RESUMEN
Background Nano-alumina (nano-Al2O3) is a widely utilized nanomaterial. Its impacts on the environment and biological systems have garnered significant attention. Zebrafish serves as a common model organism in scientific research due to its high homology with the human genome and is extensively used in toxicity studies. Objective To investigate the developmental toxicity and neurotoxicity of nano-Al2O3 exposure in zebrafish and the corresponding mechanisms of action. Method Zebrafish embryos at 6 h post-fertilization (hpf) were randomly assigned to a control group and five dose groups exposed to nano-Al2O3 at concentrations of 200, 400, 600, 800, and 1000 μg·mL−1, respectively. Thirty embryos were included in each group, and the culture medium was replaced every 24 h until 144 hpf. The hatching rates at 48 and 72 hpf and the cumulative malformation rates up to 144 hpf were calculated. At 144 hpf, a zebrafish behavior analyzer was used to record the movement trajectories of the zebrafish, and the total distance traveled and average speed were analyzed for each group. At 144 hpf, the development of dopaminergic neurons in transgenic zebrafish expressing vmat2: GFP, brain vessels in those expressing vegf: GFP, and central nervous system neurons in those expressing elavl3: EGFP were observed under a fluorescence microscope, and statistical analysis was conducted using Image Pro Plus. Real-time quantitative PCR was employed to detect the expression levels of neuron development-related genes (syn2α, gap43, dat), Lewy body formation-related gene (α-syn), and autophagy-related genes (pink1, parkin) at 144 hpf. Results Compared to the control group, the nano-Al2O3 exposed groups exhibited reduced hatching rates at 48 hpf and increased cumulative malformation rates (P<0.05), with phenomena such as delayed development, absence of the swim bladder, and body curvature. The autonomous behavioral tests revealed that the nano-Al2O3 exposed zebrafish showed a decrease in the total distance swum (P<0.001) and a significant reduction in average speed compared to the control group. The fluorescence observations indicated that the length of dopaminergic neurons in vmat2: GFP transgenic zebrafish was reduced in the nano-Al2O3 exposed groups (P<0.001). Additionally, vegf: GFP transgenic zebrafish exhibited a significant absence of brain vessels, while elavl3: EGFP transgenic zebrafish showed a weakened fluorescence intensity of central nervous system neurons (P<0.001) and a decreased length of these neurons (P<0.01). The real-time quantitative PCR analysis revealed that compared to the control group, the gene expression levels of α-syn, syn2α, dat, and gap43 were upregulated in the zebrafish exposed to nano-Al2O3 (except for the 400 μg·mL−1 exposure group) (P<0.01), while the expression levels of parkin were downregulated in the 600 and 800 μg·mL−1 nano-Al2O3 exposed groups, and the expression levels of pink1 were downregulated in all exposure groups except for the 200 μg·mL−1 group (P<0.05). Conclusion Exposure to nano-Al2O3 exhibits developmental toxicity in zebrafish larvae and induces Parkinsonism-like symptoms in zebrafish. The preliminary speculation of the mechanism suggests that it may be related to nano-Al2O3-induced mitochondrial autophagy impairment.
RESUMEN
Objective:To explore the factors associated with severe bleeding after percutaneous nephrolithotomy (PCNL) in male patients and evaluate the efficacy of interventional embolization.Methods:A retrospective case series study was conducted at Nankai Hospital of Tianjin, China, from January 2018 to October 2021. The clinical data of 230 male patients with upper urinary tract stones were analyzed. The observation indicators included age, hypertension, diabetes, renal function abnormalities, history of preoperative anticoagulant use, stone size, stone type, number of puncture channels, operation time and degree of hydronephrosis. To describe the clinical characteristics of bleeding after percutaneous nephrolithotomy in men, and analyze the factors associated with severe bleeding after PCNL. Single factor analysis was performed using the Chi-square ( χ2) test, and multivariate analysis was performed using logistic regression analysis. Results:Univariate analysis showed that diabetes mellitus ( χ2=4.90, P=0.027), abnormal renal function ( χ2=18.32, P<0.001), history of preoperative oral anticoagulants ( χ2=5.10, P=0.024), abnormal bleeding and coagulation function ( χ2=8.22, P=0.004) and the number of puncture channels ( χ2=22.08, P<0.001) were the related factors affecting bleeding after PCNL. Multivariate logistic regression analysis showed that diabetes mellitus ( P=0.032), abnormal renal function ( P<0.001), and the number of puncture channels ( P<0.001) were the independent risk factors of bleeding after PCNL. Of the 28 patients with bleeding after PCNL, 25 were treated with interventional embolization, with a technical success rate of 100.0% and a clinical success rate of 89.3%. Conclusions:For patients with renal calculi and comorbid diabetes, renal function abnormalities, and multiple punctures, relevant preventive measures should be actively administered before PCNL to reduce the risk of postoperative bleeding. For patients with severe bleeding of the kidney after PCNL, TAE is a safe and effective minimally invasive treatment method.
RESUMEN
The SARS-CoV-2 main protease (Mpro) is a major therapeutic target. The Mpro inhibitor, nirmatrelvir, is the antiviral component of Paxlovid, an orally available treatment for COVID-19. As Mpro inhibitor use increases, drug resistant mutations will likely emerge. We have established a non-pathogenic system, in which yeast growth serves as a proxy for Mpro activity, enabling rapid identification of mutants with altered enzymatic activity and drug sensitivity. The E166 residue is known to be a potential hot spot for drug resistance and yeast assays showed that an E166R substitution conferred strong nirmatrelvir resistance while an E166N mutation compromised activity. On the other hand, N142A and P132H mutations caused little to no change in drug response and activity. Standard enzymatic assays confirmed the yeast results. In turn, we solved the structures of Mpro E166R, and Mpro E166N, providing insights into how arginine may drive drug resistance while asparagine leads to reduced activity. The work presented here will help characterize novel resistant variants of Mpro that may arise as Mpro antivirals become more widely used.
RESUMEN
The SARS-CoV-2 main protease (Mpro) is the drug target of Pfizers oral drug Paxlovid. The emergence of SARS-CoV-2 variants with mutations in Mpro raised the alarm of potential drug resistance. In this study, we identified 100 naturally occurring Mpro mutations located at the nirmatrelvir binding site, among which 20 mutants, including S144M/F/A/G/Y, M165T, E166G, H172Q/F, and Q192T/S/L/A/I/P/H/V/W/C/F, showed comparable enzymatic activity to the wild-type (kcat/Km <10-fold change) and resistance to nirmatrelvir (Ki >10-fold increase). X-ray crystal structures were determined for seven representative mutants with and/or without GC-376/nirmatrelvir. Viral growth assay showed that Mpro mutants with reduced enzymatic activity led to attenuated viral replication. Overall, our study identified several drug resistant hot spots that warrant close monitoring for possible clinical evidence of Paxlovid resistance. One Sentence SummaryPaxlovid resistant SARS-CoV-2 viruses with mutations in the main protease have been identified from clinical isolates.
RESUMEN
The ongoing SARS-CoV-2 pandemic continues to be a significant threat to global health. First reported in November 2021, the Omicron variant (B.1.1.529) is more transmissible and can evade immunity better than previous SARS-CoV-2 variants, fueling an unprecedented surge in cases. To produce functional proteins from this polyprotein, SARS-CoV-2 relies on the cysteine proteases Nsp3/papain-like protease (PLpro) and Nsp5/Main Protease (Mpro)/3C-like protease to cleave at three and more than 11 sites, respectively.1 Therefore, Mpro and PLpro inhibitors are considered to be some of the most promising SARS-CoV-2 antivirals. On December 22, 2021, the Food and Drug Administration (FDA) issued an Emergency Use Authorization (EUA) for PAXLOVID, a ritonavir-boosted formulation of nirmatrelvir. Nirmatrelvir is a first-in-class orally bioavailable SARS-CoV-2 Mpro inhibitor.2 Thus, the scientific community must vigilantly monitor potential mechanisms of drug resistance, especially because SARS-CoV-2 is naive to Mpro inhibitors. Mutations have been well identified in variants to this point.3 Notably, Omicron Mpro (OMpro) harbors a single mutation- P132H. In this study we characterize the enzymatic activity, drug inhibition, and structure of OMpro while evaluating the past and future implications of Mpro mutations.
RESUMEN
The papain-like protease (PLpro) of SARS-CoV-2 is a validated antiviral drug target. PLpro is involved in the cleavage of viral polyproteins and antagonizing host innate immune response through its deubiquitinating and deISG15ylating activities, rendering it a high profile antiviral drug target. Through a FRET-based high-throughput screening, several hits were identified as PLpro inhibitors with IC50 values at the single-digit micromolar range. Subsequent lead optimization led to potent inhibitors with IC50 values ranging from 0.56 to 0.90 {micro}M. To help prioritize lead compounds for the cellular antiviral assay against SARS-CoV-2, we developed the cell-based FlipGFP assay that is suitable for quantifying the intracellular enzymatic inhibition potency of PLpro inhibitors in the BSL-2 setting. Two compounds selected from the FlipGFP-PLpro assay, Jun9-53-2 and Jun9-72-2, inhibited SARS-CoV-2 replication in Caco-2 hACE2 cells with EC50 values of 8.89 and 8.32 {micro}M, respectively, which were 3-fold more potent than GRL0617 (EC50 = 25.1 {micro}M). The X-ray crystal structures of PLpro in complex with GRL0617 showed that binding of GRL0617 to SARS-CoV-2 induced a conformational change in the BL2 loop to the more closed conformation. Overall, the PLpro inhibitors identified in this study represent promising starting points for further development as SARS-CoV-2 antivirals, and FlipGFP-PLpro assay might be a suitable surrogate for screening PLpro inhibitors in the BSL-2 setting.
RESUMEN
Alzheimer's disease (AD) is one of the major diseases that harmful to healthy elderly, and mild cognitive impairment (MCI) is the early clinical stage of AD. There is a lag in the clinical diagnosis of both diseases. An objective and reliable auxiliary diagnostic method is urgently needed to provide early diagnosis and differential indicators for AD and MCI, to predict the probability of individuals suffering from AD and MCI transforming into AD, and to reduce the overall incidence of AD and reduce the huge medical and economic burden for the country and society. Event-related potential is widely used in AD and MCI, and the resolution at the millisecond level can truly reflect the time course of cognitive processing and the degree of impairment of cognitive function in patients. In this study, we investigated the differences in the amplitude and latency of ERP components in healthy elderly, MCI and AD patients, and the correlation between ERP components and cognitive impairment. Early N170 and P200 showed high sensitivity and specificity in differentiating MCI from healthy elderly or MCI from AD. The late perception-related ERPs also showed high sensitivity and specificity in differentiating healthy elderly from MCI/AD. The differences in ERPs between MCI and AD may be related to the etiology, the degree of disease progression and the site of brain damage. The specific brain mechanism still need to be further explored and will be the focus of future research. With the progress of the research, the relationship between the specific ERP manifestations and the mechanism of brain injury as well as the impairment of cognitive function will be more clear. It is believed that the application of ERP in clinical will bring more benefits to AD and its early clinical MCI.
RESUMEN
The main protease (Mpro) of SARS-CoV-2 is a validated antiviral drug target. Several Mpro inhibitors have been reported with potent enzymatic inhibition and cellular antiviral activity, including GC376, boceprevir, calpain inhibitors II and XII, each containing a reactive warhead that covalently modifies the catalytic Cys145. In this study, we report an expedited drug discovery approach by coupling structure-based design and Ugi four-component (Ugi-4CR) reaction methodology to the design of non-covalent Mpro inhibitors. The most potent compound 23R had cellular antiviral activity similar to covalent inhibitors such as GC376. Our designs were guided by overlaying the structure of SARS-CoV Mpro + ML188 (R), a non-covalent inhibitor derived from Ug-4CR, with the X-ray crystal structures of SARS-CoV-2 Mpro + calpain inhibitor XII/GC376/UAWJ247. Binding site analysis suggests a strategy of extending the P2 and P3 substitutions in ML188 (R) to achieve optimal shape complementary with SARS-CoV-2 Mpro. Lead optimization led to the discovery of 23R, which inhibits SARS-CoV-2 Mpro and SARS-CoV-2 viral replication with an IC50 of 0.31 M and EC50 of 1.27 M, respectively. The binding and specificity of 23R to SARS-CoV-2 Mpro were confirmed in a thermal shift assay and native mass spectrometry assay. The co-crystal structure of SARS-CoV-2 Mpro with 23R revealed the P2 biphenyl fits snuggly into the S2 pocket and the benzyl group in the -methylbenzyl faces towards the core of the enzyme, occupying a previously unexplored binding site located in between the S2 and S4 pockets. Overall, this study revealed the most potent non-covalent SARS-CoV-2 Mpro inhibitors reported to date and a novel binding pocket that can be explored for Mpro inhibitor design.
RESUMEN
The main protease (Mpro) of SARS-CoV-2, the pathogen responsible for the COVID-19 pandemic, is a key antiviral drug target. While most SARS-CoV-2 Mpro inhibitors have a {gamma}-lactam glutamine surrogate at the P1 position, we recently discovered several Mpro inhibitors have hydrophobic moieties at the P1 site, including calpain inhibitors II/XII, which are also active against human cathepsin L, a host-protease that is important for viral entry. To determine the binding mode of these calpain inhibitors and establish a structure-activity relationship, we solved X-ray crystal structures of Mpro in complex with calpain inhibitors II and XII, and three analogues of GC-376, one of the most potent Mpro inhibitors in vitro. The structure of Mpro with calpain inhibitor II confirmed the S1 pocket of Mpro can accommodate a hydrophobic methionine side chain, challenging the idea that a hydrophilic residue is necessary at this position. Interestingly, the structure of calpain inhibitor XII revealed an unexpected, inverted binding pose where the P1 pyridine inserts in the S1 pocket and the P1 norvaline is positioned in the S1 pocket. The overall conformation is semi-helical, wrapping around the catalytic core, in contrast to the extended conformation of other peptidomimetic inhibitors. Additionally, the structures of three GC-376 analogues UAWJ246, UAWJ247, and UAWJ248 provide insight to the sidechain preference of the S1, S2, S3 and S4 pockets, and the superior cell-based activity of the aldehyde warhead compared with the -ketoamide. Taken together, the biochemical, computational, structural, and cellular data presented herein provide new directions for the development of Mpro inhibitors as SARS-CoV-2 antivirals.
RESUMEN
A novel coronavirus SARS-CoV-2, also called novel coronavirus 2019 (nCoV-19), started to circulate among humans around December 2019, and it is now widespread as a global pandemic. The disease caused by SARS-CoV-2 virus is called COVID-19, which is highly contagious and has an overall mortality rate of 6.96% as of May 4, 2020. There is no vaccine or antiviral available for SARS-CoV-2. In this study, we report our discovery of inhibitors targeting the SARS-CoV-2 main protease (Mpro). Using the FRET-based enzymatic assay, several inhibitors including boceprevir, GC-376, and calpain inhibitors II, and XII were identified to have potent activity with single-digit to submicromolar IC50 values in the enzymatic assay. The mechanism of action of the hits was further characterized using enzyme kinetic studies, thermal shift binding assays, and native mass spectrometry. Significantly, four compounds (boceprevir, GC-376, calpain inhibitors II and XII) inhibit SARS-CoV-2 viral replication in cell culture with EC50 values ranging from 0.49 to 3.37 M. Notably, boceprevir, calpain inhibitors II and XII represent novel chemotypes that are distinct from known Mpro inhibitors. A complex crystal structure of SARS-CoV-2 Mpro with GC-376, determined at 2.15 [A] resolution with three monomers per asymmetric unit, revealed two unique binding configurations, shedding light on the molecular interactions and protein conformational flexibility underlying substrate and inhibitor binding by Mpro. Overall, the compounds identified herein provide promising starting points for the further development of SARS-CoV-2 therapeutics.
RESUMEN
Objective:To investigate the protective effect and mechanisms of umbilical cord tissue transplantation on radiation-induced learning and memory impairment in rats.Methods:Sixty SD rats were randomly divided into three groups with 20 in each group: control group, model group (whole brain X-ray irradiation, dose 20 Gy) and treatment group (whole brain X-ray irradiation, dose 20 Gy + umbilical cord tissue transplantation). The changes of body mass were observed, and the learning and memory of rats were observed by water maze test on the 14th and 28th day after irradiation, the neuron state of hippocampus was observed by HE staining, and the expressions of NF-κB pathway related proteins and IL-6 in hippocampus were detected by Western blot.Descriptive analysis and hypothesis testing were processed by SPSS 17.0.Results:(1) On the 28th day, the escaping latency in the water maze experiment of the treatment group was significantly higher than that of the control group and lower than that of the model group (control group: (11.77±3.02) s, model group: (23.75±3.27)s, treatment group: (18.49±2.32)s; t=3.940, -2.943, both P<0.05); the number of crossing platform in the treatment group was significantly lower than that in the control group and higher than that in the model group (control group: (7.20±0.84), model group (3.60±1.14 ), treatment group (5.00±1.00); t=-3.773, 2.064, both P<0.05). (2)HE staining showed that the neurons in the control group were arranged orderly and the cytoplasm was transparent.The neurons in the model group were arranged disorderly and the contraction of the cell body was triangular or irregular.The number of neurons in the treatment group was less than that in the model group. (3) On the 14th day, the relative expression of TLR4 in the treatment group was significantly higher than that in the control group and lower than that in the model group (control group: (0.69±0.03), model group: (1.06±0.11), treatment group: (0.90±0.04); t=7.275, -2.368, both P<0.05). The relative expression of NF-κB p65 in the treatment group was significantly higher than that in the control group and lower than that in the model group (control group: (1.67±0.12), model group: (2.08 ±0.06), treatment group: (1.93±0.08); t=3.236, -2.684, both P<0.05). The relative expression of IL-6 in the treatment group was significantly higher than that in the control group and lower than that in the model group (control group: (0.77±0.08), model group: (1.12±0.07), treatment group: (0.95±0.06); t=3.274, -3.495, both P<0.05). The relative expression of Bcl-2 / Bax in the treatment group was significantly lower than that in the control group and higher than that in the model group (control group: (1.40±0.52), model group: (0.48±0.06), treatment group: (0.72±0.0 3); t=-2.263, 6.350, both P<0.05). The expression trend of IL-6 and Bcl-2 / Bax protein on the 28th day was the same as that on the 14th day. Conclusion:Cord tissue transplantation can improve the learning and memory impairment caused by radiotherapy, which may be related with the inhibition of inflammation caused by radiotherapy.
RESUMEN
Objective:To investigate the relationship between lexical semantic processing abnormalities and cognitive function and clinical symptoms in schizophrenia based on the activation diffusion model and semantic distance.Methods:All subjects matched with demographic data were randomly divided into experiment group( n=27) and control group( n=30). The semantic distance of words of different semantic categories and lexical categories were assigned at a level of 1-7.The semantic distance between the two groups was analyzed by repeated measures of variance, and the correlation analysis was conducted on the scores of the MATRICS Consensus Cognitive Battery (MCCB) and positive and negative syndrome scale (PANSS) in the experimental group. Results:The main effects of the groups in semantic distance were statistically significant( F(1, 55)=7.460, P=0.008, ηp2=0.981). The semantic distance in the experimental group (3.672±0.105)was lower than that in the control group (4.068±0.100). The main effect of the semantic category was statistically significant( F(1, 55)= 833.37, P<0.01, ηp2=0.938), and the semantic distance in the relative condition (1.965±0.074) was lower than that in the unrelative condition(5.775±0.117). Under the relative condition, concrete semantic deviation was negatively correlated with the total score of MCCB( r=-0.405, P=0.036)and speech learning ( r=-0.569, P=0.002). Abstract semantic deviation was negatively correlated with speech learning( r=-0.429, P=0.026). Under the unrelative condition, concrete semantic deviation was negatively correlated with MCCB total score ( r=-0.597, P=0.001), speech learning( r=-0.399, P=0.039)and other dimensions.Abstract semantic deviation was negatively correlated with MCCB total score( r=-0.593, P=0.001) and speech learning( r=-0.285, P=0.050). Under the relative condition, the abstract semantic deviation was positively correlated with the general symptom scale score( r=0.448, P=0.019). Under the unrelative condition, abstract vocabulary semantic deviation was positively correlated with PANSS total score( r=0.120, P=0.010), negative scale score( r=0.047, P=0.030) and general symptom scale score ( r=0.306, P=0.010). Conclusion:The semantic distance of lexical processing is abnormal in schizophrenia. The semantic deviation is related to the cognitive function index and symptom index.
RESUMEN
OBJECTIVE: To investigate the effects of manganese(Mn) and high fat diet(HFD) co-exposure on the neurological behavior and gut microbiota in mice, and to observe the correlation between them. METHODS: Specific pathogen free adult male C57 BL/6 mice were randomly divided into 4 groups. Mice in control group and Mn exposure group were fed with normal diet, while the HFD group and co-exposure group were fed with HFD. Both the Mn exposure group and the co-exposure group were exposed to 10 mg/(kg·d) manganese chloride by intraperitoneal injection, while the control group and HFD group were treated with 0.9% sodium chloride solution of the same volume, once per day for 60 consecutive days. At the end of exposure, the mice were subjected to experiments of neurological behaviors. Then, the mice were sacrificed and intestinal feces were collected. The relative abundance of gut microbiota(relative abundance>1.000%) was detected by high-throughput sequencing. RESULTS: After exposure, the body weight of the HFD group and the co-exposure group increased significantly(P<0.05), while that of the Mn exposure group decreased(P<0.05), compared with the control group. The latency, time in central, crossing, total distance and open arm time(OT%) of mice in the Mn exposure group were lower than that of the control group(P<0.05), and close arm time(CT%) prolonged(P<0.05). Compared with the control group and the HFD group, the latency, rearing, time in central, crossing, total distance, OT% and open arm entry(OE%) of mice in the co-exposure group decreased(P<0.05), and CT% increased(P<0.05). The total distance of mice in the co-exposure group was lower than that of the Mn exposure group(P<0.05). The relative abundance of Firmicutes increased(P<0.05), those of Bacteroidetes and Actinobacteria decreased in mice in the HFD group at the phylum level(P<0.05) compared with mice in the control group. The relative abundance of Firmicutes, Proteobacteria and Cyanobacteria increased(P<0.05), and Bacteroidetes and Actinobacteria decreased(P<0.05) in mice in the Mn exposure group. The relative abundance of Oscillospira, Bacteroides and Prevotella of mice in the HFD group reduced at the genus level(P<0.05) compared with the control group. The relative abundance of Lactobacillus increased in Mn exposure group(P<0.05), and Oscillospira, Bacteroides and Prevotella decreased(P<0.05). The relative abundance of Firmicutes, Cyanobacteria and Lactobacillus of mice in the co-exposure group increased(P<0.05), and those of the remaining 6 bacteria were lower(P<0.05) compared with mice in the other 3 groups. Among the mice of co-exposure group, the latency was positively correlated with Bacteroidetes(P<0.05). The rearing was positively correlated with Firmicutes(P<0.05) and negatively correlated with Actinobacteria(P<0.01). The OE% was negatively correlated with Firmicutes(P<0.05) and positively correlated with Actinobacteria(P<0.05). The crossing was positively correlated with Prevotella(P<0.05). CONCLUSION: Manganese combined with HFD had a synergistic effect on the abnormality of neurological behavior of mice. There are some correlation between the abnormality of neurological behavior and the homeostatic imbalance of intestinal flora in mice.
RESUMEN
OBJECTIVE: To explore the relationship between shift work and type 2 diabetes in oil workers. METHODS: A total of 2 666 oil workers in an oil group were selected as the study subjects using the typical sampling method. Questionnaire survey was conducted by a self-designed Questionnaire of Health Assessment for Oil Workers, and blood glucose level was measure. RESULTS: The prevalence of type 2 diabetes in the study subjects was 10.1%(268/2 666). The prevalence of type 2 diabetes in shift workers was higher than that in non-shift workers(13.1% vs 6.0%, P<0.01). After adjusting for the influence of confounding factors such as gender, body mass index, family history of diabetes, history of hypertension, history of hyperlipidemia, and physical exercise, multivariate logistic regression analysis results show that the longer the shift work length, the higher the risk of developing type 2 diabetes(P<0.01), workers with shift work(3 shifts in a day, 2 shifts operating) had a higher risk of type 2 diabetes than that in non-shift workers(P<0.05). CONCLUSION: The shift work length and shift workers with 3 shifts in a day, 2 shifts operating can increase the risk of type 2 diabetes in oil workers.
RESUMEN
Objective To investigate the effects of poly adenosine diphosphate ribose polymerase (PARP) inhibitor AG014699 on the proliferation of triple negative breast cancer (TNBC) cell line MDA?MB?231.Methods Cell proliferation and cytotoxicity test kit ( CCK?8) was used to detect the proliferation of MDA?MB?231 cells in different concentrations of AG014699 (0.1,1.0,10.0,20.0 and 40.0 mmol/L), DTX (10-9,10-8,10-7,10-6 and 10-5 mol/L) and CBP (10-6,10-5,10-4 and 10-3 mol/L).Flow cytometry was used to detect cell apoptosis and cell cycle distribution.Results The effects of AG01469 at different concentrations (0.1,1.0,10.0,20.0 and 40.0 μmol/L) on proliferation activity of MDA?MB?231 cells were (94.83 ± 3.93)%, ( 79.42 ± 5.52)%, ( 63.75 ± 4.34)%, ( 38.97 ± 8.42)%, ( 29.70 ± 3.35 )%, with statistically significant differences (F=75.54,P<0.01,different concentrations pairwise comparison: all P <0.05). The efficacy of AG014699 in combination with DTX at different concentrations (( 69.77 ±17.94)%,(58.34± 2.59)%,( 52.81 ± 2.01)%, ( 41.23 ± 3.38)%, ( 24.82 ± 0.73)%) was compared with that of single DTX (( 81.24 ± 11.91)%, ( 85.74 ± 3.10)%, ( 72.74 ± 4.66)%, ( 55.18 ± 3.19)%, (45.95±3.82)%).The differences were statistically significant (t values were -0.923,-11.748,-6.802,-5.199,-9.410,respectively,with P>0.05 at 10-9 concentration and P<0.01 at all other concentrations ). The efficacy of AG014699 combined with CBP ((78.33± 2.89)%,( 60.44± 1.95)%,( 50.55± 3.07)%, (12.07± 1.63)%) and single CBP (( 90.00 ± 6.18)%, ( 87.87 ± 2.30)%,( 76.82 ± 3.37)%,( 40.71 ±1.68)%) was compared,and the cell activity was significantly reduced,indicating statistically significant differences ( t values were -1.935,-15.756,-9.981,-21.192, respectively, and P>0.05 at 10-6 concentration,P<0.05 at all the other concentrations ).The q value was>1.15 when AG014699 was combined with 10-3 mmol/L CBP, which showed synergistic effect.When combined with other effective concentrations of DTX or CBP,the q value was between 0.85 and 1.15,showing additive effect.Conclusion PARP inhibitor AG014699 assisted DTX or CBP can inhibit the proliferation of TNBC cell line MDA?MB?231.By means of simple addition or systematic effect,it can inhibit the triple negative breast cancer.
RESUMEN
Objective To explore the impact of arterial injury on distal limb blood supply in lower limb trauma. Meth?ods Retrospective analysis of 93 patients with different levels of lower limb arterial injury admitted to our hospital from June 2014 to August 2017. There were 84 males and 9 females aged 43.54±9.90 years (ranging 25-65 years). Revascularization was performed through open reduction. Patients were divided into three groups according to their arterial injury locations. Proximal ves?sels were along the superficial femoral artery, from its beginning to the point where it was divided into the descending genicular ar?tery and direct periosteal branches. Intermediate vessels were from the dividing point on the superficial femoral artery to the popli?teal artery before it was divided into the medial inferior genicular artery. Distal vessels were from the dividing point on the poplite?al artery to the distal end of the peroneal artery. The duration from injury to revascularization in the three groups were 13.67±5.99 h, 11.15±4.43 h, and 11.92±5.48 h, respectively. There was no significant difference between groups (F=1.564, P=0.215). ISS in the three groups were 13.00±3.74, 12.77±3.81, and 11.50±3.99, respectively. There was no significant difference between groups (F=1.445, P=0.241). The following items were compared among the three groups, postoperative creatine kinase, arterial blood lac?tate and limb compartment cut. Results Creatine kinase of the intermediate vascular group was 8 743.15±6 968.48 u/L, proximal vascular group 1 467.67±1 810.27 u/L, distal vascular group 2 893.51±1 304.56 u/L. The data of intermediate vascular group were higher than those of proximal and distal vascular groups with significant difference among the groups (F=22.587,P=0.000). The lactate of the intermediate vascular group was 3.20 ± 1.51 mmol/L, proximal vascular group 1.63 ± 0.46 mmol/L, distal vascular group 1.85±0.69 mmol/L with significant difference among the groups (F=20.612,P=0.000). The compartment cut of the intermedi?ate vascular group was incised in 24, but not in 15. The proximal vascular group was not incised in 18, while 15 was incised and 21 not incised in distal vascular group. The rates of compartment cut were 61.5%, 0 and 41.7%, respectively with significant differ? ences (χ2=19.156, P=0.000). Conclusion In lower limb injuries, the intermediate vascular (from the superficial femoral artery after it is divided into the descending genicular artery and direct periosteal branches to the popliteal artery before it is divided into the medial inferior genicular artery) injury leads to the most severe distal limb ischemia.
RESUMEN
Objective To evaluate the safety and efficacy of transcatheter arterial embolization (TAE) in the management of refractory hematuria of prostatic origin (RHPO). Methods This retrospective study from 6 hospitals in china consisted of 31 patients (mean age 75.0±7.5 years, range 58 to 84 years) who underent transcatheter arterial embolization (TAE) for RHPO between February 2011 and January 2017. Patients with RHPO who had complete imaging and clinical data were enrolled. Patients with incomplete clinical data, inability to assess hemostasis, and contraindications to TAE were excluded. The cause of RHPO was benign prostatic hyperplasia (BPH) in nine patients, prostate cancer in twelve, transurethral resection of prostate in four, open prostatectomy in two and prostatic sarcoma in four. Superselective arterial embolization, non-superselective arterial embolization or intra-arterial infusion chemotherapy was performed according to the etiology and angiography. Angiographic findings, technical success rate, clinical success rate, complications were recorded. Results Of the 31 patients, 6 patients (19.4%) were with active bleeding, 4 (12.9%) with aneurysm and 27 (87.1%) with abnormal neovascularization on the angiogram. The 31 patients underwent a totle of 37 TAE, the technical success rate was 100.0%(37/37) and the recent hemostasis success rate was 90.3%(28/31). The incidence of mild complications was 38.7%(13/31), there was no serious complication associated with TAE. Conclusion TAE is a safe and effective method for the treatment of refractory hematuria of prostatic origin.
RESUMEN
Objective To investigate the relationship between lipocalintype prostaglandin dsynthase(L-PGDS) and visfatin in the lower extremity atherosclerotic plaque. Methods Collected from February 2014 to February 2016 in vascular surgery of our hospital 40 cases of femoral artery atherosclerotic plaque intima specimens (observation group), 20 cases of splenic artery, superior mesenteric artery samples (control group), the expression of visfatin and L-PGDS protein were detected by immunohistochemical staining, and the expression of visfatin and L-PGDS mRNA were determined by RT-PCR. Results The observation group visfatin protein expression was (121.42±11.07), significantly higher than the control group (72.07±12.81), and L-PGDS protein expression was (87.93±9.73), significantly lower than the control group (107.04±10.58), the difference was statistically significant (P<0.05). The relative expression of visfatin mRNA in the observation group was (0.321±0.024), which was significant higher than that of the control group (0.217±0.031), while L-PGDS mRNA was (0.203±0.018), significantly lower than the control group (0.314±0.029), the difference was statistically significant (P<0.05); The expression of L-PGDS protein was negatively correlated with the expression of visfatin protein in the plaque tissue (r=-0.617, P<0.05), visfatin mRNA and L-PGDS mRNA were negatively correlated (r=-0.645, P< 0.05). Conclusion Visfatin and L-PGDS in lower extremity atherosclerosis occurrence and development have an important relationship, both of them may play an antagonistic role.
RESUMEN
Objective To explore the relation between lower extremity deep venous thrombosis and knee injury.Methods 100 knee injury patients were operated on in our department.The difference of incidence rates of DVT,the thrombus location and incidence rates of DVT before and after operation in the two groups was compared.There were no fatal pulmonary embolism occurring in either group.Results The incidence rate of DVT in tibial plateau fracture group was 52%,that in patellar fracture was 30% (P < 0.05).DVT incidence rate of popliteal,pretibial,posterior tibial vein thrombosis in group of tibial plateau fracture was higher than that in group of patellar fracture (P < 0.05),while there was no significant difference in postoperative thrombosis between the two groups(P > 0.05).Conclusions There is a high incidence rate of DVT in knee joint injury.Which is closely related to the position of fracture and limb immobilization.
RESUMEN
Objective To investigate the efficacy of treatment and prevention of VitE on vacuous chewing move-ments (VCMs) of haloperidol-induced tardive dyskinesia (TD) rats and serum levels of brain-derived neurotrophic fac-tor ( BDNF) and total antioxidant capacity ( TAC) , and to explore the possible mechanisms.Methods Thirty-two male Sprague-Dawley (SD) rats were randomly divided into TD, P-Vit E, T-Vit E and control group (n=8), receiving to-week treatment with Haloperidol (Hal)+NS, Hal+Vit E (medicated at the baseline), Hal+VitE (medicated at the fifth week) or normal saline (NS), respectively.VCM was evaluated at each week.ELISA and spectrophotometer were used to detect the serum levels of BDNF and TAC, respectively.Results The VCM score of both TD group and T-Vit E group increased at the 2nd weekend, reached the peak at the 5th weekend.VCM score of T-Vit E group declined gradually at the 6th weekend and was significantly lower than that in the TD group [(6.5 ±3.3) vs.(27.9 ±5.8), P0.05) at the 10th weekend.There was no significant difference in VCM score between P-Vit E group and control group for ten weeks(P>0.05).At the 10th weekend, serum BDNF [(6.9 ±1.0) pg/mL] and TAC [(11.9 ±3.2) U/mL] levels of TD group were significantly lower than those of the controls [BDNF (8.6 ±2.5) pg/mL, TAC (18.2 ±5.5) U/mL] and T-Vit E group [BDNF (8.7 ±2.0) pg/mL, (18.6 ±5.9) U/mL] (P0.05).Conclusions Vit E may relieve and prevent VCM in TD model rats though alleviation of free radical damage.