Fat preference is mediated by fatty acid receptors in the oral, intestinal, and central nervous systems, but their central nervous system roles remain unclear. Here, we investigated how GPR40, a medium- and long-chain fatty acid receptor, regulates fat preference via agouti-related peptide (AgRP) neurons in the hypothalamic arcuate nucleus (ARC).

AgRP neuron-specific Gpr40 knockout mice were generated to investigate the role of GPR40 in dietary fat preference. Behavioral tests were conducted to assess dietary preferences, and metabolic analyses were performed after starvation. We also measured the activity of AgRP neurons and the expression levels of AgRP and neuropeptide Y (NPY) to explore the mechanisms.

Our results indicate that GPR40 is a novel signaling pathway that regulates fat preference in hypothalamic AgRP neurons, but not in pro-opiomelanocortin (POMC) neurons. AgRP-specific Gpr40 knockout mice displayed a reduced preference for fat. This alteration in dietary preference was not associated with behavioral anomalies such as anxiety, depression, or deficits in short-term memory. Additionally, Gpr40 deletion in ARC AgRP neurons resulted in a diminished metabolic state, increased AgRP neuronal activity, and elevated levels of AgRP and NPY peptides following starvation, leading to reduced fat intake and increased carbohydrate intake. Inhibition of AgRP neuronal activity in AgRP-specific Gpr40 knockout mice rescued the observed changes in fat preference.

GPR40 signaling in AgRP neurons plays a critical role in regulating fat preference by modulating neuronal activity and the expression of AgRP and NPY peptides.

Liver sinusoidal endothelial cells (LSECs) are highly specialized endothelial cells that form the interface between the hepatic vasculature and parenchymal cells, playing a crucial role in maintaining hepatic homeostasis. Under pathological conditions, LSECs undergo capillarization, marked by the loss of fenestrae and formation of a basement membrane, thereby impairing microcirculation and promoting fibrosis. Beyond capillarization, LSECs experience a spectrum of pathological changes-including angiogenesis, endothelial-to-mesenchymal transition (EndMT), autophagy, and senescence-all of which contribute to fibrogenesis through distinct molecular pathways. Moreover, LSECs orchestrate liver fibrotic remodeling through dynamic crosstalk with hepatic stellate cells (HSCs), hepatocytes, Kupffer cells, and immune cells, exerting both pro- and anti-fibrotic effects. This review comprehensively summarizes LSECs dysfunction in hepatic fibrosis, with a particular focus on intercellular communication and emerging therapeutic strategies. Elucidating the regulatory networks that govern LSECs behavior may uncover new opportunities for the diagnosis and treatment of chronic liver disease.

Patients with diabetes mellitus (DM) are at risk of developing diabetic nephropathy (DN), a condition whose onset and progression are linked to increased morbidity and mortality. Therefore, early recognition is crucial. Presently, this relies on the albumin excretion rate (AER) and glomerular filtration rate (GFR). Nevertheless, DN eventually affects patients with normal AER and GFR. Thus, further easy-to-handle biomarkers of DN onset/worsening are needed. Liver-type fatty acid-binding protein (L-FABP) has been associated with renal damage and could help predict/diagnose DN. We performed a literature selection to evaluate the performance of urinary excretion of such biomarker (urinary-L-FABP:uL-FABP) in predicting/diagnosing DN and its progression in diabetes. We evaluated 635 publications, 21 of which were included. Of these, 14 have cross-sectional design/arms and ten longitudinal design/arms. Cross-sectional studies showed uL-FABP to correlate with DN onset and severity in type-1 DM and type-2 DM, besides being higher than in healthy controls in the case of normoalbuminuria. Longitudinal studies showed baseline uL-FABP to predict DN onset in normoalbuminuric patients with T1DM and DN progression independently of diabetes type. The results suggest that uL-FABP is a marker of tubular damage detectable before increased albumin excretion and can represent the earliest sign of DN. Indeed, it discloses its onset and often predicts its severity in T2DM and patients with T1DM. Currently, uL-FABP can be routinely assessed and, being available as a point-of-care fast-test kit, may also become an easy-to-handle diagnostic tool for outpatients. In conclusion, uL-FABP represents a user-friendly biomarker of DN and can even predict DN progression in T2DM and T1DM over time.

Dysregulation of fatty acid uptake and triglyceride transport can induce excess triglyceride accumulation. We propose that rice protein might suppress fatty acid uptake and/or triglyceride transport. To elucidate potential mechanisms, expressions of cluster determinant 36 (CD36), microsomal triglyceride transfer protein (MTP), fatty acid transport protein-2 (FATP-2), fatty acid-binding protein-1 (FABP-1), lipoprotein lipase (LPL) and Niemann-Pick C1-like 1 (NPC1L1) were investigated in growing and adult male Wistar rats fed with caseins and rice proteins under normal and oil-enriched dietary conditions. After two weeks of feeding, rice protein depressed the gene and protein expressions of CD36, MTP, FATP-2, FABP-1 and NPC1L1, whereas rice protein up-regulated those of LPL. As a result, rice protein significantly reduced the concentrations of triglyceride and fatty acid in the plasma and liver (P < 0.05) as well as the deposit of perirenal, epididymal and mesenteric fat (P < 0.05). The present study demonstrates an association between the depression of fatty acid uptake and triglyceride transport and the triglyceride-lowering effect of rice protein.

Excessive hepatic lipid accumulation is the hallmark of metabolic dysfunction-associated steatotic liver disease (MASLD), yet its underlying mechanisms still not fully understood. In this study, we identified RNA binding motif protein 39 (Rbm39) as a key modulator of hepatic lipid homeostasis during MASLD progression. To establish in vivo MASLD model, mice were fed either a high-fat diet (HFD) or a Gubra-Amylin NASH (GAN) diet. We employed adeno-associated virus to manipulate Rbm39 expression levels to assess its role in MASLD. Transcriptome analysis was conducted to pinpoint the genes targeted by Rbm39. Western blot, RT-PCR, dual-luciferase reporter gene assays, and alternative splicing analysis were utilized to delve into the molecular mechanisms. Our results showed that Rbm39 expression was notably decreased in the livers of MASLD mice. Knockdown of hepatic Rbm39 aggravated HFD-induced hepatic steatosis and GAN diet-induced MASH, along with a notable decrease in serum lipid levels. Conversely, overexpression of Rbm39 attenuated MASLD development and progression. RNA sequencing data analysis indicated that Rbm39 regulated the expression of apolipoprotein B (Apob) and fatty acid-binding protein 4 (Fabp4), both of which are crucial for lipid transport. Mechanistically, Rbm39 enhanced the transcription of Apob by upregulating hepatocyte nuclear factor 4α (Hnf4α), while it suppressed Fabp4 transcription by regulating alternative splicing of hypoxia inducible factor-1α (Hif-1α). These findings highlight the pivotal role of Rbm39 in maintaining hepatic lipid homeostasis and suggest its potential as a therapeutic target for MASLD.

Recent research highlights a potential link between metabolic dysfunction-associated steatotic liver disease (MASLD) and intestinal barrier dysfunction. Increased intestinal permeability (IP) may facilitate the translocation of bacteria, endotoxins (e.g., lipopolysaccharides [LPS]), and pathogen-associated molecular patterns into the portal venous system, fostering a pro-inflammatory environment and contributing to liver inflammation. This study aimed to identify correlations between intestinal barrier biomarkers (occludin, LPS, and intestinal-type fatty-acid-binding proteins [I-FABP]) and MASLD. A single-center prospective cross-sectional study was conducted, including 72 MASLD patients and 68 healthy controls. Fibroscan-controlled attenuation parameter (CAP) was performed in all subjects. Blood samples were analyzed for biochemical parameters, and serum levels of occludin, LPS, and I-FABP were measured using the ELISA method with the Human occludin, LPS, and I-FABP ELISA Kit test systems (FineTest, Wuhan, China). LPS and I-FABP levels were significantly higher in MASLD patients compared to controls, with the highest LPS levels observed in the diabetic MASLD subgroup. Occludin levels showed no statistically significant differences between groups. All 3 biomarkers were positively correlated with BMI, with the highest levels in obese subjects. LPS was positively correlated with CRP levels. Using Fibroscan-CAP, we found a positive correlation between LPS and both liver stiffness and CAP score, as well as between I-FABP and liver stiffness. MASLD patients exhibit increased IP, with enterocyte injury present irrespective of diabetes status, though more pronounced in diabetic MASLD. Occludin does not appear to be a reliable biomarker for evaluating intestinal barrier function in MASLD. Obesity is linked to elevated biomarkers, suggesting an association between increased IP and obesity. I-FABP and LPS may serve as noninvasive biomarkers for assessing hepatic fibrosis and steatosis in MASLD patients. Notably, LPS, given its correlation with elevated CRP levels, could be utilized as a marker of disease progression and severity.

The equilibrium dissociation constant (K d) is a quantitative measure of the strength with which a drug binds to its receptor. Methods for determining K d typically require a priori knowledge of protein concentration or mass. We report a simple dilution method for estimation of K d using native mass spectrometry which can be applied to protein-ligand complexes involving proteins of unknown concentration, from complex mixtures, including direct tissue sampling.

Obesity, resulting from excessive adipocyte accumulation, is a primary risk for various diseases. Although its impact on hematopoietic stem cell (HSC) function has been reported, its effects on HSC differentiation remain controversial. O-GlcNAc transferase (OGT), which catalyzes the attachment of N-acetylglucosamine to serine and threonine residues in proteins, acts as a metabolic sensor capable of regulating diverse physiological processes. This study demonstrates that obesity is associated with higher peripheral monocyte levels. Adipocyte OGT is crucial for monocyte development in high-fat diet (HFD)-induced obesity, promoting an increase in peripheral blood monocytes through transcriptional activation of nonesterified fatty acids (NEFA), a critical energy substrate. Loss of adipocyte OGT decreases serum NEFA levels, reduces white adipose tissue, and inhibits HSC differentiation into monocytes in HFD-induced obesity. Mechanistically, the regulated effect of adipocyte OGT on monocyte development may be mediated by NEFA-cluster of differentiation 36/fatty acid binding protein 4 (CD36/FABP4) pathway in HSCs in HFD-induced obesity. These findings establish the critical role of adipocyte OGT in hematopoietic homeostasis and monocyte development.

Understanding breast cancer at a molecular level is essential for developing effective treatments due to its significant impact on women's mortality rates globally. Targeted medicines focus on specific proteins crucial to breast cancer progression, offering a promising treatment avenue. These proteins, often overexpressed or mutated in cancer cells, are vital for cell proliferation, division, and survival. Targeted drugs aim to inhibit these proteins, halting disease progression and sparing non-cancerous cells, which reduces side effects and improves patient quality of life. Key proteins in breast cancer treatment include HER2 (human epidermal growth factor receptor 2), ER (estrogen receptor), and PR (progesterone receptor). Drugs like Trastuzumab target HER2 to impede tumor growth in HER2-positive cancers, while hormone therapies targeting ER and PR improve outcomes for hormone receptor-positive cancers. Examining proteins such as EGFR, HER2/Neu, and ER reveals their roles in cancer pathways, with pathways like PI3K/Akt/mTOR (phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin) and MAPK (mitogen-activated protein kinase) being crucial targets for therapies, potentially revolutionizing breast cancer treatment.

The leopard coral grouper (Plectropomus leopardus), an increasingly important species in marine aquaculture, has garnered significant research interest due to its high market value. Despite extensive research on ovarian growth and development in fish, the molecular mechanisms governing lipid droplet formation and lipid deposition in P. leopardus remain poorly understood. In this study, we conducted transcriptomic analyses of P. leopardus ovaries at three developmental stages: primary growth (PG), pre-vitellogenesis (PV), and mid-vitellogenesis (MV). A total of 534,847,090 raw reads were obtained from nine cDNA libraries, leading to the identification of 19,155 genes with 13,817 genes expressed at all stages. Differential analysis showed that 1012, 2609, and 4039 genes were up-regulated, while 168, 277, and 577 genes were down-regulated in the three comparisons, respectively. Functional enrichment analyses highlighting the critical roles of differentially expressed genes (DEGs) in lipid transport (such as fatp1, fatp4, fatp6, apoeb, lpl and fabps), fatty acid metabolism (such as elovl6, acsl1, dgat2 and gpat4) and phospholipid metabolism (such as ept1, chka and pla2g15). These findings underscore their contribution to lipid droplet formation and deposition. Furthermore, key signaling pathways, including Wnt, mTOR, PPAR and PI3K/Akt, were implicated in regulating these processes. The reliability of the RNA-seq data was confirmed through qPCR validation of 10 lipid-related genes. Based on these results, we propose a model for lipid droplet formation and lipid deposition during ovarian development in P. leopardus. This study advances our understanding of ovarian development in P. leopardus and provides a foundation for future research on marine fish reproduction, with potential applications in species conservation and aquaculture management.

Endocannabinoids (eCBs) regulate synaptic function via cannabinoid receptors. While eCB signaling is well understood, the mechanisms underlying eCB synaptic transport are poorly characterized. Using 2-arachidonoylglycerol (2-AG)-mediated depolarization-induced suppression of inhibition (DSI) in the hippocampus as a readout of retrograde eCB signaling, we demonstrate that the deletion of fatty acid binding protein 5 (FABP5) impairs DSI. In FABP5 KO mice, DSI was rescued by re-expressing wild-type FABP5 but not an FABP5 mutant that does not bind 2-AG. Importantly, the deletion of astrocytic FABP5 blunted DSI, which was rescued by its re-expression in the astrocytes of FABP5 KO mice. Neuronal FABP5 was dispensable for 2-AG signaling. DSI was also rescued by expressing a secreted FABP5 variant but not by FABP7, an astrocytic FABP that does not undergo secretion. Our results demonstrate that extracellular FABP5 of astrocytic origin controls 2-AG transport and that FABP5 is adapted to coordinate intracellular and synaptic eCB transport.

Tumor acidosis alters cancer cell metabolism and favors aggressive disease progression. Cancer cells in acidic environments increase lipid droplet accumulation and oxidative phosphorylation, which are characteristics of aggressive cancers. Here, we used live imaging, shotgun lipidomics and immunofluorescence analyses of mammary and pancreatic cancer cells to demonstrate that both acute acidosis and adaptation to acidic growth drive rapid uptake of fatty acids (FAs), which are converted to triacylglycerols and stored in lipid droplets. Consistent with being independent of de novo synthesis, triacylglycerol and lipid droplet accumulation in acid-adapted cells was unaffected by FA synthetase (FAS, encoded by FASN) inhibitors. Macropinocytosis, which is upregulated in acid-adapted cells, partially contributed to FA uptake, which was independent of other protein-facilitated lipid uptake mechanisms, including uptake via CD36 and FATP2, and caveolin- and clathrin-dependent endocytosis. We propose that a major mechanism by which tumor acidosis drives FA uptake is through neutralizing protonation of negatively charged FAs allowing their diffusive, transporter-independent uptake. We suggest that this could be a major factor triggering acidosis-driven metabolic rewiring.

Subtle structural variations among fatty acids significantly influence their biological roles and health effects. However, molecular recognition of their long, flexible, and chemically inert hydrocarbon chains remains a challenge. Inspired by natural fatty acid-binding proteins (FABPs), we designed and synthesized nanotubular metallo-cavitands, termed metal-organic pillars, through the coordination-driven assembly of pillararene-derived ligands with Ag(I) salts. These biomimetic hosts feature continuous interior channels exceeding 2.6 nm, selectively binding long-chain fatty acids through precise size and shape complementarity. Saturated and trans fatty acids, with linear conformations, are effectively encapsulated and stabilized by C-H···π and van der Waals interactions. In contrast, coiled cis-polyunsaturated fatty acids, such as docosahexaenoic acid (DHA), cannot be accommodated due to structural incompatibility. This work highlights the ability of artificial receptors to emulate the recognition capabilities of natural proteins, enabling the targeting of "bad" fatty acids associated with adverse health effects.

Women develop alcohol-associated liver disease (ALD) faster than men at any level of alcohol consumption, implicating estrogen as a contributing factor. However, the precise mechanism remains unknown. Therefore, 12-weeks-old female C57BL/6N mice were subjected to either bilateral ovariectomy (OVX) or sham surgery. After a three-week recovery period, the mice were fed either a 5% ethanol (EtOH)-containing liquid diet or paired-fed control diet for 10 days followed by a single gavage dose of EtOH (5 g/kg, 30% EtOH solution). The mice were examined for serum biochemical parameters, hepatotoxicity, histology, expression of xenobiotic nuclear receptors PXR and CAR, and their target gene mRNAs and proteins in hepatic and perigonadal white adipose tissues (pgWAT). While OVX mice on a control diet significantly gained weight, EtOH significantly increased hepatotoxicity, residual EtOH levels, lipid peroxidation, and oxidative stress in sham-operated mice but not in their OVX counterparts. Additionally, in the livers and pgWAT of the sham mice, EtOH significantly increased the mRNA and/or protein levels of the major estrogen receptor ERα, PXR, CAR, and their target genes, proinflammatory cytokines and chemokines, lipogenic genes, and FGF21 levels, a predictive biomarker for ALD severity in humans, but inhibited NRF2 and its targets genes encoding NQO1 and BHMT. Unexpectedly, all these changes were attenuated in the EtOH-fed OVX mice by the upregulation of NRF2 and aryl hydrocarbon receptor (AhR) and their downstream antioxidant target genes. Together these results suggest the existence of an estrogen-regulated ERα-PXR-NRF2-signaling axis in liver and pgWAT which contributes to sexual dimorphism in ALD.

Intracellular lipid binding proteins (iLBPs) possess different characteristics, including a rigid protein structure consisting of a β-barrel, an α-helix cap, and a substantial internalized water cluster. Despite X-ray crystallographic research providing insights into the three-dimensional structures of iLBPs, the protein conformations, and the function of the internal water molecules inside the protein remain uncertain. In this study, we conducted molecular dynamics (MD) simulations on free (apo) and oleate-bound (holo) rat liver fatty acid binding proteins (rLFABPs), which are common intracellular lipid binding proteins (iLBPs) found in the liver of rats. Efforts have been made to obtain a comprehensive microscopic understanding of the conformational motions of different segments of the protein, namely, the β-strands, the helix-turn-helix (HTH) motif, and the loop regions, along with the impact of ligand binding on the microscopic structure and ordering of water molecules confined within the core and at the exterior surface of the protein. The calculations revealed fluctuating nature of the HTH region, characterized by the development and disruption of distinct secondary structural components. Furthermore, the coexistence of spatially heterogeneous ordered and disordered water molecules within the core regions of the apo and holo forms has been observed. A high degree of ordering of core water molecules has been attributed to those that are doubly coordinated. In contrast, the randomly oriented ones are found to be surrounded by three neighboring water molecules in their first coordination shells. Such non-uniform ordering of core water molecules suggests their important role in the ligand binding process for this class of proteins.

Pathogens manipulate host cell organelles to establish infection. There is extensive evidence of pathogen modulation of the endoplasmic reticulum, Golgi apparatus, mitochondria, endosomes, lysosomes, and nucleus. However, one organelle that has been largely overlooked in connection with bacterial pathogenesis is peroxisomes. Here, we demonstrate that Legionella actively recruits peroxisomes to its replication vacuole using a secreted bacterial effector protein. Defects in peroxisome metabolic function restrict expansion of the Legionella vacuole membrane and cause rupture of this compartment, inhibiting bacterial replication and leading to bacterial degradation. Similarly, peroxisome dysfunction causes Salmonella replication vacuole destabilization and reduced bacterial burden within host cells. Thus, these two intracellular bacterial pathogens exploit host cell peroxisomes to maintain their replication compartments, establishing a critical role for this organelle in disease.

Previous studies have identified a relationship between fatty acid-binding proteins (FABPs) and immune diseases. This study aimed to investigate whether a causal relationship exists between FABPs and anaphylactic shock resulting from adverse drug reactions. Single nucleotide polymorphisms associated with FABPs were utilized as instrumental variables, sourced from the National Human Genome Research Institute-European Bioinformatics Institute Catalog of human genome-wide association studies. Data on anaphylactic shock due to adverse effects of correctly administered drugs were obtained from the FinnGen database, which includes genomic and health data from 500,000 Finnish biobank donors. A two-sample Mendelian randomization analysis was conducted to explore the causality between FABPs and anaphylactic shock due to adverse drug reactions. The analysis revealed a negative causal relationship between FABP5 (odds ratio [OR] = 0.40; 95% confidence interval [CI] = 0.17-0.92; P = .032) and FABP12 (OR = 0.77; 95% CI = 0.63-0.94; P = .009) and anaphylactic shock due to adverse drug reactions. These findings were corroborated by Mendelian randomization-Egger, weighted median, and weighted mode methods. This study provides robust evidence supporting a protective relationship between FABP5 and FABP12 and anaphylactic shock due to adverse drug reactions. Further experimental studies are warranted to elucidate the causal mechanisms and associations between FABP5, FABP12, and anaphylactic shock in the context of adverse drug reactions.

PURE (Protein synthesis Using Recombinant Elements), an ideal system for ribosome display, has been successfully used for nanobody selection. However, its limitations in nanobody selection, especially for synthetic nanobody libraries, have not been clearly elucidated, thereby restricting its utilization.

The PURE ribosome display selection process was closely monitored using RNA agarose gel electrophoresis to assess the presence of mRNA molecules in each fraction, including the flow-through, washing, and elution fractions. Additionally, a real-time validation method for monitoring each biopanning round was implemented, ensuring the successful enrichment of target protein-specific binders. The selection process was further optimized by introducing a target protein elution step prior to the EDTA-mediated disassembly, as well as by altering the immobilization surfaces. Finally, the efficiency of PURE ribosome display was enhanced by replacing the spacer gene.

The efficiency of PURE ribosome display was merely 4% with an unfavourable spacer gene. Using this spacer gene, EGFP- and human fatty acid-binding protein 4-specific nanobodies from a synthetic nanobody library were we successfully identified through optimizing the selection process. Choosing a spacer gene less prone to secondary structure formation increased significantly its efficiency in displaying synthetic nanobody libraries.

Implementing a target protein elution step prior to EDTA-mediated disassembly and modifying the immobilization surfaces effectively increase selection efficiency. For PURE ribosome display, efficiency was further improved using a suitable spacer gene, enabling the display of large libraries.

Fatty acid-binding proteins (FABPs) act as lipid chaperones and play a role in the pathological processes of various lipid signaling pathways. Mitochondria are crucial for the regulation of lipid metabolism. As an aging marker, lipid-mediated mitochondrial dysfunction has been observed in the etiology of numerous diseases, including neurodegenerative diseases, metabolic syndromes, cardiovascular diseases, and tumorigenesis. Members of the FABP family have been identified to regulate mitochondrial function. Targeting FABPs specifically may provide a promising approach to improve mitochondrial function and treat age-related diseases. This review summarizes the connection between FABPs and mitochondrial function and highlights certain FABPs involved in age-related diseases that hold significant therapeutic promise.

It is now well-established that exercise can disturb various aspects of gastrointestinal integrity and function. The pathophysiology of these perturbations, termed "exercise-induced gastrointestinal syndrome (EIGS)," can lead to exercise-associated gastrointestinal symptom (Ex-GIS) inconveniences. EIGS outcomes can impact physical performance and may lead to clinical manifestation warranting medical intervention, as well as systemic responses leading to fatality. Athlete support practitioners seek prevention and management strategies for EIGS and Ex-GIS. This current position statement aimed to critically appraise the role of EIGS and Ex-GIS prevention and management strategies to inform effective evidence-based practice and establish translational application. Intervention strategies with mostly consistent beneficial outcomes include macronutrient (i.e., carbohydrate and protein) intake and euhydration before and during exercise, dietary manipulation of fermentable oligo-, di-, and mono-saccharides and polyols (FODMAP), and gut training or feeding tolerance adjustments for the specific management of Ex-GIS from gastrointestinal functional issues. Strategies that may provide benefit and/or promising outcomes, but warrant further explorations include heat mitigating strategies and certain nutritional supplementation (i.e., prebiotics and phenols). Interventions that have reported negative outcomes included low-carbohydrate high-fat diets, probiotic supplementation, pharmaceutical administration, and feeding intolerances. Owing to individual variability in EIGS and Ex-GIS outcomes, athletes suffering from EIGS and/or support practitioners that guide athletes through managing EIGS, are encouraged to undertake gastrointestinal assessment during exercise to identify underlying causal and exacerbation factor/s, and adopt evidence-based strategies that provide individualized beneficial outcomes. In addition, abstaining from prevention and management strategies that present unclear and/or adverse outcomes is recommended.

The proper formation and function of the myelin sheath, a proteolipid membrane multilayer, relies on the coordinated action of several key myelin proteins. We studied how proteins from the peripheral myelin cytoplasmic apposition-myelin basic protein (MBP), the cytoplasmic tail of myelin protein zero (P0ct), and peripheral myelin protein 2 (P2)-interact with each other and with myelin-like membranes using various techniques, such as small-angle X-ray diffraction, differential scanning calorimetry (DSC), surface plasmon resonance (SPR), and electron and live epifluorescence microscopy. DSC revealed changes in lipid interactions depending on the protein combination, with altered membrane fluidity and stability. These results were supported by SPR, which indicated that the myelin proteins may compete for membrane surface binding. Analysis of the Bragg peaks induced by the myelin proteins in lipidic environments showed both lamellar and nonlamellar phases in protein-lipid complexes, indicating the formation of nanoscale structures that may be relevant for myelin assembly. Microscopy experiments showed the formation of new membrane structures with each of the proteins separately and together. Our data indicate both synergy and competition between the three main proteins residing in the peripheral nervous system myelin major dense line. The observed direct effects of myelin proteins on lipid membrane structure and properties may be relevant to their function in myelinating cells as well as their role in myelin disorders.

Glyphosate and 2,4-D are among the most widely used herbicides globally, leading to environmental presence, food contamination, and human contact. Investigations based on current toxicological limits or populational-based herbicide exposures are warranted, and in vitro bioassays provide useful tools for toxicological screening. Thus, this study evaluated the transcriptomic implications of non-cytotoxic exposures to glyphosate, its metabolite aminomethylphosphonic acid (AMPA), or 2,4-D - or to their mixes - on hepatic cells. The half maximal effective concentration (IC50) of each herbicide was calculated (cell viability) in human hepatic C3A cells and 1000-fold lower concentrations were used for transcriptomic analysis (RNA-Seq) after 48 h exposure, resembling current toxicological limits and considering herbicide water levels (glyphosate: 0.95 µg/mL; AMPA: 3.7 µg/mL; 2,4-D: 0.56 µg/mL). Glyphosate exposure enriched MAPK-related biological processes (upregulated TNF, FOS, IGF1, and PDGFB), and downregulated genes associated with lipid metabolism (CD36 and PPARA). Many AMPA exposure-related differentially expressed genes (DEGs, such as PFKFB3, HK2, and ALDOA) were associated with glucose metabolic pathways. Glyphosate and its metabolite yielded a common molecular signature, as illustrated by principal component analysis and the function of 212 shared DEGs. The exposure to 2,4-D was associated with the JNK cascade and the solute carrier family annotations. The herbicide mixtures had a discrete effect on enhancing the impact of individual herbicides, although important epithelial-mesenchymal transition genes were exclusively modified by the mixes (COL11A2, LOXL3, SNAI1). Altogether, our data reveals new perspectives on the short-term molecular effects of herbicide exposure in liver cells, emphasizing potential avenues for further exploration.

Fatty acid-binding protein 4 (FABP4) is a key lipid binding protein expressed in microglia, which has been demonstrated to play a critical role in microglial-mediated neuroinflammation, a component of many neurodegenerative diseases. Compounds able to inhibit the function of FABP4 have shown promise in reducing microglial-mediated neuroinflammation, however, their physicochemical properties would prevent their ability to be easily formulated and traverse the blood-brain barrier (BBB) in order to access microglial FABP4. To this end, this study assessed the ability of a series of FABP4 inhibitors, with more desirable physicochemical properties, to attenuate microglial inflammation in an in vitro setting. Four inhibitors with varying affinity to FABP4, as measured by isothermal titration calorimetry (MFP-0011462, MFP-0012314, MFP-0012318, and MFP-0012328), were assessed for their ability to induce toxicity and attenuate reactive oxygen species (ROS) generation and tumour necrosis factor-α (TNF-α) release from lipopolysaccharide (LPS)-activated BV-2 microglia. All FABP4 inhibitors were determined to be soluble in the aqueous buffers at the highest concentration used in the assays (100 µM). Isothermal titration calorimetry demonstrated that the compounds had varying affinities for FABP4 (KD values of 316 nM to > 100 µM). The ability of FABP4 inhibitors to reduce LPS-mediated ROS production aligned with their KD for FABP4, with the most effective inhibitor (MFP-0012328) also able to reduce TNF-α production (by RT-qPCR) and TNF-α release from LPS-activated BV-2 cells by 17% and 25%, respectively. These studies have demonstrated that a series of FABP4 inhibitors with more appropriate physicochemical properties for BBB penetration are able to reduce microglial-mediated inflammation, which may be of benefit in diseases where overactivation of microglia leads to neurodegeneration.

Colon adenocarcinoma (COAD) ranks second in terms of cancer-related deaths. We found that fatty acid-binding protein 4 (FABP4), which is related to cell adhesion and immunity, affects the occurrence and development of COAD. This study focused on the possibility of using FABP4 as a biomarker for COAD and constructed a nomogram for predicting the survival of COAD patients.

To verify the possibility of using FABP4 as a biomarker for COAD.

A total of 453 COAD tissue samples, along with 41 normal tissue samples, were obtained from The Cancer Genome Atlas database. The difference in FABP4 expression between COAD tissues and normal tissues was analyzed, and the results were verified by immunohistochemistry. The WGCNA algorithm links FABP4 expression with an enrichment analysis and with immune cell infiltration pathways. The biological functions of FABP4 and its coexpressed genes were explored through enrichment analyses. The ESTIMATE, CIBERSORT and ssGSEA methods were used for the immune infiltration analysis. Finally, risk scores were calculated by a Cox analysis. A nomogram was constructed by combining risk scores with routine clinicopathological factors. We assessed the accuracy of survival predictions based on the C-index. The C-index ranges from 0.5 to 1.0, and in general, a C-index value greater than 0.65 indicates a reasonable estimate. The results were validated using the Gene Expression Omnibus (GEO) database.

FABP4 was significantly differentially expressed in COAD. It is a promising auxiliary biomarker for screening and diagnosis. Enrichment analyses suggested that FABP4 may influence the invasion and progression of COAD through cell adhesion. The immunological analysis revealed that FABP4 expression in COAD was significantly positively correlated with immune cell infiltration. Moreover, a nomogram to predict the survival of COAD patients was successfully constructed by integrating the calculated risk scores of 15 candidate genes and routine clinicopathological factors. This nomogram could effectively predict 1-year, 3-year, and 5-year survival (C-index = 0.786) and was verified (C-index = 0.73).

This study established FABP4 as an effective biomarker for screening, assisting in the diagnosis and determining the prognosis.

The dysregulation of bone marrow mesenchymal stem cells (BM-MSCs) is crucial in the pathogenesis of osteoporosis, and adipogenic differentiation of BM-MSCs is considered an essential factor in this process. However, the mechanisms underlying the regulation of MSC adipogenic differentiation require further investigation. MGP (Matrix Gla Protein) was reported to impair the osteogenic differentiation. However, the mechanisms through which MGP regulates osteoporosis and bone-fat imbalance in MSCs are still unclear. In this study, we confirmed that the expression of MGP upregulated in osteoporosis and has a negative correlation with BMD (bone mineral density). Gain- and loss-of-function experiments were performed to ensure the role of MGP in MSC adipogenic differentiation. Mechanistically, MGP increased intracellular free Ca2+ levels and enhanced CaMKII phosphorylation, which in turn activated RIP140 protein degradation. This led to an increase in the transcription of FABP3, ultimately promoting adipogenic differentiation in MSCs. Furthermore, we demonstrated that using recombinant adeno-associated virus 9 (rAAV9) to silence MGP has the effect of alleviating bone loss and reversing the excessive bone marrow adipose tissue in mice with osteoporosis. In summary, our research has unveiled the regulatory role of MGP/Ca2+/CaMKII/RIP140/FABP3 axis in adipogenic differentiation in MSC and it might be a promising approach for osteoporosis treatment.

Per- and polyfluoroalkyl substances (PFAS) are synthetic chemicals used extensively across industries, including semiconductor manufacturing. Semiconductors are ubiquitous, and there is increasing global demand for semiconductors, e.g., for advanced technologies and the automotive industry. Despite their extensive use, the toxicity and bioaccumulation potential of PFAS used in photolithography, a critical process in semiconductor manufacturing, remain poorly understood. Moreover, most lack experimental data and standards for testing. Here, we identified 96 photolithography-relevant PFAS and developed a computational framework to evaluate their potential hazards through protein binding. By integrating molecular dynamics (MD) and docking, we predicted the binding affinities and positions of PFAS to five proteins-liver fatty acid binding protein (LFABP), serum albumin (SA), peroxisome proliferator-activated receptors α and γ (PPARα and PPARγ), and transthyretin (TTR). These proteins were chosen as their binding with PFAS has been linked to PFAS bioaccumulation and to hepatic, reproductive, developmental, and endocrine disruption. Comparisons with empirical data demonstrated our approach balances simulation speed and robustness, better estimating absolute and relative binding affinities than docking alone. PFAS-protein binding affinities were generally positively associated with fluorinated chain length and the presence of aromatic rings, but limited by the protein binding pocket dimensions. Notably, we identified 22 PFAS with stronger predicted binding than perfluorooctane sulfonic acid (PFOS), a known hazardous PFAS, to at least one target protein, suggesting the potential for toxicological concern. By enabling proactive evaluation of PFAS that are unavailable for experimental testing, this work contributes to safeguarding environmental and human health amidst rising semiconductor demands.

Chronic unpredictable mild stress (CUMS) affects chicken immune system and welfare, causing huge losses of growth performance and welfare. Resveratrol (RSV), an antioxidant and anti-inflammatory natural plant polyphenol, is widely used for the prevention of stress related disease. The aim of this study is to explore the therapeutic effect of RSV on spleen damage in CUMS. We successfully constructed a CUMS model. A total of 288 healthy one-day-old chicks were used in this study and were divided in 3 groups, control, CUMS and CUMS+RSV group. During 42 days of age, spleen tissue samples were collected and analyzed. Transmission electron microscope (TEM), Hematoxylin and eosin (H&E) staining, immunofluorescence, qRT- PCR, Western blots, immunohistochemical staining and RNA- sequencing (RNA-seq) technology was used to determine any changes and analyzed the mRNA and enrichment pathways. Histopathology and ultrastructure showed there was a severe damage of tissues. The results of RNA-seq showed that a total of 206, 267 and 211 DEGs were identified (log2 Fold Change| >1, P < 0.05) in control -vs- CUMS group, CUMS -vs- CUMS+RSV group and control -vs- CUMS+RSV group, respectively. Through Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of the SDEGs, two immune/stress- related pathways including PPAR signaling pathway and neuroactive ligand receptor interaction were selected. The genes related to PPAR signaling pathway identified were PLIN1, MMP1, ANGPTL4 and FABP4 and Neuroactive ligand-receptor interaction genes were GRPR, NTSR1, KNG1 and AGT. The PLIN1, MMP1, ANGPTL4, FABP4, GRPR, KNG1 and AGT were up regulated and NTSR1 was down regulated in CUMS group. When compared to CUMS -vs- CUMS+RSV group, PLIN1, FABP4, KNG1 and AGT were down regulated genes and NTSR1 was up regulated gene. Taken together, KEGG pathway analyses of DEGs, verified by qRT-PCR and Western blots, the current study suggested that these data reveal the promising role of RSV in the prevention and therapy of a wide variety of tissue damage and PPAR signaling pathway, neuroactive ligand-receptor interaction in chronic unpredictable mild stress.

Fatty acid-binding protein 4 (FABP4) is an adipokine secreted from adipocytes and macrophages and is also expressed in injured, but not normal, glomerular endothelial cells. Elevated levels of urinary FABP4 (U-FABP4) have been reported to be associated with glomerular damage and increased proteinuria.

The associations of levels of U-FABP4 at baseline with future events including renal dysfunction defined by a 30% decline in estimated glomerular filtration rate (eGFR) and all-cause death were investigated in 660 patients with diabetes (type 1/2, 57/603).

During a follow-up period (median: 62 months), 90 patients (13.6%) developed renal dysfunction, and 66 patients (10.0%) died (median follow-up period 65 months). Kaplan-Meier survival curves showed that there were significant differences in cumulative incidences for a 30% decline in eGFR and all-cause death in patients divided by the tertiles of U-FABP4 level. Furthermore, multivariable Cox proportional hazard models with a restricted cubic spline showed that hazard ratios for a 30% decline in eGFR and all-cause death increased with a higher level of logarithmically transformed (log) U-FABP4 after adjustment for age, sex, type of diabetes, body mass index, current smoking habit, duration of diabetes, comorbidities of hypertension and dyslipidemia, eGFR, and the categorical classification of urinary albumin-creatinine ratio. The addition of log U-FABP4 to traditional risk factors significantly increased the discriminatory capacities for renal dysfunction in net reclassification improvement and integrated discrimination improvement and for all-cause death in NRI.

U-FABP4 is a predictive biomarker for future renal dysfunction and poor prognosis in patients with diabetes.

Fatty acid-binding protein (FABP) 4, which acts as an adipokine secreted by adipocytes, macrophages, and capillary endothelial cells, is expressed in injured glomerular cells. It has been reported that urinary (U-) FABP4 is associated with renal dysfunction and proteinuria in several glomerular kidney diseases. However, the clinical significance of U-FABP4 in diabetic kidney disease (DKD) remains undetermined.

Immunohistological analyses of FABP4 and FABP1 (liver-type FABP), an established biomarker for impaired proximal tubules, were performed in the kidneys of patients with DKD and nonobese diabetic mice (KK-Ta/Akita mice). The associations between U-FABP4 and U-FABP1 with kidney function and metabolic indices were also investigated in patients with type 1 diabetes (n = 57, mean age: 61 years) and patients with type 2 diabetes (n = 608, mean age: 65 years).

In both patients with diabetes and diabetic mice, FABP4 was expressed in injured glomeruli with increased markers of endoplasmic reticulum stress in addition to peritubular capillaries, whereas FABP1 was mainly expressed in proximal tubules. Levels of U-FABP4 and U-FABP1 were independently associated with each other, and both levels were independently associated with estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (UACR) after adjustment of age, sex, type of diabetes, duration of diabetes, and systolic blood pressure in patients with diabetes.

Urinary level of FABP4 derived from injured glomeruli with increased endoplasmic reticulum stress is independently associated with eGFR and UACR, suggesting a promising biomarker for glomerular damage in patients with diabetes.

The regulation of intramuscular fat (IMF) accumulation plays a crucial role in determining meat quality in the beef industry. In humans, fat deposition in skeletal muscle is closely associated with insulin resistance and obesity. However, its underlying mechanisms are not fully elucidated. We previously identified erucic acid (EA) as a key metabolite that may affect IMF deposition of beef using omics strategies. By utilizing bovine intramuscular preadipocytes in vitro, the study demonstrates a dose-dependent increase in lipid storage induced by EA, along with mRNA expression levels of transporters FABP4 and CD36. At a mechanistic level, EA triggers ERK1/2 phosphorylation and enhances the expression of PPARγ, FABP4, and CD36, thereby facilitating the formation of lipid droplets within preadipocytes. In vivo experiments conducted in mice support these findings, indicating that EA stimulates fat accumulation in skeletal muscles and enhances the levels of FABP4 and CD36 proteins. These outcomes not only enhance our comprehension of the molecular mechanisms governing IMF deposition but also provide insights into potential strategies for enhancing meat quality and addressing metabolic disorders linked to fat accumulation in skeletal muscles. The findings of the study contribute to existing scholarly knowledge and lay the groundwork for future research endeavors aimed at improving meat quality and metabolic well-being.

Fatty acid-binding protein 4 (FABP4), a key regulator of lipid metabolism and inflammation, has been implicated in neurodevelopmental disorders, including autism spectrum disorder (ASD). This study investigated the effects of FABP4 inhibition during gestation and lactation on offspring neurodevelopment using the selective FABP4 inhibitor BMS309403. Female mice received BMS309403 (15 mg/kg) via oral gavage from two weeks before mating to postnatal day 28 (P28). Administration of BMS309403 to mouse dams resulted in autism-like phenotypes in male offspring (behavioral tests: n = 7-10 per group; spine analysis: 6 mice per group, n = 26-38 dendrites per group), characterized by increased dendritic spine density in the prefrontal cortex, impaired vocal communication, increased repetitive behaviors, and depression-like symptoms. Fatty acid analysis (n = 4-6 per group) revealed significant alterations in maternal and fetal lipid profiles, including elevated arachidonic acid levels in maternal plasma and increased n6PUFAs in the fetal brain, suggesting a pro-inflammatory lipid environment. Principal component analysis demonstrated distinct clustering of lipid profiles between control and BMS309403-treated groups. Cytokine analysis (n = 6 per group) indicated reductions in IL-10 and IL-12(p40) in maternal plasma and decreased TNFα in the fetal plasma, suggesting dysregulation in systemic inflammatory signaling. These findings suggest that FABP4 inhibition during the perinatal period perturbs lipid metabolism and may influence neurodevelopment through systemic metabolic changes. Although the direct effects of BMS309403 on the fetal brain cannot be excluded, alteration in maternal metabolism and placental function may have contributed to the observed neurodevelopmental changes in offspring.

The intestinal remodeling during amphibian metamorphosis is essential for adapting to various ecological niches of aquatic and terrestrial habitats. However, whether and how the widespread contaminant, perfluorobutanesulfonate (PFBS) affects intestinal remodeling remains unknown. In this study, tadpoles (Lithobates catesbeianus) at the G26 stage were exposed to environmentally relevant concentrations of PFBS (0, 1, 3, and 10 μg/L) until the end of metamorphosis. PFBS exposure resulted in reduced thyroid follicular glia; down-regulation of gene transcripts related to thyroid hormone synthesis; decreased blood hormone (corticotropin-releasing hormone, thyroid-stimulating hormone, and 3,5,3'-triiodothyronine (T3)) and transthyretin concentrations; and up-regulation of gene transcripts related to thyroid hormone degrading enzymes. Moreover, exposure to PFBS induced apoptosis in single-layer columnar epithelial cells, suppressed the proliferation of intestinal stem cells, and hindered their differentiation into adult epithelial cells during intestinal remodeling. The responses of Notch and Wnt signaling pathways regulated by T3 were downregulated, and key gene transcripts (msi, pcna, and lgr5) involved in intestinal remodeling regulated by these two pathways were also downregulated. This is the first report on the effects of PFBS on amphibian metamorphosis. Overall, PFBS reduced thyroid hormone synthesis and transport by interfering with the hypothalamic-pituitary-thyroid axis and transthyretin expression, inhibited downstream Notch and Wnt signaling pathway responses, and ultimately led to incomplete intestinal remodeling to some extent.

Skeletal muscle plays a central role in the storage, synthesis, and breakdown of nutrients, yet little research has explored temporal responses of this human tissue, especially with concurrent measures of systemic biomarkers of metabolism.

To characterize temporal profiles in skeletal muscle expression of genes involved in carbohydrate metabolism, lipid metabolism, circadian clocks, and autophagy and descriptively relate them to systemic metabolites and hormones during a controlled laboratory protocol.

Ten healthy adults (9M/1F, [mean ± SD] age 30 ± 10 years; BMI 24.1 ± 2.7 kg·m-2) rested in the laboratory for 37 hours with all data collected during the final 24 hours (08:00-08:00 hours). Participants ingested hourly isocaloric liquid meal replacements alongside appetite assessments during waking before a sleep opportunity from 22:00 to 07:00 hours. Blood samples were collected hourly for endocrine and metabolite analyses, with muscle biopsies occurring every 4 hours from 12:00 to 08:00 hours the following day to quantify gene expression.

Plasma insulin displayed diurnal rhythmicity peaking at 18:04 hours. Expression of skeletal muscle genes involved in carbohydrate metabolism (Name, Acrophase [hours]: GLUT4, 14:40; PPARGC1A, 16:13; HK2, 18:24) and lipid metabolism (FABP3, 12:37; PDK4, 05:30; CPT1B, 12:58) displayed 24-hour rhythmicity that reflected the temporal rhythm of insulin. Equally, circulating glucose (00:19 hours), nonesterified fatty acids (04:56), glycerol (04:32), triglyceride (23:14), urea (00:46), C-terminal telopeptide (05:07), and cortisol (22:50) concentrations also all displayed diurnal rhythmicity.

Diurnal rhythms were present in human skeletal muscle gene expression as well systemic metabolites and hormones under controlled diurnal conditions. The temporal patterns of genes relating to carbohydrate and lipid metabolism alongside circulating insulin are consistent with diurnal rhythms being driven in part by the diurnal influence of cyclic feeding and fasting.

Overall adiposity and body fat distribution are heritable traits associated with altered risk of cardiometabolic disease and mortality. Performing rare variant (minor allele frequency<1%) association testing using exome-sequencing data from 402,375 participants in the UK Biobank (UKB) for nine overall and tissue-specific fat distribution traits, we identified 19 genes where putatively damaging rare variation associated with at least one trait (Bonferroni-adjusted P <1.58×10 -7 ) and 50 additional genes at FDR≤1% ( P ≤4.37×10 -5 ). These 69 genes exhibited significantly higher (one-sided t -test P =3.58×10 -18 ) common variant prioritisation scores than genes not significantly enriched for rare putatively damaging variation, with evidence of monotonic allelic series (dose-response relationships) among ultra-rare variants (minor allele count≤10) in 22 genes. Combining rare and common variation evidence, allelic series and longitudinal analysis, we selected 14 genes for CRISPR knockdown in human white adipose tissue cell lines. In three previously uncharacterised target genes, knockdown increased (two-sided t -test P <0.05) lipid accumulation, a cellular phenotype relevant for fat mass traits, compared to Cas9-empty negative controls: COL5A3 (fold change [FC]=1.72, P =0.0028), EXOC7 (FC=1.35, P =0.0096), and TRIP10 (FC=1.39, P =0.0157); furthermore, knockdown of PPARG (FC=0.25, P =5.52×10 -7 ) and SLTM (FC=0.51, P =1.91×10 -4 ) resulted in reduced lipid accumulation. Integrating across population-based genetic and in vitro functional evidence, we highlight therapeutic avenues for altering obesity and body fat distribution by modulating lipid accumulation.

GPR171 suppresses T cell immune responses involved in antitumour immunity, while its role in inflammatory bowel disease (IBD) pathogenesis remains unclear.

We aimed to investigate the role of GPR171 in modulating CD4+ T cell effector functions in IBD and evaluate its therapeutic potential.

We analysed GPR171 expression in colon biopsies and peripheral blood samples from patients with IBD and assessed the impact of GPR171 on CD4+ T cell differentiation through administration of its endogenous ligand (BigLEN). We further determined the role of GPR171 in dextran sulfate sodium (DSS)-induced colitis and CD45RBhighCD4+ T-cell transfer colitis model and deciphered the underlying mechanisms using RNA sequencing (RNA-seq) and lipidomics. We developed a novel BigLEN-based Fc fusion protein (BigLEN-Fc) and evaluated its potential in preventing and treating colitis.

GPR171 was markedly increased in inflamed mucosa and CD4+ T cells of patients with IBD compared with controls. BigLEN-triggered GPR171 activation inhibited Th17 cell differentiation in vitro. GPR171 deficiency exacerbated DSS- and CD45RBhighCD4+ T cell-induced colitis in mice, characterised by increased Th17 cell responses in intestinal mucosa. Mechanistically, GPR171 deficiency promoted Th17 cell differentiation and altered lipidome profile in Th17 cells via the cAMP-pCREB-FABP5 axis. Blockage of FABP5 reduced Th17 cell differentiation in vitro and ameliorated DSS-induced colitis in Gpr171 -/- mice. Furthermore, BigLEN-mutFc administration potently mitigated colitis in mice.

GPR171 deficiency promotes Th17 cell differentiation and causes lipid metabolism perturbation, contributing to intestinal inflammation in a FABP5-dependent manner. Target therapy (eg, BigLEN-Fc) represents a novel therapeutic approach for IBD treatment.

Periodontitis is recognized as one of the most prevalent oral dysbiotic inflammatory diseases, ultimately leading to the irreversible destruction of periodontal tissues. Macrophages play a pivotal role in the development and progression of periodontitis, and the feasibility of targeting them therapeutically has been established. Since metabolic switching significantly contributes to macrophage regulation, conducting an in-depth review of macrophage metabolism in periodontitis may serve as the foundation for developing innovative treatments.

This paper has been carefully reviewed to provide a comprehensive overview of the roles played by macrophages in periodontitis and associated comorbidities. Initially, detailed presentations on the metabolic reprogramming of macrophages, including glucose, lipid, and amino acid metabolism, were provided. Subsequently, dominating macrophage phenotype and metabolism under lipopolysaccharide (LPS) stimulation or during periodontitis were presented with emphasize on critical molecules involved. Furthermore, in recognition of the close association between periodontitis and several comorbidities, the interaction among macrophage metabolism, periodontitis, and related metabolic diseases, was thoroughly discussed.

Through the examination of current research on macrophage metabolic reprogramming induced by periodontitis, this review provides potential immunometabolic therapeutic targets for the future and raises many important, yet unstudied, subjects for follow-up.

Periodontitis is recognized as one of the most prevalent oral dysbiotic inflammatory diseases, ultimately leading to the irreversible destruction of periodontal tissues. Macrophages play a pivotal role in the development and progression of periodontitis, and the feasibility of targeting them therapeutically has been established. Since metabolic switching significantly contributes to macrophage regulation, conducting an in-depth review of macrophage metabolism in periodontitis may serve as the foundation for developing innovative treatments.

This paper has been carefully reviewed to provide a comprehensive overview of the roles played by macrophages in periodontitis and associated comorbidities. Initially, detailed presentations on the metabolic reprogramming of macrophages, including glucose, lipid, and amino acid metabolism, were provided. Subsequently, dominating macrophage phenotype and metabolism under lipopolysaccharide (LPS) stimulation or during periodontitis were presented with emphasize on critical molecules involved. Furthermore, in recognition of the close association between periodontitis and several comorbidities, the interaction among macrophage metabolism, periodontitis, and related metabolic diseases, was thoroughly discussed.

Through the examination of current research on macrophage metabolic reprogramming induced by periodontitis, this review provides potential immunometabolic therapeutic targets for the future and raises many important, yet unstudied, subjects for follow-up.

With few viable treatment options, glioblastoma (GBM) is still one of the most aggressive and deadly types of brain cancer. Recent developments in lipidomics have demonstrated the potential of lipid metabolism as a therapeutic target in GBM. The thorough examination of lipids in biological systems, or lipidomics, is essential to comprehending the changed lipid profiles found in GBM, which are linked to the tumor's ability to grow, survive, and resist treatment. The use of lipidomics in drug delivery and discovery is examined in this study, focusing on how it may be used to find new biomarkers, create multi-target directed ligands, and improve drug delivery systems. We also cover the use of FDA-approved medications, clinical trials that use lipid-targeted medicines, and the integration of lipidomics with other omics technologies. This study emphasizes lipidomics as a possible tool in developing more effective treatment methods for GBM by exploring various lipid-centric techniques.

Colorectal cancer (CRC) is closely linked to obesity, a condition that significantly impacts tumor progression and therapeutic resistance. Although cetuximab, an EGFR-targeting monoclonal antibody, is a cornerstone in metastatic CRC treatment, resistance often emerges, leading to poor outcomes. This study investigated the role of drug-tolerant persister (DTP) cells and their metabolic interactions within the tumor microenvironment (TME) in cetuximab resistance. Using patient-derived organoids and in vivo models, we identified the FABP4/UCP2 axis as a critical mediator of resistance. Organoids derived from cetuximab non-responders revealed upregulated FABP4 and UCP2 expression post-treatment. Coculture experiments with adipocytes showed that FABP4 and UCP2 promote lipid metabolic reprogramming, facilitating cancer cell survival in a dormant state. CRISPR/Cas9 mediated inhibition of FABP4 disrupted this metabolic interaction, sensitising resistant cells to cetuximab. In vivo, the FABP4 inhibitor BMS309403, either alone or in combination with cetuximab, significantly reduced tumor growth in resistant CRC models, highlighting its therapeutic potential. These findings establish the FABP4/UCP2 axis as a pivotal driver of cetuximab resistance in obesity-associated CRC and suggest that targeting this metabolic pathway could improve outcomes in DTP-resistant CRC patients.

As a synthetic rubber antioxidant, the environmental monitoring concentrations of N-(1,3-Dimethylbutyl)-N'-phenyl-p-phenylenediamine (6-PPD) have exceeded the risk threshold, attracting widespread attention. Although investigations into the harmful effects on zebrafish have commenced, a comprehensive exploration of its toxicological impacts and underlying molecular mechanisms remains to be conducted. By using zebrafish as a model, this study systematically evaluated 6-PPD-induced lipid metabolism disorders and inflammation response following environmental exposure. Bioinformatics analysis revealed that 6-PPD target genes enriched in the hepatitis B pathway, indicating potential hepatic toxicity via inflammatory pathways. Therefore, we hypothesize that 6-PPD could trigger hepatotoxicity through the crosstalk between lipid metabolism and inflammation. Further experiments substantiated this hypothesis by showing lipid accumulation in the liver following 6-PPD exposure, along with elevated triglyceride (TG) and total cholesterol (TC) levels, and imbalanced expression of lipid metabolism-related marker genes. Additionally, 6-PPD exposure induced the accumulation of reactive oxygen species (ROS) and inhibited the differentiation and maturation of immune cells, resulting in immune evasion. Most of these abnormalities were exacerbated in a dose-dependent manner with increasing concentrations of 6-PPD. The addition of the PPARγ pathway agonist puerarin (PUE) or NF-κB pathway inhibitor quinazoline (QNZ) to 6-PPD exposure group mitigated these toxic effects, validating our conjecture that lipid metabolism disorder and inflammatory responses may result from the regulation of the PPARγ/NF-κB pathway.