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Articles by Stephen Wigmore in JoVE
Other articles by Stephen Wigmore on PubMed
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Febrile-range Temperature but Not Heat Shock Augments the Acute Phase Response to Interleukin-6 in Human Hepatoma Cells
American Journal of Physiology. Gastrointestinal and Liver Physiology.
May, 2006 |
Pubmed ID: 16339299 The relationship between the stress protein response and the acute phase response (APPR) was studied in human hepatoma cells to investigate the hierarchy of regulation of these survival responses. Huh-7 cells were subjected to heat treatment (febrile-range temperature 40 degrees C or heat shock 43 degrees C) followed by recovery at 37 degrees C in the presence or absence of IL-6 given either before or after heat treatment. The effects on total, fractional, and acute phase protein synthesis were then analyzed by metabolic labeling, ELISA, real-time PCR, Northern blot analysis, and activation of an alpha(1)-antitrypsin reporter plasmid. Cell energetics were studied under the same conditions using an index of mitochondrial activity and measurement of cellular ATP levels. Febrile-range temperature (40 degrees C) augmented acute phase protein production when cells had been pretreated with IL-6. Pretreatment of cells with IL-6 also prevented heat shock-induced suppression of alpha(1)-antichymotrypsin (ACT) but not transferrin. mRNA expression of ACT and alpha(1)-antitrypsin reporter activation studies was consistent with transcriptional regulation of these proteins. Expression of mRNA transcripts for transferrin was increased despite protein expression being reduced by heat shock. The effects of heat shock on acute phase protein synthesis can be modified by preincubation with IL-6, whereas addition of this ligand after heat treatment has no effect on the suppressive effect of heat on the APPR. The mechanism of this action appears to be transcriptionally regulated in the case of ACT, but in the case of transferrin, it may be mediated by another process such as posttranslational modification.
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Curcumin Induces Heme Oxygenase 1 Through Generation of Reactive Oxygen Species, P38 Activation and Phosphatase Inhibition
International Journal of Molecular Medicine.
Jan, 2007 |
Pubmed ID: 17143561 Curcumin is a naturally occurring compound which is known to induce heme oxygenase 1 (HO-1), although the underlying mechanism has not been fully elucidated. This study investigates in detail the mechanism of HO-1 induction by curcumin in human hepatoma cells. There was increasing toxicity of curcumin at concentrations higher than 10 microM. Curcumin was found to induce HO-1 at doses of 10 to 25 microM. At both non-toxic and toxic doses, HO-1 induction was found to correlate with production of reactive oxygen species (ROS), suggesting a causative relationship. This was reinforced by the finding that pretreatment with the antioxidants N-acetylcysteine, vitamin E and catalase prevented HO-1 induction by curcumin. ROS production appeared to be mitochondrial in origin, and curcumin treatment resulted in depolarisation of the mitochondrial membrane potential. Nrf2 was induced by curcumin treatment, which was also partly ROS dependent. Using siRNA, Nrf2 was demonstrated to contribute to HO-1 induction. A panel of kinase inhibitors was used to examine the contribution of MAP kinases to the induction of HO-1 by curcumin. PKC and p38 MAPK activity are required for full induction of HO-1. Furthermore, curcumin also inhibited protein phosphatase activity. In conclusion, curcumin treatment results in ROS generation, activation of Nrf2 and MAP kinases and the inhibition of phosphatase activity in hepatocytes, and when curcumin is not administered in toxic doses, these multiple pathways converge to induce HO-1.
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Immune-mediated Liver Injury
Seminars in Liver Disease.
Nov, 2007 |
Pubmed ID: 17979072 Diseases with different pathogeneses share common pathways of immune-mediated injury. Autoreactive T cells destroy hepatocytes or cholangiocytes in autoimmune disease and virus-specific T cells destroy infected hepatocytes in viral hepatitis. In these conditions, antigen-specific mechanisms can be implicated but immune-mediated injury is central to diseases where there is a less-defined role for specific antigens. In all these diseases, "bystander cells" activated by the local microenvironment rather than a specific antigen are major players and amplify effector responses by recruiting natural killer and natural killer T cells, macrophages, neutrophils, eosinophils, and even platelets. Immune-mediated liver injury is driven by repeated cycles of inflammation and damage sustained by continuing recruitment, retention, and survival of effector leukocytes within the inflamed liver. These processes depend on complex interactions involving epithelial cells, stromal cells, and leukocytes shaped by the local cytokine microenvironment. Understanding these interactions will elucidate the pathogenesis of liver disease and suggest new therapies.
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Polyarteritis Nodosa, Presenting As Life-threatening Gastrointestinal Hemorrhage in a Liver Transplant Recipient
Liver Transplantation : Official Publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society.
Feb, 2008 |
Pubmed ID: 18236387 This unique case reports the first recorded episode in the medical literature of vasculitis post-liver transplantation, presenting as life-threatening gastrointestinal hemorrhage. A 52-year-old Caucasian woman underwent orthotopic liver transplantation (OLT) for autoimmune cirrhosis complicated by hepatoma and portal vein thrombosis. Late hepatic artery thrombosis led to a second liver graft. Following recovery from an episode of acute rejection, the patient presented with large volume hematemesis, melena, and hemochezia (passage of fresh blood from the rectum). Following upper and lower gastrointestinal endoscopy and surgery, angiography illustrated the presence of polyarteritis nodosa (PAN), which was successfully treated with high-dose steroid therapy. Gastrointestinal hemorrhage is an unusual presentation of vasculitis, especially PAN. The occurrence of this phenomenon post-OLT, in the presence of immunosuppression is previously unreported.
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Heat Shock Protein 90-binding Agents Protect Renal Cells from Oxidative Stress and Reduce Kidney Ischemia-reperfusion Injury
American Journal of Physiology. Renal Physiology.
Aug, 2008 |
Pubmed ID: 18562631 Heat shock proteins (Hsps) are protective in models of transplantation, yet practical strategies to upregulate them remain elusive. The heat shock protein 90-binding agent (HBA) geldanamycin and its analogs (17-AAG and 17-DMAG) are known to upregulate Hsps and confer cellular protection but have not been investigated in a model relevant to transplantation. We examined the ability of HBAs to upregulate Hsp expression and confer protection in renal adenocarcinoma (ACHN) cells in vitro and in a mouse model of kidney ischemia-reperfusion (I/R) injury. Hsp70 gene expression was increased 30-40 times in ACHN cells treated with HBAs, and trimerization and DNA binding of heat shock transcription factor-1 (HSF1) were demonstrated. A three- and twofold increase in Hsp70 and Hsp27 protein expression, respectively, was found in ACHN cells treated with HBAs. HBAs protected ACHN cells from an H2O2-mediated oxidative stress, and HSF1 short interfering RNA was found to abrogate HBA-mediated Hsp induction and protection. In vivo, Hsp70 was upregulated in the kidneys, liver, lungs, and heart of HBA-treated mice. This was associated with a functional and morphological renal protection from I/R injury. Therefore, HBAs mediate upregulation of protective Hsps in mouse kidneys which are associated with reduced I/R injury and may be useful in reducing transplant-associated kidney injury.
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The Gut Does Not Contribute to Systemic Ammonia Release in Humans Without Portosystemic Shunting
American Journal of Physiology. Gastrointestinal and Liver Physiology.
Oct, 2008 |
Pubmed ID: 18703642 The gut is classically seen as the main source of circulating ammonia. However, the contribution of the intestines to systemic ammonia production may be limited by hepatic extraction of portal-derived ammonia. Recent data suggest that the kidney may be more important than the gut for systemic ammonia production. The aim of this study was to quantify the role of the kidney, intestines, and liver in interorgan ammonia trafficking in humans with normal liver function. In addition, we studied changes in interorgan nitrogen metabolism caused by major hepatectomy. From 21 patients undergoing surgery, blood was sampled from the portal, hepatic, and renal veins to assess intestinal, hepatic, and renal ammonia metabolism. In seven cases, blood sampling was repeated after major hepatectomy. At steady state during surgery, intestinal ammonia release was equaled by hepatic ammonia uptake, precluding significant systemic release of intestinal-derived ammonia. In contrast, the kidneys released ammonia to the systemic circulation. Major hepatectomy led to increased concentrations of ammonia and amino acids in the systemic circulation. However, transsplanchnic concentration gradients after major hepatectomy were similar to baseline values, indicating the rapid institution of a new metabolic equilibrium. In conclusion, since hepatic ammonia uptake exactly equals intestinal ammonia release, the splanchnic area, and hence the gut, probably does not contribute significantly to systemic ammonia release. After major hepatectomy, hepatic ammonia clearance is well preserved, probably related to higher circulating ammonia concentrations.
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The Utilization of Liver Transplantation in the Management of Acute Liver Failure: Comparison Between Acetaminophen and Non-acetaminophen Etiologies
Liver Transplantation : Official Publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society.
Jun, 2009 |
Pubmed ID: 19479803 Liver transplantation (LT) may be life-saving in severe acute liver failure (ALF). The aim of this study was to compare the utilization of LT in acetaminophen and non-acetaminophen ALF. Between 1992 and 2006, 469 patients with ALF were admitted, and 104 underwent LT. Acetaminophen was the most common etiology, but LT proceeded more frequently in the non-acetaminophen cohort (acetaminophen: 45/326 patients received LT, 13.8%; non-acetaminophen: 59/143 patients received LT, 41.3%; P < 0.01). A retrospective analysis of the individual steps in the management of patients revealed more ALF patients in the non-acetaminophen cohort fulfilled the King's College Hospital poor prognostic criteria (non-acetaminophen: 91/143, 63.6%; acetaminophen: 165/326, 50.6%; P < 0.01), more patients had contraindications to LT in the acetaminophen cohort (acetaminophen: 99/165, 60%; non-acetaminophen: 21/91, 23.1%; P < 0.01), and survival on the LT waiting list was reduced in the acetaminophen cohort (acetaminophen: 45/66, 68.2%; non-acetaminophen: 59/70, 84.3%; P < 0.05). Post-LT survival was similar in the 2 groups. An analysis of cohorts admitted in 1993-1996 and 2002-2005 revealed that LT proceeded less commonly in acetaminophen ALF in the later cohort (1993-1996: 16/99 LT, 16.2%; 2002-2005: 4/81 LT, 5%; P < 0.01) in comparison with the non-acetaminophen cohort, in which transplantation proceeded more commonly in the later cohort (1993-1996: 11/34 LT, 32.4%; 2002-2005: 24/49 patients, 49.0%; P < 0.01). This was due to an increase in the number of patients with psychiatric contraindications to transplantation (predominantly resistant and severe alcohol dependence). In conclusion, at all decision steps between admission and emergency LT, LT is favored in non-acetaminophen patients, and nonoperative management is favored in acetaminophen ALF patients.
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The Management of an Accessory or Replaced Right Hepatic Artery During Multiorgan Retrieval: Results of an Angiographic Study
Liver Transplantation : Official Publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society.
Jun, 2010 |
Pubmed ID: 20517908 In the presence of anatomical variants such as an accessory or replaced (A/R) right hepatic artery (RHA), a conflict of interest can arise during organ retrieval between liver and pancreatic teams. This angiographic study examines the anatomy of the inferior pancreaticoduodenal artery (IPDA), its relation to the A/R RHA, and the implications for the use of livers and pancreases from multiorgan donors. Gastrointestinal angiograms performed in our institution for unrelated indications were reviewed, and the relevant arteries, their diameters, the distances between origins, the time at which variants were found, and the blood supply to relevant solid organs were recorded. A review of 122 angiograms identified 100 patients in whom both the superior mesenteric artery (SMA) and the celiac axis were cannulated synchronously; these patients composed our study cohort. The IPDA was identified in 95% of the cases. There were 8 patients with a replaced RHA and 4 with an accessory RHA. In all 12, the IPDA had an SMA origin; 3 of these shared a common origin with the A/R RHA on the SMA. In the rest, the mean distance between them was 29 mm (range = 17.8-48.3 mm). All anomalous arteries found were segmental vessels. In conclusion, the A/R RHA incidence in our series was 12%, and no case had an IPDA originating from the A/R RHA. Separate accessory RHA and IPDA origins potentially allow an uncompromised accessory RHA (with its Carrel patch) without risk of prejudice to the pancreatic graft if retrieval is accurately performed. Rarely (3%), there is a common origin between the A/R RHA and the IPDA, and back-bench reconstruction would be required to allow the use of both the liver and pancreas.
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