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1.
J Int Med Res ; 49(4): 300060521999567, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33818160

RESUMO

Holmes tremor (HT) is a rare symptomatic movement disorder characterized by a combination of resting, postural, and action tremors. HT is usually caused by lesions in the brain stem, thalamus, and cerebellum, and the pathogenesis is believed to be related to the nigrostriatal pathway and/or the cerebello-thalamo-cortical pathway. Many medications have been used to treat HT with various degrees of effectiveness. We herein present a case involving an elderly woman who developed atypical HT 23 months after cerebral hemorrhage. The atypical HT manifested as a tremor of the right limb with involuntary flexion of the distal five fingers of the right upper limb. Imaging findings suggested the existence of an old hemorrhage in the left thalamus. Specifically, diffusion tensor imaging data of the whole brain and multimodal three-dimensional medical imaging revealed significant white matter microstructural changes in the centromedian nucleus of the left thalamus. Treatment with high-dose oral levodopa was not efficient, but the symptoms gradually decreased in severity and disappeared 1 month after switching to oral clonazepam treatment.

2.
Rev Neurosci ; 2021 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-33781002

RESUMO

In mature mammalian brains, the endocannabinoid system (ECS) plays an important role in the regulation of synaptic plasticity and the functioning of neural networks. Besides, the ECS also contributes to the neurodevelopment of the central nervous system. Due to the increase in the medical and recreational use of cannabis, it is inevitable and essential to elaborate the roles of the ECS on neurodevelopment. GABAergic interneurons represent a group of inhibitory neurons that are vital in controlling neural network activity. However, the role of the ECS in the neurodevelopment of GABAergic interneurons remains to be fully elucidated. In this review, we provide a brief introduction of the ECS and interneuron diversity. We focus on the process of interneuron development and the role of ECS in the modulation of interneuron development, from the expansion of the neural stem/progenitor cells to the migration, specification and maturation of interneurons. We further discuss the potential implications of the ECS and interneurons in the pathogenesis of neurological and psychiatric disorders, including epilepsy, schizophrenia, major depressive disorder and autism spectrum disorder.

3.
Signal Transduct Target Ther ; 6(1): 134, 2021 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-33774649

RESUMO

To discover new drugs to combat COVID-19, an understanding of the molecular basis of SARS-CoV-2 infection is urgently needed. Here, for the first time, we report the crucial role of cathepsin L (CTSL) in patients with COVID-19. The circulating level of CTSL was elevated after SARS-CoV-2 infection and was positively correlated with disease course and severity. Correspondingly, SARS-CoV-2 pseudovirus infection increased CTSL expression in human cells in vitro and human ACE2 transgenic mice in vivo, while CTSL overexpression, in turn, enhanced pseudovirus infection in human cells. CTSL functionally cleaved the SARS-CoV-2 spike protein and enhanced virus entry, as evidenced by CTSL overexpression and knockdown in vitro and application of CTSL inhibitor drugs in vivo. Furthermore, amantadine, a licensed anti-influenza drug, significantly inhibited CTSL activity after SARS-CoV-2 pseudovirus infection and prevented infection both in vitro and in vivo. Therefore, CTSL is a promising target for new anti-COVID-19 drug development.

4.
Opt Lett ; 46(6): 1446-1449, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33720208

RESUMO

Underwater wireless optical communication (UWOC) has great potential to provide higher data rates and lower time delay communication compared to radio frequency and acoustic counterparts. However, UWOC systems with wide bandwidths are subject to photon absorption and scattering, which result in severe energy loss for optical beams and inter-symbol interference. To overcome these issues, this Letter interprets the UWOC system as an autoencoder (AE), named UWOC-AE, which takes advantage of the double Gamma function approximating channel impulse response of underwater optical links to learn the channel characteristics. Thus, within the AE framework, the encoder and decoder can be optimized jointly. Experiments indicate that the proposed UWOC-AE can achieve superior performance with high data rates compared to existing techniques.

5.
Adv Med Sci ; 66(1): 206-214, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33735829

RESUMO

PURPOSE: Several studies have demonstrated that C-type natriuretic peptide (CNP) stimulates osteoblastic proliferation seemly via antagonizing the expression of fibroblast growth factor (FGF)-23 in vitro. The main aim of the present study is to probe whether the post-receptor pathways of FGF-23 participate in osteogenesis caused by CNP. METHODS: Osteoblasts were cultured in the absence or presence of CNP: 0, 10, and 100 â€‹pmol/L, for 24 â€‹h, 48 â€‹h and 72 â€‹h, respectively. RESULTS: The findings of the present study indicated that osteoblastic proliferation was directly promoted by exogenous CNP in a dose-dependent manner; osteoblastic FGF-23 was significantly down-regulated by CNP at 24 â€‹h post-treatment; RAF-1, extracellular signal-regulated kinases (ERK), and P38 were substantially suppressed by CNP in a dose- and time-dependent manner; and signal transducer and activator of transcription (STAT)-1 was not changed on the premise of the down-regulated FGF-23 in osteoblasts treated with CNP. CONCLUSION: CNP may promote osteogenesis via inhibiting ERK and P38, rather than STAT-1, in the downstream of FGF-23/RAF-1 pathway.

6.
Sleep Breath ; 2021 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-33772396

RESUMO

PURPOSE: Previous studies suggest that sleep apnea hypopnea syndrome (SAHS) is an independent risk factor that contributes to certain cardiovascular events. However, there are studies arguing that patients with SAHS had lower peak troponin levels when suffering cardiovascular events compared to patients without SAHS, which indicates that there may potentially be a protective effect of SAHS. This meta-analysis aimed to assess the impact of SAHS on cardiovascular events. METHODS: Databases were searched for studies that examined cardiac biomarkers or reported angiographic data when patients with SAHS experienced cardiovascular events. The data about peak cardiac biomarkers and angiographic coronary lesion were extracted and then used to compute the pooled standardized mean difference (SMD) and 95% confidence interval (95% CI). RESULTS: Among 26 studies included in the meta-analysis, there was not a definite difference between the SAHS group and the control group for troponins (SMD, 0.05; 95% CI, [- 0.16, 0.26]), creatine kinase (SMD, - 0.08; 95% CI, [- 0.38, 0.22]), and CK-MB (SMD, - 0.11; 95% CI, [- 0.51, 0.29]). However, patients with SAHS revealed worse coronary lesion condition grading via both Gensini score (SMD, 0.63; 95% CI, [0.31, 0.95]) and SYNTAX score (SMD, 0.99; 95% CI, [0.31-1.67]). CONCLUSIONS: Ischemic preconditioning induced by the intermittent hypoxia at the early stage could generate a cardiac protection effect, which would then benefit SAHS patients encountering a major adverse cardiovascular event.

7.
Biomark Med ; 2021 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-33769075

RESUMO

Background: There was increasing evidence showing that ARID1A alterations correlated with higher tumor mutational burden, but there were limited studies focusing on the adaptive mechanisms for tumor cells to survive under excessive genomic alterations. Materials & methods: To further explore the adaptive mechanisms under ARID1A alterations, we performed RNA sequencing in ARID1A knockdown hepatocellular carcinoma cell lines, and demonstrated that decreased expression of ARID1A controlled global ribosomal proteins synthesis. The results were further confirmed by quantitative reverse transcription-PCR and bioinformatic analysis in The Cancer Genome Atlas Liver Hepatocellular Carcinoma database. Conclusion: The present study was the first to demonstrate that ARID1A might be involved in the translation pathway and served as an adaptive mechanism for tumor cells to survive under stress.

8.
Drug Des Devel Ther ; 15: 753-767, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33654381

RESUMO

Objective: The traditional Chinese medicine (TCM) formulation Xiaoyao San (XYS) has a good clinical effect in treating ischemic stroke (IS). We explored the mechanism and material basis of XYS in IS treatment. Methods: Network pharmacology was used to construct a network of XYS components and IS targets. R software was used to analyze the biological process and pathway analysis of the targets of XYS in IS treatment. In vitro, a model of apoptosis of PC12 cells induced by oxygen-glucose deprivation/reperfusion (OGD/R) was established to evaluate the neuroprotective effect of XYS and its influence on the expression of apoptotic protein-related genes. The affinity between the potentially active compounds in XYS and apoptotic proteins was evaluated by molecular docking. Results: XYS was shown to have 136 chemical components that exert potential anti-IS activity by acting on 175 proteins. Bioinformatics analysis showed that apoptosis and the phosphoinositide 3-kinase/protein kinase B (PI3K-Akt) signaling pathway were the main signaling pathways of XYS. In vitro experiments showed that XYS could improve the effect of OGD/R on PC12-cell activity (EC50 = 0.43 mg/mL) and inhibit apoptosis. The main mechanisms were related to the improvement of oxidative stress and regulation of apoptosis-related gene expression. Molecular docking showed that C22, C102 and other components in XYS had a strong affinity with apoptosis-related proteins. Conclusion: Network pharmacology, in vitro experiments, and molecular docking were used, for the first time, to study the material basis and molecular mechanism of XYS in IS treatment from the perspective of multiple targets and multiple pathways. We provided a new approach for the future study of TCM formulations in the treatment of complex diseases.

9.
Genetics ; 217(1): 1-17, 2021 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-33683370

RESUMO

Infection with antibiotic-resistant bacteria is an emerging life-threatening issue worldwide. Enterohemorrhagic Escherichia coli O157: H7 (EHEC) causes hemorrhagic colitis and hemolytic uremic syndrome via contaminated food. Treatment of EHEC infection with antibiotics is contraindicated because of the risk of worsening the syndrome through the secreted toxins. Identifying the host factors involved in bacterial infection provides information about how to combat this pathogen. In our previous study, we showed that EHEC colonizes in the intestine of Caenorhabditis elegans. However, the host factors involved in EHEC colonization remain elusive. Thus, in this study, we aimed to identify the host factors involved in EHEC colonization. We conducted forward genetic screens to isolate mutants that enhanced EHEC colonization and named this phenotype enhanced intestinal colonization (Inc). Intriguingly, four mutants with the Inc phenotype showed significantly increased EHEC-resistant survival, which contrasts with our current knowledge. Genetic mapping and whole-genome sequencing (WGS) revealed that these mutants have loss-of-function mutations in unc-89. Furthermore, we showed that the tolerance of unc-89(wf132) to EHEC relied on HLH-30/TFEB activation. These findings suggest that hlh-30 plays a key role in pathogen tolerance in C. elegans.

10.
Acta Pharmacol Sin ; 2021 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-33686245

RESUMO

Aristolochic acid I (AAI) is a well-known nephrotoxic carcinogen, which is currently reported to be also associated with hepatocellular carcinoma (HCC). Whether AAI is a direct hepatocarcinogen remains controversial. In this study we investigated the association between AAI exposure and HCC in adult rats using a sensitive rat liver bioassay with several cofactors. Formation of glutathione S-transferase placental form-positive (GST-P+) foci was used as the marker for preneoplastic lesions/clonal expansion. We first conducted a medium-term (8 weeks) study to investigate whether AAI had any tumor-initiating or -promoting activity. Then a long-term (52 weeks) study was conducted to determine whether AAI can directly induce HCC. We showed that oral administration of single dose of AAI (20, 50, or 100 mg/kg) in combination with partial hepatectomy (PH) to stimulate liver proliferation did not induce typical GST-P+ foci in liver. In the 8-week study, only high dose of AAI (10 mg · kg-1 · d-1, 5 days a week for 6 weeks) in combination with PH significantly increased the number and area of GST-P+ foci initiated by diethylnitrosamine (DEN) in liver. Similarly, only high dose of AAI (10 mg· kg-1· d-1, 5 days a week for 52 weeks) in combination with PH significantly increased the number and area of hepatic GST-P+ foci in the 52-week study. No any nodules or HCC were observed in liver of any AAI-treated groups. In contrast, long-term administration of AAI (0.1, 1, 10 mg· kg-1· d-1) time- and dose-dependently caused death due to the occurrence of cancers in the forestomach, intestine, and/or kidney. Besides, AAI-DNA adducts accumulated in the forestomach, kidney, and liver in a time- and dose-dependent manner. Taken together, AAI promotes clonal expansion only in the high-dose group but did not induce any nodules or HCC in liver of adult rats till their deaths caused by cancers developed in the forestomach, intestine, and/or kidney. Findings from our animal studies will pave the way for further large-scale epidemiological investigation of the associations between AA and HCC.

11.
Artigo em Inglês | MEDLINE | ID: mdl-33658723

RESUMO

OBJECTIVES: Silicosis is a chronic occupational lung disease. As was previously found by the authors, some proteins increased in the lung tissue of activated rats, and protein tyrosine phosphatase non-receptor type 2 (PTPN2), factor B, and vaccinia-related kinase 1 (VRK1) showed highly differential expressions. MATERIAL AND METHODS: In this study, serum and bronchoalveolar lavage fluid samples were collected from patients with silicosis and healthy people to verify the expression of PTPN2, factor B, and VRK1. The diagnostic value of differentially expressed proteins for silicosis was judged. RESULTS: The expression levels of serum PTPN2, VRK1, and factor B in patients with silicosis were significantly higher than those in the control group (p < 0.01). Higher serum PTPN2 and factor B concentrations significantly and negatively correlated with the ratio of forced expiratory volume in 1 s to forced vital capacity (FEV1/FVC), maximum vital capacity (VCmax), FEV1, and FVC, suggesting that the high expression of PTPN2 and factor B is associated with decreased pulmonary ventilation function and restrictive ventilatory impairment in patients with silicosis. All area under curve (AUC) measurements generated from single detection events were >0.744, with PTPN2 reaching the highest value (0.858). The AUC, sensitivity, and specificity for the combined diagnosis using factor B and PTPN2 were 0.907, 86.91% and 85.07%, respectively, for factor B and PTPN2. The 3 differentially expressed proteins are potential classes of predictive biomarkers for silicosis. CONCLUSIONS: Regarding the economy and test practicality, the best diagnostic combination is factor B and PTPN2 for the analysis of AUC, sensitivity and specificity.

12.
Dalton Trans ; 50(12): 4112-4118, 2021 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-33729232

RESUMO

Currently, non-centrosymmetric oxychalcogenides, a class of newly developed heteroanionic compounds, have emerged as promising candidates for IR nonlinear optical (NLO) materials due to the fact that they can combine the impressive second-harmonic generation (SHG) responses of chalcogenides with the wide energy gaps of oxides. Moreover, multiple combinations of chalcogens and the oxygen element would, in principle, lead to more new frequency-doubling building units, enabling the extensive seeking and design of new NLO-active oxychalcogenides. In this Frontiers article, the recent developments of oxychalcogenides as IR-NLO candidates are summarized. These materials can be grouped into three types in terms of their structural dimensions: (i) two-dimensional layered CaZnOS, SrZn2OS2, Sr8Ga8O3S14, Sr6Cd2Sb6O7S10 and Sr4Pb1.5Sb5O5Se8; (ii) one-dimensional chain-typed AEGeOQ2 (AE = Sr and Ba; Q = S and Se); and (iii) zero-dimensional molecular Sr3Ge2O4Se3 and α-Na3PO3S. We discuss the rich coordination environment of mixed-anion frequency-doubling building units focusing on the correlations between their non-centrosymmetric structures and NLO properties, as well as their synthetic methods. Finally, the present challenges and future perspectives in this field are also proposed.

13.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 37(3): 205-211, 2021 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-33766227

RESUMO

Objective To investigate the therapeutic effect of Bushentongluo recipe (BSTL) on bone destruction and its inhibiting effect on NF-κB/RANK/RANKL pathway in collagen-induced arthritis (CIA) rats. Methods SD rats were randomly divided into blank control group, CIA model group, methotrexate (MTX, 1 mg/kg) group, BSTL 0.5 g/kg and 2 g/kg groups, with 10 rats in each. Except the control group, the other rats were injected subcutaneously with type 2 collagen(Col2) at the base of the tail to establish CIA models. After exposure to MTX or BSTL recipe for consecutive 28 days, the pathological change of joint tissues was examined by HE staining. Immunohistochemistry was used to detect NF-κB p65 expression in synovial tissues. The cytokines and anti-Col2 levels were analyzed by ELISA. Western blotting was used to detect the expression of RANKL, RANK and osteoprotegerin (OPG) proteins. Results Compared with the CIA model group, the rats treated with 2 g/kg BSTL for 28 days had lower paw volume, arthritis index (AI), serum levels of IL-1ß, IL-18, TNF-α, anti-Col2-IgG, anti-Col2-IgG2a, RANK and RANKL, and higher level of serum OPG. Besides, Western blotting showed that the expression of NF-κB p65, RANK and RANKL proteins decreased, but the expression of OPG protein increased in BSTL 2 g/kg group. Conclusion BSTL can alleviate the rheumatoid arthritis by down-regulating the expression of NF-κB p65, RANKL, RANK proteins, up-regulating OPG protein, and inhibiting systemic inflammation.


Assuntos
Artrite Experimental , Artrite Reumatoide , Animais , Artrite Experimental/tratamento farmacológico , NF-kappa B , Osteoprotegerina , Ligante RANK , Ratos , Ratos Sprague-Dawley , Membrana Sinovial
14.
Biosens Bioelectron ; 182: 113178, 2021 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-33773379

RESUMO

DNA-based amplifiers with high programmability and accurate molecular recognition ability have become a versatile platform for target amplification. However, the random diffusion of capture probes (CPs) in most DNA amplifiers limits the target recognition efficiency, affecting the limit of detection. Herein, a high-efficient DNA amplifier was developed by localizing the CPs consisted of the unique palindromic tails and target recognition sequences on Au nanoparticle modified magnetic beads (Au@MBs). In the presence of target K-ras gene, the CPs with high local concentration and orientation could capture the target efficiently to expose their palindromic tails, which could act as primers to trigger the polymerization for target recycling. More importantly, the polymerization products could involve in the next recycle and produce abundant mimic targets (MTs) continuously, thereby achieving the detection of trace K-ras gene. Meanwhile, a novel electrochemiluminescence (ECL) indicator of a thin-layer of perylene (Pe) molecules decorated Ag microflowers (Pe@Ag MFs) was obtained based on the reaction between the perylene cation radical (Pe•+) and Ag atoms. The obtained Pe@Ag MFs exhibited desirable ECL performance because (i) a thin-layer of Pe molecules could reduce the inner filter effect and inactive emitters, (ii) the Ag MFs as coreaction accelerator could react with S2O82- to produce more SO4•- and shorten the distance between Pe•- and SO4•- to significantly enhance the ECL intensity of Pe with less energy loss. This work paves the way for the development of efficient amplification strategy and offers a paradigm for the preparation of high-efficiency ECL indicators.

15.
PLoS One ; 16(3): e0248157, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33711043

RESUMO

AIM: Shortening the length of stay (LOS) is a potential and sustainable way to relieve the pressure that type 2 diabetes mellitus (T2DM) patients placed on the public health system. METHOD: Multi-stage random sampling was used to obtain qualified hospitals and electronic medical records for patients discharged with T2DM in 2018. A box-cox transformation was adopted to normalize LOS. Multilevel model was used to verify hospital cluster effect on LOS variations and screen potential factors for LOS variations from both individual and hospital levels. RESULT: 50 hospitals and a total of 12,888 T2DM patients were included. Significant differences in LOS variations between hospitals, and a hospital cluster effect on LOS variations (t = 92.188, P<0.001) was detected. The results showed that female patients, patients with new rural cooperative' medical insurance, hospitals with more beds, and hospitals with faster bed turnovers had shorter LOS. Conversely, elderly patients, patients with urban workers' medical insurance, patients requiring surgery, patients with the International Classification of Diseases coded complication types E11.1, E11.2, E11.4, E11.5, and other complications cardiovascular diseases, grade III hospitals, hospitals with a lower doctor-to-nurse ratio, and hospitals with more daily visits per doctor had longer LOS. CONCLUSIONS: The evidence proved that hospital cluster effect on LOS variation did exist. Complications and patients features at individual level, as well as organization and resource characteristics at hospital level, had impacted LOS variations to varying degrees. To shorten LOS and better meet the medical demand for T2DM patients, limited health resources must be allocated and utilized rationally at hospital level, and the patients with the characteristics of longer LOS risk must be identified in time. More influencing factors on LOS variations at different levels are still worth of comprehensive exploration in the future.

16.
Biochem Pharmacol ; 186: 114471, 2021 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-33587918

RESUMO

Atherosclerosis (AS), characterized by pathological constriction of blood vessels due to chronic low-grade inflammation and lipid deposition, is a leading cause of human morbidity and mortality worldwide. Cell adhesion molecules (CAMs) have the ability to regulate the inflammatory response and endothelial function, as well as potentially driving plaque rupture, which all contribute to the progression of AS. Moreover, recent advances in the development of clinical agents in the cardiovascular field are based on CAMs, which show promising results in the fight against AS. Here, we review the current literature on mechanisms by which CAMs regulate atherosclerotic progression from the earliest induction of inflammation to plaques formation. In particular, we focused on therapeutic strategies based on CAMs inhibitors that prevent leukocyte from migrating to endothelium, including high-affinity antibodies and antagonists, nonspecific traditional medicinal formulas and lipid lowering drugs. The CAMs-based drug delivery nanosystem and the available data on the more reasonable and effective clinical application of CAMs inhibitors have been emphasized, raising hope for further progress in the field of AS therapy.

17.
Pulm Pharmacol Ther ; 67: 102001, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33582208

RESUMO

OBJECTIVE: CXCR1, a member of the seven-transmembrane chemokine receptor family, promotes cell proliferation and metastasis in many tumors. The present study was undertaken to explore the interrelation between CXCR1 expression and the prognosis of advanced non-small cell lung cancer (NSCLC) in addition to the efficacy of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in lung adenocarcinoma (LUAD). METHODS: The expression of CXCR1 in NSCLC tissues was assessed by immunohistochemistry. The relationships between CXCR1 expression and clinical-pathological factors were investigated. Concomitantly, the relationship between CXCR1 expression and EGFR-TKI treatment efficacy was investigated. Gene set enrichment analysis (GSEA) was employed for the exploration of pathway enrichment, tumor immune estimation resource (TIMER) and gene expression profiling interactive analysis (GEPIA) for the inspection of the interrelationship between infiltration immune cells and CXCR1. After gain-and loss-of-function of CXCR1 in NSCLC cells, qRT-PCR and Western blot were applied to measure the levels of proteins associated with the chemokine pathway (CCL3 and CXCL2) and the JAK/STAT pathway (IL9R, PIAS4 and STAT5A). RESULTS: CXCR1 significantly correlated with poor prognosis of NSCLC patients. Additionally, CXCR1 limited the clinical efficacy of EGFR-TKIs in advanced LUAD (P = 0.029). In the tumor microenvironment, CXCR1 was positively associated with infiltration levels of immune markers in lung squamous cell carcinoma (LUSC) and LUAD. High expression of CXCR1 was implicated in the NOD-like receptor (NLR), cytokine/cytokine receptor, JAK/STAT and chemokine signaling pathways in LUAD and LUSC. Overexpression of CXCR1 in NSCLC cell lines enhanced expressions of CCL3, CXCL2, IL9R, PIAS4 and STAT5A, while knockdown of CXCR1 repressed expressions of CCL3, CXCL2, IL9R, PIAS4 and STAT5A. CONCLUSION: CXCR1 is correlated with poor prognosis of NSCLC and affects the efficacy of EGFR-TKIs in LUAD.

18.
Bioorg Med Chem Lett ; 38: 127880, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33636303

RESUMO

Based on our previous research, thirty new 5-amino-1H-1,2,4-triazoles possessing 3,4,5-trimethoxyphenyl moiety were synthesized, and evaluated for antiproliferative activities. Among them, compounds IIa, IIIh, and IIIm demonstrated significant antiproliferative activities against a panel of tumor cell lines, and the promising compound IIIm dose-dependently caused G2/M phase arrest in HeLa cells. Furthermore, analogue IIa exhibited the most potent tubulinpolymerization inhibitory activity with an IC50 value of 9.4 µM, and molecular modeling studies revealed that IIa formed stable interactions in the colchicine-binding site of tubulin, suggesting that 5-amino-1H-1,2,4-triazole scaffold has potential for further investigation to develop novel tubulin polymerization inhibitors with anticancer activity.

19.
Ann Palliat Med ; 10(1): 312-322, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33545766

RESUMO

BACKGROUND: With the development of radiological technologies, radiotherapy has been gradually widely used in the clinic to intracranial tumours and become standardised. However, the related central nervous system disorders are still the most obvious complications after radiotherapy. This study aims to quantify the effectiveness of anlotinib, a small molecule inhibitor of multiple receptor tyrosine kinases, in mitigating acute phase of radiation-induced brain injury (RBI) in a mouse model. METHODS: The onset and progression of RBI were investigated in vivo. All mice, (except for the sham group) were irradiated at a single-fraction of 20 Gy and treated with different doses of anlotinib (0, 0.2 and 0.8 mg/kg, respectively). The expression levels of glial fibrillary acidic protein (GFAP), hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), and phosphorylated vascular endothelial growth factor receptor-2 (p-VEGFR2) were assessed by western blot. Histological changes were identified by luxol fast blue (LFB) staining. RESULTS: The expression levels of GFAP, HIF-1α, and VEGF were downregulated following treatment with anlotinib. However, anlotinib failed to inhibit the development of demyelination. Cerebral edema [as measured by brain water content (BWC)] was also mitigated following treatment with anlotinib. CONCLUSIONS: In summary, treatment with anlotinib significantly mitigated the adverse effects of acute RBI in a dose-dependent manner by downregulating the activation of astrocytes, improving brain hypoxia, and alleviating cerebral edema.

20.
Dig Dis Sci ; 2021 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-33570682

RESUMO

OBJECTIVE: It is still uncertain what effects pulmonary artery catheter (PAC)-guided resuscitation has on outcomes for patients with severe acute pancreatitis (SAP). Therefore, we aimed to investigate the effect of PAC on hospital mortality in patients with SAP. METHODS: We collected the data of patients with a diagnosis of SAP from January 10, 2017, to July 30, 2019. Patients were divided into a PAC group and a control group. The primary outcome measured was the day-28 mortality. Secondary outcomes included day-90 mortality, duration of ICU and hospital stay, ventilation days, usage of renal support and vasoactive agents, incidences of acute abdominal compartment syndrome, infusion volumes, and fluid balance and hemodynamic characteristics measured by the PAC. Kaplan-Meier analysis was applied to estimate survival outcomes. Complications related to PAC were also analyzed. RESULTS: There was no significant difference between the PAC group and the control group for day-28 mortality (22.7% vs. 30%, odds ratio, 0.69; 95% CI 0.31-1.52; P = 0.35). The duration of ICU stay in the PAC group was shorter (P = 0.00), and the rate of dependence on renal support treatment was lower in the PAC group than in the control group (P = 0.03). There was no difference in other secondary outcomes and no significant difference in the survival curve between the two groups (log-rank P = 0.72, X2 = 0.13). However, SAP patients inserted PAC within 24 h ICU admission showed that duration of renal support therapy in PAC patients within 24 h ICU admission (mean days, 1.60; standard deviation, 0.14) was shorter than those with 24-72 h ICU admission (mean days, 2.94; standard deviation, 0.73; P = 0.03). The organ failure rates (1 organ, 2 organs and 3 organs) were all lower in PAC patients within 24 h ICU admission than with 24-72 h ICU admission (P = 0.02, P = 0.02, P = 0.048, respectively). CONCLUSION: In patients with severe acute pancreatitis, PAC-guided fluid resuscitation shortened the duration of ICU stay, and patients in the PAC group had a lower rate of dependence on renal support, while no benefit in terms of mortality was observed. However, SAP patients inserted PAC within 24 h ICU admission showed shorter duration of renal support therapy and lower organ failure rates than those with 24-72 h ICU admission, indicating that early use of PAC, especially within 24 h, might be better for SAP patients.

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