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.

Cognitive-exercise dual-task promotes cognitive function recovery in chronic cerebral ischemia male rats through regulating PI3K/Akt signaling pathway via inhibition of EphrinA3/EphA4.

Chronic cerebral ischemia (CCI) can lead to vascular cognitive impairment, but therapeutic options are limited. Cognitive-exercise dual-task (CEDT), as a potential rehabilitation intervention, can attenuate cognitive impairment. However, the related mechanisms remain unclear. In this study, 2-vessel occlusion (2-VO) in male SD rats was performed to establish the CCI model. The rats were treated with cognitive, exercise, or CEDT intervention for 21 days. The Morris water maze (MWM) test was used to assess cognitive ability. TUNEL staining was used to detect the neuronal apoptosis. Immunofluorescence, RT-qPCR and Western blot were used to detect the protein or mRNA levels of EphrinA3, EphA4, p-PI3K, and p-Akt. The results showed that CEDT could improve performance in the MWM test, reverse the increased expression of EphrinA3 and EphA4, and the reduced expression of p-PI3K and p-Akt in CCI rats, which was superior to exercise and cognitive interventions. In vitro, oxygenglucose deprivation (OGD) challenge of astrocytes and neuronal cells were used to mimic cerebral ischemia. Immunofluorescence assay revealed that the levels of MAP-2, p-PI3K, and p-Akt were reduced in EphrinA3 overexpressed cells after OGD stimulation. Finally, the knock-down of EphrinA3 by shRNA significantly promoted the recovery of cognitive function and activation of PI3K/Akt after CEDT treatment in CCI rats. In conclusion, our study suggests that CEDT promotes cognitive function recovery after CCI by regulating the signaling axis of EphrinA3/EphA4/PI3K/Akt.

Effects of different aerobic exercises on the global cognitive function of the elderly with mild cognitive impairment: a meta-analysis.

OBJECTIVES: To summarise the effects of various types of aerobic exercise on the global cognitive function of the elderly with mild cognitive impairment (MCI). DESIGN: A meta-analysis of randomised controlled trials (RCTs). DATA SOURCES: PubMed, EMBASE and the Cochrane Library were searched for clinical RCTs from the earliest available records to March 2022. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: We included RCTs of subjects older than 60 years with MCI. The outcome indicators of cognitive function of interest were the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA). DATA EXTRACTION AND SYNTHESIS: Two researchers independently screened the literature, extracted data and evaluated the quality of the included studies, with disagreements resolved by a third researcher. The Cochrane Handbook for Systematic Reviews of Interventions was used to assess the risk of bias. Meta-analysis was performed by Review Manager V.5.3 software. Random-effect models were used for meta-analysis. RESULTS: A total of 1680 patients who participated in 20 RCTs were included in this study. Based on outcomes of MMSE analysis, the aerobic exercise, which was beneficial for global cognitive function in MCI patients, included multicomponent aerobic exercise (MD=1.79, 95% CI (1.41 to 2.17), p<0.01) and mind-body exercise (MD=1.28, 95% CI (0.83 to 1.74), p<0.01). The results of the meta-analysis of conventional aerobic exercise (MD=0.51, 95% CI (0.09 to 0.93), p=0.02) turned out to be statistically insignificant after sensitivity analysis (MD=0.14, 95% CI (-0.47 to 0.75), p=0.65). With the evaluation of MoCA, multicomponent aerobic exercise (MD=5.74, 95% CI (5.02 to 6.46), p<0.01), mind-body exercise (MD=1.29, 95% CI (0.67 to 1.90), p<0.01) and conventional aerobic exercise (MD=2.06, 95% CI (1.46 to 2.65), p<0.01) were showed significant beneficial effects for the patient. However, there was a high degree of heterogeneity between the results of multicomponent aerobic exercise (MMSE) and conventional aerobic exercise (MoCA), which was analysed and explored. CONCLUSIONS: In general, multicomponent aerobic exercise and mind-body exercise were beneficial in improving global cognitive function in the elderly with MCI. Nevertheless, the improvement effect of mind-body exercise is more reliable compared with multicomponent aerobic exercise and conventional aerobic exercise. PROSPERO REGISTRATION NUMBER: CRD42022327386.

Does higher knee hyperextension in patients with hemiplegia affect lateral and medial meniscus volume in the paretic leg? A cross-sectional study.

BACKGROUND: After stroke, an abnormal gait pattern gradually leads to knee pain and joint lesions, resulting the gait instability. However, the correlation between the knee hyperextension and gait pattern, the meniscus volume, and the water content of meniscus in paretic and non-paretic legs has not been fully investigated. Moreover, most of physicians tend to ignore this knee hyperextension. This study attempted to emphasize the importance of knee hyperextension using gait analysis and Magnetic resonance imaging (Trial registration number ChiCTR2000039641, date of registration 04/11/2020). METHODS: Eight patients with chronic hemiplegic (6 male, 2 female) volunteered to participate in this study. Participants was recruited if they had a hemiplegia following a stroke occurring more than 6 months, had an ability to walk 10 m without aids, had a Function Ambulation Category level at least 3 and above, and had a hemiplegic lower extremity identified as Brunnstrom state III or above identification. The spatial-temporal gait parameters and kinematic parameters in the paretic and the non-paretic legs and the percentage of free water content in deep and shallow layers. RESULTS: Longer time since hemiplegia led to larger angles of knee hyperextension (R = 0.56, p = 0.016), larger angles of knee hyperextension led to more tears in meniscus (R = - 0.53, - 0,57 and - 0.70), and larger angles of knee hyperextension decreased water content of the lateral meniscus in the non-paretic leg (R = - 0.91) but increased water content of the medial meniscus (R = 0.53 and 0.63). CONCLUSIONS: The knee hyperextension could not be ignored by physicians and needed to be diagnosed and treated as early as possible, the time since hemiplegia could be an indicator of sign of knee hyperextension.

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.