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Background: The gut microbiota significantly influences the onset and progression of juvenile idiopathic arthritis (JIA) and associated uveitis (JIAU); however, the causality remains unclear. This study aims to establish a causal link between gut microbiota and JIA or JIAU. Methods: Using publicly available genome-wide association studies (GAWS) summary data, we conducted a two-sample Mendelian randomisation (MR) analysis employing various methods, namely inverse variance weighted (IVW), simple mode, weighted mode, weighted median and MR-Egger regression methods, to assess the causal association between JIA or JIAU and gut microbiota. Sensitivity analyses, including Cochrane's Q test, MR-Egger intercept test, leave-one-out analysis and MR-PRESSO, were performed to evaluate the robustness of the MR results. Subsequently, reverse MR analysis was conducted to determine causality between gene-predicted gut microbiota abundance and JIA or JIAU. Results: The MR analysis revealed a causal association between gut microbiota abundance variations and JIA or JIAU risk. Specifically, the increased abundance of genus Ruminococcaceae UCG013 (OR: 0.055, 95%CI: 0.006-0.103, p = 0.026) and genus Ruminococcaceae UCG003 (ß: 0.06, 95%CI: 0.003-0.117, p = 0.041) correlated with an increased risk of JIA, while genus Lachnospiraceae UCG001 (OR: 0.833, 95%CI: 0.699~0.993, p = 0.042) was associated with a reduced risk of JIA, among others. Sensitivity analysis confirmed MR analysis robustness. Conclusions: This study provides substantial evidence supporting a causal association between genetically predicted gut microbiota and JIA or JIAU. It highlights the significant role of intestinal flora in JIA or JIAU development, suggesting their potential as novel biomarkers for diagnosis and prevention. These findings offer valuable insights to mitigate the impact of JIA or JIAU.
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Artritis Juvenil , Microbioma Gastrointestinal , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Uveítis , Humanos , Microbioma Gastrointestinal/genética , Artritis Juvenil/microbiología , Artritis Juvenil/genética , Uveítis/microbiología , Uveítis/etiología , Uveítis/genética , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido SimpleRESUMEN
Although it is well documented that mountains tend to exhibit high biodiversity, how geological processes affect the assemblage of montane floras is a matter of ongoing research. Here, we explore landform-specific differences among montane floras based on a dataset comprising 17,576 angiosperm species representing 140 Chinese mountain floras, which we define as the collection of all angiosperm species growing on a specific mountain. Our results show that igneous bedrock (granitic and karst-granitic landforms) is correlated with higher species richness and phylogenetic overdispersion, while the opposite is true for sedimentary bedrock (karst, Danxia, and desert landforms), which is correlated with phylogenetic clustering. Furthermore, we show that landform type was the primary determinant of the assembly of evolutionarily older species within floras, while climate was a greater determinant for younger species. Our study indicates that landform type not only affects montane species richness, but also contributes to the composition of montane floras. To explain the assembly and differentiation of mountain floras, we propose the 'floristic geo-lithology hypothesis', which highlights the role of bedrock and landform processes in montane floristic assembly and provides insights for future research on speciation, migration, and biodiversity in montane regions.
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Biodiversidad , Magnoliopsida , Filogenia , China , Magnoliopsida/crecimiento & desarrollo , Altitud , Fenómenos Geológicos , EcosistemaRESUMEN
BACKGROUND: Early diagnosis of hepatocellular carcinoma (HCC) can significantly improve patient survival. We aimed to develop a blood-based assay to aid in the diagnosis, detection and prognostic evaluation of HCC. METHODS: A three-phase multicentre study was conducted to screen, optimise and validate HCC-specific differentially methylated regions (DMRs) using next-generation sequencing and quantitative methylation-specific PCR (qMSP). RESULTS: Genome-wide methylation profiling was conducted to identify DMRs distinguishing HCC tumours from peritumoural tissues and healthy plasmas. The twenty most effective DMRs were verified and incorporated into a multilocus qMSP assay (HepaAiQ). The HepaAiQ model was trained to separate 293 HCC patients (Barcelona Clinic Liver Cancer (BCLC) stage 0/A, 224) from 266 controls including chronic hepatitis B (CHB) or liver cirrhosis (LC) (CHB/LC, 96), benign hepatic lesions (BHL, 23), and healthy controls (HC, 147). The model achieved an area under the curve (AUC) of 0.944 with a sensitivity of 86.0% in HCC and a specificity of 92.1% in controls. Blind validation of the HepaAiQ model in a cohort of 523 participants resulted in an AUC of 0.940 with a sensitivity of 84.4% in 205 HCC cases (BCLC stage 0/A, 167) and a specificity of 90.3% in 318 controls (CHB/LC, 100; BHL, 102; HC, 116). When evaluated in an independent test set, the HepaAiQ model exhibited a sensitivity of 70.8% in 65 HCC patients at BCLC stage 0/A and a specificity of 89.5% in 124 patients with CHB/LC. Moreover, HepaAiQ model was assessed in paired pre- and postoperative plasma samples from 103 HCC patients and correlated with 2-year patient outcomes. Patients with high postoperative HepaAiQ score showed a higher recurrence risk (Hazard ratio, 3.33, p < .001). CONCLUSIONS: HepaAiQ, a noninvasive qMSP assay, was developed to accurately measure HCC-specific DMRs and shows great potential for the diagnosis, detection and prognosis of HCC, benefiting at-risk populations.
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Carcinoma Hepatocelular , Metilación de ADN , Detección Precoz del Cáncer , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/sangre , Carcinoma Hepatocelular/diagnóstico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/sangre , Neoplasias Hepáticas/diagnóstico , Femenino , Masculino , Metilación de ADN/genética , Persona de Mediana Edad , Pronóstico , Detección Precoz del Cáncer/métodos , ADN Tumoral Circulante/sangre , ADN Tumoral Circulante/genética , Estudios de Cohortes , Biomarcadores de Tumor/sangre , Biomarcadores de Tumor/genética , Anciano , AdultoRESUMEN
Super-resolution molecular probes (SRMPs) are essential tools for visualizing drug dynamics within cells, transcending the resolution limits of conventional microscopy. In this review, we provide an overview of the principles and design strategies of SRMPs, emphasizing their role in accurately tracking drug molecules. By illuminating the intricate processes of drug distribution, diffusion, uptake, and metabolism at a subcellular and molecular level, SRMPs offer crucial insights into therapeutic interventions. Additionally, we explore the practical applications of super-resolution imaging in disease treatment, highlighting the significance of SRMPs in advancing our understanding of drug action. Finally, we discuss future perspectives, envisioning potential advancements and innovations in this field. Overall, this review serves to inform and practitioners about the utility of SRMPs in driving innovation and progress in pharmacology, providing valuable insights for drug development and optimization.
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Sondas Moleculares , Sondas Moleculares/química , Humanos , Preparaciones Farmacéuticas/metabolismo , Preparaciones Farmacéuticas/química , Preparaciones Farmacéuticas/administración & dosificación , Animales , Imagen Molecular/métodosRESUMEN
This study involved direct doping of In2O3 into silicon carbide (SiC) powder, resulting in 8.0 at% In-doped SiC powder. Subsequently, heating at 500 °C was performed to form a target, followed by the utilization of electron beam (e-beam) technology to deposit the In-doped SiC thin films with the thickness of approximately 189.8 nm. The first breakthrough of this research was the successful deposition of using e-beam technology. The second breakthrough involved utilizing various tools to analyze the physical and electrical properties of In-doped SiC thin films. Hall effect measurement was used to measure the resistivity, mobility, and carrier concentration and confirm its n-type semiconductor nature. The uniform dispersion of In ions in SiC was as confirmed by electron microscopy energy-dispersive spectroscopy and secondary ion mass spectrometry analyses. The Tauc Plot method was employed to determine the Eg values of pure SiC and In-doped SiC thin films. Semiconductor parameter analyzer was used to measure the conductivity and the I-V characteristics of devices in In-doped SiC thin films. Furthermore, the third finding demonstrated that In2O3-doped SiC thin films exhibited remarkable current density. X-ray photoelectron spectroscopy and Gaussian-resolved spectra further confirmed a significant relationship between conductivity and oxygen vacancy concentration. Lastly, depositing these In-doped SiC thin films onto p-type silicon substrates etched with buffered oxide etchant resulted in the formation of heterojunction p-n junction. This junction exhibited the rectifying characteristics of a diode, with sample current values in the vicinity of 102 mA, breakdown voltage at approximately -5.23 V, and open-circuit voltage around 1.56 V. This underscores the potential of In-doped SiC thin films for various semiconductor devices.
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Eutectic electrolytes show potential beyond conventional low-concentration electrolytes (LCEs) in zinc (Zn)-ion capacitors (ZICs) yet suffer from high viscosity and sluggish kinetics. Herein, we originally propose a universal theory of intrinsically decoupling to address these issues, producing a novel electrolyte termed "quasi-eutectic" electrolyte (quasi-EE). Joint experimental and theoretical analyses confirm its unique solution coordination structure doped with near-LCE domains. This enables the quasi-EE well inherit the advanced properties at deep-eutectic states while provide facilitated kinetics as well as lower energy barriers via a vehicle/hopping-hybridized charge transfer mechanism. Consequently, a homogeneous electroplating pattern with much enhanced Sand's time is achieved on the Zn surface, followed by a twofold prolonged service-life with drastically reduced concentration polarization. More encouragingly, the quasi-EE also delivers increased capacitance output in ZICs, which is elevated by 12.4 %-144.6 % compared to that before decoupling. Furthermore, the pouch cell with a cathodic mass loading of 36.6â mg cm-2 maintains competitive cycling performances over 600â cycles, far exceeding other Zn-based counterparts. This work offers fresh insights into eutectic decoupling and beyond.
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Luminescent chiral Tb-MOF microcrystals with the Tb2(COO)4 subunit indicated strong green mechano-luminescence under compression. Furthermore, piezofluorochromic behavior in the diamond anvil cell was observed, with the intensity tendency of decreasing-increasing-decreasing and a shortened lifetime upon compression, due to the reversible stretchable Tb-Tb interactions. The Tb-Tb distance upon compression was refined through in situ high-pressure X-ray absorption spectra, which was consistent with the tendency of the piezofluorochromic intensity. In situ high-pressure UV-vis absorption spectra, Fourier transform infrared spectra, and powder X-ray diffraction demonstrated the full recovery of Tb-MOF after over 10 GPa compressions due to the semiflexible ligand. This work not only provided an ultrastable Tb-MOF but also illustrated the relationship of the piezofluorochromic behavior with the detailed structural transformation for the first time.
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A pair of atropisomers secofumitremorgins C (1a) and D (1b), together with fifteen known alkaloids (2-16), were isolated from a saltern-derived fungus Aspergillus fumigatus GXIMD00544. The structures of atropisomers 1a and 1b were elucidated by the detailed spectroscopic data, chemical reaction and quantum chemical calculations. Compounds 1 and 8 displayed antifungal spore germination effects against plant pathogenic fungus associated with sugarcane Fusarium sp. with inhibitory rates of 53% and 77% at the concentration of 100 µM, repectively. Atropisomers 1 also exhibited antifouling potential against Balanus amphitrite larval settlement with an inhibitory rate of 96% at the concentration of 100 µM.
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Antifúngicos , Aspergillus fumigatus , Aspergillus fumigatus/efectos de los fármacos , Estructura Molecular , Animales , Antifúngicos/farmacología , Antifúngicos/química , Fusarium/química , Alcaloides/química , Alcaloides/farmacología , Alcaloides/aislamiento & purificación , Pruebas de Sensibilidad Microbiana , Thoracica/efectos de los fármacos , Larva , EstereoisomerismoRESUMEN
Mitochondria, recognized as the cellular powerhouses, are indispensable organelles responsible for crucial cellular processes, such as energy metabolism, material synthesis, and signaling transduction. Their intricate involvement in a broad spectrum of diseases, particularly cancer, has propelled the exploration of mitochondria-targeting treatment as a promising strategy for cancer therapy. Since the groundbreaking discovery of cisplatin, the trajectory of research on the development of metal complexes have been marked by continuous advancement, giving rise to a diverse array of metallodrugs characterized by variations in ligand types, metal center properties, and oxidation states. By specifically targeting mitochondria, these metallodrugs exhibit the remarkable ability to elicit various programmed cell death pathways, encompassing apoptosis, autophagy, and ferroptosis. This review primarily focuses on recent developments in transition metal-based mitochondria-targeting agents, offering a comprehensive exploration of their capacity to induce distinct cell death modes. The aim is not only to disseminate knowledge but also to stimulate an active field of research toward new clinical applications and novel anticancer mechanisms.
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Antineoplásicos , Complejos de Coordinación , Mitocondrias , Neoplasias , Humanos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Complejos de Coordinación/química , Complejos de Coordinación/farmacología , Complejos de Coordinación/síntesis química , Muerte Celular/efectos de los fármacos , Estructura Molecular , Animales , Apoptosis/efectos de los fármacosRESUMEN
The clinical application of the recombinant human granulocyte colony-stimulating factor (rhG-CSF) is restricted by its short serum half-life. Herein, site-selective modification of the N-terminus of rhG-CSF with PAL-PEG3-Ph-CHO was used to develop a long-acting rhG-CSF. The optimized conditions for rhG-CSF modification with PAL-PEG3-Ph-CHO were: reaction solvent system of 3% (w/v) Tween 20 and 30 mM NaCNBH3 in acetate buffer (20 mmol/L, pH 5.0), molar ratio of PAL-PEG3-Ph-CHO to rhG-CSF of 6:1, temperature of 20°C, and reaction time of 12 h, consequently, achieving a PAL-PEG3-Ph-rhG-CSF product yield of 70.8%. The reaction mixture was purified via preparative liquid chromatography, yielding the single-modified product PAL-PEG3-Ph-rhG-CSF with a HPLC purity exceeding 95%. The molecular weight of PAL-PEG3-Ph-rhG-CSF was 19297 Da by MALDI-TOF-MS, which was consistent with the theoretical value. The circular dichroism analysis revealed no significant change in its secondary structure compared to unmodified rhG-CSF. The PAL-PEG3-Ph-rhG-CSF retained 82.0% of the in vitro biological activity of unmodified rhG-CSF. The pharmacokinetic analyses showed that the serum half-life of PAL-PEG3-Ph-rhG-CSF was 7.404 ± 0.777 h in mice, 4.08 times longer than unmodified rhG-CSF. Additionally, a single subcutaneous dose of PAL-PEG3-Ph-rhG-CSF presented comparable in vivo efficacy to multiple doses of rhG-CSF. This study demonstrated an efficacious strategy for developing long-acting rhG-CSF drug candidates.
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Anti-PD-L1 immunotherapy, a new lung cancer treatment, is limited to a few patients due to low PD-L1 expression and tumor immunosuppression. To address these challenges, the upregulation of PD-L1 has the potential to elevate the response rate and efficiency of anti-PD-L1 and alleviate the immunosuppression of the tumor microenvironment. Herein, we developed a novel usnic acid-derived Iridium(III) complex, Ir-UA, that boosts PD-L1 expression and converts "cold tumors" to "hot". Subsequently, we administered Ir-UA combined with anti-PD-L1 in mice, which effectively inhibited tumor growth and promoted CD4+ and CD8+ T cell infiltration. To our knowledge, Ir-UA is the first iridium-based complex to stimulate the expression of PD-L1 by explicitly regulating its transcription factors, which not only provides a promising platform for immune checkpoint blockade but, more importantly, provides an effective treatment strategy for patients with low PD-L1 expression.
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Antígeno B7-H1 , Inmunoterapia , Iridio , Animales , Iridio/química , Iridio/farmacología , Antígeno B7-H1/metabolismo , Ratones , Humanos , Inmunoterapia/métodos , Factor de Transcripción Activador 3/metabolismo , Línea Celular Tumoral , Ratones Endogámicos C57BL , Microambiente Tumoral/efectos de los fármacos , Femenino , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Antineoplásicos/síntesis químicaRESUMEN
Dysregulation of IL17A drives numerous inflammatory and autoimmune disorders with inhibition of IL17A using antibodies proven as an effective treatment. Oral anti-IL17 therapies are an attractive alternative option, and several preclinical small molecule IL17 inhibitors have previously been described. Herein, we report the discovery of a novel class of small molecule IL17A inhibitors, identified via a DNA-encoded chemical library screen, and their subsequent optimization to provide in vivo efficacious inhibitors. These new protein-protein interaction (PPI) inhibitors bind in a previously undescribed mode in the IL17A protein with two copies binding symmetrically to the central cavities of the IL17A homodimer.
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ADN , Descubrimiento de Drogas , Interleucina-17 , Bibliotecas de Moléculas Pequeñas , Interleucina-17/metabolismo , Interleucina-17/antagonistas & inhibidores , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , ADN/metabolismo , ADN/química , Humanos , Animales , Relación Estructura-Actividad , Unión Proteica , RatonesRESUMEN
Triple-negative breast cancer (TNBC) is the most aggressive type of breast cancer, which owned severe resistance to platinum-based anticancer agents. Herein, we report a new metal-arene complex, Ru-TPE-PPh3, which can be synthesized in vitro and in living cells with copper catalyzed the cycloaddition reaction of Ru-azide and alkynyl (CuAAC). The complex Ru-TPE-PPh3 exhibited superior inhibition of the proliferation of TNBC MDA-MB-231 cells with an IC50 value of 4.0 µM. Ru-TPE-PPh3 could induce the over production of reactive oxygen species (ROS) to initiate the oxidative stress, and further damage the mitochondria both functionally and morphologically, as loss of mitochondrial membrane potential (MMP) and cutting the supply of adenosine triphosphate (ATP), the disappearance of cristae structure. Moreover, the damaged mitochondria evoked the occurrence of mitophagy with the autophagic flux blockage and cell death. The complex Ru-TPE-PPh3 also demonstrated excellent anti-proliferative activity in 3D MDA-MB-231 multicellular tumor spheroids (MCTSs), indicating the potential to inhibit solid tumors in living cells. This study not only provided a potent agent for the TNBC treatment, but also demonstrated the universality of the bioorthogonally catalyzed lethality (BCL) strategy through CuAAC reation.
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Antineoplásicos , Autofagia , Complejos de Coordinación , Mitocondrias , Especies Reactivas de Oxígeno , Rutenio , Neoplasias de la Mama Triple Negativas , Humanos , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/patología , Neoplasias de la Mama Triple Negativas/metabolismo , Autofagia/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/síntesis química , Rutenio/química , Rutenio/farmacología , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Especies Reactivas de Oxígeno/metabolismo , Proliferación Celular/efectos de los fármacos , Femenino , Potencial de la Membrana Mitocondrial/efectos de los fármacosRESUMEN
Dual suppression of oxidative phosphorylation (OXPHOS) and glycolysis can disrupt metabolic adaption of cancer cells, inhibiting energy supply and leading to successful cancer therapy. Herein, we have developed an α-tocopheryl succinate (α-TOS)-functionalized iridium(III) complex Ir2, a highly lipophilic mitochondria targeting anticancer molecule, could inhibit both oxidative phosphorylation (OXPHOS) and glycolysis, resulting in the energy blockage and cancer growth suppression. Mechanistic studies reveal that complex Ir2 induces reactive oxygen species (ROS) elevation and mitochondrial depolarization, and triggers DNA oxidative damage. These damages could evoke the cancer cell death with the mitochondrial-relevant apoptosis and autophagy. 3D tumor spheroids experiment demonstrates that Ir2 owned superior antiproliferation performance, as the potent anticancer agent in vivo. This study not only provided a new path for dual inhibition of both mitochondrial OXPHOS and glycolytic metabolisms with a novel α-TOS-functionalized metallodrug, but also further demonstrated that the mitochondrial-relevant therapy could be effective in enhancing the anticancer performance.
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Antineoplásicos , Proliferación Celular , Ensayos de Selección de Medicamentos Antitumorales , Glucólisis , Fosforilación Oxidativa , Humanos , Fosforilación Oxidativa/efectos de los fármacos , Glucólisis/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Proliferación Celular/efectos de los fármacos , Estructura Molecular , Animales , Iridio/química , Iridio/farmacología , Relación Estructura-Actividad , Especies Reactivas de Oxígeno/metabolismo , Relación Dosis-Respuesta a Droga , Apoptosis/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Ratones , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/síntesis química , Ratones Endogámicos BALB C , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Neoplasias/patologíaRESUMEN
In this study, two new kaurane diterpenes (16, 17), together with 12 lignans (1-12), a triterpene (15), and two other compounds (13, 14) were isolated from the woods of Agathis dammara. The structure of the new compound was determined by HR ESIMS and 1D/2D NMR spectroscopy, and its absolute configuration was determined by electronic circular dichroism (ECD) exciton chirality method. Compounds 5, 11, 14 exhibit significant hypoglycaemic activity in zebrafish, and their mechanism of action is to enhance glucose uptake in zebrafish.
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It remains a significant hurdle for discovering birefringent materials in the deep ultraviolet (DUV, λ < 200 nm). It is well-known that the OH anions are recognized for their capability to eliminate the dangling bonds from terminal oxygen atoms, promoting the ultraviolet (UV) cutoff edge blueshift and regulating the crystal structure. Here, two new barium hydroxyborates, Ba3B11O18(OH)3(H2O) (BaBOH) and Na2BaB10O16(OH)2(H2O)2 (NaBaBOH), were designed and synthesized while displaying different dimensions. Remarkably, BaBOH presents novel one-dimensional (1D) [B22O37(OH)6]∞ double-chains formed by a new fundamental building block (FBB)[B11O21(OH)3]. NaBaBOH possesses a 2D [B10O16(OH)2]∞ layer with a less common FBB [B10O19(OH)2]. They enrich the structural diversity of hydroxyborates. Moreover, NaBaBOH exhibits a broad transparent window within the DUV spectral range (<190 nm) and possesses a favorable birefringence of 0.064. Furthermore, detailed summaries and structural comparisons have been implemented for all hydroxyborates containing alkali and alkaline-earth metals. This reveals that the OH group modulation strategy can be appropriately employed for the structural design.
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Cancer treatment has faced severe obstacles due to the smart biological system of cancer cells. Herein, we report a three-in-one agent Ir-CA via attenuation of cancer cell stemness with the down-regulated biomarker CD133 expression from the mitochondria-directed chemotherapy. Over 80% of Ir-CA could accumulate in mitochondria, result in severe mitochondrial dysfunctions, and subsequently initiate mitophagy and cell cycle arrest to kill cisplatin-resistant A549R cells. In vitro and in vivo antimetastatic experiments demonstrated that Ir-CA can effectively inhibit metastasis with down-regulated MMP-2/MMP-9. RNA seq analysis and Western blotting indicated that Ir-CA also suppresses the GSTP1 expression to decrease the intracellular Pt-GS adducts, resulting in the detoxification and resensitization to cisplatin of A549R cells. In vivo evaluation indicated that Ir-CA restrains the tumor growth and has minimal side effects and superior biocompatibility. This work not only provides the first three-in-one agent to attenuate cancer cell stemness and simultaneously realize anticancer, antimetastasis, and conquer metallodrug resistance but also demonstrates the effectiveness of the mitochondria-directed strategy in cancer treatment.
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Antineoplásicos , Neoplasias , Cisplatino/farmacología , Línea Celular Tumoral , Ciclo Celular , Mitocondrias , Apoptosis , Antineoplásicos/farmacología , Antineoplásicos/metabolismo , Neoplasias/metabolismoRESUMEN
Nasopharyngeal carcinoma (NPC) is characterised by its remarkable geographical and ethnic distribution. The interplay between genetic susceptibility, environmental exposures, and Epstein-Barr virus (EBV) infections is indicated in the development of NPC. Exposure to tobacco smoking, dietary factors, and inhalants has been associated with the risk of NPC. Genetic association studies have revealed NPC-associated susceptibility loci, including genes involved in immune responses, xenobiotic metabolism, genome maintenance, and cell cycle regulation. EBV exposure timing and strain variation might play a role in its carcinogenicity, although further investigations are required. Other factors including medical history and oral hygiene have been implicated in NPC. Prevention strategies, including primary prevention and secondary prevention through early detection, are vital in reducing mortality and morbidity of NPC. The current review discusses the global and regional distribution of NPC incidences, the risk factors associated with NPC, and the public health implications of these insights. Future investigations should consider international, large-scale prospective studies to elucidate the mechanisms underlying NPC pathogenesis and develop individualized interventions for NPC.
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Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Humanos , Carcinoma Nasofaríngeo/epidemiología , Carcinoma Nasofaríngeo/etiología , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/epidemiología , Neoplasias Nasofaríngeas/etiología , Neoplasias Nasofaríngeas/genética , Factores de Riesgo , Infecciones por Virus de Epstein-Barr/complicaciones , Infecciones por Virus de Epstein-Barr/epidemiología , Incidencia , Herpesvirus Humano 4RESUMEN
The efficiency of nitrogen mustards (NMs), among the first chemotherapeutic agents against cancer, is limited by their monotonous mechanism of action (MoA). And tumor hypoxia is a significant obstacle in the attenuation of the chemotherapeutic efficacy. To repurpose the drug and combat hypoxia, herein, we constructed an organo-Ir(III) prodrug, IrCpNM, with the composition of a reactive oxygen species (ROS)-inducing moiety (Ir-arene fragment)-a hypoxic responsive moiety (azo linker)-a DNA-alkylating moiety (nitrogen mustard), and realized DNA damage response (DDR)-mediated autophagy for hypoxic lung cancer therapy for the first time. Prodrug IrCpNM could upregulate the level of catalase (CAT) to catalyze the decomposition of excessive H2O2 to O2 and downregulate the expression of the hypoxia-inducible factor (HIF-1α) to relieve hypoxia. Subsequently, IrCpNM initiates the quadruple synergetic actions under hypoxia, as simultaneous ROS promotion and glutathione (GSH) depletion to enhance the redox disbalance and severe oxidative and cross-linking DNA damages to trigger the occurrence of DDR-mediated autophagy via the ATM/Chk2 cascade and the PIK3CA/PI3K-AKT1-mTOR-RPS6KB1 signaling pathway. In vitro and in vivo experiments have confirmed the greatly antiproliferative capacity of IrCpNM against the hypoxic solid tumor. This work demonstrated the effectiveness of the DNA damage-responsive organometallic prodrug strategy with the microenvironment targeting system and the rebirth of traditional chemotherapeutic agents with a new anticancer mechanism.
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Neoplasias Pulmonares , Profármacos , Humanos , Especies Reactivas de Oxígeno/metabolismo , Profármacos/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Peróxido de Hidrógeno , Hipoxia , Autofagia , Daño del ADN , ADN , Línea Celular Tumoral , Microambiente TumoralRESUMEN
Six benzophenone derivatives, carneusones A-F (1-6), along with seven known compounds (7-13) were isolated from a strain of sponge-derived marine fungus Aspergillus carneus GXIMD00543. Their chemical structures were elucidated by detailed spectroscopic data and quantum chemical calculations. Compounds 5, 6, and 8 exhibited moderate anti-inflammatory activity on NO secretion using lipopolysaccharide (LPS)-induced RAW 264.7 cells with EC50 values of 34.6 ± 0.9, 20.2 ± 1.8, and 26.8 ± 1.7 µM, while 11 showed potent effect with an EC50 value of 2.9 ± 0.1 µM.