Antibacterial
hydrogels are attracting extensive attention in soft
tissue repair and regeneration, including bacteria-infected-wound
healing. The abuse of antibiotics leads to drug resistance. Recent
developments have demonstrated that the delivery of inorganic bactericidal
agents in hydrogels can drive the wound healing process; however,
this approach is complicated by external light stimuli, cytotoxicity,
nondegradability, and sophisticated fabrication. Herein, an inherent
antibacterial, bioresorbable hydrogel was developed by the spontaneous
self-aggregation of amphiphilic, oxadiazole-group-decorated quaternary
ammonium salts (QAS)-conjugated poly(ε-caprolactone)-poly(ethylene
glycol)-poly(ε-caprolactone) (PCEC-QAS) micellar nanoantimicrobials
for methicillin-resistant Staphylococcus aureus (MRSA)-infected
cutaneous wound healing. The PCEC-QAS hydrogel showed a stable gel
state within the temperature range of 5–50 °C and antibacterial
efficacy against both Gram-negative and -positive bacteria in vitro and in vivo. Additionally, the
PCEC-QAS hydrogel facilitated the cell spreading, proliferation, and
migration without cytotoxicity. An in vivo degradation
and skin defect healing study suggested the PCEC-QAS hydrogel was
totally absorbed without local or systemic toxicity and could promote
wound repair in the absence of drugs, cytokines, or cells. Significantly,
this hydrogel accelerated the regeneration of a MRSA-infected full-thickness
impaired skin wound by successfully reconstructing an intact and thick
epidermis similar to normal mouse skin. Collectively, a self-assembling
PCEC-QAS antibacterial hydrogel is a promising dressing material to
promote skin regeneration and prevent bacterial infection without
additional drugs, cells, light irradiation, or delivery systems, providing
a simple but effective strategy for treating dermal wounds.
New series of dipeptidyl boronate inhibitors of 20S proteasome were designed and synthesized. The comprehensive understanding of the SAR was obtained by utilizing the variation of four substituents. From the screened compounds in enzyme, novel inhibitors 49 and 50 were identified to be highly potent druglike candidates with IC(50) values of 1.2 and 1.6 nM, respectively, which showed better activities than the drug bortezomib on the market. Two hematologic human tumor cell lines, HL-60 and U266, were significantly sensitive to both candidates and showed nearly the same potency as the standard bortezomib with IC(50) values less than 10 nM. But as for most of the eight human solid tumor cell lines, both candidates were more potent than the standard with the IC(50) value range of 9.8-70 nM. The activity evaluation of the stereoisomers showed that changing R-isomers to S-isomers greatly reduced the potency and even induced inactivity.
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