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In drug discovery, selecting targeted molecules is crucial as the target could directly affect drug efficacy and the treatment outcomes. As a member of the CCN family, CTGF (also known as CCN2) is an essential regulator in the progression of various diseases, including fibrosis, cancer, neurological disorders, and eye diseases. Understanding the regulatory mechanisms of CTGF in different diseases may contribute to the discovery of novel drug candidates. Summarizing the CTGF-targeting and -inhibitory drugs is also beneficial for the analysis of the efficacy, applications, and limitations of these drugs in different disease models. Therefore, we reviewed the CTGF structure, the regulatory mechanisms in various diseases, and drug development in order to provide more references for future drug discovery.
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Factor de Crecimiento del Tejido Conjuntivo , Descubrimiento de Drogas , Humanos , Factor de Crecimiento del Tejido Conjuntivo/metabolismo , Descubrimiento de Drogas/métodos , Animales , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Oftalmopatías/tratamiento farmacológico , Oftalmopatías/metabolismo , Fibrosis , Enfermedades del Sistema Nervioso/tratamiento farmacológico , Enfermedades del Sistema Nervioso/metabolismo , Regulación de la Expresión Génica/efectos de los fármacosRESUMEN
A Cu(I)-catalyzed three-component reaction of cyclopropenes, enamines and aldehydes has been realized. This reaction proceeds via the interception of carbonyl oxonium ylide intermediates with α, ß-unsaturated iminium ions that are in situ generated from enamines and aldehydes under the catalysis of Cu(MeCN)4PF6, leading to the desired γ-butenolide derivatives in good yields and with moderate diastereoselectivities. Access to these derivatives with tethered ketone and alkynal groups will expand the structural diversity of multi-substituted butenolides.
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OBJECTIVES: Primary blast lung injury (PBLI) is the main cause of death in blast injury patients, and is often ignored due to the absence of a specific diagnosis. Circular RNAs (circRNAs) are becoming recognized as new regulators of various diseases, but the role of circRNAs in PBLI remain largely unknown. This study aimed to investigate PBLI-related circRNAs and their probable roles as new regulators in PBLI in order to provide new ideas for PBLI diagnosis and treatment. METHODS: The differentially expressed (DE) circRNA and mRNA profiles were screened by transcriptome high-throughput sequencing and validated by quantitative real-time PCR (qRT-PCR). The GO and KEGG pathway enrichment was used to investigate the potential function of DE mRNAs. The interactions between proteins were analyzed using the STRING database and hub genes were identified using the MCODE plugin. Then, Cytoscape software was used to illustrate the circRNA-miRNA-hub gene network. RESULTS: A total of 117 circRNAs and 681 mRNAs were aberrantly expressed in PBLI, including 64 up-regulated and 53 down-regulated circRNAs, and 315 up-regulated and 366 down-regulated mRNAs. GO and KEGG analysis revealed that the DE mRNAs might be involved in the TNF signaling pathway and Fanconi anemia pathway. Hub genes, including Cenpf, Ndc80, Cdk1, Aurkb, Ttk, Aspm, Ccnb1, Kif11, Bub1 and Top2a, were obtained using the MCODE plugin. The network consist of 6 circRNAs (chr18:21008725-21020999 + , chr4:44893533-44895989 + , chr4:56899026-56910247-, chr5:123709382-123719528-, chr9:108528589-108544977 + and chr15:93452117-93465245 +), 7 miRNAs (mmu-miR-3058-5p, mmu-miR-3063-5p, mmu-miR-668-5p, mmu-miR-7038-3p, mmu-miR-761, mmu-miR-7673-5p and mmu-miR-9-5p) and 6 mRNAs (Aspm, Aurkb, Bub1, Cdk1, Cenpf and Top2a). CONCLUSIONS: This study examined a circRNA-miRNA-hub gene regulatory network associated with PBLI and explored the potential functions of circRNAs in the network for the first time. Six circRNAs in the circRNA-miRNA-hub gene regulatory network, including chr18:21008725-21020999 + , chr4:44893533-44895989 + , chr4:56899026-56910247-, chr5:123709382-123719528-, chr9:108528589-108544977 + and chr15:93452117-93465245 + may play an essential role in PBLI.
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Lesión Pulmonar , MicroARNs , Humanos , Animales , Ratones , ARN Circular/genética , Redes Reguladoras de Genes , MicroARNs/genética , MicroARNs/metabolismo , ARN Mensajero/genética , Proteínas del Tejido Nervioso/genéticaRESUMEN
Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is an overactivated inflammatory response caused by direct or indirect injuries that destroy lung parenchymal cells and dramatically reduce lung function. Although some research progress has been made in recent years, the pathogenesis of ALI/ARDS remains unclear due to its heterogeneity and etiology. MicroRNAs (miRNAs), a type of small noncoding RNA, play a vital role in various diseases. In ALI/ARDS, miRNAs can regulate inflammatory and immune responses by targeting specific molecules. Regulation of miRNA expression can reduce damage and promote the recovery of ALI/ARDS. Consequently, miRNAs are considered as potential diagnostic indicators and therapeutic targets of ALI/ARDS. Given that inflammation plays an important role in the pathogenesis of ALI/ARDS, we review the miRNAs involved in the inflammatory process of ALI/ARDS to provide new ideas for the pathogenesis, clinical diagnosis, and treatment of ALI/ARDS.
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Lesión Pulmonar Aguda , MicroARNs , Síndrome de Dificultad Respiratoria , Lesión Pulmonar Aguda/metabolismo , Humanos , Inflamación/genética , Pulmón/metabolismo , MicroARNs/genética , Síndrome de Dificultad Respiratoria/genéticaRESUMEN
Chiral oxindoles are important chemical scaffolds found in many natural products, and their enantioselective synthesis thus attracts considerable attention. Highly diastereo- and enantioselective synthetic methods for constructing C3 quaternary oxindoles have been well-developed. However, the efficient synthesis of chiral 3-substituted tertiary oxindoles has been rarely reported due to the ease of racemization of the tertiary stereocenter via enolization. Therefore, we herein report on the multicomponent assembly (from N-aryl diazoamides, aldehydes, and enamines/indoles) of complex oxindoles by enantioselective cooperative catalysis. These reactions proceed under mild conditions and show broad substrate scope, affording the desired coupling products (>90 examples) with good to excellent stereocontrol. Additionally, this research also demonstrates the synthetic potential of this annulation by constructing the 6,6,5-tricyclic lactone core structure of Speradineâ A.
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Indoles , Oxindoles , Estereoisomerismo , Catálisis , Indoles/químicaRESUMEN
Phosgene (COCl2) was once used as a classic suffocation poison and currently plays an essential role in industrial production. Due to its high toxicity, the problem of poisoning caused by leakage during production, storage, and use cannot be ignored. Phosgene mainly acts on the lungs, causing long-lasting respiratory depression, refractory pulmonary edema, and other related lung injuries, which may cause acute respiratory distress syndrome or even death in severe cases. Due to the high mortality, poor prognosis, and frequent sequelae, targeted therapies for phosgene exposure are needed. However, there is currently no specific antidote for phosgene poisoning. This paper reviews the literature on the mechanism and treatment strategies to explore new ideas for the treatment of phosgene poisoning.
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Lesión Pulmonar Aguda/terapia , Fosgeno/toxicidad , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/metabolismo , Antioxidantes/uso terapéutico , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Oxigenación por Membrana Extracorpórea , Glucocorticoides/uso terapéutico , Trasplante de Células Madre Mesenquimatosas , Estrés Oxidativo/efectos de los fármacos , Pronóstico , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Oestrogen receptor É (ERÉ) is overexpressed in two-thirds of all breast cancers and involves in development and breast cancer progression. Although ERÉ-positive breast cancer could be effective treated by endocrine therapy, the endocrine resistance is still an urgent clinical problem. Thus, further understanding of the underlying mechanisms ERÉ signalling is critical in dealing with endocrine resistance in breast cancer patients. MCF-7 and T47D breast cancer cell lines are used to carry out the molecular biological experiments. Western blot is used to assess the relative protein level of ERÉ, RNF168 and actin. Real-time PCR is used the measure the relative ERÉ-related gene mRNA level. Luciferase assay is used to measure the relative ERÉ signalling activity. Chromatin immunoprecipitation is used to measure the RNF168 binding affinity to ERÉ promoter regions. WST assay and flow cytometry are used to measure the cell proliferation capacity. We use Student's t test and one-way ANOVA test for statistical data analysis. Here, we report an important role in ERÉ-positive breast cancer cells for RNF168 protein in supporting cell proliferation by driving the transcription of ERÉ. RNF168 is highly expressed in breast cancer samples, compared with normal breast tissue. In patients with breast cancer, RNF168 expression level is correlated with poor endocrine treatment outcome. Depletion of RNF168 causes decreased cell proliferation in MCF-7 and T47D cells. Besides, depletion RNF168 reduced mRNA level of ERÉ and its target genes, such as PS2 and GREB1. Chromatin immunoprecipitation revealed that ERÉ transcription is associated with RNF168 recruitment to ERÉ promoter region, suggesting that transcriptional regulation is one mechanism by which RNF168 regulates ERÉ mRNA level and ERÉ signalling in breast cancer cells. RNF168 is required for ERÉ-positive breast cancer cell proliferation and facilitate ERÉ signalling activity possibly through promoting transcription of ERÉ.
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Neoplasias de la Mama/genética , Receptor alfa de Estrógeno/genética , Regulación Neoplásica de la Expresión Génica , Ubiquitina-Proteína Ligasas/genética , Sitios de Unión , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Proliferación Celular , Receptor alfa de Estrógeno/metabolismo , Femenino , Humanos , Células MCF-7 , Proteínas de la Membrana , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Presenilina-2/genética , Presenilina-2/metabolismo , Regiones Promotoras Genéticas , Unión Proteica , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Transducción de Señal , Análisis de Supervivencia , Transcripción Genética , Ubiquitina-Proteína Ligasas/antagonistas & inhibidores , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
G2 and S-phase expressed 1 (GTSE1) regulates cell cycle progression in human cancers. However, its significance and mechanism of action in acral melanoma (AM) remain unknown. In the present study, we found that GTSE1 expression was upregulated in advanced stage/metastatic AM tissues and metastatic cell lines, and correlated with higher stage (P = .028) and poor disease-free survival (DFS) in patients with AM (P = .003). Cox regression assays validated GTSE1 expression to be an independent prognostic factor of DFS for patients with AM (P = .004). Ectopic expression of GTSE1 enhanced primary AM cell proliferation, invasion, and migration. Loss-of-function in GTSE1 attenuated metastatic AM cell proliferation and metastatic ability in vitro and in vivo. We additionally observed that inhibition of migration and invasion occurred concomitantly with a GTSE1 knockdown-mediated increase in E-cadherin and decreases in N-cadherin and Slug. We further showed that integrin subunit alpha 2 (ITGA2) interacts with GTSE1 and is a downstream effector of GTSE1. Further, ITGA2 levels were positively correlated with GTSE1 expression in human AM tissues. Ectopic ITGA2 expression rescued siGTSE1-mediated inhibition of migration and invasion, thereby restoring epithelial-to-mesenchymal transition (EMT). In conclusion, GTSE1 expression promotes AM progression and correlates with clinical outcomes of patients with AM, and may represent a promising therapeutic target to suppress AM progression.
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Regulación Neoplásica de la Expresión Génica , Melanoma/genética , Proteínas Asociadas a Microtúbulos/genética , Neoplasias Cutáneas/genética , Animales , Línea Celular Tumoral , Movimiento Celular/genética , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Melanoma/metabolismo , Melanoma/patología , Ratones Endogámicos NOD , Ratones SCID , Proteínas Asociadas a Microtúbulos/metabolismo , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Interferencia de ARN , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/patología , Análisis de Supervivencia , Trasplante HeterólogoRESUMEN
Sclerostin is a secreted glycoprotein that expresses predominantly in osteocytes and inhibits bone formation by antagonizing the Wnt/ß-catenin signaling pathway, and the loop3 region of sclerostin has recently discovered as a novel therapeutic target for bone anabolic treatment without increasing cardiovascular risk. Herein, we used a structural based virtual screening to search for small molecular inhibitors selectively targeting sclerostin loop3. A novel natural product hit ZINC4228235 (THFA) was identified as the sclerostin loop3-selective inhibitor with a Kd value of 42.43 nM against sclerostin loop3. The simplification and derivation of THFA using molecular modeling-guided modification allowed the discovery of an effective and loop3-selective small molecular inhibitor, compound (4-(3-acetamidoprop-1-yn-1-yl)benzoyl)glycine (AACA), with improved binding affinity (Kd = 15.4 nM) compared to the hit THFA. Further in-vitro experiment revealed that compound AACA could attenuate the suppressive effect of transfected sclerostin on Wnt signaling and bone formation. These results make AACA as a potential candidate for development of anti-osteoporosis agents without increasing cardiovascular risk.
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Diseño de Fármacos , Osteoporosis , Osteoporosis/tratamiento farmacológico , Humanos , Relación Estructura-Actividad , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , Bibliotecas de Moléculas Pequeñas/síntesis química , Estructura Molecular , Animales , Ratones , Descubrimiento de Drogas , Evaluación Preclínica de Medicamentos , Proteínas Adaptadoras Transductoras de Señales/antagonistas & inhibidores , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Relación Dosis-Respuesta a Droga , Modelos Moleculares , Osteogénesis/efectos de los fármacosRESUMEN
The burning loss of Al and Ti elements in superalloys during electroslag remelting has become a prevalent issue. And the existing slag system is not suitable for smelting the ATI 718PlusTM alloy. Therefore, it is imperative to develop a new slag system for smelting the ATI 718PlusTM alloy. To mitigate this issue, a thermodynamic model of the oxidation reaction of Al and Ti at the slag and alloy interface was established based on the ion and molecule coexistence theory (IMCT). The thermodynamic model was used to investigate the correlation between the equilibrium content of Al and Ti, slag composition, smelting temperature, and initial Al and Ti content of the electrode. The results indicate that while increasing the smelting temperature can effectively inhibit the burning loss of Al, it will exacerbate the burning loss of Ti. Increasing CaO and Al2O3 contents can inhibit the Al burning loss, while an increase in the TiO2 content can inhibit the Ti burning loss. Although an increase in the MgO content results in the burning loss of Al, its impact on the Al is minimal. The burning loss of Al and Ti was not affected by the change in the CaF2 content. The high Al content in ATI 718PlusTM makes it prone to burning loss of Al during the electroslag remelting. The combustion loss of Al can be reduced by increasing the Ti content in the electrode or adding a suitable amount of aluminum powder to the slag system. The accuracy of the model had been validated through experimental verification.
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Triple-negative breast cancer (TNBC) is the most lethal subtype of breast cancer. Hypoxia-activated prodrugs (HAPs) have shown promise as potential therapeutic agents for TNBC. While increasing hypoxia levels may promote the HAP activation, it raises concerns regarding HIF1α-dependent drug resistance. It is desirable to develop a targeted approach that enhances tumor hypoxia for HAP activation without promoting HIF1α-dependent drug resistance in TNBC treatment. Herein, we proposed a multi-responsive carrier-free self-assembled nanomedicine named AQ4N@CA4T1ASO. This nanomedicine first targeted tumors by the TNBC-targeting aptamers (T1), and then disassembled in the reductive and acidic conditions within tumors. The released Combretastatin 4 (CA4) could exacerbate hypoxia, thereby promoting the conversion of inactive Banoxantrone (AQ4N) to its active form, AQ4. Simultaneously, the released antisense oligonucleotide (ASO) could attenuate hypoxia-induced HIF1α mRNA expression, thereby sensitizing the tumor to chemotherapy. Overall, this smart nanomedicine represents a profound targeted therapy strategy, combining "hypoxia-potentiating, hypoxia-activated, chemo-sensitization" approaches for TNBC treatment. In vivo study demonstrated significant suppression of tumor growth, highlighting the promising potential of this nanomedicine for future clinical translation.
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Aptámeros de Nucleótidos , Subunidad alfa del Factor 1 Inducible por Hipoxia , Profármacos , Neoplasias de la Mama Triple Negativas , Profármacos/farmacología , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/metabolismo , Neoplasias de la Mama Triple Negativas/patología , Animales , Humanos , Aptámeros de Nucleótidos/farmacología , Femenino , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/antagonistas & inhibidores , Ratones , Línea Celular Tumoral , Ensayos Antitumor por Modelo de Xenoinjerto , Ratones Desnudos , Ratones Endogámicos BALB C , AntraquinonasRESUMEN
Sclerostin emerges as a novel target for bone anabolic therapy in bone diseases. Osteogenesis imperfecta (OI) and X-linked hypophosphatemia (XLH) are rare bone diseases in which therapeutic potential of sclerostin inhibition cannot be ignored. In OI, genetic/pharmacologic sclerostin inhibition promoted bone formation of mice, but responses varied by genotype and age. Serum sclerostin levels were higher in young OI-I patients, while lower in adult OI-I/III/IV. It's worth investigating whether therapeutic response of OI to sclerostin inhibition could be clinically predicted by genotype and age. In XLH, preclinical/clinical data suggested factors other than identified FGF23 contributing to XLH. Higher levels of circulating sclerostin were detected in XLH. Sclerostin inhibition promoted bone formation in Hyp mice, while restored phosphate homeostasis in age-/gender-dependent manner. The role of sclerostin in regulating phosphate metabolism deserves investigation. Sclerostin/FGF23 levels of XLH patients with/without response to FGF23-antibody warrants study to develop precise sclerostin/FGF23 inhibition strategy or synergistic/additive strategy. Notably, OI patients were associated with cardiovascular abnormalities, so were XLH patients receiving conventional therapy. Targeting sclerostin loop3 promoted bone formation without cardiovascular risks. Further, blockade of sclerostin loop3-LRP4 interaction while preserving sclerostin loop2-ApoER2 interaction could be a potential precise sclerostin inhibition strategy for OI and XLH with cardiovascular safety. The Translational Potential of this Article. Preclinical data on the molecular understanding of sclerostin inhibition in OI and therapeutic efficacy in mouse models of different genotypes, as well as clinical data on serum sclerostin levels in patients with different phenotypes of OI, were reviewed and discussed. Translationally, it would facilitate to develop clinical prediction strategies (e.g. based on genotype and age, not just phenotype) for OI patients responsive to sclerostin inhibition. Both preclinical and clinical data suggested sclerostin as another factor contributing to XLH, in addition to the identified FGF23. The molecular understanding and therapeutic effects of sclerostin inhibition on both promoting bone anabolism and improving phosphate homostasis in Hyp mice were reviewed and discussed. Translationaly, it would facilitate the development of precise sclerostin/FGF23 inhibition strategy or synergistic/additive strategy for the treatment of XLH. Cardiovascular risk could not be ruled out during sclerostin inhibition treatment, especially for OI and XLH patients with cardiovascular diseases history and cardiovascular abnormalities. Studies on the role of sclerostin in inhiting bone formation and protecting cardiovascular system were reviewed and discussed. Translationaly, blockade of sclerostin loop3-LRP4 interaction while preserving sclerostin loop2-ApoER2 interaction could be a potential precise sclerostin inhibition strategy for OI and XLH with cardiovascular safety.
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Osteogenesis imperfecta (OI) is a rare genetic disease characterized by bone fragility and bone formation. Sclerostin could negatively regulate bone formation by antagonizing the Wnt signal pathway, whereas it imposes severe cardiac ischemic events in clinic. Our team has screened an aptamer that could promote bone anabolic potential without cardiovascular risk. However, the affinity of the aptamer is lower and needs to be improved. In the study, hydrophobic quinoline molecule with unique orientations (seven subtypes) were incorporated into key sites of a bone anabolic aptamer against sclerostin to form a modified aptamer library. Among all the quinoline modifications, 5-quinoline modification could shape the molecular recognition of modified aptamers to sclerostin to facilitate enhancing its binding to sclerostin toward the highest affinity by interacting with newly participated binding sites in sclerostin. Further, 5-quinoline modification could facilitate the modified aptamer attenuating the suppressed effect of the transfected sclerostin on both Wnt signaling and bone formation marker expression levels in vitro, promoting bone anabolism in OI mice (Col1a2+/G610C). The proposed quinoline-oriented modification strategy could shape the molecular recognition of modified aptamers to proteins to facilitate enhancing its binding affinity and therapeutic potency.
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Primary blast lung injury (PBLI), caused by exposure to high-intensity pressure waves from explosions in war, terrorist attacks, industrial production, and life explosions, is associated with pulmonary parenchymal tissue injury and severe ventilation insufficiency. PBLI patients, characterized by diffused intra-alveolar destruction, including hemorrhage and inflammation, might deteriorate into acute respiratory distress syndrome (ARDS) with high mortality. However, due to the absence of guidelines about PBLI, emergency doctors and rescue teams treating PBLI patients rely on experience. The goal of this review is to summarize the mechanisms of PBLI and their cross-linkages, exploring potential diagnostic and therapeutic targets of PBLI. We summarize the pathophysiological performance and pharmacotherapy principles of PBLI. In particular, we emphasize the crosstalk between hemorrhage and inflammation, as well as coagulation, and we propose early control of hemorrhage as the main treatment of PBLI. We also summarize several available therapy methods, including some novel internal hemostatic nanoparticles to prevent the vicious circle of inflammation and coagulation disorders. We hope that this review can provide information about the mechanisms, diagnosis, and treatment of PBLI for all interested investigators.
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Traumatismos por Explosión , Trastornos de la Coagulación Sanguínea , Lesión Pulmonar , Humanos , Traumatismos por Explosión/terapia , Hemorragia , InflamaciónRESUMEN
4-Hydroxycoumarin derivatives represent one of the most important scaffolds in biologically active substances, pharmaceuticals and functional materials. Herein, we describe an efficient Pd/amine/Brønsted acid ternary-catalytic multicomponent reaction for the rapid construction of substituted 4-hydroxycoumarin derivatives with adjacent quaternary and tertiary stereocenters via convergent assembly of two in situ generated active intermediates. Furthermore, the late-stage transformations of coumarin derivatives and their in vitro trial of antitumor activity successfully demonstrated the potential utilities of the products as platform molecules.
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Nucleic acid aptamers are ssDNA or ssRNA fragments that specifically recognize targets. However, the pharmacodynamic properties of natural aptamers consisting of 4 naturally occurring nucleosides (A, G, C, T/U) are generally restricted for inferior binding affinity than the cognate antibodies. The development of high-affinity modification strategies has attracted extensive attention in aptamer applications. Chemically modified aptamers with stable three-dimensional shapes can tightly interact with the target proteins via enhanced non-covalent bonding, possibly resulting in hundreds of affinity enhancements. This review overviewed high-affinity modification strategies used in aptamers, including nucleobase modifications, fluorine modifications (2'-fluoro nucleic acid, 2'-fluoro arabino nucleic acid, 2',2'-difluoro nucleic acid), structural alteration modifications (locked nucleic acid, unlocked nucleic acid), phosphate modifications (phosphorothioates, phosphorodithioates), and extended alphabets. The review emphasized how these high-affinity modifications function in effect as the interactions with target proteins, thereby refining the pharmacodynamic properties of aptamers.
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Small noncoding RNAs, known as microRNAs (miRNAs), are vital for the regulation of diverse biological processes. miR-223, an evolutionarily conserved anti-inflammatory miRNA expressed in cells of the myeloid lineage, has been implicated in the regulation of monocyte-macrophage differentiation, proinflammatory responses, and the recruitment of neutrophils. The biological functions of this gene are regulated by its expression levels in cells or tissues. In this review, we first outline the regulatory role of miR-223 in granulocytes, macrophages, endothelial cells, epithelial cells and dendritic cells (DCs). Then, we summarize the possible role of miR-223 in chronic obstructive pulmonary disease (COPD), acute lung injury (ALI), coronavirus disease 2019 (COVID-19) and other pulmonary inflammatory diseases to better understand the molecular regulatory networks in pulmonary inflammatory diseases.
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Lipid and glucose metabolism are critical for human activities, and their disorders can cause diabetes and obesity, two prevalent metabolic diseases. Studies suggest that the bone involved in lipid and glucose metabolism is emerging as an endocrine organ that regulates systemic metabolism through bone-derived molecules. Sclerostin, a protein mainly produced by osteocytes, has been therapeutically targeted by antibodies for treating osteoporosis owing to its ability to inhibit bone formation. Moreover, recent evidence indicates that sclerostin plays a role in lipid and glucose metabolism disorders. Although the effects of sclerostin on bone have been extensively examined and reviewed, its effects on systemic metabolism have not yet been well summarized. In this paper, we provide a systemic review of the effects of sclerostin on lipid and glucose metabolism based on in vitro and in vivo evidence, summarize the research progress on sclerostin, and prospect its potential manipulation for obesity and diabetes treatment.
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Trastornos del Metabolismo de la Glucosa , Proteínas , Humanos , Obesidad , Glucosa , LípidosRESUMEN
The molecular weight of nucleic acid aptamers (20 kDa) is lower than the cutoff threshold of the renal filtration (30-50 kDa), resulting in a very short half-life, which dramatically limits their druggability. To address this, we utilized 3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N-(4-hydroxy-2-oxo-2H-chromen-6-yl)propenamide (HC) and 12-((2,5-dioxopyrrolidin-1-yl)oxy)-12-oxododecanoic acid (DA), two newly designed coupling agents, for synergistic binding to human serum albumin (HSA). Both HC and DA are conjugated to a bone anabolic aptamer (Apc001) against sclerostin to form an Apc001OC conjugate with high binding affinity to HSA. Notably, HC and DA could synergistically facilitate prolonging the half-life of the conjugated Apc001 and promoting its bone anabolic potential. Using the designed blocking peptides, the mechanism studies indicate that the synergistic effect of HC-DA on pharmacokinetics and bone anabolic potential of the conjugated Apc001 is achieved via their synergistic binding to HSA. Moreover, biweekly Apc001OC at 50 mg/kg shows comparable bone anabolic potential to the marketed sclerostin antibody given weekly at 25 mg/kg. This proposed bimolecular modification strategy could help address the druggability challenge for aptamers with a short half-life.
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Aptamers are short, single-stranded DNA or RNA oligonucleotide sequences that can bind specific targets. The molecular weight of aptamers (<20 kDa) is lower than the renal filtration threshold (30â¼50 kDa), resulting in very short half-lives in vivo, which limit their druggability. The development of long-lasting modification approaches for aptamers can help address the druggability bottleneck of aptamers. This review summarized two distinct kinds of long-lasting modification approaches for aptamers, including macromolecular modification and low-molecular-weight modification. Though it is a current approach to extend the half-life of aptamers, the macromolecular modification approach could limit the space for the dosage increases, thus causing potential compliance concerns due to large molecular weight. As for the other modification approach, the low-molecular-weight modification approach, which uses low molecular weight coupling agents (LMWCAs) to modify aptamers, could greatly increase the proportion of aptamer moiety. However, some LMWCAs could bind to other proteins, causing a decrease in the drug amounts in blood circulation. Given these issues, the outlook for the next generation of long-lasting modification approaches was proposed at the end, including improving the administration method to increase dosage for aptamer drugs modified by macromolecule and developing Artificial intelligence (AI)-based strategies for optimization of LMWCAs.