Elevated Transient Receptor Potential Melastatin 8 (TRPM8) Expression Is Correlated with Poor Prognosis in Pancreatic Cancer.

BACKGROUND The transient receptor potential melastatin 8 (TRPM8) was found to be expressed abnormally in a variety of tumors and is associated with unfavorable prognosis in human cancers. However, its clinical significance in pancreatic cancer (PC) is mostly unknown. MATERIAL AND METHODS qRT-PCR was performed to measure the expression of TRPM8 in 110 pairs of PC tissues and the adjacent non-cancerous tissues. The association of TRPM8 expression with the clinical characters of PC patients was analyzed using the chi-square test. Furthermore, the prognostic value of TRPM8 was determined with Kaplan-Meier survival curve and Cox regression analysis. RESULTS We found that the expression level of TRPM8 was significantly elevated in PC tissues compared to the non-cancerous controls (P<0.001). In addition, a close relationship was observed between elevated TRPM8 expression with large tumor size (P=0.001), advanced TNM (P=0.013), and distant metastasis (P=0.034). Survival analysis suggested that patients with high TRPM8 expression has worse OS (P=0.001) and DFS (P<0.001) than those with low TRPM8 expression. Moreover, TRPM8 was confirmed as a valuable prognostic biomarker for OS (HR=1.913; 95% CI: 1.020-3.589; P=0.043) or DFS (HR=2.374; 95% CI: 1.269-4.443; P=0.007) of PC patients. CONCLUSIONS This study shows that TRPM8 expression is significantly up-regulated in PC and it might be a useful prognostic factor for patients with PC.

The ubiquitin ligase RNF43 downregulation increases membrane expression of frizzled receptor in pancreatic ductal adenocarcinoma.

RNF43 is a novel tumor suppressor protein and known to be expressed in a multitude of tissue and dysregulated in cancers of these organs including ovarian and colorectal tissues. RNF43 expression has been shown to be expressed in mutated forms in several pancreatic cell lines. RNF43, by virtue of being an ubiquitin ligase, has the potential to ubiquitinylate membrane receptors like frizzled that subserves sensing Wnt soluble signals at the cell membrane. Thus, normally, RNF43 downregulates Wnt signaling by removing frizzled receptor from the membrane. In the present study, the expression of the tumor suppressor RNF43 was examined in human patient samples of pancreatic ductal adenocarcinoma (PDAC). Reduced levels of expression of RNF43 in PDAC were demonstrated by Western blotting. We incorporated membrane biotinylation assay to examine the expression of frizzled6 receptor in the membrane and demonstrated that it is significantly increased in PDAC tissues. This may be responsible for enhanced Wnt/beta-catenin signaling and provides the first level of evidence of a possible role of this well-known pathway in pancreatic exocrine carcinogenesis. We have utilized appropriate controls to ensure the true positivity of the findings of the present study. The contribution of Wnt/beta-catenin/RNF43 pathway in pancreatic carcinogenesis may provide for utilization of pharmacologic resources for precision-based approaches to treat pancreatic ductal adenocarcinoma.

Yes-Associated Protein in Hepatocellular Carcinoma is Associated with Tumor Differentiation and Patient Age at Diagnosis, but not Markers of HBV Infection.

BACKGROUND: It was necessary to assess the relationship between Yes-associated protein (YAP) and some clinical features of hepatocellular carcinoma (HCC), especially hepatitis B virus (HBV) correlation factors as they relate to tumorigenesis. METHODS: A tissue microarray including 84 HCC samples was retrospectively analyzed by immunohistochemistry. RESULTS: This study showed that YAP expression was associated with HCC differentiation and the patient age at diagnosis of HCC. The mean age at diagnosis of YAP(+) HCC patients was 46.19 ± 9.45 years old, which is youn- ger than 51.40 ± 12.51 years old found for YAP(-) HCC patients (< 0.048). There was no significant correlation between YAP expression and HBV correlation factors (HBsAg, HBV DNA, and the duration of hepatitis B infec- tion). CONCLUSIONS: YAP(+) HCC patients had a younger mean age at diagnosis and more poor-differentiation charac- teristics of HCC. However, there were no independent HBV correlation factors.

Identification of MicroRNAs and target genes involvement in hepatocellular carcinoma with microarray data.

The aim of the study is to identify the differentially expressed microRNAs (miRNAs) between hepatocellular carcinoma (HCC) samples and controls and provide new diagnostic potential miRNAs for HCC. The miRNAs expression profile data GSE20077 included 7 HCC samples, 1 HeLa sample and 3 controls. Differentially expressed miRNAs (DE-miRNAs) were identified by t-test and wilcox test. The miRNA with significantly differential expression was chosen for further analysis. Target genes for this miRNA were selected using TargetScan and miRbase database. STRING software was applied to construct the target genes interaction network and topology analysis was carried out to identify the hub gene in the network. And we identified the mechanism for affecting miRNA function. A total of 54 differentially expressed miRNAs were identified, in which there were 13 miRNAs published to be related to HCC. The differentially expressed hsa-miR-106b was chosen for further analysis and PTPRT (Receptor-type tyrosine-protein phosphatase T) was its potential target gene. The target genes interaction network was constructed among 33 genes, in which PTPRT was the hub gene. We got the conclusion that the differentially expressed hsa-miR-106b may play an important role in the development of HCC by regulating the expression of its potential target gene PT-PRT.

Prognostic significance of microRNA-141 expression and its tumor suppressor function in human pancreatic ductal adenocarcinoma.

Increasing evidence shows that dysregulation of microRNAs is correlated with tumor development. This study was performed to determine the expression of miR-141 and investigate its clinical significance in pancreatic ductal adenocarcinoma (PDAC). Taqman quantitative RT-PCR was used to detect miR-141 expressions in 94 PDAC tissues and 16 nontumorous pancreatic tissues. Correlations between miR-141 expression and clinicopathologic features and prognosis of patients were statistically analyzed. The effects of miR-141 expression on growth and apoptosis of PDAC cell line (PANC-1) were determined by MTT, colony formation, and flow cytometry assays. Potential target genes were identified by luciferase reporter and Western blot assays. The expression level of miR-141 in PDAC tissues was significantly lower than that in corresponding nontumorous tissues. Downregulation of miR-141 correlated with poorer pT and pN status, advanced clinical stage, and lymphatic invasion. Also, low miR-141 expression in PDAC tissues was significantly correlated with shorter overall survival, and multivariate analysis showed that miR-141 was an independent prognostic factor for PDAC patients. Further, functional researches suggested that miR-141 inhibits growth and colony formation, and enhances caspase-3-dependent apoptosis in PANC-1 cells by targeting Yes-associated protein-1 (YAP1). Therefore, miR-141 is an independent prognostic factor for PDAC patients, and functions as a tumor suppressor gene by targeting YAP1.

Expression of microRNA-218 in human pancreatic ductal adenocarcinoma and its correlation with tumor progression and patient survival.

BACKGROUND: Our aim was to analyze clinicopathologic and prognostic values of microRNA (miR)-218 in pancreatic ductal adenocarcinima (PDAC). METHODS: TaqMan quantitative RT-PCR was used to determine the expression of miR-218 in human PDAC cells and tissue samples. The association of miR-218 expression with clinicopathologic variables was analyzed. Kaplan-Meier survival analysis was performed to analyze the association of miR-218 expression with recurrence-free survival or overall survival of patients. Univariate and multivariate Cox regression analyses were performed. RESULTS: The relative level of miR-218 in PDAC cells was significantly lower than that in normal human pancreatic duct epithelial cell line. Also, the mean level of miR-218 in PDAC tissues was significantly lower than that in normal pancreatic tissues. Statistical analyses indicated that low miR-218 expression was closely associated with poor tumor differentiation, advanced tumor stage, higher incidence of lymph node metastasis, and tumor recurrence. Kaplan-Meier survival analyses showed that patients with low miR-218 expression had lower recurrence-free and overall survival than those with high miR-218 expression. Univariate and multivariate Cox regression analyses showed that miR-218 might be an independent prognostic factor. CONCLUSION: Reduced miR-218 in PDAC tissues was correlated with tumor progression, and might be an independent poor prognostic factor for patients.

Comparison analysis in synchronous and metachronous metastatic colorectal cancer based on microarray expression profile.

BACKGROUND/AIMS: Colorectal cancer (CRC) is one of the most common malignancies, and liver metastasis is one of the major causes of death of CRC. This study aimed to compare the genetic difference between metachronous lesions (MC) and synchronous lesions (SC) and explore the molecular pathology of CRC metastasis. METHODOLOGY: Microarray expression profile data (GSE10961) including 8 MC and 10 SC was downloaded from Gene Expression Omnibus. The differentially expressed genes (DEGs) between the two groups were identified based on T test. Furthermore, GO enrichment analysis was performed for the down-regulated DEGs using DAVID. Finally, Classify validation of known CRC genes based on previous studies between MC and SC samples was conducted. RESULTS: Total of 36 DEGs including 35 down-regulated DEGs and 1 up-regulated DEGs were identified. The expressional differences of the 5 informative oncogenes: EGFr, PIK3R1, PTGS2 (COX-2), PTGS1 (COX1), and ALOX5AP between SC and MC were really tiny. CONCLUSIONS: Some DEGs, such as NFAT5, OLR1, ERAP2, HOXC6 and TWIST1 might play crucial roles in the regulation of CRC metastasis (both SC and MC) and by disrupting some pathways. However, our results indeed demand further research and experiment.

TXNIP Regulates NLRP3 Inflammasome-Induced Pyroptosis Related to Aging via cAMP/PKA and PI3K/Akt Signaling Pathways.

Aging is an inevitable natural process with time-dependent dysfunction and the occurrence of various diseases, which impose heavy burdens on individuals, families, and society. It has been reported that NLRP3 inflammasome-induced pyroptosis contributes significantly to age-related diseases and aging, while TXNIP is suggested to be involved in regulating pyroptosis mediated by NLRP3. However, the mechanism between TXNIP and NLRP3 inflammasome is still unclear. In this study, we used HT-22 cells to explore the effect of TXNIP on pyroptosis and its potential association with the aging. Also, we delved into the underlying mechanisms. Our findings revealed that TXNIP significantly augmented pyroptosis in HT-22 cells, primarily by enhancing the activation of the NLRP3 inflammasome and promoting the release of proinflammatory cytokines. Remarkably, as TXNIP levels increased, we observed a corresponding rise in the number of p16-positive cells, which is indicative of aging. Furthermore, we conducted experiments to modulate the improvement of TXNIP on NLRP3 inflammasome-induced pyroptosis, that is, the PI3K activator 740 Y-P and the PKA activator DC2797 inhibited the effect, while the PI3K inhibitor LY294002 and the PKA inhibitor H89 enhanced the effect. In conclusion, our study demonstrated that TXNIP regulates NLRP3 inflammasome-induced pyroptosis in HT-22 cells related to aging via the PI3K/Akt and cAMP/PKA pathways.

rTMS improves dysphagia by inhibiting NLRP3 inflammasome activation and caspase-1 dependent pyroptosis in PD mice.

High incidence, severe consequences, unclear mechanism, and poor treatment effect happened in Parkinson's disease-related dysphagia. Repetitive transcranial magnetic stimulation is an effective treatment for dysphagia in Parkinson's disease. However, the therapeutic effect and underlying mechanism of repetitive transcranial magnetic stimulation for dysphagia in Parkinson's disease are still unknown. Neuroinflammation has been proven to be associated with dysphagia in Parkinson's disease, and NLRP3 inflammasome activation and pyroptosis are common neuroinflammatory processes. Therefore, we compared swallowing quality, NLRP3 inflammasome activation, and caspase-1 dependent pyroptosis among NS control, repetitive transcranial magnetic stimulation control, sham repetitive transcranial magnetic stimulation control, and L-Dopa control mice by tongue muscle tone detection, immunohistochemistry, immunofluorescence, western blotting, co-immunoprecipitation, and quantitative PCR. The results showed that NLRP3 inflammasome activation and caspase-1-dependent pyroptosis were involved in dysphagia in MPTP-induced Parkinson's disease mice model. Repetitive transcranial magnetic stimulation and L-dopa inhibited the above two pathways to alleviate dopaminergic neuronal damage and improve the quality of dysphagia. Repetitive transcranial magnetic stimulation (1 Hz, 1 time/3 days, 6 weeks) had the same effect on dysphagia as L-Dopa treatment (25 mg/kg/day, 6 weeks). Finally, we conclude that repetitive transcranial magnetic stimulation will be the preferred option for the treatment of dysphagia in Parkinson's disease in certain conditions such as motor complications secondary to L-Dopa and L-Dopa non-response dysphagia.

Cognitive-exercise dual-task attenuates chronic cerebral ischemia-induced cognitive impairment by activating cAMP/PKA pathway through inhibiting EphrinA3/EphA4.

BACKGROUND: The prevalence of vascular cognitive impairment induced by chronic cerebral ischemia (CCI) is increasing year by year. Cognitive-exercise dual-task intervention has shown beneficial effects on improving cognitive performance in ischemic patients. It is well known that the tyrosine kinase ligand-receptor (Ephrin-Eph) system plays an important role in synaptic transmission and that the cAMP/PKA pathway is associated with cognitive function. However, it is unclear whether they are responsible for the dual-task improving cognitive impairment in CCI. METHODS: Bilateral common carotid artery occlusion (BCCAO) in SD rats was used to establish the CCI model. The effects of dual-task and single-task on cognitive function and the expressions of EphrinA3, EphA4, cAMP, and PKA in rats were detected by the novel object recognition (NOR) test, immunofluorescence staining, quantitative real-time polymerase chain reaction (qPCR), and Western blotting (WB), respectively. Overexpression or knockdown of EphrinA3 in astrocytes or rats were constructed by lentivirus infection to verify the effects of EphrinA3/EphA4 on the cAMP/PKA pathway. RESULTS: After dual-task intervention, the discrimination index of rats increased significantly compared with the rats in the CCI group. The expressions of EphrinA3 and EphA4 were decreased, while the expressions of cAMP and PKA were increased. Furthermore, knockdown of EphrinA3 alleviated the trend of CCI-induced cognitive decline in rats and OGD-stimulated cellular damage. It also increased cAMP/PKA expression in hippocampal neurons. CONCLUSION: Cognitive-exercise dual-task can significantly improve the cognitive impairment induced by CCI, and this effect may be better than that of the cognitive or exercise single-task intervention. The improvement may be related to the inhibition of EphrinA3/EphA4, followed by activation of the cAMP/PKA pathway.

Transcription factors LvBBX24 and LvbZIP44 coordinated anthocyanin accumulation in response to light in lily petals.

Lily (Lilium spp.), a horticultural crop serving both ornamental and edible functions, derives its coloration primarily from anthocyanins. However, limited studies have been conducted on the accumulation of anthocyanins within lilies. In this study, we cloned a light-induced transcription factor named as LvBBX24 in lilies. Through genetic and biochemical analysis, we determined that LvBBX24 could upregulate the transcription of LvMYB5 and facilitate anthocyanin synthesis. Moreover, we identified that darkness promoted the degradation of LvBBX24 protein. Through screening a yeast library, we identified LvbZIP44 acts as its interacting partner. Genetic testing confirmed that LvbZIP44 also plays a role in promoting lily anthocyanin synthesis. This indicates a potential synergistic regulatory effect between LvBBX24 and LvbZIP44. Our study indicates that LvBBX24 and LvbZIP44 cooperate to regulate anthocyanin accumulation in lily petals. These findings provide compelling evidence supporting the idea that LvBBX24 and LvbZIP44 may form a looped helix surrounding the LvMYB5 promoter region to regulate anthocyanin biosynthesis.

Prolyl 4-hydroxylase P4HA1 Mediates the Interplay Between Glucose Metabolism and Stemness in Pancreatic Cancer Cells.

INTRODUCTION: Cancer stem cells (CSCs) are profoundly implicated in tumor initiation and progression as well as drug resistance and tumor recurrence of many cancer types, especially pancreatic ductal adenocarcinoma (PDAC). Previously, we revealed that prolyl 4-hydroxylase subunit alpha 1 (P4HA1) enhances the Warburg effect and tumor growth in PDAC. However, the possible connection between P4HA1 and cancer stemness in PDAC remains obscure. In this study, P4HA1-dependent cancer stemness was studied by sphere-formation assay and detection of stemness markers. METHODS: Glycolytic capacity in cancer stem cells and their parental tumor cells was investigated by glucose uptake, lactate secretion, and expression of glycolytic genes. Glycolysis inhibitors were used to determine the link between cancer stemness and glycolysis. A subcutaneous xenograft model was generated to investigate P4HA1-induced stemness and glycolysis in vivo. RESULTS: We revealed that ectopic expression of P4HA1 increased the stemness of PDAC cells as evidenced by the increased proportion of CD133+ cells, elevated sphere-formation ability, and the upregulated levels of cancer stemness-related proteins (SOX2, OCT4, and NANOG). Blocking tumor glycolysis with 2-Deoxy-D-glucose (2-DG) or a selective inhibitor of glucose transporter 1 (STF-31) significantly reduced the stem properties of PDAC cells, suggesting that P4HA1-induced glycolysis was essential for the stem-like phenotype of PDAC cells. In addition, in vivo study reaffirmed a promotive effect of P4HA1 on tumor glycolysis and cancer stemness. CONCLUSION: Collectively, our findings suggest that P4HA1 not only affects tumor metabolic reprogramming but also facilitates cancer stemness, which might be exploited as a vulnerable target for PDAC treatment.

Biomarkers of Aging and Relevant Evaluation Techniques: A Comprehensive Review.

The risk of developing chronic illnesses and disabilities is increasing with age. To predict and prevent aging, biomarkers relevant to the aging process must be identified. This paper reviews the known molecular, cellular, and physiological biomarkers of aging. Moreover, we discuss the currently available technologies for identifying these biomarkers, and their applications and potential in aging research. We hope that this review will stimulate further research and innovation in this emerging and fast-growing field.

Cognitive-exercise dual-task intervention ameliorates cognitive decline in natural aging rats via inhibiting the promotion of LncRNA NEAT1/miR-124-3p on caveolin-1-PI3K/Akt/GSK3ß Pathway.

Aging-related cognitive impairment (ARCI) is rapidly becoming a healthcare priority. However, there is currently no excellent cure for it. Cognitive-exercise dual-task intervention (CEDI) is a promising method to improve ARCI, while the underlying mechanisms remain unclear. Long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) are involved in the onset, development, and rehabilitation of ARCI. This study aimed to investigate the effects of CEDI and the role of regulation of the lncRNA NEAT1/miR-124-3p on the caveolin-1-PI3K/Akt/GSK3ß pathway in CEDI improving cognitive function. Forty 18-month-old natural aging rats were randomly assigned to four groups: exercise training group, cognitive training group, CEDI group, and aging control group, and underwent 12 weeks of intervention. A novel object recognition test was performed to determine the cognitive function, and the hippocampus was separated three days after the behavioral tests for further molecular detection. In an in vitro study, the mouse hippocampal neuronal cell line HT22 was cultured. MiR-124-3p and lncRNA NEAT1 were over-expressed or down-expressed, respectively. The expressions of related proteins, lncRNA, and miRNA were examined by WB and/or qRT-PCR. The results showed that compared with the aging control group, the CEDI group had a higher discrimination index, and significantly decreased the expressions of lncRNA NEAT1, and the protein expressions of caveolin-1 and p-GSK3ß, while significantly increased the expressions of miR-124-3p, and the protein expressions of p-PI3K and p-Akt. Inhibition of the lncRNA NEAT1 could significantly increase the protein expressions of p-PI3K and p-Akt in HT22 cells. Upregulation of miR-124-3p decreased the protein expressions of caveolin-1 and p-GSK3ß, and increased the protein expressions of p-PI3K and p-Akt significantly. Inhibition of miR-124-3p had the opposite effects. Our study demonstrated that CEDI improved cognitive function in aging rats better than a single intervention. The mechanisms of cognitive improvement could be related to the regulation of the lncRNA NEAT1/miR-124-3p on the caveolin-1-PI3K/Akt/GSK3ß pathway.

FHL family members suppress vascular endothelial growth factor expression through blockade of dimerization of HIF1α and HIF1ß.

Four and a half LIM domain (FHL) proteins belong to a family of LIM-only proteins that have been implicated in the development and progression of various types of cancers. However, the role of FHL proteins in tumor angiogenesis remains to be elucidated. Herein, we demonstrate that FHL1-3 decrease the promoter activity and expression of vascular endothelial growth factor (VEGF), the key regulator of angiogenesis in cancer growth and progression as well as an important target gene of the transcription factor hypoxia-inducible factor 1 (HIF1α/HIF1ß). FHL1-3 interacted with HIF1α both in vitro and in vivo. A single LIM domain of FHL1 was sufficient for its interaction with HIF1α. FHL1 interacted with the HIF1α region containing basic helix-loop-helix (bHLH) motif and PER-ARNT-SIM domain, both of which aid in dimerization with HIF1ß and DNA binding. FHL1-3 inhibited HIF1 transcriptional activity and HIF1-mediated VEGF expression in a hypoxia-independent manner. Moreover, FHL1 blocked HIF1α-HIF1ß heterodimerization and HIF1α recruitment to the VEGF promoter. These data suggest that FHL proteins are involved in negative regulation of VEGF possibly by interfering with the dimerization and DNA binding of HIF1 subunits and may play an important role in tumor angiogenesis.

Silencing phospholipid scramblase 1 expression by RNA interference in colorectal cancer and metastatic liver cancer.

BACKGROUND: Phospholipid scramblase 1 (PLSCR1) not only participates in the transbilayer movement of phospholipids, but also plays a role in the pathogenesis and progression of cancers. The present study aimed to evaluate the effect of silencing PLSCR1 expression by RNA interference in colorectal cancer (CRC) and metastatic liver cancer. METHODS: The expression of PLSCR1 in CRC and metastatic liver cancer samples was assessed by immunohistochemistry. The cultured cells with the highest expression were selected for subsequent experiments. We designed three siRNA oligonucleotide segments targeted at PLSCR1. Successful transfection was confirmed. The biological behavior of the cells in proliferation, adhesion, migration and invasion was determined. RESULTS: PLSCR1 protein expression increased significantly in the majority of CRC and metastatic liver cancer samples compared with normal samples. Lovo cells had the highest expression of PLSCR1. The siRNA-390 oligonucleotide segment had the best silencing effect. After transfection, Lovo cell proliferation was significantly inhibited compared with the controls in the MTT assay. Laminin and fibronectin adhesion assays showed Lovo cell adhesion was also significantly inhibited. In the migration assay, the number of migrating cells in the PLSCR1 siRNA-390 group was 50+/-12, significantly lower than the number in the siRNA-N group (115+/-28) and in the control group (118+/-31). In an invasion test, the number of invading cells in the PLSCR1 siRNA-390 group was 60+/-18, significantly lower than that in the siRNA-N group (97+/-26) and the control group (103+/-24). CONCLUSIONS: PLSCR1 is overexpressed in CRC and metastatic liver cancer. Silencing of PLSCR1 by siRNA inhibits the proliferation, adhesion, migration and invasion of Lovo cells, which suggests that PLSCR1 contributes to the tumorigenesis and tumor progression of CRC. PLSCR1 may be a potential gene therapy target for CRC and associated metastatic liver cancer.

A Novel Long-Noncoding RNA LncZFAS1 Prevents MPP+-Induced Neuroinflammation Through MIB1 Activation.

Parkinson's disease remains one of the leading neurodegenerative diseases in developed countries. Despite well-defined symptomology and pathology, the complexity of Parkinson's disease prevents a full understanding of its etiological mechanism. Mechanistically, α-synuclein misfolding and aggregation appear to be central for disease progression, but mitochondrial dysfunction, dysfunctional protein clearance and ubiquitin/proteasome systems, and neuroinflammation have also been associated with Parkinson's disease. Particularly, neuroinflammation, which was initially thought to be a side effect of Parkinson's disease pathogenesis, has now been recognized as driver of Parkinson's disease exacerbation. Next-generation sequencing has been used to identify a plethora of long noncoding RNAs (lncRNA) with important transcriptional regulatory functions. Moreover, a myriad of lncRNAs are known to be regulators of inflammatory signaling and neurodegenerative diseases, including IL-1ß secretion and Parkinson's disease. Here, LncZFAS1 was identified as a regulator of inflammasome activation, and pyroptosis in human neuroblast SH-SY5Y cells following MPP+ treatment, a common in vitro Parkinson's disease cell model. Mechanistically, TXNIP ubiquitination through MIB1 E3 ubiquitin ligase regulates NLRP3 inflammasome activation in neuroblasts. In contrast, MPP+ activates the NLPR3 inflammasome through miR590-3p upregulation and direct interference with MIB1-dependent TXNIP ubiquitination. LncZFAS overexpression inhibits this entire pathway through direct interference with miR590-3p, exposing a novel research idea regarding the mechanism of Parkinson's disease.

Effects of dual-task training in patients with post-stroke cognitive impairment: A randomized controlled trial.

Background: Evidence for the efficacy of cognitive-motor dual-task (CMDT) training in patients with post-stroke cognitive impairment (PSCI) and no dementia is still lacking. More importantly, although some studies on the cognitive effect of CMDT training show an improvement in cognitive performance, the results are still controversial, and the intervention mechanism of CMDT training on cognitive function improvement is not clear. The main purpose of this study was to analyze the effects of CMDT training on cognitive function, neuron electrophysiology, and frontal lobe hemodynamics in patients with PSCI. Methods: Here we tested the effects of CMDT training on cognitive function in PSCI patients. Forty subjects who met the criteria of PSCI were randomly assigned to control and experimental groups. CMDT training or cognitive task (CT) training was administered to each patient in the experimental and control groups, respectively. All subjects performed Mini-mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) scale before and after the intervention, and the event-related potentials (ERP) and functional near-infrared spectroscopy (fNIRS) were used to evaluate the changes in neuron electrophysiology and hemodynamics. Results: Forty patients were randomized across Beijing Rehabilitation Hospital Capital Medical University in Beijing. At the end of the intervention, 33 subjects completed the experimental process. The CMDT group showed significant improvement in the MMSE (P = 0.01) and MoCA (P = 0.024) relative to the CT group. The results of ERP and fNIRS showed that CMDT training could shorten the latency of P300 (P = 0.001) and the peak time of oxygenated hemoglobin (P = 0.004). The results showed that CMDT training shortened the response time of central neurons and significantly increased the rate of oxygen supply to the frontal lobe. Conclusion: CMDT training in patients with PSCI improved global cognitive function, which was supported by the improved neural efficiency of associated brain areas. Clinical trial registration: http://www.chictr.org.cn, identifier ChiCTR2000034862.

Cognitive-exercise dual-task intervention ameliorates cognitive decline in natural aging rats through reducing oxidative stress and enhancing synaptic plasticity.

The incidence of aging-related cognitive decline is increasing with population aging. It is urgent to explore ways to ameliorate aging-related cognitive decline. Cognitive-exercise dual-task intervention has shown beneficial effects on improving cognition in aging cohorts, but the mechanisms of the effects remain unclear. In this study, 18-month-old Sprague Dawley rats served as a model of natural aging. First, the performance in the Morris water maze test and the change in synaptophysin content in the hippocampus were used to investigate the cognitive decline of 18-month-old rats. Then, a batch of 18-month-old rats was treated with cognitive, exercise, or cognitive-exercise dual-task intervention for 12 weeks. The novel object recognition test was used to assess cognitive ability. Enzyme-linked immunosorbent assay and Western blotting were used to detect the levels of oxidative stress molecules and synaptic plasticity-related proteins. We found that cognitive-exercise dual-task intervention improved the discrimination index of natural aging rats. After dual-task intervention, the expression levels of synaptophysin, brain-derived neurotrophic factor, superoxide dismutase, and glutathione peroxidase were increased, and the expression level of lipid peroxide malondialdehyde was decreased. Furthermore, the effect of dual-task intervention on synaptic plasticity-related proteins and oxidative stress indicators was greater than that of single cognitive or exercise intervention. In conclusion, cognitive-exercise dual-task intervention can significantly ameliorate aging-related cognitive decline, and the improvement might be related to the reduction of oxidative stress and the enhancement of synaptic plasticity. The effect of cognitive-exercise dual-task intervention may be better than that of single cognitive or exercise intervention.

Increased activation of the caudate nucleus and parahippocampal gyrus in Parkinson's disease patients with dysphagia after repetitive transcranial magnetic stimulation: a case-control study.

Repetitive transcranial magnetic stimulation (rTMS) has been shown to effectively improve impaired swallowing in Parkinson's disease (PD) patients with dysphagia. However, little is known about how rTMS affects the corresponding brain regions in this patient group. In this case-control study, we examined data from 38 PD patients with dysphagia who received treatment at Beijing Rehabilitation Medicine Academy, Capital Medical University. The patients received high-frequency rTMS of the motor cortex once per day for 10 successive days. Changes in brain activation were compared via functional magnetic resonance imaging in PD patients with dysphagia and healthy controls. The results revealed that before treatment, PD patients with dysphagia showed greater activation in the precentral gyrus, supplementary motor area, and cerebellum compared with healthy controls, and this enhanced activation was weakened after treatment. Furthermore, before treatment, PD patients with dysphagia exhibited decreased activation in the parahippocampal gyrus, caudate nucleus, and left thalamus compared with healthy controls, and this activation increased after treatment. In addition, PD patients with dysphagia reported improved subjective swallowing sensations after rTMS. These findings suggest that swallowing function in PD patients with dysphagia improved after rTMS of the motor cortex. This may have been due to enhanced activation of the caudate nucleus and parahippocampal gyrus. The study protocol was approved by the Ethics Committee of Beijing Rehabilitation Hospital of Capital Medical University (approval No. 2018bkky017) on March 6, 2018 and was registered with Chinese Clinical Trial Registry (registration No. ChiCTR 1800017207) on July 18, 2018.