Lipid Regulation Research Articles

Genetic assessment of the causal effect of plasma metabolites and metabolic pathways on delirium

PurposeDelirium has a significant impact on millions of people globally and is closely linked to an unfavorable prognosis for complications. Observational studies suggest that plasma metabolites may play significant roles as markers and effectors of delirium, but causal relationships have not yet been elucidated. Based on the most recent genome-wide association study (GWAS) data, our study aims to present novel insights into the genetic relationship between delirium and plasma metabolites. This investigation offers potential clues for utilizing plasma metabolites as predictors of delirium development.MethodsWe performed a thorough Mendelian randomization (MR) analysis to investigate the causal relationship between 1,091 individual metabolites and 309 metabolite ratios in plasma with respect to delirium. Inverse-variance weighting (IVW) was employed as the primary estimation method, while MR-Egger and weighed median methods were utilized to assess the robustness of the results. Sensitivity analyses encompassing the MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO) test, Cochran Q test, leave-one-out analysis and MR Egger intercept analysis were also undertaken. Additionally, the MR Steiger test was performed to explore any potential reverse causal effect of metabolites on delirium.ResultsA total of 63 types of plasma metabolites associated with delirium were detected using the IVW method (p < 0.05). Among the known metabolites, our analysis revealed that two specific metabolites (1-palmitoyl-2-palmitoleoyl-gpc (16:0/16:1) and homovanillate) and a metabolite ratio (phosphate to oleoyl-linoleoyl-glycerol (18:1 to 18:2)) demonstrated a consistent and significant causal relationship with delirium across all analysis methods. Finally, no evidence of pleiotropy was detected in our analysis.ConclusionsOur study has revealed a causal association between blood metabolites and the risk of delirium. homovanillate is known to be associated with immunity and redox, 1-palmitoyl-2-palmitoleoyl-gpc (16:0/16:1) and metabolite ratio (phosphate to oleoyl-linoleoyl-glycerol (18:1 to 18:2)) may play a role in lipid regulation. These findings may provide fresh insights into the identification of suitable diagnostic markers and potential treatment strategies focused on specific plasma metabolites in patients with delirium. However, further experiments are required to gain a comprehensive understanding of the underlying biological mechanisms involved.

Enhancing cognitive performance and mitigating dyslipidemia: the impact of moderate aerobic training on sedentary older adults

BackgroundThe present study aimed to evaluate the effects of 24 weeks of moderate aerobic exercise on lipids and lipoprotein levels; Lipo (a) markers, and their association with cognitive performance in healthy older adults.MethodsA total of 150 healthy subjects (100 males and 50 females; age range: 65–95 years) were recruited for this study. Based on the LOTCA test score, subjects were classified into two groups: the control group (n = 50) and the cognitive impairment group (n = 100). Cognitive functioning, leisure-time physical activity (LTPA), lipid profile, total cholesterol, TG, HDL-c, LDL-C, and lipo(a) were assessed at baseline and post-24-week aerobic exercise interventions using LOTCA battery, pre-validated Global Physical Activity Questionnaire (GPAQ) version II, colorimetric, and immunoassay techniques, respectively.ResultsSignificant improvements in cognitive function and modulation in lipid profile and lipoprotein (a) markers were reported in all older subjects following 24 weeks of moderate exercise. LOTCA-7-sets scores significantly correlated with physical activity status and the regulation of lipids and Lipo (a) markers. Physically active persons showed higher cognitive performance along with a reduction in the levels of T-Cholest., TG, LDL-C, Lipo (a), and an increase in the levels of HDL-C and aerobic fitness VO2max compared with sedentary participants. Cognitive performance correlated positively with increased aerobic fitness, HDL-C, and negatively with T-Cholest., TG, LDL-C, and Lipo (a). However, a significant increase in the improvement of motor praxis, vasomotor organization, thinking operations, attention, and concentration were reported among older adults.ConclusionsThe study findings revealed that supervised moderate aerobic training for 24 weeks significantly enhances cognitive functions via mitigating older adults’ lipid profiles and lipoprotein (a). Cognitive performance is positively correlated with aerobic fitness and HDL-C level and negatively with T-Cholest., TH, LDL-C, and Lipo (a).

Oxysterol binding protein (OSBP) contributes to hepatitis E virus replication

Hepatitis E virus (HEV) is a positive-sense, single-stranded RNA virus and causes primarily acute self-limiting infections. The ORF1 of the HEV genome encodes a polyprotein around 190 kDa, which contains several putative domains, including helicase and RNA-dependent RNA polymerase. The HEV-encoded helicase is a member of the superfamily 1 helicase family and possesses multiple enzymatic functions, such as RNA 5′-triphosphatase, RNA unwinding, and NTPase, which are thought to contribute to viral RNA synthesis. However, the helicase interaction with cellular proteins remains less known. Oxysterol binding protein (OSBP) is a lipid regulator that shuffles between the Golgi apparatus and the endoplasmic reticulum for cholesterol and phosphatidylinositol-4-phosphate exchange and controls the efflux of cholesterol from cells. In this study, the RNAi-mediated silencing of OSBP significantly reduced HEV replication. Further studies indicate that the HEV helicase interacted with OSBP, shown by co-immunoprecipitation and co-localization in co-transfected cells. The presence of helicase blocked OSBP preferential translocation to the Golgi apparatus. These results demonstrate that OSBP contributes to HEV replication and enrich our understanding of the HEV-cell interactions.

The multifaceted role of PCSK9 in cancer pathogenesis, tumor immunity, and immunotherapy.

Proprotein convertase subtilisin/kexin type 9 (PCSK9), a well-known regulator of cholesterol metabolism and cardiovascular diseases, has recently garnered attention for its emerging involvement in cancer biology. The multifunctional nature of PCSK9 extends beyond lipid regulation and encompasses a wide range of cellular processes that can influence cancer progression. Studies have revealed that PCSK9 can modulate signaling pathways, such as PI3K/Akt, MAPK, and Wnt/β-catenin, thereby influencing cellular proliferation, survival, and angiogenesis. Additionally, the interplay between PCSK9 and cholesterol homeostasis may impact membrane dynamics and cellular migration, further influencing tumor aggressiveness. The central role of the immune system in monitoring and controlling cancer is increasingly recognized. Recent research has demonstrated the ability of PCSK9 to modulate immune responses through interactions with immune cells and components of the tumor microenvironment. This includes effects on dendritic cell maturation, T cell activation, and cytokine production, suggesting a role in shaping antitumor immune responses. Moreover, the potential influence of PCSK9 on immune checkpoints such as PD1/PD-L1 lends an additional layer of complexity to its immunomodulatory functions. The growing interest in cancer immunotherapy has prompted exploration into the potential of targeting PCSK9 for therapeutic benefits. Preclinical studies have demonstrated synergistic effects between PCSK9 inhibitors and established immunotherapies, offering a novel avenue for combination treatments. The strategic manipulation of PCSK9 to enhance tumor immunity and improve therapeutic outcomes presents an exciting area for further investigations. Understanding the mechanisms by which PCSK9 influences cancer biology and immunity holds promise for the development of novel immunotherapeutic approaches. This review aims to provide a comprehensive analysis of the intricate connections between PCSK9, cancer pathogenesis, tumor immunity, and the potential implications for immunotherapeutic interventions.

Hepatic IL22RA1 deficiency promotes hepatic steatosis by modulating oxysterol in the liver.

Imbalance in lipid metabolism is the main cause of nonalcoholic fatty liver disease (NAFLD). While the pathogenesis of lipid accumulation mediated by extrahepatic regulators has been extensively studied, the intrahepatic regulators modulating lipid homeostasis remain unclear. Previous studies have shown that systemic administration of interleukin-22 (IL-22) protects against NAFLD; however, the role of IL-22/IL22RA1 signaling in modulating hepatic lipid metabolism remains uncertain. This study shows hepatic IL22RA1 is vital in hepatic lipid regulation. IL22RA1 is downregulated in palmitic acid-treated mouse primary hepatocytes, as well as in the livers of NAFLD model mice and patients. Hepatocyte-specific Il22ra1 knockout (HKO) mice display diet-induced hepatic steatosis, insulin resistance, impaired glucose tolerance, increased inflammation, and fibrosis compared with flox/flox mice. This is attributed to increased lipogenesis mediated by the accumulation of hepatic oxysterols, particularly, 3 beta-hydroxy-5-cholestenoic acid (3β HCA). Mechanistically, hepatic IL22RA1 deficiency facilitates 3β HCA deposition via the activating transcription factor 3 (ATF3)/oxysterol 7 alpha-hydroxylase (CYP7B1) axis. Notably, 3β HCA facilitates lipogenesis in MPHs and human liver organoids (HLOs) by activating LXR-alpha signaling, but IL-22 treatment attenuates this effect. Additionally, restoring CYP7B1 or silencing hepatic ATF3 reduces both hepatic 3β HCA and lipid contents in HKO mice. These findings indicate that IL22RA1 plays a crucial role in maintaining hepatic lipid homeostasis in an ATF3/CYP7B1-dependent manner, and establish a link between 3β HCA and hepatic lipid homeostasis.

Unveiling the Impact of Lactic Acid Bacteria on Blood Lipid Regulation for Cardiovascular Health

Lactic acid bacteria (LAB) are a group of microorganisms which are beneficial and well-characterized with respect to the flavor and texture of food products via fermentation. The accumulated literature has suggested that dietary intake of fermented foods rich in LAB is related to different health-promoting benefits; however, in recent years, emerging evidence suggests a contribution of LAB to blood lipid regulation and cardiovascular health via certain mechanisms. Different potential mechanisms for the lipid regulatory effects of LAB may include the interaction of hydroxymethylglutaryl-CoA (HMG-CoA) reductase and bile salt hydrolase activity and bile salt metabolism; gut microbiome modulation; and regulation of mRNA expression of genes related to fat metabolism in animal models and human studies. This review comprehensively aims to answer whether/how LAB influence blood lipids in both animal models and human studies while also uncovering the underlying mechanisms linking LAB to lipid metabolism.

Natural variation in starvation sensitivity maps to a point mutation in phospholipase IPLA2-VIA in Drosophila melanogaster.

Resistance to starvation is a classic complex trait, where genetic and environmental variables can greatly modify an animal's ability to survive without nutrients. In this study, we investigate the genetic basis of starvation resistance using complementary quantitative and classical genetic mapping in Drosophila melanogaster. Using the Drosophila Genetics Reference Panel (DGRP) as a starting point, we queried the genetic basis of starvation sensitivity in one of the most sensitive DGRP lines. We localize a major effect locus modifying starvation resistance to the phospholipase iPLA2-VIA. This finding is consistent with the work of others which demonstrate the importance of lipid regulation in starvation stress. Furthermore, we demonstrate that iPLA2-VIA plays a role in the maintenance of sugar reserves post-starvation, which highlights a key dynamic between lipid remodeling, sugar metabolism and resistance to starvation stress.

A Study on the Progress of Astragalus-Coptis Chinensis Medicinal Pair in the Treatment of Diabetes Mellitus

According to the relevant studies in recent years, it was found that astragalus - Coptis Chinensis drug pair and its analogous formula have a broad prospect for the treatment of type 2 diabetes mellitus (T2DM). Pharmacological studies have shown that Coptis Chinensis possesses the pharmacological activities of antimicrobial, anti-inflammatory, anti-tumor, lipid regulating, hypoglycemic, anti-arrhythmic, and antioxidant activities[1], and Astragalus possesses the effects of enhancing the function of the immune system, antimyocardial ischemia, bi-directional regulation of blood pressure, anti-tumor, anti-aging, hypoglycemia, and protection of metabolic tissues (liver and kidneys, etc.) [2] [3], the use of Astragalus and Coptis Chinensis pairs has demonstrated significant multiple effects. Specifically, this combination not only effectively reduces blood glucose levels, but also significantly enhances the body's sensitivity to insulin, thus helping to improve the phenomenon of insulin resistance and further enhance the overall health status of patients [1][2][3]. This paper analyzes and researches the research progress of astragalus-Coptis Chinensis medicinal pair and its analogous formulae in the treatment of type 2 diabetes mellitus and the improvement of its complications through the collation and summarization of the literature, in order to lay a certain theoretical research foundation for the clinical diagnosis and treatment of type 2 diabetes mellitus by astragalus-Coptis Chinensis medicinal pair and its related formulae, prevention of diabetes mellitus complications, and rational use of medicines in diabetes mellitus clinical treatment.

Cardarin effect on the formation of histopathological and behavioral abnormalities in the lithium-pilocarpine model of temporal lobe epilepsy in rats

Epilepsy is a severe neuropsychological disease accompanied by the development of spontaneous recurrent seizures (SRS) and associated behavioral disorders that are difficult to treat. In recent years, the neuroprotective properties of agonists of peroxisome proliferator-activated receptors (PPAR α, β/δ, γ), nuclear transcription factors involved in the regulation of lipid and carbohydrate metabolism, as well as inflammatory signaling pathways involved in the pathogenesis of epilepsy, have been actively investigated. The neuroprotective properties of PPARγ agonists have been repeatedly described in models of epilepsy; the effects of PPARβ/δ agonists in these models have not been sufficiently investigated. The aim of this work was to study the effects of administering the PPARβ/δ agonist cardarin on the formation of histopathological and behavioral abnormalities in the lithium-pilocarpine model of temporal lobe epilepsy (TLE). The lithium-pilocarpine model is one of the best experimental models of chronic temporal lobe epilepsy. In this study, epilepsy was induced by administration of pilocarpine to male Wistar rats at the age of 7 weeks one day after LiCl injection. Cardarin (2.5 mg/kg) was administered daily for 7 days after pilocarpine, with the first injection one day after pilocarpine injection. Behavioral testing was performed 2‒3 months after induction of the model in the following tests: Open Field, Resident Stranger, New Object Exploration, Y Maze Spontaneous Alternation and Morris Water Maze. Brain sampling for histological studies (assessment of neuronal death, Nissl staining) was performed after the end of behavioral experiments, 95 days after TLE induction. It was shown that untreated rats with TLE exhibited significant hippocampal neuron death and behavioral disorders: increased motor activity, anxiety, memory disorders, research and communicative behavior. Caradrin did not affect the survival rate of hippocampal neurons, but reduced the manifestation of almost all the above-mentioned behavioral disorders, except for hyperactivity. Thus, this study demonstrated the promising use of PPARβ/δ agonists to attenuate the development of behavioral disorders characteristic of epilepsy.

Er-Dong-Xiao-Ke decoction regulates lipid metabolism via PPARG-mediated UCP2/AMPK signaling to alleviate diabetic meibomian gland dysfunction

Ethnopharmacological relevanceMeibomian gland dysfunction (MGD), complicated by type 2 diabetes, is associated with a high incidence of ocular surface disease, and no effective drug treatment exists. Diabetes mellitus (DM) MGD shows a notable disturbance in lipid metabolism. Er-Dong-Xiao-Ke decoction (EDXKD) has important functions in nourishing yin, clearing heat, and removing blood stasis, which are effective in the treatment of DM MGD. Aim of the studyTo observe the therapeutic effect of EDXKD on DM MGD and its underlying molecular mechanism. Materials and methodsAfter establishing a type 2 DM (T2DM)-induced MGD rat model, different doses of EDXKD and T0070907 were administered. The chemical constituents of EDXKD were identified by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and the molecular mechanism of EDXKD in treating DM MGD was predicted using network pharmacology. Lipid metabolism in DM meibomian glands (MGs) was analyzed using LC-MS/MS, and lipid biomarkers were screened and identified. Histological changes and lipid accumulation in MGs were detected by staining, and Peroxisome proliferator-activated receptor gamma (PPARG) expression in MG acinar cells was detected by immunofluorescence. The expression of lipid metabolism-related factors was detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) or western blotting. ResultsEDXKD reduced lipid accumulation in the MGs and improved the ocular surface index in DM MGD rats. The main active components of EDXKD had advantages in lipid regulation. Additionally, the PPARG signaling pathway was the key pathway of EDXKD in the treatment of DM MGD. Twelve lipid metabolites were biomarkers of EDXKD in the treatment of DM MGD, and glycerophospholipid metabolism was the main pathway of lipid regulation. Moreover, EDXKD improved lipid deposition in the acini and upregulated the expression of PPARG. Further, EDXKD regulated the PPARG-mediated UCP2/AMPK signaling network, inhibited lipid production, and promoted lipid transport. ConclusionEDXKD is an effective treatment for MGD in patients with T2DM. EDXKD can regulate lipids by regulating the PPARG-mediated UCP2/AMPK signaling network, as it reduced lipid accumulation in the MGs of DM MGD rats, promoted lipid metabolism, and improved MG function and ocular surface indices.

Dose-dependent effect of Dendrobium officinale polysaccharide on anti-aging in Caenorhabditis elegans: A metabolomics analysis focused on lipid and nucleotide metabolism regulation

Dendrobium officinale polysaccharide (DOP) has garnered attention for its potential anti-aging effects, yet the dose-dependent impact on aging, especially from a metabolomics perspective, remains less explored. Here, we investigated the dose-dependent effect of DOP on anti-aging in Caenorhabditis elegans, examining underlying mechanisms through metabolomics analysis. Based on food clearance assays, doses of 62.5, 125.0, and 250.0 mg/L of DOP were selected for lifespan experiments in C. elegans. Results indicated that both 125 and 250 mg/L DOP significantly extended lifespan, enhanced stress resistance, and preserved locomotion behavior, with superior effects observed at 250 mg/L. Metabolomics analysis revealed a dose-effect relationship between DOP concentration and 14 metabolites, primarily associated with lipid and nucleotide metabolism. Notably, metabolites including docosapentaenoic acid (DPA), arachidonic acid, uric acid, uridine 5′-diphosphogalactose (UDP-galactose), UDP-N-acetylglucosamine (UDP-GlcNAc), citric acid, l-Saccharopine, L-2-Aminoadipic acid, 5′-S-Methyl-5′-thioadenosine, 1-Linoleoyl glycerol, cyclic ADP-ribose, glycerol 3-phosphate (G3P), and adenosine exhibited increased levels with higher DOP doses, while palmitic acid levels declined with escalating DOP dose in the range from 62.5 to 250.0 mg/L. Furthermore, Pearson correlation analysis revealed strong associations between mean lifespan and levels of DPA, palmitic acid, G3P, UDP-galactose and UDP-GlcNAc. These findings underscore a significant relationship between lifespan extension and metabolic products of lipid and nucleotide metabolism in DOP-treated C. elegans, shedding light on potential mechanisms underlying anti-aging effects of DOP.

Saikosaponin antidepressant mechanism: Improving the sphingolipid metabolism in the cortex via Apolipoprotein E and triggering neurovascular coupling

BackgroundSince the pathogenesis of depression is complex, antidepressant therapy remains unsatisfactory. Recent evidence suggests a link between depression and lipid metabolism. Saikosaponin (SS) exhibits antidepression and lipid-regulating effects in modern pharmacology. However, it is unknown whether lipid regulation is the key mechanism of the SS antidepressant effect and how it works. PurposeIn this study, we investigated the relationship between the antidepressant activity of SS and the regulation of lipid metabolism and explored potential mechanisms. MethodsAPOE-/- mice, in combination with the chronic unpredictable mild stress (CUMS) model, were used to study the relationship between SS antidepressant activity and lipid metabolism through behavioral, electrophysiological techniques, and non-targeted lipidomics. Western blot, primary cell culture technology, and laser speckle cerebral blood flow imaging were employed to elucidate potential mechanisms. GraphPad Prism was used for statistical analysis, and p < 0.05 was considered statistically significant. ResultsAPOE-/- mice exhibit more severe depressive-like behavior and dysregulation of sphingolipid metabolism in CUMS. SS alleviates depressive behavior and cortical sphingolipid metabolism disorder caused by CUMS, but has no effect on APOE-/- mice. SS alleviates the imbalance between ceramide (Cer) and sphingomyelin (SM) through acidic sphingomyelinase (AMSase). In addition, SS regulates neuronal glutamate release via sphingolipid metabolism, thereby alleviating the CUMS-induced inhibition of neurovascular coupling (regulates metabotropic glutamate receptor and IP3 receptor), which ameliorates the reduction of cerebral blood flow in depressed mice. ConclusionOur study highlights the role of lipid metabolism in the antidepressant activity of SS and explores its underlying mechanisms. This study provided new insights into the better understanding of the antidepressant mechanisms of phytomedicine while increasing the possibility of lipid metabolism as a therapeutic strategy for depression.

The Role of Alpha-Synuclein in Synucleinopathy: Impact on Lipid Regulation at Mitochondria-ER Membranes.

The protein alpha-synuclein (αSyn) plays a critical role in the pathogenesis of synucleinopathy, which includes Parkinson's disease and multiple system atrophy, and mounting evidence suggests that lipid dyshomeostasis is a critical phenotype in these neurodegenerative conditions. Previously, we identified that αSyn localizes to mitochondria-associated endoplasmic reticulum membranes (MAMs), temporary functional domains containing proteins that regulate lipid metabolism, including the de novo synthesis of phosphatidylserine. In the present study, we have analyzed the lipid composition of postmortem human samples, focusing on the substantia nigra pars compacta of Parkinson's disease and controls, as well as three less affected brain regions of Parkinson's donors. To further assess synucleinopathy-related lipidome alterations, similar analyses were performed on the striatum of multiple system atrophy cases. Our data show region-and disease-specific changes in the levels of lipid species. Specifically, our data revealed alterations in the levels of specific phosphatidylserine species in brain areas most affected in Parkinson's disease. Some of these alterations, albeit to a lesser degree, are also observed multiples system atrophy. Using induced pluripotent stem cell-derived neurons, we show that αSyn contributes to regulating phosphatidylserine metabolism at MAM domains, and that αSyn dosage parallels the perturbation in phosphatidylserine levels. Our results support the notion that αSyn pathophysiology is linked to the dysregulation of lipid homeostasis, which may contribute to the vulnerability of specific brain regions in synucleinopathy. These findings have significant therapeutic implications.

(003) LOCALIZED PROVOKED VULVODYNIA: THE ROLE OF CYCLOOXYGENASE ENZYMES IN PROMOTING INFLAMMATION AND PAIN SIGNALING

Abstract Introduction Localized provoked vulvodynia (LPV) is a chronic condition in which patients experience disabling pain in the vulvar vestibule. This condition’s mechanisms are poorly understood, and the lack of adequate treatment reflects the misunderstanding of the disease’s origins. Many LPV patients attempt to treat their pain with NSAIDS, but their use has been clinically shown to be ineffective against LPV associated vulvar pain. Recent evidence, utilizing fibroblasts isolated from vestibular and vulvar tissue of LPV patients, supports a link between inflammation and symptomology of LPV. These fibroblasts have shown to be sensitive to pro-inflammatory stimuli and overproduce inflammatory mediators such as Interleukin-6 (IL-6) and Prostaglandin E2 (PGE2). Increased production of IL-6 and PGE2 correlates with decreased pain thresholds, endorsing these levels as a surrogate measure for pain. Lipidomic data collected via mass spectroscopy also demonstrates LPV fibroblast strains have dysregulated arachidonic acid metabolism, resulting in an imbalance in pro-resolving lipids. Utilizing this fibroblast model, different cyclooxygenase (COX) inhibitors were used to better illuminate the mechanism behind fibroblast inflammation in LPV. Objective Using a fibroblast cell model, we set out to better understand pathophysiology of LPV and use that information to guide development of effective and pragmatic medical treatments. Methods Fibroblast strains were generated from vulvar and vestibular tissue samples of LPV patients and non-LPV age and race-matched controls. These cells were then treated with Interleukin 1 beta (IL-1β), selective cyclooxygenase-1 inhibitor (SC560), celecoxib (selective COX-2 inhibitor), and ibuprofen (nonselective COX inhibitor) to investigate differences in cellular response when blocking different enzymes in the inflammatory pathway. IL-1β is known to induce IL-6 and PGE2 which acted as a positive control. Results were then quantified via ELISA assay. Results Vestibular and vulvar tissues showed an increase in IL-6 and PGE2 production following treatment with IL-1B. When concurrently treated with IL-1B (to stimulate inflammation) and SC560 (to inhibit COX-1 signaling) ELISA analysis showed a significant decrease in PGE2. A significant PGE2 decrease was shown with concurrent IL-1B/Ibuprofen treatment as well as with IL-1B/Celecoxib treatments. In all three cases, IL-6 signaling was generally not decreased, while PGE2 was decreased, but not to baseline levels. Ibuprofen treatment in fact showed a trend towards increased IL-6 production. Conclusions Fibroblast response to inflammation in the case of LPV is complex. COX inhibitors do not fully inhibit the pain signaling that contributes to the symptomology of LPV patients (IL-6 production remains elevated). NSAIDs leave patients with dysregulated inflammation cascades, which does not remediate pain. Future areas of study for pharmaceutical targets include investigating lipid regulation, other pain signaling mechanisms, such as transient receptor potential cation channel subfamily V member 4 (TRPV4), and combination topical NSAID use to create more appropriate and robust treatment for patients with LPV. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: SPM Therapeutics.

Effects of bisphenol A on reproduction, oxidative stress, and lipid regulation in the marine rotifer Brachionus plicatilis

This study reports the effects of bisphenol A (BPA) on the rotifer Brachionus plicatilis, focusing on growth performance, reproductive output, oxidative stress responses, and lipid metabolism genes. High BPA levels disrupted peak daily offspring production and led to oxidative stress and increased superoxide dismutase and catalase activity. The research identified distinctive monoacylglycerol O-acyltransferase (MGAT) and diacylglycerol O-acyltransferase (DGAT) genes in B. plicatilis, B. rotundiformis, and B. koreanus, enhancing understanding of lipid metabolism in these species. BPA exposure significantly altered MGAT and DGAT expression, and feeding status affected these regulatory patterns. When food was unavailable, BPA reduced DGAT2 and MGAT2a expression. However, under feeding conditions, DGAT2 and MGAT1 levels increased, indicating that nutritional status and BPA exposure interact to affect gene expression.

Gene Regulatory Mechanism of Mycobacterium Tuberculosis during Dormancy.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb) complex, is a zoonotic disease that remains one of the leading causes of death worldwide. Latent tuberculosis infection reactivation is a challenging obstacle to eradicating TB globally. Understanding the gene regulatory network of Mtb during dormancy is important. This review discusses up-to-date information about TB gene regulatory networks during dormancy, focusing on the regulation of lipid and energy metabolism, dormancy survival regulator (DosR), White B-like (Wbl) family, Toxin-Antitoxin (TA) systems, sigma factors, and MprAB. We outline the progress in vaccine and drug development associated with Mtb dormancy.

Regulator of Lipid Metabolism NHR-49 Mediates Pathogen Avoidance through Precise Control of Neuronal Activity.

Precise control of neuronal activity is crucial for the proper functioning of neurons. How lipid homeostasis contributes to neuronal activity and how much of it is regulated by cells autonomously is unclear. In this study, we discovered that absence of the lipid regulator nhr-49, a functional ortholog of the peroxisome proliferator-activated receptor (PPAR) in Caenorhabditis elegans, resulted in defective pathogen avoidance behavior against Pseudomonas aeruginosa (PA14). Functional NHR-49 was required in the neurons, and more specifically, in a set of oxygen-sensing body cavity neurons, URX, AQR, and PQR. We found that lowering the neuronal activity of the body cavity neurons improved avoidance in nhr-49 mutants. Calcium imaging in URX neurons showed that nhr-49 mutants displayed longer-lasting calcium transients in response to an O2 upshift, suggesting that excess neuronal activity leads to avoidance defects. Cell-specific rescue of NHR-49 in the body cavity neurons was sufficient to improve pathogen avoidance, as well as URX neuron calcium kinetics. Supplementation with oleic acid also improved avoidance behavior and URX calcium kinetics, suggesting that the defective calcium response in the neuron is due to lipid dysfunction. These findings highlight the role of cell-autonomous lipid regulation in neuronal physiology and immune behavior.

Lipid and Transcriptional Regulation in a Parkinson's Disease Mouse Model by Intranasal Vesicular and Hexosomal Plasmalogen‐Based Nanomedicines (Adv. Healthcare Mater. 14/2024)

Lipid and Transcriptional Regulation in a Parkinson's Disease Mouse Model by Intranasal Vesicular and Hexosomal Plasmalogen‐Based Nanomedicines (Adv. Healthcare Mater. 14/2024)

Pivotal role of intestinal cholesterol and nuclear receptor LXR in metabolic liver steatohepatitis and hepatocarcinoma

Hepatocellular carcinoma (HCC) incidence is continuously increasing worldwide, due to the rise of metabolic dysfunction-associated steatohepatitis (MASH) cases. Cholesterol is an essential driver of the metabolic dysregulations that promote HCC progression. Liver X Receptor (LXR) is a nuclear receptor best known for the regulation of lipid and cholesterol homeostasis, with a prominent function in the liver and in the intestine. Here, we aimed to explore whether modifications in intestinal lipid metabolism may contribute to the onset of HCC, particularly taking into account cholesterol metabolism and LXRs. To study the progression of MASH to HCC, we induced metabolic HCC in wild-type male mice and mice carrying an intestinal chronic activation of LXRα. Also, we analysed human hepatic transcriptome datasets. The increased consumption of fat and carbohydrates drives the intestinal activation of LXRα and accelerates the onset of the hepatic tumours. Chronic intestinal-specific activation of LXRα enhances HCC progression only in the presence of a high cholesterol intake. In HCC, despite the increased hepatic cholesterol content, LXR is not active, thus driving liver cancer development. Intriguingly, in line with these results in the mouse model, LXR transcriptome is also downregulated in human hepatocarcinoma and its expression level in liver tumours directly correlates with a decreased survival rate in patients. Overall, our findings establish the relevance of the intestine in influencing the susceptibility to MASH-HCC and point to intestinal LXRα activation as a driver of metabolic liver cancer in the presence of dietary cholesterol.

Molecular mechanism of renal lipid accumulation in diabetic kidney disease.

Diabetic kidney disease (DKD) is a leading cause of end stage renal disease with unmet clinical demands for treatment. Lipids are essential for cell survival; however, renal cells have limited capability to metabolize overloaded lipids. Dyslipidaemia is common in DKD patients and renal ectopic lipid accumulation is associated with disease progression. Unveiling the molecular mechanism involved in renal lipid regulation is crucial for exploring potential therapeutic targets. In this review, we focused on the mechanism underlying cholesterol, oxysterol and fatty acid metabolism disorder in the context of DKD. Specific regulators of lipid accumulation in different kidney compartment and TREM2 macrophages, a lipid-related macrophages in DKD, were discussed. The role of sodium-glucose transporter 2 inhibitors in improving renal lipid accumulation was summarized.