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Journal of Advanced Research Jan 2022Honokiol (HO) exerts neuroprotective effects in several animal models of Alzheimer's disease (AD), but the poor dissolution hampers its bioavailability and therapeutic...
INTRODUCTION
Honokiol (HO) exerts neuroprotective effects in several animal models of Alzheimer's disease (AD), but the poor dissolution hampers its bioavailability and therapeutic efficacy.
OBJECTIVES
A novel honokiol nanoscale drug delivery system (Nano-HO) with smaller size and excellent stability was developed in this study to improve the solubility and bioavailability of HO. The anti-AD effects of Nano-HO was determined.
METHODS
Male TgCRND8 mice were daily orally administered Nano-HO or HO at the same dosage (20 mg/kg) for 17 consecutive weeks, followed by assessment of the spatial learning and memory functions using the Morris Water Maze test (MWMT).
RESULTS
Our pharmacokinetic study indicated that the oral bioavailability was greatly improved by Nano-HO. In addition, Nano-HO significantly improved cognitive deficits and inhibited neuroinflammation via suppressing the levels of TNF-α, IL-6 and IL-1β in the brain, preventing the activation of microglia (IBA-1) and astrocyte (GFAP), and reducing β-amyloid (Aβ) deposition in the cortex and hippocampus of TgCRND8 mice. Moreover, Nano-HO was more effective than HO in modulating amyloid precursor protein (APP) processing via suppressing β-secretase, as well as enhancing Aβ-degrading enzymes like neprilysin (NEP). Furthermore, Nano-HO more markedly inhibited tau hyperphosphorylation via decreasing the ratio of p-Tau (Thr 205)/tau and regulating tau-related apoptosis proteins (caspase-3 and Bcl-2). In addition, Nano-HO more markedly attenuated the ratios of p-JNK/JNK and p-35/CDK5, while enhancing the ratio of p-GSK-3β (Ser9)/GSK-3β. Finally, Nano-HO prevented the gut microflora dysbiosis in TgCRND8 mice in a more potent manner than free HO.
CONCLUSION
Nano-HO was more potent than free HO in improving cognitive impairments in TgCRND8 mice via inhibiting Aβ deposition, tau hyperphosphorylation and neuroinflammation through suppressing the activation of JNK/CDK5/GSK-3β signaling pathway. Nano-HO also more potently modulated the gut microbiota community to protect its stability than free HO. These results suggest that Nano-HO has good potential for further development into therapeutic agent for AD treatment.
Topics: Alzheimer Disease; Animals; Biphenyl Compounds; Cognition; Cognitive Dysfunction; Gastrointestinal Microbiome; Glycogen Synthase Kinase 3 beta; Lignans; Male; Mice; Neuroinflammatory Diseases
PubMed: 35024199
DOI: 10.1016/j.jare.2021.03.012 -
EBioMedicine May 2021Coronavirus-2 (SARS-CoV-2) infection causes an acute respiratory syndrome accompanied by multi-organ damage that implicates a prothrombotic state leading to widespread...
BACKGROUND
Coronavirus-2 (SARS-CoV-2) infection causes an acute respiratory syndrome accompanied by multi-organ damage that implicates a prothrombotic state leading to widespread microvascular clots. The causes of such coagulation abnormalities are unknown. The receptor tissue factor, also known as CD142, is often associated with cell-released extracellular vesicles (EV). In this study, we aimed to characterize surface antigens profile of circulating EV in COVID-19 patients and their potential implication as procoagulant agents.
METHODS
We analyzed serum-derived EV from 67 participants who underwent nasopharyngeal swabs molecular test for suspected SARS-CoV-2 infection (34 positives and 33 negatives) and from 16 healthy controls (HC), as referral. A sub-analysis was performed on subjects who developed pneumonia (n = 28). Serum-derived EV were characterized for their surface antigen profile and tested for their procoagulant activity. A validation experiment was performed pre-treating EV with anti-CD142 antibody or with recombinant FVIIa. Serum TNF-α levels were measured by ELISA.
FINDINGS
Profiling of EV antigens revealed a surface marker signature that defines circulating EV in COVID-19. A combination of seven surface molecules (CD49e, CD209, CD86, CD133/1, CD69, CD142, and CD20) clustered COVID (+) versus COVID (-) patients and HC. CD142 showed the highest discriminating performance at both multivariate models and ROC curve analysis. Noteworthy, we found that CD142 exposed onto surface of EV was biologically active. CD142 activity was higher in COVID (+) patients and correlated with TNF-α serum levels.
INTERPRETATION
In SARS-CoV-2 infection the systemic inflammatory response results in cell-release of substantial amounts of procoagulant EV that may act as clotting initiation agents, contributing to disease severity.
FUNDING
Cardiocentro Ticino Institute, Ente ospedaliero Cantonale, Lugano-Switzerland.
Topics: Adult; Aged; Aged, 80 and over; Antigens, Surface; Biomarkers; COVID-19; Case-Control Studies; Diagnosis, Differential; Extracellular Vesicles; Female; Humans; Male; Middle Aged; Nasopharynx; SARS-CoV-2; Switzerland; Thromboplastin; Thrombosis; Tumor Necrosis Factor-alpha
PubMed: 33971404
DOI: 10.1016/j.ebiom.2021.103369 -
Molecular Carcinogenesis Feb 2017The enhancer of zeste homolog 2 (EZH2) is involved in a number of fundamental pathological processes of cancer. However, its role in DNA repair pathway is still unclear....
The enhancer of zeste homolog 2 (EZH2) is involved in a number of fundamental pathological processes of cancer. However, its role in DNA repair pathway is still unclear. Here, we have identified XPA as a novel target gene of EZH2 via a DNA repair pathway PCR array. XPA plays a pivot role in nucleotide excision repair (NER). The expression of XPA was significantly increased by EZH2 specific inhibitor GSK126 or lentiviral shEZH2 in nasopharyngeal carcinoma (NPC) CNE and 8F cell lines. Chromatin immunoprecipitation assay demonstrated that EZH2 catalyzes H3K27 trimethylation at the XPA promoters. Furthermore, we validated the negative correlation of EZH2 and XPA in a NPC tissue microarray by immunohistochemistry staining. We also found that high expression of EZH2 was positively correlated with advanced T, N, and AJCC stage of NPC; and low expression of XPA was positively correlated with advanced T and N stage. In NPC cell lines, increased XPA expression by EZH2 inhibition resulted in a more rapid removal of UVC induced 6-4PP- and CPD-DNA adducts, as well as enhanced efficiency of DNA repair after UVC irradiation as detected by the Comet assay and immunofluorescence staining of γH2Ax. Consistently, increased cell clonogenic survival, decreased apoptosis, and necrosis after UVC irradiation, and increased resistance to DNA damaging agent cisplatin was also observed in EZH2 inhibited cells. These results illustrate that EZH2 may promote carcinogenesis and cancer development of NPC by transcriptional repression of XPA gene and inactivation of NER pathway. © 2016 Wiley Periodicals, Inc.
Topics: Antineoplastic Agents; Carcinoma; Cell Line, Tumor; Cisplatin; DNA Repair; Down-Regulation; Enhancer of Zeste Homolog 2 Protein; Gene Expression Regulation, Neoplastic; Histone Code; Humans; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; Nasopharynx; Promoter Regions, Genetic; Xeroderma Pigmentosum Group A Protein
PubMed: 27253463
DOI: 10.1002/mc.22507 -
Journal of Immunology (Baltimore, Md. :... Dec 2022Nasal immunity is an ancient and conserved arm of the mucosal immune system in vertebrates. In teleost fish, we previously reported the presence of a...
Nasal immunity is an ancient and conserved arm of the mucosal immune system in vertebrates. In teleost fish, we previously reported the presence of a nasopharynx-associated lymphoid tissue (NALT) characterized by scattered immune cells located in the trout olfactory lamellae. This diffuse NALT mounts innate and adaptive immune responses to nasal infection or vaccination. In mammals, lymphoid structures such as adenoids and tonsils support affinity maturation of the adaptive immune response in the nasopharyngeal cavity. These structures, known as organized NALT (O-NALT), have not been identified in teleost fish to date, but their evolutionary forerunners exist in sarcopterygian fish. In this study, we report that the rainbow trout nasal cavity is lined with a lymphoepithelium that extends from the most dorsal opening of the nares to the ventral nasal cavity. Within the nasal lymphoepithelium we found lymphocyte aggregates called O-NALT in this study that are composed of ∼ 56% CD4+, 24% IgM+, 16% CD8α+, and 4% IgT+ lymphocytes and that have high constitutive aicda mRNA expression. Intranasal (i.n.) vaccination with live attenuated infectious hematopoietic necrosis virus triggers expansions of B and T cells and aicda expression in response to primary i.n. vaccination. IgM+ B cells undergo proliferation and apoptosis within O-NALT upon prime but not boost i.n. vaccination. Our results suggest that novel mucosal microenvironments such as O-NALT may be involved in the affinity maturation of the adaptive immune response in early vertebrates.
Topics: Animals; Gastric Mucosa; Germinal Center; Mammals; Biomarkers; Adenoids; Immunoglobulin M
PubMed: 36426979
DOI: 10.4049/jimmunol.2200396 -
Neurology India 2019
Topics: Brain; Cerebellum; Humans; Infarction; Male; Middle Aged; Palatine Tonsil
PubMed: 30860155
DOI: 10.4103/0028-3886.253573 -
Nutrients Jan 2022Pharyngitis is an inflammation of the pharynx caused by viral, bacterial, or non-infectious factors. In the present study, the anti-inflammatory efficacy of carvacrol...
Pharyngitis is an inflammation of the pharynx caused by viral, bacterial, or non-infectious factors. In the present study, the anti-inflammatory efficacy of carvacrol was assessed using an in vitro model of streptococcal pharyngitis using human tonsil epithelial cells (HTonEpiCs) induced with cell wall antigens. HTonEpiCs were stimulated by a mixture of lipoteichoic acid (LTA) and peptidoglycan (PGN) for 4 h followed by exposure to carvacrol for 20 h. Following exposure, interleukin (IL)-6, IL-8, human beta defensin-2 (HBD-2), epithelial-derived neutrophil-activating protein-78 (ENA-78), granulocyte chemotactic protein-2 (GCP-2), cyclooxygenase-2 (COX-2), tumor necrosis factor-alpha (TNF-α), and prostaglandin (PGE) were measured by enzyme-linked immunosorbent assays (ELISA). The levels of pro-inflammatory cytokines, IL-6, IL-8, ENA-78, and GCP-2 were decreased in a carvacrol dose-dependent manner. The production of HBD-2 was significantly suppressed over 24 h carvacrol treatments. PGE and COX-2 levels in the cell suspensions were affected by carvacrol treatment. TNF-α was not detected. The cell viability of all the tested carvacrol concentrations was greater than 80%, with no morphological changes. The results suggest that carvacrol has anti-inflammatory properties, and carvacrol needs to be further assessed for potential clinical or healthcare applications to manage the pain associated with streptococcal pharyngitis.
Topics: Biomarkers; Cell Wall; Cymenes; Epithelial Cells; Humans; Lipopolysaccharides; Palatine Tonsil; Peptidoglycan; Teichoic Acids
PubMed: 35276864
DOI: 10.3390/nu14030503 -
Parasites & Vectors May 2021The liver fluke Fasciola gigantica secretes excretory-secretory proteins during infection to mediate its interaction with the host. In this study, we investigated the...
BACKGROUND
The liver fluke Fasciola gigantica secretes excretory-secretory proteins during infection to mediate its interaction with the host. In this study, we investigated the immunomodulatory effects of a recombinant tegumental calcium-binding EF-hand protein 4 of F. gigantica (rFg-CaBP4) on goat monocytes.
METHODS
The rFg-CaBP4 protein was induced and purified by affinity chromatography. The immunogenic reaction of rFg-CaBP4 against specific antibodies was detected through western blot analysis. The binding of rFg-CaBP4 on surface of goat monocytes was visualized by immunofluorescence assay. The localization of CaBP4 within adult fluke structure was detected by immunohistochemical analysis. The cytokine transcription levels in response to rFg-CaBP4 were examined using ABI 7500 real-time PCR system. The expression of the major histocompatibility complex (MHC) class-II molecule (MHC-II) in response to rFg-CaBP4 protein was analyzed using Flow cytometry.
RESULTS
The isopropyl-ß-D-thiogalactopyranoside-induced rFg-CaBP4 protein reacted with rat sera containing anti-rFg-CaBP4 polyclonal antibodies in a western blot analysis. The adhesion of rFg-CaBP4 to monocytes was visualized by immunofluorescence and laser scanning confocal microscopy. Immunohistochemical analysis localized native CaBP4 to the oral sucker, pharynx, genital pore, acetabulum and tegument of adult F. gigantica. Co-incubation of rFg-CaBP4 with concanavalin A-stimulated monocytes increased the transcription levels of interleukin (IL)-2, IL-4, interferon gamma and transforming growth factor-β. However, a reduction in the expression of IL-10 and no change in the expression of tumor necrosis factor-α were detected. Additionally, rFg-CaBP4-treated monocytes exhibited a marked increase in the expression of the major histocompatibility complex (MHC) class-II molecule (MHC-II) and a decrease in MHC-I expression, in a dose-dependent manner.
CONCLUSIONS
These findings provide additional evidence that calcium-binding EF-hand proteins play roles in host-parasite interaction. Further characterization of the immunomodulatory role of rFg-CaBP4 should expand our understanding of the strategies used by F. gigantica to evade the host immune responses.
Topics: Animals; Calcium-Binding Proteins; Cytokines; Fasciola; Fascioliasis; Goats; Immunomodulation; Monocytes; Recombinant Proteins
PubMed: 34022913
DOI: 10.1186/s13071-021-04784-5 -
The Pediatric Infectious Disease Journal May 2015The incidence of necrotizing pneumococcal pneumonia has increased during the past 2 decades. We hypothesized that increased pneumococcal load or augmented inflammatory...
BACKGROUND
The incidence of necrotizing pneumococcal pneumonia has increased during the past 2 decades. We hypothesized that increased pneumococcal load or augmented inflammatory cytokine production might lead to destructive pneumococcal lung disease.
METHODS
This study enrolled prospectively 0- to 18-year-old children with a diagnosis of community-acquired pneumonia with pleural effusion admitted to 6 medical centers from March 2010 to April 2012. Children were diagnosed with pneumococcal empyema if the pleural fluid tested positive for quantitative pneumococcal (lytA) detection by real-time polymerase chain reaction. Pneumococcal empyema cases were further divided into 4 groups according to necrosis severity: (0) nonnecrosis, (1) mild necrosis, (2) cavitation and (3) bronchopleural fistula. Nasopharyngeal and pleural pneumococcal load, as well as levels of proinflammatory cytokines (TNF-α, IL-1β, IL-6, IL-8), Th1-(IL-2, IFN-γ), Th2-(IL-4, IL-10) and Th17-cytokines (IL-17), in the pleural fluid was measured.
RESULTS
Serotypes 19A and 3 accounted for 69.4% and 12.5%, respectively, of 72 cases of pneumococcal empyema. Pleural pneumococcal load was significantly higher in serotypes 19A and 3 infection than in the other strains causing infection (P = 0.006). There was a correlation between nasopharyngeal and pleural pneumococcal load (ρ = 0.35; P = 0.05). In multivariate ordinal logistic regression analysis, pleural pneumococcal load (adjusted odds ratio: 1.79; 95% confidence interval: 1.03-3.06) and IL-8 (adjusted odds ratio: 2.64; 95% confidence interval: 1.21-5.75) were independent factors associated with the severity of lung necrosis.
CONCLUSIONS
Evolution of Streptococcus pneumoniae toward increased fitness in their interaction with host and exaggerated IL-8 expression may be responsible for the increase of necrotizing pneumococcal pneumonia.
Topics: Analysis of Variance; Bacterial Load; Cytokines; Empyema; Humans; Incidence; Lung; Nasopharynx; Necrosis; Pneumonia, Pneumococcal; Prospective Studies; Radiography; Streptococcus pneumoniae
PubMed: 25461475
DOI: 10.1097/INF.0000000000000631 -
BMC Genomics Dec 2018The epithelium is the first line of defense against pathogens. Notably the epithelial cells lining the respiratory track are crucial in sensing airborne microbes and...
BACKGROUND
The epithelium is the first line of defense against pathogens. Notably the epithelial cells lining the respiratory track are crucial in sensing airborne microbes and mounting an effective immune response via the expression of target genes such as cytokines and chemokines. Gene expression regulation following microbial recognition is partly regulated by chromatin re-organization and has been described in immune cells but data from epithelial cells is not as detailed. Here, we report genome-wide changes of the H3K27ac mark, characteristic of activated enhancers and promoters, after stimulation of nasopharyngeal epithelial cells with the bacterial endotoxin Lipopolysaccharide (LPS).
RESULTS
In this study, we have identified 626 regions where the H3K27ac mark showed reproducible increase following LPS induction in epithelial cells. This indicated that sensing of LPS led to opening of the chromatin in our system. Moreover, this phenomenon seemed to happen extensively at enhancers regions and we could observe instances of Super-enhancer formation. As expected, LPS-increased H3K27ac regions were found in the vicinity of genes relevant for LPS response and these changes correlated with up-regulation of their expression. In addition, we found the induction of H3K27ac mark to overlap with the binding of one of the NF-kB members and key regulator of the innate immune response, RELA, following LPS sensing. Indeed, inhibiting the NF-kB pathway abolished the deposition of H3K27ac at the TNF locus, a target of RELA, suggesting that these two phenomena are associated.
CONCLUSIONS
Enhancers' selection and activation following microbial or inflammatory stimuli has been described previously and shown to be mediated via the NF-kB pathway. Here, we demonstrate that this is also likely to occur in the case of LPS-sensing by nasopharyngeal epithelial cells as well. In addition to validating previous findings, we generated a valuable data set relevant to the host immune response to epithelial cell colonizing or infecting pathogens.
Topics: Cell Line, Tumor; Epithelial Cells; Gene Expression Regulation; Histones; Humans; Immunity, Innate; Lipopolysaccharides; Nasopharynx; Transcription Factor RelA; Tumor Necrosis Factor-alpha
PubMed: 30587130
DOI: 10.1186/s12864-018-5295-4 -
Fish & Shellfish Immunology Jun 2020Emerging evidence suggests that bitter and sweet Taste receptors (TRs) in the airway are important sentinels of innate immunity. TRs are G protein-coupled receptors that...
Emerging evidence suggests that bitter and sweet Taste receptors (TRs) in the airway are important sentinels of innate immunity. TRs are G protein-coupled receptors that trigger downstream signaling cascades in response to activation of specific ligands. Among them, the T1R family consists of three genes: T1R1, T1R2, and T1R3, which function as heterodimers for sweet tastants and umami tastants. While the other TRs family components T2Rs function as bitter tastants. To understand the relationship between TRs and mucosal immunity in teleost, here, we firstly identified and analyzed the molecular characteristics of three TRs (T1R1, T1R3, and T2R4) in rainbow trout (Oncorhynchus mykiss). Secondly, by quantitative real-time PCR (qPCR), we detected the mRNA expression levels of T1R1, T1R3 and T2R4 and found that the three genes could be tested in all detected tissues (pharynx, buccal cavity, tongue, nose, gill, eye, gut, fin, skin) and the expression levels of T1R3 and T2R4 were higher in buccal mucosa (BM) and pharyngeal mucosa (PM) compare to other tissues. It may suggest that T1R3 and T2R4 play important roles in BM and PM. Then, to analyses the changes of expression levels of the three genes in rainbow trout infected with pathogens, we established three infection models Flavobacterium columnare (F. cloumnare), infectious hematopoietic necrosis virus (IHNV) and Ichthyophthirius multifiliis (Ich). Subsequently, by qPCR, we detected the expression profiles of TRs in the gustatory tissues (BM, PM and skin) of rainbow trout after infection with F. cloumnare, IHNV, and Ich, respectively. We found that under three different infection models, the expression of the T1R1, T1R3 and T2R4 showed their own changes in mRNA levels. And the expression levels of the T1R1, T1R3 and T2R4 changed significantly at different time points in response to three infection models, respectively, suggesting that TRs may be associated with mucosal immunity.
Topics: Amino Acid Sequence; Animals; Ciliophora Infections; Fish Diseases; Fish Proteins; Flavobacteriaceae Infections; Flavobacterium; Gene Expression Profiling; Gene Expression Regulation; Hymenostomatida; Immunity, Innate; Immunity, Mucosal; Infectious hematopoietic necrosis virus; Oncorhynchus mykiss; Phylogeny; Receptors, G-Protein-Coupled; Rhabdoviridae Infections; Sequence Alignment
PubMed: 32244029
DOI: 10.1016/j.fsi.2020.03.055