Simultaneous production of biosurfactant and extracellular unspecific peroxygenases by Moesziomyces aphidis XM01 enables an efficient strategy for crude oil degradation.

Crude oil is a hazardous pollutant that poses significant and lasting harm to human health and ecosystems. In this study, Moesziomyces aphidis XM01, a biosurfactant mannosylerythritol lipids (MELs)-producing yeast, was utilized for crude oil degradation. Unlike most microorganisms relying on cytochrome P450, XM01 employed two extracellular unspecific peroxygenases, MaUPO.1 and MaUPO.2, with preference for polycyclic aromatic hydrocarbons (PAHs) and n-alkanes respectively, thus facilitating efficient crude oil degradation. The MELs produced by XM01 exhibited a significant emulsification activity of 65.9% for crude oil and were consequently supplemented in an "exogenous MELs addition" strategy to boost crude oil degradation, resulting in an optimal degradation ratio of 72.3%. Furthermore, a new and simple "pre-MELs production" strategy was implemented, achieving a maximum degradation ratio of 95.9%. During this process, the synergistic up-regulation of MaUPO.1, MaUPO.1 and the key MELs synthesis genes contributed to the efficient degradation of crude oil. Additionally, the phylogenetic and geographic distribution analysis of MaUPO.1 and MaUPO.1 revealed their wide occurrence among fungi in Basidiomycota and Ascomycota, with high transcription levels across global ocean, highlighting their important role in biodegradation of crude oil. In conclusion, M. aphidis XM01 emerges as a novel yeast for efficient and eco-friendly crude oil degradation.

Synthesis and characterization of iron oxide nanoparticles from Lawsonia inermis and its effect on the biodegradation of crude oil hydrocarbon.

Crude oil hydrocarbons are considered major environmental pollutants and pose a significant threat to the environment and humans due to having severe carcinogenic and mutagenic effects. Bioremediation is one of the practical and promising technology that can be applied to treat the hydrocarbon-polluted environment. In this present study, rhamnolipid biosurfactant (BS) produced by Pseudomonas aeruginosa PP4 and green synthesized iron nanoparticles (G-FeNPs) from Lawsonia inermis was used to evaluate the biodegradation efficiency (BE) of crude oil. The surface analysis of G-FeNPs was carried out by using FESEM and HRTEM to confirm the size and shape. Further, the average size of the G-FeNPs was observed around 10 nm by HRTEM analysis. The XRD and Raman spectra strongly confirm the presence of iron nanoparticles with their respective peaks. The BE (%) of mixed degradation system-V (PP4+BS+G-FeNPs) was obtained about 82%. FTIR spectrum confirms the presence of major functional constituents (C=O, -CH3, C-O, and OH) in the residual oil content. Overall, this study illustrates that integrated nano-based bioremediation could be an efficient approach for hydrocarbon-polluted environments. This study is the first attempt to evaluate the G-FeNPs with rhamnolipid biosurfactant on the biodegradation of crude oil.

Molecular insights into capsular polysaccharide secretion.

Capsular polysaccharides (CPSs) fortify the cell boundaries of many commensal and pathogenic bacteria1. Through the ABC-transporter-dependent biosynthesis pathway, CPSs are synthesized intracellularly on a lipid anchor and secreted across the cell envelope by the KpsMT ABC transporter associated with the KpsE and KpsD subunits1,2. Here we use structural and functional studies to uncover crucial steps of CPS secretion in Gram-negative bacteria. We show that KpsMT has broad substrate specificity and is sufficient for the translocation of CPSs across the inner bacterial membrane, and we determine the cell surface organization and localization of CPSs using super-resolution fluorescence microscopy. Cryo-electron microscopy analyses of the KpsMT-KpsE complex in six different states reveal a KpsE-encaged ABC transporter, rigid-body conformational rearrangements of KpsMT during ATP hydrolysis and recognition of a glycolipid inside a membrane-exposed electropositive canyon. In vivo CPS secretion assays underscore the functional importance of canyon-lining basic residues. Combined, our analyses suggest a molecular model of CPS secretion by ABC transporters.

Secondary metabolite profiling of Pseudomonas aeruginosa isolates reveals rare genomic traits.

Pseudomonas aeruginosa is a ubiquitous Gram-negative opportunistic pathogen with remarkable phylogenetic and phenotypic variabilities. In this work, we applied classical molecular networking analysis to secondary metabolite profiling data from seven Pseudomonas aeruginosa strains, including five clinical isolates from the lung secretions of people with cystic fibrosis (CF). We provide three vignettes illustrating how secondary metabolite profiling aids in the identification of rare genomics traits in P. aeruginosa. First, we describe the identification of a previously unreported class of acyl putrescines produced by isolate mFLRO1. Secondary analysis of publicly available metabolomics data revealed that acyl putrescines are produced by <5% of P. aeruginosa strains. Second, we show that isolate SH3A does not produce di-rhamnolipids. Whole-genome sequencing and comparative genomics revealed that SH3A cannot produce di-rhamnolipids because its genome belongs to clade 5 of the P. aeruginosa phylogenetic tree. Previous phylogenetic analysis of thousands of P. aeruginosa strains concluded that <1% of publicly available genome sequences contribute to this clade. Last, we show that isolate SH1B does not produce the phenazine pyocyanin or rhamnolipids because it has a one-base insertion frameshift mutation (678insC) in the gene rhlR, which disrupts rhl-driven quorum sensing. Secondary analysis of the tens of thousands of publicly available genomes in the National Center for Biotechnology Information (NCBI) and the Pseudomonas Genome Database revealed that this mutation was present in only four P. aeruginosa genomes. Taken together, this study highlights that secondary metabolite profiling combined with genomic analysis can identify rare genetic traits of P. aeruginosa isolates.IMPORTANCESecondary metabolite profiling of five Pseudomonas aeruginosa isolates from cystic fibrosis sputum captured three traits present in <1%-5% of publicly available data, pointing to how our current library of P. aeruginosa strains may not represent the diversity within this species or the genetic variance that occurs in the CF lung.

Mechanisms of Dangua Fang in multi-target and multi-method regulation of glycolipid metabolism based on phosphoproteomics.

OBJECTIVE: To explore the mechanism of Dangua Fang (, DGR) in multi-target and multi-method regulation of glycolipid metabolism based on phosphoproteomics. METHODS: Sprague-Dawley rats with normal glucose levels were randomly divided into three groups, including a conventional diet control group (Group A), high-fat-high-sugar diet model group (Group B), and DGR group (Group C, high-fat-high-sugar diet containing 20.5 g DGR). After 10 weeks of intervention, the fasting blood glucose (FBG), 2 h blood glucose [PBG; using the oral glucose tolerance test (OGTT)], hemoglobin A1c (HbA1c), plasma total cholesterol (TC), and triglycerides (TG) were tested, and the livers of rats were removed to calculate the liver index. Then, hepatic portal TG were tested using the Gross permanent optimization-participatiory action planning enzymatic method and phosphoproteomics was performed using liquid chromatography with tandem mass spectrometry (LC-MS/MS) analysis followed by database search and bioinformatics analysis. Finally, cell experiments were used to verify the results of phosphoproteomics. Phosphorylated mitogen-activated protein kinase kinase kinase kinase 4 (MAP4k4) and phosphorylated adducin 1 (ADD1) were detected using western blotting. RESULTS: DGR effectively reduced PBG, TG, and the liver index (P < 0.05), and significantly decreased HbA1c, TC, and hepatic portal TG (P < 0.01), showed significant hematoxylin and eosin (HE) staining, red oil O staining, and Masson staining of liver tissue. The total spectrum was 805 334, matched spectrum was 260 471, accounting for accounting 32.3%, peptides were 19 995, modified peptides were 14 671, identified proteins were 4601, quantifiable proteins were 4417, identified sites were 15 749, and quantified sites were 14659. Based on the threshold of expression fold change ( > 1.2), DGR up-regulated the modification of 228 phosphorylation sites involving 204 corresponding function proteins, and down-regulated the modification of 358 phosphorylation sites involving 358 corresponding function proteins, which included correcting 75 phosphorylation sites involving 64 corresponding function proteins relating to glycolipid metabolism. Therefore, DGR improved biological tissue processes, including information storage and processing, cellular processes and signaling, and metabolism. The metabolic functions regulated by DGR mainly include energy production and conversion, carbohydrate transport and metabolism, lipid transport and metabolism, inorganic ion transport and metabolism, secondary metabolite biosynthesis, transport, and catabolism. In vitro phosphorylation validation based on cell experiments showed that the change trends in the phosphorylation level of MAP4k4 and ADD1 were consistent with that of previous phosphoproteomics studies. CONCLUSION: DGR extensively corrects the modification of phosphorylation sites to improve corresponding glycolipid metabolism-related protein expression in rats with glycolipid metabolism disorders, thereby regulating glycolipid metabolism through a multi-target and multi-method process.

NKT cells in the antitumor response: the ß version?

NKT cells recognize glycolipids presented by CD1d-expressing antigen-presenting cells (APCs) and include type I NKT cells with antitumor function and type II NKT cells, which have been reported to suppress the antitumor response. Some type II NKT cells recognize sulfatide, a glycosphingolipid with a sulfate modification of the sugar. Type I NKT cells recognize different glycosphingolipids. In this issue of the JCI, Nishio and colleagues showed that APCs could process sulfatide antigens, analogous to protein processing for peptide-reactive T cells. Antigen processing in lysosomes removed sulfate to generate a glycosphingolipid that stimulated type I NKT cells and thereby turned an antigen with no antitumor activity into one that not only stimulated type I NKT cells but also stimulated antitumor responses. These findings may extend to the development of glycolipid antigens that could stimulate anticancer responses via antigen processing by APCs.

Immune Enhancement Effects of Neutral Lipids, Glycolipids, Phospholipids from Halocynthia aurantium Tunic on RAW264.7 Macrophages.

Fractionated lipids of Halocynthia aurantium (Pyuridae) have been demonstrated to possess anti-inflammatory properties. However, their modulatory properties have not been reported yet. Thus, the objective of this study was to determine immune enhancing effects of fractionated lipids from H. aurantium tunic on macrophage cells. The tunic of H. aurantium was used to isolate total lipids, which were then subsequently separated into neutral lipids, glycolipids, and phospholipids. RAW264.7 cells were stimulated with different concentrations (0.5, 1.0, 2.0, and 4.0%) of each fractionated lipid. Cytotoxicity, production of NO, expression levels of immune-associated genes, and signaling pathways were then determined. Neutral lipids and glycolipids significantly stimulated NO and PGE2 production and expression levels of IL-1ß, IL-6, TNF-α, and COX-2 in a dose-dependent manner, while phospholipids ineffectively induced NO production and mRNA expression. Furthermore, it was found that both neutral lipids and glycolipids increased NF-κB p-65, p38, ERK1/2, and JNK phosphorylation, suggesting that these lipids might enhance immunity by activating NF-κB and MAPK signaling pathways. In addition, H. aurantium lipids-induced TNF-α expression was decreased by blocking MAPK or NF-κB signaling pathways. Phagocytic activity of RAW 264.7 cells was also significantly enhanced by neutral lipids and glycolipids. These results suggest that neutral lipids and glycolipids from H. aurantium tunic have potential as immune-enhancing materials.

Toxicologic effect and transcriptome analysis for sub-chronic exposure to carbendazim, prochloraz, and their combination on the liver of mice.

Carbendazim (CBZ) and prochloraz (PCZ) are broad-spectrum fungicides used in agricultural peat control. Both fungicides leave large amounts of residues in fruits and are toxic to non-target organisms. However, the combined toxicity of the fungicides to non-target organisms is still unknown. Therefore, we characterized the toxic effects of dietary supplementation with CBZ, PCZ, and their combination for 90 days in 6-week-old male Institute of Cancer Research (ICR) mice. CBZ-H (100 mg/kg day), PCZ-H (10 mg/kg day), and their combination treatments increased the relative liver weights and caused liver injury. The serum total cholesterol (TC), triglyceride (TG), glucose (Glu), pyruvate (PYR), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) levels were reduced, and synergistic toxicity was observed. Hepatic transcriptome revealed that 326 differentially expressed genes (DEGs) of liver were observed in the CBZ treatment group, 149 DEGs in the PCZ treatment group, and 272 DEGs in the combination treatment group. According to KEGG enrichment analysis, the fungicides and their combination affected lipid metabolism, amino acid metabolism, and ferroptosis. In addition, the relative mRNA levels of key genes involved in lipid metabolism were also examined. Compared with individual exposure, combined exposure to CBZ and PCZ caused a more obvious decrease in the expression of some genes related to glycolipid metabolism. Furthermore, the relative mRNA levels of some key genes in the combination treatment group were lower than those in the CBZ and PCZ treated groups. In summary, CBZ, PCZ, and their combination generally caused hepatotoxicity and glycolipid metabolism disorders, which could provide new insights for investigating the combined toxicity of multiple fungicides to animals.

Virgin Camellia Seed Oil Improves Glycolipid Metabolism in the Kidney of High Fat-Fed Rats through AMPK-SREBP Pathway.

Camellia seed oil (CO) is used as edible oil in southern China because of its excellent fatty acid composition and abundant bioactive compounds. Chronic kidney disease (CKD) is one of the most common chronic degenerative diseases in China, and active compounds in vegetable oil, like virgin olive oil, have been demonstrated to be efficacious in the management of CKD. In this study, virgin CO was refined using a standard process. The refining had minimal impact on the fatty acid composition, but significantly reduced the presence of bioactive compounds like polyphenols in CO. Sprague-Dawley (SD) rats fed with high fat diet (Group G) were treated with either virgin (Group Z) or refined CO (Group R). The oral administration of CO alleviated lipid accumulation and decreased body and kidney weight gain. Furthermore, treatment with virgin CO increased the renal ATP content. The renal expression levels of AMPK and key enzymes involved in fatty acid oxidation (CPT-1 and ACOX1) and glycolysis (HK, PFK, PK and GAPDH) were up-regulated in Group Z, thereby enhancing the ATP production. Virgin CO treatment downregulated the expression level of SREBP2 and its downstream target genes, such as ACC, FAS, and HMGCR, which reduced lipid synthesis. These findings indicate that virgin CO improves glycolipid metabolism and restores energy homeostasis in the kidneys of rats fed with a high-fat diet by modulating the AMPK-SREBP-signaling pathway, suggesting the potential of active compounds in virgin CO for managing the renal failure associated with glycolipid dysmetabolism.

Biophysical Interaction Landscape of Mycobacterial Mycolic Acids and Phenolic Glycolipids with Host Macrophage Membranes.

Lipidic adjuvant formulations consisting of immunomodulatory mycobacterial cell wall lipids interact with host cells following administration. The impact of this cross-talk on the host membrane's structure and function is rarely given enough consideration but is imperative to rule out nonspecific perturbation underlying the adjuvant. In this work, we investigated changes in the plasma membranes of live mammalian cells after exposure to mycobacterial mycolic acid (MA) and phenolic glycolipids, two strong candidates for lipidic adjuvant therapy. We found that phenolic glycolipid 1 softened the plasma membrane, lowering membrane tension and stiffness, but MA did not significantly change the membrane characteristics. Further, phenolic glycolipid 1 had a fluidizing impact on the host plasma membrane, increasing the fluidity and the abundance of fluid-ordered-disordered coexisting lipid domains. Notably, lipid diffusion was not impacted. Overall, MA and, to a lesser extent, phenolic glycolipid 1, due to minor disruption of host cell membranes, may serve as appropriate lipids in adjuvant formulations.

Vascular Endothelial Growth Factor A (VEGFA) Regulates Hepatic Lipid and Glycogen Metabolism in Schizothorax prenanti.

Vascular endothelial growth factor A (VEGFA) plays important roles in angiogenesis, inflammatory response as well as energy metabolism in mammals. However, its effect on glycolipid metabolism in fish has not been reported. In this study, we cloned and characterized the vegfa gene of Schizothorax prenanti (S. prenanti). vegfa expression was significantly higher in liver and muscle than that in other tissues. Then, the VEGFA recombinant protein was expressed in Escherichia coli and obtained after purification. VEGFA i.p. injection significantly increased the serum glucose and TG content compared with the control group. Moreover, VEGFA protein aggravated the glycogen and lipid deposition in the liver of S. prenanti. In addition, we found that VEGFA treatment increased hepatocyte glycogen and lipid droplet content and increased the levels of pAMPKα (T172). Furthermore, AMPKα inhibition attenuated the ability of VEGFA to induce TG and glycogen accumulation. These results demonstrate that VEGFA regulates hepatic lipid and glycogen metabolism through AMPKα in S. prenanti, which may contribute to a better understanding of VEGFA functions in the glycolipid metabolism of fish.

Impact of Mycobacterium tuberculosis Glycolipids on the CD4+ T Cell-Macrophage Immunological Synapse.

Mycobacterium tuberculosis cell-wall glycolipids such as mannosylated lipoarabinomannan (ManLAM) can inhibit murine CD4+ T cells by blocking TCR signaling. This results in suppression of IL-2 production, reduced T cell proliferation, and induction of CD4+ T cell anergy. This study extended these findings to the interaction between primary human CD4+ T cells and macrophages infected by mycobacteria. Exposure of human CD4+ T cells to ManLAM before activation resulted in loss of polyfunctionality, as measured by IL-2, IFN-γ, and TNF-α expression, and reduced CD25 expression. This was not associated with upregulation of inhibitory receptors CTLA-4, PD-1, TIM-3, and Lag-3. By confocal microscopy and imaging flow cytometry, ManLAM exposure reduced conjugate formation between macrophages and CD4+ T cells. ManLAM colocalized to the immunological synapse (IS) and reduced translocation of lymphocyte-specific protein tyrosine kinase (LCK) to the IS. When CD4+ T cells and Mycobacterium bovis BCG-infected monocytes were cocultured, ManLAM colocalized to CD4+ T cells, which formed fewer conjugates with infected monocytes. These results demonstrate that mycobacterial cell-wall glycolipids such as ManLAM can traffic from infected macrophages to disrupt productive IS formation and inhibit CD4+ T cell activation, contributing to immune evasion by M. tuberculosis.

Elucidating the toxic effect and disease mechanisms associated with Lyso-Gb3 in Fabry disease.

Fabry disease stems from a deficiency of alpha-galactosidase and results in the accumulation of globotriaosylceramide (Gb3). However, the production of its deacylated form globotriaosylsphingosine (lyso-Gb3) is also observed and its plasma levels have closer association with disease severity. Studies have shown that lyso-Gb3 directly affects podocytes and causes sensitisation of peripheral nociceptive neurons. However, little is understood of the mechanisms of this cytotoxicity. To study the effect on neuronal cells, we incubated SH-Sy5y cells with lyso-Gb3 at low (20 ng/mL) and high (200 ng/mL) levels, to mimic mild and classical FD serum levels. We used glucosylsphingosine as a positive control to determine specific effects of lyso-Gb3. Proteomic analyses revealed that cellular systems affected by lyso-Gb3 included cell signalling particularly protein ubiquitination and protein translation. To confirm ER/proteasome perturbations, we performed an immune enrichment of ubiquitinated proteins and demonstrated specific increased protein ubiquitination at both doses. The most ubiquitinated proteins observed included the chaperone/heat shock proteins, cytoskeletal proteins and synthesis/translation proteins. To detect proteins that interact directly with lyso-Gb3, we immobilised lyso-lipids, then incubated them with neuronal cellular extracts and identified bound proteins using mass spectrometry. Proteins that specifically bound were chaperones and included HSP90, HSP60 and the TRiC complex. In conclusion, lyso-Gb3 exposure affects pathways involved in protein translation and folding. This response is observed as increased ubiquitination and changes in signalling proteins which may explain the multiple biological processes, particularly cellular remodelling, often associated with FD.

Azido Inositol Probes Enable Metabolic Labeling of Inositol-Containing Glycans and Reveal an Inositol Importer in Mycobacteria.

Bacteria from the genus Mycobacterium include pathogens that cause serious diseases in humans and remain as difficult infectious agents to treat. Central to these challenges are the composition and organization of the mycobacterial cell envelope, which includes unique and complex glycans. Inositol is an essential metabolite for mycobacteria due to its presence in the structural core of the immunomodulatory cell envelope glycolipids phosphatidylinositol mannoside (PIM) and PIM-anchored lipomannan (LM) and lipoarabinomannan (LAM). Despite their importance to mycobacterial physiology and pathogenesis, many aspects of PIM, LM, and LAM construction and dynamics remain poorly understood. Recently, probes that allow metabolic labeling and detection of specific mycobacterial glycans have been developed to investigate cell envelope assembly and dynamics. However, these tools have been limited to peptidoglycan, arabinogalactan, and mycolic acid-containing glycolipids. Herein, we report the development of synthetic azido inositol (InoAz) analogues as probes that can metabolically label PIMs, LM, and LAM in intact mycobacteria. Additionally, we leverage an InoAz probe to discover an inositol importer and catabolic pathway in Mycobacterium smegmatis. We anticipate that in the future, InoAz probes, in combination with bioorthogonal chemistry, will provide a valuable tool for investigating PIM, LM, and LAM biosynthesis, transport, and dynamics in diverse mycobacterial organisms.

Enzymatic Glyco-Modification of Synthetic Membrane Systems.

The present report assesses the capability of a soluble glycosyltransferase to modify glycolipids organized in two synthetic membrane systems that are attractive models to mimic cell membranes: giant unilamellar vesicles (GUVs) and supported lipid bilayers (SLBs). The objective was to synthesize the Gb3 antigen (Galα1,4Galß1,4Glcß-Cer), a cancer biomarker, at the surface of these membrane models. A soluble form of LgtC that adds a galactose residue from UDP-Gal to lactose-containing acceptors was selected. Although less efficient than with lactose, the ability of LgtC to utilize lactosyl-ceramide as an acceptor was demonstrated on GUVs and SLBs. The reaction was monitored using the B-subunit of Shiga toxin as Gb3-binding lectin. Quartz crystal microbalance with dissipation analysis showed that transient binding of LgtC at the membrane surface was sufficient for a productive conversion of LacCer to Gb3. Molecular dynamics simulations provided structural elements to help rationalize experimental data.

Proteomic analysis of milk fat globule membranes from small-sized milk fat globules and their function in promoting lipid droplet fusion in bovine mammary epithelial cells.

In mammary epithelial cells, milk fat is synthesized as lipid droplets and secreted in the form of globules. Milk fat globules (MFGs) are covered by a lipid-protein membrane known as the milk fat globule membrane (MFGM). We randomly divided 12 Holstein cows into control and conjugated linoleic acid (CLA) groups. The control group was fed a basal diet, while the CLA group was fed the basal diet + CLA (15 g per kg DM) for 10 days. Cow performance, milk composition, and MFG size were measured daily. On day 10, we extracted MFGM proteins (n = 3) and identified them via quantitative proteomic analysis. We investigated the effects of the MFGM proteins from control and CLA-treated milk on the lipid droplet formation in MAC-T cells. Compared with the control group, the CLA group had reduced milk fat content (3.39 g/100 mL vs. 2.45 g/100 mL) and MFG size parameters (D[4,3] of 3.85 µm vs. 3.37 µm; D[3,2] of 3.24 µm vs. 2.83 µm). The specific surface area (SSA) increased in the CLA group. A total of 361 differentially expressed proteins were identified in the CLA group by iTRAQ quantitative proteomic analysis. Among these proteins, 100 were upregulated and 251 were downregulated (p < 0.05). In MAC-T cells, CLA-MFGM proteins increased the diameter of the lipid droplets to 1.32 µm. CLA-MFGM proteins decreased the proportion of the small lipid droplets (15.33% vs. 47.78%) and increased the proportion of the large lipid droplets (25.04% vs. 11.65%). CLA-MFGM proteins promoted lipid droplet fusion. Therefore, MFGM proteins play an important role in the regulation of the lipid droplet size.

Environmentally relevant perinatal exposure to DBP accelerated spermatogenesis by promoting the glycolipid metabolism of Sertoli cells in male offspring mice.

Since Sertoli cells (SCs) play an essential role in providing energy for spermatogenesis, the present study aimed to investigate the effects of maternal exposure to plasticizer Dibutyl phthalate (DBP) on the onset of spermatogenesis in male offspring through the metabolism pathway as well as the underlying molecular mechanism. Here, pregnant mice were treated with 0 (control), 50, 250, or 500 mg/kg/day DBP in 1 mL/kg corn oil administered daily by oral gavage from gestation day (GD) 12.5 to parturition. The in vivo results showed that 50 mg/kg/day DBP exposure could promote the expression of glucose metabolism-related proteins (GLUT3, LDHA, and MCT4) in the testis of 22 days male offspring. The in vitro results demonstrated that 0.1 mM monobutyl phthalate (MBP, the active metabolite of DBP) promoted the lactate production, glucose consumption, and glycolytic flux of immature SCs, which was paralleled by the upregulated expression of glucose metabolism-related proteins (GLUT1, GLUT3, LDHA, and MCT4). On the other hand, DBP/MBP increased fatty acid (FA) uptake, FA ß-oxidation, and ATP production by promoting the expression of CD36 in immature SCs, which might accelerate the maturity of SCs to support the onset of spermatogenesis. Therefore, our findings provided a new perspective on glycolipid metabolism to explain prenatal DBP exposure leading to earlier onset of spermatogenesis in male offspring mice.

Combined toxicity of acetamiprid and cadmium to larval zebrafish (Danio rerio) based on metabolomic analysis.

Emerging contaminants, such as neonicotinoid pesticide acetamiprid (Ace), are frequently detected in the water environment, which can interact with existing heavy metal cadmium (Cd) to produce unpredicted influence. Limited studies have evaluated the effects of multiple pollutant exposures on aquatic animals. Here, we characterized the joint toxicity of Ace and Cd exposure to zebrafish (Danio rerio). The results revealed that Cd and its combined exposure with Ace had an inhibitory effect on the growth of larval zebrafish and induced morphological defects. Combined exposure to high doses of Ace and Cd could significantly reduce the levels of TG, glucose, and pyruvate in larval zebrafish. Untargeted metabolomics revealed that Cd treatment (285) produced more differentially expressed metabolites (DEMs) than Ace treatment (115), and combined treatment produced the most DEMs (294). The KEGG pathway enrichment analysis showed that they could disrupt riboflavin metabolism, amino acid metabolism, and glycolipid metabolism in the larvae of D. rerio. ELISA showed that VB2, FMN, and FAD levels were significantly increased. In addition, gene expression analysis exhibited that the mRNA levels of essential genes related to glycolipid metabolism were substantially affected, such as PK, PEPckc, PPAR-α, and FABP6. Furthermore, targeted amino acid metabolomics confirmed that both single exposure to Cd and combined exposure to Ace and Cd altered the levels of amino acids in larvae, including ALA, ARG, MET, PRO, TYR, VAL, GLY, ORN, and PHE. Taken together, exposure to Ace and Cd, alone or in combination, exerted harmful effects on the individual development, riboflavin metabolism, glycolipid metabolism, and amino acid metabolism disorder of D. rerio. These findings highlighted that more attention should be paid to the compound toxicity of chemical mixtures to aquatic organisms.

Phenolic glycolipid-1 of Mycobacterium leprae is involved in human Schwann cell line ST8814 neurotoxic phenotype.

Leprosy is a chronic infectious disease caused by Mycobacterium leprae infection in Schwann cells. Axonopathy is considered a hallmark of leprosy neuropathy and is associated with the irreversible motor and sensory loss seen in infected patients. Although M. leprae is recognized to provoke Schwann cell dedifferentiation, the mechanisms involved in the contribution of this phenomenon to neural damage remain unclear. In the present work, we used live M. leprae to infect the immortalized human Schwann cell line ST8814. The neurotoxicity of infected Schwann cell-conditioned medium (SCCM) was then evaluated in a human neuroblastoma cell lineage and mouse neurons. ST8814 Schwann cells exposed to M. leprae affected neuronal viability by deviating glial 14 C-labeled lactate, important fuel of neuronal central metabolism, to de novo lipid synthesis. The phenolic glycolipid-1 (PGL-1) is a specific M. leprae cell wall antigen proposed to mediate bacterial-Schwann cell interaction. Therefore, we assessed the role of the PGL-1 on Schwann cell phenotype by using transgenic M. bovis (BCG)-expressing the M. leprae PGL-1. We observed that BCG-PGL-1 was able to induce a phenotype similar to M. leprae, unlike the wild-type BCG strain. We next demonstrated that this Schwann cell neurotoxic phenotype, induced by M. leprae PGL-1, occurs through the protein kinase B (Akt) pathway. Interestingly, the pharmacological inhibition of Akt by triciribine significantly reduced free fatty acid content in the SCCM from M. leprae- and BCG-PGL-1-infected Schwann cells and, hence, preventing neuronal death. Overall, these findings provide novel evidence that both M. leprae and PGL-1, induce a toxic Schwann cell phenotype, by modifying the host lipid metabolism, resulting in profound implications for neuronal loss. We consider this metabolic rewiring a new molecular mechanism to be the basis of leprosy neuropathy.

Ameliorating Effect on Glycolipid Metabolism of Spirulina Functional Formulation Combination from Traditional Chinese Medicine.

Insulin resistance is the major factor involved in the pathogenesis of type 2 diabetes. Although the oral drug metformin (MH) is widely used to reduce hyperglycemia, it is associated with adverse effects. Therefore, there is an urgent need to search for safe and natural foods that do not cause adverse effects as alternatives to commercial drugs. In this study, the active substances from Spirulina platensis, Grifola frondosa, Panax ginseng, and chromium-rich yeast were used to obtain Spirulina functional formulations (SFFs), and its therapeutic effects on mice with glycolipid metabolism disorder (GLD) were investigated. Results showed that SFFs not only improved glycolipid metabolism and reduced inflammation in mice with GLD but also showed good regenerative effects on the liver, jejunum, and cecum tissues. Moreover, SFFs could inhibit the growth of harmful microbes in the intestine and promote the proliferation of beneficial bacteria, thereby promoting the production of short-chain fatty acids and further regulating GLD. Additionally, SFFs significantly increased the expression of INS, INSR, IRS-1, PI3K, AKT-1, and GLUT-4 genes and significantly decreased that of GSK-3ß in the INS/PI3K/GLUT-4 signaling pathway. Therefore, the findings of this study suggest that SFFs can be further developed as a new class of therapeutic agents against GLD.