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BACKGROUND: Due to their crucial functional location, surgical treatment of brainstem arteriovenous malformations (AVMs) has always been challenging. For unruptured AVMs, we can determine whether radiological therapy, interventional treatment, or surgical resection is feasible based on the AVM structure. However, for ruptured AVMs, microsurgical resection and interventional embolization are effective methods to prevent further rupture. In the microsurgical resection of AVMs, we usually use a hybrid operation to confirm the AVM structure and determine if the AVM is completely resected during the surgery. METHOD: We report a case of juvenile ruptured brainstem AVM resection. The right lateral position and left suboccipital retrosigmoid approach were used. We established an interventional approach via left radial artery and set a microcatheter in the feeding artery. Methylene blue injection via a microcatheter showed the AVM structure, and we totally resected the brainstem AVM under electrophysiological monitoring and navigation. Intraoperative angiography was performed to ensure complete resection without residual nidus. CONCLUSION: This case demonstrates that the trans-radial approach is convenient and safe for special positions in hybrid operations. Methylene blue injection via a microcatheter in the feeding artery provides clearer visualization of the AVM structure under the microscope.
Assuntos
Malformações Arteriovenosas , Artéria Radial , Humanos , Angiografia , Tronco Encefálico/diagnóstico por imagem , Tronco Encefálico/cirurgia , Azul de Metileno , Artéria Radial/diagnóstico por imagem , Artéria Radial/cirurgia , AdolescenteRESUMO
Perfluorooctane sulfonate (PFOS), an officially listed persistent organic pollutant, is a widely distributed perfluoroalkyl substance. Epidemiological studies have shown that PFOS is intimately linked to the occurrence of insulin resistance (IR). However, the detailed mechanism remains obscure. In previous studies, we found that mitochondrial calcium overload was concerned with hepatic IR induced by PFOS. In this study, we found that PFOS exposure noticeably raised lysosomal calcium in L-02 hepatocytes from 0.5â¯h. In the PFOS-cultured L-02 cells, inhibiting autophagy alleviated lysosomal calcium overload. Inhibition of mitochondrial calcium uptake aggravated the accumulation of lysosomal calcium, while inhibition of lysosomal calcium outflowing reversed PFOS-induced mitochondrial calcium overload and IR. Transient receptor potential mucolipin 1 (TRPML1), the calcium output channel of lysosomes, interacted with voltage-dependent anion channel 1 (VDAC1), the calcium intake channel of mitochondria, in the PFOS-cultured cells. Moreover, we found that ATP synthase F1 subunit beta (ATP5B) interacted with TRPML1 and VDAC1 in the L-02 cells and the liver of mice under PFOS exposure. Inhibiting ATP5B expression or restraining the ATP5B on the plasma membrane reduced the interplay between TRPML1 and VDAC1, reversed the mitochondrial calcium overload and deteriorated the lysosomal calcium accumulation in the PFOS-cultured cells. Our research unveils the molecular regulation of the calcium crosstalk between lysosomes and mitochondria, and explains PFOS-induced IR in the context of activated autophagy.
Assuntos
Ácidos Alcanossulfônicos , Autofagia , Cálcio , Fluorocarbonos , Resistência à Insulina , Fígado , Lisossomos , Mitocôndrias , ATPases Mitocondriais Próton-Translocadoras , Ácidos Alcanossulfônicos/toxicidade , Fluorocarbonos/toxicidade , Animais , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Autofagia/efeitos dos fármacos , Cálcio/metabolismo , Camundongos , ATPases Mitocondriais Próton-Translocadoras/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Masculino , Canal de Ânion 1 Dependente de Voltagem/metabolismo , Linhagem Celular , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Poluentes Ambientais/toxicidade , Canais de Cátion TRPM/metabolismo , Camundongos Endogâmicos C57BLRESUMO
The compound known as Sodium arsenite (NaAsO2), which is a prevalent type of inorganic arsenic found in the environment, has been strongly associated with liver fibrosis (LF), a key characteristic of nonalcoholic fatty liver disease (NAFLD), which has been demonstrated in our previous study. Our previous research has shown that exposure to NaAsO2 triggers the activation of hepatic stellate cells (HSCs), a crucial event in the development of LF. However, the molecular mechanism is still unknown. N6-methyladenosine (m6A) modification is the most crucial post-transcriptional modification in liver disease. Nevertheless, the precise function of m6A alteration in triggering HSCs and initiating LF caused by NaAsO2 remains unknown. Here, we found that NaAsO2 induced LF and HSCs activation through TGF-ß/Smad signaling, which could be reversed by TGF-ß1 knockdown. Furthermore, NaAsO2 treatment enhanced the m6A modification level both in vivo and in vitro. Significantly, NaAsO2 promoted the specific interaction of METTL14 and IGF2BP2 with TGF-ß1 and enhanced the TGF-ß1 mRNA stability. Notably, NaAsO2-induced TGF-ß/Smad pathway and HSC-t6 cells activation might be avoided by limiting METTL14/IGF2BP2-mediated m6A modification. Our findings showed that the NaAsO2-induced activation of HSCs and LF is made possible by the METTL14/IGF2BP2-mediated m6A methylation of TGF-ß1, which may open up new therapeutic options for LF brought on by environmental hazards.
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Adenosina , Arsenitos , Células Estreladas do Fígado , Cirrose Hepática , Compostos de Sódio , Fator de Crescimento Transformador beta1 , Arsenitos/toxicidade , Células Estreladas do Fígado/efeitos dos fármacos , Compostos de Sódio/toxicidade , Cirrose Hepática/patologia , Cirrose Hepática/induzido quimicamente , Animais , Fator de Crescimento Transformador beta1/metabolismo , Adenosina/análogos & derivados , Metiltransferases/genética , Metiltransferases/metabolismo , Masculino , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/genética , Transdução de Sinais/efeitos dos fármacos , Camundongos , Humanos , Camundongos Endogâmicos C57BLRESUMO
The incidence of nonalcoholic steatohepatitis (NASH) is related with perfluorooctane sulfonate (PFOS), yet the mechanism remains ill-defined. Mounting evidence suggests that ferroptosis plays a crucial role in the initiation of NASH. In this study, we used mice and human hepatocytes L-02 to investigate the role of ferroptosis in PFOS-induced NASH and the effect and molecular mechanism of PFOS on liver ferroptosis. We found here that PFOS caused NASH in mice, and lipid accumulation and inflammatory response in the L-02 cells. PFOS induced hepatic ferroptosis in vivo and in vitro, as evidenced by the decrease in glutathione peroxidase 4 (GPX4), and the increases in cytosolic iron, acyl-CoA synthetase long-chain family member 4 (ACSL4) and lipid peroxidation. In the PFOS-treated cells, the increases in the inflammatory factors and lipid contents were reversed by ferroptosis inhibitor. PFOS-induced ferroptosis was relieved by autophagy inhibitor. The expression of mitochondrial calcium uniporter (MCU) was accelerated by PFOS, leading to subsequent mitochondrial calcium accumulation, and inhibiting autophagy reversed the increase in MCU. Inhibiting mitochondrial calcium reversed the variations in GPX4 and cytosolic iron, without influencing the change in ACSL4, induced by PFOS. MCU interacted with ACSL4 and the siRNA against MCU reversed the changes in ACSL4ï¼GPX4 and cytosolic iron systemically. This study put forward the involvement of hepatic ferroptosis in PFOS-induced NASH and identified MCU as the mediator of the autophagy-dependent ferroptosis.
Assuntos
Ácidos Alcanossulfônicos , Autofagia , Cálcio , Coenzima A Ligases , Ferroptose , Fluorocarbonos , Hepatopatia Gordurosa não Alcoólica , Ferroptose/efeitos dos fármacos , Fluorocarbonos/toxicidade , Animais , Ácidos Alcanossulfônicos/toxicidade , Camundongos , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica/patologia , Autofagia/efeitos dos fármacos , Coenzima A Ligases/metabolismo , Humanos , Cálcio/metabolismo , Canais de Cálcio/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Linhagem Celular , Hepatócitos/efeitos dos fármacosRESUMO
As a persistent organic pollutant, perfluorooctane sulfonate (PFOS) has a serious detrimental impact on human health. It has been suggested that PFOS is associated with liver inflammation. However, the underlying mechanisms are still unclear. Here, PFOS was found to elevate the oligomerization tendency of voltage-dependent anion channel 1 (VDAC1) in the mice liver and human normal liver cells L-02. Inhibition of VDAC1 oligomerization alleviated PFOS-induced nucleotide-binding domain and leucine-rich repeat protein-3 (NLRP3) inflammasome activation. Cytoplasmic membrane VDAC1 translocated to mitochondria was also observed in response to PFOS. Therefore, the oligomerization of VDAC1 occurred mainly in the mitochondria. VDAC1 was found to interact with the ATP synthase beta subunit (ATP5B) under PFOS treatment. Knockdown of ATP5B or immobilization of ATP5B to the cytoplasmic membrane alleviated the increased VDAC1 oligomerization and NLRP3 inflammasome activation. Therefore, our results suggested that PFOS induced NLRP3 inflammasome activation through VDAC1 oligomerization, a process dependent on ATP5B to transfer VDAC1 from the plasma membrane to the mitochondria. The findings offer novel perspectives on the activation of the NLRP3 inflammasome, the regulatory mode on VDAC1 oligomerization, and the mechanism of PFOS toxicity.
Assuntos
Ácidos Alcanossulfônicos , Fluorocarbonos , Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Canal de Ânion 1 Dependente de Voltagem , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Animais , Ácidos Alcanossulfônicos/toxicidade , Inflamassomos/metabolismo , Inflamassomos/efeitos dos fármacos , Canal de Ânion 1 Dependente de Voltagem/metabolismo , Canal de Ânion 1 Dependente de Voltagem/genética , Fluorocarbonos/toxicidade , Humanos , Camundongos , ATPases Mitocondriais Próton-Translocadoras/metabolismo , Linhagem Celular , Camundongos Endogâmicos C57BL , Fígado/efeitos dos fármacos , Fígado/metabolismo , Poluentes Ambientais/toxicidade , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismoRESUMO
Perfluorooctane sulfonate (PFOS) is a persistent organic pollutant and accumulated in the liver of mammals. PFOS exposure is closely associated with the development of pyroptosis. Nevertheless, the underlying mechanism is unclear. We found here that PFOS induced pyroptosis in the mice liver and L-02 cells as demonstrated by activation of the NOD-like receptor protein 3 inflammasome, gasdermin D cleavage and increased release of interleukin-1ß and interleukin-18. The level of cytoplasmic calcium was accelerated in hepatocytes upon exposure to PFOS. The phosphorylated/activated form of calcium/calmodulin-dependent protein kinase II (CaMKII) was augmented by PFOS in vivo and in vitro. PFOS-induced pyroptosis was relieved by CaMKII inhibitor. Among various CaMKII subtypes, we identified that CaMKIIγ was activated specifically by PFOS. CaMKIIγ interacted with Smad family member 3 (Smad3) under PFOS exposure. PFOS increased the phosphorylation of Smad3, and CaMKII inhibitor or CaMKIIγ siRNA alleviated PFOS-caused phosphorylation of Smad3. Inhibiting Smad3 activity was found to alleviate PFOS-induced hepatocyte pyroptosis. This study puts forward that CaMKIIγ-Smad3 is the linkage between calcium homeostasis disturbance and pyroptosis, providing a mechanistic explanation for PFOS-induced pyroptosis.
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Perfluorooctane sulfonate (PFOS) is known as a persistent organic pollutant. A significant correlation between PFOS and liver ferroptosis has been unveiled, but the precise mechanism needs to be elucidated. In prior research, we found that PFOS treatment provoked mitochondrial iron overload. In this study, we observed a gradual increase in lysosomal iron in L-O2 cells after exposure to PFOS for 0.5-24â¯h. In PFOS-exposed L-O2 cells, suppressing autophagy relieved the lysosomal iron overload. Inhibiting transient receptor potential mucolipin 1 (TRPML1), a calcium efflux channel on the lysosomal membrane, led to a further rise in lysosomal iron levels and decreased mitochondrial iron overload during PFOS treatment. Suppressing VDAC1, a subtype of voltage-dependent anion-selective channels (VDACs) on the outer mitochondrial membrane, had no impact on PFOS-triggered mitochondrial iron overload, whereas restraining VDAC2/3 relieved this condition. Although silencing VDAC2 relieved PFOS-induced mitochondrial iron overload, it had no effect on PFOS-triggered lysosomal iron overload. Silencing VDAC3 alleviated PFOS-mediated mitochondrial iron overload and led to an additional increase in lysosomal iron. Therefore, we regarded VDAC3 as the specific VDACs subtype that mediated the lysosomes-mitochondria iron transfer. Additionally, in the presence of PFOS, an enhanced association between TRPML1 and VDAC3 was found in mice liver tissue and L-O2 cells. Our research unveils a novel regulatory mechanism of autophagy on the iron homeostasis and the effect of TRPML1-VDAC3 interaction on lysosomes-mitochondria iron transfer, giving an explanation of PFOS-induced ferroptosis and shedding some light on the role of classic calcium channels in iron transmission.
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OBJECTIVES: To explore the correlations between histopathologic findings and intravoxel incoherent motion (IVIM)-derived perfusion and diffusion parameters in brain gliomas. METHODS: Thirty-two biopsy samples from twenty-one patients with newly diagnosed gliomas from a previous prospective cohort study were retrospectively analyzed. All patients underwent diffusion-weighted MRI with 22 b values (0-5000 s/mm2), followed by intraoperative MR-guided biopsy surgery and surgical resection. All 32 biopsy samples underwent immunohistochemical staining followed by quantitative analysis of cell density (cellularity), percent of MIB-1 (Ki67)-positive expression (pMIB-1), number of CD34-stained vessels (CD34-MVD), and percent of VEGF-positive expressing cells (pVEGF) using a multispectral phenotyping microscope. Based on the co-registered localized biopsy, correlation analysis was performed between the IVIM-derived biexponential model-based parameters (Dfast1500 and Dfast5000, Dslow1500 and Dslow5000, PF1500 and PF5000) and the above four pathological biomarkers and glioma grades. RESULTS: Significant positive correlations were revealed between Dfast5000 and pVEGF (rho (r) = 0.466, p = 0.007), and Dfast1500 and pVEGF (r = 0.371, p = 0.037). A significant negative correlation was revealed between PF5000 with pMIB-1 (r = - 0.456, p = 0.01). Moderate to good positive correlations were shown between Dfast5000 and glioma grades (r = 0.509, p = 0.003) and Dfast1500 and glioma grades (r = 0.476, p = 0.006). CONCLUSIONS: IVIM-DWI-derived Dfast and PF correlate, respectively, with intratumor pVEGF and pMIB-1. When using the wide-high b value scheme, IVIM-derived Dfast and PF tend to demonstrate better efficacy in evaluating malignancy-related characteristics such as angiogenesis and cellular proliferation in gliomas. KEY POINTS: ⢠Intravoxel incoherent motion-diffusion-weighted imaging (IVIM-DWI)-derived fast diffusion (Dfast) and perfusion fraction (PF) can quantitatively reflect intratumor pVEGF and pMIB-1. ⢠IVIM-DWI-derived Dfast and PF tend to demonstrate better efficacy in evaluating glioma malignancy when an optimized scheme is used. ⢠IVIM-DWI-derived Dfast5000 and PF5000 are promising non-invasive parameters correlating with pVEGF and pMIB-1 in gliomas.
Assuntos
Glioma , Fator A de Crescimento do Endotélio Vascular , Humanos , Antígeno Ki-67 , Estudos de Coortes , Estudos Retrospectivos , Glioma/diagnóstico por imagem , Glioma/cirurgia , Glioma/patologia , Imagem de Difusão por Ressonância Magnética/métodos , Movimento (Física) , Perfusão , Biópsia , Encéfalo/patologiaRESUMO
N6-methyladenosine (m6A) messenger RNA methylation is the most widespread gene regulatory mechanism affecting liver functions and disorders. However, the relationship between m6A methylation and arsenic-induced hepatic insulin resistance (IR), which is a critical initiating event in arsenic-induced metabolic syndromes such as type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD), remains unclear. Here, we showed that arsenic treatment facilitated methyltransferase-like 14 (METTL14)-mediated m6A methylation, and that METTL14 interference reversed arsenic-impaired hepatic insulin sensitivity. We previously showed that arsenic-induced NOD-like receptor protein 3 (NLRP3) inflammasome activation contributed to hepatic IR. However, the regulatory mechanisms underlying the role of arsenic toward the post-transcriptional modification of NLRP3 remain unclear. Here, we showed that NLRP3 mRNA stability was enhanced by METTL14-mediated m6A methylation during arsenic-induced hepatic IR. Furthermore, we demonstrated that arsenite methyltransferase (AS3MT), an essential enzyme in arsenic metabolic processes, interacted with NLRP3 to activate the inflammasome, thereby contributing to arsenic-induced hepatic IR. Also, AS3MT strengthened the m6A methylase association with NLRP3 to stabilize m6A-modified NLRP3. In summary, we showed that AS3MT-induced m6A modification critically regulated NLRP3 inflammasome activation during arsenic-induced hepatic IR, and we identified a novel post-transcriptional function of AS3MT in promoting arsenicosis.
Assuntos
Arsênio , Resistência à Insulina , Humanos , Arsênio/toxicidade , Arsênio/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Inflamassomos/metabolismo , Fígado , Metiltransferases/genética , Metiltransferases/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteínas NLR/metabolismoRESUMO
In general populations, insulin resistance (IR) is related to perfluorooctane sulfonate (PFOS), a persistent organic pollutant. However, the underlying mechanism remains unclear. In this study, PFOS induced mitochondrial iron accumulation in the liver of mice and human hepatocytes L-O2. In the PFOS-treated L-O2 cells, mitochondrial iron overload preceded the occurrence of IR, and pharmacological inhibition of mitochondrial iron relieved PFOS-caused IR. Both transferrin receptor 2 (TFR2) and ATP synthase ß subunit (ATP5B) were redistributed from the plasma membrane to mitochondria with PFOS treatment. Inhibiting the translocation of TFR2 to mitochondria reversed PFOS-induced mitochondrial iron overload and IR. In the PFOS-treated cells, ATP5B interacted with TFR2. Stabilizing ATP5B on the plasma membrane or knockdown of ATP5B disturbed the translocation of TFR2. PFOS inhibited the activity of plasma-membrane ATP synthase (ectopic ATP synthase, e-ATPS), and activating e-ATPS prevented the translocation of ATP5B and TFR2. Consistently, PFOS induced ATP5B/TFR2 interaction and redistribution of ATP5B and TFR2 to mitochondria in the liver of mice. Thus, our results indicated that mitochondrial iron overload induced by collaborative translocation of ATP5B and TFR2 was an up-stream and initiating event for PFOS-related hepatic IR, providing novel understandings of the biological function of e-ATPS, the regulatory mechanism for mitochondrial iron and the mechanism underlying PFOS toxicity.
Assuntos
Resistência à Insulina , Sobrecarga de Ferro , Humanos , Trifosfato de Adenosina/metabolismo , Membrana Celular/metabolismo , Ferro/metabolismo , Fígado/metabolismo , Mitocôndrias/metabolismo , Receptores da Transferrina/genética , Receptores da Transferrina/metabolismoRESUMO
Di-2-ethylhexyl phthalate (DEHP), as a common endocrine disrupting chemicals, can induce toxicity to reproductive system. However, the mechanism remains to be explored. In our study, DEHP exposure induced testicular injury in rats. The high throughput transcriptional sequencing was performed to identify differentially expressed genes (DEGs) between the treatment and control groups. KEGG analysis revealed that DEGs were enriched in apoptosis, PPARα, and ER stress pathway. DEHP up-regulated the expression of PPARα, Bax, Bim, caspase-4. GRP78, PERK, p-PERK, eIF2α, p-eIF2α, ATF4 and CHOP. This view has also been confirmed in TM3 and TM4 cells. In vitro, after pre-treatment with GW6471 (an inhibitor of PPARα) or GSK (an inhibitor of PERK), the apoptosis was inhibited and mitochondrial dysfunction was improved. Moreover, the improvement of mitochondrial dysfunction decreased the expression of PERK pathway by using SS-31(a protective agent for mitochondrial function). Interestingly, ER stress promoted the accumulation of ROS by ERO1L (the downstream of CHOP during ER stress), and the ROS further aggravated the ER stress, thus forming a feedback loop during the apoptosis. In this process, a vicious cycle consisting of PERK, eIF2α, ATF4, CHOP, ERO1L, ROS was involved. Taken together, our results suggested that mitochondrial dysfunction and ER stress-ROS feedback loop caused by PPARα activation played a crucial role in DEHP-induced apoptosis. This work provides insight into the mechanism of DEHP-induced reproductive toxicity.
Assuntos
Dietilexilftalato , Ratos , Animais , Dietilexilftalato/toxicidade , PPAR alfa/genética , Espécies Reativas de Oxigênio/metabolismo , Ratos Sprague-Dawley , Apoptose/genética , Estresse do Retículo Endoplasmático , Mitocôndrias/metabolismoRESUMO
OBJECTIVES: To construct a radiomics nomogram based on multiparametric MRI data for predicting isocitrate dehydrogenase 1 mutation (IDH +) and loss of nuclear alpha thalassemia/mental retardation syndrome X-linked expression (ATRX -) in patients with lower-grade gliomas (LrGG; World Health Organization [WHO] 2016 grades II and III). METHODS: A total of 111 LrGG patients (76 mutated IDH and 35 wild-type IDH) were enrolled, divided into a training set (n = 78) and a validation set (n = 33) for predicting IDH mutation. IDH + LrGG patients were further stratified into the ATRX - (n = 38) and ATRX + (n = 38) subtypes. A total of 250 radiomics features were extracted from the region of interest of each tumor, including that from T2 fluid-attenuated inversion recovery (T2 FLAIR), contrast-enhanced T1 WI, ASL-derived cerebral blood flow (CBF), DWI-derived ADC, and exponential ADC (eADC). A radiomics signature was selected using the Elastic Net regression model, and a radiomics nomogram was finally constructed using the age, gender information, and above features. RESULTS: The radiomics nomogram identified LrGG patients for IDH mutation (C-index: training sets = 0.881, validation sets = 0.900) and ATRX loss (C-index: training sets = 0.863, validation sets = 0.840) with good calibration. Decision curve analysis further confirmed the clinical usefulness of the two nomograms for predicting IDH and ATRX status. CONCLUSIONS: The nomogram incorporating age, gender, and the radiomics signature provided a clinically useful approach in noninvasively predicting IDH and ATRX mutation status for LrGG patients. The proposed method could facilitate MRI-based clinical decision-making for the LrGG patients. KEY POINTS: ⢠Non-invasive determination of IDH and ATRX gene status of LrGG patients can be obtained with a radiomics nomogram. ⢠The proposed nomogram is constructed by radiomics signature selected from 250 radiomics features, combined with age and gender. ⢠The proposed radiomics nomogram exhibited good calibration and discrimination for IDH and ATRX gene mutation stratification of LrGG patients in both training and validation sets.
Assuntos
Glioma , Nomogramas , Glioma/diagnóstico por imagem , Glioma/genética , Humanos , Imageamento por Ressonância Magnética/métodos , Mutação , Estudos Retrospectivos , Proteína Nuclear Ligada ao X/genéticaRESUMO
Liver fibrosis is a severe health problem worldwide, and it is characterized by the activation of hepatic stellate cells (HSCs) and excessive deposition of collagen. Prolonged arsenic exposure can induce HSCs activation and liver fibrosis. In the present study, the results showed that chronic NaAsO2 ingestion could result in liver fibrosis and oxidative stress in Sprague-Dawley rats, along with representative collagen deposition and HSCs activation. In addition, the inositol-requiring enzyme 1α (IRE1α)-endoplasmic reticulum (ER)-stress pathway was activated, and the activity of nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) was upregulated in rat livers. Simultaneously, the excessive production of reactive oxygen species (ROS) could induce HSCs activation, and NOX4 played an important role in generating ROS in vitro. Moreover, ER stress occurred with HSCs activation at the same time under NaAsO2 exposure, and during ER stress, the IRE1α pathway was responsible for NOX4 activation. Therefore, inhibition of IRE1α activation could attenuate the HSCs activation induced by NaAsO2 . In conclusion, the present study manifested that inorganic arsenic exposure could activate HSCs through IRE1α/NOX4-mediated ROS generation.
Assuntos
Estresse do Retículo Endoplasmático/genética , Endorribonucleases/genética , Cirrose Hepática/genética , Complexos Multienzimáticos/genética , NADPH Oxidase 4/genética , Proteínas Serina-Treonina Quinases/genética , Animais , Arsenitos/toxicidade , Modelos Animais de Doenças , Regulação da Expressão Gênica/genética , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Humanos , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/patologia , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/genética , Compostos de Sódio/toxicidadeRESUMO
Arsenic exposure is related to insulin resistance (IR). However, the underlying mechanism is still uncertain. NOD-like receptors containing pyrin domain 3 (NLRP3) inflammasome is a key driving factor of IR. We found that NaAsO2 caused hepatic IR, activated NLRP3 inflammasome, and inhibited glycolysis pathway in vivo. We also found that tricarboxylic acid cycle (TCA cycle) was inhibited, and the content of hepatic lactate was upregulated with the treatment of arsenic. Consistent with these findings, we found that NLRP3 inflammasome and glycolysis were involved in the development of IR in L-02 cells. Besides, inhibiting NLRP3 inflammasome upregulated aerobic glycolysis and inhibited anaerobic glycolysis. Moreover, we demonstrated that NLRP3 inflammasome could bind to pyruvate kinase, liver and RBC (PKLR). Simultaneously, insulin signaling rather than NLRP3 inflammasome activation was altered by overexpressing PKLR. In summary, after treatment with NaAsO2, NLRP3 inflammasome blocked the glycolytic pathway via binding to PKLR, which in turn caused hepatic IR. This study shed new light on the molecular mechanism underlying arsenic-induced IR.
Assuntos
Arsênio , Resistência à Insulina , Animais , Arsênio/toxicidade , Inflamassomos , Fígado , Camundongos , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Piruvato QuinaseRESUMO
Acrolein, a known toxin in tobacco smoke, has been demonstrated to be associated with inflammatory cardiovascular diseases, such as atherosclerosis. However, the definite mechanism of acrolein-induced inflammation remains unclear. Here, we report that acrolein induces reactive oxygen species (ROS) production in EAhy926 cells. Additionally, acrolein induces EAhy926 cells' inflammatory response and pyroptosis by activating NOD-like receptor protein 3 (NLRP3) inflammasome. Also, acrolein-induced cytotoxicity could be attenuated by N-acetyl-L-cysteine (NAC). Furthermore, acrolein upregulates the level of autophagy which can be reversed by NAC. Notably, the present study also indicates that autophagy inhibited by inhibitor 3-methyladenine (3MA) and siAtg7 exacerbate acrolein-induced NLRP3 inflammasome activation and pyroptosis. In summary, acrolein induced cytotoxicity by ROS-mediated NLRP3 inflammasome activation, and ROS upregulates the level of autophagy to inhibit the NLRP3 inflammasome excessive activation, indicating the bidirectional role of ROS in acrolein-induced cellular inflammation. Our results may provide novel mechanistic insights into acrolein-induced cardiovascular toxicity.
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Acroleína , Inflamassomos , Acroleína/toxicidade , Humanos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Piroptose , Espécies Reativas de OxigênioRESUMO
Exposure to arsenic is a risk factor for nonalcoholic steatohepatitis (NASH). Ferroptosis is a form of regulated cell death defined by the accumulation of lipid peroxidation. In the current study, we observed the occurrence of ferroptosis in arsenic-induced NASH by assessing ferroptosis related hallmarks. In vitro, we found that ferrostatin-1 effectively attenuated the executing of ferroptosis and NASH. Simultaneously, the expression of ACSL4 (acyl-CoA synthetase long-chain family member 4) was upregulated in rat's liver and L-02 cells exposed to arsenic. While, suppression of ACSL4 with rosiglitazone or ACSL4 siRNA remarkably alleviated arsenic-induced NASH and ferroptosis through diminishing 5-hydroxyeicosatetraenoic acid (5-HETE) content. Additionally, Mitofusin 2 (Mfn2), a physical tether between endoplasmic reticulum and mitochondria, has rarely been explored in the ferroptosis. Using Mfn2 siRNA or inositol-requiring enzyme 1 alpha (IRE1α) inhibitor, we found NASH and ferroptosis were obviously mitigated through reducing 5-HETE content. Importantly, Co-IP assay indicated that Mfn2 could interact with IRE1α and promoted the production of 5-HETE, ultimately led to ferroptosis and NASH. Collectively, our data showed that ferroptosis is involved in arsenic-induced NASH. These data provide insightful viewpoints into the mechanism of arsenic-induced NASH.
Assuntos
Arsênio , Hepatopatia Gordurosa não Alcoólica , Animais , Arsênio/toxicidade , Coenzima A Ligases , Endorribonucleases/efeitos dos fármacos , Endorribonucleases/fisiologia , Ferroptose , GTP Fosfo-Hidrolases/efeitos dos fármacos , GTP Fosfo-Hidrolases/fisiologia , Proteínas Mitocondriais/efeitos dos fármacos , Proteínas Mitocondriais/fisiologia , Complexos Multienzimáticos/efeitos dos fármacos , Complexos Multienzimáticos/fisiologia , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Proteínas Serina-Treonina Quinases/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/fisiologia , RatosRESUMO
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.
Assuntos
Trióxido de Arsênio/toxicidade , Autofagia/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Resistência à Insulina , Fígado/efeitos dos fármacos , Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo , PPAR gama/metabolismo , Taurina/farmacologia , Animais , Proteínas Relacionadas à Autofagia/metabolismo , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Gluconeogênese/efeitos dos fármacos , Glicólise/efeitos dos fármacos , Células Hep G2 , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Fígado/enzimologia , Fígado/patologia , Masculino , Camundongos Endogâmicos C57BL , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de SinaisRESUMO
PURPOSE: We evaluated the relationship between isocitrate dehydrogenase 1 (IDH1) mutation status and metabolic imaging in patients with nonenhancing supratentorial diffuse gliomas using 11C-methionine positron emission tomography (11C-MET PET). MATERIALS AND METHODS: Between June 2012 and November 2017, we enrolled 86 (38 women and 48 men; mean age, 41.9 ± 13.1 years [range, 8-67 years]) patients with newly diagnosed supratentorial diffuse gliomas. All patients underwent preoperative 11C-MET PET. Tumor samples were obtained and immunohistochemically analyzed for IDH1 mutation status. RESULTS: The mutant and wild-type IDH1 diffuse gliomas had significantly different mean maximum standardized uptake value values (2.73 [95% confidence interval, CI: 2.32-3.16] vs 3.85 [95% CI: 3.22-4.51], respectively; P = .004) and mean tumor-to-background ratio (1.90 [95% CI: 1.65-2.16] vs 2.59 [95% CI: 2.17-3.04], respectively; P = .007). CONCLUSIONS: 11C-methionine PET can noninvasively evaluate the IDH1 mutation status of patients with nonenhancing supratentorial diffuse gliomas.
Assuntos
Isocitrato Desidrogenase/genética , Metionina/química , Mutação/genética , Tomografia por Emissão de Pósitrons/métodos , Tomografia Computadorizada por Raios X/métodos , Adolescente , Adulto , Idoso , Criança , Feminino , Glioma , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto JovemRESUMO
BACKGROUND: There is a need for an imaging-based tool for measuring vascular endothelial growth factor (VEGF) expression and overall survival (OS) in patients with glioma. PURPOSE: To assess the correlation between cerebral blood flow (CBF), measured by 3D pseudo-continuous arterial spin-labeling (3D-ASL), and VEGF expression in gliomas on the basis of coregistered localized biopsy, and investigate whether CBF correlated with survival month (SM) in glioma patients. STUDY TYPE: Prospective cohort. SUBJECTS: Thirty-seven patients with gliomas from whom 63 biopsy specimens were obtained. SEQUENCE: 3D-ASL acquired with a 3.0T MR unit. ASSESSMENT: Biopsy specimens were grouped as high-grade (HGG) or low-grade glioma (LGG). CBF measurements were spatially matched with VEGF expression by coregistered localized biopsies, and the CBF value was correlated with quantitative VEGF expression for each specimen. Patients' survival information was derived and connected with CBF. STATISTICAL TESTS: Patients' OS was analyzed by Kaplan-Meier and Cox-regression methods. VEGF expression and CBF were compared in both LGG and HGG. The Spearman rank correlation was calculated for CBF and VEGF expression, SM. Significance level, P < 0.05. RESULTS: CBF-derived 3D-ASL positively correlated significantly with VEGF expression in both LGG (31 specimens) and HGG (32 specimens), r = 0.604 (P < 0.001) and r = 0.665 (P < 0.001), respectively. LGG and HGG together gave a correlation coefficient r = 0.728 (P < 0.001). Median survival for LGG and HGG patients was 34.19 and 17.17 months, respectively (P = 0.037); CBF value negatively correlated significantly with SM with r = -0.714 (P < 0.001) regardless of glioma grade. CBF was an independent risk factor for OS with HR = 1.027 (P = 0.044), 1.028 (P = 0.010) for univariate/multivariate regression analysis. DATA CONCLUSION: CBF determined by 3D-ASL correlates with VEGF expression in glioma and is an independent risk factor for OS in these patients. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2019;50:209-220.
Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/metabolismo , Glioma/diagnóstico por imagem , Glioma/metabolismo , Imageamento Tridimensional/métodos , Imageamento por Ressonância Magnética/métodos , Fator A de Crescimento do Endotélio Vascular/metabolismo , Adolescente , Adulto , Idoso , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Circulação Cerebrovascular , Feminino , Glioma/mortalidade , Glioma/patologia , Humanos , Processamento de Imagem Assistida por Computador , Biópsia Guiada por Imagem , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estudos Prospectivos , Marcadores de Spin , Taxa de SobrevidaRESUMO
BACKGROUND: Noninvasive detection of isocitrate dehydrogenase 1 mutation (IDH1(+)) and loss of nuclear alpha thalassemia/mental retardation syndrome X-linked expression ((ATRX(-)) are clinically meaningful for molecular stratification of low-grade gliomas (LGGs). PURPOSE: To study a radiomic approach based on multiparametric MR for noninvasively determining molecular status of IDH1(+) and ATRX(-) in patients with LGG. STUDY TYPE: Retrospective, radiomics. POPULATION: Fifty-seven LGG patients with IDH1(+) (n = 36 with 19 ATRX(-) and 17 ATRX(+) patients) and IDH1(-) (n = 21). FIELD STRENGTH/SEQUENCE: 3.0T MRI / 3D arterial spin labeling (3D-ASL), T2 /fluid-attenuated inversion recovery (T2 FLAIR), and diffusion-weighted imaging (DWI). ASSESSMENT: In all, 265 high-throughput radiomic features were extracted on each tumor volume of interest from T2 FLAIR and the other three parametric maps of ASL-derived cerebral blood flow (CBF), DWI-derived apparent diffusion coefficient (ADC), and exponential ADC (eADC). Optimal feature subsets were selected as using the support vector machine with a recursive feature elimination algorithm (SVM-RFE). Receiver operating characteristic curve (ROC) analysis was employed to assess the efficiency for identifying the IDH1(+) and ATRX(-) status. STATISTICAL TESTS: Student's t-test, chi-square test, and Fisher's exact test were applied to confirm whether intergroup significant differences exist between molecular subtypes decided by IDH1 and ATRX. RESULTS: Optimal SVM predictive models of IDH1(+) and ATRX(-) were established using 28 features from T2 Flair, ADC, eADC, and CBF and six features from T2 Flair, ADC, and CBF. The accuracies/AUCs/sensitivity/specifity/PPV/NPV of predicting IDH1(+) in LGG were 94.74%/0.931/100%/85.71%/92.31%/100%, and those of predicting ATRX(-) in LGG with IDH1(+) were 91.67%/0.926/94.74%/88.24%/90.00%/93.75%, respectively. DATA CONCLUSION: Using the optimal texture features extracted from multiple MR sequences or parametric maps, a promising stratifying strategy was acquired for predicting molecular subtypes of IDH1 and ATRX in LGGs. LEVEL OF EVIDENCE: 3 Technical Efficacy Stage: 2 J. Magn. Reson. Imaging 2019;49:808-817.