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Since its discovery over 35 years ago, MDM2 has emerged as an attractive target for the development of cancer therapy. MDM2's activities extend from carcinogenesis to immunity to the response to various cancer therapies. Since the report of the first MDM2 inhibitor more than 30 years ago, various approaches to inhibit MDM2 have been attempted, with hundreds of small-molecule inhibitors evaluated in preclinical studies and numerous molecules tested in clinical trials. Although many MDM2 inhibitors and degraders have been evaluated in clinical trials, there is currently no Food and Drug Administration (FDA)-approved MDM2 inhibitor on the market. Nevertheless, there are several current clinical trials of promising agents that may overcome the past failures, including agents granted FDA orphan drug or fast-track status. We herein summarize the research efforts to discover and develop MDM2 inhibitors, focusing on those that induce MDM2 degradation and exert anticancer activity, regardless of the p53 status of the cancer. We also describe how preclinical and clinical investigations have moved toward combining MDM2 inhibitors with other agents, including immune checkpoint inhibitors. Finally, we discuss the current challenges and future directions to accelerate the clinical application of MDM2 inhibitors. In conclusion, targeting MDM2 remains a promising treatment approach, and targeting MDM2 for protein degradation represents a novel strategy to downregulate MDM2 without the side effects of the existing agents blocking p53-MDM2 binding. Additional preclinical and clinical investigations are needed to finally realize the full potential of MDM2 inhibition in treating cancer and other chronic diseases where MDM2 has been implicated. SIGNIFICANCE STATEMENT: Overexpression/amplification of the MDM2 oncogene has been detected in various human cancers and is associated with disease progression, treatment resistance, and poor patient outcomes. This article reviews the previous, current, and emerging MDM2-targeted therapies and summarizes the preclinical and clinical studies combining MDM2 inhibitors with chemotherapy and immunotherapy regimens. The findings of these contemporary studies may lead to safer and more effective treatments for patients with cancers overexpressing MDM2.
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Antineoplásicos , Neoplasias , Proteínas Proto-Oncogênicas c-mdm2 , Humanos , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Animais , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Terapia de Alvo MolecularRESUMO
Adaptive behavior relies both on specific rules that vary across situations and stable long-term knowledge gained from experience. The frontoparietal control network (FPCN) is implicated in the brain's ability to balance these different influences on action. Here, we investigate how the topographical organization of the cortex supports behavioral flexibility within the FPCN. Functional properties of this network might reflect its juxtaposition between the dorsal attention network (DAN) and the default mode network (DMN), two large-scale systems implicated in top-down attention and memory-guided cognition, respectively. Our study tests whether subnetworks of FPCN are topographically proximal to the DAN and the DMN, respectively, and how these topographical differences relate to functional differences: the proximity of each subnetwork is anticipated to play a pivotal role in generating distinct cognitive modes relevant to working memory and long-term memory. We show that FPCN subsystems share multiple anatomical and functional similarities with their neighboring systems (DAN and DMN) and that this topographical architecture supports distinct interaction patterns that give rise to different patterns of functional behavior. The FPCN acts as a unified system when long-term knowledge supports behavior but becomes segregated into discrete subsystems with different patterns of interaction when long-term memory is less relevant. In this way, our study suggests that the topographical organization of the FPCN and the connections it forms with distant regions of cortex are important influences on how this system supports flexible behavior.
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Encéfalo , Rede Nervosa , Humanos , Masculino , Feminino , Adulto , Rede Nervosa/fisiologia , Rede Nervosa/diagnóstico por imagem , Encéfalo/fisiologia , Imageamento por Ressonância Magnética , Atenção/fisiologia , Adulto Jovem , Rede de Modo Padrão/fisiologia , Rede de Modo Padrão/diagnóstico por imagem , Memória de Longo Prazo/fisiologia , Mapeamento Encefálico/métodos , Lobo Parietal/fisiologia , Memória de Curto Prazo/fisiologiaRESUMO
Hydroxytryptophan serves as a chemical precursor to a variety of bioactive specialized metabolites, including the human neurotransmitter serotonin and the hormone melatonin. Although the human and animal routes to hydroxytryptophan have been known for decades, how bacteria catalyze tryptophan indole hydroxylation remains a mystery. Here we report a class of tryptophan hydroxylases that are involved in various bacterial metabolic pathways. These enzymes utilize a histidine-ligated heme cofactor and molecular oxygen or hydrogen peroxide to catalyze regioselective hydroxylation on the tryptophan indole moiety, which is mechanistically distinct from their animal counterparts from the nonheme iron enzyme family. Through genome mining, we also identify members that can hydroxylate the tryptophan indole ring at alternative positions. Our results not only reveal a conserved way to synthesize hydroxytryptophans in bacteria but also provide a valuable enzyme toolbox for biocatalysis. As proof of concept, we assemble a highly efficient pathway for melatonin in a bacterial host.
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5-Hidroxitriptofano , Melatonina , Animais , Humanos , Triptofano/metabolismo , Heme/química , Bactérias/metabolismoRESUMO
Cochlear hair cells (HCs) in the inner ear are responsible for sound detection. For HC fate specification, the master transcription factor Atoh1 is both necessary and sufficient. Atoh1 expression is dynamic and tightly regulated during development, but the cis-regulatory elements mediating this regulation remain unresolved. Unexpectedly, we found that deleting the only recognized Atoh1 enhancer, defined here as Eh1, failed to impair HC development. By using the assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq), we discovered two additional Atoh1 enhancers: Eh2 and Eh3. Notably, Eh2 deletion was sufficient for impairing HC development, and concurrent deletion of Eh1 and Eh2 or all three enhancers resulted in nearly complete absence of HCs. Lastly, we showed that Atoh1 binds to all three enhancers, consistent with its autoregulatory function. Our findings reveal that the cooperative action of three distinct enhancers underpins effective Atoh1 regulation during HC development, indicating potential therapeutic approaches for HC regeneration.
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Fatores de Transcrição Hélice-Alça-Hélice Básicos , Orelha Interna , Elementos Facilitadores Genéticos , Células Ciliadas Auditivas , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/fisiologia , Diferenciação Celular , Cóclea/citologia , Orelha Interna/citologia , Células Ciliadas Auditivas/fisiologiaRESUMO
Deciphering the functional architecture that underpins diverse cognitive functions is fundamental quest in neuroscience. In this study, we employed an innovative machine learning framework that integrated cognitive ontology with functional connectivity analysis to identify brain networks essential for cognition. We identified a core assembly of functional connectomes, primarily located within the association cortex, which showed superior predictive performance compared to two conventional methods widely employed in previous research across various cognitive domains. Our approach achieved a mean prediction accuracy of 0.13 across 16 cognitive tasks, including working memory, reading comprehension, and sustained attention, outperforming the traditional methods' accuracy of 0.08. In contrast, our method showed limited predictive power for sensory, motor, and emotional functions, with a mean prediction accuracy of 0.03 across 9 relevant tasks, slightly lower than the traditional methods' accuracy of 0.04. These cognitive connectomes were further characterized by distinctive patterns of resting-state functional connectivity, structural connectivity via white matter tracts, and gene expression, highlighting their neurogenetic underpinnings. Our findings reveal a domain-general functional network fingerprint that pivotal to cognition, offering a novel computational approach to explore the neural foundations of cognitive abilities.
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Structural motifs containing nitrogen-nitrogen (N-N) bonds are prevalent in a large number of clinical drugs and bioactive natural products. Hydrazine (N2H4) serves as a widely utilized building block for the preparation of these N-N-containing molecules in organic synthesis. Despite its common use in chemical processes, no enzyme has been identified to catalyze the incorporation of free hydrazine in natural product biosynthesis. Here, we report that a hydrazine transferase catalyzes the condensation of N2H4 and an aromatic polyketide pathway intermediate, leading to the formation of a rare N-aminolactam pharmacophore in the biosynthesis of broad-spectrum antibiotic albofungin. These results expand the current knowledge on the biosynthetic mechanism for natural products with N-N units and should facilitate future development of biocatalysts for the production of N-N-containing chemicals.
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Hidrazinas , Hidrazinas/química , Hidrazinas/metabolismo , Antibacterianos/química , Antibacterianos/biossíntese , Antibacterianos/farmacologia , Streptomyces/enzimologia , Streptomyces/metabolismo , Lactamas/química , Lactamas/metabolismo , FarmacóforoRESUMO
Polyvinyl alcohol (PVA) with abundant hydroxyl groups (-OH) has been widely used for membranes, hydrogels, and films, and its function is largely affected by the alcoholysis degree. Therefore, the development of rapid and accurate methods for alcoholysis degree determination in PVAs is important. In this contribution, we have proposed a novel fluorescence-based platform for probing the alcoholysis degree of PVA by using the (E)-N-(4-methoxyphenyl)-1-(quinolin-2-yl)methanimine (QPM)-Zn2+ complex as the reporter. The mechanism study disclosed that the strong coordination between -OH and Zn2+ induced the capture of the QPM-Zn2+ complex and promoted its subsequent immobilization into the noncrystalline area. The immobilization of the QPM-Zn2+ complex restricted its molecular rotation and reduced the nonirradiative transition, thus yielding bright emissions. In addition, the practical applications of this proposed method were further validated by the accurate alcoholysis degree determination of blind PVA samples with the confirmation of the National Standard protocol. It is expected that the developed fluorescence approach in this work might become an admissive strategy for screening the alcoholysis degree of PVA.
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Zero thermal coefficients of resistivity (ZTCR) materials exhibit minimal changes in resistance with temperature variations, making them essential in modern advanced technologies. The current ZTCR materials, which are based on the resistivity saturation effect of heavy metals, tend to function at elevated temperatures because the mean free path approaches the lower limit of the semiclassical Boltzmann theory when the temperature is sufficiently high. ZTCR materials working at low-temperatures are difficult to achieve due to electron-phonon scattering, which results in increased resistivity according to Bloch's theory. In this work, the ZTCR behavior at low-temperatures is realized in pre-microstrained Mn3NiN. The delicate balance between the resistivity contribution from electron-phonon scattering and spin-wave mediated weak localization is well revealed. A remarkable temperature coefficient of resistivity (TCR) value as low as 1.9 ppm K-1 (50 K ≤ T ≤ 200 K) is obtained, which is significantly superior to the threshold value of ZTCR behavior and the application standard of commercial ZTCR materials. The demonstration provides a unique paradigm in the design of ZTCR materials through the contraction effects of two opposite conductance mechanisms with positive and negative thermal coefficients of resistivity.
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Developing synergistic targeted therapeutics to improve treatment efficacy while reducing side effects has proven promising for anticancer therapies, but how to conveniently modulate multidrug cooperation remains a challenge. Here, a novel synergistic strategy using a G-quadruplex-programmed versatile nanorobot (G4VN) containing two subunits of DNAzyme (DzG4) and ligand-drug conjugates (LDCs) is proposed to precisely target tumors and then execute both gene silencing and chemotherapy. As the core module of this nanorobot, a well-designed G4 responding to a high level of K+ in tumor microenvironment smartly kills three birds with one stone, which makes two TfR aptamers proximate to improve their efficiency of targeting tumor cells, and in situ activates a split 10-23 DNAzyme to downregulate target mRNA expression, meanwhile promotes the cell uptake of a GSH-responsive LDCs to enhance drug efficacy. Such a design enables a potently synergistic anticancer therapy with low side effects in vivo, showing great promise for broad applications in precision disease treatment.
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Constructing concentration differences between anions and cations at the ends of an ionic conductor is an effective strategy in electricity generation for powering wearable devices. Temperature gradient or salinity gradient is the driving force behind such devices. But their corresponding power generation devices are greatly limited in actual application due to their complex structure and harsh application conditions. In this study, a novel ionic concentration gradient electric generator based on the evaporation difference of the electrolyte is proposed. The device can be constructed without the need for semipermeable membranes, and operation does not need to build a temperature difference. As a demonstration, a PVA-Na ionic hydrogel is prepared as an electrolyte for the device and achieved a thermovoltage of more than 200 mV and an energy density of 77.94 J m-2 at 323 K. Besides, the device exhibits the capability to sustain a continuous voltage output for a duration exceeding 1500 min, as well as enabling charging and discharging cycles for 100 iterations. For practical applications, a module comprising 16 sub-cells is constructed and successfully utilized to directly power a light-emitting diode. Wearable devices and their corresponding cell modules are also developed to recycle body heat.
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In this study, the copper-nickel (Cu-Ni) bimetallic electrocatalysts for electrochemical CO2 reduction reaction(CO2RR) are fabricated by taking the finely designed poly(ionic liquids) (PIL) containing abundant Salen and imidazolium chelating sites as the surficial layer, wherein Cu-Ni, PIL-Cu and PIL-Ni interaction can be readily regulated by different synthetic scheme. As a proof of concept, Cu@Salen-PIL@Ni(NO3)2 and Cu@Salen-PIL(Ni) hybrids differ significantly in the types and distribution of Ni species and Cu species at the surface, thereby delivering distinct Cu-Ni cooperation fashion for the CO2RR. Remarkably, Cu@Salen-PIL@Ni(NO3)2 provides a C2+ faradaic efficiency (FEC2+) of 80.9% with partial current density (jC 2+) of 262.9 mA cm-2 at -0.80 V (versus reversible hydrogen electrode, RHE) in 1 m KOH in a flow cell, while Cu@Salen-PIL(Ni) delivers the optimal FEC2+ of 63.8% at jC2+ of 146.7 mA cm-2 at -0.78 V. Mechanistic studies indicates that the presence of Cu-Ni interfaces in Cu@Salen-PIL@Ni(NO3)2 accounts for the preserve of high-valence Cu(I) species under CO2RR conditions. It results in a high activity of both CO2-to-CO conversion and C-C coupling while inhibition of the competitive HER.
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The emerging evidence of human infections with emerging viruses suggests their potential public health importance. A novel taxon of viruses named Statoviruses (for stool-associated Tombus-like viruses) was recently identified in the gastrointestinal tracts of multiple mammals. Here we report the discovery of respiratory Statovirus-like viruses (provisionally named Restviruses) from the respiratory tracts of five patients experiencing acute respiratory disease with Human coronavirus OC43 infection through the retrospective analysis of meta-transcriptomic data. Restviruses shared 53.1%-98.8% identities of genomic sequences with each other and 39.9%-44.3% identities with Statoviruses. The phylogenetic analysis revealed that Restviruses together with a Stato-like virus from nasal-throat swabs of Vietnamese patients with acute respiratory disease, formed a well-supported clade distinct from the taxon of Statoviruses. However, the consistent genome characteristics of Restviruses and Statoviruses suggested that they might share similar evolutionary trajectories. These findings warrant further studies to elucidate the etiological and epidemiological significance of the emerging Restviruses.
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Genoma Viral , Filogenia , Infecções Respiratórias , Humanos , China/epidemiologia , Genoma Viral/genética , Infecções Respiratórias/virologia , Infecções Respiratórias/epidemiologia , Masculino , Feminino , Estudos Retrospectivos , Sistema Respiratório/virologia , Pré-Escolar , Adulto , Criança , RNA Viral/genética , Pessoa de Meia-IdadeRESUMO
BACKGROUND: ChatGPT is a novel and online large-scale language model used as a source providing up-to-date and useful health-related knowledges to patients and clinicians. However, its performance on Helicobacter pylori infection-related questions remain unknown. This study aimed to evaluate the accuracy of ChatGPT's responses on H. pylori-related questions compared with that of gastroenterologists during the same period. METHODS: Twenty-five H. pylori-related questions from five domains: Indication, Diagnostics, Treatment, Gastric cancer and prevention, and Gut Microbiota were selected based on the Maastricht VI Consensus report. Each question was tested three times with ChatGPT3.5 and ChatGPT4. Two independent H. pylori experts assessed the responses from ChatGPT, with discrepancies resolved by a third reviewer. Simultaneously, a nationwide survey with the same questions was conducted among 1279 gastroenterologists and 154 medical students. The accuracy of responses from ChatGPT3.5 and ChatGPT4 was compared with that of gastroenterologists. RESULTS: Overall, both ChatGPT3.5 and ChatGPT4 demonstrated high accuracy, with median accuracy rates of 92% for each of the three responses, surpassing the accuracy of nationwide gastroenterologists (median: 80%) and equivalent to that of senior gastroenterologists. Compared with ChatGPT3.5, ChatGPT4 provided more concise responses with the same accuracy. ChatGPT3.5 performed well in the Indication, Treatment, and Gut Microbiota domains, whereas ChatGPT4 excelled in Diagnostics, Gastric cancer and prevention, and Gut Microbiota domains. CONCLUSION: ChatGPT exhibited high accuracy and reproducibility in addressing H. pylori-related questions except the decision for H. pylori treatment, performing at the level of senior gastroenterologists and could serve as an auxiliary information tool for assisting patients and clinicians.
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Infecções por Helicobacter , Helicobacter pylori , Infecções por Helicobacter/diagnóstico , Infecções por Helicobacter/tratamento farmacológico , Infecções por Helicobacter/microbiologia , Humanos , Helicobacter pylori/efeitos dos fármacos , Inquéritos e Questionários , Masculino , Feminino , Adulto , Pessoa de Meia-IdadeRESUMO
Brain microvascular endothelial cells (BMECs), an important component of the neurovascular unit, can promote angiogenesis and synaptic formation in ischaemic mice after brain parenchyma transplantation. Since the therapeutic efficacy of cell-based therapies depends on the extent of transplanted cell residence in the target tissue and cell migration ability, the delivery route has become a hot research topic. In this study, we investigated the effects of carotid artery transplantation of BMECs on neuronal injury, neurorepair, and neurological dysfunction in rats after cerebral ischaemic attack. Purified passage 1 endothelial cells (P1-BMECs) were prepared from mouse brain tissue. Adult rats were subjected to transient middle cerebral artery occlusion (MCAO) for 30 min. Then, the rats were treated with 5 × 105 P1-BMECs through carotid artery infusion or tail vein injection. We observed that carotid artery transplantation of BMECs produced more potent neuroprotective effects than caudal injection in MCAO rats, including reducing infarct size and alleviating neurological deficits in behavioural tests. Carotid artery-transplanted BMECs displayed a wider distribution in the ischaemic rat brain. Immunostaining for endothelial progenitor cells and the mature endothelial cell markers CD34 and RECA-1 showed that carotid artery transplantation of BMECs significantly increased angiogenesis. Carotid artery transplantation of BMECs significantly increased the number of surviving neurons, decreased the cerebral infarction volume, and alleviated neurological deficits. In addition, we found that carotid artery transplantation of BMECs significantly enhanced ischaemia-induced hippocampal neurogenesis, as measured by doublecortin (DCX) and Ki67 double staining within 2 weeks after ischaemic injury. We conclude that carotid artery transplantation of BMECs can promote cerebral angiogenesis, neurogenesis, and neurological function recovery in adult rats after ischaemic stroke. Our results suggest that carotid injection of BMECs may be a promising new approach for treating acute brain injuries.
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Auditory language comprehension recruits cortical regions that are both close to sensory-motor landmarks (supporting auditory and motor features) and far from these landmarks (supporting word meaning). We investigated whether the responsiveness of these regions in task-based functional MRI is related to individual differences in their physical distance to primary sensorimotor landmarks. Parcels in the auditory network, that were equally responsive across story and math tasks, showed stronger activation in individuals who had less distance between these parcels and transverse temporal sulcus, in line with the predictions of the "tethering hypothesis," which suggests that greater proximity to input regions might increase the fidelity of sensory processing. Conversely, language and default mode parcels, which were more active for the story task, showed positive correlations between individual differences in activation and sensory-motor distance from primary sensory-motor landmarks, consistent with the view that physical separation from sensory-motor inputs supports aspects of cognition that draw on semantic memory. These results demonstrate that distance from sensorimotor regions provides an organizing principle of functional differentiation within the cortex. The relationship between activation and geodesic distance to sensory-motor landmarks is in opposite directions for cortical regions that are proximal to the heteromodal (DMN and language network) and unimodal ends of the principal gradient of intrinsic connectivity.
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Mapeamento Encefálico , Encéfalo , Humanos , Encéfalo/fisiologia , Mapeamento Encefálico/métodos , Distanciamento Físico , Imageamento por Ressonância Magnética/métodos , IdiomaRESUMO
The impact of the Coronavirus Disease 2019 (COVID-19) on society is continuous, resulting in negative psychological consequences. Given the vulnerability and sensitivity to the environment among preschool children, their emotional and behavioral problems deserve more attention. The current study aimed to explore the impact of the epidemic on preschool children's mental health by determining the pooled prevalence of emotional and behavioral problems amidst the Coronavirus Disease 2019 pandemic and to reveal potential reasons for variations between studies. Published studies were searched in Embase, PubMed, ProQuest, PsycINFO, Web of Science, CNKI, and Wanfang. Based on the inclusion criteria outlined in this study, a total of 10 studies encompassing 38,059 participants were incorporated. Employing a random-effect model for estimating the prevalence of emotional and behavioral problems, the results revealed a pooled prevalence rate of 24.3% (95% CI, 0.15-0.38; I²=99.9%) among preschool children. This rate surpasses the pre-outbreak prevalence observed in different countries, signifying a detrimental influence of the epidemic on the mental well-being of preschoolers. Therefore, mental health care and recovery are essential for the vulnerable group during and after the public health crisis. Specific emotional and behavioral problems among preschool children are expected to be researched in the future to provide more targeted guidance for intervention.
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COVID-19 , Humanos , COVID-19/psicologia , COVID-19/epidemiologia , Pré-Escolar , Transtornos do Comportamento Infantil/epidemiologia , Transtornos do Comportamento Infantil/psicologia , Prevalência , Comportamento Problema/psicologia , Sintomas Afetivos/epidemiologia , Sintomas Afetivos/psicologia , SARS-CoV-2RESUMO
PURPOSE: To propose a straightforward and time-efficient quality assurance (QA) approach of beam time delay for respiratory-gated radiotherapy and validate the proposed method on typical respiratory gating systems, Catalyst™ and AlignRT™. METHODS: The QA apparatus was composed of a motion platform and a Winston-Lutz cube phantom (WL3) embedded with metal balls. The apparatus was first scanned in CT-Sim and two types of QA plans specific for beam on and beam off time delay, respectively, were designed. Static reference images and motion testing images of the WL3 cube were acquired with EPID. By comparing the position differences of the embedded metal balls in the motion and reference images, beam time delays were determined. The proposed approach was validated on three linacs with either Catalyst™ or AlignRT™ respiratory gating systems. To investigate the impact of energy and dose rate on beam time delay, a range of QA plans with Eclipse (V15.7) were devised with varying energy and dose rates. RESULTS: For all energies, the beam on time delays in AlignRT™ V6.3.226, AlignRT™ V7.1.1, and Catalyst™ were 92.13 ± $ \pm $ 5.79 ms, 123.11 ± $ \pm $ 6.44 ms, and 303.44 ± $ \pm $ 4.28 ms, respectively. The beam off time delays in AlignRT™ V6.3.226, AlignRT™ V7.1.1, and Catalyst™ were 121.87 ± $ \pm $ 1.34 ms, 119.33 ± $ \pm $ 0.75 ms, and 97.69 ± $ \pm $ 2.02 ms, respectively. Furthermore, the beam on delays decreased slightly as dose rates increased for all gating systems, whereas the beam off delays remained unaffected. CONCLUSIONS: The validation results demonstrate the proposed QA approach of beam time delay for respiratory-gated radiotherapy was both reproducible and time-efficient to practice for institutions to customize accordingly.
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Imagens de Fantasmas , Garantia da Qualidade dos Cuidados de Saúde , Dosagem Radioterapêutica , Planejamento da Radioterapia Assistida por Computador , Radioterapia de Intensidade Modulada , Humanos , Planejamento da Radioterapia Assistida por Computador/métodos , Radioterapia de Intensidade Modulada/métodos , Garantia da Qualidade dos Cuidados de Saúde/normas , Aceleradores de Partículas/instrumentação , Respiração , Técnicas de Imagem de Sincronização Respiratória/métodos , Neoplasias/radioterapia , Fatores de TempoRESUMO
Extracellular matrix metalloproteinase inducer (EMMPRIN) plays critical roles in the regulation of inflammation and bone metabolism. The roles of EMMPRIN signaling in osteoclasts are worthy of deep study. The present study aimed to investigate bone resorption in periodontitis through the intervention of EMMPRIN signaling. The distribution of EMMPRIN in human periodontitis was observed. RANKL-induced osteoclast differentiation of mouse bone marrow-derived macrophages (BMMs) were treated with EMMPRIN inhibitor in vitro. Rats with ligation-induced periodontitis were treated with EMMPRIN inhibitor and harvested for microcomputed tomography scanning, histologic observation, immunohistochemistry, and double immunofluorescence analysis. Positive expressions of EMMPRIN could be found in the CD68+-infiltrating cells. Downregulated EMMPRIN restrained osteoclast differentiation of BMMs in vitro, which also inhibited MMP-9 expression (*P < 0.05). In vivo, EMMPRIN inhibitor restrained ligation-induced bone resorption by decreasing tartrate-resistant acid phosphatase-positive osteoclasts. Both EMMPRIN-positive and MMP-9-positive osteoclasts were less common in the EMMPRIN inhibitor groups than in the control groups. Intervention of EMMPRIN signaling in osteoclasts could probably provide a potential therapeutic target for attenuating ligation-induced bone resorption.
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Reabsorção Óssea , Periodontite , Camundongos , Ratos , Humanos , Animais , Osteoclastos , Basigina/análise , Basigina/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Microtomografia por Raio-X , Reabsorção Óssea/patologia , Periodontite/patologia , Ligante RANK , Diferenciação CelularRESUMO
Chinese young adults (CYA), who are at an increasing risk of developing nonalcoholic fatty liver disease (NAFLD), which in turn increases the risk of liver cancer, are an ideal target population to deliver educational interventions to improve their awareness and knowledge of NAFLD and consequently reduce their risk of developing NAFLD. The purpose of this study was to determine the efficacy of two interventions to improve awareness and knowledge of NAFLD among CYA for the prevention of liver cancer. Between May and July 2021, 1373 undergraduate students aged 18 to 25 years in one university in China completed a web-based, self-administered survey distributed through WeChat app. One week after completion of the baseline survey, all eligible participants were randomly assigned to a pamphlet, a video intervention, or no intervention (control group), with follow-up assessments immediately and 1-month post-intervention. The 7-page pamphlet or 6.5-min video had information on NAFLD. Self-assessments included NAFLD awareness, lean NAFLD awareness, and knowledge scores of NAFLD. About 26% of participants had NAFLD awareness at baseline. Compared with controls, participants in both interventions showed significant improvement of awareness of NAFLD (pamphlet, + 46.0%; video, + 44.3%; control, + 18.7%; OR [95% CI], 3.13 [2.19-4.47] and 2.84 [1.98-4.08]), awareness of lean NAFLD (pamphlet, + 41.2%; video, + 43.0%; control, + 14.5%; OR [95% CI], 2.84 [1.62-4.99] and 2.61 [1.50-4.54]), and knowledge score of NAFLD (pamphlet, + 64.2%; video, + 68.9%; control, - 1.0%; OR [95% CI], 1.62 [1.47-1.80] and 1.67 [1.50-1.86]) at immediately post-intervention. Delivering NAFLD education through a pamphlet or video intervention was effective in improving the awareness and knowledge of NAFLD among CYA.
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Conhecimentos, Atitudes e Prática em Saúde , Neoplasias Hepáticas , Hepatopatia Gordurosa não Alcoólica , Humanos , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Masculino , Feminino , Adulto Jovem , Adulto , Adolescente , China , Neoplasias Hepáticas/prevenção & controle , Folhetos , Educação em Saúde , Inquéritos e Questionários , Estudantes/psicologia , População do Leste AsiáticoRESUMO
Upon pathogenic stimulation, activated neutrophils release nuclear DNA into the extracellular environment, forming web-like DNA structures known as neutrophil extracellular traps (NETs), which capture and kill bacteria, fungi, and cancer cells. This phenomenon is commonly referred to as NETosis. Inspired by this, we introduce a cell surface-constrained web-like framework nucleic acids traps (FNATs) with programmable extracellular recognition capability and cellular behavior modulation. This approach facilitates dynamic key chemical signaling molecule recognition such as adenosine triphosphate (ATP), which is elevated in the extracellular microenvironment, and triggers FNA self-assembly. This, in turn, leads to in situ tightly interwoven FNAs formation on the cell surface, thereby inhibiting target cell migration. Furthermore, it activates a photosensitizer-capturing switch, chlorin e6 (Ce6), and induces cell self-destruction. This cascade platform provides new potential tools for visualizing dynamic extracellular activities and manipulating cellular behaviors using programmable in situ self-assembling DNA molecular devices.