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Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) Omicron harbors more than 30 mutations of the spike protein and exhibits substantial immune evasion. Although previous study indicated that BNT162b2 messenger RNA vaccine induces potent cross‐clade pan‐sarbecovirus neutralizing antibodies in survivors of the infection by SARS‐CoV‐1, the neutralization activity and Fc‐mediated effector functions of these cross‐reactive antibodies elicited in SARS‐CoV‐1 survivors to Omicron subvariants still remain largely unknown. In this study, the neutralization activity and Fc‐mediated effector functions of antibodies boosted by a third dose vaccination were characterized in SARS‐CoV‐1 convalescents and healthy individuals. Potent cross‐clade broadly neutralizing antibodies were observed in SARS‐CoV‐1 survivors who received a three‐dose vaccination regimen consisting of two priming doses of CoronaVac followed by one booster dose of the protein subunit vaccine ZF2001. However, the induced antibodies exhibited both reduced neutralization and impaired Fc effector functions targeting multiple Omicron subvariants. Importantly, the data also support the notion that immune imprints resulted from SARS‐CoV‐1 infection may exacerbate the impairment of neutralization activity and Fc‐mediated effector functions to Omicron subvariants and provided invaluable information to vaccination strategy in future. [ABSTRACT FROM AUTHOR]

Stimulator of interferon genes (STING) is an essential signaling protein that is located on the endoplasmic reticulum (ER) and triggers the production of type I interferons (IFN) and proinflammatory cytokines in response to pathogenic DNA. Aberrant activation of STING is linked to autoimmune diseases. The mechanisms underlying homeostatic regulation of STING are unclear. Here, we report that UNC13D, which is associated with familial hemophagocytic lymphohistiocytosis (FHL3), is a negative regulator of the STING‐mediated innate immune response. UNC13D colocalizes with STING on the ER and inhibits STING oligomerization. Cellular knockdown and knockout of UNC13D promote the production of interferon‐β (IFN‐β) induced by DNA viruses, but not RNA viruses. Moreover, UNC13D deficiency also increases the basal level of proinflammatory cytokines. These effects are diminished by an inhibitor of STING signaling. Furthermore, the domains involved in the UNC13D/STING interaction on both proteins are mapped. Our findings provide insight into the regulatory mechanism of STING, the previously unknown cellular function of UNC13D and the potential pathogenesis of FHL3. Synopsis: STING signaling is essential for the production of type I interferons and proinflammatory cytokines in response to pathogenic DNA. UNC13D, which is associated with familial hemophagocytic lymphohistiocytosis, is a negative regulator of STING‐mediated innate immune responses. UNC13D colocalizes and directly interacts with STING on the endoplasmic reticulum and inhibits STING oligomerization.Depletion of UNC13D promote the production of interferon‐β induced by DNA viruses, but not RNA viruses.UNC13D deficiency increases the basal level of proinflammatory cytokines. [ABSTRACT FROM AUTHOR]

Background: Phosphodiesterase-4 (PDE4) has been identified as a valid therapeutic target in several inflammatory diseases. In this study, we assessed PDE4 in gingival tissue from patients with chronic periodontitis and evaluated the therapeutic effects of the PDE4 inhibitor, roflumilast, in an experimental rat model of periodontitis.Methods: Gingival tissue specimens from 20 healthy subjects and 20 patients with periodontitis were collected, and the mRNA expression levels of PDE4, interleukin (IL)-1β, and IL-6 were assessed. Ninety rats were divided randomly into three groups (30 per group): non-ligature group, ligature-induced periodontitis group (L), and ligature-induced periodontitis with roflumilast administered group (5 mg/kg/d) (L+R). Rats were euthanized on days 3, 8, and 14. Alveolar bone resorption was analyzed using microcomputed tomography. Inflammation and osteoclast number were analyzed histologically. Finally, the mRNA expression levels of PDE-4, IL-1β, IL-6, tumor necrosis factor (TNF)-α, and nuclear factor kappa B (NF-κB) were assessed in the rat gingival tissue.Results: The mRNA expression levels of PDE4, IL-1β, and IL-6 in the gingiva were significantly higher in patients with periodontitis compared with healthy individuals (P <0.05). Alveolar bone loss, degree of inflammation, number of TRAP-positive multinucleated osteoclasts, and mRNA expression levels of IL-1β, IL-6, TNF-α, NF-κB, and PDE4 in the L+R group were significantly lower than those in the L group (P <0.05).Conclusions: PDE4 expression was increased in the gingiva of patients with periodontitis. Roflumilast may decrease alveolar bone loss and the expression of inflammatory cytokines in rats with ligature-induced periodontitis. [ABSTRACT FROM AUTHOR]

The homeobox gene, LIM‐homeobox 8 (Lhx8), has previously been identified as an essential transcription factor for dental mesenchymal development. However, how Lhx8 itself is regulated and regulates odontogenesis remains poorly understood. In this study, we employed an RNAscope assay to detect the co‐expression pattern of Lhx8 and Suv39h1 in the dental mesenchyme, which coincided with the dynamic expression profiles of the early epithelium signal of Fibroblast Growth Factor 8 (FGF8) and the later mesenchymal signal Bone Morphogenetic Protein 2 (BMP2). Moreover, FGF8 activated Lhx8, whereas BMP2 repressed Lhx8 expression at the transcriptional level. The high expression of Lhx8 in the early dental mesenchyme maintained the cell fate in an undifferentiated status by interacting with Suv39h1, a histone‐lysine N‐methyltransferase constitutively expressed in the dental mesenchyme. Further in the ex vivo organ culture model, the knockdown of Suv39h1 significantly blocked the function of Lhx8 and FGF8. Mechanistically, Lhx8/Suv39h1 recognized the odontoblast differentiation‐related genes and repressed gene expression via methylating H3K9 on their promoters. Taken together, our data here suggest that Lhx8/Suv39h1 complex is inversely regulated by epithelium‐mesenchymal signals, balancing the differentiation and proliferation of dental mesenchyme via H3K9 methylation. [ABSTRACT FROM AUTHOR]

Background and Objective: Peri‐implantitis is a biofilm‐mediated infectious disease that results in progressive loss of implant‐supporting bone. As compared to its analogue periodontitis, peri‐implantitis is generally known to be more aggressive, with comparatively rapid progression and less predictable treatment outcomes, especially when advanced. An understanding of molecular mechanisms underpinning the similarities and differences between peri‐implantitis and periodontitis is essential to develop novel management strategies. This study aimed to compare long non‐coding RNAs (lncRNAs) and messenger RNA (mRNA) expression profiles between peri‐implantitis and periodontitis. Methods: Inflamed soft tissue from peri‐implantitis and periodontitis lesions, and healthy gingival tissue controls were analyzed by microarray. Cluster graphs, gene ontology (GO) analysis, and pathway analysis were performed. Quantitative real‐time PCR was employed to verify microarray results. The expression levels of RANKL and OPG in the three tissue types were also evaluated, using qRT‐PCR. Coding non‐coding (CNC) network analyses were performed. Results: Microarray analyses revealed 1079 lncRNAs and 1003 mRNAs as differentially expressed in peri‐implantitis when compared to periodontitis. The cyclooxygenase‐2 pathway was the most up‐regulated biological process in peri‐implantitis as compared to periodontitis, whereas hemidesmosome assembly was the most down‐regulated pathway. Osteoclast differentiation was relatively up‐regulated, and RANKL/OPG ratio was higher in peri‐implantitis than in periodontitis. Conclusions: The study demonstrated that peri‐implantitis and periodontitis exhibit significantly different lncRNA and mRNA expression profiles, suggesting that osteoclast differentiation‐related pathways are comparatively more active in peri‐implantitis. These data highlight potential molecular targets for periodontitis and peri‐implantitis therapy development. [ABSTRACT FROM AUTHOR]

Sympathetic signaling is involved in bone homeostasis; however, the cellular and molecular mechanisms remain unknown. In this study, we found that the psychological stress mediator adrenaline inhibited osteogenic differentiation of human bone marrow-derived stem cells (hMSC) by reducing microRNA-21 (miR-21) expression. Briefly, adrenaline significantly inhibited the osteogenic differentiation of hMSCs, as observed with both Alizarin red staining and maker gene expression (RUNX2, OSX, OCN, and OPN). During this process, miR-21 was suppressed by adrenaline via inhibition of histone acetylation, as verified by H3K9Ac chromatin immunoprecipitation (ChIP) assay. MiR-21 was confirmed to promote hMSC osteogenic differentiation, and overexpression of miR-21 reversed the impeditive effect of adrenaline on hMSC osteogenic differentiation. Our results demonstrate that down-regulation of miR-21 is responsible for the adrenaline-mediated inhibition of hMSC osteogenic differentiation. These findings indicate a regulation of bone metabolism by psychological stress and also provide a molecular basis for psychological stress-associated bone diseases. [ABSTRACT FROM AUTHOR]

Toll-like receptor 3 (TLR3) plays an important role in antiviral responses through recognizing viral double-stranded RNA produced during viral infection and mediating induction of type I IFN. TRIF is a Toll/IL-1 receptor (TIR) domain-containing adaptor protein that is associated with TLR3 and critically involved in TLR3-mediated signaling. In yeast two-hybrid screens, we identified TNF receptor-associated factor (TRAF)1 as a TRIF-interacting protein. The TRAF-C domain of TRAF1 and the TIR domain of TRIF were responsible for their interaction. Overexpression of TRAF1 inhibited TRIF- and TLR3-mediated activation of NF-κB, IFN-stimulated response element and the IFN-β promoter. Overexpression of TRIF caused caspase-dependent cleavage of TRAF1. The cleaved N-terminal but not C-terminal fragment of TRAF1 was responsible for inhibiting TRIF signaling. Mutation of the caspase cleavage site of TRAF1 or addition of the caspase inhibitor crmA inhibited TRAF1 cleavage and abolished the ability of TRAF1 to inhibit TRIF signaling, suggesting that TRIF-induced cleavage of TRAF1 is required for its inhibition of TRIF signaling. Our findings provide a novel mechanism for negative regulation of TRIF-mediated signaling. [ABSTRACT FROM AUTHOR]