Melanin-like nanoparticles were synthesized with size control through neutralization of dopamine hydrochloride with NaOH, followed by spontaneous air oxidation of dopamine. Although the particle characteristic of natural melanins was understood to be significantly affected by the biological and structural environment, melanin-lke nanoparticles can be realized through the chemical reactions only. Melanin-like nanoparticles that are <100 nm showed excellent dispersion stability in water as well as biological media and good biocompatibility to HeLa cells after the appropriate surface modification with thiol-terminated methoxy-poly(ethylene glycol) (mPEG-SH). Furthermore, the demonstrated ability of melanin-like nanoparticles to reduce 2,2-diphenyl-1-picrylhydrazyl (DPPH) suggests free radical scavenging activity of the material.

The development of technology enables the reduction of material size in science. The use of particle reduction in size from micro to nanoscale not only provides benefits to diverse scientific fields but also poses potential risks to humans and the environment. For the successful application of nanomaterials in bioscience, it is essential to understand the biological fate and potential toxicity of nanoparticles. The aim of this study was to evaluate the biological distribution as well as the potential toxicity of magnetic nanoparticles to enable their diverse applications in life science, such as drug development, protein detection, and gene delivery. We recently synthesized biocompatible silica-overcoated magnetic nanoparticles containing rhodamine B isothiocyanate (RITC) within a silica shell of controllable thickness [MNPs@SiO2(RITC)]. In this study, the MNPs@SiO2(RITC) with 50-nm thickness were used as a model nanomaterial. After intraperitoneal administration of MNPs@SiO2(RITC) for 4 weeks into mice, the nanoparticles were detected in the brain, indicating that such nanosized materials can penetrate blood-brain barrier (BBB) without disturbing its function or producing apparent toxicity. After a 4-week observation, MNPs@SiO2(RITC) was still present in various organs without causing apparent toxicity. Taken together, our results demonstrated that magnetic nanoparticles of 50-nm size did not cause apparent toxicity under the experimental conditions of this study.

Organic dye‐incorporated smart silica‐coated core–shell magnetic nanoparticles (MNP@SiO2) having dual‐functionality (‐PEG/NH2, see Figure) were easily fabricated, and the amine moieties on the NP surface were modified with maleimide functionality for specific covalent immobilization of biopolymers and bioactive small molecules. The sequence‐independent immobilization of antibodies (Ab) is highlighted; Ab‐modified MNP@SiO2 particles exhibit specific recognition for floating tumor cells or target the membrane of adherent breast cancer cells.

eIn obesity, adipocyte hypertrophy and proinflammatory responses are closely associated with the development of insulin resistance in adipose tissue. However, it is largely unknown whether adipocyte hypertrophy per se might be sufficient to provoke insulin resistance in obese adipose tissue. Here, we demonstrate that lipid-overloaded hypertrophic adipocytes are insulin resistant independent of adipocyte inflammation. Treatment with saturated or monounsaturated fatty acids resulted in adipocyte hypertrophy, but proinflammatory responses were observed only in adipocytes treated with saturated fatty acids. Regardless of adipocyte inflammation, hypertrophic adipocytes with large and unilocular lipid droplets exhibited impaired insulin-dependent glucose uptake, associated with defects in GLUT4 trafficking to the plasma membrane. Moreover, Toll-like receptor 4 mutant mice (C3H/HeJ) with high-fat-diet-induced obesity were not protected against insulin resistance, although they were resistant to adipose tissue inflammation. Together, our in vitro and in vivo data suggest that adipocyte hypertrophy alone may be crucial in causing insulin resistance in obesity.

In the search for new therapeutic agents for currently incurable diseases, attention has turned to traditionally "undruggable" targets, and collections of drug-like small molecules with high diversity and quality have become a prerequisite for new breakthroughs. To generate such collections, the diversity-oriented synthesis (DOS) strategy was developed, which aims to populate new chemical space with drug-like compounds containing a high degree of molecular diversity. The resulting DOS-derived libraries have been of great value for the discovery of various bioactive small molecules and therapeutic agents, and thus DOS has emerged as an essential tool in chemical biology and drug discovery. However, the key challenge has become how to design and synthesize drug-like small-molecule libraries with improved biological relevancy as well as maximum molecular diversity. This Perspective presents the development of privileged substructure-based DOS (pDOS), an efficient strategy for the construction of polyheterocyclic compound libraries with high biological relevancy. We envisioned the specific interaction of drug-like small molecules with certain biopolymers via the incorporation of privileged substructures into polyheterocyclic core skeletons. The importance of privileged substructures such as benzopyran, pyrimidine, and oxopiperazine in rigid skeletons was clearly demonstrated through the discovery of bioactive small molecules and the subsequent identification of appropriate target biomolecule using a method called "fluorescence difference in two-dimensional gel electrophoresis". Focusing on examples of pDOS-derived bioactive compounds with exceptional specificity, we discuss the capability of privileged structures to serve as chemical "navigators" toward biologically relevant chemical spaces. We also provide an outlook on chemical biology research and drug discovery using biologically relevant compound libraries constructed by pDOS, biology-oriented synthesis, or natural product-inspired DOS.

The development of nontoxic and biocompatible imaging agents will create new opportunities for potential applications in clinical MRI diagnosis. Synthetic melanin-like nanoparticles (MelNPs), analogous to natural sepia melanin (a major component of the cuttlefish ink), can be used as contrast agent for MRI. MelNPs complexed with paramagnetic Fe(3+) ions show much higher relaxivity values than existing MRI T1 contrast agents based on gadolinium (Gd) or manganese (Mn); MelNP values at 3T were r1 = 17 and r2 = 18 mM(-1) s(-1) (r2/r1 value of 1.1). With significant enhancement to MRI contrast, this biomimetic approach using MelNPs functionalized with paramagnetic Fe(3+) ions and surface-modified with biocompatible poly(ethylene glycol) units, could provide new insight into how melanin-based bioresponsive and therapeutic imaging probes integrate with their various biological functions.

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Background: Dysregulation of glucose homeostasis is often associated with insulin resistance and diabetes. Results: Hepatic ERR␥ expression is increased by fasting-dependent activation of the CREB-CRTC2 pathway, which leads to the induction of hepatic gluconeogenesis. Conclusion: Orphan nuclear receptor ERR␥ is a novel transcriptional regulator of hepatic gluconeogenesis. Significance: An ERR␥ inverse agonist could be a new potential therapeutic approach for the treatment of type 2 diabetes.