m6A RNA methylation: The latent string-puller in fibrosis.

Fibrosis is a pathological phenomenon characterized by the aberrant accumulation of extracellular matrix (ECM) in tissues. Fibrosis is a universally age-related disease involving that many organs and is the final stage of many chronic inflammatory diseases, which often threaten the patient's health. Undoubtedly, fibrosis has become a serious economic and health burden worldwide, However, the pathogenesis of fibrosis is complex. Further, the key molecules still remain to be unraveled. Hence, so far, there have been no effective treatments designed against the key targets of fibrosis. The methylation modification on the nitrogen atom at position 6 of adenine (m6A) is the most common mRNA modification in mammals. There is increasing evidence that m6A is actively involved in the pathogenesis of fibrosis. This review aims to highlight m6A-associated mechanisms and functions in several organic fibrosis, which implies that m6A is universal and critical for fibrosis and summarize the outlook of m6A in the treatment of fibrosis. This may light up the unknown aspects of this condition for researchers interested to explore fibrosis further.

ATRA ameliorates fibrosis by suppressing the pro-fibrotic molecule Fra2/AP-1 in systemic sclerosis.

Systemic sclerosis (SSc) is an autoimmune connective tissue disease that leads to irreversible fibrosis of the skin and the internal organs. The etiology of SSc is complex, its pathophysiology is poorly understood, and clinical therapeutic options are restricted. Thus, research into medications and targets for treating fibrosis is essential and urgent. Fos-related antigen 2 (Fra2) is a transcription factor that is a member of the activator protein-1 family. Fra2 transgenic mice were shown to have spontaneous fibrosis. All-trans retinoic acid (ATRA) is a vitamin A intermediate metabolite and ligand for the retinoic acid receptor (RAR), which possesses anti-inflammatory and anti-proliferative properties. Recent research has demonstrated that ATRA also has an anti-fibrotic effect. However, the exact mechanism is not fully understood. Interestingly, we identified potential binding sites for the transcription factor RARα to the promoter region of the FRA2 gene through JASPAR and PROMO databases. In this study, the pro-fibrotic effect of Fra2 in SSc is confirmed. SSc dermal fibroblasts and bleomycin-induced fibrotic tissues of SSc animals exhibit increased levels of Fra2. Inhibition of Fra2 expression in SSc dermal fibroblasts with Fra2 siRNA markedly decreased collagen I expression. ATRA reduced the expressions of Fra2, collagen I, and α-smooth muscle actin(α-SMA) in SSc dermal fibroblasts and bleomycin-induced fibrotic tissues of SSc mice. In addition, chromatin immunoprecipitation and dual-luciferase assays demonstrated that retinoic acid receptor RARα binds to the FRA2 promoter and modulates its transcriptional activity. ATRA decreases collagen I expression both in vivo and in vitro via the reduction of Fra2 expression. This work establishes the rationale for expanding the use of ATRA in the treatment of SSc and indicates that Fra2 can be used as an anti-fibrotic target.

Association between pre-pregnancy body mass index and the risk of preterm birth: a mediating effect of hypertensive disorders of pregnancy.

OBJECTIVE: We aim to explore the mediating effect of hypertensive disorders of pregnancy (HDP) on the relationship between pre-pregnancy body mass index (BMI) and the risk of preterm birth (PTB) in women with singleton live births. METHODS: Demographic and clinical data of 3,249,159 women with singleton live births were extracted from the National Vital Statistics System (NVSS) database in this retrospective cohort study. The associations between pre-pregnancy BMI and HDP, HDP, and PTB, and pre-pregnancy BMI and PTB were evaluated using univariate and multivariate logistic regression analyses, with odds ratios (ORs) and 95% confidence intervals (CIs). Structural equation modeling (SEM) was used to explore the mediating effect of HDP on the relationship between pre-pregnancy BMI and PTB. RESULTS: In total, 324,627 women (9.99%) had PTB. After adjustment for covariables, there were significant associations between pre-pregnancy BMI and HDP [OR = 2.07, 95% CI: 2.05-2.09)], HDP and PTB [OR = 2.54, 95% CI: (2.52-2.57)], and pre-pregnancy BMI and PTB [OR = 1.03, 95% CI: 1.02-1.03)]. The effect of pre-pregnancy BMI on PTB was significantly mediated by HDP with a mediation proportion of 63.62%, especially in women of different ages and having gestational diabetes mellitus (GDM) or not. CONCLUSION: HDP may play a mediating role in the effect of pre-pregnancy BMI on PTB risk. Women preparing for pregnancy should pay close attention to BMI, and pregnant women should monitor and develop interventions for HDP to reduce the risk of PTB.

Activating Protein-1 (AP-1): A Promising Target for the Treatment of Fibrotic Diseases.

The fibrosis of tissues and organs occurs via an aberrant tissue remodeling process characterized by an excessive deposition of extracellular matrix, which can lead to organ dysfunction, organ failure, and death. Because the pathogenesis of fibrosis remains unclear and elusive, there is currently no medication to reverse it; hence, this process deserves further study. Activating protein-1 (AP-1)-comprising Jun (c-Jun, JunB, JunD), Fos (c-fos, FosB, Fra1, and Fra2), and activating transcription factor-is a versatile dimeric transcription factor. Numerous studies have demonstrated that AP-1 plays a crucial role in advancing tissue and organ fibrosis via induction of the expression of fibrotic molecules and activating fibroblasts. This review focuses on the role of AP-1 in a range of fibrotic disorders as well as on the antifibrotic effects of AP-1 inhibitors. It also discusses the potential of AP-1 as a new therapeutic target in conditions involving tissue and organ fibrosis.

Overexpressed perforin contributes to the melanocyte destruction via epigenetic regulation in patients with vitiligo.

BACKGROUND: Perforin (PRF), a pivotal cytotoxic effector molecule of activated CD8+ T cells, has a crucial role in the pathogenesis of vitiligo. However, the mechanisms leading to the abnormal perforin expression remain poorly understood in the CD8+ T cells of vitiligo patients. OBJECTIVE: To investigate the contributions of DNA methylation to the abnormal expression of perforin in CD8+ T cells of vitiligo patients. METHODS: Skin samples and CD8+ T cells from peripheral blood were collected to detect the expression levels of perforin in vitiligo patients. The methylation status of the perforin promoter was investigated by bisulfite sequencing. The apoptosis of melanocytes co-cultured with CD8+ T cells was evaluated to determinate the cytotoxic role of perforin. RESULTS: Increased CD8+ and perforin+ cells were found in lesion of vitiligo patients. The expression levels of perforin were elevated in the CD8+ T cells from peripheral blood of vitiligo patients and their culture supernatants. The perforin promoter was hypomethylated in vitiligo CD8+ T cells. Treatment of normal CD8+ T cells with the DNA methylation inhibitor 5-Azacytidine (5-Azac) reduced the perforin methylation level and caused perforin overexpression. The methylation levels of perforin were inversely correlated with its mRNA expression in CD8+ T cells. The apoptosis rates of the melanocytes co-cultured with vitiligo- and 5-Azac-treated-normal CD8+ T cells were significantly increased compared with normal-untreated CD8+ T cells. And the apoptosis rates of melanocytes co-cultured with si-PRF-treated-vitiligo CD8+ T cells were significantly decreased compared with vitiligo-untreated CD8+ T cells. CONCLUSION: Hypomethylation of the perforin promoter contributes to its overexpression in CD8+ T cells from vitiligo patients, which then mediates the melanocyte destruction in vitiligo.

Occludin Promotes Adhesion of CD8+ T Cells and Melanocytes in Vitiligo via the HIF-1α Signaling Pathway.

Loss of melanocytes induced by activated CD8+ T cells is the pathological hallmark of vitiligo. Melanocyte-specific CD8+ T cells are recruited to the skin via chemokines, thereby releasing perforin, granzyme, and other cytotoxic substances that destroy the melanocytes. However, the mechanism of CD8+ T cells to adhere to melanocytes is unknown. Previous transcriptome sequencing results published by our group showed that the occluding (OCLN) gene was significantly upregulated in CD8+ T cells from skin lesions of vitiligo. Occludin is a crucial component of the tight junction between cells; in cells without tight junction, occludin mediates the adhesion of two cells in the form of a self-ligand. This study demonstrated that OCLN gene expression was elevated in the CD8+ T cells of vitiligo patients, and occludin mediates the adherence of CD8+ T cells to melanocytes. Besides, pathological changes in vitiligo skin lesions reveal that CD8+ T cells continuously persist in the skin lesions, which is related to the persistence of the disease. In this regard, we found that fibroblasts from vitiligo patients significantly express occludin, which may participate in the continuous retention of CD8+ T cells in the skin lesions. The pathogenesis of vitiligo is closely related to oxidative stress, and our data suggest that overexpression of hypoxia-inducible factor-1α (HIF-1α) increases the expression of occludin. Besides, ChIP-qPCR of CD8+ T cells revealed that HIF-1α directly binds to the OCLN promoter. Thus, occludin upregulation promotes the adhesion of CD8+ T cells and melanocytes via the HIF-1α signaling pathway. Our study results suggested a critical role for OCLN in the occurrence, progression, and maintenance of vitiligo. Therefore, inhibiting the expression of OCLN gene may be a potential targeted treatment strategy.

Esomeprazole alleviates fibrosis in systemic sclerosis by modulating AhR/Smad2/3 signaling.

Systemic sclerosis (SSc) is a connective tissue disease with the involvement of complex signaling pathways, such as TGF-ß/Smad2/3. SSc can lead to severe multiple organ fibrosis, but no effective therapy is currently available because of its unclear pathogenesis. Exploring new treatments is the focus of recent research on SSc. Recent studies have implied a potential antifibrotic role of esomeprazole (ESO), but with currently unidentified mechanisms. Signaling of AhR, a ligand-dependent transcription factor, has been described as a key controller of fibrosis, tumorigenesis, and immune balance. Recently, it has been reported that ESO may be an exogenous agonist of AhR signaling, while no previous study has revealed the effects of ESO on SSc and its underlying mechanisms. In this study, we demonstrate that ESO suppresses the migration of SSc dermal fibroblasts, downregulates profibrotic markers, including COLIA1, α-SMA CTGF and MMP1, and limits collagen production potentially via the activation of AhR signaling. More importantly, ESO could block Smad2/3 phosphorylation concurrently with the reduction in collagen via AhR signaling. Moreover, our results from the bleomycin (BLM)-induced SSc model in skin and lung shows that ESO ameliorates fibrosis in vivo, which in keeping with our in vitro results. We conclude that ESO is a potential therapeutic drug for SSc fibrosis.

Meta-Analytic Review of High Anxiety Comorbidity among Patients with Vitiligo.

BACKGROUND: Vitiligo is a disfiguring skin disease with profound psychosocial impacts, such as anxiety, but the reported effect sizes of associations vary. We aimed to conduct a meta-analysis to quantify the strength of association between anxiety and vitiligo and to estimate the prevalence of anxiety among individuals with vitiligo. METHODS: A systematic literature search was performed in five online databases (MEDLINE, Embase, Web of Science, Cochrane Library, and PsycINFO) from inception until March 20, 2020. All of the eligible studies were comprehensively reviewed, and all of the available data were analyzed according to our predefined criteria. RESULTS: Twenty-one studies involving 3259 patients in 11 countries were included in this meta-analysis. Compared with the healthy control group, patients with vitiligo often had concomitant anxiety (OR = 6.14 [95% CI: 3.35-11.24], I 2 = 30.1%). The pooled prevalence of anxiety in female patients was significantly higher than that in males (OR = 2.24 [95% CI: 1.31-3.84], I 2 = 0.0%). Subgroup analysis showed that the pooled prevalence of clinical anxiety disorder and anxiety symptoms was 12% (95% CI: 7%-16%, I 2 = 76.3%) and 34% (95% CI: 21%-46%, I 2 = 94.7%), respectively. No publication bias has been detected by Begg's funnel plot and Egger's test. CONCLUSION: Patients with vitiligo have high anxiety comorbidity, with female predominance. Dermatologists and psychiatrists should be vigilant to the presence of anxiety, apply appropriate interventions to reduce the psychological impacts in a timely manner, and thus promote recovery in vitiligo patients. However, due to some objective limitations (poor information about the OR and diversity in assessment tools among included studies), findings should be interpreted with caution.

Particulate matter promotes hyperpigmentation via AhR/MAPK signaling activation and by increasing α-MSH paracrine levels in keratinocytes.

Particulate matter with an aerodynamic equivalent diameter of 2.5 µm or less in ambient air (PM2.5) has become a global public and environmental problem, and the control of the PM2.5 concentration in air is an urgent problem. PM2.5 can easily penetrate the skin, activating the inflammatory response in skin, unbalancing the skin barrier function, and inducing skin aging. Hyperpigmentation is the main manifestation of skin aging and has a considerable impact on quality of life worldwide. To date, no research on the influence of PM2.5 on hyperpigmentation has been conducted. Here, we illustrate that PM2.5 can induce melanogenesis in vivo and in vitro by regulating TYR, TYRP1, TYRP2, and MITF expression via AhR/MAPK signaling activation. Furthermore, PM2.5 increased α-MSH paracrine levels, which in turn promote hyperpigmentation. Our results provide a deeper understanding of how PM2.5 disrupts skin homeostasis and function. Treatment with AhR antagonists may be a potential therapeutic strategy for hyperpigmentation induced by PM2.5.

Management strategies for dermatomyositis during the coronavirus disease 2019 outbreak.

In late 2019, the coronavirus disease 2019 (COVID-19) broke out in Wuhan and then spread over China, which greatly affected the medical practices and health care systems. With most of the hospital's outpatient services closed, the routine clinical diagnosis and treatment for patients with dermatomyositis has been disturbed. We conducted telephone follow-up for 52 patients to know the changes in the condition and the continuation of drug therapy and to ensure the continuity, safety, and effectiveness of the treatment of patients with dermatomyositis during COVID-19.

A recurrent mutation of GJB6 in a big Chinese family with Hidrotic ectodermal dysplasia.

Hidrotic ectodermal dysplasia (HED) is a rare inherited syndrome characterised by nail dystrophy, palmoplantar hyperkeratosis and alopecia. Four mutations (p.G11R, p.A88V, p.V37E and p.D50N) in gap junction beta 6 (GJB6) gene, which codes connexin30 protein, have been found to cause HED in different populations. Here, we reported a big Chinese family in which 24 patients over five generations were suffered with HED. Sequence analysis identified all 24 patients carry a recurrent missense mutation c.263C > T (p.A88V) in GJB6. Our results reveal gene testing of GJB6 is important for diagnosis, prenatal diagnosis and future gene treatment of HED.

Aryl hydrocarbon receptor signaling activation in systemic sclerosis attenuates collagen production and is a potential antifibrotic target.

Systemic sclerosis (SSc) is a systemic autoimmune disease that often leads to fibrosis of multiple organs, and there are no effective treatments. Aryl hydrocarbon receptor (AhR) is a highly evolutionarily conserved transcription factor activated by endogenous and exogenous ligands and that regulate cell proliferation, tumorigenesis and immune balance. Recently, it have reported AhR signaling may participate in fibrosis process, usually consider as a negative regulator of TGF-ß. However, the detailed relationship between AhR and SSc has not been reported yet. Here we firstly found that AhR and CYP1A1 downregulated in SSc fibroblast(n = 6). The AhR ligand-Ficz negatively regulates TGF-ß1, COL1A1 and α-SMA expression, also enhances the MMP-1 expression via the AhR signaling activation. Conversely the AhR antagonist CH223191 could inhibit this effect. Furthermore, the antifibrosis effect of AhR signaling activation was also confirmed in bleomycin induced scleroderma mouse model. In conclusion, AhR signaling activation balances the extracellular matrix (ECM) composition and deposition, which may provide a new sight to the pathogenesis of SSc and AhR signaling activation may be a potential therapy for SSc.