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1.
Artigo em Chinês | MEDLINE | ID: mdl-34624962

RESUMO

Endocrine disrupting chemicals (EDCs) are a kind of exogenous chemicals widely existing in the environment, which cause serious harm to the environment and human health. At present, the impact of this type of substance on the thyroid has attracted much attention.This review summarized the effects of EDCs on thyroid hormones, and phosphatidylinositol 3-kinase (PI3K) /protein kinase B (Akt) /mammalian target of rapamycin (mTOR) (PI3K/Akt/mTOR) signaling pathway and its role in thyroid diseases, and explore the role of PI3K/Akt/mTOR signaling pathway in EDCs-induced apoptosis and autophagy of thyroid follicular epithelial cells.This paper could provide further understandings for thyroid diseases induced by the autophagy and apoptosis of thyroid follicular epithelial cells.


Assuntos
Disruptores Endócrinos , Células Epiteliais da Tireoide , Apoptose , Autofagia , Disruptores Endócrinos/toxicidade , Humanos , Fosfatidilinositol 3-Quinase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Células Epiteliais da Tireoide/metabolismo
2.
Biomed Res Int ; 2021: 1078019, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34497845

RESUMO

Objective: To investigate the role of curcumin in regulating pathogenesis of pulmonary arterial smooth muscle cells (PASMCs) derived from pulmonary arterial hypertension (PAH) model. Methods: Male Sprague Dawley rats were injected with monocrotaline (MCT) to establish the PAH experimental model. The rats were divided into control group, MCT group, and curcumin group. At the end of the study, hemodynamic data were measured to determine pulmonary hypertension. Proliferation ability of PASMCs, a remodeling indicator of pulmonary artery and right ventricle, was detected. In addition, the morphology and function of mitochondria, antiglycolysis and antiproliferation pathways, and genes were also analyzed. Results: Curcumin may function by reversing MCT-mediated pulmonary vascular remodeling in rats. Curcumin effectively improved pulmonary vascular remodeling, promoted PASMC apoptosis, and protected mitochondrial function. In addition, curcumin treatment suppressed the PI3K/AKT pathway in PASMCs and regulated the expression of antiproliferative genes. Conclusion: Curcumin can improve energy metabolism and reverse the process of PAHS. However, there were side effects of curcumin in MCT-induced rats, suggesting that the dosage should be treated with caution and its toxicological mechanism should be further studied and evaluated.


Assuntos
Curcumina/farmacologia , Mitocôndrias/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Fosfatidilinositol 3-Quinase/metabolismo , Hipertensão Arterial Pulmonar/tratamento farmacológico , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Hemodinâmica/efeitos dos fármacos , Masculino , Mitocôndrias/metabolismo , Miócitos de Músculo Liso/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Hipertensão Arterial Pulmonar/metabolismo , Hipertensão Arterial Pulmonar/patologia , Ratos , Transdução de Sinais/efeitos dos fármacos
3.
Nutrients ; 13(7)2021 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-34371964

RESUMO

The flowering plant genus Alisma, which belongs to the family Alismataceae, comprises 11 species, including Alisma orientale, Alisma canaliculatum, and Alisma plantago-aquatica. Alismatis rhizome (Ze xie in Chinese, Takusha in Japanese, and Taeksa in Korean, AR), the tubers of medicinal plants from Alisma species, have long been used to treat inflammatory diseases, hyperlipidemia, diabetes, bacterial infection, edema, oliguria, diarrhea, and dizziness. Recent evidence has demonstrated that its extract showed pharmacological activities to effectively reverse cancer-related molecular targets. In particular, triterpenes naturally isolated from AR have been found to exhibit antitumor activity. This study aimed to describe the biological activities and plausible signaling cascades of AR and its main compounds in experimental models representing cancer-related physiology and pathology. Available in vitro and in vivo studies revealed that AR extract possesses anticancer activity against various cancer cells, and the efficacy might be attributed to the cytotoxic and antimetastatic effects of its alisol compounds, such as alisol A, alisol B, and alisol B 23-acetate. Several beneficial functions of triterpenoids found in AR might be due to p38 activation and inhibition of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathways. Moreover, AR and its triterpenes inhibit the proliferation of cancer cells that are resistant to chemotherapy. Thus, AR and its triterpenes may play potential roles in tumor attack, as well as a therapeutic remedy alone and in combination with other chemotherapeutic drugs.


Assuntos
Alisma , Antineoplásicos Fitogênicos/farmacologia , Extratos Vegetais/farmacologia , Transdução de Sinais/efeitos dos fármacos , Triterpenos/farmacologia , Animais , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Extratos Vegetais/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Rizoma , Serina-Treonina Quinases TOR/metabolismo , Triterpenos/uso terapêutico , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
4.
World J Gastroenterol ; 27(28): 4667-4686, 2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34366628

RESUMO

BACKGROUND: Sorafenib is the first-line treatment for patients with advanced hepatocellular carcinoma (HCC). Y-box binding protein 1 (YB-1) is closely correlated with tumors and drug resistance. However, the relationship between YB-1 and sorafenib resistance and the underlying mechanism in HCC remain unknown. AIM: To explore the role and related mechanisms of YB-1 in mediating sorafenib resistance in HCC. METHODS: The protein expression levels of YB-1 were assessed in human HCC tissues and adjacent nontumor tissues. Next, we constructed YB-1 overexpression and knockdown hepatocarcinoma cell lines with lentiviruses and stimulated these cell lines with different concentrations of sorafenib. Then, we detected the proliferation and apoptosis in these cells by terminal deoxynucleotidyl transferase dUTP nick end labeling, flow cytometry and Western blotting assays. We also constructed a xenograft tumor model to explore the effect of YB-1 on the efficacy of sorafenib in vivo. Moreover, we studied and verified the specific molecular mechanism of YB-1 mediating sorafenib resistance in hepatoma cells by digital gene expression sequencing (DGE-seq). RESULTS: YB-1 protein levels were found to be higher in HCC tissues than in corresponding nontumor tissues. YB-1 suppressed the effect of sorafenib on cell proliferation and apoptosis. Consistently, the efficacy of sorafenib in vivo was enhanced after YB-1 was knocked down. Furthermore, KEGG pathway enrichment analysis of DGE-seq demonstrated that the phosphoinositide-3-kinase (PI3K)/protein kinase B (Akt) signaling pathway was essential for the sorafenib resistance induced by YB-1. Subsequently, YB-1 interacted with two key proteins of the PI3K/Akt signaling pathway (Akt1 and PIK3R1) as shown by searching the BioGRID and HitPredict websites. Finally, YB-1 suppressed the inactivation of the PI3K/Akt signaling pathway induced by sorafenib, and the blockade of the PI3K/Akt signaling pathway by LY294002 mitigated YB-1-induced sorafenib resistance. CONCLUSION: Overall, we concluded that YB-1 augments sorafenib resistance through the PI3K/Akt signaling pathway in HCC and suggest that YB-1 is a key drug resistance-related gene, which is of great significance for the application of sorafenib in advanced-stage HCC.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Apoptose , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Proteínas de Transporte , Linhagem Celular Tumoral , Proliferação de Células , Resistencia a Medicamentos Antineoplásicos , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Fosfatidilinositol 3-Quinase/metabolismo , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Sorafenibe/farmacologia , Proteína 1 de Ligação a Y-Box
5.
Medicine (Baltimore) ; 100(31): e26623, 2021 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-34397798

RESUMO

BACKGROUND: Cyclin F (CCNF) dysfunction has been implicated in various forms of cancer, offering a new avenue for understanding the pathogenic mechanisms underlying hepatocellular carcinoma (HCC). We aimed to evaluate the role of CCNF in HCC using publicly available data from The Cancer Genome Atlas (TCGA). METHOD: We used TCGA data and Gene Expression Omnibus (GEO) data to analyze the differential expression of CCNF between tumor and adjacent tissues and the relationship between CCNF and clinical characteristics. We compared prognosis of patients with HCC with high and low CCNF expression and constructed receiver operating characteristic (ROC) curves. In addition, we also explored the types of gene mutations in relevant groups and conducted Gene Set Enrichment Analysis (GSEA). RESULTS: The expression of CCNF in liver cancer tissues was significantly increased compared with that in adjacent tissues, and patients with high CCNF expression had a worse prognosis than those with low CCNF expression. Patients with high CCNF expression also had more somatic mutations. High expression of CCNF hampers the prognosis independently. The GSEA showed that the "http://www.gsea-msigdb.org/gsea/msigdb/cards/BIOCARTA_WNT_PATHWAY" Wnt pathway, "http://www.gsea-msigdb.org/gsea/msigdb/cards/BIOCARTA_P53_PATHWAY" P53 pathway, "http://www.gsea-msigdb.org/gsea/msigdb/cards/HALLMARK_PI3K_AKT_MTOR_SIGNALING" PI3K/Akt/mTOR pathway, "http://www.gsea-msigdb.org/gsea/msigdb/cards/HALLMARK_NOTCH_SIGNALING" Notch pathway were enriched in patients with the high CCNF expression phenotype. CONCLUSION: High CCNF expression can be seen as an independent risk factor for poor survival in HCC. Its expression may serve as a target for the diagnosis and treatment of liver cancer.


Assuntos
Carcinoma Hepatocelular/genética , Ciclinas/genética , Neoplasias Hepáticas/genética , Transdução de Sinais/genética , Carcinoma Hepatocelular/metabolismo , Ciclinas/metabolismo , Bases de Dados Genéticas , Feminino , Expressão Gênica , Humanos , Fígado/metabolismo , Neoplasias Hepáticas/metabolismo , Masculino , Pessoa de Meia-Idade , Mutação , Fosfatidilinositol 3-Quinase/metabolismo , Prognóstico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Curva ROC , Receptores Notch/metabolismo , Taxa de Sobrevida , Serina-Treonina Quinases TOR/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Via de Sinalização Wnt/genética
6.
World J Surg Oncol ; 19(1): 232, 2021 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-34362378

RESUMO

BACKGROUND: The aim of this study is to unravel the role of Cyanidin-3-glucoside (C3G) and its potential mechanisms in lung adenocarcinoma (LUAD). METHODS: The cell clones, proliferation, apoptosis, migration, and invasion in H1299 and A549 cells were determined by colony formation assay, 5-ethynyl-20 deoxyuridine (EdU) assay, flow cytometry, and transwell assay, respectively. The expression of p53-induced gene 3 (TP53I3) was assessed and the prognostic values of TP53I3 in LUAD via the dataset from the Cancer Genome Atlas (TCGA). In addition, the mRNA and protein expressions were detected by quantitative real-time PCR (qRT-PCR) and western blot. RESULTS: C3G inhibited the proliferation, migration, and invasion of, and also promoted the apoptosis in H1299 and A549 cells. The database of TCGA showed TP53I3 was highly expressed in LUAD tissues and correlated with the poor prognosis of LUAD patients. Moreover, we also found that C3G inhibited the proliferation, migration and invasion, and promoted apoptosis in H1299 and A549 cells by downregulating TP53I3. Additionally, C3G could inhibit the activation of phosphatidylinositol 3'-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway in H1299 and A549 cells by downregulating TP53I3. CONCLUSION: This study demonstrated that C3G could inhibit the proliferation, migration and invasion, and also facilitate the apoptosis through downregulating TP53I3 and inhibiting PI3K/AKT/mTOR pathway in LUAD.


Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Antocianinas , Apoptose , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Fosfatidilinositol 3-Quinase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Prognóstico , Proteínas Proto-Oncogênicas , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo
7.
Neuroscience ; 473: 102-118, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34358633

RESUMO

Depression has huge social risks of high incidence, disability, and suicide. Its prevalence and harm in people with hyperglycemia are 2-3 times higher than in normal people. However, antidepressants with precise curative effects and clear mechanisms for patients with hyperglycemia are currently lacking. Prescriptions containing Radix Rehmannia glutinosa Libosch., a traditional medicinal herb with a wide range of nutritional and medicinal values, are often used as antidepressants in Chinese clinical medicine. Catalpol is one of the main effective compounds of Radix R. glutinosa, with multiple biological activities such as hypoglycemia. Here, the antidepressant effect of catalpol on the pathological state of streptozotocin (STZ)-induced hyperglycemia and the underlying molecular mechanisms were analyzed. Results showed that administering catalpol orally to hyperglycemic mice for 21 consecutive days significantly reversed the abnormalities in tail suspension, forced swimming, and open field tests. Catalpol also reversed the abnormal phosphorylation of phosphoinositide 3-kinase (PI3K) and protein kinase B (AKT) and the abnormal levels of nuclear factor erythroid 2-related factor 2 (Nrf2) protein, heme oxygenase-1 (HO-1), and antioxidants, including superoxide dismutase, glutathione peroxidase, glutathione-s transferase, reduced glutathione, and malondialdehyde in the hippocampus and frontal cortex of STZ-induced hyperglycemic mice. Thus, catalpol attenuates depressive-like behavior in pathological hyperglycemic state, and the antidepressant mechanism could at least be partly attributed to the upregulation of the PI3K/AKT/Nrf2/HO-1 signaling pathway in both brain regions, thus restoring the balance between oxidative and antioxidant damage. These data expanded the scientific understanding of catalpol and provided preclinical experimental evidence for its application.


Assuntos
Hiperglicemia , Fosfatidilinositol 3-Quinase , Animais , Heme Oxigenase-1/metabolismo , Humanos , Hiperglicemia/tratamento farmacológico , Glucosídeos Iridoides , Camundongos , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Fosfatidilinositol 3-Quinase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Estreptozocina/toxicidade
8.
Nutrients ; 13(7)2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34209137

RESUMO

D-Pinitol (DPIN) is a natural occurring inositol capable of activating the insulin pathway in peripheral tissues, whereas this has not been thoroughly studied in the central nervous system. The present study assessed the potential regulatory effects of DPIN on the hypothalamic insulin signaling pathway. To this end we investigated the Phosphatidylinositol-3-kinase (PI3K)/Protein Kinase B (Akt) signaling cascade in a rat model following oral administration of DPIN. The PI3K/Akt-associated proteins were quantified by Western blot in terms of phosphorylation and total expression. Results indicate that the acute administration of DPIN induced time-dependent phosphorylation of PI3K/Akt and its related substrates within the hypothalamus, indicating an activation of the insulin signaling pathway. This profile is consistent with DPIN as an insulin sensitizer since we also found a decrease in the circulating concentration of this hormone. Overall, the present study shows the pharmacological action of DPIN in the hypothalamus through the PI3K/Akt pathway when giving in fasted animals. These findings suggest that DPIN might be a candidate to treat brain insulin-resistance associated disorders by activating insulin response beyond the insulin receptor.


Assuntos
Hipotálamo/metabolismo , Inositol/análogos & derivados , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Administração Oral , Animais , Glicemia/metabolismo , Ativação Enzimática/efeitos dos fármacos , Glucagon/sangue , Homeostase , Hipotálamo/efeitos dos fármacos , Inositol/administração & dosagem , Inositol/sangue , Inositol/química , Inositol/farmacologia , Insulina/sangue , Insulina/metabolismo , Resistência à Insulina , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Fosforilação/efeitos dos fármacos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos
9.
Cell Death Dis ; 12(7): 691, 2021 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-34244479

RESUMO

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. However, there still remains a lack of effective diagnostic and therapeutic targets for this disease. Increasing evidence demonstrates that RNA modifications play an important role in the progression of HCC, but the role of the N7-methylguanosine (m7G) methylation modification in HCC has not been properly evaluated. Thus, the goal of the present study was to investigate the function and mechanism of the m7G methyltransferase WD repeat domain 4 (WDR4) in HCC as well as its clinical relevance and potential value. We first verified the high expression of WDR4 in HCC and observed that upregulated WDR4 expression increased the m7G methylation level in HCC. WDR4 promoted HCC cell proliferation by inducing the G2/M cell cycle transition and inhibiting apoptosis in addition to enhancing metastasis and sorafenib resistance through epithelial-mesenchymal transition (EMT). Furthermore, we observed that c-MYC (MYC) can activate WDR4 transcription and that WDR4 promotes CCNB1 mRNA stability and translation to enhance HCC progression. Mechanistically, we determined that WDR4 enhances CCNB1 translation by promoting the binding of EIF2A to CCNB1 mRNA. Furthermore, CCNB1 was observed to promote PI3K and AKT phosphorylation in HCC and reduce P53 protein expression by promoting P53 ubiquitination. In summary, we elucidated the MYC/WDR4/CCNB1 signalling pathway and its impact on PI3K/AKT and P53. Furthermore, the result showed that the m7G methyltransferase WDR4 is a tumour promoter in the development and progression of HCC and may act as a candidate therapeutic target in HCC treatment.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ciclina B1/metabolismo , Resistencia a Medicamentos Antineoplásicos , Proteínas de Ligação ao GTP/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Proteínas Proto-Oncogênicas c-myc/metabolismo , Sorafenibe/farmacologia , Animais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/secundário , Ciclina B1/genética , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Fator de Iniciação 2 em Eucariotos/metabolismo , Proteínas de Ligação ao GTP/genética , Regulação Neoplásica da Expressão Gênica , Células Hep G2 , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Camundongos Endogâmicos BALB C , Camundongos Nus , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Transdução de Sinais , Proteína Supressora de Tumor p53/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Artigo em Inglês | MEDLINE | ID: mdl-34119651

RESUMO

Schistosoma mansoni worms are under a milieu of external and internal signaling pathways. The life-cycle stages are exposed to enormous stimuli within the mammalian and the snail hosts and as free-living stages in the fresh water. Furthermore, there is a unique interplay between the male and the female worms involving many stimuli from the male essential for full development of the female. PI3K/Akt/mTOR is an evolutionarily divergent signal transduction pathway universal to nearly every multicellular organism. This work reviews the Schistosoma mansoni PI3K/Akt/mTOR signal pathways and the involvement of the signal in the worms' physiology concerning the uptake of glucose, reproduction and survival. The inhibitors of the signal pathway used against Schistosoma mansoni were summarized. Given the importance of the PI3K/Akt/mTOR signal pathway, its inhibition could be a promising control strategy against schistosomiasis.


Assuntos
Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Schistosoma mansoni/fisiologia , Esquistossomose mansoni/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Animais , Humanos , Esquistossomose mansoni/parasitologia , Transdução de Sinais
11.
Cell Death Dis ; 12(7): 642, 2021 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-34162834

RESUMO

Diabetic peripheral neuropathy (DPN) is the most common complication of diabetes mellitus (DM) and the dysfunction of Schwann cells plays an important role in the pathogenesis of DPN. Thioredoxin-interacting protein (TXNIP) is known as an inhibitor of thioredoxin and associated with oxidative stress and inflammation. However, whether TXNIP is involved in dysfunction of Schwann cells of DPN and the exact mechanism is still not known. In this study, we first reported that TXNIP expression was significantly increased in the sciatic nerves of diabetic mice, accompanied by abnormal electrophysiological indexes and myelin sheath structure. Similarly, in vitro cultured Schwann cells TXNIP was evidently enhanced by high glucose stimulation. Again, the function experiment found that knockdown of TXNIP in high glucose-treated RSC96 cells led to a 4.12 times increase of LC3-II/LC3-I ratio and a 25.94% decrease of cleaved caspase 3/total caspase 3 ratio. Then, DNA methyltransferase (DNMT) inhibitor 5-Aza has been reported to benefit Schwann cell in DPN, and here 5-Aza treatment reduced TXNIP protein expression, improved autophagy and inhibited apoptosis in high glucose-treated RSC96 cells and the sciatic nerves of diabetic mice. Furthermore, DNMT1 and DNMT3a upregulation were found to be involved in TXNIP overexpression in high glucose-stimulated RSC96 cells. Silencing of DNMT1 and DNMT3a effectively reversed high glucose-enhanced TXNIP. Moreover, high glucose-inhibited PI3K/Akt pathway led to DNMT1, DNMT3a, and TXNIP upregulation in RSC96 cells. Knockdown of DNMT1 and DNMT3a prevented PI3K/Akt pathway inhibition-caused TXNIP upregulation in RSC96 cells. Finally, in vivo knockout of TXNIP improved nerve conduction function, increased autophagosome and LC3 expression, and decreased cleaved Caspase 3 and Bax expression in diabetic mice. Taken together, PI3K/Akt pathway inhibition mediated high glucose-induced DNMT1 and DNMT3a overexpression, leading to cell autophagy inhibition and apoptosis via TXNIP protein upregulation in Schwann cells of DPN.


Assuntos
Proteínas de Transporte/metabolismo , Proteínas de Ciclo Celular/metabolismo , DNA (Citosina-5-)-Metiltransferase 1/metabolismo , DNA (Citosina-5-)-Metiltransferases/metabolismo , Neuropatias Diabéticas/enzimologia , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Células de Schwann/enzimologia , Nervo Isquiático/enzimologia , Tiorredoxinas/metabolismo , Animais , Apoptose , Proteínas Reguladoras de Apoptose/metabolismo , Autofagia , Proteínas Relacionadas à Autofagia/metabolismo , Glicemia/metabolismo , Proteínas de Transporte/genética , Proteínas de Ciclo Celular/genética , Linhagem Celular , DNA (Citosina-5-)-Metiltransferase 1/genética , DNA (Citosina-5-)-Metiltransferases/genética , Neuropatias Diabéticas/genética , Neuropatias Diabéticas/patologia , Modelos Animais de Doenças , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ratos , Células de Schwann/patologia , Nervo Isquiático/patologia , Transdução de Sinais , Tiorredoxinas/genética
12.
Aging (Albany NY) ; 13(10): 13626-13643, 2021 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-34091441

RESUMO

BACKGROUND: E2F2 is a member of the E2F transcription factor family and has important but not fully understood biological functions in cancers. The biological role of E2F2 in gastric cancer (GC) also remains unclear. METHODS: We examined the expression levels of E2F2 in GC using publicly available datasets such as TIMER, Oncomine, GEPIA, UALCAN, etc., and in our patient cohort, using quantitative real-time PCR, western blotting, and immunohistochemistry. We further investigated the effects of E2F2 on phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling, autophagy, and the migration and invasion of GC cells by the wound healing assay, Transwell assay and transmission electron microscopy. RESULTS: E2F2 was highly expressed in both GC tissues and cells compared with normal gastric tissues/cells. High E2F2 expression was associated with poor overall survival (OS). In addition, the expression of E2F2 in GC was strongly correlated with a variety of immune markers. E2F2 overexpression promoted the migration and invasiveness of GC cells in vitro through inhibition of PI3K/Akt/mTOR-mediated autophagy. CONCLUSION: High E2F2 expression was associated with the characteristics of invasive tumors and poor prognosis. E2F2 also had potential modulatory effects on tumor immunity. We discovered a novel function of E2F2 in the regulation of PI3K/Akt/mTOR-mediated autophagy and the downstream processes of cell migration and invasion.


Assuntos
Autofagia , Fator de Transcrição E2F2/antagonistas & inibidores , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Neoplasias Gástricas/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Idoso , Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Movimento Celular/genética , Metilação de DNA/genética , Fator de Transcrição E2F2/genética , Fator de Transcrição E2F2/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Genoma Humano , Humanos , Masculino , Análise Multivariada , Invasividade Neoplásica , Prognóstico , Receptor de Morte Celular Programada 1/metabolismo , Mapas de Interação de Proteínas/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Regulação para Cima/genética
13.
Int J Mol Sci ; 22(10)2021 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-34065317

RESUMO

Lysophosphatidic acid (LPA), a bioactive lipid produced extracellularly by autotaxin (ATX), has been known to induce various pathophysiological events, including cancer cell invasion and metastasis. Discoidin domain receptor 2 (DDR2) expression is upregulated in ovarian cancer tissues, and is closely associated with poor clinical outcomes in ovarian cancer patients. In the present study, we determined a critical role and signaling cascade for the expression of DDR2 in LPA-induced ovarian cancer cell invasion. We also found ectopic expression of ATX or stimulation of ovarian cancer cells with LPA-induced DDR2 expression. However, the silencing of DDR2 expression significantly inhibited ATX- and LPA-induced ovarian cancer cell invasion. In addition, treatment of the cells with pharmacological inhibitors of phosphoinositide 3-kinase (PI3K), Akt, and mTOR abrogated LPA-induced DDR2 expression. Moreover, we observed that HIF-1α, located downstream of the mTOR, is implicated in LPA-induced DDR2 expression and ovarian cancer cell invasion. Finally, we provide evidence that LPA-induced HIF-1α expression mediates Twist1 expression to upregulate DDR2 expression. Collectively, the present study demonstrates that ATX, and thereby LPA, induces DDR2 expression through the activation of the PI3K/Akt/mTOR/HIF-1α/Twist1 signaling axes, aggravating ovarian cancer cell invasion.


Assuntos
Receptor com Domínio Discoidina 2/metabolismo , Lisofosfolipídeos/farmacologia , Neoplasias Ovarianas/induzido quimicamente , Neoplasias Ovarianas/metabolismo , Linhagem Celular Tumoral , Feminino , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Invasividade Neoplásica/patologia , Neoplasias Ovarianas/patologia , Fosfatidilinositol 3-Quinase/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo
14.
Medicine (Baltimore) ; 100(22): e26219, 2021 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-34087900

RESUMO

BACKGROUND: Autophagy is closely related to skin cutaneous melanoma (SKCM), but the mechanism involved is unclear. Therefore, exploration of the role of autophagy-related genes (ARGs) in SKCM is necessary. MATERIALS AND METHODS: Differential expression autophagy-related genes (DEARGs) were first analysed. Univariate and multivariate Cox regression analyses were used to evaluate the expression of DEARGs and prognosis of SKCM. Further, the expression levels of prognosis-related DEARGs were verified by immunohistochemical (IHC) staining. Finally, gene set enrichment analysis (GSEA) was used to explore the underlying molecular mechanisms of SKCM. RESULTS: Five ARGs (APOL1, BIRC5, EGFR, TP63, and SPNS1) were positively correlated with the prognosis of SKCM. IHC verified the results of the differential expression of these 5 ARGs in the bioinformatics analysis. According to the receiver operating characteristic curve, the signature had a good performance at predicting overall survival in SKCM. The signature could classify SKCM patients into high-risk or low-risk groups according to distinct overall survival. The nomogram confirmed that the risk score has a particularly large impact on the prognosis of SKCM. Calibration plot displayed excellent agreement between nomogram predictions and actual observations. Principal component analysis indicated that patients in the high-risk group could be distinguished from those in low-risk group. Results of GSEA indicated that the low-risk group is enriched with aggressiveness-related pathways such as phosphatidylinositol-3-kinase/protein kinase B and mitogen-activated protein kinase signalling pathways. CONCLUSION: Our study identified a 5-gene signature. It revealed the mechanisms of autophagy that lead to the progression of SKCM and established a prognostic nomogram that can predict overall survival of patients with SKCM. The findings of this study provide novel insights into the relationship between ARGs and prognosis of SKCM.


Assuntos
Autofagia/genética , Biologia Computacional/métodos , Melanoma/genética , Neoplasias Cutâneas/patologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Apolipoproteína L1/genética , Receptores ErbB/genética , Feminino , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Melanoma/mortalidade , Proteínas de Membrana/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Nomogramas , Fosfatidilinositol 3-Quinase/metabolismo , Prognóstico , Estudos Prospectivos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Curva ROC , Fatores de Risco , Survivina/genética , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/genética
15.
Immunity ; 54(5): 976-987.e7, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33979589

RESUMO

Aerobic glycolysis-the Warburg effect-converts glucose to lactate via the enzyme lactate dehydrogenase A (LDHA) and is a metabolic feature of effector T cells. Cells generate ATP through various mechanisms and Warburg metabolism is comparatively an energy-inefficient glucose catabolism pathway. Here, we examined the effect of ATP generated via aerobic glycolysis in antigen-driven T cell responses. Cd4CreLdhafl/fl mice were resistant to Th17-cell-mediated experimental autoimmune encephalomyelitis and exhibited defective T cell activation, migration, proliferation, and differentiation. LDHA deficiency crippled cellular redox balance and inhibited ATP production, diminishing PI3K-dependent activation of Akt kinase and thereby phosphorylation-mediated inhibition of Foxo1, a transcriptional repressor of T cell activation programs. Th17-cell-specific expression of an Akt-insensitive Foxo1 recapitulated the defects seen in Cd4CreLdhafl/fl mice. Induction of LDHA required PI3K signaling and LDHA deficiency impaired PI3K-catalyzed PIP3 generation. Thus, Warburg metabolism augments glycolytic ATP production, fueling a PI3K-centered positive feedback regulatory circuit that drives effector T cell responses.


Assuntos
Trifosfato de Adenosina/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Transdução de Sinais/fisiologia , Células Th17/metabolismo , Animais , Diferenciação Celular/fisiologia , Linhagem Celular , Proliferação de Células/fisiologia , Feminino , Regulação Neoplásica da Expressão Gênica/fisiologia , Glucose/metabolismo , Doença de Depósito de Glicogênio/metabolismo , Glicólise/fisiologia , L-Lactato Desidrogenase/deficiência , L-Lactato Desidrogenase/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos
16.
Food Funct ; 12(9): 4117-4131, 2021 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-33977940

RESUMO

The hypoglycemic effects and potential mechanism of sweet potato leaf polyphenols (SPLP) on type 2 diabetes mellitus (T2DM) were investigated. Results showed that oral administration of SPLP to mice could alleviate body weight loss, decrease fasting blood glucose levels (by 64.78%) and improve oral glucose tolerance compared with those of untreated diabetic mice. Furthermore, increased fasting serum insulin levels (by 100.11%), ameliorated insulin resistance and improved hepatic glycogen (by 126.78%) and muscle glycogen (increased by 135.85%) were observed in the SPLP treatment group. SPLP also could reverse dyslipidemia, as indicated by decreased total cholesterol, triglycerides, low density lipoprotein-cholesterol and promoted high density lipoprotein-cholesterol. Histopathological analysis revealed that SPLP could relieve liver inflammation and maintain the islet structure to inhibit ß-cell apoptosis. A quantitative real-time polymerase chain reaction confirmed that SPLP could up-regulate the phosphatidylinositol 3-kinase/protein kinase B/glycogen synthase kinase-3ß signaling pathway to improve glucose metabolism and up-regulate the phosphatidylinositol 3-kinase/protein kinase B/glucose transporter 4 signaling pathway in the skeletal muscle to enhance glucose transport. This study provides useful information to support the application of SPLP as a natural product for the treatment of T2DM.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Hiperglicemia/tratamento farmacológico , Hipoglicemiantes/farmacologia , Ipomoea batatas/química , Polifenóis/farmacologia , Animais , Glicemia/análise , Peso Corporal/efeitos dos fármacos , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/patologia , Ingestão de Alimentos/efeitos dos fármacos , Transportador de Glucose Tipo 4/metabolismo , Glicogênio/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Insulina/sangue , Ilhotas Pancreáticas/patologia , Lipídeos/sangue , Fígado/patologia , Glicogênio Hepático/metabolismo , Masculino , Camundongos , Pâncreas/patologia , Fosfatidilinositol 3-Quinase/metabolismo , Folhas de Planta/química , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos
17.
Front Immunol ; 12: 626310, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33815378

RESUMO

Although B cells have been shown to contribute to the pathogenesis of rheumatoid arthritis (RA), the precise role of B cells in RA needs to be explored further. Our previous studies have revealed that adiponectin (AD) is expressed at high levels in inflamed synovial joint tissues, and its expression is closely correlated with progressive bone erosion in patients with RA. In this study, we investigated the possible role of AD in B cell proliferation and differentiation. We found that AD stimulation could induce B cell proliferation and differentiation in cell culture. Notably, local intraarticular injection of AD promoted B cell expansion in joint tissues and exacerbated arthritis in mice with collagen-induced arthritis (CIA). Mechanistically, AD induced the activation of PI3K/Akt1 and STAT3 and promoted the proliferation and differentiation of B cells. Moreover, STAT3 bound to the promoter of the Blimp-1 gene, upregulated Blimp-1 expression at the transcriptional level, and promoted B cell differentiation. Collectively, we observed that AD exacerbated CIA by enhancing B cell proliferation and differentiation mediated by the PI3K/Akt1/STAT3 axis.


Assuntos
Adiponectina/toxicidade , Artrite Experimental/enzimologia , Linfócitos B/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ativação Linfocitária/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fator de Transcrição STAT3/metabolismo , Animais , Artrite Experimental/induzido quimicamente , Artrite Experimental/imunologia , Artrite Experimental/patologia , Linfócitos B/enzimologia , Linfócitos B/imunologia , Colágeno Tipo II , Ativação Enzimática , Masculino , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Fosfatidilinositol 3-Quinase/metabolismo , Fator 1 de Ligação ao Domínio I Regulador Positivo/genética , Fator 1 de Ligação ao Domínio I Regulador Positivo/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Receptores de Adiponectina/agonistas , Receptores de Adiponectina/genética , Receptores de Adiponectina/metabolismo , Fator de Transcrição STAT3/genética , Transdução de Sinais
18.
Mol Immunol ; 135: 170-182, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33901762

RESUMO

The polymeric immunoglobulin receptor (pIgR) transports secretory immunoglobulins across mucosal epithelial cells into external secretions, playing critical roles in mucosal surface defenses, but the regulation mechanism of pIgR expression is not clarified in teleost fish. In this study, the dynamic changes of flounder (Paralichthys olivaceus) pIgR (fpIgR) and pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) mRNA expression in mucosal tissues were first analyzed post inactivated Vibrio anguillarum immunization, and increased production of TNF-α was found to correlate with increased expression of fpIgR. To determine that cytokine TNF-α influenced fpIgR expression, following confirming that natural fpIgR expressed on flounder gill (FG) cells, FG cells were incubated with various concentrations of recombinant TNF-α for different time, the results showed that the expressions of fpIgR were significantly upregulated at gene and protein levels in a dose-dependent and time-dependent manner, and similar change trend was observed for free secretory component (SC) secreted by fpIgR into the culture supernatant. After FG cells were treated with TNF-α, specific phosphoinositide 3-kinase (PI3K) inhibitor wortmannin, nuclear factor kappa-B (NF-κB) inhibitor Bay11-7082, and the mixtures of TNF-α and wortmannin / Bay11-7082 respectively, the fpIgR protein and mRNA levels, together with SC secretion, obviously decreased in wortmannin- and Bay11-7082-treated cells compared with the untreated control, and cotreatment with wortmannin / Bay11-7082 plus TNF-α resulted in lower expression compared with that upon treatment with TNF-α alone, indicating that the inhibition of PI3K and NF-κB both blocked the ability of TNF-α to increase cellular fpIgR and SC levels. Furthermore, the gene expressions of PI3K and NF-κB were upregulated and present a tendency to increase first and then decrease after TNF-α treatment of FG cells; However, the expression of PI3K mRNA was inhibited significantly by wortmannin but not by Bay11-7082, and the expression of NF-κB mRNA was suppressed obviously by Bay11-7082 but not by wortmannin, suggesting that inhibition of PI3K or NF-κB had no influence on each other. All these results collectively revealed that TNF-α could transcriptionally upregulate fpIgR expression and SC production, and this TNF-α-induced pIgR expression was regulated by complex mechanisms that involved PI3K and NF-κB signaling pathways, which provided evidences for pro-inflammatory cytokine TNF-α acting as a regulator in pIgR expression and better understanding of regulation mechanism of pIgR expression in teleost fish.


Assuntos
Regulação da Expressão Gênica/imunologia , NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Receptores de Imunoglobulina Polimérica/imunologia , Fator de Necrose Tumoral alfa/imunologia , Animais , Células Cultivadas , Linguado/imunologia , Brânquias/citologia , Brânquias/imunologia , Imunização , NF-kappa B/antagonistas & inibidores , Nitrilas/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Receptores de Imunoglobulina Polimérica/genética , Transdução de Sinais/imunologia , Sulfonas/farmacologia , Regulação para Cima/genética , Vibrio/imunologia , Wortmanina/farmacologia
19.
PLoS One ; 16(4): e0246264, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33861751

RESUMO

Tamoxifen (TAM) is a selective estrogen receptor modulator used for breast cancer patients. Prolonged use of tamoxifen is not recommended for some patients. In this study, we aimed to identify molecular targets sensitive to TAM using a genome-wide gene deletion library screening of fission yeast heterozygous mutants. From the screening, casein kinase 1 gamma 2 (CSNK1G2), a serine-/threonine protein kinase, was the most sensitive target to TAM with a significant cytotoxicity in estrogen receptor-positive (ER+) breast cancer cells but with only a slight toxicity in the case of ER- cells. In addition, tumor sphere formation and expression of breast stem cell marker genes such as CD44/CD2 were greatly inhibited by CSNK1G2 knockdown in ER+ breast cancer cells. Consistently, CSNK1G2 altered ERα activity via phosphorylation, specifically at serine (Ser)167, as well as the regulation of estrogen-responsive element (ERE) of estrogen-responsive genes such as CTSD and GREB1. However, ERα silencing almost completely blocked CSNK1G2-induced TAM sensitivity. In ER+ breast cancer cells, combined treatment with TAM and CSNK1G2 knockdown further enhanced the TAM-mediated decrease in phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR)/ribosomal protein S6 kinase (S6K) signaling but not extracellular signal-regulated kinase (ERK) signaling. Inversely, in ER- cells treated with TAM, only ERK and PI3K signaling was altered by CSNK1G2 knockdown. The CK1 inhibitor, D4476, partly mimicked the CSNK1G2 knockdown effect in ER+ breast cancer cells, but with a broader repression ranging from PI3K/AKT/mTOR/S6K to ERK signaling. Collectively, these results suggest that CSNK1G2 plays a key role in sensitizing TAM toxicity in ER+ and ER- breast cancer cells via differently regulating PI3K/AKT/mTOR/S6K and ERK signaling.


Assuntos
Antineoplásicos Hormonais/farmacologia , Neoplasias da Mama/tratamento farmacológico , Receptor alfa de Estrogênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Tamoxifeno/farmacologia , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Técnicas de Silenciamento de Genes , Humanos , Células MCF-7 , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Quinases S6 Ribossômicas/metabolismo , Serina-Treonina Quinases TOR/metabolismo
20.
BMC Cancer ; 21(1): 429, 2021 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-33874915

RESUMO

BACKGROUND: Recent evidences had shown that loss in phosphatase and tensin homolog deleted on chromosome 10 (PTEN) was associated with immunotherapy resistance, which may be attributed to the non-T-cell-inflamed tumor microenvironment. The impact of PTEN loss on tumor microenvironment, especially regarding T cell infiltration across tumor types is not well understood. METHODS: Utilizing The Cancer Genome Atlas (TCGA) and publicly available dataset of immunotherapy, we explored the correlation of PTEN expressing level or genomic loss with tumor immune microenvironment and response to immunotherapy. We further investigated the involvement of PI3K-AKT-mTOR pathway activation, which is known to be the subsequent effect of PTEN loss, in the immune microenvironment modulation. RESULTS: We reveal that PTEN mRNA expression is significantly positively correlated with CD4/CD8A gene expression and T cells infiltration especially T helpers cells, central memory T cell and effector memory T cells in multiples tumor types. Genomic loss of PTEN is associated with reduced CD8+ T cells, type 1 T helper cells, and increased type 2 T helper cells, immunosuppressed genes (e.g. VEGFA) expression. Furthermore, T cell exclusive phenotype is also observed in tumor with PI3K pathway activation or genomic gain in PIK3CA or PIK3CB. PTEN loss and PI3K pathway activation correlate with immunosuppressive microenvironment, especially in terms of T cell exclusion. PTEN loss predict poor therapeutic response and worse survival outcome in patients receiving immunotherapy. CONCLUSION: These data brings insight into the role of PTEN loss in T cell exclusion and immunotherapy resistance, and inspires further research on immune modulating strategy to augment immunotherapy.


Assuntos
Neoplasias/etiologia , Neoplasias/metabolismo , PTEN Fosfo-Hidrolase/deficiência , Linfócitos T/imunologia , Linfócitos T/metabolismo , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Bases de Dados Genéticas , Suscetibilidade a Doenças , Expressão Gênica , Genômica/métodos , Humanos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Terapia de Alvo Molecular , Neoplasias/patologia , Neoplasias/terapia , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/patologia , Linfócitos T/patologia , Serina-Treonina Quinases TOR/metabolismo , Evasão Tumoral , Microambiente Tumoral
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