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Introduction: CD36 is a membrane receptor that participates in the cellular uptake of fatty acids and lipid metabolism. CD36 overexpression favors progression of different pathologies, such as atherosclerosis and cancer. Thus, CD36 targeting has medicinal relevance. Herein, we aimed to identify human anti-CD36 single-chain variable fragment (scFv) with therapeutic potential., Methods: The semisynthetic ALTHEA Gold Plus Libraries™ were panned using recombinant human CD36. Clone selection was performed by ELISA. Analysis of scFv binding and blocking function was evaluated by flow cytometry in macrophage-like THP-1 cells and hepatocellular carcinoma HepG2 cells. The phenotypic changes induced by CD36 ligands were assessed in vitro by: i) oil red staining, ii) tumorsphere assays, and iii) RT-qPCR., Results: We identified an anti-CD36 scFv, called D11, that competes with a commercial anti-CD36 antibody with proven efficacy in disease models. D11 binds to CD36 expressed in the membrane of the cellular models employed and reduces the uptake of CD36 ligands. In macrophage-like THP-1 cells, D11 impaired the acquisition of foam cell phenotype induced by oxLDL, decreasing lipid droplet content and the expression of lipid metabolism genes. Treatment of HepG2 cells with D11 reduced lipid accumulation and the enhanced clonogenicity stimulated by palmitate., Conclusion: We discovered a new fully human scFv that is an effective blocker of CD36. Since D11 reduces the acquisition of pathogenic features induced by CD36 ligands, it could support the generation of therapeutic proteins targeting CD36., Competing Interests: JA is founder and CEO of GlobalBio, Inc. and may have commercial interest in ALTHEA Gold Plus Libraries™. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2025 Mata-Cruz, Guerrero-Rodríguez, Gómez-Castellano, Carballo-Uicab, Almagro, Pérez-Tapia and Velasco-Velázquez.)

Drug resistance is an important factor for prostate cancer (PCa) to progress into refractory PCa, and abnormal lipid metabolism usually occurs in refractory PCa, which presents great challenges for PCa therapy. Here, a cluster of differentiation 36 (CD36) inhibitor sulfosuccinimidyl oleate sodium (CD36i) and stearoyl-CoA desaturase 1 (SCD1) siRNA (siSCD1) are selected to inhibit lipid uptake and synthesis in PCa, respectively. To this end, a multiresponsive drug delivery nanosystem, HA@CD36i-TR@siSCD1 is designed. The hyaluronic acid (HA) gel "shell" of HA-TR nanosystem can release drugs in response to the acidic tumor microenvironment and hyaluronidase, and the tumor targeting (TR) cationic micellar "core" can release drugs in response to glutathione. This multiresponsive drug release is beneficial for the exogenous inhibition of lipid uptake by CD36i and the endogenous inhibition of lipid synthesis by siSCD1. The established HA-TR nanosystem has good tumor targeting ability and tumor penetration ability, and that HA@CD36i-TR@siSCD1 has good synergistic effects, which can significantly restrain the growth, invasion, and metastasis of PCa. Moreover, under high-fat conditions, the tumors are more sensitive to HA@CD36i-TR@siSCD1 treatment, almost no accumulation of lipid droplets is observed in HA@CD36i-TR@siSCD1-treated tumors, with enhanced antitumor immunity. Hence, this study provides a new treatment option for refractory PCa patients, especially those with a high-fat diet., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Cervical cancer (CC) is a prevalent gynecological malignancy. Increasing evidence suggests that circular RNAs (circRNAs) play a pivotal role in the pathogenesis of CC. However, the regulatory function of circ_ASH1L in CC remains elusive. In this study, we aim to elucidate the precise role and underlying mechanism of circ_ASH1L in the malignant progression of CC. The human CC dataset GSE102686 was extracted from the Gene Expression Omnibus (GEO) database for the analysis of differentially expressed circRNAs. Target gene prediction softwares were utilized to predict the binding of miRNAs to circ_ASH1L sponge. The expression level of circ_ASH1L in CC tissues and cells was detected by quantitative real-time polymerase chain reaction (qRT-PCR). The characteristics of circ_ASH1L were determined by RNase R digestion, actinomycin D, and nucleo-plasmic separation assays. The effects of circ_ASH1L, miR-1254, and CD36 gain-and-loss on the malignant progression of CC were investigated using Cell Counting Kit-8 (CCK-8), colony formation, flow cytometry, wound scratch, transwell, and Western blot assay. The effect of circ_ASH1L on tumorigenicity of CC cells in vivo was evaluated in nude mice through tumor xenograft assay. The targeted regulatory relationship between circ_ASH1L/miR-1254 as well as miR-1254/CD36 was validated by dual-luciferase reporter assay. We screened the differentially expressed circ_ASH1L from the GEO dataset GSE102686 and confirmed its circular structure. Furthermore, we observed a significant upregulation of circ_ASH1L in both CC tissues and cells. Overexpression of circ_ASH1L promotes proliferation, invasion, and migration of CC cells while inhibiting cell apoptosis. However, silencing circ_ASH1L showed opposite results and inhibited tumorigenicity of CC cells in nude mice. Furthermore, we have identified circ_ASH1L as a miR-1254 sponge in CC cells. Notably, our in vitro experiments demonstrated that exogenously modulating the expression of miR-1254 effectively counteracted the impact of circ_ASH1L on the malignant phenotypic characteristics of CC cells. Similarly, modulation of CD36 expression efficiently counteracted the effect of miR-1254 on the malignant biological behavior of CC cells. In conclusion, circ_ASH1L promoted the malignant progression of CC via upregulating CD36 expression through sponging miR-1254., Competing Interests: Competing interests: The authors declare no competing interests. Ethical approval and consent to participate: The study was granted approval by the Ethics Review Committee of Renmin Hospital of Wuhan University (approval number: WDRY2022-K277), conducted in accordance with the Helsinki Declaration. Written informed consent was obtained from all enrolled patients. The procedures for care and use of animals were approved by the Ethics Committee of Besser Model Biology Center (approval number: BSMS No. 2023-04-24 A), which adhered to the Guidelines for the Ethical Welfare Review of Laboratory Animals issued by the Ministry of Science and Technology of China (GB/T 35892-2018)., (© 2025. The Author(s), under exclusive licence to Springer Nature America, Inc.)

CD36 is a multifunctional protein involved in long chain fatty acid uptake and immune modulation in different cells. Recently it was reported that increased expression of CD36 is evident in the islets of diabetic obese individuals. In this present study we investigated the role of CD36 in regulating intracellular lipid accumulation and inflammation in beta cells and its implication on secretory dysfunction. Additionally, we have elucidated the potential role of fetuinA, a circulatory glycoprotein and an endogenous ligand of TLR4, for aggravating lipid accumulation and insulin secretory defects in beta cells. MIN6 mouse insulinoma cells when incubated with palmitate and fetuinA together showed activation of TLR4-NFkB inflammatory cascade and increased uptake of palmitate, which was rescued by CD36 functional inhibition or knockdown. Moreover, glucose stimulated insulin secretion was restored with consequent downregulation of IL-1β secretion. TLR4 inhibition also decreased intracellular lipid content with a reduction of CD36, suggesting functional crosstalk between them. At physiological level, excess fetuinA in the islet milieu of HFD fed C57BL/6J mice or exogenous fetuinA administration (i.p.) promoted lipid accumulation in the islets resulting in decreased insulin secretion with increased CD36 expression. Interestingly, CD36 inhibition in HFD mice with a pharmacological inhibitor Salvianolic acid B attenuated inflammation, reduced intracellular lipid accumulation in beta cells and restored insulin secretory function. Therefore, our results suggest that inhibition of CD36 protects beta cells from the derogatory effects of lipid and fetuinA and restores secretory function and can be considered as a therapeutic target for obesity mediated beta cell dysfunction., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this manuscript., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objectives: Dysregulation of lipid homeostasis pathway causes many liver diseases, including hepatic steatosis. One of the primary factors contributing to lipid accumulation is fatty acid uptake by the liver. Transmembrane protein 135 (TMEM135), which exists in mitochondria and peroxisomes, participates in intracellular lipid metabolism. This study aims to investigate the role of TMEM135 on regulating cellular lipid import in the liver., Methods: We used in vivo, ex vivo, and in vitro models of steatosis. TMEM135 knockout (TMEM135KO) and wild type (WT) mice were fed a high-fat diet (HFD) to induce hepatic steatosis. Primary mouse hepatocytes and AML12 cells were treated with free fatty acid (FFA). Additionally, TMEM135-deficient stable cells and overexpressed cells were established using AML12 cells., Results: TMEM135 deficiency mitigated lipid accumulation in the liver of HFD-fed TMEM135KO mice. TMEM135-depleted primary hepatocytes and AML12 cells exhibited less lipid accumulation when treated with FFA compared to control cells, as shown as lipid droplets. Consistently, the effect of TMEM135 depletion on lipid accumulation was completely reversed under TMEM135 overexpression conditions. CD36 expression was markedly induced by HFD or FFA, which was reduced by TMEM135 depletion. Among the SIRT family proteins, only SIRT1 expression definitely increased in the liver of HFD-fed TMEM135KO mice along with a significant increase in NAD + /NADH ratio. However, inhibition of SIRT1 in TMEM135-depleted cells using siSIRT1 or the SIRT1 inhibitor EX-527 resulted in an increase of CD36 expression and consequent TG levels., Conclusions: TMEM135 depletion attenuates CD36 expression in a SIRT1-dependent manner, thereby reducing cellular lipid uptake and hepatic steatosis., Competing Interests: Declaration of competing interest The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript., (Copyright © 2024. Published by Elsevier GmbH.)

Tumor-associated macrophages (TAM) are a heterogeneous population of myeloid cells that dictate the inflammatory tone of the tumor microenvironment. In this study, we unveiled a mechanism by which scavenger receptor cluster of differentiation 36 (CD36) suppresses TAM inflammatory states. CD36 was upregulated in TAMs and associated with immunosuppressive features, and myeloid-specific deletion of CD36 significantly reduced tumor growth. Moreover, CD36-deficient TAMs acquired inflammatory signatures including elevated type-I IFN (IFNI) production, mirroring the inverse correlation between CD36 and IFNI response observed in patients with cancer. IFNI, especially IFNβ, produced by CD36-deficient TAMs directly induced tumor cell quiescence and delayed tumor growth. Mechanistically, CD36 acted as a natural suppressor of IFNI signaling in macrophages through p38 activation downstream of oxidized lipid signaling. These findings establish CD36 as a critical regulator of TAM function and the tumor inflammatory microenvironment, providing additional rationale for pharmacologic inhibition of CD36 to rejuvenate antitumor immunity. Significance: CD36 in tumor-associated macrophages mediates immunosuppression and can be targeted as a therapeutic avenue for stimulating interferon production and increasing the efficacy of immunotherapy., (©2024 American Association for Cancer Research.)

Background: Nonalcoholic fatty liver disease (NAFLD), a chronic metabolic disorder marked by excessive lipid deposition, represents a considerable health burden with no established efficacious treatment strategy. Quinoa (Chenopodium quinoa Willd.), valued for its health benefits, is replete with flavonoid bioactives. The aims of this work are to isolate and purify flavonoids from quinoa whole grain that can intervene in NAFLD and to elucidate some of the underlying mechanisms., Results: Chenopodium quinoa Willd. flavonoids (CQWF) were obtained successfully through an optimized ultrasonic extraction methodology, followed by isolation and purification utilizing macroporous resin D101. The study then explored the therapeutic potential of CQWF and its eluted fractions in models emulating NAFLD conditions: an in vitro fatty liver cell model induced by oleic acid (OA) and palmitic acid (PA) in the HepG2 and BEL-7402 cell lines, and an in vivo high-fat diet (HFD)-induced NAFLD model in C57BL/6N mice. The findings revealed a comprehensive mitigating effect of CQWF30 on NAFLD, manifesting in reduced intracellular lipid accumulation in steatotic hepatocytes and a concerted downregulation of key lipid metabolism genes, CD36 and FASN. Administration of CQWF30 reduced triglyceride (TG) levels in both the cellular model and the livers of HFD-fed mice. It also reduced serum concentrations of TG, total cholesterol (T-CHO), low-density lipoprotein cholesterol (LDL-C), aspartate aminotransferase (AST), and alanine aminotransferase (ALT), while increasing high-density lipoprotein cholesterol (HDL-C) in the mice., Conclusion: These results highlighted the promising therapeutic capacity of CQWF, particularly CQWF30. This research advances the exploration and utilization of flavonoids derived from quinoa whole grain, providing innovative dietary intervention strategies for NAFLD. © 2024 Society of Chemical Industry., (© 2024 Society of Chemical Industry.)

The chemotherapeutic agent doxorubicin (DOX) leads to the loss of skeletal muscle and adipose tissue mass, contributing to cancer cachexia. Experimental research on the molecular mechanisms of long-term DOX treatment is modest, and its effect on both skeletal muscle and adipose tissue has not been studied in an integrative manner. Dexrazoxane (DEXRA) is used to prevent DOX-induced cancer-therapy-related cardiovascular dysfunction (CTRCD), but its impact on skeletal muscle and adipose tissue remains elusive. Therefore, this study aimed to investigate the long-term effects of DOX on adipose tissue and skeletal muscle metabolism, and evaluate whether DEXRA can mitigate these effects. To this end, 10-week-old male C57BL6/J mice ( n = 32) were divided into four groups: (1) DOX, (2) DOX-DEXRA combined, (3) DEXRA and (4) control. DOX (4 mg/kg weekly) and DEXRA (40 mg/kg weekly) were administered intraperitoneally over 6 weeks. Indirect calorimetry was used to assess metabolic parameters, followed by a molecular analysis and histological evaluation of skeletal muscle and adipose tissue. DOX treatment led to significant white adipose tissue (WAT) loss (74%) and moderate skeletal muscle loss (Gastrocnemius (GAS): 10%), along with decreased basal activity (53%) and energy expenditure (27%). A trend toward a reduced type IIa fiber cross-sectional area and a fast-to-slow fiber type switch in the Soleus muscle was observed. The WAT of DOX-treated mice displayed reduced Pparg ( p < 0.0001), Cd36 ( p < 0.0001) and Glut4 ( p < 0.05) mRNA expression-markers of fat and glucose metabolism-compared to controls. In contrast, the GAS of DOX-treated mice showed increased Cd36 ( p < 0.05) and Glut4 ( p < 0.01), together with elevated Pdk4 ( p < 0.001) mRNA expression-suggesting reduced carbohydrate oxidation-compared to controls. Additionally, DOX increased Murf1 ( p < 0.05) and Atrogin1 ( p < 0.05) mRNA expression-markers of protein degradation-compared to controls. In both the WAT and GAS of DOX-treated mice, Ppard mRNA expression remained unchanged. Overall, DEXRA failed to prevent these DOX-induced changes. Collectively, our results suggest that DOX induced varying degrees of wasting in adipose tissue and skeletal muscle, driven by distinct mechanisms. While DEXRA protected against DOX-induced CTRCD, it did not counteract its adverse effects on skeletal muscle and adipose tissue.

AMPK's role in tumor initiation and progression is controversial. Here, we provide genetic evidence that AMPK is required for metastasis in mouse models of breast cancer. In a mouse model of spontaneous breast cancer metastasis, the deletion of AMPK before and after tumor onset decreased breast cancer metastasis, and similar results were obtained after AMPK deletion in breast cancer cell lines. The deletion of AMPK induces reactive oxygen species (ROS) levels in vitro and lipid oxidation in vivo, which likely impede metastasis. Indeed, antioxidants restore the ability of AMPK-deficient tumors to metastasize. By inhibiting acetyl-coenzyme A (CoA) carboxylases 1 and 2, AMPK maintains NADPH levels by reducing NADPH consumption in fatty acid synthesis and increasing NADPH generation via fatty acid oxidation, thus increasing the dependency on auxotrophic fatty acids. Consistently, AMPK is required for the expression of the fatty acid transporter CD36 in tumors, and ectopic expression of CD36 in AMPK-deficient cells restored their ability to metastasize., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Conjugated linoleic acid (CLA) is known for antiobesity. However, the role of CLA in regulating high-fat diet (HFD)-impaired pubertal mammary gland development remains undefined. Here, pubertal female mice and HC11 cells were treated with HFD or palmitic acid (PA), supplemented with or without CLA, respectively. We found that CLA prevented impaired mammary gland development in pubertal mice exposed to HFD. In vitro, c9, t11-CLA, but not t10, c12-CLA, promoted PA-suppressed HC11 proliferation, accompanied by hindered CD36 palmitoylation and localization on the plasma membrane. Moreover, c9, t11-CLA reduced the formation of the CD36/Fyn/Lyn complex and inhibited the JNK pathway while activated the ERK pathway in PA-treated HC11. In mechanism, the activation of the JNK pathway and the inhibition of ERK abolished the c9, t11-CLA-stimulated proliferation of PA-treated HC11. In vivo verification, CLA reduced the total and cell membrane CD36 palmitoylation, suppressed the formation of the CD36/FYN/LYN complex, and inhibited the JNK pathway but activated the ERK pathway in the mammary gland of HFD-fed mice. In conclusion, CLA mitigated HFD-impaired mammary gland development of pubertal mice and PA-suppressed HC11 proliferation via CD36 palmitoylation and the downstream JNK-ERK pathway. These data suggested the potential application of CLA in ameliorating obesity-impaired pubertal mammary gland development.

Obesity is a global epidemic associated with chronic inflammation, oxidative stress, and metabolic disorders. Bariatric surgery is a highly effective intervention for sustained weight loss and the improvement of obesity-related comorbidities. However, post-surgery nutritional deficiencies, including vitamin E, remain a concern. This study investigates the role of single-nucleotide polymorphisms (SNPs) in genes related to vitamin E transport and bioavailability in determining vitamin E levels post bariatric surgery. A cohort of 140 patients with obesity undergoing bariatric surgery was analyzed. Serum vitamin E levels were measured before and one year after surgery, and SNPs in genes associated with vitamin E transport and metabolism were genotyped using PCR, DHPLC, and sequencing methods. Associations between SNPs, haplotypes, and vitamin E levels were statistically evaluated. Significant associations were observed between the APOE rs7412 SNP and serum vitamin E levels. The rare T allele was linked to lower vitamin E levels post surgery, with an increased frequency in patients with severe deficiency (<11.6 μmol/L). Haplotype analysis of APOE revealed that the ε2 haplotype (T-T) was strongly associated with vitamin E deficiency. Other SNPs, including CD36 rs1761667, SCARB1 rs4238001, and ABCA1 rs4149314, were also linked to changes in vitamin E levels, suggesting that an impaired bioavailability and transport can be the reason for low vitamin E levels post surgery. Genetic polymorphisms in APOE, CD36, SCARB1, and ABCA1 significantly influence vitamin E status after bariatric surgery. These findings highlight the importance of personalized supplementation strategies considering patients' genetic profiles to mitigate the risk of vitamin E deficiency and related complications.

Background: Immunoglobulin A Nephropathy (IgAN) is a leading cause of end-stage renal disease (ESRD), but its pathogenesis remains unclear, and specific therapies are currently lacking. Consequently, identifying novel differentially expressed genes (DEGs) and therapeutic targets is of paramount importance to IgAN., Methods: The Gene Expression Omnibus (GEO) databases GSE37460 and GSE104948, containing data from renal tissue of patients with IgAN and normal controls, were screened for DEGs, followed by enrichment pathway analysis. The potential key gene for IgAN, CD36, was identified through the single-cell sequencing dataset GSE166793 and histopathological analysis of patients with IgAN. Clinical and pathological data from patients with IgAN were collected to analyze the correlation between CD36 expression and various indicators in renal tissue, thereby evaluating the influence of CD36 on IgAN progression. The accuracy of the risk score model was assessed using receiver operating characteristic (ROC) curve analysis. Finally, CD36 expression was knocked down to explore its regulatory role in polymeric IgA1 (pIgA1)-stimulated mouse mesangial cells (MCs)., Results: CD36 was identified as a key DEG from two GEO databases and a single-cell sequencing dataset. Compared to peritumoral normal tissues, CD36 expression levels were significantly increased in the IgAN group. Statistically significant differences were observed between M0 and M1, E0 and E1, S0 and S1, C0 and C1-2 in the updated Oxford Classification. CD36 expression showed positive correlations with 24-hour proteinuria, serum creatinine, and levels of fibrosis-related and autophagy-related factors in renal tissue. Additionally, CD36 and fibrosis-related factors were significantly elevated in MCs following pIgA1 stimulation. CD36 knockdown resulted in decreased extracellular matrix (ECM) accumulation in pIgA1-stimulated MCs. RNA-seq analysis of MCs with CD36 knockdown revealed significant alterations in autophagy and CD36 silencing restored autophagy levels in MCs treated with the autophagy inhibitor 3MA., Conclusion: Our study confirmed that CD36 expression increases with the clinical progression of IgAN and CD36 knockdown alleviates MCs injury by inhibiting ECM accumulation and restoring autophagy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Lactobacillus reuteri is a well-known probiotic with beneficial effects, such as anti-insulin resistance, anti-inflammatory, and improvement of the intestinal barrier. However, the underlying mechanisms remain unclear. Here, we found that gavage of L. reuteri improved the intestinal barrier and glucose homeostasis in HFD-fed mice. Analysis of lipid metabolomics reveals a significant increase in eicosatrienoic acid (ETA) levels in mouse feces after L. reuteri gavage. We found that ETA maintain intestinal barrier integrity and improve glucose homeostasis by promoting GLP-1 secretion. Mechanistically, by using CD36 inhibitor in vivo and CD36 knockdown STC-1 cells in vitro , we elucidate that ETA activates intestinal CD36-activated PLC/IP3R/Ca 2+ signaling to promote GLP-1 secretion. In vivo administration of GLP-1R inhibitor and in vitro intestinal organoid experiments demonstrate that GLP-1 upregulates the PI3K/AKT/HIF-1α pathway by GLP-1R and increases intestinal tight junction protein expressions, which in turn enhance the intestinal barrier integrity, reduce serum LPS level, attenuate inflammation in white adipose tissue (WAT), and ultimately improve glucose homeostasis in HFD and db/db mice. Our study elucidates for the first time the mechanism by which L. reuteri and its enriched metabolite ETA inhibit WAT inflammation by ameliorating the intestinal barrier, ultimately improving glucose homeostasis, and provides a new treatment strategy for T2D.

Enoyl coenzyme A hydratase 1 (ECH1) is a secreted protein implicated in numerous metabolic disorders, yet its role in the pathogenesis of atherosclerosis remains unclear. In this study, we found higher serum ECH1 levels in coronary artery disease (CAD) patients and apolipoprotein E (ApoE) -/- mice on a western diet for 12 weeks. In vivo, aorta and aortic sinus histological staining revealed that intraperitoneal injection of recombinant ECH1 reduced aortic lesions, inflammation, and macrophage infiltration in ApoE -/- mice. In vitro, incubating peritoneal macrophages with recombinant ECH1 protein reduced oxidized low-density lipoprotein uptake and increased macrophage migration. Mechanically, we observed that recombinant ECH1 incubation led to a reduction in the protein levels of scavenger receptor cluster of differentiation 36 (CD36) in primary macrophages through the promotion of CD36 protein degradation. Additionally, we found that chloroquine (CQ), a lysosomal inhibitor, mitigated this pro-degradation effect. Taken together, our findings provide unique evidence that ECH1 can attenuate the severity of atherosclerotic plaques, especially improving the stability of plaques, by decreasing macrophage infiltration. ECH1 demonstrates its protective effect by enhancing the lysosome-dependent degradation of CD36, suggesting its potential as a viable target for the prevention and treatment of atherosclerosis., Competing Interests: Conflict of interest None., (Copyright © 2024. Published by Elsevier Inc.)

The polyunsaturated fatty acid docosahexaenoic acid (DHA) significantly influences fish growth and lipid metabolism. Nevertheless, the specific mechanism by which DHA is transported and exerts its effects remains unclear. Scavenger receptor class B type I (SCARB1) is essential for maintaining cellular cholesterol levels and regulating the immune system in mammals, as well as facilitating the uptake of fatty acids (FAs). Another class B scavenger receptor, cluster-determinant 36 (CD36), is involved in promoting the uptake and transport of long-chain fatty acids. However, the molecular characteristics of the grass carp scarb1 gene have not yet been reported, and the potential role of Scarb1 and Cd36 in mediating DHA transport and metabolism remains uncertain. This study aimed to investigate the effects of Scarb1 and Cd36 on DHA transport. Initially, grass carp scarb1-1 and scarb1-2 were cloned. Predictions were made regarding their structural characteristics, including number and presence of transmembrane domains and glycosylation sites. Furthermore, gene structure analysis revealed that scarb1-1 has two additional exons in the 3'-region compared to scarb1-2. The multiple sequence alignment indicated that Scarb1 exhibits conserved motifs and amino acid residues across vertebrates. mRNA expression of scarb1-1 was the highest in the intestine, while scarb1-2 was highest expressed in adipose tissue, with both having lower expression levels in muscle tissue. Scarb1-1 was primarily localized on the cell membrane, whereas Scarb1-2 was found in both the cell membrane and cytoplasm. After overexpression of grass carp Scarb1-1, Scarb1-2, and Cd36 in HEK 293 T cells, DHA incubation showed that only Cd36 significantly increased cellular DHA relative content, suggesting a potential role of Cd36 in DHA transport. These findings will serve as a basis for further research on fatty acid transport in fish., Competing Interests: Declaration of competing interest This study was supported by College of Animal Science and Technology, Northwest Agriculture and Forestry University. The authors disclose no conflicts of interest. All the authors listed have approved to submit to your journal., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: To investigate the role of N-glycosylation modification of proteins in adipocyte differentiation during the adipogenic process., Methods: SVF cells and adipocytes were analyzed for proteomics and intact N-glycopeptide modificationomics.Differential expression of proteins, glycoforms, and sites between the two groups was screened and subjected to Gene Ontology (GO) functional enrichment analysis, KEGG pathway enrichment analysis, and protein-protein interaction (PPI) network analysis. The top 20 most significantly differentially expressed adipogenic differentiation-related proteins were identified, and the most pronouncedly altered proteins were analyzed for glycoforms, glycan chains, and sites., Results: Proteomics analysis identified 39,392 peptides and 5208 proteins, while intact N-glycopeptide modification profiling identified 3293 intact glycopeptides, 426 proteins, and 161 glycan chains. Proteomics identified 2510 differentially expressed proteins, with CD36 (Cluster of Differentiation 36, CD36) significantly upregulated. In adipocytes, CD36 had 4 N-glycosylation sites: N79, N220, N320, N417, with N320 being a newly identified site. GO enrichment results indicated that CD36 is associated with fatty acid oxidation, lipid oxidation, and fatty acid uptake into cells., Conclusion: Multiple proteins undergo N-glycosylation modification during adipocyte differentiation, with CD36, a fatty acid translocase, being significantly expressed in adipocytes. This suggests that N-glycosylation modification of CD36 may play a crucial role in adipocyte differentiation, providing a foundation for further investigation into the function of CD36 N-glycosylation in adipocyte differentiation., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Genetic variations in taste receptors are associated with gustatory perception and obesity, which in turn affects dietary preferences. Given the increasing tendency of people with obesity choosing sweet, high-fat meals, the current study assessed the cross-regulation of two polymorphisms of the sweet taste receptor (T1R2/T1R3), rs35874116 and rs307355, on fat sensitivity in Indian adults. We investigated the association between taste sensitivity and BMI in the T1R2, T1R3, and CD36 polymorphic and non-polymorphic groups. The general labelled magnitude scale (gLMS) was used to assess the taste sensitivity of 249 participants in addition to anthropometric data. TaqMan Probe-based RT-PCR was employed to determine the polymorphisms. Additionally, the colorimetric method utilizing 3, 5-dinitro salicylic acid was used to evaluate the participants' salivary amylase activity. The mean detection thresholds for linoleic acid (LA) and sucrose were greater in individuals with obesity (i.e., 0.97 ± 0.08 mM and 0.22 ± 0.02 M, respectively) than in healthy adults (p < 0.0001), indicating lower sensitivity. Moreover, it was found that a greater proportion of persons with obesity fall into the polymorphic groups (i.e., 52% with genotype CD36 AA, 44% with genotype T1R2 CC, and 40% with genotype T1R3 TT). All three single nucleotide polymorphisms support the Hardy-Weinberg equilibrium (p = 0.78). The Pearson correlation analysis between LA and the sucrose detection threshold revealed a significant (p < 0.0001) positive relationship with an r value of 0.5299. Moreover, salivary amylase activity was significantly (p < 0.05) higher in the polymorphic sub-groups. The results of our study imply that genetic variations in T1R2/T1R3 receptors affect perception of both sweetness and fat, which may have an effect on obesity., Competing Interests: Declarations. Conflict of interest: The authors have no relevant financial or non-financial interests to disclose. The authors declare no competing interests. Ethics approval: This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Bharathiar University Human Ethics Committee (Proposal No. BUHEC-051/2020 dated 30.01.2020). Consent to participate: Informed consent was obtained from all individual participants included in the study., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

VPS28 (vacuolar protein sorting 28) is a subunit of the endosomal sorting complexes required for transport (ESCRTs) and is involved in ubiquitination. Ubiquitination is a critical system for protein degradation in eukaryotes. Considering the recent findings on the role of ubiquitination in the regulation of lipid metabolism, we hypothesized that VPS28 might affect the expression of genes involved in milk fat synthesis. To test this hypothesis, we modulated VPS28 expression in the bovine mammary epithelial cell line (MAC-T) and measured the effects on triglyceride (TG) synthesis using lentivirus-mediated techniques. The results showed that VPS28 knockdown significantly upregulated the levels of the fatty acid transporter CD36 molecule (CD36) and adipose differentiation-related protein (ADFP), leading to increased TG and fatty acid production, along with elevated ubiquitin (UB) levels, while reducing proteasome activity. In contrast, VPS28 overexpression increased CD36 levels while not significantly affecting ADFP or TG levels, with a trend toward reduced lipid droplets and increased UB expression and proteasome activity. In addition, inhibition of the ubiquitin-proteasome system and the endosomal-lysosomal pathway using epoxomicin and chloroquine, respectively, further increased CD36, ADFP, and TG levels, thereby enhancing cell viability. These in vitro findings were validated in vivo in a mouse model, where VPS28 knockdown increased mammary CD36, ADFP, UB expression, TG content, and lipid droplets without pathological changes in mammary tissue or blood TG alterations. These results confirm the pivotal role of VPS28 in regulating TG synthesis via the ubiquitination pathway, offering novel insights into the molecular mechanisms of milk fat production in a bovine cell model., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Our study examined the relationships and interactions among 30 genes related to the NOD-like receptor protein 3 (NLRP3) inflammasome. We identified 368 interconnections between these 30 genes, with NLRP3 participating in 38 interactions. The potential roles of these genes in atherosclerosis were evaluated based on protein-protein interaction networks and coexpression analysis. We identified differential expression in 20 genes, five of which were significantly upregulated: P2RX7, CASP1, CD36, GBP5, and PYCARD. We also observed a strong positive association between P2RX7 and PYCARD and as a notable negative association between RELA and CD36. Furthermore, our analysis revealed a clear association between the expression of inflammasome-associated genes and immune cell infiltration in disease specimens. To diagnose AS, a logistic regression model based on six inflammasome-related genes, achieved an Area under the curve of 0.996, indicating excellent diagnostic performance. Genomic enrichment analysis indicated that inflammasome-related genes were primarily involved in various pathways, such as hypertrophic cardiomyopathy and ribosomal function. To validate our findings, we confirmed the expression of risk genes in AS cells using qRT-PCR and Western blot techniques. Additionally, we observed a shift toward M2 polarization in THP-1 macrophages upon P2RX7 knockdown, further supporting our findings., Competing Interests: Declarations. Consent for publication: All authors provide consent for publication. Conflict of interest: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder that affects women of reproductive age and is characterized by menstrual irregularities, metabolic imbalances and infertility. The pathogenesis of PCOS is complex and not fully understood, and chronic inflammation and insulin resistance are implicated in its progression. In this study, we investigated the role of m 6 A methylation, an important epigenetic modification, in the pathogenesis of PCOS. Using methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RNA sequencing (RNA-seq), we mapped the m 6 A methylation profile in granulosa cells from patients with PCOS and identified a significant regulatory effect on gene expression. CD36 is a novel m 6 A-regulated gene that may facilitate the progression of PCOS. We demonstrated that METTL3, an m 6 A methyltransferase, modulated CD36 expression and influenced glucose metabolism and inflammatory responses in PCOS. Employing KGN cells as a model of insulin resistance, we observed that CD36 knockdown ameliorated the impaired glucose uptake and significantly reduced the production of pro-inflammatory cytokines. These findings are consistent with the results of CD36 inhibition in a mouse model of PCOS, indicating a role of CD36 in modulating the disease phenotype. Our study delineates a previously unrecognized epigenetic mechanism involving m 6 A methylation in PCOS, highlighting the potential of targeting the METTL3-CD36 axis as a therapeutic strategy for managing ovarian inflammation and metabolic dysregulation in patients with PCOS., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The type 2 scavenger receptor CD36 functions not only as a long chain fatty acid transporter, but also as a pro-inflammatory mediator. Ceramide is the simple N-acylated form of sphingosine and exerts distinct biological activity depending on its acyl chain length. Six ceramide synthases (CerS) in mammals determine the chain length of ceramide species, and CerS6 mainly produces C16-ceramide. Endotoxin-induced septic shock shows high mortality, but the pathophysiologic role of sphingolipids involved in this process has been hardly investigated. This paper aims to highlight the different role of CerS isoforms in endotoxin-induced inflammatory responses and the regulatory role of CD36 in CerS6 protein degradation with an emphasis as the potential therapeutic candidates in humans. Lipopolysaccharide (LPS), the endotoxin of the Gram-negative bacterial cell wall, was treated to induce endotoxin-induced inflammation both in vitro and in vivo. CerS6-derived C16-ceramide propagated LPS-induced inflammatory responses activating various intracellular signaling pathways, such as mitogen-activated protein kinase and nuclear factor-κB, resulting in the formation of inflammasome complex and pro-inflammatory cytokines. Mechanistically, CerS6-derived C16-ceramide augmented inflammatory responses via endoplasmic reticulum stress, and CerS6 protein stability was regulated by CD36. Finally, CerS6 protein expression and LPS-induced lethality were strikingly reduced in CD36 knockout mice. Collectively, our findings show that CerS6-derived C16-ceramide plays a pivotal role in endotoxin-induced inflammation and suggest CerS6 and its regulator CD36 as possible targets for therapy under life-threatening inflammation such as septic shock., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Schistosomiasis is characterized by egg-induced hepatic granulomas and subsequent fibrosis. Monocyte-derived macrophages play critical and plastic roles in the progression and regression of liver fibrosis, adopting different polarization phenotypes. Mammalian STE20-like protein kinase 1 (MST1), a serine/threonine kinase, has been established to act as a negative regulator of macrophage-associated inflammation. However, the specific role of MST1 in Schistosoma-induced liver fibrosis has not been fully understood. In this study, we demonstrate that macrophage MST1 functions as an inhibitor of inflammation and fibrosis following infection with Schistosoma japonicum (S. japonicum). Mice with macrophages-specific Mst1 knockout (termed Mst1△M/△M) mice developed exacerbated liver pathology, characterized by larger egg-induced granulomas, and increased fibrosis post infection. This was accompanied by enhanced production of proinflammatory cytokines (IL1B, IL6, IL23, TNFA and TGFB) and a shift in macrophage phenotype towards Ly6Chigh. Mechanistically, MST1 activation by soluble egg antigen (SEA) promoted PPARγ-mediated CD36 expression, enhancing phagocytosis and consequently upregulation of fibrolytic genes such as Arg1 and Mmps. Conversely, MST1 deletion leads to up-regulation of pro-inflammatory genes instead of fibrolytic genes in macrophages, accompanied by decreased expression of CD36 and impaired phagocytosis. Furthermore, the ablation of MST1 enhances NF-κB activation in S. japonicum-infected and SEA-stimulated macrophages, resulting in increased production of proinflammatory cytokines. Overall, our data identified MST1 as a novel regulator for egg-induced liver fibrosis via modulation of macrophage function and phenotype by CD36-mediated phagocytosis and suppression of NF-κB pathway., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Li et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Once thought to be in a terminally differentiated state, macrophages are now understood to be highly pliable, attuned and receptive to environmental cues that control and align responses. In development of purpose, the centrality of metabolic pathways has emerged. Thus, macrophage inflammatory or reparative phenotypes are tightly linked to catabolic and anabolic metabolism, with further fine tuning of specific gene expression patterns in specific settings. Single-cell transcriptome analyses have revealed a breadth of macrophage signatures, with some new influencers driving phenotype. CD36/Scavenger Receptor B2 has established roles in immunity and lipid metabolism. Macrophage CD36 is a key functional player in metabolic expression profiles that determine phenotype. Emerging data show that alterations in the microenvironment can recast metabolic pathways and modulate macrophage function, with the potential to be leveraged for therapeutic means. This review covers recent data on phenotypic characterization of homeostatic, atherosclerotic, lipid-, tumor- and metastatic-associated macrophages, with the integral role of CD36 highlighted., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Chen, Zhang, Huang and Febbraio.)

Previous studies showed that serum amyloid A (SAA) and macrophages were associated with allergic airway inflammation. However, the interaction between SAA1 and macrophages in allergic airway inflammation remains to be further elucidated. In this study, the levels of SAA1 were measured in nasal tissues from patients with eosinophilic chronic rhinosinusitis with nasal polyps (CRSwNP), house dust mite (HDM)-treated BEAS-2B cells and the tissues of mice of HDM-induced allergic airway inflammation. Human monocytes-derived macrophages and mouse bone marrow-derived macrophages (BMDMs) were exposed to SAA1, and CCL17 and the other M1/M2-related factors were evaluated using RT-PCR and/or ELISA. To test the effects of SAA1-treated BMDMs on chemotaxis and differentiation of CD4 + T cells, number of migrated cells and the levels of Th1 and Th2 were measured using flow cytometry. SAA1 receptors were examined in BMDMs and lung macrophages of model mice. CD36 neutralizing antibody was applied to explore the mechanisms of SAA1 in regulating BMDMs using RT-PCR and/or ELISA. We found that SAA1 was expressed in epithelial cells, and was increased in the nasal tissues of patients with eosinophilic CRSwNP and HDM-treated BEAS-2B- cells as well as the bronchoalveolar lavage fluid and lung tissues of mice exposed to HDM. We also found that the level of CCL17 was increased in M2 macrophages, more CD4 + T cells were recruited and proportion of Th2 was increased after the treatment of SAA1. The treatment of CD36 neutralizing antibody decreased CCL17 level in SAA1-treated M2 BMDMs. In summary, our results showed that SAA1 was increased in allergic airway inflammation, and the administration of SAA1 upregulated the expression of CCL17 in M2 macrophages via CD36 and promoted the chemotaxis of CD4 + T cells and differentiation of Th2. It may provide a new therapeutic strategy that could mediate allergic airway inflammation via suppressing SAA1 to reduce recruitment of CD4 + T cells and activation of Th2., (Copyright © 2024. Published by Elsevier B.V.)

This experiment investigated the effects of an ecologically relevant level of dim light at night (dLAN) on behavior, physiology and fat metabolism associated gene expressions in central and peripheral tissues of adult male zebra finches that were hatched and raised in 12:12 h LD cycle (Ev, day = 150 ± 5 lx; Ev, night = 0 lx) at 22 ± 2 °C temperature. Half of the birds (n = 8) were maintained on LD cycle and temperature, as before (control), to the other half of birds the 12 h dark period was dimly illuminated at ~ 5 lx (dim light at night, dLAN; Ev, day = 150 ± 5 lx; Ev, night =  ~ 5 lx) for 6 weeks. The exposure to dLAN altered the 24 h activity and feeding patterns with enhanced activity and feeding at night. Birds under dLAN fattened and gained weight, and had higher night glucose levels. Concurrently, a negative effect of dLAN was found on mRNA expression of ppar-alpha and cd36 genes involved in the fat metabolism in the hypothalamus, intestine, liver and muscle. These results suggest a more global effect of dLAN exposure on obesity and perhaps long-term health risks due to obesity-related complications to diurnal animals including humans inhabiting an urbanized environment., Competing Interests: Declarations. Conflict of interest: The authors have no competing interests to declare that are relevant to the content of this article. Ethical approval: The experiments were performed as per the approval and guidelines of the Institutional Ethics Committee of Chaudhary Charan Singh University, Meerut, India (Protocol # IAEC-2022/08)., (© 2024. The Author(s), under exclusive licence to the European Photochemistry Association, European Society for Photobiology.)

Mule ducks accumulate a large amount of fat in their livers when fed high-energy feed, which is predominantly used for producing fatty livers. Nevertheless, there is limited research on the molecular mechanisms underlying the formation of fatty liver in mule ducks. Fatty acid translocase (CD36) is a sensor for fatty acids and lipid metabolism regulator, which may play a crucial role in the accumulation of fat in the liver of mule ducks. In this study, Overexpression and CD36 gene interference for 24 h was followed by induction of liver cells with 400 µmol/L palmitic acid (PA) for 24 h. The results demonstrated that CD36 overexpression increased hepatic triglyceride content, lipid droplet deposition, oxidative stress, and cell apoptosis. However, interference with CD36 had the opposite effect. CD36 overexpression suppressed the expression of AMPK and CPT-1A genes but enhanced the expression of ACC1 and LKB1 genes, with interference yielding contrasting results. Additionally, the expression of CD36 inhibited the AMPK pathway, reduced AMPK phosphorylation, downregulated AMPK protein expression, and upregulated SREBP1 protein expression. This promoted palmitic acid-induced hepatocyte fat accumulation. In summary, CD36 promotes palmitic acid-induced fat accumulation in primary mule duck liver cells through the AMPK signaling pathway., Competing Interests: DISCLOSURES The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ying-Xiu Hu reports financial support was provided by Science and Technology Innovation Special Fund of Fujian Agriculture and Forestry University. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

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., Competing Interests: Declaration of competing interest The authors confirm that there are no conflicts of interest., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Objective: To investigate the effect of zedoarondiol on neovascularization of atherosclerotic (AS) plaque by exosomes experiment., Methods: ApoE -/- mice were fed with high-fat diet to establish AS model and treated with high- and low-dose (10, 5 mg/kg daily) of zedoarondiol, respectively. After 14 weeks, the expressions of anti-angiogenic protein thrombospondin 1 (THBS-1) and its receptor CD36 in plaques, as well as platelet activation rate and exosome-derived miR-let-7a were detected. Then, zedoarondiol was used to intervene in platelets in vitro, and miR-let-7a was detected in platelet-derived exosomes (Pexo). Finally, human umbilical vein endothelial cells (HUVECs) were transfected with miR-let-7a mimics and treated with Pexo to observe the effect of miR-let-7a in Pexo on tube formation., Results: Animal experiments showed that after treating with zedoarondiol, the neovascularization density in plaques of AS mice was significantly reduced, THBS-1 and CD36 increased, the platelet activation rate was markedly reduced, and the miR-let-7a level in Pexo was reduced (P<0.01). In vitro experiments, the platelet activation rate and miR-let-7a levels in Pexo were significantly reduced after zedoarondiol's intervention. Cell experiments showed that after Pexo's intervention, the tube length increased, and the transfection of miR-let-7a minics further increased the tube length of cells, while reducing the expressions of THBS-1 and CD36., Conclusion: Zedoarondiol has the effect of inhibiting neovascularization within plaque in AS mice, and its mechanism may be potentially related to inhibiting platelet activation and reducing the Pexo-derived miRNA-let-7a level., Competing Interests: Conflict of Interest: No conflict of interest declared. Declaration of Figures Authenticity: All figures submitted have been created by the authors who confirm that the images are original with no duplication and have not been previously published in whole or in part., (© 2024. The Chinese Journal of Integrated Traditional and Western Medicine Press and Springer-Verlag GmbH Germany, part of Springer Nature.)

The host immune system is adapted in a variety of ways by tumour microenvironment and growing tumour interacts to promote immune escape. One of these adaptations is manipulating the metabolic processes of cells in the tumour microenvironment. The growing tumour aggressively utilise glucose, its primary energy source available in tumour site, and produce lactate by Warburg effect. In such a hostile environment, tumour-infiltrating immune cells are unable to survive metabolically. Tumour-infiltrating CD4 + Treg cells, on the other hand, adapted to an alternative energy-generating system, switching from the highly-competitive glucose to the fatty-acid metabolic pathway, by down-regulating glucose-metabolising genes and up-regulating fatty-acid metabolising genes. Tregs with high-levels of the fatty acid scavenger receptor CD36, a key component of the fatty-acid metabolic pathway, aided this metabolic shift. Treg cell formation was hampered when the fatty-acid metabolic pathway was disrupted, showing that it is necessary for Treg cell development. FOXP3, the Treg lineage-specific transcription factor, regulates fatty-acid metabolism by inducing CD36 transcription. A high-fat diet enhanced Treg development while suppressing anti-tumour immunity, whereas a low-fat diet suppressed Treg development. The altered metabolism of tumour-infiltrating Treg cells enables their rapid generation and survival in the hostile tumour microenvironment, aiding cancer progression. Fascinatingly, mice fed with a low-fat diet showed a positive prognosis with chemotherapy than mice fed with a high-fat diet. Thus, a maximum efficacy of chemotherapy might be achieved by altering diet composition during chemotherapy, providing a promising indication for future cancer treatment., (© 2024 John Wiley & Sons Ltd.)

Aims/hypothesis: Microvascular dysfunction contributes to insulin resistance. CD36, a fatty acid transporter and modulator of insulin signalling, is abundant in microvascular endothelial cells. Humans carrying the minor allele (G) of CD36 coding variant rs3211938 have 50% reduced CD36 expression and show endothelial dysfunction. We aimed to determine whether G allele carriers have microvascular resistance to insulin and, if so, how this affects glucose disposal., Methods: Our multi-disciplinary approach included hyperinsulinaemic-euglycaemic clamps in Cd36 -/- and wild-type mice, and in individuals with 50% CD36 deficiency, together with control counterparts, in addition to primary human-derived microvascular endothelial cells with/without CD36 depletion., Results: Insulin clamps showed that Cd36 -/- mice have enhanced insulin-stimulated glucose disposal but reduced vascular compliance and capillary perfusion. Intravital microscopy of the gastrocnemius showed unaltered transcapillary insulin flux. CD36-deficient humans had better insulin-stimulated glucose disposal but insulin-unresponsive microvascular blood volume (MBV). Human microvascular cells depleted of CD36 showed impaired insulin activation of Akt, endothelial NO synthase and NO generation. Thus, in CD36 deficiency, microvascular insulin resistance paradoxically associated with enhanced insulin sensitivity of glucose disposal., Conclusions/interpretation: CD36 deficiency was previously shown to reduce muscle/heart fatty acid uptake, whereas here we showed that it reduced vascular compliance and the ability of insulin to increase MBV for optimising glucose and oxygen delivery. The muscle and heart respond to these energy challenges by transcriptional remodelling priming the tissue for insulin-stimulated glycolytic flux. Reduced oxygen delivery activating hypoxia-induced factors, endothelial release of growth factors or small intracellular vesicles might mediate this adaptation. Targeting NO bioavailability in CD36 deficiency could benefit the microvasculature and muscle/heart metabolism., Trial Registration: Clinicaltrials.gov NCT03012386 DATA AVAILABILITY: The RNAseq data generated in this study have been deposited in the NCBI Gene Expression Omnibus ( www.ncbi.nlm.nih.gov/geo/ ) under accession code GSE235988 ( https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE235988 )., Competing Interests: Acknowledgements: We acknowledge the help of R. Mecham (Washington University) with measurements of vessel compliance in Cd36−/− mice and the help of S. C. Beeman (Arizona State University) with ASL MRI of microvascular perfusion in the kidney. Dr. David Wasserman died on 20 June 2024 from health issues. David was the Annie Mary Lyle Professor of Molecular Physiology and Biophysics at Vanderbilt University, he contributed groundbreaking research to our understanding of the factors that regulate glucose metabolism by various organs. He also founded and directed the Mouse Metabolic Phenotyping Center, which became an international resource for studying mouse metabolism. This manuscript is dedicated to his memory as a wonderful scientist, collaborator and friend. Data availability: The RNAseq data generated in this study have been deposited in the NCBI Gene Expression Omnibus ( www.ncbi.nlm.nih.gov/geo/ ) under accession code GSE235988 ( https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE235988 ). Microarray data are available as ESM Table 2. All other data analysed for this study are available from the corresponding author upon request. Funding: We acknowledge support from the National Institute of Health (RO1DK111175 [NAA, CAS, NNA]); NHLBI R01HL157584 [CAS]; NHLBI R01 HL045095 [IJG, NAA]), Clinical Translational Science Award (CAS) and assistance from Vanderbilt Institute for Clinical and Translational Sciences (5UL1TR002243-03) and Washington University Nutrition and Obesity Center (NORC, P30 DK056341). Authors’ relationships and activities: The authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work. Contribution statement: CAS and NNA designed the human studies. CAS recruited participants, performed the insulin clamps and CAS and NNA analysed the data. VSP designed, performed and analysed all cell studies. DHW and IMW designed, performed and analysed the mice insulin clamps and insulin flux experiments. DS designed, performed and analysed the mice metabolic studies. TP performed the human genotyping, the vessel compliance assays, the immunohistochemistry and gene expression studies, and analysed the RNAseq and microarray data. CAS, VSP, TP, DS, IMW and DHW reviewed and edited the manuscript. NNA and IJG contributed to study design and to data interpretation and critically reviewed the manuscript. ERG designed the PrediXcan approach to query the Vanderbilt BioVu patient biobank, collected and analysed the PrediXcan data and edited the manuscript. All authors approved the final manuscript version. NAA conceived and designed the study, analysed the data, wrote the manuscript and is the guarantor of this work., (© 2024. The Author(s).)

Ovarian cancer (OC) is prone to peritoneum or omentum dissemination, thus giving rise to the formidable challenge of unresectable surgery and a dismal survival rate. Although niraparib holds a pivotal role in the maintenance treatment of OC, its effect on suppressing metastases during primary intervention remains enigmatic. Recently, we initiated a prospective clinical study (NCT04507841) in order to evaluate the therapeutic efficacy of neoadjuvant niraparib monotherapy for advanced OC with homologous recombination deficiency. An analysis of patient tumor burden before and after the niraparib challenge showed a remarkable vulnerability of OC intraperitoneal metastases to niraparib exposure. This killing capacity of niraparib was closely associated with the accumulation of fatty acids within the abdomen, which was confirmed by the increased susceptibility of tumor cells to niraparib treatment in the presence of fatty acids. In the context of abundant fatty acids, niraparib elevated intracellular levels of fatty acids and lipid peroxidation, leading to subsequent tumor cell ferroptosis in a p53 and BRCA-independent manner. Notably, under niraparib exposure, a critical fatty acid transporter CD36 was dramatically upregulated in tumors, facilitating excessive uptake of fatty acids. Pharmacological inhibition of either ferroptosis or CD36 impaired the anti-tumor activity of niraparib both in vitro and in murine intraperitoneal ID8 tumor models. Our findings demonstrate ferroptosis as a novel mechanism underlying the regression of OC metastases induced by niraparib, thereby offering tantalizing prospects for the frontline application of this agent in the management of OC., Competing Interests: Declaration of competing interest All authors disclosed no relevant relationships., (Copyright © 2025 The Authors. Published by Elsevier B.V. All rights reserved.)

Sodium-dependent glucose cotransporter-2 (SGLT2) inhibitors, antidiabetic drugs that reduce blood sugar levels by inhibiting glucose reabsorption in the renal proximal tubules, also ameliorate nonalcoholic fatty liver disease (NAFLD). This study aimed to examine the effects of SGLT2 inhibition on hepatic steatosis and nonalcoholic steatohepatitis (NASH) using an in vitro model of NAFLD progression. HepG2 cells and a coculture of Hepa1c1c7 and Raw 264.7 cells were treated with 400 μM palmitic acid (PA), followed by treatment with or without 10 μM empagliflozin and dapagliflozin. In HepG2 cells, PA increased hepatic lipid accumulation, the expression of pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β), exocytosis mediators (VAMP3 and SNAP23), and ER stress markers (GRP78, PERK, IRE1α, ATF6, ATF4, and CHOP), and the gene and protein expression of CD36. SGLT2 inhibitors reversed the effects of PA. SGLT2 inhibition via siRNA reduced proinflammatory-cytokine gene expression in thapsigargin-treated HepG2 cells. Transfection with CD36 siRNA reversed the elevated ATF4 and CHOP expression in PA-treated HepG2 cells. SGLT2 inhibition via an SGTL2 inhibitor and SGLT2 siRNA reduced CD36, Tnf-α, Il-6, Il-1β, Vamp2, Snap23, Atf4, and Chop expression in the PA-treated Hepa1c1c7-Raw 264.7 cell coculture and suppressed Tnf-α release in the Hepa1c1c7-Raw 264.7 cell coculture treated with lipopolysaccharide and PA. These findings indicate that SGLT2 inhibitors inhibited NAFLD progression by reducing hepatic lipid accumulation and inflammation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Lipid uptake by white adipose tissue (WAT) is critically important for storage of excess energy and to protect peripheral tissues from ectopic lipid deposition. When WAT becomes dysfunctional (i.e., with obesity), it is characterized by impaired lipid uptake and increased lipolysis which, together, promote whole-body dyslipidemia. Omega-3 polyunsaturated fatty acids (N-3 PUFA) are widely studied for their triacylglycerol (TAG)-lowering properties and cardiometabolic health benefits. One potential mechanism underlying these benefits is the modification of WAT lipid uptake; however, there are gaps in our understanding regarding the specific mechanisms by which N-3 PUFA function. Evidence to date suggests that N-3 PUFA promote TAG clearance by increasing lipoprotein lipase (LPL) activity and the abundance of fatty acid transporters. Specifically, N-3 PUFA have been shown to increase LPL activity through increased gene transcription and modifications of endogenously produced LPL regulators such as apolipoprotein C-II/III and angiopoietin-like proteins. This review presents and discusses the available in vitro and in vivo research to provide a comprehensive overview of N-3 PUFA regulation of WAT lipid uptake in healthy and obese contexts. Additionally, we highlight areas where more research is necessary to better understand the contribution of increased WAT lipid uptake in relation to the TAG-lowering properties associated with N-3 PUFA., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Activation of pericytes leads to renal interstitial fibrosis, but the regulatory mechanism of pericytes in the progression from AKI to CKD remains poorly understood. CD36 activation plays a role in the progression of CKD. However, the significance of CD36 during AKI-CKD, especially in pericyte, remains to be fully defined., Methods: GEO and DISCO database were used to analyze the expression of CD36 in pericyte during AKI-CKD; IRI to conduct AKI-CKD mouse model; Hypoxia/Reoxygenation (H/R) to induce the cell model; RT-qPCR and Western blotting to detect gene expression; IP and confocal-IF to determine the core fucosylation (CF) level of CD36. Flow cytometry (AV/PI staining) to detect the cell apoptosis and JC-1 staining to react to the change of mitochondrial membrane potential., Results: During AKI to CKD progression, CD36 expression in pericytes is higher and may be influenced by CF. Moreover, we confirmed the positive association of CD36 expression with pericyte-myofibroblast transition and the progression of AKI-CKD in an IRI mouse model and hypoxia/reoxygenation (H/R) pericytes. Notably, we discovered that FUT8 upregulates both CD36 expression and its CF level, contributing to the activation of the mitochondrial-dependent apoptosis signaling pathway in pericytes, ultimately leading to the progression of AKI-CKD., Conclusion: These results further identify FUT8 and CD36 as potential targets for the treatment in the progression of AKI-CKD., Competing Interests: Declarations Ethical approval The animal study protocol was approved by the Ethics Committee of Dalian Medical University (protocol code Doc. No. AEE24009). Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Background: Pulmonary arterial hypertension (PAH) is characterized by lipid accumulation and mitochondrial dysfunction. This study was designed to investigate the effects of hypoxia-inducible factor-1α (HIF-1α) on fatty acid uptake and mitophagy in PAH., Methods: Peripheral blood samples were obtained from PAH patients. Human pulmonary arterial smooth muscle cells and rat cardiac myoblasts H9c2 were subjected to hypoxia treatment. Male Sprague-Dawley rats were treated with monocrotaline (MCT). Right ventricular systolic pressure (RVSP), right ventricular hypertrophy index (RVHI), pulmonary artery remodeling, and lipid accumulation were measured. Cell proliferation and ROS accumulation were assessed. Mitochondrial damage and autophagosome formation were observed. Co-immunoprecipitation was performed to verify the interaction between HIF-1α and CD36/PI3K p85α., Results: HIF-1α, CD36, Parkin, and PINK1 were upregulated in PAH samples. HIF-1α knockdown or PI3K p85α knockdown restricted the expression of HIF-1α, PI3K p85α, Parkin, PINK1, and CD36, inhibited hPASMC proliferation, promoted H9c2 cell proliferation, reduced ROS accumulation, and suppressed mitophagy. CD36 knockdown showed opposite effects to HIF-1α knockdown, which were reversed by palmitic acid. The HIF-1α activator dimethyloxalylglycine reversed the inhibitory effect of Parkin knockdown on mitophagy. In MCT-induced rats, the HIF-1α antagonist 2-methoxyestradiol (2ME) reduced RVSP, RVHI, pulmonary artery remodeling, lipid accumulation, and mitophagy. Recombinant CD36 abolished the therapeutic effect of 2ME but inhibited mitophagy. Activation of Parkin/PINK1 by salidroside (Sal) promoted mitophagy to ameliorate the pathological features of PAH-like rats, and 2ME further enhanced the therapeutic outcome of Sal., Conclusion: PI3K p85α/HIF-1α induced CD36-mediated fatty acid uptake and Parkin/PINK1-dependent mitophagy to accelerate the progression of experimental PAH., Competing Interests: Declarations Ethics approval and consent to participate This study was approved by The IRB of Third Xiangya Hospital, Central South University (2020-S109), and written informed consent was obtained from each participant. The usage of the clinical samples was performed in accordance with the Declaration of Helsinki. All animal procedures were approved by the Animal Welfare Ethics Committee of the Third Xiangya Hospital, Central South University (2020sydw0211), and these experiments were in accordance with the ARRIVE guidelines. Consent for publication Written informed consent was obtained, and participants knew and agreed with the usage of their samples. Competing interests The authors have no conflict of interest to declare., (© 2024. The Author(s).)

Glioblastoma multiforme (GBM) is the most aggressive brain tumor with poor prognosis. A better understanding of mechanisms concerned in glioma invasion might be critical for treatment optimization. Given that epithelial-mesenchymal transition in tumor cells is closely associated with glioma progression and recurrence, identifying pivotal mediators in GBM EMT process is urgently needed. As a member of Fatty acid binding protein (FABP) family, FABP4 serves as chaperones for free fatty acids and participates in cellular process including fatty acid uptake, transport, and metabolism. In this study, our data revealed that FABP4 expression was elevated in human GBM samples and correlated with a mesenchymal glioma subtype. Gain of function and loss of function experiments indicated that FABP4 potently rendered glioma cells increased filopodia formation and cell invasiveness. Differential expression genes analysis and GSEA in TCGA dataset revealed an EMT-related molecular signature in FABP4-mediated signaling pathways. Cell interaction analysis suggested CD36 as a potential target regulated by FABP4. Furthermore, in vitro mechanistic experiments demonstrated that FABP4-induced CD36 expression promoted EMT via non-canonical TGFβ pathways. An intracranial glioma model was constructed to assess the effect of FABP4 on tumor progression in vivo. Together, our findings demonstrated a critical role for FABP4 in the regulation invasion and EMT in GBM, and suggest that pharmacological inhibition of FABP4 may represent a promising therapeutic strategy for treatment of GBM., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Polycystic ovary syndrome (PCOS) is a common metabolic and endocrine disorder characterized by abnormal elevation in hormone levels, with currently lacking effective treatment options. N-3 polyunsaturated fatty acids (PUFA) have broad pharmacological activity and play a beneficial role in the development of PCOS. In this study, we observed that n-3 PUFA-eicosatrienoic acid (ETA) improves the estrous cycle and ovarian morphology in dehydroepiandrosterone (DHEA)-induced PCOS mice, particularly serum hormone levels. Additionally, it suppresses the expression of CYP19A1 and E2 synthesis in human granulosa-like tumor cell line (KGN) cells. Further investigation revealed that ETA significantly upregulates the expression of CD36, cAMP, P-PKA, and FOXO1 in KGN cells and mouse ovaries to lower E2 levels. This conclusion was supported by inhibiting CD36 and FOXO1 at both the mouse and cellular levels. Additionally, ETA treatment decreased the expression of ESR1, Kiss1, Gnrh in the hypothalamus, and GnRHR, Lhβ, Egr1, Pitx1, Sf1 in the pituitary of PCOS mice. No differences were observed after ETA treatment in the CD36 and FOXO1 inhibitor groups, indicating that ETA improves PCOS mice by regulating the hypothalamic-pituitary axis through E2 synthesis inhibition. In summary, we have elucidated for the first time the mechanism by which CD36 regulates E2 synthesis in ovarian granulosa cells and demonstrated that ETA activates the CD36 receptor to inhibit E2 synthesis through the cAMP/PKA/FOXO1/CYP19A1 signaling pathway, thereby improving hormonal imbalance and treating PCOS. This provides a new strategy for the effective prevention and treatment of PCOS., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Babies born with fetal growth restriction (FGR) are at higher risk of developing cardiometabolic diseases across the life course. The reduction in substrate supply to the developing fetus that causes FGR not only alters cardiac growth and structure but may have deleterious effects on metabolism and function. Using a sheep model of placental restriction to induce FGR, we investigated key cardiac metabolic and functional markers that may be altered in FGR. We also employed phase-contrast magnetic resonance imaging MRI to assess left ventricular cardiac output (LVCO) as a measure of cardiac function. We hypothesized that signalling molecules involved in cardiac fatty acid utilisation and contractility would be impaired by FGR and that this would have a negative impact on LVCO in the late gestation fetus. Key glucose (GLUT4 protein) and fatty acid (FATP, CD36 gene expression) substrate transporters were significantly reduced in the hearts of FGR fetuses. We also found reduced mitochondrial numbers as well as abundance of electron transport chain complexes (complexes II and IV). These data suggest that FGR diminishes metabolic and mitochondrial capacity in the fetal heart; however, alterations were not correlated with fetal LVCO. Overall, these data show that FGR alters fetal cardiac metabolism in late gestation. If sustained ex utero, this altered metabolic profile may contribute to poor cardiac outcomes in FGR-born individuals after birth. KEY POINTS: Around the time of birth, substrate utilisation in the fetal heart switches from carbohydrates to fatty acids. However, the effect of fetal growth restriction (FGR) on this switch, and thus the ability of the fetal heart to effectively metabolise fatty acids, is not fully understood. Using a sheep model of early onset FGR, we observed significant downregulation in mRNA expression of fatty acid receptors CD36 and FABP in the fetal heart. FGR fetuses also had significantly lower cardiac mitochondrial abundance than controls. There was a reduction in abundance of complexes II and IV within the electron transport chain of the FGR fetal heart, suggesting altered ATP production. This indicates reduced fatty acid metabolism and mitochondrial function in the heart of the FGR fetus, which may have detrimental long-term implications and contribute to increased risk of cardiovascular disease later in life., (© 2023 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Foam cell formation plays a pivotal role in atherosclerosis-associated cardiovascular diseases. Bioactive peptides generated from marine sources have been found to provide multifunctional health advantages. In the present study, we investigated the anti-atherosclerotic effects of LLRLTDL (Bu1) and GYALPCDCL (Bu2) peptides, isolated from ark shell protein hydrolysates by assessing their inhibitory effect on oxidized LDL (oxLDL)-induced foam cell formation. The two peptides showed a promising anti-atherosclerotic effect by inhibiting foam cell formation, which was evidenced by inhibiting lipid accumulation in oxLDL-treated RAW264.7 macrophages and oxLDL-treated primary human aortic smooth muscle cells (HASMC). Two peptides effectively reduced total cholesterol, free cholesterol, cholesterol ester, and triglyceride levels by upregulating cholesterol efflux and downregulating cholesterol influx. Expression of cholesterol influx-related proteins such as SR-A1 and CD36 were reduced, whereas cholesterol efflux-related proteins such as ATP-binding cassette transporter ABCA-1 and ABCG-1 were highly expressed. In addition, Bu1 and Bu2 peptides increased PPAR-γ and LXR-α expression. However, PPAR-γ siRNA transfection reversed the foam cell formation inhibitory activity of Bu1 and Bu2 peptides. Furthermore, the synergistic effect of Bu1 and Bu2 peptides on foam cell formation inhibition was observed with PPAR-γ agonist thiazolidinediones, indicating that PPAR-γ signaling pathway plays a key role in foam cell formation of macrophages. Beyond their impact on foam cell formation, Bu1 and Bu2 peptides demonstrated anti-inflammatory potential by inhibiting the generation of pro-inflammatory cytokines and nitric oxide and NF-κB nuclear activation. Taken together, these results suggest that Bu1 and Bu2 peptides may be useful for atherosclerosis and associated anti-inflammatory therapies., (© 2024 International Union of Biochemistry and Molecular Biology.)

Background: Atherosclerosis is a progressive inflammatory disease in which macrophage foam cells play a central role in disease pathogenesis. SPA (surfactant protein A) is a lipid-associating protein involved with regulating macrophage function in various inflammatory diseases. However, the role of SPA in atherosclerosis and macrophage foam cell formation has not been investigated., Methods: SPA expression was assessed in healthy and atherosclerotic human coronary arteries and the brachiocephalic arteries of wild-type or ApoE-deficient mice fed high-fat diets for 4 weeks. Hypercholesteremic wild-type and SPA-deficient mice fed a high-fat diet for 6 weeks were investigated for atherosclerotic lesions in vivo. In vitro experiments using RAW264.7 macrophages, primary resident peritoneal macrophages extracted from wild-type or SPA-deficient mice, and human monocyte-derived macrophages from the peripheral blood of healthy donors determined the functional effects of SPA in macrophage foam cell formation., Results: SPA expression was increased in atherosclerotic lesions in humans and ApoE-deficient mice and in response to a proatherosclerotic stimulus in vitro. SPA deficiency reduced the lipid profiles induced by hypercholesterolemia, attenuated atherosclerosis, and reduced the number of lesion-associated macrophage foam cells. In vitro studies revealed that SPA deficiency reduced intracellular cholesterol accumulation and macrophage foam cell formation. Mechanistically, SPA deficiency dramatically downregulated the expression of scavenger receptor CD36 (cluster of differentiation antigen 36) cellular and lesional expression. Importantly, SPA also increased CD36 expression in human monocyte-derived macrophages., Conclusions: Our results elucidate that SPA is a novel factor promoting atherosclerosis development. SPA enhances macrophage foam cell formation and atherosclerosis by increasing scavenger receptor CD36 expression, leading to increasing cellular OxLDL influx., Competing Interests: None.

Age-related macular degeneration (AMD), the leading cause of irreversible blindness in the elderly, is primarily characterized by the degeneration of the retinal pigment epithelium (RPE). However, effective therapeutic options for dry AMD are currently lacking, necessitating further exploration into preventive and pharmaceutical interventions. This study aimed to investigate the protective effects of gastrodin on RPE cells exposed to oxidative stress. We constructed an in vitro oxidative stress model of 4-hydroxynonenal (4-HNE) and performed RNA-seq, and demonstrated the protective effect of gastrodin through mouse experiments. Our findings reveal that gastrodin can inhibit 4-HNE-induced oxidative stress, effectively improving the mitochondrial and lysosomal dysfunction of RPE cells. We further elucidated that gastrodin promotes autophagy and phagocytosis through activating the PPARα-TFEB/CD36 signaling pathway. Interestingly, these outcomes were corroborated in a mouse model, in which gastrodin maintained retinal integrity and reduced RPE disorganization and degeneration under oxidative stress. The accumulation of LC3B and SQSTM1 in mouse RPE-choroid was also reduced. Moreover, activating PPARα and downstream pathways to restore autophagy and phagocytosis, thereby countering RPE injury from oxidative stress. In conclusion, this study demonstrated that gastrodin maintains the normal function of RPE cells by reducing oxidative stress, enhancing their phagocytic function, and restoring the level of autophagic flow. These findings suggest that gastrodin is a novel formulation with potential applications in the development of AMD disease., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Deep single-cell multi-omic profiling offers a promising approach to understand and overcome drug resistance in relapsed or refractory (rr) acute myeloid leukemia (AML). Here, we combine single-cell ex vivo drug profiling (pharmacoscopy) with single-cell and bulk DNA, RNA, and protein analyses, alongside clinical data from 21 rrAML patients. Unsupervised data integration reveals reduced ex vivo response to the Bcl-2 inhibitor venetoclax (VEN) in patients treated with both a hypomethylating agent (HMA) and VEN, compared to those pre-exposed to chemotherapy or HMA alone. Integrative analysis identifies both known and unreported mechanisms of innate and treatment-related VEN resistance and suggests alternative treatments, like targeting increased proliferation with the PLK inhibitor volasertib. Additionally, high CD36 expression in VEN-resistant blasts associates with sensitivity to CD36-targeted antibody treatment ex vivo. This study demonstrates how single-cell multi-omic profiling can uncover drug resistance mechanisms and treatment vulnerabilities, providing a valuable resource for future AML research., (© 2024. The Author(s).)

Liraglutide, an analog of the incretin hormone glucagon-like peptide 1 (GLP-1), is widely used for obesity and type 2 diabetes treatment. However, there is scarce information about its effects on testicular function. Within the testis, Sertoli cells (SCs) provide nutritional support for germ cells; they metabolize glucose to lactate, which is delivered to germ cells to be used as a preferred energy substrate. Besides, SCs use fatty acids (FAs) as an energy source and store them as triacylglycerols (TAGs) within lipid droplets (LDs), which serve as an important energy reserve. In the present study, 20-day-old rat SC cultures were used to assess whether liraglutide affects their metabolic functions related to nutritional support and lipid storage. The results show that liraglutide does not modify glucose consumption or lactate production. However, it increases TAG levels and LD content. These effects are accompanied by an increase in the mRNA levels of the fatty acid transporter FAT/CD36, glycerol-3-phosphate-acyltransferase 3, and perilipins 1 and 4. The participation of the cAMP/PKA signaling pathway was explored. We observed that H89 (a PKA inhibitor) decreases the LD upregulation elicited by liraglutide, and that dibutyryl cAMP increases LD content and the expression of related genes. In summary, liraglutide promotes lipid storage in SCs through the regulation of key regulatory genes involved in FA transport, TAG synthesis, and LD formation. Considering the importance of lipid storage in SC energetic homeostasis maintenance, we postulate that liraglutide might improve the overall energetic status of the seminiferous tubule.

Fatty acids (FAs) are important for cell membrane composition, eicosanoid synthesis, and metabolic processes. Membrane proteins that facilitate FA transport into cells include FA translocase (also known as CD36) and FA transporter proteins (encoded by SLC27A genes). The present study aimed to examine expression profiles of FA transporters in the endometrium of cyclic and early pregnant gilts on days 3 to 20 after estrus and the possible regulation by conceptus signals and polyunsaturated FAs (PUFAs). The effect of PUFAs on prostaglandin (PG) synthesis and transcript abundance of genes related to FA action and metabolism, angiogenesis, and immune response was also determined. Day after estrus and reproductive status of animals affected FA transporter expression, with greater levels of CD36, SLC27A1, and SLC27A4 observed in pregnant than in cyclic gilts. Conceptus-conditioned medium and/or estradiol-17β stimulated SLC27A1 and CD36 expression. Among PUFAs, linoleic acid decreased SLC27A1 and SLC27A6 mRNA expression, while arachidonic, docosahexaenoic, and eicosapentaenoic acids increased SLC27A4 transcript abundance. Moreover, arachidonic acid stimulated ACOX1 , CPT1A , and IL1B expression and increased PGE2 and PGI2 secretion. In turn, α-linolenic acid up-regulated VEGFA, FGF2, FABP4, and PPARG mRNA expression. These results indicate the presence of an active transport of FAs in the porcine endometrium and the role of PUFAs as modulators of the uterine activity during conceptus implantation.

CD36, also known as glycoprotein IV, is classified into two distinct subgroups based on the presence or absence of its expression on monocytes. The CD36 gene spans approximately 50,000 base pairs. Historically, research has focused on identifying CD36 mutations through Sanger sequencing and next-generation sequencing (NGS), with limited exploration of haplotypes. In this study, we collected blood samples from donors with type I and type II CD36 deficiencies as well as from healthy controls, and employed single-molecule long-read sequencing (also known as Third-Generation Sequencing) of genomic DNA to analyze the genetic basis of CD36. The study identified 180 genetic variants, 12 of which were found to alter the amino acid sequence. Notably, four of these mutations (c.220 C > T; c.329&#95;330delAC; c.430-1 G > C; c.1006 + 2 T > G) are premature termination mutations that lead to protein truncation. Using Fisher's exact test, we statistically analyzed a specific haplotype, c.-132A > C and c.329&#95;330delAC, along with their clinical phenotypes, revealing a strong association between these variants in the 5' block and type I CD36 deficiency. We analyzed the CD36 gene sequences in platelet donors and patients with PTR (platelet transfusion refractoriness) and FNAIT (fetal and neonatal alloimmune thrombocytopenia), conducting a detailed haplotype analysis associated with type I CD36 deficiency and FNAIT., (© 2024. The Author(s).)

As the most frequent genetic alteration in cancer, more than half of human cancers have p53 mutations that cause transcriptional inactivation. However, how p53 modulates the immune landscape to create a niche for immune escape remains elusive. We found that cancer stem cells (CSCs) established an interleukin-34 (IL-34)-orchestrated niche to promote tumorigenesis in p53-inactivated liver cancer. Mechanistically, we discovered that Il34 is a gene transcriptionally repressed by p53, and p53 loss resulted in IL-34 secretion by CSCs. IL-34 induced CD36-mediated elevations in fatty acid oxidative metabolism to drive M2-like polarization of foam-like tumor-associated macrophages (TAMs). These IL-34-orchestrated TAMs suppressed CD8 + T cell-mediated antitumor immunity to promote immune escape. Blockade of the IL-34-CD36 axis elicited antitumor immunity and synergized with anti-PD-1 immunotherapy, leading to a complete response. Our findings reveal the underlying mechanism of p53 modulation of the tumor immune microenvironment and provide a potential target for immunotherapy of cancer with p53 inactivation., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: To investigate the effect and potential mechanism of exposure to 20 nm polystyrene nanoplastics (PS-NPs) on lipid metabolism in mice liver. Methods: An animal experimental model was designed, which was completed from September 2022 to July 2023 on the exposure omics platform of the School of Public Health at Capital Medical University and the Key Laboratory of Environment and Population Health at the Chinese Center for Disease Control and Prevention.1 mg/kg and 10 mg/kg PS-NPs tail vein mice exposure models were constructed. After exposure 7 d, serum was collected to measure the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) and air flow assisted desorption electrospray ionization-mass spectrometry imaging (AFADESI-MSI) analysis were used to analyze the mRNA levels of fatty acid esterification related genes ( Dgat1 and Dgat2 ) and lipid transport related genes ( ApoB , Cd36 , ApoE and Mttp ) and metabolites' spatial changes in liver tissue. In vivo imaging system (IVIS) and tissue shake sections were employed to observe the fluorescence biological distribution of PS-NPs. t -test or one-way ANOVA was used to explore the difference between groups. Results: The serum ALT levels were (83.97±4.58), (91.17±13.69) and (142.43±6.09) U/L in the control group, 1 mg/kg PS-NPs exposure group and 10 mg/kg PS-NPs exposure group respectively ( F =37.281, P <0.05). The relative mRNA levels of Dgat1 , Dgat2 , ApoB , Cd36 and ApoE were (1.49±0.63, 2.53±0.32, 2.45±0.54), (1.07±0.38, 1.86±0.83, 2.23±0.73), (1.01±0.13, 1.58±0.43, 2.03±0.52), (1.01±0.14, 1.55±0.37, 1.52±0.51), (1.01±0.17, 2.11±0.27, 2.39±0.93) in these three groups respectively. The differences were statistically significant ( F =11.54, 6.95, 14.90, 5.98 and 14.68, P <0.05). AFADESI-MSI analysis found that PS-NPs exposure led to a significant decrease in the levels of glutarylcarnitine and O-Linoleoylcarnitine ( t =4.12 and 3.35, P <0.05), which were associated with lipid beta oxidation. The content of triglycerides (TG) (m/z 921.726 4, t =8.69, P <0.05; m/z 919.711 4, t =3.20, P <0.05), phosphatidylic acid (PA) (m/z 895.712 3, t =3.60, P <0.05; m/z 821.526 6, t =3.36, P <0.05), lysophosphatidylcholine (LysoPC) (m/z 560.310 6, t =3.35, P <0.05; m/z 582.295 3, t =6.28, P <0.05), phosphatidylcholine (PC) (m/z 778.533 9, t =3.53, P <0.05; m/z 804.549 6, t =3.60, P <0.05; m/z 820.523 1, t =3.37, P <0.05), phosphatidylethanolamine (PE) (m/z 772.523 3, t =3.08, P <0.05) showed a significant increase in the PS-NPs exposure group. In vivo and in vitro imaging and in situ cell localization revealed that PS-NPs were mainly enriched in hepatic stellate cells and hepatic Kupffer cells in liver tissue. Conclusion: Exposure to PS-NPs induces disorder of liver lipid metabolism, which may be related to the accumulation of PS-NPs in hepatic stellate cells and hepatic Kupffer cells, providing basis for searching early biomarkers of PS-NPs exposure and further mechanism research.

Scavenger receptor type B (SR-BI) is a receptor that binds both native and altered lipoproteins. It was revealed to facilitate utilization of high-density lipoprotein HDL and significantly affect the reverse transport of cholesterol. Therefore, the objectives were to identify the possible role of the genetic variant rs4238001 in patients with myocardial infarction (MI) on serum lipid level, and how this variant could impact the response of rosuvastatin drug. The genotyping of the rs4238001 genetic polymorphism of the SR-B1 gene was performed in 300 participants, including 150 MI patients treated with 20mg/day/4 weeks of rosuvastatin and 150 healthy control using Taq man probes (FAM and VIC) by Real-time PCR technique. The concentrations of the lipid profile were evaluated. The significance of the anthropometric data was revealed in the ejection fraction and smoking status (p < 0.05) between groups. The lipid profile shows either significant differences between control and MI patients (pre-treatment) or between pre-and post-treatment of MI patients (p < 0.05), but not HDL-c (p > 0.05). The minor allele frequency MAF% of the T allele and TT genotype were more frequent in MI patients than in controls (P = 0.173; OR = 3.62; 95% CI = 0.74-17.64). CC genotype was found to be associated with response to rosuvastatin therapy with a change of % (29.08 ± 53.2; p = 0.021). In the Iraqi population, the rs4238001 polymorphism of the SR-B1 gene is associated with variations in serum lipids, and the CC genotype of the SNP is related to higher HDL-C in the lipid-lowering rosuvastatin response., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Hepatic adipogenesis has common mechanisms with adipocyte differentiation such as PPARγ involvement and the induction of adipose tissue-specific molecules. A previous report demonstrated that integrator complex subunit 6 (INTS6) is required for adipocyte differentiation. This study aimed to investigate INTS6 expression and its role in hepatic steatosis progression. The expression of INTS6 and PPARγ was examined in the liver of a mouse model of steatohepatitis and in paired liver biopsy samples from 11 patients with severe obesity and histologically proven metabolic dysfunction associated steatohepatitis (MASH) before and one year after bariatric surgery. To induce hepatocellular steatosis in vitro, an immortalized human hepatocyte cell line Hc3716 was treated with free fatty acids. In the steatohepatitis mouse model, we observed hepatic induction of INTS6, PPARγ, and adipocyte-specific genes. In contrast, β-catenin which negatively regulates PPARγ was reduced. Biopsied human livers demonstrated a strong positive correlation (r 2  = 0.8755) between INTS6 and PPARγ mRNA levels. After bariatric surgery, gene expressions of PPARγ, FABP4, and CD36 were mostly downregulated. In our in vitro experiments, we observed a concentration-dependent increase in Oil Red O staining in Hc3716 cells after treatment with the free fatty acids. Alongside this change, the expression of INTS6, PPARγ, and adipocyte-specific genes was induced. INTS6 knockdown using siRNA significantly suppressed cellular lipid accumulation together with induction of β-catenin and PPARγ downregulation. Collectively, INTS6 expression closely correlates with PPARγ. INTS6 suppression significantly reduced hepatocyte steatosis via β-catenin-PPARγ axis, indicating that INTS6 could be a novel therapeutic target for treating MASH., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Consumption of a Western diet (WD) increases CD36 expression in vascular, hepatic, and skeletal muscle tissues promoting lipid metabolic disorders and insulin resistance. We further examined the role of endothelial cell-specific CD36 (ECCD36) signaling in contributing to skeletal muscle lipid metabolic disorders, insulin resistance, and their underlying molecular mechanisms. Female ECCD36 wild-type (ECCD36 +/+ ) and knock-out (ECCD36 -/- ) mice, aged 6 wk, were provided with either a WD or a standard chow diet for a duration of 16 wk. ECCD36 +/+ WD mice were characterized by elevated fasting plasma glucose and insulin levels, increased homeostatic model assessment for insulin resistance, and glucose intolerance that was blunted in ECCD36 -/- mice. Improved insulin sensitivity in ECCD36 -/- mice was characterized by increased phosphoinositide 3-kinases/protein kinase B signaling that further augmented glucose transporter type 4 expression and glucose uptake. Meanwhile, 16 wk of WD feeding also increased skeletal muscle free fatty acid (FFA) and lipid accumulation, without any observed changes in plasma FFA levels. These lipid metabolic disorders were blunted in ECCD36 -/- mice. Moreover, ECCD36 also mediated in vitro palmitic acid-induced lipid accumulation in cultured ECs, subsequently leading to the release of FFAs into the culture media. Furthermore, consumption of a WD increased FFA oxidation, mitochondrial dysfunction, impaired mitochondrial respiratory, skeletal muscle fiber type transition, and fibrosis. These WD-induced abnormalities were blunted in ECCD36 -/- mice. These findings demonstrate that endothelial-specific ECCD36 signaling participates in skeletal muscle FFA uptake, ectopic lipid accumulation, mitochondrial dysfunction, insulin resistance, and associated skeletal muscle dysfunction in diet-induced obesity. NEW & NOTEWORTHY ECCD36 exerts "extra endothelial cell" actions in skeletal muscle insulin resistance. ECCD36 is a major mediator of Western diet-induced lipid metabolic disorders and insulin resistance in skeletal muscle. Mitochondrial dysfunction is associated with diet-induced CD36 activation and related skeletal muscle insulin resistance.