Pitfalls of Mitochondrial Redox Signaling Research

Antioxidants, Journal Year: 2023, Volume and Issue: 12(9), P. 1696 - 1696

Published: Aug. 31, 2023

Redox signaling from mitochondria (mt) to the cytosol and plasma membrane (PM) has been scarcely reported, such as in case of hypoxic cell adaptation or (2-oxo-) 2-keto-isocaproate (KIC) β-like-oxidation stimulating insulin secretion pancreatic β-cells. Mutual redox state influence between mitochondrial major compartments, matrix intracristal space, is therefore derived theoretically this article predict possible conditions, when mt-to-cytosol mt-to-PM signals may occur, well conditions which cytosolic not overwhelmed by antioxidant capacity. Possible peroxiredoxin 3 participation discussed, another specific case, whereby superoxide release diminished, whereas MnSOD activated. As a result, enhanced conversion H2O2 allows diffusion into cytosol, where it could be predominant component release. In both these ways, realized. Finally, use redox-sensitive probes disturb equilibria, hence add surplus redox-buffering compartment, they are localized. Specifically, attempts quantify net fluxes made, should taken account.

Language: Английский

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Selpercatinib combination with the mitochondria-targeted antioxidant MitoQ effectively suppresses RET–mutant thyroid cancer

npj Precision Oncology, Journal Year: 2024, Volume and Issue: 8(1)

Published: Feb. 20, 2024

Abstract Genetic alternation of REarranged during Transfection ( RET ) that leads to constitutive activation is a crucial etiological factor for thyroid cancer. known regulate mitochondrial processes, although the underlying molecular mechanisms remain unclear. We previously showed multi-kinase inhibitors vandetanib and cabozantinib increase membrane potential (Δψ m in -mutated tumor cells this effect can be exploited enrichment Δψ -sensitive agents cells. In study, we hypothesized RET-selective inhibitor, selpercatinib, and, subsequently, cell uptake mitochondria-targeted ubiquinone (MitoQ) level break homeostasis induce lethal responses show selpercatinib significantly increased , its combination with MitoQ synergistically suppressed human cells, which validated using RET-targeted genetic approaches. Selpercatinib MitoQ, combination, also CCDC6-RET fusion line xenografts mice prolonged animal survival more effectively than single treatments each agent. Moreover, treated two patients or M918T cancer, who could not take at regular doses due adverse effects, dose-reduced combination. response therapy, both reduction. The quality life one patient improved over year until relapsed. This may have therapeutic tumors intolerant doses.

Language: Английский

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Parecoxib and 5-Fluorouracil Synergistically Inhibit EMT and Subsequent Metastasis in Colorectal Cancer by Targeting PI3K/Akt/NF-κB Signaling

Biomedicines, Journal Year: 2024, Volume and Issue: 12(7), P. 1526 - 1526

Published: July 9, 2024

Colorectal cancer is one of the most common causes mortality worldwide, and innovative drugs for treatment colorectal are continually being developed. 5-Fluorouracil (5-FU) a clinical chemotherapeutic drug. Acquired resistance to 5-FU challenge in treatment. Parecoxib selective COX-2-specific inhibitor that was demonstrated inhibit metastasis cancers our previous study. This study aimed investigate synergistic antimetastatic activities parecoxib human cells determine underlying mechanisms. synergistically suppressed cells. Treatment with parecoxib/5-FU combination induced an increase E-cadherin decrease β-catenin expression. The inhibited MMP-9 activity, NF-κB pathway as well. Mechanistic analysis denoted hindered essential molecules PI3K/Akt route obstruct metastatic cancer. Furthermore, could reactive oxygen species. Our work showed capacity treating via targeting PI3K/Akt/NF-κB pathway.

Language: Английский

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Redox-crippled MitoQ potently inhibits breast cancer and glioma cell proliferation: A negative control for verifying the antioxidant mechanism of MitoQ in cancer and other oxidative pathologies

Free Radical Biology and Medicine, Journal Year: 2023, Volume and Issue: 205, P. 175 - 187

Published: June 15, 2023

Mitochondria-targeted coenzyme Q10 (Mito-ubiquinone, Mito-quinone mesylate, or MitoQ) was shown to be an effective antimetastatic drug in patients with triple-negative breast cancer. MitoQ, sold as a nutritional supplement, prevents cancer recurrence. It potently inhibited tumor growth and cell proliferation preclinical xenograft models vitro cells. The proposed mechanism of action involves the inhibition reactive oxygen species by MitoQ via redox-cycling between oxidized form, fully reduced MitoQH2 (also called Mito-ubiquinol). To corroborate this antioxidant mechanism, we substituted hydroquinone group (-OH) methoxy (-OCH3). Unlike modified dimethoxy (DM-MitoQ), lacks quinone forms. DM-MitoQ not converted MDA-MB-231 We tested antiproliferative effects both human (MDA-MB-231), brain-homing (MDA-MB-231BR), glioma (U87MG) Surprisingly, slightly more potent than (IC50 = 0.26 μM versus 0.38 μM) at inhibiting these Both mitochondrial complex I-dependent consumption 0.52 0.17 μM, respectively). This study also suggests that DM-MitoQ, which is hydrophobic analog (logP: 10.1 8.7) devoid function scavenging ability, can inhibit proliferation. conclude oxidative phosphorylation responsible for metastasis. Blunting effect using redox-crippled serve useful negative control corroborating involvement free radical-mediated processes (e.g., ferroptosis, protein oxidation/nitration) other pathologies.

Language: Английский

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Cholesterol Metabolite 27-Hydroxycholesterol Enhances the Secretion of Cancer Promoting Extracellular Vesicles by a Mitochondrial ROS-Induced Impairment of Lysosomal Function

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: May 1, 2024

Extracellular vesicles (EVs) serve as crucial mediators of cell-to-cell communication in normal physiology well diseased states, and have been largely studied regard to their role cancer progression. However, the mechanisms by which biogenesis secretion are regulated metabolic or endocrine factors remain unknown. Here, we delineate a mechanism EV is cholesterol metabolite, 27-Hydroxycholesterol (27HC), where treatment myeloid immune cells (RAW 264.7 J774A.1) with 27HC impairs lysosomal homeostasis, leading shunting multivesicular bodies (MVBs) away from degradation, towards EVs. This impairment function caused mitochondrial dysfunction subsequent increase reactive oxygen species (ROS). Interestingly, cotreatment mitochondria-targeted antioxidant rescued attenuated 27HC-mediated secretion. Overall, our findings establish how metabolite regulates paves way for development strategies regulate progression controlling

Language: Английский

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Parecoxib and 5-Fluorouracil Synergistic Inhibition of Metastasis of Colorectal Cancer Cells by Targeting Akt/NF-κB and EMT Pathways

Published: May 28, 2024

Colorectal cancer is one of the most common causes mortality worldwide, and innovative drugs for treatment colorectal are continually being revealed. 5-Fluorouracil (5-FU) a clinical chemotherapeutic drug. Acquired resistance to 5-FU challenge in cancer. Parecoxib selective COX-2-specific inhibitor, which has been demonstrated inhibit metastasis cancers our previous study. This study aimed investigate synergistic antimetastatic activities parecoxib human cells determine underlying mechanism. synergistically suppressed cells. Treatment with /5-FU combination induced an increase E-cadherin decrease β-catenin. The parecoxib/5-FU could MMP-9 MMP-2 expression activity, NF-κB pathway might be as well. Mechanistic analysis denoted that hindered essential molecules PI3K/Akt route obstruct metastatic Furthermore, reactive oxygen species. Our work showed capacity via targeting /NF-κB pathway.

Language: Английский

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Mitochondria-targeted antioxidant MitoQ radiosensitizes tumors by decreasing mitochondrial oxygen consumption

Cell Death Discovery, Journal Year: 2024, Volume and Issue: 10(1)

Published: Dec. 27, 2024

Abstract Hypoxic tumors are radioresistant stemming from the fact that oxygen promotes reactive species (ROS) propagation after water radiolysis and stabilizes irradiation-induced DNA damage. Therefore, an attractive strategy to radiosensitize solid is increase tumor oxygenation at time of irradiation, ideally above a partial pressure 10 mm-Hg which full radiosensitization can be reached. Historically, many attempts vascular O 2 delivery have had limited efficacy, but mathematical models predicted inhibiting cancer cell respiration would more effective. Here, we report mitochondria-targeted antioxidant MitoQ human breast in mice. This was not class effect, as neither MitoTEMPO nor SKQ1 shared this property. At clinically relevant nanomolar concentrations, completely abrogated consumption several lines different origins, associated with glycolytic switch. Using orthotopic mice, observed pretreating hypoxic MDA-MB-231 delayed growth both single dose irradiation fractionated radiotherapy. Oxygenated MCF7 were radiosensitized, suggesting enhancement effect MitoQ. Because already successfully passed Phase I clinical trials, our findings foster its evaluation combination

Language: Английский

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Influence of redox processes on the antioxidant activity of the symbiotic starter biomass

Food systems, Journal Year: 2023, Volume and Issue: 5(4), P. 337 - 343

Published: Jan. 9, 2023

The biological system of the microbial antioxidant protection is a subject certain level physiological oxidative process. To prevent oxidation, regulator intracellular metabolism, tripeptide glutathione, accumulated in cells. Glutathione very important for response and maintenance redox potential. Its role several metabolic adaptive symbiotic processes yeasts lactic acid bacteria not completely elucidated scientific practical interest. Glycine component polypeptide chain substances that form primary structure glutathione. aim this study was to determine an effect on activity through regulation glutathione constituent, glycine, nutrient medium obtain biomass multicomponent starter culture. As result performed investigations, direct dependence between calculated by coulometric method concentration glycine introduced into determined. It has been established addition 0.2–0.8% leads decrease results reflected publication show process development aerobic microorganisms presence reducing occurs quite actively. number increased from 1.6· 10 4 3.6· 5 CFU/g during 24-hour incubation. An increase 0.5 0.8% enhanced both anaerobic microorganisms. found 1.5% shifted toward metabolism; amount reduced culture liquid practically twofold, while oxidized test sample range 0 5%. This allows regarding as potential yeasts.

Language: Английский

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Mitochondrial Mechanisms in Immunity and Inflammatory Conditions: Beyond Energy Management

Antioxidants and Redox Signaling, Journal Year: 2023, Volume and Issue: 41(13-15), P. 845 - 864

Published: Dec. 8, 2023

Significance: The growing importance of mitochondria in the immune response and inflammation is multifaceted. Unraveling different mechanisms by which have a relevant role inflammatory beyond energy management process necessary for improving our understanding host defense pathogenesis various diseases syndromes. Critical Issues: Mitochondria are at levels, including releasing activation molecules, changing its structure function to accompany response, serving as structural base activating intermediates NLRP3 inflammasome. In this scientific journey dissecting mitochondrial mechanisms, new questions interesting aspects arise, such involvement mitochondrial-derived vesicles with putative preventing uncontrolled situations. Recent Advances: Researchers continuously rethinking acute chronic related disorders. As such, important roles centrally positioned signaling hubs regulating responses. review, we present current involved, largely known dysfunction, onset development Future Directions: emerge an multifaceted platform studying developing pharmaceutical therapeutic approaches. There many ongoing studies aimed describe effects specific targeted molecules treatments ameliorate consequences exacerbated components pathologies syndromes, resulting open area increasing research interest.

Language: Английский

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