Fibroblast growth factor (Fgf) signaling plays important roles in development and metabolism. Mouse Fgf16 was predominantly expressed in cardiomyocytes. To elucidate the physiological roles of Fgf16, we generated Fgf16 knockout mice. Although the mice were apparently normal and fertile, heart weight and cardiomyocyte cell numbers were slightly decreased at 6 months of age. However, blood pressure, heart rate, and cardiac performance were essentially unchanged. In addition, the expression of most cardiac marker genes examined was also essentially unchanged. However, the expression of Bnp was significantly decreased, indicating potential roles of Fgf16 in the heart under pathological conditions. In contrast, the proliferation of embryonic cardiomyocytes was significantly decreased, indicating that Fgf16 is a growth factor for these cells. The embryonic heart phenotype is similar to that of the Fgf9 knockout heart, indicating Fgf9 and Fgf16 to synergistically act as growth factors for embryonic cardiomyocytes.
Aims/Introduction Non‐alcoholic fatty liver disease is frequently associated with type 2 diabetes, and constitutes an important risk factor for the development of hepatic fibrosis and hepatocellular carcinoma. Because there remains no effective drug therapy for non‐alcoholic fatty liver disease associated with type 2 diabetes, we evaluated the efficacy of sodium–glucose cotransporter 2 inhibitor. Methods and Materials In the present pilot, prospective, non‐randomized, open‐label, single‐arm study, we evaluated the effect of 100 mg canagliflozin administered once daily for 12 months on serological markers, body composition measured by bioelectrical impedance analysis method and hepatic fat fraction measured by magnetic resonance imaging in type 2 diabetes patients with non‐alcoholic fatty liver disease . Results Canagliflozin significantly reduced body and fat mass, and induced a slight decrease in lean body or muscle mass that did not reach significance at 6 and 12 months. Reductions in fat mass in each body segment (trunk, arms and legs) were evident, whereas those in lean body mass were not. The hepatic fat fraction was reduced from a baseline of 17.6 ± 7.5% to 12.0 ± 4.6% after 6 months and 12.1 ± 6.1% after 12 months ( P < 0.0005 and P < 0.005), whereas serum liver enzymes and type IV collagen concentrations improved. From a mean baseline hemoglobin A1c of 8.7 ± 1.4%, canagliflozin significantly reduced hemoglobin A1c after 6 and 12 months to 7.3 ± 0.6% and 7.7 ± 0.7% ( P < 0.0005 and P < 0.01). Conclusions Canagliflozin reduced body mass, fat mass and hepatic fat content without significantly reducing muscle mass.
Iron (Fe) is an essential nutrient, but is poorly bioavailable because of its low solubility in alkaline soils; this leads to reduced agricultural productivity. To overcome this problem, we first showed that the soil application of synthetic 2′-deoxymugineic acid, a natural phytosiderophore from the Poaceae, can recover Fe deficiency in rice grown in calcareous soil. However, the high cost and poor stability of synthetic 2′-deoxymugineic acid preclude its agricultural use. In this work, we develop a more stable and less expensive analog, proline-2′-deoxymugineic acid, and demonstrate its practical synthesis and transport of its Fe-chelated form across the plasma membrane by Fe(III)•2’-deoxymugineic acid transporters. Possibility of its use as an iron fertilizer on alkaline soils is supported by promotion of rice growth in a calcareous soil by soil application of metal free proline-2’-deoxymugineic acid.
Fibroblast growth factors (Fgfs) are pleiotropic proteins involved in development, repair and metabolism. Fgf16 is predominantly expressed in the heart. However, as the heart function is essentially normal in Fgf16 knockout mice, its role has remained unclear. To elucidate the pathophysiological role of Fgf16 in the heart, we examined angiotensin II-induced cardiac hypertrophy and fibrosis in Fgf16 knockout mice. Angiotensin II-induced cardiac hypertrophy and fibrosis were significantly promoted by enhancing Tgf-β1 expression in Fgf16 knockout mice. Unexpectedly, the response to cardiac remodeling was apparently opposite to that in Fgf2 knockout mice. These results indicate that Fgf16 probably prevents cardiac remodeling, although Fgf2 promotes it. Cardiac Fgf16 expression was induced after the induction of Fgf2 expression by angiotensin II. In cultured cardiomyocytes, Fgf16 expression was promoted by Fgf2. In addition, Fgf16 antagonized Fgf2-induced Tgf-β1 expression in cultured cardiomyocytes and noncardiomyocytes. These results suggest a possible mechanism whereby Fgf16 prevents angiotensin II-induced cardiac hypertrophy and fibrosis by antagonizing Fgf2. The present findings should provide new insights into the roles of Fgf signaling in cardiac remodeling.
Oxidative stress has been linked to a number of chronic diseases, and this has aroused interest in the identification of clinical biomarkers that can accurately assess its severity. We used liquid chromatography-high resolution mass spectrometry (LC-MS) to show that oxidised and non-oxidised Met residues at position 147 of human serum albumin (Met 147) can be accurately and reproducibly quantified with stable isotope-labelled peptides. Met 147 oxidation was significantly higher in patients with diabetes than in controls. Least square multivariate analysis revealed that glycated haemoglobin (HbA 1c) and glycated albumin (GA) did not significantly influence Met 147 oxidation, but the GA/HbA 1c ratio, which reflects glycaemic excursions, independently affected Met 147 oxidation status. Continuous glucose monitoring revealed that Met 147 oxidation strongly correlates with the standard deviation of sensor glucose concentrations and the time spent with hypoglycaemia or hyperglycaemia each day. Thus, glycaemic variability and hypoglycaemia in diabetes may be associated with greater oxidation of Met 147. Renal function, high-density lipoprotein-cholesterol and serum bilirubin were also associated with the oxidation status of Met 147. In conclusion, the quantification of oxidised and non-oxidised Met 147 in serum albumin using our LC-MS methodology could be used to assess the degree of intravascular oxidative stress induced by hypoglycaemia and glycaemic fluctuations in diabetes. Oxidative stress is involved in a number of disease processes, including cardiovascular diseases 1,2 , diabetes 3-7 , chronic kidney disease 8-10 , cancer 11,12 , hypertension 2 and neurodegenerative disorders 13,14. Oxidative stress is also believed to be associated with ageing-associated disorders 15,16. Functional oxidative modification of biomolecules, including intravascular and cellular proteins, may have a causal role in the cellular dysfunctions that are involved in disease pathophysiology 17,18. The identification of clinical biomarkers of the severity of exposure to oxidative stress has been the intense focus of many researchers 19,20 , because they could be used to predict the development of major human diseases. Because the quantification of reactive oxygen species is difficult, given their very short half-lives, the measurement of stable by-products generated under conditions of oxidative stress remains a popular approach to the monitoring of free radical-influenced processes 20. Methionine (Met), a sulfur-containing amino acid, is an important antioxidant that contributes to the structure and stability of proteins 21. Met is readily oxidised to form Met sulfoxide (MetO), which can be reduced back to Met by MetO reductases 22-26. Because of this instability of Met and MetO, their quantification has not been a widely used method for the assessment of the degree of oxidative stress 27. However, we have recently found that the mass spectral intensity of serum tryptic peptides containing oxidised and non-oxidised Met residues can be very...
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