Does Cognitive-Physical Dual-Task Training Have Better Clinical Outcomes than Cognitive Single-Task Training Does? A Single-Blind, Randomized Controlled Trial.

PURPOSE: At present, there is a controversy regarding the effect of dual-task training on improving the cognitive function of people with mild cognitive impairment (MCI). This study was to develop and verify the effects of the cognitive-physical dual-task training program on the executive function of older adults with MCI. METHOD: Participants were randomly allocated to the experimental group (EG) receiving cognitive-physical dual-task training (n = 21) or the control group (CG) receiving cognitive single-task training (n = 21). RESULTS: After 16 sessions for 8 weeks, the Korean version of the Executive Function Performance Task (EFPT-K), the Frontal Assessment Battery (FAB), and Korean version of the Instrumental Activities of Daily Living (K-IADL) tests were implemented to assess people's executive function and instrumental activities during daily living. As the result, there were no significant differences in general characteristics between both groups (p > 0.05). After 16 sessions, the EG showed greater improvements in the EFPT-K (p < 0.05; η2 = 0.133), the FAB (p < 0.001; η2 = 0.305), and the K-IADL (p < 0.01; η2 = 0.221) compared to those of the CG. CONCLUSION: These results indicate that cognitive-physical dual-task training is clinically beneficial to improve the executive function and daily instrumental activities of older adults with MCI. Cognitive-physical dual-task training is a promising intervention for older adults with MCI.

3,5,6,7,8,3',4'-Heptamethoxyflavone, a Citrus Flavonoid, Inhibits Collagenase Activity and Induces Type I Procollagen Synthesis in HDFn Cells.

Citrus fruits contain various types of flavonoids with powerful anti-aging and photoprotective effects on the skin, and have thus been attracting attention as potential, efficacious skincare agents. Here, we aimed to investigate the chemical composition of Citrus unshiu and its protective effects on photoaging. We isolated and identified a bioactive compound, 3,5,6,7,8,3',4'-heptamethoxyflavone (HMF), from C. unshiu peels using ethanol extraction and hexane fractionation. HMF inhibited collagenase activity and increased type I procollagen content in UV-induced human dermal fibroblast neonatal (HDFn) cells. HMF also suppressed the expression of matrix metalloproteinases 1 (MMP-1) and induced the expression of type I procollagen protein in UV-induced HDFn cells. Additionally, HMF inhibited ultraviolet B (UVB)-induced phosphorylation of the mitogen-activated protein kinases (MAPK) cascade signaling components-ERK, JNK, and c-Jun-which are involved in the induction of MMP-1 expression. Furthermore, HMF affected the TGF-ß/Smad signaling pathway, which is involved in the regulation of type I procollagen expression. In particular, HMF induced Smad3 protein expression and suppressed Smad7 protein expression in UV-induced HDFn cells in a dose-dependent manner. These findings suggest a role for Citrusunshiu in the preparation of skincare products in future.

Evaluation of recurrence in gastric carcinoma: Comparison of contrast-enhanced computed tomography and positron emission tomography/computed tomography.

AIM: To compare the value of contrast-enhanced abdominal computed tomography (CT) and fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) for detecting gastric carcinoma recurrence. METHODS: We retrospectively examined data from 2475 patients who underwent both contrast-enhanced abdominal CT and FDG PET/CT for the surveillance of gastric carcinoma curative resection. Patients had an interval of less than 1 mo between their CT and PET/CT scans. Sixty patients who had recurrence were enrolled. Among 1896 patients who did not have recurrence, 60 were selected by simple random sampling. All CT and PET/CT images were reviewed retrospectively by two reviewers blinded to all clinical and pathologic information except curative resection due to gastric carcinoma. RESULTS: The pathological stage of the recurrence group was statistically significantly higher than that of the control group (P < 0.001). In the 60 patients who had recurrence, there were 79 recurrent lesions. Forty-four patients had only one location of recurrence, 13 patients had two locations, and 3 patients had three. In the detection of patient-based overall recurrence, no statistically significant differences existed between the two modalities (P = 0.096). However, for peritoneal carcinomatosis, CT had a statistically significantly higher sensitivity compared to PET/CT (96% vs 50%, P = 0.001). Adenocarcinoma was the most common type of gastric carcinoma. On the pathology-based analysis, CT also had a statistically significantly higher sensitivity compared to PET/CT (98% vs 80%, P = 0.035). CONCLUSION: Contrast-enhanced CT was superior to PET/CT in the detection of peritoneal carcinomatosis and pathologic type of adenocarcinoma.

Effects of Ganodermanondiol, a New Melanogenesis Inhibitor from the Medicinal Mushroom Ganoderma lucidum.

Ganoderma lucidum, a species of the Basidiomycetes class, has been attracting international attention owing to its wide variety of biological activities and great potential as an ingredient in skin care cosmetics including "skin-whitening" products. However, there is little information available on its inhibitory effect against tyrosinase activity. Therefore, the objectives of this study were to investigate the chemical composition of G. lucidum and its inhibitory effects on melanogenesis. We isolated the active compound from G. lucidum using ethanol extraction and ethyl acetate fractionation. In addition, we assayed its inhibitory effects on tyrosinase activity and melanin biosynthesis in B16F10 melanoma cells. In this study, we identified a bioactive compound, ganodermanondiol, which inhibits the activity and expression of cellular tyrosinase and the expression of tyrosinase-related protein-1 (TRP-1), TRP-2, and microphthalmia-associated transcription factor (MITF), thereby decreasing melanin production. Furthermore, ganodermanondiol also affected the mitogen-activated protein kinase (MAPK) cascade and cyclic adenosine monophosphate (cAMP)-dependent signaling pathway, which are involved in the melanogenesis of B16F10 melanoma cells. The finding that ganodermanondiol from G. lucidum exerts an inhibitory effect on tyrosinase will contribute to the use of this mushroom in the preparation of skin care products in the future.

Transcriptome and Gene Ontology (GO) Enrichment Analysis Reveals Genes Involved in Biotin Metabolism That Affect L-Lysine Production in Corynebacterium glutamicum.

Corynebacterium glutamicum is widely used for amino acid production. In the present study, 543 genes showed a significant change in their mRNA expression levels in L-lysine-producing C. glutamicum ATCC21300 than that in the wild-type C. glutamicum ATCC13032. Among these 543 differentially expressed genes (DEGs), 28 genes were up- or downregulated. In addition, 454 DEGs were functionally enriched and categorized based on BLAST sequence homologies and gene ontology (GO) annotations using the Blast2GO software. Interestingly, NCgl0071 (bioB, encoding biotin synthase) was expressed at levels ~20-fold higher in the L-lysine-producing ATCC21300 strain than that in the wild-type ATCC13032 strain. Five other genes involved in biotin metabolism or transport--NCgl2515 (bioA, encoding adenosylmethionine-8-amino-7-oxononanoate aminotransferase), NCgl2516 (bioD, encoding dithiobiotin synthetase), NCgl1883, NCgl1884, and NCgl1885--were also expressed at significantly higher levels in the L-lysine-producing ATCC21300 strain than that in the wild-type ATCC13032 strain, which we determined using both next-generation RNA sequencing and quantitative real-time PCR analysis. When we disrupted the bioB gene in C. glutamicum ATCC21300, L-lysine production decreased by approximately 76%, and the three genes involved in biotin transport (NCgl1883, NCgl1884, and NCgl1885) were significantly downregulated. These results will be helpful to improve our understanding of C. glutamicum for industrial amino acid production.

LRRK2 G2019S mutation attenuates microglial motility by inhibiting focal adhesion kinase.

In response to brain injury, microglia rapidly extend processes that isolate lesion sites and protect the brain from further injury. Here we report that microglia carrying a pathogenic mutation in the Parkinson's disease (PD)-associated gene, G2019S-LRRK2 (GS-Tg microglia), show retarded ADP-induced motility and delayed isolation of injury, compared with non-Tg microglia. Conversely, LRRK2 knockdown microglia are highly motile compared with control cells. In our functional assays, LRRK2 binds to focal adhesion kinase (FAK) and phosphorylates its Thr-X-Arg/Lys (TXR/K) motif(s), eventually attenuating FAK activity marked by decreased pY397 phosphorylation (pY397). GS-LRRK2 decreases the levels of pY397 in the brain, microglia and HEK cells. In addition, treatment with an inhibitor of LRRK2 kinase restores pY397 levels, decreased pTXR levels and rescued motility of GS-Tg microglia. These results collectively suggest that G2019S mutation of LRRK2 may contribute to the development of PD by inhibiting microglial response to brain injury.

Multi-axis shoulder abduction splint in acute burn rehabilitation: a randomized controlled pilot trial.

OBJECTIVE: The traditional thermoplastic aeroplane splint for axillary burn contracture is heavy, uncomfortable, and time consuming and difficult to put on and off. The present study tested the effectiveness of a newly designed multi-axis shoulder abduction splint with an easy-to-change angle. DESIGN: Randomized controlled parallel assessor blinded pilot. SETTING: Inpatient rehabilitation center in a general hospital. SUBJECTS: Twenty-four patients with recent (< 30 days) burns around the shoulder joint were randomized into two groups. After two dropouts, 11 patients used the new splint for four weeks and 13 patient were left unsplinted for four weeks. INTERVENTIONS: The newly designed multi-axis shoulder abduction splint keeps the shoulder abducted at the highest possible angle. MAIN OUTCOMES: The range of motion of the shoulder joint was measured at 0, 1, 2, 3, and 4 weeks. Active abduction, flexion, and external rotation were measured according to the zero position method by placing the axis of the goniometer ventral to the shoulder joint. RESULTS: Repeated-measure ANOVA revealed that the splint group developed significantly better abduction (P = 0.020) and flexion (P = 0.036) over 4 weeks than the non-splint group. ANCOVA using the initial (0 week) angle and Shoulder Burn Depth Index as covariates revealed that the splint group had significantly better abduction than the non-splint group (P = 0.013). CONCLUSION: The new multi-axis shoulder abduction splint resulted in a significant improvement in shoulder abduction angle compared to unsplinted patients.

Suppression of miR-155 Expression in IFN-γ-Treated Astrocytes and Microglia by DJ-1: A Possible Mechanism for Maintaining SOCS1 Expression.

Previously, we reported that DJ-1, encoded by a Parkinson's disease (PD)-associated gene, inhibits expression of proinflammatory mediators in interferon-gamma (IFN-γ)-treated astrocytes and microglia through inhibition of STAT1 activation. Here, using microglia and astrocytes cultured from wild-type (WT) and DJ-1-knockout (KO) mouse brains, we examined how DJ-1 regulates suppressor of cytokine signaling 1 (SOCS1), a negative feedback regulator of STAT1 (signal transducer and activator of transcription) that is also induced by STAT1. We found that IFN-γ significantly increased SOCS1 mRNA expression in WT microglia and astrocytes, but not in KO cells, although STAT1 was highly activated in these latter cells. We further found that SOCS mRNA stability was decreased in DJ-1-KO cells, an effect that appeared to be mediated by the microRNA, miR-155. IFN-γ increased the levels of miR-155 in DJ-1-KO cells but not in WT cells. In addition, an miR-155 inhibitor rescued SOCS1 expression and decreased STAT1 activation in DJ-1-KO cells. Taken together, these results suggest that DJ-1 efficiently regulates inflammation by maintaining SOCS1 expression through regulation of miR-155 levels, even under conditions in which STAT1 activation is decreased.

DJ-1 facilitates the interaction between STAT1 and its phosphatase, SHP-1, in brain microglia and astrocytes: A novel anti-inflammatory function of DJ-1.

Parkinson's disease (PD) is a progressive neurodegenerative movement disorder caused by the death of dopaminergic neurons in the substantia nigra. Importantly, altered astrocyte and microglial functions could contribute to neuronal death in PD. In this study, we demonstrate a novel mechanism by which DJ-1 (PARK7), an early onset autosomal-recessive PD gene, negatively regulates inflammatory responses of astrocytes and microglia by facilitating the interaction between STAT1 and its phosphatase, SHP-1 (Src-homology 2-domain containing protein tyrosine phosphatase-1). Astrocytes and microglia cultured from DJ-1-knockout (KO) mice exhibited increased expression of inflammatory mediators and phosphorylation levels of STAT1 (p-STAT1) in response to interferon-gamma (IFN-γ) compared to cells from wild-type (WT) mice. DJ-1 deficiency also attenuated IFN-γ-induced interactions of SHP-1 with p-STAT1 and STAT1, measured 1 and 12h after IFN-γ treatment, respectively. Subsequent experiments showed that DJ-1 directly interacts with SHP-1, p-STAT1, and STAT1. Notably, DJ-1 bound to SHP-1 independently of IFN-γ, whereas the interactions of DJ-1 with p-STAT1 and STAT1 were dependent on IFN-γ. Similar results were obtained in brain slice cultures, where IFN-γ induced much stronger STAT1 phosphorylation and inflammatory responses in KO slices than in WT slices. Moreover, IFN-γ treatment induced neuronal damage in KO slices. Collectively, these findings suggest that DJ-1 may function as a scaffold protein that facilitates SHP-1 interactions with p-STAT1 and STAT1, thereby preventing extensive and prolonged STAT1 activation. Thus, the loss of DJ-1 function may increase the risk of PD by enhancing brain inflammation.

Spatial and temporal correlation in progressive degeneration of neurons and astrocytes in contusion-induced spinal cord injury.

BACKGROUND: Traumatic spinal cord injury (SCI) causes acute neuronal death followed by delayed secondary neuronal damage. However, little is known about how microenvironment regulating cells such as microglia, astrocytes, and blood inflammatory cells behave in early SCI states and how they contribute to delayed neuronal death. METHODS: We analyzed the behavior of neurons and microenvironment regulating cells using a contusion-induced SCI model, examining early (3-6 h) to late times (14 d) after the injury. RESULTS: At the penumbra region close to the damaged core (P1) neurons and astrocytes underwent death in a similar spatial and temporal pattern: both neurons and astrocytes died in the medial and ventral regions of the gray matter between 12 to 24 h after SCI. Furthermore, mRNA and protein levels of transporters of glutamate (GLT-1) and potassium (Kir4.1), functional markers of astrocytes, decreased at about the times that delayed neuronal death occurred. However, at P1 region, ramified Iba-1+ resident microglia died earlier (3 to 6 h) than neurons (12 to 24 h), and at the penumbra region farther from the damaged core (P2), neurons were healthy where microglia were morphologically activated. In addition, round Iba-1/CD45-double positive monocyte-like cells appeared after neurons had died, and expressed phagocytic markers, including mannose receptors, but rarely expressed proinflammatory mediators. CONCLUSION: Loss of astrocyte function may be more critical for delayed neuronal death than microglial activation and monocyte infiltration.

Impaired inflammatory responses in murine Lrrk2-knockdown brain microglia.

LRRK2, a Parkinson's disease associated gene, is highly expressed in microglia in addition to neurons; however, its function in microglia has not been evaluated. Using Lrrk2 knockdown (Lrrk2-KD) murine microglia prepared by lentiviral-mediated transfer of Lrrk2-specific small inhibitory hairpin RNA (shRNA), we found that Lrrk2 deficiency attenuated lipopolysaccharide (LPS)-induced mRNA and/or protein expression of inducible nitric oxide synthase, TNF-α, IL-1ß and IL-6. LPS-induced phosphorylation of p38 mitogen-activated protein kinase and stimulation of NF-κB-responsive luciferase reporter activity was also decreased in Lrrk2-KD cells. Interestingly, the decrease in NF-κB transcriptional activity measured by luciferase assays appeared to reflect increased binding of the inhibitory NF-κB homodimer, p50/p50, to DNA. In LPS-responsive HEK293T cells, overexpression of the human LRRK2 pathologic, kinase-active mutant G2019S increased basal and LPS-induced levels of phosphorylated p38 and JNK, whereas wild-type and other pathologic (R1441C and G2385R) or artificial kinase-dead (D1994A) LRRK2 mutants either enhanced or did not change basal and LPS-induced p38 and JNK phosphorylation levels. However, wild-type LRRK2 and all LRRK2 mutant variants equally enhanced NF-κB transcriptional activity. Taken together, these results suggest that LRRK2 is a positive regulator of inflammation in murine microglia, and LRRK2 mutations may alter the microenvironment of the brain to favor neuroinflammation.

Adaptive synthesis of distance fields.

We address the computational resource requirements of 3D example-based synthesis with an adaptive synthesis technique that uses a tree-based synthesis map. A signed-distance field (SDF) is determined for the 3D exemplars, and then new models can be synthesized as SDFs by neighborhood matching. Unlike voxel synthesis approach, our input is posed in the real domain to preserve maximum detail. In comparison to straightforward extensions to the existing volume texture synthesis approach, we made several improvements in terms of memory requirements, computation times, and synthesis quality. The inherent parallelism in this method makes it suitable for a multicore CPU. Results show that computation times and memory requirements are very much reduced, and large synthesized scenes exhibit fine details which mimic the exemplars.

Dimethylsulfoxide (DMSO) induces downregulation of heme oxygenase-1 (HO-1) in HL-60 cells: involvement of HO-1 in HL-60 cell differentiation.

Heme oxygenase-1 (HO-1), an inducible enzyme with broad tissue expression, is wel1-regulated in response to hematopoietic stress and preserves vascular homeostasis. We investigated the involvement of HO-1 in HL-60 cell differentiation. Dimethyl sulfoxide (DMSO) completely decreased HO-1 expression in a time-dependent manner, but clearly induced HL-60 cell differentiation, as evidenced by a marked increase in CD11b expression. Interestingly, zinc protoporphyrin (ZnPP), a strong inhibitor of HO-1, induced HL-60 cell differentiation. In contrast, treatment with cobalt protoporphyrin (CoPP), an activator of HO-1, decreased CD11b expression. Additionally, ZnPP downregulated HO-1 protein expression in HL-60 cells, whereas CoPP induced upregulation. These results suggest that HO-1 might have a negative function in DMSO-induced HL-60 cell differentiation. This study provides the first evidence that HO-1 plays an important role in DMSO-induced HL-60 cell differentiation.

Uridine 5'-diphosphate induces chemokine expression in microglia and astrocytes through activation of the P2Y6 receptor.

Chemokines play critical roles in inflammation by recruiting inflammatory cells to injury sites. In this study, we found that UDP induced expression of chemokines CCL2 (MCP-1) and CCL3 (MIP-1α) in microglia, astrocytes, and slice cultures by activation of P2Y(6). Interestingly, CCL2 was more highly expressed than CCL3. However, CCL2 synthesis kinetics in response to UDP differed in microglia and astrocytes; microglia rapidly produced small amounts of CCL2, whereas astrocytes continuously synthesized large amounts of CCL2, resulting in a high ultimate level of the chemokine. UDP-induced chemokine expression was reduced in the presence of a specific antagonist of P2Y(6) (MRS2578) or small interfering RNA directed against the P2Y(6) gene. Inhibition of phospholipase C and calcium increase, downstream signaling pathways of Gq-coupled P2Y(6), reduced UDP-induced chemokine expression. UDP activated two calcium-activated transcription factors, NFATc1 and c2. Furthermore, inhibitors of calcineurin (a phosphatase activating NFAT) and NFAT reduced UDP-induced chemokine synthesis. We also found, using a transmigration assay, that UDP-treated astrocytes recruited monocytes. These results suggest that UDP induces chemokine expression in microglia and astrocytes of the injured brain by activation of P2Y(6) receptors.

Astrocytes in injury states rapidly produce anti-inflammatory factors and attenuate microglial inflammatory responses.

Microglia are known to be a primary inflammatory cell type in the brain. However, microglial inflammatory responses are attenuated in the injured brain compared to those in cultured pure microglia. In the present study, we found that astrocytes challenged by oxygen-glucose deprivation (OGD) or H(2) O(2) released soluble factor(s) and attenuated microglial inflammatory responses. Conditioned medium prepared from astrocytes treated with OGD (OGD-ACM) or H(2) O(2) (H(2) O(2) -ACM) significantly reduced the levels of interferon-γ (IFN-γ)-induced microglial inflammatory mediators, including inducible nitric oxide synthase, at both the mRNA and protein levels. The anti-inflammatory effect of astrocytes appeared very rapidly (within 5min), but was not closely correlated with the extent of astrocyte damage. Both OGD-ACM and H(2) O(2) -ACM inhibited STAT nuclear signaling, as evidenced by a reduction in both STAT-1/3 binding to the IFN-γ-activated site and IFN-γ-activated site promoter activity. However, both phosphorylation and nuclear translocation of STAT-1/3 was unchanged in IFN-γ-treated microglia. The active component(s) in OGD-ACM were smaller than 3kDa, and displayed anti-inflammatory effects independent of protein synthesis. These results suggest that, in the injured brain, astrocytes may act as a controller to rapidly suppress microglial activation.

A novel Ca2+/calmodulin antagonist HBC inhibits angiogenesis and down-regulates hypoxia-inducible factor.

Recent reports have shown that Ca(2+)/calmodulin (Ca(2+)/CaM) signaling plays a crucial role in angiogenesis. We previously developed a new Ca(2+)/CaM antagonist, HBC (4-{3,5-bis-[2-(4-hydroxy-3-methoxyphenyl)ethyl]-4,5-dihydropyrazol-1-yl}benzoic acid), from a curcumin-based synthetic chemical library. Here, we investigated its anti-angiogenic activity and mode of action. HBC potently inhibited the proliferation of human umbilical vascular endothelial cells with no cytotoxicity. Furthermore, HBC blocked in vitro characteristics of angiogenesis such as tube formation and chemoinvasion, as well as neovascularization of the chorioallantoic membrane of growing chick embryos in vivo. Notably, HBC markedly inhibited expression of hypoxia-inducible factor-1alpha (HIF-1alpha) at the translational level during hypoxia, thereby reducing HIF-1 transcriptional activity and expression of its major target gene, vascular endothelial growth factor. In addition, combination treatment with HBC and various HIF-1 inhibitors, including suberoylanilide hydroxamic acid, rapamycin, and terpestacin, had greater anti-angiogenic activity than treatment with each single agent. Collectively, our findings indicate that HBC is a new anti-angiogenic agent targeting HIF that can be used to explore the biological role of Ca(2+)/CaM in angiogenesis.

Cordycepin inhibits UVB-induced matrix metalloproteinase expression by suppressing the NF-kappaB pathway in human dermal fibroblasts.

Cordycepin (3-deoxyadenosine) has been shown to exhibit many pharmacological activities, including anti-cancer, anti-inflammatory, and anti-infection activities. However, the anti-skin photoaging effects of cordycepin have not yet been reported. In the present study, we investigated the inhibitory effects of cordycepin on matrix metalloproteinase-1 (MMP-1) and -3 expressions of the human dermal fibroblast cells. Western blot analysis and real-time PCR revealed cordycepin inhibited UVB-induced MMP-1 and -3 expressions in a dose-dependent manner. UVB strongly activated NF-kappaB activity, which was determined by IkappaBalpha degradation, nuclear localization of p50 and p65 subunit, and NF-kappaB binding activity. However, UVB-induced NF-kappaB activation and MMP expression were completely blocked by cordycepin pretreatment. These findings suggest that cordycepin could prevent UVB-induced MMPs expressions through inhibition of NF-kappaB activation. In conclusion, cordycepin might be used as a potential agent for the prevention and treatment of skin photoaging.

Adenosine induces hemeoxygenase-1 expression in microglia through the activation of phosphatidylinositol 3-kinase and nuclear factor E2-related factor 2.

Adenosine, a purine nucleoside, has been reported to suppress the inflammatory responses of microglia in the brain. However, the underlying mechanisms of its anti-inflammatory action are unclear at present. Here we show that adenosine reduces the increase in intracellular reactive oxygen species (ROS) through expression of an antioxidant enzyme, hemeoxygenase-1 (HO-1). The H(2)O(2)-induced intracellular ROS level was significantly low in microglia pretreated with adenosine for 3-6 h, compared with that in untreated cells. Adenosine induced HO-1 mRNA and protein expression within 3 h, which was maintained for up to 12 h. Nuclear factor E2-related factor 2 (Nrf2), a transcription factor, and phosphatidylinositol 3-kinase (PI3K) and Akt pathways appear to mediate HO-1 expression. In response to adenosine, Nrf2 translocated from the cytosol to nuclei, and bound to the antioxidant response element (ARE). Adenosine enhanced HO-1 promoter activity in an ARE-dependent manner. Moreover, the nucleoside stimulated Akt phosphorylation, and suppressors of PI3K (LY294002 and wortmannin) reduced adenosine-induced HO-1 expression. However, we propose that the effects of adenosine are independent of adenosine receptors, since agonists and antagonists of A1, A2a, and A3 had little effect on the regulation of intracellular ROS and HO-1 expression. Our results collectively suggest that adenosine acts as an endogenous regulator of brain inflammation via modulation of microglial ROS production.