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Diabetic ischemic wound treatment remains a critical clinical challenge. Neovascularization plays a significant role in wound healing during all stages of the tissue repair process. Strategies that enhance angiogenesis and neovascularization and improve ischemic pathology may promote the healing of poor wounds, particularly diabetic wounds in highly ischemic conditions. We previously identified a cyclic peptide LXW7 that specifically binds to integrin αvβ3 on endothelial progenitor cells (EPCs) and endothelial cells (ECs), activates vascular endothelial growth factor (VEGF) receptors, and promotes EC growth and maturation. In this study, we designed and synthesized a multi-functional pro-angiogenic molecule by grafting LXW7 and collagen-binding peptides (SILY) to a dermatan sulfate (DS) glycosaminoglycan backbone, named LXW7-DS-SILY, and further employed this multi-functional molecule to functionalize collagen-based extracellular matrix (ECM) scaffolds. We confirmed that LXW7-DS-SILY modification significantly promoted EPC attachment and growth on the ECM scaffolds in vitro and supported EPC survival in vivo in the ischemic environment. When applied in an established Zucker Diabetic Fatty (ZDF) rat ischemic skin flap model, LXW7-DS-SILY-functionalized ECM scaffolds loaded with EPCs significantly improved wound healing, enhanced neovascularization and modulated collagen fibrillogenesis in the ischemic environment. Altogether, this study provides a promising novel treatment to accelerate diabetic ischemic wound healing, thereby reducing limb amputation and mortality of diabetic patients.

PurposeVascular endothelial growth factor receptor 2 (VEGFR-2) and neuropilin-1 (NRP-1) are two prominent synergistic receptors overexpressed on new blood vessels in glioma and may be promising targets for antiglioma therapy. The aim of this study was to design a dual receptor targeting and blood-brain barrier (BBB) penetrating peptide-modified polyethyleneimine (PEI) nanocomplex that can efficiently deliver the angiogenesis-inhibiting secretory endostatin gene (pVAXI-En) to treat glioma.Materials and methodsWe first constructed the tandem peptide TAT-AT7 by conjugating AT7 to TAT and evaluated its binding affinity to VEGFR-2 and NRP-1, vasculature-targeting ability and BBB crossing capacity. Then, TAT-AT7-modified PEI polymer (PPTA) was synthesized, and a pVAXI-En-loaded PPTA nanocomplex (PPTA/pVAXI-En) was prepared. The physicochemical properties, cytotoxicity, transfection efficiency, capacities to cross the BBB and BTB (blood-tumor barrier) and glioma-targeting properties of PPTA/pVAXI-En were investigated. Moreover, the in vivo anti-angiogenic behaviors and anti-glioma effects of PPTA/pVAXI-En were evaluated in nude mice.ResultsThe binding affinity of TAT-AT7 to VEGFR-2 and NRP-1 was approximately 3 to 10 times greater than that of AT7 or TAT. The cellular uptake of TAT-AT7 in endothelial cells was 5-fold and 119-fold greater than that of TAT and AT7 alone, respectively. TAT-AT7 also displayed remarkable efficiency in penetrating the BBB and glioma tissue in vivo. PPTA/pVAXI-En exhibited lower cytotoxicity, stronger BBB and BTB traversing abilities, higher selective glioma targeting and better gene transfection efficiency than PEI/pVAXI-En. More importantly, PPTA/pVAXI-En significantly suppressed the tube formation and migration of endothelial cells, inhibited glioma growth, and reduced the microvasculature in orthotopic U87 glioma-bearing nude mice.ConclusionOur study demonstrates that PPTA/pVAXI-En can be exploited as an efficient dual-targeting nanocomplex to cross the BBB and BTB, and hence it represents a feasible and promising nonviral gene delivery system for effective glioma therapy.

Nitrogen‐containing corrosion inhibitors have a wide range of promising applications, and current conventional corrosion design and evaluation methods are largely based on empirical speculation and extensive exploratory experiments. Unfortunately, these efforts are often associated with high costs, long lead times, and a lot of "blind work." In this work, we have computationally screened the quantum chemical parameters of five nitrogen‐containing corrosion inhibitor molecules and their corrosion inhibition properties by a molecular simulation method based on density functional theory calculations. The ultimate relationship between the corrosion inhibition efficiency (IE) of an adsorbent and its quantum chemical parameters was analyzed using linear regression by comparing the various quantum mechanical parameters of each inhibitor molecule, as well as the fraction of electrons (ΔN) that are transferred to the metal surface from the chemisorbed inhibitor molecule. Five different nitrogen‐containing corrosion inhibitor molecules were screened based on structural similarity. Meanwhile, their corrosion inhibition performance was evaluated using the most relevant structure–activity equations. The results showed that the synergistic effect between the corrosion inhibition performance and the orbital energies of highest occupied molecular orbital and lowest unoccupied molecular orbital was optimal under the HF/6‐31G(d) method, and the corresponding structure–activity relationship was established. Based on these results, a specific inhibitor molecule was found to have excellent corrosion inhibition performance with a predicted corrosion IE of up to 94.12 %. [ABSTRACT FROM AUTHOR]

RAD51 recombinase plays a critical role for cancer cell proliferation and survival. Targeting RAD51 is therefore an attractive strategy for treating difficult-to-treat cancers, e.g. triple negative breast cancers which are often resistant to existing therapeutics. To this end, we have designed, synthesized and evaluated a panel of new RAD51 inhibitors, denoted IBR compounds. Among these compounds, we have identified a novel small molecule RAD51 inhibitor, IBR120, which exhibited a 4.8-fold improved growth inhibition activity in triple negative human breast cancer cell line MBA-MD-468. IBR120 also inhibited the proliferation of a broad spectrum of other cancer cell types. Approximately 10-fold difference between the IC50 values in normal and cancer cells were observed. Moreover, IBR120 was capable of disrupting RAD51 multimerization, impairing homologous recombination repair, and inducing apoptotic cell death. Therefore, these novel RAD51 inhibitors may serve as potential candidates for the development of pharmaceutical strategies against difficult-to-treat cancers.

BACKGROUND: Astragali Radix (also known as Astragulus) is a traditional medicinal and edible homologous plant for tonifying Qi. Honey‐processed Astragalus is a dosage form of Astragali Radix processed with honey, which exhibited better efficacy of tonifying Qi than the raw product. Polysaccharides are their main active components. RESULTS: APS2a and HAPS2a were initially isolated from Astragulus and honey‐processed Astragulus. Both of them are highly branched acidic heteropolysaccharides containing ɑ‐configuration and β‐configuration glycosidic bonds. The molecular weight and the molecular dimension of HAPS2a decreased and the GalA contained in APS2a was converted to Gal in HAPS2a. The α‐configuration galactose residue 1,3,4‐α‐Galp in the backbone of APS2a was converted to the corresponding β‐configuration galactose residue 1,3,4‐β‐Galp in the backbone of HAPS2a and the uronic acid residue T‐α‐GalpA in the sidechain of APS2a was converted to the corresponding neutral residue T‐α‐Galp in the side chain of HAPS2a. Bioactivity results showed that HAPS2a had better probiotic effects on Bacteroides ovatus, Bacteroides thetaiotaomicron, Bifidobacterium longum and Lactobacillus rhamnosus strains than APS2a. After degradation, the molecular weights of HAPS2a and APS2a decreased with the changes in their monosaccharide composition. The contents of total short‐chain fatty acids (SCFAs) and other organic acids in HAPS2a group were higher than APS2a group. CONCLUSIONS: Two novel high‐molecular‐weight polysaccharides named APS2a and HAPS2a had different probiotic activities in vitro, which might be due to their structural differences before and after honey processing. Both of them might be possibly used as an immunopotentiator in healthy foods or dietary supplement. © 2023 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]