FK506, but not cyclosporin A, prevents mitochondrial dysfunction during hypoxia in rat hepatocytes

Kaibori, Masaki; Inoue, Tomohisa; Tu, Wei; Oda, Masahiko; Kwon, A‐Hon; Kamiyama, Yasuo; Okumura, Tadayoshi

doi:10.1016/s0024-3205(01)01098-0

Cited by 34 publications

(34 citation statements)

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“…[4][5][6]43 It is possible that I/R injury results in S-nitrosylation, nitration or other modification of critical Cys or Tyr residues in the active site of ATP synthase and other components of the mitochondrial respiratory chain under elevated levels of nitrite and/or peroxynitrite. In fact, Tomkins et al recently reported that ROS can be generated through thiol modification of mitochondrial complex I.…”

Section: Reversible Inactivation Of Oxidized And/or S-nitrosylated MImentioning

confidence: 99%

“…Purified biotin-NM labeled oxidized (spots 1-31) and S-nitrosylated (spots 32-50) proteins (0.25 mg/sample) were resolved by 2-DE, and silver stained. Individual protein spots with differential intensities were excised out of this particular gel (pH range [3][4][5][6][7][8][9][10] and subjected to MS analysis following in-gel trypsin digestion. This figure represents a typical result from two separate experiments.…”

Section: Supplementary Materialsmentioning

confidence: 99%

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Oxidative Inactivation of Key Mitochondrial Proteins Leads to Dysfunction and Injury in Hepatic Ischemia Reperfusion

et al. 2008

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SummaryBackground & Aims-Ischemia-reperfusion (I/R) is a major mechanism of liver injury following hepatic surgery or transplantation. Despite numerous reports on the role of oxidative/nitrosative stress and mitochondrial dysfunction in hepatic I/R injury, the proteins that are oxidatively-modified during I/R damage are poorly characterized. This study was aimed at investigating the oxidatively-modified proteins underlying the mechanism for mitochondrial dysfunction in hepatic I/R injury. We also studied the effects of a superoxide dismutase mimetic/peroxynitrite scavenger metalloporphyrin MnTMPyP on oxidatively-modified proteins and their functions.

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Section: Reversible Inactivation Of Oxidized And/or S-nitrosylated MImentioning

confidence: 99%

Section: Supplementary Materialsmentioning

confidence: 99%

Oxidative Inactivation of Key Mitochondrial Proteins Leads to Dysfunction and Injury in Hepatic Ischemia Reperfusion

et al. 2008

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“…47 Tacrolimus can improve hepatocyte oxidation/ reduction states, with improved ketone body ratios, found to prevent ATP content deprivation under hypoxic conditions. 48 Interestingly, the same model failed to show a similar effect with cyclosporine A. 48 In cerebral ischemia studies, tacrolimus has shown protective effects from I-R associated with superior recovery of mitochondrial respiration and thus superior regeneration of high-energy phosphates, although a specific mechanism for this effect was not identified.…”

Section: Cellular Atp Contentmentioning

confidence: 99%

“…48 Other studies have shown that tacrolimus pretreatment results in decreased expression of interferon-␥ (IFN-␥), TNF-␣, ICAM-1, P-selectin, IL-1␣, IL-1␤, IL-2, IL-3, IL-5, and IL-6. 48 …”

Section: Cytokines and Intercellular Communicationmentioning

confidence: 99%

Effects of tacrolimus on ischemia-reperfusion injury

Stella

2003

Liver Transplantation

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In addition to efficacious immunosuppression for the benefit of organ transplantation, tacrolimus has diverse actions that result in amelioration of ischemia-reperfusion injury. Knowledge is accumulating rapidly on the mechanisms through which tacrolimus exerts these cytoprotective effects, including alterations in microcirculation, free radical metabolism, calcium-activated pathways, inflammatory cascades, mitochondrial stability, apoptosis, stress-response proteins, and tissue recovery. Within the nucleus, actions mediating the effects of tacrolimus appear to be dominantly influenced by interactions with the transcription factor, nuclear factor-B. Because tacrolimus is a cornerstone agent in immunosuppression regimens throughout the world and knowledge of its cellular mechanisms is evolving, it is important to update the clinical literature with this information. We reviewed the published literature with intent to portray the interactions of tacrolimus in the intricate cellular mechanisms initiated by ischemia and reperfusion. (Liver Transpl 2003;9: 105-116.)

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“…The distinction between necrosis and apoptosis can be in fact artificial, as the necrosis, in certain circumstances, can be considered to be an abortive apoptosis because of their being insufficient ATP to complete the apoptotic program. 39 Molecules with known mitochondrial protective capacity, including tacrolimus, 40 also protect against apoptosis. 41 I/R plus hepatectomy is a particularly energy-demanding situation, and preventing mitochondrial dysfunction may contribute to the beneficial effect of tacrolimus, especially when this effect seems to be independent of the immunosuppressive action.…”

Section: Discussionmentioning

confidence: 99%

Both tacrolimus and sirolimus decrease Th1/Th2 ratio, and increase regulatory T lymphocytes in the liver after ischemia/reperfusion

Arias-Dı́az

Ildefonso

Múñoz

et al. 2009

Laboratory Investigation

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The protective effects of immunosuppressants against ischemia/reperfusion (I/R) injury have been attributed to their non-specific anti-inflammatory effect. However, these effects may also depend on their effect on T lymphocytes, which are increasingly considered to be key players in I/R. Here, we studied the effects of tacrolimus and sirolimus on lymphocyte subpopulations in an I/R rat model. The animals were treated with tacrolimus, sirolimus or vehicle, before undergoing a 60-min ischemia event of the right hepatic lobe, followed by excision of the remaining liver. After 2 h, I/R rats showed increased mortality, plasma lactate dehydrogenase (LDH) levels, hepatocyte apoptosis, liver histological injury and parenchymal infiltration by neutrophils, macrophages, NK cells and T lymphocytes. Most of the changes were antagonized by both immunosuppressants. Tacrolimus augmented the proportion of cycling cells in I/R rats, whereas sirolimus showed the opposite effect. The increased Th1/Th2 ratio found in I/R livers after 2 h was reverted by immunosuppressants, which also amplified the proportion of CD4 þ CD25 þ Foxp3 þ regulatory T lymphocytes at 24 h. The protective effects of both tacrolimus and sirolimus correlated well with a decreased ratio of proinflammatory to anti-inflammatory T lymphocytes, and with an increase in the Treg proportion. This suggests a new mechanism to explain the known beneficial effect shown by immunosuppressants early after I/R.

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FK506, but not cyclosporin A, prevents mitochondrial dysfunction during hypoxia in rat hepatocytes

Cited by 34 publications

References 0 publications

Oxidative Inactivation of Key Mitochondrial Proteins Leads to Dysfunction and Injury in Hepatic Ischemia Reperfusion

Oxidative Inactivation of Key Mitochondrial Proteins Leads to Dysfunction and Injury in Hepatic Ischemia Reperfusion

Effects of tacrolimus on ischemia-reperfusion injury

Both tacrolimus and sirolimus decrease Th1/Th2 ratio, and increase regulatory T lymphocytes in the liver after ischemia/reperfusion

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