Bioactive lipids

Alzheimer's disease (AD) is characterized by extracellular amyloid-b (Ab) deposition, which activates microglia, induces neuroinflammation and drives neurodegeneration. Recent evidence indicates that soluble pre-fibrillar Ab species, rather than insoluble fibrils, are the most toxic forms of Ab. Preventing soluble Ab formation represents, therefore, a major goal in AD. We investigated whether microvesicles (MVs) released extracellularly by reactive microglia may contribute to AD degeneration. We found that production of myeloid MVs, likely of microglial origin, is strikingly high in AD patients and in subjects with mild cognitive impairment and that AD MVs are toxic for cultured neurons. The mechanism responsible for MV neurotoxicity was defined in vitro using MVs produced by primary microglia. We demonstrated that neurotoxicity of MVs results from (i) the capability of MV lipids to promote formation of soluble Ab species from extracellular insoluble aggregates and (ii) from the presence of neurotoxic Ab forms trafficked to MVs after Ab internalization into microglia. MV neurotoxicity was neutralized by the Ab-interacting protein PrP and anti-Ab antibodies, which prevented binding to neurons of neurotoxic soluble Ab species. This study identifies microglia-derived MVs as a novel mechanism by which microglia participate in AD degeneration, and suggest new therapeutic strategies for the treatment of the disease.

Most of the global sugar and ethanol supply trade comes from the harvesting of Saccharum officinarum (i.e., sugarcane). Its industrial processing results in numerous by-products and waste streams, such as tops, straw, filter cake, molasses and bagasse. The recovery of lipids (i.e., octacosanol, phytosterols, long-chain aldehydes and triterpenoids) from these residues is an excellent starting point for the development of new products for various application fields, such as health and well-being, representing an important feature of the circular economy. By selecting green scalable extraction procedures, industry can reduce its environmental impact. Refluxed ethanol extraction methods have been demonstrated to meet these characteristics. On the other hand, effective non-solvent methodologies such as molecular distillation and supercritical CO2 extraction can fractionate lipids based on high temperature and pressure application with similar yields. Sugarcane lipophilic extracts are usu...

Cystic Fibrosis (CF) is a recessive genetic disease due to mutations of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene encoding the CFTR chloride channel. The ion transport abnormalities related to CFTR mutation generate a dehydrated airway surface liquid (ASL) layer, which is responsible for an altered mucociliary clearance, favors infections and persistent inflammation that lead to progressive lung destruction and respiratory failure. The inflammatory response is normally followed by an active resolution phase to return to tissue homeostasis, which involves specialized pro-resolving mediators (SPMs). SPMs promote resolution of inflammation, clearance of microbes, tissue regeneration and reduce pain, but do not evoke unwanted immunosuppression. The airways of CF patients showed a decreased production of SPMs even in the absence of pathogens. SPMs levels in the airway correlated with CF patients' lung function. The prognosis for CF has greatly improved but there remains a critical need for more effective treatments that prevent excessive inflammation, lung damage, and declining pulmonary function for all CF patients. This review aims to highlight the recent understanding of CF airway inflammation and the possible impact of SPMs on functions that are altered in CF airways.

Alzheimer's disease (AD) is characterized by extracellular amyloid-b (Ab) deposition, which activates microglia, induces neuroinflammation and drives neurodegeneration. Recent evidence indicates that soluble pre-fibrillar Ab species, rather than insoluble fibrils, are the most toxic forms of Ab. Preventing soluble Ab formation represents, therefore, a major goal in AD. We investigated whether microvesicles (MVs) released extracellularly by reactive microglia may contribute to AD degeneration. We found that production of myeloid MVs, likely of microglial origin, is strikingly high in AD patients and in subjects with mild cognitive impairment and that AD MVs are toxic for cultured neurons. The mechanism responsible for MV neurotoxicity was defined in vitro using MVs produced by primary microglia. We demonstrated that neurotoxicity of MVs results from (i) the capability of MV lipids to promote formation of soluble Ab species from extracellular insoluble aggregates and (ii) from the presence of neurotoxic Ab forms trafficked to MVs after Ab internalization into microglia. MV neurotoxicity was neutralized by the Ab-interacting protein PrP and anti-Ab antibodies, which prevented binding to neurons of neurotoxic soluble Ab species. This study identifies microglia-derived MVs as a novel mechanism by which microglia participate in AD degeneration, and suggest new therapeutic strategies for the treatment of the disease.

Supplementary key words diabetic retinopathy • 12-and 15-HETEs • retinal vascular leakage • reduced nicotinamide adenine dinucleotide phosphate oxidase • retinal infl ammation • lipoxygenase • bioactive lipids Diabetic retinopathy (DR), the most prevalent microvascular complication of diabetes, is responsible for over 10,000 new cases of blindness every year in the United States alone (1). The risk of vision loss increases with the development of diabetic macular edema and/or retinal neovascularization (NV), the former being a direct consequence of blood-retinal barrier (BRB) dysfunction and the latter the result of widespread retinal ischemia (2). For years, signifi cant effort has been invested in elucidating the mechanisms that underlie destructive preretinal NV in DR (3). Nonetheless, considerably less is known about the molecular events that lead to BRB dysfunction that is characterized by enhanced retinal vascular permeability and recruitment of infl ammatory cells. Moreover, existing regimens of treatment carry nonspecifi c adverse effects. These include increased risk of thromboembolic incidence, neuronal toxicity, and geographic atrophy with anti-vascular endothelial growth factor (VEGF) therapies Abstract Retinal hyperpermeability and subsequent macular edema is a cardinal feature of early diabetic retinopathy (DR). Here, we investigated the role of bioactive lipid metabolites, in particular 12/15-lipoxygenase (LOX)-derived metabolites, in this process. LC/MS lipidomic screen of human retinal endothelial cells (HRECs) demonstrated that 15-HETE was the only signifi cantly increased metabolite (2.4 ± 0.4-fold, P = 0.0004) by high glucose (30 mM) treatment. In the presence of arachidonic acid, additional eicosanoids generated by 12/15-LOX, including 12-and 11-HETEs, were signifi cantly increased. Fluorescein angiography and retinal albumin leakage showed a signifi cant decrease in retinal hyperpermeability in streptozotocin-induced diabetic mice lacking 12/15-LOX compared with diabetic WT mice. Our previous studies demonstrated the potential role of NADPH oxidase in mediating the permeability effect of 12-and 15-HETEs, therefore we tested the impact of intraocular injection of 12-HETE in mice lacking the catalytic subunit of NADPH oxidase (NOX2). The permeability effect of 12-HETE was signifi cantly reduced in NOX2 ؊ / ؊ mice compared with the WT mice. In vitro experiments also showed that 15-HETE induced HREC migration and tube formation in a NOX-dependent manner. Taken together our data suggest that 12/15-LOX is implicated in DR via a NOX-dependent mechanism.-Ibrahim, A

Conventional methods for the propagation and preservation of parasites in vivo or in vitro have limitations, which include the need for labor, the initial isolation and loss of strains, bacterial and fungal contamination, and changes in the original biological and metabolic characteristics of the organism. All of these disadvantages are reduced considerably by cryopreservation. In this study, we examined the effects of different concentrations of dimethyl sulfoxide (DMSO) and glycerol on the survival rate of . Both of the two cryoprotectants examined at different concentrations showed a protective effect of . When DMSO was used as the cryoprotectant, a maximum survival rate (70%) was achieved at a concentration of 10% over a short-term duration of freezing (24 h). Glycerol at a concentration of 10% had the highest effect on cryoprotectivity after 70 days, while DMSO 20% showed the lowest cryopreservation for In conclusion, DMSO and glycerol are appropriate protective materials for t...

Despite significant advances in medical therapy and interventional strategies, the prognosis of millions of patients with acute myocardial infarction (AMI) and ischemic heart disease (IHD) remains poor. Currently, short of heart transplantation with all of its inherit limitations, there are no available treatment strategies that replace the infarcted myocardium. It is now well established that cardiomyocytes undergo continuous renewal, with contribution from bone marrow (BM)-derived stem/progenitor cells (SPCs). This phenomenon is upregulated during AMI by initiating multiple innate reparatory mechanisms through which BMSPCs are mobilized towards the ischemic myocardium and contribute to myocardial regeneration. While a role for the SDF-1/CXCR4 axis in retention of BMSPCs in bone marrow is undisputed, its exclusive role in their mobilization and homing to a highly proteolytic microenvironment, such as the ischemic/infarcted myocardium, is currently being challenged. Recent evidence ...

Body tissues are subjected to various oxygenic gradients and fluctuations and hence can become transiently hypoxic. Hypoxia-inducible factor (HIF) is the master transcriptional regulator of the cellular hypoxic response and is capable of modulating cellular metabolism, immune responses, epithelial barrier integrity, and local microbiota. Recent reports have characterized the hypoxic response to various infections. However, little is known about the role of HIF activation in the context of protozoan parasitic infections. Growing evidence suggests that tissue and blood protozoa can activate HIF and subsequent HIF target genes in the host, helping or hindering their pathogenicity. In the gut, enteric protozoa are adapted to steep longitudinal and radial oxygen gradients to complete their life cycle, yet the role of HIF during these protozoan infections remains unclear. This review focuses on the hypoxic response to protozoa and its role in the pathophysiology of parasitic infections. W...

Alpha-linolenic acid (ALA); Conjugated Linoleic acid (CLA); Conjugated linolenic acid (CLNA); Docosahexaenoic acid (DHA); Docosapentaenoic acid (DPA); Eicosapentaenoic acid (EPA); High-density lipoprotein (HDL); histone deacetylase (HDAC); Linoleic acid (LA); Long-chain fatty acid (LCFA); Low-density lipoprotein (LDL); Mediumchain fatty acid (MCFA); Medium-chain triglyceride (MCT); Monounsaturated fatty acid (MUFA); Nuclear factor κB (NFκB); Polyunsaturated fatty acid (PUFA); Punicic acid (PUA); Short-chain fatty acid (SCFA) 1.1.2. Medium-chain fatty acids Medium-chain fatty acids (MCFAs) are saturated or unsaturated fatty acids, which present 6 to carbon atoms. Caproic acid (C6:0), caprylic acid (C8:0), capric acid (C10:0) and lauric acid (C12:0) are examples of MCFAs. MCFAs are commonly found in medium-chain triglycerides (MCTs) since the latter contain MCFAs esterified to the glycerol backbone. Those triglycerides are often completely hydrolyzed to yield free fatty acids by lipases that are present in the gastrointestinal tract. When absorbed directly, MCTs enter the blood circulation and are carried to the liver where they are oxidized to ketones (R. E. Aluko, 2012). Compared with the triglycerides containing long-chain fatty acids, MCTs have a lower melting point, smaller molecular size and provide slightly lower energy (8.4 versus 9.2 kcal/g) and are liquid at room temperature (Marten & Ã, 2006). 1.1.3. Long-chain fatty acids (Unsaturated fatty acids) Long-chain fatty acids (LCFAs) are fatty acids with 14 or more linearly arranged carbon atoms, and may be saturated, having no double bonds, or unsaturated, having one or more double bonds. Unsaturated fatty acids contain one or more carbon atom in a double bond, being the three major types: monounsaturated fatty acids (MUFA), polyunsaturated fatty acids (PUFA) and trans fatty acids. The unsaturated fatty acids may exist in a cis (c) or trans (t) configuration. The cis configuration is found in most naturally unsaturated sources, the trans configuration results from technological processing, such as hydrogenation (Bozza & Viola, 2010; Orsavova et al., 2015). 1.1.3.1. Monounsaturated fatty acids MUFAs include palmitoleic (C16:1 c9), oleic (C18:1 c9), elaidic (C18:1 t9) and vaccenic acids (C18:1 c11), being oleic acid (C18:1 c9) the most abundant MUFA in the diet (Assy et al., 2010). Considering that they can be synthesized in the body, they are not essential dietary lipids. 1.1.3.2. Polyunsaturated fatty acids PUFAs are unsaturated fatty acids with two or more double bonds and their classification depend on the position of the first double bond relative to the methyl-end group. Therefore they can be subdivided into two groups: omega-6 (meaning that the double bound is 6 carbon atoms away from the terminal methyl group) and omega-3 fatty acids (meaning that the double bound is 3 carbon atoms away from the terminal methyl group). Omega-3 and omega-6 PUFAs are synthesized from the essential fatty acid alpha-linolenic acid (ALA) (C18:3 c9,c12,c15) and linoleic acid (LA) (C18:2 c9,c12), respectively. Humans and animals can metabolize these essential fatty acids to long-chain derivatives. Nevertheless, these precursors, ALA and LA, cannot be synthesized in the human body. Moreover, the human body cannot synthesize PUFAs with the first C3 and C6 double bonds from the methyl-end due to the lack of appropriate enzymes (Δ12 and Δ15 desaturases) (

Obesity continues to be one of the major global challenges in the present century and its incidence nearly tripled between 1975 and 2016. It is estimated that obesity rates are going to increase further by 2030. The available drugs for obesity have not achieved the required level of clinical effectiveness and have been associated with severe health side effects. Diet has been widely recognized as playing a central role in such disorder. Although high-fat diets are often blamed for increased obesity rates, fats are diverse and respond differently in vivo. Saturated fatty acids bind to toll-like receptor 4 (TLR 4) triggering inflammatory processes in brain, adipose tissue and liver. Besides, saturated fatty acids are responsible for increased lipid storage in adipose tissue leading to an accumulation of lipids in adipocytes. In contrast, medium-chain fatty acids, monounsaturated and polyunsaturated fatty acids are related with body weight reduction and a protective potential of both peripheral tissues and brain, in part related with their antiinflammatory capability.

Different bacteria cohabit different sites of the human body, with special relevance on the mutualistic collaboration responsible for the maintenance of the gastrointestinal tract's homeostasis. Diversification and composition of the microbiota are influenced by several factors, including diet. Several beneficial effects have been linked with microbiota modulation and its dysregulation have been associated with several pathologies. Lipids are essential elements in gut permeability, being important in the modulation of the gut microbiome. Bioactive lipids like endocannabinoids, short-chain fatty acids (SCFAs) and omega-3 fatty acids have been associated with microbiota modulation. The endocannabinoid system is involved in modulation of gastric emptying, gastrointestinal motility and inflammation. SCFAs are a source of energy to the colonic epithelium and maintain the integrity of the epithelial barrier. SCFAs also interact with the blood-brain barrier being able to modulate brain function. Omega-3 potentially restore the gut dysbiosis that is encountered in several pathologies. Thus, all these bioactive lipids have important functions in gut dysbiosis observed in pathologies like inflammatory bowel disease, obesity, Alzheimer's disease, multiple sclerosis and Parkinson's disease. Abbreviations α-linolenic acid (ALA); α-synuclein protein (αSyn); 2-Arachidonoylglycerol (2-AG); 12-hydroxyeicosatetraenoic acid (12-HETE); Blood-brain barrier (BBB); Cannabinoid receptor 1 (CB1); Central Nervous System (CNS); Docosahexaenoic acid (DHA); Eicosapentaenoic acid (EPA); Enteric nervous system (ENS); Gamma-aminobutyric acid (GABA); G-protein coupled membrane receptors (GPR); Inflammatory bowel disease (IBD); Lipopolysaccharide (LPS); Medium-chain fatty acid (MCFA); Multiple Sclerosis (MS); Mu-opioid receptors (MOR); N-acylethanolamine (NAE); Narachidonoylethanolamine (AEA); Parkinson's disease (PD); Peroxisome proliferatoractivated receptor (PPAR); Polyunsaturated fatty acids (PUFAs); Relapsing remitting multiple sclerosis (RRMS); Short-chain fatty acids (SCFAs); Wild-type (WT)

Inflammation is crucial to maintain homeostasis in the body. The contribution of fatty acids to the inflammatory process is exerted through a variety of mechanisms leading to cell surface modifications, activation of intracellular receptors that control inflammatory signaling processes, and changes in gene expression patterns. While long-chain saturated fatty acids induce NFkB pathway activation through TLR-4 binding, unsaturated fatty acids, such as monounsaturated, polyunsaturated and conjugated fatty acids anti-inflammatory ability is mediated through PPARs or GPR120. Moreover, these unsaturated fatty acids, especially omega-3 fatty acids, have immunomodulatory and cytoprotective potential, which is highly relevant for diseases with a neuroinflammatory component, such as obesity, Alzheimer's disease, multiple sclerosis and schizophrenia.

Alzheimer's disease (AD) is characterized by extracellular amyloid-b (Ab) deposition, which activates microglia, induces neuroinflammation and drives neurodegeneration. Recent evidence indicates that soluble pre-fibrillar Ab species, rather than insoluble fibrils, are the most toxic forms of Ab. Preventing soluble Ab formation represents, therefore, a major goal in AD. We investigated whether microvesicles (MVs) released extracellularly by reactive microglia may contribute to AD degeneration. We found that production of myeloid MVs, likely of microglial origin, is strikingly high in AD patients and in subjects with mild cognitive impairment and that AD MVs are toxic for cultured neurons. The mechanism responsible for MV neurotoxicity was defined in vitro using MVs produced by primary microglia. We demonstrated that neurotoxicity of MVs results from (i) the capability of MV lipids to promote formation of soluble Ab species from extracellular insoluble aggregates and (ii) from the presence of neurotoxic Ab forms trafficked to MVs after Ab internalization into microglia. MV neurotoxicity was neutralized by the Ab-interacting protein PrP and anti-Ab antibodies, which prevented binding to neurons of neurotoxic soluble Ab species. This study identifies microglia-derived MVs as a novel mechanism by which microglia participate in AD degeneration, and suggest new therapeutic strategies for the treatment of the disease.

This present study aimed to investigate the antibacterial screening of fatty acids (FAs) from Aegiceras corniculatum against human pathogens viz. Escherichia coli, Klebsiella pneumonia, Pseudomonas aeruginosa and Staphylococcus aureus. The leaf, stem, flower and pneumatophore of the species were used for the study. FAs were isolated as fatty acid methyl esters from the total extracts of A. Corniculatum and characterized using GC-FID for their compositions. Palmitic acid (C16:0) found to a chief constituent in the crude extracts of leaf, stem and flower. Whereas, In pneumatophore, methyl-cis-5,8,11,14- Eicosotetraenoic acid (PUFA, C20:4) was found to be predominant. Potential of fatty acid methyl ester against human pathogens were accessed using disc diffusion assay. Among the four pathogens investigated, fatty acid showed significant activity against Gram-negative K. pneumonia and moderate activity against Gram-positive S. aureus. In conclusion, FAs derived from A. corniculatum need...

In the first part of my thesis, I investigated the activation of erythrocyte nonselective cation (NSC) permeability and of sphingomyelinase by Plasmodium falciparum infection. Both are involved in programmed cell death in erythrocytes, also referred to as eryptosis [Lang et al., 2006; Lang et al., 2005], and meet four requirements for parasite growth at the same time: i) Development of an inwardly directed Na+ and an outwardly directed K+ ion gradient across the parasite plasma membrane, this in turn making the parasite dependent on high Na+ and low K+ ion concentration extracellularly [Brand et al., 2003]. ii) The presence of Ca2+ ions in the culture medium and a Ca2+ permeability conferred by a NSC conductance [Brand et al., 2003]. iii) Increased ceramide formation (detected in the blood of P. berghei ANKA infected mice). iv) Activity of parasitic neutral sphingomyelinase and host acid sphingomyelinase, probably to provide ceramide for membrane synthesis [Hanada et al., 2000]. In ...

Objectives The purpose of this study was to examine the bactericidal efficacy of hydrogen peroxide (H2O2) on Cutibacterium acnes (C. acnes). We hypothesize that H2O2 reduces the bacterial burden of C. acnes. Methods The effect of H2O2 was assessed by testing bactericidal effect, time course analysis, growth inhibition, and minimum bactericidal concentration. To assess the bactericidal effect, bacteria were treated for 30 minutes with 0%, 1%, 3%, 4%, 6%, 8%, or 10% H2O2 in saline or water and compared with 3% topical H2O2 solution. For time course analysis, bacteria were treated with water or saline (controls), 3% H2O2 in water, 3% H2O2 in saline, or 3% topical solution for 5, 10, 15, 20, and 30 minutes. Results were analyzed with a two-way analysis of variance (ANOVA) (p < 0.05). Results Minimum inhibitory concentration of H2O2 after 30 minutes is 1% for H2O2 prepared in saline and water. The 3% topical solution was as effective when compared with the 1% H2O2 prepared in saline o...

Retinal hyperpermeability and subsequent macular edema is a cardinal feature of early diabetic retinopathy (DR). Here, we investigated the role of bioactive lipid metabolites, in particular 12/15-lipoxygenase (12/15-LOX) derived metabolites, in this process. Liquid chromatography coupled to mass spectrometry (LC/MS) lipidomic screen of human retinal endothelial cells (HRECs) demonstrated that 15-HETE was the only significantly increased metabolite (2.4 fold, p = 0.0004) by high glucose (30mM) treatment. In the presence of arachidonic acid (AA), additional eicosanoids generated by 12/15-LOX, including 12- and 11-HETEs, were significantly increased. Fluorescein angiography (FA) and retinal albumin leakage showed a significant decrease in retinal hyperpermeability in streptozotocin-induced diabetic mice lacking 12/15-LOX compared to diabetic wild type (WT). Our previous studies demonstrated the potential role of NADPH in mediating the permeability effect of 12- and 15-HETEs, therefore ...

Retinal hyperpermeability and subsequent macular edema is a cardinal feature of early diabetic retinopathy (DR). Here, we investigated the role of bioactive lipid metabolites, in particular 12/15-lipoxygenase (12/15-LOX) derived metabolites, in this process. Liquid chromatography coupled to mass spectrometry (LC/MS) lipidomic screen of human retinal endothelial cells (HRECs) demonstrated that 15-HETE was the only significantly increased metabolite (2.4 fold, p = 0.0004) by high glucose (30mM) treatment. In the presence of arachidonic acid (AA), additional eicosanoids generated by 12/15-LOX, including 12- and 11-HETEs, were significantly increased. Fluorescein angiography (FA) and retinal albumin leakage showed a significant decrease in retinal hyperpermeability in streptozotocin-induced diabetic mice lacking 12/15-LOX compared to diabetic wild type (WT). Our previous studies demonstrated the potential role of NADPH in mediating the permeability effect of 12- and 15-HETEs, therefore ...

The enzyme fatty acid amide hydrolase (FAAH) catalyzes the in vivo degradation of the endocannabinoid anandamide, thus controlling its action at receptors. A novel FAAH inhibitor, AM3506, normalizes the elevated blood pressure and cardiac contractility of spontaneously hypertensive rats (SHR) without affecting these parameters in normotensive rats. These effects are due to blockade of FAAH and a corresponding rise in brain anandamide levels, resulting in CB 1 receptor-mediated decrease in sympathetic tone. The supersensitivity of SHR to CB 1 receptormediated cardiovascular depression is related to increased G protein coupling of CB 1 receptors. Importantly, AM3506 does not elicit hyperglycemia and insulin resistance seen with other FAAH inhibitors or in FAAH À/À mice, which is related to its inability to inhibit FAAH in the liver due to rapid hepatic uptake and metabolism. This unique activity profile offers improved therapeutic value in hypertension.

Skin and soft tissue infections (SSTIs) and acne are multi-factorial skin conditions that involve microbial invasion of the skin and underlying soft tissues; though, both have different pathogenesis. Most of these infections are caused by bacteria, affecting all age groups. Early diagnosis and appropriate antimicrobial therapy remain the cornerstone of management of SSTIs and acne. Over the years, an increase in antibiotic resistance has been reported with mupirocin and fusidic acid that makes the management of SSTIs and acne increasingly challenging. Further, these antibiotics are unable to penetrate biofilms and show their action on the microorganisms embedded deep in the polymeric matrix. In this review, we have discussed the current evidence on the efficacy and safety profile of nadifloxacin compared to other currently available antimicrobial agents. An extensive search was performed through PubMed and Medline using relevant key words. This article has highlighted nadifloxacin’s...

Alkylglycerols (alkyl-Gro) are ether lipids abundant in shark liver oil (SLO), and oral SLO or alkyl-Gro mix from this source have several in vivo biological activities including stimulation of haematopoiesis an immunological defences, or anti-tumour and anti-metastasis activities in vivo. Composition of natural alkyl-Gro mix contains several alkyl-Gro varying by chain length and unsaturation, and individual antitumour activity of each molecule present in natural mix remained unknown. We synthesized six prominent constituents of natural alkyl-Gro mix, namely 12:0, 14:0 16:0, 18:0, 16:1 n-7, and 18:1 n-9 alkyl-Gro. Using an in vivo model of grafted tumour in mice (3LL cells), we studied and compared the oral anti-tumour and anti-metastasis activities of each of these 6 alkyl-Gro. 16:1 and 18:1 alkyl-Gro showed strong activity in reducing lung metastasis number, while saturated alkyl-Gro had weaker (16:0) or no (12:0, 14:0, 18:0) effect. Spleen weights at day 20 after graft were also measured and showed tremendous variations depending on the treatment. Tumour graft resulted in a raise in spleen weight in control group, this raise was nearly abolished in 16:1 and 18:1 alkyl-Gro-treated mice, and was reduced in 14:0 and 16:0 alkyl-Gro-treated mice. Conversely, 18:0 alkyl-Gro-treated mice showed spleen weigh raise as compared with untreated grafted mice. These new data demonstrate a prominent role of unsaturation in the anti-tumour activities of alkyl-Gro.

Dendritic cells comprise a complex array of cell populations that play a leading role in immune defense. In an immature state, they have the capacity to sense and uptake different antigens. Upon capturing antigens, they become activated, mature, and migrate to lymph nodes where they present antigen-derived peptides to naïve T cells. Due to these excellent surveillance properties, dendritic cells play an important role against parasitic infections. Also, dendritic cells are an important source of IL-12, which is a fundamental proinflammatory cytokine in the control of intracellular parasites. The aim of this chapter is to review the most important characteristics and functions of dendritic cells and their role in the control of infection by parasites.

A special issue on immunology and cell biology of protozoa Infections caused by protozoan parasites are still a global health problem. Although protozoa are responsible for a significant morbidity and mortality in the developing world, they are also prevalent in the developed countries. Over many years protozoan parasites have evolved strategies to successfully invade the host and survive by evading the host immune response. Better understanding of the mechanisms of host invasion by protozoa and immune mechanisms responsible for resistance against these parasites is critical for designing new drugs and vaccines not only for preventing mortality but also for reducing the risk of spread of infection in the community. This special issue covers mini reviews and original research papers on our current understanding of immunology and cell biology of Trypanosoma,

Host-lipidome caters parasite interaction by acting as first line of recognition, attachment on the cell surface, intracellular trafficking, and survival of the parasite inside the host cell. Here, we summarize how protozoan parasites exploit host-lipidome by suppressing, augmenting, engulfing, remodeling and metabolizing lipids to achieve successful parasitism inside the host.

Alzheimer's disease (AD) is characterized by extracellular amyloid-b (Ab) deposition, which activates microglia, induces neuroinflammation and drives neurodegeneration. Recent evidence indicates that soluble pre-fibrillar Ab species, rather than insoluble fibrils, are the most toxic forms of Ab. Preventing soluble Ab formation represents, therefore, a major goal in AD. We investigated whether microvesicles (MVs) released extracellularly by reactive microglia may contribute to AD degeneration. We found that production of myeloid MVs, likely of microglial origin, is strikingly high in AD patients and in subjects with mild cognitive impairment and that AD MVs are toxic for cultured neurons. The mechanism responsible for MV neurotoxicity was defined in vitro using MVs produced by primary microglia. We demonstrated that neurotoxicity of MVs results from (i) the capability of MV lipids to promote formation of soluble Ab species from extracellular insoluble aggregates and (ii) from the presence of neurotoxic Ab forms trafficked to MVs after Ab internalization into microglia. MV neurotoxicity was neutralized by the Ab-interacting protein PrP and anti-Ab antibodies, which prevented binding to neurons of neurotoxic soluble Ab species. This study identifies microglia-derived MVs as a novel mechanism by which microglia participate in AD degeneration, and suggest new therapeutic strategies for the treatment of the disease.

Over the last two decades a large number of N-long-chain acyl amino acids have been identified in the mammalian body. The pharmacological activities of only a few of them have been investigated and some have been found to be of considerable interest. Thus arachidonoyl serine is vasodilatory and neuroprotective, arachidonoyl glycine is antinociceptive, and oleoyl serine rescues bone loss. However, the pathophysiological/biochemical roles of these amides are mostly unknown.

The present study was designed to investigate the possible prophylactic and therapeutic effect of cannabinoid receptors type1 (CB1) antagonist (AM251) on fructose-induced metabolic syndrome in rats, through administration of high fructose diet for 12 weeks. Prophylactic treatment by CB1-antagonist (AM251) significantly returned triglyceride, inflammatory, oxidative stress parameters and liver enzymes to the normal values while it significantly improved blood pressure, glucose, insulin, and IR and lipid profile but not significantly returned to the normal values. Interestingly, it significantly decreased body weight to values less than corresponding normal group. Histopathological findings confirmed that CB1-antagonist (AM251) in both prophylactic and therapeutic group improved histopathological changes of the liver and aorta induced by high fructose (60%) diet, with no drug had the upper hand of improvement of these histopathological changes.

Abstract: Bile acids are cholesterol-derived bioactive lipids that play essential roles in the maintenance of a heathy lifespan. These amphipathic molecules with detergent-like properties display numerous beneficial effects on various longevity- and healthspan-promoting processes in evolutionarily distant organisms. Recent studies revealed that lithocholic bile acid not only causes a considerable lifespan extension in yeast, but also exhibits a substantial cytotoxic effect in cultured cancer cells derived from different tissues and organisms. The molecular and cellular mechanisms underlying the robust anti-aging and anti-tumor effects of lithocholic acid have emerged. This review summarizes the current knowledge of these mechanisms, outlines the most important unanswered questions and suggests directions for future research.

Background: The interest in the mechanisms involved in Toxoplasma gondii lipid acquisition has steadily increased during the past few decades, but it remains not completely understood. Here, we investigated the biogenesis and the fate of lipid droplets (LD) of skeletal muscle cells (SkMC) during their interaction with T. gondii by confocal and electron microscopy. We also evaluated whether infected SkMC modulates the production of prostaglandin E 2 (PGE 2), cytokines interleukin-12 (IL-12) and interferon-gamma (INF-g), and also the cyclooxygenase-2 (COX-2) gene induction. Methods: Primary culture of skeletal muscle cells were infected with tachyzoites of T. gondii and analysed by confocal microscopy for observation of LD. Ultrastructural cytochemistry was also used for lipid and sarcoplasmatic reticulum (SR) detection. Dosage of cytokines (IL-12 and INF-g) by ELISA technique and enzyme-linked immunoassay (EIA) for PGE 2 measurement were employed. The COX-2 gene expression analysis was performed by real time reverse transcriptase polymerase chain reaction (qRT-PCR). Results: We demonstrated that T. gondii infection of SkMC leads to increase in LD number and area in a time course dependent manner. Moreover, the ultrastructural analysis demonstrated that SR and LD are in direct contact with parasitophorous vacuole membrane (PVM), within the vacuolar matrix, around it and interacting directly with the membrane of parasite, indicating that LD are recruited and deliver their content inside the parasitophorous vacuole (PV) in T. gondii-infected SkMC. We also observed a positive modulation of the production of IL-12 and IFN-g, increase of COX-2 mRNA levels in the first hour of T. gondii-SkMC interaction and an increase of prostaglandin E 2 (PGE 2) synthesis from 6 h up to 48 h of infection. Conclusions: Taken together, the close association between SR and LD with PV could represent a source of lipids as well as other nutrients for the parasite survival, and together with the increased levels of IL-12, INF-g and inflammatory indicators PGE 2 and COX-2 might contribute to the establishment and maintenance of chronic phase of the T. gondii infection in muscle cell.

The present study was designed to investigate the possible prophylactic and therapeutic effect of cannabinoid receptors type1 (CB1) antagonist (AM251) on fructose-induced metabolic syndrome in rats, through administration of high fructose diet for 12 weeks. Prophylactic treatment by CB1-antagonist (AM251) significantly returned triglyceride, inflammatory, oxidative stress parameters and liver enzymes to the normal values while it significantly improved blood pressure, glucose, insulin, and IR and lipid profile but not significantly returned to the normal values. Interestingly, it significantly decreased body weight to values less than corresponding normal group. Histopathological findings confirmed that CB1-antagonist (AM251) in both prophylactic and therapeutic group improved histopathological changes of the liver and aorta induced by high fructose (60%) diet, with no drug had the upper hand of improvement of these histopathological changes.

Background: Toxoplasma gondii, a common opportunistic protozoan, is a leading cause of illness and mortality among immunosuppressed individuals and during congenital infections. Current therapeutic strategies for toxoplasmosis are not fully effective at curtailing disease progression in these cases. Given the parasite ability to influence host immunity and metabolism, understanding of the metabolic alterations in the host's immune organs during T. gondii infection may enhance the understanding of the molecular mechanisms that define the pathophysiology of T. gondii infection. Methods: We investigated the global metabolic changes in the spleen of BALB/c mice at early and late stage of infection with T. gondii using LC-MS/MS-based metabolomics. Multivariate data analysis methods, principal components analysis (PCA) and partial least squares discriminant analysis (PLS-DA), were used to identify metabolites that are influenced by T. gondii infection. Results: Multivariate analyses clearly separated the metabolites of spleen of infected and control mice. A total of 132 differential metabolites were identified, 23 metabolites from acutely infected versus control mice and 109 metabolites from chronically infected versus control mice. Lipids, hormones, lactones, acids, peptides, antibiotics, alkaloids and natural toxins were the most influenced chemical groups. There were 12 shared differential metabolites between acutely infected versus control mice and chronically infected versus control mice, of which 4,4-Dimethyl-5alpha-cholesta-8,14,24-trien-3beta-ol was significantly upregulated and ubiquinone-8 was significantly downregulated. Major perturbed metabolic pathways included primary bile acid biosynthesis, steroid hormone biosynthesis, biotin metabolism, and steroid biosynthesis, with arachidonic acid metabolism being the most significantly impacted pathway. These metabolic changes suggest a multifactorial nature of the immunometabolic responses of mouse spleen to T. gondii infection. Conclusions: This study demonstrated that T. gondii infection can cause significant metabolomic alterations in the spleen of infected mice. These findings provide new insights into the molecular mechanisms that underpin the pathogenesis of T. gondii infection.

In order to exploit the potential benefits of antimicrobial combination therapy, we need a better understanding of the circumstances under which pharmacodynamic interactions expected. In this study, Pharmacodynamic interactions between silver nanoparticle (SNP) and topical antibiotics such as Cefazolin (CEF), Mupirocin (MUP), Gentamycin (GEN), Neomycin (NEO), Tetracycline (TET), Vancomycin (VAN) were investigated using the MIC test, Combination assay followed by Fractional Inhibitory concentration Index and Agar well diffusion method. SNP + MUP, SNP + NEO, SNP + VAN combinations showed Synergism (SN) and SNP + CEF, SNP + GEN, SNP + TET showed Partial synergism (PS) against Staphylococcus aureus. Four combinations (SNP + CEF, SNP + MUP, SNP + GEN, SNP + VAN) showed SN, SNP + TET showed PS and Indifferent effect (ID) were observed for SNP + NEO against Pseudomonas aeruginosa. SN was observed for SNP + CEF, SNP + GEN, SNP + NEO, SNP + TET and SNP + MUP showed ID, SNP + VAN showed PS against Escherichia coli. In addition, we elucidated the possible mechanism involved in the pharmacodynamic interaction between SNP-topical antibiotics by increased ROS level, membrane damage following protein release, K + leakage and biofilm inhibition. Thus, our findings support that conjugation of the SNP with topical antibiotics have great potential in the topical formulation when treating complex resistant bacterial infections and where there is a need of more concentration to kill pathogenic bacteria.

A special issue on immunology and cell biology of protozoa Infections caused by protozoan parasites are still a global health problem. Although protozoa are responsible for a significant morbidity and mortality in the developing world, they are also prevalent in the developed countries. Over many years protozoan parasites have evolved strategies to successfully invade the host and survive by evading the host immune response. Better understanding of the mechanisms of host invasion by protozoa and immune mechanisms responsible for resistance against these parasites is critical for designing new drugs and vaccines not only for preventing mortality but also for reducing the risk of spread of infection in the community. This special issue covers mini reviews and original research papers on our current understanding of immunology and cell biology of Trypanosoma,

A special issue on immunology and cell biology of protozoa Infections caused by protozoan parasites are still a global health problem. Although protozoa are responsible for a significant morbidity and mortality in the developing world, they are also prevalent in the developed countries. Over many years protozoan parasites have evolved strategies to successfully invade the host and survive by evading the host immune response. Better understanding of the mechanisms of host invasion by protozoa and immune mechanisms responsible for resistance against these parasites is critical for designing new drugs and vaccines not only for preventing mortality but also for reducing the risk of spread of infection in the community. This special issue covers mini reviews and original research papers on our current understanding of immunology and cell biology of Trypanosoma,

Vector-borne illnesses comprise a significant portion of human maladies, representing 17% of global infections. Transmission of vector-borne pathogens to mammals primarily occurs by hematophagous arthropods. It is speculated that blood may provide a unique environment that aids in the replication and pathogenesis of these microbes. Lipids and their derivatives are one component enriched in blood and are essential for microbial survival. For instance, the malarial parasite Plasmodium falciparum and the Lyme disease spirochete Borrelia burgdorferi, among others, have been shown to scavenge and manipulate host lipids for structural support, metabolism, replication, immune evasion, and disease severity. In this Review, we will explore the importance of lipid hijacking for the growth and persistence of these microbes in both mammalian hosts and arthropod vectors.

Keywords: Arylalkylamine N-acyltransferase Arylalkylamine N-acetyltransferase N-acyldopamine N-acylserotonin Thorax-abdomen Steady-state kinetics Drosophila melanogaster a b s t r a c t Arylalkylamine N-acyltransferase-like 2 2 (AANATL2) from Drosophila melanogaster was expressed and shown to catalyze the formation of long-chain N-acylserotonins and N-acydopamines. Subsequent identification of endogenous amounts of N-acylserotonins and colocalization of these fatty acid amides and AANATL2 transcripts gives supporting evidence that AANATL2 has a role in the biosynthetic formation of these important cell signalling lipids. (D.J. Merkler). 1 Co-first authorship. The authors recommend the change of arylalkylamine N-acetyltransferase to arylalkylamine N-acyltransferase due to the discovery of acyl-CoA substrates longer than C2 (acetyl). FEBS Letters 588 (2014) 594-599 j o u r n a l h o m e p a g e : w w w . F E B S L e t t e r s . o r g

A large and growing family of over 70 endogenous lipids of the basic structure N-acyl amide has been identified during the last 10 years. Only a few of these lipids have been characterized for biological activity, however, those that have shown a wide range of activity may act at G-protein coupled receptors (GPCRs). Like orphan GPCRs that are identified as being in the genome and expressed in tissue, the majority of these endogenous lipids many produced throughout the body, some predominately in nervous tissue, remain orphaned. Here, we give a brief history of these orphan lipids and highlight the activity of N-arachidonoyl glycine, and farnesyl pyrophosphate at the orphan receptors GPR18 and GPR92 respectively as well as summarizing the biological and pharmacological data for the recently identified N-palmitoyl glycine that suggests activity at a novel GPCR. Working to deorphanize both lipids and GPCRs together provides a unique opportunity for a greater understanding of cellular signaling and a challenge to find them all a home.

Host-lipidome caters parasite interaction by acting as first line of recognition, attachment on the cell surface, intracellular trafficking, and survival of the parasite inside the host cell. Here, we summarize how protozoan parasites exploit host-lipidome by suppressing, augmenting, engulfing, remodeling and metabolizing lipids to achieve successful parasitism inside the host.

The enzyme fatty acid amide hydrolase (FAAH) catalyzes the in vivo degradation of the endocannabinoid anandamide, thus controlling its action at receptors. A novel FAAH inhibitor, AM3506, normalizes the elevated blood pressure and cardiac contractility of spontaneously hypertensive rats (SHR) without affecting these parameters in normotensive rats. These effects are due to blockade of FAAH and a corresponding rise in brain anandamide levels, resulting in CB 1 receptor-mediated decrease in sympathetic tone. The supersensitivity of SHR to CB 1 receptormediated cardiovascular depression is related to increased G protein coupling of CB 1 receptors. Importantly, AM3506 does not elicit hyperglycemia and insulin resistance seen with other FAAH inhibitors or in FAAH À/À mice, which is related to its inability to inhibit FAAH in the liver due to rapid hepatic uptake and metabolism. This unique activity profile offers improved therapeutic value in hypertension.

New compounds are needed to treat acne and superficial infections caused by Propionibacterium acnes and Staphylococcus aureus due to the reduced effectiveness of agents used at present. Long-chain polyunsaturated fatty acids (LC-PUFAs) are attracting attention as potential new topical treatments for Gram-positive infections due to their antimicrobial potency and anti-inflammatory properties. This present study aimed to investigate the antimicrobial effects of six LC-PUFAs against P. acnes and S. aureus to evaluate their potential to treat infections caused by these pathogens. Minimum inhibitory concentrations were determined against P. acnes and S. aureus, and the LC-PUFAs were found to inhibit bacterial growth at 32–1024 mg/L. Generally, P. acnes was more susceptible to the growth inhibitory actions of LC-PUFAs, but these compounds were bactericidal only for S. aureus. This is the first report of antibacterial activity attributed to 15-hydroxyeicosapentaenoic acid (15-OHEPA) and 15-hydroxyeicosatrienoic acid (HETrE), while the anti-P. acnes effects of the six LC-PUFAs used herein are novel observations. During exposure to the LC-PUFAs, S. aureus cells were killed within 15–30 min. Checkerboard assays demonstrated that the LC-PUFAs did not antagonise the antimicrobial potency of clinical agents used presently against P. acnes and S. aureus. However, importantly, synergistic interactions against S. aureus were detected for combinations of benzoyl peroxide with 15-OHEPA, dihomo-γ-linolenic acid (DGLA) and HETrE; and neomycin with 15-OHEPA, DGLA, eicosapentaenoic acid, γ-linolenic acid and HETrE. In conclusion, LC-PUFAs warrant further evaluation as possible new agents to OPEN ACCESS Mar. Drugs 2013, 11 4545 treat skin infections caused by P. acnes and S. aureus, especially in synergistic combinations with antimicrobial agents already used clinically.

The obligate intracellular liver stage of the Plasmodium parasite represents a bottleneck in the parasite life cycle and remains a promising target for therapeutic intervention. During this stage, parasites undergo dramatic morphological changes and achieve one of the fastest replication rates among eukaryotic species. Nevertheless, relatively little is known about the parasite interactions with the host hepatocyte. Using immunofluorescence, live cell imaging and electron microscopy, we show that Plasmodium berghei parasites are surrounded by vesicles from the host late endocytic pathway. We found that these vesicles are acidic and contain the membrane markers Rab7a, CD63 and LAMP1. When host cell vesicle acidification was disrupted using ammonium chloride or Concanamycin A during the late liver stage of infection, parasite survival was not affected, but schizont size was significantly decreased. Furthermore, when the host cell endocytic pathway was loaded with BSA-gold, gold particles were found within the parasite cytoplasm, showing the transport of material from the host endocytic pathway toward the parasite interior. These observations reveal a novel Plasmodium-host interaction and suggest that vesicles from the host endolysosomal pathway could represent an important source of nutrients exploited by the fastgrowing late liver stage parasites.

The enzyme fatty acid amide hydrolase (FAAH) catalyzes the in vivo degradation of the endocannabinoid anandamide, thus controlling its action at receptors. A novel FAAH inhibitor, AM3506, normalizes the elevated blood pressure and cardiac contractility of spontaneously hypertensive rats (SHR) without affecting these parameters in normotensive rats. These effects are due to blockade of FAAH and a corresponding rise in brain anandamide levels, resulting in CB 1 receptor-mediated decrease in sympathetic tone. The supersensitivity of SHR to CB 1 receptormediated cardiovascular depression is related to increased G protein coupling of CB 1 receptors. Importantly, AM3506 does not elicit hyperglycemia and insulin resistance seen with other FAAH inhibitors or in FAAH À/À mice, which is related to its inability to inhibit FAAH in the liver due to rapid hepatic uptake and metabolism. This unique activity profile offers improved therapeutic value in hypertension.

Over the last two decades a large number of N-long-chain acyl amino acids have been identified in the mammalian body. The pharmacological activities of only a few of them have been investigated and some have been found to be of considerable interest. Thus arachidonoyl serine is vasodilatory and neuroprotective, arachidonoyl glycine is antinociceptive, and oleoyl serine rescues bone loss. However, the pathophysiological/biochemical roles of these amides are mostly unknown.

Host-lipidome caters parasite interaction by acting as first line of recognition, attachment on the cell surface, intracellular trafficking, and survival of the parasite inside the host cell. Here, we summarize how protozoan parasites exploit host-lipidome by suppressing, augmenting, engulfing, remodeling and metabolizing lipids to achieve successful parasitism inside the host.

Host-lipidome caters parasite interaction by acting as first line of recognition, attachment on the cell surface, intracellular trafficking, and survival of the parasite inside the host cell. Here, we summarize how protozoan parasites exploit host-lipidome by suppressing, augmenting, engulfing, remodeling and metabolizing lipids to achieve successful parasitism inside the host.

Syzygium polyanthum (Wight) Walp. var. polyanthum leaves are consumed as a traditional Malay treatment of hypertension. This study investigates hypotensive potential of aqueous (AESP) and residual methanolic (met-AESP) extracts of S. polyanthum leaves
and possible involvement of autonomic receptors. AESP and met-AESP (20 to 100mg/kg) were intravenously administered into anaesthetized Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats. Blood pressure and heart were monitored for
20 min. AESP and met-AESP induced significant dose-dependent hypotension, but only 100mg/kg AESP caused mild bradycardia (n = 5). AESP-induced hypotension was more potent than that of met-AESP in WKY. AESP has a faster onset time than
that of met-AESP in both WKY and SHR. However, met-AESP-induced hypotension was more sustained than that of AESP in SHR. Blockages of autonomic ganglion and alpha-adrenergic receptors using hexamethonium and phentolamine (n= 5 for each group) partially attenuated AESP-induced hypotension, suggesting involvement of alpha-adrenergic receptors. Blockages of autonomic
ganglion, alpha-adrenergic, cholinergic receptors, and nitric oxide production using hexamethonium, propranolol, atropine, and L-NAME (n = 5 for each group) partially attenuated met-AESP-induced hypotension, suggesting
involvement of alpha-adrenergic and cholinergic receptors via nitric oxide production

The enzyme fatty acid amide hydrolase (FAAH) catalyzes the in vivo degradation of the endocannabinoid anandamide, thus controlling its action at receptors. A novel FAAH inhibitor, AM3506, normalizes the elevated blood pressure and cardiac contractility of spontaneously hypertensive rats (SHR) without affecting these parameters in normotensive rats. These effects are due to blockade of FAAH and a corresponding rise in brain anandamide levels, resulting in CB1 receptor-mediated decrease in sympathetic tone. The supersensitivity of SHR to CB1 receptor-mediated cardiovascular depression is related to increased G protein coupling of CB1 receptors. Importantly, AM3506 does not elicit hyperglycemia and insulin resistance seen with other FAAH inhibitors or in FAAH−/− mice, which is related to its inability to inhibit FAAH in the liver due to rapid hepatic uptake and metabolism. This unique activity profile offers improved therapeutic value in hypertension.► Unique pharmacological profile of novel fatty acid amide hydrolase inhibitor ► Selectivity of AM3506 in FAAH inhibition in brain over liver in vivo ► AM3506 as centrally acting antihypertensive agent with minimal cardiovascular effects under normotensive conditions and without adverse metabolic effects