Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a respiratory virus that emerged in late 2019 and rapidly spread worldwide, causing the COVID-19 pandemic. The spike glycoprotein (S protein) plays a crucial role in viral target recognition and entry by interacting with angiotensin, converting enzyme 2 (ACE2), the functional receptor for the virus, via its receptor binding domain (RBD). The RBD availability for this interaction can be influenced by external factors, such as fatty acids. Linoleic acid (LA), a free fatty acid, has been shown to bind the S protein, modulating the viral infection by reducing initial target recognition. LA interacts with the fatty acid binding pocket (FABP), a potential drug target against SARS-CoV-2. In this study, we aimed to exploit the FABP as a drug target by performing a docking-based virtual screening with a library of commercially available, drug-like compounds. The virtual hits identified were then assessed in in vitro assays for the inhibition of the virus-host interaction and cytotoxicity. Binding assays targeting the spike-ACE2 interaction identified multiple compounds with inhibitory activity and low cytotoxicity.

• MeSH
• Angiotensin-Converting Enzyme 2 * metabolism   chemistry   MeSH
• Antiviral Agents pharmacology   chemistry   metabolism   MeSH
• COVID-19 virology   metabolism   MeSH
• COVID-19 Drug Treatment MeSH
• Spike Glycoprotein, Coronavirus * metabolism   chemistry   MeSH
• Linoleic Acid metabolism   chemistry   MeSH
• Humans MeSH
• Fatty Acid-Binding Proteins metabolism   MeSH
• SARS-CoV-2 * metabolism   drug effects   MeSH
• Molecular Docking Simulation * MeSH
• Protein Binding * MeSH
• Binding Sites MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

Linoleic acid (LA), an essential fatty acid, has emerged as a pivotal regulator in disorders associated with inflammation in recent years; however, the underlying mechanisms are still not completely understood. We utilized network pharmacology and experimental methodologies to elucidate the mechanisms underlying the anti-inflammatory effects of LA. Our network pharmacology analysis revealed that LA shares common targets with sepsis. These targets are enriched in various pathways comprising C-type signaling pathway, PI3K-Akt signaling pathway, toll-like receptor signaling pathway, neutrophil extracellular trap formation, AMPK signaling pathway, and autophagy-animal. These findings suggest that LA may exert regulatory effects on inflammation and autophagy during sepsis. Subsequently, we established in vivo and ex vivo models of sepsis using lipopolysaccharide (LPS) in experimental study. Treatment with LA reduced lung damage in mice with LPS-induced lung injury, and reduced tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in plasma, bronchoalveolar lavage fluid (BALF), and peritoneal lavage fluid (PLF). LA also decreased the production of TNF-α and IL-6 in RAW264.7 macrophages exposed to LPS. In LPS-induced RAW264.7 macrophages, LA induced an elevation in LC3-II while causing a reduction in p62, which was associated with downregulation of toll-like receptor 4 (TLR4). We utilized 3-methyladenine (3-MA) to inhibit the autophagic activity, which reversed the modulatory effects of LA on LC3-II and p62. 3-MA also prevented the decline in TLR4 expression along with reduction in pro-inflammatory cytokines secretion. Our findings suggest that the activation of autophagy by LA may lead to the downregulation of TLR4, thereby exerting its anti-inflammatory effects.

• MeSH
• Autophagy * drug effects   MeSH
• Linoleic Acid * pharmacology   MeSH
• Lipopolysaccharides * toxicity   MeSH
• Macrophages * drug effects   metabolism   immunology   MeSH
• Mice MeSH
• RAW 264.7 Cells MeSH
• Sepsis chemically induced   drug therapy   metabolism   immunology   MeSH
• Signal Transduction drug effects   MeSH
• Toll-Like Receptor 4 * metabolism   MeSH
• Inflammation * metabolism   drug therapy   chemically induced   pathology   MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

• MeSH
• Cardiovascular Diseases * physiopathology   prevention & control   therapy   MeSH
• Clinical Studies as Topic MeSH
• Linoleic Acid pharmacology   MeSH
• Fatty Acids, Omega-6 pharmacology   therapeutic use   MeSH
• Humans MeSH
• Fatty Acids * physiology   classification   therapeutic use   MeSH
• Fatty Acids, Omega-3 administration & dosage   pharmacology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Review MeSH

• MeSH
• Pancreatitis, Chronic metabolism   physiopathology   MeSH
• Taste Perception MeSH
• Crohn Disease metabolism   physiopathology   MeSH
• Cystic Fibrosis metabolism   physiopathology   MeSH
• Enterocytes physiology   MeSH
• Gastrointestinal Absorption physiology   MeSH
• Gastrointestinal Diseases * metabolism   physiopathology   MeSH
• Linoleic Acid metabolism   MeSH
• Humans MeSH
• Fatty Acids * physiology   metabolism   MeSH
• Food Intolerance MeSH
• Intestines metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Review MeSH

Linoleic acid (LA) not only functions as an essential nutrient, but also profoundly modulates oxidative stress and inflammatory response. However, the potential mechanisms have not been adequately researched. Hence, this study examined the potential pharmacological roles of LA and the underlying mechanisms in mice with lipopolysaccharide (LPS)-associated acute liver injury (ALI). The results indicated that treatment with LA alleviated the histopathological abnormalities in the hepatic and plasma levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and glutathione-S-transferase (GST) in mice with LPS exposure. In addition, LA inhibited the LPS-associated generation of proinflammatory factors, such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6), and downregulated the hepatic myeloperoxidase (MPO) level. In addition, the administration of LA resulted in a reduction in hepatic malondialdehyde (MDA) levels and an elevation in liver superoxide dismutase (SOD), reduced glutathione (GSH), catalase (CAT), and glutathione peroxidase (GSH-PX) levels. Further investigations revealed that LA promoted the expression of nuclear factor E2-related factor (Nrf2) and NAD(P)H: quinone oxidoreductase 1 (NQO1). In addition, the beneficial outcomes of LA on LPS-induced acute liver failure were revered when Nrf2 was pharmacologically suppressed by ML385. These experimental results demonstrated that LA supplementation attenuated LPS-associated acute hepatic impairment in mice via the activation of Nrf2.

• MeSH
• NF-E2-Related Factor 2 * metabolism   MeSH
• Liver drug effects   metabolism   pathology   MeSH
• Linoleic Acid * pharmacology   MeSH
• Chemical and Drug Induced Liver Injury * metabolism   drug therapy   pathology   prevention & control   MeSH
• Lipopolysaccharides * toxicity   MeSH
• Mice MeSH
• Oxidative Stress drug effects   MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

Omega-O-acyl ceramides such as 32-linoleoyloxydotriacontanoyl sphingosine (Cer[EOS]) are essential components of the lipid skin barrier, which protects our body from excessive water loss and the penetration of unwanted substances. These ceramides drive the lipid assembly to epidermal-specific long periodicity phase (LPP), structurally much different than conventional lipid bilayers. Here, we synthesized Cer[EOS] with selectively deuterated segments of the ultralong N-acyl chain or deuterated or 13C-labeled linoleic acid and studied their molecular behavior in a skin lipid model. Solid-state 2H NMR data revealed surprising molecular dynamics for the ultralong N-acyl chain of Cer[EOS] with increased isotropic motion toward the isotropic ester-bound linoleate. The sphingosine moiety of Cer[EOS] is also highly mobile at skin temperature, in stark contrast to the other LPP components, N-lignoceroyl sphingosine acyl, lignoceric acid, and cholesterol, which are predominantly rigid. The dynamics of the linoleic chain is quantitatively described by distributions of correlation times and using dynamic detector analysis. These NMR results along with neutron diffraction data suggest an LPP structure with alternating fluid (sphingosine chain-rich), rigid (acyl chain-rich), isotropic (linoleate-rich), rigid (acyl-chain rich), and fluid layers (sphingosine chain-rich). Such an arrangement of the skin barrier lipids with rigid layers separated with two different dynamic "fillings" i) agrees well with ultrastructural data, ii) satisfies the need for simultaneous rigidity (to ensure low permeability) and fluidity (to ensure elasticity, accommodate enzymes, or antimicrobial peptides), and iii) offers a straightforward way to remodel the lamellar body lipids into the final lipid barrier.

• MeSH
• Ceramides chemistry   MeSH
• Epidermis MeSH
• Skin chemistry   MeSH
• Linoleic Acid * MeSH
• Sphingosine analysis   MeSH
• Molecular Dynamics Simulation * MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Epidermal omega-O-acylceramides (ω-O-acylCers) are essential components of a competent skin barrier. These unusual sphingolipids with ultralong N-acyl chains contain linoleic acid esterified to the terminal hydroxyl of the N-acyl, the formation of which requires the transacylase activity of patatin-like phospholipase domain containing 1 (PNPLA1). In ichthyosis with dysfunctional PNPLA1, ω-O-acylCer levels are significantly decreased, and ω-hydroxylated Cers (ω-OHCers) accumulate. Here, we explore the role of the linoleate moiety in ω-O-acylCers in the assembly of the skin lipid barrier. Ultrastructural studies of skin samples from neonatal Pnpla1+/+ and Pnpla1-/- mice showed that the linoleate moiety in ω-O-acylCers is essential for lamellar pairing in lamellar bodies, as well as for stratum corneum lipid assembly into the long periodicity lamellar phase. To further study the molecular details of ω-O-acylCer deficiency on skin barrier lipid assembly, we built in vitro lipid models composed of major stratum corneum lipid subclasses containing either ω-O-acylCer (healthy skin model), ω-OHCer (Pnpla1-/- model), or combination of the two. X-ray diffraction, infrared spectroscopy, and permeability studies indicated that ω-OHCers could not substitute for ω-O-acylCers, although in favorable conditions, they form a medium lamellar phase with a 10.8 nm-repeat distance and permeability barrier properties similar to long periodicity lamellar phase. In the absence of ω-O-acylCers, skin lipids were prone to separation into two phases with diminished barrier properties. The models combining ω-OHCers with ω-O-acylCers indicated that accumulation of ω-OHCers does not prevent ω-O-acylCer-driven lamellar stacking. These data suggest that ω-O-acylCer supplementation may be a viable therapeutic option in patients with PNPLA1 deficiency.

• MeSH
• Acyltransferases MeSH
• Ceramides * chemistry   MeSH
• Epidermis MeSH
• Ichthyosis MeSH
• Skin * MeSH
• Linoleic Acid MeSH
• Lipase MeSH
• Mice MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

• MeSH
• Arachidonic Acid * administration & dosage   physiology   MeSH
• Linoleic Acid administration & dosage   physiology   MeSH
• Humans MeSH
• Vitamin K 1 * MeSH
• Vitamin K 2 MeSH
• Check Tag
• Humans MeSH

Triacylglycerols (TAGs) containing less common fatty acids (FAs) were isolated from the seeds of three plants (Santalum album, Crepis foetida, and Leucas aspera). These FAs had allenic (laballenic acid, Lb) and acetylenic (crepenynic, C; ximenynic acids, Xi) bonds. TAGs were analyzed on reversed-phase and chiral columns. High-resolution tandem mass spectrometry identified TAGs by positive electrospray ionization (ESI+). Twenty-two molecular species of TAGs isolated from the seed oil of Santalum album were separated by RP-HPLC and chiral HPLC methods and identified by positive electrospray ionization tandem MS detection (ESI+-MS). Two major enantiomers, i.e., sn-OOLb and sn-LLLb (O represents oleic acid; and L represents linoleic acid), were synthesized from the appropriate phosphatidylcholines. This allowed the identification of enantiomers after separation by chiral chromatography by tandem mass spectrometry. Similarly, TAGs from the seeds of Crepis foetida, and Leucas aspera were analyzed by reversed-phase chromatography and identified by mass spectrometry. Four enantiomers (sn-OOC, sn-LLC, sn-OOXi, and sn-LLXi) were synthesized. A total of six and three enantiomers of TAGs containing crepenynic and ximenynic acids, respectively, were identified by chiral column analysis. The retention times of TAGs containing allenic and acetylenic bonds were always greater on the reversed-phase column than TAGs with the same number of carbon atoms and the same unsaturation (e.g., LLL versus LLLb). From the chiral column, the regioisomers and enantiomers were eluted in the order of symmetric-asymmetric-asymmetric (i.e., sn-OCO, sn-COO, and sn-OOC). Through tandem mass spectrometry, we were able to identify and distinguish regioisomer [DAG]+-type ions, i.e., [MNH4NH3RCOOH]+, that can be considered diagnostic. Unfortunately, enantiomers and TAGs with the same numbers of carbon atoms and the same unsaturation levels have identical mass spectra, such as LLL and LLLb.

• MeSH
• Alkynes analysis   chemistry   MeSH
• Chromatography, Liquid MeSH
• Chromatography, Reverse-Phase MeSH
• Phosphatidylcholines chemistry   MeSH
• Spectrometry, Mass, Electrospray Ionization MeSH
• Linoleic Acid analysis   MeSH
• Oleic Acids analysis   MeSH
• Fatty Acids analysis   chemistry   MeSH
• Seeds chemistry   MeSH
• Stereoisomerism MeSH
• Tandem Mass Spectrometry * MeSH
• Triglycerides analysis   chemistry   isolation & purification   MeSH
• Chromatography, High Pressure Liquid * MeSH
• Publication type
• Journal Article MeSH

SCOPE: The docosahexaenoic acid ester of hydroxy linoleic acid (13-DHAHLA) is a bioactive lipid with anti-inflammatory properties from the family of fatty acid esters of hydroxy fatty acids (FAHFA). METHODS AND RESULTS: To explore the biosynthesis of 13-DHAHLA from dietary oils, C57BL/6N mice are gavaged for 8 days with various corn oil/marine oil mixtures containing the same amount of DHA. Plasma levels of omega-3 FAHFAs are influenced by the lipid composition of the mixtures but do not reflect the changes in bioavailability of polyunsaturated fatty acids in plasma. Triacylglycerol-bound DHA and linoleic acid serve as more effective precursors for 13-DHAHLA synthesis than DHA bound in phospholipids or wax esters. Both 13(S)- and 13(R)-DHAHLA inhibit antigen and PGE2 -induced chemotaxis and degranulation of mast cells to a comparable extent and 13(S)-DHAHLA is identified as the predominant isomer in mouse adipose tissue. CONCLUSION: Here, the optimal nutritional source of DHA is identified, which supports production of anti-inflammatory FAHFAs, as triacylglycerol-based marine oil and also reveals a possible role of triacylglycerols in the synthesis of FAHFA lipokines.

• MeSH
• Anti-Inflammatory Agents, Non-Steroidal blood   pharmacokinetics   MeSH
• Biological Availability MeSH
• Chemotaxis drug effects   MeSH
• Docosahexaenoic Acids pharmacokinetics   MeSH
• Linoleic Acids chemistry   MeSH
• Mast Cells drug effects   MeSH
• Mice, Inbred C57BL MeSH
• Oils chemistry   pharmacokinetics   MeSH
• Fatty Acids, Omega-3 pharmacokinetics   pharmacology   MeSH
• Stereoisomerism MeSH
• Triglycerides chemistry   MeSH
• Aquatic Organisms MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH