anti-Aβ antibody (7B6) administration on Aβ pathology and MAergic degeneration in AβPPswe/PS1dE9 mice. Injections of monoclonal antibody (mAb) 7B6 into mice (6 to 9 months of age) resulted in a modest reduction of Aβ load in the brains of AβPPswe/PS1dE9 mice. In addition, 7B6 treated AβPPswe/PS1dE9 mice had significantly higher densities of MAergic axons in both cortex and in hippocampus as compared to untreated mutant mice. For example, 7B6 treated mice showed almost 2-fold greater densities of serotonergic (5-HT) axons in the cortex compared to saline treated mice. Similar findings were observed in the catecholaminergic (TH) axons. Our results demonstrate that lowering of Aβ levels via passive Aβ immunotherapy ameliorates ongoing degenerative processes, supporting a causal link between Aβ and neurodegeneration.

Leaf spot and blight disease was observed on two-year-old seedlings of Dendropanax morbifera (Korean name: Hwangchil tree) during July of 2008 in Jindo Island, Korea. Symptoms included yellow-brown to dark brown irregularly enlarged spots frequently located along the veins of leaves. The lesions were often surrounded by chlorotic haloes. Severe leaf blight and subsequent defoliation occurred when conditions favored disease outbreak. The causal organism of the disease was identified as Alternaria panax based on morphological characteristics and sequence analysis of the internal transcribed spacer region of rDNA. A. panax isolates induced leaf spots and blight symptoms not only on D. morbifera but also on the other members of Araliaceae tested. This is the first report of foliar blight caused by A. panax on D. morbifera.

We investigated the neuroprotective effect of glucosamine (GlcN) in a rat middle cerebral artery occlusion model. At the highest dose used, intraperitoneal GlcN reduced infarct volume to 14.3% ± 7.4% that of untreated controls and afforded a reduction in motor impairment and neurological deficits. Neuroprotective effects were not reproduced by other amine sugars or acetylated-GlcN, and GlcN suppressed postischemic microglial activation. Moreover, GlcN suppressed lipopolysaccharide (LPS)-induced upregulation of proinflammatory mediators both in vivo and in culture systems using microglial or macrophage cells. The anti-inflammatory effects of GlcN were mainly attributable to its ability to inhibit nuclear factor kappaB (NF-κB) activation. GlcN inhibited LPS-induced nuclear translocation and DNA binding of p65 to both NF-κB consensus sequence and NF-κB binding sequence of inducible nitric oxide synthase promoter. In addition, we found that GlcN strongly repressed p65 transactivation in BV2 cells using Gal4-p65 chimeras system. P65 displayed increased O-GlcNAcylation in response to LPS; this effect was also reversed by GlcN. The LPS-induced increase in p65 O-GlcNAcylation was paralleled by an increase in interaction with O-GlcNAc transferase, which was reversed by GlcN. Finally, our results suggest that GlcN or its derivatives may serve as novel neuroprotective or anti-inflammatory agents., (© 2010 Wiley-Liss, Inc.)

Conventional protein kinase C (PKC) isoforms are essential serine/threonine kinases regulating many signaling networks. At cell adhesion sites, PKCalpha can impact the actin cytoskeleton through its influence on RhoGTPases, but the intermediate steps are not well known. One important regulator of RhoGTPase function is the multifunctional guanine nucleotide dissociation inhibitor RhoGDIalpha that sequesters several related RhoGTPases in an inactive form, but it may also target them through interactions with actin-associated proteins. Here, it is demonstrated that conventional PKC phosphorylates RhoGDIalpha on serine 34, resulting in a specific decrease in affinity for RhoA but not Rac1 or Cdc42. The mechanism of RhoGDIalpha phosphorylation is distinct, requiring the kinase and phosphatidylinositol 4,5-bisphosphate, consistent with recent evidence that the inositide can activate, localize, and orient PKCalpha in membranes. Phosphospecific antibodies reveal endogenous phosphorylation in several cell types that is sensitive to adhesion events triggered, for example, by hepatocyte growth factor. Phosphorylation is also sensitive to PKC inhibition. Together with fluorescence resonance energy transfer microscopy sensing GTP-RhoA levels, the data reveal a common pathway in cell adhesion linking two essential mediators, conventional PKC and RhoA.

Syndecans, cell surface heparansulfate proteoglycans, have been proposed to act as cell surface receptors and/or coreceptors to play critical roles in multiple cellular functions. However, recent reports suggest that the function of syndecans can be further extended through shedding, a cleavage of extracellular domain. Shedding constitutes an additional level for controlling the function of syndecans, providing a means to attenuate and/or regulate amplitude and duration of syndecan signals by modulating the activity of syndecans as cell surface receptors. Whether these remaining cleavage products are still capable of functioning as cell surface receptors to efficiently transduce signals inside of cells is not clear. However, shedding transforms cell surface receptor syndecans into soluble forms, which, like growth factors, may act as novel ligands to induce cellular responses by association with other cell surface receptors. It is becoming interestingly evident that shed syndecans also contribute significantly to syndecan functions in cancer biology. This review presents current knowledge about syndecan shedding and its functional significance, particularly in the context of cancer.

Plasma amyloid-β (Aβ) level could be useful as a non-invasive biomarker in Alzheimer's disease research. We compared a multiplex electrochemiluminescence detection method with a well established ELISA method for plasma Aβ quantification. Compared to the ELISA method, the electrochemiluminescence detection method demonstrates a statistically significant, but modest correlation. The reasons for this may include the differences in the affinities of antibodies, and purity and source of Aβ peptides used as standards. However, the advantages of electrochemiluminescence detection technology include short processing time and small sample volume. This comparison demonstrates the need for a further study in optimizing this system.

Expression of the cell surface adhesion receptor syndecan-2 is known to be involved in the regulation of cancer cell migration. However, the molecular mechanism of syndecan-2-mediated cell migration remains unknown. Here we report that Rac contributes to the regulation of syndecan-2-mediated cancer cell migration. Overexpression of syndecan-2 enhanced migration and invasion of human colon adenocarcinoma cells Caco-2 and HCT116 cells. In parallel with the increased cell migration/invasion, syndecan-2 overexpression enhanced Rac activity, while dominant negative Rac (RacN17) diminished syndecan-2-mediated increased cancer cell migration. In addition syndecan-2 expression increased membrane localization of Tiam1 and syndecan-2-mediated cell migration/invasion of Caco-2 cells was diminished when Tiam1 levels were knocked-down with small inhibitory RNAs. Furthermore, oligomerization-defective syndecan-2 mutants failed to increase membrane localization of Tiam1, activation of Rac and subsequent cell migration of both Caco-2 and HCT116 cells. Taken together, these results suggest that syndecan-2 regulates cell migration of colon carcinoma cells through Tiam1-dependent Rac activation in colon cancer cells., (Copyright 2009 Elsevier Inc. All rights reserved.)

Although elevated syndecan-2 expression is known to be crucial for the tumorigenic activity in colon carcinoma cells, how syndecan-2 regulates colon cancer is unclear. In human colon adenocarcinoma tissue samples, we found that both mRNA and protein expression of syndecan-2 were increased, compared with the neighboring normal epithelium, suggesting that syndecan-2 plays functional roles in human colon cancer cells. Consistent with this notion, syndecan-2-overexpressing HT-29 colon adenocarcinoma cells showed enhanced migration/invasion, anchorage-independent growth, and primary tumor formation in nude mice, paralleling their morphological changes into highly tumorigenic cells. In addition, our experiments revealed that syndecan-2 enhanced both expression and secretion of matrix metalloproteinase-7 (MMP-7), directly interacted with pro-MMP-7, and potentiated the enzymatic activity of pro-MMP-7 by activating its processing into the active MMP-7. Collectively, these data strongly suggest that syndecan-2 functions as a docking receptor for pro-MMP-7 in colon cancer cells.

Purpose: To assess the association between the visible presence of third molars and the severity of periodontal pathologic findings on teeth more anterior in the mouth., Patients and Methods: The present analysis included dentate participants, 52 to 74 years old, from the Dental Atherosclerosis Risk in Communities study who had undergone an oral examination that included periodontal probing depths (PDs) on all visible teeth, including any third molars. A PD of 4 mm or more and a clinical attachment level of 3 mm or greater were indicator variables for periodontal pathologic features. Explanatory variables were the presence or absence of visible third molars. The covariates included gender, ethnicity, age, income level, education, and smoking status. The outcome variables for periodontal pathologic features were the mean PD, extent (percentage of probing sites) of PDs of 4 mm or more, and the extent (percentage of probing sites) of a clinical attachment level of 3 mm or more. The outcomes between those with and without visible third molars were compared using descriptive statistics and chi-square tests, with significance set at P = .05. Multivariate modeling was performed using Statistical Analysis Systems SAS Proc GLM (SAS Institute, Cary, NC) to calculate the least squared means, adjusting for the study outcome variables and covariates., Results: The Dental Atherosclerosis Risk in Communities study sample included 6,793 subjects; 80% were white and 19% were black. Most (53%) were 62 to 74 years old and female (54%). Of the 6,793 participants, 2,035 (30%) had at least 1 visible third molar. The presence of a visible third molar was significantly associated with male gender, black race, age younger than the mean of 62.4 years, greater income, and never smoking (all P < .01). A greater mean PD for the first and second molars, the extent of PD of 4 mm or more at the first and second molars, and the extent of a clinical attachment level of 3 mm or more at the first and second molars were all significantly associated with the presence of a visible third molar in the unadjusted and adjusted models., Conclusions: In these middle-age and older Americans, the presence of a visible third molar was significantly associated with more severe periodontal disease on teeth more anterior in the mouth compared with those subjects with no visible third molars.

Microglia contributes significantly to brain tumor mass, particularly in astrocytic gliomas. Here, we examine the cytotoxic effects of soluble components secreted from microglia culture on glioma cells. Microglia conditioned culture medium (MCM) actively stimulated apoptotic death of glioma cells, and the effects of MCM prepared from LPS- or IFN-gamma-activated microglia were more pronounced. The cytotoxic effects were glioma-specific in that primary cultured rat astrocytes were not affected by MCM. A donor of peroxynitrite induced glioma-specific cell death. In addition, NO synthase inhibitor suppressed glioma cell death induced by activated MCM, indicating that NO is one of the key molecules responsible for glioma cytotoxicity mediated by activated MCM. However, since unstimulated resting microglia produces low or very limited level of NO, MCM may contain other critical molecule(s) that induce glioma apoptosis. To identify the proteins secreted in MCM, proteomic analysis was performed on control or activated medium. Among over 200 protein spots detected by Coomassie blue staining, we identified 26 constitutive and 28 LPS- or IFN-gamma-regulated MCM proteins. Several cathepsin proteases were markedly expressed, which were reduced upon activation. In particular, suppression of cathepsin B by the chemical inhibitors significantly reversed MCM-induced glioma cell death, implying a critical role of this protease in cytotoxicity. Our findings provide evidence on the functional implications of specific microglial-secreted proteins in glioma cytotoxicity, as well as a basis to develop a proteomic databank of both basal and activation-related proteins in microglia.

Syndecan-2, a transmembrane heparan sulfate proteoglycan, is a critical mediator in the tumorigenesis of colon carcinoma cells. We explored the function of syndecan-2 in melanoma, one of the most invasive types of cancers, and found that the expression of this protein was elevated in tissue samples from both nevus and malignant human melanomas but not in melanocytes of the normal human skin tissues. Similarly, elevated syndecan-2 expression was observed in various melanoma cell lines. Overexpression of syndecan-2 enhanced migration and invasion of melanoma cells, whereas the opposite was observed when syndecan-2 levels were knocked down using small inhibitory RNAs. Syndecan-2 expression was enhanced by fibroblast growth factor-2, which is known to stimulate melanoma cell migration; however, alpha-melanocyte-stimulating hormone decreased syndecan-2 expression and melanoma cell migration and invasion in a melanin synthesis-independent manner. Furthermore, syndecan-2 overexpression rescued the migration defects induced by alpha-melanocyte-stimulating hormone treatment. Together, these data strongly suggest that syndecan-2 plays a crucial role in the migratory potential of melanoma cells.

Syndecans are the only family of transmembrane heparan sulphate proteoglycans. Invertebrates all appear to have one Syndecan core protein, but in mammals there are four. Examination of the core protein sequences shows that the cytoplasmic domains are the most conserved. This suggests that Syndecans make important interactions and/or signalling contributions. It has been established that all syndecans can interact with proteins of the actin-associated cytoskeleton, but details of signalling have been harder to ascertain. However, it appears that Syndecans can signal, primarily to the cytoskeleton, and the details are reviewed here. Only for vertebrate syndecan-4 is there substantial detail, and it remains a challenge to dissect the functions and signalling of other vertebrate and invertebrate syndecans.

The amyloid precursor protein (APP) is the source of beta-amyloid, a pivotal peptide in the pathogenesis of Alzheimer's disease (AD). This study examines the possible effect of APP transgene expression on neuronal size by measuring the volumes of cortical neurons (microm(3)) in transgenic mouse models with familial AD Swedish mutation (APPswe), with or without mutated presenilin1 (PS1dE9), as well as in mice carrying wild-type APP (APPwt). Overexpression of APPswe and APPwt protein, but not of PS1dE9 alone, resulted in a greater percentage of medium-sized neurons and a proportionate decrease in the percentage of small-sized neurons. Our observations indicate that the overexpression of mutant (APPswe) or wild-type APP in transgenic mice is necessary and sufficient for hypertrophy of cortical neurons. This is highly suggestive of a neurotrophic effect and also raises the possibility that the lack of neuronal loss in transgenic mouse models of AD may be attributed to overexpression of APP.

Although phosphatidylinositol 4,5-bisphosphate (PIP(2)) regulates syndecan-4 function, the potential influence of syndecan-4 on PIP(2) remains unknown. GFP containing PIP(2)-binding-PH domain of phospholipase Cdelta (GFP-PHdelta) was used to monitor PIP(2). Syndecan-4 overexpression in COS-7 cells enhanced membrane translocation of GFP-PHdelta, while the opposite was observed when syndecan-4 was knocked-down. PIP(2) levels were higher in total phospholipids extracted from rat embryo fibroblasts expressing syndecan-4. Syndecan-4-induced membrane targeting of GFP-PHdelta was further enhanced by phosphoinositide-3-kinase inhibitor, but not by phospholipase C (PLC) inhibitor. Besides, both ionomycin and epidermal growth factor caused dissociation of GFP-PHdelta from plasma membrane, an effect that was significantly delayed by syndecan-4 over-expression. Collectively, these data suggest that syndecan-4 promotes plasma membrane retention of PIP(2) by negatively regulating PLC-dependent PIP(2) degradation.

Syndecan-2, a transmembrane heparan sulfate proteoglycan, is known to serve as an adhesion receptor, but details of the regulatory mechanism governing syndecan-2 cell adhesion and migration remain unclear. Here, we examined this regulatory mechanism, showing that overexpression of syndecan-2 enhanced collagen adhesion, cell migration and invasion of normal rat intestinal epithelial cells (RIE1), and increased integrin alpha2 expression levels. Interestingly, RIE1 cells transfected with either syndecan-2 or integrin alpha2 showed similar adhesion and migration patterns, and a function-blocking anti-integrin alpha2 antibody abolished syndecan-2-mediated adhesion and migration. Consistent with these findings, transfection of integrin alpha2 siRNA diminished syndecan-2-induced cell migration in HCT116 human colon cancer cells. Taken together, these results demonstrate a novel cooperation between syndecan-2 and integrin alpha2beta1 in adhesion-mediated cell migration and invasion. This interactive dynamic might be a possible mechanism underlying the tumorigenic activities of colon cancer cells.

Cell adhesion to the extracellular matrix (ECM) can activate signaling via focal adhesion kinase (FAK) leading to dynamic regulation of cellular morphology. Mechanistic basis for the lack of effective intracellular signaling by non-attached epithelial cells is poorly understood. To examine whether signaling in suspended cells is regulated by Fer cytoplasmic tyrosine kinase, we investigated the effect of ectopic Fer expression on signaling in suspended or adherent hepatocytes. We found that ectopic Fer expression in Huh7 hepatocytes in suspension or on non-permissive poly-lysine caused significant phosphorylation of FAK Tyr577, Tyr861, or Tyr925, but not Tyr397 or Tyr576. Fer-mediated FAK phosphorylation in suspended cells was independent of c-Src activity or growth factor stimulation, but dependent of cortactin expression. Consistent with these results, complex formation between FAK, Fer, and cortactin was observed in suspended cells. The Fer-mediated effect correlated with multiple membrane protrusions, even on poly-lysine. Together, these observations suggest that Fer may allow a bypass of anchorage-dependency for intracellular signal transduction in hepatocytes.

Syndecan-4, a cell surface heparan sulfate proteoglycan, is known to regulate the organization of the cytoskeleton, and oligomerization is crucial for syndecan-4 function. We therefore explored a possible regulatory effect of syndecan-4 oligomerization on the cytoskeleton. Glutathione-S-transferase-syndecan-4 proteins were used to show that syndecan-4 interacted specifically with alpha-actinin, but not paxillin, talin, and vinculin. Interestingly, only dimeric, and not monomeric, recombinant syndecan-4 interacted with alpha-actinin in the presence of phosphatidylinositol 4,5-bisphosphate (PIP2), and PIP2 potentiated the interaction of both the cytoplasmic domain syndecan-4 peptide and recombinant syndecan-4 proteins with alpha-actinin, implying that oligomerization of syndecan-4 was important for this interaction. Consistent with this notion, alpha-actinin interaction was largely absent in syndecan-4 mutants defective in transmembrane domain-induced oligomerization, and alpha-actinin-associated focal adhesions were decreased in rat embryo fibroblasts expressing mutant syndecan-4. Besides, this interaction was consistently lower with the phosphorylation-mimicking syndecan-4 mutant S183E which is known to destabilize the oligomerization of the syndecan-4 cytoplasmic domain. Taken together, the data suggest that the oligomeric status of syndecan-4 plays a crucial role in regulating the interaction of syndecan-4 with alpha-actinin.

The cell adhesion receptor, syndecan-4, regulates cellular interactions with both the extracellular matrix and soluble ligands. Accumulating evidence also suggests that cell adhesion is involved in generating reactive oxygen species (ROS). Here, we investigated the role of syndecan-4 in regulating growth factor-induced ROS generation. Rat embryo fibroblasts (REFs) overexpressing syndecan-4 exhibited increased ROS levels compared to control cells. Expression of the non-phagocytic NADH oxidase component Nox1 was increased in syndecan-4-overexpressing REFs and syndecan-4-mediated ROS generation was diminished when levels of Nox1 were knocked-down with small inhibitory RNAs. In addition, syndecan-4 enhanced platelet-derived growth factor (PDGF)-induced MAP kinase activity in parallel with ROS generation. Collectively, these data suggest that syndecan-4 regulates PDGF-induced MAP kinase activation by altering ROS generation.

We present the data and the technology, a combination of which allows us to determine the identity of proprotein convertases (PCs) related to the processing of specific protein targets including viral and bacterial pathogens. Our results, which support and extend the data of other laboratories, are required for the design of effective inhibitors of PCs because, in general, an inhibitor design starts with a specific substrate. Seven proteinases of the human PC family cleave the multibasic motifs R-X-(R/K/X)-R downward arrow and, as a result, transform proproteins, including those from pathogens, into biologically active proteins and peptides. The precise cleavage preferences of PCs have not been known in sufficient detail; hence we were unable to determine the relative importance of the individual PCs in infectious diseases, thus making the design of specific inhibitors exceedingly difficult. To determine the cleavage preferences of PCs in more detail, we evaluated the relative efficiency of furin, PC2, PC4, PC5/6, PC7, and PACE4 in cleaving over 100 decapeptide sequences representing the R-X-(R/K/X)-R downward arrow motifs of human, bacterial, and viral proteins. Our computer analysis of the data and the follow-on cleavage analysis of the selected full-length proteins corroborated our initial results thus allowing us to determine the cleavage preferences of the PCs and to suggest which PCs are promising drug targets in infectious diseases. Our results also suggest that pathogens, including anthrax PA83 and the avian influenza A H5N1 (bird flu) hemagglutinin precursor, evolved to be as sensitive to PC proteolysis as the most sensitive normal human proteins.

Microglia are the primary central nervous system immune effector cells. Microglial activation is linked to interactions with extracellular cytokines and the extracellular matrix (ECM). Astrocytomas are characterized by their diffuse nature, which is regulated by insoluble ECM components produced by the tumor cells that are largely absent from normal central nervous system tissue. The present study examined the influence of astrocytoma (C6 rat glioma) insoluble matrix components on interferon-gamma (IFN-gamma)-mediated inducible nitric-oxide synthase (iNOS) induction in microglial cells. We found that IFN-gamma-stimulated iNOS induction and nitric oxide release was greater in microglia cultured on C6 glioma cell-derived matrices compared with microglia cultured on primary rat astrocyte-derived matrices. Culture of microglia on C6 glioma cell-derived matrices also led to activation of STAT1, augmentation of IFN-gamma-induced STAT-3 activation, and an increase in IFN-gamma-activated site (GAS)-luciferase reporter activity. In addition, culture of microglia on C6 glioma cell-derived matrices activated NF-kappaB DNA binding activity and transcriptional activity. The results suggest that insoluble matrix components derived from malignant glioma cells can regulate microglia activation. These factors may include ECM components, such as fibronectin, collagen, laminin, vitronectin, and other nondiffusible compounds, and laminin seems to a critical regulator of this process. Microglia activation and subsequent brain inflammation may influence tumor growth, treatment, and metastasis. Better understanding of the regulation of microglial activation by astrocytoma-derived insoluble matrix components may be important in the development of immune-based treatment strategies against malignant brain tumors.

Membrane-type 1 matrix metalloproteinase (MT1-MMP), a transmembrane proteinase with a short cytoplasmic domain and an extracellular catalytic domain, controls a variety of physiological and pathological processes through the proteolytic degradation of extracellular or transmembrane proteins. MT1-MMP forms a complex on the cell membrane with its physiological protein inhibitor, tissue inhibitor of metalloproteinases-2 (TIMP-2). Here we show that, in addition to extracellular proteolysis, MT1-MMP and TIMP-2 control cell proliferation and migration through a non-proteolytic mechanism. TIMP-2 binding to MT1-MMP induces activation of ERK1/2 by a mechanism that does not require the proteolytic activity and is mediated by the cytoplasmic tail of MT1-MMP. MT1-MMP-mediated activation of ERK1/2 up-regulates cell migration and proliferation in vitro independently of extracellular matrix proteolysis. Proteolytically inactive MT1-MMP promotes tumor growth in vivo, whereas proteolytically active MT1-MMP devoid of cytoplasmic tail does not have this effect. These findings illustrate a novel role for MT1-MMP-TIMP-2 interaction, which controls cell functions by a mechanism independent of extracellular matrix degradation.

Amyloid plaques are composed primarily of amyloid-beta (Abeta) peptides derived from proteolytic cleavage of amyloid precursor protein (APP) and are considered to play a pivotal role in Alzheimer's disease (AD) pathogenesis. Presently, AD is diagnosed after the onset of clinical manifestations. With the arrival of novel therapeutic agents for treatment of AD, there is an urgent need for biomarkers to detect early stages of AD. Measurement of plasma Abeta has been suggested as an inexpensive and non-invasive tool to diagnose AD and to monitor Abeta modifying therapies. However, the majority of cross-sectional studies on plasma Abeta levels in humans have not shown differences between individuals with AD compared to controls. Similarly, cross-sectional studies of mouse plasma Abeta have yielded inconsistent trends in different mouse models. However, longitudinal studies appear to be more promising in humans. Recently, efforts to modify plasma Abeta levels using modulators have shown some promise. In this review, we will summarize the present data on plasma Abeta in humans and mouse models of AD. We will discuss the potential of modulators of Abeta levels in plasma, including antibodies and insulin, and the challenges associated with measuring plasma Abeta. Modulators of plasma Abeta may provide an important tool to optimize plasma Abeta levels and may improve the diagnostic potential of this approach.

Recent evidences suggest that the activation of peroxisome proliferator-activated receptor (PPAR)-gamma, which is an important transcriptional factor in adipocyte differentiation, also plays an important role in the bone microenvironment. The objective of the study was to clarify whether Pro12Ala polymorphism was related to the serum OPG levels and bone mineral metabolism in healthy Korean women. In 239 Korean women (mean age 51 years), who participated in medical check-up program in a health promotion center, anthropometric measurements, lumbar spine and femoral neck bone mineral density (BMD), bone turnover markers, such as serum total alkaline phosphatase (ALP) levels, urine deoxypyridinoline levels, and 24-h urine calcium excretion were measured. Serum levels of OPG were measured with ELISA method. DNAs were extracted from the samples and the genotyping of the Pro12Ala polymorphism (rs1801282) in the PPAR-gamma gene was performed via an allelic discrimination assay using a TaqMan probe. In addition, we examined the haplotype analysis between two polymorphisms of PPAR-gamma gene, Pro12Ala in exon B and C161T in exon 6 (rs3856806). Allelic frequencies were 0.950 for Pro allele and 0.050 for Ala allele, which was in compliance with Hardy- Weinberg equilibrium, and there was no Ala12Ala genotype among the genotyped subjects. Mean serum OPG level was significantly lower (P=0.035), and serum total ALP was significantly higher (P=0.014) in the Pro12Ala genotype group compared with the Pro12Pro genotype group, which were consistently significant even after adjustment for weight, height, and serum follicle stimulating hormone (FSH). In multiple regression analysis with serum OPG as the dependent variable and age, weight, ALP, femoral neck BMD and Pro12Ala genotype included in the model, only Pro12Ala genotype was significant determinant of serum OPG level (b=??0.136, P=0.035). The haplotype analysis with C161T polymorphism revealed that subjects with Ala and T alleles showed significantly lower serum OPG levels compared with those with Pro12Pro/CC genotype, which were consistently significant even after adjustment for age, weight, height and FSH (P=0.010). This result suggests statistically significant association of Pro12Ala polymorphisms with serum OPG levels in Korean females.

Focal adhesion kinase (FAK) mediates signal transduction in response to multiple extracellular inputs, via tyrosine phosphorylation at specific residues. We recently reported that FAK Tyr-407 phosphorylation negatively regulates the enzymatic and biological activities of FAK, unlike phosphorylation of other tyrosine residues. In this study, we further investigated the effect of FAK Tyr-407 phosphorylation on cell transformation. We found that FAK Tyr-407 phosphorylation was lower in H-Ras transformed NIH3T3 and K-Ras transformed rat-2 fibroblasts than in the respective untransformed control cells. Consistently, FAK Tyr-407 phosphorylation was decreased in parallel with cell transformation in H-Ras-inducible NIH3T3 cells and increased during trichostatin A-induced detransformation of both K-Ras transformed rat-2 fibroblasts and H-Ras transformed NIH3T3 cells. In addition, overexpression of a phosphorylation-mimicking FAK Tyr-407 mutant inhibited morphological transformation of H-Ras-inducible NIH3T3 cells and inhibited invasion activity and anchorage-independent growth of H-Ras-transformed NIH3T3 cells. Taken together, these data strongly suggest that FAK Tyr-407 phosphorylation negatively regulates transformation of fibroblasts.

Background/aims: Adipokines are associated with various metabolic disorders including insulin resistance, obesity, and dyslipidemia. Metabolic disorders have also been reported to be associated with nonalcoholic fatty liver disease (NAFLD). The aim of this study was to determine the relationship between the serum adipokine levels and the degrees of hepatic fat infiltration in NAFLD. This study also attempted to determine the independent factors influencing the serum adipokine levels in NAFLD., Methodology: Sixty-five Korean male patients were enrolled in this study. The degree of hepatic fat infiltration was classified into the following three groups according to the ultrasonographic findings: Group I, normal liver; Group II, mild fatty liver; and Group III, moderate to severe fatty liver. The anthropometric parameters, fasting serum adipokine levels including leptin, adiponectin and resistin were measured in all subjects. The level of insulin resistance was estimated using the HOMA-IR., Results: The serum leptin levels increased with increasing degree of hepatic fat infiltration (mean +/- SD: Group I, 2.052 +/- 1.071; Group II, 2.879 +/- 1.016; and Group III, 4.457 +/- 1.965 ng/mL, P < 0.001). However, the serum adiponectin and resistin levels were similar. The fasting serum insulin level was only a related factor for the changes in the serum leptin levels (P = 0.004). There were no related factors for the change in the serum adiponectin and resistin levels., Conclusions: This study suggests an indirect role for leptin in the pathogenesis of NAFLD by inducing insulin resistance, resulting in increased fasting serum insulin level.