Multi-Target Effects of Novel Synthetic Coumarin Derivatives Protecting Aß-GFP SH-SY5Y Cells against Aß Toxicity.

Alzheimer's disease (AD) is a common neurodegenerative disease presenting with progressive memory and cognitive impairments. One of the pathogenic mechanisms of AD is attributed to the aggregation of misfolded amyloid ß (Aß), which induces neurotoxicity by reducing the expression of brain-derived neurotrophic factor (BDNF) and its high-affinity receptor tropomyosin-related kinase B (TRKB) and increasing oxidative stress, caspase-1, and acetylcholinesterase (AChE) activities. Here, we have found the potential of two novel synthetic coumarin derivatives, ZN014 and ZN015, for the inhibition of Aß and neuroprotection in SH-SY5Y neuroblastoma cell models for AD. In SH-SY5Y cells expressing the GFP-tagged Aß-folding reporter, both ZN compounds reduced Aß aggregation, oxidative stress, activities of caspase-1 and AChE, as well as increased neurite outgrowth. By activating TRKB-mediated extracellular signal-regulated kinase (ERK) and AKT serine/threonine kinase 1 (AKT) signaling, these two ZN compounds also upregulated the cAMP-response-element binding protein (CREB) and its downstream BDNF and anti-apoptotic B-cell lymphoma 2 (BCL2). Knockdown of TRKB attenuated the neuroprotective effects of ZN014 and ZN015. A parallel artificial membrane permeability assay showed that ZN014 and ZN015 could be characterized as blood-brain barrier permeable. Our results suggest ZN014 and ZN015 as novel therapeutic candidates for AD and demonstrate that ZN014 and ZN015 reduce Aß neurotoxicity via pleiotropic mechanisms.

Polypeptide Composition and Topology Affect Hydrogelation of Star-Shaped Poly(L-lysine)-Based Amphiphilic Copolypeptides.

In this research, we studied the effect of polypeptide composition and topology on the hydrogelation of star-shaped block copolypeptides based on hydrophilic, coil poly(L-lysine)20 (s-PLL20) tethered with a hydrophobic, sheet-like polypeptide segment, which is poly(L-phenylalanine) (PPhe), poly(L-leucine) (PLeu), poly(L-valine) (PVal) or poly(L-alanine) (PAla) with a degree of polymerization (DP) about 5. We found that the PPhe, PLeu, and PVal segments are good hydrogelators to promote hydrogelation. The hydrogelation and hydrogel mechanical properties depend on the arm number and hydrophobic polypeptide segment, which are dictated by the amphiphilic balance between polypeptide blocks and the hydrophobic interactions/hydrogen bonding exerted by the hydrophobic polypeptide segment. The star-shaped topology could facilitate their hydrogelation due to the branching chains serving as multiple interacting depots between hydrophobic polypeptide segments. The 6-armed diblock copolypeptides have better hydrogelation ability than 3-armed ones and s-PLL-b-PPhe exhibits better hydrogelation ability than s-PLL-b-PVal and s-PLL-b-PLeu due to the additional cation-π and π-π interactions. This study highlights that polypeptide composition and topology could be additional parameters to manipulate polypeptide hydrogelation.

Biomimetic hydrogels based on L-Dopa conjugated gelatin as pH-responsive drug carriers and antimicrobial agents.

Biomimetic hydrogels which possess good biocompatibility, high degradability, and low toxicity as well as good antibacterial activity against various bacteria would potentially be promising for biomaterial applications, such as wound healing, tissue engineering, and payload delivery systems. Herein, we report the synthesis and hydrogelation of L-Dopa conjugated (GPLD) polypeptides via a versatile strategy including enzymatic cross-linking or coordinated/oxidized cross-linking with Fe3+ ions and demonstrated the feasibility of loading cancer drug and metal NPs in hydrogel matrix. The drug-loaded hydrogel was simply prepared via coordinated/oxidized cross-linking by Fe3+ and H2O2 within short gelation time. Doxorubicin (DOX) was encapsulated in the hydrogel network through the formation of metal-DOX/catechol complexes. The catechol groups acted not only as the complexing depots for DOX encapsulation but also as cross-linking depots for hydrogel formation. The mechanical strength, swelling ratio, and degradability behavior could be tuned by varying Fe3+/H2O2 or enzyme/H2O2 concentration. The as-prepared hydrogel exhibited excellent pH-responsive drug release behavior and the ability to effectively kill cancer cells by pH-triggered release of DOX. We also demonstrated that the enzymatically cross-linked hydrogels loaded with metal nanoparticles (NPs) exhibiting excellent antimicrobial activities. This multifunctional hydrogel is promising for drug delivery and antimicrobial applications.