Skin barrier dysfunction caused by endogenous or exogenous factors can lead to various disorders such as xerosis cutis, ichthyoses, and atopic dermatitis. Filaggrin is a pivotal structural protein of the stratum corneum (SC) and provides natural moisturizing factors that play a role in skin barrier functions. Filaggrin aggregates keratin filaments, resulting in the formation of a keratin network, which binds cornified envelopes and collapse keratinocytes to flattened corneocytes. This complex network contributes to the physical strength of the skin. Filaggrin is degraded by caspase-14, calpain 1, and bleomycin hydrolases into amino acids and amino acid metabolites such as trans-urocanic acid and pyrrolidone carboxylic acid, which are pivotal natural moisturizing factors in the SC. Accordingly, filaggrin is important for the pathophysiology of skin barrier disorders, and its deficiency or dysfunction leads to a variety of skin disorders. Here, the roles and biology of filaggrin, related skin diseases, and a therapeutic strategy targeting filaggrin are reviewed. In addition, several drug candidates of different mode of actions targeting filaggrin, along with their clinical efficacy, are discussed.

Skin barrier dysfunction and filaggrin

Context-dependent functions of pattern recognition receptors in cancer

The recently identified novel cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS) activates the downstream adaptor protein stimulator of interferon genes (STING) by catalysing the synthesis of cyclic GMP-AMP. This in turn initiates an innate immune response through the release of various cytokines, including type I interferon. Foreign DNA (microbial infection) or endogenous DNA (nuclear or mitochondrial leakage) can serve as cGAS ligands and lead to the activation of cGAS-STING signalling. Therefore, the cGAS-STING pathway plays essential roles in infectious diseases, sterile inflammation, tumours, and autoimmune diseases. In addition, cGAS-STING signalling affects the progression of liver inflammation through other mechanisms, such as autophagy and metabolism. In this review, we summarise recent advances in our understanding of the role of cGAS-STING signalling in the innate immune modulation of different liver diseases. Furthermore, we discuss the therapeutic potential of targeting the cGAS-STING pathway in the treatment of liver diseases.

The role of cGAS-STING signalling in liver diseases

Liver diseases represent a major global health burden accounting for approximately 2 million deaths per year worldwide. The liver functions as a primary immune organ that is largely enriched with various innate immune cells, including macrophages, dendritic cells, neutrophils, NK cells, and NKT cells. Activation of these cells orchestrates the innate immune response and initiates liver inflammation in response to the danger signal from pathogens or injured cells and tissues. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is a crucial signaling cascade of the innate immune system activated by cytosol DNA. Recognizing DNA as an immune-stimulatory molecule is an evolutionarily preserved mechanism in initiating rapid innate immune responses against microbial pathogens. The cGAS is a cytosolic DNA sensor eliciting robust immunity via the production of cyclic GMP-AMPs that bind and activate STING. Although the cGAS-STING pathway has been previously considered to have essential roles in innate immunity and host defense, recent advances have extended the role of the cGAS-STING pathway to liver diseases. Emerging evidence indicates that overactivation of cGAS-STING may contribute to the development of liver disorders, implying that the cGAS-STING pathway is a promising therapeutic target. Here, we review and discuss the role of the cGAS-STING DNA-sensing signaling pathway in a variety of liver diseases, including viral hepatitis, nonalcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), primary hepatocellular cancer (HCC), and hepatic ischemia-reperfusion injury (IRI), with highlights on currently available therapeutic options.

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The cGAS-STING Pathway: Novel Perspectives in Liver Diseases.

Background: Transmembrane proteins (TMEM) constitute a large family of proteins spanning the entirety of the lipid bilayer. However, there is still a lack of knowledge about their function or mechanism of action. In this study, we analyzed the expression of selected TMEM genes in patients with head and neck squamous cell carcinoma (HNSCC) to learn their role in tumor formation and metastasis. Materials and Methods: Using TCGA data, we analyzed the expression levels of different TMEMs in both normal and tumor samples and compared those two groups depending on clinical-pathological parameters. We selected four TMEMs whose expression was highly correlated with patient survival status and subjected them to further analysis. The pathway analysis using REACTOME and the gene set enrichment analysis (GSEA) were performed to evaluate the association of those TMEMs with genes involved in hallmarks of cancer as well as in oncogenic and immune-related pathways. In addition, the fractions of different immune cell subpopulations depending on TMEM expression were estimated in analyzed patients. The results for selected TMEMs were validated using GEO data. All analyses were performed using the R package, Statistica, and Graphpad Prism. Results: We demonstrated that 73% of the analyzed TMEMs were dysregulated in HNSCC and depended on tumor localization, smoking, alcohol consumption, or HPV infection. The expression levels of ANO1, TMEM156, TMEM173, and TMEM213 correlated with patient survival. The four TMEMs were also upregulated in HPV-positive patients. The elevated expression of those TMEMs correlated with the enrichment of genes involved in cancer-related processes, including immune response. Specifically, overexpression of TMEM156 and TMEM173 was associated with immune cell mobilization and better survival rates, while the elevated ANO1 expression was linked with metastasis formation and worse survival. Conclusions: In this work, we performed a panel of in silico analyses to discover the role of TMEMs in head and neck squamous cell carcinoma. We found that ANO1, TMEM156, TMEM173, and TMEM213 correlated with clinical status and immune responses in HNSCC patients, pointing them as biomarkers for a better prognosis and treatment. This is the first study describing such the role of TMEMs in HNSCC. Future clinical trials should confirm the potential of those genes as targets for personalized therapy of HNSCC.

The Landscape of Transmembrane Protein Family Members in Head and Neck Cancers: Their Biological Role and Diagnostic Utility

The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway induces innate immunity by activating the production of inflammatory cytokines and type I interferons. Recently, studies revealed that self-DNA from by-products of chromosome instability and tumors could activate the cGAS-STING pathway, and subsequently promote or inhibit tumor development. However, the prognostic value and correlations with immune infiltrates of the cGAS-STING pathway in hepatocellular carcinoma (HCC) have not been clarified. In the present study, we used the Molecular Signatures Database, Oncomine, UALCAN, Human Protein Atlas, Kaplan-Meier plotter, LinkedOmics, and Tumor Immune Estimation Resource databases. Overexpression of XRCC5, IRF3, TRIM21, STAT6, DDX41, TBK1, XRCC6, TREX1, PRKDC, and TMEM173 was markedly correlated with clinical stages and pathological grades in HCC. Moreover, higher mRNA expression of XRCC5, XRCC6, and PRKDC was significantly related with shorter overall survival. However, higher mRNA expression of IFI16, STAT6, NLRC3, and TMEM173 was associated with favorable overall survival. Our results suggested that the kinase targets of the cGAS-STING pathway included the SRC family of tyrosine kinases (LCK and LYN), phosphoinositide 3-kinase-related protein kinase (PIKK) family kinases (ATM and ATR), and mitogen-activated protein kinase 1 (MAPK1). Furthermore, we identified significant correlations among the expression of cGAS-STING pathway and infiltration of B cells, CD4+T cells, CD8+ T cells, macrophages, neutrophils, and dendritic cells in HCC. The expression of the cGAS-STING pathway also exhibited strong relationships with diverse immune marker sets in HCC. These findings suggest that cGAS-STING pathway members may be used as prognostic biomarkers and immunotherapeutic targets HCC patients.

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Identification of prognostic biomarkers and correlations with immune infiltrates among cGAS-STING in hepatocellular carcinoma.

JTC-801 alleviates mechanical allodynia in paclitaxel-induced neuropathic pain through the PI3K/Akt pathway

OBJECTIVE To investigate the effect of escin in relieving chemotherapy-induced peripheral neuropathic pain in rats and explore and the underlying mechanism. METHODS Eighteen SD rats were randomly divided into 3 groups (n=6), including an escin preconditioning group (treated with 4 mg/kg escin on days 1-7 and then with 2 mg/kg taxol on days 8, 10, 12, and 14), an escin postconditioning group (treated with 2 mg/kg taxol on days 1, 3, 5, and 7 and then with 4 mg/mg escin on days 8-14) and control group (treated with 2 mg/kg taxol on days 1, 3, 5, and 7 and then with saline on days 8-14). Mechanical allodynia and thermal hyperalgesia of the mice were tested on days 4, 7, 10 and 14, and the expression levels of LC3II and p62 in the spinal cord of the rats were detected using Western blotting. RESULTS The rats in both the escin preconditioning group and escin postconditioning group showed obviously increased thresholds of mechanical allodynia and thermal hyperalgesia as compared with those in the control group (P < 0.01). Western blotting showed that the expression level of LC3II was significantly increased while p62 expression was lowered in escin preconditioning group as compared with those in the control group (P < 0.05). The escin postconditioning group also showed significantly higher LC3II expression and lower p62 expression levels than the control group (P < 0.05). CONCLUSIONS Escin can alleviate chemotherapy-induced peripheral neuropathic pain in rats possibly by upregulating the expressions of autophagy-related proteins in the spinal cord.

[Escin alleviates chemotherapy-induced peripheral neuropathic pain by inducing autophagy in the spinal cord of rats].

Background Neuropathic pain is a debilitating disease caused by damage or diseases of the somatosensory nervous system. Previous research has indicated potential associations between neuropathic pain and aging. However, the mechanisms by which they are interconnected remain unclear. In this study, we aim to identify the common differentially expressed genes (co-DEGs) between neuropathic pain and aging through integrated bioinformatics methods and further explore the underlying molecular mechanisms. Methods The microarray datasets GSE24982, GSE63442, and GSE63651 were downloaded from Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) and co-DEGs were first identified. Functional enrichment analyses, protein-protein Interaction (PPI) network, module construction and hub genes identification were performed. Immune infiltration analysis was conducted. Targeted transcription factors (TFs), microRNAs (miRNAs) and potential effective drug compounds for hub genes were also predicted. Results A total of 563 and 1,250 DEGs of neuropathic pain and aging were screened, respectively. 16 genes were further identified as co-DEGs. The functional analysis emphasizes the vital roles of the humoral immune response and complement and coagulation cascades in these two diseases. Cxcl14, Fblim1, RT1-Da, Serping1, Cfd, and Fcgr2b were identified as hub genes. Activated B cell, mast cell, activated dendritic cell, CD56 bright natural killer cell, effector memory CD8 + T cell, and type 2 T helper cell were significantly up-regulated in the pain and aging condition. Importantly, hub genes were found to correlate with the activated B cell, activated dendritic cell, Gamma delta T cell, central memory CD4 + T cell and mast cell in pain and aging diseases. Finally, Spic, miR-883-5p, and miR-363-5p et al. were predicted as the potential vital regulators for hub genes. Aldesleukin, Valziflocept, MGD-010, Cinryze, and Rhucin were the potential effective drugs in neuropathic pain and aging. Conclusion This study identified co-DEGs, revealed molecular mechanisms, demonstrated the immune microenvironment, and predicted the possible TFs, miRNAs regulation networks and new drug targets for neuropathic pain and aging, providing novel insights into further research.

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Identification of the common differentially expressed genes and pathogenesis between neuropathic pain and aging

Background: N6-Methyladenosine (m6A) RNA methylation of eukaryotic mRNA is involved in the progression
 of various tumors. We aimed to investigate m6A-related genes and m6A regulators in
 hepatocellular carcinoma (HCC) and their association with prognosis in HCC.
 Methods: We downloaded liver cancer sample data from The Cancer Genome Atlas (TCGA) and the
 International Cancer Genome Consortium database. A total of 21 m6A regulators and
 1258 m6A-related genes were then analyzed by consensus clustering, Spearman’s correlation,
 GO, KEGG, LASSO Cox regression, and univariate Cox regression analyses. Finally, we
 constructed a risk prognostic model.
 Results: We obtained 192 candidate m6A-related genes and 3 m6A regulators, including YTHDF1,
 YTHDF2, and YTHDC1. The expression of these genes and regulators differed significantly
 in different stages of HCC. Based on Cox regression analysis, 19 of 98 m6A-related
 prognostic genes were obtained to construct a risk score model. The 1- and 3-year
 area under the curves (AUCs) among HCC patients were greater than 0.7. Finally, based
 on analysis of mutation differences between high- and low-risk score groups, we determined
 that TP53 had the highest mutation frequency in the high-risk HCC patient group, whereas titin
 (
 TTN) had the highest mutation frequency in the low-risk HCC patient group.
 Conclusion: This study comprehensively analyzed m6A regulators and m6A-related genes through
 an integrated bioinformatic analysis, including expression, clustering, protein–protein
 interaction, and prognosis, thus providing novel insights into the roles of m6A regulators
 and m6A-related genes in HCC.

Fang Yan

Papers

Identification of prognostic biomarkers and correlations with immune infiltrates among cGAS-STING in hepatocellular carcinoma.

JTC-801 alleviates mechanical allodynia in paclitaxel-induced neuropathic pain through the PI3K/Akt pathway

[Escin alleviates chemotherapy-induced peripheral neuropathic pain by inducing autophagy in the spinal cord of rats].

Identification of the common differentially expressed genes and pathogenesis between neuropathic pain and aging

Integration Analysis of m6A Regulators and m6A-Related Genes in Hepatocellular Carcinoma