|
1
|
Yang B, Li Z, Li P, Liang B, Liu Y, Feng E. Role of T cell metabolism in brain tumor development: a genetic and metabolic approach. BMC Neurol 2025; 25:12. [PMID: 39780065 PMCID: PMC11708232 DOI: 10.1186/s12883-024-04015-1] [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: 08/08/2024] [Accepted: 12/30/2024] [Indexed: 01/11/2025] Open
Abstract
BACKGROUND Malignant brain tumors are among the most lethal cancers. Recent studies emphasized the crucial involvement of the immune system, especially T cells, in driving tumor progression and influencing patient outcomes. The emerging field of immunometabolism has shown that metabolic pathways play a pivotal role in regulating immune responses within the tumor microenvironment. This study aims to clarify the relationships between specific T cell phenotypes, circulating metabolites, and malignant brain tumors. METHODS We utilized a multiple mendelian randomization approach to investigate the associations between T cell phenotypes and malignant brain tumors, as well as the role of plasma metabolites in mediating these interactions. Instrumental variables were selected based on stringent criteria, and multiple mendelian randomization methods were utilized to identify causal pathways and metabolites potentially mediating these effects. RESULTS Our analysis identified significant associations between seven distinct T cell phenotypes, including various CD8 + and regulatory T cell subsets, and the presence of malignant brain tumors. We also identified 87 plasma metabolites correlated with these tumors. Notably, metabolites such as octadecanedioylcarnitine (C18-DC) and eicosanedioate (C20-DC) were implicated in modulating the risk of developing malignant brain tumors. Furthermore, metabolites such as 5-dodecenoate (12:1n7) and arachidonate (20:4n6) were found to influence tumor risk, particularly in relation to CD28 - CD8 + T cells. CONCLUSION The study identifies key T cell phenotypes and plasma metabolites involved in the pathogenesis of malignant brain tumors, offering potential biomarkers and therapeutic targets for future interventions.
Collapse
Affiliation(s)
- Bo Yang
- Department of Neurosurgery, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, China
| | - Zhenyu Li
- Department of Neonatology , The First Hospital of Jilin University, Changchun, China
| | - Peiliang Li
- Department of Neurosurgery, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, China
| | - Bo Liang
- Department of Neurosurgery, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, China
| | - Yuhan Liu
- Department of Neurosurgery, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, China
| | - Enshan Feng
- Department of Neurosurgery, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, China.
| |
Collapse
|
|
2
|
Kytikova OY, Kovalenko IS, Novgorodtseva TP, Denisenko YK. The Role of Hydroxyeicosatetraenoic Acids in the Regulation of Inflammation in Bronchial Asthma. DOKL BIOCHEM BIOPHYS 2024; 519:512-520. [PMID: 39283556 DOI: 10.1134/s1607672924701126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2024] [Revised: 07/26/2024] [Accepted: 07/27/2024] [Indexed: 01/19/2025]
Abstract
Hydroperoxyeicosatetraenoic acids (HETEs) are metabolites of arachidonic acid that are oxidized by a family of enzymes including cyclooxygenase, lipoxygenase, and cytochrome P450 enzymes. These enzymes are widely present in various organs and tissues, and the HETEs they synthesize perform an important function in the regulation of immune reactions and haemostasis processes under physiological and pathophysiological conditions. More researchers confirm the role of these oxidized metabolites in modulating inflammation in asthma. The high production of HETEs in allergic and severe asthma indicates their involvement in the processes of an acute inflammatory response. On the other hand, disturbance of the metabolic transformation of arachidonic acid contributes to the development of chronic inflammation due to insufficient synthesis of mediators that resolve inflammatory processes. Several HETEs have both pro-inflammatory and anti-inflammatory effects, which underscores the ongoing interest in their involvement in the pathogenesis of asthma. At the same time, research results are scarce. Based on an analysis of the literature, the pathways of metabolic transformation of 5-HETE, 12-HETE, and 15-HETE with the participation of cyclooxygenases, lipoxygenases, and cytochrome P-450, as well as their role in asthma pathogenesis, were discussed. The PubMed database was searched for information covering the last five years using selected inclusion criteria. Information queries included the following set of keywords: "bronchial asthma, hydroxyeicosatetraenoic acids, 5-HETE, 12-HETE, 15-HETE." Literature data indicate that the role of HETEs in human physiology and pathology, including the modulation of inflammation in asthma, requires comprehensive study to selectively modulate the enzymatic pathways of arachidonic acid metabolism leading to the production of these mediators.
Collapse
Affiliation(s)
- O Yu Kytikova
- Vladivostok Branch of Far Eastern Scientific Center of Physiology and Pathology of Respiration-Institute of Medical Climatology and Rehabilitative Treatment, Vladivostok, Russia.
| | - I S Kovalenko
- Vladivostok Branch of Far Eastern Scientific Center of Physiology and Pathology of Respiration-Institute of Medical Climatology and Rehabilitative Treatment, Vladivostok, Russia
| | - T P Novgorodtseva
- Vladivostok Branch of Far Eastern Scientific Center of Physiology and Pathology of Respiration-Institute of Medical Climatology and Rehabilitative Treatment, Vladivostok, Russia
| | - Yu K Denisenko
- Vladivostok Branch of Far Eastern Scientific Center of Physiology and Pathology of Respiration-Institute of Medical Climatology and Rehabilitative Treatment, Vladivostok, Russia
| |
Collapse
|
|
3
|
Alam W, Khan H, Jan MS, W. Darwish H, Daglia M, A. Elhenawy A. In vitro 5-LOX inhibitory and antioxidant potential of isoxazole derivatives. PLoS One 2024; 19:e0297398. [PMID: 39365759 PMCID: PMC11452043 DOI: 10.1371/journal.pone.0297398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Accepted: 06/11/2024] [Indexed: 10/06/2024] Open
Abstract
5-Lipoxygenase (5-LOX) is a key enzyme involved in the biosynthesis of pro-inflammatory leukotrienes, leading to asthma. Developing potent 5-LOX inhibitors are highly attractive. In this research the previously synthesized isoxazole derivatives has been investigated against 5-LOX inhibitory and antioxidant in vitro assay. The compound 3 caused concentration dependent inhibition of 5-LOX with overall IC50 value of 8.47 μM. The investigated compounds C5 also exhibited good 5-LOX inhibitory effect. The IC50 demonstrated for C5 was 10.48. Among the 10 synthesized compounds, the potential 5-LOX inhibitory effect was reported for C6. The most potent compound which showed excellent free radical scavenging effect was C3 having IC50 value of 10.96 μM. The next most potent antioxidant activity was reported for C5 which non-significantly showed free radical scavenging effect. The IC50 value observed for C5 was 13.12 μM. Compound C6 also showed potent dose dependent antioxidant effect with IC50 value of 18.87 μM having percent inhibition of 91.63±0.55, 88.45±0.49, 83.53±0.45, 78.42±0.66 and 73.72±0.64 at concentration 1000-62.5 μg/mL respectively. Among the tested compounds, C6 was found most potent which showed significant 5-LOX percent inhibition assay and also reported the minimum IC50 value comparable to the reference drug. The in vitro 5-LOX enzymes inhibition assays of C5 and C3 also showed excellent percent inhibition and good potency next to C6. We concluded that amongst the investigated designed molecules the C3 was found best potent and showed significant dose dependent antioxidant activity against DPPH screening. The IC50 value reported for C3 was found good as compared to standard drug. Moreover, C5 and C6 also showed excellent free radical scavenging effect against DPPH assay. Computational methods have also been employed to explore the probable interaction model of inhibitors and enzyme active sites, and also to correlate the results of in silico and in vitro studies.
Collapse
Affiliation(s)
- Waqas Alam
- Department of Pharmacy, Abdul Wali Khan University Mardan, Mardan, Pakistan
| | - Haroon Khan
- Department of Pharmacy, Abdul Wali Khan University Mardan, Mardan, Pakistan
| | | | - Hany W. Darwish
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Kingdom of Saudi Arabia
| | - Maria Daglia
- Department of Pharmacy, University of Napoli Federico II, Naples, Italy
- International Research Center for Food Nutrition and Safety, Jiangsu University, Zhenjiang, China
| | - Ahmed A. Elhenawy
- Chemistry Department, Faculty of Science, Al-Azhar University, Nasr City, Cairo, Egypt
| |
Collapse
|
|
4
|
Brenna JT, Sergeeva MG, Pestov NB, Korneenko TV, Shchepinov MS. Arachidonic acid: reconciling the dichotomy of its oxidative cascade through specific deuteration. Free Radic Res 2024; 58:583-593. [PMID: 37897398 DOI: 10.1080/10715762.2023.2277145] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Revised: 10/09/2023] [Accepted: 10/18/2023] [Indexed: 10/30/2023]
Abstract
A new approach to attenuating pathological inflammatory reactions by buffering the eicosanoid pathways with oxidation-resistant hexadeuterated arachidonic acid (D-ARA) is discussed. Enzymatic processing of ARA, released by phospholipase A2, by lipoxygenases, cyclooxygenases, and cytochromes yields a wide range of bioactive eicosanoids, including pro-inflammation, pro-angiogenesis and pro-thrombosis species that, when produced in excess, are an underlying cause of pathology. Conversely, some products of ARA oxidation possess pro-resolving properties. Non-enzymatic free radical oxidation of ARA generates another large group of products such as isoprostanes and their metabolites, associated with inflammation, ischemia-reperfusion stress, and atherosclerosis. A separate group comprises reactive carbonyl derivatives that irreversibly damage diverse biomolecules. Being resistant to both enzymatic and non-enzymatic oxidation pathways due to large kinetic isotope effects, D-ARA may play a role in mitigating inflammation-related disorders and conditions, including inflammaging.
Collapse
Affiliation(s)
- J Thomas Brenna
- University of TX at Austin, Departments of Pediatrics, of Chemistry, and of Nutrition, Dell Pediatric Research Institute, Austin, TX, USA
| | - Marina G Sergeeva
- Belozersky Institute of Physical-Chemical Biology, Lomonosov Moscow State University, Moscow, Russia
| | - Nikolay B Pestov
- Chumakov Federal Scientific Center for Research and Development of Immune-and-Biological Products, Laboratory of Tick-Borne Encephalitis and other Encephalitides, Moscow, Russia
- Institute of Biomedical Chemistry, Moscow, Russia
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Group of Cross-Linking Enzymes, Moscow, Russia
| | - Tatyana V Korneenko
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Group of Cross-Linking Enzymes, Moscow, Russia
| | | |
Collapse
|
|
5
|
Corciovă A, Mircea C, Fifere A, Turin-Moleavin IA, Roşca I, Macovei I, Ivănescu B, Vlase AM, Hăncianu M, Burlec AF. Biogenic Synthesis of Silver Nanoparticles Mediated by Aronia melanocarpa and Their Biological Evaluation. Life (Basel) 2024; 14:1211. [PMID: 39337993 PMCID: PMC11433241 DOI: 10.3390/life14091211] [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: 08/01/2024] [Revised: 09/07/2024] [Accepted: 09/22/2024] [Indexed: 09/30/2024] Open
Abstract
In the present study, two A. melanocarpa berry extracts were used for the synthesis of silver nanoparticles (AgNPs). After the optimization of synthesis, the AgNPs were characterized using UV-Vis, FTIR, EDX, DLS, and STEM analyses. The stability in different media, phytotoxicity, as well as antimicrobial and antioxidant activities were also evaluated. The ideal synthesis conditions were represented by a 3 mM AgNO3 concentration, 1:9 extract:AgNO3 volume ratio, alkaline medium, and stirring at 40 °C for 120 min. The synthesis was confirmed by the surface plasmon resonance (SPR) peak at 403 nm, and the strong signal at 3 keV from the EDX spectra. FTIR analysis indicated that polyphenols, polysaccharides, and amino acids could be the compounds responsible for synthesis. Stability tests and the negative zeta potential values showed that phytocompounds also play a role in the stabilization and capping of AgNPs. The preliminary phytotoxicity studies on T. aestivum showed that both the extracts and their corresponding AgNPs had an impact on the growth of roots and shoots as well as on the microscopic structure of leaves. The synthesized AgNPs presented antimicrobial activity against S. aureus, E. coli, and C. albicans. Moreover, considering the results obtained in the lipoxygenase inhibition, the DPPH and hydroxyl scavenging activities, and the ferrous ion chelating assay, AgNPs exhibit promising antioxidant activity.
Collapse
Affiliation(s)
- Andreia Corciovă
- Faculty of Pharmacy, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Street, 700115 Iasi, Romania; (A.C.); (C.M.); (M.H.); (A.F.B.)
| | - Cornelia Mircea
- Faculty of Pharmacy, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Street, 700115 Iasi, Romania; (A.C.); (C.M.); (M.H.); (A.F.B.)
| | - Adrian Fifere
- Centre of Advanced Research in Bionanoconjugates and Biopolymers Department, “Petru Poni” Institute of Macromolecular Chemistry, 41A Grigore Ghica Voda Alley, 700487 Iasi, Romania; (A.F.); (I.-A.T.-M.); (I.R.)
| | - Ioana-Andreea Turin-Moleavin
- Centre of Advanced Research in Bionanoconjugates and Biopolymers Department, “Petru Poni” Institute of Macromolecular Chemistry, 41A Grigore Ghica Voda Alley, 700487 Iasi, Romania; (A.F.); (I.-A.T.-M.); (I.R.)
| | - Irina Roşca
- Centre of Advanced Research in Bionanoconjugates and Biopolymers Department, “Petru Poni” Institute of Macromolecular Chemistry, 41A Grigore Ghica Voda Alley, 700487 Iasi, Romania; (A.F.); (I.-A.T.-M.); (I.R.)
| | - Irina Macovei
- Faculty of Pharmacy, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Street, 700115 Iasi, Romania; (A.C.); (C.M.); (M.H.); (A.F.B.)
| | - Bianca Ivănescu
- Faculty of Pharmacy, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Street, 700115 Iasi, Romania; (A.C.); (C.M.); (M.H.); (A.F.B.)
| | - Ana-Maria Vlase
- Department of Pharmaceutical Botany, Faculty of Pharmacy, Iuliu Hațieganu University of Medicine and Pharmacy, 8 Victor Babeș Street, 400012 Cluj-Napoca, Romania;
| | - Monica Hăncianu
- Faculty of Pharmacy, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Street, 700115 Iasi, Romania; (A.C.); (C.M.); (M.H.); (A.F.B.)
| | - Ana Flavia Burlec
- Faculty of Pharmacy, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Street, 700115 Iasi, Romania; (A.C.); (C.M.); (M.H.); (A.F.B.)
| |
Collapse
|
|
6
|
Park J, Roh J, Pan J, Kim YH, Park CK, Jo YY. Role of Resolvins in Inflammatory and Neuropathic Pain. Pharmaceuticals (Basel) 2023; 16:1366. [PMID: 37895837 PMCID: PMC10610411 DOI: 10.3390/ph16101366] [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: 08/17/2023] [Revised: 09/25/2023] [Accepted: 09/25/2023] [Indexed: 10/29/2023] Open
Abstract
Chronic pain is an unpleasant experience associated with actual or potential tissue damage. Inflammatory pain alerts the body to inflammation and promotes healing; however, unresolved inflammation can lead to chronic pain. Conversely, neuropathic pain, due to somatosensory damage, can be a disease in itself. However, inflammation plays a considerable role in the progression of both types of pain. Resolvins, derived from omega-3 fatty acids, actively suppress pro-inflammatory mediators and aid in the resolution of inflammation. Resolvins alleviate various inflammatory and neuropathic pain models by reducing hypersensitivity and regulating inflammatory cytokines and glial activation in the spinal cord and dorsal root ganglia. Thus, resolvins are a promising alternative for pain management with the potential to reduce the side effects associated with conventional medications. Continued research is crucial to unlock the therapeutic potential of resolvins and integrate them into effective clinical pain management strategies. This review aimed to evaluate the literature surrounding the resolvins in inflammatory and neuropathic pain.
Collapse
Affiliation(s)
- Jaeik Park
- Gachon Pain Center and Department of Physiology, Gachon University College of Medicine, Incheon 21999, Republic of Korea; (J.P.); (J.R.); (J.P.); (Y.H.K.)
| | - Jueun Roh
- Gachon Pain Center and Department of Physiology, Gachon University College of Medicine, Incheon 21999, Republic of Korea; (J.P.); (J.R.); (J.P.); (Y.H.K.)
| | - Jingying Pan
- Gachon Pain Center and Department of Physiology, Gachon University College of Medicine, Incheon 21999, Republic of Korea; (J.P.); (J.R.); (J.P.); (Y.H.K.)
- Department of Histology and Embryology, Medical School of Nantong University, Nantong 226007, China
| | - Yong Ho Kim
- Gachon Pain Center and Department of Physiology, Gachon University College of Medicine, Incheon 21999, Republic of Korea; (J.P.); (J.R.); (J.P.); (Y.H.K.)
| | - Chul-Kyu Park
- Gachon Pain Center and Department of Physiology, Gachon University College of Medicine, Incheon 21999, Republic of Korea; (J.P.); (J.R.); (J.P.); (Y.H.K.)
| | - Youn Yi Jo
- Department of Anesthesiology and Pain Medicine, Gil Medical Center, Gachon University, Incheon 21565, Republic of Korea
| |
Collapse
|
|
7
|
Ravindran R, O’Connor E, Gupta A, Luciw PA, Khan AI, Dorreh N, Chiang K, Ikram A, Reddy S. Lipid Mediators and Cytokines/Chemokines Display Differential Profiles in Severe versus Mild/Moderate COVID-19 Patients. Int J Mol Sci 2023; 24:13054. [PMID: 37685858 PMCID: PMC10488250 DOI: 10.3390/ijms241713054] [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: 07/06/2023] [Revised: 08/15/2023] [Accepted: 08/18/2023] [Indexed: 09/10/2023] Open
Abstract
Host immune responses play a key role in COVID-19 pathogenesis. The underlying phenomena are orchestrated by signaling molecules such as cytokines/chemokines and lipid mediators. These immune molecules, including anti-SARS-CoV-2 antibodies, interact with immune cells and regulate host responses, contributing to inflammation that drives the disease. We investigated 48 plasma cytokines/chemokines, 21 lipid mediators, and anti-S protein (RBD) antibodies in COVID-19 patients (n = 56) and non-COVID-19 respiratory disease controls (n = 49), to identify immune-biomarker profiles. Cytokines/chemokines (IL-6, CXCL-10 (IP-10), HGF, MIG, MCP-1, and G-CSF) and lipid mediators (TxB2, 11-HETE, 9-HODE, 13-HODE, 5-HETE, 12-HETE, 15-HETE, 14S-HDHA, 17S-HDHA, and 5-oxo ETE) were significantly elevated in COVID-19 patients compared to controls. In patients exhibiting severe disease, pro-inflammatory cytokines/chemokines (IL-6, CXCL-10, and HGF) and anti-SARS-CoV-2 antibodies were significantly elevated. In contrast, lipid mediators involved in the reduction/resolution of inflammation, in particular, 5-HETE, 11-HETE, and 5-oxoETE, were significantly elevated in mild/moderate disease. Taken together, these immune-biomarker profiles provide insight into immune responses related to COVID-19 pathogenesis. Importantly, our findings suggest that elevation in plasma concentrations of IL-6, CXCL-10, HGF, and anti-SARS-CoV-2 antibodies can predict severe disease, whereas elevation in lipid mediators peaks early (compared to cytokines) and includes induction of mechanisms leading to reduction of inflammation, associated complications, and maintenance of homeostasis.
Collapse
Affiliation(s)
- Resmi Ravindran
- Department of Pathology and Laboratory Medicine, University of California, Davis, CA 95817, USA;
| | - Ellen O’Connor
- Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA; (E.O.); (N.D.); (K.C.)
| | - Ajay Gupta
- Division of Nephrology, Hypertension and Kidney Transplantation, Department of Medicine, University of California Irvine (UCI) School of Medicine, Irvine, CA 92868, USA;
| | - Paul A. Luciw
- Department of Pathology and Laboratory Medicine, University of California, Davis, CA 95817, USA;
| | - Aleena I. Khan
- Department of Population and Public Health, Keek School of Medicine, University of Southern California, Los Angeles, CA 90089, USA;
| | - Nasrin Dorreh
- Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA; (E.O.); (N.D.); (K.C.)
| | - Kate Chiang
- Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA; (E.O.); (N.D.); (K.C.)
| | - Aamer Ikram
- National Institutes of Health, Islamabad 45500, Pakistan;
| | - Srinivasa Reddy
- Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA; (E.O.); (N.D.); (K.C.)
| |
Collapse
|
|
8
|
Li L, Shen S, Bickler P, Jacobson MP, Wu LF, Altschuler SJ. Searching for molecular hypoxia sensors among oxygen-dependent enzymes. eLife 2023; 12:e87705. [PMID: 37494095 PMCID: PMC10371230 DOI: 10.7554/elife.87705] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Accepted: 07/09/2023] [Indexed: 07/27/2023] Open
Abstract
The ability to sense and respond to changes in cellular oxygen levels is critical for aerobic organisms and requires a molecular oxygen sensor. The prototypical sensor is the oxygen-dependent enzyme PHD: hypoxia inhibits its ability to hydroxylate the transcription factor HIF, causing HIF to accumulate and trigger the classic HIF-dependent hypoxia response. A small handful of other oxygen sensors are known, all of which are oxygen-dependent enzymes. However, hundreds of oxygen-dependent enzymes exist among aerobic organisms, raising the possibility that additional sensors remain to be discovered. This review summarizes known and potential hypoxia sensors among human O2-dependent enzymes and highlights their possible roles in hypoxia-related adaptation and diseases.
Collapse
Affiliation(s)
- Li Li
- Department of Pharmaceutical Chemistry, University of California San Francisco, San FranciscoSan FranciscoUnited States
| | - Susan Shen
- Department of Pharmaceutical Chemistry, University of California San Francisco, San FranciscoSan FranciscoUnited States
- Department of Psychiatry, University of California, San FranciscoSan FranciscoUnited States
| | - Philip Bickler
- Hypoxia Research Laboratory, University of California San Francisco, San FranciscoSan FranciscoUnited States
- Center for Health Equity in Surgery and Anesthesia, University of California San Francisco, San FranciscoSan FranciscoUnited States
- Anesthesia and Perioperative Care, University of California San Francisco, San FranciscoSan FranciscoUnited States
| | - Matthew P Jacobson
- Department of Pharmaceutical Chemistry, University of California San Francisco, San FranciscoSan FranciscoUnited States
| | - Lani F Wu
- Department of Pharmaceutical Chemistry, University of California San Francisco, San FranciscoSan FranciscoUnited States
| | - Steven J Altschuler
- Department of Pharmaceutical Chemistry, University of California San Francisco, San FranciscoSan FranciscoUnited States
| |
Collapse
|
|
9
|
Schäfer M, Reisch F, Labuz D, Machelska H, Stehling S, Püschel GP, Rothe M, Heydeck D, Kuhn H. Humanization of the Reaction Specificity of Mouse Alox15b Inversely Modified the Susceptibility of Corresponding Knock-In Mice in Two Different Animal Inflammation Models. Int J Mol Sci 2023; 24:11034. [PMID: 37446212 PMCID: PMC10341735 DOI: 10.3390/ijms241311034] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Revised: 06/28/2023] [Accepted: 06/29/2023] [Indexed: 07/15/2023] Open
Abstract
Mammalian arachidonic acid lipoxygenases (ALOXs) have been implicated in the pathogenesis of inflammatory diseases, and its pro- and anti-inflammatory effects have been reported for different ALOX-isoforms. Human ALOX15B oxygenates arachidonic acid to its 15-hydroperoxy derivative, whereas the corresponding 8-hydroperoxide is formed by mouse Alox15b (Alox8). This functional difference impacts the biosynthetic capacity of the two enzymes for creating pro- and anti-inflammatory eicosanoids. To explore the functional consequences of the humanization of the reaction specificity of mouse Alox15b in vivo, we tested Alox15b knock-in mice that express the arachidonic acid 15-lipoxygenating Tyr603Asp and His604Val double mutant of Alox15b, instead of the arachidonic acid 8-lipoxygenating wildtype enzyme, in two different animal inflammation models. In the dextran sodium sulfate-induced colitis model, female Alox15b-KI mice lost significantly more bodyweight during the acute phase of inflammation and recovered less rapidly during the resolution phase. Although we observed significant differences in the colonic levels of selected pro- and anti-inflammatory eicosanoids during the time-course of inflammation, there were no differences between the two genotypes at any time-point of the disease. In Freund's complete adjuvant-induced paw edema model, Alox15b-KI mice were less susceptible than outbred wildtype controls, though we did not observe significant differences in pain perception (Hargreaves-test, von Frey-test) when the two genotypes were compared. our data indicate that humanization of the reaction specificity of mouse Alox15b (Alox8) sensitizes mice for dextran sodium sulfate-induced experimental colitis, but partly protects the animals in the complete Freund's adjuvant-induced paw edema model.
Collapse
Affiliation(s)
- Marjann Schäfer
- Department of Biochemistry, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charitéplatz 1, D-10117 Berlin, Germany; (M.S.); (F.R.); (S.S.); (D.H.)
- Institute for Nutritional Sciences, University Potsdam, Arthur-Scheunert-Allee 114–116, D-14558 Nuthetal, Germany;
| | - Florian Reisch
- Department of Biochemistry, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charitéplatz 1, D-10117 Berlin, Germany; (M.S.); (F.R.); (S.S.); (D.H.)
- Institute for Nutritional Sciences, University Potsdam, Arthur-Scheunert-Allee 114–116, D-14558 Nuthetal, Germany;
| | - Dominika Labuz
- Department of Experimental Anesthesiology, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Hindenburgdamm 30, D-12203 Berlin, Germany; (D.L.); (H.M.)
| | - Halina Machelska
- Department of Experimental Anesthesiology, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Hindenburgdamm 30, D-12203 Berlin, Germany; (D.L.); (H.M.)
| | - Sabine Stehling
- Department of Biochemistry, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charitéplatz 1, D-10117 Berlin, Germany; (M.S.); (F.R.); (S.S.); (D.H.)
| | - Gerhard P. Püschel
- Institute for Nutritional Sciences, University Potsdam, Arthur-Scheunert-Allee 114–116, D-14558 Nuthetal, Germany;
| | - Michael Rothe
- Lipidomix GmbH, Robert-Roessle-Straße 10, D-13125 Berlin, Germany;
| | - Dagmar Heydeck
- Department of Biochemistry, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charitéplatz 1, D-10117 Berlin, Germany; (M.S.); (F.R.); (S.S.); (D.H.)
| | - Hartmut Kuhn
- Department of Biochemistry, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charitéplatz 1, D-10117 Berlin, Germany; (M.S.); (F.R.); (S.S.); (D.H.)
| |
Collapse
|
|
10
|
Rood KM, Patel N, DeVengencie IM, Quinn JP, Gowdy KM, Costantine MM, Kniss DA. Aspirin modulates production of pro-inflammatory and pro-resolving mediators in endothelial cells. PLoS One 2023; 18:e0283163. [PMID: 37098090 PMCID: PMC10128936 DOI: 10.1371/journal.pone.0283163] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Accepted: 03/02/2023] [Indexed: 04/26/2023] Open
Abstract
Endothelial cells synthesize biochemical signals to coordinate a response to insults, resolve inflammation and restore barrier integrity. Vascular cells release a variety of vasoactive bioactive lipid metabolites during the inflammatory response and produce pro-resolving mediators (e.g., Lipoxin A4, LXA4) in cooperation with leukocytes and platelets to bring a halt to inflammation. Aspirin, used in a variety of cardiovascular and pro-thrombotic disorders (e.g., atherosclerosis, angina, preeclampsia), potently inhibits proinflammatory eicosanoid formation. Moreover, aspirin stimulates the synthesis of pro-resolving lipid mediators (SPM), so-called Aspirin-Triggered Lipoxins (ATL). We demonstrate that cytokines stimulated a time- and dose-dependent increase in PGI2 (6-ketoPGF1α) and PGE2 formation that is blocked by aspirin. Eicosanoid production was caused by cytokine-induced expression of cyclooxygenase-2 (COX-2). We also detected increased production of pro-resolving LXA4 in cytokine-stimulated endothelial cells. The R-enantiomer of LXA4, 15-epi-LXA4, was enhanced by aspirin, but only in the presence of cytokine challenge, indicating dependence on COX-2 expression. In contrast to previous reports, we detected arachidonate 5-lipoxygenase (ALOX5) mRNA expression and its cognate protein (5-lipoxygenase, 5-LOX), suggesting that endothelial cells possess the enzymatic machinery necessary to synthesize both pro-inflammatory and pro-resolving lipid mediators independent of added leukocytes or platelets. Finally, we observed that, endothelial cells produced LTB4 in the absence of leukocytes. These results indicate that endothelial cells produce both pro-inflammatory and pro-resolving lipid mediators in the absence of other cell types and aspirin exerts pleiotropic actions influencing both COX and LOX pathways.
Collapse
Affiliation(s)
- Kara M Rood
- Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, College of Medicine and Wexner Medical Center, The Ohio State University, Columbus, Ohio, United States of America
| | - Niharika Patel
- Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Laboratory of Perinatal Research, College of Medicine and Wexner Medical Center, The Ohio State University, Columbus, Ohio, United States of America
| | - Ivana M DeVengencie
- Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Laboratory of Perinatal Research, College of Medicine and Wexner Medical Center, The Ohio State University, Columbus, Ohio, United States of America
| | - John P Quinn
- Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Laboratory of Perinatal Research, College of Medicine and Wexner Medical Center, The Ohio State University, Columbus, Ohio, United States of America
| | - Kymberly M Gowdy
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, College of Medicine and Wexner Medical Center, Columbus, Ohio, United States of America
- Dorothy Davis Heart and Lung Institute, College of Medicine and Wexner Medical Center, The Ohio State University, Columbus, Ohio, United States of America
| | - Maged M Costantine
- Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, College of Medicine and Wexner Medical Center, The Ohio State University, Columbus, Ohio, United States of America
| | - Douglas A Kniss
- Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, College of Medicine and Wexner Medical Center, The Ohio State University, Columbus, Ohio, United States of America
- Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Laboratory of Perinatal Research, College of Medicine and Wexner Medical Center, The Ohio State University, Columbus, Ohio, United States of America
- Department of Biomedical Engineering, College of Engineering, Fontana Labs, The Ohio State University, Columbus, Ohio, United States of America
- Infectious Disease Institute, The Ohio State University, Columbus, Ohio, United States of America
| |
Collapse
|
|
11
|
Sabbir MG, Wigle JT, Taylor CG, Zahradka P. Growth State-Dependent Expression of Arachidonate Lipoxygenases in the Human Endothelial Cell Line EA.hy926. Cells 2022; 11:cells11162478. [PMID: 36010555 PMCID: PMC9406857 DOI: 10.3390/cells11162478] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2022] [Revised: 08/05/2022] [Accepted: 08/07/2022] [Indexed: 11/30/2022] Open
Abstract
Endothelial cells regulate vascular homeostasis through the secretion of various paracrine molecules, including bioactive lipids, but little is known regarding the enzymes responsible for generating these lipids under either physiological or pathophysiological conditions. Arachidonate lipoxygenase (ALOX) expression was therefore investigated in confluent and nonconfluent EA.h926 endothelial cells, which represent the normal quiescent and proliferative states, respectively. mRNAs for ALOX15, ALOX15B, and ALOXE3 were detected in EA.hy926 cells, with the highest levels present in confluent cells compared to nonconfluent cells. In contrast, ALOX5, ALOX12, and ALOX12B mRNAs were not detected. At the protein level, only ALOX15B and ALOXE3 were detected but only in confluent cells. ALOXE3 was also observed in confluent human umbilical artery endothelial cells (HUAEC), indicating that its expression, although previously unreported, may be a general feature of endothelial cells. Exposure to laminar flow further increased ALOXE3 levels in EA.hy926 cells and HUAECs. The evidence obtained in this study indicates that proliferative status and shear stress are both important factors that mediate endothelial ALOX gene expression. The presence of ALOX15B and ALOXE3 exclusively in quiescent human endothelial cells suggests their activity likely contributes to the maintenance of a healthy endothelium.
Collapse
Affiliation(s)
- Mohammad G. Sabbir
- Canadian Centre for Agri-Food Research in Health and Medicine, St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, MB R2H 2A6, Canada
| | - Jeffrey T. Wigle
- Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, MB R2H 2A6, Canada
- Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, MB R3E 0J9, Canada
| | - Carla G. Taylor
- Canadian Centre for Agri-Food Research in Health and Medicine, St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, MB R2H 2A6, Canada
- Department of Food and Human Nutritional Sciences, University of Manitoba, Winnipeg, MB R3T 2N2, Canada
- Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, MB R3E 0J9, Canada
| | - Peter Zahradka
- Canadian Centre for Agri-Food Research in Health and Medicine, St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, MB R2H 2A6, Canada
- Department of Food and Human Nutritional Sciences, University of Manitoba, Winnipeg, MB R3T 2N2, Canada
- Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, MB R3E 0J9, Canada
- Correspondence: ; Tel.: +204-235-3507; Fax: +204-237-4018
| |
Collapse
|
|
12
|
Male Knock-in Mice Expressing an Arachidonic Acid Lipoxygenase 15B (Alox15B) with Humanized Reaction Specificity Are Prematurely Growth Arrested When Aging. Biomedicines 2022; 10:biomedicines10061379. [PMID: 35740398 PMCID: PMC9220125 DOI: 10.3390/biomedicines10061379] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Revised: 06/02/2022] [Accepted: 06/03/2022] [Indexed: 01/09/2023] Open
Abstract
Mammalian arachidonic acid lipoxygenases (ALOXs) have been implicated in cell differentiation and in the pathogenesis of inflammation. The mouse genome involves seven functional Alox genes and the encoded enzymes share a high degree of amino acid conservation with their human orthologs. There are, however, functional differences between mouse and human ALOX orthologs. Human ALOX15B oxygenates arachidonic acid exclusively to its 15-hydroperoxy derivative (15S-HpETE), whereas 8S-HpETE is dominantly formed by mouse Alox15b. The structural basis for this functional difference has been explored and in vitro mutagenesis humanized the reaction specificity of the mouse enzyme. To explore whether this mutagenesis strategy may also humanize the reaction specificity of mouse Alox15b in vivo, we created Alox15b knock-in mice expressing the arachidonic acid 15-lipoxygenating Tyr603Asp+His604Val double mutant instead of the 8-lipoxygenating wildtype enzyme. These mice are fertile, display slightly modified plasma oxylipidomes and develop normally up to an age of 24 weeks. At later developmental stages, male Alox15b-KI mice gain significantly less body weight than outbred wildtype controls, but this effect was not observed for female individuals. To explore the possible reasons for the observed gender-specific growth arrest, we determined the basic hematological parameters and found that aged male Alox15b-KI mice exhibited significantly attenuated red blood cell parameters (erythrocyte counts, hematocrit, hemoglobin). Here again, these differences were not observed in female individuals. These data suggest that humanization of the reaction specificity of mouse Alox15b impairs the functionality of the hematopoietic system in males, which is paralleled by a premature growth arrest.
Collapse
|
|
13
|
Tsiantas K, Konteles SJ, Kritsi E, Sinanoglou VJ, Tsiaka T, Zoumpoulakis P. Effects of Non-Polar Dietary and Endogenous Lipids on Gut Microbiota Alterations: The Role of Lipidomics. Int J Mol Sci 2022; 23:ijms23084070. [PMID: 35456888 PMCID: PMC9024800 DOI: 10.3390/ijms23084070] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2022] [Revised: 02/25/2022] [Accepted: 03/31/2022] [Indexed: 02/07/2023] Open
Abstract
Advances in sequencing technologies over the past 15 years have led to a substantially greater appreciation of the importance of the gut microbiome to the health of the host. Recent outcomes indicate that aspects of nutrition, especially lipids (exogenous or endogenous), can influence the gut microbiota composition and consequently, play an important role in the metabolic health of the host. Thus, there is an increasing interest in applying holistic analytical approaches, such as lipidomics, metabolomics, (meta)transcriptomics, (meta)genomics, and (meta)proteomics, to thoroughly study the gut microbiota and any possible interplay with nutritional or endogenous components. This review firstly summarizes the general background regarding the interactions between important non-polar dietary (i.e., sterols, fat-soluble vitamins, and carotenoids) or amphoteric endogenous (i.e., eicosanoids, endocannabinoids-eCBs, and specialized pro-resolving mediators-SPMs) lipids and gut microbiota. In the second stage, through the evaluation of a vast number of dietary clinical interventions, a comprehensive effort is made to highlight the role of the above lipid categories on gut microbiota and vice versa. In addition, the present status of lipidomics in current clinical interventions as well as their strengths and limitations are also presented. Indisputably, dietary lipids and most phytochemicals, such as sterols and carotenoids, can play an important role on the development of medical foods or nutraceuticals, as they exert prebiotic-like effects. On the other hand, endogenous lipids can be considered either prognostic indicators of symbiosis or dysbiosis or even play a role as specialized mediators through dietary interventions, which seem to be regulated by gut microbiota.
Collapse
Affiliation(s)
- Konstantinos Tsiantas
- Department of Food Science and Technology, University of West Attica, Ag. Spyridonos, 12243 Egaleo, Greece; (K.T.); (S.J.K.); (E.K.); (V.J.S.)
| | - Spyridon J. Konteles
- Department of Food Science and Technology, University of West Attica, Ag. Spyridonos, 12243 Egaleo, Greece; (K.T.); (S.J.K.); (E.K.); (V.J.S.)
| | - Eftichia Kritsi
- Department of Food Science and Technology, University of West Attica, Ag. Spyridonos, 12243 Egaleo, Greece; (K.T.); (S.J.K.); (E.K.); (V.J.S.)
| | - Vassilia J. Sinanoglou
- Department of Food Science and Technology, University of West Attica, Ag. Spyridonos, 12243 Egaleo, Greece; (K.T.); (S.J.K.); (E.K.); (V.J.S.)
| | - Thalia Tsiaka
- Department of Food Science and Technology, University of West Attica, Ag. Spyridonos, 12243 Egaleo, Greece; (K.T.); (S.J.K.); (E.K.); (V.J.S.)
- Institute of Chemical Biology, National Hellenic Research Foundation, 48, Vas. Constantinou Ave., 11635 Athens, Greece
- Correspondence: (T.T.); (P.Z.)
| | - Panagiotis Zoumpoulakis
- Department of Food Science and Technology, University of West Attica, Ag. Spyridonos, 12243 Egaleo, Greece; (K.T.); (S.J.K.); (E.K.); (V.J.S.)
- Institute of Chemical Biology, National Hellenic Research Foundation, 48, Vas. Constantinou Ave., 11635 Athens, Greece
- Correspondence: (T.T.); (P.Z.)
| |
Collapse
|
|
14
|
Enhancement of the Anti-Inflammatory Activity of NSAIDs by Their Conjugation with 3,4,5-Trimethoxybenzyl Alcohol. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27072104. [PMID: 35408503 PMCID: PMC9000480 DOI: 10.3390/molecules27072104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Revised: 03/21/2022] [Accepted: 03/22/2022] [Indexed: 11/16/2022]
Abstract
The synthesis of derivatives of three nonspecific COX-1 and COX-2 inhibitors, ibuprofen, ketoprofen, naproxen is presented. These acids were connected via an amide bond with an amino acid (L-proline, L-tyrosine, and beta-alanine) used as a linker. The amino acid carboxylic group was esterified with 3,4,5 trimethoxybenzyl alcohol. The activity of the novel derivatives was examined in vivo on carrageenan-induced inflammation, and in vitro, as cyclooxygenase and lipoxygenase inhibitors. It was found that the new compounds were more potent anti-inflammatory agents than the parent drugs. Thus, the ibuprofen (21) and ketoprofen (16) derivatives reduced rat paw edema by 67 and 91% (the reduction by the relevant NSAIDs was 36 and 47%, respectively). They inhibited COX-2 more than the starting drugs (21 by 67%, ibuprofen 46%, 19 by 94%, ketoprofen 49%). Docking of compounds on the active sites of COX-1 and COX-2 reflects their in vitro activity. Thus, 19 adopts an unfavorable orientation for COX-1 inhibition, but it binds effectively in the binding pocket of COX-2, in agreement with the absence of activity for COX-1 and the high inhibition of COX-2. In conclusion, the performed structural modifications result in the enhancement of the anti-inflammatory activity, compared with the parent NSAIDs.
Collapse
|
|
15
|
Heinrich L, Booijink R, Khurana A, Weiskirchen R, Bansal R. Lipoxygenases in chronic liver diseases: current insights and future perspectives. Trends Pharmacol Sci 2021; 43:188-205. [PMID: 34961619 DOI: 10.1016/j.tips.2021.12.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 11/19/2021] [Accepted: 12/01/2021] [Indexed: 02/07/2023]
Abstract
Chronic liver diseases (CLDs) caused by viral infections, alcohol/drug abuse, or metabolic disorders affect millions of people globally and have increased mortality owing to the lack of approved therapies. Lipoxygenases (LOXs) are a family of multifaceted enzymes that are responsible for the oxidation of polyunsaturated fatty acids (PUFAs) and are implicated in the pathogenesis of multiple disorders including liver diseases. This review describes the three main LOX signaling pathways - 5-, 12-, and 15-LOX - and their involvement in CLDs. We also provide recent insights and future perspectives on LOX-related hepatic pathophysiology, and discuss the potential of LOXs and LOX-derived metabolites as diagnostic biomarkers and therapeutic targets in CLDs.
Collapse
Affiliation(s)
- Lena Heinrich
- Translational Liver Research, Department of Medical Cell BioPhysics, Faculty of Science and Technology, Technical Medical Center, University of Twente, Enschede 7500 AE, The Netherlands
| | - Richell Booijink
- Translational Liver Research, Department of Medical Cell BioPhysics, Faculty of Science and Technology, Technical Medical Center, University of Twente, Enschede 7500 AE, The Netherlands
| | - Amit Khurana
- Translational Liver Research, Department of Medical Cell BioPhysics, Faculty of Science and Technology, Technical Medical Center, University of Twente, Enschede 7500 AE, The Netherlands; Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), Rheinisch-Westfälische Technische Hochschule (RWTH) University Hospital Aachen, Aachen 52074, Germany; Centre for Biomedical Engineering (CBME), Indian Institute of Technology (IIT), Hauz Khas, New Delhi 110016, India
| | - Ralf Weiskirchen
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), Rheinisch-Westfälische Technische Hochschule (RWTH) University Hospital Aachen, Aachen 52074, Germany
| | - Ruchi Bansal
- Translational Liver Research, Department of Medical Cell BioPhysics, Faculty of Science and Technology, Technical Medical Center, University of Twente, Enschede 7500 AE, The Netherlands.
| |
Collapse
|
|
16
|
Kakularam KR, Karst F, Polamarasetty A, Ivanov I, Heydeck D, Kuhn H. Paralog- and ortholog-specificity of inhibitors of human and mouse lipoxygenase-isoforms. Biomed Pharmacother 2021; 145:112434. [PMID: 34801853 DOI: 10.1016/j.biopha.2021.112434] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Revised: 11/10/2021] [Accepted: 11/12/2021] [Indexed: 01/15/2023] Open
Abstract
Lipoxygenases (ALOX-isoforms) are lipid peroxidizing enzymes, which have been implicated in cell differentiation and maturation but also in the biosynthesis of lipid mediators playing important roles in the pathogenesis of inflammatory, hyperproliferative and neurological diseases. In mammals these enzymes are widely distributed and the human genome involves six functional genes encoding for six distinct human ALOX paralogs. In mice, there is an orthologous enzyme for each human ALOX paralog but the catalytic properties of human and mouse ALOX orthologs show remarkable differences. ALOX inhibitors are frequently employed for deciphering the biological role of these enzymes in mouse models of human diseases but owing to the functional differences between mouse and human ALOX orthologs the uncritical use of such inhibitors is sometimes misleading. In this study we evaluated the paralog- and ortholog-specificity of 13 frequently employed ALOX-inhibitors against four recombinant human and mouse ALOX paralogs (ALOX15, ALOX15B, ALOX12, ALOX5) under different experimental conditions. Our results indicated that except for zileuton, which exhibits a remarkable paralog-specificity for mouse and human ALOX5, no other inhibitor was strictly paralog specific but some compounds exhibit an interesting ortholog-specificity. Because of the variable isoform specificities of the currently available ALOX inhibitors care must be taken when the biological effects of these compounds observed in complex in vitro and in vivo systems are interpreted.
Collapse
Affiliation(s)
- Kumar Reddy Kakularam
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Biochemistry, Chariteplatz 1, D-10117 Berlin, Germany
| | - Felix Karst
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Biochemistry, Chariteplatz 1, D-10117 Berlin, Germany
| | - Aparoy Polamarasetty
- Indian Institute of Petroleum and Energy, Visakhapatnam 530003, Andhra Pradesh, India
| | - Igor Ivanov
- Lomonosov Institute of Fine Chemical Technologies, MIREA - Russian Technological University, Vernadskogo Pr. 86, 119571 Moscow, Russia
| | - Dagmar Heydeck
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Biochemistry, Chariteplatz 1, D-10117 Berlin, Germany
| | - Hartmut Kuhn
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Biochemistry, Chariteplatz 1, D-10117 Berlin, Germany.
| |
Collapse
|
|
17
|
Takahashi N, Kikuchi H, Usui A, Furusho T, Fujimaru T, Fujiki T, Yanagi T, Matsuura Y, Asano K, Yamamoto K, Ando F, Susa K, Mandai S, Mori T, Rai T, Uchida S, Arita M, Sohara E. Deletion of Alox15 improves kidney dysfunction and inhibits fibrosis by increased PGD 2 in the kidney. Clin Exp Nephrol 2021; 25:445-455. [PMID: 33595729 PMCID: PMC8038997 DOI: 10.1007/s10157-021-02021-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Accepted: 01/06/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND Lipid-metabolizing enzymes and their metabolites affect inflammation and fibrosis, but their roles in chronic kidney disease (CKD) have not been completely understood. METHODS To clarify their role in CKD, we measured the mRNA levels of major lipid-metabolizing enzymes in 5/6 nephrectomized (Nx) kidneys of C57BL/6 J mice. Mediator lipidomics was performed to reveal lipid profiles of CKD kidneys. RESULTS In 5/6 Nx kidneys, both mRNA and protein levels of Alox15 were higher when compared with those in sham kidneys. With respect to in situ hybridization, the mRNA level of Alox15 was higher in renal tubules of 5/6 Nx kidneys. To examine the role of Alox15 in CKD pathogenesis, we performed 5/6 Nx on Alox15-/- mice. Alox15-/- CKD mice exhibited better renal functions than wild-type mice. Interstitial fibrosis was also inhibited in Alox15-/- CKD mice. Mediator lipidomics revealed that Alox15-/- CKD mouse kidneys had significantly higher levels of PGD2 than the control. To investigate the effects of PGD2 on renal fibrosis, we administered PGD2 to TGF-β1-stimulated NRK-52E cells and HK-2 cells, which lead to a dose-dependent suppression of type I collagen and αSMA in both cell lines. CONCLUSION Increased PGD2 in Alox15-/- CKD mouse kidneys could inhibit fibrosis, thereby resulting in CKD improvement. Thus, Alox15 inhibition and PGD2 administration may be novel therapeutic targets for CKD.
Collapse
Affiliation(s)
- Naohiro Takahashi
- Department of Nephrology, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan
| | - Hiroaki Kikuchi
- Department of Nephrology, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan
| | - Ayaka Usui
- Department of Nephrology, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan
| | - Taisuke Furusho
- Department of Nephrology, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan
| | - Takuya Fujimaru
- Department of Nephrology, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan
| | - Tamami Fujiki
- Department of Nephrology, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan
| | - Tomoki Yanagi
- Department of Nephrology, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan
| | - Yoshiaki Matsuura
- Department of Nephrology, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan
| | - Kenichi Asano
- Laboratory of Immune Regulation, The School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan
| | - Kouhei Yamamoto
- Department of Comprehensive Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Fumiaki Ando
- Department of Nephrology, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan
| | - Koichiro Susa
- Department of Nephrology, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan
| | - Shintaro Mandai
- Department of Nephrology, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan
| | - Takayasu Mori
- Department of Nephrology, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan
| | - Tatemitsu Rai
- Department of Nephrology, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan
| | - Shinichi Uchida
- Department of Nephrology, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan
| | - Makoto Arita
- Laboratory for Metabolomics, RIKEN Center for Integrative Medical Sciences (IMS), 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa, 230-0045, Japan.
- Division of Physiological Chemistry and Metabolism, Graduate School of Pharmaceutical Sciences, Keio University, Tokyo, Japan.
| | - Eisei Sohara
- Department of Nephrology, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.
| |
Collapse
|