Association of Brain-Derived Neurotrophic Factor With Cognitive Function: An Investigation of Sex Differences in Patients With Type 2 Diabetes.

OBJECTIVE: Although a reduction in brain-derived neurotrophic factor (BDNF) has been implicated as a cause of cognitive impairment in type 2 diabetes mellitus (T2DM), the role of sex in moderating this effect has not been explored. METHODS: We compared the difference in serum BDNF and performance on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) between 96 men and 134 women with T2DM. We compared this with the difference in serum BDNF and performance in the control group (104 men, 144 women). RESULTS: Patients with T2DM performed worse on most RBANS indices (η = 0.372, all p < .05); within T2DM patients, men performed worse than women on the delayed memory score (74.1 (12.1) versus 79.9 (11.5), p = .002) and on the total score (71.4 (11.5) versus 76.5 (10.8), p = .025). Serum BDNF was lower in patients with T2DM versus controls (7.5 (2.7) ng/ml versus 11.5 (2.7) ng/ml, p < .001), and in men compared with women (6.9 (2.4) versus 7.9 (2.8), p = .024). Serum BDNF levels positively correlated with delayed memory score in patients with T2DM (ß = 0.19, p = .007). However, this association was only observed in women, not in men (pinteraction = 0.04). Among healthy controls, no sex differences were noted in either RBANS or BDNF levels (η = 0.04, Cohen's d < 0.163, all p > .05). CONCLUSIONS: Our results show sex differences in poorer cognitive performance, lower BDNF concentration, and their relationship in T2DM patients, suggesting that female sex may be a protective factor for cognitive decline in T2DM patients. However, the findings should be regarded as preliminary because of the cross-sectional design and chronicity of the diabetes.

Sulforaphane Prevents Neuronal Apoptosis and Memory Impairment in Diabetic Rats.

BACKGROUND/AIMS: To explore the effects of sulforaphane (SFN) on neuronal apoptosis in hippocampus and memory impairment in diabetic rats. METHODS: Thirty male rats were randomly divided into normal control, diabetic model and SFN treatment groups (N = 10 in each group). Streptozotocin (STZ) was applied to establish diabetic model. Water Morris maze task was applied to test learning and memory. Tunel assaying was used to detect apoptosis in hippocampus. The expressions of Caspase-3 and myeloid cell leukemia 1(MCL-1) were detected by western blotting. Neurotrophic factor levels and AKT/GSK3ß pathway were also detected. RESULTS: Compared with normal control, learning and memory were apparently impaired, with up-regulation of Caspase-3 and down-regulation of MCL-1 in diabetic rats. Apoptotic neurons were also found in CA1 region after diabetic modeling. By contrast, SFN treatment prevented the memory impairment, decreased the apoptosis of hippocampal neurons. SFN also attenuated the abnormal expression of Caspase-3 and MCL-1 in diabetic model. Mechanically, SFN treatment reversed diabetic modeling-induced decrease of p-Akt, p-GSK3ß, NGF and BDNF expressions. CONCLUSION: SFN could prevent the memory impairment and apoptosis of hippocampal neurons in diabetic rat. The possible mechanism was related to the regulation of neurotropic factors and Akt/GSK3ß pathway.

Effects of depression on cognitive function in patients with diabetes in different age groups.

AIMS: To investigate the effects of depression on cognitive function in patients of different ages with diabetes mellitus (DM). METHODS: 6,549 patients with DM who were assessed using the Mini-Mental State Examination (MMSE) and Self-Rating Depression Scale (SDS) in 2016 were selected from the 2016 Kailuan Group staff physical examinations. Generalized linear regression models were used to analyze the effects of SDS index score on MMSE score in DM patients in different age groups. We also analyzed the effects of SDS index score on MMSE score in DM patients with different risk factors. RESULTS: Generalized linear regression analysis showed that higher SDS index score was associated with lower MMSE score (ß = -0.06; P < 0.01). In addition, there was an interaction effect between SDS index score and age groups on cognitive function. Meanwhile, SDS index score also has an interaction effect with level of education. CONCLUSIONS: The negative association between the degree of depression and cognitive function level increases with age in DM patients.

Forsythoside B ameliorates diabetic cognitive dysfunction by inhibiting hippocampal neuroinflammation and reducing synaptic dysfunction in ovariectomized mice.

Background: Diabetes-associated cognitive impairment (DACI) is a common complication of diabetes, and studies have shown that DACI is more severe in postmenopausal patients with diabetes. Forsythoside B (FTS⋅B) can inhibit inflammation and reduce synaptic dysfunction, which can improve cognitive function. However, it has not been confirmed whether FTS⋅B has a reversing or retarding effect on postmenopausal diabetic encephalopathy. Methods: Seven days after bilateral ovariectomy (OVX) or sham surgery, adult female C57 mice (n = 15/group) received intraperitoneal injection of streptozotocin (60 mg/kg/day/L) and citrate buffer for 5 consecutive days to induce diabetes mellitus (DM). Fourteen days later, ovariectomized diabetic mice were given intraperitoneal injection of FTS⋅B (100, 150 mg/kg/day/L) and subcutaneous injection of 17ß-estradiol (1 mg/kg) for 8 weeks [OVX + DM + low-FTS⋅B group (L-F), OVX + DM + high-FTS⋅B group (H-F), and OVX + DM + 17ß-estradiol (ER)]. In addition, the following control groups were defined: Sham, OVX, DM, and OVX + DM (O + D). Fasting plasma glucose, body weight and blood insulin levels were determined in each group of mice. Next, their cognitive function was tested through behavioral experiments. Hematoxylin & eosin (H&E) and Nissl staining were used to detect the morphological changes in the hippocampus. The aggregation of amyloid beta (Aß) and the hyperaggregation of p-tau were assessed by immunohistochemistry. Interleukin-1ß (IL-1ß), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), brain-derived neurotrophic factor (BDNF), post-synaptic density-95 (PSD-95), synaptophysin, and synapsin-1 expression in the hippocampus was detected by real-time polymerase chain reaction (RT-PCR) and western blot analysis. Results: FTS⋅B can decrease fasting glucose and blood insulin level. Behavioral results showed that cognitive decline was the most severe in the O + D group, and the ER, L-F, and H-F groups revised the cognitive decline. Compared to the O + D group, more normal morphology, which has obvious nucleoli and clear nuclear membrane, was observed by H&E and Nissl staining in the ER, L-F, and H-F groups. FTS⋅B alleviated DACI by reducing the aggregation of Aß and the hyperaggregation of p-tau in the hippocampus. Moreover, the protein and mRNA expression showed that FTS⋅B not only inhibited inflammation by decreasing IL-1ß, IL-6, and TNF-α but also modulated synaptic plasticity by increasing BDNF, PSD-95, synaptophysin, and synapsin-1. Conclusion: These results suggest that FTS⋅B may be a novel therapeutic target for postmenopausal diabetic encephalopathy treatment.

Liraglutide improves cognitive impairment via the AMPK and PI3K/Akt signaling pathways in type 2 diabetic rats.

Liraglutide is a type of glucagon­like­peptide 1 receptor agonist, which has been reported as a novel type of antidiabetic agent with numerous benefits, including cardiovascular and neuroprotective effects. To the best of our knowledge, few studies to date have reported the potential mechanism underlying the neuroprotective effects of liraglutide on rats with type 2 diabetes mellitus (T2DM). The present study aimed to investigate the neuroprotective actions of liraglutide in diabetic rats and to determine the mechanisms underlying these effects. A total of 30 male T2DM Goto­Kakizaki (GK) rats (age, 32 weeks; weight, 300­350 g) and 10 male Wistar rats (age, 32 weeks; weight, 300­350 g) were used in the present study. Wistar rats received vehicle treatment, and GK rats randomly received treatment with vehicle, low dose of liraglutide (75 µg/kg) or high dose of liraglutide (200 µg/kg) for 28 days. Cognitive deficits were evaluated using the Morris water maze test. The expression levels of phosphoinositide 3­kinase (PI3K), protein kinase B (Akt), phosphorylated (p)­Akt, AMP­activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), Beclin­1, microtubule­associated protein light chain 3 (LC)­3 II, caspase­3, B­cell lymphoma 2 (Bcl­2)­associated X protein and Bcl­2 were assessed by western blot analysis. The results demonstrated that diabetic GK rats exhibited cognitive dysfunction, whereas treatment with liraglutide alleviated the learning and memory deficits, particularly in the high­dose liraglutide group. The expression levels of Beclin­1 and LC­3 II were decreased in GK rats; however, this decrease was alleviated in the presence of liraglutide. Liraglutide also reversed T2DM model­induced increases in mTOR, and decreases in p­AMPK, PI3K and p­Akt expression, and modulated the expression of apoptosis­associated proteins. Furthermore, the administration of liraglutide inhibited apoptosis and exerted a protective effect against cognitive deficits via the activation of autophagy. In conclusion, the protective effects of liraglutide may be associated with increased mTOR expression via activation of the AMPK and PI3K/Akt signaling pathways.

Decreased serum undercarboxylated osteocalcin is associated with cognitive impairment in male patients with type 2 diabetes.

BACKGROUND: Basic and clinical researches have suggested that type 2 diabetes (T2DM) is associated with cognitive impairment, and diabetes mellitus increases the risk of cognitive impairment and dementia. Recently, some reports found that undercarboxylated osteocalcin (ucOC) could affect brain functions, and decreased in patients with T2DM. We aimed to investigate the association of serum ucOC with cognitive impairment in T2DM patients. METHODS: A total of 196 male T2DM patients without medications known to affect bone metabolism or history of bone fracture, aged ≥18years were recruited and divided into impaired cognition group and normal cognition group. We use the scores of Minimum Mental State Examination (MMSE) to evaluate the subjects' cognitive function. Detailed cognitive performance was also evaluated by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Serum ucOC was measured by Enzyme-Linked Immunosorbent Assay (ELISA) kit. RESULTS: Compared to male T2DM patients with normal cognition, the mean osteocalcin concentrations were significantly lower in male T2DM patients with impaired cognition (P<0.05). RBANS total and all indexes scores were also lower in patients with impaired cognition (all P<0.05). After adjusted effects of confounding factors, serum ucOC was positively correlated with a variety indexes of RBANS except visuospatial/constructional. CONCLUSIONS: The serum ucOC is positively correlated with RBANS scores in male T2DM patients. It suggests that serum ucOC may be involved in the development and progression of cognitive dysfunction in T2DM patients.

Cognition, serum BDNF levels, and BDNF Val66Met polymorphism in type 2 diabetes patients and healthy controls.

BACKGROUND AND AIMS: Type 2 diabetes (T2DM) is associated with cognitive deficits. However, their pathophysiological mechanisms are still unknown. Recent study suggests that brain-derived neurotrophic factor (BDNF) is correlated with cognitive deficits in T2DM patients. This study was to determine whether altered serum BDNF levels and cognitive deficits depended on the BDNF Val66Met polymorphism in T2DM. RESULTS: The BDNF Val66Met polymorphism may not contribute directly to the susceptibility to T2DM. The total and nearly all index scores (all p < 0.01) except for the attention and visuospatial/constructional indexes (both p > 0.05) of RBANS were markedly decreased in T2DM compared with healthy controls. Serum BDNF levels were significantly lower in patients than that in controls (p < 0.001), and BDNF was positively associated with delayed memory in patients (p < 0.05). The Met variant was associated with worse delayed memory performance among T2DM patients but not among normal controls. Moreover, serum BDNF was positively associated with delayed memory among Met homozygote patients (ß = 0.29, t = 2.21, p = 0.033), while serum BDNF was negatively associated the RBANS total score (ß = -0.92, t = -3.40, p = 0.002) and language index (ß = -1.17, t = -3.54, p = 0.001) among Val homozygote T2DM patients. CONCLUSIONS: BDNF gene Val66Met variation may be associated with cognitive deficits in T2DM, especially with delayed memory. The association between lower BDNF serum levels and cognitive impairment in T2DM is dependent on the BDNF Val66Met polymorphism. METHODS: We recruited 311 T2DM patients and 346 healthy controls and compared them on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), serum BDNF levels, and the BDNF Val66Met polymorphism.

Association between 1p13 polymorphisms and peripheral arterial disease in a Chinese population with diabetes.

AIMS/INTRODUCTION: Variants on chromosome 1p13 have been associated with coronary artery disease and acute myocardial infarction risk in different ethnic groups. The present study aimed to investigate the association between 1p13 polymorphisms and the development of peripheral artery disease (PAD) in a Chinese population with type 2 diabetes mellitus. MATERIALS AND METHODS: 1p13 polymorphisms, rs599839, rs646776 and rs12740374, were assessed in a cohort of 882 type 2 diabetes mellitus patients including 440 type 2 diabetes mellitus patients with PAD (DM + PAD group) and 442 patients without PAD (DM group). Genotyping was carried out using TaqMan assay. RESULTS: Compared with the DM group, the frequencies of the minor G allele of both rs599839 and rs646776 and the minor T allele of rs12740374 decreased (P = 0.013, P = 0.019 and P = 0.005, respectively), and the frequencies of rs599839 AG + GG, rs646776 AG + GG and rs12740374 CT+TT genotypes were statistically significantly decreased as well (P = 0.017, P = 0.011 and P = 0.007, respectively) in the dominant model in the DM + PAD group than in the DM group. Multivariate unconditional logistic regression analyses adjusted for age, glycated hemoglobin, triglyceride, low-density lipoprotein cholesterol, smoking, hypertension, diabetes duration, coronary heart disease and cerebral infarction showed that the genotypic distribution of rs599839 AG + GG, rs646776 AG + GG and rs12740374 CT + TT remained statistically different between the DM and DM + PAD group (P = 0.014, P = 0.003 and P = 0.004, respectively). The frequencies of haplotype GGT were statistically significantly different between groups (P = 0.08). CONCLUSIONS: The present study strongly supports that genotypes of rs599839, rs646776 and rs12740374 on 1p13 are protective factors for diabetic PAD in a Chinese population. Haplotype GGT generated by rs599839, rs646776 and rs12740374 might also decrease the risk of the disease.

[Genetic polymorphism of four X chromosome short temden repeats loci in Hebei Han population].

OBJECTIVE: To investigate the polymorphism of loci DXS6800, DXS6797, GATA172D05, DXS986 four loci in Hebei Han population. METHODS: The genome DNA of unrelated individuals,the families and rotten materials were extracted with phenol-chloroform method and Chelex-100 method,respectively. The PCR products were detected by the polyacrylamide gel electrophoresis and DNA sequencing analysis. RESULTS: Among 150 unrelated males and 150 unrelated females from Hebei Han population, 25 alleles were found in the 4 loci. One hundred and thirty-eight haplotypes of the male were detected. The haplotype diversity reached 0.9986. CONCLUSION: The findings provided the polymorphic data of DXS6800, DXS6797, GATA172D05, and DXS986 loci in Hebei Han population. The four loci are relatively abundant in polymorphic information for identification and the obtained data of Hebei Han population can be applied to the X-STR genetic data bank.

[Methylation status of the IL-10 gene promoter in the peripheral blood mononuclear cells of rheumatoid arthritis patients].

Interleukin 10(IL-10), as an immunoregulatory cytokine, plays an important role in rheumatoid arthritis (RA). IL-10 gene silencing is associated with the chromatin remodeling in differentiated Th1 and Th2 cells. To explore the relationship between IL-10 promoter methylation and gene silencing in the pathogenesis of RA, IL-10 mRNA, protein expression and promoter methylation status were analyzed in the peripheral blood mononuclear cells (PBMC) of 34 RA patients and 30 healthy controls by reverse transcriptase-polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA) and methylation specific polymerase chain reaction (MSP), respectively. The results showed that IL-10 mRNA and protein expression in RA patients seemed to be lower than that in healthy controls, but there was no statistically significant difference (P>0.05). IL-10 promoter was methylated at a frequency of 85.29% in RA cases, which was significantly higher than the percentage in healthy controls (43.33%) (c 2 =12.439, P=0.000). IL-10 promoter methylation and mRNA expression showed a strong negative correlation (r=-0.579, P=0.001). IL-10 promoter methylation, but not mRNA expression, also correlated statistically with the number of arthritic joints. However, there were no statistical correlations between IL-10 promoter methylation (or mRNA expression) and clinical indices of RA, such as the levels of erythrocyte sedimentation rate (ESR), C reactive protein (CRP) and rheumatic factor (RF) or age (P>0.05). These findings suggest that promoter methylation may be a crucial mechanism of IL-10 gene inactivation in RA and IL-10 promoter CpG island hypermethylation might be involved in the occurrence and development of RA.

[Polymorphism of five short tandem repeat loci on chromosome X in Hebei Han population].

OBJECTIVE: To investigate the polymorphism of DXS6801, DXS6809, DXS7423, DXS7424, DXS9902 five loci in Hebei Han population. METHODS: The PCR products were detected by the polyacrylamide gel electrophresis and DNA sequencing analysis. RESULTS: Among 114 irrelative males and 118 irrelative females from Hebei Han population, 31 alleles were found in the 5 loci. One hundred and one haplotypes of the male were detected and the haplotype diversity reached 0.9975. CONCLUSION: The five loci are relatively abundant in polymorphic information for identification and paternity test. And the obtained data of Hebei Han population can be applied to the X-short tandem repeat genetic data bank.

Long noncoding RNA are aberrantly expressed in human papillary thyroid carcinoma.

Long noncoding RNAs (lncRNAs) have emerged as key regulatory molecules at almost every level of gene expression regulation. The altered expression of lncRNAs is a characteristic of numerous types of cancer, and lncRNAs have been demonstrated to promote the development, invasion and metastasis of tumors through various mechanisms. However, the role of lncRNAs in papillary thyroid carcinoma (PTC) remain unclear. In the present study, differentially expressed lncRNAs and mRNAs were detected by human lncRNA microarray in three pairs of PTC and adjacent noncancerous samples. The microarray results revealed that 675 lncRNAs and 751 mRNAs were abnormally expressed in the three PTC samples compared with adjacent noncancerous samples (fold change ≥2.0; P<0.05). To validate the microarray results, 8 differentially expressed lncRNAs were randomly selected for quantitative polymerase chain reaction (qPCR). The results of qPCR were consistent with the microarray data; the 8 lncRNAs had an aberrant expression in the PTC samples compared with the adjacent noncancerous samples. Gene ontology and pathway analysis indicated that there were 7 downregulated pathways and 29 upregulated pathways in PTC. LncRNA classification and subgroup analysis revealed 7 pairs of enhancer-like lncRNA-mRNA, 9 pairs of antisense lncRNA-mRNA and 45 pairs of lncRNA-mRNA were differentially expressed between PTC and their paired noncancerous samples. In conclusion, the present study identified a series of novel PTC-associated lncRNAs. Further study with these lncRNAs is instrumental for the identification of novel target molecules that could lead to improved diagnosis and treatment for PTC.

Inhibition of microRNA-9-3p reduces lipid accumulation in HepG2 cells by targeting the expression of sirtuin type 1.

Type 2 diabetes mellitus (T2DM) is a complex metabolic disorder caused by the interaction of environmental factors and multiple genes. The genetic background of T2DM is complex and remains to be fully elucidated. MicroRNAs (miRNAs) are negative regulators of gene expression and several miRNAs are associated with the development of T2DM. However, the expression and biological function of miRNA­9­3p in lipid metabolism of patients with T2DM remain to be fully elucidated. The predominant aim of the present study was to examine the effect of miRNA­9­3p on lipid accumulation in HepG2 cells. To investigate this, an MTT assay was used to determine cell proliferation, and the effects of miRNA­9­3p on triglycerides (TG) and total cholesterol (TC) in the HepG2 cells were also examined. Reverse transcription­quantitative polymerase chain reaction and western blot analyses were used to measure the expression levels of SIRT1 at the gene and protein levels, respectively. The date revealed that downregulation of miRNA­9­3p inhibited the proliferation of HepG2 cells, and significantly reduced the accumulation of lipids, and decreased TG and TC content. In addition, the present study demonstrated that inhibition of miRNA­9­3p increased the protein expression of sirtuin type 1 (SIRT1), but had no effects on the gene expression of SIRT1. Therefore, these findings demonstrated that the inhibition of miRNA­9­3p reduced the proliferation of HepG2 cells and lipid accumulation by upregulating the expression of SIRT1, indicating its potential as a therapeutic target.

Salidroside attenuates beta amyloid-induced cognitive deficits via modulating oxidative stress and inflammatory mediators in rat hippocampus.

Beta amyloid (Aß)-induced oxidative stress and chronic inflammation in the brain are considered to be responsible for the pathogenesis of Alzheimer's disease (AD). Salidroside, the major active ingredient of Rhodiola crenulata, has been previously shown to have antioxidant and neuroprotective properties in vitro. The present study aimed to investigate the protective effects of salidroside on Aß-induced cognitive impairment in vivo. Rats received intrahippocampal Aß1-40 injection were treated with salidroside (25, 50 and 75 mg/kg p.o.) once daily for 21 days. Learning and memory performance were assessed in the Morris water maze (days 17-21). After behavioral testing, the rats were sacrificed and hippocampi were removed for biochemical assays (reactive oxygen species (ROS), superoxide dismutase (SOD), glutathione peroxidase (GPx), malondialdehyde (MDA), acetylcholinesterase (AChE), acetylcholine (ACh)) and molecular biological analysis (Cu/Zn-SOD, Mn-SOD, GPx, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, nuclear factor κB (NF-κB), inhibitor of κB-alpha (IκBα), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), receptor for advanced glycation end products (RAGE)). Our results confirmed that Aß1-40 peptide caused learning and memory deficits in rats. Further analysis demonstrated that the NADPH oxidase-mediated oxidative stress was increased in Aß1-40-injected rats. Furthermore, NF-κB was demonstrated to be activated in Aß1-40-injected rats, and the COX-2, iNOS and RAGE expression were also induced by Aß1-40. However, salidroside (50 and 75 mg/kg p.o.) reversed all the former alterations. Thus, the study indicates that salidroside may have a protective effect against AD via modulating oxidative stress and inflammatory mediators.

9p21 polymorphisms increase the risk of peripheral artery disease in the Han Chinese population.

OBJECTIVE: A case-control study to investigate the association of the 9p21 single nucleotide polymorphisms (SNPs) rs10757274 and rs10757278 (known to be associated with coronary artery disease [CAD] risk) with peripheral arterial disease (PAD), in a Han Chinese population. METHODS: The rs10757274 and rs10757278 genotypes of patients with PAD, and age- and sex-matched control subjects, were determined. Multivariate unconditional logistic regression analyses were performed, with adjustments for age, sex, hypertension, dyslipidaemia, diabetes and smoking status. RESULTS: The study included 420 patients with PAD and 418 control subjects. Variant forms of both SNPs were associated with increased risk of PAD in the total study population, when excluding patients with CAD or stroke (additive genetic model). The GG haplotype increased the risk of PAD, but this association did not remain significant after further sensitivity analysis. Both SNPs were associated with PAD risk in patients aged <65 years, but not in those aged ≥ 65 years (additive model). CONCLUSIONS: 9p21 is associated with PAD. When stratified according to age, 9p21 increases PAD risk in individuals aged <65 years, but not in those aged ≥ 65 years.