|
1
|
Zhao H, Ma Q, Lu S, Liu S, Feng Y, Liu Y, Zhang B. Pyraclostrobin-induced toxic effects in the gills of common carp (Cyprinus carpio L.): Mechanisms unveiled through biochemical, molecular, and metabolomic analyses. COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY. PART D, GENOMICS & PROTEOMICS 2025; 54:101443. [PMID: 39952084 DOI: 10.1016/j.cbd.2025.101443] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/05/2025] [Revised: 02/08/2025] [Accepted: 02/09/2025] [Indexed: 02/17/2025]
Abstract
Pyraclostrobin (PYR) is widely used in agriculture to control fungal infestations. However, the toxic effects of PYR on aquatic organisms remain poorly understood. In this study, common carp were exposed to 0.5, and 5.0 μg/L PYR for 30 days to evaluate the chronic effects on gill health via histopathological, biochemical, molecular, and metabolomic analyses. The findings revealed that exposure to PYR resulted in significant histopathological alterations, suppression of mitochondrial complex III activity, and excessive production of reactive oxygen species (ROS), including O2•- and H2O2. Additionally, PYR exposure altered the levels of superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH) while increasing the malondialdehyde (MDA) content in the gills of common carp. The protein expression levels of lysozyme (LZM), tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β), and transforming growth factor beta (TGF-β) were significantly elevated following exposure to PYR, whereas the levels of complement 3 (C3) and immunoglobulin M (IgM) were decreased. Furthermore, the amount of IL-6 decreased on day 15 before increasing on day 30. Further analysis revealed a notable increase in acid phosphatase (ACP) activity and a decrease in alkaline phosphatase (AKP) activity after 30 days of PYR exposure. Moreover, PYR exposure significantly altered the mRNA expression levels of immune-related genes (lzm, c3, and igm) and apoptosis-related genes (p53, bcl-2, bax, caspase-3, and caspase-9). Several inflammatory markers, such as NF-κB p65 protein and the mRNA levels of tlr2, tlr4, myd88, tnf-α, il-1β, il-6, and tgf-β, were also markedly changed. Metabolomic studies demonstrated that PYR influences pathways related to amino acid, nucleotide, arachidonic acid, and linoleic acid metabolism. These results indicate that PYR adversely affects gill health by inducing oxidative stress, disrupting immune and inflammatory responses, affecting apoptosis-related pathways, and altering metabolic homeostasis. This study provides new insights into the toxic mechanisms of PYR and contributes to the assessment of the ecological risks associated with its presence in aquatic ecosystems.
Collapse
Affiliation(s)
- Haoyang Zhao
- Henan International Joint Laboratory of Aquatic Ecotoxicology and Health Protection, College of Life Sciences, Henan Normal University, Xinxiang, Henan 453007, China
| | - Qingping Ma
- Henan International Joint Laboratory of Aquatic Ecotoxicology and Health Protection, College of Life Sciences, Henan Normal University, Xinxiang, Henan 453007, China
| | - Shuhan Lu
- Henan International Joint Laboratory of Aquatic Ecotoxicology and Health Protection, College of Life Sciences, Henan Normal University, Xinxiang, Henan 453007, China
| | - Shangwu Liu
- Henan International Joint Laboratory of Aquatic Ecotoxicology and Health Protection, College of Life Sciences, Henan Normal University, Xinxiang, Henan 453007, China
| | - Yiyi Feng
- Henan International Joint Laboratory of Aquatic Ecotoxicology and Health Protection, College of Life Sciences, Henan Normal University, Xinxiang, Henan 453007, China
| | - Yang Liu
- Henan International Joint Laboratory of Aquatic Ecotoxicology and Health Protection, College of Life Sciences, Henan Normal University, Xinxiang, Henan 453007, China; Journal of Henan Normal University, Xinxiang 453007, China
| | - Bangjun Zhang
- Henan International Joint Laboratory of Aquatic Ecotoxicology and Health Protection, College of Life Sciences, Henan Normal University, Xinxiang, Henan 453007, China.
| |
Collapse
|
|
2
|
Tang S, Borlak J. A comparative genomic study across 396 liver biopsies provides deep insight into FGF21 mode of action as a therapeutic agent in metabolic dysfunction-associated steatotic liver disease. Clin Transl Med 2025; 15:e70218. [PMID: 39962359 PMCID: PMC11832436 DOI: 10.1002/ctm2.70218] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Revised: 01/15/2025] [Accepted: 01/24/2025] [Indexed: 02/20/2025] Open
Abstract
BACKGROUND Metabolic dysfunction-associated steatotic liver disease (MASLD) is a systemic disease with insulin resistance at its core. It affects one-third of the world population. Fibroblast growth factor (FGF21)-based therapies are effective in lowering hepatic fat content and fibrosis resolution; yet, its molecular functions remain uncertain. To gain insight into FGF21 mode of action (MoA), we investigated the transcriptomes of MASLD liver biopsies in relation to FGF21 expression. METHODS We compared N = 66 healthy controls with 396 MASLD patients and considered clinical characteristics relative to NAS disease activity scores (steatosis, lobular inflammation and ballooning), fibrosis grades and sex. We performed comparative genomics to identify FGF21-responsive DEGs, utilised information from FGF21-transgenic and FGF21-knockout mice and evaluated DEGs following FGF21 treatment of MASLD animal models. Eventually, we explored 188 validated FGF21 targets, and for ≥10 patients showing the same changes, we constructed MASLD-associated networks to determine the effects of FGF21 in reverting metabolic dysfunction. RESULTS We identified patients with increased 30% (N = 117), decreased 40% (N = 159) or unchanged 30% (N = 120) FGF21 expression, and the differences are caused by changes in FGF21 transcriptional control with ATF4 functioning as a key regulator. Based on comparative genomics, we discovered molecular circuitries of FGF21 in MASLD, notably FGF21-dependent induction of autophagy and oxidative phosphorylation/mitochondrial respiration. Conversely, FGF21 repressed hepatic glycogen-storage, its glucose release and gluconeogenesis, and therefore reduced glucose flux in conditions of insulin resistance. Furthermore, FGF21 repressed lipid transporters, and acetyl-CoA carboxylase-β to attenuate hepatic lipid overload and lipogenesis. Strikingly, FGF21 dampened immune response by repressing complement factors, MARCO, CD163, MRC1/CD206, CD4, CD45 and pro-inflammatory cytokine receptors. It also reverted procoagulant imbalance in MASLD, stimulated extracellular matrix degradation, repressed TGFβ- and integrin-signalling and lessened liver sinusoidal endothelial cell defenestration in support of fibrosis resolution. CONCLUSIONS We gained deep insight into FGF21-MoA in MASLD. However, heterogeneity in FGF21 expression calls for molecular stratifications as to identify patients which likely benefit from FGF21-based therapies. KEY POINTS Performed comprehensive genomics across liver biopsies of 396 MASLD patients and identified patients with increased, decreased and unchanged FGF21 expression. Used genomic data from FGF21 transgenic, knock-out and animal MASLD models treated with synthetic FGF21 analogues to identify FGF21-mode-of-action and metabolic networks in human MASLD. Given the significant heterogeneity in FGF21 expression, not all patients will benefit from FGF21-based therapies.
Collapse
Affiliation(s)
- Shifang Tang
- Centre for Pharmacology and ToxicologyHannover Medical SchoolHannoverGermany
| | - Jürgen Borlak
- Centre for Pharmacology and ToxicologyHannover Medical SchoolHannoverGermany
| |
Collapse
|
|
3
|
Gayen T, Tripathi A, Mittal S, Kumari U. Assessment of cell death in the liver of Labeo rohita on exposure to an emerging contaminant aspirin: an immunofluorescent, flow cytometric and biochemical investigation. FISH PHYSIOLOGY AND BIOCHEMISTRY 2024; 50:2551-2562. [PMID: 39292407 DOI: 10.1007/s10695-024-01405-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Accepted: 09/11/2024] [Indexed: 09/19/2024]
Abstract
Aspirin is one of the most frequently detected non-steroidal anti-inflammatory drugs in aquatic environments. Despite its prevalence, toxicity possessed by aspirin to non-target organisms like fish is poorly explored. In the present study, cell death induced by different concentrations of aspirin (1, 10, and 100 µg/L) has been investigated in the liver of fish, Labeo rohita exposed for 28 days. A significant increase (p < 0.05) in the density of caspase-3 positive cells in a dose and duration-dependent manner assessed through immunofluorescent staining indicates caspase-dependent pathway of cell death which may be either through intrinsic or extrinsic pathway. The flow cytometric analysis, in addition, revealed a significant (p < 0.05) decline in the live cells and an increase in apoptotic cells in the liver of fish exposed to aspirin. Cell death due to apoptosis is further indicated by a significant increase (p < 0.05) in the Kupffer cells and tumor necrosis factor-α. The decrease in the activity of cyclooxygenase (COX) enzyme significantly (p < 0.05) in all three exposure concentrations of aspirin suggests COX-dependent pathway of cell death. The present study provides in-depth insights into aspirin-induced cell death in the liver of fish at environmentally realistic concentrations.
Collapse
Affiliation(s)
- Tuhina Gayen
- Fish Physiology Laboratory, Zoology Section, Mahila Mahavidyalaya, Banaras Hindu University, Varanasi, 221 005, India
| | - Anchal Tripathi
- Fish Physiology Laboratory, Zoology Section, Mahila Mahavidyalaya, Banaras Hindu University, Varanasi, 221 005, India
| | - Swati Mittal
- Skin Physiology Laboratory, Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi, 221 005, India
| | - Usha Kumari
- Fish Physiology Laboratory, Zoology Section, Mahila Mahavidyalaya, Banaras Hindu University, Varanasi, 221 005, India.
| |
Collapse
|
|
4
|
Ferremi FJ, Moscoso VV, Montanaro MA, Gonzalez-Baro MR, Cattaneo ER. The protumorigenic enzyme GPAT2 inhibits arachidonic acid-triggered apoptosis in breast cancer. Lipids Health Dis 2024; 23:391. [PMID: 39605002 PMCID: PMC11600616 DOI: 10.1186/s12944-024-02344-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Accepted: 10/22/2024] [Indexed: 11/29/2024] Open
Abstract
BACKGROUND Cancer is a significant health challenge and the leading cause of mortality globally. Tumor cells use multiple mechanisms to acquire their distinctive capacity for uncontrolled proliferation, one of which is the evasion of apoptosis. It has been shown that in breast, colon, and liver cancer, evasion of apoptosis is associated with the overexpression of enzymes that metabolize arachidonic acid (AA) because free AA is a strong inducer of apoptosis. Glycerol-3-phosphate acyltransferase 2 (GPAT2) is a key enzyme in AA metabolism and is highly expressed in breast and colon cancer, where it promotes the development of essential tumor features. METHODS In this work, a model of GPAT2 silencing in the human breast cancer-derived cell line MDA-MB-231 was used, and the cells were exposed to exogenous AA. The role of GPAT2 in AA-induced cell death was studied using MTT and TUNEL assays and measurements of caspase activity. The underlying molecular mechanism of cell death was assessed by qRT‒PCR. RESULTS The results showed that AA reduced cell viability only in GPAT2-silenced cells, and that this cell death was a consequence of an apoptotic process involving BNIP3 overexpression. Additionally, it was demonstrated that GPAT2 silencing triggered a compensatory mechanism by overexpressing other genes involved in AA utilization for eicosanoid biosynthesis. CONCLUSIONS We concluded that GPAT2 expression is necessary to prevent AA-induced apoptotic cell death in MDA-MB-231 cells and that the overexpression of other AA-metabolizing genes is not sufficient to compensate for the lack of GPAT2 and prevent apoptosis.
Collapse
Affiliation(s)
- Fiorella J Ferremi
- Instituto de Investigaciones Bioquímicas de La Plata Dr. Rodolfo R. Brenner, Consejo Nacional de Investigaciones Científicas y Técnicas, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, La Plata, Buenos Aires, Argentina
| | - Veronica V Moscoso
- Instituto de Investigaciones Bioquímicas de La Plata Dr. Rodolfo R. Brenner, Consejo Nacional de Investigaciones Científicas y Técnicas, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, La Plata, Buenos Aires, Argentina
| | - Mauro A Montanaro
- Instituto de Investigaciones Bioquímicas de La Plata Dr. Rodolfo R. Brenner, Consejo Nacional de Investigaciones Científicas y Técnicas, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, La Plata, Buenos Aires, Argentina
| | - Maria R Gonzalez-Baro
- Instituto de Investigaciones Bioquímicas de La Plata Dr. Rodolfo R. Brenner, Consejo Nacional de Investigaciones Científicas y Técnicas, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, La Plata, Buenos Aires, Argentina
| | - Elizabeth R Cattaneo
- Instituto de Investigaciones Bioquímicas de La Plata Dr. Rodolfo R. Brenner, Consejo Nacional de Investigaciones Científicas y Técnicas, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, La Plata, Buenos Aires, Argentina.
| |
Collapse
|
|
5
|
Riedel S, Abel S, Burger HM, Swanevelder S, Gelderblom WCA. Fumonisin B 1 protects against long-chained polyunsaturated fatty acid-induced cell death in HepG2 cells - implications for cancer promotion. BIOCHIMICA ET BIOPHYSICA ACTA. BIOMEMBRANES 2024; 1866:184310. [PMID: 38479610 DOI: 10.1016/j.bbamem.2024.184310] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Revised: 02/19/2024] [Accepted: 03/08/2024] [Indexed: 04/12/2024]
Abstract
Fumonisin B1 (FB1), a food-borne mycotoxin, is a cancer promoter in rodent liver and augments proliferation of initiated cells while inhibiting the growth of normal hepatocytes by disrupting lipid biosynthesis at various levels. HepG2 cancer cells exhibited resistance to FB1-induced toxic effects presumably due to their low content of polyunsaturated fatty acids (PUFA) even though FB1-typical lipid changes were observed, e.g. significantly increased phosphatidylethanolamine (PE), decreased sphingomyelin and cholesterol content, increased sphinganine (Sa) and sphinganine/sphingosine ratio, increased C18:1ω-9, decreased C20:4ω-6 content in PE and decreased C20:4ω-6_PC/PE ratio. Increasing PUFA content of HepG2 cells with phosphatidylcholine (PC) vesicles containing C20:4ω-6 (SAPC) or C22:6ω-3 (SDPC) disrupted cell survival, cellular redox status and induced oxidative stress and apoptosis. A partially protective effect of FB1 was evident in PUFA-enriched HepG2 cells which may be related to the FB1-induced reduction in oxidative stress and the disruption of key cell membrane constituents indicative of a resistant lipid phenotype. Interactions between different ω-6 and ω-3 PUFA, membrane constituents including cholesterol, and the glycerophospho- and sphingolipids and FB1 in this cell model provide further support for the resistant lipid phenotype and its role in the complex cellular effects underlying the cancer promoting potential of the fumonisins.
Collapse
Affiliation(s)
- Sylvia Riedel
- Biomedical Research and Innovation Platform, South African Medical Research Council, PO Box 19070, Tygerberg 7505, South Africa; Centre for Cardiometabolic Research in Africa (CARMA), Division of Medical Physiology, Faculty of Medicine and Health Sciences, Stellenbosch University, PO Box 241, Cape Town 8000, South Africa.
| | - Stefan Abel
- Applied Microbial and Health Biotechnology Institute, Cape Peninsula University of Technology, PO Box 1906, Bellville 7535, South Africa.
| | - Hester-Mari Burger
- Unit of Research Integrity, Research Directorate, Cape Peninsula University of Technology, Bellville 7535, South Africa.
| | - Sonja Swanevelder
- Biostatistics Research Unit, South African Medical Research Council, PO Box 19070, Tygerberg 7505, South Africa.
| | - Wentzel C A Gelderblom
- Department of Biochemistry, Stellenbosch University, Private Bag X1, Matieland 7602, South Africa
| |
Collapse
|
|
6
|
Day ZI, Mayfosh AJ, Baxter AA, Williams SA, Hildebrand JM, Rau TF, Poon IKH, Hulett MD. Defining a Water-Soluble Formulation of Arachidonic Acid as a Novel Ferroptosis Inducer in Cancer Cells. Biomolecules 2024; 14:555. [PMID: 38785962 PMCID: PMC11118058 DOI: 10.3390/biom14050555] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Revised: 04/29/2024] [Accepted: 05/02/2024] [Indexed: 05/25/2024] Open
Abstract
Here, we describe GS-9, a novel water-soluble fatty acid-based formulation comprising L-lysine and arachidonic acid, that we have shown to induce ferroptosis. GS-9 forms vesicle-like structures in solution and mediates lipid peroxidation, as evidenced by increased C11-BODIPY fluorescence and an accumulation of toxic malondialdehyde, a downstream product of lipid peroxidation. Ferroptosis inhibitors counteracted GS-9-induced cell death, whereas caspase 3 and 7 or MLKL knock-out cell lines are resistant to GS-9-induced cell death, eliminating other cell death processes such as apoptosis and necroptosis as the mechanism of action of GS-9. We also demonstrate that through their role of sequestering fatty acids, lipid droplets play a protective role against GS-9-induced ferroptosis, as inhibition of lipid droplet biogenesis enhanced GS-9 cytotoxicity. In addition, Fatty Acid Transport Protein 2 was implicated in GS-9 uptake. Overall, this study identifies and characterises the mechanism of GS-9 as a ferroptosis inducer. This formulation of arachidonic acid offers a novel tool for investigating and manipulating ferroptosis in various cellular and anti-cancer contexts.
Collapse
Affiliation(s)
- Zoe I. Day
- Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia; (Z.I.D.); (A.J.M.); (A.A.B.); (I.K.H.P.)
| | - Alyce J. Mayfosh
- Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia; (Z.I.D.); (A.J.M.); (A.A.B.); (I.K.H.P.)
- Wintermute Biomedical, Geelong, VIC 3220, Australia
| | - Amy A. Baxter
- Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia; (Z.I.D.); (A.J.M.); (A.A.B.); (I.K.H.P.)
| | - Scott A. Williams
- Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia; (Z.I.D.); (A.J.M.); (A.A.B.); (I.K.H.P.)
| | - Joanne M. Hildebrand
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia;
| | | | - Ivan K. H. Poon
- Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia; (Z.I.D.); (A.J.M.); (A.A.B.); (I.K.H.P.)
| | - Mark D. Hulett
- Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia; (Z.I.D.); (A.J.M.); (A.A.B.); (I.K.H.P.)
| |
Collapse
|
|
7
|
Osazuwa-Peters OL, Deveaux A, Muehlbauer MJ, Ilkayeva O, Bain JR, Keku T, Berchuck A, Huang B, Ward K, Gates Kuliszewski M, Akinyemiju T. Racial Differences in Vaginal Fluid Metabolites and Association with Systemic Inflammation Markers among Ovarian Cancer Patients: A Pilot Study. Cancers (Basel) 2024; 16:1259. [PMID: 38610937 PMCID: PMC11011195 DOI: 10.3390/cancers16071259] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2024] [Revised: 03/11/2024] [Accepted: 03/20/2024] [Indexed: 04/14/2024] Open
Abstract
The vaginal microbiome differs by race and contributes to inflammation by directly producing or consuming metabolites or by indirectly inducing host immune response, but its potential contributions to ovarian cancer (OC) disparities remain unclear. In this exploratory cross-sectional study, we examine whether vaginal fluid metabolites differ by race among patients with OC, if they are associated with systemic inflammation, and if such associations differ by race. Study participants were recruited from the Ovarian Cancer Epidemiology, Healthcare Access, and Disparities Study between March 2021 and September 2022. Our study included 36 study participants with ovarian cancer who provided biospecimens; 20 randomly selected White patients and all 16 eligible Black patients, aged 50-70 years. Acylcarnitines (n = 45 species), sphingomyelins (n = 34), and ceramides (n = 21) were assayed on cervicovaginal fluid, while four cytokines (IL-1β, IL-10, TNF-α, and IL-6) were assayed on saliva. Seven metabolites showed >2-fold differences, two showed significant differences using the Wilcoxon rank-sum test (p < 0.05; False Discovery Rate > 0.05), and 30 metabolites had coefficients > ±0.1 in a Penalized Discriminant Analysis that achieved two distinct clusters by race. Arachidonoylcarnitine, the carnitine adduct of arachidonic acid, appeared to be consistently different by race. Thirty-eight vaginal fluid metabolites were significantly correlated with systemic inflammation biomarkers, irrespective of race. These findings suggest that vaginal fluid metabolites may differ by race, are linked with systemic inflammation, and hint at a potential role for mitochondrial dysfunction and sphingolipid metabolism in OC disparities. Larger studies are needed to verify these findings and further establish specific biological mechanisms that may link the vaginal microbiome with OC racial disparities.
Collapse
Affiliation(s)
- Oyomoare L. Osazuwa-Peters
- Department of Population Health Sciences, Duke University School of Medicine, Durham, NC 27701, USA; (A.D.); (T.A.)
| | - April Deveaux
- Department of Population Health Sciences, Duke University School of Medicine, Durham, NC 27701, USA; (A.D.); (T.A.)
| | - Michael J. Muehlbauer
- Duke University School of Medicine, Duke Molecular Physiology Institute, Durham, NC 27701, USA; (M.J.M.); (O.I.); (J.R.B.)
| | - Olga Ilkayeva
- Duke University School of Medicine, Duke Molecular Physiology Institute, Durham, NC 27701, USA; (M.J.M.); (O.I.); (J.R.B.)
- Division of Endocrinology, Metabolism, and Nutrition, Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA
| | - James R. Bain
- Duke University School of Medicine, Duke Molecular Physiology Institute, Durham, NC 27701, USA; (M.J.M.); (O.I.); (J.R.B.)
- Division of Endocrinology, Metabolism, and Nutrition, Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA
| | - Temitope Keku
- Division of Gastroenterology and Hepatology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA;
| | - Andrew Berchuck
- Duke Division of Gynecologic Oncology, Duke University School of Medicine, Durham, NC 27710, USA;
| | - Bin Huang
- Kentucky Cancer Registry, University of Kentucky, Lexington, KY 40506, USA;
| | - Kevin Ward
- Georgia Cancer Registry, Emory University, Atlanta, GA 30322, USA;
| | | | - Tomi Akinyemiju
- Department of Population Health Sciences, Duke University School of Medicine, Durham, NC 27701, USA; (A.D.); (T.A.)
- Duke Cancer Institute, Duke University School of Medicine, Durham, NC 27710, USA
| |
Collapse
|
|
8
|
Morishima T, Takahashi K, Chin DWL, Wang Y, Tokunaga K, Arima Y, Matsuoka M, Suda T, Takizawa H. Phospholipid metabolic adaptation promotes survival of IDH2 mutant acute myeloid leukemia cells. Cancer Sci 2024; 115:197-210. [PMID: 37882467 PMCID: PMC10823289 DOI: 10.1111/cas.15994] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2023] [Revised: 09/15/2023] [Accepted: 09/28/2023] [Indexed: 10/27/2023] Open
Abstract
Genetic mutations in the isocitrate dehydrogenase (IDH) gene that result in a pathological enzymatic activity to produce oncometabolite have been detected in acute myeloid leukemia (AML) patients. While specific inhibitors that target mutant IDH enzymes and normalize intracellular oncometabolite level have been developed, refractoriness and resistance has been reported. Since acquisition of pathological enzymatic activity is accompanied by the abrogation of the crucial WT IDH enzymatic activity in IDH mutant cells, aberrant metabolism in IDH mutant cells can potentially persist even after the normalization of intracellular oncometabolite level. Comparisons of isogenic AML cell lines with and without IDH2 gene mutations revealed two mutually exclusive signalings for growth advantage of IDH2 mutant cells, STAT phosphorylation associated with intracellular oncometabolite level and phospholipid metabolic adaptation. The latter came to light after the oncometabolite normalization and increased the resistance of IDH2 mutant cells to arachidonic acid-mediated apoptosis. The release of this metabolic adaptation by FDA-approved anti-inflammatory drugs targeting the metabolism of arachidonic acid could sensitize IDH2 mutant cells to apoptosis, resulting in their eradication in vitro and in vivo. Our findings will contribute to the development of alternative therapeutic options for IDH2 mutant AML patients who do not tolerate currently available therapies.
Collapse
Affiliation(s)
- Tatsuya Morishima
- Laboratory of Stem Cell Stress, International Research Center for Medical Sciences (IRCMS)Kumamoto UniversityKumamotoJapan
- Laboratory of Hematopoietic Stem Cell Engineering, IRCMSKumamoto UniversityKumamotoJapan
| | - Koichi Takahashi
- Departments of Leukemia and Genomic MedicineThe University of Texas MD Anderson Cancer CenterHoustonTexasUSA
| | - Desmond Wai Loon Chin
- Cancer Science Institute of SingaporeNational University of SingaporeSingaporeSingapore
| | - Yuxin Wang
- Laboratory of Stem Cell Stress, International Research Center for Medical Sciences (IRCMS)Kumamoto UniversityKumamotoJapan
- Department of Hematology, Zhujiang HospitalSouthern Medical UniversityGuangzhouChina
| | - Kenji Tokunaga
- Department of Hematology, Rheumatology, and Infectious Diseases, Graduate School of Medical SciencesKumamoto UniversityKumamotoJapan
| | - Yuichiro Arima
- Laboratory of Developmental Cardiology, IRCMSKumamoto UniversityKumamotoJapan
- Center for Metabolic Regulation of Healthy Aging (CMHA)Kumamoto UniversityKumamotoJapan
| | - Masao Matsuoka
- Department of Hematology, Rheumatology, and Infectious Diseases, Graduate School of Medical SciencesKumamoto UniversityKumamotoJapan
| | - Toshio Suda
- Cancer Science Institute of SingaporeNational University of SingaporeSingaporeSingapore
- Laboratory of Stem Cell Regulation, IRCMSKumamoto UniversityKumamotoJapan
| | - Hitoshi Takizawa
- Laboratory of Stem Cell Stress, International Research Center for Medical Sciences (IRCMS)Kumamoto UniversityKumamotoJapan
- Center for Metabolic Regulation of Healthy Aging (CMHA)Kumamoto UniversityKumamotoJapan
| |
Collapse
|
|
9
|
Park YJ, Heo J, Kim Y, Cho H, Shim M, Im K, Lim W. Glucocorticoids alleviate particulate matter-induced COX-2 expression and mitochondrial dysfunction through the Bcl-2/GR complex in A549 cells. Sci Rep 2023; 13:18884. [PMID: 37919369 PMCID: PMC10622527 DOI: 10.1038/s41598-023-46257-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Accepted: 10/30/2023] [Indexed: 11/04/2023] Open
Abstract
Exposure to particulate matter (PM) causes mitochondrial dysfunction and lung inflammation. The cyclooxygenase-2 (COX-2) pathway is important for inflammation and mitochondrial function. However, the mechanisms by which glucocorticoid receptors (GRs) suppress COX-2 expression during PM exposure have not been elucidated yet. Hence, we examined the mechanisms underlying the dexamethasone-mediated suppression of the PM-induced COX-2/prostaglandin E2 (PGE2) pathway in A549 cells. The PM-induced increase in COX-2 protein, mRNA, and promoter activity was suppressed by glucocorticoids; this effect of glucocorticoids was antagonized by the GR antagonist RU486. COX-2 induction was correlated with the ability of PM to increase reactive oxygen species (ROS) levels. Consistent with this, antioxidant treatment significantly abolished COX-2 induction, suggesting that ROS is involved in PM-mediated COX-2 induction. We also observed a low mitochondrial membrane potential in PM-treated A549 cells, which was reversed by dexamethasone. Moreover, glucocorticoids significantly enhanced Bcl-2/GR complex formation in PM-treated A549 cells. Glucocorticoids regulate the PM-exposed induction of COX-2 expression and mitochondrial dysfunction and increase the interaction between GR and Bcl-2. These findings suggest that the COX-2/PGE2 pathway and the interaction between GR and Bcl-2 are potential key therapeutic targets for the suppression of inflammation under PM exposure.
Collapse
Affiliation(s)
- Yeon-Ji Park
- Department of Biochemistry and Molecular Biology, Ajou University School of Medicine, Suwon, Republic of Korea
- Department of Biomedical Sciences, Graduate School of Ajou University, Suwon, Republic of Korea
| | - June Heo
- Department of Biochemistry and Molecular Biology, Ajou University School of Medicine, Suwon, Republic of Korea
- Department of Biomedical Sciences, Graduate School of Ajou University, Suwon, Republic of Korea
| | - Yonghyeon Kim
- Department of Biochemistry and Molecular Biology, Ajou University School of Medicine, Suwon, Republic of Korea
- Department of Biomedical Sciences, Graduate School of Ajou University, Suwon, Republic of Korea
| | - Hyeseong Cho
- Department of Biochemistry and Molecular Biology, Ajou University School of Medicine, Suwon, Republic of Korea
- Department of Biomedical Sciences, Graduate School of Ajou University, Suwon, Republic of Korea
| | - Myeongkuk Shim
- BL Healthcare, Yongin-si, Gyeonggi-do, 16827, South Korea
| | - Kyunghyun Im
- BL Healthcare, Yongin-si, Gyeonggi-do, 16827, South Korea
| | - Wonchung Lim
- Department of Sports Medicine, College of Health Science, Cheongju University, Cheongju, 28503, South Korea.
| |
Collapse
|
|
10
|
Szrok-Jurga S, Czumaj A, Turyn J, Hebanowska A, Swierczynski J, Sledzinski T, Stelmanska E. The Physiological and Pathological Role of Acyl-CoA Oxidation. Int J Mol Sci 2023; 24:14857. [PMID: 37834305 PMCID: PMC10573383 DOI: 10.3390/ijms241914857] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Revised: 09/27/2023] [Accepted: 09/30/2023] [Indexed: 10/15/2023] Open
Abstract
Fatty acid metabolism, including β-oxidation (βOX), plays an important role in human physiology and pathology. βOX is an essential process in the energy metabolism of most human cells. Moreover, βOX is also the source of acetyl-CoA, the substrate for (a) ketone bodies synthesis, (b) cholesterol synthesis, (c) phase II detoxication, (d) protein acetylation, and (d) the synthesis of many other compounds, including N-acetylglutamate-an important regulator of urea synthesis. This review describes the current knowledge on the importance of the mitochondrial and peroxisomal βOX in various organs, including the liver, heart, kidney, lung, gastrointestinal tract, peripheral white blood cells, and other cells. In addition, the diseases associated with a disturbance of fatty acid oxidation (FAO) in the liver, heart, kidney, lung, alimentary tract, and other organs or cells are presented. Special attention was paid to abnormalities of FAO in cancer cells and the diseases caused by mutations in gene-encoding enzymes involved in FAO. Finally, issues related to α- and ω- fatty acid oxidation are discussed.
Collapse
Affiliation(s)
- Sylwia Szrok-Jurga
- Department of Biochemistry, Faculty of Medicine, Medical University of Gdansk, 80-211 Gdansk, Poland; (S.S.-J.); (J.T.); (A.H.)
| | - Aleksandra Czumaj
- Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Medical University of Gdansk, 80-211 Gdansk, Poland;
| | - Jacek Turyn
- Department of Biochemistry, Faculty of Medicine, Medical University of Gdansk, 80-211 Gdansk, Poland; (S.S.-J.); (J.T.); (A.H.)
| | - Areta Hebanowska
- Department of Biochemistry, Faculty of Medicine, Medical University of Gdansk, 80-211 Gdansk, Poland; (S.S.-J.); (J.T.); (A.H.)
| | - Julian Swierczynski
- Institue of Nursing and Medical Rescue, State University of Applied Sciences in Koszalin, 75-582 Koszalin, Poland;
| | - Tomasz Sledzinski
- Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Medical University of Gdansk, 80-211 Gdansk, Poland;
| | - Ewa Stelmanska
- Department of Biochemistry, Faculty of Medicine, Medical University of Gdansk, 80-211 Gdansk, Poland; (S.S.-J.); (J.T.); (A.H.)
| |
Collapse
|
|
11
|
Chen F, Kang R, Liu J, Tang D. The ACSL4 Network Regulates Cell Death and Autophagy in Diseases. BIOLOGY 2023; 12:864. [PMID: 37372148 DOI: 10.3390/biology12060864] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/07/2023] [Revised: 06/05/2023] [Accepted: 06/11/2023] [Indexed: 06/29/2023]
Abstract
Lipid metabolism, cell death, and autophagy are interconnected processes in cells. Dysregulation of lipid metabolism can lead to cell death, such as via ferroptosis and apoptosis, while lipids also play a crucial role in the regulation of autophagosome formation. An increased autophagic response not only promotes cell survival but also causes cell death depending on the context, especially when selectively degrading antioxidant proteins or organelles that promote ferroptosis. ACSL4 is an enzyme that catalyzes the formation of long-chain acyl-CoA molecules, which are important intermediates in the biosynthesis of various types of lipids. ACSL4 is found in many tissues and is particularly abundant in the brain, liver, and adipose tissue. Dysregulation of ACSL4 is linked to a variety of diseases, including cancer, neurodegenerative disorders, cardiovascular disease, acute kidney injury, and metabolic disorders (such as obesity and non-alcoholic fatty liver disease). In this review, we introduce the structure, function, and regulation of ACSL4; discuss its role in apoptosis, ferroptosis, and autophagy; summarize its pathological function; and explore the potential implications of targeting ACSL4 in the treatment of various diseases.
Collapse
Affiliation(s)
- Fangquan Chen
- DAMP Laboratory, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou 511436, China
| | - Rui Kang
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX 75390, USA
| | - Jiao Liu
- DAMP Laboratory, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou 511436, China
| | - Daolin Tang
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX 75390, USA
| |
Collapse
|
|
12
|
Jin ZL, Han K, Chen HY, Zhang XY, Qiao WL, Jia BX. Exploration of phytochemicals and biological functions of Kadsura coccinea pericarpium based on LC-MS and network pharmacology analysis and experimental validation. J Funct Foods 2023. [DOI: 10.1016/j.jff.2023.105493] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/10/2023] Open
|
|
13
|
Lin J, Wang S, Lan W, Ji M, Li M. Pien Tze Huang regulates phosphorylation of metabolic enzymes in mice of hepatocellular carcinoma. Sci Rep 2023; 13:1897. [PMID: 36732657 PMCID: PMC9894829 DOI: 10.1038/s41598-023-29116-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2022] [Accepted: 01/31/2023] [Indexed: 02/04/2023] Open
Abstract
The Chinese medicine formula Pien Tze Huang (PZH) has been applied to the treatment of various diseases, the reported anti-tumor mechanisms included regulation of inflammation-associated cytokine secretion and cancer growth pathways. However, the potential influence of PZH on tumor metabolism remains unclear. This study aimed to investigate the global effect of PZH on hepatocellular carcinoma (HCC) compared with the anti-tumor agent sorafenib based on tandem mass tag (TMT) label proteomic and phosphoproteomic analysis in addition to parallel reaction monitoring (PRM) verification. It was observed that PZH could inhibit tumor weight by 59-69% in different concentrations. TMT proteomic studies indicated that fructose/mannose metabolism and glucagon signaling pathway in PZH group, and arachidonic acid metabolism and PPAR signaling pathway in sorafenib group, were significantly enriched, while glycolysis/gluconeogenesis pathway was found to be enriched remarkably both in PZH and sorafenib groups in TMT phosphoproteomic study. PRM verification further indicated that both PZH and sorafenib could down-regulate phosphorylations of the glycolytic enzymes phosphofructokinases 1, fructose-bisphosphate Aldolase A, phosphoglycerate mutase 2 and lactate dehydrogenase A chain, while phosphorylations of long chain fatty acid CoA ligase in fatty acid activation and acetyl-coenzyme A synthetase in glycolysis were significantly inhibited by PZH and sorafenib, respectively. This study proposed that PZH shared a similar anti-tumor mechanism of metabolic regulation to sorafenib, but differed in the regulation of some metabolic nodes. This is the first time to uncover the relationship between the anti-tumor effect of PZH and metabolic related enzymes, which distinguished from the known mechanisms of PZH. These data provided the potential molecular basis for PZH acting as a therapeutic drug for HCC, and offered cues of manipulation on Warburg effect under the treatment of PZH.
Collapse
Affiliation(s)
- Jinxia Lin
- Zhangzhou Pientzehuang Pharmaceutical Co., Ltd., Huporoad, Zhangzhou, 363000, People's Republic of China. .,Fujian Pien Tze Huang Enterprise Key Laboratory of Natural Medicine Research and Development, Zhangzhou, 363000, Fujian, People's Republic of China.
| | - Shicong Wang
- Zhangzhou Pientzehuang Pharmaceutical Co., Ltd., Huporoad, Zhangzhou, 363000, People's Republic of China.,Fujian Pien Tze Huang Enterprise Key Laboratory of Natural Medicine Research and Development, Zhangzhou, 363000, Fujian, People's Republic of China
| | - Wenliang Lan
- Zhangzhou Pientzehuang Pharmaceutical Co., Ltd., Huporoad, Zhangzhou, 363000, People's Republic of China.,Fujian Pien Tze Huang Enterprise Key Laboratory of Natural Medicine Research and Development, Zhangzhou, 363000, Fujian, People's Republic of China
| | - Ming Ji
- Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, People's Republic of China
| | - Mei Li
- Department of Thoracic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, People's Republic of China
| |
Collapse
|
|
14
|
Differential Mobilization of the Phospholipid and Triacylglycerol Pools of Arachidonic Acid in Murine Macrophages. Biomolecules 2022; 12:biom12121851. [PMID: 36551279 PMCID: PMC9775050 DOI: 10.3390/biom12121851] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 12/06/2022] [Accepted: 12/09/2022] [Indexed: 12/14/2022] Open
Abstract
Innate immune cells such as monocytes and macrophages contain high levels of arachidonic acid (AA), part of which can be mobilized during cellular activation for the formation of a vast array of bioactive oxygenated metabolites. Monocytes and macrophages present in inflammatory foci typically incorporate large amounts of AA, not only in membrane phospholipids, but also in neutral lipids such as triacylglycerol. Thus, it was of interest to investigate the metabolic fate of these two AA pools in macrophages. Utilizing a variety of radiolabeling techniques to distinguish the phospholipid and triacylglycerol pools, we show in this paper that during an acute stimulation of the macrophages with yeast-derived zymosan, the membrane phospholipid AA pool acts as the major, if not the only, source of releasable AA. On the contrary, the AA pool in triacylglycerol appears to be used at a later stage, when the zymosan-stimulated response has declined, as a source to replenish the phospholipid pools that were consumed during the activation process. Thus, phospholipids and triacylglycerol play different in roles AA metabolism and dynamics during macrophage activation.
Collapse
|
|
15
|
Pan PK, Wang KT, Nan FH, Wu TM, Wu YS. Red Algae “Sarcodia suieae” Acetyl-Xylogalactan Downregulate Heat-Induced Macrophage Stress Factors Ddit3 and Hyou1 Compared to the Aquatic Animal Model of Nile Tilapia (Oreochromis niloticus) Brain Arachidonic Acid Expression. Int J Mol Sci 2022; 23:ijms232314662. [PMID: 36498988 PMCID: PMC9737935 DOI: 10.3390/ijms232314662] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Revised: 11/08/2022] [Accepted: 11/15/2022] [Indexed: 11/25/2022] Open
Abstract
Anthropogenic climate change is known to be an increased stress that affects aquatic animal behavior and physiological alternations, which can induce the animal's death. In order to known whether the extracted acetyl-xylogalactan function on the regulation of the external high temperature induced death, we first selected the mammalian cell line "RAW 264.7" used in the previous experiment to evaluate the extracted acetyl-xylogalactan function. We aimed to evaluate the effects of the acetyl-xylogalactan on the RAW 264.7 macrophages and Nile Tilapia stress factor expression under the heat environment. In the in vitro cell observation, we assessed the cell survival, phagocytic activity, intracellular Ca2+ level, mitochondria potential exchange, apoptotic assay findings, galactosidase activity, RNA-seq by NGS and real-time polymerase chain reaction (QPCR) expression. In the in vivo Nile Tilapia observation aimed to evaluate the blood biochemical indicator, brain metabolites exchange and the liver morphology. In our evaluation of RAW 264.7 macrophages, the RNA sequencing and real-time polymerase chain reaction (PCR) was shown to upregulate the expression of the anti-apoptosis Cflar gene and downregulate the expression of the apoptosis factors Ddit3 and Hyou1 to protect macrophages under heat stress. We already knew the extracted acetyl-xylogalactan function on the mammalian "RAW 264.7" system. Following, we used the aquatic Nile Tilapia model as the anthropogenic climate change high temperature experiment. After feeding the Nile Tilapia with the acetyl-xylogalactan, it was found to reduce the brain arachidonic acid (AA) production, which is related to the NF-κB-induced apoptosis mechanism. Combined with the in vitro and in vivo findings, the acetyl-xylogalactan was able to reduce the heat induced cell or tissue stress.
Collapse
Affiliation(s)
- Po-Kai Pan
- Department of Aquaculture, National Pingtung University of Science and Technology, Pingtung 912, Taiwan
| | - Kuang-Teng Wang
- Department of Aquaculture, National Pingtung University of Science and Technology, Pingtung 912, Taiwan
| | - Fan-Hua Nan
- Department of Aquaculture, National Taiwan Ocean University, Keelung 202, Taiwan
| | - Tsung-Meng Wu
- Department of Aquaculture, National Pingtung University of Science and Technology, Pingtung 912, Taiwan
- Correspondence: (T.-M.W.); (Y.-S.W.); Tel.: +886-8-7703202 (ext. 6223) (Y.-S.W.)
| | - Yu-Sheng Wu
- Department of Aquaculture, National Pingtung University of Science and Technology, Pingtung 912, Taiwan
- Correspondence: (T.-M.W.); (Y.-S.W.); Tel.: +886-8-7703202 (ext. 6223) (Y.-S.W.)
| |
Collapse
|
|
16
|
Liu Y, Chen Z, Li S, Ding L, Wei X, Han S, Wang P, Sun Y. Multi-omics profiling and biochemical assays reveal the acute toxicity of environmental related concentrations of Di-(2-ethylhexyl) phthalate (DEHP) on the gill of crucian carp (Carassius auratus). CHEMOSPHERE 2022; 307:135814. [PMID: 35921887 DOI: 10.1016/j.chemosphere.2022.135814] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 06/22/2022] [Accepted: 07/20/2022] [Indexed: 06/15/2023]
Abstract
Di-(2-ethylhexyl) phthalate (DEHP) is one of the most extensively utilized plasticizers in the plastic manufacturing process. It is widely used in various fields due to its low cost and excellent effect. Although there is evidence that DEHP is harmful to animal and human health, DEHP-induced gill toxicity in aquatic organisms is inconclusive, and its mechanism has not been fully elucidated. Here, we investigated the effects of DEHP acute exposure on crucian carp gills at environmentally relevant concentrations of 20, 100, and 500 μg/L. Multi-omics profiling and biochemical assays were employed to characterize the potential toxicological mechanisms. The results showed that acute exposure to 100 and 500 μg/L of DEHP leads to oxidative stress in gills, as evidenced by overproduction of reactive oxygen species (ROS), increased antioxidant enzyme activity, and the transformation of glutathione from reduced to oxidized form, resulting in lipid peroxidation. Integrative analysis of transcriptomics and metabolomics indicated that increased purine metabolism was the potential source of increased ROS. Moreover, lipid metabolism disorder, including arachidonic acid metabolism, induces inflammation. Further, DEHP causes the imbalance of the CYP enzyme system in the gill, and DEHP-induced gill toxicity in crucian carp was associated with interference with CYP450 homeostasis. Taken together, this study broadens the molecular understanding of the DEHP-induced gill toxicity in aquatic organisms and provides novel perspectives for assessing the effects of DEHP on target and non-target aquatic organisms in the environment.
Collapse
Affiliation(s)
- Yingjie Liu
- Heilongjiang River Fisheries Research Institute of Chinese Academy of Fishery Sciences, Laboratory of Quality & Safety Risk Assessment for Aquatic Products (Harbin), Ministry of Agriculture and Rural Areas, Harbin, 150070, China; College of Food Science and Technology, Shanghai Ocean University, Shanghai, 201306, China
| | - Zhongxiang Chen
- Heilongjiang River Fisheries Research Institute of Chinese Academy of Fishery Sciences, Laboratory of Quality & Safety Risk Assessment for Aquatic Products (Harbin), Ministry of Agriculture and Rural Areas, Harbin, 150070, China
| | - Shanwei Li
- Heilongjiang River Fisheries Research Institute of Chinese Academy of Fishery Sciences, Laboratory of Quality & Safety Risk Assessment for Aquatic Products (Harbin), Ministry of Agriculture and Rural Areas, Harbin, 150070, China; College of Food Science and Technology, Shanghai Ocean University, Shanghai, 201306, China
| | - Lu Ding
- Heilongjiang River Fisheries Research Institute of Chinese Academy of Fishery Sciences, Laboratory of Quality & Safety Risk Assessment for Aquatic Products (Harbin), Ministry of Agriculture and Rural Areas, Harbin, 150070, China; College of Food Science and Technology, Shanghai Ocean University, Shanghai, 201306, China
| | - Xiaofeng Wei
- Heilongjiang River Fisheries Research Institute of Chinese Academy of Fishery Sciences, Laboratory of Quality & Safety Risk Assessment for Aquatic Products (Harbin), Ministry of Agriculture and Rural Areas, Harbin, 150070, China; College of Food Science and Engineering, Dalian Ocean University, Dalian, 116023, China
| | - Shicheng Han
- Heilongjiang River Fisheries Research Institute of Chinese Academy of Fishery Sciences, Laboratory of Quality & Safety Risk Assessment for Aquatic Products (Harbin), Ministry of Agriculture and Rural Areas, Harbin, 150070, China
| | - Peng Wang
- Heilongjiang River Fisheries Research Institute of Chinese Academy of Fishery Sciences, Laboratory of Quality & Safety Risk Assessment for Aquatic Products (Harbin), Ministry of Agriculture and Rural Areas, Harbin, 150070, China
| | - Yanchun Sun
- Heilongjiang River Fisheries Research Institute of Chinese Academy of Fishery Sciences, Laboratory of Quality & Safety Risk Assessment for Aquatic Products (Harbin), Ministry of Agriculture and Rural Areas, Harbin, 150070, China; College of Food Science and Technology, Shanghai Ocean University, Shanghai, 201306, China.
| |
Collapse
|
|
17
|
Liu Y, Xia YY, Zhang T, Yang Y, Cannon RD, Mansell T, Novakovic B, Saffery R, Han TL, Zhang H, Baker PN. Complex Interactions Between Circulating Fatty Acid Levels, Desaturase Activities, and the Risk of Gestational Diabetes Mellitus: A Prospective Cohort Study. Front Nutr 2022; 9:919357. [PMID: 35898714 PMCID: PMC9313599 DOI: 10.3389/fnut.2022.919357] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Accepted: 06/13/2022] [Indexed: 11/13/2022] Open
Abstract
ObjectiveMaternal abnormal fatty acid desaturation has previously been linked to gestational diabetes mellitus (GDM). However, few studies have investigated this relationship longitudinally throughout pregnancy. In this study, we investigated the relationship between GDM and desaturase activities across the pregnancy trimesters.MethodsA total of 661 women (GDM = 189, non-GDM = 472) were selected from the Complex Lipids in Mothers and Babies (CLIMB) cohort study. Clinical information and maternal serum were collected at 11–14, 22–28, and 32–34 weeks of gestation. Totally, 20 serum fatty acids were quantified using gas chromatography–mass spectrometry (GC-MS) analysis at each timepoint. Polyunsaturated fatty acid (PUFA) product-to-precursor ratios were used to estimate desaturase and elongase activities including delta-5 desaturase, delta-6 desaturase, stearoyl-CoA desaturase, and elongase.ResultsAfter adjusting for major potential confounders including maternal age, BMI, primiparity, smoking, and alcohol consumption, we observed a significant increase in the levels of γ-linolenic acid (GLA) and eicosatrienoic acid (DGLA) in the first trimester of women with GDM, whereas GLA and DGLA were reduced in the third trimester, when compared to the non-GDM group. Arachidonic acid (AA) showed an upward trend in the GDM group throughout pregnancy. Estimated delta-6 desaturase and delta-5 desaturase activity were elevated in the first trimester (OR = 1.40, 95% CI 1.03–1.91; OR = 0.56, 95% CI 0.32–0.96) but attenuated in the third trimester (OR = 0.78, 95% CI 0.58–1.07; OR = 2.64, 95% CI 1.46–4.78) in GDM pregnancies, respective to controls. Estimated delta-9–18 desaturase activity (OR = 3.70, 95% CI 1.49–9.19) was increased in women with GDM in later pregnancy.ConclusionsOur study highlights the potential importance of fatty acid desaturase activities, particularly estimated delta-5 desaturase and delta-9–18 desaturase in the pathophysiology of GDM. These findings may have applications for the early diagnosis and management of GDM.
Collapse
Affiliation(s)
- Yue Liu
- Department of Obstetrics and Gynaecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Department of Occupational and Environmental Hygiene, School of Public Health and Management, Research Center for Medicine and Social Development, Innovation Center for Social Risk Governance in Health, Chongqing Medical University, Chongqing, China
- Mass Spectrometry Center of Maternal Fetal Medicine, Institute of Life Sciences, Chongqing Medical University, Chongqing, China
| | - Yin-Yin Xia
- Department of Occupational and Environmental Hygiene, School of Public Health and Management, Research Center for Medicine and Social Development, Innovation Center for Social Risk Governance in Health, Chongqing Medical University, Chongqing, China
- Mass Spectrometry Center of Maternal Fetal Medicine, Institute of Life Sciences, Chongqing Medical University, Chongqing, China
| | - Ting Zhang
- Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Stomatological Hospital of Chongqing Medical University, Chongqing, China
| | - Yang Yang
- Department of Obstetrics and Gynaecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Mass Spectrometry Center of Maternal Fetal Medicine, Institute of Life Sciences, Chongqing Medical University, Chongqing, China
| | - Richard D. Cannon
- Department of Oral Sciences, Sir John Walsh Research Institute, Faculty of Dentistry, University of Otago, Dunedin, New Zealand
| | - Toby Mansell
- Molecular Immunity, Murdoch Childrens Research Institute, Melbourne, VIC, Australia
- Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia
| | - Boris Novakovic
- Molecular Immunity, Murdoch Childrens Research Institute, Melbourne, VIC, Australia
- Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia
| | - Richard Saffery
- Molecular Immunity, Murdoch Childrens Research Institute, Melbourne, VIC, Australia
- Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia
| | - Ting-Li Han
- Mass Spectrometry Center of Maternal Fetal Medicine, Institute of Life Sciences, Chongqing Medical University, Chongqing, China
- Department of Obstetrics and Gynaecology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Institute of Life Sciences, Chongqing Medical University, Chongqing, China
- Ting-Li Han
| | - Hua Zhang
- Department of Obstetrics and Gynaecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Mass Spectrometry Center of Maternal Fetal Medicine, Institute of Life Sciences, Chongqing Medical University, Chongqing, China
- *Correspondence: Hua Zhang
| | - Philip N. Baker
- College of Medicine, Biological Sciences and Psychology, University of Leicester, Leicester, United Kingdom
| |
Collapse
|
|
18
|
Mohammadihaji R, Gheibi N, Amiri S, Adibzadeh S, Abdolmaleki F, Elmi A, Rahmani B, Azad M. The effect of ω-6 fatty acid on WT1 and WIF-1 genes expression and inducing apoptosis in A375 melanoma cell line. GENE REPORTS 2022. [DOI: 10.1016/j.genrep.2022.101586] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
|
|
19
|
Liu Y, Yao M, Li S, Wei X, Ding L, Han S, Wang P, Lv B, Chen Z, Sun Y. Integrated application of multi-omics approach and biochemical assays provides insights into physiological responses to saline-alkaline stress in the gills of crucian carp (Carassius auratus). THE SCIENCE OF THE TOTAL ENVIRONMENT 2022; 822:153622. [PMID: 35124035 DOI: 10.1016/j.scitotenv.2022.153622] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 01/22/2022] [Accepted: 01/29/2022] [Indexed: 06/14/2023]
Abstract
Given the decline of freshwater resources in recent years, the accessible space for freshwater aquaculture is rapidly shrinking, and aquaculture in saline-alkaline water has become a critical approach to meet the rising demand. However, the molecular mechanism behind the adverse effects of saline-alkaline water on fish and the regulatory mechanism in fish tolerance remains unclear. Here, adult crucian carp (Carassius auratus) were exposed to 60 mmol/L NaHCO3 for 30 days. It was observed that long-term carbonate alkalinity (CA) exposure not only caused gill oxidative stress but also changed the levels of several physiological parameters associated with ammonia transport, including blood ammonia, urea nitrogen (BUN), glutamine (Gln), and glutamine synthetase (GS). According to the metabolomics study, differential metabolites (DMs) engaged in various metabolic pathways, such as glycerophospholipid metabolism, sphingolipid metabolism, and arachidonic acid metabolism. In addition, transcriptomics data showed that differentially expressed genes (DEGs) were closely related to ammonia transport, apoptosis, and immunological response. In general, comprehensive multi-omics and biochemical analysis revealed that crucian carp might adopt Rh glycoprotein as a carrier to mediate ammonia transport and increase glutamine and urea synthesis under long-term high saline-alkaline stress to mitigate the adverse effects of blocked ammonia excretion. Simultaneously, saline-alkaline stress caused the destruction of the antioxidant system and the disorder of lipid metabolism in the crucian carp gills, which induced apoptosis and immunological response. To our knowledge, this is the first study to investigate fish's molecular and metabolic mechanisms under saline-alkaline stress using integrated metabolomics, transcriptomics, and biochemical assays. Overall, the results of this study provided new insights into the molecular mechanism behind the adverse effects of saline-alkaline water on fish and the regulatory mechanism in fish tolerance.
Collapse
Affiliation(s)
- Yingjie Liu
- Heilongjiang River Fisheries Research Institute of Chinese Academy of Fishery Sciences, Laboratory of Quality & Safety Risk Assessment for Aquatic Products (Harbin), Ministry of Agriculture and Rural Areas, Harbin 150070, China; College of Food Science and Technology, Shanghai Ocean University, Shanghai 201306, China
| | - Mingzhu Yao
- Heilongjiang River Fisheries Research Institute of Chinese Academy of Fishery Sciences, Laboratory of Quality & Safety Risk Assessment for Aquatic Products (Harbin), Ministry of Agriculture and Rural Areas, Harbin 150070, China; College of Food Science and Technology, Shanghai Ocean University, Shanghai 201306, China
| | - Shanwei Li
- Heilongjiang River Fisheries Research Institute of Chinese Academy of Fishery Sciences, Laboratory of Quality & Safety Risk Assessment for Aquatic Products (Harbin), Ministry of Agriculture and Rural Areas, Harbin 150070, China; College of Food Science and Technology, Shanghai Ocean University, Shanghai 201306, China
| | - Xiaofeng Wei
- Heilongjiang River Fisheries Research Institute of Chinese Academy of Fishery Sciences, Laboratory of Quality & Safety Risk Assessment for Aquatic Products (Harbin), Ministry of Agriculture and Rural Areas, Harbin 150070, China; Department of Food Science and Engineering, School of Food Science and Engineering, Dalian Ocean University, Dalian 116023, China
| | - Lu Ding
- Heilongjiang River Fisheries Research Institute of Chinese Academy of Fishery Sciences, Laboratory of Quality & Safety Risk Assessment for Aquatic Products (Harbin), Ministry of Agriculture and Rural Areas, Harbin 150070, China; College of Food Science and Technology, Shanghai Ocean University, Shanghai 201306, China
| | - Shicheng Han
- Heilongjiang River Fisheries Research Institute of Chinese Academy of Fishery Sciences, Laboratory of Quality & Safety Risk Assessment for Aquatic Products (Harbin), Ministry of Agriculture and Rural Areas, Harbin 150070, China
| | - Peng Wang
- Heilongjiang River Fisheries Research Institute of Chinese Academy of Fishery Sciences, Laboratory of Quality & Safety Risk Assessment for Aquatic Products (Harbin), Ministry of Agriculture and Rural Areas, Harbin 150070, China
| | - Bochuan Lv
- First of Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin 150006, China
| | - Zhongxiang Chen
- Heilongjiang River Fisheries Research Institute of Chinese Academy of Fishery Sciences, Laboratory of Quality & Safety Risk Assessment for Aquatic Products (Harbin), Ministry of Agriculture and Rural Areas, Harbin 150070, China
| | - Yanchun Sun
- Heilongjiang River Fisheries Research Institute of Chinese Academy of Fishery Sciences, Laboratory of Quality & Safety Risk Assessment for Aquatic Products (Harbin), Ministry of Agriculture and Rural Areas, Harbin 150070, China; College of Food Science and Technology, Shanghai Ocean University, Shanghai 201306, China.
| |
Collapse
|
|
20
|
Hu Y, Xu Q, Li H, Meng Z, Hao M, Ma X, Lin W, Kuang H. Dapagliflozin Reduces Apoptosis of Diabetic Retina and Human Retinal Microvascular Endothelial Cells Through ERK1/2/cPLA2/AA/ROS Pathway Independent of Hypoglycemic. Front Pharmacol 2022; 13:827896. [PMID: 35281932 PMCID: PMC8908030 DOI: 10.3389/fphar.2022.827896] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Accepted: 02/04/2022] [Indexed: 12/20/2022] Open
Abstract
Introduction: It is known that the metabolic disorder caused by high glucose is one of pathogenesis in diabetic retinopathy (DR), the leading cause of blindness, due to the main pathological change of apoptosis of endothelial cells (ECs). In previous studies, the potential impact of sodium glucose cotransporter-2 (SGLT-2), whose inhibitors slow the progression of DR, has not been elucidated. The purpose of the presented study was to explore the effect of SGLT-2 inhibitors dapagliflozin (DAPA) on apoptosis of diabetic mice retina and human retinal microvascular endothelial cells (HRMECs), examine the effects of dapagliflozin on HRMECs metabolism, and explore the molecular processes that affect DR. Methods and Results: The eyeballs of male streptozotocin (STZ)-induced diabetic C57BL/6N mice were evaluated. C57BL/6N mice were divided into control group (CON), diabetic untreated group (DM), diabetic dapagliflozin treatment group (DM + DAPA) and diabetic insulin treatment group (DM + INS). Hematoxylin-Eosin (HE) staining was performed to observe the pathological structure of the mice retina, and TUNEL staining to detect apoptosis of mice retinal cells. In vitro, DCFH-DA and western blot (WB) were used to evaluate ROS, Bcl-2, BAX, cleaved-caspase 3 in HRMECs and metabolomics detected the effect of dapagliflozin on the metabolism of HRMECs. And then, we performed correlation analysis and verification functions for significantly different metabolites. In vivo, dapagliflozin reduced the apoptosis of diabetic mice retina independently of hypoglycemic. In vitro, SGLT-2 protein was expressed on HRMECs. Dapagliflozin reduced the level of ROS caused by high glucose, decreased the expression of cleaved-caspase3 and the ratio of BAX/Bcl-2. Metabolomics results showed that dapagliflozin did not affect the intracellular glucose level. Compared with the high glucose group, dapagliflozin reduced the production of arachidonic acid (AA) and inhibited the phosphorylation of ERK1/2, therefore, reducing the phosphorylation of cPLA2, which is a key enzyme for arachidonic acid release. Conclusion: Collectively, results unearthed for the first time that dapagliflozin reduced apoptosis of retina induced by DM whether in vivo or in vitro. Dapagliflozin did not affect the glucose uptake while mitigated intracellular arachidonic acid in HRMECs. Dapagliflozin alleviated HRMECs apoptosis induced by high glucose through ERK/1/2/cPLA2/AA/ROS pathway.
Collapse
Affiliation(s)
- Yuxin Hu
- The Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Qian Xu
- The Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Hongxue Li
- The Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Ziyu Meng
- The Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Ming Hao
- The Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xuefei Ma
- The Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Wenjian Lin
- The Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Hongyu Kuang
- The Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| |
Collapse
|
|
21
|
Lee H, Lee JJ, Park NY, Dubey SK, Kim T, Ruan K, Lim SB, Park SH, Ha S, Kovlyagina I, Kim KT, Kim S, Oh Y, Kim H, Kang SU, Song MR, Lloyd TE, Maragakis NJ, Hong YB, Eoh H, Lee G. Multi-omic analysis of selectively vulnerable motor neuron subtypes implicates altered lipid metabolism in ALS. Nat Neurosci 2021; 24:1673-1685. [PMID: 34782793 PMCID: PMC8639773 DOI: 10.1038/s41593-021-00944-z] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Accepted: 09/16/2021] [Indexed: 12/13/2022]
Abstract
Amyotrophic lateral sclerosis (ALS) is a devastating disorder in which motor neurons degenerate, the causes of which remain unclear. In particular, the basis for selective vulnerability of spinal motor neurons (sMNs) and resistance of ocular motor neurons to degeneration in ALS has yet to be elucidated. Here, we applied comparative multi-omics analysis of human induced pluripotent stem cell-derived sMNs and ocular motor neurons to identify shared metabolic perturbations in inherited and sporadic ALS sMNs, revealing dysregulation in lipid metabolism and its related genes. Targeted metabolomics studies confirmed such findings in sMNs of 17 ALS (SOD1, C9ORF72, TDP43 (TARDBP) and sporadic) human induced pluripotent stem cell lines, identifying elevated levels of arachidonic acid. Pharmacological reduction of arachidonic acid levels was sufficient to reverse ALS-related phenotypes in both human sMNs and in vivo in Drosophila and SOD1G93A mouse models. Collectively, these findings pinpoint a catalytic step of lipid metabolism as a potential therapeutic target for ALS.
Collapse
Affiliation(s)
- Hojae Lee
- Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- The Robert Packard Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Jae Jin Lee
- Department of Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, Los Angeles, CA, USA
| | - Na Young Park
- Department of Biochemistry, College of Medicine, Dong-A University, Busan, Korea
- Department of Translational Biomedical Sciences, Graduate School of Dong-A University, Busan, Korea
| | - Sandeep Kumar Dubey
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Taeyong Kim
- Department of Biology, San Diego State University, San Diego, CA, USA
| | - Kai Ruan
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Su Bin Lim
- Department of Biochemistry and Molecular Biology, Ajou University School of Medicine, Suwon, Korea
| | - Seong-Hyun Park
- Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Shinwon Ha
- Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Irina Kovlyagina
- Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Kyung-Tai Kim
- School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea
- Jeonbuk Branch Institute, Korea Institute of Toxicology, Jeongeup, Republic of Korea
| | - Seongjun Kim
- Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Yohan Oh
- Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Biomedical Science, Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Republic of Korea
| | - Hyesoo Kim
- Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Sung-Ung Kang
- Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Mi-Ryoung Song
- School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea
| | - Thomas E Lloyd
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Cellular and Molecular Medicine Program, School of Medicine, Johns Hopkins University, Baltimore, MD, USA
| | - Nicholas J Maragakis
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Young Bin Hong
- Department of Biochemistry, College of Medicine, Dong-A University, Busan, Korea.
- Department of Translational Biomedical Sciences, Graduate School of Dong-A University, Busan, Korea.
| | - Hyungjin Eoh
- Department of Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, Los Angeles, CA, USA.
| | - Gabsang Lee
- Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
- The Robert Packard Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
- The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
| |
Collapse
|
|
22
|
A Metabolomics Investigation of the Metabolic Changes of Raji B Lymphoma Cells Undergoing Apoptosis Induced by Zinc Ions. Metabolites 2021; 11:metabo11100689. [PMID: 34677404 PMCID: PMC8540409 DOI: 10.3390/metabo11100689] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 09/30/2021] [Accepted: 10/04/2021] [Indexed: 12/22/2022] Open
Abstract
Zinc plays a pivotal role in the function of cells and can induce apoptosis in various cancer cells, including Raji B lymphoma. However, the metabolic mechanism of Zn-induced apoptosis in Raji cells has not been explored. In this study, we performed global metabolic profiling using UPLC−Orbitrap−MS to assess the apoptosis of Raji cells induced by Zn ions released from ZnO nanorods. Multivariate analysis and database searches identified altered metabolites. Furthermore, the differences in the phosphorylation of 1380 proteins were also evaluated by Full Moon kinase array to discover the protein associated Zn−induced apoptosis. From the results, a prominent increase in glycerophosphocholine and fatty acids was observed after Zn ion treatment, but only arachidonic acid was shown to induce apoptosis. The kinase array revealed that the phosphorylation of p53, GTPase activation protein, CaMK2a, PPAR−γ, and PLA−2 was changed. From the pathway analysis, metabolic changes showed earlier onset than protein signaling, which were related to choline metabolism. LC−MS analysis was used to quantify the intracellular choline concentration, which decreased after Zn treatment, which may be related to the choline consumption required to produce choline-containing metabolites. Overall, we found that choline metabolism plays an important role in Zn-induced Raji cell apoptosis.
Collapse
|
|
23
|
Tamvapee P, Watanapokasin R. Apoptosis Induction through MAPK Signaling Pathway in LoVo Cells by Fatty Acid Fraction from Rice Bran Oil. Nutr Cancer 2021; 74:2122-2132. [PMID: 34459332 DOI: 10.1080/01635581.2021.1969418] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Colorectal cancer is one of the five leading cancer incidents and mortality in Thailand and worldwide. Fatty acids (FA) are bioactive molecules which have potential as adjunctive chemotherapeutic agents. To study the effect of fatty acid fraction (FAs) extracted from organic rice bran oil on apoptosis induction and growth inhibition in human colorectal cancer cell line, LoVo cells. The results demonstrated that FAs inhibited cell viability and induced cell death via apoptosis associated with MAPKs pathway. The EC50 of FAs in LoVo was 172.80 ± 1.05 µg/ml. FAs treatment significantly increased nuclear condensation and decreased mitochondrial membrane potential. Moreover, FAs activated Bax, Caspase-9, -7 and PARP cleavage, while inhibited Bcl-2 expression. Furthermore, FAs increased p53 expression and phosphorylation of ERK and p38. FAs extracted from organic rice bran oil inhibited LoVo cell viability and induced apoptosis via MAPKs pathway. These data suggest the potential use of FAs extracted from organic rice bran oil to prevent or treat colon cancer in the future.
Collapse
Affiliation(s)
- Patamapan Tamvapee
- Department of Biochemistry, Faculty of Medicine, Srinakharinwirot University, Bangkok, Thailand
| | - Ramida Watanapokasin
- Department of Biochemistry, Faculty of Medicine, Srinakharinwirot University, Bangkok, Thailand
| |
Collapse
|
|
24
|
Park HG, Kim JH, Dancer AN, Kothapalli KS, Brenna JT. The aromatase inhibitor letrozole restores FADS2 function in ER+ MCF7 human breast cancer cells. Prostaglandins Leukot Essent Fatty Acids 2021; 171:102312. [PMID: 34303883 DOI: 10.1016/j.plefa.2021.102312] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 06/07/2021] [Accepted: 06/09/2021] [Indexed: 12/26/2022]
Abstract
PURPOSE Plasticity in fatty acid metabolism is increasingly recognized as a major feature influencing cancer progression and efficacy of treatments. Estrogen receptor positive MCF7 human breast cancer cells have long been known to have no FADS2-mediated Δ6-desaturase activity. Our objective was to examine the effect of estrogen and the "antiestrogen" aromatase inhibitor letrozole, on Δ5- and Δ6-desaturase synthesized fatty acids in vitro. METHODS Eicosa-11,14-dienoic acid (20:2n-6), a known substrate for both FADS1 and FADS2, was used as a sentinel of relative FADS2 and FADS1 activity. MCF7 cells and four additional estrogen responsive wild type cell lines (HepG2, SK-N-SH, Y79 and Caco2) were studied. FAME were quantified by GC-FID and structures identified by GCCACI-MS/MS. RESULTS In all five cell lines, estrogen caused a dose dependent decrease in sciadonic acid (5,11,14-20:3, ScA) via apparent inhibition of FADS1 activity, and had no effect on FADS2 catalyzed synthesis of dihomo-gamma linolenic acid (8,11,14-20:3; DGLA). In MCF7 cells, letrozole caused a dose dependent increase in FADS2-catalyzed DGLA synthesis, which plateaued in SK-N-SH cells. CONCLUSION Letrozole restores Δ6-desaturase mediated synthesis of the anti-inflammatory PGE1-precursor DGLA in vitro and is the first endocrine-active agent to have opposing effects on FADS1 and FADS2 catalyzed activities.
Collapse
Affiliation(s)
- Hui Gyu Park
- Dell Pediatric Research Institute, Dell Medical School, The University of Texas at Austin, 1400 Barbara Jordan Blvd, Austin, TX, 78723, USA
| | - Jae Hun Kim
- Dell Pediatric Research Institute, Dell Medical School, The University of Texas at Austin, 1400 Barbara Jordan Blvd, Austin, TX, 78723, USA
| | - Andrew N Dancer
- Dell Pediatric Research Institute, Dell Medical School, The University of Texas at Austin, 1400 Barbara Jordan Blvd, Austin, TX, 78723, USA
| | - Kumar S Kothapalli
- Dell Pediatric Research Institute, Dell Medical School, The University of Texas at Austin, 1400 Barbara Jordan Blvd, Austin, TX, 78723, USA
| | - J Thomas Brenna
- Dell Pediatric Research Institute, Dell Medical School, The University of Texas at Austin, 1400 Barbara Jordan Blvd, Austin, TX, 78723, USA.
| |
Collapse
|
|
25
|
Feng QM, Liu MM, Cheng YX, Wu XG. Comparative proteomics elucidates the dynamics of ovarian development in the Chinese mitten crab Eriocheir sinensis. COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY D-GENOMICS & PROTEOMICS 2021; 40:100878. [PMID: 34333232 DOI: 10.1016/j.cbd.2021.100878] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/06/2021] [Revised: 06/14/2021] [Accepted: 07/05/2021] [Indexed: 11/30/2022]
Abstract
Ovarian development is a complex physiological process for crustacean reproduction that is divided into the oogonium proliferation stage, endogenous vitellogenic stage, exogenous vitellogenic stage, and oocyte maturation stage. Proteomics analysis offers a feasible approach to reveal the proteins involved in the complex physiological processes of any organism. Therefore, this study performed a comparative proteomics analysis of the ovary and hepatopancreas at three key ovarian stages, including stages I (oogonium proliferation), II (endogenous vitellogenesis) and IV (exogenous vitellogenesis), of the Chinese mitten crab Eriocheir sinensis using a label-free quantitative approach. The results showed that a total of 2,224 proteins were identified, and some key proteins related to ovarian development and nutrition metabolism were differentially expressed. The 26 key proteins were mainly involved in the ubiquitin/proteasome pathway (UPP), cyclic AMP-protein kinase A (cAMP-PKA) signaling pathway, and mitogen-activated protein kinase (MAPK) signaling pathway during oogenesis. Fifteen differentially abundant proteins (DAPs) were found to participate in vitellogenesis and oocyte development, such as vitelline membrane outer layer protein 1 homolog, vitellogenin, vitellogenin receptor, heat shock 70 kDa protein cognate 3 and farnesyl pyrophosphate synthase. Forty-seven DAPs related to nutrition metabolism were identified, including the protein digestion, fatty acid metabolism, prostaglandin metabolism, lipid digestion and transportation, i.e. short-chain specific acyl-CoA dehydrogenase, acyl-CoA desaturase, fatty acid-binding protein, long-chain fatty acid CoA ligase 4, and hematopoietic prostaglandin D synthase. These results not only indicate proteins involved in ovarian development and nutrient deposition but also enhance the understanding of the regulatory pathways and physiological processes of crustacean ovarian development.
Collapse
Affiliation(s)
- Qiang-Mei Feng
- Centre for Research on Environmental Ecology and Fish Nutrition of Ministry of Agriculture and Rural Affairs, Shanghai Ocean University, Shanghai 201306, China
| | - Mei-Mei Liu
- Key Laboratory of Marine Biotechnology of Jiangsu Province, Jiangsu Ocean University, Lianyungang 222005, China.
| | - Yong-Xu Cheng
- Centre for Research on Environmental Ecology and Fish Nutrition of Ministry of Agriculture and Rural Affairs, Shanghai Ocean University, Shanghai 201306, China; Shanghai Engineering Research Center of Aquaculture, Shanghai Ocean University, Shanghai 201306, China; National Demonstration Centre for Experimental Fisheries Science Education, Shanghai Ocean University, Shanghai 201306, China
| | - Xu-Gan Wu
- Centre for Research on Environmental Ecology and Fish Nutrition of Ministry of Agriculture and Rural Affairs, Shanghai Ocean University, Shanghai 201306, China; Shanghai Engineering Research Center of Aquaculture, Shanghai Ocean University, Shanghai 201306, China; National Demonstration Centre for Experimental Fisheries Science Education, Shanghai Ocean University, Shanghai 201306, China.
| |
Collapse
|
|
26
|
Wang X, Tan Z, Chen S, Gui L, Li X, Ke D, Hou L, Leung JYS. Norethindrone causes cellular and hepatic injury in zebrafish by compromising the metabolic processes associated with antioxidant defence: Insights from metabolomics. CHEMOSPHERE 2021; 275:130049. [PMID: 33662720 DOI: 10.1016/j.chemosphere.2021.130049] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/02/2021] [Revised: 02/08/2021] [Accepted: 02/18/2021] [Indexed: 06/12/2023]
Abstract
Progestins, such as norethindrone (NET), have been increasingly detected in aquatic environments due to their extensive use for medical applications. While NET is notorious for its endocrine disrupting effects, it has been recently shown to cause cellular damage, suggesting its potential impacts on the body defence of organisms. Hence, we examined the histological features and antioxidant defence of zebrafish (Danio rerio) after exposing to NET (50 ng/L and 500 ng/L) for 72 days, followed by analysing its metabolome to explore whether NET disturbs the metabolic processes responsible for antioxidant defence. While acute mortality was not triggered, we found that antioxidant defence was substantially weakened by NET at 500 ng/L (i.e. reduced SOD and GSH levels) and hence liver injury was inflicted (i.e. elevated ALT and MDA levels), as manifested by vacuolization of liver tissues and reduced number of normal cells in the liver. Metabolomic analysis showed that the metabolic processes responsible for antioxidant defence were disrupted by NET (e.g. upregulation of nervonyl carnitine and chenodeoxycholic acid 3-sulfate; downregulation of homolanthionine and acevaltrate) and these changes can undermine antioxidant defence by suppressing Nrf2-ARE and NF-κB pathways that contribute to the synthesis of SOD and GSH. This study demonstrates how NET can compromise the body defence of aquatic organisms via metabolic disruption, suggesting that the impacts of progestins on their fitness are more detrimental than previously thought.
Collapse
Affiliation(s)
- Xiaolan Wang
- School of Life Sciences, Guangzhou University, Guangzhou, 510655, China
| | - Zhiqing Tan
- School of Life Sciences, Guangzhou University, Guangzhou, 510655, China
| | - Shanduo Chen
- School of Life Sciences, Guangzhou University, Guangzhou, 510655, China
| | - Lin Gui
- School of Life Sciences, Guangzhou University, Guangzhou, 510655, China
| | - Xinchang Li
- College of Life Science, Zhaoqing University, Zhaoqing, 526100, China
| | - Desen Ke
- School of Life Sciences, Guangzhou University, Guangzhou, 510655, China
| | - Liping Hou
- School of Life Sciences, Guangzhou University, Guangzhou, 510655, China.
| | - Jonathan Y S Leung
- Faculty of Materials and Energy, Southwest University, Chongqing, 400715, China; School of Biological Sciences, The University of Adelaide, Adelaide, 5005, Australia.
| |
Collapse
|
|
27
|
Enhanced lipid metabolism induces the sensitivity of dormant cancer cells to 5-aminolevulinic acid-based photodynamic therapy. Sci Rep 2021; 11:7290. [PMID: 33790399 PMCID: PMC8012701 DOI: 10.1038/s41598-021-86886-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Accepted: 03/22/2021] [Indexed: 01/10/2023] Open
Abstract
Cancer can develop into a recurrent metastatic disease with latency periods of years to decades. Dormant cancer cells, which represent a major cause of recurrent cancer, are relatively insensitive to most chemotherapeutic drugs and radiation. We previously demonstrated that cancer cells exhibited dormancy in a cell density-dependent manner. Dormant cancer cells exhibited increased porphyrin metabolism and sensitivity to 5-aminolevulinic acid-based photodynamic therapy (ALA-PDT). However, the metabolic changes in dormant cancer cells or the factors that enhance porphyrin metabolism have not been fully clarified. In this study, we revealed that lipid metabolism was increased in dormant cancer cells, leading to ALA-PDT sensitivity. We performed microarray analysis in non-dormant and dormant cancer cells and revealed that lipid metabolism was remarkably enhanced in dormant cancer cells. In addition, triacsin C, a potent inhibitor of acyl-CoA synthetases (ACSs), reduced protoporphyrin IX (PpIX) accumulation and decreased ALA-PDT sensitivity. We demonstrated that lipid metabolism including ACS expression was positively associated with PpIX accumulation. This research suggested that the enhancement of lipid metabolism in cancer cells induces PpIX accumulation and ALA-PDT sensitivity.
Collapse
|
|
28
|
Kim JJ, Wilbon SS, Fornoni A. Podocyte Lipotoxicity in CKD. KIDNEY360 2021; 2:755-762. [PMID: 35373048 PMCID: PMC8791311 DOI: 10.34067/kid.0006152020] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Accepted: 02/24/2021] [Indexed: 02/06/2023]
Abstract
CKD represents the ninth most common cause of death in the United States but, despite this large health burden, treatment options for affected patients remain limited. To remedy this, several relevant pathways have been identified that may lead to novel therapeutic options. Among them, altered renal lipid metabolism, first described in 1982, has been recognized as a common pathway in clinical and experimental CKD of both metabolic and nonmetabolic origin. This observation has led many researchers to investigate the cause of this renal parenchyma lipid accumulation and its downstream effect on renal structure and function. Among key cellular components of the kidney parenchyma, podocytes are terminally differentiated cells that cannot be easily replaced when lost. Clinical and experimental evidence supports a role of reduced podocyte number in the progression of CKD. Given the importance of the podocytes in the maintenance of the glomerular filtration barrier and the accumulation of TG and cholesterol-rich lipid droplets in the podocyte and glomerulus in kidney diseases that cause CKD, understanding the upstream cause and downstream consequences of lipid accumulation in podocytes may lead to novel therapeutic opportunities. In this review, we hope to consolidate our understanding of the causes and consequences of dysregulated renal lipid metabolism in CKD development and progression, with a major focus on podocytes.
Collapse
|
|
29
|
Zheng M, Wang W, Liu J, Zhang X, Zhang R. Lipid Metabolism in Cancer Cells. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1316:49-69. [PMID: 33740243 DOI: 10.1007/978-981-33-6785-2_4] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Metabolic reprogramming is one of the most critical hallmarks in cancer cells. In the past decades, mounting evidence has demonstrated that, besides the Warburg Effect, lipid metabolism dysregulation is also one of the essential characteristics of cancer cell metabolism. Lipids are water-insoluble molecules with diverse categories of phosphoglycerides, triacylglycerides, sphingolipids, sterols, etc. As the major utilization for energy storage, fatty acids are the primary building blocks for synthesizing triacylglycerides. And phosphoglycerides, sphingolipids, and sterols are the main components constructing biological membranes. More importantly, lipids play essential roles in signal transduction by functioning as second messengers or hormones. Much evidence has shown specific alterations of lipid metabolism in cancer cells. Consequently, the structural configuration of biological membranes, the energy homeostasis under nutrient stress, and the abundance of lipids in the intracellular signal transduction are affected by these alterations. Furthermore, lipid droplets accumulate in cancer cells and function adaptively to different types of harmful stress. This chapter reviews the regulation, functions, and therapeutic benefits of targeting lipid metabolism in cancer cells. Overall, this chapter highlights the significance of exploring more potential therapeutic strategies for malignant diseases by unscrambling lipid metabolism regulation in cancer cells.
Collapse
Affiliation(s)
- Minhua Zheng
- Department of Medical Genetics and Developmental Biology, The Fourth Military Medical University, Xi'an, People's Republic of China
| | - Wei Wang
- Department of Immunology, The Fourth Military Medical University, Xi'an, People's Republic of China
| | - Jun Liu
- Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, People's Republic of China
| | - Xiao Zhang
- Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, People's Republic of China
| | - Rui Zhang
- Department of Immunology, The Fourth Military Medical University, Xi'an, People's Republic of China.
- Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, People's Republic of China.
| |
Collapse
|
|
30
|
Cruz-Gil S, Fernández LP, Sánchez-Martínez R, Gómez de Cedrón M, Ramírez de Molina A. Non-Coding and Regulatory RNAs as Epigenetic Remodelers of Fatty Acid Homeostasis in Cancer. Cancers (Basel) 2020; 12:E2890. [PMID: 33050166 PMCID: PMC7599548 DOI: 10.3390/cancers12102890] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Revised: 10/05/2020] [Accepted: 10/07/2020] [Indexed: 02/06/2023] Open
Abstract
Cancer cells commonly display metabolic fluctuations. Together with the Warburg effect and the increased glutaminolysis, alterations in lipid metabolism homeostasis have been recognized as a hallmark of cancer. Highly proliferative cancer cells upregulate de novo synthesis of fatty acids (FAs) which are required to support tumor progression by exerting multiple roles including structural cell membrane composition, regulators of the intracellular redox homeostasis, ATP synthesis, intracellular cell signaling molecules, and extracellular mediators of the tumor microenvironment. Epigenetic modifications have been shown to play a crucial role in human development, but also in the initiation and progression of complex diseases. The study of epigenetic processes could help to design new integral strategies for the prevention and treatment of metabolic disorders including cancer. Herein, we first describe the main altered intracellular fatty acid processes to support cancer initiation and progression. Next, we focus on the most important regulatory and non-coding RNAs (small noncoding RNA-sncRNAs-long non-coding RNAs-lncRNAs-and other regulatory RNAs) which may target the altered fatty acids pathway in cancer.
Collapse
Affiliation(s)
| | | | | | - Marta Gómez de Cedrón
- Correspondence: (M.G.d.C.); (A.R.d.M.); Tel.: +34-67-213-49-21 (A.R.d.M.); Fax: +34-91-830-59-61 (A.R.d.M.)
| | - Ana Ramírez de Molina
- Laboratory of Molecular Oncology, IMDEA-Food Institute, CEI UAM + CSIC, 28049 Madrid, Spain; (S.C.-G.); (L.P.F.); (R.S.-M.)
| |
Collapse
|
|
31
|
Wang J, Wang Z, Yuan J, Wang J, Shen X. The positive feedback between ACSL4 expression and O-GlcNAcylation contributes to the growth and survival of hepatocellular carcinoma. Aging (Albany NY) 2020; 12:7786-7800. [PMID: 32357142 PMCID: PMC7244051 DOI: 10.18632/aging.103092] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2019] [Accepted: 04/13/2020] [Indexed: 06/01/2023]
Abstract
Acyl-CoA ligase 4 (ACSL4) has been reported to be overexpressed in hepatocellular carcinoma (HCC) and to enhance cell proliferation. However, the molecular mechanisms underlying the role of ACSL4 in HCC progression remain largely unclear. Here, we aimed to investigate whether and how O-GlcNAcylation and ACSL4 regulate each other and HCC progression. The clinical significance of ACSL4, O-GlcNAc and GLUT1 in HCC was determined by Pearson chi-squared test and Kaplan-Meier analysis. CCK-8, flow cytometry and in vivo tumour formation assays were performed to detect cell proliferation, apoptosis and tumorigenesis. IP technology was used to evaluate the relationship between ACSL4 and O-GlcNAc. ACSL4, GLUT1 and O-GlcNAc levels were elevated in HCC tissues and predicted poor prognosis in HCC patients. ACSL4 overexpression significantly promoted cell proliferation and tumorigenesis and inhibited cell apoptosis, whereas these effects were all obviously impaired when mTOR signalling was repressed or GLUT1 was downregulated. ACSL4 could be O-GlcNAcylated, and silencing of ACSL4 abolished the effects of O-GlcNAcylation on cell growth promotion and apoptosis inhibition. Collectively, this study demonstrates that ACSL4 contributes to the growth and survival of HCC by enhancing GLUT1-mediated O-GlcNAcylation. In turn, O-GlcNAcylation promotes HCC growth partially by increasing ACSL4 expression.
Collapse
Affiliation(s)
- Jiachen Wang
- Department of Minimally Invasive Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
| | - Zhao Wang
- Department of Minimally Invasive Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
| | - Jiaxiang Yuan
- Department of Minimally Invasive Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
| | - Jiaxiang Wang
- Department of Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
| | - Xinsheng Shen
- Department of Minimally Invasive Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
| |
Collapse
|
|
32
|
Gharib E, Nasri Nasrabadi P, Reza Zali M. miR-497-5p mediates starvation-induced death in colon cancer cells by targeting acyl-CoA synthetase-5 and modulation of lipid metabolism. J Cell Physiol 2020; 235:5570-5589. [PMID: 32012265 DOI: 10.1002/jcp.29488] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2019] [Accepted: 01/09/2020] [Indexed: 12/12/2022]
Abstract
Modulation of fatty acids metabolism is an appropriate strategy for starvation-induced death in tumor cancers. Colon cancer cells express a high level of acyl-CoA synthetase-5 (ACSL5), and as yet no therapeutic approach has been achieved. Herein, ACSL5-related microRNAs (miRNAs) were identified via TargetScan, and their impacts on ACSL5 and lipid content along with metabolic activity, cell cycle, migration, and invasion of colorectal cancer (CRC) cells were examined, and subsequently compared with transcriptome for better visualization of intracellular-signaling networks. In vivo analysis was performed using BALB/c mice xenograft model of CRC injected with target miRNA. Clinical significances were also evaluated in 80 CRC tumors and matched adjacent normal tissues. There was a reverse correlation between ACSL5 and miR-497-5p, which miR-497-5p overexpression modulated CRC cell proliferation and development. A similar observation was received from the in vivo examination in which intratumoral injection of miR-497-5p reversed the tumor growth in the CRC xenograft model. Downregulation of miR-497-5p correlated with tumor differentiation, tumor, node, and metastasis staging, lymph node metastasis, and poor survival in patients with CRC. These results suggested that miR-497-5p upregulation could be considered as a therapeutic strategy for modulation of lipid metabolism in colon cancer.
Collapse
Affiliation(s)
- Ehsan Gharib
- Department of Molecular Biology, Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Parinaz Nasri Nasrabadi
- Department of Molecular Biology, Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.,Department of Molecular Medicine, Institute of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology, Tehran, Iran
| | - Mohammad Reza Zali
- Department of Gastrointestinal Cancer, Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| |
Collapse
|
|
33
|
Koundouros N, Poulogiannis G. Reprogramming of fatty acid metabolism in cancer. Br J Cancer 2020; 122:4-22. [PMID: 31819192 PMCID: PMC6964678 DOI: 10.1038/s41416-019-0650-z] [Citation(s) in RCA: 965] [Impact Index Per Article: 193.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Revised: 10/21/2019] [Accepted: 11/01/2019] [Indexed: 02/08/2023] Open
Abstract
A common feature of cancer cells is their ability to rewire their metabolism to sustain the production of ATP and macromolecules needed for cell growth, division and survival. In particular, the importance of altered fatty acid metabolism in cancer has received renewed interest as, aside their principal role as structural components of the membrane matrix, they are important secondary messengers, and can also serve as fuel sources for energy production. In this review, we will examine the mechanisms through which cancer cells rewire their fatty acid metabolism with a focus on four main areas of research. (1) The role of de novo synthesis and exogenous uptake in the cellular pool of fatty acids. (2) The mechanisms through which molecular heterogeneity and oncogenic signal transduction pathways, such as PI3K-AKT-mTOR signalling, regulate fatty acid metabolism. (3) The role of fatty acids as essential mediators of cancer progression and metastasis, through remodelling of the tumour microenvironment. (4) Therapeutic strategies and considerations for successfully targeting fatty acid metabolism in cancer. Further research focusing on the complex interplay between oncogenic signalling and dysregulated fatty acid metabolism holds great promise to uncover novel metabolic vulnerabilities and improve the efficacy of targeted therapies.
Collapse
Affiliation(s)
- Nikos Koundouros
- Signalling and Cancer Metabolism Team, Division of Cancer Biology, The Institute of Cancer Research, 237 Fulham Road, London, SW3 6JB, UK
| | - George Poulogiannis
- Signalling and Cancer Metabolism Team, Division of Cancer Biology, The Institute of Cancer Research, 237 Fulham Road, London, SW3 6JB, UK.
- Division of Computational and Systems Medicine, Department of Surgery and Cancer, Imperial College London, London, SW7 2AZ, UK.
| |
Collapse
|
|
34
|
Li Y, Kasim V, Yan X, Li L, Meliala ITS, Huang C, Li Z, Lei K, Song G, Zheng X, Wu S. Yin Yang 1 facilitates hepatocellular carcinoma cell lipid metabolism and tumor progression by inhibiting PGC-1β-induced fatty acid oxidation. Theranostics 2019; 9:7599-7615. [PMID: 31695789 PMCID: PMC6831470 DOI: 10.7150/thno.34931] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2019] [Accepted: 09/08/2019] [Indexed: 12/11/2022] Open
Abstract
Lipid accumulation is a driving force in tumor development, as it provides tumor cells with both energy and the building blocks of phospholipids for construction of cell membranes. Aberrant homeostasis of lipid metabolism has been observed in various tumors; however, the molecular mechanism has not been fully elucidated. Methods: Yin yang 1 (YY1) expression in hepatocellular carcinoma (HCC) was analyzed using clinical specimens, and its roles in HCC in lipid metabolism were examined using gain- and loss-of function experiments. The mechanism of YY1 regulation on peroxisome proliferator-activated receptor gamma coactivator-1β (PGC-1β) and its downstream genes medium-chain acyl-CoA dehydrogenase (MCAD) and long-chain acyl-CoA dehydrogenase (LCAD) were investigated using molecular biology and biochemical methods. The role of YY1/ PGC-1β axis in hepatocarcinogenesis was studied using xenograft experiment. Results: This study showed that YY1 suppresses fatty acid β-oxidation, leading to increase of cellular triglyceride level and lipid accumulation in HCC cells, and subsequently induction of the tumorigenesis potential of HCC cells. Molecular mechanistic study revealed that YY1 blocks the expression of PGC-1β, an activator of fatty acid β-oxidation, by directly binding to its promoter; and thus downregulates PGC-1β/MCAD and PGC1-β/LCAD axis. Importantly, we revealed that YY1 inhibition on PGC-1β occurs irrespective of the expression of hypoxia-inducible factor-1α (HIF1-α), enabling it to promote lipid accumulation under both normoxic and hypoxic conditions. Conclusion: Our study reveals the critical role of YY1/PGC-1β axis in HCC cell lipid metabolism, providing novel insight into the molecular mechanisms associated with tumor cell lipid metabolism, and a new perspective regarding the function of YY1 in tumor progression. Thus, our study provides evidences regarding the potential of YY1 as a target for lipid metabolism-based anti-tumor therapy.
Collapse
|
|
35
|
Ayiomamitis GD, Notas G, Vasilakaki T, Tsavari A, Vederaki S, Theodosopoulos T, Kouroumalis E, Zaravinos A. Understanding the Interplay between COX-2 and hTERT in Colorectal Cancer Using a Multi-Omics Analysis. Cancers (Basel) 2019; 11:1536. [PMID: 31614548 PMCID: PMC6827032 DOI: 10.3390/cancers11101536] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2019] [Revised: 09/07/2019] [Accepted: 10/08/2019] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Cyclooxygenase 2 (COX-2) is involved in the initial steps of colorectal cancer (CRC) formation, playing a key role in the catalysis of arachidonic acid to prostaglandin E2 (PGE2). The human telomerase reverse transcriptase (hTERT or TERT) also plays an important role in colorectal cancer growth, conferring sustained cell proliferation and survival. Although hTERT induces COX-2 expression in gastric and cervical cancer, their interaction has not been investigated in the context of CRC. METHODS COX-2, PGE2 levels, and telomerase activity were evaluated by immunohistochemistry, ELISA, and TRAP assay in 49 colorectal cancer samples. PTGS1, PTGS2, PTGES3, TERT mRNA, and protein levels were investigated using RNA-seq and antibody-based protein profiling data from the TCGA and HPA projects. A multi-omics comparison was performed between PTGS2 and TERT, using RNAseq, DNA methylation, copy number variations (CNVs), single nucleotide polymorphisms (SNPs), and insertions/deletions (Indels) data. RESULTS COX-2 expression was positive in 40/49 CRCs, bearing cytoplasmic and heterogeneous staining, from moderate to high intensity. COX-2 staining was mainly detected in the stroma of the tumor cells and the adjacent normal tissues. PGE2 expression was lower in CRC compared to the adjacent normal tissue, and inversely correlated to telomerase activity in right colon cancers. COX-1 and COX-2 were anticorrelated with TERT. Isoform structural analysis revealed the most prevalent transcripts driving the differential expression of PTGS1, PTGS2, PTGES3, and TERT in CRC. COX-2 expression was significantly higher among B-Raf proto-oncogene, serine/threonine kinase, mutant (BRAFmut) tumors. Kirsten ras oncogene (KRAS) mutations did not affect COX-2 or TERT expression. The promoter regions of COX-2 and TERT were reversely methylated. CONCLUSIONS Our data support that COX-2 is involved in the early stages of colorectal cancer development, initially affecting the tumor's stromal microenvironment, and, subsequently, the epithelial cells. They also highlight an inverse correlation between COX-2 expression and telomerase activity in CRC, as well as differentially methylated patterns within the promoter regions of COX-2 and TERT.
Collapse
Affiliation(s)
- Georgios D Ayiomamitis
- Laboratory of Gastroenterology Research, University of Crete, School of Medicine, 71013 Heraklion, Greece.
- 1st Department of Surgery, Tzaneio General Hospital, 18536 Piraeus, Greece.
| | - George Notas
- Laboratory of Gastroenterology Research, University of Crete, School of Medicine, 71013 Heraklion, Greece.
- Laboratory of Experimental Endocrinology, University of Crete, School of Medicine, 71013 Heraklion, Greece.
| | - Thivi Vasilakaki
- Department of Pathology, Tzaneio General Hospital, 18536 Piraeus, Greece.
| | - Aikaterini Tsavari
- Department of Pathology, Tzaneio General Hospital, 18536 Piraeus, Greece.
| | - Styliani Vederaki
- 1st Department of Surgery, Tzaneio General Hospital, 18536 Piraeus, Greece.
| | - Theodosis Theodosopoulos
- 2nd Department of Surgery, Aretaieion Hospital, Medical School, National and Kapodistrian University of Athens, 11528 Athens, Greece.
| | - Elias Kouroumalis
- Laboratory of Gastroenterology Research, University of Crete, School of Medicine, 71013 Heraklion, Greece.
- Department of Gastroenterology and Hepatology, University Hospital of Heraklion, 71013 Heraklion, Greece.
| | - Apostolos Zaravinos
- Department of Life Sciences European University Cyprus, Nicosia 1516, Cyprus.
| |
Collapse
|
|
36
|
Role of acyl-CoA synthetase ACSL4 in arachidonic acid metabolism. Prostaglandins Other Lipid Mediat 2019; 144:106363. [DOI: 10.1016/j.prostaglandins.2019.106363] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2019] [Revised: 06/15/2019] [Accepted: 07/11/2019] [Indexed: 12/12/2022]
|
|
37
|
Bratton BA, Maly IV, Hofmann WA. Effect of polyunsaturated fatty acids on proliferation and survival of prostate cancer cells. PLoS One 2019; 14:e0219822. [PMID: 31314803 PMCID: PMC6636762 DOI: 10.1371/journal.pone.0219822] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Accepted: 07/03/2019] [Indexed: 11/23/2022] Open
Abstract
Progression of prostate cancer to lethal forms is marked by emergence of hormone-independent proliferation of the cancer cells. Nutritional and epidemiological studies have indicated that prostate cancer progression is correlated with the consumption of polyunsaturated fatty acids (PUFA). To shed additional light on the cell-level mechanisms of the observed correlation, we compared the sensitivity of hormone-dependent and hormone-independent prostate cancer cells to growth medium supplementation with free PUFAs in a cell proliferation and viability assay. Our data show that the hormone-dependent cells are comparatively insensitive to various PUFAs, at the same time as the growth and viability of hormone-independent cells lines are strongly inhibited by most of the tested PUFAs, whether n–3 or n–6. We speculate that this difference may be at least partially responsible for the observed effects of specific dietary lipids in prostate cancer. The new data strengthen the case for dietary intervention as part of potential new therapeutic strategies seeking to impede prostate cancer progression.
Collapse
Affiliation(s)
- Brenden A. Bratton
- Department of Physiology and Biophysics, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, United States of America
| | - Ivan V. Maly
- Department of Physiology and Biophysics, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, United States of America
| | - Wilma A. Hofmann
- Department of Physiology and Biophysics, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, United States of America
- * E-mail:
| |
Collapse
|
|
38
|
Li Z, Wang ZC, Li X, Abbas M, Wu SY, Ren SZ, Liu QX, Liu Y, Chen PW, Duan YT, Lv PC, Zhu HL. Design, synthesis and evaluation of novel diaryl-1,5-diazoles derivatives bearing morpholine as potent dual COX-2/5-LOX inhibitors and antitumor agents. Eur J Med Chem 2019; 169:168-184. [DOI: 10.1016/j.ejmech.2019.03.008] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2018] [Revised: 03/04/2019] [Accepted: 03/04/2019] [Indexed: 12/31/2022]
|
|
39
|
Yan XQ, Wang ZC, Zhang B, Qi PF, Li GG, Zhu HL. Dihydropyrazole Derivatives Containing Benzo Oxygen Heterocycle and Sulfonamide Moieties Selectively and Potently Inhibit COX-2: Design, Synthesis, and Anti-Colon Cancer Activity Evaluation. Molecules 2019; 24:molecules24091685. [PMID: 31052167 PMCID: PMC6539903 DOI: 10.3390/molecules24091685] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Revised: 04/17/2019] [Accepted: 04/18/2019] [Indexed: 01/19/2023] Open
Abstract
Cyclooxygenase-2 (COX-2) as a rate-limiting metabolism enzyme of arachidonic acid has been found to be implicated in tumor occurrence, angiogenesis, metastasis as well as apoptosis inhibition, regarded as an attractive therapeutic target for cancer therapy. In our research, a series of dihydropyrazole derivatives containing benzo oxygen heterocycle and sulfonamide moieties were designed as highly potent and selective COX-2 inhibitors by computer-aided drug analysis of known COX-2 inhibitors. A total of 26 compounds were synthesized and evaluated COX-2 inhibition and pharmacological efficiency both in vitro and in vivo with multi-angle of view. Among them, compound 4b exhibited most excellent anti-proliferation activities against SW620 cells with IC50 of 0.86 ± 0.02 µM than Celecoxib (IC50 = 1.29 ± 0.04 µM). The results favored our rational design intention and provides compound 4b as an effective COX-2 inhibitor available for the development of colon tumor therapeutics.
Collapse
Affiliation(s)
- Xiao-Qiang Yan
- State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210023, China.
- Jiangsu Key Laboratory of Advanced Organic Materials, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, China.
| | - Zhong-Chang Wang
- State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210023, China.
| | - Bo Zhang
- State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210023, China.
| | - Peng-Fei Qi
- State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210023, China.
| | - Gui-Gen Li
- Jiangsu Key Laboratory of Advanced Organic Materials, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, China.
| | - Hai-Liang Zhu
- State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210023, China.
| |
Collapse
|
|
40
|
Zhu XC, Zhang T. Antitumor mechanisms of cyclooxygenase and lipoxygenase. Shijie Huaren Xiaohua Zazhi 2018; 26:2029-2035. [DOI: 10.11569/wcjd.v26.i35.2029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Eicosanoids, as the metabolic product of arachidonic acid, play an important role in tumor development and metastasis. Cyclooxygenase (COX)-2 and lipoxygenase (LOX) are two key enzymes that mediate the metabolism of arachidonic acid. So far, great progress has been made on the research of COX-2 and prostaglandins, and it has been demonstrated that they can induce the imbalance between cell growth and apoptosis as well as tumor angiogenesis. LOX and its metabolites, such as hydroxyeicosatetraenoic acid (HETE) and leukotriene (LT), have received more and more attention for their role in tumor development. Research has proved that LT-B4 and 5-HETE participate in the occurrence and development of multiple tumors. Therefore, COX and LOX dual inhibitors prove a new approach to anti-tumor therapy.
Collapse
Affiliation(s)
- Xiao-Chao Zhu
- Department of General Surgery, Suqian First Hospital, Suqian 223800, Jiangsu Province, China
| | - Tuo Zhang
- Department of General Surgery, Suqian First Hospital, Suqian 223800, Jiangsu Province, China
| |
Collapse
|
|
41
|
Targeting the mitochondrial apoptosis pathway by a newly synthesized COX-2 inhibitor in pediatric ALL lymphocytes. Future Med Chem 2018; 10:2277-2289. [PMID: 30304948 DOI: 10.4155/fmc-2018-0032] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
AIM Acute lymphoblastic leukemia (ALL) is known as a barely curable malignancy. Particular mutations involved in apoptosis may have a main role in the onset of ALL in the pediatric patients. It has been proven that cycloxygenase-2 is capable of impairing the apoptosis pathway through mitochondria in tumor cells. METHODOLOGY In this study, we investigated selective toxicity of a newly synthesized chalconeferrocenyl derivative as a selective cycloxygenase-2 inhibitor in ALL and healthy B-lymphocytes, and also isolated mitochondria obtained from them. For this purpose, we evaluated the cellar parameters like viability, apoptosis/necrosis, caspase-3 activation and ATP content, and also mitochondrial parameters like mitochondrial membrane potential decline, reactive oxygen species formation, cytochrome C release and mitochondrial swelling. CONCLUSION Our results implied that this compound can selectively induce cellular and mitochondrial toxicity in cancerous ALL B-lymphocytes and obtained mitochondria from them without any detrimental effects on healthy subjects.
Collapse
|
|
42
|
Park HG, Zhang JY, Foster C, Sudilovsky D, Schwed DA, Mecenas J, Devapatla S, Lawrence P, Kothapalli KSD, Brenna JT. A rare eicosanoid precursor analogue, sciadonic acid (5Z,11Z,14Z-20:3), detected in vivo in hormone positive breast cancer tissue. Prostaglandins Leukot Essent Fatty Acids 2018; 134:1-6. [PMID: 29886893 PMCID: PMC5999340 DOI: 10.1016/j.plefa.2018.05.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2018] [Revised: 05/10/2018] [Accepted: 05/10/2018] [Indexed: 02/06/2023]
Abstract
Numerous genetic alterations of HSA 11q13 are found frequently in several cancer types, including breast cancer (BC). The 11q13 locus harbors FADS2 encoding Δ6 desaturation which is not functional in several cancer cell lines, including hormone positive MCF7 BC cells. In vitro, the non-functional FADS2 activity unmasks 18:2n-6 elongation to 20:2n-6 and Δ5 desaturation by FADS1 to yield 5Z,11Z,14Z-20:3 (sciadonic acid) rather than 5Z,8Z,11Z,14Z-20:4 (arachidonic acid). In this pilot study we aimed to determine whether 5,11,14-20:3 appears in vivo in hormone positive human BC tissue. Fatty acids were profiled in surgically removed human breast tumor and adjacent normal tissue (n = 9). Sciadonic acid was detected in three of nine breast tumor samples and was below detect limits in normal breast tissue. The internal Δ8 double bond of arachidonic acid is required for normal eicosanoid synthesis but is missing in sciadonic acid. This pilot study demonstrates for the first time in vivo sciadonic acid in hormone positive BC tissue, warranting a larger survey study to further evaluate its appearance and the functional implications.
Collapse
Affiliation(s)
- H G Park
- Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA; Dell Pediatric Research Institute and Dept. of Pediatrics, Dell Medical School, The University of Texas at Austin, 1400 Barbara Jordan Blvd, Austin, TX 78723, USA
| | - J Y Zhang
- Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA; Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA 02118, USA
| | - C Foster
- Cayuga Medical Center, 101 Dates Drive, Ithaca, NY 14850, USA
| | - D Sudilovsky
- Cayuga Medical Center, 101 Dates Drive, Ithaca, NY 14850, USA
| | - D A Schwed
- Cayuga Medical Center, 101 Dates Drive, Ithaca, NY 14850, USA
| | - J Mecenas
- Cayuga Medical Center, 101 Dates Drive, Ithaca, NY 14850, USA
| | - S Devapatla
- Cayuga Medical Center, 101 Dates Drive, Ithaca, NY 14850, USA
| | - P Lawrence
- Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA
| | - K S D Kothapalli
- Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA; Dell Pediatric Research Institute and Dept. of Pediatrics, Dell Medical School, The University of Texas at Austin, 1400 Barbara Jordan Blvd, Austin, TX 78723, USA.
| | - J T Brenna
- Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA; Dell Pediatric Research Institute and Dept. of Pediatrics, Dell Medical School, The University of Texas at Austin, 1400 Barbara Jordan Blvd, Austin, TX 78723, USA; Department of Chemistry, The University of Texas at Austin, 1400 Barbara Jordan Blvd, Austin, TX 78723, USA.
| |
Collapse
|
|
43
|
Aliwarga T, Evangelista EA, Sotoodehnia N, Lemaitre RN, Totah RA. Regulation of CYP2J2 and EET Levels in Cardiac Disease and Diabetes. Int J Mol Sci 2018; 19:E1916. [PMID: 29966295 PMCID: PMC6073148 DOI: 10.3390/ijms19071916] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2018] [Revised: 06/24/2018] [Accepted: 06/25/2018] [Indexed: 12/13/2022] Open
Abstract
Cytochrome P450 2J2 (CYP2J2) is a known arachidonic acid (AA) epoxygenase that mediates the formation of four bioactive regioisomers of cis-epoxyeicosatrienoic acids (EETs). Although its expression in the liver is low, CYP2J2 is mainly observed in extrahepatic tissues, including the small intestine, pancreas, lung, and heart. Changes in CYP2J2 levels or activity by xenobiotics, disease states, or polymorphisms are proposed to lead to various organ dysfunctions. Several studies have investigated the regulation of CYP2J2 and EET formation in various cell lines and have demonstrated that such regulation is tissue-dependent. In addition, studies linking CYP2J2 polymorphisms to the risk of developing cardiovascular disease (CVD) yielded contradictory results. This review will focus on the mechanisms of regulation of CYP2J2 by inducers, inhibitors, and oxidative stress modeling certain disease states in various cell lines and tissues. The implication of CYP2J2 expression, polymorphisms, activity and, as a result, EET levels in the pathophysiology of diabetes and CVD will also be discussed.
Collapse
Affiliation(s)
- Theresa Aliwarga
- Department of Medicinal Chemistry, University of Washington, Seattle, WA 98101, USA.
| | - Eric A Evangelista
- Department of Medicinal Chemistry, University of Washington, Seattle, WA 98101, USA.
| | - Nona Sotoodehnia
- Cardiovascular Health Research Unit, University of Washington, Seattle, WA 98195, USA.
- Department of Medicine, University of Washington, Seattle, WA 98195, USA.
- Division of Cardiology, University of Washington, Seattle, WA 98195, USA.
| | - Rozenn N Lemaitre
- Cardiovascular Health Research Unit, University of Washington, Seattle, WA 98195, USA.
| | - Rheem A Totah
- Department of Medicinal Chemistry, University of Washington, Seattle, WA 98101, USA.
| |
Collapse
|
|
44
|
Ortea I, González-Fernández MJ, Ramos-Bueno RP, Guil-Guerrero JL. Proteomics Study Reveals That Docosahexaenoic and Arachidonic Acids Exert Different In Vitro Anticancer Activities in Colorectal Cancer Cells. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2018; 66:6003-6012. [PMID: 29804451 DOI: 10.1021/acs.jafc.8b00915] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
Two polyunsaturated fatty acids, docosahexaenoic acid (DHA) and arachidonic acid (ARA), as well as derivatives, such as eicosanoids, regulate different activities, affecting transcription factors and, therefore, DNA transcription, being a critical step for the functioning of fatty-acid-derived signaling. This work has attempted to determine the in vitro anticancer activities of these molecules linked to the gene transcription regulation of HT-29 colorectal cancer cells. We applied the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide test along with lactate dehydrogenase and caspase-3 assays; proteome changes were assessed by "sequential windowed acquisition of all theoretical mass spectra" quantitative proteomics, followed by pathway analysis, to determine the affected molecular mechanisms. In all assays, DHA inhibited cell proliferation of HT-29 cells to a higher extent than ARA and acted primarily by downregulating proteasome particles, while ARA presented a dramatic effect on all six DNA replication helicase particles. The results indicated that both DHA and ARA are potential chemopreventive agent candidates.
Collapse
Affiliation(s)
- Ignacio Ortea
- Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofía , Universidad de Córdoba , E14004 Córdoba , Spain
| | - María José González-Fernández
- Food Technology Division, Agrifood Campus of International Excellence (ceiA3) , University of Almería , E40120 Almería , Spain
| | - Rebeca P Ramos-Bueno
- Food Technology Division, Agrifood Campus of International Excellence (ceiA3) , University of Almería , E40120 Almería , Spain
| | - José Luis Guil-Guerrero
- Food Technology Division, Agrifood Campus of International Excellence (ceiA3) , University of Almería , E40120 Almería , Spain
| |
Collapse
|
|
45
|
Tang Y, Zhou J, Hooi SC, Jiang YM, Lu GD. Fatty acid activation in carcinogenesis and cancer development: Essential roles of long-chain acyl-CoA synthetases. Oncol Lett 2018; 16:1390-1396. [PMID: 30008815 DOI: 10.3892/ol.2018.8843] [Citation(s) in RCA: 93] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2018] [Accepted: 05/22/2018] [Indexed: 12/12/2022] Open
Abstract
The significance of fatty acid metabolism in cancer initiation and development is increasingly accepted by scientists and the public due to the high prevalence of overweight and obese individuals. Fatty acids have different turnovers in the body: Either breakdown into acetyl-CoA to aid ATP generation through catabolic metabolism or incorporation into triacylglycerol and phospholipid through anabolic metabolism. However, these two distinct pathways require a common initial step known as fatty acid activation. Long-chain acyl-CoA synthetases (ACSLs), which are responsible for activation of the most abundant long-chain fatty acids, are commonly deregulated in cancer. This deregulation is also associated with poor survival in patients with cancer. Fatty acids physiologically regulate ACSL expression, but cancer cells could hijack certain involved regulatory mechanisms to deregulate ACSLs. Among the five family isoforms, ACSL1 and ACSL4 are able to promote ungoverned cell growth, facilitate tumor invasion and evade programmed cell death, while ACSL3 may have relatively complex functions in different types of cancer. Notably, ACSL4 is also essential for the induction of ferroptosis (another form of programmed cell death) by facilitating arachidonic acid oxidation, which makes the enzyme a desirable cancer target. The present review thus evaluates the functions of deregulated ACSLs in cancer, the possible molecular mechanisms involved and the chemotherapeutic potentials to target ACSLs. A better understanding of the pathological effects of ACSLs in cancer and the involved molecular mechanisms will aid in delineating the exact role of fatty acid metabolism in cancer and designing precise cancer prevention and treatment strategies.
Collapse
Affiliation(s)
- Yue Tang
- Department of Toxicology, School of Public Health, Guangxi Medical University, Nanning, Guangxi 530021, P.R. China.,Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases, Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Jing Zhou
- Department of Physiology, School of Preclinical Medicine, Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Shing Chuan Hooi
- Department of Physiology, Yong Loo Lim School of Medicine, National University of Singapore, Singapore 117543, Republic of Singapore
| | - Yue-Ming Jiang
- Department of Toxicology, School of Public Health, Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Guo-Dong Lu
- Department of Toxicology, School of Public Health, Guangxi Medical University, Nanning, Guangxi 530021, P.R. China.,Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases, Guangxi Medical University, Nanning, Guangxi 530021, P.R. China.,Key Laboratory of High-Incidence-Tumor Prevention and Treatment, Guangxi Medical University, Ministry of Education of China, Nanning, Guangxi 530021, P.R. China
| |
Collapse
|
|
46
|
Pascual G, Domínguez D, Benitah SA. The contributions of cancer cell metabolism to metastasis. Dis Model Mech 2018; 11:11/8/dmm032920. [PMID: 29739810 PMCID: PMC6124557 DOI: 10.1242/dmm.032920] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Metastasis remains the leading cause of cancer-related deaths worldwide, and our inability to identify the tumour cells that colonize distant sites hampers the development of effective anti-metastatic therapies. However, with recent research advances we are beginning to distinguish metastasis-initiating cells from their non-metastatic counterparts. Importantly, advances in genome sequencing indicate that the acquisition of metastatic competency does not involve the progressive accumulation of driver mutations; moreover, in the early stages of tumorigenesis, cancer cells harbour combinations of driver mutations that endow them with metastatic competency. Novel findings highlight that cells can disseminate to distant sites early during primary tumour growth, remaining dormant and untreatable for long periods before metastasizing. Thus, metastatic cells must require local and systemic influences to generate metastases. This hypothesis suggests that factors derived from our lifestyle, such as our diet, exert a strong influence on tumour progression, and that such factors could be modulated if understood. Here, we summarize the recent findings on how specific metabolic cues modulate the behaviour of metastatic cells and how they influence the genome and epigenome of metastatic cells. We also discuss how crosstalk between metabolism and the epigenome can be harnessed to develop new anti-metastatic therapies.
Collapse
Affiliation(s)
- Gloria Pascual
- Institute for Research in Biomedicine (IRB Barcelona), Oncology Department, The Barcelona Institute of Science and Technology (BIST), 08028, Barcelona, Spain
| | - Diana Domínguez
- Institute for Research in Biomedicine (IRB Barcelona), Oncology Department, The Barcelona Institute of Science and Technology (BIST), 08028, Barcelona, Spain
| | - Salvador Aznar Benitah
- Institute for Research in Biomedicine (IRB Barcelona), Oncology Department, The Barcelona Institute of Science and Technology (BIST), 08028, Barcelona, Spain .,Catalan Institution for Research and Advanced Studies (ICREA), 08010, Barcelona, Spain
| |
Collapse
|
|
47
|
Polavarapu S, Dwarakanath BS, Das UN. Arachidonic acid activates extrinsic apoptotic pathway to enhance tumoricidal action of bleomycin against IMR-32 cells. Prostaglandins Leukot Essent Fatty Acids 2018; 132:16-22. [PMID: 29735018 DOI: 10.1016/j.plefa.2018.04.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2017] [Revised: 04/02/2018] [Accepted: 04/02/2018] [Indexed: 01/07/2023]
Abstract
Bleomycin is a commonly used anti-cancer drug in the management of a variety of cancers. Previously, we showed that arachidonic acid (AA) augmented the growth inhibitory action of bleomycin on IMR-32 (human neuroblastoma cells) in vitro by enhancing oxidative stress. Despite these results, the exact molecular mechanism of cytotoxic action of bleomycin and its augmentation by AA is not known. Our current study revealed that a combination of bleomycin and AA significantly enhanced the expression of FAS gene, which is involved in programmed cell death (apoptosis) and caspases 3 and 8 compared to either bleomycin or AA alone implying that activation of extrinsic apoptotic pathway plays a major role in their (bleomycin + AA) tumoricidal action. It is interesting to note that AA by itself enhanced the expression of FAS and caspases 3 and 8 compared to control. Since caspases have a role in inflammation, cell proliferation, tumour suppression, cell differentiation, neural development and axon guidance and ageing, this may explain pleiotropic actions of AA and their metabolites.
Collapse
Affiliation(s)
- Sailaja Polavarapu
- BioScience Research Centre, Gayatri Vidya Parishad College of Engineering Campus, Madhurawada, Visakhapatnam, Andhra Pradesh 530 048, India
| | | | - Undurti N Das
- BioScience Research Centre, Gayatri Vidya Parishad College of Engineering Campus, Madhurawada, Visakhapatnam, Andhra Pradesh 530 048, India; UND Life Sciences, 2221 NW 5th St, Battle Ground, WA 98604, USA.
| |
Collapse
|
|
48
|
Shen Z, Ma Y, Ji Z, Hao Y, Yan X, Zhong Y, Tang X, Ren W. Arachidonic acid induces macrophage cell cycle arrest through the JNK signaling pathway. Lipids Health Dis 2018; 17:26. [PMID: 29426338 PMCID: PMC5807765 DOI: 10.1186/s12944-018-0673-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2017] [Accepted: 02/05/2018] [Indexed: 01/14/2023] Open
Abstract
Background Arachidonic acid (AA) has potent pro-apoptotic effects on cancer cells at a low concentration and on macrophages at a very high concentration. However, the effects of AA on the macrophage cell cycle and related signaling pathways have not been fully investigated. Herein we aim to observe the effect of AA on macrophages cell cycle. Results AA exposure reduced the viability and number of macrophages in a dose- and time-dependent manner. The reduction in RAW264.7 cell viability was not caused by apoptosis, as indicated by caspase-3 and activated caspase-3 detection. Further research illustrated that AA exposure induced RAW264.7 cell cycle arrested at S phase, and some cell cycle-regulated proteins were altered accordingly. Moreover, JNK signaling was stimulated by AA, and the stimulation was partially reversed by a JNK signaling inhibitor in accordance with cell cycle-related factors. In addition, nuclear and total Foxo1/3a and phosphorylated Foxo1/3a were elevated by AA in a dose- and time-dependent manner, and this elevation was suppressed by the JNK signaling inhibitor. Conclusion Our study demonstrated that AA inhibits macrophage viability by inducing S phase cell cycle arrest. The JNK signaling pathway and the downstream FoxO transcription factors are involved in AA-induced RAW264.7 cell cycle arrest. Electronic supplementary material The online version of this article (10.1186/s12944-018-0673-0) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
- Ziying Shen
- Laboratory Animal Center, College of Animal Sciences, Jilin University, Xi'an Road, 5333#, Jilin, 130062, China
| | - Yunqing Ma
- Laboratory Animal Center, College of Animal Sciences, Jilin University, Xi'an Road, 5333#, Jilin, 130062, China
| | - Zhonghao Ji
- Laboratory Animal Center, College of Animal Sciences, Jilin University, Xi'an Road, 5333#, Jilin, 130062, China
| | - Yang Hao
- Laboratory Animal Center, College of Animal Sciences, Jilin University, Xi'an Road, 5333#, Jilin, 130062, China
| | - Xuan Yan
- Laboratory Animal Center, College of Animal Sciences, Jilin University, Xi'an Road, 5333#, Jilin, 130062, China
| | - Yuan Zhong
- Laboratory Animal Center, College of Animal Sciences, Jilin University, Xi'an Road, 5333#, Jilin, 130062, China
| | - Xiaochun Tang
- Laboratory Animal Center, College of Animal Sciences, Jilin University, Xi'an Road, 5333#, Jilin, 130062, China
| | - Wenzhi Ren
- Laboratory Animal Center, College of Animal Sciences, Jilin University, Xi'an Road, 5333#, Jilin, 130062, China.
| |
Collapse
|
|
49
|
Pizato N, Luzete BC, Kiffer LFMV, Corrêa LH, de Oliveira Santos I, Assumpção JAF, Ito MK, Magalhães KG. Omega-3 docosahexaenoic acid induces pyroptosis cell death in triple-negative breast cancer cells. Sci Rep 2018; 8:1952. [PMID: 29386662 PMCID: PMC5792438 DOI: 10.1038/s41598-018-20422-0] [Citation(s) in RCA: 158] [Impact Index Per Article: 22.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2017] [Accepted: 01/18/2018] [Indexed: 02/07/2023] Open
Abstract
The implication of inflammation in pathophysiology of several type of cancers has been under intense investigation. Omega-3 fatty acids can modulate inflammation and present anticancer effects, promoting cancer cell death. Pyroptosis is an inflammation related cell death and so far, the function of docosahexaenoic acid (DHA) in pyroptosis cell death has not been described. This study investigated the role of DHA in triggering pyroptosis activation in breast cancer cells. MDA-MB-231 breast cancer cells were supplemented with DHA and inflammation cell death was analyzed. DHA-treated breast cancer cells triggered increased caspase-1and gasdermin D activation, enhanced IL-1β secretion, translocated HMGB1 towards the cytoplasm, and membrane pore formation when compared to untreated cells, suggesting DHA induces pyroptosis programmed cell death in breast cancer cells. Moreover, caspase-1 inhibitor (YVAD) could protect breast cancer cells from DHA-induced pyroptotic cell death. In addition, membrane pore formation showed to be a lysosomal damage and ROS formation-depended event in breast cancer cells. DHA triggered pyroptosis cell death in MDA-MB-231by activating several pyroptosis markers in these cells. This is the first study that shows the effect of DHA triggering pyroptosis programmed cell death in breast cancer cells and it could improve the understanding of the omega-3 supplementation during breast cancer treatment.
Collapse
Affiliation(s)
- Nathalia Pizato
- Department of Nutrition, University of Brasilia, Brasilia, 70910-900, Brazil
| | | | | | - Luís Henrique Corrêa
- Laboratory of Immunology and Inflammation, University of Brasilia, Brasilia, 70910-900, Brazil
| | - Igor de Oliveira Santos
- Laboratory of Immunology and Inflammation, University of Brasilia, Brasilia, 70910-900, Brazil
| | | | - Marina Kiyomi Ito
- Department of Nutrition, University of Brasilia, Brasilia, 70910-900, Brazil
| | - Kelly Grace Magalhães
- Laboratory of Immunology and Inflammation, University of Brasilia, Brasilia, 70910-900, Brazil.
| |
Collapse
|
|
50
|
Goswami S, Sharma-Walia N. Crosstalk between osteoprotegerin (OPG), fatty acid synthase (FASN) and, cycloxygenase-2 (COX-2) in breast cancer: implications in carcinogenesis. Oncotarget 2018; 7:58953-58974. [PMID: 27270654 PMCID: PMC5312288 DOI: 10.18632/oncotarget.9835] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2015] [Accepted: 05/13/2016] [Indexed: 12/26/2022] Open
Abstract
The crosstalk between malignant and nonmalignant cells in the tumor microenvironment, as maneuvered by cytokines/chemokines, drives breast cancer progression. In our previous study, we discovered Osteoprotegerin (OPG) as one of the cytokines heavily secreted by breast cancer cells. We demonstrated that OPG is expressed and secreted at very high levels from the highly invasive breast cancer cell lines SUM149PT and SUM1315MO2 as compared to normal human mammary epithelial HMEC cells. OPG was involved in modulating aneuploidy, cell proliferation, and angiogenesis in breast cancer. Mass spectrometry analysis performed in this study revealed OPG interacts with fatty acid synthase (FASN), which is a key enzyme of the fatty acid biosynthetic pathway in breast cancer cells. Further, electron microscopy, immunofluorescence, and fluorescence quantitation assays highlighted the presence of a large number of lipid bodies (lipid droplets) in SUM149PT and SUM1315MO2 cells in comparison to HMEC. We recently showed upregulation of the COX-2 inflammatory pathway and its metabolite PGE2 secretion in SUM149PT and SUM1315MO2 breast cancer cells. Interestingly, human breast cancer tissue samples displayed high expression of OPG, PGE2 and fatty acid synthase (FASN). FASN is a multifunctional enzyme involved in lipid biosynthesis. Immunofluorescence staining revealed the co-existence of COX-2 and FASN in the lipid bodies of breast cancer cells. We reasoned that there might be crosstalk between OPG, FASN, and COX-2 that sustains the inflammatory pathways in breast cancer. Interestingly, knocking down OPG by CRISPR/Cas9 gene editing in breast cancer cells decreased FASN expression at the protein level. Here, we identified cis-acting elements involved in the transcriptional regulation of COX-2 and FASN by recombinant human OPG (rhOPG). Treatment with FASN inhibitor C75 and COX-2 inhibitor celecoxib individually decreased the number of lipid bodies/cell, downregulated phosphorylation of ERK, GSK3β, and induced apoptosis by caspase-3/7 and caspase-9 activation. But a more efficient and effective decrease in lipid bodies/cell and survival kinase signaling was observed upon combining the drug treatments for the aggressive cancer cells. Collectively, the novel biological crosstalk between OPG, FASN, and COX-2 advocates for combinatorial drug treatment to block these players of carcinogenesis as a promising therapeutic target to treat highly invasive breast cancer.
Collapse
Affiliation(s)
- Sudeshna Goswami
- H. M. Bligh Cancer Research Laboratories, Department of Microbiology and Immunology, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois, U.S.A
| | - Neelam Sharma-Walia
- H. M. Bligh Cancer Research Laboratories, Department of Microbiology and Immunology, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois, U.S.A
| |
Collapse
|