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- Lund, M, et al.
(författare)
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Nitric oxide and endothelin-1 release after one-lung ventilation during thoracoabdominal esophagectomy.
- 2013
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Ingår i: Diseases of the esophagus. - : Oxford University Press (OUP). - 1120-8694. ; 26:8, s. 853-858
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Tidskriftsartikel (refereegranskat)abstract
- One-lung ventilation (OLV) is applied during esophagectomy to improve exposure during the thoracic part of the operation. Collapse of lung tissue, shunting of pulmonary blood flow, and changes in alveolar oxygenation during and after OLV may possibly induce an ischemia-reperfusion response in the lung, which may affect the pulmonary endothelium. Such a reaction might thereby contribute to the frequently occurring respiratory complications among these patients. In this small trial, 30 patients were randomized to either OLV (n= 16) or two-lung ventilation (TLV, n= 14) during esophagectomy. Central venous and arterial plasma samples were taken before and after OLV/TLV for analysis of nitrite and a metabolite of nitric oxide (NO), and also during the 1st, 2nd, 3rd, and 10th postoperative day for analysis of endothelin, another endothelium-derived vasoactive mediator. Lung biopsies were taken before and after OLV or TLV, and analyzed regarding immunofluorescence for isoform of NO synthase, a protein upregulated during inflammatory response and also vascular congestion. No changes in lung isoform of NO synthase immunofluorescence or vascular congestion were registered after neither OLV nor TLV. Plasma nitrite and endothelin levels were similar in the two study groups. We conclude that OLV does not seem to have any influence on key regulators of pulmonary vascular tone and inflammation, i.e. NO and endothelin. From this perspective, OLV seems to be a safe method, which defends its clinical position to facilitate surgical exposure during thoracoabdominal esophagectomy.
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| 4. |
- Rissler, P., et al.
(författare)
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Adriamycin cytotoxicity may stimulate growth of hepatocellular tumours in an experimental model for adjuvant systemic chemotherapy in liver transplantation
- 2005
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Ingår i: Transplant International. - : Frontiers Media SA. - 0934-0874 .- 1432-2277. ; 18:8, s. 992-1000
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Tidskriftsartikel (refereegranskat)abstract
- Adjuvant treatment with adriamycin has been suggested to improve results after liver transplantation for hepatocellular cancer. Here we have applied an animal model for evaluation of treatment with adriamycin and/or cyclosporine A on liver tumour growth. Three chemically induced rat liver tumours with various degree of differentiation were transferred to the spleens of syngenic rats. Each recipient group was divided into four subgroups, treated with adriamycin and/or cyclosporine A or none of the drugs. When the tumour was well differentiated no proliferation was found in any of the subgroups. When the tumour exhibited a more pronounced dysplasia, adriamycin stimulated tumour growth. This effect was further increased by cyclosporine. In the animals transplanted with the most aggressive tumour, adriamycin inhibited tumour growth. When given together with cyclosporine this inhibition was counteracted. These data suggest that adriamycin, especially when given together with cyclosporine, may have a stimulatory effect on liver tumour cell growth.
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| 6. |
- Xia, Ling, et al.
(författare)
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Reduction of ubiquinone by lipoamide dehydrogenase : An antioxidant regenerating pathway
- 2001
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Ingår i: European Journal of Biochemistry. - : Wiley. - 0014-2956 .- 1432-1033. ; 268:5, s. 1486-1490
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Tidskriftsartikel (refereegranskat)abstract
- Lipoamide dehydrogenase belongs to a family of pyridine nucleotide disulfide oxidoreductases and is ubiquitous in aerobic organisms. This enzyme also reduces ubiquinone (the only endogenously synthesized lipid-soluble antioxidant) to ubiquinol, the form in which it functions as an antioxidant. The reduction of ubiquinone was linear with time and exhibited turnover numbers of 5 and 1.2 min-1 in the presence and absence of zinc, respectively. The reaction was stimulated by zinc and cadmium but not by the other divalent ions tested. The zinc/cadmium-dependent stimulation of the reaction increased rapidly and linearly up to a concentration of 0.1 mM and was even further increased at 0.5 mM. At pH 6, the activity was three times higher than at physiological pH. Alteration of the NADPH : NADP+ ratio revealed that the reaction is inhibited by higher concentrations of the oxidized cofactors. FAD reduced ubiquinone in a dose-dependent manner at a considerably lower rate, suggesting that the reduction of ubiquinone by lipoamide dehydrogenase involves the FAD moiety of the enzyme.
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| 7. |
- Björnstedt, M., et al.
(författare)
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Selenium and the thioredoxin and glutaredoxin systems
- 1997
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Ingår i: Biomedical and environmental sciences. - : Elsevier. - 0895-3988 .- 2214-0190. ; 10:2-3, s. 271-279
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Tidskriftsartikel (refereegranskat)abstract
- Thioredoxin (Trx) is a small ubiquitous dithiol protein which together with the FAD-containing enzyme thioredoxin reductase (TR) and NADPH (the Trx system) is a hydrogen donor for ribonucleotide reductase essential for DNA synthesis and a general protein disulfide reductase involved in redox regulation. Selenite, selenodiglutathione (GS-Se-SG) and selenocystine are efficiently reduced by thioredoxins and also directly by NADPH and mammalian TR but not by the E. coli enzyme. Incubation of selenite or GS-Se-SG with the Trx system or with mammalian TR results in a rapid formation of selenide, which by redox cycling with oxygen may cause a large non-stoichiometric oxidation of NADPH. Selenocystine is efficiently reduced into two molecules of the selenol amino acid selenocysteine by mammalian TR with a K(m)-value (6 mumol.L-1) and a high turnover number (kappa cat 3200 min-1) almost identical to the natural substrate Trx-S2. TR also directly reduces lipid hydroperoxides and this peroxidase reaction is strongly stimulated by the presence of catalytic amounts of free selenocysteine. Glutaredoxin (Grx) which catalyzes GSH-dependent disulfide reduction also via a redox-active disulfide and Trx are both efficient electron donors to the human plasma glutathione peroxidase providing a mechanism by which human plasma glutathione peroxidase may reduce hydroperoxides in an environment almost free from glutathione. Selenate is reduced by Grx and Trx in the presence of GSH. The DNA-binding of the transcription factor AP-1 is strongly inhibited by GS-Se-SG and selenite. Furthermore, selenide formed by TR-mediated reduction of selenite and GS-Se-SG inhibits lipoxygenase and changes the electron spin resonance spectrum of the active site iron. Mammalian TR with two subunits of 57 kDa has recently been cloned and shown to be homologous to glutathione reductase. The rat enzyme contains a selenocysteine residue in a unique Cterminal position and a conserved SECIS sequence directing insertion of the selenocysteine. The discovery of selenocysteine in mammalian TR may explain the broad substrate specificity of the enzyme and the requirement of selenium for cell proliferation.
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| 8. |
- Björnstedt, M, et al.
(författare)
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Selenium in the prevention of human cancers
- 2010
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Ingår i: The EPMA journal. - : Springer Science and Business Media LLC. - 1878-5077 .- 1878-5085. ; 1:3, s. 389-95
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Tidskriftsartikel (refereegranskat)
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| 9. |
- Cunnea, P., et al.
(författare)
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Increased expression of specific thioredoxin family proteins; a pilot immunohistochemical study on human hepatocellular carcinoma
- 2007
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Ingår i: International journal of immunopathology and pharmacology. - : Biolife. - 0394-6320 .- 2058-7384. ; 20:1, s. 17-24
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Tidskriftsartikel (refereegranskat)abstract
- Hepatocellular Carcinoma (HCC) is one of the most frequent cancers worldwide, however, prognosis remains poor following its discovery. We investigate the Thioredoxin superfamily of proteins as diagnostic markers for HCC. Furthermore, we delineate possible roles of the endoplasmic reticulum member of the superfamily, ERdj5, in carcinogenesis. Using antibodies against Thioredoxin 1, Thioredoxin Reductase 1 and ERdj5, we performed immunohistochemistry on paraffin embedded liver biopsy sections from HCC patients. All three redox proteins exhibited elevated expression levels in tumor tissue compared to internal control, with ERdj5 showing a remarkable 3-fold increase. In vitro cell viability experiments using Hepatocellular Carcinoma HuH7 cells treated with ERdj5 small interfering RNA showed that ERdj5 knockdown cells exhibited less resistance to Doxorubicin (chemotherapy drug), but more resistance to Tunicamycin (Endoplasmic Stress inducer), compared to control cells. In conclusion, we introduce members of the Thioredoxin superfamily as possible immunohistochemical markers in the diagnostics of hepatocellular carcinoma and indicate a potential defensive role for ERdj5 in chemotherapeutic drug resistance.
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| 10. |
- He, Fei, et al.
(författare)
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FPR2 Shapes an Immune-Excluded Pancreatic Tumor Microenvironment and Drives T-cell Exhaustion in a Sex-Dependent Manner
- 2023
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Ingår i: Cancer Research. - : American Association for Cancer Research (AACR). - 0008-5472 .- 1538-7445. ; 83:10, s. 1628-1645
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Tidskriftsartikel (refereegranskat)abstract
- Sex-driven immune differences can affect tumor progression and the landscape of the tumor microenvironment. Deeper understanding of these differences in males and females can inform patient selection to improve sex-optimized immunotherapy treatments. In this study, single-cell RNA sequencing and protein analyses uncovered a subpopulation of myeloid cells in pancreatic lesions associated with an immune-excluded tumor phenotype and effector T-cell exhaustion exclusively in females. This myeloid subpopulation was positively correlated with poor survival and genetic signatures of M2-like macrophages and T-cell exhaustion in females. The G-protein coupled receptor formyl peptide receptor 2 (FPR2) mediated these immunosuppressive effects. In vitro, treatment of myeloid cells with a specific FPR2 antagonist prevented exhaustion and enhanced cytotoxicity of effector cells. Proteomic analysis revealed high expression of immunosuppressive secretory proteins PGE2 and galectin-9, enriched integrin pathway, and reduced proinflammatory signals like TNFα and IFNγ in female M2-like macrophages upon FPR2 agonist treatment. In addition, myeloid cells treated with FPR2 agonists induced TIM3 and PD-1 expression only in female T cells. Treatment with anti-TIM3 antibodies reversed T-cell exhaustion and stimulated their ability to infiltrate and kill pancreatic spheroids. In vivo, progression of syngeneic pancreatic tumors was significantly suppressed in FPR2 knockout (KO) female mice compared with wild-type (WT) female mice and to WT and FPR2 KO male mice. In female mice, inoculation of tumors with FPR2 KO macrophages significantly reduced tumor growth compared with WT macrophages. Overall, this study identified an immunosuppressive function of FPR2 in females, highlighting a potential sex-specific precision immunotherapy strategy.
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