Integrating analysis of mRNA expression profiles indicates Sgk1 as a key mediator in muscle-brain crosstalk during resistance exercise.

Abundant evidence has shown the protective effect of aerobic exercise on central neuronal system, however, research about resistance exercise remains limited. To evaluate the effect and potential molecular mechanisms of resistance exercise in improving cognition and mental health, three-month-old male C57BL/6J mice underwent resistance training for five weeks. Body parameters, cognitive performance and synaptic plasticity were then assessed. In both groups, total RNA from the frontal cortex, hippocampus and gastrocnemius was isolated and sequenced, GO term and KEGG analysis were performed to identify molecular mechanisms. The results from RNA sequencing were then verified by RT-PCR. Our data found that mice in training group showed reduced anxiety-like behavior and better spatial memory. Accordingly, resistance exercise specifically increased the number of thin spines without affecting the number of other kind of spines. mRNA sequence analysis showed that resistance exercise induced differential expression of hundreds of genes in the above three tissues. KEGG analysis indicated the FoxO signaling pathway the most significant changed pathway throughout the brain and muscle. GO terms analysis showed that Sgk1 was enriched in the three key cognition related BP, including long-term memory, learning or memory and memory, and the expression level of Sgk1 was positive related with cognitive performance in the water maze. In conclusion, resistance exercise improved the mental health, cognition and synaptic plasticity of mice. Integrating analysis of mRNA expression profiles in frontal cortex, hippocampus and muscle reveals Sgk1 as the key mediator in brain-muscle crosstalk.

Efficacy of Transcranial Direct Current Stimulation Over Dorsolateral Prefrontal Cortex in Patients With Minimally Conscious State.

BACKGROUND: The treatment of patients in a minimally conscious state (MCS) remains challenging. Transcranial direct current stimulation (tDCS) is a non-invasive therapeutic method in treating neurologic diseases by regulating the cortical excitability. The aim is to investigate the effect of tDCS in patients with MCS in this study. METHODS: Eleven patients in MCS were enrolled in the study. All the patients received 5 daily sessions of 20-min sham tDCS, followed by 10 sessions of 20-min real tDCS. The anodal electrode and cathodal electrodes were placed over the left dorsolateral prefrontal cortex (DLPFC) and the right eyebrow, respectively. Assessment of Coma Recovery Scale-Revised (CRS-R) scores and resting-state functional MRI (rs-fMRI) scans was conducted three times in each patient: before tDCS (baseline, T0), post-sham tDCS at week 1 (T1), and post-real tDCS at week 2 (T2). The whole-brain functional connectivity (FC) was obtained by bilaterally computing FC from six seed regions: precuneus, middle frontal gyrus, supplemental motor area, angular gyrus, superior temporal gyrus, and occipital lobe. One-way repeated measure ANOVA was used to compare the differences of CRS-R scores and FC at T0, T1, and T2. The false discovery rate correction of p < 0.001 was adopted for controlling multiple comparisons in FC analysis. RESULTS: Five patients with MCS showed obvious clinical improvement represented by increased CRS-R scores post- 2-week real tDCS. The CRS-R scores did not change post- 1-week sham treatment. No side effects were reported during the study. The FC of the bilateral supplementary motor area, right angular gyrus, and right superior temporal gyrus were significantly enhanced after 2-week real tDCS compared with that after 1-week sham-tDCS. In addition, FC of bilateral occipital lobe and right precuneus were significantly enhanced post- 2-week real tDCS compared with the baseline. CONCLUSION: Our findings indicated that tDCS over DLPFC could serve as a potentially effective therapy for improving the consciousness state in patients with MCS. The FC in rs-fMRI can be modulated by tDCS at both the stimulation site (left DLPFC) and the distant regions.

Involuntary, forced or voluntary exercise can ameliorate the cognitive deficits by enhancing levels of hippocampal NMDAR1, pAMPAR1 and pCaMKII in a model of vascular dementia.

Objectives: To investigate the effect on vascular dementia of involuntary exercise induced by functional electrical stimulation and of forced and voluntary exercise, focusing on the recovery of cognitive function and using a rat model of dementia.Methods: A demential model was created in Wistar rats who were then given forced exercise, allowed voluntary exercise (wheel running) or had exercise induced through functional electrical stimulation. Their responses were quantified using a Morris water maze and by measuring long-term potentiation in the hippocampus. Immunohistochemical staining was used to evaluate neurogenesis in the hippocampus and Nissl staining was applied to visualize viable neuron loss in the DG sector. In addition, the levels of NMDAR1, AMPAR1, pAMPAR1, pCaMKII, CaMKII, Bcl-2 and Bax in the hippocampus were assessed by western blotting.Results: All of the exercise groups showed a recovery of cognitive performance and improved long-term potentiation. The three modes of exercise all increased the number of DCX immunopositive cells and reduced losses of intact-appearing neurons in the hippocampal DG zones roughly equally. All proved about equally effective in increasing the levels of NMDAR1, pAMPAR1 and pCaMKII and increasing the Bcl-2/Bax ratio to protect neurons from apoptosis.Conclusion: Exercise induced by electrical stimulation has beneficial effects comparable to those of other types of exercise for alleviating the cognitive deficits of vascular dementia.

Nonpharmacological interventions for cancer-related cognitive impairment in adult cancer patients: A network meta-analysis.

BACKGROUND: Conventional meta-analyses can only provide direct comparison evidence, and the best options of nonpharmacological interventions for cancer-related cognitive impairment remain largely unknown. OBJECTIVES: To evaluate the comparative effects of all known nonpharmacological interventions for cancer-related cognitive impairment, and to rank the best intervention options for adult non- central nervous system cancer patients with cancer-related cognitive impairment. DESIGN: Systematic review with a new analytic approach of network meta-analysis. DATA SOURCES: Six electronic databases were searched for randomized controlled trials from January 2010 to July 2019. REVIEW METHODS: Literature screening, data extraction and quality appraisal was undertaken systematically by two independent reviewers. Quantitative network meta-analysis performed to analyze key study outcomes. The primary outcome was the effectiveness of interventions on subjective cognitive function, and the secondary outcome was the safety of nonpharmacological interventions for cancer-related cognitive impairment. RESULTS: There were 29 eligible randomized controlled trials searched, and a total of 10 interventions identified. All 29 randomized controlled trials that were included had no reported significant adverse events, therefore, these 10 nonpharmacological interventions are safe for cancer-related cognitive impairment management. In terms of effectiveness, the pooled overall effects were in favor of these 10 nonpharmacological interventions. The most effective interventions included meditation, cognitive training, cognitive rehabilitation, and exercise interventions, with a mean difference of effective size plus 95% confidence interval 10.26 (1.53, 19.00), 5.02 (1.41, 8.63), 4.88 (0.65, 9.11), and 3.82 (0.52, 7.13), respectively. Other treatment effects did not show statistically significant differences. CONCLUSIONS: This network meta-analysis found that meditation interventions, cognitive training, cognitive rehabilitation, and exercise were the most effective interventions for adult non-central nervous system cancer patients to manage cancer-related cognitive impairment. Results of this network meta-analysis contribute evidence-based data to inform medical decision-making.

Long noncoding RNA MEG3 silencing protects against hypoxia-induced pheochromocytoma-12 cell injury through inhibition of TIMP2 promoter methylation.

Hypoxia is a common pathological process caused by insufficient oxygen. Long noncoding RNAs (lncRNAs) have been proven to participate in this pathology. Hypoxia is reported to significantly reduce the secretion of tissue inhibitor of metalloproteinase 2 (TIMP2) and TIMP2 induces pheochromocytoma-12 (PC12) cell cycle arrest. Thus, our study aimed to explore the mechanism by which lncRNA maternally expressed gene 3 (MEG3) was implicated in hypoxia-induced PC12 cell injury through TIMP2 promoter methylation. To elucidate the potential biological significance of MEG3 and the regulatory mechanism between MEG3 and TIMP2, a hypoxia-induced PC12 cell injury model was generated. The hypoxia-exposed cells were subjected to a series of overexpression plasmids and short hairpin RNAs, followed by the measurement of levels of MEG3, TIMP2, lactate dehydrogenase (LDH), malondialdehyde (MDA), superoxide dismutase (SOD), reactive oxygen species (ROS), Bcl-2-associated X protein, B-cell lymphoma-2, and caspase-3, as well as the changes in MMP, cell proliferation, apoptosis, and cell cycle progression. On the basis of the findings, MEG3 was upregulated in hypoxia-injured PC12 cells. MEG3 recruited methylation proteins DNMT3a, DNMT3b, and MBD1 and accelerated TIMP2 promoter methylation, which in turn inhibited its expression. Moreover, PC12 cells following MEG3 silencing and TIMP2 overexpression exhibited significantly decreased levels of LDH, MDA, and ROS along with cell apoptosis, yet increased SOD and MMP levels, as well as cell cycle entry to the S phase and cell proliferation. In conclusion, MEG3 silencing suppresses hypoxia-induced PC12 cell injury by inhibiting TIMP2 promoter methylation. This study may provide novel therapeutic targets for hypoxia-induced injury.

Exercise improves recognition memory and synaptic plasticity in the prefrontal cortex for rats modelling vascular dementia.

OBJECTIVES: Functional electrical stimulation (FES) may induce involuntary exercise and make beneficial effects on vascular dementia (VD) by strengthening the BDNF-pCREB-mediated pathway and hippocampal plasticity. Whether FES improves recognition memory and synaptic plasticity in the prefrontal cortex (PFC) was investigated by establishing a VD model. METHODS: The VD rats were administered with two weeks of voluntary exercise, forced exercise, or involuntary exercise induced with FES. Sham-operated and control groups were also included. The behavioral changes were assessed with the novel object recognition test and novel object location test. The expression levels of key proteins related to synaptic plasticity in the PFC were also detected. RESULTS: All types of exercise improved the rats' novel object recognition index, but only voluntary exercise and involuntary exercise induced with FES improved the novel object location index. Any sort of exercise enhanced the expression of key proteins in the PFC. CONCLUSION: Involuntary exercise induced with FES can improve recognition memory in VD better than forced exercise. The mechanism is associated with increased synaptic plasticity in the PFC. FES may be a useful alternative tool for cognitive rehabilitation.

Involuntary, Forced and Voluntary Exercises Equally Attenuate Neurocognitive Deficits in Vascular Dementia by the BDNF-pCREB Mediated Pathway.

A rat model of vascular dementia was used to compare the effects of involuntary exercise induced by functional electrical stimulation (FES), forced exercise and voluntary exercise on the recovery of cognitive function recovery and its underlying mechanisms. In an involuntary exercise (I-EX) group, FES was used to induce involuntary gait-like running on ladder at 12 m/min. A forced exercise group (F-EX) and a voluntary exercise group (V-EX) exercised by wheel running. The Barnes maze was used for behavioral assessment. Brain-derived neurotrophic factor (BDNF), phosphorylated extracellular signal-regulated kinase 1 and 2 (ERK1/2) and cAMP response element binding protein (CREB) positive cells in hippocampal CA1, CA2/3 and dentate gyrus (DG) regions were evaluated using immunohistochemical methods. Western blotting was used to assess the levels of BDNF, phosphorylated protein kinase B (Akt), tropomyosin receptor kinase B (TrkB), mitogen-activated protein kinase 1 and 2 (MEK1/2), ERK1/2 and CREB in BDNF-pCREB signaling in the hippocampus and prefrontal cortex. Involuntary, forced and voluntary exercises were all found to reverse the cognitive deficits of vascular dementia with about equal effectiveness. The number of BDNF, pCREB and pERK1/2 immunopositive cells was significantly increased in the hippocampal CA1, CA2/3 and DG regions in all three exercise groups. In addition, involuntary exercise activated BDNF and the phosphorylation of Akt, TrkB, MEK1/2, ERK1/2 and CREB in the hippocampus and prefrontal cortex equally as well as voluntary or forced exercise. These results suggest that involuntary exercise induced by FES may be as beneficial for alleviating cognitive deficits after cerebral ischemia.

Involuntary, forced and voluntary exercises are equally capable of inducing hippocampal plasticity and the recovery of cognitive function after stroke.

OBJECTIVES: Forced and voluntary exercises are known to improve cognition and induce neuroprotection after stroke, however, any effects of involuntary movement induced by functional electrical stimulation (FES) are unclear. The effects of involuntary exercise induced by FES, forced and voluntary exercise on the recovery of cognitive function in vascular dementia and the regional repair of ischaemic lesions were investigated using a rat model. METHODS: Wistar rats were randomly assigned to a sham group, a vascular dementia control group (VD), an involuntary exercise group (I-Ex), a forced exercise group (F-Ex) or a voluntary exercise group (V-Ex). An object recognition test (ORT) and an object location test (OLT) were used to evaluate the recovery of cognitive function. Levels of synapsin I (SYN), synaptophysin (SYP), postsynaptic density 95 (PSD-95), microtubule-associated protein 2 (MAP-2) and Tau in the hippocampus were evaluated using western blotting and immunohistochemistry. Nissl staining was applied to visualise the loss of viable neurons from the hippocampus. RESULTS: Involuntary exercise and voluntary exercise both improved cognition in terms of ORT and OLT results. Forced exercise only improved ORT results. The levels of SYN, PSD-95, MAP-2 and Tau in the hippocampus were enhanced by all three patterns of exercise training. Moreover, all three patterns reduced losses of dendrons and neurons in the hippocampal CA1 and CA2 zones, but without significant differences among the three exercise regimens. CONCLUSION: Involuntary exercise induced by FES has beneficial effects on cognitive function after vascular dementia comparable to those of forced and voluntary exercise.