Ago2/CAV1 interaction potentiates metastasis via controlling Ago2 localization and miRNA action.

Ago2 differentially regulates oncogenic and tumor-suppressive miRNAs in cancer cells. This discrepancy suggests a secondary event regulating Ago2/miRNA action in a context-dependent manner. We show here that a positive charge of Ago2 K212, that is preserved by SIR2-mediated Ago2 deacetylation in cancer cells, is responsible for the direct interaction between Ago2 and Caveolin-1 (CAV1). Through this interaction, CAV1 sequesters Ago2 on the plasma membranes and regulates miRNA-mediated translational repression in a compartment-dependent manner. Ago2/CAV1 interaction plays a role in miRNA-mediated mRNA suppression and in miRNA release via extracellular vesicles (EVs) from tumors into the circulation, which can be used as a biomarker of tumor progression. Increased Ago2/CAV1 interaction with tumor progression promotes aggressive cancer behaviors, including metastasis. Ago2/CAV1 interaction acts as a secondary event in miRNA-mediated suppression and increases the complexity of miRNA actions in cancer.

Erythropoietin relieves neuronal apoptosis in epilepsy rats via TGF-ß/Smad signaling pathway.

This study aimed to investigate the influence of recombinant human erythropoietin (rHuEPO) on pentylenetetrazol (PTZ)-induced neuronal apoptosis in epilepsy rats, and to explore the signaling pathways related to the action. Healthy Sprague-Dawley rats aged 8 weeks old were randomly divided into 5 groups, namely, control group, PTZ model group, PTZ + rHuEPO intervention group, PTZ + SB431542 + rHuEPO intervention group and PTZ + SB431542 (TGF-ß/Smad inhibitor) intervention group. The expressions of apoptotic proteins [tumor necrosis factor receptor 1 (TNFR1) and caspase-3] and the transforming growth factor-beta (TGF-ß)/Smad signaling pathway-related proteins [phosphorylated smad3 (p-smad3) and TGF-ß1] in the brain tissues were determined via Western blotting (WB). Epilepsy was successfully induced by PTZ in the rats. The results of the TUNEL assay showed that the intervention with rHuEPO could remarkably reduce the number of PTZ-induced apoptotic neurons in the hippocampus, while SB431542 inhibitor could attenuate the protective effect of rHuEPO against neuronal apoptosis (P<0.05). In addition, the intraperitoneal injection of 50 µg/kg rHuEPO could activate the TGF-ß/Smad signaling pathway, markedly up-regulate the expressions of TGF-ß1 and p-smad3 (P<0.05), down-regulate the expressions of apoptotic proteins TNFR1 and caspase-3 (P<0.01) and reduce neuronal apoptosis. Moreover, SB431542 was able to notably repress the protective effect of rHuEPO against neuronal apoptosis, and down-regulate the expressions of p-smad3 and TGF-ß1 (P<0.01). In conclusion, the inhibitory effect of rHuEPO on nerve cell apoptosis in epilepsy rats may be realized by activating the TGF-ß/Smad signaling pathway, thus relieving neuronal apoptosis and ameliorating the symptoms of epilepsy.

Increased rapid eye movement density in Chinese patients with Parkinson's disease and RBD.

OBJECTIVE: Impaired rapid eye movement sleep is common among patients with Parkinson's disease (PD). However, information on rapid eye movement density (REM) among PD patients is currently lacking. The current study sought to characterize REM density in PD patients and to examine the associations between REM density sleep parameters and clinical manifestations. PARTICIPANTS AND METHODS: We retrospectively recruited 172 PD patients. All participants were assessed with a two-night polysomnography, and REM density was calculated. Clinical assessments were completed in PD patients before polysomnography. RESULTS: Rapid eye movement sleep behavior disorder (RBD) was observed in 93 patients (54.1%). The disease duration, UPDRS part III score, Hoehn and Yahr (H-Y) stage, and HAMA, HAMD, PDQ-39 scores, and REM density in the Parkinson's disease patients with rapid eye movement sleep behavior disorder (RBD) were significantly higher than in the patients without RBD (P < 0.05). However, NREM sleep stage 3 time (N3 time) and percentage of N3 time of total sleep time (N3%) were significantly lower in the RBD patients than in the patients without RBD (P < 0.05). The forward binary logistic regression model showed that REM density, UPDRS-III score, and N3 sleep time were associated with RBD in the PD patients. CONCLUSIONS: Our results confirm the high prevalence of RBD in patients with PD. Increased REM density was the main risk factor of RBD.

Leptin protects brain from ischemia/reperfusion-induced infarction by stabilizing the blood-brain barrier to block brain infiltration by the blood-borne neutrophils.

The cellular and molecular mechanisms underlying leptin-mediated brain protection against cerebral ischemia were investigated at the blood-brain barrier (BBB) and neutrophil level. Through the ischemia/reperfusion (I/R) animal model, we found that leptin expression level was significantly decreased in ischemic hemisphere. Brain injection with leptin (15 µg/kg, intracisternally) could block the I/R-increased BBB permeability, activation of matrix metallopeptidase 9 (MMP-9) and brain infiltration of blood-borne neutrophils to reduce the infarct volume of ischemic brain. The brain expression level of tight junction protein ZO-1 as well as number and motility of neutrophils in blood was all increased by the same injection, indicating BBB stability (rather than reduction in neutrophils) played a major role in the leptin-inhibited brain infiltration of neutrophils. Leptin-mediated protection of BBB was further confirmed in vitro, through a BBB cellular model under the in vitro ischemic condition (G/R: glucose-oxygen-serum deprivation followed by GOS restoration). The results showed that leptin again could block the G/R-increased neutrophil adherence to EC layer as well as BBB permeability, likely by stimulating the endothelial expression of ZO-1 and VE-Cadherin. The study has demonstrated that leptin could protect ischemic brain via multiple ways (other than neuronal protection), by inhibiting the BBB permeability, brain infiltration of the blood-borne neutrophils and neutrophil adherence to vascular ECs. The role of leptin in vascular biology of stroke could further support its therapeutic potential in other neurodegenerative diseases, associated with BBB disorder.

Melatonin induces cell cycle arrest and suppresses tumor invasion in urinary bladder urothelial carcinoma.

Urinary bladder urothelial carcinoma (UBUC) encompasses about 90% of all bladder cancer cases, and the mainstream treatment is the transurethral resection of the bladder tumor followed by intravesical instillation. High rates of mortality, recurrence, and progression in bladder cancer have stimulated the search for alternative adjuvant therapies. The aim of this study was to investigate the potential of melatonin as adjuvant therapy in bladder cancer. Cell viability and clonogenic ability were assessed by an MTT assay and colony formation. Cell cycle and apoptosis analysis were performed by flow cytometry and Hoechst 33342 staining, while cell metastasis capacity was measured by wound healing and transwell assays. Potential mechanisms were investigated by an oncology array and verified via western blotting. The melatonin treatment significantly reduced T24 and UMUC3 bladder cancer cell proliferation and clonogenic ability. G1 arrest and sub-G1 accumulation in the T24 and UMUC3 cells led to cell proliferation suppression and cell death, and Hoechst 33342 staining further verified the apoptosis induction directly by melatonin. Moreover, melatonin weakened cell motility and invasiveness. Based on the oncology array results, we demonstrated that melatonin exerts its anti-cancer effect by down-regulating the HIF-1α and NF-κB pathways and downstream pathways, including Bcl-2, leading to cell cycle arrest and apoptosis induction in the UBUC cells. Overall, these findings support the potential of melatonin as adjuvant therapy in bladder cancer.

Topical Prevention of Radiation Dermatitis in Breast Cancer Patients: A Network Meta-analysis of Randomized Controlled Trials.

BACKGROUND/AIM: Radiation dermatitis is a common complication of radiation therapy in breast cancer patients. Severe dermatitis may alter treatment schedules and clinical outcomes. The topical prevention strategy is the widely used option to prevent radiation dermatitis. However, the comparison between the current topical prevention strategies is insufficient. Therefore, this study aimed to investigate the topical prevention efficacy of radiation dermatitis in patients with breast cancer through a network meta-analysis. PATIENTS AND METHODS: This study followed The Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Network Meta-Analyses guidelines. A random effects model was used to compare different treatments. The treatment modality ranking was evaluated using the P-score. I2 and Cochran's Q test were used to evaluate the heterogeneity among studies. RESULTS: Forty-five studies were analyzed in this systematic review. A total of 19 studies were finally included in this meta-analysis for grade 3 or higher radiation dermatitis, which included 18 treatment arms and 2,288 patients. The forest plot showed that none of the identified regimens were superior to standard care. CONCLUSION: A more effective regimen than standard care for the prevention of grade 3 or higher radiation dermatitis in breast cancer patients was not identified. Our network meta-analysis showed that current topical prevention strategies are similarly efficacious. However, since preventing severe radiation dermatitis is an important clinical challenge, further trials should be conducted to address this issue.

Association between Blood Manganese Levels and Visceral Adipose Tissue in the United States: A Population-Based Study.

Background: Manganese (Mn) is an essential trace element with a narrow toxic margin for human health. The association between Mn exposure and adverse visceral adipose tissue (VAT) accumulation is unclear. Objective: This study aimed to estimate the associations of blood Mn levels with VAT mass or visceral obesity in the general population in the United States. Method: This cross-sectional study included data of 7297 individuals released by National Health and Nutrition Examination Survey (NHANES). VAT was quantified with dual-energy X-ray absorptiometry, and blood Mn was measured using inductively coupled plasma mass spectrometry. The generalized linear model and generalized additive model (GAM) were applied to estimate the linear and non-linear associations between Mn levels and VAT mass, respectively. Logistic regression was used to estimate the associations between blood Mn levels and the risk of visceral obesity. Results: Fully adjusted generalized linear regression revealed that individuals in the higher quantile of Mn had increased VAT mass compared with those in the lower quantile (ß per quantile change = 0.025; 95% CI of 0.017, 0.033; p < 0.001). Positive associations were also observed in males and females (males: ß per quantile change = 0.012, 95% CI of 0.002, 0.022 (p = 0.020); female: ß per quantile change = 0.036; 95% CI of 0.023, 0.048 (p < 0.001)). The GAM illustrated that the non-linear associations between blood Mn levels and VAT mass were in U-shape patterns (effective degree of freedom >1 in total participants, males, and females). A stratified analysis found significant interactions between Mn and the family income-to-poverty ratio (PIR) in males, with stronger associations in males with a PIR < 1.3 (ß = 0.109; 95% CI of 0.048, 0.170). Additional analyses revealed that individuals in the highest quantile of Mn had a 39% higher risk of visceral obesity (OR = 1.39; 95% CI of 1.15−1.69; p < 0.001). Conclusions: Higher blood Mn levels were positively associated with increased VAT mass and visceral obesity risk. The adverse VAT phenotype associated with excessive blood Mn levels should be further investigated.

Depression and associated factors in nondemented Chinese patients with Parkinson's disease.

OBJECTIVES: Depression is more common in Parkinson's disease (PD) than other chronic and disabling disorders. This study aimed to estimate the prevalence and identify potential risk factors influencing depression in 519 consecutive nondemented Chinese PD patients. PATIENTS AND METHODS: Depression was assessed using the Hamilton Rating Scale for Depression (HAMD), PD severity was assessed using Hoehn and Yahr (H&Y) staging, motor symptoms were measured with the Unified PD Rating Scale (UPDRS) part III, and the Non-Motor Symptoms Questionnaire (NMS-Quest) was used to evaluate the global non-motor symptoms (NMS). The PD Sleep Scale (PDSS), and Mini-Mental State Examination (MMSE) were also administered. RESULTS: The mean total HAMD score was 12.60±9.29, and the most prevalent depressive domain was retardation (84.4%). There were significant correlations between the total HAMD score and sex, PD-duration, UPDRS-III, H&Y stage, PD-NMS, PDSS, and MMSE. Non-motor symptoms, poor sleep quality, younger age, and cognitive dysfunction are independent predictors of depression. Among these, non-motor symptoms or sleep disturbances are the most powerful predictors of each depressive domain. We observed a significantly higher total HAMD score and domains of anxiety/somatization, mental disorder, and hopelessness in female patients. However, there was no difference in HAMD total scores and HAMD sub-items between young-onset PD and late-onset PD patients when adjusted by potential confounding factors. CONCLUSIONS: The prevalence rate of depression among nondemented Chinese PD patients is high and similar to those reported in previous studies. The presence of depression in PD patients should be routinely assessed in clinical practice.

Prevalence and risk factors for visual hallucinations in Chinese patients with Parkinson's disease.

BACKGROUND AND PURPOSE: Parkinson's disease (PD) patients frequently present visual hallucinations (VHs)·The determinants of VHs in Chinese PD patients remain largely unknown. The aim of this study was to illuminate the prevalence and clinical correlates of VHs in the Chinese population with PD. METHODS: A total of 371 consecutive, idiopathic PD patients were recruited into the study. Patients were categorized as hallucinators and nonhallucinators according to Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS). RESULTS: VHs were observed in 72 (19.4%) patients. Among them, 26.4% of the hallucinators experienced minor hallucinations, and 73.6% had complex visual hallucinations. The age, disease duration, percentage of patients using dopamine agonists, UPDRS part III, Hoehn and Yahr (H-Y) stage, and Non-Motor Symptoms Questionnaire (NMS-Quest) score in hallucinators were significantly greater than in nonhallucinators (P<0.05). The Montreal Cognitive Assessment (MOCA) and PD Sleep Scale (PDSS) scores in nonhallucinators were significantly higher than in hallucinators (P<0.05). The Hamilton Depression Scale (HAMD) and Hamilton Anxiety Scale (HAMA) scores were not different between the hallucinators and nonhallucinators. The forward binary logistic regression model showed that disease duration, dopamine agonist use, sleep quality, and cognition were associated with VHs in PD patients. CONCLUSIONS: Our results confirm the high prevalence of VHs in patients with PD. The VHs are associated with duration, dopamine agonist use, sleep quality, and cognition, and should trigger further inquiry by neurologists.

Resting State fMRI Reveals Increased Subthalamic Nucleus and Sensorimotor Cortex Connectivity in Patients with Parkinson's Disease under Medication.

Functional connectivity (FC) between the subthalamic nucleus (STN) and the sensorimotor cortex is increased in off-medication patients with Parkinson's disease (PD). However, the status of FC between STN and sensorimotor cortex in on-medication PD patients remains unclear. In this study, resting state functional magnetic resonance imaging was employed on 31 patients with PD under medication and 31 healthy controls. Two-sample t-test was used to study the change in FC pattern of the STN, the FC strength of the bilateral STN was correlated with overall motor symptoms, while unilateral STN was correlated with offside motor symptoms. Both bilateral and right STN showed increased FC with the right sensorimotor cortex, whereas only right STN FC was correlated with left-body rigidity scores in all PD patients. An additional subgroup analysis was performed according to the ratio of mean tremor scores and mean postural instability and gait difficulty (PIGD) scores, only the PIGD subgroup showed the increased FC between right STN and sensorimotor cortex under medication. Increased FC between the STN and the sensorimotor cortex was found, which was related to motor symptom severity in on-medication PD patients. Anti-PD drugs may influence the hyperdirect pathway to alleviate motor symptoms with the more effect on the tremor subtype.