Acupuncture Therapy on Dementia: Explained with an Integrated Analysis on Therapeutic Targets and Associated Mechanisms.

BACKGROUND: Dementia, mainly Alzheimer's disease (AD) and vascular dementia (VaD), remains a global health challenge. Previous studies have demonstrated the benefits of acupuncture therapy (AT) in improving dementia. Nevertheless, the therapeutic targets and integrated biological mechanisms involved remain ambiguous. OBJECTIVE: To identify therapeutic targets and biological mechanisms of AT in treating dementia by integrated analysis strategy. METHODS: By the identification of differentially expressed genes (DEGs) of AD, VaD, and molecular targets of AT active components, the acupuncture therapeutic targets associated with the biological response to AD and VaD were extracted. Therapeutic targets-based functional enrichment analysis was conducted, and multiple networks were constructed. AT-therapeutic crucial targets were captured by weighted gene co-expression network analysis (WGCNA). The interactions between crucial targets with AT active components were verified by molecular docking. RESULTS: Our results demonstrated that 132 and 76 acupuncture therapeutic targets were associated with AD and VaD. AT-therapeutic crucial targets including 58 for AD and 24 for VaD were captured by WGCNA, with 11 in shared, including NMU, GRP, TAC1, ADRA1D, and SST. In addition, 35 and 14 signaling pathways were significantly enriched by functional enrichment analysis, with 6 mutual pathways including neuroactive ligand-receptor interaction, GABAergic synapse, calcium signaling pathway, cAMP signaling pathway, chemokine signaling pathway, and inflammatory mediator regulation of TRP channels. CONCLUSION: The improvement of AD and VaD by AT was associated with modulation of synaptic function, immunity, inflammation, and apoptosis. Our study clarified the therapeutic targets of AT on dementia, providing valuable clues for complementing and combining pharmacotherapy.

Effects of Folic Acid and Vitamin B12, Alone and in Combination on Cognitive Function and Inflammatory Factors in the Elderly with Mild Cognitive Impairment: A Single-blind Experimental Design.

BACKGROUND: Folate and vitamin B12 are well-known as essential nutrients that play key roles in the normal functions of the brain. Inflammatory processes play at least some role in the pathology of AD. Effective nutritional intervention approaches for improving cognitive deficits that reduce the peripheral inflammatory cytokine levels have garnered special attention. OBJECTIVE: The present study aimed to determine whether supplementation with folic acid and vitamin B12, alone and in combination improves cognitive performance via reducing levels of peripheral inflammatory cytokines. METHODS: 240 participants with MCI were randomly assigned in equal proportion to four treatment groups: folic acid alone, vitamin B12 alone, folic acid plus vitamin B12 or control without treatment daily for 6 months. Cognition was measured with WAIS-RC. The levels of inflammatory cytokines were measured using ELISA. Changes in cognitive function or blood biomarkers were analyzed by repeatedmeasure analysis of variance or mixed-effects models. This trial has been registered with trial number ChiCTR-ROC-16008305. RESULTS: Compared with control group, the folic acid plus vitamin B12 group had significantly greater improvements in serum folate, homocysteine, vitamin B12 and IL-6, TNF-α, MCP-1. The folic acid plus vitamin B12 supplementation significantly changed the Full Scale IQ (effect size d = 0.169; P = 0.024), verbal IQ (effect size d = 0.146; P = 0.033), Information (d = 0.172; P = 0.019) and Digit Span (d = 0.187; P = 0.009) scores. Post hoc Turkey tests found that folic acid and vitamin B12 supplementation was significantly more effective than folic acid alone for all endpoints. CONCLUSIONS: The combination of oral folic acid plus vitamin B12 in MCI elderly for six months can significantly improve cognitive performance and reduce the levels of inflammatory cytokines in human peripheral blood. The combination of folic acid and vitamin B12 was significantly superior to either folic acid or vitamin B12 alone.

Effects of folic acid supplementation on cognitive function and Aß-related biomarkers in mild cognitive impairment: a randomized controlled trial.

PURPOSE: Observational studies have frequently reported that low blood folate concentrations are associated with poor cognitive performance. Our previous studies have shown the potential beneficial effect on the metabolite levels of methionine cycle and peripheral blood inflammatory cytokines from 6- and 12-month folic acid supplementation on cognitive function in mild cognitive impairment (MCI). This study aims to continue exploring the effect of 24-month folic acid supplementation on cognitive function and pathological mechanism in MCI. METHODS: 180 individuals with MCI were identified and randomly divided into intervention (folic acid 400 µg/day, n = 90) and convention (n = 90) groups. Cognitive function (WAIS-RC) and blood Aß-related biomarkers were measured at baseline and at 6, 12, 18, and 24 months. Data were analyzed using generalized estimating equation. This trial has been registered with Trial Number: ChiCTR-TRC-13003227. RESULTS: During the follow-up, scores of full scale IQ, verbal IQ, and subdomains of Information and Digit Span were significantly higher in the intervention group than those in the convention group (P < 0.05). In the intervention group, blood homocysteine, S-adenosylhomocysteine (SAH), Aß-42, and the expression of APP-mRNA were decreased (P < 0.05), while S-adenosylmethionine (SAM), SAM/SAH ratio, and the expression of DNA methyltransferase mRNA were increased (P < 0.05). CONCLUSION: Folic acid supplementation appears to improve cognitive function and reduce blood levels of Aß-related biomarkers in MCI. Larger-scale double-blind placebo-controlled randomized trials of longer duration are needed.

Folic acid supplementation improves cognitive function by reducing the levels of peripheral inflammatory cytokines in elderly Chinese subjects with MCI.

This study aimed to evaluate whether folic acid supplementation would improve cognitive performance by reducing serum inflammatory cytokine concentrations. This RCT was performed in Tianjin, China. Participants with mild cognitive impairment (MCI) were randomly assigned to the folic acid (400 µg/day) or conventional treatment groups. Neuropsychological tests were administered, and folate, homocysteine, vitamin B12, IL-6, TNF-α, Aß-42, and Aß-40 were measured at baseline and at 6- and 12-month time points.152 participants (folic acid: 77, conventional: 75) completed the trial. Significant improvements in folate (ηp2 = 0.703, P = 0.011), homocysteine (ηp2 = 0.644, P = 0.009), Aß-42 (ηp2 = 0.687, P = 0.013), peripheral IL-6 (ηp2 = 0.477, P = 0.025), TNF-α (ηp2 = 0.709, P = 0.009) levels were observed in folic acid group compared with conventional group. Folic acid supplementation improved the Full Scale Intelligence Quotient (P = 0.028; effect size d = 0.153), Information (P = 0.031; d = 0.157) and Digit Span (P = 0.009; d = 0.172) scores at 12 months compared with conventional treatment. Based on these findings, daily oral administration of a 400-µg folic acid supplement to MCI subjects for 12 months can significantly improve cognitive performance and reduce peripheral inflammatory cytokine levels.

Folic Acid Supplementation Mitigates Alzheimer's Disease by Reducing Inflammation: A Randomized Controlled Trial.

Background/Aims. Low serum folate levels can alter inflammatory reactions. Both phenomena have been linked to Alzheimer's disease (AD), but the effect of folic acid on AD itself is unclear. We quantified folate supplementation's effect on inflammation and cognitive function in patients with AD over the course of 6 months. Methods. Patients newly diagnosed with AD (age > 60 years; n = 121; mild to severe; international criteria) and being treated with donepezil were randomly assigned into two groups with (intervention group) or without (control group) supplemental treatment with folic acid (1.25 mg/d) for 6 months. The Mini-Mental State Examination (MMSE) was administered to all patients at baseline and follow-up, and blood samples were taken before and after treatment. We quantified serum folate, amyloid beta (Aß), interleukin-6 (IL-6), tumor necrosis factor α (TNFα), plasma homocysteine (Hcy), S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), and the mRNA levels of presenilin (PS), IL-6, and TNFα in leukocytes. Data were analyzed using a repeated-measures mixed model. Results. The mean MMSE was slightly increased in the intervention group compared to that in the control group (P < 0.05). Posttreatment, plasma SAM and SAM/SAH levels were significantly higher (P < 0.05), while Aß 40, PS1-mRNA, and TNFα-mRNA levels were lower in the intervention group than in the control group (P < 0.05). The Aß 42/Aß 40 ratio was also higher in the intervention group (P < 0.05). Conclusions. Folic acid is beneficial in patients with AD. Inflammation may play an important role in the interaction between folic acid and AD. This trial is registered with clinical trial registration number ChiCTR-TRC-13003246.

Lifestyle change and the prevention of cognitive decline and dementia: what is the evidence?

PURPOSE OF REVIEW: Effective pharmaceutical treatment of dementia is currently unavailable. Epidemiological work has, however, identified modifiable lifestyle factors, such as poor diet and physical and cognitive inactivity, that are associated with the risk of dementia. These factors may be useful targets for the prevention of cognitive impairment and dementia. Much recent research has, therefore, adopted an interventional focus. We review this work, highlight some methodological limitations, and provide recommendations for future research. RECENT FINDINGS: Change from a sedentary lifestyle to moderate physical activity has beneficial effects on cognitive functioning, and preliminary evidence suggests that such change may reduce the incidence of dementia. The evidence on cognitive benefits of lifestyle changes towards more intellectual engagement is insufficient. Nutritional supplements to treat deficiency may improve cognitive performance, but supplements on top of a healthy diet cannot be recommended. SUMMARY: Introduction of physical activity can reduce the risk of cognitive impairment in old age. Future research on nutritional supplements must consider the principle of an inverted U-shaped association between nutritional level and cognitive function. Work on the effects of cognitive training must use transfer tasks as primary outcome measures, and investigate whether effects of cognitive training generalize beyond the trained cognitive tasks.

γ-Tocotrienol inhibits cell viability through suppression of ß-catenin/Tcf signaling in human colon carcinoma HT-29 cells.

γ-Tocotrienol, a major component of the tocotrienol-rich fraction of palm oil, has been suggested to have antioxidant and anticancer activity as well as potent chemopreventive effects on tumor cells. In this study, the mechanisms underlying γ-tocotrienol-mediated growth inhibition of human carcinoma HT-29 cells were further investigated, especially in correlation with the involvement of ß-catenin/T-cell factor (Tcf) signaling pathway. We found that γ-tocotrienol could strongly suppress the transcriptional activity of ß-catenin/Tcf signaling pathway in HT-29 cells. γ-Tocotrienol inhibited the expression level of total ß-catenin protein but did not significantly affect the phosphorylated ß-catenin level. Meanwhile, γ-tocotrienol down-regulated the protein level of nuclear ß-catenin and induced its redistribution to cell membrane. Furthermore, γ-tocotrienol suppressed the expression of downstream target genes such as c-myc, cyclin D1 and survivin. The results demonstrated that γ-tocotrienol-inhibited growth and -induced apoptosis in HT-29 cells were accompanied by significant inhibition of ß-catenin/Tcf signaling. Blocking the expression of ß-catenin with small interfering RNA significantly suppressed the ability of γ-tocotrienol to reduce viability and induce apoptosis in HT-29 cells. Thus, our data suggested that γ-tocotrienol exerts its anticancer activity through ß-catenin/Tcf signaling, and ß-catenin is a target for γ-tocotrienol in the Wnt/ß-catenin signaling pathway.

Protective effects of bovine colostrum acid proteins on bone loss of ovariectomized rats and the ingredients identification.

SCOPE: Milk basic proteins and bovine colostrum extracts have preventive effects on osteoporosis. However, the effects of bovine colostrum acidic proteins (BCAP) on properties of bone have not been reported. This study investigated the effect of BCAP on the prevention of bone loss in ovariectomized (OVX) rats. METHODS AND RESULTS: Forty-eight 3-month old female Sprague-Dawley rats were OVX and another 12 rats underwent a sham operation (Sham). The OVX rats were randomly separated into four groups, i.e. OVX control, OVX plus 2 mg/day BCAP, OVX plus 10 mg/day BCAP, and OVX plus 50 mg/day BCAP, and were gavaged once per day for 12 wk. The effects on bone mineral content, bone mineral density, microarchitecture and biomechanical properties were determined. The bioactive ingredients in BCAP were isolated and identified. Results showed that BCAP increased the bone mineral content and bone mineral density of the femur in a dose-dependent manner. Scanning electron microscope observation and mechanical testing further confirmed the positive effects of BCAP. These positive effects attribute to the fact that osteopontin, lactoferrin, epidermal growth factor and insulin-like growth factor-2 are the dominant proteins in BCAP. CONCLUSIONS: BCAP (2-50 mg/day) could prevent osteoporosis caused by bone loss in OVX rats.