Peroxisome proliferator-activated receptor γ (PPARγ) modulators are expected to exert anti-diabetic effects without PPARγ-related adverse effects, such as fluid retention, weight gain, and bone loss. ...The present study showed that the novel tetrazole derivative KY-903 exerted similar selective PPARγ partial agonist properties to INT-131, a known PPARγ modulator, in transactivation assays, and decreased plasma glucose and triglyceride levels with increases in adiponectin levels in diabetic KK-Ay mice. These effects were similar to those of pioglitazone. Pioglitazone, but not KY-903, increased adipose tissue and heart weights. In pre-adipocytes (3T3-L1), KY-903, in contrast to pioglitazone, increased adiponectin mRNA levels without adipocyte differentiation, indicating anti-diabetic effects via adiponectin without adipogenesis. In ovariectomized rats fed a high-fat diet (OVX/HFD), KY-903 and pioglitazone decreased plasma triglyceride and non-esterified fatty acid levels and increased adiponectin levels, indicating insulin sensitization via adiponectin. KY-903 reduced body weight gain and adipose tissue weight, while pioglitazone increased heart weight and markedly reduced bone mineral density. In mesenchymal stem cell-like ST2 cells, KY-903 slightly reduced osteoblast differentiation without adipocyte differentiation, while pioglitazone markedly reduced it with adipocyte differentiation. In conclusion, KY-903 is a novel PPARγ modulator that exerts anti-diabetic effects without body weight gain or cardiac hypertrophy in diabetic mice and anti-obesity effects with minor bone loss in OVX/HFD, possibly due to increases in adiponectin levels without adipogenesis.
•We measure ice-crystal tip radii and growth rates in solutions of trehalose.•We find that the ice grows faster with a peak tip velocity near 2 wt%.•Dendrite tip in solution becomes thinner and ...sharper than that in pure water.
We use Mach-Zehnder interferometry to measure ice-crystal tip radii and growth rates in dilute aqueous solutions of trehalose over a range of concentrations. Although trehalose at high concentrations is a well-known inhibitor of ice crystal growth in aqueous solution, we find that the ice instead grows faster with the trehalose concentrations below about 8 wt%, with a peak tip velocity near 2 wt%. By directly measuring the 3D morphology of the growing ice crystals with the interferometer, we find that the dendrite tip in solution becomes thinner and sharper than that in pure water, causing the more rapid growth of ice.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Differentiation-inducing factor-1 (DIF-1), a morphogen produced by the cellular slime mold Dictyostelium discoideum, is a natural product that has attracted considerable attention for its antitumor ...properties. Here, we report a novel inhibitory effect of DIF-1 on the activation of hepatic stellate cells (HSCs) responsible for liver fibrosis. DIF-1 drastically inhibited transdifferentiation of quiescent HSCs into myofibroblastic activated HSCs in a concentration-dependent manner, thus conferring an antifibrotic effect against in the liver. Neither SQ22536, an adenylate cyclase inhibitor, nor ODQ, a guanylate cyclase inhibitor, showed any effect on the inhibition of HSC activation by DIF-1. In contrast, TWS119, a glycogen synthase kinase 3β (GSK3β) inhibitor, attenuated the inhibitory effect of DIF-1. Moreover, the level of inactive GSK3β (phosphorylated at Ser9) was significantly reduced by DIF-1. DIF-1 also inhibited nuclear translocation of β-catenin and reduced the level of non-phospho (active) β-catenin. These results suggest that DIF-1 inhibits HSC activation by disrupting the Wnt/β-catenin signaling pathway through dephosphorylation of GSK3β. We propose that DIF-1 is a possible candidate as a therapeutic agent for preventing liver fibrosis.
•A cellular slime mold product DIF-1 blocked hepatic stellate cell (HSC) activation.•An inhibitor of glycogen synthase kinase (GSK) 3β attenuated the effect of DIF-1.•The level of inactive GSK3β was significantly reduced by DIF-1.•DIF-1 reduced nuclear translocation of β-catenin and the level of active β-catenin.•DIF-1 is a possible candidate for liver fibrosis therapy to target HSC activation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Peroxisome proliferator-activated receptor γ (PPARγ) modulators are expected to exert anti-diabetic effects without PPARγ-related adverse effects, such as fluid retention, weight gain, and bone loss. ...The present study showed that the novel tetrazole derivative KY-903 exerted similar selective PPARγ partial agonist properties to INT-131, a known PPARγ modulator, in transactivation assays, and decreased plasma glucose and triglyceride levels with increases in adiponectin levels in diabetic KK-Ay mice. These effects were similar to those of pioglitazone. Pioglitazone, but not KY-903, increased adipose tissue and heart weights. In pre-adipocytes (3T3-L1), KY-903, in contrast to pioglitazone, increased adiponectin mRNA levels without adipocyte differentiation, indicating anti-diabetic effects via adiponectin without adipogenesis. In ovariectomized rats fed a high-fat diet (OVX/HFD), KY-903 and pioglitazone decreased plasma triglyceride and nonesterified fatty acid levels and increased adiponectin levels, indicating insulin sensitization via adiponectin. KY-903 reduced body weight gain and adipose tissue weight, while pioglitazone increased heart weight and markedly reduced bone mineral density. In mesenchymal stem cell-like ST2 cells, KY-903 slightly reduced osteoblast differentiation without adipocyte differentiation, while pioglitazone markedly reduced it with adipocyte differentiation. In conclusion, KY-903 is a novel PPARγ modulator that exerts anti-diabetic effects without body weight gain or cardiac hypertrophy in diabetic mice and anti-obesity effects with minor bone loss in OVX/HFD, possibly due to increases in adiponectin levels without adipogenesis.
Hepatic stellate cells (HSCs), located in the gap of hepatocytes and sinusoidal endothelial cells, transdifferentiate from quiescent form (qHSCs) into myofibroblast-like activated one (aHSCs) during ...liver injury. The expression of α-smooth muscle actin (α-SMA) and the production of type Ⅰ collagen are up-regulated in aHSCs. Therefore, the activation of HSCs is responsible for liver fibrosis and inhibiting the activation can be a novel therapeutic target for the fibrosis. In the present study, we show that differentiation-inducing factor-1 (DIF-1) that is a low molecular weight compound derived from the cellular slime mold, Dictyostelium discoideum, has a suppressive effect on HSC activation. qHSCs were isolated from ddY mice and cultured in DMEM supplemented with 10% FBS. We treated qHSCs with DIF-1 on the next day after isolation and analyzed the effect of DIF-1 on HSC activation. DIF-1 significantly suppressed the up-regulation of α-SMA. However, the effect of DIF-1 was abolished in the presence of TWS119, an activator of Wnt/β-catenin signal pathway. DIF-1 reduced the levels of non-phosphorylated β-catenin (activated β-catenin) and phosphorylated GSK3β. These results suggest that DIF-1 inhibits the Wnt/β-catenin signal pathway through dephosphorylating GSK3β, thereby suppressing HSC activation.
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