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1.
Mol Cell ; 66(5): 648-657.e4, 2017 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-28575660

RESUMO

The glycogen synthase kinase-3 (GSK3) family kinases are central cellular regulators highly conserved in all eukaryotes. In Arabidopsis, the GSK3-like kinase BIN2 phosphorylates a range of proteins to control broad developmental processes, and BIN2 is degraded through unknown mechanism upon receptor kinase-mediated brassinosteroid (BR) signaling. Here we identify KIB1 as an F-box E3 ubiquitin ligase that promotes the degradation of BIN2 while blocking its substrate access. Loss-of-function mutations of KIB1 and its homologs abolished BR-induced BIN2 degradation and caused severe BR-insensitive phenotypes. KIB1 directly interacted with BIN2 in a BR-dependent manner and promoted BIN2 ubiquitination in vitro. Expression of an F-box-truncated KIB1 caused BIN2 accumulation but dephosphorylation of its substrate BZR1 and activation of BR responses because KIB1 blocked BIN2 binding to BZR1. Our study demonstrates that KIB1 plays an essential role in BR signaling by inhibiting BIN2 through dual mechanisms of blocking substrate access and promoting degradation.


Assuntos
Proteínas de Arabidopsis/metabolismo , Arabidopsis/efeitos dos fármacos , Brassinosteroides/farmacologia , Proteínas F-Box/metabolismo , Quinase 3 da Glicogênio Sintase/metabolismo , Reguladores de Crescimento de Plantas/farmacologia , Plantas Geneticamente Modificadas/efeitos dos fármacos , Proteínas Quinases/metabolismo , Esteroides Heterocíclicos/farmacologia , Ubiquitina-Proteína Ligases/metabolismo , Arabidopsis/enzimologia , Arabidopsis/genética , Proteínas de Arabidopsis/genética , Sítios de Ligação , Domínio Catalítico , Proteínas de Ligação a DNA , Ativação Enzimática , Estabilidade Enzimática , Proteínas F-Box/genética , Genótipo , Quinase 3 da Glicogênio Sintase/genética , Mutação , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Fenótipo , Plantas Geneticamente Modificadas/enzimologia , Plantas Geneticamente Modificadas/genética , Complexo de Endopeptidases do Proteassoma/metabolismo , Ligação Proteica , Proteínas Quinases/genética , Proteólise , Transdução de Sinais/efeitos dos fármacos , Especificidade por Substrato , Ubiquitina-Proteína Ligases/genética , Ubiquitinação
2.
J Am Chem Soc ; 146(5): 3449-3457, 2024 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-38268407

RESUMO

The core features of covalent organic frameworks (COFs) are crystallinity and porosity. However, the synthesis of single-crystal COFs with monomers of diverse reactivity and adjustment of their pore structures remain challenging. Here, we show that linkers that can react with a node to form single-crystal COFs can guide other linkers that form either COFs or amorphous polymers with the node to gain single-crystal COFs with mixed components, which are homogeneous on the unit cell scale with controlled ratios. With the linker-guided crystal growth method, we created nine types of single-crystal COFs with up to nine different components, which are more complex than any known crystal. The structure of the crystal adapted approximately to that of the main component, and its pore volume could be expanded up to 8.8%. Different components lead to complex and diverse pore structures and offer the possibilities to gain positive synergies, as exemplified by a bicomponent COF with 2200 and 733% SO2 uptake capacity of that of the two pure-component counterparts at 298 K and 0.002 bar. The selectivity for separation of SO2/CO2 ranges from 1230 to 4247 for flue gas based on ideal adsorbed solution theory, recording porous crystals. The bicomponent COF also exhibits a 1300% retention time of its pure-component counterparts for SO2 in a dynamic column breakthrough experiment for deep desulfurization.

3.
J Nanobiotechnology ; 22(1): 469, 2024 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-39113060

RESUMO

On a global note, oral health plays a critical role in improving the overall human health. In this vein, dental-related issues with dentin exposure often facilitate the risk of developing various oral-related diseases in gums and teeth. Several oral-based ailments include gums-associated (gingivitis or periodontitis), tooth-based (dental caries, root infection, enamel erosion, and edentulous or total tooth loss), as well as miscellaneous diseases in the buccal or oral cavity (bad breath, mouth sores, and oral cancer). Although established conventional treatment modalities have been available to improve oral health, these therapeutic options suffer from several limitations, such as fail to eradicate bacterial biofilms, deprived regeneration of dental pulp cells, and poor remineralization of teeth, resulting in dental emergencies. To this end, the advent of nanotechnology has resulted in the development of various innovative nanoarchitectured composites from diverse sources. This review presents a comprehensive overview of different nanoarchitectured composites for improving overall oral health. Initially, we emphasize various oral-related diseases, providing detailed pathological circumstances and their effects on human health along with deficiencies of the conventional therapeutic modalities. Further, the importance of various nanostructured components is emphasized, highlighting their predominant actions in solving crucial dental issues, such as anti-bacterial, remineralization, and tissue regeneration abilities. In addition to an emphasis on the synthesis of different nanostructures, various nano-therapeutic solutions from diverse sources are discussed, including natural (plant, animal, and marine)-based components and other synthetic (organic- and inorganic-) architectures, as well as their composites for improving oral health. Finally, we summarize the article with an interesting outlook on overcoming the challenges of translating these innovative platforms to clinics.


Assuntos
Nanoestruturas , Saúde Bucal , Humanos , Nanoestruturas/química , Nanoestruturas/uso terapêutico , Animais , Doenças da Boca/tratamento farmacológico , Nanotecnologia/métodos , Cárie Dentária
4.
J Nanobiotechnology ; 22(1): 353, 2024 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-38902759

RESUMO

Chemotherapy and immunotherapy have shown no significant outcome for unresectable pancreatic ductal adenocarcinoma (PDAC). Multi-drug combination therapy has become a consensus in clinical trials to explore how to arouse anti-tumor immunity and meanwhile overcome the poorly tumoricidal effect and the stroma barrier that greatly hinders drug penetration. To address this challenge, a comprehensive strategy is proposed to fully utilize both the ferroptotic vulnerability of PDAC to potently irritate anti-tumor immunity and the desmoplasia-associated focal adhesion kinase (FAK) to wholly improve the immunosuppressive microenvironment via sustained release of drugs in an injectable hydrogel for increasing drug penetration in tumor location and averting systematic toxicity. The injectable hydrogel ED-M@CS/MC is hybridized with micelles loaded with erastin that exclusively induces ferroptosis and a FAK inhibitor defactinib for inhibiting stroma formation, and achieves sustained release of the drugs for up to 12 days. With only a single intratumoral injection, the combination treatment with erastin and defactinib produces further anti-tumor performance both in xenograft and KrasG12D-engineered primary PDAC mice and synergistically promotes the infiltration of CD8+ cytotoxic T cells and the reduction of type II macrophages. The findings may provide a novel promising strategy for the clinical treatment of PDAC.


Assuntos
Carcinoma Ductal Pancreático , Hidrogéis , Neoplasias Pancreáticas , Animais , Hidrogéis/química , Carcinoma Ductal Pancreático/tratamento farmacológico , Camundongos , Neoplasias Pancreáticas/tratamento farmacológico , Humanos , Linhagem Celular Tumoral , Microambiente Tumoral/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Sinergismo Farmacológico , Micelas , Imunoterapia/métodos
5.
J Environ Sci (China) ; 146: 39-54, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38969461

RESUMO

To improve the selective separation performance of silica nanofibers (SiO2 NFs) for cesium ions (Cs+) and overcome the defects of Prussian blue nanoparticles (PB NPs), PB/SiO2-NH2 NFs were prepared to remove Cs+ from water. Among them, 3-aminopropyltriethoxysilane (APTES) underwent an alkylation reaction with SiO2, resulting in the formation of a dense Si-O-Si network structure that decorated the surface of SiO2 NFs. Meanwhile, the amino functional groups in APTES combined with Fe3+ and then reacted with Fe2+ to form PB NPs, which anchored firmly on the aminoated SiO2 NFs surface. In our experiment, the maximum adsorption capacity of PB/SiO2-NH2 NFs was 111.38 mg/g, which was 31.5 mg/g higher than that of SiO2 NFs. At the same time, after the fifth cycle, the removal rate of Cs+ by PB/SiO2-NH2 NFs adsorbent was 75.36% ± 3.69%. In addition, the adsorption isotherms and adsorption kinetics of PB/SiO2-NH2 NFs were combined with the Freundlich model and the quasi-two-stage fitting model, respectively. Further mechanism analysis showed that the bond between PB/SiO2-NH2 NFs and Cs+ was mainly a synergistic action of ion exchange, electrostatic adsorption and membrane separation.


Assuntos
Césio , Ferrocianetos , Nanofibras , Nanopartículas , Poluentes Químicos da Água , Purificação da Água , Ferrocianetos/química , Nanofibras/química , Poluentes Químicos da Água/química , Césio/química , Adsorção , Purificação da Água/métodos , Nanopartículas/química , Dióxido de Silício/química , Cinética , Propilaminas/química , Silanos
6.
Angew Chem Int Ed Engl ; 63(7): e202317773, 2024 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-38116827

RESUMO

Enzyme-activatable near-infrared (NIR) fluorescent probes and photosensitizers (PSs) have emerged as promising tools for molecular imaging and photodynamic therapy (PDT). However, in living organisms selective retention or even enrichment of these reagents after enzymatic activation at or near sites of interest remains a challenging task. Herein, we integrate non-covalent and covalent retention approaches to introduce a novel "1-to-3" multi-effect strategy-one enzymatic stimulus leads to three types of effects-for the design of an enzyme-activatable NIR probe or PS. Using this strategy, we have constructed an alkaline phosphatase (ALP)-activatable NIR fluorogenic probe and a NIR PS, which proved to be selectively activated by ALP to switch on NIR fluorescence or photosensitizing ability, respectively. Additionally, these reagents showed significant enrichment (over 2000-fold) in ALP-overexpressed tumor cells compared to the culture medium, accompanied by massive depletion of intracellular thiols, the major antioxidants in cells. The investigation of this ALP-activatable NIR PS in an in vivo PDT model resulted in complete suppression of HeLa tumors and full recovery of all tested mice. Encouragingly, even a single administration of this NIR PS was sufficient to completely suppress tumors in mice, demonstrating the high potential of this strategy in biomedical applications.


Assuntos
Fotoquimioterapia , Fármacos Fotossensibilizantes , Humanos , Camundongos , Animais , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Células HeLa , Corantes Fluorescentes , Fosfatase Alcalina
7.
J Am Chem Soc ; 145(40): 22079-22085, 2023 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-37784238

RESUMO

Due to the enormous chemical and structural diversities and designable properties and functionalities, covalent organic frameworks (COFs) hold great promise as tailored materials for industrial applications in electronics, biology, and energy technologies. They were typically obtained as partially crystalline materials, although a few single-crystal three-dimensional (3D) COFs have been obtained recently with structures probed by diffraction techniques. However, it remains challenging to grow single-crystal COFs with controlled morphology and to elucidate the local structures of 3D COFs, imposing severe limitations on the applications and understanding of the local structure-property correlations. Herein, we develop a method for designed growth of five types of single crystalline flakes of 3D COFs with controlled morphology, front crystal facets, and defined edge structures as well as surface chemistry using surfactants that can be self-assembled into layered structures to confine crystal growth in water. The flakes enable direct observation of local structures including monomer units, pore structure, edge structure, grain boundary, and lattice distortion of 3D COFs as well as gradually curved surfaces in kinked but single crystalline 3D COFs with a resolution of up to ∼1.7 Å. In comparison with flakes of two-dimensional crystals, the synthesized flakes show much higher chemical, mechanical, and thermal stability.

8.
Anal Chem ; 95(12): 5443-5453, 2023 03 28.
Artigo em Inglês | MEDLINE | ID: mdl-36930753

RESUMO

The detection of hydrogen sulfide (H2S), the third gas signaling molecule, is a promising strategy for identifying the occurrence of certain diseases. However, the conventional single- or dual-signal detection can introduce false-positive or false-negative results, which ultimately decreases the diagnostic accuracy. To address this limitation, we developed a luminescent, photothermal, and electrochemical triple-signal detection platform by optically trapping the synthetic highly doped upconversion coupled SiO2 microbeads coated with metal-organic frameworks H-UCNP-SiO2@HKUST-1 (H-USH) to detect the concentration of H2S. The H-USH was first synthesized and proved to have stable structure and excellent luminescent, photothermal, and electrochemical properties. Under 980 nm optical trapping and 808 nm irradiation, H-USH showed great detection linearity, a low limit of detection, and high specificity for H2S quantification via triple-signal detection. Moreover, H-USH was captured by optical tweezers to realize quantitative detection of H2S content in serum of acute pancreatitis and spontaneously hypertensive rats. Finally, by analyzing the receiver operating characteristic (ROC) curve, we concluded that triple-signal detection of H2S was more accurate than single- or dual-signal detection, which overcame the problem of false-negative/positive results in the detection of H2S in actual serum samples.


Assuntos
Sulfeto de Hidrogênio , Pancreatite , Ratos , Animais , Sulfeto de Hidrogênio/química , Luminescência , Eletroquímica , Doença Aguda , Dióxido de Silício , Microesferas
9.
Anal Chem ; 95(37): 14086-14093, 2023 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-37665143

RESUMO

In recent years, optical tweezers have become a novel tool for biodetection, and to improve the inefficiency of a single trap, the development of multitraps is required. Herein, we constructed a set of hybrid multitrap optical tweezers with the balance of stability and flexibility by the combination of two different beam splitters, a diffraction optical element (DOE) and galvano mirrors (GMs), to capture polystyrene (PS) microbeads in aqueous solutions to create an 18-trap suspended array. A sandwich hybridization strategy of DNA-miRNA-DNA was adopted to detect three kinds of target miRNAs associated with triple negative breast cancer (TNBC), in which different upconversion nanoparticles (UCNPs) with red, green, and blue emissions were applied as luminescent tags to encode the carrier PS microbeads to further indicate the levels of the targets. With encoded luminescent microbeads imaged by a three-channel microscopic system, the biodetection displayed high sensitivity with low limits of detection (LODs) of 0.27, 0.32, and 0.33 fM and exceptional linear ranges of 0.5 fM to 1 nM, 0.7 fM to 1 nM, and 1 fM to 1 nM for miR-343-3p, miR-155, and miR-199a-5p, respectively. In addition, this bead-based assay method was demonstrated to have the potential for being applied in patients' serum by satisfactory standard addition recovery experiment results.


Assuntos
MicroRNAs , Humanos , MicroRNAs/genética , Microesferas , Pinças Ópticas , Poliestirenos
10.
Small ; 19(35): e2301670, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37098629

RESUMO

As an alternative to traditional oral and intravenous injections with limited efficacy, transdermal drug delivery (TDD) has shown great promise in tumor treatment. Over the past decade, natural polymers have been designed into various nanocarriers due to their excellent biocompatibility, biodegradability, and easy availability, providing more options for TDD. In addition, surface functionalization modification of the rich functional groups of natural polymers, which in turn are developed into targeted and stimulus-responsive functional materials, allows precise delivery of drugs to tumor sites and release of drugs in response to specific stimuli. It not only improves the treatment efficiency of tumor but also reduces the toxic and side effects to normal tissues. Therefore, the development of natural polymer-based TDD (NPTDD) systems has great potential in tumor therapy. In this review, the mechanism of NPTDD systems such as penetration enhancers, nanoparticles, microneedles, hydrogels and nanofibers prepared from hyaluronic acid, chitosan, sodium alginate, cellulose, heparin and protein, and their applications in tumor therapy are overviewed. This review also outlines the future prospects and current challenges of NPTDD systems for local treatment tumors.


Assuntos
Sistemas de Liberação de Medicamentos , Polímeros , Administração Cutânea , Portadores de Fármacos , Alginatos
11.
Arch Biochem Biophys ; 737: 109552, 2023 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-36828260

RESUMO

Upon ER stress, IRE1α is activated to splice XBP1 mRNA to generate XBP1s, a transcription factor that induces the expression of genes to cope with the stress. Expression of IRE1α is elevated in cancers and the IRE1α-XBP1s axis plays an important role in proliferation of cancer cells. However, the underlying mechanism is not well known. We found that ER stressors induced the expression of IRE1α, which was inhibited by depletion of XBP1s. XBP1s bound IRE1α promoter and initiated the transcription of IRE1α. These data indicate that XBP1s acts as a transcription factor of IRE1α. Overexpression of XBP1s increased the phosphorylation of JNK, a substrate of IRE1α kinase, which was inhibited by IRE1α kinase inhibitor Kira8. Overexpression of XBP1s also activated the regulated IRE1-dependent decay of mRNAs, which was suppressed by IRE1α RNase inhibitor STF083010. Moreover, we found that expression of XBP1s promoted proliferation of colon cancer cells, which was abrogated by Kira8 and STF083010. The results suggest that XBP1s functions to induce IRE1α expression and promote cancer cell proliferation. Our findings reveal a previously unknown mechanism of IRE1α expression by XBP1s and highlight the role of this regulation in proliferation of colon cancer cells, suggesting that IRE1α-targeting is a potential therapeutic strategy for colon cancer.


Assuntos
Neoplasias do Colo , Proteínas Serina-Treonina Quinases , Humanos , Proteínas Serina-Treonina Quinases/metabolismo , Fatores de Transcrição/metabolismo , Endorribonucleases , Proliferação de Células , Estresse do Retículo Endoplasmático , Proteína 1 de Ligação a X-Box/metabolismo
12.
BMC Cancer ; 23(1): 1117, 2023 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-37974093

RESUMO

BACKGROUND: RAS mutations affect prognosis in patients with metastatic colorectal cancer (mCRC) and have been identified as strong negative predictive markers for anti-epidermal growth factor receptor monoclonal antibody (anti-EGFR mAb) therapy, but many tumors containing wild-type RAS genes still do not respond to these therapies. Some additional biomarkers may have prognostic or predictive roles, but conclusions remain controversial. METHODS: We performed a meta-analysis and systematic review of randomized controlled trials comparing anti-EGFR mAb therapy with alternative therapy that investigated the prognostic and predictive impact of additional biomarkers in RAS wild-type (wt) mCRC patients. Hazard ratios (HRs) and 95% confidence intervals (CIs) for progression-free survival (PFS) and overall survival (OS) and odds ratios (ORs) for objective response rate (ORR) were calculated. The prognostic value of biomarkers was investigated by separately pooling HR and OR for different treatment groups in an individual study. The predictive value was assessed by pooling study interactions between treatment effects and biomarker subgroups. RESULTS: Thirty publications reporting on eighteen trials were selected, including a total of 13,507 patients. In prognostic analysis, BRAF mutations were associated with poorer PFS [HRs = 3.76 (2.47-5.73) and 2.69 (1.82-3.98)] and OS [HRs = 2.66 (1.95-3.65) and 2.45 (1.55-3.88)] in both the experimental and control arms; low miR-31-3p expression appeared to have longer PFS and OS. In terms of predictive effect, a lack of response to anti-EGFR therapy was observed in patients with BRAF mutant tumors (Pinteraction < 0.01 for PFS). Patients with tumors with any mutation in the KRAS/NRAS/BRAF/PIK3CA gene also showed similar results compared with all wild-type tumors (Pinteraction for PFS, OS, and ORR were < 0.01, < 0.01 and 0.01, respectively). While low miR-31-3p expression could predict PFS (Pinteraction = 0.01) and OS (Pinteraction = 0.04) benefit. The prognostic and predictive value regarding PIK3CA mutations, PTEN mutations or deletions, EGFR, EREG/AREG, HER2, HER3, and HER4 expression remains uncertain. CONCLUSIONS: In RAS wt mCRC patients receiving EGFR-targeted therapy, BRAF mutation is a powerful prognostic and therapy-predictive biomarker, with no effect found for PIK3CA mutation, PTEN mutation or deletion, but the combined biomarker KRAS/NRAS/BRAF/PIK3CA mutations predict resistance to anti-EGFR therapy. Low miR-31-3p expression may have positive prognostic and therapy predictive effects. Evidence on the prognostic and predictive roles of EGFR and its ligands, and HER2/3/4 is insufficient.


Assuntos
Neoplasias do Colo , Neoplasias Colorretais , MicroRNAs , Neoplasias Retais , Humanos , Prognóstico , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Receptores ErbB/genética , Receptores ErbB/metabolismo , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais/metabolismo , Biomarcadores , Classe I de Fosfatidilinositol 3-Quinases/genética , Mutação , Biomarcadores Tumorais/genética
13.
J Memb Sci ; 672: 121257, 2023 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-36593802

RESUMO

Coronavirus disease 2019 (COVID-19) pandemic makes protective respirators highly demanded. The respirator materials should filter out viral fine aerosols effectively, allow airflow to pass through easily, and wick away the exhalant moisture timely. However, the commonly used melt-blown nonwovens perform poorly in meeting these requirements simultaneously. Herein, dual-bionic nano-groove structured (NGS) nanofibers are fabricated to serve as protective, breathable and moisture-wicking respirator materials. The creativity of this design is that the tailoring of dual-bionic nano-groove structure, combined with the strong polarity and hydrophilicity of electrospinning polymer, not only endows the nanofibrous materials with improved particle capture ability but also enable them to wick away and transmit breathing moisture. Benefitting from the synthetic effect of hierarchical structure and the intrinsic property of polymers, the resulting NGS nanofibrous membranes show a high filtration efficiency of 99.96%, a low pressure drop of 110 Pa, and a high moisture transmission rate of 5.67 kg m-2 d-1 at the same time. More importantly, the sharp increase of breathing resistance caused by the condensation of exhaled moisture is avoided, overcoming the bottleneck faced by traditional nonwovens and paving a new way for developing protective respirators with high wear comfortability.

14.
Acta Biochim Biophys Sin (Shanghai) ; 55(11): 1749-1757, 2023 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-37814811

RESUMO

Prolyl hydroxylase 3 (PHD3) hydroxylates HIFα in the presence of oxygen, leading to HIFα degradation. PHD3 inhibits tumorigenesis. However, the underlying mechanism is not well understood. Herein, we demonstrate that PHD3 inhibits the metastasis of colon cancer cells through the occludin-p38 MAPK pathway independent of its hydroxylase activity. We find that PHD3 inhibits colon cancer cell metastasis in the presence of the PHD inhibitor DMOG, and prolyl hydroxylase-deficient PHD3(H196A) suppresses cell metastasis as well. PHD3 controls the stability of the tight junction protein occludin in a hydroxylase-independent manner. We further find that PHD3-inhibited colon cancer cell metastasis is rescued by knockdown of occludin and that occludin acts as a negative regulator of cell metastasis, implying that PHD3 suppresses metastasis through occludin. Furthermore, knockdown of occludin induces phosphorylation of p38 MAPK, and the p38 inhibitor SB203580 impedes cell migration and invasion induced by occludin knockdown, indicating that occludin functions through p38. Moreover, knockdown of occludin enhances the expression of MKK3/6, the upstream kinase of p38, while overexpression of occludin decreases its expression. Our results suggest that PHD3 inhibits the metastasis of colon cancer cells through the occludin-p38 pathway independent of its hydroxylase activity. These findings reveal a previously undiscovered mechanism underlying the regulation of cancer cell metastasis by PHD3 and highlight a noncanonical hydroxylase-independent function of PHD3 in the suppression of cancer cells.


Assuntos
Neoplasias do Colo , Neoplasias Retais , Humanos , Prolil Hidroxilases , Ocludina/genética , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Pró-Colágeno-Prolina Dioxigenase , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
15.
Diabetes Metab Res Rev ; 38(2): e3498, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34587332

RESUMO

AIMS: The aim of this study was to evaluate the association of time in range (TIR) with amputation and all-cause mortality in hospitalised patients with diabetic foot ulcers (DFUs). MATERIALS AND METHODS: A retrospective analysis was performed on 303 hospitalised patients with DFUs. During hospitalisation, TIR, mean blood glucose (MBG), coefficient of variation (CV), time above range (TAR) and time below range (TBR) of patients were determined from seven-point blood glucose profiles. Participants were grouped based on their clinical outcomes (i.e., amputation and death). Logistic regression was employed to analyse the association of TIR with amputation and all-cause mortality of inpatients with DFUs. RESULTS: Among the 303 enrolled patients, 50 (16.5%) had undergone amputation whereas seven (2.3%) were deceased. Blood glucose was determined in 41,012 samples obtained from all participants. Patients who underwent amputation had significantly lower TIR and higher MBG, CV, level 2 TAR and level 1 TBR whereas deceased patients had significantly lower TIR and higher MBG and level 2 TAR. Both amputation and all-cause mortality rate declined with an increase in TIR quartiles. Logistic regression showed association of TIR with amputation (p = 0.034) and all-cause mortality (p = 0.013) after controlling for 15 confounders. This association was similarly significant in all-cause mortality after further adjustment for CV (p = 0.022) and level 1 TBR (p = 0.021), respectively. CONCLUSIONS: TIR is inversely associated with amputation and all-cause mortality of hospitalised patients with DFUs. Further prospective studies are warranted to establish a causal relationship between TIR and clinical outcomes in patients with DFUs.


Assuntos
Diabetes Mellitus , Pé Diabético , Amputação Cirúrgica , Glicemia/análise , Automonitorização da Glicemia , Pé Diabético/complicações , Pé Diabético/cirurgia , Humanos , Estudos Retrospectivos
16.
Macromol Rapid Commun ; 43(17): e2200250, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35524950

RESUMO

2D polymer nanonets have demonstrated great potential in various application fields due to their integrated advantages of ultrafine diameter, small pore size, high porosity, excellent interconnectivity, and large specific surface area. Here, a comprehensive overview of the controlled constructions of the polymer nanonets derived from electrospinning/netting, direct electronetting, self-assembly of cellulose nanofibers, and nonsolvent-induced phase separation is provided. Then, the widely researched multifunctional applications of polymer nanonets in filtration, sensor, tissue engineering, and electricity are also given. Finally, the challenges and possible directions for further developing the polymer nanonets are also intensively highlighted.


Assuntos
Nanofibras , Polímeros , Celulose , Porosidade , Engenharia Tecidual
17.
Sensors (Basel) ; 22(7)2022 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-35408323

RESUMO

Copper ion is closely associated with the ecosystem and human health, and even a little excessive dose in drinking water may result in a range of health problems. However, it remains challenging to produce a highly sensitive, reliable, cost-effective and electromagnetic-interference interference-immune device to detect Cu2+ ion in drinking water. In this paper, a taper-in-taper fiber sensor was fabricated with high sensitivity by mode-mode interference and deposited polyelectrolyte layers for Cu2+ detection. We propose a new structure which forms a secondary taper in the middle of the single-mode fiber through two-arc discharge. Experimental results show that the newly developed fiber sensor possesses a sensitivity of 2741 nm/RIU in refractive index (RI), exhibits 3.7 times sensitivity enhancement when compared with traditional tapered fiber sensors. To apply this sensor in copper ions detection, the results present that when the concentration of Cu2+ is 0-0.1 mM, the sensitivity could reach 78.03 nm/mM. The taper-in-taper fiber sensor exhibits high sensitivity with good stability and mechanical strength which has great potential to be applied in the detection of low Cu2+ ions in some specific environments such as drinking water.


Assuntos
Água Potável , Fibras Ópticas , Cobre , Ecossistema , Humanos , Íons
18.
Int Wound J ; 19(4): 910-918, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-34520110

RESUMO

Diabetic foot ulcer (DFU) is one of the most serious and alarming diabetic complications, which often leads to high amputation rates in diabetic patients. Machine learning is a part of the field of artificial intelligence, which can automatically learn models from data and better inform clinical decision-making. We aimed to develop an accurate and explainable prediction model to estimate the risk of in-hospital amputation in patients with DFU. A total of 618 hospitalised patients with DFU were included in this study. The patients were divided into non-amputation, minor amputation or major amputation group. Light Gradient Boosting Machine (LightGBM) and 5-fold cross-validation tools were used to construct a multi-class classification model to predict the three outcomes of interest. In addition, we used the SHapley Additive exPlanations (SHAP) algorithm to interpret the predictions of the model. Our area under the receiver-operating-characteristic curve (AUC) demonstrated a 0.90, 0.85 and 0.86 predictive ability for non-amputation, minor amputation and major amputation outcomes, respectively. Taken together, our data demonstrated that the developed explainable machine learning model provided accurate estimates of the amputation rate in patients with DFU during hospitalisation. Besides, the model could inform individualised analyses of the patients' risk factors.


Assuntos
Diabetes Mellitus , Pé Diabético , Amputação Cirúrgica/efeitos adversos , Inteligência Artificial , Pé Diabético/etiologia , Pé Diabético/cirurgia , Hospitais , Humanos , Aprendizado de Máquina
19.
Int Wound J ; 19(6): 1289-1297, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34818691

RESUMO

This study aimed to explore the clinical characteristic and outcomes of inpatients with diabetic foot ulceration (DFU) in 2019 (prelockdown) and 2020 (postlockdown) due to the COVID-19 pandemic, at an emergency medical service unit. Prediction models for mortality and amputation were developed to describe the risk factors using a machine learning-based approach. Hospitalized DFU patients (N = 23) were recruited after the lockdown in 2020 and matched with corresponding inpatients (N = 23) before lockdown in 2019. Six widely used machine learning models were built and internally validated using 3-fold cross-validation to predict the risk of amputation and death in DFU inpatients under the COVID-19 pandemic. Previous DF ulcers, prehospital delay, and mortality were significantly higher in 2020 compared to 2019. Diabetic foot patients in 2020 had higher hs-CRP levels (P = .037) but lower hemoglobin levels (P = .017). The extreme gradient boosting (XGBoost) performed best in all models for predicting amputation and mortality with the highest area under the curve (0.86 and 0.94), accuracy (0.80 and 0.90), sensitivity (0.67 and 1.00), and negative predictive value (0.86 and 1.00). A long delay in admission and a higher risk of mortality was observed in patients with DFU who attended the emergency center during the COVID-19 post lockdown. The XGBoost model can provide evidence-based risk information for patients with DFU regarding their amputation and mortality. The prediction models would benefit DFU patients during the COVID-19 pandemic.


Assuntos
COVID-19 , Diabetes Mellitus , Pé Diabético , Úlcera do Pé , Amputação Cirúrgica , Proteína C-Reativa , Controle de Doenças Transmissíveis , Pé Diabético/epidemiologia , Hemoglobinas , Humanos , Pacientes Internados , Aprendizado de Máquina , Pandemias , Úlcera
20.
Anal Chem ; 92(22): 15017-15024, 2020 11 17.
Artigo em Inglês | MEDLINE | ID: mdl-33141566

RESUMO

γ-Glutamyl transpeptidase (GGT), a type of cell membrane-bound enzyme, is closely involved in a wide range of physiological and pathological processes, and a large number of fluorogenic probes have been developed to detect the activity of GGT. However, the use of these imaging reagents to visualize GGT activity in vivo is largely limited because of rapid diffusion and clearance of activated fluorophores. Herein, by merging quinone methide and a fluorogenic enzyme substrate, we report an activatable self-immobilizing near-infrared probe for the in vitro and in vivo imaging of GGT activity. This probe is initially fluorescently silent, but the selective activation by GGT is able to significantly increase its fluorescence intensity at 714 nm and covalently anchor activated fluorophores at the site of interest. We have shown that this probe induced a much stronger fluorescence on live GGT-overexpressing cells compared to regular fluorogenic probes and allowed wash-free and real-time imaging of enzyme activity. More importantly, the use of this probe in the imaging of GGT activity in U87MG tumor-bearing mice by i.v. administration indicates that this self-immobilizing reagent is capable of efficiently enhancing its retention at the detection target and thus leads to much improved detection sensitivity compared to regular fluorogenic probes. This study demonstrates the advantage of fluorogenic probes with activatable anchors in the noninvasive imaging of enzyme activity in highly dynamic in vivo systems.


Assuntos
Corantes Fluorescentes/química , Raios Infravermelhos , Imagem Molecular/métodos , gama-Glutamiltransferase/metabolismo , Animais , Linhagem Celular Tumoral , Humanos , Camundongos , gama-Glutamiltransferase/química
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