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Cabozantinib, mainly targeting cMet and vascular endothelial growth factor receptor 2, is the second-line treatment for patients with advanced hepatocellular carcinoma (HCC). However, the lower response rate and resistance limit its enduring clinical benefit. In this study, we found that cMet-low HCC cells showed primary resistance to cMet inhibitors, and the combination of cabozantinib and mammalian target of rapamycin (mTOR) inhibitor, rapamycin, exhibited a synergistic inhibitory effect on the in vitro cell proliferation and in vivo tumor growth of these cells. Mechanically, the combination of rapamycin with cabozantinib resulted in the remarkable inhibition of AKT, extracellular signal-regulated protein kinases, mTOR, and common downstream signal molecules of receptor tyrosine kinases; decreased cyclin D1 expression; and induced cell cycle arrest. Meanwhile, rapamycin enhanced the inhibitory effects of cabozantinib on the migration and tubule formation of human umbilical vascular endothelial cells and human growth factor-induced invasion of cMet inhibitor-resistant HCC cells under hypoxia condition. These effects were further validated in xenograft models. In conclusion, our findings uncover a potential combination therapy of cabozantinib and rapamycin to combat cabozantinib-resistant HCC.
Subject(s)
Animals , Humans , Anilides/pharmacology , Carcinoma, Hepatocellular/drug therapy , Cell Line, Tumor , Cell Proliferation , Endothelial Cells/metabolism , Liver Neoplasms/drug therapy , Pyridines/pharmacology , Sirolimus/pharmacology , Xenograft Model Antitumor AssaysABSTRACT
Objective:To analyze the effects of proton pump inhibitors(PPIs)on the prevention of stress ulcers(SU)in elderly patients with acute respiratory distress syndrome(ARDS), and to analyze related factors for the risk of short-term death.Methods:This study was a multicenter retrospective cohort study.Two hundred elderly ARDS patients diagnosed and treated at Peking University International Hospital, Anzhen Hospital and Ezhou Central Hospital from November 2017 to December 2019 were continuously included.These patients were treated with PPIs(omeprazole, pantoprazole, rabeprazole, lansoprazole and esomeprazole)within 48 hours after ICU admission to prevent SU and were considered as the PPI group.According to the propensity score matching method, 200 elderly ARDS patients admitted to the hospitals with similar ages, medical history and sequential organ failure assessment(SOFA)scores who did not use PPIs were selected as the control group.All patients were followed up for 30 days.Kaplan-Meier survival analysis and the log-rank test were used to compare the 30-day mortality risk between the two groups.Cox regression analysis was used to analyze the relevant factors affecting the 30-day mortality.The 30-day mortality risk and the incidence of clinically significant gastrointestinal bleeding were evaluated among patients using different PPIs.Results:The average time of PPI use was 8.4±4.4 d in the PPI group.In the control group, 38.0% of patients were treated with H 2 receptor antagonists, and the average time of use was 8.1±5.2 days.There was no significant difference in the 30-day all-cause mortality risk between the two groups(20.5% or 41 cases vs.23.5% or 47 cases, P>0.05). The incidences of clinically significant upper gastrointestinal tract bleeding(2.5% or 5 cases vs.7.0% or 14, P<0.05), gastrointestinal bleeding(5.5% or 11 cases vs.12.5% or 25 cases, P<0.05)and hospital-acquired pneumonia(9.0% or 18 vs.4.0% or 8 cases, P<0.05)had significant differences between the PPI group and the control group.Multivariate Cox regression analysis showed that age>70 years( HR=1.845, 95% CI: 1.131-3.010, P<0.05), arterial oxygen partial pressure <78.0 mmHg(1 mmHg=0.133 kPa, HR=2.143, 95% CI: 1.317-3.487, P<0.01), SOFA score>14( HR=3.603, 95% CI: 1.741-7.456, P<0.01)and blood lactic acid>3.8 mmol/L( HR=2.725, 95% CI: 1.437-5.167, P<0.01)were related factors for the 30-day mortality.Compared with the control group, there was no significant difference in 30-day mortality between the five subgroups taking different PPIs including omeprazole, pantoprazole, rabeprazole, lansoprazole and esomeprazole( P>0.05), and the incidence of clinically significant gastrointestinal bleeding was significantly reduced( P<0.05), but there was no significant difference between the five PPIs subgroups( P>0.05). Conclusions:Although PPIs have no effect on short-term death in elderly ARDS patients, it can increase the risk of hospital acquired pneumonia while reducing the occurrence of gastrointestinal bleeding.With PPI use, advanced age, low arterial oxygen partial pressure, high SOFA score and high blood lactate are risk factors for the 30-day mortality.
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BACKGROUND:Acellular matrix and annulus fibrosus-derived stem cells are both derived from the annulus tissue, and their tissue engineering complexes may have better biocompatibility. OBJECTIVE:To culture rabbit annulus fibrosus-derived stem cells on the porcine decellularized annulus fibrosus matrix, and to observe the growth of annulus fibrosus-derived stem cells on the decellularized matrix scaffold. METHODS:Decellularized annulus fibrosus matrix from porcine was prepared and detected by scanning electron microscopy, DAPI staining and Fourier transform infrared spectroscopy analysis. After isolation and culture, annulus fibrosus-derived stem cells were seeded onto the decellularized annulus fibrosus matrix. cellgrowth on the scaffolds was observed by cytoskeleton staining, inverted immunofluorescence microscopy and scanning electron microscopy to draw cellgrowth curve. RESULTS AND CONCLUSION:The prepared decellularized annulus fibrosus matrix was white and translucence liquid. The result of Fourier transform infrared spectroscopy indicated that the main component of the decellularized annulus fibrosus matrix was col agen. DAPI staining and scanning electron microscopy results showed no cells resident. The cytoskeleton staining displayed that annulus fibrosus-derived stem cells grew wel on the scaffolds at 1, 3, 7 days. These findings indicated that annulus fibrosus-derived stem cells have a good biocompatibility with the decellularized annulus fibrosus matrix in vitro.
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Intravenous and intratracheal implantation of mesenchymal stem cells (MSCs) may offer ameliorating effects on pulmonary hypertension (PH) induced by monocrotaline (MCT) in rats. The aim of this study was to examine the anti-remodeling effect of intravenous MSCs (VMSCs) and intratracheal MSCs (TMSCs) in rats with PH, and the underlying mechanisms. MSCs were isolated from rat bone marrow and cultured. PH was induced in rats by intraperitoneal injection of MCT. One week after MCT administration, the rats were divided into 3 groups in terms of different treatments: VMSCs group (intravenous injection of MSCs), TMSCs group (intratracheal injection of MSCs), PH group (no treatment given). Those receiving saline instead of MCT served as negative control (control group). Pulmonary arterial structure was pathologically observed, pulmonary arterial dynamics measured, and remodeling-associated cytokines Smad2 and Smad3 detected in the lungs, three weeks after MCT injection. The results showed that PH group versus control group had higher pulmonary arterial pressure (PAP) and wall thickness index (WTI) 21 days after MCT treatment. The expression of phosphorylated (p)-Smad2 and the ratio of p-Smad2/Smad2 were much higher in PH group than in control group. Fluorescence-labeled MSCs were extensively distributed in rats' lungs in VMSCs and TMSCs groups 3 and 14 days after transplantation, but not found in the media of the pulmonary artery. WTI and PAP were significantly lower in both VMSCs and TMSCs groups than in PH group three weeks after MCT injection. The p-Smad2 expression and the ratio of p-Smad2/Smad2 were obviously reduced in VMSCs and TMSCs groups as compared with those in PH group. In conclusion, both intravenous and intratracheal transplantation of MSCs can attenuate PAP and pulmonary artery remodeling in MCT-induced PH rats, which may be associated with the early suppression of Smad2 phosphorylation via paracrine pathways.
ABSTRACT
Intravenous and intratracheal implantation of mesenchymal stem cells (MSCs) may offer ameliorating effects on pulmonary hypertension (PH) induced by monocrotaline (MCT) in rats. The aim of this study was to examine the anti-remodeling effect of intravenous MSCs (VMSCs) and intratracheal MSCs (TMSCs) in rats with PH, and the underlying mechanisms. MSCs were isolated from rat bone marrow and cultured. PH was induced in rats by intraperitoneal injection of MCT. One week after MCT administration, the rats were divided into 3 groups in terms of different treatments: VMSCs group (intravenous injection of MSCs), TMSCs group (intratracheal injection of MSCs), PH group (no treatment given). Those receiving saline instead of MCT served as negative control (control group). Pulmonary arterial structure was pathologically observed, pulmonary arterial dynamics measured, and remodeling-associated cytokines Smad2 and Smad3 detected in the lungs, three weeks after MCT injection. The results showed that PH group versus control group had higher pulmonary arterial pressure (PAP) and wall thickness index (WTI) 21 days after MCT treatment. The expression of phosphorylated (p)-Smad2 and the ratio of p-Smad2/Smad2 were much higher in PH group than in control group. Fluorescence-labeled MSCs were extensively distributed in rats' lungs in VMSCs and TMSCs groups 3 and 14 days after transplantation, but not found in the media of the pulmonary artery. WTI and PAP were significantly lower in both VMSCs and TMSCs groups than in PH group three weeks after MCT injection. The p-Smad2 expression and the ratio of p-Smad2/Smad2 were obviously reduced in VMSCs and TMSCs groups as compared with those in PH group. In conclusion, both intravenous and intratracheal transplantation of MSCs can attenuate PAP and pulmonary artery remodeling in MCT-induced PH rats, which may be associated with the early suppression of Smad2 phosphorylation via paracrine pathways.
Subject(s)
Animals , Male , Rats , Atrial Remodeling , Physiology , Hypertension, Pulmonary , Mesenchymal Stem Cells , Pathology , Monocrotaline , Pharmacology , Pulmonary Artery , Rats, Sprague-DawleyABSTRACT
Objective To investigate the expression and distribution of 5-hydroxytryptamine 7(5-HT7)receptor in brain and intestine of rats with different subtype of irritable bowel syndrome(IBS).Methods Forty-five SD rats were divided into healthy contral.diarrhea-predominant(IBS-D)and consti pation-predominant(IBS-C)IBS groups.IBS-D and IBS-C models were established by either colonic instillation of acetic acid and restraint stress or stomach irrigation with cool water(0-4℃).The expression and distribution of 5-HT7 receptor at brain and intestine were determined by immunohistochemistry and real-time PCR.The tissue concentration of cyclic AMP(cAMP)was examined by radioimmunoassay.Results Immunohistochemistry study demonstrated that the staining of 5-HT7 receptor at hippocampus and hypothalamus were strong in IBS-C and IBS-D groups compared to control group(P＜0.01),The staining of 5-HT7 receptor at ileum,proximal colon and distal colon were higher in IBS-C group than those in control group(P＜0.05).Real-time PCR revealed that the expression of 5-HT7 receptor at hippocampus and hypothalamus were higher in IBS-C and IBS-D groups than those in control group(P＜0.05).and the expression at ileum and colon were remarkably higher in IBS-C group compared to control group(P＜0.05).The concentration of cAMP at hippocampus and hypothalamus were higher in IBS-C and IBS-D groups than those in control group(P＜0.01,P＜0.05).The cAMP level at proximal and distal colon in IBS-C group was higher than those in control group(P＜0.05).Conclusion The upregulation of 5-HT7 receptor in brain and intestine may be related with the dyskinesis and visceral paresthesia of IBS-C.
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OBJECTIVE:To study the antiulcer action of norfloxacin zinc(NF-Zn) METHODS:Acute and chronic gastric ulcer models were established in rats and the in vitro action of neutralizing hydrochloric acid and the MIC for Hp of NF-Zn were determined RESULTS:NF-Zn could inhibit the formation of acute gastric ulcer induced by ethanol,stress and salicylic acid in rats,accelerate the healing of chronic gastric ulcer produced by acetic acid,inhibit the secretion of gastric acid and increase the pH in gastric juice In vitro,NF-Zn could neutralize HCl and inhibit Hp with MIC50 of 0 5?g/ml CONCLUSION:The results suggest that the antiulcer action of NF-Zn may be related with its protection of the gastric mucosal barrier,neutralization of acid and inhibition of Hp
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OBJECTIVE:To screen the formulae of norfloxacin zinc(NF-Zn) suspended granules using uniform design METHODS:The uniform design with 5 levels and 4 factors was employed to screen five formulae of NF-Zn and sedimentation rate,granularity,dissolubility,moisture content and taste of these granules were evaluated and scored The total score of each formula was regressed with the 4 factors by computer RESULTS:The results of regression equation suggested that the optimum formula was NF-Zn 0 2g,CMS-Na 0 25g,2%PVP and manitol 0 55g in each packet CONCLUSION:It is effective and convenient to optimize the formula of NF-Zn granules by uniform design