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1.
Int J Mol Sci ; 22(16)2021 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-34445097

RESUMO

The disruption of blood-brain barrier (BBB) for multiple sclerosis (MS) pathogenesis has a double effect: early on during the onset of the immune attack and later for the CNS self-sustained 'inside-out' demyelination and neurodegeneration processes. This review presents the characteristics of BBB malfunction in MS but mostly highlights current developments regarding the impairment of the neurovascular unit (NVU) and the metabolic and mitochondrial dysfunctions of the BBB's endothelial cells. The hypoxic hypothesis is largely studied and agreed upon recently in the pathologic processes in MS. Hypoxia in MS might be produced per se by the NVU malfunction or secondary to mitochondria dysfunction. We present three different but related terms that denominate the ongoing neurodegenerative process in progressive forms of MS that are indirectly related to BBB disruption: progression independent of relapses, no evidence of disease activity and smoldering demyelination or silent progression. Dimethyl fumarate (DMF), modulators of S1P receptor, cladribine and laquinimode are DMTs that are able to cross the BBB and exhibit beneficial direct effects in the CNS with very different mechanisms of action, providing hope that a combined therapy might be effective in treating MS. Detailed mechanisms of action of these DMTs are described and also illustrated in dedicated images. With increasing knowledge about the involvement of BBB in MS pathology, BBB might become a therapeutic target in MS not only to make it impenetrable against activated immune cells but also to allow molecules that have a neuroprotective effect in reaching the cell target inside the CNS.


Assuntos
Barreira Hematoencefálica/patologia , Esclerose Múltipla/patologia , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Progressão da Doença , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Humanos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/metabolismo
2.
Nutrients ; 13(7)2021 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-34371986

RESUMO

Cardiovascular disease is the leading cause of death and disability in the Western world. In order to safeguard the structure and the functionality of the myocardium, it is extremely important to adequately support the cardiomyocytes. Two cellular organelles of cardiomyocytes are essential for cell survival and to ensure proper functioning of the myocardium: mitochondria and the sarcoplasmic reticulum. Mitochondria are responsible for the energy metabolism of the myocardium, and regulate the processes that can lead to cell death. The sarcoplasmic reticulum preserves the physiological concentration of the calcium ion, and triggers processes to protect the structural and functional integrity of the proteins. The alterations of these organelles can damage myocardial functioning. A proper nutritional balance regarding the intake of macronutrients and micronutrients leads to a significant improvement in the symptoms and consequences of heart disease. In particular, the Mediterranean diet, characterized by a high consumption of plant-based foods, small quantities of red meat, and high quantities of olive oil, reduces and improves the pathological condition of patients with heart failure. In addition, nutritional support and nutraceutical supplementation in patients who develop heart failure can contribute to the protection of the failing myocardium. Since polyphenols have numerous beneficial properties, including anti-inflammatory and antioxidant properties, this review gathers what is known about the beneficial effects of polyphenol-rich bergamot fruit on the cardiovascular system. In particular, the role of bergamot polyphenols in mitochondrial and sarcoplasmic dysfunctions in diabetic cardiomyopathy is reported.


Assuntos
Cardiomiopatias Diabéticas/fisiopatologia , Mitocôndrias/efeitos dos fármacos , Óleos Vegetais/farmacologia , Polifenóis/farmacologia , Retículo Sarcoplasmático/efeitos dos fármacos , Animais , Suplementos Nutricionais , Humanos , Miocárdio/metabolismo , Azeite de Oliva/farmacologia
3.
Inorg Chem ; 60(17): 13051-13061, 2021 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-34369147

RESUMO

The facile modification of the ligands in organometallic Ru(II)-arene complexes offers more opportunities to optimize their pharmacological profiles. Herein, three Ru(II)-arene complexes containing a glutathione S-transferase (GST) inhibitor (NBDHEX) in chelate ligand have been designed and synthesized in this study. In vitro results indicated that the ligation with NBDHEX significantly increased the activities and selectivities of the organometallic Ru(II)-arene complexes against tumor cells, especially complex 3, which was the most active compound among the tested compounds. DFT calculations and hydrolysis results demonstrated that complex 3 with more alkyl groups in the arene ligand has increased electron density at the Ru(II) center as compared with complexes 1 and 2, thus resulting in the improved hydrolysis rate, which may be responsible for its higher anticancer activity. Further studies showed that complexes 1-3 can cause the loss of the mitochondrial membrane potential and upregulate the expression of Bcl-2 and Bax in A549 cells, suggesting that complexes 1-3-induced cell death may be mediated via the mitochondrial apoptotic pathway. Thus, these findings suggested that simultaneous modification of the chelate ligands and arene rings in the organometallic Ru(II)-arene complexes is an effective way to improve their pharmacological properties.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Inibidores Enzimáticos/farmacologia , Glutationa Transferase/antagonistas & inibidores , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Complexos de Coordenação/síntese química , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Estrutura Molecular , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Rutênio/química , Pontos de Checagem da Fase S do Ciclo Celular/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Proteína X Associada a bcl-2/metabolismo
4.
ACS Appl Mater Interfaces ; 13(33): 39100-39111, 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34382406

RESUMO

In this work, a nanoplatform (FeCORM NPs) loaded with an iron-carbonyl complex was constructed. By exploiting chemodynamic therapy (CDT) and immunogenic cell death (ICD)-induced immunotherapy (IMT), the nanoparticles exhibited excellent efficacy against lung metastasis of melanoma in vivo. The iron-carbonyl compound of the nanomaterials could be initiated by both glutathione (GSH) and hydrogen peroxide (H2O2) to release CO and generate ferrous iron through ligand exchange and oxidative destruction pathways. The released CO caused mitochondria damage, whereas the generated ferrous iron led to oxidative stress via the Fenton reaction. On the other hand, the nanomaterials induced ICD-based IMT, which worked jointly with CDT to exhibit excellent effects against lung metastasis of melanoma through a mouse model. This work demonstrated how a nanoplatform, simple and stable but showing excellent efficacy against tumors, could be built using simple building blocks via a self-assembling approach. Importantly, the system took advantage of relatively high levels of GSH and H2O2 in tumors to initiate the therapeutic effects, which rendered the nanoplatform with a capability to differentiate normal cells from tumor cells. In principle, the system has great potential for future clinical applications, not only in the treatment of lung metastasis of melanoma but also in suppressing other types of tumors.


Assuntos
Antineoplásicos/química , Monóxido de Carbono/química , Compostos de Ferro/química , Neoplasias Pulmonares/tratamento farmacológico , Melanoma/metabolismo , Nanopartículas Metálicas/química , Animais , Antineoplásicos/farmacocinética , Apoptose/efeitos dos fármacos , Monóxido de Carbono/farmacocinética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desenvolvimento de Medicamentos , Feminino , Glutationa/química , Humanos , Peróxido de Hidrogênio/química , Imunoterapia/métodos , Neoplasias Pulmonares/secundário , Camundongos , Camundongos Endogâmicos BALB C , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/ultraestrutura , Neoplasias Experimentais , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos
5.
Molecules ; 26(16)2021 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-34443472

RESUMO

Feruloylacetone (FER) is a natural degradant of curcumin after heating, which structurally reserves some functional groups of curcumin. It is not as widely discussed as its original counterpart has been previously; and in this study, its anticancer efficacy is investigated. This study focuses on the suppressive effect of FER on colon cancer, as the efficacious effect of curcumin on this typical cancer type has been well evidenced. In addition, demethoxy-feruloylacetone (DFER) was applied to compare the effect that might be brought on by the structural differences of the methoxy group. It was revealed that both FER and DFER inhibited the proliferation of HCT116 cells, possibly via suppression of the phosphorylated mTOR/STAT3 pathway. Notably, FER could significantly repress both the STAT3 phosphorylation and protein levels. Furthermore, both samples showed capability of arresting HCT116 cells at the G2/M phase via the activation of p53/p21 and the upregulation of cyclin-B. In addition, ROS elevation and changes in mitochondrial membrane potential were revealed, as indicated by p-atm elevation. The apoptotic rate rose to 36.9 and 32.2% after being treated by FER and DFER, respectively. In summary, both compounds exhibited an anticancer effect, and FER showed a greater proapoptotic effect, possibly due to the presence of the methoxy group on the aromatic ring.


Assuntos
Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/patologia , Curcumina/farmacologia , Mitocôndrias/efeitos dos fármacos , Estirenos/farmacologia , Antineoplásicos/química , Antioxidantes/química , Apoptose/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Curcumina/química , Curcumina/metabolismo , Ciclina B1/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/agonistas , Fase G2/efeitos dos fármacos , Células HCT116 , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/metabolismo , Fenol/química , Fenol/farmacologia , Fosforilação/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Fator de Transcrição STAT3/metabolismo , Estirenos/química , Serina-Treonina Quinases TOR/metabolismo , Proteína Supressora de Tumor p53/agonistas
6.
Int J Mol Sci ; 22(15)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34360894

RESUMO

Disruption of retinal pigment epithelial (RPE) barrier integrity is involved in the pathology of several blinding retinal diseases including age-related macular degeneration (AMD) and diabetic retinopathy (DR), but the underlying causes and pathophysiology are not completely well-defined. Mitochondria dysfunction has often been considered as a potential candidate implicated in such a process. In this study, we aimed to dissect the role of different mitochondrial components; specifically, those of oxidative phosphorylation (OxPhos), in maintaining the barrier functionality of RPE. Electric cell-substrate impedance sensing (ECIS) technology was used to collect multi-frequency electrical impedance data to assess in real-time the barrier formation of the RPE cells. For this purpose, the human retinal pigment epithelial cell line-ARPE-19-was used and treated with varying concentrations of specific mitochondrial inhibitors that target different steps in OxPhos: Rotenone for complex I (the largest protein complex in the electron transport chain (ETC)); oligomycin for ATP synthase; and carbonyl cyanide-p-trifluoromethoxyphenyl hydrazone (FCCP) for uncoupling ATP synthesis from the accompanying ETC. Furthermore, data were modeled using the ECIS-Zθ software to investigate in depth the effects of these inhibitors on three separate barrier parameters: cell-cell interactions (Rb), cell-matrix interactions (α), and the cell membrane capacitance (Cm). The viability of ARPE-19 cells was determined by lactate dehydrogenase (LDH) Cytotoxicity Assay. The ECIS program's modeling demonstrated that FCCP and thus OxPhos uncoupling disrupt the barrier function in the ARPE-19 cells across all three components of the total resistance (Rb, α, and Cm) in a dose-dependent manner. On the other hand, oligomycin and thus ATP synthase inhibition mostly affects the ARPE-19 cells' attachment to their substrate evident by a significant decrease in α resistance in a dose-dependent manner, both at the end and throughout the duration of the experiment. On the contrary, rotenone and complex I inhibition mostly affect the ARPE-19 paracellular resistance Rb in a dose-dependent manner compared to basolateral resistance α or Cm. Our results clearly demonstrate differential roles for different mitochondrial components in maintaining RPE cell functionality in which uncoupling of OxPhos is a major contributing factor to the disruption barrier function. Such differences can be used in investigating gene expression as well as for screening of selective agents that improve the OxPhos coupling efficiency to be used in the therapeutic approach for treating RPE-related retinal diseases.


Assuntos
Barreira Hematorretiniana/metabolismo , Retinopatia Diabética/metabolismo , Células Epiteliais/metabolismo , Degeneração Macular/metabolismo , Mitocôndrias/metabolismo , Fosforilação Oxidativa/efeitos dos fármacos , Epitélio Pigmentado da Retina/metabolismo , Barreira Hematorretiniana/efeitos dos fármacos , Carbonil Cianeto p-Trifluormetoxifenil Hidrazona/farmacocinética , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Impedância Elétrica , Transporte de Elétrons/efeitos dos fármacos , Inibidores Enzimáticos/farmacocinética , Humanos , Mitocôndrias/efeitos dos fármacos , ATPases Mitocondriais Próton-Translocadoras/antagonistas & inibidores , Oligomicinas/farmacocinética , Epitélio Pigmentado da Retina/efeitos dos fármacos , Rotenona/farmacocinética
7.
Oxid Med Cell Longev ; 2021: 9990794, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34457121

RESUMO

Aims: This study is aimed at examining whether fatty acid synthase (FAS) can regulate mitochondrial function in hypoxia-induced pulmonary arterial hypertension (PAH) and its related mechanism. Results: The expression of FAS significantly increased in the lung tissue of mice with hypoxia-induced PAH, and its pharmacological inhibition by C75 ameliorated right ventricle cardiac function as revealed by echocardiographic analysis. Based on transmission electron microscopy and Seahorse assays, the mitochondrial function of mice with hypoxia was abnormal but was partially reversed after C75 injection. In vitro studies also showed an increase in the expression of FAS in hypoxia-induced human pulmonary artery smooth muscle cells (HPASMCs), which could be attenuated by FAS shRNA as well as C75 treatment. Meanwhile, C75 treatment reversed hypoxia-induced oxidative stress and activated PI3K/AKT signaling. shRNA-mediated inhibition of FAS reduced its expression and oxidative stress levels and improved mitochondrial respiratory capacity and ATP levels of hypoxia-induced HPASMCs. Conclusions: Inhibition of FAS plays a crucial role in shielding mice from hypoxia-induced PAH, which was partially achieved through the activation of PI3K/AKT signaling, indicating that the inhibition of FAS may provide a potential future direction for reversing PAH in humans.


Assuntos
4-Butirolactona/análogos & derivados , Metabolismo Energético , Ácido Graxo Sintases/antagonistas & inibidores , Hipóxia/complicações , Mitocôndrias/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Hipertensão Arterial Pulmonar/tratamento farmacológico , 4-Butirolactona/farmacologia , Animais , Apoptose , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Hipertensão Arterial Pulmonar/enzimologia , Hipertensão Arterial Pulmonar/etiologia , Hipertensão Arterial Pulmonar/patologia , Transdução de Sinais
8.
Int J Mol Sci ; 22(16)2021 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-34445139

RESUMO

Recent evidence pinpoints extracellular vesicles (EVs) as key players in intercellular communication. Given the importance of cholesterol and sphingomyelin in EV biology, and the relevance of mitochondria-associated endoplasmic reticulum membranes (MAMs) in cholesterol/sphingomyelin homeostasis, we evaluated if MAMs and sphingomyelinases (SMases) could participate in ethanol-induced EV release. EVs were isolated from the extracellular medium of BV2 microglia treated or not with ethanol (50 and 100 mM). Radioactive metabolic tracers combined with thin layer chromatography were used as quantitative methods to assay phospholipid transfer, SMase activity and cholesterol uptake/esterification. Inhibitors of SMase (desipramine and GW4869) and MAM (cyclosporin A) activities were also utilized. Our data show that ethanol increases the secretion and inflammatory molecule concentration of EVs. Ethanol also upregulates MAM activity and alters lipid metabolism by increasing cholesterol uptake, cholesterol esterification and SMase activity in microglia. Notably, the inhibition of either SMase or MAM activity prevented the ethanol-induced increase in EV secretion. Collectively, these results strongly support a lipid-driven mechanism, specifically via SMases and MAM, to explain the effect of ethanol on EV secretion in glial cells.


Assuntos
Retículo Endoplasmático/efeitos dos fármacos , Etanol/farmacologia , Vesículas Extracelulares/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Membranas Mitocondriais/efeitos dos fármacos , Esfingomielina Fosfodiesterase/metabolismo , Compostos de Anilina/farmacologia , Animais , Compostos de Benzilideno/farmacologia , Células Cultivadas , Colesterol/metabolismo , Ciclosporina/farmacologia , Retículo Endoplasmático/metabolismo , Vesículas Extracelulares/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Microglia/metabolismo , Mitocôndrias/metabolismo , Membranas Mitocondriais/metabolismo , Fosfolipídeos/metabolismo
9.
Int J Mol Sci ; 22(16)2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34445344

RESUMO

Thyroid hormones, including 3,5,3'-triiodothyronine (T3), cause a wide spectrum of genomic effects on cellular metabolism and bioenergetic regulation in various tissues. The non-genomic actions of T3 have been reported but are not yet completely understood. Acute T3 treatment significantly enhanced basal, maximal, ATP-linked, and proton-leak oxygen consumption rates (OCRs) of primary differentiated mouse brown adipocytes accompanied with increased protein abundances of uncoupling protein 1 (UCP1) and mitochondrial Ca2+ uniporter (MCU). T3 treatment depolarized the resting mitochondrial membrane potential (Ψm) but augmented oligomycin-induced hyperpolarization in brown adipocytes. Protein kinase B (AKT) and mammalian target of rapamycin (mTOR) were activated by T3, leading to the inhibition of autophagic degradation. Rapamycin, as an mTOR inhibitor, blocked T3-induced autophagic suppression and UCP1 upregulation. T3 increases intracellular Ca2+ concentration ([Ca2+]i) in brown adipocytes. Most of the T3 effects, including mTOR activation, UCP1 upregulation, and OCR increase, were abrogated by intracellular Ca2+ chelation with BAPTA-AM. Calmodulin inhibition with W7 or knockdown of MCU dampened T3-induced mitochondrial activation. Furthermore, edelfosine, a phospholipase C (PLC) inhibitor, prevented T3 from acting on [Ca2+]i, UCP1 abundance, Ψm, and OCR. We suggest that short-term exposure of T3 induces UCP1 upregulation and mitochondrial activation due to PLC-mediated [Ca2+]i elevation in brown adipocytes.


Assuntos
Tecido Adiposo Marrom/efeitos dos fármacos , Cálcio/metabolismo , Mitocôndrias/efeitos dos fármacos , Tri-Iodotironina/farmacologia , Tecido Adiposo Marrom/metabolismo , Animais , Cálcio/farmacologia , Sinalização do Cálcio/efeitos dos fármacos , Sinalização do Cálcio/fisiologia , Células Cultivadas , Metabolismo Energético/efeitos dos fármacos , Feminino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Consumo de Oxigênio/efeitos dos fármacos
10.
Int J Mol Sci ; 22(16)2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34445360

RESUMO

Multi-factorial mitochondrial damage exhibits a "vicious circle" that leads to a progression of mitochondrial dysfunction and multi-organ adverse effects. Mitochondrial impairments (mitochondriopathies) are associated with severe pathologies including but not restricted to cancers, cardiovascular diseases, and neurodegeneration. However, the type and level of cascading pathologies are highly individual. Consequently, patient stratification, risk assessment, and mitigating measures are instrumental for cost-effective individualized protection. Therefore, the paradigm shift from reactive to predictive, preventive, and personalized medicine (3PM) is unavoidable in advanced healthcare. Flavonoids demonstrate evident antioxidant and scavenging activity are of great therapeutic utility against mitochondrial damage and cascading pathologies. In the context of 3PM, this review focuses on preclinical and clinical research data evaluating the efficacy of flavonoids as a potent protector against mitochondriopathies and associated pathologies.


Assuntos
Flavonoides/uso terapêutico , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/prevenção & controle , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Citoproteção/efeitos dos fármacos , Flavonoides/farmacologia , Humanos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitofagia/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Medicina de Precisão/métodos , Prognóstico
11.
Chem Biol Interact ; 347: 109599, 2021 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-34343525

RESUMO

BACKGROUND: Geraniol, a natural monoterpene, is a component of many plant essential oils. It contains many medicinal and pharmacological properties. Doxorubicin is an anticancer drug; however, its clinical usage is limited due to its cumulative and dose-dependent cardiotoxicity. This study investigates geraniol as a protective agent against doxorubicin-induced cardiotoxicity and explores possible underlying mechanisms of action. METHODS: Male Sprague-Dawley rats were allocated into five groups. Groups 1 and 2 were administered saline and geraniol 200 mg/kg/day/orally, respectively, for 15 days. Group 3 was administered intraperitoneal doxorubicin (5 mg/kg/IP on the 5th, 10th and 15th days to achieve a cumulative dose of 15 mg/kg) to induce cardiotoxicity. The fourth and fifth groups were treated with either geraniol 100 mg/kg or 200 mg/kg orally and doxorubicin to equal the doxorubicin dose administered to Group 3. RESULTS: Treatment with geraniol significantly ameliorated cardiac damage and restored serum cardiac injury marker levels in doxorubicin treated animals. Geraniol upregulated Nrf2 and HO-1 expression, elevated total antioxidant capacity, decreased the nuclear accumulation of kappa-light-chain enhancer of activated B cells (NF-κB), decreased the phosphorylation and degradation of nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκBα), suppressed tumor necrosis factor-alpha (TNF-α), interleukin 1 beta (IL-1ß), and interleukin-18 (IL-18) levels, and restored the levels of Bax and caspase-3 and 9 in heart tissue. CONCLUSION: Geraniol may function as a potential activator of nuclear factor erythroid 2-related factor 2 (Nrf2), which subsequently improves Nrf2-dependent antioxidative signaling, diminishes apoptosis and subdues the inflammatory response. The downstream result is protection of the heart from doxorubicin-induced cardiotoxicity.


Assuntos
Monoterpenos Acíclicos/uso terapêutico , Cardiotônicos/uso terapêutico , Cardiotoxicidade/tratamento farmacológico , Cymbopogon/química , Doxorrubicina/toxicidade , Transdução de Sinais/efeitos dos fármacos , Animais , Cardiotoxicidade/patologia , Eletrocardiografia/efeitos dos fármacos , Fator de Transcrição de Proteínas de Ligação GA/metabolismo , Frequência Cardíaca/efeitos dos fármacos , Heme Oxigenase (Desciclizante)/metabolismo , Masculino , Mitocôndrias/efeitos dos fármacos , Miocárdio/patologia , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley
12.
Int J Mol Sci ; 22(15)2021 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-34361099

RESUMO

(1) Background: Ellagitannins are natural products occurring in pomegranate and walnuts. They are hydrolyzed in the gut to release ellagic acid, which is further metabolized by the microflora into urolithins, such as urolithin A (UA). Accumulation of damaged mitochondria is a hallmark of aging and age-related neurodegenerative diseases. In this study, we investigated the neuroprotective activity of the metabolite UA against mitochondrial dysfunction in a cellular model of early Alzheimer disease (AD). (2) Methods: In the present study we used SH-SY5Y-APP695 cells and its corresponding controls (SH-SY5Ymock) to assess UA's effect on mitochondrial function. Using these cells we investigated mitochondrial respiration (OXPHOS), mitochondrial membrane potential (MMP), adenosine triphosphate (ATP) production, autophagy and levels of reactive oxygen species (ROS) in cells treated with UA. Furthermore, we assessed UA's effect on the expression of genes related to mitochondrial bioenergetics, mitochondrial biogenesis, and autophagy via quantitative real-time PCR (qRT-PCR). (3) Results: Treatment of SH-SY5Y-APP695 cells suggests changes to autophagy corresponding with qRT-PCR results. However, LC3B-I, LC3B-II, and p62 levels were unchanged. UA (10 µM) reduced MMP, and ATP-levels. Treatment of cells with UA (1 µM) for 24 h did not affect ROS production or levels of Aß, but significantly increased expression of genes for mitochondrial biogenesis and OXPHOS. Mitochondrial Transcription Factor A (TFAM) expression was specifically increased in SH-SY5Y-APP695. Both cell lines showed unaltered levels of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), which is commonly associated with mitochondrial biogenesis. Results imply that biogenesis might be facilitated by estrogen-related receptor (ESRR) genes. (4) Conclusion: Urolithin A shows no effect on autophagy in SH-SY5Y-APP695 cells and its effect on mitochondrial function is limited. Instead, data suggests that UA treatment induces hormetic effects as it induces transcription of several genes related to mitochondrial biogenesis.


Assuntos
Trifosfato de Adenosina/metabolismo , Doença de Alzheimer/metabolismo , Cumarínicos/farmacologia , Mitocôndrias/metabolismo , Neuroblastoma/metabolismo , Biogênese de Organelas , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Autofagia , Metabolismo Energético , Humanos , Potencial da Membrana Mitocondrial , Mitocôndrias/efeitos dos fármacos , Neuroblastoma/tratamento farmacológico , Neuroblastoma/patologia , Espécies Reativas de Oxigênio/metabolismo , Células Tumorais Cultivadas
13.
Int J Mol Sci ; 22(15)2021 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-34360534

RESUMO

Inorganic phosphate (Pi) is an essential nutrient for living organisms and is maintained in equilibrium in the range of 0.8-1.4 mM Pi. Pi is a source of organic constituents for DNA, RNA, and phospholipids and is essential for ATP formation mainly through energy metabolism or cellular signalling modulators. In mitochondria isolated from the brain, liver, and heart, Pi has been shown to induce mitochondrial reactive oxygen species (ROS) release. Therefore, the purpose of this review article was to gather relevant experimental records of the production of Pi-induced reactive species, mainly ROS, to examine their essential roles in physiological processes, such as the development of bone and cartilage and the development of diseases, such as cardiovascular disease, diabetes, muscle atrophy, and male reproductive system impairment. Interestingly, in the presence of different antioxidants or inhibitors of cytoplasmic and mitochondrial Pi transporters, Pi-induced ROS production can be reversed and may be a possible pharmacological target.


Assuntos
Doenças Cardiovasculares/patologia , Diabetes Mellitus/patologia , Mitocôndrias/patologia , Atrofia Muscular/patologia , Fosfatos/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Animais , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/metabolismo , Diabetes Mellitus/etiologia , Diabetes Mellitus/metabolismo , Metabolismo Energético , Humanos , Mitocôndrias/efeitos dos fármacos , Atrofia Muscular/etiologia , Atrofia Muscular/metabolismo
14.
Int J Mol Sci ; 22(15)2021 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-34360581

RESUMO

Ischemic stroke is the third leading cause of death in the world, which accounts for almost 12% of the total deaths worldwide. Despite decades of research, the available and effective pharmacotherapy is limited. Some evidence underlines the beneficial properties of hydrogen sulfide (H2S) donors, such as NaSH, in an animal model of brain ischemia and in in vitro research; however, these data are ambiguous. This study was undertaken to verify the neuroprotective activity of AP39, a slow-releasing mitochondria-targeted H2S delivery molecule. We administered AP39 for 7 days prior to ischemia onset, and the potential to induce brain tolerance to ischemia was verified. To do this, we used the rat model of 90-min middle cerebral artery occlusion (MCAO) and used LC-MS/MS, RT-PCR, LuminexTM assays, Western blot and immunofluorescent double-staining to determine the absolute H2S levels, inflammatory markers, neurotrophic factor signaling pathways and apoptosis marker in the ipsilateral frontal cortex, hippocampus and in the dorsal striatum 24 h after ischemia onset. AP39 (50 nmol/kg) reduced the infarct volume, neurological deficit and reduced the microglia marker (Iba1) expression. AP39 also exerted prominent anti-inflammatory activity in reducing the release of Il-1ß, Il-6 and TNFα in brain areas particularly affected by ischemia. Furthermore, AP39 enhanced the pro-survival pathways of neurotrophic factors BDNF-TrkB and NGF-TrkA and reduced the proapoptotic proNGF-p75NTR-sortilin pathway activity. These changes corresponded with reduced levels of cleaved caspase 3. Altogether, AP39 treatment induced adaptative changes within the brain and, by that, developed brain tolerance to ischemia.


Assuntos
Isquemia Encefálica/prevenção & controle , Sulfeto de Hidrogênio/metabolismo , Infarto da Artéria Cerebral Média/complicações , Mitocôndrias/metabolismo , Compostos Organofosforados/farmacologia , Substâncias Protetoras/farmacologia , Tionas/farmacologia , Animais , Isquemia Encefálica/etiologia , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Sulfeto de Hidrogênio/análise , Masculino , Mitocôndrias/efeitos dos fármacos , Compostos Organofosforados/administração & dosagem , Substâncias Protetoras/administração & dosagem , Ratos , Ratos Sprague-Dawley , Tionas/administração & dosagem
15.
Nutrients ; 13(7)2021 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-34371916

RESUMO

White adipose tissue (WAT) is a dynamic endocrine organ that can play a significant role in thermoregulation. WAT has the capacity to adopt structural and functional characteristics of the more metabolically active brown adipose tissue (BAT) and contribute to non-shivering thermogenesis under specific stimuli. Non-shivering thermogenesis was previously thought to be uncoupling protein 1 (UCP1)-dependent however, recent evidence suggests that UCP1-independent mechanisms of thermogenesis exist. Namely, futile creatine cycling has been identified as a contributor to WAT thermogenesis. The purpose of this study was to examine the efficacy of creatine supplementation to alter mitochondrial markers as well as adipocyte size and multilocularity in inguinal (iWAT), gonadal (gWAT), and BAT. Thirty-two male and female Sprague-Dawley rats were treated with varying doses (0 g/L, 2.5 g/L, 5 g/L, and 10 g/L) of creatine monohydrate for 8 weeks. We demonstrate that mitochondrial markers respond in a sex and depot specific manner. In iWAT, female rats displayed significant increases in COXIV, PDH-E1alpha, and cytochrome C protein content. Male rats exhibited gWAT specific increases in COXIV and PDH-E1alpha protein content. This study supports creatine supplementation as a potential method of UCP1-independant thermogenesis and highlights the importance of taking a sex-specific approach when examining the efficacy of browning therapeutics in future research.


Assuntos
Tecido Adiposo Branco/efeitos dos fármacos , Regulação da Temperatura Corporal/efeitos dos fármacos , Creatina/farmacologia , Suplementos Nutricionais , Mitocôndrias/efeitos dos fármacos , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Citocromos c/metabolismo , Relação Dose-Resposta a Droga , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Feminino , Masculino , Mitocôndrias/metabolismo , Piruvato Desidrogenase (Lipoamida) , Ratos Sprague-Dawley , Fatores Sexuais , Proteína Desacopladora 1/metabolismo
16.
Nat Commun ; 12(1): 4835, 2021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34376679

RESUMO

F-ATP synthase is a leading candidate as the mitochondrial permeability transition pore (PTP) but the mechanism(s) leading to channel formation remain undefined. Here, to shed light on the structural requirements for PTP formation, we test cells ablated for g, OSCP and b subunits, and ρ0 cells lacking subunits a and A6L. Δg cells (that also lack subunit e) do not show PTP channel opening in intact cells or patch-clamped mitoplasts unless atractylate is added. Δb and ΔOSCP cells display currents insensitive to cyclosporin A but inhibited by bongkrekate, suggesting that the adenine nucleotide translocator (ANT) can contribute to channel formation in the absence of an assembled F-ATP synthase. Mitoplasts from ρ0 mitochondria display PTP currents indistinguishable from their wild-type counterparts. In this work, we show that peripheral stalk subunits are essential to turn the F-ATP synthase into the PTP and that the ANT provides mitochondria with a distinct permeability pathway.


Assuntos
Cálcio/metabolismo , Mitocôndrias/metabolismo , Poro de Transição de Permeabilidade Mitocondrial/metabolismo , ATPases Mitocondriais Próton-Translocadoras/metabolismo , Cálcio/farmacologia , Carbonil Cianeto p-Trifluormetoxifenil Hidrazona/farmacologia , Linhagem Celular Tumoral , Células HeLa , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Potencial da Membrana Mitocondrial/fisiologia , Mitocôndrias/efeitos dos fármacos , ATPases Mitocondriais Próton-Translocadoras/genética , Subunidades Proteicas/genética , Subunidades Proteicas/metabolismo , Ionóforos de Próton/farmacologia
17.
Toxicol Lett ; 350: 121-132, 2021 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-34252510

RESUMO

Silicosis is characterized by pulmonary interstitial fibrosis that arises as a result of chronic exposure to silica. The few available treatments only delay its progression. As α-lipoic acid (ALA) has been shown to have various beneficial effects, including mitoprotective, antioxidant, and anti-inflammatory effects, we hypothesized that it may exhibit therapeutic effects in pulmonary fibrosis. Therefore, in the present study, we used a murine model of silicosis to investigate whether supplementation with exogenous ALA could attenuate silica-induced pulmonary fibrosis by improving mitochondrial function. ALA was administered to the model mice via continuous intragastric administration for 28 days, and then the antioxidant and mitoprotective effects of ALA were evaluated. The results showed that ALA decreased the production of reactive oxygen species, protected mitochondria from silica-induced dysfunction, and inhibited extracellular matrix deposition. ALA also decreased hyperglycemia and hyperlipidemia. Activation of the mitochondrial AMPK/PGC1α pathway might be responsible for these ALA-mediated anti-fibrotic effects. Exogenous ALA blocked oxidative stress by activating NRF2. Taken together, these findings demonstrate that exogenous ALA effectively prevents the progression of silicosis in a murine model, likely by stimulating mitochondrial biogenesis and endogenous antioxidant responses. Therefore, ALA can potentially delay the progression of silica-induced pulmonary fibrosis.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Mitocôndrias/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/tratamento farmacológico , Dióxido de Silício/efeitos adversos , Silicose/tratamento farmacológico , Ácido Tióctico/uso terapêutico , Proteínas Quinases Ativadas por AMP/efeitos dos fármacos , Animais , Antioxidantes/metabolismo , Antioxidantes/uso terapêutico , Humanos , Masculino , Redes e Vias Metabólicas , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Modelos Animais , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/efeitos dos fármacos , Fibrose Pulmonar/metabolismo , Silicose/metabolismo , Silicose/fisiopatologia , Ácido Tióctico/metabolismo
18.
Int J Mol Sci ; 22(12)2021 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-34204592

RESUMO

NADH dehydrogenase (ubiquinone) Fe-S protein 8 (NDUFS8) is a nuclear-encoded core subunit of human mitochondrial complex I. Defects in NDUFS8 are associated with Leigh syndrome and encephalomyopathy. Cell-penetrating peptide derived from the HIV-1 transactivator of transcription protein (TAT) has been successfully applied as a carrier to bring fusion proteins into cells without compromising the biological function of the cargoes. In this study, we developed a TAT-mediated protein transduction system to rescue complex I deficiency caused by NDUFS8 defects. Two fusion proteins (TAT-NDUFS8 and NDUFS8-TAT) were exogenously expressed and purified from Escherichia coli for transduction of human cells. In addition, similar constructs were generated and used in transfection studies for comparison. The results showed that both exogenous TAT-NDUFS8 and NDUFS8-TAT were delivered into mitochondria and correctly processed. Interestingly, the mitochondrial import of TAT-containing NDUFS8 was independent of mitochondrial membrane potential. Treatment with TAT-NDUFS8 not only significantly improved the assembly of complex I in an NDUFS8-deficient cell line, but also partially rescued complex I functions both in the in-gel activity assay and the oxygen consumption assay. Our current findings suggest the considerable potential of applying the TAT-mediated protein transduction system for treatment of complex I deficiency.


Assuntos
Complexo I de Transporte de Elétrons/deficiência , Potencial da Membrana Mitocondrial , Mitocôndrias/genética , Mitocôndrias/metabolismo , NADH Desidrogenase/metabolismo , Proteínas Recombinantes de Fusão/metabolismo , Produtos do Gene tat do Vírus da Imunodeficiência Humana/metabolismo , Sequência de Aminoácidos , Linhagem Celular , Sobrevivência Celular , Células Cultivadas , Complexo de Proteínas da Cadeia de Transporte de Elétrons/genética , Complexo de Proteínas da Cadeia de Transporte de Elétrons/metabolismo , Humanos , Mitocôndrias/efeitos dos fármacos , NADH Desidrogenase/genética , Transporte Proteico , Interferência de RNA , RNA Mensageiro/genética , RNA Interferente Pequeno/genética , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/farmacologia , Produtos do Gene tat do Vírus da Imunodeficiência Humana/genética
19.
Int J Mol Sci ; 22(14)2021 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-34299032

RESUMO

Mitoflashes are spontaneous transients of the biosensor mt-cpYFP. In cardiomyocytes, mitoflashes are associated with the cyclophilin D (CypD) mediated opening of mitochondrial permeability transition pore (mPTP), while in skeletal muscle they are considered hallmarks of mitochondrial respiration burst under physiological conditions. Here, we evaluated the potential association between mitoflashes and the mPTP opening at different CypD levels and phosphorylation status by generating three CypD derived fusion constructs with a red shifted, pH stable Ca2+ sensor jRCaMP1b. We observed perinuclear mitochondrial Ca2+ efflux accompanying mitoflashes in CypD and CypDS42A (a phosphor-resistant mutation at Serine 42) overexpressed myofibers but not the control myofibers expressing the mitochondria-targeting sequence of CypD (CypDN30). Assisted by a newly developed analysis program, we identified shorter, more frequent mitoflash activities occurring over larger areas in CypD and CypDS42A overexpressed myofibers than the control CypDN30 myofibers. These observations provide an association between the elevated CypD expression and increased mitoflash activities in hindlimb muscles in an amyotrophic lateral sclerosis (ALS) mouse model previously observed. More importantly, feeding the mice with sodium butyrate reversed the CypD-associated mitoflash phenotypes and protected against ectopic upregulation of CypD, unveiling a novel molecular mechanism underlying butyrate mediated alleviation of ALS progression in the mouse model.


Assuntos
Butiratos/farmacologia , Ciclofilina D/metabolismo , Mitocôndrias/efeitos dos fármacos , Poro de Transição de Permeabilidade Mitocondrial/metabolismo , Fibras Musculares Esqueléticas/efeitos dos fármacos , Mutação , Superóxido Dismutase-1/fisiologia , Animais , Ciclofilina D/genética , Feminino , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patologia
20.
Cell Death Dis ; 12(7): 705, 2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-34262021

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is an extremely lethal cancer with limited treatment options. Cisplatin (DDP) is used as a mainstay of chemotherapeutic agents in combination with other drugs or radiotherapy for PDAC therapy. However, DDP exhibits severe side-effects that can lead to discontinuation of therapy, and the acquired drug resistance of tumor cells presents serious clinical obstacles. Therefore, it is imperative to develop a more effective and less toxic therapeutic strategy. We and others have previously discovered that dihydroartemisinin (DHA) represents a safe and promising therapeutic agent to preferentially induce cancer cell ferroptosis. In the present study, we find that DHA could intensively strengthen the cytotoxicity of DDP and significantly reduce its effective concentrations both in vitro and in vivo. Combination of DHA and DDP synergistically inhibits the proliferation and induces DNA damage of PDAC cells. Mechanically, the combinative treatment impairs mitochondrial homeostasis, characterized by destroyed mitochondrial morphology, decreased respiratory capacity, reduced ATP production, and accumulated mitochondria-derived ROS. Further studies show that ferroptosis contributes to the cytotoxic effects in PDAC cells under the challenge of DHA and DDP, together with catastrophic accumulation of free iron and unrestricted lipid peroxidation. Moreover, pharmacologic depleting of the free iron reservoir or reconstituted expression of FTH contributes to the tolerance of DHA/DDP-induced ferroptosis, while iron addition accelerates the ferroptotic cell death. In summary, these results provide experimental evidence that DHA acts synergistically with DDP and renders PDAC cells vulnerable to ferroptosis, which may act as a promising therapeutic strategy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Artemisininas/farmacologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Cisplatino/farmacologia , Ferroptose/efeitos dos fármacos , Ferro/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Trifosfato de Adenosina/metabolismo , Animais , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Dano ao DNA , Resistencia a Medicamentos Antineoplásicos , Sinergismo Farmacológico , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Invasividade Neoplásica , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Espécies Reativas de Oxigênio/metabolismo , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
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