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Two-terminal monolithic perovskite-silicon tandem solar cells demonstrate huge advantages in power conversion efficiency (PCE) compared to their respective single-junction counterparts1,2. However, suppressing interfacial recombination at the wide-bandgap perovskite/electron transport layer interface, without compromising its superior charge transport performance, remains a significant challenge for perovskite-silicon tandem cells3,4. By exploiting the nanoscale discretely distributed LiF ultrathin layer followed by an additional deposition of diammonium diiodide molecule, we have devised a bilayer intertwined passivation strategy that combines efficient electron extraction with further suppression of nonradiative recombination. We constructed perovskite-silicon tandem devices on double-side textured Czochralski (CZ)-based silicon heterojunction cell, which featured a mildly-textured front surface and a heavily-textured rear surface, leading to simultaneously enhanced photocurrent and uncompromised rear passivation. The resulting perovskite-silicon tandem achieved an independently certified stabilized PCE of 33.89%, accompanied by an impressive fill factor (FF) of 83.0% and an open-circuit voltage (Voc) of nearly 1.97 volts. To our knowledge, this represents the first reported certified efficiency of a two-junction tandem solar cell exceeding the single-junction Shockley-Queisser limit of 33.7%.
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Sex is determined by multiple factors derived from somatic and germ cells in vertebrates. We have identified amhy, dmrt1, gsdf as male and foxl2, foxl3, cyp19a1a as female sex determination pathway genes in Nile tilapia. However, the relationship among these genes is largely unclear. Here, we found that the gonads of dmrt1;cyp19a1a double mutants developed as ovaries or underdeveloped testes with no germ cells irrespective of their genetic sex. In addition, the gonads of dmrt1;cyp19a1a;cyp19a1b triple mutants still developed as ovaries. The gonads of foxl3;cyp19a1a double mutants developed as testes, while the gonads of dmrt1;cyp19a1a;foxl3 triple mutants eventually developed as ovaries. In contrast, the gonads of amhy;cyp19a1a, gsdf;cyp19a1a, amhy;foxl2, gsdf;foxl2 double and amhy;cyp19a1a;cyp19a1b, gsdf;cyp19a1a;cyp19a1b triple mutants developed as testes with spermatogenesis via up-regulation of dmrt1 in both somatic and germ cells. The gonads of amhy;foxl3 and gsdf;foxl3 double mutants developed as ovaries but with germ cells in spermatogenesis due to up-regulation of dmrt1. Taking the respective ovary and underdeveloped testis of dmrt1;foxl3 and dmrt1;foxl2 double mutants reported previously into consideration, we demonstrated that once dmrt1 mutated, the gonad could not be rescued to functional testis by mutating any female pathway gene. The sex reversal caused by mutation of male pathway genes other than dmrt1, including its upstream amhy and downstream gsdf, could be rescued by mutating female pathway gene. Overall, our data suggested that dmrt1 is the only male pathway gene tested indispensable for sex determination and functional testis development in tilapia.
Assuntos
Processos de Determinação Sexual , Tilápia , Animais , Feminino , Masculino , Regulação da Expressão Gênica no Desenvolvimento , Gônadas/metabolismo , Ovário/metabolismo , Processos de Determinação Sexual/genética , Diferenciação Sexual/genética , Testículo/metabolismo , Tilápia/genéticaRESUMO
Plasmodium falciparum multidrug resistance protein 1 (PfMDR1), an adenosine triphosphate (ATP)-binding cassette (ABC) transporter on the digestive vacuole (DV) membrane of the parasite, is associated with the resistance to antimalarial drugs. To understand the mechanisms of PfMDR1, we determined the cryo-electron microscopy structures of this transporter in different states. The transporter in the apo state shows an inward-facing conformation with a large cavity opening to the cytoplasm. Upon ATP binding and dimerization of the nucleotide-binding domains (NBDs), PfMDR1 displays an outward-facing conformation with a cavity toward the DV lumen. Drug resistance-associated mutations were investigated in both structures for their effects, and Y184F was identified as an allosteric activity-enhancing mutation. The amphiphilic substrate-binding site of PfMDR1 was revealed by the complex structure with the antimalarial drug mefloquine and confirmed by mutagenesis studies. Remarkably, a helical structure was found to hinder NBD dimerization and inhibit PfMDR1 activity. The location of this regulatory domain in the N terminus is different from the well-studied R domain in the internal linker region of other ABC transporter family members. The lack of the phosphorylation site of this domain also suggests a different regulation mechanism.
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Antimaláricos , Malária Falciparum , Humanos , Plasmodium falciparum , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/química , Microscopia Crioeletrônica , Antimaláricos/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Transportadores de Cassetes de Ligação de ATP/metabolismo , Trifosfato de Adenosina/metabolismo , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Resistência a Medicamentos/genética , Malária Falciparum/parasitologiaRESUMO
The identification of drug-target interactions (DTI) is a valuable step in the drug discovery and repositioning process. However, traditional laboratory experiments are time-consuming and expensive. Computational methods have streamlined research to determine DTIs. The application of deep learning methods has significantly improved the prediction performance for DTIs. Modern deep learning methods can leverage multiple sources of information, including sequence data that contains biological structural information, and interaction data. While useful, these methods cannot be effectively applied to each type of information individually (e.g., chemical structure and interaction network) and do not take into account the specificity of DTI data such as low- or zero-interaction biological entities. To overcome these limitations, we propose a method called MFA-DTI (Multi-feature Fusion Adopted framework for DTI). MFA-DTI consists of three modules: an interaction graph learning module that processes the interaction network to generate interaction vectors, a chemical structure learning module that extracts features from the chemical structure, and a fusion module that combines these features for the final prediction. To validate the performance of MFA-DTI, we conducted experiments on six public datasets under different settings. The results indicate that the proposed method is highly effective in various settings and outperforms state-of-the-art methods.
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Descoberta de Drogas , Laboratórios , Interações MedicamentosasRESUMO
Small muscular pulmonary artery remodeling is a dominant feature of pulmonary arterial hypertension (PAH). PSEN1 affects angiogenesis, cancer, and Alzheimer's disease. We aimed to determine the role of PSEN1 in the pathogenesis of vascular remodeling in pulmonary hypertension (PH). Hemodynamics and vascular remodeling in the Psen1-knockin and smooth muscle-specific Psen1-knockout mice were assessed. The functional partners of PSEN1 were predicted by bioinformatics analysis and biochemical experiments. The therapeutic effect of PH was evaluated by administration of the PSEN1-specific inhibitor ELN318463. We discovered that both the mRNA and protein levels of PSEN1 were increased over time in hypoxic rats, monocrotaline rats, and Su5416/hypoxia mice. Psen1 transgenic mice were highly susceptible to PH, whereas smooth muscle-specific Psen1-knockout mice were resistant to hypoxic PH. STRING analysis showed that Notch1/2/3, ß-catenin, Cadherin-1, DNER (delta/notch-like epidermal growth factor-related receptor), TMP10, and ERBB4 appeared to be highly correlated with PSEN1. Immunoprecipitation confirmed that PSEN1 interacts with ß-catenin and DNER, and these interactions were suppressed by the catalytic PSEN1 mutations D257A, D385A, and C410Y. PSEN1 was found to mediate the nuclear translocation of the Notch1 intracellular domains and activated RBP-Jκ. Octaarginine-coated liposome-mediated pharmacological inhibition of PSEN1 significantly prevented and reversed the pathological process in hypoxic and monocrotaline-induced PH. PSEN1 essentially drives the pathogenesis of PAH and interacted with the noncanonical Notch ligand DNER. PSEN1 can be used as a promising molecular target for treating PAH. PSEN1 inhibitor ELN318463 can prevent and reverse the progression of PH and can be developed as a potential anti-PAH drug.
Assuntos
Hipertensão Pulmonar , Presenilina-1 , Remodelação Vascular , Animais , Remodelação Vascular/efeitos dos fármacos , Presenilina-1/genética , Presenilina-1/metabolismo , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/patologia , Ratos , Camundongos , Camundongos Knockout , Ratos Sprague-Dawley , Masculino , Pirróis/farmacologia , Humanos , Hipóxia/metabolismo , Monocrotalina , Artéria Pulmonar/metabolismo , Artéria Pulmonar/patologia , Artéria Pulmonar/efeitos dos fármacos , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , IndóisRESUMO
BACKGROUND: Circular RNAs are highly stable regulatory RNAs that have been increasingly associated with tumorigenesis and progression. However, the role of many circRNAs in triple-negative breast cancer (TNBC) and the related mechanisms have not been elucidated. METHODS: In this study, we screened circRNAs with significant expression differences in the RNA sequencing datasets of TNBC and normal breast tissues and then detected the expression level of circRPPH1 by qRTâPCR. The biological role of circRPPH1 in TNBC was then verified by in vivo and in vitro experiments. Mechanistically, we verified the regulatory effects between circRPPH1 and ZNF460 and between circRPPH1 and miR-326 by chromatin immunoprecipitation (ChIP), fluorescence in situ hybridization assay, dual luciferase reporter gene assay and RNA pull-down assay. In addition, to determine the expression of associated proteins, we performed immunohistochemistry, immunofluorescence, and western blotting. RESULTS: The upregulation of circRPPH1 in TNBC was positively linked with a poor prognosis. Additionally, both in vivo and in vitro, circRPPH1 promoted the biologically malignant behavior of TNBC cells. Additionally, circRPPH1 may function as a molecular sponge for miR-326 to control integrin subunit alpha 5 (ITGA5) expression and activate the focal adhesion kinase (FAK)/PI3K/AKT pathway. CONCLUSION: Our research showed that ZNF460 could promote circRPPH1 expression and that the circRPPH1/miR-326/ITGA5 axis could activate the FAK/PI3K/AKT pathway to promote the progression of TNBC. Therefore, circRPPH1 can be used as a therapeutic or diagnostic target for TNBC.
Assuntos
MicroRNAs , Fatores de Transcrição , Neoplasias de Mama Triplo Negativas , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Endógeno Competitivo , Proteína-Tirosina Quinases de Adesão Focal/genética , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Fosfatidilinositol 3-Quinases/metabolismo , RNA Circular/genética , Hibridização in Situ Fluorescente , Linhagem Celular Tumoral , Integrinas/metabolismo , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Movimento Celular/genética , Proteínas de Ligação a DNA/metabolismoRESUMO
Germline sexual fate has long been believed to be determined by the somatic environment, but this idea is challenged by recent studies of foxl3 mutants in medaka. Here, we demonstrate that the sexual fate of tilapia germline is determined by the antagonistic interaction of dmrt1 and foxl3, which are transcriptionally repressed in male and female germ cells, respectively. Loss of dmrt1 rescued the germ cell sex reversal in foxl3Δ7/Δ7 XX fish, and loss of foxl3 partially rescued germ cell sex reversal but not somatic cell fate in dmrt1Δ5/Δ5 XY fish. Interestingly, germ cells lost sexual plasticity in dmrt1Δ5/Δ5 XY and foxl3Δ7/Δ7 XX single mutants, as aromatase inhibitor (AI) and estrogen treatment failed to rescue the respective phenotypes. However, recovery of germ cell sexual plasticity was observed in dmrt1/foxl3 double mutants. Importantly, mutation of somatic cell-specific foxl2 resulted in testicular development in foxl3Δ7/Δ7 or dmrt1Δ5/Δ5 mutants. Our findings demonstrate that sexual plasticity of germ cells relies on the presence of both dmrt1 and foxl3. The existence of dmrt1 and foxl3 allows environmental factors to influence the sex fate decision in vertebrates.
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Ciclídeos , Proteínas de Peixes , Proteína Forkhead Box L2 , Processos de Determinação Sexual , Diferenciação Sexual , Fatores de Transcrição , Animais , Ciclídeos/embriologia , Ciclídeos/genética , Feminino , Proteínas de Peixes/genética , Proteínas de Peixes/metabolismo , Proteína Forkhead Box L2/genética , Proteína Forkhead Box L2/metabolismo , Masculino , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
BACKGROUND: Sphaeropteris brunoniana and Alsophila latebrosa are both old relict and rare tree ferns, which have experienced the constant changes of climate and environment. However, little is known about their high-quality genetic information and related research on environmental adaptation mechanisms of them. In this study, combined with PacBio and Illumina platforms, transcriptomic analysis was conducted on the roots, rachis, and pinna of S. brunoniana and A. latebrosa to identify genes and pathways involved in environmental adaptation. Additionally, based on the transcriptomic data of tree ferns, chloroplast genes were mined to analyze their gene expression levels and RNA editing events. RESULTS: In the study, we obtained 11,625, 14,391 and 10,099 unigenes of S. brunoniana root, rachis, and pinna, respectively. Similarly, a total of 13,028, 11,431 and 12,144 unigenes were obtained of A. latebrosa root, rachis, and pinna, respectively. According to the enrichment results of differentially expressed genes, a large number of differentially expressed genes were enriched in photosynthesis and secondary metabolic pathways of S. brunoniana and A. latebrosa. Based on gene annotation results and phenylpropanoid synthesis pathways, two lignin synthesis pathways (H-lignin and G-lignin) were characterized of S. brunoniana. Among secondary metabolic pathways of A. latebrosa, three types of WRKY transcription factors were identified. Additionally, based on transcriptome data obtained in this study, reported transcriptome data, and laboratory available transcriptome data, positive selection sites were identified from 18 chloroplast protein-coding genes of four tree ferns. Among them, RNA editing was found in positive selection sites of four tree ferns. RNA editing affected the protein secondary structure of the rbcL gene. Furthermore, the expression level of chloroplast genes indicated high expression of genes related to the chloroplast photosynthetic system in all four species. CONCLUSIONS: Overall, this work provides a comprehensive transcriptome resource of S. brunoniana and A. latebrosa, laying the foundation for future tree fern research.
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Gleiquênias , Gleiquênias/genética , Transcriptoma , RNA de Cloroplastos , Metabolismo Secundário , Edição de RNA/genética , Lignina , Perfilação da Expressão Gênica , Cloroplastos/genéticaRESUMO
INTRODUCTION: Portal hypertension progression can be relieved after controlling the etiology of liver cirrhosis. Whether beta-blockers could additionally enhance the effects during treatment, particularly for small esophageal varices (EV), was unclear. This study aims to assess the efficacy of add-on carvedilol to delay EV progression during anti-hepatitis B virus (HBV) treatment in HBV-related cirrhosis. METHODS: This randomized controlled trial enrolled patients with virologically suppressed HBV-compensated cirrhosis and small/medium EV. The participants were randomly assigned to receive nucleos(t)ide analog (NUC) or carvedilol 12.5 mg plus NUC (1:1 allocation ratio). The primary end point was the progression rate of EV at 2 years of follow-up. RESULTS: A total of 238 patients (small EV, 77.3%) were randomized into 119 NUC and 119 carvedilol plus NUC (carvedilol [CARV] combination group). Among them, 205 patients (86.1%) completed paired endoscopies. EV progression rate was 15.5% (16/103) in the NUC group and 12.7% (13/102) in the CARV combination group (relative risk = 0.79, 95% confidence interval 0.36-1.75, P = 0.567). Subgroup analysis on medium EV showed the CARV combination group had a more favorable effect in promoting EV regression (43.5% vs 13.1%, P = 0.022) than NUC alone, but not in small cases ( P = 0.534). The incidence of liver-related events (decompensation, hepatocellular carcinoma, or death/liver transplantation) within 2 years was similar between the 2 groups (11.2% vs 10.4%, P = 0.881). DISCUSSION: The overall results did not show statistically significant differences between the added carvedilol strategy and NUC monotherapy in preventing EV progression in patients with virologically suppressed HBV-compensated cirrhosis. However, the carvedilol-added approach might offer improved outcomes specifically for patients with medium EV (NCT03736265).
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Vírus da Hepatite B , Neoplasias Hepáticas , Humanos , Carvedilol/uso terapêutico , Antivirais/uso terapêutico , Cirrose Hepática/tratamento farmacológicoRESUMO
Understanding the signals from the physical microenvironment is critical for deciphering the processes of neurogenesis and neurodevelopment. The discovery of how surrounding physical signals shape human developing neurons is hindered by the bottleneck of conventional cell culture and animal models. Notwithstanding neural organoids provide a promising platform for recapitulating human neurogenesis and neurodevelopment, building neuronal physical microenvironment that accurately mimics the native neurophysical features is largely ignored in current organoid technologies. Here, it is discussed how the physical microenvironment modulates critical events during the periods of neurogenesis and neurodevelopment, such as neural stem cell fates, neural tube closure, neuronal migration, axonal guidance, optic cup formation, and cortical folding. Although animal models are widely used to investigate the impacts of physical factors on neurodevelopment and neuropathy, the important roles of human stem cell-derived neural organoids in this field are particularly highlighted. Considering the great promise of human organoids, building neural organoid microenvironments with mechanical forces, electrophysiological microsystems, and light manipulation will help to fully understand the physical cues in neurodevelopmental processes. Neural organoids combined with cutting-edge techniques, such as advanced atomic force microscopes, microrobots, and structural color biomaterials might promote the development of neural organoid-based research and neuroscience.
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Células-Tronco Neurais , Neurogênese , Animais , Humanos , Organoides , Neurônios , Técnicas de Cultura de Células , Encéfalo/fisiologiaRESUMO
Transdermal drug delivery systems based on physical principles have provided a stable, efficient, and safe strategy for disease therapy. However, the intelligent device with real-time control and precise drug release is required to enhance treatment efficacy and improve patient compliance. This review summarizes the recent developments, application scenarios, and drug release characteristics of smart transdermal drug delivery systems fabricated with physical principle. Special attention is paid to the progress of intelligent design and concepts in of physical-based transdermal drug delivery technologies for real-time monitoring and precise drug release. In addition, facing with the needs of clinical treatment and personalized medicine, the recent progress and trend of physical enhancement are further highlighted for transdermal drug delivery systems in combination with pharmaceutical dosage forms to achieve better transdermal effects and facilitate the development of smart medical devices. Finally, the next generation and future application scenarios of smart physical-based transdermal drug delivery systems are discussed, a particular focus in vaccine delivery and tumor treatment.
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Inteligência , Medicina de Precisão , Humanos , Preparações de Ação Retardada , Liberação Controlada de FármacosRESUMO
Acyl-CoA-Binding Proteins (ACBPs) bind acyl-CoA esters and function in lipid metabolism. Although acbp3-1, the ACBP3 mutant in Arabidopsis thaliana ecotype Col-0, displays normal floral development, the acbp3-2 mutant from ecotype Ler-0 characterized herein exhibits defective adaxial anther lobes and improper sporocyte formation. To understand these differences and identify the role of ERECTA in ACBP3 function, the acbp3 mutants and acbp3-erecta (er) lines were analyzed by microscopy for anther morphology and high-performance liquid chromatography for lipid composition. Defects in Landsberg anther development were related to the ERECTA-mediated pathway because the progenies of acbp3-2 × La-0 and acbp3-1 × er-1 in Col-0 showed normal anthers, contrasting to that of acbp3-2 in Ler-0. Polymorphism in the regulatory region of ACBP3 enabled its function in anther development in Ler-0 but not Col-0 which harbored an AT-repeat insertion. ACBP3 expression and anther development in acbp3-2 were restored using ACBP3pro (Ler)::ACBP3 not ACBP3pro (Col)::ACBP3. SPOROCYTELESS (SPL), a sporocyte formation regulator activated ACBP3 transcription in Ler-0 but not Col-0. For anther development, the ERECTA-related role of ACBP3 is required in Ler-0, but not Col-0. The disrupted promoter regulatory region for SPL binding in Col-0 eliminates the role of ACBP3 in anther development.
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Alelos , Proteínas de Arabidopsis , Arabidopsis , Flores , Regulação da Expressão Gênica de Plantas , Regiões Promotoras Genéticas , Arabidopsis/genética , Arabidopsis/crescimento & desenvolvimento , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Inibidor da Ligação a Diazepam/metabolismo , Inibidor da Ligação a Diazepam/genética , Ecótipo , Flores/genética , Flores/crescimento & desenvolvimento , Mutação/genética , Fenótipo , Polimorfismo Genético , Regiões Promotoras Genéticas/genéticaRESUMO
BACKGROUND: The triglyceride-glucose (TyG) index is associated with the development and prognosis of coronary artery disease (CAD). However, the impact of the TyG index on CAD severity across different glucose metabolism states exhibits significant disparities in previous research. METHODS: This cross-sectional study comprised 10,433 participants from a prospective cohort. Participants were categorized into four groups based on glucose metabolism state: normal glucose regulation (NGR), prediabetes (pre-DM), diabetes mellitus (DM) without insulin prescribed (Rx), and DM with insulin Rx. The TyG index was determined by the following formula: Ln [TG (mg/dL) × FPG (mg/dL) / 2], where TG is triglycerides and FPG is fasting plasm glucose. Statistical methods such as binary logistic regression, interaction analysis, restricted cubic spline (RCS), and receiver operating characteristic (ROC) were employed to analyze the relationship between the TyG index and CAD severity across the entire population and glucose metabolism subgroups. Mediation analysis was conducted to examine the mediating effects of glycated hemoglobin (HbA1c) on these relationships. Sensitivity analysis was performed to ensure the robustness of the findings. RESULTS: Multivariable logistic regression analysis revealed a significant positive association between the TyG index and multi-vessel CAD in the entire population (OR: 1.34; 95% CI: 1.22-1.47 per 1-unit increment). Subgroup analysis demonstrated consistent positive associations in the NGR, pre-DM, and DM non-insulin Rx groups, with the highest OR observed in the NGR group (OR: 1.67; 95% CI: 1.3-2.14 per 1-unit increment). No correlation was found in the DM with insulin Rx subgroup. RCS analyses indicated the distinct dose-response relationships across different glucose metabolism subgroups. Including the TyG index in the established model slightly improved the predictive accuracy, particularly in the NGR group. Mediation analyses showed varying mediating effects of HbA1c among different glucose metabolism subgroups. Sensitivity analysis confirmed the robustness of the aforementioned relationships in the new-onset CAD population and in individuals not using antilipidemic medications. CONCLUSIONS: The TyG index positively associated with CAD severity across all glucose metabolism states, except for individuals receiving insulin treatment. Moreover, it might serve as a supplementary noninvasive predictor of CAD severity in addition to established factors, especially in NGR patients.
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Glicemia , Doença da Artéria Coronariana , Hemoglobinas Glicadas , Triglicerídeos , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Povo Asiático , Biomarcadores/sangue , Glicemia/metabolismo , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/epidemiologia , Doença da Artéria Coronariana/diagnóstico , Estudos Transversais , Diabetes Mellitus/sangue , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/epidemiologia , Hemoglobinas Glicadas/metabolismo , Hipoglicemiantes/uso terapêutico , Insulina/sangue , Insulina/uso terapêutico , Estado Pré-Diabético/sangue , Estado Pré-Diabético/diagnóstico , Estado Pré-Diabético/epidemiologia , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Índice de Gravidade de Doença , Triglicerídeos/sangueRESUMO
BACKGROUND: Hypoxic pulmonary hypertension (HPH) is a challenging lung arterial disorder with remarkably high incidence and mortality rates, and the efficiency of current HPH treatment strategies is unsatisfactory. Endothelial-to-mesenchymal transition (EndMT) in the pulmonary artery plays a crucial role in HPH. Previous studies have shown that lncRNA-H19 (H19) is involved in many cardiovascular diseases by regulating cell proliferation and differentiation but the role of H19 in EndMT in HPH has not been defined. METHODS: In this research, the expression of H19 was investigated in PAH human patients and rat models. Then, we established a hypoxia-induced HPH rat model to evaluate H19 function in HPH by Echocardiography and hemodynamic measurements. Moreover, luciferase reporter gene detection, and western blotting were used to explore the mechanism of H19. RESULTS: Here, we first found that the expression of H19 was significantly increased in the endodermis of pulmonary arteries and that H19 deficiency obviously ameliorated pulmonary vascular remodelling and right heart failure in HPH rats, and these effects were associated with inhibition of EndMT. Moreover, an analysis of luciferase activity indicated that microRNA-let-7 g (let-7 g) was a direct target of H19. H19 deficiency or let-7 g overexpression can markedly downregulate the expression of TGFßR1, a novel target gene of let-7 g. Furthermore, inhibition of TGFßR1 induced similar effects to H19 deficiency. CONCLUSIONS: In summary, our findings demonstrate that the H19/let-7 g/TGFßR1 axis is crucial in the pathogenesis of HPH by stimulating EndMT. Our study may provide new ideas for further research on HPH therapy in the near future.
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Transição Epitelial-Mesenquimal , Hipertensão Pulmonar , MicroRNAs , RNA Endógeno Competitivo , RNA Longo não Codificante , Transdução de Sinais , Fator de Crescimento Transformador beta , Animais , Feminino , Humanos , Masculino , Ratos , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal/fisiologia , Transição Epitelial-Mesenquimal/genética , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/genética , Hipertensão Pulmonar/patologia , Hipóxia/metabolismo , Hipóxia/genética , MicroRNAs/metabolismo , MicroRNAs/genética , Artéria Pulmonar/metabolismo , Artéria Pulmonar/patologia , Ratos Sprague-Dawley , Receptor do Fator de Crescimento Transformador beta Tipo I/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo I/genética , RNA Endógeno Competitivo/genética , RNA Endógeno Competitivo/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Transdução de Sinais/fisiologia , Fator de Crescimento Transformador beta/metabolismoRESUMO
Age-related macular degeneration (AMD) is the leading cause of vision loss among the elderly, which is primarily attributed to oxidative stress-induced damage to the retinal pigment epithelium (RPE). Human amniotic mesenchymal stem cells (hAMSC) were considered to be one of the most promising stem cells for clinical application due to their low immunogenicity, tissue repair ability, pluripotent potential and potent paracrine effects. The conditional medium (hAMSC-CM) and exosomes (hAMSC-exo) derived from hAMSC, as mediators of intercellular communication, play an important role in the treatment of retinal diseases, but their effect and mechanism on oxidative stress-induced retinal degeneration are not explored. Here, we reported that hAMSC-CM alleviated H2O2-induced ARPE-19 cell death through inhibiting mitochondrial-mediated apoptosis pathway in vitro. The overproduction of reactive oxygen species (ROS), alteration in mitochondrial morphology, loss of mitochondrial membrane potential and elevation of Bax/Bcl2 ratio in ARPE-19 cells under oxidative stress were efficiently reversed by hAMSC-CM. Moreover, it was found that hAMSC-CM protected cells against oxidative injury via PI3K/Akt/FoxO3 signaling. Intriguingly, exosome inhibitor GW4869 alleviated the inhibitory effect of hAMSC-CM on H2O2-induced decrease in cell viability of ARPE-19 cells. We further demonstrated that hAMSC-exo exerted the similar protective effect on ARPE-19 cells against oxidative damage as hAMSC-CM. Additionally, both hAMSC-CM and hAMSC-exo ameliorated sodium iodate-induced deterioration of RPE and retinal damage in vivo. These results first indicate that hAMSC-CM and hAMSC-exo protect RPE cells from oxidative damage by regulating PI3K/Akt/FoxO3 pathway, suggesting hAMSC-CM and hAMSC-exo will be a promising cell-free therapy for the treatment of AMD in the future.
Assuntos
Âmnio , Exossomos , Proteína Forkhead Box O3 , Células-Tronco Mesenquimais , Estresse Oxidativo , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Degeneração Retiniana , Epitélio Pigmentado da Retina , Transdução de Sinais , Humanos , Células-Tronco Mesenquimais/metabolismo , Exossomos/metabolismo , Âmnio/citologia , Meios de Cultivo Condicionados/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Degeneração Retiniana/metabolismo , Degeneração Retiniana/patologia , Degeneração Retiniana/etiologia , Proteína Forkhead Box O3/metabolismo , Epitélio Pigmentado da Retina/metabolismo , Epitélio Pigmentado da Retina/patologia , Apoptose , Células Cultivadas , Espécies Reativas de Oxigênio/metabolismo , Potencial da Membrana Mitocondrial , Western Blotting , Animais , Sobrevivência Celular , Peróxido de Hidrogênio/toxicidadeRESUMO
Chemodynamic therapy (CDT) is a novel antitumor strategy that employs Fenton or Fenton-like reactions to generate highly toxic hydroxyl radical (OHâ¢) from hydrogen peroxide (H2O2) for inducing tumor cell death. However, the antitumor efficacy of the CDT strategy is harshly limited by the redox homeostasis of tumor cells; especially the OH ⢠is easily scavenged by glutathione (GSH) and the intracellular H2O2 level is insufficient in the tumor cells. Herein, we propose the Mn2+-menadione (also known as vitamin K3, MK3) cascade biocatalysis strategy to disrupt the redox homeostasis of tumor cells and induce a OH⢠storm, resulting in enhanced CDT effect. A nanoliposome encapsulating Mn-MK3 (Mn-MK3@LP) was prepared for the treatment of hepatic tumors in this study. After Mn-MK3@LPs were taken up by tumor cells, menadione could facilitate the production of intracellular H2O2 via redox cycling, and further the cytotoxic OH ⢠burst was induced by Mn2+-mediated Fenton-like reaction. Moreover, high-valent manganese ions were reduced by GSH and the depletion of GSH further disrupted the redox homeostasis of tumor cells, thus achieving synergistically enhanced CDT. Overall, both cellular and animal experiments confirmed that the Mn-MK3@LP cascade biocatalysis nanoliposome exhibited excellent biosafety and tumor suppression efficacy. This study may provide deep insights for developing novel CDT-based strategies for tumor therapy.
Assuntos
Glutationa , Peróxido de Hidrogênio , Radical Hidroxila , Vitamina K 3 , Animais , Radical Hidroxila/química , Radical Hidroxila/metabolismo , Humanos , Camundongos , Glutationa/metabolismo , Glutationa/química , Vitamina K 3/química , Vitamina K 3/farmacologia , Biocatálise , Linhagem Celular Tumoral , Manganês/química , Oxirredução/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Lipossomos/química , Ensaios Antitumorais Modelo de Xenoenxerto , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Camundongos Nus , Células Hep G2 , Antineoplásicos/farmacologia , Antineoplásicos/química , Nanopartículas/química , FerroRESUMO
OBJECTIVE: Given the high prevalence of hypertension among Chinese adults, this population is at a significantly increased risk of severe COVID-19 complications. The purpose of this study is to assess the willingness of Chinese hypertensive adults to receive the COVID-19 vaccine and to identify the diverse factors that shape their vaccination decisions. METHODS: Sampling was conducted utilizing multistage stratified random sampling, and ultimately, a total of 886 adult hypertensive patients from Luzhou City in Southwest China were included in this study. The questionnaire design was based on the Theory of Planned Behaviour and was used to investigate their willingness to be vaccinated with COVID-19. Structural equation modeling was employed for data analysis. RESULTS: The results showed that 75.6% of hypertensive individuals were willing to receive COVID-19 vaccination. The structural equation modeling revealed that Subjective Norms (path coefficient = 0.361, CR = 8.049, P < 0.001) and Attitudes (path coefficient = 0.253, CR = 4.447, P < 0.001) had positive effects on vaccination willingness, while Perceived Behavioral Control (path coefficient=-0.004, CR=-0.127, P = 0.899) had no significant impact on Behavioral Attitudes. Mediation analysis indicated that Knowledge (indirect path coefficient = 0.032, LLCI = 0.014, ULCI = 0.058), Risk Perception (indirect path coefficient = 0.077, LLCI = 0.038, ULCI = 0.124), and Subjective Norms (indirect path coefficient = 0.044, LLCI = 0.019, ULCI = 0.087) significantly influenced vaccination willingness through Attitudes as a mediating factor. CONCLUSION: The willingness of hypertensive individuals to receive the COVID-19 vaccination is not satisfactory. The Theory of Planned Behavior provides valuable insights into understanding their vaccination intentions. Efforts should be concentrated on enhancing the subjective norms, attitudes, and knowledge about vaccination of hypertensive patients.
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Vacinas contra COVID-19 , COVID-19 , Hipertensão , Intenção , SARS-CoV-2 , Vacinação , Humanos , Hipertensão/epidemiologia , Hipertensão/psicologia , COVID-19/prevenção & controle , COVID-19/epidemiologia , COVID-19/psicologia , Masculino , Feminino , China/epidemiologia , Pessoa de Meia-Idade , Vacinas contra COVID-19/administração & dosagem , Vacinação/psicologia , Vacinação/estatística & dados numéricos , Adulto , Inquéritos e Questionários , Análise de Classes Latentes , Idoso , Conhecimentos, Atitudes e Prática em Saúde , Aceitação pelo Paciente de Cuidados de Saúde/psicologia , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Estudos Transversais , População do Leste AsiáticoRESUMO
OBJECTIVE: The purpose of this study is to systematically investigate the different phenotypes and functional analyses of macrophages in lung tissue. DATA SOURCES: A search was performed using three databases (Web of Science, Science Direct, and MEDLINE) for all relevant studies published from January 1, 2019, to December 31, 2023. STUDY SELECTIONS: This systematic review complied with the PRlSMA document's requirements, including studies related to the signaling pathway relationship between pulmonary macrophages and asthma phenotype. The search includedstudies published in English or French lanquage, and was based on title, abstract, and complete textDocuments not meeting inclusion requirements were excluded. RESULTS: We have identified studies published within the past five years that meet the criteria for inclusion in this review. We found that asthma is a heterogeneous chronic inflammatory lung disease, and lung tissue macrophages are important immune cells in the respiratory tract. Pulmonary macrophages are also heterogeneous, as they have different subgroups with varying effector functions depending on the environment. They have different phenotypes and biological functions in different disease environments. The phenotypic changes of pulmonary macrophages occur during asthma, and the study of the different phenotypes and functions of macrophages in lung tissue is of great significance for treatment. CONCLUSIONS: This review summarizes current literature and provides a detailed introduction to the role of macrophages as key inflammatory mediators in the pathogenesis of asthma, as well as existing knowledge gaps. In addition, we propose that regulatory macrophages may prevent the development of asthma by producing IL-10, and regulating the polarization of pulmonary macrophages may be a new direction for asthma treatment.
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BACKGROUND: The COVID-19 pandemic is a persistent global threat to public health. As for the emerging variants of SARS-CoV-2, it is necessary to develop vaccines that can induce broader immune responses, particularly vaccines with weak cellular immunity. METHODS: In this study, we generated a double-layered N-S1 protein nanoparticle (N-S1 PNp) that was formed by desolvating N protein into a protein nanoparticle as the core and crosslinking S1 protein onto the core surface against SARS-CoV-2. RESULTS: Vaccination with N-S1 PNp elicited robust humoral and vigorous cellular immune responses specific to SARS-CoV-2 in mice. Compared to soluble protein groups, the N-S1 PNp induced a higher level of humoral response, as evidenced by the ability of S1-specific antibodies to block hACE2 receptor binding and neutralize pseudovirus. Critically, N-S1 PNp induced Th1-biased, long-lasting, and cross-neutralizing antibodies, which neutralized the variants of SARS-CoV-2 with minimal loss of activity. N-S1 PNp induced strong responses of CD4+ and CD8+ T cells, mDCs, Tfh cells, and GCs B cells in spleens. CONCLUSIONS: These results demonstrate that N-S1 PNp vaccination is a practical approach for promoting protection, which has the potential to counteract the waning immune responses against SARS-CoV-2 variants and confer broad efficacy against future new variants. This study provides a new idea for the design of next-generation SARS-CoV-2 vaccines based on the B and T cells response coordination.
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COVID-19 , SARS-CoV-2 , Animais , Humanos , Camundongos , Linfócitos T CD8-Positivos , Formação de Anticorpos , Vacinas contra COVID-19 , Pandemias , COVID-19/prevenção & controle , Imunização , Vacinação , Anticorpos Antivirais , Anticorpos NeutralizantesRESUMO
The Nile tilapia (Oreochromis niloticus), with a system of XX/XY sex determination, is a worldwide farmed fish with a shorter sexual maturation time than that of most cultured fish. Tilapia show a spawning cycle of approximately 14 days and can be artificially propagated in the laboratory all year round to obtain genetically all female (XX) and all male (XY) fry. Its genome sequence has been opened, and a perfect gene editing platform has been established. With a moderate body size, it is convenient for taking enough blood to measure hormone level. In recent years, using tilapia as animal model, we have confirmed that estrogen is crucial for female development because 1) mutation of star2, cyp17a1 or cyp19a1a (encoding aromatase, the key enzyme for estrogen synthesis) results in sex reversal (SR) due to estrogen deficiency in XX tilapia, while mutation of star1, cyp11a1, cyp17a2, cyp19a1b or cyp11c1 affects fertility due to abnormal androgen, cortisol and DHP levels in XY tilapia; 2) when the estrogen receptors (esr2a/esr2b) are mutated, the sex is reversed from female to male, while when the androgen receptors are mutated, the sex cannot be reversed; 3) the differentiated ovary can be transdifferentiated into functional testis by inhibition of estrogen synthesis, and the differentiated testis can be transdifferentiated into ovary by simultaneous addition of exogenous estrogen and androgen synthase inhibitor; 4) loss of male pathway genes amhy, dmrt1, gsdf causes SR with upregulation of cyp19a1a in XY tilapia. Disruption of estrogen synthesis rescues the male to female SR of amhy and gsdf but not dmrt1 mutants; 5) mutation of female pathway genes foxl2 and sf-1 causes SR with downregulation of cyp19a1a in XX tilapia; 6) the germ cell SR of foxl3 mutants fails to be rescued by estrogen treatment, indicating that estrogen determines female germ cell fate through foxl3. This review also summarized the effects of deficiency of other steroid hormones, such as androgen, DHP and cortisol, on fish reproduction. Overall, these studies demonstrate that tilapia is an excellent animal model for studying reproductive endocrinology of fish.