Efficacy of non-ablative fractional 1440-nm laser therapy for treatment of facial acne scars in patients with rosacea: a prospective, interventional study.

Acne scarring is one of the most common facial skin disorders. The appropriate treatments for acne scars in patients with rosacea have not been studied. This study was designed to evaluate the efficacy and safety of non-ablative fractional 1440-nm laser (1440-nm NAFL) therapy for treatment of atrophic acne scars in patients with rosacea. In this prospective, interventional study, 32 patients with rosacea and acne scars underwent three sessions of 1440-nm NAFL therapy. Therapy efficacy, epidermal barrier function, and side effects were evaluated. Thirty patients completed and the median acne scar scores significantly reduced from 45 (30, 50) to 15 (15, 30) after three treatments (P < 0.001). The improvement score of acne scars was 2.7 ± 0.7; 22 (73.3%) were satisfied or highly satisfied. The rosacea erythema scores changed from 2.1 ± 0.4 to 1.9 ± 0.5 (P = 0.326), and flushing, burning, and stinging were not worse. The oil content after treatments was significantly reduced (P < 0.001), while there was no significant difference in other indicators of skin barrier function. The quality-of-life score decreased from 17.5 ± 3.8 to 14.1 ± 3.0 (P < 0.001). No serious side effects were observed. The 1440-nm NAFL therapy is effective in the treatment of acne scaring in patients with rosacea with little damage to the skin barrier.

Association between rosacea and cardiometabolic disease: A systematic review and meta-analysis.

BACKGROUND: Rosacea is recognized as a chronic inflammatory cutaneous disorder associated with multiple systemic illnesses. However, the association between rosacea and cardiometabolic disease (CMD) remains controversial. OBJECTIVE: To evaluate the association between rosacea and CMD by a systematic review and meta-analysis. METHODS: A comprehensive search of studies published before October 16, 2019, was performed in databases of PubMed, Embase, Cochrane Library, and Web of Science. The pooled risk ratios or standardized mean differences were calculated. RESULTS: Thirteen studies were included, representing 50,442 patients with rosacea. Patients with rosacea had higher prevalence of dyslipidemia, higher prevalence of hypertension, higher total cholesterol, higher low-density lipoprotein, higher triglycerides, higher systolic blood pressure, higher diastolic blood pressure, and higher fasting blood glucose. Rosacea was not associated with ischemic heart disease, stroke, diabetes, and high-density lipoprotein. LIMITATIONS: No subgroup analysis could be performed according to the subtypes and severity of rosacea. CONCLUSIONS: Rosacea showed a correlation with hypertension and dyslipidemia but not with ischemic heart disease, stroke, or diabetes. We advocate screening for CMD indicators among patients with rosacea, which may be helpful for diagnosis and appropriate treatment at an early stage of disease.

A Split-Face Study of Dual-Wavelength Laser on Neck and Facial Port-Wine Stains in Chinese Patients.

BACKGROUND: Although pulsed dye laser (PDL) has long been regarded as the gold standard in treating port-wine stain (PWS), advanced PWS with deeper coloration may display resistance because of limited penetration depth of 585 or 595-nm light. Recently, a dual-wavelength laser system has been reported to achieve pronounced fading in many patients. OBJECTIVE: The objective was to evaluate the efficacy and safety of a dual-wavelength laser device in treatment of neck and facial PWS in a direct side-by-side comparison. METHODS: Sixteen Chinese patients with neck and/or facial PWSs were enrolled in the study. All lesions were randomly divided into two area, treated area and adjacent untreated area. Five successive treatments using a dual-wavelength laser system (595-nm PDL combined with 1,064-nm Nd:YAG laser) were delivered on treated areas at 4- to 6-week intervals. The adjacent area was not treated as self control. Two blinded dermatologists evaluated the clinical changes by comparing the before and after photos. Erythema index (EI) values were measured with a non-invasive instrument. RESULTS: After five sessions of treatment, over 62.5% (10/16) patients achieved more than 50% (moderate or significant) improvement. The efficacy maintained at the 3-month follow-up visit. The values of EI on treated area showed a significant decrease. Adverse effects of treated area were limited. CONCLUSION: Using this split-face module, the dual-wavelength laser system is proved to be effective and well tolerated in treating neck and facial PWSs in Chinese patients. Adverse effects were minimal and acceptable.

No association between Y chromosomal haplogroups and severe acne in the Han Chinese population.

Severe acne presents sexual dimorphism in its incidence in Chinese population. It is more prevalent in males. To assess the possible Y chromosomal contribution to severe acne risk in Han Chinese males, we analyzed 2041 Y chromosomal SNPs (Y-SNPs) in 725 severe acne cases and 651 controls retrieved from our recent genome-wide association study data. After data filtering, we assigned 585 cases and 494 controls into 12 Y chromosomal haplogroups based on 307 high-confidence Y-SNPs. No statistically significant difference in the distribution of Y chromosomal haplogroup frequencies was observed between the case and control groups. Our results showed a lack of association between the incidence of severe acne and the different Y chromosomal haplogroup in the Han Chinese population.

Comparison of three problem-based learning conditions (real patients, digital and paper) with lecture-based learning in a dermatology course: a prospective randomized study from China.

BACKGROUND: The precise effect and the quality of different cases used in dermatology problem-based learning (PBL) curricula are yet unclear. AIM: To prospectively compare the impact of real patients, digital, paper PBL (PPBL) and traditional lecture-based learning (LBL) on academic results and student perceptions. METHODS: A total of 120 students were randomly allocated into either real-patients PBL (RPBL) group studied via real-patient cases, digital PBL (DPBL) group studied via digital-form cases, PPBL group studied via paper-form cases, or conventional group who received didactic lectures. Academic results were assessed through review of written examination, objective structured clinical examination and student performance scores. A five-point Likert scale questionnaire was used to evaluate student perceptions. RESULTS: Compared to those receiving lectures only, all PBL participants had better results for written examination, clinical examination and overall performance. Students in RPBL group exhibited better overall performance than those in the other two PBL groups. Real-patient cases were more effective in helping develop students' self-directed learning skills, improving their confidence in future patient encounters and encouraging them to learn more about the discussed condition, compared to digital and paper cases. CONCLUSION: Both real patient and digital triggers are helpful in improving students' clinical problem-handling skills. However, real patients provide greater benefits to students.

Efficacy and safety of non-surgical short-wave radiofrequency treatment of mild-to-moderate erythematotelangiectatic rosacea: a prospective, open-label pilot study.

Although various treatments have been proposed for the management of rosacea, achieving complete remission of persistent erythema remains challenging. Short-wave radiofrequency (SWRF) treatment has been shown to repair skin barriers and reduce chronic inflammation. However, limited studies have evaluated the effectiveness of SWRF treatment for erythematotelangiectatic rosacea (ETR). A prospective, open-label pilot study using SWRF therapy was conducted on 30 patients with mild-to-moderate ETR. During the first stage, the patients underwent a single, full-face treatment and were evaluated before and after the session, as well as on the 7th and 15th day post-treatment. During the second stage, ten treatment sessions were administered, and the patients were evaluated before and after the tenth session, as well as 1 month after the treatment. Adverse events were recorded during each treatment session, and the patients were followed up for 3 months after the last session. Twenty-eight patients completed the entire trial. On the 7th day after the single treatment, the global score (total score of flushing, persistent erythema, and telangiectasia) of ETR improved from 5.23 ± 1.09 to 4.00 ± 0.76 relative to the baseline value (p < 0.05); moreover, the overall treatment satisfaction improved from 7.27 ± 0.89 to 4.90 ± 0.91 (p < 0.05). 1 month after the tenth treatment session, the global score improved from 5.30 ± 1.01 to 3.85 ± 0.93 (p < 0.05), and the overall treatment satisfaction improved from 7.13 ± 0.85 to 5.17 ± 1.19 (p < 0.05). During the 3 month follow-up period, there were two cases of recurrence. Therefore, this report indicates that SWRF might be an effective auxiliary treatment for mild-to-moderate ETR.

Efficacy and safety of non-insulated fractional microneedle radiofrequency for treating difficult-to-treat rosacea: a 48-week, prospective, observational study.

Rosacea is a common chronic facial inflammatory skin disease. However, treatment for "difficult-to-treat rosacea" cases has not been established. This 48-week, prospective, observational study analyzed patients who underwent three non-insulated fractional microneedle radiofrequency (NFMRF) sessions at 2-month intervals. Therapy efficacy, epidermal barrier function, and side effects were evaluated. 34 subjects completed the trial. NFMRF resulted in CEA score reduction from 2.65 ± 0.59 to 1.56 ± 0.50 (P < 0.001) and mean DLQI reduction from 16.70 ± 3.55 to 10.48 ± 2.92 (P < 0.001). The successes of CEA (44.12 vs. 2.94%), IGA (91.67 vs. 25.00%), and flushing (58.82 vs. 26.47%) were observed. Among 34 patients, 22 reported "excellent" or "good" improvement and 30 were "very" or "relatively" satisfied. Skin barrier results revealed that hemoglobin content significantly decreased from 376.47 ± 71.29 at visit 0 to 161.32 ± 52.86 at visit 3. 2 of 30 patients followed-up at 6 months had a relapse at 18 and 20 weeks, respectively. No serious side effects were observed. NFMRF alone results in visible improvement and has great efficacy for difficult-to-treat rosacea without compromising patient safety or damaging the skin barrier.

Study on the roles of ß-catenin in hydrogen peroxide-induced senescence in human skin fibroblasts.

Oxidative stress is one of the most important causes of the cellular senescence process. Previous studies showed that ß-catenin can regulate FoxO3a and this association was enhanced in cells exposed to oxidative stress. It has also been reported that ß-catenin can regulate some senescence-related proteins. We propose that ß-catenin may play a crucial role in senescence of normal human primary skin fibroblasts (NHSFs). Here, we explored the roles and mechanisms of ß-catenin on H(2)O(2)-induced senescence in NHSFs. ß-catenin expression was decreased in NHSFs after H(2)O(2) treatment. Overexpression of ß-catenin in NHSFs led to a marked delay of many senescent phenotypes induced by H(2)O(2). Furthermore, overexpression of ß-catenin in NHSFs can antagonise the alteration of reactive oxygen species accumulation and some senescence-related proteins expression induced by H(2)O(2) treatment. Our data demonstrated that ß-catenin can protect NHSFs from H(2)O(2)-induced premature senescence by alleviating oxidative stress and regulating some senescence-related molecules.

Clinical Features and Risk Factors for Nasal Rosacea: A Hospital-Based Retrospective Study.

INTRODUCTION: At present, some studies have reported that nasal rosacea may be an independent disease, but phenotypic characteristics and risk factors for nasal rosacea remain unknown. This study aimed to clarify the clinical features and explore the risk factors for nasal rosacea. METHODS: A hospital-based retrospective study was conducted, including 1615 rosacea patients and 1501 healthy individuals. The patients were divided into three groups based on the involved areas of the lesions (non-nasal, intermediate and nasal rosacea group). Their demographic data and clinical features were obtained from patients' medical records, and risk factors of nasal rosacea were analyzed. RESULTS: There were 927 (57.4%), 647 (40.1%) and 41 (2.5%) cases in the non-nasal, intermediate and nasal rosacea groups, respectively. Of 41 patients with nasal rosacea, all (100.0%) had fixed erythema and 17 cases (41.5%) had phymatous changes. Compared with control group, male gender (adjusted odds ratio [aOR] = 2.39, 95% confidence interval [CI] = 1.14, 4.99), obesity (aOR = 3.19, 95% CI 1.86, 11.79) and alcohol use (aOR = 1.58, 95% CI 1.22, 5.40) were risk factors for nasal rosacea, but these three factors were not risk factors for non-nasal rosacea and intermediate rosacea groups. Among patients with nasal lesions (compared with patients without nasal phymatous changes), family history of rosacea was a risk factor (aOR = 2.12, 95% CI 1.01, 4.46) for nasal phymatous changes and Fitzpatrick IV skin type was a protective factor (aOR = 0.49, 95% CI 0.28, 0.86). CONCLUSION: Nasal rosacea has relatively specific clinical features and independent risk factors, suggesting that it may be a special type of rosacea.

Association study of tumor necrosis factor receptor type 2 M196R and toll-like receptor 2 Arg753Gln polymorphisms with acne vulgaris in a Chinese Han ethnic group.

BACKGROUND: Inflammatory cytokines such as tumor necrosis factor receptor 2 (TNFR2) and Toll-like receptor 2 (TLR2) are the main responsible mediators of inflammatory acne. Factors affecting their production may possibly influence the degree of inflammatory response and hence may account for the clinical severity of acne. However, the roles of TNFR2 and TLR2 in the pathophysiology of acne vulgaris are poorly understood. We therefore investigated the relationship between acne vulgaris susceptibility and the polymorphisms in the TNFR2 M196R as well as TLR2 Arg753Gln gene. METHODS: A total of 93 acne vulgaris patients and 90 healthy subjects from the Chinese Han ethnic group were enrolled in the study. The polymerase chain reaction restriction fragment length polymorphism technique was adopted to analyze the single-nucleotide polymorphisms of the TNFR2 M196R and TLR2 Arg753Gln gene, and to examine the association between acne vulgaris and the polymorphisms in the TNFR2 M196R as well as TLR2 Arg753Gln gene. The relationship between different genotypes and the susceptibility to acne vulgaris was analyzed. RESULTS: There is a significant difference in the frequency of TNFR2 M196R genetic polymorphisms between the moderate-acne to severe-acne subgroups and the control group (p < 0.05), and there is also a significant difference in the frequency of TLR2 Arg753Gln genetic polymorphisms between the severe-acne subgroup and control group (p < 0.05). CONCLUSION: The 196R allele of TNFR2 M196R as well as the 753Gln allele of TLR2 Arg753Gln are risk factors for acne vulgaris in Chinese Han patients, further supporting the contribution of inflammatory cytokines to the pathogenesis of acne.

Effects of skin care habits on the development of rosacea: A multi-center retrospective case-control survey in Chinese population.

BACKGROUND: Certain cosmetic habits may trigger or aggravate rosacea, while there is little published epidemiologic evidence to support this point. PURPOSE: To examine if daily skin care habits have an effect on the development of rosacea in Chinese population. METHODS: A multi-center retrospective case-control survey of 1,245 rosacea cases and 1,538 skin-healthy controls was conducted in China. Participants completed the questionnaire comprised of demographic characteristics, socioeconomic data and daily skin care habits. Data were collected retrospectively and analyzed using the chi-square test and t-test. Multivariate logistic regression analyses were used to predict rosacea. RESULTS: The multivariate logistic regression analysis highlighted some results: Dry, oily or mixed skin (OR = 6.3-6.9, P< .001), the usage of foaming cleanser (OR = 1.45, 95%CI 1.115-1.886, P = .01), make up more than 6 times a week (OR = 2.839, 95%CI 1.962-4.108, P< .001), using facial mask more than 4 times a week (OR = 2.56-3.069, P< .001), facial treatments at beauty salon more than once a week (OR = 4.946, 95%CI 2.005-12.198, P = .0018) and using beauty salon products (OR = 2.334, 95%CI 1.435-3.976, P = .0018) are positively correlated with the development of rosacea. Using of moisturizing products (OR = 0.602, 95%CI 0.386-0.983, P = .035) and sunscreen cream (OR = 0.303-0.507, P< .001 or P = .0167 for different frequency) presented significantly negative correlations with rosacea. Frequency of cleansing showed a nonlinear association with rosacea: using facial cleansers 1~3 times per week (OR = 0.647, 95%CI 0.429-0.975, P = .038) showed beneficial effects while using facial cleanser excessively (twice or more daily) (OR = 2.131, 95%CI 1.394-3.256, P< .001) positively correlated to rosacea strongly. CONCLUSIONS: Excessive use of facial cleanser (twice or more a day) and facial mask (more than 4 times a week), frequent makeup (more than 6 times a week), regular skin care in beauty salon (more than once a week), and using beauty salon products were closely correlated to the development of rosacea in Chinese population.

Willingness-to-Pay and Benefit-Cost Analysis of IPL for Rosacea Treatment: A Cross-Sectional Study in China.

BACKGROUND: Intense pulsed light (IPL), as a therapeutic approach for rosacea, had advantage in removing erythema and telangiectasia and was gradually accepted by rosacea patients, but there have been few studies on economic evaluation of this therapy. PURPOSE: This study aimed to detect willingness-to-pay (WTP) of IPL treatment for rosacea and to conduct a benefit-cost analysis (BCA) among the Chinese population, so as to provide an economic reference for doctors to make treatment decisions. MATERIALS AND METHODS: An observational, cross-sectional study assessed respondent's demographic characteristics and willingness-to-pay (WTP) of IPL and rosacea patients' clinical data and Dermatology Life Quality Index (DLQI). WTP was obtained by contingent valuation (CV) method. In brief, contrast figures of three cases treated with IPL (Case1, Case2, and Case3 represented the increasing severity of rosacea) were showed and WTP was inquired. The costs were obtained according the market and compared with WTP (benefits) to get a benefit-cost ratio (BCR). Predictors of cost-effective WTP were identified using the multivariable logistic regression model. RESULTS: A total of 303 rosacea patients and 202 controls were included in the study. The average cost of a single IPL treatment for rosacea was USD 208.04 in Changsha, China. The mean WTP for Case 1, Case 2, and Case 3 was USD 201.57, 214.64, and 221.74, respectively. WTP was statistically lower for Case 1 than that for Case 2 or Case 3 (P<0.05). The BCRs were 0.85, 1.03, and 1.06 for Case 1, Case 2, and Case 3, respectively. WTP is significantly associated with household monthly income, previous treatment cost, and DLQI after adjustments for demographic characteristics (P<0.05). CONCLUSION: IPL is an acceptable treatment for rosacea with moderate to severe erythema. For patients with relatively high income or severely impaired quality of life, IPL is an economically feasible therapy and deserves to be recommended.

Etanercept biosimilar (recombinant human tumor necrosis factor-α receptor II: IgG Fc fusion protein) and methotrexate combination therapy in Chinese patients with moderate-to-severe plaque psoriasis: a multicentre, randomized, double-blind, placebo-controlled trial.

Etanercept biosimilar recombinant human tumour necrosis factor-α receptor II: IgG Fc fusion protein (rhTNFR-Fc, trade name Yisaipu) has shown good efficacy in the treatment of moderate-to-severe plaque psoriasis. To compare the efficacy and safety of rhTNFR-Fc plus methotrexate (MTX) and rhTNFR-Fc plus placebo in Chinese patients with moderate-to-severe plaque psoriasis. In this multicentre, randomized, placebo-controlled trial, patients with moderate-to-severe plaque psoriasis were enrolled and randomly assigned in a 1:1 ratio to receive rhTNFR-Fc plus MTX or rhTNFR-Fc plus placebo. The primary endpoint was the proportion of patients achieving Psoriasis Area and Severity Index improvement of at least 75% (PASI 75) from baseline at week 24. Adverse events (AEs) were recorded to evaluate safety. Efficacy analysis was performed using the intent-to-treat principle. A total of 466 patients were enrolled and randomly received rhTNFR-Fc plus MTX (combination group, n = 233) or rhTNFR-Fc plus placebo (monotherapy group, n = 233). PASI 75 at week 24 was significantly higher in the combination group than in the monotherapy group (81.86% vs. 65.50%, p < 0.001). Similar results were observed in other PASI improvement scores at week 12 [PASI 75, 62.39% vs. 44.54% (p < 0.001); PASI 50, 87.17% vs. 75.55% (p = 0.001); and PASI 90, 34.07% vs. 18.78% (p < 0.001)] and week 24 [PASI 50, 92.48% vs. 85.59% (p = 0.019); and PASI 90, 64.16% vs. 42.36% (p < 0.001)]. Significantly more patients had a static Physicians' Global Assessment of clear or almost clear in the combination group than in the monotherapy group at week 12 (26.46% vs. 12.50%, p < 0.001) and week 24 (62.38% vs. 40.83%, p < 0.001). The most common AEs in the two groups were upper respiratory tract infection and abnormal liver function. The combination therapy of rhTNFR-Fc plus MTX was an effective therapy for moderate-to-severe plaque psoriasis with an acceptable safety and tolerability profile, indicating that it was feasible and well tolerated for patients.

Correction: miR-377 induces senescence in human skin fibroblasts by targeting DNA methyltransferase 1.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Relationship between rosacea and dietary factors: A multicenter retrospective case-control survey.

Although patients with rosacea often consult dermatologists for dietary factors that might be related to their skin disorders, few studies have been conducted to research the relationship between rosacea and dietary factors. The purpose of this study was to evaluate the potential relationship between rosacea and diet among the large Chinese population with rosacea, which would provide dietary guidelines for patients with rosacea. A multicenter case-control study was conducted. The feeding frequency 2 years before the occurrence of rosacea was collected by standardized questionnaires. Multiple logistic regression analysis was used to calculate risks related to the diet. One thousand three hundred and forty-seven patients with rosacea and 1290 controls were enrolled in our study. We found that high-frequency intake of fatty food and tea presented a positive correlation with rosacea, while high-frequency dairy product intake showed significant negative correlation with rosacea. Sweet food, coffee and spicy food appeared to be independent of any subset of rosacea in our study. However, high-frequency dairy product intake showed a borderline beneficial effect on rosacea severity. We further analyzed the correlation between diet and the subtype of rosacea. We found that high-frequency fatty intake was associated with erythematotelangiectatic rosacea (ETR) and phymatous rosacea, while high-frequency tea intake was only associated with ETR. In addition, high-frequency dairy product intake showed negative correlations with ETR and papulopustular rosacea. Rosacea is associated with some dietary factors, and our study is valuable in establishing dietary guidelines to prevent and improve rosacea.

[Clinical analysis of childhood acute generalized exanthematous pustulosis].

OBJECTIVE: To describe the etiology, clinical features and treatment of childhood acute generalized exanthematous pustulosis (AGEP). METHODS: Clinical data from 20 cases of childhood acute generalized exanthematous pustulosis from 1990 to 2008 were retrospectively reviewed. RESULTS: Eighteen cases had a history of medication, including the use of penicillin (n=6), cephalosporins (n=3), sulphonamides (n=2), algopyrin (n=2), vaccines (n=2 ) and anti-cold drugs (n=3). Fever and generalized erythematous pustules were observed in all 20 cases. Histopathologic examination revealed spongiform superficial pustules and papillary edema. The patients were asked to stop taking suspected sensitizing drugs and received glucocorticoid treatment (1-2 mg/kg daily). After 3-5 days of the treatment, symptoms were improved and the dosage of glucocorticoid was gradually reduced. All patients were healed within 20 days after treatment. CONCLUSIONS: The cause of AGEP is mainly attributed to the use of antibiotics, sulphonamides, antipyretic analgesics and vaccines in children. AGEP is characterized by fever and widespread pustular eruption of the skin. Removal of sensitizing factors and glucocorticoid administration is important in the treatment of AGEP in children.

[Establishment of systemic lupus erythematosus-like murine model with Sm mimotope].

OBJECTIVE: To establish systemic lupus erythematosus (SLE) -like murine model by immunizing BALB/C mice with Sm mimotope. METHODS: Sm mimotope was identified by screening a 12-mer random peptide library with monoclonal anti-Smith antibody. Sm mimotope was initially defined with sandwich ELISA, DNA sequencing, and deduced amino acid sequence; and BALB/C mice were subcutaneously injected with mixture phages clones. Sera Sm antibody, anti-double stranded DNA (dsDNA) antibody, and antinuclear antibody (ANA) of mice were detected using direct immunofluorescence; kidney histological changes were examined by HE staining. RESULTS: Five randomly selected peptides were sequenced and the amino acid sequences IR, SQ, and PP were detected in a higher frequency. High-titer IgG autoantibodies of dsDNA, Sm, and ANA in the sera of experiment group were detected by ELISA 28 days after having been immunized by Sm mimotope. Proteinuria was detected 33 days later; immune complex and nephritis were observed in kidney specimens. CONCLUSION: SLE-like murine model can be successfully induced by Sm phage mimotope.

Microrna-217 modulates human skin fibroblast senescence by directly targeting DNA methyltransferase 1.

DNA methyltransferase 1 (DNMT1) is a major epigenetic regulator associated with many biological processes. However, the roles and mechanisms of DNMT1 in skin aging are incompletely understood. Here we explored the role of DNMT1 in human skin fibroblasts senescence and its related regulatory mechanisms. DNMT1 expression decreased in passage-aged fibroblasts and DNMT1 silencing in young fibroblasts induced the senescence phenotype. MiR-217 is predicted to target DNMT1 mRNA and miR-217 expression increased in passage-aged fibroblasts. MiR-217 directly targeted the 3'-untranslated region (3'-UTR) of DNMT1 in HEK 293T cells and inhibited DNMT1 expression in fibroblasts. MiR-217 overexpression induced a senescence phenotype in young fibroblasts, and miR-217 downregulation in old HSFs partially reversed the senescence phenotype. However, these effects could be significantly rescued by regulating DNMT1 expression in fibroblasts. After regulating miR-217 levels, we analyzed changes in the promoter methylation levels of 24 senescent-associated genes, finding that 6 genes were significantly altered, and verified p16 and phosphorylated retinoblastoma (pRb) protein levels. Finally, an inverse correlation between DNMT1 and miR-217 expression was observed in skin tissues and different-aged fibroblasts. Together, these findings revealed that miR-217 promotes fibroblasts senescence by suppressing DNMT1-mediated methylation of p16 and pRb by targeting the DNMT1 3'-UTR.

miR-377 induces senescence in human skin fibroblasts by targeting DNA methyltransferase 1.

Skin aging is a complicated physiological process and epigenetic feature, including microRNA-mediated regulation and DNA methylation, have been shown to contribute to this process. DNA methylation is regulated by DNA methyltransferase, of which DNA methyltransferase 1 (DNMT1) is the most abundantly known. But evidence supporting its role in skin aging remains scarce, and no report regards its specifical upstream-regulating molecules in the process of skin aging so far. Here, we found that DNMT1 expression was markedly higher in young human skin fibroblasts (HSFs) than that in passage-aged HSFs, and DNMT1 knockdown significantly induced the senescence phenotype in young HSFs. We predicted the upstream miRNAs which could regulate DNMT1 with miRNA databases and found miR-377 had high homology with a sequence in the 3'-UTR of human DNMT1 mRNA. We confirmed that miR-377 was a potential regulator of DNMT1 by luciferase reporter assays. miR-377 expression in passage-aged HSFs was markedly higher than that in the young HSFs. miR-377 overexpression promoted senescence in young HSFs, and inhibition of miR-377 reduced senescence in passage-aged HSFs. Moreover, these functions were mediated by targeting DNMT1. Microfluidic PCR and next-generation bisulfite sequencing of 24 senescent-associated genes' promoters revealed alterations of the promoter methylation levels of FoxD3, p53, and UTF1 in HSFs treated with miR-377 mimics or inhibitors. We also verified that the miR-377-mediated changes in p53 expression could be reversed by regulation of DNMT1 in HSFs. Similarly, there was a negative correlation between miR-377 and DNMT1 expression in young and photoaged HSFs, HSFs, or skin tissues from UV-unexposed areas of different aged donors. Our results highlight a novel role for miR-377-DNMT1-p53 axis in HSF senescence. These findings shed new light on the mechanisms of skin aging and identify future opportunities for its therapeutic prevention.