Yonit Marcus

Angiotensin 1-7 as Means to Prevent the Metabolic Syndrome: Lessons From the Fructose-Fed Rat Model

We studied the effects of chronic angiotensin 1-7 (Ang 1-7) treatment in an experimental model of the metabolic syndrome, i.e., rats given high-fructose/low-magnesium diet (HFrD). Rats were fed on HFrD for 24 weeks with and without Ang 1-7 (576 µg/kg/day, s.c., Alzet pumps). After 6 months, Ang 1-7–treated animals had lower body weight (−9.5%), total fat mass (detected by magnetic resonance imaging), and serum triglycerides (−51%), improved glucose tolerance, and better insulin sensitivity. Similar metabolic effects were also evident, albeit in the absence of weight loss, in rats first exposed to HFrD for 5 months and then subjected to short-term (4 weeks) treatment with Ang 1-7. Six months of Ang 1-7 treatment were associated with lower plasma renin activity (−40%) and serum aldosterone (−48%), less hepatosteatatitis, and a reduction in epididymal adipocyte volume. The marked attenuation of macrophage infiltration in white adipose tissue (WAT) was associated with reduced levels of the pP65 protein in the epididymal fat tissue, suggesting less activation of the nuclear factor-κB (NFκB) pathway in Ang 1-7–treated rats. WAT from Ang 1-7–treated rats showed reduced NADPH-stimulated superoxide production. In single muscle fibers (myofibers) harvested and grown ex vivo for 10 days, myofibers from HFrD rats gave rise to 20% less myogenic cells than the Ang 1-7–treated rats. Fully developed adipocytes were present in most HFrD myofiber cultures but entirely absent in cultures from Ang 1-7–treated rats. In summary, Ang 1-7 had an ameliorating effect on insulin resistance, hypertriglyceridemia, fatty liver, obesity, adipositis, and myogenic and adipogenic differentiation in muscle tissue in the HFrD rats.

Muscle function and fat content in relation to sarcopenia, obesity and frailty of old age--An overview.

BACKGROUND AND AIM In western countries, the proportion of people over age 60 is increasing faster than any other group. This is linked to higher rates of obesity. Older age, co-morbidities and obesity are all associated with frailty syndrome. In the core of both frailty and sarcopenia there are dysfunction and deterioration of the muscle and the fat tissues. This overview interlinks the phenotypes presented in older adults such as sarcopenia and frailty-alone and with relation to obesity, muscle function and fat tissue accumulation. RECENT FINDINGS Observational studies have well described the loss of muscle mass and strength through the years of adult life, both components of frailty and sarcopenia. They have shown that these changes are associated with dysmetabolism and functional deterioration, independent of common explanatory variables. In the metabolic mechanism core of this link, insulin resistance and higher ectopic fat accumulation may play a role. Basic experiments have partially validated this hypothesis. Whether there is a synergistic effect of obesity and frailty phenotype on morbidity risk is still questionable and currently under investigation; however, few cohort studies have shown that the frail-obese or sarcopenic-obese group have higher probability for metabolic complications. SUMMARY Muscle mass loss and fat accumulation in the muscle in the elderly, with or without the presence of obesity, may explain some of the functional and metabolic defects shown in the frail, sarcopenic population.

Turning low-molecular-weight drugs into prolonged acting prodrugs by reversible pegylation: a study with gentamicin.

Pegylation is a powerful technology to prolong the action of proteins in vivo, but it is impractical for low-molecular-weight (LMW) drugs, which are usually inactivated upon such modification. Here, we have applied a recently developed strategy of reversible pegylation to gentamicin, a LMW antibiotic. Variable length polyethyleneglycol (PEG-SH) chains were covalently linked to gentamicin using two heterobifunctional agents, each containing a spontaneously hydrolyzable bond. The inactive derivatives regained full antibacterial potency upon incubation under physiological conditions in vitro, and following systemic administration to rats, they released native active gentamicin with half-lives 7- to 15-fold greater than those of systemically administered nonderivatized gentamicin. In conclusion, reversibly pegylated prodrug derivatives of gentamicin were found to be capable of releasing gentamicin for prolonged periods in vivo. Most importantly, the major drawback of conventional pegylation, namely, the loss of pharmacological potency following irreversible derivatization, has been overcome.

Engineering prolonged-acting prodrugs employing an albumin-binding probe that undergoes slow hydrolysis at physiological conditions

Here we describe the design and application of OSu-FMS-MAL-S-(CH(2))(15)-COOH, an agent that associates with albumin while linked to a peptide or a protein with sufficient affinity (Ka=2 to 2.6 x 10(5)M(-1)) to protract the action of short- lived peptides and proteins in vivo. Under physiological conditions this probe undergoes spontaneous hydrolysis with the concomitant reactivation of inactive conjugates. Intravenously administered (125)I-labeled-Insulin-FMS-MAL-S-(CH(2))(15)-COOH to rats shows half-life of 17+/-2h, exceeding 5.2 times that obtained with intravenously administered (125)I-labeled Insulin. In mice this derivative facilitates glucose-lowering effect over a period of 24h, yielding AUC five times greater than that obtained by a similar dose of insulin-detemir. Similarly, subcutaneous administration of Exendin-4-FMS-MAL-S-(CH(2))(15)-COOH into mice facilitated prolonged and stable reduction in glucose level, yielding a t(1/2) value of 28+/-2h, exceeding the effect of exendin-4 4.7 folds. The inactive derivative gentamicin-FMS-MAL-S-(CH(2))(15)-COOH regained its full antibacterial potency upon incubation at physiological conditions yielding a t(1/2) value of 7.1+/-0.2h. In conclusion, the albumin-binding probe we introduced enables to prolong the action of any amino containing molecule in vivo, without the drawback of inactivation that often occurs upon such derivatization.

Angiotensin 1–7 Is a Negative Modulator of Aldosterone Secretion In Vitro and In Vivo

Angiotensin (1–7) [Ang 1–7] is a 7 amino acid peptide generated predominantly from Ang II by the action of Ang-converting enzyme 2. We previously showed that Ang 1–7 reduced plasma aldosterone and plasma renin activity in high fructose–fed rats, and that the reduction in circulating aldosterone seemed to accord a parallel reduction in plasma renin activity. Here, we tested the possibility that Ang 1–7 affects aldosterone secretion acting directly in glomerulosa cells. First, as detected by immunofluorescence, the receptor for Ang 1–7, Mas1 is localized predominantly at the rat adrenal subcapsular region. Second, in isolated rat glomerulosa cells incubates, Ang 1–7 attenuated the aldosterone response to Ang II, with the strongest effect seen on Ang II (10−9 M) (control 22±2.5 pg/105 cells; Ang II [10−9 M] 189±11 pg/105 cells; Ang II [10−9 M]+Ang 1–7 [10−6 M] 33±3.6 pg/105 cells; P<0.001) and the largest effect on adrenocorticotropic hormone (10−8 M) (control 30±3.4 pg/105 cells; ACTH [10−8 M] 409±32.5 pg/105 cells; ACTH [10−8 M]+Ang 1–7 [10−6 M] 280±12.5 pg/105 cells; P<0.001). In contrast, Ang 1–7 did not affect the aldosterone response to potassium (K+). In rats subjected to a low-salt diet for 7 days, continuous infusion of Ang 1–7 (576 &mgr;g/kg per day) resulted in a lesser rise in aldosterone (salt deplete+Ang 1–7, 16.4±4.8 ng/dL) compared with rats receiving vehicle (salt deplete+vehicle, 27.6±5.3 ng/dL; P<0.01) but did not modify plasma renin activity. Taken together, these results indicate that Ang 1–7 can act as a negative modulator of aldosterone secretion in vitro and in vivo.

Cognitive impairment and the association between frailty and functional deficits are linked to abdominal obesity in the elderly

OBJECTIVE To evaluate whether specific obesity phenotypes in community-dwelling elderly: (a) affect differently the relationship between frailty and functional impairment and (b) are related to cognitive impairment. STUDY DESIGN A post-hoc cross-sectional analysis of the last Israeli national health and nutrition survey of the elderly (≥ 65 yrs.; n = 1619). MAIN OUTCOME MEASURES We implemented a previously validated frailty model based on frailty-related variables that were obtained in the survey. Mild cognitive impairment was defined using the Mini-Mental State Examination (a score <24 and >17). The Katzs scale of activities of daily living was used for functional assessment. Data were clustered according to different obesity phenotypes using measured body mass index (BMI) and waist circumference (WC). RESULTS The link between frailty and disability was most prominent in subjects with abdominal obesity who were non-obese by BMI: compared with non-obese subjects as defined by WC and BMI, the odds ratio (OR) for functional limitations in this phenotype was 8.34 (95 % CI, 2.14-32.48) for pre-frail subjects and 69.26 (10.58-453.55) for frail subjects. The rate of cognitive impairment was 3.3 times higher (p = .023) in women who were obese by WC but not by BMI. CONCLUSIONS In elderly people with a large WC and BMI < 30 kg/m2, disability is more tightly linked to frailty than for any other form of obesity. Cognitive impairment was more prominent in women with central obesity and BMI < 30 kg/m2 than in the other anthropometric phenotypes. WC should be used for early detection of individuals at risk of progression of frailty to functional incapacity.

LBOS 01-02 CLUSTERING OF SILENT HYPOTENSIVE EPISODES IN THE MORNING/LATE-MORNING HOURS IN SUBJECTS TREATED FOR HYPERTENSION.

Objective: We have previously noted morning/late-morning hypotension (M/LM) in some hypertensive subjects. Here we intended to establish its prevalence in relation to daytime blood pressure (BP) in general. Design and Method: Daytime hypotension was defined as systolic BP<110mmHg or ≥25% lower than the mean 3 first awake recordings provided that it was also < 85% of the mean 24 h systolic-BP. We evaluated 781 ABPM (Spacelabs 90207/902017A) recordings from 179 subjects with normal BP and 602 hypertensive subjects. Results: Daytime hypotension (mean systolic pressure [SP] during hypotension 101+/−1 mmHg) was more common in subjects receiving antihypertensive drugs than in untreated hypertensive subjects [158/336 (43%) vs. 76/266 (29%); p < 0.05]. In treated hypertensive subjects hypotensive episodes tended to cluster in the M/LM hours [08:00–12:00]: in nearly 50% (76/158) of treated patients with daytime [06:00–23:00] hypotension, hypotensive episodes were detected in the M/LM, as compared to 19/79 (24%;) in untreated hypertensive subjects (p < 0.05). Clustering analysis revealed that M/LM hypotension was more prevalent, compared to other daytime hours in treated, but not in untreated hypertensive subjects (OR- 1.69 and 0.87, respectively; p < 0.0005). Among treated hypertensive subjects, M/LM clustering was seen in the uncontrolled subjects (p < 0.0005) but not in controlled patients. However, daytime SP was higher in treated subjects free of daytime hypotension compared to those with falls in BP (136 ± 14 vs. 130 ± 14; t-test, p < 0.0001). SP during M/LM falls was lower in controlled than in uncontrolled hypertensive subjects (93+/−7 vs. 103+/−12mmHg; p < 0. 0001). Age (68 ± 1.7 vs. 64 ± 1; p < 0.0001) was higher among treated subjects with M/LM falls compared with treated subjects without M/LM falls. Conclusions: Daytime hypotensive episodes are common and tend to cluster in the M/LM hours in treated older hypertensive subjects, particularly in the setting of uncontrolled hypertension. Age, dosing time and circadian decline in hormones affecting blood pressure may play a role in this phenomenon.