Associations among multidomain lifestyles, chronic diseases, and dementia in older adults: a cross-sectional analysis of a cohort study.

Background: Unhealthy lifestyles and chronic diseases are commonly seen and treatable factors in older adults and are both associated with dementia. However, the synergistic effect of the interaction of lifestyles and chronic diseases on dementia is unknown. Methods: We determined independent associations of multidomain lifestyles and chronic diseases (cerebrovascular disease, diabetes, and hypertension) with dementia and examined their synergistic impact on dementia among older adults. The data were drawn from the Hubei Memory and Aging Cohort Study. We created a summary score of six factors for multidomain lifestyles. Dementia was diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders IV. Logistic regression and multiple correspondence analyses were used to explore the relationships among multidomain lifestyles, chronic diseases, and dementia. A sensitivity analysis was performed to minimize the interference of reverse causality and potential confounders. Results: Independent associations with dementia were found in unhealthy (OR = 1.90, 95% CI: 1.38-2.61) and intermediate healthy lifestyles (OR, 3.29, 2.32-4.68), hypertension (OR, 1.21, 1.01-1.46), diabetes (OR, 1.30, 1.04-1.63), and cerebrovascular disease (OR, 1.39, 1.12-1.72). Interactions of diabetes (p = 0.004), hypertension (p = 0.004), and lifestyles were significant, suggesting a combined impact on dementia. Sensitivity analysis supported the strong association among multidomain lifestyles, chronic diseases, and dementia prevalence. Conclusion: An unhealthy lifestyle was associated with a higher prevalence of dementia, regardless of whether the participants had chronic diseases; however, this association was stronger in individuals with chronic diseases. Multidomain lifestyles and chronic diseases may have an enhanced impact on dementia.

Prevalence and risk factors for subjective cognitive decline and the correlation with objective cognition among community-dwelling older adults in China: Results from the Hubei memory and aging cohort study.

INTRODUCTION: The prevalence and risk factors for subjective cognitive decline (SCD) and its correlation with objective cognition decline (OCD) among community-dwelling older adults is inconsistent. METHODS: Older adults underwent neuropsychological and clinical evaluations to reach a consensus on diagnoses. RESULTS: This study included 7486 adults without mild cognitive impairment and dementia (mean age: 71.35 years [standard deviation = 5.40]). The sex-, age-, and residence-adjusted SCD prevalence was 58.33% overall (95% confidence interval: 58.29% to 58.37%), with higher rates of 61.25% and 59.87% in rural and female subgroups, respectively. SCD global and OCD language, SCD memory and OCD global, SCD and OCD memory, and SCD and OCD language were negatively correlated in fully adjusted models. Seven health and lifestyle factors were associated with an increased risk for SCD. DISCUSSION: SCD affected 58.33% of older adults and may indicate concurrent OCD, which should prompt the initiation of preventative intervention for dementia. HIGHLIGHTS: SCD affects 58.33% of older adults in China. SCD may indicate concurrent objective cognitive decline. Difficulty finding words and memory impairments may indicate a risk for AD. The presence of SCD may prompt preventative treatment initiation of MCI or dementia. Social network factors may be initial targets for the early prevention of SCD.

Dynamic regulation and key roles of ribonucleic acid methylation.

Ribonucleic acid (RNA) methylation is the most abundant modification in biological systems, accounting for 60% of all RNA modifications, and affects multiple aspects of RNA (including mRNAs, tRNAs, rRNAs, microRNAs, and long non-coding RNAs). Dysregulation of RNA methylation causes many developmental diseases through various mechanisms mediated by N 6-methyladenosine (m6A), 5-methylcytosine (m5C), N 1-methyladenosine (m1A), 5-hydroxymethylcytosine (hm5C), and pseudouridine (Ψ). The emerging tools of RNA methylation can be used as diagnostic, preventive, and therapeutic markers. Here, we review the accumulated discoveries to date regarding the biological function and dynamic regulation of RNA methylation/modification, as well as the most popularly used techniques applied for profiling RNA epitranscriptome, to provide new ideas for growth and development.

GENE EXPRESSION LEVEL, IMMUNOLOCALIZATION, AND FUNCTION OF FATTY ACID-BINDING PROTEIN FROM SCHISTOSOMA JAPONICUM.

The Schistosoma japonicum fatty acid-binding protein (FABP) is used in the cell membrane to absorb and transport fatty acids, which cannot be resynthesized by the organism and combined with hydrophobic ligands. Among the 5 stages of the worm life cycle examined, FABP messenger ribonucleic acid (mRNA) expression was highest in male adult worms, followed by the liver-stage schistosome, and was the lowest in the lung-stage schistosome. The fabp gene-coding region was cloned and expressed to obtain recombinant S. japonicum FABP (rSjFABP) with a molecular weight of approximately 18 kDa. Mice were then immunized against rSjFABP to prepare anti-FABP serum. Using immunohistochemical techniques, FABP protein was found to localize to the eggshell, parenchyma, and digestive tract. Double-stranded RNA-mediated knockdown of FABP mRNA by RNA interference decreased the number of transcripts by >70%. Moreover, the egg production rate decreased, whereas the abnormal egg ratio was significantly increased in the FABP-silenced group compared with the negative control group (P < 0.05). These results demonstrate that FABP localizes in adults and in various stages. FABP contributes to the egg-laying capacity of adults, which may be related to the reproductive function of S. japonicum.

ALDH2 and Cancer Therapy.

Aldehyde dehydrogenase 2 (ALDH2) is a member of ALDH family. ALDH1 has been widely recognized for its roles in carcinogenesis and cancer therapy; however, investigation for ALDH2 in cancer is seldom mentioned. The ALDH2 point mutation ALDH2*2 is the most frequent human gene variant, and it is present in approximately 560 million East Asians. ALDH2*2 demonstrates its effect on alcohol consumption limiting and alcoholism developing protection, and this variant is recently found to have an important impact on human health. This chapter focuses on its potential effect on cancer therapy, especially for chemotherapeutics with anthracyclines.

Annonaceous acetogenin mimic AA005 suppresses human colon cancer cell growth in vivo through downregulation of Mcl-1.

Annonaceous acetogenins are a well-established family of natural products with significant bioactivities, especially high cytotoxic and antitumor activities. AA005 is an annonaceous acetogenin mimic that has shown significant cytotoxicity against a variety of cancer cell lines, but its in vivo antitumor effects have not been demonstrated so far, and its anticancer mechanisms remain ambiguous. In this study, we investigated the effects of AA005 on human colon cancer cell lines in vivo. Human colon carcinoma cell line SW620 xenograft nude mice were treated with AA005 (5 mg/kg/day, i.p.) for 21 days. AA005 administration markedly inhibited the tumor growth via promoting nuclear translocation of apoptosis-inducing factor (AIF) and inducing AIF-dependent cell death. Subsequent studies in human colon carcinoma cell lines SW620 and RKO in vitro revealed that after the colon cancer cells exposed to AA005, downregulation of a B-cell lymphoma 2 family protein, myeloid cell leukemia-1 (Mcl-1), was an early event due to the inhibition of Mcl-1 mRNA level and protein synthesis in a time-dependent manner. Intriguingly, knockdown of Mcl-1 using small interfering RNA markedly accelerated the nuclear translocation of AIF and upregulation of receptor interacting protein-1, and enhanced AA005-mediated lethality, whereas ectopic expression of Mcl-1 substantially attenuated AA005-mediated lethality in the colon cancer cells. Finally, silencing Mcl-1 expression markedly enhanced AA005-induced lethality in SW620 xenograft nude mice, demonstrating a pivotal role of Mcl-1 downregulation in mediating the in vivo antitumor effects of AA005. Taken together, this study demonstrates for the first time the anticancer effects of AA005 against human colon cancer cell lines in vivo, which is mediated through the downregulation of Mcl-1.

Polymorphism of the DNA methyltransferase 1 gene is associated with the susceptibility to essential hypertension in male.

Essential hypertension is a leading global public health issue, billions of people suffered from it every year. Recently, multiple evidence suggests that DNA methylation play an important role in regulating blood pressure. Here, we tested the risk for essential hypertension conferred by single nucleotide polymorphisms (SNPs) within DNA methyltransferase 1 (DNMT1). Three loci (rs2228611, rs2228612, and rs16999593) were selected to be analyzed in 3410 cases and 1307 normal controls in southern Chinese aged 60 or above. No significant association with essential hypertension was observed for rs2228612 and rs16999593. A higher risk of essential hypertension was found in the minor A allele of rs2228611 in the codominant and recessive model (P < 0.05). After stratified by sex, this association was found in male but not female. Furthermore, this difference was abolished after BMI adjustment in the whole population and reduced in male. In addition, the mutation rate of rs2228611 was higher in the obesity group compared with the normal weight group of male. Intriguingly, rs2228611 was also a risk factor of essential hypertension in normal weight male. These findings indicated that rs2228611 might contribute to male hypertension via BMI-dependent mechanisms in obesity male and BMI-independent mechanisms in normal weight male.

VHL deficiency augments anthracycline sensitivity of clear cell renal cell carcinomas by down-regulating ALDH2.

The von Hippel-Lindau (VHL) is deficient in ∼70% of clear-cell renal cell carcinomas (ccRCC), which contributes to the carcinogenesis and drug resistance of ccRCC. Here we show that VHL-deficient ccRCC cells present enhanced cytotoxicity of anthracyclines in a hypoxia-inducible factor-independent manner. By subtractive proteomic analysis coupling with RNAi or overexpression verification, aldehyde dehydrogenase 2 (ALDH2) is found to be transcriptionally regulated by VHL and contributes to enhanced anthracyclines cytotoxicity in ccRCC cells. Furthermore, VHL regulates ALDH2 expression by directly binding the promoter of -130 bp to -160 bp to activate the transcription of hepatocyte nuclear factor 4 alpha (HNF-4α). In addition, a positive correlation is found among the protein expressions of VHL, HNF-4α and ALDH2 in ccRCC samples. These findings will deepen our understanding of VHL function and shed light on precise treatment for ccRCC patients.

The association between BMI and gallbladder cancer risk: a meta-analysis.

Obesity is a known cause of gallstone formation and gallstones increases the risk of gallbladder cancer (GBC), but the relation of body mass index (BMI) to GBC remains incompletely understood. To help elucidate the role of obesity in GBC, we performed a meta-analysis of the relationship between BMI and GBC risk. PUBMED and EMBASE databases were searched up to April 17, 2016. Fifteen articles with 5902 cases were identified. Random-effects models and dose-response meta-analyses were used to pool study results. Compared to normal weight, the pooled relative risks (RRs) and the corresponding 95% confidence intervals (CI) of GBC for overweight and obesity is 1.10 (0.98-1.23) and 1.58 (1.43-1.75) respectively. The RRs and 95% CI of overweight and obesity in man are 0.98 (0.90-1.08) and 1.43 (1.19-1.71), while the corresponding RRs in woman are 1.29 (1.08-1.55) and 1.68 (1.41-2.00) when compared to normal weight. A nonlinear dose-response relationship between BMI and risk of GBC was found (P=0.001), and the risk increased by 4% for each 1 kg/m2 increment in BMI. When adjusted for sex, at the point of BMI=25 kg/m2, the RRs (95% CIs) for women and men were 1.13 (1.01-1.25) and 0.98 (0.90-1.07) respectively. The corresponding RRs (95%CIs) at the point of BMI=30 kg/m2 were 1.56(1.39-1.75) vs. 1.24(1.06-1.44). These results suggest that association of obesity and risk of GBC is stronger in woman. Furthermore, overweight is only associated with GBC in woman. A even stricter weight control might be necessary for woman to prevent GBC.

Phosphoproteomics study on the activated PKCδ-induced cell death.

The proteolytic activation of protein kinase Cδ (PKCδ) generates a catalytic fragment called PKCδ-CF, which induces cell death. However, the mechanisms underlying PKCδ-CF-mediated cell death are largely unknown. On the basis of an engineering leukemic cell line with inducible expression of PKCδ-CF, here we employ SILAC-based quantitative phosphoproteomics to systematically and dynamically investigate the overall phosphorylation events during cell death triggered by PKCδ-CF expression. Totally, 3000 phosphorylation sites were analyzed. Considering the fact that early responses to PKCδ-CF expression initiate cell death, we sought to identify pathways possibly related directly with PKCδ by further analyzing the data set of phosphorylation events that occur in the initiation stage of cell death. Interacting analysis of this data set indicates that PKCδ-CF triggers complicated networks to initiate cell death, and motif analysis and biochemistry verification reveal that several kinases in the downstream of PKCδ conduct these networks. By analysis of the specific sequence motif of kinase-substrate, we also find 59 candidate substrates of PKCδ from the up-regulated phosphopeptides, of which 12 were randomly selected for in vitro kinase assay and 9 were consequently verified as substrates of PKCδ. To our greatest understanding, this study provides the most systematic analysis of phosphorylation events initiated by the cleaved activated PKCδ, which would vastly extend the profound understanding of PKCδ-directed signal pathways in cell death. The MS data have been deposited to the ProteomeXchange with identifier PXD000225.

PKCδ enhances C/EBPα degradation via inducing its phosphorylation and cytoplasmic translocation.

Our previous study has shown that PKCδ stimulates proteasome-dependent degradation of C/EBPα, which partially contributes to PKCδ-mediated apoptosis. However, the molecular interrelationship between these two important proteins is still unknown. In this study, we reported that C/EBPα was phosphorylated by activated PKCδ on three serines, two of which were reported for the first time. Phosphorylated C/EBPα underwent cytoplasmic translocation, which led to the inactivation of its transcriptional activity. Inactive cytoplasmic C/EBPα was finally subjected to proteasome degradation. This work reveals the exquisite molecular events linking activated PKCδ and C/EBPα degradation during cell apoptosis.

Acidic leucine-rich nuclear phosphoprotein 32 family member B (ANP32B) contributes to retinoic acid-induced differentiation of leukemic cells.

The acidic leucine-rich nuclear phosphoprotein 32B (ANP32B) is a member of a conserved superfamily of nuclear proteins whose functions are largely unknown. In our previous work, ANP32B was identified as a novel direct substrate for caspase-3 and acted as a negative regulator for leukemic cell apoptosis. In this work, we provided the first demonstration that ANP32B expression was down-regulated during differentiation induction of leukemic cells by all-trans retinoic acid (ATRA). Knockdown of ANP32B expression by specific shRNA enhanced ATRA-induced leukemic cell differentiation, while ectopic expression of ANP32B attenuated it, indicating an inhibitory role of ANP32B against leukemic cell differentiation. Furthermore, luciferase reporter assay revealed that ANP32B might exert this role through inhibiting the ATRA dependent transcriptional activity of retinoic acid receptor (RARα). These data will shed new insights into understanding the biological functions of ANP32B protein.

Apoptosis-inducing factor is a target gene of C/EBPα and participates in adipocyte differentiation.

Besides the contribution in cell death, apoptosis-inducing factor (AIF) also exerts roles in other cellular activities, which are largely unknown. The CCAAT-enhancer binding protein alpha (C/EBPα) is required for differentiation of adipocytes and granulocytes. Here we report that, during 3T3-L1 adipocyte differentiation, AIF expression is robustly upregulated via transcriptional regulation by C/EBPα. The upregulated effect is also confirmed by knockdown and ectopic expression of C/EBPα in U937 and MCF-7 cells respectively with and without endogenous expression of C/EBPα protein. We also reveal that AIF knockdown attenuates 3T3-L1 adipocyte differentiation, presumably due to the mitochondrial respiratory chain deficiency. These results provide evidence for the role of AIF in adipocyte differentiation.

[Effects of Yi Fu Ning soft gelatin capsules on reproductive endocrine-immune function of ovariectomized rats].

OBJECTIVE: To investigate the effect of Yi Fu Ning Soft Gelatin Capsules (YFN) on reproductive endocrine-immune function of ovariectomized rats. METHODS: 60 3-month old female Sprague-Dawley rats were used, 50 of them were ovariectomized and randomly divided into 5 groups: ovariectomizy (OVX) group, OVX with diethylstilbestrol tablets (DT) group, OVX with YFN (high dose, middle dose and low dose) group. The others were sham-operated group. The rats were administrated initially in the 4th week after the operation. After drugs had been given for 12 weeks the rats were sacrificed, blood serum hormone, IL-2 content and T lymphocyte subpopulation were detected with methods radioimmunoassay and flow cytometry (FCM). RESULTS: (1) Compared with sham group, the level of serum E2, Te and P significantly decreased (P < 0.01), FSH, LH content significantly increased; Blood T lymphocyte subpopulation CD3+ cells, CD4+ cells and CD4+/CD8+ ratio significantly decreased, serum IL-2 content also significantly decreased (P < 0.01). (2) Compared with model group, after treated by YFN, the level of serum E2 and P significantly increased (P < 0.01), serum FSH and LH content significantly decreased; T lymphocyte subpopulation CD3+ cells, CD4+ cells and CD4+/CD8+ ratio were improved significantly and serum interleukin-2 (IL-2) content increased significantly. CONCLUSION: YFN can increase serum sexual hormone content,reduce the level of FSH and LH, and improve imbalanced T lymphocyte subpopulation, stimulate IL-2 excretion, which means YFN can regulate inordinate reproductive endocrine-immune network in ovariectomized rats.

[Effects of the mixture of Rhizoma Curcumae and Oviducts Ranae on estrogen and its receptor expressions in ovariectomized rats].

OBJECTIVE: To study the effect of the mixture of Rhizoma Curcumae (YFN) and Oviducts Ranae on serum estrogen and spleen estrogen receptor expressions and its effect on reproductive endocrine-immune network in ovariectomized (OVX) rats. METHODS: Female SD rat models of climacteric syndrome (CS) were established by ovariectomy. After administration of YFN in the rats for 12 consecutive weeks, the serum estrogen levels (E2, FSH, LH, T, and P) and interleukin-2 were determined using radioimmunoassay, and the expression levels of estrogen receptor in the spleen were detected with immunofluorescence assay. RESULTS: The serum E2, T, P, and interleukin-2 levels (P<0.01) and spleen estrogen receptor expression (P<0.05) were significantly increased after high-dose YFN administration in the OVX rats as compared with the levels in the untreated OVX rats. YFN also resulted in lowered serum FSH and LH levels, but the changes were not statistically significant. CONCLUSION: YFN can increase the serum estrogen levels and estrogen receptor expression in the spleen of OVX rats, suggesting its clinical potential for relieving CS.

[Expression of SARS spike gene in Shizomycete pombe].

The viral spike protein is the main surface antigen of the coronavirus, and it could be useful in the research of clinical diagnosis, SARS vaccine and the structure biology.According to the analysis of the main antigen of the SARS spike protein, 5 fragments of the whole spike gene were cloned, and ligated to the vector pNMT1. Through electroporation transformantion to TCP1, the recombinant S. pombe strains capable of expressing the 5 fragments were constructed. SDS-PAGE or Western blot analysis of the induced expression products demonstrated that the 5 recombinant proteins were expressed in the fission yeast respectively.