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[This corrects the article DOI: 10.1371/journal.pbio.3001134.].
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AMPA receptors (AMPARs) play a critical role in synaptic plasticity and learning and memory, and dysfunction or dysregulation of AMPARs could lead to various neurological and psychiatric disorders, such as Alzheimer's disease (AD). However, the dynamics and/or longitudinal changes of AMPARs in vivo during AD pathogenesis remain elusive. Here, employing 5xFAD SEP-GluA1 KI mice, we investigated endogenous AMPA receptor dynamics in a whisker deflection-associated Go/No-go learning paradigm. We found a significant increase in synaptosomal AMPA receptor subunits GluA1 in WT mice after learning, while no such changes were detected in 7-mo-old 5xFAD mice. Daily training led to an increase in endogenous spine surface GluA1 in Control mice, while this increase was absent in 5xFAD-KI mice which correlates with its learning defects in Go/No-go paradigm. Furthermore, we demonstrated that the onset of abnormal AMPAR dynamics corresponds temporally with microglia and astrocyte overactivation. Our results have shown that impairments in endogenous AMPA receptor dynamics play an important role in learning deficits in 5xFAD mice and AD pathogenesis.
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Doença de Alzheimer , Receptores de AMPA , Humanos , Animais , Camundongos , Aprendizagem , Astrócitos , MicrogliaRESUMO
Monolayer transition metal dichalcogenides (TMDs) are considered promising building blocks for next-generation photonic and optoelectronic devices, owing to their fascinating optical properties. However, their inherent weak light absorption and low quantum yield severely hinder their practical applications. Here, we report up to 18000-fold photoluminescence (PL) enhancement in a monolayer WSe2-coupled plasmonic nanocavity. A spectroscopy-assisted nanomanipulation technique enables the assembly of a nanocavity with customizable resonances to simultaneously enhance the excitation and emission processes. In particular, precise control over the magnetic cavity mode facilitates spectral and spatial overlap with the exciton, resulting in plasmon-exciton intermediate coupling that approaches the maximum emission rate in the hybrid system. Meanwhile, the cavity mode exhibits high radiation directivity, which overwhelmingly directs surface-normal PL emission and leads to a 17-fold increase in the collection efficiency. Our approach opens up a new avenue to enhance the PL intensity of monolayer TMDs, facilitating their implementation in highly efficient optoelectronic devices.
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To understand how upregulated isoglutaminyl cyclase (isoQC) is involved in the initiation of diseases such as cancer, we developed a human KYSE30 carcinoma cell model in which isoQC was stably overexpressed. GO and KEGG analysis of the DEGs (228) and DEPs (254) respectively implicated isoQC on the proliferation invasion and metastasis of cells and suggested that isoQC might participate in the regulation of MAPK, RAS, circadian rhythm, and related pathways. At the functional level, isoQC-overexpressing KYSE30 cells showed enhanced proliferation, migration, and invasion capacity. Next, we decided to study the precise effect of isoQC overexpression on JNK, p-JNK, AKT, p-AKT, ERK, p-ERK, and PER2, as RNA levels of these proteins are significantly correlated with signal levels indicated in RNA-Seq analysis, and these candidates are the top correlated DEPs enriched in RT-qPCR analysis. We saw that only p-ERK expression was inhibited, while PER2 was increased. These phenotypes were inhibited upon exposure to PER2 inhibitor KL044, which allowed for the restoration of p-ERK levels. These data support upregulated isoQC being able to promote cancer cell proliferation and migration in vitro, likely by helping to regulate the MAPK and RAS signaling pathways, and the circadian protein PER2 might be a potential mediator.
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Aminoaciltransferases , Movimento Celular , Proliferação de Células , Sistema de Sinalização das MAP Quinases , Humanos , Proliferação de Células/genética , Movimento Celular/genética , Sistema de Sinalização das MAP Quinases/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Proteínas Circadianas Period/genética , Proteínas Circadianas Period/metabolismo , Invasividade Neoplásica , Regulação para Cima , Neoplasias/genética , Neoplasias/patologia , Neoplasias/metabolismoRESUMO
Mapping the small venous vasculature of the hippocampus in vivo is crucial for understanding how functional changes of hippocampus evolve with age. Oxygen utilization in the hippocampus could serve as a sensitive biomarker for early degenerative changes, surpassing hippocampal tissue atrophy as the main source of information regarding tissue degeneration. Using an ultrahigh field (7T) susceptibility-weighted imaging (SWI) sequence, it is possible to capture oxygen-level dependent contrast of submillimeter-sized vessels. Moreover, the quantitative susceptibility mapping (QSM) results derived from SWI data allow for the simultaneous estimation of venous oxygenation levels, thereby enhancing the understanding of hippocampal function. In this study, we proposed two potential imaging markers in a cohort of 19 healthy volunteers aged between 20 and 74 years. These markers were: 1) hippocampal venous density on SWI images and 2) venous susceptibility (Δχvein) in the hippocampus-associated draining veins (the inferior ventricular veins (IVV) and the basal veins of Rosenthal (BVR) using QSM images). They were chosen specifically to help characterize the oxygen utilization of the human hippocampus and medial temporal lobe (MTL). As part of the analysis, we demonstrated the feasibility of measuring hippocampal venous density and Δχvein in the IVV and BVR at 7T with high spatial resolution (0.25 × 0.25 × 1 mm3). Our results demonstrated the in vivo reconstruction of the hippocampal venous system, providing initial evidence regarding the presence of the venous arch structure within the hippocampus. Furthermore, we evaluated the age effect of the two quantitative estimates and observed a significant increase in Δχvein for the IVV with age (p=0.006, r2 = 0.369). This may suggest the potential application of Δχvein in IVV as a marker for assessing changes in atrophy-related hippocampal oxygen utilization in normal aging and neurodegenerative diseases such as AD and dementia.
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Veias Cerebrais , Imageamento por Ressonância Magnética , Humanos , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Imageamento por Ressonância Magnética/métodos , Veias Cerebrais/diagnóstico por imagem , Oxigênio , Hipocampo/diagnóstico por imagem , AtrofiaRESUMO
Lung cancer is the first leading cause of cancer-related death in the United States, with lung adenocarcinoma as the major subtype accounting for 40% of all cases. To improve patient survival, image-based prognostic models were developed due to the ready availability of pathological images at diagnosis. However, the application of these models is hampered by two main challenges: the lack of publicly available image datasets with high-quality survival information and the poor interpretability of conventional convolutional neural network models. Here, we integrated matched transcriptomic and H&E staining data from TCGA (The Cancer Genome Atlas) to develop an image-based prognostic model, termed Deep-learning based Cell Graph (DeepCG) model. Instead of survival data, we used a gene signature to predict patient prognostic risks, which was then used as labels for training DeepCG. Importantly, by employing graph structures to capture cell patterns, DeepCG can provide cell-level interpretation, which was more biologically relevant than previous region-level insights. We validated the prognostic values of DeepCG in independent datasets and demonstrated its ability to identify prognostically informative cells in images.
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Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Humanos , Modelos de Riscos Proporcionais , Adenocarcinoma de Pulmão/patologia , Neoplasias Pulmonares/patologia , Prognóstico , Perfilação da Expressão GênicaRESUMO
The development of a heme-responsive biosensor for dynamic pathway regulation in eukaryotes has never been reported, posing a challenge for achieving the efficient synthesis of multifunctional hemoproteins and maintaining intracellular heme homeostasis. Herein, a biosensor containing a newly identified heme-responsive promoter, CRISPR/dCas9, and a degradation tag N-degron was designed and optimized to fine-tune heme biosynthesis in the efficient heme-supplying Pichia pastoris P1H9 chassis. After identifying literature-reported promoters insensitive to heme, the endogenous heme-responsive promoters were mined by transcriptomics, and an optimal biosensor was screened from different combinations of regulatory elements. The dynamic regulation pattern of the biosensor was validated by the transcriptional fluctuations of the HEM2 gene involved in heme biosynthesis and the subsequent responsive changes in intracellular heme titers. We demonstrate the efficiency of this regulatory system by improving the production of high-active porcine myoglobin and soy hemoglobin, which can be used to develop artificial meat and artificial metalloenzymes. Moreover, these findings can offer valuable strategies for the synthesis of other hemoproteins.
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Técnicas Biossensoriais , Heme , Hemeproteínas , Heme/biossíntese , Heme/genética , Heme/metabolismo , Hemeproteínas/genética , Hemeproteínas/metabolismo , Hemeproteínas/biossíntese , Transcriptoma/genética , Saccharomycetales/genética , Saccharomycetales/metabolismo , Animais , Sistemas CRISPR-Cas , Engenharia Metabólica , Regiões Promotoras GenéticasRESUMO
Copper (Cu) is essential for plant growth and development. IRON MAN (IMA) is a family of small peptides that can bind both iron (Fe) and Cu ions. It was reported that IMAs mediate Fe homeostasis in Arabidopsis thaliana. However, it remains unclear whether IMAs are involved in Cu homeostasis. The transcript abundance of IMA genes decreased in response to Cu deficiency. The combined disruption of all IMA genes caused enhanced tolerance to Cu deficiency and resulted in an increase in the transcript abundance of Cu uptake genes, whereas the overexpression of IMA1 or IMA3 led to the opposite results. Protein interaction assays indicated that IMAs interact with Cu-DEFICIENCY INDUCED TRANSCRIPTION FACTOR1 (CITF1), which is a positive regulator of the Cu uptake genes. Further studies showed that IMAs not only interfere with the DNA binding of CITF1 but also repress the transcriptional activation activity of CITF1, hence resulting in downregulation of the Cu uptake genes. Genetic analyses indicated that IMAs modulate Cu homeostasis in a CITF1-dependent manner. Our findings indicate that IMAs inhibit the functions of CITF1 in regulating Cu deficiency responses, thereby providing a conceptual framework for comprehending the regulation of Cu homeostasis.
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Proteínas de Arabidopsis , Arabidopsis , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos , Humanos , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Cobre/farmacologia , Cobre/metabolismo , Arabidopsis/metabolismo , Homeostase , Regulação da Expressão Gênica de PlantasRESUMO
Suaeda salsa L. is a typical halophyte with high value as a vegetable. Here, we report a 447.98 Mb, chromosomal-level genome of S. salsa, assembled into nine pseudomolecules (contig N50 = 1.36 Mb) and annotated with 27,927 annotated protein-coding genes. Most of the assembled S. salsa genome, 58.03%, consists of transposable elements. Some gene families including HKT1, NHX, SOS and CASP related to salt resistance were significantly amplified. We also observed expansion of genes encoding protein that bind the trace elements Zn, Fe, Cu and Mn, and genes related to flavonoid and α-linolenic acid metabolism. Many expanded genes were significantly up-regulated under salinity, which might have contributed to the acquisition of salt tolerance in S. salsa. Transcriptomic data showed that high salinity markedly up-regulated salt-resistance related genes, compared to low salinity. Abundant metabolic pathways of secondary metabolites including flavonoid, unsaturated fatty acids and selenocompound were enriched, which indicates that the species is a nutrient-rich vegetable. Particularly worth mentioning is that there was no significant difference in the numbers of cis-elements in the promoters of salt-related and randomly selected genes in S. salsa when compared with Arabidopsis thaliana, which may affirm that plant salt tolerance is a quantitative rather than a qualitative trait in terms of promoter evolution. Our findings provide deep insight into the adaptation of halophytes to salinity from a genetic evolution perspective.
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Soil salinity is often heterogeneous in saline fields. Nonuniform root salinity increases nitrate uptake into cotton (Gossypium hirsutum) root portions exposed to low salinity, which may be regulated by root portions exposed to high salinity through a systemic long-distance signaling mechanism. However, the signals transmitted between shoots and roots and their precise molecular mechanisms for regulating nitrate uptake remain unknown. Here, we showed that nonuniform root salinity treatment using split-root systems increases the expression of C-TERMINALLY ENCODED PEPTIDE (GhCEP) genes in high-saline-treated root portions. GhCEP peptides originating in high-saline-treated root portions act as ascending long-distance mobile signals transported to the shoots to promote the expression of CEP DOWNSTREAM (GhCEPD) genes by inducing the expression of CEP receptor (GhCEPR) genes. The shoot-derived GhCEPD polypeptides act as descending mobile signals transported to the roots through the phloem, increasing the expression of nitrate transport genes NITRATE TRANSPORTER 1.1 (GhNRT1.1), GhNRT2.1, and GhNRT1.5 in nonsaline-treated root portions, thereby increasing nitrate uptake in the nonsaline-treated root portions. This study indicates that GhCEP and GhCEPD signals are transported between roots and shoots to increase nitrate uptake in cotton, and the transport from the nonsaline root side is in response to nonuniform root salinity distribution.
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Gossypium , Nitratos , Gossypium/metabolismo , Nitratos/metabolismo , Salinidade , Transporte de Íons , Estresse Salino , Raízes de Plantas/metabolismoRESUMO
OBJECTIVES: Obstructive sleep apnea (OSA) is associated with abnormal glucose and lipid metabolism. However, whether there is an independent association between Sleep Apnea-Specific Hypoxic Burden (SASHB) and glycolipid metabolism disorders in patients with OSA is unknown. METHODS: We enrolled 2,173 participants with suspected OSA from January 2019 to July 2023 in this study. Polysomnographic variables, biochemical indicators, and physical measurements were collected from each participant. Multiple linear regression analyses were used to evaluate independent associations between SASHB, AHI, CT90 and glucose as well as lipid profile. Furthermore, logistic regressions were used to determine the odds ratios (ORs) for abnormal glucose and lipid metabolism across various SASHB, AHI, CT90 quartiles. RESULTS: The SASHB was independently associated with fasting blood glucose (FBG) (ß = 0.058, P = 0.016), fasting insulin (FIN) (ß = 0.073, P < 0.001), homeostasis model assessment of insulin resistance (HOMA-IR) (ß = 0.058, P = 0.011), total cholesterol (TC) (ß = 0.100, P < 0.001), total triglycerides (TG) (ß = 0.063, P = 0.011), low-density lipoprotein cholesterol (LDL-C) (ß = 0.075, P = 0.003), apolipoprotein A-I (apoA-I) (ß = 0.051, P = 0.049), apolipoprotein B (apoB) (ß = 0.136, P < 0.001), apolipoprotein E (apoE) (ß = 0.088, P < 0.001) after adjustments for confounding factors. Furthermore, the ORs for hyperinsulinemia across the higher SASHB quartiles were 1.527, 1.545, and 2.024 respectively, compared with the lowest quartile (P < 0.001 for a linear trend); the ORs for hyper-total cholesterolemia across the higher SASHB quartiles were 1.762, 1.998, and 2.708, compared with the lowest quartile (P < 0.001 for a linear trend) and the ORs for hyper-LDL cholesterolemia across the higher SASHB quartiles were 1.663, 1.695, and 2.316, compared with the lowest quartile (P < 0.001 for a linear trend). Notably, the ORs for hyper-triglyceridemia{1.471, 1.773, 2.099} and abnormal HOMA-IR{1.510, 1.492, 1.937} maintained a consistent trend across the SASHB quartiles. CONCLUSIONS: We found SASHB was independently associated with hyperinsulinemia, abnormal HOMA-IR, hyper-total cholesterolemia, hyper-triglyceridemia and hyper-LDL cholesterolemia in Chinese Han population. Further prospective studies are needed to confirm that SASHB can be used as a predictor of abnormal glycolipid metabolism disorders in patients with OSA. TRIAL REGISTRATION: ChiCTR1900025714 { http://www.chictr.org.cn/ }; Prospectively registered on 6 September 2019; China.
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Hipóxia , Apneia Obstrutiva do Sono , Humanos , Masculino , Feminino , Estudos Transversais , Pessoa de Meia-Idade , Adulto , Hipóxia/sangue , Hipóxia/epidemiologia , Apneia Obstrutiva do Sono/epidemiologia , Apneia Obstrutiva do Sono/sangue , Apneia Obstrutiva do Sono/diagnóstico , Glicemia/metabolismo , Transtornos do Metabolismo dos Lipídeos/epidemiologia , Transtornos do Metabolismo dos Lipídeos/sangue , Transtornos do Metabolismo dos Lipídeos/diagnóstico , Idoso , Polissonografia , Metabolismo dos Lipídeos/fisiologia , Resistência à Insulina/fisiologiaRESUMO
Breast carcinoma (BC) ranks as a predominant malignancy and constitutes the second principal cause of mortality among women globally. Epirubicin stands as the drug of choice for BC therapeutics. Nevertheless, the emergence of chemoresistance has significantly curtailed its therapeutic efficacy. The resistance mechanisms to Epirubicin remain not entirely elucidated, yet they are conjectured to stem from diminished tumor vascular perfusion and resultant hypoxia consequent to Epirubicin administration. In our investigation, we meticulously scrutinized the Gene Expression Omnibus database for EPDR1, a gene implicated in hypoxia and Epirubicin resistance in BC. Subsequently, we delineated the impact of EPDR1 on cellular proliferation, motility, invasive capabilities, and interstitial-related proteins in BC cells, employing methodologies such as the CCK-8 assay, Transwell assay, and western blot analysis. Our research further unveiled that hypoxia-induced miR-181a-5p orchestrates the regulation of BC cell duplication, migration, invasion, and interstitial-related protein expression via modulation of EPDR1. In addition, we identified TRPC1, a gene associated with EPDR1 expression in BC, and substantiated that EPDR1 influences BC cellular dynamics through TRPC1-mediated modulation of the PI3K/AKT signaling cascade. Our findings underscore the pivotal role of EPDR1 in the development of BC. EPDR1 was found to be expressed at subdued levels in BC tissues, Epirubicin-resistant BC cells, and hypoxic BC cells. The overexpression of EPDR1 curtailed BC cell proliferation, motility, invasiveness, and the expression of interstitial-related proteins. At a mechanistic level, the overexpression of hypoxia-induced miR-181a-5p was observed to inhibit the EPDR1/TRPC1 axis, thereby activating the PI3K/AKT signaling pathway and diminishing the sensitivity to Epirubicin in BC cells. In summation, our study demonstrates that the augmentation of hypoxia-induced miR-181a-5p diminishes Epirubicin sensitivity in BC cells by attenuating EPDR1/TRPC1 expression, thereby invigorating the PI3K/AKT signaling pathway. This exposition offers a theoretical foundation for the application of Epirubicin in BC therapy, marking a significant contribution to the existing body of oncological literature.
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Neoplasias da Mama , MicroRNAs , Humanos , Feminino , Epirubicina/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Regulação para Cima , Transdução de Sinais/genética , Proliferação de Células/genética , Hipóxia/genética , Linhagem Celular TumoralRESUMO
BACKGROUND: The choroid plexus (ChP), a densely vascularized structure, has drawn increasing attention for its involvement in brain homeostasis and waste clearance. While the volumetric changes have been explored in many imaging studies, few studies have investigated the vascular degeneration associated with aging in the ChP. PURPOSE: To investigate the sub-structural characteristics of the ChP, particularly the vascular compartment using high-resolution 7T imaging enhanced with Ferumoxytol, an ultrasmall super-paramagnetic iron oxide, which greatly increase the susceptibility contrast for vessels. STUDY TYPE: Prospective. SUBJECTS: Forty-nine subjects without neurological disorders (age: 21-80 years; 42 ± 17 years; 20 females). FIELD STRENGTH/SEQUENCE: 7-T with 2D and 3D T2* GRE, 3D MPRAGE T1, 2D TSE T2, and 2D FLAIR. ASSESSMENT: The vascular and stromal compartments of the ChP were segmented using K-means clustering on post-contrast 2D GRE images. Visual and qualitative assessment of ChP vascular characteristics were conducted independently by three observers. Vascular density (Volvessel/VolChP ratio) and susceptibility change (Δχ) induced by Ferumoxytol were analyzed on 3D GRE-derived susceptibility-weighted imaging and quantitative susceptibility mapping, respectively. STATISTICAL TESTS: Independent t-test, Mann-Whitney U test, and Chi-square test were utilized for group comparisons. The relationship between age and ChP's vascular alterations was examined using Pearson's correlation. Intra-class coefficient was calculated for inter-observer agreement. A P value <0.05 was considered statistically significant. RESULTS: 2D GRE images demonstrated superior contrast and accurate delineation of ChP substructures (ICC = 0.86). Older subjects exhibited a significantly smaller vascular density (16.5 ± 4.34%) and lower Δχ (22.10 ± 12.82 ppb) compared to younger subjects (24.85 ± 6.84% and 34.64 ± 12.69 ppb). Vascular density and mean Δχ within the ChP negatively correlated with age (r = -0.48, and r = -0.45). DATA CONCLUSION: Ferumoxytol-enhanced 7T images can demonstrate ChP alterations in elderly with decreased vascular density and expansion of nonvascular compartment. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 2.
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Cell death is a vital event in life. Infections and injuries cause lytic cell death, which gives rise to danger signals that can further induce cell death, inflammation, and tissue damage. The mevalonate (MVA) pathway is an essential, highly conserved and dynamic metabolic pathway. Here, we discover that farnesyl pyrophosphate (FPP), a metabolic intermediate of the MVA pathway, functions as a newly identified danger signal to trigger acute cell death leading to neuron loss in stroke. Harboring both a hydrophobic 15-carbon isoprenyl chain and a heavily charged pyrophosphate head, FPP leads to acute cell death independent of its downstream metabolic pathways. Mechanistically, extracellular calcium influx and the cation channel transient receptor potential melastatin 2 (TRPM2) exhibit essential roles in FPP-induced cell death. FPP activates TRPM2 opening for ion influx. Furthermore, in terms of a mouse model constructing by middle cerebral artery occlusion (MCAO), FPP accumulates in the brain, which indicates the function of the FPP and TRPM2 danger signal axis in ischemic injury. Overall, our data have revealed a novel function of the MVA pathway intermediate metabolite FPP as a danger signal via transient receptor potential cation channels.
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Morte Celular/efeitos dos fármacos , Fosfatos de Poli-Isoprenil/farmacologia , Sesquiterpenos/farmacologia , Animais , Bário/farmacologia , Cálcio/farmacologia , Morte Celular/genética , Células Cultivadas , Embrião de Mamíferos , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fosfatos de Poli-Isoprenil/metabolismo , Ratos , Ratos Sprague-Dawley , Sesquiterpenos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Estrôncio/farmacologiaRESUMO
Triggering receptor expressed on myeloid cells 1 (TREM1) is a cell surface receptor expressed on neutrophils, monocytes and some tissue macrophages, where it functions as an immunoregulator that controls myeloid cell responses. The activation of TREM1 is suggested to be an upregulation-based, ligands-induced and structural multimerization-mediated process, in which damage- and pathogen-associated molecular patterns play important roles. Activated TREM1 initiates an array of downstream signaling pathways that ultimately result in the production of pro-inflammatory cytokines and chemokines, whereby it functions as an amplifier of inflammation and is implicated in the pathogenesis of many inflammation-associated diseases. Over the past decade, there has been growing evidence for the involvement of TREM1 overactivation in tumor stroma inflammation and cancer progression. Indeed, it was shown that TREM1 promotes tumor progression, immunosuppression, and resistance to therapy by activating tumor-infiltrating myeloid cells. TREM1-deficiency or blockade provide protection against tumors and reverse the resistance to anti-PD-1/PD-L1 therapy and arginine-deprivation therapy in preclinical models. Here, we first review the structure, activation modes and signaling pathways of TREM1 and emphasize the role of soluble TREM1 as a biomarker of infection and cancer. We then focus on the role of TREM1 in cancer and systematically summarize its expression patterns, upregulation mechanisms and functions in tumor development and progression. Lastly, we discuss the therapeutic prospects of TREM1 inhibition, via effective pharmacological inhibitors, in treating cancer and other diseases.
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Neoplasias , Transdução de Sinais , Receptor Gatilho 1 Expresso em Células Mieloides , Receptor Gatilho 1 Expresso em Células Mieloides/metabolismo , Receptor Gatilho 1 Expresso em Células Mieloides/antagonistas & inibidores , Receptor Gatilho 1 Expresso em Células Mieloides/genética , Humanos , Neoplasias/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Neoplasias/genética , Neoplasias/patologia , Animais , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologiaRESUMO
Alzheimer's disease (AD) is a major cause of dementia and one of the most common chronic diseases affecting the aging population. Because AD is considered a public health priority, there is a critical need to discover novel and effective agents for the treatment of this condition. In view of the known contribution of up-regulated glutaminyl cyclase (QC) and glycogen synthase kinase-3ß (GSK-3ß) to the initiation of AD, we previously evaluated a series of dual inhibitors containing maleimide and imidazole motifs as potential anti-AD agents. Here, we assessed another series of hybrids containing maleimide and imidazole motifs to gain an in-depth understanding of the structure-activity relationship (SAR). Based on the primary screening, the introduction of 5-methyl imidazole at one side of the molecule did not enhance the QC-specific inhibitory activity of these hybrids (2, IC50 = 1.22 µM), although the potency was increased by 2' substitution on the maleimide motif at the other side of the molecule. Interestingly, compounds containing 5-methyl imidazole exhibited stronger GSK-3ß-specific inhibitory activity (2, IC50 = 0.0021 µM), and the electron-withdrawing group and 2' and 3' substitution were favorable. Further investigation of substitutions on the maleimide motif in compounds 14-35 revealed that QC-specific inhibition in the presence of piperidine was improved by introduction of a methoxy group (R2). Increasing the linker length and introduction of a methoxy group (R2) also increased the GSK-3ß-specific inhibitory potency. These findings were further confirmed by molecular docking analysis of 33 and 24 with QC and GSK-3ß. Overall, these hybrids exhibited enhanced inhibitory potency against both QC and GSK-3ß, highlighting an important strategy for improving the potency of hybrids as dual-targeting anti-AD agents.
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Aminoaciltransferases , Glicogênio Sintase Quinase 3 beta , Imidazóis , Maleimidas , Relação Estrutura-Atividade , Maleimidas/química , Maleimidas/farmacologia , Maleimidas/síntese química , Imidazóis/química , Imidazóis/farmacologia , Imidazóis/síntese química , Humanos , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Glicogênio Sintase Quinase 3 beta/metabolismo , Aminoaciltransferases/antagonistas & inibidores , Aminoaciltransferases/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/síntese química , Estrutura Molecular , Doença de Alzheimer/tratamento farmacológico , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Quinase 3 da Glicogênio Sintase/metabolismo , Relação Dose-Resposta a DrogaRESUMO
Ulcerative colitis (UC) is a chronic inflammatory disease that targets the colon and has seen an increasing prevalence worldwide. In our pursuit of new diagnostic and therapeutic approaches for UC, we undertook a sequencing of colons from UC mouse models. We focused on analyzing their differentially expressed genes (DEGs), enriching pathways, and constructing protein-protein interaction (PPI) and Competing Endogenous RNA (ceRNA) networks. Our analysis highlighted novel DEGs such as Tppp3, Saa3, Cemip, Pappa, and Nr1d1. These DEGs predominantly play roles in pathways like cytokine-mediated signaling, extracellular matrix organization, extracellular structure organization, and external encapsulating structure organization. This suggests that the UC pathogenesis is intricately linked to the interactions between immune and non-immune cells with the extracellular matrix (ECM). To corroborate our findings, we also verified certain DEGs through quantitative real-time PCR. Within the PPI network, nodes like Stat3, Il1b, Mmp3, and Lgals3 emerged as significant and were identified to be involved in the crucial cytokine-mediated signaling pathway, which is central to inflammation. Our ceRNA network analysis further brought to light the role of the Smad7 Long non-coding RNA (lncRNA). Key MicroRNA (miRNAs) in the ceRNA network were pinpointed as mmu-miR-17-5p, mmu-miR-93-5p, mmu-miR-20b-5p, mmu-miR-16-5p, and mmu-miR-106a-5p, while central mRNAs included Egln3, Plagl2, Sema7a, Arrdc3, and Stat3. These insights imply that ceRNA networks are influential in UC progression and could provide further clarity on its pathogenesis. In conclusion, this research deepens our understanding of UC pathogenesis and paves the way for potential new diagnostic and therapeutic methods. Nevertheless, to solidify our findings, additional experiments are essential to confirm the roles and molecular interplay of the identified DEGs in UC.
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Colite Ulcerativa , MicroRNAs , Animais , Camundongos , Colite Ulcerativa/genética , Intestinos , Inflamação/genética , MicroRNAs/genética , Modelos Animais de DoençasRESUMO
Triple-negative breast cancer is one of the most malignant subtypes in clinical practice, and it is urgent to find new therapies. The p21-activated kinase I (PAK1) has been considered to be an attractive therapeutic target for TNBC. In this study, we designed and synthesized a series of novel PROTAC PAK1 degraders by conjugating VHL or CRBN ligase ligands to PAK1 inhibitors which are connected by alkyl chains or PEG chains. The most promising compound, 19s, can significantly degrade PAK1 protein at concentrations as low as 0.1 µM, and achieves potent anti-proliferative activity with an IC50 value of 1.27 µM in MDA-MB-231 cells. Additionally, 19s exhibits potent anti-migration activity in vitro and induces rapid tumor regression in vivo. Collectively, these findings document that 19s is a potent and novel PAK1 degrader with promising potential for TNBC treatment.
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Glutaminyl cyclase (QC) plays a crucial role in the early stages of Alzheimer's disease (AD), thus inhibition of QC may be a promising strategy for the treatment of early AD. Therefore, QC inhibitors with novel chemical scaffolds may contribute to the development of additional anti-AD agents. We conducted a virtual screening of 3 million compounds from the Chemdiv and Enamine databases, to discover potential scaffolds for QC inhibitors. Three scaffolds, 120974, 147706, and 141449, were selected from this structure-based virtual screening through a combination of pharmacophore modeling, a receptor-ligand pharmacophore model, and the GALAHAD model, and furtherly filtered by chelation with zinc ion and docking properties. Consequently, three compounds, 1, 2, and 3, were designed and synthesized based on these three scaffolds, respectively. The IC50 of compounds 1 and 3 against QC were 14.19 ± 4.21 and 4.34 ± 0.35 µM, respectively. Our results indicate that the new scaffolds selected using a virtual screening process exhibit potential as novel QC inhibitors.
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Doença de Alzheimer , Aminoaciltransferases , Humanos , Aminoaciltransferases/antagonistas & inibidores , Aminoaciltransferases/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Simulação de Acoplamento MolecularRESUMO
Forte is an open-source library specialized in multireference electronic structure theories for molecular systems and the rapid prototyping of new methods. This paper gives an overview of the capabilities of Forte, its software architecture, and examples of applications enabled by the methods it implements.