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BACKGROUND: For patients with acute paraplegia caused by spinal giant cell tumor (GCT) who require emergency decompressive surgery, there is still a lack of relevant reports on surgical options. This study is the first to present the case of an acute paraplegic patient with a thoracic spinal GCT who underwent an emergency total en bloc spondylectomy (TES). Despite tumor recurrence, three-level TES was repeated after denosumab therapy. CASE SUMMARY: A 27-year-old female patient who underwent single-level TES in an emergency presented with sudden severe back pain and acute paraplegia due to a thoracic spinal tumor. After emergency TES, the patient's spinal cord function recovered, and permanent paralysis was avoided. The postoperative histopathological examination revealed that the excised neoplasm was a rare GCT. Unfortunately, the tumor recurred 9 months after the first surgery. After 12 months of denosumab therapy, the tumor size was reduced, and tumor calcification. To prevent recurrent tumor progression and provide a possible cure, a three-level TES was performed again. The patient returned to an active lifestyle 1 month after the second surgery, and no recurrence of GCT was found at the last follow-up. CONCLUSION: This patient with acute paraplegia underwent TES twice, including once in an emergency, and achieved good therapeutic results. TES in emergency surgery is feasible and safe when conditions permit; however, it may increase the risk of tumor recurrence.
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Background: Nuclear factor interleukin 3 (NFIL3) mainly focuses on the regulation of the circadian rhythm and immune system. However, the potential role of NFIL3 in human cancers has not been studied extensively. Methods: We retrieved original data from the TCGA, TARGET, and GTEx datasets via the UCSC Xena browser (http://genome.ucsc.edu/) and integrated them using R version 3.6.4. NFIL3 expression was assessed using resources such as UCSC, GEPIA (http://gepia.cancer-pku.cn/), Kaplan-Meier Plotter (KM Plotter; https://kmplot.com/), and the Human Protein Atlas (HPA; https://www.proteinatlas.org/) databases. To investigate the prognostic implications of NFIL3, we utilized GEPIA, Kaplan-Meier Plotter, and PrognoScan (http://www.abren.net/PrognoScan/) datasets. For a comprehensive analysis across multiple cancer types, we employed pan-cancer data from UCSC, examining associations between NFIL3 expression and genomic heterogeneity, tumor mutational burden (TMB), microsatellite instability (MSI), tumor purity, and neoantigens. Furthermore, we explored the relationships between NFIL3 expression and the infiltration of immune cells and the expression of immune checkpoint genes. In the context of ovarian cancer, we validated the expression and functional relevance of NFIL3. Cell Counting Kit 8 (CCK8) assays were conducted to assess cell proliferation, while scratch and transwell assays were employed to evaluate cell migration capabilities. We further examined the interaction between NFIL3 and the p53 signaling pathway through quantitative real-time polymerase chain reaction (qRT-PCR), Western blot analysis, immunofluorescence confocal, and Coimmunoprecipitation (Co-IP) assays. Results: In general, NFIL3 expression in cancerous tissues exhibited diminished levels when compared to normal tissue samples. Notably, NFIL3 expression demonstrated a robust correlation with several pivotal aspects, including prognosis, immune cell infiltration, immune checkpoint-related genes, TMB, MSI, tumor purity, and the presence of neoantigens. Experimental investigations involving scratch assays, transwell assays, and assessments of cell proliferation in ovarian cancer cells have provided indications that NFIL3 may exert influence over cell migration and proliferation processes. Moreover, a substantial association between NFIL3 and the p53 signaling pathway was discerned through Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, with subsequent validation through qRT-PCR, Western blot analysis, immunofluorescence confocal, and co-immunoprecipitation (Co-IP) assays. Conclusions: Therefore, we concluded NFIL3 may serve as a possible prognostic and immunological pan-cancer biomarker.
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Objective To develop a method for rapid determination of the dissolution of cefixime capsules,to explore the consistency of the dissolution curves of the generic and reference preparations in different media,and to assess the reliability of the in vitro dissolution evaluation method according to the results of bioequivalence studies.Methods The dissolution test was performed by the paddle method at 50 r·min-1,using pH1.2 hydrochloric acid solution,pH6.8 phosphate buffer solution,pH7.5 phosphate buffer solution,and water as the dissolution media.And a high-performance liquid chromatography(HPLC)method with a core-shell column was established to determine the dissolution curves of the generic and reference preparations respectively.The bioequivalence of the generic and reference preparations was evaluated through the bioequivalence(BE)test.Results The similarity factors(f2)of the three batches of the generic and reference preparations in the four media were greater than 60.The fasting and postprandial pharmacokinetic parameters(Cmax,AUC0-t,AUC0-∞)of the generic and reference preparations in hu-mans were all in line with the bioequivalence standard.Conclusion The in vitro dissolution behavior of the generic and refer-ence preparations was consistent,and the two preparations were bioequivalent.The method is simple and quick,and it can be em-ployed to measure the dissolution of cefixime capsules,which can provide references for the consistency evaluation of cefixime capsules.
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Clinical data of a child with SIM1 gene mutation-related obesity who visited Beijing Children′s Hospital, Capital Medical University in February 2022 was retrospectively analyzed.This 5-year-and-4-month-old girl was admitted for early onset obesity.She showed obesity at 29 months old, accompanied by severe obstructive sleep apnea syndrome.The patient and her mother had heterozygous variations in the SIM1 gene.Literature has reported a total of 42 patients with obesity caused by SIM1 gene mutations from different families in the world, and nearly 1/3 of patients had clinical manifestations beyond obesity, such as developmental delay, cognitive and behavioral problems, mild dysmorphic appearance, and neuroendocrine abnormalities.The patient in this study was mainly characterized by early onset obesity.At present, 58 SIM1 gene mutations are found to be related to obesity, which are mostly concentrated in the C-terminal domain.The allele frequency of p. T46R and p. D707H has reached 9.5%; therefore, p.T46R and p. D707H are considered hot spot variations, suggesting that SIM1 gene analysis should be improved for patients with early onset obesity.
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Objective:To evaluate the effects of different types of psychological interventions on the fear of cancer recurrence through a network Meta-analysis.Methods:Randomized controlled trials on the effects of different types of psychological interventions on the fear of cancer recurrence were retrieved from PubMed, PsycINFO, Web of Science, The Cochrane Library, Embase, EBSCO, China Biomedical Literature Database, CNKI, Wanfang Database and Vip Database. The retrieval period was from the establishment of the database to December, 31 2022. Two researchers conducted literature screening, extraction and quality evaluation, and used Stata14.0 software to conduct network Meta-analysis.Results:A total of 29 pieces of research involving 3 068 cancer patients and 11 psychological intervention measures. The results of network Meta-analysis showed that narrative therapy, PERMA(Positive, Engagement, Relationship, Meaning, Accomplishment) happiness theory model, acceptance and commitment therapy and cognitive behavior therapy had statistically significant differences in the intervention effect on the fear of cancer recurrence compared with conventional nursing ( SMD values were -1.93--0.83, all P<0.05); there was no significant difference among narrative therapy, PERMA happiness model, acceptance and commitment therapy and gratitude-expansion behavior theory (all P>0.05). The results of the cumulative probability map showed the best intervention was narrative therapy. Conclusions:The results of this study suggest that narrative therapy, acceptance and commitment therapy, and cognitive behavior therapy may be effective psychological intervention measures to improve the fear of cancer recurrence. However, more studies are still needed for further verification.
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Objective To establish the fingerprint of Fangshu Qingre mixture and evaluate its quality in combination with chemical pattern recognition.Methods Using 3,5-O-dicaffeoyl quinic acid as the reference peak,ultra performance liquid chrmatography(UPLC)fingerprint of 10 batches of Fangshu Qingre mixture were established with Similarity Evaluation System for Chromatographic Fingerprint of TCM(2012 edition).The common peaks were identified and similarity evaluation were conducted,to determine the attribution of each common peak.The cluster analysis(CA),principal component analysis(PCA)and orthogonal partial least squares method-discriminant analysis(OPLS-DA)in the chemical pattern recognition method were used to determine the differential components affecting the quality of the preparations.Results There were 31 common peaks in the fingerprints of 10 batches of Fangshu Qingre mixture,and their similarities were between 0.975 and 0.996.Six common peaks were identified,including peak 9(chlorogenic acid),peak 19(luteolin-7-O-β-D-glucoside),peak 21(3,5-O-dicafeoyl quinic acid),peak 23(hesperidin),peak 29(linarin),and peak 31(patchoulone).CA and PCA divided 10 batches of Fangshu Qingre mixture into 3 categories.The results of PCA showed that the cumulative variance contribution rate of principal components 1~6 was 95.947%.The results of OPLS-DA showed that there were 13 peaks VIP greater than 1,which was the difference component.Conclusion The method is simple and sensitive,can be used to evaluate the quality of Fangshu Qingre mixture.
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BACKGROUND@#Controversy exists as to the optimal treatment approach for ostial left anterior descending (LAD) or ostial left circumflex artery (LCx) lesions. Drug-coated balloons (DCB) may overcome some of the limitations of drug-eluting stents (DES). Therefore, we investigated the security and feasibility of the DCB policy in patients with ostial LAD or ostial LCx lesions, and compared it with the conventional DES-only strategy.@*METHODS@#We retrospectively enrolled patients with de novo ostial lesions in the LAD or LCx who underwent interventional treatment. They were categorized into two groups based on their treatment approach: the DCB group and the DES group. The treatment strategies in the DCB group involved the use of either DCB-only or hybrid strategies, whereas the DES group utilized crossover or precise stenting techniques. Two-year target lesion revascularization was the primary endpoint, while the rates of major adverse cardiovascular events, cardiac death, target vessel myocardial infarction, and vessel thrombosis were the secondary endpoints. Using propensity score matching, we assembled a cohort with comparable baseline characteristics. To ensure result analysis reliability, we conducted sensitivity analyses, including interaction, and stratified analyses.@*RESULTS@#Among the 397 eligible patients, 6.25% of patients who were planned to undergo DCB underwent DES. A total of 108 patients in each group had comparable propensity scores and were included in the analysis. Two-year target lesion revascularization occurred in 5 patients (4.90%) and 16 patients (16.33%) in the DCB group and the DES group, respectively (odds ratio = 0.264, 95% CI: 0.093-0.752, P = 0.008). Compared with the DES group, the DCB group demonstrated a lower major adverse cardiovascular events rate (7.84% vs. 19.39%, P = 0.017). However, differences with regard to cardiac death, non-periprocedural target vessel myocardial infarction, and definite or probable vessel thrombosis between the groups were non-significant.@*CONCLUSIONS@#The utilization of the DCB approach signifies an innovative and discretionary strategy for managing isolated ostial lesions in the LAD or LCx. Nevertheless, a future randomized trial investigating the feasibility and safety of DCB compared to the DES-only strategy specifically for de novo ostial lesions in the LAD or LCx is highly warranted.
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Objective:This study aimed to compare the detection efficacy of transrectal ultrasound-guided transrectal cognitive fusion targeted+ systematic prostate biopsy and transperineal cognitive fusion targeted + systematic biopsy in patients with suspected prostate cancer (PCa). In addition, the relative clinical characteristics of PCa were evaluated.Methods:A total of 385 patients with suspected prostate cancer in the affiliated hospital of Qingdao University from May 2019 to November 2019 were retrospectively analyzed. All patients met the prostate biopsy criterion, who underwent transrectal(n=275)and transperineal(n=110)prostate biopsy respectively. There were no significant differences of mean age [(70.7±7.3)years vs.(69.2±8.4) years], PSA [(55.12±116.96)ng/ml vs. (63.41±315.34)ng/ml], prostate volume [(55.96±35.26)ml vs. (64.35±55.99)ml] between two groups. According to preoperative prostate magnetic resonance imaging combined with intraoperative ultrasound, 2-4 needles targeted puncture of suspected lesion were performed, followed by 12 needle systematic prostate biopsy. The detection rate of prostate cancer between two biopsy ways were compared. The related factors of PCa including age, prostate volume and PSA level were collected for univariable and multivariable logistic analysis. The cancer detection rate was compared and logistic regression was used to assess the impact of patient characteristics on PCa detection.Results:For all patients, the detection rate with cancer between transrectal group and transperineal group were 121/275(40.0%) and 67/110(60.9%), respectively. The transperineal group detected a higher rate of PCa ( P=0.003)and more clinically significant prostate cancers (csPCa) (54.6% vs.36.7%, P=0.001) than that of the transrectal group, there were significant differences between two groups ( P<0.05). Univariate and multivariate logistic regression analysis revealed that PSA( OR=1.025, P=0.001) and prostate volume( OR=0.984, P=0.001)were two independent factors for the detection rate of prostate cancer between two biopsy ways( P<0.05). The effect of age on the detection rate of PCa in the transperieal group was significantly lower than that of the transrectal group( OR=0.037, P=0.238 vs. OR=0.053, P=0.002). Conclusion:The transperieal biopsy could find more PCa than the transrectal biopsy. PSA level and prostate volume could affect the detection rate of cancer between two prostate biopsy ways.
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Storkhead box 1 (STOX1) is a winged helix transcription factor structurally and functionally related to the forkhead family of transcription factors. Recent studies have highlighted its role in the central nervous system and revealed hints in the development of glioma. However, the expression profiles of STOX1, its association with clinicopathological characteristics, and potential functions in glioma remain unknown. In this study, we analyzed three publicly available datasets including CGGA, TCGA, and Rembrandt and revealed a grade-dependent reduction in STOX1 expression in glioma (P < 0.001). Chi-square test demonstrated that low STOX1 expression was significantly associated with older age at initial diagnosis (P < 0.001), less IDH1 mutation (P < 0.001), and advanced WHO grade (P < 0.001). Moreover, multivariate Cox regression analysis showed that STOX1 expression may serve as a novel independent prognostic biomarker in glioma patients. Bioinformatic functional analysis (GSEA) predicted that STOX1 was related to many key cancer pathways including P53 signaling pathway (P < 0.01), DNA replication (P < 0.05), homologous recombination (P < 0.05), and Wnt signaling pathway (P < 0.05). Taken together, these findings suggested that STOX1 may be used as a novel predictive molecular biomarker for glioma grading and overall patient survival. Further investigations on the functional roles and therapeutic value of STOX1 in glioma are warranted.
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Clinical evidence shows that chronic pain and depression often accompany each other, but the underlying pathogenesis of comorbid chronic pain and depression remains mostly undetermined. Biotechnology is gradually revealing the phenotype and function of microglia, with great progress regarding microglia's role in neurodegeneration, depression, chronic pain, and other conditions. This article summarizes the role of microglia in chronic pain, depression, and comorbidities, which is conducive to finding new targets to treat chronic pain and depression.
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Dolor Crónico/fisiopatología , Depresión/fisiopatología , Microglía , Animales , Comorbilidad , HumanosRESUMEN
This study aims to investigate metabolic activities of psoralidin in human liver microsomes( HLM) and intestinal microsomes( HIM),and to identify cytochrome P450 enzymes( CYPs) and UDP-glucuronosyl transferases( UGTs) involved in psoralidin metabolism as well as species differences in the in vitro metabolism of psoralen. First,after incubation serial of psoralidin solutions with nicotinamide adenine dinucleotide phosphate( NADPH) or uridine 5'-diphosphate-glucuronic acid( UDPGA)-supplemented HLM or HIM,two oxidic products( M1 and M2) and two conjugated glucuronides( G1 and G2) were produced in HLM-mediated incubation system,while only M1 and G1 were detected in HIM-supplemented system. The CLintfor M1 in HLM and HIM were 104. 3,and57. 6 μL·min~(-1)·mg~(-1),respectively,while those for G1 were 543. 3,and 75. 9 μL·min~(-1)·mg~(-1),respectively. Furthermore,reaction phenotyping was performed to identify the main contributors to psoralidin metabolism after incubation of psoralidin with NADPH-supplemented twelve CYP isozymes( or UDPGA-supplemented twelve UGT enzymes),respectively. The results showed that CYP1 A1( 39. 5 μL·min~(-1)·mg~(-1)),CYP2 C8( 88. 0 μL·min~(-1)·mg~(-1)),CYP2 C19( 166. 7 μL·min~(-1)·mg~(-1)),and CYP2 D6( 9. 1 μL·min~(-1)·mg~(-1)) were identified as the main CYP isoforms for M1,whereas CYP2 C19( 42. 0 μL·min~(-1)·mg~(-1)) participated more in producing M2. In addition,UGT1 A1( 1 184. 4 μL·min~(-1)·mg~(-1)),UGT1 A7( 922. 8 μL·min~(-1)·mg~(-1)),UGT1 A8( 133. 0 μL·min~(-1)·mg~(-1)),UGT1 A9( 348. 6 μL·min~(-1)·mg~(-1)) and UGT2 B7( 118. 7 μL·min~(-1)·mg~(-1)) played important roles in the generation of G1,while UGT1 A9( 111. 3 μL·min~(-1)·mg~(-1)) was regarded as the key UGT isozyme for G2. Moreover,different concentrations of psoralidin were incubated with monkey liver microsomes( MkLM),rat liver microsomes( RLM),mice liver microsomes( MLM),dog liver microsomes( DLM) and mini-pig liver microsomes( MpLM),respectively. The obtained CLintwere used to evaluate the species differences.Phase Ⅰ metabolism and glucuronidation of psoralidinby liver microsomes showed significant species differences. In general,psoralidin underwent efficient hepatic and intestinal metabolisms. CYP1 A1,CYP2 C8,CYP2 C19,CYP2 D6 and UGT1 A1,UGT1 A7,UGT1 A8,UGT1 A9,UGT2 B7 were identified as the main contributors responsible for phase Ⅰ metabolism and glucuronidation,respectively. Rat and mini-pig were considered as the appropriate model animals to investigate phase Ⅰ metabolism and glucuronidation,respectively.
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Animales , Perros , Ratones , Ratas , Benzofuranos , Cumarinas , Glucurónidos , Glucuronosiltransferasa/metabolismo , Cinética , Microsomas Hepáticos/metabolismo , Fenotipo , Especificidad de la Especie , Porcinos , Porcinos Enanos/metabolismoRESUMEN
To explore the mechanism of Shouhui Tongbian Capsules in treating constipation by means of network pharmacology and molecular docking approach. Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP) and Bioinfoematics Analysis Tool for Molecular Mechanism of Traditional Chinese Medicine(BATMAN) were applied to obtain chemical components and potential targets of eight herbs in Shouhui Tongbian Capsules according to the screening principles of oral availability(OB)≥30% and drug-like property(DL)≥0.18. Disease targets relating to constipation were screened out through GeneCards, PharmGkb and other databases, drug targets were integrated with disease targets, and intersection targets were exactly the potential action targets of Shouhui Tongbian Capsules for treating constipation; PPI network of potential targets was constructed using STRING platform, and GO(gene ontology) analysis and KEGG(Kyoto encyclopedia of genes and genomes) pathway data were obtained to conduct enrichment analysis and predict its mechanism of action. Cytoscape 3.6.1 was used to construct a network of "medicinal materials-chemical components-drug targets", and the network topology analysis was carried out on the PPI network to obtain its main components and key targets. Molecular docking between components and key targets of Shouhui Tongbian Capsules verified the accuracy of network pharmacological analysis results. The PPI network analysis showed 92 chemical components, including quercetin, stigmaste-rol, aloe-emodin, rhein, and key targets for instance AKT1, MAPK1, IL6, JUN, TNF and TP53. The enrichment analysis of KEGG screened out 157 signal pathways(P<0.01), mainly involving interleukin 17 signaling pathway, AGE-RAGE signaling pathway in diabetic complications, thyroid hormone signaling pathway. Quercetin, resveratrol and lysine with top degree value had a rational conformation in docking site of protein crystal complexes. This study preliminarily showed that various active ingredients in Shouhui Tongbian Capsules could regulate multiple signaling pathways, increase intestinal smoothness and peristalsis function, ensure smooth intestinal lumen, and play a role in treating constipation by acting on key targets, such as AKT1, MAPK1, IL6 and JUN.
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Humanos , Cápsulas , Estreñimiento/genética , Medicamentos Herbarios Chinos , Medicina Tradicional China , Simulación del Acoplamiento MolecularRESUMEN
The current spreading novel coronavirus SARS-CoV-2 is highly infectious and pathogenic. In this study, we screened the gene expression of three SARS-CoV-2 host receptors (ACE2, DC-SIGN and L-SIGN) and DC status in bulk and single cell transcriptomic datasets of upper airway, lung or blood of smokers, non-smokers and COVID-19 patients. We found smoking increased DC-SIGN gene expression and inhibited DC maturation and its ability of T cell stimulation. In COVID-19, DC-SIGN gene expression was interestingly decreased in lung DCs but increased in blood DCs. Strikingly, DCs shifted from cDCs to pDCs in COVID-19, but the shift was trapped in an immature stage (CD22+ or ANXA1+ DC) with MHCII downregulation in severe cases. This observation indicates that DCs in severe cases stimulate innate immune responses but fail to specifically recognize SARS-CoV-2. Our study provides insights into smoking effect on COVID-19 risk and the profound modulation of DC function in severe COVID-19. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=139 SRC="FIGDIR/small/20245316v1_ufig1.gif" ALT="Figure 1"> View larger version (59K): org.highwire.dtl.DTLVardef@11a509borg.highwire.dtl.DTLVardef@a1faeforg.highwire.dtl.DTLVardef@619bb4org.highwire.dtl.DTLVardef@357bf5_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsSmoking upregulates the expression of ACE2 and CD209 and inhibits DC maturation in lungs. SARS-CoV-2 modulates the DCs proportion and CD209 expression differently in lung and blood. Severe infection is characterized by DCs less capable of maturation, antigen presentation and MHCII expression. DCs shift from cDCs to pDCs with SARS-CoV-2 infection but are trapped in an immature stage in severe cases.
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Myocardial ischaemia is usually accompanied by inflammatory response which plays a critical role in the myocardial healing and scar formation, while persistent inflammatory response contributes greatly to the myocardial remodeling and consequent heart failure. Metformin (Met), a widely used hypoglycemic drug, has increasingly been shown to exert remarkable cardioprotective effect on ischaemic myocardial injury such as acute myocardial infarction (AMI). However, the underlying mechanisms are still far from being fully understood. In this study, a mouse model of AMI was established through ligating the left anterior descending coronary artery (LAD), 100 mg/kg Met was given immediately after operation once daily for 3 days. It was demonstrated that Met effectively improved the cardiac haemodynamics (LVSP, LVEDP, +dp/dt, -dp/dt), diminished the infarct size, alleviated the disarrangement of myocardial cells and reduced the infiltration of inflammatory cells (macrophages, neutrophils and lymphocytes) in the heart of AMI mice. Mechanistically, Met decreased the expression of NLRP3 and enhanced the accumulation of LC3 puncta in F4/80-positive macrophages in the heart of AMI mice. Single cell suspension of cardiac macrophages was prepared from AMI mice and exhibited increased NLRP3 mRNA and protein expression. In contrast, Met decreased the expression of NLRP3 and p62, whereas increased the ratio of LC3II/LC3I. Additionally, both conditioned medium from H9c2 cardiomyocytes exposed to hydrogen peroxide (H9c2-H2O2-CM) and combination of mtDNA and ATP (mtDNA-ATP) increased the expression of NLRP3 and cleaved caspase-1 (p10) as well as intracellular ROS production in RAW264.7 macrophages, which were abrogated by Met treatment. Strikingly, chloroquine (CQ), 3-methyladenine (3-MA) and knockdown of autophagy-related gene (Atg5) abrogated the inhibitory effects of Met on H9c2-H2O2-CM and mtDNA-ATP-induced NLRP3 expression, release of IL-1ß and IL-18 as well as ROS production in RAW264.7 macrophages. Collectively, these findings suggest that Met protects against ischaemic myocardial injury through alleviating autophagy-ROS-NLRP3 axis-mediated inflammatory response in macrophages.
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Autofagia , Inflamación/patología , Macrófagos/patología , Metformina/uso terapéutico , Isquemia Miocárdica/patología , Isquemia Miocárdica/prevención & control , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Adenosina Trifosfato/metabolismo , Animales , Autofagia/efectos de los fármacos , ADN Mitocondrial/metabolismo , Femenino , Hemodinámica/efectos de los fármacos , Peróxido de Hidrógeno/toxicidad , Macrófagos/efectos de los fármacos , Macrófagos/ultraestructura , Masculino , Metformina/farmacología , Ratones , Ratones Endogámicos C57BL , Isquemia Miocárdica/fisiopatología , Miocardio/patología , Células RAW 264.7 , RatasRESUMEN
The human UDP-glucuronosyltransferase 1A1 (UGT1A1), one of the most essential conjugative enzymes, is responsible for the metabolism and detoxification of bilirubin and other endogenous substances, as well as many different xenobiotic compounds. Deciphering UGT1A1 relevance to human diseases and characterizing the effects of small molecules on the activities of UGT1A1 requires reliable tools for probing the function of this key enzyme in complex biological matrices. Herein, an easy-to-use assay for highly-selective and sensitive monitoring of UGT1A1 activities in various biological matrices, using liquid chromatography with fluorescence detection (LC-FD), has been developed and validated. The newly developed LC-FD based assay has been confirmed in terms of sensitivity, specificity, precision, quanti-tative linear range and stability. One of its main advantages is lowering the limits of detection and quantification by about 100-fold in comparison to the previous assay that used the same probe substrate, enabling reliable quantification of lower amounts of active enzyme than any other method. The precision test demonstrated that both intra- and inter-day variations for this assay were less than 5.5%. Further-more, the newly developed assay has also been successfully used to screen and characterize the regu-latory effects of small molecules on the expression level of UGT1A1 in living cells. Overall, an easy-to-use LC-FD based assay has been developed for ultra-sensitive UGT1A1 activities measurements in various biological systems, providing an inexpensive and practical approach for exploring the role of UGT1A1 in human diseases, interactions with xenobiotics, and characterization modulatory effects of small mole-cules on this conjugative enzyme.
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To investigate the effects of exogenous NaHS on myelin basic protein (MBP) and learning and memory of hippocampal neurons in mice with spinocerebellar ataxia type 3 (SCA3) and its therapeutic significance. Twelve male normal mice were randomly selected as normal control group (NC Group), and 48 SCA3 mice were randomly selected as SCA3 model group (M Group), low dose group (NL Group, 10 μmol/kg), medium dose group (NM Group, 50μmol/kg) and high dose group (NH Group, 100 μmol/kg), 12 rats in each group. The drug treated groups were injected with NaHS intraperitoneally once a day for 4 weeks. The changes of learning and memory ability of SCA3 mice before and after the intervention of different doses of NaHS were determined by Morris water maze, the content of hydrogen sulfide (HS) in hippocampus was measured by spectrophotometry, the expression of MBP was detected by immunohistochemistry, and the morphological changes of neuron myelin sheath were observed by electron microscope. Compared with the control group, the learning and memory ability of SCA3 mice was decreased significantly (P<0.05), and the content of HS in hippocampus was decreased (P<0.05). After different doses of exogenous NaHS treatment, the learning and memory ability was improved in different degrees (P<0.05), and the contents of HS and MBP in hippocampus of SCA3 mice were also improved in different degrees (P<0.05). Exogenous NaHS may increase the contents of HS and MBP in the hippocampus of SCA3 mice, which may have a protective effect on the neurons, and then improve the learning and memory ability of SCA3 mice, and provide a new idea for the treatment of SCA3.
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To enhance efficiency, convenience, and safety of Parkinson's disease (PD) treatment for geriatric patients, an advanced suspension of Levodopa/Benserazide hydrochloride (LD/BH) has been prepared by cation-exchange resin and used to synchronize sustained release of LD and BH by optimizing coating parameters and prescription. For the purpose, LD and BH were immobilized on the surface of cation-exchange resin, respectively. Based on HPLC results, the cation-exchange resin showed high loading capacity. The studies on drug loading mechanism indicated that both drugs were immobilized by electrostatic interaction rather than physical adsorption. After PEG modification, pretreated drug-resin complexes were coated by emulsion-solvent evaporation method. In order to control drug release in a sustained manner, coating parameters of drug-resin microcapsules were optimized respectively by single-factor analysis. Further, coating prescription of the microcapsules was optimized to synchronize sustained release of LD and BH in vitro by orthogonal design. Utilizing optimal LD-resin microcapsules and BH-resin microcapsules, LD/BH suspension, containing both of them, was prepared by an optimal formulation and characterized by accelerated test and pharmacokinetic study in vivo. The accelerated test confirmed high stability of LD/BH suspension. According to pharmacokinetic results in vivo, in contrast with LD/BH commercial tablets, LD/BH suspensions did not only synchronize sustained release of both drugs but also show good bioequivalence. As LD/BH sustained release suspension can synchronize sustained release of multiple active ingredients by oral administration, the suspension presents promising oral dosage forms for geriatric patients with PD. An advanced Levodopa/Benserazide hydrochloride (LD/BH) suspension, prepared by cation-exchange resin and optimized microencapsulation, synchronizes sustained releases of LD and BH in vivo to benefit Parkinson's disease treatment for geriatric patients.
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Antiparkinsonianos/administración & dosificación , Antiparkinsonianos/química , Benserazida/administración & dosificación , Benserazida/química , Levodopa/administración & dosificación , Levodopa/química , Administración Oral , Animales , Antiparkinsonianos/farmacocinética , Benserazida/farmacocinética , Cápsulas , Resinas de Intercambio de Catión , Preparaciones de Acción Retardada , Combinación de Medicamentos , Composición de Medicamentos , Levodopa/farmacocinética , Lípidos/química , Masculino , Ratas , Suspensiones , Comprimidos RecubiertosRESUMEN
Proangiogenesis is generally regarded as an effective approach for treating ischemic heart disease. Vascular endothelial growth factor (VEGF)-A is a strong and essential proangiogenic factor. Reactive oxygen species (ROS), endoplasmic reticulum (ER) stress, and autophagy are implicated in the process of angiogenesis. This study is designed to clarify the regulatory mechanisms underlying VEGF-A, ROS, ER stress, autophagy, and angiogenesis in acute myocardial infarction (AMI). A mouse model of AMI was successfully established by occluding the left anterior descending coronary artery. Compared with the sham-operated mice, the microvessel density, VEGF-A content, ROS production, expression of vascular endothelial cadherin, positive expression of 78 kDa glucose-regulated protein/binding immunoglobulin protein (GRP78/Bip), and LC3 puncta in CD31-positive endothelial cells of the ischemic myocardium were overtly elevated. Moreover, VEGF-A exposure predominantly increased the expression of beclin-1, autophagy-related gene (ATG) 4, ATG5, inositol-requiring enzyme-1 (IRE-1), GRP78/Bip, and LC3-II/LC3-I as well as ROS production in the human umbilical vein endothelial cells (HUVECs) in a dose and time-dependent manner. Both beclin-1 small interfering RNA and 3-methyladenine treatment predominantly mitigated VEGF-A-induced tube formation and migration of HUVECs, but they failed to elicit any notable effect on VEGF-A-increased expression of GRP78/Bip. Tauroursodeoxycholic acid not only obviously abolished VEGF-A-induced increase of IRE-1, GRP78/Bip, beclin-1 expression, and LC3-II/LC3-I, but also negated VEGF-A-induced tube formation and migration of HUVECs. Furthermore, N-acetyl- l-cysteine markedly abrogated VEGF-A-increased ROS production, IRE-1, GRP78/Bip, beclin-1 expression, and LC3-II/LC3-I in the HUVECs. Taken together, our data demonstrated that increased spontaneous production of VEGF-A may induce angiogenesis after AMI through initiating ROS-ER stress-autophagy axis in the vascular endothelial cells.
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Infarto del Miocardio/patología , Infarto del Miocardio/fisiopatología , Neovascularización Fisiológica , Factor A de Crecimiento Endotelial Vascular/fisiología , Acetilcisteína/farmacología , Animales , Autofagia/efectos de los fármacos , Autofagia/fisiología , Beclina-1/antagonistas & inhibidores , Beclina-1/genética , Beclina-1/fisiología , Modelos Animales de Enfermedad , Chaperón BiP del Retículo Endoplásmico , Estrés del Retículo Endoplásmico/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Isquemia Miocárdica/patología , Isquemia Miocárdica/fisiopatología , ARN Interferente Pequeño/genética , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Objective :To study influence of folic acid ,vitamin B6 and vitamin B12 on vascular endothelial function serum level of homocysteine (Hcy) and living quality in hypertensive patients with acute cerebral infraction .Meth‐ods :A total of 92 hypertensive patients with acute cerebral infraction treated in our hospital from Feb 2016 to Oct 2017 were randomly and equally divided into routine treatment group and combined treatment group (received folic acid ,vitamin B6 and vitamin B12 based on routine treatment group ).Two groups were both treated for 12 weeks Flow‐mediated dilation (FMD) ,serum levels of Hcy and nitric oxide (NO ) , United States National Institutes of Health Stroke Score (NIHSS) score and Barthel index score before and after treatment were compared between two groups.Results :Compared with before treatment ,after treatment ,there were significant reductions in serum level of Hcy and NIHSS score ,and significant rise in Barthel index score in two groups ,and there was significant rise in serum level of NO [ (50. 20 ± 11.18) μmol/L vs.(66. 53 ± 10. 66) μmol/L] in combined treatment group , P<0. 01 all.Before and after treatment , there were no significant difference in FMD in two groups , and no significant difference in serum level of NO in routine treatment group , P>0.05 all.Compare with routine treatment group after treatment ,there were significant reductions in serum level of Hcy [ (21.58 ± 2.24 ) μmol/L vs.(17.27 ± 2.19) μmol/L] and NIHSS score [(20. 39 ± 3. 19) scores vs .(16.12 ± 1.15) scores] ,and significant rise in NO level [ (53.76 ± 11. 67) μmol/L比(66.53 ± 10. 66) μmol/L] ,Barthel index score [ (62.27 ± 20.58) scores vs .(79. 58 ± 21. 24) scores] in combined treatment group , P=0.001 all.Conclusion :Folic acid ,vitamin B6 and vitamin B12 can effectively improve vascular endothelial function ,reduce serum level of Hcy ,increase serum level of NO ,improve neurological function and activities of living quality ,which is worth extending .
RESUMEN
Objective To investigate the outcomes of patients with diabetic retinopathy (DR) in Shanghai communities and the influencing factors.Methods From October 2015 to April 2016,533 type 2 diabetic patients with DR were selected by target sampling and cluster random sampling method from six community health service centers in Shanghai.Patients were followed up for 1 year.The demographic information,physical examination,laboratory tests and eye fundus exam results were documented and the DR was graded.The factors associated with the regression of DR were analyzed.Results Total 478 patients,including 280 females (58.6%) and 198 males (41.4%),were followed up for 1 year.The mean age of patients was (64±7) years and the mean disease duration was (8.85±4.20) years.The original DR lesion was remitted in 35 patients with an improvement rate of 7.3%;while the original DR lesion was aggravated in 29 patients with a progression rate of 6.1%.Ordinal logistic regression analysis revealed that age (OR=0.197,95%CI:0.056-0.699),body mass index (BMI) (OR=0.383,95%CI:0.171-0.856),glycosylated hemoglobin (HbAlc) (OR=0.287,95%CI:0.102-0.803),triglycerides (TG) (OR=0.541,95%CI:0.295-0.991),urinary albumin to creatinine ratio (ACR)(OR=0.218,95%CI:0.066-0.720) were associated with DR in type 2 diabetic patients.Conclusion The regression of DR is closely related to age,BMI,glucose,serum lipids and renal function,so it is suggested that lowering BMI,controlling glucose and serum lipids and maintaining normal kidney function are necessary for preventing the progression and promoting the improvement of DR in diabetic patients.