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1.
Prague Med Rep ; 120(2-3): 84-94, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31586507

RESUMO

Ageing is associated with the accumulation of damage to all the macromolecules within and outside cells leading to progressively more cellular and tissue defects and resulting in age-related frailty, disability and disease. As a result of the aging process the bone deteriorates in composition, structure and function. Age-related musculoskeletal losses are a major public health burden because they can cause physical disability and increased mortality. We tried to find out on a small set of old women, without risk factors for osteoporosis, what caused them the loss of bone minerals. All 492 women had just only one risk factor - the old age. Laboratory findings have shown a decreased serum C telopeptide and low serum alkaline phosphatase circulating markers, used to quantify bone resorption and formation, and very low level of vitamin D. Very low level of vitamin D that disrupted calcium absorption through the intestine, and decreased calcemia increased parathyroid hormone levels with resulting bone effect. The manifestation of physiological aging is worsening eyesight, peripheral neuropathy, depression, worsening of physical condition, skin aging, sarcopenia and bone mineral loss. Senile osteoporosis, which is not caused by known risk factors for osteoporosis, does not appear to be a separate disease, but is part of the physiological process of aging. Treatment of senile osteoporosis should be focused on the control of secondary hyperparathyroidism by administration of vitamin D and calcium. The risk of fractures in the advanced age is determined by a large number of factors ranging from hazards in the home environment to frailty and poor balance.


Assuntos
Envelhecimento/sangue , Envelhecimento/patologia , Fosfatase Alcalina/sangue , Densidade Óssea , Cálcio/metabolismo , Colágeno Tipo I/sangue , Feminino , Humanos , Osteogênese , Osteoporose/sangue , Hormônio Paratireóideo/sangue , Peptídeos/sangue , Vitamina D/sangue
2.
Medicine (Baltimore) ; 98(42): e17629, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31626147

RESUMO

The potential relationship between coronary artery calcium (CAC) and colorectal adenoma has been widely indicated. This study aimed to investigate the relationship between the risk of colorectal adenoma and CAC progression in asymptomatic Korean adults who underwent serial assessments by colonoscopy and CAC scan.A total of 754 asymptomatic participants, who had undergone serial CAC scans and colonoscopies for screening, were enrolled. Changes in CAC were assessed according to the absolute change between baseline and follow-up results. CAC progression was defined using Multi-Ethnic Study of Atherosclerosis method. Risk for adenoma at follow-up colonoscopy was determined using hazard ratio (HR) by Cox regression. The area under the receiver operating characteristic (ROC) curve was measured.The mean follow-up duration was 3.4 ± 2.5 years. CAC progression was found in 215 participants (28.5%). Participants with adenoma at index colonoscopy showed a higher rate of CAC progression than those without (38.8% vs 23.6%, P < .01). In participants with adenoma at index colonoscopy, CAC progression significantly increased the cumulative risk for adenoma at follow-up colonoscopy (HR = 1.48, 95% confidence interval [CI] 1.06-2.06, log-rank P = .021). In multivariate analysis, male sex (HR = 2.57, 95% CI 1.22-5.42, P = .013), ≥3 adenomas at index colonoscopy (HR = 2.60, 95% CI 1.16-5.85, P = .021), and CAC progression (HR = 2.74, 95% CI 1.48-5.08, P = .001) increased the risk of adenoma at follow-up colonoscopy. In participants without adenoma at index colonoscopy, neither baseline CAC presence nor CAC progression increased the risk of adenoma at follow-up colonoscopy. The interaction between CAC progression and adenoma at index colonoscopy was significant in multivariable model (P = .005). In the ROC analysis, AUC of CAC progression for adenoma at follow-up colonoscopy was 0.625 (95% CI 0.567-0.684, P < .001) in participants with adenoma at index colonoscopy.Participants with CAC progression, who are at high risk of coronary atherosclerosis, may need to be considered for follow-up evaluation of colorectal adenoma, especially those with adenoma at index colonoscopy.


Assuntos
Adenoma/complicações , Cálcio/metabolismo , Neoplasias Colorretais/complicações , Doença da Artéria Coronariana/etiologia , Vasos Coronários/diagnóstico por imagem , Medição de Risco/métodos , Calcificação Vascular/etiologia , Adenoma/diagnóstico , Doenças Assintomáticas , Colonoscopia , Neoplasias Colorretais/diagnóstico , Angiografia Coronária/métodos , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/epidemiologia , Vasos Coronários/metabolismo , Progressão da Doença , Feminino , Seguimentos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada Multidetectores , Curva ROC , República da Coreia/epidemiologia , Estudos Retrospectivos , Fatores de Risco , Calcificação Vascular/diagnóstico , Calcificação Vascular/epidemiologia
3.
Protein Pept Lett ; 26(10): 751-757, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31618170

RESUMO

BACKGROUND: NMAAP1 plays a role in regulating macrophage differentiation to the M1 type and exerting antitumoral functions. It is not clear what role and mechanism NMAAP1 does play in the reversal of macrophages from M1 to M2. METHODS: We detected the typing of macrophages with high or low expression of NMAAP1 by QPCR and ELISA, and detected the colocalization of NMAAP1 and endogenous IP3R by laser confocal microscopy, and detected the protein expression in cells by Western-blotting. RESULTS: Our study found that knockdown NMAAP1 in RAW264.7 cells induced macrophage polarization to the M2 type and up-regulation of NMAAP1 in RAW264.7 cells maintain M1 Phenotype even in the presence of IL-4, a stronger inducer of the M2 type. Additionally, Coimmunoprecipitation revealed a protein-protein interaction between NMAAP1 and IP3R and then activates key molecules in the PKC-dependent Raf/MEK/ERK and Ca2+/CaM/CaMKII signaling pathways. Activation of PKC (Thr638/641), ERK1/2 (Thr202/Tyr204) and CaMKII (Thr286) is involved in the regulation of cell differentiation. CONCLUSION: NMAAP1 interacts with IP3R, which in turn activates the PKC-dependent Raf/MEK/ERK and Ca2+/CaM/CaMKII signaling pathways. These results provide a new explanation of the mechanism underlying M1 differentiation.


Assuntos
Cálcio/metabolismo , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Macrófagos/metabolismo , Proteínas de Membrana/metabolismo , Transdução de Sinais , Animais , Diferenciação Celular , Citocinas/metabolismo , Regulação da Expressão Gênica , Humanos , Macrófagos/citologia , Proteínas de Membrana/genética , Camundongos , Fenótipo , Ligação Proteica , Células RAW 264.7 , RNA Interferente Pequeno/metabolismo , Regulação para Cima
4.
Cell Physiol Biochem ; 53: 794-804, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31661199

RESUMO

BACKGROUND/AIMS: Red blood cell (RBC) death could contribute to anemia in chronic kidney disease (CKD) patients. Recent observational research has suggested a relationship between RBC death (eryptosis) and hypoxemia in hemodialysis patients. Thus, we studied the isolated and joint effects of a uremic toxin (indoxyl sulfate; IS) and hypoxia on RBC biology. METHODS: We incubated RBC from healthy donors with IS at concentrations of 0.01mM, 0.09mM and 0.17mM under both normoxic (21% O2) and hypoxic (5% O2) conditions for 24 hours. Eryptosis was evaluated by RBC phosphatidylserine (PS) exposure, cell volume, and cytosolic calcium which were quantified by Annexin-V+, forward scatter, and Fluo-3AM+ binding, respectively. RBC redox balance was reported by reactive oxygen species (ROS) production and intracellular reduced glutathione (GSH). Analyses were performed by flow cytometry. RESULTS: Hypoxia induced a 2-fold ROS production compared to normoxia. PS exposure and cytosolic calcium increased, while cell volume decreased by hypoxia and likewise by IS. IS increased ROS production in a dose-dependent manner under conditions of both normoxia and hypoxia. The same conditions promoted a GSH decrease with IS intensifying the hypoxia-induced effects. CONCLUSION: In summary, our results indicate that the concurrent presence of hypoxia and uremia augments RBC death and may therefore, contribute to the genesis of anemia in CKD.


Assuntos
Eriptose/efeitos dos fármacos , Eritrócitos/química , Indicã/toxicidade , Adulto , Cálcio/metabolismo , Citosol/metabolismo , Eritrócitos/efeitos dos fármacos , Eritrócitos/metabolismo , Feminino , Glutationa , Humanos , Hipóxia , Masculino , Oxirredução , Fosfatidilserinas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Uremia/patologia , Adulto Jovem
5.
Nature ; 574(7779): 543-548, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31645720

RESUMO

Multicellular organisms have co-evolved with complex consortia of viruses, bacteria, fungi and parasites, collectively referred to as the microbiota1. In mammals, changes in the composition of the microbiota can influence many physiologic processes (including development, metabolism and immune cell function) and are associated with susceptibility to multiple diseases2. Alterations in the microbiota can also modulate host behaviours-such as social activity, stress, and anxiety-related responses-that are linked to diverse neuropsychiatric disorders3. However, the mechanisms by which the microbiota influence neuronal activity and host behaviour remain poorly defined. Here we show that manipulation of the microbiota in antibiotic-treated or germ-free adult mice results in significant deficits in fear extinction learning. Single-nucleus RNA sequencing of the medial prefrontal cortex of the brain revealed significant alterations in gene expression in excitatory neurons, glia and other cell types. Transcranial two-photon imaging showed that deficits in extinction learning after manipulation of the microbiota in adult mice were associated with defective learning-related remodelling of postsynaptic dendritic spines and reduced activity in cue-encoding neurons in the medial prefrontal cortex. In addition, selective re-establishment of the microbiota revealed a limited neonatal developmental window in which microbiota-derived signals can restore normal extinction learning in adulthood. Finally, unbiased metabolomic analysis identified four metabolites that were significantly downregulated in germ-free mice and have been reported to be related to neuropsychiatric disorders in humans and mouse models, suggesting that microbiota-derived compounds may directly affect brain function and behaviour. Together, these data indicate that fear extinction learning requires microbiota-derived signals both during early postnatal neurodevelopment and in adult mice, with implications for our understanding of how diet, infection, and lifestyle influence brain health and subsequent susceptibility to neuropsychiatric disorders.


Assuntos
Extinção Psicológica/fisiologia , Medo/fisiologia , Metabolômica , Microbiota/fisiologia , Neurônios/fisiologia , Animais , Antibacterianos/farmacologia , Transtorno Autístico/metabolismo , Sangue/metabolismo , Cálcio/metabolismo , Líquido Cefalorraquidiano/química , Líquido Cefalorraquidiano/metabolismo , Sinais (Psicologia) , Espinhas Dendríticas/efeitos dos fármacos , Espinhas Dendríticas/patologia , Espinhas Dendríticas/fisiologia , Extinção Psicológica/efeitos dos fármacos , Medo/efeitos dos fármacos , Fezes/química , Vida Livre de Germes , Indicã/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Microbiota/efeitos dos fármacos , Microbiota/imunologia , Inibição Neural , Neuroglia/patologia , Neuroglia/fisiologia , Neurônios/efeitos dos fármacos , Neurônios/imunologia , Neurônios/patologia , Fenilpropionatos/metabolismo , Córtex Pré-Frontal/citologia , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/imunologia , Córtex Pré-Frontal/fisiologia , Esquizofrenia/metabolismo , Transcriptoma , Nervo Vago/fisiologia
6.
J Agric Food Chem ; 67(44): 12283-12292, 2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31610118

RESUMO

In this study, the binding mechanism, morphological, and conformational analysis of the complex of a sea cucumber ovum derived octapeptide (EDLAALEK) with Ca2+ as well as its calcium delivery behavior via the gastrointestinal (GI) tract were investigated. The Ca2+ specifically bound to two carboxyl oxygen atoms of C-terminal Glu and Asp on the EDLAALEK peptide at a stoichiometric ratio of 1:1. Calcium coordination induced the self-assembly of the EDLAALEK peptide, resulting in the formation of a nanocomposite with a crystal structure. Furthermore, the formed nanocomposite went through dissociation and self-assembly during in vitro GI digestion, accompanied by the release and rechelation of Ca2+, which was related to changes in their secondary structure. Nevertheless, the GI digests of the EDLAALEK-calcium complex could significantly enhance Ca2+ absorption across Caco-2 cell monolayers. The findings suggest that the sea cucumber ovum derived peptide has the potential as an efficient nanocarrier to transport calcium through the GI system.


Assuntos
Cálcio/química , Nanoestruturas/química , Óvulo/química , Peptídeos/química , Pepinos-do-Mar/química , Animais , Transporte Biológico , Células CACO-2 , Cálcio/metabolismo , Trato Gastrointestinal/metabolismo , Humanos
7.
Int Braz J Urol ; 45(5): 901-909, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31626518

RESUMO

PURPOSE: It has been reported that calcitonin receptor (CALCR) gene polymorphisms might be associated with calcium stone urolithiasis. Owing to mixed and inconclusive results, we conducted a meta-analysis to summarize and clarify this association. MATERIALS AND METHODS: A systematic search of studies on the association between CALCR gene polymorphisms and calcium stone urolithiasis susceptibility was conducted in databases. RESULTS: Odds ratios and 95% confi dence intervals were used to pool the effect size. Five articles were included in our meta-analysis. CONCLUSIONS: CALCR rs1801197 might be associated with increased risk of calcium stone urolithiasis. There is insufficient data to fully confirm the association between CALCR rs1042138 and calcium stone urolithiasis susceptibility. Well-designed studies with larger sample size and more subgroups are required to validate the risk identified in the current meta-analysis.


Assuntos
Polimorfismo de Nucleotídeo Único , Receptores da Calcitonina/genética , Urolitíase/genética , Cálcio/metabolismo , Feminino , Estudos de Associação Genética , Humanos , Masculino , Medição de Risco , Fatores de Risco
8.
Cell Physiol Biochem ; 53(3): 573-586, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31529929

RESUMO

BACKGROUND/AIMS: In our recent work, the importance of GSK3ß-mediated phosphorylation of presenilin-1 as crucial process to establish a Ca2+ leak in the endoplasmic reticulum and, subsequently, the pre-activation of resting mitochondrial activity in ß-cells was demonstrated. The present work is a follow-up and reveals the importance of GSK3ß-phosphorylated presenilin-1 for responsiveness of pancreatic islets and ß-cells to elevated glucose in terms of cytosolic Ca2+ spiking and insulin secretion. METHODS: Freshly isolated pancreatic islets and the two pancreatic ß-cell lines INS-1 and MIN-6 were used. Cytosolic Ca2+ was fluorometrically monitored using Fura-2/AM and cellular insulin content and secretion were measured by ELISA. RESULTS: Our data strengthened our previous findings of the existence of a presenilin-1-mediated ER-Ca2+ leak in ß-cells, since a reduction of presenilin-1 expression strongly counteracted the ER Ca2+ leak. Furthermore, our data revealed that cytosolic Ca2+ spiking upon administration of high D-glucose was delayed in onset time and strongly reduced in amplitude and frequency upon siRNA-mediated knock-down of presenilin-1 or the inhibition of GSK3ß in the pancreatic ß-cells. Moreover, glucose-triggered initial insulin secretion disappeared by depletion from presenilin-1 and inhibition of GSK3ß in the pancreatic ß-cells and isolated pancreatic islets, respectively. CONCLUSION: These data complement our previous work and demonstrate that the sensitivity of pancreatic islets and ß-cells to glucose illustrated as glucose-triggered cytosolic Ca2+ spiking and initial but not long-lasting insulin secretion crucially depends on a strong ER Ca2+ leak that is due to the phosphorylation of presenilin-1 by GSK3ß, a phenomenon that might be involved in the development of type 2 diabetes.


Assuntos
Retículo Endoplasmático/metabolismo , Glucose/farmacologia , Células Secretoras de Insulina/metabolismo , Ilhotas Pancreáticas/metabolismo , Presenilina-1/metabolismo , Animais , Antracenos/farmacologia , Cálcio/metabolismo , Linhagem Celular , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Retículo Endoplasmático/efeitos dos fármacos , Humanos , Secreção de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/efeitos dos fármacos , Ilhotas Pancreáticas/efeitos dos fármacos , MAP Quinase Quinase 4/antagonistas & inibidores , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo
9.
Life Sci ; 235: 116810, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31472147

RESUMO

AIMS: Previous reports have demonstrated that melatonin exists in multiple extrapineal sites, and higher amounts of melatonin are present in human follicular fluid than in serum, which indicates that it might play key roles in human oocyte maturation and subsequent embryonic development. Melatonin has been shown to be a potent antioxidant and might be beneficial to human oocytes during in vitro maturation (IVM). However, the underlying mechanisms of melatonin action during IVM have not been thoroughly investigated. MAIN METHODS: Immunofluorescence staining, western blotting, and ELISA were applied to investigate whether melatoninergic components are expressed in the cultured human ovarian cumulus cells. TMRE staining and Fluo-4 AM staining were performed to detect the mitochondrial membrane potential and intracellular Ca2+ levels of immature human oocytes respectively. KEY FINDINGS: First, cultured human ovary cumulus cells synthesized melatonin in vitro, and it expressed serotonin (the precursor of melatonin) and the two key enzymes, i.e. N-acetyltransferase (NAT) and hydroxyindole-O-methyltransferase (HIOMT). Additionally, the results suggest that melatonin maintains the mitochondrial membrane potential and decrease excessive Ca2+ levels in immature human oocytes during IVM. SIGNIFICANCE: In conclusion, we provide evidence that the melatoninergic components were expressed in cultured human ovarian cumulus cells, and melatonin might reduce oxidative stress of human oocytes by ameliorating mitochondrial function. In view of the significant clinical value that immature human oocytes have in assisted reproductive technology (ART), our findings highlight a potential treatment strategy of using melatonin to improve mitochondrial function and to enhance the quality of human oocytes during IVM.


Assuntos
Antioxidantes/farmacologia , Cálcio/metabolismo , Melatonina/farmacologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Oócitos/efeitos dos fármacos , Antioxidantes/análise , Feminino , Humanos , Técnicas de Maturação in Vitro de Oócitos , Melatonina/análise , Mitocôndrias/metabolismo , Oócitos/citologia , Oócitos/metabolismo , Estresse Oxidativo
10.
Life Sci ; 235: 116802, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31472150

RESUMO

Substrate stiffness is essential for cell functions, but the mechanisms by which cell sense mechanical cues are still unclear. Here we show that the frequency and the amplitude of spontaneous Ca2+ oscillations were greater in chick cardiomyocytes cultured on the stiff substrates than that on the soft substrates. The spontaneous Ca2+ oscillations were increased on stiff substrates. However, an eliminated dependence of the Ca2+ oscillations on substrate stiffness was observed after applying blocker of the large-conductance Ca2+-activated K+ (BK) channels. In addition, the activity of BK channels in cardiomyocytes cultured on the stiff substrates was decreased. These results provide compelling evidences to show that BK channels are crucial in substrate stiffness-dependent regulation of the Ca2+ oscillation in cardiomyocytes.


Assuntos
Sinalização do Cálcio , Cálcio/metabolismo , Ventrículos do Coração/metabolismo , Canais de Potássio Ativados por Cálcio de Condutância Alta/metabolismo , Miócitos Cardíacos/metabolismo , Animais , Embrião de Galinha , Galinhas , Miócitos Cardíacos/citologia , Especificidade por Substrato
11.
J Agric Food Chem ; 67(40): 11035-11043, 2019 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-31517486

RESUMO

Ca2+-binding proteins (CaBPs) are widely distributed as Ca2+ sensor relay proteins that regulate various cellular processes, including Ca2+ homeostasis. Diamide insecticides such as cyantraniliprole kill insects by disrupting the Ca2+ homeostasis in muscle cells. However, less attention has been paid to the roles of CaBPs in response to insecticides. In this study, two CaBP genes (BtCaBP1 and BtCaBP2) were identified in the whitefly, Bemisia tabaci (Gennadius) (Hemiptera: Aleyrodidae), and their functions in response to cyantraniliprole were investigated. After expression of BtCaBP1 and BtCaBP2 in vitro, the results of Ca2+ imaging and cytotoxicity assay revealed that the overexpression of each of the BtCaBPs stabilized Ca2+ concentration in the cytoplasm after exposure to cyantraniliprole and decreased the toxicity of cyantraniliprole against Sf9 cells. However, the knockdown of BtCaBP1 or BtCaBP2 in vivo significantly increased the toxicity of cyantraniliprole to B. tabaci. Taken together, these results provide evidence that BtCaBP1 and BtCaBP2 play a role in response to cyantraniliprole exposure through stabilization of Ca2+ concentration in whiteflies.


Assuntos
Proteínas de Ligação ao Cálcio/metabolismo , Clonagem Molecular , Hemípteros/efeitos dos fármacos , Hemípteros/genética , Proteínas de Insetos/metabolismo , Inseticidas/farmacologia , Pirazóis/farmacologia , ortoaminobenzoatos/farmacologia , Sequência de Aminoácidos , Animais , Cálcio/metabolismo , Proteínas de Ligação ao Cálcio/genética , Hemípteros/classificação , Hemípteros/metabolismo , Proteínas de Insetos/genética , Filogenia
12.
Life Sci ; 235: 116841, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31494173

RESUMO

Indanyloxyacetic acid-94 (IAA-94), an intracellular chloride channel blocker, is shown to ablate cardioprotection rendered by ischemic preconditioning (IPC), N (6)-2-(4-aminophenyl) ethyladenosine or the PKC activator phorbol 12-myristate 13-acetate and cyclosporin A (CsA) in both ex-vivo and in-vivo ischemia-reperfusion (IR) injury. Thus signifying the role of the IAA-94 sensitive chloride channels in mediating cardio-protection upon IR injury. Although IAA-94 sensitive chloride currents are recorded in cardiac mitoplast, there is still a lack of understanding of the mechanism by which IAA-94 increases myocardial infarction (MI) by IR injury. Mitochondria are the key arbitrators of cell life and death pathways. Both oxidative stress and calcium overload in the mitochondria, elicit pathways resulting in the opening of mitochondrial permeability transition pore (mPTP) leading to cell death. Therefore, in this study we explored the role of IAA-94 in MI and in maintaining calcium retention capacity (CRC) of cardiac mitochondria after IR. IAA-94 inhibited the CRC of the isolated cardiac mitochondria in a concentration-dependent manner as measured spectrofluorimetrically using calcium green-5 N. Interestingly, IAA-94 did not change the mitochondrial membrane potential. Further, CsA a blocker of mPTP opening could not override the effect of IAA-94. We also showed for the first time that IAA-94 perfusion after ischemic event augments MI by reducing the CRC of mitochondria. To conclude, our results demonstrate that the mechanism of IAA-94 mediated cardio-deleterious effects is via modulating the mitochondria CRC, thereby playing a role in mPTP opening. These findings highlight new pharmacological targets, which can mediate cardioprotection from IR injury.


Assuntos
Cálcio/metabolismo , Glicolatos/efeitos adversos , Infarto do Miocárdio/metabolismo , Animais , Ciclosporina/farmacologia , Relação Dose-Resposta a Droga , Glicolatos/antagonistas & inibidores , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias Cardíacas/metabolismo , Infarto do Miocárdio/induzido quimicamente , Ratos
13.
Chem Biol Interact ; 312: 108814, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31509734

RESUMO

Nanotechnology is a growing science that may provide several new applications for medicine, food preservation, diagnostic technologies, and sanitation. Despite its beneficial applications, there are several questions related to the safety of nanomaterials for human use. The development of nanotechnology is associated with some concerns because of the increased risk of carcinogenesis following exposure to nanomaterials. The increased levels of reactive oxygen species (ROS) that are due to exposure to nanoparticles (NPs) are primarily responsible for the genotoxicity of metal NPs. Not all, but most metal NPs are able to directly produce free radicals through the release of metal ions and through interactions with water molecules. Furthermore, the increased production of free radicals and the cell death caused by metal NPs can stimulate reduction/oxidation (redox) reactions, leading to the continuous endogenous production of ROS in a positive feedback loop. The overexpression of inflammatory mediators, such as NF-kB and STATs, the mitochondrial malfunction and the increased intracellular calcium levels mediate the chronic oxidative stress that occurs after exposure to metal NPs. In this paper, we review the genotoxicity of different types of metal NPs and the redox mechanisms that amplify the toxicity of these NPs.


Assuntos
Nanopartículas Metálicas/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Animais , Cálcio/metabolismo , Dano ao DNA/efeitos dos fármacos , Aditivos Alimentares/química , Humanos , Nanopartículas Metálicas/química , Nanopartículas Metálicas/uso terapêutico , Neoplasias/tratamento farmacológico , Oxirredução , Espécies Reativas de Oxigênio/metabolismo
14.
Nat Cell Biol ; 21(9): 1152-1163, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31481791

RESUMO

Ca2+/calmodulin-dependent kinase II (CaMKII) is a multifunctional serine/threonine kinase family, and its δ isoform is predominant in the heart. Excessive CaMKII activation plays a pivotal role in the pathogenesis of severe heart conditions, including myocardial infarction, cardiomyopathy and heart failure. However, the identity of CaMKII splice variants and the mechanism(s) underlying CaMKII-mediated cardiac pathology remain elusive. Here, we show that CaMKII-δ9, the most abundant CaMKII-δ splice variant in human heart, potently promotes cardiomyocyte death, cardiomyopathy and heart failure by disrupting cardiomyocyte genome stability. Mechanistically, CaMKII-δ9, but not the previously well-studied CaMKII-δ2 and CaMKII-δ3, targets the ubiquitin-conjugating enzyme E2T (UBE2T) for phosphorylation and degradation, disrupting UBE2T-dependent DNA repair and leading to the accumulation of DNA damage and genome instability. These findings not only reveal a crucial role of CaMKII in the regulation of DNA repair, but also mark the CaMKII-δ9-UBE2T-DNA damage pathway as an important therapeutic target for cardiomyopathy and heart failure.


Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Reparo do DNA/genética , Enzimas de Conjugação de Ubiquitina/metabolismo , Animais , Cálcio/metabolismo , Cardiomiopatias/metabolismo , Insuficiência Cardíaca/metabolismo , Humanos , Camundongos , Miócitos Cardíacos/metabolismo , Fosforilação , Isoformas de Proteínas/metabolismo , Enzimas de Conjugação de Ubiquitina/genética
15.
Int J Nanomedicine ; 14: 6539-6553, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31496699

RESUMO

Aim: This paper reports on the incorporation of oleic acid (OA) within nanostructured lipid carriers (OA-NLC) to improve the anti-inflammatory effects in the presence of albumin. Materials and methods: NLCs produced via hot high-shear homogenization/ultrasonication were characterized in terms of particle size, zeta potential, and toxicity. We examined the effects of OA-NLC on neutrophil activities. Dermatologic therapeutic potential was also elucidated by using a murine model of leukotriene B4-induced skin inflammation. Results: In the presence of albumin, OA-NLC but not free OA inhibited superoxide generation and elastase release. Topical administration of OA-NLC alleviated neutrophil infiltration and severity of skin inflammation. Conclusion: OA incorporated within NLC can overcome the interference of albumin, which would undermine the anti-inflammatory effects of OA. OA-NLC has potential therapeutic effects in topical ointments.


Assuntos
Portadores de Fármacos/química , Inflamação/patologia , Lipídeos/química , Nanoestruturas/química , Neutrófilos/fisiologia , Ácido Oleico/química , Soroalbumina Bovina/farmacologia , Pele/patologia , Administração Tópica , Adulto , Animais , Cálcio/metabolismo , Bovinos , Morte Celular/efeitos dos fármacos , Portadores de Fármacos/administração & dosagem , Humanos , Leucotrieno B4 , Lipídeos/toxicidade , Masculino , Camundongos Endogâmicos BALB C , Nanoestruturas/administração & dosagem , Nanoestruturas/toxicidade , Nanoestruturas/ultraestrutura , Ativação de Neutrófilo/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Ácido Oleico/toxicidade , Elastase Pancreática/metabolismo , Superóxidos/metabolismo , Adulto Jovem
16.
J Agric Food Chem ; 67(37): 10285-10295, 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31443611

RESUMO

Fluoride (F) is capable of promoting abnormal proliferation and differentiation in primary cultured mouse osteoblasts (OB cells), although the underlying mechanism responsible remains rare. This study aimed to explore the roles of wingless and INT-1 (Wnt) signaling pathways and screen appropriate doses of calcium (Ca2+) to alleviate the sodium fluoride (NaF)-induced OB cell toxicity. For this, we evaluated the effect of dickkopf-related protein 1 (DKK1) and Ca2+ on mRNA levels of wingless/integrated 3a (Wnt3a), low-density lipoprotein receptor-related protein 5 (LRP5), dishevelled 1 (Dv1), glycogen synthase kinase 3ß (GSK3ß), ß-catenin, lymphoid enhancer binding factor 1 (LEF1), and cellular myelocytomatosis oncogene (cMYC), as well as Ccnd1 (Cyclin D1) in OB cells challenged with 10-6 mol/L NaF for 24 h. The demonstrated data showed that F significantly increased the OB cell proliferation rate. Ectogenic 0.5 mg/L DKK1 significantly inhibited the proliferation of OB cells induced by F. The mRNA expression levels of Wnt3a, LRP5, Dv1, LEF1, ß-catenin, cMYC, and Ccnd1 were significantly increased in the F group, while significantly decreased in the 10-6 mol/L NaF + 0.5 mg/L DKK1 (FY) group. The mRNA expression levels of Wnt3a, LRP5, ß-catenin, and cMYC were significantly decreased in the 10-6 mol/L NaF + 2 mmol/L CaCl2 (F+CaII) group. The protein expression levels of Wnt3a, Cyclin D1, cMYC, and ß-catenin were significantly increased in the F group, whereas they were decreased in the F+CaII group. However, the mRNA and protein expression levels of GSK3ß were significantly decreased in the F group while significantly increased in the F+CaII group. In summary, F activated the canonical Wnt/ß-catenin pathway and changed the related gene expression and ß-catenin protein location in OB cells, promoting cell proliferation. Ca2+ supplementation (2 mmol/L) reversed the expression levels of genes and proteins related to the canonical Wnt/ß-catenin pathway.


Assuntos
Cálcio/metabolismo , Fluoretos/efeitos adversos , Osteoblastos/efeitos dos fármacos , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Animais , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Suplementos Nutricionais/análise , Glicogênio Sintase Quinase 3 beta/genética , Glicogênio Sintase Quinase 3 beta/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Masculino , Camundongos , Osteoblastos/classificação , Osteoblastos/metabolismo , Proteínas Wnt/genética , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/genética
17.
Int J Nanomedicine ; 14: 6151-6163, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31447557

RESUMO

Background: Precise control and induction of the differentiation of stem cells to osteoblasts by artificial biomaterials are a promising strategy for rapid bone regeneration and reconstruction. Purpose: In this study, gold nanoparticles (AuNPs)-loaded hydroxyapatite (HA-Au) nanocomposites were designed to guide the osteogenic differentiation of human bone marrow-derived mesenchymal stem cells (hMSCs) through the synergistic effects of both AuNPs and HA. Materials and methods: The HA-Au nanoparticles were synthesized and characterized by several analytical techniques. Cell viability and proliferation of hMSCs were characterized by CCK-8 test. Cellular uptake of nanoparticles was observed by transmission electron microscope. For the evaluation of osteogenic differentiation, alkaline phosphatase (ALP) activity and staining, Alizarin red staining, and a quantitative real-time polymerase chain reaction (RT-PCR) analysis were performed. In order to examine specific signaling pathways, RT-PCR and Western blotting assay were performed. Results: The results confirmed the successful synthesis of HA-Au nanocomposites. The HA-Au nanoparticles showed good cytocompatibility and internalized into hMSCs at the studied concentrations. The increased level of ALP production, deposition of calcium mineralization, as well as the expression of typical osteogenic genes, indicated the enhancement of osteogenic differentiation of hMSCs. Moreover, the incorporation of Au could activate the Wnt/ß-catenin signaling pathway, which seemed to be the molecular mechanism underlying the osteoinductive capability of HA-Au nanoparticles. Conclusion: The HA-Au nanoparticles exerted a synergistic effect on accelerating osteogenic differentiation of hMSCs, suggesting they may be potential candidates for bone repair and regeneration.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Durapatita/farmacologia , Ouro/química , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Nanopartículas Metálicas/química , Osteogênese , Via de Sinalização Wnt/efeitos dos fármacos , Fosfatase Alcalina/metabolismo , Cálcio/metabolismo , Diferenciação Celular/genética , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/enzimologia , Nanopartículas Metálicas/ultraestrutura , Osteoblastos/citologia , Osteoblastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Osteogênese/genética
18.
BMC Plant Biol ; 19(1): 368, 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31429706

RESUMO

BACKGROUND: We previously reported the involvement of nitric oxide (NO) and cyclic nucleotide-gated ion channel 6 (CNGC6) in the responses of plants to heat shock (HS) exposure. To elucidate their relationship with heat tolerance in Arabidopsis thaliana, we examined the effects of HS on several groups of seedlings: wild type, cngc6, and cngc6 complementation and overexpression lines. RESULTS: After HS exposure, the level of NO was lower in cngc6 seedlings than in wild-type seedlings but significantly elevated in the transgenic lines depending on CNGC6 expression level. The treatment of seeds with calcium ions (Ca2+) enhanced the NO level in Arabidopsis seedlings under HS conditions, whereas treatment with EGTA (a Ca2+ chelator) reduced it, implicating that CNGC6 stimulates the accumulation of NO depending on an increase in cytosolic Ca2+ ([Ca2+]cyt). This idea was proved by phenotypic observations and thermotolerance testing of transgenic plants overexpressing NIA2 and NOA1, respectively, in a cngc6 background. Western blotting indicated that CNGC6 stimulated the accumulation of HS proteins via NO. CONCLUSION: These data indicate that CNGC6 acts upstream of NO in the HS pathway, which improves our insufficient knowledge of the initiation of plant responses to high temerature.


Assuntos
Proteínas de Arabidopsis/metabolismo , Arabidopsis/metabolismo , Cálcio/metabolismo , Canais de Cátion Regulados por Nucleotídeos Cíclicos/metabolismo , Óxido Nítrico/metabolismo , Termotolerância , Arabidopsis/genética , Proteínas de Arabidopsis/genética , Canais de Cálcio/metabolismo , Canais de Cátion Regulados por Nucleotídeos Cíclicos/genética , Citosol/metabolismo , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Resposta ao Choque Térmico , Mutação , Nitrato Redutase/genética , Nitrato Redutase/metabolismo , Óxido Nítrico Sintase/genética , Óxido Nítrico Sintase/metabolismo , Plântula/genética , Plântula/metabolismo
19.
J Agric Food Chem ; 67(34): 9618-9629, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31381342

RESUMO

Astrocytes provide nutritional support, regulate inflammation, and perform synaptic functions in the human brain. Although butylated hydroxyanisole (BHA) is a well-known antioxidant, several studies in animals have indicated BHA-mediated liver toxicity, retardation in reproductive organ development and learning, and sleep deficit. However, the specific effects of BHA on human astrocytes and the underlying mechanisms are yet unclear. Here, we investigated the antigrowth effects of BHA through cell cycle arrest and downregulation of regulatory protein expression. The typical cell proliferative signaling pathways, phosphoinositide 3-kinase/protein kinase B and extracellular signal-regulated kinase 1/2, were downregulated in astrocytes after BHA treatment. BHA increased the levels of pro-apoptotic proteins, such as BAX, cytochrome c, cleaved caspase 3, and cleaved caspase 9, and decreased the level of anti-apoptotic protein BCL-XL. It also increased the cytosolic calcium level and the expression of endoplasmic reticulum stress proteins. Treatment with BAPTA-AM, a calcium chelator, attenuated the increased levels of ER stress proteins and cleaved members of the caspase family. We further performed an in vivo evaluation of the neurotoxic effect of BHA on zebrafish embryos and glial fibrillary acidic protein, a representative astrocyte biomarker, in a gfap:eGFP zebrafish transgenic model. Our results provide clear evidence of the potent cytotoxic effects of BHA on human astrocytes, which lead to disruption of the brain and nerve development.


Assuntos
Astrócitos/efeitos dos fármacos , Hidroxianisol Butilado/toxicidade , Cálcio/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Neurotoxinas/toxicidade , Animais , Astrócitos/metabolismo , Caspase 3/metabolismo , Caspase 9/metabolismo , Linhagem Celular , Citocromos c/metabolismo , Citosol/efeitos dos fármacos , Citosol/metabolismo , Humanos , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Peixe-Zebra
20.
Pan Afr Med J ; 33: 43, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31384358

RESUMO

Carpopedal spasm have various causes ranging from dsyselecrolytemia, syndromic, metabolic or endocrine causes. Any of these could cause a decrease in ionized calcium and tetany. Excessive vomiting leading to alkalosis, hypokaleamia and decreased ionised calcium should be kept in mind for early etiological diagnosis of carpopedal spasm. We report a case of 4-year-old boy presenting with a history of recurrent painful spasm and flexion of bilateral hands following excessive vomiting and electrolyte derangement.


Assuntos
Espasmo/etiologia , Vômito/complicações , Desequilíbrio Hidroeletrolítico/complicações , Cálcio/metabolismo , Pré-Escolar , Mãos , Humanos , Masculino , Desequilíbrio Hidroeletrolítico/etiologia
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