Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 374
Filtrar
Mais filtros

País/Região como assunto
Tipo de documento
Intervalo de ano de publicação
1.
PLoS Biol ; 22(4): e3002582, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38683874

RESUMO

Muscarinic acetylcholine receptors are prototypical G protein-coupled receptors (GPCRs), members of a large family of 7 transmembrane receptors mediating a wide variety of extracellular signals. We show here, in cultured cells and in a murine model, that the carboxyl terminal fragment of the muscarinic M2 receptor, comprising the transmembrane regions 6 and 7 (M2tail), is expressed by virtue of an internal ribosome entry site localized in the third intracellular loop. Single-cell imaging and import in isolated yeast mitochondria reveals that M2tail, whose expression is up-regulated in cells undergoing integrated stress response, does not follow the normal route to the plasma membrane, but is almost exclusively sorted to the mitochondria inner membrane: here, it controls oxygen consumption, cell proliferation, and the formation of reactive oxygen species (ROS) by reducing oxidative phosphorylation. Crispr/Cas9 editing of the key methionine where cap-independent translation begins in human-induced pluripotent stem cells (hiPSCs), reveals the physiological role of this process in influencing cell proliferation and oxygen consumption at the endogenous level. The expression of the C-terminal domain of a GPCR, capable of regulating mitochondrial function, constitutes a hitherto unknown mechanism notably unrelated to its canonical signaling function as a GPCR at the plasma membrane. This work thus highlights a potential novel mechanism that cells may use for controlling their metabolism under variable environmental conditions, notably as a negative regulator of cell respiration.


Assuntos
Respiração Celular , Mitocôndrias , Receptor Muscarínico M2 , Animais , Humanos , Camundongos , Proliferação de Células , Células HEK293 , Células-Tronco Pluripotentes Induzidas/metabolismo , Mitocôndrias/metabolismo , Fosforilação Oxidativa , Consumo de Oxigênio , Espécies Reativas de Oxigênio/metabolismo , Receptor Muscarínico M2/metabolismo , Receptor Muscarínico M2/genética , Estresse Fisiológico
2.
PLoS Biol ; 20(1): e3001522, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-35061665

RESUMO

Nonalcoholic fatty liver disease (NAFLD) affects approximately a quarter of the population worldwide, and persistent overnutrition is one of the major causes. However, the underlying molecular basis has not been fully elucidated, and no specific drug has been approved for this disease. Here, we identify a regulatory mechanism that reveals a novel function of Rab2A in the progression of NAFLD based on energy status and PPARγ. The mechanistic analysis shows that nutrition repletion suppresses the phosphorylation of AMPK-TBC1D1 signaling, augments the level of GTP-bound Rab2A, and then increases the protein stability of PPARγ, which ultimately promotes the hepatic accumulation of lipids in vitro and in vivo. Furthermore, we found that blocking the AMPK-TBC1D1 pathway in TBC1D1S231A-knock-in (KI) mice led to a markedly increased GTP-bound Rab2A and subsequent fatty liver in aged mice. Our studies also showed that inhibition of Rab2A expression alleviated hepatic lipid deposition in western diet-induced obesity (DIO) mice by reducing the protein level of PPARγ and the expression of PPARγ target genes. Our findings not only reveal a new molecular mechanism regulating the progression of NAFLD during persistent overnutrition but also have potential implications for drug discovery to combat this disease.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Proteínas Ativadoras de GTPase/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Proteínas rab de Ligação ao GTP/metabolismo , Envelhecimento , Animais , Regulação da Expressão Gênica , Técnicas de Introdução de Genes , Células Hep G2 , Humanos , Metabolismo dos Lipídeos/fisiologia , Camundongos , Hepatopatia Gordurosa não Alcoólica/metabolismo , PPAR gama/genética , PPAR gama/metabolismo , Proteínas rab de Ligação ao GTP/genética
3.
Crit Rev Immunol ; 44(6): 49-61, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38848293

RESUMO

BACKGROUND: Sustained expression of the long noncoding RNA (lncRNA) LINC01106 in tumors is crucial for the malignant phenotype of tumor cells. Nevertheless, the mechanisms and clinical effects of LINC01106 in lung adenocarcinoma (LUAD) are limited. This study shows the effect of vir-like m6A methyltransferase-associated (KIAA1429)-mediated N6-methyladenosine (m6A) modification on steady LINC01106 expression on LUAD progression. METHODS: Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to determine LINC01106 and KIAA1429 levels in LUAD tissues. Transwell, 5-ethynyl-2'-deoxyuridine (EdU), and cell counting kit-8 (CCK-8) assays were used to analyze the functional roles of LINC01106. A xenograft was constructed to verify the function of silencing LINC01106 in tumor growth. The regulatory role of LINC01106 was investigated using methylated RNA immunoprecipitation (MeRIP), qRT-PCR, and the actinomycin D assay. Western blotting was used to identify key proteins in the JAK/STAT3 (JAK2, STAT3) pathway. RESULTS: LINC01106 and KIAA1429 were highly expressed in LUAD, and LINC01106 was interconnected with high tumor grade, stage, and poor prognosis. Data revealed that LINC01106 inhibition reduced LUAD cell proliferation, invasion, and migration and restrained LUAD cell tumorigenicity. In addition, LINC01106 silencing reduced phosphorylated JAK2 and STAT3 levels. KIAA1429-mediated LINC01106 enhances its m6A modification and expression in LUAD cells. Moreover, KIAA1429 promotion eliminated the malignant phenotypic suppression induced by low expression in LUAD cells. CONCLUSION: This study showed that KIAA1429 enhanced LINC01106 m6A modification to promote LUAD development. These results may lead to a better understanding of the mechanism of KIAA1429-m6A-LINC01106 in LUAD and offer a valuable therapeutic target for LUAD.


Assuntos
Adenocarcinoma de Pulmão , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares , RNA Longo não Codificante , Fator de Transcrição STAT3 , Transdução de Sinais , Humanos , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT3/genética , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/metabolismo , Adenocarcinoma de Pulmão/patologia , Animais , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos , Proliferação de Células/genética , Linhagem Celular Tumoral , Adenosina/análogos & derivados , Adenosina/metabolismo , Metiltransferases/metabolismo , Metiltransferases/genética , Camundongos Nus , Janus Quinase 2/metabolismo , Janus Quinase 2/genética , Movimento Celular/genética , Feminino , Janus Quinases/metabolismo , Masculino , Proteínas de Ligação a RNA
4.
Nucleic Acids Res ; 51(15): 7951-7971, 2023 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-37395406

RESUMO

The fidelity of alternative splicing (AS) patterns is essential for growth development and cell fate determination. However, the scope of the molecular switches that regulate AS remains largely unexplored. Here we show that MEN1 is a previously unknown splicing regulatory factor. MEN1 deletion resulted in reprogramming of AS patterns in mouse lung tissue and human lung cancer cells, suggesting that MEN1 has a general function in regulating alternative precursor mRNA splicing. MEN1 altered exon skipping and the abundance of mRNA splicing isoforms of certain genes with suboptimal splice sites. Chromatin immunoprecipitation and chromosome walking assays revealed that MEN1 favored the accumulation of RNA polymerase II (Pol II) in regions encoding variant exons. Our data suggest that MEN1 regulates AS by slowing the Pol II elongation rate and that defects in these processes trigger R-loop formation, DNA damage accumulation and genome instability. Furthermore, we identified 28 MEN1-regulated exon-skipping events in lung cancer cells that were closely correlated with survival in patients with lung adenocarcinoma, and MEN1 deficiency sensitized lung cancer cells to splicing inhibitors. Collectively, these findings led to the identification of a novel biological role for menin in maintaining AS homeostasis and link this role to the regulation of cancer cell behavior.


Assuntos
Processamento Alternativo , Neoplasias Pulmonares , Animais , Humanos , Camundongos , Processamento Alternativo/genética , Instabilidade Genômica/genética , Neoplasias Pulmonares/genética , Estruturas R-Loop , RNA Polimerase II/genética , RNA Polimerase II/metabolismo , RNA Mensageiro/metabolismo
5.
Chem Soc Rev ; 53(9): 4349-4373, 2024 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-38619095

RESUMO

Contact-electro-catalysis (CEC) is an emerging field that utilizes electron transfer occurring at the liquid-solid and even liquid-liquid interfaces because of the contact-electrification effect to stimulate redox reactions. The energy source of CEC is external mechanical stimuli, and solids to be used are generally organic as well as in-organic materials even though they are chemically inert. CEC has rapidly garnered extensive attention and demonstrated its potential for both mechanistic research and practical applications of mechanocatalysis. This review aims to elucidate the fundamental principle, prominent features, and applications of CEC by compiling and analyzing the recent developments. In detail, the theoretical foundation for CEC, the methods for improving CEC, and the unique advantages of CEC have been discussed. Furthermore, we outline a roadmap for future research and development of CEC. We hope that this review will stimulate extensive studies in the chemistry community for investigating the CEC, a catalytic process in nature.

6.
Nano Lett ; 24(33): 10169-10176, 2024 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-39109989

RESUMO

Organic solvent nanofiltration (OSN) membranes with high separation performance and excellent stability in aggressive organic solvents are urgently desired for chemical separation. Herein, we utilized a polyfunctional arylamine tetra-(4-aminophenyl) ethylene (TAPE) to prepare a highly cross-linked polyamide membrane with a low molecular weight cut-off (MWCO) of 312 Da. Owing to its propeller-like conformation, TAPE formed micropores within the polyamide membrane and provided fast solvent transport channels. Importantly, the rigid conjugated skeleton and high connectivity between micropores effectively prevented the expansion of the polyamide matrix in aggressive organic solvents. The membrane maintained high separation performance even immersed in N,N-dimethylformamide for 90 days. Based on the aggregation-induced emission (AIE) effect of TAPE, the formation of polyamide membrane can be visually monitored by fluorescence imaging technology, which achieved visual guidance for membrane fabrication. This work provides a vital foundation for utilizing polyfunctional monomers in the interfacial polymerization reaction to prepare high-performance OSN membranes.

7.
Small ; 20(2): e2305303, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37658494

RESUMO

Tribovoltaic nanogenerators (TVNG) represent a fantastic opportunity for developing low-frequency energy harvesting and self-powered sensing, by exploiting their real-time direct-current (DC) output. Here, a thorough study of the effect of relative humidity (RH) on a TVNG consisting of 4H-SiC (n-type) and metallic copper foil (SM-TVNG) is presented. The SM-TVNG shows a remarkable sensitivity to RH and an abnormal RH dependence. When RH increases from ambient humidity up to 80%, an increasing electrical output is observed. However, when RH rises from 80% to 98%, the signal output not only decreases, but its direction reverses as it crosses 90% RH. This behavior differs greatly from that of a Si-based TVNG, whose output constantly increases with RH. The behavior of the SM-TVNG might result from the competition between the built-in electric field induced by metal-semiconductor contact and a strong triboelectric electric field induced by solid-liquid triboelectrification under high RH. The authors also demonstrated that both SM-TVNG and Si-based TVNG can work effectively as-is even fully submerged in deionized water. This mechanism can affect other devices and be applied to design self-powered sensors working under high RH or underwater.

8.
Small ; 20(21): e2310117, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38155494

RESUMO

Chemical mechanical polishing (CMP) offers a promising pathway to smooth third-generation semiconductors. However, it is still a challenge to reduce the use of additional oxidants or/and energy in current CMP processes. Here, a new and green atomically smoothing method: Piezocatalytic-CMP (Piezo-CMP) is reported. Investigation shows that the Piezo-CMP based on tetragonal BaTiO3 (t-BT) can polish the rough surface of a reaction sintering SiC (RS-SiC) to the ultra-smooth surface with an average surface roughness (Ra) of 0.45 nm and the rough surface of a single-crystal 4H-SiC to the atomic planarization Si and C surfaces with Ra of 0.120 and 0.157 nm, respectively. In these processes, t-BT plays a dual role of piezocatalyst and abrasive. That is, it piezo-catalytically generates in-situ active oxygen species to selectively oxidize protruding sites of SiC surface, yielding soft SiO2, and subsequently, it acts as a usual abrasive to mechanically remove these SiO2. This mechanism is further confirmed by density functional theory (DFT) calculation and molecular simulation. In this process, piezocatalytic oxidation is driven only by the original pressure and friction force of a conventional polishing process, thus, the piezo-CMP process do not require any additional oxidant and energy, being a green and effective polishing method.

9.
Oncology ; 102(4): 337-342, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-37647883

RESUMO

INTRODUCTION: The aim was to investigate the risk factors for recurrence after transurethral resection of bladder tumor (TURBT) in patients with non-muscle invasive bladder cancer (NMIBC) and to provide a basis for clinical prevention of recurrence of NMIBC. METHODS: From January 2012 to December 2020, 592 patients with NMIBC who underwent TURBT attending the Second Affiliated Hospital of Xi'an Jiaotong University were retrospectively included in this study. Patients were divided into relapse and relapse-free groups according to whether relapse occurred within 2 years. Ultimately, 72 patients were included in the relapse group and 350 patients were included in the relapse-free group. Observation indicators included age, sex, smoking, underlying disease (hypertension, diabetes, coronary heart disease), two or more lesions, tumor size, hematuria, pathology grading (low, medium, high), staging (Ta, T1), muscular invasion in initial pathology, tumor base (sessile, pedunculated), use of intravesical drug (pirarubicin, bacillus Calmette-Guerin [BCG], mitomycin, hydroxycamptothecin, gemcitabine). RESULTS: In this study, the 2-year recurrence rate of NMIBC patients after TURBT was 17.06%. There were significant differences in comparison of pirarubicin, BCG, and mitomycin treatment between the two groups (p < 0.05). To avoid missing risk factors for recurrence, factors with p < 0.1 were analyzed. The results of univariate logistic regression analysis showed that NMIBC patients with BCG treatment (OR = 5.088, 95% CI = 1.444-17.73, p = 0.012), high pathology grading (OR = 0.415, 95% CI = 0.197-0.880, p = 0.023), T1 stage (OR = 2.097, 95% CI = 0.996-4.618, p = 0.059), mitomycin treatment (OR = 5.029, 95% CI = 1.149-21.77, p = 0.031), and pirarubicin treatment (OR = 1.794, 95% CI = 1.079-3.030, p = 0.024) had significantly higher risk of recurrence within 2 years after TURBT. The results of multivariate logistic regression analysis showed that NMIBC patients with high pathology grading (OR = 0.4030, 95% CI = 0.1702-0.8426, p = 0.0241), pirarubicin treatment (OR = 1.961, 95% CI = 1.159-3.348, p = 0.0125), and BCG treatment (OR = 6.201, 95% CI = 1.275-29.73, p = 0.0190) had significantly higher risk of recurrence within 2 years after TURBT. CONCLUSION: Our study highlights the importance of postoperative surveillance and individualized treatment for patients with NMIBC. Our findings show that high pathology grading, pirarubicin treatment, and BCG treatment are independent risk factors for recurrence after TURBT in patients with NMIBC. However, caution is warranted when interpreting our findings due to the small sample size and the need for further research to confirm the negative impact of mitomycin and BCG on recurrence rates.


Assuntos
Doxorrubicina/análogos & derivados , Neoplasias não Músculo Invasivas da Bexiga , Neoplasias da Bexiga Urinária , Humanos , Seguimentos , Estudos Retrospectivos , Vacina BCG/uso terapêutico , Ressecção Transuretral de Bexiga , Recidiva Local de Neoplasia/patologia , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/cirurgia , Neoplasias da Bexiga Urinária/patologia , Mitomicina/uso terapêutico , Fatores de Risco , Recidiva , Invasividade Neoplásica
10.
Neurochem Res ; 49(10): 2699-2724, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-38916813

RESUMO

Dysfunction of Schwann cells, including cell apoptosis, autophagy inhibition, dedifferentiation, and pyroptosis, is a pivotal pathogenic factor in induced diabetic peripheral neuropathy (DPN). Histone deacetylases (HDACs) are an important family of proteins that epigenetically regulate gene transcription by affecting chromatin dynamics. Here, we explored the effect of HDAC1 on high glucose-cultured Schwann cells. HDAC1 expression was increased in diabetic mice and high glucose-cultured RSC96 cells, accompanied by cell apoptosis. High glucose also increased the mitochondrial pathway apoptosis-related Bax/Bcl-2 and cleaved caspase-9/caspase-9 ratios and decreased endoplasmic reticulum response-related GRP78, CHOP, and ATF4 expression in RSC96 cells (P < 0.05). Furthermore, overexpression of HDAC1 increased the ratios of Bax/Bcl-2, cleaved caspase-9/caspase-9, and cleaved caspase-3 and reduced the levels of GRP78, CHOP, and ATF4 in RSC96 cells (P < 0.05). In contrast, knockdown of HDAC1 inhibited high glucose-promoted mitochondrial pathway apoptosis and suppressed the endoplasmic reticulum response. Moreover, RNA sequencing revealed that U4 spliceosomal RNA was significantly reduced in HDAC1-overexpressing RSC96 cells. Silencing of U4 spliceosomal RNA led to an increase in Bax/Bcl-2 and cleaved caspase-9 and a decrease in CHOP and ATF4. Conversely, overexpression of U4 spliceosomal RNA blocked HDAC1-promoted mitochondrial pathway apoptosis and inhibited the endoplasmic reticulum response. In addition, alternative splicing analysis of HDAC1-overexpressing RSC96 cells showed that significantly differential intron retention (IR) of Rpl21, Cdc34, and Mtmr11 might be dominant downstream targets that mediate U4 deficiency-induced Schwann cell dysfunction. Taken together, these findings indicate that HDAC1 promotes mitochondrial pathway-mediated apoptosis and inhibits the endoplasmic reticulum stress response in high glucose-cultured Schwann cells by decreasing the U4 spliceosomal RNA/IR of Rpl21, Cdc34, and Mtmr11.


Assuntos
Apoptose , Chaperona BiP do Retículo Endoplasmático , Estresse do Retículo Endoplasmático , Glucose , Histona Desacetilase 1 , Mitocôndrias , Células de Schwann , Animais , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Estresse do Retículo Endoplasmático/fisiologia , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Células de Schwann/metabolismo , Células de Schwann/efeitos dos fármacos , Glucose/metabolismo , Mitocôndrias/metabolismo , Chaperona BiP do Retículo Endoplasmático/metabolismo , Camundongos , Histona Desacetilase 1/metabolismo , Masculino , Diabetes Mellitus Experimental/metabolismo , Ratos , Camundongos Endogâmicos C57BL , Linhagem Celular
11.
Langmuir ; 40(32): 16972-16980, 2024 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-39078705

RESUMO

Based on the heterogeneous composite design of C3N4 and TiO2, composite photocatalysts of C3N4@TiO2 (with varied molar ratios of C3N4 to TiO2) were synthesized by a water bath method to degrade RhB in wastewater. The composition, morphology, structure, and photocatalytic properties of the materials were assessed through a variety of characterization techniques. The results show that TiO2 nanoparticles are uniformly coated on two-dimensional g-C3N4 nanosheets, forming relatively dense heterostructures within the C3N4@TiO2 composite. Due to the synergistic effect derived from the heterogeneous component and appropriate proportion of C3N4 and TiO2, the light absorption range is extended, and the separation/transport performance of photon-generated carrier is improved. As a result, TCNT-3 (where the molar ratio of C3N4 to TiO2 is 1:1) presents remarkable photocatalytic performance, the degradation rate of which for 60 min is 99.8%, and the reaction rate constant is calculated to be 0.0872 min-1. Moreover, the degradation efficiency remains 94.4% after 5 cycles, indicating the superior cycle stability.

12.
Pharmacol Res ; 209: 107412, 2024 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-39303771

RESUMO

The influence of gut microbiota on transient receptor potential (TRP) channels has been identified as an important element in the development of gastrointestinal conditions, yet its involvement in cancer progression is not as thoroughly understood. This review explores the multifaceted roles of TRP channels in oncogenesis and emphasizes their significance in cancer progression and therapeutic outcomes. Critical focus was placed on the influence of traditional medicines, such as traditional Chinese medicine (TCM) related aromatic medicines, on TRP channel functions. Moreover, we explored the interplay between the gut microbiota and TRP channels in cancer signaling, highlighting the therapeutic potential of targeting this axis in cancer treatment. The impact of current therapies on TRP channel function was examined, demonstrating the need for a comprehensive understanding of how different modalities affect TRP channels in cancer. Technological advancements, including artificial intelligence (AI) tools and computer-aided drug development (CADD), have been discussed in the context of leveraging TRP channels for innovative cancer therapies. Future directions emphasize the potential applications of TRP channel research in advancing cancer treatment and enhancing patients' well-being.

13.
Environ Sci Technol ; 58(26): 11855-11863, 2024 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-38875312

RESUMO

Polyamide (PA)-based nanofiltration (NF) membranes have demonstrated extensive applications for a sustainable water-energy-environment nexus. A rational control of interfacial polymerization (IP) is highly efficacious to enhance NF separation performance yet remains a technical challenge. Herein, we proposed a regulation strategy of constructing amphiphilic molybdenum disulfide/cetyltrimethylammonium bromide interlayer atop the Kevlar hydrogel substrate. The amphiphilic nanosheet interlayered NF membrane exhibited a crumpled PA surface with an elevated cross-linking degree of 76.9%, leading to an excellent water permeance (16.8 L m-2 h-1 bar-1) and an impressive Na2SO4 rejection (99.1%). Meanwhile, the selectivity coefficient of Na2SO4/NaCl of the optimized TFC membrane reached 91, surpassing those of the recently reported NF membranes. Moreover, the optimized membrane exhibited a desirable rejection of over 90% against Mn2+ and Cu2+ in actual textile wastewater. Importantly, the underlying NF membrane formation mechanism was elucidated via both experiments and molecular simulations. The synchronous control of mass and heat transfer of IP process offers a new methodology for the state-of-the-art membrane fabrication, which opens more avenues in softening of brackish water and purification of industrial wastewater containing heavy metal ions.


Assuntos
Membranas Artificiais , Polimerização , Purificação da Água , Purificação da Água/métodos , Nanoestruturas/química , Molibdênio/química
14.
J Fluoresc ; 2024 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-38676771

RESUMO

As one of the most significant parameters in cellular microenvironment, viscosity levels could be used to determine the metabolic process of bioactive substances within cells. Abnormal viscosity levels are closely associated with a series of diseases. Therefore, the design and synthesis of fluorescent probes that can monitor changes of intracellular viscosity in real-time is of great significance for the study of disease development process. Here, a new viscosity-recognized NIR fluorescence probe W1 based on quinoline-malonitrile is synthesized, and it is not susceptible to interference substances. Besides, AIE probe W1 shows fast response, excellent photostability, low cytotoxicity, good linear relationship between fluorescence intensity value and viscosity. Based on the above advantages, probe W1 is used to image the change of viscosity level in the cell model induced by nystatin.

15.
Bioorg Chem ; 150: 107612, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38986418

RESUMO

The high level of tyrosinase leads to the generation of neuromelanin, further causing the abnormality of redox-related protein level and mediating the occurrence and development of Parkinson's disease (PD). However, the existing tyrosinase inhibitors are mostly natural product extracts or polyphenolic derivatives, which hindered them from penetrating the blood-brain barrier (BBB). Herein, we obtained a novel tyrosinase inhibitor, 2-06 (tyrosinase: monophenolase IC50 = 70.44 ± 22.69 µM, diphenolase IC50 = 1.89 ± 0.64 µM), through the structure-based screening method. The compound 2-06 presented good in vitro and in vivo safety, and can inhibit the tyrosinase and melanogenesis in B16F10. Moreover, this compound showed neuroprotective effects and Parkinsonism behavior improving function. 2-06 was proved to penetrate the BBB and enter the central nervous system (CNS). The exploration of the binding mode between 2-06 and tyrosinase provided the foundation for the subsequent structural optimization. This is the first research to develop a central-targeting tyrosinase inhibitor, which is crucial for in-depth study on the new strategy for utilizing tyrosinase inhibitors to treat PD.


Assuntos
Relação Dose-Resposta a Droga , Descoberta de Drogas , Inibidores Enzimáticos , Monofenol Mono-Oxigenase , Doença de Parkinson , Monofenol Mono-Oxigenase/antagonistas & inibidores , Monofenol Mono-Oxigenase/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/síntese química , Animais , Relação Estrutura-Atividade , Camundongos , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Estrutura Molecular , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/síntese química , Humanos , Masculino , Simulação de Acoplamento Molecular , Barreira Hematoencefálica/metabolismo
16.
Cell Mol Life Sci ; 80(11): 325, 2023 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-37831180

RESUMO

Increasing evidence indicates that circular RNAs (circRNAs) accumulate in aging tissues and nonproliferating cells due to their high stability. However, whether upregulation of circRNA expression mediates stem cell senescence and whether circRNAs can be targeted to alleviate aging-related disorders remain unclear. Here, RNA sequencing analysis of differentially expressed circRNAs in long-term-cultured mesenchymal stem cells (MSCs) revealed that circSERPINE2 expression was significantly increased in late passages. CircSERPINE2 small interfering RNA delayed MSC senescence and rejuvenated MSCs, while circSERPINE2 overexpression had the opposite effect. RNA pulldown followed by mass spectrometry revealed an interaction between circSERPINE2 and YBX3. CircSERPINE2 increased the affinity of YBX3 for ZO-1 through the CCAUC motif, resulting in the sequestration of YBX3 in the cytoplasm, inhibiting the association of YBX3 with the PCNA promoter and eventually affecting p21 ubiquitin-mediated degradation. In addition, our results demonstrated that senescence-related downregulation of EIF4A3 gave rise to circSERPINE2. In vivo, intra-articular injection of si-circSerpine2 restrained native joint-resident MSC senescence and cartilage degeneration in mice with aging-related osteoarthritis. Taken together, our findings provide strong evidence for a regulatory role for the circSERPINE2/YBX3/PCNA/p21 axis in MSC senescence and the therapeutic potential of si-circSERPINE2 in alleviating aging-associated syndromes, such as osteoarthritis.


Assuntos
Células-Tronco Mesenquimais , Osteoartrite , Camundongos , Animais , Antígeno Nuclear de Célula em Proliferação , RNA Circular/genética , RNA Circular/metabolismo , Células-Tronco Mesenquimais/metabolismo , Senescência Celular/genética , RNA Interferente Pequeno/metabolismo , Osteoartrite/metabolismo
17.
Lipids Health Dis ; 23(1): 265, 2024 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-39175030

RESUMO

BACKGROUND: The chronic digestive condition gallstones is quite common around the world, the development of which is closely related to oxidative stress, inflammatory response and abnormalities of lipid metabolism. In the last few years, as a novel biomarker of lipid metabolism, the non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio (NHHR) has garnered significant interest. However, its relationship with gallstones has not been studied yet. METHODS: 3,772 people, all under 50, were included in this study, and their full data came from the National Health and Nutrition Examination Survey (NHANES) database for the years 2017-2020. Information on gallstones was obtained through self-reported questionnaires. Smoothed curve fitting multifactorial logistic regression was utilized to evaluate the connection of NHHR with gallstone formation incidence. Subsequently, subgroup analysis and interaction tests were applied. Finally, to create a prediction model, logistic regression and feature screening by last absolute shrinkage and selection operator (LASSO) were used. The resulting model was displayed using a nomogram. RESULTS: In multivariate logistic regression that accounted for all factors, there was a 77% increase in the likelihood of gallstones for every unit rise in lnNHHR (OR 1.77 [CI 1.11-2.83]). Following NHHR stratification, the Q4 NHHR level was substantially more linked to the risk of gallstones than the Q1 level (OR 1.86 [CI 1.04-3.32]). This correlation was stronger in women, people under 35, smokers, abstainers from alcohol, non-Hispanic White people, those with excessively high cholesterol, people with COPD, and people without diabetes. After feature screening, a predictive model and visualized nomogram for gallstones were constructed with an AUC of 0.785 (CI 0.745-0.819), which was assessed by DCA to be clinically important. CONCLUSION: In the group of people ≤ 50 years of age, elevated NHHR levels were substantially linked to a higher incidence of gallstones. This correlation was stronger in several specific groups such as females, under 35 years of age, smokers, and so on. Predictive models constructed using the NHHR have potential clinical value in assessing gallstone formation.


Assuntos
HDL-Colesterol , Cálculos Biliares , Inquéritos Nutricionais , Humanos , Feminino , Cálculos Biliares/sangue , Cálculos Biliares/epidemiologia , Masculino , Pessoa de Meia-Idade , Adulto , HDL-Colesterol/sangue , Estudos Transversais , Fatores de Risco , Modelos Logísticos , Estados Unidos/epidemiologia , Colesterol/sangue , Biomarcadores/sangue
18.
BMC Public Health ; 24(1): 2498, 2024 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-39272038

RESUMO

BACKGROUND: Thyroid disorders(TD) poses a significant health threat to Americans due to its high incidence rate. Obesity, a common factor linked to thyroid disorders, has garnered increasing attention. While Body mass index (BMI) is a widely used obesity index, it fails to account for the distribution of muscle and fat in the body. Recently, tMFR has emerged as a crucial obesity index in clinical research, warranting further investigation into its association with TD. OBJECTIVE: Exploring the association between tMFR and thyroid disorders. METHOD: A comprehensive survey and data analysis were conducted using the NHANES database to investigate the relationship between tMFR and the risk of TD. This study utilized multiple logistic regression, smooth curve fitting, and subgroup analysis across four periods from 2011 to 2018. RESULT: A total of 11,912 subjects were included in the study, showing a prevalence of 7.14% for TD. The research indicated that tMFR had an inverse correlation with the risk of TD in a comprehensive model (OR = 0.90, 95% CI 0.82 to 1.00). When tMFR was divided into quartiles (Q1-Q4), individuals in the highest quartile had a 28% lower risk of TD than those in Q1 (OR = 0.72, 95% CI 0.57 to 0.91). Analysis using smoothed curve fitting demonstrated a nonlinear relationship between tMFR and TD risk, with the inflection point for tMFR saturation effect identified as 1.5. Subgroup analysis further confirmed the strong association between tMFR and TD risk. Receiver operating characteristic (ROC) curve analysis indicated that tMFR exhibited superior predictive ability for TD relative to BMI. CONCLUSION: The study found a negative association between tMFR and the risk of TD; however, additional prospective studies are required to validate these findings.


Assuntos
Inquéritos Nutricionais , Doenças da Glândula Tireoide , Humanos , Estudos Transversais , Masculino , Feminino , Doenças da Glândula Tireoide/epidemiologia , Pessoa de Meia-Idade , Adulto , Estados Unidos/epidemiologia , Tecido Adiposo , Fatores de Risco , Índice de Massa Corporal , Obesidade/epidemiologia , Idoso , Adulto Jovem , Prevalência , Músculo Esquelético
19.
Molecules ; 29(6)2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38542947

RESUMO

According to ancient Chinese books, bear grease has the effects of strengthening muscles and bones, which is beneficial for weakness, but there is relatively little research on it. Thus, the extraction of it is beneficial for compensating for research in this area. In this study, a uniform experimental design method was used to optimize the extraction process of bear grease by enzymatic hydrolysis extraction, and the extraction rate can reach 81.89% under optimized extraction conditions. Furthermore, the components of bear grease obtained by this study were analyzed by GC-MS, and the results showed that ursolic oil was rich in unsaturated fatty acids (67.51%), which was higher than that of the traditional method (66.92%). The composition of bear grease extracted by the enzymatic method was also better than that extracted by the traditional method. In addition, bear grease obtained in this study had the obvious activity of promoting hair growth. The length, weight, and number of hair follicles in the depilation area of mice in the high-dose group were significantly different from those in the blank group (p < 0.01). This study optimized the extraction process of bear grease and conducted a preliminary analysis of its fatty acid composition, which is expected to provide some reference for the development of the medicinal value of bear grease.


Assuntos
Ursidae , Animais , Camundongos , Ácidos Graxos/análise , Ácidos Graxos Insaturados/análise , Hidrólise , Cabelo/química
20.
Angew Chem Int Ed Engl ; 63(18): e202401716, 2024 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-38372050

RESUMO

High-capacity Ni-rich layered oxides are promising cathode materials for fabrication of lithium-ion batteries (LIBs) with high energy density. However, thermal runaway of LIBs with these cathodes leads to great safety concerns. In this study, single crystalline LiNi0.9Co0.05Mn0.05O2 (NCM-SC) has been prepared and a flexible optical fiber was buried inside the pouch-type LIBs with NCM-SC cathode to in situ study its real-time temperature evolution during charge/discharge process. NCM-SC exhibits an enhanced Li+ ions transportation efficiency and electrode reaction kinetics, which can effectively reduce the generation of polarization heat and mitigate the internal temperature rise of the pouch-type battery. Meanwhile, solid-electrolyte interface (SEI) film decomposition and gas accumulation are effectively alleviated, due to the enhanced thermal stability of SEI film formed on NCM-SC. Moreover, the single crystal architecture can effectively retard layered to spinal and rock-salt phase transition, mitigate the crack formation and structural collapse. Consequently, NCM-SC exhibits an excellent electrochemical performance and enhanced thermal stability.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA