Clinical efficacy of ulinastatin in the treatment of unliquefied pyogenic liver abscess complicated by septic shock: A randomized controlled trial.

INTRODUCTION: This study determined the therapeutic effect of ulinastatin (UTI) on unliquefied pyogenic liver abscesses complicated by septic shock (UPLA-SS). METHODS: This was a randomized controlled trial involving patients with UPLA-SS who underwent treatment at our hospital between March 2018 and March 2022. The patients were randomly divided into control (n = 51) and study groups (n = 48). Both groups received routine treatment, but the study group received UTI (200,000 units q8h for >3 days). Differences in liver function, inflammatory indices, and effectiveness between the two groups were recorded. RESULTS: Following treatment, the white blood cell count, and lactate, C-reactive protein, procalcitonin, tumor necrosis factor-α, and interleukin-6 levels were significantly decreased in all patients compared to the admission values (p < .05). The study group had a faster decline with respect to the above indices compared to the control group (p < .05). The study group length of intensive care unit stay, fever duration, and vasoactive drug maintenance time were all significantly shorter than the control group (p < .05). The total bilirubin, alanine aminotransferase, and aspartate aminotransferase levels were significantly lower in the study and control groups after treatment compared to before treatment (p < .05); however, the study group had a faster recovery of liver function than the control group (p < .05). The overall mortality rate was 14.14% (14/99); 10.41% of the study group patients died and 17.65% of the control group patients died, but there was no statistically significant difference between the two groups (p > .05). CONCLUSION: UTI combined with conventional treatment significantly controlled the infection symptoms, improved organ function, and shortened the treatment time in patients with UPLA-SS.

Lipidome Analysis in Brain and Peripheral Plasma Following Milk Fat Globule Membrane Supplementation in Rodents.

SCOPE: Milk fat globule membrane (MFGM) is an essential component of milk. Bovine MFGM (bMFGM) has been shown to support cognitive development and increase relative concentrations of serum phospholipids. This study investigates bioavailability of bMFGM components after oral administration in two preclinical models to explore whether dietary bMFGM induces parallel changes to plasma and brain lipidomes. METHODS AND RESULTS: Transgenic APOE*3.Leiden mice (n = 18 per group) and Sprague-Dawley rats (n = 12 per group) are fed bMFGM-enriched (MFGM+) or Control diet, followed by phospholipid profile-determination in plasma, hippocampus, and prefrontal cortex tissue by targeted mass spectrometry. Multivariate analysis of lipidomic profiles demonstrates a separation between MFGM+ and Control plasma across rodents. In plasma, sphingomyelins contributed the most to the separation of lipid patterns among both models, where three sphingomyelins (d18:1/14:0, d18:1/23:0, d18:1/23:1[9Z]) are consistently higher in the circulation of MFGM+ groups. A similar trend is observed in rat prefrontal cortex, although no significant separation of the brain lipidome is demonstrated. CONCLUSION: bMFGM-enriched diet alters plasma phospholipid composition in rodents, predominantly increasing sphingomyelin levels in the systemic circulation with similar, but non-significant, trends in central brain regions. These changes may contribute to the beneficial effects of bMFGM on neurodevelopment during early life.

Metabolic and Epigenetic Regulation of SMAD7 by STC1 Ameliorates Lung Fibrosis.

As shown in our previous studies, the intratracheal-administration of STC1 (stanniocalcin-1) ameliorates pulmonary fibrosis by reducing oxidative and endoplasmic reticulum stress through the uncoupling of respiration in a bleomycin-treated mouse model. However, the overall effect of STC1 on metabolism was not examined. Therefore, we first conducted a comprehensive metabolomics analysis to screen the overall metabolic changes induced by STC1 in an alveolar epithelial cell line using capillary electrophoresis time-of-flight mass spectrometry. The results were subsequently validated in multiple alveolar epithelial and fibroblast cell lines by performing precise analyses of each substance. STC1 stimulated glycolysis, acetyl-CoA synthesis, and the methionine and cysteine-glutathione pathways, which are closely related to the uncoupling of respiration, modulation of epigenetics, and reduction in oxidative stress. These results are consistent with our previous study. Subsequently, we focused on the inhibitory factor SMAD7, which exerts an antifibrotic effect and is susceptible to epigenetic regulation. STC1 upregulates SMAD7 in an uncoupling protein 2-dependent manner, induces demethylation of the SMAD7 promoter region and acetylation of the SMAD7 protein in human alveolar epithelial and fibroblast cell lines and a bleomycin-treated mouse model, and subsequently attenuates fibrosis. The antifibrotic effects of STC1 may partially depend on the regulation of SMAD7. In the evaluation using lung tissue from patients with idiopathic pulmonary fibrosis, SMAD7 expression and acetylation were high in the alveolar structure-preserving region and low in the fibrotic region. The intratracheal administration of STC1 may prevent the development of pulmonary fibrosis by regulating the metabolism-mediated epigenetic modification of SMAD7 in patients.

LRG-1 promotes fat graft survival through the RAB31-mediated inhibition of hypoxia-induced apoptosis.

Autologous adipose tissue is an ideal soft tissue filling material, and its biocompatibility is better than that of artificial tissue substitutes, foreign bodies and heterogeneous materials. Although autologous fat transplantation has many advantages, the low retention rate of adipose tissue limits its clinical application. Here, we identified a secretory glycoprotein, leucine-rich-alpha-2-glycoprotein 1 (LRG-1), that could promote fat graft survival through RAB31-mediated inhibition of hypoxia-induced apoptosis. We showed that LRG-1 injection significantly increased the maintenance of fat volume and weight compared with the control. In addition, higher fat integrity, more viable adipocytes and fewer apoptotic cells were observed in the LRG-1-treated groups. Furthermore, we discovered that LRG-1 could reduce the ADSC apoptosis induced by hypoxic conditions. The mechanism underlying the LRG-1-mediated suppression of the ADSC apoptosis induced by hypoxia was mediated by the upregulation of RAB31 expression. Using LRG-1 for fat grafts may prove to be clinically successful for increasing the retention rate of transplanted fat.

Added bovine milk fat globule membrane in formula: Growth, body composition, and safety through age 2: An RCT.

OBJECTIVE: The aim of this study was to assess the effects of an experimental formula (EF) with added whey protein-lipid concentrate (5 g/L; source of bovine milk fat globule membrane [bMFGM]) on growth, body composition, and safety through 24 mo of age in term infants. METHODS: This was a double-blinded, randomized controlled trial conducted in Santiago, Chile. Infants were enrolled before 120 d and randomized to receive standard cow's milk-based formula (SF) or EF through the first year of life. Breastfed infants were the reference (HM). Growth (weight-for-age [WAZ], length-for-age [LAZ], BMI-for-age [BAZ], headcircumference-for-age [HCZ] z-scores); body composition (fat mass [FM] and fat-free mass, percentage body fat [%BF]); and adverse events through day 730 were recorded. Outcome trajectories were analyzed using a single generalized estimating equation testing the interaction between group and visit. RESULTS: We recruited 582 infants (HM = 235; SF = 174; EF = 173); 478 (>80%) completed the study. At baseline, only WAZ was different between the formula groups (0.14 lower in EF versus SF group, P = 0.035). WAZ, LAZ, and BAZ trajectories were higher from baseline to days 365 and 730 in EF or SF compared with HM (all P < 0.05). No differences in changes in body composition were observed between the formula groups. For EF versus HM, %BF was lower at day 180; however, this difference reversed from day 365. Fat-free mass was higher in formula groups compared with HM at all time points. No group difference in adverse event incidence rate was detected. CONCLUSION: During the first 2 y of life, infant formula with added bMFGM supports typical growth and safety compared with a standard formula.

Extracellular vesicle-mediated delivery of circDYM alleviates CUS-induced depressive-like behaviours.

Major depressive disorder (MDD) is the most prevalent psychiatric disorder worldwide and severely limits psychosocial function and quality of life, but no effective medication is currently available. Circular RNAs (circRNAs) have been revealed to participate in the MDD pathological process. Targeted delivery of circRNAs without blood-brain barrier (BBB) restriction for remission of MDD represents a promising approach for antidepressant therapy. In this study, RVG-circDYM-extracellular vesicles (RVG-circDYM-EVs) were engineered to target and preferentially transfer circDYM to the brain, and the effect on the pathological process in a chronic unpredictable stress (CUS) mouse model of depression was investigated. The results showed that RVG-circDYM-EVs were successfully purified by ultracentrifugation from overexpressed circDYM HEK 293T cells, and the characterization of RVG-circDYM-EVs was successfully demonstrated in terms of size, morphology and specific markers. Beyond demonstrating proof-of-concept for an RNA drug delivery technology, we observed that systemic administration of RVG-circDYM-EVs efficiently delivered circDYM to the brain, and alleviated CUS-induced depressive-like behaviours, and we discovered that RVG-circDYM-EVs notably inhibited microglial activation, BBB leakiness and peripheral immune cells infiltration, and attenuated astrocyte disfunction induced by CUS. CircDYM can bind mechanistically to the transcription factor TAF1 (TATA-box binding protein associated factor 1), resulting in the decreased expression of its downstream target genes with consequently suppressed neuroinflammation. Taken together, our findings suggest that extracellular vesicle-mediated delivery of circDYM is effective for MDD treatment and promising for clinical applications.

Effect of Ulinastatin Combined with Xingnaojing Injection on Severe Traumatic Craniocerebral Injury and Its Influence on Oxidative Stress Response and Inflammatory Response.

OBJECTIVE: This study is aimed at exploring the effect of ulinastatin combined with Xingnaojing injection on severe traumatic craniocerebral injury and its influence on oxidative stress response and inflammatory response in patients. METHODS: A total of 100 patients with severe traumatic craniocerebral injury admitted to our hospital from January 2018 to January 2020 were selected and equally assigned into a study group (50 cases) and a control group (50 cases) according to a random sampling method. Patients in study group received treatment of ulinastatin combined with Xingnaojing injection, while those in control group were treated with ulinastatin only. The study compared the two groups on the oxidative stress response, inflammatory response, the therapeutic effect, and the incidence rate of adverse reactions. RESULTS: It is observed that patients in study group obtained lower levels of free cortisol (FC) and norepinephrine (NE) in the serum and higher level of total thyroxine (TT4) after treatment compared with those in control group with significant difference (P < 0.05); in the meantime, they were examined to have significantly fewer oxidative stress response products, lower serum inflammatory factor level, and serum indicator levels of craniocerebral injury as opposed to those in control group, suggesting significant differences (P < 0.05); study group demonstrated higher treatment response rate and lower incidence rate of adverse reactions compared with control group with a significant difference (P < 0.05). CONCLUSION: The study found that ulinastatin combined with Xingnaojing infection has a significant effect in the treatment of severe traumatic craniocerebral injury, which can reduce the degree of craniocerebral injury and the level of inflammatory factors in the serum of patients. It is worthy of being promoted and applied clinically.

Intra-Articular Administration of a Synthetic Lubricin in Canine Stifles.

OBJECTIVE: The aim of this study was to evaluate the functional, systemic, synovial and articular changes after intra-articular administration of a synthetic lubricin within healthy canine stifles. STUDY DESIGN: A prospective randomized blinded placebo-controlled study composed of 10 dogs equally divided into either a treatment group (intra-articular synthetic lubricin injection, n = 5) or control group (saline, n = 5). Clinical (orthopaedic examination, gait observation, gait analysis), biochemical (complete blood count and biochemistry profile) and local tissue outcomes (joint fluid analysis, joint capsule and articular cartilage histopathology) were evaluated over a time period of 3 months. RESULTS: No significant differences between the treatment group and control group were identified with regard to baseline patient parameters. No clinically significant orthopaedic examination abnormalities, gait abnormalities, biochemical alterations, joint fluid alterations or histopathological alterations were identified over the course of the study. CONCLUSION: The synthetic lubricin studied herein is both biocompatible and safe for a single administration within the canine stifle joint. Further research is necessary to evaluate the clinical efficacy of the synthetic lubricin in canine osteoarthritic joints.

The Effects of Chronic Consumption of Lipid-Rich and Delipidated Bovine Dairy Milk on Brown Adipose Tissue Volume in Wild-Type Mice.

Brown adipose tissue (BAT) activation is associated with increased energy expenditure by inducing non-shivering thermogenesis. The ingestion of a milk fat globule membrane (MFGM) supplement and a high calorie diet are reported gateways into BAT activation. However, little is known about the effect of the MFGM and high calorie diets on BAT volume. To gain insight into this, mice were maintained on a high-fat (HF) or low-fat (LF) diet in conjunction with either full-cream (FC) or skim bovine dairy milk (BDM). After being maintained on their respective diets for 13 weeks, their body composition, including BAT volume, was measured using X-ray microtomography. A high calorie diet resulted in an increase in the BAT volume and mice consuming an HF diet in conjunction with FC BDM had a significantly greater BAT volume than all the other groups. Conversely, mice consuming an HF diet in addition to skim milk had a lower BAT volume compared to the HF control. The data presented suggest that the consumption of a high calorie diet in conjunction with FC BDM increases the BAT volume in wild-type mice. This study may provide valuable insight into future studies investigating BAT volume and BAT activity in relation to environmental factors, including diet.

Activation of AdipoR1 with rCTRP9 Preserves BBB Integrity through the APPL1/AMPK/Nrf2 Signaling Pathway in ICH Mice.

BACKGROUND: The disruption of the blood brain barrier (BBB) is the key factor leading to neurological impairment after intracerebral hemorrhage (ICH) injury. Adiponectin receptor 1 (AdipoR1) has an important effect contributing to the integrity of BBB. As a homologue of adiponectin, recombinant C1q/TNF-related protein 9 (rCTRP9) has neuroprotective effect in cerebrovascular diseases. The aim of this study was to investigate the protective effect of AdipoR1 activation with rCTRP9 on BBB integrity after ICH injury and the potential mechanisms. METHODS: 177 male mice were subjected in this study. ICH was induced by injecting collagenase into the right basal ganglia. rCTRP9 was treated intranasally at 1 hour after ICH. Selective siRNA was administered prior to ICH. Western blot, immunofluorescence staining, neurobehavioral tests, and BBB permeability were evaluated. RESULTS: ICH increased the expression of endogenous AdipoR1 and CTRP9. Administration of rCTRP9 ameliorated neurological deficits and reduced the BBB permeability at 24 hours in ICH mice. Furthermore, rCTRP9 promoted the expression of AdipoR1, APPL1, p-AMPK, Nrf2, and tight junctional proteins. The intervention of specific siRNA of AdipoR1, APPL1, and p-AMPK reversed the protective effects of rCTRP9. CONCLUSIONS: Activation of AdipoR1 with rCTRP9 improved neurological functions and preserved BBB integrity through the APPL1/AMPK/Nrf2 signaling pathway in ICH mice. Therefore, CTRP9 could serve as a promising therapeutic method to alleviate BBB injury following ICH in patients.

Infant Formula with Added Bovine Milk Fat Globule Membrane and Modified Iron Supports Growth and Normal Iron Status at One Year of Age: A Randomized Controlled Trial.

Inclusion of bovine-derived milk fat globule membrane (bMFGM) or bMFGM components in infant formulas (IFs) may support healthy brain development. This double-blind, prospective trial evaluated growth, tolerance, and iron status in infants receiving added bMFGM and modified protein, iron, and arachidonic acid (ARA) concentrations in IF. Healthy term infants were randomized to: control (marketed, routine cow's milk-based IF/100 kcal: 2.1 g protein, 1.8 mg iron, 34 mg ARA) or INV-MFGM (investigational cow's milk-based IF/100 kcal: 1.9 g protein, 1.2 mg iron, 25 mg ARA and whey protein-lipid concentrate, 5 g/L (source of bMFGM)). Anthropometrics, stool characteristics, fussiness, and gassiness through day 365 and blood markers of iron status at day 365 were evaluated. The primary outcome was rate of weight gain from 14-120 days of age. Of 373 infants enrolled (control: 191, INV-MFGM: 182), 275 completed the study (control: 141; INV-MFGM: 134). No group differences in growth rate (g/day) from day 14-120 or study discontinuation were detected. Few group differences in growth or parent-reported fussiness, gassiness, or stool characteristics were detected. No group differences were detected in hemoglobin, hematocrit, or incidence of anemia. In healthy term infants, bMFGM and modified protein, iron, and ARA concentrations in a cow's milk-based IF were well-tolerated, associated with adequate growth throughout the first year of life, and supported normal iron status at one year of age.

From Mum to Bum: An Observational Study Protocol to Follow Digestion of Human Milk Oligosaccharides and Glycoproteins from Mother to Preterm Infant.

The nutritional requirements of preterm infants are challenging to meet in neonatal care, yet crucial for their growth, development and health. Aberrant maturation of the gastrointestinal tract and the microbiota could affect the digestion of human milk and its nutritional value considerably. Therefore, the main objective of the proposed research is to investigate how the intestinal microbiota of preterm and full-term infants differ in their ability to extract energy and nutrients from oligosaccharides and glycoproteins in human milk. This pilot study will be an observational, single-center study performed at the Neonatal Intensive Care Unit at Isala Women and Children's Hospital (Zwolle, The Netherlands). A cohort of thirty mother-infant pairs (preterm ≤30 weeks of gestation, n = 15; full-term 37-42 weeks of gestation, n = 15) will be followed during the first six postnatal weeks with follow-up at three- and six-months postnatal age. We will collect human milk of all mothers, gastric aspirates of preterm infants and fecal samples of all infants. A combination of 16S rRNA amplicon sequencing, proteomics, peptidomics, carbohydrate analysis and calorimetric measurements will be performed. The role of the microbiota in infant growth and development is often overlooked yet offers opportunities to advance neonatal care. The 'From Mum to Bum' study is the first study in which the effect of a preterm gut microbiota composition on its metabolic capacity and subsequent infant growth and development is investigated. By collecting human milk of all mothers, gastric aspirates of preterm infants and fecal samples of all infants at each timepoint, we can follow digestion of human milk from the breast of the mother throughout the gastrointestinal tract of the infant, or 'From Mum to Bum'.

Influence of nimodipine combined with ulinastatin on neurological function and inflammatory reaction in patients with cerebral vasospasm after subarachnoid hemorrhage.

OBJECTIVE: This study aimed to discuss the influence of nimodipine+ulinastatin on the neurological function and inflammatory reaction in patients with cerebral vasospasm (CVS) after subarachnoid hemorrhage (SAH). METHODS: Overall, 90 patients with CVS after SAH who were admitted to our hospital were enrolled in this study and randomly divided into research and control groups (n = 45 for both groups). On the basis of conventional therapy, patients in the control group were injected with ulinastatin and those in the research group were injected with ulinastatin+nimodipine through an intravenous drip for 7 days with the others the same as those of the control group. RESULTS: Blood flow velocity in all cerebral arteries was lower in the research group than in the control group after treatment (P < 0.05). Calcitonin gene-related peptide and nitric oxide levels were higher in the research group than in the control group after treatment (P < 0.05). Endothelin levels were lower in the research group than in the control group (P < 0.05). The total effective rate was higher in the research group than in the control group (P < 0.05). Glasgow Coma Scale scores were higher in the research group than in the control group (P < 0.05). CONCLUSION: The drug combination of nimodipine and ulinastatin improved blood flow and neurological function in patients with CVS after SAH and enhanced the therapeutic efficacy; the underlying mechanism may be associated with the regulation of vascular endothelial dilatation function and the inhibition of relevant inflammatory factors' expression.

Healthy Breastfeeding Infants Consume Different Quantities of Milk Fat Globule Membrane Lipids.

The human milk fat globule membrane (MFGM) contains important lipids for growing infants. Anthropometric measurements, milk samples, and infant milk intake were collected in a cohort of eleven healthy mother-infant dyads during exclusive breastfeeding from birth to six months. One hundred and sixty-six MFGM lipids were analysed using liquid chromatography-mass spectrometry, and the infant intake was calculated. The concentrations and intake were compared and associations between infant intake and growth characteristics explored. The lipid concentrations and infant intake varied widely between mother-infant dyads and between months one and three. The infant intake for many species displayed positive correlations with infant growth, particularly phospholipid species. The high variation in lipid intake is likely an important factor in infant growth, with strong correlations identified between the intake of many MFGM lipids and infant head circumference and weight. This study highlights the need for intake measurements and inclusion in cohort studies to elucidate the role of the human milk lipidome in infant growth and development.

Traditional Chinese medicine for septic patients undergoing ulinastatin therapy: A meta-analysis.

PURPOSE: This study aimed to assess the efficacy of traditional Chinese medicine (TCM) in septic patients treated with ulinastatin. METHODS: PubMed, EmBase, and the Cochrane library were searched up to January 2021 to identify randomized controlled trials. The weight mean difference (WMD) and relative risk (RR) with 95% confidence intervals were used with the random-effects model. RESULTS: Twenty-three randomized controlled trials with 1903 septic patients were included. TCM significantly reduced the APACHE II score (WMD: -5.18; P < .001), interleukin-6 (WMD: -63.00; P < .001), tumor necrosis factor-α (WMD: -8.86; P < .001), c-reactive protein (WMD: -9.47; P < .001), mechanical ventilation duration (WMD: -3.98; P < .001), intensive care unit stay (WMD: -4.18; P < .001), procalcitonin (WMD: -0.53; P < .001), lipopolysaccharide (WMD: -9.69; P < .001), B-type natriuretic peptide (WMD: -159.87; P < .001), creatine kinase isoenzyme MB (WMD: -45.67; P < .001), cardiac troponin I (WMD: -0.66; P < .001), and all-cause mortality risk (RR: 0.55; P < .001). CONCLUSIONS: TCM lowers inflammation levels and reduces the risk of all-cause mortality for septic patients.

The Impact of Milk Fat Globule Membrane with Exercise on Age-Related Degeneration of Neuromuscular Junctions.

Morphological changes in neuromuscular junctions (NMJs), which are synapses formed between α-motor neurons and skeletal muscle fibers, are considered to be important in age-related motor dysfunction. We have previously shown that the intake of dietary milk fat globule membrane (MFGM) combined with exercise attenuates age-related NMJ alterations in the early phase of aging. However, it is unclear whether the effect of MFGM with exercise on age-related NMJ alterations persists into old age, and whether intervention from old age is still effective when age-related changes in NMJs have already occurred. In this study, 6- or 18-month-old mice were treated with a 1% MFGM diet and daily running wheel exercise until 23 or 24 months of age, respectively. MFGM treatment with exercise was effective in suppressing the progression of age-related NMJ alterations in old age, and even after age-related changes in NMJs had already occurred. Moreover, the effect of MFGM intake with exercise was not restricted to NMJs but extended to the structure and function of peripheral nerves. This study demonstrates that MFGM intake with exercise may be a novel approach for improving motor function in the elderly by suppressing age-related NMJ alterations.

Development of a monoclonal antibody against PRRSV glycoprotein 3 using an immuodominant peptide as immunogen.

Glycoprotein 3 (GP3), a highly glycosylated membrane protein, is a protective antigen and minor structural protein of porcine reproductive and respiratory syndrome virus (PRRSV), and plays a crucial role in virus assembly and infection. In the present study, we synthesized 23 overlapping peptides span GP3 protein sequence and used pig anti-PRRSV serums to identify immunodominant peptides by indirect ELISA. Five immunodominant peptides GP3-P3, P4, P5, P6 and P7 were identified and GP3-P4 (P55LCPTRQAAAEILEPGKS72) was conjugated to carrier protein BSA. One mAb 1E5 against GP3 was generated from BALB/c mice immunized with the conjugates BSA-P4. The Characterization of mAb was identified by Western blot, Dot-ELISA, IPMA and IFA. We found that mAb 1E5 can specifically react with HP-PRRSV strains but not C-PRRSV or NADC30-like PRRSV strains tested in this study. Site-directed alanine substitution analysis revealed that 8 amino acid residues were involved in antibody binding, among them E65, L67 and P69 were critical residue recognized by mAb 1E5. Taken together, this study provided a novel strategy for generating specific mAbs against virus proteins by using immunodominant peptides as targets, and the mAb 1E5 may be useful for development of rapid differential detection method differentiating HP-PRRSV from C-PRRSV and NADC30-like PRRSV.

Genetically engineered exosomes display RVG peptide and selectively enrich a neprilysin variant: a potential formulation for the treatment of Alzheimer's disease.

Exosome is a promising next generation nano-based drug delivery vehicle. However, the unknown molecular mechanisms underlying its natural tissue tropism and the relatively low quantity of naturally enriched molecules of therapeutic value hamper exosome's clinical application. The aim of the research was to create a targeted and highly efficacious exosome formulation for the treatment of Alzheimer's disease (AD). Genetic engineering techniques combined with co-transfection of parental cells were employed to create an exosome formulation that displays RVG peptide on its surface targeting α7-nAChR and simultaneously enriches a neprilysin variant with increased specificity and efficacy in degrading ß amyloid peptide (Aß). The exosome formulation was preferentially internalised into cell lines in an α7-nAChR expression level-dependent manner. When incubated with Aß-producing N2a cells, it significantly decreased intracellular and secreted Aß40 levels, a potency that is superior to exosomes derived from adipose-derived stem cell. When systemically administered into mice, the exosome formulation was preferentially targeted to the hippocampus region of the brain and significantly decreased the expression of proinflammatory genes, IL1α, TNFα and NF-κB, and simultaneously increased the expression of anti-inflammatory gene, IL10. Our exosome formulation may be explored as an over-the-counter treatment for AD.

Single-component multilayered self-assembling nanoparticles presenting rationally designed glycoprotein trimers as Ebola virus vaccines.

Ebola virus (EBOV) glycoprotein (GP) can be recognized by neutralizing antibodies (NAbs) and is the main target for vaccine design. Here, we first investigate the contribution of the stalk and heptad repeat 1-C (HR1C) regions to GP metastability. Specific stalk and HR1C modifications in a mucin-deleted form (GPΔmuc) increase trimer yield, whereas alterations of HR1C exert a more complex effect on thermostability. Crystal structures are determined to validate two rationally designed GPΔmuc trimers in their unliganded state. We then display a modified GPΔmuc trimer on reengineered protein nanoparticles that encapsulate a layer of locking domains (LD) and a cluster of helper T-cell epitopes. In mice and rabbits, GP trimers and nanoparticles elicit cross-ebolavirus NAbs, as well as non-NAbs that enhance pseudovirus infection. Repertoire sequencing reveals quantitative profiles of vaccine-induced B-cell responses. This study demonstrates a promising vaccine strategy for filoviruses, such as EBOV, based on GP stabilization and nanoparticle display.

Whole and Isolated Protein Fractions Differentially Affect Gastrointestinal Integrity Markers in C57Bl/6 Mice Fed Diets with a Moderate-Fat Content.

Various proteins or protein fractions reportedly positively affect gastrointestinal integrity and inflammation in diets providing >45% energy as fat. This study tested whether benefits were seen in diets providing 30% of energy as fat. Purified diets (PD) with isolated soy protein (ISP), dried whole milk powder (DWMP), milk fat globule membrane (MFGM), or milk protein concentrate (MPC) as protein sources were fed to C57BL/6J mice (n = 15/diet group) for 13 weeks. MFGM-fed mice were heaviest (p < 0.005) but remained within breeder norms. Growth rates and gut motility were similar for all PD-fed mice. FITC-dextran assessed gut permeability was lowest in DWMP and MFGM (p = 0.054); overall, plasma endotoxin and unprovoked circulating cytokines indicated a non-inflammatory state for all PD-fed mice. Despite differences in cecal butyrate and intestinal gene expression, all PDs supported gastrointestinal health. Whole milk provided more positive effects compared to its fractions. However, ISP-fed mice showed a >370%, (p < 0.006) increase in colonic myeloperoxidase activity indicative of tissue neutrophil infiltration. Surprisingly, FITC-dextran and endotoxin outcomes were many folds better in PD-fed mice than mice (strain, vendor, age and sex matched) fed a "chow-type" nutritionally adequate non-PD. Additional variables within a diet's matrix appear to affect routine indicators or gastrointestinal health.