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Left untreated nonalcoholic fatty liver disease (NAFLD) can progress to nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma. The observed failure of clinical trials in NASH may suggest that current model systems do not fully recapitulate human disease, and/or hallmark pathological features of NASH may not be driven by the same pathway in every animal model let alone in each patient. Identification of a model-agnostic disease-associated node can spur the development of effective drugs for the treatment of liver disease. Glycerol-3-phosphate acyltransferase1 (GPAT1) plays a pivotal role in lipid accumulation by shunting fats away from oxidation. In the present study, hepatic GPAT 1 expression was evaluated in three etiologically different models of NAFLD. Compared to the sham cohort, hepatic GPAT 1 mRNA levels were elevated by ∼5-fold in steatosis and NASH with fibrosis with immunofluorescent staining revealing increased GPAT1 in the fatty liver. A significant and direct correlation ( r = 0.88) was observed between hepatic GPAT 1 mRNA expression and severity of the liver disease. Picrosirius red staining revealed a logarithmic relation between hepatic GPAT 1 mRNA expression and scar. These data suggest that hepatic GPAT1 is an early disease-associated model-agnostic node in NAFLD and form the basis for the development of a potentially successful therapeutic against NASH., Competing Interests: The authors declare no competing financial interest., (Copyright © 2020 American Chemical Society.)

Ipomoeassin F, the flagship congener of a resin glycoside family exhibited single-digit nanomolar IC50 values against several cancer cell lines. To facilitate drug discovery based on this unique yet underexplored natural product, we performed the most sophisticated SAR studies of ipomoeassin F to date, which not only greatly bettered our understanding of its pharmacophore but also led to the discovery of two new derivatives (3 and 27) with similar potency but improved synthetic profile. The work presented here opens new avenues toward harnessing the medicinal potential of the ipomoeassin family of glycolipids in the future.

Ipomoeassin F, a macrolide glycoresin containing an embedded disaccharide, possesses potent in vitro antitumor activity with an unknown mechanism of function. It inhibits tumor cell growth with single-digit nanomolar IC50 values, superior to many clinical chemotherapeutic drugs. To facilitate translation of its bioactivity into protein function for drug development, we report here a new synthesis for the gram-scale production of ipomoeassin F (3.8% over 17 linear steps) from commercially available starting materials. The conformation-controlled subtle reactivity differences of the hydroxyl groups in carbohydrates were utilized to quickly construct the disaccharide core, which, along with judicial selection of protecting groups, made the current synthesis very efficient. The same strategy was also applied to the smooth preparation of the 11R-epimer of ipomoeassin F for the first time. Cytotoxicity assays demonstrated the crucial role of the natural 11S configuration. In addition, cell cycle analyses and apoptosis assays on ipomoeassin F and/or its epimer were conducted. This work has laid a solid foundation for understanding the medicinal potential of the ipomoeassin family of glycolipids in the future.

Au@Cu2O core-shell nanostructures are fabricated to have a plasmon enhancement effect using Au nanorods (Au NRs) as a plasmon-tailorable core. By varying the concentration of Au NRs, we can tune the shell thickness in the range of 10-25 nm. The shell is composed of Cu2O nanocrystallites. Because of the thin shells, the extinction spectra at wavelength >500 nm are dominated by the Au core. However, the large dielectric constant of the shell causes an obvious red shift of the surface plasmon resonance (SPR) band of the Au nanorod. Besides, transverse octupolar SPR appears as a result of the anisotropy of the core and the high dielectric constant of the shell. The anisotropic geometry of the Au NR is found to support the octupolar resonances at smaller sizes than for their spherical counterpart. Theoretical simulations indicate that the transverse SPR bands are divided into two resonances, which are dipolar- and octupolar-dominant, respectively. The Cu2O shell degrades via a defect-mediated oxidative pathway, which is aggravated upon longitudinal SPR excitation. The SPR-mediated local field enhancement and resonance energy transfer are found to enhance the excitation of the defect states in the shell, thus providing a simple yet selective probing strategy for defect states.

Growth kinetics plays an important role in the shape control of nanocrystals (NCs). Herein, we presented a unique way to fine-tune the growth kinetics via oxidative etching activated by copper ions. For the overgrowth of gold nanorods (Au NRs), competitive adsorption of dissolved oxygen on rod surface was found to slow down the overgrowth rate. Copper ions were able to remove the adsorbed oxygen species from the Au surface via oxidative etching, thus exposing more reaction sites for Au deposition. In this way, copper ions facilitated the overgrowth process. Furthermore, Cu(2+) rather than Cu(+) acted as the catalyst for the oxidative etching. Comparative study with Ag(+) indicated that Cu(2+) cannot regulate NC shapes via an underpotential deposition mechanism. In contrast, Ag(+) led to the formation of Au tetrahexahedra (THH) and a slight decrease of the growth rate at similar growth conditions. Combining the distinct roles of the two ions enabled elongated THH to be produced. Copper ions activating the O2 pathway suggested that dissolved oxygen has a strong affinity for the Au surface. Moreover, the results of NC-sensitized singlet oxygen ((1)O2) indicated that the absorbed oxygen species on the surface of Au NCs bounded with low-index facets mainly existed in the form of molecular O2.

In the well-developed seed-mediated growth of gold nanorods (GNRs), adding the proper amount of Cu(2+) ions in the growth solution leads to significant narrowing in the size distribution of the resultant GNRs, especially for those with shorter aspect ratios (corresponding longitudinal surface plasmon resonance (LSPR) peaks shorter than 750 nm). Cu(2+) ions were found to be able to catalyze the oxidative etching of gold seeds by oxygen, thus mediating subsequent growth kinetics of the GNRs. At proper Cu(2+) concentrations, the size distribution of the original seeds is greatly narrowed via oxidative etching. The etched seeds are highly reactive and grow quickly into desired GNRs with significantly improved size distribution. A similar mechanism can be employed to tune the end cap of the GNRs. Except for copper ions, no observable catalytic effect is observed from other cations presumably due to their lower affinity to oxygen. Considering the widespread use of seed-mediated growth in the morphology-controlled synthesis of noble metal nanostructures, the tailoring in seed reactivity we presented herein could be extended to other systems.