There is an increased incidence of heart failure in individuals with diabetes mellitus (DM). The coexistence of kidney disease in DM exacerbates the cardiovascular prognosis. Researchers have attempted to combine the critical features of heart failure, using transverse aortic constriction, with DM in mice, but variable findings have been reported. Furthermore, kidney outcomes have not been assessed in this setting; thus its utility as a model of heart failure in DM and kidney disease is unknown. We generated a mouse model of obesity, hyperglycemia, and mild kidney pathology by feeding male C57BL/6J mice a high-fat diet (HFD). Cardiac pressure overload was surgically induced using transverse aortic constriction (TAC). Normal diet (ND) and sham controls were included. Heart failure risk factors were evident at 8-wk post-TAC, including increased left ventricular mass (+49% in ND and +35% in HFD), cardiomyocyte hypertrophy (+40% in ND and +28% in HFD), and interstitial and perivascular fibrosis (Masson's trichrome and picrosirius red positivity). High-fat feeding did not exacerbate the TAC-induced cardiac outcomes. At 11 wk post-TAC in a separate mouse cohort, echocardiography revealed reduced left ventricular size and increased left ventricular wall thickness, the latter being evident in ND mice only. Systolic function was preserved in the TAC mice and was similar between ND and HFD. Thus combined high-fat feeding and TAC in mice did not model the increased incidence of heart failure in DM patients. This model, however, may mimic the better cardiovascular prognosis seen in overweight and obese heart failure patients.

No abstract

No abstract

BackgroundParathyroid hormone (PTH) is required for the maintenance of normal bone physiology. This study describes the properties of a sustained-release formulation of recombinant human PTH (rhPTH) using chitosan and silk fibroin microparticles as carriers for drug delivery, developed using a spray-drying method.Material/MethodsChitosan, silk fibroin, and chitosan/silk fibroin microparticles loaded with rhPTH were studied with scanning electron microscopy (SEM) to estimate the particle size and surface morphology. The in vitro release of rhPTH was used to assess the developed formulation. The effect of the spray-drying process was assessed by powder X-ray diffraction (PXRD) of the microparticles. Quantification of the released rhPTH was performed by enzyme-linked immune sorbent assay (ELISA). Fourier-transform infrared spectroscopy (FTIR) was used to determine the differences in the absorption frequency of samples.ResultsSurface morphology of the final formulation showed the absence of pure crystals of chitosan and silk fibroin in the final formulation and FTIR demonstrated electrostatic interactions between chitosan and silk fibroin, which was supported by PXRD. The chitosan/silk fibroin microparticles loaded with rhPTH showed an entrapment efficiency (EE) that ranged from 60.36–72.99% with a 50% rhPTH release profile at pH 7.5 in 24 hours. There was no particle aggregation in blood and little hemolysis, indicating stability of the rhPTH-loaded microparticles.ConclusionsA silk fibroin/chitosan microparticle formulation loaded with rhPTH was shown to be stable and to provide sustained-release of rhPTH, supporting a potential role of this formulation in the treatment of bone diseases including osteoporosis and bone fracture.

Aim The measurement of glomerular filtration rate (GFR) in experimental rodents is pivotal to understanding the progression of kidney disease and benefits of treatment strategies. A non‐invasive clearance device has been developed, which measures transcutaneous decay of injected FITC‐sinistrin in conscious rodents. The technique was validated against the well‐established plasma clearance method in the same mice, but on consecutive days, using only models of uninephrectomy and polycystic kidney disease. We aimed to validate this widely used technique in the same lean or obese mice, at the same time. Methods Five‐week‐old male C57BL/6J mice were randomised to a high fat diet (n = 12) or normal diet (n = 11) for 10 weeks. Transcutaneous and plasma clearance of FITC‐sinistrin were measured simultaneously in each mouse. Results In lean mice, there was a positive correlation between transcutaneous and plasma derived GFR (P < .01, R2 = .704), although there was an approximate 40% underestimation by the transcutaneous method (P < .0001). In obese mice, no correlation was observed between transcutaneous and plasma derived GFR, nor elimination half‐life which removes any effect of the conversion factor and injected dose. The limits of agreement in a Bland‐Altman plot were narrower when we used new conversion factors derived from mice in the current study and, in lean mice, a generic conversion factor which assumes 20% extracellular volume. Conclusion The non‐invasive clearance device may be useful for serial GFR measurements in lean and healthy mice, provided validation studies have been carried out, but its utility in obesity requires further study.