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Roth P, Stanley J, Chamoun-Emanuelli A, Whitfield-Cargile C, Coleman M. Fecal extract from obese horses induces an inflammatory response by murine macrophages in vitro. Am J Vet Res 2022; 83:419-425. [PMID: 35113795 DOI: 10.2460/ajvr.21.02.0024] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
OBJECTIVE To compare the inflammatory response of murine macrophages exposed to the enteric microbiome of obese horses versus nonobese horses. SAMPLE Fecal samples from 12 obese horses (body condition score ≥ 7/9) and 12 nonobese horses (body condition score 4 to 5/9) with similar dietary management. PROCEDURES Fecal supernatant was prepared from frozen fecal samples. RAW 264.7 macrophage cells were exposed to the fecal extract. Inflammatory cytokine (interleukin-1β, tumor necrosis factor-α, and interleukin-6) gene expression was quantified via real-time quantitative reverse transcription PCR assay, and cytokine concentration was quantified via ELISA. Lipopolysaccharide was evaluated in fecal extract via chromo-limulus amoebocyte lysate assay. RESULTS Compared with fecal extracts from nonobese horses, fecal extracts from obese horses presented higher concentrations of lipopolysaccharide and induced a heightened expression of the proinflammatory cytokines interleukin-1β, tumor necrosis factor-α, and interleukin-6 from macrophages. CLINICAL RELEVANCE The increased levels of inflammatory markers induced in murine macrophages by the microbiome of obese horses in vitro suggested important differences in the enteric microbial composition of these horses, compared with nonobese horses. Overall, this study showed that the microbiome may play a role in mediating an inflammatory response within the gastrointestinal tract of obese horses. Mechanisms of obesity in the horse have not been fully elucidated. Improved understanding of the pathophysiology of disease will guide future research into potential diagnostic and therapeutic interventions for equine obesity.
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2
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Foster VS, Rash LD, King GF, Rank MM. Acid-Sensing Ion Channels: Expression and Function in Resident and Infiltrating Immune Cells in the Central Nervous System. Front Cell Neurosci 2021; 15:738043. [PMID: 34602982 PMCID: PMC8484650 DOI: 10.3389/fncel.2021.738043] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Accepted: 08/30/2021] [Indexed: 11/15/2022] Open
Abstract
Peripheral and central immune cells are critical for fighting disease, but they can also play a pivotal role in the onset and/or progression of a variety of neurological conditions that affect the central nervous system (CNS). Tissue acidosis is often present in CNS pathologies such as multiple sclerosis, epileptic seizures, and depression, and local pH is also reduced during periods of ischemia following stroke, traumatic brain injury, and spinal cord injury. These pathological increases in extracellular acidity can activate a class of proton-gated channels known as acid-sensing ion channels (ASICs). ASICs have been primarily studied due to their ubiquitous expression throughout the nervous system, but it is less well recognized that they are also found in various types of immune cells. In this review, we explore what is currently known about the expression of ASICs in both peripheral and CNS-resident immune cells, and how channel activation during pathological tissue acidosis may lead to altered immune cell function that in turn modulates inflammatory pathology in the CNS. We identify gaps in the literature where ASICs and immune cell function has not been characterized, such as neurotrauma. Knowledge of the contribution of ASICs to immune cell function in neuropathology will be critical for determining whether the therapeutic benefits of ASIC inhibition might be due in part to an effect on immune cells.
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Affiliation(s)
- Victoria S. Foster
- Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD, Australia
| | - Lachlan D. Rash
- School of Biomedical Sciences, The University of Queensland, St Lucia, QLD, Australia
| | - Glenn F. King
- Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD, Australia
- Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Queensland, St Lucia, QLD, Australia
| | - Michelle M. Rank
- Anatomy and Physiology, Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, VIC, Australia
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3
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Kawakami T, Koike A, Amano F. Sodium bicarbonate regulates nitric oxide production in mouse macrophage cell lines stimulated with lipopolysaccharide and interferon γ. Nitric Oxide 2018; 79:45-50. [PMID: 30063984 DOI: 10.1016/j.niox.2018.07.008] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2018] [Revised: 07/27/2018] [Accepted: 07/27/2018] [Indexed: 01/22/2023]
Abstract
Macrophages are known to play pivotal roles in host-defense through inflammation via both innate and acquired immune systems, and so on. In an earlier paper, we showed the influence of the type of culture medium, Ham's F-12 or DMEM, on activated macrophage phenotypes induced by LPS and IFNγ. The production of nitric oxide (NO), pro-inflammatory cytokines such as TNFα and IL-1β, as well as the induction of superoxide-generating activity of J774.1/JA-4 cells was different depending on the type of culture medium. In this present study, we showed that sodium bicarbonate concentrations in these culture media, 14 mM in Ham's F-12 and 44 mM in DMEM, were crucial to explaining the differences in the induction of activated macrophage phenotypes, especially in that of iNOS. A concentration-dependent change in pH did not result in any remarkable difference in iNOS expression or NO production. Moreover, high sodium bicarbonate in culture medium increased not only NO production but also TNFα production in the activated macrophages. These results suggest that sodium bicarbonate would be a regulatory factor of NO and TNFα production in macrophages and that its concentration has a crucial role in macrophage activation.
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Affiliation(s)
- Tomoya Kawakami
- Laboratory of Biodefense & Regulation, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka, 569-1094, Japan
| | - Atsushi Koike
- Laboratory of Biodefense & Regulation, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka, 569-1094, Japan
| | - Fumio Amano
- Laboratory of Biodefense & Regulation, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka, 569-1094, Japan.
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4
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Besen BAMP, Gobatto ALN, Melro LMG, Maciel AT, Park M. Fluid and electrolyte overload in critically ill patients: An overview. World J Crit Care Med 2015; 4:116-129. [PMID: 25938027 PMCID: PMC4411563 DOI: 10.5492/wjccm.v4.i2.116] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2014] [Revised: 12/24/2014] [Accepted: 03/05/2015] [Indexed: 02/06/2023] Open
Abstract
Fluids are considered the cornerstone of therapy for many shock states, particularly states that are associated with relative or absolute hypovolemia. Fluids are also commonly used for many other purposes, such as renal protection from endogenous and exogenous substances, for the safe dilution of medications and as “maintenance” fluids. However, a large amount of evidence from the last decade has shown that fluids can have deleterious effects on several organ functions, both from excessive amounts of fluids and from their non-physiological electrolyte composition. Additionally, fluid prescription is more common in patients with systemic inflammatory response syndrome whose kidneys may have impaired mechanisms of electrolyte and free water excretion. These processes have been studied as separate entities (hypernatremia, hyperchloremic acidosis and progressive fluid accumulation) leading to worse outcomes in many clinical scenarios, including but not limited to acute kidney injury, worsening respiratory function, higher mortality and higher hospital and intensive care unit length-of-stays. In this review, we synthesize this evidence and describe this phenomenon as fluid and electrolyte overload with potentially deleterious effects. Finally, we propose a strategy to safely use fluids and thereafter wean patients from fluids, along with other caveats to be considered when dealing with fluids in the intensive care unit.
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Hårdstedt M, Lindblom S, Hong J, Nilsson B, Korsgren O, Ronquist G. A novel model for studies of blood-mediated long-term responses to cellular transplants. Ups J Med Sci 2015; 120:28-39. [PMID: 25322825 PMCID: PMC4389005 DOI: 10.3109/03009734.2014.965290] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
AIMS Interaction between blood and bio-surfaces is important in many medical fields. With the aim of studying blood-mediated reactions to cellular transplants, we developed a whole-blood model for incubation of small volumes for up to 48 h. METHODS Heparinized polyvinyl chloride tubing was cut in suitable lengths and sealed to create small bags. Multiple bags, with fresh venous blood, were incubated attached to a rotating wheel at 37°C. Physiological variables in blood were monitored: glucose, blood gases, mono- and divalent cations and chloride ions, osmolality, coagulation (platelet consumption, thrombin-antithrombin complexes (TAT)), and complement activation (C3a and SC5b-9), haemolysis, and leukocyte viability. RESULTS Basic glucose consumption was high. Glucose depletion resulted in successive elevation of extracellular potassium, while sodium and calcium ions decreased due to inhibition of energy-requiring ion pumps. Addition of glucose improved ion balance but led to metabolic acidosis. To maintain a balanced physiological environment beyond 6 h, glucose and sodium hydrogen carbonate were added regularly based on analyses of glucose, pH, ions, and osmotic pressure. With these additives haemolysis was prevented for up to 72 h and leukocyte viability better preserved. Despite using non-heparinized blood, coagulation and complement activation were lower during long-term incubations compared with addition of thromboplastin and collagen. CONCLUSION A novel whole-blood model for studies of blood-mediated responses to a cellular transplant is presented allowing extended observations for up to 48 h and highlights the importance of stringent evaluations and adjustment of physiological conditions.
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Affiliation(s)
- Maria Hårdstedt
- Department of Immunology, Genetics and Pathology, Clinical Immunology, The Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
- Center for Clinical Research Dalarna-Uppsala University, Falun, Sweden
| | - Susanne Lindblom
- Department of Immunology, Genetics and Pathology, Clinical Immunology, The Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
| | - Jaan Hong
- Department of Immunology, Genetics and Pathology, Clinical Immunology, The Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
| | - Bo Nilsson
- Department of Immunology, Genetics and Pathology, Clinical Immunology, The Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
| | - Olle Korsgren
- Department of Immunology, Genetics and Pathology, Clinical Immunology, The Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
| | - Gunnar Ronquist
- Department of Medical Sciences, Clinical Chemistry, Uppsala University, Uppsala, Sweden
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Öörni K, Rajamäki K, Nguyen SD, Lähdesmäki K, Plihtari R, Lee-Rueckert M, Kovanen PT. Acidification of the intimal fluid: the perfect storm for atherogenesis. J Lipid Res 2014; 56:203-14. [PMID: 25424004 DOI: 10.1194/jlr.r050252] [Citation(s) in RCA: 75] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Atherosclerotic lesions are often hypoxic and exhibit elevated lactate concentrations and local acidification of the extracellular fluids. The acidification may be a consequence of the abundant accumulation of lipid-scavenging macrophages in the lesions. Activated macrophages have a very high energy demand and they preferentially use glycolysis for ATP synthesis even under normoxic conditions, resulting in enhanced local generation and secretion of lactate and protons. In this review, we summarize our current understanding of the effects of acidic extracellular pH on three key players in atherogenesis: macrophages, apoB-containing lipoproteins, and HDL particles. Acidic extracellular pH enhances receptor-mediated phagocytosis and antigen presentation by macrophages and, importantly, triggers the secretion of proinflammatory cytokines from macrophages through activation of the inflammasome pathway. Acidity enhances the proteolytic, lipolytic, and oxidative modifications of LDL and other apoB-containing lipoproteins, and strongly increases their affinity for proteoglycans, and may thus have major effects on their retention and the ensuing cellular responses in the arterial intima. Finally, the decrease in the expression of ABCA1 at acidic pH may compromise cholesterol clearance from atherosclerotic lesions. Taken together, acidic extracellular pH amplifies the proatherogenic and proinflammatory processes involved in atherogenesis.
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Percival SL, McCarty S, Hunt JA, Woods EJ. The effects of pH on wound healing, biofilms, and antimicrobial efficacy. Wound Repair Regen 2014; 22:174-86. [DOI: 10.1111/wrr.12125] [Citation(s) in RCA: 251] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2013] [Accepted: 09/04/2013] [Indexed: 12/21/2022]
Affiliation(s)
- Steven L. Percival
- Research & Development; Scapa Healthcare; Greater Manchester United Kingdom
- Surface Science Research Centre; University of Liverpool; Liverpool United Kingdom
- Clinical Engineering; United Kingdom Centre for Tissue Engineering; Institute of Ageing and Chronic Disease; University of Liverpool; Liverpool United Kingdom
| | - Sara McCarty
- Clinical Engineering; United Kingdom Centre for Tissue Engineering; Institute of Ageing and Chronic Disease; University of Liverpool; Liverpool United Kingdom
| | - John A. Hunt
- Clinical Engineering; United Kingdom Centre for Tissue Engineering; Institute of Ageing and Chronic Disease; University of Liverpool; Liverpool United Kingdom
| | - Emma J. Woods
- Research & Development; Scapa Healthcare; Greater Manchester United Kingdom
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Kareva I, Hahnfeldt P. The emerging "hallmarks" of metabolic reprogramming and immune evasion: distinct or linked? Cancer Res 2013; 73:2737-42. [PMID: 23423980 DOI: 10.1158/0008-5472.can-12-3696] [Citation(s) in RCA: 79] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
The role of the immune system in tumor elimination has been shown to be increasingly ambiguous, as many tumors not only escape recognition by the adaptive immune response but also even prime the immune cells to promote tumor growth. This effect is achieved through a number of mechanisms, which include both direct interference with the cells of the adaptive immune response and indirect immunosuppression achieved through modification of the tumor microenvironment. We propose that through upregulation of glycolysis and the consequent lowering of pH in the tumor microenvironment, tumors can take advantage of a pH control system, already exploited by specific immune cell subpopulations, to gain control of the immune system and suppress both cytotoxic and antigen-presenting cells. This is accomplished through the direct competition of tumor cells with actively proliferating glycolytic immune cells for glucose and indirectly through the creation by the tumor of a microenvironment that interferes with maturation and activation of antigen-presenting cells and naïve cytotoxic T cells. Immunosuppressive properties of an acidic microenvironment in the vicinity of the tumor can thus provide additional benefits for upregulation of glycolysis by tumor cells, suggesting that the two emerging "hallmarks of cancer," altered glucose metabolism and immune suppression, are in fact fundamentally linked.
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Affiliation(s)
- Irina Kareva
- Center of Cancer Systems Biology, St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, Massachusetts 02135, USA
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Oliver KM, Lenihan CR, Bruning U, Cheong A, Laffey JG, McLoughlin P, Taylor CT, Cummins EP. Hypercapnia induces cleavage and nuclear localization of RelB protein, giving insight into CO2 sensing and signaling. J Biol Chem 2012; 287:14004-11. [PMID: 22396550 PMCID: PMC3340129 DOI: 10.1074/jbc.m112.347971] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Carbon dioxide (CO2) is increasingly being appreciated as an intracellular signaling molecule that affects inflammatory and immune responses. Elevated arterial CO2 (hypercapnia) is encountered in a range of clinical conditions, including chronic obstructive pulmonary disease, and as a consequence of therapeutic ventilation in acute respiratory distress syndrome. In patients suffering from this syndrome, therapeutic hypoventilation strategy designed to reduce mechanical damage to the lungs is accompanied by systemic hypercapnia and associated acidosis, which are associated with improved patient outcome. However, the molecular mechanisms underlying the beneficial effects of hypercapnia and the relative contribution of elevated CO2 or associated acidosis to this response remain poorly understood. Recently, a role for the non-canonical NF-κB pathway has been postulated to be important in signaling the cellular transcriptional response to CO2. In this study, we demonstrate that in cells exposed to elevated CO2, the NF-κB family member RelB was cleaved to a lower molecular weight form and translocated to the nucleus in both mouse embryonic fibroblasts and human pulmonary epithelial cells (A549). Furthermore, elevated nuclear RelB was observed in vivo and correlated with hypercapnia-induced protection against LPS-induced lung injury. Hypercapnia-induced RelB processing was sensitive to proteasomal inhibition by MG-132 but was independent of the activity of glycogen synthase kinase 3β or MALT-1, both of which have been previously shown to mediate RelB processing. Taken together, these data demonstrate that RelB is a CO2-sensitive NF-κB family member that may contribute to the beneficial effects of hypercapnia in inflammatory diseases of the lung.
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Affiliation(s)
- Kathryn M Oliver
- School of Medicine and Medical Science, UCD Conway Institute for Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland
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Pascoe MC, Crewther SG, Carey LM, Crewther DP. Inflammation and depression: why poststroke depression may be the norm and not the exception. Int J Stroke 2011; 6:128-35. [PMID: 21371275 DOI: 10.1111/j.1747-4949.2010.00565.x] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Ischaemic stroke often precedes the appearance of clinical depression. Poststroke depression in turn influences the prognostic outcome. In the interest of advancing our understanding of the biological mechanisms underlying the development of poststroke depression, this systematic review explores the immunological processes driving the development of inflammation-related cell death in mood-related brain regions. Particular attention has been paid to cytokine-driven intrinsic apoptosis factors, including intracellular calcium, glutamate excitotoxicity and free radicals that appear in the brain following ischaemic damage and whose presence significantly increases the likelihood of clinically defined depression.
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Affiliation(s)
- Michaela C Pascoe
- Brain Sciences Institute, Swinburne University, Melbourne, Vic, Australia
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11
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Vishvakarma NK, Singh SM. Immunopotentiating effect of proton pump inhibitor pantoprazole in a lymphoma-bearing murine host: Implication in antitumor activation of tumor-associated macrophages. Immunol Lett 2010; 134:83-92. [PMID: 20837061 DOI: 10.1016/j.imlet.2010.09.002] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2010] [Revised: 08/28/2010] [Accepted: 09/05/2010] [Indexed: 01/20/2023]
Abstract
Proton pump inhibitors (PPI) are being considered for antineoplastic therapeutic regimens due to their ability to reverse H(+) homeostasis in tumor microenvironment and induce tumor cell death. In order to explore additional mechanism(s) underlying antitumor action of PPI, the present investigation was undertaken to investigate the effect of a PPI pantoprazole (PPZ) on the activation of tumor-associated macrophages (TAM) to tumoricidal state in a murine model of a transplantable T cell lymphoma of spontaneous origin growing in ascitic form. In vivo administration of PPZ to tumor-bearing mice resulted in an enhanced TAM recruitment in tumor microenvironment with M1 macrophage phenotype and augmented activation of TAM to tumoricidal state along with expression of tumor cytotoxic molecules. The study also demonstrates that TAM activating action of PPZ is of indirect nature mediated via its antitumor activity, reversal of tumor-induced immunosuppression and a consequent shift of cytokine balance in the tumor microenvironment favoring polarization of macrophages to M1 type. The study further shows that adoptive transfer of TAM harvested from PPZ-administered tumor-bearing hosts causes an efficient retardation of tumor growth. Possible mechanisms and significance of these observations with respect to the designing of antitumor therapy using PPI are discussed.
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MESH Headings
- 2-Pyridinylmethylsulfinylbenzimidazoles/pharmacology
- Animals
- Ascitic Fluid/drug effects
- Ascitic Fluid/immunology
- Ascitic Fluid/pathology
- Blotting, Western
- Cell Survival/immunology
- Cells, Cultured
- Coculture Techniques
- Cytotoxicity, Immunologic/immunology
- Female
- Immunotherapy, Adoptive
- Interleukin-1/metabolism
- Lymphoma, T-Cell/immunology
- Lymphoma, T-Cell/pathology
- Lymphoma, T-Cell/therapy
- Macrophage Activation/drug effects
- Macrophage Activation/immunology
- Macrophages/immunology
- Macrophages/metabolism
- Macrophages/transplantation
- Male
- Mice
- Mice, Inbred BALB C
- Microscopy, Fluorescence
- Pantoprazole
- Phagocytosis/immunology
- Proton Pump Inhibitors/pharmacology
- Receptors, Interleukin-2/metabolism
- Tumor Cells, Cultured
- Tumor Microenvironment/drug effects
- Tumor Microenvironment/immunology
- Tumor Necrosis Factor-alpha/metabolism
- Vascular Endothelial Growth Factor A/metabolism
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Fluid Resuscitation and Immunomodulation in the Critically III. Intensive Care Med 2007. [DOI: 10.1007/0-387-35096-9_7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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13
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Fukamachi T, Lao Q, Okamura S, Saito H, Kobayashi H. CTIB (C-Terminus protein of IkappaB-beta): a novel factor required for acidic adaptation. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2006; 584:219-28. [PMID: 16802610 DOI: 10.1007/0-387-34132-3_16] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/10/2023]
Affiliation(s)
- Toshihiko Fukamachi
- Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan
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