Accumulation Of Fatty Acids Research Articles

Conceptual study of Non-Alcoholic Fatty Liver Disease and its management in Ayurveda

Non-alcoholic Fatty liver Disease (NAFLD) is a condition with excessive fat deposition in liver on refers to a broad spectrum of disorders characterized by fatty infiltration of the liver steatosis, steatohepatitis and cirrhosis. It is a growing cause of liver injury globally and is present in developed and developing countries. NAFLD is a broad term which describes the build up of excessive fat in the liver cells (hepatocytes) in the absence of excessive alcohol intake. It is a growing worldwide, due to obesity and insulin resistance leading to liver accumulation of triglycerides and free fatty acids. NAFLD encompasses a spectrum of liver Pathology with different clinical prognoses, from the simple accumulation of triglycerides within hepatocytes to more progressive steatosis with associated hepatitis, fibrosis, cirrhosis and in some cases hepatocellular Carcinoma. It is a global epidemic that ranges from isolated hepatic steatosis (NAFL) to Steatosis Plus inflammation (NASH) with or without fibrosis. Ayurveda described different types of Non-Communicable diseases, and NAFLD is one among them. In Ayurveda NAFLD can be interpreted as a Santarpanotha Vikara caused by Kapha Medo Dushti, getting Sthanasamshraya in Yakrit, which is Raktavaha Srotasmula and Pittasthana. In the initial stage of NAFLD, Kapha Meda Dushti occurs when Pitta gets involved in the pathogenesis, inflammatory changes occur which leads to the next stage of disease i.e., Non alcoholic steatohepatitis (NASH), When Vata comes involved fibrosis occurs which may end up in cirrhosis. So, the management should be the breakdown of pathological factors like Agnivaigunya, Srotorodha and Kaphamedo Dushti. This review will give a better knowledge of etiopathogenesis.

Flavonoids from Rhododendron nivale Hook. f ameliorate alcohol-associated liver disease via activating the PPARα signaling pathway

Background: Flavonoids are increasingly recognized for their potent antioxidant properties and potential therapeutic roles in the management of alcohol-associated liver disease (ALD). Extracts derived from Rhododendron nivale Hook. f. (FRN) have been shown to influence glutathione metabolism in aging animal models, exhibiting notable antioxidant effects. However, the specific impact of FRN on ALD remains insufficiently explored. Hypothesis/PurposeThis study seeks to elucidate the efficacy of FRN in alleviating the pathology associated with ALD, delving into the underlying molecular mechanisms that facilitate its protective effects. Study Design: We employed network pharmacology to predict the functional roles and pathway enrichments associated with FRN targets. Both a murine model of ALD and in vitro cellular models were utilized to clarify the mechanistic basis by which FRN mitigates ALD. Methods: FRN was extracted and characterized according to well-established methodologies outlined in our previous studies. Potential functions and pathways implicated by FRN were predicted through network pharmacology analyses. A combination of liver transcriptomics, targeted lipidomics, molecular biology techniques, and antagonists of relevant targets were employed to investigate the mechanisms through which FRN exerts its protective effects in ALD. Results: Network pharmacology identified multiple target genes modulated by FRN, particularly those within critical ALD-related signaling pathways, such as PPARα signaling and fatty acids (FAs) degradation. Notably, treatment with FRN in the ALD murine model led to a significant attenuation of hepatic lipid accumulation and a restoration of serum AST and ALT to baseline ranges. Subsequent validation through liver transcriptomics and molecular biology techniques revealed an upregulation of PPARα expression concomitant with a downregulation of ACSL1 in FRN-treated ALD mice. Targeted lipidomic and bioinformatic analyses from cellular assays demonstrated that FRN substantially reduced the accumulation of long-chain fatty acids in hepatocytes. Importantly, the reversal of FRN's protective effects on lipid accumulation through the PPARα antagonist GW6471 provides compelling evidence for the critical role of PPARα signaling modulation in mediating the beneficial impact of FRN on ALD. Conclusion: Our research highlights FRN's capacity to alleviate ALD through PPARα pathway activation, paving the way for innovative treatment strategies. This underscores the significance of natural compounds in pharmacotherapy, suggesting that FRN may provide an effective alternative for managing ALD.

A novel tubular single-chamber microbial electrolysis cell for efficient methane production from industrial potato starch wastewater

The integration of microbial electrolysis cells (MEC) with anaerobic digestion (AD) shows great promise for enhancing methane production from high-COD wastewater. However, an efficient MEC-AD reactor design remains elusive. Here, a novel tubular single-chamber MEC-AD reactor was constructed to treat potato starch wastewater (COD over 20000mg/L). The concentric and compact design of the stainless-steel cathode and anode reduced internal resistance, resulting in enhanced methane production. Applying -0.2V vs. Ag/AgCl to the anode increased methane production by 1.73 times compared to the open circuit and halved hydraulic retention time. Moreover, the reactor achieved an average methane content of 82.57%, which was 23.89% higher than the open circuit. The reactor showed a total COD removal of 92.2%, which was 24% higher than the open circuit. Additionally, base consumption to maintain pH was reduced to one-sixth of that in conventional AD, preventing volatile fatty acid accumulation. Microbial analysis showed Geobacter (63.4%) and Methanobacterium (96.8%) were highly enriched in the anode and cathode biofilms, respectively. The proportion of fermentative bacteria also increased in the MEC-AD system. These results demonstrate the effectiveness of the tubular single-chamber MEC-AD reactor in enhancing methane production from potato starch wastewater, with strong potential for scale-up applications.

Enhancement of the anaerobic biodegradation efficiency of azo dye by anthraquinone-loaded biochar biofilm: factors affecting biofilm formation and the enhancement mechanism

Carbon-based materials that serve as microbial carriers, and the role of surface-formed biofilms in anaerobic digestion, merit further investigation. This study explored the role and mechanism behind the biodegradation enhancement of biofilms formed onto anthraquinone-loaded biochar (AQS-BC) surfaces through the anaerobic decolorization process of azo dye Reactive Red 2, and optimized the conditions for AQS-BC biofilm formation. The results indicated that the AQS-BC biofilm system exhibited high treatment efficiency and stability in RR2 anaerobic decolorization. RR2 led to the accumulation of volatile fatty acids (VFAs) and inhibition of methane production, while the presence of AQS increased methane production. The effects of sludge concentration, contact time, carbon source concentration, and RR2 concentration on biofilm maturity were also analyzed. Combining biochemical characteristics, electrochemical properties, surface structure, and microbial community analysis, a mechanism for the anaerobic decolorization of RR2 via AQS-BC as a microbial carrier was proposed. This study provides insights into the roles of biofilms in the anaerobic wastewater treatment processes.Graphical

Exploring the inhibitory activity and mechanism on lipid production in 3T3-L1 cells by hot water extract derived from Acacia confusa flowers.

Acacia confusa Merr. (Fabaceae) (A. confusa) is a native tree species of Taiwan, commonly found in the low-altitude mountains and hilly areas of the Hengchun Peninsula. This evergreen, perennial, and large-sized tree was the focus of a study that employed various chromatographic and spectroscopic methods to analyze the hot water extract of its flowers. The analysis revealed that the major components of the extract were myricitrin, quercitrin, europetin-3-O-rhamnoside, and chalconaringenin-2'-xyloside, with respective concentrations of approximately 0.22, 0.02, 0.26, and 0.10mg/g of the flowers. Subsequent cell assays were conducted to assess the inhibitory effect of the extract on lipid synthesis in fat cells. Oil Red O staining results indicated that the extract significantly suppressed fatty acid accumulation in 3T3-L1 cells, with the most pronounced effect observed at a concentration of 180μg/ml. Furthermore, the hot water extract of A. confusa flowers was found to increase the phosphorylation of AMP-activated protein kinase (AMPK), decrease the phosphorylation of cAMP response element-binding protein (CREB), and reduce the expression of glucocorticoid receptor (GR) protein. This, in turn, inhibited the expression of downstream transcription factors such as CCAT/ehancer binding proteins α (C/EBPα), CCAT/ehancer binding proteins β (C/EBPβ), CCAT/ehancer binding proteins δ (C/EBPδ), peroxisome proliferation-actived receptor γ (PPARγ), and sterol regulatory element binding proteins-1 (SREBP-1). Consequently, the expression of lipid synthesis-related proteins acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS), and fatty acid translocase (CD36) was reduced, ultimately inhibiting lipid generation. Therefore, the hot water extract of A. confusa flowers shows potential for development as a weight-loss tea.

Microbial community acclimation during anaerobic digestion of high-oil food waste

Anaerobic digestion is one of the most promising options for the disposal of biodegradable food waste. However, the relatively high content of oil in food waste inhibits the conversion efficiency of anaerobic digestion because of the accumulation of long-chain fatty acids (LCFAs). In this study, activated anaerobic sludge was acclimated to accommodate high-oil conditions. The methane yield of high-oil food waste digested by the acclimated sludge increased by 24.9% compared to that digested by the raw sludge. To determine the internal changes in the acclimated sludge, the shifts in the microbial communities during the acclimation period were investigated via high-throughput sequencing (HTS) based on the 16 S rRNA gene. The results indicated that Bacteroidetes, Firmicutes, Chloroflexi and Proteobacteria were the dominant bacteria at the phylum level. The acclimation time allows some functional bacterial taxa to proliferate, such as Clostridium and Longilinea, which are able to degrade LCFAs and turn them into small organic molecules that also have nutrient value for other bacteria. Among the archaeal communities, the hydrogenotrophic methanogen Methanobacterium nearly supplanted the acetotrophic methanogen Methanosaeta. The time profiles of volatile fatty acids (VFAs) and pH during this period provided additional evidence for the success of the acclimation. This study demonstrated the effectiveness of acclimation and the dynamic of microbial communities, which further contributed to the management and resource utilization of high-oil food waste.

Nuciferine Alleviates High-Fat Diet- and ApoE-/--Induced Hepatic Steatosis and Ferroptosis in NAFLD Mice via the PPARα Signaling Pathway.

Nonalcoholic fatty liver disease (NAFLD) causes significant global mortality and healthcare costs with no recommended pharmacological intervention for clinical management. Nuciferine (Nuc) is an alkaloid with aromatic rings, abundantly found in Nelumbo nucifera Gaertn. In this study, we explored the protective mechanisms of Nuc against hepatic steatosis and ferroptosis in NAFLD. High-fat diet (HFD) and healthy male ApoE-/- mice were used to induce NAFLD and a hypercholesterolemia model. Nuc was administered to the mice for four consecutive weeks from the ninth week. Various assessments, including histopathology, RNA sequencing, lipid metabolism, and ferroptosis-related protein expression, showed that Nuc alleviated hepatic steatosis and ferroptosis. We further showed that Nuc improves fatty acid accumulation and ferroptosis through the PPARα signaling pathway in mice and RSL3-treated AML-12 cells. The PPARα inhibitor GW6471 blocked Nuc's protective effects, leading to excess accumulation of iron ions. Thus, Nuc may be a potential therapeutic agent for NAFLD.

Self-enhancement of bioenergy recovery from anaerobically digesting WAS with novel iron-based metal-organic framework assistance: Insights into electron transfer and metabolic pathways

Inadequate methane production and insufficient hydrolysis-acidification activity impede the practical application of anaerobic digestion (AD) of waste activated sludge (WAS). Recently, metal-organic framework (MOF) materials attains promising capability of controlling proton/electron transfer in AD processes. This study used a typical iron-based MOF and MIL-88A(Fe) to improve the methane production via digesting WAS. These materials were prepared via a one-step hydrothermal method. The findings indicated that the addition of 150 mg MIL-88A(Fe)/g WAS VS resulted in a 57.23% increase in accumulated methane production and a 43.84% increase in daily maximum methane production. The methane production rate (Rmax) also increased from 22.25 to 29.14 mL/g VS/d. The enhanced electron transfer capacity, improved hydrolysis of WAS, boosted acetate generation, and mitigated accumulation of volatile fatty acids (VFAs) collectively contributed to the better methane yield in the MIL-88A(Fe)-added system. The significant enrichment of Methanobacterium and Methanosaeta along with the up-regulation of key methanogenesis enzyme-encoding genes jointly suggested that the CO2 reduction and methanogenesis were strengthened. Moreover, MIL-88A(Fe) stimulated the production of c-type cytochrome and e-pili, facilitating direct interspecies electron transfer (DIET) between norank-f-SC-I-84 and Methanobacterium. This study provided new solutions for improving methane production and offered insights into the mechanism of enhanced methanogenesis of AD in the presence of MIL-88A(Fe).

A Scoping Review on Hepatoprotective Mechanism of Herbal Preparations through Gut Microbiota Modulation.

Liver diseases cause millions of deaths globally. Current treatments are often limited in effectiveness and availability, driving the search for alternatives. Herbal preparations offer potential hepatoprotective properties. Disrupted gut microbiota is linked to liver disorders. This scoping review aims to explore the effects of herbal preparations on hepatoprotective mechanisms, particularly in the context of non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and hepatic steatosis, with a focus on gut microbiota modulation. A systematic search was performed using predetermined keywords in four electronic databases (PubMed, Scopus, EMBASE, and Web of Science). A total of 55 studies were included for descriptive analysis, covering study characteristics such as disease model, dietary model, animal model, intervention details, comparators, and study outcomes. The findings of this review suggest that the hepatoprotective effects of herbal preparations are closely related to their interactions with the gut microbiota. The hepatoprotective mechanisms of herbal preparations are shown through their effects on the gut microbiota composition, intestinal barrier, and microbial metabolites, which resulted in decreased serum levels of liver enzymes and lipids, improved liver pathology, inhibition of hepatic fatty acid accumulation, suppression of inflammation and oxidative stress, reduced insulin resistance, and altered bile acid metabolism.

The Impact of Biotechnologically Produced Lactobionic Acid on Laying Hens' Productivity and Egg Quality during Early Laying Period.

Lactobionic acid (Lba), an oligosaccharide aldonic acid, has demonstrated various health-promoting benefits and applications in diverse areas. Lba has been recognized for its multifunctional properties, such as metal ion chelation and calcium sequestration. This study aimed to evaluate the effects of supplementing the diet of early-laying hens with Lba (EXP group) on their performance and the physical-chemical properties, and nutritional quality of eggs. The 12-week study involved 700 Sonja breed hens per group, with the EXP group's diet enriched with 2% of biotechnologically produced Lba, while the control group (CON) received no Lba supplementation. Lba supplementation influenced both the hen's performance and egg quality, particularly in terms of egg production and fatty acid accumulation. Performance in the EXP group was significantly improved (p < 0.05), showing a 4.6-8.9% increase compared to the CON group at all experiment stages. Lba also promoted an increase in monounsaturated fatty acid (MUFA) content, particularly palmitoleic and vaccenic acids. Overall, Lba supplementation enhanced both the productivity of laying hens and the nutritional value of eggs during the early laying period.

Impact of Organic Load on Methane Yields and Kinetics during Anaerobic Digestion of Sugarcane Bagasse: Optimal Feed-to-Inoculum Ratio and Total Solids of Reactor Working Volume

The effect of increasing organic load on the specific methane yields (SMYs) and kinetics of methane production during the anaerobic digestion (AD) of sugarcane bagasse (SB) was investigated in batch experiments at 37 °C. The organic load of the batch AD system was increased based on an increase in the feed-to-inoculum (F/I) ratio (T1–T5) and increase in the Total Solids (TS)% of the working volume (T6–T10). The results show that in both the treatment sets, an increase in organic load led to a decrease in SMY. Higher organic loads in terms of F/I ratio (T4 and T5) were inhibited due to Volatile Fatty Acid (VFA) accumulation. On the other hand, higher organic loads (T8, T9 and T10) in terms of the higher TS% of the working volume was inhibited by the accumulation of NH4-N. Thus, an organic load of 50 gVS/L at an F/I ratio = 1.0 and TS = 10% (T3) was found to be the highest organic load that had no significant inhibitions among the tested treatments. The results from the kinetic studies show that the first-order kinetic model is the best fit for the SMY data, with average differences% of 2.32% and 3.13% for treatments T1–T5 and T6–T10, respectively.

Fatty acids from nutrition sources for preterm infants and their effect on plasma fatty acid profiles

BackgroundIn preterm infants, IV administration of fat is less well tolerated compared to intake via the enteral route, often resulting in hypertriglyceridemia. It is therefore recommended that parenteral fat intake should not exceed 3.5 to 4.0 g/kg/d whereas human milk can provide up to 8 g/kg/d. It is unknown whether such hypertriglyceridemic conditions are caused by a uniform increase of all fatty acids or it is linked to an elevation of distinct fatty acids due to an unbalanced intake. Obviously, both scenarios could potentially influence the formulation of novel lipid solutions for preterm infants. Objective of this exploratory study was to compare fatty acid profiles between a) different nutritional sources and corresponding plasma samples, b) plasma of infants fed breast milk versus those receiving lipid emulsion, and c) plasma of infants with normal versus elevated triglyceride levels.MethodsForty-seven preterm infants < 36 weeks of gestation were included; fatty acid profiles were measured in serum samples and corresponding nutritional sources (breast milk and lipid emulsion) using gas chromatography/mass spectrometry.ResultsCompared to breast milk levels, plasma contained significantly lower C8:0, C10:0, C12:0, C14:0, C19:1n9, C18:3n3 (p < 0.0001). In contrast, relative abundance of C16:0, C18:0 and C20:4n6 was higher in plasma than in corresponding breast milk samples (p < 0.001) and lipid emulsion (p < 0.01). Compared to the corresponding lipid emulsion, the abundance of C18:2n6 and C18:3n3 was significantly lower in plasma (p < 0.001). Fatty acid profiles in plasma of infants fed breast milk compared to lipid emulsion were not markedly different. Hypertriglyceridemic samples showed elevated levels for C18:1n9 and C16:0 when compared with normotriglyceridemic samples.ConclusionsOur study reveals that lipid levels in plasma show both depletion and enrichment of distinct fatty acids which do not seem to be closely related to dietary intake. A more detailed understanding of fatty acid flux rates is needed, like the understanding of amino acid metabolism and is supported by the finding that hypertriglyceridemia might be a state of selective fatty acid accumulation. This would allow to develop more balanced diets for intensive care and potentially improve clinical outcomes.

Activation of NOD1 on tumor-associated macrophages augments CD8+ T cell-mediated antitumor immunity in hepatocellular carcinoma.

The efficacy of immunotherapy targeting the PD-1/PD-L1 pathway in hepatocellular carcinoma (HCC) is limited. NOD-like receptors (NLRs) comprise a highly evolutionarily conserved family of cytosolic bacterial sensors, yet their impact on antitumor immunity against HCC remains unclear. In this study, we uncovered that NOD1, a well-studied member of NLR family, exhibits predominant expression in tumor-associated macrophages (TAMs) and correlates positively with improved prognosis and responses to anti-PD-1 treatments in patients with HCC. Activation of NOD1 in vivo augments antitumor immunity and enhances the effectiveness of anti-PD-1 therapy. Mechanistically, NOD1 activation resulted in diminished expression of perilipin 5, thereby hindering fatty acid oxidation and inducing free fatty acid accumulation in TAMs. This metabolic alteration promoted membrane localization of the costimulatory molecule OX40L in a lipid modification-dependent manner, thereby activating CD8+ T cells. These findings unveil a previously unrecognized role for NOD1 in fortifying antitumor T cell immunity in HCC, potentially advancing cancer immunotherapy.

Identification of transcription factor BnHDG4-A08 as a novel candidate associated with the accumulation of oleic, linoleic, linolenic, and erucic acid in Brassica napus.

We screened 47 significantly associated haplotype blocks for oleic, linoleic, linolenic, and erucic acid, with 17 blocks influencing multiple traits. A novel candidate of transcription factor BnHDG4 A08 influencing oleic, linoleic, linolenic, and erucic acid was identified, by a joint strategy of haplotype-based genome-wide association study, genomic resequencing, gene cloning, and co-expression network Fatty acid (FA) composition determines the quality and economic value of rapeseed oil (Brassica napus). However, the molecular network of FAs is unclear. In the current study, multi-strategies of haplotype-based genome-wide association study (GWAS), genomic resequencing, gene cloning, and co-expression network were joint to reveal novel genetic factors influencing FA accumulation in rapeseed. We identified 47 significantly associated haplotype blocks for oleic, linoleic, linolenic, and erucic acid, with 17 blocks influencing multiple traits, using a haplotype-based GWAS with phenotype data from 203 Chinese semi-winter accessions. A total of 61 rapeseed orthologs involved in acyl-lipid metabolism, carbohydrate metabolism, or photosynthesis were identified in these 17 blocks. Among these genes, BnHDG4-A08, encoding a class IV homeodomain leucine-zipper transcription factor, exhibited two single-nucleotide polymorphisms (SNPs) in the exon and intron, with significant associations with oleic, linoleic, linolenic, and erucic acid. Gene cloning further validated two SNPs in the exon of BnHDG4-A08 in a population with 75 accessions, leading to two amino acid changes (T372A and P366L) and significant variation of oleic, linoleic, linolenic, and erucic acid. A competitive allele-specific PCR (KASP) marker based on the SNPs was successfully developed and validated. Moreover, 98 genes exhibiting direct interconnections and high weight values with BnHDG4-A08 were identified through co-expression network analysis using transcriptome data from 13 accessions. Our study identified a novel FA candidate of transcription factor BnHDG4-A08 influencing oleic, linoleic, linolenic, and erucic acid. This gene provides a potential promising gene resource for the novel mechanistic understanding of transcription factors regulating FA accumulation.

Immunometabolic Chaos in Septic Shock.

Septic shock is associated with over 40% mortality. The immune response in septic shock is tightly regulated by cellular metabolism and transitions from early hyper-inflammation to later hypo-inflammation. Patients are susceptible to secondary infections during hypo-inflammation. The magnitude of the metabolic dysregulation and the effect of plasma metabolites on the circulating immune cells in septic shock are not reported. We hypothesized that the accumulated plasma metabolites affect the immune response in septic shock during hypo-inflammation. Our study took a unique approach. Using peripheral blood from adult septic shock patients and healthy controls, we studied: 1. Whole blood stimulation ± E. Coli lipopolysaccharide (LPS: endotoxin) to analyze plasma TNF protein, and 2. Plasma metabolomic profile by Metabolon. Inc. 3. We exposed peripheral blood mononuclear cells (PBMCs) from healthy controls to commercially available carbohydrate, amino acid, and fatty acid metabolites and studied the response to LPS. We report that: 1. The whole blood stimulation of the healthy control group showed a significantly upregulated TNF protein, while the septic shock group remained endotoxin tolerant, a biomarker for hypo-inflammation. 2. A significant accumulation of carbohydrate, amino acid, fatty acid, ceramide, sphingomyelin, and TCA cycle pathway metabolites in septic shock plasma. 3. In vitro exposure to five metabolites repressed while two metabolites upregulated the inflammatory response of PBMCs to LPS. We conclude that the endotoxin-tolerant phenotype of septic shock is associated with a simultaneous accumulation of plasma metabolites from multiple metabolic pathways, and these metabolites fundamentally influence the immune response profile of circulating cells.

Natural variation in GhKASI_A05 modulates cottonseed oil content in Gossypium hirsutum L

Cotton is of great economic value because of its fiber that is used in natural textile commodities and its seeds that contain an edible oil with a high content of unsaturated fatty acids and biodiesel applications. Here, we reported that GhKASI_A05 was associated with the cottonseed oil content (SOC) in a natural population via candidate gene association analysis. An 11-bp Indel located in the GhKASI_A05 promoter was found to contribute to SOC and differential expression in upland cotton inbred accessions. Interaction analysis showed that GhWRI1, an AP2/EREBP family transcription factor, that reportedly functions in plant seed oil and fatty acids (FAs) accumulation, directly bound to AW-box cis-elements in two haplotypes of the GhKASI_A05 promoter and activated the expression of GhKASI_A05 at different levels. The seed-specific overexpression of GhKASI_A05 resulted in increased seed size, weight, and protein content, and C16:0 and C18:1 contents but reduced SOC. Our results provide new insights into the biological function of GhKASI in SOC and effective strategies for cotton breeding in the future.

Systemic deficits in lipid homeostasis promote aging-associated impairments in B cell progenitor development.

Organismal aging has been associated with diverse metabolic and functional changes across tissues. Within the immune system, key features of physiological hematopoietic cell aging include increased fat deposition in the bone marrow, impaired hematopoietic stem and progenitor cell (HSPC) function, and a propensity towards myeloid differentiation. This shift in lineage bias can lead to pre-malignant bone marrow conditions such as clonal hematopoiesis of indeterminate potential (CHIP) or clonal cytopenias of undetermined significance (CCUS), frequently setting the stage for subsequent development of age-related cancers in myeloid or lymphoid lineages. At the systemic as well as sub-cellular level, human aging has also been associated with diverse lipid alterations, such as decreased phospholipid membrane fluidity that arises as a result of increased saturated fatty acid (FA) accumulation and a decay in n-3 polyunsaturated fatty acid (PUFA) species by the age of 80 years, however the extent to which impaired FA metabolism contributes to hematopoietic aging is less clear. Here, we performed comprehensive multi-omics analyses and uncovered a role for a key PUFA biosynthesis gene, ELOVL2 , in mouse and human immune cell aging. Whole transcriptome RNA-sequencing studies of bone marrow from aged Elovl2 mutant (enzyme-deficient) mice compared with age-matched controls revealed global down-regulation in lymphoid cell markers and expression of genes involved specifically in B cell development. Flow cytometric analyses of immune cell markers confirmed an aging-associated loss of B cell markers that was exacerbated in the bone marrow of Elovl2 mutant mice and unveiled CD79B, a vital molecular regulator of lymphoid progenitor development from the pro-B to pre-B cell stage, as a putative surface biomarker of accelerated immune aging. Complementary lipidomic studies extended these findings to reveal select alterations in lipid species in aged and Elovl2 mutant mouse bone marrow samples, suggesting significant changes in the biophysical properties of cellular membranes. Furthermore, single cell RNA-seq analysis of human HSPCs across the spectrum of human development and aging uncovered a rare subpopulation (<7%) of CD34 + HSPCs that expresses ELOVL2 in healthy adult bone marrow. This HSPC subset, along with CD79B -expressing lymphoid-committed cells, were almost completely absent in CD34 + cells isolated from elderly (>60 years old) bone marrow samples. Together, these findings uncover new roles for lipid metabolism enzymes in the molecular regulation of cellular aging and immune cell function in mouse and human hematopoiesis. In addition, because systemic loss of ELOVL2 enzymatic activity resulted in down-regulation of B cell genes that are also associated with lymphoproliferative neoplasms, this study sheds light on an intriguing metabolic pathway that could be leveraged in future studies as a novel therapeutic modality to target blood cancers or other age-related conditions involving the B cell lineage.

RIPK4 promotes oxidative stress and ferroptotic death through the downregulation of ACSM1

One of the most critical axes for cell fate determination is how cells respond to excessive reactive oxygen species (ROS)-oxidative stress. Extensive lipid peroxidation commits cells to death via a distinct cell death paradigm termed ferroptosis. However, the molecular mechanism regulating cellular fates to distinct ROS remains incompletely understood. Through siRNA against human receptor-interacting protein kinase (RIPK) family members, we found that RIPK4 is crucial for oxidative stress and ferroptotic death. Upon ROS induction, RIPK4 is rapidly activated, and the kinase activity of RIPK4 is indispensable to induce cell death. Specific ablation of RIPK4 in kidney proximal tubules protects mice from acute kidney injury induced by cisplatin and renal ischemia/reperfusion. RNA sequencing revealed the dramatically decreased expression of acyl-CoA synthetase medium-chain (ACSM) family members induced by cisplatin treatment which is compromised in RIPK4-deficient mice. Among these ACSM family members, suppression of ACSM1 strongly augments oxidative stress and ferroptotic cell death with induced expression of ACS long-chain family member 4, an important component for ferroptosis execution. Our lipidome analysis revealed that overexpression of ACSM1 leads to the accumulation of monounsaturated fatty acids, attenuation of polyunsaturated fatty acid (PUFAs) production, and thereby cellular resistance to ferroptosis. Hence, knockdown of ACSM1 resensitizes RIPK4 KO cells to oxidative stress and ferroptotic death. In conclusion, RIPK4 is a key player involved in oxidative stress and ferroptotic death, which is potentially important for a broad spectrum of human pathologies. The link between the RIPK4-ASCM1 axis to PUFAs and ferroptosis reveals a unique mechanism to oxidative stress-induced necrosis and ferroptosis.

Impact of Neurotransmitters on the Fatty Acid Composition and the Pigments of the Green Microalga Scenedesmus quadricauda

Apart from their functions in the nervous system of animals, neurotransmitters operate as regulatory agents and signals in diverse kingdoms of life. Some neurotransmitters have recently been revealed to exert specific effects on microalgae, predominantly functioning as algal growth stimulators. This article presents new data on the effects of such neurotransmitters as serotonin, norepinephrine, dopamine, histamine, and acetylcholine on the fatty acid and pigment composition of the green microalga Scenedesmus quadricauda (Turp.) Breb. K-1149. It was established that acetylcholine and, to a lesser extent, histamine increased the total fatty acid content of S. quadricauda cells, whereas serotonin and dopamine decreased the fatty acid content. Acetylcholine, histamine, and norepinephrine elevated the percentage of polyunsaturated fatty acids; in contrast, serotonin and dopamine increased the share of saturated fatty acids. Acetylcholine and, to a lesser extent, norepinephrine increased the total chlorophyll content per gram of dry weight in S. quadricauda, while histamine decreased the chlorophyll content. Histamine also increased the chlorophyll a/chlorophyll b and carotenoid/chlorophyll ratios, which were decreased by dopamine. The data obtained are of biotechnological and ecological interest. The stimulation of fatty acid accumulation and the increase in the percentage of polyunsaturated species was caused by the neurotransmitters acetylcholine and histamine at low (1–10 μM) concentrations, which potentially enables facilitating the biotechnological production of health-promoting preparations for therapeutic and cosmetic purposes. However, other neurotransmitters (dopamine and serotonin) tested increased the relative content of saturated fatty acids; therefore, they apparently can be used to stimulate biofuel production, since saturated fatty acid-rich lipids are advantageous raw materials for biodiesel production. The impact of neurotransmitters on microalgal fatty acid composition and photosystem components may be considered in terms of ongoing chemical interaction between microalgae and other aquatic ecosystem components that are known to produce neurotransmitters.

Oleanolic acid promotes porcine oocyte maturation by activating the Nrf2/HO-1 signalling pathway

This study investigated the potential role and underlying mechanisms of oleanolic acid (OA), a pentacyclic triterpene with antioxidant and anti-inflammatory properties, in porcine oocytes during in vitro maturation (IVM). The results showed that supplementation with 5 μM OA during IVM resulted in a greater percentage of mature oocytes, parthenogenetically activated embryos and somatic cell nuclear-transferred embryos. This was evidenced by significant increases in the rate of first polar body expulsion, the expansion of cumulus granulosa cells and the total cell number in blastocysts. Further analysis revealed that OA promoted fatty acid accumulation and upregulated the mRNA expression of genes involved in fatty acid β-oxidation. OA significantly increased the intracellular mitochondrial membrane potential and ATP levels and effectively inhibited BAX/BCL2 and Cleaved Caspase3 protein expression. Notably, OA increased the protein levels of intracellular Nrf2 and HO-1, and the GSH levels and the activities of the antioxidant enzymes SOD and catalase (CAT), while reducing ROS levels. Mechanistically, OA activated the Nrf2/HO-1 signalling pathway, which is crucial for regulating the expression of antioxidant-related targets in IVM porcine oocytes. Our findings indicated that OA improved antioxidant capacity by activating the Nrf2/HO-1 signalling pathway, thereby promoting porcine oocyte maturation.