Blimp-1 Upregulation by Multiple Ligands via EGFR Transactivation Inhibits Cell Migration in Keratinocytes and Squamous Cell Carcinoma.

B lymphocyte-induced maturation protein-1 (Blimp-1) is a transcriptional repressor and plays a crucial role in the regulation of development and functions of various immune cells. Currently, there is limited understanding about the regulation of Blimp-1 expression and cellular functions in keratinocytes and cancer cells. Previously we demonstrated that EGF can upregulate Blimp-1 gene expression in keratinocytes, playing a negative role in regulation of cell migration and inflammation. Because it remains unclear if Blimp-1 can be regulated by other stimuli beyond EGF, here we further investigated multiple stimuli for their regulation of Blimp-1 expression in keratinocytes and squamous cell carcinoma (SCC). We found that PMA, TNF-α, LPS, polyIC, H2O2 and UVB can upregulate the protein and/or mRNA levels of Blimp-1 in HaCaT and SCC cells. Concomitant EGFR activation was observed by these stimuli, and EGFR inhibitor gefitinib and Syk inhibitor can block Blimp-1 gene expression caused by PMA. Reporter assay of Blimp-1 promoter activity further indicated the involvement of AP-1 in PMA-, TNF-α-, LPS- and EGF-elicited Blimp-1 mRNA expression. Confocal microscopic data indicated the nuclear loclization of Blimp-1, and such localization was not changed by stimuli. Moreover, Blimp-1 silencing enhanced SCC cell migration. Taken together, Blimp-1 can be transcriptionally upregulated by several stimuli in keratinocytes and SCC via EGFR transactivation and AP-1 pathway. These include growth factor PMA, cytokine TNF-α, TLR ligands (LPS and polyIC), and ROS insults (H2O2 and UVB). The function of Blimp-1 as a negative regulator of cell migration in SCC can provide a new therapeutic target in SCC.

Association of rosacea with depression and anxiety: A systematic review and meta-analysis.

BACKGROUND: Rosacea is associated with several comorbidities, but its relationship with psychiatric disorders remains controversial. We aimed to investigate the association of rosacea with depression and anxiety. METHODS: A systematic review was performed of relevant observational studies in the PubMed, Web of Science, Embase, and Wanfang databases from inception to June 8, 2021. The inclusion criteria for eligible studies were observational studies comparing the incidence or prevalence of depression or anxiety between patients with rosacea and individuals without rosacea. We conducted meta-analyses with a random-effects model. The main outcome was pooled analysis of prevalence or incidence of depression and anxiety in patients with rosacea. RESULTS: We included nine studies with 101,114,209 patients with rosacea. A pooled analysis from cross-sectional and case-control studies revealed that patients with rosacea were significantly more likely to have depression (crude odds ratio [OR], 2.855; 95% confidence interval [CI], 1.258-6.481) and anxiety (crude OR, 2.373; 95% CI, 1.448-3.888) than matched controls; however, adjusted ORs showed no significant association. Furthermore, the meta-analysis from cohort studies indicated that patients with rosacea have significantly higher risks of developing depression (adjusted incidence rate ratio [IRR], 2.443; 95% CI, 1.603-3.723) and anxiety (adjusted IRR, 2.181; 95% CI, 1.660-2.864). LIMITATIONS: Data for a subgroup analysis based on different demographic factors were insufficient. CONCLUSIONS: Current findings provide more evidence that rosacea is significantly associated with depression and anxiety, and rosacea may predispose patients to develop depression and anxiety. Clinicians should be aware of the psychological aspects of rosacea.

Antineutrophil Cytoplasmic Antibodies and Organ-Specific Manifestations in Eosinophilic Granulomatosis with Polyangiitis: A Systematic Review and Meta-Analysis.

BACKGROUND: Eosinophilic granulomatosis with polyangiitis (EGPA), also known as Churg-Strauss syndrome, is a rare and often severe systemic vasculitis associated with antineutrophil cytoplasmic antibodies (ANCAs). EGPA can affect multiple organ systems, but the relationships between ANCA status and the organ-specific manifestations of EGPA in previous reports were inconsistent. OBJECTIVE: To investigate the association of the ANCA status with organ-specific manifestations in EGPA. METHODS: We performed a systematic review of studies published before March 16, 2020, in the PubMed, Embase, Web of Science, and Cochrane Library databases. The primary outcome was the association of ANCA status with organ-specific involvements of EGPA. Odds ratios (ORs) and 95% CIs were calculated using a random-effects model. RESULTS: A total of 24 cross-sectional studies with 2527 patients with EGPA, including 921 ANCA-positive patients and 1606 ANCA-negative patients, were included in the meta-analysis. The significant results of pooled analyses revealed that compared with patients with EGPA with negative ANCA status, patients with EGPA with positive ANCA status had higher risks of peripheral neuropathy (OR, 1.701), renal involvement (OR, 5.097), and cutaneous purpura (OR, 1.746) and lower risks of pulmonary infiltrates (OR, 0.589) and cardiac involvement (OR, 0.427). The pooled analysis also revealed no significant association of ANCA status with asthma and involvements of the central nervous system, gastrointestinal tract, or skin. CONCLUSIONS: This study provides more evidence that patients with EGPA may exhibit different features of disease based on their ANCA status.

Serum lipids and risk of atherosclerosis in xanthelasma palpebrarum: A systematic review and meta-analysis.

BACKGROUND: The association between dyslipidemia and xanthelasma palpebrarum (XP) remains controversial, and no definite evidence has indicated atherosclerosis risk in patients with XP. OBJECTIVE: The present study was a systematic review and meta-analysis to elucidate the association of serum lipid profiles and risk of atherosclerotic diseases with XP. METHODS: We systematically searched for the eligible comparative studies published before April 15, 2019, in the databases of PubMed, Web of Science, Embase, and Cochrane Library. A random-effects model was used to calculate the standard mean difference with 95% confidence interval for each pooled estimate. RESULTS: The qualitative analyses included 15 case-control studies with 854 patients with XP. Compared with the controls, the patients with XP had significantly higher serum levels of total cholesterol and low-density lipoproteins, significantly higher apolipoprotein B levels, and relatively lower apolipoprotein A1 levels, and the carotid intima-media thickness was significantly higher. CONCLUSION: Patients with XP had significantly higher serum levels of atherogenic low-density lipoproteins and bore significantly higher risk of atherosclerosis than the controls. Careful monitoring and targeted intervention for prevention of cardiovascular diseases is essential for these patients.

Efficacy of Autologous Platelet-Rich Plasma Combined With Ablative Fractional Carbon Dioxide Laser for Acne Scars: A Systematic Review and Meta-Analysis.

BACKGROUND: Acne scars are common and challenging clinical complications of acne vulgaris. Ablative fractional carbon dioxide (CO2) laser is a well-established treatment for acne scars; however, some postlaser adverse effects have been noted. Autologous platelet-rich plasma (PRP) can improve tissue regeneration. Several studies have investigated the efficacy of combination therapy of CO2 laser and PRP for acne scars. OBJECTIVES: The authors sought to conduct a meta-analysis of the efficacy of PRP combined with ablative fractional CO2 laser for treating acne scars by examining clinical trial results. METHODS: A systematic review was performed by searching PubMed, Embase, Cochrane Library, and Web of Science, and a meta-analysis was conducted to assess the clinical outcomes after combination therapy of PRP and ablative fractional CO2 laser compared with laser alone. RESULTS: We identified 4 eligible studies for the meta-analysis, including 3 randomized controlled trials. Our results demonstrated that clinical improvement after combination therapy was significantly higher than that after laser alone (odds ratio = 2.992, P = 0.001). Regarding major side effects, patients who underwent combination therapy experienced significantly shorter duration of crust compared with CO2 laser alone (standard mean difference = -1.140, P < 0.001); relatively shorter durations of erythema and edema were also noted after combination therapy. Furthermore, patient satisfaction rates were significantly higher after combination therapy than after laser alone (odds ratio = 3.169, P = 0.002). CONCLUSIONS: The combination of autologous PRP and ablative fractional CO2 laser has synergistic positive effects on the clinical outcomes for acne scars and can accelerate the recovery of laser-damaged skin.

BLIMP1 transcriptionally induced by EGFR activation and post-translationally regulated by proteasome and lysosome is involved in keratinocyte differentiation, migration and inflammation.

BACKGROUND: B lymphocyte-induced maturation protein-1 (BLIMP1) is a transcriptional repressor, and plays a crucial role in the regulation of development and functions of various immune cells. Currently, there is limited understanding about the regulation of BLIMP1 expression in keratinocytes and crosstalk between EGFR and BLIMP1 in skin homeostasis. OBJECTIVE: The aim of the study was to investigate the regulation and functional link between EGFR and BLIMP1 in human epidermal keratinocytes. METHODS: Immunoblotting and Q-PCR were used to determine the molecular mechanism of BLIMP1 expression induced by EGFR in primary human epidermal keratinocytes (NHEK) and HaCaT cells. In functional assay, effects of BLIMP1 knockdown on EGFR-mediated cytokine production, differentiation, and migration in NHEK were evaluated by Q-PCR, ELISA, immunoblotting, and/or wound-healing assay. RESULTS: EGFR activation by EGFR ligands could upregulate the protein and mRNA levels of BLIMP1 in NHEK and HaCaT cells. This effect was dependent on PKC, p38, and ERK activation. Additionally, the stability of BLIMP1 protein was under the control of the proteasome and lysosome degradation systems. EGF could also upregulate BLIMP1 expression in skin squamous cell carcinomas. In addition, BLIMP1 knockdown enhanced the EGFR-mediated IL8, CXCL5 and IL6 gene expression and keratinocyte migration, but reduced the EGFR-mediated suppression of differentiation marker K10. CONCLUSIONS: Our findings shed new insights into the regulation of BLIMP1 expression by EGFR-mediated gene transcription and proteasome/lysosome-mediated degradation in keratinocytes. Functionally, BLIMP1 is a negative regulator of EGF-induced inflammation and migration in keratinocytes, and exerts a gene-specific regulation on keratinocyte differentiation.

Spleen tyrosine kinase mediates the actions of EPO and GM-CSF and coordinates with TGF-ß in erythropoiesis.

Erythropoietin (EPO) and GM-CSF are involved in erythropoiesis, while TGF-ß inhibits proliferation but potentiates differentiation of erythroblasts. Since Syk inhibitor may induce anemia side effect in clinic, here we investigated the role of Syk in the biological actions of EPO and GM-CSF in erythropoiesis. In human erythroleukemia cell line TF-1, Syk inhibitor R406 exerts an enhancement effect with TGF-ß to decrease cell viability, either in the absence or presence of EPO or GM-CSF. Such effect of R406 results from the reduced cell cycle progression and increased cell apoptosis. Notably, unlike Syk, Src family kinases are not involved in the viability control of TF-1 cells. Signaling studies showed that Syk is required for STAT5 and ERK activation induced by EPO, and Akt and ERK activation induced by GM-CSF. Nevertheless, R406 does not change the Smad2/3 signal caused by TGF-ß, and TGF-ß neither affects above signal pathways of EPO and GM-CSF. Of note, Syk is constitutively associated with EPOR in plasma membrane and can bind to STAT5 at active status upon EPO stimulation. Furthermore, EPO-induced hemoglobin γ expression was reduced by R406. In BFU-E and CFU-E colony formation assays in Syk-deficient erythroid progenitor cells, we confirmed the essential role of Syk in erythropoiesis mediated by EPO. Taken together, Syk is a novel upstream signaling molecule of EPOR, and contributes to erythroblast proliferation, survival and differentiation.