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Administration of recombinant tPA (rtPA, or trade name Alteplase®) is an FDA-approved therapy for acute ischemic stroke (AIS), but poses the risk of hemorrhagic complications. Recombinant tPA can be rapidly inactivated by the endogenous inhibitor, plasminogen activator inhibitor 1 (PAI-1). In this work, we study a novel treatment approach that combines a PAI-1 inhibitor, PAItrap4, with a reduced dose of rtPA to address the hemorrhagic concern of rtPA. PAItrap4 is a highly specific and very potent protein-based inhibitor of PAI-1, comprising of a variant of uPA serine protease domain, human serum albumin, and a cyclic RGD peptide. PAItrap4 efficiently targets and inhibits PAI-1 on activated platelets, and also possesses a long half-life in vivo. Our results demonstrate that PAItrap4 effectively counteracts the inhibitory effects of PAI-1 on rtPA, preserving rtPA activity based on amidolytic and clot lysis assays. In an in vivo murine stroke model, PAItrap4, together with low-dose rtPA, enhances the blood perfusion in the stroke-affected areas, reduces infarct size, and promotes neurological recovery in mice. Importantly, such treatment does not increase the amount of cerebral hemorrhage, thus reducing the risk of cerebral hemorrhage. In addition, PAItrap4 does not compromise the normal blood coagulation function in mice, demonstrating its safety as a therapeutic agent. These findings highlight this combination therapy as a promising alternative for the treatment of ischemic stroke, offering improved safety and efficacy. [ABSTRACT FROM AUTHOR]

Horizontal gene transfer (HGT) is an important driving force for virulence evolution of pathogens, however, functions of these transferred genes are still not fully investigated. Here, an HGT effector, CcCYT was reported to contribute to virulence of a mycoparasite, Calcarisporium cordycipiticola to the host Cordyceps militaris, an important mushroom. Cccyt was predicted to be horizontally transferred from Actinobacteria ancestor by phylogenetic, synteny, GC content and codon usage pattern analyses. The transcript of Cccyt was sharply up-regulated at the early stage of infecting C. militaris. This effector was localized to the cell wall and contributed to the virulence of C. cordycipiticola without affecting its morphology, mycelial growth, conidiation, and resistance to abiotic stress. CcCYT can firstly bind the septa, and finally cytoplasm of the deformed hyphal cells of C. militaris. Pull-down assay coupled mass spectrometry revealed that proteins with which CcCYT interacted were related to protein process, folding and degradation. GST-Pull down assay confirmed that C. cordycipiticola effector CcCYT can interact with host protein CmHSP90 to inhibit the immune response of host. The results provided functional evidence that HGT is an important driving force for the virulence evolution and will be helpful for revealing the interaction between mycoparasite and mushroom host. [Display omitted] • C. cordycipiticola Cccyt was originated from a cross-kingdom gene transfer event. • CcCYT is a typical effector located to the cell wall of C. cordycipiticola. • Cccyt is not necessary for growth but contributes to virulence of C. cordycipiticola. • CcCYT binds the septa of C. militaris and interacts with a host heat shock protein. [ABSTRACT FROM AUTHOR]

Chitosan- N -2-hydroxypropyl trimethyl ammonium chloride (QTS) was prepared by reaction of chitosan (CS) and glycidyl trimethylammonium chloride. Later, O -acetyl-chitosan- N -2-hydroxypropyl trimethyl ammonium chloride (AQTS) was synthesized by reaction of QTS with acetic acid in the presence of SOCl 2 . Both derivatives were characterized by FTIR, 1 H NMR, TGA, and XRD techniques. The degree of quaternization of QTS was 85.5%, and the degree of acetyl (DA) of AQTS was from 1.63 to 2.31. Compared with CS, the solubility of QTS and AQTS was improved at different levels, especially AQTS, it could be dissolved in many organic solvents, water, and aqueous solution. Notably, the solubility of AQTS in organic solvents increased as DA increased, while the solubility in water was reversed. The results of CS, QTS, and AQTS against Escherichia coli and Staphylococcus aureus showed that QTS and AQTS exhibited higher antibacterial activity than CS, and the antibacterial activity of AQTS decreased with increased DA. Moreover, the inhibition effect was AQTS1 (DA 1.63) > AQTS2 (DA 2.02) > QTS > AQTS3 (DA 2.31). On the basis of the results of the present study, it could be emphasized that hydrophobicity and positive charge density might strongly affect the antibacterial activity of quaternary ammonium chitosan derivatives. [ABSTRACT FROM AUTHOR]

A novel amphipathic chitosan derivative, N -benzoyl- O -acetyl-chitosan (BACS), was prepared by using the selective partial acylation of chitosan (CS), benzoyl chloride, and acetic acid under high-intensity ultrasound. The chemical structure and physical properties of BACS were characterized by FTIR, 1 H NMR, TGA, and XRD techniques. The degrees of substitution of benzoyl and acetyl for the chitosan derivatives were 0.26 and 1.15, respectively, which were calculated from the peak areas in NMR spectra by using the combined integral methods. The foaming properties of CS and BACS were determined and the results suggested BACS had better foam capacity and stability than those of chitosan. In addition, the antimicrobial activities of CS and BACS were also investigated against two species of bacteria ( Escherichia coli and Staphylococcus aureus ) and a fungus ( Aspergillus niger ), the results indicated that the antibacterial and antifungal activities of BACS were much stronger than those of the parent chitosan. These findings suggested that BACS was preferable for use as a food additive with a dual role of both foaming agent and food preservative. [ABSTRACT FROM AUTHOR]