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As a type of intelligent dimming film, polymer-dispersed liquid crystals (PDLCs) have been widely applied in various fields, such as smart windows, light shutters and displays. The properties of PDLCs are greatly influenced by the structure of the raw materials. In this work, the impact of crosslinking agents with different cyclic or chain groups was investigated by comparing the electro-optical performance and the morphology of the polymer matrix in the as-made PDLC films. It was found that the incorporation of large steric groups into the crosslinking agents can alter the morphology of the polymer matrix and thus affect the electro-optical properties. However, the impact is distinct when the spatial structure or rigidity is different. Besides, a combination of crosslinking agents with flexible alkyl-chain structures and steric structures can further reduce the threshold voltage while keeping the high contrast ratio. After detailed comparison, an optimized combination of BDDA/TCDDA in a weight ratio of 1/1 is selected to demonstrate the enhanced properties of the as-constructed film with a thickness of 20 µm. It exhibits low threshold voltage (8.2 V), low saturation voltage (21.2 V) and a high contrast ratio (203) simultaneously. This research offers an optimizing method from the crosslinking agent perspective and is anticipated to promote the further improvement of the PDLC's performance.
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OBJECTIVE: This study aimed to investigate the structure of the mitral valve in patients undergoing mitral valvuloplasty (MVP) using real-time three-dimensional transesophageal echocardiography (RT-3D-TEE). The main objective was to study the relationship between intraoperative annuloplasty ring size and mitral valve structure dimensions, with a focus on exploring the application value of RT-3D-TEE in MVP. METHODS: A total of 28 patients with degenerative mitral regurgitation (DMR), who underwent MVP between February and September 2022, as well as 12 normal control cases, were enrolled in this study. The MV annulus and leaflets were quantitatively analyzed using MVN software. RESULTS: The DMR group exhibited significantly greater dimensions in various parameters of the mitral valve, including the anterolateral-to-posteromedial diameter (DAlPm ), anterior-to-posterior diameter (DAP ), annulus height (HA ), three-dimensional annulus circumference (CA3D ), two-dimensional annulus area (AA2D ), anterior leaflet area (Aant ), posterior leaflet area (Apost ), anterior leaflet length (Lant ), posterior leaflet length (Lpost ), and tenting volume (Vtent ) compared to the control group. CONCLUSION: Real-time three-dimensional transesophageal echocardiography provides valuable insights into the morphological structure of the mitral valve and lesion location. It can aid in surgical decision-making, validate the success of MVP, and potentially reduce mortality and complications associated with mitral valve repair procedures.
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Valvuloplastia con Balón , Ecocardiografía Tridimensional , Ecocardiografía Transesofágica , Insuficiencia de la Válvula Mitral , Humanos , Ecocardiografía Tridimensional/métodos , Ecocardiografía Transesofágica/métodos , Electrocardiografía , Válvula Mitral/diagnóstico por imagen , Válvula Mitral/cirugía , Insuficiencia de la Válvula Mitral/diagnóstico por imagen , Insuficiencia de la Válvula Mitral/cirugíaRESUMEN
Reducing mitochondrial oxidative stress has become an important strategy to prevent neuronal death in ischemic stroke. Previous studies have shown that 20(R)-ginsenoside Rg3 can significantly improve behavioral abnormalities, reduce infarct size, and decrease the number of apoptotic neurons in cerebral ischemia/reperfusion injury rats. However, it remains unclear whether 20(R)-ginsenoside Rg3 can inhibit mitochondrial oxidative stress in ischemic stroke and the potential molecular mechanism. In this study, we found that 20(R)-ginsenoside Rg3 notably inhibited mitochondrial oxidative stress in middle cerebral artery occlusion/reperfusion (MCAO/R) rats and maintained the stability of mitochondrial structure and function. Treatment with 20(R)-ginsenoside Rg3 also decreased the levels of mitochondrial fission proteins (Drp1 and Fis1) and increased the levels of fusion proteins (Opa1, Mfn1, and Mfn2) in MCAO/R rats. Furthermore, we found that 20(R)-ginsenoside Rg3 promoted nuclear aggregation of nuclear factor erythroid2-related factor 2 (Nrf2) but did not affect Kelch-like ECH-associated protein-1 (Keap1), resulting in the downstream expression of antioxidants. In in vitro oxygen-glucose deprivation/reperfusion stroke models, the results of PC12 cells treated with 20(R)-ginsenoside Rg3 were consistent with animal experiments. After transfection with Nrf2 short interfering RNA (siRNA), the protective effect of 20(R)-ginsenoside Rg3 on PC12 cells was reversed. In conclusion, the inhibition of mitochondrial oxidative stress plays a vital position in the anti-cerebral ischemia-reperfusion injury of 20(R)-ginsenoside Rg3, and its neuroprotective mechanism is related to the activation of the nuclear factor erythroid2-related factor 2/heme oxygenase 1 signaling pathway.
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Isquemia Encefálica , Ginsenósidos , Accidente Cerebrovascular Isquémico , Fármacos Neuroprotectores , Daño por Reperfusión , Ratas , Animales , Ratas Sprague-Dawley , Estrés Oxidativo , Factor 2 Relacionado con NF-E2/metabolismo , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Fármacos Neuroprotectores/farmacología , Transducción de Señal , Daño por Reperfusión/prevención & control , Infarto de la Arteria Cerebral MediaRESUMEN
In recent years, clear aligner can enhance individual appearance with dental defects, so it used more and more widely. However, in manufacturing process, there are still some problems, such as low degree of automation and high equipment cost. The problem of coordinate system mismatch between gingival curve point cloud and dental CAD model is faced to. The PCA-ICP registration algorithm is proposed, which includes coarse match algorithm and improve-ICP registration algorithm. The principal component analysis (PCA) based method can roughly find the posture relationship between the two point clouds. Using z-level dynamic hierarchical, the ICP registration can accurately find the posture between these two clouds. The final registration maximum distance error is 0.03 mm, which is smaller than robot machining error. Secondly, the clear aligner machining process is conducted to verify the registration effectiveness. Before machining, the path is generated based on the well registered gingival curve. After full registration, the tool path is calculated by establishing a local coordinate system between the workpiece and the tool to avoid interference. This path is calculated and generated as an executable program for ABB industrial robots. Finally, the robot was used for flexible cutting of clear aligners and was able to extract products, ensuring the effectiveness of the proposed research. This method can effectively solve the limitations of traditional milling path planning under such complex conditions.
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Prostate cancer (PCa) remains a significant cause of morbidity and mortality among men worldwide. A number of genes have been implicated in prostate tumorigenesis, but the mechanisms underlying their dysregulation are still incompletely understood. Evidence has established the competing endogenous RNA (ceRNA) theory as a novel regulatory mechanism for post-transcriptional alterations. Yet, a comprehensive characterization of ceRNA network in PCa lacks. Here we utilize stringent in-silico methods to construct a large ceRNA network across different PCa stages, and provide experimental demonstration for the competing regulation among protumorigenic SEC23A, PHTF2, and their corresponding ceRNA pairs. Using machine learning, we establish a ceRNA-based signature (ceRNA_sig) predictive of androgen receptor (AR) activity, tumor aggressiveness, and patient outcomes. Importantly, we identify miR-375 as a key node in PCa ceRNA network, which is upregulated in PCa relative to normal tissues. Forced expression of miR-375 significantly inhibits, while its inhibition promotes, aggressive behaviors of both AR+ and AR- PCa cells in vitro and in vivo. Mechanistically, we show that miR-375 predominantly targets genes possessing oncogenic roles (e.g., proliferation, DNA repair, and metastasis), and thus release targets with tumor suppressive functions. This action model well clarifies why an upregulated miRNA plays a tumor suppressive role in PCa. Together, our study provides new insights into understanding of transcriptomic aberrations during PCa evolution, and nominates miR-375 as a potential therapeutic target for combating aggressive PCa.
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Regulación Neoplásica de la Expresión Génica , Redes Reguladoras de Genes , MicroARNs , Neoplasias de la Próstata , MicroARNs/genética , Humanos , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Masculino , Ratones , Animales , Regulación hacia Arriba/genética , Línea Celular Tumoral , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismo , Genes Supresores de Tumor , Proliferación Celular/genética , ARN Endógeno CompetitivoRESUMEN
Aging exhibits several hallmarks in common with cancer, such as cellular senescence, dysbiosis, inflammation, genomic instability, and epigenetic changes. In recent decades, research into the role of cellular senescence on tumor progression has received widespread attention. While how senescence limits the course of cancer is well established, senescence has also been found to promote certain malignant phenotypes. The tumor-promoting effect of senescence is mainly elicited by a senescence-associated secretory phenotype, which facilitates the interaction of senescent tumor cells with their surroundings. Targeting senescent cells therefore offers a promising technique for cancer therapy. Drugs that pharmacologically restore the normal function of senescent cells or eliminate them would assist in reestablishing homeostasis of cell signaling. Here, we describe cell senescence, its occurrence, phenotype, and impact on tumor biology. A "one-two-punch" therapeutic strategy in which cancer cell senescence is first induced, followed by the use of senotherapeutics for eliminating the senescent cells is introduced. The advances in the application of senotherapeutics for targeting senescent cells to assist cancer treatment are outlined, with an emphasis on drug categories, and the strategies for their screening, design, and efficient targeting. This work will foster a thorough comprehension and encourage additional research within this field.
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Mutations in IDH1 are commonly observed across various cancers, causing the conversion of α-KG to 2-HG. Elevated levels of 2-HG disrupt histone and DNA demethylation processes, promoting tumor development. Consequently, there is substantial interest in developing small molecule inhibitors targeting the mutant enzymes. Herein, we report a structure-based high-throughput virtual screening strategy using a natural products library, followed by hit-to-lead optimization. Through this process, we discover a potent compound, named 11s, which exhibited significant inhibition to IDH1 R132H and IDH1 R132C with IC50 values of 124.4 and 95.7 nM, respectively. Furthermore, 11s effectively reduced 2-HG formation, with EC50 values of 182 nM in U87 R132H cell, and 84 nM in HT-1080 cell. In addition, 11s significantly reduced U87 R132H and HT-1080 cell proliferation with GC50 values of 3.48 and 1.38 µM, respectively. PK-PD experiments further confirmed that compound 11s significantly decreased 2-HG formation in an HT-1080 xenograft mouse model, resulting in notable suppression of tumor growth without apparent loss in body weight.
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Antineoplásicos , Productos Biológicos , Proliferación Celular , Relación Dosis-Respuesta a Droga , Descubrimiento de Drogas , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos , Isocitrato Deshidrogenasa , Humanos , Relación Estructura-Actividad , Isocitrato Deshidrogenasa/antagonistas & inhibidores , Isocitrato Deshidrogenasa/genética , Isocitrato Deshidrogenasa/metabolismo , Productos Biológicos/farmacología , Productos Biológicos/química , Productos Biológicos/síntesis química , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/síntesis química , Animales , Proliferación Celular/efectos de los fármacos , Ratones , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Estructura Molecular , Mutación , Línea Celular Tumoral , Evaluación Preclínica de Medicamentos , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/patología , Neoplasias Experimentales/metabolismoRESUMEN
Introduction: Osteosarcoma, the prevailing primary bone malignancy among children and adolescents, is frequently associated with treatment failure primarily due to its pronounced metastatic nature. Methods: This study aimed to establish potential associations between hub genes and subtypes for the treatment of metastatic osteosarcoma. Differentially expressed genes were extracted from patients diagnosed with metastatic osteosarcoma and a control group of non-metastatic patients, using the publicly available gene expression profile (GSE21257). The intersection of these gene sets was determined by focusing on endoplasmic reticulum (ER) stress-related genes sourced from the GeneCards database. We conducted various analytical techniques, including functional and pathway enrichment analysis, WGCNA analysis, protein-protein interaction (PPI) network construction, and assessment of immune cell infiltration, using the intersecting genes. Through this analysis, we identified potential hub genes. Results: Osteosarcoma subtype models were developed using molecular consensus clustering analysis, followed by an examination of the associations between each subtype and hub genes. A total of 138 potential differentially expressed genes related to endoplasmic reticulum (ER) stress were identified. These genes were further investigated using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA) pathways. Additionally, the PPI interaction network revealed 38 interaction relationships among the top ten hub genes. The findings of the analysis revealed a strong correlation between the extent of immune cell infiltration and both osteosarcoma metastasis and the expression of hub genes. Notably, the differential expression of the top ten hub genes was observed in osteosarcoma clusters 1 and 4, signifying their significant association with the disease. Conclusion: The identification of ten key genes linked to osteosarcoma metastasis and endoplasmic reticulum stress bears potential clinical significance. Additionally, exploring the molecular subtype of osteosarcoma has the capacity to guide clinical treatment decisions, necessitating further investigations and subsequent clinical validations.
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Infections caused by drug-resistant bacteria have become a new challenge in infection treatment, gravely endangering public health. Chloramphenicol (CL) is a well-known antibiotic which has lost its efficacy due to bacterial resistance. To address this issue, herein we report the design, synthesis and biological evaluations of novel triphenylphosphonium chloramphenicol conjugates (TPP+-CL). Study results indicated that compounds 39 and 42 possessed remarkable antibacterial effects against clinically isolated methicillin-resistant Staphylococcus aureus (MRSA) with MIC values ranging from 1 to 2 µg/mL, while CL was inactive to the tested MRSA strains. In addition, these conjugates exhibited rapid bactericidal properties and low toxicity, and did not readily induced bacterial resistance, obviously outperforming the parent drug CL. In a mouse model infected with a clinically isolated MRSA strain, compound 39 at a dose of 20 mg/kg exhibited a comparable or even better in vivo anti-MRSA efficacy than the golden standard drug vancomycin, while no toxicity was observed.
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Staphylococcus aureus Resistente a Meticilina , Infecciones Estafilocócicas , Animales , Ratones , Cloranfenicol/farmacología , Pruebas de Sensibilidad Microbiana , Antibacterianos , Infecciones Estafilocócicas/tratamiento farmacológico , Infecciones Estafilocócicas/microbiologíaRESUMEN
Smart windows with synergetic light modulation have heightened demands for applications in smart cars and novel buildings. However, improving the on-demand energy-saving efficiency is quite challenging due to the difficulty of modulating sunlight with a broad bandwidth in an energy-saving way. Herein, a smart window with switchable near-infrared light transmittance and passive radiative cooling is prepared via a monomer design strategy and photoinduced polymerization. The effects of hydrogen bonds and fluorine groups in acrylate monomers on the electro-optical properties as well as microstructures of polymer-dispersed liquid crystal films have been systematically studied. Some films show a high contrast ratio of 90.4 or a low threshold voltage (Vth) of 2.0 V, which can be roll-to-roll processed in a large area. Besides, the film has a superior indoor temperature regulation ability due to its passive radiative cooling and controllable near-infrared light transmittance properties. Its radiative cooling efficiency is calculated to be 142.69 W/m2 and NIR transmittance could be switched to below 10%. The introduction of a carboxylic monomer and fluorinated monomer into the system endows the film with a highly efficient temperature management capability. The film has great potential for applications in fields such as flexible smart windows, camouflage materials, and so on.
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Piperazine is an important functional unit of many clinically approved drugs, including chemotherapeutic agents. In the current study, methyl piperazine was incorporated and eight salicylaldehyde-derived piperazine-functionalized hydrazone ONN-donor ligands (L) and their Pt(II) complexes (L-PtCl) were prepared. The structures of all these ligands (L1-L8) and Pt(II) complexes (C1-C8) were determined using 1H and 13C NMR, UV-vis, FT-IR and HR-ESI MS analyses, whereas the structures of C1, C5, C6, C7 and C8 were determined in the solid state using single crystal X-ray diffraction analysis. Solution state stabilities of C3, C4, C5 and C6 were determined via time-dependent UV-vis spectroscopy. All these complexes (C1-C8) were studied for their anticancer effect in pancreatic ductal adenocarcinoma cells, including BxPC3, MIAPaCa-2 and PANC1 cells. C1-C8 displayed a potential cytotoxic effect in all these cancer cells, among which C5, C6 and C8 showed the strongest inhibitory effect in comparison with standard chemotherapeutic agents, including 5-fluorouracil (5-FU), cisplatin (CP), oxaliplatin and doxorubicin (DOX). C5, C6 and C8 suppressed the growth of pancreatic cancer cells in a dose-dependent manner. Moreover, C5, C6 and C8 inhibited clonogenic potential and invasion ability and induced apoptosis in PANC1 cells. Importantly, C5, C6 and C8 synergized the anticancer effect with PARP inhibitors, including olaparib, veliparib and niraparib, in pancreatic cancer cells, thus suggesting an important role of C5, C6 and C8 in induction of apoptosis in combination with PARP inhibitors. C5 combined with PARP inhibitors induced caspase3/7 activity and suppressed ATP production. Mechanistically, C5, C6 and C8 inhibited EZH2 protein expression to suppress EZH2-dependent tumorigenesis. Overall, these results highlighted the importance of these piperazine-functionalized Pt(II) complexes as potential anticancer agents to suppress pancreatic ductal adenocarcinoma tumorigenesis by targeting the EZH2-dependent pathway.
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Aldehídos , Antineoplásicos , Apoptosis , Proteína Potenciadora del Homólogo Zeste 2 , Hidrazonas , Neoplasias Pancreáticas , Piperazina , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Apoptosis/efectos de los fármacos , Humanos , Hidrazonas/química , Hidrazonas/farmacología , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/metabolismo , Ligandos , Aldehídos/química , Aldehídos/farmacología , Piperazina/química , Piperazina/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/química , Inhibidores de Poli(ADP-Ribosa) Polimerasas/síntesis química , Proteína Potenciadora del Homólogo Zeste 2/antagonistas & inhibidores , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Línea Celular Tumoral , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/patología , Carcinoma Ductal Pancreático/metabolismo , Proliferación Celular/efectos de los fármacos , Piperazinas/farmacología , Piperazinas/química , Ensayos de Selección de Medicamentos Antitumorales , Sinergismo Farmacológico , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/síntesis química , Compuestos Organoplatinos/farmacología , Compuestos Organoplatinos/química , Compuestos Organoplatinos/síntesis químicaRESUMEN
Sensitive and selective acetone detection is of great significance in the fields of environmental protection, industrial production, and individual health monitoring from exhaled breath. To achieve this goal, bimetallic Au@Pt core-shell nanospheres (BNSs) functionalized-electrospun ZnFe2O4 nanofibers (ZFO NFs) are prepared in this work. Compared to pure NFs-650 analogue, the ZFO NFs/BNSs-2 sensor exhibits a stronger mean response (3.32 vs 1.84), quicker response/recovery speeds (33 s/28 s vs 54 s/42 s), and lower operating temperature (188 vs 273 °C) toward 0.5 ppm acetone. Note that an experimental detection limit of 30 ppb is achieved, which ranks among the best cases reported thus far. Besides the demonstrated excellent repeatability, humidity-enhanced response, and long-term stability, the selectivity toward acetone is remarkably improved after BNSs functionalization. Through material characterizations and DFT calculations, all these improvements could be attributed to the boosted oxygen vacancies and abundant Schottky junctions between ZFO NFs and BNSs, and the synergistic catalytic effect of BNSs. This work offers an alternative strategy to realize selective subppm acetone under high-humidity conditions catering for the future requirements of noninvasive breath diabetes diagnosis in the field of individual healthcare.
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Acetona , Pruebas Respiratorias , Oro , Nanofibras , Nanosferas , Platino (Metal) , Acetona/análisis , Acetona/química , Nanofibras/química , Oro/química , Pruebas Respiratorias/métodos , Nanosferas/química , Platino (Metal)/química , Humanos , Límite de Detección , Oxígeno/química , Técnicas Electroquímicas/métodosRESUMEN
Polymer-stabilized liquid crystal (PSLC) is a promising material toward the practical application of serving as energy-saving reverse-mode smart windows owing to its superior electro-optical (E-O) properties, simple and efficient processability, and compatibility to most practical circumstances. However, its feeble peel strength originated from low polymer content and poor adhesion between polymer networks and substrates inhibited its large-scale flexible film production. It is still a challenging task to derive good mechanical properties and superior E-O performance for PSLCs at the same time. In this study, a highly durable liquid crystal/polymer composite film showing enhanced peel strength and excellent E-O properties was attained by simultaneously building photoreactive self-assemble alignment layers through an efficient one-step method and the sculpture of a patterned polymer wall structure. This film has comprehensive ascendant E-O properties of lower driving voltages, faster response times, and higher contrast ratio, together with an over 30 times lift of the peel strength. The effectuation mechanisms of the alignment, E-O properties, peel-strength, microstructures, and cyclic durability of the films have been systematically studied. This novel liquid crystal/polymer composite film demonstrates advantages in every aspect of performance compared to traditional PSLC devices, which hoards promising applications in smart windows for cars and buildings.
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Angiotensin-converting enzyme 2 (ACE2) is a major cell entry receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The induction of ACE2 expression may serve as a strategy by SARS-CoV-2 to facilitate its propagation. However, the regulatory mechanisms of ACE2 expression after viral infection remain largely unknown. Using 45 different luciferase reporters, the transcription factors SP1 and HNF4α were found to positively and negatively regulate ACE2 expression, respectively, at the transcriptional level in human lung epithelial cells (HPAEpiCs). SARS-CoV-2 infection increased the transcriptional activity of SP1 while inhibiting that of HNF4α. The PI3K/AKT signaling pathway, activated by SARS-CoV-2 infection, served as a crucial regulatory node, inducing ACE2 expression by enhancing SP1 phosphorylation-a marker of its activity-and reducing the nuclear localization of HNF4α. However, colchicine treatment inhibited the PI3K/AKT signaling pathway, thereby suppressing ACE2 expression. In Syrian hamsters (Mesocricetus auratus) infected with SARS-CoV-2, inhibition of SP1 by either mithramycin A or colchicine resulted in reduced viral replication and tissue injury. In summary, our study uncovers a novel function of SP1 in the regulation of ACE2 expression and identifies SP1 as a potential target to reduce SARS-CoV-2 infection.
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Enzima Convertidora de Angiotensina 2 , COVID-19 , SARS-CoV-2 , Factor de Transcripción Sp1 , Humanos , Enzima Convertidora de Angiotensina 2/genética , Colchicina , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , SARS-CoV-2/metabolismo , Factor de Transcripción Sp1/metabolismoRESUMEN
Histopathological heterogeneity is a hallmark of prostate cancer (PCa). Using spatial and parallel single-nucleus transcriptomics, we report an androgen receptor (AR)-positive but neuroendocrine-null primary PCa subtype with morphologic and molecular characteristics of small cell carcinoma. Such small cell-like PCa (SCLPC) is clinically aggressive with low AR, but high stemness and proliferation, activity. Molecular characterization prioritizes protein translation, represented by up-regulation of many ribosomal protein genes, and SP1, a transcriptional factor that drives SCLPC phenotype and overexpresses in castration-resistant PCa (CRPC), as two potential therapeutic targets in AR-indifferent CRPC. An SP1-specific inhibitor, plicamycin, effectively suppresses CRPC growth in vivo. Homoharringtonine, a Food And Drug Administration-approved translation elongation inhibitor, impedes CRPC progression in preclinical models and patients with CRPC. We construct an SCLPC-specific signature capable of stratifying patients for drug selectivity. Our studies reveal the existence of SCLPC in admixed PCa pathology, which may mediate tumor relapse, and establish SP1 and translation elongation as actionable therapeutic targets for CRPC.
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Neoplasias de la Próstata Resistentes a la Castración , Masculino , Humanos , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismo , Recurrencia Local de Neoplasia , Factores de Transcripción/metabolismo , Biosíntesis de Proteínas , Línea Celular Tumoral , Regulación Neoplásica de la Expresión GénicaRESUMEN
The high prevalence of methicillin-resistant Staphylococcus aureus (MRSA) strains and the formation of non-growing, dormant "persisters" subsets help bacteria evade antibiotic treatment and enhance bacterial resistance, which poses a serious threat to human life and health. It is urgent to discover novel antibacterial therapies effective against MRSA persisters. Thymol is a common nutraceutical with weak antibacterial and antitumor activities. A series of Thymol triphenylphosphine (TPP) conjugates (TPP-Thy3) was designed and synthesized. These compounds showed significantly improved inhibitory activity against Gram-positive bacteria compared with Thymol. Among them, Thy3d displayed a low probability of resistance selection and showed excellent biocompatibility. Interestingly, Thy3d elicited a rapid killing effect of MRSA persisters (99.999%) at high concentration. Fluorescence experiments, electron microscopy, molecular dynamics simulation and bilayer experiment confirmed that Thy3d conjugates exerted potent antimicrobial activity by disrupting the integrity of the membrane of bacterial even the persister. Furthermore, Thy3d exhibited considerable efficacy in a mouse model of subcutaneous murine MRSA infection. In summary, TPP-Thy3 conjugates are a series of novel antibacterial agents and could serve as a new therapeutic strategy for combating antibiotic resistance.