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1.
Mol Med Rep ; 27(6)2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37203390

RESUMO

Integrins act as cell­matrix adhesion molecules involved in cell attachment to the extracellular matrix and generate signals that respond to cancer metastasis. Integrin α5ß1 is a heterodimer with α5 and ß1 subunits and mediates cell adhesion and migration of cancer cells. Integrins are transcriptionally regulated by the Janus kinase (JAK)/STAT signaling pathways. Our previous study revealed that Helicobacter pylori increased the levels of reactive oxygen species (ROS), which activate JAK1/STAT3 in gastric cancer AGS cells in vitro. Astaxanthin (ASX) has been reported to be an effective antioxidant and anticancer nutrient. The present study investigated whether ASX suppresses H. pylori­induced integrin α5 expression, cell adhesion and migration and whether ASX reduces ROS levels and suppresses phosphorylation of JAK1/STAT3 in gastric cancer AGS cells stimulated with H. pylori. The effect of ASX was determined using a dichlorofluorescein fluorescence assay, western blot analysis, adhesion assay and wound­healing assay in AGS cells stimulated with H. pylori. The results demonstrated that H. pylori increased the expression levels of integrin α5, without affecting integrin ß1, and increased cell adhesion and migration of AGS cells. ASX reduced ROS levels and suppressed JAK1/STAT3 activation, integrin α5 expression, cell adhesion and migration of H. pylori­stimulated AGS cells. In addition, both a JAK/STAT inhibitor, AG490, and an integrin α5ß1 antagonist, K34C, suppressed cell adhesion and migration in H. pylori­stimulated AGS cells. AG490 inhibited integrin α5 expression in AGS cells stimulated with H. pylori. In conclusion, ASX inhibited H. pylori­induced integrin α5­mediated cell adhesion and migration by decreasing the levels of ROS and suppressing JAK1/STAT3 activation in gastric epithelial cells.


Assuntos
Helicobacter pylori , Neoplasias Gástricas , Humanos , Células Epiteliais/metabolismo , Mucosa Gástrica/metabolismo , Helicobacter pylori/fisiologia , Integrina alfa5/metabolismo , Integrina alfa5beta1/metabolismo , Janus Quinase 1/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Fator de Transcrição STAT3/metabolismo , Neoplasias Gástricas/patologia
2.
Molecules ; 28(3)2023 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-36770846

RESUMO

Disruption of apoptosis leads to cancer cell progression; thus, anticancer agents target apoptosis of cancer cells. Reactive oxygen species (ROS) induce apoptosis by activating caspases and caspase-dependent DNase, leading to DNA fragmentation. ROS increase the expression of apoptotic protein Bax, which is mediated by activation of nuclear factor-κB (NF--κB). Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is an important source of endogenous ROS, and its activation is involved in apoptosis. Lutein, an oxygenated carotenoid and known antioxidant, is abundant in leafy dark green vegetables, such as spinach and kale, and in yellow-colored foods, such as corn and egg yolk. High amounts of lutein increase ROS levels and exhibit anticancer activity. However, its anticancer mechanism remains unclear. This study aimed to determine whether lutein activates NADPH oxidase to produce ROS and induce apoptosis in gastric cancer AGS cells. Lutein increased ROS levels and promoted the activation of NADPH oxidase by increasing the translocation of NADPH oxidase subunit p47 phox to the cell membrane. It increased NF-κB activation and apoptotic indices, such as Bax, caspase-3 cleavage, and DNA fragmentation, and decreased Bcl-2, cell viability, and colony formation in AGS cells. The specific NADPH oxidase inhibitor ML171, and the known antioxidant N-acetyl cysteine reversed lutein-induced cell death, DNA fragmentation, and NF-κB DNA-binding activity in AGS cells. These results suggest that lutein-induced ROS production is dependent on NADPH oxidase, which mediates NF-κB activation and apoptosis in gastric cancer AGS cells. Therefore, lutein supplementation may be beneficial for increasing ROS-mediated apoptosis in gastric cancer cells.


Assuntos
NF-kappa B , Neoplasias Gástricas , Humanos , Espécies Reativas de Oxigênio/metabolismo , NF-kappa B/metabolismo , Neoplasias Gástricas/tratamento farmacológico , Luteína/farmacologia , Antioxidantes/farmacologia , Proteína X Associada a bcl-2 , Apoptose , Caspases , NADPH Oxidases/metabolismo
3.
Nutrients ; 14(19)2022 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-36235593

RESUMO

Oxidative stress induces DNA damage which can be repaired by DNA repair proteins, such as Ku70/80. Excess reactive oxygen species (ROS) stimulate the activation of caspase-3, which degrades Ku 70/80. Cells with decreased Ku protein levels undergo apoptosis. Astaxanthin exerts antioxidant activity by inducing the expression of catalase, an antioxidant enzyme, in gastric epithelial cells. Therefore, astaxanthin may inhibit oxidative stress-induced DNA damage by preventing Ku protein degradation and thereby suppressing apoptosis. Ku proteins can be degraded via ubiquitination and neddylation which adds ubiquitin-like protein to substrate proteins. We aimed to determine whether oxidative stress decreases Ku70/80 expression through the ubiquitin-proteasome pathway to induce apoptosis and whether astaxanthin inhibits oxidative stress-induced changes in gastric epithelial AGS cells. We induced oxidative stress caused by the treatment of ß-D-glucose (G) and glucose oxidase (GO) in the cells. As a result, the G/GO treatment increased ROS levels, decreased nuclear Ku protein levels and Ku-DNA-binding activity, and induced the ubiquitination of Ku80. G/GO increased the DNA damage marker levels (γ-H2AX; DNA fragmentation) and apoptosis marker annexin V-positive cells and cell death. Astaxanthin inhibited G/GO-induced alterations, including Ku degradation in AGS cells. MLN4924, a neddylation inhibitor, and MG132, a proteasome inhibitor, suppressed G/GO-mediated DNA fragmentation and decreased cell viability. These results indicated that G/GO-induced oxidative stress causes Ku protein loss through the ubiquitin-proteasome pathway, resulting in DNA fragmentation and apoptotic cell death. Astaxanthin inhibited oxidative stress-mediated apoptosis via the reduction of ROS levels and inhibition of Ku protein degradation. In conclusion, dietary astaxanthin supplementation or astaxanthin-rich food consumption may be effective for preventing or delaying oxidative stress-mediated cell damage by suppressing Ku protein loss and apoptosis in gastric epithelial cells.


Assuntos
Antioxidantes , Complexo de Endopeptidases do Proteassoma , Anexina A5/metabolismo , Anexina A5/farmacologia , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Apoptose , Caspase 3/metabolismo , Catalase/metabolismo , DNA/metabolismo , Proteínas de Ligação a DNA/genética , Células Epiteliais/metabolismo , Glucose/metabolismo , Glucose Oxidase/metabolismo , Glucose Oxidase/farmacologia , Autoantígeno Ku/metabolismo , Estresse Oxidativo , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma/farmacologia , Proteólise , Espécies Reativas de Oxigênio/metabolismo , Ubiquitinas/metabolismo , Ubiquitinas/farmacologia , Xantofilas
4.
Mol Med Rep ; 26(4)2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35946453

RESUMO

Acute pancreatitis is a severe inflammatory disease of the pancreas. In experimental acute pancreatitis, cerulein induces the expression of interleukin­6 (IL­6) by activating Janus kinase (JAK) 2/signal transducer and activator of transcription (STAT) 3 in pancreatic acinar cells. Ligands of peroxisome proliferator activated receptor­Î³ (PPAR­Î³) and suppressor of cytokine signaling (SOCS) 3 inhibit IL­6 expression by suppressing JAK2/STAT3 in cerulein­stimulated pancreatic acinar AR42J cells. Lutein, an oxygenated carotenoid, upregulates and activates PPAR­Î³ to regulate inflammation in a renal injury model. The present study aimed to determine whether lutein activated PPAR­Î³ and induced SOCS3 expression in unstimulated AR42J cells, and whether lutein inhibited activation of JAK2/STAT3 and IL­6 expression via activation of PPAR­Î³ and SOCS3 expression in cerulein­stimulated AR42J cells. The anti­inflammatory mechanism of lutein was determined using reverse transcription­quantitative PCR, western blot analysis and enzyme­linked immunosorbent assay in AR42J cells stimulated with or without cerulein. In another experiment, cells were treated with lutein and the PPAR­Î³ antagonist GW9662 or the PPAR­Î³ agonist troglitazone prior to cerulein stimulation to determine the involvement of PPAR­Î³ activation. The results indicated that lutein increased PPAR­Î³ and SOCS3 levels in unstimulated cells. Cerulein increased phospho­specific forms of JAK2 and STAT3, and mRNA and protein expression of IL­6, but decreased SOCS3 levels in AR42J cells. Cerulein­induced alterations were suppressed by lutein or troglitazone. GW9662 alleviated the inhibitory effect of lutein on JAK2/STAT3 activation and IL­6 expression in cerulein­stimulated cells. In conclusion, lutein inhibited the activation of JAK2/STAT3 and reduced IL­6 levels via PPAR­Î³­mediated SOCS3 expression in pancreatic acinar cells stimulated with cerulein.


Assuntos
Ceruletídeo , Pancreatite , Células Acinares/metabolismo , Doença Aguda , Humanos , Interleucina-6/metabolismo , Luteína , PPAR gama/genética , PPAR gama/metabolismo , Pancreatite/metabolismo , Fator de Transcrição STAT3/metabolismo , Proteína 3 Supressora da Sinalização de Citocinas/genética , Proteína 3 Supressora da Sinalização de Citocinas/metabolismo , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Troglitazona
5.
Nutrients ; 14(16)2022 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-36014933

RESUMO

Helicobacter pylori (H. pylori) increases production of reactive oxygen species (ROS) and activates signaling pathways associated with gastric cell invasion, which are mediated by matrix metalloproteinases (MMPs). We previously demonstrated that H. pylori activated mitogen-activated protein kinase (MAPK) and increased expression of MMP-10 in gastric epithelial cells. MMPs degrade the extracellular matrix, enhancing tumor invasion and cancer progression. The signaling pathway of phosphatidylinositol 3-kinase (PI3K)/serine/threonine protein kinase B (AKT)/mammalian target of rapamycin (mTOR) is associated with MMP expression. ROS activates PIK3/AKT/mTOR signaling in cancer. Astaxanthin, a xanthophyll carotenoid, shows antioxidant activity by reducing ROS levels in gastric epithelial cells infected with H. pylori. This study aimed to determine whether astaxanthin inhibits MMP expression, cell invasion, and migration by reducing the PI3K/AKT/mTOR signaling in H. pylori-infected gastric epithelial AGS cells. H. pylori induced PIK3/AKT/mTOR and NF-κB activation, decreased IκBα, and induced MMP (MMP-7 and -10) expression, the invasive phenotype, and migration in AGS cells. Astaxanthin suppressed these H. pylori-induced alterations in AGS cells. Specific inhibitors of PI3K, AKT, and mTOR reversed the H. pylori-stimulated NF-κB activation and decreased IκBα levels in the cells. In conclusion, astaxanthin suppressed MMP expression, cell invasion, and migration via inhibition of PI3K/AKT/mTOR/NF-κB signaling in H. pylori-stimulated gastric epithelial AGS cells.


Assuntos
Infecções por Helicobacter , Helicobacter pylori , Células Epiteliais/metabolismo , Mucosa Gástrica/metabolismo , Infecções por Helicobacter/patologia , Helicobacter pylori/genética , Humanos , Metaloproteinases da Matriz/metabolismo , Inibidor de NF-kappaB alfa/metabolismo , NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Sirolimo , Serina-Treonina Quinases TOR/metabolismo , Xantofilas/metabolismo , Xantofilas/farmacologia
6.
Nutrients ; 14(15)2022 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-35956382

RESUMO

Helicobacter pylori (H. pylori) is a Gram-negative bacterium that colonizes the gastric mucosa and triggers various stomach diseases. H. pylori induces reactive oxygen species (ROS) production and DNA damage. The heterodimeric Ku70/Ku80 protein plays an essential role in the repair of DNA double-strand breaks (DSB). Oxidative stress stimulate apoptosis and DNA damage that can be repaired by Ku70/80. However, excessive reactive oxygen species (ROS) can cause Ku protein degradation, resulting in DNA fragmentation and apoptosis. α-lipoic acid (α-LA), which is found in organ meats such as liver and heart, spinach, broccoli, and potatoes, quenches free radicals, chelates metal ions, and reduces intracellular DNA damage induced by oxidative stress. Here, we investigated whether H. pylori decreases Ku70/80 and induces apoptosis, and whether α-LA inhibits changes induced by H. pylori. We analyzed ROS, DNA damage markers (γ-H2AX, DNA fragmentation), levels of Ku70/80, Ku-DNA binding activity, Ku80 ubiquitination, apoptosis indices (Bcl-2, Bax, apoptosis-inducing factor (AIF), and caspase-3), and viability in a human gastric epithelial adenocarcinoma cell line (AGS). H. pylori increased ROS, DNA damage markers, Ku80 ubiquitination, and consequently induced apoptosis. It also decreased nuclear Ku70/80 levels and Ku-DNA-binding activity; increased Bax expression, caspase-3 cleavage, and truncated AIF; but decreased Bcl-2 expression. These H. pylori-induced alterations were inhibited by α-LA. The antioxidant N-acetylcysteine and proteasome inhibitor MG-132 suppressed H. pylori-induced cell death and decreased nuclear Ku70/80 levels. The results show that oxidative stress induced Ku70/80 degradation via the ubiquitin-proteasome system, leading to its nuclear loss and apoptosis in H. pylori-infected cells. In conclusion, α-LA inhibited apoptosis induced by H. pylori by reducing ROS levels and suppressing the loss of Ku70/80 proteins in AGS cells.


Assuntos
Infecções por Helicobacter , Helicobacter pylori , Ácido Tióctico , Apoptose , Caspase 3/metabolismo , DNA/metabolismo , Células Epiteliais/metabolismo , Mucosa Gástrica/metabolismo , Infecções por Helicobacter/microbiologia , Helicobacter pylori/genética , Humanos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Ácido Tióctico/farmacologia , Proteína X Associada a bcl-2/metabolismo
7.
Mol Med Rep ; 26(2)2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35730599

RESUMO

Cerulein­induced pancreatitis resembles human acute pancreatitis in terms of pathological events, such as enzymatic activation and inflammatory cell infiltration in the pancreas. Cerulein is a cholecystokinin analog that increases levels of reactive oxygen species (ROS) and interleukin­6 (IL­6) expression level in pancreatic acinar cells. Serum levels of resistin, which is secreted from adipocytes, are reportedly higher in patients with acute pancreatitis than in healthy individuals. Previously, it was shown that the adipokine resistin can aggravate the cerulein­induced increase in ROS levels and IL­6 expression level in pancreatic acinar cells. Peroxisome proliferator­activated receptor­gamma (PPAR­Î³) is a key regulator of the transcription and expression of antioxidant enzymes, including heme oxygenase 1 (HO­1) and catalase. α­lipoic acid, a naturally occurring dithiol antioxidant, can prevent cerulein­induced pancreatic damage in rats. In the present study, it was aimed to investigate whether α­lipoic acid can attenuate the cerulein/resistin­induced increase in IL­6 expression and ROS levels via PPAR­Î³ activation in pancreatic acinar AR42J cells. The anti­inflammatory mechanism of α­lipoic acid was determined using reverse transcription­quantitative PCR, western blot analysis, enzyme­linked immunosorbent assay, immunofluorescence staining and fluorometry. Treatment with cerulein and resistin increased ROS levels and IL­6 expression level, which were inhibited by α­lipoic acid in pancreatic acinar cells. α­lipoic acid increased the nuclear translocation and expression level of PPAR­Î³ and the expression levels of its target genes: HO­1 and catalase. The PPAR­Î³ antagonist GW9662 and HO­1 inhibitor zinc protoporphyrin reversed the inhibitory effect of α­lipoic acid on cerulein/resistin­induced increase in ROS and IL­6 levels. In conclusion, α­lipoic acid inhibits the cerulein/resistin­induced increase in ROS production and IL­6 expression levels by activating PPAR­Î³ and inducing the expression of HO­1 and catalase in pancreatic acinar cells.


Assuntos
Pancreatite , Ácido Tióctico , Células Acinares/metabolismo , Doença Aguda , Animais , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Catalase/metabolismo , Ceruletídeo/toxicidade , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , PPAR gama/genética , PPAR gama/metabolismo , Pâncreas/patologia , Pancreatite/induzido quimicamente , Pancreatite/tratamento farmacológico , Pancreatite/metabolismo , Ratos , Espécies Reativas de Oxigênio/metabolismo , Resistina/metabolismo , Ácido Tióctico/farmacologia
8.
Nutrients ; 14(5)2022 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-35268019

RESUMO

Helicobacter pylori (H. pylori) causes gastric diseases by increasing reactive oxygen species (ROS) and interleukin (IL)-8 expression in gastric epithelial cells. ROS and inflammatory responses are regulated by the activation of nuclear factor erythroid-2-related factor 2 (Nrf2) and the expression of Nrf2 target genes, superoxide dismutase (SOD) and heme oxygenase-1 (HO-1). We previously demonstrated that Korean red ginseng extract (RGE) decreases H. pylori-induced increases in ROS and monocyte chemoattractant protein 1 in gastric epithelial cells. We determined whether RGE suppresses the expression of IL-8 via Nrf2 activation and the expression of SOD and HO-1 in H. pylori-infected gastric epithelial AGS cells. H. pylori-infected cells were treated with RGE with or without ML385, an Nrf2 inhibitor, or zinc protoporphyrin (ZnPP), a HO-1 inhibitor. Levels of ROS and IL-8 expression; abundance of Keap1, HO-1, and SOD; levels of total, nuclear, and phosphorylated Nrf2; indices of mitochondrial dysfunction (reduction in mitochondrial membrane potential and ATP level); and SOD activity were determined. As a result, RGE disturbed Nrf2-Keap1 interactions and increased nuclear Nrf2 levels in uninfected cells. H. pylori infection decreased the protein levels of SOD-1 and HO-1, as well as SOD activity, which was reversed by RGE treatment. RGE reduced H. pylori-induced increases in ROS and IL-8 levels as well as mitochondrial dysfunction. ML385 or ZnPP reversed the inhibitory effect of RGE on the alterations caused by H. pylori. In conclusion, RGE suppressed IL-8 expression and mitochondrial dysfunction via Nrf2 activation, induction of SOD-1 and HO-1, and reduction of ROS in H. pylori-infected cells.


Assuntos
Mucosa Gástrica , Infecções por Helicobacter , Interleucina-8 , Fator 2 Relacionado a NF-E2 , Panax , Extratos Vegetais , Linhagem Celular Tumoral , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Células Epiteliais/virologia , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patologia , Mucosa Gástrica/virologia , Infecções por Helicobacter/metabolismo , Infecções por Helicobacter/patologia , Infecções por Helicobacter/virologia , Helicobacter pylori , Humanos , Interleucina-8/biossíntese , Interleucina-8/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Mitocôndrias/química , Mitocôndrias/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Panax/metabolismo , Extratos Vegetais/metabolismo , Extratos Vegetais/farmacologia , Espécies Reativas de Oxigênio/análise , Espécies Reativas de Oxigênio/metabolismo
9.
J Cancer Prev ; 26(3): 195-206, 2021 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-34703822

RESUMO

Pancreatic stellate cells (PSCs) are activated by inflammatory stimuli, such as TNF-α or viral infection. Activated PSCs play a crucial role in the development of chronic pancreatitis. Polyinosinic-polycytidylic acid (poly (I:C)) is structurally similar to double-stranded RNA and mimics viral infection. Docosahexaenoic acid (DHA) exhibits anti-inflammatory activity. It inhibited fibrotic mediators and reduced NF-κB activity in the pancreas of mice with chronic pancreatitis. The present study aimed to investigate whether DHA could suppress cytokine expression in PSCs isolated from rats. Cells were pre-treated with DHA or the antioxidant N-acetylcysteine (NAC) and stimulated with TNF-α or poly (I:C). Treatment with TNF-α or poly (I:C) increased the expression of monocyte chemoattractant protein 1 (MCP-1) and chemokine C-X3-C motif ligand 1 (CX3CL1), which are known chemoattractants, and enhanced intracellular and mitochondrial reactive oxygen species (ROS) production and NF-κB activity, but reduced mitochondrial membrane potential (MMP). Increased intracellular and mitochondrial ROS accumulation, cytokine expression, MMP disruption, and NF-κB activation were all prevented by DHA in TNF-α- or poly (I:C)-treated PSCs. NAC suppressed TNF-α- or poly (I:C)-induced expression of MCP-1 and CX3CL1. In conclusion, DHA inhibits poly (I:C)- or TNF-α-induced cytokine expression and NF-κB activation by reducing intracellular and mitochondrial ROS in PSCs. Consumption of DHA-rich foods may be beneficial in preventing chronic pancreatitis by inhibiting cytokine expression in PSCs.

10.
Mol Med Rep ; 24(6)2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34608499

RESUMO

Astaxanthin (ASX), a red­colored xanthophyll carotenoid, functions as an antioxidant or pro­oxidant. ASX displays anticancer effects by reducing or increasing oxidative stress. Reactive oxygen species (ROS) promote cancer cell death by necroptosis mediated by receptor­interacting protein kinase 1 (RIP1) and RIP3. NADPH oxidase is a major source of ROS that may promote necroptosis in some cancer cells. The present study aimed to investigate whether ASX induces necroptosis by increasing NADPH oxidase activity and ROS levels in gastric cancer AGS cells. AGS cells were treated with ASX with or without ML171 (NADPH oxidase 1 specific inhibitor), N­acetyl cysteine (NAC; antioxidant), z­VAD (pan­caspase inhibitor) or Necrostatin­1 (Nec­1; a specific inhibitor of RIP1). As a result, ASX increased NADPH oxidase activity, ROS levels and cell death, and these effects were suppressed by ML171 and NAC. Furthermore, ASX induced RIP1 and RIP3 activation, ultimately inducing mixed lineage kinase domain­like protein (MLKL) activation, lactate dehydrogenase (LDH) release and cell death. Moreover, the ASX­induced decrease in cell viability was reversed by Nec­1 treatment and RIP1 siRNA transfection, but not by z­VAD. ASX did not increase the ratio of apoptotic Bax/anti­apoptotic Bcl­2, the number of Annexin V­positive cells, or caspase­9 activation, which are apoptosis indices. In conclusion, ASX induced necroptotic cell death by increasing NADPH oxidase activity, ROS levels, LDH release and the number of propidium iodide­positive cells, as well as activating necroptosis­regulating proteins, RIP1/RIP3/MLKL, in gastric cancer AGS cells. The results of this study demonstrated the necroptotic effect of ASX on gastric cancer AGS cells, which required NADPH oxidase activation and RIP1/RIP3/MLKL signaling in vitro.


Assuntos
NADPH Oxidases/metabolismo , Necroptose , Espécies Reativas de Oxigênio/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Neoplasias Gástricas/metabolismo , Adenocarcinoma/metabolismo , Animais , Antituberculosos/farmacologia , Apoptose , Morte Celular , Linhagem Celular Tumoral , Células Epiteliais , Humanos , Imidazóis , Indóis , L-Lactato Desidrogenase/metabolismo , NADPH Oxidases/efeitos dos fármacos , Proteínas Quinases/metabolismo , Ratos , Xantofilas/farmacologia
11.
Mediators Inflamm ; 2021: 5587297, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34349610

RESUMO

Acute pancreatitis is a common clinical condition with increasing the proinflammatory mediators, including interleukin-6 (IL-6). Obesity is a negative prognostic factor in acute pancreatitis. Obese patients with acute pancreatitis have a higher systemic inflammatory response rate. Levels of serum resistin, an adipocytokine secreted by fat tissues, increase with obesity. Cerulein, a cholecystokinin analog, induces calcium (Ca2+) overload, oxidative stress, and IL-6 expression in pancreatic acinar cells, which are hallmarks of acute pancreatitis. A recent study showed that resistin aggravates the expression of inflammatory cytokines in cerulein-stimulated pancreatic acinar cells. We aimed to investigate whether resistin amplifies cerulein-induced IL-6 expression and whether astaxanthin (ASX), an antioxidant carotenoid with anti-inflammatory properties, inhibits ceruelin/resistin-induced IL-6 expression in pancreatic acinar AR42J cells. We found that resistin enhanced intracellular Ca2+ levels, NADPH oxidase activity, intracellular reactive oxygen species (ROS) production, NF-κB activity, and IL-6 expression in cerulein-stimulated AR42J cells, which were inhibited by ASX in a dose-dependent manner. The calcium chelator BAPTA-AM inhibited cerulein/resistin-induced NADPH oxidase activation and ROS production. Antioxidant N-acetyl cysteine (NAC) and ML171, a specific NADPH oxidase 1 inhibitor, suppressed cerulein/resistin-induced ROS production, NF-κB activation, and IL-6 expression. In conclusion, ASX inhibits IL-6 expression, by reducing Ca2+ overload, NADPH oxidase-mediated ROS production, and NF-κB activity in cerulein/resistin-stimulated pancreatic acinar cells. Consumption of ASX-rich foods could be beneficial for preventing or delaying the incidence of obesity-associated acute pancreatitis.


Assuntos
Células Acinares/metabolismo , Ceruletídeo/química , Interleucina-6/metabolismo , Pâncreas/metabolismo , Resistina/química , Células Acinares/efeitos dos fármacos , Adipocinas/metabolismo , Animais , Anti-Inflamatórios/química , Cálcio/química , Cálcio/metabolismo , Linhagem Celular , Quelantes/química , NADPH Oxidases/metabolismo , Obesidade/metabolismo , Estresse Oxidativo , Pâncreas/efeitos dos fármacos , Ratos , Espécies Reativas de Oxigênio , Xantofilas/farmacologia
12.
Molecules ; 26(11)2021 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-34073777

RESUMO

House dust mites (HDM) are critical factors in airway inflammation. They activate respiratory epithelial cells to produce reactive oxygen species (ROS) and activate Toll-like receptor 4 (TLR4). ROS induce the expression of inflammatory cytokines in respiratory epithelial cells. Lycopene is a potent antioxidant nutrient with anti-inflammatory activity. The present study aimed to investigate whether HDM induce intracellular and mitochondrial ROS production, TLR4 activation, and pro-inflammatory cytokine expression (IL-6 and IL-8) in respiratory epithelial A549 cells. Additionally, we examined whether lycopene inhibits HDM-induced alterations in A549 cells. The treatment of A549 cells with HDM activated TLR4, induced the expression of IL-6 and IL-8, and increased intracellular and mitochondrial ROS levels. TAK242, a TLR4 inhibitor, suppressed both HDM-induced ROS production and cytokine expression. Furthermore, lycopene inhibited the HDM-induced TLR4 activation and cytokine expression, along with reducing the intracellular and mitochondrial ROS levels in HDM-treated cells. These results collectively indicated that the HDM induced TLR4 activation and increased intracellular and mitochondrial ROS levels, thus resulting in the induction of cytokine expression in respiratory epithelial cells. The antioxidant lycopene could inhibit HDM-induced cytokine expression, possibly by suppressing TLR4 activation and reducing the intracellular and mitochondrial ROS levels in respiratory epithelial cells.


Assuntos
Citocinas/metabolismo , Mediadores da Inflamação/metabolismo , Licopeno/farmacologia , Pyroglyphidae/metabolismo , Mucosa Respiratória/metabolismo , Receptor 4 Toll-Like/metabolismo , Células A549 , Animais , Humanos , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Sulfonamidas/farmacologia , Receptor 4 Toll-Like/antagonistas & inibidores
13.
Molecules ; 26(6)2021 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-33809289

RESUMO

Matrix metalloproteinases (MMPs), key molecules of cancer invasion and metastasis, degrade the extracellular matrix and cell-cell adhesion molecules. MMP-10 plays a crucial role in Helicobacter pylori-induced cell-invasion. The mitogen-activated protein kinase (MAPK) signaling pathway, which activates activator protein-1 (AP-1), is known to mediate MMP expression. Infection with H. pylori, a Gram-negative bacterium, is associated with gastric cancer development. A toxic factor induced by H. pylori infection is reactive oxygen species (ROS), which activate MAPK signaling in gastric epithelial cells. Peroxisome proliferator-activated receptor γ (PPAR-γ) mediates the expression of antioxidant enzymes including catalase. ß-Carotene, a red-orange pigment, exerts antioxidant and anti-inflammatory properties. We aimed to investigate whether ß-carotene inhibits H. pylori-induced MMP expression and cell invasion in gastric epithelial AGS (gastric adenocarcinoma) cells. We found that H. pylori induced MMP-10 expression and increased cell invasion via the activation of MAPKs and AP-1 in gastric epithelial cells. Specific inhibitors of MAPKs suppressed H. pylori-induced MMP-10 expression, suggesting that H. pylori induces MMP-10 expression through MAPKs. ß-Carotene inhibited the H. pylori-induced activation of MAPKs and AP-1, expression of MMP-10, and cell invasion. Additionally, it promoted the expression of PPAR-γ and catalase, which reduced ROS levels in H. pylori-infected cells. In conclusion, ß-carotene exerts an inhibitory effect on MAPK-mediated MMP-10 expression and cell invasion by increasing PPAR-γ-mediated catalase expression and reducing ROS levels in H. pylori-infected gastric epithelial cells.


Assuntos
Mucosa Gástrica/efeitos dos fármacos , Helicobacter pylori/patogenicidade , Metaloproteinase 10 da Matriz/metabolismo , Inibidores de Metaloproteinases de Matriz/farmacologia , beta Caroteno/farmacologia , Catalase/metabolismo , Linhagem Celular , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/enzimologia , Células Epiteliais/microbiologia , Mucosa Gástrica/enzimologia , Mucosa Gástrica/microbiologia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Infecções por Helicobacter/complicações , Infecções por Helicobacter/enzimologia , Infecções por Helicobacter/patologia , Helicobacter pylori/efeitos dos fármacos , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Metaloproteinase 10 da Matriz/genética , Invasividade Neoplásica/patologia , Invasividade Neoplásica/prevenção & controle , PPAR gama/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Neoplasias Gástricas/enzimologia , Neoplasias Gástricas/etiologia , Neoplasias Gástricas/patologia , Fator de Transcrição AP-1/metabolismo
14.
J Cancer Prev ; 26(1): 64-70, 2021 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-33842407

RESUMO

House dust mite (HDM) is one of the significant causes for airway inflammation such as asthma. It induces oxidative stress and an inflammatory response in the lungs through the release of chemokines such as interleukin-8 (IL-8). Reactive oxygen species (ROS) activate inflammatory signaling mediators such as mitogen-activated protein kinases (MAPKs) and redox-sensitive transcription factors including NF-κB and AP-1. Ascorbic acid shows an antioxidant and anti-inflammatory activities in various cells. It ameliorated the symptoms of HDM-induced rhinitis. The present study was aimed to investigate whether HDM could induce IL-8 expression through activation of MAPKs, NF-κB, and AP-1 and whether ascorbic acid could inhibit HDM-stimulated IL-8 expression by reducing ROS and suppressing activation of MAPKs, NF-κB, and AP-1 in respiratory epithelial H292 cells. H292 cells were treated with HDM (5 µg/mL) in the absence or presence of ascorbic acid (100 or 200 µM). HDM treatment increased ROS levels, and activated MAPKs, NF-κB, and AP-1 and thus, induced IL-8 expression in H292 cells. Ascorbic acid reduced ROS levels and inhibited activation of MAPKs, NF-κB and AP-1 and L-8 expression in H292 cells. In conclusion, consumption of ascorbic acid-rich foods may be beneficial for prevention of HDM-mediated respiratory inflammation by suppressing oxidative stress-mediated MAPK signaling pathways and activation of NF-kB and AP-1.

15.
Int J Mol Sci ; 22(4)2021 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-33672594

RESUMO

High alcohol intake results in the accumulation of non-oxidative ethanol metabolites such as fatty acid ethyl esters (FAEEs) in the pancreas. High FAEE concentrations mediate pancreatic acinar cell injury and are associated with alcoholic pancreatitis. Treatment with ethanol and the fatty acid palmitoleic acid (EtOH/POA) increased the levels of palmitoleic acid ethyl ester and induced zymogen activation and cytokine expression in pancreatic acinar cells. EtOH/POA induces nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-mediated reactive oxygen species (ROS) production and pancreatic acinar cell injury. Lycopene, a bright-red carotenoid, is a potent antioxidant due to its high number of conjugated double bands. This study aimed to investigate whether lycopene inhibits the EtOH/POA-induced increase in ROS production, zymogen activation, and expression of the inflammatory cytokine IL-6 in EtOH/POA-stimulated pancreatic acinar AR42J cells. EtOH/POA increased the ROS levels, NADPH oxidase and NF-κB activities, zymogen activation, IL-6 expression, and mitochondrial dysfunction, which were inhibited by lycopene. The antioxidant N-acetylcysteine and NADPH oxidase 1 inhibitor ML171 suppressed the EtOH/POA-induced increases in ROS production, NF-κB activation, zymogen activation, and IL-6 expression. Therefore, lycopene inhibits EtOH/POA-induced mitochondrial dysfunction, zymogen activation, and IL-6 expression by suppressing NADPH oxidase-mediated ROS production in pancreatic acinar cells.


Assuntos
Células Acinares/patologia , Inflamação/patologia , Licopeno/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Pâncreas Exócrino/patologia , Acetilcisteína/farmacologia , Células Acinares/efeitos dos fármacos , Trifosfato de Adenosina/metabolismo , Animais , Linhagem Celular , DNA/metabolismo , Inibidores Enzimáticos/farmacologia , Precursores Enzimáticos/metabolismo , Etanol , Ácidos Graxos Monoinsaturados , Interleucina-6/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , NADPH Oxidases/metabolismo , NF-kappa B/metabolismo , Ligação Proteica/efeitos dos fármacos , Ratos , Espécies Reativas de Oxigênio/metabolismo
16.
Nutrients ; 12(6)2020 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-32545395

RESUMO

Helicobacter pylori (H. pylori) infection leads to the massive apoptosis of the gastric epithelial cells, causing gastric ulcers, gastritis, and gastric adenocarcinoma. Autophagy is a cellular recycling process that plays important roles in cell death decisions and can protect cells by preventing apoptosis. Upon the induction of autophagy, the level of the autophagy substrate p62 is reduced and the autophagy-related ratio of microtubule-associated proteins 1A/1B light chain 3B (LC3B)-II/LC3B-I is heightened. AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) are involved in the regulation of autophagy. Astaxanthin (AST) is a potent anti-oxidant that plays anti-inflammatory and anti-cancer roles in various cells. In the present study, we examined whether AST inhibits H. pylori-induced apoptosis through AMPK-mediated autophagy in the human gastric epithelial cell line AGS (adenocarcinoma gastric) in vitro. In this study, H. pylori induced apoptosis. Compound C, an AMPK inhibitor, enhanced the H. pylori-induced apoptosis of AGS cells. In contrast, metformin, an AMPK activator, suppressed H. pylori-induced apoptosis, showing that AMPK activation inhibits H. pylori-induced apoptosis. AST inhibited H. pylori-induced apoptosis by increasing the phosphorylation of AMPK and decreasing the phosphorylation of RAC-alpha serine/threonine-protein kinase (Akt) and mTOR in H. pylori-stimulated cells. The number of LC3B puncta in H. pylori-stimulated cells increased with AST. These results suggest that AST suppresses the H. pylori-induced apoptosis of AGS cells by inducing autophagy through the activation of AMPK and the downregulation of its downstream target, mTOR. In conclusion, AST may inhibit gastric diseases associated with H. pylori infection by increasing autophagy through the activation of the AMPK pathway.


Assuntos
Antineoplásicos , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Células Epiteliais/microbiologia , Células Epiteliais/fisiologia , Gastrite/microbiologia , Gastrite/fisiopatologia , Infecções por Helicobacter , Helicobacter pylori , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Anti-Inflamatórios , Antioxidantes , Apoptose/genética , Autofagia/genética , Linhagem Celular Tumoral , Mucosa Gástrica/citologia , Humanos , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Xantofilas/farmacologia
17.
Pharmacology ; 105(9-10): 586-597, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32018260

RESUMO

INTRODUCTION: The accumulation of amyloid-ß (Aß) plaque in the brain is a characteristic feature of Alzheimer's disease (AD) and the cause of fatal oxidative damage to neuronal cells. Korean red ginseng (RG) is used extensively in traditional medicine and is known to have anti-oxidative and anti-inflammatory properties. OBJECTIVE: This study aims to investigate whether Korean RG extract inhibits Aß-induced neuronal apoptosis. METHODS: Human neuronal cells (SH-SY5Y cells) were stimulated with Aß (5 µmol/L) and treated with RG dissolved in phosphate-buffered saline (0.2, 2, 20 µg/mL). RESULTS: RG suppressed the reduction of cell viability and the increase in apoptotic factors (Bax/Bcl-2 ratio and caspase-3 activity) in Aß-treated cells. RG suppressed Aß-induced increases in intracellular and mitochondrial reactive oxygen species (ROS) levels and mitochondrial dysfunction (determined by low mitochondrial membrane potential and oxygen consumption rate) in a dose-dependent manner. RG inhibited nuclear factor kappa-light-chain-enhancer of activated B cells (NF-ĸB) activation and expression of the pro-apoptotic gene Nucling in Aß-treated cells. CONCLUSION: RG confers protection against neuronal apoptosis by reducing ROS levels and suppressing mitochondrial dysfunction and NF-κB activation, which results in suppression of NF-κB-mediated activation of Nucling expression in Aß-treated cells. Supplementation with RG may be beneficial for preventing Aß-induced neuronal cell death associated with AD.


Assuntos
Apoptose/efeitos dos fármacos , Proteínas de Membrana/metabolismo , Fármacos Neuroprotetores/farmacologia , Panax/química , Extratos Vegetais/farmacologia , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Doença de Alzheimer/prevenção & controle , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/toxicidade , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , NF-kappa B/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo
18.
Free Radic Res ; 54(11-12): 799-809, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31401888

RESUMO

Oxidative stress-induced DNA cleavage and apoptosis in pancreatic acinar cells has been implicated in the pathogenesis of acute pancreatitis. Thus, an efficient DNA repair process is key to prevention of apoptotic pancreatic acinar cell death. Ataxia telangiectasia mutated (ATM), a sensor of DNA breaks, functions by recruiting DNA repair proteins to initiate the DNA repair process. In the present study, we investigated whether H2O2 produced by the action of glucose oxidase on α-D-glucose (G/GO) induces apoptosis in pancreatic acinar AR42J cells through an alteration of the level of ATM. As a result, G/GO induced apoptosis by promoting a loss of cell viability, increase in Bax, decrease in Bcl-2, cleavage of poly (ADP-ribose) polymerase (PARP) and fragmentation of DNA. In addition, ATM cleavage along with elevated levels of calpain and caspase-3 activity was induced by G/GO. By using ATM siRNA, we demonstrated that reduction in ATM levels enhanced G/GO-induced apoptosis. Moreover, inhibition of calpain activity by calpeptin or calpastatin, or by inhibition of caspase-3 with z-DEVD, suppressed G/GO-induced apoptosis and ATM cleavage. Collectively, these findings suggest that proteolysis of ATM is the underlying mechanism of apoptosis of pancreatic acinar cells caused by exposure to oxidative stress.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Ataxia Telangiectasia/metabolismo , Calpaína/metabolismo , Caspase 3/metabolismo , Neoplasias Pancreáticas/metabolismo , Células Acinares/metabolismo , Células Acinares/patologia , Animais , Apoptose/fisiologia , Linhagem Celular Tumoral , Humanos , Estresse Oxidativo/fisiologia , Neoplasias Pancreáticas/patologia , Ratos
19.
J Cancer Prev ; 25(4): 244-251, 2020 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-33409257

RESUMO

Helicobacter pylori is recognized as a risk factor for gastric carcinogenesis. The chronic exposure of gastric epithelium to H. pylori induces a prolonged inflammatory state that may progress to gastric cancer. Astaxanthin, a pinkish antioxidant carotenoid, abundant in marine organisms, is known for its protective effect against inflammation and multiple types of cancer. The purpose of this study was to examine the effect of astaxanthin on H. pylori-induced oxidative injury, inflammation, and oncogene expression in gastric mucosal tissues of the infected mice. Mice were inoculated using oral gavage with H. pylori suspension (108 colony forming unit of H. pylori/0.1 mL) for three days, after which they were fed astaxanthin-supplemented diet (5 mg/kg body weight/day for seven weeks). The effects of astaxanthin on H. pylori-induced increase in lipid peroxide (LPO) production, myeloperoxidase (MPO) activity, expression of the inflammatory cytokine IFN-γ and oncogenes (c-myc and cyclin D1), and the accompanying histologic changes in gastric mucosal tissues were evaluated. H. pylori infection increased the level of LPO, MPO activity, and the expression of IFN-γ, c-myc, and cyclin D1 in gastric mucosal tissues of mice. H. pylori infection induced neutrophil infiltration and hyperplasia of gastric mucosa. Astaxanthin supplementation attenuated these effects. In conclusion, consumption of astaxanthin-rich foods may prevent H. pylori-associated oxidative damage and inflammatory and oncogenic responses in gastric mucosal tissues.

20.
Antioxidants (Basel) ; 8(12)2019 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-31835889

RESUMO

Helicobacter pylori infection causes the hyper-proliferation of gastric epithelial cells that leads to the development of gastric cancer. Overexpression of tumor necrosis factor receptor associated factor (TRAF) is shown in gastric cancer cells. The dietary antioxidant ß-carotene has been shown to counter hyper-proliferation in H. pylori-infected gastric epithelial cells. The present study was carried out to examine the ß-carotene mechanism of action. We first showed that H. pylori infection decreases cellular IBα levels while increasing cell viability, NADPH oxidase activity, reactive oxygen species production, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-B) activation, and TRAF1 and TRAF2 gene expression, as well as protein-protein interaction in gastric epithelial AGS cells. We then demonstrated that pretreatment of cells with ß-carotene significantly attenuates these effects. Our findings support the proposal that ß-carotene has anti-cancer activity by reducing NADPH oxidase-mediated production of ROS, NF-B activation and NF-B-regulated TRAF1 and TRAF2 gene expression, and hyper-proliferation in AGS cells. We suggest that the consumption of ß-carotene-enriched foods could decrease the incidence of H. pylori-associated gastric disorders.

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