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Background: Pannexin 3 (PANX3) is a channel-forming glycoprotein that enables nutrient-induced inflammation in vitro, and genetic linkage data suggest that it regulates body mass index. Here, we characterized inflammatory and metabolic parameters in global Panx3 knockout (KO) mice in the context of forced treadmill running (FEX) and high-fat diet (HFD). Methods: C57BL/6N (WT) and KO mice were randomized to either a FEX running protocol or no running (SED) from 24 until 30 weeks of age. Body weight was measured biweekly, and body composition was measured at 24 and 30 weeks of age. Male WT and KO mice were fed a HFD from 12 to 28 weeks of age. Metabolic organs were analyzed for a panel of inflammatory markers and PANX3 expression. Results: In females there were no significant differences in body composition between genotypes, which could be due to the lack of PANX3 expression in female white adipose tissue, while male KOs fed a chow diet had lower body weight and lower fat mass at 24 and 30 weeks of age, which was reduced to the same extent as 6 weeks of FEX in WT mice. In addition, male KO mice exhibited significantly lower expression of multiple pro-inflammatory genes in white adipose tissue compared to WT mice. While on a HFD body weight differences were insignificant, multiple inflammatory genes were significantly different in quadriceps muscle and white adipose tissue resulting in a more anti-inflammatory phenotype in KO mice compared to WT. The lower fat mass in male KO mice may be due to significantly fewer adipocytes in their subcutaneous fat compared to WT mice. Mechanistically, adipose stromal cells (ASCs) cultured from KO mice grow significantly slower than WT ASCs. Conclusion: PANX3 is expressed in male adult mouse adipose tissue and may regulate adipocyte numbers, influencing fat accumulation and inflammation.

Introduction.Lateral medullary syndrome (LMS) is the most common of the crossed brainstem syndromes involving the posterior circulation. The typical clinical pattern (i.e., classical Wallenberg syndrome) includes ipsilateral Horner syndrome, hoarseness, nystagmus, dysphagia, dizziness, ataxia, and crossed pain and temperature sensory loss (i.e., ipsilateral face and contralateral body). There are several patterns of sensory dysfunction according to the site of lesion. Although some sources still cite cardioembolism or atherothrombotic occlusions as the main causes of lateral medullary infarctions, it is increasingly recognized vertebral artery dissection (VAD) as the chief etiology. Patients and Methods.We report on nine patients presenting with LMS due to confirmed VAD in predominantly young individuals (6 men, age range 23-54 years). Results.Most patients presented with sudden headache or neck pain, ataxia and nystagmus (n=7). On neurological examination the majority (n=7) had crossed sensory loss of the classical Wallenberg pattern and all but two had Horner syndrome. At 6-month follow-up no deaths or recurrences were observed: five patients were completely asymptomatic, three patients persisted with mild or moderate deficits and one was unable to walk without assistance. Seven patients had dysphagia that evolved unevenly within the 6-month follow-up period. We also discuss on the clinical and neuroanatomical correlates behind the LMS variants. Conclusion.VAD should be suspected in patients presenting with LMS and headache or neck pain. The functional and recurrence prognosis is fairly good. Given the intricacy of the medulla anatomy and the serendipitous nature of ischemia after VAD, a missing sign from the original Wallenberg’s description is not incompatible with a lateral medullary infarction.

Renal damage can result from of a variety of insults, including exposure to nephrotoxins, chronic illness, and acute conditions. During wound healing, macrophages infiltrate injured kidney tissue to clear damaged cells and regulate reparative responses, while resident fibroblasts deposit extracellular matrix to promote healing. However, these reparative processes are often dysregulated, especially during severe and chronic insults, resulting in tissue inflammation and fibrosis, and ultimately, long-term disease. Therefore, kidney inflammation and fibrosis present barriers to repair after renal injury. In addition, regenerative capacity is determined by nicotinamide adenine dinucleotide (NAD+) production and consumption. This chapter is a review of natural products and their mechanisms of action that may provide benefit in renal regeneration, with specific focus on compounds that target inflammation and fibrosis, and that promote NAD+ supply.

Supplemental material, sj-docx-1-hol-10.1177_09596836221074035 for Stingless bees (Hymenoptera: Apidae) in Holocene copal and Defaunation resin from Eastern Africa indicate Recent biodiversity change by M��nica M Sol��rzano-Kraemer, Robin Kunz, J��rg U Hammel, Enrique Pe��alver, Xavier Delcl��s and Michael S Engel in The Holocene

El objetivo de esta investigaci��n es aproximar al lector al conocimiento de la cer��mica, los materiales, la ac��stica y la simbolog��a presentes en la botella antropomorfa de triple elipsoide comunicante con doble silbato de la cultura Bah��a de la Rep��blica del Ecuador mediante el estudio multidisciplinar del artefacto sonoro. En dicho estudio se plante�� la aplicaci��n de una metodolog��a cualitativa y cuantitativa desarrollada a trav��s de la investigaci��n documental, complementada con t��cnicas de an��lisis de materiales en laboratorio, m��tricas ac��sticas, ensayos de posibilidades sonoras y producci��n de r��plicas en arcilla. Estos aportes permiten definir la botella como un objeto ac��stico complejo en el cual confluyen m��ltiples conocimientos desarrollados durante m��s de mil a��os de evoluci��n. ENGLISH: Organological Structure and Sound Effect of an Anthropomorphic Triple Ellipsoid Bottle with Double Whistle from the Bahia Culture of Ecuador (600 BC���650 AD). The purpose of this research is to bring the reader closer to the knowledge of ceramics, materials, acoustics and symbology present in the anthropomorphic bottle of triple communicating ellipsoid with double whistle of the Bahia culture of the Republic of Ecuador through the multidisciplinary study of the sonorous artifact. In this study, the application of a qualitative and quantitative methodology developed through documentary research, complemented with techniques of analysis of materials in the laboratory, acoustic metrics, tests of sound possibilities and production of clay replicas was proposed. These contributions allow us to define the bottle as a complex acoustic object in which multiple knowledge developed during more than a thousand years of evolution converge.

Pannexin 3 (PANX3) is a channel-forming glycoprotein that enables nutrient-induced inflammation in vitro, and genetic linkage data suggest that it regulates body mass index. Here, we characterized inflammatory and metabolic parameters in global Panx3 knockout (KO) mice in the context of forced treadmill running (FEX) and high-fat diet (HFD).C57BL/6N (WT) and KO mice were randomized to either a FEX running protocol or no running (SED) from 24 until 30 weeks of age. Body weight was measured biweekly, and body composition was measured at 24 and 30 weeks of age. Male WT and KO mice were fed a HFD from 12 to 28 weeks of age. Metabolic organs were analyzed for a panel of inflammatory markers and PANX3 expression.In females there were no significant differences in body composition between genotypes, which could be due to the lack of PANX3 expression in female white adipose tissue, while male KOs fed a chow diet had lower body weight and lower fat mass at 24 and 30 weeks of age, which was reduced to the same extent as 6 weeks of FEX in WT mice. In addition, male KO mice exhibited significantly lower expression of multiple pro-inflammatory genes in white adipose tissue compared to WT mice. While on a HFD body weight differences were insignificant, multiple inflammatory genes were significantly different in quadriceps muscle and white adipose tissue resulting in a more anti-inflammatory phenotype in KO mice compared to WT. The lower fat mass in male KO mice may be due to significantly fewer adipocytes in their subcutaneous fat compared to WT mice. Mechanistically, adipose stromal cells (ASCs) cultured from KO mice grow significantly slower than WT ASCs.PANX3 is expressed in male adult mouse adipose tissue and may regulate adipocyte numbers, influencing fat accumulation and inflammation.

Vitamin D appears to either promote or inhibit neovascularization in a disease context-dependent manner. The effects of vitamin D, alone or in combination with niacin, on endothelial cell (EC) angiogenic function and on revascularization in obese animals with peripheral ischemia are unknown. Here, we report that supplementation of high palmitate medium with vitamin D, niacin or both vitamins increased EC tube formation, which relies primarily on cell migration, and also maintained tube stability over time. Transcriptomic analyses revealed that both vitamins increased stress response and anti-inflammatory gene expression. However, vitamin D decreased cell cycle gene expression and inhibited proliferation, while niacin induced stable expression of miR-126-3p and -5p and maintained cell proliferation in high palmitate. To assess vascular regeneration, diet-induced obese mice received vitamin D, niacin or both vitamins following hind limb ischemic injury. Niacin, but not vitamin D or combined treatment, improved recovery of hind limb use. Histology of tibialis anterior sections revealed no improvements in revascularization, regeneration, inflammation or fibrosis with vitamin D or combined treatment. In summary, although both vitamin D and niacin increased angiogenic function of EC cultures in high fat, only niacin improved recovery of hind limb use following ischemic injury in obese mice. It is possible that inhibition of cell proliferation by vitamin D in high-fat conditions limits vascular regeneration and recovery from peripheral ischemia in obesity.

Predicting gender by the first name is not a simple task. In many applications, especially in the natural language processing (NLP) field, this task may be necessary, mainly when considering foreign names. In this paper, we examined and implemented several machine learning algorithms, such as extra trees, KNN, Naive Bayes, SVM, random forest, gradient boosting, light GBM, logistic regression, ridge classifier, and deep neural network models, such as MLP, RNN, GRU, CNN, and BiLSTM, to classify gender through the first name. A dataset of Brazilian names is used to train and evaluate the models. We analyzed the accuracy, recall, precision, f1 score, and confusion matrix to measure the models' performances. The results indicate that the gender prediction can be performed from the feature extraction strategy looking at the names as a set of strings. Some models accurately predict gender in more than 95% of the cases. The recurrent models overcome the feedforward models in this binary classification problem., 8 pages, 12 figures

Joint homeostasis failure can result in osteoarthritis (OA). Currently, there are no treatments to alter disease progression in OA, but targeting early changes in cellular behavior has great potential. Recent data show that nuclear receptors contribute to the pathogenesis of OA and could be viable therapeutic targets, but their molecular mechanisms in cartilage are incompletely understood. This study examines global changes in gene expression after treatment with agonists for four nuclear receptor implicated in OA (LXR, PPARδ, PPARγ, and RXR). Murine articular chondrocytes were treated with agonists for LXR, PPARδ, PPARγ, or RXR and underwent microarray, qPCR, and cellular lipid analyses to evaluate changes in gene expression and lipid profile. Immunohistochemistry was conducted to compare two differentially expressed targets (Txnip, Gsta4) in control and cartilage-specific PPARδ knockout mice subjected to surgical destabilization of the medial meniscus (DMM). Nuclear receptor agonists induced different gene expression profiles with many responses affecting lipid metabolism. LXR activation downregulated gene expression of proteases involved in OA, whereas RXR agonism decreased expression of ECM components and increased expression of Mmp13. Functional assays indicate increases in cell triglyceride accumulation after PPARγ, LXR, and RXR agonism but a decrease after PPARδ agonism. PPARδ and RXR downregulate the antioxidant Gsta4, and PPARδ upregulates Txnip. Wild-type, but not PPARδ-deficient mice, display increased staining for Txnip after DMM. Collectively, these data demonstrate that nuclear receptor activation in chondrocytes primarily affects lipid metabolism. In the case of PPARδ, this change might lead to increased oxidative stress, possibly contributing to OA-associated changes. Key message Nuclear receptors regulate metabolic genes in chondrocytes.Nuclear receptors affect triglyceride levels.PPARδ mediates regulation of oxidative stress markers.Nuclear receptors are promising therapeutic targets for osteoarthritis. Electronic supplementary material The online version of this article (doi:10.1007/s00109-016-1501-5) contains supplementary material, which is available to authorized users.

As nonalcoholic fatty liver disease progresses to end-stage diseases, including fibrosis, cirrhosis and hepatocellular carcinoma, fibrotic activated hepatic stellate cells and cancerous epithelial cells can become abundant, changing the cellular composition of this organ. Despite potentially residing within the same diseased tissue, direct comparisons of global gene expression between activated hepatic stellate cells and hepatocellular carcinoma cells are lacking. Here we provide data collected using Affymetrix GeneChip microarrays to identify differential gene expression in cultured primary human activated hepatic stellate cells compared to HepG2 human hepatoma cells. The dataset includes many genes involved in intermediary metabolism which were investigated in greater depth in our associated article (A.M. Hetherington, C.G. Sawyez, E. Zilberman, A.M. Stoianov, D.L. Robson, J.M. Hughes-Large, et al., 2016) [1]. Pathway analyses of known protein coding genes down-regulated or up-regulated by greater than 2.0-fold are also provided.

Low dose niacin and vitamin D can directly improve human microvascular endothelial cell angiogenic function under lipotoxic conditions Peters et al.,2019. Despite exerting similar benefits on in vitro angiogenic function, these vitamins are known to signal through independent receptors, raising the possibility that differential changes in gene expression may underlie these effects. Here we provide data collected using Affymetrix GeneChip microarrays to compare gene expression in human microvascular endothelial cells treated for 16 h with growth medium containing BSA alone, or BSA complexed with the saturated fatty acid palmitate, and supplemented with 10 μM niacin or 10 nM vitamin D (1,25-dihydroxyvitamin D3). Data sets of differential gene expression included many genes involved in cellular stress responses. Pathway analyses of genes specific to vitamin D treatment identified a robust overrepresentation of pathways related to the cell cycle and DNA replication and repair.

V Perrone,1 C Veronesi,1 M Nica,2 D Colombo,2 L Degli Esposti,1 R Castello31Clicon S.R.L. Health, Economics and Outcomes Research, Ravenna, Italy; 2Novartis Pharma, Origgio, VA, Italy; 3Division of General Medicine, University Hospital of Verona, Verona, ItalyAbstract: Sex-related differences have been shown to deeply affect health-related aspects of patients. However, the lack of gender-specific analysis makes it difficult to advance personalized medicine in terms of a gender-based approach. The aim of the present study was to describe gender-specific features of patients diagnosed with heart failure (HF), with a focus on the clinical presentation. Data were collected from a properly designed database and referred to an Italian hospital. Patients aged ≥18 years with a primary or secondary diagnosis of HF between 1 January 2012 and 31 December 2016 were included, and their demographic and clinical characteristics were analyzed according to gender. Of the 719 HF patients included, 317 (44.1%) were male and 402 (55.9%) were female. Women tended to be older compared to men (82.4±8.8 years and 77.1±10.6 years, respectively). As for clinical presentation, 62.1% of female and 38.3% of male patients had preserved ejection fraction, and 56.1% of men and 58.2% of women suffered from atrial fibrillation. The left atrium was partially compromised in 62.4% of male and 63% of female patients, while right atrium dysfunction tended to be more frequent in male patients compared to female patients (29.1% and 25.5%, respectively). In conclusion, gender-specific features of a cohort of HF patients from a clinical setting were accurately described.Keywords: gender, specific characteristics, heart failure, clinical setting

Medicinal use of mushrooms has been documented since ancient times, and in the modern world, mushrooms have a longstanding history of use in Eastern medicine. Recent interest in plant-based diets in Westernized countries has brought increasing attention to the use of mushrooms and mushroom-derived compounds in the prevention and treatment of chronic diseases. Edible mushrooms are the most abundant food sources of the modified amino acid, ergothioneine. This compound has been shown to accumulate in almost all cells and tissues, but preferentially in those exposed to oxidative stress and injury. The demonstrated cytoprotectant effect of ergothioneine has led many to suggest a potential therapeutic role for this compound in chronic conditions that involve ongoing oxidative stress and inflammation, including cardiovascular and metabolic diseases. However, the in vivo effects of ergothioneine and its underlying therapeutic mechanisms in the whole organism are not as clear. Moreover, there are no well-defined, clinical prevention and intervention trials of ergothioneine in chronic disease. This review highlights the cellular and molecular mechanisms of action of ergothioneine and its potential as a Traditional, Complementary and Alternative Medicine for the promotion of cardiometabolic health and the management of the most common manifestations of cardiometabolic disease.

Prolonged, isocaloric, time-restricted feeding (TRF) protocols can promote weight loss, improve metabolic dysregulation, and mitigate non-alcoholic fatty liver disease (NAFLD). In addition, 3-day, severe caloric restriction can improve liver metabolism and glucose homeostasis prior to significant weight loss. Thus, we hypothesized that short-term, isocaloric TRF would improve NAFLD and characteristics of metabolic syndrome in diet-induced obese male mice. After 26 weeks of ad libitum access to western diet, mice either continued feeding ad libitum or were provided with access to the same quantity of western diet for 8 h daily, over the course of two weeks. Remarkably, this short-term TRF protocol modestly decreased liver tissue inflammation in the absence of changes in body weight or epidydimal fat mass. There were no changes in hepatic lipid accumulation or other characteristics of NAFLD. We observed no changes in liver lipid metabolism-related gene expression, despite increased plasma free fatty acids and decreased plasma triglycerides in the TRF group. However, liver Grp78 and Txnip expression were decreased with TRF suggesting hepatic endoplasmic reticulum (ER) stress and activation of inflammatory pathways may have been diminished. We conclude that two-week, isocaloric TRF can potentially decrease liver inflammation, without significant weight loss or reductions in hepatic steatosis, in obese mice with NAFLD.

Inhibition of eukaryotic elongation factor 1A1 (EEF1A1) with the marine compound didemnin B decreases lipotoxic HepG2 cell death in vitro and improves early stage non-alcoholic fatty liver disease (NAFLD) in young genetically obese mice. However, the effects of didemnin B on NAFLD in a model of long-term diet-induced obesity are not known. We investigated the effects of didemnin B on NAFLD severity and metabolic parameters in western diet-induced obese mice, and on the cell types that contribute to liver inflammation and fibrosis in vitro. Male 129S6 mice were fed either standard chow or western diet for 26 weeks, followed by intervention with didemnin B (50 μg/kg) or vehicle by intraperitoneal (i.p.) injection once every 3 days for 14 days. Didemnin B decreased liver and plasma triglycerides, improved oral glucose tolerance, and decreased NAFLD severity. Moreover, didemnin B moderately increased hepatic expression of genes involved in ER stress response (Perk, Chop), and fatty acid oxidation (Fgf21, Cpt1a). In vitro, didemnin B decreased THP-1 monocyte proliferation, disrupted THP-1 monocyte-macrophage differentiation, decreased THP-1 macrophage IL-1β secretion, and decreased hepatic stellate cell (HSteC) proliferation and collagen secretion under both basal and lipotoxic (high fatty acid) conditions. Thus, didemnin B improves hepatic steatosis, glucose tolerance, and blood lipids in obesity, in association with moderate, possibly hormetic, upregulation of pathways involved in cell stress response and energy balance in the liver. Furthermore, it decreases the activity of the cell types implicated in liver inflammation and fibrosis in vitro. These findings highlight the therapeutic potential of partial protein synthesis inhibition in the treatment of NAFLD.

Background/Aims: Nonalcoholic fatty liver disease (NAFLD) progression to fibrosis, cirrhosis and hepatocellular carcinoma, alters the cellular composition of this organ. During late-stage NAFLD, fibrotic and possibly cancerous cells can proliferate and, like normal hepatocytes, are exposed to high concentrations of fatty acids from both surrounding tissue and circulating lipid sources. We hypothesized that primary human activated hepatic stellate cells and epithelial hepatoma (HepG2) cells respond differently to lipotoxic conditions, and investigated the mechanisms involved. Methods: Primary activated hepatic stellate cells and HepG2 cells were exposed to pathophysiological concentrations of fatty acids and comparative studies of lipid metabolic and stress response pathways were performed. Results: Both cell types remained proliferative during exposure to a combination of palmitate plus oleate reflective of the general saturated versus unsaturated fatty acid composition of western diets. However, exposure to either high palmitate or high oleate alone induced cytotoxicity in activated stellate cells, while only palmitate caused cytotoxicity in HepG2 cells. mRNA microarray and biochemical comparisons revealed that stellate cells stored markedly less fatty acids as neutral lipids, and had reduced capacity for beta-oxidation. Similar to previous observations in HepG2 cells, palmitate, but not oleate, induced ER stress and actin stress fiber formation in activated stellate cells. In contrast, oleate, but not palmitate, induced the inflammatory signal TXNIP, decreased cytoskeleton proteins, and decreased cell polarity preceding cell death in activated stellate cells. Conclusions: Palmitate-induced lipotoxicity was associated with ER stress pathways in both primary activated hepatic stellate cells and epithelial hepatoma cells, whereas high oleate caused lipotoxicity only in activated stellate cells, possibly through a distinct mechanism involving disruption of cytoskeleton components. This may have implications for optimal dietary fatty acid compositions during various stages of NAFLD.

Delia Colombo,1 Emanuela Zagni,1 Mihaela Nica,1 Sara Rizzoli,2 Alessandra Ori,2 Gilberto Bellia1 1Patient Access, Novartis Farma S.p.A., Origgio, Varese, 2MediNeos Observational Research, Modena, Italy Background: MetaGeM is a wide gender-medicine project comprising post hoc and meta-analyses by gender of clinical outcomes, therapeutic approaches, and safety data from previously conducted observational studies to explore possible gender differences in real-life clinical settings. We report the results of the safety meta-analysis of seven MetaGeM studies, evaluating gender differences in adverse event (AE) incidence and severity. Methods: Data were collected between February 2002 and July 2013. Male and female patients were compared for the main safety variables, using Student’s t-test, χ² test, or Fisher’s exact test as appropriate. As supportive analysis, a logistic regression model was estimated to evaluate associations between gender and outcome. Results: In total, 4,870 patients (46% females, 54% males) were included in the analysis; age was higher for females (mean ± standard deviation 61.2±18.3 years) than males (56.3±16.6 years). Overall, 264 AEs were reported (59.1% in males). There were no significant gender differences in the percentage of patients with at least one AE: 3.0% for females versus 3.9% for males, χ² test P>0.05. According to the logistic regression model results, no association between gender and AEs occurrence seems to exist. A statistically significant gender difference in the percentage of drug-related AEs emerged (37.6% in females vs 20.8% in males, χ² P=0.0039). Slightly significantly more AEs in females were addressed with treatment compared with males (78.1%vs 66.7%, χ² P=0.0485). Total serious AEs (SAEs) were 47 (72% in males). The frequency of patients with ≥1 SAE was 0.6% in females versus 1.2% in males (χ² test P=0.0246). Conclusion: This safety analysis on a large sample of almost 5,000 patients with different diseases and treated with a wide range of different drugs provides a useful overview on possible gender differences in drug tolerability, which may be helpful in more accurately designing future clinical trials from a gender-specific perspective. Keywords: gender, drugs, safety, adverse events, meta-analysis

The systemic lipid modifying drug, niacin, can directly improve human microvascular endothelial cell angiogenic function under lipotoxic conditions, possibly through activation of niacin receptors “Niacin receptor activation improves human microvascular endothelial cell angiogenic function during lipotoxicity” (Hughes-Large et al. 2014). Here we provide accompanying data collected using Affymetrix GeneChip microarrays to identify changes in gene expression in human microvascular endothelial cells treated with 10 μM niacin. Statistical analyses of robust multi-array average (RMA) values revealed that only 16 genes exhibited greater than 1.3-fold differential expression. Of these 16, only 5 were identified protein coding genes, while 3 of the remaining 11 genes appeared to be small nuclear/nucleolar RNAs. Altered expression of EFCAB4B, NAP1L2, and OR13C8 was confirmed by real time quantitative PCR. Keywords: Vascular biology, Endothelial cells, Niacin, Lipids

Purpose of review Non-alcoholic fatty liver disease (NAFLD) appears to be independently associated with the development of atherosclerosis. The biological mechanisms underlying this association are complex, and likely involve liver-resident cell types other than hepatocytes. Thus, we review recent evidence that non-parenchymal hepatic cell responses to lipid excess contribute to the pathogenesis of both NAFLD and atherosclerosis. Recent findings Significant independent associations between NAFLD and atherosclerosis have been identified through cross-sectional studies and meta-analyses. Mechanistic studies in cell cultures and in rodent models suggest that liver-resident macrophages, activated hepatic stellate cells (HSC) and liver sinusoidal endothelial cells (LSEC) mount lipotoxic responses under NAFLD conditions which can contribute to the progression of both NAFLD and atherosclerosis. Summary Non-parenchymal hepatic cell types exhibit some similarity in their responses to lipid excess, and in their pathogenic mechanisms, which likely contribute to the coordinated progression of NAFLD and atherosclerosis. In response to lipotoxic conditions, macrophages, Kupffer cells and HSC initiate robust inflammatory responses, whereas LSEC generate excess reactive oxygen species (ROS). The extent to which inflammatory cytokines and ROS produced by non-parenchymal cells contribute to the progression of both NAFLD and atherosclerosis warrants further investigation.

Objective : Niacin (nicotinic acid) as a monotherapy can reduce vascular disease risk, but its mechanism of action remains controversial, and may not be dependent on systemic lipid modifying effects. Niacin has recently been shown to improve endothelial function and vascular regeneration, independent of correcting dyslipidemia, in rodent models of vascular injury and metabolic disease. As a potential biosynthetic precursor for NAD + , niacin could elicit these vascular benefits through NAD + -dependent, sirtuin (SIRT) mediated responses. Alternatively, niacin may act through its receptor, GPR109A, to promote endothelial function, though endothelial cells are not known to express this receptor. We hypothesized that niacin directly improves endothelial cell function during exposure to lipotoxic conditions and sought to determine the potential mechanism(s) involved. Methods and results : Angiogenic function in excess palmitate was assessed by tube formation following treatment of human microvascular endothelial cells (HMVEC) with either a relatively low concentration of niacin (10 μM), or nicotinamide mononucleotide (NMN) (1 μM), a direct NAD + precursor. Although both niacin and NMN improved HMVEC tube formation during palmitate overload, only NMN increased cellular NAD + and SIRT1 activity. We further observed that HMVEC express GRP109A. Activation of this receptor with either acifran or MK-1903 recapitulated niacin-induced improvements in HMVEC tube formation, while GPR109A siRNA diminished the effect of niacin. Conclusion : Niacin, at a low concentration, improves HMVEC angiogenic function under lipotoxic conditions, likely independent of NAD + biosynthesis and SIRT1 activation, but rather through niacin receptor activation.

International audience; Despite considerable progress in the management of major risk factors over recent decades, cardiovascular diseases (CVD) attributable to atherosclerosis are still a predominant cause of death worldwide. This is due, in large part, to the expansion of risk factors related to obesity such as insulin resistance and diabetes [1]. In fact, the risk of developing CVD in adults with diabetes is two to four times higher than in those without diabetes. Moreover, it is well established that insulin resistance and hyperglycemia promote atherosclerosis, leading to coronary artery disease. Yet the underlying mechanisms linking diabetes and atherosclerosis are still not completely understood. To overcome this lack of understanding, numerous studies have been conducted, using mouse models with targeted deletion in intimal cells, to evaluate the impact of impaired insulin signaling at the level of the arterial wall on atherosclerosis development and progression [2]. Taken together, this work highlights the critical consequences of altered insulin signaling, in both macrophages and endothelial cells, in atherogenesis and the formation of advanced plaques. In humans, comparative analyses of atherosclerotic plaques from diabetic and non-diabetic individuals have revealed some important differences in the quality and composition of plaques between these groups. Lesions from diabetic patients are characterized by a larger necrotic core, increased inflammation, neovascularization, intra-plaque hemorrhage, and calcification [3], [4], [5], [6] and [7]. Higher macrophage and T-cell content, along with increased proportions of apoptotic macrophages and smooth muscle cells, may contribute to this larger necrotic area [4] and [8]. When combined with the increased prevalence of thin-cap fibroatheroma and fibrocalcific atheroma, observed using Virtual Histology intravascular ultrasound in vessels of diabetic patients [5], these alterations of plaque morphology may explain the higher risk of acute coronary syndrome in diabetic patients. Indeed, coronary lesions of patients with diabetes mellitus are more vulnerable to rupture and subsequent thrombosis [3] and [6].

In this work, we synthesized substances and evaluated the potential leishmanicidal activity. Thirty-four (34) compounds from different chemical classes were selected for a simple synthesis in overall good yields, eight of which are not described in the literature. From the 34 compounds evaluated for preliminary leishmanicidal activity, three can be considered as prototypes for the development of leishmanicidal agents. Computational chemistry calculations, including comparative modeling of the enzyme arginase from Leishmania amazonensis and a molecular docking simulation of the synthesized molecules into the active site of the model were carried out. Key words: Leishmaniasis, arginase, molecular docking, thiourea, bisguanidine, amidine, biological evaluation, comparative modeling

Niacin can reduce vascular disease risk in individuals with metabolic syndrome, but in light of recent large randomized controlled trials outcomes, its biological actions and clinical utility remain controversial. Niacin can improve endothelial function, vascular inflammation, and vascular regeneration, independent of correcting dyslipidemia, in various lean rodent models of vascular injury. Here, we tested whether niacin could directly improve endothelial cell angiogenic function during combined exposure to excess fatty acids and hypoxia, and whether intervention with niacin during continued feeding of western diet could improve revascularization and functional recovery in obese, hyperlipidemic mice with peripheral ischemia. Treatment with niacin (10 μmol/L) increased human microvascular endothelial cell angiogenic function during exposure to high fatty acids and hypoxia (2% oxygen), as determined by tube formation on Matrigel. To assess revascularization in vivo, we used western diet‐induced obese mice with unilateral hind limb femoral artery ligation and excision. Treatment for 14 days postinjury with once daily i.p. injections of a low dose of niacin (50 mg/kg) improved recovery of hind limb use, in association with enhanced revascularization and decreased inflammation of the tibialis anterior muscle. These effects were concomitant with decreased plasma triglycerides, but not increased plasma apoAI. Thus, niacin improves endothelial tube formation under lipotoxic and hypoxic conditions, and moreover, promotes revascularization and functional hind limb recovery following ischemic injury in diet‐induced obese mice with hyperlipidemia. These data may have implications for niacin therapy in the treatment of peripheral ischemic vascular disease associated with metabolic syndrome.

Cardiovascular disease (CVD) is the most prevalent disease worldwide and there is intense interest in pharmaceutical approaches to reduce the burden of this chronic, aging-related condition. The sirtuin (SIRT) family of NAD(+)-dependent protein deacetylases and ADP-ribosyltransferases have emerged as exciting targets for CVD management that can impact the cardiovascular system both directly and indirectly, the latter by modulating whole body metabolism. SIRT1-4 regulate the activities of a variety of transcription factors, coregulators, and enzymes that improve metabolic control in adipose tissue, liver, skeletal muscle, and pancreas, particularly during obesity and aging. SIRT1 and 7 can control myocardial development and resist stress- and aging-associated myocardial dysfunction through the deacetylation of p53 and forkhead box O1 (FoxO1). By modulating the activity of endothelial nitric oxide synthase (eNOS), FoxO1, and p53, and the expression of angiotensin II type 1 receptor (AT1R), SIRT1 also promotes vasodilatory and regenerative functions in endothelial and smooth muscle cells of the vascular wall. Given the array of potentially beneficial effects of SIRT activation on cardiovascular health, interest in developing specific SIRT agonists is well-substantiated. Because SIRT activity depends on cellular NAD+ availability, enzymes involved in NAD+ biosynthesis, including nicotinamide phosphoribosyltransferase (Nampt), may also be valuable pharmaceutical targets for managing CVD. Herein we review the actions of the SIRT proteins on the cardiovascular system and consider the potential of modulating SIRT activity and NAD+ availability to control CVD.

Elongation factor 1A-1 (eEF1A-1) has non-canonical functions in regulation of the actin cytoskeleton and apoptosis. It was previously identified through a promoter-trap screen as a mediator of fatty acid-induced cell death (lipotoxicity), and was found to participate in this process downstream of ER stress. Since ER stress is implicated in the pathogenesis of nonalcoholic fatty liver disease (NAFLD), we investigated the mechanism of action of eEF1A-1 in hepatocyte lipotoxicity. HepG2 cells were exposed to excess fatty acids, followed by assessments of ER stress, subcellular localization of eEF1A-1, and cell death. A specific inhibitor of eEF1A-1 elongation activity, didemnin B, was used to determine whether its function in protein synthesis is involved in lipotoxicity. Within 6 h, eEF1A-1 protein was modestly induced by high palmitate, and partially re-localized from its predominant location at the ER to polymerized actin at the cell periphery. This early induction and subcellular redistribution of eEF1A-1 coincided with the onset of ER stress, and was later followed by cell death. Didemnin B did not prevent the initiation of ER stress by high palmitate, as indicated by eIF2α phosphorylation. However, consistent with sustained inhibition of eEF1A-1-dependent elongation activity, didemnin B prevented the recovery of protein synthesis and increase in GRP78 protein that are normally associated with later phases of the response to ongoing ER stress. This resulted in decreased palmitate-induced cell death. Our data implicate eEF1A-1, and its function in protein synthesis, in hepatocyte lipotoxicity.

The deleterious consequences of fatty acid (FA) and neutral lipid accumulation in nonadipose tissues, such as the heart, contribute to the pathogenesis of type 2 diabetes. To elucidate mechanisms of FA-induced cell death, or lipotoxicity, we generated Chinese hamster ovary (CHO) cell mutants resistant to palmitate-induced death and isolated a clone with disruption of eukaryotic elongation factor (eEF) 1A-1. eEF1A-1 involvement in lipotoxicity was confirmed in H9c2 cardiomyoblasts, in which small interfering RNA-mediated knockdown also conferred palmitate resistance. In wild-type CHO and H9c2 cells, palmitate increased reactive oxygen species and induced endoplasmic reticulum (ER) stress, changes accompanied by increased eEF1A-1 expression. Disruption of eEF1A-1 expression rendered these cells resistant to hydrogen peroxide- and ER stress-induced death, indicating that eEF1A-1 plays a critical role in the cell death response to these stressors downstream of lipid overload. Disruption of eEF1A-1 also resulted in actin cytoskeleton defects under basal conditions and in response to palmitate, suggesting that eEF1A-1 mediates lipotoxic cell death, secondary to oxidative and ER stress, by regulating cytoskeletal changes critical for this process. Furthermore, our observations of oxidative stress, ER stress, and induction of eEF1A-1 expression in a mouse model of lipotoxic cardiomyopathy implicate this cellular response in the pathophysiology of metabolic disease.

Microsomal triglyceride transfer protein (MTP) is necessary for hepatocyte assembly and secretion of apolipoprotein (apo)B100-containing lipoproteins. The citrus flavonoid naringenin, like insulin, decreased MTP expression in HepG2 cells, resulting in inhibition of apoB100 secretion; however, the mechanism for naringenin is independent of insulin receptor substrate-1/2. Recently, it was reported that insulin decreased MTP expression in HepG2 cells via the mitogen-activated protein kinase (MAPK)/extracellular signal–regulated kinase (ERK) (MAPKerk) pathway. We hypothesized that naringenin acts via a similar mechanism. Inhibition of MAPK kinase (MEK) 1/2 in HepG2 cells significantly attenuated the naringenin- and insulin-induced reduction in MTP expression. Both naringenin and insulin increased ERK1/2 phosphorylation, which was completely inhibited by MEK1/2 inhibition and enhanced by inhibition of MAPKp38, a negative regulator of MAPKerk activity. Inhibition of MEK1/2 significantly attenuated both the naringenin- and insulin-induced decrease in apoB100 secretion demonstrating a direct link between MAPKerk activation and apoB100 secretion. Furthermore, both compounds increased MAPKp38 activation, and therefore inhibition of MAPKp38 amplified thenaringenin- and insulin-induced decrease in apoB100 secretion. We conclude that MAPKerk signaling in hepatocytes is critical for inhibition of apoB100 secretion by naringenin and insulin. Therefore, naringenin may prove useful for activating insulin-signaling pathways important for regulation of hepatocyte lipid homeostasis.

The grapefruit flavonoid, naringenin, is hypocholesterolemic in vivo, and inhibits basal apolipoprotein B (apoB) secretion and the expression and activities of both ACAT and microsomal triglyceride transfer protein (MTP) in human hepatoma cells (HepG2). In this report, we examined the effects of naringenin on apoB kinetics in oleate-stimulated HepG2 cells and determined the contribution of microsomal lumen cholesteryl ester (CE) availability to apoB secretion. Pulse-chase studies of apoB secretion and intracellular degradation were analyzed by multicompartmental modeling. The model for apoB metabolism in HepG2 cells includes an intracellular compartment from which apoB can be either secreted or degraded by both rapid and slow pathways. In the presence of 0.1 mM oleic acid, naringenin (200 micro M) reduced the secretion of newly synthesized apoB by 52%, due to a 56% reduction in the rate constant for secretion. Intracellular degradation was significantly increased due to a selective increase in rapid degradation, while slow degradation was unaffected. Incubation with either N-acetyl-leucinyl-leucinyl-norleucinal (ALLN) or lactacystin showed that degradation via the rapid pathway was largely proteasomal. Although these changes in apoB metabolism were accompanied by significant reductions in CE synthesis and mass, subcellular fractionation experiments comparing naringenin to specific ACAT and HMG-CoA reductase inhibitors revealed that reduced accumulation of newly synthesized CE in the microsomal lumen is not consistently associated with reduced apoB secretion. However, naringenin, unlike the ACAT and HMG-CoA reductase inhibitors, significantly reduced lumenal TG accumulation. We conclude that naringenin inhibits apoB secretion in oleate-stimulated HepG2 cells and selectively increases intracellular degradation via a largely proteasomal, rapid kinetic pathway. Although naringenin inhibits ACAT, CE availability in the endoplasmic reticulum (ER) lumen does not appear to regulate apoB secretion in HepG2 cells. Rather, inhibition of TG accumulation in the ER lumen via inhibition of MTP is the primary mechanism blocking apoB secretion.

s / Osteoarthritis and Cartilage 22 (2014) S57–S489 S370 micro computed tomography (mCT, Skyscan 1172, 4.5 um resolution) of the knee at 3, 7, 14, 28, 56, 84, 112 days (n 8 per group). Changes in subchondral bone at 28 days post DMM (n 1⁄4 6) were measured separating the subchondral plate from the subchondral tabecular structures. Results: Osteophytes were identified in 70% of mice by day 7 post DMM and in all mice by day 14. At day 7 most samples had 1 or 2 osteophytes, with somehavingup to 4 osteophytes by day 14. Fromday 28onwards the osteophytes fused and formed into one or two large osteophytes. Osteophytes increased in size and bone content with time, plateauing by day 112. The trabeculae of the subchondral bone at day 28 showed a significant (p

Objective Osteoarthritis (OA) is a serious disease of the entire joint, characterized by articular cartilage degeneration, subchondral bone changes, osteophyte formation, and synovial hyperplasia. Currently, there are no pharmaceutical treatments that can slow the disease progression, resulting in greatly reduced quality of life for patients and the need for joint replacement surgeries in many cases. The lack of available treatments for OA is partly due to our incomplete understanding of the molecular mechanisms that promote disease initiation and progression. The purpose of the present study was to examine the role of the nuclear receptor peroxisome proliferator–activated receptor δ (PPARδ) as a promoter of cartilage degeneration in a mouse model of posttraumatic OA. Methods Mouse chondrocytes and knee explants were treated with a pharmacologic agonist of PPARδ (GW501516) to evaluate changes in gene expression, histologic features, and matrix glycosaminoglycan breakdown. In vivo, PPARδ was specifically deleted from the cartilage of mice. Histopathologic scoring according to the Osteoarthritis Research Society International (OARSI) system and immunohistochemical analysis were used to compare mutant and control mice subjected to surgical destabilization of the medial meniscus (DMM). Results In vitro, PPARδ activation by GW501516 resulted in increased expression of several proteases in chondrocytes, as well as aggrecan degradation and glycosaminoglycan release in knee joint explants. In vivo, cartilage-specific PPARδ–knockout mice did not display any abnormalities of skeletal development but showed marked protection in the DMM model of posttraumatic OA (as compared to control littermates). OARSI scoring and immunohistochemical analyses confirmed strong protection of mutant mice from DMM-induced cartilage degeneration. Conclusion These data demonstrate a catabolic role of endogenous PPARδ in posttraumatic OA and suggest that pharmacologic inhibition of PPARδ is a promising therapeutic strategy.

Our preliminary studies showed that in mildly hypercholesterolemic rats with chemically induced breast cancer, dietary orange juice reduced total plasma cholesterol and dietary grapefruit juice tended to reduce VLDL + LDL cholesterol. We therefore investigated whether orange juice and grapefruit juice (double strength) could influence cholesterol metabolism in rabbits with high LDL cholesterol levels induced by feeding a semipurified, cholesterol-free, casein diet. In animals fed the experimental diet for 3 weeks, replacing drinking water with either orange juice or grapefruit juice reduced serum LDL cholesterol by 43% and 32%, respectively (p < 0.05). This was associated with total liver cholesterol reduction in the orange juice group (-18%, p < 0.05) and with hepatic cholesterol ester reduction in both juice groups (-42%, p < 0.05). The juices were not acting as intestinal sequestrants since neither increased fecal cholesterol or bile acid excretion. In fact, cholesterol excretion was decreased in both orange juice and grapefruit juice group by 44% and 48%, respectively (p < 0.05). These results suggest that the reduction of LDL cholesterol induced by dietary citrus juices could be due to endogenous effects of juice components, possibly flavonoids.

BackgroundSeveral studies have addressed the epidemiology of community-associated Staphylococcus aureus (CA-SA) in Europe; nonetheless, a comprehensive perspective remains unclear. In this study, we aimed to describe the population structure of CA-SA and to shed light on the origin of methicillin-resistant S. aureus (MRSA) in this continent.Methods and findingsA total of 568 colonization and infection isolates, comprising both MRSA and methicillin-susceptible S. aureus (MSSA), were recovered in 16 European countries, from community and community-onset infections. The genetic background of isolates was characterized by molecular typing techniques (spa typing, pulsed-field gel electrophoresis and multilocus sequence typing) and the presence of PVL and ACME was tested by PCR. MRSA were further characterized by SCCmec typing. We found that 59% of all isolates were associated with community-associated clones. Most MRSA were related with USA300 (ST8-IVa and variants) (40%), followed by the European clone (ST80-IVc and derivatives) (28%) and the Taiwan clone (ST59-IVa and related clonal types) (15%). A total of 83% of MRSA carried Panton-Valentine leukocidin (PVL) and 14% carried the arginine catabolic mobile element (ACME). Surprisingly, we found a high genetic diversity among MRSA clonal types (ST-SCCmec), Simpson's index of diversity = 0.852 (0.788-0.916). Specifically, about half of the isolates carried novel associations between genetic background and SCCmec. Analysis by BURP showed that some CA-MSSA and CA-MRSA isolates were highly related, suggesting a probable local acquisition/loss of SCCmec.ConclusionsOur results imply that CA-MRSA origin, epidemiology and population structure in Europe is very dissimilar from that of USA.

Publisher Summary This chapter discusses one of the major barriers to renal regeneration, namely cell and tissue aging. Aging of the vasculature, a process that can profoundly limit functional repair and regeneration, will be emphasized. Molecular pathways that regulate cellular aging will be reviewed, focusing on the production and consumption pathways of the oxidized form of nicotinamide adenine dinucleotide (NAD+), including sirtuin-1 (SIRT1)-dependent cascades, cascades that are emerging as key determinants of regeneration versus aging. It is well accepted that preventing the insults that can lead to renal damage is preferable to managing renal disease once it has manifest. This is a feasible strategy in some instances, avoidance of high blood pressure being a prime example. However, as with many conditions, preventing renal damage often is not an option because the pathology has advanced beyond the point at which such a strategy is relevant. The notion of tissue regeneration is emerging an attractive potential therapy. Although considered as a therapeutic strategy, regeneration is also an innate property of adult organs, albeit often of limited capacity. Strategies that harness the innate regenerative capacity of organs may prove to be an effective mode of regenerative medicine. However, the innate response to severe or sustained kidney damage is primarily fibrosis, not regeneration. This reality highlights a challenge to the field of regenerative nephrology, as the barriers to innate renal regeneration will also be barriers to therapeutic regenerative strategies.

This work deals with the development of composite pipes for riser application in deep water. Initially, an epoxy resin system was toughened by rubber CTBN addition (10 wt%) as a way of improving the flexibility of future risers. Mechanical and thermal analyses were carried out for characterizing the polymeric systems. As expected, due to the fact that the modulus of the CTBN is much lower than that of the epoxy phase, the tensile modulus decreased with the addition of CTBN, from 3.45 to 2.75 GPa, and the elongation at fracture increased from 2.96 to 5.24%. On the other hand, the glass transition temperature (Tg) of the CTBN-epoxy system changed from 141°C to 136°C. Later, composite tubes were prepared and mechanically characterized. The influence of matrix toughening and the number of composite layers on the mechanical behavior of the tubes were studied using hydrostatic and split-disk tests. In both tests, the results indicate that the matrix plays an important role in composite fracture processes. In the split-disk tests, the tensile strength and the elongation at fracture increased with the addition of CTBN, from 731 to 831 MPa and from 2.34 to 3.09%, respectively. In the case of the hydrostatic tests, the pipes colapse and bursting pressures increased about 14% and 19%, respectively, with the rubber addition to the polymeric matrix. At last, it was verified that the strength of the tubes increases linearly with the number of layers. These results confirm the feasibility of the developed tubes for application as risers in deep water.

Polyploid endothelial cells are found in aged and atherosclerotic arteries. However, whether increased chromosome content has an impact on endothelial cell function is unknown. We show here that human aortic endothelial cells become tetraploid as they approach replicative senescence. Furthermore, accumulation of tetraploid endothelial cells was accelerated during growth in high glucose. Interestingly, induction of polyploidy was completely prevented by modest overexpression of the NAD+regenerating enzyme, nicotinamide phosphoribosyltransferase (Nampt). To determine the impact of polyploidy on endothelial cell function, independent of replicative senescence, we induced tetraploidy using the spindle poison, nocodazole. Global gene expression analyses of tetraploid endothelial cells revealed a dysfunctional phenotype characterized by a cell cycle arrest profile (decreased CCNE2/A2, RBL1, BUB1B; increased CDKN1A) and increased expression of genes involved in inflammation ( IL32, TNFRSF21/10C, PTGS1) and extracellular matrix remodeling ( COL5A1, FN1, MMP10/14). The protection from polyploidy conferred by Nampt was not associated with enhanced poly(ADP-ribose) polymerase-1 or sirtuin (SIRT) 2 activity, but with increased SIRT1 activity, which reduced cellular reactive oxygen species and the associated oxidative stress stimulus for the induction of polyploidy. We conclude that human aortic endothelial cells are prone to chromosome duplication that, in and of itself, can induce characteristics of endothelial dysfunction. Moreover, the emergence of polyploid endothelial cells during replicative aging and glucose overload can be prevented by optimizing the Nampt-SIRT1 axis.

Endothelial dysfunction is a characteristic of aging-related vascular disease and is worsened during diabetes. High glucose can impair endothelial cell (EC) function through cellular accumulation of reactive oxygen species, an insult that can also limit replicative lifespan. Nicotinamide phosphoribosyltransferase (Nampt), also known as PBEF and visfatin, is rate-limiting for NAD+ salvage from nicotinamide and confers resistance to oxidative stress via SIRT1. We therefore sought to determine if Nampt expression could resist the detrimental effects of high glucose and confer a survival advantage to human vascular EC in this pathologic environment. Human aortic EC were infected with retrovirus encoding eGFP or eGFP-Nampt, and FACS-selected to yield populations with similar, modest transgene expression. Using a chronic glucose exposure model we tracked EC populations to senescence, assessed cellular metabolism, and determined in vitro angiogenic function. Overexpression of Nampt increased proliferation and extended replicative lifespan, and did so preferentially during glucose overload. Nampt expression delayed markers of senescence and limited reactive oxygen species accumulation in high glucose through a modest increase in aerobic glycolysis. Furthermore, tube networks formed by Nampt-overexpressing EC were more extensive and glucose-resistant, in accordance with SIRT1-mediated repression of the anti-angiogenic transcription factor, FoxO1. We conclude that Nampt enables proliferating human EC to resist the oxidative stress of aging and of high glucose, and to productively use excess glucose to support replicative longevity and angiogenic activity. Enhancing endothelial Nampt activity may thus be beneficial in scenarios requiring EC-based vascular repair and regeneration during aging and hyperglycemia, such as atherosclerosis and diabetes-related vascular disease.

Cardiovascular disease (CVD) is the most prevalent disease worldwide and there is intense interest in pharmaceutical approaches to reduce the burden of this chronic, aging-related condition. The sirtuin (SIRT) family of NAD(+)-dependent protein deacetylases and ADP-ribosyltransferases have emerged as exciting targets for CVD management that can impact the cardiovascular system both directly and indirectly, the latter by modulating whole body metabolism. SIRT1-4 regulate the activities of a variety of transcription factors, coregulators, and enzymes that improve metabolic control in adipose tissue, liver, skeletal muscle, and pancreas, particularly during obesity and aging. SIRT1 and 7 can control myocardial development and resist stress- and aging-associated myocardial dysfunction through the deacetylation of p53 and forkhead box O1 (FoxO1). By modulating the activity of endothelial nitric oxide synthase (eNOS), FoxO1, and p53, and the expression of angiotensin II type 1 receptor (AT1R), SIRT1 also promotes vasodilatory and regenerative functions in endothelial and smooth muscle cells of the vascular wall. Given the array of potentially beneficial effects of SIRT activation on cardiovascular health, interest in developing specific SIRT agonists is well-substantiated. Because SIRT activity depends on cellular NAD+ availability, enzymes involved in NAD+ biosynthesis, including nicotinamide phosphoribosyltransferase (Nampt), may also be valuable pharmaceutical targets for managing CVD. Herein we review the actions of the SIRT proteins on the cardiovascular system and consider the potential of modulating SIRT activity and NAD+ availability to control CVD.

Antillopsyche mexicana, new species Figs. 5���6 Antillopsyche mexicana differs from all other recent and fossil species by the forked pair of long spines of tergum X. In the hind wing apical fork 3 is very short compared with those of all other fossil species from Dominican amber. Adult. Length of forewing 3.9 mm (holotype), 3.6 mm (paratype). General structure and forewing and hind wing venation typical for genus (Figs. 5, 6 A),in hind wing fork 3 is remarkably short compared with other fossil species from Dominican amber. Male genitalia (Figs. 6 C, 6 D). Tergum IX in lateral view with preanal appendage apically rounded, more than 2 times as long as wide, flat. Tergum X with mesal process deeply forked into 2 elongate lobes, as long as the apex of preanal appendage. Inferior appendage oval, approximately as long as preanal appendage, with acuminate basodorsal appendage, bent mesad. Apices of lobes of tergum X, preanal appendages, and inferior appendages all extend equally far posteriad, and are slightly surpassed by phallus (Fig. 6 C). Phallus jacketed by laterodorsal membrane, apex membranous, without cluster of spines Holotype male: Embedded in Mexican amber together with another male (paratype) and in the amber collection of the Instituto de Historia Natural y Ecologia, Museum of Paleontology, Tuxtla Guti��rrez, Chiapas, collection no.: IHNFA 232. Paratype: Embedded in Mexican amber together with the holotype, in the amber collection of the Instituto de Historia Natural y Ecologia, Museum of Paleontology, Tuxtla Guti��rrez, Chiapas, collection no.: IHNFA 232, male. Etymology. Named in recognition of the type country and the first evidence of the genus Antillopsyche in Mexico., Published as part of Wichard, Wilfried, Sol��rzano, M��nica M., Kraemer & Luer, Claus, 2006, First caddisfly species from Mexican amber (Insecta: Trichoptera), pp. 37-48 in Zootaxa 1378 on pages 43-44, DOI: 10.5281/zenodo.175015

Family Hydropsychidae Curtis Plectropsyche is a small genus with only 2 recent species, P. hoogstraali Ross, the type species, and P. pitelli Denning. It belongs to the subfamily Hydropsychinae, which was reviewed by Ross & Unzicker (1977) and recently evaluated by Schefter (2005). Plectropsyche is found today in Mexico and Costa Rica. Nothing is published about the immature stages or the biology of the species (Flint et al. 1999). Based on the key of Schefter (2005) the genus Plectropsyche is characterized by a number of characters, including the position of crossvein cu near crossvein m-cu and the fusion of Cu 2 and A 1 at or before the wing margin in the forewing, by the presence of fork III and the absence of crossvein m in the hind wing, the absence of episternal warts on the prothorax, and the presence of bundles of seta on the foreleg tarsal claws. In the male genitalia (Ross & Unzicker 1977) the genus Plectropsyche is characterized by the basal segment of the inferior appendage being at least twice as long as the apical segment and the apex of the phallus with endothecal processes and lobules of the endothecal lobe., Published as part of Wichard, Wilfried, Sol��rzano, M��nica M., Kraemer & Luer, Claus, 2006, First caddisfly species from Mexican amber (Insecta: Trichoptera), pp. 37-48 in Zootaxa 1378 on page 41, DOI: 10.5281/zenodo.175015, {"references":["Ross, H. H. & Unzicker, J. D. (1977) The relationships of the genera of American Hydropsychinae as indicated by phallic structures (Trichoptera, Hydropsychidae). Journal of the Georgia Entomological Society, 12, 298 - 312.","Schefter, P. W. (2005) Re-evaluation of genera in the subfamily Hydropsychinae (Trichoptera: Hydropsychidae). Aquatic Insects, 27, 133 - 154.","Flint, O. S., Jr., Holzenthal, R. W. & Harris, S. C. (1999) Catalog of the Neotropical Caddisflies (Insecta: Trichoptera). Ohio Biological Survey, Columbia. 239 pp."]}

Plectropsyche alvarezi, new species Figs. 3���4. Plectropsyche alvarezi possesses the diagnostic structures of the genus. The new fossil species differs from the 2 extant species by the position of crossvein cu very near crossvein m-cu in the forewing and by the slender, hook-shaped endothecal processes of endophallus. Adult. Length of forewing 4.9 mm (holotype), 5.3 mm (paratype). General structure and forewing venation typical for genus (Figs. 3, 4 A). Maxillary palp segment 1 as long as segment 2, segment 5 equal to or slightly longer than segments 1���4. Proepisternal warts very probably absent, but not discernable in the amber fossil. Tibial spurs 2,4, 4. Forewing forks 1���5 and discoidal, median and thyridial cells present, crossvein cu very close to m-cu and Cu 2, A 1 fused before the forewing margin. Hind wing with forks 1, 2, 3, and 5 present; crossvein m lost (from ventral view of male paratype). Male genitalia (Fig. 4 B). The length of the inferior appendage is in a ratio of at least 2: 1 (basal segment: apical segment). Basal segment of inferior appendage enlarged, rounded; apical segment finger-like, elongate, bent mesad. Apex of phallus with pair of slender, dorsal rounded hooks (endothecal processes), lateroventrally with lobules (probably a pair, but in amber fossil not clearly visible). Holotype male: Embedded in Mexican amber in the amber collection of the Instituto de Historia Natural y Ecologia, Museum of Paleontology, Tuxtla Guti��rrez, Chiapas, collection no.: IHNFA 0 67. Paratype: Embedded in Mexican amber in the amber collection of the Instituto de Historia Natural y Ecologia, Museum of Paleontology, Tuxtla Guti��rrez Chiapas, collection no.: IHNFA 0 88, male. Etymology: Dedicated to Prof. Miguel Alvarez del Toro (1917���1996), naturalist and founder of the Museum of Natural History and Zoo in Chiapas, Mexico., Published as part of Wichard, Wilfried, Sol��rzano, M��nica M., Kraemer & Luer, Claus, 2006, First caddisfly species from Mexican amber (Insecta: Trichoptera), pp. 37-48 in Zootaxa 1378 on pages 41-42, DOI: 10.5281/zenodo.175015

Xiphocentron (Xiphocentron) chiapasi, new species Figs. 7���8 This first fossil species of the genus Xiphocentron from Mexico is characterized by the male genitalia and differs from recent species by the pair of long mesal, spines of sternum IX. Adult. Length of forewing 3.1 mm (holotype), 3.2 mm (paratype). General structure and forewing venation typical for genus (Figs. 7, 8 A). Tibial spurs 2, 4, 3; hind leg with 2 preapical spurs and single, modified apical spur (Fig. 8 D). Male genitalia (Figs. 8 B, 8 C). Sternum IX apically with pair of long mesal spines. Inferior appendage slender, curving evenly dorsad and mesad, inner surface of broad middle section with brush of black setae (characteristic of subgenus Xiphocentron), apical section with elongate spine angled mesad and dorsad; both inferior appendages touch apically (holotype, Fig. 8 B) or intersect at the apical spines (paratype, Fig. 8 C). Phallus slender, tubular, open at apex, extending about 2 / 3 as far as preanal appendage or inferior appendage. Holotype male: Embedded in Mexican amber in the collection of G.O. Poinar, Jr., Oregon State University, Corvallis, Oregon, USA, collection no.: TR 2���10. Paratype: Embedded in Mexican amber in the amber collection of the Instituto de Historia Natural y Ecologia, Museum of Paleontology, Tuxtla Guti��rrez, Chiapas, collection no.: IHNFA 0 28, male. Etymology: Named for the Mexican state where the amber was found., Published as part of Wichard, Wilfried, Sol��rzano, M��nica M., Kraemer & Luer, Claus, 2006, First caddisfly species from Mexican amber (Insecta: Trichoptera), pp. 37-48 in Zootaxa 1378 on pages 46-48, DOI: 10.5281/zenodo.175015

Cell dysfunction and death induced by lipid accumulation in nonadipose tissues, or lipotoxicity, may contribute to the pathogenesis of obesity and type 2 dia- betes. However, the mechanisms leading to lipotoxic cell death are poorly understood. We recently reported that, in Chinese hamster ovary (CHO) cells and in H9c2 cardiomyo- blasts, lipid overload induced by incubation with 500 mM palmitate leads to intracellular accumulation of reactive oxy- gen species, which subsequently induce endoplasmic re- ticulum (ER) stress and cell death. Here, we show that palmitate also impairs ER function through a more direct mechanism. Palmitate was rapidly incorporated into satu- rated phospholipid and triglyceride species in microsomal membranes of CHO cells. The resulting membrane re- modeling was associated with dramatic dilatation of the ER and redistribution of protein-folding chaperones to the cy- tosol within 5 h, indicating compromised ER membrane integrity. Increasing b-oxidation, through the activation of AMP-activated protein kinase, decreased palmitate incor- poration into microsomes, decreased the escape of chap- erones to the cytosol, and decreased subsequent caspase activation and cell death. Thus, palmitate rapidly increases the saturated lipid content of the ER, leading to compro- mised ER morphology and integrity, suggesting that impairment of the structure and function of this organelle is involved in the cellular response to fatty acid overload.— Borradaile, N. M., X. Han, J. D. Harp, S. E. Gale, D. S. Ory, and J. E. Schaffer. Disruption of endoplasmic reticulum structure and integrity in lipotoxic cell death. J. Lipid Res. 2006. 47: 2726-2737.

Cardiomyopathy is associated with both rare genetic metabolic abnormalities and highly prevalent diseases characterized by elevated serum triglycerides and nonesterified fatty acids, such as obesity and type 2 diabetes. In these disorders, an imbalance between fatty acid uptake and utilization leads to the inappropriate accumulation of free fatty acids and neutral lipids within cardiomyocytes. Through the process of lipotoxicity, this lipid overload causes cellular dysfunction, cell death, and eventual organ dysfunction. This review focuses on lipotoxicity in the heart, with an emphasis on the contribution of this process to the pathogenesis of cardiomyopathy associated with obesity, diabetes, and the metabolic syndrome. The magnitude of the current worldwide epidemic of obesity and type 2 diabetes suggests that understanding the pathogenesis of cardiac complications associated with these diseases will contribute substantially to improvements in health care.

The flavonoid naringenin improves hyperlipidemia and hyperglycemia in streptozotocin-treated rats. In HepG2 human hepatoma cells, naringenin inhibits apolipoprotein B (apoB) secretion primarily by inhibiting microsomal triglyceride transfer protein and enhances LDL receptor (LDLr)-mediated apoB-containing lipoprotein uptake. Phosphatidylinositol 3-kinase (PI3K) activation by insulin increases sterol regulatory element-binding protein (SREBP)-1 and LDLr expression and inhibits apoB secretion in hepatocytes. Thus, we determined whether naringenin activates this pathway. Insulin and naringenin induced PI3K-dependent increases in cytosolic and nuclear SREBP-1 and LDLr expression. Similar PI3K-mediated increases in SREBP-1 were observed in McA-RH7777 rat hepatoma cells, which express predominantly SREBP-1c. Reductions in HepG2 cell media apoB with naringenin were partially attenuated by wortmannin, whereas the effect of insulin was completely blocked. Both treatments reduced apoB100 secretion in wild-type and LDLr−/− mouse hepatocytes to the same extent. Insulin and naringenin increased HepG2 cell PI3K activity and decreased insulin receptor substrate (IRS)-2 levels. In sharp contrast to insulin, naringenin did not induce tyrosine phosphorylation of IRS-1. We conclude that naringenin increases LDLr expression in HepG2 cells via PI3K-mediated upregulation of SREBP-1, independent of IRS-1 phosphorylation. Although this pathway may not regulate apoB secretion in primary hepatocytes, PI3K activation by this novel mechanism may explain the insulin-like effects of naringenin in vivo.

The grapefruit flavonoid, naringenin, is hypocholesterolemic in vivo, and inhibits basal apolipoprotein B (apoB) secretion and the expression and activities of both ACAT and microsomal triglyceride transfer protein (MTP) in human hepatoma cells (HepG2). In this report, we examined the effects of naringenin on apoB kinetics in oleate-stimulated HepG2 cells and determined the contribution of microsomal lumen cholesteryl ester (CE) availability to apoB secretion. Pulse-chase studies of apoB secretion and intracellular degradation were analyzed by multicompartmental modeling. The model for apoB metabolism in HepG2 cells includes an intracellular compartment from which apoB can be either secreted or degraded by both rapid and slow pathways. In the presence of 0.1 mM oleic acid, naringenin (200 micro M) reduced the secretion of newly synthesized apoB by 52%, due to a 56% reduction in the rate constant for secretion. Intracellular degradation was significantly increased due to a selective increase in rapid degradation, while slow degradation was unaffected. Incubation with either N-acetyl-leucinyl-leucinyl-norleucinal (ALLN) or lactacystin showed that degradation via the rapid pathway was largely proteasomal. Although these changes in apoB metabolism were accompanied by significant reductions in CE synthesis and mass, subcellular fractionation experiments comparing naringenin to specific ACAT and HMG-CoA reductase inhibitors revealed that reduced accumulation of newly synthesized CE in the microsomal lumen is not consistently associated with reduced apoB secretion. However, naringenin, unlike the ACAT and HMG-CoA reductase inhibitors, significantly reduced lumenal TG accumulation. We conclude that naringenin inhibits apoB secretion in oleate-stimulated HepG2 cells and selectively increases intracellular degradation via a largely proteasomal, rapid kinetic pathway. Although naringenin inhibits ACAT, CE availability in the endoplasmic reticulum (ER) lumen does not appear to regulate apoB secretion in HepG2 cells. Rather, inhibition of TG accumulation in the ER lumen via inhibition of MTP is the primary mechanism blocking apoB secretion.