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Colorectal cancer (CRC) is one of the world's most common and deadly cancers. According to GLOBOCAN2020's global incidence rate and mortality estimates, CRC is the third main cause of cancer and the second leading cause of cancer-related deaths worldwide. The US Food and Drug Administration has approved auranofin for the treatment of rheumatoid arthritis. It is a gold-containing chemical that inhibits thioredoxin reductase. Auranofin has a number of biological activities, including anticancer activity, although it has not been researched extensively in CRC, and the mechanism of action on CRC cells is still unknown. The goal of this research was to see how Auranofin affected CRC cells in vivo and in vitro . The two chemical libraries were tested for drugs that make CRC cells more responsive. The CCK-8 technique was used to determine the cell survival rate. The invasion, migration, and proliferation of cells were assessed using a transwell test and a colony cloning experiment. An electron microscope was used to observe autophagosome formation. Western blotting was also used to determine the degree of expression of related proteins in cells. Auranofin's tumor-suppressing properties were further tested in a xenograft tumor model of human SW620 CRC cells. Auranofin dramatically reduced the occurrence of CRC by decreasing the proliferation, migration, and invasion of CRC cells, according to our findings. Through a mTOR-dependent mechanism, auranofin inhibits the epithelial-mesenchymal transition (EMT) and induces autophagy in CRC cells. Finally, in-vivo tests revealed that auranofin suppressed tumor growth in xenograft mice while causing no harm. In summary, auranofin suppresses CRC cell growth, invasion, and migration. Auranofin inhibits the occurrence and progression of CRC by decreasing EMT and inducing autophagy in CRC cells via a mTOR-dependent mechanism. These findings suggest that auranofin could be a potential chemotherapeutic medication for the treatment of human CRC.
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Auranofina , Neoplasias Colorrectales , Humanos , Animales , Ratones , Auranofina/farmacología , Auranofina/uso terapéutico , Línea Celular Tumoral , Serina-Treonina Quinasas TOR/metabolismo , Neoplasias Colorrectales/patología , Autofagia , Transición Epitelial-Mesenquimal , Movimiento Celular , Proliferación Celular , Regulación Neoplásica de la Expresión GénicaRESUMEN
Oridonin, which is an ent-kaurene diterpenoid isolated from traditional Chinese medicine Rabdosia rubescens, displays various bioactivities, including anti-inflammation, anti-bacteria and anti-tumor. This study aimed to investigate the effect of oridonin on apoptosis of triple-negative breast cancer MDA-MB-231 cells and its underlying mechanisms. The inhibitory effect of oridonin on proliferation of MDA-MB-231 cells was measured by MTT assay; Apoptosis was analyzed by flow cytometry with PI staining and Annexin V-FITC/PI staining; Intracellular reactive oxygen species (ROS) level was determined by ROS detection kit, and expressions of PARP, Bcl-2, caspase-3 were analyzed by Western blot. The results showed that oridonin exhibited a significant effect in inducing apoptosis of MDA-MB-231 cells, enhancing intracellular ROS level, down-regulating expression of Bcl-2 protein, and promoting cleavage of caspase-3 and its substrate PARP. These results indicated that the apoptosis-inducing effect of oridonin on MDA-MB-231 cells might be correlated with increase of intracellular ROS level, down-regulation of Bcl-2 protein and activation of caspase-3.
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Apoptosis/efectos de los fármacos , Diterpenos de Tipo Kaurano/farmacología , Especies Reactivas de Oxígeno/metabolismo , Caspasa 3/metabolismo , Línea Celular Tumoral , Proliferación Celular , Humanos , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Neoplasias de la Mama Triple NegativasRESUMEN
Objective: The Lactate-to-Albumin Ratio (LAR) has been applied as a new predictor in sepsis, heart failure, and acute respiratory failure. However, the role of LAR in predicting all-cause mortality in patients with acute pancreatitis has not been evaluated. Therefore, this study aimed to elucidate the correlation between LAR and 28-d all-cause mortality in patients with Acute Pancreatitis (AP). Methods: This study is a retrospective cohort study with the data from the MIMIC-IV (v1.0) database. We included adult patients with acute pancreatitis who were admitted to the intensive care unit in the study. The primary outcome was to evaluate the ability of LAR to predict death at 28-d of hospital admission in patients with AP. Results: A total of 539 patients with acute pancreatitis were included in this study. They were divided into a survival group (486 patients) and a death group (53 patients) according to whether they survived within 28-d of admission, and the mortality rate of patients within 28-d of admission was 9.8%. LAR was shown to be an independent predictor of all-cause mortality within 28-d of admission in patients with AP by multivariate COX regression analysis (HR, 1.59; 95% CI, 1.23 - 2.05; P < 0.001). the Area Under the Curve (AUC) value for LAR was 74.26% (95% CI: 67.02% - 81.50%), which was higher than that for arterial blood lactate (AUC = 71.25%) and serum albumin (AUC = 65.92%) alone. It was not inferior even when compared to SOFA (AUC = 75.15%). The optimal cutoff value for separating the survival and death groups according to Receiver Operating Characteristic (ROC) was found to be 1.1124. plotting Kaplan-Meier analysis with this cutoff value showed that patients with LAR ≥ 1.1124 had significantly higher all-cause mortality within 28-d of admission than those with LAR < 1.1124 (P < 0.001). The final subgroup analysis showed no significant interaction of LAR with each subgroup (P for interaction: 0.06 - 0.974). Conclusion: LAR can be used as an independent predictor of all-cause mortality in AP patients within 28-d of admission, with superior prognostic performance than arterial blood lactate or serum albumin alone.
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Pancreatitis , Adulto , Humanos , Estudios Retrospectivos , Ácido Láctico , Enfermedad Aguda , Albúmina SéricaRESUMEN
AIM: To investigate the distribution of amoxicillin in the gastric juice and gastric mucosa of rats and to investigate the effects of proton pump inhibitor rabeprazole on amoxicillin concentrations in various compartments. METHODS: One hundred and sixty anesthetized rats were divided into five groups, and given intravenously different doses of amoxicillin or amoxicillin and rabeprazole. The pH value and volume of gastric juice was aspirated were measured and separated gastric mucosa was homogenized. The concentrations of amoxicillin in the plasma, gastric juice and gastric mucosa were measured by high performance liquid chromatography (HPLC). RESULTS: The maximum concentrations of amoxicillin in gastric juice and gastric mucosa were significantly lower than those in plasma (P<0.001). Concentrations in the glandular stomach mucosa were higher than those in the forestomach mucosa. Rabeprazole did not significantly change the pharmacokinetic parameters of amoxicillin in the plasma and did not alter gastric antibiotic clearance or the gastric transfer fraction of amoxicillin in gastric juice. However, rabeprazole did increase the amoxicillin concentration and pH value in gastric juice and reduced the volume of the gastric juice. CONCLUSION: Amoxicillin could penetrate the gastric mucosa and achieve therapeutic concentrations at the target site after transfer from the blood to the stomach. Rabeprazole increased the amoxicillin concentration in gastric juice by decreasing the gastric juice volume but did not affect its concentration in blood or gastric mucosa.
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2-Piridinilmetilsulfinilbencimidazoles/farmacología , Amoxicilina/farmacocinética , Antibacterianos/farmacocinética , Jugo Gástrico/metabolismo , Mucosa Gástrica/metabolismo , Inhibidores de la Bomba de Protones/farmacología , Animales , Cromatografía Líquida de Alta Presión , Masculino , Rabeprazol , Ratas , Ratas WistarRESUMEN
OBJECTIVE: To investigate the effect of small interfering RNA (siRNA)-mediated silencing of monocarboxylate transporter 1 (MCT1) on the sensitivity of drug-resistant nasopharyngeal carcinoma HNE1/DDP cells to cisplatin (DDP)-induced apoptosis and explore the possible mechanism. METHODS: The expression of MCT1 was analyzed in HNE1 and HNE1/DDP cells and in HNE1/DDP cells transfected with siRNA using Western blot. MTT assay was used to assess the inhibitory effect of different concentrations of DDP alone or in combination with MCT1 siRNA on the proliferation of HNE1/DDP cells. The apoptosis of cells treated with MCT1 siRNA or/and DDP (8 µmol/L) was assessed using flow cytometry with PI staining, and the mitochondrial membrane potential was detected using JC-1 staining assay; the expressions of Mcl-1, Bak, Bcl-2, and Bax were analyzed using Western blotting. RESULTS: HNE1/DDP cells showed a high expression of MCT1, and MCT1 silencing using siRNA significantly increased the sensitivity of HNE1/DDP cells to DDP (P<0.05) and partly reversed DDP resistance of the cells. MCT1 silencing enhanced the sensitivity of HNE1/DDP cells to DDP-induced apoptosis. Treatment of HNE1/DDP cells with MCT1 siRNA combined with 8 µmol/L DDP for 24 h resulted in an apoptotic rate of (51.23∓2.86)%, significantly higher than that in cells treated with MCT1 siRNA or DDP alone (P<0.05). The combined treatment also reduced the mitochondrial membrane potential, down-regulated the expression of Mcl-1 and Bcl-2, and up-regulated the expression of Bax in the DDP-resistant cells. CONCLUSION: MCT1 siRNA can enhance the sensitivity of HNE1/DDP cells to DDP-induced apoptosis, the mechanism of which may involve the down-regulation of Mcl-1 and Bcl-2 and up-regulation of Bax expression.
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OBJECTIVE: To investigate the role of monocarboxylate transporter 1 (MCT1) in enhancing the sensitivity of breast cancer cells to 3-bromopyruvate (3-BrPA). METHODS: The inhibitory effect of 3-BrPA on the proliferation of breast cancer cells was assessed with MTT assay, and brominated propidium bromide single staining flow cytometry was used for detecting the cell apoptosis. An ELISA kit was used to detect the intracellular levels of hexokinase II, lactate dehydrogenase, lactate, and adenosine triphosphate, and Western blotting was performed to detect the expression of MCT1. MDA-MB-231 cells were transiently transfected with MCT1 cDNA for over-expressing MCT1, and the effect of 3-BrPA on the cell proliferation and adenosine triphosphate level was deteced. RESULTS: 3-BrPA did not produce significant effects on the proliferation and apoptosis of MDA-MB-231 cells, and the cells treated with 200 µmol/L 3-BrPA for 24 h showed an inhibition rate and an apoptosis rate of only 8.72% and 7.8%, respectively. The same treatment, however, produced an inhibition rate and an apoptosis rate of 84.6% and 82.3% in MCF-7 cells, respectively. In MDA-MB-231 cells with MCT1 overexpression, 200 µmol/L 3-BrPA resulted in an inhibition rate of 72.44%, significantly higher than that in the control cells (P<0.05); treatment of the cells with 25, 50, 100, and 200 µmol/L 3-BrPA for 6 h resulted in intracellular adenosine triphosphate levels of 96.98%, 88.44%, 43.3% and 27.56% relative to the control level respectively. CONCLUSION: MCT1 can enhance the sensitivity of breast cancer cells to 3-BrPA possibly by transporting 3-BrPA into cells to inhibit cell glycolysis.
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Neoplasias de la Mama/metabolismo , Proliferación Celular , Transportadores de Ácidos Monocarboxílicos/metabolismo , Piruvatos/farmacología , Simportadores/metabolismo , Apoptosis , Línea Celular Tumoral , HumanosRESUMEN
BACKGROUND & OBJECTIVE: Cyclooxygenase (COX) plays an important role in tumorigenesis and development. Many inhibitors of COX could inhibit proliferation and induce apoptosis of cancer cells. This study was to observe the inhibitory effect of Aspisol on growth of transplanted breast cancer in C3H mice and the effects of Aspisol on tumor cell apoptosis and the expression of Caspase-3 and COX-2, and explore the mechanisms. METHODS: The suspension of breast cancer cells was injected subcutaneously into forelimb axillas of C3H mice to establish xenograft models. From the next day, the mice received intraperitoneal injection of different concentrations of Aspisol once a day for 28 days; the mice received injection of 5-fluorouracil (5-FU) were used as positive controls, and the mice received injection of normal saline (NS) were used as negative controls. The inhibition rate of tumor growth was calculated. Tumor cell apoptosis was detected by TUNEL assay. The expression of Caspase-3 and COX-2 was detected by immunohistochemistry. RESULTS: The inhibition rate of tumor growth was 38.9% in 175 mg/kg Aspisol group, 48.2% in 350 mg/kg Aspisol group, 47.0% in 700 mg/kg Aspisol group, and 60.4% in 10 mg/kg 5-FU group. Typical apoptotic morphologic changes were seen in the 4 groups. Caspase-3 expression was significantly higher and COX-2 expression was significantly lower in Aspisol groups than in NS group. CONCLUSIONS: Aspisol may inhibit the growth of transplanted breast cancer in C3H mice, and induce tumor cell apoptosis. The mechanism may be correlated to down-regulation of COX-2 and up-regulation of Caspase-3.