Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 125
Filtrar
1.
J Biol Chem ; 299(11): 105351, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37838174

RESUMO

Breast cancer stem cells are mainly responsible for poor prognosis, especially in triple-negative breast cancer (TNBC). In a previous study, we demonstrated that ε-Sarcoglycan (SGCE), a type Ⅰ single-transmembrane protein, is a potential oncogene that promotes TNBC stemness by stabilizing EGFR. Here, we further found that SGCE depletion reduces breast cancer stem cells, partially through inhibiting the transcription of FGF-BP1, a secreted oncoprotein. Mechanistically, we demonstrate that SGCE could interact with the specific protein 1 transcription factor and translocate into the nucleus, which leads to an increase in the transcription of FGF-BP1, and the secreted FBF-BP1 activates FGF-FGFR signaling to promote cancer cell stemness. The novel SGCE-Sp1-FGF-BP1 axis provides novel potential candidate diagnostic markers and therapeutic targets for TNBC.


Assuntos
Células-Tronco Neoplásicas , Sarcoglicanas , Fator de Transcrição Sp1 , Neoplasias de Mama Triplo Negativas , Humanos , Linhagem Celular Tumoral , Proliferação de Células , Células-Tronco Neoplásicas/metabolismo , Sarcoglicanas/metabolismo , Transdução de Sinais , Fator de Transcrição Sp1/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo
2.
Cancer Immunol Immunother ; 73(11): 225, 2024 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-39235488

RESUMO

BACKGROUND: Genome instability (GI) is a hallmark of esophageal squamous cell carcinoma (ESCC) while factors affecting GI remain unclear. METHODS: Here, we aimed to characterize genomic events representing specific mechanisms of GI based on 201 ESCC samples and validated our findings at the patient, single-cell and cancer cell-line levels, including a newly generated multi-omics dataset of the trial NCT04006041. RESULTS: A two-gene (AHNAK and AHNAK2) mutation signature was identified to define the "AHNAK1/2-mutant" cancer subtype. Single-cell-assisted multi-omics analysis showed that this subtype had a higher neoantigen load, active antigen presentation, and proficient CD8 + T cell infiltrations, which were validated at pan-cancer levels. Mechanistically, AHNAK1/2-mutant ESCC was characterized by impaired response of TGF-ß and the inefficient alternative end-join repair (Alt-EJ) that might promote GI. Knockdown of AHNAK in ESCC cell lines resulted in more Alt-EJ events and increased sensitivities to cisplatin. Furthermore, this two-gene signature accurately predicted better responses to DNA-damaging therapy in various clinical settings (HR ≈ 0.25). The two-gene signature predicted higher pCR rates in ESCCs receiving neoadjuvant immunotherapy-involved treatment. Finally, a molecular classification scheme was built and outperformed established molecular typing models in the prognosis stratification of ESCC patients. CONCLUSION: Our study extended our understanding of the AHNAK family in promoting GI and selecting treatment responders of ESCC.


Assuntos
Neoplasias Esofágicas , Imunoterapia , Proteínas de Membrana , Proteínas de Neoplasias , Fator de Crescimento Transformador beta , Animais , Feminino , Humanos , Masculino , Camundongos , Linhagem Celular Tumoral , Proteínas do Citoesqueleto , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/terapia , Neoplasias Esofágicas/imunologia , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/terapia , Carcinoma de Células Escamosas do Esôfago/imunologia , Carcinoma de Células Escamosas do Esôfago/patologia , Imunoterapia/métodos , Proteínas de Membrana/genética , Mutação , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/imunologia , Prognóstico , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo
3.
J Med Virol ; 96(9): e29922, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39295292

RESUMO

This study retrospectively analyzed the genetic characteristics of influenza A H3N2 (A/H3N2) viruses circulating in New South Wales (NSW), the Australian state with the highest number of influenza cases in 2022, and explored the phylodynamics of A/H3N2 transmission within Australia during this period. Sequencing was performed on 217 archived specimens, and A/H3N2 evolution and spread within Australia were analyzed using phylogenetic and phylodynamic methods. Hemagglutinin genes of all analyzed NSW viruses belonged to subclade 3C.2a1b.2a.2 and clustered together with the 2022 vaccine strain. Complete genome analysis of NSW viruses revealed highly frequent interclade reassortments between subclades 3C.2a1b.2a.2 and 3C.2a1b.1a. The estimated earliest introduction time of the dominant subgroup 3C.2a1b.2a.2a.1 in Australia was February 22, 2022 (95% highest posterior density: December 19, 2021-March 13, 2022), following the easing of Australian travel restrictions, suggesting a possible international source. Phylogeographic analysis revealed that Victoria drove the transmission of A/H3N2 viruses across the country during this season, while NSW did not have a dominant role in viral dissemination to other regions. This study highlights the importance of continuous surveillance and genomic characterization of influenza viruses in the postpandemic era, which can inform public health decision-making and enable early detection of novel strains with pandemic potential.


Assuntos
COVID-19 , Vírus da Influenza A Subtipo H3N2 , Influenza Humana , Filogenia , Humanos , Vírus da Influenza A Subtipo H3N2/genética , Vírus da Influenza A Subtipo H3N2/classificação , Vírus da Influenza A Subtipo H3N2/isolamento & purificação , Influenza Humana/epidemiologia , Influenza Humana/virologia , Influenza Humana/transmissão , Estudos Retrospectivos , COVID-19/epidemiologia , COVID-19/transmissão , COVID-19/virologia , COVID-19/prevenção & controle , Austrália/epidemiologia , New South Wales/epidemiologia , SARS-CoV-2/genética , SARS-CoV-2/classificação , Filogeografia , Estações do Ano , Genoma Viral/genética , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Vírus Reordenados/genética , Vírus Reordenados/classificação
4.
Bioorg Chem ; 147: 107367, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38626492

RESUMO

Lung cancer is the leading cause of cancer deaths worldwide. Non-small cell lung cancer (NSCLC) accounts for 80-85% of all lung cancers. Euphorbia kansui yielded 13-oxyingenol-dodecanoate (13OD), an ingenane-type diterpenoid, which had a strong cytotoxic effect on NSCLC cells. The underlying mechanism and potential target, however, remained unknown. The study found that 13OD effectively inhibited the cell proliferation and colony formation of NSCLC cells (A549 and H460 cells), with less toxicity in normal human lung epithelial BEAS-2B cells. Moreover, 13OD can cause mitochondrial dysfunction, and apoptosis in NSCLC cells. Mechanistically, the transcriptomics results showed that differential genes were mainly enriched in the mTOR and AMPK signaling pathways, which are closely related to cellular autophagy, the related indicators were subsequently validated. Additionally, bafilomycin A1 (Baf A1), an autophagy inhibitor, reversed the mitochondrial damage caused by 13OD. Furthermore, the Omics and Text-based Target Enrichment and Ranking (OTTER) method predicted ULK1 as a potential target of 13OD against NSCLC cells. This hypothesis was further confirmed using molecular docking, the cellular thermal shift assay (CETSA), and Western blot analysis. Remarkably, ULK1 siRNA inhibited 13OD's toxic activity in NSCLC cells. In line with these findings, 13OD was potent and non-toxic in the tumor xenograft model. Our findings suggested a possible mechanism for 13OD's role as a tumor suppressor and laid the groundwork for identifying targets for ingenane-type diterpenoids.


Assuntos
Proteína Homóloga à Proteína-1 Relacionada à Autofagia , Carcinoma Pulmonar de Células não Pequenas , Proliferação de Células , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Proliferação de Células/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Relação Estrutura-Atividade , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/metabolismo , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/antagonistas & inibidores , Estrutura Molecular , Diterpenos/farmacologia , Diterpenos/química , Apoptose/efeitos dos fármacos , Animais , Camundongos , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/química , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química
5.
J Asian Nat Prod Res ; : 1-13, 2024 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-38347741

RESUMO

Gastric cancer is one of the common malignant tumors. It is reported that daphne-type diterpenes have inhibitory effects on gastric cancer cells, but the mechanism is still unknown. To explore the detailed mechanism of the anticancer effect of daphne-type diterpenes, we carried out an integrated network pharmacology prediction study and selected an effective component (yuanhuacine, YHC) for the following validation in silico and in vitro. The result showed that daphne-type diterpenes exerted an anti-tumor effect by targeting proto-oncogene tyrosine-protein kinase SRC as well as regulating the Ras/MAPK signaling pathway, which caused the apoptosis and mitochondrial damage in gastric cancer cells.

6.
Angew Chem Int Ed Engl ; 63(37): e202406246, 2024 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-38934471

RESUMO

Terpene synthases (TPSs) play pivotal roles in generating diverse terpenoids through complex cyclization pathways. Protein engineering of TPSs offers a crucial approach to expanding terpene diversity. However, significant potential remains untapped due to limited understanding of the structure-function relationships of TPSs. In this investigation, using a joint approach of molecular dynamics simulations-assisted engineering and site-directed mutagenesis, we manipulated the aromatic residue cluster (ARC) of a bifunctional terpene synthase (BFTPS), Pestalotiopsis fici nigtetraene synthase (PfNS). This led to the discovery of previously unreported catalytic functions yielding different cyclization patterns of sesterterpenes. Specifically, a quadruple variant (F89A/Y113F/W193L/T194W) completely altered PfNS's function, converting it from producing the bicyclic sesterterpene nigtetraene to the tricyclic ophiobolin F. Additionally, analysis of catalytic profiles by double, triple, and quadruple variants demonstrated that the ARC functions as a switch, unprecedently redirecting the production of 5/11 bicyclic (Type B) sesterterpenes to 5/15 bicyclic (Type A) ones. Molecular dynamics simulations and theozyme calculations further elucidated that, in addition to cation-π interactions, C-H⋅⋅⋅π interactions also play a key role in the cyclization patterns. This study offers a feasible strategy in protein engineering of TPSs for various industrial applications.


Assuntos
Alquil e Aril Transferases , Simulação de Dinâmica Molecular , Sesterterpenos , Sesterterpenos/química , Sesterterpenos/metabolismo , Alquil e Aril Transferases/metabolismo , Alquil e Aril Transferases/química , Domínio Catalítico , Engenharia de Proteínas
7.
Small ; 19(47): e2302587, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37454336

RESUMO

Nanozyme-driven catalytic antibacterial therapy has become a promising modality for bacterial biofilm infections. However, current catalytic therapy of biofilm wounds is severely limited by insufficient catalytic efficiency, excessive inflammation, and deep tissue infection. Drawing from the homing mechanism of natural macrophages, herein, a hollow mesoporous biomimetic single-atomic nanozyme (SAN) is fabricated to actively target inflamed parts, suppress inflammatory factors, and eliminate deeply organized bacteria for enhance biofilm eradication. In the formulation, this biomimetic nanozyme (Co@SAHSs@IL-4@RCM) consists of IL-4-loaded cobalt SANs-embedded hollow sphere encapsulate by RAW 264.7 cell membrane (RCM). Upon accumulation at the infected sites through the specific receptors of RCM, Co@SAHS catalyze the conversion of hydrogen peroxide into hydroxyl radicals and are further amplify by NIR-II photothermal effect and glutathione depletion to permeate and destroy biofilm structure. This behavior subsequently causes the dissociation of RCM shell and the ensuing release of IL-4 that can reprogram macrophages, enabling suppression of oxidative injury and tissue inflammation. The work paves the way to engineer alternative "all-in-one" SANs with an immunomodulatory ability and offers novel insights into the design of bioinspired materials.


Assuntos
Biomimética , Interleucina-4 , Humanos , Antibacterianos/farmacologia , Biofilmes , Peróxido de Hidrogênio , Inflamação
8.
Diabet Med ; 40(6): e15086, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36924086

RESUMO

BACKGROUND: Most commercially available automated insulin delivery (AID) systems are not approved for pregnancy use. Information regarding use of the Tandem t:slim X2 insulin pump with Control-IQ™ technology in pregnancy is lacking. AIMS: This case series aimed to explore glycaemic and qualitative experiences of four early adopters of Control-IQ technology in pregnancy. METHODS: Participants used Control-IQ technology in pregnancy and postpartum and consented to analysis of glycaemic data and semi-structured interviews. RESULTS: Case 1 began Control-IQ technology at 10 weeks gestation. Her pregnancy glucose time-in-range (3.5-7.8 mmol/L [63-140 mg/dL]) increased from 58.7% to 73.3% by third trimester. Cases 2-4 began using Control-IQ technology 0-2 months preconception. Pregnancy time-in-range glucose increased from 73.4% to 78.7%, 78% to 83.6%, and 46.5% to 71.9% between first and third trimesters, respectively. A mid-pregnancy decline in time-in-range glucose was observed in two of the four participants related to suboptimal pump setting adjustments and delays in sensor and infusion set replacement. No diabetic ketoacidosis or severe hypoglycaemia occurred. All participants reported reduced diabetes management burden and improved sleep with Control-IQ technology use. CONCLUSIONS: Early adopters of Control-IQ technology safely used this system off-label in pregnancy and reported reduced diabetes management burden and improved sleep. The largest glycaemic improvements were observed among those with the lowest pregnancy time-in-range glucose at the beginning of pregnancy. Participants with low pregnancy glucose time-in-range increased their time-in-range with Control-IQ technology use and participants with high pregnancy glucose time-in-range maintained and increased their time-in-range with less diabetes management burden.


Assuntos
Diabetes Mellitus Tipo 1 , Pancreatopatias , Humanos , Gravidez , Feminino , Insulina/uso terapêutico , Hipoglicemiantes/uso terapêutico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Resultado do Tratamento , Estudos Cross-Over , Glicemia , Glucose , Sistemas de Infusão de Insulina , Automonitorização da Glicemia
9.
Virol J ; 20(1): 272, 2023 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-37993935

RESUMO

BACKGROUND: Human respiratory syncytial virus (RSV) is a leading cause of acute lower respiratory tract infection and hospitalization, especially in children. Highly mutagenic nature and antigenic diversity enable the RSV to successfully survive in human population. We conducted a molecular epidemiological study during 2017-2021 to investigate the prevalence and genetic characteristics of RSV. METHODS: A total of 6499 nasopharyngeal (NP) swabs were collected from hospitalized children at Department of Pediatrics, Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou, Guangdong, China. All NP swab specimens were preliminary screened for common respiratory viruses and then tested for RSV using specific PCR assays. Partial G genes of RSV were amplified for phylogenetic analysis and genetic characterization. RESULTS: The overall detection rate for common respiratory viruses was 16.12% (1048/6499). Among those, 405 specimens (6.20%, 405/6499) were found positive for RSV. The monthly distribution of RSV and other respiratory viruses was variable, and the highest incidence was recorded in Autumn and Winter. Based on the sequencing of hypervariable region of G gene, 93 RSV sequences were sub-grouped into RSV-A (56, 60.2%) and RSV-B (37, 39.8%). There was no coinfection of RSV-A and RSV-B in the tested samples. Phylogenetic analysis revealed that RSV-A and RSV-B strains belonged to ON1 and BA9 genotypes respectively, indicating predominance of these genotypes in Guangzhou. Several substitutions were observed which may likely change the antigenicity and pathogenicity of RSV. Multiple glycosylation sites were noticed, demonstrating high selection pressure on these genotypes. CONCLUSION: This study illustrated useful information about epidemiology, genetic characteristics, and circulating genotypes of RSV in Guangzhou China. Regular monitoring of the circulating strains of RSV in different parts of China could assist in the development of more effective vaccines and preventive measures.


Assuntos
Infecções por Vírus Respiratório Sincicial , Vírus Sincicial Respiratório Humano , Infecções Respiratórias , Humanos , Criança , Lactente , Vírus Sincicial Respiratório Humano/genética , Epidemiologia Molecular , Infecções por Vírus Respiratório Sincicial/epidemiologia , Criança Hospitalizada , Filogenia , China/epidemiologia , Infecções Respiratórias/epidemiologia , Genótipo
10.
Org Biomol Chem ; 21(35): 7095-7099, 2023 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-37622281

RESUMO

Here we report a strategy for the facile assembly of fused 3-trifluoromethyl-1,2,4-triazoles, which are difficult to synthesize using traditional strategies, in 50-96% yields through a triethylamine-promoted intermolecular [3 + 2] cycloaddition pathway. This protocol features high efficiency, good functional group tolerance, mild conditions, and easy operation. Furthermore, a gram-scale reaction and product derivatizations were carried out smoothly to illustrate the practicability of this method.

11.
Rev Med Virol ; 32(5): e2375, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35775736

RESUMO

Acute respiratory infection is the third most frequent cause of mortality worldwide, causing over 4.25 million deaths annually. Although most diagnosed acute respiratory infections are thought to be of viral origin, the aetiology often remains unclear. The advent of next-generation sequencing (NGS) has revolutionised the field of virus discovery and identification, particularly in the detection of unknown respiratory viruses. We systematically reviewed the application of NGS technologies for detecting respiratory viruses from clinical samples and outline potential barriers to the routine clinical introduction of NGS. The five databases searched for studies published in English from 01 January 2010 to 01 February 2021, which led to the inclusion of 52 studies. A total of 14 different models of NGS platforms were summarised from included studies. Among these models, second-generation sequencing platforms (e.g., Illumina sequencers) were used in the majority of studies (41/52, 79%). Moreover, NGS platforms have proven successful in detecting a variety of respiratory viruses, including influenza A/B viruses (9/52, 17%), SARS-CoV-2 (21/52, 40%), parainfluenza virus (3/52, 6%), respiratory syncytial virus (1/52, 2%), human metapneumovirus (2/52, 4%), or a viral panel including other respiratory viruses (16/52, 31%). The review of NGS technologies used in previous studies indicates the advantages of NGS technologies in novel virus detection, virus typing, mutation identification, and infection cluster assessment. Although there remain some technical and ethical challenges associated with NGS use in clinical laboratories, NGS is a promising future tool to improve understanding of respiratory viruses and provide a more accurate diagnosis with simultaneous virus characterisation.


Assuntos
COVID-19 , Vírus da Influenza A , Infecções Respiratórias , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Vírus da Influenza B , Infecções Respiratórias/diagnóstico , SARS-CoV-2
12.
World J Surg Oncol ; 21(1): 387, 2023 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-38110961

RESUMO

BACKGROUND: Many controversies still exist concerning the optimal extent of lymphadenectomy during esophagectomy in esophageal squamous cell carcinoma (ESCC). The objective of this study was to explore the characteristics of 4R metastasis and evaluate the clinical value of 4R node dissection in ESCC. METHODS: A total of 736 ESCC patients who underwent radical esophagectomy between 2005 and 2013 were retrospectively collected, among which 393 ones underwent 4R dissection. Propensity score matching (PSM) method was applied to reduce the effects of confounding variables between the 4R dissection and non-dissection groups to analyze overall survival. RESULTS: Patients showed a low 4R metastasis rate of 5.1% (20/393) (5.2%, 5.8%, and 1.8% for upper, middle, and lower tumors, respectively). Correlation analyses identified that 4R metastasis was significantly associated with station 2R metastasis (p < 0.001) and pathologic tumor-node-metastasis (pTNM) stage (p < 0.001). All 4R metastases were observed in stages IIIB and IVA. Moreover, patients with station 4R dissection failed to achieve significantly improved overall survival compared with those without 4R dissection, regardless of tumor stage (overall: p = 0.696; stage 0-IIIA: p = 0.317; stage IIIB-IVA: p = 0.619). CONCLUSION: 4R metastasis is likely to be associated with more aggressive disease, and routine 4R node dissection might not be necessary for ESCC patients.


Assuntos
Carcinoma de Células Escamosas , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Humanos , Carcinoma de Células Escamosas do Esôfago/cirurgia , Carcinoma de Células Escamosas do Esôfago/patologia , Carcinoma de Células Escamosas/patologia , Neoplasias Esofágicas/patologia , Estudos Retrospectivos , Metástase Linfática/patologia , Excisão de Linfonodo , Esofagectomia/métodos , Linfonodos/patologia , Estadiamento de Neoplasias
13.
J Environ Sci (China) ; 124: 397-413, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36182148

RESUMO

Coal is widely utilized as an important energy source, but coal-fired power plant was considered to be an important anthropogenic lead emission source. In the present study, the distribution characteristics of lead in coal and combustion by-products are reviewed. Specifically, lead is mainly transferred to ash particles and the formation and migration mechanisms of particulate lead are summarized. Also, targeted measures are proposed to control the formation of fine particulate lead as well as to increase the removal efficiency during the low-temperature flue gas clean process. In detail, interactions between gaseous lead and some coal-bearing minerals or added adsorbents could obviously suppress the formation of fine particulate lead. On the other hand, some efforts (including promoting capture of fine particles, reducing resistivity of particles and strengthening the gas-liquid contact) could be made to improve the fine particulate lead removal capacity. Notably, the formation mechanism of fine particulate lead is still unclear due to the limitations of research methods. Some differences in the removal principles of fine particles and particulate lead make the lead emission precisely control a great challenge. Finally, the environmental potential risk of lead emission from flue gas and ash residues is addressed and further discussed.


Assuntos
Poluentes Atmosféricos , Poluentes Atmosféricos/análise , China , Carvão Mineral/análise , Cinza de Carvão/química , Poeira , Monitoramento Ambiental/métodos , Gases , Chumbo , Material Particulado/análise , Centrais Elétricas
14.
Angew Chem Int Ed Engl ; 62(37): e202218643, 2023 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-37541669

RESUMO

In their recent Angewandte Chemie publication (doi: 10.1002/anie.202112063), Cen, Wang, Zhou et al. reported the crystal structure of a ternary complex of the non-heme iron endoperoxidase FtmOx1 (PDB entry 7ETK). The biochemical data assessed in this study were from a retracted study (doi: 10.1038/nature15519) by Zhang, Liu, Zhang et al.; no additional biochemical data were included, yet there was no discussion on the source of the biochemical data in the report by Cen, Wang, Zhou et al. Based on this new crystal structure and subsequent QM/MM-MD calculations, Cen, Wang, Zhou et al. concluded that their work provided evidence supporting the CarC-like mechanistic model for FtmOx1 catalysis. However, the authors did not accurately describe either the CarC-like model or the COX-like model, and they did not address the differences between them. Further, and contrary to their interpretations in the manuscript, the authors' data are consistent with the COX-like model once the details of the CarC-like and COX-like models have been carefully analyzed.


Assuntos
Biocatálise , Modelos Moleculares , Estrutura Terciária de Proteína
15.
Angew Chem Int Ed Engl ; 62(11): e202218128, 2023 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-36647763

RESUMO

Proteolysis targeting chimeras (PROTACs) technology is an emerging approach to degrade disease-associated proteins. Here, we report carbon-dot (CD)-based PROTACs (CDTACs) that degrade membrane proteins via the ubiquitin-proteasome system. CDTACs can bind to programmed cell death ligand 1 (PD-L1), recruit cereblon (CRBN) to induce PD-L1 ubiquitination, and degrade them with proteasomes. Fasting-mimicking diet (FMD) is also used to enhance the cellular uptake and proteasome activity. More than 99 % or 90 % of PD-L1 in CT26 or B16-F10 tumor cells can be degraded by CDTACs, respectively. Furthermore, CDTACs can activate the stimulator of interferon genes (STING) pathway to trigger immune responses. Thus, CDTACs with FMD treatment effectively inhibit the growth of CT26 and B16-F10 tumors. Compared with small-molecule-based PROTACs, CDTACs offer several advantages, such as efficient membrane protein degradation, targeted tumor accumulation, immune system activation, and in vivo detection.


Assuntos
Neoplasias , Complexo de Endopeptidases do Proteassoma , Humanos , Complexo de Endopeptidases do Proteassoma/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Antígeno B7-H1/metabolismo , Proteólise , Proteínas/metabolismo , Neoplasias/tratamento farmacológico , Imunoterapia
16.
Small ; 18(26): e2200895, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35638464

RESUMO

Oxidative stress and local overactive inflammation have been considered major obstacles in diabetic wound treatment. Although antiphlogistic tactics have been reported widely, they are also challenged by pathogen contamination and compromised angiogenesis. Herein, a versatile integrated nanoagent based on 2D reductive covalent organic frameworks coated with antibacterial immuno-engineered exosome (PCOF@E-Exo) is reported to achieve efficient and comprehensive combination therapy for diabetic wounds. The E-Exo is collected from TNF-α-treated mesenchymal stem cells (MSCs) under hypoxia and encapsulated cationic antimicrobial carbon dots (CDs). This integrated nanoagent not only significantly scavenges reactive oxygen species and induces anti-inflammatory M2 macrophage polarization, but also stabilizes hypoxia-inducible factor-1α (HIF-1α). More importantly, the PCOF@E-Exo exhibits intriguing bactericide capabilities toward Gram-negative, Gram-positive, and drug-resistant bacteria, showing favorable intracellular bacterial destruction and biofilm permeation. In vivo results demonstrate that the synergetic impact of suppressing oxidative injury and tissue inflammation, promoting angiogenesis and eradicating bacterial infection, could significantly accelerate the infected diabetic fester wound healing with better therapeutic benefits than monotherapy or individual antibiotics. The proposed strategy can inspire further research to design more delicate platforms using the combination of immunotherapy with other therapeutic methods for more efficient ulcerated diabetic wounds treatments.


Assuntos
Diabetes Mellitus , Exossomos , Células-Tronco Mesenquimais , Humanos , Inflamação , Neovascularização Patológica , Cicatrização
17.
Bioorg Chem ; 129: 106183, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36209565

RESUMO

Sesquiterpene lactones possess excellent anti-tumor activity in multiple cancer cell lines, including glioma, the most common type of malignant brain tumor with high mortality. However, the detailed mechanism of this type of constituent, especially the potential target for anti-glioma effect, is still unclear. Here, we collected 52 sesquiterpene lactones from Elephantopus scaber Linn. for network pharmacology analysis. The results demonstrated that the targets of the active components were markedly enriched on the pathways in cancer, which were closely related to cell proliferation regulation. Next, the Gene Expression Omnibus (GEO) and DisGeNET were analyzed by bioinformatics, and 429 glioma-related targets were obtained. Furtherly, 34 common targets of compounds and glioma were revealed, and they were significantly enriched in MAPK signaling pathway. Subsequently, we constructed a common target-compound network, and glutathione S-transferase Pi 1 (GSTP1) had the highest degree value, which explained its significance in the network. Therefore, we speculated that the compounds might exert an anti-glioma effect by targeting GSTP1. To verify the above results, we obtained part of sesquiterpene lactones isolated from E. scaber in our laboratory and evaluated their activities against glioma U87 cells. Among these sesquiterpene lactones (1-27), compounds 1 (elephantopinolide A), 2 (cis-scabertopin) and 3 (elephantopinolide F) exhibited the strongest inhibitory effect, and the IC50 values were 4.22 ± 0.14 µM, 4.28 ± 0.21 µM and 1.79 ± 0.24 µM, respectively. The results from molecular docking, cellular thermal shift assay (CETSA), as well as RT-PCR and Western blot analysis suggested that the compounds exerted an inhibitory effect by targeting GSTP1. Meanwhile, the compounds also activated JNK/STAT3 signaling pathway. Furthermore, we found that 1, 2 and 3 could suppress cell proliferation and also induce mitochondrial dysfunction as well as oxidative stress, eventually leading to cellular apoptosis. Taken together, this study revealed that sesquiterpene lactones from E. scaber could be a promising therapeutic strategy for the treatment of glioma by targeting GSTP1.


Assuntos
Antineoplásicos , Asteraceae , Neoplasias , Sesquiterpenos , Humanos , Lactonas/farmacologia , Simulação de Acoplamento Molecular , Antineoplásicos/farmacologia , Compostos Fitoquímicos , Neoplasias/tratamento farmacológico , Linhagem Celular Tumoral , Glutationa S-Transferase pi
18.
Mol Plant Microbe Interact ; 34(5): 511-523, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33630651

RESUMO

Similar to pathogenic bacteria, rhizobia can inject effector proteins into host cells directly to promote infection via the type III secretion system (T3SS). Nodulation outer protein P (NopP), a specific T3SS effector of rhizobia, plays different roles in the establishment of multiple rhizobia-legume symbiotic systems. Mesorhizobium amorphae CCNWGS0123 (GS0123), which infects Robinia pseudoacacia specifically, secretes several T3SS effectors, including NopP. Here, we demonstrate that NopP is secreted through T3SS-I of GS0123 during the early stages of infection, and its deficiency decreases nodule nitrogenase activity of R. pseudoacacia nodules. A trafficking protein particle complex subunit 13-like protein (TRAPPC13) has been identified as a NopP target protein in R. pseudoacacia roots by screening a yeast two-hybrid library. The physical interaction between NopP and TRAPPC13 is verified by bimolecular fluorescence complementation and coimmunoprecipitation assays. In addition, subcellular localization analysis reveals that both NopP and its target, TRAPPC13, are colocalized on the plasma membrane. Compared with GS0123-inoculated R. pseudoacacia roots, some genes associated with cell wall remodeling and plant innate immunity down-regulated in ΔnopP-inoculated roots at 36 h postinoculation. The results suggest that NopP in M. amorphae CCNWGS0123 acts in multiple processes in R. pseudoacacia during the early stages of infection, and TRAPPC13 could participate in the process as a NopP target.[Formula: see text] Copyright © 2021 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.


Assuntos
Mesorhizobium , Rhizobium , Robinia , Mesorhizobium/genética , Simbiose , Sistemas de Secreção Tipo III/genética
19.
Ann Surg Oncol ; 28(7): 3930-3938, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33249523

RESUMO

BACKGROUND: The bilateral recurrent laryngeal nerve (RLN) lymph nodes are the most common metastatic site for esophageal squamous cell carcinoma (ESCC); however, the RLNs are susceptible to injury during dissection. Clinically, there is an urgent need to determine an effective diagnostic method for RLN nodes to help achieve selective nodal dissection and avoid potential serious complications by performing more conservative surgery for those with nonmetastatic nodes. Here, we innovatively applied endobronchial ultrasonography (EBUS) and investigated its diagnostic performance for preoperative evaluation of RLN nodes in ESCC patients. PATIENTS AND METHODS: All 81 enrolled ESCC patients underwent preoperative EBUS and CT examinations. The ability of EBUS and CT to detect RLN node metastasis was evaluated based on the resulting sensitivity, specificity, accuracy, positive predictive value (PPV), and negative predictive value (NPV). RESULTS: The diagnostic performance of EBUS was superior to that of CT; in particular, EBUS of the left RLN (L-RLN) nodes presented the best sensitivity, specificity, PPV, NPV, and accuracy compared with EBUS evaluations of the right RLN (R-RLN) nodes, CT of the L-RLN and R-RLN nodes. Moreover, EBUS combined with CT increased the NPV relative to that of EBUS or CT alone, promoting the ability to identify true-negative RLN nodes. In particular, the NPVs of the combined modality were 100% for both the L- and R-RLN nodes in early-T-stage (T1-T2) ESCC. CONCLUSIONS: EBUS is an efficient tool for RLN node evaluation, and the combination with CT may provide better guidance for selective RLN node dissection in ESCC patients.


Assuntos
Carcinoma de Células Escamosas , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Neoplasias de Cabeça e Pescoço , Neoplasias Pulmonares , Carcinoma de Células Escamosas/diagnóstico por imagem , Carcinoma de Células Escamosas/cirurgia , Neoplasias Esofágicas/diagnóstico por imagem , Neoplasias Esofágicas/cirurgia , Carcinoma de Células Escamosas do Esôfago/diagnóstico por imagem , Carcinoma de Células Escamosas do Esôfago/cirurgia , Esofagectomia , Humanos , Excisão de Linfonodo , Linfonodos/diagnóstico por imagem , Linfonodos/cirurgia , Metástase Linfática , Nervo Laríngeo Recorrente/diagnóstico por imagem , Nervo Laríngeo Recorrente/cirurgia , Estudos Retrospectivos
20.
BMC Infect Dis ; 21(1): 748, 2021 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-34344310

RESUMO

BACKGROUND: Human Adenoviruses (HAdVs) cause a wide array of illnesses in all age groups. They particularly cause frequent morbidity among children. In China, human adenovirus types 3, 4, 7, 11, 14, 21, and 55 have caused at least seven outbreaks since 2000. However, limited studies are available regarding the epidemiological patterns and diversity of HAdVs types among hospitalized patients with respiratory tract infections (RTIs). METHODS: To understand the epidemiology and subtype distribution of HAdV infections associated with RTIs in China, nasal swab (NS) clinical samples were collected from 4129 patients in a Guangzhou hospital between August 2017 and October 2019. PCR, sequencing, and phylogenetic analysis were performed on these specimens to identify HAdV subtypes. RESULTS: HAdV was successfully sequenced in 99 (2.4%) of the 4129 NS specimens, with the highest HAdV prevalence (6.3%) found in children between the ages of 5 and 10 years. Among HAdV-positive specimens, the most prevalent genotypes identified were HAdV-B3 (55.6%) and HAdV-B7 (25.3%). The most common symptoms in the HAdV-infected patients were fever (100%), cough (80.8%), and rhinorrhea (71.8%). HAdV infections were detected throughout the year with a relatively higher prevalence in summer. CONCLUSION: All ages suffer adenovirus infections, but young children are at the greatest risk. This study data demonstrates that at least three species of HAdVs (species B, C, and E) are circulating in Guangzhou City, China. As antiviral therapies and type-specific vaccines become available, such epidemiological data will be useful in guiding therapy and public health interventions.


Assuntos
Infecções por Adenovirus Humanos , Adenovírus Humanos , Infecções Respiratórias , Infecções por Adenovirus Humanos/epidemiologia , Adenovírus Humanos/genética , Criança , Pré-Escolar , China/epidemiologia , Humanos , Lactente , Tipagem Molecular , Filogenia , Infecções Respiratórias/epidemiologia , Análise de Sequência de DNA , Centros de Atenção Terciária
SELEÇÃO DE REFERÊNCIAS
Detalhe da pesquisa