Muramyl‐dipeptide‐induced mitochondrial proton leak in macrophages is associated with upregulation of uncoupling protein 2 and the production of reactive oxygen and reactive nitrogen species

El-Khoury, Takla G.; Bahr, George M.; Echtay, Karim S.

doi:10.1111/j.1742-4658.2011.08226.x

Cited by 9 publications

(7 citation statements)

References 40 publications

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“…32 UCP1, UCP2, and UCP3 are thought to differ in the nature of their uncoupling activity and of their potential physiological roles. 35 Similarly, stimulation of murine macrophages by the immune modulator muramyl dipeptide rapidly upregulates the expression of UCP2, 36 and pretreatment with vitamin E attenuates upregulation of UCP2. UCP2 and 3 have been involved in a number of postulated functions in energy regulation, including regulation of insulin secretion or ROS production and control of the immune response (reviewed in Echtay).…”

Section: Discussionmentioning

confidence: 99%

“…UCP2 mRNA has been found in several tissues including liver, brain, pancreas, adipose tissue, immune cells, spleen, kidney, and the central nervous system while UCP3 is mainly present in the skeletal muscle. 36 In addition, endothelial cells treated with Ucp2 antisense oligonucleotides 37 have been shown to present increased ROS production. 32 Although the physiological function of UCP2 is still not completely elucidated, its ability to reduce mitochondrial ROS formation is widely accepted.…”

Section: Discussionmentioning

confidence: 99%

“…These findings suggest that the muramyl dipeptide-induced ROS upregulates UCP2 expression in order to counteract the effects of the immune modulators on mitochondrial respiratory efficiency. 36 In addition, endothelial cells treated with Ucp2 antisense oligonucleotides 37 have been shown to present increased ROS production. Moreover, in pancreatic islets, when UCP2 activity is suppressed by the use of Ucp2-knockout mouse, mitochondrial membrane potential, islet superoxide production, ATP levels, and insulin secretion are raised significantly.…”

Section: Discussionmentioning

confidence: 99%

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Absence of effect of the antiretrovirals Duovir and Viraday on mitochondrial bioenergetics

Fadel

Bahr

Echtay

2018

J of Cellular Biochemistry

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Most toxicity associated with antiretroviral drugs is thought to result from disruption of mitochondrial function. Unfortunately, there are no validated laboratory markers for clinically assessing the onset of mitochondrial toxicity associated with antiretroviral therapy. In a previous study on mitochondrial hepatocytes, the protease inhibitor lopimune was shown to induce mitochondrial toxicity by increasing reactive oxygen species (ROS) production and decreasing respiratory control ratio (RCR) reflecting compromised mitochondrial efficiency in adenosine triphosphate production. Mitochondrial dysfunction and ROS production were directly correlated with the expression of uncoupling protein 2 (UCP2). In the current study we aim to determine the toxicity of nucleoside or nucleotide and nonnucleoside reverse-transcriptase inhibitors, Duovir and Viraday on liver mitochondria isolated from treated mice by monitoring UCP2 expression. Our results showed that both Duovir and Viraday had no effect on mitochondrial respiration states 2, 3, 4, and on RCR. In addition, ROS generation and UCP2 expression were not affected. In conclusion, our results indicate the difference in the mechanism of action of distinct classes of antiretroviral drugs on mitochondrial functions and may associate UCP2 expression with subclinical mitochondrial damage as marker of cellular oxidative stress.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Absence of effect of the antiretrovirals Duovir and Viraday on mitochondrial bioenergetics

Fadel

Bahr

Echtay

2018

J of Cellular Biochemistry

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“…In accordance with previous data, we confirmed increased hepatic UCP-2 mRNA levels, 2 days after Hpx [ 97 , 98 ], however, MSC administration potentiated this expression. In the mitochondria, UCP-2 functions as an uncoupler when it is activated by superoxide and other metabolites of lipids and proteins [ 99 , 100 ]. The proton leak via UCP-2 decreases reactive oxygen species (ROS) production and protects from oxidative stress [ 101 – 103 ].…”

Section: Discussionmentioning

confidence: 99%

Administration of multipotent mesenchymal stromal cells restores liver regeneration and improves liver function in obese mice with hepatic steatosis after partial hepatectomy

et al. 2017

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BackgroundThe liver has the remarkable capacity to regenerate in order to compensate for lost or damaged hepatic tissue. However, pre-existing pathological abnormalities, such as hepatic steatosis (HS), inhibits the endogenous regenerative process, becoming an obstacle for liver surgery and living donor transplantation.Recent evidence indicates that multipotent mesenchymal stromal cells (MSCs) administration can improve hepatic function and increase the potential for liver regeneration in patients with liver damage. Since HS is the most common form of chronic hepatic illness, in this study we evaluated the role of MSCs in liver regeneration in an animal model of severe HS with impaired liver regeneration.MethodsC57BL/6 mice were fed with a regular diet (normal mice) or with a high-fat diet (obese mice) to induce HS. After 30 weeks of diet exposure, 70% hepatectomy (Hpx) was performed and normal and obese mice were divided into two groups that received 5 × 105 MSCs or vehicle via the tail vein immediately after Hpx.ResultsWe confirmed a significant inhibition of hepatic regeneration when liver steatosis was present, while the hepatic regenerative response was promoted by infusion of MSCs. Specifically, MSC administration improved the hepatocyte proliferative response, PCNA-labeling index, DNA synthesis, liver function, and also reduced the number of apoptotic hepatocytes.These effects may be associated to the paracrine secretion of trophic factors by MSCs and the hepatic upregulation of key cytokines and growth factors relevant for cell proliferation, which ultimately improves the survival rate of the mice.ConclusionsMSCs represent a promising therapeutic strategy to improve liver regeneration in patients with HS as well as for increasing the number of donor organs available for transplantation.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-016-0469-y) contains supplementary material, which is available to authorized users.

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“…UCP 2 is expressed in a number of tissues, including adipose tissues, the immune system, and pancreatic islets. [ 14 , 15 ] Several studies indicated an important role of UCP 2 in insulin/glucose homeostasis, and also demonstrated the regulation of insulin secretion by UCP 2, which possibly correlates with obesity, β-cell dysfunction, and type 2 diabetes. [ 16 , 17 ] UCP 3 expression is tissue-specific and is mostly confined to skeletal muscles, cardiac muscles, and fat tissues.…”

Section: Introductionmentioning

confidence: 99%

Serum levels of uncoupling proteins in patients with differential insulin resistance

Pan

Lee

Chou³

et al. 2017

Medicine

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The uncoupling protein (UCP) belongs to a family of energy-dissipating proteins in mitochondria. Increasing evidences have indicated that UCPs have immense impact on glucose homeostasis and are key proteins in metabolic syndrome. For applying the findings to clinical practice, we designed a study to explore the association between serum UCPs 1–3 and insulin resistance. This investigation prospectively recorded demographical parameter and collected blood samples of 1071 participants from 4 districts in Northeastern Taiwan during the period from August 2013 to July 2014. Propensity score matching by age and sex in patients with top and bottom third homeostasis model assessment of insulin resistance (HOMA-IR) levels was performed, and 326 subjects were enrolled for further studies. The mean age of the patients was 59.4 years and the majority of them (65.5%) were females. The prevalence of metabolic syndrome was 35.5%. Our results demonstrated that serum UCPs 1–3 were significantly associated with differences in HOMA-IR levels. Multiple logistic regression analysis indicated that low UCP 1 and features of metabolic syndrome, namely hypertension, diabetes, body mass index, and high-density lipoprotein, were independent determinants for high HOMA-IR levels. We thus determined that low serum UCP 1 is a predictor for high resistance to insulin.

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Muramyl‐dipeptide‐induced mitochondrial proton leak in macrophages is associated with upregulation of uncoupling protein 2 and the production of reactive oxygen and reactive nitrogen species

Cited by 9 publications

References 40 publications

Absence of effect of the antiretrovirals Duovir and Viraday on mitochondrial bioenergetics

Absence of effect of the antiretrovirals Duovir and Viraday on mitochondrial bioenergetics

Administration of multipotent mesenchymal stromal cells restores liver regeneration and improves liver function in obese mice with hepatic steatosis after partial hepatectomy

Serum levels of uncoupling proteins in patients with differential insulin resistance

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