Poly(2‐acrylamido‐2‐methyl‐1‐propanesulfonic acid) and its copolymer hydrogels are typical polyelectrolyte gels with extremely high swelling capacity that are widely used in industry. It's common to ...consider these hydrogels as weak materials that are difficult to toughen. Reported here is a facile strategy to transform swollen and weak poly(acrylamide‐co‐2‐acrylamido‐2‐methyl‐1‐propanesulfonic acid) P(AAm‐co‐AMPS) hydrogels to tough ones by forming strong sulfonate–Zr4+ metal‐coordination complexes. The resultant hydrogels with moderate water content possess high stiffness, strength, and fracture energy, which can be tuned over 3–4 orders of magnitude by controlling the composition and metal‐to‐ligand ratio. Owing to the dynamic nature of the coordination bonds, these hydrogels show rate‐ and temperature‐dependent mechanical performances, as well as good self‐recovery properties. This strategy is universal, as manifested by the drastically improved mechanical properties of hydrogels of various natural and synthetic sulfonate‐containing polymers. The toughened hydrogels can be converted to the original swollen ones by breaking up the metal‐coordination complexes in alkaline solutions. The reversible brittle–tough transition and concomitant dramatic volume change of polyelectrolyte hydrogels afford diverse applications, as demonstrated by the design of a tubular grasper with holding force a thousand times its own weight for objects with different geometries. It is envisioned that these hydrogels enable versatile applications in the biomedical and engineering fields.
Reversible transformation of polyelectrolyte hydrogels between swollen, weak states and collapsed, tough states is realized by formation and breaking up of robust metal‐coordination complexes. The dramatic variations of the gels’ volume and mechanical properties over 3–4 orders of magnitude enable the design of a hydrogel‐based tubular grasper with high holding force, i.e., thousand times its own weight, to grip objects with different geometries.
Abstract Exosomes as a unique subtype of small extracellular vesicles (sEVs) have attracted increasing interest in recent years in the fields of mesenchymal stromal cell (MSC) research. Studies have ...confirmed that exosomes derived from MSCs preserve immunosuppressive phenotype and can mimic therapeutic benefits of their parent cells. This review briefly summarizes most recent findings on the potential of exosomes as an alternative of therapeutic MSCs, focusing on the role of MSCs and their secreted exosomes in regulation of immune cells, preclinical and clinical evidence of therapeutic outcomes of MSC exosomes, and the biodistribution and pharmacokinetic profile of systemically administered exosomes. It is appreciated that exosomes from MSCs of different sources have variable contents including inflammatory mediators, tropic factors, signaling molecules, and nucleic acids (DNA, mRNA, microRNA and long non-coding RNA). Diverse functions of exosomes derived from different sources are expected. More importantly, exosomes isolated in vitro may not mirror that from in vivo, where donor MSCs are exposed to specific disease or injury-related conditions. Simulating in vivo microenvironment by pretreatment of MSCs with relevant chemical mediators may lead to their secretion of therapeutically more efficient exosomes/sEVs. However, we know very little about the key molecules involved and the differences between exosomes released under different conditions. These issues would be of tremendous interest to preclinical research that pursues exosome biology-underlain therapeutic mechanisms of MSCs. Further studies are expected to demonstrate the superiority of MSC-derived exsomes/sEVs as a pharmaceutical entity with regard to efficacy, safety, and practicability.
Abstract
More than 100 distinct chemical modifications to RNA have been characterized so far. However, the prevalence, mechanisms and functions of various RNA modifications remain largely unknown. To ...provide transcriptome-wide landscapes of RNA modifications, we developed the RMBase v2.0 (http://rna.sysu.edu.cn/rmbase/), which is a comprehensive database that integrates epitranscriptome sequencing data for the exploration of post-transcriptional modifications of RNAs and their relationships with miRNA binding events, disease-related single-nucleotide polymorphisms (SNPs) and RNA-binding proteins (RBPs). RMBase v2.0 was expanded with ∼600 datasets and ∼1 397 000 modification sites from 47 studies among 13 species, which represents an approximately 10-fold expansion when compared with the previous release. It contains ∼1 373 000 N6-methyladenosines (m6A), ∼5400 N1-methyladenosines (m1A), ∼9600 pseudouridine (Ψ) modifications, ∼1000 5-methylcytosine (m5C) modifications, ∼5100 2′-O-methylations (2′-O-Me), and ∼2800 modifications of other modification types. Moreover, we built a new module called 'Motif' that provides the visualized logos and position weight matrices (PWMs) of the modification motifs. We also constructed a novel module termed 'modRBP' to study the relationships between RNA modifications and RBPs. Additionally, we developed a novel web-based tool named 'modMetagene' to plot the metagenes of RNA modification along a transcript model. This database will help researchers investigate the potential functions and mechanisms of RNA modifications.
Biofilms that contribute to the persistent bacterial infections pose serious threats to global public health, mainly due to their resistance to antibiotics penetration and escaping innate immune ...attacks by phagocytes. Here, we report a kind of surface-adaptive gold nanoparticles (AuNPs) exhibiting (1) a self-adaptive target to the acidic microenvironment of biofilm, (2) an enhanced photothermal ablation of methicillin-resistant Staphylococcus aureus (MRSA) biofilm under near-infrared (NIR) light irradiation, and (3) no damage to the healthy tissues around the biofilm. Originally, AuNPs were readily prepared by surface modification with pH-responsive mixed charged zwitterionic self-assembled monolayers consisting of weak electrolytic 11-mercaptoundecanoic acid (HS-C10-COOH) and strong electrolytic (10-mercaptodecyl)trimethylammonium bromide (HS-C10-N4). The mixed charged zwitterion-modified AuNPs showed fast pH-responsive transition from negative charge to positive charge, which enabled the AuNPs to disperse well in healthy tissues (pH ∼7.4), while quickly presenting strong adherence to negatively charged bacteria surfaces in MRSA biofilm (pH ∼5.5). Simultaneous AuNP aggregation within the MRSA biofilm enhanced the photothermal ablation of MRSA biofilm under NIR light irradiation. The surrounding healthy tissues showed no damage because the dispersed AuNPs had no photothermal effect under NIR light. In view of the above advantages as well as the straightforward preparation, AuNPs developed in this work may find potential applications as a useful antibacterial agent in the areas of healthcare.
Ischemia‐reperfusion injury (IRI) and cardiac allograft vasculopathy (CAV) remain unsolved complications post–heart transplant (Tx). The antioxidant transcription factor Nuclear factor erythroid ...2‐related factor 2 (Nrf2) has been suggested to inhibit reactive oxygen species‐mediated NF‐κB activation. We hypothesized that Nrf2 inhibits NF‐κB activation post–Tx and suppresses IRI and the subsequent development of CAV. IRI and CAV were investigated in murine heterotopic Tx models, respectively. Nrf2 wild‐type (WT) and KO mice were used as donors. Sulforaphane was used as an Nrf2 agonist. In saline‐treated animals following 24 hours of reperfusion in isogenic grafts, Nrf2‐KO showed significantly less SOD1/2 activity compared with WT. Nrf2‐KO displayed significantly high total and phosphorylated p65 expressions and percentage of cells with nuclear p65. mRNA levels of NF‐κB‐mediated proinflammatory genes were also high. Graft dysfunction, apoptosis, and caspase‐3 activity were significantly higher in Nrf2‐KO. In the allograft studies, graft beating score was significantly weaker in Nrf2‐KO compared with WT. Nrf2‐KO also demonstrated significantly more coronary luminal narrowing. In WT animals, sulforaphane successfully augmented all the protective effects of Nrf2 with increase of SOD2 activity. Nrf2 inhibits NF‐κB activation and protects against IRI via its antioxidant properties and suppresses the subsequent development of CAV.
The antioxidant transcription factor nuclear factor erythroid 2–related factor 2 inhibits nuclear factor‐kappaB activation and protects against ischemia‐reperfusion injury via its antioxidant properties and suppresses the subsequent development of cardiac allograft vasculopathy.
Vascular restenosis after balloon dilation is largely caused by the over‐proliferation of smooth muscle cells, which is triggered and exacerbated by local excessive inflammation and oxidative stress. ...The excessive inflammatory and oxidative stress cause tissue/cell damage, hamper endothelial functions, and worsen intimal hyperplasia and restenosis. A high level of reactive oxygen species (ROS) overproduction is regarded as the main culprit. Therefore, efficiently inhibiting ROS over‐production or weightily depleting them is of great significance. Herein, a “ROS‐responsive/scavenging prodrug” is introduced into balloon coating for the treatment of vascular restenosis. A reversible phenylboronic ester‐bearing caffeic acid (CA) macromolecular prodrug (PBC) is designed for the controlled and on‐demand dual‐drug release triggered by the local high ROS level; the released CA and 4‐hydroxybenzyl alcohol exhibit efficient antioxidant and anti‐inflammatory effects by scavenging ROS, thereby regulating vascular microenvironment and protecting endothelium functions. To accelerate endothelium regeneration, pro‐endothelial microRNA‐126 is further introduced. The ROS‐responsive/scavenging prodrug/miRNA balloon coating efficiently prevents intimal hyperplasia, alleviates local inflammation, and improves endothelium healing in a rat abdominal aorta restenosis model, which may provide applicative perspectives for next‐generation drug‐coated balloons and other cardiovascular diseases treatment.
A reversible phenylboronic ester‐bearing caffeic acid (CA) macromolecular prodrug (PBC) is designed for the controlled and on‐demand dual‐antioxidant release (CA and 4‐hydroxybenzyl alcohol (HBA)) triggered by the local high reactive oxygen species (ROS) level, thereby exhibiting antioxidant and anti‐inflammatory effects; the pro‐endothelial microRNA‐126 is introduced to further accelerate endothelialization. This ROS‐responsive/scavenging prodrug/miRNA balloon coating efficiently inhibits long‐term vascular restenosis.
A high-entropy (Bi0.2Na0.2K0.2Ba0.2Ca0.2)TiO3 (BNKBCT) ceramic is successfully fabricated by using flash sintering technique. The synthesis and densification of BNKBCT are simultaneously carried out ...by a stepwise current-ramping flash sintering process. Despite the presence of excessive Na+ and K+ ions, single-phase perovskite ceramics are obtained with uniform elemental distribution. The dielectric characterization reveals the relaxor ferroelectric nature of BNKBCT ceramic. Moreover, the discharge energy storage density and efficiency of the as-prepared BNKBCT ceramic are 0.684 J/cm3 and 87.5% under the electric field of 129 kV/cm, respectively. These results indicate that the introduction of high entropy is a viable strategy to tune the properties of electrical ceramics.
The abnormal transcriptional regulation of non-coding RNAs (ncRNAs) and protein-coding genes (PCGs) is contributed to various biological processes and linked with human diseases, but the underlying ...mechanisms remain elusive. In this study, we developed ChIPBase v2.0 (http://rna.sysu.edu.cn/chipbase/) to explore the transcriptional regulatory networks of ncRNAs and PCGs. ChIPBase v2.0 has been expanded with ∼10 200 curated ChIP-seq datasets, which represent about 20 times expansion when comparing to the previous released version. We identified thousands of binding motif matrices and their binding sites from ChIP-seq data of DNA-binding proteins and predicted millions of transcriptional regulatory relationships between transcription factors (TFs) and genes. We constructed 'Regulator' module to predict hundreds of TFs and histone modifications that were involved in or affected transcription of ncRNAs and PCGs. Moreover, we built a web-based tool, Co-Expression, to explore the co-expression patterns between DNA-binding proteins and various types of genes by integrating the gene expression profiles of ∼10 000 tumor samples and ∼9100 normal tissues and cell lines. ChIPBase also provides a ChIP-Function tool and a genome browser to predict functions of diverse genes and visualize various ChIP-seq data. This study will greatly expand our understanding of the transcriptional regulations of ncRNAs and PCGs.
Extracellular vesicles (EVs) have emerged as important regulators of inter‐cellular and inter‐organ communication, in part via the transfer of their cargo to recipient cells. Although circulating EVs ...have been previously studied as biomarkers of aging, how circulating EVs change with age and the underlying mechanisms that contribute to these changes are poorly understood. Here, we demonstrate that aging has a profound effect on the circulating EV pool, as evidenced by changes in concentration, size, and cargo. Aging also alters particle function; treatment of cells with EV fractions isolated from old plasma reduces macrophage responses to lipopolysaccharide, increases phagocytosis, and reduces endothelial cell responses to vascular endothelial growth factor compared to cells treated with young EV fractions. Depletion studies indicate that CD63+ particles mediate these effects. Treatment of macrophages with EV‐like particles revealed that old particles increased the expression of EV miRNAs in recipient cells. Transfection of cells with microRNA mimics recapitulated some of the effects seen with old EV‐like particles. Investigation into the underlying mechanisms using bone marrow transplant studies revealed circulating cell age does not substantially affect the expression of aging‐associated circulating EV miRNAs in old mice. Instead, we show that cellular senescence contributes to changes in particle cargo and function. Notably, senolytic treatment of old mice shifted plasma particle cargo and function toward that of a younger phenotype. Collectively, these results demonstrate that senescent cells contribute to changes in plasma EVs with age and suggest a new mechanism by which senescent cells can affect cellular functions throughout the body.
Senescent cells accumulate in the body with aging and alter circulating extracellular vesicle microRNA content. This can be replicated in young mice by inducing senescence using sub‐lethal irradiation. Conversely, removal of senescent cells in aged mice by senolytic treatment restores circulating extracellular vesicle microRNA expression to that of a younger phenotype.
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