Honokiol: A non-adipogenic PPARγ agonist from nature

Background

Peroxisome proliferator-activated receptor gamma (PPARγ) agonists are clinically used to counteract hyperglycemia. However, so far experienced unwanted side effects, such as weight gain, promote the search for new PPARγ activators.

Methods

We used a combination of in silico, in vitro, cell-based and in vivo models to identify and validate natural products as promising leads for partial novel PPARγ agonists.

Results

The natural product honokiol from the traditional Chinese herbal drug Magnolia bark was in silico predicted to bind into the PPARγ ligand binding pocket as dimer. Honokiol indeed directly bound to purified PPARγ ligand-binding domain (LBD) and acted as partial agonist in a PPARγ-mediated luciferase reporter assay. Honokiol was then directly compared to the clinically used full agonist pioglitazone with regard to stimulation of glucose uptake in adipocytes as well as adipogenic differentiation in 3T3-L1 pre-adipocytes and mouse embryonic fibroblasts. While honokiol stimulated basal glucose uptake to a similar extent as pioglitazone, it did not induce adipogenesis in contrast to pioglitazone. In diabetic KKAy mice oral application of honokiol prevented hyperglycemia and suppressed weight gain.

Conclusion

We identified honokiol as a partial non-adipogenic PPARγ agonist in vitro which prevented hyperglycemia and weight gain in vivo.

General significance

This observed activity profile suggests honokiol as promising new pharmaceutical lead or dietary supplement to combat metabolic disease, and provides a molecular explanation for the use of Magnolia in traditional medicine.     

The impact of land use and climate change on surface runoff and groundwater in Cimanuk watershed,Indonesia

Limnology - The Cimanuk River with a total watershed area of 4010.8 km2 flowing from the Garut Regency to Indramayu Delta is the longest in West Java Province. However, the cumulative...     

A new genus of rodent from Wallacea (Rodentia: Muridae: Murinae: Rattini), and its implication for biogeography and Indo‐Pacific Rattini systematics

We describe Halmaheramys bokimekot Fabre, Pagès, Musser, Fitriana, Semiadi & Helgen gen. et sp. nov. , a new genus and species of murine rodent from the North Moluccas, and study its phylogenetic placement using both molecular and morphological data. We generated a densely sampled mitochondrial and nuclear DNA data set that included most genera of Indo‐Pacific Murinae, and used probabilistic methodologies to infer their phylogenetic relationships. To reconstruct their biogeographical history, we first dated the topology and then used a Lagrange analysis to infer ancestral geographic areas. Finally, we combined the ancestral area reconstructions with temporal information to compare patterns of murine colonization among Indo‐Pacific archipelagos. We provide a new and comprehensive molecular phylogenetic reconstruction for Indo‐Pacific Murinae, with a focus on the Rattus division. Using previous results and those presented in this study, we define a new Indo‐Pacific group within the Rattus division, composed of Bullimus, Bunomys, Paruromys, Halmaheramys, Sundamys, and Taeromys. Our phylogenetic reconstructions revealed a relatively recent diversification from the Middle Miocene to Plio‐Pleistocene associated with several major dispersal events. We identified two independent Indo‐Pacific dispersal events from both western and eastern Indo‐Pacific archipelagos to the isolated island of Halmahera, which led to the speciations of H. bokimekot gen. et sp. nov. and Rattus morotaiensis Kellogg, 1945. We propose that a Middle Miocene collision between the Halmahera and Sangihe arcs may have been responsible for the arrival of the ancestor of Halmaheramys to eastern Wallacea. Halmaheramys bokimekot gen. et sp. nov. is described in detail, and its systematics and biogeography are documented and illustrated. © 2013 The Linnean Society of London     

Discovery of a novel IKK-β inhibitor by ligand-based virtual screening techniques

Various inflammatory stimuli that activate the nuclear factor kappa B (NF-κB) signaling pathway converge on a serine/threonine kinase that displays a key role in the activation of NF-κB: the I kappa B kinase β (IKK-β). Therefore, IKK-β is considered an interesting target for combating inflammation and cancer. In our study, we developed a ligand-based pharmacophore model for IKK-β inhibitors. This model was employed to virtually screen commercial databases, giving a focused hit list of candidates. Subsequently, we scored by molecular shape to rank and further prioritized virtual hits by three-dimensional shape-based alignment. One out of ten acquired and biologically tested compounds showed inhibitory activity in the low micromolar range on IKK-β enzymatic activity in vitro and on NF-κB transactivation in intact cells. Compound 8 (2-(1-adamantyl)ethyl 4-[(2,5-dihydroxyphenyl)methylamino]benzoate) represents a novel chemical class of IKK-β inhibitors and shows that the presented model is a valid approach for identification and development of new IKK-β ligands.     

Convection of waters in Lakes Maninjau and Singkarak,tropical oligomictic lakes

The ecology of a lake is mainly controlled by mixing processes; particularly, in tropical oligomictic lakes, the occurrence frequency and magnitude of convection govern the vertical mixing of chemicals and organisms. In this study, vertical profiles of water temperature, dissolved oxygen, electric conductivity, turbidity, and chlorophyll a were measured in 2014, 2015, 2017, and 2018 in two Sumatran deep lakes, Lakes Maninjau and Singkarak. In Lake Maninjau, intensive surveys on the profiles were also conducted in three different seasons in 2018. The comparison of the profiles between 2015 and 2017 indicated the events of large convection down to the lake bottoms happened in both of the lakes. Similarly, small convection down to around 30 m depth was found in the period between May and Jul, 2018. Air temperature drops up to five degrees centigrade were observed in these periods, confirmed by the changes in lake surface temperature estimated by MODIS imagery for the lakes. The magnitudes of the convective events were discussed with the observed amounts of heat loss and the estimated heat transfer through lake surface. Furthermore, the influences of such events on anoxic hypolimnetic waters were evaluated and considered from the view of climate change.

     

Polyacetylenes from Notopterygium incisum–New Selective Partial Agonists of Peroxisome Proliferator-Activated Receptor-Gamma

Peroxisome proliferator-activated receptor gamma (PPARγ) is a key regulator of glucose and lipid metabolism and therefore an important pharmacological target to combat metabolic diseases. Since the currently used full PPARγ agonists display serious side effects, identification of novel ligands, particularly partial agonists, is highly relevant. Searching for new active compounds, we investigated extracts of the underground parts of Notopterygium incisum, a medicinal plant used in traditional Chinese medicine, and observed significant PPARγ activation using a PPARγ-driven luciferase reporter model. Activity-guided fractionation of the dichloromethane extract led to the isolation of six polyacetylenes, which displayed properties of selective partial PPARγ agonists in the luciferase reporter model. Since PPARγ activation by this class of compounds has so far not been reported, we have chosen the prototypical polyacetylene falcarindiol for further investigation. The effect of falcarindiol (10 µM) in the luciferase reporter model was blocked upon co-treatment with the PPARγ antagonist T0070907 (1 µM). Falcarindiol bound to the purified human PPARγ receptor with a K_i of 3.07 µM. In silico docking studies suggested a binding mode within the ligand binding site, where hydrogen bonds to Cys285 and Glu295 are predicted to be formed in addition to extensive hydrophobic interactions. Furthermore, falcarindiol further induced 3T3-L1 preadipocyte differentiation and enhanced the insulin-induced glucose uptake in differentiated 3T3-L1 adipocytes confirming effectiveness in cell models with endogenous PPARγ expression. In conclusion, we identified falcarindiol-type polyacetylenes as a novel class of natural partial PPARγ agonists, having potential to be further explored as pharmaceutical leads or dietary supplements.     

Effect of outer wing separation on lift and thrust generation in a flapping wing system

We explore the implementation of wing feather separation and lead-lagging motion to a flapping wing. A biomimetic flapping wing system with separated outer wings is designed and demonstrated. The artificial wing feather separation is implemented in the biomimetic wing by dividing the wing into inner and outer wings. The features of flapping, lead-lagging, and outer wing separation of the flapping wing system are captured by a high-speed camera for evaluation. The performance of the flapping wing system with separated outer wings is compared to that of a flapping wing system with closed outer wings in terms of forward force and downward force production. For a low flapping frequency ranging from 2.47 to 3.90 Hz, the proposed biomimetic flapping wing system shows a higher thrust and lift generation capability as demonstrated by a series of experiments. For 1.6 V application (lower frequency operation), the flapping wing system with separated wings could generate about 56% higher forward force and about 61% less downward force compared to that with closed wings, which is enough to demonstrate larger thrust and lift production capability of the separated outer wings. The experiments show that the outer parts of the separated wings are able to deform, resulting in a smaller amount of drag production during the upstroke, while still producing relatively greater lift and thrust during the downstroke.