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1.
Nat Commun ; 12(1): 5725, 2021 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-34593796

RESUMO

Although psycho-social stress is a well-known factor that contributes to the development of cancer, it remains largely unclear whether and how environmental eustress influences malignant diseases and regulates cancer-related therapeutic responses. Using an established eustress model, we demonstrate that mice living in an enriched environment (EE) are protected from carcinogen-induced liver neoplasia and transplantable syngeneic liver tumors, owning to a CD8+ T cell-dependent tumor control. We identify a peripheral Neuro-Endocrine-Immune pathway in eustress, including Sympathetic nervous system (SNS)/ß-adrenergic receptors (ß-ARs)/CCL2 that relieves tumor immunosuppression and overcomes PD-L1 resistance to immunotherapy. Notably, EE activates peripheral SNS and ß-ARs signaling in tumor cells and tumor infiltrated myeloid cells, leading to suppression of CCL2 expression and activation of anti-tumor immunity. Either blockade of CCL2/CCR2 or ß-AR signaling in EE mice lose the tumor protection capability. Our study reveales that environmental eustress via EE stimulates anti-tumor immunity, resulting in more efficient tumor control and a better outcome of immunotherapy.


Assuntos
Resistencia a Medicamentos Antineoplásicos/imunologia , Inibidores de Checkpoint Imunológico/farmacologia , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Neuroimunomodulação , Estresse Psicológico/imunologia , Animais , Antígeno B7-H1/antagonistas & inibidores , Tetracloreto de Carbono/administração & dosagem , Tetracloreto de Carbono/toxicidade , Quimiocina CCL2/antagonistas & inibidores , Quimiocina CCL2/metabolismo , Dietilnitrosamina/administração & dosagem , Dietilnitrosamina/toxicidade , Células Estreladas do Fígado , Hepatócitos , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Fígado/efeitos dos fármacos , Fígado/imunologia , Fígado/patologia , Neoplasias Hepáticas Experimentais/induzido quimicamente , Neoplasias Hepáticas Experimentais/imunologia , Neoplasias Hepáticas Experimentais/patologia , Masculino , Camundongos , Organoides , Receptores Adrenérgicos beta/metabolismo , Receptores CCR2/antagonistas & inibidores , Receptores CCR2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Sistema Nervoso Simpático/imunologia , Evasão Tumoral , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
2.
Molecules ; 26(14)2021 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-34299510

RESUMO

Cratoxylum formosum ssp. pruniflorum (Kurz) Gogelein (CP) is an indigenous plant found mainly in southeast Asia. Several in vitro studies have confirmed its activity against hepatocellular carcinoma; however, in vivo studies of the effect of CP on liver cancer are needed. This study investigated the effect of CP on early-stage hepatocarcinogenesis in rat liver when using diethylnitrosamine (DEN) as a carcinogen. Immunohistochemistry was used to detect (a) upregulation of glutathione S-transferase placental (GST-P) positive foci, (b) the proliferating cell nuclear antigen PCNA, and (c) apoptotic cells in the liver as indicators of early-stage carcinogenesis. Immunohistochemical parameters were observed in rats given CP orally following DEN injection. Rats given DEN presented overexpression of GST-P positive foci, PCNA, and apoptotic cells, indicating the formation of cancerous tissues, and these effects were diminished by CP treatment. CP thus inhibited hepatocarcinogenic effects in an animal model. These results could help plan further in vivo studies and support the use of CP to prevent processes that promote the pathogenesis of hepatocellular carcinoma in humans.


Assuntos
Anticarcinógenos/farmacologia , Carcinogênese/efeitos dos fármacos , Carcinoma Hepatocelular/tratamento farmacológico , Clusiaceae/química , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Fígado/efeitos dos fármacos , Animais , Carcinógenos/farmacologia , Carcinoma Hepatocelular/induzido quimicamente , Carcinoma Hepatocelular/metabolismo , Dietilnitrosamina/farmacologia , Glutationa Transferase/metabolismo , Fígado/metabolismo , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas Experimentais/induzido quimicamente , Neoplasias Hepáticas Experimentais/metabolismo , Masculino , Antígeno Nuclear de Célula em Proliferação/metabolismo , Ratos , Ratos Wistar
3.
Molecules ; 26(9)2021 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-34063148

RESUMO

This study aimed to evaluate the cancer chemopreventive activity of vanillic acid (VA) in diethylnitrosamine- and 1,2-dimethylhydrazine-induced liver and colon carcinogenesis in rats. VA did not induce the formation of hepatic glutathione S-transferase placental form (GST-P) positive foci and colonic aberrant crypt foci, demonstrating no carcinogenic activity. VA (75 mg kg-1 body weight) could significantly reduce the number and areas of hepatic GST-P positive foci when administered before carcinogen injections, but no such effect was seen when it was administered after carcinogen injection. No protection was seen in the colon when VA was treated before or after carcinogen injection. Immunohistochemical studies demonstrated the decreased expression of proliferating cell nuclear antigen and the induction of apoptosis. Mechanistic studies showed that VA significantly induced the expression of GSTA-5 and Nrf-2 genes, which are associated with the detoxification system. Likewise, the antiproliferative effect was noticed by the reduction of Cyclin D1 expression. The apoptotic activity may be due to the upregulation of Caspase-3 and Bad levels and downregulation of the Bcl-2 level. These data suggest that VA exhibited significant protection against diethylnitrosamine- and 1,2-dimethylhydrazine-induced hepatocarcinogenesis, which might be related to the induction of the detoxifying enzyme, the reduction of proliferation and the induction of apoptosis.


Assuntos
Carcinogênese/patologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Substâncias Protetoras/uso terapêutico , Ácido Vanílico/uso terapêutico , 1,2-Dimetilidrazina , Alanina Transaminase/sangue , Animais , Apoptose/efeitos dos fármacos , Aspartato Aminotransferases/sangue , Carcinogênese/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Dietilnitrosamina , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/genética , Masculino , Tamanho do Órgão/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Ratos Wistar , Ácido Vanílico/química , Ácido Vanílico/farmacologia
4.
J Pharm Biomed Anal ; 202: 114132, 2021 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-34000519

RESUMO

N-nitrosodiethanolamine (NDELA) is a carcinogenic contaminant of concern in the cosmetics industry. Contaminated raw material, degradation, reactions of ingredients of the formulation, or migration of packaging material can be responsible for the presence of NDELA in the final product. Liquid chromatography coupled to tandem mass spectrometry is the most widely accepted technique for the quantitation of NDELA in cosmetic products. Still, there is no consensus regarding the sample preparation procedure. The aim of this work was to evaluate the performance of two-dimensional liquid chromatography coupled with tandem mass spectrometry for the determination of NDELA in shampoo. In the first dimension an Oasis HLB SPE-column was used and in the second dimension a CSH C18 column. NDELA-d8 was used as an internal standard. The 2D-LC parameters were optimized by a central composite multivariate design. However, before quantitation, a sample preparation step using solid-phase extraction was necessary to eliminate compounds present in the formulation, especially surfactants that were not compatible with the chromatographic columns. Moreover, the complex matrices and singular compositions of shampoo from different manufacturers required adjustments of the sample preparation procedure for each sample. The limit of quantitation of the method for the determination of NDELA in shampoo was in the range of 5-10 ng g-1. The accuracy of the method at the LOQ (10 ng g-1) was 114 % and the inter-day precision of 15.3 % (n = 9). One sample out of 12 presented an NDELA concentration of 54 ng g-1.


Assuntos
Dietilnitrosamina , Espectrometria de Massas em Tandem , Cromatografia Líquida de Alta Pressão , Dietilnitrosamina/análogos & derivados , Extração em Fase Sólida
5.
Biomed Pharmacother ; 139: 111636, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33957566

RESUMO

This study was designed to reveal the protective effects of dietary supplementation of curcumin against renal cell tumours and oxidative stress induced by renal carcinogen iron nitrilotriacetate (Fe-NTA) in ddY male mice. The results showed that mice treated with a renal carcinogen, Fe-NTA, a 35% renal cell tumour incidence was noticed, whereas renal cell tumour occurrence was elevated to 80% in Fe-NTA promoted and N-diethylnitrosamine (DEN)-initiated mice as compared with saline- treated mice. No incidence of tumours has been observed in DEN-initiated non-promoted mice. Diet complemented with 0.5% and 1.0% curcumin fed prior to, during and after treatment with Fe-NTA in DEN-initiated animals, tumour incidence was reduced dose-dependently to about 45% and 30% respectively. Immunohistochemical studies also revealed the increased formation of 4-hydroxy-2-nonenal (HNE)-modified protein adducts and 8-hydroxy-2'-deoxyguanosine (8-OHdG) in kidney tissue of mice treated with an intraperitoneal injection of Fe-NTA (6.0 mg Fe/kg body weight.). Furthermore, Fe-NTA treatment of mice also resulted in significant elevation of malondialdehyde (MDA), serum urea, and creatinine and decreases renal glutathione. However, the changes in most of these parameters were attenuated dose-dependently by prophylactic treatment of animals with 0.5% and 1% curcumin diet, this may be due to its antioxidative impact of curcumin. These results suggest that intake of curcumin is beneficial for the prevention of renal cell tumours and oxidative stress damage mediated by renal carcinogen, Fe-NTA.


Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Antioxidantes/uso terapêutico , Carcinoma de Células Renais/induzido quimicamente , Carcinoma de Células Renais/tratamento farmacológico , Curcumina/uso terapêutico , Neoplasias Renais/induzido quimicamente , Neoplasias Renais/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , 8-Hidroxi-2'-Desoxiguanosina , Aldeídos , Animais , Anticarcinógenos/farmacologia , Nitrogênio da Ureia Sanguínea , Carcinógenos , Creatinina/sangue , Dieta , Dietilnitrosamina , Relação Dose-Resposta a Droga , Compostos Férricos , Masculino , Camundongos , Ácido Nitrilotriacético/análogos & derivados
6.
World J Gastroenterol ; 27(14): 1435-1450, 2021 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-33911466

RESUMO

BACKGROUND: Cyanidin-3-O-glucoside (cyan) exhibits antioxidant and anticancer properties. The cell cycle proteins and antimitotic drugs might be promising therapeutic targets in hepatocellular carcinoma. AIM: To investigate the effect of cyan administration on cell cycle in hepatic precancerous lesion (PCL) induced by diethylnitrosamine/2-acetylaminofluorene (DEN/2-AAF) in Wistar rats. METHODS: In vivo, DEN/2-AAF-induced hepatic PCL, rats were treated with three doses of cyan (10, 15, and 20 mg/kg/d, for four consecutive days per week for 16 wk). Blood and liver tissue samples were collected for measurement of the followings; alpha fetoprotein (AFP) liver function and RNA panel differential expression was evaluated via real time polymerase chain reaction. Histopathological examination of liver sections stained with H&E and immunohistochemical study using glutathione S-transferase placental (GSTP) and proliferating cell nuclear antigen (PCNA) antibodies were assessed. RESULTS: Cyan administration mitigated the effect of DEN/2-AFF induced PCL, decreased AFP levels, and improved liver function. Remarkably, treatment with cyan dose dependently decreased the long non-coding RNA MALAT1 and tubulin gamma 1 mRNA expressions and increased the levels of miR-125b, all of which are involved in cell cycle and mitotic spindle assembly. Of note, cyan decreased GSTP foci percent area and PCNA positively stained nuclei. CONCLUSION: Our results indicated that cyan could be used as a potential therapeutic agent to inhibit liver carcinogenesis in rat model via modulation of cell cycle.


Assuntos
Neoplasias Hepáticas Experimentais , Neoplasias Hepáticas , Lesões Pré-Cancerosas , Animais , Antocianinas , Dietilnitrosamina/toxicidade , Feminino , Glucosídeos/farmacologia , Glutationa Transferase , Fígado , Neoplasias Hepáticas Experimentais/induzido quimicamente , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Lesões Pré-Cancerosas/induzido quimicamente , Lesões Pré-Cancerosas/tratamento farmacológico , Gravidez , Ratos , Ratos Wistar
7.
Environ Sci Pollut Res Int ; 28(32): 43515-43527, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33834342

RESUMO

The study examines the prophylactic action of artichoke leaf hydroethanolic extract (ALE) and artichoke flower head hydroethanolic extract (AFE) against diethylnitrosamine (DEN)/acetylaminofluorene (AAF)-induced lung cancer in Wistar rats. To chemically induce lung cancer, DEN was injected intraperitoneally twice a week for a fortnight at a dose of 150 mg/kg body weight (b.w.), followed by oral supplementation of AAF four times a week for 3 weeks at a dose of 20 mg/kg b.w. The DEN/AAF-administered rats were orally supplemented with ALE or AFE at a dose of 100 mg/kg b.w. for 17 weeks starting from the 1st week of DEN injection to the 17th week of the experiment. The lung cancerous injuries resulting from DEN/AAF-administration were significantly improved by the treatment with ALE and AFE as observed in histological examination. In addition, there was a significant reduction in lung lipid peroxidation, with resultant elevation in antioxidant enzymatic activity of glutathione-S-transferase, glutathione peroxidase, glutathione reductase, and superoxide dismutase as well as glutathione content in DEN/AAF-supplemented rats treated with ALE and AFE as compared to DEN/AAF-administered control. The lung tumor suppressor protein (p53) and B-cell lymphoma-2 (Bcl-2) mRNA expression significantly increased in the rats treated with ALE and AFE. In conclusion, the finding showed that ALE and AFE produced anti-cancer prophylactic effects against DEN/AAF-induced lung cancer in rats via suppression of oxidative stress and improved apoptotic signal induction.


Assuntos
Cynara scolymus , Neoplasias Pulmonares , Animais , Dietilnitrosamina/toxicidade , Flores , Fígado/metabolismo , Neoplasias Pulmonares/induzido quimicamente , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/prevenção & controle , Estresse Oxidativo , Extratos Vegetais/metabolismo , Folhas de Planta , Ratos , Ratos Wistar
8.
Arh Hig Rada Toksikol ; 72(1): 1-5, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33787187

RESUMO

In 2018, some sartan medicinal products were reported to be contaminated with nitrosamine compounds, which are potent mutagenic carcinogens. Two nitrosamines received particular attention: N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA). These have since been confirmed in different types of medicinal products, including ranitidine and metformin. Consequently, the European Medicines Agency (EMA) started an investigation into the cause of contamination and an assessment of the risk to patients taking contaminated medicinal products. The main source of contamination were changes in production, which involves combinations of amines and nitrogen compounds and the use of specific catalysts and reagents. Withdrawals of medicinal products that took place in Croatia did not lead to a shortage of sartan- or metformin-containing medicines. Moreover, ranitidine had been preventively withdrawn all over the EU, including Croatia, creating shortages at the time, but was subsequently replaced with therapeutic alternatives.


Assuntos
Nitrosaminas , Carcinógenos , Dietilnitrosamina , Dimetilnitrosamina , Contaminação de Medicamentos , Humanos
9.
Mol Carcinog ; 60(6): 377-390, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33765333

RESUMO

The potential role of hepatocytes versus hepatic progenitor cells (HPC) on the onset and pathogenesis of hepatocellular carcinoma (HCC) has not been fully clarified. Because the administration of 2-acetylaminofluorene (2AAF) followed by a partial hepatectomy, selectively induces the HPC proliferation, we investigated the effects of chronic 2AAF administration on the HCC development caused by the chronic administration of the carcinogen diethylnitrosamine (DEN) for 16 weeks in the rat. DEN + 2AAF protocol impeded weight gain of animals but promoted prominent hepatomegaly and exacerbated liver alterations compared to DEN protocol alone. The tumor areas detected by γ-glutamyl transferase, prostaglandin reductase-1, and glutathione S-transferase Pi-1 liver cancer markers increased up to 80% as early as 12 weeks of treatment, meaning 6 weeks earlier than DEN alone. This protocol also increased the number of Ki67-positive cells and those of CD90 and CK19, two well-known progenitor cell markers. Interestingly, microarray analysis revealed that DEN + 2AAF protocol differentially modified the global gene expression signature and induced the differential expression of 30 genes identified as HPC markers as early as 6 weeks of treatment. In conclusion, 2AAF induces the early appearance of HPC markers and as a result, accelerates the hepatocarcinogenesis induced by DEN in the rat. Thus, since 2AAF simultaneously administrated with DEN enriches HPC during hepatocarcinogenesis, we propose that DEN + 2AAF protocol might be a useful tool to investigate the cellular origin of HCC with progenitor features.


Assuntos
2-Acetilaminofluoreno/toxicidade , Carcinoma Hepatocelular/induzido quimicamente , Dietilnitrosamina/toxicidade , Neoplasias Hepáticas/induzido quimicamente , Células-Tronco/efeitos dos fármacos , Animais , Carcinógenos/toxicidade , Carcinoma Hepatocelular/patologia , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Hepatomegalia/induzido quimicamente , Hepatomegalia/patologia , Neoplasias Hepáticas/patologia , Masculino , Ratos Endogâmicos F344 , Células-Tronco/patologia , Fator de Crescimento Transformador beta1/genética
10.
Theranostics ; 11(10): 4743-4758, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33754025

RESUMO

Aims: Emerging evidence is demonstrating that rapid regeneration of remnant liver elicited by associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) may be attenuated in fibrotic livers. However, the molecular mechanisms responsible for this process are largely unknown. It is widely acknowledged that the TGFß1 signaling axis plays a major role in liver fibrosis. Therefore, the aims of this study were to elucidate the underlying mechanism of liver regeneration during ALPPS with or without fibrosis, specifically focusing on TGFß1 signaling. Approach: ALPPS was performed in rat models with N-diethylnitrosamine-induced liver fibrosis and no fibrosis. Functional liver remnant regeneration and expression of TGFß1 were analyzed during the ALPPS procedures. Adeno-associated virus-shTGFß1 and the small molecule inhibitor LY2157299 (galunisertib) were used separately or in combination to inhibit TGFß1 signaling in fibrotic rats. Results: Liver regeneration following ALPPS was lower in fibrotic rats than non-fibrotic rats. TGFß1 was a key mediator of postoperative regeneration in fibrotic liver. Interestingly, AAV-shTGFß1 accelerated the regeneration of fibrotic functional liver remnant and improved fibrosis, while LY2157299 only enhanced liver regeneration. Moreover, combination treatment elicited a stronger effect. Conclusions: Inhibition of TGFß1 accelerated regeneration of fibrotic liver, ameliorated liver fibrosis, and improved liver function following ALPPS. Therefore, TGFß1 is a promising therapeutic target in ALPPS to improve fibrotic liver reserve function and prognosis.


Assuntos
Hepatectomia/métodos , Hepatócitos/metabolismo , Cirrose Hepática/metabolismo , Regeneração Hepática/fisiologia , Fígado/fisiologia , Fator de Crescimento Transformador beta1/metabolismo , Animais , Tetracloreto de Carbono/toxicidade , Dietilnitrosamina/toxicidade , Células Estreladas do Fígado/metabolismo , Ligadura , Fígado/efeitos dos fármacos , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/patologia , Regeneração Hepática/efeitos dos fármacos , Veia Porta/cirurgia , Cultura Primária de Células , Pirazóis/farmacologia , Quinolinas/farmacologia , Ratos , Transdução de Sinais , Fator de Crescimento Transformador beta1/antagonistas & inibidores
11.
Mediators Inflamm ; 2021: 6661937, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33531877

RESUMO

Diethylnitrosamine (DEN) is a well-known hepatocarcinogen, and its oral administration causes severe liver damage including cancer. DEN induces the pathogenesis of the liver through reactive oxygen species mediated inflammation and modulation of various biological activities. 6-Gingerol, a major component of ginger, is reported to prevent liver diseases by reducing the oxidative stress and proinflammatory mediators. The present study investigated the hepatoprotective effects of 6-gingerol through the measurement of oxidative stress, anti-inflammatory markers, liver function enzyme parameter, and histopathological analysis. The rats were randomly divided into four groups as the control, DEN treated (50 mg/kg b.w.), DEN+6-gingerol (each 50 mg/kg b.w.), and 6-gingerol only. To evaluate the hepatoprotective effects, liver function enzymes (ALT, AST, and ALP), oxidative stress markers (SOD, GSH, GST, and TAC), lipid peroxidation, inflammatory markers (CRP, TNF-α, IL-6, and ICAM1), haematoxylin and eosin staining, Sirius red staining, immunohistochemistry, and electron microscopy were performed. The results showed a significant increase in liver function enzymes, oxidative stress, and inflammatory markers in the DEN-treated group as compared to the control group. Besides this, altered architecture of hepatocytes (infiltration of inflammatory cells, congestion, blood vessel dilation, and edema), abundant collagen fiber and organelle structures like distorted shaped and swollen mitochondria, and broken endoplasmic reticulum were noticed. The administration of 6-gingerol significantly ameliorated the biochemical and histopathological changes. The increased expression of TNF-α protein was noticed in the DEN-treated group whereas the administration of 6-gingerol significantly decreased the expression of this protein. Based on these findings, it can be suggested that 6-gingerol may be an alternative therapy for the prevention and treatment of liver diseases.


Assuntos
Anti-Inflamatórios/farmacologia , Catecóis/farmacologia , Doença Hepática Crônica Induzida por Substâncias e Drogas/tratamento farmacológico , Dietilnitrosamina , Álcoois Graxos/farmacologia , Gengibre/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Albuminas/química , Animais , Compostos de Bifenilo , Sequestradores de Radicais Livres , Radicais Livres , Glutationa/metabolismo , Peróxido de Hidrogênio , Técnicas In Vitro , Inflamação/tratamento farmacológico , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Mitocôndrias/metabolismo , Picratos , Ratos
12.
Biomed Pharmacother ; 137: 111335, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33581648

RESUMO

Liver cancer is a critical clinical condition with augmented malignancy, rapid progression, and poor prognosis. Liver cancer often initiates as fibrosis, develops as cirrhosis, and results in cancer. For centuries, medicinal plants have been incorporated in various liver-associated complications, and recently, research has recognized that many bioactive compounds from medicinal plants may interact with targets related to liver disorders. Phyllanthin from the Phyllanthus species is one such compound extensively used by folklore practitioners for various health benefits. However, most practices continue to be unrecognized scientifically. Hence, in this work, we investigated the protective role of phyllanthin on diethylnitrosamine (DEN) induced liver carcinoma in Wistar Albino rats and the anti-tumor potential on human hepatocellular carcinoma (HCC) HepG2 cells. The DEN-challenged liver cancer in experimental rats caused increased liver weight, 8-OHD, hepatic tissue injury marker, lipid peroxidation, and tumor markers levels. Remarkably, phyllanthin counteracted the DEN effect by ameliorating all the liver function enzymes, oxidative DNA damage, and tumor-specific markers by enhanced anti-oxidant capacity and induced caspase-dependent apoptosis through the mTOR/ PI3K signaling pathway. MTT assay demonstrated that phyllanthin inhibited the HepG2 cell growth in a dose-dependent manner. Fascinatingly, phyllanthin did not demonstrate any substantial effect on the normal cell line, HL7702. In addition, HepG2 cells were found in the late apoptotic stage upon treatment with phyllanthin as depicted by acridine orange/ethidium bromide staining. Overall, this work offers scientific justification that phyllanthin can be claimed to be a safe candidate with potential chemotherapeutic activity against HCC.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Lignanas/farmacologia , Neoplasias Hepáticas/prevenção & controle , 8-Hidroxi-2'-Desoxiguanosina/metabolismo , Animais , Antineoplásicos Fitogênicos/uso terapêutico , Antioxidantes/uso terapêutico , Apoptose/genética , Biomarcadores Tumorais/metabolismo , Peso Corporal/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Dietilnitrosamina/toxicidade , Modelos Animais de Doenças , Células Hep G2 , Humanos , Lignanas/uso terapêutico , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Fosfatidilinositol 3-Quinase/efeitos dos fármacos , Fosfatidilinositol 3-Quinase/genética , Proteínas Proto-Oncogênicas c-akt/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/genética , Ratos Wistar , Serina-Treonina Quinases TOR/efeitos dos fármacos , Serina-Treonina Quinases TOR/genética
13.
Eur Rev Med Pharmacol Sci ; 25(2): 710-721, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33577025

RESUMO

OBJECTIVE: To study the association of inflammatory factors and hepatocarcinoma stem cells of induced liver cancer rats. MATERIALS AND METHODS: 30 SD male healthy rats were selected. 10 rats were given water as normal control group. 10 rats only were implemented laparotomy as sham operation group. The remaining 10 rats were the liver cancer model group and treated with diethylnitrosamine (DEN) to induce liver cancer. Real-time quantitative PCR was used to detect the related inflammatory factors in HCC tissues, including interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), transforming growth factor-ß1 (TGF-ß), human interleukin-1α (IL-1α), human interleukin 1ß (IL-1ß) and levels of hepatocarcinoma stem cells indicators CD90, CD133, Alpha-fetoprotein (AFP). Correlation analysis was used to analyze the correlation between inflammatory factors and hepatocarcinoma stem cells markers CD90 and CD133. RESULTS: The expression levels of IL-6, MCP-1 and TGF-ß of HCC tissues in liver cancer model group were significantly higher than those in the control group and the sham operation group. The expression levels of CD90 and CD133 of tissues in the liver cancer model group were significantly higher than those in the control group and the sham operation group. The differences were statistically significant (p<0.001). By inhibiting related inflammatory factors, the growth, migration and invasion of liver cancer cells were significantly inhibited, and apoptosis was promoted. Correlation analysis results showed that the expression changes of IL-6, MCP-1 and TGF-ß were significantly positively correlated with CD90 up-regulation (p<0.05), while the expression changes of IL-6, MCP-1 and TGF-ß were significantly positively correlated with CD133 up-regulation (p<0.05). CONCLUSIONS: The inflammatory factors IL-6, MCP-1 and TGF-ß are closely related to hepatocarcinoma stem cells, which play an important role in promoting the occurrence and deterioration of liver cancer.


Assuntos
Biomarcadores Tumorais/genética , Quimiocina CCL2/genética , Interleucina-6/genética , Neoplasias Hepáticas/metabolismo , Células-Tronco Neoplásicas/metabolismo , Fator de Crescimento Transformador beta1/genética , Administração Oral , Animais , Apoptose , Biomarcadores Tumorais/metabolismo , Proliferação de Células , Quimiocina CCL2/metabolismo , Dietilnitrosamina/administração & dosagem , Modelos Animais de Doenças , Interleucina-6/metabolismo , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas/patologia , Masculino , Células-Tronco Neoplásicas/patologia , Ratos , Ratos Sprague-Dawley , Fator de Crescimento Transformador beta1/metabolismo
14.
Phytother Res ; 35(6): 3365-3376, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33624311

RESUMO

Morus nigra is a rich source of anthocyanins, phytochemicals that have anticancer effects. This study aimed to investigate the effects of M. nigra extract (MNE) on diethylnitrosamine (DEN)-induced hepatocellular carcinoma (HCC). Male Sprague-Dawley rats were assigned into four groups (n = 10): control, DEN, and DEN +100 or 400 mg/kg of MNE. After 4 months, the DEN group showed a significant mortality rate, hepatic lipid peroxidation, dysplastic nodules in the cirrhotic liver, and an increase of blood bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP). Also, the body weight gain, blood albumin and glucose, liver antioxidant capacity (thiol groups), and some hematological parameters (RBC, hematocrit, hemoglobin, and platelet) were significantly decreased in the DEN group. MNE significantly increased survival, reduced the size of HCC nodules, improved liver oxidant/antioxidant status, and prevented the above-mentioned changes in the blood (except ALP, glucose, and platelet). Quantitative real-time PCR showed that MNE decreased the expression of Wnt4 and ß-catenin, while had no significant effect on PI3K, Akt, and PTEN expression. The MNE did not exhibit antiproliferative activity against HepG2 liver cancer cells. In conclusion, MNE exhibits a hepatoprotective effect through inhibiting oxidative stress and Wnt4/ß-catenin pathway and therefore prolongs the survival of rats with HCC.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Morus/química , Extratos Vegetais/farmacologia , Alanina Transaminase/sangue , Animais , Antioxidantes/metabolismo , Aspartato Aminotransferases/sangue , Bilirrubina/sangue , Carcinoma Hepatocelular/patologia , Dietilnitrosamina/efeitos adversos , Células Hep G2 , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Neoplasias Hepáticas/patologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
15.
Nat Commun ; 12(1): 645, 2021 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-33510150

RESUMO

Hepatocellular carcinoma (HCC) is the most predominant primary malignancy in the liver. Genotoxic and genetic models have revealed that HCC cells are derived from hepatocytes, but where the critical region for tumor foci emergence is and how this transformation occurs are still unclear. Here, hyperpolyploidization of hepatocytes around the centrilobular (CL) region is demonstrated to be closely linked with the development of HCC cells after diethylnitrosamine treatment. We identify the CL region as a dominant lobule for accumulation of hyperpolyploid hepatocytes and preneoplastic tumor foci formation. We also demonstrate that upregulation of Aurkb plays a critical role in promoting hyperpolyploidization. Increase of AURKB phosphorylation is detected on the midbody during cytokinesis, causing abscission failure and hyperpolyploidization. Pharmacological inhibition of AURKB dramatically reduces nucleus size and tumor foci number surrounding the CL region in diethylnitrosamine-treated liver. Our work reveals an intimate molecular link between pathological hyperpolyploidy of CL hepatocytes and transformation into HCC cells.


Assuntos
Carcinoma Hepatocelular/genética , Transformação Celular Neoplásica/genética , Hepatócitos/metabolismo , Neoplasias Hepáticas/genética , Fígado/metabolismo , Poliploidia , Lesões Pré-Cancerosas/genética , Animais , Carcinoma Hepatocelular/induzido quimicamente , Carcinoma Hepatocelular/metabolismo , Transformação Celular Neoplásica/induzido quimicamente , Transformação Celular Neoplásica/metabolismo , Células Cultivadas , Dietilnitrosamina/toxicidade , Feminino , Hepatócitos/efeitos dos fármacos , Humanos , Fígado/efeitos dos fármacos , Fígado/patologia , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Microscopia Confocal , Lesões Pré-Cancerosas/induzido quimicamente , Lesões Pré-Cancerosas/metabolismo
16.
Food Funct ; 12(3): 1063-1078, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33443517

RESUMO

According to population-based studies, lung cancer has become one of the leading causes of death globally in males and is also rising in females at an alarming rate. The aim of this study was to exploit the inherent properties of eugenol to restrict the growth of cancer cells in a tobacco-related human carcinogen NDEA-induced lung carcinogenesis model in vivo as a chemopreventive agent. More precisely, by utilizing its abundance in nature, eugenol (a component of clove) was utilized to establish the molecular mechanism of chemoprevention in the NDEA-induced mouse lung carcinogenesis model in a substantial cost-effective manner and was validated in the A549 human lung cancer cell line. Our study especially targeted the tiny, drug-resistant, and most virulent subpopulation of cancer cells called CSCs by targeting their regulator molecule ß-catenin. The non-toxic dosage of eugenol was shown to enhance apoptosis, simultaneously suppressing cell proliferation in the lung tissue of carcinogen-treated mice without affecting the normal mice. Combining cellular apoptosis and proliferation, eugenol showed an exceptional chemopreventive potential in this lung carcinogenesis model. Importantly, eugenol strongly restricted the lung carcinoma in the mild dysplastic stage as a chemopreventive agent. The molecular analysis remarkably depicted the restriction of ß-catenin nuclear transportation. The minimized total ß-catenin pool and induced N-terminal Ser37 phosphorylation form after eugenol treatment resulted in its cytoplasmic degradation. Consequently, CSC markers such as CD44, Oct4, EpCAM, and Notcht1, whose expression is dependent on ß-catenin decreased significantly, as proven by IHC, ICC, and WB analysis both in vivo and in vitro. The in vitro secondary sphere formation assay also proved the remarkably repressed CSC population, and hence the virulence. In another way, eugenol was proven to significantly enhance the degradation of ß-catenin when treated with the CK1α inhibitor D4476 in vitro by Western blot. CK1α in the Wnt/ß-catenin pathway plays a crucial role for tagging with the N-terminal Ser45 phosphorylation of ß-catenin, which ultimately opens a position for the decisive phosphorylation by GSK3ß at the Ser37 residue to take place. Thus, the conclusive extermination of CSCs achieved that was associated with recurrence due to treatment failure. That can help to achieve a longer and better quality of life in a natural, economical way.


Assuntos
Eugenol/farmacologia , beta Catenina/metabolismo , Células A549 , Animais , Apoptose , Dietilnitrosamina/toxicidade , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/induzido quimicamente , Neoplasias Pulmonares/tratamento farmacológico , Camundongos , Neoplasias Experimentais/induzido quimicamente , Neoplasias Experimentais/tratamento farmacológico , beta Catenina/genética
17.
Mol Biol Rep ; 48(1): 551-562, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33393006

RESUMO

Recently, our group showed that Romidepsin, a histone deacetylase inhibitor (HDACi), suppressed diethylnitrosamine (DEN)-induced hepatocellular carcinoma (HCC) in mice. In the present study, we investigated the effect of Romidepsin-treatment on gene expression levels of components of Bmp and Notch signaling pathways, which are both known to be aberrantly regulated in hepatocarcinogenesis. Total RNA from liver tissue samples and paraffin-embedded livers were retrieved from a recent experiment where C57BL/6 mice were treated with Romidepsin 10 months after DEN challenge and sacrificed 2 months later. RT qPCR was used for quantification of gene expression and immunohistochemistry for in situ protein detection. Regarding Bmp pathway, Romidepsin HCC-suppression was found to correlate significantly with Bmp2 and Bmp7 ligand up- and down-regulation, respectively. Intracellularly, Romidepsin-treated HCC mice exhibited a significant elevation of Bmp-inhibitor Smurf2 and Bmp-target gene Id3, as compared to the HCC untreated controls. Concerning Notch signaling, higher expression levels of ligands Jag1/Dll4, accompanied by a decreased expression of receptor Notch2, were identified in the Romidepsin-treated group. Τhe anti-oncogenic effect of Romidepsin, also correlated significantly with an increased expression of Hes1 target, as well as an up- and down-regulation of Klf4 and Sox9 transcription factors, respectively. Moreover, the cancer-related genes Snai2 and p21, known to be involved in many signaling pathways, including Bmp and Notch, were also found to be downregulated in Romidepsin-treated mice. Romidepsin HCC suppression is associated with gene expression deregulation of selective components of both Bmp and Notch signaling cascades.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Depsipeptídeos/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Animais , Proteína Morfogenética Óssea 2/genética , Proteína Morfogenética Óssea 7/genética , Carcinoma Hepatocelular/induzido quimicamente , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dietilnitrosamina/toxicidade , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Endogâmicos C57BL , Receptor Notch2/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
18.
Molecules ; 26(2)2021 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-33445792

RESUMO

This study investigated the cancer chemopreventive effects of an acidic methanol extract of purple rice husk on chemically induced carcinogenesis in rats. This purple rice husk extract (PRHE) had high polyphenol contents. Vanillic acid was a major phenolic compound in PRHE. Three major anthocyanins found in PRHE were malvidin-3-glucoside, peonidin-3-glucoside and cyanidin-3-glucoside. PRHE was not toxic and clastogenic in rats. The LD50 of PRHE was greater than 2000 mg kg-1 body weight (BW). The oral administration of 300 or 1000 mg kg-1 BW of PRHE for 28 days significantly decreased the number of micronucleated hepatocytes in diethylnitrosamine-initiated rats. The inhibitory mechanisms were associated with the reduction of cytochrome P450 2E1 expression and induction of some detoxifying enzymes in the liver. In addition, treatment with 500 mg kg-1 BW of PRHE for eight weeks did not induce preneoplastic lesions in the liver and colon. It significantly inhibited hepatic glutathione-S-transferase positive foci formation induced by diethylnitrosamine and 1,2-dimethylhydrazine by suppression of hepatocyte proliferation and induction of apoptosis. In conclusion, PRHE did not present toxicity, clastogenicity or carcinogenicity in rats. It exhibited cancer chemopreventive properties against chemically induced early stages rat hepatocarcinogenesis. Anthocyanins and vanillic acid might be candidate anticarcinogenic compounds in purple rice husk.


Assuntos
Carcinogênese/patologia , Oryza/química , Extratos Vegetais/farmacologia , 3,3'-Diaminobenzidina , Animais , Apoptose/efeitos dos fármacos , Carcinogênese/efeitos dos fármacos , Dietilnitrosamina , Fígado/efeitos dos fármacos , Fígado/enzimologia , Masculino , Extratos Vegetais/química , Antígeno Nuclear de Célula em Proliferação/metabolismo , Ratos Wistar , Testes de Toxicidade Aguda , Xenobióticos/metabolismo
19.
Biomed Pharmacother ; 133: 110963, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33190034

RESUMO

BACKGROUND: Cleistocalyx nervosum var. paniala is a local fruit mainly cultivated in the north of Thailand. Our previous study has reported that the methanol extract of C. nervosum seed presented antimutagenicity in a Salmonella mutation assay. The present study focused on the effect of a low-polar extract of C. nervosum seed on the early stages of diethylnitrosamine (DEN)- and dimethylhydrazine (DMH)-induced carcinogenesis in rats. METHODS: Dried C. nervosum seed powder was extracted using dichloromethane. To study its effect on the initiation stage of carcinogenesis of rats, they were fed with various doses of C. nervosum seed extract (CSE) for 21 days. DEN injection was used to initiate hepatocarcinogenesis and partial hepatectomy was performed to amplify mutated hepatocytes resulting in micronucleated hepatocyte formation. To study the role of CSE on the promotion stage, rats were injected with DEN and DMH to induce preneoplastic lesions and the numbers of glutathione S-transferase placental form (GST-P) positive foci in the liver and aberrant crypt foci (ACF) in the colon were measured. This was followed by CSE administration for 10 weeks. The inhibitory mechanisms of CSE on initiation and promotion stages, including xenobiotic metabolism, cell proliferation and apoptosis, were investigated. RESULTS: The total phenolic content in CSE was 80.34 ± 2.29 mg gallic acid equivalents (GAE) per g of extract and 2,4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone was found to be a major flavonoid. The main terpenoids in CSE were ß-selinene, α-selinene, γ-selinene and o-cymene while 24(Z)-methyl-25-homocholesterol was a major phytosterol. CSE significantly decreased the number of micronucleated hepatocytes in DEN-initiated rats and enhanced the activities of hepatic glutathione S-transferase and UDP-glucuronyltransferase. Furthermore, the formation of preneoplastic lesions in the liver and colon was statistically reduced by CSE. CSE also diminished cell proliferation in the liver and colon indicated by the number of PCNA positive cells. However, CSE did not alter the numbers of apoptotic hepatocytes and colonocytes in DEN- and DMH-initiated rats. CONCLUSIONS: The dichloromethane extract of C. nervosum seed demonstrated chemopreventive effects on chemically-induced carcinogenesis in both initiation and promotion stages in rats. The inhibitory mechanism might be involved in the modulation of hepatic detoxifying enzymes and suppression of hepatocyte and colonocyte proliferation.


Assuntos
Anticarcinógenos/farmacologia , Transformação Celular Neoplásica/efeitos dos fármacos , Colo/efeitos dos fármacos , Neoplasias do Colo/prevenção & controle , Neoplasias Hepáticas/prevenção & controle , Fígado/efeitos dos fármacos , Extratos Vegetais/farmacologia , Sementes , Syzygium , Animais , Anticarcinógenos/isolamento & purificação , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Transformação Celular Neoplásica/induzido quimicamente , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Colo/metabolismo , Colo/patologia , Neoplasias do Colo/induzido quimicamente , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Dietilnitrosamina , Relação Dose-Resposta a Droga , Fígado/metabolismo , Fígado/patologia , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Micronúcleos com Defeito Cromossômico/efeitos dos fármacos , Extratos Vegetais/isolamento & purificação , Ratos Wistar , Sementes/química , Syzygium/química
20.
Life Sci ; 265: 118827, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33253720

RESUMO

BACKGROUND: Most hepatocellular carcinoma cases are diagnosed at late stages of the disease, which makes it the second cause of cancer mortality worldwide. For advanced-stage patients, chemotherapeutic drugs are the best treatment option; however, their adverse effects and high cost are still major obstacles for effective treatment. Spirulina microalga is a rich source of nutritional and bioactive elements and potential pharmaceuticals, which has an -proliferative effect against several cancer cell lines. It also has a prophylactic effect against the early stages of some cancer models, including hepatocellular carcinoma. AIMS: The present study was carried out to evaluate the therapeutic anticarcinogenic effect of spirulina against advanced murine hepatocellular carcinoma. MAIN METHODS: Hepatocarcinoma was induced by a single injection of diethylnitrosamine (100 mg/kg, intraperitoneally) followed by 22 weekly injections of carbon-tetrachloride (0.5 mg/kg, i.p). Spirulina (250 and 500 mg/kg bw) was given orally, from week 25 to 28, after the establishment of hepatocellular carcinoma. KEY FINDINGS: Spirulina inhibited HCC structural and functional alterations, manifested by improving the survival rate, significantly decreasing the tumor marker AFP, and the count and size of the hepatic nodules, as well as downstaging HCC. This was accompanied with the augmentation of the endogenous antioxidant capacity, apoptosis (Bax) and the tumor suppressor protein (p53), as well as the suppression of tissue levels of the lipid peroxidation marker (MDA) and neoangiogenesis marker (VEGF). SIGNIFICANCE: In conclusion, spirulina has an anticarcinogenic effect against advanced hepatocellular carcinoma exerted through activating the tumor suppressor protein p53 and apoptosis, and suppressing oxidative stress and angiogenesis.


Assuntos
Anticarcinógenos/farmacologia , Carcinoma Hepatocelular/prevenção & controle , Neoplasias Hepáticas/prevenção & controle , Spirulina/química , Animais , Anticarcinógenos/administração & dosagem , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/patologia , Dietilnitrosamina/toxicidade , Relação Dose-Resposta a Droga , Peroxidação de Lipídeos/efeitos dos fármacos , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Neovascularização Patológica/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Taxa de Sobrevida , Proteína Supressora de Tumor p53/metabolismo
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