[Sitagliptin inhibits lipopolysaccharide-induced inflammatory response in human gingival fibroblasts by blocking nuclear factor-κB signaling pathway].

OBJECTIVES: This study was performed to clarify the effects of sitagliptin on Porphyromonas gingivalis-lipopolysaccharide (LPS)-induced inflammatory response in human gingival fibroblasts (HGFs), explore the molecular mechanism of its roles, and provide a foundation for clinical therapeutics in periodontitis. METHODS: Healthy gingival samples were collected from the donors. HGFs were isolated with enzymic digestion method and identified. The effects of LPS and sitagliptin on cell viability were detected by cell-counting kit-8 (CCK8). The mRNA levels of inflammatory cytokines, namely, interleukin (IL)-6, IL-8, C-C motif ligand 2 (CCL2), and superoxide dismutase 2 (SOD2), were evaluated by quantity real-time polymerase chain reaction (qRT-PCR) and enzyme-linked immune sorbent assay (ELISA) was used to measure the secretion protein levels of IL-6, IL-8, and CCL2. Western blot analysis was used to further investigate the activation of nuclear factor (NF)-κB signaling pathway. The effect of NF-κB pathway inhibitor BAY11-7082 on LPS-induced HGF inflammatory cytokines at the gene level was verified by qRT-PCR. RESULTS: Low concentrations of sitagliptin (0.1, 0.25, and 0.5 µmol·L-1) did not affect HGF growth in 24 and 48 h, whereas high concentrations of sitagliptin (5-1 000 µmol·L-1) significantly inhibited cell proliferation. Sitagliptin suppressed 5 µg·mL-1 of LPS-induced IL-6, IL-8, CCL2, and SOD2 gene expression levels in HGF in a concentration-dependent manner. Furthermore, sitagliptin significantly decreased the elevated secretion of IL-6, IL-8, and CCL2 protein induced by LPS. Western blot analysis showed that 0.5 µmol·L-1 of sitagliptin significantly inhibited LPS-induced NF-κB signaling pathway activation. Results of qRT-PCR analysis indicated that 0.5 µmol·L-1 of sitagliptin and 5 µmol·L-1 of BAY11-7082 significantly inhibited LPS-induced IL-6, IL-8, CCL2, and SOD2 gene expressions. CONCLUSIONS: Sitagliptin could significantly inhibit LPS-induced HGF inflammatory response by blocking the NF-κB signaling pathway activation.

Gait Characteristics and Brain Activity in Parkinson's Disease with Concomitant Postural Abnormalities.

To explore the underlying pathogenic mechanism of Parkinson's disease (PD) with concomitant postural abnormalities (PDPA) through the relationship between its gait and brain function characteristics. PD patients from the neurology outpatient clinic at Ruijin Hospital were recruited and grouped according to whether postural abnormalities (including camptocormia and Pisa syndrome) were present. PD-related scale assessments, three-dimensional gait tests and brain resting-state functional magnetic imaging were performed and analyzed. The gait characteristics independently associated with PDPA were decreased pelvic obliquity angle and progressive downward movement of the center of mass during walking. PDPA features included decreased functional connectivity between the left insula and bilateral supplementary motor area, which was significantly correlated with reduced Berg Balance Scale scores. Functional connectivity between the right insula and bilateral middle frontal gyrus was decreased and significantly correlated with a decreased pelvic obliquity angle and poor performance on the Timed Up and Go test. Moreover, through diffusion tensor imaging analysis, the average fractional anisotropy value of the fibers connecting the left insula and left supplementary motor area was shown to be decreased in PDPA. There is decreased functional connectivity among the insula, supplementary motor area and middle frontal gyrus with structural abnormalities between the left insula and the left supplementary motor area; these changes in brain connectivity are probably among the causes of gait dysfunction in PDPA and provide some clues regarding the pathogenic mechanisms of PDPA.

DJ-1 Inhibits α-Synuclein Aggregation by Regulating Chaperone-Mediated Autophagy.

α-Synuclein misfolding and aggregation play an important role in the pathogenesis of Parkinson's disease (PD). Loss of function and mutation of the PARK7/DJ-1 gene cause early-onset familial PD. DJ-1 can inhibit α-synuclein aggregation, and may function at an early step in the aggregation process. Soluble wild-type (WT) α-synuclein is mainly degraded by chaperone-mediated autophagy (CMA), and impairment of CMA is closely related to the pathogenesis of PD. Here, we investigated whether DJ-1 could reduce α-synuclein accumulation and aggregation by CMA. DJ-1 knockout mice and DJ-1 siRNA knockdown SH-SY5Y cells were used to investigate the potential mechanisms underlying the relationship between DJ-1 deficiency and α-synuclein aggregation. First, we confirmed that DJ-1 deficiency increased the accumulation and aggregation of α-synuclein in both SH-SY5Y cells and PD animal models, and overexpression of DJ-1 in vitro effectively decreased α-synuclein levels. α-Synuclein overexpression activated CMA by elevating the levels of lysosome-associated membrane protein type-2A (LAMP2A), but DJ-1 deficiency suppressed upregulation of LAMP2A. DJ-1 deficiency downregulated the level of lysosomal 70 kDa heat-shock cognate protein (HSC70) but not the levels of that in homogenates. Further studies showed that DJ-1 deficiency accelerated the degradation of LAMP2A in lysosomes, leading to the aggregation of α-synuclein. Our study suggests that DJ-1 deficiency aggravates α-synuclein aggregation by inhibiting the activation of CMA and provides further evidence of the molecular interaction between PD-related proteins via the CMA pathway.

Association of rapid eye movement sleep behavior disorder with sleep-disordered breathing in Parkinson's disease.

OBJECTIVE: Rapid eye movement (REM) sleep behavior disorder (RBD) and sleep-disordered breathing (SDB) are two major sleep disturbances observed in patients with Parkinson's disease (PD). However, prior studies exploring the clinical correlations between RBD and SDB in PD have been limited. We aimed to investigate the relationship between RBD and SDB in PD using a case-control study. METHODS: A total of 46 PD patients with Hoehn-Yahr stages ranging from 1 to 3 participated in the present study. Participants underwent polysomnography to diagnose the presence of RBD and SDB, and were classified into groups, accordingly. SDB was defined as an apnea-hypopnea index greater than 5. Comparison of clinical and sleep-respiratory parameters was performed among them. RESULTS: SDB was more frequent in the RBD group than in the non-RBD group (51.4% vs 9.1%, p = 0.016). PD patients with RBD had significantly reduced mean SaO2 and more severe sleep apnea-related parameters during total sleep and non-REM sleep in comparison with non-RBD PD patients. However, there were no differences on the REM-related apnea/hypopnea variables between participants with and without RBD (p > 0.05). Both the frequency of RBD and RBD screening questionnaire (RBDSQ) scores were higher in the participants with SDB than in the participants without SDB (p <0.05). Furthermore, a significant negative correlation was found between RBDSQ and mean SaO2 in all participants. CONCLUSIONS: In PD patients, SDB is more frequent and more severe in patients with RBD than in patients without, and RBD increases the risk of hypoxemia during sleep.

Transcranial sonography of the substantia nigra and its correlation with DAT-SPECT in the diagnosis of Parkinson's disease.

INTRODUCTIONS: Transcranial sonography (TCS) of the substantia nigra is a new and promising method to diagnose Parkinson's disease (PD) but its effectiveness is controversial. METHODS: All 55 PD patients involved in the study underwent single photon emission computed tomography (SPECT) imaging using the labeled dopamine transporter radiotracer (99m)Tc-TRODAT-1 to assess nigrostriatal dopaminergic function. The echogenicity of the substantia nigra was measured by TCS in all patients who received DAT-SPECT scanning. Finally, statistical analysis was carried out to determine the diagnostic accuracy of TCS as well as its correlation with (99m)Tc-TRODAT-1 SPECT, its positive predictive value (PPV), and negative predictive value (NPV). RESULTS: Contralateral striatal (99m)Tc-TRODAT-1 uptake was significantly reduced compared to ipsilateral striatal uptake, and had a negative correlation with UPDRS-Ⅲ(r = -0.334, p = 0.013), disease duration (r = -0.393, p = 0.003) and H-Y stage (r = -0.330, p = 0.014). After TCS measurement, the contralateral SN echogenic area was similar to the ipsilateral SN echogenic area (27.77 ± 13.19 vs 25.98 ± 11.94 mm(2), p = 0.402, n = 24). No correlation was identified between TCS and UPDRS-Ⅲ (r = 0.383, p = 0.065), disease duration (r = 0.371, p = 0.075) or H-Y stage (r = 0.259, p = 0.222). The sensitivity and specificity of SN TCS for the diagnosis of PD were calculated as 64.70% and 60% according to DAT-SPECT, respectively, while the positive predictive value and negative predictive value was calculated as 91.67% and 20%, respectively. CONCLUSIONS: Compared to DAT-SPECT, TCS is a non-radioactive and convenient procedure to perform. In our investigation, TCS had no correlation with DAT-SPECT. However, the high positive predictive value of TCS highlights its possible utility as a routine diagnostic test.

Hyposmia correlates with SNCA variant and non-motor symptoms in Chinese patients with Parkinson's disease.

BACKGROUND: Hyposmia plays an important role in the early and differential diagnosis of Parkinson's disease (PD); however its underlying mechanism is poorly understood. The aim of the present study is to explore the clinical phenotypic and genotypic correlation of hyposmia in Chinese PD patients. METHODS: Olfactory function evaluated by 16-item odor identification test from Sniffin' Sticks (SS-16) of 218 Chinese Han PD patients and 110 healthy controls was compared. 186 patients also had the genetic information of two positive GWAS-linked SNCA loci (rs11931074, rs894278) previously validated in our center. The associations of hyposmia with SNCA variants and disease phenotypic characteristics including motor symptoms (UPDRS motor score) and other common NMSs (clinical possible RBD-cpRBD, depression and chronic constipation) were analyzed. RESULTS: Nearly 39.9% (n = 87) of PD reported subjective complaints of hyposmia, while 60.1% (n = 131) patients had objective hyposmia (SS-16 < 8.3). Patients with hyposmia had older age (p = 0.001), later onset age (p = 0.020), higher SCOPA-AUT scores (p = 0.011), higher percentage of chronic constipation (p = 0.001) and cpRBD (p = 0.003). Binary logistic regression analysis revealed that ageing (OR = 1.058; 95%CI: 1.012-1.106; p = 0.013), chronic constipation (OR = 2.072; 95% CI: 1.157-3.710; p = 0.014) and cpRBD (OR = 2.234; 95% CI: 1.040-4.797; p = 0.039) were independent influential factors of hyposmia in Chinese PD patients. Subgroup analysis of patients with both clinical and genetic results demonstrated that after adjusting for age, sex, chronic constipation and cpRBD, rs11931074 TT genotype may increase the risk of hyposmia in PD (OR = 3.24 95% CI = 1.23-8.51, p = 0.017) compared to GG genotype via an additive model. CONCLUSIONS: Age, cpRBD, chronic constipation and SNCA rs11931074 may correlate with hyposmia in Chinese PD patients.

Small peptide inhibitor of JNK3 protects dopaminergic neurons from MPTP induced injury via inhibiting the ASK1-JNK3 signaling pathway.

INTRODUCTION AND AIMS: The ASK1-JNK3 signaling pathway plays a pivotal role in the pathogenesis of Parkinson's disease (PD). The specific binding of ß-arrestin2 to JNK3 is essential for activation of the ASK1-JNK3 cascade, representing a potential therapeutic target for preventing dopaminergic neuronal death in PD. The aim of this study was to identify a novel strategy for the prevention of dopaminergic neuronal death in PD. METHODS: Based on the specific binding of ß-arrestin2 to JNK3, a 21-amino-acid fusion peptide, termed JNK3-N-Tat, was synthesized. We evaluated the ability of this peptide to inhibit the binding of ß-arrestin2 to its target domain in JNK3 in vitro and in vivo. RESULTS: The JNK3-N-Tat peptide inhibited activation of the ASK1-JNK3 cascade by disrupting the interaction between ß-arrestin2 and JNK3. JNK3-N-Tat exerted beneficial effects through pathways downstream of JNK3 and improved mitochondrial function, resulting in attenuated MPP+/MPTP-induced damage. JNK3-N-Tat protected mesencephalic dopaminergic neurons against MPTP-induced toxicity. CONCLUSIONS: JNK3-N-Tat, a JNK3-inhibitory peptide, protects dopaminergic neurons against MPP+/MPTP-induced injury by inhibiting the ASK1-JNK3 signaling pathway.

Salivary DJ-1 could be an indicator of Parkinson's disease progression.

OBJECTIVE: The goal of the current investigation was to explore whether salivary DJ-1 could be a potential biomarker for monitoring disease progression in Parkinson's disease (PD) by evaluating the association between salivary DJ-1 concentrations and nigrostriatal dopaminergic function. METHODS: First, in 74 patients with PD and 12 age-matched normal controls, single photon emission computed tomography (SPECT) imaging with labeled dopamine transporters (DAT) ((99m)Tc-TRODAT-1), which has been used for measuring DAT density in PD was prformed. Then, the DJ-1 level in their saliva was analyzed by quantitative and sensitive Luminex assay and compared to caudate or putamen DAT density. Finally, based on the above, our cross-section study was carried out in 376 research volunteers (285 patients with PD and 91 healthy controls) to measure salivary DJ-1 level. RESULTS: From our analysis, we found a correlation between salivary concentration of DJ-1 and putamen nucleus uptake of (99m)Tc-TRODAT-1 in the PD group. Although salivary DJ-1 levels were not affected by UPDRS scores, gender, age, and pharmacotherapy, DJ-1 levels in H&Y 4 stage of PD were higher than those in H&Y 1-3 stage as well as those in healthy controls. Salivary DJ-1 also decreased significantly in mixed type PD patients compared to the tremor-dominant type (TDT) and akinetic-rigid dominant type (ARDT) PD patients. CONCLUSIONS: According to the investigation in a large cohort, we reported for the first time the prognostic potential of the salivary DJ-1 as a biomarker for evaluating nigrostriatal dopaminergic function in PD.

Using gastrocnemius sEMG and plasma α-synuclein for the prediction of freezing of gait in Parkinson's disease patients.

Freezing of gait (FOG) is a complicated gait disturbance in Parkinson's disease (PD) and a relevant subclinical predictor algorithm is lacking. The main purpose of this study is to explore the potential value of surface electromyograph (sEMG) and plasma α-synuclein levels as predictors of the FOG seen in PD. 21 PD patients and 15 normal controls were recruited. Motor function was evaluated using the Unified Parkinson's Disease Rating Scale (UPDRS) and Freezing of gait questionnaire (FOG-Q). Simultaneously, gait analysis was also performed using VICON capture system in PD patients and sEMG data was recorded as well. Total plasma α-synuclein was quantitatively assessed by Luminex assay in all participants. Recruited PD patients were classified into two groups: PD patients with FOG (PD+FOG) and without FOG (PD-FOG), based on clinical manifestation, the results of the FOG-Q and VICON capture system. PD+FOG patients displayed higher FOG-Q scores, decreased walking speed, smaller step length, smaller stride length and prolonged double support time compared to the PD-FOG in the gait trial. sEMG data indicated that gastrocnemius activity in PD+FOG patients was significantly reduced compared to PD-FOG patients. In addition, plasma α-synuclein levels were significantly decreased in the PD+FOG group compared to control group; however, no significant difference was found between the PD+FOG and PD-FOG groups. Our study revealed that gastrocnemius sEMG could be used to evaluate freezing gait in PD patients, while plasma α-synuclein might discriminate freezing of gait in PD patients from normal control, though no difference was found between the PD+FOG and PD-FOG groups.

CT findings of a gastrointestinal stromal tumor arising from small bowel.

Gastrointestinal stromal tumors (GISTs), the most common mesenchymal tumors of the gastrointestinal tract, arise from interstitial cells of Cajal. Most of them are composed of spindle cells and mimic leiomyoma morphologically. Nearly all GISTs demonstrate positive staining for CD-117 at immunohistochemistry examination, which helps to distinguish them from true leiomyomas. We describe the CT findings of a GIST of small bowel. At plain CT scan, the tumor was of homogeneous iso-attenuation. After intravenous administration of contrast materials, a well-defined exophytic growth mass with avid homogeneous enhancement was demonstrated. The mucosal layer over the mass was intact and fat plane between the mass and adjacent GI wall was preserved. A diagnosis of GIST was suggested and was then confirmed by positive staining for CD-117.

A hole in the skull: CT manifestations of a solitary plasmacytoma in skull.

Plasmacytoma can present as multiple myeloma, solitary plasmacytoma of the bone (SPB), or extramedullary plasmacytoma. SPB is a rare entity that composes of malignant plasma cells and involves the bone to form only one or two lesions without evidence of disease dissemination. It accounts for only 4% of malignant plasma cell tumors. We report a case of SPB in the skull in a 59-year-old male. CT scan revealed an 8 cm ×9 cm osteolytic lesion on the scalp of skull with a well demarcated margin. A cake-like mass was revealed at CT soft tissue window. The mass was completely excised and histological examination revealed plasmacytoma. The diagnosis of SPB was established after ruling out multiple myeloma.

Cognitive impairment and the associated risk factors among the elderly in the Shanghai urban area: a pilot study from China.

OBJECTIVES: Our study aimed to investigate the prevalence of cognitive impairment(CI) and the associated risk factors among elderly people in Shanghai urban area, China. METHODS: A population-based survey was conducted among people aged 55 years or older in urban areas of Shanghai. Face-to-face interviews were carried out to collect information including demographic characteristics, medical history, and medication use, etc. The validated Chinese version of the Mini-Mental State Examination(MMSE) was used to screen subjects with CI, and the criteria of CI were adjusted for education levels. RESULTS: A total of 3,176 home-living residents (≥55 years old) were included in the study. Among them, 266 people (102 men and 164 women) were identified as cognition impaired, with a prevalence of 8.38% (266/3,176, 95% CI: (8.26, 8.49)) for both genders, 9.21% (102/1,107,95% CI: (9.18, 9.33)) for men and 7.93% (164/2,069, 95% CI: (7.80, 8.09)) for women, respectively. Furthermore, we found that several significant risk factors, including social factors(education, number of children, marriage status, and family structure), physiological factors (age, blood glucose level, and obesity), factors on living styles(physical exercise, diet & chronic diseases), and genetic factor(ApoE), associated with CI onset. CONCLUSIONS: This study confirms the high prevalence of CI among the elderly population in the Shanghai urban in China, similar to previous epidemiologic studies in Western countries. The putative risk factors associated with CI merit further investigated.

Extracellular signal-regulated kinase is involved in alpha-synuclein-induced mitochondrial dynamic disorders by regulating dynamin-like protein 1.

Compounding evidence suggests that alpha-synuclein (SNCA) plays an important role in the pathogenesis of Parkinson's disease (PD) by inducing neurotoxicity. Mitochondria are highly dynamic organelles that undergo fusion and fission processes, the imbalance of which has been viewed as a key trigger for PD. However, the underlying relationship between SNCA and mitochondrial dynamics remains unclear. This study demonstrated that SNCA overexpression not only altered mitochondrial morphology, but also significantly increased the translocation of mitochondrial fission protein dynamin-like protein 1 (DLP1). To further investigate the mechanism of SNCA's effect on mitochondrial dynamics, the proteomic technique, stable isotope labeling of amino acid in cell cultures (SILAC), was used. The extracellular signal-regulated kinase (ERK) was confirmed to be involved in the regulation of DLP1 and SNCA-mediated neurotoxicity. Finally, additional results demonstrated that SNCA inducing both mitochondrial dynamic disorders and neurotoxicity could be ameliorated by curcumin through ERK inhibition, which implied that the agent could be used to prevent and treat PD in the future.

Application of odor identification test in Parkinson's disease in China: a matched case-control study.

As one of the most common non-motor symptoms in Parkinson's disease (PD), hyposmia is of great importance in establishing the early diagnosis of PD. To date, there are still no studies on the application of the 16-item odor identification test from Sniffin' Sticks (SS-16) in Chinese patients with PD. The aim of this study was to investigate the validity of SS-16 in Chinese PD patients (n=110) compared with age and gender matched controls (n=110), and to explore the associated factors with olfactory function in PD patients. The 16 odors in the original odor identification test were retained but some alternative descriptions were developed before applications. Mean identification scores in patients were significantly lower than in controls (7.3 ± 2.8 VS. 11.6 ± 2.0 P<0.01), with 66.4% of patients had an impairment of odor identification as evaluated by 95% confidential interval of the identification score of the control group. Receiver operating characteristic curves revealed 86% sensitivity and 81% specificity in separating PD and healthy controls with a cut-off value of 9.5. Multiple linear regression analysis revealed that autonomic dysfunction was a significant influential factor of odor identification scores in patients with PD. In conclusion, SS-16 provides a valid instrument for olfactory assessment in Chinese PD patients, and hyposmia may correlate with autonomic dysfunction in patients with PD.

PPARgamma agonist curcumin reduces the amyloid-beta-stimulated inflammatory responses in primary astrocytes.

Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder. Accumulating data indicate that astrocytes play an important role in the neuroinflammation related to the pathogenesis of AD. It has been shown that microglia and astrocytes are activated in AD brain and amyloid-beta (Abeta) can increase the expression of cyclooxygenase 2 (COX-2), interleukin-1, and interleukin-6. Suppressing the inflammatory response caused by activated astrocytes may help to inhibit the development of AD. Curcumin is a major constituent of the yellow curry spice turmeric and proved to be a potential anti-inflammatory drug in arthritis and colitis. There is a low age-adjusted prevalence of AD in India, a country where turmeric powder is commonly used as a culinary compound. Curcumin has been shown to suppress activated astroglia in amyloid-beta protein precursor transgenic mice. The real mechanism by which curcumin inhibits activated astroglia is poorly understood. Here we report that the expression of COX-2 and glial fibrillary acidic protein were enhanced and that of peroxisome proliferator-activated receptor gamma (PPARgamma) was decreased in Abeta(25-35)-treated astrocytes. In line with these results, nuclear factor-kappaB translocation was increased in the presence of Abeta. All these can be reversed by the pretreatment of curcumin. Furthermore, GW9662, a PPARgamma antagonist, can abolish the anti-inflammatory effect of curcumin. These results show that curcumin might act as a PPARgamma agonist to inhibit the inflammation in Abeta-treated astrocytes.