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Plant diseases, which seriously damage crop production, are in most cases caused by fungal pathogens. In this study, we found that the Raf-like MAPKKKs STY8 (SERINE/THREONINE/TYROSINE KINASE 8), STY17, and STY46 negatively regulate resistance to the fungal pathogen Botrytis cinerea through jasmonate response in Arabidopsis. Moreover, STY8/STY17/STY46 homologs negatively contribute to chitin signaling. We further identified MKK7 as the MAPKK component interacting with STY8/STY17/STY46 homologs. MKK7 positively contributes to resistance to B. cinerea and chitin signaling. Furthermore, we found that STY8/STY17/STY46 homologs negatively affect the accumulation of MKK7, in accordance with the opposite roles of MKK7 and STY8/STY17/STY46 homologs in defense against B. cinerea. These results provide new insights into the mechanisms precisely regulating plant immunity via Raf-like MAPKKKs.
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Proteínas de Arabidopsis , Arabidopsis , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Quinasas Quinasa Quinasa PAM/metabolismo , Botrytis/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Quitina/metabolismo , Enfermedades de las Plantas/microbiología , Regulación de la Expresión Génica de las Plantas , Resistencia a la Enfermedad/genéticaRESUMEN
Recurrent respiratory papillomatosis (RRP) is a rare benign tumor caused mainly by the infection of the respiratory tract epithelial cells by the human papillomavirus (HPV) type 6/11. However, the specific mechanisms underlying the inhibition of the host's innate immune response by HPV remain unclear. For this purpose, we employed single-cell RNA sequencing to analyze the states of various immune cells in RRP samples post-HPV infection and utilized a cellular model of HPV infection to elucidate the mechanisms by which HPV evades the innate immune system in RRP. The results revealed distinct immune cell heterogeneity in RRP and demonstrated that HPV11 E7 can inhibit the phosphorylation of the stimulator of interferon genes protein, thereby circumventing the body's antiviral response. In vitro co-culture experiments demonstrated that stimulation of macrophages to produce interferon-beta induced the death of HPV-infected epithelial cells, also reducing HPV viral levels. In summary, our study preliminarily identifies the potential mechanisms by which HPV evades the host's antiviral immune response, as well as the latent antiviral functions exhibited by activated macrophages. This research serves as an initial exploration of antiviral immune evasion in RRP, laying a solid foundation for investigating immunotherapeutic approaches for the disease.IMPORTANCESurgical tumor reduction is the most common treatment for recurrent respiratory papillomatosis (RRP). One of the characteristics of RRP is its persistent recurrence, and multiple surgeries are usually required to control the symptoms. Recently, some adjuvant therapies have shown effectiveness, but none of them can completely clear human papillomavirus (HPV) infection, and thus, a localized antiviral immune response is significant for disease control; after all, HPV infection is limited to the epithelium. Inhibition of interferon-beta (IFN-ß) secretion by HPV11 E7 viral proteins in epithelial cells by affecting stimulator of interferon genes phosphorylation may account for the persistence of low-risk HPV replication in the RRP. Moreover, suppression of the IFN-I pathway in RRP cell types might provide clues regarding the hyporeactive function of local immune cells. However, activation of macrophage groups to produce IFN-ß can still destroy HPV-infected cells.
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Papillomavirus Humano 11 , Proteínas E7 de Papillomavirus , Infecciones por Papillomavirus , Infecciones del Sistema Respiratorio , Adulto , Femenino , Humanos , Masculino , Células Epiteliales/virología , Células Epiteliales/inmunología , Papillomavirus Humano 11/genética , Papillomavirus Humano 11/inmunología , Evasión Inmune , Inmunidad Innata , Interferón beta/metabolismo , Interferón beta/inmunología , Interferón beta/genética , Macrófagos/inmunología , Macrófagos/virología , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Proteínas E7 de Papillomavirus/metabolismo , Proteínas E7 de Papillomavirus/genética , Proteínas E7 de Papillomavirus/inmunología , Infecciones por Papillomavirus/inmunología , Infecciones por Papillomavirus/virología , Infecciones del Sistema Respiratorio/virología , Infecciones del Sistema Respiratorio/inmunologíaRESUMEN
BACKGROUND: Cardiac valve disease is observed in 2.5% of the general population and 10% of the elderly people. Effective pharmacological treatments are currently not available, and patients with severe cardiac valve disease require surgery. PROX1 (prospero-related homeobox transcription factor 1) and FOXC2 (Forkhead box C2 transcription factor) are transcription factors that are required for the development of lymphatic and venous valves. We found that PROX1 and FOXC2 are expressed in a subset of valvular endothelial cells (VECs) that are located on the downstream (fibrosa) side of cardiac valves. Whether PROX1 and FOXC2 regulate cardiac valve development and disease is not known. METHODS: We used histology, electron microscopy, and echocardiography to investigate the structure and functioning of heart valves from Prox1ΔVEC mice in which Prox1 was conditionally deleted from VECs. Isolated valve endothelial cells and valve interstitial cells were used to identify the molecular mechanisms in vitro, which were tested in vivo by RNAScope, additional mouse models, and pharmacological approaches. The significance of our findings was tested by evaluation of human samples of mitral valve prolapse and aortic valve insufficiency. RESULTS: Histological analysis revealed that the aortic and mitral valves of Prox1ΔVEC mice become progressively thick and myxomatous. Echocardiography revealed that the aortic valves of Prox1ΔVEC mice are stenotic. FOXC2 was downregulated and PDGF-B (platelet-derived growth factor-B) was upregulated in the VECs of Prox1ΔVEC mice. Conditional knockdown of FOXC2 and conditional overexpression of PDGF-B in VECs recapitulated the phenotype of Prox1ΔVEC mice. PDGF-B was also increased in mice lacking FOXC2 and in human mitral valve prolapse and insufficient aortic valve samples. Pharmacological inhibition of PDGF-B signaling with imatinib partially ameliorated the valve defects of Prox1ΔVEC mice. CONCLUSIONS: PROX1 antagonizes PDGF-B signaling partially via FOXC2 to maintain the extracellular matrix composition and prevent myxomatous degeneration of cardiac valves.
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Enfermedades de las Válvulas Cardíacas , Prolapso de la Válvula Mitral , Animales , Humanos , Ratones , Células Endoteliales/metabolismo , Enfermedades de las Válvulas Cardíacas/genética , Enfermedades de las Válvulas Cardíacas/prevención & control , Enfermedades de las Válvulas Cardíacas/metabolismo , Válvula Mitral/metabolismo , Prolapso de la Válvula Mitral/metabolismo , Factores de Transcripción/metabolismo , Proteínas Proto-Oncogénicas c-sis/metabolismoRESUMEN
BACKGROUND: Alfalfa (Medicago sativa L.) is the most widely planted legume forage and one of the most economically valuable crops in the world. Serine hydroxymethyltransferase (SHMT), a pyridoxal phosphate-dependent enzyme, plays crucial roles in plant growth, development, and stress responses. To date, there has been no comprehensive bioinformatics investigation conducted on the SHMT genes in M. sativa. RESULTS: Here, we systematically analyzed the phylogenetic relationship, expansion pattern, gene structure, cis-acting elements, and expression profile of the MsSHMT family genes. The result showed that a total of 15 SHMT members were identified from the M. sativa genome database. Phylogenetic analysis demonstrated that the MsSHMTs can be divided into 4 subgroups and conserved with other plant homologues. Gene structure analysis found that the exons of MsSHMTs ranges from 3 to 15. Analysis of cis-acting elements found that each of the MsSHMT genes contained different kinds of hormones and stress-related cis-acting elements in their promoter regions. Expression and function analysis revealed that MsSHMTs expressed in all plant tissues. qRT-PCR analysis showed that MsSHMTs induced by ABA, Salt, and drought stresses. CONCLUSIONS: These results provided definite evidence that MsSHMTs might involve in growth, development and adversity responses in M. sativa, which laid a foundation for future functional studies of MsSHMTs.
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Regulación de la Expresión Génica de las Plantas , Glicina Hidroximetiltransferasa , Medicago sativa , Familia de Multigenes , Filogenia , Estrés Fisiológico , Medicago sativa/genética , Estrés Fisiológico/genética , Glicina Hidroximetiltransferasa/genética , Glicina Hidroximetiltransferasa/metabolismo , Genoma de Planta , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Perfilación de la Expresión Génica , Sequías , Regiones Promotoras GenéticasRESUMEN
Wearable, noninvasive sensors enable the continuous monitoring of metabolites in sweat and provide clinical information related to an individual's health and disease states. Uric acid (UA) is a key indicator highly associated with gout, hyperuricaemia, hypertension, kidney disease, and Lesch-Nyhan syndrome. However, the detection of UA levels typically relies on invasive blood tests. Therefore, developing a wearable device for noninvasive monitoring of UA concentrations in sweat could facilitate real-time personalized disease prevention. Here, we introduce 1,3,6,8-pyrene tetrasulfonic acid sodium salt (PyTS) as a bifunctional molecule functionalized with Ti3C2Tx via π-π conjugation to design nonenzymatic wearable sensors for sensitive and selective detection of UA concentration in human sweat. PyTS@Ti3C2Tx provides many oxidation-reduction active groups to enhance the electrocatalytic ability of the UA oxidation reaction. The PyTS@Ti3C2Tx-based electrochemical sensor demonstrates highly sensitive detection of UA in the concentration range of 5 µM-100 µM, exhibiting a lower detection limit of 0.48 µM compared to the uricase-based sensor (0.84 µM). In volunteers, the PyTS@Ti3C2Tx-based wearable sensor is integrated with flexible microfluidic sweat sampling and wireless electronics to enable real-time monitoring of UA levels during aerobic exercise. Simultaneously, it allows for comparison of blood UA levels via a commercial UA analyzer. Herein, this study provides a promising electrocatalyst strategy for nonenzymatic electrochemical UA sensor, enabling noninvasive real-time monitoring of UA levels in human sweat and personalized disease prevention.
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Técnicas Biosensibles , Nitritos , Elementos de Transición , Dispositivos Electrónicos Vestibles , Humanos , Ácido Úrico/análisis , Titanio/análisis , Sudor/químicaRESUMEN
BACKGROUND: Aconitum carmichaelii Debx. has been widely used as a traditional medicinal herb for a long history in China. It is highly susceptible to various dangerous diseases during the cultivation process. Downy mildew is the most serious leaf disease of A. carmichaelii, affecting plant growth and ultimately leading to a reduction in yield. To better understand the response mechanism of A. carmichaelii leaves subjected to downy mildew, the contents of endogenous plant hormones as well as transcriptome sequencing were analyzed at five different infected stages. RESULTS: The content of 3-indoleacetic acid, abscisic acid, salicylic acid and jasmonic acid has changed significantly in A. carmichaelii leaves with the development of downy mildew, and related synthetic genes such as 9-cis-epoxycarotenoid dioxygenase and phenylalanine ammonia lyase were also significant for disease responses. The transcriptomic data indicated that the differentially expressed genes were primarily associated with plant hormone signal transduction, plant-pathogen interaction, the mitogen-activated protein kinase signaling pathway in plants, and phenylpropanoid biosynthesis. Many of these genes also showed potential functions for resisting downy mildew. Through weighted gene co-expression network analysis, the hub genes and genes that have high connectivity to them were identified, which could participate in plant immune responses. CONCLUSIONS: In this study, we elucidated the response and potential genes of A. carmichaelii to downy mildew, and observed the changes of endogenous hormones content at different infection stages, so as to contribute to the further screening and identification of genes involved in the defense of downy mildew.
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Aconitum , Enfermedades de las Plantas , Reguladores del Crecimiento de las Plantas , Transcriptoma , Enfermedades de las Plantas/microbiología , Enfermedades de las Plantas/genética , Aconitum/genética , Reguladores del Crecimiento de las Plantas/metabolismo , Hojas de la Planta/microbiología , Hojas de la Planta/genética , Perfilación de la Expresión Génica , Regulación de la Expresión Génica de las PlantasRESUMEN
The function-oriented synthesis of polyoxometalate (POM) nanoclusters has become an increasingly important area of research. Herein, the well-known broad-spectrum anticancer drug Ge-132 which contains GeIV as potential heteroatoms and carboxyl coordination sites, is introduced to the POM system, leading to the first organogermanium functionalized GeIV-SbIII-templating POM nanocluster Na4[H2N(CH3)2]16 H18[Sm4(H2O)12W4O14Ge(CH2CH2COOH)]2[SbW9O33]4[Ge(CH2CH2COOH) SbW15O54]2·62H2O (1). An unprecedented organogermanium templating Dawson-like [Ge(CH2CH2COOH)SbW15O54]12- building block is discovered. To take advantage of the potential pharmaceutical activity of such an organogermanium-functionalized POM cluster, 1 is further composited with gold nanoparticles (NPs) to prepare 1-Au NPs, which doubles the blood circulation time of 1-based nanodrug. Efficient separation of photogenerated charges in 1-Au NPs largely boosts the photothermal conversion efficiency (PCE = 55.0%), which is nearly 2.1 times that of either single 1 (PCE = 26.7%) or Au NPs (PCE = 26.2%), and simultaneously facilitate the generation of toxic activate reactive oxygen species in tumor microenvironment. Based on these findings, it is demonstrated that 1-Au NPs are a multifunctional and renal clearable nanomedicine with great potential in photoacoustic imaging guiding photothermal-chemodynamic therapy for breast cancer.
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Atherosclerosis ï¼ASï¼ is the primary reason behind cardiovascular diseases, leading to approximately one-third of global deaths. Developing a novel multi-model probe to detect AS is urgently required. Macrophages are the primary cells from which AS genesis occurs. Utilizing natural macrophage membranes coated on the surface of nanoparticles is an efficient delivery method to target plaque sites. Herein, Fe3 O4 -Cy7 nanoparticles (Fe3 O4 -Cy7 NPs), functionalized using an M2 macrophage membrane and a liposome extruder for Near-infrared fluorescence and Magnetic resonance imaging, are synthesized. These macrophage membrane-coated nanoparticles (Fe3 O4 @M2 NPs) enhance the recognition and uptake using active macrophages. Moreover, they inhibit uptake using inactive macrophages and human coronary artery endothelial cells. The macrophage membrane-coated nanoparticles (Fe3 O4 @M0 NPs, Fe3 O4 @M1 NPs, Fe3 O4 @M2 NPs) can target specific sites depending on the macrophage membrane type and are related to C-C chemofactor receptor type 2 protein content. Moreover, Fe3 O4 @M2 NPs demonstrate excellent biosafety in vivo after injection, showing a significantly higher Fe concentration in the blood than Fe3 O4 -Cy7 NPs. Therefore, Fe3 O4 @M2 NPs effectively retain the physicochemical properties of nanoparticles and depict reduced immunological response in blood circulation. These NPs mainly reveal enhanced targeting imaging capability for atherosclerotic plaque lesions.
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Aterosclerosis , Nanopartículas , Humanos , Células Endoteliales , Nanopartículas/química , Imagen por Resonancia Magnética/métodos , Aterosclerosis/diagnóstico por imagenRESUMEN
BACKGROUND: Major depressive disorder (MDD) is a common mental illness that affects millions of people worldwide and imposes a heavy burden on individuals, families and society. Previous studies on MDD predominantly focused on neurons and employed bulk homogenates of brain tissues. This paper aims to decipher the relationship between oligodendrocyte lineage (OL) development and MDD at the single-cell resolution level. METHODS: Here, we present the use of a guided regularized random forest (GRRF) algorithm to explore single-nucleus RNA sequencing profiles (GSE144136) of the OL at four developmental stages, which contains dorsolateral prefrontal cortex of 17 healthy controls (HC) and 17 MDD cases, generated by Nagy C et al. We prioritized and ordered differentially expressed genes (DEGs) based on Nagy et al., which could predominantly discriminate cells in the four developmental stages and two adjacent developmental stages of the OL. We further screened top-ranked genes that distinguished between HC and MDD in four developmental stages. Moreover, we estimated the performance of the GRRF model via the area under the curve value. Additionally, we validated the pivotal candidate gene Malat1 in animal models. RESULTS: We found that, among the four developmental stages, the onset development of OL (OPC2) possesses the best predictive power for distinguishing HC and MDD, and long noncoding RNA MALAT1 has top-ranked importance value in candidate genes of four developmental stages. In addition, results of fluorescence in situ hybridization assay showed that Malat1 plays a critical role in the occurrence of depression. CONCLUSIONS: Our work elucidates the mechanism of MDD from the perspective of OL development at the single-cell resolution level and provides novel insight into the occurrence of depression.
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Trastorno Depresivo Mayor , ARN Largo no Codificante , Humanos , Trastorno Depresivo Mayor/genética , Trastorno Depresivo Mayor/metabolismo , Linaje de la Célula/genética , Hibridación Fluorescente in Situ , ARN Largo no Codificante/metabolismo , Corteza Prefrontal/metabolismo , Perfilación de la Expresión Génica , Expresión GénicaRESUMEN
This study aims to explore the impact and underlying mechanism of sulforaphane (SFN) intervention on the migration and invasion of lung adenocarcinoma induced by 7, 8-dihydroxy-9, 10-epoxy-benzo (a) pyrene (BPDE). Human lung adenocarcinoma A549 cells were exposed to varying concentrations of BPDE (0.25, 0.50, and 1.00 µM) and subsequently treated with 5 µM SFN. Cell viability was determined using CCK8 assay, while migration and invasion were assessed using Transwell assays. Lentivirus transfection was employed to establish NLRP12 overexpressing A549 cells. ELISA was utilized to quantify IL-33, CXCL12, and CXCL13 levels in the supernatant, while quantitative real-time PCR (qRT-PCR) and Western Blot were used to analyze the expression of NLRP12 and key factors associated with canonical and non-canonical NF-κB pathways. Results indicated an increase in migratory and invasive capabilities, concurrent with heightened expression of IL-33, CXCL12, CXCL13, and factors associated with both canonical and non-canonical NF-κB pathways. Moreover, mRNA and protein levels of NLRP12 were decreased in BPDE-stimulated A549 cells. Subsequent SFN intervention attenuated BPDE-induced migration and invasion of A549 cells. Lentivirus-mediated NLRP12 overexpression not only reversed the observed phenotype in BPDE-induced cells but also led to a reduction in the expression of critical factors associated with both canonical and non-canonical NF-κB pathways. Collectively, we found that SFN could inhibit BPDE-induced migration and invasion of A549 cells by upregulating NLRP12, thereby influencing both canonical and non-canonical NF-κB pathways.
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Adenocarcinoma del Pulmón , Movimiento Celular , Isotiocianatos , Neoplasias Pulmonares , Invasividad Neoplásica , Sulfóxidos , Humanos , Isotiocianatos/farmacología , Sulfóxidos/farmacología , Movimiento Celular/efectos de los fármacos , Células A549 , Adenocarcinoma del Pulmón/patología , Adenocarcinoma del Pulmón/metabolismo , Adenocarcinoma del Pulmón/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , 7,8-Dihidro-7,8-dihidroxibenzo(a)pireno 9,10-óxido/toxicidad , Anticarcinógenos/farmacología , FN-kappa B/metabolismo , Supervivencia Celular/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacosRESUMEN
Stimuli-responsive behaviors and controlled release in liposomes are pivotal in nanomedicine. To this end, we present an approach using a photoresponsive azobenzene nanocluster (AzDmpNC), prepared from azobenzene compounds through melting and aggregation. When integrated with liposomes, they form photoresponsive vesicles. The morphology and association with liposomes were investigated by using transmission electron microscopy. Liposomes loaded with calcein exhibited a 9.58% increased release after UV exposure. To gain insights into the underlying processes and elucidate the mechanisms involved. The molecular dynamic simulations based on the reactive force field and all-atom force field were employed to analyze the aggregation of isomers into nanoclusters and their impacts on phospholipid membranes, respectively. The results indicate that the nanoclusters primarily aggregate through π-π and T-stacking forces. The force density inside the cis-isomer of AzDmpNC formed after photoisomerization is lower, leading to its easier dispersion, rapid diffusion, and penetration into the membrane, disrupting the densification.
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Compuestos Azo , Liposomas , Simulación de Dinámica Molecular , Compuestos Azo/química , Compuestos Azo/efectos de la radiación , Liposomas/química , Nanopartículas/química , Rayos Ultravioleta , Fluoresceínas/química , Procesos FotoquímicosRESUMEN
The development of polyoxometalate chemistry not only is derived from the continuous discovery of novel polyoxometalates (POMs) but also stems from the exploitation of their new functionalities. In this work, we obtained a rigid sulfur-containing heterocyclic ligand-linking aggregate [N(CH3)4]10Na6H6[Ce8(H2O)26W8(HTDA)2(TDA)2O20][SeW4O18]2[SeW9O33]4·112H2O (1) (H2TDA = 2,5-thiophenedicarboxylic acid). Its polyanionic unit consists of one [Ce4(H2O)13W4O10(HTDA)(TDA)O10]18+ cluster and two kinds of Keggin-type [SeW4O18] and [SeW9O33] segments. It is noteworthy that H2TDA ligands not only work as connectors to link two symmetrical {[Ce4(H2O)13W4(HTDA)(TDA)O10][SeW4O18][SeW9O33]2}11- units but also function as ornaments to graft to the polyanionic backbone. Furthermore, 1 and 3,4-ethylenedioxythiophene (EDOT) were deposited on the glassy carbon electrode (GCE) by the electropolymerization (EPM) method, resulting in a 1-poly(3,4-ethylenedioxythiophene) (1-PEDOT) composite film, which can provide sufficient binding sites to immobilize Au nanoparticles (Au NPs). Hereafter, the Au NPs-immobilized 1-PEDOT modified electrode (Au/1-PEDOT/GCE) was used to construct an electrochemical aptasensor to detect mucin 1, showing a low detection limit of 29.5 fM in the Tris solution. This work not only demonstrates that rigid heterocyclic ligands are beneficial for the creation of novel rare-earth-substituted selenotungstate hybrids but also provides more enlightenment for POM-based materials used for electrochemical detection of cancer markers.
RESUMEN
Advances in polyoxometalate (POM) self-assembly chemistry are always accompanied by new developments in molecular blocks. The exploration and discovery of uncommon building blocks offer great possibilities for generating unprecedented POM clusters. An intriguing SbIII-WVI-cotemplated antimonotungstate [H2N(CH3)2]11Na[SbW9O33]Er2(H2O)2Sb2[SbWVIW15O57]·22H2O (1) was synthesized, which comprises a classical trivacant Keggin [SbW9O33]9- ({SbW9}) fragment and an unclassical lacunary Dawson-like [SbWVIW15O57]15- ({SbWVIW15}) subunit. Notably, the Dawson-like {SbWVIW15} subunit is the first example of a [SbO3]3- and [WVIO6]6- mixed-heteroatom-directing POM segment. Hexacoordinated [WVIO6]6- can not only serve as the heteroatom function but its additional oxygen sites can also link to lanthanide, main-group metal, and transition-metal centers to form the innovative structure. {SbWVIW15} and {SbW9} subunits are joined by the heterometallic [Er2(H2O)2Sb2O17]22- cluster to give rise to an asymmetric sandwich-type architecture. To further realize its potential application in electrochemical sensing, a conductive 1@rGO composite was obtained by the electrochemical deposition of 1 with graphene oxide (GO). Using a 1@rGO-modified glassy carbon electrode as the working electrode, an electrochemical biosensor for detecting the antidepressant drug paroxetine (PRX) was successfully constructed. This work can provide a viable strategy for synthesizing mixed-heteroatom-directing POMs and demonstrates the application of POM-based materials for the electrochemical detection of drug molecules.
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A novel tartronic acid decorated hexa-CeIII-incorporated phospho(III)tungstate aggregate (C4H12NO)6Na18H2[(HPW8O31)2[W11O39]2(H2TAD)4(H2O)4W4Ce6H2P2O14]·84H2O (1, H3TAD = tartronic acid) was synthesized by a one-step assembly strategy. Its main skeleton is constructed from two [W11O39]12- fragments, two [HPIIIW8O31]10- segments and one H2TAD--ornamented dodecanuclear heterometallic [W4Ce6H2PIII2O14(H2TAD)4(H2O)4]18+ cluster. In the structure, the [HPIIIO3]2- groups not only work as the heteroatom template to induce the formation of lacunary [HPIIIW8O31]10- segments but also function as the connector to bridge Ce3+ cations. With the help of a reaction strategy of combining ultrasonication treatment with the continuous ion layer adsorption method, the 1/CdS composite was constructed and exhibits prominent photoelectrochemical activity. The 1/CdS composite was used as a photoelectrochemical sensor for oxytetracycline detection at 0 V (vs Ag/AgCl), which displays excellent properties with quick response and low limit of detection (0.042 nM). This work can provide some helpful references in the construction of novel PIII-induced polyoxometalates consisting of different building blocks and can extend the applications of polyoxometalate-based nanocomposites into photoelectrochemical detection for antibiotics as well as biomolecules.
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Deep generative models have become crucial tools in de novo drug design. In current models for multiobjective optimization in molecular generation, the scaffold diversity is limited when multiple constraints are introduced. To enhance scaffold diversity, we herein propose a local scaffold diversity-contributed generator (LSDC), which can be utilized to generate diverse lead compounds capable of satisfying multiple constraints. Compared to the state-of-the-art methods, molecules generated by LSDC exhibit greater diversity when applied to the generation of inhibitors targeting the NOD-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3). We present 12 molecules, some of which feature previously unreported scaffolds, and demonstrate their reasonable docking binding modes. Consequently, the modification of selected scaffolds and subsequent bioactivity evaluation lead to the discovery of two potent NLRP3 inhibitors, A22 and A14, with IC50 values of 38.1 nM and 44.43 nM, respectively. And the oral bioavailability of compound A14 is very high (F is 83.09% in mice). This work contributes to the discovery of novel NLRP3 inhibitors and provides a reference for integrating AI-based generation with wet experiments.
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Diseño de Fármacos , Proteína con Dominio Pirina 3 de la Familia NLR , Animales , Ratones , Proteína con Dominio Pirina 3 de la Familia NLR/química , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismoRESUMEN
Bronchopulmonary dysplasia (BPD) is a chronic respiratory disease in newborns, which severely influences the health of infants and lacks effective clinical treatment strategies. The pathogenesis of BPD is correlated to enhanced inflammation and activated oxidative stress (OS). The application of antioxidants and anti-inflammatory treatment could be hot spots for BPD treatment. Nesfatin-1, a peptide with a suppressive property against inflammation, was tested herein for its potential therapeutic value in BPD. Neonatal SD rats were stimulated with hyperoxia, followed by being intraperitoneally administered with 20 µg/kg/day Nesfatin-1 for 2 weeks. Decreased RAC value in lung tissues, increased wet weight/dry weight (W/D) pulmonary ratio and bronchoalveolar lavage fluid (BALF) proteins, elevated cytokine release in BALF, increased malondialdehyde (MDA) content, and declined superoxide dismutase (SOD) activity were observed in BPD rats, all of which were sharply mitigated by Nesfatin-1. Rat epithelial type II cells (AECIIs) were handled with hyperoxia, and then cultured with 1 and 10 nM Nesfatin-1. Reduced cell viability, elevated lactate dehydrogenase production, elevated cytokine secretion, elevated MDA content, and decreased SOD activity were observed in hyperoxia-handled AECIIs, all of which were markedly alleviated by Nesfatin-1. Furthermore, activated nuclear factor-κB (NF-κB) signaling observed in both BPD rats and hyperoxia-handled AECIIs were notably repressed by Nesfatin-1. Collectively, Nesfatin-1 alleviated hyperoxia-triggered BPD by repressing inflammation and OS via the NF-κB signaling pathway.
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Displasia Broncopulmonar , Hiperoxia , Animales , Humanos , Recién Nacido , Ratas , Animales Recién Nacidos , Displasia Broncopulmonar/tratamiento farmacológico , Displasia Broncopulmonar/etiología , Displasia Broncopulmonar/metabolismo , Citocinas/metabolismo , Modelos Animales de Enfermedad , Hiperoxia/metabolismo , Inflamación/metabolismo , Pulmón/metabolismo , FN-kappa B/metabolismo , Ratas Sprague-Dawley , Transducción de Señal , Superóxido Dismutasa/metabolismoRESUMEN
Erianin, a natural compound derived from Dendrobium, has shown significant anticancer properties against a wide range of cancer cells. Despite the identification of multiple mechanisms of action for erianin, none of these mechanisms fully account for its broad-spectrum effect. In this study, we aimed to identify the cellular target and underlying mechanism responsible for the broad-spectrum antitumor effects of erianin. We found that erianin effectively inhibited tubulin polymerization in cancer cells and purified tubulin. Through competition binding assays and X-ray crystallography, it was revealed that erianin bound to the colchicine site of ß-tubulin. Importantly, the X-ray crystal structure of the tubulin-erianin complex was solved, providing clear insight into the orientation and position of erianin in the colchicine-binding site. Erianin showed activity against paclitaxel-resistant cells, evidenced by G2/M cell cycle arrest, apoptosis-related PARP and Caspase-3 cleavage, and in vivo xenograft studies. The study concluded that erianin bound reversibly to the colchicine site of ß-tubulin, inhibited tubulin polymerization, and displayed anticancer activity against paclitaxel-resistant cells, offering valuable insights for further exploration as potential anticancer agents.
Asunto(s)
Antineoplásicos , Proliferación Celular , Colchicina , Resistencia a Antineoplásicos , Ensayos de Selección de Medicamentos Antitumorales , Tubulina (Proteína) , Humanos , Tubulina (Proteína)/metabolismo , Tubulina (Proteína)/química , Colchicina/farmacología , Colchicina/química , Colchicina/metabolismo , Sitios de Unión , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Animales , Resistencia a Antineoplásicos/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Relación Estructura-Actividad , Estructura Molecular , Relación Dosis-Respuesta a Droga , Ratones , Apoptosis/efectos de los fármacos , Taxoides/farmacología , Taxoides/química , Moduladores de Tubulina/farmacología , Moduladores de Tubulina/química , Cristalografía por Rayos X , Hidrocarburos Aromáticos con Puentes/química , Hidrocarburos Aromáticos con Puentes/farmacología , Ratones Desnudos , Línea Celular Tumoral , Productos Biológicos/química , Productos Biológicos/farmacología , Bibencilos/química , Bibencilos/farmacología , FenolRESUMEN
Hypervirulent Klebsiella pneumoniae (hvKP) is a highly lethal opportunistic pathogen that elicits more severe inflammatory responses compared to classical Klebsiella pneumoniae (cKP). In this study, we investigated the interaction between hvKP infection and the anti-inflammatory immune response gene 1 (IRG1)-itaconate axis. Firstly, we demonstrated the activation of the IRG1-itaconate axis induced by hvKP, with a dependency on SYK signaling rather than STING. Importantly, we discovered that exogenous supplementation of itaconate effectively inhibited excessive inflammation by directly inhibiting SYK kinase at the 593 site through alkylation. Furthermore, our study revealed that itaconate effectively suppressed the classical activation phenotype (M1 phenotype) and macrophage cell death induced by hvKP. In vivo experiments demonstrated that itaconate administration mitigated hvKP-induced disturbances in intestinal immunopathology and homeostasis, including the restoration of intestinal barrier integrity and alleviation of dysbiosis in the gut microbiota, ultimately preventing fatal injury. Overall, our study expands the current understanding of the IRG1-itaconate axis in hvKP infection, providing a promising foundation for the development of innovative therapeutic strategies utilizing itaconate for the treatment of hvKP infections.
Asunto(s)
Infecciones por Klebsiella , Klebsiella pneumoniae , Humanos , Klebsiella pneumoniae/genética , Disbiosis/tratamiento farmacológico , Infecciones por Klebsiella/tratamiento farmacológico , Inflamación/tratamiento farmacológico , Alquilación , Quinasa SykRESUMEN
BACKGROUND: The prevalence of risk prediction models for skin tears in the elderly is growing; however, there is still debate regarding the usefulness and suitability of these models for clinical use and additional study. OBJECTIVE: The purpose of this work is to perform a systematic review and meta-analysis of published research on skin tear risk prediction models in the elderly. METHODS: We conducted a comprehensive search of various databases, including Cumulative Index to Nursing and Allied Health Literature (CINAHL), Embase, PubMed, Web of Science, MEDLINE, Scopus, The Cochrane Library, Wanfang Database, China Science and Technology Journal Database (VIP), and China National Knowledge Infrastructure (CNKI), from the beginning until November 27, 2023. Data extraction from the chosen studies encompassed various elements, such as study design, sample size, outcome definition, data source, predictors, model development, and performance. The assessment of bias and applicability was conducted using the Prediction Model Risk of Bias Assessment Tool (PROBAST) checklist. The Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis (TRIPOD) checklist was utilized to assess the transparency in reporting the prediction models-a meta-analysis of the most common predictors to assess predictor reliability. In addition, a narrative synthesis was carried out to provide an overview of the qualities, bias risk, and effectiveness of the current models. The reporting procedures of this meta-analysis conformed to the 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA 2020) statement. RESULTS: Out of the initially retrieved 1499 studies, this review included eight prediction models from eight selected studies. All the studies employed logistic regression to develop prediction models for skin tears. The prevalence of skin tears in the elderly varied from 3.0% to 33.3%. Senile purpura and a history of previous skin tears were the most commonly utilized predictors. The reported values for the area under the curve (AUC) ranged from 0.765 to 0.854. All the studies exhibited a high risk of bias, primarily due to inadequate reporting in the outcome and analysis domains. Furthermore, serious questions concerning their applicability were highlighted by four studies. CONCLUSION: Based on the PROBAST checklist, the current models for predicting skin tears in the elderly showed a high risk of bias. The development of new prediction models with bigger sample sizes, appropriate study designs, and external validation from multiple sources ought to be the primary focus of future research. PATIENT OR PUBLIC CONTRIBUTION: There was no patient or public contribution to this systematic review. REGISTRATION: PROSPERO registration number: CRD42023494387.
RESUMEN
The aim of this study was to explore gestational weight gain (GWG) trajectories and their associations with adverse pregnancy outcomes. A retrospective cohort study including 11,064 women with gestational diabetes mellitus (GDM) was conducted between 2015 and 2019 in China. The latent class trajectory model was used to identify GWG trajectories, and logistic regression was performed to examine odds ratio (OR) of pregnancy outcomes. Three trajectories of GWG were identified in these 11,604 women with GDM. Trajectory 1: 64.02% of women had sustained moderate GWG throughout pregnancy; Trajectory 2: 17.75% of women showed a high initial GWG but followed by a low GWG from the third trimester until delivery; Trajectory 3: 18.23% had low initial GWG but followed by drastic GWG from the second trimester until delivery. Compared with pregnant women with Trajectory 1, women with Trajectory 2 had a higher risk of large for gestational age (adjusted odds ratio [AOR]: 1.29, 95% confidence interval [CI]: 1.12-1.48) but at a lower risk of having hypertensive disorders of pregnancy (AOR: 0.76, 95% CI: 0.57-0.96). Women in Trajectory 3 were more likely to develop small for gestational age (AOR: 2.12, 95% CI: 1.62-2.78), low birthweight (AOR: 1.49, 95% CI: 1.07-2.08), preterm birth (AOR: 1.28, 95% CI: 1.05-1.63), caesarean section (AOR: 1.26, 95% CI: 1.112-1.42) and hypertensive disorders of pregnancy (AOR: 2.24, 95% CI: 1.82-2.76). The association of GWG trajectory with adverse pregnancy outcomes differs across prepregnancy body mass index and GWG categories. Women with a slow initial GWG but followed by drastic GWG had higher risks of adverse pregnancy outcomes. Early clinical recognition of poor GWG trajectory will contribute to early intervention in high-risk groups to minimise adverse outcomes.