Task demands dissociate the effects of muscarinic M-1 receptor blockade and protein kinase C inhibition on attentional performance in rats

The cholinergic system is known to be necessary for normal attentional processing. However, the receptors and mechanisms mediating the effects of acetylcholine on attention remain unclear. Previous work in our laboratory suggested that cholinergic muscarinic receptors are critical for maintaining performance in an attention-demanding task in rats. We examined the role of the muscarinic M-1 receptor and protein kinase C (PKC), which is activated by the M-1 receptor, in attention task performance. Rats were trained in an attention-demanding task requiring discrimination of brief (500, 100, 25 ms) visual signals from trials with no signal presentation. The effects of muscarinic M-1 receptor blockade were assessed by administering dicyclomine (0-5.0 mg/kg). The effects of PKC inhibition were assessed by administering chelerythrine chloride (0-2.0 mg/kg). Dicyclomine decreased the accuracy of detecting longer signals in this attention task, including when attentional demands were increased by flashing a houselight throughout the session. Chelerythrine chloride decreased the accuracy of signal detection in the standard version of the task but not when the houselight was flashed throughout the session. The present findings indicate that muscarinic M-1 receptors are critical for maintaining performance when attentional demands are increased, and that PKC activity may contribute to some aspects of attentional performance

An extract of Artemisia dracunculus L. stimulates insulin secretion from β cells, activates AMPK and suppresses inflammation

© 2015 Elsevier Ireland Ltd. All rights reserved. Ethnopharmacological relevance Artemisia dracunculus L. (Russian tarragon) is a perennial herb belonging to the family Compositae and has a history of medicinal use in humans, particularly for treatment of diabetes. Aim of the study: In this study a defined plant extract from A. dracunculus L. (termed PMI-5011) is used to improve beta(β) cells function and maintain β cell number in pancreatic islets as an alternative drug approach for successful treatment of diabetes. Materials and methods Mouse and human pancreatic beta cells were treated with defined plant extract of A. dracunculus L. (PMI-5011) to understand the mechanism(s) that influence beta cell function and β cell number. Results We found that the PMI-5011 enhances insulin release from primary β cells, isolated mouse and human islets and it maintains β cell number. Insulin released by PMI-5011 is associated with the activation of AMP-activated protein kinase (AMPK), and protein kinase B (PKB). Furthermore, PMI-5011 suppresses LPS/INFγ-induced inflammation and inflammatory mediator(s) in macrophages. PMI-5011 inhibited Nitric oxide (NO) production and expression of inducible nitric oxide synthase (iNOS) at the protein level and also attenuated pro-inflammatory cytokine (IL-6) production in macrophages. Conclusion PMI-5011 has potential therapeutic value for diabetes treatment via increasing insulin release from β cells and decreases capacity of macrophages to combat inflammation

Demonstration of an online tool to assist managed care formulary evidence-based decision making: meta-analysis of topical prostaglandin analog efficacy

BACKGROUND: The purpose of this paper was to demonstrate the use of an online service for conducting a systematic review and meta-analysis of the efficacy of topical prostaglandin analogs in reducing intraocular pressure (IOP) in glaucoma and ocular hypertension. METHODS: An online service provider (Doctor Evidence) reviewed and extracted data from the peer-reviewed literature through September 2009. Randomized controlled studies of at least three months’ duration assessing at least two prostaglandin analogs in patients with primary open-angle glaucoma, ocular hypertension, or normal-tension glaucoma were included. The primary endpoint was mean IOP. Summary estimates were created using random-effects models. The Q Chi-square test was used to assess statistical heterogeneity. RESULTS: Sixteen studies satisfied the inclusion criteria and were analyzed. On average, greater IOP-lowering was seen with bimatoprost relative to latanoprost (1 mmHg, P = 0.025) and travoprost (0.8 mmHg, P = 0.033) based on mean IOP after 12–26 weeks of treatment. No statistical difference was observed in IOP-lowering between latanoprost and travoprost (P = 0.841). Findings were similar to previously published meta-analyses of topical prostaglandin analogs. CONCLUSION: Systematic reviews relying on meta-analytic techniques to create summary statistics are considered to be the “gold standard” for synthesizing evidence to support clinical decision-making. However, the process is time-consuming, labor-intensive, and outside the capability of most formulary managers. We have demonstrated the effectiveness of a commercial service that facilitates the process of conducting such reviews

Hepatic IKKε expression is dispensable for high-fat feeding-induced increases in liver lipid content and alterations in glucose tolerance

© 2020 the American Physiological Society. There are endocrine and immunological changes that occur during onset and progression of the overweight and obese states. The inhibitor of nuclear factor-κB kinase-ε (IKKε) was originally described as an inducible protein kinase; whole body gene deletion or systemic pharmaceutical targeting of this kinase improved insulin sensitivity and glucose tolerance in mice. To investigate the primary sites of action associated with IKKε during weight gain, we describe the first mouse line with conditional elimination of IKKε in the liver (IKKεAlb-/-). IKKεAlb-/- mice and littermate controls gain weight, show similar changes in body composition, and do not display any improvements in insulin sensitivity or whole body glucose tolerance. These studies were conducted using breeder chow diets and matched low- vs. high-fat diets. While glycogen accumulation in the liver is reduced in IKKεAlb-/- mice, lipid storage in liver is similar in IKKεAlb-/- mice and littermate controls. Our results using IKKεAlb-/-mice suggest that the primary action of this kinase to impact insulin sensitivity during weight gain lies predominantly within extrahepatic tissues

Hepatic autophagy contributes to the metabolic response to dietary protein restriction

© 2016 Elsevier Inc. All rights reserved. Autophagy is an essential cellular response which acts to release stored cellular substrates during nutrient restriction, and particularly plays a key role in the cellular response to amino acid restriction. However, there has been limited work testing whether the induction of autophagy is required for adaptive metabolic responses to dietary protein restriction in the whole animal. Here, we found that moderate dietary protein restriction led to a series of metabolic changes in rats, including increases in food intake and energy expenditure, the downregulation of hepatic fatty acid synthesis gene expression and reduced markers of hepatic mitochondrial number. Importantly, these effects were also associated with an induction of hepatic autophagy. To determine if the induction of autophagy contributes to these metabolic effects, we tested the metabolic response to dietary protein restriction in BCL2-AAA mice, which bear a genetic mutation that impairs autophagy induction. Interestingly, BCL2-AAA mice exhibit exaggerated responses in terms of both food intake and energy expenditure, whereas the effects of protein restriction on hepatic metabolism were significantly blunted. These data demonstrate that restriction of dietary protein is sufficient to trigger hepatic autophagy, and that disruption of autophagy significantly alters both hepatic and whole animal metabolic response to dietary protein restriction

Reduced adipose tissue oxygenation in human obesity evidence for rarefaction, macrophage chemotaxis, and inflammation without an angiogenic response

OBJECTIVE-Based on rodent studies, we examined the hypothesis that increased adipose tissue (AT) mass in obesity without an adequate support of vascularization might lead to hypoxia, macrophage infiltration, and inflammation. RESEARCH DESIGN AND METHODS-Oxygen partial pressure (AT pO 2) and AT temperature in abdominal AT (9 lean and 12 overweight/obese men and women) was measured by direct insertion of a polarographic Clark electrode. Body composition was measured by dual-energy X-ray absorptiometry, and insulin sensitivity was measured by hyperinsulinemic-euglycemic clamp. Abdominal subcutaneous tissue was used for staining, quantitative RT-PCR, and chemokine secretion assay. RESULTS-AT pO 2 was lower in overweight/obese subjects than lean subjects (47 ± 10.6 vs. 55 ± 9.1 mmHg); however, this level of pO 2 did not activate the classic hypoxia targets (pyruvate dehydrogenase kinase and vascular endothelial growth factor [VEGF]). AT pO 2 was negatively correlated with percent body fat (R =-0.50, P \u3c 0.05). Compared with lean subjects, overweight/ obese subjects had 44% lower capillary density and 58% lower VEGF, suggesting AT rarefaction (capillary drop out). This might be due to lower peroxisome proliferator-activated receptor γ1 and higher collagen VI mRNA expression, which correlated with AT pO 2 (P \u3c 0.05). Of clinical importance, AT pO 2 negatively correlated with CD68 mRNA and macrophage inflammatory protein 1α secretion (R =-0.58, R =-0.79, P \u3c 0.05), suggesting that lower AT pO 2 could drive AT inflammation in obesity. CONCLUSIONS-Adipose tissue rarefaction might lie upstream of both low AT pO 2 and inflammation in obesity. These results suggest novel approaches to treat the dysfunctional AT found in obesity. © 2009 by the American Diabetes Association

Weight gain reveals dramatic increases in skeletal muscle extracellular matrix remodeling

Context: In animal models of obesity, chronic inflammation and dysregulated extracellular matrix remodeling in adipose tissue leads to insulin resistance. Whether similar pathophysiology occurs in humans is not clear. Objective: The aim of this study was to test whether 10% weight gain induced by overfeeding triggers inflammation and extracellular matrix remodeling (gene expression, protein, histology) in skeletal muscleandsc adipose tissue in humans.Wealso investigated whether such remodelingwas associated with an impaired metabolic response (hyperinsulinemic-euglycemic clamp). Design, Setting, Participants, and Intervention: Twenty-nine free-living males were fed 40% over their baseline energy requirements for 8 weeks. Results: Ten percent body weight gain prompted dramatic up-regulation of a repertoire of extracellular matrix remodeling genes in muscle and to a lesser degree in adipose tissue. The amount of extracellular matrix genes in the muscle were directly associated with the amount of lean tissue deposited during overfeeding. Despite weight gain and impaired insulin sensitivity, there was no change in local adipose tissue or systemic inflammation, but there was a slight increase in skeletal muscle inflammation. Conclusion:Wepropose that skeletal muscle extracellular matrix remodeling is another feature of the pathogenic milieu associated with energy excess and obesity, which, if disrupted, may contribute to the development of metabolic dysfunction. © 2014 by the Endocrine Society

Liquid Sucrose Consumption Promotes Obesity and Impairs Glucose Tolerance Without Altering Circulating Insulin Levels

© 2018 The Obesity Society Objective: Multiple factors contribute to the rising rates of obesity and to difficulties in weight reduction that exist in the worldwide population. Caloric intake via sugar-sweetened beverages may be influential. This study tested the hypothesis that liquid sucrose intake promotes obesity by increasing serum insulin levels and tissue lipid accumulation. Methods: C57BL/6J mice were given 30% sucrose in liquid form. Changes in weight gain, body composition, energy expenditure (EE), and tissue lipid content were measured. Results: Mice drinking sucrose gained more total body mass (TBM), had greater fat mass, and displayed impaired glucose tolerance relative to control mice. These metabolic changes occurred without alterations in circulating insulin levels and despite increases in whole body EE. Lipid accrued in liver, but not skeletal muscle, of sucrose-consuming mice. Oxygen consumption (VO2) correlated with fat-free mass and moderately with TBM, but not with fat mass. ANCOVA for treatment effects on EE, with TBM, VO2, lean body mass, and fat-free mass taken as potential covariates for EE, revealed VO2 as the most significant correlation. Conclusions: Weight gain induced by intake of liquid sucrose in mice is associated with lipid accrual in liver, but not skeletal muscle, and occurs without an increase in circulating insulin