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Anticoagulant effects during extracorporeal circulation of human blood a Schematic drawing of the continuous recirculation within an ex vivo circuit that included a dialysis column and a reservoir (Blood pool). Whole blood from healthy donors is pumped via mechanical roller pump to the dialyzer through the closed extracorporeal circuit, while the dialysate solution flows in the opposite direction through the device and into a waste container (Dialysate drain). The dialyzer and dialysate are heated to ~30 °C. b The plasma clotting time (APTT) in the presence of one of the anticoagulant strategies (Ori + T + H or Aptarray) at the indicated time points. The samples were collected from the infusion port. c The representative photographs (scale bars, 2 cm) and SEM images (scale bars, 200 μm) of filters collected from the post circulation dialyzer after following the different anticoagulation strategies.
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Effective and safe hemodialysis is essential for patients with acute kidney injury and chronic renal failures. However, the development of effective anticoagulant agents with safe antidotes for use during hemodialysis has proven challenging. Here, we describe DNA origami-based assemblies that enable the inhibition of thrombin activity and thrombus...
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... directly to DNA or using systems based on ligand or avidin-biotin binding (21)(22)(23)(24)(25)(26)(27)(28)(29)(47)(48)(49)(50)(51)(52). However, DNA origami research using aptamers has mainly focused on functionalizing the DNA origami using already established aptamers (53)(54)(55)(56). Therefore, a system that uses DNA origami and aptamers to elucidate the structure of proteins, as in this study, is a new approach that has never been used. ...
NCYM, a Homininae-specific oncoprotein, is the first de novo gene product experimentally shown to have oncogenic functions. NCYM stabilizes MYCN and β-catenin via direct binding and inhibition of GSK3β and promotes cancer progression in various tumors. Thus, the identification of compounds that binds to NCYM and structural characterization of the complex of such compounds with NCYM are required to deepen our understanding of the molecular mechanism of NCYM function and eventually to develop anticancer drugs against NCYM. In this study, the DNA aptamer that specifically binds to NCYM and enhances interaction between NCYM and GSK3β were identified for the first time using systematic evolution of ligands by exponential enrichment (SELEX). The structural properties of the complex of the aptamer and NCYM were investigated using atomic force microscopy (AFM) in combination with truncation and mutation of DNA sequence, pointing to the regions on the aptamer required for NCYM binding. Further analysis was carried out by small-angle X-ray scattering (SAXS). Structural modeling based on SAXS data revealed that when isolated, NCYM shows high flexibility, though not as a random coil, while the DNA aptamer exists as a dimer in solution. In the complex state, models in which NCYM was bound to a region close to an edge of the aptamer reproduced the SAXS data. Therefore, using a combination of SELEX, AFM, and SAXS, the present study revealed the structural properties of NCYM in its functionally active form, thus providing useful information for the possible future design of novel anti-cancer drugs targeting NCYM.
... Especially, DNA nanostructures have emerged as versatile and promising nanocarriers for cargo delivery, which greatly boosts the advances of precise medicine. However, myriad DNA strands with complicated sequences and even computer simulation software often are required to assemble multifunctional DNA nanostructures for available biomedical applications [16][17][18][19][20]. Recently, the advent of self-assembled DNA nanospheres has significantly simplified the synthesis process, even without complicated sequence design and operation procedures. ...
Self-assembled DNA nanospheres, as versatile and ideal vehicles, have offered new opportunities to create intelligent delivery systems for precise bioimaging and cancer therapy, due to their good biostability and cell permeability, large loading capacity, and programmable self–assembly behaviors. DNA nanospheres can be synthesized by the self–assembly of Y–shaped DNA monomers, ultra–long single-stranded DNA (ssDNA), and even metal–DNA coordination. Interestingly, they are size–controllable by varying some parameters including concentration, reaction time, and mixing ratio. This review summarizes the design of DNA nanospheres and their extensive biomedical applications. First, the characteristics of DNA are briefly introduced, and different DNA nanostructures are mentioned. Then, the design of DNA nanospheres is emphasized and classified into three main categories, including Y–shaped DNA unit self-assembly by Watson–Crick base pairing, liquid crystallization and the dense packaging of ultra–long DNA strands generated via rolling circle amplification (RCA), and metal–DNA coordination–driven hybrids. Meanwhile, the advantages and disadvantages of different self–assembled DNA nanospheres are discussed, respectively. Next, the biomedical applications of DNA nanospheres are mainly focused on. Especially, DNA nanospheres serve as promising nanocarriers to deliver functional nucleic acids and drugs for biosensing, bioimaging, and therapeutics. Finally, the current challenges and perspectives for self-assembled DNA nanospheres in the future are provided.
... 相较于上述方法, 使用核酸适配体或DNA结合蛋 白可省略DNA链进行特殊化学修饰这一步骤. 核酸适 配体是一段具有特殊序列, 能够特异性结合多种目标 分子的DNA或RNA链段(图1(b)-iv). 通过使用结合蛋白 质的核酸适配体, 可在DNA骨架上组装多蛋白纳米阵 列 [13] 、包覆核酸适配体的DNA折纸纳米管 [14] 、纳米 盘 [14] 等结构, 且已成功应用于血液透析和蛋白质检测 等领域. 此外, 使用DNA结合蛋白也能免去对DNA进 行修饰的步骤. ...
... 相较于上述方法, 使用核酸适配体或DNA结合蛋 白可省略DNA链进行特殊化学修饰这一步骤. 核酸适 配体是一段具有特殊序列, 能够特异性结合多种目标 分子的DNA或RNA链段(图1(b)-iv). 通过使用结合蛋白 质的核酸适配体, 可在DNA骨架上组装多蛋白纳米阵 列 [13] 、包覆核酸适配体的DNA折纸纳米管 [14] 、纳米 盘 [14] 等结构, 且已成功应用于血液透析和蛋白质检测 等领域. 此外, 使用DNA结合蛋白也能免去对DNA进 行修饰的步骤. ...
... However, the protein itself is easily inactivated by enzymatic degradation and difficult to penetrate cell membrane, which limits its application [242,243]. Researchers have developed a series of DNA origami nanostructurebased carriers to escort proteins to target cellular locations [39,[244][245][246][247]. Recently, DNA tetrahedron nanocarriers have also been explored for protein delivery. ...
DNA nanostructures constructed under the guidance of DNA nanotechnology have developed rapidly for the last two decades, standing at the forefront in the biomedical field. Among them, DNA tetrahedron nanostructure (DTN) has emerged as one of the most representative DNA nanostructures. DTN was easily formed by one-step annealing of four single-stranded DNA. Due to its unique advantages such as simple and stable structural composition, high synthesis efficiency, uniform nanometer size, high programmability, and good biocompatibility, DTN has been widely used in biological detection, biological imaging, drug delivery, and other fields, and shows a great potential. Especially in the detection of cancer-related biomarkers and the delivery of anticancer drugs, nano-platforms based on DTN has achieved great success. In this review, we focus on the applications of DTN in cancer diagnosis and therapy, as well as the challenges and prospects.
... 17,[38][39][40][41][42] Even greater efforts are being made in preclinical development of aptamer-based therapeutics. [43][44][45][46] However, many nucleic acid aptamers developed using the traditional SELEX process do not meet the requirement for therapeutic applications. 47 X-Aptamers were considered to be the next generation aptamers. ...
Severe acute pancreatitis (AP) is associated with a high mortality rate. Cold-inducible RNA binding protein (CIRP) can be released from cells in inflammatory conditions and extracellular CIRP acts as a damage-associated molecular pattern. This study aims to explore the role of CIRP in the pathogenesis of AP and evaluate the therapeutic potential of targeting extracellular CIRP with X-aptamers. Our results showed that serum CIRP concentrations were significantly increased in AP mice. Recombinant CIRP triggered mitochondrial injury and ER stress in pancreatic acinar cells. CIRP-/- mice suffered less severe pancreatic injury and inflammatory responses. Using a bead-based X-aptamer library, we identified an X-aptamer that specifically binds to CIRP (XA-CIRP). Structurally, XA-CIRP blocked the interaction between CIRP and TLR4. Functionally, it reduced CIRP-induced pancreatic acinar cell injury in vitro and L-arginine-induced pancreatic injury and inflammation in vivo. Thus, targeting extracellular CIRP with X-aptamers may be a promising strategy to treat AP.
... These results can not be explained by differences in binding affinity as the aptamer HD22 is the stronger binder of thrombin. (Zhao et al., 2021). Instead they are more likely to be ascribed to differences in binding stoichiometry, given that it has previously been shown (Tasset et al., 1997) that two TBA aptamers can bind one thrombin molecule simultaneously, whereas this is not the case for HD22, which can only bind at exosite II. ...
A plug-and-play sandwich assay platform for the aptamer-based detection of molecular targets using linear dichroism (LD) spectroscopy as a read-out method has been demonstrated. A 21-mer DNA strand comprising the plug-and-play linker was bioconjugated onto the backbone of the filamentous bacteriophage M13, which gives a strong LD signal due to its ready alignment in linear flow. Extended DNA strands containing aptamer sequences that bind the protein thrombin, TBA and HD22, were then bound to the plug-and-play linker strand via complementary base pairing to generate aptamer-functionalised M13 bacteriophages. The secondary structure of the extended aptameric sequences required to bind to thrombin was checked using circular dichroism spectroscopy, with the binding confirmed using fluorescence anisotropy measurements. LD studies revealed that this sandwich sensor design is very effective at detecting thrombin down to pM levels, indicating the potential of this plug-and-play assay system as a new label-free homogenous detection system based on aptamer recognition.
... For example, the designed DNA sequences can develop a specific secondary structure and switch their configuration under the interaction of metal ions, 44,45 small molecules, 46,47 and proteins. 47,48 Once stimulated, the switchable DNA structures can act as procedures to drive dynamic assembly/disassembly of NCs for changing the imaging performance of NCs, resulting in responsive signals. These elegant characteristics indicate that DNA is a reliable baseband for NCs to realize efficient biomedical imaging. ...
DNA-mediated programming is emerging as an effective technology that enables controlled dynamic assembly/disassembly of inorganic nanocrystals (NC) with precise numbers and spatial locations for biomedical imaging applications. In this review, we will begin with a brief overview of the rules of NC dynamic assembly driven by DNA ligands, and the research progress on the relationship between NC assembly modes and their biomedical imaging performance. Then, we will give examples on how the driven program is designed by different interactions through the configuration switching of DNA-NC conjugates for biomedical applications. Finally, we will conclude with the current challenges and future perspectives of this emerging field. Hopefully, this review will deepen our knowledge on the DNA-guided precise assembly of NCs, which may further inspire the future development of smart chemical imaging devices and high-performance biomedical imaging probes.
... Correspondingly, the administration of exogenous accessible DNA can directly react with RONS to reduce cell damage and alleviate AKI. Moreover, DNA has excellent inherent biocompatibility and biodegradability [176,177]. Therefore, DNA is extremely promising as a drug (Fig. 10A) [164]. tFNAs had high stability and were stable in DNase-rich cell lysates for up to 9 h tFNAs were preferentially taken up by the kidney (Fig. 10B), and renal function was recovered in the rhabdomyolysis-induced AKI (RM-AKI) mouse model (Fig. 10C). ...
Currently, there are no clinical drugs available to treat acute kidney injury (AKI). Given the high prevalence and high mortality rate of AKI, the development of drugs to effectively treat AKI is a huge unmet medical need and a research hotspot. Although existing evidence fully demonstrates that reactive oxygen and nitrogen species (RONS) burst at the AKI site is a major contributor to AKI progression, the heterogeneity, complexity, and unique physiological structure of the kidney make most antioxidant and anti-inflammatory small molecule drugs ineffective because of the lack of kidney targeting and side effects. Recently, nanodrugs with intrinsic kidney targeting through the control of size, shape, and surface properties have opened exciting prospects for the treatment of AKI. Many antioxidant nanodrugs have emerged to address the limitations of current AKI treatments. In this review, we systematically summarized for the first time about the emerging nanodrugs that exploit the pathological and physiological features of the kidney to overcome the limitations of traditional small-molecule drugs to achieve high AKI efficacy. First, we analyzed the pathological structural characteristics of AKI and the main pathological mechanism of AKI: hypoxia, harmful substance accumulation-induced RONS burst at the renal site despite the multifactorial initiation and heterogeneity of AKI. Subsequently, we introduced the strategies used to improve renal targeting and reviewed advances of nanodrugs for AKI: nano-RONS-sacrificial agents, antioxidant nanozymes, and nanocarriers for antioxidants and anti-inflammatory drugs. These nanodrugs have demonstrated excellent therapeutic effects, such as greatly reducing oxidative stress damage, restoring renal function, and low side effects. Finally, we discussed the challenges and future directions for translating nanodrugs into clinical AKI treatment.
... 339−344 In one representative work, DNA origami was used as a cytotoxic protein vehicle for cancer therapy. 344 Rectangular DNA origami sheets were constructed to decorate ssDNA-tagged ribonuclease (RNase) A molecules via hybridization. MUC-1 aptamer strands that targeted mucin 1 (glycoproteins overexpressed on the surface of MCF 7 cells) were attached to the edges of the origami sheets to enhance the breast cancer cell internalization of the nanocarriers. ...
... They also presented a DNA origami-based, thrombin-binding aptamer nanoarray for a controllable anticoagulation study. 344 Two types of thrombinrecognizable aptamers that could bind different exosites of the protein were decorated on the surface of a rectangular DNA origami sheet with precisely controlled inter-distances. The potent protein binding affinity of the bivalent aptamer array was achieved when the inter-aptamer spacing was controlled to be 5.4 nm, which matched the dimension of the thrombin molecules (∼4 nm). ...
DNA nanotechnology is a unique field, where physics, chemistry, biology, mathematics, engineering, and materials science can elegantly converge. Since the original proposal of Nadrian Seeman, significant advances have been achieved in the past four decades. During this glory time, the DNA origami technique developed by Paul Rothemund further pushed the field forward with a vigorous momentum, fostering a plethora of concepts, models, methodologies, and applications that were not thought of before. This review focuses on the recent progress in DNA origami-engineered nanomaterials in the past five years, outlining the exciting achievements as well as the unexplored research avenues. We believe that the spirit and assets that Seeman left for scientists will continue to bring interdisciplinary innovations and useful applications to this field in the next decade.
... In several trials, liver fibrosis is a complex, combined molecular and cell mechanism that has been well observed in humans as well as laboratory animals and, as such, has been called a reversible process (Bae et al., 2018;Podgórska et al., 2020;Ezhilarasan and Najimi, 2021;Zhao et al., 2021). Other studies have nevertheless shown that the complete regeneration is not accomplished and the liver cells stay on the verge of reactivating quickly into myofibroblasts, as deteriorating stimuli occur and a more serious level of fibrosis is promoted (Berumen et al., 2020;Marcelin et al., 2020;Yavuz et al., 2020). ...
Background: Hepatic fibrosis is one of the most common lesions during chronic hepatic diseases. It is a significant health issue in many countries because it can lead to cirrhosis and ultimately liver failure without careful treatment. No successful management to treat this condition has been established so far. Some medicinal plants are particularly important in this sense because of the intrinsic healing ability of their plants, as well as their long-term therapeutic capabilities and few side effects. The hepatoprotective role of desert date oil (DDO) is clearly indicated in recent studies; however, the accurate mechanisms are still unknown. Objectives: The present study was designed to investigate the hepatoprotective, antioxidant, and antifibrotic effects of desert date oil against the hepatic damage and oxidative stress induced by thioacetamide (TAA) administration in male rats. Material & Methods: In this study, 40 healthy adult albino rats were divided into four groups: group 1 (control), group 2 received orally DDO (500 mg/kg b.wt/orally every day), group 3 was injected intraperitoneally by TAA by intraperitoneal (I.P.) injection of 200 mg/kg b.wt, twice weekly to induce liver fibrosis, group 4 was injected by I.P. TAA and received DDO orally every day by the same doses as above. At the end of the experiment (8 weeks), the rats of different groups were sacrificed, and blood samples were collected for the determination of the liver function tests. Then, the abdomen of rats of different groups was opened, where the liver was removed, weighted and cut into small pieces; some pieces were homogenized to measure the oxidative (malondialdehyde [MDA]) (MDA) and antioxidative parameters (superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx), while other pieces were processed for different histological and immunohistochemical techniques. Results: The present study revealed that TAA administration to rats resulted in a significant decrease in body weight gain with an increased liver/body weight ratio (liver weight index). In addition, the levels of liver enzymes (ALT, AST, and ALP) and total bilirubin were significantly increased, while the levels of total protein and albumin were statistically decreased. TAA led to a significant increase in MDA, a lipid peroxidation marker, with a concomitant decrease in antioxidant enzymes (SOD, CAT, and GPx) when compared with the control group. The histopathological examination showed abnormal changes characterized by an obvious increase in the collagen content, and bridging fibrosis with the hepatic cells showed various degenerative changes in the cytoplasm and nucleus. The administration of DDO along with TAA resulted in improvements in all biochemical tests and histopathological changes and significantly attenuated TAA-induced oxidative damage. Conclusion: This study revealed that desert date oil has antifibrotic and hepatoprotective effects against the liver fibrosis, biochemical and structural changes induced by TAA administration in rats; possibly due to its antioxidant properties. Additionally, the obtained results
