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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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2
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Paz AA, Jiménez TA, Ibarra-Gonzalez J, Astudillo-Maya C, Beñaldo FA, Figueroa EG, Llanos AJ, Gonzalez-Candia A, Herrera EA. Gestational hypoxia elicits long-term cardiovascular dysfunction in female guinea pigs. Life Sci 2025; 361:123282. [PMID: 39615619 DOI: 10.1016/j.lfs.2024.123282] [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: 09/05/2024] [Revised: 11/21/2024] [Accepted: 11/26/2024] [Indexed: 01/06/2025]
Abstract
BACKGROUND Gestational hypoxia (GH) has been implicated in the developmental programming of cardiovascular diseases (CVDs) in the offspring, with most studies focusing on males, conversely, the effects on female cardiovascular health remain understudied. We aimed to investigate the impact of GH on the cardiovascular system of female guinea pig offspring from the early postnatal period to adulthood. METHODS Pregnant guinea pigs were subjected to normoxic or hypoxic conditions from gestational day 30 until delivery (∼70 days). Female offspring were monitored with biometric parameters and peripheral vascular function (ultrasound) from birth to one year old. In addition, we assessed cardiovascular structure, oxidative stress, inflammatory state (IHC, qPCR, and immunoblot assays), and thoracic aorta reactivity (wire-myography) at one year of age. KEY FINDINGS GH increased heart rate and peripheral pulsatility index. At one year old, GH-exposed females exhibited cardiac remodeling, characterized by increased left ventricular luminal area and coronary artery muscle occupation. Furthermore, GH increased aortic vascular wall, intima-media thickness and contractile capacity. This was accompanied by reduced endothelium-dependent vasodilation and enhanced oxidative stress. Additionally, GH increased collagen deposition and oxidative stress in the right ventricle, accompanied by reduced antioxidant enzymes expression and reduced inflammatory mediator levels. SIGNIFICANCE GH exerts long-lasting effects on the cardiovascular health of female guinea pig offspring, contributing to cardiac remodeling, vascular dysfunction, oxidative stress, and inflammatory changes. These findings highlight the importance of GH as a risk factor for developing CVDs in female offspring and emphasize the need for sex-specific interventions to mitigate adverse long-term gestational effects.
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Affiliation(s)
- Adolfo A Paz
- Laboratorio de Función y Reactividad Vascular, ICBM, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Tamara A Jiménez
- Laboratorio de Función y Reactividad Vascular, ICBM, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Julieta Ibarra-Gonzalez
- Laboratorio de Función y Reactividad Vascular, ICBM, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Cristian Astudillo-Maya
- Laboratorio de Función y Reactividad Vascular, ICBM, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Felipe A Beñaldo
- Laboratorio de Función y Reactividad Vascular, ICBM, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Esteban G Figueroa
- Instituto de Ciencias de la Salud, Universidad de O'Higgins, Rancagua, Chile
| | - Aníbal J Llanos
- Laboratorio de Función y Reactividad Vascular, ICBM, Facultad de Medicina, Universidad de Chile, Santiago, Chile; International Center for Andean Studies (INCAS), Universidad de Chile, Putre, Chile
| | | | - Emilio A Herrera
- Laboratorio de Función y Reactividad Vascular, ICBM, Facultad de Medicina, Universidad de Chile, Santiago, Chile; International Center for Andean Studies (INCAS), Universidad de Chile, Putre, Chile.
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Plum M, Beier JP, Ruhl T. Delayed cutaneous wound healing in young and old female mice is associated with differential growth factor release but not inflammatory cytokine secretion. Biogerontology 2025; 26:37. [PMID: 39775106 PMCID: PMC11711145 DOI: 10.1007/s10522-024-10179-7] [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: 11/20/2024] [Accepted: 12/26/2024] [Indexed: 01/11/2025]
Abstract
The capacity for tissue repair during wound healing declines with age. A chronic low but systemic inflammatory status, often called "inflammaging", is considered a key factor that contributes to impaired tissue regeneration. This phenomenon has been substantiated by an increased number of immune cells in wound-tissue of old mice. Although immune cells coordinate an inflammatory response by their secretome the composition of the wound milieu has not been examined. In young (2 months) and old (18 months) female mice, excision wounds were induced using a punch biopsy device, i.e., the healing progress occurred through secondary intention. The closure rate was analyzed for 7 days. At days 1, 3 and 7 post-surgery, wound specimen were investigated for immunohistochemical detection of granulocytes, M1-macrophages and mesenchymal stem cells of the skin. The concentrations of inflammatory cytokines and regenerative growth factors were determined in tissue homogenates by ELISA. The carbonyl assay was used to determine protein oxidation. In old mice, the wound closure was delayed between days 1 and 3 post-surgery, as was the peak of immune cell infiltration. There was no age effect on the concentration of inflammatory cytokines, but wounds of young animals contained higher number of mesenchymal stem cells and increased levels of growth factors. Protein oxidation was increased with age. The present study suggests that a reduced regenerative capacity rather than an enhanced inflammatory score affected the tissue regeneration process in old mice.
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Affiliation(s)
- Melissa Plum
- Department of Plastic Surgery, Hand Surgery-Burn Center, University Hospital RWTH Aachen, Pauwelsstraße 30, 52074, Aachen, Germany
| | - Justus P Beier
- Department of Plastic Surgery, Hand Surgery-Burn Center, University Hospital RWTH Aachen, Pauwelsstraße 30, 52074, Aachen, Germany
| | - Tim Ruhl
- Department of Plastic Surgery, Hand Surgery-Burn Center, University Hospital RWTH Aachen, Pauwelsstraße 30, 52074, Aachen, Germany.
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4
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Xia CC, Chen HT, Deng H, Huang YT, Xu GQ. Reactive oxygen species and oxidative stress in acute pancreatitis: Pathogenesis and new therapeutic interventions. World J Gastroenterol 2024; 30:4771-4780. [PMID: 39649547 PMCID: PMC11606378 DOI: 10.3748/wjg.v30.i45.4771] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2024] [Revised: 09/27/2024] [Accepted: 10/29/2024] [Indexed: 11/13/2024] Open
Abstract
Acute pancreatitis (AP) is a common acute gastrointestinal disorder affecting approximately 20% of patients with systemic inflammatory responses that may cause pancreatic and peripancreatic fat necrosis. This condition often progresses to multiple organ failure, significantly increasing morbidity and mortality. Oxidative stress, characterized by an imbalance between the body's reactive oxygen species (ROS) and antioxidants, activates the inflammatory signaling pathways. Although the pathogenesis of AP is not fully understood, ROS are increasingly recognized as critical in the disease's progression and development. Modulating the oxidative stress pathway has shown efficacy in mitigating the progression of AP. Despite numerous basic studies examining this pathway, comprehensive reviews of recent research remain sparse. This systematic review offers an in-depth examination of the critical role of oxidative stress in the pathogenesis and progression of AP and evaluates the therapeutic potential of antioxidant interventions in its management.
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Affiliation(s)
- Chuan-Chao Xia
- Department of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Hong-Tan Chen
- Department of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Hao Deng
- Department of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Yi-Ting Huang
- Department of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Guo-Qiang Xu
- Department of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
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Tian L, Luo Y, Ren J, Zhao C. The Role of Oxidative Stress in Hypomagnetic Field Effects. Antioxidants (Basel) 2024; 13:1017. [PMID: 39199261 PMCID: PMC11352208 DOI: 10.3390/antiox13081017] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2024] [Revised: 08/12/2024] [Accepted: 08/19/2024] [Indexed: 09/01/2024] Open
Abstract
The geomagnetic field (GMF) is crucial for the survival and evolution of life on Earth. The weakening of the GMF, known as the hypomagnetic field (HMF), significantly affects various aspects of life on Earth. HMF has become a potential health risk for future deep space exploration. Oxidative stress is directly involved in the biological effects of HMF on animals or cells. Oxidative stress occurs when there is an imbalance favoring oxidants over antioxidants, resulting in cellular damage. Oxidative stress is a double-edged sword, depending on the degree of deviation from homeostasis. In this review, we summarize the important experimental findings from animal and cell studies on HMF exposure affecting intracellular reactive oxygen species (ROS), as well as the accompanying many physiological abnormalities, such as cognitive dysfunction, the imbalance of gut microbiota homeostasis, mood disorders, and osteoporosis. We discuss new insights into the molecular mechanisms underlying these HMF effects in the context of the signaling pathways related to ROS. Among them, mitochondria are considered to be the main organelles that respond to HMF-induced stress by regulating metabolism and ROS production in cells. In order to unravel the molecular mechanisms of HMF action, future studies need to consider the upstream and downstream pathways associated with ROS.
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Affiliation(s)
- Lanxiang Tian
- Key Laboratory of Earth and Planetary Physics, Institute of Geology and Geophysics, Chinese Academy of Sciences, Beijing 100029, China; (Y.L.); (J.R.); (C.Z.)
- College of Earth and Planetary Sciences, University of Chinese Academy of Sciences, Beijing 100049, China
- Beijing National Observatory of Space Environment, Institute of Geology and Geophysics, Chinese Academy of Sciences, Beijing 100029, China
| | - Yukai Luo
- Key Laboratory of Earth and Planetary Physics, Institute of Geology and Geophysics, Chinese Academy of Sciences, Beijing 100029, China; (Y.L.); (J.R.); (C.Z.)
- College of Earth and Planetary Sciences, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Jie Ren
- Key Laboratory of Earth and Planetary Physics, Institute of Geology and Geophysics, Chinese Academy of Sciences, Beijing 100029, China; (Y.L.); (J.R.); (C.Z.)
- College of Earth and Planetary Sciences, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Chenchen Zhao
- Key Laboratory of Earth and Planetary Physics, Institute of Geology and Geophysics, Chinese Academy of Sciences, Beijing 100029, China; (Y.L.); (J.R.); (C.Z.)
- College of Earth and Planetary Sciences, University of Chinese Academy of Sciences, Beijing 100049, China
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Zhou Y, Zhang X, Baker JS, Davison GW, Yan X. Redox signaling and skeletal muscle adaptation during aerobic exercise. iScience 2024; 27:109643. [PMID: 38650987 PMCID: PMC11033207 DOI: 10.1016/j.isci.2024.109643] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/25/2024] Open
Abstract
Redox regulation is a fundamental physiological phenomenon related to oxygen-dependent metabolism, and skeletal muscle is mainly regarded as a primary site for oxidative phosphorylation. Several studies have revealed the importance of reactive oxygen and nitrogen species (RONS) in the signaling process relating to muscle adaptation during exercise. To date, improving knowledge of redox signaling in modulating exercise adaptation has been the subject of comprehensive work and scientific inquiry. The primary aim of this review is to elucidate the molecular and biochemical pathways aligned to RONS as activators of skeletal muscle adaptation and to further identify the interconnecting mechanisms controlling redox balance. We also discuss the RONS-mediated pathways during the muscle adaptive process, including mitochondrial biogenesis, muscle remodeling, vascular angiogenesis, neuron regeneration, and the role of exogenous antioxidants.
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Affiliation(s)
- Yingsong Zhou
- Faculty of Sports Science, Ningbo University, Ningbo, China
| | - Xuan Zhang
- School of Wealth Management, Ningbo University of Finance and Economics, Ningbo, China
| | - Julien S. Baker
- Centre for Health and Exercise Science Research, Hong Kong Baptist University, Kowloon Tong 999077, Hong Kong
| | - Gareth W. Davison
- Sport and Exercise Sciences Research Institute, Ulster University, Belfast BT15 IED, UK
| | - Xiaojun Yan
- School of Marine Sciences, Ningbo University, Ningbo, China
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Guo J, Li R, Ouyang Z, Tang J, Zhang W, Chen H, Zhu Q, Zhang J, Zhu G. Insights into the mechanism of transcription factors in Pb 2+-induced apoptosis. Toxicology 2024; 503:153760. [PMID: 38387706 DOI: 10.1016/j.tox.2024.153760] [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: 10/19/2023] [Revised: 02/12/2024] [Accepted: 02/19/2024] [Indexed: 02/24/2024]
Abstract
The health risks associated with exposure to heavy metals, such as Pb2+, are increasingly concerning the public. Pb2+ can cause significant harm to the human body through oxidative stress, autophagy, inflammation, and DNA damage, disrupting cellular homeostasis and ultimately leading to cell death. Among these mechanisms, apoptosis is considered crucial. It has been confirmed that transcription factors play a central role as mediators during the apoptosis process. Interestingly, these transcription factors have different effects on apoptosis depending on the concentration and duration of Pb2+ exposure. In this article, we systematically summarize the significant roles of several transcription factors in Pb2+-induced apoptosis. This information provides insights into therapeutic strategies and prognostic biomarkers for diseases related to Pb2+ exposure.
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Affiliation(s)
- Jingchong Guo
- The First Clinical Medical College of Nanchang University, Nanchang 330006, China
| | - Ruikang Li
- The First Clinical Medical College of Nanchang University, Nanchang 330006, China
| | - Zhuqing Ouyang
- The First Clinical Medical College of Nanchang University, Nanchang 330006, China
| | - Jiawen Tang
- The First Clinical Medical College of Nanchang University, Nanchang 330006, China
| | - Wei Zhang
- Department of Anatomy, Medical College of Nanchang University, Nanchang 330006, China
| | - Hui Chen
- Department of Anatomy, Medical College of Nanchang University, Nanchang 330006, China
| | - Qian Zhu
- Department of Anatomy, Medical College of Nanchang University, Nanchang 330006, China
| | - Jing Zhang
- Department of Anatomy, Medical College of Nanchang University, Nanchang 330006, China.
| | - Gaochun Zhu
- Department of Anatomy, Medical College of Nanchang University, Nanchang 330006, China.
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8
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Yamamoto S, Ogasawara N, Mitsuhashi Y, Takano K, Yokota SI. The clarithromycin-binding proteins NIPSNAP1 and 2 regulate cytokine production through mitochondrial quality control. Sci Rep 2024; 14:2354. [PMID: 38287119 PMCID: PMC10824736 DOI: 10.1038/s41598-024-52582-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Accepted: 01/20/2024] [Indexed: 01/31/2024] Open
Abstract
The mechanism underlying the anti-inflammatory effect of macrolide antibiotics, such as clarithromycin (CAM), remains to be clarified. The CAM-binding proteins 4-nitrophenylphosphatase domain and non-neuronal synaptosomal associated protein 25 (SNAP25)-like protein homolog (NIPSNAP) 1 and 2 are involved in the immune response and mitochondrial homeostasis. However, the axis between CAM-NIPSNAP-mitochondria and Toll-like receptor (TLR) and their molecular mechanisms remain unknown. In this study, we sought to elucidate the relationship between mitochondrial homeostasis mediated by NIPSNAP1 and 2 and the immunomodulatory effect of CAM. NIPSNAP1 or 2 knockdown (KD) by RNA interference impaired TLR4-mediated interleukin-8 (IL-8) production. Similar impairment was observed upon treatment with mitochondrial function inhibitors. However, IL-8 secretion was not impaired in NIPSNAP1 and 2 individual knockout (KO) and double KO (DKO) cells. Moreover, the oxygen consumption rate (OCR) in mitochondria measured using a flex analyzer was significantly reduced in NIPSNAP1 or 2 KD cells, but not in DKO cells. CAM also dose-dependently reduced the OCR. These results indicate that CAM suppresses the IL-8 production via the mitochondrial quality control regulated by temporary functional inhibition of NIPSNAP1 and 2. Our findings provide new insight into the mechanisms underlying cytokine production, including the TLR-mitochondria axis, and the immunomodulatory effects of macrolides.
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Affiliation(s)
- Soh Yamamoto
- Department of Microbiology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Noriko Ogasawara
- Department of Microbiology, Sapporo Medical University School of Medicine, Sapporo, Japan.
- Department of Otolaryngology-Head and Neck Surgery, Sapporo Medical University School of Medicine, Sapporo, Japan.
| | - Yukari Mitsuhashi
- Department of Microbiology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Kenichi Takano
- Department of Otolaryngology-Head and Neck Surgery, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Shin-Ichi Yokota
- Department of Microbiology, Sapporo Medical University School of Medicine, Sapporo, Japan
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Amador-Martínez I, Aparicio-Trejo OE, Bernabe-Yepes B, Aranda-Rivera AK, Cruz-Gregorio A, Sánchez-Lozada LG, Pedraza-Chaverri J, Tapia E. Mitochondrial Impairment: A Link for Inflammatory Responses Activation in the Cardiorenal Syndrome Type 4. Int J Mol Sci 2023; 24:15875. [PMID: 37958859 PMCID: PMC10650149 DOI: 10.3390/ijms242115875] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 10/25/2023] [Accepted: 10/30/2023] [Indexed: 11/15/2023] Open
Abstract
Cardiorenal syndrome type 4 (CRS type 4) occurs when chronic kidney disease (CKD) leads to cardiovascular damage, resulting in high morbidity and mortality rates. Mitochondria, vital organelles responsible for essential cellular functions, can become dysfunctional in CKD. This dysfunction can trigger inflammatory responses in distant organs by releasing Damage-associated molecular patterns (DAMPs). These DAMPs are recognized by immune receptors within cells, including Toll-like receptors (TLR) like TLR2, TLR4, and TLR9, the nucleotide-binding domain, leucine-rich-containing family pyrin domain-containing-3 (NLRP3) inflammasome, and the cyclic guanosine monophosphate (cGMP)-adenosine monophosphate (AMP) synthase (cGAS)-stimulator of interferon genes (cGAS-STING) pathway. Activation of these immune receptors leads to the increased expression of cytokines and chemokines. Excessive chemokine stimulation results in the recruitment of inflammatory cells into tissues, causing chronic damage. Experimental studies have demonstrated that chemokines are upregulated in the heart during CKD, contributing to CRS type 4. Conversely, chemokine inhibitors have been shown to reduce chronic inflammation and prevent cardiorenal impairment. However, the molecular connection between mitochondrial DAMPs and inflammatory pathways responsible for chemokine overactivation in CRS type 4 has not been explored. In this review, we delve into mechanistic insights and discuss how various mitochondrial DAMPs released by the kidney during CKD can activate TLRs, NLRP3, and cGAS-STING immune pathways in the heart. This activation leads to the upregulation of chemokines, ultimately culminating in the establishment of CRS type 4. Furthermore, we propose using chemokine inhibitors as potential strategies for preventing CRS type 4.
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Affiliation(s)
- Isabel Amador-Martínez
- Posgrado en Ciencias Biológicas, Universidad Nacional Autónoma de México, Ciudad Universitaria, Mexico City 04510, Mexico; (I.A.-M.); (A.K.A.-R.)
- Departamento de Fisiopatología Cardio-Renal, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City 14080, Mexico; (O.E.A.-T.); (L.G.S.-L.)
| | - Omar Emiliano Aparicio-Trejo
- Departamento de Fisiopatología Cardio-Renal, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City 14080, Mexico; (O.E.A.-T.); (L.G.S.-L.)
| | - Bismarck Bernabe-Yepes
- Departamento de Biomedicina Cardiovascular, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City 14080, Mexico;
| | - Ana Karina Aranda-Rivera
- Posgrado en Ciencias Biológicas, Universidad Nacional Autónoma de México, Ciudad Universitaria, Mexico City 04510, Mexico; (I.A.-M.); (A.K.A.-R.)
- Laboratorio F-315, Departamento de Biología, Facultad de Química, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico;
| | - Alfredo Cruz-Gregorio
- Departamento de Fisiología, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City 14080, Mexico;
| | - Laura Gabriela Sánchez-Lozada
- Departamento de Fisiopatología Cardio-Renal, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City 14080, Mexico; (O.E.A.-T.); (L.G.S.-L.)
| | - José Pedraza-Chaverri
- Laboratorio F-315, Departamento de Biología, Facultad de Química, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico;
| | - Edilia Tapia
- Departamento de Fisiopatología Cardio-Renal, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City 14080, Mexico; (O.E.A.-T.); (L.G.S.-L.)
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10
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Veltman CHJ, Pennings JLA, van de Water B, Luijten M. An Adverse Outcome Pathway Network for Chemically Induced Oxidative Stress Leading to (Non)genotoxic Carcinogenesis. Chem Res Toxicol 2023. [PMID: 37156502 DOI: 10.1021/acs.chemrestox.2c00396] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/10/2023]
Abstract
Nongenotoxic (NGTX) carcinogens induce cancer via other mechanisms than direct DNA damage. A recognized mode of action for NGTX carcinogens is induction of oxidative stress, a state in which the amount of oxidants in a cell exceeds its antioxidant capacity, leading to regenerative proliferation. Currently, carcinogenicity assessment of environmental chemicals primarily relies on genetic toxicity end points. Since NGTX carcinogens lack genotoxic potential, these chemicals may remain undetected in such evaluations. To enhance the predictivity of test strategies for carcinogenicity assessment, a shift toward mechanism-based approaches is required. Here, we present an adverse outcome pathway (AOP) network for chemically induced oxidative stress leading to (NGTX) carcinogenesis. To develop this AOP network, we first investigated the role of oxidative stress in the various cancer hallmarks. Next, possible mechanisms for chemical induction of oxidative stress and the biological effects of oxidative damage to macromolecules were considered. This resulted in an AOP network, of which associated uncertainties were explored. Ultimately, development of AOP networks relevant for carcinogenesis in humans will aid the transition to a mechanism-based, human relevant carcinogenicity assessment that involves a substantially lower number of laboratory animals.
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Affiliation(s)
- Christina H J Veltman
- Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), 3720 BA Bilthoven, The Netherlands
- Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research (LACDR), Leiden University, 2333 CC Leiden, The Netherlands
| | - Jeroen L A Pennings
- Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), 3720 BA Bilthoven, The Netherlands
| | - Bob van de Water
- Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research (LACDR), Leiden University, 2333 CC Leiden, The Netherlands
| | - Mirjam Luijten
- Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), 3720 BA Bilthoven, The Netherlands
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11
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Cheng Y, Xia Q, Lu Z, Luan X, Fan L, Wang Z, Luo D. Maslinic acid attenuates UVB-induced oxidative damage in HFF-1 cells. J Cosmet Dermatol 2023. [PMID: 36943873 DOI: 10.1111/jocd.15730] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2022] [Revised: 02/02/2023] [Accepted: 03/07/2023] [Indexed: 03/23/2023]
Abstract
BACKGROUND Oxidative damage is one of the major mechanisms of ultraviolet B (UVB)-induced damage to the skin. Maslinic acid (MA) is a natural compound of pentacyclic triterpene acids. It has been proved to have anti-inflammatory and antioxidant properties. OBJECTIVE This study aimed to explore the effects of MA on oxidative damage in human foreskin fibroblast cells (HFF-1) and the potential molecular mechanisms. METHODS A specific dose of UVB radiation was used to induce oxidative damage in HFF-1. Based on this, we performed measurements of cell proliferation, reactive oxygen species (ROS) levels, antioxidant enzyme activity, inflammation-related mediators, and NF-κB nuclear localization with or without the addition of MA. RESULTS MA significantly promoted cell proliferation viability at 10 and 20 μM. The addition of MA 24 h before UVB irradiation was more effective at enhancing cell proliferation and also produced lower ROS levels compared to co-cultured fibroblasts and MA for 24 h after irradiation. However, there was no statistically significant difference between groups at concentrations of 10 and 20 μM. The pretreatment group with MA had elevated superoxide dismutase and catalase activities, decreased IL-6 generation, and lowered mRNA levels of IL-6, TNF-α and MMP3 in comparison with the UVB-irradiated group without additional MA. Meanwhile, the nuclear translocation of NF-κB and the degradation of IκB were inhibited by MA pretreatment. CONCLUSION Taken together, these findings suggest that MA may alleviate UVB-induced oxidative damage in HFF-1 by inhibiting the nuclear translocation of NF-κB.
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Affiliation(s)
- Yuxin Cheng
- Department of Dermatology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Qingyue Xia
- Department of Dermatology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Zhiyu Lu
- Department of Dermatology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Xingbao Luan
- Department of Dermatology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Lipan Fan
- Department of Dermatology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Zhaopeng Wang
- Department of Dermatology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Dan Luo
- Department of Dermatology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
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12
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Gain C, Song S, Angtuaco T, Satta S, Kelesidis T. The role of oxidative stress in the pathogenesis of infections with coronaviruses. Front Microbiol 2023; 13:1111930. [PMID: 36713204 PMCID: PMC9880066 DOI: 10.3389/fmicb.2022.1111930] [Citation(s) in RCA: 52] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Accepted: 12/23/2022] [Indexed: 01/15/2023] Open
Abstract
Coronaviruses can cause serious respiratory tract infections and may also impact other end organs such as the central nervous system, the lung and the heart. The coronavirus disease 2019 (COVID-19) has had a devastating impact on humanity. Understanding the mechanisms that contribute to the pathogenesis of coronavirus infections, will set the foundation for development of new treatments to attenuate the impact of infections with coronaviruses on host cells and tissues. During infection of host cells, coronaviruses trigger an imbalance between increased production of reactive oxygen species (ROS) and reduced antioxidant host responses that leads to increased redox stress. Subsequently, increased redox stress contributes to reduced antiviral host responses and increased virus-induced inflammation and apoptosis that ultimately drive cell and tissue damage and end organ disease. However, there is limited understanding how different coronaviruses including SARS-CoV-2, manipulate cellular machinery that drives redox responses. This review aims to elucidate the redox mechanisms involved in the replication of coronaviruses and associated inflammation, apoptotic pathways, autoimmunity, vascular dysfunction and tissue damage that collectively contribute to multiorgan damage.
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Affiliation(s)
| | | | | | | | - Theodoros Kelesidis
- Department of Medicine, Division of Infectious Diseases, University of California, Los Angeles, Los Angeles, CA, United States
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13
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Acertannin attenuates LPS-induced inflammation by interrupting the binding of LPS to the TLR4/MD2 complex and activating Nrf2-mediated HO-1 activation. Int Immunopharmacol 2022; 113:109344. [DOI: 10.1016/j.intimp.2022.109344] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 10/01/2022] [Accepted: 10/09/2022] [Indexed: 11/05/2022]
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Aranda-Rivera AK, Cruz-Gregorio A, Pedraza-Chaverri J, Scholze A. Nrf2 Activation in Chronic Kidney Disease: Promises and Pitfalls. Antioxidants (Basel) 2022; 11:antiox11061112. [PMID: 35740009 PMCID: PMC9220138 DOI: 10.3390/antiox11061112] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Revised: 06/01/2022] [Accepted: 06/01/2022] [Indexed: 11/16/2022] Open
Abstract
The nuclear factor erythroid 2-related factor 2 (Nrf2) protects the cell against oxidative damage. The Nrf2 system comprises a complex network that functions to ensure adequate responses to redox perturbations, but also metabolic demands and cellular stresses. It must be kept within a physiologic activity range. Oxidative stress and alterations in Nrf2-system activity are central for chronic-kidney-disease (CKD) progression and CKD-related morbidity. Activation of the Nrf2 system in CKD is in multiple ways related to inflammation, kidney fibrosis, and mitochondrial and metabolic effects. In human CKD, both endogenous Nrf2 activation and repression exist. The state of the Nrf2 system varies with the cause of kidney disease, comorbidities, stage of CKD, and severity of uremic toxin accumulation and inflammation. An earlier CKD stage, rapid progression of kidney disease, and inflammatory processes are associated with more robust Nrf2-system activation. Advanced CKD is associated with stronger Nrf2-system repression. Nrf2 activation is related to oxidative stress and moderate uremic toxin and nuclear factor kappa B (NF-κB) elevations. Nrf2 repression relates to high uremic toxin and NF-κB concentrations, and may be related to Kelch-like ECH-associated protein 1 (Keap1)-independent Nrf2 degradation. Furthermore, we review the effects of pharmacological Nrf2 activation by bardoxolone methyl, curcumin, and resveratrol in human CKD and outline strategies for how to adapt future Nrf2-targeted therapies to the requirements of patients with CKD.
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Affiliation(s)
- Ana Karina Aranda-Rivera
- Laboratory F-315, Department of Biology, Faculty of Chemistry, National Autonomous University of Mexico, Mexico City 04510, Mexico; (A.K.A.-R.); (A.C.-G.); (J.P.-C.)
| | - Alfredo Cruz-Gregorio
- Laboratory F-315, Department of Biology, Faculty of Chemistry, National Autonomous University of Mexico, Mexico City 04510, Mexico; (A.K.A.-R.); (A.C.-G.); (J.P.-C.)
| | - José Pedraza-Chaverri
- Laboratory F-315, Department of Biology, Faculty of Chemistry, National Autonomous University of Mexico, Mexico City 04510, Mexico; (A.K.A.-R.); (A.C.-G.); (J.P.-C.)
| | - Alexandra Scholze
- Department of Nephrology, Odense University Hospital, 5000 Odense C, Denmark
- Institute of Clinical Research, University of Southern Denmark, 5000 Odense C, Denmark
- Correspondence:
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15
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Haga M, Okada M. Systems approaches to investigate the role of NF-κB signaling in aging. Biochem J 2022; 479:161-183. [PMID: 35098992 PMCID: PMC8883486 DOI: 10.1042/bcj20210547] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Revised: 01/06/2022] [Accepted: 01/10/2022] [Indexed: 12/14/2022]
Abstract
The nuclear factor-κB (NF-κB) signaling pathway is one of the most well-studied pathways related to inflammation, and its involvement in aging has attracted considerable attention. As aging is a complex phenomenon and is the result of a multi-step process, the involvement of the NF-κB pathway in aging remains unclear. To elucidate the role of NF-κB in the regulation of aging, different systems biology approaches have been employed. A multi-omics data-driven approach can be used to interpret and clarify unknown mechanisms but cannot generate mechanistic regulatory structures alone. In contrast, combining this approach with a mathematical modeling approach can identify the mechanistics of the phenomena of interest. The development of single-cell technologies has also helped clarify the heterogeneity of the NF-κB response and underlying mechanisms. Here, we review advances in the understanding of the regulation of aging by NF-κB by focusing on omics approaches, single-cell analysis, and mathematical modeling of the NF-κB network.
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Affiliation(s)
- Masatoshi Haga
- Laboratory for Cell Systems, Institute for Protein Research, Osaka University, Suita, Osaka 565-0871, Japan
- Basic Research Development Division, ROHTO Pharmaceutical Co., Ltd., Ikuno-ku, Osaka 544-8666, Japan
| | - Mariko Okada
- Laboratory for Cell Systems, Institute for Protein Research, Osaka University, Suita, Osaka 565-0871, Japan
- Center for Drug Design and Research, National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, Osaka 567-0085, Japan
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16
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Early life exposure to house dust mite allergen prevents experimental allergic asthma requiring mitochondrial H 2O 2. Mucosal Immunol 2022; 15:154-164. [PMID: 34580428 PMCID: PMC8738138 DOI: 10.1038/s41385-021-00458-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 09/08/2021] [Accepted: 09/13/2021] [Indexed: 02/04/2023]
Abstract
Immune tolerance to allergens in early-life decreases the risk for asthma in later life. Here we show establishment of stable airway tolerance to the allergen, house dust mite (HDM), by exposing newborn mice repeatedly to a low dose of the allergen. Lung dendritic cells (DCs) from tolerized mice induced a low Th2 response in vitro mirroring impact of tolerance in vivo. In line with our previous finding of increased mitochondrial H2O2 production from lung DCs of mice tolerized to ovalbumin, depletion of mitochondrial H2O2 in MCAT mice abrogated HDM-induced airway tolerance (Tol) with elevated Th2 effector response, airway eosinophilia, and increased airway hyperreactivity. WT-Tol mice displayed a decrease in total, cDC1 and cDC2 subsets in the lung as compared to that in naive mice. In contrast, the lungs of MCAT-Tol mice showed 3-fold higher numbers of cDCs including those of the subsets as compared to that in WT mice. Our study demonstrates an important role of mitochondrial H2O2 in constraining lung DC numbers towards establishment of early-life airway tolerance to allergens.
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17
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Nica IC, Stan MS, Popescu RG, Nicula N, Ducu R, Diamandescu L, Dinischiotu A. Fe-N Co-Doped Titanium Dioxide Nanoparticles Induce Cell Death in Human Lung Fibroblasts in a p53-Independent Manner. Int J Mol Sci 2021; 22:ijms22179627. [PMID: 34502536 PMCID: PMC8431805 DOI: 10.3390/ijms22179627] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 08/31/2021] [Accepted: 09/02/2021] [Indexed: 12/19/2022] Open
Abstract
The advancement of nanotechnology in the last decade has developed an abundance of novel and intriguing TiO2-based nanomaterials that are widely used in many sectors, including industry (as a food additive and colorant in cosmetics, paints, plastics, and toothpaste) and biomedicine (photoelectrochemical biosensing, implant coatings, drug delivery, and new emerging antimicrobial agents). Therefore, the increased use of engineered nanomaterials in the industry has raised serious concern about human exposure and their unexpected cytotoxic effects. Since inhalation is considered the most relevant way of absorbing nanomaterials, different cell death mechanisms induced in MRC-5 lung fibroblasts, following the exposure to functionalized TiO2 NPs, were investigated. Long-term exposure to TiO2 nanoparticles co-doped with 1% of iron and nitrogen led to the alteration of p53 protein activity and the gene expression controlled by this suppressor (NF-kB and mdm2), DNA damage, cell cycle disruptions at the G2/M and S phases, and lysosomal membrane permeabilization and the subsequent release of cathepsin B, triggering the intrinsic pathway of apoptosis in a Bax- and p53-independent manner. Our results are of major significance, contributing to the understanding of the mechanisms underlying the interaction of these nanoparticles with in vitro biological systems, and also providing useful information for the development of new photocatalytic nanoparticles that are active in the visible spectrum, but with increased biocompatibility.
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Affiliation(s)
- Ionela Cristina Nica
- Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Bucharest, 91-95 Splaiul Independentei, 050095 Bucharest, Romania; (I.C.N.); (R.G.P.); (A.D.)
- Research Institute of the University of Bucharest–ICUB, University of Bucharest, 050657 Bucharest, Romania
| | - Miruna S. Stan
- Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Bucharest, 91-95 Splaiul Independentei, 050095 Bucharest, Romania; (I.C.N.); (R.G.P.); (A.D.)
- Research Institute of the University of Bucharest–ICUB, University of Bucharest, 050657 Bucharest, Romania
- Correspondence: ; Tel./Fax: +40-21-318-15-75
| | - Roua G. Popescu
- Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Bucharest, 91-95 Splaiul Independentei, 050095 Bucharest, Romania; (I.C.N.); (R.G.P.); (A.D.)
| | - Nicoleta Nicula
- Environment/Energy and Climate Change Department, National Institute for Research and Development in Electrical Engineering ICPE—CA, 313 Splaiul Unirii, 030138 Bucharest, Romania; (N.N.); (R.D.)
| | - Robert Ducu
- Environment/Energy and Climate Change Department, National Institute for Research and Development in Electrical Engineering ICPE—CA, 313 Splaiul Unirii, 030138 Bucharest, Romania; (N.N.); (R.D.)
| | - Lucian Diamandescu
- National Institute of Materials Physics (NIMP), Atomistilor 405A, Magurele, 077125 Bucharest, Romania;
| | - Anca Dinischiotu
- Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Bucharest, 91-95 Splaiul Independentei, 050095 Bucharest, Romania; (I.C.N.); (R.G.P.); (A.D.)
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18
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Aranda-Rivera AK, Cruz-Gregorio A, Aparicio-Trejo OE, Ortega-Lozano AJ, Pedraza-Chaverri J. Redox signaling pathways in unilateral ureteral obstruction (UUO)-induced renal fibrosis. Free Radic Biol Med 2021; 172:65-81. [PMID: 34077780 DOI: 10.1016/j.freeradbiomed.2021.05.034] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 05/14/2021] [Accepted: 05/25/2021] [Indexed: 02/07/2023]
Abstract
Unilateral ureteral obstruction (UUO) is an experimental rodent model that mimics renal fibrosis associated with obstructive nephropathy in an accelerated manner. After UUO, the activation of the renin-angiotensin system (RAS), nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOXs) and mitochondrial dysfunction lead to reactive oxygen species (ROS) overproduction in the kidney. ROS are secondary messengers able to induce post-translational modifications (PTMs) in redox-sensitive proteins, which activate or deactivate signaling pathways. Therefore, in UUO, it has been proposed that ROS overproduction causes changes in said pathways promoting inflammation, oxidative stress, and apoptosis that contribute to fibrosis development. Furthermore, mitochondrial metabolism impairment has been associated with UUO, contributing to renal damage in this model. Although ROS production and oxidative stress have been studied in UUO, the development of renal fibrosis associated with redox signaling pathways has not been addressed. This review focuses on the current information about the activation and deactivation of signaling pathways sensitive to a redox state and their effect on mitochondrial metabolism in the fibrosis development in the UUO model.
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Affiliation(s)
- Ana Karina Aranda-Rivera
- Laboratorio F-315, Departamento de Biología, Facultad de Química, Universidad Nacional Autónoma de México, 04510, Ciudad de México, Mexico; Posgrado en Ciencias Biológicas, Universidad Nacional Autónoma de México, Ciudad Universitaria, Laboratorio F-225, Ciudad de México, 04510, Mexico.
| | - Alfredo Cruz-Gregorio
- Laboratorio F-225, Departamento de Biología, Facultad de Química, Universidad Nacional Autónoma de México, 04510, Ciudad de México, Mexico.
| | - Omar Emiliano Aparicio-Trejo
- Laboratorio F-315, Departamento de Biología, Facultad de Química, Universidad Nacional Autónoma de México, 04510, Ciudad de México, Mexico.
| | - Ariadna Jazmín Ortega-Lozano
- Laboratorio F-315, Departamento de Biología, Facultad de Química, Universidad Nacional Autónoma de México, 04510, Ciudad de México, Mexico.
| | - José Pedraza-Chaverri
- Laboratorio F-315, Departamento de Biología, Facultad de Química, Universidad Nacional Autónoma de México, 04510, Ciudad de México, Mexico.
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19
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Huang LJ, Mao XT, Li YY, Liu DD, Fan KQ, Liu RB, Wu TT, Wang HL, Zhang Y, Yang B, Ye CQ, Zhong JY, Chai RJ, Cao Q, Jin J. Multiomics analyses reveal a critical role of selenium in controlling T cell differentiation in Crohn's disease. Immunity 2021; 54:1728-1744.e7. [PMID: 34343498 DOI: 10.1016/j.immuni.2021.07.004] [Citation(s) in RCA: 115] [Impact Index Per Article: 28.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 05/21/2021] [Accepted: 07/07/2021] [Indexed: 12/13/2022]
Abstract
Inflammatory bowel disease (IBD) mainly includes Crohn's disease (CD) and ulcerative colitis (UC). Immune disorders play an essential role in the pathogenesis of these two IBDs, but the differences in the immune microenvironment of the colon and their underlying mechanisms remain poorly investigated. Here we examined the immunological features and metabolic microenvironment of untreated individuals with IBD by multiomics analyses. Modulation of CD-specific metabolites, particularly reduced selenium, can obviously shape type 1 T helper (Th1) cell differentiation, which is specifically enriched in CD. Selenium supplementation suppressed the symptoms and onset of CD and Th1 cell differentiation via selenoprotein W (SELW)-mediated cellular reactive oxygen species scavenging. SELW promoted purine salvage pathways and inhibited one-carbon metabolism by recruiting an E3 ubiquitin ligase, tripartite motif-containing protein 21, which controlled the stability of serine hydroxymethyltransferase 2. Our work highlights selenium as an essential regulator of T cell responses and potential therapeutic targets in CD.
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Affiliation(s)
- Ling-Jie Huang
- Department of Gastroenterology, Sir Run Run Shaw Hospital, College of Medicine Zhejiang University, Hangzhou 310016, China
| | - Xin-Tao Mao
- MOE Laboratory of Biosystem Homeostasis and Protection and Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
| | - Yi-Yuan Li
- Key Laboratory for Developmental Genes and Human Disease, Ministry of Education, Institute of Life Sciences, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing 210096, China
| | - Dan-Dan Liu
- MOE Laboratory of Biosystem Homeostasis and Protection and Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
| | - Ke-Qi Fan
- MOE Laboratory of Biosystem Homeostasis and Protection and Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
| | - Rong-Bei Liu
- Department of Gastroenterology, Sir Run Run Shaw Hospital, College of Medicine Zhejiang University, Hangzhou 310016, China
| | - Ting-Ting Wu
- Department of Gastroenterology, Sir Run Run Shaw Hospital, College of Medicine Zhejiang University, Hangzhou 310016, China
| | - Hao-Li Wang
- MOE Laboratory of Biosystem Homeostasis and Protection and Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
| | - Yu Zhang
- Department of Gastroenterology, Sir Run Run Shaw Hospital, College of Medicine Zhejiang University, Hangzhou 310016, China
| | - Bing Yang
- MOE Laboratory of Biosystem Homeostasis and Protection and Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
| | - Cun-Qi Ye
- MOE Laboratory of Biosystem Homeostasis and Protection and Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
| | - Jiang-Yan Zhong
- MOE Laboratory of Biosystem Homeostasis and Protection and Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
| | - Ren-Jie Chai
- Key Laboratory for Developmental Genes and Human Disease, Ministry of Education, Institute of Life Sciences, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing 210096, China; Co-Innovation Center of Neuroregeneration, Nantong University, Nantong 226001, China; Institute for Stem Cell and Regeneration, Chinese Academy of Science, Beijing 100101, China
| | - Qian Cao
- Department of Gastroenterology, Sir Run Run Shaw Hospital, College of Medicine Zhejiang University, Hangzhou 310016, China.
| | - Jin Jin
- Department of Gastroenterology, Sir Run Run Shaw Hospital, College of Medicine Zhejiang University, Hangzhou 310016, China; MOE Laboratory of Biosystem Homeostasis and Protection and Life Sciences Institute, Zhejiang University, Hangzhou 310058, China.
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20
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Mancini OK, Acevedo M, Fazez N, Cuillerier A, Ruiz AF, Huynh DN, Burelle Y, Ferbeyre G, Baron M, Servant MJ. Oxidative stress-induced senescence mediates inflammatory and fibrotic phenotypes in fibroblasts from systemic sclerosis patients. Rheumatology (Oxford) 2021; 61:1265-1275. [PMID: 34115840 DOI: 10.1093/rheumatology/keab477] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 05/28/2021] [Indexed: 12/15/2022] Open
Abstract
OBJECTIVE Systemic sclerosis (SSc) is an autoimmune connective tissue disorder characterized by inflammation and fibrosis. Although constitutive activation of fibroblasts is proposed to be responsible for the fibrotic and inflammatory features of the disease, the underlying mechanism remains elusive and, effective therapeutic targets are still lacking. The aim of this study was to evaluate the role of oxidative stress-induced senescence and its contribution to the pro-fibrotic and pro-inflammatory phenotypes of fibroblasts from SSc patients. METHODS Dermal fibroblasts were isolated from SSc (n = 13) and healthy (n = 10) donors. Fibroblast's intracellular and mitochondrial reactive oxygen species were determined by flow cytometry. Mitochondrial function measured by Seahorse XF24 analyzer. Fibrotic and inflammatory gene expressions were assessed by qPCR and key pro-inflammatory components of the fibroblasts' secretome (interleukin (IL) 6 and IL8) were quantified by ELISA. RESULTS Compared to healthy fibroblasts, SSc fibroblasts displayed higher levels of both intracellular and mitochondrial ROS. Oxidative stress in SSc fibroblasts induced the expression of fibrotic genes and activated the transforming growth factor-β-activated kinase 1 (TAK1) -IκB kinase β (IKKβ)- interferon regulatory factor 5 (IRF5) inflammatory signaling cascade. These cellular responses paralleled the presence of a DNA damage response, a senescence-associated secretory phenotype and a fibrotic response. Treatment of SSc fibroblasts with ROS scavengers reduced their pro-inflammatory secretome production and fibrotic gene expression. CONCLUSIONS Oxidative stress-induced cellular senescence in SSc fibroblasts underlies their pro-inflammatory and pro-fibrotic phenotypes. Targeting redox imbalance of SSc fibroblasts enhances their in vitro functions and could be of relevance for SSc therapy.
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Affiliation(s)
| | | | - Nesrine Fazez
- Faculty of Pharmacy, Université de Montréal, Québec, Canada
| | - Alexanne Cuillerier
- Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ontario, Canada
| | - Ana Fernandez Ruiz
- Département de biochimie et médecine moléculaire, Université de Montréal, Montréal, Québec, Canada
| | - David N Huynh
- Faculty of Pharmacy, Université de Montréal, Québec, Canada
| | - Yan Burelle
- Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ontario, Canada
| | - Gerardo Ferbeyre
- Département de biochimie et médecine moléculaire, Université de Montréal, Montréal, Québec, Canada
| | - Murray Baron
- McGill University, Jewish General Hospital, Montréal, Québec, Canada
| | - Marc J Servant
- Faculty of Pharmacy, Université de Montréal, Québec, Canada
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21
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Hwang I, Tang D, Paik J. Oxidative stress sensing and response in neural stem cell fate. Free Radic Biol Med 2021; 169:74-83. [PMID: 33862161 PMCID: PMC9594080 DOI: 10.1016/j.freeradbiomed.2021.03.043] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 03/13/2021] [Accepted: 03/25/2021] [Indexed: 12/22/2022]
Abstract
Neural stem/progenitor cells (NSPCs) contribute to the physiological cellular turnover of the adult brain and make up its regenerative potential. It is thus essential to understand how different factors influence their proliferation and differentiation to gain better insight into potential therapeutic targets in neurodegenerative diseases and traumatic brain injuries. Recent evidences indicate the roles of redox stress sensing and coping mechanisms in mediating the balance between NSPC self-renewal and differentiation. Such mechanisms involve direct cysteine modification, signaling and metabolic reprogramming, epigenetic alterations and transcription changes leading to adaptive responses like autophagy. Here, we discuss emerging findings on the involvement of redox sensors and effectors and their mechanisms in influencing changes in cellular redox potential and NSPC fate.
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Affiliation(s)
- Inah Hwang
- R&D Center, OneCureGEN Co., Ltd, Daejeon, 34141, Republic of Korea; Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, 10021, USA
| | - Deanna Tang
- University of Chicago, Chicago, IL, 60637, USA
| | - Jihye Paik
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, 10021, USA.
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22
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Liu W, Yi Y, Zhang C, Zhou B, Liao L, Liu W, Hu J, Xu Q, Chen J, Lu J. The Expression of TRIM6 Activates the mTORC1 Pathway by Regulating the Ubiquitination of TSC1-TSC2 to Promote Renal Fibrosis. Front Cell Dev Biol 2021; 8:616747. [PMID: 33634104 PMCID: PMC7901959 DOI: 10.3389/fcell.2020.616747] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Accepted: 12/14/2020] [Indexed: 02/04/2023] Open
Abstract
Renal fibrosis is considered as the final pathway of all types of kidney diseases, which can lead to the progressive loss of kidney functions and eventually renal failure. The mechanisms behind are diversified, in which the mammalian target of rapamycin (mTOR) pathway is one of the most important regulatory pathways that accounts for the disease. Several processes that are regulated by the mTOR pathway, such as autophagy, epithelial-mesenchymal transition (EMT), and endoplasmic reticulum (ER) stress, are tightly associated with renal fibrosis. In this study, we have reported that the expression of tripartite motif-containing (TRIM) protein 6, a member of TRIM family protein, was highly expressed in renal fibrosis patients and positively correlated with the severity of renal fibrosis. In our established in vitro and in vivo renal fibrosis models, its expression was upregulated by the Angiotensin II-induced nuclear translocation of nuclear factor-κB (NF-κB) p50 and p65. In HK2 cells, the expression of TRIM6 promoted the ubiquitination of tuberous sclerosis proteins (TSC) 1 and 2, two negative regulators of the mTORC1 pathway. Moreover, the knockdown of TRIM6 was found efficient for alleviating renal fibrosis and inhibiting the downstream processes of EMT and ER in both HK2 cells and 5/6-nephrectomized rats. Clinically, the level of TRIM6, TSC1/2, and NF-κB p50 was found closely related to renal fibrosis. As a result, we have presented the first study on the role of TRIM6 in the mTORC1 pathway in renal fibrosis models and our findings suggested that TRIM6 may be a potential target for the treatment of renal fibrosis.
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Affiliation(s)
- Weiwei Liu
- Department of Nephrology, Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yang Yi
- Department of Nephrology, Jing'an District Central Hospital of Shanghai/ Jing'an Branch, Huashan Hospital, Fudan University, Shanghai, China
| | - Chuanfu Zhang
- Department of Nephrology, Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Baojuan Zhou
- Department of Nephrology, Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Lin Liao
- Department of Nephrology, Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Wenrui Liu
- Department of Nephrology, Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jing Hu
- Department of Nephrology, Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Qiming Xu
- Department of Nephrology, Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jie Chen
- Department of Nephrology, Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jianrao Lu
- Department of Nephrology, Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China
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Mehling R, Schwenck J, Lemberg C, Trautwein C, Zizmare L, Kramer D, Müller A, Fehrenbacher B, Gonzalez-Menendez I, Quintanilla-Martinez L, Schröder K, Brandes RP, Schaller M, Ruf W, Eichner M, Ghoreschi K, Röcken M, Pichler BJ, Kneilling M. Immunomodulatory role of reactive oxygen species and nitrogen species during T cell-driven neutrophil-enriched acute and chronic cutaneous delayed-type hypersensitivity reactions. Theranostics 2021; 11:470-490. [PMID: 33391487 PMCID: PMC7738859 DOI: 10.7150/thno.51462] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Accepted: 09/25/2020] [Indexed: 12/20/2022] Open
Abstract
Rationale: Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are important regulators of inflammation. The exact impact of ROS/RNS on cutaneous delayed-type hypersensitivity reaction (DTHR) is controversial. The aim of our study was to identify the dominant sources of ROS/RNS during acute and chronic trinitrochlorobenzene (TNCB)-induced cutaneous DTHR in mice with differently impaired ROS/RNS production. Methods: TNCB-sensitized wild-type, NADPH oxidase 2 (NOX2)- deficient (gp91phox-/-), myeloperoxidase-deficient (MPO-/-), and inducible nitric oxide synthase-deficient (iNOS-/-) mice were challenged with TNCB on the right ear once to elicit acute DTHR and repetitively up to five times to induce chronic DTHR. We measured ear swelling responses and noninvasively assessed ROS/RNS production in vivo by employing the chemiluminescence optical imaging (OI) probe L-012. Additionally, we conducted extensive ex vivo analyses of inflamed ears focusing on ROS/RNS production and the biochemical and morphological consequences. Results: The in vivo L-012 OI of acute and chronic DTHR revealed completely abrogated ROS/RNS production in the ears of gp91phox-/- mice, up to 90 % decreased ROS/RNS production in the ears of MPO-/- mice and unaffected ROS/RNS production in the ears of iNOS-/- mice. The DHR flow cytometry analysis of leukocytes derived from the ears with acute DTHR confirmed our in vivo L-012 OI results. Nevertheless, we observed no significant differences in the ear swelling responses among all the experimental groups. The histopathological analysis of the ears of gp91phox-/- mice with acute DTHRs revealed slightly enhanced inflammation. In contrast, we observed a moderately reduced inflammatory immune response in the ears of gp91phox-/- mice with chronic DTHR, while the inflamed ears of MPO-/- mice exhibited the strongest inflammation. Analyses of lipid peroxidation, 8-hydroxy-2'deoxyguanosine levels, redox related metabolites and genomic expression of antioxidant proteins revealed similar oxidative stress in all experimental groups. Furthermore, inflamed ears of wild-type and gp91phox-/- mice displayed neutrophil extracellular trap (NET) formation exclusively in acute but not chronic DTHR. Conclusions: MPO and NOX2 are the dominant sources of ROS/RNS in acute and chronic DTHR. Nevertheless, depletion of one primary source of ROS/RNS exhibited only marginal but conflicting impact on acute and chronic cutaneous DTHR. Thus, ROS/RNS are not a single entity, and each species has different properties at certain stages of the disease, resulting in different outcomes.
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Rius-Pérez S, Pérez S, Martí-Andrés P, Monsalve M, Sastre J. Nuclear Factor Kappa B Signaling Complexes in Acute Inflammation. Antioxid Redox Signal 2020; 33:145-165. [PMID: 31856585 DOI: 10.1089/ars.2019.7975] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Significance: Nuclear factor kappa B (NF-κB) is a master regulator of the inflammatory response and represents a key regulatory node in the complex inflammatory signaling network. In addition, selective NF-κB transcriptional activity on specific target genes occurs through the control of redox-sensitive NF-κB interactions. Recent Advances: The selective NF-κB response is mediated by redox-modulated NF-κB complexes with ribosomal protein S3 (RPS3), Pirin (PIR). cAMP response element-binding (CREB)-binding protein (CBP)/p300, peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α), activator protein-1 (AP-1), signal transducer and activator of transcription 3 (STAT3), early growth response protein 1 (EGR-1), and SP-1. NF-κB is cooperatively coactivated with AP-1, STAT3, EGR-1, and SP-1 during the inflammatory process, whereas NF-κB complexes with CBP/p300 and PGC-1α regulate the expression of antioxidant genes. PGC-1α may act as selective repressor of phospho-p65 toward interleukin-6 (IL-6) in acute inflammation. p65 and nuclear factor erythroid 2-related factor 2 (NRF2) compete for binding to coactivator CBP/p300 playing opposite roles in the regulation of inflammatory genes. S-nitrosylation or tyrosine nitration favors the recruitment of specific NF-κB subunits to κB sites. Critical Issues: NF-κB is a redox-sensitive transcription factor that forms specific signaling complexes to regulate selectively the expression of target genes in acute inflammation. Protein-protein interactions with coregulatory proteins, other transcription factors, and chromatin-remodeling proteins provide transcriptional specificity to NF-κB. Furthermore, different NF-κB subunits may form distinct redox-sensitive homo- and heterodimers with distinct affinities for κB sites. Future Directions: Further research is required to elucidate the whole NF-κB interactome to fully characterize the complex NF-κB signaling network in redox signaling, inflammation, and cancer.
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Affiliation(s)
- Sergio Rius-Pérez
- Department of Physiology, Faculty of Pharmacy, University of Valencia, Valencia, Spain
| | - Salvador Pérez
- Department of Physiology, Faculty of Pharmacy, University of Valencia, Valencia, Spain
| | - Pablo Martí-Andrés
- Department of Physiology, Faculty of Pharmacy, University of Valencia, Valencia, Spain
| | - María Monsalve
- Instituto de Investigaciones Biomédicas "Alberto Sols" (CSIC-UAM), Madrid, Spain
| | - Juan Sastre
- Department of Physiology, Faculty of Pharmacy, University of Valencia, Valencia, Spain
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25
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Sun J, Wang J, Li L, Wu Z, Chen X, Yuan J. ROS induced by spring viraemia of carp virus activate the inflammatory response via the MAPK/AP-1 and PI3K signaling pathways. FISH & SHELLFISH IMMUNOLOGY 2020; 101:216-224. [PMID: 32224280 DOI: 10.1016/j.fsi.2020.03.056] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Revised: 03/25/2020] [Accepted: 03/25/2020] [Indexed: 06/10/2023]
Abstract
Spring viraemia of carp virus (SVCV) can cause a high mortality in common carp (Cyprinus carpio), and its main pathological processes include the inflammatory response. However, the detailed mechanism is still unclear. Reactive oxygen species (ROS) have been shown to play critical roles in the immune response, including inflammation, in different models. Our previous studies have demonstrated that SVCV infection results in the accumulation of ROS, including H2O2, in epithelioma papulosum cyprini (EPC) cells. In this study, we aimed to explore the relationship between H2O2 accumulation and inflammation during SVCV infection. After EPC cells were infected with SVCV, the expression levels of the inflammatory factors tumor necrosis factor (TNF)-α, cyclooxygenase (COX)-2, and interleukin (IL)-8 were up-regulated, while the expression of the anti-inflammatory factor interleukin (IL)-10 was down-regulated, compared with that in mock-infected EPC cells. The antioxidant N-acetyl-l-cysteine (NAC) could dampen the increased TNF-ɑ and COX-2 expression induced by SVCV and H2O2, suggesting a relationship between ROS accumulation and inflammation during SVCV infection. Dual luciferase reporter assays demonstrated that SVCV could not activate the NF-κB pathway. In addition, inhibition of NF-κB by pyrrolidine dithiocarbamate (PDTC) treatment had no effect on the expression of inflammatory factors. Furthermore, inhibition of the ERK, JNK, and p38MAPK signaling pathways by U0126, SP600125, and SB203580, respectively, reduced the expression of TNF-ɑ, COX-2, and IL-8, indicating that these three signaling pathways were all involved in the inflammatory response after SVCV infection. In addition, the PI3K signaling pathway was involved in the expression of the chemokine IL-8 in the SVCV-induced inflammatory response. We also showed that inhibition of the MAPK or PI3K signaling pathway facilitated the expression of SVCV-G as well as increased the SVCV viral titer. Altogether these results reveal the mechanism of the SVCV-mediated inflammatory response. Thus, targeting these signaling pathways may provide novel treatment strategies for SVCV-mediated diseases.
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Affiliation(s)
- Jie Sun
- Department of Aquatic Animal Medicine, College of Fisheries, Huazhong Agricultural University, Wuhan, 430070, People's Republic of China
| | - Jingwen Wang
- Department of Aquatic Animal Medicine, College of Fisheries, Huazhong Agricultural University, Wuhan, 430070, People's Republic of China
| | - Lijuan Li
- Department of Aquatic Animal Medicine, College of Fisheries, Huazhong Agricultural University, Wuhan, 430070, People's Republic of China; Hubei Engineering Research Center for Aquatic Animal Diseases Control and Prevention, Wuhan, 430070, People's Republic of China
| | - Zhixin Wu
- Department of Aquatic Animal Medicine, College of Fisheries, Huazhong Agricultural University, Wuhan, 430070, People's Republic of China; Hubei Engineering Research Center for Aquatic Animal Diseases Control and Prevention, Wuhan, 430070, People's Republic of China
| | - Xiaoxuan Chen
- Department of Aquatic Animal Medicine, College of Fisheries, Huazhong Agricultural University, Wuhan, 430070, People's Republic of China; Hubei Engineering Research Center for Aquatic Animal Diseases Control and Prevention, Wuhan, 430070, People's Republic of China
| | - Junfa Yuan
- Department of Aquatic Animal Medicine, College of Fisheries, Huazhong Agricultural University, Wuhan, 430070, People's Republic of China; Hubei Engineering Research Center for Aquatic Animal Diseases Control and Prevention, Wuhan, 430070, People's Republic of China; Key Lab of Freshwater Animal Breeding, Ministry of Agriculture, Wuhan, 430070, People's Republic of China.
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26
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Zhang P, Li T, Wu X, Nice EC, Huang C, Zhang Y. Oxidative stress and diabetes: antioxidative strategies. Front Med 2020; 14:583-600. [PMID: 32248333 DOI: 10.1007/s11684-019-0729-1] [Citation(s) in RCA: 273] [Impact Index Per Article: 54.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2019] [Accepted: 10/29/2019] [Indexed: 12/20/2022]
Abstract
Diabetes mellitus is one of the major public health problems worldwide. Considerable recent evidence suggests that the cellular reduction-oxidation (redox) imbalance leads to oxidative stress and subsequent occurrence and development of diabetes and related complications by regulating certain signaling pathways involved in β-cell dysfunction and insulin resistance. Reactive oxide species (ROS) can also directly oxidize certain proteins (defined as redox modification) involved in the diabetes process. There are a number of potential problems in the clinical application of antioxidant therapies including poor solubility, storage instability and nonselectivity of antioxidants. Novel antioxidant delivery systems may overcome pharmacokinetic and stability problem and improve the selectivity of scavenging ROS. We have therefore focused on the role of oxidative stress and antioxidative therapies in the pathogenesis of diabetes mellitus. Precise therapeutic interventions against ROS and downstream targets are now possible and provide important new insights into the treatment of diabetes.
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Affiliation(s)
- Pengju Zhang
- Department of Pharmacology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, 610041, China
| | - Tao Li
- Department of Pharmacology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, 610041, China
| | - Xingyun Wu
- Department of Pharmacology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, 610041, China
| | - Edouard C Nice
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia
| | - Canhua Huang
- Department of Pharmacology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, 610041, China.
| | - Yuanyuan Zhang
- Department of Pharmacology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, 610041, China.
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27
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Peters C, Kouakanou L, Kabelitz D. A comparative view on vitamin C effects on αβ- versus γδ T-cell activation and differentiation. J Leukoc Biol 2020; 107:1009-1022. [PMID: 32034803 DOI: 10.1002/jlb.1mr1219-245r] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Revised: 12/06/2019] [Accepted: 01/13/2020] [Indexed: 12/19/2022] Open
Abstract
Vitamin C (VitC) is an essential vitamin that needs to be provided through exogenous sources. It is a potent anti-oxidant, and an essential cofactor for many enzymes including a group of enzymes that modulate epigenetic regulation of gene expression. Moreover, VitC has a significant influence on T-cell differentiation, and can directly interfere with T-cell signaling. Conventional CD4 and CD8 T cells express the αβ TCR and recognize peptide antigens in the context of MHC presentation. The numerically small population of γδ T cells recognizes antigens in an MHC-independent manner. γδ T cells kill a broad variety of malignant cells, and because of their unique features, are interesting candidates for cancer immunotherapy. In this review, we summarize what is known about the influence of VitC on T-cell activation and differentiation with a special focus on γδ T cells. The known mechanisms of action of VitC on αβ T cells are discussed and extrapolated to the effects observed on γδ T-cell activation and differentiation. Overall, VitC enhances proliferation and effector functions of γδ T cells and thus may help to increase the efficacy of γδ T cells applied as cancer immunotherapy in adoptive cell transfer.
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Affiliation(s)
- Christian Peters
- Institute of Immunology, Christian-Albrechts-University Kiel, Kiel, Germany
| | - Léonce Kouakanou
- Institute of Immunology, Christian-Albrechts-University Kiel, Kiel, Germany
| | - Dieter Kabelitz
- Institute of Immunology, Christian-Albrechts-University Kiel, Kiel, Germany
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28
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Iron homeostasis and oxidative stress: An intimate relationship. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2019; 1866:118535. [DOI: 10.1016/j.bbamcr.2019.118535] [Citation(s) in RCA: 518] [Impact Index Per Article: 86.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Revised: 07/23/2019] [Accepted: 08/18/2019] [Indexed: 02/07/2023]
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29
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Thimmulappa RK, Chattopadhyay I, Rajasekaran S. Oxidative Stress Mechanisms in the Pathogenesis of Environmental Lung Diseases. OXIDATIVE STRESS IN LUNG DISEASES 2019. [PMCID: PMC7120104 DOI: 10.1007/978-981-32-9366-3_5] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Globally, respiratory diseases are major cause of disability and mortality, and more alarmingly, it disproportionately affects developing countries, which is largely attributed to poor quality of air. Tobacco smoke and emissions from combustion of fossil fuel and biomass fuel are the major airborne pollutants affecting human lung health. Oxidative stress is the dominant driving force by which the airborne pollutants exert their toxicity in lungs and cause respiratory diseases. Most airborne pollutants are associated with intrinsic oxidative potential and, additionally, stimulate endogenous production of reactive oxygen species (ROS) and reactive nitrogen species (RNS). Elevated ROS and RNS in lungs modulate redox signals and cause irreversible damage to critical biomolecules (lipids, proteins and DNA) and initiate various pathogenic cellular process. This chapter provides an insight into oxidative stress-linked pathogenic cellular process such as lipid peroxidation, inflammation, cell death, mitochondrial dysfunction, endoplasmic reticulum stress, epigenetic changes, profibrotic signals and mucus hypersecretion, which drive the development and progression of lung diseases. Lungs are associated with robust enzymatic and non-enzymatic (GSH, ascorbic acid, uric acid, vitamin E) antioxidant defences. However, sustained production of free radicals due to continuous exposures to airborne pollutants overwhelms lung antioxidant defences and causes oxidative injury. Preclinical studies have demonstrated the critical roles and therapeutic potential of upregulating lung antioxidants for intervention of respiratory diseases; however, so far clinical benefits in antioxidant supplementation trials have been minimal and conflicting. Antioxidants alone may not be effective in treatment of respiratory diseases; however it could be a promising adjunctive therapy.
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30
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Fouani L, Kovacevic Z, Richardson DR. Targeting Oncogenic Nuclear Factor Kappa B Signaling with Redox-Active Agents for Cancer Treatment. Antioxid Redox Signal 2019; 30:1096-1123. [PMID: 29161883 DOI: 10.1089/ars.2017.7387] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
SIGNIFICANCE Nuclear factor kappa B (NF-κB) signaling is essential under physiologically relevant conditions. However, aberrant activation of this pathway plays a pertinent role in tumorigenesis and contributes to resistance. Recent Advances: The importance of the NF-κB pathway means that its targeting must be specific to avoid side effects. For many currently used therapeutics and those under development, the ability to generate reactive oxygen species (ROS) is a promising strategy. CRITICAL ISSUES As cancer cells exhibit greater ROS levels than their normal counterparts, they are more sensitive to additional ROS, which may be a potential therapeutic niche. It is known that ROS are involved in (i) the activation of NF-κB signaling, when in sublethal amounts; and (ii) high levels induce cytotoxicity resulting in apoptosis. Indeed, ROS-induced cytotoxicity is valuable for its capabilities in killing cancer cells, but establishing the potency of ROS for effective inhibition of NF-κB signaling is necessary. Indeed, some cancer treatments, currently used, activate NF-κB and may stimulate oncogenesis and confer resistance. FUTURE DIRECTIONS Thus, combinatorial approaches using ROS-generating agents alongside conventional therapeutics may prove an effective tactic to reduce NF-κB activity to kill cancer cells. One strategy is the use of thiosemicarbazones, which form redox-active metal complexes that generate high ROS levels to deliver potent antitumor activity. These agents also upregulate the metastasis suppressor, N-myc downstream regulated gene 1 (NDRG1), which functions as an NF-κB signaling inhibitor. It is proposed that targeting NF-κB signaling may proffer a new therapeutic niche to improve the efficacy of anticancer regimens.
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Affiliation(s)
- Leyla Fouani
- Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, University of Sydney, Sydney, Australia
| | - Zaklina Kovacevic
- Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, University of Sydney, Sydney, Australia
| | - Des R Richardson
- Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, University of Sydney, Sydney, Australia
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31
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Murad HY, Yu H, Luo D, Bortz EP, Halliburton GM, Sholl AB, Khismatullin DB. Mechanochemical Disruption Suppresses Metastatic Phenotype and Pushes Prostate Cancer Cells toward Apoptosis. Mol Cancer Res 2019; 17:1087-1101. [PMID: 30617107 DOI: 10.1158/1541-7786.mcr-18-0782] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2018] [Revised: 10/22/2018] [Accepted: 01/03/2019] [Indexed: 12/30/2022]
Abstract
Chemical-based medicine that targets specific oncogenes or proteins often leads to cancer recurrence due to tumor heterogeneity and development of chemoresistance. This challenge can be overcome by mechanochemical disruption of cancer cells via focused ultrasound (FUS) and sensitizing chemical agents such as ethanol. We demonstrate that this disruptive therapy decreases the viability, proliferation rate, tumorigenicity, endothelial adhesion, and migratory ability of prostate cancer cells in vitro. It sensitized the cells to TNFR1-- and Fas--mediated apoptosis and reduced the expression of metastatic markers CD44 and CD29. Using a prostate cancer xenograft model, we observed that the mechanochemical disruption led to complete tumor regression in vivo. This switch to a nonaggressive cell phenotype was caused by ROS and Hsp70 overproduction and subsequent impairment of NFκB signaling. FUS induces mechanical perturbations of diverse cancer cell populations, and its combination with agents that amplify and guide remedial cellular responses can stop lethal cancer progression. IMPLICATIONS: Mechanochemical disruption therapy in which FUS is combined with ethanol can be curative for locally aggressive and castration-resistant prostate cancer.
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Affiliation(s)
- Hakm Y Murad
- Department of Biomedical Engineering, Tulane University, New Orleans, Louisiana.,Tulane Institute for Integrative Engineering for Health and Medicine, Tulane University, New Orleans, Louisiana
| | - Heng Yu
- Department of Biomedical Engineering, Tulane University, New Orleans, Louisiana.,Tulane Institute for Integrative Engineering for Health and Medicine, Tulane University, New Orleans, Louisiana
| | - Daishen Luo
- Department of Biomedical Engineering, Tulane University, New Orleans, Louisiana.,Tulane Institute for Integrative Engineering for Health and Medicine, Tulane University, New Orleans, Louisiana
| | - Emma P Bortz
- Department of Biomedical Engineering, Tulane University, New Orleans, Louisiana.,Tulane Institute for Integrative Engineering for Health and Medicine, Tulane University, New Orleans, Louisiana
| | - Gray M Halliburton
- Department of Biomedical Engineering, Tulane University, New Orleans, Louisiana.,Tulane Institute for Integrative Engineering for Health and Medicine, Tulane University, New Orleans, Louisiana
| | - Andrew B Sholl
- Department of Pathology and Laboratory Medicine, Tulane University, New Orleans, Louisiana
| | - Damir B Khismatullin
- Department of Biomedical Engineering, Tulane University, New Orleans, Louisiana. .,Tulane Institute for Integrative Engineering for Health and Medicine, Tulane University, New Orleans, Louisiana.,Tulane Cancer Center, Tulane University, New Orleans, Louisiana
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32
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Lim HS, Kim YJ, Kim BY, Park G, Jeong SJ. The Anti-neuroinflammatory Activity of Tectorigenin Pretreatment via Downregulated NF-κB and ERK/JNK Pathways in BV-2 Microglial and Microglia Inactivation in Mice With Lipopolysaccharide. Front Pharmacol 2018; 9:462. [PMID: 29867470 PMCID: PMC5954245 DOI: 10.3389/fphar.2018.00462] [Citation(s) in RCA: 80] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2017] [Accepted: 04/19/2018] [Indexed: 12/14/2022] Open
Abstract
The activation of microglia is decisively involved with the neurodegeneration observed in many neuroinflammatory pathologies, such as multiple sclerosis, Parkinson’s disease, and Alzheimer’s disease. Tectorigenin (TEC) is an isoflavone isolated from various medicinal plants, such as Pueraria thunbergiana Benth, Belamcanda chinensis, and Iris unguicularis. In the present study, the neuroinflammatory effects of TEC were evaluated in both lipopolysaccharide (LPS)-treated BV-2 microglial and mouse models. TEC remarkably inhibited reactive oxygen species (ROS) generation. TEC also inhibits the production and expression of nitric oxide (NO), prostaglandin E2 (PGE2), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) in LPS-stimulated BV-2 cells. In addition, TEC suppressed the LPS-induced activation of nuclear factor-κB (NF-κB), phosphorylation of extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase (JNK) to regulate the inflammatory mediators, such as inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2), TNF-α, and IL-6. These results indicate that TEC may inhibit neuronal inflammation through the downregulation of inflammatory mediators, including iNOS, COX-2, TNF-α, and IL-6 by suppressing NF-κB/ERK/JNK-related signaling pathways. Furthermore, cotreatment with TEC and ERK inhibitor SCH772984 or JNK inhibitor SP600125 suppressed the overproduction of LPS-induced NO production in BV-2 cells. Consistent with the results of in vitro experiments, an LPS-induced brain inflammation mouse model, administration of TEC effectively decrease the levels of malondialdehyde, iNOS in hippocampus, and prevented increases in the levels of TNF-α and IL-6 in the serum. TEC showed marked attenuation of microglial activation. Finally, TEC inhibited protein expression of toll-like receptor 4 and myeloid differentiation factor 88 in LPS-activated BV-2 microglia and mouse models. Taken altogether, the cumulative findings suggested that TEC holds the potential to develop as a neuroprotective drug for the intervention of neuroinflammatory disorders.
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Affiliation(s)
- Hye-Sun Lim
- Herbal Medicine Research Division, Korea Institute of Oriental Medicine, Daejeon, South Korea
| | - Yu Jin Kim
- Herbal Medicine Research Division, Korea Institute of Oriental Medicine, Daejeon, South Korea.,College of Pharmacy, Chungnam National University, Daejeon, South Korea
| | - Bu-Yeo Kim
- Herbal Medicine Research Division, Korea Institute of Oriental Medicine, Daejeon, South Korea
| | | | - Soo-Jin Jeong
- Herbal Medicine Research Division, Korea Institute of Oriental Medicine, Daejeon, South Korea.,Korean Medicine Life Science, University of Science & Technology, Daejeon, South Korea
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33
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Abstract
The transcription factor nuclear factor-κB (NF-κB) modulates gene expression in diverse cellular processes such as innate immune response, embryogenesis and organ development, cell proliferation and apoptosis, and stress responses to a variety of noxious stimuli. When cellular production of reactive oxygen species (ROS) overwhelms its antioxidant capacity, it leads to a state of oxidative stress, which in turn contributes to the pathogenesis of several human diseases. Different models of oxidative stress have been studied to elucidate the effects of oxidant stress on NF-κB related activities. ROS can both activate and repress NF-κB signaling in a phase and context dependent manner. The NF-κB pathway can have both anti- and pro-oxidant roles in the setting of oxidative stress. In this review, we focus on role of oxidative stress on different mediators of the NF-κB pathway, and the role of NF-κB activation in the modulation of oxidative stress. A greater understanding of the complex interplay between the NF-κB signaling and oxidative stress may lead to the development of therapeutic strategies for the treatment of a myriad of human diseases for which oxidative stress has an etiologic role.
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Affiliation(s)
- Krithika Lingappan
- Department of Pediatrics, Section of Neonatology, Texas Children’s Hospital, Baylor College of Medicine, Houston, Texas, USA. Address: 1102 Bates Avenue, MC: FC530.01, Houston, Texas 77030
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34
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Dürr C, Hanna BS, Schulz A, Lucas F, Zucknick M, Benner A, Clear A, Ohl S, Öztürk S, Zenz T, Stilgenbauer S, Li-Weber M, Krammer PH, Gribben JG, Lichter P, Seiffert M. Tumor necrosis factor receptor signaling is a driver of chronic lymphocytic leukemia that can be therapeutically targeted by the flavonoid wogonin. Haematologica 2018; 103:688-697. [PMID: 29326123 PMCID: PMC5865430 DOI: 10.3324/haematol.2017.177808] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Accepted: 01/11/2018] [Indexed: 12/19/2022] Open
Abstract
Chronic lymphocytic leukemia is a malignancy of mature B cells that strongly depend on microenvironmental factors, and their deprivation has been identified as a promising treatment approach for this incurable disease. Cytokine array screening of 247 chronic lymphocytic leukemia serum samples revealed elevated levels of tumor necrosis factor (TNF) receptor-1 which were associated with poor clinical outcome. We detected a microenvironment-induced expression of TNF receptor-1 in chronic lymphocytic leukemia cells in vitro, and an aberrantly high expression of this receptor in the proliferation centers of patients’ lymph nodes. Stimulation of TNF receptor-1 with TNF-α enhanced nuclear factor κ-light-chain-enhancer of activated B cells (NFκB) activity and viability of chronic lymphocytic leukemia cells, which was inhibited by wogonin. The therapeutic effects of wogonin were analyzed in mice after adoptive transfer of Eμ-T-cell leukemia 1 (TCL1) leukemic cells. Wogonin treatment prevented leukemia development when given early after transplantation. The treatment of full-blown leukemia resulted in the loss of the TNF receptor-1 on chronic lymphocytic leukemia cells and their mobilization to blood. Targeting TNF receptor-1 signaling is therefore proposed for the treatment of chronic lymphocytic leukemia.
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Affiliation(s)
- Claudia Dürr
- Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Bola S Hanna
- Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Angela Schulz
- Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Fabienne Lucas
- Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, UK
| | - Manuela Zucknick
- Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Oslo Center for Biostatistics and Epidemiology; Department of Biostatistics, Institute of Basic Medical Sciences, University of Oslo, Norway
| | - Axel Benner
- Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Andrew Clear
- Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, UK
| | - Sibylle Ohl
- Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Selcen Öztürk
- Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Thorsten Zenz
- Molecular Therapy in Haematology and Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), and Department of Medicine V, University Hospital Heidelberg, Germany
| | | | - Min Li-Weber
- Division of Immunogenetics, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Peter H Krammer
- Division of Immunogenetics, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - John G Gribben
- Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, UK
| | - Peter Lichter
- Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Martina Seiffert
- Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany
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Catechol Groups Enable Reactive Oxygen Species Scavenging-Mediated Suppression of PKD-NFkappaB-IL-8 Signaling Pathway by Chlorogenic and Caffeic Acids in Human Intestinal Cells. Nutrients 2017; 9:nu9020165. [PMID: 28230729 PMCID: PMC5331596 DOI: 10.3390/nu9020165] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2016] [Revised: 02/05/2017] [Accepted: 02/13/2017] [Indexed: 01/22/2023] Open
Abstract
Chlorogenic acid (CHA) and caffeic acid (CA) are phenolic compounds found in coffee, which inhibit oxidative stress-induced interleukin (IL)-8 production in intestinal epithelial cells, thereby suppressing serious cellular injury and inflammatory intestinal diseases. Therefore, we investigated the anti-inflammatory mechanism of CHA and CA, both of which inhibited hydrogen peroxide (H2O2)-induced IL-8 transcriptional activity. They also significantly suppressed nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) transcriptional activity, nuclear translocation of the p65 subunit, and phosphorylation of IκB kinase (IKK). Additionally, upstream of IKK, protein kinase D (PKD) was also suppressed. Finally, we found that they scavenged H2O2-induced reactive oxygen species (ROS) and the functional moiety responsible for the anti-inflammatory effects of CHA and CA was the catechol group. Therefore, we conclude that the presence of catechol groups in CHA and CA allows scavenging of intracellular ROS, thereby inhibiting H2O2-induced IL-8 production via suppression of PKD-NF-κB signaling in human intestinal epithelial cells.
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36
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Amatngalim GD, Schrumpf JA, Henic A, Dronkers E, Verhoosel RM, Ordonez SR, Haagsman HP, Fuentes ME, Sridhar S, Aarbiou J, Janssen RAJ, Lekkerkerker AN, Hiemstra PS. Antibacterial Defense of Human Airway Epithelial Cells from Chronic Obstructive Pulmonary Disease Patients Induced by Acute Exposure to Nontypeable Haemophilus influenzae: Modulation by Cigarette Smoke. J Innate Immun 2017; 9:359-374. [PMID: 28171878 DOI: 10.1159/000455193] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2016] [Accepted: 12/19/2016] [Indexed: 12/31/2022] Open
Abstract
Antimicrobial proteins and peptides (AMPs) are a central component of the antibacterial activity of airway epithelial cells. It has been proposed that a decrease in antibacterial lung defense contributes to an increased susceptibility to microbial infection in smokers and patients with chronic obstructive pulmonary disease (COPD). However, whether reduced AMP expression in the epithelium contributes to this lower defense is largely unknown. We investigated the bacterial killing activity and expression of AMPs by air-liquid interface-cultured primary bronchial epithelial cells from COPD patients and non-COPD (ex-)smokers that were stimulated with nontypeable Haemophilus influenzae (NTHi). In addition, the effect of cigarette smoke on AMP expression and the activation of signaling pathways was determined. COPD cell cultures displayed reduced antibacterial activity, whereas smoke exposure suppressed the NTHi-induced expression of AMPs and further increased IL-8 expression in COPD and non-COPD cultures. Moreover, smoke exposure impaired NTHi-induced activation of NF-κB, but not MAP-kinase signaling. Our findings demonstrate that the antibacterial activity of cultured airway epithelial cells induced by acute bacterial exposure was reduced in COPD and suppressed by cigarette smoke, whereas inflammatory responses persisted. These findings help to explain the imbalance between protective antibacterial and destructive inflammatory innate immune responses in COPD.
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Affiliation(s)
- Gimano D Amatngalim
- Department of Pulmonology, Leiden University Medical Center, Leiden, The Netherlands
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Abstract
Peroxiredoxins (Prxs) constitute a major family of peroxidases, with mammalian cells expressing six Prx isoforms (PrxI to PrxVI). Cells produce hydrogen peroxide (H2O2) at various intracellular locations where it can serve as a signaling molecule. Given that Prxs are abundant and possess a structure that renders the cysteine (Cys) residue at the active site highly sensitive to oxidation by H2O2, the signaling function of this oxidant requires extensive and highly localized regulation. Recent findings on the reversible regulation of PrxI through phosphorylation at the centrosome and on the hyperoxidation of the Cys at the active site of PrxIII in mitochondria are described in this review as examples of such local regulation of H2O2 signaling. Moreover, their high affinity for and sensitivity to oxidation by H2O2 confer on Prxs the ability to serve as sensors and transducers of H2O2 signaling through transfer of their oxidation state to bound effector proteins.
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Affiliation(s)
- Sue Goo Rhee
- Yonsei Biomedical Research Institute, Yonsei University College of Medicine, Seoul 120-752, Korea;
| | - In Sup Kil
- Yonsei Biomedical Research Institute, Yonsei University College of Medicine, Seoul 120-752, Korea;
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38
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O. Temajo N, Howard N. The divergence between the virus and cellular oxidative stress as separate environmental agents that trigger autoimmunity originates from their different procedural mechanisms of activating the same molecular entity: the transcription factor NF-kappa B. AIMS ALLERGY AND IMMUNOLOGY 2017. [DOI: 10.3934/allergy.2017.2.50] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
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39
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Szoltysek K, Walaszczyk A, Janus P, Kimmel M, Widlak P. Irradiation with UV-C inhibits TNF-α-dependent activation of the NF-κB pathway in a mechanism potentially mediated by reactive oxygen species. Genes Cells 2016; 22:45-58. [PMID: 27976481 DOI: 10.1111/gtc.12455] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2016] [Accepted: 10/30/2016] [Indexed: 12/25/2022]
Abstract
Pathways depending on the NF-κB transcription factor are essential components of cellular response to stress. Plethora of stimuli modulating NF-κB includes inflammatory signals, ultraviolet radiation (UV) and reactive oxygen species (ROS), yet interference between different factors affecting NF-κB remains relatively understudied. Here, we aim to characterize the influence of UV radiation on TNF-α-induced activity of the NF-κB pathway. We document inhibition of TNF-α-induced activation of NF-κB and subsequent suppression of NF-κB-regulated genes in cells exposed to UV-C several hours before TNF-α stimulation. Accumulation of ROS and subsequent activation of NRF2, p53, AP-1 and NF-κB-dependent pathways, with downstream activation of antioxidant mechanisms (e.g., SOD2 and HMOX1 expression), is observed in the UV-treated cells. Moreover, NF-κB inhibition is not observed if generation of UV-induced ROS is suppressed by chemical antioxidants. It is noteworthy that stimulation with TNF-α also generates a wave of ROS, which is suppressed in cells pre-treated by UV. We postulate that irradiation with UV-C activates antioxidant mechanisms, which in turn affect ROS-mediated activation of NF-κB by TNF-α. Considering a potential cross talk between p53 and NF-κB, we additionally compare observed effects in p53-proficient and p53-deficient cells and find the UV-mediated suppression of TNF-α-activated NF-κB in both types of cells.
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Affiliation(s)
- Katarzyna Szoltysek
- Maria Skłodowska-Curie Memorial Cancer Center and Institute of Oncology, Wybrzeze Armii Krajowej 15, Gliwice, Poland
| | - Anna Walaszczyk
- Maria Skłodowska-Curie Memorial Cancer Center and Institute of Oncology, Wybrzeze Armii Krajowej 15, Gliwice, Poland
| | - Patryk Janus
- Maria Skłodowska-Curie Memorial Cancer Center and Institute of Oncology, Wybrzeze Armii Krajowej 15, Gliwice, Poland.,Systems Engineering Group, Silesian University of Technology, Akademicka 16, Gliwice, Poland
| | - Marek Kimmel
- Systems Engineering Group, Silesian University of Technology, Akademicka 16, Gliwice, Poland.,Departments of Statistics and Bioengineering, Rice University, 6100 Main Street, Houston, TX, USA
| | - Piotr Widlak
- Maria Skłodowska-Curie Memorial Cancer Center and Institute of Oncology, Wybrzeze Armii Krajowej 15, Gliwice, Poland
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40
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Reyes-Quiroz ME, Alba G, Sáenz J, Geniz I, Jiménez J, Martín-Nieto J, Santa-María C, Sobrino F. Platelet-activating factor and hydrogen peroxide exert a dual modulatory effect on the transcription of LXRα and its target genes in human neutrophils. Int Immunopharmacol 2016; 38:357-66. [DOI: 10.1016/j.intimp.2016.05.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2015] [Revised: 04/29/2016] [Accepted: 05/03/2016] [Indexed: 11/25/2022]
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41
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Zhou Y, Wu Z, Cao X, Ding L, Wen Z, Bian JS. HNO suppresses LPS-induced inflammation in BV-2 microglial cells via inhibition of NF-κB and p38 MAPK pathways. Pharmacol Res 2016; 111:885-895. [PMID: 27507578 DOI: 10.1016/j.phrs.2016.08.007] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2016] [Revised: 08/01/2016] [Accepted: 08/04/2016] [Indexed: 11/26/2022]
Abstract
Both hydrogen sulfide (H2S) and nitric oxide (NO) are important gaseous mediators. We and others previously reported that these two gases react with each other to generate a new mediator, nitroxyl (HNO), and regulate cardiovascular functions. In this study, we demonstrated for the first time that the interaction between the two gases also existed in microglia. The biological functions of HNO in microglial cells were further studied with Angeli's salt (AS), an HNO donor. We found that AS attenuated lipopolysaccharide (LPS)-evoked production of reactive oxygen species (ROS) and pro-inflammatory cytokines (e.g. IL-1β and TNFα) through downregulating the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). HNO significantly reduced the phosphorylation of p38 mitogen-activated protein kinase (MAPK) and the activation of nuclear factor-κB (NF-κB) through suppression of phosphorylation p65 and IκBα. The above effects were abolished by l-cysteine, an HNO scavenger, but were not mimicked by nitrite, another product of AS during generating HNO. A Cys-179-to-Ala mutation in inhibitory κB kinase β (IKKβ) mimicked the effect of HNO on LPS-induced NF-κB activation. Interestingly, AS abolished the inflammation in cells overexpressing WT-IKKβ, but had no significant effect in cells overexpressing C179A-IKKβ. These data suggest that HNO may act on C179 to prevent IKKβ-dependent inflammation. Taken together, our data demonstrated for the first time that H2S interacts with NO to generate HNO in microglial cells. HNO produces anti-inflammatory effects through suppressing the IKKβ dependent NF-κB activation and p38 MAPK pathways.
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Affiliation(s)
- Yebo Zhou
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117600, Singapore
| | - Zhiyuan Wu
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117600, Singapore
| | - Xu Cao
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117600, Singapore
| | - Lei Ding
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117600, Singapore
| | - ZhengShun Wen
- Zhejiang Provincial Engineering Technology Research Center of Marine Biomedical Products, Food and Pharmacy College, Zhejiang Ocean University, Zhoushan 316000, China
| | - Jin-Song Bian
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117600, Singapore.
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42
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Mitochondrial H2O2 in Lung Antigen-Presenting Cells Blocks NF-κB Activation to Prevent Unwarranted Immune Activation. Cell Rep 2016; 15:1700-14. [PMID: 27184852 DOI: 10.1016/j.celrep.2016.04.060] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2015] [Revised: 03/10/2016] [Accepted: 04/15/2016] [Indexed: 12/21/2022] Open
Abstract
Inhalation of environmental antigens such as allergens does not always induce inflammation in the respiratory tract. While antigen-presenting cells (APCs), including dendritic cells and macrophages, take up inhaled antigens, the cell-intrinsic molecular mechanisms that prevent an inflammatory response during this process, such as activation of the transcription factor NF-κB, are not well understood. Here, we show that the nuclear receptor PPARγ plays a critical role in blocking NF-κB activation in response to inhaled antigens to preserve immune tolerance. Tolerance induction promoted mitochondrial respiration, generation of H2O2, and suppression of NF-κB activation in WT, but not PPARγ-deficient, APCs. Forced restoration of H2O2 in PPARγ-deficient cells suppressed IκBα degradation and NF-κB activation. Conversely, scavenging reactive oxygen species from mitochondria promoted IκBα degradation with loss of regulatory and promotion of inflammatory T cell responses in vivo. Thus, communication between PPARγ and the mitochondria maintains immune quiescence in the airways.
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43
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Lin Q, Mathieu O, Tompkins TA, Buckley ND, Green-Johnson JM. Modulation of the TNFα-induced gene expression profile of intestinal epithelial cells by soy fermented with lactic acid bacteria. J Funct Foods 2016. [DOI: 10.1016/j.jff.2016.02.047] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
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44
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Jones JT, Qian X, van der Velden JLJ, Chia SB, McMillan DH, Flemer S, Hoffman SM, Lahue KG, Schneider RW, Nolin JD, Anathy V, van der Vliet A, Townsend DM, Tew KD, Janssen-Heininger YMW. Glutathione S-transferase pi modulates NF-κB activation and pro-inflammatory responses in lung epithelial cells. Redox Biol 2016; 8:375-82. [PMID: 27058114 PMCID: PMC4827796 DOI: 10.1016/j.redox.2016.03.005] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2016] [Accepted: 03/22/2016] [Indexed: 01/30/2023] Open
Abstract
Nuclear Factor kappa B (NF-κB) is a transcription factor family critical in the activation of pro- inflammatory responses. The NF-κB pathway is regulated by oxidant-induced post-translational modifications. Protein S-glutathionylation, or the conjugation of the antioxidant molecule, glutathione to reactive cysteines inhibits the activity of inhibitory kappa B kinase beta (IKKβ), among other NF-κB proteins. Glutathione S-transferase Pi (GSTP) is an enzyme that has been shown to catalyze protein S-glutathionylation (PSSG) under conditions of oxidative stress. The objective of the present study was to determine whether GSTP regulates NF-κB signaling, S-glutathionylation of IKK, and subsequent pro-inflammatory signaling. We demonstrated that, in unstimulated cells, GSTP associated with the inhibitor of NF-κB, IκBα. However, exposure to LPS resulted in a rapid loss of association between IκBα and GSTP, and instead led to a protracted association between IKKβ and GSTP. LPS exposure also led to increases in the S-glutathionylation of IKKβ. SiRNA-mediated knockdown of GSTP decreased IKKβ-SSG, and enhanced NF-κB nuclear translocation, transcriptional activity, and pro-inflammatory cytokine production in response to lipopolysaccharide (LPS). TLK117, an isotype-selective inhibitor of GSTP, also enhanced LPS-induced NF-κB transcriptional activity and pro-inflammatory cytokine production, suggesting that the catalytic activity of GSTP is important in repressing NF-κB activation. Expression of both wild-type and catalytically-inactive Y7F mutant GSTP significantly attenuated LPS- or IKKβ-induced production of GM-CSF. These studies indicate a complex role for GSTP in modulating NF-κB, which may involve S-glutathionylation of IKK proteins, and interaction with NF-κB family members. Our findings suggest that targeting GSTP is a potential avenue for regulating the activity of this prominent pro-inflammatory and immunomodulatory transcription factor.
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Affiliation(s)
- Jane T Jones
- Department of Pathology and Laboratory Medicine, The University of Vermont, Burlington, VT, United States
| | - Xi Qian
- Department of Pathology and Laboratory Medicine, The University of Vermont, Burlington, VT, United States
| | - Jos L J van der Velden
- Department of Pathology and Laboratory Medicine, The University of Vermont, Burlington, VT, United States
| | - Shi Biao Chia
- Department of Pathology and Laboratory Medicine, The University of Vermont, Burlington, VT, United States
| | - David H McMillan
- Department of Pathology and Laboratory Medicine, The University of Vermont, Burlington, VT, United States
| | - Stevenson Flemer
- Department of Chemistry, The University of Vermont, Burlington, VT, United States
| | - Sidra M Hoffman
- Department of Pathology and Laboratory Medicine, The University of Vermont, Burlington, VT, United States
| | - Karolyn G Lahue
- Department of Pathology and Laboratory Medicine, The University of Vermont, Burlington, VT, United States
| | - Robert W Schneider
- Department of Pathology and Laboratory Medicine, The University of Vermont, Burlington, VT, United States
| | - James D Nolin
- Department of Pathology and Laboratory Medicine, The University of Vermont, Burlington, VT, United States
| | - Vikas Anathy
- Department of Pathology and Laboratory Medicine, The University of Vermont, Burlington, VT, United States
| | - Albert van der Vliet
- Department of Pathology and Laboratory Medicine, The University of Vermont, Burlington, VT, United States
| | - Danyelle M Townsend
- Department of Pharmaceutical and Biomedical Sciences, Medical University of South Carolina, Charleston, SC, United States
| | - Kenneth D Tew
- Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, SC, United States
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45
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Tao S, Zhang Y, Yuan C, Gao J, Wu F, Wang Z. Oxidative stress and immunotoxic effects of bisphenol A on the larvae of rare minnow Gobiocypris rarus. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2016; 124:377-385. [PMID: 26595511 DOI: 10.1016/j.ecoenv.2015.11.014] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/16/2015] [Revised: 11/06/2015] [Accepted: 11/06/2015] [Indexed: 06/05/2023]
Abstract
Bisphenol A (BPA), a known endocrine disrupting chemical, is ubiquitous in the aquatic environment and can pose risk to the health of aquatic organisms. Studies on immunotoxicity of BPA in aquatic organisms are limited. In this study, rare minnow (Gobiocypris rarus) larvae were exposed to 1, 225 and 1000μg/L BPA for 7 days. Inflammatory effects of BPA exposure were assessed from the increased production of nitric oxide (NO) and reactive oxygen species (ROS), the change of iNOS mRNA and other TLRs-associated immune gene expression. Our findings provide evidences that different concentrations of BPA can induce a toxic response in fish to produce reactive free radicals which can affect the function of T lymphocytes and decrease the transcription levels of cytokine genes. The excess production of H2O2, induced oxidative stress and suppressed TLR4/NF-κB signaling, leading to immunosuppressive effects in fish larvae. The present results suggest that BPA has the potential to induce oxidative stress accompanied by immunosuppression in rare minnow larvae.
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Affiliation(s)
- Shiyu Tao
- College of Animal Science and Technology, Northwest A&F University, Shaanxi Key Laboratory of Molecular Biology for Agriculture, Yangling, Shaanxi 712100, China
| | - Yingying Zhang
- College of Animal Science and Technology, Northwest A&F University, Shaanxi Key Laboratory of Molecular Biology for Agriculture, Yangling, Shaanxi 712100, China
| | - Cong Yuan
- College of Animal Science and Technology, Northwest A&F University, Shaanxi Key Laboratory of Molecular Biology for Agriculture, Yangling, Shaanxi 712100, China
| | - Jiancao Gao
- College of Animal Science and Technology, Northwest A&F University, Shaanxi Key Laboratory of Molecular Biology for Agriculture, Yangling, Shaanxi 712100, China
| | - Feili Wu
- College of Animal Science and Technology, Northwest A&F University, Shaanxi Key Laboratory of Molecular Biology for Agriculture, Yangling, Shaanxi 712100, China
| | - Zaizhao Wang
- College of Animal Science and Technology, Northwest A&F University, Shaanxi Key Laboratory of Molecular Biology for Agriculture, Yangling, Shaanxi 712100, China.
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46
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Ghandadi M, Behravan J, Abnous K, Mosaffa F. Reactive Oxygen Species Mediate TNF-⍺ Cytotoxic Effects in the Multidrug-Resistant Breast Cancer Cell Line MCF-7/MX. Oncol Res Treat 2015; 39:54-9. [DOI: 10.1159/000442144] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2015] [Accepted: 10/22/2015] [Indexed: 11/19/2022]
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47
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Broekgaarden M, Weijer R, van Gulik TM, Hamblin MR, Heger M. Tumor cell survival pathways activated by photodynamic therapy: a molecular basis for pharmacological inhibition strategies. Cancer Metastasis Rev 2015; 34:643-90. [PMID: 26516076 PMCID: PMC4661210 DOI: 10.1007/s10555-015-9588-7] [Citation(s) in RCA: 189] [Impact Index Per Article: 18.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Photodynamic therapy (PDT) has emerged as a promising alternative to conventional cancer therapies such as surgery, chemotherapy, and radiotherapy. PDT comprises the administration of a photosensitizer, its accumulation in tumor tissue, and subsequent irradiation of the photosensitizer-loaded tumor, leading to the localized photoproduction of reactive oxygen species (ROS). The resulting oxidative damage ultimately culminates in tumor cell death, vascular shutdown, induction of an antitumor immune response, and the consequent destruction of the tumor. However, the ROS produced by PDT also triggers a stress response that, as part of a cell survival mechanism, helps cancer cells to cope with the PDT-induced oxidative stress and cell damage. These survival pathways are mediated by the transcription factors activator protein 1 (AP-1), nuclear factor E2-related factor 2 (NRF2), hypoxia-inducible factor 1 (HIF-1), nuclear factor κB (NF-κB), and those that mediate the proteotoxic stress response. The survival pathways are believed to render some types of cancer recalcitrant to PDT and alter the tumor microenvironment in favor of tumor survival. In this review, the molecular mechanisms are elucidated that occur post-PDT to mediate cancer cell survival, on the basis of which pharmacological interventions are proposed. Specifically, pharmaceutical inhibitors of the molecular regulators of each survival pathway are addressed. The ultimate aim is to facilitate the development of adjuvant intervention strategies to improve PDT efficacy in recalcitrant solid tumors.
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Affiliation(s)
- Mans Broekgaarden
- Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
| | - Ruud Weijer
- Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
| | - Thomas M van Gulik
- Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
| | - Michael R Hamblin
- Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA, USA
- Department of Dermatology, Harvard Medical School, Boston, MA, USA
- Harvard-MIT Division of Health Sciences & Technology, Cambridge, MA, USA
| | - Michal Heger
- Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
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48
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Toniolo A, Buccellati C, Trenti A, Trevisi L, Carnevali S, Sala A, Bolego C. Antiinflammatory and antioxidant effects of H2O2 generated by natural sources in Il1β-treated human endothelial cells. Prostaglandins Other Lipid Mediat 2015; 121:190-8. [PMID: 26391839 DOI: 10.1016/j.prostaglandins.2015.09.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2015] [Revised: 08/07/2015] [Accepted: 09/16/2015] [Indexed: 10/23/2022]
Abstract
Specific reactive oxygen species (ROS) from different sources, might lead to different and even opposite, cellular effects. We studied the production of specific ROS resulting from the exposure of human umbilical veins endothelial cells (HUVEC) to H2O2 derived from the natural antioxidant epigallocathechin gallate (EGCG) or from the exposure to IL-1β using a fluorogenic probe and flow cytometry, and evaluated by western blot analysis and immunocytochemistry the associated expression of transcription factors sensitive to both inflammatory and oxidative stress, such as NF-κB and Nrf2, and some downstream activated genes such as cyclooxygenase-2 (COX-2) and hemeoxygenase 1 (HO-1). The results obtained showed that exogenously-generated H2O2 induce anti-inflammatory and antioxidant effects in HUVECs counteracting the pro-inflammatory and pro-oxidant effect of IL-1β related to the production of superoxide anions. The underlying mechanisms resulting from the extracellular production of H2O2, include (1) Nrf2 nuclear translocation and the enhanced expression of antioxidant enzymes such as HO-1, and (2) the previously unreported inhibition of NF-κB and COX-2 expression. Overall, these findings provide evidence that the production of specific reactive oxygen species finely tunes endothelial cell function and might be relevant for the reappraisal of the effects of exogenous antioxidants in the context of cardiovascular diseases.
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Affiliation(s)
- Alice Toniolo
- Department of Pharmaceuticaland Pharmacological Sciences, University of Padova, Italy
| | - Carola Buccellati
- Department of Pharmacological and Biomolecular Sciences, University of Milan, Italy
| | - Annalisa Trenti
- Department of Pharmaceuticaland Pharmacological Sciences, University of Padova, Italy
| | - Lucia Trevisi
- Department of Pharmaceuticaland Pharmacological Sciences, University of Padova, Italy
| | - Silvia Carnevali
- Department of Pharmacological and Biomolecular Sciences, University of Milan, Italy
| | - Angelo Sala
- Department of Pharmacological and Biomolecular Sciences, University of Milan, Italy; Institute of Biomedicine and Molecular Immunology, National Research Council, Palermo, Italy.
| | - Chiara Bolego
- Department of Pharmaceuticaland Pharmacological Sciences, University of Padova, Italy
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49
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Prasad RG, Choi YH, Kim GY. Shikonin Isolated from Lithospermum erythrorhizon Downregulates Proinflammatory Mediators in Lipopolysaccharide-Stimulated BV2 Microglial Cells by Suppressing Crosstalk between Reactive Oxygen Species and NF-κB. Biomol Ther (Seoul) 2015; 23:110-8. [PMID: 25767678 PMCID: PMC4354311 DOI: 10.4062/biomolther.2015.006] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2015] [Revised: 01/29/2015] [Accepted: 02/05/2015] [Indexed: 11/17/2022] Open
Abstract
According to the expansion of lifespan, neuronal disorder based on inflammation has been social problem. Therefore, we isolated shikonin from Lithospermum erythrorhizon and evaluated anti-inflammatory effects of shikonin in lipopolysaccharide (LSP)-stimulated BV2 microglial cells. Shikonin dose-dependently inhibits the expression of the proinflammatory mediators, nitric oxide (NO), prostaglandin E2 (PGE2), and tumor necrosis factor-α (TNF-α) as well as their main regulatory genes and products such as inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2), and TNF-α in LPS-stimulated BV2 microglial cells. Additionally, shikonin suppressed the LPS-induced DNA-binding activity of nuclear factor-κB (NF-κB) to regulate the key regulatory genes of the proinflammatory mediators, such as iNOS, COX-2, and TNF-α, accompanied with downregulation of reactive oxygen species (ROS) generation. The results indicate that shikonin may downregulate the expression of proinflammatory genes involved in the synthesis of NO, PGE2, and TNF-α in LPS-treated BV2 microglial cells by suppressing ROS and NF-κB. Taken together, our results revealed that shikonin exerts downregulation of proinflammatory mediators by interference the ROS and NF-κB signaling pathway.
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Affiliation(s)
| | - Yung Hyun Choi
- Department of Biochemistry, College of Oriental Medicine, Dongeui University, Busan 614-051, Republic of Korea
| | - Gi-Young Kim
- Department of Marine Life Sciences, Jeju National University, Jeju 690-756, Republic of Korea
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50
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Abstract
Acute pancreatitis is an inflammatory process of the pancreatic gland that eventually may lead to a severe systemic inflammatory response. A key event in pancreatic damage is the intracellular activation of NF-κB and zymogens, involving also calcium, cathepsins, pH disorders, autophagy, and cell death, particularly necrosis. This review focuses on the new role of redox signaling in acute pancreatitis. Oxidative stress and redox status are involved in the onset of acute pancreatitis and also in the development of the systemic inflammatory response, being glutathione depletion, xanthine oxidase activation, and thiol oxidation in proteins critical features of the disease in the pancreas. On the other hand, the release of extracellular hemoglobin into the circulation from the ascitic fluid in severe necrotizing pancreatitis enhances lipid peroxidation in plasma and the inflammatory infiltrate into the lung and up-regulates the HIF-VEGF pathway, contributing to the systemic inflammatory response. Therefore, redox signaling and oxidative stress contribute to the local and systemic inflammatory response during acute pancreatitis.
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