The nutritional value of milk fat depends on lipid and fatty acid composition. This study characterized the lipidomics and fatty acid positional distribution of milk from nine mammalian species: cow, buffalo, yak, goat, sheep, camel, mare, donkey, and human. Lipid molecular species were profiled by liquid chromatography-tandem mass spectrometry. Fatty acid positional distribution was determined using NH₂ and Si solid-phase extraction, selective sn-1/3 hydrolysis by Candida antarctica lipase B, and sn-2 monoacylglycerol quantification by gas chromatography-mass spectrometry. Ruminant milks showed high compositional similarity and differed from camel and monogastric milks. Compared to human milk, animal milks had higher triacylglycerols, phosphatidylcholines, phosphatidylethanolamines, and sphingomyelins, but lower free fatty acids and diacylglycerols. Short-chain fatty acids consistently occupied sn-1/3 positions, whereas medium-chain, long-chain, odd-chain, and branched-chain fatty acids favored sn-2 position. Monogastric milks exhibited sn-2 preference for palmitic acid and other saturated fatty acids and sn-1/3 preference for unsaturated fatty acids; ruminant and camel milks showed the reverse. Bray-Curtis analysis identified donkey milk as the closest lipidomic analog to human milk, followed by mare milk. These findings provide a systematic reference for evaluating mammalian milks and data for humanized infant formula lipid design.
Nonalcoholic fatty liver disease (NAFLD), also termed metabolic dysfunction‑associated fatty liver disease is a problem across the world. The most important factor of the increase in NAFLD prevalence is the insulin resistance. This study is the first clinical trial with the aim of determining the effect of Pistacia atlantica Sub. Kurdica gum on glycemic indices especially insulin resistance in patients with nonalcoholic fatty liver disease. In this double-blind randomized clinical trial 50 patients with nonalcoholic fatty liver disease were randomized into two groups: those given syrup containing Pistacia atlantica sub. Kurdica gum (Group A), those on placebo (Group B). Over a two-month period, Group A given syrup containing 500 mg of P. atlantica sub. Kurdica gum per each tablespoon and Group B given syrup without P. atlantica sub. Kurdica gum. Anthropometric measures, biochemical indices and physical activity were evaluated at the beginning and end of the intervention. We observed a significant decrease in fatty liver grade in group A (P = 0.03). The mean of fasting serum insulin and the insulin-resistance index (HOMA-IR) decreased significantly (P = 0.002, P < 0.001) and quantitative insulin sensitivity check index (QUICKI) increased from baseline in group A (P = 0.001). Fasting blood sugar (FBS) decreased significantly from baseline in group A (P = 0.019), but the mean changes between group not significant (P = 0.061). Weight had significant decrease in group A (P < 0.001). Pistacia atlantica sub. Kurdica gum can decrease insulin resistance, increase insulin sensitivity and subsequently improvement NAFLD in patient with nonalcoholic fatty liver disease. It is suggested that clinical trials be conducted in the long duration of the intervention, as well as a larger sample size. Registration number of Clinical trial: IRCT20231219060466N1 (https://irct.behdasht.gov.ir/).
Fatty acid synthase (FASN) is a key rate-limited, dimeric multi-enzyme complex in the de novo lipogenesis pathway. Each FASN monomer contains seven catalytic domains, which coordinate the stepwise conversion of acetyl-CoA into fatty acids. While FASN has been extensively studied in cultured cells, particularly for its oncogenic role, its functions in the germline and early embryonic development remain elusive. A major challenge is that the FASN dysfunction typically causes embryonic lethality in animal models, which complicates detailed functional analysis and the identification of compensatory genetic interactors during development. To overcome this limitation and identify novel genetic suppressors of the FASN gene, we utilized a temperature-sensitive allele, fasn-1(g43ts) (A1424T), in the genetically tractable model Caenorhabditis elegans, to conduct unbiased forward genetic screens. We isolated 22 suppressor lines that significantly restored embryonic viability in the fasn-1(g43ts) mutant at the non-permissive temperature. Using a combination of MIP-MAP genomic mapping and a customized bioinformatic pipeline, we identified six mutations in the ptr-6 gene, which encodes a protein containing a patched domain associated with the Hedgehog-like signaling pathway. To validate this genetic suppression, we recreated one of the loss-of-function mutations, ptr-6[W701*], in the fasn-1(g43ts) background using CRISPR/Cas9 gene editing. Notably, ptr-6[W701*] robustly rescued the embryonic lethality and permeability defects caused by fasn-1 loss-of-function. Taken together, our findings expand the genetic regulatory network of fatty acid synthase during early embryogenesis and highlight ptr-6 and Hedgehog-like signaling pathway as potential genetic modifiers of FASN-associated developmental and metabolic disorders.
This study evaluated the effects of diets supplemented with different doses of potassium bicarbonate (KHCO3) on lactation performance, milk fatty acid composition, nutrient digestibility, ruminal fermentation, and serum parameters in peak-lactation dairy cows. Sixty multiparous Holstein cows (69.8 ± 21.2 d in milk; 41.2 ± 5.4 kg/d milk yield) were randomly assigned to diets containing 0% (CON), 0.75%, or 1.50% KHCO3 (dry matter basis) for an 8-wk treatment period. Data were analyzed using a mixed model with dietary treatment, time, and their interaction as fixed effects and cow as a random effect. Linear and quadratic responses were assessed using preplanned contrasts. Diets supplemented with KHCO3 had no effect on dry matter intake (DMI) and milk yield. However, 3.5% fat-corrected milk (FCM) tended to increase linearly, milk fat concentration increased linearly, and FCM/DMI exhibited linear and quadratic increases with increasing KHCO3 supplementation. Apparent digestibility of neutral detergent fiber and acid detergent fiber increased linearly, accompanied by a linear increase in the molar proportion of acetate with increasing KHCO3. In contrast, total volatile fatty acid concentration exhibited a quadratic response. Ruminal pH exhibited a quadratic increase with increasing KHCO3 addition, whereas ruminal ammonia-N and the molar proportions of butyrate, valerate, and isovalerate showed linear and quadratic decreases. Blood urea nitrogen concentration decreased linearly, with no effects on serum indicators of energy metabolism, liver function, or antioxidant capacity. Milk concentrations of C10:0, C12:0, and cis-9, trans-11 CLA increased linearly, whereas the trans-10 to trans-11 C18:1 ratio decreased linearly with increasing KHCO3 supplementation. Overall, supplementation with KHCO3 during peak lactation improved fiber digestibility and favored trans-11 biohydrogenation, thereby improving milk fat content and feed efficiency. Under the conditions of this study, a dietary inclusion of 0.75% KHCO3 was sufficient to support a more favorable ruminal fermentation profile and productive performance in dairy cows.
Type 2 diabetes mellitus (T2DM) is a multidimensional metabolic disorder characterized by hyperglycemia, insulin insensitivity, and dysfunction and degeneration of β-cells. Increase in the levels of free fatty acids (FFAs) in blood plasma is a typical symptom of obesity and metabolic syndrome, which influences the mechanisms of insulin resistance and β-cell impairment. Acute increase in FFA levels blocks glucose uptake by insulin-sensitive skeletal muscles while chronic increase in FFA levels results in hepatic insulin resistance which causes gluconeogenic flux and lipotoxicity in pancreatic βcells. FFA-induced insulin resistance involves various molecular pathways and generation of lipid intermediates (diacylglycerol and ceramides), activation of serine/threonine kinases (PKC), induction of oxidative and endoplasmic reticulum stresses, and inflammatory signaling via nuclear factor-κB (NF-κB) and toll-like receptor (TLR) signaling pathways. Recent studies have indicated that the fetuin-A-FFA complex is an important endogenous ligand of TLR4 that causes inflammation and metabolic dysregulation. In addition, certain FFAs, especially ω-6 polyunsaturated fatty acids, can elicit ferroptosis which is a new form of lipid peroxidation-mediated cell death in β-cells, thereby expanding the extent of FFA-mediated lipotoxicity. This review covers recent information on the mechanisms and clinical factors related to the role of FFAs in insulin resistance and T2DM pathogenesis, and the contribution of experimental research towards developing therapeutic strategies in normalizing the levels of FFA and inhibiting downstream lipotoxicity-related pathways.
Prenatal exposure to per- and polyfluoroalkyl substances (PFAS) may disrupt maternal fatty acid (FA) metabolism; however, compartment-specific responses, nonmonotonic dose-response relationships (NMDRs), and mixture effects remain insufficiently characterized. We quantified 14 plasma PFAS and comprehensively profiled FAs, FA-class distributions, health-related indices, and product-to-precursor ratios in plasma (n = 192) and red blood cells (RBCs; n = 119) from pregnant women in China. Associations were assessed using multiple linear regression (MLR), restricted cubic splines (RCS), and Bayesian kernel machine regression (BKMR). Perfluorooctane sulfonate (PFOS) was the predominant PFAS, with a median concentration of 3.90 ng/mL, accounting for 45.9% of the total PFAS burden. MLR revealed distinct compartment-specific patterns. In plasma, PFOS and PFOS-related metrics were inversely associated with long-chain n-3 polyunsaturated FAs (PUFAs), including EPA, DHA, Σn-3, and EPA + DHA (β = -0.83 to -0.44), and positively associated with saturation- and n-6-dominant ratios, including Σn-6/Σn-3, ARA/DHA, and ΣSFA/ΣPUFA (β = 0.35-0.78). In RBCs, associations were fewer and were mainly characterized by inverse relationships of total PFAS and long-chain PFAS with arachidonic acid and n-3 PUFA biomarkers (β = -0.75 to -0.65). RCS identified significant NMDRs only in plasma, primarily exhibiting inverted U-shaped or threshold-type patterns, with PFOS breakpoints of approximately 3.00-7.39 ng/mL, corresponding to the 30th-80th percentiles, within environmentally relevant exposure ranges; stronger disruptions were observed above these thresholds. BKMR supported compartment-specific mixture effects, showing nonlinear, PFOS-dominated associations in plasma, with posterior inclusion probabilities of 0.93-1.00, but largely linear and more distributed contributions in RBCs, where saturation ratios increased and n-6 PUFAs decreased with increasing co-exposure. Overall, real-world prenatal PFAS exposure was associated with PUFA depletion and a shift toward more saturated and potentiall pro-inflammatory FA profiles through compartment-specific and nonlinear pathways.
The gut microbiota is critical for host defense against influenza. Polysaccharides are known for their microbiota-modulating and immunomodulatory activities; however, the anti-influenza efficacy of homogeneous Abrus cantoniensis polysaccharides (ACP) remains unexplored. The present study seeks to clarify the protective role of ACP in influenza and explore its underlying molecular mechanisms. Initially, crude polysaccharides were extracted via ethanol precipitation and subsequently purified by gel chromatography. Systematic structural characterization of ACP was then performed using carbohydrate chemistry techniques, including scanning electron microscopy (SEM), Fourier-transform infrared spectroscopy (FTIR), ultraviolet (UV) spectroscopy, and nuclear magnetic resonance (NMR). The therapeutic efficacy of ACP was assessed by monitoring various indicators such as body weight, survival rate, viral load, and pulmonary pathological changes in mouse models. Furthermore, to elucidate the biological mechanism underlying ACP's anti-influenza activity via regulation of pulmonary interferon-beta (IFN-β) immune networks by intestinal acetate-producing microbiota, multi-omics analyses integrating metagenomics, metabolomics, gene knockout, immunofluorescence, and Western blot were conducted. Finally, the potential anti-influenza effects of ACP via the gut-lung axis were evaluated based on in vivo and in vitro detection of protein expression of IFN-β, free fatty acid receptor 2 (FFAR2), and mitochondrial antiviral signaling protein (MAVS), as well as antiviral interferon-stimulated genes (ISGs). In this study, we purified a novel polysaccharide, ACP-A1, with a backbone of→4)-α-D-Glcp-(1→,→4)-β-D-Galp-(1→, and →4,6)-α-D-Glcp-(1→ linkages and α-D-Glcp-(1→ branches at O-6. In H1N1-infected mice, oral ACP-A1 alleviated weight loss, increased survival, and reduced lung inflammation and viral load. Metagenomic and targeted metabolomic analyses showed that ACP-A1 enriched Limosilactobacillus reuteri and elevated acetate levels. Fecal microbiota transplantation, FFAR2 inhibition, and MAVS knockout experiments demonstrated that ACP-A1 enhances the FFAR2/MAVS/IFN-β antiviral pathway via microbial-derived acetate. Collectively, our findings elucidate that ACP mitigates influenza virus-induced lung dysfunction by promoting the proliferation of acetate-producing gut microbiota, particularly Limosilactobacillus reuteri, and activating the FFAR2/MAVS/IFN-β antiviral axis in pulmonary immune cells. These findings establish ACP-A1 as a natural polysaccharide regulating IFN-β homeostasis, highlighting its potential for influenza prevention.
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a global metabolic epidemic with no specific effective therapy, characterized by hepatic steatosis and excessive hepatocyte apoptosis. This study explored the protective effects and mechanisms of Ganoderic acid A (GA-A) against MASLD. In high-fat diet (HFD)-fed mice and palmitic acid (PA)-stimulated HepG2 cells, GA-A notably relieved hepatic steatosis, liver injury, lipid metabolic disorders and hepatocyte apoptosis. Acetyl-CoA carboxylase (ACC) was identified as a direct target of GA-A via protein microarray, molecular docking, SPR, CETSA and Co-IP assays. Mechanistically, GA-A activated the AMPK-ACC pathway and suppressed ACC activity. Application of the ACC inhibitor ND646 and ACC silencing partially abrogated GA-A's therapeutic effects, confirming both ACC-dependent and independent actions. Collectively, GA-A directly targets ACC to ameliorate MASLD, indicating its potential as a promising candidate drug for this metabolic liver disease.
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Elevated circulating nonesterified fatty acids (NEFA) represent a key pathological feature in dairy cows with fatty liver. Palmitic acid (PA), a major component of NEFA, can be enzymatically attached to proteins via a reversible post-translational modification known as palmitoylation, which potently modulates protein activity and function. Studies have revealed that aberrant hepatic palmitoylation is a crucial mechanism promoting lipid accumulation in non-ruminants. Nevertheless, the extent and pathological relevance of hepatic protein palmitoylation in dairy cows with fatty liver have largely remained unexplored. Therefore, this study was conducted to determine the status of hepatic protein palmitoylation in dairy cows with fatty liver and to elucidate its functional role in the development of hepatic steatosis. Blood and liver samples were collected from 10 dairy cows with fatty liver (hepatic triglyceride [TG] content >5%) and 10 control cows (hepatic TG content <1%) that had a similar number of lactations (median: 3, range: 2 to 4) and days in milk (median: 9 d, range: 5 to 14 d). To determine the effects of NEFA on palmitoylation, hepatocytes isolated from calves were treated with 1.2 mM NEFA for 12 h. To investigate the effects of palmitoylation on lipid accumulation in bovine hepatocytes, the cells were treated with 1.2 mM NEFA for 12 h in the presence or absence of a palmitoylation inhibitor (2-bromohexadecanoic acid). The results revealed that dairy cows with fatty liver exhibited liver injury and elevated hepatic palmitoyl-CoA content. Moreover, fatty liver dairy cows showed higher hepatic mRNA abundance of ZDHHC4/5/14/20 and lower mRNA abundance of ZDHHC3/19/21/23/24. In contrast, the mRNA abundance of depalmitoylase-related genes, including lysophospholipase 1 (LYPLA1 and LYPLA2), palmitoyl-protein thioesterase 1 (PPT1 and PPT2) and abhydrolase domain containing 17 (ABHD17A, ABHD17B and ABHD17C), was lower in the liver of cows with fatty liver than in control cows. Consistently, a greater abundance of palmitoylated proteins was observed in the liver of dairy cows with fatty liver. In vitro, NEFA treatment induced lipid accumulation, cell injury, and aberrant protein palmitoylation in bovine hepatocytes. Additionally, the upregulation of palmitoyltransferases and downregulation of depalmitoylases observed in cows with fatty liver were recapitulated in NEFA-treated bovine hepatocytes. Importantly, pharmacological inhibition of palmitoylation significantly alleviated NEFA-induced lipid accumulation and cell damage in bovine hepatocytes. Overall, these findings establish protein palmitoylation as both a critical pathological mechanism and a promising therapeutic target for fatty liver in dairy cows.
Omega-3 (n-3) fatty acid consumption is recommended during pregnancy due to its beneficial effects on fetal development, particularly brain formation. Although there are various recommendations regarding its use, ideal intake levels are not well established. Western diets, rich in vegetable oils, increase lipid bioavailability, and the effects of excessive exposure to fatty acids during development are not yet fully understood. This study evaluated the long-term effects of maternal supplementation with n-3 and n-6 fatty acids on offspring skeletal muscle. Wistar rats were divided into three groups: control (CT), fish oil (FO; n-3), and soybean oil (SO; n-6). Supplementation (4 g/kg) began before mating and continued through gestation and lactation. After weaning, male offspring were maintained on standard chow without further supplementation and were euthanized at 60 d of age. Compared with the CT group, the FO and SO groups showed reduced body size, increased adiposity, and elevated plasma cholesterol and triglycerides. In the plantar muscle, both supplemented groups exhibited decreased length and cross-sectional area, as well as a lower proportion of type I and IIA fibers. Histological analysis revealed increased capillary density, number of myonuclei, and neuromuscular junction area. Molecular markers indicated reduced GLUT4 expression and increased MMP9 levels, with the FO group showing more pronounced changes. The present study demonstrates that excessive maternal fatty acid exposure during critical developmental windows induces persistent skeletal muscle remodeling in male offspring. Early exposure was associated with shifts in fiber type composition, altered fiber size, increased collagen deposition, structural changes to the neuromuscular junctions, and a reduced myonuclear domain, despite maintenance on a standard diet post-weaning.
Secondary "keto" bile acids (BAs) are produced by the gut microbiome and contain one or more ketones on the steroid core. Plasma concentrations of keto BAs are limited by hepatic reductase activity, leading to hydroxylation of keto BAs. Although the aldo-keto reductase 1 (AKR1) family is implicated, it is not known which enzymes provide this function in the liver. We hypothesized that AKR1C1 and AKR1C4 metabolize 3-keto BAs. Six BAs with 3-keto groups were tested as potential substrates using purified, recombinant His6-tagged AKR1C1-4, and kinetic parameters were determined. AKR1C1 and AKR1C4 were found to exhibit isoform-specific substrate specificity, which may be explained in part by the hydroxylation pattern at carbon 12 of the BA core. This may suggest distinct biological roles in mediating BA homeostasis in humans. Both enzymes produced only α-OH products, as determined by liquid chromatography-mass spectrometry. We further hypothesized that fatty acids would impair reductase activity. AKR1C4 was more susceptible to inhibition compared to AKR1C1, but unsaturated fatty acids, such as linoleic acid, were the most potent inhibitors for both. We observed a 2- to 10-fold difference in the IC50 of fatty acids for AKR1C4 depending on the tested substrate. Further mechanistic and structure-function studies aim to characterize the substrate-specific kinetic and inhibition patterns observed and to evaluate the translational impact of AKR activity on plasma BA concentrations and cellular signaling. SIGNIFICANCE STATEMENT: Keto bile acids are bioactive secondary metabolites that are reduced upon enterohepatic recycling to the liver. Here, the substrate specificity, kinetics, and inhibition potential of 2 aldo-keto reductase enzymes, AKR1C1 and AKR1C4, were evaluated. This study suggests that AKR1C1 and AKR1C4 exhibit disparate substrate specificity patterns, reductase activity, and susceptibility to inhibition by fatty acids, which may have broad implications in understanding changes in bile acid homeostasis in metabolic diseases.
The improvement of meat quality by selenium (Se) supplementation has been well documented; however, the effects and underlying mechanisms by which Se-enriched yeast modulates meat quality remain unclear. This study aimed to investigate the effects of Se-enriched yeast on meat quality and its molecular characteristics in finishing pigs. All pigs were fed a Se-deficient diet (SeD) or the same diet supplemented with 0.3, 1, 3, or 5 mg Se/kg (CT, SY1, SY3, and SY5). Compared with SeD, Se-enriched yeast supplementation, especially SY3, improved marbling score, intramuscular fat content, antioxidant capacity, and fatty acid composition in the LD muscle (P < 0.05). Lipidomic analysis revealed that Se-enriched yeast supplementation altered the abundances of multiple lipid species, while transcriptomic analysis showed significant enrichment of pathways related to unsaturated fatty acid and glycerophospholipid metabolism (P < 0.05). Integrated analyses further identified glycerophospholipid metabolism as a key pathway associated with major lipids, including phosphatidylcholine (PC) and phosphatidylethanolamine (PE), along with regulatory genes glycerol-3-phosphate acyltransferase 3 (GPAT3) and phosphatidylserine decarboxylase (PISD). Correlation analysis indicated that stearoyl-CoA desaturase (SCD), elongation of very long chain fatty acids protein 4 (ELOVL4), and GPAT3 play crucial roles in lipid synthesis. Se-enriched yeast supplementation at 3 mg/kg improved meat quality, primarily through the regulation of glycerophospholipid metabolism, enhancement of membrane stability, and lipid homeostasis. These findings offer mechanistic insights into the role of Se-enriched yeast and highlight its potential as an effective feed additive for improving meat quality in finishing pigs.
Cancer cells reprogram their metabolism to fulfill their high energetic demand. Lipid metabolism is most often reprogrammed for cancer cell survival and tumor development. The role of alternative oncogenic NF-κB/RelB subunit in the reprogramming of lipid metabolism in cancer is unknown. Here we report that RelB plays a central role at the crossroads of lipid storage and liberation of fatty acids from the lipid droplets to feed the fatty acid oxidation (FAO) and mitochondrial energetic metabolism. High RelB expression defines a subset of hepatocellular carcinoma (HCC) patients and cell lines with a peculiar gene expression profile enriched in lipid catabolic-related genes, including lipases. Functional studies revealed that high RelB activation controls the expression of major lipolytic lipases, including adipose triglyceride lipase (ATGL) and monoglyceride lipase (MAGL), and impacts on HCC cell survival, migration, and tumor development in vivo. Altogether, we uncovered that RelB is a central regulator of the lipid metabolism plasticity and an energy homeostasis sensor in cancer cells.
Phthalates are widely used as plasticizers in consumer products and are suspected to be metabolism-disrupting chemicals. Di-isononyl phthalate (DINP) is commonly recognized as less hazardous substitute for more studied di(2-ethylhexyl) phthalate (DEHP). The effects of DINP on hepatic lipid metabolism were studied using C57BL/6J mice with diet-induced obesity, and human HepaRG and C3A cell lines. The mice were orally exposed to 0, 1.5, 15 or 150 mg/kg bw/d DINP for 20 weeks, followed by assessment of glucose and insulin tolerance, hepatic histology, transcriptome and metabolome. The cells were exposed to DINP and its metabolites, followed by measurement of mitochondrial function and nuclear receptor activation. The highest dose of DINP decreased hepatic lipid droplets and slightly attenuated weight gain and glucose tolerance of the mice. DINP exposure elevated acylcarnitine levels, indicating altered fatty acid beta-oxidation, which was accompanied by enrichment in mitochondrial and peroxisomal lipid metabolism pathways at transcriptomics level. In vitro, monoisononyl phthalate (MINP), the primary metabolite of DINP, increased mitochondrial respiration and beta-oxidation in presence of long-chain fatty acids. DINP metabolites activated peroxisome proliferator-activated receptors (PPARs) of both mouse and human, with an activation profile partially distinct from DEHP. Our findings indicate that DINP remodels hepatic lipid metabolism through its active metabolites via PPARs at high doses, with additional modes of action at lower exposure levels. Due to species-specific differences in nuclear receptor activation potencies, the adverse or potentially beneficial nature of these effects in humans remains ambiguous.
Producing biodiesel from alternative biomass sources is a promising strategy for sustainable energy systems. This study evaluated urban landfill leachate treated by an advanced oxidative process (AOP) as an alternative to synthetic media for microalgae cultivation aimed at biodiesel production. The leachate was treated under ultraviolet (UV) irradiation with hydrogen peroxide in a photochemical system. A 22 factorial design assessed the effects of UV lamp power (0, 15, and 28 W) and hydrogen peroxide feeding time (90, 120, and 150 min). UV power significantly affected leachate degradation, reaching 57.3% reduction in total organic carbon. Treated leachate was then used as a culture medium for Nannochloropsis gaditana at concentrations of 50%, 80%, and 100% (v/v). The highest biomass productivity (381.62 mg L-1 day-1) and lipid productivity (115.87 mg L-1 day-1) were obtained with 50% treated leachate combined with conventional medium. Fatty acid analysis showed predominance of saturated and monounsaturated fatty acids, indicating favorable cetane number and oxidative stability, despite possible cold-flow limitations. The results demonstrate the potential of treated landfill leachate for microalgal cultivation and biodiesel production within a circular bioeconomy approach.
The severity of periodontitis, a chronic inflammatory disease, correlates with gingival tissue senescence. This study aimed to characterise the heterogeneous functions of these senescent cells and to define the mechanisms driving gingival fibroblast (GF) senescence, thereby assessing cellular senescence as a potential therapeutic target. We analysed cellular senescence changes in gingival tissues during periodontitis by integrating human gingival single-cell RNA sequencing (scRNA-seq) datasets. Biomarkers for a senescence-based diagnostic model for periodontitis were identified, and a potential drug targeting a key biomarker was screened. The effects of this drug on GF senescence were validated using an in vitro model induced by lipopolysaccharide (LPS) in primary human GFs (hGFs), alongside an in vivo experimental periodontitis mouse model induced by ligature. ScRNA-seq revealed an increase in senescence across various cell types in periodontitis-affected gingival tissues, with GFs being the predominant senescent cell population. Senescence levels in GFs were elevated in both human and mouse periodontitis tissues. A diagnostic model for periodontitis was developed based on a cellular senescence-associated 3-gene signature. Further mechanistic investigation showed that CYP1B1 drives LPS-induced hGF senescence by suppressing fatty acid metabolism. Ultimately, pinocembrin was found to attenuate senescence of GFs and ameliorate experimental periodontitis in mice, an effect mediated primarily through the downregulation of CYP1B1. Cellular senescence is increased in gingival tissues during periodontitis. Targeting senescent GFs presents a promising therapeutic strategy for the treatment of periodontitis. Periodontitis-related tissue destruction involves cellular senescence, yet the responsible gingival cell populations and molecular mechanisms remain undefined. CYP1B1-driven suppression of fatty acid metabolism underlies gingival fibroblast senescence, the predominant senescent process in periodontitis, and is attenuated by pinocembrin. CYP1B1 represents a novel therapeutic target for periodontitis. Pinocembrin warrants further preclinical evaluation as a promising adjunct to periodontal therapy.
Cisplatin (DDP) is a widely used chemotherapeutic agent, but its clinical application is limited by dose-dependent nephrotoxicity. Although metabolic dysregulation is a hallmark of DDP-induced acute kidney injury (AKI), the specific changes in fatty acid oxidation (FAO)-associated metabolic programs and the enzymes linking metabolic disturbances to cell death remain incompletely defined. In this study, targeted metabolomic profiling of the kidney revealed a marked blockade of FAO, evidenced by the accumulation of fatty acids and a decrease in downstream acylcarnitines. Among FAO-related enzymes, acyl-CoA synthetase short-chain family member 2 (ACSS2) emerged as the most significantly downregulated enzyme, which was further confirmed in an ischemia/reperfusion AKI model. ACSS2 overexpression in HK-2 cells aggravated DDP-induced inflammation and apoptosis, whereas ACSS2 knockdown significantly reduced cytotoxicity and pro-inflammatory cytokine production. Furthermore, pharmacological inhibition of ACSS2 in vivo alleviated DDP-induced AKI characterized by reduced oxidative stress and improved renal function. Together, these findings indicate that targeting ACSS2 may represent a promising therapeutic strategy to mitigate DDP-induced renal injury.
Lysophosphatidylcholine acyltransferase 3 (LPCAT3), a membrane-bound O-acyltransferase, is well known for enriching phospholipids (PLs) with polyunsaturated fatty acids (PUFAs) and thereby driving ferroptosis. However, accumulating evidence indicates that LPCAT3 is not merely a ferroptosis effector but a broader integrator of non-ferroptotic functions, such as autophagy, endoplasmic reticulum homeostasis, and inflammatory signaling. Herein, we provide an overview of LPCAT3 functions that explicitly extend beyond ferroptosis. We first provide a comprehensive review of the structural and enzymatic characteristics of LPCAT3, along with its diverse regulatory mechanisms of expression. Subsequently, we summarize how LPCAT3-mediated PL remodeling modulates membrane biophysical properties and further elucidate the downstream effects of this remodeling on the regulation of autophagy, endoplasmic reticulum homeostasis, and inflammatory signaling pathways. Finally, we systematically review the pivotal roles of LPCAT3 in the pathogenesis of multiple human diseases, including neurodegenerative diseases, stroke, atherosclerosis (AS), diabetes mellitus, obesity (OB), non-alcoholic fatty liver disease (NAFLD), and cancer. This review aims to elucidate the functions of LPCAT3 beyond its role in regulating ferroptosis and may provide new insights into its involvement in human diseases.
Modulation of mitochondrial dynamics is a viable strategy for lifespan extension. Reactive oxygen species (ROS) play key roles in aging, acting either as signaling molecules to facilitate longevity-associated processes or as stimulators of oxidative stress, exerting deleterious effects on physiological functions. The hybrid molecule MC1 is designed by integrating melatonin and catechol moieties to reconstruct mitochondrial dynamics and selectively regulate the generation of ROS. MC1 combats cell senescence under oxidative stress and DNA damage, and reprograms the mitochondrial energy metabolism by inhibiting the tricarboxylic acid cycle and glycolysis, while initiating fatty acid oxidation to increase energy production. More importantly, MC1 significantly extends the lifespan of Caenorhabditis elegans, accompanied by an improvement in muscle strength and physiological functions. The lifespan-extending effect of MC1 arises from its intervention in mitochondrial membrane fusion, the electron transport chain, and differential modulation of ROS. Regulating mitochondrial dynamics and ROS production shows great potential for longevity extension.