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1.
Chemosphere ; 242: 124959, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31669990

RESUMO

Long-term exposure to arsenic can cause liver injury and fibrosis. The activation of hepatic stellate cells (HSCs) plays an essential role in the process of liver fibrosis. We found that NaAsO2 caused liver damage and fibrosis in vivo, accompanied by excessive collagen deposition and HSCs activation. In addition, NaAsO2 upregulated autophagy flux, elevated the level of cytoplasmic cathepsin B (CTSB), and activated the NOD-like receptors containing pyrin domain 3 (NLRP3) inflammasome in a subtle way. Consistent with these findings in vivo, we demonstrated that NaAsO2-induced activation of HSCs depended on CTSB-mediated NLRP3 inflammasome activation in HSC-t6 cells and rats primary HSCs. Moreover, inhibition of autophagy decreased the cytoplasmic CTSB and alleviated the activation of the NLRP3 inflammasome, thereby attenuating the NaAsO2-induced HSCs activation. In summary, these results indicated that NaAsO2 induced HSCs activation via autophagic-CTSB-NLRP3 inflammasome pathway. These findings may provide a novel insight into the potential mechanism of NaAsO2-induced liver fibrosis.


Assuntos
Arsênico/toxicidade , Autofagia , Catepsina B/metabolismo , Células Estreladas do Fígado/metabolismo , Inflamassomos/fisiologia , Cirrose Hepática/induzido quimicamente , Animais , Arsênico/metabolismo , Inflamassomos/metabolismo , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/patologia , Masculino , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Ratos
2.
J Hazard Mater ; 384: 121390, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31735470

RESUMO

Chronic arsenic exposure is a significantly risk factor for pancreatic dysfunction and type 2 diabetes (T2D). Ferroptosis is a newly identified iron-dependent form of oxidative cell death that relies on lipid peroxidation. Previous data have indicated that ferroptosis is involved in various diseases, including cancers, neurodegenerative diseases, and T2D. However, the concrete effect and mechanism of ferroptosis on pancreatic dysfunction triggered by arsenic remains unknown. In this study, we verified that ferroptosis occurred in animal models of arsenic-induced pancreatic dysfunction through assessing proferroptotic markers and morphological changes in mitochondria. In vitro, arsenic caused execution of ferroptosis in a dose-dependent manner, which could be significantly reduced by ferrostatin-1. Additionally, arsenic damaged mitochondria manifested as diminishing of mitochondrial membrane potential, reduced cytochrome c level and production of mitochondrial reactive oxygen species (MtROS) in MIN6 cells. Using the Mito-TEMPO, we found the autophagy level and subsequent ferroptotic cell death induced by arsenic were both alleviated. With autophagy inhibitor chloroquine, we further revealed that ferritin regulated ferroptosis through the MtROS-autophagy pathway. Collectively, NaAsO2-induced ferroptotic cell death is relied on the MtROS-dependent autophagy by regulating the iron homeostasis. Ferroptosis is involved in pancreatic dysfunction triggered by arsenic, and arsenic-induced ferroptosis involves MtROS, autophagy, ferritin.

3.
Toxicology ; 428: 152304, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31586597

RESUMO

Zearalenone (ZEA), one of the mycotoxins widely found in food and feed, can stimulate an inflammatory reaction. In the present study, we demonstrated that ZEA induced the activation of NLRP3 inflammasome even pyroptotic cell death in rat Insulinoma Cell Line (INS-1). Meanwhile, according to the results of western blot and TEM, the level of autophagy was elevated by ZEA, which protected against the activation of NLRP3 inflammasome and inflammatory response caused by ZEA. Furthermore, we indicated that ZEA-induced NF-κB p65 activation contributed to the activation of the NLRP3 inflammasome, inflammatory response, and pyroptosis in INS-1 cells, which were indicated by western blot and immunofluorescence, and the activation of NF-κB p65 induced by ZEA was autophagy-dependent. This study demonstrates that ZEA induces NLRP3-dependent pyroptosis via activation of NF-κB modulated by autophagy in INS-1 cells.

4.
Chem Biol Interact ; 311: 108795, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31419397

RESUMO

Citreoviridin (CIT), a mycotoxin and ATP synthase inhibitor, is regarded as one of aetiology factors of cardiac beriberi and Keshan disease. Thiamine (VB1) and selenium (Se) improve the recovery of these two diseases respectively. The underlying mechanisms of cardiotoxic effect of CIT and cardioprotective effect of VB1 and Se have not been fully elucidated. In this study, we found that ectopic ATP synthase was more sensitive to CIT treatment than mitochondrial ATP synthase in H9c2 cardiomyocytes. CIT inhibited the transcriptional activity of peroxisome proliferator activated receptor gamma (PPAR-γ) in mice hearts and H9c2 cells. PPAR-γ agonist attenuated the inhibitory effect of CIT on mechanistic target of rapamycin complex 2 (mTORC2) and stimulatory effect of CIT on autophagy in cardiomyocytes. CIT induced apoptosis through lysosomal-mitochondrial axis in cardiomyocytes. PPAR-γ agonist and autophagy inhibitor alleviated CIT-induced apoptosis and accelerated cardiac biomarker. VB1 and Se accelerated the basal transcriptional activity of PPAR-γ in mice hearts and H9c2 cells. Furthermore, VB1 and Se reversed the effect of CIT on PPAR-γ, autophagy and apoptosis. Our findings defined PPAR-γ-mTORC2-autophagy pathway as the key link between CIT cardiotoxicity and cardioprotective effect of VB1 and Se. The present study would shed new light on the pathogenesis of cardiomyopathy and the cardioprotective mechanism of micronutrients.


Assuntos
Apoptose/efeitos dos fármacos , Aurovertinas/farmacologia , Autofagia/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Selênio/farmacologia , Tiamina/farmacologia , Animais , Aquaporinas/genética , Aquaporinas/metabolismo , Peso Corporal/efeitos dos fármacos , Linhagem Celular , Masculino , Alvo Mecanístico do Complexo 2 de Rapamicina/genética , Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo , Camundongos , Camundongos Endogâmicos ICR , Miocárdio/metabolismo , Miocárdio/patologia , PPAR gama/agonistas , PPAR gama/genética , PPAR gama/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Proteína X Associada a bcl-2/metabolismo
5.
Free Radic Biol Med ; 141: 393-407, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31279968

RESUMO

Exposure to fine particular matter (≤2.5 µM, PM2.5) contributes to increased risk of obesity and type 2 diabetes. Hydroxytyrosol (HT), a simple polyphenol found in virgin olive oil, is considered to be beneficial for cardiovascular and metabolic disorders. The current study determined whether HT could improve PM2.5-induced adiposity and insulin resistance (IR), and explored the underlying mechanisms. Fifteen adult female C57BL/6j mice on a chow diet were randomly divided into three groups receiving (1) sterile PBS, (2) PM2.5 suspended in sterile PBS (1 mg/mL) and (3) PM2.5+HT (50 mg/kg/day). PM2.5/PBS exposure was administered by oropharynx instillation every other day and HT supplementation was achieved by gavage every day. Four-week PM2.5 exposure did not affect body weight, but significantly increased visceral fat mass. The abdominal adiposity coincided with adipocyte hypertrophy and proliferation in visceral white adipose tissue (WAT), as well as decreased metabolic activity in brown adipose tissue and subcutaneous WAT. PM2.5 enhanced the oxidative stress by diminishing antioxidant enzyme activities in liver and serum, whereas contents of 4-hydroxynonenal (4-HNE), malondialdehyde (MDA) levels in liver and serum were elevated. These changes were accompanied by macrophage infiltration and activation of NF-κB pathway in the liver. Moreover, PM2.5 exposure led to glucose intolerance and insulin insensitivity, impaired hepatic glycogenesis, and decreased insulin-stimulated Akt phosphorylation in peripheral tissues. Importantly, HT treatment prevented PM2.5-induced visceral adipogenesis, oxidative stress, hepatic inflammation and NF-κB activation, systemic and peripheral IR. In vitro, after HepG2 cells were incubated with PM2.5 (0, 5, 25, 50, 100 and 200 µg/mL), reduced glutathione depletion and 4-HNE, 8-hydroxy-2'-deoxyguanosine, MDA increment in a dose-dependent manner were observed; likewise, insulin-stimulated glucose uptake decreased in a dose-dependent manner. Further, with antioxidant NAC and NF-κB inhibitor PDTC, we confirmed that HT attenuated PM2.5-induced IR through restraining NF-κB activation evoked by oxidative stress. In addition, HT could expand gut microbiota richness, reduce pathogenic bacteria and accommodate the microbial architecture in PM2.5-exposed mice, which were correlated with parameters of adiposity, oxidative stress and glycometabolism. HT could effectively correct imbalanced oxidative stress triggered by PM2.5, in turn ameliorated NF-κB pathway and insulin signaling. Gut microbiota may mediate the actions of HT.

6.
Toxicology ; 425: 152238, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31226464

RESUMO

The cardiotoxicity of doxorubicin (DOX) limits its clinical use in the treatment of a variety of solid tumors and malignant hematologic disease. However, the mechanism by which it causes cardiotoxicity is not fully understood. Apoptosis has been regarded as one of mechanisms underlying the cardiotoxic effects of DOX. In our study, we found that treatment of human umbilical vein endothelial cells (HUVECs) with DOX induced autophagy and apoptosis in a dose- and time-dependent manner. Treatment with DOX induced autophagy at earlier time (3 h), then lysosomal membrane permeabilization (LMP) altered after treatment for 12 h which followed by the release of cathepsin D (CTSD). Lysosome-associated membrane proteins-1 and -2 (LAMP1 and LAMP2) were decreased in DOX-treated cells. Additionally, DOX induced the collapse of mitochondrial transmembrane potential, reduction of translocase of the outer mitochondrial membrane-20 (TOM-20), and release of cytochrome c. Furthermore, autophagy inhibitor 3-MA relieved DOX-induced apoptosis as assessed by the expression of cleaved caspase-3, cleaved caspase-9 and TUNEL assay. CTSD inhibitor, pepstatin A, upregulated TOM-20 and suppressed the mitochondria release of cytochrome c as well as apoptosis under DOX stress. Pyrroloquinoline quinine (PQQ), a new B vitamin, ameliorated aforementioned phenomenon. In conclusion, our results suggested that DOX-induced apoptosis was autophagy-dependent via lysosomal-mitochondrial axis. PQQ had an ability to protect cell from autophagy-dependent apoptosis induced by DOX via lysosomal-mitochondrial axis to some extent. This study provided new mechanistic insight toward understanding the pathogenesis of DOX-induced cardiotoxicity and the protection effect of PQQ.

7.
Int J Biochem Cell Biol ; 112: 50-60, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31059810

RESUMO

Long-term and low-dose exposure to inorganic arsenic is associated with type 2 diabetes (T2D). In this study, C57BL/6 mice exposed to As2O3 showed impaired glucose tolerance, decrease in insulin sensitivity and insulin resistance were observed in the skeletal muscle and myotubes of mice that underwent As2O3 treatment. Decreased insulin-stimulated glucose uptake (ISGU) was also shown by the As2O3-treated myotubes. Moreover, the accumulation of ectopic fat in mice skeletal muscle and myotubes was observed after As2O3 treatment. The upregulated expression of autophagy-associated proteins and the increased number of acidic vesicular organelles (AVOs) indicated that autophagy was stimulated in the skeletal muscle and myotubes of mice after undergoing As2O3 treatment. TAU could prevent the effect of As2O3 on mice skeletal muscle and myotubes, as mentioned above. The impaired ISGU, decreased insulin-associated proteins expression, and increased TAG content caused by As2O3 were reversed by N-acetylcysteine (NAC) and 3-methyladenine (3-MA), and the As2O3-induced autophagy was inhibited by NAC, indicating involvement of ROS-autophagy pathway in the mechanism of As2O3-induced IR and lipid metabolism disorder. In summary, TAU protect against the As2O3-induced IR and ectopic fat accumulation in mice skeletal muscle and myotubes via ROS-autophagy pathway.

8.
Toxicol Mech Methods ; 29(6): 445-456, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30890009

RESUMO

Di-(2-ethylhexyl) phthalate (DEHP) is an environmental endocrine disruptor widely employed in plastic bags, industrial paints, cosmetics and food packaging, which has been reported to be harmful to human physical health. Many studies have shown that DEHP causes reproductive system toxicity, but its cytotoxicity to islet cells is few to unknown. In our research, it was found that DEHP could induce apoptosis in INS-1 cells via autophagy and oxidative stress. Taurine, a sulfur-containing ß-amino acid, could reverse DEHP-induced oxidative stress imbalance. Meanwhile, taurine could reduce DEHP-induced excessive autophagy. The interaction between oxidative stress and autophagy has been investigated in this study. After pretreated with autophagy interventional agents, it was found that autophagy was capable of alleviating oxidative stress and ROS production in DEHP-treated INS-1 cells. And down-regulated ROS production by NAC could also turn over uploaded autophagy. Our research provides a perspective about the mechanism of cytotoxicity of DEHP to INS-1 cells and taurine protective effect.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Dietilexilftalato/toxicidade , Poluentes Ambientais/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Taurina/farmacologia , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Ratos , Espécies Reativas de Oxigênio/metabolismo
9.
Food Chem Toxicol ; 125: 392-402, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30660605

RESUMO

Low-level inorganic arsenic (iAs) in drinking water is a risk factor for ß cells dysfunction. Taurine (Tau) is a kind of semi-essential ß amino acid, and beneficial for ß cell function. However, the effects of Tau on arsenic trioxide (As2O3) induced ß cells dysfunction and related mechanisms are still uncertain. Here, we found that Tau relieved As2O3-induced endoplasmic reticulum (ER) stress, inflammation and pyroptosis in rat pancreas. In INS-1 cells, with NOD-like receptor family pyrin domain-containing 3 (NLRP3) inhibitor pretreatment, As2O3-induced activation of pyroptosis was decreased; with tumor necrosis factor-α (TNF-α) inhibitor pretreatment, As2O3-induced activation of NLRP3 inflammasome and pyroptosis were decreased; further, with the inositol-requiring enzyme 1 alpha (IRE1α) inhibitor, As2O3-induced induction of TNF-α was decreased. Tau markedly protected As2O3-induced ß cells dysfunction by reducing the phosphorylation of IRE1α, production of TNF-α, activation of NLRP3 inflammasome and pyroptosis. Our results revealed that ER stress dependent inflammation and pyroptosis are critical pathogenic components of As2O3-induced ß cell dysfunction. Moreover, TNF-α was a critical signaling node that linked As2O3-induced ER stress and pyroptosis. Tau was an effective supplement against As2O3-induced ß cells dysfunction through the pathway as mentioned above.


Assuntos
Trióxido de Arsênio/efeitos adversos , Células Secretoras de Insulina/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Piroptose/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Taurina/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Linhagem Celular Tumoral , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Endorribonucleases/metabolismo , Feminino , Inflamassomos/efeitos dos fármacos , Inflamação/tratamento farmacológico , Complexos Multienzimáticos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Gravidez , Proteínas Serina-Treonina Quinases/metabolismo , Ratos Wistar , Fator de Necrose Tumoral alfa/metabolismo
10.
Chem Biol Interact ; 300: 123-130, 2019 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-30677399

RESUMO

The activation of hepatic stellate cells (HSCs) is a key event in the development of hepatic fibrosis caused by arsenic. However, it is unclear how arsenic induces the activation of HSCs. In the present study, we found that arsenic trioxide (As2O3) induced liver tissue damage, stimulated autophagy and HSCs activation, and increased collagen accumulation in the liver of mice. Supplemented with taurine (Tau) attenuated the changes mentioned above caused by As2O3. In human hepatic stellate cell line LX-2 cells, we found that As2O3-induced activation of HSCs was autophagy-dependent, and we found that peroxisome proliferator activated receptors alpha (PPARα) played an important role in arsenic-induced HSCs activation. In addition, inhibiting autophagy and PPARα alleviated the activation of HSCs and lipid droplet loss induced by As2O3. Moreover, we found that Tau alleviated As2O3-induced elevation of autophagy and PPARα expression, and activation of the HSCs. Our results indicated that autophagy was regulated by PPARα and was involved in lipid droplet loss during the activation of HSCs. Tau alleviated As2O3-induced HSCs activation by inhibiting the PPARα/autophagy pathway. These findings give an innovative insight into the association of PPARα, autophagy, the activation of HSCs and hepatic fibrosis induced by As2O3.


Assuntos
Trióxido de Arsênio/toxicidade , Autofagia/efeitos dos fármacos , PPAR alfa/metabolismo , Taurina/farmacologia , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Células Estreladas do Fígado/citologia , Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/metabolismo , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas de Ligação a RNA/metabolismo
11.
J Cell Physiol ; 234(4): 5143-5152, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30362509

RESUMO

Inorganic arsenic (iAs) is reportedly associated with the increased incidence of type 2 diabetes in the population. Here, we found that iAs exposure significantly decreased the expression of glycolytic genes and glycogen content and increased gluconeogenesis gene levels in C57/BL6J mice. The expression of peroxisome proliferator-activated receptor γ (PPARγ), and mechanistic target of rapamycin complex 2 (mTORC2) were decreased in the livers of iAs-treated mice. Furthermore, in iAs-treated HepG2 cells, we found that PPARγ agonist rosiglitazone (RGS) increased the expression of mTORC2, inhibited autophagy, and improved glucose metabolism. mTORC2 agonist palmitic acid inhibited autophagy and improved glucose metabolism as well as the autophagosome formation inhibitor 3-methyladenine. Taurine, a natural compound, reversed impaired glucose metabolism and decreased expression of PPARγ and mTORC2 induced by iAs in mice liver and HepG2 cells. These data indicated that taurine administration could ameliorate iAs-induced insulin resistance through activating PPARγ-mTORC2 signalling and subsequently inhibiting hepatic autophagy.

12.
Biomed Pharmacother ; 109: 815-822, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30551535

RESUMO

Arsenic was an established carcinogen and toxicant, occurring in drinking water and food. Arsenic was increasingly being blamed as a risk factor for diabetes mellitus. Recent studies have found that arsenic could induce the generation of reactive oxygen species (ROS) and mitochondria were the major targets of ROS. Damage mitochondria could be removed by mitophagy and mitophagy played a defensive role against cellular apoptosis. To investigate whether the arsenic could induce the injury in mitochondria, we treated Wistar rat offsprings and INS-1 cells with As2O3 and sodium arsenite, respectively. Our results showed that arsenic induced the generation of ROS in both rat offsprings' pancreas and INS-1 cells. The generation of ROS induced by arsenic could inhibit the expression of PPARγ. PPARγ is a major impact on mitochondrial function. The inhibition of PPARγ induced the reduction of PINK1 signaling and the upregulation of Bax. PINK1 signaling was one of the classical pathways of mitophagy. The inhibition of mitophagy induced the activation of apoptosis both in rat offsprings' pancreas and INS-1 cells. After treated with Rosiglitazone (RGS, PPARγ receptor agonist), PPARγ was rescued, the expression of PINK1 significantly increasing and the apoptosis was restrained. We used Taurine (Tau) as the protective agent both in rat offsprings' pancreas and INS-1 cells, after treated with Tau, the production of ROS was decreased significantly and the downgrade of PPARγ was rescued.


Assuntos
Arsênico/toxicidade , Células Secretoras de Insulina/efeitos dos fármacos , Pâncreas/efeitos dos fármacos , Pâncreas/lesões , Taurina/farmacologia , Animais , Células Cultivadas , Feminino , Células Secretoras de Insulina/metabolismo , Masculino , Pâncreas/metabolismo , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo
13.
J Agric Food Chem ; 66(46): 12376-12384, 2018 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-30392375

RESUMO

Patulin (PAT) is a compound produced by fungi including those of the Aspergillus, Penicillium, and Byssochlamys species. PAT has been linked with negative outcomes in certain microorganisms and animal species, but how it causes hepatotoxicity is poorly understood. In this study, we determined that, by treating HepG2 cells using PAT, these cells could be induced to rapidly undergo autophagy, and this was followed within 12 h of treatment by lysosomal membrane permeabilization (LMP) and cathepsin B release. We were able to block these outcomes if cells were treated with 3-methyladenine (3MA), an inhibitor of autophagy, prior to PAT treatment. Moreover, PAT-induced collapse of mitochondrial membrane potential (ΔΨm) depended both on cathepsin B and autophagy. 3MA was further able to reduce the induction of apoptosis in response to PAT, suggesting that autophagy is a driving mechanism for this apoptotic induction. Inhibiting cathepsin B using CA-074 Me further reduced PAT-induced collapses of ΔΨm, mitochondiral cytochrome c release, and apoptosis. We also found that extended treatment of HepG2 cells using PAT over a period of 24 h led to the impairment of mitophagy such that morphologically swollen mitochondria accumulated within cells, and PINK1 failed to colocalize with LC3. Together these data reveal that PAT treatment can promote the induction of apoptosis in HepG2 cells in a manner dependent upon autophagy that progresses via the lysosomal-mitochondrial axis. This study thereby affords new insights into the mechanisms by which PAT drives hepatotoxicity.


Assuntos
Autofagia/efeitos dos fármacos , Lisossomos/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Patulina/toxicidade , Apoptose/efeitos dos fármacos , Citocromos c/metabolismo , Células Hep G2 , Humanos , Fígado/citologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Lisossomos/metabolismo , Mitocôndrias/metabolismo , Espécies Reativas de Oxigênio/metabolismo
14.
Cell Death Dis ; 9(10): 946, 2018 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-30237538

RESUMO

Arsenic exposure causes nonalcoholic steatohepatitis (NASH). Inflammation is a key contributor to the pathology of nonalcoholic fatty liver disease (NAFLD), including NASH. However, it is unclear how arsenic induces inflammation. In mouse livers, we show that arsenic trioxide (As2O3) induced NASH, increased autophagy and NLRP3 inflammasome activation, increased lipid accumulation, and resulted in dysregulation of lipid-related genes. Supplemented with taurine (Tau) attenuated the inflammation and autophagy caused by As2O3. In HepG2 cells, we found that As2O3-induced pyroptotic cell death was dependent upon the activation of NLRP3 inflammasome, which was CTSB-dependent. In addition, inhibiting autophagy alleviated the As2O3-induced increase of cytosolic CTSB expression and subsequent release of LDH, activation of the NLRP3 inflammasome, and pyroptosis. Moreover, we found that Tau alleviated As2O3-induced elevation of autophagy, CTSB expression, and activation of the NLRP3 inflammasome, and reduced the release of LDH, pyroptotic cell death, and inflammation. Interestingly, As2O3-induced lipid accumulation could not be alleviated by either inhibition of autophagy nor by inhibition of CTSB. Additionally, neither inhibition of the NLRP3 inflammasome or Tau treatment could alleviate lipid accumulation. These results demonstrated that As2O3-induced pyroptosis involves autophagy, CTSB, and the NLRP3 inflammasome cascade, and that Tau alleviates As2O3-induced liver inflammation by inhibiting the autophagic-CTSB-NLRP3 inflammasomal pathway rather than decreasing lipid accumulation. These findings give insight into the association of autophagy, inflammation, pyroptosis, and NASH induced by As2O3.


Assuntos
Arsênico/toxicidade , Inflamação/metabolismo , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Piroptose/efeitos dos fármacos , Taurina/uso terapêutico , Animais , Autofagia/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Hep G2 , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Eletrônica de Transmissão , Hepatopatia Gordurosa não Alcoólica/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais/efeitos dos fármacos
15.
Toxicology ; 410: 26-40, 2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-30205151

RESUMO

Acrolein is a common environmental pollutant that has been linked to cardiovascular diseases, such as atherosclerosis (AS). Increasing evidence demonstrates that acrolein impairs the cardiovascular system by targeting vascular endothelial cells, but the underlying mechanisms haven't been completely elucidated. In human umbilical vein endothelial cells (HUVECs), we observed that acrolein treatment induced cell reactive oxygen species (ROS) generation, autophagy, pyroptosis and reduced cell migration. In addition, exposure to acrolein resulted in NLRP3 inflammasome activation as evidenced by cleavage of caspase-1 and downstream mature interleukin (IL)-1ß and IL-18 secretion. Knockdown of NLRP3 by small interfering RNA remarkably suppressed acrolein-induced pyroptosis and increased cell migration. Moreover, the scavenging ROS relieved the autophagy, NLRP3 inflammasome activation and pyroptosis. Furthermore, the role of autophagy in the acrolein-medicated pyroptosis and cell migration was investigated. In our study, 3-methyladenine (3-MA), an autophagy inhibitor, aggravated NLRP3 inflammasome activation, pyroptosis and decreased cell migration, rapamycin (Rapa), an autophagy inducer, alleviated aforementioned phenomenon under acrolein stress. Besides, we found damaged mitochondrion accentuated NLRP3 inflammasome and pyroptosis in acrolein-treated cells. In conclusion, it is possible that acrolein induced cell pyroptosis and suppressed cell migration via ROS-dependent autophagy. What's more, NLRP3 inflammasome activation plays a key role in this process.


Assuntos
Acroleína/farmacologia , Autofagia/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Inflamassomos/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/efeitos dos fármacos , Piroptose/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Proteínas Associadas aos Microtúbulos/sangue , Proteína 3 que Contém Domínio de Pirina da Família NLR/biossíntese , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Espécies Reativas de Oxigênio
16.
Toxicol In Vitro ; 52: 146-153, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29902662

RESUMO

Acrolein, a highly reactive α,ß-unsaturated aldehyde, is a toxic component of cigarette smoke. As a lipid peroxidation biomarker, acrolein plays an important role in a wide variety of disease states, such as neurodegenerative, Alzheimer's disease, diabetes and atherosclerosis. Endothelial cell injury is one of the initiating factors of atherosclerosis, but the underlying molecular mechanisms remain unclear. Our study primarily focused on acrolein-induced autophagy-dependent apoptosis and the possible molecular mechanism. The results showed that treatment with acrolein increased the number of intracellular GFP-LC3 II punctuates and the expression of autophagosome biomarker LC3-II, with the low dose (25 µM) or at the early stage of treatment (3 h). Following treatment of EAhy926 cells with acrolein for 6 h, lysosomal permeabilization changed, and cathepsin B (CB) was released. Additionally, acrolein induced the collapse of mitochondrial transmembrane potential, and cytochrome c was released. Furthermore, caspase-3 and caspase-9 activation showed that acrolein induced EAhy926 cell apoptosis. Autophagy inhibitor 3MA and CB inhibitor CA-074 Me (CA) attenuated acrolein-induced apoptosis. Collectively, our results suggested that acrolein-induced apoptosis is autophagy-dependent, occurring via injury to lysosomes and mitochondria. This study provides new mechanistic insight toward understanding the pathogenesis of acrolein-related disorders.


Assuntos
Acroleína/toxicidade , Lisossomos/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Catepsina B , Linhagem Celular , Citocromos c , Humanos , Mitocôndrias/fisiologia
17.
Toxicol Ind Health ; 34(9): 589-595, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29764313

RESUMO

n-Hexane is an organic solvent widely used in industry. 2,5-Hexanedione (2,5-HD), the major neurotoxic metabolite of n-hexane, decreases the levels of neurofilaments (NFs) in neurons. Neurogenesis occurs throughout life, and the hippocampal dentate gyrus is one of two major brain areas showing neurogenesis in adulthood. In the current study, rats were intraperitoneally injected with normal saline solution or 2,5-HD five times per week for five continuous weeks. 2,5-HD was administered to the low-dose and high-dose groups at 200 and 400 mg/kg/day, respectively. Then, immunoreactive cells were counted in the hippocampal granule cell layer (GCL) and subgranular zone (SGZ). Ki67+ cells significantly decreased in the high-dose group, while the percentage of proliferative Sox2+ cells significantly increased, consistent with high hippocampal Sox2 expression. Additionally, western blotting showed that exposure to high doses of 2,5-HD led to decreased NF-L in both the cortex and hippocampus, whereas low doses led to a significant reduction in the cortex only. In conclusion, 2,5-HD increases the percentage of proliferating neural stem and progenitor (Sox2+) cells in the SGZ/GCL.


Assuntos
Proliferação de Células/efeitos dos fármacos , Hexanonas/toxicidade , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Fatores de Transcrição SOXB1/análise , Animais , Hipocampo/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Fatores de Transcrição SOXB1/metabolismo
18.
Chem Biol Interact ; 288: 24-31, 2018 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-29604266

RESUMO

Patulin (PAT) is a secondary metabolite produced by certain species of Penicillium, Byssochlamys and Aspergillus. It has been shown to induce liver toxicity, but the possible molecular mechanisms are not completely elucidated. In our study, we treated Human Hepatoma G2 (HepG2) cells by 3-methyladenine (3-MA), an autophagosome formation inhibitor, and rapamycin, an autophagosome formation stimulator. The results showed that 3-MA protected the HepG2 cells against PAT cytotoxicity, while rapamycin decreased the cell viability. Thus, autophagy may play an important role in PAT-induced toxicity. To uncover the mechanism by which cells decrease proliferation and activation of autophagy, we found that collapses of mitochondrial membrane potential (ΔΨm) and reactive oxygen species (ROS) level were increased under treatment with PAT. Further, we elucidated that the expression of p-Akt1 and p-MTOR was inhibited during this process. N-acetyl-l-cysteine (NAC), a ROS inhibitor, protected against PAT-induced cytotoxicity, decreased the protein expression of LC3-II, and up-regulated the level of p-Akt1 and p-MTOR. These findings suggested that PAT-induced autophagic cell death was ROS-dependent in HepG2 cells. In conclusion, it is possible that PAT elicited autophagy through ROS-Akt1-MTOR pathway in the HepG2 cells.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Patulina/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Acetilcisteína/farmacologia , Antineoplásicos/farmacologia , Regulação para Baixo/efeitos dos fármacos , Células Hep G2 , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Patulina/química , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Regulação para Cima/efeitos dos fármacos
19.
Food Chem Toxicol ; 111: 19-26, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29111283

RESUMO

Inorganic arsenic is a worldwide environmental pollutant. Arsenic's relationship with the incidence of diabetes arouses concerns on its etiological mechanism. In this study, the glucose-stimulated insulin secretion (GSIS) from isolated pancreatic islets of As2O3-treated mice was significantly lower than that of control mice. It indicated that the effect of As2O3-inhibited GSIS was pancreatic islet-autonomous. The level of phospho-PERK (p-PERK), a biomarker of endoplasmic reticulum (ER) stress, in pancreas of As2O3-treated mice was increased significantly. After treatment with NaAsO2, the p-PERK level in INS-1 rat pancreatic ß- cells was increased correspondingly. After treatment with PERK inhibitor, the GSIS from isolated pancreatic islets of As2O3-treated mice was recovered. Arsenic induced autophagy in pancreatic islets, as evidenced by elevated LC3-II level and depressed P62 level in vivo and in vitro. In NaAsO2-treated INS-1 cells, the initiation of ER stress preceded the stimulation of autophagy, which was a key factor controlling pancreatic ß cell function. Furthermore, knockdown of PERK attenuated NaAsO2-induced autophagy in INS-1 cells. These data indicated that arsenic impaired ß cell function through ER stress-autophagy pathway. The present study will provide new mechanistic insights into arsenic-related diabetes.


Assuntos
Autofagia/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Insulina/metabolismo , Ilhotas Pancreáticas/efeitos dos fármacos , Óxidos/toxicidade , Adenina/análogos & derivados , Adenina/farmacologia , Animais , Trióxido de Arsênio , Arsenicais , Biomarcadores , Indóis/farmacologia , Secreção de Insulina , Camundongos , Camundongos Endogâmicos C57BL , Organismos Livres de Patógenos Específicos , Técnicas de Cultura de Tecidos , eIF-2 Quinase/antagonistas & inibidores
20.
Toxicol In Vitro ; 44: 49-56, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28655635

RESUMO

Mono-(2-ethylhexyl) phthalate (MEHP) is an active metabolite of di-(2-ethylhexyl) phthalate (DEHP). MEHP has toxic effects on cardiovascular system, but the possible molecular mechanisms are not completely elucidated. In our study, 3-methyladenine (3-MA), an autophagosome formation inhibitor, protected the EA.hy926 cells against MEHP cytotoxicity, and rapamycin, an autophagosome formation stimulator, further decreased the cell viability in the MEHP-treated EA.hy926 cells. Thus, autophagy may play an important role in MEHP-induced toxicity. MEHP increased the autophagosome number in EA.hy926 cells detected under transmission electron microscope. Collapses of ΔΨm and reactive oxygen species (ROS) level were increased in a dose-dependent manner under treatment with 0-200µM MEHP for 24h. N-acetyl-l-cysteine (NAC), a ROS inhibitor, protected against MEHP-induced cytotoxicity and decreased the protein expression of LC3-II. These findings suggested that MEHP-induced autophagic cell death was ROS-dependent in EA.hy926 cells. Knockdown of Akt1 with Akt1 siRNA aggravated MEHP-induced cell death, and insulin, an Akt1 activator, alleviated MEHP-induced cell death. These results were consistent with the expression of LC3-II using western blot. The phospho-Akt1(Ser473) (p-Akt1) level was enhanced after pretreatment with NAC. In conclusion, it is possible that ROS elicited autophagy through Akt1 pathway in the MEHP-treated EA.hy926 cells.


Assuntos
Dietilexilftalato/análogos & derivados , Células Endoteliais/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/genética , Acetilcisteína/farmacologia , Adenina/análogos & derivados , Adenina/farmacologia , Autofagia/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Dietilexilftalato/toxicidade , Células Endoteliais/metabolismo , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Proteínas Associadas aos Microtúbulos/metabolismo , RNA Interferente Pequeno/genética , Espécies Reativas de Oxigênio/metabolismo , Sirolimo/farmacologia
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