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1.
Braz. J. Pharm. Sci. (Online) ; 58: e18984, 2022. graf
Article in English | LILACS | ID: biblio-1364429

ABSTRACT

Interferon-ß-1a (INF-ß-1a) has gained significant attention due to its emerging applications in the treatment of different human diseases. Therefore, many researchers have attempted to produce it in large quantities and also in a biologically active form using different expression systems. In the present study, we aimed to improve the expression level of INF-ß-1a by Pichia pastoris using optimization of culture conditions. The codon-optimized INF-ß- 1a gene was cloned into pPICZαA plasmid under the control of alcohol oxidase I (AOX1) promoter. The protein expression was induced using different concentrations of methanol at different pHs and temperatures. The biological activity of produced protein was evaluated by anti-proliferative assay. The ideal culture conditions for the expression of INF-ß-1a by P. pastoris were found to be induction with 2% methanol at pH 7.0 culture medium at 30 C which yielded a concentration of 15.5 mg/L INF-ß-1a in a shake flask. Our results indicate that differences in glycosylation pattern could result in different biological activities as INF- ß-1a produced by P. pastoris could significantly more reduce the cell viability of HepG-2 cells, a hepatocellular carcinoma cell line, than a commercially available form of this protein produced by CHO


Subject(s)
Pichia/classification , Interferon-beta/agonists , Carcinoma, Hepatocellular/pathology , Process Optimization , Codon , Cells , Carcinoma, Hepatocellular , Hydrogen-Ion Concentration
2.
Rev. colomb. cir ; 37(1): 96-105, 20211217. fig, tab
Article in Spanish | LILACS | ID: biblio-1357579

ABSTRACT

Introducción. La resección quirúrgica es el tratamiento de elección de las neoplasias primarias y secundarias del hígado. Los pacientes con hepatocarcinoma de los segmentos centrales representan un reto, siendo la hepatectomía extendida la técnica más usada, sin embargo, el riesgo postquirúrgico de falla hepática es alto, dado que la resección puede comprometer entre el 65 % y el 80 % del volumen hepático. La mesohepatectomía es una alternativa que permite dejar un volumen hepático residual suficiente. El objetivo de este trabajo es presentar nuestra experiencia en el tratamiento de pacientes con hepatocarcinomas en segmentos centrales a quienes se les realizó mesohepatectomía. Serie de casos. Se presentan tres pacientes no cirróticos, con hepatocarcinoma en los segmentos 4, 5 y 8, que fueron atendidos en el Hospital San Vicente Fundación, en las sedes de Medellín y de Rionegro, entre 2018 y 2020. Resultados. La mesohepatectomía se realizó mediante ligadura selectiva de los pedículos del segmento 4 y del sector anterior derecho. Se utilizó aspirador ultrasónico y endograpadora para la transección hepática. La duración de la maniobra de Pringle varió entre 16 y 43 minutos. El sangrado promedio fue de 1000 ml. Solo un paciente presentó fuga biliar tipo B. No hubo mortalidad a 30 días. Conclusiones. La mesohepatectomía es una alternativa segura para pacientes con tumores en los segmentos centrales, que permite disminuir el riesgo de falla hepática luego de la resección.


Introduction. Surgical resection is the treatment of choice for primary and secondary neoplasms of the liver. Patients with central segment hepatocarcinoma represent a challenge, with extended hepatectomy being the most widely used technique. However, the postsurgical risk of liver failure is high since resection can compromise between 65% and 80% of liver volume. Mesohepatectomy is an alternative that allows a sufficient residual liver volume to be left. The objective of this work is to present treatment of patients with central segment hepatocarcinoma.Clinical cases. Three non-cirrhotic patients are presented, with hepatocarcinoma in segments 4, 5 and 8, who were treated at the San Vicente Fundación Hospital in Medellín and Rionegro, between 2018 and 2020.Results. Mesohepatectomy was performed by selective ligation of the pedicles of segment 4 and the right anterior sector. An ultrasonic aspirator and endostapler were used for liver transection. The duration of the Pringle ma-neuver ranged from 16 to 43 minutes. The average bleeding was 1000 cc. Only one patient had type B bile leakage. There was no 30-day mortality.Conclusions. Mesohepatectomy is a safe alternative for patients with tumors in the central segments, which reduces the risk of liver failure after resection.


Subject(s)
Humans , Liver Failure , Carcinoma, Hepatocellular , Liver Cirrhosis , Hepatectomy
3.
Rev. cuba. med. mil ; 50(3): e1095, 2021. graf
Article in Spanish | LILACS, CUMED | ID: biblio-1357318

ABSTRACT

Introducción: El carcinoma hepatocelular es un tumor hipervascular compuesto por vasos sanguíneos anormales, constituye la forma más frecuente de cáncer primario del hígado. Alrededor del 90 por ciento de estos tumores se desarrollan sobre una enfermedad hepática previa. Un aumento en la carga vascular debido a la hipertensión portal conlleva a sangrado. Objetivo: Presentar un paciente a quien se le practicó laparotomía exploradora de urgencia por hemoperitoneo de gran cuantía secundario a una rotura intratumoral sobre un hígado cirrótico. Caso clínico: Paciente de 66 años de edad, con antecedentes patológicos de diabetes mellitus tipo 2, hiperplasia benigna de próstata, alcoholismo crónico y cirrosis hepática. Acudió al cuerpo de guardia por dolor abdominal difuso y signos de hipovolemia aguda. Se realizó laparotomía de urgencia y se constata hemoperitoneo de gran cuantía, secundario a una rotura intratumoral. Se le realizó aspiración de contenido hemático, electrocoagulación y compresión por empaquetamiento. Se controló el sangrado. El paciente tuvo una evolución tórpida y falleció 24 horas posteriores a la laparotomía. Conclusiones: El hemoperitoneo secundario a rotura de un carcinoma hepatocelular, es una complicación poco frecuente, pero fatal; por lo que se hace necesario su estudio para lograr un diagnóstico y tratamiento oportuno(AU)


Introduction: Hepatocellular carcinoma is a hypervascular tumor made up of abnormal blood vessels. It is the most frequent form of primary liver cancer. About 90 percent of these tumors develop over a previous liver disease. An increase in vascular load due to portal hypertension leads to bleeding. Objective: To present a patient who underwent emergency exploratory laparotomy due to large hemoperitoneum secondary to an intratumoral rupture of a cirrhotic liver. Clinical case: A 66-year-old male patient with a pathological history of type 2 diabetes mellitus, benign prostatic hyperplasia, chronic alcoholism and liver cirrhosis. He came to emergency due to diffuse abdominal pain, as well as signs of acute hypovolemia. An emergency laparotomy was performed, confirming a large hemoperitoneum secondary to an intratumoral rupture. Blood content aspiration, electrocoagulation and compression by packing were performed, managing to control bleeding. He had a torpid evolution, dying 24 hours after the laparotomy. Conclusions: Hemoperitoneum secondary to rupture of a hepatocellular carcinoma is a rare, but fatal complication; therefore, its study is necessary to achieve a timely diagnosis and treatment(AU)


Subject(s)
Humans , Male , Aged , Prostatic Hyperplasia , Carcinoma, Hepatocellular , Hypovolemia , Hemoperitoneum , Liver Cirrhosis , Liver Neoplasms
4.
Electron. j. biotechnol ; 52: 21-29, July. 2021. ilus, tab, graf
Article in English | LILACS | ID: biblio-1283484

ABSTRACT

BACKGROUND: Super-paramagnetic iron oxide nanoparticles (SPION) contain a chemotherapeutic drug and are regarded as a promising technique for improving targeted delivery into cancer cells. RESULTS: In this study, the fabrication of 5-fluorouracil (5-FU) was investigated with loaded Dextran (DEXSPION) using the co-precipitation technique and conjugated by folate (FA). These nanoparticles (NPs) were employed as carriers and anticancer compounds against liver cancer cells in vitro. Structural, magnetic, morphological characterization, size, and drug loading activities of the obtained FA-DEX-5-FUSPION NPs were checked using FTIR, VSM, FESEM, TEM, DLS, and zeta potential techniques. The cellular toxicity effect of FA-DEX-5-FU-SPION NPs was evaluated using the MTT test on liver cancer (SNU-423) and healthy cells (LO2). Furthermore, the apoptosis measurement and the expression levels of NF-1, Her-2/neu, c-Raf-1, and Wnt-1 genes were evaluated post-treatment using flow cytometry and RT-PCR, respectively. The obtained NPs were spherical with a suitable dispersity without noticeable aggregation. The size of the NPs, polydispersity, and zeta were 74 ± 13 nm, 0.080 and 45 mV, respectively. The results of the encapsulation efficiency of the nano-compound showed highly colloidal stability and proper drug maintenance. The results indicated that FA-DEX-5-FU-SPION demonstrated a sustained release profile of 5-FU in both phosphate and citrate buffer solutions separately, with higher cytotoxicity against SNU-423 cells than against other cells types. These findings suggest that FA-DEX-SPION NPs exert synergistic effects for targeting intracellular delivery of 5-FU, apoptosis induction, and gene expression stimulation. CONCLUSIONS: The findings proved that FA-DEX-5-FU-SPION presented remarkable antitumor properties; no adverse subsequences were revealed against normal cells.


Subject(s)
Humans , Carcinoma, Hepatocellular/drug therapy , Fluorouracil/administration & dosage , Liver Neoplasms/drug therapy , Polymers , Gene Expression/drug effects , Drug Delivery Systems , Apoptosis/drug effects , Reverse Transcriptase Polymerase Chain Reaction , Delayed-Action Preparations , Nanoparticles/administration & dosage , Magnetite Nanoparticles , Flow Cytometry
5.
Rev. Assoc. Méd. Rio Gd. do Sul ; 65(2): 01022105, Abr. - Jun. 2021.
Article in Portuguese | LILACS | ID: biblio-1367471

ABSTRACT

RESUMO A hemocromatose hereditária (HH) é uma doença genética autossômica recessiva, a mais comum encontrada em caucasianos, causada pelo acúmulo de ferro em diferentes órgãos, predominantemente no fígado, causando sua disfunção. As mutações hereditárias relacionadas ao gene HFE representam quase 90% dos casos de hemocromatose entre as populações de descendência europeia. A absorção excessiva do ferro ocasiona acúmulo em órgãos como coração, pâncreas e fígado ocasionando diversas manifestações clínicas. Além dos sintomas gerais, a progressiva sobrecarga de ferro causa uma das principais complicações, a cirrose hepática. A regressão da fibrose pode ser alcançada após o tratamento, promovendo a remoção do estímulo e restaurando a função do fígado. Caso a HH não seja tratada ou o tratamento não tenha sido efetivo, o paciente pode evoluir para um estado fibrótico de cirrose irreversível, que pode culminar com o carcinoma hepatocelular (CHC), complicação responsável por 45% das mortes em pacientes com HH. Nesse sentido, nota-se a importância de compreender os métodos diagnósticos, rastreamento e tratamento, de maneira a possibilitar manejos precoces e evitar complicações potencialmente fatais. Além disso, o fato da população dos estados do sul do Brasil ser composta em sua maioria por descendentes norte-europeus - os mais acometidos pela HH - justifica a importância de literaturas e estudos clínicos mais recentes e realizados nessa região com o objetivo de compreender a evolução clínica da doença e estabelecer medidas preventivas para a manifestação de lesões hepáticas. PALAVRAS-CHAVE: Hemocromatose, HFE, diagnóstico, cirrose hepática, carcinoma hepatocelular


ABSTRACT Hereditary hemochromatosis (HH) is an autosomal recessive genetic disease, the most common found in Caucasians, caused by the accumulation of iron in different organs, predominantly in the liver, causing its dysfunction. Inherited mutations related to the HFE gene represent almost 90% of cases of hemochromatosis among populations of European descent. Excessive iron absorption causes accumulation in organs such as the heart, pancreas and liver, causing several clinical manifestations. In addition to the general symptoms, progressive iron overload causes one of the main complications, liver cirrhosis. Regression of fibrosis can be achieved after treatment, promoting stimulus removal and restoring liver function. If HH is not treated or the treatment has not been effective, the patient may progress to a fibrotic state of irreversible cirrhosis, which can culminate in hepatocellular carcinoma (HCC), a complication responsible for 45% of deaths in patients with HH. In this sense, the importance of understanding diagnostic methods, screening and treatment is noted, in order to enable early management and avoid potentially fatal complications. In addition, the fact that the population of the southern states of Brazil is composed mostly of North European descendants ­ the most affected by HH ­ justifies the importance of more recent literature and clinical studies carried out in this region in order to understand the clinical course of the disease and establish preventive measures for the manifestation of liver damage. KEYWORDS: Hemochromatosis, HFE, diagnosis, liver cirrhosis, hepatocellular carcinoma


Subject(s)
Humans , Diagnosis , Hemochromatosis Protein , Hemochromatosis , Liver Cirrhosis , Carcinoma, Hepatocellular
6.
Medicina (B.Aires) ; 81(3): 346-358, jun. 2021. graf
Article in English | LILACS | ID: biblio-1346469

ABSTRACT

Abstract Hepatocellular carcinoma (HCC) is the most common primary liver tumor. Hexachlorobenzene (HCB) is an endocrine disruptor and a liver tumor promoter. Deregulation of thyroid hormone (TH) homeostasis may play a significant role in early neoplastic transformation. The aim of this study was to evaluate the relation between TH metabolism and the regulation of cell growth in an in vivo and in vitro model. We examined the role of transforming growth factor-β1 (TGF-β1) on TH deiodinase expression and hepatocyte proliferation. An initiation (DEN)/promotion (HCB) tumor model from rat liver and HepG2 cells were used. We evaluated PCNA, p21, p27, SMAD2/3, TGF-β1, deiodinase 1 (D1), D3, protein expression levels; D1 and D3 mRNA expression; TH and TGF-β1, D1, D3, and GST-P protein levels in focal/non-focal areas. In vivo, HCB decreased triiodothyronine (T3) and D1 mRNA levels and increased thyroxine (T4) and D3 mRNA levels in liver from DEN+HCB vs. DEN group. HCB increased protein levels from D3, TGF-β1, and PCNA and decreased D1 in focal-areas. In vitro, HCB increased PCNA, pSMAD 2/3, and TGF-β1 protein levels and mRNA expression and decreased p21 and p27 protein levels. Exogenous T3 treatment prevent HCB induced molecular alterations related to hepatocyte proliferation whereas T4 did not have any effect. These effects were prevented by using a TGF-β1 receptor II inhibitor. Results suggest that alteration of TH homeostasis, through D1 function, play a key role in hepatocyte proliferation and that TGF-β1-SMAD pathway is involved in this process confirming their role in early neoplastic transformation in HCC.


Resumen El hepatocarcinoma (HCC) es un tumor hepático primario. El hexaclorobenceno (HCB) es un disruptor endocrino y un promotor de tumores hepáticos. La desregulación de la homeostasis de las hormonas tiroideas (HT) puede ser un proceso importante para la transformación neoplásica temprana. Nuestro objetivo fue evaluar la relación entre el metabolismo de las HT y la regulación de la prolifera ción celular. Se utilizó un modelo tumoral de iniciación (DEN)/promoción (HCB) de hígado de rata (in vivo) (DEN/ HCB) y células HepG2 (in vitro). Evaluamos los niveles de PCNA, p21, p27, SMAD2/3, TGF-β1, D1, D3, ARNm de D1 y D3, HT y los niveles de TGF-β1, D1, D3 y GST-P en áreas focales/no focales. In vivo, HCB disminuyó los niveles de T3 y ARNm de la D1 y aumentó los niveles de T4 y ARNm de D3 del grupo DEN + HCB frente al grupo DEN. El HCB aumentó los niveles de D3, TGF-β1 y PCNA y disminuyó el D1 en las áreas focales. In vitro, HCB aumentó los niveles de PCNA, pSMAD 2/3 y TGF-β1 y la expresión de ARNm mientras que disminuyó los niveles de p21 y p27. El tratamiento con T3 exógeno previno las alteraciones moleculares relacionadas con la proliferación hepatocitaria. Estos efectos se evitaron utilizando un inhibidor del receptor II de TGF-β1. Los resultados sugieren que la alteración de la homeostasis de HT, a través de la D1 y la vía TGF-β1-SMAD, juega un papel clave en la proliferación celular y en las transformaciones neoplásicas tempranas en el HCC.


Subject(s)
Animals , Rats , Carcinoma, Hepatocellular , Transforming Growth Factor beta1 , Iodide Peroxidase/genetics , Liver Neoplasms , Cell Proliferation
7.
Int. j. med. surg. sci. (Print) ; 8(2): 1-12, jun. 2021. graf, ilus
Article in English | LILACS | ID: biblio-1284445

ABSTRACT

Background/aim: Autophagic cell death and apoptosis of tumor cells has become one of the main objectives in cancer treatment, whereas tumor cell lines are mainly used in studies for providing important data for the evaluation of potential anti cancer substances. In this study, our objective was to evaluate morphological and biochemical changes including rate of apoptosis and Alpha Fetoprotein (AFP) levels at different concentrations of Carnosic Acid (CA) on Human Hepatocellular Carcinoma HepG2 Cells.Materials and methods: Human Hepatocellular Carcinoma (7th passage HepG2 cells) Cell lines were cultured on 11 µM D263M schott glass coverslips placed in 12-well plates and were treated with DMSO, 1, 2.5, 5 and 10 µM concentrations of CA for 24, 48 and 72 hours. Morphological and biochemical data were recorded daily including apoptosis rates demonstrated by Caspase 3, Annexin V expressions under inverted light and Immunofluorescence microscopy, then data were analyzed for statistical significance. AFP, albumin and total protein levels were analyzed spectrophotometricaly for biochemical evaluation.Results: Our results showed that CA significantly inhibited HepG2 cell proliferation in a dose and time dependant manner and significantly caused the formation of autophagic vacuoles starting from 5µM and reaching significance at 10 µM concentrations. Significant decrease was observed in AFP when 48 and 72 hours expressions were examined, with the lowest level reached at 72 hours in the 10 µM CA group. Additionally, increase in albumin levels reached significance only in the 48 h group whereas non-significant increases were also observed in 24 h and 72 h groups.Conclusion: Our current study demonstrates significant increase in apoptosis rates by Carnosic Acid mainly at 10µM concentrations, supporting its anticancer effect on HepG2 cells. These findings are also supported by changes in biochemical analyses of Albumin and AFP levels at 10 µM concentrations.


Antecedentes / objetivos: La muerte celular autofágica y la apoptosis de células tumorales se ha convertido en uno de los principales objetivos en el tratamiento del cáncer, mientras que las líneas celulares tumorales se utilizan principalmente en estudios para proporcionar datos importantes para la evaluación de posibles sustancias anticancerígenas. En este estudio, nuestro objetivo fue evaluar los cambios morfológicos y bioquímicos, incluida la tasa de apoptosis y los niveles de alfa fetoproteína (AFP) a diferentes concentraciones de ácido carnósico (CA) en células de carcinoma hepatocelular humano HepG2.Materiales y métodos: Carcinoma hepatocelular humano (HepG2).Las líneas celulares se cultivaron en cubreobjetos de vidrio Schott D263M de 11 µM colocados en placas de 12 pocillos y se trataron con DMSO, concentraciones de CA 1, 2,5, 5 y 10 µM durante 24, 48 y 72 horas. Los datos morfológicos y bioquímicos se registraron diariamente, incluidas las tasas de apoptosis demostradas por Caspasa 3, las expresiones de Anexina V bajo luz invertida y microscopía de inmunofluorescencia, luego se analizaron los datos para determinar la significación estadística. Los niveles de AFP, albúmina y proteínas totales se analizaron espectrofotométricamente para evaluación bioquímica.Resultados: Nuestros resultados mostraron que CA inhibió significativamente la proliferación de células HepG2 de una manera dependiente de la dosis y el tiempo y causó significativamente la formación de vacuolas autofágicas comenzando desde 5 µM y alcanzando significancia a concentraciones de 10 µM. Se observó una disminución significativa en la AFP cuando se examinaron las expresiones de 48 y 72 horas, alcanzando el nivel más bajo a las 72 horas en el grupo de CA 10 µM. Además, el aumento en los niveles de albúmina alcanzó significación solo en el grupo de 48 h, mientras que también se observaron aumentos no significativos en los grupos de 24 hy 72 h.Conclusión: Nuestro estudio demuestra un aumento significativo en las tasas de apoptosis por el ácido carnósico principalmente a concentraciones de 10 µM, lo que respalda su efecto anticancerígeno en las células HepG2. Estos hallazgos también están respaldados por cambios en los análisis bioquímicos de los niveles de albúmina y AFP a concentraciones de 10 µM.


Subject(s)
Humans , Carcinoma, Hepatocellular/drug therapy , Abietanes/administration & dosage , Hep G2 Cells/drug effects , Liver Neoplasms/drug therapy , Cell Survival , Cells, Cultured , Apoptosis/drug effects , Microscopy, Fluorescence
8.
Arq. gastroenterol ; 58(1): 82-86, Jan.-Mar. 2021. tab, graf
Article in English | LILACS | ID: biblio-1248979

ABSTRACT

ABSTRACT BACKGROUND: Hepatocellular carcinoma (HCC) is the most frequent primary cancer of the liver and cirrhosis is considered a pre-malignant disease. In this context, the evolutionary sequence from low grade dysplastic nodule and high grade dysplastic nodule (HGDN) to early HCC and advanced HCC has been studied. The differential diagnosis between HGDN and early HCC is still a challenge, especially in needle biopsies OBJECTIVE: To evaluate an immunohistochemistry panel to differentiate dysplastic nodules and HCC. METHODS: Patients with cirrhosis who underwent surgical resection or liver transplantation were included. The sensitivity, specificity and accuracy for the diagnosis of neoplasia were analyzed by evaluating five markers: heat shock protein 70, glypican 3, glutamine synthetase, clathrin heavy chain and beta-catenin. P≤0.05 was considered statistically significant. RESULTS: One hundred and fifty-six nodules were included; of these, 57 were HCC, 14 HGDN, 18 low grade dysplastic nodules and 67 regenerative macronodules. Sensitivity of HCC diagnosis was 64.9% for glypican 3 and 77.2% for glutamine syntetase, while specificity was 96.0% and 96.0% respectively. When the panel of four markers was considered (excluding beta catenin), the specificity ranged from 87.9% for one positive marker to 100% for at least three markers. The best accuracy for HCC diagnosis was obtained with at least two positive markers, which was associated with a sensitivity of 82.5% and specificity of 99%. CONCLUSION: Differential diagnosis of dysplastic nodules and HCC by morphological criteria can be challenging. Immunomarkers are useful and should be used for the differential diagnosis between HCC and HGDN.


RESUMO CONTEXTO: O carcinoma hepatocelular (CHC) é o câncer primário do fígado mais frequente e a cirrose é considerada uma doença pré-maligna. Nesse contexto, a sequência evolutiva do nódulo displásico de baixo grau e nódulo displásico de alto grau (NDAG) para CHC precoce e CHC avançado tem sido estudada. O diagnóstico diferencial entre NDAG e CHC precoce ainda é um desafio, principalmente em biópsias por agulha. OBJETIVO: Avaliar um painel de imunohistoquímica para diferenciar nódulos displásicos de CHC. MÉTODOS: Foram incluídos pacientes com cirrose submetidos à ressecção cirúrgica ou transplante de fígado. A sensibilidade, especificidade e acurácia para o diagnóstico da neoplasia foram analisadas avaliando cinco marcadores: proteína de choque térmico 70kDa, glipican 3, glutamina sintetase, clatrina de cadeia pesada e beta-catenina. P≤0,05 foi considerado estatisticamente significativo. RESULTADOS: Cento e cinquenta e seis nódulos foram incluídos; destes, 57 eram CHC, 14 NDAG, 18 nódulos displásicos de baixo grau e 67 macronódulos regenerativos. A sensibilidade do diagnóstico de CHC foi de 64,9% para glipican 3 e 77,2% para glutamina sintetase, enquanto a especificidade foi de 96,0% e 96,0%, respectivamente. Quando o painel de quatro marcadores foi considerado (excluindo beta catenina), a especificidade variou de 87,9% para um marcador positivo a 100% para pelo menos três marcadores. A melhor acurácia para o diagnóstico de CHC foi obtida com pelo menos dois marcadores positivos, o que foi associado a uma sensibilidade de 82,5% e especificidade de 99%. CONCLUSÃO: O diagnóstico diferencial de nódulos displásicos e CHC por critérios morfológicos pode ser desafiador. Imunomarcadores são úteis e devem ser usados para o diagnóstico diferencial entre CHC e NDAG.


Subject(s)
Humans , Carcinoma, Hepatocellular/diagnosis , Neoplasms/diagnosis , Immunohistochemistry , Diagnosis, Differential , Liver Cirrhosis/diagnosis
9.
Braz. j. med. biol. res ; 54(9): e10390, 2021. graf
Article in English | LILACS | ID: biblio-1249337

ABSTRACT

Sorafenib (SOR) resistance is still a significant challenge for the effective treatment of hepatocellular carcinoma (HCC). The mechanism of sorafenib resistance remains unclear. Several microRNAs (miRNAs) have been identified as playing a role in impairing the sensitivity of tumor cells to treatment. We examined the mechanism behind the role of miR-92b in mediating sorafenib resistance in HCC cells. We detected that miR-92b expression was significantly upregulated in SOR-resistant HepG2/SOR cells compared to parental HepG2/WT cells. After transfection with miR-92b inhibitor, the proliferation of HepG2/SOR cells was remarkably weakened and rates of apoptosis significantly increased. PTEN was considered to be a functional target of miR-92b according to a luciferase reporter assay. Knockdown of PTEN significantly impaired the ability of miR-92b inhibitor on increasing sorafenib sensitivity of HepG2/SOR cells. Furthermore, we confirmed by western blotting and immunofluorescence that miR-92b can mediate sorafenib resistance by activating the PI3K/AKT/mTOR pathway in HCC cells by directly targeting PTEN. These findings further validate the mechanism of miR-92b in SOR resistance in HCC treatment.


Subject(s)
Humans , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/drug therapy , Drug Resistance, Neoplasm , MicroRNAs/genetics , Sorafenib/pharmacology , Liver Neoplasms/genetics , Liver Neoplasms/drug therapy , Signal Transduction , Gene Expression Regulation, Neoplastic , Phosphatidylinositol 3-Kinases/metabolism , Cell Line, Tumor , Cell Proliferation , PTEN Phosphohydrolase/genetics , TOR Serine-Threonine Kinases
10.
Braz. j. med. biol. res ; 54(7): e10213, 2021. tab, graf
Article in English | LILACS | ID: biblio-1249312

ABSTRACT

Sevoflurane (SEVO) is widely applied as an anesthetic, which exerts antitumor capacity in various cancers, including hepatocellular carcinoma (HCC). Previous studies indicated that long non-coding RNA KCNQ1 opposite strand/antisense transcript 1 (KCNQ1OT1) was upregulated, while microRNA-29a-3p (miR-29a-3p) was downregulated in HCC. Thus, we aimed to explore the roles of KCNQ1OT1 and miR-29a-3p in HCC cells exposed to SEVO. Cell proliferation, apoptosis, migration, and invasion were assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, flow cytometry, and transwell assays, respectively. The levels of genes were determined by quantitative real-time polymerase chain reaction (qRT-PCR) or western blot. Furthermore, the interaction between miR-29a-3p and KCNQ1OT1 or chromebox protein homolog 3 (CBX3) was predicted by Starbase or Targetscan, and then confirmed by dual-luciferase reporter assay. We found that the levels of KCNQ1OT1 and CBX3 were decreased, while miR-29a-3p was increased in SEVO-treated HCC cells. KCNQ1OT1 overexpression weakened the inhibitory effects of SEVO on HCC cell proliferation, apoptosis, migration, and invasion. Interestingly, KCNQ1OT1 bound to miR-29a-3p, and miR-29a-3p targeted CBX3. KCNQ1OT1 upregulated CBX3 level by repressing miR-29a-3p expression. Furthermore, KCNQ1OT1 exerted tumor promotion in HCC cells via suppressing miR-29a-3p to regulate CBX3 expression. Collectively, our findings demonstrated that KCNQ1OT1 regulated the antitumor effects of SEVO on HCC cells through modulating the miR-29a-3p/CBX3 axis, providing a theoretical basis for the treatment of HCC.


Subject(s)
Humans , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/drug therapy , Potassium Channels, Voltage-Gated , MicroRNAs/genetics , Liver Neoplasms/genetics , Liver Neoplasms/drug therapy , Chromosomal Proteins, Non-Histone , RNA, Long Noncoding/genetics , Sevoflurane/pharmacology
11.
Braz. j. med. biol. res ; 54(4): e10273, 2021. tab, graf
Article in English | LILACS | ID: biblio-1153542

ABSTRACT

Vascular invasion and systemic immune-inflammation index (SII) are risk factors for the prognosis of patients with hepatocellular carcinoma. At present, the correlation between the two is not clear. This meta-analysis explored the relationship between preoperative SII and vascular invasion in patients with hepatocellular carcinoma. According to the search formula, the Pubmed, Embase, Cochrane, Web of Science, and CNKI databases were searched for the relevant research until March 2020. After the quality evaluation of the included literature, the odds ratio (OR) and its corresponding 95% confidence interval (CI) were used as the effect measure. Stata 15. 0 software was used for statistical analysis. The meta-analysis eventually included seven retrospective cohort studies of 3583 patients with hepatocellular carcinoma. The results showed that the choice of SII cut-off value affects SII's efficiency in predicting the risk of vascular invasion. In the cohort of studies with appropriate SII cut-off value, the high SII preoperative group had a higher risk of vascular invasion (OR=2.62; 95%CI: 2.07-3.32; P=0.000) and microvascular invasion (OR=1.82; 95%CI: 1.01-3.25; P=0.045) than the low SII group. The tumor diameter (OR=2.88; 95%CI: 1.73-4. 80; P=0.000) of the high SII group was larger than that of the low SII group. There was no publication bias in this study (Begg's test, P=0.368). As a routine, cheap, and easily available index, SII can provide a certain reference value for clinicians to evaluate vascular invasion before operation.


Subject(s)
Humans , Carcinoma, Hepatocellular/surgery , Liver Neoplasms/surgery , Retrospective Studies , Risk Factors , Inflammation
12.
Article in English | WPRIM | ID: wpr-879952

ABSTRACT

The pathogenesis of hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) is complicated with the crosstalk of multiple factors and the multi-step processes. The main mechanisms underlying the HBV-induced HCC include:①integration of HBV DNA into the host hepatocyte genome to alter gene function at the insertion site,resulting in host genome instability and expression of carcinogenic truncated proteins;②HBV gene mutations at S,C,and X coding regions in the genome;③HBV X gene-encoded HBx protein activates proto-oncogenes and inhibits tumor suppressor genes,leading to the HCC occurrence. In this article,the recent research progress on the molecular mechanism of HBV-induced HCC is comprehensively reviewed,so as to provide insights into the prevention,early prediction and postoperative adjuvant therapy of HCC.


Subject(s)
Carcinoma, Hepatocellular , Hepatitis B/complications , Hepatitis B virus/genetics , Hepatocytes , Humans , Liver Neoplasms
13.
Chinese Journal of Hepatology ; (12): 216-226, 2021.
Article in Chinese | WPRIM | ID: wpr-879636

ABSTRACT

In order to standardize the effective prevention, early screening and diagnosis of the population at risk of primary liver cancer, the Chinese Society of Hepatology and Chinese Medical Association organized the relevant domestic experts to formulate the "Consensus on Secondary Prevention of Primary Liver Cancer (2021 version)," based on the basic, clinical and preventive research progress, combined with the actual situation at home and abroad, so as to provide an important basis for the prevention, screening and early diagnosis of primary liver cancer in the population of chronic liver disease.


Subject(s)
Carcinoma, Hepatocellular/prevention & control , Consensus , Gastroenterology , Humans , Liver Cirrhosis , Liver Neoplasms/prevention & control , Mass Screening , Secondary Prevention
14.
Chinese Journal of Hepatology ; (12): 25-40, 2021.
Article in Chinese | WPRIM | ID: wpr-879635

ABSTRACT

The age-adjusted incidence of primary liver cancer (PLC) has been declining in China. However, PLC cases in China account for 55% globally. The disease burden is still high and the 5-year survival rate was not improved significantly in the past two decades. This guideline outlines PLC screening in the risk populations, both in hospital and community. Liver cirrhosis and chronic hepatitis B are the main causes of PLC in China. For better PLC surveillance and screening in clinical practices, it is recommended to stratify population at the risk into 4 risk levels, namely, low-risk, intermediate-risk, high-risk, and extremely high-risk.The lifelong surveillance is suggested for those at the risk of PLC. The intervals and tools for surveillance and screening are recommended based on the risk levels. Abdominal ultrasonography combined with serum alpha-fetoprotein examination (routine surveillance) every 6 months is recommended for those at a high risk of PLC.Routine surveillance every 3 months and enhanced CT/MRI examination every 6-12 months are recommended for those at an extremely high risk of PLC. The surveillance interval can be extended every 1 year or longer for those at a low-risk or at an intermediate-risk of PLC, because their annual incidence of PLC is very low. The cost-effectiveness of these recommendations remains to be evaluated.


Subject(s)
Carcinoma, Hepatocellular , China/epidemiology , Early Detection of Cancer , Hepatitis B, Chronic , Humans , Liver Cirrhosis , Liver Neoplasms/epidemiology
15.
Article in Chinese | WPRIM | ID: wpr-879195

ABSTRACT

Network Meta-analysis was used to evaluate the efficacy and safety of different oral Chinese patent medicines combined with transcatheter arterial chemoembolization(TACE) in the treatment of primary liver cancer. Randomized controlled trials of oral Chinese patent medicines for primary liver cancer were retrieved from CNKI, Wanfang, VIP, SinoMed, PubMed, Cochrane Library and EMbase databases from inception to May 2020. According to the Cochrane recommendation standard, the quality of the included articles was evaluated, and the data were analyzed by RevMan, R software and GeMTC software. A total of 10 kinds of oral Chinese patent medicines and 68 RCTs were included. Network Meta-analysis results showed that: as compared with TACE alone, 10 kinds of oral Chinese patent medicines combined with TACE showed advantages in effective rate, 1-year survival rate, 2-year survival rate, KPS score improvement rate and reduced adverse reaction incidence. In the pairwise comparison of oral Chinese patent medicines, the results showed that Cidan Capsules were superior to Jinlong Capsules and Xihuang Pills in 1-year survival rate. According to the probabi-lity ranking results: Shenyi Capsules and Ganfule were more obvious in improving the effective rate; Cidan Capsules and Shenyi Capsules were more effective in improving the 1-year survival rate; Pingxiao Capsules and Shenyi Capsules had better efficacy in improving 2-year survival rate; Huaier Granules and Shenyi Capsules had better efficacy in improving the quality of life; Huisheng Oral Liquid and Ganfule were more effective in reducing the incidence of adverse reactions(such as nausea, vomiting and leukocytosis). The current evidence showed that oral Chinese patent medicine combined with TACE was superior to TACE alone in efficacy and safety. In terms of the effective rate, 1-year survival rate, 2-year survival rate, KPS score improvement rate and reduced adverse reaction incidence, the optimal treatment measures were Shenyi Capsules, Cidan Capsules, Pingxiao Capsules, Huaier Granules and Huisheng Oral Liquid in turn. However, due to the limitations of the research, the current level of evidence is not high, and clear conclusions and evi-dence strength still need to be further verified and improved by high-quality researches.


Subject(s)
Carcinoma, Hepatocellular/drug therapy , Chemoembolization, Therapeutic , China , Drugs, Chinese Herbal , Humans , Liver Neoplasms/drug therapy , Network Meta-Analysis , Nonprescription Drugs , Quality of Life
16.
Frontiers of Medicine ; (4): 155-169, 2021.
Article in English | WPRIM | ID: wpr-880972

ABSTRACT

Hepatic resection represents the first-line treatment for patients with resectable hepatocellular carcinoma (HCC). However, the 5-year recurrence rates of HCC after surgery have been reported to range from 50% to 70%. In this review, we evaluated the available evidence for the efficiency of adjuvant treatments to prevent HCC recurrence after curative liver resection. Antiviral therapy has potential advantages in terms of reducing the recurrence rate and improving the overall survival (OS) and/or disease-free survival of patients with hepatitis-related HCC. Postoperative adjuvant transarterial chemoembolization can significantly reduce the intrahepatic recurrence rate and improve OS, especially for patients with a high risk of recurrence. The efficacy of molecular targeted drugs as an adjuvant therapy deserves further study. Adjuvant adoptive immunotherapy can significantly improve the clinical prognosis in the early stage. Randomized controlled trial (RCT) studies evaluating adjuvant immune checkpoint inhibitors are ongoing, and the results are highly expected. Adjuvant hepatic artery infusion chemotherapy might be beneficial in patients with vascular invasion. Huaier granule, a traditional Chinese medicine, has been proved to be effective in prolonging the recurrence-free survival and reducing extrahepatic recurrence. The efficiency of other adjuvant treatments needs to be further confirmed by large RCT studies.


Subject(s)
Carcinoma, Hepatocellular/therapy , Chemoembolization, Therapeutic , Chemotherapy, Adjuvant , Hepatectomy , Humans , Liver Neoplasms/therapy , Neoplasm Recurrence, Local , Treatment Outcome
17.
Frontiers of Medicine ; (4): 170-177, 2021.
Article in English | WPRIM | ID: wpr-880966

ABSTRACT

Nanosecond pulsed electric field (nsPEF) is a novel, nonthermal, and minimally invasive modality that can ablate solid tumors by inducing apoptosis. Recent animal experiments show that nsPEF can induce the immunogenic cell death of hepatocellular carcinoma (HCC) and stimulate the host's immune response to kill residual tumor cells and decrease distant metastatic tumors. nsPEF-induced immunity is of great clinical importance because the nonthermal ablation may enhance the immune memory, which can prevent HCC recurrence and metastasis. This review summarized the most advanced research on the effect of nsPEF. The possible mechanisms of how locoregional nsPEF ablation enhances the systemic anticancer immune responses were illustrated. nsPEF stimulates the host immune system to boost stimulation and prevail suppression. Also, nsPEF increases the dendritic cell loading and inhibits the regulatory responses, thereby improving immune stimulation and limiting immunosuppression in HCC-bearing hosts. Therefore, nsPEF has excellent potential for HCC treatment.


Subject(s)
Animals , Carcinoma, Hepatocellular/therapy , Cell Line, Tumor , Immunity , Liver Neoplasms/therapy , Neoplasm Recurrence, Local
18.
J. venom. anim. toxins incl. trop. dis ; 27: e20210039, 2021. tab, graf, ilus
Article in English | LILACS, VETINDEX | ID: biblio-1351021

ABSTRACT

Background Hepatitis C virus (HCV) infection is a major worldwide health problem that can cause liver fibrosis and hepatocellular carcinoma (HCC). The clinical treatment of HCV infection mainly relies on the use of direct-acting antivirals (DAAs) that are usually expensive and have side effects. Therefore, achieving the discovery of more successful agents is always urgent. In this context, antiviral compounds that inhibit viral infections and disease progression with important therapeutic activities have been identified in animal venoms including arthropod toxins. This indicates that arthropod venoms represent a good natural source of promising candidates for new antivirals. Methods The antiviral activity of the wasp venom (WV), isolated from the Oriental hornet (Vespa orientalis), was assessed using cell culture technique with human hepatocellular carcinoma-derived cell line (Huh7it-1) and the recombinant strain of HCV genotype 2a (JFH1). Results The results revealed that WV inhibited HCV infectivity with 50% inhibitory concentration (IC50) of 10 ng/mL, while the 50% cytotoxic concentration (CC50) was 11,000 ng/mL. Time of addition experiment showed that the WV blocked HCV attachment/entry to the cells probably through virucidal effect. On the other hand, the venom showed no inhibitory effect on HCV replication. Conclusion WV can inhibit the entry stage of HCV infection at non-cytotoxic concentrations. Therefore, it could be considered a potential candidate for characterization of natural anti-HCV agents targeting the entry step.(AU)


Subject(s)
Antiviral Agents , Wasp Venoms , Carcinoma, Hepatocellular
19.
Article in English | WPRIM | ID: wpr-888509

ABSTRACT

Proteasome is the eukaryotic organelle responsible for degradation of short-lived proteins and involved in maintaining cellular protein homeostasis. It has been reported that during the occurrence and development of hepatocellular carcinoma (HCC), the regulatory particle subunits of proteasome regulate a series of tumor-related proteins, and proliferation, survival-associated signaling molecules, including PTEN gene, P53, Bcl-2, Bcl-2 interacting mediator of cell death (Bim), cyclin-dependent kinase 4(CDK4), transforming growth factor β receptor (TGFBR), E2F1, growth factor receptor-bound protein 2 (GRB2) . Meanwhile, these subunits regulate some tumor-associated pathway protein, such as signal transducer and activator of transcription 3 (STAT3) and protein kinase B (AKT), inducing their malfunction to promote the occurrence, proliferation, invasion and metastasis of HCC. The core particle subunits are more to perform the degradation of HCC-related proteins, so inhibitors targeting the core particle show a good anti-tumor effect. This review summarizes the current research progress on the regulation and mechanism of proteasome subunits in promoting the occurrence and development .


Subject(s)
Carcinoma, Hepatocellular , Cell Line, Tumor , Cell Proliferation , Humans , Liver Neoplasms , Proteasome Endopeptidase Complex/metabolism , STAT3 Transcription Factor/metabolism , Signal Transduction
20.
Chinese Journal of Hepatology ; (12): 648-658, 2021.
Article in Chinese | WPRIM | ID: wpr-888408

ABSTRACT

Liver malignant tumors are one of the most common causes of cancer-related deaths in China. Selective internal yttrium-90 radioembolization therapy ((90)Y-SIRT) is a kind of promising local minimally invasive method, and its effectiveness and safety has been confirmed in clinical application over the past two decades. Moreover, it has been approved by the U.S. National Comprehensive Cancer Network and other international guidelines for the topical treatment of patients with liver malignancies. Taking into account the complexity of the (90)Y-SIRT and the need for multidisciplinary collaboration to improve the safety and success rate of treatment, the Nuclear Medicine Expert Committee of the Chinese society of Clinical Oncology, along with Beijing Nuclear Medicine Quality Control and Improvement Center invited experts from surgical oncology, interventional medicine, nuclear medicine, and other related fields to discuss and form a consensus on the clinical diagnosis, treatment and management, which mainly included definition, indications and contraindications, treatment procedures, postoperative follow-up, adverse reactions and complications, radiation safety management, etc. Herein, we provide the reference guidance to establish (90)Y-SIRT standardized management and treatment system various units for relevant practitioners.


Subject(s)
Carcinoma, Hepatocellular/radiotherapy , China , Consensus , Humans , Liver Neoplasms/radiotherapy , Microspheres , Yttrium Radioisotopes
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