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1.
Chem Sci ; 15(32): 12964-12972, 2024 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-39148778

RESUMO

Benefiting from high energy density of ultrahigh-nickel cathode materials and good safety of PEO-based electrolytes, PEO-based ultrahigh-nickel solid-state lithium batteries (SLMBs) are considered to be new-generation energy storage devices. However, the incompatibility of ultrahigh-nickel cathode materials and PEO-based electrolytes is the main challenge due to serious interfacial side reactions. Therefore, the modification of the cathode/electrolyte interface is crucial. Herein, the residual lithium on the surface of LiNi0.9Co0.06Mn0.04O2 is utilized to construct an interfacial coating layer by reacting with H3BO3. The in situ formed xLi2O-B2O3 coating layer (LBO1-NCM) with high ionic conductivity can be regulated with different crystal structures during the sintering process. Besides, an all-solid-state three-electrode cell is fabricated, which verifies that the xLi2O-B2O3 coating can effectively stabilize the interface. Astonishingly, uneven Li anode deposition is observed in SLMBs, which is caused by the breakage of PEO molecular chains due to the strong oxidation of the cathode, while this crosstalk is also suppressed by the xLi2O-B2O3 coating layer. Consequently, Li|PEO|LBO1-NCM achieves a substantially improved electrochemical performance, exhibiting 90.5% of capacity retention after 100 cycles for the coin cell and 80.3% of capacity retention after 200 cycles for the pouch cell. Apparently, the targeted modification of interfaces should be paid as much attention as electrolyte optimization in SLMBs.

2.
ACS Nano ; 18(33): 22518-22532, 2024 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-39109485

RESUMO

The matching of poly(ethylene oxide) (PEO)-based electrolytes with ultrahigh-nickel cathode materials is crucial for designing new-generation high-energy-density solid-state lithium metal batteries (SLMBs), but it is limited by serious interfacial side reactions between PEO and ultrahigh-nickel materials. Here, a high-concentration electrolyte (HCE) interface with a customized Li+ solvation sheath is constructed between the cathode and the electrolyte. It induces the formation of an anion-regulated robust cathode/electrolyte interface (CEI), reduces the unstable free-state solvent, and finally achieves the compatibility of PEO-based electrolytes with ultrahigh-nickel cathode materials. Meanwhile, the corrosion of the Al current collector caused by lithium bis(trifluoromethanesulfonyl)imide (LiTFSI) ions is prevented by lithium difluoro(oxalato)borate (LiDFOB) ions. The synergistic effect of the double lithium salt is achieved by a well-tailored ratio of TFSI- and DFOB- in the first solvation sheath of Li+. Compared with reported PEO-based SLMBs matched with ultrahigh-nickel (Ni ≥ 90%) cathodes, the SLMB in this work delivers a high discharge specific capacity of 216.4 mAh g-1 (0.1C) even at room temperature. This work points out a direction to optimize the cathode/electrolyte interface.

3.
Infect Med (Beijing) ; 3(2): 100107, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38872909

RESUMO

Tuberculosis is a chronic infectious disease, caused by Mycobacterium tuberculosis, that seriously endangers human health. Skeletal tuberculosis is the most common type of extrapulmonary tuberculosis and tuberculous arthritis is the second most common type of skeletal tuberculosis. We report a case series of patients with tuberculous arthritis, two of whom had no joint disease in the past and presented as monoarthritis. The final patient had a history of rheumatoid arthritis, with polyarthritis that was aggravated during treatment with glucocorticoids and immunosuppressive drugs. This series of cases can contribute to early diagnosis and treatment with appropriate infection control measures.

4.
Life Sci ; 342: 122513, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38387700

RESUMO

BACKGROUND: The epidermic microbiota plays crucial roles in the pathogenesis of atopic dermatitis (AD), a common inflammatory skin disease. Melatonin (MLT) has been shown to ameliorate skin damage in AD patients, yet the underlying mechanism is unclear. METHODS: Using 2,4-dinitrofluorobenzene (DNFB) to induce an AD model, MLT intervention was applied for 14 days to observe its pharmaceutical effect. Skin lesions were observed using HE staining, toluidine blue staining and electron microscopy. Dermal proinflammatory factor (IL-4 and IL-13) and intestinal barrier indices (ZO1 and Occludin) were assessed by immunohistochemistry and RT-qPCR, respectively. The dysbiotic microbiota was analyzed using 16S rRNA sequencing. RESULTS: MLT significantly improved skin lesion size; inflammatory status (mast cells, IgE, IL-4, and IL-13); and the imbalance of the epidermal microbiota in AD mice. Notably, Staphylococcus aureus is the key bacterium associated with dysbiosis of the epidermal microbiota and may be involved in the fine modulation of mast cells, IL-4, IL-13 and IgE. Correlation analysis between AD and the gut revealed that intestinal dysbiosis occurred earlier than that of the pathological structure in the gut. CONCLUSION: Melatonin reverses DNFB-induced skin damage and epidermal dysbiosis, especially in S. aureus.


Assuntos
Dermatite Atópica , Melatonina , Microbiota , Dermatopatias , Humanos , Camundongos , Animais , Dermatite Atópica/induzido quimicamente , Dermatite Atópica/tratamento farmacológico , Dinitrofluorbenzeno/toxicidade , Melatonina/farmacologia , Interleucina-13 , Staphylococcus aureus , Interleucina-4/farmacologia , RNA Ribossômico 16S/genética , Disbiose/patologia , Pele , Dermatopatias/patologia , Imunoglobulina E
5.
Pest Manag Sci ; 80(2): 613-626, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37740940

RESUMO

BACKGROUND: Tribe Zyginelline leafhoppers can transmit plant viruses and are important pests that affect agriculture, forestry, and animal husbandry, causing serious economic losses. The potential distribution patterns of Zyginellini will change under climate change. Therefore, the best-performing random forest and maximum entropy models among 12 commonly used ecological niche models, alongside an ensemble model, were selected to predict the changes in habitat suitability distribution of Zyginellini under current and future climate scenarios [represented by two shared socio-economic pathways (SSPs), namely SSP126 and SSP585, for three periods (2050s, 2070s, and 2090s)] in China and the Indo-China Peninsula for the first time. RESULTS: The results revealed that the distribution of Zyginellini was mainly dominated by minimum temperature of coldest month. Under current and future climate scenarios, Zyginellini was mostly distributed southeast of the 400 mm equivalent precipitation line in China, and Vietnam. Under the future SSP126 scenario, the alert areas will mainly be concentrated in Hunan, Jiangxi, Zhejiang, Anhui, and Hebei in China, alongside Myanmar and Thailand in the Indo-China Peninsula. Meanwhile, in the SSP585 scenario, the alert areas in China will increase, whereas there will be little change in the Indo-China Peninsula. Interestingly, from the current to the future, the cores of Zyginelline distribution occurred around rivers and mountains, and shifted from Guizhou along the Yuanjiang River system to higher latitudes in Hunan. CONCLUSION: Zyginellini prefers higher latitude river-mountain systems under climate change. Our results will contribute to effective pest control strategies and biogeographical research for Zyginellini alongside other Cicadellidae insects. © 2023 Society of Chemical Industry.


Assuntos
Mudança Climática , Hemípteros , Animais , Rios , Modelos Teóricos , Temperatura Baixa , China , Ecossistema
6.
iScience ; 26(12): 108556, 2023 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-38125015

RESUMO

Spaceflight is physically demanding and can negatively affect astronauts' health. It has been shown that the human gut microbiota and cardiac function are affected by spaceflight and simulated spaceflight. This study investigated the effects of the gut microbiota on simulated spaceflight-induced cardiac remodeling using 10° of head-down bed rest (HDBR) in rhesus macaques and 30° of hindlimb unloading (HU) in mice. The gut microbiota, fecal metabolites, and cardiac remodeling were markedly affected by HDBR in macaques and HU in mice, cardiac remodeling in control mice was affected by the gut microbiota of HU mice and that of HU mice was protected by the gut microbiota of control mice, and there was a correlation between cardiac remodeling and the gut microbial-derived metabolite trimethylamine N-oxide. These findings suggest that spaceflight can affect cardiac remodeling by modulating the gut microbiota and fecal metabolites.

7.
BMC Psychol ; 11(1): 241, 2023 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-37612743

RESUMO

BACKGROUND: Online game addiction has become a prominent public concern, particularly among emerging adults, warranting in-depth investigation. Despite prior cross-sectional research indicating a negative correlation between gratitude and online gaming addiction, a dearth of longitudinal research exists in this area. Furthermore, the underlying mechanisms that explain the link between gratitude and online gaming addiction remain poorly understood, highlighting a critical research gap in the field. METHODS: To bridge this gap, our study adopted a three-wave longitudinal design and constructed a multiple mediation model. Over the course of one year, data was collected from a sample of Chinese undergraduates, with 319 students participating at Time 1, 305 at Time 2, and 292 at Time 3. Participants were administered online self-report surveys, enabling the acquisition of valuable data regarding their levels of gratitude, online game addiction, self-control, and loneliness. RESULTS: The findings revealed a negative correlation between gratitude measured at Time 1 and online game addiction assessed at Time 3. Further analysis demonstrated that both self-control and loneliness played multiple mediating roles at Time 2 in the link between gratitude and online game addiction. CONCLUSION: These research findings shed light on the underlying mechanisms between gratitude and online game addiction, which provide implications for developing interventions (e.g., interventions based on gratitude) for reducing young adults' online game addiction.


Assuntos
Povo Asiático , Transtorno de Adição à Internet , Estudantes , Humanos , Adulto Jovem , Comportamento Aditivo/prevenção & controle , Comportamento Aditivo/psicologia , Estudos Transversais , Lacunas de Evidências , Estudantes/psicologia , Transtorno de Adição à Internet/prevenção & controle , Transtorno de Adição à Internet/psicologia , Universidades , Emoções
8.
BMC Psychol ; 11(1): 189, 2023 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-37386513

RESUMO

BACKGROUND: With the popularity of mobile socialization, people have become more closely connected with their phones. While people enjoy the convenience that phones bring (e.g., accessing information and socializing), they also feel anxious about missing out on certain information. Previous researches have shown that fear of missing out (FoMO) can trigger depressive symptoms, however, the underlying psychological mechanisms are not yet clear. In addition, limited research has explored this issue in the context of mobile social media. METHODS: To address this research gap, we surveyed 486 Chinese college students (278 males and 208 females, mean age = 19.95 years, SD = 1.14) and all participants completed a self-report questionnaire including mobile social media-related FoMO scale, phubbing scale, social exclusion scale, and the patient health questionnaire-9. The data were analyzed by SPSS24.0 and the Process macro and developed a mediating and moderating model incorporating phubbing and social exclusion. RESULTS: The results showed that (1) mobile social media-related FoMO (MSM-related FoMO) can significantly and positively predict depressive symptoms among college students; (2) phubbing partially mediates the relationship between MSM-related FoMO and depressive symptoms; (3) the direct predictive effect of MSM-related FoMO on depressive symptoms is moderated by social exclusion. CONCLUSION: These findings are not only valuable for understanding the underlying mechanisms linking MSM-related FoMO and depressive symptoms, but also contribute to the development of psychological intervention programs (e.g., interventions based on social exclusion or phubbing) aiming at reducing college students' depressive symptoms.


Assuntos
Mídias Sociais , Feminino , Humanos , Masculino , Adulto Jovem , Depressão , Medo , Isolamento Social
9.
iScience ; 26(5): 106615, 2023 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-37250329

RESUMO

Spaceflight is rigorous and dangerous environment which can negatively affect astronauts' health and the entire mission. The 60 days of 6° head-down bed rest (HDBR) experiment provided us with an opportunity to trace the change of gut microbiota under simulated microgravity. The gut microbiota of volunteers was analyzed and characterized by 16S rRNA gene sequencing and metagenomic sequencing. Our results showed that the composition and function of the volunteers' gut microbiota were markedly was affected by 60 days of 6° HDBR. We further confirmed the species and diversity fluctuations. Resistance and virulence genes in the gut microbiota were also affected by 60 days of 6° HDBR, but the species attributions remained stable. The human gut microbiota affected by 60 days of 6° HDBR which was partially consistent with the effect of spaceflight, this implied that HDBR was a simulation of how spaceflight affects the human gut microbiota.

10.
Appl Nurs Res ; 69: 151656, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36635011

RESUMO

BACKGROUND: Family resilience plays a crucial role in protecting the mental health and family stability of infertile patients. However, information associated with infertile families resilience is scarce. The double ABC-X model provides a roadmap for this, helps organize knowledge, and lays the foundation for knowledge development. AIMS: To describe the current situation of family resilience of infertile women, and to test the predictive theoretical model of family resilience based on infertility stigma, individual resilience, coping style, and posttraumatic growth. DESIGN: A cross-sectional study. METHODS: A convenience sample of 372 infertile women undergoing in vitro fertilization were recruited between April and August 2020. The Chinese-Family Resilience Assessment Scale, Infertility Stigma Scale, Simplified Coping Style Questionnaire, Chinese version of Connor-Davidson Resilience Scale, and Chinese version of Post Traumatic Growth Inventory were used to measure family resilience, infertility stigma, individual resilience, coping style, and posttraumatic growth. Structural equation models were used to analyze the relationship among these variables. RESULTS: The results showed that family resilience was related to infertility stigma, positive coping, and individual resilience. Moreover, the path analysis indicated that positive coping and individual resilience mediated the effects of infertility stigma on family resilience. CONCLUSIONS: A high level of stigma among infertile women should be identified. Interventions for targeting positive coping and individual resilience might ultimately increase their family resilience.


Assuntos
Infertilidade Feminina , Resiliência Psicológica , Feminino , Humanos , Infertilidade Feminina/terapia , Infertilidade Feminina/psicologia , Estudos Transversais , Saúde da Família , Adaptação Psicológica , Fertilização in vitro , Inquéritos e Questionários
11.
Clin Rheumatol ; 42(1): 135-143, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36074221

RESUMO

OBJECTIVES: To explore the value of plasmablasts in predicting disease relapse in IgG4-related diseases (IgG4-RD). METHODS: Treatment-naïve IgG4-RD patients treated with glucocorticoid (GC) monotherapy or leflunomide (LEF) and GC combination therapy diagnosed at the Chinese PLA General Hospital during February 2017 and January 2018 were included in this study. The absolute plasmablast count was measured by using the absolute count tubes with flow cytometry. Patients were categorized into high and low plasmablast level groups by defining the median number of plasmablasts as the cut-off value. The characteristics of the clinical manifestations between the two groups were compared. In addition, the correlation of plasmablast count with other indicators and its clinical value in predicting disease relapse were evaluated. RESULTS: Data of 37 treatment-naïve IgG4-RD patients were analyzed. The median (IQR) absolute count of plasmablasts was 4.0 (2.8-7.5)/µL, which was correlated with the lymphocyte percentage, serum IgG, IgG4, and IgG4/IgG. The baseline absolute count of plasmablasts was an independent risk factor for disease relapse in IgG4-RD patients (HR, 1.199; 95% CI, 1.030-1.396, P = 0.019), and the application of LEF was an independent protective factor (HR, 0.283; 95% CI, 0.106-0.759, p = 0.012). CONCLUSIONS: The present study preliminarily indicated that baseline absolute plasmablast count may independently predict disease relapse in patients with IgG4-RD treated with GC monotherapy or LEF and GC combination therapy. More efforts are still needed to be performed in the future. Key Points • The absolute count of plasmablasts is correlated with the lymphocyte percentage, serum IgG, IgG4 and IgG4/IgG. • The baseline absolute plasmablast count may predict disease relapse in patients with IgG4-RD treated with GC monotherapy or LEF and GC combination therapy. • The application of LEF is an independent protective factor for disease relapse in IgG4-RD.


Assuntos
Doença Relacionada a Imunoglobulina G4 , Humanos , Doença Relacionada a Imunoglobulina G4/diagnóstico , Doença Relacionada a Imunoglobulina G4/tratamento farmacológico , Plasmócitos , Leflunomida/uso terapêutico , Doença Crônica , Recidiva , Imunoglobulina G
13.
Gut Microbes ; 14(1): 2143221, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36394293

RESUMO

ß-N-acetylhexosaminidases (EC3.2.1.52), which belong to the glycosyl hydrolase family GH20, are important enzymes for oligosaccharides modification. Numerous microbial ß-N-acetylhexosaminidases have been investigated for applications in biology, biomedicine and biotechnology. Akkermansia muciniphila is an anaerobic intestinal commensal bacterium which possesses specific ß-N-acetylhexosaminidases for gut mucosal layer colonization and mucin degradation. In this study, we assessed the in vitro mucin glycan cleavage activity of the A. muciniphila ß-N-acetylhexosaminidase Am2136 and demonstrated its ability that hydrolyzing the ß-linkages joining N-acetylglucosamine to a wide variety of aglycone residues, which indicated that Am2136 may be a generalist ß-N-acetylhexosaminidase. Structural and enzyme activity assay experiments allowed us to probe the essential function of the inter-domain interactions in ß23-ß33. Importantly, we revealed that the hydrolysis activity of Am2136 was enhanced by nucleotides. We further speculated that this activation mechanism might be associated with the conformational motions between domain III and IV. To our knowledge, this is the first report of nucleotide effector regulated ß-N-acetylhexosaminidase, to reveal its novel biological functions. These findings contribute to understanding the distinct properties within the GH20 family and lay a certain foundation to develop controllable glycan hydrolyzing catalysts.Abbreviations: OD600 - optical cell densities at 600 nm; LB - Luria-Bertani; IPTG - isopropyl ß-D-1-thiogalactopyranoside; PMSF - phenylmethanesulfonyl fluoride; rmsd - root mean square deviation; GlcNAc - N-acetyl-ß-D-glucosamine; GalNAc - N-acetyl-ß-D-galactosamine; Gal - galactose.


Assuntos
Microbioma Gastrointestinal , beta-N-Acetil-Hexosaminidases , beta-N-Acetil-Hexosaminidases/química , beta-N-Acetil-Hexosaminidases/metabolismo , Especificidade por Substrato , Verrucomicrobia/metabolismo , Mucinas/metabolismo , Nucleotídeos/metabolismo
14.
Psychol Res Behav Manag ; 15: 2449-2459, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36097599

RESUMO

Purpose: Infertility has adverse effects on the quality of life (QoL) of infertile couples. Previous studies found important associations between sexual function, self-esteem and QoL, but mainly focused on one individual's approach rather than both partners. This study adopted a dyadic approach to evaluate the relationship between sexual function and QoL in couples with infertility through mediation and improving self-esteem. Patients and Methods: Between October 2020 and January 2021, 428 couples with infertility (n=856) undergoing in-vitro fertilization (IVF) at a tertiary hospital in Hefei, China, were registered for the current descriptive cross-sectional research. The dyads' sociodemographic and clinical features, as well as their sexual function, self-esteem, and QoL were evaluated. The Fertility quality of life scale (FertiQoL), Rosenberg Self-Esteem Scale (RSES), Female Sexual Function Index (FSFI), and International Index of Erectile Function-15 (IIEF-15) were used to evaluate the participants. The Actor-Partner Interdependence Mediation Model (APIMeM) was utilized to examine data from the dyadic relationships. Results: According to the APIMeM analysis, sexual function of individuals with infertility was directly and indirectly connected with their QoL, mediated through their self-esteem. The women's sexual function was found to be positively associated with their partner's QoL, with the women's self-esteem acting as a complete mediator. The men's sexual function was found to be positively associated with partner's QoL, with the men's self-esteem acting as a complete mediator. Conclusion: The findings suggest that boosting participants' self-esteem can help them and their partners have a better QoL. Also, therapies aimed at improving and sustaining self-esteem of couples with infertility could help mitigate the negative influence of low sexual function on their QoL.

16.
J Anal Methods Chem ; 2021: 8854025, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34925934

RESUMO

This study aimed to develop a method, followed by gas chromatography-mass spectrometry, for detecting 37 pesticides in Chrysanthemum indicum (C. indicum) and investigating the decrease in the matrix-induced enhancement effect. The influence of QuEChERS extraction and matrix solid-phase dispersion (MSPD) on the recovery and matrix effect (ME) was compared. extraction and matrix solid-phase dispersion (MSPD) on the recovery and matrix effect (ME) was compared to decrease the ME. The cleanup sorbents, volume and type of solvent, and treatment time were optimized. The accuracy (as recovery), precision (as relative standard deviation, RSD), linearity, limit of quantitation, and limit of detection were determined. The recoveries at the three levels using mixed standard solution ranged between 76% and 120% with RSD ≤15%, and 76% and 120% with RSD ≤11% for MSPD and QuEChERS extraction, respectively. The results suggested that the ME for 21 pesticides was in the range of 80%-120% after MSPD and 15% after QuEChERS extraction. QuEChERS extraction was simpler and faster than MSPD. This methodology was applied in the analysis of 27 C. indicum samples; phorate was most frequently detected (63.0% of the sample).

17.
Acta Crystallogr D Struct Biol ; 77(Pt 12): 1614-1623, 2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34866616

RESUMO

Akkermansia muciniphila, an anaerobic Gram-negative bacterium, is a major intestinal commensal bacterium that can modulate the host immune response. It colonizes the mucosal layer and produces nutrients for the gut mucosa and other commensal bacteria. It is believed that mucin desulfation is the rate-limiting step in the mucin-degradation process, and bacterial sulfatases that carry out mucin desulfation have been well studied. However, little is known about the structural characteristics of A. muciniphila sulfatases. Here, the crystal structure of the premature form of the A. muciniphila sulfatase AmAS was determined. Structural analysis combined with docking experiments defined the critical active-site residues that are responsible for catalysis. The loop regions I-V were proposed to be essential for substrate binding. Structure-based sequence alignment and structural superposition allow further elucidation of how different subclasses of formylglycine-dependent sulfatases (FGly sulfatases) adopt the same catalytic mechanism but exhibit diverse substrate specificities. These results advance the understanding of the substrate-recognition mechanisms of A. muciniphila FGly-type sulfatases. Structural variations around the active sites account for the different substrate-binding properties. These results will enhance the understanding of the roles of bacterial sulfatases in the metabolism of glycans and host-microbe interactions in the human gut environment.


Assuntos
Sulfatases/química , Acetilglucosamina/metabolismo , Akkermansia/enzimologia , Catálise , Cristalografia por Raios X , Humanos , Simulação de Acoplamento Molecular , Conformação Proteica , Alinhamento de Sequência , Especificidade por Substrato , Sulfatases/isolamento & purificação , Sulfatases/metabolismo
18.
Zootaxa ; 5005(3): 349-357, 2021 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-34811254

RESUMO

Two new species of the leafhopper tribe Erythroneurini from Guizhou province, China, Arboridia (Arboridia) huajiangensis sp. nov. and Arboridia (Arborifera) changlingensis sp. nov. are described and illustrated. The ovipositor of A. huajiangensis sp. nov. is photographed and described. A key distinguishing all known species of the genus in China is provided.


Assuntos
Hemípteros , Animais , China
19.
DNA Cell Biol ; 40(7): 1009-1025, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34061680

RESUMO

The vascular endothelium, which plays an essential role in maintaining the normal shape and function of blood vessels, is a natural barrier between the circulating blood and the vascular wall tissue. The endothelial damage can cause vascular lesions, such as atherosclerosis and restenosis. After the vascular intima injury, the body starts the endothelial repair (re-endothelialization) to inhibit the neointimal hyperplasia. Endothelial progenitor cell is the precursor of endothelial cells and plays an important role in the vascular re-endothelialization. However, re-endothelialization is inevitably affected in vivo and in vitro by factors, which can be divided into two types, namely, promotion and inhibition, and act on different links of the vascular re-endothelialization. This article reviews these factors and related mechanisms.


Assuntos
Células Progenitoras Endoteliais/metabolismo , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiologia , Animais , Artérias/lesões , Movimento Celular , Células Progenitoras Endoteliais/fisiologia , Humanos , Transdução de Sinais/genética , Lesões do Sistema Vascular/fisiopatologia , Veias/lesões
20.
Theranostics ; 10(12): 5384-5397, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32373219

RESUMO

Rationale: The existence of primary and acquired drug resistance is the main obstacle for the effect of multi-kinase inhibitor sorafenib and regorafenib in advanced hepatocellular carcinoma (HCC). However, plenty of patients did not significantly benefit from sorafenib treatment and little is known about the mechanism of drug resistance. Methods: Laser capture microdissection was used to acquire matched normal liver and tumor tissues on formalin-fixed paraffin-embedded specimens collected before sorafenib therapy from the first surgery of 119 HCC patients. Ultra-deep sequencing (~1000×) targeting whole exons of 440 genes in microdissected specimens and siRNA screen in 7 cell lines were performed to find mutations associated with differential responses to sorafenib. Patient-derived xenograft models were employed to determine the role of TP53 in response to sorafenib. Lentiviruses harboring wild-type and c.G52C-mutant OCT4 were applied to explore the function of OCT4 in resistance to sorafenib. ChIP-PCR assay for analysis of OCT4 transcriptional activity was performed to explore the affinity with the KITLG promoter. Statistical analyses were used to associate levels of p53 and OCT4 with tumor features and patient outcomes. Results: Total 1,050 somatic mutations and 26 significant driver genes were identified. SiRNA screening in 7 HCC cell lines was further performed to identify mutations associated with differential responses to sorafenib. A recurrent nonsynonymous mutation c.G52C in OCT4 (OCT4mut) was strongly associated with good response to sorafenib, whereas the stop-gain mutation in TP53 showed the opposite outcome both in vitro and in vivo. OCT4wt-induced stem cell factor (encoded by KITLG gene, SCF) expression and cross-activation of c-KIT/FLT3-BRAF signals were identified indispensably for sorafenib resistance, which could be reversed by the combination of c-KIT tyrosine kinase inhibitors or neutralizing antibody against SCF. Mechanistically, an OCT4 binding site in upstream of KITLG promoter was identified with a higher affinity to wildtype of OCT4 rather than G52C-mutant form, which is indispensable for OCT4-induced expression of KITLG and sorafenib resistance. Conclusion: Our study reported a novel somatic mutation in OCT4 (c.G52C) responsible for the sorafenib effect, and also shed new light on the treatment of HCC through the combination of specific tyrosine kinase inhibitors according to individual genetic patterns.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Sorafenibe/uso terapêutico , Carcinoma Hepatocelular/genética , Proliferação de Células/genética , Humanos , Neoplasias Hepáticas/genética , Masculino , Mutação/genética , Fator 3 de Transcrição de Octâmero/genética , Compostos de Fenilureia/uso terapêutico , Piridinas/uso terapêutico , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
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