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1.
Am J Reprod Immunol ; 92(1): e13892, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38958252

RESUMO

PURPOSE: Non-obstructive azoospermia (NOA) is a severe and common cause of male infertility. Currently, the most reliable predictor of sperm retrieval success in NOA is histopathology, but preoperative testicular biopsy often increases the difficulty of sperm retrieval surgery. This study aims to explore the characteristics of N6-methyladenosine (m6A) modification in NOA patients and investigate the potential biomarkers and molecular mechanisms for pathological diagnosis and treatment of NOA using m6A-related genes. METHODS: NOA-related datasets were downloaded from the GEO database. Based on the results of LASSO regression analysis, a prediction model was established from differentially expressed m6A-related genes, and the predictive performance of the model was evaluated using ROC curves. Cluster analysis was performed based on differentially expressed m6A-related genes to evaluate the differences in different m6A modification patterns in terms of differentially expressed genes (DEGs), biological features, and immune features. RESULTS: There were significant differences in eight m6A-related genes between NOA samples and healthy controls. The ROC curves showed excellent predictive performance for the diagnostic models constructed with ALKBH5 and FTO. DEGs of two m6A modification subtypes indicated the influence of m6A-related genes in the biological processes of mitosis and meiosis in NOA patients, and there were significant immune differences between the two subtypes. CONCLUSION: The NOA pathological diagnostic models constructed with FTO and ALKBH5 have good predictive ability. We have identified two different m6A modification subtypes, which may help predict sperm retrieval success rate and treatment selection in NOA patients.


Assuntos
Adenosina , Azoospermia , Biologia Computacional , Humanos , Azoospermia/genética , Masculino , Biologia Computacional/métodos , Adenosina/análogos & derivados , Adenosina/metabolismo , Perfilação da Expressão Gênica , Biomarcadores , Homólogo AlkB 5 da RNA Desmetilase/genética , Transcriptoma
2.
J Colloid Interface Sci ; 674: 677-685, 2024 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-38950466

RESUMO

The construction and regulation of built-in electric field (BIEF) are considered effective strategies for enhancing the oxygen evolution reaction (OER) performance of transition metal-based electrocatalysts. Herein, we present a strategy to regulate the electronic structure of nickel-iron layered double hydroxide (NiFe-LDH) by constructing and enhancing the BIEF induced by in-situ heterojunction transformation. This concept is demonstrated through the design and synthesis of Ag2S@S/NiFe-LDH (p-n heterojunction) and Ag@S/NiFe-LDH (Mott-Schottky heterojunction). Benefiting from the larger BIEF of Mott-Schottky heterojunction, efficient electron transfer occurs at the interface between silver (Ag) and NiFe-LDH. As a result, Ag@S/NiFe-LDH exhibits excellent OER performance, requiring only a 232 mV overpotential at 1 M KOH to achieve a current density of 100 mA cm-2, with a small Tafel slope of 73 mV dec-1, as well as excellent electrocatalytic durability. Density functional theory (DFT) calculations further verified that stronger BIEF in Mott-Schottky heterojunction enhances the electron interaction at the interfaces, reduces the energy barrier for the rate-determining step (RDS), and accelerates the OER kinetics. This work provides an effective strategy for designing catalyst with larger BIEF to enhance electrocatalytic activity.

3.
J Cancer ; 15(13): 4386-4405, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38947398

RESUMO

Background: TMEM132A is a transmembrane protein that regulates gastric cancer cell malignancy and overall survival in bladder cancer patients. However, while some studies have investigated the involvement of TMEM132A in specific cancers, further systematic studies are required to elucidate its specific mechanisms of action in different cancer types. Methods: We investigated the pan-cancer role of TMEM132A using several databases. We analyzed TMEM132A expression and its correlation with clinical survival, immune checkpoints, tumor stemness score, prognostic value, immunomodulators, genomic profiles, immunological characteristics, immunotherapy and functional enrichment. Results: First, it was observed that TMEM132A expression levels were higher in the majority of tumors compared to non-tumor tissues. In addition, high TMEM132A expression may have a higher prognostic value in some cancers. Furthermore, TMEM132A was significantly associated with immune checkpoints, immunomodulators, prognosis, immunomodulatory genes, tumor stemness score, cell function status and immune infiltration in most tumors. Further analysis of TMEM132A-related gene enrichment, mutation sites and types, RNA modification and genomic heterogeneity showed that the major mutations of TMEM132A were missense mutations and that TMEM132A plays a very important role in UCEC, LUAD and LIHC. Finally, these results suggest that high TMEM132A expression may be associated with a better response to specific immunotherapies. Conclusion: This comprehensive study uncovers an important function for TMEM132A in different types of cancer. It also has the potential to identify TMEM132A as a potential biomarker for predicting treatment response. This may help us to better understand how TMEM132A plays a role in cancer and provide valuable insights for developing personalised treatments.

4.
Environ Res ; 259: 119516, 2024 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-38950813

RESUMO

The rapid increase of mcr-positive Klebsiella pneumoniae (K. pneumoniae) has received considerable attention and poses a major public health concern. Here, we systematically analyzed the global distribution of mcr-positive K. pneumoniae isolates based on published articles as well as publicly available genomes. Combining strain information from 78 articles and 673 K. pneumoniae genomes, a total of 1000 mcr-positive K. pneumoniae isolates were identified. We found that mcr-positive K. pneumoniae has disseminated widely worldwide, especially in Asia, with a higher diversity of sequence types (STs). These isolates were disseminated in 57 countries and were associated with 12 different hosts. Most of the isolates were found in China and were isolated from human sources. Moreover, MLST analysis showed that ST15 and ST11 accounted for the majority of mcr-positive K. pneumoniae, which deserve sustained attention in further surveillance programs. mcr-1 and mcr-9 were the dominant mcr variants in mcr-positive K. pneumoniae. Furthermore, a Genome-wide association study (GWAS) demonstrated that mcr-1- and mcr-9-producing genomes exhibited different antibiotic resistance genes (ARGs) and mobile genetic elements (MGEs), thereby indicating a distinct evolutionary path. Notably, the phylogenetic analysis suggested that certain mcr-positive K. pneumoniae genomes from various geographical areas and hosts harbored a high degree of genetic similarities (<20 SNPs), suggesting frequent cross-region and cross-host clonal transmission. Overall, our results emphasize the significance of monitoring and exploring the transmission and evolution of mcr-positive K. pneumoniae in the context of "One health".

5.
ISA Trans ; 2024 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-38960857

RESUMO

In this study, an ultra-high-precision pneumatic force servo system (UPFSS) is proposed. On the one hand, a novel air-floating pneumatic cylinder (AFPC) with an air-floating piston capable of independent air supply and exhaust is developed for this system, and its special flow channel design allows the air-floating piston to be suspended in the cylinder without being constrained by the pressure in the chambers. The friction force of the AFPC is less than 0.0049 N. On the other hand, a leakage chamber is constructed to simulate the clearance between the air-floating piston and the cylinder wall, and a fuzzy proportional integral (FPI)-based pressure control system (PCS) is designed for the simulated leakage chamber. Furthermore, a novel particle swarm optimization algorithm integrating Gaussian mutation and fuzzy theory (IGF-PSO) is presented. After testing, the IGF-PSO algorithm is found to have outstanding optimization performance. Then, the parameters of the FPI controller are optimized through the IGFPSO algorithm. Experimental comparisons reveal that the steady-state error achieved by the parameter-optimized pressure controller in response to the leakage condition is about 38 % smaller than that achieved by the pressure controller with parameters obtained using the trial-and-error method. Finally, the UPFSS is tested by using the optimized PCS to supply compressed air to the chamber of the AFPC. The results show that the UPFSS achieves a steady-state error of no more than 0.0279 N in the continuous step response within the range of 240 N.

6.
IEEE Trans Cybern ; PP2024 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-38976456

RESUMO

This article investigates the finite-time control problem of the switched affine systems via an event-triggered strategy. It is well known that the existence of affine terms brings great difficulties in analysis of the finite-time property of such systems. Furthermore, the design of the globally feasible event-triggered mechanism (ETM) under a finite-time control framework is challenging. Thus, a two-step hybrid control scheme is proposed in this article. The first step focuses on the event-triggered finite-time control for practical stability, while the second step aims to achieve finite-time stabilization. Particularly, in step one, by constructing the intersection between the affine term's threshold and feasible state region of the established ETM, it is verified that the Zeno behavior can be excluded. Thereafter, an affine state-dependent switching law and sufficient conditions are provided for achieving practical stability. Meanwhile, an estimation for the practical settling time to enter the bounded set is provided. In step two, the criteria for finite-time stabilization of the considered systems are further presented, and an overall settling-time upper bound is derived. Finally, a numerical example is illustrated to demonstrate the effectiveness of our proposed method.

7.
iScience ; 27(7): 110180, 2024 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-38993666

RESUMO

PARP inhibitors (PARPi) are efficacious in BRCA1-null tumors; however, their utility is limited in tumors with functional BRCA1. We hypothesized that pharmacologically reducing BRCA1 protein levels could enhance PARPi effectiveness in BRCA1 wild-type tumors. To identify BRCA1 downregulating agents, we generated reporter cell lines using CRISPR-mediated editing to tag endogenous BRCA1 protein with HiBiT. These reporter lines enable the sensitive measurement of BRCA1 protein levels by luminescence. Validated reporter cells were used in a pilot screen of epigenetic-modifying probes and a larger screen of more than 6,000 compounds. We identified 7 compounds that could downregulate BRCA1-HiBiT expression and synergize with olaparib. Three compounds, N-acetyl-N-acetoxy chlorobenzenesulfonamide (NANAC), A-443654, and CHIR-124, were validated to reduce BRCA1 protein levels and sensitize breast cancer cells to the toxic effects of olaparib. These results suggest that BRCA1-HiBiT reporter cells hold promise in developing agents to improve the clinical utility of PARPi.

8.
Heliyon ; 10(12): e33092, 2024 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-38994057

RESUMO

Objective: This study aimed to explore disulfidptosis-related clusters of triple-negative breast cancer (TNBC) and build a reliable disulfidptosis-related gene signature for forecasting TNBC prognosis. Methods: The disulfidptosis-related clusters of TNBC were identified based on public datasets, and a comparative analysis was conducted to assess their differences in the overall survival (OS) and immune cell infiltration. Morever, the differentially expressed genes (DEGs) between clusters were recognized. Then, the prognostic DEGs were then chosen. A prognostic signature was constructed by the prognostic DEGs, followed by nomogram construction, drug sensitivity, immune correlation, immunotherapy response prediction, and cluster association analyses. Results: Two disulfidptosis-related clusters of TNBC were identified, which had different OS and macrophage infiltration. Moreover, 235 DEGs were identified between two clusters. A prognostic signature was then constructed by five prognostic DEGs including HLA-DQA2, CCL13, GBP1, LAMP3, and SLC7A11. This signature was highly valuable in predicting prognosis. A nomogram was built by risk score and AJCC stage, which could forecast OS accurately. Moreover, patients with high-risk scores exhibited greater sensitivity to chemotherapy drugs such as lapatinib and had a lower immunotherapy response. Conclusions: Two TNBC clusters linked to disulfidptosis were identified, with different OS and immune cell infiltration. Moreover, a five-disulfidptosis-related gene signature may be a powerful prognostic biomarker for TNBC.

9.
Eur J Radiol ; 178: 111594, 2024 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-38986232

RESUMO

PURPOSE: To explore the predictive value of dual-layer spectral detector CT (SDCT) quantitative parameters for determining differentiation grade, lymphovascular invasion (LVI) and perineural invasion (PNI) in colorectal adenocarcinoma (CRAC) patients. METHODS: A total of 106 eligible patients with CRAC were included in this study. Spectral parameters, including CT values at 40 and 100 keV, the effective atomic number (Zeff), the iodine concentration (IC), the slope of the spectral Hounsfield unit (HU) curve (λHU), and the normalized iodine concentration (NIC) in the arterial phase (AP) and venous phase (VP), were compared according to the differentiation grade and the status of LVI and PNI. The diagnostic accuracies of the quantitative parameters with statistical significance were determined via receiver operating characteristic (ROC) curves, and the area under the curve (AUC) was calculated. RESULTS: There were 57 males and 49 females aged 43-86 (69 ± 10) years. The measured values of the spectral quantitative parameters of the CRAC were consistent within the observer (ICC range: 0.800-0.926). The 40 keV-AP, IC-AP, NIC-AP, 40 keV-VP, and IC-VP were significantly different among the different differentiation grades in the CRAC (P = 0.040, AUC = 0.673; P = 0.035, AUC = 0.684; P = 0.031, AUC = 0.639; P = 0.044, AUC = 0.663 and P = 0.035, AUC = 0.666, respectively). A statistically significant difference was observed in 40 keV-VP, 100 keV-VP, Zeff-VP, IC-VP, and λHU-VP between LVI-positive and LVI-negative patients (P = 0.003, AUC = 0.688; P = 0.015, AUC = 0.644; P = 0.001, AUC = 0.688; P = 0.001, AUC = 0.703 and P = 0.003, AUC = 0.677, respectively). There were no statistically significant differences in the values of the spectral parameters of the PNI state of patients with CRAC (P > 0.05). CONCLUSION: The quantitative parameters of SDCT had good diagnostic efficacy in differentiating between different grades and statuses of LVI in patients with CRAC; however, SDCT did not have value for identifying the state of PNI.

10.
Nanoscale ; 2024 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-39046363

RESUMO

Conventional nanomedicines typically employ a significant amount of excipients as carriers for therapeutic delivery, resulting in generally low drug-loading and compromised anti-cancer efficacy. Here, we propose a small-molecule nanomedicine (CMC NP) directly assembled using a chemotherapeutic drug (chlorambucil, CBL) and a phototherapeutic agent (chlorin e6, Ce6), and stabilized by metal coordination. The CMC NP exhibits exceptionally high drug loading (89.21%), robust stability, and smart disassembly in response to glutathione (GSH). Such a straightforward yet multifunctional delivery strategy could be a better alternative to overcome the above shortcomings of conventional nanomedicines while achieving enhanced efficacy. The CMC NP not only directly induces CBL-induced chemotherapy but also elicits synergistic antitumor responses through Ce6-mediated photodynamic and photothermal therapies. Owing to the multifaceted efforts from photodynamic, photothermal and chemo-therapies, the CMC NP exhibits excellent antitumor efficacy with negligible systemic toxicity which is untenable in traditional CBL-induced chemotherapy. Therefore, this study provides a feasible strategy for overcoming existing challenges and presents a potential opportunity to augment the clinical therapeutic effectiveness associated with conventional nanomedicine.

11.
Reprod Toxicol ; : 108664, 2024 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-39038763

RESUMO

Cadmium (Cd) is a well-recognized male reproductive toxicant that can cause testicular germ cell apoptosis. However, the underlying mechanism needs investigation. CG-1 mouse spermatogonia (spg) cells were treated with 20µM cadmium chloride (CdCl2) for 24h. Cell apoptosis was measured, and the expressions of key genes and protein biomarkers involved in endoplasmic reticulum (ER) stress were detected, respectively. Untargeted metabolomics was performed to identify different metabolites, and transcriptome analysis was conducted to screen differentially expressed genes (DEGs). Our results indicated that CdCl2 exposure caused cell apoptosis, and DEGs were involved in several apoptosis-related pathways. Moreover, CdCl2 exposure apparently increased the mRNA and protein expressions levels of both GRP78 and ATF6α, disrupting the expression of various metabolites, particularly amino acids. Conclusively, our study reveals the pathway of CdCl2 toxicity on mouse spg, providing a deep understanding of CdCl2-induced testicular toxicity.

12.
J Am Chem Soc ; 146(29): 20323-20332, 2024 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-38995375

RESUMO

Addressing the sluggish kinetics in the alkaline hydrogen oxidation reaction (HOR) is a pivotal yet challenging step toward the commercialization of anion-exchange membrane fuel cells (AEMFCs). Here, we have successfully immobilized indium (In) atoms in an orderly fashion into platinum (Pt) nanoparticles supported by reduced graphene oxide (denoted as O-Pt3In/rGO), significantly enhancing alkaline HOR kinetics. We have revealed that the ordered atomic matrix enables uniform and optimized hydrogen binding energy (HBE), hydroxyl binding energy (OHBE), and carbon monoxide binding energy (COBE) across the catalyst. With a mass activity of 2.3066 A mg-1 at an overpotential of 50 mV, over 10 times greater than that of Pt/C, the catalyst also demonstrates admirable CO resistance and stability. Importantly, the AEMFC implementing this catalyst as the anode catalyst has achieved an impressive power output compared to Pt/C. This work not only highlights the significance of constructing ordered oxophilic sites for alkaline HOR but also sheds light on the design of well-structured catalysts for energy conversion.

13.
Animals (Basel) ; 14(13)2024 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-38998099

RESUMO

The study determined the impacts of dietary fermented residues' (FBR) inclusion on growth, nutrient utilization, carcass characteristics, and meat properties in fattening pigs. Seventy-two robust pigs were randomly assigned to two experimental groups (Duroc × Landrace × Yorkshire, thirty-six pigs each). Each group was subjected to a 52-day trial, during which they received either a corn-soybean meal-based diet or diet enhanced with a 10% addition of FBR. Consequently, adding 10% FBR caused a significant decrease in the digestive utilization of crude dietary components in fattening pigs (p < 0.05) but showed no significant impact on the growth performance. Additionally, FBR inclusion increased the marbling scores (p < 0.05) and total antioxidant functions (p < 0.05) of muscle tissues, indicating improved meat quality. Gender affected backfat depth, with barrows showing thicker backfat depth. In conclusion, dietary supplementation with 10% FBR in finishing pigs influenced the meat quality by improving the marbling score and antioxidant performance while reducing digestibility without compromising growth performance.

14.
Cell Death Dis ; 15(7): 491, 2024 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-38982043

RESUMO

IL-17+ γδ T cells (γδ T17) are kick-starters of inflammation due to their strict immunosurveillance of xenobiotics or cellular damages and rapid response to pro-inflammatory stimulators. IL-27 is a well-recognized pleiotropic immune regulator with potent inhibitory effects on type 17 immune responses. However, its actions on γδ T17 mediated inflammation and the underlying mechanisms are less well understood. Here we find that IL-27 inhibits the production of IL-17 from γδ T cells. Mechanistically, IL-27 promotes lipolysis while inhibits lipogenesis, thus reduces the accumulation of lipids and subsequent membrane phospholipids, which leads to mitochondrial deactivation and ensuing reduction of IL-17. More importantly, Il27ra deficient γδ T cells are more pathogenic in an imiquimod-induced murine psoriasis model, while intracutaneous injection of rmIL-27 ameliorates psoriatic inflammation. In summary, this work uncovered the metabolic basis for the immune regulatory activity of IL-27 in restraining γδ T17 mediated inflammation, which provides novel insights into IL-27/IL-27Ra signaling, γδ T17 biology and the pathogenesis of psoriasis.


Assuntos
Interleucina-17 , Metabolismo dos Lipídeos , Mitocôndrias , Psoríase , Animais , Mitocôndrias/metabolismo , Camundongos , Psoríase/patologia , Psoríase/imunologia , Psoríase/metabolismo , Interleucina-17/metabolismo , Camundongos Endogâmicos C57BL , Inflamação/patologia , Inflamação/metabolismo , Pele/patologia , Pele/metabolismo , Pele/imunologia , Pele/efeitos dos fármacos , Modelos Animais de Doenças , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Transdução de Sinais , Humanos
15.
Psychol Res Behav Manag ; 17: 2641-2652, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39006891

RESUMO

Objective: Based on Conservation of resources theory, process model of emotion regulation and attachment theory, the present study examined how psychological capital affects anxiety through the mediation of emotion regulation strategies and explored the moderating role of parent-child relationship. Methods: Using a longitudinal study method, 962 college students were surveyed twice at one-year intervals. Results: (1) College students' emotion regulation strategies (including cognitive reappraisal and expressive suppression) partially mediated psychological capital and anxiety mood; (2) parent-child relationship moderated the pathways of psychological capital and expressive suppression on anxiety, respectively. Conclusion: College students with higher levels of parent-child relationship had stronger predictive effects of psychological capital and weaker predictive effects of expressive suppression on anxiety mood. The research findings clarify the combined effects of emotion regulation and parent-child relationships on anxiety among college students, providing valuable reference for the design and implementation of interventions to promote individual psychological well-being.

16.
J Nanobiotechnology ; 22(1): 422, 2024 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-39014416

RESUMO

Vascularization plays a significant role in promoting the expedited process of bone regeneration while also enhancing the stability and viability of artificial bone implants. Although titanium alloy scaffolds were designed to mimic the porous structure of human bone tissues to facilitate vascularization in bone repair, their biological inertness restricted their broader utilization. The unique attribute of Metal-organic framework (MOF) MIL-53(Fe), known as "breathing", can facilitate the efficient adsorption of extracellular matrix proteins and thus provide the possibility for efficient interaction between scaffolds and cell adhesion molecules, which helps improve the bioactivity of the titanium alloy scaffolds. In this study, MIL-53(Fe) was synthesized in situ on the scaffold after hydrothermal treatment. The MIL-53(Fe) endowed the scaffold with superior protein absorption ability and preferable biocompatibility. The scaffolds have been shown to possess favorable osteogenesis and angiogenesis inducibility. It was indicated that MIL-53(Fe) modulated the mechanotransduction process of endothelial cells and induced increased cell stiffness by promoting the adsorption of adhesion-mediating extracellular matrix proteins to the scaffold, such as laminin, fibronectin, and perlecan et al., which contributed to the activation of the endothelial tip cell phenotype at sprouting angiogenesis. Therefore, this study effectively leveraged the intrinsic "breathing" properties of MIL-53 (Fe) to enhance the interaction between titanium alloy scaffolds and vascular endothelial cells, thereby facilitating the vascularization inducibility of the scaffold, particularly during the sprouting angiogenesis phase. This study indicates that MIL-53(Fe) coating represents a promising strategy to facilitate accelerated and sufficient vascularization and uncovers the scaffold-vessel interaction from a biomechanical perspective.


Assuntos
Neovascularização Fisiológica , Alicerces Teciduais , Titânio , Titânio/química , Humanos , Alicerces Teciduais/química , Neovascularização Fisiológica/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Estruturas Metalorgânicas/química , Estruturas Metalorgânicas/farmacologia , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Osteogênese/efeitos dos fármacos , Ligas/química , Células Endoteliais da Veia Umbilical Humana , Próteses e Implantes , Mecanotransdução Celular , Adesão Celular/efeitos dos fármacos , Engenharia Tecidual/métodos
17.
Phytother Res ; 2024 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-39031847

RESUMO

Traditional Chinese Medicine (TCM), as a unique medical model in China, has been shown to be effective in the treatment of many diseases. It has been proven that TCM can increase the pain threshold, increase the level of endorphins and enkephalins in the body, and reduce the body's response to adverse stimuli. In recent years, TCM scholars have made valuable explorations in the field of pain treatment, using methods such as internal and external application of TCM and acupuncture to carry out research on pain treatment and have achieved more satisfactory results. TCM treats pain in a variety of ways, and with the discovery of a variety of potential bioactive substances for pain treatment. With the new progress in the research of other TCM treatment methods for pain, TCM will have greater potential in the clinical application of pain.

18.
Chem Commun (Camb) ; 2024 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-39010756

RESUMO

A green process for the direct C(sp2)-H decarboxylative alkylsulfonylation of enamides under metal- and additive-free conditions is reported. This reaction employs phenyliodine(III) dicarboxylates as the alkyl radical precursors and DABCO·(SO2)2 as the sulfur dioxide surrogate. Diverse (E)-alkylsulfonyl enamides are generated in moderate to good yields with high stereoselectivity under extremely mild conditions via a radical process. A broad substrate scope and excellent functional group tolerance are presented. Moreover, a cascade alkylsulfonylation/cyclization reaction of N-methacryloyl enamides occurs smoothly, giving rise to various alkylsulfonylated pyrrolidones.

19.
mBio ; : e0154924, 2024 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-38953350

RESUMO

Metabolism in host cells can be modulated after viral infection, favoring viral survival or clearance. Here, we report that lipid droplet (LD) synthesis in host cells can be modulated by yin yang 1 (YY1) after porcine reproductive and respiratory syndrome virus (PRRSV) infection, resulting in active antiviral activity. As a ubiquitously distributed transcription factor, there was increased expression of YY1 upon PRRSV infection both in vitro and in vivo. YY1 silencing promoted the replication of PRRSV, whereas YY1 overexpression inhibited PRRSV replication. PRRSV infection led to a marked increase in LDs, while YY1 knockout inhibited LD synthesis, and YY1 overexpression enhanced LD accumulation, indicating that YY1 reprograms PRRSV infection-induced intracellular LD synthesis. We also showed that the viral components do not colocalize with LDs during PRRSV infection, and the effect of exogenously induced LD synthesis on PRRSV replication is nearly lethal. Moreover, we demonstrated that YY1 affects the synthesis of LDs by regulating the expression of lipid metabolism genes. YY1 negatively regulates the expression of fatty acid synthase (FASN) to weaken the fatty acid synthesis pathway and positively regulates the expression of peroxisome proliferator-activated receptor gamma (PPARγ) to promote the synthesis of LDs, thus inhibiting PRRSV replication. These novel findings indicate that YY1 plays a crucial role in regulating PRRSV replication by reprogramming LD synthesis. Therefore, our study provides a novel mechanism of host resistance to PRRSV and suggests potential new antiviral strategies against PRRSV infection.IMPORTANCEPorcine reproductive and respiratory virus (PRRSV) has caused incalculable economic damage to the global pig industry since it was first discovered in the 1980s. However, conventional vaccines do not provide satisfactory protection. It is well known that viruses are parasitic pathogens, and the completion of their replication life cycle is highly dependent on host cells. A better understanding of host resistance to PRRSV infection is essential for developing safe and effective strategies to control PRRSV. Here, we report a crucial host antiviral molecule, yin yang 1 (YY1), which is induced to be expressed upon PRRSV infection and subsequently inhibits virus replication by reprogramming lipid droplet (LD) synthesis through transcriptional regulation. Our work provides a novel antiviral mechanism against PRRSV infection and suggests that targeting YY1 could be a new strategy for controlling PRRSV.

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