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Andrea Moretti, Jianfeng Li, Stefano Donini, Robert W Sobol, Menico Rizzi, Silvia Garavaglia
The aldehyde dehydrogenase family 1 member A3 (ALDH1A3) catalyzes the oxidation of retinal to the pleiotropic factor retinoic acid using NAD(+). The level of ALDHs enzymatic activity has been used as a cancer stem cell marker and seems to correlate with tumour aggressiveness. Elevated ALDH1A3 expression in mesenchymal glioma stem cells highlights the potential of this isozyme as a prognosis marker and drug target. Here we report the first crystal structure of human ALDH1A3 complexed with NAD(+) and the product all-trans retinoic acid (REA)...
October 19, 2016: Scientific Reports
Josep Martí-Solans, Olga V Belyaeva, Nuria P Torres-Aguila, Natalia Y Kedishvili, Ricard Albalat, Cristian Cañestro
The bloom of genomics is revealing gene loss as a pervasive evolutionary force generating genetic diversity that shapes the evolution of species. Outside bacteria and yeast, however, the understanding of the process of gene loss remains elusive, especially in the evolution of animal species. Here, using the dismantling of the retinoic acid metabolic gene network (RA-MGN) in the chordate Oikopleura dioica as a case study, we combine approaches of comparative genomics, phylogenetics, biochemistry, and developmental biology to investigate the mutational robustness associated to biased patterns of gene loss...
September 2016: Molecular Biology and Evolution
Mousumi Majumder, Xiping Xin, Ling Liu, Elena Tutunea-Fatan, Mauricio Rodriguez-Torres, Krista Vincent, Lynne-Marie Postovit, David Hess, Peeyush K Lala
Cancer stem-like cells (SLC) resist conventional therapies, necessitating searches for SLC-specific targets. We established that cyclo-oxygenase(COX)-2 expression promotes human breast cancer progression by activation of the prostaglandin(PG)E-2 receptor EP4. Present study revealed that COX-2 induces SLCs by EP4-mediated NOTCH/WNT signaling. Ectopic COX-2 over-expression in MCF-7 and SKBR-3 cell lines resulted in: increased migration/invasion/proliferation, epithelial-mesenchymal transition (EMT), elevated SLCs (spheroid formation), increased ALDH activity and colocalization of COX-2 and SLC markers (ALDH1A, CD44, β-Catenin, NANOG, OCT3/4, SOX-2) in spheroids...
September 2016: Stem Cells
Nathaniel B Goldstein, Maranke I Koster, Laura G Hoaglin, Michael J Wright, Steven E Robinson, William A Robinson, Dennis R Roop, David A Norris, Stanca A Birlea
To characterize the gene expression profile of regenerated melanocytes in the narrow band UVB (NBUVB)-treated vitiligo epidermis and their precursors in the hair follicle, we present here a strategy of RNA isolation from in situ melanocytes using human frozen skin. We developed a rapid immunostaining protocol using the NKI-beteb antibody, which labels differentiated and precursor melanocytes, followed by fluorescent laser capture microdissection. This technique enabled the direct isolation, from melanocyte and adjacent keratinocyte populations, of satisfactory quality RNA that was successfully amplified and analysed by qRT-PCR...
October 2016: Experimental Dermatology
A Unguryte, E Bernotiene, E Bagdonas, S Garberyte, N Porvaneckas, C Jorgensen
OBJECTIVE: To determine in human articular chondrocytes the activity of Aldehyde dehydrogenase (ALDH), which are reported as stem/progenitor cell marker in various adult tissues and evaluate gene expression of ALDH1A isoforms. DESIGN: ALDH activity was evaluated by flow cytometry with Aldefluor™ assay in cells, isolated from human osteoarthritic (OA) cartilage. Its coexpression with surface markers was identified. Cells were sorted according to ALDH activity, and gene expression in sorted populations (ALDH(+) and ALDH(-)) was analyzed by RTq-PCR with Taqman(®) assay...
May 2016: Osteoarthritis and Cartilage
Samuel L Arnold, Faith Stevison, Nina Isoherranen
Protein quantification based on peptides using LC-MS/MS has emerged as a promising method to measure biomarkers, protein drugs, and endogenous proteins. However, the best practices for selection, optimization, and validation of the quantification peptides are not well established, and the influence of different matrices on protein digestion, peptide stability, and MS detection has not been systematically addressed. The aim of this study was to determine how biological matrices affect digestion, detection, and stability of peptides...
January 5, 2016: Analytical Chemistry
Mingli Sun, Haishan Zhao, Qinghuan Xiao, Zhaojin Yu, Zhiguo Song, Weifan Yao, Hongtao Tang, Shu Guan, Feng Jin, Minjie Wei
This study investigated the expression of ALDH1A1 and β-catenin in breast cancer patients, and analyzed the correlation of their combined expression with clinicopathological features, chemotherapeutic responses, and prognosis of breast cancer patients. In total 276 human breast cancer tissues and 80 benign hyperplasia tissues were included. The expression of ALDH1A1 and β-catenin was examined using tissue microarray-based immunohistochemistry. ROC curve analysis was performed to determine an optimal cut-off score for the expression of ALDH1A1 and β-catenin, based on the survival status of breast cancer patients...
December 2015: Oncology Reports
Faith Stevison, Jing Jing, Sasmita Tripathy, Nina Isoherranen
Vitamin A (retinol) and its active metabolite, all-trans-retinoic acid (atRA), play critical roles in regulating the differentiation, growth, and migration of immune cells. Similarly, as critical signaling molecules in the regulation of the cell cycle, retinoids are important in cancers. Concentrations of atRA are tightly regulated in tissues, predominantly by the availability of retinol, synthesis of atRA by ALDH1A enzymes and metabolism and clearance of atRA by CYP26 enzymes. The ALDH1A and CYP26 enzymes are expressed in several cell types in the immune system and in cancer cells...
2015: Advances in Pharmacology
Chanchal Mandal, Ji Hyun Park, Hyung Tae Lee, Hyemyung Seo, Il Yup Chung, Ihn Geun Choi, Kyoung Hwa Jung, Young Gyu Chai
The objective of the present study was to investigate the changes in gene expression in the fetal brain (forebrain and hippocampus) caused by maternal binge alcohol consumption. Pregnant C57BL/6J mice were treated intragastrically with distilled phosphate-buffered saline (PBS) or ethanol (2.9 g/kg) from embryonic day (ED) 8-12. Microarray analysis revealed that a significant number of genes were altered at ED 18 in the developing brain. Specifically, in hippocampus, nuclear factor one alpha (Nfia) and three N-methyl-D-aspartate (Nmda) receptors (Nmdar1, Nmdar2b, and Nmdar2d) were down-regulated...
June 26, 2015: Neuroscience Letters
J Xi, J Yue, Z Yang
Retinoic acid (RA) plays a crucial role in cellular proliferation, differentiation, and apoptosis. The physiological activity of RA begins early in development and continues throughout an organism's life. RA distribution is tightly controlled by the RA synthetases ALDH1As and the metabolic enzymes CYP26s. We analyzed the expressions of ALDH1As and CYP26s in whole embryos during zebrafish (Danio rerio) development and in adult zebrafish organs, by quantitative reverse transcriptase polymerase chain reaction analysis...
2015: Genetics and Molecular Research: GMR
Samuel L M Arnold, Travis Kent, Cathryn A Hogarth, Michael D Griswold, John K Amory, Nina Isoherranen
all-trans retinoic acid (atRA), the active metabolite of vitamin A, is an essential signaling molecule. Specifically the concentrations of atRA are spatiotemporally controlled in target tissues such as the liver and the testes. While the enzymes of the aldehyde dehydrogenase 1A family (ALDH1A) are believed to control the synthesis of atRA, a direct relationship between altered ALDH1A activity and tissue atRA concentrations has never been shown. To test whether inhibition of ALDH1A enzymes decreases atRA concentrations in a tissue specific manner, the potent ALDH1A inhibitor WIN 18,446 was used to inhibit ALDH1A activity in mice...
June 1, 2015: Biochemical Pharmacology
Samuel L Arnold, Travis Kent, Cathryn A Hogarth, Stefan Schlatt, Bhagwat Prasad, Michael Haenisch, Thomas Walsh, Charles H Muller, Michael D Griswold, John K Amory, Nina Isoherranen
Retinoic acid (RA), the active metabolite of vitamin A, is required for spermatogenesis and many other biological processes. RA formation requires irreversible oxidation of retinal to RA by aldehyde dehydrogenase enzymes of the 1A family (ALDH1A). While ALDH1A1, ALDH1A2, and ALDH1A3 all form RA, the expression pattern and relative contribution of these enzymes to RA formation in the testis is unknown. In this study, novel methods to measure ALDH1A protein levels and intrinsic RA formation were used to accurately predict RA formation velocities in individual human testis samples and an association between RA formation and intratesticular RA concentrations was observed...
February 2015: Journal of Lipid Research
Roger S Holmes
Vertebrate ALDH1A-like genes encode cytosolic enzymes capable of metabolizing all-trans-retinaldehyde to retinoic acid which is a molecular 'signal' guiding vertebrate development and adipogenesis. Bioinformatic analyses of vertebrate and invertebrate genomes were undertaken using known ALDH1A1, ALDH1A2 and ALDH1A3 amino acid sequences. Comparative analyses of the corresponding human genes provided evidence for distinct modes of gene regulation and expression with putative transcription factor binding sites (TFBS), CpG islands and micro-RNA binding sites identified for the human genes...
June 5, 2015: Chemico-biological Interactions
Lei Wan, Hsueh-Li Tan, Jennifer M Thomas-Ahner, Dennis K Pearl, John W Erdman, Nancy E Moran, Steven K Clinton
Consumption of tomato products containing the carotenoid lycopene is associated with a reduced risk of prostate cancer. To identify gene expression patterns associated with early testosterone-driven prostate carcinogenesis, which are impacted by dietary tomato and lycopene, wild-type (WT) and transgenic adenocarcinoma of the mouse prostate (TRAMP) mice were fed control or tomato- or lycopene-containing diets from 4 to 10 weeks of age. Eight-week-old mice underwent sham surgery, castration, or castration followed by testosterone repletion (2...
December 2014: Cancer Prevention Research
Brooke A C Longville, Denise Anderson, Mathew D Welch, Ursula R Kees, Wayne K Greene
The class 1A aldehyde dehydrogenase (ALDH1A) subfamily of genes encode enzymes that function at the apex of the retinoic acid (RA) signalling pathway. We detected aberrant expression of ALDH1A genes, particularly ALDH1A2, in a majority (72%) of primary paediatric T cell acute lymphoblastic leukaemia (T-ALL) specimens. ALDH1A expression was almost exclusive to T-lineage, but not B-lineage, ALL. To determine whether ALDH1A expression may have relevance to T-ALL cell growth and survival, the effect of inhibiting ALDH1A function was measured on a panel of human ALL cell lines...
January 2015: British Journal of Haematology
Mousumi Majumder, Xiping Xin, Ling Liu, Gannareddy V Girish, Peeyush K Lala
We previously established that COX-2 overexpression promotes breast cancer progression and metastasis. As long-term use of COX-2 inhibitors (COX-2i) can promote thrombo-embolic events, we tested an alternative target, prostaglandin E2 receptor EP4 subtype (EP4), downstream of COX-2. Here we used the highly metastatic syngeneic murine C3L5 breast cancer model to test the role of EP4-expressing macrophages in vascular endothelial growth factor (VEGF)-C/D production, angiogenesis, and lymphangiogenesis in situ, the role of EP4 in stem-like cell (SLC) functions of tumor cells, and therapeutic effects of an EP4 antagonist RQ-15986 (EP4A)...
September 2014: Cancer Science
Theodore J Sanders, Neil E McCarthy, Edward M Giles, Katherine L M Davidson, Myriam L R Haltalli, Sophie Hazell, James O Lindsay, Andrew J Stagg
BACKGROUND & AIMS: Reduced generation of all-trans retinoic acid (RA) by CD103(+) intestinal dendritic cells (DCs) is linked to intestinal inflammation in mice. However, the role of RA in intestinal inflammation in humans is unclear. We investigated which antigen-presenting cells (APCs) produce RA in the human intestine and whether generation of RA is reduced in patients with Crohn's disease (CD). METHODS: Ileal and colonic tissues were collected from patients with CD during endoscopy or surgery, and healthy tissues were collected from subjects who were undergoing follow-up because of rectal bleeding, altered bowel habits, or cancer (controls)...
May 2014: Gastroenterology
Rajeev Rudraraju, Bart G Jones, Sherri L Surman, Robert E Sealy, Paul G Thomas, Julia L Hurwitz
Morbidity and mortality due to viral infections are major health concerns, particularly when individuals are vitamin A deficient. Vitamin A deficiency significantly impairs mucosal IgA, a first line of defense against virus at its point of entry. Previous reports have suggested that CD11c(Hi) dendritic cells (DCs) of the gastrointestinal tract produce retinaldehyde dehydrogenase (ALDH1A), which metabolizes vitamin A precursors to retinoic acid to support normal mucosal immunity. Given that the upper respiratory tract (URT) and gastrointestinal tract share numerous characteristics, we asked if the CD11c(Hi) DCs of the URT might also express ALDH1A...
2014: PloS One
Elyse K Paterson, Hsiang Ho, Rubina Kapadia, Anand K Ganesan
Aldehyde dehydrogenase 1A1 (ALDH1A1), an enzyme that catalyses the conversion of lipid aldehydes to lipid carboxylic acids, plays pleiotropic roles in UV-radiation resistance, melanogenesis and stem cell maintenance. In this study, a combination of RNAi and pharmacologic approaches were used to determine which ALDH1A1 substrates and products regulate melanogenesis. Initial studies revealed that neither the UV-induced lipid aldehyde 4-hydroxy-2-nonenal nor the ALDH1A1 product all-trans retinoic acid appreciably induced melanogenesis...
March 2013: Experimental Dermatology
Daniel Leclerc, Yuanhang Cao, Liyuan Deng, Leonie G Mikael, Qing Wu, Rima Rozen
SCOPE: Inadequate folate intake increases risk for colorectal cancer. We previously showed that low-folate diets induced intestinal tumors in BALB/c mice, but not in C57BL/6 mice. We suggested that DNA damage, altered methylation, and reduced apoptosis could contribute to tumorigenesis in this model. METHODS AND RESULTS: To identify genes involved in tumorigenesis, we compared gene expression profiles in preneoplastic intestine of BALB/c and C57BL/6 mice-fed low folate...
April 2013: Molecular Nutrition & Food Research
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