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BACKGROUND@#Liver cancer is largely resistant to chemotherapy. This study aimed to identify the effective chemotherapeutics for β-catenin-activated liver cancer which is caused by gain-of-function mutation of catenin beta 1 ( CTNNB1 ), the most frequently altered proto-oncogene in hepatic neoplasms.@*METHODS@#Constitutive β-catenin-activated mouse embryonic fibroblasts (MEFs) were established by deleting exon 3 ( β-catenin Δ(ex3)/+ ), the most common mutation site in CTNNB1 gene. A screening of 12 widely used chemotherapy drugs was conducted for the ones that selectively inhibited β-catenin Δ(ex3)/+ but not for wild-type MEFs. Untargeted metabolomics was carried out to examine the alterations of metabolites in nucleotide synthesis. The efficacy and selectivity of methotrexate (MTX) on β-catenin-activated human liver cancer cells were determined in vitro . Immuno-deficient nude mice subcutaneously inoculated with β-catenin wild-type or mutant liver cancer cells and hepatitis B virus ( HBV ); β-catenin lox(ex3)/+ mice were used, respectively, to evaluate the efficacy of MTX in the treatment of β-catenin mutant liver cancer.@*RESULTS@#MTX was identified and validated as a preferential agent against the proliferation and tumor formation of β-catenin-activated cells. Boosted nucleotide synthesis was the major metabolic aberration in β-catenin-active cells, and this alteration was also the target of MTX. Moreover, MTX abrogated hepatocarcinogenesis of HBV ; β-catenin lox(ex3)/+ mice, which stimulated concurrent Ctnnb1- activated mutation and HBV infection in liver cancer.@*CONCLUSION@#MTX is a promising chemotherapeutic agent for β-catenin hyperactive liver cancer. Since repurposing MTX has the advantages of lower risk, shorter timelines, and less investment in drug discovery and development, a clinical trial is warranted to test its efficacy in the treatment of β-catenin mutant liver cancer.
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Mice , Animals , Humans , Methotrexate/therapeutic use , Mice, Nude , beta Catenin/metabolism , Fibroblasts/metabolism , Liver Neoplasms/metabolism , Hepatitis B virus , NucleotidesABSTRACT
ObjectiveTo investigate the pharmacodynamic characteristics and explore the molecular mechanism of Honghua oral liquid （HOL） in relieving neuropathic pain （NP）. MethodHealthy male SD rats were randomly assigned into sham group， model group， low-， medium-， high-dose （0.5， 1.0， 2.0 mL·kg-1·d-1， respectively） HOL groups， and a positive drug （pregabalin， 25 mg·kg-1·d-1） group， with 6 rats in each group. Spinal nerve ligation （SNL） of L5 was conducted in other groups except the sham group. Drug administration was performed 3 days after the SNL surgery for 2 consecutive weeks， and samples were collected after the end of the administration. During the treatment period， the mechanical pain threshold and cold pain threshold were determined to measure the pain-relieving effect of HOL. Transcriptome sequencing was performed on hippocampal tissue samples from the sham， model， and high-dose HOL groups， and differentially expressed genes between the sham group and the model group as well as the model group and HOL high-dose group were obtained. After pathway enrichment analysis， we selected the targets which were closely related to neuroinflammation for validation， and predicted the specific binding sites of the major active components in HOL with the targets through molecular docking. In addition， the serum levels of tumor necrosis factor-α （TNF-α） and interleukin-10 （IL-10） were determined by enzyme-linked immunosorbent assay （ELISA） to evaluate the effect of HOL on neuroinflammation in NP rats. ResultCompared with the sham group， SNL decreased the mechanical pain threshold and cold pain threshold （P<0.05）. Compared with the model group， HOL recovered the mechanical pain threshold and cold pain threshold （P<0.05）. The transcriptome data showed that 376 differentially expressed genes （DEGs） were identified between the model group and the sham group， including 124 upregulated genes and 252 downregulated genes， and 194 DEGs between the model group and the high-dose HOL group， including 33 upregulated genes and 161 downregulated genes. Among them， insulin-like growth factor 1（IGF1）， matrix metallopeptidase-2 （MMP-2）， matrix metallopeptidase-14 （MMP-14）， erb-B2 receptor tyrosine kinase 2 （ERBB2）， and integrin subunit alpha 5 （ITGA5） associated with NP were selected for further validation. The Real-time fluorescence quantitative polymerase chain reaction（Real-time PCR） results showed that compared with the sham group， the modeling up-gurelated the mRNA levels of the above five molecules in the hippocampus （P<0.01）. Compared with model group， HOL down-regulated the mRNA levels of these molecules （P<0.01）. The molecular docking results showed that the main active components of safflower， hydroxysafflor yellow A， kaempferol， and quercetin， formed stable hydrogen bonds with the amino acid residues of IGF1， MMP-2， MMP-14， ERBB2， and ITGA5. The enzyme-linked immunosorbent assay（ELISA） results showed that compared with those in the sham group， the serum levels of TNF-α and IL-10 were out of balance in the model rats （P<0.01）. Compared with the model group， HOL lowered the level of the pro-inflammatory cytokine TNF-α （P<0.01） and elevated that of the anti-inflammatory cytokine IL-10 （P<0.05）. ConclusionHOL exerts analgesic effect on SNL rats by inhibiting neuroinflammation.
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Objective:To investigate the significance of ventricular intracranial pressure monitoring in the treatment of traumatic multiple intracranial hematoma (TMIH).Methods:The clinical data of 14 TMIH patients treated with ventricular intracranial pressure monitoring from January 2016 to August 2021 in Beijing Luhe Hospital, Capital Medical University were analyzed retrospectively. The patients were followed up 6 months after injury, and the Glasgow outcome score (GOS) was assessed.Results:All the 14 patients successfully completed ventricular intracranial pressure probe placement. Among them, 8 patients recovered well after continuous monitoring of ventricular intracranial pressure and continuous cerebrospinal fluid drainage. Their ventricular intracranial pressure probe was placed for 5 to 10 (7.3 ± 2.2) d, with no intracranial infection occurred; and their GOS was 5 scores 6-month follow-up after injury. Six cases underwent craniotomy for hematoma removal due to the expansion of intracranial hematoma or aggravation of edema, and decompressive craniectomy was performed during the operation; 6-month follow-up after injury, GOS of 5 scores was in 3 cases, 4 scores in 2 cases, 3 scores in 1 case.Conclusions:The condition of TMIH patients is complex and changeable, and ventricular intracranial pressure monitoring can improve the prognosis of TMIH patients.
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Objective:To observe the changes of macular microvascular structure and macular pigment density (MPOD) in eyes with macular edema (ME) secondary to retinal vein occlusion (RVO), and preliminarily analyze their correlation.Methods:A prospective clinical study. A total of 62 eyes of 62 patients with monocular RVO secondary ME (RVO-ME) diagnosed in the Ophthalmology Hospital of Xi'an No.1 Hospital from July 2020 to May 2021 were included in this study. There were 33 males with 33 eyes, 29 females with 29 eyes. The age was 58.30±12.15 years. The course of disease from the onset of symptoms to medical treatment was 12.29±7.65 days. All patients underwent best corrected visual acuity (BCVA), optical coherence tomography angiography (OCTA) and MPOD test. BCVA examination was performed using a standard logarithmic visual acuity chart, which was converted to logarithm of minimum angle of resolution (logMAR). The vascular density (VD), vascular skeletal density (SD), foveal avascular area (FAZ) and central macular thickness (CMT) of the superficial retinal capillary plexus (SCP) in the range of 3 mm×3 mm in the macular area of bilateral eyes were measured by OCTA. MPOD was measured by heterochromatic scintillation photometry. Bilateral eyes passed examination in 37 cases. The eyes of 25 patients failed to pass the test. The changes of macular VD, SD, FAZ area, CMT and MPOD between the affected eyes and the contralateral eyes were compared. The MPOD of the affected eye and the contralateral eye was compared by paired t test. FAZ area, CMT, VD, SD, and logMAR BCVA were tested by paired Wilcoxon signed rank sum test. Spearman rank correlation test was used to analyze the correlation between macular blood flow density (VD, SD) and foveal morphology (FAZ area, CMT) with logMAR BCVA and MPOD. Results:Compared with contralateral eyes, VD ( Z=-5.981) and SD ( Z=-6.021) were decreased, FAZ area ( Z=-2.598) and CMT ( Z=-6.206) were increased, and the differences were statistically significant ( P<0.05). In 37 patients who passed MPOD test in bilateral eyes, the MPOD value of the affected eye was lower than that of the contralateral eye, and the difference was statistically significant ( t=-2.930, P<0.05). Compared with the affected eye which failed to pass the MPOD detection, macular VD ( Z=-2.807) and SD ( Z=-2.460) were increased, FAZ area ( Z=-4.297) and CMT ( Z=-3.796) were decreased in the affected eye which passed the MPOD test, and the differences were statistically significant ( P<0.05). Correlation analysis showed that logMAR BCVA in the affected eye was negatively correlated with macular VD and SD ( r=-0.298, -0.461; P<0.05), which was positively correlated with FAZ area and CMT ( r=0.487, 0.789; P<0.05). MPOD in the affected eye was negatively correlated with logMAR BCVA ( r=-0.344, P<0.05). MPOD in the contralateral eye was positively correlated with CMT ( r=0.358, P<0.05). Conclusions:The VD and SD of macular SCP are decreased, FAZ area is enlarged, CMT is thickened, and MPOD is decreased in RVO-ME eyes. MPOD is negatively correlated with logMAR BCVA.
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Objective:To investigate the effects of compound matrine injection on the proliferation of bladder cancer cell line BIU-87 and bladder orthotopic transplantated tumor in nude mice.Methods:BIU-87 cells in logarithmic growth phase were divided into experimental group (adding 300.00, 150.00, 75.00, 37.50, 18.75 μl/ml compound matrine injection 200μl) and negative control group (adding equal volume of culturing medium). The proliferation inhibition rate and the half inhibitory concentration ( IC50) of BIU-87 cells were detected and calculated by methyl thiazole tetrazolium (MTT) method. Twenty BALB/c-nu female nude mice were injected with 100 μl of BIU-87 cell suspension with a cell density of 2×10 7/ml in the bladder to establish an animal model of bladder orthotopic transplanted tumor. After 24 hours of perfusion of BIU-87 cell suspension, intravesical perfusion administration (100 μl per nude mouse) was started, and the mice were divided into compound matrine injection group (intravesical perfusion of matrine solution) and pirarubicin group (intravesical perfusion of 1 mg/ml pirarubicin), model control group (intravesical perfusion of the same volume of sterile water), blank control group (without intravesical perfusion of BIU-87 cell suspension or administration). The observation time was 90 d. The survival status and bladder wet weight of the animals were observed and recorded, and the tumor formation rate, tumor inhibition rate and life prolongation rate were calculated. Results:Different concentrations of compound matrine injection acted on BIU-87 cells for 48 hours, and the absorbance ( A) values ??of 300.00, 150.00, 75.00, 37.50, 18.75 μl/ml compound matrine injection group and negative control group were 0.027±0.006, 0.065±0.010, 1.695±0.105, 2.387±0.017, 2.427±0.134 and 2.721±0.080 ( F = 742.67, P < 0.05), the A values ??of each concentration of compound matrine injection group were compared with the negative control group, and the differences were statistically significant (all P < 0.05). The IC50 of compound matrine injection on BIU-87 cells was 70.05 μl/ml. On the 90th day of observation, the bladder wet weights of nude mice in blank control group, model control group, pirarubicin group and compound matrine injection group were (0.018±0.004) mg, (0.422±0.130) mg, (0.219±0.136) mg and (0.237±0.113) mg ( F = 14.01, P < 0.001), and the survival time of nude mice was (90±0) d, (54±12) d, (72±4) d and (69±8) d ( F = 18.53, P < 0.001). The inhibition rates of bladder cancer in the pirarubicin group and compound matrine injection group were 48.10% and 43.84%, and the life prolongation rates of the nude mice were 34.95% and 29.53%. Conclusions:Compound matrine injection can inhibit the proliferation of BIU-87 cells in a concentration-dependent manner. Compound matrine injection can increase the tumor inhibition rate and prolong the survival time of nude mice models of bladder orthotopic transplanted tumor.
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Objective:To investigate the risk factors of in-hospital mortality in elderly patients with traumatic brain injury (TBI).Methods:A case control study was conducted on 709 elderly patients with TBI admitted to Luhe Hospital, Capital Medical University from January 2012 to October 2018, including 468 males and 241 females; aged 60-97 years [(70.4±8.5)years]. Patients were divided into death group ( n=82) and survival group ( n=627) based on death or not during hospitalization. Data of the two groups were documented, including gender, age, causes of injury (traffic accident injury, fall injury, assault injury or others), history of comorbidities (hypertension, coronary heart disease, diabetes or coronary heart disease), Glasgow coma score (GCS) on admission, operation modalities (trepanation and drainage, hematoma evacuation, decompressive craniectomy or intracranial pressure monitoring), complications (pneumonia, stress ulcer, electrolyte imbalance, hypoproteinemia or secondary epilepsy) and length of hospitalization. Univariate analysis was used to analyze the correlation between the above factors and in-hospital mortality in elderly patients with TBI. Multivariate Logistic regression analysis was used to determine the independent risk factors for their in-hospital mortality. Results:Univariate analysis showed that sex, causes of injury, hypertension, cerebral infarction, diabetes, GCS on admission, hematoma evacuation, decompressive craniectomy, intracranial pressure monitoring, pneumonia, stress ulcer and length of hospital stay were correlated with in-hospital mortality in elderly patients with TBI ( P<0.05 or 0.01), while there was no correlation with age, history of coronary heart disease, trepanation and drainage, electrolyte imbalance, hypoproteinemia and secondary epilepsy (all P>0.05). Multivariate Logistic regression analysis showed that fall injury ( OR=0.28, 95% CI 0.08-0.96, P<0.05), hypertension ( OR=0.29, 95% CI 0.10-0.84, P<0.05),GCS of 9-12 points on admission ( OR=12.98, 95% CI 4.70-35.84, P<0.01), GCS of 3-8 points on admission ( OR=33.67, 95% CI 14.01-80.93, P<0.01) and length of hospital stay<11 days ( OR=0.06, 95% CI 0.02-0.13, P<0.01) were significantly associated with their in-hospital mortality. Conclusions:Fall injury, hypertension, GCS≤12 points on admission and length of hospital stay <11 days are independent risk factors for in-hospital mortality in elderly patients with TBI, especially that patients with GCS of 3-8 points on admission have higher in-hospital modality than patients with GCS≥ 9 points, indicating the importance of above independent risk factors in evaluating outcome.
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Immune checkpoints are the crucial regulators of immune system and play essential roles in maintaining self-tolerance, preventing autoimmune responses, and minimizing tissue damage by regulating the duration and intensity of the immune response. Furthermore, immune checkpoints are usually overexpressed in cancer cells or noninvasive cells in tumor tissues and are capable of suppressing the antitumor response. Based on substantial physiological analyses as well as preclinical and clinical studies, checkpoint molecules have been evaluated as potential therapeutic targets for the treatment of multiple types of cancers. In the last few years, extensive evidence has supported the immunoregulatory effects of traditional Chinese medicines (TCMs). The main advantage of TCMs and natural medicine is that they usually contain multiple active components, which can act on multiple targets at the same time, resulting in additive or synergistic effects. The strong immune regulation function of traditional Chinese medicine on immune checkpoints has also been of great interest. For example,
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A series of 2-(((5-akly/aryl-1-pyrazol-3-yl)methyl)thio)-5-alkyl-6-(cyclohexylmethyl)-pyrimidin-4(3)-ones were synthesized and their anti-HIV-1 activities were evaluated. Most of these compounds were highly active against wild-type (WT) HIV-1 strain (IIIB) with EC values in the range of 0.0038-0.4759 μmol/L. Among those compounds, had an EC value of 3.8 nmol/L and SI (selectivity index) of up to 25,468 indicating excellent activity against WT HIV-1. anti-HIV-1 activity and resistance profile studies suggested that compounds and displayed potential anti-HIV-1 activity against laboratory adapted strains and primary isolated strains including different subtypes and tropism strains (ECs range from 4.3 to 63.6 nmol/L and 18.9-219.3 nmol/L, respectively). On the other hand, it was observed that those two compounds were less effective with EC values of 2.77 and 4.87 μmol/L for HIV-1A (K103N + Y181C). The activity against reverse transcriptase (RT) was also evaluated for those compounds. Both and obtained sub-micromolar IC values showing their potential in RT inhibition. The pharmacokinetics examination in rats indicated that compound has acceptable pharmacokinetic properties and bioavailability. Preliminary structure-activity relationships and molecular modeling studies were also discussed.
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BACKGROUND@#The incidence and mortality of lung cancer often rank first in all malignant tumors. DNA methylation, as one of epigenetics, often participates in the development and progression of tumors. CDO1 as a tumor suppressor gene always undergoes methylation changes early in tumor development. Therefore, this study aims to discuss the value of CDO1 methylation in the early diagnosis of lung cancer.@*METHODS@#Peripheral blood samples were collected from tumor patients and healthy people. Detection of the methylation level of CDO1 in plasma by sulfite modification and quantitative real-time PCR.@*RESULTS@#The level of gene methylation in peripheral blood of lung cancer patients was significantly higher than that of benign lung disease patients and healthy people. The methylation level of CDO1 was significantly different in the stratified comparison of gender, lymph node metastasis and tumor-node-metastasis (TNM) stage (P<0.05). The sensitivity and specificity of CDO1 were 52.2% and 78.6%, respectively. The overall accuracy of the diagnosis was significantly higher than that of the clinical tumor markers, and the sensitivity of CDO1 to stage I and II patients was the highest (40.8%, 47.1%). In addition, CDO1 could effectively increase the sensitivity of diagnosis in multiple joint examinations.@*CONCLUSIONS@#Detecting the methylation level of CDO1 has a potentially huge advantage for the early diagnosis of lung cancer.
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BACKGROUND@#Lung cancer is the most common malignancy world-wide. Small cell lung cancer is the deadliest subtype of lung cancer, which features such as rapid growth, early metastasis, and high vascularization. Apatinib is a vascular endothelial growth factor receptor 2 inhibitor independently developed in China, which has a significant inhibition in a variety of solid tumors. The purpose of this study is to investigate the effects of Apatinib alone or Apatinib combined with mammalian target of rapamycin (mTOR) inhibitor, CCI-779, on small cell lung cancer cell line NCI-H446 in vitro.@*METHODS@#The small cell lung cancer cell line NCI-H446 was grew in vitro. The effects of Apatinib alone or Apatinib combined with CCI-779 on proliferation, apoptosis, cell cycle and migration of NCI-H446 small cell lung cancer cells were detected by CCK8; FACS and transwell assays were also carried out; Western blot assays were used to detect vascular endothelial growth factor and cell cycle related protein expression.@*RESULTS@#CCK8 assays showed that high concentration of Apatinib could inhibit the proliferation of NCI-H446 cells. Apoptosis assays showed that high concentration of Apatinib could induce NCI-H446 cell apoptosis. Transwell assays showed that high concentration of Apatinib could inhibit NCI-H446 cell migration. After combined with mTOR inhibitor CCI-779, low concentration of Apatinib could inhibit the proliferation and migration of NCI-H446 small cell lung cancer cells and induce apoptosis.@*CONCLUSIONS@#Apatinib has a concentration-dependent effect on the small cell lung cancer cell line NCI-H446. High concentration of Apatinib can inhibit the proliferation and migration of NCI-H446 small cell lung cancer cells, induce apoptosis. Apatinib combined with the mTOR inhibitor CCI-779 can sensitize the NCI-H446 cells to Apatinib.