Anti-CD44 monoclonal antibody, clone IQ3/0 [CF405M]

Significance: Inflammation is a critical aspect of injury repair. Nonresolving inflammation, however, is perpetuated by the local generation of extracellular matrix-derived damage-associated molecular pattern molecules (DAMPs), such as the extra domain A (EDA) isoform of fibronectin and hyaluronic acid (HA) that promote the eventual acquisition of a fibrotic response. DAMPs contribute to the inflammatory environment by engaging Toll-like, integrin, and CD44 receptors while stimulating transforming growth factor (TGF)-beta signaling to activate a fibroinflammatory genomic program leading to the development of chronic disease. Recent Advances: Signaling through TLR4, CD44, and the TGF-beta pathways impact the amplitude and duration of the innate immune response to endogenous DAMPs synthesized in the context of tissue injury. New evidence indicates that crosstalk among these three networks regulates phase transitions as well as the repertoire of expressed genes in the wound healing program determining, thereby, repair outcomes. Clarifying the molecular mechanisms underlying pathway integration is necessary for the development of novel therapeutics to address the spectrum of fibroproliferative diseases that result from maladaptive tissue repair. Critical Issues: There is an increasing appreciation for the role of DAMPs as causative factors in human fibroinflammatory disease regardless of organ site. Defining the involved intermediates essential for the development of targeted therapies is a daunting effort, however, since various classes of DAMPs activate different direct and indirect signaling pathways. Cooperation between two matrix-derived DAMPs, HA, and the EDA isoform of fibronectin, is discussed in this review as is their synergy with the TGF-beta network. This information may identify nodes of signal intersection amenable to therapeutic intervention. Future Directions: Clarifying mechanisms underlying the DAMP/growth factor signaling nexus may provide opportunities to engineer the fibroinflammatory response to injury and, thereby, wound healing outcomes. The identification of shared and unique DAMP/growth factor-activated pathways is critical to the design of optimized tissue repair therapies while preserving the host response to bacterial pathogens.

Developing new strategies to enhance drug accumulation in the tumor and therapeutic efficacy is of great importance in the field of tumor therapy. Herein, a peanut-like multifunctional nanomedicine (CuS-PGH NMs) made of CuS nanoparticles encapsulated in poly(l-lysine)(PLL)/glucose oxidase (GOx)-hyaluronic acid (HA) shells has been constructed via layer-by-layer (LbL) assembly, and shows good biocompatibility and effective multi-gradient therapy. Because of the enhanced permeability and retention (EPR) effect, the CuS-PGH NMs could significantly enhance the cellular uptake by tumors overexpressing CD44 receptors, which respond to hyaluronidase (HAase)-triggered surface charge conversion. Once internalized by the tumor, GOx was the first to be exposed and could effectively deplete endogenous glucose for starvation therapy, and the excess H2O2 was then converted into highly toxic hydroxyl radicals (OH) via a Cu+-mediated Fenton-like reaction for chemodynamic therapy (CDT). Meanwhile, the as-obtained Cu+ ions accompanied the regenerated less-active Cu2+ ions. Interestingly, the high content of H2O2 could, in turn, accelerate Cu2+/Cu+ conversion to promote the Cu+-H2O2 reaction for enhanced chemodynamic therapy (CDT), thereby achieving efficient tumor growth suppression via synergistic starvation/CDT therapy. Subsequently, owing to the strong NIR-II absorption capability of CuS-PGH NMs, effective photothermal tumor ablation of the weakened tumor cells could be realized with the precise guidance of NIR-II PAI. This multi-gradient therapeutic strategy has been demonstrated to have excellent antitumor activity with minimal nonspecific damages, and offers a new avenue to precise tumor therapy.