A pilot study of patch Holter electrocardiograph recordings in healthy cats

Background: A patch Holter electrocardiograph (P-Holter) is cordless, making it lightweight, unlike the conventional Holter electrocardiograph (C-Holter). A P-Holter can also take continuous measurements for up to 14 days without replacing the battery or SD card.Aim: To compare the performance of the P-Holter and the C-Holter in healthy cats. Additionally, we aimed to investigate whether multiday recordings with the P-Holter decrease sympathetic nerve activity or improve the accuracy of arrhythmia detection.Methods: Five healthy domestic short-haired cats were used for this study. Both a P-Holter and C-Holter were used on the first day, but only the P-Holter was used on days 2–6. The evaluated variables were the analyzable time of both Holter types, heart rate (HR), HR variability (HRV), and the number of arrhythmia occurrences.Results: For two out of the five cats, measurement of P-Holter was interrupted. Eventually, continuous recordings using the P-Holters were able to be collected from all individuals for 6 days. The 24 hours analyzable time from the P-Holter and C-Holter was almost identical (p = 0.94). The 24 hours mean HR did not differ across Holter types (p = 0.67). In addition, the timing of the occurrences of arrhythmias was almost identical to the P-Holter and C-Holter. Results of HRV suggested that sympathetic nerve activity was likely to decrease and vagal nerve activity was likely to increase after 4–5 days of measurement, compared to the second day of measurement (p < 0.05). When only the P-Holter was installed, the number of arrhythmia occurrences was similar on days 2–6.Conclusion: In this study, the P-Holter may be as useful as the C-Holter in cats with suspected intermittent arrhythmias, although the P-Holters were placed on cats without a clinical indication. However, cats may have individual differences in their adaptation to the device. P-Holter recordings taken for more than 4–5 days may allow the cat to acclimate to the device and reduce sympathetic nerve activity. The accuracy of arrhythmia detection across multiday P-Holter recordings requires further investigation using clinical cases

Chronic unpredictable stress regulates visceral adipocyte-mediated glucose metabolism and inflammatory circuits in male rats

Chronic psychological stress is a prominent risk factor involved in the pathogenesis of many complex diseases, including major depression, obesity, and type II diabetes. Visceral adipose tissue is a key endocrine organ involved in the regulation of insulin action and an important component in the development of insulin resistance. Here, we examined for the first time the changes on visceral adipose tissue physiology and on adipocyte-associated insulin sensitivity and function after chronic unpredictable stress in rats. Male rats were subjected to chronic unpredictable stress for 35 days. Total body and visceral fat was measured. Cytokines and activated intracellular kinase levels were determined using high-throughput multiplex assays. Adipocyte function was assessed via tritiated glucose uptake assay. Stressed rats showed no weight gain, and their fat/lean mass ratio increased dramatically compared to control animals. Stressed rats had significantly higher mesenteric fat content and epididymal fat pad weight and demonstrated reduced serum glucose clearing capacity following glucose challenge. Alterations in fat depot size were mainly due to changes in adipocyte numbers and not size. High-throughput molecular screening in adipocytes isolated from stressed rats revealed activation of intracellular inflammatory, glucose metabolism, and MAPK networks compared to controls, as well as significantly reduced glucose uptake capacity in response to insulin stimulation. Our study identifies the adipocyte as a key regulator of the effects of chronic stress on insulin resistance, and glucose metabolism, with important ramifications in the pathophysiology of several stress-related disease states

The in vitro effects of resistin on the innate immune signaling pathway in isolated human subcutaneous adipocytes

Context: Obesity-associated inflammation is a contributory factor in the pathogenesis of type 2 diabetes mellitus (T2DM); the mechanisms underlying the progression to T2DM are unclear. The adipokine resistin has demonstrated pro-inflammatory properties in relation to obesity and T2DM. Objective: To characterize resistin expression in human obesity and address the role of resistin in the innate immune pathway. Furthermore, examine the influence of lipopolysaccharide, recombinant human resistin (rhResistin), insulin and rosiglitazone in human adipocytes. Finally, analyze the effect of rhResistin on the expression of components of the NF-κB pathway and insulin signaling cascade. Methods: Abdominal subcutaneous adipose tissue was obtained from patients undergoing elective liposuction surgery (n = 35, aged: 36-49 yr; BMI: 26.5 ± 5.9 kg/m2). Isolated adipocytes were cultured with rhResistin (10-50 ng/ml). The level of cytokine secretion from isolated adipocytes was examined by ELISA. The effect of rhResistin on protein expression of components of the innate immune pathway was examined by Western blot. Results: In-vitro studies demonstrated that antigenic stimuli increase resistin secretion (P < 0.001) from isolated adipocytes. Pro-inflammatory cytokine levels were increased in response to rhResistin (P < 0.001); this was attenuated by rosiglitazone (P < 0.01). When examining components of the innate immune pathway, rhResistin stimulated Toll-like receptor-2 protein expression. Similarly, mediators of the insulin signaling pathway, phosphospecific JNK1 and JNK2, were upregulated in response to rhResistin. Conclusion: Resistin may participate in more than one mechanism to influence pro-inflammatory cytokine release from human adipocytes; potentially via the integration of NF-κB and JNK signaling pathways

Palmitoleic acid prevents palmitic acid-induced macrophage activation and consequent p38 MAPK-mediated-skeletal muscle insulin resistance

Obesity and saturated fatty acid (SFA) treatment are both associated with skeletal muscle insulin resistance (IR) and increased macrophage infiltration. However, the relative effects of SFA and unsaturated fatty acid (UFA)-activated macrophages on muscle are unknown. Here, macrophages were treated with palmitic acid, palmitoleic acid or both and the effects of the conditioned medium (CM) on C2C12 myotubes investigated. CM from palmitic acid-treated J774s (palm-mac-CM) impaired insulin signalling and insulin-stimulated glycogen synthesis, reduced Inhibitor κBα and increased phosphorylation of p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase in myotubes. p38 MAPK inhibition or siRNA partially ameliorated these defects, as did addition of tumour necrosis factor-α blocking antibody to the CM. Macrophages incubated with both FAs generated CM that did not induce IR, while palmitoleic acid-mac-CM alone was insulin sensitising. Thus UFAs may improve muscle insulin sensitivity and counteract SFA-mediated IR through an effect on macrophage activation

Human Rho guanine nucleotide exchange factor 11 gene is associated with schizophrenia in a Japanese population

ObjectiveThe human Rho guanine nucleotide exchange factor 11 (ARHGEF11) gene is one of the candidate genes for type 2 diabetes mellitus (T2DM). ARHGEF11 is mapped to chromosome 1q21, which has susceptible risk loci for T2DM and schizophrenia. We hypothesized that ARHGEF11 contributes to the pathogenesis of schizophrenia. MethodWe selected eight single nucleotide polymorphisms of ARHGEF11 that had significant associations with T2DM for a case-control association study of 490 patients with schizophrenia and 500 age-matched and sex-matched controls. ResultsWe did not find any differences in allelic, genotypic associations, or minor allele frequencies with schizophrenia. Analysis of the rs6427340-rs6427339 haplotype and the rs822585-rs6427340-rs6427339 haplotype combination provided significant evidence of an association with schizophrenia (global permutations p=0.00047 and 0.0032, respectively). C-C of the rs6427340-rs6427339 haplotype and A-C-C of the rs822585-rs6427340-rs6427339 haplotype carried higher risk factors for schizophrenia (permutation p=0.0010 and 0.0018, respectively). A-C-T of the rs822585-rs6427340-rs6427339 haplotype had a possible protective effect (permutation p=0.031). ConclusionThese results provide new evidence that ARHGEF11 may constitute a risk factor for schizophrenia

JNK signalling in cancer: In need of new, smarter therapeutic targets

Copyright © 2013 The British Pharmacological Society. This is the accepted version of the following article: Bubici, C. and Papa, S. (2014), JNK signalling in cancer: in need of new, smarter therapeutic targets. British Journal of Pharmacology, 171: 24–37, which has been published in final form at http://onlinelibrary.wiley.com/doi/10.1111/bph.12432/abstract.The JNKs are master protein kinases that regulate many physiological processes, including inflammatory responses, morphogenesis, cell proliferation, differentiation, survival and death. It is increasingly apparent that persistent activation of JNKs is involved in cancer development and progression. Therefore, JNKs represent attractive targets for therapeutic intervention with small molecule kinase inhibitors. However, evidence supportive of a tumour suppressor role for the JNK proteins has also been documented. Recent studies showed that the two major JNK proteins, JNK1 and JNK2, have distinct or even opposing functions in different types of cancer. As such, close consideration of which JNK proteins are beneficial targets and, more importantly, what effect small molecule inhibitors of JNKs have on physiological processes, are essential. A number of ATP-competitive and ATP-non-competitive JNK inhibitors have been developed, but have several limitations such as a lack of specificity and cellular toxicity. In this review, we summarize the accumulating evidence supporting a role for the JNK proteins in the pathogenesis of different solid and haematological malignancies, and discuss many challenges and scientific opportunities in the targeting of JNKs in cancer.Kay Kendall Leukemia Fund, Italian Association for Cancer Research and Foundation for Liver Research

Selective Inactivation of c-Jun NH2-Terminal Kinase in Adipose Tissue Protects Against Diet-Induced Obesity and Improves Insulin Sensitivity in Both Liver and Skeletal Muscle in Mice

OBJECTIVE Obesity is associated with increased activation of the c-Jun NH2-terminal kinase (JNK) in several metabolic organs, including adipose tissue, liver, and skeletal muscle. In this study, we aimed to define the role of JNK activation in adipose tissue in the development of obesity-related insulin resistance. RESEARCH DESIGN AND METHODS Transgenic mice with adipose tissue–specific overexpression of dominant-negative JNK (ap2-dn-JNK) under the transcriptional control of the aP2 gene promoter were generated and subjected to metabolic characterization together with the wild-type littermates. RESULTS On a high-fat diet (HFD), the ap2-dn-JNK mice displayed a marked suppression of both JNK1 and JNK2 activation in their adipose tissue, accompanied by a marked reduction in weight gain, fat mass, and size of the adipocytes. The transgenic mice were resistant to the deleterious impact of an HFD on systemic insulin sensitivity, glucose tolerance, and hepatic steatosis. Reduced hepatic gluconeogenesis was evident in in vivo and ex vivo studies and showed greater insulin-induced glucose uptake in skeletal muscles. These changes were accompanied by reduced macrophage infiltration in adipose tissue, decreased production of proinflammatory adipokines, and increased expression of adiponectin. Indirect calorimetry analysis showed that the transgenic mice had significant increases in oxygen consumption and reductions in respiration exchange rates compared with their wild-type littermates. CONCLUSIONS Selective suppression of JNK activation in adipose tissue alone is sufficient to counteract HFD-induced obesity and its associated metabolic dysregulations, in part through an increase in energy expenditure and a decrease in systemic inflammation

Obesity-Related Upregulation of Monocyte Chemotactic Factors in Adipocytes : Involvement of Nuclear Factor-κB and c-Jun NH2-Terminal Kinase Pathways

OBJECTIVE—We sought to evaluate the entire picture of all monocyte chemotactic factors that potentially contribute to adipose tissue macrophage accumulation in obesity