Therapeutic strategies focusing on immune dysregulation and neuroinflammation in rosacea.

Rosacea is a complex inflammatory condition characterized by papulopustular lesions and erythema on the central face for which there is no cure. The development of rosacea is influenced by both external triggers and genetics, but the common pathophysiology is overactivation of the immune system. Here, we review the current data on proinflammatory cytokines and dysregulation of the neurovascular system as targetable components of rosacea. Amelioration of cutaneous and gastrointestinal dysbiosis and other external factors impacts the immune state and has been observed to improve rosacea. While multiple treatments exist, many patients do not achieve their goals for rosacea control and highlights an unmet need for dermatologic care. Current interventions encompass topical/oral drugs, light devices, and avoidance of triggers management. Additional understanding of the underlying pathogenesis may help us develop novel targeted therapeutic strategies to improve rosacea.

Associations of novel complete blood count-derived inflammatory markers with psoriasis: a systematic review and meta-analysis.

Psoriasis is an immune-mediated disorder which primarily affects skin and has systemic inflammatory involvement. Neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation index (SII), and monocyte-to-lymphocyte ratio (MLR) are novel complete blood count (CBC)-derived markers which can reflect systemic inflammation. This study aimed to systematically investigate the associations of NLR, PLR, SII, and MLR with psoriasis. This study was performed in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement. A comprehensive search of Pubmed, Embase, Scopus, and Google Scholar was conducted for relevant studies. Observational studies evaluating the correlations of NLR, PLR, SII, or MLR with psoriasis were included. The primary outcomes were the associations of these inflammatory markers with the presence and severity of psoriasis. The random-effect model was applied for meta-analysis. 36 studies comprising 4794 psoriasis patients and 55,121 individuals in total were included in the meta-analysis. All inflammatory markers were significantly increased in psoriasis groups compared to healthy controls (NLR: MD = 0.59, 95% CI: 0.47-0.7; PLR: MD = 15.53, 95% CI: 8.48-22.58; SII: MD = 111.58, 95% CI: 61.49-161.68; MLR: MD = 0.034, 95% CI: 0.021-0.048; all p < 0.001). Between-group mean differences in NLR and PLR were positively correlated with the mean scores of Psoriasis Area Severity Index (NLR: p = 0.041; PLR: p = 0.021). NLR, PLR, SII, and MLR are associated with the presence of psoriasis. NLR and PLR serve as significant indicators of psoriasis severity. These novel CBC-derived markers constitute potential targets in the screening and monitoring of psoriasis.

Streptococcus mutans PrsA mediates AtlA secretion contributing to extracellular DNA release and biofilm formation in the pathogenesis of infective endocarditis.

The role of secretion chaperone-regulated virulence proteins in the pathogenesis of infective endocarditis (IE) induced by viridans streptococci such as Streptococcus mutans is unclear. In this study, we investigated the contribution of the foldase protein PrsA, a putative parvulin-type peptidyl-prolyl isomerase, to the pathogenesis of S. mutans-induced IE. We found that a prsA-deficient strain had reduced virulence in terms of formation of vegetation on damaged heart valves, as well as reduced autolysis activity, eDNA release and biofilm formation capacity. The secretion and surface exposure of AtlA in vitro was reduced in the prsA-deficient mutant strain, and complementation of recombinant AtlA in the culture medium restored a wild type biofilm phenotype of the prsA-deficient mutant strain. This result suggests that secretion and surface localization of AtlA is regulated by PrsA during biofilm formation. Together, these results demonstrate that S. mutans PrsA could regulate AtlA-mediated eDNA release to contribute to biofilm formation in the pathogenesis of IE.

Activation of Deoxyribonuclease I by Nicotinamide as a New Strategy to Attenuate Tetracycline-Resistant Biofilms of Cutibacterium acnes.

Biofilms of Cutibacterium (C.) acnes (formerly Propionibacterium acnes) are responsible for the persistence and antibiotic resistance of acne vulgaris. In addition to the standard treatments for acne vulgaris, a common adjunctive treatment is the topical administration of nicotinamide (NAM). However, the effects of NAM on biofilms of C. acnes have never been explored. This study comprehensively investigates the effects of NAM against biofilms of C. acnes using in vitro and in vivo approaches. The results showed that NAM potentiated the efficacy of suboptimal dosing of tetracycline against C. acnes. Moreover, NAM alone decreased the formation and increased the degradation of biofilms in C. acnes. The antibiofilm effect of NAM against C. acnes was further enhanced in combination with deoxyribonuclease (DNase) I, an enzyme with known antibiofilm properties. The computational molecular docking, surface plasmon resonance analysis, and enzymatic kinetic assay demonstrated that NAM binds to DNase I and accelerated its reaction. In conclusion, NAM activates DNase I to attenuate biofilms of C. acnes. This offers valuable insights into the strategies against biofilms that are worth elaborating on in other biofilm-related chronic cutaneous infections in the future.

Paired Transcriptomic and Proteomic Analysis Implicates IL-1ß in the Pathogenesis of Papulopustular Rosacea Explants.

Papulopustular rosacea (PPR) is a chronic inflammatory skin disease with limited treatment options. Although multiple pathways have been described to be upregulated in PPR, a mechanistic understanding of the key drivers and interaction between pathways in PPR pathology is lacking. In this study, we utilized PPR skin biopsy explants to integrate both differentially expressed genes and differentially expressed proteins in paired nonlesional and lesional PPR tissue (n = 5 patients). The results of this study identified 92 differentially expressed genes and 20 differentially expressed proteins between paired PPR lesional and nonlesional explants. MAPK and TNF signaling pathways were the most significantly upregulated pathways in PPR lesional tissue and aligned with differently expressed proteins identified in this study. Both MAPK and TNF signaling pathways highlighted IL-1ß as a potential central mediator for PPR pathogenesis. In support of this, stimulation of nonlesional explants with IL-1ß resulted in transcriptomic and proteomic profiles similar to those of lesional PPR. In this integrative transcriptomic and quantitative protein analysis, we identified several inflammatory genes, proteins, and pathways, which may be contributing to PPR, as well as highlighted a potential role of IL-1ß in driving inflammation in PPR.

Durvalumab-induced de novo annular psoriasiform drug eruption successfully treated with a combination of narrowband ultraviolet B phototherapy and topical treatment.

Immune checkpoint inhibitors, including anti-programmed death 1 and anti-programmed death ligand 1, have become prominent treatment options for various types of cancers. However, immune checkpoint inhibitors are associated with various cutaneous adverse events, one of which is psoriasiform drug eruption. Some cases of psoriasiform drug eruption can only be controlled through the cessation of immune checkpoint inhibitors and administration of systemic immunosuppressants, such as corticosteroids and methotrexate. However, no clear guideline is available on the management of this specific rash, and the use of systemic immunosuppressants is contraindicated in selected conditions. In this article, we report a case of annular psoriasiform drug eruption induced by an anti-programmed death ligand 1 monoclonal antibody, durvalumab. The patient responded well to the combination of phototherapy and topical treatment, which allowed continuation of durvalumab treatment without concomitant systemic immunosuppressants in a 2-year follow up.

Utility of Gram staining for diagnosis of Malassezia folliculitis.

Malassezia folliculitis (MalF) mimics acne vulgaris and bacterial folliculitis in clinical presentations. The role of Gram staining in rapid diagnosis of MalF has not been well studied. In our study, 32 patients were included to investigate the utility of Gram staining for MalF diagnosis. The final diagnoses of MalF were determined according to clinical presentation, pathological result and treatment response to antifungal agents. Our results show that the sensitivity and specificity of Gram staining are 84.6% and 100%, respectively. In conclusion, Gram staining is a rapid, non-invasive, sensitive and specific method for MalF diagnosis.

Meeting the Challenges of Acne Treatment in Asian Patients: A Review of the Role of Dermocosmetics as Adjunctive Therapy.

Conventional acne treatment presents several challenges such as intolerable side effects and antibiotic resistance. Dermocosmetic products may be used to reduce these unwanted effects. Dermocosmetics include skin cleansers, topical sebum-controllers, skin antimicrobial/anti-inflammatory agents, moisturizers, sunscreens, and camouflage products. Appropriate use of these products may help augment the benefit of acne treatment, minimize side effects, and reduce the need for topical antibiotics. In Asia, there is currently limited scientific data on the application and recommendations for dermocosmetic use in acne vulgaris (AV). This article reviews the evidence on dermocosmetics for AV and provides practice recommendations as discussed during the 4(th) Asia-Pacific Acne Leaders' Summit held in Bangkok, Thailand, on 7 and 8 February 2015. Through a premeeting survey, a series of plenary lectures, a stepwise program of discussion sessions, and Medline article review, the Expert Panel set forth relevant recommendations on the role of dermocosmetics as adjunct for treating AV in Asian patients.

CSE1L Links cAMP/PKA and Ras/ERK pathways and regulates the expressions and phosphorylations of ERK1/2, CREB, and MITF in melanoma cells.

The Ras/ERK (extracellular signal-regulated protein kinase) and cAMP/PKA (protein kinase A) pathways are essential for the transcriptional activities of CREB (cAMP response element binding protein) and MITF (microphthalmia-associated transcription factor) in melanogenesis and the progression of melanoma. However, the interaction between Ras/ERK and cAMP/PKA pathways in the melanogenesis and progression of melanoma is not fully known. Here, we report that CSE1L (chromosome segregation 1-like protein) regulates cAMP/PKA-induced CREB and MITF expressions as well as Ras-induced ERK1/2 phosphorylation. IBMX, a cAMP/PKA activator, treatment induced CSE1L phosphorylation and augmented Ras-induced ERK1/2 phosphorylation. CSE1L knockdown by CSE1L shRNA expression vectors inhibited Ras-induced ERK1/2 phosphorylation and melanogenesis in melanoma cells. CSE1L overexpression increased phospho-CREB expression; CSE1L knockdown also inhibited Ras-induced phospho-CREB, MITF, and tyrosinase expressions, regardless of the presence of IBMX. This study identifies CSE1L links and controls the Ras/ERK and cAMP/PKA pathways in the melanogenesis of melanoma cells. Melanomas frequently develop drug resistance via paradoxical activation of Ras/Raf/MEK/ERK or alternatively activated Ras/ERK and cAMP/PKA pathways. Thus CSE1L may be a potential target for treating melanomas that harbor Ras mutations or are resistant to drugs targeting Raf/MEK/ERK. © 2015 Wiley Periodicals, Inc.

Early decline in serum phospho-CSE1L levels in vemurafenib/sunitinib-treated melanoma and sorafenib/lapatinib-treated colorectal tumor xenografts.

BACKGROUND: Although targeted therapies have improved the clinical outcomes of cancer treatment, tumors resistance to targeted drug are often detected too late and cause mortality. CSE1L is secreted from tumor and its phosphorylation is regulated by ERK1/2. ERK1/2 is located downstream of various growth factor receptors and kinases, the targets of most targeted drugs. Serum phospho-CSE1L may be a marker for monitoring the efficacy of targeted therapy. METHODS: We used mice tumor xenograft model to study the assay of serum phosphorylated CSE1L for early detecting the efficacy of targeted drugs. The phosphorylation status of CSE1L in vemurafenib and sorafenib treated tumor cells were assayed by immunoblotting with antibody against phosphorylated CSE1L. RESULTS: Ras activation increased phospho-CSE1L expression in B16F10 melanoma cells. Vemurafenib and sorafenib treatment did not significantly reduce the total CSE1L levels; however, they inhibited ERK1/2 and CSE1L phosphorylation in A375 melanoma cells and HT-29 colorectal cancer cells. In the melanoma xenograft model, serum phospho-CSE1L level declined 5 days after vemurafenib/sunitinib treatment and 3 days after sorafenib/lapatinib treatment in the HT-29 colon cancer xenograft model. Vemurafenib/sunitinib and sorafenib/lapatinib treatments resulted in tumor regression. CONCLUSIONS: Our results indicated that serum phospho-CSE1L is useful for early detecting the efficacy of targeted therapy in initial treatment and for monitoring emerging secondary drug resistance to facilitate timely therapeutic decision making.

High expression of cytoplasmic phosphorylated CSE1L in malignant melanoma but not in benign nevi: phosphorylated CSE1L for the discrimination between melanoma and benign nevi.

Melanoma is difficult to treat when it has metastasized. Discrimination between melanoma and benign nevi in melanocytic lesions is crucial for identifying melanomas and consequently improving melanoma treatment and prognosis. The chromosome segregation 1-like (CSE1L) protein has been implicated in cancer progression and is regulated by phosphorylation by extracellular signal-regulated kinase 1/2 (ERK1/2) signaling, a critical pathway in melanoma progression. We studied phosphorylated CSE1L expression in human melanoma and benign nevi specimens. Immunohistochemistry with tissue microarray using antibody against phosphorylated CSE1L showed that melanomas exhibited considerable staining for phosphorylated CSE1L (100%, 34/34), whereas the benign nevi showed only faint staining (0%, 0/34). Melanomas mainly exhibited cytoplasmic phospho-CSE1L distribution, whereas the benign nevi mainly exhibited nuclear phospho-CSE1L distribution. Moreover, immunohistochemistry with anti-CSE1L antibody revealed that CSE1L mainly exhibited cytoplasmic/nuclear distribution and nuclear distribution was the dominant. Immunofluorescence with B16F10 melanoma cells showed cytoplasmic distribution of phospho-CSE1L and nuclear distribution of CSE1L. Our results indicated that nuclear CSE1L is mainly non-phosphorylated CSE1L and is involved in gene regulation and cytoplasmic CSE1L is mainly phosphorylated CSE1L and is involved in cytoplasmic signaling regulation in melanocytic tumorigenesis. Furthermore, immunohistochemical analysis of cytoplasmic phospho-CSE1L may aid in the diagnosis of melanoma.

Hepatitis B virus quantification and detection of YMDD mutants in a single reaction by real-time PCR and annealing curve analysis.

BACKGROUND: Long-term antiviral therapy, although effective for treatment of hepatitis B, might select the emergence of drug-resistant hepatitis B virus (HBV) mutants. Detection of HBV mutants and determination of viral titre are two crucial parameters for monitoring treatment response and occurrence of mutants. In this study, we take lamivudine resistance as an example to develop a method that can determine both parameters in a single-tube PCR reaction. METHODS: The method contained two consecutive steps: in the first step, real-time PCR was used for quantification; in the second step, a novel annealing curve analysis was used for detecting YMDD mutants. For accurate quantification, PCR primers and hybridization probes were chosen from highly conserved regions to ensure the equivalent amplification of all HBV genotypes. Within the sensor probe, there were signature nucleotide polymorphisms that could effectively differentiate YMDD mutants from wild type by distinct melting temperatures (Tm) values. The clinical applicability of the assay was tested in serial samples from 90 patients receiving lamivudine treatment. RESULTS: This assay could readily differentiate YMDD, YIDD and YVDD mutants by their distinct Tm values. The quantification results showed great consistency in a linear range from 10(3) to 10(11) copies/ml. Moreover, this assay could detect YMDD mutants accounting for < or = 10% of the total viral population. Its clinical feasibility has been verified in primary specimens. CONCLUSIONS: The newly designed YMDD detection method is simple, sensitive, cost-effective, time-saving and provides a useful tool for follow-up of patients treated with lamivudine or other antiviral drugs.