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1.
Acta Pharmaceutica Sinica ; (12): 3252-3260, 2021.
Article in Chinese | WPRIM | ID: wpr-906843

ABSTRACT

Drug combination can effectively enhance the anti-tumor effect, reduce the drug dose, and improve medication safety. The use of nano-carrier for drug co-delivery can effectively avoid the differences in drug delivery behavior in vivo. Triptolide and celastrol are the main anti-tumor active components of Tripterygium wilfordii Hook f. Modern studies have shown that the combination of triptolide and celastrol can significantly enhance the antitumor effect, but they are limited by poor water solubility and low tumor tissue delivery rate. In this study, a biomimetic erythrocyte membrane liposome co-loaded with triptolide and celastrol was prepared to characterize the morphology, particle size, potential, drug release, serum stability, and other properties. The immunogenicity, uptake behavior, and anti-cell proliferation ability of the biomimetic liposome was compared. All the animal experiments were carried out in accordance with protocol evaluated and approved by the Ethics Committee of Chengdu University of Traditional Chinese Medicine (Chengdu, China). The results showed that the biomimetic erythrocyte membrane liposome co-loaded with triptolide and celastrol (C+T/RBCm@Lip) in this study had an average particle size of 119.12 ± 2.78 nm and a spherical "core-shell" structure. The zeta potential value was -16.9 ± 1.2 mV, and the drug release behavior in vitro was slow. In addition, the process of coating the cell membrane maintained the characteristics of erythrocyte membrane protein, had good stability in serum, and could effectively avoid the recognition and clearance of macrophages, without causing immunogenicity in vivo. The uptake effect of co-loaded biomimetic liposomes on HepG2 hepatocellular carcinoma cells was enhanced compared with that of uncoated cell membrane liposomes, and the inhibitory effect on proliferation of HepG2 cells was enhanced. In conclusion, the biomimetic liposomes coated with erythrocyte membrane prepared in this study is beneficial to the anti-tumor delivery of triptolide and celastrol, and could enhance the inhibitory effect on the growth of HepG2 liver cancer cells, providing a new idea for the anti-tumor application of Tripterygium wilfordii Hook f.

2.
Article in Chinese | WPRIM | ID: wpr-906138

ABSTRACT

Objective:Considering the efficacy of Gegen Qinliantang (GQT) in releasing exterior and clearing interior to alleviate dampness-heat dysentery, we analyzed the mechanism of the chloroform extract of GQT in alleviating enterotoxicity caused by irinotecan to provide an experimental basis for the development of GQT. Method:Kunming mice (<italic>n</italic>=60) were randomly divided into a blank group, a model group, a loperamide group (positive drug of loperamide hydrochloride capsule, 0.4 mg·kg<sup>-1</sup>), and high- (2.3 g·kg<sup>-1</sup>) and low-dose (1.16 g·kg<sup>-1</sup>) GQT chloroform extract groups. The mouse model of delayed diarrhea was established by intraperitoneal injection of irinotecan hydrochloride (CPT-11, 55 mg·kg<sup>-1</sup>) for four consecutive days, meanwhile, the mice in the blank group only received the same volume of normal saline. Corresponding drugs were administered by gavage on the fifth day, respectively, while the ones in the blank group and model group were given distilled water for five consecutive days. The general condition of mice in each group was observed, and diarrhea indexes of mice were recorded. Pathological changes in colon tissues of mice were observed by hematoxylin-eosin (HE) staining. The tumor necrosis factor (TNF)-<italic>α</italic>, interleukin (IL)-1<italic>β</italic>, cyclooxygenase (COX)-2, intercellular adhesion molecule (ICAM)-1, glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), malondialdehyde (MDA) and nitric oxide (NO) levels in colon tissues were detected with the assay kits. Furthermore, the expression levels of Kelch sample epoxy chloropropane associated protein 1 (Keap1), nuclear factor E<sub>2</sub> related factor 2 (Nrf2), tight junction protein-1 (ZO-1), heme oxygenase-1 (HO-1) and tight junction protein (Occludin) were detected by Western blot. Result:Compared with the blank group, the model group showed declined body weight and reduced contents of GSH-Px and SOD (<italic>P</italic><0.01), whereas increased diarrhea indexes and TNF-<italic>α</italic>, IL-1<italic>β</italic>, COX-2, ICAM-1, MDA and NO levels (<italic>P</italic><0.01). Abundant inflammatory cells and colonic mucosa with defects, swelling, bleeding, and inflammatory exudation were revealed by HE staining in the mice of the model group. The expression levels of Keap1, Nrf2, ZO-1, HO-1 and Occludin in colon tissues significantly declined (<italic>P</italic><0.01). Compared with the model group, the loperamide group and the high- and low-dose GQT chloroform extract groups exhibited improved weight loss, reduced diarrhea indexes, diminished TNF-<italic>α</italic>,<italic> </italic>IL-1<italic>β</italic>, COX-2, ICAM-1, MDA and NO, and elevated GSH-Px and SOD. HE staining indicated that the cells were compactly arranged with clear nuclei in the high- and low-dose GQT chloroform extract groups, and the expression levels of Keap1, Nrf2, HO-1, Occludin, and ZO-1 were up-regulated. Conclusion:GQT chloroform extract may alleviate CPT-11-induced delayed diarrhea by regulating inflammation and oxidative stress for enhancing the intestinal barrier function. These findings are expected to provide a reference for exploring the toxicity-attenuating effect of Chinese medicinals on chemotherapy drugs and for developing famous classical formulas.

3.
Article in Chinese | WPRIM | ID: wpr-879815

ABSTRACT

OBJECTIVE@#To explore the clinical characteristics and genetic findings of patients with infantile intrahepatic cholestasis.@*METHODS@#The clinical data were collected in children who were admitted to the Department of Gastroenterology in Children's Hospital, Capital Institute of Pediatrics from June 2017 to June 2019 and were suspected of inherited metabolic diseases. Next generation sequencing based on target gene panel was used for gene analysis in these children. Sanger sequencing technology was used to verify the genes of the members in this family.@*RESULTS@#Forty patients were enrolled. Pathogenic gene variants were identified in 13 patients (32%), including @*CONCLUSIONS@#The etiology of infantile intrahepatic cholestasis is complex. Next generation sequencing is helpful in the diagnosis of infantile intrahepatic cholestasis.


Subject(s)
Alagille Syndrome/genetics , Child , Cholestasis, Intrahepatic/genetics , Citrullinemia , Genetic Testing , High-Throughput Nucleotide Sequencing , Humans , Mitochondrial Membrane Transport Proteins , Mutation
4.
Article in Chinese | WPRIM | ID: wpr-826722

ABSTRACT

OBJECTIVE@#To observe the effect of early intervention of bone-nearby acupuncture (BNA) combined with electroacupuncture (EA) on the expression of histone deacetylase1(HDAC1), histone deacetylase 2 (HDAC2) andμ-opioid recepter (MOR) in dorsal root ganglia (DRG) of bone cancer pain-morphine tolerance (BCP-MT) rats, and to explore its possible mechanism.@*METHODS@#A total of 35 SD rats were randomized into a sham BCP group (=6), a BCP group (=7), a MT group (=7), a BNA+EA group (=8) and a shame BNA group (=7). Except of the sham BCP group, cancer cell inoculation operation at left tibia was given in the other 4 groups to establish the bone cancer pain model. In the MT group, the BNA+EA group and the shame BNA group, intraperitoneal injection of morphine hydrochloride was given to establish the morphine tolerance model. After the operation, bone-nearby acupuncture combined with electroacupuncture was applied at "Zusanli" (ST 36) and "Kunlun" (BL 60) in the BNA+EA group, with dilatational wave, 2 Hz/100 Hz in frequency, 0.5 to 1.5 mA in intensity. Intervention in the shame BNA group was applied at the same time and acupoints as those in the BNA+EA group, the needles were pierced the skin without any electrical stimulation. The needles were retained for 30 min, once a day for continuous 7 days in both BNA+EA and shame BNA groups. Before and 10, 11, 15, 22 days after the operation, the left paw withdrawal threshold (PWT) was measured in the 5 groups. The levels of HDAC1, HDAC2 and MOR in DRG were detected by Western blot.@*RESULTS@#Ten days after the cancer cell inoculation operation, the PWT of the BCP, MT, BNA+EA and sham BNA groups was decreased compared with the sham BCP group (0.05); the PWT of the BNA+EA group was increased compared with the MT and sham BNA group (<0.01). In the BCP group, the DRG levels of HDAC1 and HDCA2 were increased, while the level of MOR was decreased compared with the sham BCP group (<0.05, <0.01). In the MT group, the DRG level of HDAC1 was increased compared with the BCP group (<0.05). In the BNA+EA group, the DRG level of HDAC1 was decreased compared with the MT group and the sham BNA group (<0.01, <0.05), while the level of MOR was increased (<0.01).@*CONCLUSION@#Early intervention of bone-nearby acupuncture combined with electroacupuncture can relieve the morphine tolerance in bone cancer pain rats, it may relate to down-regulating the expression of HDAC1 and up-regulating the expression of MOR in the dorsal root ganglia.


Subject(s)
Acupuncture Points , Animals , Bone Neoplasms , Cancer Pain , Therapeutics , Drug Tolerance , Electroacupuncture , Ganglia, Spinal , Metabolism , Histone Deacetylases , Metabolism , Morphine , Random Allocation , Rats , Rats, Sprague-Dawley , Receptors, Opioid, mu , Metabolism
5.
Chinese Medical Journal ; (24): 684-688, 2018.
Article in English | WPRIM | ID: wpr-690556

ABSTRACT

<p><b>Background</b>Previous studies conducted in various geographical and ethnical populations have shown that Alpha-1-antitrypsin (Alpha-1-AT) expression affects the occurrence and progression of chronic obstructive pulmonary disease (COPD). We aimed to explore the associations of rs9944155AG, rs1051052AG, and rs1243166AG polymorphisms in the Alpha-1-AT gene with the risk of COPD in Uygur population in the Kashgar region.</p><p><b>Methods</b>From March 2013 to December 2015, a total of 225 Uygur COPD patients and 198 healthy people were recruited as cases and controls, respectively, in Kashgar region. DNA was extracted according to the protocol of the DNA genome kit, and Sequenom MassARRAY single-nucleotide polymorphism technology was used for genotype determination. Serum concentration of Alpha-1-AT was detected by enzyme-linked immunosorbent assay. A logistic regression model was used to estimate the associations of polymorphisms with COPD.</p><p><b>Results</b>The rs1243166-G allele was associated with a higher risk of COPD (odds ratio [OR] = 2.039, 95% confidence interval [CI]: 1.116-3.725, P = 0.019). In cases, Alpha-1-AT levels were the highest among participants carrying rs1243166 AG genotype, followed by AA and GG genotype (χ = 11.89, P = 0.003). Similarly, the rs1051052-G allele was associated with a higher risk of COPD (OR = 19.433, 95% CI: 8.783-43.00, P < 0.001). The highest Alpha-1-AT levels were observed in cases carrying rs1051052 AA genotype, followed by cases with AG and GG genotypes (χ = 122.45, P < 0.001). However, individuals with rs9944155-G allele exhibited a lower risk of COPD than those carrying the rs9944155-A allele (OR = 0.121, 95% CI: 0.070-0.209, P < 0.001). In both cases and controls, no significant difference in Alpha-1-AT levels was observed among various rs9944115 genotypes.</p><p><b>Conclusions</b>rs1243166, rs9944155, and rs1051052 sites of Alpha-1-AT may be associated with the COPD morbidity in Uygur population. While rs1243166-G allele and rs1051052-G allele are associated with an increased risk of developing COPD, rs9944155-G allele is a protect locus in Uygur population. Alpha-1-AT levels in Uygur COPD patients were lower than those in healthy people and differed among patients with different rs1051052 AG and rs1243166 AG genotypes.</p>


Subject(s)
Aged , Alleles , Female , Gene Frequency , Genetics , Genetic Predisposition to Disease , Genetics , Genotype , Humans , Male , Middle Aged , Odds Ratio , Polymorphism, Single Nucleotide , Genetics , Pulmonary Disease, Chronic Obstructive , Genetics , alpha 1-Antitrypsin , Genetics
6.
Chinese Medical Journal ; (24): 2132-2136, 2012.
Article in English | WPRIM | ID: wpr-244399

ABSTRACT

<p><b>BACKGROUND</b>Mutations in fumarylacetoacetate hydrolase (FAH) gene can lead to tyrosinemia type 1 (HT1), a relatively rare autosomal recessive disorder. To date, no molecular genetic defects of HT1 in China have been described. We investigated a Chinese family with a HT1 child to identify mutations in FAH.</p><p><b>METHODS</b>DNA sequencing was used for mutations screening in FAH gene. Real-time polymerase chain reaction (PCR) was performed to determine the FAH gene expression level. To confirm the presence of degradation by the nonsense-mediated mRNA decay pathway (NMD), the fragments containing R237X mutations were analyzed by primer introduced restriction analysis-polymerase chain reaction (PIRA-PCR) and cDNA sequencing. Finally, the effects of the mutations reported in this study were predicted by online softwares.</p><p><b>RESULTS</b>A boy aged 3 years and 8 months was diagnosed clinically with HT1 based on his manifestations and biochemical abnormalities. Screening of FAH gene revealed two heterozygous mutations R237X and L375P transmitted from his mother and father respectively. In this pedigree, the amount of FAH mRNA relative to a healthy control was 0.44 for the patient, 0.77 for his mother and 1.07 for his father. Moreover, both PIRA-PCR and cDNA sequencing showed significant reduction of the FAH mRNA with R237X nonsense mutation. The missense mutation of L375P was not reported previously and prediction software showed that this mutation decreased the stability of protein structure and affected protein function.</p><p><b>CONCLUSIONS</b>This is the first case of HT1 analyzed by molecular genetics in China. The R237X mutation in FAH down- regulates the FAH gene expression, and the L375P mutation perhaps interrupts the secondary structure of FAH protein.</p>


Subject(s)
Child, Preschool , China , Humans , Hydrolases , Genetics , Male , Molecular Sequence Data , Mutation , Mutation, Missense , Genetics , Nonsense Mediated mRNA Decay , Genetics , Real-Time Polymerase Chain Reaction , Tyrosinemias , Genetics
7.
Chinese Journal of Pediatrics ; (12): 571-574, 2012.
Article in Chinese | WPRIM | ID: wpr-348581

ABSTRACT

<p><b>OBJECTIVE</b>Congenital esophageal stenosis owing to tracheobronchial remnants (TBR) is a rare condition. This study was conducted to understand the clinical features of TBR.</p><p><b>METHOD</b>The data of the four cases with TBR admitted to our hospital and 76 patients identified from the literature were reviewed. The clinical manifestation, X-ray, endoscopy, biopsy and treatment were studied retrospectively.</p><p><b>RESULT</b>Of the total of 80 cases, 45 were male, 33 were female, and for 2 cases the gender was unknown. Symptoms of dysphagia and regurgitation developed at the age of 1-day to 12-month. Definitive treatment was carried out at the age of 1-month to 16-year. Twenty-seven patients had associated anomalies with esophageal atresia being the most prevalent. X-ray esophagography showed segmental stenosis at the distal third of the esophagus in all patients except three. An abrupt narrow segment at the lower esophagus with marked proximal dilatation was found in 32 cases. Esophagography of 12 cases showed distal esophageal stenosis with tapered narrowing. Esophagography of 20 cases showed flask-shaped shadow of distal esophageal stenosis and one patient showed linear projection of barium at the level of stenosis. Endoscopy found almost complete obstruction of the lower esophageal lumen without signs of the esophagitis or reflux. Esophagoscopic dilatation of the stenosis was attempted in 24 cases, but was ineffective, and 3 patients suffered esophageal perforation. Seventy-nine patients underwent resection of the stenotic segment. Histologic examination of the resected specimen showed cartilage, mucus glands, resembling bronchal tissue. Post-operative complication included anastomotic stenosis, anastomotic leakage, hiatal hernia, and gastroesophageal reflux.</p><p><b>CONCLUSION</b>TBR should be suspected in patients who present with a typical history of dysphagia after ingestion of solid food. Esophagography and esophagoscopy are the essential means for diagnosis. TBR should be different from achalasia and should be diagnosed by biopsy. Operation is the only choice of treatment.</p>


Subject(s)
Anastomosis, Surgical , Barium Sulfate , Biopsy , Child, Preschool , Choristoma , Dilatation , Esophageal Atresia , Esophageal Perforation , Esophageal Stenosis , Diagnosis , Pathology , General Surgery , Esophagoscopy , Female , Follow-Up Studies , Humans , Infant , Male , Postoperative Complications , Epidemiology , Retrospective Studies , Tracheoesophageal Fistula
8.
Chinese Journal of Biotechnology ; (12): 824-830, 2007.
Article in Chinese | WPRIM | ID: wpr-327940

ABSTRACT

In order to produce relatively large amounts of recombinant human intestinal trefoil factor and assess its biological activity. The expression plasmid pPIC9-hITF containing AOX1 promotor and the sequences of secreting signal peptides was transformed into the yeast cells. Then through selection, positive transformants were cultivated in fermentation basal salts medium in a 5L fermenter to obtain large amount product with low cost. The secreted peptides were then purified by a combination of ionic exchange chromatography and molecular sieve. To verify the product, electrospray mass spectrometry analyses was used to determine the structure of rhITF and Western Blotting was performed to test the immunological activity. Furthermore, the biological activity of the peptide was examined by experiments from cell to tissue. The nucleotide sequence of rhITF was the same as expected. With a 5-L fermenter, 253mg of hITF was isolated at the purity of 96% from 3.5 L of yeast fermentation broth. The expression level for recombinant human ITF in this yeast system was 73.33mg/L. In our study, we provided a way to gain a production among milligram to gram of recombinant human ITF by the use of a yeast expression system. As human ITF are difficult to purify in any significant amount from tissue extraction, the way described may become a valuable tool in obtaining pure peptide for further studies of trefoil peptide function.


Subject(s)
Cell Movement , Epithelial Cells , Cell Biology , Fermentation , Humans , Intestine, Small , Cell Biology , Peptides , Genetics , Metabolism , Pichia , Genetics , Metabolism , Recombinant Proteins , Genetics , Pharmacology , Trefoil Factor-2
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