Publications by authors named "Yan Bo Li"

59 Publications

Copper(I)-Catalyzed Asymmetric Alkylation of Unsymmetrical Secondary Phosphines.

J Am Chem Soc 2021 Jul 23;143(26):9912-9921. Epub 2021 Jun 23.

CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Centre for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China.

A copper(I)-catalyzed asymmetric alkylation of HPArAr with alkyl halides is uncovered, which provides an array of -stereogenic phosphines in generally high yield and enantioselectivity. The electrophilic alkyl halides enjoy a broad substrate scope, including allyl bromides, propargyl bromide, benzyl bromides, and alkyl iodides. Moreover, 11 unsymmetrical diarylphosphines (HPArAr) serve as competent pronucleophiles. The present methodology is also successfully applied to catalytic asymmetric double and triple alkylation, and the corresponding products were obtained in moderate diastereo- and excellent enantioselectivities. Some P NMR experiments indicate that bulky HPPhMes exhibits weak competitively coordinating ability to the Cu(I)-bisphosphine complex, and thus the presence of stoichiometric HPArAr does not affect the enantioselectivity significantly. Therefore, the high enantioselectivity in this reaction is attributed to the high performance of the unique Cu(I)-(,)-TANIAPHOS complex in asymmetric induction. Finally, one monophosphine and two bisphosphines prepared by the present reaction are employed as efficient chiral ligands to afford three structurally diversified Cu(I) complexes, which demonstrates the synthetic utility of the present methodology.
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http://dx.doi.org/10.1021/jacs.1c04112DOI Listing
July 2021

Nomogram for Early Prediction of Pathological Complete Response to Neoadjuvant Chemotherapy in Breast Cancer Using Dynamic Contrast-enhanced and Diffusion-weighted MRI.

Acad Radiol 2021 Feb 13. Epub 2021 Feb 13.

Department of Breast Imaging, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, P.R. China. Electronic address:

Rationale And Objectives: The study investigated the potential of the combined use of dynamic contrast-enhanced MRI and diffusion-weighted imaging in predicting the pathological complete response (pCR) of neoadjuvant chemotherapy (NAC) after two cycles of NAC.

Materials And Methods: Eighty-seven patients with breast cancer who underwent MR examination before and after two cycles of NAC were enrolled. The patients were randomly assigned to a training cohort and a validation cohort (3:1 ratio). MRI parameters including tumor longest diameter, time-signal intensity curve, early enhanced ratio (E), maximal enhanced ratio and ADC value were measured, and percentage change in MRI parameters were calculated. Univariate analysis and multivariate logistic regression analysis were used to evaluate independent predictors of pCR in the training cohort. The validation cohort was used to test the prediction model, and the nomogram was created based on the prediction model.

Results: This study demonstrated that the ADC value after two cycles of NAC (OR = 1.041, 95% CI (1.002, 1.081); p = 0.037), percentage decrease in E (OR = 0.927, 95% CI (0.881, 0.977); p =0.004) and percentage decrease in tumor size (OR = 0.948, 95% CI (0.909, 0.988); p = 0.011) were significantly important for independently predicting pCR. The prediction model yielded AUC of 0.939 and 0.944 in the training cohort and the validation cohort, respectively.

Conclusion: The combined use of dynamic contrast-enhanced MRI and diffusion-weighted imaging could accurately predict pCR after two cycles of NAC. The prediction model and the nomogram had strong predictive value to NAC.
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http://dx.doi.org/10.1016/j.acra.2021.01.023DOI Listing
February 2021

Liraglutide protects palmitate-induced INS-1 cell injury by enhancing autophagy mediated via FoxO1.

Mol Med Rep 2021 02 23;23(2). Epub 2020 Dec 23.

Department of Endocrinology, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China.

Type 2 diabetes mellitus (T2DM) is characterized by insulin resistance and a progressive loss in mass and function of pancreatic β-cells. In T2DM, lipotoxicity leads to β-cells dysfunction and decreases its number. Autophagy serves a crucial role in maintaining the normal islet architecture and the function of β-cells. Moreover, glucagon-like peptide-1 (GLP-1) and its analogs have beneficial roles in pancreatic β-cells. However, the protective effects of GLP-1 agents on palmitate (PA)-induced pancreatic β-cells and their underlying mechanisms are not fully elucidated. Forkhead box O1 (FoxO1) can prevent pancreatic β-cells from apoptosis. Whether GLP-1 protects against PA-induced β-cells injury via FoxO1 remains unknown. The present study exposed INS-1 cells to PA to establish a T2DM injury model. Cell viability was evaluated using a Cell Counting Kit-8 assay, and apoptosis was determined via western blotting. Furthermore, autophagy was examined using western blotting, immunofluorescence and transmission electron microscopy. Silencing FoxO1 was used to inhibit the activities of FoxO1. The results suggested that the GLP-1 analog liraglutide enhanced the cell viability, inhibited the protein expression of cleaved caspase-3 and increased the expression levels of microtubule-associated protein 1 light chain3 (LC3) II/I, and FoxO1 in INS-1 cells. The autophagy inhibitor chloroquine inhibited the protective effects of liraglutide on INS-1 cells. Silencing of FoxO1 decreased the expression levels of LC3-II and attenuated the protection of liraglutide on the viability of INS-1 cells. In conclusion, the results indicated that liraglutide ameliorated the PA-induced islet β-cells injury via the upregulation of autophagy-mediated by FoxO1.
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http://dx.doi.org/10.3892/mmr.2020.11786DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789139PMC
February 2021

Copper(I)-Catalyzed Asymmetric 1,4-Conjugate Hydrophosphination of α,β-Unsaturated Amides.

J Am Chem Soc 2020 Nov 11;142(47):20098-20106. Epub 2020 Nov 11.

CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Centre for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China.

A catalytic asymmetric conjugate hydrophosphination of α,β-unsaturated amides is accomplished by virtue of the strong nucleophilicity of copper(I)-PPh species, which provides an array of chiral phosphines bearing an amide moiety in high to excellent yields with excellent enantioselectivity. Furthermore, the dynamic kinetic resolution of unsymmetrical diarylphosphines (HPArAr) is successfully carried out through the copper(I)-catalyzed conjugate addition to α,β-unsaturated amides, which affords -chiral phosphines with good-to-high diastereoselectivity and high enantioselectivity. H NMR studies show that the precoordination of HPPh to copper(I)-bisphosphine complex is critical for the efficient deprotonation by Barton's Base. Moreover, the relative stability of the copper(I)-(,)-TANIAPHOS complex in the presence of excessive HPPh, confirmed by P NMR studies, is pivotal for the high asymmetric induction, as the ligand exchange between bisphosphine and HPPh would significantly reduce the enantioselectivity. At last, a double catalytic asymmetric conjugate hydrophosphination furnishes the corresponding product in high yield with high diastereoselectivity and excellent enantioselectivity, which is transformed to a chiral pincer palladium complex in moderate yield. This chiral palladium complex is demonstrated as an excellent catalyst in the asymmetric conjugate hydrophosphination of chalcone.
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http://dx.doi.org/10.1021/jacs.0c09654DOI Listing
November 2020

Neurogenic inflammation in fulminant myocarditis: May be a trigger.

Med Hypotheses 2020 Jun 9;139:109563. Epub 2020 Jan 9.

Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, PR China; Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, Wuhan 430060, PR China.

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http://dx.doi.org/10.1016/j.mehy.2020.109563DOI Listing
June 2020

Role of autophagy in LPS‑induced inflammation in INS‑1 cells.

Mol Med Rep 2019 Jun 19;19(6):5211-5218. Epub 2019 Apr 19.

Department of Endocrinology, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China.

Inflammation has been implicated in the pathogenesis of type 2 diabetes (T2D), which is a progressive disease characterized by pancreatic β‑cell dysfunction and apoptosis with consequential insufficient insulin secretion. Autophagy is necessary to maintain the structure, mass and function of pancreatic β‑cells. The present study investigated the crosstalk between autophagy and inflammasome activation in T2D. INS‑1 cells were stimulated with lipopolysaccharide. Apoptosis and reactive oxygen species (ROS) formation were measured using flow cytometry, and cell proliferation was measured using Cell Counting Kit‑8 solution. Autophagy was assayed using western blotting and transmission electron microscopy. The expression levels of interleukin‑1β (IL‑1β) and caspase‑1 were detected by western blotting. The results demonstrated that inhibiting autophagy using 3‑methyladenine (3‑MA) promoted INS‑1 cell apoptosis. This response was correlated with an increase in ROS production and the inflammatory response, including IL‑1β maturation and caspase‑1 activation. Furthermore, when ROS were inhibited using N‑acetyl‑L‑cysteine, inflammation was decreased. These results demonstrated that inhibition of autophagy enhanced inflammatory injury via the ROS‑mediated activation of the Nod‑like receptor pyrin domain‑containing protein 3 inflammasome. Autophagy may have a protective effect by mitigating inflammation in T2D, which may provide a novel approach for T2D treatment.
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http://dx.doi.org/10.3892/mmr.2019.10172DOI Listing
June 2019

SIRT3 Protects Rotenone-induced Injury in SH-SY5Y Cells by Promoting Autophagy through the LKB1-AMPK-mTOR Pathway.

Aging Dis 2018 Apr 1;9(2):273-286. Epub 2018 Apr 1.

1Department of Neurology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.

SIRT3 is a class III histone deacetylase that modulates energy metabolism, genomic stability and stress resistance. It has been implicated as a potential therapeutic target in a variety of neurodegenerative diseases, including Parkinson's disease (PD). Our previous study demonstrates that SIRT3 had a neuroprotective effect on a rotenone-induced PD cell model, however, the exact mechanism is unknown. In this study, we investigated the underlying mechanism. We established a SIRT3 stable overexpression cell line using lentivirus infection in SH-SY5Y cells. Then, a PD cell model was established using rotenone. Our data demonstrate that overexpression of SIRT3 increased the level of the autophagy markers LC3 II and Beclin 1. After addition of the autophagy inhibitor 3-MA, the protective effect of SIRT3 diminished: the cell viability decreased, while the apoptosis rate increased; α-synuclein accumulation enhanced; ROS production increased; antioxidants levels, including SOD and GSH, decreased; and MMP collapsed. These results reveal that SIRT3 has neuroprotective effects on a PD cell model by up-regulating autophagy. Furthermore, SIRT3 overexpression also promoted LKB1 phosphorylation, followed by activation of AMPK and decreased phosphorylation of mTOR. These results suggest that the LKB1-AMPK-mTOR pathway has a role in induction of autophagy. Together, our findings indicate a novel mechanism by which SIRT3 protects a rotenone-induced PD cell model through the regulation of autophagy, which, in part, is mediated by activation of the LKB1-AMPK-mTOR pathway.
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http://dx.doi.org/10.14336/AD.2017.0517DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5963348PMC
April 2018

Resveratrol attenuates type 2 diabetes mellitus by mediating mitochondrial biogenesis and lipid metabolism via Sirtuin type 1.

Exp Ther Med 2018 Jan 30;15(1):576-584. Epub 2017 Oct 30.

Department of Hematology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China.

The rising incidence of type 2 diabetes mellitus (T2DM) is a major public health problem and novel therapeutic strategies are required to prevent and treat T2DM. It has been demonstrated that resveratrol (RSV) may prevent T2DM by targeting Sirtuin type 1 (SIRT1), indicating that SIRT1 may be a novel therapeutic target for T2DM prevention. In the present study, a T2DM rat model was established by administering a high fat diet and streptozotocin (STZ) injections. Measurements of blood glucose and insulin confirmed successful establishment of the T2DM model. RSV was used to treat rats with STZ-induced T2DM and the results indicated that RSV reversed the STZ-induced downregulation of peroxisome proliferator-activated receptor-γ coactivator-1α, SIRT1 and forkhead box protein O 3a. Furthermore, RSV modulated the activity of superoxide dismutase and malondialdehyde, which are associated with oxidative stress. , cells from the insulinoma cell line clone 1E were pretreated with palmitic acid (PA) to simulate a high fat environment. The results of reverse transcription-quantitative polymerase chain reaction indicated that PA suppressed the expression of SIRT1 in a dose- and time-dependent manner. Furthermore, PA modulated the expression of mitochondrial biogenesis-associated, lipid metabolism-associated and β-cell-associated genes, whereas RSV treatment ameliorated the PA-induced changes in the expression of these genes via SIRT1. The results of the present study suggest that RSV participates in the prevention of T2DM by regulating the expression of mitochondrial genes associated with biogenesis, lipid metabolism and β-cells via SIRT1. The results of the current study provide an insight into the mechanisms by which SIRT1 inhibits T2DM and may be used as a basis for future studies.
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http://dx.doi.org/10.3892/etm.2017.5400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5769236PMC
January 2018

Detection of SNPs of T2DM susceptibility genes by a ligase detection reaction-fluorescent nanosphere technique.

Anal Biochem 2018 01 9;540-541:38-44. Epub 2017 Nov 9.

Department of Endocrinology, The Second Hospital of Jilin University, Changchun 130000, China.

Objective: To establish a high throughput, low cost, and simple nanotechnology-based method for the detection of single nucleotide polymorphism (SNP) loci in type 2 diabetes mellitus (T2DM).

Methods: Multiplex ligase detection reaction (LDR) amplification was performed using fluorescently labeled magnetic nanosphere-bound upstream LDR probes and downstream probes labeled with a unique fluorescent group for each SNP locus. The amplified LDR products were separated by magnetic nanospheres and then scanned by fluorescence spectroscopy. Four SNP loci associated with T2DM were detected, including the rs13866634 locus in SLC30A8, rs10811661in CDKN2A/2B, rs1111875 in the HHEX gene, and rs7903146 in the TCF7L2 gene. The SNP genotype was also determined by DNA sequencing as a control.

Results: The SNP genotypes of the four gene loci determined by the nanosphere-based multiplex LDR method were consistent with the DNA sequencing results. The accuracy rate was 100%.

Conclusion: A method based on multiplex PCR and LDR was established for simultaneous detection of four SNP loci of T2DM susceptibility genes.
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http://dx.doi.org/10.1016/j.ab.2017.11.003DOI Listing
January 2018

Endoplasmic reticulum stress induced by lipopolysaccharide is involved in the association between inflammation and autophagy in INS‑1 cells.

Mol Med Rep 2017 Nov 24;16(5):5787-5792. Epub 2017 Aug 24.

Department of Endocrinology, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China.

Type 2 diabetes is a chronic inflammatory disease. Autophagy, the dynamic process of lysosomal degradation of damaged organelles and proteins, may protect β‑cells from destruction by inflammation in type 2 diabetes. The present study investigated the role of autophagy, inflammation and endoplasmic reticulum (ER) stress in type 2 diabetes. INS‑1 cells were incubated with lipopolysaccharide. The chemical chaperone 4‑phenylbutyric acid was used to inhibit ER stress, and 3‑methyadenine (3‑MA) was used to inhibit autophagy. Apoptosis was detected by flow cytometry and cell proliferation using Cell Counting kit‑8 solution. Light chain‑3B, interleukin (IL) 1β, caspase‑1 and C/EBP homologous protein production were assessed by western blotting, and rat activating transcription factor 4 and rat binding immunoglobulin heavy chain protein gene expression were determined by real‑time reverse transcription‑polymerase chain reaction. The results showed that inhibiting autophagy with 3‑MA unexpectedly contributed to cell death in β‑cells. This response was associated with an increase in inflammatory cytokines, including IL1β and caspase‑1. Inhibiting ER stress with 4‑phenylbutyric acid led to a decrease in cell apoptosis. These results showed that autophagy may have a protective effect by reducing inflammatory cytokines in β‑cells. In addition, the inositol‑requiring enzyme 1 pathway mediated the ER stress associated with autophagy and inflammatory cytokines (IL1β and caspase‑1). Therefore, inflammatory cytokines may be critical signalling nodes, which are associated with ER stress‑mediated β‑cell death.
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http://dx.doi.org/10.3892/mmr.2017.7350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5865759PMC
November 2017

Impact of Different Levels of iPTH on All-Cause Mortality in Dialysis Patients with Secondary Hyperparathyroidism after Parathyroidectomy.

Biomed Res Int 2017 5;2017:6934706. Epub 2017 Jun 5.

Department of Nephrology, Cangzhou People's Hospital, Cangzhou, China.

Background: Secondary hyperparathyroidism (SHPT) usually required parathyroidectomy (PTX) when drugs treatment is invalid. Analysis was done on the impact of different intact parathyroid hormone (iPTH) after the PTX on all-cause mortality.

Methods: An open, retrospective, multicenter cohort design was conducted. The sample included 525 dialysis patients with SHPT who had undergone PTX.

Results: 404 patients conformed to the standard, with 36 (8.91%) deaths during the 11 years of follow-up. One week postoperatively, different levels of serum iPTH were divided into four groups: A: ≤20 pg/mL; B: 21-150 pg/mL; C: 151-600 pg/mL; and D: >600 pg/mL. All-cause mortality in groups with different iPTH levels appeared as follows: A (8.29%), B (3.54%), C (10.91%), and D (29.03%). The all-cause mortality of B was the lowest, with D the highest. We used group A as reference (hazard ratio (HR) = 1) compared with the other groups, and HRs on groups B, C, and D appeared as 0.57, 1.43, and 3.45, respectively.

Conclusion: The all-cause mortality was associated with different levels of iPTH after the PTX. We found that iPTH > 600 pg/mL appeared as a factor which increased the risk of all-cause mortality. When iPTH levels were positively and effectively reducing, the risk of all-cause mortality also decreased. The most appropriate level of postoperative iPTH seemed to be 21-150 pg/mL.
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http://dx.doi.org/10.1155/2017/6934706DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5474544PMC
March 2018

Tongxinluo improves cognition by decreasing β-amyloid in spontaneous hypertensive rats.

Brain Res 2017 05 6;1663:151-160. Epub 2017 Mar 6.

Department of Neurology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China. Electronic address:

β-Amyloid (Aβ) accumulation in the brain is the major pathophysiology of Alzheimer disease (AD). Hypertension is a risk factor for AD by promoting Aβ deposition. Traditional Chinese medicinal compound tongxinluo (TXL) can improve blood circulation and endothelium-dependent vasodilation. This study investigates the effects of TXL on cognition and Aβ using spontaneously hypertensive rats (SHRs). TXL was intragastrically administered to SHRs at low-dose, mid-dose and high-dose for 15, 30 or 60days. Cognition was evaluated with a Morris Water Maze (MWM). Aβ in the brain was detected by western blot, ELISA and Thioflavin-S staining. Western blot and RT-PCR were employed to exam the expression of receptor for advanced glycation end products (RAGE), low-density lipoprotein receptor-related protein-1 (LRP-1) and amyloid precursor protein (APP). After TXL treatment for 60days, compared with the vehicle, the number of crossed platform and the time spent in the target quadrant increased in parallel with the increasing length of treatment in MWM. Moreover, the Aβ in the hippocampus significantly decreased compared to the vehicle group, both in western blot and ELISA. Additionally, TXL reduced RAGE expression in a dose- and time-depended manner, but LRP-1 expression had no difference between TXL groups and vehicle groups. Furthermore, the β-secretase expression was significantly decreased compared to the vehicle group, but APP expression had no difference. In conclusion, TXL improved cognition and decreased Aβ in SHRs in a dose- and time-dependent manner, the underlying mechanism may involved in inhibiting RAGE and β-secretase expression.
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http://dx.doi.org/10.1016/j.brainres.2017.03.005DOI Listing
May 2017

Autophagy-lysosome dysfunction is involved in Aβ deposition in STZ-induced diabetic rats.

Behav Brain Res 2017 03 20;320:484-493. Epub 2016 Oct 20.

Department of Neurology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China. Electronic address:

β-Amyloid (Aβ) deposition has a central role in the pathogenesis of Alzheimer disease (AD). Previous studies have indicated that as a risk factor for AD, diabetes mellitus (DM) could induce Aβ deposition in the brain, but the mechanism is not fully elucidated. Autophagy-lysosome is a cellular pathway involved in protein and organelle degradation. In the present study, we used streptozotocin (STZ)-induced diabetic rats to investigate whether autophagy-lysosome is related to Aβ clearance in DM. We found that DM rats had a longer escape latency and less frequent entry into the target zone than that of the control group (p<0.05) in the Morris water maze test. Meanwhile, hippocampal neuron damage and apoptosis (p<0.05) were found in the DM rats. The Aβ expression in the hippocampus significantly increased in the DM group compared with the control group (p<0.05). The markers of autophagy, beclin-1 and LC3 II, were increased (p<0.05), whereas LC3 I was decreased (p<0.05), and the ratio of LC3 II / I was increased as the time advanced (p<0.01). LAMP1 and LAMP2, which are the markers of lysosome function, were decreased in the hippocampus of DM rats (p<0.05). The Aβ deposition was correlated with beclin-1, LC3 II, and LC3 I positively (p<0.05), but with LAMP1 and LAMP2 negatively (p<0.05). These findings indicate that DM activated autophagy, but lysosome function was impaired. Autophagy-lysosome dysfunction may be involved in the Aβ deposition in diabetic cognitive impairment.
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http://dx.doi.org/10.1016/j.bbr.2016.10.031DOI Listing
March 2017

Variations in the Obesity Gene "LEPR" Contribute to Risk of Type 2 Diabetes Mellitus: Evidence from a Meta-Analysis.

J Diabetes Res 2016 18;2016:5412084. Epub 2016 Apr 18.

Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China.

Leptin is a hormone protein regulating food intake and energy expenditure. A number of studies have evaluated the genetic effect of leptin (LEP) and leptin receptor (LEPR) genes on T2DM. This study aimed to investigate the association between these gene polymorphisms and T2DM by a systematic review and meta-analysis. Published studies were identified through extensive search in PubMed and EMBASE. A total of 5143 T2DM cases and 5021 controls from 14 articles were included in this study. Five functional variants in LEPR were well evaluated. Meta-analysis showed that rs1137101 (p.R223Q) was significantly associated with T2DM in all genetic models: allele model (OR = 1.27, 95% confidence interval (CI) = 1.13-1.42), dominant model (OR = 1.19, 95% CI = 1.05-1.35), homozygote model (OR = 1.82, 95% CI = 1.38-2.39), and recessive model (OR = 1.75, 95% CI = 1.35-2.28), with minimal heterogeneity and no indication of publication bias. Similar associations with T2DM were also found for rs62589000 (p.P1019P) and 3'UTR ins/del, although the data was obtained from a small number of studies. For the other two polymorphisms rs1137100 (p.R109K) and rs8179183 (p.K656N), they were not significantly associated with T2DM. Our results provide robust evidences for the genetic association of rs1137101 (p.R223Q) in LEPR with T2DM susceptibility.
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http://dx.doi.org/10.1155/2016/5412084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4852360PMC
June 2017

Genetic Investigation of Complement Pathway Genes in Type 2 Diabetic Retinopathy: An Inflammatory Perspective.

Mediators Inflamm 2016 16;2016:1313027. Epub 2016 Feb 16.

Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China.

Diabetic retinopathy (DR) has complex multifactorial pathogenesis. This study aimed to investigate the association of complement pathway genes with susceptibility to DR. Eight haplotype-tagging SNPs of SERPING1 and C5 were genotyped in 570 subjects with type 2 diabetes: 295 DR patients (138 nonproliferative DR [NPDR] and 157 proliferative DR [PDR]) and 275 diabetic controls. Among the six C5 SNPs, a marginal association was first detected between rs17611 and total DR patients (P = 0.009, OR = 0.53 for recessive model). In stratification analysis, a significant decrease in the frequencies of G allele and GG homozygosity for rs17611 was observed in PDR patients compared with diabetic controls (Pcorr = 0.032, OR = 0.65 and Pcorr = 0.016, OR = 0.37, resp.); it was linked with a disease progression. A haplotype AA defined by the major alleles of rs17611 and rs1548782 was significantly predisposed to PDR with increased risk of 1.54 (Pcorr = 0.023). Regarding other variants in C5 and SERPING1, none of the tagging SNPs had a significant association with DR and its subgroups (all P > 0.05). Our study revealed an association between DR and C5 polymorphisms with clinical significance, whereas SERPING1 is not a major genetic component of DR. Our data suggest a link of complement pathway with DR pathogenesis.
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http://dx.doi.org/10.1155/2016/1313027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4771919PMC
December 2016

Variance of Serum Lipid Levels in Stroke Subtypes.

Clin Lab 2015 ;61(10):1509-14

Background: An increasing number of epidemiological studies have identified a close relationship between dyslipidemia and atherosclerotic stroke. Indeed, lipid metabolism is significantly different among the different ischemic stroke subtypes. There are few studies available regarding risk factors for specific subtypes of ischemic stroke, and in particular, there is little evidence about the role of dyslipidemia. The aim of this study is to determine the relationship between acute ischemic stroke subtype and serum lipid level.

Methods: The levels of serum lipid including TC, TG, LDL-C, HDL-C, apoA, apoB, apoE, and LP (a) were tested in 362 ischemic stroke patients and 181 healthy controls. Lipid levels were analyzed in stroke subtypes according to the TOAST classification.

Results: Levels of TC, TG, LDL-C, apoA, apoB, apoE, and LP (a) were significantly higher and HDL-C levels were significantly lower in the patient group relative to control. The TC/HDL-C ratio, TG/HDL-C ratio, and LDL-C/HDL-C ratio were remarkably higher in the patient group. The levels of TC, TG, LDL-C, apoA, apoB, apoE, and LP(a) were markedly higher and HDL-C was markedly lower in the large-artery atherosclerosis stroke subtype relative to the cardioembolism subtype. Compared with the small-vessel occlusion group, the level of LP(a), TC, and TC/HDL-C were strikingly higher in the cardioembolism group. The TC/HDL-C ratio was different among subgroups, with the large-artery atherosclerosis group exhibiting the highest value. For TC, TG, LDL-C, apoA, apoB, apoE, LP(a), TC/HDL-C, TG/HDL-C, and LDL-C/HDL-C levels a statistically significant difference was found between the large-artery atherosclerosis group and the small-vessel occlusion group.

Conclusions: We found that LDL-C and TC levels may be independent predictors for the occurrence of large-artery atherosclerotic stroke.
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http://dx.doi.org/10.7754/clin.lab.2015.150118DOI Listing
December 2015

Role of the calpain on the development of diabetes mellitus and its chronic complications.

Biomed Pharmacother 2015 Aug 15;74:187-90. Epub 2015 Aug 15.

Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, China. Electronic address:

Diabetes mellitus (DM) is associated with acute and chronic complications that cause major morbidity and significant mortality. Calpains, a family of Ca(2+)-dependent cytosolic cysteine proteases, can modulate their substrates' structure and function through limited proteolytic activity. Calpain is a ubiquitous calcium-sensitive protease that is essential for normal physiologic function. However, alterations in calcium homeostasis lead to pathologic activation of calpain in diabetes mellitus. Since not much is known on the relationship between calpain and diabetes mellitus, this review outlines the contribution of calpain to chronic complications of diabetes mellitus, such as diabetic cardiomyopathy, diabetic nephropathy and diabetic retinopathy.
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http://dx.doi.org/10.1016/j.biopha.2015.08.008DOI Listing
August 2015

Recent advances in understanding the biochemical and molecular mechanism of diabetic retinopathy.

Biomed Pharmacother 2015 Aug 13;74:145-7. Epub 2015 Aug 13.

Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China. Electronic address:

Diabetic retinopathy (DR) is one of the most common microvascular complications of diabetes and remains a major cause of preventable blindness among adults at working age. DR involves an abnormal pathology of major retinal cells, including retinal pigment epithelium, microaneurysms, inter-retinal oedema, haemorrhage, exudates (hard exudates) and intraocular neovascularization. Hyperglycemia is the driving force for the development of diabetic retinopathy. The exact cause of diabetic nephropathy is unknown, but various postulated mechanisms are: hyperglycemia, advanced glycosylation products, activation of cytokines. In this review article, we have discussed a number of diabetes-induced metabolites such as glucose, advanced glycation end products, protein kinase C and oxidative stress and other related factors that are implicated in the pathophysiology of the DR. An understanding of the biochemical and molecular changes especially early in the DR may lead to new and effective therapies towards prevention and amelioration of DR.
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http://dx.doi.org/10.1016/j.biopha.2015.08.002DOI Listing
August 2015

In vitro mechanistic study of endosulfan-induced spermatogenic cell apoptosis in the mouse.

Toxicol Ind Health 2016 Sep 29;32(9):1550-63. Epub 2015 Jan 29.

Department of Health Toxicology and Health Chemistry, School of Public Health, Capital Medical University, Beijing, People's Republic of China Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, People's Republic of China.

To investigate the mechanisms of endosulfan-induced reproductive toxicity, the spermatogenic cell lines (GC-1 spg) of mice were treated with 0, 6, 12, and 24 μg/ml endosulfan for 24 h in vitro The results showed that endosulfan induced apoptosis as well as oxidative stress and mitochondrial dysfunction. Reactive oxygen species and damage of mitochondrial structure were considered as major factors to GC-1 spg cells apoptosis. We further examined the expression of apoptosis-related proteins in mitochondria pathway by Western blot and immunohistochemistry analysis as well as activities. The results showed that endosulfan significantly improved the expressions of cytochrome c and B-cell lymphoma 2 (Bcl-2)-associated X protein and increased the activities of caspases 9 and 3 as well as the downregulation of the expression of Bcl-2 in GC-1 spg cells. The results suggested that exposure to endosulfan might induce the apoptosis of spermatogenic cells via mitochondria-dependent pathway mediated by oxidative stress resulting in the damage of mitochondrial structure and mitochondrial dysfunction.
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http://dx.doi.org/10.1177/0748233714567525DOI Listing
September 2016

Autophagy regulates insulin resistance following endoplasmic reticulum stress in diabetes.

J Physiol Biochem 2015 Jun 30;71(2):319-27. Epub 2015 Jan 30.

Department of Endocrinology, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150001, China.

Autophagy is a kind of cell biological process that maintains the cell's energy level under nutrient-poor conditions, regulates the turnover of abnormal or aged proteins, and disposes of dysfunctional organelles. The autophagy system is activated as a novel signaling pathway in response to endoplasmic reticulum stress (ER stress)-induced insulin resistance (IR). Defective autophagy may be closely related to insulin resistance. There are at least three mechanistically distinct arms of ER stress that regulate the expression of key genes which not only function within the secretory pathway but also affect broad aspects of cell fate and the metabolism of proteins, amino acids, and lipids. ER stress-stimulated insulin resistance is mediated by the autophagy-dependent process. In settings of chronic ER stress, the associated autophagy may contribute to pathophysiological processes involved in a number of prevalent diseases, including diabetes. Whether autophagy plays a protective or harmful role in diabetes awaits further analysis. In this review, we will summarize the current knowledge about the emerging role of autophagy in ER stress-induced insulin resistance. Strategies to take advantage of the potential protective effect of autophagy remain important in the overall treatment of insulin resistance and type 2 diabetes.
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http://dx.doi.org/10.1007/s13105-015-0384-1DOI Listing
June 2015

Endoplasmic reticulum stress is involved in the connection between inflammation and autophagy in type 2 diabetes.

Gen Comp Endocrinol 2015 Jan 27;210:124-9. Epub 2014 Sep 27.

Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, No. 23 You zheng Street Nan Gang District, Harbin 150001, China. Electronic address:

Type 2 diabetes is a chronic inflammatory disease. A number of studies have clearly demonstrated that cytokines such as interleukin 1β (IL1β) contribute to pancreatic inflammation, leading to impaired glucose homeostasis and diabetic disease. There are findings which suggest that islet β-cells can secrete cytokines and cause inflammatory responses. In this process, thioredoxin-interacting protein (TXNIP) is induced by endoplasmic reticulum (ER) stress, which further demonstrates a potential role for ER stress in innate immunity via activation of the NOD-like receptor (NLRP) 3/caspase1 inflammasome and in diabetes pathogenesis via the release of cytokines. Recent developments have also revealed a crucial role for the autophagy pathway during ER stress and inflammation. Autophagy is an intracellular catabolic system that not only plays a crucial role in maintaining the normal islet architecture and intracellular insulin content but also represents a form of programmed cell death. In this review, we focus on the roles of autophagy, inflammation, and ER stress in type 2 diabetes but, above all, on the connections among these factors.
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http://dx.doi.org/10.1016/j.ygcen.2014.09.006DOI Listing
January 2015

Effects of endosulfan on the immune function of erythrocytes, and potential protection by testosterone propionate.

J Toxicol Sci 2014 ;39(5):701-10

Department of Physiology, Yanjing Medical College, Capital Medical University, China.

While the immunotoxicity of endosulfan has been studied, little is known about its influence on immune function associated with erythrocytes (RBC). The aim of this study was to investigate the possible effects of endosulfan, and any possible mitigation by testosterone propionate (TP), on erythrocyte immune function in a mouse model. To this end, rosette formation [as erythrocyte C3b receptor(E-C3bR) and erythrocyte immune complexes (E-IC)], as well as measures of the erythrocyte C3b receptor rosette-forming enhancing rate (RFER; reflecting immunoenhancing factor activity) and C3b receptor rosette-forming inhibitory rate (RFIR; reflecting immunosuppressive factor activity) were performed. The effects of RBC on regulating NK cell function or T-cell adherence were also analyzed. Lastly, to begin to assess potential mechanisms by which endosulfan could impact on the measured endpoints, CD35, CD58, and CD59 expression on RBC was evaluated; expression/mRNA levels of complement receptor I-related gene/protein y (Crry) on cells/splenic tissues was also assessed. The data show that E-C3bR rosette ratios decreased, and those of E-IC increased, due to endosulfan treatment. In these hosts, RFER (i.e., immunoenhancing factor in plasma) was decreased, but RFIR (i.e., immunosuppressive factor) was unchanged.There were no clear effects from endosulfan on RBC regulatory function against NK or T-cells. Lastly, Crry mRNA levels in tissues/cells from these mice were significantly decreased; however, CD59 and CD58 expression levels were unaffected. The data also show that TP co-treatment reversed or mitigated effects of endosulfan on each endpoint, in part, by two possible mechanisms; the TP may be increasing the activity of the innate immune enhancing factor, or, an anti-oxidant effect of TP might help to protect membrane structures and increase Crry stability on the RBC.
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http://dx.doi.org/10.2131/jts.39.701DOI Listing
April 2015

Protective effects of testosterone propionate on reproductive toxicity caused by Endosulfan in male mice.

Environ Toxicol 2016 Feb 31;31(2):142-53. Epub 2014 Jul 31.

Department of Toxicology and Hygienic Chemistry, School of Public Health, Capital Medical University, Beijing, 100069, China.

To investigate the protective effect of testosterone propionate (TP) on reproductive toxicity caused by endosulfan in male mice, three group experiments were designed: the control group received 0 and 0, the endosulfan group received 0.8 and 0, and the endosulfan + TP group received 0.8 mg/kg/d endosulfan and 10 mg/kg/d TP, respectively. The results showed that TP significantly prevented the declines of concentration and motility rates in sperm, reduced the rate of sperm abnormalities in epididymis; and antagonized the decreases in spermatogenous cell and sperm numbers in testes induced by endosulfan. TP also decreased the numbers of cavities formed, prevented the decreases of plasma testosterone and androgen receptor (AR) mRNA in testicular tissue, alleviated the increase of LH induced by endosulfan. It is likely that TP relieve the reproductive toxicity by reversing the endosulfan-induced decreases in testosterone secretion and AR expression that resulted from the alteration of Leydig cell function.
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http://dx.doi.org/10.1002/tox.22029DOI Listing
February 2016

Exposure to silica nanoparticles causes reversible damage of the spermatogenic process in mice.

PLoS One 2014 8;9(7):e101572. Epub 2014 Jul 8.

Department of Health Toxicology and Health Chemistry, School of Public Health, Capital Medical University, Beijing, China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, China.

Environmental exposure to nanomaterials is inevitable, as nanomaterials have become part of our daily life now. In this study, we firstly investigated the effects of silica nanoparticles on the spermatogenic process according to their time course in male mice. 48 male mice were randomly divided into control group and silica nanoparticle group with 24 mice per group, with three evaluation time points (15, 35 and 60 days after the first dose) per group. Mice were exposed to the vehicle control and silica nanoparticles at a dosage of 20 mg/kg every 3 days, five times over a 13-day period, and were sacrificed at 15, 35 and 60 days after the first dose. The results showed that silica nanoparticles caused damage to the mitochondrial cristae and decreased the levels of ATP, resulting in oxidative stress in the testis by days 15 and 35; however, the damage was repaired by day 60. DNA damage and the decreases in the quantity and quality of epididymal sperm were found by days 15 and 35; but these changes were recovered by day 60. In contrast, the acrosome integrity and fertility in epididymal sperm, the numbers of spermatogonia and sperm in the testes, and the levels of three major sex hormones were not significantly affected throughout the 60-day period. The results suggest that nanoparticles can cause reversible damage to the sperms in the epididymis without affecting fertility, they are more sensitive than both spermatogonia and spermatocytes to silica nanoparticle toxicity. Considering the spermatogenesis time course, silica nanoparticles primarily influence the maturation process of sperm in the epididymis by causing oxidative stress and damage to the mitochondrial structure, resulting in energy metabolism dysfunction.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0101572PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4086902PMC
March 2015

Liraglutide Improves the Survival of INS-1 Cells by Promoting Macroautophagy.

Int J Endocrinol Metab 2013 1;11(3):184-90. Epub 2013 Jul 1.

The Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, Harbin, China.

Background: Type 2 diabetes mellitus (T2D) is a metabolic disease characterized by dysfunction of pancreatic beta cell and insulin resistance. Liraglutide, which has many special anti-diabetes biological effects, is found to inhibit beta cell death and ameliorate endoplasmic reticulum stress (ERs) induced by free fatty acid (FFA). Macroautophagy (hereafter referred to as autophagy) altered by FFA is also associated with the dysfunction or death of pancreatic beta cells.

Objectives: We aim at proving that Liraglutide improves the survival of INS-1 cells by promoting autophagy.

Materials And Methods: Cell survival was assessed by CCK8 assay. The percentage of apoptotic cells was determined by flow cytometric assay after Annexin V-FITC/PI staining. Expression of LC3 was detected by western blotting. MDC staining and transmission electron microscopy (TEM) were used in the measurement of autophagy.

Results: Apoptosis induced by PA in INS-1 cells was significantly resolved after Liraglutide treatment. Simultaneously, autophagy was enhanced with the treatment of PA and Liraglutide.

Conclusions: Liraglutide appears to protect INS-1 cells from apoptosis FFA-induced by promoting autophagy.

Conclusions: These findings provide a novel role for GLP-1 analogue in preventing or treating with T2D.
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http://dx.doi.org/10.5812/ijem.8088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3860108PMC
December 2013

Autophagy, a novel target for chemotherapeutic intervention of thyroid cancer.

Cancer Chemother Pharmacol 2014 Mar 4;73(3):439-49. Epub 2013 Dec 4.

The First Affiliated Hospital of Harbin Medical University, No. 23, Youzheng Street, Nangang District, Harbin, Heilongjiang province, China.

Purpose: Thyroid cancers with unsatisfactory curative effect nowadays are the most common malignant tumors of the endocrine system. Apoptosis evasion, a hallmark of cancer, has driven the search of stimulating novel cell death way in cancer therapy. This review aims to explore the relationship between autophagy and thyroid cancer, especially the chemotherapy agents which are based on autophagy in treating thyroid cancers.

Methods: A computerized literature search of MEDLINE was performed using the following search terms: autophagy and thyroid cancer.

Results: Recent studies have found that several chemotherapeutic agents and knockdown of specific microRNA may contribute to autophagic tumor cell death in most thyroid cancer types.

Conclusions: Stimulating autophagy may be an effective alternative treatment to most types of thyroid cancer.
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http://dx.doi.org/10.1007/s00280-013-2363-yDOI Listing
March 2014

Association of paraoxonase gene polymorphisms with diabetic nephropathy and retinopathy.

Mol Med Rep 2013 Dec 2;8(6):1845-51. Epub 2013 Oct 2.

Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China.

Emerging reports have revealed a potential association of paraoxonase (PON) gene polymorphisms with diabetic nephropathy (DN) and diabetic retinopathy (DR). However, the identification of susceptible genes and the quantification of associated risks are elusive owing to a lack of reproducibility. Therefore, a meta‑analysis was conducted in the present study to improve the understanding of the effect of PON1 and PON2 on DN and DR. A total of 10 articles, involving 2,877 patients and 3,246 controls met the inclusion criteria. Functional variants (n=4) were evaluated, including rs662 (p.Q192R) and rs854560 (p.L55M) in PON1; and rs7493 (p.S311C) and rs12026 (p.A148G) in PON2. Overall, PON1‑L55M was found to be significantly associated with DR in all the genetic models: allele [odds ratio (OR)=2.42; 95% confidence interval (CI), 1.91‑3.07]; dominant (OR=5.76; 95% CI, 3.14‑10.55), homozygote (OR=10.53; 95% CI, 5.59‑19.86), heterozygote (OR=3.62; 95% CI, 1.94‑6.74), and recessive (OR=3.56; 95% CI, 2.61‑4.86), with no evidence of between‑study heterogeneity. However, such associations were not detected in DN and the other three polymorphisms did not show any associations with DN or DR. The current meta‑analysis highlighted results for the risk of association of PON1‑55L with DR. The results also indicated that PON2 gene polymorphisms, as well as PON1‑Q192R, may not confer major genetic risk to DN or DR. Additional studies are required to enrich the understanding of PON genes, particularly for its functional role in DR.
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http://dx.doi.org/10.3892/mmr.2013.1710DOI Listing
December 2013

Involvement of endoplasmic reticulum stress in apoptosis of testicular cells induced by low-dose radiation.

J Huazhong Univ Sci Technolog Med Sci 2013 Aug 1;33(4):551-558. Epub 2013 Aug 1.

Key Laboratory of Radiobiology of Ministry of Health, School of Public Health, Jilin University, Changchun, 130021, China.

The study examined the role of endoplasmic reticulum stress (ERS) and signaling pathways of inositol-requiring enzyme-1 (IRE1), RNA-activated protein kinase-like ER kinase (PERK) and activating transcription factor-6 (ATF6) in apoptosis of mouse testicular cells treated with low-dose radiation (LDR). In the dose-dependent experiment, the mice were treated with whole-body X-ray irradiation at different doses (25, 50, 75, 100 or 200 mGy) and sacrificed 12 h later. In the time-dependent experiment, the mice were exposed to 75 mGy X-ray irradiation and killed at different time points (3, 6, 12, 18 or 24 h). Testicular cells were harvested for experiments. H(2)O(2) and NO concentrations, and Ca(2+)-ATPase activity were detected by biochemical assays, the calcium ion concentration ([Ca(2+)]i) by flow cytometry using fluo-3 probe, and GRP78 mRNA and protein expressions by quantitative real-time RT-PCR (qRT-PCR) and Western blotting, respectively. The mRNA expressions of S-XBP1, JNK, caspase-12 and CHOP were measured by qRT-PCR, and the protein expressions of IRE1α, S-XBP1, p-PERK, p-eIF2α, ATF6 p50, p-JNK, pro-caspase-12, cleaved caspase-12 and CHOP by Western blotting. The results showed that the concentrations of H2O2 and NO, the mRNA expressions of GRP78, S-XBP1, JNK, caspase-12 and CHOP, and the protein expressions of GRP78, S-XBP1, IRE1α, p-PERK, p-eIF2α, ATF6 p50, p-JNK, pro-caspase-12, cleaved caspase-12 and CHOP were significantly increased in a time- and dose-dependent manner after LDR. But the [Ca(2+)]i and Ca(2+)-ATPase activities were significantly decreased in a time- and dose-dependent manner. It was concluded that the ERS, regulated by IRE1, PERK and ATF6 pathways, is involved in the apoptosis of testicular cells in LDR mice, which is associated with ERS-apoptotic signaling molecules of JNK, caspase-12 and CHOP.
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http://dx.doi.org/10.1007/s11596-013-1157-0DOI Listing
August 2013

Association of CFH and CFB gene polymorphisms with retinopathy in type 2 diabetic patients.

Mediators Inflamm 2013 24;2013:748435. Epub 2013 Jun 24.

Department of Endocrinology, First Affiliated Hospital of Harbin Medical University, 23 Post Road, Nangang Region, Harbin, Heilongjiang 150001, China.

Objectives: The complement system is a key component of innate immunity and has been implicated in the pathogenesis of diabetic retinopathy (DR). This study aimed at investigating whether polymorphisms of two genes in the complement pathway, complement factor H (CFH) and complement factor B (CFB), are associated with DR.

Methods: 552 well-defined subjects with type 2 diabetes, consisting of 277 DR patients and 275 diabetic controls, were recruited. Four Tag-SNPs rs1048709, rs537160, rs4151657, and rs2072633 in CFB and rs800292 (I62V) in CFH were examined using TaqMan Genotyping Assays.

Results: There were significant increases in the frequencies of A allele and AA genotype for rs1048709 in DR patients compared with diabetic controls (P(corr) = 0.035, OR = 1.42; P(corr) = 0.02, OR = 2.27, resp.): meanwhile, significant decreases in the frequencies of A allele and AA genotype for rs800292 were observed in DR patients compared with diabetic controls (P(corr) = 0.04, OR = 0.72; P(corr) = 0.015, OR = 0.51, resp.). Joint effect of these two loci was also identified. Moreover, rs800292/AA genotype was found to be related with delayed progression to DR.

Conclusions: CFH-rs800292 and CFB-rs1048709 are associated with the presence of DR, which strengthens the concept that complement system plays an important role in the pathogenesis of DR.
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http://dx.doi.org/10.1155/2013/748435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3707223PMC
February 2014

Liraglutide prevents high glucose level induced insulinoma cells apoptosis by targeting autophagy.

Chin Med J (Engl) 2013 Mar;126(5):937-41

Department of Endocrinology, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, China.

Background: The pathophysiology of type 2 diabetes is progressive pancreatic beta cell failure with consequential reduced insulin secretion. Glucotoxicity results in the reduction of beta cell mass in type 2 diabetes by inducing apoptosis. Autophagy is essential for the maintenance of normal islet architecture and plays a crucial role in maintaining the intracellular insulin content by accelerating the insulin degradation rate in beta cells. Recently more attention has been paid to the effect of autophagy in type 2 diabetes. The regulatory pathway of autophagy in controlling pancreatic beta cells is still not clear. The aim of our study was to evaluate whether liraglutide can inhibit apoptosis and modulate autophagy in vitro in insulinoma cells (INS-1 cells).

Methods: INS-1 cells were incubated for 24 hours in the presence or absence of high levels of glucose, liraglutide (a long-acting human glucagon-like peptide-1 analogue), or 3-methyadenine (3-MA). Cell viability was measured using the Cell Counting Kit-8 (CCK8) viability assay. Autophagy of INS-1 cells was tested by monodansylcadaverine (MDC) staining, an autophagy fluorescent compound used for the labeling of autophagic vacuoles, and by Western blotting of microtubule-associated protein I light chain 3 (LC3), a biochemical markers of autophagic initiation.

Results: The viability of INS-1 cells was reduced after treatment with high levels of glucose. The viability of INS-1 cells was reduced and apoptosis was increased when autophagy was inhibited. The viability of INS-1 cells was significantly increased by adding liraglutide to supplement high glucose level medium compared with the cells treated with high glucose levels alone.

Conclusions: Apoptosis and autophagy were increased in rat INS-1 cells when treated with high level of glucose, and the viability of INS-1 cells was significantly reduced by inhibiting autophagy. Liraglutide protected INS-1 cells from high glucose level-induced apoptosis that is accompanied by a significant increase of autophagy, suggesting that liraglutide plays a role in beta cell apoptosis by targeting autophagy. Thus, autophagy may be a new target for the prevention or treatment of diabetes.
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March 2013
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