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Neuroscience Letters Sep 2023Maternal immune activation is one of the environmental risk factors for offspring to develop psychiatric disorders. A synthetic viral mimetic immunogen,...
Maternal immune activation is one of the environmental risk factors for offspring to develop psychiatric disorders. A synthetic viral mimetic immunogen, polyinosinic-polycytidylic acid (poly(I:C)), is used to induce maternal immune activation in animal models of psychiatric disorders. In the mouse poly(I:C) model, the existence of segment filamentous bacteria (SFB) in the maternal intestine has been reported to be important for the induction of ASD-related behavioral alterations as well as atypical cortical development called cortical patches. This study aimed to elucidate the effect of a single poly(I:C) injection during embryonic day (E) 9 to E16 on offspring's behavior in the ensured absence of maternal SFB by vancomycin drinking in C57BL/6N mice. The cortical patches were not found at either injection timings with poly(I:C) or PBS vehicle, tested in male or female offspring at postnatal day 0 or 1. Prepulse inhibition was decreased in male adult offspring most strongly at poly(I:C) injection timings later than E11, whereas a modest but significant decrease was observed in female offspring with an injection during E12 to E15. The decrease in social interaction was observed in female offspring most conspicuously at injection timings later than E11, whereas a significant decrease was observed in male offspring with an injection during E12 to E15. In conclusion, this study indicated that behavioral alterations could be induced without maternal SFB. The effect on behavior was substantially different between males and females.
Topics: Humans; Mice; Adult; Animals; Female; Male; Mice, Inbred C57BL; Poly I-C; Disease Models, Animal; Bacteria; Cytoskeleton
PubMed: 37652351
DOI: 10.1016/j.neulet.2023.137467 -
Frontiers in Immunology 2023Both bacterial and viral diseases are a major threat to farmed fish. As the antiviral immune mechanisms in lumpfish ( L.) are poorly understood, lumpfish leukocytes were...
BACKGROUND
Both bacterial and viral diseases are a major threat to farmed fish. As the antiviral immune mechanisms in lumpfish ( L.) are poorly understood, lumpfish leukocytes were stimulated with poly(I:C), a synthetic analog of double stranded RNA, which mimic viral infections, and RNA sequencing was performed.
METHODS
To address this gap, we stimulated lumpfish leukocytes with poly(I:C) for 6 and 24 hours and did RNA sequencing with three parallels per timepoint. Genome guided mapping was performed to define differentially expressed genes (DEGs).
RESULTS
Immune genes were identified, and transcriptome-wide analyses of early immune responses showed that 376 and 2372 transcripts were significantly differentially expressed 6 and 24 hours post exposure (hpe) to poly(I:C), respectively. The most enriched GO terms when time had been accounted for, were immune system processes (GO:0002376) and immune response (GO:0006955). Analysis of DEGs showed that among the most highly upregulated genes were TLRs and genes belonging to the RIG-I signaling pathway, including LGP2, STING and MX, as well as IRF3 and IL12A. RIG-I was not identified, but analyses showed that genes encoding proteins involved in pathogen recognition, cell signaling, and cytokines of the TLR and RIG-I signaling pathway are mostly conserved in lumpfish when compared to mammals and other teleost species.
CONCLUSIONS
Our analyses unravel the innate immune pathways playing a major role in antiviral defense in lumpfish. The information gathered can be used in comparative studies and lay the groundwork for future functional analyses of immune and pathogenicity mechanisms. Such knowledge is also necessary for the development of immunoprophylactic measures for lumpfish, which is extensively cultivated for use as cleaner fish in the aquaculture for removal of sea lice from Atlantic salmon ( L.).
Topics: Animals; Transcriptome; Poly I-C; Perciformes; Antiviral Agents; Immunity; Mammals
PubMed: 37388730
DOI: 10.3389/fimmu.2023.1198211 -
Ecotoxicology and Environmental Safety Dec 2022Pathogenic microorganisms that are ubiquitous in the environment threaten human health and food safety. Polyinosinic:polycytidylic acid (Poly (I:C)) is a macromolecule...
Pathogenic microorganisms that are ubiquitous in the environment threaten human health and food safety. Polyinosinic:polycytidylic acid (Poly (I:C)) is a macromolecule with a double-stranded RNA structure, which is often used to simulate viruses. Our previous study found that Poly (I:C) maternal stimulation could affect the reproduction of laying hens and their offspring, but the underlying mechanism needed to be explored. In the present study, splenic transcriptomes were sequenced and analyzed from two groups (Poly (I:C) treatment as the challenged group and saline treatment as the control) and in three generations (maternal stimulated F0 hens, unchallenged F1 and F2 generations). The results showed that Poly (I:C) maternal stimulation affected gene expression patterns in laying hens and their offspring. A total of 27 differentially expressed genes (DEGs) with the same regulating trend were discovered in the F0 and F1 generations, indicating an influence of the intergenerational transmission effect. Functional enrichment analysis of Gene Ontology (GO) showed that lymphocyte differentiation, positive regulation of leukocyte differentiation, positive regulation of MAPK cascade, and T cell differentiation were the common biological processes between F0 and F1 generations, revealing Poly (I:C) could affect the immunity of the treated F0 hens and the unchallenged subsequent generations. Further study showed that pathways associated with growth, development, biosynthesis, and metabolism of F2 chicks were also affected by Poly (I:C) maternal stimulation. Correlation analysis between DEGs and reproductive traits revealed that PHLDA2 (pleckstrin homology-like domain family A member 2) and PODN (podocan) with inheritable effect were highly correlated with egg-laying rate and egg weight in F1 hens, suggesting their potential long-term role in regulating reproductive traits. ARHGAP40, FGB, HRH4, PHLDA2, PODN, NTSR1, and NMU were supposed to play important roles in regulating chickens' immunity and reproductive traits. This study reveals the far-reaching effect on transcriptome induced by Poly (I:C), reflecting the influence of the mother's living environment on the offspring. It is an important reference for future research into the multi-generational transmission of maternal stimulation and harmful environmental factors.
Topics: Humans; Animals; Female; Chickens; Poly I-C; Reproduction; Oviposition; Transcriptome
PubMed: 36288637
DOI: 10.1016/j.ecoenv.2022.114216 -
Life Sciences Jun 2016Keratinocytes are the predominant cells in the epidermis, exerting their primary role of physical barrier through sophisticated differentiation process. In addition,...
AIMS
Keratinocytes are the predominant cells in the epidermis, exerting their primary role of physical barrier through sophisticated differentiation process. In addition, keratinocytes contribute to the activation of innate immunity, providing the surveillant role against external pathogens. It has been known that chronic skin inflammatory disease such as psoriasis can be provoked by viral pathogens including double-stranded RNA. In this study, we demonstrated that rosmarinic acid (RA) has an inhibitory potential on inflammatory reaction induced by double-stranded RNA mimic poly(I:C) in epidermal keratinocytes.
MAIN METHODS
We cultured human epidermal keratinocytes and induced inflammatory reaction by poly(I:C) treatment. The effect of RA on inflammatory reaction of keratinocytes was determined by RT-PCR and Western blot.
KEY FINDINGS
RA significantly inhibited poly(I:C)-induced expression of inflammatory cytokines including IL-1β, IL-6, IL-8, CCL20, and TNF-α, and downregulated NF-κB signaling pathway in human keratinocytes. In addition, RA significantly inhibited poly(I:C)-induced inflammasome activation, in terms of secretion of active form of IL-1β and caspase-1. Furthermore, RA markedly inhibited poly(I:C)-induced NLRP3 and ASC expression.
SIGNIFICANCE
These results indicate that RA can inhibit poly(I:C)-induced inflammatory reaction of keratinocytes, and suggest that it may be a potential candidate for the treatment of psoriasis.
Topics: Cells, Cultured; Cinnamates; Cytokines; Depsides; Humans; Inflammation; Keratinocytes; Poly I-C; Rosmarinic Acid
PubMed: 27210890
DOI: 10.1016/j.lfs.2016.05.023 -
The Journal of Investigative Dermatology Oct 2022
Topics: Keratinocytes; Poly I-C; RNA, Double-Stranded; Transcriptome
PubMed: 35395221
DOI: 10.1016/j.jid.2022.03.015 -
International Journal of Molecular... Aug 2022Poly (I:C) can work as an immunostimulant and a viral vaccine; however, its functional mechanism in aquatic animals needs to be further investigated. In this study,...
Poly (I:C) can work as an immunostimulant and a viral vaccine; however, its functional mechanism in aquatic animals needs to be further investigated. In this study, comparative transcriptomic analyses were performed to investigate the effects of poly (I:C) on at 12 h and 48 h postinjection. A total of 194 and 294 differentially expressed genes were obtained in the liver and spleen, respectively. At 12 h, poly (I:C) injection could significantly influence the function of the metabolism-related pathways and immune-related pathways in the liver through the upregulation of the genes , , , , and , and the downregulation of the genes , , , and . At 48 h, poly (I:C) could enhance the liver energy metabolism by upregulating the genes and , while it also induced some injury in the cells with the downregulation of the genes and . In the spleen, poly (I:C) could regulate the fish immunity and inflammatory response by upregulating the genes , , , and , and by downregulating the genes , , , , , and at 12 h, and at 48 h, the poly (I:C) had a similar influence as that in the liver. Intersection analyses demonstrated that and were the main functional genes that contributed to the health of the liver. Ten and four genes participated in maintaining the health of the two tissues after 12 h and 48 h, respectively. In summary, our results provided a new insight into ploy (I:C) application in , and it also helped us to better understand the fish response mechanism to the viral vaccine injection.
Topics: Animals; Liver; Perciformes; Poly I-C; Spleen; Transcriptome; Viral Vaccines; Vitamin D3 24-Hydroxylase
PubMed: 36077207
DOI: 10.3390/ijms23179801 -
Physiology & Behavior Apr 2021Central fatigue is a condition associated with impairment of the central nervous system often leading to the manifestation of a range of debilitating symptoms. Fatigue...
Central fatigue is a condition associated with impairment of the central nervous system often leading to the manifestation of a range of debilitating symptoms. Fatigue can be a consequence of systemic inflammation following an infection. Administration of lipopolysaccharide (LPS) and polyriboinosinic:polyribocytidlic (poly I:C) to animals can induce systemic inflammation by mimicking a bacterial or viral infection respectively and therefore have been used as models of fatigue. We evaluated a range of phenotypic behaviors exhibited in the LPS and poly I:C animal models to assess whether they adequately replicate fatigue symptomology in humans. In addition to standard observation- and intervention-based behavioral assessments, we used powerful in-cage monitoring technology to quantify rodent behavior without external interference. LPS and poly I:C treated Sprague Dawley rats displayed 'sickness behaviors' of elevated temperature, weight loss and reduced activity in the open field test and with in-cage monitoring within 24 h post-treatment, but only LPS-treated rats displayed these behaviors beyond these acute timepoints. Once sickness behavior diminished, LPS-treated rats exhibited an increase in reward-seeking and motivation behaviors. Overall, these results suggest that the LPS animal model produces an extensive and sustained fatigue-like phenotype, whereas the poly I:C model only produced acute effects. Our results suggest that the LPS animal model is a more suitable candidate for further studies on central fatigue-like behavior.
Topics: Animals; Behavior, Animal; Disease Models, Animal; Fatigue; Illness Behavior; Lipopolysaccharides; Poly I-C; Rats; Rats, Sprague-Dawley
PubMed: 33529685
DOI: 10.1016/j.physbeh.2021.113347 -
Frontiers in Immunology 2022Recent studies have shown that corn-derived cationic α-D-glucan nanoparticles, known as Nano-11, significantly increase the immune response when used as a vaccine...
Recent studies have shown that corn-derived cationic α-D-glucan nanoparticles, known as Nano-11, significantly increase the immune response when used as a vaccine adjuvant in mice and in pigs. Furthermore, the nanoparticles can be formulated with other immunostimulators such as poly(I:C), which further enhances the immune response. The current experiments were aimed at elucidating the mechanism of action of Nano-11 alone and in combination with poly(I:C). The effect of these adjuvants on porcine monocyte-derived dendritic cells (Mo-DCs) was determined by RNA-sequencing, supplemented with flow cytometry, cytokine analysis, and Western blots. Adsorption of poly(I:C) to Nano-11 reduced its cytotoxicity for Mo-DCs. Exposure of Mo-DCs to Nano-11 and Nano-11/poly(I:C) induced differential expression of 979 and 2016 genes, respectively. Gene Ontology enrichment and KEGG pathway analysis revealed many changes in gene expression related to inflammation, innate immunity, immune response to infections, and metabolism. Nano-11 and Nano-11/poly(I:C) induced maturation of the Mo-DCs as indicated by increased expression of costimulatory molecules and MHC II. Increased expression of genes downstream of p38 MAPK activation revealed a role for this signaling pathway in the activation of Mo-DCs by the adjuvants. This was confirmed by Western blot and inhibition of TNF-secretion upon incubation with the p38 inhibitor SB203580. These experiments provide insights into the mechanism of action of the novel adjuvants Nano-11 and Nano-11/poly(I:C).
Topics: Adjuvants, Immunologic; Adjuvants, Pharmaceutic; Animals; Cytokines; Dendritic Cells; Glucans; Mice; Nanoparticles; Poly I-C; RNA; Swine; p38 Mitogen-Activated Protein Kinases
PubMed: 36131928
DOI: 10.3389/fimmu.2022.990900 -
Journal of Interferon Research 1981A soluble complex of poly I:C and poly-L-lysine (poly I:C/poly-L-lysine) has been prepared that induces high titers of circulating interferon in monkeys. By limiting the...
A soluble complex of poly I:C and poly-L-lysine (poly I:C/poly-L-lysine) has been prepared that induces high titers of circulating interferon in monkeys. By limiting the molar ratio of lysine to nucleotide to 0.5, a complex was formed that was soluble up to 2.0 mg poly I:C/ml of phosphate-buffered saline. Complexes of poly I:C with poly-L-lysine of various molecular weights, and in a constant ratio (0.5) of lysine to nucleotide, were evaluated for capacity to induce serum interferon in grivet monkeys. Substantial enhancement (10- to 100-fold) of the capacity of poly I:C to induce interferon in grivet monkeys was observed using poly I:C complexed with poly-L-lysines of molecular weight 10(4) daltons or greater. The poly I:C/poly-L-lysine as an effective inducer of interferon in grivet monkeys, rhesus monkeys, chimpanzees and marmosets. A high interferon titer (greater than 100 units/ml blood) was maintained in grivet monkeys by repeated daily administration of the complex. No long-term hyporesponsiveness was noted following repeat inductions over a period of months. The serum interferon produced in monkeys in response to poly I:C/poly-L-lysine resembled human leukocyte interferon in its biological characteristics.
Topics: Animals; Chlorocebus aethiops; Drug Combinations; Interferon Inducers; Molecular Weight; Peptides; Poly I-C; Polylysine; Solubility
PubMed: 7202031
DOI: 10.1089/jir.1981.1.539 -
Pharmaceutical Research Apr 2011To develop a novel polyethylenimine (PEI)-based polymeric carrier for tumor-targeted delivery of cytotoxic double-stranded RNA polyinosinic:polycytidylic acid,...
PURPOSE
To develop a novel polyethylenimine (PEI)-based polymeric carrier for tumor-targeted delivery of cytotoxic double-stranded RNA polyinosinic:polycytidylic acid, poly(I:C). The novel carrier should be chemically less complex but at least as effective as a previously developed tetra-conjugate containing epidermal growth factor (EGF) as targeting ligand, polyethylene glycol (PEG) as shielding spacer, 25 kDa branched PEI as RNA binding and endosomal buffering agent, and melittin as endosomal escape agent.
METHODS
Novel conjugates were designed employing a simplified synthetic strategy based on 22 kDa linear polyethylenimine (LPEI), PEG spacers, and recombinant EGF. The efficacy of various conjugates (different PEG spacers, with and without targeting EGF) in poly(I:C)-mediated cell killing was evaluated in vitro using two human U87MG glioma cell lines. The most effective polyplex was tested for in vivo activity in A431 tumor xenografts.
RESULTS
Targeting conjugate LPEI-PEG2 kDa-EGF was found as most effective in poly(I:C)-triggered killing of tumor cells in vitro. The efficacy correlated with glioma cell EGFR levels. Repeated intravenous administration of poly(I:C) polypexes strongly retarded growth of A431 human tumor xenograft in mice.
CONCLUSIONS
The optimized LPEI-PEG2 kDa-EGF conjugate displays reduced chemical complexity and efficient poly(I:C)-mediated killing of EGFR overexpressing tumors in vitro and in vivo.
Topics: Animals; Antineoplastic Agents; Cell Culture Techniques; Cell Line, Tumor; Cell Survival; Drug Carriers; Epidermal Growth Factor; ErbB Receptors; Glioblastoma; Humans; Mice; Mice, Nude; Poly I-C; Polyethylene Glycols; Polyethyleneimine; Xenograft Model Antitumor Assays
PubMed: 20694527
DOI: 10.1007/s11095-010-0225-4