Structure-Guided Design and Synthesis of a Mitochondria-Targeting Near-Infrared Fluorophore with Multimodal Therapeutic Activities.

An urgent challenge for imaging-guided disease-targeted multimodal therapy is to develop the appropriate multifunctional agents to meet the requirements for potential applications. Here, a rigid cyclohexenyl substitution in the middle of a polymethine linker and two asymmetrical amphipathic N-alkyl side chains to indocyanine green (ICG) (the only FDA-approved NIR contrast agent) are introduced, and a new analog, IR-DBI, is developed with simultaneous cancer-cell mitochondrial targeting, NIR imaging, and chemo-/PDT/PTT/multimodal therapeutic activities. The asymmetrical and amphipathic structural modification renders IR-DBI a close binding to albumin protein site II to form a drug-protein complex and primarily facilitates its preferential accumulation at tumor sites via the enhanced permeability and retention (EPR) effect. The released IR-DBI dye is further actively taken up by cancer cells through organic-anion-transporting polypeptide transporters, and the lipophilic cationic property leads to its selective accumulation in the mitochondria of cancer cells. Finally, based on the high albumin-binding affinity, IR-DBI is modified into human serum albumin (HSA) via self-assembly to produce a nanosized complex, which exhibits significant improvement in the cancer targeting and multimodal cancer treatment with better biocompatibility. This finding may present a practicable strategy to develop small-molecule-based cancer theranostic agents for simultaneous cancer diagnostics and therapeutics.

Design of a potent antibiotic peptide based on the active region of human defensin 5.

Human defensin 5 (HD5) is a broad-spectrum antibacterial peptide with a C-terminal active region. To promote the development of this peptide into an antibiotic, we initially substituted Glu21 with Arg because it is an electronegative residue located around the active region. Although detrimental to dimer formation, the E21R substitution markedly enhanced the antibacterial activity of HD5 and increased its ability to penetrate cell membranes, demonstrating that increasing the electropositive charge compensated for the effect of dimer disruption. Subsequently, a partial Arg scanning mutagenesis was performed, and Thr7 was selected for replacement with Arg to further strengthen the antibacterial activity. The newly designed peptide, T7E21R-HD5, exhibited potent antibacterial activity, even in saline and serum solutions. In contrast to monomeric E21R-HD5, T7E21R-HD5 assembled into an atypical dimer with parallel ß strands, thus expanding the role of increasing electropositive charge in bactericidal activity and providing a useful guide for further defensin-derived antibiotic design.

The reproductive effects in rats after chronic oral exposure to low-dose depleted uranium.

This two-generation study evaluated the effects of depleted uranium (DU) on reproduction in rats. Across two generations, Wistar rats (30/sex/group) were maintained on feed containing DU at dose levels of 0 (control group), 4 (DU4 group), or 40 (DU40 group) mg kg⁻¹ day⁻¹ for 4 months prior to mating. After 4 months of exposure, the pregnancy rate, normal labour rate, and survival rate of offspring produced by F1 rats were all significantly decreased as compared to the control group, and especially in the DU40 group, these parameters fell by half to two-thirds, while no adverse effects were evident in F0 rats. The uranium content in the testes and ovaries of F1 rats in the DU4 and DU40 groups was significantly higher than that found in F0 rats. The levels of sex hormone in the serum were disorder in both generations. The enzymes related to spermiogenesis were also significantly different between generations, and the damage was more severe in F1 rats. In conclusion, the reproductive effects in F0 rats were slight after chronic oral exposure to DU, while the effects were obvious in F1 rats.

A study assessing the genotoxicity in rats after chronic oral exposure to a low dose of depleted uranium.

PURPOSE: The aim of this study was to evaluate the potential genotoxicity induced by chronic oral exposure to depleted uranium (DU). MATERIALS AND METHODS: Weanling Wistar rats (F(0)), 50/sex/group, were exposed to DU in food at doses of 0, 4, or 40 mg kg(-1)day(-1) for four months. They were subsequently mated, resulting in the birth of F(1) rats. Fifty F(l) weanlings/sex/group were exposed for four months to the same dose levels as their parents. After four months, the uranium content in the tissues, the potential damage to the genetic material, and pathomorphological changes of the testicles were observed in both F(0) and F(1) rats. The genotoxicity of DU was evaluated by the following methods: sperm abnormality assessment, the bone-marrow micronucleus test, and the comet assay. RESULTS: Uranium content in F(1) rats was significantly higher than that in F(0) rats in both the kidney and ovary (p < 0.05). The sperm abnormality rate, marrow cell micronuclei rate, comet tail length, and tailed cell percentage increased in each treatment group in each generation compared with the control group (p < 0.05). When comparing F(1) with F(0) rats, significant differences were detected for most of the indicators, with F(1) rats always exhibiting more damage (p < 0.05). With regard to pathomorphological changes in the testicles, the sperm displayed atypical changes, including thickening of the anachromasis nucleolus, which seemed to be more severe in F(1) rats. CONCLUSION: Genotoxicity may be induced in rats after chronic oral exposure to a low dose of DU.

Protective effect of an extract from Periplaneta americana on hematopoiesis in irradiated rats.

PURPOSE: To investigate the protective effect of W(11)-a(12), an extract from Periplaneta americana, on hematopoiesis in irradiated rats. MATERIALS AND METHODS: Wistar rats receiving total body irradiation of (60)Co gamma-rays alone or with combined radiation and skin wound injury were used in this study. W(11)-a(12) was applied either topically into the skin wounds or systemically by intraperitoneal injection. The numbers of white blood cells in peripheral blood, the nucleated cells and the colony-forming unit of granulocyte/macrophage progenitors (CFU-GM) in bone marrow were measured, respectively. RESULTS: Topical application of W(11)-a(12) into skin wounds in rats with combined 6 Gy total body irradiation and skin wound injury could increase the neutrophils and macrophages in the wounded area and the nucleated cells in bone marrow at 24 h and 48 h, while the peripheral white blood cells did not show significant change. However, in rats with 4 Gy total body irradiation alone, the peripheral white blood cells, bone marrow nucleated cells and the number of colony-forming unit of granulocyte-macrophage progenitors were all significantly higher in the treatment groups by intraperitoneal injection of W(11)-a(12) than those in the control groups by injection of normal saline at days 3 and days 5 after radiation. CONCLUSIONS: W(11)-a(12) showed a protective effect on hematopoiesis after total body irradiation and could increase the inflammatory cells in wounded tissues at the initiation stage after irradiation, which will benefit the management of combined radiation and skin wound injury.