RESUMO
Hepatocellular carcinoma (HCC) is one of the most fatal solid malignancies worldwide. Evidence suggests that thrombin stimulates tumor progression via fibrin formation and platelet activation. Meanwhile, we also found a correlation between thrombin and HCC through bioinformatics analysis. Dabigatran is a selective, direct thrombin inhibitor that reversibly binds to thrombin. Dabigatran was used as the lead agent in this study, and 19 dabigatran derivatives were designed and synthesized based on docking mode. The thrombin-inhibitory activity of the derivative AX-2 was slightly better than that of dabigatran. BX-2, a prodrug of AX-2, showed a fairly strong inhibitory effect on thrombin-induced platelet aggregation, and effectively antagonized proliferation of HCC tumor cells induced by thrombin at the cellular level. Furthermore, BX-2 reduced tumor volume, weight, lung metastasis, and secondary tumor occurrence in nude mouse models. BX-2 combined with sorafenib increased sorafenib efficacy. This study lays the foundation for discovering new anti-HCC mechanism based on thrombin. BX-2 can be used as an anti-HCC drug lead for further research.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Camundongos , Animais , Dabigatrana/farmacologia , Dabigatrana/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Trombina/metabolismo , Sorafenibe/farmacologia , Neoplasias Hepáticas/tratamento farmacológicoRESUMO
Background: Trastuzumab (TRA) shows significant efficacy in patients with human epidermal growth factor receptor 2 (HER2)-positive gastric cancer (GC). While TRA can help treat HER2-positive breast cancer, TRA resistance is a key clinical challenge. Nestin reportedly regulates the cellular redox homeostasis in lung cancer. This study aimed at identifying the functions of Nestin on the TRA sensitivity of HER2-positive GC cells. Methods: Real-time polymerase chain reaction (PCR) and Western blotting (WB) were performed to explore the association between the mRNA and protein expression profiles, respectively, of Nestin and the Keap1-Nrf2 pathway. The influence of Nestin overexpression on the in vitro sensitivity of GC cells to TRA was explored by Cell Counting Kit-8 (CCK-8) assay, colony formation assay, reactive oxygen species (ROS) detection, and flow cytometry. Results: TRA treatment caused Nestin downregulation in two HER2-positive GC cell lines (MKN45 and NCI-N87). Nestin overexpression reduced the sensitivity of GC cells to TRA. The expression and activity of Nrf2 and relevant downstream antioxidant genes were increased by Nestin overexpression. Nestin overexpression also significantly suppressed TRA-induced apoptosis and ROS generation. In vivo tumor growth experiment with female BALB/c nude mice indicated that Nestin upregulation restored the tumor growth rate which was inhibited by TRA treatment. Conclusions: Collectively, the inhibitory effect of Nestin on the TRA sensitivity of cells to TRA was confirmed in this study. These results imply that the antioxidant Nestin-Nrf2 axis may play a role in the mechanism underlying the resistance of GC cells to TRA.
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Not Abstract.
RESUMO
OBJECTIVE: To observe the efficacy of ursodeoxycholic acid (UDCA) combined with glucocorticoids in the treatment of autoimmune hepatitis-primary biliary cirrhosis (AIH-PBC) overlap syndrome. METHODS: 19 patients with AIH-PBC overlap syndrome were divided randomly into two groups: initiate combined group and initiate UDCA-monotherapy group. Biochemical responses and pathological features before and after treatment were analyzed retrospectively with student's t test, Wilcoxon rank sum test and Fisher's exact method. RESULTS: In the initiate combination group, biochemical responses in terms of AIH features (ALT decline to normal, IgG is less than or equal to 16 g/L) and PBC features (ALP decline ≥ 40% or to normal) were achieved. In UDCA-monotherapy group, no statistical difference existed in biochemical responses before adding glucocorticoids, whereas the levels of ALT, AST, GLB and IgG decreased significantly when combined with glucocorticoids. No statistical difference of rates of biochemical responses eixted between the two groups, whereas variance could be seen in different pathological stages. Alleviation of inflammatory infiltration after therapy appeared in 3 patients. CONCLUSION: Combination therapy of UDCA with glucocorticoids could be suitable for AIH-PBC overlap syndrome. Early treatment is of benefit for achieving better biochemical response and pathological improvement.
Assuntos
Glucocorticoides/uso terapêutico , Hepatite Autoimune/tratamento farmacológico , Cirrose Hepática Biliar/tratamento farmacológico , Ácido Ursodesoxicólico/uso terapêutico , Adulto , Alanina Transaminase/análise , Quimioterapia Combinada , Feminino , Glucocorticoides/administração & dosagem , Hepatite Autoimune/complicações , Humanos , Imunoglobulina G/análise , Cirrose Hepática Biliar/complicações , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Ácido Ursodesoxicólico/administração & dosagemRESUMO
OBJECTIVE: To assess the therapeutic effect of primary biliary cirrhosis(PBC) in different stages with ursodeoxycholic acid (UDCA). METHODS: 91 patients with PBC were divided into 4 periods based on levels of liver test and symptoms. Clinical manifestations, biochemical changes and pathological changes were observed for 2 years on UDCA therapy. RESULTS: The levels of alkaline phosphatase (ALP) and glutamyltranspetidase (GGT) at the second PBC period were declined by 51.9% and 67.3% respectively after a 6-month UDCA therapy. The biochemical responses were 81.25% (Paris criteria) and 93.75% (Barcelona criteria). The levels of ALP and GGT at the third PBC period were declined by 48.8% and 46.6% after 6 months of UDCA therapy, and the biochemical responses were 36.84% (Paris criteria) and 57.89% (Barcelona criteria). Symptoms like fatigue, pruritus and jaundice after UDCA therapy were better than before. Same results also appeared at the fourth period. 11 patients in different periods underwent pathological examinations before and after UDCA therapy and no progression found in the first and the second periods, however difference found in the third and the fourth periods with the lymphocyte infiltration was less than before UDCA treatment. CONCLUSION: Good biochemical responds appear in patients at the second, third and forth periods after UDCA therapy, in which the second period is best. Symptoms could be improved after UDCA treatment. Early UDCA therapy is benefit for slowing down the progression of liver pathology.
Assuntos
Cirrose Hepática Biliar/tratamento farmacológico , Cirrose Hepática Biliar/patologia , Ácido Ursodesoxicólico/uso terapêutico , Adulto , Progressão da Doença , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
Autoimmune hepatitis (AIH) is a complex multifactorial liver disease with unknown etiology. It may be induced by certain triggers that cause immune disorders and autoimmune attack in genetically susceptible individuals, which ultimately results in chronic persistent interface inflammation of the liver. The diagnosis of AIH is made based on comprehensive evaluation score system. All AIH patients should receive interventions and the mainstay therapy is prednisone alone or in combination with azathioprine. Further exploratory researches on refractory AIH have been developed. Liver transplantation is still the only effective option for patients with decompensated cirrhosis or hepatic failure.