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Human milk oligosaccharides (HMOs) and the milk fat globule membrane (MFGM) represent novel treatments for cow's milk allergy (CMA). They exhibit the beneficial attribute of diminishing nutrient damage when compared to conventional enzymatic digestion of milk proteins. However, the effects and mechanisms underlying the synergistic interaction between HMOs and the MFGM in allergy treatment remain unclear. Consequently, this study was undertaken to assess the protective properties of HMOs and the MFGM against CMA and to elucidate their potential mechanisms in a mouse model of β-lactoglobulin (BLG)-induced allergy. The findings demonstrated that HMOs and the MFGM could significantly reduce the allergy score and splenic index, and they diminished the levels of inflammatory mediators (total immunoglobulin E (IgE), specific IgE, histamine, and mMCP-1), while concurrently bolstering tight junctions ( ZO-1 , claudin-1 , and occludin ), and reducing intestinal permeability. Notably, HMOs and the MFGM exhibited optimal synergy. In addition, HMOs and the MFGM synergistically mitigated the immune response to Th2 overactivity in allergy by the promotion of Th1 and Treg cell responses, thereby suppressing the levels of inflammatory cytokines IL-4 and IL-5. Analysis of the gut microbiota and its metabolic activities revealed that HMOs and the MFGM increased the abundance of Lactobacillus and Butyricicoccus , leading to higher production of butyrate. Furthermore, these beneficial bacteria and the resultant butyrate also contributed to the suppression of allergy-associated bacterial populations such as Desulfovibrio and Rikenellaceae . In summary, HMOs and the MFGM acted in synergy to modulate inflammatory responses and ameliorate barrier damage, contributing to the mitigation of CMA, a process potentially linked to gut microbiota dynamics and the resultant butyrate metabolism. This effect may be related to the gut microbiota and its metabolic production of butyrate.

Active vitamin D, known for its role in promoting osteoporosis, has immunomodulatory effects according to the latest evidence. Eldecalcitol (ED-71) is a representative of the third-generation novel active vitamin D analogs, and its specific immunological mechanisms in ameliorating diabetic osteoporosis remain unclear. We herein evaluated the therapeutic effects of ED-71 in the context of type 2 diabetes mellitus (T2DM), delving into its underlying mechanisms. In a T2DM mouse model, ED-71 attenuated bone loss and marrow adiposity. Simultaneously, it rectified imbalanced glucose homeostasis and dyslipidemia, ameliorated pancreatic β-cell damage and hepatic glycolipid metabolism disorder. Subsequently, in mice injected with the Treg cell-depleting agent CD25, we observed that the beneficial effects of ED-71 mentioned earlier were partially contingent on the Treg subsets ratio. Mechanistically, ED-71 promoted the differentiation of CD4 + T cells into Treg subsets, facilitating Ca 2+ influx and the expression of ORAI1 and STIM1, pivotal proteins in store-operated Ca 2+ entry (SOCE). The SOCE inhibitor, 2-APB, partially attenuated the positive effects of ED-71 observed in the above results. Overall, ED-71 regulates SOCE-mediated Treg cell differentiation, accomplishing the dual purpose of simultaneously ameliorating diabetic osteoporosis and glucolipid metabolic disorders, showcasing its potential in osteoimmunity therapy and interventions for diseases involving SOCE., (© 2024. The Author(s).)

Coronary atherosclerotic heart disease (CHD) is a primary cardiovascular disease caused by atherosclerosis (AS), which is characterized by chronic inflammation and lipid oxidative deposition. Molecular hydrogen (H 2 ) is an effective anti-inflammatory agent and has potential to ameliorate glycolipid metabolism disorders, which is believed to exert beneficial effects on the prevention and treatment of CHD. It is suggested that H 2 reduces inflammation in CHD by regulating multiple pathways, including NF-κB inflammatory pathway, pyroptosis, mitophagy, endoplasmic reticulum (ER) stress, and Nrf2 antioxidant pathway. Additionally, H 2 may improve glycolipid metabolism by mediation of PI3K and AMPK signalling pathways, contributing to inhibition of the occurrence and development of CHD. This review elaborates pathogenesis of CHD and evaluates the role of H 2 in CHD. Moreover, possible molecular mechanisms have been discussed and speculated, aiming to provide more strategies and directions for subsequent studies of H 2 in CHD., 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.)

To investigate whether Liraglutide combined with Jinlida granules affects glycolipid metabolism and islet function in the treatment of type 2 diabetes mellitus (T2DM), a control group and an observation group were established with 90 T2DM patients. The control group was given Jinlida treatment and the observation group was given liraglutide combined treatment for 12 weeks. The clinical efficacy, glycolipid metabolism, bone metabolism, islet function, and endothelial function. The curative effect of the observation group was better than that of the control group. After treatment, FBG, 2hPG, HbAlc, TC, TG, and LDL-C in the observation group were lower and HDL-C was higher than those in the control group (P < 0.05). After treatment, the observation group showed higher bone mineral density, osteocalcin, FINS, and HOMA-β and lower HOMA-IR than the control group (P < 0.05). After treatment, endothelin-1 level in the observation group was lower than that in the control group, and the NO level was higher (P < 0.05). No significant difference was found in the incidence of adverse reactions between the two groups (P > 0.05). Liraglutide combined with Jinlida in T2DM can improve glucose, lipid, and bone metabolism, promote the recovery of islet function, and enhance vascular endothelial function.

Objective: To explore the comparative effectiveness of nutritional supplements in improving glycolipid metabolism and endocrine function in patients with polycystic ovary syndrome (PCOS)., Method: Randomized controlled clinical trials on the effects of nutritional supplements in PCOS patients were searched in PubMed, Embase, Cochrane Library, and Web of Science from their establishments to March 15, 2023. Then, literature screening, data extraction, and network meta-analysis were performed. This study was registered at PROSPERO (registration number CRD 42023441257)., Result: Forty-one articles involving 2,362 patients were included in this study. The network meta-analysis showed that carnitine, inositol, and probiotics reduced body weight and body mass index (BMI) compared to placebo, and carnitine outperformed the other supplements (SUCRAs: 96.04%, 97.73%, respectively). Omega-3 lowered fasting blood glucose (FBG) (SUCRAs: 93.53%), and chromium reduced fasting insulin (FINS) (SUCRAs: 72.90%); both were superior to placebo in improving insulin resistance index (HOMA-IR), and chromium was more effective than Omega-3 (SUCRAs: 79.99%). Selenium was potent in raising the quantitative insulin sensitivity index (QUICKI) (SUCRAs: 87.92%). Coenzyme Q10 was the most effective in reducing triglycerides (TG), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C) levels (SUCRAs: 87.71%, 98.78%, and 98.70%, respectively). Chromium and probiotics decreased TG levels, while chromium and vitamin D decreased TC levels. No significant differences were observed in high-density lipoprotein cholesterol (HDL-C), total testosterone (TT), sex-hormone binding globulin (SHBG), and C-reactive protein (CRP) between nutritional supplements and placebo., Conclusion: Carnitine was relatively effective in reducing body mass, while chromium, Omega-3, and selenium were beneficial for improving glucose metabolism. Meanwhile, coenzyme Q10 was more efficacious for improving lipid metabolism. However, publication bias may exist, and more high-quality clinical randomized controlled trials are needed., Competing Interests: The authors declare that they have no competing interests., (© 2023 Hu et al.)

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline and currently there are no available treatments. Alongside the conventional Aβ and tau hypotheses, neuroinflammation and metabolism disruption have also been regarded as crucial hallmarks of AD. In this study, a novel Chinese formula Nao Tan Qing (NTQ) was developed and shown to improve AD. In vivo experiments showed that NTQ significantly mitigated cognitive impairment, Aβ burden and neuroinflammation in a transgenic AD mouse model (5×FAD). Network pharmacology results revealed that the active components of NTQ could target inflammatory and metabolic pathways. In addition, hippocampal transcriptomics suggested that NTQ regulated signaling pathways related to inflammation and lipid metabolism. Consistently, serum metabolomics further indicated that NTQ could modulate glycolipid metabolism. In summary, a combination of systems pharmacology analysis and biological validation study demonstrates that NTQ could alleviate behavioral abnormality and pathological alterations of AD by targeting glycolipid metabolism and neuroinflammation, and is accordingly a potential therapeutic agent for AD., Competing Interests: Conflict of interest The authors declare no conflicts of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objective: This study investigated the potential mechanisms behind the beneficial effects of Fructus Zanthoxyli (FZ) against type 2 diabetes mellitus (T2DM) based on network pharmacology and experimental validation., Methods: Ultra-high-performance liquid chromatography coupled with hybrid quadrupole-orbitrap high-resolution mass spectrometry, and gas chromatography-mass spectrometry were used to identify the constituents of FZ. Next, the differentially expressed genes linked to the treatment of diabetes with FZ were screened using online databases (including Gene Expression Omnibus database and Swiss Target Prediction online database), and the overlapping genes and their enrichment were analyzed by Kyoto Encyclopedia of Genes and Genomes (KEGG). Finally, the pathway was verified by in vitro experiments, and cell staining with oil red and Nile red showed that the extract of FZ had a therapeutic effect on T2DM., Results: A total of 43 components were identified from FZ, and 39 differentially expressed overlapping genes were screened as the possible targets of FZ in T2DM. The dug component-target network indicated that PPARA, PPARG, PIK3R3, JAK2 and GPR88 might be the core genes targeted by FZ in the treatment of T2DM. Interestingly, the enrichment analysis of KEGG showed that effects of FZ against T2DM were closely correlated with the adenosine monophosphate-activated protein kinase (AMPK) and phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) signaling pathways. In vitro experiments further confirmed that FZ significantly inhibited palmitic acid-induced lipid formation in HepG2 cells. Moreover, FZ treatment was able to promote the AMPK and PI3K/Akt expressions in HepG2 cells., Conclusion: Network pharmacology combined with experimental validation revealed that FZ extract can improve the glycolipid metabolism disorder of T2DM via activation of the AMPK/PI3K/Akt pathway., (Copyright © 2022 Shanghai Changhai Hospital. Published by Elsevier B.V. All rights reserved.)

Context: Diabetes mellitus (DM) represents an emerging epidemic, poses serious threats to human health, and can seriously compromise patients' quality of life (QoL). Currently, no cure exists for DM. Some studies have found that both liraglutide and dapagliflozin have great therapeutic potential in preventing and treating DM and its complications., Objective: The study aimed to examine the impact of liraglutide plus dapagliflozin on high uric acid (UA) and microalbuminuria (MAU) in patients with diabetes mellitus (DM) complicated with metabolic syndrome (MS)., Design: The research team designed a randomized controlled trial., Setting: The study took place at the Second Affiliated Hospital of Nanjing Medical University in Nanjing, Jiangsu, China., Participants: Participants were 125 patients with DM complicated with MS who were treated in the outpatient clinic of the endocrinology department at the hospital between January 1, 2020 and December 31, 2021, with 68 in the intervention group and 57 in the control group., Intervention: The intervention and control groups both received 0.6 mg of liraglutide. The intervention group also received 5 mg of dapagliflozin once a day. The dosages were increased at one week after baseline based on the participant's condition., Outcome Measures: Therapeutic effects, glycolipid metabolism, inflammation, uric acid (UA), microalbuminuria (MAU), cardiac function, and quality of life (QoL) were compared between the two groups., Results: Postintervention, the clinical efficacy was significantly higher in the intervention group than in the control group. The intervention group had significantly lower glycolipid metabolism and inflammatory-factor levels than the control group UA and MAU had declined in both groups but were significantly lower in the intervention group. The left ventricular ejection fraction (LVEF) increased and the left ventricular end diastolic diameter (LVEDd) decreased in both groups, but the intervention group had significantly greater changes as compared with those in the control group. The intervention group was also superior to the control group in patients' QoL., Conclusions: Liraglutide plus dapagliflozin has highly therapeutic effect for patients with DM complicated with MS and can effectively reduce UA and MAU levels. The current research team will launch a more comprehensive analysis as soon as possible to obtain the most accurate results.

What Is Fabry Disease & What Is This Study About?: Fabry disease is a rare genetic condition that affects many different cells and organs in the body. People have Fabry disease when they inherit a GLA gene containing an error from one or both of their parents. This causes an enzyme in their body called alpha-galactosidase (also called α- Gal ) to not work properly. In people without Fabry disease, a-Gal breaks down fats called glycolipids . In people with Fabry disease, as a-Gal does not work properly, glycolipids build up in the body, particularly in the cells of the kidney, heart, nerves, and the cells that line blood vessels. People who have Fabry disease can receive an enzyme replacement therapy (ERT for short) called agalsidase beta , which acts as a substitute for a-Gal. Although both males and females can have Fabry disease, it generally affects males more severely than females, and symptoms in females can vary significantly. Several researchers have studied the long-term effects of agalsidase beta ERT in males, but there have been fewer studies in females. This study looked at women with Fabry disease who started receiving agalsidase beta treatment when they were at least 18 years old, using information from the Fabry Registry (the largest worldwide database that collects and stores information about people with Fabry disease). The researchers evaluated heart muscle thickness (thickening can be a sign of poor heart health) and kidney function from 5 years before women with Fabry disease started agalsidase beta treatment to 5 years after they started treatment., What Were the Study Results?: Before women with Fabry disease started treatment, their heart muscle tended to thicken over time. After starting treatment, their heart muscle thickening slowed. Kidney function was similar to that of unaffected people both before and after treatment., What Do the Results of the Study Mean?: This study provides a unique insight into the effects of agalsidase beta in women with Fabry disease. The findings suggest that agalsidase beta may slow heart muscle thickening and maintain normal kidney function in women with Fabry disease. Clinical Trial Registration : NCT00196742 (ClinicalTrials.gov).

The soaring global prevalence of diabetes makes it urgent to explore new drugs with high efficacy and safety. Nanomaterial-derived bioactive agents are emerging as one of the most promising candidates for biomedical application. In the present study, we investigated the anti-diabetic effects of a functionalized gadofullerene (GF) using obese db/db and non-obese mouse model of type 2 diabete mellitus (MKR) mouse type 2 diabetes mellitus (T2DM) models. In both mouse models, the diabetic phenotypes, including hyperglycemia, impaired glucose tolerance, and insulin sensitivity, were ameliorated after two or four weeks of intraperitoneal administration of GF. GF lowered blood glucose levels in a dose-dependent manner. Importantly, the restored blood glucose levels could persist ten days after withdrawal of GF treatment. The hepatic AKT/GSK3β/FoxO1 pathway is shown to be the main target of GF for rebalancing gluconeogenesis and glycogen synthesis in vivo and in vitro. Furthermore, GF treatment significantly reduced weight gain of db/db mice with reduced hepatic fat storage by the inhibition of de novo lipogenesis through mTOR/S6K/SREBP1 pathway. Our data provide compelling evidence to support the promising application of GF for the treatment of T2DM., Competing Interests: Conflict of interest The authors declares that they do not have any commercial or associative interest that represents a conflict of interest in connection with the work submitted., (Copyright © 2021 Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, and Genetics Society of China. Published by Elsevier Ltd. All rights reserved.)

Background: This study evaluated E-selectin inhibition with GMI-1271 (Uproleselan [GMI]) alone and in combination with the standard of care low-molecular-weight heparin (LMWH) to improve vein recanalization, decrease vein wall inflammation and protect against adverse bleeding in a primate model. We sought to examine this novel treatment of venous thrombosis., Methods: Using a well-documented primate animal model, iliac vein thrombosis was induced by balloon occlusion of the iliac vein for 6 hours. Starting on day 2 after thrombosis, animals began treatment in two phases. In phase one, nontreated controls received no treatment (n = 5) vs animals treated with the E-selectin inhibitor GMI, 25 mg/kg, subcutaneous (SC), once daily (n = 4) for 21 days (previously published data). In phase two, animals were treated with GMI plus a combination of LMWH 1.5 mg/kg or 40 mg (GMI + LMWHc) SC once daily (n = 8) for 19 days; and animals treated with LMWH 1.5 mg/kg or 40 mg (LMWHc) SC once daily (n = 6) for 19 days. Animals were evaluated by magnetic resonance venography for vein recanalization and inflammation by gadolinium extravasation, duplex ultrasound, coagulation tests (thromboelastography, bleeding time, prothrombin time, activated partial thromboplastin time, fibrinogen) and complete blood count at baseline, days 2, 7, 14, and 21 at euthanasia. Statistical analysis included using unpaired t test with Welch's correction for direct comparisons and one-way analysis of variance for comparison between the groups., Results: Percent vein recanalization by magnetic resonance venography was highest in the GMI alone group followed by GMI + LMWHc, both significantly different from control. On ultrasound examination, animals treated with GMI alone had no decrease in open vein lumen by day 21, whereas decreases were observed in groups GMI + LMWHc (-26%), LMWHc (-27%), and controls (-80%). Vein wall inflammation decreased significantly in all treated groups. Intimal fibrosis and intimal thickness was best preserved in the GMI alone group. An analysis of total vein wall collagen revealed a trend in all treatment groups of decreasing vein wall collagen. No clinically significant bleeding events were noted in any group. The LMWH groups trended to have prolonged coagulation test values, whereas E-selectin inhibition with GMI did not cause clinically significant changes in coagulation measures., Conclusions: Treatment with E-selectin inhibition results in improved vein recanalization, a decrease in vein wall inflammation and vein wall intimal thickness and fibrosis, with no changes in markers of coagulation. E-selectin inhibition with GMI alone is superior to E-selectin inhibition combined with LMWH, LMWH alone, and no treatment in this deep vein thrombosis model of iliac vein thrombosis., (Copyright © 2021. Published by Elsevier Inc.)

sp 2 -Iminosugar glycolipids (sp 2 -IGLs) represent a consolidated family of glycoconjugate mimetics encompassing a monosaccharide-like glycone moiety with a pseudoamide-type nitrogen replacing the endocyclic oxygen atom of carbohydrates and an axially-oriented lipid chain anchored at the pseudoanomeric position. The combination of these structural features makes them promising candidates for the treatment of a variety of conditions, spanning from cancer and inflammatory disorders to parasite infections. The exacerbated anomeric effect associated to the putative sp 2 -hybridized N-atom imparts chemical and enzymatic stability to sp 2 -IGLs and warrants total α-anomeric stereoselectivity in the key glycoconjugation step. A variety of O -, N -, C - and S -pseudoglycosides, differing in glycone configurational patterns and lipid nature, have been previously prepared and evaluated. Here we expand the chemical space of sp 2 -IGLs by reporting the synthesis of α-d-gluco-configured analogs with a bicyclic (5 N ,6 O -oxomethylidene)nojirimycin (ONJ) core incorporating selenium at the glycosidic position. Structure-activity relationship studies in three different scenarios, namely cancer, Leishmaniasis and inflammation, convey that the therapeutic potential of the sp 2 -IGLs is highly dependent, not only on the length of the lipid chain (linear aliphatic C 12 vs. C 8 ), but also on the nature of the glycosidic atom (nitrogen vs. sulfur vs. selenium). The ensemble of results highlights the α-dodecylseleno-ONJ-glycoside as a promising multitarget drug candidate.

The purpose of this study was to evaluate the relieving effect of tilapia head glycolipids (TH-GLs) on dextran sulfate sodium (DSS)-induced colitis in mice and to further explore its mechanism. Mice were orally administered 3% (w/v) DSS to establish a model of ulcerative colitis (UC), and subsequently treated with TH-GLs or sulfasalazine. In addition, the expression of key targets in the intestinal mucosal barrier and the inflammatory signal pathway were studied by combining immunochemical analysis techniques. The results showed that varying doses of TH-GLs can significantly improve colon lesions caused by DSS, reduce histological scores, increase mucus secretion, extend colon length, increase weight, and inhibit the occurrence of inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), Interleukin-1β (IL-1β), and Interleukin- 6 (IL-6). Further, studies have shown that TH-GLs increase the secretion of MUC2 and up-regulate the expression of tight junction related proteins, such as ZO-1 and Occludin. In addition, TH-GLs significantly down-regulated the protein expression levels of TNF-α, IKK-β, and nuclear factor-κB (NF-κB). Here, we have elucidated the potential mechanism of TH-GLs in protecting mice with colitis. In general, this study shows that TH-GLs could improve the symptoms of UC by improving the gut barrier and inhibiting inflammatory signals, which provides a scientific basis for future clinical applications., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Previous studies have shown that berberine can improve metabolic disturbances in non-psychiatric patients, but no clinical research has been conducted in schizophrenia. This study was a randomized, double-blind, placebo-controlled clinical trial. Eligible patients diagnosed with schizophrenia were randomized to receive placebo or berberine (900mg/day) as an adjunctive treatment for eight weeks. Peripheral glycolipid metabolism parameters were measured at baseline, week 4, and week 8. Sixty-five patients were included, and forty-nine patients completed the 8-week trial. Berberine led to significant declines in total cholesterol, low-density lipoprotein cholesterol, fasting serum insulin, and insulin resistance(all p<0.05) compared with placebo. Baseline body mass index and serum prolactin concentration could predict the effect of berberine on insulin resistance. Berberine adjunctive treatment may reduce the risk of glycolipid metabolic disturbances in patients with schizophrenia., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Covering: up to 2020 This short review surveys aspects of glycolipid-based natural products and their biological relevance in multiple sclerosis (MS). The role of isolated gangliosides in disease models is discussed together with an overview of ganglioside-inspired small molecule drugs and imaging probes. The discussion is extended to neurodegeneration in a more general context and addresses the need for more efficient synthetic methods to generate (glyco)structures that are of therapeutic relevance.

TLRs, including TLR4, play a crucial role in inflammatory-based diseases, and TLR4 has been identified as a therapeutic target for pharmacological intervention. In previous studies, we investigated the potential of FP7, a novel synthetic glycolipid active as a TLR4 antagonist, to inhibit haematopoietic and non-haematopoietic MyD88-dependent TLR4 pro-inflammatory signalling. The main aim of this study was to investigate the action of FP7 and its derivative FP12 on MyD88-independent TLR4 signalling in THP-1 derived macrophages. Western blotting, Ab array and ELISA approaches were used to explore the effect of FP7 and FP12 on TRIF-dependent TLR4 functional activity in response to LPS and other endogenous TLR4 ligands in THP-1 macrophages. A different kinetic in the inhibition of endotoxin-driven TBK1, IRF3 and STAT1 phosphorylation was observed using different LPS chemotypes. Following activation of TLR4 by LPS, data revealed that FP7 and FP12 inhibited TBK1, IRF3 and STAT1 phosphorylation which was associated with down-regulation IFN-β and IP-10. Specific blockage of the IFN type one receptor showed that these novel molecules inhibited TRIF-dependent TLR4 signalling via IFN-β pathways. These results add novel information on the mechanism of action of monosaccharide FP derivatives. The inhibition of the TRIF-dependent pathway in human macrophages suggests potential therapeutic uses for these novel TLR4 antagonists in pharmacological interventions on inflammatory diseases.

Background: Recent years have witnessed a considerable increase in clinical trials of new investigational agents for Fabry disease (FD). Several trials investigating different agents are currently in progress; however, lack of standardisation results in challenges to interpretation and comparison. To facilitate the standardisation of investigational programs, we have developed a common framework for future clinical trials in FD., Methods and Findings: A broad consensus regarding clinical outcomes and ways to measure them was obtained via the Delphi methodology. 35 FD clinical experts from 4 continents, representing 3389 FD patients, participated in 3 rounds of Delphi procedure. The aim was to reach a consensus regarding clinical trial design, best treatment comparator, clinical outcomes, measurement of those clinical outcomes and inclusion and exclusion criteria. Consensus results of this initiative included: the selection of the adaptative clinical trial as the ideal study design and agalsidase beta as ideal comparator treatment due to its longstanding use in FD. Renal and cardiac outcomes, such as glomerular filtration rate, proteinuria and left ventricular mass index, were prioritised, whereas neurological outcomes including cerebrovascular and white matter lesions were dismissed as a primary or secondary outcome measure. Besides, there was a consensus regarding the importance of patient-related outcomes such as general quality of life, pain, and gastrointestinal symptoms. Also, unity about lysoGb3 and Gb3 tissue deposits as useful surrogate markers of the disease was obtained. The group recognised that cardiac T1 mapping still has potential but requires further development before its widespread introduction in clinical trials. Finally, patients with end-stage renal disease or renal transplant should be excluded unless a particular group for them is created inside the clinical trial., Conclusion: This consensus will help to shape the future of clinical trials in FD. We note that the FDA has, coincidentally, recently published draft guidelines on clinical trials in FD and welcome this contribution., (Copyright © 2021. Published by Elsevier Inc.)

Diabetic retinopathy (DR) is one of the most common complications of Diabetes Mellitus (DM) and is directly associated with inflammatory processes. Currently, neuro-inflammation is considered an early event in DR and proceeds via microglia polarization. A hallmark of DR is the presence of retinal reactive gliosis. Here we report the beneficial effect of ( S S ,1 R )-1-docecylsulfiny-5 N ,6 O -oxomethylidenenojirimycin (( Ss )-DS-ONJ), a member of the sp 2 -iminosugar glycolipid (sp 2 -IGL) family, by decreasing iNOS and inflammasome activation in Bv.2 microglial cells exposed to pro-inflammatory stimuli. Moreover, pretreatment with ( Ss )-DS-ONJ increased Heme-oxygenase (HO)-1 as well as interleukin 10 (IL10) expression in LPS-stimulated microglial cells, thereby promoting M2 (anti-inflammatory) response by the induction of Arginase-1. The results strongly suggest that this is the likely molecular mechanism involved in the anti-inflammatory effects of ( S S )-DS-ONJ in microglia. ( S S )-DS-ONJ further reduced gliosis in retinal explants from type 1 diabetic BB rats, which is consistent with the enhanced M2 response. In conclusion, targeting microglia polarization dynamics in M2 status by compounds with anti-inflammatory activities offers promising therapeutic interventions at early stages of DR., 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 © 2021 Cano-Cano, Alcalde-Estévez, Gómez-Jaramillo, Iturregui, Sánchez-Fernández, García Fernández, Ortiz Mellet, Campos-Caro, López-Tinoco, Aguilar-Diosdado, Valverde and Arroba.)

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., Competing Interests: The authors declare no conflict of interest.

Naxitamab (DANYELZA ® , naxitamab-gqgk) is a humanised (IgG1) anti-GD2 (hu3F8) monoclonal antibody was developed by the Memorial Sloan Kettering Cancer Center (with commercial rights licenced to Y-mAbs therapeutics Inc.) for the treatment of neuroblastoma, osteosarcoma and other GD2-positive cancers. Naxitamab was recently granted accelerated approval by the US FDA for marketing as treatment (in combination with granulocyte-macrophage colony-stimulating factor) for paediatric patients at least one year of age and adult patients with relapsed or refractory high-risk neuroblastoma in the bone or bone marrow demonstrating a partial response, minor response, or stable disease to prior therapy. This article summarizes the milestones in the development of naxitamab leading to this first approval.

Immunotherapies for cancers may cause severe and life-threatening cardiotoxicities. The underlying mechanisms are complex and largely elusive. Currently, there are several ongoing clinical trials based on the use of activated invariant natural killer T (iNKT) cells. The potential cardiotoxicity commonly associated with this particular immunotherapy has yet been carefully evaluated. The present study aims to determine the effect of activated iNKT cells on normal and β-adrenergic agonist (isoproterenol, ISO)-stimulated hearts. Mice were treated with iNKT stimulants, α-galactosylceramide (αGC) or its analog OCH, respectively, to determine their effect on ISO-induced cardiac injury. We showed that administration of αGC (activating both T helper type 1 (Th1)- and T helper type 2 (Th2)-liked iNKT cells) significantly accelerated the progressive cardiac injury, leading to enhanced cardiac hypertrophy and cardiac fibrosis with prominent increases in collagen deposition and TGF-β1, IL-6, and alpha smooth muscle actin expression. In contrast to αGC, OCH (mainly activating Th2-liked iNKT cells) significantly attenuated the progression of cardiac injury and cardiac inflammation induced by repeated infusion of ISO. Flow cytometry analysis revealed that αGC promoted inflammatory macrophage infiltration in the heart, while OCH was able to restrain the infiltration. In vitro coculture of αGC- or OCH-pretreated primary peritoneal macrophages with primary cardiac fibroblasts confirmed the profibrotic effect of αGC and the antifibrotic effect of OCH. Our results demonstrate that activating both Th1- and Th2-liked iNKT cells is cardiotoxic, while activating Th2-liked iNKT cells is likely cardiac protective, which has implied key differences among subpopulations of iNKT cells in their response to cardiac pathological stimulation.

Microbial surfactants (biosurfactants) are a broad category of surface-active biomolecules with multifunctional properties. They self-assemble in aqueous solutions and are adsorbed on various interfaces, causing a decrease in surface tension, as well as interfacial tension, solubilization of hydrophobic compounds, and low critical micellization concentrations. Microbial biosurfactants have been investigated and applied in several fields, including bioremediation, biodegradation, food industry, and cosmetics. Biosurfactants also exhibit anti-microbial, anti-biofilm, anti-cancer, anti-inflammatory, wound healing, and immunomodulatory activities. Recently, it has been reported that biosurfactants can increase the immune responses and disease resistance of fish. Among various microbial surfactants, lipopeptides, glycolipids, and phospholipids are predominantly investigated. This review presents the various immunological activities of biosurfactants, mainly glycolipids and lipopeptides. The applications of biosurfactants in aquaculture, as well as their immunomodulatory activities, that make them novel therapeutic candidates have been also discussed in this review.

Research on milk fat globule membrane (MFGM) is gaining traction. The interest is two-fold; on the one hand, it is a unique trilayer structure with specific secretory function. On the other hand, it is the basis for ingredients with the presence of phospho- and sphingolipids and glycoproteins, which are being used as food ingredients with valuable functionality, in particular, for use as a supplement in infant nutrition. This last application is at the center of this Review, which aims to contribute to understanding MFGM's function in the proper development of immunity, cognition, and intestinal trophism, in addition to other potential effects such as prevention of diseases including cardiovascular disease, impaired bone turnover and inflammation, skin conditions, and infections as well as age-associated cognitive decline and muscle loss. The phospholipid composition of MFGM from bovine milk is quite like human milk and, although there are some differences due to dairy processing, these do not result in a chemical change. The MFGM ingredients, as used to improve the formulation in different clinical studies, have indeed increased the presence of phospholipids, sphingolipids, glycolipids, and glycoproteins with the resulting benefits of different outcomes (especially immune and cognitive outcomes) with no reported adverse effects. Nevertheless, the precise mechanism(s) of action of MFGM remain to be elucidated and further basic investigation is warranted., Competing Interests: The authors J.F., Y.P., F.V. and R.J.-F. declare no conflict of interest. L.B. and S.W. are employees of Mead Johnson Nutrition-RB, Medical and Scientific Affairs.

The endothelial cell adhesion molecule E-selectin is a key component of the bone marrow hematopoietic stem cell (HSC) vascular niche regulating balance between HSC self-renewal and commitment. We now report in contrast, E-selectin directly triggers signaling pathways that promote malignant cell survival and regeneration. Using acute myeloid leukemia (AML) mouse models, we show AML blasts release inflammatory mediators that upregulate endothelial niche E-selectin expression. Alterations in cell-surface glycosylation associated with oncogenesis enhances AML blast binding to E-selectin and enable promotion of pro-survival signaling through AKT/NF-κB pathways. In vivo AML blasts with highest E-selectin binding potential are 12-fold more likely to survive chemotherapy and main contributors to disease relapse. Absence (in Sele -/- hosts) or therapeutic blockade of E-selectin using small molecule mimetic GMI-1271/Uproleselan effectively inhibits this niche-mediated pro-survival signaling, dampens AML blast regeneration, and strongly synergizes with chemotherapy, doubling the duration of mouse survival over chemotherapy alone, whilst protecting endogenous HSC.

Purpose: The partial ineffectiveness and side effects of inflammatory bowel disease (IBD) current therapies drive basic research to look for new therapeutic target in order to develop new drug lead. Considering the pivotal role played by toll-like receptors (TLRs) in gut inflammation, we evaluate here the therapeutic effect of the synthetic glycolipid TLR4 antagonist FP7., Methods: The anti-inflammatory effect of FP7, active as TLR4 antagonist, was evaluated on peripheral blood mononuclear cells (PBMCs) and lamina propria mononuclear cells (LPMCs) isolated from IBD patients, and in a mouse model of ulcerative colitis., Results: FP7 strongly reduced the inflammatory responses induced by lipopolysaccharide (LPS) in vitro, due to its capacity to compete with LPS for the binding of TLR4/MD-2 receptor complex thus inhibiting both the MyD88- and TRIF-dependent inflammatory pathways. Colitic mice treated with FP7 exhibit reduced colonic inflammation and decreased levels of pro-inflammatory cytokines., Conclusions: This study suggests that TLR4 chemical modulation can be an effective therapeutic approach to IBD. The selectivity of FP7 on TLR4 makes this molecule a promising drug lead for new small molecules-based treatments.

Background: Evidence has provided support for the beneficial effects of milk fat globule membrane (MFGM) on inflammation in the intestinal tract. The objective of this study was to investigate the effects of MFGM on a rat model of necrotizing enterocolitis (NEC) and its potential mechanism of action., Methods: Sixty-two newborn Sprague Dawley rats were randomly divided into 4 experimental groups: Breast-fed normal, formula fed (FF), FF + 6 g/L MFGM, and FF + 12 g/L MFGM. The FF rats and the FF rats supplemented with MFGM were exposed to asphyxia/cold stress to induce NEC. Body weight, histological score, survival time, oxidative stress injury, enterocyte proliferation/apoptosis, and inflammatory response were assessed. Meanwhile, lipopolysaccharide (LPS)-stimulated IEC-6 enterocytes were used as a model to test the anti-inflammatory effects of MFGM., Results: Supplementation with 12 g/L MFGM alleviated body weight loss, reduced the incidence of NEC, increased the survival rate, and attenuated the severity of bowel damage in the NEC rat model. Furthermore, 12 g/L MFGM administration inhibited the protein expression of toll-like receptor 4 (TLR4) in the animal model. In IEC-6 enterocytes, the upregulation of TLR4, myeloid differentiation primary response gene 88 (MyD88), phosphorylated nuclear factor-κB (NF-κB) p65 subunit, and the nuclear translocation of NF-κBp65 induced by LPS was partially inhibited by MFGM pretreatment., Conclusion: Our findings suggested that MFGM has beneficial effects on neonatal rats with NEC by suppressing inflammation via the TLR4/MyD88/NF-κB pathway., (© 2018 American Society for Parenteral and Enteral Nutrition.)

Hyperpigmentation is caused by excessive production of melanin in melanocytes. Mannosylerythritol lipids (MELs) are glycolipid biosurfactants that are abundantly produced by yeasts and used commercially in cosmetics. However, the potential depigmenting efficacy of MELs has not been evaluated. In this study, the depigmentary effect of MELs was tested in primary normal human melanocytes (NHMs), α-melanocyte-stimulating hormone (MSH)-stimulated B16 cells (murine melanoma cells) and a human skin equivalent (MelanoDerm) using photography, Fontana-Masson (F&M) staining and two-photon microscopy. Mannosylerythritol lipids significantly decreased the melanin contents in NHMs and α-MSH-stimulated B16 cells. Consistent with these findings, MELs treatment had a clear whitening effect in a human skin equivalent, brightening the tissue colour and reducing the melanin content. The molecular mechanism underlying the anti-melanogenic effect of MELs treatment was examined by real-time PCR and Western blotting. Mechanistically, MELs clearly suppressed the gene expression levels of representative melanogenic enzymes, including tyrosinase, Tyrp-1 and Tyrp-2, by inhibiting the ERK/CREB/MiTF signalling pathway in NHMs. This work demonstrates for the first time that MELs exert whitening effects on human melanocytes and skin equivalent. Thus, we suggest that MELs could be developed as a potent anti-melanogenic agent for effective whitening, beyond their use as a biosurfactant in cosmetics., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Sulfoquinovosylacylpropanediol (SQAP) is a novel potent radiosensitizer that inhibits angiogenesis in vivo and results in increased oxigenation and reduced tumor volume. We investigated the distribution, metabolism, and excretion of SQAP in male KSN-nude mice transplanted with a human pulmonary carcinoma, Lu65. For the metabolism analysis, a 2 mg (2.98 MBq)/kg of [glucose-U- 14 C]-SQAP (CP-3839) was intravenously injected. The injected SQAP was decomposed into a stearic acid and a sulfoquinovosylpropanediol (SQP) in the body. The degradation was relatively slow in the carcinoma tissue.1,3-propanediol[1- 14 C]-SQAP (CP-3635) was administered through intravenous injection of a 1 mg (3.48 MBq)/kg dose followed by whole body autoradiography of the mice. The autoradiography analysis demonstrated that SQAP rapidly distributed throughout the whole body and then quickly decreased within 4 hours except the tumor and excretion organs such as liver, kidney. Retention of SQAP was longer in tumor parts than in other tissues, as indicated by higher levels of radioactivity at 4 hours. The radioactivity around the tumor had also completely disappeared within 72 hours.

Microglial activation has long been recognized as a hallmark of neuroinflammation. Recently, the bacillus Calmette-Guerin (BCG) vaccine has been reported to exert neuroprotective effects against several neurodegenerative disorders. Trehalose-6,6'-dibehenate (TDB) is a synthetic analogue of trehalose-6,6'-dimycolate (TDM, also known as the mycobacterial cord factor) and is a new adjuvant of tuberculosis subunit vaccine currently in clinical trials. Both TDM and TDB can activate macrophages and dendritic cells through binding to C-type lectin receptor Mincle; however, its action mechanism in microglia and their relationship with neuroinflammation are still unknown. In this article, we found that TDB inhibited LPS-induced M1 microglial polarization in primary microglia and BV-2 cells. However, TDB itself had no effects on IKK, p38, and JNK activities or cytokine expression. In contrast, TDB activated ERK1/2 through PLC-γ1/PKC signaling and in turn decreased LPS-induced NF-κB nuclear translocation. Furthermore, TDB-induced AMPK activation via PLC-γ1/calcium/CaMKKβ-dependent pathway and thereby enhanced M2 gene expressions. Interestingly, knocking out Mincle did not alter the anti-inflammatory and M2 polarization effects of TDB in microglia. Conditional media from LPS-stimulated microglial cells can induce in vitro neurotoxicity, and this action was attenuated by TDB. Using a mouse neuroinflammation model, we found that TDB suppressed LPS-induced M1 microglial activation and sickness behavior, but promoted M2 microglial polarization in both WT and Mincle -/- mice. Taken together, our results suggest that TDB can act independently of Mincle to inhibit LPS-induced inflammatory response through PLC-γ1/PKC/ERK signaling and promote microglial polarization towards M2 phenotype via PLC-γ1/calcium/CaMKKβ/AMPK pathway. Thus, TDB may be a promising therapeutic agent for the treatment of neuroinflammatory diseases.

Introduction: Sickle cell disease (SCD) is an inherited disease with lifelong morbidity, whose complications include frequent acute painful vaso-occlusive episodes (VOEs) that often require hospitalization. The only pharmacotherapy currently in regular use for SCD management is hydroxyurea (hydroxycarbamide)., Areas Covered: We review recent advances in pharmacotherapy for SCD and summarize promising synthetic agents that are in late-stage development (phase 3) for SCD., Expert Opinion: Emerging SCD therapies have been developed to target specific pathophysiological mechanisms of the disease, as either preventative or abortive approaches to VOEs. Continuous-use pharmacotherapeutics in late-phase development for VOE prevention include voxelotor (GBT440), which elevates hemoglobin oxygenation, and prasugrel, a platelet activation inhibitor. However, at least in the near future, it is probable that biological molecules will play a primary role in SCD preventative therapy; in combination with hydroxyurea, crizanlizumab, an anti-P-selectin monoclonal antibody, appears to reduce VOE frequency, while L -glutamine was the first substance licensed by the FDA for use in SCD in 20 years. Synthetic drugs, however, may represent key approaches for the management of individuals upon hospitalization for VOE, a major challenge for SCD. For example, rivipansel (GMI-1070), a pan-selectin inhibitor, has shown encouraging effects on hospitalization time and opioid use.

Responsive drug release in tumor mitochondria is a pre-requisite for mitochondria-targeted drug delivery systems to improve the efficacy of this promising therapeutic modality. To this end, a photothermal stimulation strategy for mitochondria-responsive drug release along with heat shock is developed to maximize the antitumor effects with minimal side effects. Methods: This strategy relies on mitochondrial-targeted delivery of doxorubicin (DOX) through a photothermal and lipophilic agent IR-780 iodide (IR780)-modified glycolipid conjugates (CSOSA), which can synergistically triggers high-level reactive oxygen species (ROS) to kill tumor cells. Results: Specifically, upon laser irradiation, the photothermal conversion by IR780-CSOSA can not only weaken the hydrophobic interaction between the core of micelles and DOX and trigger unexpected micelle swelling to release DOX in mitochondria for the amplification of ROS, but also induce mitochondria-specific heat shock to promote the fast evolution of ROS at the same locus to eradicate cancer cells in a more effective way. Furthermore, IR780-CSOSA micelles may independently realize the real-time diagnosis and imaging on multiple tumor models. Deep penetration into tumors by IR780-CSOSA/DOX micelles can be manipulated under laser irradiation. Conclusion: Such multifunctional IR780-CSOSA/DOX micelles with integration of mitochondria-responsive drug release and heat shock are demonstrated to be superior to the non-mitochondria-responsive therapy. This study opens up new avenues for the future cancer diagnosis and treatment., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

Care of the musculoskeletal system, including the muscles, joints, and bones, is important for a healthy life expectancy in today's aging society. The aim of this randomized, double-blind, placebo-controlled study was to investigate the effect of consumption of milk-fat globule membrane (MFGM) and glucosamine on joint function and physical performance. Participants were healthy Japanese men and women, aged 60-74 y, with a history of mild knee or low back pain at rest. They were randomized to receive tablets containing MFGM 1.0 g+glucosamine 1.5 g or placebo tablets for 8 wk. We assessed passive range of motion, active range of motion (self-reported VAS score), JKOM and JLEQ, and physical performance. Data were available for analysis for 25 participants in the active treatment group and 28 in the placebo group. The active group showed significant improvements in passive range of motion at the knee and active range of motion at both the knee and low back. The active group also showed significant improvements in some physical performance, including obstacle walking speed and speed of ascending stairs. The findings of this study suggest that consumption of a combination of MFGM and glucosamine may improve joint function and physical performance.

Background: Fabry disease is an X-linked lysosomal storage disorder and shows globotriosylceramide (Gb3) accumulation in multiple organs, resulting from a deficiency of α-galactosidase. In patients with Fabry disease, cardiovascular disease occurs at an early age. Previous studies have shown that serum levels of high-density lipoprotein-cholesterol (HDL-C) increase in this disease, yet its clinical significance for cardiovascular disease remains unclear., Methods and results: In order to determine why the serum HDL-cholesterol is high in various cardiovascular diseases of Fabry disease patients, we evaluated the serum lipid profiles, ocular vascular lesions, and levels of serum vascular endothelial growth factor (VEGF) and intercellular adhesion molecule-1 in 69 patients with Fabry disease diagnosed by genetic examination. The serum HDL-C/total cholesterol (T-Chol) ratio was significantly high, especially in male patients (41.5±1.7%) regardless of body mass index. Ocular vascular lesions were more likely to occur in female patients with a high HDL-C/T-Chol ratio compared with most male patients. Female patients with a high HDL-C/T-Chol ratio also presented a high serum VEGF level, suggesting that vascular endothelium dysfunction and arteriosclerotic changes progress more severely than in patients with a normal HDL-C/T-Chol ratio. In most patients, enzyme replacement therapy improved serum Gb3 and lyso-Gb3 levels, but these Gb3 and lyso-Gb3 still remained higher than in healthy controls, which appears to result in continuous vascular arteriosclerotic changes., Conclusions: We concluded that increased low-density lipoprotein-cholesterol uptake to the vascular wall caused by endothelial dysfunction is likely to contribute to the high HDL-C/T-Chol ratio observed in Fabry disease patients.

TLRs, including TLR4, have been shown to play a crucial role in cardiovascular inflammatory-based diseases. The main goal of this study was to determine the potential of FP7, a synthetic glycolipid active as a TLR4 antagonist, to modulate haematopoietic and non-haematopoietic vascular TLR4 pro-inflammatory signalling. HUVEC, human THP-1 monocytes, THP-1-derived macrophages, mouse RAW-264.7 macrophages and Angiotensin II-infused apolipoprotein E-deficient mice were in vitro and in vivo models, respectively. Western blotting, Ab array and ELISA approaches were used to explore the effect of FP7 on TLR4 functional activity in response to bacterial LPS ( in vitro) and endogenous ligands of sterile inflammation ( in vitro and in vivo). Following activation of TLR4, in vitro and in vivo data revealed that FP7 inhibited p38 MAPK and p65 NF-kB phosphorylation associated with down-regulation of a number of TLR4-dependent pro-inflammatory proteins. In addition to inhibition of LPS-induced TLR4 signalling, FP7 negatively regulated TLR4 activation in response to ligands of sterile inflammation (hydroperoxide-rich oxidised LDL, in vitro and Angiotensin II infusion, in vivo). These results demonstrate the ability of FP7 to negatively regulate in vitro and in vivo haematopoietic and non-haematopoietic vascular TLR4 signalling both in humans and mice, suggesting the potential therapeutic use of this TLR4 antagonist for pharmacological intervention of vascular inflammatory diseases.

Chronic inflammatory skin diseases such as psoriasis have a significant impact on society. Currently, the major topical treatments have many side effects, making their continued use in patients difficult. Microalgae have emerged as a source of bio-active molecules such as glycolipids with potent anti-inflammatory properties. We aimed to investigate the effects of a glycolipid ( MGMG-A ) and a glycolipid fraction ( MGDG ) obtained from the microalga Isochrysis galbana on a TPA-induced epidermal hyperplasia murine model. In a first set of experiments, we examined the preventive effects of MGMG-A and MGDG dissolved in acetone on TPA-induced hyperplasia model in mice. In a second step, we performed an in vivo permeability study by using rhodamine-containing cream, ointment, or gel to determinate the formulation that preserves the skin architecture and reaches deeper. The selected formulation was assayed to ensure the stability and enhanced permeation properties of the samples in an ex vivo experiment. Finally, MGDG -containing cream was assessed in the hyperplasia murine model. The results showed that pre-treatment with acetone-dissolved glycolipids reduced skin edema, epidermal thickness, and pro-inflammatory cytokine production (TNF-α, IL-1β, IL-6, IL-17) in epidermal tissue. The in vivo and ex vivo permeation studies showed that the cream formulation had the best permeability profile. In the same way, MGDG -cream formulation showed better permeation than acetone-dissolved preparation. MGDG -cream application attenuated TPA-induced skin edema, improved histopathological features, and showed a reduction of the inflammatory cell infiltrate. In addition, this formulation inhibited epidermal expression of COX-2 in a similar way to dexamethasone. Our results suggest that an MGDG -containing cream could be an emerging therapeutic strategy for the treatment of inflammatory skin pathologies such as psoriasis., Competing Interests: The authors declare no conflict of interest.

Introduction: Neonatal sepsis is a systemic inflammation occurring in neonates because of a proven infection within the first 28days of birth. It is the third leading cause of morbidity and mortality in the newborns. The mechanism(s) underlying the systemic inflammation in neonatal sepsis has not been completely understood. We hypothesize that the deficiency of milk fat globule-epidermal growth factor-factor 8 (MFG-E8), a protein commonly found in human milk, could be responsible for the increased inflammatory response leading to morbidity and mortality in neonatal sepsis., Methods: Male and female newborn mice aged 5-7days were injected intraperitoneally with 0.9mg/g body weight cecal slurry (CS). At 10h after CS injection, they were euthanized, and blood, lungs and gut tissues were obtained for further analyses. Control newborn mice underwent similar procedures with the exception of the CS injection. In duplicate newborn mice after CS injection, they were returned to their respective cages with their mothers and were closely monitored for 7days and survival rate recorded., Results: At 10h after CS injection, serum LDH in the MFG-E8 knockout (KO) newborn mice was significantly increased by 58% and serum IL-6, IL-1β and TNF-α in the MFG-E8KO newborn mice were also significantly increased by 56%, 65%, and 105%, respectively, from wild type (WT) newborn mice. There were no significant difference between WT control and MFG-E8 control newborn mice. The lung architecture was severely damaged and a significant 162% increase in injury score was observed in the CS MFG-E8KO newborn mice. The MPO, TUNEL staining, and cytokine levels in the lungs and the intestine in CS MFG-E8KO newborn mice were significantly increased from CS WT newborn mice. Similarly, intestinal integrity was also compromised in the CS MFG-E8KO newborn mice. In a survival study, while the mortality rate within 7days was only 29% in the CS WT newborn mice, 80% of the CS MFG-E8KO newborn mice died during the same time period with the majority of mortality occurring within 48h., Conclusion: The deficiency in MFG-E8 caused increases in inflammation, tissue injury, neutrophil infiltration and apoptosis, which led to morbidity and mortality in murine neonatal sepsis. These studies suggest that MFG-E8 has a protective role in fighting against neonatal sepsis., (Copyright © 2017 Elsevier Inc. All rights reserved.)

A PG-tb1 hapten from the West Beijing strains of Mycobacterium tuberculosis cell wall has been efficiently synthesized and conjugated to CRM 197 in a simple way as linker-equipped carbohydrate by applying squaric acid chemistry for an original neoglycoprotein, creating a potent T-dependent conjugate vaccine. The intermediate monoester can be easily purified and the degree of incorporation can be monitored by MALDI-TOF mass spectrometry. After administered systemically in mice without any adjuvant, the conjugate induced high antigen-specific IgG levels in serum. Furthermore, following the third immunization, significant antibody titers frequently exceeding 0.8 million were observed in the sera of mice vaccinated with PG-CRM 197 conjugate which showed the potential for preparation of TB vaccine., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Glycolipids are the major constituent of the thylakoid membrane of higher plants and have a variety of biological and pharmacological activities. However, anti-inflammatory effects of glycolipids on vascular endothelial cells have not been elucidated. Here, we investigated the effect of glycolipids extracted from spinach on lipopolysaccharides (LPS)-induced endothelial inflammation and evaluated the underlying molecular mechanisms. Treatment with glycolipids from spinach had no cytotoxic effects on cultured human umbilical vein endothelial cells (HUVECs) and significantly blocked the expression of LPS-induced interleukin (IL)-6, monocyte chemoattractant protein-1 (MCP-1), vascular cell adhesion molecule-1 (VCAM-1), and intracellular adhesion molecule-1 (ICAM-1) in them. Glycolipids treatment also effectively suppressed monocyte adhesion to HUVECs. Treatment with glycolipids inhibited LPS-induced NF-κB phosphorylation and nuclear translocation. In addition, glycolipids treatment significantly promoted endothelial nitric oxide synthase (eNOS) activation and nitric oxide (NO) production in HUVECs. Furthermore, glycolipids treatment blocked LPS-induced inducible NOS (iNOS) expression in HUVECs. Pretreatment with a NOS inhibitor attenuated glycolipids-induced suppression of NF-κB activation and adhesion molecule expression, and abolished the glycolipids-mediated suppression of monocyte adhesion to HUVECs. These results indicate that glycolipids suppress LPS-induced vascular inflammation through attenuation of the NF-κB pathway by increasing NO production in endothelial cells. These findings suggest that glycolipids from spinach may have a potential therapeutic use for inflammatory vascular diseases., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Synthetic alkyl lipids, such as the ether lipids edelfosine (1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine) and ohmline (1-O-hexadecyl-2-O-methyl-rac-glycero-3-β-lactose), are forming a class of antitumor agents that target cell membranes to induce apoptosis and to decrease cell migration/invasion, leading to the inhibition of tumor and metastasis development. In this review, we present the structure-activity relationship of edelfosine and ohmline, and we point out differences and similarities between these two amphiphilic compounds. We also discuss the mechanisms of action of these synthetic alkyl ether lipids (involving, among other structures and molecules, membrane domains, Fas/CD95 death receptor signaling, and ion channels), and highlight a key role for lipid rafts in the underlying process. The reorganization of lipid raft membrane domains induced by these alkyl lipids affects the function of death receptors and ion channels, thus leading to apoptosis and/or inhibition of cancer cell migration. The possible therapeutic use of these alkyl lipids and the clinical perspectives for these lipids in prevention or/and treatment of tumor development and metastasis are also discussed., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: The milk-fat-globule membrane (MFGM) contains phospholipids and membrane glycoproteins that have been shown to affect pathogen colonization and gut barrier integrity., Objective: In the present study, we determined whether commercial heat-treated MFGM can increase resistance to diarrheagenic Escherichia coli., Methods: A randomized, placebo-controlled, double-blind, 4-wk parallel-intervention study was conducted in healthy adults. Participants were randomly assigned to a milk protein concentrate rich in MFGM [10 g Lacprodan PL-20 (Arla Foods Ingredients Group P/S), twice daily; n = 30; MFGM group) or a control [10 g Miprodan 30 (sodium caseinate), twice daily; n = 28]. After 2 wk, participants were orally challenged with live, attenuated diarrheagenic E. coli (10(10) colony-forming units). Primary outcomes were infection-induced diarrhea and fecal diarrheagenic E. coli excretion. Secondary outcomes were gastrointestinal symptoms [Gastrointestinal Symptom Rating Scale (GSRS)], stool frequency, and stool consistency (Bristol Stool Scale)., Results: Diarrheagenic E. coli resulted in increased fecal output, lower relative fecal dry weight, increased fecal E. coli numbers, and an increase in stool frequency and gastrointestinal complaints at day 1 after challenge. MFGM significantly decreased the E. coli-induced changes in reported stool frequency (1.1 ± 0.1 stools/d in the MFGM group; 1.6 ± 0.2 stools/d in the control group; P = 0.04) and gastrointestinal complaints at day 2 (1.1 ± 0.5 and 2.5 ± 0.6 GSRS scores in the MFGM and control groups, respectively; P = 0.05). MFGM did not affect fecal wet weight and E. coli excretion at day 2 after challenge., Conclusions: The attenuated diarrheagenic E. coli strain transiently induced mild symptoms of a food-borne infection, with complete recovery of reported clinical symptoms within 2 d. The present diarrheagenic E. coli challenge trial conducted in healthy adults indicates that a milk concentrate rich in natural, bioactive phospho- and sphingolipids from the MFGM may improve in vivo resistance to diarrheagenic E. coli. This trial was registered at clinicaltrials.gov as NCT01800396., (© 2016 American Society for Nutrition.)

Inhibitory effects of trehalose liposomes (DMTre) composed of 30mol% l-α-dimyristoylphosphatidylcholine (DMPC) and 70mol% trehalose surfactants on the growth of lymphoblastic leukemia (MOLT-4) cells in vitro and therapeutic effects of DMTre for xenograft mice model of carcinoma in vivo were examined. DMTre inhibited the growth of MOLT-4 cells in a dose-dependent manner due to apoptosis. The activation of caspase-3, -8, and 9 was obtained for MOLT-4 cells after the treatment with DMTre. The clustering of lipid rafts in plasma membranes of MOLT-4 cells was examined with a marker Cholera toxin subunit B conjugates Alexa Fluor (CTB), which binds to the pentasaccharide chains of ganglioside GM1 on the cellular surfaces. The clustering of lipid rafts in plasma membranes of MOLT-4 cells was observed after the treatment with DMTre. Therapeutic effects of DMTre were obtained for xenograft mice model of carcinoma in vivo., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Sophorolipids are surface active glycolipids consisting of a hydrophilic sophorose unit and a hydrophobic portion composed of a fatty acid tail. Crude sophorolipid sample contains both acidic and lactonic forms of sophorolipid with different degrees of acetylation and varying lengths of the fatty acid chains depending on the substrates used in the production process. Carboxylic end in the acidic form of the fatty acid is free, whereas in the lactonic form, it is internally esterified. Sophorolipids show different physicochemical properties with wide range of applications for each structural compound. Lactonic form of sophorolipids shows surface tension reducing ability and biological activity, whereas the acidic form possesses better foam forming ability and higher solubility. Presence of acetyl groups gives hydrophilic nature to the sophorolipids which promotes its antiviral and cytokine-stimulating properties. The aim of this review is to explore and suggest the plausibility of sophorolipids as therapeutic and prophylactic agents for the treatment of viral diseases.

Inhibition of excessive Toll-like receptor 4 (TLR4) signaling is a therapeutic approach pursued for many inflammatory diseases. We report that Mannoside Glycolipid Conjugates (MGCs) selectively blocked TLR4-mediated activation of human monocytes and monocyte-derived dendritic cells (DCs) by lipopolysaccharide (LPS). They potently suppressed pro-inflammatory cytokine secretion and maturation of DCs exposed to LPS, leading to impaired T cell stimulation. MGCs did not interfere with LPS and could act in a delayed manner, hours after LPS stimulation. Their inhibitory action required both the sugar heads and the lipid chain, although the nature of the sugar and the structure of the lipid tail could be modified. They blocked early signaling events at the cell membrane, enhanced internalization of CD14 receptors, and prevented colocalization of CD14 and TLR4, thereby abolishing NF-κB nuclear translocation. When the best lead conjugate was tested in a mouse model of LPS-induced acute lung inflammation, it displayed an anti-inflammatory action by suppressing the recruitment of neutrophils. Thus, MGCs could serve as promising leads for the development of selective TLR4 antagonistic agents for inflammatory diseases.

Treatment of vaso-occlusive crises (VOC) or events in sickle cell disease (SCD) remains limited to symptom relief with opioids. Animal models support the effectiveness of the pan-selectin inhibitor GMI-1070 in reducing selectin-mediated cell adhesion and abrogating VOC. We studied GMI-1070 in a prospective multicenter, randomized, placebo-controlled, double-blind, phase 2 study of 76 SCD patients with VOC. Study drug (GMI-1070 or placebo) was given every 12 hours for up to 15 doses. Other treatment was per institutional standard of care. All subjects reached the composite primary end point of resolution of VOC. Although time to reach the composite primary end point was not statistically different between the groups, clinically meaningful reductions in mean and median times to VOC resolution of 41 and 63 hours (28% and 48%, P = .19 for both) were observed in the active treatment group vs the placebo group. As a secondary end point, GMI-1070 appeared safe in acute vaso-occlusion, and adverse events were not different in the two arms. Also in secondary analyses, mean cumulative IV opioid analgesic use was reduced by 83% with GMI-1070 vs placebo (P = .010). These results support a phase 3 study of GMI-1070 (now rivipansel) for SCD VOC. This trial was registered at www.clinicaltrials.gov as #NCT01119833.

Objectives: Observational studies have shown that even in high-income countries formula-fed infants have a higher incidence of acute otitis media (AOM), and gastrointestinal and respiratory tract infections during the first year of life compared with breast-fed infants. We hypothesized that components of the milk fat globule membrane (MFGM) may be responsible for some of these differences and that supplementation with bovine MFGM would decrease the infectious morbidity in formula-fed infants., Methods: In a double-blind randomized controlled trial, 160 formula-fed infants received experimental formula (EF) supplemented with bovine MFGM (EF) or unsupplemented standard formula (SF) from <2 months until 6 months of age. A breast-fed reference group consisted of 80 infants. Disease symptoms, health care contacts, and medication were recorded by the parents until 12 months of age. Serum immunoglobulin G for 10 pneumococcal serotypes was analyzed at 6 months of age., Results: The cumulative incidence of AOM during the intervention was lower in the EF group than in the SF group (1% vs 9%, P = 0.034), and did not differ from the breast-fed reference group (0%, P = 1.0). The incidence (25% vs 43%, P = 0.021) and longitudinal prevalence (P = 0.012) of antipyretic use were significantly lower in the EF group than in the SF group. Serum immunoglobulin G concentrations against pneumococcal serotypes 1, 5, and 14 were lower in the EF group than in the SF group., Conclusions: Supplementation of formula with bovine MFGM reduces the risk of AOM, decreases antipyretics use in formula-fed infants, and has immunomodulatory effects on humoral response against pneumococcus vaccine.

Introduction: Under conditions of blood flow, selectins mediate the intercellular adhesion between erythrocytes, leukocytes, platelets and vascular endothelium that contribute to vaso-occlusion and tissue damage in sickle cell disease (SCD). Therefore, selectin antagonists have the potential to ameliorate SCD., Areas Covered: In this review, the author discusses the cellular and molecular basis of vaso-occlusion in SCD, and presents evidence that selectin-mediated cell adhesion has clinical importance in this disorder. The author discusses molecular structure of human selectins and their physiological ligands and highlights clinical trials of selectin-targeted therapy of SCD. Herein, the author also assesses the benefits and limitations of the selectin antagonists that are currently under evaluation for SCD, and offers suggestions for the future., Expert Opinion: In Phase I and II clinical trials, rivipansel and heparin demonstrated promising efficacy and safety in SCD. Although selectin blockade could potentially impair immune response, an increased incidence of infection was not reported in SCD patients treated with heparin (n = 127) or rivipansel (n = 111). The efficacy and safety findings from Phase I and II clinical studies are encouraging the commencement of Phase III studies to further evaluate selectin-targeted therapy in SCD.

Recent insights into the pathogenesis of microvascular occlusion downstream of the sickled red cell have revealed new therapeutic targets for sickle cell disease (SCD). After the formation of sickle cells, tissue injury spurs inflammation, which leads to receptor-mediated contacts between sickle cells, leukocytes, and vascular endothelium. Specifically, selectins decelerate sickled red cells and leukocytes in the circulation to facilitate endothelial adhesion and other cell-cell interactions, ultimately leading to vascular occlusion. Invariant NKT (iNKT) cells, activated during reperfusion, generate a broad inflammatory response, which further increases cellular adhesion and vascular occlusion. Novel therapies are in development that target selectins and iNKT cells to prevent or interrupt the vicious cycle of adhesion and inflammation. Although the therapies hold promise for the treatment of SCD, an underappreciated threat to their development is poor access to care for people with SCD. Unless the majority of people with SCD have access to consistent, high-quality care, they will not have the opportunity to participate in a clinical trial or receive any new therapy, regardless of its efficacy., (© 2015 by The American Society of Hematology. All rights reserved.)

Aquatic microbes produce diverse secondary metabolites with interesting biological activities. Cytotoxic metabolites have the potential to become lead compounds or drugs for cancer treatment. Many cytotoxic compounds, however, show undesirable toxicity at higher concentrations. Such undesirable activity may be reduced or eliminated by using lower doses of the cytotoxic compound in combination with another compound that modulates its activity. Here, we have examined the cytotoxicity of four microbial metabolites [ethyl N-(2-phenethyl) carbamate (NP-1), Euglenophycin, Anabaenopeptin, and Glycolipid 652] using three in vitro cell lines [human breast cancer cells (MCF-7), mouse neuroblastoma cells (N2a), and rat pituitary epithelial cells (GH4C1)]. The compounds showed variable cytotoxicity, with Euglenophycin displaying specificity for N2a cells. We have also examined the modulatory power of NP-1 on the cytotoxicity of the other three compounds and found that at a permissible concentration (125 µg/mL), NP-1 sensitized N2a and MCF-7 cells to Euglenophycin and Glycolipid 652 induced cytotoxicity.