HCV poly U/UC sequence-induced inflammation leads to metabolic disorders in vulvar lichen sclerosis.
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ABSTRACT:
SUBMITTER: Cong Q
PROVIDER: S-EPMC8321666 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:While VLS is a serious skin disease affecting women in an annoying, embarrassing, and prolonged way worldwide, its pathogenesis and molecular characteristics are still unexploreed. Previous studies have suggested the correlation between inflammation or microRNA and VLS, but the lack of comprehensive understanding on its mechanism prevents the development of precision medicine for it. For a long time, VLS has been speculated as an autoimmune disease (Tran, Tan et al., 2019). This hypothesis was derived from several clinical observations: (1) VLS is frequently observed in women with an autoimmune diseases called Turner Syndrome (Chakhtoura, Vigoureux et al., 2014) ; (2) Many VLS patients also develop various autoimmune diseases (Kreuter, Kryvosheyeva et al., 2013, Song, Xiaoli et al., 2018) ; (3) VLS patients may also have higher frequency of certain HLA antigens, though few immunological consequence has been studied (Sideri, Rognoni et al., 1988). Microarray assay found upregulation of Th1, microRNA-155 and relative transcripts using VLS and healthy donors biopsies (Ren, Zhao et al., 2018, Terlou, Santegoets et al., 2012). However, the person-to-person genotype variation can hardly eliminate without using normal tissues from the same patient; and the PCR-based measurement of transcriptome of microarray limited the data interpretation and assumption validation. In this article, we performed multi-omics analyses on VLS paired-samples from the same patients as well as the normal ones from healthy donors. RNA-seq analysis revealed VLS patients are suffering from abnormally high inflammation with impressive anti-virus features. In-depth analysis of their transcriptome identified a remarkable enrichment of HCV poly U/UC sequence in VLS transcriptome, which might contribute to the onset of VLS. Multi-omics results indicated various inflammation-induced metabolic disorders in VLS samples, which might serve as therapeutic targets for precision medicine.
2021-06-15 | GSE166620 | GEO
Project description:HCV poly U/UC sequences induced abnormal inflammation leads to metabolic disorders in Vulvar Lichen Sclerosis
| PRJNA701431 | ENA
Project description:Vulvar lichen sclerosus (LS) is a chronic, inflammatory dermatosis that may lead to scarring of the vulva and sexual dysfunction. LS affects women of all ages and often goes unrecognized and underreported. Uncertainty continues to exist around its pathogenesis, histologic diagnosis, and treatment. However, there have been great advances in our understanding of autoimmunogenic targets in disease formation and progression. In addition, there has been recent investigation of potential non-steroid-based treatments, including platelet-rich plasma therapy and energy-based modalities such as the fractional CO2 laser, photodynamic therapy, and high intensity focused ultrasound. Refinement of surgical techniques for restoring vulvar anatomy and treating clitoral phimosis, introital stenosis, and vulvar granuloma fissuratum is leading to improved patient outcomes. This review summarizes current perspectives on the pathogenesis, symptomatology, diagnosis, and treatment for vulvar lichen sclerosus.
| S-EPMC6970240 | biostudies-literature
Project description:Vulvar lichen sclerosus (VLS) is a chronic inflammatory disorder, which affects women of all ages. The aim of this review is to focus on first-line, second-line, and maintenance therapies as well as follow-up of women with VLS. With numerous controversies, we decided to conduct a scoping review on this subject. A review protocol was developed, and the Knowledge Resource Services website was used to run a search of articles pertaining to VLS with keywords "Vulvar," "Vulval," and "Lichen Sclerosus." The search was limited to published data from the last 10 years, i.e., July 2009 onward, and researches published in English language. A total of 338 articles pertaining to VLS were obtained. Out of this, 62 were original articles related to management of VLS. Effective treatments such as high-potency topical steroids are now the standard of care and first-line treatment. Follow-up may be done every three to six months for the first two years and then at least yearly to ensure adequacy of treatment and encourage compliance. Long-term follow-up in specialist clinics is recommended for women who have persistent complaints, thickened skin, or history of neoplastic lesion. Monitoring young patients yearly is recommended as there are chances of recurrence.
| S-EPMC7995233 | biostudies-literature
Project description:Viral infection of mammalian cells triggers the innate immune response through non-self recognition of pathogen associated molecular patterns (PAMPs) in viral nucleic acid. Accurate PAMP discrimination is essential to avoid self recognition that can generate autoimmunity, and therefore should be facilitated by the presence of multiple motifs in a PAMP that mark it as non-self. Hepatitis C virus (HCV) RNA is recognized as non-self by RIG-I through the presence of a 5'-triphosphate (5'-ppp) on the viral RNA in association with a 3' poly-U/UC tract. Here we define the HCV PAMP and the criteria for RIG-I non-self discrimination of HCV by examining the RNA structure-function attributes that impart PAMP function to the poly-U/UC tract. We found that the 34 nucleotide poly-uridine "core" of this sequence tract was essential for RIG-I activation, and that interspersed ribocytosine nucleotides between poly-U sequences in the RNA were required to achieve optimal RIG-I signal induction. 5'-ppp poly-U/UC RNA variants that stimulated strong RIG-I activation efficiently bound purified RIG-I protein in vitro, and RNA interaction with both the repressor domain and helicase domain of RIG-I was required to activate signaling. When appended to 5'-ppp RNA that lacks PAMP activity, the poly-U/UC U-core sequence conferred non-self recognition of the RNA and innate immune signaling by RIG-I. Importantly, HCV poly-U/UC RNA variants that strongly activated RIG-I signaling triggered potent anti-HCV responses in vitro and hepatic innate immune responses in vivo using a mouse model of PAMP signaling. These studies define a multi-motif PAMP signature of non-self recognition by RIG-I that incorporates a 5'-ppp with poly-uridine sequence composition and length. This HCV PAMP motif drives potent RIG-I signaling to induce the innate immune response to infection. Our studies define a basis of non-self discrimination by RIG-I and offer insights into the antiviral therapeutic potential of targeted RIG-I signaling activation.
| S-EPMC3410852 | biostudies-literature
Project description:BACKGROUND/AIM:Differentiated vulvar intraepithelial neoplasia (dVIN) and lichen sclerosus (LS) can give rise to vulvar squamous cell carcinoma (VSCC), but genetic evidence is currently still limited. We aimed to determine genetic abnormalities in VSCC and backtrack these abnormalities in the dVIN and LS lesions. MATERIALS AND METHODS:DNA from VSCC and patient-matched dVIN and LS samples of twelve patients was collected. High-resolution genome-wide copy number analysis was performed and subsequently, we sequenced TP53. RESULTS:Copy number alterations were identified in all VSCC samples. One dVIN lesion presented with three copy number alterations that were preserved in the paired VSCC sample. Targeted sequencing of TP53 identified mutations in five VSCCs. All five mutations were traced back in the dVIN (n=5) or the LS (n=1) with frequencies ranging from 3-19%. CONCLUSION:Our data provide genetic evidence for a clonal relationship between VSCC and dVIN or LS.
| S-EPMC7078831 | biostudies-literature
Project description:Vulvar lichen sclerosus (VLS) is a chronic inflammatory dermatosis that affects female anogenital skin. Although VLS is considered a T cell-mediated autoimmune disease, the diagnosis criteria, molecular mechanism, and universally accepted therapies for this disease remain largely unresolved. To explore disease pathogenesis and potential biomarkers, we performed an RNA-Seq-based transcriptome analysis to profile the gene expression of VLS lesions. Differentially expressed gene (DEG) analysis revealed profound changes in expressions of coding genes, microRNAs, and long non-coding RNAs. Pathway and network analysis suggested that T cell activation-associated genes, including CD3G, CD3D, CD8B, LAT, LCK, ZAP70, CCR5, CXCR3, CXCL9, CXCL10, and CXCL11, were highly expressed in VLS, while NR4A family genes (NR4A1, NR4A2, NR4A3), whose coding products inhibit T cell activity, were significantly downregulated, suggesting heightened T cell response in VLS. Neutrophil chemoattractant genes CXCL1, CXCL2, CXCL3, CXCL8, and their cognate receptor CXCR2 were downregulated, suggesting dampened neutrophil activity. We also found the downregulation of genes involved in cell cycle progression, including cyclins (CCNB1, CCNB2, CCNL1, CCNE1, and CCNK) and centrosome factors (CENPA, CENPE, CENPF, and CENPN), while microRNA-203a and let-7, microRNAs known to inhibit cell growth, were found to be upregulated. These data collectively indicate that cell proliferation in VLS is compromised. In sum, these findings comprehensively deciphered key regulatory genes and networks in VLS, which could further our understanding of disease mechanisms and point toward therapeutic strategies.
| S-EPMC9247155 | biostudies-literature
Project description:BACKGROUND AND PURPOSE:Sunitinib is a small-molecule TK inhibitor associated with hepatotoxicity. The mechanisms of its toxicity are still unclear. EXPERIMENTAL APPROACH:In the present study, mice were treated with 60, 150, and 450 mg·kg-1 sunitinib to evaluate sunitinib hepatotoxicity. Sunitinib metabolites and endogenous metabolites in liver, serum, faeces, and urine were analysed using ultra-performance LC electrospray ionization quadrupole time-of-flight MS-based metabolomics. KEY RESULTS:Four reactive metabolites and impaired clearance of sunitinib in liver played a dominant role in sunitinib-induced hepatotoxicity. Using a non-targeted metabolomics approach, various metabolic pathways, including mitochondrial fatty acid ?-oxidation (?-FAO), bile acids, lipids, amino acids, nucleotides, and tricarboxylic acid cycle intermediates, were disrupted after sunitinib treatment. CONCLUSIONS AND IMPLICATIONS:These studies identified significant alterations in mitochondrial ?-FAO and bile acid homeostasis. Activation of PPAR? and inhibition of xenobiotic metabolism may be of value in attenuating sunitinib hepatotoxicity.
| S-EPMC6555861 | biostudies-literature
Project description:ObjectiveTo estimate the efficacy of fractionated carbon dioxide (CO2) laser therapy for vulvar lichen sclerosus.MethodsWe conducted a prospective, double-blind, randomized, sham-controlled, trial conducted in a clinic specializing in vulvar disorders. The study participants were 40 women with active vulvar lichen sclerosus confirmed with biopsy who were abstaining from topical and systemic treatments for at least 4 weeks before enrollment. Women were randomized in a 1:1 ratio to receive either five sham laser treatments or five fractionated CO2 treatments in a 24-week period. Study participants, treating clinicians, and the evaluating pathologist were blinded. The primary endpoint was the change in the histopathology scale score between pretreatment and posttreatment biopsies. We estimated 20 per group for 80% power to detect a 40% reduction in the histopathology scale score with up to 10% attrition. A secondary endpoint was the change in the validated CSS (Clinical Scoring System for Vulvar Lichen Sclerosus).ResultsFrom November 2018 to June 2020, 40 women were randomized to participate in the trial, and 37 women (19 fractionated CO2, 18 sham) were included in an intention-to-treat (ITT) analysis. Three women were excluded from the ITT analysis because they did not have posttreatment biopsies and, therefore, a posttreatment histopathology scale score could not be obtained. There was a 0.20 reduction (improvement) in histopathology scale score from baseline in the active treatment group (95% CI -1.1, 0.80, P=.74) and a 0.1 increase from baseline in the sham treatment group (95% CI -0.90, 1.0, P=.91). The change in histopathology scale score between the active and sham arm was not statistically significant (95% CI -1.14, 1.06, P=.76).ConclusionFractionated CO2 is not an effective monotherapy treatment for vulvar lichen sclerosus.Clinical trial registrationClinicalTrials.gov, NCT03665584.Funding sourceAdditional funding for this study was supplied by El.En Group, Florence, Italy, the manufacturer of the laser used in this study. In addition, El.En Group supplied the laser used in the study.
| S-EPMC8132913 | biostudies-literature
Project description:BACKGROUND:Vulvar lichen sclerosus et atrophicus (VLSA) is a chronic inflammatory skin disease of unknown etiology that mainly affects postmenopausal and perimenopausal women. The primary clinical symptoms of VLSA are itching, burning pain, and dyspareunia that can results in decreased quality of life. Existing therapies including topical corticosteroid ointment, topical calcineurin inhibitors, estrogens, are not very effective for treatment of VLSA. OBJECTIVE:To evaluate the effectiveness and safety of 5-aminolevulinic acid mediated photodynamic therapy (ALA-PDT) in the treatment of VLSA. MATERIALS AND METHODS:Ten patients with VLSA who had failed conventional treatment received ALA-PDT. 10% 5-ALA in an oil-in-water emulsion was applied to the lesions and occluded with plastic film for 3?h, when the lesions were irradiated with 100?mW/cm2, 635 ± 15?nm red light for 20?min. Treatments were repeated three times at 2-week intervals. Objective and subjective symptoms and signs of the vulvar lesions based on horizontal visual analogue scales were recorded at each treatment and 1, 3, and 6 months after the last session. The quality of life was assessed using dermatology life quality index (DLQI) questionnaire. RESULTS:All patients completed three ALA-PDT treatments and the follow-up visits. Clinical symptoms of itching disappeared completely in nine patients, one patient had itching decreased from severe to mild. All subjects showed objective improvement in lesions. The DLQI of all cases improved after treatment. The main side-effects of ALA-PDT were pain, erythema, and swelling. Side-effects were transient and tolerable. All patients reported being "satisfied" or "very satisfied" with their outcomes. CONCLUSIONS:ALA-PDT is an effective and safe approach for the treatment of VLSA.
| S-EPMC5922423 | biostudies-literature