China Initiative for Multi-Domain Intervention (CHINA-IN-MUDI) to Prevent Cognitive Decline: Study Design and Progress.

BACKGROUND: Alzheimer's disease (AD), the most common type of irreversible dementia, is predicted to affect 152 million people by 2050. Evidence from large-scale preventive randomized controlled trials (RCTs) on modifiable risk variables in Europe has shown that multi-domain lifestyle treatments for older persons at high risk of dementia may be practical and effective. Given the substantial differences between the Chinese and European populations in terms of demographics and living conditions, direct adoption of the European program in China remains unfeasible. Although a RCT has been conducted in China previously, its participants were mainly from rural areas in northern China and, thus, are not representative of the entire nation.There is an urgent need to establish cohorts that represent different economic, cultural, and geographical situations in order to explore implementation strategies and evaluate the effects of early multi-domain interventions more comprehensively and accurately. MEDTODS: We developed an integrated intervention procedure implemented in urban neighborhood settings, namely China Initiative for Multi-Domain Intervention (CHINA-IN-MUDI). CHINA-IN-MUDI is a 2-year multicenter open-label cluster-randomised controlled trial centered around a Chinese-style multi-domain intervention to prevent cognitive decline. Participants aged 60-80 years were recruited from a nationally representative study, i.e. China Healthy Aging and Dementia Study cohort. An external harmonization process was carried out to preserve the original FINGER design. Subsequently, we standardized a series of Chinese-style intervention programs to align with cultural and socioeconomic status. Additionally, we expanded the secondary outcome list to include genomic and proteomic analyses. To enhance adherence and facilitate implementation, we leveraged an e-health application. RESULTS: Screening commenced in July 2022. Currently, 1,965 participants have been randomized into lifestyle intervention (n = 772) and control groups (n = 1,193). Both the intervention and control groups exhibited similar baseline characteristics. Several lifestyle and vascular risk factors were present, indicating a potential window of opportunity for intervention. The intervention will be completed by 2025. CONCLUSIONS: This project will contribute to the evaluation of the effectiveness and safety of intervention strategies in controlling AD risk and reducing clinical events, providing a basis for public health decision-making in China.

[MicroRNA and sensorineural hearing loss].

Hearing loss caused by disorders throughout the cochlea or auditory pathway called sensorineural hearing loss. The etiology of sensorineural deafness is complex and diverse, and the sensory epithelial cell damage of the inner ear spiral is the main pathological change. MicroRNAs play a role in the regulation of gene expression by inhibiting or degrading the mRNA of target genes. More and more studies have shown that microRNA plays an important role in the development of sensorineural deafness. This article will review the process of microRNA involvement in the development of sensorineural hearing loss.

[Metformin's effect on 5-fluorouracil,cisplatin,paclitaxel in laryngocarcinoma Hep-2 cells].

Objective:To investigate metformin's effect on chemosensitivity of chemotherapeutic drug 5-fluorouracil in laryngocarcinoma Hep-2 cells. Investigate the variation trend of protein expression of AMPK pathway in the combined effect.Method:Laryngocarcinoma Hep-2 cells were treated with different concentrations of 5-fluorouracil in vitro together with or without metformin for 72 h. Use MTT assay to investigate the influence on the inhibition rate to Hep-2 cells. Hep-2 cells were treated with cisplatin, 5-fluorouracil or paclitaxel with or without metformin. Use Western blot assay to investigate the expression level of AMPKα, P21 or Cyclin D1 protein. Result:5-fluorouracil and metformin could inhibit the proliferation of Hep-2 cells. 5-fluorouracil in low concentration combined with metformin could increase the proliferation inhibition rate of Hep-2 cells. In the circumstances of using 5-fluorouracil in high concentration with metformin , the cell proliferation inhibition rate of combining group makes no differences with the single-drug group. The combination of metformin and 5-fluorouracil produced an antagonism action in Hep-2 cells.Western blot assay showed that metformin, cisplatin, 5-fluorouracil could have caused the increase of expression level of AMPK-α, P21 and Cyclin D1 in Hep-2 cells while Paclitaxel could have cause the decrease of expression level of Cyclin D1. Using combined drug could cause the change of protein expression. Conclusion:5-fluorouracil has been found to inhibit the proliferation of Hep-2 cells. Metformin has an antagonism on the anticancer effect to 5-fluorouracil in Hep-2 cells, and this antagonistic effect occurred partially through molecular signal pathways of AMPK-α, P21 and Cyclin D1 and it's significantly related to the cell cycle arrest.

PTEN activation through K163 acetylation by inhibiting HDAC6 contributes to tumour inhibition.

Phosphatase and tensin homologue deleted on chromosome 10 (PTEN), an important tumour-suppressor gene, is mutated, downregulated or dysfunctional in many tumours. The phosphatase activity of PTEN depends on membrane translocation (activation). As promising anti-cancer agents, histone deacetylase (HDAC) inhibitors, particularly trichostatin A (TSA), can promote PTEN membrane translocation, but the underlying mechanism remains unknown. In this study, we revealed that non-selective HDAC inhibitors, namely, TSA or suberoylanilide hydroxamic acid (SAHA), induced PTEN membrane translocation through PTEN acetylation at K163 by inhibiting HDAC6. K163 acetylation inhibited the interaction of the PTEN C-tail with the remaining part of PTEN, resulting in PTEN membrane translocation. Overexpression of wild-type PTEN, but not K163-mutated PTEN, facilitated the inhibition of cell proliferation, migration and invasion, as well as xenograft tumour growth, induced by SAHA or tubastatin A, an HDAC6-specific inhibitor. These results indicated that PTEN activation by inhibiting HDAC6 significantly contributed to tumour inhibition. Therefore, non-selective HDAC or HDAC6-specific inhibitors may be more clinically suitable to treat tumours without PTEN mutations or deletions.

[Effects of dihydroartemisinin on the apoptosis of Fadu cells].

Objective:To investigate the effect of dihydroartemisinin (DHA) on the apoptosis of Fadu cells.Method:Fadu cells were treated with DMSO or different doses of DHA for 24 or 48 h.After that, IC50 values of DHA were calculated based on the cell viability tested via MTT assay, the cell morphology was observed,the percentage of apoptotic cells was analyzed with the Annexin V-FITC Apoptosis Detection Kit, and some important regulators of apoptosis, such as Bcl-2, Bcl-xl, Mcl-1, Bax, and C-PARP were determined by Western blotting.Result:Certain doses of DHA significantly inhibited the proliferation and induced apoptosis of Fadu cells in a dose and time dependent manners. DHA also downregulated the expression of antiapoptotic proteins (Bcl-2, Bcl-xl, and Mcl-1) and upregulated the expression of proapoptotic proteins (Bax and C-PARP).Conclusion:DHA remarkably inhibited proliferation and induction of apoptosis in Fadu cells via affecting proteins of Bcl-2 family. DHA may be a promising drug to treat hypopharyngeal carcinoma.

Valproic acid increases white matter repair and neurogenesis after stroke.

Acute treatment of stroke with histone deacetylase (HDAC) inhibitors has been shown to reduce ischemic cell damage; however, it is unclear whether delayed treatment with HDAC inhibitors will contribute to the brain repair and plasticity. In the present study, we investigated the effects of delayed treatment of stroke with a pan HDAC inhibitor, valproic acid (VPA), on white matter injury and neurogenesis during stroke recovery. Administration of VPA at a dose of 100mg/kg for 7 days starting 24h after middle cerebral artery occlusion (MCAo) in rats significantly improved neurological outcome measured 7-28 days post-MCAo. In addition, the VPA treatment significantly increased oligodendrocyte survival and newly generated oligodendrocytes, which was associated with elevation of myelinated axonal density in the ischemic boundary 28 days after MCAo. VPA treatment also increased the expression of glutamate transporter 1 (GLT1) in the ischemic boundary after stroke, and increased acetylated histone H4 expression in neuroblasts and the number of new neurons in striatal ischemic boundary region. This study provides new evidence that the delayed VPA treatment enhances white matter repair and neurogenesis in ischemic brain, which may contribute to improved functional outcome.

Cerebrospinal fluid tau, Abeta1-42 and inflammatory cytokines in patients with Alzheimer's disease and vascular dementia.

In this study we aimed to evaluate the possibility of using cerebrospinal fluid (CSF) tau, Abeta(1-42) and inflammatory cytokines for diagnosis of Alzheimer's disease (AD) and vascular dementia (VD). We measured levels of total tau (T-tau), phospho-tau (P-tau), Abeta(1-42), IL-6, and TNFalpha in CSF in groups of AD, VD, and controls using enzyme-linked immunosorbent assay (ELISA). T-tau level was found significantly higher in groups of AD (t = 3.015, P < 0.01) and VD (t = 2.872, P < 0.01) than in controls. IL-6 level as also higher in AD (t = 2.883, P < 0.01) and VD (t = 3.032, P < 0.01) than in controls. Both T-tau and IL-6 were not significantly different between AD and VD (P > 0.05). The group of AD had remarkably higher P-tau (t = 4.261 and 3.883, respectively, P < 0.01) and lower Abeta(1-42) (t = 3.883 and 4.129, respectively, P < 0.01), as compared with those in VD and controls. TNFalpha level in AD was significantly higher than that in controls (t = 2.745, P < 0.01), but lower than in VD (t = 3.032, P < 0.01). Our data suggested that increment of T-tau and IL-6 levels in CSF was useful for screening AD and VD in certain population, while descending Abeta(1-42) and ascending TNFalpha in CSF are preferable to diagnose AD. In addition, a higher level of CSF P-tau might support AD diagnosis.