Propionate suppresses hepatic gluconeogenesis via GPR43/AMPK signaling pathway.

Short-chain fatty acids (SCFAs) such as acetate, propionate, and butyrate are generated by gut microbial fermentation of dietary fiber. SCFAs may exert multiple beneficial effects on human lipid and glucose metabolism. However, their actions and underlying mechanisms are not fully elucidated. In this study, we examined the direct effects of propionate on hepatic glucose and lipid metabolism using human HepG2 hepatocytes. Here, we demonstrate that propionate at a physiologically-relevant concentration effectively suppresses palmitate-enhanced glucose production in HepG2 cells but does not affect intracellular neutral lipid levels. Our results indicated that propionate can decline in gluconeogenesis by down-regulation of glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK) through activation of AMP-activated protein kinase (AMPK), which is a major regulator of the hepatic glucose metabolism. Mechanistic studies also revealed that propionate-stimulated AMPK phosphorylation can be ascribed to Ca2+/calmodulin-dependent protein kinase kinase ß (CaMKKß) activation in response to an increase in intracellular Ca2+ concentration. Moreover, siRNA-mediated knockdown of the propionate receptor GPR43 prevented propionate-inducible activation of AMPK and abrogates the gluconeogenesis-inhibitory action. Thus, our data indicate that the binding of propionate to hepatic GPR43 elicits CaMKKß-dependent activation of AMPK through intracellular Ca2+ increase, leading to suppression of gluconeogenesis. The present study suggests the potential efficacy of propionate in preventive and therapeutic management of diabetes.

Palmitate induces insulin resistance in human HepG2 hepatocytes by enhancing ubiquitination and proteasomal degradation of key insulin signaling molecules.

Obesity-associated insulin resistance is a major pathogenesis of type 2 diabetes mellitus and is characterized by defects in insulin signaling. High concentrations of plasma free fatty acids (FFAs) are involved in the etiology of obesity-associated insulin resistance. However, the detailed mechanism by which FFAs contribute to the development of insulin resistance is not yet fully understood. We investigated the molecular basis of insulin resistance elicited by FFAs using the human hepatocyte cell line HepG2. Among major human FFAs, palmitate markedly inhibited insulin-stimulated phosphorylation of key insulin signaling molecules such as insulin receptor, insulin receptor substrate-1, and Akt, indicating that palmitate is the principal inducer of insulin resistance. We revealed that palmitate facilitates ubiquitination of the key insulin signaling molecules, and subsequently elicits their proteasomal degradation. Furthermore, we demonstrated that inhibition of ubiquitination by the ubiquitin-activating enzyme E1 inhibitor PYR41 significantly prevents palmitate-inducible insulin resistance but not by the proteasome inhibitor MG132, implying that ubiquitinated signaling molecules may be dysfunctional. In conclusion, inhibition of ubiquitination of the key insulin signaling molecules may be a potential strategy for preventing and treating obesity-associated insulin resistance.

Homochiral 1D helical chain based on an achiral Cu(II) complex.

Self-assembly of an achiral [Cu(L)] complex produced a homochiral helical chain [Cu(L)](3)·2H(2)O (1) (L = 2-dimethylaminoethyl(oxamato)). Interestingly, complex 1 obtained in our laboratory exhibits only a left-handed helical chain without any chiral source. Single-crystal X-ray analysis revealed the absolute structure and homochirality of its helical chain structure in the space group of P3(2). Solid-state circular dichroism (CD) spectra confirmed the high enantio excess of the crystals obtained in different synthesis batches. Magnetic susceptibility measurements reveal a relatively strong intrachain antiferromagnetic interaction between Cu(II) centers via an oxamato bridge (J = -74.4 cm(-1)).

Proving that a genome-edited organism is not GMO.

A genome-edited agricultural product that is proven to contain no exogenous DNA is not subject to genetically modified organism (GMO) regulations in some countries. However, whether such proof is definitive is often disputed. We discuss the approaches to substantially proving that a genome-edited organism is not GMO, while considering social aspects.

Moisturization of the Surgical Field during Cancer Resection Reduces Perioperative Complications in Reconstruction Surgery.

Background: Intraoperative tissue desiccation is a risk factor for infection and wound necrosis. We hypothesized that maintaining a moist environment in the surgical field would reduce perioperative complications in free flap reconstruction for head and neck cancer surgery. Methods: A total of 331 patients who underwent free flap reconstruction after head and neck cancer surgery from January 2013 to December 2017 at Osaka International Cancer Institute were included in the study. We classified patients into two groups: those in whom saline was sprayed only during reconstruction (control group: 162 patients) and those in whom saline was sprayed in the surgical field intermittently during cancer resection and reconstruction (moisturized group: 169 patients). We compared perioperative complications, including intraoperative arterial anastomotic thrombosis, between the two groups. Other candidate risk factors for intraoperative arterial thrombosis that were assessed included a history of preoperative irradiation, history of neck surgery, advanced age, and flap type. Results: Rates of abscess formation and intraoperative arterial thrombosis were significantly lower in the moisturized group than in the control group (6.5% versus 12.7%, P < 0.05 and 3.0% versus 11.1%, P < 0.01, respectively). Binomial logistic regression analysis revealed that, in addition to no moisturization during cancer resection, advanced age and jejunal flap use were significant risk factors for intraoperative arterial thrombosis. Conclusions: Moisturization of the surgical field during cancer resection reduced the rate of perioperative complications in free flap reconstruction. Although simple, preventing desiccation of the surgical field by spraying saline solution intermittently had significant benefits on postoperative complications.

Dual functional characteristic of human aquaporin 10 for solute transport.

BACKGROUND/AIMS: Although aquaglyceroporins have been generally believed to operate in a channel mode, which is of nonsaturable nature, for glycerol as well as for water, we recently found that human aquaporin 9 (hAQP9) operates in a carrier-mediated mode, which is of saturable nature, for glycerol. Based on the finding, we assumed that such a characteristic might be shared by the other aquaglyceroporins and examined the functional characteristics of hAQP10, which is an intestine-specific aquaglyceroporin. METHODS: Transport assays were conducted using Xenopus laevis oocytes expressing hAQP10 derived from the microinjected cRNA. RESULTS: The transport of glycerol by hAQP10 was found to be highly saturable with a Michaelis constant of 10.4 µM and specifically inhibited by several glycerol analogs such as monoacetin. Furthermore, when glycerol was preloaded in hAQP10-expressing oocytes, its efflux was trans-stimulated by extracellular glycerol. These results indicate the involvement of a carrier-mediated mechanism in glycerol transport by hAQP10. Interestingly, a channel mechanism was also found to be involved in part in hAQP10-mediated glycerol transport. CONCLUSION: The present study unveiled the uniquely dual functional characteristic of hAQP10 as a carrier/channel for solute transport, providing a novel insight into its operation mechanism, which would help further elucidate its physiological role.

Passive stretching produces Akt- and MAPK-dependent augmentations of GLUT4 translocation and glucose uptake in skeletal muscles of mice.

Muscle contraction is accompanied by passive stretching or deformation of cells and tissues. The present study aims to clarify whether or not acute passive stretching evokes glucose transporter 4 (GLUT4) translocation and glucose uptake in skeletal muscles of mice. Passive stretching mainly induced GLUT4 translocation from an intracellular membrane-rich fraction (PF5) to a plasma membrane-rich fraction (F2) and accelerated glucose uptake in hindlimb muscles; whereas electrical stimulation, which mimics physical exercise in vivo, and insulin, each induced GLUT4 translocation from an intracellular membrane-rich fraction (PF5) to a fraction rich in plasma membrane (F2), and to one rich in transverse tubules (PF3), along with subsequent glucose uptake. Mechanical stretching increased phosphorylation of Akt and p38 mitogen-activated protein kinase (p38 MAPK), but it had no apparent effect on the activity of AMP-activated protein kinase (AMPK). Electrical stimulation augmented the activity of not only AMPK but also phosphorylation of Akt and p38 MAPK. Our results suggest that passive stretching produces translocation of GLUT4 mainly from the fraction rich in intracellular membrane to that rich in plasma membrane, and that the glucose uptake could be Akt- and p38 MAPK-dependent, but AMPK-independent manners.

Coumarin-4-ylmethoxycarbonyls as phototriggers for alcohols and phenols.

Caged compounds can be used to regulate the spatial and temporal dynamics of signaling molecules in live cells. Photochemical properties of coumarin-4-ylmethoxy carbonates (1a-d) are investigated to construct caged compounds of hydroxy-containing molecules. All the compounds possess desired properties as phototriggers for alcohols and phenols. The 6-bromo-7-hydroxycoumarin-4-ylmethoxycarbonyl (Bhcmoc) group has the highest photochemical efficiency and is applied to make caged compounds of 1,2-dioctanoylglycerol (diC(8)), Tyr-OMe, and adenosine. [reaction: see text]

Safranal, a novel protein tyrosine phosphatase 1B inhibitor, activates insulin signaling in C2C12 myotubes and improves glucose tolerance in diabetic KK-Ay mice.

SCOPE: Protein tyrosine phosphatase 1B (PTP1B) negatively regulates insulin signaling by tyrosine dephosphorylation of insulin receptor, and its increased activity and expression is implicated in the pathogenesis of insulin resistance. Hence, PTP1B inhibition is anticipated to improve insulin resistance in type 2 diabetic subjects. The aim of this study was to find a novel PTP1B inhibitor from medicinal food and to evaluate its antidiabetic effects. METHODS AND RESULTS: We found that saffron (Crocus sativus L.), which is used both as a spice and as a traditional medicine, potently inhibits PTP1B activity. Analyses of saffron extracts demonstrated that safranal, the saffron's aroma compound, is a principal PTP1B inhibitor, and induces a ligand-independent activation of insulin signaling in cultured myotubes. Our data implied that the molecular mechanism underlying the inactivation of PTP1B could be attributed to the covalent modification of the catalytic cysteinyl thiol by safranal through a Michael addition. Furthermore, safranal significantly enhanced glucose uptake through the translocation of glucose transporter 4. We also demonstrated that 2-wk oral administration of 20 mg/kg/day safranal improved impaired glucose tolerance in type 2 diabetic KK-A(y) mice. CONCLUSION: Our results strongly suggest the usefulness of safranal in antidiabetic treatment for type 2 diabetic subjects.

Functional characterization of human aquaporin 9 as a facilitative glycerol carrier.

The mechanism of glycerol transport by human aquaporin 9 (hAQP9), which is a liver-specific AQP water channel and can also transport glycerol, was investigated by using the Xenopus laevis oocyte expression system. It was found that specific glycerol uptake by hAQP9 was concentration-dependent (saturable) at 25 degrees C, conforming to the Michaelis-Menten kinetics with the maximum transport rate (J(max)) of 0.84 pmol/min/oocyte and the Michaelis constant (K(m)) of 9.2 microM, and temperature-dependent, being reduced by about 70% when temperature was lowered from 25 degrees C to 4 degrees C. Such dependences on concentration and temperature are characteristic of a carrier-mediated type of mechanism rather than a channel type, which is expected not to depend on them. Furthermore, several glycerol-related compounds, such as monoacetin, were found to specifically inhibit hAQP9-mediated glycerol uptake, indicating a possibility of competition with glycerol. hAQP9-mediated glycerol uptake was, however, found not to require Na+. All these results suggest that hAQP9 functions as a facilitative carrier for glycerol, although it had been believed to function as a channel. Findings in the present study provide novel insight into its glycerol-transporting mechanism and would help exploring a possibility that hAQP9 inhibitors might help lower blood glucose level by reducing gluconeogenesis by limiting hepatic glycerol uptake.

Benign mass lesions deep inside the temporal bone: imaging diagnosis for proper management.

CONCLUSION: Among mass lesions inside the temporal bone, benign tumors and cholesteatomas can be differentiated by contrast enhancement in T1-weighted images (T1WI) and by diffusion-weighted images (DWI). Moreover, DWI will also facilitate discrimination between cholesteatomas accompanied by granulation and other non-neoplastic lesions such as mucoceles and cholesterol granulomas. OBJECTIVES: To review the imaging characteristics of mass lesions inside the temporal bone and to investigate pertinent imaging modalities for differential diagnosis, which is crucial for appropriate treatment planning. PATIENTS AND METHODS: This was a retrospective case series study of six patients seen between 2002 and 2005 with mass lesions deep inside the temporal bone. RESULTS: One patient had facial schwannoma, two had glomus jugulare tumor, and three had cholesteatoma. Plain high resolution CT gave few clues to the nature of the mass lesions. MRI study provided us with better clues: contrast enhancement on T1WI was observed only in benign tumors and only cholesteatomas showed high intensity on DWI. With the assistance of neurosurgeons, surgery was successfully performed in all cases.