Structural changes in the retina and serum HMGB1 levels are associated with decreased cognitive function in patients with Parkinson's disease.

BACKGROUND: Cognitive impairment is a serious nonmotor symptom in patients with Parkinson's disease (PD). Currently, there are few studies investigating the relationship of serum markers and retinal structural changes with cognitive function in PD. OBJECTIVE: To investigate the relationship between retinal structural changes, serum high mobility group box-1 (HMGB1) levels and cognitive function and motor symptoms in PD patients. METHODS: Eighty-nine participants, including 47 PD patients and 42 healthy subjects, were enrolled. PD patients were divided into Parkinson's disease with normal cognitive (PD-NC), Parkinson's disease with mild cognitive impairment (PD-MCI), and Parkinson's disease with dementia (PDD) groups. The motor and nonmotor symptoms of PD patients were evaluated with clinical scale. Serum HMGB1 levels were detected by enzyme-linked immunosorbent assay (ELISA), and ganglion cell-inner plexiform layer complex (GCIPL) thickness changes in the macula were quantitatively analyzed by swept source optical coherence tomography (SS-OCT) in all patients. RESULTS: Compared with the control group, the macular GCIPL (t = -2.308, P = 0.023) was thinner and serum HMGB1 (z = -2.285, P = 0.022) was increased in PD patients. Macular GCIPL thickness in patients with PD-MCI and PDD were significantly lower than that in PD-NC patients, but there were no significant difference between the PD-MCI and PDD groups. Serum HMGB1 levels in patients with PD-MCI and PDD were significantly higher than those in PD-NC patients, and serum HMGB1 levels in PDD patients were higher than those in PD-MCI patients. Correlation analysis showed that serum HMGB1 levels in PD patients were positively correlated with disease duration, HY stage, UPDRS-I score, UPDRS-III score, and UPDRS total score and negatively correlated with MOCA score. Macular GCIPL thickness was negatively correlated with HY stage and positively correlated with MOCA score, and macular GCIPL thickness was negatively correlated with serum HMGB1 level. Logistic regression analysis showed that elevated serum HMGB1 level, thinner macular GCIPL thickness, and higher HY stage were independent risk factors for Parkinson's disease with cognitive impairment (PD-CI). The areas under the receiver operating characteristic curve (AUC) for the serum HMGB1 level and macular GCIPL thickness-based diagnosis of PD-MCI, PDD and PD-CI based on in patients with PD were 0.786 and 0.825, 0.915 and 0.856, 0.852 and 0.841, respectively. The AUC for the diagnosis of PD-MCI, PDD and PD-CI with serum HMGB1 level and GCIPL thickness combined were 0.869, 0.967 and 0.916, respectively. CONCLUSION: The macular GCIPL thickness and serum HMGB1 level are potential markers of cognitive impairment in PD patients, and their combination can significantly improve the accuracy of the diagnosis of cognitive impairment in PD.

Clinical findings of hyperechoic substantia nigra in patients with Parkinson's disease.

This study aims to analyse hyperechoic substantia nigra (HSN) characteristics and the correlation of HSN with clinical features and blood biomarkers in patients with Parkinson's disease (PD). Transcranial sonography (TCS) evaluations of the substantia nigra (SN) were performed in 40 healthy controls and 71 patients with PD, including patients with SN hyperechogenicity (SN+) and those with normal SN echogenicity (SN-). Evaluation of motor and non-motor symptoms was assessed by a series of rating scales. The uricase method was used to determine serum uric acid (UA) levels, and enzyme-linked immunosorbent assay (ELISA) was used to measure plasma interleukin (IL)-1ß levels. TCS showed 92.50% specificity and 61.97% sensitivity in differentiating PD patients from controls. The area of SN+ contralateral to the side of initial motor symptoms (SNcontra) was larger than that ipsilateral to the side of initial motor symptoms (SNipsi). The PDSN+ group had lower Argentine Hyposmia Rating Scale (AHRS) scores and UA levels than the PDSN- group. Binary logistic regression analysis revealed that AHRS scores and UA levels could be independent predictors for HSN. The larger SN echogenic area (SNL) sizes positively correlated with plasma IL-1ß levels in PD patients with SN+. The present study provides further evidence of the potential of SN echogenicity as an imaging biomarker for PD diagnosis. PD patients with HSN have more severe non-motor symptoms of hyposmia. HSN in PD patients is related to the mechanism of abnormal iron metabolism and microglial activation.

Increased plasma lipocalin-2 levels are associated with nonmotor symptoms and neuroimaging features in patients with Parkinson's disease.

Lipocalin-2 (LCN2) is essential for the regulation of neuroinflammation and cellular uptake of iron. This study aimed to evaluate plasma LCN2 levels and explore their correlation with clinical and neuroimaging features in Parkinson's disease (PD) patients. Enzyme-linked immunosorbent assay (ELISA) was used to measure plasma LCN2 levels in 120 subjects. Evaluation of motor symptoms and nonmotor symptoms in PD patients was assessed by the associated scales. Voxel-based morphometry (VBM) was used to evaluate brain volume alterations, and quantitative susceptibility mapping (QSM) was used to quantitatively analyze brain iron deposition in 46 PD patients. Plasma LCN2 levels were significantly higher in PD patients than those in healthy controls. LCN2 levels were negatively correlated with Montreal Cognitive Assessment (MoCA) scores, total brain gray matter volume (GMV), and GMV/total intracranial volume (TIV) ratio, but positively correlated with Hamilton Anxiety Rating Scale (HAMD) scores and mean QSM values of the bilateral substantial nigra (SN). Receiver operating characteristic (ROC) curves confirmed that plasma LCN2 levels had good predictive accuracy for PD. The results suggest that plasma LCN2 levels have potential as a biomarker for the diagnosis of PD. LCN2 may be a therapeutic target for neuroinflammation and brain iron deposition.

Upregulation of ESPL1 is associated with poor prognostic outcomes in endometrial cancer.

BACKGROUND: Extra spindle pole bodies-like 1 (ESPL1) is known to play a crucial role in the segregation of sister chromatids during mitosis. Overexpression of ESPL1 is considered to have oncogenic effects in various human cancers. However, the specific biological function of ESPL1 in endometrial cancer (EC) remains unclear. METHODS: The TCGA and GEO databases were utilized to assess the expression of ESPL1 in EC. Immunohistochemistry was utilized to detect separase expression in EC samples. Kaplan-Meier survival analysis and Cox regression analysis were performed to evaluate the diagnostic and prognostic significance of ESPL1 in EC. Gene Set Enrichment Analysis (GSEA) was employed to explore the potential signaling pathway of ESPL1 in EC. Cell proliferation and colony formation ability were analyzed using CCK-8 and colony formation assay. RESULTS: Our analysis revealed that ESPL1 is significantly upregulated in EC, and its overexpression is associated with advanced clinical characteristics and unfavourable prognostic outcomes. Suppression of ESPL1 attenuated proliferation of EC cell line. CONCLUSION: The upregulation of ESPL1 is associated with advanced disease and poor prognosis in EC patients. These findings suggest that ESPL1 has the potential to serve as a diagnostic and prognostic biomarker in EC, highlighting its significance in the management of EC patients.

The expression of ESPL1 was higher in EC tissue than normal endometrial tissue.ESPL1 could be a potential prognostic marker for EC.

Diagnostic value of plasma SIRT1 levels and whole-brain gray matter volume in Parkinson's disease patients with cognitive impairment.

OBJECTIVE: This study was designed to investigate the diagnostic value of plasma SIRT1 levels and whole-brain gray matter (GM) volume in Parkinson's disease (PD) patients with cognitive impairment. METHODS: Automated enzymatic analysis was performed to measure plasma SIRT1 levels in 80 healthy controls and 77 PD patients. Motor symptoms and nonmotor symptoms in PD patients were assessed using the corresponding scales. A Siemens MAGNETOM Prisma 3 T MRI scanner was used to acquire images in 35 of 77 PD patients. RESULTS: Plasma SIRT1 levels in PD patients were lower than those in healthy controls. Plasma SIRT1 levels were negatively correlated with the age, Unified Parkinson's Disease Rating Scale Part III (UPDRS-III) scores, anxiety, depression, excessive daytime sleepiness (EDS), quality of life, and especially cognitive impairment. Thus, it showed that plasma SIRT1 levels were relevant to visuospatial/executive function, memory, and language. Receiver-operating characteristic (ROC) analysis confirmed that plasma SIRT1 levels had good diagnostic accuracy for PD with anxiety and EDS. Furthermore, plasma SIRT1 levels had a significant positive correlation with GM volume in the whole brain, and ROC analysis confirmed that plasma SIRT1 levels and the total GM volume had good diagnostic accuracy for PD with cognitive impairment. CONCLUSIONS: This study showed that plasma SIRT1 levels were correlated with the nonmotor symptoms of anxiety, depression, EDS, and especially cognitive impairment as well as the total GM volume. Furthermore, the combination of plasma SIRT1 levels and the total GM volume had good diagnostic accuracy for PD with cognitive impairment.

CDK6 is a novel predictive and prognosis biomarker correlated with immune infiltrates in multiple human neoplasms, including small cell lung carcinoma.

The roles of cyclin-dependent kinase 6 (CDK6) in various cancers, including small cell lung carcinoma (SCLC), remain unclear. Here, 111,54 multi-center samples were investigated to determine the expression, clinical significance, and underlying mechanisms of CDK6 in 34 cancers. The area under the curve (AUC), Cox regression analysis, and the Kaplan-Meier curves were used to explore the clinical value of CDK6 in cancers. Gene set enrichment analysis and correlation analysis were performed to detect potential CDK6 mechanisms. CDK6 expression was essential in 24 cancer cell types. Abnormal CDK6 expression was observed in 14 cancer types (e.g., downregulated in breast invasive carcinoma; p < 0.05). CDK6 allowed six cancers to be distinguished from their controls (AUC > 0.750). CDK6 expression was a prognosis marker for 13 cancers (e.g., adrenocortical carcinoma; p < 0.05). CDK6 was correlated with several immune-related signaling pathways and the infiltration levels of certain immune cells (e.g., CD8+ T cells; p < 0.05). Downregulated CDK6 mRNA and protein levels were observed in SCLC (p < 0.05, SMD = - 0.90). CDK6 allowed the identification of SCLC status (AUC = 0.91) and predicted a favorable prognosis for SCLC patients (p < 0.05). CDK6 may be a novel biomarker for the prediction and prognosis of several cancers, including SCLC.

Electrochemical Phenyl-Carbonyl Coupling Reaction of Aromatic Aldehydes or Ketones.

An electrochemical phenyl-carbonyl coupling reaction of aromatic aldehydes or ketones to synthesize 4-(hydroxy(phenyl)methyl)benzaldehyde derivatives has been developed. The method shows high chemoselectivity, broad functional group compatibility, atom economy, and environmental benignity and has good potential applicability.

Correlation between serum IGF-1 and EGF levels and neuropsychiatric and cognitive in Parkinson's disease patients.

BACKGROUND: Insulin-like growth factor 1 (IGF-1) and epidermal growth factor (EGF) exert neuroprotective effects in Parkinson's disease (PD). To date, studies on the relationships between serum IGF-1 and EGF levels and nonmotor symptoms in PD patients have been rare. METHODS: A Siemens automatic chemical analyzer was used to determine serum IGF-1 levels, and enzyme-linked immunosorbent assay was used to detect serum EGF levels in 100 healthy controls and 100 PD patients, including those in the early (n = 49) and middle-late (n = 51) stage of the disease. Evaluation of motor symptoms and nonmotor symptoms in PD patients was assessed by the associated scales. RESULTS: Serum IGF-1 and EGF levels were higher in PD patients than in healthy controls, and serum IGF-1 and EGF levels were higher in early stage PD patients than in middle-late stage PD patients. Serum IGF-1 levels were significantly negatively correlated with anxiety, depression, and cognitive dysfunction; serum EGF levels were significantly negatively correlated with cognitive dysfunction. Combining IGF-1 and EGF in the diagnosis of PD was more valuable than using a single factor in the diagnosis. CONCLUSIONS: This study shows that serum IGF-1 levels were correlated with the nonmotor symptoms of anxiety, depression, and cognitive dysfunction and that EGF levels were correlated with cognitive dysfunction. The combination of IGF-1 and EGF increased the value for a PD diagnosis. This is the first report of the simultaneous detection of IGF-1 and EGF levels to explore the correlation with nonmotor symptoms of PD.

High-efficiency fluorescent coordination polymer nanoparticles co-doped with Ce3+/Tb3+ ions for curcumin detection.

Curcumin (Cur) possesses diverse biological and pharmacologic effects. It is widely used as a food additive and therapeutic medicine. A study to determine a sensitive detection method for Cur is necessary and meaningful. In this work, double rare earth ions co-doped fluorescent coordination polymer nanoparticles (CPNPs) were developed for the Cur detection. The CPNPs were synthesized by using adenosine monophosphate (AMP) as bridge ligands via coordination self-assembly with Ce3+ and Tb3+. The AMP-Ce/Tb CPNPs exhibited the characteristic green fluorescence of Tb3+ and had high luminescence efficiency. Under the optimal conditions, the fluorescence intensity of AMP-Ce/Tb CPNPs could be significantly quenched by Cur. The fluorescence quenching extent at λex/λem of 300 nm/544 nm showed a good linear relationship with the Cur concentration in the range of 10 to 1000 nM. The detection limit was as low as 8.0 nM (S/N = 3). This method was successfully applied to the determination of Cur in real samples with satisfactory results. The luminescence mechanism of AMP-Ce/Tb CPNPs and the fluorescence quenching mechanism of the CPNPs by Cur were both examined.

Low serum uric acid levels are associated with the nonmotor symptoms and brain gray matter volume in Parkinson's disease.

BACKGROUND: Uric acid (UA) plays a protective role in Parkinson's disease (PD). To date, studies on the relationship between serum UA levels and nonmotor symptoms and brain gray matter volume in PD patients have been rare. METHODS: Automated enzymatic analysis was used to determine serum UA levels in 68 healthy controls and 88 PD patients, including those at the early (n = 56) and middle-late (n = 32) stages of the disease. Evaluation of motor symptoms and nonmotor symptoms in PD patients was assessed by the associated scales. Image acquisition was performed using a Siemens MAGNETOM Prisma 3 T MRI scanner. RESULTS: Serum UA levels in early stage PD patients were lower than those in healthy controls, and serum UA levels in the middle-late stage PD patients were lower than those in the early stage PD patients. Serum UA levels were significantly negatively correlated with the disease course, dysphagia, anxiety, depression, apathy, and cognitive dysfunction. ROC assessment confirmed that serum UA levels had good predictive accuracy for PD with dysphagia, anxiety, depression, apathy, and cognitive dysfunction. Furthermore, UA levels were significantly positively correlated with gray matter volume in whole brain. CONCLUSIONS: This study shows that serum UA levels were correlated with the nonmotor symptoms of dysphagia, anxiety, depression, apathy, and cognitive dysfunction and the whole-brain gray matter volume. That is the first report examining the relationships between serum UA and clinical manifestations and imaging features in PD patients.

Plasma arylsulfatase A levels are associated with cognitive function in Parkinson's disease.

BACKGROUND: Arylsulfatase A (ARSA), a lysosomal enzyme, has been shown to inhibit the aggregation and propagation of α-synuclein (α-syn) through its molecular chaperone function. The relationship between ARSA levels and Parkinson's disease (PD) in the Chinese Han population remains controversial, and few quantitative research studies have investigated the relationship between plasma ARSA levels and PD. OBJECTIVES: The purpose of this study was to investigate the relationships between ARSA levels and cognitive function in PD patients and to evaluate the association of ARSA and α-syn levels with nonmotor symptoms. METHODS: Enzyme-linked immunosorbent assay (ELISA) was used to measure the plasma ARSA and α-syn levels in 50 healthy controls, 120 PD patients (61 PD patients with no cognitive impairment (PD-NCI) and 59 PD patients with cognitive impairment (PD-CI)). Motor symptoms and nonmotor symptoms (cognitive function, Unified Parkinson's Disease Rating Scale (UPDRS) score, depression, anxiety, constipation, olfactory dysfunction, sleep disruption, and other symptoms) were assessed with the relevant scales. The Kruskal-Wallis H test was used for comparison between groups, and Pearson/Spearman analysis was used for correlation analysis. RESULTS: The plasma ARSA concentrations were lower in the PD-CI group than in the PD-NCI group. The plasma α-syn levels in the PD-CI group were higher than those in the healthy control group, and the plasma ARSA levels were correlated with the Mini-Mental State Examination (MMSE scores) and Hoehn and Yahr (H-Y) stage. CONCLUSION: We used a quantitative assessment method to show that low plasma ARSA levels and high α-syn levels are related to cognitive impairment in PD patients. Plasma ARSA levels gradually decrease with PD progression.

Clinical significance of cyclin-dependent kinase inhibitor 2C expression in cancers: from small cell lung carcinoma to pan-cancers.

BACKGROUND: Cyclin-dependent kinase inhibitor 2C (CDKN2C) was identified to participate in the occurrence and development of multiple cancers; however, its roles in small cell lung carcinoma (SCLC) remain unclear. METHODS: Differential expression analysis of CDKN2C between SCLC and non-SCLC were performed based on 937 samples from multiple centers. The prognosis effects of CDKN2C in patients with SCLC were detected using both Kaplan-Meier curves and log-rank tests. Using receiver-operating characteristic curves, whether CDKN2C expression made it feasible to distinguish SCLC was determined. The potential mechanisms of CDKN2C in SCLC were investigated by gene ontology terms and signaling pathways (Kyoto Encyclopedia of Genes and Genomes). Based on 10,080 samples, a pan-cancer analysis was also performed to determine the roles of CDKN2C in multiple cancers. RESULTS: For the first time, upregulated CDKN2C expression was detected in SCLC samples at both the mRNA and protein levels (p of Wilcoxon rank-sum test < 0.05; standardized mean difference = 2.86 [95% CI 2.20-3.52]). Transcription factor FOXA1 expression may positively regulate CDKN2C expression levels in SCLC. High CDKN2C expression levels were related to the poor prognosis of patients with SCLC (hazard ratio > 1, p < 0.05) and showed pronounced effects for distinguishing SCLC from non-SCLC (sensitivity, specificity, and area under the curve ≥ 0.95). CDKN2C expression may play a role in the development of SCLC by affecting the cell cycle. Furthermore, the first pan-cancer analysis revealed the differential expression of CDKN2C in 16 cancers (breast invasive carcinoma, etc.) and its independent prognostic significance in nine cancers (e.g., adrenocortical carcinoma). CDKN2C expression was related to the immune microenvironment, suggesting its potential usefulness as a prognostic marker in immunotherapy. CONCLUSIONS: This study identified upregulated CDKN2C expression and its clinical significance in SCLC and other multiple cancers, suggesting its potential usefulness as a biomarker in treating and differentiating cancers.

Expression and prognostic significance of the P53-related DNA damage repair proteins checkpoint kinase 1 (CHK1) and growth arrest and DNA-damage-inducible 45 alpha (GADD45A) in human oral squamous cell carcinoma.

DNA damage repair is a key factor in the maintenance of cell genome stability, plays an important role in the regulation of tumour evolution, and can affect the prognosis of cancer patients. This study aimed to detect the protein expression of the DNA damage repair protein P53 and its upstream and downstream regulators, CHK1, GADD45A, and MDM2, in oral squamous cell carcinoma (OSCC), in order to analyse the association between the expression of these proteins and overall survival, and to assess their prognostic implications for OSCC patients. The expression of the above proteins was detected by immunohistochemistry in 80 human OSCC tissue samples and in non-cancerous tissue samples. Compared to that in the non-cancerous tissue, the expression of CHK1, GADD45A, and MDM2 in OSCC tissue was significantly increased. The protein expression of the tumour suppressor gene P53 was also increased. Patients with high CHK1 and MDM2 expression levels had a reduced survival time and a poor prognosis, whereas patients with high GADD45A expression levels had a good prognosis. Our results indicate that high CHK1 expression is an independent risk factor for poor OSCC prognosis, and that CHK1 may be a potential target for OSCC clinical treatment.

Evaluation of metastatic niches in distant organs after surgical removal of tumor-bearing lymph nodes.

BACKGROUND: Surgical removal of primary tumors can promote the incidence of tumor metastasis. However, molecular mechanisms underlying this process remain unclear. METHODS: We inoculated tumor cells expressing luciferase gene  into subiliac lymph node (SiLN) of the MXH10/Mo-lpr/lpr mice. The tumor-bearing SiLNs were surgically removed at a certain period of time after inoculation. RESULTS: In vivo bioluminescence imaging system and histological staining revealed metastasis in lung, proper axillary lymph node (PALN) and liver. The lung metastasis rate in SiLN removal groups was significantly higher than in the control group using Fisher exact test. Mann-Whitney U-test indicated that the luciferase-positive tumor cells in the lung and liver were significantly higher than in the control groups. The lung samples in SiLN removal groups had strong expression of lysine oxidase (LOX). Moreover, the number of CD11b+ cells in the lung and liver in the SiLN removal groups was significantly increased, which was positively correlated with LOX expression level. In addition, the condition of LOX and CD11b in liver was similar to lung. In the SiLN surgical removal groups, the matrix metalloproteinase (MMP)-2 and VEGFA expression in the lung tissues was significantly higher than in the control groups; the collagen fibers per area around the pulmonary vessels was quite significantly lower and negatively correlated with the expression of MMP-2 by Spearman's analysis. Our data indicated that the reticular fibers were deposited and disordered in the tumor tissues of the lungs in the removal groups, and the reticular fibers per area was higher than in the control groups. The tumor cells in the PALN of control groups were significantly higher than in the SiLN removal groups, and CD169+ and CD11c+ cells were also higher than in the SiLN removal groups. CONCLUSIONS: Altogether, surgical removal of the tumor-bearing lymph node promoted tumor metastasis through changing the niche in lung and liver. Treatment targeting the metastatic niche might be an effective strategy to prevent tumor metastasis, thereby possibly increasing the survival and reducing the incidence of metastasis in cancer patients.

A fast kernel extreme learning machine based on conjugate gradient.

Kernel extreme learning machine (KELM) introduces kernel leaning into extreme learning machine (ELM) in order to improve the generalization ability and stability. But the Penalty parameter in KELM is randomly set and it has a strong impact on the performance of KELM. A fast KELM combining the conjugate gradient method (CG-KELM) is presented in this paper. The CG-KELM computes the output weights of the neural network by the conjugate gradient iteration method. There is no penalty parameter to be set in CG-KELM. Therefore, the CG-KELM has good generalization ability and fast learning speed. The simulations in image restoration show that CG-KELM outperforms KELM. The CG-KELM provides a balanced method between KELM and ELM.

Conformational Change of Human Checkpoint Kinase 1 (Chk1) Induced by DNA Damage.

Phosphorylation of Chk1 by ataxia telangiectasia-mutated and Rad3-related (ATR) is critical for checkpoint activation upon DNA damage. However, how phosphorylation activates Chk1 remains unclear. Many studies suggest a conformational change model of Chk1 activation in which phosphorylation shifts Chk1 from a closed inactive conformation to an open active conformation during the DNA damage response. However, no structural study has been reported to support this Chk1 activation model. Here we used FRET and bimolecular fluorescence complementary techniques to show that Chk1 indeed maintains a closed conformation in the absence of DNA damage through an intramolecular interaction between a region (residues 31-87) at the N-terminal kinase domain and the distal C terminus. A highly conserved Leu-449 at the C terminus is important for this intramolecular interaction. We further showed that abolishing the intramolecular interaction by a Leu-449 to Arg mutation or inducing ATR-dependent Chk1 phosphorylation by DNA damage disrupts the closed conformation, leading to an open and activated conformation of Chk1. These data provide significant insight into the mechanisms of Chk1 activation during the DNA damage response.

Potentiation of hepatic stellate cell activation by extracellular ATP is dependent on P2X7R-mediated NLRP3 inflammasome activation.

Purinergic receptor P2x7 (P2x7R) is a key modulator of liver inflammation and fibrosis. The present study aimed to investigate the role of P2x7R in hepatic stellate cells activation. Lipopolysaccharide (LPS) or the conditioned medium (CM) from LPS-stimulated RAW 264.7 mouse macrophages was supplemented to human hepatic stellate cells, LX-2 for 24h and P2x7R selective antagonist A438079 (10µM) was supplemented to LX-2 cells 1h before LPS or CM stimulation. In addition LX-2 cells were primed with LPS for 4h and subsequently stimulated for 30min with 3mM of adenosine 5'-triphosphate (ATP). A438079 was supplemented to LX-2 cells 10min prior to ATP. Directly treated with LPS on LX-2 cells, mRNA expressions of interleukin (IL)-1ß, IL-18 and IL-6 were increased, as well as mRNA expressions of P2x7R, caspase-1, apoptosis-associated speck-like protein containing CARD (ASC) and NOD-like receptor family, pyrin domain containing 3 (NLRP3) mRNA. LPS also increased α-smooth muscle actin (α-SMA) and type I collagen mRNA expressions, as well as collagen deposition. Interestingly treatment of LX-2 cells with LPS-activated CM exhibited the greater increase of above factors than those in LX-2 cells directly treated with LPS. Pretreatment of A438079 on LX-2 cells stimulated by LPS or LPS-activated CM both suppressed IL-1ß mRNA expression. LPS combined with ATP dramatically increased protein synthesis and cleavage of IL-1ß and its mRNA level than those in HSC treated with LPS or ATP alone. Additionally LX-2 cells primed with LPS and subsequently stimulated for 30min with ATP greatly increased mRNA and protein expression of caspase-1, NLRP3 and P2x7R, as well as liver fibrosis markers, α-SMA and type I collagen. These events were remarkably suppressed by A438079 pretreatment. siRNA against P2x7R reduced protein expression of NLRP3 and α-SMA, and suppressed deposition and secretion of type I collagen. The involvement of P2X7R-mediated NLRP3 inflammasome activation in IL-1ß production of HSC might contribute to ECM deposition and suggests that blockade of the P2x7R-NLRP3 inflammasome axis represents a potential therapeutic target to liver fibrosis.

Pd-Catalyzed Arylperfluoroalkylation of Unactivated Olefins for the Synthesis of Heterocycles.

An efficient and highly practical palladium-catalyzed arylperfluoroalkylation of unactivated olefins is presented here. A variety of perfluoroalkylated heterocyclic derivatives can be obtained in high regioselectivity. The reaction proceeds mildly without the electronic activation of the aryl group and features high generality, low-cost fluoroalkylated sources and good functional-group compatibility.

Onset of bladder and motor symptoms in multiple system atrophy: differences according to phenotype.

PURPOSE: To compare the order of presentation of bladder and motor symptoms between multiple system atrophy phenotypes. METHODS: Medical records were retrospectively reviewed in 144 patients. RESULTS: Bladder symptoms occurred either before or within 12 months after onset of motor symptoms in significantly more patients with the cerebellar phenotype than the parkinsonian phenotype (80 vs. 53%, p = 0.003); similar results were observed for urinary incontinence (79 vs. 45%, p = 0.001). CONCLUSIONS: Urinary dysfunction is more likely to appear either before or shortly after motor symptoms in the cerebellar phenotype than in the parkinsonian phenotype.

Association of the COQ2 V393A variant with risk of multiple system atrophy in East Asians: a case-control study and meta-analysis of the literature.

Recent studies in Japan have associated multiple system atrophy (MSA), a neurodegenerative disease of uncertain etiology, with polymorphism in the COQ2 gene. This led us to explore whether the same polymorphism is associated with MSA in Han Chinese and more broadly in East Asians. We conducted a case-control study with 82 Han Chinese with probable MSA and 484 gender- and age-matched healthy subjects, genotyping them using the ligase detection reaction. The results were meta-analyzed together with data from four previous studies to gain a broader picture of possible disease associations in East Asian populations. The COQ2 variants M78V and R337X were not detected in our Han Chinese patients or controls; only the heterozygous V393A variant (CT genotype) was detected. The frequency of this genotype was significantly higher in patients (7.3%) than in controls (1.86%; OR 4.17, 95% CI 1.44-12.04, p = 0.004). Subgroup analysis among patients showed a significant association of V393A with MSA involving cerebellar signs (MSA-C; OR 4.59, 95% CI 1.36-15.48, p = 0.007), but not with MSA involving parkinsonism (MSA-P). Meta-analysis of our results in Han Chinese with data from case-control studies in Japan, Korea, mainland China and Taiwan showed a significant association of V393A with MSA (OR 2.05, 95% CI 1.29-3.25, p = 0.002), which subgroup analysis showed to be significant for MSA-C (OR 2.75, 95% CI 1.98-3.84, p < 0.001) but not for MSA-P (OR 1.25, 95% CI 0.64-2.46, p = 0.51). These findings provide evidence that the previously reported association of COQ2 V393A polymorphism with increased risk of MSA in Japanese also applies to Han Chinese, as well as more broadly to other East Asian populations. This association may be particularly strong for MSA-C.