5mC modification of steroid hormone biosynthesis-related genes orchestrates feminization of channel catfish induced by high-temperature.

To elucidate the mechanism behind channel catfish feminization induced by high temperature, gonad samples were collected from XY pseudo-females and wild-type females and subjected to high-throughput sequencing for Whole-Genome-Bisulfite-Seq (WGBS) and transcriptome sequencing (RNA-Seq). The analysis revealed 50 differentially methylated genes between wild-type females and XY pseudo-females, identified through the analysis of KEGG pathways and GO enrichment in the promoter of the genome and differentially methylated regions (DMRs). Among these genes, multiple differential methylation sites observed within the srd5a2 gene. Repeatability tests confirmed 7 differential methylation sites in the srd5a2 gene in XY pseudo-females compared to normal males, with 1 specific differential methylation site (16608174) distinguishing XY pseudo-females from normal females. Interestingly, the expression of these genes in the transcriptome showed no difference between wild-type females and XY pseudo-females. Our study concluded that methylation of the srd5a2 gene sequence leads to decreased expression, which inhibits testosterone synthesis while promoting the synthesis of 17ß-estradiol from testosterone. This underscores the significance of the srd5a2 gene in the sexual differentiation of channel catfish, as indicated by the ipu00140 KEGG pathway analysis.

High-fat diet consumption promotes adolescent neurobehavioral abnormalities and hippocampal structural alterations via microglial overactivation accompanied by an elevated serum free fatty acid concentration.

Mounting evidence suggests that high-fat diet (HFD) consumption increases the risk for depression, but the neurophysiological mechanisms involved remain to be elucidated. Here, we demonstrated that HFD feeding of C57BL/6J mice during the adolescent period (from 4 to 8 weeks of age) resulted in increased depression- and anxiety-like behaviors concurrent with changes in neuronal and myelin structure in the hippocampus. Additionally, we showed that hippocampal microglia in HFD-fed mice assumed a hyperactive state concomitant with increased PSD95-positive and myelin basic protein (MBP)-positive inclusions, implicating microglia in hippocampal structural alterations induced by HFD consumption. Along with increased levels of serum free fatty acids (FFAs), abnormal deposition of lipid droplets and increased levels of HIF-1α protein (a transcription factor that has been reported to facilitate cellular lipid accumulation) within hippocampal microglia were observed in HFD-fed mice. The use of minocycline, a pharmacological suppressor of microglial overactivation, effectively attenuated neurobehavioral abnormalities and hippocampal structural alterations but barely altered lipid droplet accumulation in the hippocampal microglia of HFD-fed mice. Coadministration of triacsin C abolished the increases in lipid droplet formation, phagocytic activity, and ROS levels in primary microglia treated with serum from HFD-fed mice. In conclusion, our studies demonstrate that the adverse influence of early-life HFD consumption on behavior and hippocampal structure is attributed at least in part to microglial overactivation that is accompanied by an elevated serum FFA concentration and microglial aberrations represent a potential preventive and therapeutic target for HFD-related emotional disorders.

Three-dimensional relationships between condylar volume and dentoskeletal characteristics in Class II hyperdivergent female adults.

BACKGROUND: This study aimed to determine the differences among various volumes of condylar osseous patterns and the corresponding dentoskeletal characteristics based on the risk of temporomandibular disorder. METHODS: Craniofacial spiral computed tomography data of 60 Class II hyperdivergent female adults were divided into normal, resorptive, flattened, and osteophyte groups based on condylar osseous forms. The condylar volumes of each group were compared, and their correlations with the dentoskeletal characteristics were assessed in three dimensions. Pairwise least significant difference tests were used to examine individual pairwise differences between groups, and one-way analysis of variance was used to measure differences among multiple groups. Pearson correlation and Spearman rank correlation analyses were used to determine the correlation between condylar volume and dentofacial characteristics. Statistical significance was established at p < 0.05. RESULTS: The condylar volume in the normal group was significantly greater than that in the changed groups, with no significant differences between the subgroups. The decrease in condylar volume was associated with a retruded and clockwise-rotated mandible with shorter rami. Condylar volume was negatively correlated with overjet, the alveolar height of the lower anterior and posterior teeth, sagittal inclinations of the lower teeth, intermolar width of the mandibular first molars, and width between the corresponding alveolar crests. CONCLUSION: Multiple three-dimensional dentoskeletal characteristics of Class II hyperdivergent female adults are correlated with condylar bony changes, regardless of the form. These results could be helpful in indicating potential pathological changes in the temporomandibular joint and in making proper treatment plans for these patients.

Ultra-slim flexible bronchoscopy-guided topical hemostatic drugs administration for the management of life-threatening refractory pulmonary hemorrhage in a preterm infant: Case report.

Pulmonary hemorrhage (PH) is a rare acute catastrophic event with high mortality among neonates, especially preterm infants. Primary treatments included pulmonary surfactant, high-frequency oscillatory ventilation, epinephrine, coagulopathy management, and intermittent positive pressure ventilation. However, there are still challenges in diagnosing and treating refractory or focal pulmonary hemorrhages. Ultra-slim bronchoscopy has been widely used in the field of critically ill children and is increasingly being done in neonates with critical respiratory disease in recent years. In this study, we report a case with refractory pulmonary hemorrhage in premature infants, which was finally diagnosed as localized hemorrhage in the upper left lobe and cured by ultra-slim bronchoscopy-guided topical hemostatic drug administration. Bronchoscopy is an optional, safe, and practicable technique for early diagnosis and direct injection therapy of neonatal PH in managing life-threatening PH.

Enhanced PDGFR/Wnt/ß-catenin activity of mesenchymal stem cells with high migration ability rescue bone loss of osteoporosis.

Osteoporosis is a widespread disease characterized by bone mass loss and microarchitectural deterioration. The side effects of clinical drugs make mesenchymal stem cells (MSCs)-based therapy gain increasing focus in the treatment of osteoporosis. MSCs need to migrate to the site of damage and undergo differentiation in order to participate in the subsequent bone repair process. Therefore, the homing ability of MSCs may be related to the repair ability. Here, we proposed a novel method to screen MSCs with high migration capacity and confirmed that these MSCs exhibited higher osteogenic differentiation ability both in vivo and in vitro. Further results indicated that MSCs with high migration ability could partly rescue the bone loss of ovarectomized (OVX) rats. Higher expression of Platelet-derived growth factors receptor ß- (PDGFRß) and more nuclear transduction of ß-catenin in MSCs with high migration ability may be responsible for biological functions. This article may provide a method to improve the efficacy of MSCs-based therapy in the clinic.

Exposure to multiple metals and prevalence for preeclampsia in Taiyuan, China.

BACKGROUND: Several studies with small sample size have reported inconsistent associations between single metal and preeclampsia (PE). Very few studies have investigated metal mixtures and PE. METHODS: Blood concentrations of chromium (Cr), cadmium, mercury (Hg), arsenic (As), lead (Pb), nickel, cobalt, and antimony were measured using inductively coupled plasma-mass spectrometry among 427 PE women and 427 matched controls from Taiyuan, China. Multivariate logistic regression models, weighted quantile sum (WQS) regression, and principal component analysis were employed to examine exposure to single metals and metal mixtures in relation to PE. RESULTS: An increased prevalence of PE was associated with Cr (OR = 1.76, 95% CI: 1.18, 2.62 and 1.90, 1.22, 2.93 for the middle and high vs. low), Hg (OR = 1.60, 95% CI: 1.08, 2.38 for the high vs. low) and As (OR = 1.64, 95% CI: 1.07, 2.52 for the middle vs. low). The WQS index, predominated by Cr, Hg, Pb, and As, was positively associated with PE. A principal component characterized by Cr and As also exhibited excessive association with PE. The highest PE prevalence was found among women who were overweight/obese before pregnancy and had high Cr levels compared to women who had pre-pregnancy normal body mass index (BMI) and low Cr levels. CONCLUSIONS: Our study provided evidence that exposure to multiple metals was associated with increased prevalence of PE, and the observed association with multiple metals was dominated by Cr, As. Our study also suggested that pre-pregnancy BMI might modify the association between Cr and PE.

Zinc Levels and Birth Weight in Pregnant Women with Gestational Diabetes Mellitus: A Matched Cohort Study in China.

BACKGROUND: Zinc (Zn) has been suggested to impact fetal growth. However, the effect may be complicated by gestational diabetes mellitus (GDM) due to its impact on fetal growth and placental transport. This study aims to investigate whether GDM modifies the association between Zn levels and birth weight. METHOD: A cohort matched by GDM was established in Taiyuan, China, between 2012 and 2016, including 752 women with GDM and 744 women without. Dietary Zn intake was assessed during pregnancy. Maternal blood (MB) and cord blood (CB) Zn levels were measured at birth. Birth weight was standardized as the z score and categorized as high (HBW, >4000 g) and low (LBW, <2500 g) groups. Multivariate linear regression and multinomial logistic regression were used to examine the association between Zn levels and birth weight in offspring born to women with or without GDM. RESULTS: 88.8% (N = 1328) of the population had inadequate Zn intake during pregnancy. In women with GDM, MB Zn level was inversely associated with birth weight (ß = -.17; 95% confidence interval (CI), -0.34 to -0.01), while CB Zn level was positively associated with birth weight (ß = .38; 95% CI, 0.06-0.70); suggestive associations were observed between MB Zn level and LBW (odds ratio 2.01; 95% CI, 0.95-4.24) and between CB Zn level and HBW (odds ratio 2.37; 95% CI, 1.08-5.21). CONCLUSIONS: GDM may modify the associations between MB and CB Zn levels and birth weight in this population characterized by insufficient Zn intake. These findings suggest a previously unidentified path of adverse effects of GDM.

Prognostic Correlation of an Autophagy-Related Gene Signature in Patients with Head and Neck Squamous Cell Carcinoma.

Considerable evidence indicates that autophagy plays a vital role in the biological processes of various cancers. The aim of this study is to evaluate the prognostic value of autophagy-related genes in patients with head and neck squamous cell carcinoma (HNSCC). Transcriptome expression profiles and clinical data acquired from The Cancer Genome Atlas (TCGA) database were analyzed by Cox proportional hazards model and Kaplan-Meier survival analysis to screen autophagy-related prognostic genes that were significantly correlated with HNSCC patients' overall survival. Functional enrichment analyses were performed to explore biological functions of differentially expressed autophagy-related genes (ARGs) identified in HNSCC patients. Six ARGs (EGFR, HSPB8, PRKN, CDKN2A, FADD, and ITGA3) identified with significantly prognostic values for HNSCC were used to construct a risk signature that could stratify patients into the high-risk and low-risk groups. This signature demonstrated great value in predicting prognosis for HNSCC patients and was indicated as an independent prognostic factor in terms of clinicopathological characteristics (sex, age, clinical stage, histological grade, anatomic subdivision, alcohol history, smoking status, HPV status, and mutational status of the samples). The prognostic signature was also validated by data from the Gene Expression Omnibus (GEO) database and International Cancer Genome Consortium (ICGC). In conclusion, this study provides a novel autophagy-related gene signature for predicting prognosis of HNSCC patients and gives molecular insights of autophagy in HNSCC.

Multiple metal concentrations and gestational diabetes mellitus in Taiyuan, China.

BACKGROUND: The association between multiple metal concentrations and gestational diabetes mellitus (GDM) is poorly understood. METHODS: A total of 776 women with GDM and an equal number of controls were included in the study. Concentrations of metals in participants' blood (nickel (Ni), arsenic (As), cadmium (Cd), antimony (Sb), thallium (Tl), mercury (Hg), lead (Pb)) were measured using inductively coupled plasma-mass. We used unconditional logistical regression models to estimate the associations between metals and GDM. We also employed weighted quantile sum (WQS) regression and principal components analysis (PCA) to examine metal mixtures in relation to GDM. RESULTS: An increased risk of GDM was associated with As (OR = 1.49, 95% CI: 1.11, 2.01 for the 2nd tertile vs. the 1st tertile) and Hg (OR = 1.43, 95% CI: 1.09, 1.88 for the 3rd tertile vs. the 1st tertile). In WQS analysis, the WQS index was significantly associated with GDM (OR = 1.20, 95% CI: 1.02, 1.41). The major contributor to the metal mixture index was Hg (69.2%), followed by Pb (12.8%), and As (11.3%). Based on PCA, the second principal component, which was characterized by Hg, Ni, and Pb, was associated with an increased risk of GDM (OR = 1.46, 95% CI: 1.02, 2.08 for the highest quartile vs. the lowest quartile). CONCLUSIONS: Our study results suggest that high metal levels are associated with an increased risk of GDM, and this increased risk is mainly driven by Hg and, to a lesser extent, by Ni, Pb, and As.

SOS1 gene polymorphisms are associated with gestational diabetes mellitus in a Chinese population: Results from a nested case-control study in Taiyuan, China.

Gestational diabetes mellitus is a growing public health concern due to its large disease burden; however, the underlying pathophysiology remains unclear. Therefore, we examined the relationship between 107 single-nucleotide polymorphisms in insulin signalling pathway genes and gestational diabetes mellitus risk using a nested case-control study. The SOS1 rs7598922 GA and AA genotype were statistically significantly associated with reduced gestational diabetes mellitus risk ( ptrend = 0.0006) compared with GG genotype. At the gene level, SOS1 was statistically significantly associated with gestational diabetes mellitus risk after adjusting for multiple comparisons. Moreover, AGGA and GGGG haplotypes in SOS1 gene were associated with reduced risk of gestational diabetes mellitus. Our study provides evidence for an association between the SOS1 gene and risk of gestational diabetes mellitus; however, its role in the pathogenesis of gestational diabetes mellitus will need to be verified by further studies.

Polymorphisms in Sex Hormone Metabolism Genes and Risk of Preeclampsia in Taiyuan, China.

OBJECTIVE: Aberrant synthesis and metabolism of sex hormone are likely to be associated with alterations in vascular function in preeclampsia (PE). The study aims to investigate whether single nucleotide polymorphisms (SNPs) in sex hormone-related genes are associated with PE. METHOD: We performed a nested case-control study including 436 pregnant women (203 PE and 233 healthy or normal pregnant women) to investigate associations between 96 SNPs in 28 sex hormone-related genes and risk of PE. RESULTS: TXNRD2/COMT rs3788314 and SULT1A2/SULT1A1 rs4788073 were associated with an increased risk of PE overall (ptrend = 0.004 and 0.003, respectively), early-onset PE (ptrend = 0.007 and 0.009, respectively), and severe PE (ptrend = 0.002 and 0.005, respectively). Additionally, CYP17A1 rs4919690 and rs4919687 and LHCGR rs10180731 were associated with an increased risk of severe PE (ptrend = 0.005, 0.006, and 0.014, respectively), while GNRHR rs2630488 was associated with a decreased risk of severe PE (ptrend = 0.014). We also observed that HSD17B3 rs8190512 was associated with a decreased risk of early-onset PE (ptrend = 0.003). We observed strong linkage disequilibrium in SULF1 (rs10106958, rs7813987, and rs6990375). CONCLUSIONS: Our study suggested that genetic polymorphisms in TXNRD2/COMT, SULT1A2/SULT1A1, CYP17A1, HSD17B3, GNRHR, LHCGR, and SULF1 might play a role in PE, especially in early-onset PE and severe PE. Future studies are warranted to replicate the observed associations and their functional mechanisms.

Obeservations on association between third molar agenesis and craniofacial morphology.

OBJECTIVE: This study was designed to examine the relationship between third molar agenesis and skeletal morphology in the Chinese population. MATERIALS AND METHODS: A total of 1043 patients' records were analyzed with panoramic radiographs and cephalograms. Congenitally missing third molars were assessed with respect to gender, jaw, and side, and assessed in various types of facial morphology. Linear, angular, and proportional cephalometric measurements were analyzed and compared among the samples. For the evaluation of results, the following statistics were used: the Pearson χ 2 test, one-way ANOVA, and the Student-Newman-Keuls method. RESULTS: The overall prevalence of third molar agenesis was 28.7%. Missing third molars were more common in the maxilla and on the right side, while the difference was not statistically significant (P > 0.05) between genders. Every hypodontia group had a smaller SN-GoGn angle, Y-axis-FH angle, and a larger S-Go/N-Me ratio. The group with third molar agenesis in both jaws had smaller SNA and Wits values. The frequency of third molar agenesis in subjects with a Class II malocclusion was significantly lower than in other types of malocclusion (P < 0.05), and the incidence of third molar agenesis in hypodivergent growth pattern was higher than in other patterns (P < 0.05). CONCLUSION: The results demonstrate a possible association between third molar agenesis and both sagittal and vertical craniofacial morphology.

Polymorphisms in Inflammatory Mediator Genes and Risk of Preeclampsia in Taiyuan, China.

Excessive maternal inflammatory response is involved in the pathogenesis of preeclampsia. Few epidemiologic studies have investigated the associations between genetic variations in the inflammatory mediator genes and preeclampsia risk, and these studies have reached inconsistent results. We examined 31 single-nucleotide polymorphisms in IL-1A, IL-1B, IL-1R1, IL-2RA, IL-5RA, IL-6, IL-6R, TNFSF11, TNFRSF11A, IL-28RA, IRAK4, and KIT genes and the risk of preeclampsia and its clinical subtypes in a nested case-control study including 203 preeclampsia cases and 233 controls. We found that IL-1R1, IL-5RA, IL-6R, and TNFSF11 were associated with the risk of preeclampsia. Although the significant associations observed for preeclampsia overall were mainly seen for late-onset preeclampsia and severe preeclampsia, IL-6R (rs2229238) and TNFSF11 (rs9525643) polymorphisms were associated with the risk of early-onset preeclampsia. TNFSF11 (rs2200287 and rs2148072) polymorphisms were associated with risk of mild preeclampsia. Our study provided the first evidence that genetic variations in inflammatory mediator genes IL-1R1, IL-6R, TNFSF11, and IL-5RA were associated with preeclampsia risk, and the risk varied by preeclampsia subtypes.

Polymorphisms in complement genes and risk of preeclampsia in Taiyuan, China.

BACKGROUND AND OBJECTIVES: Altered immune response may be a part of the pathogenesis of preeclampsia. The few epidemiologic studies that have investigated the associations between genetic variations in the complement system genes and preeclampsia risk have reached inconsistent results. The aim of this study is to determine if polymorphisms in the complement system genes could influence the risk of preeclampsia. METHODS: We examined 51 SNPs in the C3, C5, C6, MASP1, MBL2 and CD55 genes and the risk of preeclampsia and its clinical subtypes in a nested case-control study of 203 preeclampsia cases and 233 controls. RESULTS: Both C6 and MASP1 were associated with the risk of preeclampsia. C6 (rs7444800, rs4957381) and MASP1 (rs1108450, rs3774282, rs698106) polymorphisms were associated with the risk of early-onset preeclampsia and severe preeclampsia, while MASP1 (rs1357134, rs698090) polymorphisms were associated with the risk of late-onset preeclampsia and severe preeclampsia. CONCLUSIONS: Our study provided novel evidence that genetic variations in complement genes C6 and MASP1were associated with preeclampsia risk, and that the risk varied by preeclampsia subtypes.

[Ambient PM2.5 during pregnancy and risk on preterm birth].

OBJECTIVE: To investigate the association between ambient fine particulate matter with aerodynamic diameter less than 2.5 µm (PM2.5) and the risk on preterm birth. METHODS: A total of 1 882 pregnant women with local residency of Taiyuan city and underwent delivery at the First Hospital of Shanxi Medical University with the dates of conception between January 1 and December 31, 2013, were enrolled in the study. Information on general demographics, home address and history on pregnancy, lifestyle and related environmental factors were collected through in-person interview. Birth outcomes and maternal complications were abstracted from medical records. Data on the amount of daily average PM2.5 from 8 monitor points in Taiyuan city, between March 1, 2012 and December 31, 2013 were also collected. Individual exposure during pregnancy were calculated using the inverse-distance weighting method, based on home address. Multivariate unconditional logistic regression model was used to examine the associations among PM2.5 exposure, risk of preterm birth and related clinical subtypes. RESULTS: The overall incidence of preterm birth was 8.21% (151/1 839)in 1 839 pregnant women. Exposure to ambient PM2.5 during the second week prior to delivery was associated with an increased risk of preterm birth (OR=1.087, 95% CI: 1.001-1.182 per 10 µg/m(3) increase) and mild preterm birth (OR=1.099, 95% CI: 1.007-1.200 per 10 µg/m(3)). Compared to data from the China Environmental Air Quality Standard, higher level of exposure (≥75 µg/m(3)) of PM2.5 during the second week before delivery was associated with an increased risk of preterm birth (OR=1.008, 95%CI: 1.000-1.017) but the association was mainly seen for mild preterm birth (OR=1.010, 95%CI: 1.001-1.018). CONCLUSIONS: RESULTS from our study showed that exposure to high level of PM2.5 during late pregnancy would increase the risk of preterm birth. Future large studies are needed to examine the association by preterm clinical subtypes and to elucidate potential underlying mechanisms.

Astroglial U87 Cells Protect Neuronal SH-SY5Y Cells from Indirect Effect of Radiation by Reducing DNA Damage and Inhibiting Fas Mediated Apoptotic Pathway in Coculture System.

Recent studies provide the evidence that indirect effects of radiation could lead to neuronal cells death but underlying mechanism is not completely understood. On the other hand astroglial cells are known to protect neuronal cells against stress conditions in vivo and invitro. Yet, the fate of neuronal cells and the neuroprotective effect of coculture system (with glial cells) in response to indirect radiation exposure remain rarely discussed. Here, we purpose that the indirect effect of radiation may induce DNA damage by cell cycle arrest and receptor mediated apoptotic cascade which lead to apoptotic death of neuronal SH-SY5Y cells. We also hypothesized that coculture (with glial U87) may relieved the neuronal SH-SY5Y cells from toxicity of indirect effects radiation by reducing DNA damage and expression of apoptotic proteins in vitro. In the present study irradiated cell conditioned medium (ICCM) was used as source of indirect effect of radiation. Neuronal SH-SY5Y cells were exposed to ICCM with and without coculture with (glial U87) in transwell coculture system respectively. Various endpoints such as, cell survival number assay, Annexin V/PI assay, cell cycle analysis by flow cytometer, mRNA level of Fas receptor by q RT-PCR, expression of key apoptotic proteins by western blot and estimation of neurotrophic factors by ELISA method were analyzed into neuronal SH-SY5Y cells with and without co culture after ICCM exposure respectively. We found that ICCM induced DNA damage in neuronal SH-SY5Y cells by significant increase in cell cycle arrest at S-phase (***P < 0.001) which was further supported by over expression of P53 protein (**P < 0.01). While coculture (with glial U87), significantly reduced the ICCM induced cell cycle arrest and expression of P53 ((###) P < 0.001) neuronal SH-SY5Y cells. Further investigation of the underlying apoptotic mechanism revealed that in coculture system; ICCM induced elevated level of FAS mRNA level was significantly reduced ((###) P < 0.001) in neuronal SH-SY5Y cells which was followed by significant reduction in expression of key apoptotic protein i.e., FADD ((###) P < 0.001), caspase-8 ((###) P < 0.001), and cleaved caspase-3 ((###) P < 0.001) as compare to neuronal SH-SY5Y cells which received ICCM without coculture. Intriguingly, concentration of neurotrophic factors such as, GDNF and BDNF were significantly increased ((###) P < 0.001) in neuronal SH-SY5Y after coculture (with glial U87) cells. Hence, these findings infer that the receptor mediated pathway could be the one way through which indirect effects of radiation cause neurotoxicity. However, in co-cultures system (with glial U87) neuronal SH-SY5Y depicts remarkable resistance against ICCM induced neurotoxicity.

Glial U87 cells protect neuronal SH-SY5Y cells from indirect effect of radiation by reducing oxidative stress and apoptosis.

Recent studies have demonstrated the role of indirect effect of radiation in neurodegeneration. However, the role of glial cells in neuroprotection against indirect effect of radiation is still not clear, although they are known to protect neurons under stress conditions in central nervous system. Our study showed that indirect effect of radiation increased the oxidative stress that further enhances the expression of key apoptotic proteins and leads to neuronal cell death. We also investigated the indirect effect of radiation on neuronal cells in the presence of glial cells in a transwell co-culture system, while our analysis was focused on neuronal cells. Irradiated cell-conditioned medium (ICCM) was used as source of indirect radiation and neuroprotective effect was analyzed by various endpoints. It was observed that ICCM-induced reactive oxidative species level was significantly reduced in SH-SY5Y cells co-cultured with glial U87 cells, which might help to maintain the integrity of mitochondrial membrane potential. Increased levels of antioxidant enzyme superoxide dismutase and antioxidant glutathione were observed in SH-SY5Y cells co-cultured with glial U87 cells. Moreover, it was also observed that co-culture with glial cells inhibits the expression of ICCM-induced apoptotic proteins, i.e. Bax, cytochrome c, and caspase-3 in SH-SY5Y cells. Hence, it can be speculated that in co-culture system glial cells may protect the neuronal SH-SY5Y cells by reducing the ICCM-induced oxidative stress and apoptotic death.

A newly discovered neurotoxin ADTIQ associated with hyperglycemia and Parkinson's disease.

BACKGROUND: Diabetes is associated with an increased risk of Parkinson's disease (PD). Number of studies have suggested that methylglyoxal (MGO) induced by diabetes is related to PD. However, very little is known about its molecular mechanism. On other hand, 1-acetyl-6, 7- dihydroxyl-1, 2, 3, 4- Tetrahydroisoquinoline(ADTIQ) is a dopamine (DA)-derived tetrahydroisoquinoline (TIQ), a novel endogenous neurotoxins, which was first discovered in frozen Parkinson's disease human brain tissue. While ADTIQ precursor methylglyoxal was also found in diabetic patients related to the glucose metabolism and diabetic patients. METHODS: LC-MS/MS, 1H NMR and infrared spectroscopy identified the structure of ADTIQ. The Annexin V-FITC/PI, MTT and western blot analysis were used to measure the neurotoxicity of ADTIQ. The levels of ADTIQ and methylglyoxal were detected by LC-MS/MS. RESULTS: Here we report the chemical synthesis of ADTIQ, demonstrate its biosynthesis in SH-SY5Y neuroblastoma cell line and investigate its role in the pathogenesis of PD. In addition, a significant increase in the level of ADTIQ was detected in the brains of transgenic mice expressing mutant forms (A53T or A30P) of α-synuclein. ADTIQ also reduced the cell viability and induced mitochondrial apoptosis in dopaminergic cells, suggesting that ADTIQ acts as an endogenous neurotoxin and potentially involved in the pathogenesis of PD. Methylglyoxal, a major byproduct of glucose metabolism and abnormalities in glucose metabolism could influence the levels of ADTIQ. Consistent with the hypothesis, increased levels of ADTIQ and methylglyoxal were detected in the striatum of diabetic rats and SH-SY5Y cells cultured in the presence of high glucose concentrations. CONCLUSIONS: Increased levels of ADTIQ could be related with Hyperglycemia and death of dopaminergic neurons. GENERAL SIGNIFICANCE: The increased levels of ADTIQ could be a reason of dopamine neuron dysfunction in diabetes. Therefore, ADTIQ may play a key role in increasing the risk for PD in patients with diabetes.

Salsolinol Damaged Neuroblastoma SH-SY5Y Cells Induce Proliferation of Human Monocyte THP-1 Cells Through the mTOR Pathway in a Co-culture System.

Despite extensive efforts to study the inflammatory process in the central nervous system of Parkinson's disease (PD) patients, little is known about the role of peripheral blood mononuclear cells (PBMCs) in PD. In the present study, we used an in vitro co-culture system to study the role of the human monocyte cell line THP-1 in medium conditioned by the neuroblastoma cell line SH-SY5Y damaged with the endogenous neurotoxin 1-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline (Salsolinol, Sal) in co-culture with the human glioma cell line U87. For this purpose, SH-SY5Y and U87 co-cultures were treated with Sal, and this conditioned medium containing mediators, including the potential effector CCL2, was isolated and applied to THP-1 cells. This treatment resulted in approximately 19 % cell proliferation as well as activation of mTOR and induction of phosphorylated 4E-BP1, S6K1, PI3K, and AKT proteins. Treatment with rapamycin, an mTOR inhibitor, attenuated the proliferation of THP-1 cells. U87 glial cells were essential for this as medium conditioned without them had no effect on THP-1 cells. These results suggest a positive effect of THP-1 cells on Sal-induced neurotoxicity in a cellular model of PD and this is likely mediated by the enhancement of cell proliferation through activation of the mTOR signaling pathway. Hence, PBMCs and their mTOR signaling pathway could be of therapeutic benefit in treating the endogenous neurotoxin-induced neuroinflammation in PD.