To explore the change of motor cognitive function in pituitary tumor rats after operation.

To study the changes of motor and cognitive function of pituitary tumor rats after the operation. Methods: The experiment was divided into three groups: control group, model group and operation group (30 animals for each group). Female Fischer344 rats were selected. Model group rats were subcutaneously embedded with 10 mg estrogen sustained-release pump to induce a pituitary tumor model, and control group rats were subcutaneously embedded with a normal saline sustained-release pump as control. The operation group was successfully treated by microsurgery after the model was established. The quantitative expressions of PTTG, FGF-2 and VEGF were detected by Western blot. Morris test was used to detect the spatial learning and memory ability of rats. Western blot results showed that compared with the model group, the expression of the operation group was decreased, but still higher than that of the control group (p < 0.05). The water maze test results showed that the incubation period of searching the safe island in the model group was significantly longer than that in the control group on the 8th and 9th day after the injury, and the difference was statistically significant (p < 0.05). The incubation period of searching the safe island on the 8th and 9th day after injury in the operation group was significantly shorter than that in the control group. Through the detection of behavioral-related experimental and protein, the motor memory of rats after pituitary tumor surgery can be improved to some extent.

Maternal and neonatal blood vitamin D status and neurodevelopment at 24 months of age: a prospective birth cohort study.

BACKGROUND: This study aimed to explore the relationship of 25-hydroxyvitamin D [25(OH)D] in three trimesters and at birth with neurodevelopment at 24 months of age. METHODS: From 2013 to 2016, pregnant women from the Shanghai Birth Cohort in China were recruited for the study. Altogether, 649 mother-infant pairs were included. Serum 25(OH)D was measured with mass spectrometry in three trimesters, and cord blood was divided into deficiency (< 20 and < 12 ng/mL, respectively), insufficiency (20-30 and 12-20 ng/mL, respectively), and sufficiency (≥ 30 and ≥ 20 ng/mL, respectively). Bayley-III scale was used to assess cognitive, language, motor, social-emotional, and adaptive behavior development at 24 months of age. The Bayley-III scores were grouped into quartiles, and scores within the lowest quartile were defined as suboptimal development. RESULTS: After adjusting for confounding factors, cord blood 25(OH)D in the sufficient group was positively correlated with cognitive [ß = 11.43, 95% confidence interval (CI) = 5.65-17.22], language (ß = 6.01, 95% CI = 1.67-10.3), and motor scores (ß = 6.43, 95% CI = 1.73-11.1); cord blood 25(OH)D in the insufficient group was also positively correlated with cognitive scores (ß = 9.42, 95% CI = 3.74-15.11). Additionally, sufficient vitamin D status in the four periods and persistent 25(OH)D ≥ 30 ng/mL throughout pregnancy were associated with a lower risk of suboptimal cognitive development in adjusted models, although the effects were attenuated after applying the false discovery rate adjustment. CONCLUSIONS: Cord blood 25(OH)D ≥ 12 ng/mL has a significant positive association with cognitive, language, and motor development at 24 months of age. Sufficient vitamin D status in pregnancy might be a protective factor for suboptimal neurocognition development at 24 months of age.

Fufang Xueshuantong alleviates diabetic retinopathy by activating the PPAR signalling pathway and complement and coagulation cascades.

ETHNOPHARMACOLOGICAL RELEVANCE: Fufang Xueshuantong (FXST) is a traditional Chinese patent medicine composed of Panax notoginseng (Burkill) F.H.Chen (Araliaceae), Salvia miltiorrhiza Bunge (Lamiaceae), Astragalus propinquus Schischkin (Leguminosae), and Scrophularia ningpoensis Hemsl. (Scrophulariaceae). It has been widely used for the treatment of diabetic retinopathy (DR) and exerts a positive clinical therapeutic effect. AIM OF THE STUDY: The aim of this study was to observe the effect of FXST on diabetic rat retinas and investigate its pharmacological mechanism for improving DR. METHODS: The diabetic rat model was established by intraperitoneal injection of streptozotocin. The rats were divided into a normal group, diabetic group, and FXST group. The rats in the FXST group were treated with FXST by intragastric administration for 12 weeks while other rats were given the same volume of normal saline. The haemodynamic parameters of the central retinal artery in the rats were measured by ultrasound. Haematoxylin-eosin staining was utilised to observe the pathological structural changes in the retina. The apoptosis of retinal nerve cells was detected by terminal deoxynucleotidyl transferase dUTP nick end labelling. RNA sequencing was used to screen the differentially expressed genes (DEGs), and enrichment analyses were performed. The DEGs were validated through real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR). RESULTS: The peak systolic velocity, end diastolic velocity, and mean velocity decreased while the resistance index and pulsatility index increased in the diabetic rat retinas. FXST also improved haemodynamics. In contrast with the diabetic group, FXST allayed the disorder and oedema of the retinal structure in addition to reversing the reductions in retinal thickness and retinal ganglion cell number. It also decreased the apoptosis index of retinal cells. A total of 1134 DEGs were identified by RNA sequencing in the FXST group compared to the diabetic group, including 814 upregulated genes and 320 downregulated genes. These genes were enriched in the complement and coagulation cascades as well as the peroxisome proliferator-activated receptor (PPAR) signalling pathway. Several DEGs, including PPAR gamma, perilipin 4, acyl-CoA dehydrogenase long chain, CD55 molecule, and plasminogen activator urokinase, were identified by qRT-PCR, and the results were consistent with the RNA sequencing data. CONCLUSIONS: FXST alleviates DR by improving the haemodynamics and morphological alterations of diabetic rat retinas, which are mediated by complement and coagulation cascades and the PPAR signalling pathway.

HuoXue JieDu formula improves diabetic retinopathy in rats by regulating microRNAs.

ETHNOPHARMACOLOGICAL RELEVANCE: HuoXue JieDu Formula (HXJDF) originates from classical formulas and was formed based on clinical experience. It is composed of Euonymus alatus (Thunb.) Siebold, Panax notoginseng (Burkill) F.H. Chen, the roots of Anguina kirilowii (Maxim.) Kuntze, and Coptis omeiensis (C. Chen) C.Y.Cheng. HXJDF prevents the deterioration of diabetic retinopathy. AIM OF THE STUDY: To evaluate the effects of HXJDF on diabetic retinopathy in rats and investigate the roles of miRNAs in the effects of HXJDF. MATERIALS AND METHODS: A single intraperitoneal injection of streptozotocin (STZ) (65 mg/kg) was used to induce diabetes in rats. Rats were divided into three groups: normal, diabetic, and diabetic + HXJDF. Rats were treated with HXJDF (15.4 g/kg) or water by oral gavage for twelve weeks. At the end of the treatment, rats were anaesthetized, and retinal haemodynamic changes were measured. Then, the retinas were removed and examined by haematoxylin and eosin (HE) staining and TUNEL assays. In addition, miRNA expression profiling was performed using miRNA microarrays and further validated by quantitative real-time PCR (qRT-PCR). RESULTS: Diabetes reduced peak systolic velocity (PSV), end-diastolic velocity (EDV), mean velocity (MV) and central retinal vein velocity (CRV) but increased the resistance index (RI) and pulsatility index (PI). In addition, in the diabetic group, retinal cell arrangement was disordered and loosely arranged, the retinal thickness and retinal ganglion cell (RGC) number decreased, and retinal cell apoptosis increased. In addition, 11 miRNAs were upregulated and 4 miRNAs were downregulated. After treatment, HXJDF improved retinal haemodynamics and morphologic changes, restored retinal thickness and RGC number and decreased retinal cell apoptosis. Furthermore, the changes in miRNA expression were significantly abolished by HXJDF. CONCLUSION: HXJDF may prevent DR by regulating the expression of miRNAs.

Insulin-Like Growth Factor Axis Biomarkers and Gestational Diabetes Mellitus: A Systematic Review and Meta-Analysis.

The insulin-like growth factor (IGF) axis has been implicated in glucose homeostasis. It is plausible to hypothesize that the IGF axis is involved in the development of gestational diabetes mellitus (GDM). In a systematic review of the evidence on IGF axis biomarkers in relation to GDM, we searched the PubMed and EMBASE for publications up to May 31, 2018, on the associations of circulating IGF axis biomarkers with GDM. Eligible studies must meet the pre-specified quality assessment criteria. Meta-analyses were conducted where there were at least three studies on the same biomarker at the same gestational age window-early (<20 weeks), mid (20-29 weeks), or late (30+ weeks) gestation. Twelve studies were included (484 GDM, 1755 euglycemic pregnancies). Meta-analyses showed that GDM was consistently associated with higher IGF-I concentrations in mid-gestation (six studies) and late gestation (six studies). There were only two studies on IGF-I in early gestation and GDM with inconsistent findings. GDM was associated with lower IGFBP-2 concentrations in early, mid-, or late gestation, according to data from one or two studies. GDM was associated with higher IGFBP-3 concentrations in late gestation according to a meta-analysis of five studies. There was no association with GDM for IGFBP-3 in early or mid-gestation, according to data from one study. Other IGF axis biomarkers (IGF-II, IGFBP-1,-4,-5-6, and -7) showed no or inconsistent associations, and the data at early gestation were scanty or absent. Available evidence is suggestive but inconclusive concerning whether the IGF axis is involved in the development of GDM. More studies on IGF axis biomarkers in early gestation are warranted. If a specific IGF axis molecule is proven to be involved in the development of GDM, this may point to a new molecular target for designing interventions to reduce the incidence of GDM.

Comparison of Placebo Effect between Asian and Caucasian Type 2 Diabetic Patients: A Meta-Analysis.

BACKGROUND: Placebo was defined as any therapy that is used for its nonspecific psychological and physiologic effect but has no specific pharmacologic impact on the condition being treated. Besides medication therapies, studies have found that the optimal dietary approach as well as physical activity and education are useful to control hyperglycemia in patients with type 2 diabetes (T2DM). The aim of this study was to evaluate the placebo effects of antidiabetic therapies in Asian and Caucasian T2DM patients and make a comparison between the two ethnicities. METHODS: A search using the MEDLINE database, EMBASE, and Cochrane Database was performed, from when recording began until December 2016. The main concepts searched in English were sulfonylurea (SU); alpha glucosidase inhibitors (AGI); metformin (MET); thiazolidinediones (TZD); dipeptidyl peptidase-4 inhibitors (DPP-4i); sodium-glucose cotransporter 2 inhibitors (SGLT2i); glucagon-like peptide-1 receptor agonist (GLP-1RA); type 2 diabetes (T2DM); placebo controlled; and randomized controlled trials. Using the Cochrane instrument, we evaluated the adequacy of randomization, allocation concealment procedures, and blinding. RESULTS: This study included 63 studies with a total of 7096 Asian patients involved and 262 studies with a total of 27,477 Caucasian patients involved. In Caucasian population, the use of placebo led to significant reductions of glycosylated hemoglobin (HbA1c), -0.683% (P = 0.008) in SU monotherapy treatment, -0.193% (P = 0.001) in DPP-4i treatment, and -0.230% (P < 0.001) in SGLT2i treatment, respectively. In Asian population, the use of placebo resulted in significant decreases of HbA1c, -0.162% (P = 0.012) in DPP-4i treatment and -0.269% (P = 0.028) in GLP-1RA add-on therapy, respectively. The placebo also significantly reduced body weight. In Caucasian population, placebo use resulted in 0.833 kg (P = 0.006) weight loss by SU treatment and 0.953 kg (P = 0.006) weight loss by GLP-1RA treatment. In Asian population, the placebo led to a weight change of 0.612 kg (P < 0.001) by GLP-1RA analog treatment. The changes of HbA1c and weight due to the placebo effect in other treatments were not significant in both Asian and Caucasian population. Comparisons of the placebo effect on HbA1c change and weight change in each treatment group indicated that no significant difference was found between Asian and Caucasian population. CONCLUSIONS: The overall differences of the placebo effect on HbA1c changes as well as on body weight changes were not significant between Asian and Caucasian T2DM patients. The placebo effect on HbA1c changes and weight changes was not associated with baseline age, gender, baseline body mass index, baseline HbA1c, duration of diabetes, or study duration.

Genetic variants and increased risk of meningioma: an updated meta-analysis.

PURPOSE: Various genetic variants have been reported to be linked to an increased risk of meningioma. However, no confirmed conclusion has been obtained. The purpose of the study was to investigate potential meningioma-associated gene polymorphisms, based on published evidence. MATERIALS AND METHODS: An updated meta-analysis was performed in September 2016. After electronic database searching and study screening, we selected eligible case-control studies and extracted data for meta-analysis, using Mantel-Haenszel statistics. P-values, pooled odds ratios (ORs), and 95% confidence intervals were calculated. RESULTS: We finally selected eight genes with ten polymorphisms: MLLT10 rs12770228, CASP8 rs1045485, XRCC1 rs1799782, rs25487, MTHFR rs1801133, rs1801131, MTRR rs1801394, MTR rs1805087, GSTM1 null/present, and GSTT1 null/present. Results of meta-analyses showed that there was increased meningioma risk in case groups under all models of MLLT10 rs12770228 (all OR >1, P<0.001), compared with control groups. Similar results were observed under the allele, homozygote, dominant, and recessive models of MTRR rs1801394 (all OR >1, P<0.05), and the heterozygote and dominant models of MTHFR rs1801131 in the Caucasian population (all OR >1, P<0.05). However, no significantly increased meningioma risks were observed for CASP8 rs1045485, XRCC1 rs25487, rs1799782, MTHFR rs1801133, MTR rs1805087, or GSTM1/GSTT1 null mutations. CONCLUSION: Our updated meta-analysis provided statistical evidence for the role of MLLT10 rs12770228, MTRR rs1801394, and MTHFR rs1801131 in increased susceptibility to meningioma.

Inhibition of activated Ras suppresses multiple oncogenic Hub genes in human epithelial tumors.

Cancer cells may involve diverse mutations, but they often rely on continued expression of a single oncoprotein for survival, as a response to targeting this protein. Generally, Ras is overexpressed in human epithelial tumors and cancellation of activated Ras inhibits carcinoma cell proliferation and differentiation ability, and induces apoptotosis of tumor cells. However, the mechanisms of inhibition of activated Ras that suppress the malignancy activity of human epithelial tumors remain to be illuminated. We utilized text-mining of MEDLINE abstracts with natural language processing to establish the Ras biologic association network, and identified several interactions of this network with the Ras pathway. Our investigation not only examined the expression of Ras and Hub genes (PIK3CA, MDM2, CCND1, EGFR, JUN, MYC, VEGFA, ERK1 and ERK2) but also confirmed inhibition of activated Ras reduced expression of multiple oncogene in vitro studies. Our studies provide strong support for the conclusion that cancellation of activated Ras specifically regulates defective Ras pathways in human tumor cells.

IL-24 Induces Apoptosis via Upregulation of RNA-Activated Protein Kinase and Enhances Temozolomide-Induced Apoptosis in Glioma Cells.

Human interleukin-24 (IL-24) has been found recently to play a tumor-suppressor role in a variety of tumors, including gliomas. However, the exact mechanism of glioma tumor suppression by IL-24 remains unclear. We collected by surgery 30 gliomas at different grades and evaluated IL-24 and double-stranded RNA-activated protein kinase (PKR) expression using fluorescence quantitative real-time PCR and immunohistochemical techniques. Two human glioma cell lines, U87 and U251, were transfected with Ad5F35-IL24 via recombinant adenovirus-mediated gene transfer and apoptosis, as well as PKR and eIF-2α expression analyzed. The results showed that IL-24 and PKR expression decreased with increasing tumor grade. Compared with cells of the control groups, Ad5F35-IL24-infected U87 and U251 cells exhibited a significantly increased apoptosis and elevated PKR, eIF-2α, p-PKR, and p-eIF-2α levels, while the expression of Bcl-2 was decreased. Finally, IL-24 also sensitized apoptosis of glioma cells to temozolomide (TMZ). This study indicates that IL-24 upregulates expression and activation of PKR, further increasing expression and activation of eIF-2α, and decreasing Bcl-2 to promote apoptosis. IL-24 also increases chemosensitivity of glioma cells to TMZ.

Overexpressed let-7a inhibits glioma cell malignancy by directly targeting K-ras, independently of PTEN.

BACKGROUND: Altered expression of micro(mi)RNAs has been shown to be associated with tumorigenesis and tumor progression. The expression of phosphatase and tensin homolog (PTEN) plays an important role in glioma and is regarded as a prognostic marker of glioma patients. The goal of this study was to investigate the function of lethal (let)-7a miRNA in glioma cell lines with different PTEN phenotypes. METHODS: One hundred ninety-eight glioma tissues were used to profile miRNA expression. RESULTS: Let-7a was shown to have lower expression in high-grade glioma than in low-grade glioma. Low expression of let-7a was correlated with poor prognosis of primary glioblastoma patients. We demonstrated that K-ras was a functional target for let-7a to induce cell cycle arrest, apoptosis, and inhibition of cell migration and invasion in vitro. Our further results showed no difference in malignancy inhibition induced by let-7a in 4 glioma cells, including U87 (PTEN null), U251 (PTEN mutant), LN229 (PTEN wild type), and LN229 (PTEN small interfering RNA). The phosphatidylinositol-3 kinase/Akt and mitogen-activated protein kinase/extracellular signal-regulated kinase pathways were inhibited by let-7a, and the inhibition effects had no difference in 4 glioma cells. We demonstrated that let-7a could induce suppression of glioma in vivo by generating a glioma xenograft model. CONCLUSION: Our results indicated that let-7a suppresses its target transcript K-ras and inhibits glioma malignancy independent of PTEN expression.

MiRNA-181b suppresses IGF-1R and functions as a tumor suppressor gene in gliomas.

MicroRNAs (miRNAs) are single-stranded, 18- to 23-nt RNA molecules that function as regulators of gene expression. Previous studies have shown that microRNAs play important roles in human cancers, including gliomas. Here, we found that expression levels of miR-181b were decreased in gliomas, and we identified IGF-1R as a novel direct target of miR-181b. MiR-181b overexpression inhibited cell proliferation, migration, invasion, and tumorigenesis by targeting IGF-1R and its downstream signaling pathways, PI3K/AKT and MAPK/ERK1/2. Overexpression of IGF-1R rescued the inhibitory effects of miR-181b. In clinical specimens, IGF-1R was overexpressed, and its protein levels were inversely correlated with miR-181b expression. Taken together, our results indicate that miR-181b functions in gliomas to suppress growth by targeting the IGF-1R oncogene and that miR-181b may serve as a novel therapeutic target for gliomas.

[Expression of RAS protein in glioma and its effect on the growth of human glioma cells].

OBJECTIVE: To study the expression of RAS protein in human glioma tissues and its influence on tumor growth. METHODS: RAS protein expression in glioma tissues was determined by immunohistochemical (IHC) staining. Subsequently, MTT cell proliferation assay, flow cytometry and Western blotting were used to assay U251 cells with reduced RAS expression. RESULTS: The expression of RAS in glioma was increased and strongly correlated with pathological grade. Downregulation of RAS resulted in glioma cells growth suppression and increased apoptosis. CONCLUSION: The expression level of RAS protein in human glioma was increased. Downregulation of RAS can inhibit glioblastoma cell growth through the RAS signal pathway.

MiR-181d acts as a tumor suppressor in glioma by targeting K-ras and Bcl-2.

PURPOSE: Recently, several microRNAs (miRNAs) were reported to be involved in the modulation of glioma development. The aim of our study was to determine the effect of miR-181d on the growth of glioma and to investigate whether this growth is modulated by targeting K-ras and Bcl-2. METHODS: Real-time PCR was used to analyze the expression of miR-181d in human glioma samples and glioma cell lines. Apoptosis, cell cycle, and proliferation (MTT) assays were performed to assess the phenotypic changes in glioma cells. Immunohistochemistry was used to determine the expression of K-ras and Bcl-2 in glioma tissues, and a luciferase reporter assay was carried out to confirm whether K-ras and Bcl-2 are direct targets of miR-181d. Western blotting was used to identify the potential signaling pathways affected glioma cell growth by miR-181d. In vivo, xenograft tumors were examined for an anti-glioma effect of miR-181d. RESULTS: MiR-181d was down-regulated in human glioma samples and up-regulated in transfected glioma cells. Ectopic expression of miR-181d suppressed proliferation and triggered cell cycle arrest and apoptosis in glioma cell lines. K-ras and Bcl-2 were identified as direct targets of miR-181d and were up-regulated in glioma samples. The results showed evidence linking the tumor suppressor activity of miR-181d in glioma cells with the K-ras-related PI3K/AKT and MAPK/ERK pathways. Furthermore, xenograft tumors from miR-181d-treated U251 cells were suppressed in vivo. CONCLUSION: MiR-181d may act as a glioma suppressor by targeting K-ras and Bcl-2.

MicroRNA-7 regulates glioblastoma cell invasion via targeting focal adhesion kinase expression.

BACKGROUND: Invasion growth is the most characteristic biological phenotype of glioblastoma, but the molecular mechanism in glioma cell invasion is poorly understood. Recent data have showed that microRNA plays an essential role in tumor invasion. Our study aimed to explore the mechanism of miR-7 involved in the control of glioblastoma cell invasion. METHODS: Glioma cell invasion was evaluated by transwell and scratch assays after up-regulation of miR-7 using miR-7 mimics in U87 and U251 cells. Luciferase reporter assay was used to determine focal adhesion kinase (FAK) as a target of miR-7. The levels of miR-7, matrix metalloproteinases (MMP)-2 and MMP-9 mRNA were detected by PCR assay, and the levels of FAK, MMP-2, MMP-9, total and phosphorylation serine/threonine kinase (AKT), and extracellular signal-regulated kinase (ERK) 1/2 were measured by Western blotting analysis. RESULTS: Over-expression of miR-7 inhibited the invasion and migration activity of U87 and U251 cells. And up-regulation of miR-7 reduced FAK protein expression, Further, luciferase reporter assay showed that miR-7 modulated FAK expression directly by binding 3'UTR of FAK mRNA. In addition, miR-7 repressed p-ERK1/2 and p-AKT level, MMP-2 and MMP-9 expression. Finally, the inverse relationship between FAK and miR-7 expression was certificated in human glioma tissues. CONCLUSION: To our knowledge, these data indicate for the first time that miR-7 directly regulates cell invasion by targeting FAK in glioblastoma and that miR-7 could be a potential therapeutic target for glioblastoma intervention.