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1.
Arch Biochem Biophys ; 688: 108402, 2020 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-32418909

RESUMO

A/J mouse is a model of age-related hearing loss (AHL). Mutation in the citrate synthase (Cs) gene of the mouse plays an important role in the hearing loss and degeneration of cochlear cells. To investigate the pathogenesis of cochlear cell damage in A/J mice resulted from Cs mutation, we downregulated the expression level of CS in HEI-OC1, a cell line of mouse cochlea, by shRNA. The results showed that low CS expression led to low ability of cell proliferation. Further study revealed an increase level of reactive oxygen species (ROS), activation of ATF6 mediated endoplasmic reticulum stress (ERS) and high expression levels of caspase12 and Bax in the cells. Moreover, the AEBSF, an ATF6 inhibitor, could reduce the expression levels of caspase-12 and Bax by inhibiting the hydrolysis of ATF6 in the cells. Finally, antioxidant alpha-lipoic acid (ALA) reduced the ROS levels and the apoptotic signals in the cell model with low CS expression. We therefore conclude that the ERS mediated apoptosis, which is triggered by ROS, may be involved in the cell degeneration in the cochleae of A/J mice.


Assuntos
Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Citrato (si)-Sintase/metabolismo , Estresse do Retículo Endoplasmático/fisiologia , Estresse Oxidativo/efeitos dos fármacos , Ácido Tióctico/farmacologia , Fator 6 Ativador da Transcrição/antagonistas & inibidores , Animais , Apoptose/fisiologia , Caspase 12/metabolismo , Linhagem Celular , Proliferação de Células/fisiologia , Regulação para Baixo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Camundongos , Mitocôndrias/metabolismo , Modelos Biológicos , Estresse Oxidativo/fisiologia , Presbiacusia/fisiopatologia , Espécies Reativas de Oxigênio/metabolismo , Sulfonas/farmacologia , Proteína X Associada a bcl-2/metabolismo
2.
PLoS One ; 15(4): e0231770, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32298377

RESUMO

The Warburg effect, a hallmark of cancer, has recently been identified as a metabolic limitation of Chinese Hamster Ovary (CHO) cells, the primary platform for the production of monoclonal antibodies (mAb). Metabolic engineering approaches, including genetic modifications and feeding strategies, have been attempted to impose the metabolic prevalence of respiration over aerobic glycolysis. Their main objective lies in decreasing lactate production while improving energy efficiency. Although yielding promising increases in productivity, such strategies require long development phases and alter entangled metabolic pathways which singular roles remain unclear. We propose to apply drugs used for the metabolic therapy of cancer to target the Warburg effect at different levels, on CHO cells. The use of α-lipoic acid, a pyruvate dehydrogenase activator, replenished the Krebs cycle through increased anaplerosis but resulted in mitochondrial saturation. The electron shuttle function of a second drug, methylene blue, enhanced the mitochondrial capacity. It pulled on anaplerotic pathways while reducing stress signals and resulted in a 24% increase of the maximum mAb production. Finally, the combination of both drugs proved to be promising for stimulating Krebs cycle activity and mitochondrial respiration. Therefore, drugs used in metabolic therapy are valuable candidates to understand and improve the metabolic limitations of CHO-based bioproduction.


Assuntos
Anticorpos Monoclonais/biossíntese , Ciclo do Ácido Cítrico/fisiologia , Glicólise/efeitos dos fármacos , Engenharia Metabólica/métodos , Azul de Metileno/farmacologia , Ácido Tióctico/farmacologia , Animais , Células CHO , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cricetulus , Glucose/metabolismo , Glutamina/metabolismo , Glicólise/fisiologia , Ácido Láctico/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Azul de Metileno/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Fosforilação Oxidativa/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Respiração , Ácido Tióctico/metabolismo
3.
Int J Mol Sci ; 21(7)2020 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-32218158

RESUMO

Radiation therapy is a standard treatment for patients with head and neck cancer. However, radiation exposure to the head and neck induces salivary gland (SG) dysfunction. Alpha lipoic acid (ALA) has been reported to reduce radiation-induced toxicity in normal tissues. In this study, we investigated the effect of ALA on radiation-induced SG dysfunction. Male Sprague-Dawley rats were assigned to the following treatment groups: control, ALA only (100 mg/kg, intraperitoneally), irradiation only, and ALA administration 24 h or 30 min prior to irradiation. The neck area, including SGs, was irradiated evenly at 2 Gy/min (total dose, 18 Gy) using a photon 6 MV linear accelerator. The rats were sacrificed at 2, 6, 8, and 12 weeks after irradiation. Radiation decreased SG weight, saliva secretion, AQP5 expression, parasympathetic innervation (GFRα2 and AchE expression), regeneration potentials (Shh and Ptch expression), salivary trophic factor levels (brain-derived neurotrophic factor and neurturin), and stem cell expression (Sca-1). These features were restored by treatment with ALA. This study demonstrated that ALA can rescue radiation-induced hyposalivation by preserving parasympathetic innervation and regenerative potentials.


Assuntos
Lesões Experimentais por Radiação/tratamento farmacológico , Glândulas Salivares/efeitos dos fármacos , Ácido Tióctico/farmacologia , Animais , Peso Corporal/efeitos dos fármacos , Masculino , Tamanho do Órgão/efeitos dos fármacos , Lesões Experimentais por Radiação/patologia , Ratos Sprague-Dawley , Glândulas Salivares/patologia
4.
Acta Trop ; 206: 105449, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32194067

RESUMO

Lipoic acid (LA) has been shown to possess protective effects against liver fibrosis mainly by induction of apoptosis of activated hepatic stellate cells, but the mechanism of LA activity in liver fibrosis has yet to be completely explained. LA occurs naturally in mitochondria as a coenzyme. In this study, we used mice with schistosomiasis-induced liver fibrosis and mouse hepatocarcinoma cell line 1C1C7 as models to investigate the mitochondrial mechanism of LA treatment for liver fibrosis. Western blot, real-time PCR and oxygen consumption rate (OCR) test were used. In the livers of mice with liver fibrosis, the mRNA levels of LA synthetic pathway enzymes, including MCAT, OXSM, MECR, and LIAS, were significantly reduced. Livers of mice with liver fibrosis showed degenerative signs, such as mitochondrial edema, a reduced mitochondrial crest and matrix density, or vacuolation; the activities of mitochondrial complexes I, II, IV, and V were also decreased in these livers. The expression of phosphorylation Drp1 (p-Drp1) was decreased in the livers of mice with liver fibrosis, indicating increased mitochondrial fission activity, whereas OPA1 and MFN1 expression was reduced, denoting decreased activity of mitochondrial fusion. To understand the mitochondrial mechanism of LA treatment for liver fibrosis, p-Drp1, OPA1, and MFN1 expression were detected at the protein level in mouse hepatocarcinoma cell line 1C1C7 stimulated by LA. OPA1 and MFN1 were not significantly altered, but p-Drp1 was significantly increased. The results suggest that LA may alleviate liver fibrosis through upregulating p-Drp1. This study provides a new insight into the mechanism of the protective effect of LA against schistosomiasis-induced liver fibrosis, which demonstrates that LA is required for the maintenance of mitochondrial function by upregulating p-Drp1 expression to inhibit mitochondrial fission.


Assuntos
Dinaminas/metabolismo , Cirrose Hepática/tratamento farmacológico , Esquistossomose/complicações , Ácido Tióctico/farmacologia , Animais , Linhagem Celular Tumoral , Feminino , Cirrose Hepática/etiologia , Cirrose Hepática/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Dinâmica Mitocondrial/efeitos dos fármacos , Fosforilação , Regulação para Cima
5.
Environ Toxicol ; 35(7): 738-746, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32061150

RESUMO

Microcystins (MCs), as the most dominant bloom-forming strains in eutrophic surface water, can induce hepatotoxicity by oxidative stress. Alpha-lipoic acid (α-LA) is a super antioxidant that can induce the synthesis of antioxidants, such as glutathione (GSH), by nuclear factor erythroid 2-related factor 2 (Nrf2). However, the potential molecular mechanism of α-LA regeneration of GSH remains unclear. The present study aimed to investigate whether α-LA could reduce the toxicity of MCs induced in human hepatoma (HepG2), Bel7420 cells, and BALB/c mice by activating Nrf2 to regenerate GSH. Results showed that exposure to 10 µM microcystin-leucine arginine (MC-LR) reduced viability of HepG2 and Bel7402 cells and promoted the formation of reactive oxygen species (ROS) compared with untreated cells. Moreover, the protection of α-LA included reducing the level of ROS, increasing superoxide dismutase activity, and decreasing malondialdehyde. Levels of reduced glutathione (rGSH) and rGSH/oxidized glutathione were significantly increased in cells cotreated with α-LA and MC-LR compared to those treated with MC-LR alone, indicating an ability of α-LA to attenuate oxidative stress and MC-LR-induced cytotoxicity by increasing the amount of rGSH. α-LA can mediate GSH regeneration through the Nrf2 pathway under the action of glutathione reductase in MC-LR cell lines. Furthermore, the data also showed that α-LA-induced cytoprotection against MC-LR is associated with Nrf2 mediate pathway in vivo. These findings demonstrated the potential of α-LA to resist MC-LR-induced oxidative damage of liver.


Assuntos
Antioxidantes/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Glutationa/metabolismo , Microcistinas/toxicidade , Fator 2 Relacionado a NF-E2/metabolismo , Ácido Tióctico/farmacologia , Animais , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Glutationa Redutase/metabolismo , Células Hep G2 , Humanos , Malondialdeído/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo
6.
Environ Toxicol ; 35(6): 683-696, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32061141

RESUMO

Methylmercury (MeHg) is a potent neurotoxin,which leads to a wide range of intracellular effects. The molecular mechanismsassociated to MeHg-induced neurotoxicity have not been fully understood.Oxidative stress, as well as synaptic glutamate (Glu) dyshomeostasis have beenidentified as two critical mechanisms during MeHg-mediated cytotoxicity. Here,we developed a rat model of MeHg poisoning to evaluate its neurotoxic effectsby focusing on cellular oxidative stress and synaptic Glu disruption. Inaddition, we investigated the neuroprotective role of alpha-lipoic acid (α-LA), a natural antioxidant, todeeply explore the underlying interaction between them. Fifty-six rats wererandomly divided into four groups: saline control, MeHg treatment (4 or 12µmol/kg MeHg), and α-LApre-treatment (35 µmol/kg α-LA+12µmol/kg MeHg). Rats exposed to 12 µmol/kg MeHg induced neuronal oxidativestress, with ROS accumulation and cellular antioxidant system impairment. Nrf2 andxCT pathways were activated with MeHg treatment. The enzymatic or non-enzymaticof cellular GSH synthesis were also disrupted by MeHg. On the other hand, the abnormalactivities of GS and PAG disturbed the "Glu-Gln cycle", leading to NMDARsover-activation, Ca2+ overload, and the calpain activation, which acceleratedNMDARs degradation. Meanwhile, the high expressions of phospho-p44/42 MAPK,phospho-p38 MAPK, phospho-CREB, and the high levels of caspase 3 and Bax/Bcl-2 finallyindicated the neuronal apoptosis after MeHg exposure. Pre-treatment with α-LA significantly preventedMeHg-induced neurotoxicity. In conclusion, the oxidative stress and synapticGlu dyshomeostasis contributed to MeHg-induced neuronal apoptosis. Alpha-LAattenuated these toxic effects through mechanisms of anti-oxidation andindirect Glu dyshomeostasis prevention.


Assuntos
Apoptose/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Ácido Glutâmico/metabolismo , Compostos de Metilmercúrio/toxicidade , Neurônios/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Antioxidantes/metabolismo , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Masculino , Neurônios/metabolismo , Neurônios/patologia , Síndromes Neurotóxicas/metabolismo , Síndromes Neurotóxicas/patologia , Oxirredução , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Ácido Tióctico/farmacologia
7.
Ecotoxicol Environ Saf ; 192: 110238, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32036095

RESUMO

Mercury (Hg) is an extremely dangerous environmental contaminant, responsible for human diseases including neurological disorders. However, the mechanisms of inorganic Hg (iHg)-induced cell death and toxicity are little known. Dihydrolipoic acid (DHLA) is the reduced form of a naturally occurring compound lipoic acid, which act as a potent antioxidant through multiple mechanisms. So we hypothesized that DHLA has an inhibitory role on iHg-cytotoxicity. The purposes of this research were to investigate mechanism/s of cytotoxicity of iHg, as well as, the cyto-protection of DHLA against iHg induced toxicity using PC12 cells. Treatment of PC12 cells with HgCl2 (Hg2+) (0-2.5 µM) for 48 h resulted in significant toxic effects, such as, cell viability loss, high level of lactate dehydrogenase (LDH) release, DNA damage, cellular glutathione (GSH) level decrease and increased Hg accumulation. In addition, protein level expressions of akt, p-akt, mTOR, GR, NFkB, ERK1, Nrf2 and HO-1 in cells were downregulated; and cleaved caspase 3 and cytochrome c release were upregulated after Hg2+ (2.5 µM) exposure and thus inducing apoptosis. Hg2+induced apoptosis was also confirmed by flow cytometry. However, pretreatment with DHLA (50 µM) for 3 h before Hg2+ (2.5 µM) exposure showed inhibition against iHg2+-induced cytotoxicity by reversing cell viability loss, LDH release, DNA damage, GSH decrease and inhibiting Hg accumulation. Moreover, DHLA pretreatment reversed the protein level expressions of akt, p-akt, mTOR, GR, NFkB, ERK1, Nrf2, HO-1, cleaved caspase 3 and cytochrome c. In conclusion, results showed that DHLA could attenuate Hg2+-induced cytotoxicity via limiting Hg accumulation, boosting up of antioxidant defense, and inhibition of apoptosis in cells.


Assuntos
Apoptose/efeitos dos fármacos , Poluentes Ambientais/toxicidade , Mercúrio/toxicidade , Ácido Tióctico/análogos & derivados , Animais , Antioxidantes/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Dano ao DNA , Poluentes Ambientais/metabolismo , Glutationa/metabolismo , Mercúrio/metabolismo , Células PC12 , Ratos , Transdução de Sinais/efeitos dos fármacos , Ácido Tióctico/farmacologia
8.
Int J Nanomedicine ; 15: 729-734, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32099361

RESUMO

Background: Recently, use of nanotechnology in biomedical applications such as drug delivery and diagnostic and therapeutic tools has increased greatly. This study evaluated gold nanoparticle (GNPs)-induced nephrotoxic effects in rats in vivo, and examined protective effects of alpha-lipoic acid (α-Lip) and Vitamin E (Vit E) against nephrotoxicity, lipid peroxidation, and inflammatory kidney damage induced by GNPs. Materials and Methods: Twenty-four male Wistar-Kyoto rats (220-240 g, 12 weeks old) were dosed with 50 µL of 10 nm GNPs administered intraperitoneally with or without 200 mg/kg/day Vit E or 200 mg/kg/day α-Lip. Serum was prepared for biochemical analyses. Kidney function was evaluated through measurement of creatinine (CR), uric acid (URIC), and blood urea nitrogen (BUN). Oxidative stress and lipid peroxidation were evaluated by measurement of reduced glutathione (GSH) and malondialdehyde (MDA) in kidney tissue homogenates. Results and Conclusions: The results showed a significant rise in serum kidney function biomarkers including urea, URIC, CR, and BUN in GNP-treated rats compared to normal control rats. Furthermore, GNPs led to decreased GSH and elevated MDA levels. Vit E or α-Lip supplementation showed a beneficial effect against nephrotoxicity, lipid peroxidation, and inflammatory kidney damage induced by GNPs. This study suggests that use of natural antioxidants in combination with GNPs may be a useful tool in preventing GNPs toxicity.


Assuntos
Ouro/toxicidade , Inflamação/induzido quimicamente , Peroxidação de Lipídeos/efeitos dos fármacos , Nanopartículas Metálicas/toxicidade , Ácido Tióctico/farmacologia , Vitamina E/farmacologia , Animais , Biomarcadores/metabolismo , Creatinina/sangue , Glutationa/metabolismo , Inflamação/patologia , Rim/efeitos dos fármacos , Rim/metabolismo , Masculino , Malondialdeído/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos Endogâmicos WKY , Ácido Úrico/sangue
9.
Carbohydr Polym ; 234: 115927, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32070546

RESUMO

Natural active compounds with antioxidant properties and other potential health benefits, like quercetin (Qu), have aroused wide concern for developing bio-functional products. However, their applications are hindered by their intrinsic poor water solubility and chemical instability. In this paper, a natural antioxidant alpha lipoic acid (ALA) was grafted onto chitosan (CS) to synthesize a novel graft polymer (CS-graft-ALA). In particular, this graft-polymer could self-assemble into spherical nanomicelles in water, with a low critical micelle concentration (CMC) of 0.0076 mg/mL. As a robust and active nanocarrier, the CS-graft-ALA micelles showed high efficiency in encapsulating Qu and dispersing Qu in water. As found, the antioxidant activity of Qu was effectively enhanced when entrapped within CS-graft-ALA micelles. Moreover, CS-graft-ALA micelles could significantly improve the photo-stability and temperature-stability of Qu. The Qu/CS-graft-ALA micelles with excellent water dispersability, stability and improved antioxidant activity hold a great potential for wide applications.


Assuntos
Antioxidantes/farmacologia , Quitosana/farmacologia , Polímeros/farmacologia , Quercetina/farmacologia , Ácido Tióctico/farmacologia , Antioxidantes/síntese química , Antioxidantes/química , Compostos de Bifenilo/antagonistas & inibidores , Quitosana/química , Micelas , Estrutura Molecular , Tamanho da Partícula , Picratos/antagonistas & inibidores , Polímeros/síntese química , Polímeros/química , Quercetina/química , Solubilidade , Propriedades de Superfície , Ácido Tióctico/química , Água/química
10.
Environ Toxicol Pharmacol ; 75: 103323, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31935550

RESUMO

BACKGROUND: Exposure to arsenic has been reported to affect the nervous system in a number of ways. Various epidemiological studies suggest cognitive impairment in subjects following exposure to environmental arsenic. The goal of the present study was to determine if supplementation of exogenous α-lipoic acid (ALA) could ameliorate sodium arsenite (NaAsO2) induced adverse effects on learning and memory and synaptic connectivity in rat hippocampus. METHODS: Accordingly, NaAsO2 alone (1.5/2.0 mg/kg bw) or NaAsO2 along with ALA (70 mg/kg bw) was administered by intraperitoneal (i.p.) route from postnatal day (PND) 4-17 to Wistar rat pups (experimental groups) and the Control groups received either distilled water or no treatment at all. After carrying out Elevated Plus Maze (EPM) and Morris Water Maze (MWM) test, the fresh brain tissues were collected on PND 18 and processed for Golgi Cox staining. RESULTS: Observations of MWM test revealed impaired learning and memory in iAs alone treated animals as against those co-exposed to iAs and ALA. In Golgi stained hippocampal sections of iAs alone treated animals, decreased dendritic arborization and reduced number of spines in pyramidal neurons (CA1) and granule cells (DG) was observed whereas neuronal morphology was preserved in the controls and ALA supplemented groups CONCLUSIONS: These observations are suggestive of beneficial effects of ALA on iAs induced effects on learning and memory as well as on hippocampal neuronal morphology.


Assuntos
Arsenitos/toxicidade , Substâncias Protetoras/farmacologia , Compostos de Sódio/toxicidade , Ácido Tióctico/farmacologia , Animais , Hipocampo/efeitos dos fármacos , Plasticidade Neuronal , Ratos Wistar , Memória Espacial
11.
Eur J Med Chem ; 186: 111880, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31753513

RESUMO

To date, drugs that hit a single target are inadequate for the treatment of neurodegenerative diseases, such as Alzheimer's or Parkinson's diseases. The development of multitarget ligands, able to interact with the different pathways involved in the progession of these disorders, represents a great challenge for medicinal chemists. In this context, we report here the synthesis and biological evaluation of phenol-lipoyl hybrids (SV1-13), obtained via a linking strategy, to take advantage of the synergistic effect due to the antioxidant portions and anti-amyloid properties of the single constituents present in the hybrid molecule. Biological results showed that SV5 and SV10 possessed the best protective activity against Aß1-42 induced neurotoxicity in differentiated SH-SY5Y cells. SV9 and SV10 showed remarkable antioxidant properties due to their ability to counteract the damage caused by H2O2 in SHSY-5Y-treated cells. Hovewer, SV5, showing moderate antioxidant and good neuroprotective activities, resulted the best candidate for further experiments since it also resulted stable both simulated and plasma fluids.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/antagonistas & inibidores , Antioxidantes/farmacologia , Fármacos Neuroprotetores/farmacologia , Fragmentos de Peptídeos/antagonistas & inibidores , Fenóis/farmacologia , Ácido Tióctico/farmacologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Antioxidantes/síntese química , Antioxidantes/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Fragmentos de Peptídeos/metabolismo , Fenóis/síntese química , Fenóis/química , Agregados Proteicos/efeitos dos fármacos , Relação Estrutura-Atividade , Ácido Tióctico/síntese química , Ácido Tióctico/química , Células Tumorais Cultivadas
12.
Biochim Biophys Acta Rev Cancer ; 1873(1): 188317, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31669587

RESUMO

We discuss how lipoic acid (LA), a natural antioxidant, induces apoptosis and inhibits proliferation, EMT, metastasis and stemness of cancer cells. Furthermore, owing to its ability to reduce chemotherapy-induced side effects and chemoresistance, LA appears to be a promising compound for cancer treatment.


Assuntos
Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Carcinogênese/efeitos dos fármacos , Ácido Tióctico/farmacologia , Apoptose/genética , Carcinogênese/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos
13.
Eur J Pharmacol ; 868: 172871, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-31846627

RESUMO

Niacin has been widely used as an antihyperlipidemic drug, but the flushing effect restricted its clinical application. Here, we developed novel niacin-lipoic acid dimers which lead to better lipid modulation, higher synergistic effects and less side effects. We utilized molecular docking simulation to design a novel series of niacin-lipoic acid dimers. The compound N-(2-(5-(1,2-dithiolan-3-yl)pentanamido)ethyl)nicotinamide (N2L) was selected for the in vitro and in vivo evaluation, including the agonist activity in CHO-hGPR109A cells, cell protective effects in HT22 and HUVECs cells, flushing effect in guinea pigs and rats, lipid modulation in C57BL/6 mice and high fat diet-rats and atherosclerotic lesions regulation in apolipoprotein E null mice. N2L worked as potent and selective agonists for the high affinity niacin receptor GPR109A. N2L retained antioxidation and cytoprotection of lipoic acid. In addition, N2L displayed a good therapeutic index regarding lipid modulation and atherosclerotic lesions regulation, and minimized niacin-induced vasodilation (flushing) effect in vivo. N2L showed effective treatment regarding to lipid regulation and atherosclerosis inhibition effects, also with excellent antioxidant effects, safety profiles and non-flushing. All these results suggest N2L promising application prospects in the drug development for the treatment of atherosclerosis.


Assuntos
Aterosclerose/tratamento farmacológico , Dislipidemias/tratamento farmacológico , Rubor/prevenção & controle , Hipolipemiantes/farmacologia , Animais , Aterosclerose/sangue , Aterosclerose/diagnóstico , Linhagem Celular , Cricetulus , Dimerização , Modelos Animais de Doenças , Desenho de Fármacos , Dislipidemias/sangue , Dislipidemias/diagnóstico , Feminino , Rubor/induzido quimicamente , Células Endoteliais da Veia Umbilical Humana , Humanos , Hipolipemiantes/química , Hipolipemiantes/uso terapêutico , Lipídeos/sangue , Masculino , Camundongos , Camundongos Knockout para ApoE , Simulação de Acoplamento Molecular , Niacina/química , Niacina/farmacologia , Niacina/uso terapêutico , Ratos , Ácido Tióctico/química , Ácido Tióctico/farmacologia , Ácido Tióctico/uso terapêutico
14.
Theriogenology ; 143: 139-147, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31874366

RESUMO

The present study was conducted to evaluate the effects of alpha-lipoic acid (ALA) on quantitative and qualitative indices of mouse embryos challenged by lipopolysaccharide (LPS). Having determined the effective concentrations of LPS (1 mg/mL) that could reduce blastocyst formation rate by around 50% and the optimal concentration of ALA (10 µM) that could attenuate the toxic effects of LPS on blastocyst formation, the following indices were defined: inner cell mass and trophectoderm cell numbers, blastocyst mitochondrial distribution, ROS and GSH levels, as well as the relative expression of Tlr-4. Nrf-2 and Tnf-RI/P-60 receptor involved in inflammatory pathways. Finally, embryos derived from the experimental and control groups were transferred to synchronized recipients and their implantation rate and post-implantation capacity were determined. Treatment with LPS resulted in an increase in intracellular ROS level (P ≤ 0.05), and remarkable decreases (P ≤ 0.05) in intracellular GSH content, mitochondrial mass, and blastocyst quality. ALA attenuated all the aforementioned negative effects of LPS. The relative expression levels of Nrf-2 and Tnf-RI/P-60 receptor (P ≤ 0.05) significantly increased in response to LPS, and treatment with ALA significantly reduced the relative expression of Tnf-RI/P-60. ALA also improved the post-implantation developmental capacity of embryos treated with LPS. In conclusion, our findings indicate that the reproductive toxicity of LPS could be overcome by ALA treatment. These effects were mainly due to the improvements made in intracellular antioxidant capacity as well as suppression of some inflammatory elements, especially the main receptor of TNF-α, the Tnf-RI/P-60, involved in induction of apoptosis. These observations have important implications for dairy farming and treatment of infertility.


Assuntos
Blastocisto/efeitos dos fármacos , Lipopolissacarídeos/toxicidade , Ácido Tióctico/farmacologia , Animais , Técnicas de Cultura Embrionária , Desenvolvimento Embrionário/efeitos dos fármacos , Feminino , Masculino , Camundongos , Gravidez
15.
PLoS One ; 14(12): e0226769, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31877176

RESUMO

The production of reactive oxygen species (ROS) by cisplatin is one of the major mechanisms of cisplatin-induced cytotoxicity. We examined the preventive effect of α-lipoic acid (LA) on cisplatin-induced toxicity via its antioxidant effects on in vitro and ex vivo culture systems. To elucidate the mechanism of the antioxidant activity of LA, NRF2 was inhibited using NRF2 siRNA, and the change in antioxidant activity of LA was characterized. MTT assays showed that LA was safe at concentrations up to 0.5 mM in HEI-OC1 cells and had a protective effect against cisplatin-induced cytotoxicity. Intracellular ROS production in HEI-OC1 cells was rapidly increased by cisplatin for up to 48 h. However, treatment with LA significantly reduced the production of ROS and increased the expression of the antioxidant proteins HO-1 and SOD1. Ex vivo, the organs of Corti of the group pretreated with LA exhibited better preservation than the group that received cisplatin alone. We also confirmed the nuclear translocation of NRF2 after LA administration, and that NRF2 inhibition decreased the antioxidant activity of LA. Together, these results indicate that the antioxidant activity of LA was through the activation of the NRF2/HO-1 antioxidant pathway.


Assuntos
Antineoplásicos/efeitos adversos , Antioxidantes/farmacologia , Cisplatino/efeitos adversos , Heme Oxigenase-1/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Ácido Tióctico/farmacologia , Animais , Linhagem Celular , Células Cultivadas , Camundongos , Camundongos Endogâmicos C57BL , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos
16.
Acta Biochim Pol ; 66(4): 627-632, 2019 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-31883320

RESUMO

The aim of the study presented here was an attempt to answer the question posed in the title: Is the mechanism of nitroglycerin tolerance associated with aldehyde dehydrogenase (ALDH) activity? Here, we investigated the effect of administration (separately or jointly) of lipoic acid (LA), nitroglycerin (GTN), and disulfiram (DSF; an irreversible in vivo inhibitor of all ALDH isozymes (including ALDH2)), on the development of tolerance to GTN. We also assessed the total activity of ALDH in the rat liver homogenates. Our data revealed that not only DSF and GTN inhibited the total ALDH activity in the rat liver, but LA also proved to be an inhibitor of this enzyme. At the same time, the obtained results demonstrated that the GTN tolerance did not develop in GTN, DSF and LA jointly treated rats, but did develop in GTN and DSF jointly treated rats. This means that the ability of LA to prevent GTN tolerance is not associated with the total ALDH activity in the rat liver. In this context, the fact that animals jointly receiving GTN and DSF developed tolerance to GTN, and in animals that in addition to GTN and DSF also received LA such tolerance did not develop, is - in our opinion - a sufficient premise to conclude that the nitrate tolerance certainly is not caused by a decrease in the activity of any of the ALDH isoenzymes present in the rat liver, including ALDH2. However, many questions still await an answer, including the basic one: What is the mechanism of tolerance to nitroglycerin?


Assuntos
Aldeído-Desidrogenase Mitocondrial/antagonistas & inibidores , Dissulfiram/farmacologia , Tolerância a Medicamentos/genética , Nitroglicerina/farmacologia , Aldeído Desidrogenase 1/antagonistas & inibidores , Aldeído Desidrogenase 1/genética , Aldeído-Desidrogenase Mitocondrial/genética , Animais , Humanos , Oxirredução/efeitos dos fármacos , Ratos , Ácido Tióctico/farmacologia
17.
Oxid Med Cell Longev ; 2019: 1974982, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31885774

RESUMO

The exogenous lipoic acid (LA) is successfully used as a drug in the treatment of many diseases. It is assumed that after administration, LA is transported to the intracellular compartments and reduced to dihydrolipoic acid (DHLA) which is catalyzed by NAD(P)H-dependent enzymes. The purpose of this study was to investigate whether LA can attenuate cardiovascular disturbances induced by ethanol (EtOH) and disulfiram (DSF) administration separately or jointly in rats. For this purpose, we measured systolic and diastolic blood pressure, recorded electrocardiogram (ECG), and estimated mortality of rats. We also studied the activity of aldehyde dehydrogenase (ALDH) in the rat liver. It was shown for the first time that LA partially attenuated the cardiac arrhythmia (extrasystoles and atrioventricular blocks) induced by EtOH and reduced the EtOH-induced mortality of animals, which suggests that LA may have a potential for use in cardiac disturbance in conditions of acute EtOH intoxication. The administration of EtOH, LA, and DSF separately or jointly affected the ALDH activity in the rat liver since a significant decrease in the activity of the enzyme was observed in all treatment groups. The results indicating that LA is an inhibitor of ALDH activity are very surprising.


Assuntos
Inibidores de Acetaldeído Desidrogenases/efeitos adversos , Pressão Sanguínea/efeitos dos fármacos , Sistema Cardiovascular/efeitos dos fármacos , Depressores do Sistema Nervoso Central/efeitos adversos , Dissulfiram/efeitos adversos , Etanol/efeitos adversos , Ácido Tióctico/uso terapêutico , Animais , Masculino , Ratos , Ratos Wistar , Ácido Tióctico/farmacologia
18.
Curr Med Sci ; 39(6): 920-928, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31845223

RESUMO

The aim of the present study was to observe the protective effects of α-lipoic acid (ALA) on vascular injury in rats with hyperuricemia (HUA). The ALA treatment groups (10, 30 and 90 mg/kg, respectively) were administered with ALA via gavage for 2 weeks. Subsequently, the levels of blood urea nitrogen (BUN), creatinine (CREA), uric acid (UA), total cholesterol (TC), high density lipoprotein-C (HDL-C) and low density lipoprotein-C (LDL-C) were measured; the activities of glutathione peroxidase (GSH-Px), catalase (CAT), malonaldehyde (MDA), superoxide dismutase (SOD) and xanthine oxidase (XOD) were also determined. The thoracic aorta of rats in each experimental group was observed under a light microscope; ultrastructural analysis was performed. SOD and CAT protein contents were investigated by Western blotting. The results revealed that: i) Compared with the model group, the levels of UA were decreased in the ALA groups and the levels of BUN, CREA, TC, and LDL-C decreased in the 30 and 90 mg/kg ALA groups (P<0.05); ii) compared with the model group, the activities of GSH-Px, SOD and XOD were increased and the levels of MDA were reduced in the 90 mg/kg ALA group (P<0.05); and iii) in the model and 10 mg/kg ALA groups, edema and shedding were observed in endothelial cells. Compared with the model and 10 mg/kg ALA groups, the 30 and 90 mg/kg ALA groups exhibited fewer swollen endothelial cells. In summary, the results of the present study indicated that HUA resulted in vascular oxidative stress injury and decreased the activity of antioxidative enzymes, which leads to endothelial cell damage and vascular lesions. ALA may serve as a therapeutic agent for the treatment of HUA-induced endothelial dysfunction.


Assuntos
Antioxidantes/administração & dosagem , Hiperuricemia/tratamento farmacológico , Ácido Tióctico/administração & dosagem , Lesões do Sistema Vascular/prevenção & controle , Animais , Antioxidantes/farmacologia , Nitrogênio da Ureia Sanguínea , Catalase/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Glutationa Peroxidase/metabolismo , Hiperuricemia/induzido quimicamente , Hiperuricemia/complicações , Masculino , Malondialdeído/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Superóxido Dismutase/metabolismo , Ácido Tióctico/farmacologia
19.
Bratisl Lek Listy ; 120(11): 843-848, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31747765

RESUMO

INTRODUCTION: The aim of this study is to investigate the effects of obstructive jaundice on the liver and effectivity of alpha­lipoic acid on liver damage and oxidative stress. MATERIALS AND METHODS: Thirty­six male Sprague­Dawley rats were divided into 3 groups per 12 animals, namely into Group I (control group): the bile duct was only mobilized by laparotomy, Group II (bile duct ligation group - BDL): the common bile duct was closed with clips and OJ was caused after laparotomy, and Group III (bile duct ligation and alpha­lipoic acid group - BDL+LA): after closing the common bile duct, LA was administered in an intramuscular dose of 50 mg/kg for 10 days. On the 10th day, malondialdehyde, glutathione and superoxide dismutase levels were measured in liver and histopathological evaluation was performed. RESULTS: AST (U/L)/ALT(U/L) in groups I, II and III were 155.33/51.83, 445.28/165.89, 380.78/173.33, respectively (p < 0.005). Superoxide dismutase and glutathione levels were lower in patient groups than in the control group (0.31 µl/g vs 0.36 µl/g; p < 0.05). After the lipoic acid treatment, none of the biochemical markers of liver improved. Only the increase in superoxide dismutase (0.31 µl/g and 0.34 µl/g in groups II and III, respectively) and glutathione levels (0.16 µl/g and 0.22 µl/g in groups II and III, respectively) was statistically significant (p < 0.05). CONCLUSIONS: Histopathological damage was statistically significantly decreased and antioxidant levels were statistically significantly increased after LA treatment (Tab. 1, Fig. 6, Ref. 23).


Assuntos
Icterícia Obstrutiva/tratamento farmacológico , Estresse Oxidativo , Ácido Tióctico/farmacologia , Animais , Antioxidantes/análise , Ductos Biliares , Glutationa/análise , Humanos , Ligadura , Fígado/química , Fígado/efeitos dos fármacos , Masculino , Malondialdeído/análise , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Superóxido Dismutase/análise
20.
Artigo em Inglês | MEDLINE | ID: mdl-31739465

RESUMO

Cadmium exposure contributes to internal organ dysfunction and the development of chronic diseases. The aim of the study was to assess the alleviating effect of α-lipoic acid and/or magnesium on cadmium-induced oxidative stress and disorders in bone metabolism, kidney and liver function, and hematological and biochemical parameters changes. Male rats were exposed to cadmium (30 mg Cd/kg of feed) for three months. Some animals exposed to Cd were supplemented with magnesium (150 mg Mg/kg of feed) and/or with α-lipoic acid (100 mg/kg body weight, four times a week). Cd intake inhibited body weight gain and lowered hemoglobin concentration, whereas it increased the activities of liver enzymes, as well as the level of oxidative stress, CTX-1 (C-terminal telopeptide of type I collagen, bone resorption marker), and CRP (C-reactive protein, marker of inflammation); it decreased vitamin D3, GSH (reduced glutathione), and the serum urea nitrogen/creatinine index. Mg and/or α-lipoic acid supplementation increased the antioxidant potential, and partially normalized the studied biochemical parameters. The obtained results show that both magnesium and α-lipoic acid decrease oxidative stress and the level of inflammatory marker, as well as normalize bone metabolism and liver and kidney function. Combined intake of α-lipoic acid and magnesium results in reinforcement of the protective effect; especially, it increases antioxidant defense.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Cádmio/toxicidade , Magnésio/farmacologia , Ácido Tióctico/farmacologia , Animais , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar
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