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1.
World J Clin Cases ; 10(13): 4042-4049, 2022 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-35665125

RESUMO

BACKGROUND: In recent years, the incidence of colorectal cancer (CRC) has increased annually, which has seriously threatened the health and quality of life of patients. In the treatment of CRC, both laparoscopic and radical resection are widely used. AIM: To explore and discuss clinical efficacy and postoperative inflammatory response of laparoscopic and open radical resection of CRC. METHODS: A total of 96 patients with CRC diagnosed in our hospital from March 2016 to April 2021 were selected, and were divided into the study group (n = 48) and control group (n = 48) using a simple random method. The control group was treated with open radical resection of CRC, and the study group was treated with laparoscopic radical resection of CRC. The perioperative conditions (operation time, intraoperative blood loss, the recovery time of gastrointestinal function, number of lymph node dissections and length of hospital stay), inflammatory response index levels [interleukin (IL)-6, IL-8, IL-10, C-reactive protein (CRP)] before and after operation, pain stress response indices [levels of neuropeptide (NPY), prostaglandin E2 (PGE2), 5-hydroxytryptamine (5-HT)], and the incidence of the complications between the two groups were counted. RESULTS: The operation time in the study group was (186.18 ± 33.54 min), which was longer than that of the control group (129.38 ± 26.83 min), but the intraoperative blood loss (111.34 ± 21.45 mL), recovery time of gastrointestinal function (25.35 ± 4.55 h), and hospital stay (10.09 ± 2.38 d) were better than those in the control group (163.77 ± 32.41 mL, 36.06 ± 7.13 h, 13.51 ± 3.66 d) (P < 0.05). There was no significant difference in the number of lymph node dissections between the study group (15.19 ± 3.04) and the control group (16.20 ± 2.98) (P > 0.05). There was no significant difference between the levels of serum IL-6 (9.79 ± 4.11 ng/mL), IL-8 (3.79 ± 1.71 ng/L), IL-10 (48.96 ± 12.51 ng/L) and CRP (7.98 ± 2.33 mg/L) in the study group and the control group (10.56 ± 3.78 ng/mL, 4.08 ± 1.45 ng/L, 50.13 ± 11.67 ng/L, 8.29 ± 2.60 mg/L) before the operation (P > 0.05). After the operation, there was no significant difference between the levels of serum IL-6 (19.11 ± 6.68 ng/mL). There was no significant difference in serum NPY (109.79 ± 13.46 UG/L), PGE2 (269.54 ± 37.34 ng/L), 5-HT (151.70 ± 18.86 ng/L) between the study group and the control group (113.29 ± 15.01 UG/L, 273.91 ± 40.04 ng/L, 148.85 ± 20.45 ng/L) before the operation (P > 0.05). The incidence of the complications in the study group (4.17%) was lower than that of the control group (18.75%) (P < 0.05). CONCLUSION: Laparoscopic radical resection of CRC can reduce surgical trauma, inflammatory response and pain stress caused by surgery, which shortens rehabilitation of patients, with a low incidence of complications.

2.
Front Cardiovasc Med ; 9: 874795, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35665262

RESUMO

Background: The use of anticoagulants is an established strategy to prevent stroke, embolism, and cardiovascular mortality in patients with atrial fibrillation (AF), but its role in the prevention of incident diabetes is unclear. We aimed to investigate this question by using participant data from cohort studies. Methods: We conducted a meta-analysis of participants to investigate the impact of direct oral anticoagulants (DOACs) on the risk of new-onset diabetes in AF patients. The collection of related data was performed in the PubMed and EMBASE databases until December 2021, including studies associated with evaluating the correlation between DOACs and incident diabetes. The hazard ratios (HRs) and 95% confidence intervals (CIs) were adjusted by the random-effects model with an inverse variance method. Results: Two cohort studies with a total of 24,434 patients were included in this study (warfarin: n = 6,906; DOACs: n = 17,528). Compared with warfarin, the use of DOACs could reduce the incident diabetic risk in AF patients (HR = 0.75, 95%CI: 0.68-0.82). Investigations about the effects of three major classes of DOACs showed that the individual use of dabigatran (HR = 0.76, 95%CI: 0.64-0.90), rivaroxaban (HR = 0.74, 95%CI: 0.64-0.87), apixaban (HR = 0.74, 95%CI: 0.60-0.92) and the combined use of rivaroxaban and apixaban (HR = 0.74, 95%CI: 0.66-0.84) could reduce the risk of new-onset diabetes compared with warfarin. This risk reduction effect could be observed in both male and female groups (HR = 0.73, 95%CI: 0.64-0.84, P < 0.00001; HR = 0.82, 95%CI: 0.82-0.99, P = 0.04). Conclusions: Treatment with DOACs compared with warfarin reduced the risk of new-onset diabetes in both male and female patients with AF.

3.
Artigo em Inglês | MEDLINE | ID: mdl-35680738

RESUMO

An effective method of iron extraction from bauxite residue was explored, and iron was used to prepare iron carbon composite material, which have a good adsorption effect on the heavy metal cadmium. After acid washing, acid leaching, Fe(III) reduction and ferrous oxalate decomposition, FeSO4·H2O(RM) was successfully extracted from bauxite residue, and the iron loss was only 4.35%. FexOy-BC(RM) nanocomposite materials were prepared by loading FeSO4·H2O(RM) onto walnut shell biochar (BC) (a kind of agricultural and forestry waste) by an in situ reduction and oxidation method. The results showed that the adsorption effect of FexOy-BC(RM) on Cd(II) was better than that of commercial FexOy-BC. XPS, TEM, SEM characterization analysis showed that FexOy-BC(RM) immobilized Cd(II) by adsorption, complexation, etc.to achieve a highly efficient adsorption of heavy metal Cd(II) in wastewater.

4.
ACS Biomater Sci Eng ; 8(6): 2508-2517, 2022 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-35648631

RESUMO

Ferroptosis is a novel type of regulated cell death characterized by the accumulation of lipid peroxides to lethal levels. Most tumor cells are extremely vulnerable to ferroptosis due to the high levels of reactive oxygen species (ROS) produced by their active metabolism. Therefore, tumor cells rely on glutathione (GSH) to reduce lipid peroxides catalyzed by glutathione peroxidase 4 (GPX4), and this pathway is also an important target for a variety of drugs that promote tumor cell ferroptosis. Herein, RSL3@PCA was designed to simultaneously deplete intracellular GSH and inhibit the activity of GPX4, thereby significantly promoting tumor cell ferroptosis. RSL3@PCA was successfully prepared by encapsulating a selective inhibitor of GPX4 into acid-responsive nanoparticle PCA. After being taken up by tumor cells, the acid-responsive nanoparticle gradually degraded to release cinnamaldehyde (CA) and the encapsulated RSL3. CA and RSL3 block the reduction of lipid peroxides in cells, thereby inducing ferroptosis. By a cytotoxicity assay and 4T1 cell xenotransplantation model, we confirmed that RSL3@PCA has excellent inhibition of tumor growth without significant toxicity to normal cells and tissues and still has a good therapeutic effect on tumor cells that are resistant to conventional chemotherapy drugs. This work provides new drug combinations for promoting ferroptosis in tumor cells without severe side effects in normal organs.


Assuntos
Ferroptose , Acroleína/análogos & derivados , Carbolinas/farmacologia , Morte Celular/fisiologia , Peroxidação de Lipídeos/fisiologia , Peróxidos Lipídicos/farmacologia , Micelas
5.
Orthop Surg ; 2022 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-35656704

RESUMO

OBJECTIVE: To compare the effect of percutaneous endoscopic lumbar discectomy (PELD) using a double-cannula guide tube (DGT), traditional PELD, and open lumbar discectomy (OLD) to treat large lumbar disc herniations (LLDHs). METHODS: Seventy patients who presented with LLDH without cauda equina syndrome and were treated with surgery in our hospital from October 2015 to October 2017 were included. The detailed index included the visual analog scale (VAS) for back and radicular leg pain and the Oswestry Disability Index (ODI) in the immediate preoperative period and at the final follow-up. The operation time, radiation exposure time, surgical satisfaction rate, and modified MacNab criteria score were also recorded. RESULTS: The leg and back pain of the patients in these groups improved significantly in the postoperative period. No significant differences were observed in leg pain improvement between the other two groups; however, patients in the PELD group (with or without DGT) presented with significantly higher improvement in back pain than the OLD group (t = 9.965, p < 0.001). The final ODI scores were 12.1 ± 4.9, 11.2 ± 2.9, and 16.4 ± 3.6 in the PELD, PELD-DGT, and OLD groups, respectively. Patients in the PELD and PELD-DGT groups presented with significantly lower postoperative ODI scores than those in the OLD group (t = 20.834, p < 0.001). The mean postoperative hospital stays were significantly shorter in the PELD group and PELD with DGT group than in the OLD group (t = 46.688, p < 0.001). The mean operation time was significantly shorter in the PELD-DGT group than those in the PELD group (t = 25.281, p = 0.001). No perioperative complications were observed in either group. Based on the modified MacNab criteria, excellent and good outcomes were achieved in 20 out of 21 patients (95.2%) in the PELD group, 23 out of 24 patients (95.8%) in the PELD-DGT group, and 22 out of 25 patients (88.0%) in the OLD group. The rates of excellent and good outcomes were higher in the PELD and PELD-DGT groups than in the OLD group, but there were no significant differences (χ2  = 1.454, p = 0.835). CONCLUSIONS: PELD using DGT is a safe and effective option for LLDH and features advantages such as improvements in back pain, a lower hospitalization cost than OLD, a shorter operation time, and less fluoroscopy than traditional PELD.

6.
Theranostics ; 12(8): 3911-3927, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35664077

RESUMO

Rationale: Synergistic treatment strategies for two or more drugs have gradually developed as the main options in clinics for cholangiocarcinoma (CCA) owing to the complicated crosstalk between the tumor and stroma. However, the different synergetic mechanisms pose great challenges to the dosages and order of administration of drugs. Thus, a strategy for exploring and intervening in mutual targets derived from stromal cells and cholangiocarcinoma cells was proposed. Methods: Genes with overexpression patterns in tumors and displaying a significant association with overall survival were identified from RNA-seq data of human CCA patients and CCA mouse models. Western blotting, qRT-PCR, immunofluorescence (IF), colony formation and flow cytometry assays were conducted to determine the biological roles of the key oncogene in cholangiocarcinoma and stromal cells respectively. Additionally, a dual-targeting drug delivery system (AA-HA-ODA) for cancer-associated fibroblasts (CAFs) and tumor cells was constructed to verify the effectiveness of intervening the screened genes in vivo. Results: Polo-like kinase 1 (PLK1) was verified to play vital role in the malignant proliferation of CCA by regulating the cell cycle pathway. PLK1 also decreased stromal production by regulating the CAF phenotype. In addition, a PLK1 inhibitor (Ro3280) loaded dual-targeting drug delivery system (AA-HA-ODA) was prepared and exhibited high affinity for CAFs and cholangiocarcinoma cells. The in vivo distribution pattern and antitumor efficacy of AA-HA-ODA/Ro also verify the effectiveness of inhibiting PLK1 in CCA in vivo. Conclusion: In summary, PLK1 is a mutual target derived from tumor cells and stroma due to its crucial role in the proliferation of tumor cells and stroma regulation in CAFs, which might provide enlightenment for multitarget treatment strategies and guidance for clinical cholangiocarcinoma treatment.


Assuntos
Neoplasias dos Ductos Biliares , Fibroblastos Associados a Câncer , Colangiocarcinoma , Animais , Neoplasias dos Ductos Biliares/tratamento farmacológico , Neoplasias dos Ductos Biliares/patologia , Ductos Biliares Intra-Hepáticos/metabolismo , Ductos Biliares Intra-Hepáticos/patologia , Fibroblastos Associados a Câncer/metabolismo , Proteínas de Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Colangiocarcinoma/metabolismo , Humanos , Camundongos , Proteínas Proto-Oncogênicas
7.
Microb Cell Fact ; 21(1): 107, 2022 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-35655187

RESUMO

BACKGROUND: Cordyceps militaris, a kind of edible and medicinal fungus widely accepted in East Asia, has attracted much attention as a potential cell factory for producing adenosine analogs. Despite the rapid development in gene editing techniques and genome modeling, the diversity of DNA elements in C. militaris was too short to achieve rational heterogeneous expression for metabolic engineering studies. RESULTS: In this study, PtrpC, a kind of promoter with a relatively appropriate expression level and small size, was selected as a monomer for promoter library construction. Through in vitro BioBricks assembly, 9 overlapping PtrpC promoters with different copy numbers as well as reporter gene gfp were connected and subsequently integrated into the genome of C. militaris. Both the mRNA transcription level and the expression level of gene gfp gradually increased along with the copy number of the overlapping promoter NPtrpC and peaked at 7. In the meantime, no significant difference was found in either the biomass or morphological characteristic of engineered and wild-type strains. CONCLUSIONS: This study firstly expanded the overlapping promoter strategy used in model microorganism in C. militaris. It was a proof-of-concept in fungi synthetic biology and provide a general method to pushed the boundary of promoter engineering in edible mushroom.


Assuntos
Cordyceps , Clonagem Molecular , Cordyceps/genética , Biblioteca Gênica , Genes Reporter , Regiões Promotoras Genéticas
8.
Dalton Trans ; 51(24): 9357-9368, 2022 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-35674094

RESUMO

Precise control of the structures and magnetic properties of a molecular material constitutes an important challenge to realize tailor-made magnetic function. Herein, we report that the ligand-directed coordination self-assembly of a dianionic cobalt(II) mononuclear complex and selective organic linkers has led to two distinct dicobalt(II) complexes, [Co2(pdms)2(bpym)3]·2MeCN (1) and [Co(pdms)(bipm)]2·3DMF (2) (H2pdms = 1,2-bis(methanesulfonamide)benzene; bpym = 2,2'-bipyrimidine; bimp = 1,4-bis[(1H-imidazol-1-yl)methyl]benzene). Structural analyses revealed that complexes 1 and 2 are discrete binuclear molecules containing two neutral {Co(pdms)} species bridged by bpym and bimp ligands, respectively, forming an exchange-coupled CoII2 dimer and a rare CoII2 metallocycle. Magnetic studies found that 1 exhibits considerable antiferromagnetic interactions transferred by the bpym bridge while negligible magnetic interactions in 2 due to the long bimp ligands. Interestingly, both the complexes show significant magnetic anisotropy and thus exhibit slow magnetic relaxation under an external dc field originating from spin-lattice relaxation. Detailed theoretical calculations were further applied to understand the magnetic interactions and magnetic anisotropy in 1 and 2. The foregoing results highlight that coordination solids with programmed structures and magnetic properties can be designed and prepared through a judicious selection of molecular complex building blocks and organic linkers.

9.
Accid Anal Prev ; 174: 106756, 2022 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-35728451

RESUMO

Analyzing speed mean and variance is vital to safety management in urban roadway networks. However, modeling speed mean and variance on structured roads could be influenced by the spatial effects, which are rarely addressed in the existing studies. The inadequacy may lead to biased conclusions when considering vehicle speed as a surrogate safety measure. The current study focuses on developing a Bayesian modeling approach with three types of spatial effects, i.e., spatial correlation, spatial heterogeneity, and spillover effect. To capture the spatial correlation, the study employs the intrinsic conditional autoregressive (ICAR) models, spatial lag models (SLM), and spatial error models (SEM). Spatial heterogeneity and spillover effect are considered by the random parameters approach and spatially lagged covariates (SLCs). Speed data are collected from the float cars running on 134 urban arterials in Chengdu, China. The results indicate that the random parameters ICAR model with SLCs (RPICAR-SLC) outperforms others in terms of goodness-of-fit, accuracy, and efficiency for modeling speed mean, while the random parameters ICAR model (RPICAR) is the best for modeling speed variance. Moreover, RPICAR-SLC and RPICAR models are beneficial to address spatial correlation of residuals, explaining the unobserved influence among the observations, and are less likely to cause biased or overestimated parameters. The study also discusses how traffic conditions, road characteristics, traffic management strategies, and facilities on roadway networks influence speed mean and variance. The findings highlight the importance of multi-type spatial effects on modeling speed mean and variance along the structured roadways.

10.
Front Pharmacol ; 13: 926802, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35721121

RESUMO

Perinatal hypoxia-ischemia remains the most common cause of acute neonatal brain injury and is associated with a high death rate and long-term neurological abnormalities such as memory and cognitive deficits and dyskinesia. Hypoxia-ischemia triggers an inflammatory cascade in the brain that is amplified by the activation of immune cells and the influx of peripheral immune cells into the brain parenchyma in response to cellular injury. Thus, acute cerebral hypoxic-ischemic inflammation is a major contributor to the pathogenesis of newborn hypoxic-ischemic brain injury. Lactate is a glycolysis end product that can regulate inflammation through histone lactylation, a unique posttranslational modification that was identified in recent studies. The purpose of this review is to outline the recent improvements in our understanding of microglia-mediated hypoxic-ischemic inflammation and to further discuss how histone lactylation regulates inflammation by affecting macrophage activation. These findings may suggest that epigenetic reprogramming-associated lactate input is linked to disease outcomes such as acute neonatal brain injury pathogenesis and the therapeutic effects of drugs and other strategies in relieving neonatal hypoxic-ischemic brain injury. Therefore, improving our knowledge of the reciprocal relationships between histone lactylation and inflammation could lead to the development of new immunomodulatory therapies for brain damage in newborns.

11.
Front Cardiovasc Med ; 9: 910580, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35722104

RESUMO

Vascular smooth muscle cells (VSMCs) are the primary cell type involved in the atherosclerosis process; senescent VSMCs are observed in both aged vessels and atherosclerotic plaques. Factors associated with the atherosclerotic process, including oxidative stress, inflammation, and calcium-regulating factors, are closely linked to senescence in VSMCs. A number of experimental studies using traditional cellular aging markers have suggested that anti-aging biochemical agents could be used to treat atherosclerosis. However, doubt has recently been cast on such potential due to the increasingly apparent complexity of VSMCs status and an incomplete understanding of the role that these cells play in the atherosclerosis process, as well as a lack of specific or spectrum-limited cellular aging markers. The utility of anti-aging drugs in atherosclerosis treatment should be reevaluated. Promotion of a healthy lifestyle, exploring in depth the characteristics of each cell type associated with atherosclerosis, including VSMCs, and development of targeted drug delivery systems will ensure efficacy whilst evaluation of the safety and tolerability of drug use should be key aims of future anti-atherosclerosis research. This review summarizes the characteristics of VSMC senescence during the atherosclerosis process, the factors regulating this process, as well as an overview of progress toward the development and application of anti-aging drugs.

12.
Front Cardiovasc Med ; 9: 813419, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35722107

RESUMO

Background: Intraocular bleeding is a devastating adverse event for patients with atrial fibrillation (AF) receiving anticoagulant therapy. It is unknown whether non-vitamin K oral anticoagulants (NOACs) compared with warfarin can reduce the risk of intraocular bleeding in patients with AF. Herein, we conducted a meta-analysis to evaluate the effect of NOACs vs. warfarin on intraocular bleeding in the AF population. Methods: Studies were systematically searched from the Embase, PubMed, and Cochrane databases until April 2022. We included studies if they enrolled patients with AF and compared the intraocular bleeding risk between NOACs and warfarin and if they were randomized controlled trials (RCTs) or observational cohort studies. The random-effects model was chosen to evaluate the pooled odds ratios (ORs) and 95% confidence intervals (CIs). Results: A total of 193,980 patients with AF from 5 randomized controlled trials (RCTs) and 1 cohort study were included. The incidence of intraocular bleeding among AF patients treated with warfarin and NOACs was 0.87% (n = 501/57346) and 0.61% (n = 836/136634), respectively. In the pooled analysis with the random-effects model, the use of NOACs was not significantly associated with the risk of intraocular bleeding (OR = 0.74; 95% CI 0.52-1.04, P = 0.08) compared with warfarin use. In addition, the sensitivity analysis with the fixed-effects model suggested that NOAC users had a lower incidence of intraocular bleeding than patients with warfarin (OR = 0.57; 95% CI 0.51-0.63, P < 0.00001). Conclusions: Our current meta-analysis suggested that the use of NOACs had no increase in the incidence of intraocular bleeding compared with warfarin use in patients with AF. Whether the use of NOACs is superior to warfarin needs more research to confirm.

13.
J Sci Food Agric ; 2022 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-35727099

RESUMO

BACKGROUND: Black rice contains a variety of bioactive substances which contribute to the high nutritional value of black rice wine (BRW). However, the dense bran layer of black rice retards the fermentation rate and reduces the dissolution of active components. Hence, this study aims to investigate the effects of pre-gelatinization (PG) before cooking and cellulase (CE) addition during fermentation on the fermentation performance of BRW and its antioxidant activity. RESULTS: PG combined with CE treatments (PGCE) increases the alcohol content, free amino acid (FAA) content, volatile flavor content and total antioxidant activity of BRW by 90.81%, 15.36%, 38.05% and 19.56% respectively compared with the control group. Scanning electron microscopy (SEM), low-field nuclear magnetic resonance (LF-NMR) and texture properties analysis indicate that PG treatment increases gelatinization degree of starch during cooking, decreases bound water content in cooked black rice and promotes unbound water release. CE destroys the aleurone layer structure, facilitates the release of unbound water and the exposure of rice starch, thus increases the reaction area and extravasation content significantly, which is beneficial to microbial growth and fermentation. Incomplete aleurone layer also promotes the dissolution of anthocyanins, phenols and other active substances, increasing the antioxidant activities of BRW. CONCLUSION: PG and CE treatments reduce the fermentation time and improve the quality of BRW by destroying the black rice structure. This article is protected by copyright. All rights reserved.

14.
Traffic Inj Prev ; : 1-7, 2022 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-35709312

RESUMO

OBJECTIVE: While a large amount of work has been conducted on different types of crash injury severity models, model selection uncertainty remains a critical issue in traffic safety research. The objective of this study is to handle model selection uncertainty by combining multiple models. METHODS: Motorcycle crashes in Michigan from 2010 to 2014 are collected for the analysis. A model averaging approach is used to integrate useful information from three commonly used crash injury severity models: multinomial logit model, ordered logit model, and ordered probit model to deal with the situation where the model selection uncertainty exists in crash data analysis. The ratios of model posterior probabilities between models are used to quantify the model selection uncertainty. In addition, the effectiveness of the method is illustrated by comparing it with the single-best model. RESULTS: The ratios of model posterior probabilities among models approximate to 1. It means that three models have the same importance in statistical analysis of motorcycle injury severity, resulting in model selection uncertainty. The comparison between the results of model averaging approach and single-best model shows that the single-best model tends to overestimate the effects of risk factors on motorcycle injury severities because of ignoring the model selection uncertainty; parameter errors and confidence intervals of model averaging are greater and wider than those of the single-best model due to between-model uncertainty included in the model averaging; some risk factors are significant in the model averaging approach while not in the single-best model. Results from model averaging approach reveal that drunk or riding under influence, angle/sideswipe/head on crashes, speed limit of 35 mph or higher, and signal control play significant roles in the motorcycle crashes. CONCLUSIONS: The study contributes to the existing crash injury-severity literature by developing a model averaging approach to explore the relationship between motorcyclist's injury-severity and its contributing factors. The model averaging approach overcomes the limitations of the current crash injury-severity modeling approaches by (1) revealing the potential model selection uncertainty among injury-severity models with model posterior probabilities; (2) more reliably accounting for the effects of risk factors on motorcyclist' injury severities through integrating all information from the candidate models; and (3) better presenting the underlying unreliability of the analysis results from each individual model.

15.
Front Cardiovasc Med ; 9: 903354, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35711361

RESUMO

Torsades de Pointes (TdP) occurred in a 68-year-old female with epidermal growth factor receptor (EGFR) mutant lung cancer administered osimertinib, the third-generation EGFR tyrosine kinase inhibitor (TKI). Electrocardiogram (ECG) recorded at Tdp showed QT prolongation (QTc = 515 ms), to which a Traditional Chinese Medicine (TCM) named "Litsea Cubeba" may have contributed. After discontinuation of osimertinib and Litsea Cubeba, magnesium supplementation, potassium supplementation, lidocaine infusion, and the pacemaker frequency adjustment, Tdp terminated. However, QT prolongation sustained at discharge (QTc = 528 ms), partly because of the emergency use of amiodarone. Osimertinib may prolong the QT interval leading to TdP, especially when multiple risk factors to lengthen QT interval are incidentally overlapped. Thus, regular monitoring of ECG and appropriate management of concomitant drugs are highly recommended.

16.
J Trace Elem Med Biol ; 73: 127003, 2022 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-35660562

RESUMO

BACKGROUND: As an emerging nanomaterial, nano-alumina is widely used in chemical engineering, food and medicine due to its special physical and chemical properties, and its potential health hazards have attracted attention. OBJECTIVE: Aim of this study is to understanding the effect and possible mechanism of nano-alumina on cognitive function in mice. METHODS: Male healthy ICR mice were randomly assigned and given nasal drops of saline, nano-alumina (different doses) and micro-alumina for 30 days, respectively. Morris water maze test, step down test and open field test were used to detect learning and memory ability. Blood brain permeability was observed by immunofluorescence staining and lanthanum nitrate tracing, histopathological abnormalities in mice hippocampus was observed by thionine staining, the final determination of oxidative stress level in brain tissue was measured by using oxidative stress index detection kit and the level of LC3-Ⅱ and Caspase-3, 8, 9 proteins were detected by western blot. RESULTS: In the cerebral cortex of mice exposed to nano-alumina particles, lanthanum nitrate particles adhered to vascular endothelial cells, and the expression of ZO-1 and Occuldin decreased and morphology was disordered; most neurons in hippocampus CA3 region showed balloon-like swelling and degeneration, nucleoli disappeared and apical dendrites broke; mice exposed to nano-alumina, the escape latency in Morris water maze increased compared with the control group(P < 0.05),and the residence time in the original platform quadrant shortened significantly(P < 0.05);the platform latency was significantly shortened and the number of errors increased in the step down test compared with the control group; the residence time in the center of mice the nano-alumina treated was significantly increased in open field test (P < 0.05). CONCLUSION: The nano-alumina particles could be transported into the central nervous system via blood-brain barrier and olfactory bulb, impair learning and memory function in mice, which is more serious than the micro-alumina particles. The apoptosis of mice neurons caused by nano-alumina particles maybe due to the mixed neurotoxic effect of oxidative stress and the elemental toxicity of aluminum itself.

17.
Small ; : e2201585, 2022 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-35644863

RESUMO

To overcome the autophagy compromised mechanism of protective cellular processes by "eating"/"digesting" damaged organelles or potentially toxic materials with autolysosomes in tumor cells, lysosomal impairment can be utilized as a traditional autophagy dysfunction route for tumor therapy; however, this conventional one-way autophagy dysfunction approach is always limited by the therapeutic efficacy. Herein, an innovative pharmacological strategy that can excessively provoke autophagy via endoplasmic reticulum (ER) stress is implemented along with lysosomal impairment to enhance autophagy dysfunction. In this work, the prepared tellurium double-headed nanobullets (TeDNBs) with controllable morphology are modified with human serum albumin (HSA) which facilitates internalization by tumor cells. On the one hand, ER stress can be stimulated by upregulating the phosphorylation eukaryotic translation initiation factor 2 (P-eIF2α) owing to the production of tellurite (TeO3 2- ) in the specifical hydrogen peroxide-rich tumor environment; thus, autophagy overstimulation occurs. On the other hand, OME can deacidify and impair lysosomes by downregulating lysosomal-associated membrane protein 1 (LAMP1), therefore blocking autolysosome formation. Both in vitro and in vivo results demonstrate that the synthesized TeDNBs-HSA/OME (TeDNBs-HO) exhibit excellent therapeutic efficacy by autophagy dysfunction through ER stress induction and lysosomal damnification. Thus, TeDNBs-HO is verified to be a promising theranostic nanoagent for effective tumor therapy.

18.
Acta Pharm Sin B ; 12(5): 2358-2373, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35646525

RESUMO

Obesity is increasingly prevalent globally, searching for therapeutic agents acting on adipose tissue is of great importance. Equisetin (EQST), a meroterpenoid isolated from a marine sponge-derived fungus, has been reported to display antibacterial and antiviral activities. Here, we revealed that EQST displayed anti-obesity effects acting on adipose tissue through inhibiting adipogenesis in vitro and attenuating HFD-induced obesity in mice, doing so without affecting food intake, blood pressure or heart rate. We demonstrated that EQST inhibited the enzyme activity of 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1), a therapeutic target of obesity in adipose tissue. Anti-obesity properties of EQST were all offset by applying excessive 11ß-HSD1's substrates and 11ß-HSD1 inhibition through knockdown in vitro or 11ß-HSD1 knockout in vivo. In the 11ß-HSD1 bypass model constructed by adding excess 11ß-HSD1 products, EQST's anti-obesity effects disappeared. Furthermore, EQST directly bond to 11ß-HSD1 protein and presented remarkable better intensity on 11ß-HSD1 inhibition and better efficacy on anti-obesity than known 11ß-HSD1 inhibitor. Therefore, EQST can be developed into anti-obesity candidate compound, and this study may provide more clues for developing higher effective 11ß-HSD1 inhibitors.

19.
Br J Radiol ; : 20220035, 2022 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-35611637

RESUMO

OBJECTIVE: Local therapy (LT) could potentially prolong the survival of patient with advanced epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) receiving tyrosine kinase inhibitors (TKIs) and harboring oligometastatic/oligoprogressive disease (OMD/OPD). However, the optimal imaging method for identifying patients with OMD/OPD remains controversial. The objective of this study was to investigate the clinical value of incorporating PET/CT in detecting patients with OMD/OPD. METHODS: Consecutive cases with metastatic EGFR-mutant NSCLC undergoing first-line EGFR-TKI treatment were retrospectively screened and those receiving baseline PET/CT and brain magnetic resonance imaging (MRI) or complete conventional imaging (CIM), including brain MRI, chest computed tomography (CT), abdomen ultrasound or CT and bone scintigraphy were included. OMD/OPD was defined as metastases/progressions documented at a maximum of five lesions and three organs, otherwise was defined as multiple metastatic/progressive disease (MMD/MPD). Progression-free survival (PFS) and overall survival (OS) were analyzed. RESULTS: Of the 392 patients evaluated, baseline OMD was detected in 22.7% (53/233) of patients by PET/CT and in 18.2% (29/159) of patients by CIM (p = 0.171). Among the patients evaluated with baseline PET/CT, patients with OMD had longer PFS (p = 0.016) and tendency of improved OS (p = 0.058) than those with MMD. However, this result was not observed with patients evaluated using baseline CIM. With a median follow-up of 24.2 (range, 1.1-124.6) months, 297 patients had their first disease progression (FPD), of whom 164 (55.2%) had adequate imaging scans to analyze the tumor distributions at FPD comprehensively. OPD was detected in 63.0% (34/54) and 35.0% (39/110) of patients among the PET/CT and CIM assessed group (p = 0.003), respectively. Among the PET/CT assessed group, patients with OPD had significantly longer post-progressive overall survival (OS2) than those with MPD (p = 0.011). However, no significant difference of OS2 in the CIM assessed group was found. CONCLUSION: Patients with OMD/OPD, evaluated by PET/CT but not CIM, generally had more favorable survival outcomes than those with MMD/MPD among patients with metastatic NSCLC undergoing first-line EGFR-TKI treatment. ADVANCES IN KNOWLEDGE: PET/CT seems to affect the survival of patients under first-line EGFR-TKI treated metastatic NSCLC with OMD/OPD.

20.
Eur J Med Chem ; 238: 114489, 2022 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-35640328

RESUMO

Human dihydroorotate dehydrogenase (hDHODH) is a key enzyme in the de novo synthesis pathway of pyrimidine nucleotide in cells. The moderate efficiency of teriflunomide, an approved hDHODH inhibitor for the treatment of multiple sclerosis, limited its therapeutic application of malignancy. Herein, thirty-seven novel teriflunomide derivatives with a biphenyl scaffold were designed, synthesized and evaluated. As a result, the optimal compound A37 exhibited a potent hDHODH inhibitory activity with an IC50 value of 10.2 nM, which was about 40-fold stronger than that of teriflunomide (IC50 = 407.8 nM), and showed favorable antiproliferative activities against HCT116 cells with an IC50 value of 0.3 µM. Meanwhile, A37 displayed an acceptable safety profile at an oral dosage of 400 mg/kg in the acute toxicity assay, and exhibited a promising antitumor effect with tumor growth inhibition rate of 54.4% at an oral dosage of 30 mg/kg in HCT116 xenograft model. These results indicate that A37 is an efficacious hDHODH inhibitor with potential in the treatment of colorectal carcinoma.

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