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Simple Summary: The inclusion of phytogenic additives in diets for ruminants has shown a positive impact on the growth and health of animals. However, information on the effects of phytogenic additives on dietary energetics, meat quality, and gene expression in ruminants is limited. This study aimed to evaluate the effects of a polyherbal phytogenic additive on the growth performance, dietary energetics, carcass and meat traits, blood metabolites, and gene expression of finishing lambs. The polyherbal phytogenic additive improves feed intake, weight gain, feed efficiency, and dietary energy utilization efficiency. Likewise, the effects observed at the genetic level indicate that the polyherbal phytogenic additive improves energy production and antioxidant status in finishing lambs. This study aimed to evaluate the effects of supplementation with a polyherbal phytogenic additive (PPA) on the productive performance, dietary energetics, blood metabolites, carcass traits, meat quality, and gene expression of finishing lambs. Thirty-six male Pelibuey lambs (23.61 ± 0.57 kg body weight (BW)) were housed in individual pens and assigned to four treatments (n = 9) with different doses of PPA: 0 (CON), 2.5 (PPAL), 5 (PPAM), and 7.5 (PPAH) g of PPA/kg of DM for 56 days. Average daily gain, dry matter intake, and observed dietary net energy for maintenance and weight gain increased linearly (p < 0.05) in lambs supplemented with PPAH. A linear reduction (p = 0.02) in FCR was detected in lambs fed PPAM and PPAH. The PPAH supplementation linearly increased (p < 0.001) Longissimus dorsi muscle area, but other carcass traits were not affected (p > 0.05) by PPA doses. The physicochemical characteristics of the meat and the hematological parameters of the lambs were not affected (p > 0.05) by the PPA doses. The glucose, uric acid, creatinine, and bilirubin serum concentrations decreased linearly (p < 0.05) in lambs supplemented with PPAM and PPAH. Gene ontology analyses showed that nine biological processes were modified (p < 0.05), including DNA replication, drug metabolism–cytochrome P450, oxidative phosphorylation, and chemical carcinogenesis–reactive oxygen species. In conclusion, high doses (7.5 g/kg DM) of PPA can improve growth performance and dietary energy utilization efficiency in finishing lambs. Likewise, gene expression analysis indicates that supplementation with high doses of PPA could improve energy production and antioxidant status in finishing lambs. [ABSTRACT FROM AUTHOR]

Phospholipids are crucial structural components of cells. Phosphatidylcholine and phosphatidylethanolamine (both synthesized via the Kennedy pathway) and phosphatidylserine undergo interconversion. The dysregulation of this process is implicated in various diseases. This paper discusses the role of enzymes involved in the interconversion of phosphatidylcholine, phosphatidylethanolamine, and phosphatidylserine, specifically phosphatidylethanolamine N-methyltransferase (PEMT), phosphatidylserine synthases (PTDSS1 and PTDSS2), and phosphatidylserine decarboxylase (PISD), with a focus on their biochemical properties. Additionally, we describe the effects of the deregulation of these enzymes and their roles in both oncological and non-oncological diseases, including nonalcoholic fatty liver disease (NAFLD), Alzheimer's disease, obesity, insulin resistance, and type II diabetes. Current knowledge on inhibitors of these enzymes as potential therapeutic agents is also reviewed, although in most cases, inhibitors are yet to be developed. The final section of this article presents a bioinformatic analysis using the GEPIA portal to explore the significance of these enzymes in cancer processes. [ABSTRACT FROM AUTHOR]

Cholesterol homeostasis is pivotal for cellular function. Acyl-coenzyme A:cholesterol acyltransferase 1 (ACAT1), also abbreviated as SOAT1, is an enzyme responsible for catalyzing the storage of excess cholesterol to cholesteryl esters. ACAT1 is an emerging target to treat diverse diseases including atherosclerosis, cancer, and neurodegenerative diseases. F12511 is a high-affinity ACAT1 inhibitor. Previously, we developed a stealth liposome-based nanoparticle to encapsulate F12511 to enhance its delivery to the brain and showed its efficacy in treating a mouse model for Alzheimer's disease (AD). In this study, we introduce F26, a close derivative of F12511 metabolite in rats. F26 was encapsulated in the same DSPE-PEG2000/phosphatidylcholine (PC) liposome-based nanoparticle system. We employed various in vitro and in vivo methodologies to assess F26's efficacy and toxicity compared to F12511. The results demonstrate that F26 is more effective and durable than F12511 in inhibiting ACAT1, in both mouse embryonic fibroblasts (MEFs), and in multiple mouse tissues including the brain tissues, without exhibiting any overt systemic or neurotoxic effects. This study demonstrates the superior pharmacokinetic and safety profile of F26 in wild-type mice, and suggests its therapeutic potential against various neurodegenerative diseases including AD. [ABSTRACT FROM AUTHOR]

Intestinal mucus serves as the first line barrier within the mucosa to protect against microbiota attack due to its water-repellent properties, which are the result of the high abundance of phosphatidylcholine bound to mucins. A deficiency of mucus phosphatidylcholine predisposes it to mucosal inflammation by the attack of commensal microbiota, as it is intrinsically low in ulcerative colitis. However, for precipitation of an acute inflammatory episode, mucus phosphatidylcholine has to fall below the critical level required for mucosal protection. Bacterial ectophospholipase could be a candidate for further thinning of the mucus phosphatidylcholine shield as shown, for example, with the ectophospholipase containing Helicobacter pylori bacterium. Despite supporting evidence for this mechanism in the intestine, the responsible ectophospholipase-carrying bacteria species are still to be defined. Applying phosphatidylcholine to the lumen can serve to fill up empty mucin-binding sites in ulcerative colitis as well as provide a substrate for the ectophospholipase-carrying bacteria preventing their attacks on the mucus phosphatidylcholine layer. Evidence supporting this concept comes from clinical trials in humans with ulcerative colitis as well as from colitis mouse models where phosphatidylcholine was substituted in the lumen. An alternative strategy could involve adding non-absorbable phospholipase inhibitors to the intestinal lumen, which has been shown to be effective in a mouse model of ulcerative colitis. Bacterial phospholipase should be considered a pathogenetic factor of the intestinal microbiota and therapeutic strategies should be developed to prevent their hyperactivity for clinical improvement of intestinal inflammation. [ABSTRACT FROM AUTHOR]

Phosphatidylcholine (PC) is an essential lipid for liver health and lipoprotein metabolism, but its circulating levels have rarely been studied in patients with cirrhosis. Chronic hepatitis C virus (HCV) infection causes lipid abnormalities and is a major cause of cirrhosis. Effective HCV elimination with direct-acting antivirals (DAAs) is associated with the normalization of serum low-density lipoprotein cholesterol levels. Since PC is abundant in all lipoprotein particles, this study analyzed the association between serum PC species levels and liver cirrhosis before and after HCV eradication. Therefore, 27 PC species were measured by Fourier Transform Mass Spectrometry in the serum of 178 patients with chronic HCV infection at baseline and in 176 of these patients at the end of therapy. The PC species did not correlate with viral load, and the levels of 13 PC species were reduced in patients infected with genotype 3a compared to those affected with genotype 1. Four PC species were slightly elevated 12 weeks after DAA initiation, and genotype-related changes were largely normalized. Patients with HCV and cirrhosis had higher serum levels of PC 30:0 and 32:0 before and at the end of therapy. PC species containing polyunsaturated fatty acids were mostly decreased in cirrhosis. The levels of polyunsaturated, but not saturated, PC species were inversely correlated with the model of the end-stage liver disease score. A receiver operating characteristic curve analysis showed area under the curve values of 0.814 and 0.826 for PC 32:0 and 0.917 and 0.914 for % PC 32:0 (relative to the total PC levels) for the classification of cirrhosis at baseline and at the end of therapy, respectively. In conclusion, the specific upregulation of PC 32:0 in cirrhosis before and after therapy may be of diagnostic value in HCV-related cirrhosis. [ABSTRACT FROM AUTHOR]

Our recent findings revealed that human adipose tissues (AT)-derived extracellular vesicles (adiposomes) vary in cargo among obese and lean individuals. The main objective of this study was to investigate the adiposomal lipid profiles and their correlation with cardiometabolic risk factors. AT samples were collected from obese subjects and lean controls and analyzed for their characteristics and lipid content. In addition, we measured the correlation between adiposomal lipid profiles and body composition, glucose and lipid metabolic profiles, brachial artery vasoreactivity, AT arteriolar flow-induced dilation, and circulating markers such as IL-6, C-reactive protein, and nitric oxide (NO). Compared to lean controls, adiposomes isolated from obese subjects were higher in number after normalization to AT volume. The two major lipid classes differentially expressed were lysophosphatidylcholine/phosphatidylcholine (LPC/PC) and ceramides (Cer). All lipids in the LPC/PC class were several-fold lower in adiposomes from obese subjects compared to lean controls, on top of which were PC 18:2, PC 18:1, and PC 36:3. Most ceramides were markedly upregulated in the obese group, especially Cer d37:0, Cer d18:0, and Cer d39:0. Regression analyses revealed associations between adiposomal lipid profiles and several cardiometabolic risk factors such as body mass index (BMI), fat percentage, insulin resistance, arteriolar and brachial artery vasoreactivity, NO bioavailability, and high-density lipoproteins (HDL-C). We conclude that the ability of adiposomes from obese subjects to disrupt cardiometabolic function could be partly attributed to the dysregulated lipid cargo. [ABSTRACT FROM AUTHOR]

Choline is an essential nutrient, with high requirements during fetal and postnatal growth. Tissue concentrations of total choline are tightly regulated, requiring an increase in its pool size proportional to growth. Phosphatidylcholine and sphingomyelin, containing a choline headgroup, are constitutive membrane phospholipids, accounting for >85% of total choline, indicating that choline requirements are particularly high during growth. Daily phosphatidylcholine secretion via bile for lipid digestion and very low-density lipoproteins for plasma transport of arachidonic and docosahexaenoic acid to other organs exceed 50% of its hepatic pool. Moreover, phosphatidylcholine is required for converting pro-apoptotic ceramides to sphingomyelin, while choline is the source of betaine as a methyl donor for creatine synthesis, DNA methylation/repair and kidney function. Interrupted choline supply, as during current total parenteral nutrition (TPN), causes a rapid drop in plasma choline concentration and accumulating deficit. The American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) defined choline as critical to all infants requiring TPN, claiming its inclusion in parenteral feeding regimes. We performed a systematic literature search in Pubmed with the terms "choline" and "parenteral nutrition", resulting in 47 relevant publications. Their results, together with cross-references, are discussed. While studies on parenteral choline administration in neonates and older children are lacking, preclinical and observational studies, as well as small randomized controlled trials in adults, suggest choline deficiency as a major contributor to acute and chronic TPN-associated liver disease, and the safety and efficacy of parenteral choline administration for its prevention. Hence, we call for choline formulations suitable to be added to TPN solutions and clinical trials to study their efficacy, particularly in growing children including preterm infants. [ABSTRACT FROM AUTHOR]

Glycerophospholipids have hydrophobic and hydrophilic moieties. Previous studies suggest that phospholipids with different moieties have different effects on rodent behavior; however, the relationship between chemical structures and behavioral effects remains unclear. To clarify the functions of phospholipid moieties, we injected male rats with phospholipids with different moieties and conducted behavioral tests. Exploratory activity was reduced by phosphatidylethanolamine (PE)(18:0/22:6) but not PE(18:0/18:0) or PE(18:0/20:4). Conversely, exploratory activity was increased by plasmanyl PE(16:0/22:6), which harbors an alkyl–ether linkage, but not by phosphatidylcholine (PC)(16:0/22:6) or plasmanyl PC(16:0/22:6). Docosahexaenoic acid (DHA)(22:6) and an alkyl–ether linkage in PE were thus postulated to be involved in exploratory activity. Anxiety-like behavior was reduced by plasmenyl PC(18:0/20:4), which harbors a vinyl–ether linkage, but not by PC(18:0/20:4) or plasmanyl PC(18:0/20:4), suggesting the anxiolytic effects of vinyl–ether linkage. The activation of social interaction was suppressed by PE(18:0/18:0), PE(18:0/22:6), PC(16:0/22:6), plasmanyl PE(16:0/22:6), and plasmanyl PC(16:0/22:6) but not by PE(18:0/20:4), plasmenyl PE(18:0/20:4), or plasmanyl PC(18:0/22:6). DHA may suppress social interaction, whereas arachidonic acid(20:4) or a combination of alkyl–ether linkage and stearic acid(18:0) may restore social deficits. Our findings indicate the characteristic effects of different phospholipid moieties on rat behavior, and may help to elucidate patterns between chemical structures and their effects. [ABSTRACT FROM AUTHOR]

Polysaccharide-based systems have very good emulsifying and stabilizing properties, and starch plays a leading role. Their modifications should add new quality features to the product to such an extent that preserves the structure-forming properties of native starch. The aim of this manuscript was to examine the physicochemical characteristics of the combinations of starch with phospholipids or lysozymes and determine the effect of starch modification (surface hydrophobization or biological additives) and preparation temperature (before and after gelatinization). Changes in electrokinetic potential (zeta), effective diameter, and size distribution as a function of time were analyzed using the dynamic light scattering and microelectrophoresis techniques. The wettability of starch-coated glass plates before and after modification was checked by the advancing and receding contact angle measurements, as well as the angle hysteresis, using the settle drop method as a complement to profilometry and FTIR. It can be generalized that starch dispersions are more stable than analogous n-alkane/starch emulsions at room and physiological temperatures. On the other hand, the contact angle hysteresis values usually decrease with temperature increase, pointing to a more homogeneous surface, and the hydrophobization effect decreases vs. the thickness of the substrate. Surface hydrophobization of starch carried out using an n-alkane film does not change its bulk properties and leads to improvement of its mechanical and functional properties. The obtained specific starch-based hybrid systems, characterized in detail by switchable wettability, give the possibility to determine the energetic state of the starch surface and understand the strength and specificity of interactions with substances of different polarities in biological processes and their applicability for multidirectional use. [ABSTRACT FROM AUTHOR]

We aimed to investigate the associations between maternal intake of folate, vitamin B12, B6, B2, methionine, choline, phosphatidylcholine and betaine during the period surrounding pregnancy and offspring weight outcomes from birth to early adulthood. These associations were examined among 2454 mother–child pairs from the Nurses' Health Study II and Growing Up Today Study. Maternal energy-adjusted nutrient intakes were derived from food frequency questionnaires. Birth weight, body size at age 5 and repeated BMI measurements were considered. Overweight/obesity was defined according to the International Obesity Task Force (<18 years) and World Health Organization guidelines (18+ years). Among other estimands, we report relative risks (RRs) for offspring ever being overweight with corresponding 95% confidence intervals across quintiles of dietary factors, with the lowest quintile as the reference. In multivariate-adjusted models, higher maternal intakes of phosphatidylcholine were associated with a higher risk of offspring ever being overweight (RRQ5vsQ1 = 1.16 [1.01–1.33] p-trend: 0.003). The association was stronger among offspring born to mothers with high red meat intake (high red meat RRQ5vsQ1 = 1.50 [1.14–1.98], p-trend: 0.001; low red meat RRQ5vsQ1 = 1.05 [0.87–1.27], p-trend: 0.46; p-interaction = 0.13). Future studies confirming the association between a higher maternal phosphatidylcholine intake during pregnancy and offspring risk of being overweight or obese are needed. [ABSTRACT FROM AUTHOR]

This study investigated the incorporation of nervonic acid into the chemical structure of phosphatidylcholine via a lipase-catalyzed acidolysis reaction to obtain a functional phospholipid. Lipase immobilization was conducted, and Amberlite XAD7-HP was selected as a carrier to immobilize phospholipase A1 (PLA1) for subsequent experiments. The main acidolysis reaction parameters, including enzyme load, substrate ratio, temperature, and water content, were studied against the reaction time. The optimum reaction conditions obtained were enzyme load, 20%; reaction temperature, 55 °C; water content, 1%; and reaction time, 9 h. The maximum incorporation of nervonic acid into phosphatidylcholine was 48 mol%, with PC recovery at 61.6 mol%. The positional distribution of structured phosphatidylcholine shows that nervonic acid was found in the sn-1 position due to enzyme specificity and in the sn-2 position, possibly due to acyl migration. [ABSTRACT FROM AUTHOR]

Non-alcoholic metabolic-associated steatohepatitis (MASH) is a condition characterized by increasingly high prevalence and incidence, and also represents an important unmet medical need when it comes to effective pharmacotherapy. In this work, we aimed to explore the therapeutic possibilities of the synergistic combined use of glycyrrhizinic acid (GA) and phosphatidylcholine (PC) to prevent experimental MASH. Adult C57Bl/6 mice were used to model dietary/toxic MASH and treated orally by either GA (34.3 mg/kg/d) or a GA + PC combination (34.3 + 158.1 mg/kg/d) for 3 months. Animal locomotion, behaviour, short-term memory, physical performance, neuromuscular joint function, blood biochemistry, and oxidative stress marker levels were evaluated, followed by histological examination of the liver, skeletal muscle and sciatic nerve with tissue ammonia and lipid content determination. Real-time polymerase chain reaction was used to measure the relative expression of several pathogenetic transcript markers. GA and PC showed moderate additive synergism in their anti-inflammatory, antioxidant, hypoammonaemic, hypoglycaemic, and pro-cognitive activities. Differential effects of the agents were seen in regard to anxiety- and depression-like behaviour as well as gene expression. Our results indicate partial pharmacological synergism between GA and PC and validate further research of its potential clinical applications. [ABSTRACT FROM AUTHOR]

The coming of the hyper-aged society in Taiwan prompts us to investigate the relationship between the metabolic status of sarcopenic patients and their most adverse outcome–death. We studied the association between any plasma metabolites and the risk for mortality among older Taiwanese sarcopenic patients. We applied a targeted metabolomic approach to study the plasma metabolites of adults aged ≥65 years, and identified the metabolic signature predictive of the mortality of sarcopenic patients who died within a 5.5-year follow-up period. Thirty-five sarcopenic patients who died within the follow-up period (Dead cohort) had shown a specific plasma metabolic signature, as compared with 54 patients who were alive (Alive cohort). Only 10 of 116 non-sarcopenic individuals died during the same period. After multivariable adjustment, we found that sex, hypertension, tetradecanoyl-carnitine (C14-carnitine), and docosahexaenoic acid (DHA)-containing phosphatidylcholine diacyl (PCaa) C38:6 and C40:6 were important risk factors for the mortality of sarcopenic patients. Low PCaa C38:6 levels and high C14-carnitine levels correlated with an increased mortality risk; this was even the same for those patients with hypertension (HTN). Our findings suggest that plasma PCaa C38:6 and acylcarnitine C14-carnitine, when combined, can be a better early biomarker for evaluating the mortality risk of sarcopenia patients. [ABSTRACT FROM AUTHOR]

Type 2 diabetes (T2D) is a global public health issue characterized by excess weight, abdominal obesity, dyslipidemia, hyperglycemia, and a progressive increase in insulin resistance. Human population studies of T2D development and its effects on systemic metabolism are confounded by many factors that cannot be controlled, complicating the interpretation of results and the identification of early biomarkers. Aged, sedentary, and overweight/obese non-human primates (NHPs) are one of the best animal models to mimic spontaneous T2D development in humans. We sought to identify and distinguish a set of plasma and/or fecal metabolite biomarkers, that have earlier disease onset predictability, and that could be evaluated for their predictability in subsequent T2D studies in human cohorts. In this study, a single plasma and fecal sample was collected from each animal in a colony of 57 healthy and dysmetabolic NHPs and analyzed for metabolomics and lipidomics. The samples were comprehensively analyzed using untargeted and targeted LC/MS/MS. The changes in each animal's disease phenotype were monitored using IVGTT, HbA1c, and other clinical metrics, and correlated with their metabolic profile. The plasma and fecal lipids, as well as bile acid profiles, from Healthy, Dysmetabolic (Dys), and Diabetic (Dia) animals were compared. Following univariate and multivariate analyses, including adjustments for weight, age, and sex, several plasma lipid species were identified to be significantly different between these animal groups. Medium and long-chain plasma phosphatidylcholines (PCs) ranked highest at distinguishing Healthy from Dys animals, whereas plasma triglycerides (TG) primarily distinguished Dia from Dys animals. Random Forest (RF) analysis of fecal bile acids showed a reduction in the secondary bile acid glycoconjugate, GCDCA, in diseased animals (AUC 0.76[0.64, 0.89]). Moreover, metagenomics results revealed several bacterial species, belonging to the genera Roseburia, Ruminococcus, Clostridium, and Streptococcus, to be both significantly enriched in non-healthy animals and associated with secondary bile acid levels. In summary, our results highlight the detection of several elevated circulating plasma PCs and microbial species associated with fecal secondary bile acids in NHP dysmetabolic states. The lipids and metabolites we have identified may help researchers to differentiate individual NHPs more precisely between dysmetabolic and overtly diabetic states. This could help assign animals to study groups that are more likely to respond to potential therapies where a difference in efficacy might be anticipated between early vs. advanced disease. [ABSTRACT FROM AUTHOR]

Mammalian cell membranes composed of a mixture of glycerophospholipids, the relative composition of individual phospholipids and the dynamic flux vary between cells. In addition to their structural role, membrane phospholipids are involved in cellular signalling and immunomodulatory functions. In this study, we investigate the molecular membrane composition and dynamic flux of phosphatidylcholines in CD15+ leucocytes and CD3+ lymphocytes extracted from patients with acute respiratory distress syndrome (ARDS). We identified compositional variations between these cell types, where CD15+ cells had relatively higher quantities of alkyl-acyl PC species and CD3+ cells contained more arachidonoyl-PC species. There was a significant loss of arachidonoyl-PC in CD3+ cells in ARDS patients. Moreover, there were significant changes in PC composition and the methyl-D9 enrichment of individual molecular species in CD15+ cells from ARDS patients. This is the first study to perform an in vivo assessment of membrane composition and dynamic changes in immunological cells from ARDS patients. [ABSTRACT FROM AUTHOR]

Lipid droplets (LDs) are intracellular organelles that play important roles in cellular lipid metabolism; they change their sizes and numbers in response to both intracellular and extracellular signals. Changes in LD size reflect lipid synthesis and degradation and affect many cellular activities, including energy supply and membrane synthesis. Here, we focused on the function of the endoplasmic reticulum–plasma membrane tethering protein Ice2 in LD dynamics in the fungal pathogen Candida albicans (C. albicans). Nile red staining and size quantification showed that the LD size increased in the ice2Δ/Δ mutant, indicating the critical role of Ice2 in the regulation of LD dynamics. A lipid content analysis further demonstrated that the mutant had lower phosphatidylcholine levels. As revealed with GFP labeling and fluorescence microscopy, the methyltransferase Cho2, which is involved in phosphatidylcholine synthesis, had poorer localization in the plasma membrane in the mutant than in the wild-type strain. Interestingly, the addition of the phosphatidylcholine precursor choline led to the recovery of normal-sized LDs in the mutant. These results indicated that Ice2 regulates LD size by controlling intracellular phosphatidylcholine levels and that endoplasmic reticulum–plasma membrane tethering proteins play a role in lipid metabolism regulation in C. albicans. This study provides significant findings for further investigation of the lipid metabolism in fungi. [ABSTRACT FROM AUTHOR]

Ceramides and other sphingolipids are implicated in vascular dysfunction and inflammation. They have been suggested as potential biomarkers for hypertension. However, their specific association with hypertension prevalence and onset requires further investigation. This study aimed to identify specific ceramide and phosphatidylcholine species associated with hypertension prevalence and onset. The 2002 FINRISK (Finnish non-communicable risk factor survey) study investigated the association between coronary event risk scores (CERT1 and CERT2) and hypertension using prevalent and new-onset hypertension groups, both consisting of 7722 participants, over a span of 10 years. Ceramide and phosphatidylcholine levels were measured using tandem liquid chromatography-mass spectrometry. Ceramide and phosphatidylcholine ratios, including ceramide (d18:1/18:0), ceramide (d18:1/24:1), phosphatidylcholine (16:0/16:0), and the ratio of ceramide (d18:1/18:0)/(d18:1/16:0), are consistently associated with both prevalence and new-onset hypertension. Ceramide (d18:1/24:0) was also linked to both hypertension measures. Adjusting for covariates, CERT1 and CERT2 showed no-longer-significant associations with hypertension prevalence, but only CERT2 predicted new-onset hypertension. Plasma ceramides and phosphatidylcholines are crucial biomarkers for hypertension, with imbalances potentially contributing to its development. Further research is needed to understand the underlying mechanisms by which ceramides will contribute to the development of hypertension. [ABSTRACT FROM AUTHOR]

Lysosomes are degradative organelles that facilitate the removal and recycling of potentially cytotoxic materials and mediate a variety of other cellular processes, such as nutrient sensing, intracellular signaling, and lipid metabolism. Due to these central roles, lysosome dysfunction can lead to deleterious outcomes, including the accumulation of cytotoxic material, inflammation, and cell death. We previously reported that cationic amphiphilic drugs, such as imipramine, alter pH and lipid metabolism within macrophage lysosomes. Therefore, the ability for imipramine to induce changes to the lipid content of isolated macrophage lysosomes was investigated, focusing on sphingomyelin, cholesterol, and glycerophospholipid metabolism as these lipid classes have important roles in inflammation and disease. The lysosomes were isolated from control and imipramine-treated macrophages using density gradient ultracentrifugation, and mass spectrometry was used to measure the changes in their lipid composition. An unsupervised hierarchical cluster analysis revealed a clear differentiation between the imipramine-treated and control lysosomes. There was a significant overall increase in the abundance of specific lipids mostly composed of cholesterol esters, sphingomyelins, and phosphatidylcholines, while lysophosphatidylcholines and ceramides were overall decreased. These results support the conclusion that imipramine's ability to change the lysosomal pH inhibits multiple pH-sensitive enzymes in macrophage lysosomes. [ABSTRACT FROM AUTHOR]

Mammary fat plays a profound role in the postnatal development of mammary glands. However, the specific types (white, brown, or beige) of adipocytes in mammary fat and their potential regulatory effects on modulating mammary gland development remain poorly understood. This study aimed to investigate the role of the browning of mammary fat on pubertal mammary gland development and explore the underlying mechanisms. Thus, the mammary gland development and the serum lipid profile were evaluated in mice treated with CL316243, a β3-adrenoceptor agonist, to induce mammary fat browning. In addition, the proliferation of HC11 cells co-cultured with brown adipocytes or treated with the altered serum lipid metabolite was determined. Our results showed that the browning of mammary fat by injection of CL316243 suppressed the pubertal development of mice mammary glands, accompanied by the significant elevation of serum dioleoylphosphocholine (DOPC). In addition, the proliferation of HC11 was repressed when co-cultured with brown adipocytes or treated with DOPC. Furthermore, DOPC suppressed the activation of the PI3K/Akt pathway, while the DOPC-inhibited HC11 proliferation was reversed by SC79, an Akt activator, suggesting the involvement of the PI3K/Akt pathway in the DOPC-inhibited proliferation of HC11. Together, the browning of mammary fat suppressed the development of the pubertal mammary gland, which was associated with the elevated serum DOPC and the inhibition of the PI3K/Akt pathway. [ABSTRACT FROM AUTHOR]

It has been proposed that lipid oxidation reactions in edible oils primarily occur in reverse micelles (RM) of amphiphilic components. While the prooxidative effect of RM has been demonstrated, the mechanism involved is not fully understood. Both reductions and enhancements in the antioxidant efficacy (AE) of α-tocopherol and Trolox have been observed in different studies when phosphatidylcholine (PC) was added and PC RM were formed. However, most of these investigations employed lipid systems consisting of stripped vegetable oil diluted in saturated medium-chain triacylglycerols (MCT) and utilized antioxidant concentrations well below those found in edible oils. These two specific factors were investigated in the present study. The effect of RM of purified egg yolk PC on the AE of 1.16 mmol kg−1 α-tocopherol or Trolox in stripped sunflower oil (SSO) was studied by the Rancimat (100 °C) and oven (50 °C) tests. Increasing PC concentrations (50–1000 ppm) had no significant impact on α-tocopherol, but substantial reductions in AE were observed for Trolox. This phenomenon may be attributed to the partitioning of Trolox into the pre-existing PC micelles, suggesting that primary oxidation reactions occurred in the continuous lipid phase. In addition, the effectiveness of both antioxidants decreased significantly in the presence of PC when a low antioxidant concentration (0.06 mmol kg−1) was assayed in SSO:MCT (1:3, w/w). [ABSTRACT FROM AUTHOR]

Morphological features of the nanoform of a phospholipid composition (NFPh), which can be used as an individual pharmaceutic agent or as a platform for designing drug delivery systems, have been studied using atomic force microscopy (AFM). NFPh has been developed, and its characteristics have been investigated using conventional drug analysis methods, including the determination of the mean diameter of nanosized vesicles in the emulsion via dynamic light scattering (DLS). Using DLS, the mean diameter of the vesicles was found to be ~20 nm. AFM imaging of the surface has revealed four types of objects related to NFPh: (1) compact objects; (2) layer fragments; (3) lamellar structures; and (4) combined objects containing the compact and extended parts. For type (4) objects, it has been found that the geometric ratio of the volume of the convex part to the total area of the entire object is constant. It has been proposed that these objects formed owing to fusion of vesicles of the same size (with the same surface-to-volume ratio). It has been shown that this is possible for vesicles with diameters of 20 nm. This diameter is in good coincidence with the value obtained using DLS. [ABSTRACT FROM AUTHOR]

This study shows the possibility of using gallic acid (GA) and/or methyl gallate (MG) accompanied by phosphatidylcholine (PC) instead of tert-butylhydoquinone (TBHQ) for frying purposes. The antioxidants and PC were added in the concentrations of 1.2 mM and 500–2000 mg/kg, respectively. Oxidative stability index (OSI) and the kinetics of change in conjugated dienes (LCD), carbonyls (LCO), and acid value (AV) were used to assess the antioxidative treatments. GA alone and GA/MG (50:50) plus PC at 2000 mg/kg yielded the same OSI as that of TBHQ (18.4 h). The latter was of the highest frying performance in preventing the formation of LCD (rn = 0.0517/h and tT = 10.6 h vs. rn = 0.0976/h and tT = 4.5 h for TBHQ), LCO (rn = 0.0411/h and tT = 12.7 h vs. rn = 0.15/h and tT = 4.3 h for TBHQ), and hydrolytic products (AVm = 37.8 vs. 24.0 for TBHQ); rn: normalized the maximum rate of LCD/LCO accumulation; tT: the time at which the rate of LCD/LCO accumulation is maximized; AVm: quantitative measure of hydrolytic stability. [ABSTRACT FROM AUTHOR]

Cold is an important environmental stress affecting the growth, productivity, and geographic distribution of tree species. Oaks are important for environmental conservation and wood supplies. Oak metabolites respond to low temperatures (LTs). In this study, the physiological and metabolic responses of two oak species to cold stress were investigated and compared. The field observations and physiological responses showed that Quercus wutaishanica was more cold-tolerant than Q. acutissima. After frost, the one-year-old twigs of Q. wutaishanica had higher survival rates, accumulated more soluble sugar and protein, and exhibited higher superoxide dismutase (SOD) activity than those of Q. acutissima. Untargeted metabolomics identified 102 and 78 differentially accumulated metabolites in Q. acutissima and Q. wutaishanica, respectively, when the leaves were subjected to LTs (4 °C for 24 h). The carbohydrate and flavonoid metabolites contributed to the cold tolerance of both oak species. Succinate, an intermediate in the citric acid cycle, was significantly inhibited by LTs, a potential energy conservation strategy. Unlike Q. acutissima, Q. wutaishanica underwent metabolic reprogramming that significantly increased the contents of phosphatidylcholine, gallic acid, oxidized glutathione, shikimate, and phenylpyruvate under LTs. Our data provide a reference for characterizing the mechanisms involved in the response of oak species to cold temperatures and enhancing the cold tolerance of forest trees. [ABSTRACT FROM AUTHOR]

Callistemon citrinus has several biological effects; it is anti-inflammatory, anti-obesogenic, antioxidant, hepatoprotection, and chemoprotective. Its bioactive compounds include terpenoids, phenolic acids, and flavonoids which have low oral bioavailability and absorption. This study aimed at developing phytosomes of C. citrinus to improve oral bioavailability and absorption. Phytosomes were formulated with soybean phosphatidylcholine and C. citrinus leaf extract using the thin layer sonication method. Phytosomes were evaluated by scanning electron microscopy (SEM), entrapment efficiency, solubility, and particle size determination. Antioxidant capacity and total phenolic, flavonoid, and terpenoid contents were also measured. The in vivo anti-obesogenic activity was evaluated. Phytosomes loaded with C. citrinus (P C.c) extract had small spherical shapes. The average particle size was 129.98 ± 18.30 nm, encapsulation efficiency 80.49 ± 0.07%, and solubility 90.00%; the stability study presented no significant changes in the average particle size at 20 °C. P C.c presented high antioxidant capacity. For the first time, ellagic acid is reported in this plant. The in vivo obesity study showed a strong anti-obesogenic activity of phytosomes with C. citrinus to reduce 40% body weight as well as morphometric and biochemical parameters. [ABSTRACT FROM AUTHOR]

Physical activity (PA) is known to have beneficial effects on health, primarily through its antioxidative stress properties. However, the specific metabolic pathways that underlie these effects are not fully understood. This study aimed to investigate the metabolic pathways that are involved in the protective effects of moderate PA in non-obese and healthy individuals. Data on 305 young, non-obese participants were obtained from the Qatar Biobank. The participants were classified as active or sedentary based on their self-reported PA levels. Plasma metabolomics data were collected and analyzed to identify differences in metabolic pathways between the two groups. The results showed that active participants had increased activation of antioxidative, stress-related pathways, including lysoplasmalogen, plasmalogen, phosphatidylcholine, vitamin A, and glutathione. Additionally, there were significant associations between glutathione metabolites and certain clinical traits, including bilirubin, uric acid, hemoglobin, and iron. This study provides new insights into the metabolic pathways that are involved in the protective effects of moderate PA in non-obese and healthy individuals. The findings may have implications for the development of new therapeutic strategies that target these pathways. [ABSTRACT FROM AUTHOR]

Phosphatidylserine (PS) has significant biological and nutritional effects and finds wide applications in the food, pharmaceutical, and chemical industries. To produce high-value PS efficiently, phospholipase D (PLD)-induced transphosphatidylation of low-value phosphatidylcholine (PC) with L-serine has been explored. In this research, we purified recombinant PLD from Streptomyces antibioticus SK-3 using ion exchange chromatography and gel filtration chromatography. Subsequently, we thoroughly characterized the purified enzyme and optimized the transphosphatidylation conditions to identify the most favorable settings for synthesizing PS in a biphasic system. The purified recombinant PLD displayed a robust transphosphatidylation function, facilitating efficient catalysis in the synthesis of PS. Under the optimal conditions (butyl acetate/enzyme solution 1:1, L-serine 160 mg/mL, soybean lecithin 2 mg/mL, and MgCl2 15 mM, at 50 °C for 2.5 h with shaking), we achieved a conversion rate of 91.35% and a productivity of 0.73 g/L/h. These results demonstrate the applicability of the process optimization strategy for using the candidate enzyme in the efficient synthesis of PS. Overall, this study presents a novel and scalable approach for the efficient large-scale synthesis of PS. [ABSTRACT FROM AUTHOR]

Hepatic ischemia/reperfusion injury (IRI) can seriously impair liver function. It is initiated by oxidative stress, resulting in inflammation and apoptosis-induced cellular damage. Glutathione (GSH) prevents oxidative stress. S-Adenosylmethionine (SAMet) is a GSH synthesis precursor that avoids the deficit in SAMet-synthetase activity and contributes to intracellular ATP repletion. It also acts as a methyl group donor, stabilizing hepatocyte membranes, among other functions. This study investigated the effect of SAMet on bacterial translocation and levels of proinflammatory cytokines, oxidative stress and apoptosis markers in male Wistar rats subjected to hepatic IRI. Animals were randomly divided into six groups: (1) sham operation, (3) animals undergoing 60 min of ischemia of the right lateral lobe for temporary occlusion of the portal vein and hepatic artery plus 10 min of reperfusion, and (5) the same as (3) but with a reperfusion period of 120 min. Groups 2, 4 and 6, respectively, are the same as (1), (3) and (5), except that animals received SAMet (20 mg/kg) 15 min before ischemia. GSH, ATP, lipid peroxidation (LPO), TNF-α, IL-1β, IL-6, total caspase-1 and caspase-9, total and cleaved caspase-3, and phosphatidylcholine were determined in the liver. Endotoxin, TNF-α, IL-1β, IL-6, IL-10 and LPO in vena cava and portal vein blood samples were also measured. Endotoxin and LPO levels as well as proinflammatory cytokines and apoptotic markers increased significantly in animals undergoing IRI, both after 10 and 120 min of reperfusion. IRI produced a significant decrease in GSH, ATP, portal IL-10 and phosphatidylcholine. SAMet treatment prevented these effects significantly and increased survival rate. The study suggests that SAMet exerts protective effects in hepatic IRI. [ABSTRACT FROM AUTHOR]

Cholesterol is essential for cellular function and is stored as cholesteryl esters (CEs). CEs biosynthesis is catalyzed by the enzymes acyl-CoA:cholesterol acyltransferase 1 and 2 (ACAT1 and ACAT2), with ACAT1 being the primary isoenzyme in most cells in humans. In Alzheimer's Disease, CEs accumulate in vulnerable brain regions. Therefore, ACATs may be promising targets for treating AD. F12511 is a high-affinity ACAT1 inhibitor that has passed phase 1 safety tests for antiatherosclerosis. Previously, we developed a nanoparticle system to encapsulate a large concentration of F12511 into a stealth liposome (DSPE-PEG2000 with phosphatidylcholine). Here, we injected the nanoparticle encapsulated F12511 (nanoparticle F) intravenously (IV) in wild-type mice and performed an HPLC/MS/MS analysis and ACAT enzyme activity measurement. The results demonstrated that F12511 was present within the mouse brain after a single IV but did not overaccumulate in the brain or other tissues after repeated IVs. A histological examination showed that F12511 did not cause overt neurological or systemic toxicity. We then showed that a 2-week IV delivery of nanoparticle F to aging 3xTg AD mice ameliorated amyloidopathy, reduced hyperphosphorylated tau and nonphosphorylated tau, and reduced neuroinflammation. This work lays the foundation for nanoparticle F to be used as a possible therapy for AD and other neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

The main focus when considering treatment of non-healing and infected wounds is tied to the microbial, particularly bacterial, burden within the wound bed. However, as fungal contributions in these microbial communities become more recognized, the focus needs to be broadened, and the remaining participants in the complex wound microbiome need to be addressed in the development of new treatment strategies. In this study, lecithin/chitosan nanoparticles loaded with clotrimazole were tailored to eradicate one of the most abundant fungi in the wound environment, namely C. albicans. Moreover, this investigation was extended to the building blocks and their organization within the delivery system. In the evaluation of the novel nanoparticles, their compatibility with keratinocytes was confirmed. Furthermore, these biocompatible, biodegradable, and non-toxic carriers comprising clotrimazole (~189 nm, 24 mV) were evaluated for their antifungal activity through both disk diffusion and microdilution methods. It was found that the activity of clotrimazole was fully preserved upon its incorporation into this smart delivery system. These results indicate both that the novel carriers for clotrimazole could serve as a therapeutic alternative in the treatment of fungi-infected wounds and that the building blocks and their organization affect the performance of nanoparticles. [ABSTRACT FROM AUTHOR]

ATP-binding cassette subfamily A member 3 (ABCA3) is a lipid transporter within alveolar type II cells. Patients with bi-allelic variants in ABCA3 may suffer from a variable severity of interstitial lung disease. We characterized and quantified ABCA3 variants' overall lipid transport function by assessing the in vitro impairment of its intracellular trafficking and pumping activity. We expressed the results relative to the wild type, integrated the quantitative readouts from eight different assays and used newly generated data combined with previous results to correlate the variants' function and clinical phenotype. We differentiated normal (within 1 normalized standard deviation (nSD) of the wild-type mean), impaired (within 1 to 3 nSD) and defective (beyond 3 nSD) variants. The transport of phosphatidylcholine from the recycling pathway into ABCA3+ vesicles proved sensitive to the variants' dysfunction. The sum of the quantitated trafficking and pumping predicted a clinical outcome. More than an approximately 50% loss of function was associated with considerable morbidity and mortality. The in vitro quantification of ABCA3 function enables detailed variant characterization, substantially improves the phenotype prediction of genetic variants and possibly supports future treatment decisions. [ABSTRACT FROM AUTHOR]

Hsp70.1 has a dual function as a chaperone protein and lysosomal stabilizer. In 2009, we reported that calpain-mediated cleavage of carbonylated Hsp70.1 causes neuronal death by inducing lysosomal rupture in the hippocampal CA1 neurons of monkeys after transient brain ischemia. Recently, we also reported that consecutive injections of the vegetable oil-peroxidation product 'hydroxynonenal' induce hepatocyte death via a similar cascade in monkeys. As Hsp70.1 is also related to fatty acid β-oxidation in the liver, its deficiency causes fat accumulation. The genetic deletion of betaine-homocysteine S-methyltransferase (BHMT) was reported to perturb choline metabolism, inducing a decrease in phosphatidylcholine and resulting in hepatic steatosis. Here, focusing on Hsp70.1 and BHMT disorders, we studied the mechanisms of hepatocyte degeneration and steatosis. Monkey liver tissues with and without hydroxynonenal injections were compared using proteomics, immunoblotting, immunohistochemical, and electron microscopy-based analyses. Western blotting showed that neither Hsp70.1 nor BHMT were upregulated, but an increased cleavage was observed in both. Proteomics showed a marked downregulation of Hsp70.1, albeit a two-fold increase in the carbonylated BHMT. Hsp70.1 carbonylation was negligible, in contrast to the ischemic hippocampus, which was associated with ~10-fold increments. Although histologically, the control liver showed very little lipid deposition, numerous tiny lipid droplets were seen within and around the degenerating/dying hepatocytes in monkeys after the hydroxynonenal injections. Electron microscopy showed permeabilization/rupture of lysosomal membranes, dissolution of the mitochondria and rough ER membranes, and proliferation of abnormal peroxisomes. It is probable that the disruption of the rough ER caused impaired synthesis of the Hsp70.1 and BHMT proteins, while impairment of the mitochondria and peroxisomes contributed to the sustained generation of reactive oxygen species. In addition, hydroxynonenal-induced disorders facilitated degeneration and steatosis in the hepatocytes. [ABSTRACT FROM AUTHOR]

Due to a worldwide increase in obesity and metabolic disorders such as type 2 diabetes, synthetic sweeteners such as aspartame are frequently used to substitute sugar in the diet. Possible uncertainties regarding aspartame's ability to induce oxidative stress, amongst others, has led to the recommendation of a daily maximum dose of 40 to 50 mg per kg. To date, little is known about the effects of this non-nutritive sweetener on cellular lipid homeostasis, which, besides elevated oxidative stress, plays an important role in the pathogenesis of various diseases, including neurodegenerative diseases such as Alzheimer's disease. In the present study, treatment of the human neuroblastoma cell line SH-SY5Y with aspartame (271.7 µM) or its three metabolites (aspartic acid, phenylalanine, and methanol (271.7 µM)), generated after digestion of aspartame in the human intestinal tract, resulted in significantly elevated oxidative stress associated with mitochondrial damage, which was illustrated with reduced cardiolipin levels, increased gene expression of SOD1/2, PINK1, and FIS1, and an increase in APF fluorescence. In addition, treatment of SH-SY5Y cells with aspartame or aspartame metabolites led to a significant increase in triacylglycerides and phospholipids, especially phosphatidylcholines and phosphatidylethanolamines, accompanied by an accumulation of lipid droplets inside neuronal cells. Due to these lipid-mediating properties, the use of aspartame as a sugar substitute should be reconsidered and the effects of aspartame on the brain metabolism should be addressed in vivo. [ABSTRACT FROM AUTHOR]

The in vivo roles of lysophospholipase, which cleaves a fatty acyl ester of lysophospholipid, remained unclear. Recently, we have unraveled a previously unrecognized physiological role of the lysophospholipase PNPLA7, a member of the Ca2+-independent phospholipase A2 (iPLA2) family, as a key regulator of the production of glycerophosphocholine (GPC), a precursor of endogenous choline, whose methyl groups are preferentially fluxed into the methionine cycle in the liver. PNPLA7 deficiency in mice markedly decreases hepatic GPC, choline, and several metabolites related to choline/methionine metabolism, leading to various symptoms reminiscent of methionine shortage. Overall metabolic alterations in the liver of Pnpla7-null mice in vivo largely recapitulate those in methionine-deprived hepatocytes in vitro. Reduction of the methyl donor S-adenosylmethionine (SAM) after methionine deprivation decreases the methylation of the PNPLA7 gene promoter, relieves PNPLA7 expression, and thereby increases GPC and choline levels, likely as a compensatory adaptation. In line with the view that SAM prevents the development of liver cancer, the expression of PNPLA7, as well as several enzymes in the choline/methionine metabolism, is reduced in human hepatocellular carcinoma. These findings uncover an unexplored role of a lysophospholipase in hepatic phospholipid catabolism coupled with choline/methionine metabolism. [ABSTRACT FROM AUTHOR]

Gemfibrozil is a drug that has been used for over 40 years to lower triglycerides in blood. As a ligand for peroxisome proliferative-activated receptor-alpha (PPARα), which is expressed in many tissues, it induces the transcription of numerous genes for carbohydrate and lipid-metabolism. However, nothing is known about how intracellular lipid-homeostasis and, in particular, triglycerides are affected. As triglycerides are stored in lipid-droplets, which are known to be associated with many diseases, such as Alzheimer's disease, cancer, fatty liver disease and type-2 diabetes, treatment with gemfibrozil could adversely affect these diseases. To address the question whether gemfibrozil also affects intracellular lipid-levels, SH-SY5Y, HEK and Calu-3 cells, representing three different metabolically active organs (brain, lung and kidney), were incubated with gemfibrozil and subsequently analyzed semi-quantitatively by mass-spectrometry. Importantly, all cells showed a strong increase in intracellular triglycerides (SH-SY5Y: 170.3%; HEK: 272.1%; Calu-3: 448.1%), suggesting that the decreased triglyceride-levels might be due to an enhanced cellular uptake. Besides the common intracellular triglyceride increase, a cell-line specific alteration in acylcarnitines are found, suggesting that especially in neuronal cell lines gemfibrozil increases the transport of fatty acids to mitochondria and therefore increases the turnover of fatty acids for the benefit of additional energy supply, which could be important in diseases, such as Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Plasma trimethylamine n-oxide (TMAO) concentration increases in responses to feeding TMAO, choline, phosphatidylcholine, L-carnitine, and betaine but it is unknown whether concentrations change following a mixed macronutrient tolerance test (MMTT) with limited amounts of TMAO precursors. In this proof-of-concept study, we provided healthy female and male adults (n = 97) ranging in age (18–65 years) and BMI (18–44 kg/m2) a MMTT (60% fat, 25% sucrose; 42% of a standard 2000 kilo calorie diet) and recorded their metabolic response at fasting and at 30 min, 3 h, and 6 h postprandially. We quantified total exposure to TMAO (AUC-TMAO) and classified individuals by the blood draw at which they experienced their maximal TMAO concentration (TMAO-response groups). We related AUC-TMAO to the 16S rRNA microbiome, to two SNPs in the exons of the FMO3 gene (rs2266782, G>A, p.Glu158Lys; and rs2266780, A>G, p.Glu308Gly), and to a priori plasma metabolites. We observed varying TMAO responses (timing and magnitude) and identified a sex by age interaction such that AUC-TMAO increased with age in females but not in males (p-value = 0.0112). Few relationships between AUC-TMAO and the fecal microbiome and FMO3 genotype were identified. We observed a strong correlation between AUC-TMAO and TNF-α that depended on TMAO-response group. These findings promote precision nutrition and have important ramifications for the eating behavior of adults who could benefit from reducing TMAO exposure, and for understanding factors that generate plasma TMAO. [ABSTRACT FROM AUTHOR]

Simple Summary: The application of non-steroidal anti-inflammatory drugs (NSAIDs) in cancer therapy has been a widely studied topic for almost four decades. This review summarizes the information about the role of chronic inflammation in the process of carcinogenesis and the evidence regarding the anti-cancer activity of the most frequently used NSAIDs. Despite the promising results of NSAIDs, the possibilities of the practical application of this group of drugs in chemoprevention and cancer therapies on a clinical basis are still impossible due to individual side effects. The main concern is their gastrointestinal toxicity. For this reason, several strategies are still under investigation to reduce toxicity and improve the efficacy of NSAIDs. In this review, we emphasize the effectiveness of combinations of NSAIDs with chemotherapeutic drugs in in vitro and in vivo models as well as in clinical trials. We also present new concepts based on the molecular hybridization of anti-inflammatory drugs with other biologically active molecules, such as phospholipids and terpenes, as solutions for reducing NSAID side effects. The production of derivatives with enhanced biological potentials could also be carried out to target rare types of cancers. Therefore, this manuscript provides new insight into the possibilities of re-purposing NSAIDs for new, outside-the-current-scope applications. Non-steroidal anti-inflammatory drugs (NSAIDs) express anti-tumoral activity mainly by blocking cyclooxygenase-2 involved in the synthesis of prostaglandins. Therefore, in the last few decades, many have attempted to explore the possibilities of applying this group of drugs as effective agents for the inhibition of neoplastic processes. This review summarizes the evidence presented in the literature regarding the anti-tumoral actions of NSAIDs used as monotherapies as well as in combination with conventional chemotherapeutics and natural products. In several clinical trials, it was proven that combinations of NSAIDs and chemotherapeutic drugs (CTDs) were able to obtain suitable results. The combination with phospholipids may resolve the adverse effects of NSAIDs and deliver derivatives with increased antitumor activity, whereas hybrids with terpenoids exhibit superior activity against their parent drugs or physical mixtures. Therefore, the application of NSAIDs in cancer therapy seems to be still an open chapter and requires deep and careful evaluation. The literature's data indicate the possibilities of re-purposing anti-inflammatory drugs currently approved for cancer treatments. [ABSTRACT FROM AUTHOR]

Smoking-derived nicotine (N) and oral contraceptive (OC) synergistically exacerbate ischemic brain damage in females, and the underlying mechanisms remain elusive. In a previous study, we showed that N + OC exposure altered brain glucose metabolism in females. Since lipid metabolism complements glycolysis, the current study aims to examine the metabolic fingerprint of fatty acids in the brain of female rats exposed to N+/−OC. Adolescent and adult Sprague–Dawley female rats were randomly (n = 8 per group) exposed to either saline or N (4.5 mg/kg) +/−OC (combined OC or placebo delivered via oral gavage) for 16–21 days. Following exposure, brain tissue was harvested for unbiased metabolomic analysis (performed by Metabolon Inc., Morrisville, NC, USA) and the metabolomic profile changes were complemented with Western blot analysis of key enzymes in the lipid pathway. Metabolomic data showed significant accumulation of fatty acids and phosphatidylcholine (PC) metabolites in the brain. Adolescent, more so than adult females, exposed to N + OC showed significant increases in carnitine-conjugated fatty acid metabolites compared to saline control animals. These changes in fatty acyl carnitines were accompanied by an increase in a subset of free fatty acids, suggesting elevated fatty acid β-oxidation in the mitochondria to meet energy demand. In support, β-hydroxybutyrate was significantly lower in N + OC exposure groups in adolescent animals, implying a complete shunting of acetyl CoA for energy production via the TCA cycle. The reported changes in fatty acids and PC metabolism due to N + OC could inhibit post-translational palmitoylation of membrane proteins and synaptic vesicle formation, respectively, thus exacerbating ischemic brain damage in female rats. [ABSTRACT FROM AUTHOR]

Administration of systemic retinoids such as acitretin has not been approved yet for pediatric patients. An adverse event of retinoid-therapy that occurs with lower prevalence in children than in adults is hyperlipidemia. This might be based on the lack of comorbidities in young patients, but must not be neglected. Especially for the development of the human brain up to young adulthood, dysbalance of lipids might be deleterious. Here, we provide for the first time an in-depth analysis of the influence of subchronic acitretin-administration on lipid composition of brain parenchyma of young wild type mice. For comparison and to evaluate the systemic effect of the treatment, liver lipids were analogously investigated. As expected, triglycerides increased in liver as well as in brain and a non-significant increase in cholesterol was observed. However, specifically brain showed an increase in lyso-phosphatidylcholine and carnitine as well as in sphingomyelin. Group analysis of lipid classes revealed no statistical effects, while single species were tissue-dependently changed: effects in brain were in general more subtly as compared to those in liver regarding the mere number of changed lipid species. Thus, while the overall impact of acitretin seems comparably small regarding brain, the change in individual species and their role in brain development and maturation has to be considered. [ABSTRACT FROM AUTHOR]

Background and Objectives: Receptors of the advanced glycation products (RAGE) are activated to promote cell death and contributes to chronic diseases such as diabetes and inflammation. Advanced glycation end products (AGEs), which interact with RAGE are complex compounds synthesized during diabetes development and are presumed to play a significant role in pathogenesis of diabetes. Phosphatidylcholine (PC), a polyunsaturated fatty acid found in egg yolk, mustard, and soybean, is thought to exert anti-inflammatory activity. We investigated the effects of PC on AGEs-induced hepatic and renal cell injury. Materials and Methods: In this study, we evaluated cytokine and NF-κB/MAPK signal pathway activity in AGEs induced human liver (HepG2) cells and human kidney (HK2) cells with and without PC treatment. Results: PC reduced RAGE expression and attenuated levels of inflammatory cytokines and NF-kB/MAPK signaling. Moreover, cells treated with PC exhibited a significant reduction in cytotoxicity, oxidative stress, and inflammatory factor levels. Conclusions: These findings suggest that PC could be an effective functional material for hepatic and renal injury involving with oxidative stress caused by AGEs during diabetic conditions. [ABSTRACT FROM AUTHOR]

Phosphatidylinositol-specific phospholipase C (PI-PLC) enzymes are a virulence factor in many Gram-positive organisms. The specific activity of the Bacillus thuringiensis PI-PLC is significantly increased by adding phosphatidylcholine (PC) to vesicles composed of the substrate phosphatidylinositol, in part because the inclusion of PC reduces the apparent Kd for the vesicle binding by as much as 1000-fold when comparing PC-rich vesicles to PI vesicles. This review summarizes (i) the experimental work that localized a site on BtPI-PLC where PC is bound as a PC choline cation—Tyr-π complex and (ii) the computational work (including all-atom molecular dynamics simulations) that refined the original complex and found a second persistent PC cation—Tyr-π complex. Both complexes are critical for vesicle binding. These results have led to a model for PC functioning as an allosteric effector of the enzyme by altering the protein dynamics and stabilizing an 'open' active site conformation. [ABSTRACT FROM AUTHOR]

Urothelium is a transitional, stratified epithelium that lines the lower urinary tract, providing a tight barrier to urine whilst retaining the capacity to stretch and rapidly resolve damage. The role of glycerophospholipids in urothelial barrier function is largely unknown, despite their importance in membrane structural integrity, protein complex assembly, and the master regulatory role of PPARγ in urothelial differentiation. We performed lipidomic and transcriptomic characterisation of urothelial differentiation, revealing a metabolic switch signature from fatty acid synthesis to lipid remodelling, including 5-fold upregulation of LPCAT4. LPCAT4 knockdown urothelial cultures exhibited an impaired proliferation rate but developed elevated trans-epithelial electrical resistances upon differentiation, associated with a reduced and delayed capacity to restitute barrier function after wounding. Specific reduction in 18:1 PC fatty acyl chains upon knockdown was consistent with LPCAT4 specificity, but was unlikely to elicit broad barrier function changes. However, transcriptomic analysis of LPCAT4 knockdown supported an LPC-induced reduction in DAG availability, predicted to limit PKC activity, and TSPO abundance, predicted to limit endogenous ATP. These phenotypes were confirmed by PKC and TSPO inhibition. Together, these data suggest an integral role for lipid mediators in urothelial barrier function and highlight the strength of combined lipidomic and transcriptomic analyses for characterising tissue homeostasis. [ABSTRACT FROM AUTHOR]

Polar lipids were extracted from residual biomass of hemp (Cannabis sativa L.) by-products with EtOH and partitioned into aqueous and chloroform fractions. The chloroform fractions were studied for their lipid composition using solid-phase extraction (SPE) followed by UHPLC/HRMS and NMR analyses. The 1H NMR and gravimetric yield of SPE indicated triacylglycerols covered ≥ 51.3% of the chloroform fraction of hemp seed hulls and hemp cake. UHPLC/HRMS analyses of remaining polar lipids led to the identification of nine diacylglycerols (DAGs), six lysophosphatidylcholines (LPCs), five lysophosphatidylethanolamines (LPEs), eight phosphatidylethanolamines (PEs), and thirteen phosphatidylcholines (PCs) for the first time from hemp seed hulls. The regiospecificity of fatty acyl substitutes in glycerol backbone of individual phospholipids were assigned by analyzing the diagnostic fragment ions and their intensities. The heat-map analysis suggested that DAG 18:2/18:2, 1-LPC 18:2, 1-LPE 18:2, PE 18:2/18:2, and PC 18:2/18:2 were the predominant molecules within their classes, supported by the fact that linoleic acid was the major fatty acid covering > 41.1% of the total fatty acids determined by GC-FID analysis. The 31P NMR analysis confirmed the identification of phospholipids and suggested PC covers ≥ 37.9% of the total phospholipid present in hemp by-products. HPLC purification led to the isolation of 1,2-dilinoleoylphosphatidylcholine and 1-palmitoyl-2-linoleoylphosphatidylcholine. These two major PCs further confirmed the UHPLC/HRMS finding. [ABSTRACT FROM AUTHOR]

Isoprenoids are natural compounds essential for a great number of cellular functions. One of them is farnesol (FOH), which can reduce cell proliferation, but its low solubility in aqueous solvents limits its possible clinical use as a pharmacological tool. One alternative is the use of cyclodextrins (CDs) which house hydrophobic molecules forming inclusion complexes. To assess FOH potential application in anticancer treatments, Sulfobutylated β-cyclodextrin Sodium Salt (SBE-β-CD) was selected, due to it has high solubility, approbation by the FDA, and numerous studies that ensure its safety to be administered parenterally or orally without nephrotoxicity associated. The therapeutic action of farnesol and complex were studied in different carcinoma cells, compared with a normal cell line. Farnesol showed selectivity, affecting the viability of colon and liver cancer cells more than in breast cancer cells and fibroblasts. All cells suffered apoptosis after being treated with 150 μM of free FOH, but the complex reduced their cell viability between 50 and 75%. Similar results were obtained for both types of isomers, and the addition of phosphatidylcholine reverses this effect. Finally, cell cycle analysis corroborates the action of FOH as inducer of a G0/G1 phase; when the cells were treated using the complex form, this viability was reduced, reaching 50% in the case of colon and liver, 60% in fibroblasts, and only 75% in breast cancer. [ABSTRACT FROM AUTHOR]

Legionella spp. cause Legionnaires' disease with pneumonia as the predominant clinical symptom. L. gormanii is the second most prevalent causative agent of community-acquired pneumonia after L. pneumophila. The study aimed to characterize the lipidome of L. gormanii membranes and the importance of these analyses in bacterial chemotaxonomy. Lipidomic analyses based on ultra-high performance liquid chromatography-mass spectrometry allowed the detection of individual molecular species of a wide range of L. gormanii membrane lipids contained in the outer (OM) and inner membranes (IM). The lipid profile comprised glycerolipids (triglycerides, diglycerides), phospholipids (phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, cardiolipin), and sphingolipids (ceramides, hexosylceramides). The most abundant lipid fraction in the IM and OM were phospholipids. The lipidomic analysis showed that two independent phosphatidylcholine (PC) synthesis pathways operating in L. gormanii: the PE-methylation (PmtA) pathway and the PC synthase (Pcs) pathway. Comparison of the molecular profile of PC species contained in the lipids of L. gormanii membranes cultured on the medium, with and without exogenous choline, showed quantitative differences in the PC pool. An unusual feature of the L. gormanii lipids was the presence of ceramides and hexosylceramides, which are typical components of eukaryotic cells and a very small group of bacteria. To the best of our knowledge, this is the first report of the occurrence of ceramides in Legionella bacteria. [ABSTRACT FROM AUTHOR]

Patatin-like phospholipase domain-containing protein 6 (PNPLA6), originally called Neuropathy Target Esterase (NTE), belongs to a family of hydrolases with at least eight members in mammals. PNPLA6/NTE was first identified as a key factor in Organophosphate-induced delayed neuropathy, a degenerative syndrome that occurs after exposure to organophosphates found in pesticides and nerve agents. More recently, mutations in PNPLA6/NTE have been linked with a number of inherited diseases with diverse clinical symptoms that include spastic paraplegia, ataxia, and chorioretinal dystrophy. A conditional knockout of PNPLA6/NTE in the mouse brain results in age-related neurodegeneration, whereas a complete knockout causes lethality during embryogenesis due to defects in the development of the placenta. PNPLA6/NTE is an evolutionarily conserved protein that in Drosophila is called Swiss-Cheese (SWS). Loss of SWS in the fly also leads to locomotory defects and neuronal degeneration that progressively worsen with age. This review will describe the identification of PNPLA6/NTE, its expression pattern, and normal role in lipid homeostasis, as well as the consequences of altered NPLA6/NTE function in both model systems and patients. [ABSTRACT FROM AUTHOR]

Lipid vesicles (liposomes) are a unique and fascinating type of polymolecular aggregates, obtained from bilayer-forming amphiphiles—or mixtures of amphiphiles—in an aqueous medium. Unilamellar vesicles consist of one single self-closed bilayer membrane, constituted by the amphiphiles and an internal volume which is trapped by this bilayer, whereby the vesicle often is spherical with a typical desired average diameter of either about 100 nm or tens of micrometers. Functionalization of the external vesicle surface, basically achievable at will, and the possibilities of entrapping hydrophilic molecules inside the vesicles or/and embedding hydrophobic compounds within the membrane, resulted in various applications in different fields. This review highlights a few of the basic studies on the phase behavior of polar lipids, on some of the concepts for the controlled formation of lipid vesicles as dispersed lamellar phase, on some of the properties of vesicles, and on the challenges of efficiently loading them with hydrophilic or hydrophobic compounds for use as delivery systems, as nutraceuticals, for bioassays, or as cell-like compartments. Many of the large number of basic studies have laid a solid ground for various applications of polymolecular aggregates of amphiphilic lipids, including, for example, cubosomes, bicelles or—recently most successfully—nucleic acids-containing lipid nanoparticles. All this highlights the continued importance of fundamental studies. The life-saving application of mRNA lipid nanoparticle COVID-19 vaccines is in part based on year-long fundamental studies on the formation and properties of lipid vesicles. It is a fascinating example, which illustrates the importance of considering (i) details of the chemical structure of the different molecules involved, as well as (ii) physical, (iii) engineering, (iv) biological, (v) pharmacological, and (vii) economic aspects. Moreover, the strong demand for interdisciplinary collaboration in the field of lipid vesicles and related aggregates is also an excellent and convincing example for teaching students in the field of complex molecular systems. [ABSTRACT FROM AUTHOR]

The vibrational signature in the far-infrared region of two different phospholipids, phosphatidylcholine (PC) and phosphatidylethanolamine (PE), was investigated as a function of relative humidity from 0 to 75% in order to evaluate the effect of headgroup composition on the formation of intermolecular interactions. The substructures of the frequency region between 50 and 300 cm−1 were identified, and changes in the frequency and intensity of the related vibrations with hydration were analyzed. Interestingly, in PE, two additional vibrational bands with respect to PC were found at 162 and 236 cm−1 and assigned to intermolecular hydrogen bonds between the hydrogen-bond-donating groups, - NH 3 + , and hydrogen-bond-accepting groups, —P—O− and —COO, of adjacent molecules. The presence of these interactions also affected the penetration of water, severely reducing the hydration capability of PE lipids. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to characterize the disorder of lipid metabolism in hepatocellular carcinoma (HCC). HCC is a worldwide disease. The research into the disorder of lipid metabolism in HCC is very limited. Study of lipid metabolism in liver cancer tissue may have the potential to provide new insight into HCC mechanisms. Methods: A lipidomics study of HCC based on Ultra high performance liquid chromatography-electronic spray ionization-QTOF mass spectrometer (UPLC-ESI-QTOF MS) and Matrix assisted laser desorption ionization-fourier transform ion cyclotron resonance mass spectrometer (MALDI-FTICR MS) was performed. Results: Triacylglycerols (TAGs) with the number of double bond (DB) > 2 (except 56:5 and 56:4 TAG) were significantly down-regulated; conversely, others (except 52:2 TAG) were greatly up-regulated in HCC tissues. Moreover, the more serious the disease was, the higher the saturated TAG concentration and the lower the polyunsaturated TAG concentration were in HCC tissues. The phosphatidylcholine (PC), phosphatidylethanolamine (PE) and phosphatidylinositol (PI) were altered in a certain way. Sphingomyelin (SM) was up-regulated and ceramide (Cer) were down-regulated in HCC tissues. Conclusions: To our knowledge, this is the first such report showing a unique trend of TAG, PC, PE and PI. The use of polyunsaturated fatty acids, like eicosapentanoic and docosahexanoic acid, as supplementation, proposed for the treatment of Non-alcoholic steatohepatitis (NASH), may also be effective for the treatment of HCC. [ABSTRACT FROM AUTHOR]

Study objectives were to examine the impact of feeding a mixture of choline forms, or a diet high in glycerophosphocholine (GPC) on maternal immune function and offspring growth during lactation. Lactating Sprague-Dawley rat dams (n = 6/diet) were randomized to one of three diets, providing 1 g/kg total choline: Control (100% free choline (FC)), Mixed Choline (MC; 50% phosphatidylcholine (PC), 25% FC, 25% GPC), or High GPC (HGPC; 75% GPC, 12.5% PC, 12.5% FC). At 3 weeks, cell phenotypes and cytokine production with Concanavalin A (ConA)-or lipopolysaccharide (LPS)-stimulated splenocytes and mesenteric lymphocytes were measured. Feeding MC or HGPC diets improved pups' growth compared to Control (+22% body weight, p < 0.05). In spleen, MC-and HGPC-fed dams had higher proportions of cytotoxic (CD8+) T cells expressing CD27, CD71 and CD127, total B cells (CD45RA+) and dendritic cells (OX6+OX62+), and produced less IL-6 and IFN- after ConA than Control-fed dams (p < 0.05). MC and HGPC LPS-stimulated splenocytes produced less IL-1β and IL-6 than Control. ConA-stimulated mesenteric lymphocytes from MC and HGPC dams produced more IL-2 and IFN- than Control (p < 0.05). In summary, feeding a mixture of choline forms during lactation improved offspring growth and resulted in a more efficient maternal immune response following mitogenic immune challenge. [ABSTRACT FROM AUTHOR]