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1.
J Exp Clin Cancer Res ; 38(1): 464, 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31718684

RESUMO

BACKGROUND: Prostate cancer (PCa) is a leading cause of cancer-related death in males worldwide. Exacerbated inflammation and angiogenesis have been largely demonstrated to contribute to PCa progression. Diverse naturally occurring compounds and dietary supplements are endowed with anti-oxidant, anti-inflammatory and anti-angiogenic activities, representing valid compounds to target the aberrant cytokine/chemokine production governing PCa progression and angiogenesis, in a chemopreventive setting. Using mass spectrometry analysis on serum samples of prostate cancer patients, we have previously found higher levels of carnitines in non-cancer individuals, suggesting a protective role. Here we investigated the ability of Acetyl-L-carnitine (ALCAR) to interfere with key functional properties of prostate cancer progression and angiogenesis in vitro and in vivo and identified target molecules modulated by ALCAR. METHODS: The chemopreventive/angiopreventive activities ALCAR were investigated in vitro on four different prostate cancer (PCa) cell lines (PC-3, DU-145, LNCaP, 22Rv1) and a benign prostatic hyperplasia (BPH) cell line. The effects of ALCAR on the induction of apoptosis and cell cycle arrest were investigated by flow cytometry (FC). Functional analysis of cell adhesion, migration and invasion (Boyden chambers) were performed. ALCAR modulation of surface antigen receptor (chemokines) and intracellular cytokine production was assessed by FC. The release of pro-angiogenic factors was detected by a multiplex immunoassay. The effects of ALCAR on PCa cell growth in vivo was investigated using tumour xenografts. RESULTS: We found that ALCAR reduces cell proliferation, induces apoptosis, hinders the production of pro inflammatory cytokines (TNF-α and IFN-γ) and of chemokines CCL2, CXCL12 and receptor CXCR4 involved in the chemotactic axis and impairs the adhesion, migration and invasion capabilities of PCa and BPH cells in vitro. ALCAR exerts angiopreventive activities on PCa by reducing production/release of pro angiogenic factors (VEGF, CXCL8, CCL2, angiogenin) and metalloprotease MMP-9. Exposure of endothelial cells to conditioned media from PCa cells, pre-treated with ALCAR, inhibited the expression of CXCR4, CXCR1, CXCR2 and CCR2 compared to those from untreated cells. Oral administration (drinking water) of ALCAR to mice xenografted with two different PCa cell lines, resulted in reduced tumour cell growth in vivo. CONCLUSIONS: Our results highlight the capability of ALCAR to down-modulate growth, adhesion, migration and invasion of prostate cancer cells, by reducing the production of several crucial chemokines, cytokines and MMP9. ALCAR is a widely diffused dietary supplements and our findings provide a rational for studying ALCAR as a possible molecule for chemoprevention approaches in subjects at high risk to develop prostate cancer. We propose ALCAR as a new possible "repurposed agent' for cancer prevention and interception, similar to aspirin, metformin or beta-blockers.


Assuntos
Acetilcarnitina/farmacologia , Indutores da Angiogênese/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Regulação para Baixo , Células Endoteliais da Veia Umbilical Humana , Humanos , Masculino , Camundongos , Camundongos Nus , Células PC-3 , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Neurosci Lett ; 706: 36-42, 2019 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-31078678

RESUMO

Ketamine, an anesthetic, is a non-competitive antagonist of the calcium-permeable N-methyl-d-aspartate (NMDA) receptor. High concentrations of ketamine have been implicated in cardiotoxicity and neurotoxicity. Often, these toxicities are thought to be mediated by reactive oxygen species (ROS). However, findings to the contrary showing ketamine reducing ROS in mammalian cells and neurons in vitro, are emerging. Here, we determined the effects of ketamine on ROS levels in zebrafish larvae in vivo. Based on our earlier studies demonstrating reduction in ATP levels by ketamine, we hypothesized that as a calcium antagonist, ketamine would also prevent ROS generation, which is a by-product of ATP synthesis. To confirm that the detected ROS in a whole organism, such as the zebrafish larva, is specific, we used diphenyleneiodonium (DPI) that blocks ROS production by inhibiting the NADPH Oxidases (NOX). Upon 20 h exposure, DPI (5 and 10 µM) and ketamine at (1 and 2 mM) reduced ROS in the zebrafish larvae in vivo. Using acetyl l-carnitine (ALCAR), a dietary supplement, that induces mitochondrial ATP synthesis, we show elevated ROS generation with increasing ALCAR concentrations. Combined, ketamine and ALCAR counter-balanced ROS generation in the larvae suggesting that ketamine and ALCAR have opposing effects on mitochondrial metabolism, which may be key to maintaining ROS homeostasis in the larvae and affords ALCAR the ability to prevent ketamine toxicity. These results for the first time show ketamine's antioxidative and ALCAR's prooxidative effects in a live vertebrate.


Assuntos
Acetilcarnitina/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Ketamina/farmacologia , Neurônios/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Animais , Embrião não Mamífero/efeitos dos fármacos , Microscopia de Fluorescência , Neurônios/metabolismo , Oniocompostos/farmacologia , Peixe-Zebra
3.
Neurochem Res ; 44(10): 2405-2412, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31041669

RESUMO

Neonatal hypoxia-ischemia (HI) is a common cause of brain injury in infants. Acute kidney injury frequently occurs after birth asphyxia and is associated with adverse outcome. Treatment with acetyl-L-carnitine (ALCAR) after HI protects brain and improves outcome. Rat pups underwent carotid ligation and 75 min hypoxia on postnatal day 7 to determine effects of HI on kidney which is understudied in this model. HI + ALCAR pups were treated at 0, 4 and 24 h after HI. The organic cation/carnitine transporter 2 (OCTN2), transports ALCAR and functions to reabsorb carnitine and acylcarnitines from urine. At 24 h after injury OCTN2 levels were significantly decreased in kidney from HI pups, 0.80 ± 0.04 (mean ± SEM, p < 0.01), compared to sham controls 1.03 ± 0.04, and HI + ALCAR pups 1.11 ± 0.06. The effect of HI on the level of pyruvate dehydrogenase (PDH) was determined since kidney has high energy requirements. At 24 h after HI, kidney PDH/ß-actin ratios were significantly lower in HI pups, 0.98 ± 0.05 (mean ± SEM, p < 0.05), compared to sham controls 1.16 ± 0.06, and HI + ALCAR pups 1.24 ± 0.03, p < 0.01. Treatment of pups with ALCAR after HI prevented the decrease in renal OCTN2 and PDH levels at 24 h after injury. Protection of PDH and OCTN2 after HI would improve energy metabolism in kidney, maintain tissue carnitine levels and overall carnitine homeostasis which is essential for neonatal health.


Assuntos
Acetilcarnitina/farmacologia , Lesões Encefálicas/tratamento farmacológico , Hipóxia-Isquemia Encefálica/tratamento farmacológico , Rim/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Transporte Biológico/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Carnitina/análogos & derivados , Carnitina/farmacologia , Feminino , Hipóxia/tratamento farmacológico , Hipóxia-Isquemia Encefálica/metabolismo , Masculino , Ratos Sprague-Dawley
4.
Neuropharmacology ; 150: 145-152, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-30917915

RESUMO

Stress-related psychiatric disorders are mental conditions that affect mood, cognition and behavior and arise because of the impact of prolonged stress on the central nervous system (CNS). Acetyl-L-carnitine (ALC) is an acetyl ester of L-carnitine that easily crosses the blood-brain barrier and was recently found to be decreased in patients with major depressive disorder. ALC plays a role in energy metabolism and is widely consumed as a nutritional supplement to improve physical performance. In this study, our objective was to evaluate the effects of ALC treatment (0.1 mg/L, 10 min) for 7 days on behavior and oxidative stress in zebrafish subjected to unpredictable chronic stress (UCS) protocol. Behavioral outcomes were assessed in the novel tank test, and parameters of oxidative status (lipid peroxidation and antioxidant defenses) were evaluated in the brain using colorimetric methods. According to our previous findings, UCS increased anxiety-like behavior and lipid peroxidation, while it decreased non-protein thiol levels and superoxide dismutase activity. However, ALC reversed the anxiety-like behavior and oxidative damage in stressed animals, while it was devoid of effect in control animals. Although our data reinforce the neuroprotective potential of ALC in the treatment of psychiatric disorders related to stress, further investigations are required to clarify its mechanisms of action and confirm its efficacy.


Assuntos
Acetilcarnitina/farmacologia , Antioxidantes/farmacologia , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Acetilcarnitina/uso terapêutico , Animais , Antioxidantes/uso terapêutico , Encéfalo/metabolismo , Feminino , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/metabolismo , Peixe-Zebra
5.
Int J Radiat Biol ; 95(3): 298-306, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30496017

RESUMO

PURPOSE: The aim of the present study was to evaluate the effect of acetyl-l-carnitine (ALC) and N-acetyl cysteine (NAC) on ionizing radiation (IR)-induced cytotoxicity and change in DNA damage-related genes in House Ear Institute-Organ of Corti 1 (HEI-OC1) cells. METHODS: HEI-OC1 cells were irradiated with 5 Gy radiation and treated by eight combinations of NAC and/or ALC: control, NAC, ALC, IR, NAC + IR, ALC + NAC, ALC + IR, and ALC + NAC + IR. Cell viability, apoptotic cell death, and DNA damage were measured at the 72nd hour. Eighty-four IR-induced DNA-damage-related genes were determined by RT-PCR gene array and >10-fold changes were considered significant. RESULTS: IR decreased cell viability by about 50% at 72 hours of incubation. In particular, the ALC and/or NAC combination before IR protected the HEI-OC1 cells (p < .05). Single and combination treatment prior to IR led to lower apoptotic cell death (p < .05). There was a significant lower DNA damage in ALC + NAC + IR group compared to IR group (p < .05). Expressions of Brca2, Xpc, Mlh3, Rad51, Xrcc2, Hus1, Rad9a, Cdkn1a, Gadd45a which are the DNA-repair genes were found to be significantly higher in NAC + ALC + IR group than those in individual treatment of ALC or NAC. CONCLUSIONS: ALC and/or NAC treatment prior to IR led to higher cell viability and lower apoptotic cell damage compared to the IR group. The results of the study show that the ALC + NAC combination treatment inhibits DNA damage and induces DNA-repair genes to repair radiation damage, and this combination treatment is more effective against radiation-induced DNA damage than NAC or ALC therapy individually.


Assuntos
Acetilcarnitina/farmacologia , Acetilcisteína/farmacologia , Dano ao DNA , Órgão Espiral/efeitos dos fármacos , Órgão Espiral/efeitos da radiação , Animais , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Reparo do DNA/efeitos dos fármacos , Reparo do DNA/efeitos da radiação , Interações Medicamentosas , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos da radiação , Camundongos , Órgão Espiral/citologia , Órgão Espiral/metabolismo
7.
Reprod Fertil Dev ; 31(2): 386-394, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30309436

RESUMO

The effects of acetyl-l-carnitine (ALC) supplementation during IVM on subsequently vitrified buffalo oocytes were evaluated, followed by determination of the mitochondrial DNA copy number, measurement of mitochondrial membrane potential (MMP) and identification of the lipid profile of oocyte membranes as markers of oocyte quality after vitrification. Supplementation with ALC during IVM significantly improved the rates of oocyte cleavage and morula and blastocyst formation, and increased MMP after vitrification compared with unsupplemented vitrified oocytes (P<0.05). Using a bidirectional orthogonal projection to latent structures discriminant analysis based on positive ion matrix-assisted laser desorption ionisation time-of-flight mass spectrometry data, five phospholipid ions (m/z 728.7 (phosphatidylcholine (PC) 32:3), 746.9 (PC 32:5), 760.6 (PC 34:1), 768.8 (PC P-36:3) and 782.6 (PC 36:4); P<0.05) were identified as significantly more abundant in fresh oocytes than in unsupplemented vitrified oocytes. Meanwhile, three phospholipid ions (m/z 734.6 (PC 32:0), 760.6 (PC 34:1), and 782.6 (PC 36:4); P<0.05) were more abundant in ALC-supplemented vitrified oocytes than in unsupplemented vitrified oocytes. Therefore, supplementation with ALC during IVM may improve buffalo oocyte quality after vitrification by enhancing mitochondrial function and altering the phospholipid composition of vitrified oocyte membranes.


Assuntos
Acetilcarnitina/farmacologia , Desenvolvimento Embrionário/efeitos dos fármacos , Lipídeos de Membrana/metabolismo , Mitocôndrias/efeitos dos fármacos , Oócitos/efeitos dos fármacos , Animais , Búfalos , Criopreservação/métodos , Feminino , Técnicas de Maturação in Vitro de Oócitos , Mitocôndrias/metabolismo , Oócitos/metabolismo , Vitrificação
8.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 35(5): 438-442, 2019 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-31894677

RESUMO

OBJECTIVE: To observe the effects of different doses of acetyl-L-carnitine (ALC) on hindlimb motor function and spinal cord tissue structure in rats with spinal cord injury. The study will provide theoretical and experimental evidences for acetyl-L-carnitine's clinical treatment. METHODS: Fifty-five SD rats aged 8-10 weeks were randomly divided into high, medium and low-dose drug intervention (SCI + ALC) group, injury group (SCI) and sham group for behavioral evaluation, MAD and SOD detection, as well as HPLC detection and HE staining. BBB scores and Rivlin experiments were performed to evaluate hindlimb motor function in each group. The morphology and structure of spinal cord tissue was detected by HE staining. Another 9 rats were randomly divided into Sham group, SCI group and ALC group for TUMEL detection of apoptosis. RESULTS: The BBB scores of the high, medium, and low dose SCI+ALC groups were significantly higher than those in the SCI group. The medium and high-dose ALC groups had significant differences (P<0.01), and the hindlimb motor function was significantly improved in rats. The maximum tilt angle of the Rivlin experiment was observed. The SCI+ALC group had a significantly increased angle compared with the SCI group (P<0.05), the medium and high-dose ALC group had a significant difference (P<0.01). Compared with the SCI group, the tissue structure of ALC high-dose group was improved significantly, the number of inflammatory cells and red blood cells was decreased, and the nucleolus of the nerve cells was unclear. The SOD activity of the SCI+ALC group was significantly higher than that of the SCI group, while the MDA content was significantly decreased(P<0.05), the middle and high dose ALC groups were significantly different (P<0.01). HPLC chromatogram showed that the SCI+ALC fresh serum sample and the ALC standard solution had the same absorption spectrum at 260 nm, while the Sham group and SCI group serum samples did not show spectral values there, which indicated that the same substance as the standard existed in the sample of SCI+ALC group. TUNEL staining showed that the apoptosis signal was occasionally seen in the sham group, and the apoptosis signal was significantly decreased in the ALC high-dose group compared with the SCI group(P<0.05). CONCLUSION: ALC can promote the recovery of hindlimb motor function in rats with spinal cord injury, inhibit oxidative stress and apoptosis, and repair the damaged spinal cord tissue.


Assuntos
Acetilcarnitina , Traumatismos da Medula Espinal , Medula Espinal , Acetilcarnitina/farmacologia , Acetilcarnitina/uso terapêutico , Animais , Membro Posterior/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Medula Espinal/efeitos dos fármacos , Traumatismos da Medula Espinal/tratamento farmacológico , Resultado do Tratamento
10.
Theriogenology ; 118: 80-89, 2018 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-29885644

RESUMO

Oocyte quality is one of the important factors in female fertility, in vitro maturation (IVM), and subsequent embryonic development. In the present study, we assessed whether acetyl-l-carnitine (ALC) supplementation during in vitro maturation of buffalo oocytes could improve oocyte quality and subsequent embryonic development. To determine the optimal level of ALC supplementation, we matured cumulus-oocyte complexes in maturation medium supplemented with 0, 2.5, and 5 mM ALC. The oocytes with a polar body were selected for parthenogenetic activation (PA) and in vitro fertilization (IVF). We found that oocytes matured in 2.5 mM ALC had significantly higher PA blastocyst rate (P < 0.05) and blastocyst cell number than those of unsupplemented oocytes (P < 0.05) and a significantly higher IVF blastocyst rate than that of oocytes matured in 5 mM ALC (P < 0.05). In all further experiments, we supplemented the maturation medium with 2.5 mM ALC. We then tested whether ALC supplementation could improve various markers of oocytes and cumulus cells. We compared cell proliferation; concentrations of reactive oxygen species (ROS), intracellular ATP, estradiol, and progesterone; mitochondrial distribution; mitochondrial DNA copy number (mtDNA); and expression levels of four genes encoding oocyte-derived factors (GDF9, BMP15) and steroid hormones (StAR, P450scc) between the supplemented and unsupplemented oocytes and cumulus cells. Cumulus cells matured with ALC supplementation were more prolific than those matured without ALC supplementation (P < 0.05). Oocytes treated with ALC had lower concentrations of intracellular ROS (P < 0.05) and a higher rate of diffuse mitochondrial distributions (P < 0.05) than those of untreated oocytes. Additionally, the mtDNA was higher in the ALC-treated oocytes (P < 0.05) and cumulus cells (P < 0.05) than that in the untreated cells. The ALC-treated maturation medium had a higher postmaturation concentration of estradiol than that of the untreated medium (P < 0.05). Finally, the gene expression levels of P450scc and GDF9 were greater in ALC-treated oocytes and cumulus cells than those in untreated cells (P < 0.05). Therefore, in buffalo, our results suggest that ALC affects mitochondrial function, regulates oocyte-derived paracrine factors, and increases the production of steroid hormones, leading to increased quality of matured oocytes and improved embryonic development in vitro.


Assuntos
Acetilcarnitina/farmacologia , Búfalos , Desenvolvimento Embrionário/efeitos dos fármacos , Técnicas de Maturação in Vitro de Oócitos/veterinária , Oócitos/efeitos dos fármacos , Acetilcarnitina/administração & dosagem , Animais , Blastocisto/fisiologia , Proliferação de Células/efeitos dos fármacos , Meios de Cultura , Células do Cúmulo/efeitos dos fármacos , Células do Cúmulo/fisiologia , DNA Mitocondrial/análise , Desenvolvimento Embrionário/fisiologia , Estradiol/análise , Feminino , Fertilização In Vitro/veterinária , Técnicas de Maturação in Vitro de Oócitos/métodos , Oócitos/química , Oócitos/fisiologia , Espécies Reativas de Oxigênio/análise
11.
Biomed Pharmacother ; 103: 1302-1311, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29864912

RESUMO

Multiple sclerosis (MS) is a progressive inflammatory autoimmune demyelinating disease of the brain and spinal cord. Glucocorticoids (GCs) are the standard treatment of MS, however they have several drawbacks like oxidative stress and apoptosis. This study was designed to evaluate some possible antioxidant, anti-apoptotic and immune modulatory effects of Acetyl-l-carnitine (ALCAR) when used either alone or as an add-on therapy with dexamethasone for treatment of a relapsing-remitting (RR) experimental autoimmune encephalomyelitis (EAE) as a model of MS. This experiment was performed on 50 female Sprague Dawley rats divided into; normal control group, untreated EAE group, EAE group treated by dexamethasone, EAE group treated by ALCAR, and EAE group treated by both dexamethasone and ALCAR. The clinical score of the motor deficit of EAE was recorded daily. At the end of experiment, rats were sacrificed and the brain and spinal cord were processed for assessment of reduced glutathione (GSH), malondialdehyde (MDA) and caspase-3 activity. Histopathological changes and immunohistochemical expression of Bcl-2 and CD4+ T cell were carried out. Combination of both dexamethasone and ALCAR provided marked antioxidant and anti-apoptotic effects represented by significant decrease in MDA, caspase-3 and significant increase in GSH, Bcl-2 expression, and it also exhibited marked immunosuppressive effect represented by significant decrease in CD4+ T cells expression with significant improvement in clinical outcome when compared to untreated EAE group or to dexamethasone treated group. These findings pave the way for using ALCAR as an adjuvant therapy during long-term use of dexamethasone in MS.


Assuntos
Acetilcarnitina/uso terapêutico , Antioxidantes/uso terapêutico , Apoptose , Encefalomielite Autoimune Experimental/tratamento farmacológico , Acetilcarnitina/farmacologia , Animais , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Biomarcadores/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Linfócitos T CD4-Positivos/imunologia , Caspase 3/metabolismo , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Feminino , Glutationa/metabolismo , Malondialdeído/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Paralisia/complicações , Paralisia/patologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos Sprague-Dawley , Medula Espinal/metabolismo , Medula Espinal/patologia
12.
Cell Death Dis ; 9(6): 596, 2018 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-29789529

RESUMO

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease caused by the degeneration of upper and lower motor neurons. Defects in axonal transport have been observed pre-symptomatically in the SOD1G93A mouse model of ALS, and have been proposed to play a role in motor neuron degeneration as well as in other pathologies of the nervous system, such as Alzheimer's disease and hereditary neuropathies. In this study, we screen a library of small-molecule kinase inhibitors towards the identification of pharmacological enhancers of the axonal retrograde transport of signalling endosomes, which might be used to normalise the rate of this process in diseased neurons. Inhibitors of p38 mitogen-activated protein kinases (p38 MAPK) were identified in this screen and were found to correct deficits in axonal retrograde transport of signalling endosomes in cultured primary SOD1G93A motor neurons. In vitro knockdown experiments revealed that the alpha isoform of p38 MAPK (p38 MAPKα) was the sole isoform responsible for SOD1G93A-induced transport deficits. Furthermore, we found that acute treatment with p38 MAPKα inhibitors restored the physiological rate of axonal retrograde transport in vivo in early symptomatic SOD1G93A mice. Our findings demonstrate the pathogenic effect of p38 MAPKα on axonal retrograde transport and identify a potential therapeutic strategy for ALS.


Assuntos
Esclerose Amiotrófica Lateral/enzimologia , Esclerose Amiotrófica Lateral/patologia , Transporte Axonal , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Acetilcarnitina/farmacologia , Animais , Transporte Axonal/efeitos dos fármacos , Modelos Animais de Doenças , Ativação Enzimática/efeitos dos fármacos , Membro Posterior/efeitos dos fármacos , Membro Posterior/fisiopatologia , Imidazóis/farmacologia , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurônios Motores/efeitos dos fármacos , Neurônios Motores/metabolismo , Músculos/efeitos dos fármacos , Músculos/fisiopatologia , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Quinazolinonas/farmacologia , Receptores de Fator de Crescimento Neural/metabolismo , Superóxido Dismutase/metabolismo , Toxina Tetânica/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
13.
BMC Res Notes ; 11(1): 307, 2018 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-29769094

RESUMO

OBJECTIVE: Infections with the mosquito transmitted dengue virus (DENV) are a significant public health burden in many parts of the world. Despite the introduction of a commercial vaccine in some parts of the world, the majority of the populations at risk of infection remain unprotected against this disease, and there is currently no treatment for DENV infection. Natural compounds offer the prospect of cheap and sustainable therapeutics to reduce the disease burden during infection, and thus potentially alleviate the risk of more severe disease. This study evaluated the potential anti-DENV 2 activity of five natural compounds namely melatonin, α-tocopherol, folic acid, acetyl-L-carnitine and resveratrol in two different cell lines. RESULTS: Screening of the compounds showed that one compound (acetyl-L-carnitine) showed no effect on DENV infection, three compounds (melatonin, α-tocopherol and folic acid) slightly increased levels of infection, while the 5th compound, resveratrol, showed some limited anti-DENV activity, with resveratrol reducing virus output with an EC50 of less than 25 µM. These results suggest that some commonly taken natural compounds may have beneficial effects on DENV infection, but that others may potentially add to the disease burden.


Assuntos
Acetilcarnitina/farmacologia , Antivirais/farmacologia , Vírus da Dengue/efeitos dos fármacos , Dengue/tratamento farmacológico , Ácido Fólico/farmacologia , Melatonina/farmacologia , Estilbenos/farmacologia , alfa-Tocoferol/farmacologia , Células HEK293 , Células Hep G2 , Humanos , Resveratrol
14.
Cancer Lett ; 429: 100-116, 2018 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-29678548

RESUMO

Carnitines play an important role in the energy exchange in cells, and are involved in the transport of fatty acids across the inner mitochondrial membrane. l-Acetylcarnitine (ALCAR) is an acetic acid ester of carnitine that has higher bioavailability and is considered a fat-burning energizer supplement. We previously found that in serum samples from prostate cancer (PCa) patients, 3 carnitine family members were significantly decreased, suggesting a potential protective role of carnitine against PCa. Several studies support beneficial effects of carnitines on cancer, no study has investigated the activities of carnitine on tumor angiogenesis. We examined whether ALCAR acts as an "angiopreventive" compound and studied the molecular mechanisms involved. We found that ALCAR was able to limit inflammatory angiogenesis by reducing stimulated endothelial cell and macrophage infiltration in vitro and in vivo. Molecularly, we show that ALCAR downregulates VEGF, VEGFR2, CXCL12, CXCR4 and FAK pathways. ALCAR blocked the activation of NF-κB and ICAM-1 and reduced the adhesion of a monocyte cell line to endothelial cells. This is the first study showing that ALCAR has anti-angiogenic and anti-inflammatory properties and might be an attractive candidate for cancer angioprevention.


Assuntos
Acetilcarnitina/farmacologia , Inibidores da Angiogênese/farmacologia , Receptores CXCR4/metabolismo , Transdução de Sinais/efeitos dos fármacos , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Animais , Adesão Celular/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Células Endoteliais da Veia Umbilical Humana/citologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/fisiologia , Humanos , Masculino , Camundongos Endogâmicos C57BL , Monócitos/citologia , Monócitos/efeitos dos fármacos , Neovascularização Fisiológica/efeitos dos fármacos , Receptores CXCR4/genética , Transdução de Sinais/genética , Células THP-1 , Fator de Necrose Tumoral alfa/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética
15.
Neurobiol Aging ; 67: 108-119, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29656010

RESUMO

Hearing acuity and sound localization are affected by aging and may contribute to cognitive dementias. Although loss of sensorineural conduction is well documented to occur with age, little is known regarding short-term synaptic plasticity in central auditory nuclei. Age-related changes in synaptic transmission properties were evaluated at the mouse calyx of Held, a sign-inverting relay synapse in the circuit for sound localization, in juvenile adults (1 month old) and late middle-aged (18-21 months old) mice. Synaptic timing and short-term plasticity were severely disrupted in older mice. Surprisingly, acetyl-l-carnitine (ALCAR), an anti-inflammatory agent that facilitates mitochondrial function, fully reversed synaptic transmission delays and defects in short-term plasticity in aged mice to reflect transmission similar to that seen in juvenile adults. These findings support ALCAR supplementation as an adjuvant to improve short-term plasticity and potentially central nervous system performance in animals compromised by age and/or neurodegenerative disease.


Assuntos
Acetilcarnitina/farmacologia , Envelhecimento , Anti-Inflamatórios/farmacologia , Vias Auditivas/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Sinapses/fisiologia , Transmissão Sináptica/efeitos dos fármacos , Acetilcarnitina/uso terapêutico , Animais , Anti-Inflamatórios/uso terapêutico , Percepção Auditiva/efeitos dos fármacos , Percepção Auditiva/fisiologia , Feminino , Audição/fisiologia , Perda Auditiva Neurossensorial/tratamento farmacológico , Perda Auditiva Neurossensorial/fisiopatologia , Perda Auditiva Neurossensorial/psicologia , Masculino , Camundongos Endogâmicos C57BL , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/fisiopatologia , Doenças Neurodegenerativas/psicologia , Transmissão Sináptica/fisiologia
16.
Reprod Biol Endocrinol ; 16(1): 5, 2018 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-29373970

RESUMO

BACKGROUND: L-carnitine (LC), and its acetylated form, acetyl L-carnitine (ALC), have immense functional capabilities to regulate the oxidative and metabolic status of the female reproductive system. The vulnerability of this system to free radicals demand for advanced strategies to combat them. For this purpose, the 'quasi vitamins' LC and ALC can be used either individually, or in combination with each other or with other antioxidants. MAIN BODY: This review (a) summarizes the effects of carnitines on female fertility along with the findings from various in vivo and in vitro studies involving human, animal and assisted reproductive technology, and (b) proposes their mechanism of actions in improving female fertility through their integrated actions on reducing cellular stress, maintaining hormonal balance and enhancing energy production. They reportedly aid ß-oxidation in oocytes, maintain its cell membrane stability by acetylation of phospholipids and amphiphilic actions, prevent free radical-induced DNA damage and also stabilize acetyl Co-A/Co-A ratio for adequate acetyl storage as energy supply to maintain the robustness of reproductive cells. CONCLUSION: While both LC and ALC have their applications in improving female fertility, ALC is preferred for its better antioxidant properties and LC for amelioration of energy supply to the cells. These beneficial effects show great promise in its application as a treatment option for women facing infertility disorders.


Assuntos
Acetilcarnitina/fisiologia , Carnitina/fisiologia , Infertilidade Feminina/metabolismo , Acetilcarnitina/farmacologia , Animais , Antioxidantes/farmacologia , Antioxidantes/fisiologia , Carnitina/farmacologia , Feminino , Radicais Livres/metabolismo , Humanos , Infertilidade Feminina/tratamento farmacológico , Estresse Oxidativo , Vitaminas/farmacologia , Vitaminas/fisiologia
17.
Mol Neurobiol ; 55(1): 583-602, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-27975173

RESUMO

Parkinson's disease is accompanied by nonmotor symptoms including cognitive impairment, which precede the onset of motor symptoms in patients and are regulated by dopamine (DA) receptors and the mesocorticolimbic pathway. The relative contribution of DA receptors and astrocytic glutamate transporter (GLT-1) in cognitive functions is largely unexplored. Similarly, whether microglia-derived increased immune response affects cognitive functions and neuronal survival is not yet understood. We have investigated the effect of acetyl-L-carnitine (ALCAR) on cognitive functions and its possible underlying mechanism of action in 6-hydroxydopamine (6-OHDA)-induced hemiparkinsonian rats. ALCAR treatment in 6-OHDA-lesioned rats improved memory functions as confirmed by decreased latency time and path length in the Morris water maze test. ALCAR further enhanced D1 receptor levels without altering D2 receptor levels in the hippocampus and prefrontal cortex (PFC) regions, suggesting that the D1 receptor is preferentially involved in the regulation of cognitive functions. ALCAR attenuated microglial activation and release of inflammatory mediators through balancing proinflammatory and anti-inflammatory cytokines, which subsequently enhanced the survival of mature neurons in the CA1, CA3, and PFC regions and improved cognitive functions in hemiparkinsonian rats. ALCAR treatment also improved glutathione (GSH) content, while decreasing oxidative stress indices, inducible nitrogen oxide synthase (iNOS) levels, and astrogliosis resulting in the upregulation of GLT-1 levels. Additionally, ALCAR prevented the loss of dopaminergic (DAergic) neurons in ventral tagmental area (VTA)/substantia nigra pars compacta (SNpc) regions of 6-OHDA-lesioned rats, thus maintaining the integrity of the nigrostriatal pathway. Together, these results demonstrate that ALCAR treatment in hemiparkinsonian rats ameliorates neurodegeneration and cognitive deficits, hence suggesting its therapeutic potential in neurodegenerative diseases.


Assuntos
Acetilcarnitina/uso terapêutico , Memória , Microglia/patologia , Neurônios/patologia , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/fisiopatologia , Receptores de Dopamina D1/metabolismo , Regulação para Cima , Acetilcarnitina/administração & dosagem , Acetilcarnitina/farmacologia , Animais , Linhagem Celular , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Transportador 2 de Aminoácido Excitatório/metabolismo , Gliose/patologia , Glutationa/metabolismo , Mediadores da Inflamação/metabolismo , Masculino , Memória/efeitos dos fármacos , Microglia/efeitos dos fármacos , Microglia/metabolismo , Atividade Motora/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neuroproteção/efeitos dos fármacos , Óxido Nítrico Sintase Tipo II/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Oxidopamina , Doença de Parkinson/patologia , Ratos Sprague-Dawley , Regulação para Cima/efeitos dos fármacos
18.
Biol Trace Elem Res ; 184(2): 422-435, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29189995

RESUMO

Augmentation of mitochondrial oxidative stress through activating a series of deadly events has implicated as the main culprit of arsenic toxicity and therapeutic approaches based on improving mitochondrial function hold a great promise for attenuating the arsenic-induced toxicity. Acetyl-L-carnitine (ALC) through balancing the coenzyme A (CoA)/acyl-CoA ratio plays an important role in mitochondrial metabolism and thereby can help protect hippocampal neurons from oxidative damage. In the present study, we aimed to explore the effect of arsenic interactions on the mitochondrial function in the hippocampus of rats. Rats were randomly divided into five groups of control (distilled water), sodium arsenite (NaAsO2, 20 mg/kg), and co-treatment of NaAsO2 with various doses of ALC in three groups (100, 200, 300 mg/kg) and were treated orally for 21 consecutive days. Our results point out that arsenic exposure caused oxidative stress in rats' hippocampus, which led to the reactive oxygen species (ROS) generation, mitochondrial swelling, the collapse of the mitochondrial membrane potential, and release of cytochrome c. It also altered Bcl-2/Bax expression ratio and increased caspase-3 and caspase-9 activities. Furthermore, arsenic exposure via activation of NF-κB and microglia increased inflammation. ALC could concentration-dependently counteract the arsenic-induced oxidative stress, modulate the antioxidant defense capacity, and improve mitochondrial functions. In addition, ALC decreased the expression of both death-associated proteins and of inflammatory markers. These findings indicate that ALC improved the arsenic-induced hippocampal mitochondrial dysfunction which underlines the importance of ALC in providing a possible therapeutic strategy for the prevention of arsenic-induced neurodegeneration.


Assuntos
Acetilcarnitina/farmacologia , Arsênico/toxicidade , Mitocôndrias/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Acetilcarnitina/administração & dosagem , Administração Oral , Animais , Antioxidantes/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/metabolismo , Distribuição Aleatória , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Complexo Vitamínico B/administração & dosagem , Complexo Vitamínico B/farmacologia
19.
Environ Toxicol Pharmacol ; 58: 11-20, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29278859

RESUMO

Industrial and agricultural developments in recent years have resulted in the excessive discharge of arsenic into the environment, making arsenic toxicity a major worldwide concern. Oxidative stress is considered the primary mechanism for arsenic toxicity. The main objective of this study was to evaluate acetyl-l-carnitine's (ALC) protective ability against the arsenic-induced hepatotoxicity. For this purpose, male Wistar rats were distributed randomly into 5 groups of 8 rats each: control, arsenic (5 mg/kg) and arsenic plus ALC (5 mg/kg; 100, 200, 300 mg/kg). The animals were gavaged for 21 consecutive days. Liver tissue samples were extracted 24 h after the last treatment and were later analyzed for biochemical and histological alterations. The arsenic-induced oxidative damage was confirmed by elevation of malondialdehyde (MDA), a lipid peroxidation byproduct, as well as depletion in physiological antioxidant content such as superoxide dismutase (SOD) and catalase (CAT). Furthermore, alterations in mitochondrial functions including a significant decrease of mitochondrial outer membrane potential and reactive oxygen species (ROS) generation increase, mitochondrial swelling, release of cytochrome c and consequent activation of caspase-3 and caspase-9 and initiation of apoptosis, was observed following arsenic administration. Moreover, the inflammation was confirmed by the overexpression of inflammatory mediators such as NF-ĸB and IL-1 and IL-6. The present study demonstrated that ALC ameliorates arsenic-induced oxidative damage, mitochondrial dysfunction, apoptosis, inflammation and histological damage. ALC's protective features against arsenic hepatotoxicity may be due to this agent's antioxidant and anti-inflammatory properties as well as its stabilizing effects on mitochondrial function.


Assuntos
Acetilcarnitina/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Arsênico/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Acetilcarnitina/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Caspase 9/metabolismo , Catalase/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Citocromos c/metabolismo , Glutationa/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Malondialdeído/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismo , Fator de Transcrição RelA/metabolismo
20.
Aging Clin Exp Res ; 30(2): 133-138, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28534301

RESUMO

A long history of diabetes mellitus and increasing age are associated with the onset of diabetic neuropathy, a painful and highly disabling complication with a prevalence peaking at 50% among elderly diabetic patients. Acetyl-L-carnitine (ALC) is a molecule derived from the acetylation of carnitine in the mitochondria that has an essential role in energy production. It has recently been proposed as a therapy to improve the symptoms of diabetic neuropathy. ALC is widely distributed in mammalian tissues, including the brain, blood-brain barrier, brain neurons, and astrocytes. Aside from its metabolic activity, ALC has demonstrated cytoprotective, antioxidant, and antiapoptotic effects in the nervous system. It exerts an analgesic action by reducing the concentration of glutamate in the synapses. It facilitates nerve regeneration and damage repair after primary trauma: its positive effects on metabolism promote the synthesis, fluidity, and functionality of neuronal membranes, increase protein synthesis, and improve the axonal transport of neurofilament proteins and tubulin. It also amplifies nerve growth factor responsiveness, an effect that is believed to enhance overall neurite growth. ALC has been proposed for the treatment of various neurological and psychiatric diseases, such as mood disorders and depression, dementias, Alzheimer's disease, and Parkinson's disease, because synaptic energy states and mitochondrial dysfunction are core factors in their pathogenesis.


Assuntos
Acetilcarnitina/uso terapêutico , Analgésicos/uso terapêutico , Neuropatias Diabéticas/tratamento farmacológico , Dor/tratamento farmacológico , Acetilcarnitina/farmacologia , Idoso , Doença de Alzheimer/tratamento farmacológico , Analgésicos/farmacologia , Humanos , Mitocôndrias/metabolismo
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