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1.
Nature ; 632(8024): 267-272, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38987606

RESUMO

The fermionic Hubbard model (FHM)1 describes a wide range of physical phenomena resulting from strong electron-electron correlations, including conjectured mechanisms for unconventional superconductivity. Resolving its low-temperature physics is, however, challenging theoretically or numerically. Ultracold fermions in optical lattices2,3 provide a clean and well-controlled platform offering a path to simulate the FHM. Doping the antiferromagnetic ground state of a FHM simulator at half-filling is expected to yield various exotic phases, including stripe order4, pseudogap5, and d-wave superfluid6, offering valuable insights into high-temperature superconductivity7-9. Although the observation of antiferromagnetic correlations over short10 and extended distances11 has been obtained, the antiferromagnetic phase has yet to be realized as it requires sufficiently low temperatures in a large and uniform quantum simulator. Here we report the observation of the antiferromagnetic phase transition in a three-dimensional fermionic Hubbard system comprising lithium-6 atoms in a uniform optical lattice with approximately 800,000 sites. When the interaction strength, temperature and doping concentration are finely tuned to approach their respective critical values, a sharp increase in the spin structure factor is observed. These observations can be well described by a power-law divergence, with a critical exponent of 1.396 from the Heisenberg universality class12. At half-filling and with optimal interaction strength, the measured spin structure factor reaches 123(8), signifying the establishment of an antiferromagnetic phase. Our results provide opportunities for exploring the low-temperature phase diagram of the FHM.

2.
Proc Natl Acad Sci U S A ; 121(3): e2314245121, 2024 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-38194460

RESUMO

Transcription-coupled nucleotide excision repair (TC-NER) is a highly conserved DNA repair pathway that removes bulky lesions in the transcribed genome. Cockayne syndrome B protein (CSB), or its yeast ortholog Rad26, has been known for decades to play important roles in the lesion-recognition steps of TC-NER. Another conserved protein ELOF1, or its yeast ortholog Elf1, was recently identified as a core transcription-coupled repair factor. How Rad26 distinguishes between RNA polymerase II (Pol II) stalled at a DNA lesion or other obstacles and what role Elf1 plays in this process remains unknown. Here, we present cryo-EM structures of Pol II-Rad26 complexes stalled at different obstacles that show that Rad26 uses a common mechanism to recognize a stalled Pol II, with additional interactions when Pol II is arrested at a lesion. A cryo-EM structure of lesion-arrested Pol II-Rad26 bound to Elf1 revealed that Elf1 induces further interactions between Rad26 and a lesion-arrested Pol II. Biochemical and genetic data support the importance of the interplay between Elf1 and Rad26 in TC-NER initiation. Together, our results provide important mechanistic insights into how two conserved transcription-coupled repair factors, Rad26/CSB and Elf1/ELOF1, work together at the initial lesion recognition steps of transcription-coupled repair.


Assuntos
Reparo por Excisão , Parada Cardíaca , Humanos , Cognição , Dano ao DNA , RNA Polimerase II/genética , Saccharomyces cerevisiae/genética
3.
PLoS Comput Biol ; 20(7): e1012271, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-39078811

RESUMO

Melanoma showcases a complex interplay of genetic alterations and intra- and inter-cellular morphological changes during metastatic transformation. While pivotal, the role of specific mutations in dictating these changes still needs to be fully elucidated. Telomerase promoter mutations (TERTp mutations) significantly influence melanoma's progression, invasiveness, and resistance to various emerging treatments, including chemical inhibitors, telomerase inhibitors, targeted therapy, and immunotherapies. We aim to understand the morphological and phenotypic implications of the two dominant monoallelic TERTp mutations, C228T and C250T, enriched in melanoma metastasis. We developed isogenic clonal cell lines containing the TERTp mutations and utilized dual-color expression reporters steered by the endogenous Telomerase promoter, giving us allelic resolution. This approach allowed us to monitor morpholomic variations induced by these mutations. TERTp mutation-bearing cells exhibited significant morpholome differences from their wild-type counterparts, with increased allele expression patterns, augmented wound-healing rates, and unique spatiotemporal dynamics. Notably, the C250T mutation exerted more pronounced changes in the morpholome than C228T, suggesting a differential role in metastatic potential. Our findings underscore the distinct influence of TERTp mutations on melanoma's cellular architecture and behavior. The C250T mutation may offer a unique morpholomic and systems-driven advantage for metastasis. These insights provide a foundational understanding of how a non-coding mutation in melanoma metastasis affects the system, manifesting in cellular morpholome.


Assuntos
Aprendizado Profundo , Melanoma , Mutação , Regiões Promotoras Genéticas , Telomerase , Telomerase/genética , Telomerase/metabolismo , Regiões Promotoras Genéticas/genética , Melanoma/genética , Melanoma/patologia , Humanos , Linhagem Celular Tumoral , Metástase Neoplásica/genética , Biologia Computacional , Fenótipo , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia
4.
PLoS Comput Biol ; 20(9): e1012491, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39348424

RESUMO

Understanding the mechanisms of the cellular aging processes is crucial for attempting to extend organismal lifespan and for studying age-related degenerative diseases. Yeast cells divide through budding, providing a classical biological model for studying cellular aging. With their powerful genetics, relatively short cell cycle, and well-established signaling pathways also found in animals, yeast cells offer valuable insights into the aging process. Recent experiments suggested the existence of two aging modes in yeast characterized by nucleolar and mitochondrial declines, respectively. By analyzing experimental data, this study shows that cells evolving into those two aging modes behave differently when they are young. While buds grow linearly in both modes, cells that consistently generate spherical buds throughout their lifespan demonstrate greater efficacy in controlling bud size and growth rate at young ages. A three-dimensional multiscale chemical-mechanical model was developed and used to suggest and test hypothesized impacts of aging on bud morphogenesis. Experimentally calibrated model simulations showed that during the early stage of budding, tubular bud shape in one aging mode could be generated by locally inserting new materials at the bud tip, a process guided by the polarized Cdc42 signal. Furthermore, the aspect ratio of the tubular bud could be stabilized during the late stage as observed in experiments in this work. The model simulation results suggest that the localization of new cell surface material insertion, regulated by chemical signal polarization, could be weakened due to cellular aging in yeast and other cell types, leading to the change and stabilization of the bud aspect ratio.


Assuntos
Senescência Celular , Modelos Biológicos , Morfogênese , Saccharomyces cerevisiae , Saccharomyces cerevisiae/crescimento & desenvolvimento , Morfogênese/fisiologia , Senescência Celular/fisiologia , Simulação por Computador , Biologia Computacional , Transdução de Sinais/fisiologia
5.
J Biol Chem ; 299(10): 105230, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37689116

RESUMO

Macrophages must respond appropriately to pathogens and other pro-inflammatory stimuli in order to perform their roles in fighting infection. One way in which inflammatory stimuli can vary is in their dynamics-that is, the amplitude and duration of stimulus experienced by the cell. In this study, we performed long-term live cell imaging in a microfluidic device to investigate how the pro-inflammatory genes IRF1, CXCL10, and CXCL9 respond to dynamic interferon-gamma (IFNγ) stimulation. We found that IRF1 responds to low concentration or short duration IFNγ stimulation, whereas CXCL10 and CXCL9 require longer or higherconcentration stimulation to be expressed. We also investigated the heterogeneity in the expression of each gene and found that CXCL10 and CXCL9 have substantial cell-to-cell variability. In particular, the expression of CXCL10 appears to be largely stochastic with a subpopulation of nonresponding cells across all the stimulation conditions tested. We developed both deterministic and stochastic models for the expression of each gene. Our modeling analysis revealed that the heterogeneity in CXCL10 can be attributed to a slow chromatin-opening step that is on a similar timescale to that of adaptation of the upstream signal. In this way, CXCL10 expression in individual cells can remain stochastic in response to each pulse of repeated stimulation, which we also validated by experiments. Together, we conclude that pro-inflammatory genes in the same signaling pathway can respond to dynamic IFNγ stimulus with very different response features and that upstream signal adaptation can contribute to shaping heterogeneous gene expression.


Assuntos
Quimiocina CXCL10 , Quimiocina CXCL9 , Regulação da Expressão Gênica , Fator Regulador 1 de Interferon , Macrófagos , Quimiocina CXCL10/genética , Quimiocina CXCL10/metabolismo , Quimiocina CXCL9/genética , Quimiocina CXCL9/metabolismo , Interferon gama/farmacologia , Macrófagos/metabolismo , Transdução de Sinais/genética , Células RAW 264.7 , Animais , Camundongos , Fator Regulador 1 de Interferon/genética , Fator Regulador 1 de Interferon/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/imunologia , Simulação por Computador , Análise de Célula Única , Adjuvantes Imunológicos/farmacologia
6.
J Am Chem Soc ; 146(5): 3545-3552, 2024 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-38277257

RESUMO

Atom-precise metal nanoclusters (NCs) with large bulk (nuclearity >60) are important species for insight into the embryonic phase of metal nanoparticles and their top-down etching synthesis. Herein, we report a metastable rod-shaped 70-nuclei copper-hydride NC, [Cl@Cu70H22(PhC≡C)29(CF3COO)16]2+ (Cu70), with Cl- as the template, in which the Cl@Cu59 kernel adopts a distinctive metal packing mode along the bipolar direction, and the protective ligand shell exhibits corresponding site differentiation. In terms of metal nuclearity, Cu70 is the largest alkynyl-stabilized Cu-hydride cluster to date. As a typical highly active intermediate, Cu70 could undergo a transformation into a series of robust modularly assembled Cu clusters (B-type Cu8, A-A-type Cu22, A-B-type Cu23, and A-B-A-type Cu38) upon etching by p-tert-butylthiacalix[4]arene (H4TC4A), which could not be achieved by "one-pot" synthetic methods. Notably, the patterns of A and B blocks in the Cu NCs could be effectively modulated by employing appropriate counterions and blockers, and the modular assembly mechanism was illustrated through comprehensive solution chemistry analysis using HR-ESI-MS. Furthermore, catalytic investigations reveal that Cu38 could serve as a highly efficient catalyst for the cycloaddition of propargylic amines with CO2 under mild conditions. This work not only enriched the family of high-nuclear copper-hydride NCs but also provided new insights into the growth mechanism of metal NCs.

7.
Anal Chem ; 2024 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-39014979

RESUMO

Traditional visual biosensing platforms rely on color to display detection results, which can be influenced by individual visual abilities, equipment, parameters, and lighting conditions during photo capture. This limitation significantly impedes the advancement of next-generation portable electrochemical biosensors. Therefore, we propose a visual biosensing device that utilizes distance as an indicator, enabling the facile determination of the length of discoloration, which is inversely proportional to the concentration of the target analyte. The separation of the Signal Generation (SG) and Signal Output (SO) regions effectively mitigates potential interference from the sample color. Additionally, the SG region can be disassembled to facilitate electrochemical impedance spectroscopy (EIS) detection in laboratory settings, enabling dual-mode detection. Meanwhile, the utilization of piezoelectric nanogenerators (PENG) empowers the entire point-of-care testing (POCT) sensing device, effectively addressing the issue of a limited battery life. The biosensing device exhibited a satisfactory linear range (EIS mode, 5 pg/L to 5 mg/L; visual mode, 0.5 ng/L to 5 mg/L) and a low limit of detection (EIS mode, 2.3 pg/L; visual mode, 0.14 ng/L) with S/N = 3 for ochratoxin A (OTA) under optimized conditions. The self-powered and cost-effective dual-mode biosensing platform developed for OTA detection offers clear and easily interpretable results, demonstrating a high accuracy in laboratory settings.

8.
Biochem Biophys Res Commun ; 735: 150451, 2024 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-39094233

RESUMO

Cerebral small vascular disease (CSVD) has a high incidence worldwide, but its pathological mechanisms remain poorly understood due to the lack of proper animal models. The current animal models of CSVD have several limitations such as high mortality rates and large-sized lesions, and thus it is urgent to develop new animal models of CSVD. Ultrasound can activate protoporphyrin to produce reactive oxygen species in a liquid environment. Here we delivered protoporphyrin into cerebral small vessels of rat brain through polystyrene microspheres with a diameter of 15 µm, and then performed transcranial ultrasound stimulation (TUS) on the model rats. We found that TUS did not affect the large vessels or cause large infarctions in the brain of model rats. The mortality rates were also comparable between the sham and model rats. Strikingly, TUS induced several CSVD-like phenotypes such as cerebral microinfarction, white matter injuries and impaired integrity of endothelial cells in the model rats. Additionally, these effects could be alleviated by antioxidant treatment with N-acetylcysteine (NAC). As control experiments, TUS did not lead to cerebral microinfarction in the rat brain when injected with the polystyrene microspheres not conjugated with protoporphyrin. In sum, we generated a rat model of CSVD that may be useful for the mechanistic study and drug development for CSVD.


Assuntos
Doenças de Pequenos Vasos Cerebrais , Modelos Animais de Doenças , Protoporfirinas , Ratos Sprague-Dawley , Animais , Doenças de Pequenos Vasos Cerebrais/patologia , Doenças de Pequenos Vasos Cerebrais/diagnóstico por imagem , Protoporfirinas/farmacologia , Masculino , Ratos , Encéfalo/patologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/diagnóstico por imagem , Ondas Ultrassônicas , Acetilcisteína/farmacologia , Microesferas
9.
Small ; : e2407220, 2024 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-39410732

RESUMO

Multiple resonance thermally activated delayed fluorescence (MR-TADF) materials are applied in organic light-emitting diodes (OLEDs) due to their high efficiency and color purity. However, the inherent planar structure of MR emitters presents significant challenges, including concentration-induced emission quenching, spectral redshift and broadening. To address these issues, two orthorhombic asymmetric conformational materials, SBNO and SBNOS, have been developed. Both MR-TADF emitters incorporate a sterically hindered spiro-carbon bridge to minimize intermolecular chromophore interactions. Consequently, the spectra of the SBNOS-based devices exhibit only a 4 nm redshift and a 7 nm broadening of the full-width at half maximum (FWHM) across a doping ratio range of 1-100 wt%. The steric effect produces pure green OLEDs with a CIE y of 0.69 and enhances performance, achieving a maximum external quantum efficiency (EQEmax) of up to 32.7%. The referent BNO without spiro skeleton suffers from serious spectral redshift and broadening as well as a lower device efficiency. This research demonstrates a promising approach to developing MR-TADF devices that resist redshift and broadening while maintaining high color purity and efficiency.

10.
Small ; 20(29): e2310952, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38377230

RESUMO

Salt scaling poses a significant obstacle to the practical implementation of solar-driven evaporation for desalination. Attempts to mitigate scaling by enhancing mass transfer often lead to a compromise in evaporation efficiency due to associated heat loss. In the present work, a novel seesaw evaporator with a Janus structure to harness scaling for periodic self-descaling is reported. The seesaw evaporators are facilely fabricated by delignifying balsa wood and subsequently single-sided spray-coating it with soot and polydimethylsiloxane (PDMS). This unique Janus structure enables the evaporator to float on the brine while ensuring an ample supply of solution for evaporation. During evaporation, salt ions are transported directionally toward the cocked end of the evaporator to form scaling, triggering the seesaw evaporator to flip once a threshold is reached. The accumulated salts re-dissolve back into the solution. By adjusting the tilt angle, the evaporator can achieve an impressive evaporation rate of up to 2.65 kg m-2 h-1 when evaporating an 8 wt.% NaCl solution. Remarkably, these evaporators maintain a stable evaporation rate during prolonged 120 h operation and produce ≈3.93-6.35 L m⁻2·day⁻¹ of freshwater from simulated brines when assembled into an evaporation device.

11.
J Nutr ; 154(7): 1970-1984, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38692354

RESUMO

BACKGROUND: Leucine, a branched-chain amino acid, participates in the regulation of lipid metabolism and the composition of the intestinal microbiota. However, the related mechanism remains unclear. OBJECTIVES: Here, we aimed to reveal the potential mechanisms by which hepatic CYP7A1 (a rate-limiting enzyme for bile acid [BA] synthesis) and gut microbiota coregulate BA synthesis under leucine deprivation. METHODS: To this end, 8-wk-old C57BL/6J mice were fed with either regular diets or leucine-free diets for 1 wk. Then, we investigated whether secondary BAs were synthesized by Turicibacter sanguinis in 7-wk-old C57BL/6J germ-free mice gavaged with T. sanguinis for 2 wk by determining BA concentrations in the plasma, liver, and cecum contents using liquid chromatography-tandem mass spectrometry. RESULTS: The results showed that leucine deprivation resulted in a significant increase in total BA concentration in the plasma and an increase in the liver, but no difference in total BA was observed in the cecum contents before and after leucine deprivation. Furthermore, leucine deprivation significantly altered BA profiles such as taurocholic acid and ω-muricholic acid in the plasma, liver, and cecum contents. CYP7A1 expression was significantly upregulated in the liver under leucine deprivation. Leucine deprivation also regulated the composition of the gut microbiota; specifically, it significantly upregulated the relative abundance of T. sanguinis, thus enhancing the conversion of primary BAs into secondary BAs by intestinal T. sanguinis in mice. CONCLUSIONS: Overall, leucine deprivation regulated BA profiles in enterohepatic circulation by upregulating hepatic CYP7A1 expression and increasing intestinal T. sanguinis abundance. Our findings reveal the contribution of gut microbiota to BA metabolism under dietary leucine deprivation.


Assuntos
Ácidos e Sais Biliares , Colesterol 7-alfa-Hidroxilase , Microbioma Gastrointestinal , Leucina , Fígado , Camundongos Endogâmicos C57BL , Regulação para Cima , Animais , Colesterol 7-alfa-Hidroxilase/metabolismo , Colesterol 7-alfa-Hidroxilase/genética , Ácidos e Sais Biliares/metabolismo , Leucina/metabolismo , Fígado/metabolismo , Camundongos , Masculino , Actinobacteria/metabolismo , Multiômica
12.
Exp Physiol ; 109(2): 190-201, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37845840

RESUMO

Diabetic cardiomyopathy (DCM) is a significant cause of heart failure in patients with diabetes, and its pathogenesis is closely related to myocardial mitochondrial injury and functional disability. Studies have shown that the development of diabetic cardiomyopathy is related to disorders in mitochondrial metabolic substrates, changes in mitochondrial dynamics, an imbalance in mitochondrial Ca2+ regulation, defects in the regulation of microRNAs, and mitochondrial oxidative stress. Physical activity may play a role in resistance to the development of diabetic cardiomyopathy by improving myocardial mitochondrial biogenesis, the level of autophagy and dynamic changes in fusion and division; enhancing the ability to cope with oxidative stress; and optimising the metabolic substrates of the myocardium. This paper puts forward a new idea for further understanding the specific mitochondrial mechanism of the occurrence and development of diabetic cardiomyopathy and clarifying the role of exercise-mediated myocardial mitochondrial changes in the prevention and treatment of diabetic cardiomyopathy. This is expected to provide a new theoretical basis for exercise to reduce diabetic cardiomyopathy symptoms.


Assuntos
Diabetes Mellitus , Cardiomiopatias Diabéticas , Humanos , Cardiomiopatias Diabéticas/metabolismo , Cardiomiopatias Diabéticas/patologia , Mitocôndrias Cardíacas/metabolismo , Miocárdio/metabolismo , Exercício Físico , Estresse Oxidativo , Diabetes Mellitus/metabolismo
13.
Inorg Chem ; 63(43): 20501-20509, 2024 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-39403728

RESUMO

Nanocluster catalysts typically face challenges in balancing stability with catalytic efficiency. This study introduces a unique bismuth-oxo cluster, solely protected by two ring-opened calixarenes, which demonstrates not only enhanced structural stability but also superior catalytic performance in the sustained conversion of CO2 to HCOOH via electrocatalysis. For the first time, we reveal that under specific solvothermal conditions, tert-butylcalix[8]arene (TBC[8]) can undergo in situ oxidative cleavage of its C-C bond, leading to ring-opened polyphenolic molecules. These molecules serve as protective ligands for the bismuth-oxo cluster, bestowing exceptional structural stability and offering a more flexible and diverse configuration compared to intact TBC[8]. This adaptability promotes the exposure of active bismuth sites on the cluster surface, enhancing catalytic efficiency. Notably, the Bi10 cluster, featuring a monobismuth active site, achieves an exceptional formate production efficiency of 98.79% at -1.25 V vs RHE while maintaining superb durability over 8 h. The stability and catalytic processes of Bi10 surpass those of the Bi13 cluster, which is structurally reinforced by two intact TBC[8] molecules and stabilized by four benzoic ligands. Through in situ infrared spectroscopy and density functional theory calculations, we demonstrate that the monobismuth active site in Bi10 more effectively stabilizes the *OCHO intermediate, thereby promoting the electrocatalytic reduction of CO2 to HCOOH compared to Bi13. This comparative performance underscores the potential of ring-opened calixarene ligands in enhancing the functionality of nanocluster catalysts.

14.
BMC Infect Dis ; 24(1): 647, 2024 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-38937679

RESUMO

BACKGROUND: Refractory Helicobacter pylori (H. pylori) infection inevitably increase the difficulty of drug selection. Here, we described our experience with the use of a novel tetravalent IgY against H. pylori for the treatment of patients with refractory H. pylori infection. METHODS: Patients were randomly assigned to receive the standard quadruple therapy (amoxicillin, clarithromycin, omeprazole and bismuth potassium citrate ) for 2 weeks or 250 mg of avian polyclonal IgY orally twice a day for 4 weeks. The binding efficacy of IgY to H. pylori antigens was detected by western blotting13. C-urea breath test was performed to evaluate the eradication therap's efficacy. The side effects of IgY were evaluated via various routine tests. The questionnaire was used to gather clinical symptoms and adverse reactions. RESULTS: Western blot analysis showed that tetravalent IgY simultaneously bind to VacA, HpaA, CagA and UreB of H. pylori. Tetravalent IgY had an eradication rate of 50.74% in patients with refractory H. pylori and an inhibition rate of 50.04% against DOB (delta over baseline) of 13C-urea. The symptom relief rate was 61.76% in thirty-four patients with clinical symptoms, and no adverse reactions were observed during tetravalent IgY treatment period. CONCLUSIONS: Polyclonal avian tetravalent IgY reduced H. pylori infection, and showed good efficacy and safety in the treatment of refractory H. pylori infection patients, which represented an effective therapeutic option of choice for patients with refractory H. pylori infection.


Assuntos
Antibacterianos , Infecções por Helicobacter , Helicobacter pylori , Imunoglobulinas , Humanos , Infecções por Helicobacter/tratamento farmacológico , Masculino , Feminino , Helicobacter pylori/efeitos dos fármacos , Pessoa de Meia-Idade , Imunoglobulinas/uso terapêutico , Imunoglobulinas/administração & dosagem , Adulto , Antibacterianos/uso terapêutico , Antibacterianos/efeitos adversos , Resultado do Tratamento , Idoso , Quimioterapia Combinada , Claritromicina/uso terapêutico , Amoxicilina/uso terapêutico , Amoxicilina/administração & dosagem , Adulto Jovem , Anticorpos Antibacterianos/uso terapêutico
15.
Acta Pharmacol Sin ; 45(8): 1571-1581, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38632319

RESUMO

Liver receptor homolog-1 (LRH-1), a member of the nuclear receptor superfamily, is a ligand-regulated transcription factor that plays crucial roles in metabolism, development, and immunity. Despite being classified as an 'orphan' receptor due to the ongoing debate surrounding its endogenous ligands, recent researches have demonstrated that LRH-1 can be modulated by various synthetic ligands. This highlights the potential of LRH-1 as an attractive drug target for the treatment of inflammation, metabolic disorders, and cancer. In this review, we provide an overview of the structural basis, functional activities, associated diseases, and advancements in therapeutic ligand research targeting LRH-1.


Assuntos
Descoberta de Drogas , Receptores Citoplasmáticos e Nucleares , Humanos , Animais , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores Citoplasmáticos e Nucleares/química , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Ligantes , Doenças Metabólicas/tratamento farmacológico , Doenças Metabólicas/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo
16.
Acta Pharmacol Sin ; 45(9): 1964-1977, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38698214

RESUMO

The retinoic acid receptor-related orphan receptor γ (RORγ) is regarded as an attractive therapeutic target for the treatment of prostate cancer. Herein, we report the identification, optimization, and evaluation of 1,2,3,4-tetrahydroquinoline derivatives as novel RORγ inverse agonists, starting from high throughput screening using a thermal stability shift assay (TSA). The representative compounds 13e (designated as XY039) and 14a (designated as XY077) effectively inhibited the RORγ transcriptional activity and exhibited excellent selectivity against other nuclear receptor subtypes. The structural basis for their inhibitory potency was elucidated through the crystallographic study of RORγ LBD complex with 13e. Both 13e and 14a demonstrated reasonable antiproliferative activity, potently inhibited colony formation and the expression of AR, AR regulated genes, and other oncogene in AR positive prostate cancer cell lines. Moreover, 13e and 14a effectively suppressed tumor growth in a 22Rv1 xenograft tumor model in mice. This work provides new and valuable lead compounds for further development of drugs against prostate cancer.


Assuntos
Antineoplásicos , Proliferação de Células , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares , Neoplasias da Próstata , Quinolinas , Masculino , Animais , Humanos , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Neoplasias da Próstata/metabolismo , Quinolinas/farmacologia , Quinolinas/química , Quinolinas/uso terapêutico , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/agonistas , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/antagonistas & inibidores , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Estrutura-Atividade , Agonismo Inverso de Drogas , Camundongos , Camundongos Nus , Descoberta de Drogas , Ensaios Antitumorais Modelo de Xenoenxerto , Camundongos Endogâmicos BALB C
17.
Environ Res ; 255: 119162, 2024 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-38762003

RESUMO

In order to evaluate the impact of salinity gradients on the aniline biodegradation system, six reactors at salinity concentrations (0%-5%) were established. The results presented the salinity except for 5% imposed negligible effects on aniline degradation performance. Nitrification had prominent resistance to salinity (0%-1.5%) while were significantly restrained when salinity increased. The total nitrogen (TN) removal efficiency of Z4 (1.5%) was 20.5% higher than Z1 (0%) during the stable operation phase. Moreover, high throughput sequencing analysis showed that halophilic bacterium, such as Halomonas, Rhodococcus, remained greater survival advantages in high salinity system. The substantial enrichment of Flavobacterium, Dokdonella, Paracoccus observed in Z4 ensured its excellent nitrogen removal performance. The close cooperation among dominant functional bacteria was strengthened when salt content was below 1.5% while exceeding 1.5% led to the collapse of metabolic capacity through integrating the toxicity of aniline and high osmotic pressure.


Assuntos
Compostos de Anilina , Biodegradação Ambiental , Poluentes Químicos da Água , Compostos de Anilina/toxicidade , Poluentes Químicos da Água/toxicidade , Estresse Salino , Bactérias/metabolismo , Bactérias/genética , Reatores Biológicos/microbiologia , Salinidade
18.
Curr Pain Headache Rep ; 28(11): 1167-1176, 2024 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-38907791

RESUMO

PURPOSE OF REVIEW: To explore the mechanism and therapeutic effect of sympathetic nerve regulation on neuropathic pain. RECENT FINDINGS: A comprehensive search was conducted in the PubMed and CNKI libraries, using the following keywords: stele ganglion block, neuropathic pain, sympathetic nerve block, sympathetic chemical destruction, and sympathetic radiofrequency thermocoagulation. We selected and critically reviewed research articles published in English that were related to sympathetic modulation in the treatment of neuropathic pain. The collected literature will be classified according to content and reviewed in combination with experimental results and clinical cases. Neuropathic pain was effectively treated with sympathetic regulation technology. Its mechanism includes the inhibition of sympathetic nerve activity, regulation of the inflammatory response, and inhibition of pain transmission, which greatly alleviates neuropathic pain in patients. Stellate ganglion blocks, thoracic and lumbar sympathectomies, chemical destruction, and radiofrequency thermocoagulation have been widely used to treat neuropathic pain. Sympathetic regulation can effectively relieve pain symptoms and improve the patient's quality of life by inhibiting sympathetic nerve activity, reducing the production and release of pain-related mediators, and inhibiting pain transmission. CT-guided radiofrequency thermocoagulation of the thoracic and lumbar sympathetic nerves is effective and durable, with few complications, and is recommended as a treatment for intractable neuropathic pain.


Assuntos
Bloqueio Nervoso Autônomo , Neuralgia , Humanos , Neuralgia/terapia , Neuralgia/fisiopatologia , Bloqueio Nervoso Autônomo/métodos , Sistema Nervoso Simpático/fisiopatologia , Simpatectomia/métodos , Eletrocoagulação/métodos , Gânglio Estrelado/fisiopatologia
19.
J Med Internet Res ; 26: e55576, 2024 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-39348685

RESUMO

BACKGROUND: Osteoarthritis (OA) is a chronic musculoskeletal disease that causes pain, functional disability, and an economic burden. Nonpharmacological treatments are at the core of OA management. However, limited access to these services due to uneven regional local availability has been highlighted. Internet-based telehealth (IBTH) programs, providing digital access to abundant health care resources, offer advantages, such as convenience and cost-effectiveness. These characteristics make them promising strategies for the management of patients with OA. OBJECTIVE: This study aimed to evaluate the effectiveness of IBTH programs in the management of patients with hip or knee OA. METHODS: We systematically searched 6 electronic databases to identify trials comparing IBTH programs with conventional interventions for hip and knee OA. Studies were selected based on inclusion and exclusion criteria, focusing on outcomes related to function, pain, and self-efficacy. Standardized mean differences (SMDs) with 95% CIs were calculated to compare outcome measures. Heterogeneity was assessed using I² and χ² tests. The methodological quality of the selected studies and the quality of evidence were also evaluated. RESULTS: A total of 21 studies with low-to-high risk of bias were included in this meta-analysis. The pooled results showed that IBTH has a superior effect on increasing function (SMD 0.30, 95% CI 0.23-0.37, P<.001), relieving pain (SMD -0.27, 95% CI -0.34 to -0.19, P<.001), and improving self-efficacy for pain (SMD 0.21, 95% CI 0.08-0.34, P<.001) compared to the conventional intervention group. Subgroup analysis revealed that IBTH with exercise can significantly alleviate pain and improve function and self-efficacy, but IBTH with cognitive-behavioral therapy only had the effect of reducing pain. CONCLUSIONS: The meta-analysis provides moderate-quality evidence that IBTH programs have a beneficial effect on improving function, relieving pain, and improving self-efficacy compared to conventional interventions in patients with hip or knee OA. Limited evidence suggests that the inclusion of exercise regimens in IBTH programs is recommended. TRIAL REGISTRATION: PROSPERO CRD42024541111; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=541111.


Assuntos
Internet , Osteoartrite do Quadril , Osteoartrite do Joelho , Telemedicina , Humanos , Osteoartrite do Quadril/terapia , Osteoartrite do Joelho/terapia
20.
Luminescence ; 39(3): e4717, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38504447

RESUMO

Tetracyclines are currently the most commonly used class of antibiotics, and their residue issue significantly impacts public health safety. In this study, a surface modification of perovskite with cetyltrimethylammonium bromide led to the generation of stable electrochemiluminescence (ECL) emitters in aqueous systems and improved the biocompatibility of perovskite. A perovskite quantum dot-based ECL sensing strategy was developed. Utilizing the corresponding aptamer of the antibiotics, strain displacement reactions were triggered, disrupting the ECL quenching system composed of perovskite and Ag nanoclusters (Ag NCs) on the electrode surface, generating a signal to achieve quantitative detection of several common tetracycline antibiotics. The perovskite quantum dot provided a strong and stable initial signal, while the efficient catalytic activity of the silver cluster enhanced the recognition sensitivity. Tetracycline, chlortetracycline, and oxytetracycline were used as examples to demonstrate the differentiation and quantitative detection through this method. In addition, the aptasensor exhibited analytical performance with the linear range (0.1-10 µM OTC) and good recovery rates of 94.7% to 101.6% in real samples. This approach has the potential to become a sensitive and practical approach for assessing antibiotic residues.


Assuntos
Aptâmeros de Nucleotídeos , Técnicas Biossensoriais , Compostos de Cálcio , Nanopartículas Metálicas , Óxidos , Titânio , Tetraciclina , Técnicas Eletroquímicas/métodos , Medições Luminescentes/métodos , Antibacterianos , Tetraciclinas , Técnicas Biossensoriais/métodos , Nanopartículas Metálicas/química , Aptâmeros de Nucleotídeos/química
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