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Mitochondria are an autonomous organelle that plays a crucial role in the metabolic aspects of a cell. Cortical spreading depression (CSD) and fluctuations in the cerebral blood flow have for long been mechanisms underlying migraine. It is a neurovascular disorder with a unilateral manifestation of disturbing, throbbing and pulsating head pain. Migraine affects 2.6% and 21.7% of the general population and is the major cause of partial disability in the age group 15-49. Higher mutation rates, imbalance in concentration of physiologically relevant molecules and oxidative stress biomarkers have been the main themes of discussion in determining the role of mitochondrial disability in migraine. The correlation of migraine with other disorders like hemiplegic migraine; mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes [MELAS]; tension-type headache (TTH); cyclic vomiting syndrome (CVS), ischaemic stroke; and hypertension has helped in the assessment of the physiological and morphogenetic basis of migraine. Here, we have reviewed the different nuances of mitochondrial dysfunction and migraine. The different mtDNA polymorphisms that can affect the generation and transmission of nerve impulse has been highlighted and supported with research findings. In addition to this, the genetic basis of migraine pathogenesis as a consequence of mutations in nuclear DNA that can, in turn, affect the synthesis of defective mitochondrial proteins is discussed along with a brief overview of epigenetic profile. This review gives an overview of the pathophysiology of migraine and explores mitochondrial dysfunction as a potential underlying mechanism. Also, therapeutic supplements for managing migraine have been discussed at different junctures in this paper.

Significance While increasing evidence associates the disruption of circadian rhythms with pathologic conditions, including obesity, type 2 diabetes, and nonalcoholic fatty liver diseases (NAFLD), the involved mechanisms are still poorly described. Here, we show that, in both humans and mice, the pathogenesis of NAFLD is associated with the disruption of the circadian clock combined with perturbations of the growth hormone and sex hormone pathways. However, while this condition protects mice from the development of fibrosis and insulin resistance, it correlates with increased fibrosis in humans. This suggests that the perturbation of the circadian clock and its associated disruption of the growth hormone and sex hormone pathways are critical for the pathogenesis of metabolic and liver diseases.

The Coronavirus disease 2019 (COVID-19) pandemic is overwhelming the healthcare systems. Identification of systemic reactions underlying COVID-19 will lead to new biomarkers and therapeutic targets for monitoring and early intervention in this viral infection. We performed targeted metabolomics covering up to 630 metabolites within several key metabolic pathways in plasma samples of 20 hospitalized COVID-19 patients and 37 matched controls. Plasma metabolic signatures specifically differentiated severe COVID-19 from control patients. The identified metabolic signatures indicated distinct alterations in both lipid and amino acid metabolisms in COVID-19 compared to control patient plasma. Systems biology-based analyses identified sphingolipid, tryptophan, tyrosine, glutamine, arginine, and arachidonic acid metabolism as mostly impacted pathways in COVID-19 patients. Notably, gamma-aminobutyric acid (GABA) was significantly reduced in COVID-19 patients and GABA plasma levels allowed for stratification of COVID-19 patients with high sensitivity and specificity. The data reveal large metabolic disturbances in COVID-19 patients and suggest use of GABA as potential biomarker and therapeutic target for the infection. Supplementary information The online version contains supplementary material available at 10.1007/s00109-022-02177-4.

Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases worldwide and is often associated with aspects of metabolic syndrome. Despite its prevalence and the importance of early diagnosis, there is a lack of robustly validated biomarkers for diagnosis, prognosis and monitoring of disease progression in response to a given treatment. In this Review, we provide an overview of the contribution of metabolomics and lipidomics in clinical studies to identify biomarkers associated with NAFLD and nonalcoholic steatohepatitis (NASH). In addition, we highlight the key metabolic pathways in NAFLD and NASH that have been identified by metabolomics and lipidomics approaches and could potentially be used as biomarkers for non-invasive diagnostic tests. Overall, the studies demonstrated alterations in amino acid metabolism and several aspects of lipid metabolism including circulating fatty acids, triglycerides, phospholipids and bile acids. Although we report several studies that identified potential biomarkers, few have been validated.

Adaptive metabolic response to injury includes the utilization of alternative energy substrates – such as ketone bodies (KB) – to protect the brain against further damage. Here, we examined cerebral ketone metabolism in patients with traumatic brain injury (TBI; n = 34 subjects) monitored with cerebral microdialysis to measure total brain interstitial tissue KB levels (acetoacetate and β-hydroxybutyrate). Nutrition – from fasting vs. stable nutrition state – was associated with a significant decrease of brain KB (34.7 [10th–90th percentiles 10.7–189] µmol/L vs. 13.1 [6.5–64.3] µmol/L, p

Resolution of inflammation in the periphery was once thought to be a passive process, but new research now suggests it is an active process mediated by specialized pro-resolving lipid mediators (SPM) derived from omega-3 polyunsaturated fatty acids (n-3 PUFA). However, this has yet to be illustrated in neuroinflammation. The purpose of this study was to measure resolution of neuroinflammation and to test whether increasing brain docosahexaenoic acid (DHA) affects the resolution of neuroinflammation. C57Bl/6 mice, fat-1 mice and their wildtype littermates, fed either fish oil or safflower oil, received lipopolysaccharide (LPS) in the left lateral ventricle. Animals were then euthanized at various time points for immunohistochemistry, gene expression, and lipidomic analyses. Peak microglial activation was observed at 5 days post-surgery and the resolution index was 10 days. Of the approximately 350 genes significantly changed over the 28 days post LPS injection, 130 were uniquely changed at 3 days post injection. No changes were observed in the bioactive mediator pools. However, a few lysophospholipid species were decreased at 24hr post surgery. When brain DHA is increased, microglial cell density did not resolve faster and did not alter gene expression. In conclusion, resolution of neuroinflammation appears to be independent of SPM. Increasing brain DHA had no effect in this model.

The gut microbiome and lipid metabolism are both recognized as essential components in the maintenance of metabolic health. The mechanisms involved are multifactorial and (especially for microbiome) poorly defined. A strategic approach to investigate the complexity of the microbial influence on lipid metabolism would facilitate determination of relevant molecular mechanisms for microbiome-targeted therapeutics. E. coli is associated with obesity and metabolic syndrome and we used this association in conjunction with gnotobiotic models to investigate the impact of E. coli on lipid metabolism. To address the complexities of the integration of the microbiome and lipid metabolism, we developed transcriptomics-driven lipidomics (TDL) to predict the impact of E. coli colonization on lipid metabolism and established mediators of inflammation and insulin resistance including arachidonic acid metabolism, alterations in bile acids and dietary lipid absorption. A microbiome-related therapeutic approach targeting these mechanisms may therefore provide a therapeutic avenue supporting maintenance of metabolic health., Integrative Lipidomics: Microbiome regulation of lipid metabolism Microbes multifactorially impact host lipid metabolism bearing a significant impact in health and disease. A team led by Mojgan Masoodi and Scott Parkinson at Nestlé Institute of Health Sciences (NIHS) developed an integrative data driven approach for predictive lipidomics investigations of host-microbial impacts on lipid metabolism. Results of in-vivo studies with germ-free mice inoculated with E. coli and in-vitro studies demonstrated the multifactorial nature of the impact of E. coli on arachidonic acid metabolism in the ileum and altered host inflammation and lipid absorption. The findings provide insights into understanding the host-microbiome interactions and identifying microbiome-related solutions for maintaining health and tackling disease. The systems approach presented is applicable to investigate broad range of microbiome dependent and independent alterations in host lipid metabolism.

A dysregulated response to systemic inflammation is a common pathophysiological feature of most conditions encountered in the intensive care unit (ICU). Recent evidence indicates that a dysregulated inflammatory response is involved in the pathogenesis of various ICU-related disorders associated with high mortality, including sepsis, acute respiratory distress syndrome, cerebral and myocardial ischemia, and acute kidney injury. Moreover, persistent or non-resolving inflammation may lead to the syndrome of persistent critical illness, characterized by acquired immunosuppression, catabolism and poor long-term functional outcomes. Despite decades of research, management of many disorders in the ICU is mostly supportive, and current therapeutic strategies often do not take into account the heterogeneity of the patient population, underlying chronic conditions, nor the individual state of the immune response. Fatty acid-derived lipid mediators are recognized as key players in the generation and resolution of inflammation, and their signature provides specific information on patients’ inflammatory status and immune response. Lipidomics is increasingly recognized as a powerful tool to assess lipid metabolism and the interaction between metabolic changes and the immune system via profiling lipid mediators in clinical studies. Within the concept of precision medicine, understanding and characterizing the individual immune response may allow for better stratification of critically ill patients as well as identification of diagnostic and prognostic biomarkers. In this review, we provide an overview of the role of fatty acid-derived lipid mediators as endogenous regulators of the inflammatory, anti-inflammatory and pro-resolving response and future directions for use of clinical lipidomics to identify lipid mediators as diagnostic and prognostic markers in critical illness.

Infections after surgical interventions are assumed to be caused by contamination. We show by analyzing multicentric data of 6561 patients that surgical infections as well as sepsis had a predominantly enteric microbial signature irrespective of the type of surgery, suggesting failure of intestinal bacterial compartmentalization. In mice, we reveal that hepatic surgery induced dysregulation of intestinal and hepatic type 3 innate lymphoid cells (ILC3s) and intestinal leakage resulting in enteric bacterial translocation via lymphatic vessels. In the absence of hepatic ILC3s, inflammasome activation and the induction of antimicrobial peptide encoding genes, bacteria colonized remote systemic organs and impaired surgical outcomes. Conversely, mammalian-microbial commensalism is required for the education of host immunity to ensure optimal hepatic healing responses. In fact, microbial-derived products were sufficient for the induction of proliferative transcriptional networks in the mouse liver, as illustrated by serum transfer experiments, mass spectrometry and RNA expression analysis, indicating that the balanced exposure of the host to commensals is essential for recovery. This study reveals the intestinal origin of microbes causing complications after surgical interventions and highlights host protective mechanisms of controlled commensalism that prevent infections.One Sentence SummaryIntestinal bacteria cause surgical infections

Rationale Long-chain fatty acyl-coenzyme As (FA-CoAs) are important bioactive molecules, playing key roles in biosynthesis of fatty acids, membrane trafficking and signal transduction. Development of sensitive analytical methods for profiling theses lipid species in various tissues is critical to understand their biological activity. A high-pressure liquid chromatography/tandem mass spectrometry method has been developed for the quantitative analysis and screening of long-chain FACoAs in liver, brain, muscle and adipose tissue. Methods The sample preparation method consists of tissue homogenization, extraction with organic solvent and reconstitution in an ammonium hydroxide buffer. Extracts are separated by liquid chromatography (LC) on a reversed-phase column and detected by electrospray ionization tandem mass spectrometry (ESI-MS/MS) in positive mode. An additional neutral loss scan allows for untargeted FA-CoAs screening. Results Extraction was optimized for low sample load (10 mg) of four tissue types (liver, brain, muscle and adipose tissue) with recoveries between 60–140% depending on the analyte and tissue type. Targeted quantification was validated for ten FA-CoAs in the range 0.1–500 ng/mL with accuracies between 85–120%. Conclusions We have developed and validated a LC/MS/MS method for the quantifications and screening of long-chain FA-CoAs in four different types of mammalian tissue. The extraction method is straightforward and long-chain FA-CoA species can be quantified using only minimum amount of tissue. Copyright © 2016 John Wiley & Sons, Ltd.

Background An aim of weight loss is to reduce the risk of type 2 diabetes (T2D) in obese subjects. However, the relation with long-term glycemic improvement remains unknown. Objective We evaluated the changes in lipid composition during weight loss and their association with long-term glycemic improvement. Design We investigated the plasma lipidome of 383 obese, nondiabetic patients within a randomized, controlled dietary intervention in 8 European countries at baseline, after an 8-wk low-caloric diet (LCD) (800-1000 kcal/d), and after 6 mo of weight maintenance. Results After weight loss, a lipid signature identified 2 groups of patients who were comparable at baseline but who differed in their capacities to lose weight and improve glycemic control. Six months after the LCD, one group had significant glycemic improvement [homeostasis model assessment of insulin resistance (HOMA-IR) mean change: -0.92; 95% CI: -1.17, -0.67)]. The other group showed no improvement in glycemic control (HOMA-IR mean change: -0.26; 95% CI: -0.64, 0.13). These differences were sustained for ≥1 y after the LCD. The same conclusions were obtained with other endpoints (Matsuda index and fasting insulin and glucose concentrations). Significant differences between the 2 groups were shown in leptin gene expression in adipose tissue biopsies. Significant differences were also observed in weight-related endpoints (body mass index, weight, and fat mass). The lipid signature allowed prediction of which subjects would be considered to be insulin resistant after 6 mo of weight maintenance [validation's receiver operating characteristic (ROC) area under the curve (AUC): 71%; 95% CI: 62%, 81%]. This model outperformed a clinical data-only model (validation's ROC AUC: 61%; 95% CI: 50%, 71%; P = 0.01). Conclusions In this study, we report a lipid signature of LCD success (for weight and glycemic outcome) in obese, nondiabetic patients. Lipid changes during an 8-wk LCD allowed us to predict insulin-resistant patients after 6 mo of weight maintenance. The determination of the lipid composition during an LCD enables the identification of nonresponders and may help clinicians manage metabolic outcomes with further intervention, thereby improving the long-term outcome and preventing T2D. This trial was registered at clinicaltrials.gov as NCT00390637.

Scope Docosahexaenoic acid (DHA, 22:6n-3) is crucial for optimal neuronal development and function, but the brain has a poor capacity to synthesize this fatty acid. When consumed acutely esterified to phosphatidylcholine, DHA is more efficient at targeting the brain than when consumed esterified to triacylglycerol. However, the brain DHA bioavailability of other forms of DHA-containing phospholipids, after oral ingestion, is unknown. The objective of this study is to compare brain uptake of DHA after acute gavage with different DHA carriers. Methods and results Ten-week-old rats were gavaged with 3 H-labeled DHA esterified to phosphatidylcholine (DHA-PtdCho), phosphatidylethanolamine (DHA-PtdEtn), phosphatidylserine (DHA-PtdSer) or triacylglycerol (DHA-TG). Six hours post-gavage, the animals were euthanized and radioactivity was quantified in the cortex and serum lipid classes. Radioactivity recovered in cortex total phospholipids was similar between the DHA-PtdCho and DHA-PtdSer groups and were 5.8 and 6.7 times higher than in the DHA-TG group, respectively. Serum total lipid radioactivity was higher in the DHA-PtdSer group than in the DHA-PtdCho and DHA-PtdEtn groups, but not compared to the DHA-TG group. Conclusion These results suggest that different mechanisms must be present to explain the serum and brain bioavailability differences between DHA-PtdCho and DHA-PtdSer, but these require further investigation.

Ketones represent an important alternative fuel for the brain under glucose hypo-metabolic conditions induced by neurological diseases or aging, however their metabolic consequences in healthy brains remain unclear. Here we report that ketones can increase the redox NAD+/NADH ratio in the resting brain of healthy young adults. As NAD is an important energetic and signaling metabolic modulator, these results provide mechanistic clues on how nutritional ketosis might contribute to the preservation of brain health.

Nonesterified fatty acids are important biological molecules which have multiple functions such as energy storage, gene regulation, or cell signaling. Comprehensive profiling of nonesterified fatty acids in biofluids can facilitate studying and understanding their roles in biological systems. For these reasons, we have developed and validated a high-throughput, nontargeted lipidomics method coupling liquid chromatography to high-resolution mass spectrometry for quantitative analysis of nonesterified fatty acids. Sufficient chromatographic separation is achieved to separate positional isomers such as polyunsaturated and branched-chain species and quantify a wide range of nonesterified fatty acids in human plasma samples. However, this method is not limited only to these fatty acid species and offers the possibility to perform untargeted screening of additional nonesterified fatty acid species.

The microbiome has been demonstrated to play an integral role in the maintenance of many aspects of health that are also associated with aging. In order to identify areas of potential exploration and intervention, we simultaneously characterized age-related alterations in gut microbiome, muscle physiology and serum proteomic and lipidomic profiles in aged rats to define an integrated signature of the aging phenotype. We demonstrate that aging skews the composition of the gut microbiome, in particular by altering the Sutterella to Barneseilla ratio, and alters the metabolic potential of intestinal bacteria. Age-related changes of the gut microbiome were associated with the physiological decline of musculoskeletal function, and with molecular markers of nutrient processing/availability, and inflammatory/immune status in aged versus adult rats. Altogether, our study highlights that aging leads to a complex interplay between the microbiome and host physiology, and provides candidate microbial species to target physical and metabolic decline during aging by modulating gut microbial ecology.

Recent studies suggest that at least two pools of plasma docosahexaenoic acid (DHA) can supply the brain: non-esterified DHA (NE-DHA) and lysophosphatidylcholine (lysoPtdCho)-DHA. In contrast to NE-DHA, brain uptake of lysoPtdCho-DHA appears to be mediated by a specific transporter, but whether both forms of DHA supply undergo the same metabolic fate, particularly with regards to enrichment of specific phospholipid (PL) subclasses, remains to be determined. This study aimed to evaluate brain uptake of NE-DHA and lysoPtdCho-DHA into brain PL classes. Fifteen-week-old rats were infused intravenously with radiolabelled NE-14C-DHA or lysoPtdCho-14C-DHA (n=4/group) over five mins to achieve a steady-state plasma level. PLs were extracted from the brain and separated by thin layer chromatography and radioactivity was quantified by liquid scintillation counting. The net rate of entry of lysoPtdCho-DHA into the brain was between 59% and 86% lower than the net rate of entry of NE-DHA, depending on the PL class. The proportion of total PL radioactivity in the lysoPtdCho-14C-DHA group compared to the NE-14C-DHA group was significantly higher in choline glycerophospholipids (ChoGpl) (48% vs 28%, respectively) but lower in ethanolamine glycerophospholipids (EtnGpl) (32% vs 46%, respectively). In both groups, radioactivity was disproportionally high in phosphatidylinositol and ChoGpl but low in phosphatidylserine and EtnGpl compared to the corresponding DHA pool size. This suggests that DHA undergoes extensive PL remodeling after entry into the brain.

Oleoylethanolamide (OEA) is a bioactive lipid that stimulates nuclear and G protein-coupled receptors and regulates appetite and fat metabolism. It has not previously been shown to have a role in cancer. However, a mass spectrometry-based lipidomics platform revealed the presence of high amounts of OEA in the plasma of chronic lymphocytic leukemia (CLL) patients compared with normal donors. CLL cells produced OEA and the magnitude of plasma OEA levels was related directly to the circulating leukemic cell number. OEA from CLL cells was increased by URB-597, an inhibitor of fatty acid amide hydrolase (FAAH), and decreased by inflammatory mediators that downregulate expression of N-acylphosphatidylethanolamine-specific phospholipase D (NAPE-PLD). These enzymes degrade and synthesize OEA, respectively. Nonphysiologic doses of OEA prevented spontaneous apoptosis of CLL cells in a receptor-independent manner that was mimicked by its free fatty acid (FFA) derivative oleate. However, OEA-containing supernatants from CLL cells induced lipolysis in adipocytes, lipid products from adipocytes protected CLL cells from cytotoxic chemotherapy, and increased levels of FFAs were found in CLL plasma that correlated with OEA. We suggest OEA is a lipolytic factor produced by CLL cells to fuel their growth with a potential role in drug resistance and cancer cachexia.

The polyunsaturated fatty acids (PUFA) arachidonic acid (AA, n-6) and eicosapentaenoic acid (EPA, n-3) are precursors of eicosanoids and other lipid mediators which have critical roles in inflammation. The mediators formed from the different PUFA have different potencies. We hypothesised that metabolic changes associated with colonic mucosal inflammation would modify the bioavailability of the eicosanoid precursors AA and EPA.Colonic mucosa biopsies were obtained from patients with ulcerative colitis and from matched controls. Inflammation was graded endoscopically and histologically. Esterified and non-esterified fatty acids were determined within the biopsies using gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry, respectively.Biopsy samples were collected from 69 UC patients (54 providing both inflamed and non-inflamed mucosa) and 69 controls. Inflamed mucosa had higher AA (p0.001) and lower EPA (p0.010) contents and a higher AA:EPA ratio (p0.001). Inflamed mucosa also had higher docosapentaenoic acid (DPA) and docosahexaenoic acid (DHA) and lower linoleic acid (LA) and α-linolenic acid (α-LNA) contents (all p0.001), compared to non-inflamed and controls. There were significant correlations between severity of inflammation and contents of AA, DPA and DHA (positive correlations) and of LA, α-LNA and EPA (negative correlations).Higher AA, AA:EPA ratio, DPA and DHA and lower LA, α-LNA and EPA are seen in inflamed mucosa in UC and correlate with severity of inflammation. This suggests an alteration in fatty acid metabolism in the inflamed gut mucosa, which may offer novel targets for intervention and should be considered if nutritional strategies are used.

Schönfeld and Reiser recently hypothesized that fatty acid β-oxidation is a source of oxidative stress in the brain. To test this hypothesis, we inhibited brain mitochondrial β-oxidation with methyl palmoxirate (MEP) and measured oxidative polyunsaturated fatty acid (PUFA) metabolites in the rat brain. Upon MEP treatment, levels of several nonenzymatic auto-oxidative PUFA metabolites were reduced with few effects on enzymatically derived metabolites. Our finding confirms the hypothesis that reduced fatty acid β-oxidation decreases oxidative stress in the brain and β-oxidation inhibitors may be a novel therapeutic approach for brain disorders associated with oxidative stress.

Nonesterified fatty acids are important biological molecules which have multiple functions such as energy storage, gene regulation, or cell signaling. Comprehensive profiling of nonesterified fatty acids in biofluids can facilitate studying and understanding their roles in biological systems. For these reasons, we have developed and validated a high-throughput, nontargeted lipidomics method coupling liquid chromatography to high-resolution mass spectrometry for quantitative analysis of nonesterified fatty acids. Sufficient chromatographic separation is achieved to separate positional isomers such as polyunsaturated and branched-chain species and quantify a wide range of nonesterified fatty acids in human plasma samples. However, this method is not limited only to these fatty acid species and offers the possibility to perform untargeted screening of additional nonesterified fatty acid species.

Long-chain fatty acyl-coenzyme As (FA-CoAs) are important bioactive molecules, playing key roles in biosynthesis of fatty acids, membrane trafficking and signal transduction. Development of sensitive analytical methods for profiling theses lipid species in various tissues is critical to understand their biological activity. A high-pressure liquid chromatography/tandem mass spectrometry method has been developed for the quantitative analysis and screening of long-chain FACoAs in liver, brain, muscle and adipose tissue.The sample preparation method consists of tissue homogenization, extraction with organic solvent and reconstitution in an ammonium hydroxide buffer. Extracts are separated by liquid chromatography (LC) on a reversed-phase column and detected by electrospray ionization tandem mass spectrometry (ESI-MS/MS) in positive mode. An additional neutral loss scan allows for untargeted FA-CoAs screening.Extraction was optimized for low sample load (10 mg) of four tissue types (liver, brain, muscle and adipose tissue) with recoveries between 60-140% depending on the analyte and tissue type. Targeted quantification was validated for ten FA-CoAs in the range 0.1-500 ng/mL with accuracies between 85-120%.We have developed and validated a LC/MS/MS method for the quantifications and screening of long-chain FA-CoAs in four different types of mammalian tissue. The extraction method is straightforward and long-chain FA-CoA species can be quantified using only minimum amount of tissue. Copyright © 2016 John WileySons, Ltd.

We present a high-throughput, nontargeted lipidomics approach using liquid chromatography coupled to high-resolution mass spectrometry for quantitative analysis of nonesterified fatty acids. We applied this method to screen a wide range of fatty acids from medium-chain to very long-chain (8 to 24 carbon atoms) in human plasma samples. The method enables us to chromatographically separate branched-chain species from their straight-chain isomers as well as separate biologically important ω-3 and ω-6 polyunsaturated fatty acids. We used 51 fatty acid species to demonstrate the quantitative capability of this method with quantification limits in the nanomolar range; however, this method is not limited only to these fatty acid species. High-throughput sample preparation was developed and carried out on a robotic platform that allows extraction of 96 samples simultaneously within 3 h. This high-throughput platform was used to assess the influence of different types of human plasma collection and preparation on the nonesterified fatty acid profile of healthy donors. Use of the anticoagulants EDTA and heparin has been compared with simple clotting, and only limited changes have been detected in most nonesterified fatty acid concentrations.

Through evolution, most of the living species have acquired a time keeping system to anticipate daily changes caused by the rotation of the Earth. In all of the systems this pacemaker is based on a molecular transcriptional/translational negative feedback loop able to generate rhythmic gene expression with a period close to 24 hours. Recent evidences suggest that post-transcriptional regulations activated mostly by systemic cues play a fundamental role in the process, fine tuning the time keeping system and linking it to animal physiology. Among these signals, we consider the role of lipid transport and metabolism regulated by SCP2. Mice harboring a deletion of the Scp2 locus present a modulated diurnal accumulation of lipids in the liver and a perturbed activation of several signaling pathways including PPARα, SREBP, LRH-1, TORC1 and its upstream regulators. This defect in signaling pathways activation feedbacks upon the clock by lengthening the circadian period of animals through post-translational regulation of core clock regulators, showing that rhythmic lipid transport is a major player in the establishment of rhythmic mRNA and protein expression landscape.

The field of lipidomics has evolved vastly since its creation 15 years ago. Advancements in mass spectrometry have allowed for the identification of hundreds of intact lipids and lipid mediators. However, due to the release of fatty acids from the phospholipid membrane in the brain caused by ischemia, identifying the neurolipidome has been challenging. Microwave fixation has been shown to reduce the ischemia-induced release of several lipid mediators. Therefore, this study aimed to develop a method combining high-resolution tandem mass spectrometry (MS/MS), high-energy head-focused microwave fixation and statistical modeling, allowing for the measurement of intact lipids and lipid mediators in order to eliminate the ischemia-induced release of fatty acids and identify the rat neurolipidome. In this study, we demonstrated the ischemia-induced production of bioactive lipid mediators, and the reduction of variability by using microwave fixation in combination with liquid chromatography (LC)-MS/MS. We have also illustrated for the first time that microwave fixation eliminates the alterations in intact lipid species following ischemia. While many phospholipid species were unchanged by ischemia, other intact lipid classes such as diacylglycerol were lower in concentration following microwave fixation compared to ischemia. This article is protected by copyright. All rights reserved.

Excessive ultraviolet radiation (UVR) exposure induces erythema, mediated in part by prostaglandin-E(2) (PGE(2)). While keratinocytes are a major PGE(2) source, epidermal melanocytes (EM) also express PGE(2)-production machinery. It is unclear whether EM-produced PGE(2) contributes to UVR-induced skin inflammation, and whether this is correlated with melanogenesis. Epidermal melanocytes were cultured from skin phototype-1 and -4 donors, followed by assessment of PGE(2) production and melanogenesis. Epidermal melanocytes expressed cytoplasmic phospholipase-A(2), cyclooxygenase-1, cytoplasmic prostaglandin-E synthase and microsomal prostaglandin-E synthase-1, -2. Epidermal melanocytes produced PGE(2) under basal conditions, which increased further after arachidonic acid stimulation. Epidermal melanocytes expressed cyclooxygenase-2 (COX-2) mRNA and a selective COX-2 inhibitor (NS-398) reduced PGE(2) production. Ultraviolet B-induced PGE(2) production was positively correlated with skin phototype-1, despite variability between individual EM donors. By contrast, there was no correlation between PGE(2) production by EM and their melanogenic status. Thus, EM may contribute to UVR-induced erythema, with role of donor skin phototype more important than their melanogenic status.

There is growing interest in the use of mesenchymal stem cells (MSC) for immune therapy. Clinical trials that use MSC for treatment of therapy resistant graft versus host disease, Crohn's disease and organ transplantation have initiated. Nevertheless, the immunomodulatory effects of MSC are only partly understood. Clinical trials that are supported by basic research will lead to better understanding of the potential of MSC for immunomodulatory applications and to optimization of such therapies. In this manuscript we review some recent literature on the mechanisms of immunomodulation by MSC in vitro and animal models, present new data on the secretion of pro-inflammatory and anti-inflammatory cytokines, chemokines and prostaglandins by MSC under resting and inflammatory conditions and discuss the hopes and expectations of MSC-based immune therapy. (C) 2010 Elsevier B.V. All rights reserved.

Sunburn is a commonly occurring acute inflammatory process, with dermal vasodilatation and leukocyte infiltration as central features. Ultraviolet (UV) B-induced hydrolysis of membrane phospholipids releases polyunsaturated fatty acids, and their subsequent metabolism by cyclooxygenases (COXs) and lipoxygenases (LOXs) may produce potent eicosanoid mediators modulating different stages of the inflammation. Our objective was to identify candidate eicosanoids formed during the sunburn reaction in relation to its clinical and histological course. We exposed skin of healthy humans (n=32) to UVB and, for 72 h, examined expression of proinflammatory and anti-inflammatory eicosanoids using LC/ESI-MS/MS, and examined immunohistochemical expression of COX-2, 12-LOX, 15-LOX, and leukocyte markers, while quantifying clinical erythema. We show that vasodilatory prostaglandins (PGs) PGE2, PGF2α, and PGE3 accompany the erythema in the first 24–48 h, associated with increased COX-2 expression at 24 h. Novel, potent leukocyte chemoattractants 11-, 12-, and 8-monohydroxy-eicosatetraenoic acid (HETE) are elevated from 4 to 72 h, in association with peak dermal neutrophil influx at 24 h, and increased dermal CD3+ lymphocytes and 12- and 15-LOX expression from 24 to 72 h. Anti-inflammatory metabolite 15-HETE shows later expression, peaking at 72 h. Sunburn is characterized by overlapping sequential profiles of increases in COX products followed by LOX products that may regulate subsequent events and ultimately its resolution.—Rhodes, L. E., Gledhill, K., Masoodi, M., Haylett, A. K., Brownrigg, M., Thody, A. J., Tobin, D. J., Nicolaou, A. The sunburn response in human skin is characterized by sequential eicosanoid profiles that may mediate its early and late phases.

Bioactive lipid mediators derived from polyunsaturated fatty acids (PUFA) exhibit a range of tissue- and cell-specific activities in many physiological and pathological processes. Electrospray ionisation tandem mass spectrometry coupled to liquid chromatography (LC/ESI-MS/MS) is a sensitive, versatile analytical methodology for the qualitative and quantitative analysis of lipid mediators. Here we present an LC/ESI-MS/MS assay for the simultaneous analysis of twenty mono- and poly-hydroxy-fatty acid derivatives of linoleic, arachidonic, eicosapentaenoic and docosahexaenoic acids. The assay was linear over the concentration range 1-100 pg/microL, whilst the limits of detection and quantitation were 10-20 and 20-50 pg, respectively. The recovery of the extraction methodology varied from 76-122% depending on the metabolite. This system is useful for profiling a range of biochemically related potent mediators including the newly discovered resolvins and protectins, and their precursor hydroxyeicosapentaenoic and hydroxydocosahexaenoic acids, and, consequently, advance our understanding of the role of PUFA in health and disease.

Medium-chain triglycerides have been used as part of a ketogenic diet effective in reducing epileptic episodes. The health benefits of the derived medium-chain fatty acids (MCFAs) are thought to result from the stimulation of liver ketogenesis providing fuel for the brain. We tested whether MCFAs have direct effects on energy metabolism in induced pluripotent stem cell-derived human astrocytes and neurons. Using single-cell imaging, we observed an acute pronounced reduction of the mitochondrial electrical potential and a concomitant drop of the NAD(P)H signal in astrocytes, but not in neurons. Despite the observed effects on mitochondrial function, MCFAs did not lower intracellular ATP levels or activate the energy sensor AMP-activated protein kinase. ATP concentrations in astrocytes were unaltered, even when blocking the respiratory chain, suggesting compensation through accelerated glycolysis. The MCFA decanoic acid (300 μM) promoted glycolysis and augmented lactate formation by 49.6%. The shorter fatty acid octanoic acid (300 μM) did not affect glycolysis but increased the rates of astrocyte ketogenesis 2.17-fold compared with that of control cells. MCFAs may have brain health benefits through the modulation of astrocyte metabolism leading to activation of shuttle systems that provide fuel to neighboring neurons in the form of lactate and ketone bodies.-Thevenet, J., De Marchi, U., Santo Domingo, J., Christinat, N., Bultot, L., Lefebvre, G., Sakamoto, K., Descombes, P., Masoodi, M., Wiederkehr, A. Medium-chain fatty acids inhibit mitochondrial metabolism in astrocytes promoting astrocyte-neuron lactate and ketone body shuttle systems.

Introduction: Previous studies have shown that cognition is improved by providing AD patients with an alternate energy source: ketones derived from either ketogenic diet or supplementation with med...