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The Journal of Pharmacology and... Nov 2023Pompe disease is a rare glycogen storage disorder caused by a deficiency in the lysosomal enzyme acid -glucosidase, which leads to muscle weakness, cardiac and...
Pompe disease is a rare glycogen storage disorder caused by a deficiency in the lysosomal enzyme acid -glucosidase, which leads to muscle weakness, cardiac and respiratory failure, and early mortality. Alglucosidase alfa, a recombinant human acid -glucosidase, was the first approved treatment of Pompe disease, but its uptake into skeletal muscle via the cation-independent mannose-6-phosphate (M6P) receptor (CIMPR) is limited. Avalglucosidase alfa has received marketing authorization in several countries for infantile-onset and/or late-onset Pompe disease. This recently approved enzyme replacement therapy (ERT) was glycoengineered to maximize CIMPR binding through high-affinity interactions with ∼7 bis-M6P moieties. Recently, small molecules like the glucosylceramide synthase inhibitor miglustat were reported to increase the stability of recombinant human acid -glucosidase, and it was suggested that an increased serum half-life would result in better glycogen clearance. Here, the effects of miglustat on alglucosidase alfa and avalglucosidase alfa stability, activity, and efficacy in Pompe mice were evaluated. Although miglustat increased the stability of both enzymes in fluorescent protein thermal shift assays and when incubated in neutral pH buffer over time, it reduced their enzymatic activity by ∼50%. Improvement in tissue glycogen clearance and transcriptional dysregulation in Pompe mice correlated with M6P levels but not with miglustat coadministration. These results further substantiate the crucial role of CIMPR binding in lysosomal targeting of ERTs. SIGNIFICANCE STATEMENT: This work describes important new insights into the treatment of Pompe disease using currently approved enzyme replacement therapies (ERTs) coadministered with miglustat. Although miglustat increased the stability of ERTs in vitro, there was no positive impact to glycogen clearance and transcriptional correction in Pompe mice. However, increasing mannose-6-phosphate levels resulted in increased cell uptake in vitro and increased glycogen clearance and transcriptional correction in Pompe mice, further underscoring the crucial role of cation-independent mannose-6-phosphate receptor-mediated lysosomal targeting for ERTs.
PubMed: 37679046
DOI: 10.1124/jpet.123.001593 -
FASEB Journal : Official Publication of... Nov 2023The complement system is a complex, tightly regulated protein cascade involved in pathogen defense and the pathogenesis of several diseases. Thus, the development of...
The complement system is a complex, tightly regulated protein cascade involved in pathogen defense and the pathogenesis of several diseases. Thus, the development of complement modulators has risen as a potential treatment for complement-driven inflammatory pathologies. The enzymatically inactive MAP-2 has been reported to inhibit the lectin pathway by competing with its homologous serine protease MASP-2. The membrane-bound complement inhibitor CD55 acts on the C3/C5 convertase level. Here, we fused MAP-2 to the four N-terminal domains of CD55 generating a targeted chimeric inhibitor to modulate complement activation at two different levels of the complement cascade. Its biological properties were compared in vitro with the parent molecules. While MAP-2 and CD55 alone showed a minor inhibition of the three complement pathways when co-incubated with serum (IC50 = 60.98, 36.10, and 97.01 nM on the classical, lectin, and alternative pathways, respectively), MAP-2:CD55 demonstrated a potent inhibitory activity (IC50 = 2.94, 1.76, and 12.86 nM, respectively). This inhibitory activity was substantially enhanced when pre-complexes were formed with the lectin pathway recognition molecule mannose-binding lectin (IC50 = 0.14 nM). MAP-2:CD55 was also effective at protecting sensitized sheep erythrocytes in a classical hemolytic assay (CH50 = 13.35 nM). Finally, the chimeric inhibitor reduced neutrophil activation in full blood after stimulation with Aspergillus fumigatus conidia, as well as phagocytosis of conidia by isolated activated neutrophils. Our results demonstrate that MAP-2:CD55 is a potent complement inhibitor reinforcing the idea that engineered fusion proteins are a promising design strategy for identifying and developing drug candidates to treat complement-mediated diseases.
Topics: Animals; Sheep; Complement Activation; Complement System Proteins; CD55 Antigens; Lectins; Transcription Factors; Complement Inactivating Agents; Mannose-Binding Protein-Associated Serine Proteases
PubMed: 37823685
DOI: 10.1096/fj.202300571R -
Bioorganic & Medicinal Chemistry Letters Mar 2024Hydrogen sulfide (HS) plays a critical role in cancer biology. Herein, we developed a series of glycosidase-triggered hydrogen sulfide (HS) donors by connecting sugar...
Hydrogen sulfide (HS) plays a critical role in cancer biology. Herein, we developed a series of glycosidase-triggered hydrogen sulfide (HS) donors by connecting sugar moieties (including glucose, galactose and mannose) to COS donors via a self-immolative spacer. In the presence of corresponding glycosidases, HS was gradually released from these donors in PBS buffer with releasing efficiencies from 36 to 67 %. HS release was also detected by HS probe WSP-1 after treatment HepG2 cells with Man1. Cytotoxicities of these glycosylated HS donors were evaluated against HepG2 by MTT assay. Among them, Man1 and Man2 exhibited an obvious reduction of cell viability in HepG2 cells, with cell viability as 37.6 % for 80 μM of Man. Consistently, significant apoptosis was observed in HepG2 cells after treatment with Man1 and Man2. Finally, We evaluated the potential of Man1 for combination therapy with doxorubicin. A synergistic effect was observed between Man1 and Doxorubicin in HepG2 and Hela cells. All these results indicated glycosidase-activated HS donorshave promising potential for cancer therapy.
Topics: Humans; HeLa Cells; Hydrogen Sulfide; Sulfur Oxides; Doxorubicin; Glycoside Hydrolases
PubMed: 38316370
DOI: 10.1016/j.bmcl.2024.129644 -
Drug Delivery Dec 2023Hepatocellular carcinoma (HCC) is a malignant tumor leading cancer-associated high mortality worldwide. Unfortunately, the most commonly used drug therapeutics not only...
Hepatocellular carcinoma (HCC) is a malignant tumor leading cancer-associated high mortality worldwide. Unfortunately, the most commonly used drug therapeutics not only lack of target ability and efficiency, but also exhibit severe systemic toxicity to normal tissues. Thus, effective and targeted nanodrug of HCC therapy is emerging as a more important issue. Here, we design and develop the novel nanomicelles, namely Mannose-polyethylene glycol 600-Nitroimidazole (Man-NIT). This micelle compound with high purity comprise two parts, which can self-assemble into nanoscale micelle. The outer shell is selected mannose as hydrophilic moiety, while the inner core is nitroimidazole as hydrophobic moiety. In the cell experiment, Man-NIT was more cellular uptake by HCCLM3 cells due to the mannose modification. Mannose as a kind of glucose transporter 1 (GLUT1) substrate, can specifically recognize and bind to over-expressed GLUT1 on carcinoma cytomembrane. The nitroimidazole moiety of Man-NIT was reduced by the over-expressed nitroreductase with reduced nicotinamide adenine dinucleotide phosphate (NADPH) as the cofactor, resulting in transient deletion of NADPH and glutathione (GSH). The increase of reactive oxygen species (ROS) in HCCLM3 cells disturbed the balance of redox, and finally caused the death of tumor cells. Additional in vivo experiment was conducted using twenty-four male BALB/c nude mice to build the tumor model. The results showed that nanomicelles were accumulated in the liver of mice. The tumor size and pathological features were obviously improved after nanomicelles treatment. It indicates that namomicelles have a tumor inhibition effect, especially Man-NIT, which may be a potential nanodrug of chemotherapeutics for HCC therapy.
Topics: Male; Mice; Animals; Carcinoma, Hepatocellular; NADP; Glucose Transporter Type 1; Liver Neoplasms; Micelles; Mice, Nude; Mannose; Cell Line, Tumor
PubMed: 36579634
DOI: 10.1080/10717544.2022.2162160 -
Annals of Translational Medicine Aug 2023
PubMed: 37675326
DOI: 10.21037/atm-23-1550 -
Microorganisms May 2024Conjugation of carbohydrates to nanomaterials has been extensively studied and recognized as an alternative in the biomedical field. Dendrimers synthesized with mannose...
Conjugation of carbohydrates to nanomaterials has been extensively studied and recognized as an alternative in the biomedical field. Dendrimers synthesized with mannose at the end group and with entrapped zero-valent copper/silver could be a potential candidate against bacterial proliferation. This study is aimed at investigating the bactericidal activity of metal-glycodendrimers. The Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction was used to synthesize a new mannosylated dendrimer containing 12 mannopyranoside residues in the periphery. The enterotoxigenic fimbriae 4 (ETEC:F4) viability, measured at 600 nm, showed the half-inhibitory concentration (IC) of metal-free glycodendrimers (D), copper-loaded glycodendrimers (D:Cu) and silver-loaded glycodendrimers (D:Ag) closed to 4.5 × 10, 3.5 × 10 and to 1.0 × 10 µg/mL, respectively, and minimum inhibitory concentration (MIC) of D, D:Cu and D:Ag of 2.0, 1.5 and 1.0 × 10 µg/mL, respectively. The release of bacteria contents onto broth and the inhibition of ETEC:F4 biofilm formation increased with the number of metallo-glycodendrimer materials, with a special interest in silver-containing nanomaterial, which had the highest activity, suggesting that glycodendrimer-based materials interfered with bacteria-bacteria or bacteria-polystyrene interactions, with bacteria metabolism and can disrupt bacteria cell walls. Our findings identify metal-mannose-dendrimers as potent bactericidal agents and emphasize the effect of entrapped zero-valent metal against ETEC:F4.
PubMed: 38792795
DOI: 10.3390/microorganisms12050966 -
Small (Weinheim An Der Bergstrasse,... Jun 2024Osteoarthritis (OA) is a dynamic condition characterized by cartilage damage and synovial inflammation. Ozone (O) shows potential therapeutic effects owing to its...
Osteoarthritis (OA) is a dynamic condition characterized by cartilage damage and synovial inflammation. Ozone (O) shows potential therapeutic effects owing to its anti-inflammatory properties; however, its high reactivity and short half-life substantially limit its effectiveness in OA treatment. In this study, an ozone-rich thermosensitive nanocomposite hydrogel loaded with D-mannose is developed for OA treatment. Briefly, O is encapsulated in nanoparticles (NPs) composed of perfluorotributylamine and fluorinated hyaluronic acid to improve its stability. Next, D-mannose is conjugated with α-amino of the hydroxypropyl chitin (HPCH) via Schiff base to prepare MHPCH. These nanoparticles are encapsulated in MHPCH to produce O NPs@MHPCH. In vitro cell experiments demonstrate that the O NPs@MHPCH treatment significantly reduced VEGF and inflammation levels, accompanied by a decrease in inflammatory factors such as IL-1β, IL-6, TNF-α, and iNOS. Furthermore, O NPs@MHPCH promotes the expression of collagen II and aggrecan and stimulates chondrocyte proliferation. Additionally, in vivo studies show that O NPs@MHPCH significantly alleviated OA by reducing synovial inflammation, cartilage destruction, and subchondral bone remodeling. O NPs@MHPCH offers a promising option for improving the efficacy of O therapy and reducing the risk of synovial inflammation and cartilage degeneration in OA.
Topics: Nanocomposites; Osteoarthritis; Animals; Ozone; Anti-Inflammatory Agents; Hydrogels; Mannose; Cartilage; Mice; Male; Injections; Chondrocytes
PubMed: 38279613
DOI: 10.1002/smll.202309597 -
Food & Function Jan 2024Delayed mucosal healing and impaired intestinal epithelial barrier function have been implicated in the pathogenesis of ulcerative colitis (UC). Accordingly, restoration...
Delayed mucosal healing and impaired intestinal epithelial barrier function have been implicated in the pathogenesis of ulcerative colitis (UC). Accordingly, restoration of epithelial barrier function as a means to reshape mucosal homeostasis represents an important strategy for use in the treatment of UC. In this study, we examined the role and mechanisms of D-mannose in the recovery of colitis as assessed in both animal and cell models. We found that D-mannose ameliorated inflammation, promoted mucosal healing in the colon and therefore was able to induce the recovery of UC. Furthermore, D-mannose increased the expression of tight junction (TJ) proteins and reduced the intestinal permeability during the recovery of colitis. Moreover, D-mannose inhibited M1 macrophage polarization and promoted M2 macrophage polarization inducing AMPK phosphorylation while reducing mTOR phosphorylation in both models. In addition, increased TJ protein expression and decreased paracellular permeability were observed in NCM460 cells when incubated with the supernatants of D-mannose-treated RAW264.7 cells, suggesting that M1/M2 polarization induced by D-mannose modulates the expression of TJ proteins. Further study showed that D-mannose significantly upregulated the expression of TJ proteins in DSS-treated NCM460 cells by inducing AMPK phosphorylation, indicating a direct protective effect on epithelial cells. Finally, the protective effects of D-mannose were significantly abrogated by the presence of compound C, an AMPK inhibitor. Taken together, our data indicate that D-mannose can alleviate inflammation and foster epithelial restitution in UC recovery by inducing the TJ protein expression, which are achieved by inducing AMPK phosphorylation in the epithelium and/or macrophages.
Topics: Animals; Mice; AMP-Activated Protein Kinases; Mannose; Phosphorylation; Intestinal Mucosa; Colitis; Colitis, Ulcerative; Inflammation; Tight Junction Proteins; Dextran Sulfate; Mice, Inbred C57BL; Disease Models, Animal; Colon
PubMed: 38099724
DOI: 10.1039/d3fo03146b -
Carbohydrate Research Sep 20232-Deoxy-d-glucose (2-DG), a compound known to interfere with d-glucose and d-mannose metabolism, has been tested as a potential anticancer and antiviral agent....
2-Deoxy-d-glucose (2-DG), a compound known to interfere with d-glucose and d-mannose metabolism, has been tested as a potential anticancer and antiviral agent. Preclinical and clinical studies focused on 2-DG have highlighted several limitations related to 2-DG drug-like properties, such as poor pharmacokinetic properties. To overcome this problem, we proposed design and synthesis of novel 2-DG prodrugs that subsequently could be tested using a variety of biochemical and molecular methods. We narrowed here our focus to esters of 2-DG as potential prodrugs based on the hypothesis that ubiquitous esterases will regenerate 2-DG, leading to increased circulation time of drug and adequate organ and tumor penetration. Testing this hypothesis in vitro and, especially, in vivo requires significant amounts of respective pure mono- and previously unknown di-acetylated water-soluble derivatives of 2-DG. Development of their efficient and practical method of synthesis was imperative. We describe novel facile and scalable syntheses of seven selectively acetylated water-soluble derivatives of 2-DG and present a detailed H and C NMR analysis of all final products. X-ray diffraction analysis has been performed for compound WP1122 that was selected for detailed preclinical and subsequent clinical evaluation as potential anticancer or antiviral agent.
Topics: Glucose; Antimetabolites; Mannose; Prodrugs; Deoxyglucose; Antiviral Agents
PubMed: 37356236
DOI: 10.1016/j.carres.2023.108861 -
Journal of Advanced Research Apr 2024It is widely acknowledged that dietary habits have profound impacts on human health and diseases. As the most important sweeteners and energy sources in human diets,... (Review)
Review
BACKGROUND
It is widely acknowledged that dietary habits have profound impacts on human health and diseases. As the most important sweeteners and energy sources in human diets, hexoses take part in a broad range of physiopathological processes. In recent years, emerging evidence has uncovered the crucial roles of hexoses, such as glucose, fructose, mannose, and galactose, in controlling the differentiation or function of immune cells.
AIM OF REVIEW
Herein, we reviewed the latest research progresses in the hexose-mediated modulation of immune responses, provided in-depth analyses of the underlying mechanisms, and discussed the unresolved issues in this field.
KEY SCIENTIFIC CONCEPTS OF REVIEW
Owing to their immunoregulatory effects, hexoses affect the onset and progression of various types of immune disorders, including inflammatory diseases, autoimmune diseases, and tumor immune evasion. Thus, targeting hexose metabolism is becoming a promising strategy for reversing immune abnormalities in diseases.
PubMed: 38631430
DOI: 10.1016/j.jare.2024.04.014