Publications by authors named "Yilin Yan"

23 Publications

  • Page 1 of 1

NLRP3 promotes immune escape by regulating immune checkpoints: A pan-cancer analysis.

Int Immunopharmacol 2022 Jan 10;104:108512. Epub 2022 Jan 10.

Department of Hepatobiliary Pancreatic Surgery, the First Hospital of Ningbo City, Ningbo 315010, China. Electronic address:

NLRP3 plays a pathogenic role in tumorigenesis by regulating innate and acquired immunity, apoptosis, differentiation, and intestinal microbes in tumors. Our research aimed to investigate the role of NLRP3 in pan-cancers based on multi-omics data in the TCGA database. Most types of tumors showed increased expression of NLRP3. Among them, the overexpressed NLRP3 in liver hepatocellular carcinoma (LIHC) and ovarian cancer (OV) indicated worse overall survival (OS). Further analysis also confirmed overexpressed NLRP3 in colon cancer (COAD) indicated a high probability of microsatellite instability (MSI) and low tumor mutational burden (TMB), which indicated a better response to immune checkpoint inhibitors (ICIs). Interestingly, overexpression of NLRP3 was closely related to high infiltration of immune cells (T cells, B cells, etc.) and overexpressed immune checkpoints (PD-1, PD-L1, LAG3, etc.). These results demonstrated NLRP3 promoted immune escape in cancers. Finally, we investigated the expression of various immune checkpoints by treating NLRP3 inhibitor MCC950 during the co-culture of peripheral blood mononuclear cells (PBMC) and LIHC cell line Hep3B. MCC950 significantly repressed the expression of PD-L1 and LAG3, and promoted the apoptosis rate of Hep3B. In conclusion, our research demonstrated the role of NLRP3 in pan-cancer, especially in LIHC. Inhibition of NLRP3 promoted the killing effect of T cells to cancer cells by repressing the expression of immune checkpoints.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.intimp.2021.108512DOI Listing
January 2022

PDE4B Induces Epithelial-to-Mesenchymal Transition in Bladder Cancer Cells and Is Transcriptionally Suppressed by CBX7.

Front Cell Dev Biol 2021 16;9:783050. Epub 2021 Dec 16.

Department of Urology, Tongji Hospital, Tongji University School of Medicine, Shanghai, China.

Urinary bladder cancer (UBC) is a common malignant tumor with high incidence. Advances in the diagnosis and treatment of this disease demand the identification of novel therapeutic targets. Multiple studies demonstrated that PDE4B level was upregulated in malignancies and high PDE4B expression was correlated with poor outcomes. Herein, we identified that PDE4B was a potential therapeutic target in UBC. We confirmed that PDE4B expression was correlated with aggressive clinicopathological characteristics and unfavorable prognosis. Functional studies demonstrated that ectopic expression of PDE4B promoted UBC cells proliferation, migration and invasion, whereas PDE4B depletion suppressed cancer cell aggressiveness. We also identified CBX7 as a regulator of PDE4B to suppress the expression of PDE4B at the transcription level in a PRC1-dependent manner. Moreover, our results indicated that PDE4B induced epithelial-to-mesenchymal transition (EMT) in UBC cells β-catenin pathway, whereas inhibition of PDE4B by its small molecule inhibitor, rolipram, effectively reversed the PDE4B overexpression-induced effects. To sum up, our results indicated that PDE4B acts as an oncogene by promoting UBC cell migration and invasion β-catenin/EMT pathway.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fcell.2021.783050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8716816PMC
December 2021

A Novel Ferroptosis-Related Prognostic Signature Reveals Macrophage Infiltration and EMT Status in Bladder Cancer.

Front Cell Dev Biol 2021 20;9:712230. Epub 2021 Aug 20.

Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Bladder cancer (BC) belongs to one of the most common and highly heterogeneous malignancies. Ferroptosis is a newly discovered regulated cell death (RCD), characterized by accumulation of toxic lipid peroxides, and plays a crucial role in tumor progression. Here, we conducted a comprehensive analysis on the transcriptomics data of ferroptosis-related genes in BC based on The Cancer Genome Atlas (TCGA) and three Gene Expression Omnibus (GEO) datasets. In our study, a 6-gene signature was identified based on the potential prognostic ferroptotic regulatory genes. Furthermore, our signature revealed a good independent prognostic ability in BC. Patients with low-risk score exhibited higher FGFR3 mutation rates while high risk score had a positive association with higher RB1 mutation rates. Meanwhile, higher proportions of macrophages were observed in high BC risk group simultaneously with four methods. Unexpectedly, the risk score showed a significant positive correlation with epithelial-mesenchymal transition (EMT) status. Functional assays indicated that CRYAB and SQLE knockdown was associated with attenuated invasion capacity. Our study revealed a ferroptosis-related risk model for predicting prognostic and BC progression. Our results indicate that targeting ferroptosis may be a therapeutic strategy for BC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fcell.2021.712230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8417704PMC
August 2021

Antiproliferative effects of mealworm larvae (Tenebrio molitor) aqueous extract on human colorectal adenocarcinoma (Caco-2) and hepatocellular carcinoma (HepG2) cancer cell lines.

J Food Biochem 2021 07 1;45(7):e13778. Epub 2021 Jun 1.

School of Food and Biological Engineering, Jiangsu University, Zhenjiang, Jiangsu, China.

Recently, insects have aroused the interest of researchers as potential therapeutic resources against malignant diseases such as cancer. In this study, the effects of aqueous extracts from mysore thorn borer (MTB) (Anoplophora chinensis) and mealworm larvae (MWL) (Tenebrio molitor) against cancer cells were investigated. MWL aqueous extract showed higher antiproliferative effects against Caco-2 and HepG2 cells compared to MTB. The IC (48 hr) of MWL aqueous extract were 11.44 and 20 mg/ml for Caco-2 and HepG2 respectively. Flow cytometry analysis showed that MWL aqueous extract induced apoptosis in Caco-2 and HepG2 increasing from 2.06% to 74.34% and from 0.04% to 42.14% after 24 hr respectively. Caspase activity assay showed that apoptosis was mediated via death receptor pathway mediated by caspase-8 and -9 followed by the activation of caspase-3; caspase-3 may have induced DNA damage and cell death. These effects may be correlated to its free amino acids. The results of this study demonstrate the potentials of MWL in the development of natural anticancer therapeutics in the future. PRACTICAL APPLICATIONS: Natural nutraceuticals from insects might be useful for the treatment and prevention of cancers such as colorectal and liver cancer. In recent years, edible insects have caught the attention of researchers, because of their potential as an alternative source of food and nutraceuticals. The results of our study showed that MWL extract might provide important anticancer compounds against colon and liver cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jfbc.13778DOI Listing
July 2021

CBX7 suppresses urinary bladder cancer progression via modulating AKR1B10-ERK signaling.

Cell Death Dis 2021 05 25;12(6):537. Epub 2021 May 25.

Department of Laboratory Animal Science, Fudan University, 200032, Shanghai, China.

The chromobox (CBX) proteins mediate epigenetic gene silencing and have been implicated in the cancer development. By analyzing eight CBX family members in TCGA dataset, we found that chromobox 7 (CBX7) was the most strikingly downregulated CBX family member in urinary bladder cancer (UBC), as compared to normal tissues. Though dysregulation of CBX7 has been reported in multiple cancers, its specific role and clinical relevance in UBC remain unclear. Herein, we found that frequent downregulation of CBX7 in UBC specimens, which was due to its promoter hypermethylation, was correlated with poor prognosis. The ectopic expression of CBX7 suppressed UBC cell proliferation, migration, invasion, and cancer stemness, whereas CBX7 depletion promoted cancer cell aggressiveness. Importantly, CBX7 overexpression in UBC cells inhibited tumorigenicity, whereas CBX7 depletion promoted the tumor development, indicating its tumor-suppressive role in UBC. Using RNA-seq and chromosome immunoprecipitation (ChIP) assays, we identified aldo-keto reductase family 1 member 10 (AKR1B10) as a novel downstream target of CBX7, which was negatively modulated by CBX7 in a PRC1-dependent manner and involved in stimulating ERK signaling. Consistently, AKR1B10 overexpression induced cancer cell aggressiveness, whereas suppression of AKR1B10 by siRNA or its small molecular inhibitor, oleanolic acid, reversed the CBX7 deficiency-induced cellular effects. AKR1B10 overexpression was negatively associated with CBX7 downregulation and predicted poor clinical outcomes in UBC patients. Taken together, our results indicate that CBX7 functions as a tumor suppressor to downregulate AKR1B10 and further inactivates ERK signaling. This CBX7/AKR1B10/ERK signaling axis may provide a new therapeutic strategy against UBC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41419-021-03819-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8149849PMC
May 2021

TEAD4 as a Prognostic Marker Promotes Cell Migration and Invasion of Urinary Bladder Cancer via EMT.

Onco Targets Ther 2021 10;14:937-949. Epub 2021 Feb 10.

Department of Urology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200080, People's Republic of China.

Purpose: As a member of TEA Domain Transcription Factors (TEADs), TEAD4 was found to be upregulated in urinary bladder cancer (UBC). This study focused on investigating the clinical value and potential functions of TEAD4 in UBC.

Materials And Methods: Patients' samples, TCGA-BLCA and multiple GEO datasets were applied to explore the expression pattern of TEAD4 in UBC. Cox regression and Kaplan-Meier survival analyses were carried out to evaluate the prognostic significance of TEAD4 in UBC. Wound healing and transwell assays were performed to explore the biological functions of TEAD4 in UBC cells.

Results: The results of TCGA-BLCA, GEO datasets, Western blotting and immunohistochemistry staining (IHC) indicated that TEAD4 was strikingly elevated in UBC tissues as compared to their normal counterparts, and upregulation of TEAD4 was significantly correlated with clinical stage, pathological grade and poor clinical outcome. Functional studies demonstrated that TEAD4 knockdown suppressed cell migration and invasion by reducing the expression of epithelial-mesenchymal transition (EMT) related markers and transcription regulators.

Conclusion: Our results suggest that TEAD4 may serve as a novel prognostic biomarker and a promising therapeutic target for UBC, and act as a pro-tumorigenic gene to promote cell migration and invasion by inducing EMT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2147/OTT.S290425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882801PMC
February 2021

Identification of a novel immune microenvironment signature predicting survival and therapeutic options for bladder cancer.

Aging (Albany NY) 2020 12 19;13(2):2780-2802. Epub 2020 Dec 19.

Department of Urology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200080, China.

Few studies have investigated the potential of tumor immune microenvironment genes as indicators of urinary bladder cancer. Here, we sought to establish an immune-related gene signature for determining prognosis and treatment options. We developed a ten-gene tumor immune microenvironment signature and evaluated its prognostic capacity on internal and external cohorts. Multivariate Cox regression and nomogram analyses revealed the prognostic risk model as an independent and effective indicator of prognosis. We observed lower proportions of CD8+ T cells, dendritic cells, regulatory T cells, higher proportions of macrophages and neutrophils in high UBC risk group. UBC tissues with high-risk score tend to exhibit high TP53 and RB1 mutation rates, high PD1/PD-L1 expression and poor-survival basal squamous subtypes, while those with low-risk score tend to have high FGFR3 mutation rates and luminal papillary subtypes. Unexpectedly, we found a highly significant positive correlation between glycolytic genes and risk score, highlighting metabolic competition in tumor ecosystem and potential therapeutic avenues. Our study thus revealed a tumor immune microenvironment signature for predicting prognostic and response to immune checkpoint inhibitors against bladder cancer. Prospective studies are required to further test the predictive capacity of this model.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/aging.202327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880321PMC
December 2020

Identification of glycogene-type and validation of ST3GAL6 as a biomarker predicts clinical outcome and cancer cell invasion in urinary bladder cancer.

Theranostics 2020 8;10(22):10078-10091. Epub 2020 Aug 8.

State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.

Urinary bladder cancer (UBC) is one of the most common causes of morbidity and mortality worldwide characterized by a high risk of invasion and metastasis; however, the molecular classification biomarkers and underlying molecular mechanisms for UBC patient stratification on clinical outcome need to be investigated. A systematic transcriptomic analysis of 185 glycogenes in the public UBC datasets with survival information and clinicopathological parameters were performed using unsupervised hierarchical clustering. The gene signature for glycogene-type classification was identified using Limma package in R language, and correlated to 8 known molecular features by Gene Set Variation Analysis (GSVA). The clinical relevance and function of a glycogene was characterized by immunohistochemistry in UBC patient samples, and quantitative RT-PCR, Western blotting, promoter activity, MAL II blotting, immunofluorescence staining, wound healing, and transwell assays in UBC cells. A 14-glycogene signature for glycogene-type classification was identified. Among them, ST3GAL6, a glycotransferase to transfer sialic acid to 3'-hydroxyl group of a galactose residue, showed a significant negative association with the subtype with luminal feature in UBC patients (n=2,130 in total). Increased ST3GAL6 was positively correlated to tumor stage, grade, and survival in UBCs from public datasets or our cohort (n=52). Transcription factor GATA3, a luminal-specific marker for UBC, was further identified as a direct upstream regulator of ST3GAL6 to negatively regulate its transactivation. ST3GAL6 depletion decreased MAL II level, cell invasion and migration in 5637 and J82 UBC cells. ST3GAL6 could reverse the effects of GATA3 on global sialylation and cell invasion in SW780 cells. Herein, we successfully identified a novel 14-gene signature for glycogene-type classification of UBC patients. ST3GAL6 gene, from this signature, was demonstrated as a potential biomarker for poor outcomes and cell invasion in UBCs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7150/thno.48711DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7481430PMC
May 2021

Assessing IRAK4 Functions in ABC DLBCL by IRAK4 Kinase Inhibition and Protein Degradation.

Cell Chem Biol 2020 12 3;27(12):1500-1509.e13. Epub 2020 Sep 3.

Medicinal Chemistry, Janssen (China) Research & Development Center, Shanghai 201210, China. Electronic address:

The interleukin-1 receptor-activated kinase 4 (IRAK4) belongs to the IRAK family of serine/threonine kinases and plays a central role in the innate immune response. However, the function of IRAK4 in tumor growth and progression remains elusive. Here we sought to determine the enzymatic and scaffolding functions of IRAK4 in activated B-cell-like diffuse large B cell lymphoma (ABC DLBCL). We chose a highly selective IRAK4 kinase inhibitor to probe the biological effects of kinase inhibition and developed a series of IRAK4 degraders to evaluate the effects of protein degradation in ABC DLBCL cells. Interestingly, the results demonstrated that neither IRAK4 kinase inhibition nor protein degradation led to cell death or growth inhibition, suggesting a redundant role for IRAK4 in ABC DLBCL cell survival. IRAK4 degraders characterized in this study provide useful tools for understanding IRAK4 protein scaffolding function, which was previously unachievable using pharmacological perturbation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.chembiol.2020.08.010DOI Listing
December 2020

Hepcidin protects against iron overload-induced inhibition of bone formation in zebrafish.

Fish Physiol Biochem 2019 Feb 25;45(1):365-374. Epub 2018 Oct 25.

Department of Orthopedics, Nanjing Medical University Affiliated Wuxi Second Hospital, Wuxi, 214000, China.

Iron overload increases the risk of osteoporosis, which leads to an increase in the incidences of bone fracture after menopause. In vitro studies have demonstrated that excess iron can inhibit osteoblast activity. Hepcidin, a central regulator of iron homeostasis, prevents iron overload, and thus, it is considered to have anti-osteoporosis effects. In this study, a zebrafish model was employed to investigate the therapeutic role of hepcidin in iron overload-induced inhibition of bone formation. Our results show that ferric ammonium citrate (FAC) treatment decreased osteoblast-specific gene expression (runx2a, runx2b, and bglap) and bone mineralization in the zebrafish embryo, accompanied with increased whole-body iron levels and oxidative stress. Bone mineralization and osteoblast-specific gene expression increased with the microinjection of hepcidin-flag Capped-mRNA into zebrafish embryos. Moreover, the whole-body iron content and oxidative stress in the iron-overloaded zebrafish embryos decreased when microinjection of hepcidin preceded the FAC treatment. Therefore, our study suggests that hepcidin could prevent and rescue reduced bone formation caused by FAC treatment by preventing iron absorption.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10695-018-0568-zDOI Listing
February 2019

Combination chemotherapy with Zyflamend reduced the acquired resistance of bladder cancer cells to cisplatin through inhibiting NFκB signaling pathway.

Onco Targets Ther 2018 30;11:4413-4429. Epub 2018 Jul 30.

Department of Urology, Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, Nanjing, China,

Background: Cisplatin-based chemotherapy is mainstay treatment in urinary bladder cancer (UBC). However, tumor recurrence frequently occurs with the acquisition of cisplatin resistance. We explored the potential effect of a polyherbal preparation, Zyflamend, on UBC cells resistant to cisplatin treatment.

Methods: To establish a cisplatin-resistant human bladder cancer cell line, T24 cells were cultured in increasing concentrations of cisplatin for more than 10 months. These cells (T24R) were then treated with different concentrations of Zyflamend, and both proliferation and activity of nuclear factor kappaB (NFκB) signaling pathway were examined. To test the synergistic effect between Zyflamend and cisplatin, we treated T24R cells either with Zyflamend or cisplatin alone, or in combination. Apoptotic effect was evaluated by Annexin V/propidium iodide double staining, and the levels of the proteins involved in cell cycle and anti-apoptosis were examined by Western blotting. Finally, mice with palpable xenograft were treated either with cisplatin and Zyflamend alone or in combination for 28 days before they were sacrificed for measuring the sizes and weights of the tumor tissues. In addition, proliferation and apoptosis markers were examined by immunohistochemistry.

Results: Comparing to that in the parental T24 cells, NFκB is constitutively active in cisplatin-resistant T24R cells. Zyflamend is capable of inhibiting the growth of T24, T24R, as well as another UBC cell line J82 in a concentration-dependent manner. Mechanistically, Zyflamend suppresses NFκB-mediated cell proliferation, survival, and invasion/angiogenesis and induces apoptosis. In addition, Zyflamend significantly increased the sensitivity of T24R and J82 cells to cisplatin treatment and these findings were confirmed in T24R xenograft model with reduced proliferation index and decreased expression of RelA and its downstream target MMP9.

Conclusion: Zyflamend is capable of counteracting bladder cancer resistance to cisplatin by repressing proliferation and inducing apoptosis through targeting NFκB signaling pathway.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2147/OTT.S162255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6072829PMC
July 2018

Enhancing Multimedia Imbalanced Concept Detection Using VIMP in Random Forests.

Proc IEEE Int Conf Inf Reuse Integr 2016 Jul 19;2016:601-608. Epub 2016 Dec 19.

Department of Public Health Sciences, Division of Biostatistics Miller School of Medicine, University of Miami, Miami, FL, USA.

Recent developments in social media and cloud storage lead to an exponential growth in the amount of multimedia data, which increases the complexity of managing, storing, indexing, and retrieving information from such big data. Many current content-based concept detection approaches lag from successfully bridging the semantic gap. To solve this problem, a multi-stage random forest framework is proposed to generate predictor variables based on multivariate regressions using variable importance (VIMP). By fine tuning the forests and significantly reducing the predictor variables, the concept detection scores are evaluated when the concept of interest is rare and imbalanced, i.e., having little collaboration with other high level concepts. Using classical multivariate statistics, estimating the value of one coordinate using other coordinates standardizes the covariates and it depends upon the variance of the correlations instead of the mean. Thus, conditional dependence on the data being normally distributed is eliminated. Experimental results demonstrate that the proposed framework outperforms those approaches in the comparison in terms of the Mean Average Precision (MAP) values.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1109/IRI.2016.87DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5600875PMC
July 2016

Hepcidin inhibition on the effect of osteogenesis in zebrafish.

Biochem Biophys Res Commun 2016 07 24;476(1):1-6. Epub 2016 May 24.

Department of Orthopedics, The Second Affiliated Hospital of Soochow University, 1055 Sanxiang Road, Suzhou 215004, China; Osteoporosis Diagnosis and Treatment Technology, Institute of Soochow University, 1055 Sanxiang Road, Suzhou 215004, China. Electronic address:

Iron overload, as a risk factor for osteoporosis, can result in the up-regulation of Hepcidin, and Hepcidin knockout mice display defects in their bone microarchitecture. However, the molecular and genetic mechanisms underlying Hepcidin deficiency-derived bone loss remain unclear. Here, we show that hepcidin knockdown in zebrafish using morpholinos leads to iron overload. Furthermore, a mineralization delay is observed in osteoblast cells in hepcidin morphants, and these defects could be partially restored with microinjection of hepcidin mRNA. Quantitative real-time PCR analyses revealed the osteoblast-specific genes alp, runx2a, runx2b, and sp7 in morphants are down-regulated. Furthermore, we confirmed qRT-PCR results by in situ hybridization and found down-regulated genes related to osteoblast function in hepcidin morphants. Most importantly, we revealed that hepcidin was capable of removing whole-body iron which facilitated larval recovery from the reductions in bone formation and osteogenesis induced by iron overload.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbrc.2016.05.118DOI Listing
July 2016

Targeted disruption of sp7 and myostatin with CRISPR-Cas9 results in severe bone defects and more muscular cells in common carp.

Sci Rep 2016 Mar 15;6:22953. Epub 2016 Mar 15.

Center for Circadian Clocks, Soochow University, Suzhou 215123, Jiangsu, China.

The common carp (Cyprinus carpio) as one of the most important aquaculture fishes produces over 3 million metric tones annually, approximately 10% the annual production of the all farmed freshwater fish worldwide. However, the tetraploidy genome and long generation-time of the common carp have made its breeding and genetic studies extremely difficult. Here, TALEN and CRISPR-Cas9, two versatile genome-editing tools, are employed to target common carp bone-related genes sp7, runx2, bmp2a, spp1, opg, and muscle suppressor gene mstn. TALEN were shown to induce mutations in the target coding sites of sp7, runx2, spp1 and mstn. With CRISPR-Cas9, the two common carp sp7 genes, sp7a and sp7b, were mutated individually, all resulting in severe bone defects; while mstnba mutated fish have grown significantly more muscle cells. We also employed CRISPR-Cas9 to generate double mutant fish of sp7a;mstnba with high efficiencies in a single step. These results demonstrate that both TALEN and CRISPR-Cas9 are highly efficient tools for modifying the common carp genome, and open avenues for facilitating common carp genetic studies and breeding.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/srep22953DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4791634PMC
March 2016

Cyclophilin D deficiency attenuates mitochondrial and neuronal perturbation and ameliorates learning and memory in Alzheimer's disease.

Nat Med 2008 Oct 21;14(10):1097-105. Epub 2008 Sep 21.

Department of Surgery, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, New York 10032, USA.

Cyclophilin D (CypD, encoded by Ppif) is an integral part of the mitochondrial permeability transition pore, whose opening leads to cell death. Here we show that interaction of CypD with mitochondrial amyloid-beta protein (Abeta) potentiates mitochondrial, neuronal and synaptic stress. The CypD-deficient cortical mitochondria are resistant to Abeta- and Ca(2+)-induced mitochondrial swelling and permeability transition. Additionally, they have an increased calcium buffering capacity and generate fewer mitochondrial reactive oxygen species. Furthermore, the absence of CypD protects neurons from Abeta- and oxidative stress-induced cell death. Notably, CypD deficiency substantially improves learning and memory and synaptic function in an Alzheimer's disease mouse model and alleviates Abeta-mediated reduction of long-term potentiation. Thus, the CypD-mediated mitochondrial permeability transition pore is directly linked to the cellular and synaptic perturbations observed in the pathogenesis of Alzheimer's disease. Blockade of CypD may be a therapeutic strategy in Alzheimer's disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/nm.1868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2789841PMC
October 2008

M35 oxidation induces Abeta40-like structural and dynamical changes in Abeta42.

J Am Chem Soc 2008 Apr 1;130(16):5394-5. Epub 2008 Apr 1.

Biology Department, Center for Biotechnology and Interdisciplinary Studies, Rensselear Polytechnic Institute, Troy, New York 12180, USA.

Oxidizing a single M35 residue of Abeta leads to delayed aggregation and reduced toxicity. To understand the molecular mechanism of this effect, we examined the structural and dynamical consequences of M35 oxidation. We found the mobility of the C-terminal residues of Abeta42 is greatly enhanced upon M35 oxidation. In contrast, methyl groups in the central hydrophobic cluster become less flexible. Taken together, we conclude that Abeta42ox undergoes Abeta40-like structural and dynamical changes, which contribute to its reduced aggregation and toxicity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/ja711189cDOI Listing
April 2008

Methyl dynamics of the amyloid-beta peptides Abeta40 and Abeta42.

Biochem Biophys Res Commun 2007 Oct 14;362(2):410-4. Epub 2007 Aug 14.

Biology Department, Rensselear Polytechnic Institute, Troy, NY 12180, USA.

To probe the role of side chain dynamics in Abeta aggregation, we studied the methyl dynamics of native Abeta40 and Abeta42 by measuring cross relaxation rates with interleaved data collection. The methyl groups in the C-terminus are in general more rigid in Abeta42 than in Abeta40, consistent with previous results from backbone (15)N dynamics. This lends support to the hypothesis that a rigid C-terminus in Abeta42 may serve as an internal aggregation seed. Interestingly, two methyl groups of V18 located in the central hydrophobic cluster are more mobile in Abeta42 than in Abeta40, most likely due to the paucity of V18 intra-molecular interactions in Abeta42. V18 may then be more available for inter-molecular interactions to form Abeta42 aggregates. Thus, the side chain mobility of the central hydrophobic cluster may play an important role in Abeta aggregation and may contribute to the difference in aggregation propensity between Abeta40 and Abeta42.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbrc.2007.07.198DOI Listing
October 2007

Abeta40 protects non-toxic Abeta42 monomer from aggregation.

J Mol Biol 2007 Jun 12;369(4):909-16. Epub 2007 Apr 12.

Center for Biotechnology and Interdisciplinary Studies, Biology Department, Rensselaer Polytechnic Institute, Troy, NY 12180, USA.

Abeta40 and Abeta42 are the predominant Abeta species in the human body. Toxic Abeta42 oligomers and fibrils are believed to play a key role in causing Alzheimer's disease (AD). However, the role of Abeta40 in AD pathogenesis is not well established. Emerging evidence indicates a protective role for Abeta40 in AD pathogenesis. Although Abeta40 is known to inhibit Abeta42 fibril formation, it is not clear whether the inhibition acts on the non-toxic monomer or acts on the toxic Abeta42 oligomers. In contrast to conventional methods that detect the appearance of fibrils, in our study Abeta42 aggregation was monitored by the decreasing NMR signals from Abeta42 monomers. In addition, differential NMR isotope labelling enabled the selective observation of Abeta42 aggregation in a mixture of Abeta42 and Abeta40. We found Abeta40 monomers inhibit the aggregation of non-toxic Abeta42 monomers, in an Abeta42/Abeta40 ratio-dependent manner. NMR titration revealed that Abeta40 monomers bind to Abeta42 aggregates with higher affinity than Abeta42 monomers. Abeta40 can also release Abeta42 monomers from Abeta42 aggregates. Thus, Abeta40 likely protects Abeta42 monomers by competing for the binding sites on pre-existing Abeta42 aggregates. Combining our data with growing evidence from transgenic mice and human genetics, we propose that Abeta40 plays a critical, protective role in Alzheimer's by inhibiting the aggregation of Abeta42 monomer. Abeta40 itself, a peptide already present in the human body, may therefore be useful for AD prevention and therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jmb.2007.04.014DOI Listing
June 2007

Conserved function of caspase-8 in apoptosis during bony fish evolution.

Gene 2007 Jul 27;396(1):134-48. Epub 2007 Mar 27.

Department of Animal Development and Physiology, Graduate School of Biostudies, Kyoto University, Kyoto 606-8501, Japan.

Caspase-8, a member of the caspase family, plays an important role in apoptotic signal transduction in mammals. Here we report the identification and characterization of the caspase-8 (casp8) gene in the zebrafish Danio rerio. The zebrafish casp8 gene has a genomic organization similar to mammalian casp8 genes, consisting of 10 exons. By chromosome mapping, we found that casp8 maps on linkage group 6 (LG6), a zebrafish chromosome segment orthologous to the long arm of human Chr. 2, which carries CASP8. In contrast, the zebrafish casp10-like gene and the cflar gene separately localize on LG9 and LG11, respectively, and these genes form a cluster with CASP8 on the human chromosome. This chromosomal segregation is unique to fish but not other vertebrates. Furthermore, we examined the function of zebrafish Casp8 protein in mammalian cells, and showed that it has pro-apoptotic activity when overexpressed. In addition, this molecule was capable of transmitting apoptotic signals mediated through not only Fas but also the TNF receptor in mouse Casp8-deficient cells. Expression analysis showed that casp8 is maternally expressed, and transcripts continue to be present throughout embryogenesis and into larval stages. These results show that zebrafish casp8 has a structure and function similar to mammalian CASP8 orthologs, and our study suggests that the role of caspase-8 in the apoptotic signal pathway has been conserved over at least 450 million years of vertebrate evolution.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.gene.2007.03.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2064871PMC
July 2007

The Alzheimer's peptides Abeta40 and 42 adopt distinct conformations in water: a combined MD / NMR study.

J Mol Biol 2007 May 7;368(5):1448-57. Epub 2007 Mar 7.

Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY 12180, USA.

The role of peptides Abeta40 and Abeta42 in the early pathogenesis of Alzheimer's disease (AD) is frequently emphasized in the literature. It is known that Abeta42 is more prone to aggregation than Abeta40, even though they differ in only two (IA) amino acid residues at the C-terminal end. A direct comparison of the ensembles of conformations adopted by the monomers in solution has been limited by the inherent flexibility of the unfolded peptides. Here, we characterize the conformations of Abeta40 and Abeta42 in water by using a combination of molecular dynamics (MD) and measured scalar (3)J(HNHalpha) data from NMR experiments. We perform replica exchange MD (REMD) simulations and find that classical forcefields reproduce the NMR data quantitatively when the sampling is extended to the microseconds time-scale. Using the quantitative agreement of the NMR data as a validation of the model, we proceed to compare the conformational ensembles of the Abeta40 and Abeta42 peptide monomers. Our analysis confirms the existence of structured regions within the otherwise flexible Abeta peptides. We find that the C terminus of Abeta42 is more structured than that of Abeta40. The formation of a beta-hairpin in the sequence (31)IIGLMVGGVVIA involving short strands at residues 31-34 and 38-41 (in bold) reduces the C-terminal flexibility of the Abeta42 peptide and may be responsible for the higher propensity of this peptide to form amyloids.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jmb.2007.02.093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1978067PMC
May 2007

Surface plasmon resonance and nuclear magnetic resonance studies of ABAD-Abeta interaction.

Biochemistry 2007 Feb 25;46(7):1724-31. Epub 2007 Jan 25.

Department of Biology, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, New York 12180, USA.

Abeta binding alcohol dehydrogenase (ABAD) is an NAD-dependent mitochondrial dehydrogenase. The binding between ABAD and Abeta is likely a direct link between Abeta and mitochondrial toxicity in Alzheimer's disease. In this study, surface plasmon resonance (SPR) was employed to determine the temperature dependence of the affinity of the ABAD-Abeta interaction. A van't Hoff analysis revealed that the ABAD-Abeta association is driven by a favorable entropic change (DeltaS = 300 +/- 30 J mol-1 K-1) which overcomes an unfavorable enthalpy change (DeltaH = 49 +/- 7 kJ/mol). Therefore, hydrophobic interactions and changes in protein dynamics are the dominant driving forces of the ABAD-Abeta interaction. This is the first dissection of the entropic and enthalpic contribution to the energetics of a protein-protein interaction involving Abeta. SPR confirmed the conformational changes in the ABAD-Abeta complex after Abeta binding, consistent with differences seen in the crystal structures of free ABAD and the ABAD-Abeta complex. Saturation transfer difference (STD) NMR experiments directly and unambiguously demonstrated the inhibitory effect of Abeta on the ABAD-NAD interaction. Conversely, NAD inhibits the Abeta-ABAD interaction. Binding of Abeta and binding of NAD to ABAD are likely mutually exclusive. Thus, Abeta binding induces conformational and subsequently functional changes in ABAD, which may have a role in the mechanism of Abeta toxicity in Alzheimer's disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/bi061314nDOI Listing
February 2007

Abeta42 is more rigid than Abeta40 at the C terminus: implications for Abeta aggregation and toxicity.

J Mol Biol 2006 Dec 23;364(5):853-62. Epub 2006 Sep 23.

Biology Department, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY 12180, USA.

Abeta40 and Abeta42 are the major forms of amyloid beta peptides (Abeta) in the brain. Although Abeta42 differs from Abeta40 by only two residues, Abeta42 is much more prone to aggregation and more toxic to neurons than Abeta40. To probe whether dynamics contribute to such dramatic difference in function, backbone ps-ns dynamics of native Abeta monomers were characterized by 15N spin relaxation at 273.3 K and 800 MHz. Abeta42 aggregates much faster than Abeta40 in the NMR tube. The effect of Abeta aggregation was removed from the relaxation measurement by interleaved data collection. R1, R2 and nuclear Overhauser enhancement (NOE) values are similar in Abeta40 and Abeta42, except at the C terminus, indicating Abeta42 and Abeta40 monomers have identical global motions. Comparisons of the spectral density function J(0.87omegaH) and order parameters (S2) indicate that the Abeta42 C terminus is more rigid than the Abeta40 C terminus. At 280.4 K and 287.6 K, the Abeta42 C terminus remains more rigid than the Abeta40 C terminus, suggesting such a dynamical difference is likely present at the physiological temperature. The Abeta42 monomer likely has less configurational entropy due to restricted motion in the C terminus and may pay a smaller entropic price to form fibrils than the Abeta40 monomer. We hypothesize that the entropic difference between Abeta40 and Abeta42 monomers might partly account for the fact that Abeta42 is the major Abeta species in parenchymal senile plaques in most Alzheimer's diseased brains in spite of the predominance of Abeta40 in plasma. The increased rigidity of the Abeta42 C terminus is likely due to its pre-ordering for beta-conformation present in soluble oligomers and fibrils. The Abeta42 C terminus may therefore serve as an internal seed for aggregation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jmb.2006.09.046DOI Listing
December 2006

Sex-specific recombination rates in zebrafish (Danio rerio).

Genetics 2002 Feb;160(2):649-57

Institute of Neuroscience, University of Oregon, Eugene, Oregon 97403, USA.

In many organisms, the rate of genetic recombination is not uniform along the length of chromosomes or between sexes. To compare the relative recombination rates during meiosis in male and female zebrafish, we constructed a genetic map based on male meiosis. We developed a meiotic mapping panel of 94 androgenetic haploid embryos that were scored for genetic polymorphisms. The resulting male map was compared to female and sex-average maps. We found that the recombination rate in male meiosis is dramatically suppressed relative to that of female meiosis, especially near the centromere. These findings have practical applications for experimental design. The use of exclusively female meiosis in a positional cloning project maximizes the ratio of genetic map distance to physical distance. Alternatively, the use of exclusively male meiosis to localize a mutation initially to a linkage group or to maintain relationships of linked alleles minimizes recombination, thereby facilitating some types of analysis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1461993PMC
http://dx.doi.org/10.1093/genetics/160.2.649DOI Listing
February 2002
-->