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1.
Eur. j. psychiatry ; 37(1): 15-23, enero 2023.
Artigo em Inglês | IBECS | ID: ibc-213937

RESUMO

Background and objectives: Despite the growing pieces of evidence on the relationship between the altered expression level of miRNAs and major depressive disorder (MDD), few studies have focused on the relationship between the altered expression of miRNAs and the severity of depressive symptoms. This study aimed to investigate the relationship between the expression level of miRNA-4485 and the severity of depressive symptoms in major depressive disorder (MDD) patients.MethodsEighty MDD patients without antidepressants and 45 healthy controls were placed and tested for the expression level of miRNA-4485 using quantitative RT‒PCR. At the same time, the Hamilton Depression Scale (HAMD) was used to assess depression symptoms for MDD patients. Twenty-nine out of 80 MDD patients were selected for miRNA expression level testing and symptomatology assessments before and after three weeks of treatment.ResultsThe expression level of miRNA-4485 in the MDD group was significantly overexpressed compared to that in healthy controls (P < 0.05), and the expression level of miRNA-4485 in the higher HAMD group was also much higher than that in the lower HAMD group and healthy controls (P < 0.05). The expression level of miRNA-4485 in MDD patients was negatively correlated with HAMD total score, anxiety/somatization, and bodyweight factor score (P < 0.05), accounting for 9.4%, 12.4% and 5.7%, respectively. MiRNA-4485 significantly predicted MDD and the severity of depressive symptoms (P < 0.05). Compared with that before treatment, the expression level of miRNA-4485 was significantly downregulated after treatment, while the patient's depressive symptoms were improved (p < 0.05). The improvement in depressive symptoms was positively correlated with the downregulation of miRNA-4485, which could significantly predict the effects of antidepressant treatment on MDD (P < 0.05). (AU)


Assuntos
Humanos , Transtorno Depressivo Maior , MicroRNAs , Depressão , Ansiedade , Terapêutica
2.
Adv Sci (Weinh) ; : e2205907, 2023 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-36658721

RESUMO

Oxide-based photoelectrodes commonly generate deep trap states associated with various intrinsic defects such as vacancies, antisites, and dislocations, limiting their photoelectrochemical properties. Herein, it is reported that rhombohedral GaFeO3 (GFO) thin-film photoanodes exhibit defect-inactive features, which manifest themselves by negligible trap-states-associated charge recombination losses during photoelectrochemical water splitting. Unlike conventional defect-tolerant semiconductors, the origin of the defect-inactivity in GFO is the strongly preferred antisite formation, suppressing the generation of other defects that act as deep traps. In addition, defect-inactive GFO films possess really appropriate oxygen vacancy concentration for the oxygen evolution reaction (OER). As a result, the as-prepared GFO films achieve the surface charge transfer efficiency (ηsurface ) of 95.1% for photoelectrochemical water splitting at 1.23 V versus RHE without any further modification, which is the highest ηsurface reported of any pristine inorganic photoanodes. The onset potential toward the OER remarkably coincides with the flat band potential of 0.43 V versus RHE. This work not only demonstrates a new benchmark for the surface charge transfer yields of pristine metal oxides for solar water splitting but also enriches the arguments for defect tolerance and highlights the importance of rational tuning of oxygen vacancies.

3.
Cost Eff Resour Alloc ; 21(1): 7, 2023 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-36653783

RESUMO

This article aims to summarize the development and challenges of real-world data (RWD) and real-world evidence (RWE) in China and introduce a unique opportunity for medical devices to gain accelerated regulatory approval in China by utilizing RWE generated in a free trade pilot zone "Boao Lecheng" in Hainan Province. In 2020, the National Medical Products Administration (NMPA) issued a draft guideline on the "Use of real-world data to support clinical evaluation for medical devices", suggesting that RWE derived from RWD could support clinical evaluation throughout the life cycle of a medical device. Meanwhile, the Chinese government has allowed qualified RWD collected in Boao Lecheng to support registration application of innovative medical devices and drugs in China. These medical devices and drugs should have been approved abroad, but not in China yet, and met urgent and unmet medical needs in China. The article also presents the successful story of an innovative Glaucoma drainage tube as the first medical device approved in China using RWE generated in Boao Lecheng in 2020. Although we are witnessing an increased interest in RWE, a few challenges remain, e.g., limited data accessibility and data sharing, concerns on data quality, etc. Collaborations among relevant stakeholders in the RWE research are vital to address the challenges.

4.
Mol Cells ; 2023 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-36694914

RESUMO

Papillary thyroid carcinoma (PTC) is the most common subtype of thyroid carcinoma. Despite a good prognosis, approximately a quarter of PTC patients are likely to relapse. Previous reports suggest an association between S-phase kinase-associated protein 2 (SKP2) and the prognosis of thyroid cancer. SKP1 is related to apoptosis of PTC cells; however, its role in PTC remains largely elusive. This study aimed to understand the expression and molecular mechanism of SKP2 in PTC. SKP2 expression was upregulated in PTC tissues and closely associated with clinical diagnosis. In vitro and in vivo knockdown of SKP2 expression in PTC cells suppressed cell growth and proliferation and induced apoptosis. SKP2 depletion promoted cell autophagy under glucose deprivation. SKP2 interacted with PH domain leucine-rich repeat protein phosphatase-1 (PHLPP1), triggering its degradation by ubiquitination. Furthermore, SKP2 activates the AKT-related pathways via PHLPP1, which leads to the cytoplasmic translocation of SKP2, indicating a reciprocal regulation between SKP2 and AKT. In conclusion, the upregulation of SKP2 leads to PTC proliferation and survival, and the regulatory network among SKP2, PHLPP1, and AKT provides novel insight into the molecular basis of SKP2 in tumor progression.

5.
Ecol Evol ; 13(1): e9702, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36620412

RESUMO

Hubei Shishou Milu National Nature Reserve is an ideal place to restore the wild population of Père David's deer (Elaphurus davidianus). Understanding foraging ecology and diet composition is essential for assessing population development or establishing long-term effective conservation measures for endangered species. However, little is known about the diet composition of Père David's deer and its diet selection mechanism. In this study, we used stable isotope technology to investigate the diet composition of Père David's deer according to various tissues (i.e., fur, muscle, liver, heart, and feces) and seasons, and evaluated the correlation between the nutrient composition of plants and diet composition. Bayesian isotope analysis showed that the autumn and winter diet estimated by fur and fecal samples indicated a diet dominated by C3 grasses (42.7%-57.2%, mean), while the summer diet estimated by muscle and liver samples was dominated by C3 forbs (30.9%-41.6%, mean). The Pearson correlation test indicated that the contribution of winter diet composition reflected by fur and fecal samples was associated with correlations with crude protein (r = .666, p < .01) and soluble sugars (r = .695, p < .01). The results indicated that crude protein and soluble sugars were important factors influencing the winter diet selection of Père David's deer. In the context of the current reintroduction facing many challenges, such as habitat fragmentation, wetland degradation, and human disturbance, comprehensively evaluating the diet selection mechanism of Père David's deer under different resource specificities and temporal changes should be considered in the future.

6.
Opt Express ; 31(1): 555-563, 2023 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-36606991

RESUMO

This paper presents a method to measure the three-dimensional distribution of uniaxial stress based on Terahertz Time Domain Spectroscopy (THz-TDS). The measurement principle was first established, which combines the computed tomography (CT) method and the photo-elastic effects. A classic filtered back-projection algorithm is adopted to calculate the three-dimensional stress fields from THz-TDS scanning images. Then, in verification experiment, the uniaxial stress distribution in the compressed cylinder and the stretched screw is obtained based on the measurement principle. Finally, the reliability of the proposed method has been verified by comparing the experiment results with the finite element simulation. A reasonable agreement is obtained.

7.
J Fungi (Basel) ; 9(1)2023 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-36675913

RESUMO

An effective selection marker is necessary for genetic engineering and functional genomics research in the post-genomic era. Isaria javanica is an important entomopathogenic fungus with a broad host range and prospective biocontrol potentials. Given that no antibiotic marker is available currently in this fungus, developing an effective selection marker is necessary. In this study, by applying overlap PCR and split-marker deletion strategy, combining PEG-mediated protoplasm transformation method, the uridine auxotrophy gene (ura3) in the I. javanica genome was knocked out. Then, using this transformation system, the pH response transcription factor gene (IjpacC) was disrupted successfully. Loss of IjpacC gene results in an obvious decrease in conidial production, but little impact on mycelial growth. The virulence of the ΔIjpacC mutant on caterpillars is similar to that of the wild-type strain. RT-qPCR detection shows that expression level of an acidic-expressed S53 gene (IF1G_06234) in ΔIjpacC mutant is more significantly upregulated than in the wild-type strain during the fungal infection on caterpillars. Our results indicate that a markerless transformation system based upon complementation of uridine auxotrophy is successfully developed in I. javanica, which is useful for exploring gene function and for genetic engineering to enhance biological control potential of the fungus.

8.
Pulm Pharmacol Ther ; 78: 102187, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36603742

RESUMO

INTRODUCTION: The aim of this study was to compare the efficacy and safety of 3 years of HDM subcutaneous immunotherapy (HDM-SCIT) in allergic asthma (AA) children with mono- and polysensitized. METHODS: This was a retrospective observational study, 51 AA children (aged 4-14 years) who had completed 3 years of standardized HDM-SCIT were enrolled in. Based on skin prick tests (SPT) and allergen-specific IgE antibody (sIgE) test results, children were classified into two groups: the monosensitized group (n = 31) and the polysensitized group (n = 20). Total asthma symptoms score (TASS), total medication score (TMS), visual analog scale (VAS) scores, fractional exhaled nitric oxide (FeNO), lung function parameters, and adverse reactions were evaluated before treatment and at 6 months, 1, 2, 3 years of HDM-SCIT. RESULTS: In terms of effectiveness, compared to baseline, TASS, TMS, VAS, FeNO and lung function parameters were significantly improved in both groups after 3 years of HDM-SCIT (all P < 0.05). The comparison between the two groups showed that efficacy indicators were no statistically significant difference at follow-up time points (all P > 0.05) except PEF%pred at 6 months (P = 0.048). In terms of security, the number of adverse reactions in both groups also no statistical difference between the two groups (all P > 0.05). CONCLUSION: This study confirmed that no significant difference was observed in the clinical efficacy and safety of HDM-SCIT between mono-and polysensitized children with allergic asthma.


Assuntos
Asma , Rinite Alérgica , Animais , Humanos , Criança , Pyroglyphidae , Asma/terapia , Imunoterapia/efeitos adversos , Imunoterapia/métodos , Resultado do Tratamento , Estudos Retrospectivos , Rinite Alérgica/diagnóstico , Rinite Alérgica/terapia , Alérgenos , Dessensibilização Imunológica/efeitos adversos , Dessensibilização Imunológica/métodos
9.
BMC Med Res Methodol ; 23(1): 9, 2023 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-36635634

RESUMO

BACKGROUND: To investigate the reporting of prognostic prediction model studies in obstetric care through a cross-sectional survey design. METHODS: PubMed was searched to identify prognostic prediction model studies in obstetric care published from January 2011 to December 2020. The quality of reporting was assessed by the TRIPOD checklist. The overall adherence by study and the adherence by item were calculated separately, and linear regression analysis was conducted to explore the association between overall adherence and prespecified study characteristics. RESULTS: A total of 121 studies were included, while no study completely adhered to the TRIPOD. The results showed that the overall adherence was poor (median 46.4%), and no significant improvement was observed after the release of the TRIPOD (43.9 to 46.7%). Studies including both model development and external validation had higher reporting quality versus those including model development only (68.1% vs. 44.8%). Among the 37 items required by the TRIPOD, 10 items were reported adequately with an adherence rate over of 80%, and the remaining 27 items had an adherence rate ranging from 2.5 to 79.3%. In addition, 11 items had a report rate lower than 25.0% and even covered key methodological aspects, including blinding assessment of predictors (2.5%), methods for model-building procedures (4.5%) and predictor handling (13.5%), how to use the model (13.5%), and presentation of model performance (14.4%). CONCLUSIONS: In a 10-year span, prognostic prediction studies in obstetric care continued to be poorly reported and did not improve even after the release of the TRIPOD checklist. Substantial efforts are warranted to improve the reporting of obstetric prognostic prediction models, particularly those that adhere to the TRIPOD checklist are highly desirable.


Assuntos
Lista de Checagem , Humanos , Prognóstico , Estudos Transversais , Modelos Lineares
11.
J Ovarian Res ; 16(1): 7, 2023 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-36624470

RESUMO

OBJECTIVE: To determine the optimal endometrial preparation protocol for a frozen embryo transfer in patients with endometriosis. DESIGN: Retrospective cohort study. SETTING: Tertiary care academic medical center. PATIENT(S): One thousand four hundred thirteen patients with endometriosis who underwent oocyte aspiration from 2015 to 2020 and frozen embryo transfer from 2016 to 2020 and received natural cycle, hormone replacement treatment with or without GnRHa pretreatment endometrial preparation. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Clinical pregnancy rate, live birth rate, miscarriage rate, multiple pregnancy rate, biochemical pregnancy rate and ectopic pregnancy rate. Singleton live births were assessed for perinatal outcomes and obstetric complications. RESULT(S): There were no differences in clinical pregnancy outcomes or prenatal outcomes among the three commonly used endometrial preparation protocols for frozen embryo transfer cycles in patients with endometriosis. Results remained after screening variables using univariate logistic regression into multivariate logistic regression. No advantages or disadvantages were found among the three endometrial preparation protocols in patients with endometriosis. CONCLUSION(S): Natural cycle, hormone replacement cycle, or hormone replacement treatment with GnRHa pretreatment showed no superiority or inferiority in pregnancy and perinatal outcomes in patients with endometriosis.


Assuntos
Endometriose , Gravidez , Feminino , Humanos , Estudos Retrospectivos , Endometriose/terapia , Resultado da Gravidez , Taxa de Gravidez , Transferência Embrionária/métodos , Nascido Vivo , Criopreservação , Hormônios
12.
BMC Complement Med Ther ; 23(1): 9, 2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36627617

RESUMO

BACKGROUND: Tripterygium wilfordii Hook. F. (TwHF), a traditional Chinese medicine, is widely used in the treatment of rheumatoid arthritis. Due to multiorgan toxicity, particularly hepatotoxicity, the application of TwHF is restricted. To clarify the hepatotoxic substances, zebrafish, hepatocytes and macrophages were used for screening based on hepatotoxic injury patterns. This study provides a basis for further elucidation of the hepatotoxic mechanism of TwHF. METHODS: First, 12 compounds were selected according to the chemical categories of TwHF. The fluorescence area and fluorescence intensity of zebrafish livers were observed and calculated. The viability of two hepatocyte lines was detected by CCK8 assay. TNF-α and IL-1ß mRNA expression in bone marrow-derived macrophages was used to evaluate macrophage activation, a factor of potential indirect hepatotoxicity. Finally, the hepatotoxic characteristics of 4 representative components were verified in mice in vivo. RESULTS: Parthenolide, triptolide, triptonide, triptobenzene H, celastrol, demethylzeylasteral, wilforlide A, triptotriterpenic acid A and regelidine significantly reduced the fluorescence area and fluorescence intensity of zebrafish livers. The viability of L-02 or AML-12 cells was significantly inhibited by parthenolide, triptolide, triptonide, celastrol, demethylzeylasteral, and triptotriterpenic acid A. Parthenolide, triptolide, triptonide, celastrol, demethylzeylasteral and triptobenzene H significantly increased TNF-α and IL-1ß mRNA levels in macrophages, while triptophenolide, hypodiolide and wilforine significantly reduced TNF-α and IL-1ß mRNA levels. Triptotriterpenic acid A, celastrol and triptobenzene H at a dose of 10 mg/kg significantly increased the levels of mouse serum alanine aminotransferase and aspartate aminotransferase and aggravated liver inflammation. CONCLUSIONS: Parthenolide, triptolide, triptonide, celastrol, demethylzeylasteral, triptotriterpenic acid A and triptobenzene H might be the main hepatotoxic components of TwFH. Among them, only triptotriterpenic acid A presents direct hepatotoxicity. Triptobenzene H exerts indirect liver damage by activating macrophages. Parthenolide, triptolide, triptonide, celastrol, and demethylzeylasteral can directly and indirectly cause liver injury.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Camundongos , Animais , Tripterygium/química , Peixe-Zebra , Fator de Necrose Tumoral alfa , RNA Mensageiro
13.
Bioorg Med Chem ; 78: 117133, 2023 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-36599263

RESUMO

In this article, we designed and synthesized a series of novel thiophene-triazine derivatives bearing arylurea unit as potent dual PI3K/mTOR inhibitors. The cytotoxicity of all the target compounds were evaluated against nine cancer cell lines (breast cancer cell line MCF-7, lung cancer cell lines A549, NCI-H460, H2228 and H1975, cervical cancer cell lines Hela and Hela-MDR, ovarian cancer cell lines Ovcar-2 and glioma U87MG) and the kinase inhibitory activity against PI3K/mTOR kinases was also tested. The results demonstrated that most of the target compounds exhibited moderate to excellent activity and high selectivity against one or more cancer cell lines. Among them, seven compounds displayed better activity than lead compound GDC-0941. The inhibitory activity of the most promising compound on nine cancer cell lines was 302.5 times better than that of GDC-0941 with the IC50 values as low as 0.008 ± 0.002 µM, and the inhibitory activity against PI3Kα and mTOR kinase was excellent, with the IC50 values of 177.41 and 12.24 nM, respectively, indicating that it was a potential dual PI3Kα/mTOR inhibitor. The Structure-Activity Relationships (SARs) indicated that the introduction of the arylurea group significantly improved the cellular and kinase activities of the target compounds. Moreover, the results of toxicity and hemolysis experiments demonstrated that the most promising compound had low toxicity and good safety. The results of PCR assay and molecular docking modes showed that it was a potential PI3K/mTOR inhibitor, which was worthy of further study.


Assuntos
Antineoplásicos , Fosfatidilinositol 3-Quinases , Humanos , Linhagem Celular Tumoral , Fosfatidilinositol 3-Quinases/metabolismo , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Serina-Treonina Quinases TOR , Triazinas/farmacologia , Antineoplásicos/farmacologia , Proliferação de Células , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais
14.
Clin Cancer Res ; 2023 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-36622702

RESUMO

PURPOSE: The optimal dose schedule of vincristine, irinotecan and temozolomide (VIT) in relapsed or refractory Ewing sarcoma patients requires clarification. PATIENTS AND METHODS: Patients with relapsed or refractory Ewing sarcoma were randomly assigned (1:1) to either a shorter dx5 schedule (irinotecan 50mg/m2/d D1-5, vincristine 1.4mg/m2 D1) or protracted dx5x2 schedule (irinotecan 20mg/m2/d D1-5,8-12, vincristine 1.4mg/m2 D1,8) together with temozolomide (100mg/m2/d D1-5). Patients were treated every 3 weeks for up to eight cycles until progression or unacceptable toxic effects occurred. The primary endpoint was objective response rate at 12 weeks (ORR12w). Secondary endpoints were progression-free survival (PFS), overall survival (OS) and safety. RESULTS: A total of 46 patients presenting with relapsed or refractory Ewing sarcoma were randomly assigned to the dx5 (n=24) or dx5x2(n=22) schedules. Median follow-up was 10.7 months in the dx5 group and 8.3 months in the dx5x2 group. ORR12w was lower for dx5 (5/24 [20.8%]) patients than for dx5x2 (12/22[54.5%]; p=0.019), but no significant difference was found in PFS ( median PFS: 2.3 months for dx5 vs 4.3 months for dx5x2) or OS (median OS: 14.8 months for dx5 and 12.8 months for dx5x2). Patients receiving the dx5 schedule reported more grade 3 and 4 adverse events (AEs) than those receiving dx5x2, including diarrhea/abdominal pain, vomiting/nausea. CONCLUSIONS: The protracted dx5x2 VIT schedule showed superior efficacy and favorable tolerability compared with the shorter dx5 VIT schedule in patients with relapsed or refractory Ewing sarcoma.

15.
J Environ Sci (China) ; 126: 396-407, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-36503766

RESUMO

Based on the experimental and theoretical methods, the NO selective catalytic oxidation process was proposed. The experimental results indicated that lattice oxygen was the active site for NO oxide over the α-MnO2(110) surface. In the theoretical study, DFT (density functional theory) and periodic slab modeling were performed on an α-MnO2(110) surface, and two possible NO oxidation mechanisms over the surface were proposed. The non-defect α-MnO2(110) surface showed the highest stability, and the surface Os (the second layer oxygen atoms) position was the most active and stable site. O2 molecule enhanced the joint adsorption process of two NO molecules. The reaction process, including O2 dissociation and O=N-O-O-N=O formation, was calculated to carry out the NO catalytic oxidation mechanism over α-MnO2(110). The results showed that NO oxidation over the α-MnO2(110) surface exhibited the greatest possibility following the route of O=N-O-O-N=O formation. Meanwhile, the formation of O=N-O-O-N=O was the rate-determining step.


Assuntos
Compostos de Manganês , Óxidos , Catálise , Oxigênio , Modelos Teóricos
16.
J Environ Sci (China) ; 127: 641-651, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-36522093

RESUMO

Non-thermal plasma (NTP) surface modification technology is a new method to control the surface properties of materials, which has been widely used in the field of environmental protection because of its short action time, simple process and no pollution. In this study, Cu/ACF (activated carbon fiber loaded with copper) adsorbent was modified with NTP to remove H2S and PH3 simultaneously under low temperature and micro-oxygen condition. Meanwhile, the effects of different modified atmosphere (air, N2 and NH3), specific energy input (0-13 J/mL) and modification time (0-30 min) on the removal of H2S and PH3 were investigated. Performance test results indicated that under the same reaction conditions, the adsorbent modified by NH3 plasma with 5 J/mL for 10 min had the best removal effect on H2S and PH3. CO2 temperature-programmed desorption and X-ray photoelectron spectroscopy (XPS) analyzes showed that NH3 plasma modification could introduce amino functional groups on the surface of the adsorbent, and increase the types and number of alkaline sites on the surface. Brunauer-Emmett-Teller and scanning electron microscopy showed that NH3 plasma modification did not significantly change the pore size structure of the adsorbent, but more active components were evenly exposed to the surface, thus improving the adsorption performance. In addition, X-ray diffraction and XPS analysis indicated that the consumption of active components (Cu and Cu2O) and the accumulation of sulfate and phosphate on the surface and inner pores of the adsorbent are the main reasons for the deactivation of the adsorbent.


Assuntos
Gases em Plasma , Adsorção , Carvão Vegetal , Óxidos de Enxofre , Espectroscopia Fotoeletrônica
17.
Int J Cardiol ; 372: 6-14, 2023 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-36513282

RESUMO

BACKGROUND: Timely and appropriate transformation of macrophage phenotypes from proinflammatory to anti-inflammatory is essential for cardiac repair after myocardial infarction (MI). Chemokine-like receptor 1 (CMKLR1), which is expressed on macrophages, is regulated by proinflammatory and anti-inflammatory stimuli. However, the contribution of CMKLR1 to macrophage phenotypic transformation and the role it plays in modulating cardiac repair after MI remain unclear. METHODS: CMKLR1 knockout (CMKLR1-/-) mice were generated by CRISPR/Cas-mediated genome engineering. A model of murine MI was induced by permanent ligation along the left anterior descending artery. Cardiac function was evaluated by echocardiography. Infarct size and collagen deposition were detected by Masson's trichrome staining. Cardiac macrophages were obtained by fluorescence-activated cell sorting. The protein and mRNA expression of associated molecules was determined by Western blotting and qRT-PCR. RESULTS: We demonstrated that macrophages highly expressed CMKLR1 and accumulated in murine infarcted hearts during the anti-inflammatory reparative phase of MI. CMKLR1 deficiency impaired cardiac function, increased infarct size, induced maladaptive cardiac remodeling, and decreased long-term survival after MI. Furthermore, CMKLR1 deficiency impeded macrophage phenotypic transformation from M1 to M2 in vivo and in vitro. In addition, we demonstrated that CMKLR1 signaling through the PI3K/Akt/mTOR pathway stimulated C/EBPß activation while simultaneously limiting NF-κB activation, thereby promoting anti-inflammatory and prohibiting proinflammatory macrophage polarization. CONCLUSIONS: Our results reveal that CMKLR1 deficiency impedes macrophage phenotypic transformation and cardiac repair after MI involving the PI3K/AKT/mTOR pathway. CMKLR1 may thus represent a potential therapeutic target for MI.


Assuntos
Infarto do Miocárdio , Fosfatidilinositol 3-Quinases , Camundongos , Animais , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Macrófagos/metabolismo , Serina-Treonina Quinases TOR , Fenótipo , Quimiocinas/metabolismo , Miocárdio/metabolismo , Camundongos Endogâmicos C57BL
18.
Artigo em Inglês | MEDLINE | ID: mdl-36529071

RESUMO

Atherosclerosis (AS) is a metabolic disorder commonly correlated with a high-fat diet (HFD). There are many endogenous metabolic changes associated with AS development. Gualou-Xiebai (GLXB) is a traditional Chinese medicine herb pair that has been used to treat AS. However, the mechanism of GLXB herb pair on the process of AS is still essentially unknown. In this study, aortic histopathological examination and biochemical analyses were used to validate the anti-atherosclerotic effects of GLXB herb pair on ApoE-/- mice during the disease course of AS. The mechanism of GLXB herb pair were performed by metabolomics approach based on ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS). As a result, GLXB herb pair has protective effects on AS lesion development and improves blood lipid levels in ApoE-/- mice. A total of 34, 39, and 49 metabolites were found to be profoundly altered in the 9-week, 14-week, and 19-week model groups compared with the corresponding control groups. Among them, 16, 18, and 18 metabolites showed a trend toward normal levels after pharmacological intervention. Metabolic pathway analysis found that GLXB herb pair mainly affects glycerophospholipid metabolism, pentose and glucuronate interconversions in 9 weeks; linoleic acid metabolism, cysteine and methionine metabolism, and arachidonic acid metabolism in 14 weeks; arachidonic acid metabolism and pentose and glucuronate interconversions in 19 weeks. The results demonstrated that GLXB herb pair mainly played a therapeutic role by regulating glycerophospholipid metabolism and pentose and glucuronate interconversions in the whole process of AS.


Assuntos
Aterosclerose , Medicamentos de Ervas Chinesas , Animais , Camundongos , Apolipoproteínas E , Ácido Araquidônico , Aterosclerose/tratamento farmacológico , Aterosclerose/metabolismo , Biomarcadores , Cromatografia Líquida de Alta Pressão/métodos , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Glicerofosfolipídeos , Metabolômica/métodos , Aorta/efeitos dos fármacos
19.
Neural Regen Res ; 18(5): 1067-1075, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-36254995

RESUMO

Although many therapeutic interventions have shown promise in treating spinal cord injury, focusing on a single aspect of repair cannot achieve successful and functional regeneration in patients following spinal cord injury . In this study, we applied a combinatorial approach for treating spinal cord injury involving neuroprotection and rehabilitation, exploiting cell transplantation and functional sensorimotor training to promote nerve regeneration and functional recovery. Here, we used a mouse model of thoracic contusive spinal cord injury to investigate whether the combination of bone marrow mesenchymal stem cell transplantation and exercise training has a synergistic effect on functional restoration. Locomotor function was evaluated by the Basso Mouse Scale, horizontal ladder test, and footprint analysis. Magnetic resonance imaging, histological examination, transmission electron microscopy observation, immunofluorescence staining, and western blotting were performed 8 weeks after spinal cord injury to further explore the potential mechanism behind the synergistic repair effect. In vivo, the combination of bone marrow mesenchymal stem cell transplantation and exercise showed a better therapeutic effect on motor function than the single treatments. Further investigations revealed that the combination of bone marrow mesenchymal stem cell transplantation and exercise markedly reduced fibrotic scar tissue, protected neurons, and promoted axon and myelin protection. Additionally, the synergistic effects of bone marrow mesenchymal stem cell transplantation and exercise on spinal cord injury recovery occurred via the PI3K/AKT/mTOR pathway. In vitro, experimental evidence from the PC12 cell line and primary cortical neuron culture also demonstrated that blocking of the PI3K/AKT/mTOR pathway would aggravate neuronal damage. Thus, bone marrow mesenchymal stem cell transplantation combined with exercise training can effectively restore motor function after spinal cord injury by activating the PI3K/AKT/mTOR pathway.

20.
EBioMedicine ; 87: 104418, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36584593

RESUMO

Metabolism regulates cardiovascular biology through multiple mechanisms, including epigenetic modifications. Over the past two decades, experimental and preclinical studies have highlighted the critical roles of histone modifications in cardiovascular development, homeostasis, and diseases. The widely studied histone acetylation is critical in cardiovascular biology and diseases, and inhibitors of histone deacetylases show therapeutic values. In addition to lysine acetylation, a series of novel non-acetyl lysine acylations have recently been recognized. These non-acetyl lysine acylations have been demonstrated to have physiological and pathological functions, and recent studies have analyzed the roles of these non-acetyl lysine acylations in cardiovascular biology. Herein, we review the current advances in the understanding of non-acetyl lysine acylations in cardiovascular biology and discuss open questions and translational perspectives. These new pieces of evidence provide a more extensive insight into the epigenetic mechanisms underlying cardiovascular biology and help assess the feasibility of targeting acylations to treat cardiovascular diseases.


Assuntos
Histonas , Lisina , Humanos , Acetilação , Histonas/metabolismo , Lisina/metabolismo , Acilação , Processamento de Proteína Pós-Traducional , Biologia
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