Intracellular Construction of Cathepsin B-Guided Gadolinium Nanoparticles for Enhanced T2 -Weighted MR Tumor Imaging.

Magnetic resonance imaging (MRI) is a superior and noninvasive imaging technique with unlimited tissue penetration depth and superb spatiotemporal resolution, however, using intracellular self-assembly of Gd-containing nanoparticles to enhance the T2 -weighted MR contrast of cancer cells in vivo for precise tumor MRI is rarely reported. The lysosomal cysteine protease cathepsin B (CTSB) is regarded as an attractive biomarker for the early diagnosis of cancers and metastasis. Herein, taking advantage of a biocompatible condensation reaction, a "smart" Gd-based CTSB-responsive small molecular contrast agent VC-Gd-CBT is developed, which can self-assemble into large intracellular Gd-containing nanoparticles by glutathione reduction and CTSB cleavage to enhance the T2 -weighted MR contrast of CTSB-overexpressing MDA-MB-231 cells at 9.4 T. In vivo T2 -weighted MRI studies using MDA-MB-231 murine xenografts show that the T2 -weighted MR contrast change of tumors in VC-Gd-CBT-injected mice is distinctly larger than the mice injected with the commercial agent gadopentetate dimeglumine, or co-injected with CTSB inhibitor and VC-Gd-CBT, indicating that the accumulation of self-assembled Gd-containing nanoparticles at tumor sites effectively enhances the T2 -weighted MR tumor imaging. Hence, this CTSB-targeted small molecule VC-Gd-CBT has the potential to be employed as a T2 contrast agent for the clinical diagnosis of cancers at an early stage.

Lysosome-Targeted and Fluorescence-Turned "On" Cytotoxicity Induced by Alkaline Phosphatase-Triggered Self-Assembly.

Selectively inducing lysosomal membrane permeabilization (LMP) is a promising strategy for cancer therapy. But integrating alkaline phosphatase (ALP)-instructed self-assembly and lysosome-targeting to induce LMP for selective killing of cancer cells was not reported. Herein, a pyrene-peptide conjugate Py-Phe-Phe-Glu-Tyr(H2 PO3 )-Gly-lyso (Py-Yp-Lyso) is rationally designed and demonstrated for its lysosome-targeting cytotoxicity on cancer cells, together with its pyrene (Py) excimer fluorescence turning "on" at 480 nm. In vitro results showed that, Py-Yp-Lyso is efficiently dephosphorylated by ALP to yield Py-Phe-Phe-Glu-Tyr-Gly-lyso (Py-Y-Lyso) which self-assembles into nanofibers. Cell experiments verified that, after being taken up by HeLa cells, the excimer fluorescence of Py-Yp-Lyso assemblies has turned "on" and the assemblies specifically target the lysosomes, inducing LMP and ultimate cancer cell death. In vivo experiments indicated that Py-Yp-Lyso has the highest inhibition effect on HeLa tumors among the four compounds studied. This is anticipated for applying Py-Yp-Lyso to treat cancers in the clinic in the future.

Receptor tyrosine kinases-instructed release of its inhibitor from hydrogel to delay ovarian aging.

Premature ovarian failure (POF) is the most frequently occurred disease in ovary. Direct inhibition of mammalian target of rapamycin (mTOR) activity can treat woman POF but brings adverse effects to women. Herein, by rational design of a hydrogelator Nap-Phe-Phe-Asp-Arg-Leu-Tyr-OH (Y) and co-assembling Y with an inhibitor of receptor tyrosine kinase (RTK, an upstream kinase of mTOR), Ala-Glu-Ala-Ala-Leu-Tyr-Lys-Asn-Leu-Leu-His-Ser-OH (Inh), to form hydrogel Gel Y + Inh, we develop a "smart" strategy of RTK-responsive disassembly of the hydrogel to release Inh. Release of Inh moderately inhibits the activity of mTOR and therefore delays ovarian aging. Oocyte and zygote experiments show that Gel Y + Inh improves both meiotic maturation of the oocytes and early embryonic development of the zygotes. In vivo animal experiments indicate that Gel Y + Inh effectively delays ovarian aging in aged mice by down regulation of mTOR activity, stimulation of ovaries to secrete estrogen and progesterone, and development of more antral follicles for reproduction. We expect that our new hydrogel Gel Y + Inh could be applied to treat woman POF, as well as delay ovarian aging, in clinic in the near future.

Medial frontal negativity reflects advantageous inequality aversion of proposers in the ultimatum game: An ERP study.

Inequality aversion is a typical form of fairness preferences, which can explain the behaviors in many social exchange situations such as the ultimatum game (UG). There are two kinds of inequality aversion-disadvantageous inequality aversion of responders and advantageous inequality aversion of proposers in the ultimatum game. Although neuroscience research has reported neural correlates of disadvantageous inequality aversion, there are still debates about advantageous inequality aversion of proposers. In this paper, we developed a variant of ultimatum game in which participants played the UG as proposers. On each trial, first, the offer was randomly presented, then, participants as proposers decided whether to choose this offer; next, responders decided whether to accept or not. Offers that responders got 1-20% of the pie are defined as advantageous unfair offers of proposers, whereas offers that responders got 31-50% are defined as fair offers. Event-related brain potentials recorded from the participants showed that more negative-going medial frontal negativity (MFN) was elicited by advantageous unfair offers compared to fair offers in the early time window (250-350ms), which suggested that proposers were averse to advantageous inequality.

Modulating activity in the orbitofrontal cortex changes trustees' cooperation: A transcranial direct current stimulation study.

Trust is one of the most important factors in human society, as it pervades almost all domains of the society. The trusting behavior of trustors is dependent on the belief about the cooperative (reciprocal) level of trustees. Thence what are the motives underlying the cooperative behavior? An important explanation is that guilt aversion can motivate cooperative behavior. The right orbitofrontal cortex (OFC) is the guilt-specific region, while there is little understanding on the causal effect of this network. We explored the causal effect of the OFC on cooperative behavior using transcranial direct current stimulation (tDCS). Sixty participants played the trust game as trustees, and they received either anodal tDCS over the right OFC and simultaneously cathodal electrode over the right dorsolateral prefrontal cortex (DLPFC), or sham stimulation. Experimental results showed that participants as trustees transferred back more money in the tDCS treatment than sham stimulation. This suggests that the activity of the right OFC has causal effects on cooperative behavior.