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1.
Nat Immunol ; 18(9): 1035-1045, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28759003

RESUMO

MLL4 is an essential subunit of the histone H3 Lys4 (H3K4)-methylation complexes. We found that MLL4 deficiency compromised the development of regulatory T cells (Treg cells) and resulted in a substantial decrease in monomethylated H3K4 (H3K4me1) and chromatin interaction at putative gene enhancers, a considerable portion of which were not direct targets of MLL4 but were enhancers that interacted with MLL4-bound sites. The decrease in H3K4me1 and chromatin interaction at the enhancers not bound by MLL4 correlated with MLL4 binding at distant interacting regions. Deletion of an upstream MLL4-binding site diminished the abundance of H3K4me1 at the regulatory elements of the gene encoding the transcription factor Foxp3 that were looped to the MLL4-binding site and compromised both the thymic differentiation and the inducible differentiation of Treg cells. We found that MLL4 catalyzed methylation of H3K4 at distant unbound enhancers via chromatin looping, which identifies a previously unknown mechanism for regulating the T cell enhancer landscape and affecting Treg cell differentiation.


Assuntos
Diferenciação Celular/genética , Cromatina/metabolismo , Fatores de Transcrição Forkhead/genética , Histona-Lisina N-Metiltransferase/genética , Histonas/metabolismo , Linfócitos T Reguladores , Animais , Sistemas CRISPR-Cas , Citocinas/imunologia , Citometria de Fluxo , Regulação da Expressão Gênica , Immunoblotting , Técnicas In Vitro , Metilação , Camundongos
2.
Genes Dev ; 35(9-10): 713-728, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33888555

RESUMO

MED1 often serves as a surrogate of the general transcription coactivator complex Mediator for identifying active enhancers. MED1 is required for phenotypic conversion of fibroblasts to adipocytes in vitro, but its role in adipose development and expansion in vivo has not been reported. Here, we show that MED1 is not generally required for transcription during adipogenesis in culture and that MED1 is dispensable for adipose development in mice. Instead, MED1 is required for postnatal adipose expansion and the induction of fatty acid and triglyceride synthesis genes after pups switch diet from high-fat maternal milk to carbohydrate-based chow. During adipogenesis, MED1 is dispensable for induction of lineage-determining transcription factors (TFs) PPARγ and C/EBPα but is required for lipid accumulation in the late phase of differentiation. Mechanistically, MED1 controls the induction of lipogenesis genes by facilitating lipogenic TF ChREBP- and SREBP1a-dependent recruitment of Mediator to active enhancers. Together, our findings identify a cell- and gene-specific regulatory role of MED1 as a lipogenesis coactivator required for postnatal adipose expansion.


Assuntos
Tecido Adiposo/crescimento & desenvolvimento , Regulação da Expressão Gênica no Desenvolvimento/genética , Lipogênese/genética , Subunidade 1 do Complexo Mediador/genética , Subunidade 1 do Complexo Mediador/metabolismo , Tecido Adiposo/metabolismo , Tecido Adiposo Marrom/embriologia , Animais , Células Cultivadas , Dieta , Camundongos , Ligação Proteica/genética
3.
Cell ; 153(6): 1266-80, 2013 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-23727112

RESUMO

The DNA damage response (DDR) protein 53BP1 protects DNA ends from excessive resection in G1, and thereby favors repair by nonhomologous end-joining (NHEJ) as opposed to homologous recombination (HR). During S phase, BRCA1 antagonizes 53BP1 to promote HR. The pro-NHEJ and antirecombinase functions of 53BP1 are mediated in part by RIF1, the only known factor that requires 53BP1 phosphorylation for its recruitment to double-strand breaks (DSBs). Here, we show that a 53BP1 phosphomutant, 53BP18A, comprising alanine substitutions of the eight most N-terminal S/TQ phosphorylation sites, mimics 53BP1 deficiency by restoring genome stability in BRCA1-deficient cells yet behaves like wild-type 53BP1 with respect to immunoglobulin class switch recombination (CSR). 53BP18A recruits RIF1 but fails to recruit the DDR protein PTIP to DSBs, and disruption of PTIP phenocopies 53BP18A. We conclude that 53BP1 promotes productive CSR and suppresses mutagenic DNA repair through distinct phosphodependent interactions with RIF1 and PTIP.


Assuntos
Proteínas de Transporte/metabolismo , Proteínas Cromossômicas não Histona/metabolismo , Reparo do DNA por Junção de Extremidades , Proteínas de Ligação a DNA/metabolismo , Switching de Imunoglobulina , Proteínas Nucleares/metabolismo , Proteínas de Ligação a Telômeros/metabolismo , Animais , Linfócitos B/metabolismo , Proteína BRCA1/metabolismo , Proteínas Cromossômicas não Histona/genética , Quebras de DNA de Cadeia Dupla , Proteínas de Ligação a DNA/genética , Embrião de Mamíferos/citologia , Embrião de Mamíferos/metabolismo , Fibroblastos/metabolismo , Instabilidade Genômica , Camundongos , Mutação , Proteína 1 de Ligação à Proteína Supressora de Tumor p53
4.
Mol Cell ; 78(6): 1114-1132.e10, 2020 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-32446320

RESUMO

Bromodomain-containing protein 4 (BRD4) is a cancer therapeutic target in ongoing clinical trials disrupting primarily BRD4-regulated transcription programs. The role of BRD4 in cancer has been attributed mainly to the abundant long isoform (BRD4-L). Here we show, by isoform-specific knockdown and endogenous protein detection, along with transgene expression, the less abundant BRD4 short isoform (BRD4-S) is oncogenic while BRD4-L is tumor-suppressive in breast cancer cell proliferation and migration, as well as mammary tumor formation and metastasis. Through integrated RNA-seq, genome-wide ChIP-seq, and CUT&RUN association profiling, we identify the Engrailed-1 (EN1) homeobox transcription factor as a key BRD4-S coregulator, particularly in triple-negative breast cancer. BRD4-S and EN1 comodulate the extracellular matrix (ECM)-associated matrisome network, including type II cystatin gene cluster, mucin 5, and cathepsin loci, via enhancer regulation of cancer-associated genes and pathways. Our work highlights the importance of targeted therapies for the oncogenic, but not tumor-suppressive, activity of BRD4.


Assuntos
Neoplasias da Mama/metabolismo , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/fisiologia , Fatores de Transcrição/metabolismo , Fatores de Transcrição/fisiologia , Animais , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Genes Homeobox , Proteínas de Homeodomínio/metabolismo , Humanos , Camundongos , Invasividade Neoplásica , Proteínas Nucleares/metabolismo , Isoformas de Proteínas/metabolismo , Proteínas/antagonistas & inibidores , Proteínas/metabolismo , Transcrição Gênica/genética , Neoplasias de Mama Triplo Negativas/genética
5.
Cell ; 151(3): 547-58, 2012 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-23101625

RESUMO

Retroviral overexpression of reprogramming factors (Oct4, Sox2, Klf4, c-Myc) generates induced pluripotent stem cells (iPSCs). However, the integration of foreign DNA could induce genomic dysregulation. Cell-permeant proteins (CPPs) could overcome this limitation. To date, this approach has proved exceedingly inefficient. We discovered a striking difference in the pattern of gene expression induced by viral versus CPP-based delivery of the reprogramming factors, suggesting that a signaling pathway required for efficient nuclear reprogramming was activated by the retroviral, but not CPP approach. In gain- and loss-of-function studies, we find that the toll-like receptor 3 (TLR3) pathway enables efficient induction of pluripotency by viral or mmRNA approaches. Stimulation of TLR3 causes rapid and global changes in the expression of epigenetic modifiers to enhance chromatin remodeling and nuclear reprogramming. Activation of inflammatory pathways are required for efficient nuclear reprogramming in the induction of pluripotency.


Assuntos
Peptídeos Penetradores de Células/metabolismo , Reprogramação Celular , Imunidade Inata , Células-Tronco Pluripotentes Induzidas/metabolismo , Transdução de Sinais , Linhagem Celular , Fibroblastos/metabolismo , Humanos , Inflamação/metabolismo , Fator 4 Semelhante a Kruppel , NF-kappa B/metabolismo , Fator 3 de Transcrição de Octâmero/metabolismo , Retroviridae/metabolismo , Receptor 3 Toll-Like/metabolismo
6.
Proc Natl Acad Sci U S A ; 121(9): e2314620121, 2024 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-38381784

RESUMO

Photon-controlled pyroptosis activation (PhotoPyro) is a promising technique for cancer immunotherapy due to its noninvasive nature, precise control, and ease of operation. Here, we report that biomolecular photoredox catalysis in cells might be an important mechanism underlying PhotoPyro. Our findings reveal that the photocatalyst lutetium texaphyrin (MLu) facilitates rapid and direct photoredox oxidation of nicotinamide adenine dinucleotide, nicotinamide adenine dinucleotide phosphate, and various amino acids, thereby triggering pyroptosis through the caspase 3/GSDME pathway. This mechanism is distinct from the well-established role of MLu as a photodynamic therapy sensitizer in cells. Two analogs of MLu, bearing different coordinated central metal cations, were also explored as controls. The first control, gadolinium texaphyrin (MGd), is a weak photocatalyst but generates reactive oxygen species (ROS) efficiently. The second control, manganese texaphyrin (MMn), is ineffective as both a photocatalyst and a ROS generator. Neither MGd nor MMn was found to trigger pyroptosis under the conditions where MLu was active. Even in the presence of a ROS scavenger, treating MDA-MB-231 cells with MLu at concentrations as low as 50 nM still allows for pyroptosis photo-activation. The present findings highlight how biomolecular photoredox catalysis could contribute to pyroptosis activation by mechanisms largely independent of ROS.


Assuntos
Metaloporfirinas , Piroptose , Espécies Reativas de Oxigênio/metabolismo
7.
Immunity ; 45(1): 60-73, 2016 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-27396958

RESUMO

Durable antibody production after vaccination or infection is mediated by long-lived plasma cells (LLPCs). Pathways that specifically allow LLPCs to persist remain unknown. Through bioenergetic profiling, we found that human and mouse LLPCs could robustly engage pyruvate-dependent respiration, whereas their short-lived counterparts could not. LLPCs took up more glucose than did short-lived plasma cells (SLPCs) in vivo, and this glucose was essential for the generation of pyruvate. Glucose was primarily used to glycosylate antibodies, but glycolysis could be promoted by stimuli such as low ATP levels and the resultant pyruvate used for respiration by LLPCs. Deletion of Mpc2, which encodes an essential component of the mitochondrial pyruvate carrier, led to a progressive loss of LLPCs and of vaccine-specific antibodies in vivo. Thus, glucose uptake and mitochondrial pyruvate import prevent bioenergetic crises and allow LLPCs to persist. Immunizations that maximize these plasma cell metabolic properties might thus provide enduring antibody-mediated immunity.


Assuntos
Células Produtoras de Anticorpos/imunologia , Glucose/metabolismo , Mitocôndrias/metabolismo , Plasmócitos/imunologia , Ácido Pirúvico/metabolismo , Animais , Transporte Biológico Ativo , Respiração Celular , Células Cultivadas , Glicosilação , Humanos , Imunoglobulinas/biossíntese , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pró-Proteína Convertase 2/genética , Pró-Proteína Convertase 2/metabolismo , Estresse Fisiológico/imunologia
8.
Nucleic Acids Res ; 51(11): 5634-5646, 2023 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-37158237

RESUMO

In this study, we specifically visualized DNA molecules at their AT base pairs after in vitro phage ejection. Our AT-specific visualization revealed that either end of the DNA molecule could be ejected first with a nearly 50% probability. This observation challenges the generally accepted theory of Last In First Out (LIFO), which states that the end of the phage λ DNA that enters the capsid last during phage packaging is the first to be ejected, and that both ends of the DNA are unable to move within the extremely condensed phage capsid. To support our observations, we conducted computer simulations that revealed that both ends of the DNA molecule are randomized, resulting in the observed near 50% probability. Additionally, we found that the length of the ejected DNA by LIFO was consistently longer than that by First In First Out (FIFO) during in vitro phage ejection. Our simulations attributed this difference in length to the stiffness difference of the remaining DNA within the phage capsid. In conclusion, this study demonstrates that a DNA molecule within an extremely dense phage capsid exhibits a degree of mobility, allowing it to switch ends during ejection.


Assuntos
Bacteriófago lambda , DNA Viral , Empacotamento do Genoma Viral , Bacteriófago lambda/fisiologia , DNA Viral/metabolismo , Capsídeo/metabolismo
9.
Eur Heart J ; 2024 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-38993069

RESUMO

BACKGROUND AND AIMS: Concerns about the safety of coronavirus disease 2019 (COVID-19) vaccines in patients with atrial fibrillation/flutter (AF/AFL) have arisen due to reports of thrombo-embolic events following COVID-19 vaccination in the general population. This study aimed to evaluate the risk of thrombo-embolic events after COVID-19 vaccination in patients with AF/AFL. METHODS: This was a modified self-controlled case-series study using a comprehensive nationwide-linked database provided by the National Health Insurance Service in South Korea to calculate incidence rate ratios (IRRs) of thrombo-embolic events. The study population included individuals aged ≥12 years who were either vaccinated (e.g. one or two doses) or unvaccinated during the period from February to December 2021. The primary outcome was a composite of thrombo-embolic events, including ischaemic stroke, transient ischaemic attack, and systemic thromboembolism. The risk period was defined as 0-21 days following COVID-19 vaccination. RESULTS: The final analysis included 124 127 individuals with AF/AFL. The IRR of thrombo-embolic events within 21 days after COVID-19 vaccination, compared with that during the unexposed control period, was 0.93 [95% confidence interval (CI) 0.77-1.12]. No significant risk variations were noted by sex, age, or vaccine type. However, patients without anticoagulant therapy had an IRR of 1.88 (95% CI 1.39-2.54) following vaccination. CONCLUSIONS: In patients with AF/AFL, COVID-19 vaccination was generally not associated with an increased risk of thrombo-embolic events. However, careful individual risk assessment is required when advising vaccination for those not on oral anticoagulant, as these patients exhibited an increased risk of thrombo-embolic events post-vaccination.

10.
Chem Soc Rev ; 53(10): 5264-5290, 2024 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-38619389

RESUMO

The energy storage and vehicle industries are heavily investing in advancing all-solid-state batteries to overcome critical limitations in existing liquid electrolyte-based lithium-ion batteries, specifically focusing on mitigating fire hazards and improving energy density. All-solid-state lithium-sulfur batteries (ASSLSBs), featuring earth-abundant sulfur cathodes, high-capacity metallic lithium anodes, and non-flammable solid electrolytes, hold significant promise. Despite these appealing advantages, persistent challenges like sluggish sulfur redox kinetics, lithium metal failure, solid electrolyte degradation, and manufacturing complexities hinder their practical use. To facilitate the transition of these technologies to an industrial scale, bridging the gap between fundamental scientific research and applied R&D activities is crucial. Our review will address the inherent challenges in cell chemistries within ASSLSBs, explore advanced characterization techniques, and delve into innovative cell structure designs. Furthermore, we will provide an overview of the recent trends in R&D and investment activities from both academia and industry. Building on the fundamental understandings and significant progress that has been made thus far, our objective is to motivate the battery community to advance ASSLSBs in a practical direction and propel the industrialized process.

11.
Curr Issues Mol Biol ; 46(5): 4580-4594, 2024 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-38785546

RESUMO

The proto-oncogene MYC is frequently dysregulated in patients with diffuse large B-cell lymphoma (DLBCL) and plays a critical role in disease progression. To improve the clinical outcomes of patients with DLBCL, the development of strategies to target MYC is crucial. The use of medicinal plants for developing anticancer drugs has garnered considerable attention owing to their diverse mechanisms of action. In this study, 100 plant extracts of flora from the Republic of Korea were screened to search for novel agents with anti-DLBCL effects. Among them, Ajania pacifica (Nakai) K. Bremer and Humphries extract (APKH) efficiently suppressed the survival of DLBCL cells, while showing minimal toxicity toward normal murine bone marrow cells. APKH suppressed the expression of anti-apoptotic BCL2 family members, causing an imbalance between the pro-apoptotic and anti-apoptotic BCL2 members. This disrupted mitochondrial membrane potential, cytochrome c release, and pro-caspase-3 activation and eventually led to DLBCL cell death. Importantly, MYC expression was markedly downregulated by APKH and ectopic expression of MYC in DLBCL cells abolished the pro-apoptotic effects of APKH. These results demonstrate that APKH exerts anti-DLBCL effects by inhibiting MYC expression. Moreover, when combined with doxorubicin, an essential component of the CHOP regimen (cyclophosphamide, doxorubicin, vincristine, and prednisone), APKH synergistically enhanced the therapeutic effect of doxorubicin. This indicates that APKH may overcome drug resistance, which is common in patients with refractory/relapsed DLBCL. To identify compounds with anti-DLBCL activities in APKH, the chemical profile analysis of APKH was performed using UPLC-QTOF/MSe analysis and assessed for its anticancer activity. Based on the UPLC-QTOF/MSe chemical profiling, it is conceivable that APKH may serve as a novel agent targeting MYC and sensitizing drug-resistant DLBCL cells to CHOP chemotherapy. Further studies to elucidate how the compounds in APKH exert tumor-suppressive role in DLBCL are warranted.

12.
Br J Cancer ; 130(9): 1571-1584, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38467827

RESUMO

BACKGROUND: Molecular analysis of advanced tumors can increase tumor heterogeneity and selection bias. We developed a robust prognostic signature for gastric cancer by comparing RNA expression between very rare early gastric cancers invading only mucosal layer (mEGCs) with lymph node metastasis (Npos) and those without metastasis (Nneg). METHODS: Out of 1003 mEGCs, all Npos were matched to Nneg using propensity scores. Machine learning approach comparing Npos and Nneg was used to develop prognostic signature. The function and robustness of prognostic signature was validated using cell lines and external datasets. RESULTS: Extensive machine learning with cross-validation identified the prognostic classifier consisting of four overexpressed genes (HDAC5, NPM1, DTX3, and PPP3R1) and two downregulated genes (MED12 and TP53), and enabled us to develop the risk score predicting poor prognosis. Cell lines engineered to high-risk score showed increased invasion, migration, and resistance to 5-FU and Oxaliplatin but maintained sensitivity to an HDAC inhibitor. Mouse models after tail vein injection of cell lines with high-risk score revealed increased metastasis. In three external cohorts, our risk score was identified as the independent prognostic factor for overall and recurrence-free survival. CONCLUSION: The risk score from the 6-gene classifier can successfully predict the prognosis of gastric cancer.


Assuntos
Biomarcadores Tumorais , Mucosa Gástrica , Neoplasias Gástricas , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Neoplasias Gástricas/mortalidade , Humanos , Prognóstico , Animais , Camundongos , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Mucosa Gástrica/patologia , Mucosa Gástrica/metabolismo , Metástase Linfática/genética , Feminino , Masculino , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Aprendizado de Máquina , Pessoa de Meia-Idade
13.
Biochem Biophys Res Commun ; 720: 150072, 2024 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-38749187

RESUMO

The Eph receptor, a prototypically large receptor protein tyrosine kinase, interacts with ephrin ligands, forming a bidirectional signaling system that impacts diverse brain functions. Eph receptors and ephrins mediate forward and reverse signaling, affecting neurogenesis, axon guidance, and synaptic signaling. While mammalian studies have emphasized their roles in neurogenesis and synaptic plasticity, the Drosophila counterparts are less studied, especially in glial cells, despite structural similarities. Using RNAi to modulate Eph/ephrin expression in Drosophila neurons and glia, we studied their roles in brain development and sleep and circadian behavior. Knockdown of neuronal ephrin disrupted mushroom body development, while glial knockdown had minimal impact. Surprisingly, disrupting ephrin in neurons or glial cells altered sleep and circadian rhythms, indicating a direct involvement in these behaviors independent from developmental effects. Further analysis revealed distinct sleep phenotypes between neuronal and glial knockdowns, underscoring the intricate interplay within the neural circuits that govern behavior. Glia-specific knockdowns showed altered sleep patterns and reduced circadian rhythmicity, suggesting an intricate role of glia in sleep regulation. Our findings challenge simplistic models of Eph/ephrin signaling limited to neuron-glia communication and emphasize the complexity of the regulatory networks modulating behavior. Future investigations targeting specific glial subtypes will enhance our understanding of Eph/ephrin signaling's role in sleep regulation across species.


Assuntos
Ritmo Circadiano , Efrinas , Corpos Pedunculados , Neuroglia , Neurônios , Transdução de Sinais , Sono , Animais , Neuroglia/metabolismo , Sono/fisiologia , Sono/genética , Ritmo Circadiano/fisiologia , Neurônios/metabolismo , Efrinas/metabolismo , Efrinas/genética , Corpos Pedunculados/metabolismo , Proteínas de Drosophila/metabolismo , Proteínas de Drosophila/genética , Receptores da Família Eph/metabolismo , Receptores da Família Eph/genética , Drosophila melanogaster/metabolismo , Drosophila melanogaster/fisiologia , Drosophila melanogaster/genética , Drosophila/metabolismo
14.
Microb Pathog ; 193: 106771, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38969185

RESUMO

Despite modern advances in food hygiene, food poisoning due to microbial contamination remains a global problem, and poses a great threat to human health. Especially, Listeria monocytogenes and Staphylococcus aureus are gram-positive bacteria found on food-contact surfaces with biofilms. These foodborne pathogens cause a considerable number of food poisoning and infections annually. Ovomucin (OM) is a water-insoluble gel-type glycoprotein in egg whites. Enzymatic hydrolysis can be used to improve the bioactive properties of OM. This study aimed to investigate whether ovomucin hydrolysates (OMHs) produced using five commercial enzymes (Alcalase®, Bromelain, α-Chymotrypsin, Papain, and Pancreatin) can inhibit the biofilm formation of L. monocytogenes ATCC 15313, L. monocytogenes H7962, S. aureus KCCM 11593, and S. aureus 7. Particularly, OMH prepared with papain (OMPP; 500 µg/mL) significantly inhibited biofilm formation in L. monocytogenes ATCC 15313, L. monocytogenes H7962, S. aureus KCCM 11593, and S. aureus 7 by 85.56 %, 80.28 %, 91.70 %, and 79.00 %, respectively. In addition, OMPP reduced the metabolic activity, exopolysaccharide production (EPS), adhesion ability, and gene expression associated with the biofilm formation of these bacterial strains. These results suggest that OMH, especially OMPP, exerts anti-biofilm effects against L. monocytogenes and S. aureus. Therefore, OMPP can be used as a natural anti-biofilm agent to control food poisoning in the food industry.


Assuntos
Antibacterianos , Biofilmes , Listeria monocytogenes , Ovomucina , Staphylococcus aureus , Biofilmes/efeitos dos fármacos , Listeria monocytogenes/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Antibacterianos/farmacologia , Ovomucina/farmacologia , Ovomucina/metabolismo , Hidrólise , Aderência Bacteriana/efeitos dos fármacos , Papaína/metabolismo , Testes de Sensibilidade Microbiana , Quimotripsina/metabolismo , Hidrolisados de Proteína/farmacologia , Hidrolisados de Proteína/metabolismo
15.
Bioorg Med Chem ; 98: 117578, 2024 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-38154348

RESUMO

As the ß-phenyl-α,ß-unsaturated carbonyl (PUSC) structure was previously identified to play a key role in tyrosinase inhibition, 14 analogs with a PUSC structure built on a thiazol-4(5H)-one scaffold were synthesized using Knoevenagel condensation to serve as potential tyrosinase inhibitors. Through mushroom tyrosinase inhibition experiments, two analogs 9 and 11 were identified as potent tyrosinase inhibitors, with 11 exhibiting an IC50 value of 0.4 ± 0.01 µM, which indicates its 26-fold greater potency than kojic acid. Kinetic studies using Lineweaver-Burk plots revealed that 9 and 11 are competitive and mixed-type inhibitors, respectively; these kinetic results were supported by docking simulations. According to the B16F10 cell-based experiments, 9 and 11 inhibited melanogenesis more effectively than kojic acid due to their potent cellular tyrosinase inhibitory activity. In addition, analogs 9 and 11 exhibited moderate-to-strong antioxidant capacity, scavenging ABTS+, DPPH, and ROS radicals. In particular, analog 12 with a catechol moiety exhibited very strong ROS-scavenging activity, similar to Trolox. These results suggest that analogs 9 and 11, which exhibit potent tyrosinase inhibitory activity in mushroom and mammalian cells and anti-melanogenic effects in B16F10 cells, are promising antibrowning agents for crops and skin lightening agents for hyperpigmentation-related diseases.


Assuntos
Agaricales , Monofenol Mono-Oxigenase , Animais , Antioxidantes/farmacologia , Relação Estrutura-Atividade , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Cinética , Espécies Reativas de Oxigênio , Simulação de Acoplamento Molecular , Melaninas , Mamíferos/metabolismo
16.
Bioorg Med Chem ; 110: 117832, 2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-39002182

RESUMO

Tyrosinase is a metalloenzyme that contains copper(II) ions. We designed and synthesized eight known low-molecular-weight 2-mercaptobenzoxazole (2-MBO) analogs as tyrosinase inhibitors. Our focus was on the mercapto functional group, which interacts with copper ions. Analogs 1-3 exhibited mushroom tyrosinase inhibitory activity at the nanomolar level and demonstrated strong potency with extremely low half-maximal inhibitory concentration (IC50) values of 80-90 nM for l-dopa and 100-240 nM for l-tyrosine. Analogs 2, 4, and 5 showed the most potent anti-melanogenic effects in B16F10 cells, and their mode of action was demonstrated by kinetic analysis. Their anti-melanogenic effects were similar to the tyrosinase inhibition results, suggesting that their anti-melanogenic effects could be attributed to their tyrosinase inhibitory ability. Experiments using copper-chelating activity assays and changes in tyrosinase inhibitory activity with and without CuSO4 demonstrated that 2-MBO analogs inhibit tyrosinase activity by chelating the copper ions of tyrosinase. In conclusion, the 2-MBO analogs show potential as anti-melanogenic agents with potent tyrosinase inhibitory activity.


Assuntos
Desenho de Fármacos , Inibidores Enzimáticos , Monofenol Mono-Oxigenase , Monofenol Mono-Oxigenase/antagonistas & inibidores , Monofenol Mono-Oxigenase/metabolismo , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Camundongos , Animais , Relação Estrutura-Atividade , Estrutura Molecular , Agaricales/enzimologia , Melaninas/metabolismo , Melaninas/antagonistas & inibidores , Relação Dose-Resposta a Droga , Linhagem Celular Tumoral , Cobre/química , Cobre/farmacologia
17.
Bioorg Chem ; 150: 107586, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38955001

RESUMO

Compounds with sulfhydryl substituents and azole compounds exhibit potent anti-tyrosinase potency. 2-Thiobenzothiazole (2-TBT), a hybrid structure of sulfhydryl and azole, exists in two tautomeric forms, with the thione form being predominant according to several studies. 2-TBT derivatives were synthesized as potential tyrosinase inhibitors as the thione tautomeric form has the same N-CS moiety as phenylthiourea (PTU), which is suitable for chelation with the copper ions present in the tyrosinase active site. Eight of the ten 2-TBT derivatives inhibited the monophenolase and diphenolase activities of mushroom tyrosinase, with IC50 values of 0.02-0.83 µM. Kinetic studies and molecular dynamics simulations were performed to determine their mode of action and confirm that the 2-TBT derivatives bind to the tyrosinase active site with high stability. Derivatives 3, 4, 8, and 10 strongly inhibited melanogenesis in B16F10 cells in a pattern similar to the results of cellular tyrosinase inhibition, thereby suggesting that their ability to inhibit melanogenesis was due to their tyrosinase inhibitory activity. In a depigmentation experiment using zebrafish embryos, all 2-TBT derivatives showed better potency than kojic acid, even at 400 to 2000 times lower concentration, and 1 and 10 reduced zebrafish larva pigmentation more strongly than PTU even at 20 times lower concentration. Experiments investigating the changes in tyrosinase inhibitory activity of 2-TBT derivatives in the presence and absence of CuSO4 and their copper chelating ability supported that these derivatives exert their anti-melanogenic effect by chelating the copper ions of tyrosinase. These results suggest that 2-TBT derivatives are promising candidates for the treatment of hyperpigmentation-related disorders.


Assuntos
Benzotiazóis , Inibidores Enzimáticos , Melaninas , Monofenol Mono-Oxigenase , Peixe-Zebra , Animais , Camundongos , Agaricales/enzimologia , Benzotiazóis/farmacologia , Benzotiazóis/química , Benzotiazóis/síntese química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/síntese química , Melaninas/antagonistas & inibidores , Melaninas/metabolismo , Estrutura Molecular , Monofenol Mono-Oxigenase/antagonistas & inibidores , Monofenol Mono-Oxigenase/metabolismo , Feniltioureia/química , Feniltioureia/farmacologia , Relação Estrutura-Atividade
18.
J Korean Med Sci ; 39(4): e36, 2024 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-38288537

RESUMO

BACKGROUND: Consistent uptake of colorectal cancer (CRC) screening is important to reduce the incidence and mortality from advanced-stage CRC and increase the survival rate of the patients. We conducted a longitudinal study to determine the factors affecting CRC screening compliance in Korean adults using individual-level linked data from the Korean National Health and Nutrition Examination Survey, Korean National Health Insurance Service, and Korean Health Insurance Review and Assessment Service. METHODS: We selected 3,464 adults aged 50-79 years as the study population and followed them for 12 years (January 2007-December 2018). The outcome variable was the level of adherence to CRC screening, categorized as nonadherent, intermittently adherent, and consistently adherent. An ordinal logistic regression model was designed to determine the socioeconomic factors, family history of CRC, and medical conditions that could facilitate the consistent uptake of CRC screening. RESULTS: The results showed a significant and positive association between consistent uptake of CRC screening and the 100-150% income category (odds ratio [OR], 1.710; 95% confidence interval [CI], 1.401-2.088); clerical, sales and service job category (OR, 1.962; 95% CI, 1.582-2.433); residency at medium-sized cities (OR, 1.295; 95% CI, 1.094-1.532); high-school graduation (OR, 1.440; 95% CI, 1.210-1.713); married status (OR, 2.281; 95% CI, 1.946-2.674); use of employment-based national health insurance (OR, 1.820; 95% CI, 1.261-2.626); use of private insurance (OR, 2.259; 95% CI, 1.970-2.589); no disability (OR, 1.428; 95% CI, 1.175-1.737); family history of CRC (OR, 2.027; 95% CI, 1.514-2.714); and history of colorectal neoplasm (OR, 1.216; 95% CI; 1.039-1.422). CONCLUSION: The lack of regular participation in CRC screening programs in the Republic of Korea was found to be an issue that requires attention. Policies on CRC screening must place increased emphasis on strengthening educational and public relations initiatives.


Assuntos
Neoplasias Colorretais , Detecção Precoce de Câncer , Humanos , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/epidemiologia , Estudos Longitudinais , Programas de Rastreamento , Inquéritos Nutricionais , República da Coreia/epidemiologia , Estudos Multicêntricos como Assunto , Pessoa de Meia-Idade , Idoso
19.
Sensors (Basel) ; 24(11)2024 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-38894186

RESUMO

Smart wearable sensors are increasingly integrated into everyday life, interfacing with the human body to enable real-time monitoring of biological signals. This study focuses on creating high-sensitivity capacitive-type sensors by impregnating polyester-based 3D spacer fabric with a Carbon Nanotube (CNT) dispersion. The unique properties of conductive particles lead to nonlinear variations in the dielectric constant when pressure is applied, consequently affecting the gauge factor. The results reveal that while the fabric without CNT particles had a gauge factor of 1.967, the inclusion of 0.04 wt% CNT increased it significantly to 5.210. As sensor sensitivity requirements vary according to the application, identifying the necessary CNT wt% is crucial. Artificial intelligence, particularly the Multilayer Perception (MLP) model, enables nonlinear regression analysis for this purpose. The MLP model created and validated in this research showed a high correlation coefficient of 0.99564 between the model predictions and actual target values, indicating its effectiveness and reliability.

20.
Nano Lett ; 23(24): 11526-11532, 2023 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-38079244

RESUMO

Fe3GaTe2, a recently discovered van der Waals ferromagnet, demonstrates intrinsic ferromagnetism above room temperature, necessitating a comprehensive investigation of the microscopic origins of its high Curie temperature (TC). In this study, we reveal the electronic structure of Fe3GaTe2 in its ferromagnetic ground state using angle-resolved photoemission spectroscopy and density functional theory calculations. Our results establish a consistent correspondence between the measured band structure and theoretical calculations, underscoring the significant contributions of the Heisenberg exchange interaction (Jex) and magnetic anisotropy energy to the development of the high-TC ferromagnetic ordering in Fe3GaTe2. Intriguingly, we observe substantial modifications to these crucial driving factors through doping, which we attribute to alterations in multiple spin-splitting bands near the Fermi level. These findings provide valuable insights into the underlying electronic structure and its correlation with the emergence of high-TC ferromagnetic ordering in Fe3GaTe2.

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