Effect of emodin and sandostatin on metabolism of eicosanoids in acute necrotizing pancreatitis

INTRODUCTIONIn order to study the therapeutic mechanisms ofemodin,an extract of Rhubarb （Rhizoma et RadixRhei,a traditional Chinese herbal medicine）,andsandostatin in the treatment of acute necrotizingpancreatitis （ANP）,we used the two drugs in ratmodels of the disease and observed the changes ofplasma thromboxane-2（TXB2）,6-keto-prostaglandin F1α(6-keto-PGF1α)and prostaglandinE2（PEG2）.

Role of Eicosanoids on Renal Hemodynamics in Mesangioproliferative Nephritis

Theroleofleukocyte-andplatelet-derivedeicosanoidsonrenalhemody-namicswasinvestigatedinratmesangioproliferativenephritisinducedbyanti-Thy1.1antibodies.Acutedecrementsinglomerularfiltrationrate(GFR)andrenalbloodflow(RBF)wereasociatedwithincrementsinglomerularleukocytecountsandintheglomerularsynthesisofthromboxane(TX)B2,leukotriene(LT)B4and12-hydroxye-icosatetraenoicacid(12-HETE).Leukocytedepletionsignificantlyelimilatedtheen-hancedglomerulareicosanoidsynthesisandcompletelyamelioratedthedecrementinGFRandRBF.Likewise,combinedpretreatmentofratswithaTXsynthetasein-hibitorandanarachidonate5-lipoxygenaseinhibitorblockedthedecrementsinGFRandRBFandtheincrementsinglomerularsynthesisofTXB2andLTB4.Selectiveinhibi-tionofTXsynthetaseor5-lipoxygenasealoneonlypartialyamelioratedthedecrementsinGFRandRBF.Inratswithplateletdepletion,theglomerularsynthesisof12-HETEwasabolishedanddecrementinRBFbutnotGFRwasameliorated.Thesedataindicatedtheinfiltratingleukocytesandplateletsmediatethechangesinrenalhemody-namicsinaparacrinemannerviasynthesisofeicosanoidsinamodelofmesangiopro-liferativenephritis.

The 2-Series Eicosanoids in Cancer: Future Targets for Glioma Therapy?

The 2-series eicosanoids are structurally related lipid-soluble hormones synthesized by cyclooxygenase enzymes from arachidonic acid. These compounds have well-established roles in the inflammatory response and the coagulation cascade. More recently, the eicosanoids have garnered attention for their potential roles in cancers of the lung, colon, breast, and brain. In this paper, we review the contributions of the different cyclooxygenase metabolites (i.e. prostaglandins, prostacyclins and thromboxanes) to cancer development, progression and recurrence, with special attention paid to their relevance to glioma biology. Our review suggests that 2-series eicosanoids merit further study as possible targets for therapy in patients with glioma.

Hyperhomocysteinemia dysregulates plasma levels of polyunsaturated fatty acids-derived eicosanoids

Hyperhomocysteinemia(HHcy)contributes to the incidence of many cardiovascular diseases(CVD).Our group have previously established crucial roles of eicosanoids and homocysteine in the incidence of vascular injury in diabetic retinopathy and renal injury.Using cystathionine-β-synthase heterozygous mice(cβs^(+/-))as a model of HHcy,the current study was designed to determine the impact of homocysteine on circulating levels of lipid mediators derived from polyunsaturated fatty acids(PUFA).Plasma samples were isolated from wild-type(WT)and cβs^(+/-)mice for the assessment of eicosanoids levels using LC/MS.Plasma 12/15-lipoxygenase(12/15-LOX)activity significantly decreased in cβs^(+/-)vs.WT control mice.LOX-derived metabolites from both omega-3 and omega-6 PUFA were also reduced in cβs^(+/-)mice compared to WT control(P<0.05).Contrary to LOX metabolites,cytochrome P450(CYP)metabolites from omega-3 and omega-6 PUFA were significantly elevated in cβs^(+/-)mice compared to WT control.Epoxyeicosatrienoic acids(EETs)are epoxides derived from arachidonic acid(AA)metabolism by CYP with anti-inflammatory properties and are known to limit vascular injury,however their physiological role is limited by their rapid degradation by soluble epoxide hydrolase(sEH)to their corresponding diols(DiHETrEs).In cβs^(+/-)mice,a significant decrease in the plasma EETs bioavailability was obvious as evident by the decrease in EETs/DiHETrEs ratio relative to WT control mice.Cyclooxygenase(COX)metabolites were also significantly decreased in cβs^(+/-)vs.WT control mice.These data suggest that HHcy impacts eicosanoids metabolism through decreasing LOX and COX metabolic activities while increasing CYP metabolic activity.The increase in AA metabolism by CYP was also associated with increase in sEH activity and decrease in EETs bioavailability.Dysregulation of eicosanoids metabolism could be a contributing factor to the incidence and progression of HHcy-induced CVD.

Involvement of eicosanoids in the pathogenesis of pancreatic cancer: the roles of cyclooxygenase-2 and 5-lipoxygenase

The interplay between inflammation and cancer progression is a growing area of research. A combination of clinical, epidemiological, and basic science investigations indicate that there is a relationship between inflammatory changes in the pancreas and neoplastic progression. Diets high in ω-6 polyunsaturated fatty acids provide increased substrate for arachidonic acid metabolism by cyclooxygenase-2(COX-2) and 5-lipoxygenase(5-LOX) to form eicosanoids. These eicosanoids directly contribute to pancreatic cancer cell proliferation. Both COX-2 and 5-LOX are upregulated in multiple cancer types, including pancreatic cancer. In vitro studies using pancreatic cancer cell lines have demonstrated upregulation of COX-2 and 5-LOX at both the mRNA and protein levels. When COX-2 and 5-LOX are blocked via a variety of mechanisms, cancer cell proliferation is abrogated both in vitro and in vivo.The mechanism of COX-2 has been shown to include effects on apoptosis as well as angiogenesis. 5-LOX has been implicated in apoptosis. The use of COX-2 and 5-LOX inhibitors in clinical studies in patients with pancreatic cancer has been limited. Patient enrollment has been restricted to those with advanced disease which makes evaluation of these drugs as chemopreventive agents difficult. COX-2 and 5-LOX expression have been shown to be present during the early neoplastic changes of pancreatic cancer, well before progression to invasive disease. This indicates that the ideal role for these interventions is early in the disease process as preventive agents, perhaps in patients with chronic pancreatitis or hereditary pancreatitis.

Eicosanoids mediate nodulation reactions to bacterial Escherichia coil K 12 infections in larvae of the oriental blowfly, Chrysomya megacephala

Nodulation is the predominant cellular defense reaction to bacterial challenges in insects. In this study, third instar larvae of Chrysomya megacephala were injected with bacteria, Escherichia coli K 12 （10^6 CFU/mL, 2μL）, immediately prior to injection of inhibitors of eicosanoid biosynthesis, which sharply reduced nodulation response. Test larvae were treated with specific inhibitors ofphospholipase A2 （dexamethasone）, cyclo- oxygenase （indomethacin, ibuprofen and piroxicam）, dual cyclo-oxygenase/lipoxygenase （phenidone） and lipoxygenase （esculetin） and these reduced nodulation except esculetin. The influence of bacteria was obvious within 2 h of injection （5 nodules/larva）, and increased to a maximum after 8 h （with 15 nodules/larva）, and then significantly reduced over 24 h （9 nodules/larva）. The inhibitory influence of dexamethasone was apparent within 2 h of injection （4 vs. 5 nodules/larva）, and nodulation was significantly reduced, compared to control, over 24 h （5 vs. 8 nodules/larva）. Increased dosages of ibuprofen, indomethacin, piroxicam and phenidone led to decreased numbers of nodules. Nodules continued to exist during the pupal stage. However, the effects of dexamethasone were reversed by treating bacteria-injected insects with an eicosanoid-precursor polyunsaturated fatty acid, arachidonic acid. These findings approved our view that eicosanoid can mediate cellular defense mechanisms in response to bacterial infections in another Dipteran insect C. rnegacephala.

Hypertrophic Scar Formation and Wound Healing Modulation Fatty Acids as Modulators of Severe Scars

Scar tissue usually generates severe discomfort in the short and long term. Common symptoms include anesthetics sequelae, pruritus, joint malfunction, new wounds on the scar surface, and pain. There are several treatments for scars, like compression, topical or intralesional steroid infiltration, 5-fluorouracil, dermabrasion, and surgeries with new scar tissue. For adult patients, it is easier to choose the treatment. However, compression is commonly applied in children to prevent treatments that have adverse effects. This study reports the outcomes of 15 patients submitted to abdominoplasty, traumatic wounds and post-burn scar treatments, which showed significant changes after the continuous use of an ointment composed of petrolatum, cod liver oil, BHT, Chamomilla recutita (chamomile) oil, Helianthus annuus (sunflower) oil, and Prunus amygdalus dulcis (sweet almond) oil. As components of the stratum corneum, unsaturated fatty acids influence the cutaneous structural and immune status and permeability. They also interfere with the maturation and differentiation of the stratum corneum and inhibit the production of proinflammatory eicosanoids, reactive species (ROS and RNS), and cytokines, thereby influencing the inflammatory response and possibly wound healing. This article aims to share our experience with the regular use of an ointment in adult and pediatric patients for three months. The increase in proinflammatory cytokine production at wound sites, resulting in a noninvasive, therapeutical, and effective cutaneous wound healing and scarring modulation, may provide a physiopathological explanation for the fast improvement of scars.

Cysteinyl leukotrienes and their receptors: Bridging inflammation and colorectal cancer

Long-standing inflammation has emerged as a hallmark of neoplastic transformation of epithelial cells and may be a limiting factor of successful conventional tumor therapies.A complex milieu composed of distinct stromal and immune cells,soluble factors and inflammatory mediators plays a crucial role in supporting and promoting various types of cancers.An augmented inflammatory response can predispose a patient to colorectal cancer(CRC).Common risk factors associated with CRC development include diet and lifestyle,altered intestinal microbiota and commensals,and chronic inflammatory bowel diseases.Cysteinyl leukotrienes are potent inflammatory metabolites synthesized from arachidonic acid and have a broad range of functions involved in the etiology of various pathologies.This review discusses the important role of cysteinyl leukotriene signaling in linking inflammation and CRC.

Eicosanoid pathway in colorectal cancer:Recent updates

Enzymatic metabolism of the 20 C polyunsaturated fatty acid(PUFA) arachidonic acid(AA) occurs via the cyclooxygenase(COX) and lipoxygenase(LOX) pathways, and leads to the production of various bioactive lipids termed eicosanoids. These eicosanoids have a variety of functions, including stimulation of homeostatic responses in the cardiovascular system, induction and resolution of inflammation, and modulation of immune responses against diseases associated with chronic inflammation, such as cancer. Because chronic inflammation is essential for the development of colorectal cancer(CRC), it is not surprising that many eicosanoids are implicated in CRC. Oftentimes, these autacoids work in an antagonistic and highly temporal manner in inflammation; therefore, inhibition of the pro-inflammatory COX-2 or 5-LOX enzymes may subsequently inhibit the formation of their essential products, or shunt substrates from one pathway to another, leading to undesirable side-effects. A better understanding of these different enzymes and their products is essential not only for understanding the importance of eicosanoids, but also for designing more effective drugs that solely target the inflammatory molecules found in both chronic inflammation and cancer. In this review, we have evaluated the cancer promoting and anti-cancer roles of different eicosanoids in CRC, and highlighted the most recent literature which describes how those molecules affect not only tumor tissue, but also the tumor microenvironment. Additionally, we have attempted to delineate the roles that eicosanoids with opposing functions play in neoplastic transformation in CRC through their effects on proliferation, apoptosis, motility, metastasis, and angiogenesis.

Cytochrome P450 monooxygenase-mediated eicosanoid pathway:A potential mechanistic linkage between dietary fatty acid consumption and colon cancer risk

Human consumption of linoleic acid(LA,18:2ω-6,abundant in vegetable oils)is very high.Animal experiments showed that excessive LA intake increased azoxymethane-induced colon tumorigenesis,however,the impact of excessive LA on colon cancer in human is not conclusive,making it difficult to make dietary recommendations for optimal intake of LA.Understanding the molecular mechanisms of LA on colon tumorigenesis could help to clarify its health effect,and facilitate development of mechanismbased strategies for preventing colon cancer.Recent studies show that the previously unappreciated cytochrome P450 monooxygenase-mediated eicosanoid pathway is upregulated in colon cancer and plays critical roles in its pathogenesis,and could contribute to the effects of dietary LA,as well asω-3 fatty acids,on colon tumorigenesis.In this review,we will discuss recent studies about the roles of cytochrome P450 monooxygenases in fatty acid metabolism and its roles in colonic inflammation and colon cancer,and how this information could help us to clarify the health impacts of dietary fatty acids.

Creating Benefits from Omega-3 Functional Foods and Nutraceuticals

Foods currently eaten by Americans have abundant amounts of essential omega-6 (n-6) nutrients and relatively few omega-3 (n-3) nutrients. The average omega 3 - 6 balance score of typical US foods is about –6. This imbalance causes the average American to accumulate tissue proportions of n-3 and n-6 highly unsaturated fatty acids (HUFA) with about 77% n-6 in HUFA. This HUFA balance links to many chronic health conditions that are made worse by overabundant actions of food-based omega-6 HUFA. Americans currently spend more on treating food-based health conditions than they spend on food. Less medication is needed to treat signs and symptoms when a key dietary cause of the signs and symptoms is prevented. Informed food producers can readily prepare and market new food products with more n-3 and less n-6 nutrients to reverse the current national nutrient imbalance and help people attain and maintain a healthy HUFA balance. New functional foods and nutraceuticals will help consumers shift their financial resources from treating signs and symptoms caused by HUFA imbalance to preventing the nutrient imbalance that causes the need to treat.

Leukotriene-A4-Hydrolase and Basic Aminopeptidase Activities Are Related with Collagen-Induced Arthritis in a Compartment-Dependent Manner

Objective: Previous study demonstrated the involvement of basic aminopeptidase (APB) activity in the development of collagen-induced arthritis (CIA). Two zinc dependent metalloenzymes (EC 3.4.11.6 and EC 3.3.2.6) are known to exhibit concomitantly APB and leukotriene-A4-hydrolase (LT-A4-H) activities. Influence of the interrelationship between both activities on arthritic processes, however, is presently uncertain. This study aimed to compare these activities in CIA. Methods: CIA was induced in rats and arthritis was assessed macroscopically. Ultracentrifugation was used to separate soluble (S) and solubilized membrane-bound (M) fractions from peripheral blood mononuclear cells (PBMCs) and synovial tissue (ST). Enzyme immunoassay was used to measure LT-A4-H activity, and Real Time Polymerase Chain Reaction was used for evaluating EC 3.4.11.6 and EC 3.3.2.6 gene expressions. Results: The existence of genes for EC 3.3.2.6 and EC 3.4.11.6 was demonstrated in the ST. Compared with control, LT-A4-H activity increased in synovial fluid (SF) and in S-PBMCs of CIA-arthritic and CIA-resistant and in M-ST of CIA-resistant, while it decreased in M-PBMCs of CIA-arthritic and CIA-resistant. In all these locations APB activity remained unchanged or inversely correlated with LT-A4-H activity. Conclusions: LT-A4-H and APB activities in joint-related samples are associated, for the first time, with EC 3.3.2.6 and EC 3.4.11.6 genes, exhibiting a compartment-dependent differential modulation of their specificity, efficiency and/or affinity or an inverse concurrent pattern. Changes in LT-A4-H activity have implications for development or resistance to arthritis in CIA model with a potential to be a diagnostic tool.

Nutrition and metabolism in poultry: role of lipids in early diet

Modern strains of broiler chickens are selected for fast growth and are marketed anywhere from 36 to 49 days after a21-day incubational period. For a viable healthy chick, all the necessary nutrients required for growth and development must be provided by the hen through the fertilized egg. The current feeding strategies for improved growth, health and productivity are targeted towards chicks after hatching. Considering the fact that developing chick embryo spends over 30 % of its total life span inside the hatching egg relying on nutrients deposited by the breeder hen, investigations on nutritional needs during pre-hatch period will improve embryonic health, hatchability and chick viability. In this context, investigations on hatching egg lipid quality is of utmost importance because, during incubation, egg fat is the major source of energy and sole source of essential omega-6（n-6） and omega-3（n-3） fatty acids to the chick embryo.Due to the unique roles of n-3 and n-6 fatty acids in growth, immune health, and development of central nervous system, this review will focus on the role of early exposure to essential fatty acids through maternal diet and hatching egg and its impact on progeny in meat-type broiler chickens.

Dietary arachidonate in milk replacer triggers dual benefits of PGE2 signaling in LPS-challenged piglet alveolar macrophages

Background: Respiratory infections challenge the swine industry, despite common medicinal practices. The dual signaling nature of PGE2(supporting both inflammation and resolution) makes it a potent regulator of immune cell function. Therefore, the use of dietary long chain n-6 PUFA to enhance PGE2 effects merits investigation.Methods: Day-old pigs(n = 60) were allotted to one of three dietary groups for 21 d(n = 20/diet), and received either a control diet(CON, arachidonate = 0.5% of total fatty acids), an arachidonate(ARA)-enriched diet(LC n-6,ARA = 2.2%), or an eicosapentaenoic(EPA)-enriched diet(LC n-3, EPA = 3.0%). Alveolar macrophages and lung parenchymal tissue were collected for fatty acid analysis. Isolated alveolar macrophages were stimulated with LPS in situ for 24 h, and m RNA was isolated to assess markers associated with inflammation and eicosanoid production.Culture media were collected to assess PGE2 secretion. Oxidative burst in macrophages was measured by: 1)oxygen consumption and extracellular acidification(via Seahorse), 2) cytoplasmic oxidation and 3) nitric oxide production following 4, 18, and 24 h of LPS stimulation.Results: Concentration of ARA(% of fatty acids, w/w) in macrophages from pigs fed LC n-6 was 86% higher than CON and 18% lower in pigs fed LC n-3(P < 0.01). Following LPS stimulation, abundance of COX-2 and TNF-α mRNA(P < 0.0001), and PGE2 secretion(P < 0. 01) were higher in LC n-6 PAM vs. CON. However, ALOX5 abundance was1.6-fold lower than CON. Macrophages from CON and LC n-6 groups were 4-fold higher in ALOX12/15 abundance(P < 0.0001) compared to LC n-3. Oxygen consumption and extracellular acidification rates increased over 4 h following LPS stimulation(P < 0.05) regardless of treatment. Similarly, increases in cytoplasmic oxidation(P < 0.001)and nitric oxide production(P < 0.002) were observed after 18 h of LPS stimulation but were unaffected by diet.Conclusions: We infer that enriching diets with arachidonic acid may be an effective means to enhance a stronger innate immunologic response to respiratory challenges in neonatal pigs. However, further work is needed to examine long-term safety, clinical efficacy and economic viability.

Postpartum meloxicam administration alters plasma haptoglobin, polyunsaturated fatty acid, and oxylipid concentrations in postpartum ewes

Background: Postpartum inflammation is a natural and necessary response;however, a dysfunctional inflammatory response can be detrimental to animal productivity. The objective of this study was to determine the effects of a non-steroidal anti-inflammatory drug(meloxicam) on ewe postpartum inflammatory response, ewe plasma polyunsaturated fatty acid and oxylipid concentrations, and lamb growth.Results: After lambing, 36 Hampshire and Hampshire × Suffolk ewes were sequentially assigned within type of birth to control(n = 17) or meloxicam orally administered on d 1 and 4 of lactation(MEL;90 mg, n = 19). Milk and blood samples were collected on d 1(prior to treatment) and d 4. Milk glucose-6-phosphate was not affected by MEL. Plasma haptoglobin(Hp) concentrations were less for MEL ewes;control ewes with greater d 1 Hp concentrations had elevated Hp on d 4, but this was not the case for MEL-treated ewes. Treatment with MEL increased plasma arachidonic acid concentration by more than 4-fold in ewes rearing singles but decreased concentrations of 9,10-dihydroxyoctadecenoic acid, prostaglandin F2α, 8-iso-prostaglandin E2, and 8,9-dihydroxyeicosatetraenoic acid. Nine oxylipids in plasma had interactions of treatment with d 1 Hp concentration,all of which revealed positive associations between d 1 Hp and d 4 oxylipid concentrations for CON, but neutral or negative relationships for MEL. MEL decreased 13-hydroxyoctadecadienoic acid:13-oxooctadecadienoic acid ratio and tended to increase 9-hydroxyoctadecadienoic acid:9-oxooctadecadienoic acid ratio(both dependent on d 1 values), indicating progressive metabolism of linoleic acid-derived oxylipids occurred by enzymatic oxidation after MEL treatment. Meloxicam reduced oxylipids generated across oxygenation pathways, potentially due to an improved redox state.Conclusions: Postpartum MEL treatment of ewes decreased plasma concentrations of Hp and several oxylipids,with the greatest impact in ewes with biomarkers reflecting a greater inflammatory state before treatment. Antiinflammatory strategies may help resolve excessive postpartum inflammation in some dams.

Morphofunctional characterization of hemocytes in black soldier fly larvae

In insects,the cell-mediated immune response involves an active role of hemo-cytes in phagocytosis,nodulation,and encapsulation.Although these processes have been well documented in multiple species belonging to different insect orders,information con-cerning the immune response,particularly the hemocyte types and their specific function in the black soldier fly Hermetia illucens,is still limited.This is a serious gap in knowledge given the high economic relevance of H.illucens larvae in waste management strategies and considering that the saprophagous feeding habits of this dipteran species have likely shaped its immune system to efficiently respond to infections.The present study repre-sents the first detailed characterization of black soldier fly hemocytes and provides new insights into the cell-mediated immune response of this insect.In particular,in addition to prohemocytes,we identified five hemocyte types that mount the immune response in the larva,and analyzed their behavior,role,and morphofunctional changes in response to bac-terial infection and injection of chromatographic beads.Our results demonstrate that the circulating phagocytes in black soldier fly larvae are plasmatocytes.These cells also take part in nodulation and encapsulation with granulocytes and lamellocyte-like cells,devel-oping a starting core for nodule/capsule formation to remove/encapsulate large bacterial aggregates/pathogens from the hemolymph,respectively.These processes are supported by the release of melanin precursors from crystal cells and likely by mobilizing nutrient reserves in newly circulating adipohemocytes,which could thus trophically support other hemocytes during the immune response.Finally,the regulation of the cell-mediated im-mune response by eicosanoids was investigated.

Increased Soluble Epoxide Hydrolase Activity Positively Correlates with Mortality in Heart Failure Patients with Preserved Ejection Fraction:Evidence from Metabolomics

Epoxyeicosatrienoic acids(EETs)have pleiotropic endogenous cardiovascular protective effects and can be hydrolyzed to the corresponding dihydroxyeicosatrienoic acids by soluble epoxide hydrolase(sEH).Heart failure with preserved ejection fraction(HFpEF)has shown an increased prevalence and worse prognosis over the decades.However,the role of sEH activ-ity in HFpEF remains unclear.We enrolled 500 patients with HFpEF and 500 healthy controls between February 2010 and March 2016.Eight types of sEH-related eicosanoids were measured according to target metabolomics,and their correlation with clinical endpoints was also analyzed.The primary endpoint was cardiac mortality,and the secondary endpoint was a composite of cardiac events,including heart failure(HF)readmission,cardiogenic hospitalization,and all-cause mortal-ity.Furthermore,the effect of sEH inhibitors on cardiac diastolic function in HFpEF was investigated in vivo and in vitro.Patients with HFpEF showed significantly enhanced EET degradation by the sEH enzyme compared with healthy controls.More importantly,sEH activity was positively correlated with cardiac mortality in patients with HFpEF,especially in older patients with arrhythmia.A consistent result was obtained in the multiple adjusted models.Decreased sEH activity by the sEH inhibitor showed a significant effective effect on the improvement of cardiac diastolic function by ameliorating lipid disorders in cardiomyocytes of HFpEF mouse model.This study demonstrated that increased sEH activity was associated with cardiac mortality in patients with HFpEF and suggested that sEH inhibition could be a promising therapeutic strategy to improve diastolic cardiac function.Clinical trial identifier:NCT03461107(https://clini caltr ials.gov).

A target lipidomics approach to investigate the acute inflammatory irritation induced by indolealkylamines from Chansu water fraction in rats

Chansu has demonstrated adverse reactions in clinical settings,which is associated with its toxicity and limits its clinical applications.But there are methodological limitations for drug safety evaluation.In the current study,ultra-high performance liquid chromatography,lipidomic profiling,and molecular docking were used to systemically assess Chansu-induced acute inflammatory irritation and further identify the underlying drug targets.Compared with the EtOAc extract,Chansu water fraction containing indolealkylamines caused acute inflammatory irritation in rats,including acute pain(spontaneous raising foot reaction),and inflammation(paw edema).At the molecular level,lipids analysis revealed significantly higher levels of pro-inflammatory mediators of the COX and LOX pathways.However,anti-inflammatory mediators from the CYP 450,ALA,and DHA pathways markedly decreased after exposure to Chansu water fraction.Moreover,four indolealkylamines from Chansu showed a high theoretical affinity to a known irritation target,5-HT_(2A)R.These results suggest that Chansu-induced inflammatory irritation is related to the distinct dysregulation of inflammatory lipids,and peripheral 5-HT_(2A)R is a potential target for irritation therapy.The strategy used in this study can be a crucial approach in the safety evaluation of natural medicinal substances.

Endogenous cannabinoids may regulate chronic inflammation in aspirin-exacerbated respiratory disease

Aspirin-exacerbated respiratory disease(AERD)is characterized by the triad of chronic rhinosinusitis with nasal polyposis,adult-onset asthma and non-IgE mediated reactions to aspirin and other cyclooxygenase-1(COX-1)inhibitors.Patients with AERD are dependent on COX-1 activity to maintain production of prostaglandin(PG)species,such as PGE2,which maintain physiologic levels of inflammation and limit the production of pro-inflammatory cysteinyl leukotrienes.The endogenous cannabinoid system is a family of immunomodulatory lipids and their innate g-protein coupled receptors that are closely related to arachidonic acid and may modulate inflammation via several pathways,including the direct production of metabolically active prostaglandin glycerol-esters.A recent pilot study has identified the significant up-regulation of the peripherally expressed,type-2 cannabinoid receptor(CB2)in AERD nasal polyps versus control tissues from patients with either allergic fungal rhinosinusitis or no history of chronic sinonasal inflammation.These early findings suggest the involvement of increased endogenous cannabinoid activity in prostaglandin deficient states such as AERD.Future study is needed to explore the significance of these findings,with specific investigation of the impact of CB2 activation on markers of airway inflammation,as well as the potential to measure CB2 expression as a screening biomarker for the evaluation of unrecognized disease.

Deciphering lipid dysregulation in ALS:from mechanisms to translational medicine

Lipids,defined by low solubility in water and high solubility in nonpolar solvents,can be classified into fatty acids,glycerolipids,glycerophospholipids,sphingolipids,and sterols.Lipids not only regulate integrity and fluidity of biologi-cal membranes,but also serve as energy storage and bioactive molecules for signaling.Causal mutations in SPTLC1(serine palmitoyltransferase long chain subunit 1)gene within the lipogenic pathway have been identified in amyo-trophic lateral sclerosis(ALS),a paralytic and fatal motor neuron disease.Furthermore,lipid dysmetabolism within the central nervous system and circulation is associated with ALS.Here,we aim to delineate the diverse roles of different lipid classes and understand how lipid dysmetabolism may contribute to ALS pathogenesis.Among the different lipids,accumulation of ceramides,arachidonic acid,and lysophosphatidylcholine is commonly emerging as detri-mental to motor neurons.We end with exploring the potential ALS therapeutics by reducing these toxic lipids.