Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 554
Filtrar
1.
PLoS One ; 15(10): e0237643, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33064729

RESUMO

We previously reported that maternal cigarette smoke (CS) exposure resulted in impairment of central chemoreception and induced mitochondrial dysfunction in offspring parafacial respiratory group (pFRG), the kernel for mammalian central chemoreception. We also found that hydrogen sulfide (H2S) could attenuate maternal CS exposure-induced impairment of central chemoreception in the rat offspring in vivo. Mitochondrial ATP sensitive potassium (mitoKATP) channel has been reported to play a significant role in mitochondrial functions and protect against apoptosis in neurons. Thus, we hypothesize here that mitoKATP channel plays a role in the protective effects of H2S on neonatal central chemoreception in maternal CS-exposed rats. Our findings revealed that pretreatment with NaHS (donor of H2S, 22.4mM) reversed the central chemosensitivity decreased by maternal CS exposure, and also inhibited cell apoptosis in offspring pFRG, however, 5-HD (blocker of mitoKATP channels, 19mM) attenuated the protective effects of NaHS. In addition, NaHS declined pro-apoptotic proteins related to mitochondrial pathway apoptosis in CS rat offspring pFRG, such as Bax, Cytochrome C, caspase9 and caspase3. NaHS or 5-HD alone had no significant effect on above indexes. These results suggest that mitoKATP channels play an important role in the protective effect of H2S against impairment of central chemoreception via anti-apoptosis in pFRG of rat offspring exposed to maternal CS.


Assuntos
Células Quimiorreceptoras/efeitos dos fármacos , Fumar Cigarros/efeitos adversos , Sulfeto de Hidrogênio/metabolismo , Exposição Materna/efeitos adversos , Canais de Potássio/metabolismo , Animais , Animais Recém-Nascidos , Apoptose/efeitos dos fármacos , Células Quimiorreceptoras/patologia , Células Quimiorreceptoras/fisiologia , Feminino , Bulbo/efeitos dos fármacos , Bulbo/patologia , Bulbo/fisiopatologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Substâncias Protetoras/metabolismo , Substâncias Protetoras/farmacologia , Ratos , Ratos Sprague-Dawley , Mecânica Respiratória/efeitos dos fármacos , Mecânica Respiratória/fisiologia , Sulfetos/metabolismo , Sulfetos/farmacologia
2.
Chem Biol Interact ; 329: 109213, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32739323

RESUMO

Phytoestrogens are plant-derived substances with a similar structure to 17-beta-estradiol, which have protective roles in estrogen-dependent diseases. Isoflavones, the most well-known subgroup of phytoestrogens, play protective roles against chemicals-induced liver injuries through several molecular mechanisms. Hepatoprotective effects of isoflavones are, partly, associated with their antioxidant, anti-inflammatory, immunomodulatory, and anti-fibrotic properties. Besides, isoflavones can reduce gut-derived endotoxins, accelerate alcohol metabolism, stimulate detoxification of hepatotoxic chemicals, suppress the bioactivation of these chemicals, inhibit hepatocytes apoptosis, and restore autophagy activity during chemicals-induced liver diseases. This review provides a summary of the molecular mechanisms underlying the hepatoprotective effects of isoflavones. It seems that further studies are needed to investigate the hepatoprotective potential of isoflavones in patients with different stages of chemicals-induced liver injuries.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Isoflavonas/metabolismo , Substâncias Protetoras/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Modelos Animais de Doenças , Inflamação/prevenção & controle , Isoflavonas/farmacologia , Isoflavonas/uso terapêutico , Metabolismo dos Lipídeos/efeitos dos fármacos , Cirrose Hepática/metabolismo , Cirrose Hepática/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/metabolismo , Substâncias Protetoras/farmacologia
3.
Life Sci ; 257: 118043, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32621922

RESUMO

BACKGROUND: Alveolar macrophages (AMs) are the primary targets of silicosis. Blockade of autophagy may aggravate the apoptosis of AMs. Trehalose (Tre), a transcription factor EB (TFEB) activator, may impact the autophagy-lysosomal system in AMs during silicosis. However, the mechanism by which Tre acts upon AMs in silicosis is unknown. METHODS: We collected AMs from twenty male workers exposed to silica and divided them into observer and silicosis patient groups. AMs from the two groups were then exposed to Tre. Western blot was used to measure the expression of autophagy-associated proteins. Lysosomal-associated membrane protein 1 (LAMP1) expression was observed using immunofluorescence and western blot. Apoptosis of the AMs was detected by TUNEL assay and western blot. RESULTS: Tre induced localization of TFEB to the nucleus in the AMs of both groups. After Tre exposure, LAMP1 levels increased and LC3 levels decreased in the AMs of both groups, suggesting that Tre may increase the function of the autophagy-lysosomal system. The LC3-II/I ratio in the Tre-exposed AMs was lower than in the AMs not exposed to Tre. The LC3-II/I ratio in AMs subjected to Tre plus Bafilomycin (Baf) was higher than the ratio in cells exposed to Tre or Baf individually. Additionally, p62 levels decreased after Tre stimulation in the AMs of both groups. This indicates that Tre may accelerate the process of autophagic degradation. We also found decreased levels of cleaved caspase-3 after Tre treatment in the AMs of both groups. However, p-mTOR (Ser2448) and p-mTOR (Ser2481) levels did not change significantly after Tre treatment, suggesting that the mTOR signaling pathway was not affected by Tre treatment. CONCLUSION: Our findings suggest that the restoration of autophagy-lysosomal function by Tre may be a potential protective strategy against silicosis.


Assuntos
Silicose/tratamento farmacológico , Trealose/metabolismo , Trealose/farmacologia , Adulto , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Humanos , Glicoproteínas de Membrana Associadas ao Lisossomo/metabolismo , Lisossomos/metabolismo , Macrófagos Alveolares/efeitos dos fármacos , Macrófagos Alveolares/metabolismo , Masculino , Pessoa de Meia-Idade , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/metabolismo , Transdução de Sinais/efeitos dos fármacos , Silicose/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Fatores de Transcrição
4.
Chem Biol Interact ; 327: 109162, 2020 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-32524993

RESUMO

Hundreds of millions of people worldwide are exposed to unacceptable levels of carcinogenic inorganic arsenic. Animal models have shown that selenium and arsenic are mutually protective through the formation and elimination of the seleno-bis(S-glutathionyl) arsinium ion [(GS)2AsSe]-. Consistent with this, human selenium deficiency in arsenic-endemic regions is associated with arsenic-induced disease, leading to the initiation of human selenium supplementation trials. In contrast to the protective effect observed in vivo, in vitro studies have suggested that selenite increases arsenite cellular retention and toxicity. This difference might be explained by the rapid conversion of selenite to selenide in vivo. In the current study, selenite did not protect the human hepatoma (HepG2) cell line against the toxicity of arsenite at equimolar concentrations, however selenide increased the IC50 by 2.3-fold. Cytotoxicity assays of arsenite + selenite and arsenite + selenide at different molar ratios revealed higher overall mutual antagonism of arsenite + selenide toxicity than arsenite + selenite. Despite this protective effect, in comparison to 75Se-selenite, HepG2 cells in suspension were at least 3-fold more efficient at accumulating selenium from reduced 75Se-selenide, and its accumulation was further increased by arsenite. X-ray fluorescence imaging of HepG2 cells also showed that arsenic accumulation, in the presence of selenide, was higher than in the presence of selenite. These results are consistent with a greater intracellular availability of selenide relative to selenite for protection against arsenite, and the formation and retention of a less toxic product, possibly [(GS)2AsSe]-.


Assuntos
Arsenitos/toxicidade , Substâncias Protetoras/farmacologia , Ácido Selenioso/farmacologia , Compostos de Selênio/farmacologia , Arsênico/metabolismo , Arsenitos/metabolismo , Células Hep G2 , Humanos , Inativação Metabólica/efeitos dos fármacos , Substâncias Protetoras/metabolismo , Radioisótopos/metabolismo , Ácido Selenioso/metabolismo , Selênio/metabolismo , Compostos de Selênio/metabolismo , Radioisótopos de Selênio/metabolismo
5.
Life Sci ; 256: 117915, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32504752

RESUMO

AIMS: Autonomic dysfunction in arterial hypertension affects cardiorespiratory control and gastric motility and has been characterized by increased sympathetic and reduced parasympathetic activity. In the present work we investigated the effects of anticholinesterase drugs [donepezil (DON) or pyridostigmine (PYR)] on cardiovascular, autonomic, and gastric parameters in L-NAME-induced hypertensive rats. MATERIALS AND METHODS: Daily oral gavage of L-NAME (70 mg/kg/day) was performed over 14 days in male Wistar rats (180-220 g), whereas daily oral gavage of DON or PYR (1.6 and 22 mg/kg/day, respectively) started 2 days after the L-NAME treatment initiation and lasted 12 days. The development of hypertension was verified by tail plethysmography technique. After the end of treatments, the animals were subjected to experimental protocols (6-12 animals per group; total number of animals used: 78). KEY FINDINGS: L-NAME hypertensive animals had no alterations in heart rate (HR) and intrinsic HR, but showed reduction in baroreflex sensitivity, parasympathetic tone, and gastric motility; and the sympathetic tone, chemoreflex sensitivity, and the LF (low frequency) band of systolic arterial pressure (SAP) variability were increased. DON or PYR attenuated the increase in mean arterial pressure (MAP) induced by L-NAME. Both anticholinesterase drugs were effective in preventing the decrease in baroreflex sensitivity, parasympathetic tone and gastric motility, and also prevented the increases in peripheral chemoreflex response and cardiac sympathetic tone. SIGNIFICANCE: Acetylcholinesterase inhibition with DON or PYR is a promising pharmacological approach to increase parasympathetic function, thus preventing the hypertension-induced alterations in the cardiovascular, gastrointestinal and autonomic systems.


Assuntos
Acetilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Hipertensão/prevenção & controle , NG-Nitroarginina Metil Éster/efeitos adversos , Substâncias Protetoras/farmacologia , Brometo de Piridostigmina/farmacologia , Animais , Pressão Arterial/efeitos dos fármacos , Sistema Nervoso Autônomo/efeitos dos fármacos , Barorreflexo/efeitos dos fármacos , Sistema Cardiovascular/efeitos dos fármacos , Inibidores da Colinesterase/metabolismo , Modelos Animais de Doenças , Donepezila/metabolismo , Donepezila/farmacologia , Frequência Cardíaca , Hipertensão/metabolismo , Masculino , Substâncias Protetoras/metabolismo , Brometo de Piridostigmina/metabolismo , Ratos , Ratos Wistar , Estômago/efeitos dos fármacos , Volume Sistólico
6.
Life Sci ; 256: 117924, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32522568

RESUMO

AIMS: Osteoarthritis (OA) is a common degenerative joint disease characterized by cartilage degeneration and joint inflammation. As its pathogenesis remains unclear, there are no effective treatments established. Circular RNA (circRNA), microRNA (miRNA), and other noncoding RNAs participate in OA development; however, the effects and mechanisms of circRNA and miRNA in OA remain unknown. MAIN METHODS: Cartilage miRNA was examined in patients with and without OA. KEY FINDINGS: CircRNA-9119 and phosphatase and tensin homolog (PTEN) expression decreased in OA-affected cartilage and interleukin (IL)-1ß-induced chondrocytes, and miR-26a expression significantly decreased in normal cells and tissues. CircRNA-9119 overexpression restored chondrocyte growth, whereas IL-1ß treatment impaired chondrocyte growth. Annexin V-FITC & PI flow cytometry and Bcl-2/Bax ratio measurement indicated that the apoptosis of IL-1ß-treated articular chondrocytes was decreased by circRNA-9119 upregulation. Bioinformatic prediction and the dual-luciferase reporter assay indicated that circRNA-9119 served as a miR-26a sponge and that miR-26a targeted the 3'-UTR of PTEN. Transfection of chondrocytes with a circRNA-9119-overexpressing vector revealed downregulation of miR-26a expression. Furthermore, circRNA-9119 overexpression induced PTEN expression. In addition, a miR-26a mimic induced IL-1ß-induced chondrocyte apoptosis, and circRNA-9119 overexpression inhibited IL-1ß-induced chondrocyte apoptosis. SIGNIFICANCE: CircRNA-9119 is an important regulator of IL-1ß-treated chondrocytes through the miR-26a/PTEN axis, possibly contributing to OA development.


Assuntos
Condrócitos/metabolismo , Interleucina-1beta/metabolismo , Osteoartrite/tratamento farmacológico , Substâncias Protetoras/metabolismo , RNA Circular/metabolismo , Regiões 3' não Traduzidas , Apoptose/efeitos dos fármacos , Cartilagem/metabolismo , Cartilagem Articular/metabolismo , Linhagem Celular , Condrócitos/citologia , Regulação para Baixo , Matriz Extracelular/metabolismo , Humanos , MicroRNAs/genética , PTEN Fosfo-Hidrolase/metabolismo , Monoéster Fosfórico Hidrolases/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Regulação para Cima , Proteína X Associada a bcl-2/metabolismo
7.
Chemosphere ; 256: 127038, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32470728

RESUMO

Baicalein is a flavonoid that is widely found in plants. Studies have shown that baicalein has anti-inflammatory, anti-cancer, and liver-protective effects. However, the effects of baicalein on TAA-induced toxicity and the underlying molecular mechanisms in zebrafish larvae are still unknown. Here, we investigated the effects of baicalein on liver development and its anti-inflammatory effects in zebrafish larvae. The results showed that baicalein has significant anti-embryonic developmental toxicity and significant antioxidant and anti-inflammatory capabilities in TAA-induced zebrafish larvae and promotes liver development and cell proliferation, reduces the expression of apoptotic proteins, and induces the expression of anti-apoptotic proteins. At the molecular level of TAA-treated zebrafish larvae, there was a decrease in the relative expression levels of mRNAs of three subfamilies, P38, ERK1, and ERK2, of the MAPK-signaling pathway and of the products of peroxisome proliferator-activated receptor (PPAR)α. Compared with TAA-treated zebrafish larvae, zebrafish larvae treated with baicalein showed an increase in the relative expression levels of P38, ERK1, and ERK2 mRNAs and the downstream products of PPARα. When MAPK signal inhibitor (SB203580) was added, it was found that liver development was inhibited and baicalin had no protective effect on TAA induced hepatotoxicity in zebrafish larvae. The results showed baicalein can protect the zebrafish larvae against toxicity induced by TAA through MAPK signal pathway. Several molecular mechanisms discovered in this study may help in the development of new drugs.


Assuntos
Flavanonas/toxicidade , Tioacetamida/toxicidade , Peixe-Zebra/fisiologia , Animais , Anti-Inflamatórios/metabolismo , Antioxidantes/metabolismo , Flavonoides , Larva/efeitos dos fármacos , Fígado/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , PPAR alfa , Substâncias Protetoras/metabolismo , Transdução de Sinais/efeitos dos fármacos
8.
Gene ; 754: 144775, 2020 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-32428696

RESUMO

Myocardial ischemia/reperfusion (I/R) injury is a common consequence of restored blood supply after acute myocardial infarction (AMI), but its underlying mechanisms remain largely elusive. In this study, we aimed to investigate the functional role of long non-coding RNA PVT1 in hypoxia/reoxygenation (H/R)-treated AC16 cardiomyocytes. Our experimental results demonstrated that H/R treatment impaired the viability and increased the apoptosis of AC16 cells, and knockdown of PVT1 blocked the H/R injury. Besides, PVT1 knockdown also reduced excessive autophagy in H/R-treated AC16 cells. Furthermore, we confirmed that PVT1 might serve as a ceRNA for miR-186 in AC16 cells, and rescue experiments showed that miR-186 inhibition blocked the effects of PVT1 knockdown in H/R-treated AC16 cells. In summary, this study implied that PVT1 might be a promising therapeutic target for treating myocardial I/R injury.


Assuntos
Apoptose , Autofagia , Proteína Beclina-1/metabolismo , MicroRNAs/genética , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miócitos Cardíacos/metabolismo , RNA Longo não Codificante/antagonistas & inibidores , Proteína Beclina-1/genética , Células Cultivadas , Regulação da Expressão Gênica , Humanos , Hipóxia/fisiopatologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Miócitos Cardíacos/patologia , Oxigênio/metabolismo , Substâncias Protetoras/metabolismo , RNA Longo não Codificante/genética
9.
Environ Health Perspect ; 128(4): 47011, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32352317

RESUMO

BACKGROUND: Polychlorinated biphenyls (PCBs) are environmental toxicants; PCB exposure has been associated with adverse effects on wildlife and humans. However, the mechanisms underlying these adverse effects are not fully understood. The steroid and xenobiotic receptor [SXR; also known as the pregnane X receptor (PXR) and formally known as NR1I2] is a nuclear hormone receptor that regulates inducible metabolism of drugs and xenobiotics and is activated or inhibited by various PCB congeners. OBJECTIVES: The aim of this study was to investigate the effects of exposure to PCB-153, the most prevalent PCB congener in human tissues, on SXR knockout mice (SXRKO) and to elucidate the role of SXR in PCB-153 metabolism and promotion of its harmful effects. METHODS: Wild-type (WT) and SXRKO mice were chronically or perinatally exposed to a low dose (54µg/kg/d) of PCB-153. Blood, livers, and spleens were analyzed using transcriptome sequencing (RNA-seq) and molecular techniques to investigate the impacts of exposure on metabolism, oxidative stress, and hematological parameters. RESULTS: SXRKO mice perinatally exposed to PCB-153 displayed elevated oxidative stress, symptoms of hemolytic anemia, and premature death. Transcriptomal analysis revealed that expression of genes involved in metabolic processes was altered in SXRKO mice. Elevated levels of the PCB-153 metabolite, 3-OH-PCB-153, were found in exposed SXRKO mice compared to exposed WT mice. Blood hemoglobin (HGB) levels were lower throughout the lifespan, and the occurrence of intestinal tumors was larger in SXRKO mice chronically exposed to PCB-153 compared to vehicle and WT controls. DISCUSSION: Our results suggest that altered metabolism induced by SXR loss of function resulted in the accumulation of hydroxylated metabolites upon exposure to PCB-153, leading to oxidative stress, hemolytic anemia, and tumor development in a mouse model. These results support a major role for SXR/PXR in protection against xenobiotic-induced oxidative stress by maintaining proper metabolism in response to PCB-153 exposure. This role of SXR could be generally applicable to other environmental toxicants as well as pharmaceutical drugs. https://doi.org/10.1289/EHP6262.


Assuntos
Poluentes Ambientais/metabolismo , Exposição Materna/efeitos adversos , Bifenilos Policlorados/metabolismo , Receptor de Pregnano X/metabolismo , Substâncias Protetoras/metabolismo , Animais , Feminino , Masculino , Camundongos , Camundongos Knockout
10.
Life Sci ; 253: 117626, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32247002

RESUMO

AIMS: Postoperative cognitive dysfunction (POCD) is a common postoperative complication that is associated with increased morbidity and mortality. However, the mechanism of pathogenesis of POCD still remains largely unknown. The aim of the study was to investigate the function and mechanism of lncRNA PCAI in POCD. MATERIALS AND METHODS: Knockdown and overexpression studies were performed to analyze the function of lncRNA PCAI in cultured BV-2 cell lines treated with LPS to mimic the neuroinflammation. Real-time PCR, western blot, ELISA were used to determine the expression level of inflammation markers. Rescue experiment was performed to prove the relationship between PCAI and SUZ12. RESULTS: We found that the expression of lncRNA PCAI was decreased with the increasing concentrations of LPS. Knockdown of lncRNA PCAI inhibited the cell death rates and attenuated the cell inflammation via ELISA and real-time PCR. Besides, downregulated of lncRNA PCAI can protect the mitochondrial function via membrane potential assay. Overexpression of lncRNA PCAI can promote the cell death and inflammation response induced by LPS. We also provided mechanism study about lncRNA PCAI that negatively regulating SUZ12. Rescue experiment also verified the results. CONCLUSION: We performed comprehensive study of functional analysis of lncRNA PCAI in POCD and proved its mechanism, which negatively regulate SUZ12. Our study provided new clues for the clinical intervention and targets for POCD.


Assuntos
Disfunção Cognitiva/etiologia , Hipocampo/metabolismo , Inflamação/metabolismo , Complicações Cognitivas Pós-Operatórias/prevenção & controle , Complicações Pós-Operatórias/prevenção & controle , RNA Longo não Codificante/genética , Animais , Linhagem Celular , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Inflamação/patologia , Camundongos , Membranas Mitocondriais/metabolismo , Complexo Repressor Polycomb 2/genética , Substâncias Protetoras/metabolismo , Substâncias Protetoras/farmacologia
11.
Proc Natl Acad Sci U S A ; 117(12): 6918-6927, 2020 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-32161131

RESUMO

Singlet oxygen (1O2), the major reactive oxygen species (ROS) produced in chloroplasts, has been demonstrated recently to be a highly versatile signal that induces various stress responses. In the fluorescent (flu) mutant, its release causes seedling lethality and inhibits mature plant growth. However, these drastic phenotypes are suppressed when EXECUTER1 (EX1) is absent in the flu ex1 double mutant. We identified SAFEGUARD1 (SAFE1) in a screen of ethyl methanesulfonate (EMS) mutagenized flu ex1 plants for suppressor mutants with a flu-like phenotype. In flu ex1 safe1, all 1O2-induced responses, including transcriptional rewiring of nuclear gene expression, return to levels, such as, or even higher than, those in flu Without SAFE1, grana margins (GMs) of chloroplast thylakoids (Thys) are specifically damaged upon 1O2 generation and associate with plastoglobules (PGs). SAFE1 is localized in the chloroplast stroma, and release of 1O2 induces SAFE1 degradation via chloroplast-originated vesicles. Our paper demonstrates that flu-produced 1O2 triggers an EX1-independent signaling pathway and proves that SAFE1 suppresses this signaling pathway by protecting GMs.


Assuntos
Proteínas de Arabidopsis/metabolismo , Arabidopsis/crescimento & desenvolvimento , Estresse Oxidativo , Substâncias Protetoras/metabolismo , Plântula/crescimento & desenvolvimento , Oxigênio Singlete/toxicidade , Tilacoides/metabolismo , Arabidopsis/genética , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Cloroplastos/efeitos dos fármacos , Cloroplastos/metabolismo , Cloroplastos/patologia , Regulação da Expressão Gênica de Plantas , Luz , Mutação , Espécies Reativas de Oxigênio/metabolismo , Plântula/genética , Plântula/metabolismo , Tilacoides/efeitos dos fármacos , Tilacoides/patologia
12.
Biochim Biophys Acta Bioenerg ; 1861(5-6): 148183, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32173384

RESUMO

Photosynthetic organisms are frequently exposed to excess light conditions and hence to photo-oxidative stress. To counteract photo-oxidative damage, land plants and most algae make use of non- photochemical quenching (NPQ) of excess light energy, in particular the rapidly inducible and relaxing qE-mechanism. In vascular plants, the constitutively active PsbS protein is the key regulator of qE. In the green algae C. reinhardtii, however, qE activation is only possible after initial high-light (HL) acclimation for several hours and requires the synthesis of LHCSR proteins which act as qE regulators. The precise function of PsbS, which is transiently expressed during HL acclimation in C. reinhardtii, is still unclear. Here, we investigated the impact of different PsbS amounts on HL acclimation characteristics of C. reinhardtii cells. We demonstrate that lower PsbS amounts negatively affect HL acclimation at different levels, including NPQ capacity, electron transport characteristics, antenna organization and morphological changes, resulting in an overall increased HL sensitivity and lower vitality of cells. Contrarily, higher PsbS amounts do not result in a higher NPQ capacity, but nevertheless provide higher fitness and tolerance towards HL stress. Strikingly, constitutively expressed PsbS protein was found to be degraded during HL acclimation. We propose that PsbS is transiently required during HL acclimation for the reorganization of thylakoid membranes and/or antenna proteins along with the activation of NPQ and adjustment of electron transfer characteristics, and that degradation of PsbS is essential in the fully HL acclimated state.


Assuntos
Proteínas de Algas/metabolismo , Chlamydomonas reinhardtii/metabolismo , Chlamydomonas reinhardtii/efeitos da radiação , Transferência de Energia , Luz , Substâncias Protetoras/metabolismo , Proteínas de Algas/ultraestrutura , Chlamydomonas reinhardtii/ultraestrutura , Processos Fotoquímicos , Complexo de Proteína do Fotossistema I/metabolismo , Complexo de Proteína do Fotossistema II/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Tilacoides/metabolismo
13.
Biomed Environ Sci ; 33(2): 77-88, 2020 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-32131955

RESUMO

Objective: Di-(2-ethylhexyl) phthalate (DEHP) is a ubiquitous environmental contaminant. As an endocrine disruptor, it seriously threatens human health and ecological environmental safety. This study examines the impact of intervention with soybean isoflavones (SIF) on DEHP-induced toxicity using a metabonomics approach. Methods: Rats were randomly divided into control (H), SIF-treated (A, 86 mg/kg body weight), DEHP-treated (B, 68 mg/kg), and SIF plus DEHP-treated (D) groups. Rats were given SIF and DEHP daily through diet and gavage, respectively. After 30 d of treatment, rat urine was tested using UPLC/MS with multivariate analysis. Metabolic changes were also evaluated using biochemical assays. Results: Metabolomics analyses revealed that p-cresol glucuronide, methyl hippuric acid, N1-methyl-2-pyridone-5-carboxamide, lysophosphatidycholine [18:2 (9Z, 12Z)] {lysoPC [18:2 (9Z, 12Z)]}, lysoPC (16:0), xanthosine, undecanedioic acid, and N6-acetyl-l-lysine were present at significantly different levels in control and treatment groups. Conclusion: SIF supplementation partially protects rats from DEHP-induced metabolic abnormalities by regulating fatty acid metabolism, antioxidant defense system, amino acid metabolism, and is also involved in the protection of mitochondria.


Assuntos
Dietilexilftalato/toxicidade , Disruptores Endócrinos/toxicidade , Poluentes Ambientais/toxicidade , Isoflavonas/urina , Metaboloma , Substâncias Protetoras/metabolismo , Soja/química , Animais , Feminino , Plastificantes/toxicidade , Ratos , Ratos Wistar , Urinálise
14.
Am J Pathol ; 190(4): 799-816, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32220420

RESUMO

Roundabout guidance receptor 2 (ROBO2) plays an important role during early kidney development. ROBO2 is expressed in podocytes, inhibits nephrin-induced actin polymerization, down-regulates nonmuscle myosin IIA activity, and destabilizes kidney podocyte adhesion. However, the role of ROBO2 during kidney injury, particularly in mature podocytes, is not known. Herein, we report that loss of ROBO2 in podocytes [Robo2 conditional knockout (cKO) mouse] is protective from glomerular injuries. Ultrastructural analysis reveals that Robo2 cKO mice display less foot process effacement and better-preserved slit-diaphragm density compared with wild-type littermates injured by either protamine sulfate or nephrotoxic serum (NTS). The Robo2 cKO mice also develop less proteinuria after NTS injury. Further studies reveal that ROBO2 expression in podocytes is up-regulated after glomerular injury because its expression levels are higher in the glomeruli of NTS injured mice and passive Heymann membranous nephropathy rats. Moreover, the amount of ROBO2 in the glomeruli is also elevated in patients with membranous nephropathy. Finally, overexpression of ROBO2 in cultured mouse podocytes compromises cell adhesion. Taken together, these findings suggest that kidney injury increases glomerular ROBO2 expression that might compromise podocyte adhesion and, thus, loss of Robo2 in podocytes could protect from glomerular injury by enhancing podocyte adhesion that helps maintain foot process structure. Our findings also suggest that ROBO2 is a therapeutic target for podocyte injury and podocytopathy.


Assuntos
Nefropatias/prevenção & controle , Glomérulos Renais/citologia , Podócitos/citologia , Substâncias Protetoras/metabolismo , Receptores Imunológicos/deficiência , Adulto , Animais , Feminino , Humanos , Nefropatias/metabolismo , Nefropatias/patologia , Glomérulos Renais/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Podócitos/metabolismo , Proteinúria/metabolismo , Proteinúria/patologia , Proteinúria/prevenção & controle , Ratos
15.
PLoS One ; 15(2): e0228415, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32084149

RESUMO

Ribose-cysteine is a synthetic compound designed to increase glutathione (GSH) synthesis. Low levels of GSH and the GSH-dependent enzyme, glutathione peroxidase (GPx), is associated with cardiovascular disease (CVD) in both mice and humans. Here we investigate the effect of ribose-cysteine on GSH, GPx, oxidised lipids and atherosclerosis development in apolipoprotein E-deficient (apoE-/-) mice. Female 12-week old apoE-/- mice (n = 15) were treated with 4-5 mg/day ribose-cysteine in drinking water for 8 weeks or left untreated. Blood and livers were assessed for GSH, GPx activity and 8-isoprostanes. Plasma alanine transferase (ALT) and lipid levels were measured. Aortae were quantified for atherosclerotic lesion area in the aortic sinus and brachiocephalic arch and 8-isoprostanes measured. Ribose-cysteine treatment significantly reduced ALT levels (p<0.0005) in the apoE-/- mice. Treatment promoted a significant increase in GSH concentrations in the liver (p<0.05) and significantly increased GPx activity in the liver and erythrocytes of apoE-/-mice (p<0.005). The level of 8-isoprostanes were significantly reduced in the livers and arteries of apoE-/- mice (p<0.05 and p<0.0005, respectively). Ribose-cysteine treatment showed a significant decrease in total and low density lipoprotein (LDL) cholesterol (p<0.05) with no effect on other plasma lipids with the LDL reduction likely through upregulation of scavenger receptor-B1 (SR-B1). Ribose-cysteine treatment significantly reduced atherosclerotic lesion area by >50% in both the aortic sinus and brachiocephalic branch (p<0.05). Ribose-cysteine promotes a significant GSH-based antioxidant effect in multiple tissues as well as an LDL-lowering response. These effects are accompanied by a marked reduction in atherosclerosis suggesting that ribose-cysteine might increase protection against CVD.


Assuntos
Antioxidantes/administração & dosagem , Apolipoproteínas E/deficiência , Aterosclerose/prevenção & controle , Cisteína/administração & dosagem , Substâncias Protetoras/administração & dosagem , Ribose/administração & dosagem , Animais , Antioxidantes/metabolismo , Aterosclerose/metabolismo , Aterosclerose/patologia , Cisteína/metabolismo , Feminino , Lipídeos/análise , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Oxirredução , Substâncias Protetoras/metabolismo , Ribose/metabolismo
16.
Nitric Oxide ; 96: 35-43, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31954804

RESUMO

Within the body, NO is produced by nitric oxide synthases via converting l-arginine to citrulline. Additionally, NO is also produced via the NOS-independent nitrate-nitrite-NO pathway. Unlike the classical pathway, the nitrate-nitrite-NO pathway is oxygen independent and viewed as a back-up function to ensure NO generation during ischaemia/hypoxia. Dietary nitrate and nitrite have emerged as substrates for endogenous NO generation and other bioactive nitrogen oxides with promising protective effects on cardiovascular and metabolic function. In brief, inorganic nitrate and nitrite can decrease blood pressure, protect against ischaemia-reperfusion injury, enhance endothelial function, inhibit platelet aggregation, modulate mitochondrial function and improve features of the metabolic syndrome. However, many questions regarding the specific mechanisms of these protective effects on cardiovascular and metabolic diseases remain unclear. In this review, we focus on nitrate/nitrite bioactivation, as well as the potential mechanisms for nitrate/nitrite-mediated effects on cardiovascular and metabolic diseases. Understanding how dietary nitrate and nitrite induce beneficial effect on cardiovascular and metabolic diseases could open up novel therapeutic opportunities in clinical practice.


Assuntos
Diabetes Mellitus/metabolismo , Hipertensão Pulmonar/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Nitratos/metabolismo , Nitritos/metabolismo , Substâncias Protetoras/metabolismo , Animais , Pressão Sanguínea/efeitos dos fármacos , Endotélio Vascular/metabolismo , Humanos , Microbiota/fisiologia , Boca/microbiologia , Agregação Plaquetária/efeitos dos fármacos
17.
Sci Rep ; 10(1): 386, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31941974

RESUMO

Polycystin 2 (PC2 or TRPP1, formerly TRPP2) is a calcium-permeant Transient Receptor Potential (TRP) cation channel expressed primarily on the endoplasmic reticulum (ER) membrane and primary cilia of all cell and tissue types. Despite its ubiquitous expression throughout the body, studies of PC2 have focused primarily on its role in the kidney, as mutations in PC2 lead to the development of autosomal dominant polycystic kidney disease (ADPKD), a debilitating condition for which there is no cure. However, the endogenous role that PC2 plays in the regulation of general cellular homeostasis remains unclear. In this study, we measure how PC2 expression changes in different pathological states, determine that its abundance is increased under conditions of cellular stress in multiple tissues including human disease, and conclude that PC2-deficient cells have increased susceptibility to cell death induced by stress. Our results offer new insight into the normal function of PC2 as a ubiquitous stress-sensitive protein whose expression is up-regulated in response to cell stress to protect against pathological cell death in multiple diseases.


Assuntos
Lesão Renal Aguda/patologia , Morte Celular , Cardiopatias/patologia , Hepatopatia Gordurosa não Alcoólica/patologia , Substâncias Protetoras/metabolismo , Traumatismo por Reperfusão/patologia , Canais de Cátion TRPP/metabolismo , Lesão Renal Aguda/etiologia , Lesão Renal Aguda/metabolismo , Animais , Cálcio/metabolismo , Retículo Endoplasmático/metabolismo , Cardiopatias/etiologia , Cardiopatias/metabolismo , Homeostase , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mutação , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Estresse Oxidativo , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/metabolismo , Canais de Cátion TRPP/genética
18.
Chem Commun (Camb) ; 56(7): 1085-1088, 2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-31894779

RESUMO

We report an elastase-responsive, H2S-releasing hydrogel prepared by covalently crosslinking a mixture of carboxymethylcellulose and poly(ethylene glycol) with an elastase-degradable peptide functionalized with an H2S-releasing S-aroylthiooxime (SATO) unit. Addition of elastase triggered a gel-to-sol transition, which exposed SATOs, leading to more and longer H2S release compared to untriggered gels.


Assuntos
Carboximetilcelulose Sódica/farmacologia , Hidrogéis/farmacologia , Sulfeto de Hidrogênio/metabolismo , Elastase de Leucócito/metabolismo , Polietilenoglicóis/farmacologia , Animais , Carboximetilcelulose Sódica/síntese química , Carboximetilcelulose Sódica/metabolismo , Linhagem Celular , Doxorrubicina/toxicidade , Humanos , Hidrogéis/síntese química , Hidrogéis/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Oximas/síntese química , Oximas/metabolismo , Oximas/farmacologia , Polietilenoglicóis/síntese química , Polietilenoglicóis/metabolismo , Substâncias Protetoras/síntese química , Substâncias Protetoras/metabolismo , Substâncias Protetoras/farmacologia , Ratos
19.
Chemosphere ; 246: 125794, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31918102

RESUMO

Environmental contamination by heavy metals, such as lead (Pb), can lead to severe immune dysfunction. MicroRNAs (miRNAs) are involved in regulating immunity. Whether Pb can regulate neutrophil apoptosis through miRNA, and whether selenium (Se) can antagonize this response are still unknown. We treated neutrophils with 12.5 µM (CH3OO)2Pb and 1 µM Na2SeO3 for 3 h, after which apoptosis was evaluated using acrideine orange/ethidium bromide (AO/EB) dual fluorescent staining and flow cytometry. The results showed that neutrophil apoptosis was significantly increased following Pb exposure, and that this response was prevented upon Se addition. Pb up-regulates miR-16-5p and leads to the subsequent down-regulation of the target genes phosphoinositide-3-kinase regulatory subunit 1 (PiK3R1), insulin-like growth factor 1 receptor (IGF1R), and phosphatidylinositol 3 kinase (Pi3K)-protein kinase B (AKT), followed by activation of the tumor protein P53 (P53)-B-cell lymphoma-2 (Bcl-2)/Bcl-2-Associated X protein (Bax)-cytochrome c (Cytc)-Caspase 9 (mitochondrial apoptotic pathway) and the tumor necrosis factor receptor superfamily member 6 (Fas)-Fas-associated death domain protein (Fadd)-Caspase 8 (death receptor pathway). Pb also triggered oxidative stress and indirectly activated the mitochondrial apoptotic pathway. We conclude that miR-16-5p plays a key role in the apoptosis of neutrophils exposed to Pb by down-regulating the expression of PiK3R1 and IGFR1, thereby activating the mitochondrial apoptotic pathway and death receptor pathway. Se can prevent Pb-induced apoptosis.


Assuntos
Poluentes Ambientais/toxicidade , Chumbo/toxicidade , MicroRNAs/metabolismo , Neutrófilos/efeitos dos fármacos , Fosfatidilinositol 3-Quinase/metabolismo , Substâncias Protetoras/metabolismo , Receptor IGF Tipo 1/metabolismo , Selênio/metabolismo , Animais , Apoptose/efeitos dos fármacos , Galinhas/metabolismo , Galinhas/fisiologia , Chumbo/metabolismo , MicroRNAs/genética , Mitocôndrias/metabolismo , Neutrófilos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Selênio/química , Proteína Supressora de Tumor p53
20.
J Recept Signal Transduct Res ; 40(1): 15-23, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31960779

RESUMO

Objective: Inflammation-mediated thyroid cell dysfunction and apoptosis increases the like-hood of hypothyroidism.Aim: Our aim in the present study is to explore the role of mitochondrial elongation factor 1 (Mief1) in thyroid cell dysfunction induced by TNFα.Materials and methods: Different doses of TNFα were used to incubate with thyroid cells in vitro. The survival rate, apoptotic index and proliferation capacity of thyroid cells were measured. Cellular energy metabolism and endoplasmic reticulum function related to protein synthesis were detected.Results: In response to TNFα treatment, the levels of Mief1 were increased, coinciding with a drop in the viability of thyroid cells in vitro. Loss of Mief1 attenuates TNFα-induced cell death through reducing the ratio of cell apoptosis. Further, we found that Mief1 deletion reversed cell energy metabolism and this effect was attributable to mitochondrial protection. Mief1 knockdown sustained mitochondrial membrane potential and reduced mitochondrial ROS overproduction. In addition, Mief1 knockdown also reduced endoplasmic reticulum stress, as evidenced by decreased levels of Chop and Caspase-12. Finally, our data verified that TNFα treatment inhibited the activity of AMPK-PTEN pathway whereas Mief1 deletion reversed the activity of AMPK and thus promoted the upregulation of PTEN. However, inhibition of AMPK-PTEN pathways could abolish the beneficial effects exerted by Mief1 deletion on thyroid cells damage and dysfunction.Conclusions: Altogether, our data indicate that immune abnormality-mediated thyroid cell dysfunction and death are alleviated by Mief1 deletion possible driven through reversing the activity of AMPK-PTEN pathways.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Apoptose , PTEN Fosfo-Hidrolase/metabolismo , Fatores de Alongamento de Peptídeos/metabolismo , Transdução de Sinais , Glândula Tireoide/patologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Deleção de Genes , Substâncias Protetoras/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/farmacologia , Regulação para Cima/efeitos dos fármacos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA