Chain Length-dependent Manner Research Articles

Groundwater solutes influence the adsorption of short-chain perfluoroalkyl acids (PFAA) to colloidal activated carbon and impact performance for in situ groundwater remediation

Subsurface injection of colloidal activated carbon (CAC) is an in situ remediation strategy for perfluoroalkyl acids (PFAA), but the influence of groundwater solutes on longevity is uncertain, particularly for short-chain PFAA. We quantify the impact of inorganic anions, dissolved organic matter (DOM), and stabilizing polymer on PFAA adsorption to a commercial CAC. Surface characterization supported PFAA chain-length dependent adsorption results and mechanisms are provided. Inorganic anions decreased adsorption for short-chain PFAA (<7 perfluorinated carbons) due to competitive effects, while long-chain PFAA (≥ 7 perfluorinated carbons) were less impacted. DOM decreased adsorption of all PFAA in a chain-length dependent manner. High DOM concentrations (10 mg/L, ∼5 mg OC/L) decreased PFOA adsorption by a factor of 2, PFPeA by one order of magnitude, and completely hindered PFBA adsorption. High MW DOM has less impact on short-chain PFAA than low MW DOM, possibly due to differences in the ability to access CAC micropores. Low DOM concentrations (1 mg/L, ∼0.5 mg OC/L) did not impact adsorption. CMC (90 kDa average MW) had negligible impact on PFAA adsorption likely due to minimal CAC surface coverage. Longevity modeling demonstrated that groundwater solutes limit the capacity for PFAA in a CAC barrier, particularly for short-chain PFAA.

Potentiation of Lipotoxicity in Human EndoC-βH1 β-Cells by Glucose is Dependent on the Structure of Free Fatty Acids.

Lipotoxicity is a significant element in the development of type 2 diabetes mellitus (T2DM). Since pro-diabetic nutritional patterns are associated with hyperglycemia as well as hyperlipidemia, the study analyzes the effects of combining these lipid and carbohydrate components with a special focus on the structural fatty acid properties such as increasing chain length (C16-C20) and degree of saturation with regard to the role of glucolipotoxicity in human EndoC-βH1 β-cells. β-cell death induced by saturated FFAs is potentiated by high concentrations of glucose in a chain length-dependent manner starting with stearic acid (C18:0), whereas toxicity remains unchanged in the case of monounsaturated FFAs. Interference with FFA desaturation by overexpression and inhibition of stearoyl-CoA-desaturase, which catalyzes the rate-limiting step in the conversion of long-chain saturated into corresponding monounsaturated FFAs, does not affect the potentiating effect of glucose, but FFA desaturation reduces lipotoxicity and plays an important role in the formation of lipid droplets. Crucial elements underlying glucolipotoxicity are ER stress induction and cardiolipin peroxidation in the mitochondria. In the context of nutrition, the data emphasize the importance of the lipid component in glucolipotoxicity related to the development of β-cell dysfunction and death in the manifestation of T2DM.

Branched Chondroitin Sulfate Oligosaccharides Derived from the Sea Cucumber Acaudina molpadioides Stimulate Neurite Outgrowth.

Fucosylated chondroitin sulfate (FCS) from the sea cucumber Acaudina molpadioides (FCSAm) is the first one that was reported to be branched by disaccharide GalNAc-(α1,2)-Fuc3S4S (15%) and sulfated Fuc (85%). Here, four size-homogenous fractions, and seven oligosaccharides, were separated from its β-eliminative depolymerized products. Detailed NMR spectroscopic and MS analyses revealed the oligomers as hexa-, hepta-, octa-, and nonasaccharide, which further confirmed the precise structure of native FCSAm: it was composed of the CS-E-like backbone with a full content of sulfation at O-4 and O-6 of GalNAc in the disaccharide repeating unit, and the branches consisting of sulfated fucose (Fuc4S and Fuc2S4S) and heterodisaccharide [GalNAc-(α1,2)-Fuc3S4S]. Pharmacologically, FCSAm and its depolymerized derivatives, including fractions and oligosaccharides, showed potent neurite outgrowth-promoting activity in a chain length-dependent manner. A comparison of analyses among oligosaccharides revealed that the sulfate pattern of the Fuc branches, instead of the heterodisaccharide, could affect the promotion intensity. Fuc2S4S and the saccharide length endowed the neurite outgrowth stimulation activity most.

NIR-activated nanosystems with self-modulated bacteria targeting for enhanced biofilm eradication and caries prevention

The efficacious delivery of antimicrobial drugs to intractable oral biofilms remains a challenge due to inadequate biofilm penetration and lack of pathogen targeting. Herein, we have developed a microenvironment-activated poly(ethylene glycol) (PEG)-sheddable nanoplatform to mediate targeted delivery of drugs into oral biofilms for the efficient prevention of dental caries. The PEGylated nanoplatform with enhanced biofilm penetration is capable of deshielding the PEG layer under slightly acidic conditions in a PEG chain length-dependent manner to re-expose the bacteria-targeting ligands, thereby facilitating targeted codelivery of ciprofloxacin (CIP) and IR780 to the bacteria after accumulation within biofilms. The nanoplatform tends to induce bacterial agglomeration and suffers from degradation in the acidic oral biofilm microenvironment, triggering rapid drug release on demand around bacterial cells. The self-modulating nanoplatform under near-infrared (NIR) irradiation accordingly displays greatly augmented potency in oral biofilm penetration and disruption compared with drugs alone. Topical oral treatment with nanoplatforms involving synergetic pharmacological and photothermal/photodynamic trinary therapy results in robust biofilm dispersion and efficacious suppression of severe tooth decay in rats. This versatile nanoplatform can promote local accumulation and specific drug transport into biofilms and represents a new paradigm for targeted drug delivery for the management of oral biofilm-associated infections.

Comparison of functionality and structural stability of bacteriorhodopsin reconstituted in partially fluorinated dimyristoylphosphatidylcholine liposomes with different perfluoroalkyl chain lengths

Amphiphilic molecules with one or more perfluoroalkyl groups (Rf, CnF2n+1), which show peculiar interfacial properties, are attracting much attention in membrane protein science. We recently have developed a partially fluorinated dimyristoylphosphatidylcholine (DMPC) with a perfluorobutyl group in the hydrophobic chain terminal (F4-DMPC) and demonstrated that F4-DMPC is a promising material for incorporating membrane proteins. Moreover, we have found out that membrane properties of a series of partially fluorinated DMPCs with different Rf chain lengths (Fn-DMPCs) vary in a significant Rf chain length-dependent manner. In the present study, structural and functional properties of a membrane protein bacteriorhodopsin (bR) in the Fn-DMPC (n = 4, 6, and 8) membranes (bR/Fn-DMPC) are investigated using several physicochemical techniques. Regardless of the Rf chain lengths, bR/Fn-DMPCs retain native-like structural and functional properties at 30 °C, unlike bR molecules in DMPC vesicles. In particular, bR/F6-DMPC, which is in the fluid phase at 30 °C, shows flash-induced transient absorption changes very similar to the native purple membrane (PM) and very high thermal stability of bR trimers comparable to the PM. Structural and functional properties of bR/Fn-DMPCs are discussed compared to the PM and bR/DMPC.

Size matters: TLR4-mediated effects of α-(1,5)-linear arabino-oligosaccharides in macrophage-like cells depend on their degree of polymerization

Linear arabino-oligosaccharides (LAOS) produced from controlled enzymatic hydrolysis of arabinans from sugar beet are well-known because of their chain-length dependent prebiotic effects. However, it is not clear if these α-(1,5)-linked arabinose oligosaccharides can interact directly with immune system cells, as well as if its degree of polymerization (DP) influences possible biological effects. Four high purity LAOS with distinct DP were tested in macrophage-like cells exposed or not to LPS. Results shown that LAOS interact with Toll-like receptor (TLR) 4 in a chain length-dependent manner. LAOS with higher DP induce stimulatory effects mainly through the TLR4/MyD88 pathway, thereby enhancing the release of tumor necrosis factor alpha (TNF-α), interleukin (IL-) 1β, 6, 12, and chemokines including MCP-1, RANTES, IL-8, and IP-10. Notably, LAOS with lower DP appears to have an opposite effect to those counterparts with higher DP, as they does not induce the secretion of cytokines and chemokines in macrophages-like cells, while also inhibit TLR4-mediated effects induced by both lipopolysaccharide and LAOS with higher DP. These findings provide not only insights into potential biological effects of LAOS, but also reveal that controlled enzymatic hydrolysis of sugar beet arabinans may lead to dietary oligosaccharides with desired biological properties.

Physico-chemical and gel properties of heat-induced pasteurized liquid egg white gel: effect of alkyl chain length of alcohol

ABSTRACT The influence of alcohols with different alkyl chain length (methanol, ethanol and propanol) on the physicochemical properties (turbidity, surface hydrophobicity, exposed and total free sulfhydryl groups, denaturation temperature; Tm ) of pasteurized liquid egg white (PLEW), including gel properties (gel hardness and expressible liquid) and microstructure of heat-induced PLEW gel prepared at 75°C were studied. The results showed that alkyl chain length of alcohol and alcohol concentration had no impact on the total free sulfhydryl groups, but significantly increased the turbidity, surface hydrophobicity, exposed free sulfhydryl groups, gel hardness and expressible water. Increase the alkyl chain length of alcohol also significantly decreased the Tm and the total enthalpy change during heat-induced gelation of PLEW. Addition of 5% alcohol altered the microstructure of the PLEW gels in an alkyl chain length dependent manner.

A new fucosylated glycosaminoglycan containing disaccharide branches from Acaudina molpadioides: Unusual structure and anti-intrinsic tenase activity

A fucosylated glycosaminoglycan (AmFG) was extracted from the sea cucumber Acaudina molpadioides. And a series of oligosaccharides were purified from the size-homogeneous fractions, which were prepared from the β-eliminative depolymerized AmFG. According to “bottom-up” strategy, the precise structure of AmFG was elucidated by analyzing the structures of these purified oligosaccharides, combining with NMR analysis of its free-radical depolymerized product. It contained a CS-E-like backbone, and each GlcUA was branched with a mono- or di-sulfated fucose (Fuc) at O-3. Intriguingly, besides two types of monosaccharide branches, Fuc2S4S (60 %) and Fuc4S (25 %), that were common in FG, AmFG also contained an unusual disaccharide branch GalNAc-α1,2-Fuc3S4S (15 %); this is the first report of such a structure in a glycosaminoglycan. Biological assays indicated that native AmFG and its oligosaccharides had potent anticoagulant and intrinsic tenase (iXase) inhibitory activities in a chain length-dependent manner. For these oligosaccharides, octasaccharide was the minimum structural fragment for potent anti-iXase activity, and the disaccharide branch might enhance this activity.

ABCG1 contributes to suberin formation in Arabidopsis thaliana roots

Diffusion barriers enable plant survival under fluctuating environmental conditions. They control internal water potential and protect against biotic or abiotic stress factors. How these protective molecules are deposited to the extracellular environment is poorly understood. We here examined the role of the Arabidopsis ABC half-size transporter AtABCG1 in the formation of the extracellular root suberin layer. Quantitative analysis of extracellular long-chain fatty acids and aliphatic alcohols in the atabcg1 mutants demonstrated altered root suberin composition, specifically a reduction in longer chain dicarboxylic acids, fatty alcohols and acids. Accordingly, the ATP-hydrolyzing activity of heterologous expressed and purified AtABCG1 was strongly stimulated by fatty alcohols (C26–C30) and fatty acids (C24–C30) in a chain length dependent manner. These results are a first indication for the function of AtABCG1 in the transport of longer chain aliphatic monomers from the cytoplasm to the apoplastic space during root suberin formation.

Structure and dynamics of short-chain polymerized ionic liquids.

Combining experimental results obtained with X-ray scattering and field-gradient nuclear magnetic resonance (NMR) and an assessment of new and previous dielectric and rheology data, our study focuses on the molecular weight (Mw) evolution of local structure and dynamics in a homologous series of covalently bonded ionic liquids. Performed on a family of electrolytes with a tailored degree of ionic decoupling, this study reveals the differences between monomeric and oligomeric melts with respect to their structural organization, mass and charge transport, and molecular diffusion. Our study demonstrates that for the monomeric compound, the broadband conductivity and mechanical spectra reflect the same underlying distribution of activation barriers and that the Random Barrier Model describes fairly well both the ionic and structural relaxation processes in these materials. Moreover, the oligomers with chains comprising ten segments only exhibit both structural and dynamical fingerprints of a genuine polymer. A comparison of conductivity levels estimated using the self-diffusion coefficients probed via NMR and those probed directly with dielectric spectroscopy reveals the emerging of ion correlations which are affecting the macroscopic charge transport in these materials in a chain-length dependent manner.

The relevance of ceramides and their synthesizing enzymes for multiple sclerosis.

Ceramide synthases (CerS) synthesize chain length specific ceramides (Cer), which mediate cellular processes in a chain length-dependent manner. In experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), we observed that the genetic deletion of CerS2 suppresses EAE pathology by interaction with granulocyte-colony stimulating factor (G-CSF) signaling and CXC motif chemokine receptor 2 (CXCR2) expression, leading to impaired neutrophil migration. In the present study, we investigated the importance of Cers and their synthesizing/metabolizing enzymes in MS. For this purpose, a longitudinal study with 72 MS patients and 25 healthy volunteers was performed. Blood samples were collected from healthy controls and MS patients over 1- or 3-year periods, respectively. Immune cells were counted using flow cytometry, ceramide levels were determined using liquid chromatography-tandem mass spectrometry, and mRNA expression was analyzed using quantitative PCR. In white blood cells, C16-LacCer and C24-Cer were down-regulated in MS patients in comparison with healthy controls. In plasma, C16-Cer, C24:1-Cer, C16-GluCer, and C24:1-GluCer were up-regulated and C16-LacCer was down-regulated in MS patients in comparison with healthy controls. Blood samples from MS patients were characterized by an increased B-cell number. However, there was no correlation between B-cell number and Cer levels. mRNA expression of Cer metabolizing enzymes and G-CSF signaling enzymes was significantly increased in MS patients. Interestingly, G-CSF receptor (G-CSFR) and CXCR2 mRNA expression correlated with CerS2 and UDP-glucose Cer glucosyltransferase (UGCG) mRNA expression. In conclusion, our results indicate that Cer metabolism is linked to G-CSF signaling in MS.

Polysialic Acid in Human Plasma Can Compensate the Cytotoxicity of Histones.

The innate immune system has numerous mechanisms to fight against pathogens, including the formation of neutrophil extracellular traps (NETs). By spreading out chromatin, antimicrobial peptides and enzymes, neutrophils efficiently trap pathogens like bacteria and facilitate their elimination. During this process, high concentrations of extracellular histones can be reached. Several researchers have demonstrated that the cytotoxic characteristics of these histones can trigger diseases like sepsis. Interestingly, the carbohydrate polysialic acid (polySia) can bind histones and reduce histone-mediated cytotoxicity in a chain length-dependent manner. In the present study, we examined the chain length of polySia in plasma and tested its ability to decrease the cytotoxic characteristics of extracellular histones. Remarkably, we detected polySia not only in the soluble fraction of plasma, but also on enriched extracellular vesicles (EVs). Chain length analysis revealed that polySia chains originating from human plasma can consists of more than 40 sialic acid residues and show a cytoprotective effect against extracellular histones. Intriguingly, polySia is not only present in human plasma but also in fish and other branches of vertebrates. Thus, polySia is a physiological element in plasma and may represent a natural buffer for extracellular histones.

Corrigendum: Inulin-Type Fructans Modulates Pancreatic-Gut Innate Immune Responses and Gut Barrier Integrity during Experimental Acute Pancreatitis in a Chain Length-Dependent Manner.

[This corrects the article on p. 1209 in vol. 8, PMID: 29018453.].

Enzymatically synthesized megalo-type isomaltosaccharides enhance the barrier function of the tight junction in the intestinal epithelium.

Megalo-type isomaltosaccharides are an enzymatically synthesized foodstuff produced by transglucosylation from maltodextrin, and they contain a mid-chain length polymer of D-glucose with α-1,6-glycoside linkages. The injection of a solution of megalo-type isomaltosaccharides (1-4%(w/v), average DP=12.6), but not oligo-type isomaltosaccharides (average DP=3.3), into the intestinal lumen dose-dependently reduced the transport rates of tight junction permeable markers in a ligated loop of the anesthetized rat jejunum. Application of the megalosaccharide also suppressed the transport of tight junction markers and enhanced transepithelial electrical resistance (TEER) in Caco-2 cell monolayers. Cholesterol sequestration by methyl-β-cyclodextrin in the Caco-2 monolayers abolished the effect of megalosaccharide. Treatment with anti-caveolin-1 and a caveolae inhibitor, but not clathrin-dependent endocytosis and macropinocytosis inhibitors, suppressed the increase in TEER. These results indicate that isomaltosaccharides promote the barrier function of tight junctions in the intestinal epithelium in a chain-length dependent manner and that caveolae play a role in the effect.

Linear ubiquitin chain induces apoptosis and inhibits tumor growth.

Ubiquitination of proliferating cell nuclear antigen (PCNA) plays an important role in DNA damage response. Ectopic expression of PCNA fused at either terminus with ubiquitin (Ub) lacking two C-terminal glycine residues induces translesion DNA synthesis which resembles synthesis mediated by PCNA monoubiquitination. PCNA fused with Ub containing the C-terminal Gly residues at the C-terminus can be further polyubiquitinated in a Gly-dependent manner, which inhibits cell proliferation and induces ATR-dependent replication checkpoint. In this study, we surprisingly found that PCNA fused to a head-to-tail linear Ub chain induces apoptosis in a Ub chain length-dependent manner. Further investigation revealed that the apoptotic effect is actually induced by the linear Ub chain independently from PCNA, as the Ub chain fused to GFP or an epitope tag still efficiently induces apoptosis. It is revealed that the artificial linear Ub chain differs from endogenously encoded linear Ub chains in that its Ubs contain a Ub-G76S substitution, making the Ub chain resistant to cleavage by deubiquitination enzymes. We demonstrated in this study that ectopic expression of the artificial Ub chain alone in cultured human cancer cells is sufficient to inhibit tumor growth in a xenograft mouse model, making the linear Ub chain a putative anti-cancer agent.

Inulin-Type Fructans Modulates Pancreatic-Gut Innate Immune Responses and Gut Barrier Integrity during Experimental Acute Pancreatitis in a Chain Length-Dependent Manner.

Acute pancreatitis (AP) is a common abdominal inflammatory disorder and one of the leading causes of hospital admission for gastrointestinal disorders. No specific pharmacological or nutritional therapy is available but highly needed. Inulin-type fructans (ITFs) are capable of modifying gut immune and barrier homeostasis in a chemistry-dependent manner and hence potentially applicable for managing AP, but their efficacy in AP has not been demonstrated yet. The current study aimed to examine and compare modulatory effects of ITFs with different degrees of fermentability on pancreatic–gut immunity and barrier function during experimentally induced AP in mice. BALB/c mice were fed short (I)- or long (IV)-chain ITFs supplemented diets for up to 3 days before AP induction by caerulein. Attenuating effects on AP development were stronger with ITF IV than with ITF I. We found that long-chain ITF IV attenuated the severity of AP, as evidenced by reduced serum amylase levels, lipase levels, pancreatic myeloperoxidase activity, pancreatic edema, and histological examination demonstrating reduced pancreatic damage. Short-chain ITF I demonstrated only partial protective effects. Both ITF IV and ITF I modulated AP-associated systemic cytokine levels. ITF IV but not ITF I restored AP-associated intestinal barrier dysfunction by upregulating colonic tight junction modulatory proteins, antimicrobial peptides, and improved general colonic histology. Additionally, differential modulatory effects of ITF IV and ITF I were observed on pancreatic and gut immunity: ITF IV supplementation prevented innate immune cell infiltration in the pancreas and colon and tissue cytokine production. Similar effects were only observed in the gut with ITF I and not in the pancreas. Lastly, ITF IV but not ITF I downregulated AP-triggered upregulation of IL-1 receptor-associated kinase 4 (IRAK-4) and phosphor-c-Jun N-terminal kinase (p-JNK), and a net decrease of phosphor-nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) p65 (p-NF-κB p65) nuclear translocation and activation in the pancreas. Our findings demonstrate a clear chain length-dependent effect of inulin on AP. The attenuating effects are caused by modulating effects of long-chain inulin on the pancreatic–gut immunity via the pancreatic IRAK-4/p-JNK/p-NF-κBp65 signaling pathway and on prevention of disruption of the gut barrier.

Circulating levels of sphingosine-1-phosphate are elevated in severe, but not mild psoriasis and are unresponsive to anti-TNF-α treatment.

Sphingolipids are bioactive molecules with a putative role in inflammation. Alterations in sphingolipids, in particular ceramides, have been consistently observed in psoriatic skin. Herein, we quantified the circulating sphingolipid profile in individuals with mild or severe psoriasis as well as healthy controls. In addition, the effects of anti-TNF-α treatment were determined. Levels of sphingoid bases, including sphingosine-1-phosphate (S1P), increased in severe (P < 0.001; n = 32), but not in mild (n = 32), psoriasis relative to healthy controls (n = 32). These alterations were not reversed in severe patients (n = 16) after anti-TNF-α treatment despite significant improvement in psoriasis lesions. Circulating levels of sphingomyelins and ceramides shifted in a fatty acid chain length-dependent manner. These alterations were also observed in psoriasis skin lesions and were associated with changes in mRNA levels of ceramide synthases. The lack of S1P response to treatment may have pathobiological implications due to its close relation to the vascular and immune systems. In particular, increased levels of sphingolipids and especially S1P in severe psoriasis patients requiring biological treatment may potentially be associated with cardiovascular comorbidities. The fact that shifts in S1P levels were not ameliorated by anti-TNF-α treatment, despite improvements in the skin lesions, further supports targeting S1P receptors as therapy for severe psoriasis.

Lack of ceramide synthase 2 suppresses the development of experimental autoimmune encephalomyelitis by impairing the migratory capacity of neutrophils.

Ceramide synthases (CerS) synthesise ceramides of defined acyl chain lengths, which are thought to mediate cellular processes in a chain length-dependent manner. In experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), we observed a significant elevation of CerS2 and its products, C24-ceramides, in CD11b(+) cells (monocytes and neutrophils) isolated from blood. This result correlates with the clinical finding that CerS2 mRNA expression and C24-ceramide levels were significantly increased by 2.2- and 1.5-fold, respectively, in white blood cells of MS patients. The increased CerS2 mRNA/C24-ceramide expression in neutrophils/monocytes seems to mediate pro-inflammatory effects, since a specific genetic deletion of CerS2 in blood cells or a total genetic deletion of CerS2 significantly delayed the onset of clinical symptoms, due to a reduced infiltration of immune cells, in particular neutrophils, into the central nervous system. CXCR2 chemokine receptors, expressed on neutrophils, promote the migration of neutrophils into the central nervous system, which is a prerequisite for the recruitment of further immune cells and the inflammatory process that leads to the development of MS. Interestingly, neutrophils isolated from CerS2 null EAE mice, as opposed to WT EAE mice, were characterised by significantly lower CXCR2 receptor mRNA expression resulting in their reduced migratory capacity towards CXCL2. Most importantly, G-CSF-induced CXCR2 expression was significantly reduced in CerS2 null neutrophils and their migratory capacity was significantly impaired. In conclusion, our data strongly indicate that G-CSF-induced CXCR2 expression is regulated in a CerS2-dependent manner and that CerS2 thereby promotes the migration of neutrophils, thus, contributing to inflammation and the development of EAE and MS.

Phase behavior of the DOPE + DOPC + alkanol system.

Small- and wide-angle X-ray diffraction was used to study the effect of 1-alkanols, as simple models of general anesthetics, (abbreviation CnOH, n = 8-18 is the even number of carbons in the aliphatic chain) on the lamellar to hexagonal Lα→ H(II) phase transition in the dioleoylphosphatidylethanolamine-dioleoylphosphatidylcholine = 3 : 1 mol/mol (DOPE + DOPC) system. All studied CnOHs were found to decrease the phase transition temperature of the DOPE + DOPC system in a CnOH chain length and concentration dependent manner and thus promote the formation of the HII phase. Anesthetically active C8OH and C10OH were found to decrease the lattice parameter d of the Lα phase, however longer non-anesthetic CnOHs increased the parameter d; this effect being more pronounced with increasing CnOH concentration. The lattice parameter of the HII phase was decreased in the presence of all CnOHs, even at the lowest concentrations studied. In the scope of the indirect mechanism of general anesthesia observed changes in the lattice parameter d (reflecting changes in the bilayer thickness) due to the intercalation of C8OH and C10OH might induce changes in the activity of integral membrane proteins engaged in neuronal pathways.

Intracellular long-chain acyl CoAs activate TRPV1 channels.

TRPV1 channels are an important class of membrane proteins that play an integral role in the regulation of intracellular cations such as calcium in many different tissue types. The anionic phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2) is a known positive modulator of TRPV1 channels and the negatively charged phosphate groups interact with several basic amino acid residues in the proximal C-terminal TRP domain of the TRPV1 channel. We and other groups have shown that physiological sub-micromolar levels of long-chain acyl CoAs (LC-CoAs), another ubiquitous anionic lipid, can also act as positive modulators of ion channels and exchangers. Therefore, we investigated whether TRPV1 channel activity is similarly regulated by LC-CoAs. Our results show that LC-CoAs are potent activators of the TRPV1 channel and interact with the same PIP2-binding residues in TRPV1. In contrast to PIP2, LC-CoA modulation of TRPV1 is independent of Ca2+ i, acting in an acyl side-chain saturation and chain-length dependent manner. Elevation of LC-CoAs in intact Jurkat T-cells leads to significant increases in agonist-induced Ca2+ i levels. Our novel findings indicate that LC-CoAs represent a new fundamental mechanism for regulation of TRPV1 channel activity that may play a role in diverse cell types under physiological and pathophysiological conditions that alter fatty acid transport and metabolism such as obesity and diabetes.