Novel Sprayable Antioxidative Dressing Based on Fullerene and Curdlan for Accelerating Chronic Wound Healing.

The effective treatment of chronic wounds represents a critical global medical challenge demanding urgent attention. Persistent inflammation, driven by an excess of reactive oxygen radicals, sets in motion a detrimental cycle leading to chronic wounds and impeding the natural healing process. This study develops a sprayable wound dressing by covalently grafting amino fullerene to carboxymethylated curdlan (CMC-C).

Curdlan-Decorated Fullerenes Mitigate Immune-Mediated Hepatic Injury for Autoimmune Hepatitis Therapeutics via Reducing Macrophage Infiltration.

Autoimmune hepatitis (AIH) is a severe immune-mediated inflammatory liver disease whose standard of care is immunosuppressive treatment with inevitable undesired outcomes. Macrophage is acknowledged to aggravate liver damage, providing a promising AIH therapeutic target. Accordingly, in this study, a kind of curdlan-decorated fullerene nanoparticle (Cur-F) is fabricated to alleviate immune-mediated hepatic injury for treating AIH via reducing macrophage infiltration in a concanavalin A (Con A)-induced AIH mouse model.

RNA sequencing reveals a complete picture of a homozygous missense variant in a patient with VPS13D movement disorder: a case report and review of the literature.

RNA sequencing (RNA-seq) is a complementary diagnostic tool to exome sequencing (ES), only recently clinically available to undiagnosed patients post-ES, that provides functional information on variants of unknown significance (VUS) by evaluating its effect on RNA transcription. ES became clinically available in the early 2010s and promised an agnostic platform for patients with a neurological disease, especially for those who believed to have a genetic etiology. However, the massive data generated by ES pose challenges in variant interpretation, especially for rare missense, synonymous, and deep intronic variants that may have a splicing effect.

Construction and characterization of folate-functionalized curdlan-trilysine siRNA delivery platform for in vivo hepatic carcinoma treatment.

RNA interference technology is a powerful tool with substantially clinical prospects for carcinoma therapy, in which efficiency and specificity of delivery of dsRNA remains a critical issue. Herein, aiming at delivery of dsRNA in efficient and safe way, we constructed targeting delivery platform (CTL-PEG-FA) by grafting curdlan with trilysine through click reaction, then modifying with PEG linked folic acid. The CTL-PEG-FA vector exhibited excellent gene binding capacity to condense siRNA and dramatically reduced cytotoxicity.

miR-143 Regulates Lysosomal Enzyme Transport across the Blood-Brain Barrier and Transforms CNS Treatment for Mucopolysaccharidosis Type I.

During brain maturation, cation-independent mannose-6-phosphate receptor (CI-MPR), a key transporter for lysosomal hydrolases, decreases significantly on the blood-brain barrier (BBB). Such a phenomenon leads to poor brain penetration of therapeutic enzymes and subsequent failure in reversing neurological complications in patients with neuropathic lysosomal storage diseases (nLSDs), such as Hurler syndrome (severe form of mucopolysaccharidosis type I [MPS I]). In this study, we discover that upregulation of microRNA-143 (miR-143) contributes to the decline of CI-MPR on the BBB during development.

Preparation and cell activities of lactosylated curdlan-triornithine nanoparticles for enhanced DNA/siRNA delivery in hepatoma cells.

A long-anticipated cancer therapy would deliver the right type of therapeutic agents to the target in control with minimal systemic toxicity. The purpose of this study was to prepare lactosylated curdlan-triornithine nanocarriers (CTOLs), and target deliver gene to hepatoma cells. Structures and biophysical properties had been elucidated with physical and chemical methods.

Getting the Most: Enhancing Efficacy by Promoting Erythropoiesis and Thrombopoiesis after Gene Therapy in Mice with Hurler Syndrome.

Novel strategies are needed to solve the conundrum of achieving clinical efficacy with high vector copy numbers (VCNs) in hematopoietic stem cells (HSCs) while attempting to minimize the potential risk of oncogenesis in lentiviral vector (LV)-mediated gene therapy clinical trials. We previously reported the benefits of reprogramming erythroid-megakaryocytic (EMK) cells for high-level lysosomal enzyme production with less risk of activating oncogenes in HSCs. Herein, using a murine model of mucopolysaccharidosis type I (MPS I) with a deficiency of α-L-iduronidase (IDUA), we sought to determine the transgene minimum effective doses (MEDs) in major organs, and if a transient increase of IDUA-containing red blood cells and platelets by repeated phlebotomy would provide further therapeutic benefits in diseased mice after EMK-restricted LV-mediated gene therapy.

"Click" chemistry mediated construction of cationic curdlan nanocarriers for efficient gene delivery.

A cationic group has been quantitatively and selectively introduced into C6 position of each glucose units of Curdlan by "Click Chemistry" successfully. The resulting cationic Curdlan-Imidazole-lysine polymers (Cur-6-100Lys) exhibit excellent water solubility. Structure of the Cur-6-100Lys complexes was verified by FTIR and NMR spectroscopic measurements, and analysis of Cur-6-100Lys by GPC, DLS and SEM revealed that they have stoichiometric, nanosized spheroidal structures.

PEGylation of 6-amino-6-deoxy-curdlan for efficient in vivo siRNA delivery.

RNA interference (RNAi) is an evolutionarily conserved gene-silencing phenomenon that shows great promise for developing new therapies. However, the development of small interfering RNA (siRNA)-based therapies need to establish efficient delivery system that silences target genes with siRNA doses that is clinically feasible in humans. Here we report synthesis and in vivo study of a novel PEGylated curdlan-based nanoparticle, designated as 6AC-100PEG, obtained by conjugation of mPEG 2000 to 6-amino-6-deoxy-curdlan.

Cell Type-Specific Delivery of RNAi by Ligand-Functionalized Curdlan Nanoparticles: Balancing the Receptor Mediation and the Charge Motivation.

Tissue-specific delivery of therapeutic RNAi has great potential for clinical applications. Receptor-mediated endocytosis plays a crucial role in targeted delivery of biotherapeutics including short interfering RNA (siRNA). Previously we reported a novel Curdlan-based nanoparticle for intracellular delivery of siRNA.

Preparation of novel curdlan nanoparticles for intracellular siRNA delivery.

RNA interference (RNAi) down-regulates gene expression post-transcriptionally, which is a therapeutically significant phenomenon that could potentially reduce the level of disease related proteins that are undruggable by conventional small molecular approaches. However, clinical application of small interference RNAs (siRNAs) requires design of potent siRNA sequences and development of safe and efficient delivery systems. To create a biocompatible siRNA delivery agent, we chemically modified natural polysaccharide curdlan in a regioselective manner to introduce amino group in the glucose units.

Normalization and improvement of CNS deficits in mice with Hurler syndrome after long-term peripheral delivery of BBB-targeted iduronidase.

Mucopolysaccharidosis type I (MPS I) is a progressive lysosomal storage disorder with systemic and central nervous system (CNS) involvement due to deficiency of α-L-iduronidase (IDUA). We previously identified a receptor-binding peptide from apolipoprotein E (e) that facilitated a widespread delivery of IDUAe fusion protein into CNS. In this study, we evaluated the long-term CNS biodistribution, dose-correlation, and therapeutic benefits of IDUAe after systemic, sustained delivery via hematopoietic stem cell (HSC)-mediated gene therapy with expression restricted to erythroid/megakaryocyte lineages.

Platelets are efficient and protective depots for storage, distribution, and delivery of lysosomal enzyme in mice with Hurler syndrome.

Use of megakaryocytes/platelets for transgene expression may take advantage of their rapid turnover and protective storage in platelets and reduce the risk of activating oncogenes in hematopoietic stem and progenitor cells (HSCs). Here, we show that human megakaryocytic cells could overexpress the lysosomal enzyme, α-l-iduronidase (IDUA), which is deficient in patients with mucopolysaccharidosis type I (MPS I). Upon megakaryocytic differentiation, the amount of released enzyme increased rapidly and steadily by 30-fold.

Deep evolutionary conservation of an intramolecular protein kinase activation mechanism.

DYRK-family kinases employ an intramolecular mechanism to autophosphorylate a critical tyrosine residue in the activation loop. Once phosphorylated, DYRKs lose tyrosine kinase activity and function as serine/threonine kinases. DYRKs have been characterized in organisms from yeast to human; however, all entities belong to the Unikont supergroup, only one of five eukaryotic supergroups.

Characterization of a domain that transiently converts class 2 DYRKs into intramolecular tyrosine kinases.

Dual-specificity tyrosine phosphorylation-regulated kinases (DYRKs) autophosphorylate an essential tyrosine residue in their activation loop and phosphorylate their substrates on serine and threonine residues. Phosphorylation of the activation loop tyrosine occurs intramolecularly, is mediated by a short-lived transitional intermediate during protein maturation, and is required for functional serine-threonine kinase activity of DYRKs. The DYRK family is separated into two subclasses.

Metabolism of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) by human CYP1B1 genetic variants.

Human cytochrome P450 1B1 (CYP1B1) plays a critical role in the metabolic activation of a variety of procarcinogens, including 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). The existence of human CYP1B1 missense genetic variants has been demonstrated, but their activities in metabolizing PhIP are unknown. In this study, we expressed 15 naturally occurring CYP1B1 variants (with either single or multiple amino acid substitutions) and determined their activity changes in metabolizing PhIP to its two major metabolites, 2-hydroxyamino-PhIP and 4'-hydroxy-PhIP.

Genetic variation of human cytochrome p450 reductase as a potential biomarker for mitomycin C-induced cytotoxicity.

The importance of genetic variation in clinical response to various drugs is now well recognized. Identification of genetic biomarkers that can predict efficacy and toxicity of chemotherapeutic drugs in cancer patients holds great promise in treatment improvement and cost reduction. Mitomycin C (MMC) is a common anticancer drug used for the treatment of numerous types of tumors.

Effect of genetic variation on human cytochrome p450 reductase-mediated paraquat cytotoxicity.

Paraquat (1,1'-dimethyl-4,4'-bipyridylium dichloride) is a widely used herbicide and is highly toxic to human and animals. The mechanisms of paraquat toxicity involve the generation of superoxide anion through the process of redox cycling. NADPH-cytochrome P450 oxidoreductase (POR) has been reported to be a major enzyme for one-electron reduction of paraquat that initiates the redox cycling.

[Initial application of brain protection device in dilatation and stenting of carotid and vertebral artery stenosis].

Objective: To report the initial application of brain protection device in the dilatation and stenting of atherosclerotic stenosis of the carotid and vertebral artery.

Methods: Eighteen patients with 21 atherosclerotic stenoses of the carotid or vertebral artery underwent dilatation and/or stenting with brain protection device (filterwire or angioguard). The clinical results were summarized and the indispensability and feasibility of the device was discussed.