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Bojic D, Aujla T, Sugihara J, Wong A, Keshavjee S, Liu M. Thyroid hormone protects human lung epithelial cells from cold preservation and warm reperfusion-induced injury. J Transl Med 2024; 22:221. [PMID: 38429788 PMCID: PMC10908176 DOI: 10.1186/s12967-024-05024-x] [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: 12/11/2023] [Accepted: 02/23/2024] [Indexed: 03/03/2024] Open
Abstract
BACKGROUND Cellular stress associated with static-cold storage (SCS) and warm reperfusion of donor lungs can contribute to ischemia-reperfusion (IR) injury during transplantation. Adding cytoprotective agents to the preservation solution may be conducive to reducing graft deterioration and improving post-transplant outcomes. METHODS SCS and warm reperfusion were simulated in human lung epithelial cells (BEAS-2B) by exposing cells to low potassium dextran glucose solution at 4 °C for different periods and then switching back to serum-containing culture medium at 37 °C. Transcriptomic analysis was used to explore potential cytoprotective agents. Based on its results, cell viability, caspase activity, cell morphology, mitochondrial function, and inflammatory gene expression were examined under simulated IR conditions with or without thyroid hormones (THs). RESULTS After 18 h SCS followed by 2 h warm reperfusion, genes related to inflammation and cell death were upregulated, and genes related to protein synthesis and metabolism were downregulated in BEAS-2B cells, which closely mirrored gene profiles found in thyroid glands of mice with congenital hypothyroidism. The addition of THs (T3 or T4) to the preservation solution increases cell viability, inhibits activation of caspase 3, 8 and 9, preserves cell morphology, enhances mitochondrial membrane potential, reduces mitochondrial superoxide production, and suppresses inflammatory gene expression. CONCLUSION Adding THs to lung preservation solutions may protect lung cells during SCS by promoting mitochondrial function, reducing apoptosis, and inhibiting pro-inflammatory pathways. Further in vivo testing is warranted to determine the potential clinical application of adding THs as therapeutics in lung preservation solutions.
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Affiliation(s)
- Dejan Bojic
- Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
- Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - Tanroop Aujla
- Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
- Department of Physiology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - Junichi Sugihara
- Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
| | - Aaron Wong
- Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
- Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - Shaf Keshavjee
- Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
- Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada
- Department of Surgery, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - Mingyao Liu
- Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada.
- Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
- Department of Physiology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
- Department of Surgery, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
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Mourouzis I, Apostolaki V, Trikas A, Kokkinos L, Alexandrou N, Avdikou M, Giannoulopoulou M, Vassi A, Tseti I, Pantos C. The Potential of Thyroid Hormone Therapy in Severe COVID-19: Rationale and Preliminary Evidence. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2022; 19:ijerph19138063. [PMID: 35805716 PMCID: PMC9265958 DOI: 10.3390/ijerph19138063] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Revised: 06/27/2022] [Accepted: 06/27/2022] [Indexed: 02/01/2023]
Abstract
Tissue hypoxia is one of the main pathophysiologic mechanisms in sepsis and particularly in COVID-19. Microvascular dysfunction, endothelialitis and alterations in red blood cell hemorheology are all implicated in severe COVID-19 hypoxia and multiorgan dysfunction. Tissue hypoxia results in tissue injury and remodeling with re-emergence of fetal programming via hypoxia-inducible factor-1α (HIF-1a)-dependent and -independent pathways. In this context, thyroid hormone (TH), a critical regulator of organ maturation, may be of relevance in preventing fetal-like hypoxia-induced remodeling in COVID-19 sepsis. Acute triiodothyronine (T3) treatment can prevent cardiac remodeling and improve recovery of function in clinical settings of hypoxic injury as acute myocardial infarction and by-pass cardiac surgery. Furthermore, T3 administration prevents tissue hypoxia in experimental sepsis. On the basis of this evidence, the use of T3 treatment was proposed for ICU (Intensive Care Unit) COVID-19 patients (Thy-Support, NCT04348513). The rationale for T3 therapy in severe COVID-19 and preliminary experimental and clinical evidence are discussed in this review.
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Affiliation(s)
- Iordanis Mourouzis
- Department of Pharmacology, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Ave., Goudi, 11527 Athens, Greece; (I.M.); (V.A.); (A.T.); (I.T.)
| | - Vassiliki Apostolaki
- Department of Pharmacology, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Ave., Goudi, 11527 Athens, Greece; (I.M.); (V.A.); (A.T.); (I.T.)
| | - Athanasios Trikas
- Department of Pharmacology, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Ave., Goudi, 11527 Athens, Greece; (I.M.); (V.A.); (A.T.); (I.T.)
| | - Leonidas Kokkinos
- Department of Anesthesiology, ELPIS General Hospital of Athens, 11522 Athens, Greece; (L.K.); (N.A.); (M.A.); (M.G.); (A.V.)
| | - Natassa Alexandrou
- Department of Anesthesiology, ELPIS General Hospital of Athens, 11522 Athens, Greece; (L.K.); (N.A.); (M.A.); (M.G.); (A.V.)
| | - Maria Avdikou
- Department of Anesthesiology, ELPIS General Hospital of Athens, 11522 Athens, Greece; (L.K.); (N.A.); (M.A.); (M.G.); (A.V.)
| | - Myrto Giannoulopoulou
- Department of Anesthesiology, ELPIS General Hospital of Athens, 11522 Athens, Greece; (L.K.); (N.A.); (M.A.); (M.G.); (A.V.)
| | - Aimilia Vassi
- Department of Anesthesiology, ELPIS General Hospital of Athens, 11522 Athens, Greece; (L.K.); (N.A.); (M.A.); (M.G.); (A.V.)
| | - Ioulia Tseti
- Department of Pharmacology, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Ave., Goudi, 11527 Athens, Greece; (I.M.); (V.A.); (A.T.); (I.T.)
| | - Constantinos Pantos
- Department of Pharmacology, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Ave., Goudi, 11527 Athens, Greece; (I.M.); (V.A.); (A.T.); (I.T.)
- Correspondence: ; Tel.: +30-210-746-2560; Fax: +30-210-746-2562
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Effects of Thyroid Hormone on Tissue Hypoxia: Relevance to Sepsis Therapy. J Clin Med 2021; 10:jcm10245855. [PMID: 34945151 PMCID: PMC8703810 DOI: 10.3390/jcm10245855] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2021] [Revised: 11/29/2021] [Accepted: 12/10/2021] [Indexed: 01/14/2023] Open
Abstract
Tissue hypoxia occurs in various conditions such as myocardial or brain ischemia and infarction, sepsis, and trauma, and induces cellular damage and tissue remodeling with recapitulation of fetal-like reprogramming, which eventually results in organ failure. Analogies seem to exist between the damaged hypoxic and developing organs, indicating that a regulatory network which drives embryonic organ development may control aspects of heart (or tissue) repair. In this context, thyroid hormone (TH), which is a critical regulator of organ maturation, physiologic angiogenesis, and mitochondrial biogenesis during fetal development, may be of important physiological relevance upon stress (hypoxia)-induced fetal reprogramming. TH signaling has been implicated in hypoxic tissue remodeling after myocardial infarction and T3 prevents remodeling of the postinfarcted heart. Similarly, preliminary experimental evidence suggests that T3 can prevent early tissue hypoxia during sepsis with important physiological consequences. Thus, based on common pathways between different paradigms, we propose a possible role of TH in tissue hypoxia after sepsis with the potential to reduce secondary organ failure.
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Peters J, Roumeliotis S, Mertens PR, Liakopoulos V. Thyroid hormone status in patients with impaired kidney function. Int Urol Nephrol 2021; 53:2349-2358. [PMID: 33682051 DOI: 10.1007/s11255-021-02800-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Accepted: 02/08/2021] [Indexed: 11/24/2022]
Abstract
PURPOSE We aimed to investigate the prevalence of thyroid hormone abnormalities and the relationship between free triiodothyronine (fT3), thyroid stimulating hormone (TSH) and free thyroxine (fT4) serum levels with kidney function and proteinuria in 4108 subsequent patients admitted to a Nephrology Clinic at a tertiary Medical Centre. METHODS All patients were categorized based on their estimated glomerular filtration rate (eGFR) as follows: normal-eGFR ≥ 60 ml/min, mild kidney impairment-30 ≤ eGFR < 60 ml/min, and severe kidney impairment-eGFR < 30 ml/min. RESULTS Subjects with normal eGFR presented a laboratory constellation of hypothyroidism in 3.38% and "low-T3 syndrome" in 8.28%, while subjects with severe kidney impairment were diagnosed with hypothyroidism in 2.82% and "low-T3 syndrome" in 22.9%. Multivariate regression analysis showed that eGFR was a strong independent predictor of serum fT3 levels in patients with eGFR < 60 ml/min. Impaired kidney function was associated with low fT4 and fT3 but not TSH. Our findings showed an inverse correlation of fT3 and fT4 levels and proteinuria range. FT4 inversely correlated with the extent of proteinuria in all subgroups of patients. In contrast, the inverse correlation of fT3 serum levels and proteinuria disappeared in patients with eGFR < 60 ml/min. CONCLUSION In a large cohort of inpatients, the prevalence of low-T3 syndrome was 2.5 times higher in patients with advanced kidney disease, compared to those with normal kidney function. In advanced CKD, both eGFR and proteinuria were strongly correlated with thyroid hormones. Therefore, close screening of the "thyroid profile" in patients with any stage of CKD, especially to those with proteinuria, might be warranted.
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Affiliation(s)
- Juliane Peters
- Clinic of Nephrology and Hypertension, Diabetes and Endocrinology, Otto-Von-Guericke University Magdeburg, Magdeburg, Germany
| | - Stefanos Roumeliotis
- Division of Nephrology and Hypertension, 1st Department of Internal Medicine, School of Medicine, AHEPA Hospital, Aristotle University of Thessaloniki, St. Kyriakidi 1, 54636, Thessaloniki, Greece
| | - Peter R Mertens
- Clinic of Nephrology and Hypertension, Diabetes and Endocrinology, Otto-Von-Guericke University Magdeburg, Magdeburg, Germany
| | - Vassilios Liakopoulos
- Division of Nephrology and Hypertension, 1st Department of Internal Medicine, School of Medicine, AHEPA Hospital, Aristotle University of Thessaloniki, St. Kyriakidi 1, 54636, Thessaloniki, Greece.
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El Agaty SM. Triiodothyronine attenuates the progression of renal injury in a rat model of chronic kidney disease. Can J Physiol Pharmacol 2018; 96:603-610. [PMID: 29406830 DOI: 10.1139/cjpp-2017-0252] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
This study was designed to investigate whether and how triiodothyronine (T3) affects renal function in an experimental model of chronic kidney disease. Twenty-four female rats were divided into the following groups: sham-operated control group (n = 8), 5/6 nephrectomized group (Nx, n = 8), and 5/6 nephrectomized group treated with T3 for 2 weeks (T3-Nx, n = 8). T3 administration significantly decreased serum levels of urea, creatinine, tumour necrosis factorα, and interleukin-6 compared with serum levels in the Nx group. The levels of malondialdehyde, transforming growth factor β, fibronectin, and collagen IV, as well as the expression of inducible nitric oxide synthase, nuclear factor κB, poly(ADP-ribose) polymerase, caspase-3, and Bax were all significantly decreased, though not normalized, in the remnant kidney of rats in the T3-Nx group compared with Nx rats. Glutathione, heme oxygenase-1 levels, as well as endothelial nitric oxide synthase expression were increased in the remnant kidney of the T3-Nx group. Histological studies revealed focal necrosis of renal tubules associated with inflammatory cell infiltration and fibrosis in the Nx group. These changes were alleviated in T3-Nx rats. This study showed that T3 administration attenuated the clinical and histological signs of renal injury in 5/6 nephrectomized rats by mitigating renal oxidative stress, inflammation, apoptosis, and fibrosis.
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Affiliation(s)
- Sahar M El Agaty
- Physiology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
- Physiology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
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Effects of the Administration of Thyroid Hormones in Cases of Hepatic Ischemia and Reperfusion Injury. Int Surg 2018. [DOI: 10.9738/intsurg-d-17-00108.1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Objective:
Hepatic ischemia and reperfusion (IR) injury is the most important cause of cellular death and hepatic dysfunction following liver transplantation and resection. Our aim in this study is to reveal the early stage effects of thyroid hormone levels on hepatic IR injury that effectively act on cellular homeostasis.
Methods:
Forty-six male Wistar albino rats were divided into 6 groups as follows: euthyroid-sham (n = 8), euthyroid with IR injury (n = 8), hyperthyroid-sham (n = 7), hyperthyroid with IR injury (n = 7), hypothyroid-sham (n = 8), and hypothyroid with IR injury (n = 8). After 90 minutes of partial hepatic ischemia, 90 minutes of reperfusion was applied. Liver tissue malondialdehyde (MDA) levels, catalase (CAT), glutathion peroxidase, and superoxide dismutase (SOD) enzyme activities were measured. Hepatic tissue was immunohistochemically analyzed.
Results:
MDA levels of liver tissue were analyzed, and hepatic MDA levels in the hyper-IR group were found to be significantly lower (P = 0.002) than those of the hypo-IR and euthyroid-IR groups. Serum CAT levels did not differ between control groups, whereas CAT values in the hyper-IR group were detected to be significantly lower than in the euthyroid-IR and hypothyroid-IR groups (P = 0.003). However, levels of SOD and glutathione peroxidase (GPX) were not affected by the functional state of the thyroid. No statistically significant difference was seen in the results of the histopathologic evaluation and immunohistochemical staining of the liver tissue.
Conclusion:
The administration of thyroid hormone within a short time before IR injury may have protective effects.
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Orman S, Karaman K, Basok BI, Kisa U, Ceyran AB, Bostanci EB. Effects of Thyroid Hormone Therapy on Cut-Surface Healing of the Remnant Stomach with Short-Term Weight Loss Alterations after Sleeve Gastrectomy. J INVEST SURG 2017. [PMID: 28635514 DOI: 10.1080/08941939.2017.1280566] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
BACKGROUND The hypothalamic-pituitary-tyhroid axis is directly affected by drastic changes in energy stores. The aim of the present study was to determine the effects of triiodothyronine (T3) treatment on cut-surface healing of remnant stomach with weight loss alterations after sleeve gastrectomy (SG). METHODS Thirty male Wistar Albino rats were divided into three groups: sham (n = 6), control (n = 12), and experimental (n = 12). Control and experimental group rats underwent sleeve gastrectomy. Experimental group rats received a single dose of T3 (400 mg/100 g) on the first postoperative day whereas control group rats received 0.9% NaCl. All rats were sacrificed on the seventh postoperative day. RESULTS In the group of rats receiving T3, levels of FT3 were significantly higher and that of FT4 were significantly lower compared with both the control and sham group rats (p <.05). No significant difference was found between control and T3 group rats in terms of weight loss (p >.05). Microscopic examination of the cut surface of remnant stomach in the control group rats revealed significantly more severe tissue necrosis, edema, and disruption of mucosal epithelium than in the T3 group rats (p <.05). On the other hand, bridging of the submucosal and muscular layers, tissue granulation, fibroblast accumulation, neoangiogenesis, and collagen deposition in the T3 group rats were significantly higher than in the control group rats (p <.05). CONCLUSIONS Sleeve gastrectomy did not significantly alter thyroid hormone levels in short term. T3 hormone therapy seems to deliver constructive therapeutic effects for wound healing while causing no adverse effect on weight reduction.
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Affiliation(s)
- Suleyman Orman
- a Department of Gastroenterological Surgery , Istanbul Medeniyet University Goztepe Teaching and Research Hospital , Istanbul , Turkey
| | - Kerem Karaman
- b Department of General Surgery , Sakarya University Faculty of Medicine , Sakarya , Turkey
| | - Banu Isbilen Basok
- c Department of Biochemistry , Istanbul Medeniyet University Goztepe Teaching and Research Hospital , Istanbul , Turkey
| | - Ucler Kisa
- d Department of Biochemistry , Kirikkale University Faculty of Medicine , Kirikkale , Turkey
| | - Ayse Bahar Ceyran
- e Department of Pathology , Istanbul Medeniyet University Goztepe Teaching and Research Hospital , Istanbul , Turkey
| | - Erdal Birol Bostanci
- b Department of General Surgery , Sakarya University Faculty of Medicine , Sakarya , Turkey
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Thyroid hormone in the frontier of cell protection, survival and functional recovery. Expert Rev Mol Med 2015; 17:e10. [DOI: 10.1017/erm.2015.8] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Thyroid hormone (TH) exerts important actions on cellular energy metabolism, accelerating O2consumption with consequent reactive oxygen species (ROS) generation and redox signalling affording cell protection, a response that is contributed by redox-independent mechanisms. These processes underlie genomic and non-genomic pathways, which are integrated and exhibit hierarchical organisation. ROS production led to the activation of the redox-sensitive transcription factors nuclear factor-κB, signal transducer and activator of transcription 3, activating protein 1 and nuclear factor erythroid 2-related factor 2, promoting cell protection and survival by TH. These features involve enhancement in the homeostatic potential including antioxidant, antiapoptotic, antiinflammatory and cell proliferation responses, besides higher detoxification capabilities and energy supply through AMP-activated protein kinase upregulation. The above aspects constitute the molecular basis for TH-induced preconditioning of the liver that exerts protection against ischemia-reperfusion injury, a strategy also observed in extrahepatic organs of experimental animals and with other types of injury, which awaits application in the clinical setting. Noteworthy, re-adjusting TH to normal levels results in several beneficial effects; for example, it lengthens the cold storage time of organs for transplantation from brain-dead donors; allows a superior neurological outcome in infants of <28 weeks of gestation; reduces the cognitive side-effects of lithium and improves electroconvulsive therapy in patients with bipolar disorders.
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Videla LA, Fernández V, Cornejo P, Vargas R, Morales P, Ceballo J, Fischer A, Escudero N, Escobar O. T 3-induced liver AMP-activated protein kinase signaling: Redox dependency and upregulation of downstream targets. World J Gastroenterol 2014; 20:17416-17425. [PMID: 25516653 PMCID: PMC4265600 DOI: 10.3748/wjg.v20.i46.17416] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2014] [Revised: 06/06/2014] [Accepted: 07/30/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the redox dependency and promotion of downstream targets in thyroid hormone (T3)-induced AMP-activated protein kinase (AMPK) signaling as cellular energy sensor to limit metabolic stresses in the liver.
METHODS: Fed male Sprague-Dawley rats were given a single ip dose of 0.1 mg T3/kg or T3 vehicle (NaOH 0.1 N; controls) and studied at 8 or 24 h after treatment. Separate groups of animals received 500 mg N-acetylcysteine (NAC)/kg or saline ip 30 min prior T3. Measurements included plasma and liver 8-isoprostane and serum β-hydroxybutyrate levels (ELISA), hepatic levels of mRNAs (qPCR), proteins (Western blot), and phosphorylated AMPK (ELISA).
RESULTS: T3 upregulates AMPK signaling, including the upstream kinases Ca2+-calmodulin-dependent protein kinase kinase-β and transforming growth factor-β-activated kinase-1, with T3-induced reactive oxygen species having a causal role due to its suppression by pretreatment with the antioxidant NAC. Accordingly, AMPK targets acetyl-CoA carboxylase and cyclic AMP response element binding protein are phosphorylated, with the concomitant carnitine palmitoyltransferase-1α (CPT-1α) activation and higher expression of peroxisome proliferator-activated receptor-γ co-activator-1α and that of the fatty acid oxidation (FAO)-related enzymes CPT-1α, acyl-CoA oxidase 1, and acyl-CoA thioesterase 2. Under these conditions, T3 induced a significant increase in the serum levels of β-hydroxybutyrate, a surrogate marker for hepatic FAO.
CONCLUSION: T3 administration activates liver AMPK signaling in a redox-dependent manner, leading to FAO enhancement as evidenced by the consequent ketogenic response, which may constitute a key molecular mechanism regulating energy dynamics to support T3 preconditioning against ischemia-reperfusion injury.
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Kim SM, Kim SW, Jung YJ, Min SI, Min SK, Kim SJ, Ha J. Preconditioning with thyroid hormone (3,5,3-triiodothyronine) prevents renal ischemia-reperfusion injury in mice. Surgery 2014; 155:554-61. [DOI: 10.1016/j.surg.2013.10.005] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2013] [Accepted: 10/07/2013] [Indexed: 11/16/2022]
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Crawford RS, Albadawi H, Robaldo A, Peck MA, Abularrage CJ, Yoo HJ, Lamuraglia GM, Watkins MT. Divergent systemic and local inflammatory response to hind limb demand ischemia in wild-type and ApoE-/- mice. J Surg Res 2013; 183:952-62. [PMID: 23528286 DOI: 10.1016/j.jss.2013.02.042] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2013] [Revised: 02/18/2013] [Accepted: 02/20/2013] [Indexed: 12/18/2022]
Abstract
BACKGROUND We designed studies to determine whether the ApoE-/- phenotype modulates the local skeletal muscle and systemic inflammatory (plasma) responses to lower extremity demand ischemia. The ApoE-/- phenotype is an experimental model for atherosclerosis in humans. METHODS Aged female ApoE-/- and C57BL6 mice underwent femoral artery ligation, then were divided into sedentary and demand ischemia (exercise) groups on day 14. We assessed baseline and postexercise limb perfusion and hind limb function. On day 14, animals in the demand ischemia group underwent daily treadmill exercise through day 28. Sedentary mice were not exercised. On day 28, we harvested plasma and skeletal muscle from ischemic limbs from sedentary and exercised mice. We assayed muscle for angiogenic and proinflammatory proteins, markers of skeletal muscle regeneration, and evidence of skeletal muscle fiber maturation. RESULTS Hind limb ischemia was similar in ApoE-/- and C57 mice before the onset of exercise. Under sedentary conditions, plasma vascular endothelial cell growth factor and interleukin-6, but not keratinocyte chemoattractant factor (KC) or macrophage inflammatory protein-2 (MIP-2), were higher in ApoE (P < 0.0001). After exercise, plasma levels of vascular endothelial cell growth factor, KC, and MIP-2, but not IL-6, were lower in ApoE (P < 0.004). The cytokines KC and MIP-2 in muscle were greater in exercised ApoE-/- mice compared with C57BL6 mice (P = 0.01). Increased poly-ADP-ribose activity and mature muscle regeneration were associated with demand ischemia in the C57BL6 mice, compared with the ApoE-/- mice (P = 0.01). CONCLUSIONS Demand limb ischemia in the ApoE-/- phenotype exacerbated the expression of select systemic cytokines in plasma and blunted indices of muscle regeneration.
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Affiliation(s)
- Robert S Crawford
- Division of Vascular and Endovascular Surgery, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
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Thyroid hormone and tissue repair: new tricks for an old hormone? J Thyroid Res 2013; 2013:312104. [PMID: 23533950 PMCID: PMC3596953 DOI: 10.1155/2013/312104] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2012] [Accepted: 01/26/2013] [Indexed: 12/11/2022] Open
Abstract
Although the role of thyroid hormone during embryonic development has long been recognized, its role later in adult life remains largely unknown. However, several lines of evidence show that thyroid hormone is crucial to the response to stress and to poststress recovery and repair. Along this line, TH administration in almost every tissue resulted in tissue repair after various injuries including ischemia, chemical insults, induction of inflammation, or exposure to radiation. This novel action may be of therapeutic relevance, and thyroid hormone may constitute a paradigm for pharmacologic-induced tissue repair/regeneration.
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Preservation strategies to reduce ischemic injury in kidney transplantation: pharmacological and genetic approaches. Curr Opin Organ Transplant 2011; 16:180-7. [PMID: 21415820 DOI: 10.1097/mot.0b013e3283446b1d] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
PURPOSE OF REVIEW In the current graft shortage, it is paramount to improve the quality of transplanted organs. Organ preservation represents an underused therapeutic window with great potential to reduce ischaemia-reperfusion injury (IRI) and improve graft quality. Herein, we review strategies using this window as well as other promising work targeting IRI pathways using pharmacological treatments and gene therapy. RECENT FINDINGS We highlight studies using molecules administered during kidney preservation to target key components of IRI such as inflammation, oxidative stress, mitochondrial activity and the coagulation pathway. We further expose recent studies of gene therapy directed against inflammation or apoptosis during cold storage. Other pathways with potential therapeutic molecules are cited. SUMMARY The use of cold preservation as a therapeutic window to deliver pharmacological or gene therapy treatments can significantly improve both short-term and long-term graft outcomes. Even if human gene therapy remains hampered by the quantity of agent needed and the potential harmfulness of the vector, it clearly offers a wide array of possibilities for the future. Although gene therapy is still too immature, we expose pharmacological strategies which can readily be applied to the clinic and improve both transplantation success rates and the patients' quality of life.
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