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A pharmacologic approach to male contraception remains a longstanding challenge in medicine. Toward this objective, we explored the spermatogenic effects of a selective small-molecule inhibitor (JQ1) of the bromodomain and extraterminal (BET) subfamily of epigenetic reader proteins. Here, we report potent inhibition of the testis-specific member BRDT, which is essential for chromatin remodeling during spermatogenesis. Biochemical and crystallographic studies confirm that occupancy of the BRDT acetyl-lysine binding pocket by JQ1 prevents recognition of acetylated histone H4. Treatment of mice with JQ1 reduced seminiferous tubule area, testis size, and spermatozoa number and motility without affecting hormone levels. Although JQ1-treated males mate normally, inhibitory effects of JQ1 evident at the spermatocyte and round spermatid stages cause a complete and reversible contraceptive effect. These data establish a new contraceptive that can cross the blood:testis boundary and inhibit bromodomain activity during spermatogenesis, providing a lead compound targeting the male germ cell for contraception.
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Azepinas/farmacologia , Anticoncepcionais Masculinos/farmacologia , Proteínas Nucleares/antagonistas & inibidores , Triazóis/farmacologia , Animais , Azepinas/química , Barreira Hematotesticular , Anticoncepcionais Masculinos/química , Feminino , Humanos , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Modelos Moleculares , Proteínas Nucleares/química , Estrutura Terciária de Proteína , Contagem de Espermatozoides , Motilidade dos Espermatozoides/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos , Testículo/citologia , Testículo/efeitos dos fármacos , Triazóis/químicaRESUMO
Correction for 'Reactive oxygen nanobiocatalysts: activity-mechanism disclosures, catalytic center evolutions, and changing states' by Sujiao Cao et al., Chem. Soc. Rev., 2023, https://doi.org/10.1039/d3cs00087g.
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Benefiting from low costs, structural diversities, tunable catalytic activities, feasible modifications, and high stability compared to the natural enzymes, reactive oxygen nanobiocatalysts (RONBCs) have become dominant materials in catalyzing and mediating reactive oxygen species (ROS) for diverse biomedical and biological applications. Decoding the catalytic mechanism and structure-reactivity relationship of RONBCs is critical to guide their future developments. Here, this timely review comprehensively summarizes the recent breakthroughs and future trends in creating and decoding RONBCs. First, the fundamental classification, activity, detection method, and reaction mechanism for biocatalytic ROS generation and elimination have been systematically disclosed. Then, the merits, modulation strategies, structure evolutions, and state-of-art characterisation techniques for designing RONBCs have been briefly outlined. Thereafter, we thoroughly discuss different RONBCs based on the reported major material species, including metal compounds, carbon nanostructures, and organic networks. In particular, we offer particular insights into the coordination microenvironments, bond interactions, reaction pathways, and performance comparisons to disclose the structure-reactivity relationships and mechanisms. In the end, the future challenge and perspectives for RONBCs are also carefully summarised. We envision that this review will provide a comprehensive understanding and guidance for designing ROS-catalytic materials and stimulate the wide utilisation of RONBCs in diverse biomedical and biological applications.
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OBJECTIVE: Many cancers engage embryonic genes for rapid growth and evading the immune system. SOX9 has been upregulated in many tumours, yet the role of SOX9 in mediating immunosuppressive tumour microenvironment is unclear. Here, we aim to dissect the role of SOX9-mediated cancer stemness attributes and immunosuppressive microenvironment in advanced gastric adenocarcinoma (GAC) for novel therapeutic discoveries. METHODS: Bulk RNAseq/scRNA-seq, patient-derived cells/models and extensive functional studies were used to identify the expression and functions of SOX9 and its target genes in vitro and in vivo. Immune responses were studied in PBMCs or CD45+ immune cells cocultured with tumour cells with SOX9high or knockout and the KP-Luc2 syngeneic models were used for efficacy of combinations. RESULTS: SOX9 is one of the most upregulated SOX genes in GAC and highly expressed in primary and metastatic tissues and associated with poor prognosis. Depletion of SOX9 in patient-derived GAC cells significantly decreased cancer stemness attributes, tumour formation and metastases and consistently increased CD8+ T cell responses when cocultured with PBMCs/CD45+ cells from GAC patients. RNA sequencing identified the leukaemia inhibitory factor (LIF) as the top secreted molecule regulated by SOX9 in tumour cells and was enriched in malignant ascites and mediated SOX9-induced M2 macrophage repolarisation and inhibited T cell function. CONCLUSION: Epithelial SOX9 is critical in suppressing CD8+ T cell responses and modified macrophage function in GAC through the paracrine LIF factor. Cotargeting LIF/LIFR and CSF1R has great potential in targeting SOX9-mediated cancer stemness, T cell immunosuppression and metastases suggesting the novel combination therapy against advanced GAC.
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Adenocarcinoma , Neoplasias Gástricas , Humanos , Microambiente Tumoral , Adenocarcinoma/genética , Adenocarcinoma/patologia , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Imunossupressores , Terapia de Imunossupressão , Fatores de Transcrição SOX9/genéticaRESUMO
Non-invasive cancer treatment strategies that enable local non-thermal ablation, hypoxia relief, and reactive oxygen species (ROS) production to achieve transiently destroying tumor tissue and long-term killing tumor cells would greatly facilitate their clinical applications. However, continuously generating oxygen cavitation nuclei, reducing the transient cavitation sound intensity threshold, relieving hypoxia, and improving its controllability in the ablation area still remains a significant challenge. Here, in this work, an Mn-coordinated polyphthalocyanine sonocavitation agent (Mn-SCA) with large d-π-conjugated network and atomic Mn-N sites is identified for the non-thermal sonocavitation and sonodynamic therapy in the liver cancer ablation. In the tumor microenvironment, the catalytical generation of oxygen assists cavitation formation and generates microjets to ablate liver cancer tissue and relieve hypoxia, this work reports for the first time to utilize the enzymatic properties of Mn-SCA to lower the cavitation threshold in situ. Moreover, under pHIFU irradiation, high reactive oxygen species (ROS) production can be achieved. The two merits in liver cancer ablation are demonstrated by cell destruction and high tumor inhibition efficiency. This work will help deepen the understanding of cavitation ablation and the sonodynamic mechanisms related to the nanostructures and guide the design of sonocavitation agents with high ROS production for solid tumor ablation.
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Ablação por Ultrassom Focalizado de Alta Intensidade , Neoplasias Hepáticas , Humanos , Espécies Reativas de Oxigênio , Hipóxia , Oxigênio , Neoplasias Hepáticas/terapia , Catálise , Linhagem Celular Tumoral , Microambiente TumoralRESUMO
Constructing highly effective biocatalysts with controllable coordination geometry for eliminating reactive oxygen species (ROS) to address the current bottlenecks in stem-cell-based therapeutics remains challenging. Herein, inspired by the coordination structure of manganese-based antioxidase, we report a manganese-coordinated polyphthalocyanine-based biocatalyst (Mn-PcBC) with axial Mn-N5 sites and 2D d-π-conjugated networks that serves as an artificial antioxidase to rescue stem cell fate. Owing to the unique chemical and electronic structures, Mn-PcBC displays efficient, multifaceted, and robust ROS-scavenging activities, including elimination of H2 O2 and O2 â - . Consequently, Mn-PcBC efficiently rescues the bioactivity and functionality of stem cells in high-ROS-level microenvironments by protecting the transcription of osteogenesis-related genes. This study offers essential insight into the crucial functions of axially coordinated Mn-N5 sites in ROS scavenging and suggests new strategies to create efficient artificial antioxidases for stem-cell therapies.
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Manganês , Células-Tronco , Espécies Reativas de Oxigênio , Manganês/química , Diferenciação CelularRESUMO
BACKGROUND: Gastric adenocarcinoma (GAC) is a lethal disease with limited therapeutic options. Genetic alterations in chromatin remodelling gene AT-rich interactive domain 1A (ARID1A) and mTOR pathway activation occur frequently in GAC. Targeting the mechanistic target of rapamycin (mTOR) pathway in unselected patients has failed to show survival benefit. A deeper understanding of GAC might identify a subset that can benefit from mTOR inhibition. METHODS: Genomic alterations in ARID1A were analysed in GAC. Mouse gastric epithelial cells from CK19-Cre-Arid1Afl/fl and wild-type mice were used to determine the activation of oncogenic genes due to loss of Arid1A. Functional studies were performed to determine the significance of loss of ARID1A and the sensitivity of ARID1A-deficient cancer cells to mTOR inhibition in GAC. RESULTS: More than 30% of GAC cases had alterations (mutations or deletions) of ARID1A and ARID1A expression was negatively associated with phosphorylation of S6 and SOX9 in GAC tissues and patient-derived xenografts (PDXs). Activation of mTOR signalling (increased pS6) and SOX9 nuclear expression were strongly increased in Arid1A-/- mouse gastric tissues which could be curtailed by RAD001, an mTOR inhibitor. Knockdown of ARID1A in GAC cell lines increased pS6 and nuclear SOX9 and increased sensitivity to an mTOR inhibitor which was further amplified by its combination with fluorouracil both in vitro and in vivo in PDXs. CONCLUSIONS: The loss of ARID1A activates pS6 and SOX9 in GAC, which can be effectively targeted by an mTOR inhibitor. Therefore, our studies suggest a new therapeutic strategy of clinically targeting the mTOR pathway in patients with GAC with ARID1A deficiency.
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Adenocarcinoma/etiologia , Proteínas de Ligação a DNA/fisiologia , Fatores de Transcrição SOX9/fisiologia , Transdução de Sinais/fisiologia , Neoplasias Gástricas/etiologia , Serina-Treonina Quinases TOR/fisiologia , Fatores de Transcrição/fisiologia , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Animais , Técnicas de Cultura de Células , Linhagem Celular Tumoral , Proliferação de Células , Camundongos , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologiaRESUMO
Exploring highly active, stable electrocatalysts with earth-abundant metal centers for the oxygen reduction reaction (ORR) is essential for sustainable energy conversion. Due to the high cost and scarcity of platinum, it is a general trend to develop metal-N-C (M-N-C) electrocatalysts, especially those prepared from the zeolite imidazolate framework (ZIF) to replace/minimize usage of noble metals in ORR electrocatalysis for their amazingly high catalytic efficiency, great stability, and readily-tuned electronic structure. In this review, the most pivotal advances in mechanisms leading to declined catalytic performance, synthetic strategies, and design principles in engineering ZIF-derived M-N-C for efficient ORR catalysis, are presented. Notably, this review focuses on how to improve intrinsic ORR activity, such as M-Nx -Cy coordination structures, doping metal-free heteroatoms in M-N-C, dual/multi-metal sites, hydrogen passivation, and edge-hosted M-Nx . Meanwhile, how to increase active sites density, including formation of M-N complex, spatial confinement effects, and porous structure design, are discussed. Thereafter, challenges and future perspectives of M-N-C are also proposed. The authors believe this instructive review will provide experimental and theoretical guidance for designing future, highly active ORR electrocatalysts, and facilitate their applications in diverse ORR-related energy technologies.
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Zeolitas , Catálise , Hidrogênio , Oxigênio/química , PlatinaRESUMO
Currently, the development of advanced 2D nanomaterials has become an interdisciplinary subject with extensive studies due to their extraordinary physicochemical performances. Beyond graphene, the emerging 2D-material-derived electrocatalysts (2D-ECs) have aroused great attention as one of the best candidates for heterogeneous electrocatalysis. The tunable physicochemical compositions and characteristics of 2D-ECs enable rational structural engineering at the molecular/atomic levels to meet the requirements of different catalytic applications. Due to the lack of instructive and comprehensive reviews, here, the most recent advances in the nanostructure and catalytic center design and the corresponding structure-function relationships of emerging 2D-ECs are systematically summarized. First, the synthetic pathways and state-of-the-art strategies in the multifaceted structural engineering and catalytic center design of 2D-ECs to promote their electrocatalytic activities, such as size and thickness, phase and strain engineering, heterojunctions, heteroatom doping, and defect engineering, are emphasized. Then, the representative applications of 2D-ECs in electrocatalytic fields are depicted and summarized in detail. Finally, the current breakthroughs and primary challenges are highlighted and future directions to guide the perspectives for developing 2D-ECs as highly efficient electrocatalytic nanoplatforms are clarified. This review provides a comprehensive understanding to engineer 2D-ECs and may inspire many novel attempts and new catalytic applications across broad fields.
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Grafite , Nanoestruturas , Catálise , Nanoestruturas/químicaRESUMO
Novel bionanocatalysts have opened a new era in fighting multidrug-resistant (MDR) bacteria. They can kill bacteria by elevating the level of reactive oxygen species (ROS) in the presence of chemicals like H2 O2 . However, ROSs' ultrashort diffusion distance limit their bactericidal activity. We present a nanohook-equipped bionanocatalyst (Ni@Co-NC) with bacterial binding ability that shows robust ROS-generating capacity under physiological H2 O2 levels. The Ni@Co-NC's pH-dependent performance confines its effects to the biofilm microenvironment, leaving healthy tissue unaffected. Furthermore, it can generate heat upon NIR laser irradiation, enhancing its catalytic performance while achieving heat ablation against bacteria. With the Ni@Co-NC's synergistic effects, bacterial populations fall by >99.99 %. More surprisingly, the mature biofilm shows no recurrence after treatment with the Ni@Co-NC, demonstrating its tremendous potential for treating MDR bacterial related infections.
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Antibacterianos/farmacologia , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Nanopartículas Metálicas/química , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Antibacterianos/química , Biofilmes/efeitos dos fármacos , Cobalto , Desinfecção , Concentração de Íons de Hidrogênio , Raios Infravermelhos , Lasers , Staphylococcus aureus Resistente à Meticilina/metabolismo , Testes de Sensibilidade Microbiana , Níquel , Espécies Reativas de Oxigênio/metabolismoRESUMO
Developing low-cost electrocatalysts for efficient and robust oxygen evolution reaction (OER) is the key for scalable water electrolysis, for instance, NiFe-based materials. Decorating NiFe catalysts with other transition metals offers a new path to boost their catalytic activities but often suffers from the low controllability of the electronic structures of the NiFe catalytic centers. Here, we report an interfacial atom-substitution strategy to synthesize an electrocatalytic oxygen-evolving NiFeV nanofiber to boost the activity of NiFe centers. The electronic structure analyses suggest that the NiFeV nanofiber exhibits abundant high-valence Fe via a charge transfer from Fe to V. The NiFeV nanofiber supported on a carbon cloth shows a low overpotential of 181â mV at 10â mA cm-2 , along with long-term stability (>20â h) at 100â mA cm-2 . The reported substitutional growth strategy offers an effective and new pathway for the design of efficient and durable non-noble metal-based OER catalysts.
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OBJECTIVE: Gastro-oesophageal cancers (GEC) are resistant to therapy and lead to poor prognosis. The cancer stem cells (CSCs) and antiapoptotic pathways often confer therapy resistance. We sought to elucidate the antitumour action of a BCL-2 inhibitor, AT101 in GEC in vitro, in vivo and in a clinical trial. METHODS: Extensive preclinical studies in vitro and in vivo were carried out to establish the mechanism action of AT101 on targeting CSCs and antiapoptotic proteins. A pilot clinical trial in patients with GEC was completed with AT-101 added to standard chemoradiation. RESULTS: Overexpression of BCL-2 and MCL-1 was noted in gastric cancer tissues (GC). AT-101 induced apoptosis, reduced proliferation and tumour sphere formation in MCL-1/BCL-2 high GC cells. Interestingly, AT101 dramatically downregulated genes (YAP-1/Sox9) that control CSCs in GEC cell lines regardless of BCL-2/MCL-1 expression. Addition of docetaxel to AT-101 amplified its antiproliferation and induced apoptosis effects. In vivo studies confirmed the combination of AT101 and docetaxel demonstrated stronger antitumour activity accompanied with significant decrease of CSCs biomarkers (YAP1/SOX9). In a pilot clinical trial, 13 patients with oesophageal cancer (EC) received AT101 orally concurrently with chemoradiation. We observed dramatic clinical complete responses and encouraging overall survival in these patients. Clinical specimen analyses revealed that AT-101 dramatically reduced the expression of CSCs genes in treated EC specimens indicating antitumour activity of AT101 relies more on its anti-CSCs activity. CONCLUSIONS: Our preclinical and clinical data suggest that AT-101 overcomes resistance by targeting CSCs pathways suggesting a novel mechanism of action of AT101 in patients with GEC.
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Antineoplásicos Fitogênicos/farmacologia , Neoplasias Esofágicas/tratamento farmacológico , Gossipol/análogos & derivados , Células-Tronco Neoplásicas/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Neoplasias Gástricas/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Modelos Animais de Doenças , Docetaxel/farmacologia , Neoplasias Esofágicas/genética , Feminino , Gossipol/farmacologia , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Projetos Piloto , Proteínas Proto-Oncogênicas c-bcl-2/genética , Neoplasias Gástricas/genéticaRESUMO
OBJECTIVE: Peritoneal carcinomatosis (PC; malignant ascites or implants) occurs in approximately 45% of advanced gastric adenocarcinoma (GAC) patients and associated with a poor survival. The molecular events leading to PC are unknown. The yes-associated protein 1 (YAP1) oncogene has emerged in many tumour types, but its clinical significance in PC is unclear. Here, we investigated the role of YAP1 in PC and its potential as a therapeutic target. METHODS: Patient-derived PC cells, patient-derived xenograft (PDX) and patient-derived orthotopic (PDO) models were used to study the function of YAP1 in vitro and in vivo. Immunofluorescence and immunohistochemical staining, RNA sequencing (RNA-Seq) and single-cell RNA-Seq (sc-RNA-Seq) were used to elucidate the expression of YAP1 and PC cell heterogeneity. LentiCRISPR/Cas9 knockout of YAP1 and a YAP1 inhibitor were used to dissect its role in PC metastases. RESULTS: YAP1 was highly upregulated in PC tumour cells, conferred cancer stem cell (CSC) properties and appeared to be a metastatic driver. Dual staining of YAP1/EpCAM and sc-RNA-Seq revealed that PC tumour cells were highly heterogeneous, YAP1high PC cells had CSC-like properties and easily formed PDX/PDO tumours but also formed PC in mice, while genetic knockout YAP1 significantly slowed tumour growth and eliminated PC in PDO model. Additionally, pharmacologic inhibition of YAP1 specifically reduced CSC-like properties and suppressed tumour growth in YAP1high PC cells especially in combination with cytotoxics in vivo PDX model. CONCLUSIONS: YAP1 is essential for PC that is attenuated by YAP1 inhibition. Our data provide a strong rationale to target YAP1 in clinic for GAC patients with PC.
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Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Adenocarcinoma/secundário , Neoplasias Peritoneais/secundário , Neoplasias Gástricas/patologia , Animais , Técnicas de Cultura de Células , Humanos , Camundongos , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas de Sinalização YAPRESUMO
OBJECTIVE: Peritoneal carcinomatosis (PC) occurs frequently in patients with gastric adenocarcinoma (GAC) and confers a poor prognosis. Multiplex profiling of primary GACs has been insightful but the underpinnings of PC's development/progression remain largely unknown. We characterised exome/transcriptome/immune landscapes of PC cells from patients with GAC aiming to identify novel therapeutic targets. DESIGN: We performed whole-exome sequencing (WES) and whole transcriptome sequencing (RNA-seq) on 44 PC specimens (43 patients with PC) including an integrative analysis of WES, RNA-seq, immune profile, clinical and pathological phenotypes to dissect the molecular pathogenesis, identifying actionable targets and/or biomarkers and comparison with TCGA primary GACs. RESULTS: We identified distinct alterations in PC versus primary GACs, such as more frequent CDH1 and TAF1 mutations, 6q loss and chr19 gain. Alterations associated with aggressive PC phenotypes emerged with increased mutations in TP53, CDH1, TAF1 and KMT2C, higher level of 'clock-like' mutational signature, increase in whole-genome doublings, chromosomal instability (particularly, copy number losses), reprogrammed microenvironment, enriched cell cycle pathways, MYC activation and impaired immune response. Integrated analysis identified two main molecular subtypes: 'mesenchymal-like' and 'epithelial-like' with discriminating response to chemotherapy (31% vs 71%). Patients with the less responsive 'mesenchymal-like' subtype had high expression of immune checkpoint T-Cell Immunoglobulin And Mucin Domain-Containing Protein 3 (TIM-3), its ligand galectin-9, V-domain Ig suppressor of T cell activation (VISTA) and transforming growth factor-ß as potential therapeutic immune targets. CONCLUSIONS: We have uncovered the unique mutational landscape, copy number alteration and gene expression profile of PC cells and defined PC molecular subtypes, which correlated with PC therapy resistance/response. Novel targets and immune checkpoint proteins have been identified with a potential to be translated into clinics.
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Adenocarcinoma/secundário , Neoplasias Peritoneais/secundário , Neoplasias Gástricas/genética , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Instabilidade Cromossômica , Variações do Número de Cópias de DNA/genética , DNA de Neoplasias/genética , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular/métodos , Mutação , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Peritoneais/genética , Neoplasias Peritoneais/imunologia , Ploidias , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/imunologia , Sequenciamento do Exoma/métodosRESUMO
Osteoarthritis (OA) is a common joint disease in the middle and old age group with obvious cartilage damage, and the regeneration of cartilage is the key to alleviating or treating OA. In stem cell therapy, bone marrow stem cell (BMSC) has been confirmed to have cartilage regeneration ability. However, the role of stem cells in promoting articular cartilage regeneration is severely limited by their low homing rate. Stromal cell-derived factor-1α (SDF-1α) plays a vital role in MSC migration and involves activation, mobilization, homing and retention. So, we aim to develop SDF-1α-loaded microbubbles MB(SDF-1α), and to verify the migration of BMSCs with the effect of ultrasound combined with MB(SDF-1α) in vitro and in vivo. The characteristics of microbubbles and the content of SDF-1α were examined in vitro. To evaluate the effect of ultrasound combined with chemotactic microbubbles on stem cell migration, BMSCs were injected locally and intravenously into the knee joint of the OA model, and the markers of BMSCs in the cartilage were detected. We successfully prepared MB(SDF-1α) through covalent bonding with impressive SDF-1α loading efficacy loading content. In vitro study, ultrasound combined with MB(SDF-1α) group can promote more stem cell migration with highest migrating cell counts, good cell viability and highest CXCR4 expression. In vivo experiment, more BMSCs surface markers presented in the ultrasound combined with MB(SDF-1α) group with or without exogenous BMSCs administration. Hence, ultrasound combined with MB(SDF-1α) could promote the homing of BMSCs to cartilage and provide a novel promising therapeutic approach for OA.
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Quimiocina CXCL12/farmacologia , Quimiotaxia/efeitos dos fármacos , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/efeitos dos fármacos , Microbolhas , Osteoartrite do Joelho/terapia , Terapia por Ultrassom , 5'-Nucleotidase/biossíntese , 5'-Nucleotidase/genética , Animais , Células Cultivadas , Masculino , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Osteoartrite do Joelho/fisiopatologia , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Receptores CXCR4/biossíntese , Receptores CXCR4/genética , Proteínas Recombinantes/farmacologia , Antígenos Thy-1/biossíntese , Antígenos Thy-1/genética , Regulação para CimaRESUMO
Paclitaxel (PTX) resistance in most epithelial ovarian cancers (EOCs) with increasing membrane expression of mucin 16 (MUC16) is mediated by the Toll-like receptor-myeloid differentiation factor 2/myeloid differentiation factor 88 (TLR4-MD2/MyD88) signaling pathway. 6-Shogaol (6S), an α,ß-unsaturated carbonyl compound with lipophilic property, can block PTX-induced formation of the TLR4-MD2 complex that activates the MyD88/NF-κB signaling pathway. Herein, to improve the effectiveness of 6S, augment the sensibility of PTX, and enhance the targeting ability of PTX-resistant cancer therapies, we report a class of 6S-loaded phase transition nanobubbles conjugated with the MUC16 antibody (6S@NBs-MUC16A), which can enhance the sensitivity of PTX to EOC cells through ultrasound-controlled targeted-delivery of 6S. The 6S@NB-MUC16A could enhance the targeting efficiency and organizational distribution of 6S in MyD88+ EOC area, and the 1 MHz ultrasound can be used as an initiator to trigger the "explosion" of nanobubbles and promote the 6S release. Furthermore, in vivo assessment results indicate that ultrasound-augmented 6S@NB-MUC16A can significantly improve the response of EOC to PTX and the inhibition ratio of tumor growth compared to the control-treated with PTX alone, and exhibit less toxicity to the critical organs. The ultrasound-augmented 6S@NB-MUC16A with less cytotoxicity could be a potentially useful nanosystem to surmount PTX resistance in EOC, which provides potential possibilities for the applications in the biological field.
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Antineoplásicos/farmacologia , Catecóis/farmacologia , Paclitaxel/farmacologia , Transição de Fase , Animais , Catecóis/administração & dosagem , Catecóis/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sistemas de Liberação de Medicamentos , Resistencia a Medicamentos Antineoplásicos , Feminino , Camundongos , Camundongos Nus , Fator 88 de Diferenciação Mieloide , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Recently emerging graphene-based 2D nanoplatforms with multiple therapeutic modalities provide enormous opportunities to combat pathogenic bacterial infections. However, because these materials suffer from complicated synthesis, massive dosage requirements, and abundant nonlocalized heat, much more simplified, tunable, and localized eradication approaches are urgently required. Herein, we report on the fabrication of the metal-organic-framework (MOF)-derived 2D carbon nanosheets (2D-CNs) with phase-to-size transformation and localized bacterial eradication capabilities for augmented anti-infective therapy. The MOF-derived, ZnO-doped carbon on graphene (ZnO@G) is first synthesized and then anchored with phase transformable thermally responsive brushes (TRB) by in situ polymerization to yield the TRB-ZnO@G. The TRB-ZnO@G exhibits flexible 2D nanostructures, high photothermal activities, sustained Zn2+ ions release, and ON-OFF switchable phase-to-size transformation abilities. Notably, the near-infrared-triggered formation of TRB-ZnO@G-bacteria aggregations enables localized massive Zn2+ ions penetration, physical cutting, and hyperthermia killing, which synergistically enhance the disruption of bacterial membranes and intracellular substances. The obtained novel 2D-CNs not only present robust and localized multiple bacterial eradication capabilities with nearly 100% bactericidal efficiency at low concentrations but also possess rapid and safe skin wound disinfection via a short-time photothermal treatment without damaging normal skin tissues or causing accumulative toxicities, thus presenting great potential for broad-spectrum eradication of pathogenic bacteria.
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Anti-Infecciosos/farmacologia , Infecções Bacterianas/tratamento farmacológico , Estruturas Metalorgânicas/química , Nanoestruturas/química , Anti-Infecciosos/química , Bactérias/efeitos dos fármacos , Infecções Bacterianas/microbiologia , Carbono/química , Desinfecção , Grafite/química , Humanos , Estruturas Metalorgânicas/uso terapêutico , Óxido de Zinco/químicaRESUMO
BACKGROUND: PVT1 has emerged as an oncogene in many tumor types. However, its role in Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC) is unknown. The aim of this study was to assess the role of PVT1 in BE/EAC progression and uncover its therapeutic value against EAC. METHODS: PVT1 expression was assessed by qPCR in normal, BE, and EAC tissues and statistical analysis was performed to determine the association of PVT1 expression and EAC (stage, metastases, and survival). PVT1 antisense oligonucleotides (ASOs) were tested for their antitumor activity in vitro and in vivo. RESULTS: PVT1 expression was up-regulated in EACs compared with paired BEs, and normal esophageal tissues. High expression of PVT1 was associated with poor differentiation, lymph node metastases, and shorter survival. Effective knockdown of PVT1 in EAC cells using PVT1 ASOs resulted in decreased cell proliferation, invasion, colony formation, tumor sphere formation, and reduced proportion of ALDH1A1+ cells. Mechanistically, we discovered mutual regulation of PVT1 and YAP1 in EAC cells. Inhibition of PVT1 by PVT1 ASOs suppressed YAP1 expression through increased phosphor-LATS1and phosphor-YAP1 while knockout of YAP1 in EAC cells significantly suppressed PVT1 levels indicating a positive regulation of PVT1 by YAP1. Most importantly, we found that targeting both PVT1 and YAP1 using their specific ASOs led to better antitumor activity in vitro and in vivo. CONCLUSIONS: Our results provide strong evidence that PVT1 confers an aggressive phenotype to EAC and is a poor prognosticator. Combined targeting of PVT1 and YAP1 provided the highest therapeutic index and represents a novel therapeutic strategy.
Assuntos
Adenocarcinoma/genética , Adenocarcinoma/mortalidade , Biomarcadores Tumorais , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/mortalidade , Regulação Neoplásica da Expressão Gênica , RNA Longo não Codificante/genética , Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Adenocarcinoma/tratamento farmacológico , Animais , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células , Modelos Animais de Doenças , Neoplasias Esofágicas/tratamento farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Modelos Biológicos , Prognóstico , Fatores de Transcrição/antagonistas & inibidores , Proteínas de Sinalização YAPRESUMO
BACKGROUND: Overexpression of Galectin-3 (Gal-3), a ß-galactoside binding protein, has been noted in many tumour types but its functional significance and clinical utility in gastric adenocarcinoma (GAC) are not well known. METHODS: We studied 184 GAC patients characterised by histologic grade, sub-phenotypes (diffuse vs intestinal), and ethnicity (Asians vs North Americans). Immunohistochemistry was performed to assess the expression of Gal-3 in human GACs and we correlated it to the clinical outcomes. Cell proliferation, invasion, co-immunoprecipitation and kinase activity assays were done in genetically stable Gal-3 overexpressing GC cell lines and the parental counterparts to delineate the mechanisms of action and activity of inhibitors. RESULTS: Most patients were men, Asian, and had a poorly differentiated GAC. Gal-3 was over-expressed in poorly differentiated (P=0.002) tumours and also in diffuse sub-phenotype (P=0.02). Gal-3 overexpression was associated with shorter overall survival (OS; P=0.026) in all patients. Although, Gal-3 over-expression was not prognostic in the Asian cohort (P=0.337), it was highly prognostic in the North American cohort (P=0.001). In a multivariate analysis, Gal-3 (P=0.001) and N-stage (P=<0.001) were independently prognostic for shorter OS. Mechanistically, Gal-3 induced c-MYC expression through increasing RalA activity and an enhanced YAP1/RalA/RalBP complex to confer an aggressive phenotype. YAP1/BET bromodomain inhibitors reduced Gal-3-mediated aggressive phenotypes in GAC cells. CONCLUSIONS: Gal-3 is an independent prognostic marker of shorter OS and a novel therapeutic target particularly in diffuse type GAC in North American patients.