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Organ morphogenesis needs orchestration of a series of cellular events, including cell division, cell shape change, cell rearrangement and cell death. Cytokinesis, the final step of cell division, is involved in the control of organ size, shape and function. Mechanistically, it is unclear how the molecules involved in cytokinesis regulate organ size and shape. Here, we demonstrate that the centralspindlin complex coordinates cell division and epithelial morphogenesis by regulating cytokinesis. Loss of the centralspindlin components CYK-4 and ZEN-4 disrupts cell division, resulting in altered cell arrangement and malformation of the Caenorhabditis elegans spermatheca. Further investigation revealed that most spermathecal cells undergo nuclear division without completion of cytokinesis. Germline mutant-based analyses suggest that CYK-4 regulates cytokinesis of spermathecal cells in a GTPase activator activity-independent manner. Spermathecal morphology defects can be enhanced by double knockdown of rho-1 and cyk-4, and partially suppressed by double knockdown of cdc-42 and cyk-4. Thus, the centralspindlin components CYK-4 and ZEN-4, together with RHO-1 and CDC-42, are central players of a signaling network that guides spermathecal morphogenesis by enabling completion of cytokinesis.
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Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Animais , Caenorhabditis elegans/metabolismo , Citocinese/genética , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Cinesinas/metabolismo , Proteínas Ativadoras de GTPase/metabolismo , Morfogênese/genética , Proteínas rho de Ligação ao GTP/genética , Proteínas rho de Ligação ao GTP/metabolismoRESUMO
Patients with Hutchinson-Gilford progeria syndrome (HGPS) present with a number of premature aging phenotypes, including DNA damage accumulation, and many of them die of cardiovascular complications. Although vascular pathologies have been reported, whether HGPS patients exhibit cardiac dysfunction and its underlying mechanism is unclear, rendering limited options for treating HGPS-related cardiomyopathy. In this study, we reported a cardiac atrophy phenotype in the LmnaG609G/G609G mice (hereafter, HGPS mice). Using a GFP-based reporter system, we demonstrated that the efficiency of nonhomologous end joining (NHEJ) declined by 50% in HGPS cardiomyocytes in vivo, due to the attenuated interaction between γH2AX and Progerin, the causative factor of HGPS. As a result, genomic instability in cardiomyocytes led to an increase of CHK2 protein level, promoting the LKB1-AMPKα interaction and AMPKα phosphorylation, which further led to the activation of FOXO3A-mediated transcription of atrophy-related genes. Moreover, inhibiting AMPK enlarged cardiomyocyte sizes both in vitro and in vivo. Most importantly, our proof-of-concept study indicated that isoproterenol treatment significantly reduced AMPKα and FOXO3A phosphorylation in the heart, attenuated the atrophy phenotype, and extended the mean lifespan of HGPS mice by ~21%, implying that targeting cardiac atrophy may be an approach to HGPS treatment.
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Senilidade Prematura , Progéria , Humanos , Camundongos , Animais , Progéria/metabolismo , Coração , Dano ao DNA , Instabilidade Genômica , Proteínas Quinases Ativadas por AMP/genética , Lamina Tipo A/genética , Lamina Tipo A/metabolismoRESUMO
Highly soluble salts and gas mediated therapies are emerging antitumor strategies. However, the therapeutic efficacy remains restricted by difficulty in delivering them to the tumor site and poorly controlled release in deep tissues. Here, an intelligent wireless photoactivated targeted nanosystem is designed for delivering LiCl and H2 to tumors for therapy. LiCl causes cell death by inhibiting the activity of GSK-3ß. H2 selectively interacts with reactive oxygen species in the tumor, leading to redox stress, which induces apoptosis. The significant heat generated by the nanosystem not only kills tumor cells but also accelerates the dissolution of LiCl and the release of H2. The rapid dissolution of LiCl leads to a surge in intracellular osmotic pressure, which further intensifies the redox stress response and enhances the efficiency of therapy. The nanosystem shows efficient tumor therapeutic capability via synergistic effects of hyperthermia/redox stress amplification/GSK-3ß activity inhibition.
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Apoptose , Hipertermia Induzida , Glicogênio Sintase Quinase 3 beta/farmacologia , Morte Celular , Espécies Reativas de Oxigênio/metabolismoRESUMO
BACKGROUND: A large portion of idiopathic and familial dilated cardiomyopathy (DCM) cases have no obvious causal genetic variant. Although altered response to metabolic stress has been implicated, the molecular mechanisms underlying the pathogenesis of DCM remain elusive. The JMJD family proteins, initially identified as histone deacetylases, have been shown to be involved in many cardiovascular diseases. Despite their increasingly diverse functions, whether JMJD family members play a role in DCM remains unclear. METHODS: We examined Jmjd4 expression in patients with DCM, and conditionally deleted and overexpressed Jmjd4 in cardiomyocytes in vivo to investigate its role in DCM. RNA sequencing, metabolites profiling, and mass spectrometry were used to dissect the molecular mechanism of Jmjd4-regulating cardiac metabolism and hypertrophy. RESULTS: We found that expression of Jmjd4 is significantly decreased in hearts of patients with DCM. Induced cardiomyocyte-specific deletion of Jmjd4 led to spontaneous DCM with severely impaired mitochondrial respiration. Pkm2, the less active pyruvate kinase compared with Pkm1, which is normally absent in healthy adult cardiomyocytes but elevated in cardiomyopathy, was found to be drastically accumulated in hearts with Jmjd4 deleted. Jmjd4 was found mechanistically to interact with Hsp70 to mediate degradation of Pkm2 through chaperone-mediated autophagy, which is dependent on hydroxylation of K66 of Pkm2 by Jmjd4. By enhancing the enzymatic activity of the abundant but less active Pkm2, TEPP-46, a Pkm2 agonist, showed a significant therapeutic effect on DCM induced by Jmjd4 deficiency, and heart failure induced by pressure overload, as well. CONCLUSIONS: Our results identified a novel role of Jmjd4 in maintaining metabolic homeostasis in adult cardiomyocytes by degrading Pkm2 and suggest that Jmjd4 and Pkm2 may be therapeutically targeted to treat DCM, and other cardiac diseases with metabolic dysfunction, as well.
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Cardiomiopatia Dilatada , Insuficiência Cardíaca , Humanos , Miócitos Cardíacos/metabolismo , Cardiomiopatia Dilatada/patologia , Insuficiência Cardíaca/patologiaRESUMO
The extracellular matrix (ECM) in the tumor microenvironment (TME) and upregulated immune checkpoints (ICs) on antitumor immune cells impede the infiltration and killing effect of T cells, creating an immunosuppressive TME. Herein, a cholesterol oxidase (CHO) and lysyl oxidase inhibitor (LOX-IN-3) co-delivery copper-dibenzo-[g,p]chrysene-2,3,6,7,10,11,14,15-octaol single-site nanozyme (Cu-DBCO/CL) was developed. The conjugated organic ligand and well-distributed Cu-O4 sites endow Cu-DBCO with unique redox capabilities, enabling it to catalyze O2 and H2O2 to ·O2- and ·OH. This surge of reactive oxygen species (ROS) leads to impaired mitochondrial function and insufficient ATP supply, impacting the function of copper-transporting ATPase-1 and causing dihydrolipoamide S-acetyltransferase oligomerization-mediated cuproptosis. Moreover, multiple ROS storms and glutathione peroxidase 4 depletion also induce lipid peroxidation and trigger ferroptosis. Simultaneously, the ROS-triggered release of LOX-IN-3 reshapes the ECM by inhibiting lysyl oxidase activity and further enhances the infiltration of cytotoxic T lymphocytes (CD8+ T cells). CHO-triggered cholesterol depletion not only increases ·OH generation but also downregulates the expression of ICs such as PD-1 and TIM-3, restoring the antitumor activity of tumor-infiltrating CD8+ T cells. Therefore, Cu-DBCO/CL exhibits efficient properties in activating a potent antitumor immune response by cascade-enhanced CD8+ T cell viability. More importantly, ECM remodeling and cholesterol depletion could suppress the metastasis and proliferation of the tumor cells. In short, this immune nanoremodeler can greatly enhance the infiltration and antitumor activity of T cells by enhancing tumor immunogenicity, remodeling ECM, and downregulating ICs, thus achieving effective inhibition of tumor growth and metastasis.
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Linfócitos T CD8-Positivos , Neoplasias , Humanos , Proteína-Lisina 6-Oxidase , Cobre , Peróxido de Hidrogênio , Espécies Reativas de Oxigênio , Colesterol , Linhagem Celular Tumoral , Imunoterapia , Microambiente TumoralRESUMO
BACKGROUND & AIMS: Intestinal fibrosis is a significant complication of Crohn's disease (CD). Gut microbiota reactive Th17 cells are crucial in the pathogenesis of CD; however, how Th17 cells induce intestinal fibrosis is still not completely understood. METHODS: In this study, T-cell transfer model with wild-type (WT) and Areg-/- Th17 cells and dextran sulfate sodium (DSS)-induced chronic colitis model in WT and Areg-/- mice were used. CD4+ T-cell expression of AREG was determined by quantitative reverse-transcriptase polymerase chain reaction and enzyme-linked immunosorbent assay. The effect of AREG on proliferation/migration/collagen expression in human intestinal myofibroblasts was determined. AREG expression was assessed in healthy controls and patients with CD with or without intestinal fibrosis. RESULTS: Although Th1 and Th17 cells induced intestinal inflammation at similar levels when transferred into Tcrßxδ-/- mice, Th17 cells induced more severe intestinal fibrosis. Th17 cells expressed higher levels of AREG than Th1 cells. Areg-/- mice developed less severe intestinal fibrosis compared with WT mice on DSS insults. Transfer of Areg-/- Th17 cells induced less severe fibrosis in Tcrßxδ-/- mice compared with WT Th17 cells. Interleukin (IL)6 and IL21 promoted AREG expression in Th17 cells by activating Stat3. Stat3 inhibitor suppressed Th17-induced intestinal fibrosis. AREG promoted human intestinal myofibroblast proliferation, motility, and collagen I expression, which was mediated by activating mammalian target of rapamycin and MEK. AREG expression was increased in intestinal CD4+ T cells in fibrotic sites compared with nonfibrotic sites from patients with CD. CONCLUSIONS: These findings reveal that Th17-derived AREG promotes intestinal fibrotic responses in experimental colitis and human patients with CD. Thereby, AREG might serve as a potential therapeutic target for fibrosis in CD.
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Colite , Doença de Crohn , Animais , Humanos , Camundongos , Anfirregulina/genética , Anfirregulina/metabolismo , Colite/metabolismo , Colágeno/metabolismo , Doença de Crohn/patologia , Sulfato de Dextrana/efeitos adversos , Fibrose , Mucosa Intestinal/patologia , Camundongos Endogâmicos C57BL , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Miofibroblastos/patologia , Células Th17/metabolismo , Serina-Treonina Quinases TOR/metabolismoRESUMO
Although research on photodynamic therapy (PDT) of malignant tumor has made considerable progress in recent years, it is a remaining challenge to extend PDT to the second near-infrared window (NIR-II) along with real-time and accurate NIR-II fluorescence imaging to determine drug enrichment status and achieve high treatment efficacy. In this work, lanthanide nanoparticles (Ln NPs)-based nanoplatform (LCR) equipped with photosensitizer Chlorin e6 (Ce6) and targeting molecular NH2-PEG1000-cRGDfK are developed, which can achieve NIR-II photodynamic therapy (PDT) and NIR-II fluorescence imaging by dual channel excitation. Under 808 nm excitation, Nd3+ in the outer layer can absorb the energy and transfer inward to emit strong NIR-II emissions (1064 and 1525 nm). Due to the low background noise of NIR-II light and the targeting effect of NH2-PEG1000-cRGDfK, LCR can recognize tiny tumor tissue (≈3 mm) and monitor drug distribution in vivo. Under 1530 nm excitation, internal Er3+ can be self-sensitized, generating intense upconversion emission (662 nm) that can effectively activate Ce6 for in vivo PDT due to the deep tissue penetration of NIR-II light. This study provides a paradigm of theranostic nanoplatform for both real-time fluorescence imaging and PDT of orthotopic breast tumor in NIR-II window.
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Electrocatalytic nitrogen reduction reaction (NRR) paves a sustainable way to produce NH3 but suffering from the relatively low NH3 yield and poor selectivity. High-performance NRR catalysts and a deep insight into the structure-performance relationship are higher desired. Herein, a molten-salt approach is developed to synthesize tiny CeO2 nanoparticles anchored by ultra-thin MoN nanosheets as advanced catalysts for NRR. Specifically, a considerably high NH3 yield rate of 27.5 µg h-1 mg-1 with 17.2% Faradaic efficiency (FE) can be achieved at -0.3 V vs (RHE) under ambient conditions. Experimental and density functional theory (DFT) calculations further point out that the incorporation of MoN with CeO2 can promotes the enlargement of the electron deficient area of nitrogen vacancy site. The enlarged electron deficient area contributes to the accommodation of lone pair electrons of N2, which dramatically improves the N2 adsorption/activation and the key intermediates (*NNH and *NH3) generation, thus boosting the NRR performance.
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Adult mammalian cardiomyocytes have minimal cell cycle capacity, which leads to poor regeneration after cardiac injury such as myocardial infarction. Many positive regulators of cardiomyocyte cell cycle and cardioprotective signals have been identified, but extracellular signals that suppress cardiomyocyte proliferation are poorly understood. We profiled receptors enriched in postnatal cardiomyocytes, and found that very-low-density-lipoprotein receptor (Vldlr) inhibits neonatal cardiomyocyte cell cycle. Paradoxically, Reelin, the well-known Vldlr ligand, expressed in cardiac Schwann cells and lymphatic endothelial cells, promotes neonatal cardiomyocyte proliferation. Thrombospondin1 (TSP-1), another ligand of Vldlr highly expressed in adult heart, was then found to inhibit cardiomyocyte proliferation through Vldlr, and may contribute to Vldlr's overall repression on proliferation. Mechanistically, Rac1 and subsequent Yap phosphorylation and nucleus translocation mediate the regulation of the cardiomyocyte cell cycle by TSP-1/Reelin-Vldlr signaling. Importantly, Reln mutant neonatal mice displayed impaired cardiomyocyte proliferation and cardiac regeneration after apical resection, while cardiac-specific Thbs1 deletion and cardiomyocyte-specific Vldlr deletion promote cardiomyocyte proliferation and are cardioprotective after myocardial infarction. Our results identified a novel role of Vldlr in consolidating extracellular signals to regulate cardiomyocyte cell cycle activity and survival, and the overall suppressive TSP-1-Vldlr signal may contribute to the poor cardiac repair capacity of adult mammals.
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Infarto do Miocárdio , Trombospondina 1 , Animais , Camundongos , Proliferação de Células , Células Endoteliais/metabolismo , Ligantes , Mamíferos , Camundongos Knockout , Infarto do Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Regeneração , Trombospondina 1/metabolismoRESUMO
Protein-based biomaterials attract growing interests due to their encoded and programmable robust mechanical properties, superelasticity, plasticity, shape adaptability, excellent interfacial behavior, etc., derived from sequence-guided backbone structures, particularly compared to chemically synthetic counterparts in materials science and biomedical engineering. For example, protein materials have been successfully fabricated as (1) artificial implants (man-made tendons, cartilages, or dental tissues), due to programmable chemistry and biocompatibility; (2) smart biodevices with temperature/light-response and self-healing effects; and (3) impact resistance materials having great mechanical performance due to biomimetics. However, the existing method of regenerating protein materials from natural sources has two critical issues, low yield and structural damage, making it unable to meet demands. Therefore, it is crucial to develop an alternative strategy for fabricating protein materials. Heterologous expression of natural proteins with a modular assembly approach is an effective strategy for material preparation. Standardized, easy-to-assemble protein modules with specific structures and functions are developed through experimental and computational tools based on natural functional protein sequences. Through recombination and heterologous expression, these artificial protein modules become keys to material fabrication. Undergoing an assembly process similar to supramolecular self-assembly of proteins in cells, biomimetic modules can be fabricated for formation of macroscopic materials such as fibers and adhesives. This strategy inspired by synthetic biology and supramolecular chemistry is important for improving target protein yields and assembly integrity. It also preserves and optimizes the mechanical functions of structural proteins, accelerating the design and fabrication of artificial protein materials.In this Account, we overview recent studies on fabricating biomimetic protein materials to elucidate the concept of modular assembly. We discuss the design of biomimetic structural proteins at the molecular level, providing a wealth of details determining the bulk properties of materials. Additinally, we describe the modular self-assembly and assembly driven by inducing molecules, and mechanical properties and applications of resulting fibers. We used these strategies to develop fiber materials with high tensile strength, high toughness, and properties such as anti-icing and high-temperature resistance. We also extended this approach to design protein-based adhesives with ultra-strong adhesion, biocompatibility, and biodegradability for surgical applications such as wound sealing and healing. Other protein materials, including films and hydrogels, have been developed through chemical assembly routes. Finally, we describe exploiting synthetic biology and chemistry to overcome bottlenecks in structural protein modular design, biosynthesis, and material assembly and our perspectives for future development in structural biomaterials.
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Materiais Biomiméticos , Biomimética , Humanos , Biomimética/métodos , Proteínas , Materiais Biocompatíveis , Materiais Biomiméticos/química , Sequência de AminoácidosRESUMO
In this work, we developed two kinds of co-crystal assemblies systems, consisting of discrete mononuclear Yb3+ and Er3+ and mononuclear Yb3+ and Pr3+, which can achieve Er3+ and Pr3+ upconversion luminescence, respectively, by Yb3+ sensitization under 980â nm excitation. The structure and composition of two co-crystal assemblies were determined by single crystal X-ray diffraction. By investigation of the series of two assemblies, respectively, it is found that the strongest upconversion luminescence is both obtained when the molar ratio of Yb3+ and Ln3+ (Ln=Er or Pr) is 1 : 1. The energy transfer mechanism of Er3+ assemblies is determined as energy transfer upconversion, while that of Pr3+ assemblies is determined as energy transfer upconversion and cooperative sensitization upconversion. This is the first example of Pr3+ upconversion luminescence at the molecular dimension at room temperature, which enriches the research in the field of upconversion luminescence with lanthanide complexes.
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BACKGROUND: Therapeutic drug monitoring (TDM) plays a crucial role in the management of Crohn's disease (CD) patients receiving infliximab (IFX). While reactive TDM has been more commonly utilized previously, recent research suggests that proactive TDM may offer greater benefits for patients. OBJECTIVE: To compare treatment outcomes among patients receiving different monitoring modalities of IFX. METHODS: This was a retrospective cohort study that enrolled 142 CD patients who initiated IFX therapy at the First Affiliated Hospital of Nanjing Medical University from January 2014 to June 2021. The patients were divided into a reactive (n = 43) and proactive (n = 99) group. The outcome measures included sustained clinical response and remission rates, biological remission rates, endoscopic response and remission rates achieved in both groups at weeks 30 and 54. The incidence of adverse events (AEs), changes in IFX trough concentrations (TCs) and treatment adjustments within 54 weeks were also evaluated. RESULTS: Kaplan-Meier analysis demonstrated that the proactive group exhibited significantly higher cumulative probabilities of sustained clinical response, sustained clinical remission, and endoscopic response by Week 54. Compared to the reactive group, patients in the proactive group achieved significantly reduced rates of AEs-related hospitalization and surgery. After adjusting treatment strategies, the median concentration and the proportion of patients achieved an effective therapeutic concentration (TC > 3 µg/mL) at Week 54 was both significantly higher in the proactive group. CONCLUSIONS: Proactive TDM of IFX plays a more crucial role in timely adjustment of treatment strategies and maintenance of effective concentrations, thereby contributing to the outcomes for CD patients.
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Doença de Crohn , Monitoramento de Medicamentos , Fármacos Gastrointestinais , Infliximab , Humanos , Doença de Crohn/tratamento farmacológico , Fármacos Gastrointestinais/efeitos adversos , Infliximab/uso terapêutico , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Aquatic environments are complicated systems that contain different types of nanoparticles (NPs). Nevertheless, recent studies of NP toxicity, and especially those that have focused on bioaccumulation have mostly investigated only a single type of NPs. Assessments of the environmental risks of NPs that do not consider co-exposure regimes may lead to inaccurate conclusions and ineffective environmental regulation. Thus, the present study examined the effects of differently sized silica NPs (SiO2 NPs) on the uptake of iron oxide NPs (Fe2O3 NPs) by the zooplankton Daphnia magna. Both SiO2 NPs and Fe2O3 NPs were well dispersed in the experimental medium without significant heteroaggregation. Although all three sizes of SiO2 NPs inhibited the uptake of Fe2O3 NPs, the underlying mechanisms differed. SiO2 NPs smaller than the average mesh size (â¼200 nm) of the filtering apparatus of D. magna reduced the accumulation of Fe2O3 NPs through uptake competition, whereas larger SiO2 NPs inhibited the uptake of Fe2O3 NPs mainly by reducing the water filtration rate of the daphnids. Overall, in evaluations of the risks of NPs in the natural environment, the different mechanisms underlying the effects of NPs of different sizes on the uptake of dissimilar NPs should be considered.
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Nanopartículas , Poluentes Químicos da Água , Animais , Daphnia magna , Daphnia , Dióxido de Silício/farmacologia , Nanopartículas/toxicidade , Nanopartículas Magnéticas de Óxido de Ferro , Poluentes Químicos da Água/toxicidadeRESUMO
Rare earth elements (REEs) are a group of critical minerals and extensively employed in new material manufacturing. However, separation of lanthanides is difficult because of their similar chemical natures. Current lanthanide leaching and separation methods require hazardous compounds, resulting in severe environmental concerns. Bioprocessing of lanthanides offers an emerging class of tools for REE separation due to mild leaching conditions and highly selective separation scenarios. In the course of biopreparation, engineered microbes not only dissolve REEs from ores but also allow for selective separation of the lanthanides. In this review, we present an overview of recent advances in microbes and proteins used for the biomanufacturing of lanthanides and discuss high value-added applications of REE-derived biomaterials. We begin by introducing the fundamental interactions between natural microbes and REEs. Then we discuss the rational design of chassis microbes for bioleaching and biosorption. We also highlight the investigations on REE binding proteins and their applications in the synthesis of high value-added biomaterials. Finally, future opportunities and challenges for the development of next generation lanthanide-binding biological systems are discussed.
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Elementos da Série dos Lantanídeos , Metais Terras Raras , Metais Terras Raras/químicaRESUMO
Structural proteins have evolved over billions of years and offer outstanding mechanical properties, such as resilience, toughness and stiffness. Advances in modular protein engineering, polypeptide modification, and synthetic biology have led to the development of novel biomimetic structural proteins to perform in biomedical and military fields. However, the development of customized structural proteins and assemblies with superior performance remains a major challenge, due to the inherent limitations of biosynthesis, difficulty in mimicking the complexed macroscale assembly, etc. This review summarizes the approaches for the design and production of biomimetic structural proteins, and their chemical modifications for multiscale assembly. Furthermore, we discuss the function tailoring and current applications of biomimetic structural protein assemblies. A perspective of future research is to reveal how the mechanical properties are encoded in the sequences and conformations. This review, therefore, provides an important reference for the development of structural proteins-mimetics from replication of nature to even outperforming nature.
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Materiais Biomiméticos , Materiais Biomiméticos/química , Proteínas , Peptídeos/químicaRESUMO
Sargassaceae, the most abundant family in Fucales, was recently formed through the merging of the two former families Sargassaceae and Cystoseiraceae. It is widely distributed in the world's oceans, notably in tropical coastal regions, with the exception of the coasts of Antarctica and South America. Numerous bioactivities have been discovered through investigations of the chemical diversity of the Sargassaceae family. The secondary metabolites with unique structures found in this family have been classified as terpenoids, phlorotannins, and steroids, among others. These compounds have exhibited potent pharmacological activities. This review describes the new discovered compounds from Sargassaceae species and their associated bioactivities, citing 136 references covering from March 1975 to August 2023.
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Phaeophyceae , Humanos , Oceanos e Mares , Regiões AntárticasRESUMO
To explore the effect of miR-29b-3p on fibrosis and hypertrophy of ligamentum flavum (LF) in lumbar spinal stenosis (LSS) and its underlying mechanism. Patients with LSS and lumbar disc herniation (LDH) (control) undergoing posterior lumbar laminectomy were included in this study. Human LF samples were obtained for LF cell isolation, RNA, and protein extraction. Histomorphological analysis of LF was performed using hematoxylin-eosin (HE) staining. After isolation, culture, and transfection of primary LF cells, different transfection groups were constructed: NC-mimic, miR-29b-3p-mimic, NC-inhibitor, and miR-29b-3p-inhibitor. Quantitative real time polymerase chain reaction (qRT-PCR) was performed to detect the expression of miR-29b-3p in LF and LF cells. Western blot analysis detected the protein expressions of P16 and CyclinD1. ELISA detected the protein expressions of TGF-ß1, Smad2, Smad3, TLR4, Type I collagen, and Type III collagen. Finally, LF cell viability was detected using the Cell Counting Kit-8 (CCK8) assay. The thickness of LF was significantly thicker in the LSS group compared to the LDH group (p < 0.05), accompanied by a higher calcification degree, more fibroblasts, and a larger area of collagen fiber proliferation. miR-29b-3p expression was significantly lower in LSS-derived LF tissues and cells than in LDH-derived tissues and cells (both p < 0.05). Compared to the NC-mimic group, the miR-29b-3p-mimic group exhibited significantly higher miR-29b-3p expression, decreased protein expressions of Type I collagen, Type III collagen, TGF-ß1, Smad2, Smad3, TLR4, P16, and CyclinD1, and inhibited LF cell proliferation (all p < 0.05). As expected, the miR-29b-3p-inhibitor group displayed contrasting expression patterns (all p < 0.05). Compared to the phosphate buffer saline (PBS) group, the Trimethylamine-N-Oxide (TMAO) group showed significantly increased expressions of TGF-ß1, Smad2, Smad3, TLR4, Type I collagen, Type III collagen, P16, and CyclinD1, as well as enhanced LF cell proliferation (all p < 0.05). However, there was no significant difference between the TMAO group and the Ang II group (all p > 0.05). Upregulation of miR-29b-3p expression may play a role in improving LF fibrosis and hypertrophy in LSS by inhibiting P16 expression and suppressing the activation of the TGF-ß/Smad signaling pathway. This finding offers new insights into future gene modification therapy for this patient population.
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Pyroptosis is an effective anti-tumor strategy. However, monometallic pyroptosis biotuners have not been explored until now. Here, we discover for the first time that biodegradable monometallic Al can act as a pyroptosis biotuner for tumor therapy. pH-sensitive Al nanoparticles (Al@P) are obtained by equipping polyethylene glycol-b-(poly(methyl methacrylate)-co-poly(4-vinylpyridine), which can exert their effect at the tumor site without affecting normal cells. The H2 and Al3+ release by Al@P in the acidic environment of tumors disrupts the redox balance and ionic homeostasis in tumor cells, thus generating large amounts of reactive oxygen species (ROS), leading to caspase-1 activation, gasdermin D cleavage, and IL-1ß/LDH release, which induces canonical pyroptotic death. Meanwhile, the prodrug Doxorubicin (Pro-DOX) is successfully loaded onto Al@P (Al@P-P) and can be activated by ROS to release DOX in the tumor cells, thus further improving the tumor-killing efficiency. Ultimately, Al@P-P is degradable and exhibits efficient tumor inhibition.
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Metacrilatos , Neoplasias , Polietilenoglicóis , Piroptose , Humanos , Alumínio/farmacologia , Espécies Reativas de Oxigênio , Neoplasias/tratamento farmacológico , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêuticoRESUMO
Hydrocracking catalysis is a key route to plastic waste upgrading, but the acid site-driven C-C cleavage step is relatively sluggish in conventional bifunctional catalysts, dramatically effecting the overall efficiency. We demonstrate here a facile and efficient way to boost the reactivity of acid sites by introducing Ce promoters into Pt/HY catalysts, thus achieving a better metal-acid balance. Remarkably, 100 % of low-density polyethylene (LDPE) can be converted with 80.9 % selectivity of liquid fuels over the obtained Pt/5Ce-HY catalysts at 300 °C in 2â h. For comparison, Pt/HY only gives 38.8 % of LDPE conversion with 21.3 % selectivity of liquid fuels. Through multiple experimental studies on the structure-performance relationship, the Ce species occupied in the supercage are identified as the actual active sites, which possess remarkably-improved adsorption capability towards short-chain intermediates.
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The variability of CO2 hydrogenation reaction demands new potential strategies to regulate the fine structure of the catalysts for optimizing the reaction pathways. Herein, we report a dual-site strategy to boost the catalytic efficiency of CO2-to-methanol conversion. A new descriptor, τ, was initially established for screening the promising candidates with low-temperature activation capability of CO2, and sequentially a high-performance catalyst was fabricated centred with oxophilic Mo single atoms, who was further decorated with Pt nanoparticles. In CO2 hydrogenation, the obtained dual-site catalysts possess a remarkably-improved methanol generation rate (0.27â mmol gcat. -1 h-1). For comparison, the singe-site Mo and Pt-based catalysts can only produce ethanol and formate acid at a relatively low reaction rate (0.11â mmol gcat. -1 h-1 for ethanol and 0.034â mmol gcat. -1 h-1 for formate acid), respectively. Mechanism studies indicate that the introduction of Pt species could create an active hydrogen-rich environment, leading to the alterations of the adsorption configuration and conversion pathways of the *OCH2 intermediates on Mo sites. As a result, the catalytic selectivity was successfully switched.