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1.
Front Bioeng Biotechnol ; 10: 881544, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35497337

RESUMO

Breast cancer is one of the most common types of cancer. Patients are often concerned about regional recurrence after breast cancer surgery. Radiotherapy plays a vital role in reducing recurrence and prolonging the survival of patients undergoing breast-conserving surgery and high-risk mastectomy. However, 8-15% of patients still have disease progression due to radiation resistance. Therefore, new strategies for combination radiotherapy sensitization must be investigated. In this study, an implantable drug loading system, sunitinib nanoparticles @ matrix metalloproteinases -response hydrogel (NSMRH), uses enzyme-sensitive hydrogel as a carrier to load sunitinib nanoparticles, was identified. The releasing profile demonstrated that sunitinib nanoparticles may be continuously released from the hydrogels. Functional experiments revealed that, when paired with NSMRH, radiation may significantly inhibit tumor cell proliferation, migration, and invasion in vitro. Further animal experiments showed that NSMRH combined with radiotherapy could more effectively control the recurrence of subcutaneous xenograft tumors, prolong the survival time, and have no obvious toxicity in nude mice. Finally, by studying the molecular mechanism of NSMRH, it was hypothesized that in breast cancer cells, NSMRH cooperated with sensitized radiotherapy, mainly due to significantly blocking the G2/M phase, reducing the DNA repair efficiency, inhibiting tumor angiogenesis, promoting apoptosis, and reversing the abnormal expression of platelet-derived growth factor receptor alpha (PDGFRA) after radiotherapy. These findings suggest that NSMRH's radiation sensitization and anti-tumor activity may aid in the development of a novel method in future clinical applications.

2.
Ther Clin Risk Manag ; 18: 457-465, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35493708

RESUMO

Purpose: Few evidence-based predictive tools are available to evaluate major adverse cardio- and cerebro-vascular events (MACCEs) before major noncardiac surgery. We sought to develop a new simple but effective tool for estimating surgical risk. Patients and Methods: Using a nested case-control study design, we recruited 105 patients who experienced MACCEs and 481 patients without MACCEs during hospitalization from 10,507 patients undergoing major noncardiac surgery in Beijing Chaoyang hospital. Least absolute shrinkage and selection operator (LASSO) regression and likelihood ratio were applied to screen 401 potential features for logistic regression. A nomogram was constructed using the selected variables. Results: Chronic heart failure, valvular heart disease, preoperative serum creatinine >2.0 mg/dL, ASA class, neutrophil count and age were most associated with in-hospital MACCEs among all the factors. A new prediction model established based on these showed a good discriminatory ability (AUC, 0.758 [95% confidence interval (CI), 0.708-0.808] and a well-performed calibration curve (Hosmer-Lemeshow χ2 = 7.549, p = 0.479), which upheld in the 10-fold cross-validation (AUC, 0.742 [95% CI, 0.718-0.767]. This model also demonstrated an improved performance in comparison to the modified Revised Cardiac Risk Index (RCRI) score (increase in AUC by 0.119 [95% CI, 0.056-0.180]; NRI, 0.445 [95% CI, 0.237-0.653]; IDI, 0.133 [95% CI, 0.087-0.178]. The decision curve analysis showed a positive net benefit of our new model. Conclusion: Our nomogram, which relies upon simple clinical characteristics and laboratory tests, is able to predict MACCEs in patients undergoing major noncardiac surgery. This prediction shows better discrimination than the standardized modified RCRI score, laying a promising foundation for further large-scale validation.

3.
Comput Math Methods Med ; 2022: 1411943, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35516453

RESUMO

To explore the application of intelligent algorithm-based ultrasound in the evaluation of polycystic ovary syndrome (PCOS) and the endocrine and metabolic changes of PCOS, 44 patients diagnosed with PCOS were recruited and rolled into three groups regarding detection methods. Backpropagation algorithm-based ultrasonic detection was adopted for the patients in the experimental group. The patients in the control group were tested by conventional ultrasound. In addition, 18 healthy volunteers were selected as the normal group. The results showed that the images processed by the backpropagation algorithm were substantially better than the traditional ultrasound images (P < 0.05), and the image display was clearer. S, A, and S/A ratios measured by two different detection methods were 7.8 mm2, 3.5 mm2, and 0.449 in the experimental group, respectively, which were significantly different from 6.3 mm2, 2.6 mm2, and 0.413 in the control group (P < 0.05). The PI and RI values of the interstitial ovarian artery in the experimental group were lower than those in the control group, and the systolic peak velocity (PSV) and end diastolic velocity (EDV) values were higher than those in the control group (P < 0.05). Compared with the control group, the ovarian volume, interstitial vascularization-flow index (VFI), and flow index (FI) in the experimental group were substantially increased, and the total number of detected follicles was more (P < 0.05). The level of follicle-stimulating hormone (FSH) in PCOS patients was substantially lower than that in normal controls (P < 0.05). The LH, E2, P, and T of PCOS patients were substantially higher than those of normal controls (P < 0.05). Ultrasound on account of the backpropagation algorithm can directly display the three-dimensional structure of the ovary and follicle and accurately measure the ovarian volume and follicle number. Endocrine and metabolic indicators can provide objective information for the clinical diagnosis of PCOS and can be used as a way of clinical evaluation of PCOS.


Assuntos
Síndrome do Ovário Policístico , Algoritmos , Feminino , Hormônio Foliculoestimulante , Humanos , Síndrome do Ovário Policístico/diagnóstico por imagem , Ultrassonografia/métodos
4.
J Exp Clin Cancer Res ; 41(1): 172, 2022 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-35546239

RESUMO

BACKGROUND: Lung cancer is the leading cause of cancer death, partially owing to its extensive heterogeneity. The analysis of intertumor heterogeneity has been limited by an inability to concurrently obtain tissue from synchronous metastases unaltered by multiple prior lines of therapy. METHODS: In order to study the relationship between genomic, epigenomic and T cell repertoire heterogeneity in a rare autopsy case from a 32-year-old female never-smoker with left lung primary late-stage lung adenocarcinoma (LUAD), we did whole-exome sequencing (WES), DNA methylation and T cell receptor (TCR) sequencing to characterize the immunogenomic landscape of one primary and 19 synchronous metastatic tumors. RESULTS: We observed heterogeneous mutation, methylation, and T cell patterns across distinct metastases. Only TP53 mutation was detected in all tumors suggesting an early event while other cancer gene mutations were later events which may have followed subclonal diversification. A set of prevalent T cell clonotypes were completely excluded from left-side thoracic tumors indicating distinct T cell repertoire profiles between left-side and non left-side thoracic tumors. Though a limited number of predicted neoantigens were shared, these were associated with homology of the T cell repertoire across metastases. Lastly, ratio of methylated neoantigen coding mutations was negatively associated with T-cell density, richness and clonality, suggesting neoantigen methylation may partially drive immunosuppression. CONCLUSIONS: Our study demonstrates heterogeneous genomic and T cell profiles across synchronous metastases and how restriction of unique T cell clonotypes within an individual may differentially shape the genomic and epigenomic landscapes of synchronous lung metastases.

5.
Natl Sci Rev ; 9(5): nwab210, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35547957

RESUMO

Tracing the closure of oceans with irregular margins and the formation of an orocline are crucial for understanding plate reconstruction and continental assembly. The eastern Central Asian Orogenic Belt, where the Mongol-Okhotsk orocline is situated, is one of the world's largest magmatic provinces. Using a large data set of U-Pb zircon ages, we updated the timing of many published igneous rocks, which allowed us to recognize tightly 'folded' linear Carboniferous-Jurassic magmatic belts that wrap around the Mongol-Okhotsk suture and their migrations both sutureward and suture-parallel. The new successive magmatic belts reveal a rollback, scissor-like (or zipper-like) closure of the Mongol-Okhotsk Ocean that was fundamentally controlled by coeval subduction rollback and rotation of the Siberian and Mongolian-Erguna blocks. This study also demonstrates the complex mechanisms and processes of the closure of an ocean with irregular margins and the formation of a consequent orocline.

6.
Artigo em Inglês | MEDLINE | ID: mdl-35571728

RESUMO

Aloe barbadensis Miller (Aloe) known as a common succulent perennial herb had been traditionally used in constipation for more than 1,000 years. Aloe contained anthraquinones and other active compounds which had laxative effect and could modulate constipation. However, the therapeutic effects and mechanisms of aloe in constipation were still unclear. To explore the therapeutic effects and mechanisms of aloe in treating constipation, we employed network pharmacology, molecular docking, and mice experiments in this study. Our network pharmacology indicated that beta-carotene, sitosterol, campest-5-en-3beta-ol, CLR, arachidonic acid, aloe-emodin, quercetin, and barbaloin were the main active ingredients of aloe in treating constipation. Besides, the MAPK signaling pathway was the principal pathway utilized by aloe in treating constipation. Molecular docking results revealed that beta-carotene and sitosterol were acting as interference factors in attenuating inflammation by binding to an accessory protein of ERK, JNK, AKT, and NF-κB p65. Otherwise, in vivo experiments, we used diphenoxylate-induced constipation mice model to explore the therapeutic effects and mechanisms of aloe. Results showed that aloe modulated the constipation mice by reducing the discharge time of first melena, improving the fecal conditions, increasing the gastric intestinal charcoal transit ratio, and improving the intestinal secretion in small intestine. Besides, aloe played an important regulation in promoting intestinal motility sufficiency and the levels of neurotransmitters balance with 5-HT, SP, and VIP on constipation mice. Moreover, aloe significantly inhibited the mRNA and proteins expressions of ERK, JNK, AKT and NF-κB p65 in colon. Our study proved that aloe could reverse diphenoxylate-induced changes relating to the intestinal motility, intestinal moisture, and inhibition of the MAPK (ERK, JNK)/AKT/NF-κB p65 inflammatory pathway. Our study provided experimental evidences of the laxative effect of aloe, which was beneficial to the further research and development of aloe.

7.
Front Pediatr ; 10: 833434, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35573962

RESUMO

Aim: We sought to identify the clinical characteristics and risk factors for cardiac mortality in pediatric patients with primary dilated cardiomyopathy (DCM) in China. Methods: A total of 138 pediatric patients who were consecutively diagnosed with primary DCM from January 2011 to December 2020 were included. We assessed patients' clinical symptoms and performed laboratory examinations, electrocardiography, and echocardiography. Results: Of these patients, 79 (57%) had severe systolic dysfunction (left ventricular ejection fraction of < 30%), 79 (57.2%) developed DCM before 12 months of age, 62 (45%) were male, 121 (87.7%) presented with advanced heart failure (cardiac functional class III/IV), and 54 (39.1%) presented with arrhythmia. At a median follow-up of 12 months, the overall cardiac mortality rate was 33%, and 40 of 46 deaths occurred within 6 months following DCM diagnosis. A multivariate Cox regression analysis identified several independent cardiac death predictors, including an age of 12 months to 5 years [hazard ratio (HR) 2.799; 95% confidence interval (CI) 1.160-6.758; P = 0.022] or 10-15 years (HR 3.617; 95% CI 1.336-9.788; P = 0.011) at diagnosis, an elevated serum alanine aminotransferase (ALT) concentration (≥ 51.5 U/L) (HR 2.219; 95% CI 1.06-4.574; P = 0.031), and use of mechanical ventilation (HR 4.223; 95% CI 1.763-10.114; P = 0.001). Conclusion: The mortality rate of primary DCM without transplantation is high. Age, an elevated serum ALT concentration, and the need for mechanical ventilation predict mortality in patients with primary DCM, providing new insights into DCM risk stratification.

8.
Clin Appl Thromb Hemost ; 28: 10760296221100806, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35538853

RESUMO

PURPOSE: To analyze the relationship between monocyte count and preoperative deep venous thrombosis (DVT) in older patients with hip fracture. METHODS: Consecutive older patients with hip fracture undergoing surgery were included from January 2014 to December 2021. Monocyte count was measured on admission, and Doppler ultrasonography was performed for DVT screening prior to surgery. Univariate and multivariate logistic regression analyses were used to assess the association between monocyte count and DVT. RESULTS: A total of 674 patients were finally included, and 128 patients (19.0%) were diagnosed with preoperative DVT. Patients with DVT exhibited a higher monocyte count than patients without DVT [0.55 (0.43-0.72) × 109/L versus 0.49 (0.38-0.63) × 109/L, P = 0.007]. Multivariate logistic regression analysis showed that a high monocyte count (> 0.6 × 109/L) was independently associated with a higher risk of DVT (OR = 1.705, 95% CI: 1.121-2.593, P = 0.013), and for every 0.1 × 109/L increase in monocyte count, the risk of DVT increased by 8.5% (OR = 1.085, 95% CI: 1.003-1.174, P = 0.041). Other risk factors associated with DVT included intertrochanteric fracture (OR = 1.596, 95% CI: 1.022-2.492, P = 0.040), and elevated fibrinogen level (OR = 1.236, 95% CI: 1.029-1.484, P = 0.023). CONCLUSION: A high monocyte count is associated with an increased risk of DVT in older patients with hip fracture. Future studies should evaluate the potential role of monocyte in the prevention and treatment of thrombosis.

9.
Food Funct ; 2022 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-35543179

RESUMO

Nonylphenol (NP) exposure has become a crucial inducement of male reproductive disorders in the world. Therefore, it is urgent to seek solutions to alleviate the toxicity of NP. This study was oriented toward studying the protective effects of Macrolepiota procera mycelium polysaccharides (MMP) on NP-induced reproductive impairments. After NP administration, declined sperm amounts and testis index, increased the deformity rate of sperms, aberrant hormone secretion and testicular pathological injury were observed, corporately leading to reproductive capacity attenuation. Importantly, MMP significantly reversed the foregoing changes in NP-treated mice. Notably, it has been observed that the MMP therapy remarkably improved oxidative stress, apoptosis, autophagy and inflammatory responses, and suppressed the Akt/mTOR signaling pathway in testicular tissues. These results manifested that MMP might be a promising treatment strategy for ameliorating the biotoxicity of NP.

10.
J Extracell Vesicles ; 11(5): e12218, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35524455

RESUMO

Research on tumour cell-derived small extracellular vesicles (sEVs) that regulate tumour microenvironment (TME) has provided strategies for targeted therapy of head and neck squamous cell carcinoma (HNSCC). Herein, we demonstrated that sEVs derived from HNSCC cancer cells carried CD73 (sEVsCD73 ), which promoted malignant progression and mediated immune evasion. The sEVsCD73 phagocytosed by tumour-associated macrophages (TAMs) in the TME induced immunosuppression. Higher CD73high TAMs infiltration levels in the HNSCC microenvironment were correlated with poorer prognosis, while sEVsCD73 activated the NF-κB pathway in TAMs, thereby inhibiting immune function by increasing cytokines secretion such as IL-6, IL-10, TNF-α, and TGF-ß1. The absence of sEVsCD73 enhanced the sensitivity of anti-PD-1 therapy through reversed immunosuppression. Moreover, circulating sEVsCD73 increased the risk of lymph node metastasis and worse prognosis. Taken together, our study suggests that sEVsCD73 derived from tumour cells contributes to immunosuppression and is a potential predictor of anti-PD-1 responses for immune checkpoint therapy in HNSCC.


Assuntos
5'-Nucleotidase/imunologia , Vesículas Extracelulares , Neoplasias de Cabeça e Pescoço , Vesículas Extracelulares/metabolismo , Neoplasias de Cabeça e Pescoço/metabolismo , Humanos , Macrófagos/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Microambiente Tumoral
11.
Mol Cancer ; 21(1): 97, 2022 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-35395767

RESUMO

BACKGROUND: N6-methyladenosine (m6A) RNA modification plays a critical role in various physiological and pathological conditions. However, the role of m6A modification in head and neck squamous cell carcinoma (HNSCC) remains elusive. METHODS: In this study, the expression of m6A demethylases was detected by HNSCC tissue microarray. m6A-RNA immunoprecipitation (MeRIP) sequencing and RNA sequencing were used to identify downstream targets of ALKBH5. Comprehensive identification of RNA-binding proteins by mass spectrometry (ChIRP-MS) was used to explore the m6A "readers". Tumor-infiltrating lymphocytes were analyzed in SCC7-bearing xenografts in C3H mice. RESULTS: Here, we demonstrate the downregulation of m6A status and upregulation of two demethylases in HNSCC. Silencing the m6A demethylase alkB homolog 5, RNA demethylase (ALKBH5) suppresses tumor progression in vitro and in vivo. m6A-RNA immunoprecipitation sequencing reveals that ALKBH5 downregulates the m6A modification of DDX58 mRNA. Moreover, RIG-I, encoded by the DDX58 mRNA, reverses the protumorigenic characteristics of ALKBH5. ChIRP-MS demonstrates that HNRNPC binds to the m6A sites of DDX58 mRNA to promote its maturation. ALKBH5 overexpression inhibits RIG-I-mediated IFNα secretion through the IKKε/TBK1/IRF3 pathway. The number of tumor-infiltrating lymphocytes in C3H immunocompetent mice is reduced by ALKBH5 overexpression and restored by IFNα administration. Upregulation of AKLBH5 negatively correlates with RIG-I and IFNα expression in HNSCC patients. CONCLUSIONS: These findings unveil a novel mechanism of immune microenvironment regulation mediated by m6A modification through the ALKBH5/RIG-I/IFNα axis, providing a rationale for therapeutically targeting epitranscriptomic modulators in HNSCC.


Assuntos
Homólogo AlkB 5 da RNA Desmetilase , Neoplasias de Cabeça e Pescoço , Quinase I-kappa B , Carcinoma de Células Escamosas de Cabeça e Pescoço , Homólogo AlkB 5 da RNA Desmetilase/genética , Homólogo AlkB 5 da RNA Desmetilase/metabolismo , Animais , Proteína DEAD-box 58 , Neoplasias de Cabeça e Pescoço/genética , Humanos , Quinase I-kappa B/metabolismo , Fator Regulador 3 de Interferon/metabolismo , Interferon-alfa , Camundongos , Camundongos Endogâmicos C3H , RNA Mensageiro/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Microambiente Tumoral
12.
ACS Appl Mater Interfaces ; 14(15): 17444-17453, 2022 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-35411771

RESUMO

High-voltage sodium metal batteries are a highly intriguing battery technology in view of their resource sustainability, cost efficiency, and ultrahigh energy density. However, developing a high-performance electrolyte, compatible with both high-voltage cathodes and highly reactive sodium metal anodes, is extremely challenging. In this work, we delicately formulate a ternary phosphate electrolyte, composing of a cost-effective sodium bis(trifluoromethane sulfonyl) imide salt, a nonflammable triethyl phosphate (TEP) solvent, and a fluoroethylene carbonate (FEC) co-solvent. By rationally tailoring the TEP/FEC ratio, the ternary phosphate electrolyte displays a well-balanced performance, not only enabling highly efficient sodium deposition (an average Coulombic efficiency of 95.7% for Na//Cu cells) but also inheriting the intrinsic anodic stability (≥4.5 V vs Na+/Na) and nonflammability of phosphates. As a consequence, high-voltage Na3V2(PO4)2F3 cathode-based sodium metal cells (Na3V2(PO4)2F3//Na) deliver remarkable cyclic stability (97.9% capacity retention after 300 cycles), which is among the best for Na3V2(PO4)2F3-based batteries. This work may guide the electrolyte design principles and is highly enlightening in developing high energy density sodium-based batteries.

13.
Nat Commun ; 13(1): 1797, 2022 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-35379845

RESUMO

Methylthioadenosine phosphorylase, an essential enzyme for the adenine salvage pathway, is often deficient (MTAPdef) in tumors with 9p21 loss and hypothetically renders tumors susceptible to synthetic lethality by antifolates targeting de novo purine synthesis. Here we report our single arm phase II trial (NCT02693717) that assesses pemetrexed in MTAPdef urothelial carcinoma (UC) with the primary endpoint of overall response rate (ORR). Three of 7 enrolled MTAPdef patients show response to pemetrexed (ORR 43%). Furthermore, a historic cohort shows 4 of 4 MTAPdef patients respond to pemetrexed as compared to 1 of 10 MTAP-proficient patients. In vitro and in vivo preclinical data using UC cell lines demonstrate increased sensitivity to pemetrexed by inducing DNA damage, and distorting nucleotide pools. In addition, MTAP-knockdown increases sensitivity to pemetrexed. Furthermore, in a lung adenocarcinoma retrospective cohort (N = 72) from the published BATTLE2 clinical trial (NCT01248247), MTAPdef associates with an improved response rate to pemetrexed. Our data demonstrate a synthetic lethal interaction between MTAPdef and de novo purine inhibition, which represents a promising therapeutic strategy for larger prospective trials.


Assuntos
Carcinoma de Células de Transição , Antagonistas do Ácido Fólico , Neoplasias da Bexiga Urinária , Antagonistas do Ácido Fólico/farmacologia , Antagonistas do Ácido Fólico/uso terapêutico , Humanos , Estudos Prospectivos , Estudos Retrospectivos
14.
Gerontology ; : 1-15, 2022 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-35468611

RESUMO

INTRODUCTION: Senescent cells play a key role in the initiation and development of various age-related diseases. Human umbilical vein endothelial cells (HUVECs) senescence is closely associated with age-related cardiovascular diseases. Accumulating evidence has demonstrated that senolytics, the combination of dasatinib and quercetin (D+Q), could selectively eliminate senescent cells. N6-methyladenosine (m6A), the most abundant internal transcript modification, greatly influences RNA metabolism and modulates gene expression. We aimed to investigate whether RNA m6A functions in lipopolysaccharide (LPS)-induced HUVECs senescence and D+Q suppress HUVECs senescence by regulating RNA m6A. METHODS: Senescence-associated ß-galactosidase activity, western blot, and real-time quantitative polymerase chain reaction were performed to demonstrate that D+Q suppress HUVECs senescence. Methylated RNA immunoprecipitation (MeRIP)-qPCR assay and RIP-qPCR confirmed that RNA m6A plays a key role in the suppression of HUVECs senescence by D+Q. Chromatin immunoprecipitation and mRNA stability assay were carried out to prove that D+Q alleviate HUVECs senescence in a YTHDF2-dependent manner. RESULTS: Here, we demonstrate that D+Q alleviate LPS-induced senescence in HUVECs via inhibiting autocrine and paracrine of the senescence-associated secretory phenotype (SASP). We further confirm that D+Q alleviate HUVECs senescence via the TNF receptor-associated factor 6 (TRAF6)-MAPK pathway. Mechanically, this study validates that D+Q suppress SASP by upregulating m6A reader YTHDF2. Besides, YTHDF2 regulates the stability of MAP2K4 and MAP4K4 mRNAs. CONCLUSION: Collectively, we first identified that D+Q alleviate LPS-induced senescence in HUVECs via the TRAF6-MAPK-NF-κB axis in a YTHDF2-dependent manner, providing novel ideas for clinical treatment of age-related cardiovascular diseases.

15.
Dev Psychobiol ; 64(4): e22273, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35452550

RESUMO

Studies of humans, mammalian animals, and chicks reveal that embryonic opioid exposure (EOE) changes the response to pharmacological rewards in postnatal individuals, which may be an outcome of permanent alterations to neural systems. However, the mechanism behind this alteration remains unclear. GABA transmitter has a trophic effect on early GABAergic neuronal development, and EOE decreases GABA concentration in developing brains. Here, we determined whether the development of inhibitory transmission was affected by EOE and whether altered GABA release was the underlying mechanism. We revealed that morphine administration in the early but not the late embryonic period decreased inhibitory transmission in the striatum of chicks. Meanwhile, day-old chicks with early embryonic morphine exposure showed increased psychomotor activity after acute morphine injection compared with saline-exposed chicks. Furthermore, GABA injection in the chick embryo following morphine administration mitigated damage to GABA transmission and recovered the behavioral response to acute morphine injection in chicks. Collectively, our findings suggest that abnormal GABA release in the early embryonic period induced by opioid exposure is attributable to functional and structural developments of the GABA synapse, and that the dysfunction of striatal GABA transmission may be linked to enhanced psychomotor response during initial drug exposure in postnatal life.


Assuntos
Analgésicos Opioides , Morfina , Analgésicos Opioides/farmacologia , Animais , Embrião de Galinha , Galinhas , Corpo Estriado , Mamíferos , Morfina/farmacologia , Ácido gama-Aminobutírico
16.
BMC Cancer ; 22(1): 474, 2022 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-35488236

RESUMO

BACKGROUND: The Lauren classification of gastric tumors strongly correlates with prognosis. The purpose of this study was to explore the specific molecular mechanism of Lauren classification of gastric cancer and provide a possible theoretical basis for the treatment of gastric cancer. METHODS: We standardized the gene expression data of five Gene Expression Omnibus gastric cancer databases and constructed a Weighted Co-expression Network Analysis (WGCNA) model based on clinicopathological information. The overall survival (OS) and disease-free survival (DFS) curves were extracted from the Cancer Genome Atlas (TCGA) and GSE62254 databases. Western blotting was used to measure protein expression in cells and tissues. Scratch and transwell experiments were used to test the migration ability of tumor cells. Immunohistochemistry was used to measure tissue protein expression in clinical tissue samples to correlate to survival data. RESULTS: The WGCNA model demonstrated that blue cyan was highly correlated with the Lauren classification of the tumor (r = 0.24, P = 7 × 1016). A protein-protein interaction network was used to visualize the genes in the blue cyan module. The OS and PFS TCGA analysis revealed that LMOD1 was a gene of interest. The proportion of diffuse gastric cancer patients with high expression of LMOD1 was significantly higher than that of intestinal type patients. LMOD1 promoted the migration of gastric cancer cells by regulating the FAK-Akt/mTOR pathway in vitro. Additionally, a Gene Set Enrichment Analysis using the TCGA and GSE62254 databases, and western blot data, showed that LMOD1 could promote an epithelial-mesenchymal transition (EMT), thus potentially affecting the occurrence of peritoneal metastasis of gastric cancer. Immunohistochemistry showed that LMOD1 was highly expressed in cancer tissues, and the prognosis of patients with high LMOD1 expression was poor. CONCLUSION: LMOD1 is an oncogene associated with diffuse gastric cancer and can affect the occurrence and development of EMT by regulating the FAK-Akt/mTOR pathway. LMOD1 can therefore promote peritoneal metastasis of gastric cancer cells and can be used as a novel therapeutic target for gastric cancer.


Assuntos
Neoplasias Peritoneais , Neoplasias Gástricas , Autoantígenos , Linhagem Celular Tumoral , Movimento Celular/genética , Proteínas do Citoesqueleto/genética , Humanos , Oncogenes , Neoplasias Peritoneais/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias Gástricas/patologia , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo
17.
Behav Brain Res ; 428: 113885, 2022 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-35398229

RESUMO

YZG-331 is a synthetic novel derivates of N6-(4-hydroxybenzyl) adenine riboside (NHBA), which has potent sedative and hypnotic effects based on our previous study. We are now aiming to investigate the mechanism of YZG-331. In this research, the behavioral studies showed that YZG-331 (4, 8, 16 mg/kg, i.g.) could reduce the spontaneous locomotor activity in mice, which could be blocked by AM (non-selective adenosine receptor antagonist), DPCPX (adenosine A1 receptor (A1R) antagonist), and SCH58261 (adenosine A2a receptor (A2aR) antagonist). Moreover, YZG-331 no longer exerted sedative effect in A1R or A2aR knockdown mice. YZG-331 (2.5, 5, 10 mg/kg, i.g.) prolonged sleeping time in pentobarbital sodium treated mice, which can be prevented by DPCPX or SCH58261. The above results demonstrated that YZG-331 exerted sedative and hypnotic effects through A1R and A2aR. In addition, it was found that YZG-331 (25, 50, 100 µM) decreased intracellular calcium level and YZG-331 (10 mg/kg, i.g.) decreased CaMKII phosphorylation (pCaMKII) level in mouse hypothalamus and cortex. In summary, this study indicated that activation of A1R/ A2aR and down regulation of Ca2+-CaMKII signaling pathway were involved in the sedative and hypnotic effects of YZG-331.


Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina , Hipnóticos e Sedativos , Adenosina/análogos & derivados , Adenosina/farmacologia , Animais , Hipnóticos e Sedativos/farmacologia , Camundongos , Pentobarbital/farmacologia , Receptor A1 de Adenosina/metabolismo , Receptor A2A de Adenosina/metabolismo
18.
Talanta ; 245: 123418, 2022 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-35472683

RESUMO

Neurotransmitters (NTs) and their metabolites play crucial roles in the regulation of the sleep-wake cycle. Thus, a comprehensive quantitative analysis of NTs would be useful in elucidating the potential mechanisms involved in sedative-hypnotic activities. In this study, we developed a high-throughput quantitative method based on a two-dimensional chromatography-mass spectrometry technique to simultaneously analyze 63 NTs and their metabolites in rat plasma, brain homogenate, and microdialysis samples from five different sleep-associated regions of the brain. Moreover, this method was used to study the neurochemical mechanism of an adenosine analog sedative-hypnotic candidate YZG-331. Most of the correlations between NTs were lost after the administration of the sedative, particularly in the caudate putamen (CPu) and dorsal raphe nucleus (DRN), indicating that the sleep-wake balance was affected. Administration of the adenosine analog YZG-331 could act similar as accumulation of adenosine, inducing adenosine and its metabolite adenine were decreased significantly in the CPu, accompanying with GABA, aspartate, and glutamate changed slightly by the communications between different neurons to further promote sleep. In addition, YZG-331 affected the metabolism of tryptophan and serotonin (5-HT) in the DRN and orbital frontal cortex (OFC). Melatonin and 5-hydroxyindole-3-acetic acid (a metabolite of 5-HT) were significantly increased in the OFC, and the levels of glutamate/glutamine, asparagine, and adrenaline were altered. Sleep homeostasis is a balance between the duration of sleep and wakefulness and is coordinated by all NTs. The high-throughput quantitative method introduced in this study may aid in revealing the temporal cohesion among NTs, evaluating sleep homeostasis, and determining the effects of sedative-hypnotic drugs.

19.
Sci Total Environ ; 831: 154881, 2022 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-35364156

RESUMO

Widespread presence of plastic mulch has led to macroplastic (MaP) pollution. While this issue is widely explored in aquatic ecosystems, MaP pollution on land has been neglected. In 2019, we conducted a large-scale survey of MaPs in Northwest China in 0-30 cm soil with long-term mulching. Samples of MaP debris were collected from 67 sites across Gansu, east Qinghai, and north Shannxi Provinces. All visible MaP pieces for each site were separated and weighed. The mass of each MaP piece was calibrated by size measured in digital images. The MaP mass averaged 47.2 kg ha-1, and the number of MaPs averaged 266.2 pieces ha-1. The mass and number of MaPs varied from site to site. The mean size of MaPs was 19.5 cm2 piece-1 or 28.0 mg piece-1. More importantly, the number of small MaP pieces (<5 and 5-20 cm2 piece-1) accounted for 76.7% of the total number of MaPs detected, and small-sized plastic debris (<10 and 10-25 mg piece-1) were detected in 70.1% of the sampling sites. The percentage of small fragments increased before 15-year of mulching and then declined. However, the amount of medium-large debris (20-50 and >50 cm2 piece-1) showed a trend opposite to that of small fragments. The percentage of MaPs was greater in the small size group than in the medium-large size group. The arid to semi-arid area exhibited higher MaP contamination compared with the semi-arid to the semi-humid area. These observations indicate that plastic debris residing in soil tend to be fragmented, making plastic film recovery more challenging and causing severe soil pollution. Further studies are required to regulate plastic mulch methods and explore the degradation process.

20.
J Agric Food Chem ; 70(16): 4889-4898, 2022 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-35416043

RESUMO

Chitinase is one of the most important glycoside hydrolyases, widely existing in bacteria, fungi, insects, and plants. It is involved in fungal cell wall remodeling and insect molting. Chitinase inhibitors are an effective means of controlling pathogens and pests. Natural product argifin is a 17-membered pentapeptide that exhibits efficient chitinase inhibitory activity. However, the complexity of the synthetic process results in a lot of restrictions for wide range of applications. In this work, we designed a series of azamacrolide chitinase inhibitors based on the structural features of argifin that have high inhibitory activities against bacterial and insectile chitinase. The most potent chitinase inhibitor compound 19c exhibited IC50 values of 56 nM and 110 nM against OfChi-h and SmChiB, respectively. The molecular docking and molecular dynamics simulations revealed that all inhibitors were bound to the -1 subsite of chitinases via N-methylcarbamoylguanidinyl as well as argifin. Finally, a bioactivity assay against pests was carried out. Compound 18a showed 80% mortality for Mythimna separata at a concentration of 50 mg/L. Besides, insecticides 19b and 19c exhibited high mortality against Plutella xylostella (76 and 73% mortalities at 50 mg/L, respectively).


Assuntos
Quitinases , Inseticidas , Mariposas , Animais , Quitinases/química , Inibidores Enzimáticos/química , Insetos/metabolismo , Inseticidas/farmacologia , Simulação de Acoplamento Molecular , Mariposas/metabolismo
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