Objective To investigate the effects and underlying mechanisms of human placental chorionic plate-derived mesenchymal stem cells (hpcMSCs) on cognitive dysfunction, neuroinflammation, neuronal damage and synaptic plasticity in a mouse model of stroke. Methods A mouse model of middle cerebral artery occlusion (MCAO) was adopted. The mice were randomly divided into three groups: sham operation group, MCAO group and hpcMSCs treatment group, with seven mice in each group. The hpcMSCs treatment group received hpcMSCs transplantation on the 1st, 3rd and 10th day after MCAO. One month after MCAO, the cognitive ability of the mice was evaluated by Morris water maze and Y maze behavioral tests; the morphological changes and synaptic functions of hippocampal neurons were analyzed by HE staining, Nissl staining, Golgi staining and immunofluorescence staining techniques; the density and activation status of microglia was analyzed by Fluorescent labeling method; the levels of tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β) and IL-6 in brain tissue were analyzed by ELISA; the expressions of phosphorylated-mitogen-activated protein kinase kinase 1 (p-MEK1), phosphorylated-extracellular regulated protein kinase (p-ERK) and phosphorylated-cAMP-response element binding protein (p-CREB) and other proteins related to neuroprotection in the signal pathways were detected by Western blotting; and electrophysiological detection was performed using hippocampal slices in vitro. Results Compared with the MCAO group, mice in the hpcMSCs treatment group showed significant improvements, including improved cognitive ability, alleviated neuroinflammation (demonstrated by reduced microglial activation and decreased levels of inflammatory factors TNF-α, IL-1β and IL-6), and increased neuronal density with normalized morphology of neurons in the hippocampal CA1 region. The treatment group also demonstrated a significantly increased number of Nissl-positive cells and density of dendritic spines of hippocampal neurons, along with restored frequency of miniature excitatory postsynaptic potential (mEPSP). Moreover, hpcMSCs treatment significantly increased the expression levels of p-MEK1, p-ERK and p-CREB in the hippocampus. Conclusion Transplantation of hpcMSCs ameliorates cognitive dysfunction and hippocampal neuronal injury in stroke mice through the reduction of neuroinflammation, restoration of hippocampal neuronal function, promotion of synaptic plasticity and activation of the MEK/ERK/CREB signaling pathway. These findings suggest a new potential therapeutic approach for post-stroke neural repair.
Animals ; Hippocampus/physiopathology* ; Mice ; Cognitive Dysfunction/etiology* ; Mesenchymal Stem Cell Transplantation ; Male ; Neurons/metabolism* ; Stroke/metabolism* ; Humans ; Neuroinflammatory Diseases/therapy* ; Female ; Cyclic AMP Response Element-Binding Protein/metabolism* ; Disease Models, Animal ; Mesenchymal Stem Cells/cytology* ; Mice, Inbred C57BL

OBJECTIVES: The integrated endoplasmic reticulum stress inhibitor (ISRIB) is a selective inhibitor of the protein kinase R-like endoplasmic reticulum kinase (PERK) signaling pathway within endoplasmic reticulum stress (ERS) and can improve spatial and working memory in aged mice. Although ERS and oxidative stress are tightly interconnected, it remains unclear whether ISRIB alleviates cognitive impairment by restoring the balance between ERS and oxidative stress. This study aims to investigate the effects and mechanisms of ISRIB on lipopolysaccharide (LPS)-induced cognitive impairment in mice. METHODS: Eight-week-old male ICR mice were randomly divided into 3 groups: Normal saline (NS) group, LPS group, and ISRIB+LPS group. NS and LPS groups received daily intraperitoneal injections of normal saline for 7 days; on day 7, LPS group mice received intraperitoneal LPS (0.83 mg/kg) to establish a cognitive impairment model. ISRIB+LPS group received ISRIB (0.25 mg/kg) intraperitoneally for 7 days, with LPS injected 30 minutes after ISRIB on day 7. Cognitive ability was evaluated by the novel place recognition test (NPRT). Real-time fluorogenic quantitative PCR (RT-qPCR) was used to detect changes in nitric oxide synthase (NOS), superoxide dismutase-1 (SOD-1), and catalase (CAT) gene expression in the hippocampus and prefrontal cortex. Oxidative stress markers malondialdehyde (MDA), glutathione (GSH), and oxidized glutathione (GSSG), were measured in hippocampal and prefrontal cortex tissues. RESULTS: Compared with the NS group, mice in LPS group showed a significant reduction in novel place recognition ratio, upregulation of hippocampal NOS-1 and NOS-2 mRNA, downregulation of SOD-1 and CAT mRNA, increased MDA and GSSG, decreased GSH, and reduced GSH/GSSG ratio (all P<0.05). Compared with the LPS group, mice in ISRIB+LPS group exhibited significantly improved novel place recognition, downregulated NOS-1 and NOS-2 mRNA, upregulated SOD-1 and CAT mRNA, decreased MDA and GSSG, increased GSH, and an elevated GSH/GSSG ratio in the hippocampus (all P<0.05). No significant changes were observed in the prefrontal cortex. CONCLUSIONS ISRIB improves LPS-induced cognitive impairment in mice by restoring the oxidative/antioxidant balance in the hippocampus.
Animals ; Lipopolysaccharides ; Male ; Mice, Inbred ICR ; Cognitive Dysfunction/drug therapy* ; Mice ; Oxidative Stress/drug effects* ; Endoplasmic Reticulum Stress/drug effects* ; Hippocampus/drug effects* ; Nitric Oxide Synthase Type II/genetics* ; Guanidines/pharmacology* ; eIF-2 Kinase/antagonists & inhibitors* ; Signal Transduction/drug effects* ; Superoxide Dismutase/metabolism*

OBJECTIVES: To explore the therapeutic mechanism of Chaihu Shugan (CHSG) Decoction for improving cognitive impairment in rats with epilepsy induced by lithium chloride and pilocarpine. METHODS: Male SD rat models of cognitive impairment model after epilepsy induced by intraperitoneal injection with lithium chloride and pilocarpine were randomly divided into 5 groups (n=12) for treatment with daily gavage of saline, donepezil (90 mg/kg), or CHSG Decoction at 2.5, 5.0, 10, 20 and 40 g/kg for 4 consecutive weeks, with 10 rats with intraperitoneal injection with saline as the blank control group. Morris water maze test was used to evaluate cognitive and behavioral changes of the rats after treatment. The mRNA and protein expressions of ASIC1, NR1, NR2A and NR2B in the hippocampus of rats were detected using RT-qPCR and Western blotting. RESULTS: Compared with those with saline treatment, the rat models treated with CHSG Decoction at 5 and 10 g/kg showed significantly shortened escape latency and prolonged stay in the target quadrant with increased number of platform crossings in Morris water maze test. CHSG Decoction treatment at the two doses significantly increased ASIC1, NR1, NR2A and NR2B protein expressions in the hippocampus of the rat models, and their mRNA expression levels were all increased significantly after the treatment at the doses above 2.5 g/kg. CONCLUSIONS CHSG Decoction can improve cognitive impairment in rats after epilepsy possibly by regulating the expression and channel activity of NMDAR protein and its subunit protein via upregulating ASIC1 to modulate neuronal excitability and synaptic plasticity in the hippocampus.
Animals ; Hippocampus/drug effects* ; Receptors, N-Methyl-D-Aspartate/metabolism* ; Acid Sensing Ion Channels/metabolism* ; Rats, Sprague-Dawley ; Male ; Rats ; Epilepsy/complications* ; Cognitive Dysfunction/drug therapy* ; Drugs, Chinese Herbal/therapeutic use* ; Up-Regulation ; Maze Learning

OBJECTIVES: To explore the mechanisms of Qingre Lidan Jiedu Recipe (QLJR) for improving cognitive dysfunction in rats with high copper load. METHODS: Seventy-five male SD rats were randomized into normal control group, model group, QLJR group, penicillamine (PCA) group, and QLJR+ PCA group. Except for those in the control group, all the rats were fed a high-copper diet for 12 weeks. The effects of the treatments on cognitive function of the rats were assessed using the Barnes maze and passive avoidance tests. Hippocampal expressions of NIX, FUNDC1 and LC3 of the rats were detected using Western blotting and immunofluorescence staining, and changes in mitochondrial morphology were observed with transmission electron microscopy. RESULTS: Behavioral tests showed prolonged target hole latency, shortened latency to enter the dark chamber, and increased error counts of the rats in the model group, which were significantly improved in QLJR+PCA group; the error counts were significantly lower in QLJR+PCA group than in either QLJR or PCA group. Among all the groups, the hippocampal expressions of NIX and FUNDC1 were the lowest and LC3 I/II expression the highest in the model group; NIX and FUNDC1 expressions were significantly higher and LC3 I expression was lower in QLJR+PCA group than in QLJR group and PCA group. Immunofluorescence staining revealed weakened NIX and FUNDC1 expressions and enhanced LC3 expression in the hippocampus of the rats in the model group as compared with those in the normal control and QLJR+PCA groups, but their expressions did not differ significantly between QLJR and PCA groups. The rats in the model group showed obvious structural disarray of the mitochondria, which were improved in all the treatment groups. CONCLUSIONS QLJR improves cognitive dysfunction in rats with high copper load possibly by regulating mitophagy.
Animals ; Male ; Rats, Sprague-Dawley ; Rats ; Drugs, Chinese Herbal/therapeutic use* ; Copper/toxicity* ; Mitophagy/drug effects* ; Hippocampus/drug effects* ; Cognition Disorders/drug therapy* ; Cognitive Dysfunction/chemically induced*

BACKGROUND AND OBJECTIVE

Mindfulness-based interventions (MBI), a novel treatment, and cognitive behavioral therapy (CBT), the standard treatment, are both effective in treating anxiety in adolescents. This study determined the effectiveness of mindfulness-based interventions versus cognitive behavioral therapy in reducing symptoms of anxiety among adolescents experiencing social anxiety through a systematic review and meta-analysis.

A systematic approach was used to identify eligible studies. Electronic databases, reference lists of relevant articles, and gray literature were searched. Data was analyzed using RevMan to calculate standard mean differences with 95% confidence intervals and subgroups. Heterogeneity was measured using visual assessment, the I2 statistic, and chi-square test.

Randomized controlled trials comparing MBI to CBT for adolescents diagnosed with social anxiety or social phobia disorder were analyzed, with non-randomized studies being excluded. Structured searches in electronic databases, reference lists, and gray literature were conducted by four independent reviewers who initially identified potential articles through title and abstract screening. After a comprehensive review of full-text articles and a consensus-building process, the selection of included articles was finalized. Data was analyzed using RevMan to calculate standard mean differences with 95% confidence intervals and to examine subgroups, with heterogeneity being assessed through visual evaluation, the I² statistic, and chi-square tests. Total number of participants was 255; 101 were male and 158 were women. Mean age was 27.5 years old, and diagnosed with Social Anxiety Disorder, Social Phobia, or DSM-IV-Defined-Anxiety-Disorder. They were divided into two groups: 125 participated in 8- to 12-week MBI sessions lasting 2 hours each, while 130 underwent 2-hour CBT sessions spanning 8, 12, or 14 weeks. There is moderate quality of evidence reporting non-significant difference on MBI vs CBT's effectiveness in alleviating symptoms of social anxiety [mean (95% CI) = -0.04 (-0.58, 0.51)].

Study found that there were no significant differences between Mindfulness-Based Interventions and Cognitive Behavioral Therapy in reducing social anxiety in adolescents. Mindfulness interventions have advantages in terms of cost-effectiveness for reducing symptoms of anxiety. Future research should include larger sample sizes and longer follow-up periods to further assess long-term effects of these interventions.

OBJECTIVE: To investigate the effect of moxibustion on central insulin resistance related proteins of the rats suffering from diabetic cognitive decline, and analyze the underlying mechanism of moxibustion for cognition improvement. METHODS: Using the intraperitoneal injection of STZ combined with a high-fat diet, the rat model of diabetic cognitive decline were prepared. Twenty successfully-modeled rats were assigned randomly into a model group and a moxibustion group, 10 rats in each one. Besides, a blank group was set up with 10 rats collected. In the moxibustion group, suspending moxibustion was applied to "Baihui" (GV20), "Shenting" (GV24) and "Dazhui" (GV14) at the same time, 20 min in each intervention, once a day, and 6 interventions were delivered weekly and the duration of treatment was consecutive 4 weeks. The random blood glucose was measured using glucometer, and the learning-memory ability was detected by water maze test. HE staining was used to observe the morphology of neurons in the hippocampal tissue, real-time PCR assay was to detect mRNA expression of insulin receptor substrate 1 (IRS1), phosphatidylinositol 3-kinase (PI3K) and protein kinase B (AKT) in the hippocampal tissue. The Western blot method was employed to detect the protein expression of IRS1, PI3K, AKT, phosphorylated IRS1 (p-IRS1), phosphorylated PI3K (p-PI3K) and phosphorylated AKT (p-AKT) in the hippocampal tissue, and the ratio of p-IRS1/IRS1, p-PI3K/PI3K and p-AKT/AKT was calculated separately. The immunofluorescence intensity of p-IRS1, p-PI3K, and p-AKT was measured using immunofluorescence. RESULTS: Compared with the blank group, the rats of the model group exhibited higher random blood glucose (P<0.001), longer escape latency (P<0.001), severe pathological damage in the hippocampus, lower mRNA expression of IRS1, PI3K, and AKT (P<0.001), reduced ratio of p-IRS1/IRS1, p-PI3K/PI3K and p-AKT/AKT (P<0.001), and declined immunofluorescence intensity of p-IRS1, p-PI3K, and p-AKT in the hippocampal tissue (P<0.001). In comparison with the model group, for the rats of the moxibustion group, the random blood glucose decreased (P<0.05), the escape latency was shortened (P<0.01), the hippocampal pathological damage was attenuated, the mRNA expression of IRS1, PI3K and AKT increased (P<0.01), the ratio of p-IRS1/IRS1, p-PI3K/PI3K and p-AKT/AKT was elevated (P<0.01, P<0.05), and the immunofluorescence intensity of p-IRS1, p-PI3K, and p-AKT in the hippocampal tissue was strengthened (P<0.01, P<0.05). CONCLUSION In diabetic rats experiencing cognitive decline, moxibustion can enhance the learning-memory ability, which may be attributed to modulating the protein expression of IRS1, PI3K, and AKT, and their phosphorylation, activating insulin signal transduction, and reducing central insulin resistance.
Animals ; Moxibustion ; Insulin Resistance ; Rats ; Male ; Insulin Receptor Substrate Proteins/genetics* ; Rats, Sprague-Dawley ; Humans ; Proto-Oncogene Proteins c-akt/genetics* ; Cognitive Dysfunction/genetics* ; Diabetes Mellitus, Experimental/therapy* ; Hippocampus/metabolism* ; Acupuncture Points ; Phosphatidylinositol 3-Kinases/genetics*

The paper introduces the diagnostic and therapeutic ideas and clinical experience of Professor LIU Zhibin in treatment with acupuncture for Parkinson's disease with mild cognitive impairment. Professor LIU believes that the basic pathogenesis of Parkinson's disease with mild cognitive impairment refers to the deficiency of liver and kidney, and the loss of mind control. Therefore, the treatment focuses on nourishing the liver and kidney, regulating the governor vessel, opening the brain orifice, and regulating the mind. The point prescription is composed of Tongdu Tiaoshen zhen (the points for promoting the circulating of the governor vessel and regulating the mind, i.e. four-mind needles [Extra], Shenting [GV24], bilateral Benshen [GB13] and Fengfu [GV16]), xiusanzhen (three-olfaction needles, including bilateral Yingxiang [LI20] and Yintang [GV24⁺]) and zhichan bazhen (eight anti-tremble needles, i.e. Baihui [GV20], Lianquan [CV23], and Hegu [LI4], Waiguan [TE5], Taichong [LR3], Zusanli [ST36], Sanyinjiao [SP6] and Taixi [KI3] on the affected side). Besides, the prescription is modified according to the syndrome, and the special technique of bone-touching needling is combined to enhance the therapeutic effect.
Humans ; Acupuncture Therapy ; Parkinson Disease/psychology* ; Cognitive Dysfunction/complications* ; Male ; Acupuncture Points ; Female ; Aged ; Middle Aged

OBJECTIVE: To observe the clinical efficacy of acupuncture on mild cognitive impairment (MCI) and its effect on gut microbiota. METHODS: A total of 62 MCI patients were randomly divided into an experimental group (31 cases, 2 cases dropped out) and a control group (31 cases). Both groups received exercise and cognitive training. In addition, the experimental group underwent acupuncture treatment at acupoints including Baihui (GV20), Sishencong (EX-HN1), and bilateral Fengchi (GB20), Xuanzhong (GB39), Zusanli (ST36), Yanglao (SI6), Xinshu (BL15), and etc., once every other day, three times per week, for a total of 12 weeks. Before and after treatment, the Montreal cognitive assessment (MoCA) and mini-mental state examination (MMSE) scores were evaluated in the two groups, changes in gut microbiota were detected using 16S rDNA sequencing technology. The clinical efficacy was assessed after treatment. RESULTS: Compared before treatment, MoCA and MMSE scores were increased in both groups after treatment (P<0.001), with higher scores in the experimental group than those in the control group (P<0.001, P<0.05). After treatment, the relative abundance of Faecalibacterium, Clostridia, and Ruminococcaceae was increased in the experimental group compared with that before treatment (P<0.05). Moreover, the relative abundance of Faecalibacterium in the experimental group was higher than that in the control group (P<0.05). The total effective rate was 82.8% (24/29) in the experimental group, which was higher than 61.3% (19/31) in the control group (P<0.05). CONCLUSION Acupuncture could improve cognitive dysfunction in patients with MCI, and its mechanism may be related to increasing the relative abundance of butyrate-producing bacteria such as Faecalibacterium, Clostridia, and Ruminococcaceae, maintaining the intestinal barrier, and inhibiting related inflammatory responses.
Humans ; Acupuncture Therapy ; Gastrointestinal Microbiome ; Cognitive Dysfunction/psychology* ; Male ; Female ; Aged ; Middle Aged ; Acupuncture Points ; Treatment Outcome ; Aged, 80 and over ; Cognition

OBJECTIVE: To observe the effects of moxibustion at different temperatures on cognitive function and blood glucose levels in patients with cognitive impairment associated with type 2 diabetes mellitus (T2DM). METHODS: A total of 66 T2DM patients with cognitive impairment were randomly assigned to a high-temperature group (22 cases, 1 case dropped out, 1 case was eliminated), a medium-temperature group (22 cases, 2 cases were eliminated), and a low-temperature group (22 cases, 2 cases were eliminated). All groups received moxibustion at Baihui (GV20), Dazhui (GV14), and Shenting (GV24) based on their existing glycemic control treatment. Moxibustion temperatures were maintained at 44-46 ℃ (high-temperature group), 41-43 ℃ (medium-temperature group), and 38-40 ℃ (low-temperature group), respectively, for 20 min per session, every other day, 3 times a week for 3 months. The Montreal cognitive assessment (MoCA) score, mini-mental state examination (MMSE) score, short-term memory (STM) accuracy and average reaction time, Rey-Osterrieth complex figure (ROCF) score, fasting plasma glucose (FPG), and glycated hemoglobin (HbA1c) were assessed before and after treatment. Clinical efficacy was evaluated after treatment. RESULTS: After treatment, MMSE scores in all three groups were higher than those before treatment (P<0.05). In the high-temperature group, the total MoCA score and the scores of visuospatial and executive function, memory and delayed recall, attention, naming, language, and abstraction were higher than those before treatment (P<0.05); the scores of ROCF copy, immediate recall, and delayed recall were higher than those before treatment (P<0.05); the HbA1c level was lower than that before treatment (P<0.05). In the medium-temperature group, the total MoCA score and the scores of memory and delayed recall, attention, and language were higher than those before treatment (P<0.05). STM accuracy was higher than before treatment (P<0.05), and STM average reaction time was shorter than before treatment (P<0.05) in both the high-temperature and medium-temperature groups. After treatment, the total MoCA score and the scores of visuospatial and executive function, memory and delayed recall, attention, and language in the high-temperature group were higher than those in the medium- and low-temperature groups (P<0.05); MMSE score, STM accuracy, and ROCF immediate recall and delayed recall scores were higher than those in the medium- and low-temperature groups (P<0.05); STM average reaction time was shorter than that in the medium- and low-temperature groups (P<0.05); HbA1c level was lower than that in the low-temperature group (P<0.05). The total MoCA score, attention score, and MMSE score in the medium-temperature group were higher than those in the low-temperature group (P<0.05), and STM average reaction time was shorter than that in the low-temperature group (P<0.05). There were no statistically significant differences in FPG within or between the three groups before and after treatment (P>0.05). The total effective rates were 75.0% (15/20) in the high-temperature group, 50.0% (10/20) in the medium-temperature group, and 15.0% (3/20) in the low-temperature group; the total effective rate in the high-temperature group was significantly higher than that in the low-temperature group (P<0.05). CONCLUSION Moxibustion at different temperatures has a dose-effect relationship in treating cognitive impairment in T2DM patients. A temperature range of 44-46 ℃ is more effective in improving cognitive function and stabilizing average blood glucose levels over 2-3 months.
Humans ; Diabetes Mellitus, Type 2/therapy* ; Male ; Female ; Moxibustion ; Middle Aged ; Aged ; Cognitive Dysfunction/psychology* ; Cognition ; Temperature ; Blood Glucose/metabolism* ; Adult ; Acupuncture Points

OBJECTIVE: To investigate the effects of Huayu Tongluo (transforming stasis and unblocking collaterals) moxibustion on cognitive function and insulin resistance in patients with type 2 diabetes mellitus (T2DM) and cognitive decline. METHODS: Ninety patients with T2DM and cognitive decline were randomly divided into a moxibustion group (n=45, 3 cases dropped out, 2 cases were eliminated) and a waiting moxibustion group (n=45, 2 cases dropped out). Both groups received routine hypoglycemic treatment for 12 weeks. The moxibustion group additionally received Huayu Tongluo moxibustion at Baihui (GV20), Shenting (GV24), and Dazhui (GV14). Pressing moxibustion was applied to Baihui (GV20) for 20 min, while suspended moxibustion was applied to Shenting (GV24) and Dazhui (GV14) for 20 min each. Treatments of moxibustion were administered every other day (three times per week) for 12 weeks. All patients were followed up for 12 weeks, during which their original hypoglycemic medication regimen was maintained. Before treatment, after 12 weeks of treatment, and at the 12-week follow-up, the scores of Montreal cognitive assessment (MoCA), mini-mental state examination (MMSE), Addenbrooke's cognitive examination Ⅲ (ACE-Ⅲ), symbol digit modalities test (SDMT), and Athens insomnia scale (AIS) and the insulin resistance index (HOMA-IR) were observed in the two groups. RESULTS: Compared with before treatment, the MoCA scores, MMSE scores, ACE-Ⅲ subscale scores (attention, memory, language fluency, language, visuospatial ability) and total scores, and SDMT scores were increased (P<0.01), while the AIS scores were decreased (P<0.05) in the moxibustion group after treatment and at follow-up. Compared with before treatment, the MMSE score, ACE-Ⅲ subscale scores (memory, attention) and total score after treatment, as well as the ACE-Ⅲ subscale scores (language, memory, attention) and total score, and SDMT score at follow-up were increased (P<0.05, P<0.01) in the waiting moxibustion group. Compared with before treatment, HOMA-IR was decreased in both groups after treatment and at follow-up (P<0.01). At follow-up, ACE-Ⅲ subscale scores (attention, memory), and the total score in the moxibustion group were lower than those after treatment (P<0.05, P<0.01), and the ACE-Ⅲ language subscale score, total ACE-Ⅲ score, and SDMT score in the waiting moxibustion group were higher than those after treatment (P<0.01, P<0.05). After treatment and at follow-up, compared with the waiting moxibustion group, the moxibustion group had higher MoCA scores, MMSE scores, SDMT scores, ACE-Ⅲ subscale scores (attention, memory, language fluency) and total scores (P<0.05, P<0.01), and lower HOMA-IR (P<0.05). CONCLUSION Huayu Tongluo moxibustion can effectively improve cognitive function in patients with T2DM and cognitive decline. This improvement may be associated with the reduction in insulin resistance.
Humans ; Insulin Resistance ; Diabetes Mellitus, Type 2/complications* ; Male ; Female ; Moxibustion ; Middle Aged ; Aged ; Cognition ; Acupuncture Points ; Adult ; Cognitive Dysfunction/therapy*