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Through the l - to d - type amino acid substitution and attachment of solubilizing tags, the novel proteolysis-resistant and water-soluble fluorescent probes were developed, which could achieve the sensitive "turn on" sensing of heparin. [Display omitted] • The first systematic structural optimizations were conducted on the promising fluorescent probe TPE-1 for heparin sensing. • The novel d -type peptide based fluorescent probes were developed for the highly sensitive "turn on" sensing of heparin. • The representative heparin probe XH-6 was demonstrated to possess extremely high proteolytic stability and good solubility. Developing "turn on" fluorescent probes was desirable for the detection of the effective anticoagulant agent heparin in clinical applications. Through combining the aggregation induced emission (AIE) fluorogen tetraphenylethene (TPE) and heparin specific binding peptide AG73, the promising "turn on" fluorescent probe TPE-1 has been developed. Nevertheless, although TPE-1 could achieve the sensitive and selective detection of heparin, the low proteolytic stability and undesirable poor solubility may limit its widespread applications. In this study, seven TPE-1 derived fluorescent probes were rationally designed, efficiently synthesized and evaluated. The stability and water solubility were systematically estimated. Especially, to achieve real-time monitoring of proteolytic stability, the novel Abz/Dnp-based "turn on" probes that employ the internally quenched fluorescent (IQF) mechanism were designed and synthesized. Moreover, the detection ability of synthetic fluorescent probes for heparin were systematically evaluated. Importantly, the performance of d -type peptide fluorescent probe XH-6 indicated that d -type amino acid substitutions could significantly improve the proteolytic stability without compromising its ability of heparin sensing, and attaching solubilizing tag 2-(2-aminoethoxy) ethoxy) acid (AEEA) could greatly enhance the solubility. Collectively, this study not only established practical strategies to improve both the water solubility and proteolytic stability of "turn on" fluorescent probes for heparin sensing, but also provided valuable references for the subsequent development of enzymatic hydrolysis-resistant d -type peptides based fluorescent probes. [ABSTRACT FROM AUTHOR]

Extracellular vesicles are composed of loaded soluble substances and lipid bilayers; these include apoptotic bodies, exosomes, and microvesicles. Extracellular vesicles, as carriers of biological information between cells, have been recognized for their role in the diagnosis and treatment of cardiovascular diseases. The biogenesis of extracellular vesicles is closely related to autophagy. Moreover, extracellular vesicles further affect autophagy levels in target cells through their transmitted contents. Autophagy is a catabolic cell process that maintains cell homeostasis by eliminating misfolded proteins and damaged organelles. Existing studies have revealed that extracellular vesicles and autophagy share molecular mechanisms with notable crosstalk, including, perspectives such as amphisomes and "secretory autophagy." In this review, we first introduce the biogenesis of extracellular vesicles and the classic views of autophagy before moving onto the crosstalk between extracellular vesicles and autophagy. Finally, we discuss the research progress of extracellular vesicles and autophagy in cardiovascular pathophysiology. [ABSTRACT FROM AUTHOR]

The cytotoxic peptide LVTX-8, recently isolated from spider Lycosa vittata , is considered as a potential precursor for further anticancer drug development. In this study, a series of novel LVTX-8-based analogues and cytotoxic conjugates were rationally designed, synthesized, and systematically evaluated. Compared with the parent LVTX-8, peptides 825 and 827 not only possessed higher proteolytic stability, but also exhibited significantly improved anticancer durability and greatly reduced hemolysis. [Display omitted] • Ten spider toxin peptide LVTX-8-based analogues were designed and efficiently synthesized. • Their anticancer efficacy, serum stability, hemolytic activity, time-kill kinetics, anticancer mode of action, and subcellular localizations were evaluated systematically. • In particular, peptides 825 and 827 not only possessed higher proteolytic stability, but also exhibited significantly improved anticancer durability. • In addition, peptides 825 and 827 exhibited greatly reduced hemolysis, as well as higher selectivity to cancer cells than to human erythrocytes. Cytotoxic peptides derived from spider venoms have been considered as promising candidates for anticancer treatment. The novel cell penetrating peptide LVTX-8, which is a 25-residue amphipathic α-helical peptide isolated from spider Lycosa vittata , exhibited potent cytotoxicity and is a potential precursor for further anticancer drug development. Nevertheless, LVTX-8 may be easily degraded by multiple proteases, inducing the proteolytic stability problem and short half-life. In this study, ten LVTX-8-based analogs were rationally designed and the efficient manual synthetic method was established by the DIC/Oxyma based condensation system. The cytotoxicity of synthetic peptides was systematically evaluated against seven cancer cell lines. Seven of the derived peptides exhibited high cytotoxicity towards tested cancer in vitro , which was better than or comparable to that of natural LVTX-8. In particular, both N -acetyl and C-hydrazide modified LVTX-8 (8 2 5) and the conjugate methotrexate (MTX)-GFLG-LVTX-8 (8 2 7) possessed more durable anticancer efficiency, higher proteolytic stability, as well as lower hemolysis. Finally, we confirmed that LVTX-8 could disrupt the integrity of cell membrane, target the mitochondria and reduce the mitochondrial membrane potential to induce the cell death. Taken together, the structural modifications were conducted on LVTX-8 for the first time and the stability significantly improved derivatives 825 and 827 may provide useful references for the modifications of cytotoxic peptides. [ABSTRACT FROM AUTHOR]