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Pancreatobililary cancers are fatal solid tumors that pose a significant threat to human life. It is imperative to investigate novel small molecule active compounds for controlling these cancers. Heterocyclic compounds (e.g. gemcitabine) and multi-substituted alkenes (e.g. resveratrol) are commonly applied in tumor treatment. Researchers have proposed that the synthesis of new trisubstituted alkenes containing heteroaromatic rings by combining these two scaffolds may be a fresh strategy to develop new active molecules. In this study, we utilized alkenyl bromide and heteroaryl boronic acid as substrates, employing Suzuki coupling to generate a series of triarylethylenes featuring nitrogen, oxygen, and sulfur atoms. Through in vitro experiments, the results indicated that some compounds exhibited remarkable anti-tumor efficacy (e.g. IC50[3be, GBC-SD] = 0.13 µM and IC50[3be, PANC-1] = 0.27 µM). The results further demonstrated that the antitumor efficacy of these compounds was dependent on the heteroatom, π-system, skeleton-bonding site, and substituent type.
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Cancer stands as a serious malady, posing substantial risks to human well-being and survival. This underscores the paramount necessity to explore and investigate novel antitumor medications. Nitrogen-containing compounds, especially those derived from natural sources, form a highly significant category of antitumor agents. Among these, antitumor agents with six-membered aromatic nitrogen heterocycles have consistently attracted the attention of chemists and pharmacologists. Accordingly, we present a comprehensive summary of synthetic strategies and clinical implications of these compounds in this review. This entails an in-depth analysis of synthesis pathways for pyridine, quinoline, pyrimidine, and quinazoline. Additionally, we explore the historical progression, targets, mechanisms of action, and clinical effectiveness of small molecule inhibitors possessing these structural features.
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Antineoplásicos , Compuestos Heterocíclicos , Humanos , Compuestos Heterocíclicos/farmacología , Compuestos Heterocíclicos/química , Nitrógeno/química , Antineoplásicos/farmacología , Antineoplásicos/químicaRESUMEN
Ubiquilin-2 (UBQLN2) mutations lead to familial amyotrophic lateral sclerosis (FALS)/and frontotemporal dementia (FTLD) through unknown mechanisms. The combination of iPSC technology and CRISPR-mediated genome editing technology can generate an iPSC-derived motor neuron (iPSC-MN) model with disease-relevant mutations, which results in increased opportunities for disease mechanism research and drug screening. In this study, we introduced a UBQLN2-P497H mutation into a healthy control iPSC line using CRISPR/Cas9, and differentiated into MNs to study the pathology of UBQLN2-related ALS. Our in vitro MN model faithfully recapitulated specific aspects of the disease, including MN apoptosis. Under sodium arsenite (SA) treatment, we found differences in the number and the size of UBQLN2+ inclusions in UBQLN2P497H MNs and wild-type (WT) MNs. We also observed cytoplasmic TAR DNA-binding protein (TARDBP, also known as TDP-43) aggregates in UBQLN2P497H MNs, but not in WT MNs, as well as the recruitment of TDP-43 into stress granules (SGs) upon SA treatment. We noted that UBQLN2-P497H mutation induced MNs DNA damage, which is an early event in UBQLN2-ALS. Additionally, DNA damage led to an increase in compensation for FUS, whereas UBQLN2-P497H mutation impaired this function. Therefore, FUS may be involved in DNA damage repair signaling.
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Esclerosis Amiotrófica Lateral , Células Madre Pluripotentes Inducidas , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Esclerosis Amiotrófica Lateral/metabolismo , Proteínas Relacionadas con la Autofagia/genética , Proteínas Relacionadas con la Autofagia/metabolismo , ADN/metabolismo , Daño del ADN , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Neuronas Motoras/metabolismo , Mutación , Factores de Transcripción/metabolismoRESUMEN
Duchenne muscular dystrophy (DMD), the most common lethal muscular disorder, affects 1 in 5000 male births. It is caused by mutations in the X-linked dystrophin gene (DMD), and there is no effective treatment currently. Gene addition is a promising strategy owing to its universality for patients with all gene mutations types. In this study, we describe a site-specific gene addition strategy in induced pluripotent stem cells (iPSCs) derived from a DMD patient with exon 50 deletion. By using transcription activator-like effector nickases (TALENickases), the mini-dystrophin cassette was precisely targeted at the ribosomal RNA gene (rDNA) locus via homologous recombination with high targeting efficiency. The targeted clone retained the main pluripotent properties and was differentiated into cardiomyocytes. Significantly, the dystrophin expression and membrane localization were restored in the genetic corrected iPSCs and their derived cardiomyocytes. More importantly, the enhanced spontaneous contraction was observed in modified cardiomyocytes. These results provide a proof of principle for an efficient targeted gene addition for DMD gene therapy and represents a significant step toward precisely therapeutic for DMD.
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ADN Ribosómico/genética , Distrofina/genética , Terapia Genética/métodos , Células Madre Pluripotentes Inducidas/metabolismo , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/terapia , Diferenciación Celular , Línea Celular , Técnicas de Reprogramación Celular , Distrofina/metabolismo , Exones , Expresión Génica , Marcación de Gen/métodos , Humanos , Células Madre Pluripotentes Inducidas/citología , Mutación con Pérdida de Función , Masculino , Distrofia Muscular de Duchenne/orina , Miocitos Cardíacos/citología , Miocitos Cardíacos/metabolismo , Prueba de Estudio Conceptual , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Eliminación de Secuencia , Orina/citologíaRESUMEN
In recent years, significant advancements have been made in the synthesis and application of 1,3-dienes. This specific structural motif has garnered significant attention from researchers in materials science and biology due to its unique aggregation-induced emission (AIE) properties and extensive conjugation systems. The luminescent characteristics of these compounds are notably influenced by the geometry of the two double bonds. Therefore, it is essential to consolidate stereoselective synthetic strategies for 1,3-dienes. This comprehensive review seeks to elucidate the diverse techniques employed to attain stereo-control in the synthesis of 1,3-diene-based AIE luminogens (AIEgens). Particular emphasis is placed on comprehending the determinants of stereoselectivity and exploring the array of substrates amenable to these methods. Furthermore, the review underscores the AIE properties exhibited by these compounds and their extensive utility in organic light-emitting diodes (OLEDs), stimuli-responsive materials, sensors, bioimaging, and photodynamic therapy (PDT).
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Adsorption is considered to be one of the most effective methods to remove radioiodine from the solution. However, developing highly efficient adsorbents and the rapid recovery of the used adsorbents is still a challenge. Here, a series of Cu/Fe3O4 bimetallic mutual-doping magnetic aerogels (Cu/Fe3O4-BMMA) were synthesized. Based on the in-situ bimetallic co-gelation process, the high dispersion of Cu in the aerogel was realized, providing conditions for the efficient elimination of I2. The Fe3+ in the initial gel was reduced to magnetic Fe3O4 during the preparation process, allowing for the quick recovery of the adsorbent through the application of a magnetic field. The adsorption experiments showed that Cu/Fe3O4-BMMA has good I2 adsorption capacity (631.3 mg/g) and fast capture kinetics (equilibrium time < 30 min). In addition, Cu/Fe3O4-BMMA was able to effectively remove trace I2 in the solution from ppm level (1.0 ppm) down to ppb level (≤30 ppb). The adsorbed I2 was converted into stable CuI, avoiding secondary pollution due to desorption. Overall, this study provides a potentially efficient iodine capture material for long-term decay storage of radioactive iodine.
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Small extracellular vesicles (sEVs) have emerged as promising therapeutic agents and drug delivery vehicles. Targeted modification of sEVs and their contents using genetic modification strategies is one of the most popular methods. This study investigated the effects of p53 fusion with arrestin domain-containing protein 1 (ARRDC1) and CD63 on the generation of sEVs, p53 loading efficiency, and therapeutic efficacy. Overexpression of either ARRDC1-p53 (ARP) or CD63-p53 (CDP) significantly elevated p53 mRNA and protein levels. The incorporation of ARRDC1 and CD63 significantly enhanced HEK293T-sEV biogenesis, evidenced by significant increases in sEV-associated proteins TSG101 and LAMP1, resulting in a boost in sEV production. Importantly, fusion with ARRDC1 or CD63 substantially increased the efficiency of loading both p53 fusion proteins and its mRNA into sEVs. sEVs equipped with ARP or CDP significantly enhanced the enrichment of p53 fusion proteins and mRNA in p53-null H1299 cells, resulting in a marked increase in apoptosis and a reduction in cell proliferation, with ARP-sEVs demonstrating greater effectiveness than CDP-sEVs. These findings underscore the enhanced functionality of ARRDC1- and CD63-modified sEVs, emphasizing the potential of genetic modifications in sEV-based therapies for targeted cancer treatment.
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Apoptosis , Vesículas Extracelulares , Tetraspanina 30 , Proteína p53 Supresora de Tumor , Humanos , Tetraspanina 30/metabolismo , Tetraspanina 30/genética , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/genética , Proteína p53 Supresora de Tumor/metabolismo , Proteína p53 Supresora de Tumor/genética , Células HEK293 , Línea Celular Tumoral , Proliferación Celular , Complejos de Clasificación Endosomal Requeridos para el Transporte/metabolismo , Complejos de Clasificación Endosomal Requeridos para el Transporte/genética , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/genética , ARN Mensajero/metabolismo , ARN Mensajero/genética , Proteína 1 de la Membrana Asociada a los LisosomasRESUMEN
Pancreatic cancer (PC) is a highly malignant cancer characterized by poor prognosis, high heterogeneity, and intricate heterocellular systems. Selecting an appropriate experimental model for studying its progression and treatment is crucial. Patient-derived models provide a more accurate representation of tumor heterogeneity and complexity compared to cell line-derived models. This review initially presents relevant patient-derived models, including patient-derived xenografts (PDXs), patient-derived organoids (PDOs), and patient-derived explants (PDEs), which are essential for studying cell communication and pancreatic cancer progression. We have emphasized the utilization of these models in comprehending intricate intercellular communication, drug responsiveness, mechanisms underlying tumor growth, expediting drug discovery, and enabling personalized medical approaches. Additionally, we have comprehensively summarized single-cell analyses of these models to enhance comprehension of intercellular communication among tumor cells, drug response mechanisms, and individual patient sensitivities.
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Organoides , Neoplasias Pancreáticas , Análisis de la Célula Individual , Microambiente Tumoral , Humanos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/metabolismo , Análisis de la Célula Individual/métodos , Animales , Organoides/metabolismo , Microambiente Tumoral/genética , Comunicación Celular/genética , Medicina de PrecisiónRESUMEN
Due to the critical importance of capturing radioiodine from aquatic environments for human health and ecosystems, developing highly efficient adsorbent materials with rapid kinetics for capturing iodide ions in aqueous solutions is urgently needed. Although extensive research has been conducted on iodine adsorption in gas and organic phases, limited research has been dedicated to adsorption in aqueous solutions. An effective technique for removing iodide was proposed using Ag@Cu-based MOFs synthesized by incorporating Ag into calcined HKUST-1 with varying mass ratios of Ag/Cu-C. Extensive characterization using SEM, XRD, XPS, and nitrogen adsorption-desorption analysis confirmed successful incorporation of Ag in Cu-C. Batch adsorption experiments were conducted, demonstrating that the 5% Ag@Cu-C material exhibited a high adsorption capacity of 247.1 mg g-1 at pH 3. Mechanism investigations revealed that Cu0 and dissolved oxygen in water generate Cu2O and H2O2, while Ag and a small amount of CuO generate Ag2O and Cu2O. Furthermore, iodide ions in the solution are captured by Cu+ and Ag+ adsorption sites. These findings highlighted the potential of Ag@Cu-based MOFs as highly effective adsorbents for iodine anions removal in radioactive wastewater.
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Yodo , Monitoreo de Radiación , Contaminantes Químicos del Agua , Humanos , Yoduros , Radioisótopos de Yodo/análisis , Ecosistema , Peróxido de Hidrógeno , Agua/química , Contaminantes Químicos del Agua/análisis , Adsorción , Cinética , SolucionesRESUMEN
AIMS: The ubiquilin-like protein ubiquilin 2 (UBQLN2) is associated with amyotrophic lateral sclerosis and frontotemporal degeneration (ALS/FTD). The biological function of UBQLN2 has previously been shown to be related to stress granules (SGs). In this study, we aimed to clarify the regulatory relationship between UBQLN2 and SGs. METHODS: In this study, we transfected UBQLN2-WT or UBQLN2-P497H plasmids into cell lines (HEK293T, HeLa), and observed the process of SG dynamics by immunofluorescence. Meanwhile, immunoblot analyses the protein changes of stress granules related components. RESULTS: We observed that ubiquilin 2 colocalizes with the SG component proteins G3BP1, TIA-1, ATXN2, and PABPC1. In cells expressing WT UBQLN2 or P497H mutants, in the early stages of SG formation under oxidative stress, the percentage of cells with SGs and the number of SGs per cell decreased to varying degrees. Between WT and mutant, there was no significant difference in eIF2α activity after stress treatment. Interestingly, the UBQLN2 P497H mutant downregulates the level of TIA-1. In addition, the overexpression of the UBQLN2 P497H mutant inhibited the phosphorylation of 4E-BP1 and affected the nucleoplasmic distribution of TDP-43. CONCLUSIONS: Ubiquilin 2 colocalizes with the SG component proteins G3BP1, TIA-1, ATXN2, and PABPC1. It participates in regulating SG dynamics. And UBQLN2 mutation affects the assembly of stress granules by regulating TIA-1. In addition, the overexpression of the UBQLN2 P497H mutant inhibited the phosphorylation of 4E-BP1 and affected the nuclear and cytoplasmic distribution of TDP-43. These provide new insights into the role of UBQLN2 in oxidative stress and the pathogenesis of ALS.
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Proteínas Adaptadoras Transductoras de Señales/genética , Esclerosis Amiotrófica Lateral/genética , Proteínas Relacionadas con la Autofagia/genética , Mutación/genética , Gránulos de Estrés , Esclerosis Amiotrófica Lateral/metabolismo , ADN Helicasas , Demencia Frontotemporal/genética , Demencia Frontotemporal/metabolismo , Células HEK293 , Humanos , Proteínas de Unión a Poli-ADP-Ribosa , ARN Helicasas , Proteínas con Motivos de Reconocimiento de ARN , Antígeno Intracelular 1 de las Células TRESUMEN
The uniform dispersion of graphene oxide (GO) and strong interfacial bonding are the key factors in achieving the high mechanical strength of GO/polymer composites. It is still challenging to prepare GO/PA66 composites with uniform GO dispersion by the in situ polymerization method. In this paper, we prepare GO/PA66 salt nanocomposite by in situ precipitating PA66 salt with GO in ethanol. The GO/PA66 nanocomposite fibers are then fabricated using the as-prepared GO/PA66 salt by in situ polymerizing and melt spinning. By tuning the GO content, the tensile strength and Young's modulus of the GO/PA66 fibers are increased from 265 ± 18 to 710 ± 14 MPa (containing 0.3 wt% GO) and from 1.1 ± 0.08 to 3.8 ± 0.19 GPa (containing 0.5 wt% GO), respectively. The remarkable improvements are attributed to the uniform dispersion of GO in the GO/PA66 salt nanocomposite via ionic bonding and hydrogen bonding in the in situ precipitation process, and the covalent interfacial bonding between the GO and PA66 during the in situ polymerization process. This work sheds light on the easy fabrication of high-performance PA66-based nanocomposites.
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Nonagenarians with acute ischemic stroke tend to have a higher mortality and morbidity than younger patients. Tirofiban is a glycoprotein IIb/IIIa antagonist that has a therapeutic potential for ischemic stroke. Here, we provide a case report of a 93-year-old male patient with acute ischemic stroke. He presented with right-sided hemiparesis for 2 hours (National Institute of Health Stroke Scale, NIHSS = 23). Immediate treatment with endovascular tirofiban infusion achieved an improvement of intracranial blood flow and a progressively decreased NIHSS one day after admission (NIHSS = 16) and then seven days after admission (NIHSS = 7). After a follow-up of 90 days, the modified ranking score was 2. This case report suggests that endovascular application with tirofiban may be a favorable option for treating nonagenarians presenting with acute ischemic stroke and warrants further study.
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Genipin, a natural compound derived from the fruit of Gardenia jasminoides, possesses numerous biological properties. The aim of the present study was to investigate the anticancer effects of genipin in human bladder cancer. T24 and 5637 bladder cancer cells were treated with different concentrations of genipin (0-200 µM) and tested for cell viability, colony formation, cell cycle progression and apoptosis. A xenograft model of bladder cancer was established to determine the anticancer effect of genipin in vivo. The involvement of the phosphoinositide-3 kinase (PI3K)/Akt pathway in the action of genipin was examined. Genipin treatment significantly inhibited the viability and clonogenic growth of bladder cancer cells and inhibited the growth of T24 xenograft tumors, compared with vehicle controls (P<0.05). Genipin-treated cells exhibited a cell cycle arrest at the G0/G1-phase, which was accompanied by a deregulation of numerous cell cycle regulators. Genipin-treated cells demonstrated a significant increase in the percentage of apoptotic cells, loss of mitochondrial membrane potential, Bax translocation to the mitochondria and the release of cytochrome c to the cytosol. Additionally, genipin treatment significantly (P<0.05) reduced the phosphorylation levels of PI3K and Akt in bladder cancer cells. Importantly, genipin-mediated anticancer effects were reversed by the overexpression of constitutively active Akt. In conclusion, to the best of our knowledge, the present study demonstrates for the first time the growth inhibitory effects of genipin in bladder cancer cells, and indicates its potential as a natural anticancer agent for bladder cancer.