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1.
Pestic Biochem Physiol ; 204: 106101, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39277423

RESUMO

Riptortus pedestris (Hemiptera: Alydidae), a common agricultural pest, is the major causative agent of "soybean staygreen." However, the interactions between chemosensory proteins (CSPs) in R. pedestris and host plant volatiles have yet to be comprehensively studied. In this study, we performed real-time fluorescence quantitative polymerase chain reaction (PCR) to analyze the antennal expression of RpedCSP22 and subsequently analyzed the interactions between 21 soybean volatiles, five aggregation pheromones, and RpedCSP22 protein in vitro using a protein expression system, molecular docking, site-directed mutagenesis, and fluorescence competitive binding experiments. The RpedCSP22 protein showed binding affinity to three soybean volatiles (benzaldehyde, 4-ethylbenzaldehyde, and 1-octene-3-ol), with optimal binding observed under neutral pH conditions, and lost binding ability after site-directed mutagenesis. In subsequent RNA interference (RNAi) studies, gene silencing was more than 90 %, and in silenced insects, electroantennographic responses were reduced by more than 75 % compared to non-silenced insects. Moreover, Y-tube olfactory behavioral assessments revealed that the attraction of R. pedestris to the three soybean volatiles was significantly attenuated. These findings suggest that RpedCSP22 plays an important role in the recognition of host plant volatiles by R. pedestris andprovides a theoretical basis for the development of novel inhibitors targeting pest behavior.


Assuntos
Glycine max , Proteínas de Insetos , Compostos Orgânicos Voláteis , Animais , Glycine max/metabolismo , Proteínas de Insetos/metabolismo , Proteínas de Insetos/genética , Proteínas de Insetos/química , Compostos Orgânicos Voláteis/metabolismo , Mutagênese Sítio-Dirigida , Simulação de Acoplamento Molecular , Hemípteros/metabolismo , Hemípteros/genética , Antenas de Artrópodes/metabolismo , Feromônios/metabolismo , Heterópteros/metabolismo , Heterópteros/genética
2.
J Inflamm Res ; 17: 6143-6158, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39262652

RESUMO

Objective: To investigate the effects of inhibiting the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome on neuronal damage and chronic pro-inflammatory responses during epileptogenesis in a mouse model of pilocarpine-induced status epilepticus (SE). Methods: Mice were randomly allocated into three groups: control, SE, and SE + MCC 950. The expression patterns of M1 and M2 microglial biomarkers in the hippocampus were quantified using Western blotting, quantitative real-time polymerase chain reaction, enzyme-linked immunosorbent assay, and immunofluorescence staining. Additionally, seizure susceptibility, video-electroencephalography recording, Morris water maze test, and brain immunofluorescence staining were performed to evaluate the epileptic brain 4 weeks post-SE. Results: Within 72 hours post-SE, hippocampal microglia demonstrated a preferential polarization towards the M1 phenotype, a trend that was mitigated by NLRP3 inflammasome inhibition. During epileptogenesis, SE mice treated with NLRP3 inflammasome inhibition exhibited reduced neuronal damage, improved cognitive function, decreased seizure susceptibility, and attenuated chronic pro-inflammatory responses. Conclusion: Inhibition of NLRP3 inflammasome post-SE effectively ameliorates neuronal loss, seizure susceptibility, and cognitive dysfunction during epileptogenesis. This neuroprotective effect may be mediated through the mitigation of chronic pro-inflammatory responses within the epileptic brain.

3.
Front Public Health ; 12: 1419305, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39185128

RESUMO

There is intense competition among pharmaceutical companies with the rapid growth of the global pharmaceutical industry. In recent years, China has continuously increased the reform of the medical system. Technology mergers and acquisitions (M&A) in China's pharmaceutical industry have emerged in this complex policy and economic background. This paper conducts an empirical study from the dual perspectives of financial performance and innovation performance, based on unbalanced panel data of Chinese listed pharmaceutical firms from 2012 to 2022. The impact of technology M&A on firm performance is analyzed in terms of the heterogeneity of firm characteristics. Meanwhile, the relationship between R&D investment in technology M&A and firm performance is examined. The results show that technology M&A can promote the performance of pharmaceutical companies, and R&D investment has a mediating effect on the impact of technology M&A on corporate performance. Based on the above findings, this study enriches the relevant literature on technology M&A in the pharmaceutical industry, provides warnings and suggestions for pharmaceutical companies to improve corporate performance through technology M&A, and provides reference materials for future policy formulation.


Assuntos
Indústria Farmacêutica , China , Humanos , Pesquisa Empírica , Investimentos em Saúde
4.
Front Immunol ; 15: 1413485, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39144142

RESUMO

Millions of microorganisms make up the complex microbial ecosystem found in the human gut. The immune system's interaction with the gut microbiota is essential for preventing inflammation and maintaining intestinal homeostasis. Numerous metabolic products that can cross-talk between immune cells and the gut epithelium are metabolized by the gut microbiota. Traumatic injury elicits a great and multifaceted immune response in the minutes after the initial offense, containing simultaneous pro- and anti-inflammatory responses. The development of innovative therapies that improve patient outcomes depends on the gut microbiota and immunological responses to trauma. The altered makeup of gut microbes, or gut dysbiosis, can also dysregulate immunological responses, resulting in inflammation. Major human diseases may become more common as a result of chronic dysbiosis and the translocation of bacteria and the products of their metabolism beyond the mucosal barrier. In this review, we briefly summarize the interactions between the gut microbiota and the immune system and human disease and their therapeutic probiotic formulations. We also discuss the immune response to traumatic injury.


Assuntos
Disbiose , Microbioma Gastrointestinal , Ferimentos e Lesões , Humanos , Microbioma Gastrointestinal/imunologia , Disbiose/imunologia , Animais , Ferimentos e Lesões/imunologia , Ferimentos e Lesões/microbiologia , Probióticos/uso terapêutico , Sistema Imunitário/imunologia , Sistema Imunitário/metabolismo , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Mucosa Intestinal/metabolismo , Inflamação/imunologia , Inflamação/microbiologia
6.
JACC Asia ; 4(7): 573-575, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-39101107
7.
Int J Biol Sci ; 20(10): 4055-4073, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39113713

RESUMO

In the context of diabetes, endothelial cells frequently exhibit compromised intercellular junctions and accelerated cellular senescence simultaneously. The precise mechanisms underlying these issues and the identification of effective treatments remain largely undefined. Our findings reveal that human umbilical vein endothelial cells (HUVECs) can counteract senescence and uphold the integrity of intercellular junctions under mildly to moderately elevated glucose levels (10 mM and 15 mM) via two primary mechanisms: i) The acetylation of NRF2 at lysine residues K56, K68, and K52 prevents its ubiquitination, enhancing the transcription of antioxidant genes GST, SOD1, and GPX1. This activity diminishes cytoplasmic oxidative stress, thereby mitigating endothelial cell senescence. ii) The interaction between the Neh2 domain of NRF2 and the PAS-B domain of HIF-2α within the nucleus curtails the attachment of HIF-2α to the NOX4/p22phox promoter. This action lessens oxidative stress near the cell membrane, maintaining intercellular junctions by safeguarding the disulfide bonds in occludin and E-cadherin from disruption. However, these protective strategies prove insufficient under severe hyperglycemic conditions (25 mM). Further investigation has identified Oltipraz, an activator of NRF2, as also promoting the degradation of HIF-2α. Through its simultaneous modulation of NRF2 and HIF-2α, Oltipraz significantly reduces cellular senescence and prevents the deterioration of intercellular junctions in HUVECs subjected to high glucose concentrations (25 mM). Our research positions Oltipraz as a promising therapeutic candidate for mitigating diabetes-induced vascular endothelial damage, potentially offering benefits against diabetes-related atherosclerosis and valvular calcification.


Assuntos
Senescência Celular , Células Endoteliais da Veia Umbilical Humana , Junções Intercelulares , Fator 2 Relacionado a NF-E2 , Transdução de Sinais , Humanos , Fator 2 Relacionado a NF-E2/metabolismo , Senescência Celular/fisiologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Junções Intercelulares/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Estresse Oxidativo , Diabetes Mellitus/metabolismo , Glucose/metabolismo
8.
Brain Behav ; 14(7): e3586, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38970230

RESUMO

BACKGROUND: Patients with myocardial infarction (MI) frequently experience a heightened incidence of depression, thereby increasing the risk of adverse cardiovascular events. Consequently, early detection and intervention in depressive symptoms among patients with MI are imperative. Shexiang Baoxin Pills (SBP), a Chinese patent medicine employed for the treatment of MI, exhibits diverse mechanisms targeting this condition. Nevertheless, its therapeutic efficacy on postmyocardial infarction depressive symptoms remains unclear. The aim of this study is to investigate the effectiveness and mechanism of SBP in managing depression during acute myocardial infarction (AMI). METHODS: A rat model combining MI and depression was established, and the rats were randomly divided into four groups: the model (MOD) group, SBP group, Fluoxetine (FLX) group, and Sham group. After 28 days of drug intervention, cardiac function was assessed using echocardiography while behavior was evaluated through sucrose preference test (SPT), forced swimming test (FST), and open-field test (OFT). Additionally, levels of inflammatory factors in serum and hippocampus were measured along with NLRP3 inflammasome-related protein expression via Western blotting and immunofluorescence. RESULTS: SBP can enhance cardiac function in rats with AMI and depression, while significantly ameliorating depressive-like behavior. Compared to the Sham group, levels of IL-1ß, IL-18, TNF-α, and other inflammatory factors were markedly elevated in the MOD group. However, expressions of these inflammatory factors were reduced to varying degrees following treatment with SBP or FLX. Analysis of NLRP3 inflammasome-related proteins in the hippocampus revealed a significant upregulation of IL-1ß, IL-18, NLRP3, ASC, caspase-1, and GSDMD in the MOD group; conversely, these measures were significantly attenuated after SBP intervention. CONCLUSION: We have observed a significant amelioration in depression-like behavior upon SBP administration during the treatment of AMI, suggesting that this effect may be attributed to the inhibition of NLRP3-mediated pyroptosis. (The main findings are summarized in the graphical abstract in the supplementary file.).


Assuntos
Antidepressivos , Depressão , Medicamentos de Ervas Chinesas , Inflamassomos , Infarto do Miocárdio , Proteína 3 que Contém Domínio de Pirina da Família NLR , Ratos Sprague-Dawley , Animais , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/complicações , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/administração & dosagem , Ratos , Depressão/tratamento farmacológico , Depressão/etiologia , Antidepressivos/farmacologia , Antidepressivos/administração & dosagem , Masculino , Inflamassomos/metabolismo , Inflamassomos/efeitos dos fármacos , Modelos Animais de Doenças , Transdução de Sinais/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos
9.
Pestic Biochem Physiol ; 203: 106005, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39084800

RESUMO

Odorant-binding proteins (OBPs) play key roles in host plant location by insects, and can accordingly serve as important targets for the development of attractants. In this study, we detected the high expression of SlitOBP34 in male antennae of Spodoptera litura. Subsequently, the fluorescence competitive binding experiments displayed that the SlitOBP34 protein has binding affinity for different ligands. Then, protein-ligand interaction analyses found the presence of six amino acid residues may serve as key recognition sites. Further electroantennographic and biobehavioral assessments revealed that the electrophysiological responses of male antennae were evoked in response to stimulation with the six identified host volatiles, and that these volatiles attracted male moths to varying extents. Notably, low concentrations of benzaldehyde, 1-hexanol, and cis-3-hexenyl acetate were found to have significant attractant effects on male moths, thereby identifying these three host volatiles as potential candidates for the development of male attractants. These findings advance our current understanding of the olfactory-encoded mechanisms of host plants selection in S. litura and have enabled us to develop novel adult attractants for controlling the pest in the future.


Assuntos
Antenas de Artrópodes , Proteínas de Insetos , Receptores Odorantes , Spodoptera , Compostos Orgânicos Voláteis , Animais , Spodoptera/efeitos dos fármacos , Masculino , Receptores Odorantes/metabolismo , Proteínas de Insetos/metabolismo , Proteínas de Insetos/genética , Compostos Orgânicos Voláteis/metabolismo , Compostos Orgânicos Voláteis/farmacologia , Antenas de Artrópodes/metabolismo , Hexanóis/farmacologia , Hexanóis/metabolismo , Acetatos/metabolismo , Acetatos/farmacologia , Benzaldeídos
10.
Front Public Health ; 12: 1406254, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39035183

RESUMO

In 2018, China began to gradually promote the pilot policy of centralized band purchasing of medicines. Implementing this policy has resulted in a significant decrease in drug prices. However, there needs to be a clear consensus on the impact and mechanism of action on the innovation of pharmaceutical companies. Therefore. Taking the data of Chinese Shanghai and Shenzhen A-share pharmaceutical listed companies from 2016 to 2022 as a sample, this paper empirically investigates the impact of the centralized banded purchasing policy of drugs on the innovation of pharmaceutical enterprises by using a double difference model and further analyzes the mechanism of its action. The results show that implementing the centralized banded purchasing policy can promote pharmaceutical enterprises' innovation input and output, which is robust under the parallel trend and placebo tests. Further exploring the impact mechanism of the centralized band purchasing policy on pharmaceutical enterprises' innovation, it can be found that it promotes innovation inputs through three channels: government subsidies, enterprise profits, and operating income. In addition, the impact of centralized band purchasing on enterprise innovation is heterogeneous in terms of region, enterprise nature, and scale. Therefore, the positive effects of the centralized band purchasing policy on promoting innovation in pharmaceutical enterprises should be fully recognized, and enterprise heterogeneity should be taken into account when implementing the policy. This study provides empirical evidence on the implementation effect of the centralized banded purchasing policy and provides lessons for continuously optimizing the policy to promote the high-quality development of pharmaceutical enterprises.


Assuntos
Indústria Farmacêutica , China , Custos de Medicamentos , Indústria Farmacêutica/economia , Pesquisa Empírica , Preparações Farmacêuticas/economia
11.
BMC Med Inform Decis Mak ; 24(1): 187, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38951831

RESUMO

BACKGROUND: Accurate measurement of hemoglobin concentration is essential for various medical scenarios, including preoperative evaluations and determining blood loss. Traditional invasive methods are inconvenient and not suitable for rapid, point-of-care testing. Moreover, current models, due to their complex parameters, are not well-suited for mobile medical settings, which limits the ability to conduct frequent and rapid testing. This study aims to introduce a novel, compact, and efficient system that leverages deep learning and smartphone technology to accurately estimate hemoglobin levels, thereby facilitating rapid and accessible medical assessments. METHODS: The study employed a smartphone application to capture images of the eye, which were subsequently analyzed by a deep neural network trained on data from invasive blood test data. Specifically, the EGE-Unet model was utilized for eyelid segmentation, while the DHA(C3AE) model was employed for hemoglobin level prediction. The performance of the EGE-Unet was evaluated using statistical metrics including mean intersection over union (MIOU), F1 Score, accuracy, specificity, and sensitivity. The DHA(C3AE) model's performance was assessed using mean absolute error (MAE), mean-square error (MSE), root mean square error (RMSE), and R^2. RESULTS: The EGE-Unet model demonstrated robust performance in eyelid segmentation, achieving an MIOU of 0.78, an F1 Score of 0.87, an accuracy of 0.97, a specificity of 0.98, and a sensitivity of 0.86. The DHA(C3AE) model for hemoglobin level prediction yielded promising outcomes with an MAE of 1.34, an MSE of 2.85, an RMSE of 1.69, and an R^2 of 0.34. The overall size of the model is modest at 1.08 M, with a computational complexity of 0.12 FLOPs (G). CONCLUSIONS: This system presents a groundbreaking approach that eliminates the need for supplementary devices, providing a cost-effective, swift, and accurate method for healthcare professionals to enhance treatment planning and improve patient care in perioperative environments. The proposed system has the potential to enable frequent and rapid testing of hemoglobin levels, which can be particularly beneficial in mobile medical settings. TRIAL REGISTRATION: The clinical trial was registered on the Chinese Clinical Trial Registry (No. ChiCTR2100044138) on 20/02/2021.


Assuntos
Aprendizado Profundo , Hemoglobinas , Smartphone , Humanos , Hemoglobinas/análise , Pessoa de Meia-Idade , Masculino , Aplicativos Móveis , Feminino
12.
Circulation ; 149(25): 2002-2020, 2024 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-38885303

RESUMO

Myocardial infarction is a cardiovascular disease characterized by a high incidence rate and mortality. It leads to various cardiac pathophysiological changes, including ischemia/reperfusion injury, inflammation, fibrosis, and ventricular remodeling, which ultimately result in heart failure and pose a significant threat to global health. Although clinical reperfusion therapies and conventional pharmacological interventions improve emergency survival rates and short-term prognoses, they are still limited in providing long-lasting improvements in cardiac function or reversing pathological progression. Recently, cardiac patches have gained considerable attention as a promising therapy for myocardial infarction. These patches consist of scaffolds or loaded therapeutic agents that provide mechanical reinforcement, synchronous electrical conduction, and localized delivery within the infarct zone to promote cardiac restoration. This review elucidates the pathophysiological progression from myocardial infarction to heart failure, highlighting therapeutic targets and various cardiac patches. The review considers the primary scaffold materials, including synthetic, natural, and conductive materials, and the prevalent fabrication techniques and optimal properties of the patch, as well as advanced delivery strategies. Last, the current limitations and prospects of cardiac patch research are considered, with the goal of shedding light on innovative products poised for clinical application.


Assuntos
Infarto do Miocárdio , Humanos , Infarto do Miocárdio/terapia , Infarto do Miocárdio/fisiopatologia , Animais , Alicerces Teciduais
13.
Int J Cardiol ; 412: 132305, 2024 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-38944350

RESUMO

BACKGROUND: Bempedoic acid exhibits promising potential in hyperlipidemia therapy and preventing cardiovascular events. However, investigations into its adverse drug reactions remain scant. This study seeks to utilize data mining techniques with the FDA Adverse Event Reporting System (FAERS) database to assess adverse drug events (ADEs) linked to bempedoic acid. METHODS: Based on the drug's market release timeline, we extracted data from the FAERS database covering the fourth quarter of 2020 through the fourth quarter of 2023 for disproportionality analysis. RESULTS: This study gathered a total of 5,797,543 adverse event case reports, of which 735 were linked to bempedoic acid. These reports covered 19 System Organ Classes (SOCs) and 22 Preferred Terms (PTs). Predominantly, the musculoskeletal and nervous systems were implicated in these adverse events. By conducting PT-level screening, various signals for ADEs were detected, including myalgia (ROR 30.33, PRR 28.51, IC 4.83, EBGM 28.47), arthralgia (n = 34, ROR 6.34, PRR 6.09, IC 2.61, EBGM 6.09), tendon disorders (ROR 99.57, PRR 98.75, IC 6.62, EBGM 98.28), and dizziness (ROR 3.18, PRR 3.13, IC 1.65, EBGM 3.13). Particularly noteworthy was the hypertensive crisis (ROR 28.63, PRR 28.51, IC 4.83, EBGM 28.47), which exhibited a robust signal strength, an observation previously unreported in clinical studies and drug labeling. CONCLUSION: While our results are largely consistent with the drug's specifications, several new adverse reaction signals, such as hypertensive crisis, have not been previously documented. Therefore, further investigations are necessary to assess these unlabeled adverse reactions, offering crucial support for the clinical utilization of bempedoic acid.


Assuntos
Sistemas de Notificação de Reações Adversas a Medicamentos , Ácidos Dicarboxílicos , Farmacovigilância , United States Food and Drug Administration , Humanos , Estados Unidos , Ácidos Dicarboxílicos/efeitos adversos , Masculino , Feminino , Pessoa de Meia-Idade , Bases de Dados Factuais , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Adulto , Idoso , Ácidos Graxos
14.
Int J Mol Sci ; 25(11)2024 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-38891776

RESUMO

Neural tube defects (NTDs), which are caused by impaired embryonic neural tube closure, are one of the most serious and common birth defects. Peptidyl-prolyl cis/trans isomerase 1 (Pin1) is a prolyl isomerase that uniquely regulates cell signaling by manipulating protein conformation following phosphorylation, although its involvement in neuronal development remains unknown. In this study, we explored the involvement of Pin1 in NTDs and its potential mechanisms both in vitro and in vivo. The levels of Pin1 expression were reduced in NTD models induced by all-trans retinoic acid (Atra). Pin1 plays a significant role in regulating the apoptosis, proliferation, differentiation, and migration of neurons. Moreover, Pin1 knockdown significantly was found to exacerbate oxidative stress (OS) and endoplasmic reticulum stress (ERs) in neuronal cells. Further studies showed that the Notch1-Nrf2 signaling pathway may participate in Pin1 regulation of NTDs, as evidenced by the inhibition and overexpression of the Notch1-Nrf2 pathway. In addition, immunofluorescence (IF), co-immunoprecipitation (Co-IP), and GST pull-down experiments also showed that Pin1 interacts directly with Notch1 and Nrf2. Thus, our study suggested that the knocking down of Pin1 promotes NTD progression by inhibiting the activation of the Notch1-Nrf2 signaling pathway, and it is possible that this effect is achieved by disrupting the interaction of Pin1 with Notch1 and Nrf2, affecting their proteostasis. Our research identified that the regulation of Pin1 by retinoic acid (RA) and its involvement in the development of NTDs through the Notch1-Nrf2 axis could enhance our comprehension of the mechanism behind RA-induced brain abnormalities.


Assuntos
Peptidilprolil Isomerase de Interação com NIMA , Defeitos do Tubo Neural , Tretinoína , Animais , Feminino , Humanos , Camundongos , Apoptose/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Tubo Neural/metabolismo , Tubo Neural/efeitos dos fármacos , Defeitos do Tubo Neural/metabolismo , Defeitos do Tubo Neural/genética , Defeitos do Tubo Neural/induzido quimicamente , Neurônios/metabolismo , Neurônios/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/genética , Peptidilprolil Isomerase de Interação com NIMA/metabolismo , Peptidilprolil Isomerase de Interação com NIMA/genética , Estresse Oxidativo/efeitos dos fármacos , Receptor Notch1/metabolismo , Receptor Notch1/genética , Transdução de Sinais/efeitos dos fármacos , Tretinoína/metabolismo , Tretinoína/farmacologia
15.
Int J Mol Sci ; 25(11)2024 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-38892011

RESUMO

Non-alcoholic fatty liver disease (NAFLD) is a clinicopathological syndrome characterized by diffuse hepatocellular steatosis due to fatty deposits in hepatocytes, excluding alcohol and other known liver injury factors. However, there are no specific drugs for the clinical treatment of NAFLD. Therefore, research on the pathogenesis of NAFLD at the cellular and molecular levels is a promising approach to finding therapeutic targets and developing targeted drugs for NAFLD. Pin1 is highly expressed during adipogenesis and contributes to adipose differentiation, but its specific mechanism of action in NAFLD is unclear. In this study, we investigated the role of Pin1 in promoting the development of NAFLD and its potential mechanisms in vitro and in vivo. First, Pin1 was verified in the NAFLD model in vitro using MCD diet-fed mice by Western Blot, RT-qPCR and immunohistochemistry (IHC) assays. In the in vitro study, we used the oleic acid (OA) stimulation-induced lipid accumulation model and examined the lipid accumulation in each group of cells by oil red O staining as well as BODIPY staining. The results showed that knockdown of Pin1 inhibited lipid accumulation in hepatocytes in an in vitro lipid accumulation model and improved lipid indices and liver injury levels. Moreover, in vivo, WT and Pin1-KO mice were fed a methionine-choline deficient (MCD) diet for 4 weeks to induce the NAFLD model. The effects of Pin1 on lipid accumulation, hepatic fibrosis, and oxidative stress were evaluated by biochemical analysis, glucose and insulin tolerance tests, histological analysis, IHC, RT-qPCR and Western blot assays. The results indicate that Pin1 knockdown significantly alleviated hepatic steatosis, fibrosis and inflammation in MCD-induced NAFLD mice, improved glucose tolerance and alleviated insulin resistance in mice. Further studies showed that the AMPK/ACC1 signalling pathway might take part in the process by which Pin1 regulates NAFLD, as evidenced by the inhibition of the AMPK/ACC1 pathway. In addition, immunofluorescence (IF), coimmunoprecipitation (Co-IP) and GST pull-down experiments also showed that Pin1 interacts directly with ACC1 and inhibits ACC1 phosphorylation levels. Our study suggests that Pin1 promotes NAFLD progression by inhibiting the activation of the AMPK/ACC1 signalling pathway, and it is possible that this effect is achieved by Pin1 interacting with ACC1 and inhibiting the phosphorylation of ACC1.


Assuntos
Peptidilprolil Isomerase de Interação com NIMA , Hepatopatia Gordurosa não Alcoólica , Animais , Peptidilprolil Isomerase de Interação com NIMA/metabolismo , Peptidilprolil Isomerase de Interação com NIMA/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Hepatopatia Gordurosa não Alcoólica/etiologia , Camundongos , Masculino , Camundongos Knockout , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Metabolismo dos Lipídeos , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças , Ligação Proteica , Acetil-CoA Carboxilase
16.
Nat Commun ; 15(1): 4883, 2024 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-38849395

RESUMO

The human methyltransferase and transcriptional coactivator MLL4 and its paralog MLL3 are frequently mutated in cancer. MLL4 and MLL3 monomethylate histone H3K4 and contain a set of uncharacterized PHD fingers. Here, we report a novel function of the PHD2 and PHD3 (PHD2/3) fingers of MLL4 and MLL3 that bind to ASXL2, a component of the Polycomb repressive H2AK119 deubiquitinase (PR-DUB) complex. The structure of MLL4 PHD2/3 in complex with the MLL-binding helix (MBH) of ASXL2 and mutational analyses reveal the molecular mechanism which is conserved in homologous ASXL1 and ASXL3. The native interaction of the Trithorax MLL3/4 complexes with the PR-DUB complex in vivo depends solely on MBH of ASXL1/2, coupling the two histone modifying activities. ChIP-seq analysis in embryonic stem cells demonstrates that MBH of ASXL1/2 is required for the deubiquitinase BAP1 recruitment to MLL4-bound active enhancers. Our findings suggest an ASXL1/2-dependent functional link between the MLL3/4 and PR-DUB complexes.


Assuntos
Proteínas de Ligação a DNA , Histona-Lisina N-Metiltransferase , Ligação Proteica , Proteínas Repressoras , Proteínas Supressoras de Tumor , Ubiquitina Tiolesterase , Proteínas Supressoras de Tumor/metabolismo , Proteínas Supressoras de Tumor/genética , Humanos , Histona-Lisina N-Metiltransferase/metabolismo , Histona-Lisina N-Metiltransferase/genética , Ubiquitina Tiolesterase/metabolismo , Ubiquitina Tiolesterase/genética , Proteínas Repressoras/metabolismo , Proteínas Repressoras/genética , Animais , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/genética , Camundongos , Elementos Facilitadores Genéticos , Células HEK293 , Dedos de Zinco PHD , Histonas/metabolismo
17.
Int Immunopharmacol ; 136: 112184, 2024 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-38824904

RESUMO

BACKGROUND: Despite the availability of established surgical and chemotherapy options, the treatment of bladder cancer (BCa) patients remains challenging. While immunotherapy has emerged as a promising approach, its benefits are limited to a subset of patients. The exploration of additional targets to enhance the efficacy of immunotherapy is a valuable research direction. METHOD: High endothelial venules (HEV) ssGSEA analysis was conducted using BEST. Through the utilization of R packages Limma, Seurat, SingleR, and Harmony, analyses were performed on spatial transcriptomics, bulk RNA-sequencing (bulk RNA-seq), and single-cell RNA sequencing (scRNA-seq) data, yielding HEV-related genes (HEV.RGs). Molecular subtyping analysis based on HEV.RGs was conducted using R package MOVICS, and various machine learning-integrated algorithm was employed to construct prognostic model. LDLRAD3 was validated through subcutaneous tumor formation in mice, HEV induction, Western blot, and qPCR. RESULTS: A correlation between higher HEV levels and improved immune response and prognosis was revealed by HEV ssGSEA analysis in BCa patients receiving immunotherapy. HEV.RGs were identified in subsequent transcriptomic analyses. Based on these genes, BCa patients were stratified into two molecular clusters with distinct survival and immune infiltration patterns using various clustering-integrated algorithm. Prognostic model was developed using multiple machine learning-integrated algorithm. Low LDLRAD3 expression may promote HEV generation, leading to enhanced immunotherapy efficacy, as suggested by bulk RNA-seq, scRNA-seq analyses, and experimental validation of LDLRAD3. CONCLUSIONS: HEV served as a predictive factor for immune response and prognosis in BCa patients receiving immunotherapy. LDLRAD3 represented a potential target for HEV induction and enhancing the efficacy of immunotherapy.


Assuntos
Biomarcadores Tumorais , Aprendizado de Máquina , Transcriptoma , Neoplasias da Bexiga Urinária , Neoplasias da Bexiga Urinária/imunologia , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/terapia , Humanos , Animais , Biomarcadores Tumorais/genética , Prognóstico , Camundongos , Imunoterapia/métodos , Vênulas , Algoritmos , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica
18.
J Agric Food Chem ; 72(21): 12003-12013, 2024 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-38748811

RESUMO

Insect gustatory receptors (GRs) aid in the precise identification of deterrent or stimulant compounds associated with food, mating, and egg-laying. Thus, they are promising targets for developing efficient insecticides. Here, 61 GRs in the chemosensory organs of Spodoptera litura larvae and adults were identified. Among them, SlitGR206 exhibited larval labium (LL)-specific expression characteristics. To explore the role of SlitGR206, a bacterial expression system was established to produce high-quality double-stranded RNA (dsRNA) and suppress SlitGR206 expression in LL. Subsequent behavioral assessments revealed that SlitGR206 silencing influenced larval feeding preferences and absorption. Moreover, it was found to reduce the ability of larvae to forage the five crucial host odorants. These findings demonstrate that SlitGR206 likely plays an indirect regulatory role in host recognition, consequently affecting foraging behavior. This provides a crucial foundation for the analysis of functional diversity among insect GRs and the precise development of nucleic acid pesticides in the future.


Assuntos
Comportamento Alimentar , Proteínas de Insetos , Larva , Spodoptera , Animais , Spodoptera/metabolismo , Spodoptera/fisiologia , Spodoptera/genética , Spodoptera/crescimento & desenvolvimento , Larva/metabolismo , Larva/crescimento & desenvolvimento , Larva/fisiologia , Proteínas de Insetos/metabolismo , Proteínas de Insetos/genética , Receptores de Superfície Celular/metabolismo , Receptores de Superfície Celular/genética
19.
Nat Commun ; 15(1): 4228, 2024 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-38762498

RESUMO

Cross-modal analysis of the same whole brain is an ideal strategy to uncover brain function and dysfunction. However, it remains challenging due to the slow speed and destructiveness of traditional whole-brain optical imaging techniques. Here we develop a new platform, termed Photoacoustic Tomography with Temporal Encoding Reconstruction (PATTERN), for non-destructive, high-speed, 3D imaging of ex vivo rodent, ferret, and non-human primate brains. Using an optimally designed image acquisition scheme and an accompanying machine-learning algorithm, PATTERN extracts signals of genetically-encoded probes from photobleaching-based temporal modulation and enables reliable visualization of neural projection in the whole central nervous system with 3D isotropic resolution. Without structural and biological perturbation to the sample, PATTERN can be combined with other whole-brain imaging modalities to acquire the whole-brain image with both high resolution and morphological fidelity. Furthermore, cross-modal transcriptome analysis of an individual brain is achieved by PATTERN imaging. Together, PATTERN provides a compatible and versatile strategy for brain-wide cross-modal analysis at the individual level.


Assuntos
Encéfalo , Furões , Imageamento Tridimensional , Técnicas Fotoacústicas , Animais , Encéfalo/diagnóstico por imagem , Técnicas Fotoacústicas/métodos , Imageamento Tridimensional/métodos , Camundongos , Algoritmos , Aprendizado de Máquina , Tomografia/métodos , Processamento de Imagem Assistida por Computador/métodos , Ratos , Masculino
20.
Anal Sci ; 40(6): 1129-1141, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38558384

RESUMO

Acetaminophen (AC) can inhibit the synthesis of prostaglandins in the body, and has antipyretic and analgesic effects. In this paper, a two-step microwave impregnation method was used to prepare anthraquinone (AQ)-doped carbon composite, which were applied to the surface modification of glassy carbon electrodes (GCE) for the determination of acetaminophen (AC) using differential pulse voltammetry (DPV). The composites were characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), Raman and Fourier infrared spectroscopy (FT-IR). The results showed that anthraquinone was successfully modified on the surface of activated carbon. The peak current of AC increased with its concentration in the range of 0.1 µM to 700 µM (R2 = 0.998) and a detection limit of 0.05 µM was obtained with 20%AQ doped carbon electrochemical sensor (20%AQ-C/GCE). Electrochemical Impedance Spectroscopy (EIS) test results indicated that the charge transfer resistance (Rct) of 20%AQ-C/GCE is only the one-fourth of that of bare GCE. The proposed 20%AQ-C/GCE sensor has good stability, reproducibility and selectivity for the detection of AC. The sensor is also suitable for the detection of real samples, indicating its good practicality.


Assuntos
Acetaminofen , Antraquinonas , Técnicas Eletroquímicas , Eletrodos , Acetaminofen/análise , Antraquinonas/química , Carbono/química , Carvão Vegetal/química , Limite de Detecção , Eletroquímica , Propriedades de Superfície
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