Hepatic fibrosis progresses concomitantly with a variety of biomechanical alternations, especially increased liver stiffness. These biomechanical alterations have long been considered as pathological consequences. Recently, growing evidence proposes that these alternations result in the fibrotic biomechanical microenvironment, which drives the activation of hepatic stellate cells (HSCs). Here, an inorganic ascorbic acid-oxidase (AAO) mimicking nanozyme loaded with liquiritigenin (LQ) is developed to trigger remodeling of the fibrotic biomechanical microenvironment. The AAO mimicking nanozyme is able to consume intracellular ascorbic acid, thereby impeding collagen I deposition by reducing its availability. Simultaneously, LQ inhibits the transcription of lysyl oxidase like 2 (LOXL2), thus impeding collagen I crosslinking. Through its synergistic activities, the prepared nanosystem efficiently restores the fibrotic biomechanical microenvironment to a near-normal physiological condition, promoting the quiescence of HSCs and regression of fibrosis. This strategy of remodeling the fibrotic biomechanical microenvironment, akin to "pulling the rug out from under", effectively treats hepatic fibrosis in mice, thereby highlighting the importance of tissue biomechanics and providing a potential approach to improve hepatic fibrosis treatment.

• MeSH
• Biomechanical Phenomena MeSH
• Cellular Microenvironment drug effects   MeSH
• Flavanones pharmacology   chemistry   MeSH
• Liver Cirrhosis * drug therapy   metabolism   pathology   MeSH
• Hepatic Stellate Cells * metabolism   cytology   drug effects   MeSH
• Collagen Type I metabolism   MeSH
• Ascorbic Acid * pharmacology   metabolism   chemistry   MeSH
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

Current diabetic retinopathy (DR) treatment involves blood glucose regulation combined with laser photocoagulation or intravitreal injection of vascular endothelial growth factor (VEGF) antibodies. However, due to the complex pathogenesis and cross-interference of multiple biochemical pathways, these interventions cannot block disease progression. Recognizing the critical role of the retinal microenvironment (RME) in DR, it is hypothesized that reshaping the RME by simultaneously inhibiting primary and secondary blood-retinal barrier (BRB) injury can attenuate DR. For this, a glucose-responsive hydrogel named Cu-PEI/siMyD88@GEMA-Con A (CSGC) is developed that effectively delivers Cu-PEI/siMyD88 nanoparticles (NPs) to the retinal pigment epithelium (RPE). The Cu-PEI NPs act as antioxidant enzymes, scavenging ROS and inhibiting RPE pyroptosis, ultimately blocking primary BRB injury by reducing microglial activation and Th1 differentiation. Simultaneously, MyD88 expression silence in combination with the Cu-PEI NPs decreases IL-18 production, synergistically reduces VEGF levels, and enhances tight junction proteins expression, thus blocking secondary BRB injury. In summary, via remodeling the RME, the CSGC hydrogel has the potential to disrupt the detrimental cycle of cross-interference between primary and secondary BRB injury, providing a promising therapeutic strategy for DR.

• MeSH
• Cellular Microenvironment drug effects   MeSH
• Diabetic Retinopathy * drug therapy   metabolism   MeSH
• Glucose * metabolism   MeSH
• Blood-Retinal Barrier * metabolism   drug effects   MeSH
• Hydrogels * pharmacology   MeSH
• Disease Models, Animal MeSH
• Mice MeSH
• Nanoparticles MeSH
• Retina drug effects   metabolism   MeSH
• Retinal Pigment Epithelium metabolism   drug effects   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

The remarkably diverse affinity of alginate (ALG) macromolecules for polyvalent metal ions makes cross-linked alginate gels an outstanding biomaterial. Surprisingly, however, very little is known about their interactions and structural transformations in physiological environments. To bridge this gap, we prepared a set of ALG gels cross-linked by various ions and monitored their structural changes at different media simulating gastric and intestinal fluids and cellular environments. For these studies, we used multinuclear solid-state NMR (ss-NMR) spectroscopy, which revealed a range of competitive ion-exchange and interconversion reactions, the rate of which strongly depended on the nature of the cross-linking metal ions. Depending on the environment, ALG chains adopted different forms, such as acidic (hydro)gels stabilized by strong hydrogen bonds, and/or weakly cross-linked Na/H-gels. Simultaneously, the exchanged polyvalent ions extensively interacted with the environment even forming in some cases insoluble phosphate microdomains directly deposited in the ALG bead matrix. The extent of the transformations and incorporation of secondary phases into the alginate beads followed the size and electronegativity of the cross-linking ions. Overall, the applied combination of various macroscopic and biological tests with multinuclear ss-NMR revealed a complex pathway of alginate beads transformations in physiological environments.

• MeSH
• Alginates chemistry   pharmacology   MeSH
• Biocompatible Materials chemistry   pharmacology   MeSH
• Cellular Microenvironment drug effects   MeSH
• Gels chemistry   pharmacology   MeSH
• Metals chemistry   MeSH
• Humans MeSH
• Magnetic Resonance Spectroscopy MeSH
• Cross-Linking Reagents chemistry   pharmacology   MeSH
• Hydrogen Bonding drug effects   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Mesenchymal stem cells (MSCs) represent a population of cells which have the ability to regulate reactivity of T and B lymphocytes by multiple mechanisms. The immunoregulatory activities of MSCs are strictly influenced by the cytokine environment. Here we show that two functionally distinct cytokines, interleukin-4 (IL-4) and interferon-γ (IFN-γ), significantly potentiate the ability of MSCs to inhibit IL-10 production by activated regulatory B cells (Bregs). However, MSCs in the presence of IL-4 or IFN-γ inhibit the IL-10 production by different mechanisms. Preincubation of MSCs with IFN-γ led to the suppression, but pretreatment with IL-4 of neither MSCs nor B cells resulted in the suppression of IL-10 production. The search for candidate regulatory molecules expressed in cytokine-treated MSCs revealed different patterns of the gene expression. Pretreatment of MSCs with IFN-γ, but not with IL-4, induced expression of indoleamine-2,3-dioxygenase, cyclooxygenase-2 and programmed cell death-ligand 1. To identify the molecule(s) responsible for the suppression of IL-10 production, we used specific inhibitors of the putative regulatory molecules. We found that indomethacine, an inhibitor of cyclooxygenase-2 (Cox-2) activity, completely abrogated the inhibition of IL-10 production in cultures containing MSCs and IFN-γ, but had no effect on the suppression in cell cultures containing MSCs and IL-4. The results show that MSCs can inhibit the response of B cells to one stimulus by different mechanisms in dependence on the cytokine environment and thus support the idea of the complexity of immunoregulatory action of MSCs.

• MeSH
• Lymphocyte Activation drug effects   immunology   MeSH
• Programmed Cell Death 1 Receptor genetics   immunology   metabolism   MeSH
• Cellular Microenvironment drug effects   immunology   MeSH
• Cyclooxygenase 2 genetics   immunology   metabolism   MeSH
• Cytokines immunology   metabolism   pharmacology   MeSH
• Enzyme-Linked Immunosorbent Assay MeSH
• Gene Expression drug effects   genetics   immunology   MeSH
• Indoleamine-Pyrrole 2,3,-Dioxygenase genetics   immunology   metabolism   MeSH
• Interferon-gamma pharmacology   MeSH
• Interleukin-10 immunology   metabolism   MeSH
• Interleukin-4 pharmacology   MeSH
• Interleukin-6 genetics   immunology   metabolism   MeSH
• Coculture Techniques MeSH
• Cells, Cultured MeSH
• Mesenchymal Stem Cells drug effects   immunology   metabolism   MeSH
• Mice MeSH
• Reverse Transcriptase Polymerase Chain Reaction MeSH
• B-Lymphocytes, Regulatory drug effects   immunology   metabolism   MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH