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.

Mucus-Penetrating Nanoassembly as Potential Oral Phototherapeutic Formulation against Multi-Drug Resistant Helicobacter pylori Infection.

Helicobacter pylori (H. pylori) infection presents increasing challenges to antibiotic therapies in limited penetration through gastric mucus, multi-drug resistance (MDR), biofilm formation, and intestinal microflora dysbiosis. To address these problems, herein, a mucus-penetrating phototherapeutic nanomedicine (RLs@T780TG) against MDR H. pylori infection is engineered. The RLs@T780TG is assembled with a near-infrared photosensitizer T780T-Gu and an anionic component rhamnolipids (RLs) for deep mucus penetration and light-induced anti-H. pylori performances. With optimized suitable size, hydrophilicity and weak negative surface, the RLs@T780TG can effectively penetrate through the gastric mucus layer and target the inflammatory site. Subsequently, under irradiation, the structure of RLs@T780TG is disrupted and facilitates the T780T-Gu releasing to target the H. pylori surface and ablate multi-drug resistant (MDR) H. pylori. In vivo, RLs@T780TG phototherapy exhibits impressive eradication against H. pylori. The gastric lesions are significantly alleviated and intestinal bacteria balance is less affected than antibiotic treatment. Summarily, this work provides a potential nanomedicine design to facilitate in vivo phototherapy in treatment of H. pylori infection.

Polar lipid-enriched milk fat globule membrane supplementation in maternal high-fat diet promotes intestinal barrier function and modulates gut microbiota in male offspring.

Intestinal development plays a critical role in physiology and disease in early life and has long-term effects on the health status throughout the lifespan. Maternal high-fat diet (HFD) fuels the inflammatory reaction and metabolic syndrome, disrupts intestinal barrier function, and alters gut microbiota in offspring. The aim of this study was to evaluate whether polar lipid-enriched milk fat globule membrane (MFGM-PL) supplementation in maternal HFD could promote intestinal barrier function and modulate gut microbiota in male offspring. Obese female rats induced by HFD were supplemented with MFGM-PL during pregnancy and lactation. The offspring were fed HFD for 11 weeks after weaning. MFGM-PL supplementation to dams fed HFD decreased the body weight gain and ameliorated abnormalities of serum insulin, lipids, and inflammatory cytokines in offspring at weaning. Maternal MFGM-PL supplementation promoted the intestinal barrier by increasing the expression of Ki-67, lysozyme, mucin 2, zonula occludens-1, claudin-3, and occludin. Additionally, MFGM-PL supplementation to HFD dams improved gut dysbiosis in offspring. MFGM-PL increased the relative abundance of Akkermansiaceae, Ruminococcaceae, and Blautia. Concomitantly, maternal MFGM-PL treatment increased short-chain fatty acids of colonic contents and G-protein-coupled receptor (GPR) 41 and GPR 43 expressions in the colon of offspring. Importantly, the beneficial effects of maternal MFGM-PL intervention persisted to offspring's adulthood, as evidenced by increased relative abundance of norank_f_Muribaculaceae, Peptostreptococcaceae and Romboutsia and modulated the taxonomic diversity of gut microbiota in adult offspring. In summary, maternal MFGM-PL supplementation improved intestinal development in the offspring of dams fed with HFD, which exerted long-term beneficial effects on offspring intestinal health.

Regulation of glucolipid metabolism and gut microbiota by green and black teas in hyperglycemic mice.

A high-sugar and -fat diet (HSFD) has become a primary risk factor for diabetes, and dietary intervention shows a substantial effect on the prevention and management of hyperglycemia. In this study, the chemical compositions of the aqueous extracts of stir-fried green tea (GT) and congou black tea (BT) were compared. Moreover, their potential mechanisms and regulatory effects on hepatic glycolipid metabolism and gut microbiota disorders in hyperglycemic mice were further explored. Our results show that GT or BT intervention had a prominent regulatory effect on glycolipid metabolism. Moreover, they could significantly regulate the levels of serum metabolic signatures, the activities of key enzymes in liver glucose metabolism, and the expression of genes or proteins related to glycolipid metabolism via activating the IRS-1-PI3K/AKT-GLUT2 signaling pathway. Significantly, GT or BT administration adjusted the composition and diversity of the gut microbiota, mainly reflecting a significant increase in the abundance of beneficial bacteria (including Allobaculum, Lactobacillus, and Turicibacter) and reducing the abundance of harmful or conditionally pathogenic bacteria (mainly including Clostridiales and Bacteroides). Our results suggest that dietary supplementation with GT or BT could exert a practical anti-diabetic effect. Meanwhile, BT intervention showed a better regulation effect on glycolipid metabolism. This study reveals that GT and BT have excellent potential for developing anti-diabetic food.

The mechanisms of Qizhu Tangshen formula in the treatment of diabetic kidney disease: Network pharmacology, machine learning, molecular docking and experimental assessment.

BACKGROUND: Qizhu Tangshen Formula (QZTS) has been shown therapeutic effects on diabetic kidney disease (DKD). However, to date, the pharmacological mechanisms remain vague. METHODS: To explore the underlying mechanisms of QZTS in treating DKD using network pharmacology, machine learning, molecular docking and experimental assessment. RESULTS: First, we found that QZTS improved glycolipid metabolism disorder, decreased proteinuria and alleviated kidney tissue injury in DKD model KKAy mice. Then, by integrating multiple databases, a total of 96 targets of 74 active compounds in QZTS and 759 DKD-related genes were acquired. Next, we identified 13 hub targets of QZTS in DKD by three rank algorithms, including functional similarity, topological similarity and shortest path. Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses demonstrated that the pathways mainly centered on the processes of glycolipid metabolism disorder, inflammation and angiogenesis. Among them, VEGF signaling pathway was significantly enriched. Molecular docking showed that key active compounds of QZTS all had relatively good binding affinity with predicted hub targets. Finally, animal experiments found that QZTS significantly inhibited the secretion of plasma VEGF and downregulated the protein and mRNA expression levels of AKT, p38MAPK and VEGFR2. CONCLUSION: Our results indicated that QZTS treated DKD via multiple targets and pathways and the VEGF signaling pathway may be highly involved in this process.

Exploring Active Ingredients, Beneficial Effects, and Potential Mechanism of Allium tenuissimum L. Flower for Treating T2DM Mice Based on Network Pharmacology and Gut Microbiota.

Forty compounds were isolated and characterized from A. tenuissimum flower. Among them, twelve flavonoids showed higher α-glucosidase inhibition activities in vitro than acarbose, especially kaempferol. The molecular docking results showed that the binding of kaempferol to α-glucosidase (GAA) could reduce the hydrolysis of substrates by GAA and reduce the glucose produced by hydrolysis, thus exhibiting α-glucosidase inhibition activities. The in vivo experiment results showed that flavonoids-rich A. tenuissimum flower could decrease blood glucose and reduce lipid accumulation. The protein expression levels of RAC-alpha serine/threonine-protein kinase (AKT1), peroxisome proliferator activated receptor gamma (PPARG), and prostaglandin G/H synthase 2 (PTGS2) in liver tissue were increased. In addition, the Firmicutes/Bacteroidetes (F/B) ratio was increased, the level of gut probiotics Bifidobacterium was increased, and the levels of Enterobacteriaceae and Staphylococcus were decreased. The carbohydrate metabolism, lipid metabolism, and other pathways related to type 2 diabetes mellitus were activated. This study indicating flavonoids-rich A. tenuissimum flower could improve glycolipid metabolic disorders and inflammation in diabetic mice by modulating the protein expression and gut microbiota.

[Jiangtang Sanhuang tablet inhibits endoplasmic reticulum stress and autophagy in diabetic mouse islet cells].

OBJECTIVE: To investigate effects of Jiangtang Sanhuang tablet (JTSHT) for regulating blood glucose and alleviating islet cell damage in db/db mice and its protective effects against endoplasmic reticulum stress (ERS) and autophagy induced by glycolipid toxicity. METHODS: Forty db/db mice were randomized into 4 groups for daily intragastric administration of saline, JTSHT of 2.64 and 1.32 g/kg, and metformin at 0.225g/kg for 8 weeks, using 10 C57BL/6J mice as the normal control. After the treatments, the metabolic indexes of the mice were measured, and morphological changes of the islet cells were observed. A mouse islet cell line (MIN6) was exposed to high glucose (22 mmol/L glucose) and 0.1 mmol/L palmitic acid, followed by treatment with the sera from JTSHT- or saline- treated SD rats, alone or in combination with SP600125, and the changes in cell apoptosis, ERS and autophagy were evaluated using flow cytometry, RT-qPCR and Western blotting. RESULTS: In db/db mice, treatment with JTSHT significantly improved glucose and lipid metabolism (P < 0.05) and suppressed progressive weight gain (P < 0.05) without significant effect on drinking water volume (P > 0.05). JTSHT was also found to promote repair of islet cell injuries. In the cell experiments, high glucose exposure significantly increased apoptosis rate of MIN6 cells (P < 0.05), which was obviously lowered by treatment with JTSHT-treated rat serum (P < 0.05). Western blotting showed that JTSHT significantly reduced the level of ERS and autophagy caused by glycolipid toxicity in MIN6 cells (P < 0.05). Interference with ERS using SP600125 significantly attenuated the protective effect of JTSHT against MIN6 cell injury, apoptosis and autophagy induced by glycolipid toxicity (P < 0.05). CONCLUSION: JTSHT has protective effects against glycolipid toxicity in MIN6 cells possibly by inhibiting ERS and autophagy.

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.

Multi-Omics Revealed the Protective Effects of Rhamnolipids in Lipopolysaccharide Challenged Broilers.

Rhamnolipid (RL) is a glycolipid biosurfactant and exhibits the following outstanding characteristics: strong antibacterial properties, low toxicity, and high biodegradability. The present research was conducted to explore the protective effects and mechanisms of rhamnolipids as an alternative to antibiotics in LPS (lipopolysaccharide)-challenged broilers. 16S rRNA gene sequencing and metabolomics were used for analyzing the cecal microbial composition and serum metabolites. Dietary antibiotics and RLS supplementation decreased the weight loss rate, enhanced serum immunoglobulin levels, reduced serum diamine oxidase and D-lactate acid concentration, and improved the symptoms of intestinal bleeding and villus height, when broilers were challenged with LPS. The addition of RLS in the diet enhanced serum interleukin-4 and interleukin-10 contents and reduced serum interleukin-6 and tumor necrosis factor-α levels in LPS-challenged broilers compared with the antibiotics group. Spearman's correlation analysis revealed that RLS may alleviate LPS-induced inflammatory responses through altering the 6-methoxymellein level in broilers. The genus Bacteroides may contribute to the decreased weight loss rate via regulating the serum lysoPC [20:5(5Z,8Z,11Z,14Z,17Z)] secretion. RLS alleviates LPS-induced intestinal injury, enhances the growth and immunity, ameliorates intestinal microflora, and improves serum metabolites in LPS-challenged broilers. RLS exhibited better protective effect than antibiotic supplementation in the diet of LPS-challenged broilers. These findings provide potential regulation strategies and novel insights for RLS enhancing its protective effect in LPS-challenged broilers.

Isolation, Optimization, and Structural Characterization of Glycolipid Biosurfactant Produced by Marine Isolate Shewanella algae B12 and Evaluation of Its Antimicrobial and Anti-biofilm Activity.

Biosurfactants are microbial-derived compounds with surface and emulsifying activities. Environmental and industrial applications make glycolipid biosurfactants particularly interesting among the several categories of biosurfactants. A potential glycolipid biosurfactant resource, Shewanella algae, was isolated from marine samples at the Persian Gulf. The glycolipid biosurfactant caused a reduction in water surface tension from 72 to 43 mN/m with a 0.25 mg/mL critical micelle concentration (CMC). Two-level factorial design was then applied for optimization of biosurfactant production, where a maximal reduction of culture broth surface tension (31 mN/m) acquired in the presence of crude oil (0.5%, v/v), NaNO3 (0.2 g/L), NH4Cl (0.7 g/L), and peptone (0.5 g/L). GC-MS analysis of the culture broth showed when crude oil was used as the sole carbon source, S. algae was able to degrade most of its alkane components. Nuclear magnetic resonance (NMR) and Fourier transform infrared (FTIR) spectroscopy revealed the glycolipid structure of biosurfactant. The glycolipid biosurfactant exhibited considerable growth inhibition of clinical bacterial pathogens and disrupted the preformed biofilms of Bacillus cereus (83%), Streptococcus pneumoniae (53%), Pseudomonas aeruginosa (92%), Escherichia coli (64%), Klebsiella pneumoniae (87%), and Acinetobacter sp. (72%). In conclusion, the glycolipid biosurfactant secreted by S. algae exhibited a wide range of functional properties and was evidenced as a promising candidate for biomedical application.

Investigation on the surface-active and antimicrobial properties of a natural glycolipid product.

Glycolipids are a group of sugar-containing lipids with versatile functions. In this study, a natural glycolipid product was obtained from soy lecithin, and its emulsifying, oil-gelling, antibacterial and antiviral properties were investigated. A silica-based extraction method on a preparative scale was used to recover the glycolipid product (GLP) from soy lecithin. The GLP consisted of three different glycolipid classes: acylated sterol glucoside (64.16%), sterol glucoside (25.57%) and cerebroside (6.71%). As an emulsifier, the GLP was able to form a stable water-in-oil emulsion. The GLP exhibited a good oil-gelling property, capable of gelling rapeseed oil at a concentration of 6%. For the investigated microorganisms (Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus), the GLP did not show any antibacterial effects. The GLP exerted antiviral activity against lentivirus, but not adenovirus. The results of this study help in enriching the knowledge on the properties of naturally occurring glycolipids, which may find potential applications in the food, pharmaceutical and related industries.

Synthetic Glycolipids as Molecular Vaccine Adjuvants: Mechanism of Action in Human Cells and In Vivo Activity.

Modern adjuvants for vaccine formulations are immunostimulating agents whose action is based on the activation of pattern recognition receptors (PRRs) by well-defined ligands to boost innate and adaptive immune responses. Monophosphoryl lipid A (MPLA), a detoxified analogue of lipid A, is a clinically approved adjuvant that stimulates toll-like receptor 4 (TLR4). The synthesis of MPLA poses manufacturing and quality assessment challenges. Bridging this gap, we report here the development and preclinical testing of chemically simplified TLR4 agonists that could sustainably be produced in high purity and on a large scale. Underpinned by computational and biological experiments, we show that synthetic monosaccharide-based molecules (FP compounds) bind to the TLR4/MD-2 dimer with submicromolar affinities stabilizing the active receptor conformation. This results in the activation of MyD88- and TRIF-dependent TLR4 signaling and the NLRP3 inflammasome. FP compounds lack in vivo toxicity and exhibit adjuvant activity by stimulating antibody responses with a potency comparable to MPLA.

Milk Polar Lipids Supplementation to Obese Rats During Pregnancy and Lactation Benefited Skeletal Outcomes of Male Offspring.

SCOPE: Dietary intervention to obese dams during pregnancy and lactation period provides avenues for improving metabolic profiles of the offspring. In the current study, the effects of polar lipids-enriched milk fat globule membrane (MFGM-PL) supplementation to obese dams during pregnancy and lactation on the skeletal outcomes of male offspring are investigated. METHODS AND RESULTS: MFGM-PL is supplemented to obese rats induced by high-fat diet during pregnancy and lactation at a dose of 400 mg kg-1 body weight. Results show that maternal MFGM-PL supplementation significantly ameliorates the stunted skeletal growth of male offspring at weaning. In adulthood offspring, maternal MFGM-PL supplementation protects against high-fat diet (HFD)-induced bone microstructure degeneration and bone marrow adipocyte accumulation. Further investigation shows that maternal supplementation of MFGM-PL significantly ameliorates insulin resistance and increases the mRNA expression of growth hormone releasing hormone (GHRH) in the hypothalamus of HFD offspring. The growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis is subsequently enhanced in MFGM-PL + HFD offspring, contributing to the beneficial skeletal outcomes. CONCLUSION: The findings suggest that maternal MFGM-PL supplementation of HFD dam during pregnancy and lactation shows desirable effects on fetal skeletal development, with lasting beneficial programming impacts on skeletal outcomes of offspring.

Investigation on spectral and biomedical characterization of rhamnolipid from a marine associated bacterium Pseudomonas aeruginosa (DKB1).

Bio-surfactants are a principal group of significant molecules obtained from the microbial sources expressed with distinctive characteristics like biodegradation of hydrocarbons and also have different biomedical properties. The present investigation aims to assess the biomedical properties of synthesized bio-surfactant, rhamnolipid from Pseudomonas aeruginosa (DKB1) under in vitro conditions. The candidate bacterium P. aeruginosa (DKB1) was isolated from oil-polluted fishing harbors of Kanyakumari coast. Initially, the bio-surfactant production by this candidate strain was confirmed by oil displacement assay, hemolytic assay, drop collapse assay and emulsification index. Further, the production of bio-surfactant was achieved through submerged fermentation process using Bushnell-Haas mineral salts medium supplemented with 2% olive oil. The yield of the bio-surfactant was attained as 2.4 g/l and confirmed as rhamnolipid through blue agar plate assay; further, the extracted rhamnolipid was purified and characterized through standard procedures. In stability studies, the rhamnolipid could withstand up to pH 12, temperature 100 °C and 15% of NaCl concentration. The biomedical application of rhamnolipid (30 µg ml-1) was determined by antibacterial, antioxidant and cytotoxic studies. It exhibited a maximum growth inhibition against Bacillus subtilis (26 mm) with the MIC value of 8 µg ml-1. In antioxidant test, rhamnolipid expressed significant (P < 0.0001) inhibition of total reducing power (44.11%), DPPH activity (61.60%), hydroxyl radical (83.30%) and nitric oxide (51.86%) scavenging ability at 100 µg ml-1with the respective IC50 values of 130.50, 77.18, 52.08 and 95.43 µg ml-1. The anticancer activity of the rhamnolipid was assessed with the help of MTT test against MCF-7, HT-29 and E-143 cancer cell lines individually, and the viability of the cells was observed, respectively, as 10.24, 17.66 and 13.50% at 250 µg ml-1concentration with the respective IC50 values of 140.2, 81.02 and 138.9 µg ml-1. From the results, it could be concluded that the rhamnolipid produced by P. aeruginosa (DKB1) isolated from oil-polluted area has effective biomedical properties.

N-palmitoyl-D-glucosamine, a Natural Monosaccharide-Based Glycolipid, Inhibits TLR4 and Prevents LPS-Induced Inflammation and Neuropathic Pain in Mice.

Toll-like receptors (TLRs) are key receptors through which infectious and non-infectious challenges act with consequent activation of the inflammatory cascade that plays a critical function in various acute and chronic diseases, behaving as amplification and chronicization factors of the inflammatory response. Previous studies have shown that synthetic analogues of lipid A based on glucosamine with few chains of unsaturated and saturated fatty acids, bind MD-2 and inhibit TLR4 receptors. These synthetic compounds showed antagonistic activity against TLR4 activation in vitro by LPS, but little or no activity in vivo. This study aimed to show the potential use of N-palmitoyl-D-glucosamine (PGA), a bacterial molecule with structural similarity to the lipid A component of LPS, which could be useful for preventing LPS-induced tissue damage or even peripheral neuropathies. Molecular docking and molecular dynamics simulations showed that PGA stably binds MD-2 with a MD-2/(PGA)3 stoichiometry. Treatment with PGA resulted in the following effects: (i) it prevented the NF-kB activation in LPS stimulated RAW264.7 cells; (ii) it decreased LPS-induced keratitis and corneal pro-inflammatory cytokines, whilst increasing anti-inflammatory cytokines; (iii) it normalized LPS-induced miR-20a-5p and miR-106a-5p upregulation and increased miR-27a-3p levels in the inflamed corneas; (iv) it decreased allodynia in peripheral neuropathy induced by oxaliplatin or formalin, but not following spared nerve injury of the sciatic nerve (SNI); (v) it prevented the formalin- or oxaliplatin-induced myelino-axonal degeneration of sciatic nerve. SIGNIFICANCE STATEMENT We report that PGA acts as a TLR4 antagonist and this may be the basis of its potent anti-inflammatory activity. Being unique because of its potency and stability, as compared to other similar congeners, PGA can represent a tool for the optimization of new TLR4 modulating drugs directed against the cytokine storm and the chronization of inflammation.

Milk Fat Globule Membrane as a Modulator of Infant Metabolism and Gut Microbiota: A Formula Supplement Narrowing the Metabolic Differences between Breastfed and Formula-Fed Infants.

SCOPE: Milk fat globule membrane (MFGM) is an important component of milk that has previously been removed in the manufacture of infant formulas, but has recently gained attention owing to its potential to improve immunological, cognitive, and metabolic health. The goal of this study is to determine whether supplementing MFGM in infant formula would drive desirable changes in metabolism and gut microbiota to elicit benefits observed in prior studies. METHODS AND RESULTS: The serum metabolome and fecal microbiota are analyzed using 1 H NMR spectroscopy and 16S rRNA gene sequencing respectively in a cohort of Chinese infants given a standard formula or a formula supplemented with an MFGM-enriched whey protein fraction. Supplementing MFGM suppressed protein degradation pathways and the levels of insulinogenic amino acids that are typically enhanced in formula-fed infants while facilitating fatty acid oxidation and ketogenesis, a feature that may favor brain development. MFGM supplementation did not induce significant compositional changes in the fecal microbiota but suppressed microbial diversity and altered microbiota-associated metabolites. CONCLUSION: Supplementing MFGM in a formula reduced some metabolic gaps between formula-fed and breastfed infants.

The bio-surfactant mannosylerythritol lipid acts as a selective antibacterial agent to modulate rumen fermentation.

Methyl-mannosylerythritol lipid (MEL), a new sugar esterified lipid synthesized by Pseudozyma aphidis, was assessed for its functionality in modulating rumen fermentation and microbiota toward more propionate and less methane production. A pure culture study using rumen representatives showed that MEL selectively inhibited the growth of most Gram-positive bacteria including Streptococcus bovis, ruminococci, and Fibrobacter succinogenes, but not Gram-negative bacteria such as Megasphaera elsdenii, Succinivibrio dextrinosolvens, and Selenomonas ruminantium. A batch culture study revealed that MEL significantly decreased methane production in a dose-dependent manner with accumulation of hydrogen, while propionate production was enhanced. A continuous culture (Rusitec) study confirmed all of these changes. A feeding study revealed that sheep fed a MEL diet showed an increased proportion of propionate, while proportions of acetate and butyrate were decreased without affecting total VFA level. These changes disappeared after cessation of MEL feeding. Based on these results, dietary application of MEL can favorably modify rumen fermentation in terms of the efficiency of dietary energy utilization.

Dietary Milk Fat Globule Membrane Restores Decreased Intestinal Mucosal Barrier Development and Alterations of Intestinal Flora in Infant-Formula-Fed Rat Pups.

SCOPE: Milk fat globule membrane (MFGM), which contains abundant polar lipids and glycoproteins, can narrow the gap in growth and development between breast-fed and infant-formula-fed babies. The objective of this study is to evaluate the effect of MFGM supplementation in infant formula on intestinal epithelium maturation, tight junctions, and gut colonization in rat pups. METHODS AND RESULTS: Sprague Dawley rat pups consume one of the five diets from postnatal day 8, including rat breastfeeding (BF), infant formula (IF), and infant formula containing MFGM at 260 mg kg-1 body weight (BW), 520 mg kg-1 BW, or 1040 mg kg-1 BW. Results show that MFGM supplementation in infant formula can facilitate intestinal mucosal barrier maturation via promoting intestinal proliferation and differentiation, and increasing tight junction proteins. In addition, compared with that of the IF pups, the intestinal flora composition of MFGM-supplemented pups is more similar to that of BF pups. CONCLUSION: MFGM supplementation in infant formula can restore the intestinal development in infant-formula-fed pups, which suggests that the supplementation of MFGM in infant formula can better mimic breast milk.

Hypoxia Promotes Prostate Cancer Aggressiveness by Upregulating EMT-Activator Zeb1 and SK3 Channel Expression.

Hypoxia is a well-established feature of prostate cancer (PCa) and is associated with disease aggressiveness. The hypoxic microenvironment initiates multiple adaptive responses including epithelial-to-mesenchymal transition (EMT) and a remodeling of calcium homeostasis involved in cancer progression. In the present study, we identified a new hypoxia signaling pathway with a positive feedback loop between the EMT transcription factor Zeb1 and SK3, a Ca2+-activated K+ channel, which leads to amplifying store-operated Ca2+ entry. Zeb1 and SK3 channel were strongly upregulated by hypoxia both in vitro and ex vivo in organotypic cultures of human PCa. Taking into account the sensitivity of the SK3 channel to the membrane lipid composition, we identified lipids such as Ohmline (an alkyl ether lipid and SK3 inhibitor), linoleic acid (LA) and eicosapentaenoic acid (EPA) (fatty acids associated with indolent PCa), which were able to completely abrogate the hypoxia-induced changes in Zeb1 expression. Ultimately, better understanding of this new hypoxia-induced EMT pathway may allow to develop adjuvant therapeutic strategies, in order to control PCa aggressiveness and improve treatment outcomes.

Rhamnolipid-assisted mycoremediation of polycyclic aromatic hydrocarbons by Trametes hirsuta coupled with enhanced ligninolytic enzyme production.

The present study deals with the development of a wood assisted fungal system (WAFS) from wood chips using Trametes hirsuta to remove polycyclic aromatic hydrocarbons (PAHs) in BRW. The WAFS exhibited a 1.4-fold higher ligninolytic enzyme production than free fungi in the effluent. Further, to understand PAHs bioremediation by T. hirsuta, biodegradation along with biosorption were studied in model PAHs, phenanthrene (Phe) and benzo (a) pyrene (BaP), in the presence of synthesized rhamnolipids. The WAFS mineralized up to an average of 91.26% Phe and 87.72 % BaP along with biosorption of 12.35% Phe and 18.36 % BaP within 12 days. Thus, the addition of rhamnolipids showed 1.2-fold enhanced biodegradation. However, rhamnolipid concentrations beyond 50 ppm reduced the degradation efficiency of WAFS. Moreover, the degradation capability of total aromatic hydrocarbon (TAH) in biorefinery wastewater by WAFS is 1.8-fold higher than that of free fungi, which confirms the effectiveness of the system. Implications: Simultaneous application of white-rot fungus along with surfactant into a pollutant environment affects the microenvironment of the fungus and reduces the production of their degradative enzymes. In addition, the requirement of periodical supplement of external nutrient in the real-time matrix for the growth of white rot fungi may trigger competitive growth of indigenous microorganisms. Considering this glitch, the current work utilizes the carpenter waste for the strategical develop a wood assisted fungal system to protect the microenvironment of the fungi in the presence of rhamnolipids and contribute to their survival in real time matrix, with enhanced PAHs degradation efficiency.