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1.
Spectrochim Acta A Mol Biomol Spectrosc ; 264: 120270, 2022 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-34438115

RESUMO

Hypochlorite plays a significant role in physiological processes, particularly regulation of lysosomal functions, and is involved in various diseases. Thus, it is crucial to develop highly sensitive and selective molecule tools to detect HClO in lysosomes. Herein, a novel 2H-benzo[h]chromene-pyridine derivative (1) was synthesized through condensation reaction, which exhibited a notable deep-red emission at 640 nm in pure water. This deep-red emission was specifically quenched by adding ClO-. The response of probe 1 toward ClO- was rapid (within 10 s), sensitive (detection limit of 0.012 µM), and effective over a wide range of pH (1.0-12.0). Due to the existence of morpholine as the lysosome-targeting unit, the probe was successfully utilized to monitor lysosomal ClO-. Moreover, the probe 1 was also applied to detecting ClO- in zebrafish.


Assuntos
Corantes Fluorescentes , Ácido Hipocloroso , Animais , Humanos , Lisossomos , Imagem Óptica , Água , Peixe-Zebra
2.
Front Mol Neurosci ; 14: 729975, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34803603

RESUMO

The medial prefrontal cortex (mPFC), a key part of the brain networks that are closely related to the regulation of behavior, acts as a key regulator in emotion, social cognition, and decision making. Astrocytes are the majority cell type of glial cells, which play a significant role in a number of processes and establish a suitable environment for the functioning of neurons, including the brain energy metabolism. Astrocyte's dysfunction in the mPFC has been implicated in various neuropsychiatric disorders. Glucose is a major energy source in the brain. In glucose metabolism, part of glucose is used to convert UDP-GlcNAc as a donor molecule for O-GlcNAcylation, which is controlled by a group of enzymes, O-GlcNAc transferase enzyme (OGT), and O-GlcNAcase (OGA). However, the role of O-GlcNAcylation in astrocytes is almost completely unknown. Our research showed that astrocytic OGT could influence the expression of proteins in the mPFC. Most of these altered proteins participate in metabolic processes, transferase activity, and biosynthetic processes. GFAP, an astrocyte maker, was increased after OGT deletion. These results provide a framework for further study on the role of astrocytic OGT/O-GlcNAcylation in the mPFC.

3.
Environ Pollut ; 293: 118489, 2021 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-34780754

RESUMO

Detecting pesticide residues in human serum is a challenging process due to trace-level chronic exposure. Several methods using magnetic adsorbents have been developed for analyzing pesticide residue levels in human serum, but it is still difficult to achieve lower quantitative levels, and the adsorption mechanism for extracting pesticides is unclear. Herein, we propose a feasibility concept of using C18-functionalized magnetic nanoparticles for the adsorption of target pesticides, focusing on the extensively used weakly polar pesticides based on molecular dynamics (MD) simulations. To support this, the facilitated target nanoparticles of Fe3O4@SiO2-C18 were synthesized at a size of 12-13 nm with a magnetic saturation of 40 emu/g. After optimizing and establishing the extraction conditions (1.8 mL C18 modifier, 10 mg sorbents, 3 min adsorption time, 1000 µL ACN for desorption eluent at pH 3.8 and 5 min desorption time), which exhibited recovery = 72.3%-118.3% with RSDs = 0.03-6.57, linearity at 0.01-10 ng/mL with R2 = 0.9561-0.9993, and LODs = 0.01-0.30 ng/mL for the 11 weakly polar pesticides in human serum. Furthermore, the mechanism by which the C18 group selectively extracts weakly polar pesticides was confirmed by binding van der Waals and electrostatic interactions under stable and strong binding energy. The extraction process of efficient adsorption and desorption with C18 functional magnetite nanoparticles suggests a simple method for detecting weakly polar pesticides. The concept may lead to a general approach to analyzing multiple pesticide residues in human serum at trace levels.

4.
Antiviral Res ; 197: 105211, 2021 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-34826506

RESUMO

AB-506, a small-molecule inhibitor targeting the HBV core protein, inhibits viral replication in vitro (HepAD38 cells: EC50 of 0.077 µM, CC50 > 25 µM) and in vivo (HBV mouse model: ∼3.0 log10 reductions in serum HBV DNA compared to the vehicle control). Binding of AB-506 to HBV core protein accelerates capsid assembly and inhibits HBV pgRNA encapsidation. Furthermore, AB-506 blocks cccDNA establishment in HBV-infected HepG2-hNTCP-C4 cells and primary human hepatocytes, leading to inhibition of viral RNA, HBsAg, and HBeAg production (EC50 from 0.64 µM to 1.92 µM). AB-506 demonstrated activity across HBV genotypes A-H and maintains antiviral activity against nucleos(t)ide analog-resistant variants in vitro. Evaluation of AB-506 against a panel of core variants showed that T33N/Q substitutions results in >200-fold increase in EC50 values, while L30F, L37Q, and I105T substitutions showed an 8 to 20-fold increase in EC50 values in comparison to the wild-type. In vitro combinations of AB-506 with NAs or an RNAi agent were additive to moderately synergistic. AB-506 exhibits good oral bioavailability, systemic exposure, and higher liver to plasma ratios in rodents, a pharmacokinetic profile supporting clinical development for chronic hepatitis B.

5.
J Clin Lab Anal ; : e24096, 2021 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-34752662

RESUMO

AIM: Gestational diabetes mellitus (GDM) is the most common metabolic disorder during pregnancy. Accumulating studies have reported metabolites that are significantly associated with the development of GDM. However, studies on the metabolism of placenta, the most important organ of maternal-fetal energy and material transport, are extremely rare. This study aimed to identify and discuss the relationship between differentially expressed metabolites (DEM) and clinical parameters of the mothers and newborns. METHODS: In this study, metabolites from 63 placenta tissues (32 GDM and 31 normal controls) were assayed by ultra-performance liquid chromatography-high resolution mass spectrometry (UPLC-HRMS). RESULTS: A total of 1297 annotated metabolites were detected, of which 87 significantly different in GDM placenta. Lipids and lipid-like molecules accounted for 62.1% of DEM as they were significantly enriched via the "biosynthesis of unsaturated fatty acids" and "fatty acid biosynthesis" pathways. Linoleic acid and α-linolenic acid appeared to be good biomarkers for the prediction and diagnosis of GDM. In addition, the level of PC(14:0/18:0) was negatively correlated with neonatal weight. 14 metabolites significantly different in male and female offspring, with the most increase in female newborns. CONCLUSION: Even if maternal blood glucose level is well controlled, there are still metabolic abnormalities in GDM. Lipids and lipid-like molecules were the main differential metabolites, especially unsaturated fatty acids.

6.
Elife ; 102021 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-34647520

RESUMO

Osteoblast differentiation is sequentially characterized by high rates of proliferation followed by increased protein and matrix synthesis, processes that require substantial amino acid acquisition and production. How osteoblasts obtain or maintain intracellular amino acid production is poorly understood. Here, we identify SLC1A5 as a critical amino acid transporter during bone development. Using a genetic and metabolomic approach, we show SLC1A5 acts cell autonomously to regulate protein synthesis and osteoblast differentiation. SLC1A5 provides both glutamine and asparagine which are essential for osteoblast differentiation. Mechanistically, glutamine and to a lesser extent asparagine support amino acid biosynthesis. Thus, osteoblasts depend on Slc1a5 to provide glutamine and asparagine, which are subsequently used to produce non-essential amino acids and support osteoblast differentiation and bone development.


Assuntos
Sistema ASC de Transporte de Aminoácidos/genética , Asparagina/biossíntese , Desenvolvimento Ósseo/genética , Glutamina/biossíntese , Antígenos de Histocompatibilidade Menor/genética , Osteoblastos/metabolismo , Osteogênese , Sistema ASC de Transporte de Aminoácidos/metabolismo , Animais , Feminino , Camundongos , Antígenos de Histocompatibilidade Menor/metabolismo
7.
Mol Hum Reprod ; 27(11)2021 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-34643696

RESUMO

Evidence accumulated in recent years has revealed that neutrophils are involved in the initial establishment of endometriosis, which is well-known as a chronic inflammatory disease. So far, why and how neutrophils promote the formation of early endometriosis are still unclear. In this study, using a mouse model of endometriosis, we demonstrated that endometriosis mice (EMs mice) had a significantly increased number of neutrophils in peritoneal fluids and lesions, and increased levels of granulocyte colony-stimulating factor (G-CSF) and IL-6 in serum and peritoneal fluids compared to the control group. In the neutrophils and uterine fragments co-injection experiment, neutrophils regulated by G-CSF and IL-6 had a similar effect to neutrophils from EMs mice, increasing the number, area, weight and microvessel density (MVD) of endometriotic lesions. Blocking the effect of G-CSF and IL-6 in EMs mice resulted in a decrease in the number, area and weight of endometriotic lesions. Following the depletion of neutrophils in vivo using a anti-Ly6G antibody, the MVD in the lesions of mice treated with neutrophils from EMs mice and neutrophils from pG/pI6 mice were significantly reduced. Neutrophils from EMs mice and neutrophils from pG/pI6 mice altered the expression levels of Mmp9, Bv8 and Trail genes compared to the neutrophils from PBS-treated mice. IL-6 together with G-CSF induced a higher expression of phospho-STAT3 and STAT3 in neutrophils. These findings suggest that neutrophils modulated by G-CSF and IL-6 through the STAT3 pathway alter the expression levels of the angiogenesis-related genes Mmp9, Bv8 and Trail, and may promote the establishment of early endometriosis.

8.
Mol Genet Metab ; 134(3): 257-266, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34635437

RESUMO

Propionic acidemia (PA) is an autosomal recessive metabolic disorder after gene encoding propionyl-CoA carboxylase, Pcca or Pccb, is mutated. This genetic disorder could develop various complications which are ascribed to dysregulated propionyl-CoA metabolism in organs. However, the effect of attenuated PCC on propionyl-CoA metabolism in different organs remains to be fully understood. We investigated metabolic perturbations in organs of Pcca-/-(A138T) mice (a mouse model of PA) under chow diet and acute administration of [13C3]propionate to gain insight into pathological mechanisms of PA. With chow diet, the metabolic alteration is organ dependent. l-Carnitine reduction induced by propionylcarnitine accumulation only occurs in lung and liver of Pcca-/- (A138T) mice. [13C3]Propionate tracing data demonstrated that PCC activity was dramatically reduced in Pcca-/-(A138T) brain, lung, liver, kidney, and adipose tissues, but not significantly changed in Pcca-/-(A138T) muscles (heart and skeletal muscles) and pancreas, which was largely supported by PCCA expression data. The largest expansion of propionylcarnitine in Pcca-/-(A138T) heart after acute administration of propionate indicated the vulnerability of heart to high circulating propionate. The overwhelming propionate in blood also stimulated ketone production from the increased fatty acid oxidation in Pcca-/-(A138T) liver by lowering malonyl-CoA, which has been observed in cases where metabolic decompensation occurs in PA patients. This work shed light on organ-specific metabolic alternations under varying severities of PA.

9.
J Agric Food Chem ; 69(44): 13200-13216, 2021 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-34709825

RESUMO

Nontarget data acquisition for target analysis (nDATA) workflows using liquid chromatography-high-resolution accurate mass (LC-HRAM) spectrometry, spectral screening software, and a compound database have generated interest because of their potential for screening of pesticides in foods. However, these procedures and particularly the instrument processing software need to be thoroughly evaluated before implementation in routine analysis. In this work, 25 laboratories participated in a collaborative study to evaluate an nDATA workflow on high moisture produce (apple, banana, broccoli, carrot, grape, lettuce, orange, potato, strawberry, and tomato). Samples were extracted in each laboratory by quick, easy, cheap, effective, rugged, and safe (QuEChERS), and data were acquired by ultrahigh-performance liquid chromatography (UHPLC) coupled to a high-resolution quadrupole Orbitrap (QOrbitrap) or quadrupole time-of-flight (QTOF) mass spectrometer operating in full-scan mass spectrometry (MS) data-independent tandem mass spectrometry (LC-FS MS/DIA MS/MS) acquisition mode. The nDATA workflow was evaluated using a restricted compound database with 51 pesticides and vendor processing software. Pesticide identifications were determined by retention time (tR, ±0.5 min relative to the reference retention times used in the compound database) and mass errors (δM) of the precursor (RTP, δM ≤ ±5 ppm) and product ions (RTPI, δM ≤ ±10 ppm). The elution profiles of all 51 pesticides were within ±0.5 min among 24 of the participating laboratories. Successful screening was determined by false positive and false negative rates of <5% in unfortified (pesticide-free) and fortified (10 and 100 µg/kg) produce matrices. Pesticide responses were dependent on the pesticide, matrix, and instrument. The false negative rates were 0.7 and 0.1% at 10 and 100 µg/kg, respectively, and the false positive rate was 1.1% from results of the participating LC-HRAM platforms. Further evaluation was achieved by providing produce samples spiked with pesticides at concentrations blinded to the laboratories. Twenty-two of the 25 laboratories were successful in identifying all fortified pesticides (0-7 pesticides ranging from 5 to 50 µg/kg) for each produce sample (99.7% detection rate). These studies provide convincing evidence that the nDATA comprehensive approach broadens the screening capabilities of pesticide analyses and provide a platform with the potential to be easily extended to a larger number of other chemical residues and contaminants in foods.


Assuntos
Resíduos de Praguicidas , Praguicidas , Cromatografia Líquida de Alta Pressão , Cromatografia Líquida , Contaminação de Alimentos/análise , Frutas/química , Resíduos de Praguicidas/análise , Praguicidas/análise , Espectrometria de Massas em Tandem , Verduras , Fluxo de Trabalho
10.
J Biomater Appl ; : 8853282211051871, 2021 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-34672223

RESUMO

In this study, the surface of the covered stent was treated by plasma technology to introduce amino functional groups, and glutaraldehyde and heparin were successfully grafted to prepare a heparin-functionalized covered stent (HPLCS). The preparation parameters such as plasma treatment power, plasma treatment time, concentration of glutaraldehyde and heparin, and pH of heparin solution were studied in detail. The functionalized heparin covered stent can make the titer of heparin reach 1.23 ± 0.03 IU/cm2. In animal experiments, after implantation in pigs for 6 months, the titer of heparin can still reach 0.93 ± 0.05 IU/cm2. This work provides a good method for preparing heparin covered stent.

11.
Yi Chuan ; 43(9): 910-920, 2021 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-34702703

RESUMO

Xanthomonas campestris pv. campestris (Xcc) is a vascular pathogen that causes black rot in host. It is an important model strain for studying the interaction between the phytopathogen and plants. In Xcc, global transcription regulator HpaR1 that belongs to the GntR family regulates many cellular processes such as the movement and synthesis of extracellular polysaccharides and extracellular enzymes, and is associated with hypersensitive response (HR) and pathogenicity. On the other hand, the global transcriptional regulator Clp regulates the secretion and synthesis of extracellular enzymes and extracellular polysaccharides, and is associated with the pathogenicity of Xanthomonas. Previous studies have shown that both HpaR1 and Clp bind to the promoter region of the glycoside hydrolase encoding gene (named ghy gene). This study investigates the molecular mechanism of the co-regulation of HpaR1 and Clp on the expression of ghy gene. Through electrophoresis mobility shift assay (EMSA), we found that both HpaR1 and Clp bind to the promoter regions of gene ghy in vitro. Both HpaR1 and Clp also bind to the promoter regions of gene ghy in vivo by chromatin immunoprecipitation (ChIP) assays. DNase I footprinting and 5'-RACE assays showed that both HpaR1 and Clp bind to the -35 region upstream of the ghy promoter. The HpaR1 binding site was located upstream of the Clp binding site. RT-qPCR and in vitro transcription assays showed that HpaR1 negatively while Clp positively regulates the transcription of gene ghy. Furthermore, HpaR1 inhibits the activation of Clp on the transcription of gene ghy in vitro. Our findings indicate that HpaR1 and Clp exhibit opposite effect on the transcription of gene ghy. It is speculated that HpaR1 may regulate the expression of gene ghy by inhibiting the activity of RNA polymerase.


Assuntos
Xanthomonas campestris , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Regulação Bacteriana da Expressão Gênica , Glicosídeo Hidrolases/genética , Glicosídeos , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Xanthomonas campestris/genética , Xanthomonas campestris/metabolismo
12.
Curr Oncol ; 28(5): 3758-3770, 2021 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-34677239

RESUMO

BACKGROUND: 5-Hydroxymethylcytosine (5hmC) with dynamic existence possesses multiple regulatory functions. Whereas, 5hmC's impact on small hepatocellular carcinoma (SHCC) remains unclear. The present work focused on characterizing 5hmC content within SHCC and assessing the possibility of using global genomic 5hmC level as the predicative factor of clinical outcome. METHODS: This study applied ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) in measuring 5mC, 5fC and 5hmC contents. In addition, immunohistochemistry (IHC) was adopted to measure CK19 and 5hmC contents. RESULTS: Research showed 5mC, 5hmC, and 5fC contents from global genomics of SHCC reduced extensively compared with healthy samples (p < 0.001). Moreover, SHCC was associated with lymph node metastasis (LNM). Greater 5mC and 5hmC levels were observed in non-metastasis group compared with the metastasis group (p < 0.001). Correlation analysis between the HBV DNA level and 5mC, 5fC and 5hmC levels exhibited that HBV DNA was associated with 5mC, 5hmC, and 5fC content reduction, which was verified in the cytological experiments. Moreover, 5hmC content had a negative correlation with the expression level of CK19 in SHCC. The decrease in 5hmC and CK19 containing 5hmC positive cell (called CK195hmC+) should be ascribed to the bad prognosis among SHCC patients. CONCLUSIONS: The contents of 5hmC and CK195hmC+ of genomic DNA might be adopted for predicting SHCC survival as an important biomarker.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Biomarcadores , Carcinoma Hepatocelular/genética , DNA , Metilação de DNA , Humanos , Neoplasias Hepáticas/genética , Prognóstico , Espectrometria de Massas em Tandem
13.
J Craniofac Surg ; 32(7): 2542-2545, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34705363

RESUMO

OBJECTIVES: Aimed to explore the correlation between the volume of the sphenoid sinuses (SS) and sex, age, pneumatization and its anatomical variant types. MATERIAL AND METHODS: Retrospectively evaluated high-resolution computed tomography images of 170 individuals; were studied by ITK-SNAP software to measure the volume of SS. RESULTS: The average volume of SS was a significant difference between the gender, the volume of SS in the elderly group (≥65 years old) showed a downward trend. The volume of the SS in the variants of the anterior clinoid processes, pterygoid processes, greater wings, and clivus were significantly higher than in the nonvariants (P < 0.05). With the expansion of pneumatization, the optic nerve (CNII) type 3-4, the internal carotid artery (ICA) type 2-3 and the septal insertion on the ICA have a larger volume, while the occurrence of septal insertion on only the CNII was not correlated with the volume (P > 0.05). CONCLUSIONS AND SIGNIFICANCE: The volume of SS is closely related to age, sex, the type of pneumatization and anatomical variation. High-resolution computed tomography can facilitate a precise study of anatomical variations and adjacent structures and help ensure the safety of an operation.


Assuntos
Osso Esfenoide , Seio Esfenoidal , Idoso , Variação Anatômica , Humanos , Estudos Retrospectivos , Osso Esfenoide/diagnóstico por imagem , Seio Esfenoidal/diagnóstico por imagem , Tomografia Computadorizada por Raios X
14.
Front Oncol ; 11: 725988, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34631555

RESUMO

Background: Liver metastases (LM) are the most common tumors encountered in the liver and continue to be a significant cause of morbidity and mortality. Identification of the primary tumor of any LM is crucial for the implementation of effective and tailored treatment approaches, which still represents a difficult problem in clinical practice. Methods: The resection or biopsy specimens and associated clinicopathologic data were archived from seven independent centers between January 2017 and December 2020. The primary tumor sites of liver tumors were verified through evaluation of available medical records, pathological and imaging information. The performance of a 90-gene expression assay for the determination of the site of tumor origin was assessed. Result: A total of 130 LM covering 15 tumor types and 16 primary liver tumor specimens that met all quality control criteria were analyzed by the 90-gene expression assay. Among 130 LM cases, tumors were most frequently located in the colorectum, ovary and breast. Overall, the analysis of the 90-gene signature showed 93.1% and 100% agreement rates with the reference diagnosis in LM and primary liver tumor, respectively. For the common primary tumor types, the concordance rate was 100%, 95.7%, 100%, 93.8%, 87.5% for classifying the LM from the ovary, colorectum, breast, neuroendocrine, and pancreas, respectively. Conclusion: The overall accuracy of 93.8% demonstrates encouraging performance of the 90-gene expression assay in identifying the primary sites of liver tumors. Future incorporation of the 90-gene expression assay in clinical diagnosis will aid oncologists in applying precise treatments, leading to improved care and outcomes for LM patients.

15.
Int J Nanomedicine ; 16: 6129-6140, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34511910

RESUMO

Purpose: With the development of nanomedicine, microwave ablation enhanced by multifunctional nanoplatforms has been widely studied for synergistic cancer therapy. Though scientists have got a lot of significant achievements in this field, the detailed molecular mechanisms and potential targets of microwave ablation enhanced by multifunctional nanoplatforms still need further exploration. In this study, we found that a kind of magnetite Fe3O4 nanoparticles (Fe3O4 NPs) could induce severe endoplasmic reticulum stress and activate cancer apoptosis under the irradiation of mild microwave. Methods: In this study, plenty of studies including cell immunofluorescence, mitochondrial membrane potential, electron microscopy, atomic force microscopy and microwave ablation in vivo were conducted to explore the molecular mechanisms and potential targets of microwave ablation enhanced by the Fe3O4 NPs. Results: The IRE1-ASK1-JNK pathway was strongly activated in A375 cells treated with both Fe3O4 NPs and mild microwave. The endoplasmic reticulum of the A375 cells was significantly dilated and exhibited ballooning degeneration. By investigating the mitochondrial membrane potential (ΔΨm), we found that the mitochondria of cancer cells had been significantly damaged under microwave treatment coupled with Fe3O4 NPs. In addition, melanoma of B16F10-bearing mice had also been effectively inhibited after being treated with Fe3O4 NPs and microwave. Conclusion: In this study, we found that a kind of magnetite Fe3O4 nanoparticles could induce severe ER stress and activate cancer apoptosis under mild microwave irradiation. Apparent apoptosis had been observed in the A375 cells under a scanning electron microscope and transmission electron microscope. Moreover, melanoma had also been inhibited effectively in vivo. As a result, the endoplasmic reticulum stress is a promising target with clinical potential in nanomedicine and cancer therapy.


Assuntos
Nanopartículas de Magnetita , Neoplasias , Animais , Apoptose , Linhagem Celular Tumoral , Estresse do Retículo Endoplasmático , Óxido Ferroso-Férrico , Sistema de Sinalização das MAP Quinases , Camundongos , Micro-Ondas , Neoplasias/tratamento farmacológico , Proteínas Serina-Treonina Quinases
16.
Chemosphere ; 282: 131120, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34470165

RESUMO

This study evaluated the adverse effects of low-dose imidacloprid (IMI) on the characteristics of sperm from male Wistar rats. Thirty mature male rats were equally divided into three groups and orally administered vehicle (Control Group), acceptable daily intake (ADI) concentration of IMI (Group 1), and IMI at a dose 10-fold that of the ADI (Group 2) for 90 days. The findings revealed that IMI caused abnormalities in sperm concentrations and morphologies, accompanied by an imbalance of the gonadal hormone testosterone. Histopathological damage and decrease of testosterone levels were observed in testes from rats treated with IMI. However, estradiol and gonadotropin levels were unchanged after IMI treatment. IMI inhibited the activity of cytochrome P450 3A4 (CYP3A4) and left itself existed in the organism of rats. The indicators relating to sperms and CYP3A4 activity were recovered when rats were co-treated with IMI and CYP3A4 inducer rifampicin together. These results indicated that low-dose IMI exposure caused sperm abnormalities through affecting on the spermiogenesis in testis. Inhibition of CYP3A4 activity by IMI largely contributed to its sperm toxicity. Thus, IMI exposure at doses close to real-world settings resulted in sperm toxicity on rats, which might be a potential risk factor for human reproductive diseases.


Assuntos
Citocromo P-450 CYP3A , Espermatogênese , Animais , Masculino , Neonicotinoides/toxicidade , Nitrocompostos , Ratos , Ratos Wistar , Espermatozoides , Testículo , Testosterona
17.
Front Endocrinol (Lausanne) ; 12: 705773, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34539567

RESUMO

Background: The molecular etiology and the genotype-phenotype correlation of congenital hypothyroidism (CH) remain unclear. Methods: We performed genetic analysis in 42 newborns with CH using whole-exome sequencing. Patients were divided into a single-gene group and a multi-gene group according to the number of affected genes, or divided into a monoallelic group, a biallelic group, and an oligogenic group according to the pattern of the detected variants. The clinical characteristics were compared between groups. Results: Thyroid dysgenesis (TD) was observed in 10 patients and goiter in 5 patients, whereas 27 patients had normal-sized gland-in-situ (GIS). We identified 58 variants in five genes in 29 patients. The genes with the most frequent variants were DUOX2 (70.7%), followed by TSHR (12.1%), DUOXA2 (10.3%), and TPO (5.2%). Variants in the genes causing dyshormonogenesis (DH) were more common than those in the genes causing TD (87.9% versus 12.1%). Among the patients with detected variants, 26 (89.7%) were harboring a single gene variant (single-gene group), which include 22 patients harboring biallelic variants (biallelic group) and four patients harboring monoallelic variants (monoallelic group). Three (10.3%) patients harbored variants in two or three genes (multi-gene group or oligogenic group). Compared with the single-gene group, the levothyroxine (L-T4) dose at 1 year of age was higher in the multi-gene group (p = 0.018). A controllable reduction in the L-T4 dose was observed in 25% of patients in the monoallelic group and 59.1% of patients in the biallelic group; however, no patients with such reduction in the L-T4 dose were observed in the oligogenic group. Conclusions: Patients with normal-sized GIS accounted for the majority of our cohort. Genetic defects in the genes causing DH were more common than those in the genes causing TD, with biallelic variants in DUOX2 being dominant. DH might be the leading pathophysiology of CH in Chinese individuals.

18.
Accid Anal Prev ; 162: 106395, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34563647

RESUMO

Currently, the road safety performance of a national- or province-level is absorbing much attention from practitioners and academics. A variety of models based on Data Envelopment Analysis (DEA) have been presented to appraise road safety performance in previous literature. However, the main weakness of these methods is that the decision-maker's psychological behavior is neglected. Besides, Cross Efficiency Method (CEM) adopts the weighted average to aggregate the cross efficiencies which may lead to information loss. To address these limitations, a hybrid road safety evaluation model was constructed by integrating CEM, regret theory, and Weighted Aggregated Sum Product Assessment (WASPAS) to appraise the road safety performance of Chinese provinces. In the presented model, regret theory is employed to depict the psychological behavior of the decision-maker. Then entropy weight method is utilized to calculate the weight of self-evaluation and peer-evaluation. To reduce information loss, WASPAS is adopted to fuse the cross efficiencies and derive the ranking of decision-making units. Finally, the presented model is employed to assess the road safety efficiency in the province of mainland China. The results show that the mean of road safety efficiency score for the eastern, central, and western areas is gradually decreasing. Furthermore, the outcomes of a comparative analysis represent that the results obtained by the proposed model outperform the CEM and DEA road safety model.


Assuntos
Acidentes de Trânsito , Emoções , Acidentes de Trânsito/prevenção & controle , China , Humanos
19.
J Am Heart Assoc ; 10(18): e022170, 2021 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-34482712

RESUMO

Background Prenatal and postnatal insults can induce a physiological state that leaves offspring later in life vulnerable to subsequent challenges (stressors) eliciting cardiometabolic diseases including hypertension. In this study, we investigated whether maternal angiotensin II-induced hypertension in rats sensitizes postweaning high-fat diet (HFD)-elicited hypertensive response and whether this is associated with autonomic dysfunction and altered central mechanisms controlling sympathetic tone in offspring. Methods and Results When eating a low-lard-fat diet, basal mean arterial pressure of male offspring of normotensive or hypertensive dams were comparable. However, HFD feeding significantly increased mean arterial pressure in offspring of normotensive and hypertensive dams, but the elevated mean arterial pressure induced by HFD was greater in offspring of hypertensive dams, which was accompanied by greater sympathetic tone and enhanced pressor responses to centrally administrated angiotensin II or leptin. HFD feeding also produced comparable elevations in cardiac sympathetic activity and plasma levels of angiotensin II, interleukin-6, and leptin in offspring of normotensive and hypertensive dams. Reverse transcriptase polymerase chain reaction analyses in key forebrain regions implicated in the control of sympathetic tone and blood pressure indicated that HFD feeding led to greater increases in mRNA expression of leptin, several components of the renin-angiotensin system and proinflammatory cytokines in offspring of hypertensive dams when compared with offspring of normotensive dams. Conclusions The results indicate that maternal hypertension sensitized male adult offspring to HFD-induced hypertension. Increased expression of renin-angiotensin system components and proinflammatory cytokines, elevated brain reactivity to pressor stimuli, and augmented sympathetic drive to the cardiovascular system likely contributed.

20.
BMC Infect Dis ; 21(1): 1015, 2021 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-34583653

RESUMO

BACKGROUND: The morbidity of rifampicin/multidrug-resistant tuberculous meningitis (RR/MDR-TBM) has shown an increasing trend globally. Its mortality rate is significantly higher than that of non-rifampicin/multidrug-resistant tuberculous meningitis (NRR/MDR-TBM). This article aimed to explore risk factors related to RR/MDR-TBM, and compare therapeutic effects of linezolid (LZD)- and non-linezolid-containing regimen for RR/MDR-TB patients in Shenzhen city. Furthermore, we aimed to find a better therapy for pathogen-negative TBM with RR/MDR-TBM related risk factors. METHODS: We conducted a retrospective study enrolling 137 hospitalized cases with confirmed TBM from June 2014 to March 2020. All patients were divided into RR/MDR-TBM group (12 cases) and NRR/MDR-TBM group (125 cases) based on GeneXpert MTB/RIF and (or) phenotypic drug susceptibility test results using cerebral spinal fluid (CSF). The risk factors related to RR/MDR-TBM were investigated through comparing clinical and examination features between the two groups. The mortality rate of RR/MDR-TBM patients treated with different regimens was analyzed to compare their respective therapeutic effects. A difference of P < 0.05 was considered statistically significant. RESULTS: Most patients (111/137, 81%) were from southern or southwestern China, and a large proportion (72/137, 52.55%) belonged to migrant workers. 12 cases were RR/MDR-TBM (12/137, 8.8%) while 125 cases were NRR/MDR-TBM (125/137, 91.2%). The proportion of patients having prior TB treatment history in the RR/MDR-TBM group was significantly higher than that of the NRR/MDR-TBM group (6/12 vs. 12/125, 50% vs. 10.5%, P < 0.01). No significant difference was observed on other clinical and examination features between the two groups. Mortality was significantly lower in RR/MDR-TBM patients on linezolid-containing treatment regimen than those who were not (0/7 versus 3/5, 0% versus 60%, P = 0.045). CONCLUSIONS: The main related risk factor of RR/MDR-TBM is the history of anti-tuberculosis treatment. Linezolid-containing regimen appears to lower mortality rate of RR/MDR-TBM significantly in our study. We think Linezolid should be evaluated prospectively in the treatment of RR/MDR-TBM.


Assuntos
Mycobacterium tuberculosis , Tuberculose Meníngea , Tuberculose Resistente a Múltiplos Medicamentos , Antituberculosos/uso terapêutico , China/epidemiologia , Humanos , Linezolida/uso terapêutico , Estudos Retrospectivos , Rifampina/uso terapêutico , Tuberculose Meníngea/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico
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