| 1. |
- Avram, Vlad F., et al.
(författare)
-
Cell-Permeable Succinate Rescues Mitochondrial Respiration in Cellular Models of Statin Toxicity
- 2021
-
Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 22:1
-
Tidskriftsartikel (refereegranskat)abstract
- Statins are the cornerstone of lipid-lowering therapy. Although generally well tolerated, statin-associated muscle symptoms (SAMS) represent the main reason for treatment discontinuation. Mitochondrial dysfunction of complex I has been implicated in the pathophysiology of SAMS. The present study proposed to assess the concentration-dependent ex vivo effects of three statins on mito-chondrial respiration in viable human platelets and to investigate whether a cell-permeable prodrug of succinate (complex II substrate) can compensate for statin-induced mitochondrial dysfunction. Mitochondrial respiration was assessed by high-resolution respirometry in human platelets, acutely exposed to statins in the presence/absence of the prodrug NV118. Statins concentration-dependently inhibited mitochondrial respiration in both intact and permeabilized cells. Further, statins caused an increase in non-ATP generating oxygen consumption (uncoupling), severely limiting the OXPHOS coupling efficiency, a measure of the ATP generating capacity. Cerivastatin (commercially withdrawn due to muscle toxicity) displayed a similar inhibitory capacity compared with the widely prescribed and tolerable atorvastatin, but did not elicit direct complex I inhibition. NV118 increased succinate-supported mitochondrial oxygen consumption in atorvastatin/cerivastatin-exposed platelets leading to normalization of coupled (ATP generating) respiration. The results acquired in isolated human platelets were validated in a limited set of experiments using atorvastatin in HepG2 cells, reinforcing the generalizability of the findings.
|
|
| 2. |
- Avram, Vlad Florian, et al.
(författare)
-
Improvement of platelet respiration by cell-permeable succinate in diabetic patients treated with statins
- 2021
-
Ingår i: Life. - : MDPI AG. - 0024-3019 .- 2075-1729. ; 11:4
-
Tidskriftsartikel (refereegranskat)abstract
- Diabetes mellitus (DM) is the most severe metabolic disease that reached the level of a global pandemic and is associated with high cardiovascular morbidity. Statins are the first-line lipid- lowering therapy in diabetic patients with or without a history of atherosclerotic disease. Although well tolerated, chronic treatment may result in side effects that lead to treatment interruption. Mitochondrial dysfunction has emerged as a central pathomechanism in DM- and statin-induced side effects. Assessment of mitochondrial respiration in peripheral platelets has been increasingly used as a mirror of organ mitochondrial dysfunction. The present study aimed to assess the: (i) changes in mitochondrial respiration elicited by statins in patients with type 2 DM and (ii) the effects of cell-permeable succinate (NV118) on respiratory parameters in platelets harvested from these patients. No significant changes were found in global mitochondrial respiration of intact platelets isolated from diabetic patients treated with either atorvastatin or rosuvastatin. Similarly, no significant changes in mitochondrial respiration of permeabilized platelets were found between diabetic patients treated with atorvastatin and healthy controls. Acute ex vivo administration of NV118 significantly improved respiration in isolated platelets. These results prompt further research on the role of permeable succinate as a therapeutic alternative for improving mitochondrial function in metabolic pathologies and point to the role of peripheral platelets as a potential biomarker of treatment response.
|
|
| 3. |
- Bengzon, Johan, et al.
(författare)
-
Apoptosis and proliferation of dentate gyrus neurons after single and intermittent limbic seizures
- 1997
-
Ingår i: Proceedings of the National Academy of Sciences. - 1091-6490. ; 94:19, s. 10432-10437
-
Tidskriftsartikel (refereegranskat)abstract
- Neuronal apoptosis was observed in the rat dentate gyrus in two experimental models of human limbic epilepsy. Five hours after one hippocampal kindling stimulation, a marked increase of in situ terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling (TUNEL) of fragmented DNA was observed in nuclei located within and on the hilar border of the granule cell layer and in the polymorphic region. Forty kindling stimulations with 5-min interval produced higher numbers of labeled nuclei compared with one stimulation. The increase of TUNEL-positive nuclei was prevented by the protein synthesis inhibitor cycloheximide but not affected by the N-methyl-D-aspartate receptor antagonist MK-801. Kainic acid-induced seizures lead to a pattern of labeling in the hippocampal formation identical to that evoked by kindling. A large proportion of cells displaying TUNEL-positive nuclei was double-labeled by the neuron-specific antigen NeuN, demonstrating the neuronal identity of apoptotic cells. Either 1 or 40 kindling stimulations also gave rise to a marked increase of the number of cells double-labeled with the mitotic marker bromodeoxyuridine and NeuN in the subgranular zone and on the hilar border of the dentate granule cell layer. The present data show that single and intermittent, brief seizures induce both apoptotic death and proliferation of dentate gyrus neurons. We hypothesize that these processes, occurring early during epileptogenesis, are primary events in the development of hippocampal pathology in animals and possibly also in patients suffering from temporal lobe epilepsy.
|
|
| 4. |
- Beţiu, Alina Maria, et al.
(författare)
-
Dose-dependent effects of acetaminophen and ibuprofen on mitochondrial respiration of human platelets
-
Ingår i: Molecular and Cellular Biochemistry. - 0300-8177.
-
Tidskriftsartikel (refereegranskat)abstract
- Acetaminophen and ibuprofen are widely used over-the-counter medications to reduce fever, pain, and inflammation. Although both drugs are safe in therapeutic concentrations, self-medication is practiced by millions of aged patients with comorbidities that decrease drug metabolism and/or excretion, thus raising the risk of overdosage. Mitochondrial dysfunction has emerged as an important pathomechanism underlying the organ toxicity of both drugs. Assessment of mitochondrial oxygen consumption in peripheral blood cells is a novel research field Cu several applications, including characterization of drug toxicity. The present study, conducted in human platelets isolated from blood donor-derived buffy coat, was aimed at assessing the acute, concentration-dependent effects of each drug on mitochondrial respiration. Using the high-resolution respirometry technique, a concentration-dependent decrease of oxygen consumption in both intact and permeabilized platelets was found for either drug, mainly by inhibiting complex I-supported active respiration. Moreover, ibuprofen significantly decreased the maximal capacity of the electron transport system already from the lowest concentration. In conclusion, platelets from healthy donors represents a population of cells easily available, which can be routinely used in studies assessing mitochondrial drug toxicity. Whether these results can be recapitulated in patients treated with these medications is worth further investigation as potential peripheral biomarker of drug overdose.
|
|
| 5. |
- Bețiu, Alina M., et al.
(författare)
-
Cell‐permeable succinate rescues mitochondrial respiration in cellular models of amiodarone toxicity
- 2021
-
Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 22:21
-
Tidskriftsartikel (refereegranskat)abstract
- Amiodarone is a potent antiarrhythmic drug and displays substantial liver toxicity in hu-mans. It has previously been demonstrated that amiodarone and its metabolite (desethylamioda-rone, DEA) can inhibit mitochondrial function, particularly complexes I (CI) and II (CII) of the elec-tron transport system in various animal tissues and cell types. The present study, performed in human peripheral blood cells, and one liver‐derived human cell line, is primarily aimed at assessing the concentration‐dependent effects of these drugs on mitochondrial function (respiration and cellular ATP levels). Furthermore, we explore the efficacy of a novel cell‐permeable succinate prodrug in alleviating the drug‐induced acute mitochondrial dysfunction. Amiodarone and DEA elicit a con-centration‐dependent impairment of mitochondrial respiration in both intact and permeabilized platelets via the inhibition of both CI‐ and CII‐supported respiration. The inhibitory effect seen in human platelets is also confirmed in mononuclear cells (PBMCs) and HepG2 cells. Additionally, amiodarone elicits a severe concentration‐dependent ATP depletion in PBMCs, which cannot be explained solely by mitochondrial inhibition. The succinate prodrug NV118 alleviates the respiratory deficit in platelets and HepG2 cells acutely exposed to amiodarone. In conclusion, amiodarone severely inhibits metabolism in primary human mitochondria, which can be counteracted by in-creasing mitochondrial function using intracellular delivery of succinate.
|
|
| 6. |
- Bețiu, Alina M., et al.
(författare)
-
Mitochondrial Effects of Common Cardiovascular Medications : The Good, the Bad and the Mixed
- 2022
-
Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 23:21
-
Forskningsöversikt (refereegranskat)abstract
- Mitochondria are central organelles in the homeostasis of the cardiovascular system via the integration of several physiological processes, such as ATP generation via oxidative phosphorylation, synthesis/exchange of metabolites, calcium sequestration, reactive oxygen species (ROS) production/buffering and control of cellular survival/death. Mitochondrial impairment has been widely recognized as a central pathomechanism of almost all cardiovascular diseases, rendering these organelles important therapeutic targets. Mitochondrial dysfunction has been reported to occur in the setting of drug-induced toxicity in several tissues and organs, including the heart. Members of the drug classes currently used in the therapeutics of cardiovascular pathologies have been reported to both support and undermine mitochondrial function. For the latter case, mitochondrial toxicity is the consequence of drug interference (direct or off-target effects) with mitochondrial respiration/energy conversion, DNA replication, ROS production and detoxification, cell death signaling and mitochondrial dynamics. The present narrative review aims to summarize the beneficial and deleterious mitochondrial effects of common cardiovascular medications as described in various experimental models and identify those for which evidence for both types of effects is available in the literature.
|
|
| 7. |
- Borlongan, C V, et al.
(författare)
-
Cyclosporine-A enhances choline acetyltransferase immunoreactivity in the septal region of adult rats
- 2000
-
Ingår i: Neuroscience Letters. - 0304-3940. ; 279:2, s. 73-76
-
Tidskriftsartikel (refereegranskat)abstract
- Cyclosporine-A (CsA) is the primary anti-rejection drug used for organ and neural transplantation therapy. In addition to its immunosuppressive action, CsA has been recently shown to exert neuroprotective and neurotrophic effects in the central nervous system when able to cross the blood-brain barrier. Postulated mechanisms for these CsA-induced beneficial effects include the drug's powerful inhibition of the calcium-dependent phosphatase calcineurin (CN) and blockade of the assembly of the mitochondrial permeability transition pore. We report here, for the first time, that adult Wistar rats treated with CsA (10 mg/kg per day, i.p. for 9 days) displayed significantly reduced septal CN expression in combination with enhanced levels of septal choline acetyltransferase (ChAT) immunoreactivity as compared to controls. The observed enhancement of septal ChAT immunoreactivity suggests potential therapeutic utility of CsA for brain disorders characterized by alterations of the cholinergic system.
|
|
| 8. |
- Burguillos Garcia, Miguel, et al.
(författare)
-
Microchannel Acoustophoresis does not Impact Survival or Function of Microglia, Leukocytes or Tumor Cells.
- 2013
-
Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:5
-
Tidskriftsartikel (refereegranskat)abstract
- The use of acoustic forces to manipulate particles or cells at the microfluidic scale (i.e. acoustophoresis), enables non-contact, label-free separation based on intrinsic cell properties such as size, density and compressibility. Acoustophoresis holds great promise as a cell separation technique in several research and clinical areas. However, it has been suggested that the force acting upon cells undergoing acoustophoresis may impact cell viability, proliferation or cell function via subtle phenotypic changes. If this were the case, it would suggest that the acoustophoresis method would be a less useful tool for many cell analysis applications as well as for cell therapy.
|
|
| 9. |
- Chumarina, Margarita, et al.
(författare)
-
Cellular alterations identified in pluripotent stem cell-derived midbrain spheroids generated from a female patient with progressive external ophthalmoplegia and parkinsonism who carries a novel variation (p.Q811R) in the POLG1 gene
- 2019
-
Ingår i: Acta Neuropathologica Communications. - : Springer Science and Business Media LLC. - 2051-5960. ; 7:1
-
Tidskriftsartikel (refereegranskat)abstract
- Variations in the POLG1 gene encoding the catalytic subunit of the mitochondrial DNA polymerase gamma, have recently been associated with Parkinson's disease (PD), especially in patients diagnosed with progressive external ophthalmoplegia (PEO). However, the majority of the studies reporting this association mainly focused on the genetic identification of the variation in POLG1 in PD patient primary cells, and determination of mitochondrial DNA copy number, providing little information about the cellular alterations existing in patient brain cells, in particular dopaminergic neurons. Therefore, through the use of induced pluripotent stem cells (iPSCs), we assessed cellular alterations in novel p.Q811R POLG1 (POLG1Q811R) variant midbrain dopaminergic neuron-containing spheroids (MDNS) from a female patient who developed early-onset PD, and compared them to cultures derived from a healthy control of the same gender. Both POLG1 variant and control MDNS contained functional midbrain regionalized TH/FOXA2-positive dopaminergic neurons, capable of releasing dopamine. Western blot analysis identified the presence of high molecular weight oligomeric alpha-synuclein in POLG1Q811R MDNS compared to control cultures. In order to assess POLG1Q811R-related cellular alterations within the MDNS, we applied mass-spectrometry based quantitative proteomic analysis. In total, 6749 proteins were identified, with 61 significantly differentially expressed between POLG1Q811R and control samples. Pro-And anti-inflammatory signaling and pathways involved in energy metabolism were altered. Notably, increased glycolysis in POLG1Q811R MDNS was suggested by the increase in PFKM and LDHA levels and confirmed using functional analysis of glycolytic rate and oxygen consumption levels. Our results validate the use of iPSCs to assess cellular alterations in relation to PD pathogenesis, in a unique PD patient carrying a novel p.Q811R variation in POLG1, and identify several altered pathways that may be relevant to PD pathogenesis.
|
|
| 10. |
- Cung, T. -T., et al.
(författare)
-
Cyclosporine before PCI in Patients with Acute Myocardial Infarction
- 2015
-
Ingår i: New England Journal of Medicine. - 0028-4793. ; 373:11, s. 1021-1031
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND Experimental and clinical evidence suggests that cyclosporine may attenuate reperfusion injury and reduce myocardial infarct size. We aimed to test whether cyclosporine would improve clinical outcomes and prevent adverse left ventricular remodeling. METHODS In a multicenter, double-blind, randomized trial, we assigned 970 patients with an acute anterior ST-segment elevation myocardial infarction (STEMI) who were undergoing percutaneous coronary intervention (PCI) within 12 hours after symptom onset and who had complete occlusion of the culprit coronary artery to receive a bolus injection of cyclosporine (administered intravenously at a dose of 2.5 mg per kilogram of body weight) or matching placebo before coronary recanalization. The primary outcome was a composite of death from any cause, worsening of heart failure during the initial hospitalization, rehospitalization for heart failure, or adverse left ventricular remodeling at 1 year. Adverse left ventricular remodeling was defined as an increase of 15% or more in the left ventricular end-diastolic volume. RESULTS A total of 395 patients in the cyclosporine group and 396 in the placebo group received the assigned study drug and had data that could be evaluated for the primary outcome at 1 year. The rate of the primary outcome was 59.0% in the cyclosporine group and 58.1% in the control group (odds ratio, 1.04; 95% confidence interval, 0.78 to 1.39; P = 0.77). Cyclosporine did not reduce the incidence of the separate clinical components of the primary outcome or other events, including recurrent infarction, unstable angina, and stroke. No significant difference in the safety profile was observed between the two treatment groups. CONCLUSIONS In patients with anterior STEMI who had been referred for primary PCI, intravenous cyclosporine did not result in better clinical outcomes than those with placebo and did not prevent adverse left ventricular remodeling at 1 year. (Funded by the French Ministry of Health and NeuroVive Pharmaceutical; CIRCUS ClinicalTrials.gov number, NCT01502774; EudraCT number, 2009-013713-99.)
|
|
