RXR nuclear receptor signaling modulates lipid metabolism and triggers lysosomal clearance of alpha-synuclein in neuronal models of synucleinopathy.

Disease-modifying strategies for Parkinson disease (PD), the most common synucleinopathy, represent a critical unmet medical need. Accumulation of the neuronal protein alpha-synuclein (αS) and abnormal lipid metabolism have each been implicated in PD pathogenesis. Here, we elucidate how retinoid-X-receptor (RXR) nuclear receptor signaling impacts these two aspects of PD pathogenesis. We find that activated RXR differentially regulates fatty acid desaturases, significantly reducing the transcript levels of the largely brain-specific desaturase SCD5 in human cultured neural cells and PD patient-derived neurons. This was associated with reduced perilipin-2 protein levels in patient neurons, reversal of αS-induced increases in lipid droplet (LD) size, and a reduction of triglyceride levels in human cultured cells. With regard to αS proteostasis, our study reveals that RXR agonism stimulates lysosomal clearance of αS. Our data support the involvement of Polo-like kinase 2 activity and αS S129 phosphorylation in mediating this benefit. The lowering of cellular αS levels was associated with reduced cytotoxicity. Compared to RXR activation, the RXR antagonist HX531 had the opposite effects on LD size, SCD, αS turnover, and cytotoxicity, all supporting pathway specificity. Together, our findings show that RXR-activating ligands can modulate fatty acid metabolism and αS turnover to confer benefit in cellular models of PD, including patient neurons. We offer a new paradigm to investigate nuclear receptor ligands as a promising strategy for PD and related synucleinopathies.

Fatty Acid Origin of Insect Pheromones.

Pheromones are utilized to a great extent in insects. Many of these pheromones are biosynthesized through a pathway involving fatty acids. This chapter will provide examples where the biosynthetic pathways of fatty acid-derived pheromones have been studied in detail. These include pheromones from Lepidoptera, Coleoptera, and Hymenoptera. Many species of Lepidoptera utilize fatty acids as precursors to pheromones with a functional group that include aldehydes, alcohols, and acetate esters. In addition, the biosynthesis of hydrocarbons will be briefly examined because many insects utilize hydrocarbons or modified hydrocarbons as pheromones.

Human adaptations to diet: Biological and cultural coevolution.

Modern humans evolved in Africa some 200,000 years ago, and since then, human populations have expanded and diversified to occupy a broad range of habitats and use different subsistence modes. This has resulted in different adaptations, such as differential responses to diseases and different abilities to digest or tolerate certain foods. The shift from a subsistence strategy based on hunting and gathering during the Palaeolithic to a lifestyle based on the consumption of domesticated animals and plants in the Neolithic can be considered one of the most important dietary transitions of Homo sapiens. In this text, we review four examples of gene-culture coevolution: (i) the persistence of the enzyme lactase after weaning, which allows the digestion of milk in adulthood, related to the emergence of dairy farming during the Neolithic; (ii) the population differences in alcohol susceptibility, in particular the ethanol intolerance of Asian populations due to the increased accumulation of the toxic acetaldehyde, related to the spread of rice domestication; (iii) the maintenance of gluten intolerance (celiac disease) with the subsequent reduced fitness of its sufferers, related to the emergence of agriculture and (iv) the considerable variation in the biosynthetic pathway of long-chain polyunsaturated fatty acids in native populations with extreme diets.

FADS1/2 control lipid metabolism and ferroptosis susceptibility in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) has limited therapeutic options, is highly metastatic and characterized by early recurrence. Lipid metabolism is generally deregulated in TNBC and might reveal vulnerabilities to be targeted or used as biomarkers with clinical value. Ferroptosis is a type of cell death caused by iron-dependent lipid peroxidation which is facilitated by the presence of polyunsaturated fatty acids (PUFA). Here we identify fatty acid desaturases 1 and 2 (FADS1/2), which are responsible for PUFA biosynthesis, to be highly expressed in a subset of TNBC with a poorer prognosis. Lipidomic analysis, coupled with functional metabolic assays, showed that FADS1/2 high-expressing TNBC are susceptible to ferroptosis-inducing agents and that targeting FADS1/2 by both genetic interference and pharmacological approach renders those tumors ferroptosis-resistant while unbalancing PUFA/MUFA ratio by the supplementation of exogenous PUFA sensitizes resistant tumors to ferroptosis induction. Last, inhibiting lipid droplet (LD) formation and turnover suppresses the buffering capacity of LD and potentiates iron-dependent cell death. These findings have been validated in vitro and in vivo in mouse- and human-derived clinically relevant models and in a retrospective cohort of TNBC patients.

Effects of temperature up-shift and UV-A radiation on fatty acids content and expression of desaturase genes in cyanobacteria Microcystis aeruginosa: stress tolerance and acclimation responses.

Temperature up-shift and UV-A radiation effects on growth, lipid damage, fatty acid (FA) composition and expression of desaturase genes desA and desB were investigated in the cyanobacteria Microcystis aeruginosa. Although UV-A damaging effect has been well documented, reports on the interactive effects of UV radiation exposure and warming on cyanobacteria are scarce. Temperature and UV-A doses were selected based on the physiological responses previously obtained by studies with the same M. aeruginosa strain used in this study. Cells pre-grown at 26 °C were incubated at the same temperature or 29 °C and exposed to UV-A + PAR and only PAR for 9 days. Growth rate was significantly affected by UV-A radiation independently of the temperature throughout the experiment. High temperature produced lipid damage significantly higher throughout the experiment, decreasing at day 9 as compared to 26 °C. In addition, the cells grown at 29 °C under UV-A displayed a decrease in polyunsaturated FA (PUFA) levels, with ω3 PUFA being mostly affected at the end of exposure. Previously, we reported that UV-A-induced lipid damage affects differentially ω3 and ω6 PUFAs. We report that UV-A radiation leads to an upregulation of desA, possibly due to lipid damage. In addition, the temperature up-shift upregulates desA and desB regardless of the radiation. The lack of lipid damage for UV-A on ω3 could explain the lack of transcription induction of desB. The significant ω6 decrease at 26 °C in cells exposed to UV-A could be due to the lack of upregulation of desA.

Arabidopsis diacylglycerol acyltransferase1 mutants require fatty acid desaturation for normal seed development.

Diacylglycerol acyltransferase1 (DGAT1) is the major enzyme that synthesizes triacylglycerols (TAG) during Arabidopsis seed development. Mutant dgat1 seeds possess low oil content in addition to a high polyunsaturated fatty acid (PUFA) composition. Two genes encoding endoplasmic reticulum localized desaturase enzymes, fatty acid desaturase2 (FAD2) and fatty acid desaturase3 (FAD3), were upregulated in both dgat1-1 and dgat1-2 developing seeds. Crosses between both dgat1 mutant alleles and fad2-1 failed to generate plants homozygous for both dgat1 and fad2. Reciprocal crosses with wild-type plants demonstrated that both male and female dgat1 fad2 gametophytes were viable. Siliques from DGAT1/dgat1-1 fad2-1/fad2-1 and dgat1-1/dgat1-1 FAD2/fad2-1 possessed abnormal looking seeds that were arrested in the torpedo growth stage. Approximately 25% of the seeds exhibited this arrested phenotype, genetically consistent with them possessing the double homozygous dgat1 fad2 genotype. In contrast, double homozygous dgat1-1 fad3-2 mutant plants were viable. Seeds from these plants possessed higher levels of 18:2 while their fatty acid content was lower than dgat1 mutant controls. The results are consistent with a model where in the absence of DGAT1 activity, desaturation of fatty acids by FAD2 becomes essential to provide PUFA substrates for phospholipid:diacylglycerol acyltransferase (PDAT) to synthesize TAG. In a dgat1 fad2 mutant, seed development is aborted because TAG is unable to be synthesized by either DGAT1 or PDAT.

Fatty Acids and Their Lipogenic Enzymes in Anorexia Nervosa Clinical Subtypes.

Disordered eating behavior differs between the restricting subtype (AN-R) and the binging and purging subtype (AN-BP) of anorexia nervosa (AN). Yet, little is known about how these differences impact fatty acid (FA) dysregulation in AN. To address this question, we analyzed 26 FAs and 7 FA lipogenic enzymes (4 desaturases and 3 elongases) in 96 women: 25 AN-R, 25 AN-BP, and 46 healthy control women. Our goal was to assess subtype-specific patterns. Lauric acid was significantly higher in AN-BP than in AN-R at the fasting timepoint (p = 0.038) and displayed significantly different postprandial changes 2 h after eating. AN-R displayed significantly higher levels of n-3 alpha-linolenic acid, stearidonic acid, eicosapentaenoic acid (EPA), docosapentaenoic acid, and n-6 linoleic acid and gamma-linolenic acid compared to controls. AN-BP showed elevated EPA and saturated lauric acid compared to controls. Higher EPA was associated with elevated anxiety in AN-R (p = 0.035) but was linked to lower anxiety in AN-BP (p = 0.043). These findings suggest distinct disordered eating behaviors in AN subtypes contribute to lipid dysregulation and eating disorder comorbidities. A personalized dietary intervention may improve lipid dysregulation and enhance treatment effectiveness for AN.

Loss of function mutations at the tomato SSI2 locus impair plant growth and development by altering the fatty acid desaturation pathway.

The stearoyl-ACP desaturase (SACPD) is a key enzyme in the regulation of saturated to unsaturated fatty acid ratio, playing a crucial role in regulating membrane stability and fluidity, as well as photosynthesis efficiency, which makes it an important research focus in crop species. This study reports the characterization and molecular cloning of pale dwarf (pad), a new tomato (Solanum lycopersicum L.) T-DNA recessive mutant, which exhibits a dwarf and chlorotic phenotype. Functional studies of the T-DNA tagged gene were conducted, including phylogenetic analysis, expression and metabolomic analyses, and generation of CRISPR/Cas9 knockout lines. The cloning of T-DNA flanking genomic sequences and a co-segregation analysis found the pad phenotype was caused by a T-DNA insertion disrupting the tomato homologue of the Arabidopsis SUPPRESSOR OF SALICYLIC ACID INSENSITIVITY 2 (SlSSI2), encoding a plastid localized isoform of SACPD. The phenotype of CRISPR/Cas9 SlSSI2 knockout lines confirmed that the morphological abnormalities in pad plants were due to SlSSI2 loss of function. Functional, metabolomic and expression analyses proved that SlSSI2 disruption causes deficiencies in 18:1 fatty acid desaturation and leads to diminished jasmonic acid (JA) content and increased salicylic acid (SA) levels. Overall, these results proved that SSI2 plays a crucial role in the regulation of polyunsaturated fatty acid profiles in tomato, and revealed that SlSSI2 loss of function results in an inhibited JA-responsive signalling pathway and a constitutively activated SA-mediated defence signalling response. This study lays the foundation for further research on tomato SACPDs and their role in plant performance and fitness.

Atropine does not prevent hypoxemia and bradycardia in tracheal intubation in the pediatric emergency department: observational study / O uso da atropina não previne hipoxemia e bradicardia na intubação traqueal no departamento de emergência pediátrica: estudo observacional

ABSTRACT Objective: The benefit of atropine in pediatric tracheal intubation is not well established. The objective of this study was to evaluate the effect of atropine on the incidence of hypoxemia and bradycardia during tracheal intubations in the pediatric emergency department. Methods: This is a single-center observational study in a tertiary pediatric emergency department. Data were collected on all tracheal intubations in patients from 31 days to incomplete 20 years old, performed between January 2016 and September 2020. Procedures were divided into two groups according to the use or not of atropine as a premedication during intubation. Records with missing data, patients with cardiorespiratory arrest, cyanotic congenital heart diseases, and those with chronic lung diseases with baseline hypoxemia were excluded. The primary outcome was hypoxemia (peripheral oxygen saturation ≤88%), while the secondary outcomes were bradycardia (decrease in heart rate >20% between the maximum and minimum values) and critical bradycardia (heart rate <60 bpm) during intubation procedure. Results: A total of 151 tracheal intubations were identified during the study period, of which 126 were eligible. Of those, 77% had complex, chronic underlying diseases. Atropine was administered to 43 (34.1%) patients and was associated with greater odds of hypoxemia in univariable analysis (OR: 2.62; 95%CI 1.15-6.16; p=0.027) but not in multivariable analysis (OR: 2.07; 95%CI 0.42-10.32; p=0.37). Critical bradycardia occurred in only three patients, being two in the atropine group (p=0.26). Bradycardia was analyzed in only 42 procedures. Atropine use was associated with higher odds of bradycardia in multivariable analysis (OR: 11.00; 95%CI 1.3-92.8; p=0.028). Conclusions: Atropine as a premedication in tracheal intubation did not prevent the occurrence of hypoxemia or bradycardia during intubation procedures in pediatric emergency.

RESUMO Objetivo: Avaliar o efeito da atropina na incidência de hipoxemia e bradicardia durante a intubação orotraqueal no departamento de emergência pediátrica. Métodos: Estudo observacional, realizado em departamento de emergência pediátrica terciário em que foram analisados os registros de intubações orotraqueais de pacientes com 31 dias a 20 anos incompletos, entre janeiro de 2016 e setembro de 2020. Os procedimentos foram divididos em dois grupos de acordo com o uso ou não da atropina como pré-medicação durante a intubação. Foram excluídos os procedimentos com falhas no preenchimento dos dados, pacientes com parada cardiorrespiratória, cardiopatias congênitas cianóticas, e aqueles com pneumopatias crônicas com hipoxemia basal. O desfecho primário foi hipoxemia (saturação periférica de oxigênio ≤88%), enquanto os desfechos secundários foram bradicardia (queda >20% entre a frequência cardíaca máxima e mínima) e bradicardia crítica (frequência cardíaca <60 bpm) durante o procedimento de intubação Resultados: Foram identificados 151 procedimentos de intubação orotraqueal, sendo 126 elegíveis para o estudo. Desses, 77% tinham doenças subjacentes complexas e crônicas. A atropina foi administrada em 43 (34,1%) pacientes e foi associada a maiores chances de hipoxemia na análise univariada (OR: 2,62; IC95% 1,15-6,16; p=0,027), porém, não na análise multivariada (OR: 2,073; IC95% 0,416-10,32; p=0,373). A bradicardia crítica ocorreu em apenas três pacientes, sendo dois no grupo atropina (p=0,268). A bradicardia foi analisada em apenas 42 procedimentos. O uso de atropina foi associado a maior probabilidade de bradicardia (OR: 11,00; IC95% 1,3-92,8; p=0,028) na análise multivariável. Conclusões: Atropina como pré-medicação na intubação orotraqueal não evitou a ocorrência de hipoxemia ou bradicardia durante os procedimentos de intubação na emergência pediátrica.

Key FAD2, FAD3, and SAD Genes Involved in the Fatty Acid Synthesis in Flax Identified Based on Genomic and Transcriptomic Data.

FAD (fatty acid desaturase) and SAD (stearoyl-ACP desaturase) genes play key roles in the synthesis of fatty acids (FA) and determination of oil composition in flax (Linum usitatissimum L.). We searched for FAD and SAD genes in the most widely used flax genome of the variety CDC Bethune and three available long-read assembled flax genomes-YY5, 3896, and Atlant. We identified fifteen FAD2, six FAD3, and four SAD genes. Of all the identified genes, 24 were present in duplicated pairs. In most cases, two genes from a pair differed by a significant number of gene-specific SNPs (single nucleotide polymorphisms) or even InDels (insertions/deletions), except for FAD2a-1 and FAD2a-2, where only seven SNPs distinguished these genes. Errors were detected in the FAD2a-1, FAD2a-2, FAD3c-1, and FAD3d-2 sequences in the CDC Bethune genome assembly but not in the long-read genome assemblies. Expression analysis of the available transcriptomic data for different flax organs/tissues revealed that FAD2a-1, FAD2a-2, FAD3a, FAD3b, SAD3-1, and SAD3-2 were specifically expressed in embryos/seeds/capsules and could play a crucial role in the synthesis of FA in flax seeds. In contrast, FAD2b-1, FAD2b-2, SAD2-1, and SAD2-2 were highly expressed in all analyzed organs/tissues and could be involved in FA synthesis in whole flax plants. FAD2c-2, FAD2d-1, FAD3c-1, FAD3c-2, FAD3d-1, FAD3d-2, SAD3-1, and SAD3-2 showed differential expression under stress conditions-Fusarium oxysporum infection and drought. The obtained results are essential for research on molecular mechanisms of fatty acid synthesis, FAD and SAD editing, and marker-assisted and genomic selection for breeding flax varieties with a determined fatty acid composition of oil.

FADS2 function at the major cancer hotspot 11q13 locus alters fatty acid metabolism in cancer.

Dysregulation of fatty acid metabolism and de novo lipogenesis is a key driver of several cancer types through highly unsaturated fatty acid (HUFA) signaling precursors such as arachidonic acid. The human chromosome 11q13 locus has long been established as the most frequently amplified in a variety of human cancers. The fatty acid desaturase genes (FADS1, FADS2 and FADS3) responsible for HUFA biosynthesis localize to the 11q12-13.1 region. FADS2 activity is promiscuous, catalyzing biosynthesis of several unsaturated fatty acids by Δ6, Δ8, and Δ4 desaturation. Our main aim here is to review known and putative consequences of FADS2 dysregulation due to effects on the 11q13 locus potentially driving various cancer types. FADS2 silencing causes synthesis of sciadonic acid (5Z,11Z,14Z-20:3) in MCF7 cells and breast cancer in vivo. 5Z,11Z,14Z-20:3 is structurally identical to arachidonic acid (5Z,8Z,11Z,14Z-20:4) except it lacks the internal Δ8 double bond required for prostaglandin and leukotriene synthesis, among other eicosanoids. Palmitic acid has substrate specificity for both SCD and FADS2. Melanoma, prostate, liver and lung cancer cells insensitive to SCD inhibition show increased FADS2 activity and sapienic acid biosynthesis. Elevated serum mead acid levels found in hepatocellular carcinoma patients suggest an unsatisfied demand for arachidonic acid. FADS2 circular RNAs are at high levels in colorectal and lung cancer tissues. FADS2 circular RNAs are associated with shorter overall survival in colorectal cancer patients. The evidence thusfar supports an effort for future research on the role of FADS2 as a tumor suppressor in a range of neoplastic disorders.

[Features of the metabolism of polyunsaturated fatty acids in type 2 diabetes mellitus].

Type 2 diabetes mellitus (T2DM) is a widespread disease with a high risk of cardiovascular complications, disability and mortality. The progression of T2DM is closely related to lipid metabolism disorders, caused both by insufficient intake of polyunsaturated fatty acids (PUFAs), and by a violation of their endogenous metabolism. Desaturase enzymes, FADS1/2, are involved in the regulation of PUFA metabolism. Violation of the functioning of FADS1/2 and their genes leads to a change in the biosynthesis of PUFAs and the fatty acid composition of cell membranes. The purpose of this research was to summarize the data of modern literature on the metabolism of PUFAs and the effect of FADS genetic variants on the fatty acid composition of cell membranes in T2DM. Material and methods. The search and analysis of publications was carried out using the PubMed, MEDLINE, Web of Science databases, mainly for the last 10 years, using the search keywords: polyunsaturated fatty acids, fatty acid desaturases, desaturase genes, type 2 diabetes mellitus. Results. In the pathogenesis of T2DM and its complications, many factors play a role, including impaired PUFA metabolism. A large evidence base has been accumulated on the effect of PUFAs on cardiometabolic risk factors in T2DM. The effect of desaturase activity on the fatty acid composition of cells was identified as the most important link in the metabolism of PUFAs. Focusing on the modulation of desaturase activity and studying the polymorphism of fatty acid desaturase genes may be a useful therapeutic option in the treatment of patients with T2DM and its complications. Conclusion. A promising direction of scientific research in the treatment and prevention of T2DM and its complications is the study of genetic mechanisms associated with the metabolism of PUFAs and their metabolites.

Functionally diverse front-end desaturases are widespread in the phylum Annelida.

Aquatic single-cell organisms have long been believed to be unique primary producers of omega-3 long-chain (≥C20) polyunsaturated fatty acids (ω3 LC-PUFA). Multiple invertebrates including annelids have been discovered to possess methyl-end desaturases enabling key steps in the de novo synthesis of ω3 LC-PUFA, and thus potentially contributing to their production in the ocean. Along methyl-end desaturases, the repertoire and function of further LC-PUFA biosynthesising enzymes is largely missing in Annelida. In this study we examined the front-end desaturase gene repertoire across the phylum Annelida, from Polychaeta and Clitellata, major classes of annelids comprising most annelid diversity. We further characterised the functions of the encoded enzymes in selected representative species by using a heterologous expression system based in yeast, demonstrating that functions of Annelida front-end desaturases have highly diversified during their expansion in both terrestrial and aquatic ecosystems. We concluded that annelids possess at least two front-end desaturases with Δ5 and Δ6Δ8 desaturase regioselectivities, enabling all the desaturation reactions required to convert the C18 precursors into the physiologically relevant LC-PUFA such as eicosapentaenoic and arachidonic acids, but not docosahexaenoic acid. Such a gene complement is conserved across the different taxonomic groups within Annelida.

Unveiling the MUFA-Cancer Connection: Insights from Endogenous and Exogenous Perspectives.

Monounsaturated fatty acids (MUFAs) have been the subject of extensive research in the field of cancer due to their potential role in its prevention and treatment. MUFAs can be consumed through the diet or endogenously biosynthesized. Stearoyl-CoA desaturases (SCDs) are key enzymes involved in the endogenous synthesis of MUFAs, and their expression and activity have been found to be increased in various types of cancer. In addition, diets rich in MUFAs have been associated with cancer risk in epidemiological studies for certain types of carcinomas. This review provides an overview of the state-of-the-art literature on the associations between MUFA metabolism and cancer development and progression from human, animal, and cellular studies. We discuss the impact of MUFAs on cancer development, including their effects on cancer cell growth, migration, survival, and cell signaling pathways, to provide new insights on the role of MUFAs in cancer biology.

Exogenous tetracosahexaenoic acid modifies the fatty acid composition of human primary T lymphocytes and Jurkat T cell leukemia cells contingent on cell type.

Tetracosahexaenoic acid (24:6ω-3) is an intermediate in the conversion of 18:3ω-3 to 22:6ω-3 in mammals. There is limited information about whether cells can assimilate and metabolize exogenous 24:6ω-3. This study compared the effect of incubation with 24:6ω-3 on the fatty acid composition of two related cell types, primary CD3+ T lymphocytes and Jurkat T cell leukemia, which differ in the integrity of the polyunsaturated fatty acid (PUFA) biosynthesis pathway. 24:6ω-3 was only detected in either cell type when cells were incubated with 24:6ω-3. Incubation with 24:6ω-3 induced similar increments in the amount of 22:6ω-3 in both cell types and modified the homeoviscous adaptations fatty acid composition induced by activation of T lymphocytes. The effect of incubation with 18:3ω-3 compared to 24:6ω-3 on the increment in 22:6ω-3 was tested in Jurkat cells because primary T cells cannot convert 18:3ω-3 to 22:6ω-3. The increment in the 22:6ω-3 content of Jurkat cells incubated with 24:6ω-3 was 19.5-fold greater than that of cells incubated with 18:3ω-3. Acyl-coA oxidase siRNA knockdown decreased the amount of 22:6ω-3 and increased the amount of 24:6ω-3 in Jurkat cells. These findings show exogenous 24:6ω-3 can be incorporated into primary human T lymphocytes and Jurkat cells and induces changes in fatty acid composition consistent with its conversion to 22:6ω-3 via a mechanism involving peroxisomal ß-oxidation that is regulated independently from the integrity of the upstream PUFA synthesis pathway. One further implication is that consuming 24:6ω-3 may be an effective alternative means of achieving health benefits attributed to 20:5ω-3 and 22:6ω-3.

Stearoyl-CoA Desaturases1 Accelerates Non-Small Cell Lung Cancer Metastasis by Promoting Aromatase Expression to Improve Estrogen Synthesis.

Metastases contribute to the low survival rate of non-small cell lung cancer (NSCLC) patients. Targeting lipid metabolism for anticancer therapies is attractive. Accumulative evidence shows that stearoyl-CoA desaturases1 (SCD1), a key enzyme in lipid metabolism, enables tumor metastasis and the underlying mechanism remains unknown. In this study, immunohistochemical staining of 96 clinical specimens showed that the expression of SCD1 was increased in tumor tissues (p < 0.001). SCD1 knockdown reduced the migration and invasion of HCC827 and PC9 cells in transwell and wound healing assays. Aromatase (CYP19A1) knockdown eliminated cell migration and invasion caused by SCD1 overexpression. Western blotting assays demonstrated that CYP19A1, along with ß-catenin protein levels, was reduced in SCD1 knocked-down cells, and estrogen concentration was reduced (p < 0.05) in cell culture medium measured by enzyme-linked immunosorbent assay. SCD1 overexpression preserving ß-catenin protein stability was evaluated by coimmunoprecipitation and Western blotting. The SCD1 inhibitor A939572, and a potential SCD1 inhibitor, grape seed extract (GSE), significantly inhibited cell migration and invasion by blocking SCD1 and its downstream ß-catenin, CYP19A1 expression, and estrogen concentration. In vivo tumor formation assay and a tail vein metastasis model indicated that knockdown of SCD1 blocked tumor growth and metastasis. In conclusion, SCD1 could accelerate metastasis by maintaining the protein stability of ß-catenin and then promoting CYP19A1 transcription to improve estrogen synthesis. SCD1 is expected to be a promised therapeutic target, and its novel inhibitor, GSE, has great therapeutic potential in NSCLC.

Evolution of Linoleic Acid Biosynthesis Paved the Way for Ecological Success of Termites.

Termites are dominant animals of tropical terrestrial ecosystems. Their success is due to their eusocial organization as well as their ability to digest dead plant tissues. While being extremely abundant, the termite diet is poor in crucial nutrients, such as fatty acids. Linoleic acid (LA) is a precursor for many vital biomolecules, and most animals depend on its dietary supply. Termites count among the exceptions known to produce LA de novo, presumably via the action of an unknown Δ12 fatty acyl desaturase (FAD) introducing the second double bond into monounsaturated oleic acid. Here, we search for the evolutionary origin of LA biosynthesis in termites. To this end, we compile the repertoire of FAD homologs from 57 species of termites and their closest relatives, the cockroaches, analyze FAD phylogeny, and identify a potential Δ12 FAD branch, which arose through duplication of a likely Δ9 FAD. We functionally characterize both paralogs and identify the Δ9 activity in the ancestral FAD-A1a and the Δ12 activity responsible for LA biosynthesis in FAD-A1b. Through the combination of homology modeling and site-directed mutagenesis, we pinpoint structural features possibly contributing to the distinct functions, regiospecificities, and substrate preferences of the two enzymes. We confirm the presence of both paralogs in all 36 studied species of the Blattoidea lineage (Blattidae, Lamproblattidae, Cryptocercidae, and termites) and conclude that we identified an evolutionary event important for the ecological success of termites, which took place in their cockroach ancestors roughly 160 My and remained conserved throughout termite diversification into 3,000 extant species.

SCD1 deficiency exacerbates osteoarthritis by inducing ferroptosis in chondrocytes.

Background: Osteoarthritis (OA) is a severe joint disease that causes cartilage destruction and mobility loss. Abnormal fatty acid metabolism of chondrocytes plays a role in OA development. Stearoyl-CoA desaturase (SCD1) is a rate-limiting enzyme in the anabolism of unsaturated fatty acids. This study aimed to investigate the role of the SCD1 protein in the degenerative process of OA. Methods: The GSE176199 gene expression profile dataset was analyzed by Gene Set Enrichment Analysis (GSEA). An animal model of OA was established using C57BL/6J wild-type (WT) (n=40) and SCD1 knockout (SCD1-KO) (n=20) mice. The histological scoring method of the Osteoarthritis Research Society International (OARSI) was used to quantify the degree of cartilage degeneration. The expression of SCD1 protein and relevant ferroptosis indicators were evaluated. Results: The GSEA analysis showed that unsaturated fatty acid synthesis was inhibited in human OA chondrocytes. Meanwhile, the expression of SCD1 protein was significantly reduced in human OA articular cartilage. SCD1-KO mice exhibited early OA and accelerated cartilage loss after destabilization of medial meniscus (DMM)-induced OA. Furthermore, we found that the SCD1-PPARG axis regulates articular cartilage homeostasis via a mechanism involving the induction of ferroptosis-related gene expression in ATDC5 chondrocytes. Conclusions: SCD1 deficiency exacerbates OA by inducing ferroptosis in chondrocytes.

Drought priming triggers diverse metabolic adjustments and induces chilling tolerance in chickpea (Cicer arietinum L.).

Chickpea (Cicer arietinum L.) suffers from chilling stress at the reproductive stage (<15 °C) which leads to significant yield loss. This study presents a comprehensive plant response to drought priming and its effect on chilling tolerance during the reproductive stage in two chickpea cultivars PBG1 and PBG5. Lipidome profiling (Fatty acid methyl esters analysis), metabolome profiling (GC-MS based untargeted analysis), fatty acid desaturases and antioxidative gene expression (qRT-PCR) were analyzed to monitor physiological and biochemical events after priming during flowering, podding and seed filling stages. Drought priming alleviated membrane damage and chlorophyll degradation by increasing membrane unsaturated fatty acids (18:3) along with up-regulation of various fatty acid desaturases (CaFADs) genes and antioxidative machinery during flowering and improved seed yield in PBG5. PCA, HCA, and KEGG pathway analysis of 87 identified metabolites showed that metabolites were regulated differently in both cultivars under non-primed and primed conditions. The plant response was more apparent at flowering and podding stages which coincided with chilling temperature (<15 °C). Drought priming stimulated many important genes, especially FADs, antioxidative proteins and accumulation of key metabolites (proline and TCA intermediates) required for defense especially in PBG5. This explains that plant's response to drought priming not only depends on developmental stage, and temperature regime (<15 °C) but also on the genotypic-specificity.

Relationship between estimated desaturase enzyme activity and metabolic syndrome in a longitudinal study.

Desaturase enzyme activities (DEA) are associated with several metabolic diseases. The aim of the present study was to assess the relationship between estimated plasma DEA and the metabolic syndrome (MetS), as well as their relationship with individual components of the MetS. We conducted a longitudinal study of 148 participants recruited at random from the PREDIMED trial (Hospital Clinic site). At baseline and after 1 year of follow-up, DEA were estimated from product/precursor ratios of individual plasma fatty acids. Logistic regressions were used to assess the relationship of estimated DEA MetS, adjusted for potential cofounders. Estimated Δ5 desaturase (D5D) activity was associated with lower risk of MetS, whereas stearoyl-CoA (SCD)-16 and SCD-18 were negatively associated with MetS status. SCD-16, SCD-18, and Δ6 desaturase (D6D) were positively associated with triglycerides, SCD-18 was inversely associated with HDL-cholesterol. Estimated D6D activity was found to be associated with increases in diastolic blood pressure. In contrast, D5D was negatively associated with triglycerides, diastolic blood pressure and waist circumference. The present longitudinal study suggests that estimated SCD-16, SCD-18, and D6D have a negative impact in MetS and its components, whereas D5D may have beneficial effects for metabolic health.