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Chang L, Qin C, Wu J, Jiang H, Xu Q, Chen J, Xu X, Zhang X, Guan M, Deng X. The crosstalk between glutathione metabolism and non-coding RNAs in cancer progression and treatment resistance. Redox Biol 2025; 84:103689. [PMID: 40403492 DOI: 10.1016/j.redox.2025.103689] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2025] [Revised: 05/11/2025] [Accepted: 05/18/2025] [Indexed: 05/24/2025] Open
Abstract
Excessive reactive oxygen species (ROS) are closely associated with the initiation and progression of cancers. As the most abundant intracellular antioxidant, glutathione (GSH) plays a critical role in regulating cellular ROS levels, modulating physiological processes, and is intricately linked to tumor progression and drug resistance. However, the underlying mechanisms remain not fully elucidated. Non-coding RNAs (ncRNAs), including long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), are key regulators of GSH levels. Different ncRNAs modulate various pathways involved in GSH metabolism, and these regulatory targets have the potential to serve as therapeutic targets for enhancing cancer treatment. In this review, we summarize the functions of GSH metabolism and highlight the significance of ncRNA-mediated regulation of GSH in cancer progression, drug resistance, and clinical applications.
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Affiliation(s)
- Lu Chang
- Department of Laboratory Medicine, Huashan Hospital Fudan University, Shanghai, 200040, China
| | - Chao Qin
- Department of Laboratory Medicine, Huashan Hospital Fudan University, Shanghai, 200040, China
| | - Jianbo Wu
- Department of Laboratory Medicine, Huashan Hospital Fudan University, Shanghai, 200040, China
| | - Haoqin Jiang
- Department of Laboratory Medicine, Huashan Hospital Fudan University, Shanghai, 200040, China
| | - Qianqian Xu
- Department of Laboratory Medicine, Huashan Hospital Fudan University, Shanghai, 200040, China
| | - Jian Chen
- Department of Laboratory Medicine, Huashan Hospital Fudan University, Shanghai, 200040, China
| | - Xiao Xu
- Department of Laboratory Medicine, Huashan Hospital Fudan University, Shanghai, 200040, China
| | - Xinju Zhang
- Department of Laboratory Medicine, Huashan Hospital Fudan University, Shanghai, 200040, China
| | - Ming Guan
- Department of Laboratory Medicine, Huashan Hospital Fudan University, Shanghai, 200040, China.
| | - Xuan Deng
- Department of Laboratory Medicine, Huashan Hospital Fudan University, Shanghai, 200040, China.
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Khademnematolahi S, Ponist S, Svik K, Drafi F, Slovak L, Muchova J, Mindang EL, Ahmad W, Bauerova K. Therapeutic Effects of Two Different Molecular Weights of Orally Administered Hyaluronan, Both as Monotherapy and in Combination with Methotrexate in a Rat Model of Arthritis. Int J Mol Sci 2025; 26:3958. [PMID: 40362197 PMCID: PMC12071860 DOI: 10.3390/ijms26093958] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2025] [Revised: 04/02/2025] [Accepted: 04/17/2025] [Indexed: 05/15/2025] Open
Abstract
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by joint inflammation and systemic involvement. This study investigates the therapeutic potential of oral hyaluronan (HA) with different molecular weights (SHA: 0.99 MDa and VHA: 1.73 MDa) as monotherapy and in combination with methotrexate (MTX) in a preclinical adjuvant arthritis (AA) model in Lewis rats. The aim was to evaluate the impact of these treatments on biometric, inflammatory, and oxidative stress parameters. The preliminary study tested two doses of HA (0.5 mg/kg and 5 mg/kg), and the pivotal study focused on the combination of 0.5 mg/kg HA with 0.3 mg/kg MTX. Based on our experimental findings on combined therapy, the MTX + SHA combination demonstrated superior efficacy compared to MTX + VHA and MTX monotherapy. Specifically, the MTX + SHA regimen significantly promoted weight gain and reduced hind-paw volume in all monitored experimental days. This treatment markedly reduced plasmatic IL-17A levels (day 21) and GGT activity in both the spleen and joints (day 28), showing the most pronounced effects among all groups, including the MTX monotherapy group. The MTX + VHA combination showed a therapeutic response comparable to MTX alone, indicating no additional benefit. These findings suggest a superior efficacy of the MTX + SHA combination in comparison to other studied treatments. The overall efficacy can be ranked as: MTX ≈ MTX + VHA < MTX + SHA.
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Affiliation(s)
- Sasan Khademnematolahi
- Centre of Experimental Medicine SAS, Institute of Experimental Pharmacology and Toxicology, 841 04 Bratislava, Slovakia; (S.K.); (S.P.); (K.S.); (F.D.); (W.A.)
- Faculty of Natural Sciences, Comenius University, 814 99 Bratislava, Slovakia
| | - Silvester Ponist
- Centre of Experimental Medicine SAS, Institute of Experimental Pharmacology and Toxicology, 841 04 Bratislava, Slovakia; (S.K.); (S.P.); (K.S.); (F.D.); (W.A.)
| | - Karol Svik
- Centre of Experimental Medicine SAS, Institute of Experimental Pharmacology and Toxicology, 841 04 Bratislava, Slovakia; (S.K.); (S.P.); (K.S.); (F.D.); (W.A.)
| | - Frantisek Drafi
- Centre of Experimental Medicine SAS, Institute of Experimental Pharmacology and Toxicology, 841 04 Bratislava, Slovakia; (S.K.); (S.P.); (K.S.); (F.D.); (W.A.)
| | - Lukas Slovak
- State Institute for Drug Control, 825 08 Bratislava, Slovakia;
| | - Jana Muchova
- Institute of Medical Chemistry, Biochemistry and Clinical Biochemistry, Faculty of Medicine, Comenius University, 811 08 Bratislava, Slovakia;
| | - Elisabeth Louise Mindang
- Department of Animal Biology and Physiology, Faculty of Science, University of Yaounde I, Yaoundé P.O. Box 337, Cameroon;
| | - Waqar Ahmad
- Centre of Experimental Medicine SAS, Institute of Experimental Pharmacology and Toxicology, 841 04 Bratislava, Slovakia; (S.K.); (S.P.); (K.S.); (F.D.); (W.A.)
- Faculty of Natural Sciences, Comenius University, 814 99 Bratislava, Slovakia
| | - Katarina Bauerova
- Centre of Experimental Medicine SAS, Institute of Experimental Pharmacology and Toxicology, 841 04 Bratislava, Slovakia; (S.K.); (S.P.); (K.S.); (F.D.); (W.A.)
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Sastre J, Pérez S, Sabater L, Rius-Pérez S. Redox signaling in the pancreas in health and disease. Physiol Rev 2025; 105:593-650. [PMID: 39324871 DOI: 10.1152/physrev.00044.2023] [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: 12/04/2023] [Revised: 09/11/2024] [Accepted: 09/17/2024] [Indexed: 09/27/2024] Open
Abstract
This review addresses oxidative stress and redox signaling in the pancreas under healthy physiological conditions as well as in acute pancreatitis, chronic pancreatitis, pancreatic cancer, and diabetes. Physiological redox homeodynamics is maintained mainly by NRF2/KEAP1, NF-κB, protein tyrosine phosphatases, peroxisome proliferator-activated receptor-γ coactivator 1α (PGC1α), and normal autophagy. Depletion of reduced glutathione (GSH) in the pancreas is a hallmark of acute pancreatitis and is initially accompanied by disulfide stress, which is characterized by protein cysteinylation without increased glutathione oxidation. A cross talk between oxidative stress, MAPKs, and NF-κB amplifies the inflammatory cascade, with PP2A and PGC1α as key redox regulatory nodes. In acute pancreatitis, nitration of cystathionine-β synthase causes blockade of the transsulfuration pathway leading to increased homocysteine levels, whereas p53 triggers necroptosis in the pancreas through downregulation of sulfiredoxin, PGC1α, and peroxiredoxin 3. Chronic pancreatitis exhibits oxidative distress mediated by NADPH oxidase 1 and/or CYP2E1, which promotes cell death, fibrosis, and inflammation. Oxidative stress cooperates with mutant KRAS to initiate and promote pancreatic adenocarcinoma. Mutant KRAS increases mitochondrial reactive oxygen species (ROS), which trigger acinar-to-ductal metaplasia and progression to pancreatic intraepithelial neoplasia (PanIN). ROS are maintained at a sufficient level to promote cell proliferation, while avoiding cell death or senescence through formation of NADPH and GSH and activation of NRF2, HIF-1/2α, and CREB. Redox signaling also plays a fundamental role in differentiation, proliferation, and insulin secretion of β-cells. However, ROS overproduction promotes β-cell dysfunction and apoptosis in type 1 and type 2 diabetes.
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Affiliation(s)
- Juan Sastre
- Department of Physiology, Faculty of Pharmacy, University of Valencia, Valencia, Spain
| | - Salvador Pérez
- Department of Physiology, Faculty of Pharmacy, University of Valencia, Valencia, Spain
| | - Luis Sabater
- Liver, Biliary and Pancreatic Unit, Hospital Clínico, Department of Surgery, Faculty of Medicine, University of Valencia, Valencia, Spain
| | - Sergio Rius-Pérez
- Department of Physiology, Faculty of Pharmacy, University of Valencia, Valencia, Spain
- Department of Cell Biology, Functional Biology and Physical Anthropology, Faculty of Biology, University of Valencia, Valencia, Spain
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Tiek D, Song X, Yu X, Wu R, Iglesia R, Catezone A, McCortney K, Walshon J, Horbinski C, Jamshidi P, Castellani R, Vassar R, Miska J, Hu B, Cheng SY. Oxidative stress induced protein aggregation via GGCT produced pyroglutamic acid in drug resistant glioblastoma. iScience 2025; 28:111769. [PMID: 39949960 PMCID: PMC11821397 DOI: 10.1016/j.isci.2025.111769] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Revised: 09/13/2024] [Accepted: 01/06/2025] [Indexed: 02/16/2025] Open
Abstract
Drug resistance is a major barrier to cancer therapies and remains poorly understood. Recently, non-mutational mechanisms of drug resistance have been proposed where a more plastic metabolic response can play a major role. Here, we show that upon drug resistance, glioblastoma (GBM) cells have increased oxidative stress, mitochondria function, and protein aggregation. Gamma (γ)-glutamylcyclotranserase (GGCT), an enzyme in the γ-glutamyl cycle for glutathione production, located on chromosome 7 which is commonly amplified in GBM is also increased upon resistance. We further observe that the byproduct of GGCT-pyroglutamic acid-can bind aggregating proteins and that genetic and pharmacological inhibition of GGCT prevents protein aggregation. Finally, we found increased protein aggregation, GGCT expression, and pyroglutamic acid staining in recurrent GBM patient samples, adjacent non-tumor brain, and Alzheimer's brains. These findings suggest a new pathway for protein aggregation within drug resistant brain cancer that should be further studied in other brain disorders.
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Affiliation(s)
- Deanna Tiek
- The Ken & Ruth Davee Department of Neurology, The Lou and Jean Malnati Brain Tumor Institute, The Robert H. Lurie Comprehensive Cancer Center, Simpson Querrey Institute for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Xiao Song
- The Ken & Ruth Davee Department of Neurology, The Lou and Jean Malnati Brain Tumor Institute, The Robert H. Lurie Comprehensive Cancer Center, Simpson Querrey Institute for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Xiaozhou Yu
- The Ken & Ruth Davee Department of Neurology, The Lou and Jean Malnati Brain Tumor Institute, The Robert H. Lurie Comprehensive Cancer Center, Simpson Querrey Institute for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Runxin Wu
- The Ken & Ruth Davee Department of Neurology, The Lou and Jean Malnati Brain Tumor Institute, The Robert H. Lurie Comprehensive Cancer Center, Simpson Querrey Institute for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Rebeca Iglesia
- The Ken & Ruth Davee Department of Neurology, The Lou and Jean Malnati Brain Tumor Institute, The Robert H. Lurie Comprehensive Cancer Center, Simpson Querrey Institute for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Alicia Catezone
- Departments of Pathology and Neurological Surgery, The Lou and Jean Malnati Brain Tumor Institute, The Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Katy McCortney
- Departments of Pathology and Neurological Surgery, The Lou and Jean Malnati Brain Tumor Institute, The Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Jordain Walshon
- Departments of Pathology and Neurological Surgery, The Lou and Jean Malnati Brain Tumor Institute, The Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Craig Horbinski
- Departments of Pathology and Neurological Surgery, The Lou and Jean Malnati Brain Tumor Institute, The Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Pouya Jamshidi
- Department of Pathology, Northwestern University Feinberg School of Medicine, The Mesulam Center for Cognitive Neurology and Alzheimer’s Disease, Chicago, IL 60611, USA
| | - Rudolph Castellani
- Department of Pathology, Northwestern University Feinberg School of Medicine, The Mesulam Center for Cognitive Neurology and Alzheimer’s Disease, Chicago, IL 60611, USA
| | - Robert Vassar
- The Ken & Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, The Mesulam Center for Cognitive Neurology and Alzheimer’s Disease, Chicago, IL 60611, USA
| | - Jason Miska
- Department of Neurosurgery, The Lou and Jean Malnati Brain Tumor Institute, The Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Bo Hu
- The Ken & Ruth Davee Department of Neurology, The Lou and Jean Malnati Brain Tumor Institute, The Robert H. Lurie Comprehensive Cancer Center, Simpson Querrey Institute for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Shi-Yuan Cheng
- The Ken & Ruth Davee Department of Neurology, The Lou and Jean Malnati Brain Tumor Institute, The Robert H. Lurie Comprehensive Cancer Center, Simpson Querrey Institute for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
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Di Girolamo FG, Mearelli F, Sturma M, Fiotti N, Teraž K, Ivetac A, Nunnari A, Vinci P, Šimunič B, Pišot R, Biolo G. Initial Glutathione Depletion During Short-Term Bed Rest: Pinpointing Synthesis and Degradation Checkpoints in the γ-Glutamyl Cycle. Antioxidants (Basel) 2024; 13:1430. [PMID: 39765759 PMCID: PMC11672811 DOI: 10.3390/antiox13121430] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Revised: 11/05/2024] [Accepted: 11/13/2024] [Indexed: 01/11/2025] Open
Abstract
Hypokinesia triggers oxidative stress and accelerates the turnover of the glutathione system via the γ-glutamyl cycle. Our study aimed to identify the regulatory checkpoints controlling intracellular glutathione levels. We measured the intermediate substrates of the γ-glutamyl cycle in erythrocytes from 19 healthy young male volunteers before and during a 10-day experimental bed rest. Additionally, we tracked changes in glutathione levels and specific metabolite ratios up to 21 days of bed rest. Using gas chromatography-mass spectrometry and the internal standard technique, we observed a 9 ± 9% decrease in glutathione levels during the first 5 days of bed rest, followed by an 11 ± 9% increase from the 5th to the 10th day, nearly returning to baseline ambulatory levels. The cysteinyl-glycine-to-glutathione ratio, reflecting γ-glutamyl cyclotransferase activity (a key enzyme in glutathione breakdown), rose by 14 ± 22% in the first 5 days and then fell by 10 ± 14% over the subsequent 5 days, again approaching baseline levels. Additionally, the γ-glutamyl cysteine-to-cysteine ratio, indicative of γ-glutamyl cysteine synthetase activity (crucial for glutathione synthesis), increased by 12 ± 30% on day 5 and by 29 ± 41% on day 10 of bed rest. The results observed on day 21 of bed rest confirm those seen on day 10. By calculating the ratio of product concentration to precursor concentration, we assessed the efficiency of these key enzymes in glutathione turnover. These results were corroborated by directly measuring glutathione synthesis and degradation rates in vivo using stable isotope techniques. Our findings reveal significant changes in glutathione kinetics during the initial days of bed rest and identify potential therapeutic targets for maintaining glutathione levels.
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Affiliation(s)
- Filippo Giorgio Di Girolamo
- Department of Medical Surgical and Health Sciences, ASUGI, University of Trieste, 34127 Trieste, Italy; (F.G.D.G.); (M.S.); (N.F.); (K.T.); (A.I.)
- Hospital Pharmacy, Cattinara Hospital, Azienda Sanitaria Universitaria Giuliano Isontina, 34148 Trieste, Italy
| | - Filippo Mearelli
- Clinica Medica, Department of Medical Surgical and Health Sciences, ASUGI, University of Trieste, 34127 Trieste, Italy; (F.M.); (A.N.); (P.V.)
| | - Mariella Sturma
- Department of Medical Surgical and Health Sciences, ASUGI, University of Trieste, 34127 Trieste, Italy; (F.G.D.G.); (M.S.); (N.F.); (K.T.); (A.I.)
| | - Nicola Fiotti
- Department of Medical Surgical and Health Sciences, ASUGI, University of Trieste, 34127 Trieste, Italy; (F.G.D.G.); (M.S.); (N.F.); (K.T.); (A.I.)
| | - Kaja Teraž
- Department of Medical Surgical and Health Sciences, ASUGI, University of Trieste, 34127 Trieste, Italy; (F.G.D.G.); (M.S.); (N.F.); (K.T.); (A.I.)
- Institute for Kinesiology Research, Science and Research Centre Koper, 6000 Koper, Slovenia; (B.Š.); (R.P.)
| | - Alja Ivetac
- Department of Medical Surgical and Health Sciences, ASUGI, University of Trieste, 34127 Trieste, Italy; (F.G.D.G.); (M.S.); (N.F.); (K.T.); (A.I.)
| | - Alessio Nunnari
- Clinica Medica, Department of Medical Surgical and Health Sciences, ASUGI, University of Trieste, 34127 Trieste, Italy; (F.M.); (A.N.); (P.V.)
| | - Pierandrea Vinci
- Clinica Medica, Department of Medical Surgical and Health Sciences, ASUGI, University of Trieste, 34127 Trieste, Italy; (F.M.); (A.N.); (P.V.)
| | - Boštjan Šimunič
- Institute for Kinesiology Research, Science and Research Centre Koper, 6000 Koper, Slovenia; (B.Š.); (R.P.)
| | - Rado Pišot
- Institute for Kinesiology Research, Science and Research Centre Koper, 6000 Koper, Slovenia; (B.Š.); (R.P.)
| | - Gianni Biolo
- Department of Medical Surgical and Health Sciences, ASUGI, University of Trieste, 34127 Trieste, Italy; (F.G.D.G.); (M.S.); (N.F.); (K.T.); (A.I.)
- Clinica Medica, Department of Medical Surgical and Health Sciences, ASUGI, University of Trieste, 34127 Trieste, Italy; (F.M.); (A.N.); (P.V.)
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Pružinská K, Chrastina M, Khademnematolahi S, Vyletelová V, Gajdošová L, Pastvová L, Dráfi F, Poništ S, Pašková Ľ, Kucharská J, Sumbalová Z, Muchová J, Martiniaková S, Bauerová K. Astaxanthin, Compared to Other Carotenoids, Increases the Efficacy of Methotrexate in Rat Adjuvant Arthritis. Int J Mol Sci 2024; 25:8710. [PMID: 39201397 PMCID: PMC11354740 DOI: 10.3390/ijms25168710] [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] [Revised: 07/31/2024] [Accepted: 08/02/2024] [Indexed: 09/02/2024] Open
Abstract
This in vivo study performed in rat adjuvant arthritis aims to advance the understanding of astaxanthin's therapeutic properties for the possible treatment of rheumatoid arthritis (RA) in monotherapy and along with the standard RA treatment, methotrexate (MTX), in combination therapy. The main goal was to elucidate astaxanthin's full therapeutic potential, evaluate its dose dependency, and compare its effects in monotherapy with other carotenoids such as β-carotene and β-cryptoxanthin (KXAN). Moreover, potential differences in therapeutic activity caused by using different sources of astaxanthin, synthetic (ASYN) versus isolated from Blakeslea trispora (ASTAP), were evaluated using one-way ANOVA (Tukey-Kramer post hoc test). KXAN was the most effective in reducing plasma MMP-9 levels in monotherapy, significantly better than MTX, and in reducing hind paw swelling. The differences in the action of ASTAP and ASYN have been observed across various biometric, anti-inflammatory, and antioxidative parameters. In combined therapy with MTX, the ASYN + MTX combination proved to be better. These findings, especially the significant anti-arthritic effect of KXAN and ASYN + MTX, could be the basis for further preclinical studies.
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Affiliation(s)
- Katarína Pružinská
- Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Malá Hora 10701/4A, 036 01 Martin, Slovakia;
- Institute of Experimental Pharmacology and Toxicology, Centre of Experimental Medicine SAS, 841 04 Bratislava, Slovakia; (M.C.); (S.K.); (F.D.); (S.P.)
| | - Martin Chrastina
- Institute of Experimental Pharmacology and Toxicology, Centre of Experimental Medicine SAS, 841 04 Bratislava, Slovakia; (M.C.); (S.K.); (F.D.); (S.P.)
| | - Sasan Khademnematolahi
- Institute of Experimental Pharmacology and Toxicology, Centre of Experimental Medicine SAS, 841 04 Bratislava, Slovakia; (M.C.); (S.K.); (F.D.); (S.P.)
- Faculty of Natural Sciences, Comenius University in Bratislava, Ilkovičova 6, 842 15 Bratislava, Slovakia
| | - Veronika Vyletelová
- Faculty of Pharmacy, Comenius University in Bratislava, Odbojárov 10, 832 32 Bratislava, Slovakia; (V.V.); (Ľ.P.)
| | - Lívia Gajdošová
- Institute of Medical Chemistry, Biochemistry and Clinical Biochemistry, Faculty of Medicine, Comenius University, Sasinkova 2, 813 72 Bratislava, Slovakia; (L.G.); (L.P.); (Z.S.); (J.M.)
| | - Lucia Pastvová
- Institute of Medical Chemistry, Biochemistry and Clinical Biochemistry, Faculty of Medicine, Comenius University, Sasinkova 2, 813 72 Bratislava, Slovakia; (L.G.); (L.P.); (Z.S.); (J.M.)
| | - František Dráfi
- Institute of Experimental Pharmacology and Toxicology, Centre of Experimental Medicine SAS, 841 04 Bratislava, Slovakia; (M.C.); (S.K.); (F.D.); (S.P.)
| | - Silvester Poništ
- Institute of Experimental Pharmacology and Toxicology, Centre of Experimental Medicine SAS, 841 04 Bratislava, Slovakia; (M.C.); (S.K.); (F.D.); (S.P.)
| | - Ľudmila Pašková
- Faculty of Pharmacy, Comenius University in Bratislava, Odbojárov 10, 832 32 Bratislava, Slovakia; (V.V.); (Ľ.P.)
| | - Jarmila Kucharská
- Pharmacobiochemical Laboratory of Third Department of Internal Medicine, Faculty of Medicine, Comenius University in Bratislava, Špitálska 24, 813 72 Bratislava, Slovakia;
| | - Zuzana Sumbalová
- Institute of Medical Chemistry, Biochemistry and Clinical Biochemistry, Faculty of Medicine, Comenius University, Sasinkova 2, 813 72 Bratislava, Slovakia; (L.G.); (L.P.); (Z.S.); (J.M.)
| | - Jana Muchová
- Institute of Medical Chemistry, Biochemistry and Clinical Biochemistry, Faculty of Medicine, Comenius University, Sasinkova 2, 813 72 Bratislava, Slovakia; (L.G.); (L.P.); (Z.S.); (J.M.)
| | - Silvia Martiniaková
- Department of Food Technology, Institute of Food Science and Nutrition, Faculty of Chemical and Food Technology, Slovak University of Technology in Bratislava, Radlinského 9, 812 37 Bratislava, Slovakia;
| | - Katarína Bauerová
- Institute of Experimental Pharmacology and Toxicology, Centre of Experimental Medicine SAS, 841 04 Bratislava, Slovakia; (M.C.); (S.K.); (F.D.); (S.P.)
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Zhang T, Yao C, Zhou X, Liu S, Qi L, Zhu S, Zhao C, Hu D, Shen W. Glutathione‑degrading enzymes in the complex landscape of tumors (Review). Int J Oncol 2024; 65:72. [PMID: 38847236 PMCID: PMC11173371 DOI: 10.3892/ijo.2024.5660] [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: 01/30/2024] [Accepted: 04/24/2024] [Indexed: 06/12/2024] Open
Abstract
Glutathione (GSH)‑degrading enzymes are essential for starting the first stages of GSH degradation. These enzymes include extracellular γ‑glutamyl transpeptidase (GGT) and intracellular GSH‑specific γ‑glutamylcyclotransferase 1 (ChaC1) and 2. These enzymes are essential for cellular activities, such as immune response, differentiation, proliferation, homeostasis regulation and programmed cell death. Tumor tissue frequently exhibits abnormal expression of GSH‑degrading enzymes, which has a key impact on the development and spread of malignancies. The present review summarizes gene and protein structure, catalytic activity and regulation of GSH‑degrading enzymes, their vital roles in tumor development (including regulation of oxidative and endoplasmic reticulum stress, control of programmed cell death, promotion of inflammation and tumorigenesis and modulation of drug resistance in tumor cells) and potential role as diagnostic biomarkers and therapeutic targets.
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Affiliation(s)
- Tianyi Zhang
- Department of Acupuncture, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, P.R. China
- School of Acupuncture-moxibustion and Tuina, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, P.R. China
| | - Chongjie Yao
- School of Acupuncture-moxibustion and Tuina, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, P.R. China
- Department of Rehabilitation, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, P.R. China
| | - Xu Zhou
- School of Acupuncture-moxibustion and Tuina, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, P.R. China
| | - Shimin Liu
- School of Acupuncture-moxibustion and Tuina, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, P.R. China
- Shanghai Research Institute of Acupuncture and Meridian, Shanghai 200030, P.R. China
| | - Li Qi
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, P.R. China
| | - Shiguo Zhu
- School of Basic Medical Sciences, Center for Traditional Chinese Medicine and Immunology Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, P.R. China
| | - Chen Zhao
- School of Acupuncture-moxibustion and Tuina, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, P.R. China
| | - Dan Hu
- School of Acupuncture-moxibustion and Tuina, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, P.R. China
| | - Weidong Shen
- Department of Acupuncture, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, P.R. China
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Tabata S, Endo H, Makinoshima H, Soga T, Inoue M. The γ-glutamyl cycle serves as an amino acids supply system in colorectal cancer organoids under chronic hypoxia. Biochem Biophys Res Commun 2024; 714:149977. [PMID: 38663093 DOI: 10.1016/j.bbrc.2024.149977] [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: 03/19/2024] [Revised: 04/13/2024] [Accepted: 04/21/2024] [Indexed: 05/07/2024]
Abstract
Malignant tumors are characterized by a hypoxic microenvironment, and metabolic reprogramming is necessary to ensure energy production and oxidative stress resistance. Although the microenvironmental properties of tumors vary under acute and chronic hypoxia, studies on chronic hypoxia-induced metabolic changes are limited. In the present study, we performed a comprehensive metabolic analysis in a chronic hypoxia model using colorectal cancer (CRC) organoids, and identified an amino acid supply system through the γ-glutamyl cycle, a glutathione recycling pathway. We analyzed the metabolic changes caused by hypoxia over time and observed that chronic hypoxia resulted in an increase in 5-oxoproline and a decrease in oxidized glutathione (GSSG) compared to acute hypoxia. These findings suggest that chronic hypoxia induces metabolic changes in the γ-glutamyl cycle. Moreover, inhibition of the γ-glutamyl cycle via γ-glutamyl cyclotransferase (GGCT) and γ-glutamyl transferase 1 (GGT1) knockdown significantly reversed chronic hypoxia-induced upregulation of 5-oxoproline and several amino acids. Notably, GGT1 knockdown downregulated the intracellular levels of γ-glutamyl amino acids. Conclusively, these results indicate that the γ-glutamyl cycle serves as an amino acid supply system in CRC under chronic hypoxia, which provides fresh insight into cancer metabolism under chronic hypoxia.
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Affiliation(s)
- Sho Tabata
- Institute for Advanced Biosciences, Keio University, Tsuruoka, Tsuruoka, 997-0052, Japan; Tsuruoka Metabolomics Laboratory, National Cancer Center, Tsuruoka, 997-0052, Japan; Shonai Regional Industry Promotion Center, Tsuruoka, 997-0052, Japan; Division of Translational Informatics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, 277-8577, Japan.
| | - Hiroko Endo
- Department of Biochemistry, Osaka International Cancer Institute, Osaka, Japan
| | - Hideki Makinoshima
- Tsuruoka Metabolomics Laboratory, National Cancer Center, Tsuruoka, 997-0052, Japan; Shonai Regional Industry Promotion Center, Tsuruoka, 997-0052, Japan; Division of Translational Informatics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, 277-8577, Japan
| | - Tomoyoshi Soga
- Institute for Advanced Biosciences, Keio University, Tsuruoka, Tsuruoka, 997-0052, Japan; Human Biology-Microbiome-Quantum Research Center (WPI-Bio2Q), Keio University, Tokyo, 108-8345 Japan
| | - Masahiro Inoue
- Department of Biochemistry, Osaka International Cancer Institute, Osaka, Japan; Department of Clinical Bio-resource Research and Development, Graduate School of Medicine, Kyoto University, Kyoto, 606-8501, Japan
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9
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Kumar M, Leekha A, Nandy S, Kulkarni R, Martinez-Paniagua M, Rahman Sefat KMS, Willson RC, Varadarajan N. Enzymatic depletion of circulating glutamine is immunosuppressive in cancers. iScience 2024; 27:109817. [PMID: 38770139 PMCID: PMC11103382 DOI: 10.1016/j.isci.2024.109817] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2023] [Revised: 03/13/2024] [Accepted: 04/24/2024] [Indexed: 05/22/2024] Open
Abstract
Although glutamine addiction in cancer cells is extensively reported, there is controversy on the impact of glutamine metabolism on the immune cells within the tumor microenvironment (TME). To address the role of extracellular glutamine, we enzymatically depleted circulating glutamine using PEGylated Helicobacter pylori gamma-glutamyl transferase (PEG-GGT) in syngeneic mouse models of breast and colon cancers. PEG-GGT treatment inhibits growth of cancer cells in vitro, but in vivo it increases myeloid-derived suppressor cells (MDSCs) and has no significant impact on tumor growth. By deriving a glutamine depletion signature, we analyze diverse human cancers within the TCGA and illustrate that glutamine depletion is not associated with favorable clinical outcomes and correlates with accumulation of MDSC. Broadly, our results help clarify the integrated impact of glutamine depletion within the TME and advance PEG-GGT as an enzymatic tool for the systemic and selective depletion (no asparaginase activity) of circulating glutamine in live animals.
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Affiliation(s)
- Monish Kumar
- William A. Brookshire Department of Chemical and Biomolecular Engineering, University of Houston, Houston, TX 77204, USA
| | - Ankita Leekha
- William A. Brookshire Department of Chemical and Biomolecular Engineering, University of Houston, Houston, TX 77204, USA
| | - Suman Nandy
- William A. Brookshire Department of Chemical and Biomolecular Engineering, University of Houston, Houston, TX 77204, USA
| | - Rohan Kulkarni
- William A. Brookshire Department of Chemical and Biomolecular Engineering, University of Houston, Houston, TX 77204, USA
| | - Melisa Martinez-Paniagua
- William A. Brookshire Department of Chemical and Biomolecular Engineering, University of Houston, Houston, TX 77204, USA
| | - K. M. Samiur Rahman Sefat
- William A. Brookshire Department of Chemical and Biomolecular Engineering, University of Houston, Houston, TX 77204, USA
| | - Richard C. Willson
- William A. Brookshire Department of Chemical and Biomolecular Engineering, University of Houston, Houston, TX 77204, USA
| | - Navin Varadarajan
- William A. Brookshire Department of Chemical and Biomolecular Engineering, University of Houston, Houston, TX 77204, USA
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10
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Okada Y. Physiology of the volume-sensitive/regulatory anion channel VSOR/VRAC: part 2: its activation mechanisms and essential roles in organic signal release. J Physiol Sci 2024; 74:34. [PMID: 38877402 PMCID: PMC11177392 DOI: 10.1186/s12576-024-00926-3] [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: 05/05/2024] [Accepted: 06/01/2024] [Indexed: 06/16/2024]
Abstract
The volume-sensitive outwardly rectifying or volume-regulated anion channel, VSOR/VRAC, which was discovered in 1988, is expressed in most vertebrate cell types, and is essentially involved in cell volume regulation after swelling and in the induction of cell death. This series of review articles describes what is already known and what remains to be uncovered about the functional and molecular properties as well as the physiological and pathophysiological roles of VSOR/VRAC. This Part 2 review article describes, from the physiological and pathophysiological standpoints, first the pivotal roles of VSOR/VRAC in the release of autocrine/paracrine organic signal molecules, such as glutamate, ATP, glutathione, cGAMP, and itaconate, as well as second the swelling-independent and -dependent activation mechanisms of VSOR/VRAC. Since the pore size of VSOR/VRAC has now well been evaluated by electrophysiological and 3D-structural methods, the signal-releasing activity of VSOR/VRAC is here discussed by comparing the molecular sizes of these organic signals to the channel pore size. Swelling-independent activation mechanisms include a physicochemical one caused by the reduction of intracellular ionic strength and a biochemical one caused by oxidation due to stimulation by receptor agonists or apoptosis inducers. Because some organic substances released via VSOR/VRAC upon cell swelling can trigger or augment VSOR/VRAC activation in an autocrine fashion, swelling-dependent activation mechanisms are to be divided into two phases: the first phase induced by cell swelling per se and the second phase caused by receptor stimulation by released organic signals.
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Affiliation(s)
- Yasunobu Okada
- National Institute for Physiological Sciences (NIPS), 5-1 Higashiyama, Myodaiji, Okazaki, Aichi, 444-8787, Japan.
- Department of Integrative Physiology, Graduate School of Medicine, Akita University, Akita, Japan.
- Department of Physiology, School of Medicine, Aichi Medical University, Nagakute, Japan.
- Graduate University for Advanced Studies (SOKENDAI), Hayama, Kanagawa, Japan.
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11
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Fei C, Zhen X, Shiqiang Z, Jun P. Frontier knowledge and future directions of programmed cell death in clear cell renal cell carcinoma. Cell Death Discov 2024; 10:113. [PMID: 38443363 PMCID: PMC10914743 DOI: 10.1038/s41420-024-01880-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 02/17/2024] [Accepted: 02/21/2024] [Indexed: 03/07/2024] Open
Abstract
Clear cell renal cell carcinoma (ccRCC) is one of the most common renal malignancies of the urinary system. Patient outcomes are relatively poor due to the lack of early diagnostic markers and resistance to existing treatment options. Programmed cell death, also known as apoptosis, is a highly regulated and orchestrated form of cell death that occurs ubiquitously throughout various physiological processes. It plays a crucial role in maintaining homeostasis and the balance of cellular activities. The combination of immune checkpoint inhibitors plus targeted therapies is the first-line therapy to advanced RCC. Immune checkpoint inhibitors(ICIs) targeted CTLA-4 and PD-1 have been demonstrated to prompt tumor cell death by immunogenic cell death. Literatures on the rationale of VEGFR inhibitors and mTOR inhibitors to suppress RCC also implicate autophagic, apoptosis and ferroptosis. Accordingly, investigations of cell death modes have important implications for the improvement of existing treatment modalities and the proposal of new therapies for RCC. At present, the novel modes of cell death in renal cancer include ferroptosis, immunogenic cell death, apoptosis, pyroptosis, necroptosis, parthanatos, netotic cell death, cuproptosis, lysosomal-dependent cell death, autophagy-dependent cell death and mpt-driven necrosis, all of which belong to programmed cell death. In this review, we briefly describe the classification of cell death, and discuss the interactions and development between ccRCC and these novel forms of cell death, with a focus on ferroptosis, immunogenic cell death, and apoptosis, in an effort to present the theoretical underpinnings and research possibilities for the diagnosis and targeted treatment of ccRCC.
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Affiliation(s)
- Cao Fei
- Department of Urology, Pelvic Floor Disorders Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, 518107, China
- Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, 518107, China
| | - Xu Zhen
- Department of Urology, Pelvic Floor Disorders Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, 518107, China
- Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, 518107, China
| | - Zhang Shiqiang
- Department of Urology, Pelvic Floor Disorders Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, 518107, China.
| | - Pang Jun
- Department of Urology, Pelvic Floor Disorders Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, 518107, China.
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12
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Zheng R, Wang C, Liu R, Cai R, Sun C. Physiological and metabolic insights into the first cultured anaerobic representative of deep-sea Planctomycetes bacteria. eLife 2024; 12:RP89874. [PMID: 38265071 PMCID: PMC10945688 DOI: 10.7554/elife.89874] [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] [Indexed: 01/25/2024] Open
Abstract
Planctomycetes bacteria are ubiquitously distributed across various biospheres and play key roles in global element cycles. However, few deep-sea Planctomycetes members have been cultivated, limiting our understanding of Planctomycetes in the deep biosphere. Here, we have successfully cultured a novel strain of Planctomycetes (strain ZRK32) from a deep-sea cold seep sediment. Our genomic, physiological, and phylogenetic analyses indicate that strain ZRK32 is a novel species, which we propose be named: Poriferisphaera heterotrophicis. We show that strain ZRK32 replicates using a budding mode of division. Based on the combined results from growth assays and transcriptomic analyses, we found that rich nutrients, or supplementation with NO3- or NH4+ promoted the growth of strain ZRK32 by facilitating energy production through the tricarboxylic acid cycle and the Embden-Meyerhof-Parnas glycolysis pathway. Moreover, supplementation with NO3- or NH4+ induced strain ZRK32 to release a bacteriophage in a chronic manner, without host cell lysis. This bacteriophage then enabled strain ZRK32, and another marine bacterium that we studied, to metabolize nitrogen through the function of auxiliary metabolic genes. Overall, these findings expand our understanding of deep-sea Planctomycetes bacteria, while highlighting their ability to metabolize nitrogen when reprogrammed by chronic viruses.
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Affiliation(s)
- Rikuan Zheng
- CAS and Shandong Province Key Laboratory of Experimental Marine Biology & Center of Deep Sea Research, Institute of Oceanology, Chinese Academy of SciencesQingdaoChina
- Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and TechnologyQingdaoChina
- Center of Ocean Mega-Science, Chinese Academy of SciencesQingdaoChina
| | - Chong Wang
- CAS and Shandong Province Key Laboratory of Experimental Marine Biology & Center of Deep Sea Research, Institute of Oceanology, Chinese Academy of SciencesQingdaoChina
- Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and TechnologyQingdaoChina
- Center of Ocean Mega-Science, Chinese Academy of SciencesQingdaoChina
| | - Rui Liu
- CAS and Shandong Province Key Laboratory of Experimental Marine Biology & Center of Deep Sea Research, Institute of Oceanology, Chinese Academy of SciencesQingdaoChina
- Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and TechnologyQingdaoChina
- Center of Ocean Mega-Science, Chinese Academy of SciencesQingdaoChina
| | - Ruining Cai
- CAS and Shandong Province Key Laboratory of Experimental Marine Biology & Center of Deep Sea Research, Institute of Oceanology, Chinese Academy of SciencesQingdaoChina
- Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and TechnologyQingdaoChina
- Center of Ocean Mega-Science, Chinese Academy of SciencesQingdaoChina
- College of Earth Science, University of Chinese Academy of SciencesBeijingChina
| | - Chaomin Sun
- CAS and Shandong Province Key Laboratory of Experimental Marine Biology & Center of Deep Sea Research, Institute of Oceanology, Chinese Academy of SciencesQingdaoChina
- Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and TechnologyQingdaoChina
- Center of Ocean Mega-Science, Chinese Academy of SciencesQingdaoChina
- College of Earth Science, University of Chinese Academy of SciencesBeijingChina
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13
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Hecht F, Zocchi M, Alimohammadi F, Harris IS. Regulation of antioxidants in cancer. Mol Cell 2024; 84:23-33. [PMID: 38029751 PMCID: PMC10843710 DOI: 10.1016/j.molcel.2023.11.001] [Citation(s) in RCA: 23] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Revised: 10/19/2023] [Accepted: 11/01/2023] [Indexed: 12/01/2023]
Abstract
Scientists in this field often joke, "If you don't have a mechanism, say it's ROS." Seemingly connected to every biological process ever described, reactive oxygen species (ROS) have numerous pleiotropic roles in physiology and disease. In some contexts, ROS act as secondary messengers, controlling a variety of signaling cascades. In other scenarios, they initiate damage to macromolecules. Finally, in their worst form, ROS are deadly to cells and surrounding tissues. A set of molecules with detoxifying abilities, termed antioxidants, is the direct counterpart to ROS. Notably, antioxidants exist in the public domain, touted as a "cure-all" for diseases. Research has disproved many of these claims and, in some cases, shown the opposite. Of all the diseases, cancer stands out in its paradoxical relationship with antioxidants. Although the field has made numerous strides in understanding the roles of antioxidants in cancer, many questions remain.
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Affiliation(s)
- Fabio Hecht
- Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY 14642, USA; Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 14642, USA
| | - Marco Zocchi
- Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY 14642, USA; Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 14642, USA
| | - Fatemeh Alimohammadi
- Department of Pharmacology and Physiology, University of Rochester, Rochester, NY 14642, USA; Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 14642, USA
| | - Isaac S Harris
- Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY 14642, USA; Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 14642, USA.
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14
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Lapenna D. Glutathione and glutathione-dependent enzymes: From biochemistry to gerontology and successful aging. Ageing Res Rev 2023; 92:102066. [PMID: 37683986 DOI: 10.1016/j.arr.2023.102066] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2023] [Revised: 08/24/2023] [Accepted: 09/04/2023] [Indexed: 09/10/2023]
Abstract
The tripeptide glutathione (GSH), namely γ-L-glutamyl-L-cysteinyl-glycine, is an ubiquitous low-molecular weight thiol nucleophile and reductant of utmost importance, representing the central redox agent of most aerobic organisms. GSH has vital functions involving also antioxidant protection, detoxification, redox homeostasis, cell signaling, iron metabolism/homeostasis, DNA synthesis, gene expression, cysteine/protein metabolism, and cell proliferation/differentiation or death including apoptosis and ferroptosis. Various functions of GSH are exerted in concert with GSH-dependent enzymes. Indeed, although GSH has direct scavenging antioxidant effects, its antioxidant function is substantially accomplished by glutathione peroxidase-catalyzed reactions with reductive removal of H2O2, organic peroxides such as lipid hydroperoxides, and peroxynitrite; to this antioxidant activity also contribute peroxiredoxins, enzymes further involved in redox signaling and chaperone activity. Moreover, the detoxifying function of GSH is basically exerted in conjunction with glutathione transferases, which have also antioxidant properties. GSH is synthesized in the cytosol by the ATP-dependent enzymes glutamate cysteine ligase (GCL), which catalyzes ligation of cysteine and glutamate forming γ-glutamylcysteine (γ-GC), and glutathione synthase, which adds glycine to γ-GC resulting in GSH formation; GCL is rate-limiting for GSH synthesis, as is the precursor amino acid cysteine, which may be supplemented as N-acetylcysteine (NAC), a therapeutically available compound. After its cell export, GSH is degraded extracellularly by the membrane-anchored ectoenzyme γ-glutamyl transferase, a process occurring, as GSH synthesis and export, in the γ-glutamyl cycle. GSH degradation occurs also intracellularly by the cytoplasmic enzymatic ChaC family of γ-glutamyl cyclotransferase. Synthesis and degradation of GSH, together with its export, translocation to cell organelles, utilization for multiple essential functions, and regeneration from glutathione disulfide by glutathione reductase, are relevant to GSH homeostasis and metabolism. Notably, GSH levels decline during aging, an alteration generally related to impaired GSH biosynthesis and leading to cell dysfunction. However, there is evidence of enhanced GSH levels in elderly subjects with excellent physical and mental health status, suggesting that heightened GSH may be a marker and even a causative factor of increased healthspan and lifespan. Such aspects, and much more including GSH-boosting substances administrable to humans, are considered in this state-of-the-art review, which deals with GSH and GSH-dependent enzymes from biochemistry to gerontology, focusing attention also on lifespan/healthspan extension and successful aging; the significance of GSH levels in aging is considered also in relation to therapeutic possibilities and supplementation strategies, based on the use of various compounds including NAC-glycine, aimed at increasing GSH and related defenses to improve health status and counteract aging processes in humans.
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Affiliation(s)
- Domenico Lapenna
- Dipartimento di Medicina e Scienze dell'Invecchiamento, and Laboratorio di Fisiopatologia dello Stress Ossidativo, Center for Advanced Studies and Technology (CAST, former CeSI-MeT, Center of Excellence on Aging), Università degli Studi "G. d'Annunzio" Chieti Pescara, U.O.C. Medicina Generale 2, Ospedale Clinicizzato "Santissima Annunziata", Via dei Vestini, 66100 Chieti, Italy.
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15
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Georgiou-Siafis SK, Tsiftsoglou AS. The Key Role of GSH in Keeping the Redox Balance in Mammalian Cells: Mechanisms and Significance of GSH in Detoxification via Formation of Conjugates. Antioxidants (Basel) 2023; 12:1953. [PMID: 38001806 PMCID: PMC10669396 DOI: 10.3390/antiox12111953] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2023] [Revised: 10/18/2023] [Accepted: 10/23/2023] [Indexed: 11/26/2023] Open
Abstract
Glutathione (GSH) is a ubiquitous tripeptide that is biosynthesized in situ at high concentrations (1-5 mM) and involved in the regulation of cellular homeostasis via multiple mechanisms. The main known action of GSH is its antioxidant capacity, which aids in maintaining the redox cycle of cells. To this end, GSH peroxidases contribute to the scavenging of various forms of ROS and RNS. A generally underestimated mechanism of action of GSH is its direct nucleophilic interaction with electrophilic compounds yielding thioether GSH S-conjugates. Many compounds, including xenobiotics (such as NAPQI, simvastatin, cisplatin, and barbital) and intrinsic compounds (such as menadione, leukotrienes, prostaglandins, and dopamine), form covalent adducts with GSH leading mainly to their detoxification. In the present article, we wish to present the key role and significance of GSH in cellular redox biology. This includes an update on the formation of GSH-S conjugates or GSH adducts with emphasis given to the mechanism of reaction, the dependence on GST (GSH S-transferase), where this conjugation occurs in tissues, and its significance. The uncovering of the GSH adducts' formation enhances our knowledge of the human metabolome. GSH-hematin adducts were recently shown to have been formed spontaneously in multiples isomers at hemolysates, leading to structural destabilization of the endogenous toxin, hematin (free heme), which is derived from the released hemoglobin. Moreover, hemin (the form of oxidized heme) has been found to act through the Kelch-like ECH associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor-2 (Nrf2) signaling pathway as an epigenetic modulator of GSH metabolism. Last but not least, the implications of the genetic defects in GSH metabolism, recorded in hemolytic syndromes, cancer and other pathologies, are presented and discussed under the framework of conceptualizing that GSH S-conjugates could be regarded as signatures of the cellular metabolism in the diseased state.
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Affiliation(s)
| | - Asterios S. Tsiftsoglou
- Laboratory of Pharmacology, Department of Pharmaceutical Sciences, School of Health Sciences, Aristotle University of Thessaloniki (AUTh), 54124 Thessaloniki, Greece;
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16
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Chrastina M, Dráfi F, Pružinská K, Poništ S, Kamga KS, Khademnematolahi S, Bilka F, Novák P, Pašková Ľ, Bauerová K. Crocus sativus L. Extract (Saffron) Effectively Reduces Arthritic and Inflammatory Parameters in Monotherapy and in Combination with Methotrexate in Adjuvant Arthritis. Nutrients 2023; 15:4108. [PMID: 37836391 PMCID: PMC10574733 DOI: 10.3390/nu15194108] [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: 08/18/2023] [Revised: 09/18/2023] [Accepted: 09/20/2023] [Indexed: 10/15/2023] Open
Abstract
Rheumatoid arthritis (RA), an autoimmune disease, is characterized by inflammation that affects not only the liver but also other organs and the musculoskeletal system. The standard therapy for RA is methotrexate (MTX), which has safety limitations. The extract from Crocus sativus L. (saffron-SF) is also known for its anti-inflammatory effects. Therefore, we decided to investigate the potential benefit of SF in monotherapy via two doses (SF1-25 mg/kg of b.w.; SF2-50 mg/kg of b.w.) and in combination with MTX (0.3 mg/kg of b.w., twice a week) using adjuvant arthritis in rats. To evaluate these therapeutic settings, we used biometric, immunological, and biochemical parameters, as well as the relative gene expression of the mRNA in the liver. Our results showed a statistically significant increase in the experimental animals' body weight and the arthritic score (AS) on day 14 for monotherapy with SF1 and SF2. The change of hind paw volume (CHPV) was significant only for SF2 monotherapy on the 14th day of the experiment. A combination of SF1 and SF2 with MTX significantly modulated all the biometric parameters during the experimental period. Additionally, AS and CHPV improved considerably compared to MTX monotherapy on day 21. Furthermore, all monotherapies and combination therapies were significant for the biochemical parameter γ-glutamyl transferase (GGT) in the joint. GGT activity in the spleen was less pronounced; only MTX in combination with SF1 significantly modified this parameter. The higher dose of SF monotherapy (SF2) was similarly significant with respect to immunological parameters, such as plasmatic IL-17A, IL-1β, and MMP-9 on day 21. The combination of both doses of SF with MTX significantly improved these immunological parameters, except for C-reactive protein (CRP), which was influenced only by the higher dose of SF2 in combination with MTX in plasma at the end of the experiment. A different effect was found for the relative expression of CD36 mRNA, where only SF1 significantly decreased gene expression in the liver. However, the relative gene mRNA expression of IL-1β in the liver was significantly reduced by the SF monotherapies and the combination of both SF doses with MTX. Our findings showed SF's partial antiarthritic and anti-inflammatory potential in monotherapy, but the effect was stronger in combination with MTX.
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Affiliation(s)
- Martin Chrastina
- Institute of Experimental Pharmacology and Toxicology, Centre of Experimental Medicine SAS, 841 04 Bratislava, Slovakia; (M.C.); (K.P.); (S.P.); (K.S.K.); (S.K.)
- Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Malá Hora 10701/4A, 036 01 Martin, Slovakia
| | - František Dráfi
- Institute of Experimental Pharmacology and Toxicology, Centre of Experimental Medicine SAS, 841 04 Bratislava, Slovakia; (M.C.); (K.P.); (S.P.); (K.S.K.); (S.K.)
| | - Katarína Pružinská
- Institute of Experimental Pharmacology and Toxicology, Centre of Experimental Medicine SAS, 841 04 Bratislava, Slovakia; (M.C.); (K.P.); (S.P.); (K.S.K.); (S.K.)
- Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Malá Hora 10701/4A, 036 01 Martin, Slovakia
| | - Silvester Poništ
- Institute of Experimental Pharmacology and Toxicology, Centre of Experimental Medicine SAS, 841 04 Bratislava, Slovakia; (M.C.); (K.P.); (S.P.); (K.S.K.); (S.K.)
| | - Kevine Silihe Kamga
- Institute of Experimental Pharmacology and Toxicology, Centre of Experimental Medicine SAS, 841 04 Bratislava, Slovakia; (M.C.); (K.P.); (S.P.); (K.S.K.); (S.K.)
- Faculty of Science, University of Yaoundé 1, Yaoundé P.O. Box 812, Cameroon
- Faculty of Medicine and Biomedical Sciences, University of Yaoundé 1, Yaoundé P.O. Box 1364, Cameroon
| | - Sasan Khademnematolahi
- Institute of Experimental Pharmacology and Toxicology, Centre of Experimental Medicine SAS, 841 04 Bratislava, Slovakia; (M.C.); (K.P.); (S.P.); (K.S.K.); (S.K.)
- Faculty of Natural Sciences, Comenius University in Bratislava, Ilkovičova 6, 842 15 Bratislava, Slovakia
| | - František Bilka
- Faculty of Pharmacy, Comenius University in Bratislava, Odbojárov 10, 832 32 Bratislava, Slovakia; (F.B.); (P.N.); (Ľ.P.)
| | - Peter Novák
- Faculty of Pharmacy, Comenius University in Bratislava, Odbojárov 10, 832 32 Bratislava, Slovakia; (F.B.); (P.N.); (Ľ.P.)
| | - Ľudmila Pašková
- Faculty of Pharmacy, Comenius University in Bratislava, Odbojárov 10, 832 32 Bratislava, Slovakia; (F.B.); (P.N.); (Ľ.P.)
| | - Katarína Bauerová
- Institute of Experimental Pharmacology and Toxicology, Centre of Experimental Medicine SAS, 841 04 Bratislava, Slovakia; (M.C.); (K.P.); (S.P.); (K.S.K.); (S.K.)
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Kharouba M, Patel DD, Jaber RH, Mahmoud SH. Metabolomic Analysis in Neurocritical Care Patients. Metabolites 2023; 13:745. [PMID: 37367902 DOI: 10.3390/metabo13060745] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 06/07/2023] [Accepted: 06/09/2023] [Indexed: 06/28/2023] Open
Abstract
Metabolomics is the analytical study of metabolites in biological matrices using high-throughput profiling. Traditionally, the metabolome has been studied to identify various biomarkers for the diagnosis and pathophysiology of disease. Over the last decade, metabolomic research has grown to include the identification of prognostic markers, the development of novel treatment strategies, and the prediction of disease severity. In this review, we summarized the available evidence on the use of metabolome profiling in neurocritical care populations. Specifically, we focused on aneurysmal subarachnoid hemorrhage, traumatic brain injury, and intracranial hemorrhage to identify the gaps in the current literature and to provide direction for future studies. A primary literature search of the Medline and EMBASE databases was conducted. Upon removing duplicate studies, abstract screening and full-text screening were performed. We screened 648 studies and extracted data from 17 studies. Based on the current evidence, the utility of metabolomic profiling has been limited due to inconsistencies amongst studies and a lack of reproducible data. Studies identified various biomarkers for diagnosis, prognosis, and treatment modification. However, studies evaluated and identified different metabolites, resulting in an inability to compare the study results. Future research towards addressing the gaps in the current literature, including reproducing data on the use of specific metabolite panels, is needed.
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Affiliation(s)
- Maged Kharouba
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G 2E1, Canada
| | - Dimple D Patel
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G 2E1, Canada
| | - Rami H Jaber
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G 2E1, Canada
| | - Sherif Hanafy Mahmoud
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G 2E1, Canada
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18
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Ito T, Ohkama-Ohtsu N. Degradation of glutathione and glutathione conjugates in plants. JOURNAL OF EXPERIMENTAL BOTANY 2023; 74:3313-3327. [PMID: 36651789 DOI: 10.1093/jxb/erad018] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Accepted: 01/12/2023] [Indexed: 06/08/2023]
Abstract
Glutathione (GSH) is a ubiquitous, abundant, and indispensable thiol for plants that participates in various biological processes, such as scavenging reactive oxygen species, redox signaling, storage and transport of sulfur, detoxification of harmful substances, and metabolism of several compounds. Therefore knowledge of GSH metabolism is essential for plant science. Nevertheless, GSH degradation has been insufficiently elucidated, and this has hampered our understanding of plant life. Over the last five decades, the γ-glutamyl cycle has been dominant in GSH studies, and the exoenzyme γ-glutamyl transpeptidase has been regarded as the major GSH degradation enzyme. However, recent studies have shown that GSH is degraded in cells by cytosolic enzymes such as γ-glutamyl cyclotransferase or γ-glutamyl peptidase. Meanwhile, a portion of GSH is degraded after conjugation with other molecules, which has also been found to be carried out by vacuolar γ-glutamyl transpeptidase, γ-glutamyl peptidase, or phytochelatin synthase. These findings highlight the need to re-assess previous assumptions concerning the γ-glutamyl cycle, and a novel overview of the plant GSH degradation pathway is essential. This review aims to build a foundation for future studies by summarizing current understanding of GSH/glutathione conjugate degradation.
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Affiliation(s)
- Takehiro Ito
- United Graduate School of Agricultural Science, Tokyo University of Agriculture and Technology, 3-5-8, Saiwai-cho, Fuchu, Tokyo, 183-8509, Japan
- RIKEN Center for Sustainable Resource Science, 1-7-22, Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, 230-0045, Japan
| | - Naoko Ohkama-Ohtsu
- Institute of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8, Saiwai-cho, Fuchu, Tokyo, 183-8509, Japan
- Institute of Global Innovation Research, Tokyo University of Agriculture and Technology, 3-5-8, Saiwai-cho, Fuchu, Tokyo, 183-8509, Japan
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19
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Peng W, Wen L, Jiang R, Deng J, Chen M. CHAC2 promotes lung adenocarcinoma by regulating ROS-mediated MAPK pathway activation. J Cancer 2023; 14:1309-1320. [PMID: 37283797 PMCID: PMC10240664 DOI: 10.7150/jca.84036] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2023] [Accepted: 04/19/2023] [Indexed: 06/08/2023] Open
Abstract
An imbalance in ROS (reactive oxidative species) and the antioxidant barrier regulates the process of tumorigenesis. GSH has a key effect in preventing cells from oxidative damage by scavenging ROS. The role of CHAC2, an enzyme regulating GSH, in lung adenocarcinoma remains unknown. Here, RNA sequencing data analysis and immunohistochemistry (IHC) assays of lung adenocarcinoma and normal lung tissues were used to verify the expression of CHAC2. The effect of CHAC2 on the proliferation abilities of lung adenocarcinoma cells was examined using a series of overexpression or knockout assays. RNA sequencing and IHC results showed that the expression level of CHAC2 in lung adenocarcinoma was higher than that in normal lung tissues. CCK-8, colony formation and subcutaneous xenograft experiments in BALB/c nude mice showed that in vitro and in vivo CHAC2 promoted the growth capacity of lung adenocarcinoma cells. Subsequent immunoblot, immunohistochemistry and flow cytometry experiments showed that CHAC2 increased ROS by reducing GSH in lung adenocarcinoma and that the elevated ROS activated the MAPK pathway. Our investigation identified a new role for CHAC2 and elucidated the mechanism by which CHAC2 promotes lung adenocarcinoma progression.
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Affiliation(s)
- Weilin Peng
- Department of Thoracic Surgery, the Second Xiangya Hospital of Central South University, 410011, Changsha, China
| | - Long Wen
- Department of Respiratory Medicine, the First Hospital of ChangSha, 410011, Changsha, China
| | - Rong Jiang
- Department of Respiratory Medicine, the First Hospital of ChangSha, 410011, Changsha, China
| | - Jie Deng
- Department of Respiratory Medicine, the First Hospital of ChangSha, 410011, Changsha, China
| | - Mingjiu Chen
- Department of Thoracic Surgery, the Second Xiangya Hospital of Central South University, 410011, Changsha, China
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20
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Farhat F, Wasim S, Rehman L, Abidi SMA. Affinity purification, identification, and biochemical characterization of Gamma-glutamyl transpeptidase, a membrane anchored enzyme of Gigantocotyle explanatum. Parasitol Res 2023; 122:915-926. [PMID: 36719531 DOI: 10.1007/s00436-023-07786-7] [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: 10/28/2022] [Accepted: 01/25/2023] [Indexed: 02/01/2023]
Abstract
Gamma-glutamyl transpeptidase is an enzyme that facilitates the transfer of glutamyl groups from glutamyl peptides to other peptides or water. Additionally, it also participates in important processes such as amino acid transport, cellular redox control, drug detoxification, apoptosis, and DNA fragmentation in a various organism. In the present study, GGT activity in Gigantocotyle explanatum was examined in order to characterize the enzyme in the helminth system. GGT is isolated using membrane solubilization and purified through affinity column chromatography (Con-A Sepharose column). Km and Vmax values, as well as the optimal pH, optimal temperature, and incubation period, are also determined using enzyme kinetics. The hetero-dimeric property of the enzyme is demonstrated by the purified GGT, which yielded two subunits of 65.5 and 55 kDa. The optimal pH and temperature are found to be 8.0 and 37 °C, respectively. While assessing the optimal incubation time of the enzyme, it was observed that the purified GGT not only retained its functional integrity up to 15 min but also reflected considerable thermostability at higher temperatures, by retaining 78% and 25% of its initial activities at 50 °C and 60 °C, respectively. One millimolar concentration of 6-Diazo-5-Oxo Nor-isoleucine (DON), a specific inhibitor of GGT, completely abolished GGT activity. These results suggest that GGT in these worms is a catalytically active enzyme with distinguishing characteristics that can be used for further study to comprehend its function in amphistome biology and in host-parasite relationships, especially since the potential therapeutic candidacy of the GGT enzyme has already been indicated in these groups of organisms.
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Affiliation(s)
- Faiza Farhat
- Section of Parasitology, Department of Zoology, Aligarh Muslim University, Uttar Pradesh, Aligarh, 202002, India.
| | - Sobia Wasim
- College of Medicine, Gachon University, Incheon, South Korea
| | - Lubna Rehman
- Department of Lymphoma/Myeloma, MD Anderson Cancer Center, The University of Texas, Houston, TX, USA
| | - S M A Abidi
- Section of Parasitology, Department of Zoology, Aligarh Muslim University, Uttar Pradesh, Aligarh, 202002, India
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21
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Al-Temimi AA, Al-Mossawi AEB, Al-Hilifi SA, Korma SA, Esatbeyoglu T, Rocha JM, Agarwal V. Glutathione for Food and Health Applications with Emphasis on Extraction, Identification, and Quantification Methods: A Review. Metabolites 2023; 13:465. [PMID: 37110125 PMCID: PMC10141022 DOI: 10.3390/metabo13040465] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 02/27/2023] [Accepted: 03/13/2023] [Indexed: 04/29/2023] Open
Abstract
Glutathione is a naturally occurring compound that plays a crucial role in the cellular response to oxidative stress through its ability to quench free radicals, thus mitigating the risk of potential damage, including cell death. While glutathione is endogenously present in different plants and animal cells, their concentration varies considerably. The alteration in glutathione homeostasis can be used as a potential marker for human diseases. In the case of the depletion of endogenous glutathione, exogenous sources can be used to replenish the pool. To this end, both natural and synthetic glutathione can be used. However, the health benefit of glutathione from natural sources derived from fruits and vegetables is still debated. There is increasingly growing evidence of the potential health benefits of glutathione in different diseases; however, the determination and in situ quantification of endogenously produced glutathione remains a major challenge. For this reason, it has been difficult to understand the bioprocessing of exogenously delivered glutathione in vivo. The development of an in situ technique will also aid in the routine monitoring of glutathione as a biomarker for different oxidative stress-mediated diseases. Furthermore, an understanding of the in vivo bioprocessing of exogenously delivered glutathione will also aid the food industry both towards improving the longevity and profile of food products and the development of glutathione delivery products for long-term societal health benefits. In this review, we surveyed the natural plant-derived sources of glutathione, the identification and quantification of extracted glutathione from these sources, and the role of glutathione in the food industry and its effect on human health.
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Affiliation(s)
- Anfal Alwan Al-Temimi
- Department of Food Science, College of Agriculture, University of Basrah, Basrah 61014, Iraq (S.A.A.-H.)
| | - Aum-El-Bashar Al-Mossawi
- Department of Food Science, College of Agriculture, University of Basrah, Basrah 61014, Iraq (S.A.A.-H.)
| | - Sawsan A. Al-Hilifi
- Department of Food Science, College of Agriculture, University of Basrah, Basrah 61014, Iraq (S.A.A.-H.)
| | - Sameh A. Korma
- Department of Food Science, Faculty of Agriculture, Zagazig University, Zagazig 44519, Egypt
- School of Food Science and Engineering, South China University of Technology, Guangzhou 510641, China
| | - Tuba Esatbeyoglu
- Department of Food Development and Food Quality, Institute of Food Science and Human Nutrition, Gottfried Wilhelm Leibniz University Hannover, Am Kleinen Felde 30, 30167 Hannover, Germany;
| | - João Miguel Rocha
- Universidade Católica Portuguesa, CBQF—Centro de Biotecnologia e Química Fina—Laboratório Associado, Escola Superior de Biotecnologia, Rua Diogo Botelho 1327, 4169-005 Porto, Portugal
| | - Vipul Agarwal
- Cluster for Advanced Macromolecular Design (CAMD), School of Chemical Engineering, University of New South Wales, Sydney, NSW 2052, Australia
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22
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Plasma Metabolite Signatures in Male Carriers of Genetic Variants Associated with Non-Alcoholic Fatty Liver Disease. Metabolites 2023; 13:metabo13020267. [PMID: 36837886 PMCID: PMC9964056 DOI: 10.3390/metabo13020267] [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: 01/19/2023] [Revised: 02/01/2023] [Accepted: 02/11/2023] [Indexed: 02/16/2023] Open
Abstract
Both genetic and non-genetic factors are important in the pathophysiology of non-alcoholic fatty liver disease (NAFLD). The aim of our study was to identify novel metabolites and pathways associated with NAFLD by including both genetic and non-genetic factors in statistical analyses. We genotyped six genetic variants in the PNPLA3, TM6SF2, MBOAT7, GCKR, PPP1R3B, and HSD17B13 genes reported to be associated with NAFLD. Non-targeted metabolomic profiling was performed from plasma samples. We applied a previously validated fatty liver index to identify participants with NAFLD. First, we associated the six genetic variants with 1098 metabolites in 2 339 men without NAFLD to determine the effects of the genetic variants on metabolites, and then in 2 535 men with NAFLD to determine the joint effects of genetic variants and non-genetic factors on metabolites. We identified several novel metabolites and metabolic pathways, especially for PNPLA3, GCKR, and PPP1R38 variants relevant to the pathophysiology of NAFLD. Importantly, we showed that each genetic variant for NAFLD had a specific metabolite signature. The plasma metabolite signature was unique for each genetic variant, suggesting that several metabolites and different pathways are involved in the risk of NAFLD. The FLI index reliably identifies metabolites for NAFLD in large population-based studies.
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23
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Enhanced Anti-Inflammatory Effect of the Combination of Lactiplantibacillus plantarum LS/07 with Methotrexate Compared to Their Monotherapies Studied in Experimental Arthritis. Molecules 2022; 28:molecules28010297. [PMID: 36615489 PMCID: PMC9822002 DOI: 10.3390/molecules28010297] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Revised: 12/14/2022] [Accepted: 12/23/2022] [Indexed: 12/31/2022] Open
Abstract
The gut microbiome (GM) of rheumatic arthritis (RA) patients is often altered in composition and function. Moreover, methotrexate (MTX), one of the most frequently used disease-modifying antirheumatic drugs, is known to negatively affect GM composition. The modulation of immune system activity is one of the therapeutic benefits of probiotics. The aim of the current investigation was to determine the impact of MTX therapy combined with one of the Lactobacillus strains, Lactoplantibacillus plantarum LS/07 (LB), on adjuvant arthritis (AA) in rats. Methods focused on biometric and inflammatory parameters in AA, particularly on plasmatic levels of IL-17A, MMP-9, and MCP-1, and the activities of gamma-glutamyl transferase in the spleen and joints were applied. Enhancing the effect of MTX, LB positively influenced all biometric and inflammatory parameters. The findings of the present study may be of help in proposing novel therapeutic strategies for RA patients.
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24
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Zhang HM, Li ZY, Dai ZT, Wang J, Li LW, Zong QB, Li JP, Zhang TC, Liao XH. Interaction of MRPL9 and GGCT Promotes Cell Proliferation and Migration by Activating the MAPK/ERK Pathway in Papillary Thyroid Cancer. Int J Mol Sci 2022; 23:ijms231911989. [PMID: 36233293 PMCID: PMC9570013 DOI: 10.3390/ijms231911989] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Revised: 09/16/2022] [Accepted: 09/22/2022] [Indexed: 11/06/2022] Open
Abstract
Thyroid cancer remains the most common endocrine malignancy worldwide, and its incidence has steadily increased over the past four years. Papillary Thyroid Cancer (PTC) is the most common differentiated thyroid cancer, accounting for 80–85% of all thyroid cancers. Mitochondrial proteins (MRPs) are an important part of the structural and functional integrity of the mitochondrial ribosomal complex. It has been reported that MRPL9 is highly expressed in liver cancer and promotes cell proliferation and migration, but it has not been reported in PTC. In the present study we found that MRPL9 was highly expressed in PTC tissues and cell lines, and lentivirus-mediated overexpression of MRPL9 promoted the proliferation and migration ability of PTC cells, whereas knockdown of MRPL9 had the opposite effect. The interaction between MRPL9 and GGCT (γ-glutamylcyclotransferase) was found by immunofluorescence and co-immunoprecipitation experiments (Co-IP). In addition, GGCT is highly expressed in PTC tissues and cell lines, and knockdown of GGCT/MRPL9 in vivo inhibited the growth of subcutaneous xenografts in nude mice and inhibited the formation of lung metastases. Mechanistically, we found that knockdown of GGCT/MRPL9 inhibited the MAPK/ERK signaling pathway. In conclusion, our study found that the interaction of GGCT and MRPL9 modulates the MAPK/ERK pathway, affecting the proliferation and migration of PTC cells. Therefore, GGCT/MRPL9 may serve as a potential biomarker for PTC monitoring and PTC treatment.
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Affiliation(s)
- Hui-Min Zhang
- Institute of Biology and Medicine, College of Life and Health Sciences, Wuhan University of Science and Technology, Wuhan 430070, China
| | - Zi-Yi Li
- Institute of Biology and Medicine, College of Life and Health Sciences, Wuhan University of Science and Technology, Wuhan 430070, China
| | - Zhou-Tong Dai
- Institute of Biology and Medicine, College of Life and Health Sciences, Wuhan University of Science and Technology, Wuhan 430070, China
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Jun Wang
- Institute of Biology and Medicine, College of Life and Health Sciences, Wuhan University of Science and Technology, Wuhan 430070, China
| | - Le-Wei Li
- Institute of Biology and Medicine, College of Life and Health Sciences, Wuhan University of Science and Technology, Wuhan 430070, China
| | - Qi-Bei Zong
- Institute of Biology and Medicine, College of Life and Health Sciences, Wuhan University of Science and Technology, Wuhan 430070, China
| | - Jia-Peng Li
- Institute of Biology and Medicine, College of Life and Health Sciences, Wuhan University of Science and Technology, Wuhan 430070, China
| | - Tong-Cun Zhang
- Institute of Biology and Medicine, College of Life and Health Sciences, Wuhan University of Science and Technology, Wuhan 430070, China
- Correspondence: (T.-C.Z.); (X.-H.L.)
| | - Xing-Hua Liao
- Institute of Biology and Medicine, College of Life and Health Sciences, Wuhan University of Science and Technology, Wuhan 430070, China
- Correspondence: (T.-C.Z.); (X.-H.L.)
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25
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The ChaC family of γ-glutamyl cyclotransferases is required for Leishmania to switch to a slow growth state and for long-term survival of the parasite. J Biol Chem 2022; 298:102510. [PMID: 36126772 PMCID: PMC9586994 DOI: 10.1016/j.jbc.2022.102510] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Revised: 09/12/2022] [Accepted: 09/14/2022] [Indexed: 11/24/2022] Open
Abstract
The ChaC family of γ-glutamyl cyclotransferases is conserved throughout all Kingdoms and catalyzes the degradation of GSH. So far, the ChaC family proteins in trypanosomal parasites are missing in the literature. Here, we report two members of the ChaC family of γ-glutamyl cyclotransferases (LmChaC2a and LmChaC2b) in the unicellular pathogen Leishmania. Activity measurements suggest that these proteins catalyze degradation of GSH but no other γ-glutamyl peptides. Recombinant LmChaC2a protein shows ∼17-fold lower catalytic efficiency (kcat ∼ 0.9 s−1) than LmChaC2b (kcat ∼ 15 s−1), although they showed comparable Km values (∼1.75 mM for LmChaC2a and ∼2.0 mM for LmChaC2b) toward GSH. qRT-PCR and Western blot analyses suggest that the LmChaC2a protein was found to be constitutively expressed, whereas LmChaC2b was regulated by sulfur stress. To investigate its precise physiological function in Leishmania, we generated overexpressed, knockout, and complement cell lines. Flow cytometric analyses show the presence of a higher intracellular GSH concentration and lower intracellular ROS level, indicative of a more reductive environment in null mutants. We found LmChaC2-expressing cells grow in GSH-containing sulfur-limited media, while the null mutants failed to grow, suggesting that LmChaC2 is crucial for cell growth with GSH as the only sulfur source. Null mutants, although reach the stationary phase rapidly, display impaired long-term survival, indicating that LmChaC2-mediated GSH degradation is necessary for prolonged survival. In vivo studies suggest that LmChaC2-dependent controlled GSH degradation promotes chronic infection by the parasite. Altogether, these data indicate that LmChaC2 plays an important role in GSH homeostasis in Leishmania.
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Development of a Clinical Prognostic Model for Metabolism-Related Genes in Squamous Lung Cancer and Correlation Analysis of Immune Microenvironment. BIOMED RESEARCH INTERNATIONAL 2022; 2022:6962056. [PMID: 36110123 PMCID: PMC9470302 DOI: 10.1155/2022/6962056] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/27/2022] [Revised: 08/01/2022] [Accepted: 08/16/2022] [Indexed: 12/23/2022]
Abstract
Background The incidence of squamous lung cancer (LUSC) has substantially increased. Systematic studies of metabolic genomic patterns are fundamental for the treatment and prediction of LUSC. Because cancer metabolism and immune cell metabolism have been studied in depth, metabolism and the state and function of immune cells have become key factors in tumor development. This also indicates that metabolic genes and the tumor immune microenvironment (TME) are crucial in tumor treatment. This study is aimed at dissecting the connection between TME and LUSC digestion-related qualities. Methods The information used in this study was obtained from The Cancer Genome Atlas dataset. Metabolism-related genes in patients with LUSC were screened, and relevant clinical data were collated. Next, genes associated with prognosis were screened using univariate COX regression and LASSO regression analyses. Finally, a timer database study was conducted to analyze the molecular mechanisms of immune cell infiltration of LUSC prognosis-related metabolic genes at the immune cell level. Results Nine metabolism-related genes were identified: ADCY7, ALDH3B1, CHIA, CYP2C18, ENTPD6, GGCT, HPRT1, PLA2G1B, and PTGIS. A clinical prediction model for LUSC based on metabolism-related genes was constructed. In addition, 22 subpopulations of tumor-infiltrating immune cells (TIIC) in the TME were analyzed using the CIBERSORT algorithm. Finally, we used the TIMER database to analyze the immune infiltration of LUSC and the relationship between metabolism-related genes and immune cells. Conclusion Our study identified metabolic genes associated with the prognosis of LUSC, which are important markers for its diagnosis, clinically relevant assessments, and prognosis. The relationship between metabolic genes with prognostic impact and immune infiltration was also analyzed, and a metabolic gene-based clinical prediction model was identified, providing a new perspective for LUSC treatment.
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27
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Ito T, Kitaiwa T, Nishizono K, Umahashi M, Miyaji S, Agake S, Kuwahara K, Yokoyama T, Fushinobu S, Maruyama‐Nakashita A, Sugiyama R, Sato M, Inaba J, Hirai MY, Ohkama‐Ohtsu N. Glutathione degradation activity of γ-glutamyl peptidase 1 manifests its dual roles in primary and secondary sulfur metabolism in Arabidopsis. THE PLANT JOURNAL : FOR CELL AND MOLECULAR BIOLOGY 2022; 111:1626-1642. [PMID: 35932489 PMCID: PMC9804317 DOI: 10.1111/tpj.15912] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 07/09/2022] [Accepted: 07/20/2022] [Indexed: 06/08/2023]
Abstract
Glutathione (GSH) functions as a major sulfur repository and hence occupies an important position in primary sulfur metabolism. GSH degradation results in sulfur reallocation and is believed to be carried out mainly by γ-glutamyl cyclotransferases (GGCT2;1, GGCT2;2, and GGCT2;3), which, however, do not fully explain the rapid GSH turnover. Here, we discovered that γ-glutamyl peptidase 1 (GGP1) contributes to GSH degradation through a yeast complementation assay. Recombinant proteins of GGP1, as well as GGP3, showed high degradation activity of GSH, but not of oxidized glutathione (GSSG), in vitro. Notably, the GGP1 transcripts were highly abundant in rosette leaves, in agreement with the ggp1 mutants constantly accumulating more GSH regardless of nutritional conditions. Given the lower energy requirements of the GGP- than the GGCT-mediated pathway, the GGP-mediated pathway could be a more efficient route for GSH degradation than the GGCT-mediated pathway. Therefore, we propose a model wherein cytosolic GSH is degraded chiefly by GGP1 and likely also by GGP3. Another noteworthy fact is that GGPs are known to process GSH conjugates in glucosinolate and camalexin synthesis; indeed, we confirmed that the ggp1 mutant contained higher levels of O-acetyl-l-Ser, a signaling molecule for sulfur starvation, and lower levels of glucosinolates and their degradation products. The predicted structure of GGP1 further provided a rationale for this hypothesis. In conclusion, we suggest that GGP1 and possibly GGP3 play vital roles in both primary and secondary sulfur metabolism.
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Affiliation(s)
- Takehiro Ito
- United Graduate School of Agricultural ScienceTokyo University of Agriculture and Technology3‐5‐8, Saiwai‐choFuchuTokyo183‐8509Japan
- RIKEN Center for Sustainable Resource Science1‐7‐22, Suehiro‐cho, Tsurumi‐kuYokohamaKanagawa230‐0045Japan
| | - Taisuke Kitaiwa
- Graduate School of AgricultureTokyo University of Agriculture and Technology3‐5‐8, Saiwai‐choFuchuTokyo183‐8509Japan
| | - Kosuke Nishizono
- Graduate School of AgricultureTokyo University of Agriculture and Technology3‐5‐8, Saiwai‐choFuchuTokyo183‐8509Japan
| | - Minori Umahashi
- Graduate School of AgricultureTokyo University of Agriculture and Technology3‐5‐8, Saiwai‐choFuchuTokyo183‐8509Japan
| | - Shunsuke Miyaji
- Graduate School of AgricultureTokyo University of Agriculture and Technology3‐5‐8, Saiwai‐choFuchuTokyo183‐8509Japan
| | - Shin‐ichiro Agake
- Institute of Global Innovation ResearchTokyo University of Agriculture and Technology3‐5‐8, Saiwai‐choFuchuTokyo183‐8509Japan
| | - Kana Kuwahara
- Faculty of AgricultureTokyo University of Agriculture and Technology3‐5‐8, Saiwai‐choFuchuTokyo183‐8509Japan
| | - Tadashi Yokoyama
- Institute of AgricultureTokyo University of Agriculture and Technology3‐5‐8, Saiwai‐choFuchuTokyo183‐8509Japan
- Faculty of Food and Agricultural SciencesFukushima UniversityKanayagawa 1Fukushima‐shiFukushima960‐1296Japan
| | - Shinya Fushinobu
- Department of BiotechnologyThe University of Tokyo1‐1‐1 YayoiBunkyo‐kuTokyo113‐8657Japan
- Collaborative Research Institute for Innovative MicrobiologyThe University of Tokyo1‐1‐1 YayoiBunkyo‐kuTokyo113‐8657Japan
| | - Akiko Maruyama‐Nakashita
- Graduate School of Bioresource and Bioenvironmental ScienceKyushu University744 MotookaNishi‐kuFukuoka819‐0395Japan
| | - Ryosuke Sugiyama
- RIKEN Center for Sustainable Resource Science1‐7‐22, Suehiro‐cho, Tsurumi‐kuYokohamaKanagawa230‐0045Japan
- Department of PharmacyNational University of Singapore4 Science Drive 2117544SingaporeSingapore
- Present address:
Graduate School of Pharmaceutical SciencesChiba University1‐8‐1, Inohana, Chuo‐kuChiba260‐8675Japan
| | - Muneo Sato
- RIKEN Center for Sustainable Resource Science1‐7‐22, Suehiro‐cho, Tsurumi‐kuYokohamaKanagawa230‐0045Japan
| | - Jun Inaba
- RIKEN Center for Sustainable Resource Science1‐7‐22, Suehiro‐cho, Tsurumi‐kuYokohamaKanagawa230‐0045Japan
| | - Masami Yokota Hirai
- RIKEN Center for Sustainable Resource Science1‐7‐22, Suehiro‐cho, Tsurumi‐kuYokohamaKanagawa230‐0045Japan
- Graduate School of Bioagricultural ScienceNagoya UniversityFuro‐cho, Chikusa‐kuNagoyaAichi464‐8601Japan
| | - Naoko Ohkama‐Ohtsu
- Institute of Global Innovation ResearchTokyo University of Agriculture and Technology3‐5‐8, Saiwai‐choFuchuTokyo183‐8509Japan
- Institute of AgricultureTokyo University of Agriculture and Technology3‐5‐8, Saiwai‐choFuchuTokyo183‐8509Japan
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Combining metabolome and clinical indicators with machine learning provides some promising diagnostic markers to precisely detect smear-positive/negative pulmonary tuberculosis. BMC Infect Dis 2022; 22:707. [PMID: 36008772 PMCID: PMC9403968 DOI: 10.1186/s12879-022-07694-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Accepted: 08/22/2022] [Indexed: 11/30/2022] Open
Abstract
Background Tuberculosis (TB) had been the leading lethal infectious disease worldwide for a long time (2014–2019) until the COVID-19 global pandemic, and it is still one of the top 10 death causes worldwide. One important reason why there are so many TB patients and death cases in the world is because of the difficulties in precise diagnosis of TB using common detection methods, especially for some smear-negative pulmonary tuberculosis (SNPT) cases. The rapid development of metabolome and machine learning offers a great opportunity for precision diagnosis of TB. However, the metabolite biomarkers for the precision diagnosis of smear-positive and smear-negative pulmonary tuberculosis (SPPT/SNPT) remain to be uncovered. In this study, we combined metabolomics and clinical indicators with machine learning to screen out newly diagnostic biomarkers for the precise identification of SPPT and SNPT patients. Methods Untargeted plasma metabolomic profiling was performed for 27 SPPT patients, 37 SNPT patients and controls. The orthogonal partial least squares-discriminant analysis (OPLS-DA) was then conducted to screen differential metabolites among the three groups. Metabolite enriched pathways, random forest (RF), support vector machines (SVM) and multilayer perceptron neural network (MLP) were performed using Metaboanalyst 5.0, “caret” R package, “e1071” R package and “Tensorflow” Python package, respectively. Results Metabolomic analysis revealed significant enrichment of fatty acid and amino acid metabolites in the plasma of SPPT and SNPT patients, where SPPT samples showed a more serious dysfunction in fatty acid and amino acid metabolisms. Further RF analysis revealed four optimized diagnostic biomarker combinations including ten features (two lipid/lipid-like molecules and seven organic acids/derivatives, and one clinical indicator) for the identification of SPPT, SNPT patients and controls with high accuracy (83–93%), which were further verified by SVM and MLP. Among them, MLP displayed the best classification performance on simultaneously precise identification of the three groups (94.74%), suggesting the advantage of MLP over RF/SVM to some extent. Conclusions Our findings reveal plasma metabolomic characteristics of SPPT and SNPT patients, provide some novel promising diagnostic markers for precision diagnosis of various types of TB, and show the potential of machine learning in screening out biomarkers from big data. Supplementary Information The online version contains supplementary material available at 10.1186/s12879-022-07694-8.
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Glutathione-dependent redox balance characterizes the distinct metabolic properties of follicular and marginal zone B cells. Nat Commun 2022; 13:1789. [PMID: 35379825 PMCID: PMC8980022 DOI: 10.1038/s41467-022-29426-x] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Accepted: 03/11/2022] [Indexed: 11/13/2022] Open
Abstract
The metabolic principles underlying the differences between follicular and marginal zone B cells (FoB and MZB, respectively) are not well understood. Here we show, by studying mice with B cell-specific ablation of the catalytic subunit of glutamate cysteine ligase (Gclc), that glutathione synthesis affects homeostasis and differentiation of MZB to a larger extent than FoB, while glutathione-dependent redox control contributes to the metabolic dependencies of FoB. Specifically, Gclc ablation in FoB induces metabolic features of wild-type MZB such as increased ATP levels, glucose metabolism, mTOR activation, and protein synthesis. Furthermore, Gclc-deficient FoB have a block in the mitochondrial electron transport chain (ETC) due to diminished complex I and II activity and thereby accumulate the tricarboxylic acid cycle metabolite succinate. Finally, Gclc deficiency hampers FoB activation and antibody responses in vitro and in vivo, and induces susceptibility to viral infections. Our results thus suggest that Gclc is required to ensure the development of MZB, the mitochondrial ETC integrity in FoB, and the efficacy of antiviral humoral immunity. Follicular and marginal zone B (FoB and MZB, respectively) cells have divergent metabolic characteristics. Here the authors show that deficiency of glutamate cysteine ligase (Gclc), the enzyme for glutathione synthesis, differentially impacts FoB and MZB homeostasis, while specifically impeding FoB activation and downstream antiviral immunity.
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Ho T, Ahmadi S, Kerman K. Do glutathione and copper interact to modify Alzheimer's disease pathogenesis? Free Radic Biol Med 2022; 181:180-196. [PMID: 35092854 DOI: 10.1016/j.freeradbiomed.2022.01.025] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 01/20/2022] [Accepted: 01/24/2022] [Indexed: 12/11/2022]
Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disorder first described in 1906 that is currently estimated to impact ∼40 million people worldwide. Extensive research activities have led to a wealth of information on the pathogenesis, hallmarks, and risk factors of AD; however, therapeutic options remain extremely limited. The large number of pathogenic factors that have been reported to potentially contribute to AD include copper dyshomeostasis as well as increased oxidative stress, which is related to alterations to molecular antioxidants like glutathione (GSH). While the individual roles of GSH and copper in AD have been studied by many research groups, their interactions have received relatively little attention, although they appear to interact and affect each other's regulation. Existing knowledge on how GSH-copper interactions may affect AD is sparse and lacks focus. This review first highlights the most relevant individual roles that GSH and copper play in physiology and AD, and then collects and assesses research concerning their interactions, in an effort to provide a more accessible and understandable picture of the role of GSH, copper, and their interactions in AD.
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Affiliation(s)
- Talia Ho
- Department of Physical and Environmental Sciences, University of Toronto Scarborough, 1265 Military Trail, Toronto, ON, M1C 1A4, Canada; Department of Molecular Genetics, University of Toronto, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada.
| | - Soha Ahmadi
- Department of Physical and Environmental Sciences, University of Toronto Scarborough, 1265 Military Trail, Toronto, ON, M1C 1A4, Canada; Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, ON, M5S 3H6, Canada.
| | - Kagan Kerman
- Department of Physical and Environmental Sciences, University of Toronto Scarborough, 1265 Military Trail, Toronto, ON, M1C 1A4, Canada; Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, ON, M5S 3H6, Canada.
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Jaiswal D, Nenwani M, Mishra V, Wangikar PP. Probing the metabolism of γ-glutamyl peptides in cyanobacteria via metabolite profiling and 13 C labeling. THE PLANT JOURNAL : FOR CELL AND MOLECULAR BIOLOGY 2022; 109:708-726. [PMID: 34727398 DOI: 10.1111/tpj.15564] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 10/20/2021] [Accepted: 10/25/2021] [Indexed: 06/13/2023]
Abstract
Cyanobacteria are attractive model organisms for the study of photosynthesis and diurnal metabolism and as hosts for photoautotrophic production of chemicals. Exposure to bright light or environmental pollutants and a diurnal lifestyle of these prokaryotes may result in significant oxidative stress. Glutathione is a widely studied γ-glutamyl peptide that plays a key role in managing oxidative stress and detoxification of xenobiotics in cyanobacteria. The functional role and biosynthesis pathways of this tripeptide have been studied in detail in various phyla, including cyanobacteria. However, other γ-glutamyl peptides remain largely unexplored. We use an integrated approach to identify a number of γ-glutamyl peptides based on signature mass fragments and mass shifts in them in 13 C and 15 N enriched metabolite extracts. The newly identified compounds include γ-glutamyl dipeptides and derivatives of glutathione. Carbon backbones of the former turn over much faster than that of glutathione, suggesting that they follow a distinct biosynthesis pathway. Further, transients of isotopic 13 C enrichment show positional labeling in these peptides, which allows us to delineate the alternative biosynthesis pathways. Importantly, the amino acid of γ-glutamyl dipeptides shows much faster turnover compared to the glutamate moiety. The significant accumulation of γ-glutamyl dipeptides under slow-growth conditions combined with the results from dynamic 13 C labeling suggests that these compounds may act as reservoirs of amino acids in cyanobacteria.
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Affiliation(s)
- Damini Jaiswal
- Department of Chemical Engineering, Indian Institute of Technology Bombay, Powai, Mumbai, 400076, India
| | - Minal Nenwani
- Department of Chemical Engineering, Indian Institute of Technology Bombay, Powai, Mumbai, 400076, India
| | - Vivek Mishra
- Department of Chemical Engineering, Indian Institute of Technology Bombay, Powai, Mumbai, 400076, India
| | - Pramod P Wangikar
- Department of Chemical Engineering, Indian Institute of Technology Bombay, Powai, Mumbai, 400076, India
- DBT-PAN IIT Centre for Bioenergy, Indian Institute of Technology Bombay, Powai, Mumbai, 400076, India
- Wadhwani Research Centre for Bioengineering, Indian Institute of Technology Bombay, Powai, Mumbai, 400076, India
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Emerging role of ferroptosis in breast cancer: New dawn for overcoming tumor progression. Pharmacol Ther 2021; 232:107992. [PMID: 34606782 DOI: 10.1016/j.pharmthera.2021.107992] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 09/02/2021] [Accepted: 09/07/2021] [Indexed: 02/08/2023]
Abstract
Breast cancer has become a serious threat to women's health. Cancer progression is mainly derived from resistance to apoptosis induced by procedures or therapies. Therefore, new drugs or models that can overcome apoptosis resistance should be identified. Ferroptosis is a recently identified mode of cell death characterized by excess reactive oxygen species-induced lipid peroxidation. Since ferroptosis is distinct from apoptosis, necrosis and autophagy, its induction successfully eliminates cancer cells that are resistant to other modes of cell death. Therefore, ferroptosis may become a new direction around which to design breast cancer treatment. Unfortunately, the complete appearance of ferroptosis in breast cancer has not yet been fully elucidated. Furthermore, whether ferroptosis inducers can be used in combination with traditional anti- breast cancer drugs is still unknown. Moreover, a summary of ferroptosis in breast cancer progression and therapy is currently not available. In this review, we discuss the roles of ferroptosis-associated modulators glutathione, glutathione peroxidase 4, iron, nuclear factor erythroid-2 related factor-2, superoxide dismutases, lipoxygenase and coenzyme Q in breast cancer. Furthermore, we provide evidence that traditional drugs against breast cancer induce ferroptosis, and that ferroptosis inducers eliminate breast cancer cells. Finally, we put forward prospect of using ferroptosis inducers in breast cancer therapy, and predict possible obstacles and corresponding solutions. This review will deepen our understanding of the relationship between ferroptosis and breast cancer, and provide new insights into breast cancer-related therapeutic strategies.
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Xu L, Leng C, Chen L, Dong H, Chen Y, Chen X. Hypothyroidism is a predictive factor of superior antitumour efficacy of programmed death 1 inhibitors in hepatocellular carcinoma. Int J Cancer 2021; 150:472-481. [PMID: 34536292 DOI: 10.1002/ijc.33813] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 08/13/2021] [Accepted: 09/09/2021] [Indexed: 12/19/2022]
Abstract
Programmed death 1 (PD-1) inhibitors are widely used for treatment of hepatocellular carcinoma (HCC). Hypothyroidism is commonly associated with this therapy, although the mechanism underlying this complication and effects on patient prognosis remain unclear. We retrospectively analysed the data of patients with HCC who received anti-PD-1 therapy at Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology between January 2018 and May 2020. Based on thyroid function evaluation, patients were categorised into hypothyroidism group and nonhypothyroidism group. Follow-up was completed on February 28, 2021. The primary endpoint of our study was progression free survival (PFS). The study included 74 patients, and the disease control rate was higher in hypothyroidism group (62.7%, 27/43) than in nonhypothyroidism group (36.4%, 11/31) (P = .020). The PFS was longer in hypothyroidism group (7.44 months) than in nonhypothyroidism group (5.68 months) (P = .006). Additionally, the PFS of patients with hypothyroidism before immunotherapy (6.27 months) was also longer than that in nonhypothyroidism group (5.68 months), although the difference was statistically nonsignificant (P = .527). Cox regression analysis showed that the hazard ratios of hypothyroidism, Child-Pugh grade B at initial admission and serum gamma-glutamyl transferase levels >71 U/L before immunotherapy were 0.404 (95% confidence interval [CI]: 0.207-0.791, P = .008), 2.753 (95%CI: 1.127-6.455, P = .026) and 2.469 (95%CI: 1.155-5.277, P = .020), respectively. Hypothyroidism was associated with prognosis in patients with HCC treated with PD-1 inhibitors, and prognosis was more favourable in patients with hypothyroidism than in those without hypothyroidism. Hypothyroidism and the Child-Pugh grade at initial admission were independently associated with patient prognosis.
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Affiliation(s)
- Lei Xu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Chao Leng
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Lin Chen
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Hanhua Dong
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yifa Chen
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Xiaoping Chen
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.,Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
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Niu B, Liao K, Zhou Y, Wen T, Quan G, Pan X, Wu C. Application of glutathione depletion in cancer therapy: Enhanced ROS-based therapy, ferroptosis, and chemotherapy. Biomaterials 2021; 277:121110. [PMID: 34482088 DOI: 10.1016/j.biomaterials.2021.121110] [Citation(s) in RCA: 558] [Impact Index Per Article: 139.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 08/18/2021] [Accepted: 08/27/2021] [Indexed: 01/17/2023]
Abstract
Glutathione (GSH) is an important member of cellular antioxidative system. In cancer cells, a high level of GSH is indispensable to scavenge excessive reactive oxygen species (ROS) and detoxify xenobiotics, which make it a potential target for cancer therapy. Plenty of studies have shown that loss of intracellular GSH makes cancer cells more susceptible to oxidative stress and chemotherapeutic agents. GSH depletion has been proved to improve the therapeutic efficacy of ROS-based therapy (photodynamic therapy, sonodynamic therapy, and chemodynamic therapy), ferroptosis, and chemotherapy. In this review, various strategies for GSH depletion used in cancer therapy are comprehensively summarized and discussed. First, the functions of GSH in cancer cells are analyzed to elucidate the necessity of GSH depletion in cancer therapy. Then, the synthesis and metabolism of GSH are briefly introduced to bring up some crucial targets for GSH modulation. Finally, different approaches to GSH depletion in the literature are classified and discussed in detail according to their mechanisms. Particularly, functional materials with GSH-consuming ability based on nanotechnology are elaborated due to their unique advantages and potentials. This review presents the ingenious application of GSH-depleting strategy in cancer therapy for improving the outcomes of various therapeutic regimens, which may provide useful guidance for designing intelligent drug delivery system.
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Affiliation(s)
- Boyi Niu
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China
| | - Kaixin Liao
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China
| | - Yixian Zhou
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China
| | - Ting Wen
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China
| | - Guilan Quan
- College of Pharmacy, Jinan University, Guangzhou, 510632, China
| | - Xin Pan
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China.
| | - Chuanbin Wu
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China; College of Pharmacy, Jinan University, Guangzhou, 510632, China.
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Revealing transcriptional and post-transcriptional regulatory mechanisms of γ-glutamyl transferase and keratin isoforms as novel cooperative biomarkers in low-grade glioma and glioblastoma multiforme. Genomics 2021; 113:2623-2633. [PMID: 34118380 DOI: 10.1016/j.ygeno.2021.06.014] [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: 09/11/2020] [Revised: 04/08/2021] [Accepted: 06/07/2021] [Indexed: 01/22/2023]
Abstract
Gamma-glutamyltransferase (GGT) and keratins (KRT) are key factors in regulating tumor progression rely on emerging evidence. However, the prognostic values of GGT and KRT isoforms and their regulation patterns at transcriptional and post-transcriptional levels have been rarely studied. In this study, we aimed to identify cooperative prognostic biomarker signature conducted by GGT and KRT genes for overall survival prediction and discrimination in patients with low-grade glioma (LGG) and glioblastoma multiforme (GBM). To this end, we employed a differential expression network analysis on LGG-NORMAL, GBM-NORMAL, and LGG-GBM datasets. Then, all the differentially expressed genes related to a GO term "GGT activity" were excluded. After that, for obtained potential biomarkers genes, differentially expressed lncRNAs were used to detect cis-regulatory elements (CREs) and trans-regulatory elements (TREs). To scrutinize the regulation on the cytoplasm, potential interactions between these biomarker genes and DElncRNAs were predicted. Our analysis, for the first time, revealed that GGT6, KRT33B, and KRT75 in LGG, GGT2, and KRT75 in GBM and KRT75 for LGG to GBM transformation tumors can be novel cooperative prognostic biomarkers that may be applicable for early detection of LGG, GBM, and LGG to GBM transformation tumors. Consequently, KRT75 was the most important gene being regulated at both transcriptional and post-transcriptional levels significantly. Furthermore, CREs and their relative genes were coordinative up-regulated or down-regulated suggesting CREs as regulation points of these genes. In the end, up-regulation of most DElncRNAs that had physical interaction with target genes pints out that the transcripted genes may have obstacles for translation process.
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Bioflavonoid Robinin from Astragalus falcatus Lam. Mildly Improves the Effect of Metothrexate in Rats with Adjuvant Arthritis. Nutrients 2021; 13:nu13041268. [PMID: 33924354 PMCID: PMC8069410 DOI: 10.3390/nu13041268] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 04/08/2021] [Accepted: 04/10/2021] [Indexed: 11/17/2022] Open
Abstract
Anti-inflammatory potential of orally administrated bioflavonoid-robinin, active sub-stance of original drug Flaroninum™ (FL), was investigated in the combination with methotrexate (MTX) and in monotherapy in rats suffering from adjuvant-induced arthritis (AA). Robinin (kaempferol-3-O-robinoside-7-O-rhamnoside) was isolated from the aerial parts of Astragalus falcatus Lam. The monotherapy with robinin was not efficient in alleviating symptoms of AA. The combination of MTX with robinin was similarly active as MTX alone in reducing the hind paw volume and change of body weight during the whole experiment. The combination, however, reduced plasma levels of Interleukin-17Aand activity of gamma-glutamyl transferase in joint more efficiently then MTX alone. Our results demonstrate that the novel combination of robinin and MTX mildly improved the reduction of inflammation in experimental arthritis.
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Yao X, Steven Xu X, Yang Y, Zhu Z, Zhu Z, Tao F, Yuan M. Stratification of population in NHANES 2009-2014 based on exposure pattern of lead, cadmium, mercury, and arsenic and their association with cardiovascular, renal and respiratory outcomes. ENVIRONMENT INTERNATIONAL 2021; 149:106410. [PMID: 33548850 DOI: 10.1016/j.envint.2021.106410] [Citation(s) in RCA: 75] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Revised: 01/15/2021] [Accepted: 01/18/2021] [Indexed: 05/10/2023]
Abstract
BACKGROUND Environmental exposure to toxic metals is an important risk factor to human health. Traditional methods have examined associations between a health endpoint and exposure to heavy metals by either univariate or multiple regression. In the setting of ubiquitous heterogeneous environmental exposures, statistical methods that incorporate mixed exposures are increasingly relevant and may provide new insight into the association between metal exposure and important cardiovascular, renal and respiratory outcomes. OBJECTIVE The objective of this study was to classify the population of National Health and Nutrition Examination Survey (NHANES) into different exposure subgroups using modern unsupervised clustering methods based on lead, cadmium, mercury, and arsenic measured in urine or whole blood, and to assess the association between the identified exposure groups and twelve important health endpoints. METHODS We analyzed a sub-cohort of 9662 subjects participating in the 6 cycles (2003-2004 to 2013-2014) of NHANES study. The urine levels of 3 heavy metals (total arsenic, lead, cadmium) and blood levels of 3 heavy metals (lead, cadmium and mercury) were analyzed using a two-step approach. In the first step, we stratified the population into subgroups using unsupervised clustering (k-medoids) based on levels of metals either in urine or in blood. Then, we examine the association between 12 health endpoints and identified exposure subgroups while controlling for age, sex, race/ethnicity, education, smoking status, BMI, and urinary creatinine. RESULTS The k-medoids algorithm clustered NHANES population into 2 groups based on either blood or urinary levels of heavy metals. The concentrations of all the three heavy metals were significantly different between the identified groups in blood (p < 2.2e-16) or in urine (p = 0). The group with higher concentrations was defined as the "high-exposure" group, while the group with lower concentrations was defined as "low-exposure" group. Association analysis with health outcomes suggested that the high-exposure group according to either blood or urinary metal levels had significantly higher total mortality (1.63-1.64 times higher, p < 0.0001), mortality caused by malignant neoplasms (2.05-2.62 times higher, p < 0.0002), Gamma-glutamyl transferase (GGT) (1.03-1.05 times higher, p < 0.0001). In addition, the high-exposure group based on blood levels was also significantly associated with SBP, death related to hypertension, heart disease and chronic lower respiratory disease, while the high-exposure group based on urinary concentrations had higher mortality related to nephritis. CONCLUSIONS We proposed an unsupervised clustering method to stratify the population into high- and low-exposure groups based on the co-exposure of heavy metals. The high-exposure groups, characterized by higher metal concentrations, had significant higher GGT, SBP, DBP, and mortality rates suggesting the detrimental effects of exposure to these heavy metals. The stratification of the NHANES population based on exposure patterns provides an informative method to study the impact of metal exposures on health outcomes.
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Affiliation(s)
- Xu Yao
- School of Public Health Administration, Anhui Medical University, Hefei 230032, Anhui, China
| | | | - Yaning Yang
- Department of Statistics and Finance, University of Science and Technology of China, Hefei 230026, Anhui, China
| | - Zhi Zhu
- Department of Statistics and Finance, University of Science and Technology of China, Hefei 230026, Anhui, China
| | - Zhao Zhu
- School of Public Health Administration, Anhui Medical University, Hefei 230032, Anhui, China
| | - Fangbiao Tao
- School of Public Health Administration, Anhui Medical University, Hefei 230032, Anhui, China
| | - Min Yuan
- School of Public Health Administration, Anhui Medical University, Hefei 230032, Anhui, China.
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Erhardt P, Bachmann K, Birkett D, Boberg M, Bodor N, Gibson G, Hawkins D, Hawksworth G, Hinson J, Koehler D, Kress B, Luniwal A, Masumoto H, Novak R, Portoghese P, Sarver J, Serafini MT, Trabbic C, Vermeulen N, Wrighton S. Glossary and tutorial of xenobiotic metabolism terms used during small molecule drug discovery and development (IUPAC Technical Report). PURE APPL CHEM 2021. [DOI: 10.1515/pac-2018-0208] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Abstract
This project originated more than 15 years ago with the intent to produce a glossary of drug metabolism terms having definitions especially applicable for use by practicing medicinal chemists. A first-draft version underwent extensive beta-testing that, fortuitously, engaged international audiences in a wide range of disciplines involved in drug discovery and development. It became clear that the inclusion of information to enhance discussions among this mix of participants would be even more valuable. The present version retains a chemical structure theme while expanding tutorial comments that aim to bridge the various perspectives that may arise during interdisciplinary communications about a given term. This glossary is intended to be educational for early stage researchers, as well as useful for investigators at various levels who participate on today’s highly multidisciplinary, collaborative small molecule drug discovery teams.
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Affiliation(s)
- Paul Erhardt
- Center for Drug Design and Development , University of Toledo , Toledo , Ohio , USA
| | | | - Donald Birkett
- Department of Clinical Pharmacology , Flinders University , Adelaide , Australia (now Emeritus), (TGM)
| | - Michael Boberg
- Metabolism and Isotope Chemistry , Bayer , AG , Germany (now undetermined), (TGM)
| | - Nicholas Bodor
- Center for Drug Discovery , University of Florida , Belle Glade , FL , USA (now Emeritus Grad Res Prof/CEO Bodor Labs), (TGM)
| | - Gordon Gibson
- School of Biomedical and Life Sciences, University of Surrey , Surrey , UK (now deceased), (TGM)
| | - David Hawkins
- Huntingdon Life Sciences , Huntingdon , UK (now retired), (TGM)
| | - Gabrielle Hawksworth
- Department of Medicine and Therapeutics , University Aberdeen , Aberdeen , UK (now deceased), (TGM)
| | - Jack Hinson
- Division of Toxicology , University Arkansas for Medical Sciences , Little Rock , Arkansas , USA (now Emeritus Dist Prof), (TGM)
| | - Daniel Koehler
- Department of Pharmacology , University of Toledo , Toledo , Ohio , USA, (ST)
| | - Brian Kress
- Department of Medicinal and Biological Chemistry , University of Toledo , Toledo , Ohio , USA, (ST)
| | | | - Hiroshi Masumoto
- Drug Metabolism , Daiichi Pharm. Corp., Ltd. , Chuo , Tokyo , Japan (now retired), (TGM)
| | - Raymond Novak
- Institute of Environmental Health Science, Wayne State University , Detroit , Michigan , USA (now undetermined), (TGM)
| | - Phillip Portoghese
- Department of Medicinal Chemistry , University of Minnesota , Minneapolis , Minnesota , USA (now same), (TGM)
| | - Jeffrey Sarver
- Department of Pharmacology , University of Toledo , Toledo , Ohio , USA, (ST)
| | - M. Teresa Serafini
- Department of Pharmacokinetics and Drug Metabolism , Laboratories Dr. Esteve, S.A. , Barcelona , Spain (now Head Early ADME), (TGM)
| | | | - Nico Vermeulen
- Department of Pharmacochemistry , Vrije University , Amsterdam , Netherlands (now Emeritus Section Molecular Toxicology), (TGM)
| | - Steven Wrighton
- Eli Lilly, Inc. , Indianapolis , Indiana , USA (now retired), (TGM)
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Li P, Sundh D, Ji B, Lappa D, Ye L, Nielsen J, Lorentzon M. Metabolic Alterations in Older Women With Low Bone Mineral Density Supplemented With Lactobacillus reuteri. JBMR Plus 2021; 5:e10478. [PMID: 33869994 PMCID: PMC8046097 DOI: 10.1002/jbm4.10478] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Accepted: 02/03/2021] [Indexed: 12/13/2022] Open
Abstract
Osteoporosis and its associated fractures are highly prevalent in older women. Recent studies have shown that gut microbiota play important roles in regulating bone metabolism. A previous randomized controlled trial (RCT) found that supplementation with Lactobacillus reuteri ATCC PTA 6475 (L.reuteri) led to substantially reduced bone loss in older women with low BMD. However, the total metabolic effects of L. reuteri supplementation on older women are still not clear. In this study, a post hoc analysis (not predefined) of serum metabolomic profiles of older women from the previous RCT was performed to investigate the metabolic dynamics over 1 year and to evaluate the effects of L. reuteri supplementation on human metabolism. Distinct segregation of the L. reuteri and placebo groups in response to the treatment was revealed by partial least squares‐discriminant analysis. Although no individual metabolite was differentially and significantly associated with treatment after correction for multiple testing, 97 metabolites responded differentially at any one time point between L. reuteri and placebo groups (variable importance in projection score >1 and p value <0.05). These metabolites were involved in multiple processes, including amino acid, peptide, and lipid metabolism. Butyrylcarnitine was particularly increased at all investigated time points in the L. reuteri group compared with placebo, indicating that the effects of L. reuteri on bone loss are mediated through butyrate signaling. Furthermore, the metabolomic profiles in a case (low BMD) and control population (high BMD) of elderly women were analyzed to confirm the associations between BMD and the identified metabolites regulated by L. reuteri supplementation. The amino acids, especially branched‐chain amino acids, showed association with L. reuteri treatment and with low BMD in older women, and may serve as potential therapeutic targets. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
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Affiliation(s)
- Peishun Li
- Department of Biology and Biological Engineering Chalmers University of Technology Gothenburg Sweden
| | - Daniel Sundh
- Geriatric Medicine, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy University of Gothenburg Gothenburg Sweden
| | - Boyang Ji
- Department of Biology and Biological Engineering Chalmers University of Technology Gothenburg Sweden
| | - Dimitra Lappa
- Department of Biology and Biological Engineering Chalmers University of Technology Gothenburg Sweden
| | - Lingqun Ye
- Department of Biology and Biological Engineering Chalmers University of Technology Gothenburg Sweden
| | - Jens Nielsen
- Department of Biology and Biological Engineering Chalmers University of Technology Gothenburg Sweden.,Novo Nordisk Foundation Center for Biosustainability Technical University of Denmark Kgs. Lyngby Denmark.,BioInnovation Institute Copenhagen Denmark
| | - Mattias Lorentzon
- Geriatric Medicine, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy University of Gothenburg Gothenburg Sweden.,Region Västra Götaland, Geriatric Medicine Clinic Sahlgrenska University Hospital Mölndal Sweden.,Mary MacKillop Institute for Health Research Australian Catholic University Melbourne Victoria Australia
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Suzuki H. γ-Glutamyltranspeptidase essential for the metabolism of γ-glutamyl compounds in bacteria and its application. Biosci Biotechnol Biochem 2021; 85:1295-1313. [DOI: 10.1093/bbb/zbab043] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Accepted: 02/27/2021] [Indexed: 01/09/2023]
Abstract
ABSTRACT
The enzymatic characteristics of γ-glutamyltranspeptidase were elucidated. The catalytic nucleophile of the enzymatic reaction of Escherichia coli γ-glutamyltranspeptidase was identified as the Oγ of the N-terminal Thr-residue of the small subunit. It was demonstrated that the inactive precursor of γ-glutamyltranspeptidase is processed autocatalytically and intramolecularly into the active heterodimeric mature enzyme via an ester intermediate. The catalytic nucleophile of this processing reaction was identified as the same Oγ atom of the N-terminal Thr-residue of the small subunit. These results were also supported by the three-dimensional structures of the γ-glutamyl enzyme intermediate and of the precursor-mimicked T391A nonprocessable mutant enzyme. Applications of transpeptidation and hydrolysis activities of bacterial γ-glutamyltranspeptidases were developed. Using transpeptidation activity, efficient enzymatic production of useful γ-glutamyl compounds, such as prodrug for Parkinson's disease, theanine and kokumi compound, was enabled. Hydrolysis activity was used as glutaminase and the mutant enzymes gaining glutaryl-7-aminocephalosporanic acid acylase activity were isolated.
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Affiliation(s)
- Hideyuki Suzuki
- Division of Applied Biology, Kyoto Institute of Technology, Goshokaido-cho Matsugasaki Sakyo-ku, Kyoto, Japan
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41
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Brown AL, Sok P, Taylor O, Woodhouse JP, Bernhardt MB, Raghubar KP, Kahalley LS, Lupo PJ, Hockenberry MJ, Scheurer ME. Cerebrospinal Fluid Metabolomic Profiles Associated With Fatigue During Treatment for Pediatric Acute Lymphoblastic Leukemia. J Pain Symptom Manage 2021; 61:464-473. [PMID: 32889041 PMCID: PMC7914130 DOI: 10.1016/j.jpainsymman.2020.08.030] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 07/22/2020] [Accepted: 08/24/2020] [Indexed: 12/21/2022]
Abstract
CONTEXT Cancer-related fatigue (CRF) is one of the most distressing and persistent symptoms reported during pediatric acute lymphoblastic leukemia (ALL) therapy; however, information on the pathways underlying CRF severity is limited. OBJECTIVES We conducted global metabolomics profiling of cerebrospinal fluid (CSF) samples to provide insight into the underlying mechanisms of CRF. METHODS Fatigue in pediatric ALL patients (2012-2017) was assessed during postinduction therapy approximately six months after diagnosis. Postinduction CSF was collected from 171 participants, comprising discovery (n = 86) and replication (n = 85) cohorts. We also conducted secondary validation using diagnostic CSF from 48 replication cohort participants. CSF metabolomic profiling was performed using gas chromatography-mass spectrometry (MS) and liquid chromatography-MS/MS. Kendall's rank correlation was used to evaluate associations between metabolite abundance and CRF. False discovery rate was used to account for multiple comparisons. RESULTS Participants were 56% males and 59% Hispanic with a mean age at diagnosis of 8.5 years. A total of 274 CSF-derived metabolites were common to the discovery and replication cohorts. Eight metabolites were significantly associated with fatigue in the discovery cohort (P < 0.05), of which three were significant in the replication cohort, including false discovery rate-corrected associations with gamma-glutamylglutamine (Pcombined = 6.2E-6) and asparagine (Pcombined = 3.5E-4). Notably, the abundance of gamma-glutamylglutamine in diagnostic CSF samples was also significantly associated with fatigue (P = 0.0062). CONCLUSION The metabolites identified in our assessment have been implicated in neurotransmitter transportation and glutathione recycling, suggesting that glutamatergic pathways or oxidative stress may contribute to ALL-associated CRF. This information could inform targeted therapies for reducing CRF in at-risk individuals.
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Affiliation(s)
- Austin L Brown
- Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.
| | - Pagna Sok
- Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA
| | - Olga Taylor
- Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA
| | - John P Woodhouse
- Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA
| | - M Brooke Bernhardt
- Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA
| | | | - Lisa S Kahalley
- Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA
| | - Philip J Lupo
- Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA
| | | | - Michael E Scheurer
- Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA
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Yang T, Liu S, Liu H, Long M, Chen P, Zhang X, Xu M, Rao Z. Semi-quantitative activity assays for high-throughput screening of higher activity gamma glutamyl transferase and enzyme immobilization to efficiently synthesize L-theanine. J Biotechnol 2021; 330:9-16. [PMID: 33636215 DOI: 10.1016/j.jbiotec.2021.02.011] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 11/25/2020] [Accepted: 02/18/2021] [Indexed: 11/17/2022]
Abstract
The bio-production of theanine is currently of significant interest due to its wide applications in food and healthcare products. Gamma glutamyl transferase (GGT) has been widely applied in L-theanine synthesis, but L-theanine yields remain prohibitively low for commercial production. In this study, a robust high-throughput screening process for isolating GGT mutants was developed through a combination of error-prone PCR techniques and a colorimetric reaction. The co-expression of PrsA lipoprotein enhances the secretion of GGT, thus GGT could be obtained quickly and easily without crushing cells. Random mutations on ggt genes were introduced by using error-prone PCR kits to build a large mutant library. A colorless compound generated by the reaction between NH4+ (released from L-theanine synthesis) and OPA was measured quantitatively by UV/visible spectroscopy when mixed with TCA and DMSO. Approximately 30 positive clones with improved color formation on the 96-well plates were identified, and mutants T413P and T463S with more than by 30 % higher transpeptidation activity versus the original GGT were isolated. To improve the operational stability and economical use, mutant GGT was immobilized on a prepared oxidized cellulose nanofiber membrane. The remaining activity of immobilized GGT was 88 % versus 72 % of free enzyme over 15 h. A fed-batch conversion was performed with the immobilized GGT, and over 70 g/L L-theanine could be accumulated within 18 h after feeding twice. Versus other studies, this is one of the best L-theanine synthesis systems using immobilized GGT.
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Affiliation(s)
- Taowei Yang
- The Key Laboratory of Industrial Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi, Jiangsu Province 214122, China.
| | - Shuanying Liu
- The Key Laboratory of Industrial Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi, Jiangsu Province 214122, China
| | - Huiling Liu
- The Key Laboratory of Industrial Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi, Jiangsu Province 214122, China
| | - Mengfei Long
- The Key Laboratory of Industrial Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi, Jiangsu Province 214122, China
| | - Pengcheng Chen
- The Key Laboratory of Industrial Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi, Jiangsu Province 214122, China
| | - Xian Zhang
- The Key Laboratory of Industrial Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi, Jiangsu Province 214122, China
| | - Meijuan Xu
- The Key Laboratory of Industrial Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi, Jiangsu Province 214122, China
| | - Zhiming Rao
- The Key Laboratory of Industrial Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi, Jiangsu Province 214122, China.
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Calabrese V, Scuto M, Salinaro AT, Dionisio G, Modafferi S, Ontario ML, Greco V, Sciuto S, Schmitt CP, Calabrese EJ, Peters V. Hydrogen Sulfide and Carnosine: Modulation of Oxidative Stress and Inflammation in Kidney and Brain Axis. Antioxidants (Basel) 2020; 9:antiox9121303. [PMID: 33353117 PMCID: PMC7767317 DOI: 10.3390/antiox9121303] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Revised: 12/11/2020] [Accepted: 12/14/2020] [Indexed: 02/06/2023] Open
Abstract
Emerging evidence indicates that the dysregulation of cellular redox homeostasis and chronic inflammatory processes are implicated in the pathogenesis of kidney and brain disorders. In this light, endogenous dipeptide carnosine (β-alanyl-L-histidine) and hydrogen sulfide (H2S) exert cytoprotective actions through the modulation of redox-dependent resilience pathways during oxidative stress and inflammation. Several recent studies have elucidated a functional crosstalk occurring between kidney and the brain. The pathophysiological link of this crosstalk is represented by oxidative stress and inflammatory processes which contribute to the high prevalence of neuropsychiatric disorders, cognitive impairment, and dementia during the natural history of chronic kidney disease. Herein, we provide an overview of the main pathophysiological mechanisms related to high levels of pro-inflammatory cytokines, including interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and neurotoxins, which play a critical role in the kidney–brain crosstalk. The present paper also explores the respective role of H2S and carnosine in the modulation of oxidative stress and inflammation in the kidney–brain axis. It suggests that these activities are likely mediated, at least in part, via hormetic processes, involving Nrf2 (Nuclear factor-like 2), Hsp 70 (heat shock protein 70), SIRT-1 (Sirtuin-1), Trx (Thioredoxin), and the glutathione system. Metabolic interactions at the kidney and brain axis level operate in controlling and reducing oxidant-induced inflammatory damage and therefore, can be a promising potential therapeutic target to reduce the severity of renal and brain injuries in humans.
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Affiliation(s)
- Vittorio Calabrese
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95125 Catania, Italy; (M.S.); (S.M.); (M.L.O.); (V.G.); (S.S.)
- Correspondence: (V.C.); (A.T.S.)
| | - Maria Scuto
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95125 Catania, Italy; (M.S.); (S.M.); (M.L.O.); (V.G.); (S.S.)
| | - Angela Trovato Salinaro
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95125 Catania, Italy; (M.S.); (S.M.); (M.L.O.); (V.G.); (S.S.)
- Correspondence: (V.C.); (A.T.S.)
| | - Giuseppe Dionisio
- Department of Molecular Biology and Genetics, Research Center Flakkebjerg, Aarhus University, Forsøgsvej 1, 4200 Slagelse, Denmark;
| | - Sergio Modafferi
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95125 Catania, Italy; (M.S.); (S.M.); (M.L.O.); (V.G.); (S.S.)
| | - Maria Laura Ontario
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95125 Catania, Italy; (M.S.); (S.M.); (M.L.O.); (V.G.); (S.S.)
| | - Valentina Greco
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95125 Catania, Italy; (M.S.); (S.M.); (M.L.O.); (V.G.); (S.S.)
| | - Sebastiano Sciuto
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95125 Catania, Italy; (M.S.); (S.M.); (M.L.O.); (V.G.); (S.S.)
| | - Claus Peter Schmitt
- Centre for Pediatric and Adolescent Medicine, University of Heidelberg, 69120 Heidelberg, Germany; (C.P.S.); (V.P.)
| | - Edward J. Calabrese
- Department of Environmental Health Sciences, Morrill I, N344, University of Massachusetts, Amherst, MA 01003, USA;
| | - Verena Peters
- Centre for Pediatric and Adolescent Medicine, University of Heidelberg, 69120 Heidelberg, Germany; (C.P.S.); (V.P.)
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Corti A, Belcastro E, Dominici S, Maellaro E, Pompella A. The dark side of gamma-glutamyltransferase (GGT): Pathogenic effects of an 'antioxidant' enzyme. Free Radic Biol Med 2020; 160:807-819. [PMID: 32916278 DOI: 10.1016/j.freeradbiomed.2020.09.005] [Citation(s) in RCA: 64] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 08/26/2020] [Accepted: 09/01/2020] [Indexed: 12/16/2022]
Abstract
Having long been regarded as just a member in the cellular antioxidant systems, as well as a clinical biomarker of hepatobiliary diseases and alcohol abuse, gamma-glutamyltransferase (GGT) enzyme activity has been highlighted by more recent research as a critical factor in modulation of redox equilibria within the cell and in its surroundings. Moreover, due to the prooxidant reactions which can originate during its metabolic function in selected conditions, experimental and clinical studies are increasingly involving GGT in the pathogenesis of several important disease conditions, such as atherosclerosis, cardiovascular diseases, cancer, lung inflammation, neuroinflammation and bone disorders. The present article is an overview of the laboratory findings that have prompted an evolution in interpretation of the significance of GGT in human pathophysiology.
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Affiliation(s)
- Alessandro Corti
- Dept. of Translational Research NTMS, University of Pisa Medical School, Italy
| | - Eugenia Belcastro
- Dept. of Translational Research NTMS, University of Pisa Medical School, Italy
| | - Silvia Dominici
- Dept. of Translational Research NTMS, University of Pisa Medical School, Italy
| | - Emilia Maellaro
- Dept. of Molecular and Developmental Medicine, University of Siena, Italy
| | - Alfonso Pompella
- Dept. of Translational Research NTMS, University of Pisa Medical School, Italy.
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Stolzenberg-Solomon RZ, Derkach A, Moore S, Weinstein S, Albanes D, Sampson J. Associations between metabolites and pancreatic cancer risk in a large prospective epidemiological study. Gut 2020; 69:2008-2015. [PMID: 32060129 PMCID: PMC7980697 DOI: 10.1136/gutjnl-2019-319811] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Revised: 01/17/2020] [Accepted: 01/20/2020] [Indexed: 12/15/2022]
Abstract
OBJECTIVE To assess whether prediagnostic metabolites were associated with incident pancreatic ductal adenocarcinoma (PDAC) in a prospective cohort study. DESIGN We conducted an untargeted analysis of 554 known metabolites measured in prediagnostic serum (up to 24 years) to determine their association with incident PDAC in a nested case-control study of male smokers (372 matched case-control sets) and an independent nested case-control study that included women and non-smokers (107 matched sets). Metabolites were measured using Orbitrap Elite or Q-Exactive high-resolution/accurate mass spectrometers. Controls were matched to cases by age, sex, race, date of blood draw, and follow-up time. We used conditional logistic regression adjusted for age to calculate ORs and 95% CIs for a 1 SD increase in log-metabolite level separately in each cohort and combined the two ORs using a fixed-effects meta-analysis. RESULTS Thirty-one metabolites were significantly associated with PDAC at a false discovery rate <0.05 with 12 metabolites below the Bonferroni-corrected threshold (p<9.04×10-5). Similar associations were observed in both cohorts. The dipeptides glycylvaline, aspartylphenylalanine, pyroglutamylglycine, phenylalanylphenylalanine, phenylalanylleucine and tryptophylglutamate and amino acids aspartate and glutamate were positively while the dipeptides tyrosylglutamine and α-glutamyltyrosine, fibrinogen cleavage peptide DSGEGDFXAEGGGVR and glutathione-related amino acid cysteine-glutathione disulfide were inversely associated with PDAC after Bonferroni correction. Five top metabolites demonstrated significant time-varying associations (p<0.023) with the strongest associations observed 10-15 years after participants' blood collection and attenuated thereafter. CONCLUSION Our results suggest that prediagnostic metabolites related to subclinical disease, γ-glutamyl cycle metabolism and adiposity/insulin resistance are associated with PDAC.
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Affiliation(s)
- Rachael Z. Stolzenberg-Solomon
- Metabolic Epidemiology Branch, Division Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, United States
| | - Andriy Derkach
- Biostatistics Branch, Division Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, United States
| | - Steven Moore
- Metabolic Epidemiology Branch, Division Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, United States
| | - Stephanie Weinstein
- Metabolic Epidemiology Branch, Division Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, United States
| | - Demetrius Albanes
- Metabolic Epidemiology Branch, Division Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, United States
| | - Joshua Sampson
- Biostatistics Branch, Division Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, United States
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Anethole Dithiolethione Increases Glutathione in Kidney by Inhibiting γ-Glutamyltranspeptidase: Biochemical Interpretation and Pharmacological Consequences. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:3562972. [PMID: 33062138 PMCID: PMC7539083 DOI: 10.1155/2020/3562972] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 08/28/2020] [Accepted: 09/10/2020] [Indexed: 01/10/2023]
Abstract
Aims Anethole dithiolethione (ADT) is a marketed drug to treat xerostomia. Its mechanism of action is still unknown, but several preclinical studies indicate that it is able to increase intracellular glutathione (GSH) and protect against oxidative stress. Here, we investigated the molecular mechanisms behind these effects. Results Oral treatment of rats confirmed the GSH enhancing properties of ADT; among the different organs examined in this study, only the kidney showed a significant GSH increase that was already observed at low-dose treatments. The increase in GSH correlated with a decrease in γ-glutamyltranspeptidase (γ-GT) activity of the different tissues. In vitro and ex vivo experiments with tubular renal cells and isolated perfused rat kidney showed that the cellular uptake of intact GSH was correlated with the extracellular concentrations of GSH. Conclusion s. The prominent in vivopharmacological effect of ADT was a marked increase of GSH concentration in the kidney and a decrease of some systemic and renal biomarkers of oxidative stress. In particular, by inhibition of γ-GT activity, it decreased the production cysteinylglycine, a thiol that has prooxidant effects as the consequence of its autooxidation. The activity of ADT as GSH enhancer in both the circulation and the kidney was long-lasting. All these characteristics make ADT a promising drug to protect the kidney, and in particular proximal tubule cells, from xenobiotic-induced damage.
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Zaragozá R. Transport of Amino Acids Across the Blood-Brain Barrier. Front Physiol 2020; 11:973. [PMID: 33071801 PMCID: PMC7538855 DOI: 10.3389/fphys.2020.00973] [Citation(s) in RCA: 103] [Impact Index Per Article: 20.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Accepted: 07/16/2020] [Indexed: 01/17/2023] Open
Abstract
The blood-brain-barrier (BBB), present in brain capillaries, constitutes an essential barrier mechanism for normal functioning and development of the brain. The presence of tight junctions between adjacent endothelial cells restricts permeability and movement of molecules between extracellular fluid and plasma. The protein complexes that control cell-cell attachment also polarize cellular membrane, so that it can be divided into luminal (blood-facing) and abluminal (brain) sides, and each solute that enters/leaves the brain must cross both membranes. Several amino acid (AA) transport systems with different distributions on both sides of the BBB have been described. In a broad sense, there are at least five different systems of facilitative transporters and all of them are found in the luminal membrane. Some of these transporters are very specific for a small group of substrates and are located exclusively on the luminal side of the BBB. However, the two major facilitative carriers, system L and system y+, are located in both membranes, although asymmetrically. The position of these Na+-independent transporters ensures AA availability in the brain and also its bidirectional transport across the endothelial cells. On the other hand, there are several Na+-dependent transport systems that transport AAs against its concentration gradient together with the movement of Na+ ions. The majority of these active transporters are present exclusively at the abluminal membrane and are responsible for AA efflux from the brain into the endothelial cells. Since they are Na+-coupled, the sodium pump Na+/K+-ATPase is also highly expressed on this abluminal side of the BBB. Once inside the cell, the facilitative transporters located in the luminal membranes mediate export from the endothelial cell to the blood. In summary, the polarized distribution of these transport systems between the luminal and abluminal membranes, and the fact that more than one transporter may carry the same substrate, ensures supply and excretion of AAs in and out of the brain, thereby controlling its homeostasis and proper function.
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Affiliation(s)
- Rosa Zaragozá
- Department of Human Anatomy and Embriology, School of Medicine, IIS INCLIVA, University of Valencia, Valencia, Spain
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Zajic DE, Podrabsky JE. Metabolomics analysis of annual killifish ( Austrofundulus limnaeus) embryos during aerial dehydration stress. Physiol Genomics 2020; 52:408-422. [PMID: 32776802 DOI: 10.1152/physiolgenomics.00072.2020] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
The annual killifish, Austrofundulus limnaeus, survives in ephemeral ponds in the coastal deserts of Venezuela. Persistence through the dry season is dependent on drought-resistant eggs embedded in the pond sediments during the rainy season. The ability of these embryos to enter drastic metabolic dormancy (diapause) during normal development enables A. limnaeus to survive conditions lethal to most other aquatic vertebrates; critical to the survival of the species is the ability of embryos to survive months and perhaps years without access to liquid water. Little is known about the molecular mechanisms that aid in survival of the dry season. This study aims to gain insight into the mechanisms facilitating survival of dehydration stress due to aerial exposure by examining metabolite profiles of dormant and developing embryos. There is strong evidence for unique metabolic profiles based on developmental stage and length of aerial exposure. Actively developing embryos exhibit more robust changes; however, dormant embryos respond in an active manner and significantly alter their metabolic profile. A number of metabolites accumulate in aerial-exposed embryos that may play an important role in survival, including the identification of known antioxidants and neuroprotectants. In addition, a number of unique metabolites not yet discussed in the dehydration literature are identified, such as lanthionine and 2-hydroxyglutarate. Despite high oxygen availability, embryos accumulate the anaerobic end product lactate. This paper offers an overview of the metabolic changes occurring that may support embryonic survival during dehydration stress due to aerial incubation, which can be functionally tested using genetic and pharmacological approaches.
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Affiliation(s)
- Daniel E Zajic
- Department of Biology, Portland State University, Portland, Oregon.,Health, Human Performance, and Athletics Department, Linfield University, McMinnville, Oregon
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Azarova IE, Klyosova EY, Churilin MI, Samgina TA, Konoplya AI, Polonikov AV. Genetic and biochemical investigation of the gamma-glutamylcyclotransferase role in predisposition to type 2 diabetes mellitus. ECOLOGICAL GENETICS 2020; 18:215-228. [DOI: 10.17816/ecogen16293] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/28/2024]
Abstract
Background. Imbalance in the system of redox homeostasis is an important link in the pathogenesis of type 2 diabetes (T2D). Gamma-glutamyl cyclotransferase is an antioxidant defense enzyme directly involved in the metabolism of glutathione, an endogenous antioxidant.
The aim of the study was to examine the association of single nucleotide polymorphisms (SNP) rs38420 (G A), rs4270 (T C), rs6462210 (C T) and rs28679 (G A) in GGCT gene with the risk of developing T2D.
Materials and Methods. The study included 1022 T2D patients and 1064 healthy volunteers. Genotyping of GGCT gene loci was performed using iPLEX technology on a MassARRAY Analyzer 4 genome time-of-flight mass spectrometer (Agena Bioscience).
Results. As a result, we identified for the first time the association of SNP rs4270 in the GGCT gene with the risk of T2D in the Russian population. We have also established genetic and environmental interactions associated with predisposition to the disease: protective effect of gamma-glutamyl cyclotransferase gene was observed only in non-smokers under condition of daily consumption of fresh vegetables and fruits, whereas in persons with insufficient consumption of plant foods, as well as in all smoking patients protective effect of GGCT was not observed. In patients with T2D, the level of hydrogen peroxide and glutathione monomer was sharply increased compared to the controls. SNP rs4270 was also found to be associated with elevated levels of reduced glutathione in the plasma of type 2 diabetics.
Conclusion. Thus, for the first time it was established that polymorphic locus rs4270 in the GGCT gene is associated with a predisposition to T2D, but its relationship with the disease is modulated by smoking and fresh plant foods consumption.
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Cho HM, Lee DW, Park JJ, Choi HM, Cho NP. Risk factors of head and neck cancer mortality compared with those of all-cause and all-cancer mortalities. J Oral Sci 2020; 62:365-370. [PMID: 32624546 DOI: 10.2334/josnusd.19-0368] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/01/2022]
Abstract
This study aimed to clarify the risk factors of head and neck cancer (HNC) mortality, relative to those of all-cause and all-cancer mortalities, using the Korean National Health Insurance Service-Health Screening Cohort (NHIS-HEALS) data set. Data from 238 HNC deaths, 14,769 all-cancer deaths, and 38,086 all-cause deaths were extracted during a median follow-up period of 9.5 years. Baseline characteristics were assessed via chi-square tests, t tests, and multivariable logistic regression. HNC mortality was found to be positively associated with male sex, past and current smoking habits, moderate-to-heavy alcohol consumption, and being underweight. In addition, serum gamma-glutamyltransferase level was found to be significantly elevated in cases of HNC mortality. In contrast, obesity, a history of diabetes, and fasting blood glucose levels were found to be inversely associated with overall HNC mortality. Among the HNC subtypes, mortality due to laryngeal cancer was most strongly associated with past and heavy cigarette smoking, and mortality due to oro-/hypopharyngeal cancer was most strongly associated with heavy alcohol consumption. The present study demonstrates that this nationwide, population-based NHIS-HEALS data set can provide useful information for health research and policy development.
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Affiliation(s)
- Hye Min Cho
- Department of Oral Pathology and Institute of Oral Bioscience, School of Dentistry, Jeonbuk National University
| | - Dae-Woo Lee
- Department of Pediatric Dentistry and Institute of Oral Bioscience, School of Dentistry, Jeonbuk National University
| | - Jeong Jae Park
- Regional Cardiovascular Center, Wonkwang University Hospital
| | - Hye Mi Choi
- Department of Statistics, Research Institute of Applied Statistics, Jeonbuk National University
| | - Nam-Pyo Cho
- Department of Oral Pathology and Institute of Oral Bioscience, School of Dentistry, Jeonbuk National University
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