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Small (Weinheim An Der Bergstrasse,... Jun 2024Increased expression of immune check point genes, such as PD-L1, is one of the main reasons for immunosuppression, especially for colon cancer. Development of novel...
Increased expression of immune check point genes, such as PD-L1, is one of the main reasons for immunosuppression, especially for colon cancer. Development of novel therapeutic strategies is of great importance to improve the prognosis. In this study, outer membrane vesicles (OMV) derived from Gram-negative bacteria are engineered to immune checkpoint blockade nanosystem for efficient elicitation of anti-tumor immunity. Briefly, the OMVs are engineered with Lyp1-Traptavidin (S52G, R53D mutant of streptavidin) fusion protein displayed on the surface. The Lyp-1 endows the OMV with the capacity to target tumor tissues, while the Traptavidin ensures easy decoration of biotinylated anti-PD-L1 and biotinylated M6P (mannose 6-phosphate). The simultaneously anchored anti-PD-L1 and M6P (ligand for cation-independent mannose 6-phosphate receptor) on the engineered OMVs coordinately direct the membrane PD-L1 to lysosome for degradation, and thus unleash the anti-tumor immunity. With syngeneic tumor model, the engineered OMVs are confirmed to boost immunity, inhibit cancer growth, and thus prolong survival. Together, A proposed OMV-based modular nanosystem that enables assembly of biotinylated anti-PD-L1 and M6P on the surface for tumor-targeted immune checkpoint blockade.
PubMed: 38934533
DOI: 10.1002/smll.202400770 -
Frontiers in Immunology 2024Immune cells play a crucial role in the development and progression of pancreatic cancer, yet the causal relationship remains uncertain due to complex immune...
BACKGROUND
Immune cells play a crucial role in the development and progression of pancreatic cancer, yet the causal relationship remains uncertain due to complex immune microenvironments and conflicting research findings. Mendelian randomization (MR), this study aims to delineate the causal relationships between immune cells and pancreatic cancer while identifying intermediary factors.
METHODS
The genome-wide association study (GWAS) data on immune cells, pancreatic cancer, and plasma metabolites are derived from public databases. In this investigation, inverse variance weighting (IVW) as the primary analytical approach to investigate the causal relationship between exposure and outcome. Furthermore, this study incorporates MR-Egger, simple mode, weighted median, and weighted mode as supplementary analytical approaches. To ensure the reliability of our findings, we further assessed horizontal pleiotropy and heterogeneity and evaluated the stability of MR results using the Leave-one-out method. In conclusion, this study employed mediation analysis to elucidate the potential mediating effects of plasma metabolites.
RESULTS
Our investigation revealed a causal relationship between immune cells and pancreatic cancer, highlighting the pivotal roles of CD11c+ monocytes (odds ratio, OR=1.105; 95% confidence interval, 95%CI: 1.002-1.218; P=0.045), HLA DR+ CD4+ antigen-presenting cells (OR=0.920; 95%CI: 0.873-0.968; P=0.001), and HLA DR+ CD8br T cells (OR=1.058; 95%CI: 1.002-1.117; P=0.041) in pancreatic cancer progression. Further mediation analysis indicated that oxalate (proportion of mediation effect in total effect: -11.6%, 95% CI: -89.7%, 66.6%) and the mannose to trans-4-hydroxyproline ratio (-19.4, 95% CI: -136%, 96.8%) partially mediate the relationship between HLA DR+ CD8br T cells and pancreatic cancer in nature. In addition, our analysis indicates that adrenate (-8.39%, 95% CI: -18.3%, 1.54%) plays a partial mediating role in the association between CD11c+ monocyte and pancreatic cancer, while cortisone (-26.6%, 95% CI: 138%, -84.8%) acts as a partial mediator between HLA DR+ CD4+ AC and pancreatic cancer.
CONCLUSION
This MR investigation provides evidence supporting the causal relationship between immune cell and pancreatic cancer, with plasma metabolites serving as mediators. Identifying immune cell phenotypes with potential causal effects on pancreatic cancer sheds light on its underlying mechanisms and suggests novel therapeutic targets.
Topics: Humans; Pancreatic Neoplasms; Mendelian Randomization Analysis; Genome-Wide Association Study; Monocytes; Risk Factors; Genetic Predisposition to Disease; Polymorphism, Single Nucleotide
PubMed: 38933268
DOI: 10.3389/fimmu.2024.1402113 -
Journal of Agricultural and Food... Jun 2024The human intestinal mucus layer protects against pathogenic microorganisms and harmful substances, whereas it also provides an important colonization niche for...
The human intestinal mucus layer protects against pathogenic microorganisms and harmful substances, whereas it also provides an important colonization niche for mutualistic microbes. The main functional components of mucus are heavily glycosylated proteins, called mucins. Mucins can be cleaved and utilized by intestinal microbes. The mechanisms between intestinal microbes and the regulation of mucin glycosylation are still poorly understood. In this study, mucus was produced by HT29-MTX-E12 cells under Semi-Wet interface with Mechanical Stimulation. Cells were exposed to pasteurized nonpathogenic bacteria , , and to evaluate influence on glycosylation patterns. Following an optimized protocol, O- and N-glycans were efficiently and reproducibly released, identified, and semiquantified using MALDI-TOF-MS and PGC-LC-MS/MS. Exposure of cells to bacteria demonstrated increased diversity of sialylated O-glycans and increased abundance of high mannose N-glycans in produced mucus. Furthermore, changes in glycan ratios were observed. It is speculated that bacterial components interact with the enzymatic processes in glycan production and that pasteurized bacteria influence glycosyltransferases or genes involved. These results highlight the influence of pasteurized bacteria on glycosylation patterns, stress the intrinsic relationship between glycosylation and microbiota, and show the potential of using produced mucus to study glycosylation behavior.
PubMed: 38932522
DOI: 10.1021/acs.jafc.4c01401 -
Vaccines Jun 2024This study focuses on the development and characterization of an intranasal vaccine platform using adjuvanted nanoparticulate delivery of swine influenza A virus...
This study focuses on the development and characterization of an intranasal vaccine platform using adjuvanted nanoparticulate delivery of swine influenza A virus (SwIAV). The vaccine employed whole inactivated H1N2 SwIAV as an antigen and STING-agonist ADU-S100 as an adjuvant, with both surface adsorbed or encapsulated in mannose-chitosan nanoparticles (mChit-NPs). Optimization of mChit-NPs included evaluating size, zeta potential, and cytotoxicity, with a 1:9 mass ratio of antigen to NP demonstrating high loading efficacy and non-cytotoxic properties suitable for intranasal vaccination. In a heterologous H1N1 pig challenge trial, the mChit-NP intranasal vaccine induced cross-reactive sIgA antibodies in the respiratory tract, surpassing those of a commercial SwIAV vaccine. The encapsulated mChit-NP vaccine induced high virus-specific neutralizing antibody and robust cellular immune responses, while the adsorbed vaccine elicited specific high IgG and hemagglutinin inhibition antibodies. Importantly, both the mChit-NP vaccines reduced challenge heterologous viral replication in the nasal cavity higher than commercial swine influenza vaccine. In summary, a novel intranasal mChit-NP vaccine platform activated both the arms of the immune system and is a significant advancement in swine influenza vaccine design, demonstrating its potential effectiveness for pig immunization.
PubMed: 38932376
DOI: 10.3390/vaccines12060647 -
Microorganisms Jun 2024This study demonstrates that can produce exopolysaccharides (EPSs) using alternative carbon sources, such as sugarcane molasses and glycerol. After screening 22 strains...
This study demonstrates that can produce exopolysaccharides (EPSs) using alternative carbon sources, such as sugarcane molasses and glycerol. After screening 22 strains of Lactobacillus to determine which achieved the highest production of EPS based on dry weight at 37 °C, the strain Ke8 () was selected for new experiments. The EPS obtained using glycerol and glucose as carbon sources was classified as a heteropolysaccharide composed of glucose and mannose, containing 1730 g.mol, consisting of 39.4% carbohydrates and 18% proteins. The EPS obtained using molasses as the carbon source was characterized as a heteropolysaccharide composed of glucose, galactose, and arabinose, containing 1182 g.mol, consisting of 52.9% carbohydrates and 11.69% proteins. This molecule was characterized using Size Exclusion Chromatography (HPLC), Gas chromatography-mass spectrometry (GC-MS), Fourier-transform infrared spectroscopy (FTIR), and proton nuclear magnetic resonance spectroscopy (H-NMR). The existence of polysaccharides was confirmed via FT-IR and NMR analyses. The results obtained suggest that can grow in media that use alternative carbon sources such as glycerol and molasses. These agro-industry residues are inexpensive, and their use contributes to sustainability. The lack of studies regarding the use of for the production of EPS using renewable carbon sources from agroindustry should be noted.
PubMed: 38930541
DOI: 10.3390/microorganisms12061159 -
Antioxidants (Basel, Switzerland) May 2024Co-fermentation with bacteria and enzymes can reduce sugar content in palm kernel cake (PKC); however, the chemical changes and their effects on cell functionality are...
Palm Kernel Cake Extracts Obtained from the Combination of Bacterial Fermentation and Enzymic Hydrolysis Promote Swine Small Intestine IPEC-J2 Cell Proliferation and Alleviate LPS-Induced Inflammation In Vitro.
Co-fermentation with bacteria and enzymes can reduce sugar content in palm kernel cake (PKC); however, the chemical changes and their effects on cell functionality are unclear. This study investigated the active components in pre-treated PKC extracts and their effects on pig small intestine IPEC-J2 cell proliferation and LPS-induced inflammation. The extracts contained 60.75% sugar, 36.80% mannose, 1.75% polyphenols and 0.59% flavone, as determined by chemical analyses, suggesting that the extracts were palm kernel cake oligosaccharides (PKCOS). Then, we found that 1000 µg/mL PKCOS counteracted the decrease in cell viability (CCK8 kit) caused by LPS induction by 5 µg/mL LPS ( < 0.05). Mechanistic studies conducted by RNA-seq and qPCR analyses suggested PKCOS promoted cell proliferation through the upregulation of , , and in the PI3K/MAPK signalling pathway; alleviated inflammation caused by LPS via the downregulation of the target genes and in association with apoptosis; and regulated the expression of the antioxidant genes , and to exert positive antioxidant effects ( < 0.05). Furthermore, PKCOS upregulated (encoding SLGT1), and in the glycolytic pathway ( < 0.05), suggesting cell survival. In summary, PKCOS has positive effects on promoting swine intestine cell proliferation against inflammation.
PubMed: 38929121
DOI: 10.3390/antiox13060682 -
International Journal of Molecular... Jun 2024We aimed to investigate the characteristics of serum metabolomics in aneurysmal subarachnoid hemorrhage patients (aSAH) with different 3-month outcomes (good = modified...
We aimed to investigate the characteristics of serum metabolomics in aneurysmal subarachnoid hemorrhage patients (aSAH) with different 3-month outcomes (good = modified Rankin score: 0-3 vs. poor = mRS 4-6). We collected serum samples from 46 aSAH patients at 24 (D1) and 168 (D7) hours after injury for analysis by liquid chromatography-mass spectrometry. Ninety-six different metabolites were identified. Groups were compared using multivariate (orthogonal partial least squares discriminant analysis), univariate, and receiving operator characteristic (ROC) methods. We observed a marked decrease in serum homocysteine levels at the late phase (D7) compared to the early phase (D1). At both D1 and D7, mannose and sorbose levels were notably higher, alongside elevated levels of kynurenine (D1) and increased 2-hydroxybutyrate, methyl-galactoside, creatine, xanthosine, p-hydroxyphenylacetate, N-acetylalanine, and N-acetylmethionine (all D7) in the poor outcome group. Conversely, levels of guanidinoacetate (D7) and several amino acids (both D1 and D7) were significantly lower in patients with poor outcomes. Our results indicate significant changes in energy metabolism, shifting towards ketosis and alternative energy sources, both in the early and late phases, even with adequate enteral nutrition, particularly in patients with poor outcomes. The early activation of the kynurenine pathway may also play a role in this process.
Topics: Humans; Subarachnoid Hemorrhage; Male; Female; Middle Aged; Metabolomics; Metabolome; Aged; Adult; Homocysteine; Kynurenine; Biomarkers; Prognosis; Hydroxybutyrates
PubMed: 38928303
DOI: 10.3390/ijms25126597 -
The Journal of Antibiotics Jun 2024A novel actinomycete, designated as TPMA0078, was isolated from a soil sample collected in Shinjuku, Tokyo, Japan. 16S rRNA gene sequence analysis indicated that strain...
A novel actinomycete, designated as TPMA0078, was isolated from a soil sample collected in Shinjuku, Tokyo, Japan. 16S rRNA gene sequence analysis indicated that strain TPMA0078 belongs to the genus Actinoplanes and is closely related to Actinoplanes regularis IFO 12514 (99.86% 16S rRNA gene sequence similarity). The spores of strain TPMA0078 were motile, and the sporangia were cylindrical. The diamino acids in the cell wall peptidoglycan of strain TPMA0078 were meso-diaminopimelic acid and 3OH-meso-diaminopimelic acid. Whole-cell sugars were glucose and mannose, with galactose as a minor component. The major cellular fatty acids identified were iso-C, iso-C, and anteiso-C. The predominant menaquinone was MK-9(H), and the principal polar lipid was phosphatidylethanolamine. These chemotaxonomic properties of strain TPMA0078 were consistent with those of Actinoplanes. Meanwhile, digital DNA-DNA hybridization and average nucleotide identity values showed low relatedness between strain TPMA0078 and A. regularis NBRC 12514. Furthermore, several phenotypic properties of strain TPMA0078 distinguished it from those of closely related species. Based on its genotypic and phenotypic characteristics, strain TPMA0078 represents a novel species of the genus Actinoplanes, for which the name Actinoplanes kirromycinicus sp. nov. is proposed. The type strain is TPMA0078 (=NBRC 116422 = TBRC 18262).
PubMed: 38926493
DOI: 10.1038/s41429-024-00756-w -
Scientific Reports Jun 2024Cerebrospinal fluid metabolomics is a promising research technology in the elucidation of nervous system disorders. Therefore, in this work, a cerebrospinal fluid (CSF)...
Cerebrospinal fluid metabolomics is a promising research technology in the elucidation of nervous system disorders. Therefore, in this work, a cerebrospinal fluid (CSF) metabolomics method using liquid chromatography coupled to mass spectrometry was optimized and validated to cover a wide range of metabolites. An acceptable coefficient of variance regarding instrumental, within-lab and intra-assay precision was found for 95, 70 and 96 of 102 targeted metabolites, together with 1256, 676 and 976 untargeted compounds, respectively. Moreover, approximately 75% of targeted metabolites and 50% of untargeted compounds displayed good linearity across different dilution ranges. Consequently, metabolic alterations in CSF of dogs with idiopathic epilepsy (IE) were studied by comparing CSF of dogs diagnosed with IE (Tier II) to dogs with non-brain related disease. Targeted metabolome analysis revealed higher levels of cortisol, creatinine, glucose, hippuric acid, mannose, pantothenol, and 2-phenylethylamine (P values < 0.05) in CSF of dogs with IE, whereas CSF of dogs with IE showed lower levels of spermidine (P value = 0.02). Untargeted CSF metabolic fingerprints discriminated dogs with IE from dogs with non-brain related disease using Orthogonal Partial Least Squares Discriminant Analysis (R(Y) = 0.997, Q(Y) = 0.828), from which norepinephrine was putatively identified as an important discriminative metabolite.
Topics: Animals; Dogs; Epilepsy; Metabolomics; Dog Diseases; Metabolome; Chromatography, Liquid; Male; Biomarkers; Female
PubMed: 38926488
DOI: 10.1038/s41598-024-64777-z -
Discovery Medicine Jun 2024Facilitating the healing process of skin post-trauma is crucial for minimizing infection risks and reinstating normal tissue functionality. While past studies have...
BACKGROUND
Facilitating the healing process of skin post-trauma is crucial for minimizing infection risks and reinstating normal tissue functionality. While past studies have established astaxanthin (ASX) as an effective compound in promoting wound healing, the precise mechanism of its action remains unclear. Consequently, the objective of this study was to explore the impact of ASX on the acute wound healing of rat skin by modulating macrophage polarization.
METHODS
Eighteen male SD rats were randomly assigned to control, dimethylsulfoxide (DMSO), and ASX groups. Acute skin wounds were induced in the rats, and the effects of different treatments on wound area and healing were assessed. Hematoxylin-eosin (H&E) staining was employed to detect histopathological changes in the skin, while Masson staining was utilized to observe collagen expression. Immunohistochemistry was conducted to identify clusters of differentiation (CD) 206 macrophages in the tissues. Furthermore, enzyme-linked immunosorbent assay (ELISA) was used to measure the levels of inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin (IL)-6, IL-8, IL-10, IL-4, and IL-13. The expression of inducible nitric oxide synthase (iNOS), arginase (Arg)-1, and mannose receptor C-type 1 (Mrc1) proteins in the injured skin of rats was assessed through Western blot analysis.
RESULTS
On postoperative days 7 and 14, the ASX treatment demonstrated notable reductions in inflammatory cell infiltration and inflammatory cytokine expression when compared to the Control and DMSO groups. This was accompanied by evident improvements in the pathological changes in skin tissue, characterized by the regeneration of new epidermis, dermal repair, and increased thickness of granulation, contributing to enhanced scar formation. Furthermore, ASX therapy exhibited an upregulation in the expression levels of collagen I and collagen III, along with markers indicative of M2 macrophages. These findings collectively signify the accelerated progression of wound healing attributed to ASX intervention.
CONCLUSIONS
In summary, these findings collectively indicate that ASX facilitates the healing of rat skin wounds by suppressing inflammatory responses and fostering M2 macrophage polarization. Consequently, ASX holds promise as a potentially effective drug for the treatment of skin wounds.
Topics: Animals; Wound Healing; Male; Macrophages; Rats; Rats, Sprague-Dawley; Xanthophylls; Collagen; Skin; Cytokines; Macrophage Activation
PubMed: 38926104
DOI: 10.24976/Discov.Med.202436185.108