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Targeted drug delivery is constantly updated with a better understanding of the physiological and pathological features of various diseases. Depending on high safety, good compliance and many other undeniable advantages, attempts have been undertaken to complete an intravenous-to-oral conversion of targeted drug delivery. However, oral delivery of particulates to systemic circulation is highly challenging due to the biochemical aggressivity and immune exclusion in the gut that restrain absorption and access to the bloodstream. Little is known about the feasibility of targeted drug delivery via oral administration (oral targeting) to a remote site beyond the gastrointestinal tract. To this end, this review proactively contributes to a special dissection on the feasibility of oral targeting. We discussed the theoretical basis of oral targeting, the biological barriers of absorption, the in vivo fate and transport mechanisms of drug vehicles, and the effect of structural evolution of vehicles on oral targeting as well. At last, a feasibility analysis on oral targeting was performed based on the integration of currently available information. The innate defense of intestinal epithelium does not allow influx of more particulates into the peripheral blood through enterocytes. Therefore, limited evidence and lacking exact quantification of systemically exposed particles fail to support much success with oral targeting. Nevertheless, the lymphatic pathway may serve as a potentially alternative portal of peroral particles into the remote target sites via M-cell uptake.
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Owing to the inherent shortcomings of traditional therapeutic drugs in terms of inadequate therapeutic efficacy and toxicity in clinical treatment, nanomedicine designs have received widespread attention with significantly improved efficacy and reduced non-target side effects. Nanomedicines hold tremendous theranostic potential for treating, monitoring, diagnosing, and controlling various diseases and are attracting an unfathomable amount of input of research resources. Against the backdrop of an exponentially growing number of publications, it is imperative to help the audience get a panorama image of the research activities in the field of nanomedicines. Herein, this review elaborates on the development trends of nanomedicines, emerging nanocarriers, in vivo fate and safety of nanomedicines, and their extensive applications. Moreover, the potential challenges and the obstacles hindering the clinical translation of nanomedicines are also discussed. The elaboration on various aspects of the research trends of nanomedicines may help enlighten the readers and set the route for future endeavors.
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Radiation induced lung injury (RILI) is a common complication after radiation therapy of breast tumors and bone marrow transplantation pretreatment, and it is a critical limiting factor of radiotherapy doses in patients. Once RILI progresses to the radiation-induced pulmonary fibrosis stage, it seriously reduces the patient’s quality of life, while causing the patient’s respiratory failure and eventually leading to death. Ionizing radiation (IR) can induce cell injuries, including apoptosis, epithelial-mesenchymal transition, senescence, pyroptosis and ferroptosis, and these injuries can play an important role in the occurrence and development of radioactive lung injury. Starting from discussion of the occurrence of different forms of injury in different cells after IR stimulation, this review summarizes the pathogenesis of RILI and its clinical prevention and treatment.
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ObjectiveTo investigate common dyadic coping (CDC) in linking with marital satisfaction and quality of life (QOL) in patients with brain injury and their spouses in a rehabilitation facility by using common fate model (CFM). MethodsFrom October, 2022 to June, 2023, 101 brain injury inpatients and their spouses in Beijing Bo'ai Hospital completed the questionnaire of Dyadic Coping Inventory, Kansas Marital Satisfaction Scale and World Health Organization Quality of Life. ResultsThe level of CDC between patients and their spouses significantly positively correlated with their marital satisfaction for both partners (β = 0.814, P < 0.001), as well as correlated with their quality of life (β = 0.271, P = 0.038; β = 0.481, P < 0.001). For the dimensions of QOL, the physical, psychological, social relationship and environmental dimensions significantly positive correlated with the CDC for the spouses, and only psychological and social relationship dimensions for the patients. ConclusionFacing the stress of brain injury, the level of CDC within couples can positively predict their marital satisfaction and QOL, and effect seems stronger for the spouses. It is advisable to consider both brain injured patients and their spouses as a whole to promote psychological adaptation and improve rehabilitation outcomes.
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The long-circulating effect is revisited by simultaneous monitoring of the drug payloads and nanocarriers following intravenous administration of doxorubicin (DOX)-loaded methoxy polyethylene glycol-polycaprolactone (mPEG-PCL) nanoparticles. Comparison of the kinetic profiles of both DOX and nanocarriers verifies the long-circulating effect, though of limited degree, as a result of pegylation. The nanocarrier profiles display fast clearance from the blood despite dense PEG decoration; DOX is cleared faster than the nanocarriers. The nanocarriers circulate longer than DOX in the blood, suggesting possible leakage of DOX from the nanocarriers. Hepatic accumulation is the highest among all organs and tissues investigated, which however is reversely proportionate to blood circulation time. Pegylation and reduction in particle size prove to extend circulation of drug nanocarriers in the blood with simultaneous decrease in uptake by various organs of the mononuclear phagocytic system. It is concluded that the long-circulating effect of mPEG-PCL nanoparticles is reconfirmed by monitoring of either DOX or the nanocarriers, but the faster clearance of DOX suggests possible leakage of a fraction of the payloads. The findings of this study are of potential translational significance in design of nanocarriers towards optimization of both therapeutic and toxic effects.
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Peptides that are composed of dextrorotary (d)-amino acids have gained increasing attention as a potential therapeutic class. However, our understanding of the in vivo fate of d-peptides is limited. This highlights the need for whole-body, quantitative tracking of d-peptides to better understand how they interact with the living body. Here, we used mouse models to track the movement of a programmed death-ligand 1 (PD-L1)-targeting d-dodecapeptide antagonist (DPA) using positron emission tomography (PET). More specifically, we profiled the metabolic routes of [64Cu]DPA and investigated the tumor engagement of [64Cu/68Ga]DPA in mouse models. Our results revealed that intact [64Cu/68Ga]DPA was primarily eliminated by the kidneys and had a notable accumulation in tumors. Moreover, a single dose of [64Cu]DPA effectively delayed tumor growth and improved the survival of mice. Collectively, these results not only deepen our knowledge of the in vivo fate of d-peptides, but also underscore the utility of d-peptides as radiopharmaceuticals.
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BACKGROUND: Yougui Decoction is an empirical prescription for the treatment of glucocorticoid-associated femoral head necrosis. Literature has shown that the pathogenesis of glucocorticoid-associated femoral head necrosis is associated with glucocorticoid-induced autophagy down-regulation and fate change in bone marrow mesenchymal stem cells. OBJECTIVE: To investigate the effect of Yougui Decoction on autophagy and fate of bone marrow mesenchymal stem cells in model rats of glucocorticoid-associated femoral head necrosis. METHODS: We used Escherichia coli endotoxin combined with high-dose dexamethasone to make the rat models of early femoral head necrosis. Forty SHR rats were randomly divided into five groups: blank control group, model group, high-dose Yougui Decoction group, medium-dose Yougui Decoction group and low-dose Yougui Decoction group. After 6 weeks of intervention, medullary cavity tissue of the rat proximal femur was taken for hematoxylin-eosin staining and immunohistochemical staining of autophagy proteins LC3 II, P53 and beclin-1. After culture and induction of bone marrow mesenchymal stem cells, alizarin red staining, bone alkaline phosphatase quantification, oil red staining and MTT determination were performed and western blot assay was used to quantitatively measure the expression of LC3 II, P53 and beclin-1 proteins. RESULTS AND CONCLUSION: (1) Immunohistochemistry and western blot assay results showed that Yougui Decoction significantly increased autophagy protein LC3 II, P53 and beclin 1 expression in a dose-dependent manner. (2) Alizarin red staining, oil red staining and bone alkaline phosphatase quantification suggested that Yougui Decoction could significantly interfere with the fate of bone marrow mesenchymal stem cells, up-regulate their osteogenic differentiation and down-regulate their adipogenic differentiation in a dose-dependent manner. (3) MTT results suggested that Yougui Decoction significantly improved the proliferation ability of bone marrow mesenchymal stem cells, but had no significant differences in different doses. (4) To conclude, Yougui Decoction can significantly improve the autophagy expression, change the cell fate, up-regulate osteogenic differentiation and down-regulate adipogenic differentiation of bone marrow mesenchymal stem cells in the rat models of glucocorticoid-associated femoral head necrosis, which provides certain basis for elucidating the mechanism of Yougui Decoction in treating glucocorticoid-associated femoral head necrosis.
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Nanocrystal formulations have been explored to deliver poorly water-soluble drug molecules. Despite various studies of nanocrystal formulation and delivery, much more understanding needs to be gained into absorption mechanisms and kinetics of drug nanocrystals at various levels, ranging from cells to tissues and to the whole body. In this study, nanocrystals of tetrakis (4-hydroxyphenyl) ethylene (THPE) with an aggregation-induced emission (AIE) property was used as a model to explore intracellular absorption mechanism and dissolution kinetics of nanocrystals. Cellular uptake studies were conducted with KB cells and characterized by confocal microscopy, flow cytometry, and quantitative analyses. The results suggested that THPE nanocrystals could be taken up by KB cells directly, as well as in the form of dissolved molecules. The cellular uptake was found to be concentration- and time-dependent. In addition, the intracellular THPE also could be exocytosed from cells in forms of dissolved molecules and nanocrystals. Kinetic modeling was conducted to further understand the cellular mechanism of THPE nanocrystals based on first-order ordinary differential equations (ODEs). By fitting the kinetic model against experimental measurements, it was found that the initial nanocrystal concentration had a great influence on the dynamic process of dissolution, cellular uptake, and exocytosis of THPE nanocrystals. As the nanocrystal concentration increased in the culture media, dissolution of endocytosed nanocrystals became enhanced, subsequently driving the efflux of THPE molecules from cells.
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Self-microemulsifying drug delivery systems (SMEDDSs) have recently returned to the limelight of academia and industry due to their enormous potential in oral delivery of biomacromolecules. However, information on gastrointestinal lipolysis and trans-epithelial transport of SMEDDS is rare. Aggregation-caused quenching (ACQ) fluorescent probes are utilized to visualize the
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In this study, self-discriminating hybrid nanocrystals was utilized to explore the biological fate of quercetin hybrid nanocrystals (QT-HNCs) with diameter around 280 nm (QT-HNCs-280) and 550 nm (QT-HNCs-550) following oral and intravenous administration and the contribution of integral nanocrystals to oral bioavailability enhancement of QT was estimated by comparing the absolute exposure of integral QT-HNCs and total QT in the liver. Results showed that QT-HNCs could reside
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Current advances of immunotherapy have greatly changed the way of cancer treatment. At the same time, a great number of nanoparticle-based cancer immunotherapies (NBCIs) have also been explored to elicit potent immune responses against tumors. However, few NBCIs are nearly in the clinical trial which is mainly ascribed to a lack understanding of
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The use of lipid nanocarriers for drug delivery applications is an active research area, and a great interest has particularly been shown in the past two decades. Among different lipid nanocarriers,
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During early embryonic development, cell fate commitment represents a critical transition or "tipping point" of embryonic differentiation, at which there is a drastic and qualitative shift of the cell populations. In this study, we presented a computational approach, scGET, to explore the gene-gene associations based on single-cell RNA sequencing (scRNA-seq) data for critical transition prediction. Specifically, by transforming the gene expression data to the local network entropy, the single-cell graph entropy (SGE) value quantitatively characterizes the stability and criticality of gene regulatory networks among cell populations and thus can be employed to detect the critical signal of cell fate or lineage commitment at the single-cell level. Being applied to five scRNA-seq datasets of embryonic differentiation, scGET accurately predicts all the impending cell fate transitions. After identifying the "dark genes" that are non-differentially expressed genes but sensitive to the SGE value, the underlying signaling mechanisms were revealed, suggesting that the synergy of dark genes and their downstream targets may play a key role in various cell development processes.The application in all five datasets demonstrates the effectiveness of scGET in analyzing scRNA-seq data from a network perspective and its potential to track the dynamics of cell differentiation. The source code of scGET is accessible at https://github.com/zhongjiayuna/scGET_Project.
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Atherosclerosis (AS) is a lipid-driven chronic inflammatory disease occurring at the arterial subendothelial space. Macrophages play a critical role in the initiation and development of AS. Herein, targeted codelivery of anti-miR 155 and anti-inflammatory baicalein is exploited to polarize macrophages toward M2 phenotype, inhibit inflammation and treat AS. The codelivery system consists of a carrier-free strategy (drug-delivering-drug, DDD), fabricated by loading anti-miR155 on baicalein nanocrystals, named as baicalein nanorods (BNRs), followed by sialic acid coating to target macrophages. The codelivery system, with a diameter of 150 nm, enables efficient intracellular delivery of anti-miR155 and polarizes M1 to M2, while markedly lowers the level of inflammatory factors and . In particular, intracellular fate assay reveals that the codelivery system allows for sustained drug release over time after internalization. Moreover, due to prolonged blood circulation and improved accumulation at the AS plaque, the codelivery system significantly alleviates AS in animal model by increasing the artery lumen diameter, reducing blood pressure, promoting M2 polarization, inhibiting secretion of inflammatory factors and decreasing blood lipids. Taken together, the codelivery could potentially be used to treat vascular inflammation.
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Determinar la utilidad del protocolo FATE (Focused Assessment with Transthoracic Echocardiography) en la evaluación de los pacientes en shock. ingresados al Servicio de Cuidados Intermedios del Hospital Central Universitario Dr. "Antonio María Pineda", Barquisimeto, Venezuela en el período agosto-octubre 2019, Métodos: se realizó un estudio descriptivo transversal, de 30 pacientes, con promedio de edad de 56,86 ± 15,85 años, Resultados: predominó el grupo de 71-80 años (23,33%), de sexo masculino (63,33%). Según la clasificación del shock por Weil y Shubin el 50% presentó shock distributivo (todos por sepsis), 20% cardiogénico, 16,67% hipovolémico y obstructivo. 13,33% Los principales hallazgos ecocardiográficos fueron presencia de derrame pleural bilateral (33,33%), derrame pleural unilateral (30%) y derrame pericárdico (23,33%). Además, 26,67% presentaron espesor miocárdico patológico, 33,33% dimensiones de VD-VI aumentadas, 46,67% función sistólica ventricular alterada; sumado al hecho que 70% de la contractibilidad y 60% de la visualización pulmonar eran patológicas. El valor cualitativo del protocolo FATE resultó en: 43,33% soportaba la información disponible, 26,67% añadió información decisiva a la terapéutica, 23,33% agregó nueva información y 6,67% información fue pobre por mala ventana. La mortalidad a los 7 días fue de 43,33%, siendo más frecuente en pacientes con shock distributivo (61,54%), seguido de cardiogénico (23,08%) y obstructivo (15,38%), no hubo defunciones por shock hipovolémico. Los valores cualitativos del protocolo FATE en pacientes fallecidos; por shock distributivo 37,5%, soportó la información disponible y agregó nueva información, respectivamente. En cambio en 100% de los fallecidos por shock cardiogénico y obstructivo, el protocolo FATE añadió información decisiva a la terapéutica. Los resultados demuestran la importancia del Protocolo FATE en el manejo de pacientes con shock(AU)
To determine the usefulness of the FATE protocol (Focused Assessment with Transthoracic Echocardiography) in the evaluation of patients in shock admitted to the Intermediate Care Unit of the "University Hospital Antonio Maria Pineda" in Barquisimeto, Venezuela, during the period August-October 2019, Methods: A descriptive cross-sectional study was done, selecting 30 patients, with an average age of 56.86 ± 15.85 years; the most affected group was 71-80 years old (23.33%), with a predominance of the male sex (63.33%) Results: According to the classification of shock by Weil and Shubin, 50% were found to have distributive shock (all due to sepsis), 20% cardiogenic, 16.67% hypovolemic and obstructive 13.33%. The main echocardiographic findings were the presence of bilateral pleural effusion (33.33%), unilateral pleural effusion (30%) and pericardial effusion (23.33%). In addition, 26.67% presented pathological myocardial thickness, 33.33% increased RV-LV dimensions, 46.67% impaired ventricular systolic function; also, 70% of contractibility and 60% of pulmonary visualization were pathological. The qualitative value of the FATE protocol resulted in: 43.33% supported the available information, 26.67% added decisive information to the therapy, 23.33% added new information and 6.67% information was poor due to a bad US window. (Mortality at 7 days was 43.33%, being more frequent in patients with distributive shock (61.54%), followed by cardiogenic (23.08%) and obstructive (15.38%); there were no deaths due to hypovolemic shock. The qualitative values of the FATE protocol in patients with distributive shock who died, was that 37.5% In contrast, in 100% of those who died by cardiogenic and obstructive shock, the FATE protocol added decisive information to the therapy. Conclusion:The results demonstrate the importance of the FATE Protocol in the management of patients with shock(AU)
Subject(s)
Humans , Male , Female , Aged , Aged, 80 and over , Shock, Cardiogenic/physiopathology , Blood Volume , Ultrasonography , Focused Assessment with Sonography for Trauma , Pulmonary Embolism , Intensive Care Units , Myocardial InfarctionABSTRACT
The stem/progenitor cell has long been regarded as a central cell type in development, homeostasis, and regeneration, largely owing to its robust self-renewal and multilineage differentiation abilities. The balance between self-renewal and stem/progenitor cell differentiation requires the coordinated regulation of cell cycle progression and cell fate determination. Extensive studies have demonstrated that cell cycle states determine cell fates, because cells in different cell cycle states are characterized by distinct molecular features and functional outputs. Recent advances in high-resolution epigenome profiling, single-cell transcriptomics, and cell cycle reporter systems have provided novel insights into the cell cycle regulation of cell fate determination. Here, we review recent advances in cell cycle-dependent cell fate determination and functional heterogeneity, and the application of cell cycle manipulation for cell fate conversion. These findings will provide insight into our understanding of cell cycle regulation of cell fate determination in this field, and may facilitate its potential application in translational medicine.
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The in vivo fate is a crucial factor that governs the successful translation of nanoformulations. However, one of the current biggest challenges is with the real-time monitoring of the body of the nanoparticles themselves. Conventional radioactive or fluorescent probes give signals even after they are disassociated from the particle matrix, generating interference to bioimaging and leading to misjudgment of results. Environment-responsive fluorescent dyes are regarded as promising tools due to signal switching in response to the changes in the environment. Currently, there are three categories of dyes in bioimaging of nanoparticles based on Förster resonance energy transfer (FRET), aggregation-induced emission (AIE) and aggregation-caused quenching (ACQ). They have similar characteristics that strong fluorescence is emitted when they are embedded in the matrix of nanocarriers, whereas the fluorescence quenches upon release from the matrix due to dissociation of nanocarriers. The fluorescence switching reflects the existing status of the nanocarriers and therefore helps to interpret the in vivo behaviors. FRET and AIE probes have been widely used in elucidating the interactions between nanoparticles and cell models. However, they show intrinsic defects in studying in vivo fate of nanoparticles. ACQ-based dyes are sensitive to water, a universal factor in the biological environment. Therefore, with the help of bioimaging equipment, the in vivo trafficking process of nanoparticles can be unraveled. This review article tends to provide an overview on the rationale, pros and cons and applications of the three categories of environment-responsive fluorescent dyes in the investigation of the in vivo fate of nanocarriers.
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The stem/progenitor cell has long been regarded as a central cell type in development, homeostasis, and regeneration, largely owing to its robust self-renewal and multilineage differentiation abilities. The balance between self-renewal and stem/progenitor cell differentiation requires the coordinated regulation of cell cycle progression and cell fate determination. Extensive studies have demonstrated that cell cycle states determine cell fates, because cells in different cell cycle states are characterized by distinct molecular features and functional outputs. Recent advances in high-resolution epigenome profiling, single-cell transcriptomics, and cell cycle reporter systems have provided novel insights into the cell cycle regulation of cell fate determination. Here, we review recent advances in cell cycle-dependent cell fate determination and functional heterogeneity, and the application of cell cycle manipulation for cell fate conversion. These findings will provide insight into our understanding of cell cycle regulation of cell fate determination in this field, and may facilitate its potential application in translational medicine.
Subject(s)
Animals , Humans , Cell Cycle , Cell Physiological Phenomena , Epigenomics , G1 Phase , G2 Phase , Translational Research, BiomedicalABSTRACT
BACKGROUND AND OBJECTIVES: Proficient differentiation of human pluripotent stem cells (hPSCs) into specific lineages is required for applications in regenerative medicine. A growing amount of evidences had implicated hormones and hormone-like molecules as critical regulators of proliferation and lineage specification during in vivo development. Therefore, a deeper understanding of the hormones and hormone-like molecules involved in cell fate decisions is critical for efficient and controlled differentiation of hPSCs into specific lineages. Thus, we functionally and quantitatively compared the effects of diverse hormones (estradiol 17-β (E2), progesterone (P4), and dexamethasone (DM)) and a hormone-like molecule (retinoic acid (RA)) on the regulation of hematopoietic and neural lineage specification. METHODS AND RESULTS: We used 10 nM E2, 3 μM P4, 10 nM DM, and 10 nM RA based on their functional in vivo developmental potential. The sex hormone E2 enhanced functional activity of hematopoietic progenitors compared to P4 and DM, whereas RA impaired hematopoietic differentiation. In addition, E2 increased CD34⁺CD45⁺ cells with progenitor functions, even in the CD43⁻ population, a well-known hemogenic marker. RA exhibited lineage-biased potential, preferentially committing hPSCs toward the neural lineage while restricting the hematopoietic fate decision. CONCLUSIONS: Our findings reveal unique cell fate potentials of E2 and RA treatment and provide valuable differentiation information that is essential for hPSC applications.
Subject(s)
Humans , Dexamethasone , Induced Pluripotent Stem Cells , Pluripotent Stem Cells , Progesterone , Regenerative Medicine , TretinoinABSTRACT
Sialylation, or the covalent addition of sialic acid to the terminal end of glycoproteins, is a biologically important modification that is involved in embryonic development, neurodevelopment, reprogramming, oncogenesis and immune responses. In this review, we have given a comprehensive overview of the current literature on the involvement of sialylation in cell fate decision during development, reprogramming and cancer progression. Sialylation is essential for early embryonic development and the deletion of UDP-GlcNAc 2-epimerase, a rate-limiting enzyme in sialic acid biosynthesis, is embryonically lethal. Furthermore, the sialyltransferase ST6GAL1 is required for somatic cell reprogramming, and its downregulation is associated with decreased reprogramming efficiency. In addition, sialylation levels and patterns are altered during cancer progression, indicating the potential of sialylated molecules as cancer biomarkers. Taken together, the current evidences demonstrate that sialylation is involved in crucial cell fate decision.