SIRT4 promotes neuronal apoptosis in models of Alzheimer's disease via the STAT2-SIRT4-mTOR pathway.

Alzheimer's disease (AD) is the leading cause of dementia and presents a considerable disease burden. Its pathology involves substantial neuronal loss, primarily attributed to neuronal apoptosis. Although sirtuin 4 (SIRT4) has been implicated in regulating apoptosis in various diseases, the role of SIRT4 in AD pathology remains unclear. The study employed APP/PS1 mice as an animal model of AD and amyloid-ß (Aß)1-42-treated HT-22 cells as an AD cell model. SIRT4 expression was determined by quantitative real-time polymerase chain reaction, western blot, and immunofluorescence. A Sirt4 knockdown model was established by intracranial injection of lentivirus-packaged sh-SIRT4 and cellular lentivirus transfection. Immunohistochemistry and flow cytometry were used to examine Aß deposition in mice and apoptosis, respectively. Protein expression was assessed by western blot analysis. The UCSC and JASPAR databases were used to predict upstream transcription factors of SIRT4. Subsequently, the binding of transcription factors to SIRT4 was analyzed using a dual-luciferase assay and chromatin immunoprecipitation. SIRT4 expression was upregulated in both APP/PS1 mice and Aß-treated HT-22 cells in comparison to their respective control groups. Sirt4 knockdown in animal and cellular models of AD resulted in reduced apoptosis, decreased Aß deposition, and amelioration of learning and memory impairments in mice. Mechanistically, SIRT4 modulates apoptosis via the mTOR pathway and is negatively regulated by the transcription factor signal transducer and activator of transcription 2 (STAT2). Our study findings suggest that targeting the STAT2-SIRT4-mTOR axis may offer a new treatment approach for AD.

Genetic polymorphism of clopidogrel metabolism related gene CYP2C19 gene in Chinese from Foshan area of Guangdong Province.

BACKGROUND: The CYP2C19 gene is highly polymorphic, and CYP2C19 is involved in the broad interindividual variability of the clinical efficacy of certain clinical medications, such as clopidogrel. However, data on the CYP2C19 genotype in the Chinese population of the Foshan area of Guangdong Province are scarce. The purpose of this study was to determine CYP2C19 genetic polymorphisms in patients in the Foshan area and to compare the CYP2C19 genotype frequencies in different populations to determine the allele distribution pattern to identify the most appropriate prescription. METHODS: The CYP2C19 gene was detected in 1231 patients on a gene chip platform, and the genotype frequencies of CYP2C19 in Foshan populations from different populations were compared. RESULTS: The frequencies of CYP2C19*1, *2 and *3 in the Foshan population were 63.89%, 30.46% and 5.65%, respectively. For the three metabolic types, the frequency associated with the rapid metabolism type (*1/*1) was 41.51 [95% confidence interval (CI) 40.11 to 42.91%]; that for the intermediate metabolism type (*1/*2, *1/*3) was 44.76% (95% CI 43.34 to 46.18) and that for the slow metabolism type (*2/*2, *2/*3, *3/*3) was 13.73% (95% CI 12.75 to 14.71%). In the Foshan population, the frequencies of the CYP2C19 *2 and *3 alleles were similar to those previously reported for Chinese and other Asian populations. CONCLUSION: Our study is a report on the genetic basis of CYP2C19 polymorphism in the Foshan population. Our results will potentially contribute to the improvement of pharmacotherapy effectiveness by providing personalized medicine for the Foshan population.

The inhibition of PGAM5 suppresses seizures in a kainate-induced epilepsy model via mitophagy reduction.

Background: Epilepsy is a common neurological disease, and excessive mitophagy is considered as one of the major triggers of epilepsy. Mitophagy is a crucial pathway affecting reactive oxygen species. Phosphoglycerate mutase 5 (PGAM5) is a protein phosphatase present in mitochondria that regulates many biological processes including mitophagy and cell death. However, the mechanism of PGAM5 in epilepsy remains unclear. The purpose of the present study was to examine whether PGAM5 affects epilepsy through PTEN-induced putative kinase 1 (PINK1)-mediated mitophagy. Methods: After the knockdown of PGAM5 expression by the adeno-associated virus, an epilepsy model was created by kainic acid. Next, the seizure activity was recorded by local field potentials before evaluating the level of mitochondrial autophagy marker proteins. Lastly, the ultrastructure of mitochondria, neuronal damage and oxidative stress levels were further observed. Results: A higher PGAM5 level was found in epilepsy, and its cellular localization was in neurons. The interactions between PGAM5 and PINK1 in epilepsy were further found. After the knockdown of PGAM5, the level of PINK1 and light chain 3B was decreased and the expression of the translocase of the inner mitochondrial membrane 23 and translocase of the outer mitochondrial membrane 20 were both increased. Knockdown of PGAM5 also resulted in reduced neuronal damage, decreased malondialdehyde levels, decreased reactive oxygen species production and increased superoxide dismutase activity. In addition, the duration of spontaneous seizure-like events (SLEs), the number of SLEs and the time spent in SLEs were all reduced in the epilepsy model after inhibition of PGAM5 expression. Conclusion: Inhibition of PGAM5 expression reduces seizures via inhibiting PINK1-mediated mitophagy.

SPIB acts as a tumor suppressor by activating the NFkB and JNK signaling pathways through MAP4K1 in colorectal cancer cells.

Spi-B transcription factor (SPIB) is a member of the E-twenty-six (ETS) transcription factor family. Previous studies have shown that the expression of SPIB is downregulated in human colorectal cancer tissues. The purpose of our study was to explore the biological function and related mechanism of SPIB in colorectal cancer cells. Our study found that SPIB could inhibit the proliferation, migration and invasion of CRC cells; inhibit angiogenesis; and induce CRC cells cycle arrest in G2/M phase and promote the apoptosis of CRC cells. We also found that compared with the control group, the 50% inhibitory concentration (IC50) values of oxaliplatin and 5-FU in the SPIB overexpression group were significantly reduced. Western blot results showed that the overexpression of SPIB upregulated cleaved-PARP(c-PARP), nuclear factor kB p65 (NFkB p65), phospho-NFkB p65 (p-NFkB P65), JNK1, and C-Jun protein expression levels compared with the control group. The silence of SPIB downregulated c-PARP, NFκB p65, p-NFκB p65, JNK1, and C-Jun protein expression levels. A dual-luciferase reporter assay showed that SPIB could activate the promoter of MAP4K1 and enhance the expression of MAP4K1. After silencing MAP4K1, the protein expression levels of c-PARP, NFkB P65, p-NFkB P65, JNK1, and C-Jun were downregulated. In summary, we found that SPIB is a tumor suppressor in colorectal cancer cells and that SPIB sensitizes colorectal cancer cells to oxaliplatin and 5-FU, SPIB exerts its anti-colorectal cancer effect by activating the NFkB and JNK signaling pathways through MAP4K1. The above findings may provide a reference for new molecular markers and therapeutic targets for CRC.

The psychological impact on patients with memory disorders and their caregivers during COVID-19.

BACKGROUND: COVID-19 is erupting globally. Mass quarantine had been implemented all around China which could influence the psychological status of patients with memory disorders and their caregivers. AIM: To investigate the psychological impact of mass quarantine on patients with memory disorders and their caregivers in China. METHODS: We completed a cross-sectional study in 787 patients and their caregivers registered from 2010 to 2019 in Memory Clinic, The First Affiliated Hospital of Chongqing Medical University, by telephone interviews. The performance in neuropsychiatric symptoms (NPSs), sleep, nutrition, chronic diseases of patients, and the burden of care, anxiety and depression of caregivers was assessed by six assessment scales (MNA-SF, PSQI, NPI, RSS, PHQ-9 and GAD-7). RESULTS: Only 68 (8.6%) patients worried about the outbreak of COVID-19. The prevalence of NPSs among all subjects was nearly 60.0%. Approximately 50.0% of the caregivers reported distress. More than 70.0% of patients remained stable in NPSs. However, anxiety, depression, aberrant motor disorder and delusion were exacerbated (22.9%, 18.6%, 17.1% and 16.8%, respectively). Appetite and eating disorder led alleviation rate by 25.8% while disappearing rate of agitation led by 5.8%. 7.5% of caregivers manifested depressive symptoms while 4.9% expressed anxiety symptoms, and 40.8% showed care burden. The coefficients of RSS and PHQ-9, RSS and GAD-7, RSS and NPI-D, PHQ-9 and GAD-7 were 0.7, 0.5, 0.5 and 0.6, respectively (p < 0.01). CONCLUSION: Changes in NPSs during COVID-19 were observed in some patients with memory disorders and their caregivers, and adherence to medication contributed to the stabilization of NPSs.

The Neuropsychiatric Changes After COVID-19 Quarantine in Patients With Cognitive Impairment and Their Caregivers in Chongqing, China: A Cohort Study.

BACKGROUND: The follow-up study on neuropsychiatric changes after the lifting of coronavirus disease 2019 (COVID-19) quarantine in patients with cognitive impairment and their caregivers is still lacking, and relative information is needed to formulate more comprehensive healthcare prevention measures worldwide. AIMS: To provide data on the changes in neuropsychiatric performance after the lifting of COVID-19 quarantine in patients with cognitive disorders and their caregivers. METHODS: Two surveys in Chongqing, China were conducted via telephonic interview with 531 patients and their caregivers. The baseline survey was performed from February 11 to 23, 2020, and the follow-up was from October 24 to November 9, 2020. The data of neuropsychiatric symptoms (NPSs), sleep, nutrition, and chronic diseases of patients, as well as the burden of care, anxiety, and depression of caregivers were evaluated. RESULTS: Significant alleviation of NPSs after the lifting of COVID-19 quarantine was observed in patients with mild cognitive impairment (MCI) and dementia (both P < 0.05). Compared with baseline, the prevalence for NPSs of all participants dropped from 57.94 to 38.82%. Among NPS subdomains, apathy displayed the biggest decline at follow-up by 10.72%, followed by nighttime behavior by 8.65%. Mixed effect generalized estimation equation analysis showed significant amelioration in hallucination, depression, apathy, irritability, aberrant motor behavior, and nighttime behavior (all P < 0.05), with the most prominent changes in nighttime behavior and apathy. Among the patients with unsatisfactory control of chronic disease, the medication adherence rate dropped by approximately 30% after the lifting of quarantine. More importantly, around 13% increase of care burden was observed among the caregivers at follow-up, with both depression and anxiety rising by nearly 4%. CONCLUSION: The prolonged quarantine may exacerbate NPS in patients with memory disorders, while the care burden and mental stability of the caregivers after the pandemic should also be concerned.

[Species composition and community structure of coniferous-broadleaved mixed forest in Xiaolong Mountain, Gansu Province, Northwest China]. / 甘肃小陇山暖温带针阔混交林物种组成和群落结构.

Xiaolong Mountain, located in warm temperate subtropical transition zone, is one of the important biodiversity conservation areas in China. We analyzed species composition, community structure, and habitat preferences of all woody plant species with DBH (diameter at breast height)≥1 cm in a 6 hm2 plot in Xiaolong Mountain, Gansu Province, Northwest China. A total of 29251 individuals (41735 stems) belonging to 33 families, 65 genera, and 124 species were recorded. The 28 species with importance value ≥1 contributed 82.9% to the total abundance. The top four species with the highest importance value were Quercus aliena var. acuteserrata, Betula platyphylla, Lindera aggregata var. playfairii and Corylus heterophylla. The structure of DBH size class of all stems showed an inverse 'J' type, indicating a successful regeneration tendency in the understory. Results from the indicator species analysis showed that 11 species had significant habitat prefe-rences, an two species (Ostrya japonica and Acer stachyophyllum subsp. betulifolium) had the most obvious preferences. Results from the redundancy analysis and partial methods showed that topographic factors played a dominant role in determining species distribution.

ADAMTS8 is frequently down-regulated in colorectal cancer and functions as a tumor suppressor.

Colorectal cancer (CRC) is known for being a great threat to human health due to its high incidence and mortality. ADAMTS8 that belongs to the zinc metalloproteinases family acts as a tumor suppressor and is silenced by CpG methylation in several carcinomas through previous studies, but its functions in CRC remain unknown. In this report, we analyzed its expression in CRC cell lines and primary CRC tumor tissues. The results showed that ADAMTS8 was significantly down-regulated in CRC cell lines and primary tumor tissues and its expression was restored in Lovo cell lines with treatment DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine and TSA. Over-expression of ADAMTS8 in HCT116 and HT-29 resulted in inhibited cell proliferation and induced apoptosis. We also observed that ADAMTS8 suppressed cell invasion and migration. In addition, ADAMTS8 induced cell cycle arrest in G2/M phase. Furthermore, we found that ADAMTS8 led to the decrease of BCL-XL, phospho-GSK3ß, ß-catenin and c-myc as well as increase of cleaved caspase-9, Bax and PARP. Our findings suggest that ADAMTS8 may be considered as a functional tumor suppressor gene in CRC and has the potential to be developed as a valuable biomarker.

Cadherin-11 is inactivated due to promoter methylation and functions in colorectal cancer as a tumour suppressor.

Background: The cadherin-11 (CDH11, OB-cadherin) gene is a member of the cadherin family and is located on chromosome 16q22.1. Previous studies have revealed that cadherins play significant roles in the development of many human malignancies. Increasing evidence has identified CDH11 as a functional tumour suppressor, which is commonly silenced by promoter methylation, but the functions of this gene in colorectal cancer (CRC) have been unclear. Methods: The CDH11 expression in primary CRC tissues and cell lines was investigated by qRT-PCR, RT-PCR and immunohistochemistry. The promoter methylation status of CDH11 was measured by methylation-specific PCR (MSP). Cell proliferation assay, colony formation assay, flow cytometry analysis, wound-healing assay, transwell assay and in vivo experiments were used to investigate the function of CDH11 in CRC. The mechanisms of CDH11 also were explored by western blots. Results: Our study suggests that CDH11 downregulation in CRC due to its promoter methylation and induced cell cycle arrest in G0/G1 phase and apoptosis, suppressing tumor cell proliferation, colony formation, migration and invasion by affecting the NF-kB signaling pathway. Conclusion: Overall, CDH11 may be considered as a functional tumour suppressor gene (TSG) in CRC, CDH11 has the potential to serve as a valuable prognostic marker for colorectal cancer.