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Hypertrophic scar causes serious functional and cosmetic problem, but no treatment method is known to achieve a satisfactory therapeutic effect. However, mesenchymal stem cells show a possible cure prospect. Here, we investigated the effect of interleukin-10-modified adipose-derived mesenchymal stem cells (IL-10-ADMSC) on the formation of hypertrophic scar. In vitro, IL-10-ADMSC could highly express IL-10 and exhibited stronger inhibition of hypertrophic scar fibroblasts (HSFs) proliferation, migration, and extracellular matrix synthesis (the expression of collagen I, collagen III, FN, and α-SMA protein) than ADMSC. In vivo, we found that IL-10-ADMSC speeded up wound healing time and reduced scar area and scar outstanding height. Same as in vitro, IL-10-ADMSC also exhibited stronger inhibition of extracellular matrix synthesis (the expression of collagen I, collagen III protein) in wound than ADMSC. In addition, we also found that IL-10-ADMSC is also a stronger inhibitory effect on inflammation in wound than ADMSC, and IL-10-ADMSC inhibited TGF-β/Smads and NF-κB pathway. In conclusion, IL-10-ADMSC demonstrated the ability to prevent hypertrophic scar formation. And its possible molecular mechanism might be related to IL-10-ADMSC inhibiting the proliferation and migration of the synthesis of extracellular matrix of HSFs, and IL-10-ADMSC inhibited the inflammation during the wound healing.

Bruton's tyrosine kinase (BTK) inhibitors suppressing the aberrant activation of BTK have led to a paradigm shift in the therapy of B-cell malignancies. However, there is an urgent need to discover more selective covalent BTK inhibitors owing to the off-target adverse effects of the approved inhibitor, ibrutinib. Herein, we disclose the discovery and preliminary activity studies of novel BTK inhibitors carrying 1-amino-1H-imidazole-5-carboxamide as a hinge binder. The most potent BTK inhibitor 26 demonstrates impressive selectivity, favorable pharmacokinetic properties, and robust antitumor efficacy in vivo, which indicates its potential as a novel therapeutic option for B-cell lymphomas. Importantly, to the best of our knowledge, this is the first example of a 1-amino-1H-imidazole-5-carboxamide scaffold used as the hinge binder of kinase inhibitors, which will largely expand the chemical diversity of kinase inhibitors.

Human serum albumin (HSA) is a major interacting-partner of Alzheimer’s amyloid-β (Aβ) peptide in the plasma and has emerged as a promising therapeutic target. HSA inhibits Aβ fibrillization, but the underlying molecular mechanism is not well elucidated. In this work, we investigated the role of HSA in the early stages of Aβ aggregation by simulating the binding process of multiple Aβ monomers and protofibrils to HSA with extensive molecular dynamics simulations. HSA could simultaneously trap multiple Aβ monomers and accommodate the formation of nonfibrillar Aβ oligomers after binding. In particular, domains I and III show stronger binding capacities and hold preferable interaction sites for oligomers. Consequently, HSA prevents the formation of fibrillar oligomers in water, thus interfering with the nucleation process. On the other aspect, when protofibrils are preformed, HSA tends to block the β-strand spanning the central hydrophobic core located at the protofibril end, preventing the addition of monomers to protofibrils. Furthermore, Aβ protofibril structures are severely disrupted both globally and locally. Thus, further growth of protofibrils to fibrils is impeded by HSA. Our results collectively indicate that HSA performs multipronged regulatory functions in the early stages of Aβ aggregation. Our work advances the understanding of the amyloid inhibition of Aβ by HSA and provides theoretical guidance for developing rational therapies of Alzheimer’s disease.

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