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The motor features of Parkinson's disease result from loss of dopaminergic neurons in the substantia nigra with autophagy dysfunction being closely linked to this disease. While a large body of work focusing on protein effectors of autophagy has been reported, regulation of autophagy by lipids has garnered far less attention. Therefore, we sought to identify endogenous lipid molecules that act as signaling mediators of autophagy in differentiated SH-SY5Y cells, a commonly used dopaminergic neuron-like cell model. In order to accomplish this goal, we assessed the role of a fatty acid-binding protein (FABP) family member on autophagy due to its function as an intracellular lipid chaperone. We focused specifically upon FABP5 due to its heightened expression in dopaminergic neurons within the substantia nigra and SH-SY5Y cells. Here, we report that knockdown of FABP5 resulted in suppression of autophagy in differentiated SH-SY5Y cells suggesting the possibility of an autophagic role for an interacting lipid. A lipidomic screen of FABP5-interacting lipids uncovered hits that include 5-oxo-eicosatetraenoic acid (5OE) and its precursor metabolite, arachidonic acid (AA). Additionally, other long-chain fatty acids were found to bind FABP5, such as stearic acid (SA), hydroxystearic acid (HSA), and palmitic acid (PA). The addition of 5OE, SA, and HSA but not AA or PA, led to potent inhibition of autophagy in SH-SY5Y cells. To identify potential molecular mechanisms for autophagy inhibition by these lipids, RNA-Seq was performed which revealed both shared and divergent signaling pathways between the lipid-treated groups. These findings suggest a role for these lipids in modulating autophagy through diverse signaling pathways and could represent novel therapeutic targets for Parkinson's disease. [ABSTRACT FROM AUTHOR]

The current study aimed to assess the influence of dietary inclusion of cyanobacterium Arthrospira platensis NIOF17/003 as a dry material and as a free-lipid biomass (FL) on the growth performance, body composition, redox status, immune responses, and gene expression of whiteleg shrimp, Litopenaeus vannamei postlarvae. L. vannamei were fed five different supplemented diets; the first group was fed on an un-supplemented diet as a negative control group (C-N), the second group was fed on a commercial diet supplemented with 2% of A. platensis complete biomass as a positive control group (C-P20), whereas, the three remaining groups were fed on a commercial diet supplemented with graded amounts of FL at 1%, 2%, and 3% (FL10, FL20, and FL30, respectively). The obtained results indicated that the diet containing 1% FL significantly increased the growth performance, efficiency of consumed feed, and survival percentage of L. vannamei compared to both C-N and C-P20 groups. As for the carcass analysis, diets containing A. platensis or its FL at higher levels significantly increased the protein, lipid, and ash content compared to the C-N group. Moreover, the shrimp group fed on C-P20 and FL10 gave significantly stimulated higher digestive enzyme activities compared with C-N. The shrimp fed C-P20 or FL exhibited higher innate immune responses and promoted their redox status profile. Also, the shrimp fed a low FL levels significantly upregulated the expression of both the peroxiredoxin (Prx) and prophenoloxidase (PPO1) genes than those receiving C-N. The current results recommended that dietary supplementation with 1% FL is the most effective treatment in promoting the performance and immunity of whiteleg shrimp. [ABSTRACT FROM AUTHOR]

This retrospective study aimed to evaluate the effects on the clinical signs of poisoning and adverse effects of intravenous lipid emulsion treatment in 82 animals (dogs and cats) with suspected poisonings over 18 months. Physical examination parameters and state of consciousness were documented every hour after the intravenous administration of a bolus of 2 ml/kg and 0.25 ml/kg/min over 60 minutes of a 20% intravenous lipid emulsion. The modified Glasgow coma scale and laboratory findings (blood gas analysis, triglyceride, lactate) were evaluated initially and three hours after discontinuing intravenous lipid emulsion administration. A statistical evaluation of the occurrence of adverse effects and the development of laboratory values was performed. A decrease in respiratory rate in the second control (8–12 hours) after ILE was observed. Three hours after completing of the intravenous lipid emulsion, triglyceride concentration increased about 10 times (p <0.001). Venous carbon dioxide partial pressure, bicarbonate, base excess, as well as the electrolytes sodium, potassium and ionized calcium decreased significantly (p <0.001). Patients who experienced a worsening of the modified Glasgow coma scale had a higher increase in triglyceride concentrations (p = 0.041) and plasma lactate (p = 0.034) and a larger decrease in bicarbonate concentrations (p = 0.053) compared to others. About 54% (n = 44) of the patients showed adverse effects which could be attributed to the administration of intravenous lipid emulsion and may be associated with a higher triglyceride increase. All of them were completely reversible within 33 hours. Adverse effects associated with intravenous lipid emulsion therapy were observed in half of the patients and were associated with a higher increase in triglycerides. [ABSTRACT FROM AUTHOR]

Food allergy is widely recognized as a significant health issue, having escalated into a global epidemic, subsequently giving rise to the development of numerous additional complications. Currently, the sole efficient method to curb the progression of allergy is through the implementation of an elimination diet. The increasing number of newly identified allergens makes it harder to completely remove or avoid them effectively. The immunoreactivity of proteins of bacterial origin remains an unexplored topic. Despite the substantial consumption of microbial proteins in our diets, the immunologic mechanisms they might induce require thorough validation. This stands as the primary objective of this study. The primary objective of this study was to evaluate the effects of bacterial proteins on the intestinal barrier and immune system parameters during hypersensitivity induction in both developing and mature organisms. The secondary objective was to evaluate the role of lipids in the immunoreactivity programming of these bacterial proteins. Notably, in this complex, comprehensively designed in vitro, in vivo, and ex vivo trial, the immunoreactivity of various bacterial proteins will be examined. In summary, the proposed study intends to address the knowledge gaps regarding the effects of Lactobacillus microbial proteins on inflammation, apoptosis, autophagy, and intestinal barrier integrity in a single study. [ABSTRACT FROM AUTHOR]

Peptidoglycan (PG) and most surface glycopolymers and their modifications are built in the cytoplasm on the lipid carrier undecaprenyl phosphate (UndP). These lipid-linked precursors are then flipped across the membrane and polymerized or directly transferred to surface polymers, lipids, or proteins. Despite its essential role in envelope biogenesis, UndP is maintained at low levels in the cytoplasmic membrane. The mechanisms by which bacteria distribute this limited resource among competing pathways is currently unknown. Here, we report that the Bacillus subtilis transcription factor SigM and its membrane-anchored anti-sigma factor respond to UndP levels and prioritize its use for the synthesis of the only essential surface polymer, the cell wall. Antibiotics that target virtually every step in PG synthesis activate SigM-directed gene expression, confounding identification of the signal and the logic of this stress-response pathway. Through systematic analyses, we discovered 2 distinct responses to these antibiotics. Drugs that trap UndP, UndP-linked intermediates, or precursors trigger SigM release from the membrane in <2 min, rapidly activating transcription. By contrasts, antibiotics that inhibited cell wall synthesis without directly affecting UndP induce SigM more slowly. We show that activation in the latter case can be explained by the accumulation of UndP-linked wall teichoic acids precursors that cannot be transferred to the PG due to the block in its synthesis. Furthermore, we report that reduction in UndP synthesis rapidly induces SigM, while increasing UndP production can dampen the SigM response. Finally, we show that SigM becomes essential for viability when the availability of UndP is restricted. Altogether, our data support a model in which the SigM pathway functions to homeostatically control UndP usage. When UndP levels are sufficiently high, the anti-sigma factor complex holds SigM inactive. When levels of UndP are reduced, SigM activates genes that increase flux through the PG synthesis pathway, boost UndP recycling, and liberate the lipid carrier from nonessential surface polymer pathways. Analogous homeostatic pathways that prioritize UndP usage are likely to be common in bacteria. How do bacteria distribute the use of the lipid carrier, UndP, to the various pathways that require it? This study shows that the Bacillus subtilis transcription factor sigma-M and its membrane-anchored anti-sigma factor monitor UndP levels and prioritize its use for cell wall synthesis. [ABSTRACT FROM AUTHOR]

Background: Past studies have demonstrated that patients diagnosed with rheumatoid arthritis (RA) often exhibit abnormal levels of lipids. Furthermore, certain lipid-modifying medications have shown effectiveness in alleviating clinical symptoms associated with RA. However, the current understanding of the causal relationship between lipids, lipid-modifying medications, and the risk of developing RA remains inconclusive. This study employed Mendelian randomization (MR) to investigate the causal connection between lipids, lipid-modifying drugs, and the occurrence of RA. Methods: We obtained genetic variation for lipid traits and drug targets related to lipid modification from three sources: the Global Lipids Genetics Consortium (GLGC), UK Biobank, and Nightingale Health 2020. The genetic data for RA were acquired from two comprehensive meta-analyses and the R8 of FINNGEN, respectively. These variants were employed in drug-target MR analyses to establish a causal relationship between genetically predicted lipid-modifying drug targets and the risk of RA. For suggestive lipid-modified drug targets, we conducted Summary-data-based Mendelian Randomization (SMR) analyses and using expression quantitative trait loci (eQTL) data in relevant tissues. In addition, we performed co-localization analyses to assess genetic confounders. Results: Our analysis revealed no significant causal relationship between lipid and RA. We observed that the genetically predicted 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) -mediated low density lipoprotein cholesterol (LDL-C) (OR 0.704; 95% CI 0.56, 0.89; P = 3.43×10−3), Apolipoprotein C-III (APOC3) -mediated triglyceride (TG) (OR 0.844; 95% CI 0.77, 0.92; P = 1.50×10−4) and low density lipoprotein receptor (LDLR) -mediated LDL-C (OR 0.835; 95% CI 0.73, 0.95; P = 8.81×10−3) were significantly associated with a lowered risk of RA. while Apolipoprotein B-100 (APOB) -mediated LDL-C (OR 1.212; 95%CI 1.05,1.40; P = 9.66×10−3) was significantly associated with an increased risk of RA. Conclusions: Our study did not find any supporting evidence to suggest that lipids are a risk factor for RA. However, we observed significant associations between HMGCR, APOC3, LDLR, and APOB with the risk of RA. [ABSTRACT FROM AUTHOR]

Lipids stored in lipid-bodies (LBs) in host cells are potential sources of fatty acids for pathogens. However, the mechanism of recruitment of LBs from the host cells by pathogens to acquire fatty acids is not known. Here, we have found that Leishmania specifically upregulates the expression of host Rab18 and its GEF, TRAPPC9 by downregulating the expression of miR-1914-3p by reducing the level of Dicer in macrophages via their metalloprotease gp63. Our results also show that miR-1914-3p negatively regulates the expression of Rab18 and its GEF in cells. Subsequently, Leishmania containing parasitophorous vacuoles (Ld-PVs) recruit and retain host Rab18 and TRAPPC9. Leishmania infection also induces LB biogenesis in host cells and recruits LBs on Ld-PVs and acquires FLC12-labeled fatty acids from LBs. Moreover, overexpression of miR-1914-3p in macrophages significantly inhibits the recruitment of LBs and thereby suppresses the multiplication of parasites in macrophages as parasites are unable to acquire fatty acids. These results demonstrate a novel mechanism how Leishmania acquire fatty acids from LBs for their growth in macrophages. Author summary: Leishmania donovani which causes fatal disease known as visceral leishmaniasis, is dependent on its host to scavenge fatty acids for its survival. But, how Leishmania get fatty acids from host macrophages is not known. Lipid bodies are unique organelles that contain neutral lipids and fatty acids, therefore, LBs in macrophages could be the potential source of fatty acids for parasites. We have found that Leishmania upregulate the expression of host Rab18 and its GEF by downregulating the expression of miR-1914-3p in infected macrophages via the Ld-gp63-mediated inhibition of dicer expression. As biogenesis of LBs is shown to be regulated by Rab18, we have found that Leishmania infection induces LB biogenesis in macrophages and subsequently recruits LBs along with Rab18 and its GEF on Leishmania containing parasitophorous vacuoles. Finally, parasites-containing vacuoles acquire FLC12-labeled fatty acids from LBs to meet their nutritional requirement. We have also shown that overexpression of miR-1914-3p in macrophages significantly inhibits the recruitment of LBs and thereby suppresses the growth of parasites in macrophages as parasites are unable to acquire nutrients from LBs. These results demonstrate how Leishmania acquire nutrients like fatty acids from LBs for their proliferation in macrophages. [ABSTRACT FROM AUTHOR]

Vacuolar pathogens reside in membrane-bound compartments within host cells. Maintaining the integrity of this compartment is paramount to bacterial survival and replication as it protects against certain host surveillance mechanisms that function to eradicate invading pathogens. Preserving this compartment during bacterial replication requires expansion of the vacuole membrane to accommodate the increasing number of bacteria, and yet, how this is accomplished remains largely unknown. Here, we show that the vacuolar pathogen Legionella pneumophila exploits multiple sources of host cell fatty acids, including inducing host cell fatty acid scavenging pathways, in order to promote expansion of the replication vacuole and bacteria growth. Conversely, when exogenous lipids are limited, the decrease in host lipid availability restricts expansion of the replication vacuole membrane, resulting in a higher density of bacteria within the vacuole. Modifying the architecture of the vacuole prioritizes bacterial growth by allowing the greatest number of bacteria to remain protected by the vacuole membrane despite limited resources for its expansion. However, this trade-off is not without risk, as it can lead to vacuole destabilization, which is detrimental to the pathogen. However, when host lipid resources become extremely scarce, for example by inhibiting host lipid scavenging, de novo biosynthetic pathways, and/or diverting host fatty acids to storage compartments, bacterial replication becomes severely impaired, indicating that host cell fatty acid availability also directly regulates L. pneumophila growth. Collectively, these data demonstrate dual roles for host cell fatty acids in replication vacuole expansion and bacterial proliferation, revealing the central functions for these molecules and their metabolic pathways in L. pneumophila pathogenesis. Author summary: The pathogenesis of bacteria depends on their ability to avoid detection and killing by the host immune system while simultaneously competing with the host for nutrients. Here, we demonstrate that host cell fatty acids are paramount to the intracellular survival and replication of the bacterial pathogen Legionella. Legionella infection induces host cell fatty acid scavenging allowing for critical expansion of its replication vacuole, which protects against recognition by host surveillance pathways, and mediates robust bacterial proliferation. However, if host cell fatty acid availability becomes limited, vacuole membrane expansion is constrained, often leading to vacuole destabilization, and bacterial growth is restricted. Our findings reveal a central role for host cell fatty acids and their metabolic pathways in bacterial pathogenesis, whereby both the host and the pathogen define a gradient of available host fatty acids that can be manipulated by either organism to their benefit. [ABSTRACT FROM AUTHOR]

Objective: To investigate the anti-cancer efficacy of ENB101-LNP, an ionizable lipid nanoparticles (LNPs) encapsulating siRNA against E6/E7 of HPV 16, in combination therapy with cisplatin in cervical cancer in vitro and in vivo. Methods: CaSki cells were treated with ENB101-LNP, cisplatin, or combination. Cell viability assessed the cytotoxicity of the treatment. HPV16 E6/E7 gene knockdown was verified with RT-PCR both in vitro and in vivo. HLA class I and PD-L1 were checked by flow cytometry. A xenograft model was made using CaSki cells in BALB/c nude mice. To evaluate anticancer efficacy, mice were grouped. ENB101-LNP was given three times weekly for 3 weeks intravenously, and cisplatin was given once weekly intraperitoneally. Tumor growth was monitored. On day 25, mice were euthanized; tumors were collected, weighed, and imaged. Tumor samples were analyzed through histopathology, immunostaining, and western blot. Results: ENB101-LNP and cisplatin synergistically inhibit CaSki cell growth. The combination reduces HPV 16 E6/E7 mRNA and boosts p21 mRNA, p53, p21, and HLA class I proteins. In mice, the treatment significantly blocked tumor growth and promoted apoptosis. Tumor inhibition rates were 29.7% (1 mpk ENB101-LNP), 29.6% (3 mpk), 34.0% (cisplatin), 47.0% (1 mpk ENB101-LNP-cisplatin), and 68.8% (3 mpk ENB101-LNP-cisplatin). RT-PCR confirmed up to 80% knockdown of HPV16 E6/E7 in the ENB101-LNP groups. Immunohistochemistry revealed increased p53, p21, and HLA-A expression with ENB101-LNP treatments, alone or combined. Conclusion: The combination of ENB101-LNP, which inhibits E6/E7 of HPV 16, with cisplatin, demonstrated significant anticancer activity in the xenograft mouse model of cervical cancer. [ABSTRACT FROM AUTHOR]

Nonalcoholic steatohepatitis (NASH) occurs worldwide and is characterized by lipid accumulation in hepatocytes, hepatic inflammation, fibrosis, and an increased risk of cirrhosis. Although a major proportion of NASH patients exhibit obesity and insulin resistance, 20% lack a high body mass and are categorized as "non-obese NASH". Time-restricted feeding (TRF), limiting daily food intake within certain hours, improves obesity, lipid metabolism, and liver inflammation. Here, we determined whether TRF affects NASH pathology induced by a choline-deficient high-fat diet (CDAHFD), which does not involve obesity. TRF ameliorated the increase in epididymal white adipose tissue and plasma alanine transaminase and aspartate transaminase levels after 8 weeks of a CDAHFD. Although gene expression of TNF alpha in the liver was suppressed by TRF, it did not exhibit a suppressive effect on hepatic lipid accumulation, gene expression of cytokines and macrophage markers (Mcp1, IL1b, F4/80), or fibrosis, as evaluated by Sirius red staining and western blot analysis of alpha-smooth muscle actin. A CDAHFD-induced increase in gene expression related to fibrogenesis (Collagen 1a1 and TGFβ) was neither suppressed by TRF nor that of alpha-smooth muscle actin but was increased by TRF. Our results indicated that TRF has a limited suppressive effect on CDAHFD-induced NASH pathology. [ABSTRACT FROM AUTHOR]

Stable isotope ratios in organisms can be used to estimate dietary source contributions, but lipids must first be accounted for to interpret values meaningfully. Lipids are depleted in heavy isotopes because during lipid synthesis light isotopes of carbon (12C) and hydrogen (1H) are preferentially incorporated. Prior work in larval lampreys has noted unusual lipid effects, which suggest lipids are enriched in the heavy isotope of carbon (13C), but still depleted in the heavy isotope of hydrogen (deuterium; 2H); nitrogen, a relatively rare element in lipids, has not been identified as being as sensitive to lipid content. Our objective was to determine if stable isotope ratios of hydrogen, carbon, and nitrogen behaved as expected in larval lampreys, or if their lipids presented different isotopic behavior. The δ2H, δ13C, and δ15N were measured from the muscle of four lamprey species before and after lipid extraction. In addition, muscle of least brook lamprey (Lampetra aepyptera) was collected every three months for a year from two streams in Maryland. Isotopic ratios were measured in bulk and lipid-extracted muscles, as well as in extracted lipids. The difference between muscle samples before and after lipid extraction (Δδ2H, Δδ13C, Δδ15N) was positively related to lipid proxy (%H or C:N ratio) and were fit best by linear models for Δδ2H and Δδ15N, and by a non-linear model for Δδ13C. The difference between lipid-extracted muscle and lipid δ13C (ΔMLδ13C) was negative and varied between months (ANOVA, F3,53 = 5.05, p < 0.005). Our work suggests that while lipids are often depleted in 13C, this is not a universal rule; however, the depletion of 2H in lipid synthesis appears broadly true. [ABSTRACT FROM AUTHOR]

The biochemical composition of Antarctic krill, Euphausia superba, is largely determined by their feeding behaviour. As they supply energy for animals of a higher trophic level and are also commercialized for human consumption, the interest in research on the species is high. Lipids, especially phospholipids, make up a high proportion of dry weight in krill. Seasonal changes are well documented in the fingerprint of free fatty acids analysed after hydrolysis of phospholipids, but the underlying intact polar lipids are rarely considered. In this study, we evaluated the compositions of intact phospholipids (IPLs) in the stomach, digestive gland and hind gut of Antarctic krill caught in summer and autumn at the Antarctic Peninsula region. Using high-resolution mass spectrometry, the fatty acid composition of 179 intact phospholipids could be resolved. Most IPLs were phosphatidylcholines, followed by phosphatidylethanolamines. Several very long chain polyunsaturated fatty acids up to 38:8, which have not been reported in krill before, were identified. The composition shifted to higher molecular weight IPLs with a higher degree of unsaturation for summer samples, especially for samples of the digestive gland. The data supplied in this paper provides new insights into lipid dynamics between summer and autumn usually described by free fatty acid biomarkers. [ABSTRACT FROM AUTHOR]

Background: Parenteral (intravenous) nutrition is lifesaving for patients with intestinal failure, but long-term use of parenteral nutrition often leads to liver disease. SEFA-6179 is a synthetic medium-chain fatty acid analogue designed to target multiple fatty acid receptors regulating metabolic and inflammatory pathways. We hypothesized that SEFA-6179 would prevent hepatosteatosis and lipotoxicity in a murine model of parenteral nutrition-induced hepatosteatosis. Methods: Two in vivo experiments were conducted. In the first experiment, six-week-old male mice were provided an ad lib fat-free high carbohydrate diet (HCD) for 19 days with orogastric gavage of either fish oil, medium-chain triglycerides, or SEFA-6179 at a low (0.3mmol/kg) or high dose (0.6mmol/kg). In the second experiment, six-week-old mice were provided an ad lib fat-free high carbohydrate diet for 19 days with every other day tail vein injection of saline, soybean oil lipid emulsion, or fish oil lipid emulsion. Mice then received every other day orogastric gavage of medium-chain triglyceride vehicle or SEFA-6179 (0.6mmol/kg). Hepatosteatosis was assessed by a blinded pathologist using an established rodent steatosis score. Hepatic lipid metabolites were assessed using ultra-high-performance liquid chromatography-mass spectrometry. Effects of SEFA-6179 on fatty acid oxidation, lipogenesis, and fatty acid uptake in human liver cells were assessed in vitro. Results: In the first experiment, mice receiving the HCD with either saline or medium-chain triglyceride treatment developed macrovesicular steatosis, while mice receiving fish oil or SEFA-6179 retained normal liver histology. In the second experiment, mice receiving a high carbohydrate diet with intravenous saline or soybean oil lipid emulsion, along with medium chain triglyceride vehicle treatment, developed macrovescular steatosis. Treatment with SEFA-6179 prevented steatosis. In each experiment, SEFA-6179 treatment decreased arachidonic acid metabolites as well as key molecules (diacylglycerol, ceramides) involved in lipotoxicity. SEFA-6179 increased both β- and complete fatty oxidation in human liver cells, while having no impact on lipogenesis or fatty acid uptake. Conclusions: SEFA-6179 treatment prevented hepatosteatosis and decreased toxic lipid metabolites in a murine model of parenteral nutrition-induced hepatosteatosis. An increase in both β- and complete hepatic fatty acid oxidation may underlie the reduction in steatosis. [ABSTRACT FROM AUTHOR]

Long-term high-fat feeding results in intramyocellular lipid accumulation, leading to insulin resistance. Intramyocellular lipid accumulation is related to an energy imbalance between excess fat intake and fatty acid consumption. Alternating current electromagnetic field exposure has been shown to enhance mitochondrial metabolism in the liver and sperm. Therefore, we hypothesized that alternating current electromagnetic field exposure would ameliorate high-fat diet-induced intramyocellular lipid accumulation via activation of fatty acid consumption. C57BL/6J mice were either fed a normal diet (ND), a normal diet and exposed to an alternating current electromagnetic field (ND+EMF), a high-fat diet (HFD), or a high-fat diet and exposed to an alternating current electromagnetic field (HFD+EMF). Electromagnetic field exposure was administered 8 hrs/day for 16 weeks using an alternating current electromagnetic field device (max.180 mT, Hokoen, Utatsu, Japan). Tibialis anterior muscles were collected for measurement of intramyocellular lipids, AMPK phosphorylation, FAT/CD-36, and carnitine palmitoyltransferase (CPT)-1b protein expression levels. Intramyocellular lipid levels were lower in the HFD + EMF than in the HFD group. The levels of AMPK phosphorylation, FAT/CD-36, and CPT-1b protein levels were higher in the HFD + EMF than in the HFD group. These results indicate that alternating current electromagnetic field exposure decreases intramyocellular lipid accumulation via increased fat consumption. [ABSTRACT FROM AUTHOR]

The cuticles of ecdysozoan animals are barriers to material loss and xenobiotic insult. Key to this barrier is lipid content, the establishment of which is poorly understood. Here, we show that the p-glycoprotein PGP-14 functions coincidentally with the sphingomyelin synthase SMS-5 to establish a polar lipid barrier within the pharyngeal cuticle of the nematode C. elegans. We show that PGP-14 and SMS-5 are coincidentally expressed in the epithelium that surrounds the anterior pharyngeal cuticle where PGP-14 localizes to the apical membrane. pgp-14 and sms-5 also peak in expression at the time of new cuticle synthesis. Loss of PGP-14 and SMS-5 dramatically reduces pharyngeal cuticle staining by Nile Red, a key marker of polar lipids, and coincidentally alters the nematode's response to a wide-range of xenobiotics. We infer that PGP-14 exports polar lipids into the developing pharyngeal cuticle in an SMS-5-dependent manner to safeguard the nematode from environmental insult. Author summary: An infinite number of small molecules have the potential to threaten life. Not surprisingly then, animals have evolved multiple mechanisms to defend against such threats. One defense mechanism employed by many animals is the creation of an outer protective layer called the cuticle. Lipids within the cuticle act as a barrier to retard small molecule passage into the underlying tissues. Water-loving small molecules cannot traverse a lipid barrier and fat-loving molecules can get trapped within the barrier. How this lipid barrier is established is incompletely understood. Here, we describe our discovery of a conserved protein called PGP-14 that is expressed in the tissue that makes the cuticle that protects the mouth and pharynx of the nematode worm C. elegans. We show that PGP-14 peaks in expression at the end of new cuticle synthesis and is necessary for lipid deposition within it. Without PGP-14, many small molecules adversely accumulate within the animal and consequently kill it. Hence, PGP-14 is a key component employed by the animal to help protect it from small molecule threats. [ABSTRACT FROM AUTHOR]

Locating potential mates in non-native habitats is one of the most important challenges faced by invasive vertebrate species. The Argentine black and white tegu lizard (Salvator merianae) is a major invasive reptile species in the contiguous United States and is rapidly expanding its range across Florida and the Southeast, in part due to inadequate management strategies and tools. Because a wide array of reptiles, especially squamates (snakes and lizards), have been well-studied for their reliance on chemical cues to locate conspecifics, our project aimed to isolate chemical cues from tegus and assess the ability of adult males and females to use only these cues to make navigation decisions within a Y-maze. Previously, we found that both males and females can follow conspecific scent trails, but the nature of the specific cues used by the tegus was unknown. In this study, we extracted skin lipids from male and female shed skins acquired during the breeding season then tested the extracts for bioactivity at different dilutions prior to Y-maze trials. Both sexes showed positive reactions (e.g., tongue-flicking, nose taps, scratching) to 2:1 skin lipid:hexane dilutions. In the Y-maze, males (n = 7) and females (n = 7) were run in three types of trailing scenarios with these skin lipid extracts: Male-only (pooled lipid extracts from male shed skins), Female-only (extracts from female shed skins), and Male vs. female. Regardless of the tegu lipid type present, tegus preferred to follow the conspecific lipid trail when paired with a neutral control (peanut oil; 2:1 dilution). They also preferred opposite-sex skin lipid trails when paired with same-sex skin lipid trails. We analyzed our results further by comparing them to those of Richard, Bukovich, et al. (2020). We found a synchronization effect of the skin lipids: sex differences in behavior detectable in the scent trail trials were absent when only conspecific skin lipids were present in the environment. Our results indicate that skin lipids alone are sufficient to facilitate mate tracking in S. merianae, these chemical cues induce reliable behavior, and extracted skin lipids have potential for modifying movement patterns of an invasive reptile in their non-native range. If leveraged in concert with current tegu management strategies (i.e., trapping), extracted skin lipids have the potential to bolster management efficacy but field trials are a requisite next step. [ABSTRACT FROM AUTHOR]

Animals integrate developmental and nutritional signals before committing crucial resources to growth and reproduction; however, the pathways that perceive and respond to these inputs remain poorly understood. Here, we demonstrate that DRL-1 and FLR-4, which share similarity with mammalian mitogen-activated protein kinases, maintain lipid homeostasis in the C. elegans intestine. DRL-1 and FLR-4 function in a protein complex at the plasma membrane to promote development, as mutations in drl-1 or flr-4 confer slow growth, small body size, and impaired lipid homeostasis. To identify factors that oppose DRL-1/FLR-4, we performed a forward genetic screen for suppressors of the drl-1 mutant phenotypes and identified mutations in flr-2 and fshr-1, which encode the orthologues of follicle stimulating hormone and its putative G protein–coupled receptor, respectively. In the absence of DRL-1/FLR-4, neuronal FLR-2 acts through intestinal FSHR-1 and protein kinase A signaling to restrict growth. Furthermore, we show that opposing signaling through DRL-1 and FLR-2 coordinates TIR-1 oligomerization, which modulates downstream p38/PMK-1 activity, lipid homeostasis, and development. Finally, we identify a surprising noncanonical role for the developmental transcription factor PHA-4/FOXA in the intestine where it restricts growth in response to impaired DRL-1 signaling. Our work uncovers a complex multi-tissue signaling network that converges on p38 signaling to maintain homeostasis during development. The proper distribution of resources between developmental programs and stress responses ensures survival and reproductive fitness. This study identifies a neurohormone pathway and two intestinal MAP kinases that exert opposite effects on intestinal p38/PMK-1 signaling to maintain energy homeostasis in the nematode C. elegans. [ABSTRACT FROM AUTHOR]

Brown bears (Ursus arctos) prepare for winter by overeating and increasing adipose stores, before hibernating for up to six months without eating, drinking, and with minimal movement. In spring, the bears exit the den without any damage to organs or physiology. Recent clinical research has shown that specific lipids and lipid profiles are of special interest for diseases such as diabetes type 1 and 2. Furthermore, rodent experiments show that lipids such as sulfatide protects rodents against diabetes. As free-ranging bears experience fat accumulation and month-long physical inactivity without developing diabetes, they could possibly be affected by similar protective measures. In this study, we investigated whether lipid profiles of brown bears are related to protection against hibernation-induced damage. We sampled plasma from 10 free-ranging Scandinavian brown bears during winter hibernation and repeated sampling during active state in the summer period. With quantitative shotgun lipidomics and liquid chromatography-mass spectrometry, we profiled 314 lipid species from 26 lipid classes. A principal component analysis revealed that active and hibernation samples could be distinguished from each other based on their lipid profiles. Six lipid classes were significantly altered when comparing plasma from active state and hibernation: Hexosylceramide, phosphatidylglycerol, and lysophosphatidylglycerol were higher during hibernation, while phosphatidylcholine ether, phosphatidylethanolamine ether, and phosphatidylinositol were lower. Additionally, sulfatide species with shorter chain lengths were lower, while longer chain length sulfatides were higher during hibernation. Lipids that are altered in bears are described by others as relevant for and associated with diabetes, which strengthens their position as potential effectors during hibernation. From this analysis, a range of lipids are suggested as potential protectors of bear physiology, and of potential importance in diabetes. [ABSTRACT FROM AUTHOR]

Lipid droplets (LDs) are ubiquitous organelles that facilitate neutral lipid storage in cells, including energy-dense triglycerides. They are found in all investigated metazoan embryos where they are thought to provide energy for development. Intriguingly, early embryos of diverse metazoan species asymmetrically allocate LDs amongst cellular lineages, a process which can involve massive intracellular redistribution of LDs. However, the biological reason for asymmetric lineage allocation is unknown. To address this issue, we utilize the Drosophila embryo where the cytoskeletal mechanisms that drive allocation are well characterized. We disrupt allocation by two different means: Loss of the LD protein Jabba results in LDs adhering inappropriately to glycogen granules; loss of Klar alters the activities of the microtubule motors that move LDs. Both mutants cause the same dramatic change in LD tissue inheritance, shifting allocation of the majority of LDs to the yolk cell instead of the incipient epithelium. Embryos with such mislocalized LDs do not fully consume their LDs and are delayed in hatching. Through use of a dPLIN2 mutant, which appropriately localizes a smaller pool of LDs, we find that failed LD transport and a smaller LD pool affect embryogenesis in a similar manner. Embryos of all three mutants display overlapping changes in their transcriptome and proteome, suggesting that lipid deprivation results in a shared embryonic response and a widespread change in metabolism. Excitingly, we find abundant changes related to redox homeostasis, with many proteins related to glutathione metabolism upregulated. LD deprived embryos have an increase in peroxidized lipids and rely on increased utilization of glutathione-related proteins for survival. Thus, embryos are apparently able to mount a beneficial response upon lipid stress, rewiring their metabolism to survive. In summary, we demonstrate that early embryos allocate LDs into specific lineages for subsequent optimal utilization, thus protecting against oxidative stress and ensuring punctual development. Author summary: Embryos of diverse animal species sort their lipid droplets into specific cell lineages early in development. Here we prevent Drosophila embryo's ability to undergo this asymmetric inheritance through two separate genetic perturbations. We then investigate the effects on subsequent embryogenesis, finding developmental delays and an inability to consume the mislocalized lipid droplets. We find a similar delay for embryos which receive fewer lipid droplets from their mothers. To understand how embryos respond to limited access to lipid droplets, we investigate the global transcriptome and proteome in the mutants and find alterations to the expression of hundreds of metabolism genes, including for enzymes that transport sugar across cell membranes, break down fat, or protect against oxidative stress. We test if the upregulated genes have beneficial functions for lipid-deprived embryos. We find that zygotic knock down of the upregulated oxidative stress response genes GSS and GSTT4 as well as the lipase ATGL lowers hatching success in LD-deprived genetic backgrounds, but not wild type. In summary, we find that early lipid droplet lineage sorting sets the stage for metabolic success in subsequent embryogenesis. [ABSTRACT FROM AUTHOR]

The hydrophilic polymer polyethylene glycol-grafted phospholipid has been used extensively in the study of artificial vesicles, nanomedicine, and antimicrobial peptides/proteins. In this research, the effects of 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N- [methoxy (polyethylene glycol)-2000] (abbreviated PEG-DOPE) on the deformation and poration of giant unilamellar vesicles (GUVs)-induced by anionic magnetite nanoparticles (NPs) have been investigated. For this, the size of the NPs used was 18 nm, and their concentration in the physiological solution was 2.00 μg/mL. GUVs were prepared using the natural swelling method comprising 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) and PEG-DOPE. The mole% of PEG-DOPE in the membranes were 0, 2, and 5%. The degree of deformation of the GUVs was quantified by the parameter compactness (Com), which is 1.0 for the spherical-shaped GUVs. The value of Com increases with time during the interactions of NPs with GUVs for any concentration of PEG-DOPE, but the rate of increase is significantly influenced by the PEG-DOPE concentration in the membranes. The average compactness increases with the increase of PEG-DOPE%, and after 60 min of NPs interaction, the values of average compactness for 0, 2, and 5% PEG-DOPE were 1.19 ± 0.02, 1.26 ± 0.03 and 1.35 ± 0.05, respectively. The fraction of deformation (Frd) also increased with the increase of PEG-DOPE%, and at 60 min, the values of Frd for 0 and 5% PEG-DOPE were 0.47 ± 0.02 and 0.63 ± 0.02, respectively. The fraction of poration (Frp) increased with the increase of PEG-DOPE, and at 60 min, the values of Frp for 0 and 5% PEG-DOPE were 0.25 ± 0.02 and 0.48 ± 0.02, respectively. Hence, the presence of PEG-grafted phospholipid in the membranes greatly enhances the anionic magnetite NPs-induced deformation and poration of giant vesicles. [ABSTRACT FROM AUTHOR]

Objective: The association between blood lipid levels and the risk of gastric cancer (GC) is well known. Therefore, to clarify this association, all relevant prospective cohort studies were included in this meta-analysis. Methods: Our study was registered in PROSPERO (CRD42022354899) prior to its commencement. A systematic review and meta-analysis were conducted in accordance with the PRISMA recommendations. Chinese databases (CNKI, CBM, Wanfang, and VIP) and English databases (PubMed, Embase, Web of Science, and the Cochrane Library) were systematically searched up to October 2022. This study included all relevant cohort studies that reported hazard ratios (HRs) or relative risks (RRs) and their corresponding 95% confidence intervals (95% CIs) to examine the association between various lipid profiles (e.g., total cholesterol, triglycerides, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol) and the risk of developing gastric cancer (GC). Fixed effects or random effects models were used based on the level of heterogeneity among the studies, and these models were employed to obtain pooled hazard ratios. Additionally, sensitivity analysis and publication bias analysis were conducted to ensure the robustness and reliability of the findings. Results: After conducting a systematic search, a total of 10 studies were selected out of 10,525 papers involving a total of 5,564,520 individuals. Among these individuals, there were 41,408 GC cases. The analysis revealed that the highest versus lowest serum total cholesterol (TC) concentration was associated with a pooled hazard ratio of 0.89 (95% CI = 0.87–0.92, I2 = 15%). For triglycerides (TGs), the hazard ratio was 1.00 (95% CI = 0.96–1.04, I2 = 37%), while for high-density lipoprotein cholesterol (HDL-C), the hazard ratio was 0.90 (95% CI = 0.86–0.93, I2 = 0%). The hazard ratio for low-density lipoprotein cholesterol (LDL-C) was 0.96 (95% CI = 0.91–1.00, I2 = 0%). Conclusions: Based on the results of this meta-analysis, it was found that serum TC and HDL-C levels were inversely correlated with the risk of GC. No association was observed between serum TG levels and the risk of GC. Similarly, no association was found between serum LDL-C levels and the risk of GC. [ABSTRACT FROM AUTHOR]

Although hemolytic lipids have been discovered from many human pathogens including Group B Streptococcus (GBS), strategies that neutralize their function are lacking. GBS is a leading cause of pregnancy-associated neonatal infections, and adult GBS infections are on the rise. The GBS hemolytic lipid toxin or granadaene, is cytotoxic to many immune cells including T and B cells. We previously showed that mice immunized with a synthetic nontoxic analog of granadaene known as R-P4 had reduced bacterial dissemination during systemic infection. However, mechanisms important for R-P4 mediated immune protection was not understood. Here, we show that immune serum from R-P4-immunized mice facilitate GBS opsonophagocytic killing and protect naïve mice from GBS infection. Further, CD4+ T cells isolated from R-P4-immunized mice proliferated in response to R-P4 stimulation in a CD1d- and iNKT cell-dependent manner. Consistent with these observations, R-P4 immunized mice lacking CD1d or CD1d-restricted iNKT cells exhibit elevated bacterial burden. Additionally, adoptive transfer of iNKT cells from R-P4 vaccinated mice significantly reduced GBS dissemination compared to adjuvant controls. Finally, maternal R-P4 vaccination provided protection against ascending GBS infection during pregnancy. These findings are relevant in the development of therapeutic strategies targeting lipid cytotoxins. Author summary: Although many pathogens encode lipid toxins that contribute to disease pathogenesis, strategies to neutralize these toxins are lacking. The hemolytic lipid toxin encoded by Group B Streptococcus (GBS) is a major virulence factor that promotes disease including preterm births, in utero fetal injury and morbidity of human neonates and adults. No strategies exist to mitigate the effects of the GBS toxin, and neutralizing antibodies have not been isolated from infected patients. The global burden of GBS disease remains high with approximately 4 million neonatal deaths occurring worldwide each year and increasing rates of infections occur in adults. Using chemical synthesis, we synthesized a derivative of GBS toxin known as R-P4. We show that vaccination with this non-toxic analog induces the production of antibodies that promotes GBS killing, confers protection to naïve mice, neutralizes the cytotoxic activity and diminishes GBS infection during pregnancy. Furthermore, we show that lipid analog mediated protection requires antigen presentation by host molecules such as CD1d and immune responses of CD1d restricted T cells such as iNKT cells. These results provide the foundation for the design of novel therapeutic strategies that target lipid cytotoxins. Despite observations that lipid toxins continue to increase the severity and rate of infections caused by pathogens such as GBS, Mycobacteria and Pseudomonas, strategies to neutralize these toxins remain undefined. Our results indicate that a nontoxic analog of one such toxin can induce protective immunity during systemic and pregnancy associated infection, through lipid antigen presentation which provides the foundation for promising future strategies to neutralize the effect of lipid toxins during human infections. [ABSTRACT FROM AUTHOR]

Specialized pro-resolving mediators (SPMs) have recently emerged as promising therapeutic approaches for neuropathic pain (NP). We evaluated the effects of oral treatment with the SPM Maresin 1 (MaR1) on behavioral pain responses and spinal neuroinflammation in male and female C57BL/6J mice with spared nerve injury (SNI)-induced NP. MaR1, or vehicle, was administered once daily, on post-surgical days 3 to 5, by voluntary oral intake. Sensory-discriminative and affective-motivational components of pain were evaluated with von Frey and place escape/avoidance paradigm (PEAP) tests, respectively. Spinal microglial and astrocytic activation were assessed by immunofluorescence, and the spinal concentration of cytokines IL-1β, IL-6, IL-10, and macrophage colony-stimulating factor (M-CSF) were evaluated by multiplex immunoassay. MaR1 treatment reduced SNI-induced mechanical hypersensitivity on days 7 and 11 in both male and female mice, and appeared to ameliorate the affective component of pain in males on day 11. No definitive conclusions could be drawn about the impact of MaR1 on the affective-motivational aspects of pain in female mice, since repeated suprathreshold mechanical stimulation of the affected paw in the dark compartment did not increase the preference of vehicle-treated SNI females for the light side, during the PEAP test session (a fundamental assumption for PAEP's validity). MaR1 treatment also reduced ipsilateral spinal microglial and astrocytic activation in both sexes and marginally increased M-CSF in males, while not affecting cytokines IL-1β, IL-6 and IL-10 in either sex. In summary, our study has shown that oral treatment with MaR1 (i) produces antinociception even in an already installed peripheral NP mouse model, and (ii) this antinociception may extend for several days beyond the treatment time-frame. These therapeutic effects are associated with attenuated microglial and astrocytic activation in both sexes, and possibly involve modulation of M-CSF action in males. [ABSTRACT FROM AUTHOR]

Fatty acids (FA) in follicular fluid (FF) are present in an esterified form [triglycerides, cholesterol esters and phospholipids] or as non-esterified FA, which partly originate from blood. However, a comprehensive comparison of blood vs. FF FA in various lipid classes is missing. The aim of this study was to determine the distribution of the FA composition in each lipid class of serum and FF, and to investigate their mutual correlations. A total of 74 patients undergoing assisted reproductive technology treatment were involved in the study. Both in serum as well as FF, saturated FA and mono-unsaturated FA were predominant in non-esterified FA and triglycerides fractions while poly-unsaturated FA were mainly present in phospholipids and cholesterol esters fractions, although phospholipids also contained high proportions of saturated FA. Irrespective of the lipid class, the FA proportions differed between serum and FF (P < 0.05). Despite these differences, most of the FA in triglycerides, phospholipids and cholesterol esters of FF were well correlated with their proportions in serum. Nevertheless, only weak to moderate associations (r < 0.60) were observed for the majority of the FA in the non-esterified FA fraction. Differences in FA product/precursor-ratios were found between serum and FF, such as higher C20:4n-6 to C18:2n-6 and C20:5n-3 to C18:3n-3 in FF. FA metabolism (e.g. desaturation and elongation) takes place in cells of the intrafollicular micro-environment. Moreover, good correlations between esterified FA in serum and FF suggest esterified FA in blood could be representative of esterified FA in FF. [ABSTRACT FROM AUTHOR]

Background: Lipids and glucose concentrations in the blood rise during pregnancy period. Poor control of these analytes results in cardio metabolic dysfunction. Despite this, there are no documented studies which investigate lipids and glucose among pregnant women in Tigrai, northern Ethiopia. Objective: The objective of this study was to assess lipid and glucose levels and identify their correlates among pregnant women in Tigrai, northern Ethiopia. Method: We conducted a facility-based cross sectional study comprising of systematically selected 200 pregnant women from July to October 2021. Those who were severely ill were excluded from the study. We used a structured questionnaire to collect socio-demographic and clinical characteristics of pregnant women. Lipids such as triglycerides, low density lipoprotein, cholesterol and blood glucose were also measured using Cobas C311 chemistry machine from plasma samples. The data were analyzed using SPSS version 25. Logistic regression was performed and statistical significance was declared at p-value < 0.05. Result: Proportion of pregnant women with cholesterol, triglyceride, low density lipoprotein and blood glucose levels above the upper limit of the normal range used for clinical decision were 26.5%, 43%, 44.5% and 21%, respectively. Pregnant women's income > = 10,000 ETB (AOR = 3.35; 95%CI: 1.46–7.66), age (AOR = 3.16; 95%CI: 1.03–9.68), gestational age 29–37 weeks (AOR = 8.02; 95%CI: 2.69–23.90) and having systolic blood pressure greater than 120 mmHg (AOR = 3.99; 95%CI: 1.64–9.75) demonstrated statistically significant association with raised levels of lipids. Conclusion and recommendation: Proportion of pregnant women with out of normal range values of lipids, particularly triglycerides and low density lipoprotein, is high. Gestational age is a strong predictor of increase in blood levels for both lipids. Provision of life style related health education and dietary intake to pregnant mothers matters. Moreover, monitoring lipid profile and glucose level during antenatal care period is essential. [ABSTRACT FROM AUTHOR]

The regulation of lipid stores is a central process for the physiology and ecology of fishes. Seasonal variation in lipid stores has been directly linked to survival of fishes across periods of food deprivation. We assessed whether a seasonally changing photoperiod was correlated to seasonal changes in energetic status to help better understand these important processes. Groups of first feeding Chinook salmon fry were introduced to a seasonal photoperiod cycle, but the point of entrance into the seasonal cycle varied from near the winter solstice (December), to either side of the spring equinox (February & May). Temperature and feeding rate were similar for all treatments. Subsequently, condition factor and whole body lipid content were assessed through a seasonal progression. Throughout most of the experiment, length and weight did not differ between the different photoperiod treatments, however whole body lipid and Fulton's condition factor did. Furthermore, changes in both whole body lipid and Fulton's condition factor in all treatment groups followed a similar seasonal pattern that was inversely related to day length (highest K and lipid levels found during days with the least light). These results suggest that regardless of age or size, there is a correlation between seasonal changes in photoperiod and changes in body composition in juvenile Chinook salmonids. [ABSTRACT FROM AUTHOR]

Objective: The risk of ischemic stroke with intracranial stenosis is associated with various serum lipid levels. However, the effects of changes in the lipid profile on the risk of in-stent restenosis have not been verified. Therefore, we investigated the association between the occurrence of in-stent restenosis at 12-month follow-up and changes in various lipid profiles. Methods: In this retrospective cohort study, we included ischemic stroke patients who had undergone intracranial stenting for symptomatic intracranial stenosis between February 2010 and May 2020. We collected data about serum low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), and triglyceride (TG) levels, and calculated the TC/HDL-C and LDL-C/HDL-C ratios at baseline and after 12 months. We conducted multivariable logistic regression analyses to verify the association between various lipid profile changes and in-stent restenosis at 12 months. Results: Among the 100 patients included in the study (mean age, 60.8 ± 10.0 years; male: 80 [80.0%]), in-stent restenosis was found in 13 (13.0%) patients. The risk of in-stent restenosis of more than 50% was significantly decreased when TC/HDL-C ratio (odds ratio [OR] 0.22, [95% confidence interval (CI) 0.05–0.87]) and LDL-C/HDL-C ratio (OR 0.23, [95% CI 0.06–0.93]) decreased or when HDL-C levels (OR 0.10, [95% CI 0.02–0.63]) were increased at 12 months compared with baseline measurements. Conclusions: Improvement of HDL-C levels, TC/HDL-C ratio, and LDL-C/HDL-C ratio were associated with decreased risk of in-stent restenosis at 12-month follow-up. Management and careful monitoring of various lipid profiles including HDL-C levels, TC/HDL-C ratio, and LDL-C/HDL-C ratio may be important to prevent in-stent restenosis in patients with intracranial stenting. [ABSTRACT FROM AUTHOR]

Algal extracts are sources of bioactive substances with applications in the development of novel alternative drugs against several diseases, including trichomoniasis sexually transmitted infection caused by Trichomonas vaginalis. Factors such as clinical failures and resistant strains limit the success of the existing drugs available for treating this disease. Therefore, searching for viable alternatives to these drugs is essential for the treatment of this disease. The present study was conducted for, in vitro and in silico characterization of extracts obtained from marine macroalgae Gigartina skottsbergii at stages gametophidic, cystocarpic, and tetrasporophidic. In addition, antiparasitic activity of these extracts against the ATCC 30236 isolate of T. vaginalis, their cytotoxicity, and gene expression of trophozoites after treatment were evaluated. The minimum inhibitory concentration and 50% inhibition concentration were determined for each extract. Results: In vitro analysis of the extracts' anti-T. vaginalis activity revealed an inhibitory effect of 100%, 89.61%, and 86.95% for Gigartina skottsbergii at stages gametophidic, cystocarpic, and tetrasporophidic, respectively, at 100 μg/mL. In silico analysis revealed the interactions between constituents of the extracts and enzymes from T. vaginalis, with significant free energy values obtained for the binding. None of the extract concentrations exhibited cytotoxic effects on VERO cell line compared to control, while cytotoxicity on HMVII vaginal epithelial cells line was observed at 100 μg/mL (30% inhibition). Gene expression analysis revealed differences in the expression profile of T. vaginalis enzymes between the extract-treated and control groups. According to these results, Gigartina skottsbergii extracts exhibited satisfactory antiparasitic activity. [ABSTRACT FROM AUTHOR]

Microalgal domestication is an expanding research field that aims to multiply and accelerate the potential of microalgae for various biotechnological purposes. We investigated the stability of improved lipid traits and genetic changes of a domesticated strain of the haptophyte Tisochrysis lutea, TisoS2M2, previously obtained by a mutation-selection improvement program. After 7 years of maintenance, TisoS2M2 still displayed improved lipid traits compared with the native strain, demonstrating that a mutation-selection improvement program is suitable for obtaining a domesticated strain with stable, improved phenotype over time. We identified specific genetic variations between the native and domesticated strains and focused on the dynamics of transposable elements (TEs). DNA transposons mainly caused specific TE indels of the domesticated strain TisoS2M2, and some specific TE indels may have impacted genes associated to the neutral lipid pathway. We revealed transposition events for TEs in T. lutea and discussed on the potential role of the improvement program on their activity. [ABSTRACT FROM AUTHOR]

The promise of therapeutic nucleic acids has long been tempered by difficulty in overcoming biological barriers to their delivery. The past two decades have seen the development of ionizable lipid nanoparticles as a vehicle for nucleic acid delivery and their translation to the clinic. Over the past 20 years, lipid-based nanoparticles have been engineered to overcome the biological barriers to nucleic acid delivery. This Perspective looks at their development for use in vaccines, immunotherapies, protein replacement therapies, and gene therapies. [ABSTRACT FROM AUTHOR]

Rhodotorula toruloides is a non-conventional, oleaginous yeast able to naturally accumulate high amounts of microbial lipids. Constraint-based modeling of R. toruloides has been mainly focused on the comparison of experimentally measured and model predicted growth rates, while the intracellular flux patterns have been analyzed on a rather general level. Hence, the intrinsic metabolic properties of R. toruloides that make lipid synthesis possible are not thoroughly understood. At the same time, the lack of diverse physiological data sets has often been the bottleneck to predict accurate fluxes. In this study, we collected detailed physiology data sets of R. toruloides while growing on glucose, xylose, and acetate as the sole carbon source in chemically defined medium. Regardless of the carbon source, the growth was divided into two phases from which proteomic and lipidomic data were collected. Complemental physiological parameters were collected in these two phases and altogether implemented into metabolic models. Simulated intracellular flux patterns demonstrated the role of phosphoketolase in the generation of acetyl-CoA, one of the main precursors during lipid biosynthesis, while the role of ATP citrate lyase was not confirmed. Metabolic modeling on xylose as a carbon substrate was greatly improved by the detection of chirality of D-arabinitol, which together with D-ribulose were involved in an alternative xylose assimilation pathway. Further, flux patterns pointed to metabolic trade-offs associated with NADPH allocation between nitrogen assimilation and lipid biosynthetic pathways, which was linked to large-scale differences in protein and lipid content. This work includes the first extensive multi-condition analysis of R. toruloides using enzyme-constrained models and quantitative proteomics. Further, more precise kcat values should extend the application of the newly developed enzyme-constrained models that are publicly available for future studies. Author summary: Transition towards a biobased, circular economy to reduce the industrial dependence on fossil-based resources requires new technologies. One of the options is to convert available biomass feedstocks into valuable chemicals using microbes as biocatalysts. Rhodotorula toruloides is a nonpathogenic, nonconventional yeast that has recently emerged as one of the most promising yeasts for sustainable production of chemicals and fuels due to its natural ability to synthesize large amounts of lipids. However, its unique metabolic properties are not yet fully understood. We have computationally predicted metabolic fluxes in R. toruloides while growing in economically viable growth conditions inducing lipid accumulation and analyzed them together with absolute proteome quantification. Our holistic approach has highlighted metabolic pathways important for lipid biosynthesis and revealed metabolic trade-offs associated with NADPH allocation during lipogenesis. In addition, our work highlighted the necessity for accurate computational approaches in characterizing enzymatic kinetic properties that would improve the metabolic studies of R. toruloides. [ABSTRACT FROM AUTHOR]

Thermogenesis in brown adipose tissue (BAT) uses intracellular triglycerides, circulating free fatty acids and glucose as the main substrates. The objective of the current study was to analyse the role of CD36 fatty acid translocase in regulation of glucose and fatty acid utilisation in BAT. BAT isolated from spontaneously hypertensive rat (SHR) with mutant Cd36 gene and SHR-Cd36 transgenic rats with wild type variant was incubated in media containing labeled glucose and palmitate to measure substrate incorporation and oxidation. SHR-Cd36 versus SHR rats showed significantly increased glucose incorporation into intracellular lipids associated with reduced glycogen synthase kinase 3β (GSK-3β) protein expression and phosphorylation and increased oxidation of exogenous palmitate. It can be concluded that CD36 enhances glucose transport for lipogenesis in BAT by suppressing GSK-3β and promotes direct palmitate oxidation. [ABSTRACT FROM AUTHOR]

Cellular distributions of the sphingolipid ceramide-1-phosphate (C1P) impact essential biological processes. C1P levels are spatiotemporally regulated by ceramide-1-phosphate transfer protein (CPTP), which efficiently shuttles C1P between organelle membranes. Yet, how CPTP rapidly extracts and inserts C1P into a membrane remains unknown. Here, we devise a multiscale simulation approach to elucidate biophysical details of CPTP-mediated C1P transport. We find that CPTP binds a membrane poised to extract and insert C1P and that membrane binding promotes conformational changes in CPTP that facilitate C1P uptake and release. By significantly disrupting a lipid's local hydrophobic environment in the membrane, CPTP lowers the activation free energy barrier for passive C1P desorption and enhances C1P extraction from the membrane. Upon uptake of C1P, further conformational changes may aid membrane unbinding in a manner reminiscent of the electrostatic switching mechanism used by other lipid transfer proteins. Insertion of C1P into an acceptor membrane, eased by a decrease in membrane order by CPTP, restarts the transfer cycle. Most notably, we provide molecular evidence for CPTP's ability to catalyze C1P extraction by breaking hydrophobic C1P–membrane contacts with compensatory hydrophobic lipid–protein contacts. Our work, thus, provides biophysical insights into how CPTP efficiently traffics C1P between membranes to maintain sphingolipid homeostasis and, additionally, presents a simulation method aptly suited for uncovering the catalytic mechanisms of other lipid transfer proteins. Author summary: Critical cellular processes require spatiotemporal regulation of sphingolipid levels among organelle membranes. Programmed cell death and inflammation, for example, are impacted by the distribution of ceramide-1-phosphate (C1P). C1P levels are specifically altered by ceramide-1-phosphate transfer protein (CPTP), which mediates C1P intermembrane transport. Using a multiscale simulation approach tailored to studying lipid transport, we elucidate key steps in the molecular mechanism used by CPTP to rapidly transport C1P between membranes: Through conformational changes that are coupled to membrane binding, CPTP significantly disrupts C1P's local hydrophobic environment in a membrane and catalyzes its extraction. Since this catalytic mechanism is biophysically related to that of passive lipid transport, it may be ubiquitously used by lipid transport proteins to rapidly traffic lipids between membranes and ensure membrane homeostasis. Our multiscale simulation approach offers a framework to test this hypothesis and, thus, further our molecular knowledge of how lipid transfer proteins function to regulate cellular lipid distributions. [ABSTRACT FROM AUTHOR]

Kawasaki Disease (KD) is an acute inflammatory disorder associated with systemic vasculitis. Intravenous immunoglobulin (IVIG) is an effective therapy for KD, yet, about 20% of cases show IVIG resistance with persistent inflammation. The lipid profile in IVIG-resistant KD patients and the relationship between lipid characteristics and IVIG resistance remain unknown. In this study, serum samples from twenty KD patients with different IVIG responses (sensitive, intermediate, or resistant) were collected both before and after treatment, and lipidomic analysis was performed using high-performance liquid chromatography-mass spectrometry. As a result, before treatment, six lipid species were found as the most variant features, in which all the top decreased lipids in the IVIG-resistant group were lysophosphatidylcholine (LPC) and lysophosphatidylethanolamine (LPE), suggesting the potential to be IVIG-resistant markers in pretreatment diagnosis. During treatment, lipidomic changes showed a weaker response in the IVIG-resistant group. After treatment, LPC and LPE species exhibited lower in the IVIG-resistant group and negative correlation with the inflammatory markers, indicating that the unique metabolism may occur among IVIG-responsiveness. These results might contribute to diagnosing IVIG-resistant patients more accurately for alternative therapy and to a better understanding of how lipid metabolism is associated with IVIG sensitiveness/resistance in KD. [ABSTRACT FROM AUTHOR]

Intestinal ischemia-reperfusion injury leads to proinflammatory responses via gut-derived mediators, and accumulating evidence suggests that exosomes secreted by intestinal epithelial cells are involved in the development of systemic inflammation. Studies have reported changes in protein, lipid, and microRNA (miRNA) expression; however, considering the different experimental conditions, information on the relationships among these biomolecules remains insufficient. The aim of this study was to elucidate the multiple changes that simultaneously occur in exosomes after ischemic stimulation. Here, differentiated human intestinal Caco-2 cells were exposed to 95% air (normoxia group) or 5% O2 (hypoxia group) for 6 h. Cells in each group were subsequently incubated for 24 h in an atmosphere of 5% CO2 plus 95% air. The conditioned medium of each group was collected for isolating intestinal epithelial cell-derived exosomes. Together with proteome analyses, lipid analyses, and miRNA quantification, biological functional assays were performed using monocytic NF-κB reporter cells. Lipid metabolism-related protein expression was upregulated, miRNA levels were slightly altered, and unsaturated fatty acid-containing lysophosphatidylcholine concentration increased after hypoxia and reoxygenation injury; this suggested that the changes in exosomal components associated with ischemia-reperfusion injury activates inflammation, including the NF-κB pathway. This study elucidated the multiple changes that co-occur in exosomes after ischemic stimulation and partially clarified the mechanism underlying exosome-mediated inflammation after intestinal ischemic recanalization. [ABSTRACT FROM AUTHOR]

Failures in mitophagy, a process by which damaged mitochondria are cleared, results in neurodegeneration, while enhancing mitophagy promotes the survival of dopaminergic neurons. Using an artificial intelligence platform, we employed a natural language processing approach to evaluate the semantic similarity of candidate molecules to a set of well-established mitophagy enhancers. Top candidates were screened in a cell-based mitochondrial clearance assay. Probucol, a lipid-lowering drug, was validated across several orthogonal mitophagy assays. In vivo, probucol improved survival, locomotor function, and dopaminergic neuron loss in zebrafish and fly models of mitochondrial damage. Probucol functioned independently of PINK1/Parkin, but its effects on mitophagy and in vivo depended on ABCA1, which negatively regulated mitophagy following mitochondrial damage. Autophagosome and lysosomal markers were elevated by probucol treatment in addition to increased contact between lipid droplets (LDs) and mitochondria. Conversely, LD expansion, which occurs following mitochondrial damage, was suppressed by probucol and probucol-mediated mitophagy enhancement required LDs. Probucol-mediated LD dynamics changes may prime the cell for a more efficient mitophagic response to mitochondrial damage. Failures in mitophagy, a process by which damaged mitochondria are cleared, results in neurodegeneration, while enhancing mitophagy promotes the survival of dopaminergic neurons. This study shows that the effects of Probucol on lipid droplet expansion can augment mitophagy in neurons, leading to locomotor improvements in zebrafish and fly models of Parkinson's disease. [ABSTRACT FROM AUTHOR]

Atherosclerosis and cardiovascular events can be prevented, or treated, using statin therapy, either alone or in combination with ezetimibe. Chronic inflammation, vascular proliferation, and the development of atherosclerosis are also influenced by 25-hydroxycholesterol (25-OHC). The aim of the study was to compare the direct pleiotropic effects of two commonly-used statins (atorvastatin, rosuvastatin), ezetimibe, and their combinations, on the mRNA expression of pro-inflammatory IL1β, IL-18 and IL-23 and anti-inflammatory TGFβ, IL-35 (EBI3, IL-12 subunits), IL-10 and IL-37, in endothelial cells damaged by 25-OHC. It also analyzed IL-35 expression at the protein level. HUVECs were stimulated with atorvastatin (5 μM), rosuvastatin (10 μM), ezetimibe (1.22 μM), atorvastatin-ezetimibe (5 μM + 1.22 μM) or rosuvastatin-ezetimibe (10 μM + 1.22 μM), with or without pre-incubation with 10 μg/mL 25-OHC. mRNA expression was analyzed by real-time PCR. The protein level of IL-35 was analyzed by ELISA. In the pre-stimulated HUVECs, atorvastatin and rosuvastatin decreased mRNA expression of IL1β, IL-18, IL-23, TGFβ, IL35 and increased mRNA expression of IL-10 and IL-37 compared to 25-OHC. Furthermore, only incubation with rosuvastatin and rosuvastatin-ezetimibe decreased IL-35 mRNA and protein levels. Ezetimibe down-regulated only IL1β. Treatment with rosuvastatin-ezetimibe and atorvastatin-ezetimibe reversed the effect of 25-OHC in IL1β, IL-18 and IL-35 mRNA expression. In conclusion, rosuvastatin has the strongest anti-inflammatory effects and is the best at reducing the effect of oxysterols. Both statins exert a greater anti-inflammatory effect than ezetimibe. The anti-inflammatory effect of the combination therapies appears to be based on the effects of the statins alone and not their combination with ezetimibe. [ABSTRACT FROM AUTHOR]

It is well established that patients with Gaucher disease, as well as carriers of the disease have an increased risk for developing Parkinson's disease. A plethora of evidence suggests that disturbed α-Synuclein homeostasis is the link between Gaucher disease and Parkinson's disease. The pathogenic mechanism linking these entities is still a topic of debate and both gain- and loss-of-function theories have been put forward, which however are not mutually exclusive. In the present study we expanded our previous studies to include not only Gaucher disease patients but also Gaucher disease carriers and Gaucher disease patients following Enzyme Replacement Therapy. In these groups we investigated α-Synuclein in red blood cell membranes in association with lipid abnormalities described in Gaucher disease. These included glucosylceramide and its species, glucosylsphingosine, glucosylcholesterol and plasmalogens. Increased oligomerization of α-Synuclein in red blood cell membranes was observed not only in Gaucher disease patients but also in carriers of the disease. There were no qualitative differences in the lipids identified in the groups studied. However, significant quantitative differences compared to controls were observed in Gaucher disease patients but not in Gaucher disease carriers. Enzyme Replacement Therapy reversed the biochemical defects and normalized α-Synuclein homeostasis, providing for the first time evidence in human subjects that such homeostatic dysregulation is reversible. Further studies investigating α-Synuclein status during the differentiation of erythroid progenitors could provide new data on the pathogenic mechanism of α-Synuclein oligomerization in this system. [ABSTRACT FROM AUTHOR]

Purpose: To prospectively assess the effect of a single and regular application of either a cationic nanoemulsion of mineral oil (CN) or perfluorohexyloctane (F6H8) on the lipid layer of the tear film and higher order aberrations (HOA) in patients with Dry Eye Disease (DED). Methods: Fifty-seven patients with a lipid layer thickness (LLT) ≤ 75 interferometric colour units (ICU) were included in the study. In group A (20 patients) the effect of a single drop of F6H8 or CN on HOA and LLT was assessed immediately after application and up to two hours later. For long term effects (Group B) 37 patients applied CN or F6H8 five times a day for 12 weeks. Measurement of LLT, HOA, non-invasive-tear-break-up-time (NIBUT) and meibography were assessed prior to as well as at 4 weeks and 12 weeks after initiation of treatment. Our study is registered in the "German Clinical Trials Register" under the trial number: DRKS00028696. Results: CN led to an increase of the LLT from 46.8 ± 16.9 ICU to 76.3 ± 23.5 ICU (p = 0.021) and to an increase of HOA from 0.43 ± 0.06 μm to 0.48 ± 0.08 μm immediately after application (p = 0.027). There was no correlation between the increase of LLT and HOA (r = -0.04; p = 0.90). In group B an increase of LLT was observed in the F6H8 group from 45.8 ± 8.8 ICU at baseline to 66.7 ± 19.5 ICU at 12 weeks (p = 0.002). No changes of HOA were measured throughout the observation period in group B. After 12 weeks CN increased NIBUT from 9.9 ± 5.3 seconds to 15.5 ± 5.6 seconds (p = 0.04). F6H8 increased NIBUT from 12.4 ± 5.9 seconds to 16.9 ± 4.7 seconds (p = 0.02) after 12 weeks. Conclusion: CN leads to a short-term increase in LLT and HOA, but only immediately after application. In contrast F6H8 does lead to an increase of LLT after regular long-term use but has no effect on HOA. The regular application of lipid-based products does not seem to decrease the quality of vision as measured in HOA. Instead, CN and F6H8, both are able to stabilize the tear film after regular application. [ABSTRACT FROM AUTHOR]

Background and aims: The LDL cholesterol (LDL-C) treatment goals recommended by the 2019 ESC/EAS guidelines are only achieved in a minority of patients. The study objective was to estimate the impact of bempedoic acid treatment on LDL-C target attainment, drug costs, and atherosclerotic cardiovascular disease (ASCVD) events. The simulation used a Monte Carlo approach in a representative cohort of German outpatients at high or very-high cardiovascular risk. Additionally to statins, consecutive treatment with ezetimibe, bempedoic acid, and a PCSK9 inhibitor was simulated in patients not achieving their LDL-C goal. Considered were scenarios without and with bempedoic acid (where bempedoic acid was replaced by a PCSK9 inhibitor when LDL-C was not controlled). Results: The simulation cohort consisted of 105,577 patients, of whom 76,900 had very-high and 28,677 high cardiovascular risk. At baseline, 11.2% of patients achieved their risk-based LDL-C target. Sequential addition of ezetimibe and bempedoic acid resulted in target LDL-C in 33.1% and 61.9%, respectively. Treatment with bempedoic acid reduced the need for a PCSK9 inhibitor from 66.6% to 37.8% and reduced drug costs by 35.9% per year on stable lipid-lowering medication. Compared to using only statins and ezetimibe, this approach is projected to prevent additional 6,148 ASCVD events annually per 1 million patients, whereas PCSK9 inhibition alone would prevent 7,939 additional ASCVD events annually. Conclusions: A considerably larger proportion of cardiovascular high- and very-high-risk patients can achieve guideline-recommended LDL-C goals with escalated lipid-lowering medication. Bempedoic acid is projected to substantially decrease the need for PCSK9 inhibitor treatment to achieve LDL-C targets, associated with reduced drug costs albeit with fewer prevented events. [ABSTRACT FROM AUTHOR]

Aedes aegypti is the primary vector of dengue virus (DENV) and other arboviruses. Previous literature suggests that vertebrate and invertebrate lipids and the nutritional status of mosquitoes modify virus infection. Here, we developed a vertebrate lipid-depleted Ae. aegypti cell line to investigate if chronic depletion of vertebrate lipids normally present in a blood meal and insect cell culture medium would impact cell growth and virus infection. Chronic depletion of vertebrate lipids reduced cell size and proliferation, although cells retained equivalent total intracellular lipids per cell by reducing lipolysis and modifying gene expression related to sugar and lipid metabolism. Downregulation of innate immunity genes was also observed. We hypothesized that chronic depletion of vertebrate lipids would impact virus infection; however, the same amount of DENV was produced per cell. This study reveals how Ae. aegypti cells adapt in the absence of vertebrate lipids, and how DENV can replicate equally well in cells that contain predominately vertebrate or invertebrate lipids. Author summary: Aedes aegypti is a major threat to public health. Ae. aegypti is the primary vector of dengue virus types 1–4 (DENV 1–4), zika virus (ZIKV), chikungunya virus (CHIKV), and yellow fever virus (YFV). Ae. aegypti acquires arboviruses from a vertebrate host during blood feeding. Blood feeding introduces vertebrate-specific factors into the mosquito that may be important for both mosquito and virus. This study reveals that Ae. aegypti adapts to depletion of vertebrate lipids by inhibiting lipolysis and promoting de novo synthesis of invertebrate lipids, and that DENV can replicate equally well without high concentrations of cholesterol and other vertebrate lipid species. Understanding how disease vectors adapt to nutritional changes will identify novel strategies for vector control and disease mitigation. [ABSTRACT FROM AUTHOR]

P5A ATPases are expressed in the endoplasmic reticulum (ER) of all eukaryotic cells, and their disruption results in pleiotropic phenotypes related to severe ER stress. They were recently proposed to function in peptide translocation although their specificity have yet to be confirmed in reconstituted assays using the purified enzyme. A general theme for P-type ATPases is that binding and transport of substrates is coupled to hydrolysis of ATP in a conserved allosteric mechanism, however several independent reports have shown purified Spf1p to display intrinsic spontaneous ATP hydrolytic activity after purification. It has never been determined to what extend this spontaneous activity is caused by uncoupling of the enzyme. In this work we have purified a functional tagged version of the Saccharomyces cerevisiae P5A ATPase Spf1p and have observed that the intrinsic ATP hydrolytic activity of the purified and re-lipidated protein can be stimulated by specific detergents (C12E8, C12E10 and Tween20) in mixed lipid/detergent micelles in the absence of any apparent substrate. We further show that this increase in activity correlate with the reaction temperature and the anisotropic state of the mixed lipid/detergent micelles and further that this correlation relies on three highly conserved phenylalanine residues in M1. This suggests that at least part of the intrinsic ATP hydrolytic activity is allosterically coupled to movements in the TM domain in the purified preparations. It is suggested that free movement of the M1 helix represent an energetic constraint on catalysis and that this constraint likely is lost in the purified preparations resulting in protein with intrinsic spontaneous ATP hydrolytic activity. Removal of the N-terminal part of the protein apparently removes this activity. [ABSTRACT FROM AUTHOR]

Ferroptosis is an iron-dependent form of regulated cell death associated with uncontrolled membrane lipid peroxidation and destruction. Previously, we showed that dietary dihomo-gamma-linolenic acid (DGLA; 20: 3(n-6)) triggers ferroptosis in the germ cells of the model organism, Caenorhabditis elegans. We also demonstrated that ether lipid-deficient mutant strains are sensitive to DGLA-induced ferroptosis, suggesting a protective role for ether lipids. The vinyl ether bond unique to plasmalogen lipids has been hypothesized to function as an antioxidant, but this has not been tested in animal models. In this study, we used C. elegans mutants to test the hypothesis that the vinyl ether bond in plasmalogens acts as an antioxidant to protect against germ cell ferroptosis as well as to protect from whole-body tert-butyl hydroperoxide (TBHP)-induced oxidative stress. We found no role for plasmalogens in either process. Instead, we demonstrate that ether lipid-deficiency disrupts lipid homeostasis in C. elegans, leading to altered ratios of saturated and monounsaturated fatty acid (MUFA) content in cellular membranes. We demonstrate that ferroptosis sensitivity in both wild type and ether-lipid deficient mutants can be rescued in several ways that change the relative abundance of saturated fats, MUFAs and specific polyunsaturated fatty acids (PUFAs). Specifically, we reduced ferroptosis sensitivity by (1) using mutant strains unable to synthesize DGLA, (2) using a strain carrying a gain-of-function mutation in the transcriptional mediator MDT-15, or (3) by dietary supplementation of MUFAs. Furthermore, our studies reveal important differences in how dietary lipids influence germ cell ferroptosis versus whole-body peroxide-induced oxidative stress. These studies highlight a potentially beneficial role for endogenous and dietary MUFAs in the prevention of ferroptosis. Author summary: Ferroptosis is a regulated form of cell death driven by excess production of lipid peroxides. Understanding ferroptosis is important because this type of cell death is associated with disease states such as neurodegeneration and various renal, liver, and lung diseases. In addition, with more knowledge of regulatory mechanisms, induction of ferroptosis could be harnessed to control tumor growth. To examine specific lipid contributions to ferroptosis sensitivity, we used mutant strains of the small roundworm Caenorhabditis elegans exhibiting a range of altered lipid compositions to examine how cellular and dietary lipids influence ferroptosis and oxidative stress sensitivity. We found that the accumulation of lipid peroxides correlates with cell death but that plasmalogens, a subset of ether lipids that are proposed to act as cellular antioxidants, do not protect from ferroptosis or oxidative stress. Instead, ether lipid biosynthesis contributes to lipid homeostasis in membranes. In their absence, membrane saturated fatty acids are increased, while membrane monounsaturated fatty acids (MUFAs) are less abundant. Restoring membrane MUFAs reduces lipid peroxides and contributes to cellular resistance to ferroptotic cell death. These studies suggest that dietary MUFAs could prevent ferroptosis in disease. [ABSTRACT FROM AUTHOR]

Aim: In United Arab Emirates, cardiovascular disease (CVD) is a leading cause of mortality and 22% of CVD deaths are attributable to acute myocardial infarction (MI). Adherence to guidelines for lipid management is incompletely described in the Middle East. This study aimed to characterize lipid lowering therapy (LLT) patterns and the risk of subsequent cardiovascular events (CVEs) in the first year after MI. Methods: This was a retrospective cohort study using the Dubai Real-World Claims Database, including all patients discharged with MI between January 01, 2015 and December 31, 2018, followed-up until December 31, 2019. Results: In the first year after MI, 8.42% of 4,595 patients included experienced at least one recurrent MI (rate 6.77 events/100 person-years [PYs]), 2.94% had one revascularization (cumulative rate 0.55 events/100 PYs) and 2.66% had one hospitalization due to unstable angina (cumulative rate 5.16 new events/100 PYs). The majority (60.40%) of the patients presented with LDL-C levels ≥ 70 mg/dL after MI. In the first year after MI, 93.45% of the patients received LLT, mainly high-intensity statin (67.79%); with a minority of patients receiving statin + ezetimibe (4.55%), PCSK9i (0.20%) or ezetimibe alone (0.07%). Conclusion: Patients hospitalized with MI in Dubai present an increased risk of CVEs in their first-year post-discharge. Majority of the patients presented with LDL-C levels above 70 mg/dL, which indicates suboptimal lipid control with existing LLT, particularly in high-risk patients. [ABSTRACT FROM AUTHOR]

Psychological problems commonly experienced by patients with type 2 diabetes mellitus (T2DM) cause diabetes fatigue conditions that can further worsen the treatment prognosis. We conducted this investigation to determine the effectiveness of a resilience-based Islamic program on diabetes fatigue and health-related quality of life (HRQoL) by measuring the biochemical indicators of T2DM. This was a quasi-experimental study performed from May to August 2021, in which 80 respondents aged 18–64 years diagnosed with T2DM were included through purposive sampling at a male:female sex ratio of 1:1 in the control group and 17:23 in the treatment group. A resilience-based Islamic program (a combination of stress management, mindfulness, prayer, and dhikr (the ritual formula of Sufi brotherhood recited devotionally in praise of Allah and as a means of attaining ecstatic experience)) was implemented in the treatment group for six sessions by blended online and offline interventions. Multidimensional Fatigue Inventory-20 and World Health Organization Quality of Life, Brief Form were used to evaluate diabetes fatigue and HRQoL. Blood tests were performed to measure HbA1c, total antioxidant serum, insulin, cholesterol, triglyceride, high-density lipoprotein cholesterol (HDL-c), and low-density lipoprotein cholesterol (LDL-c) levels from baseline to 3 months. Statistical analyses were conducted using paired t test, Wilcoxon signed-rank test, independent t test, and Mann–Whitney U test. The resilience-based Islamic program had a beneficial impact on the levels of HbA1c (p < 0.001), lipid profile (triglyceride) (p = 0.011), HDL-c (p = 0.01), LDL-c (p < 0.001), total antioxidant serum (p = 0.001), insulin (p < 0.001), diabetes fatigue (p < 0.05), and HRQoL (p < 0.05) in patients of the treatment group. The results of biochemical tests related to T2DM also indicated a reduction in diabetes fatigue and an increase in HRQoL due to the resilience-based Islamic program. Considering that a patient's resilience to diabetes is an important factor in the management of diabetes fatigue, the resilience-based Islamic program can be applied at public health centers and community levels to increase T2DM resilience. [ABSTRACT FROM AUTHOR]

Background: Despite lipid-lowering and antiplatelet therapy, the pattern of residual lipoproteins seems relevant to long-term cardiovascular outcomes. This study aims to evaluate the effects of combined therapies, commonly used in subjects with acute myocardial infarction, in the quality of low-density lipoprotein (LDL) particles. Methods: Prospective, open-label trial, included patients with acute myocardial infarction. Patients were randomized to antiplatelet treatment (ticagrelor or clopidogrel) and subsequently to lipid-lowering therapy (rosuvastatin or simvastatin/ezetimibe) and were followed up for six months. Nonlinear optical properties of LDL samples were examined by Gaussian laser beam (Z-scan) to verify the oxidative state of these lipoproteins, small angle X-ray scattering (SAXS) to analyze structural changes on these particles, dynamic light scattering (DLS) to estimate the particle size distribution, ultra violet (UV)-visible spectroscopy to evaluate the absorbance at wavelength 484 nm (typical from carotenoids), and polyacrylamide gel electrophoresis (Lipoprint) to analyze the LDL subfractions. Results: Simvastatin/ezetimibe with either clopidogrel or ticagrelor was associated with less oxidized LDL, and simvastatin/ezetimibe with ticagrelor to lower cholesterol content in the atherogenic subfractions of LDL, while rosuvastatin with ticagrelor was the only combination associated with increase in LDL size. Conclusions: The quality of LDL particles was influenced by the antiplatelet/lipid-lowering strategy, with ticagrelor being associated with the best performance with both lipid-lowering therapies. Trial registration: NCT02428374. [ABSTRACT FROM AUTHOR]

Pregnant and lactating women have been discouraged from using cannabis by Health Canada. However, the increasing rate of cannabis use among pregnant women has presented an urgent need to investigate its physiological effects during the perinatal period. During pregnancy, the mammary gland (MG) undergoes remodeling, which involves alveolar differentiation of mammary epithelial cells (MECs), which is essential for breast milk production and secretion. Limited evidence has been reported on the impact of cannabis or its components, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), on MG development or MEC differentiation. In this study, we investigated the effects of THC and CBD on the differentiation of MECs by assessing changes in cellular viability, lipid accumulation, and gene and protein expression of major milk protein and lipid synthesizing markers. using the HC11 cells as a model. We hypothesized that THC and CBD will negatively impact the synthesis of milk proteins and lipids, as well as lipid markers in HC11 cells. Our results demonstrated that THC and CBD reduced cellular viability at concentrations above 30μM and 20μM, respectively. Relative to control, 10μM THC and 10μM CBD reduced mRNA levels of milk proteins (CSN2 and WAP), lipid synthesizing and glucose transport markers (GLUT 1, HK2, FASN, FABP4, PLIN2 and LPL), as well as whey acidic protein and lipid levels. In addition, co-treatment of a CB2 antagonist with THC, and a CB2 agonist with CBD, reversed the impact of THC and CBD on the mRNA levels of key markers, respectively. In conclusion, 10μM THC and CBD altered the differentiation of HC11 cells, in part via the CB2 receptor. [ABSTRACT FROM AUTHOR]

Halocynthia aurantium is a marine organism that has been considered a promising source for bio-functional materials. Total lipids were extracted from H. aurantium tunic, and then they were separated into neutral lipids, glycolipids, and phospholipids. In the present study, fatty acid profiles of three lipids and their anti-inflammatory effects in RAW264.7 cells were investigated. Among the lipid classes, phospholipids showed the diversity of fatty acid constituents, compared with the glycolipids and neutral lipids. Three lipids contain different contents of fatty acids depending on the kinds of lipids. The most contents were saturated fatty acids (SFAs, 53–69% of the fatty acids) and monounsaturated fatty acids (MUFAs, 15–17% of fatty acids) and polyunsaturated fatty acids (PUFAs, 14–32% of fatty acids) are followed. H. aurantium lipids not only dose-dependently inhibited nitric oxide production but also reduced the expression of inflammatory cytokine genes such as TNF-α, IL-1β, and IL-6 in LPS-stimulated macrophages. It was also demonstrated that the expression of COX-2 was dose-dependently suppressed. Moreover, H. aurantium lipids decreased phosphorylation of NF-κB p-65, p38, ERK1/2, and JNK, suggesting that three lipids from H. aurantium tunic provide anti-inflammatory effects through NF-κB and MAPK signaling. These results indicate that H. aurantium is a potential source for anti-inflammation. [ABSTRACT FROM AUTHOR]

Background: The role of cholesterol levels in the development of atrial fibrillation (AF) is still controversial. In addition, whether and to what extent apolipoproteins are associated with the risk of AF is rarely studied. In this study, we aimed to investigate the association between blood lipid levels in midlife and subsequent risk of new-onset AF. Methods and findings: This population-based study included 65,136 individuals aged 45 to 60 years without overt cardiovascular diseases (CVDs) from the Swedish Apolipoprotein-Related Mortality Risk (AMORIS) cohort. Lipids were measured in 1985 to 1996, and individuals were followed until December 31, 2019 for incident AF (i.e., study outcome). Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using Cox regression, adjusting for age, sex, and socioeconomic status. Over a mean follow-up of 24.2 years (standard deviation 7.5, range 0.2 to 35.9), 13,871 (21.3%) incident AF cases occurred. Higher levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) were statistically significantly associated with a lower risk of AF during the first 5 years of follow-up (HR = 0.61, 95% CI: 0.41 to 0.99, p = 0.013; HR = 0.64, 95% CI: 0.45 to 0.92, p = 0.016), but not thereafter (HR ranging from 0.94 [95% CI: 0.89 to 1.00, p = 0.038] to 0.96 [95% CI: 0.77 to 1.19, p > 0.05]). Lower levels of high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A-I (ApoA-I) and higher triglycerides (TG)/HDL-C ratio were statistically significantly associated with a higher risk of AF during the entire follow-up (HR ranging from 1.13 [95% CI: 1.07 to 1.19, p < 0.001] to 1.53 [95% CI: 1.12 to 2.00, p = 0.007]). Apolipoprotein B (ApoB)/ApoA-I ratio was not associated with AF risk. The observed associations were similar among those who developed incident heart failure (HF)/coronary heart disease (CHD) and those who did not. The main limitations of this study include lack of adjustments for lifestyle factors and high blood pressure leading to potential residual confounding. Conclusions: High TC and LDL-C in midlife was associated with a lower risk of AF, but this association was present only within 5 years from lipid measurement and not thereafter. On the contrary, low HDL-C and ApoA-I and high TG/HDL-C ratio were associated with an increased risk of AF over almost 35 years of follow-up. ApoB/ApoA-I ratio was not associated with AF risk. Mozhu Ding and colleagues investigate investigate the association between blood lipid levels in midlife and subsequent risk of new-onset atrial fibrillation in Sweden. Author summary: Why was this study done?: High cholesterol level is an established risk factor for cardiovascular diseases (CVDs), such as coronary heart disease (CHD). However, the role of cholesterol levels in the development of atrial fibrillation (AF), a very common cardiac arrhythmia in older adults, is debated. Compared to cholesterols, apolipoprotein B (ApoB), apolipoprotein A-I (ApoA-I), and their ratios have been shown to better predict CVD, but whether and how they are associated with AF is unclear. What did the researchers do and find?: In this large Swedish cohort with blood-based biomarker information, 65,136 individuals free of overt CVD and aged 45 to 60 years at lipid measurement were followed for up to 35 years for new-onset AF. High levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) were associated with a lower risk of AF (hazard ratio, HR = 0.61, 95% confidence interval (CI): 0.41 to 0.99, p = 0.013; HR = 0.64, 95% CI: 0.45 to 0.92, p = 0.016), but this association was present only during the first 5 years since lipid measurement. On the contrary, low levels of high-density lipoprotein cholesterol (HDL-C) and ApoA-I and a high triglyceride (TG)/HDL-C ratio were associated with an increased risk of AF throughout the follow-up time (HR ranging from 1.13 [95% CI: 1.07 to 1.19, p < 0.001] to 1.53 [95% CI: 1.12 to 2.00, p = 0.007]). High ApoB/ApoA-I ratio was not associated with the risk of subsequent AF. What do these findings mean?: Dyslipidemia expressed by a high TC or LDL-C, or a poor atherogenic to anti-atherogenic balance, does not seem to be associated with an increased risk of developing AF. Instead, the findings suggest that metabolic syndrome and inflammation, as indicated by low HDL-C and ApoA-I and a high TG/HDL-C ratio, may play a role in the onset of AF. [ABSTRACT FROM AUTHOR]

Chronic hepatitis B virus (HBV) infection is characterized by the presence of high circulating levels of non-infectious lipoprotein-like HBV surface antigen (HBsAg) particles thought to contribute to chronic immune dysfunction in patients. Lipid and metabolomic analysis of humanized livers from immunodeficient chimeric mice (uPA/SCID) revealed that HBV infection dysregulates several lipid metabolic pathways. Small molecule inhibitors of lipid biosynthetic pathway enzymes acetyl-CoA carboxylase (ACC), fatty acid synthase, and subtilisin kexin isozyme-1/site-1 protease in HBV-infected HepG2-NTCP cells demonstrated potent and selective reduction of extracellular HBsAg. However, a liver-targeted ACC inhibitor did not show antiviral activity in HBV-infected liver chimeric mice, despite evidence of on-target engagement. Our study suggests that while HBsAg production may be dependent on hepatic de novo lipogenesis in vitro, this may be overcome by extrahepatic sources (such as lipolysis or diet) in vivo. Thus, a combination of agents targeting more than one lipid metabolic pathway may be necessary to reduce HBsAg levels in patients with chronic HBV infection. [ABSTRACT FROM AUTHOR]