Comparison of tretinoin 0.05% cream and 3% alcohol‐based salicylic acid preparation in the treatment of acne vulgaris

Background  No single effective topical treatment is available for treating all pathogenic factors causing acne vulgaris (AV). Salicylic acid (SA), tretinoin (all‐TRA) and clindamycin phosphate (CDP) are known to to be effective agents depending on their comedolytic and anti‐inflammatory properties. Objective  To compare the efficacy and tolerability of SA and CDP combination (SA + CDP) with all‐TRA and CDP (all‐TRA + CDP) in patients with mild to moderate facial AV. Methods  Forty‐six patients aged between 18 and 35 years were enrolled in a 12‐week prospective, single‐blind, randomized and comparative clinical study. Efficacy was assessed by lesion counts, global improvement, quality of life index and measurement of skin barrier functions. Local side effects were also evaluated. Results  Both combinations were effective in reducing total lesion (TL), inflammatory lesion (IL) and non‐inflammatory lesion (NIL) counts and showed significant global improvement as evaluated by the investigator. At the end of the study, there was no significant difference between the two groups in terms of all lesion counts. In addition, TL counts decreased faster in the all‐TRA + CDP group compared with those in the SA + CDP group, with a significant difference between the two groups occurring as early as 2 weeks. Safety evaluations demonstrated that the incidence of mild to moderate side effects generally peaked at week 2 and declined gradually thereafter. Both combinations did not have an effect on stratum corneum hydration, although skin sebum values decreased with SA + CDP treatment. Conclusions  Combination of SA + CDP and all‐TRA + CDP was effective in decreasing lesion counts and well tolerated with minimal local cutaneous reactions in patients with mild to moderate AV.     

S‐allyl cysteine inhibits TNF‐α‐induced inflammation in HaCaT keratinocytes by inhibition of NF‐ κB‐dependent gene expression via sustained ERK activation

Tumor necrosis factor‐α (TNF‐α)‐induced keratinocyte inflammation plays a key role in the pathogenesis of multiple inflammatory skin diseases. Here we investigated the anti‐inflammatory effect of S‐allyl cysteine (SAC) on TNF‐α‐induced HaCaT keratinocyte cells and the mechanism behind its anti‐inflammatory potential. SAC was found to inhibit TNF‐α‐stimulated cytokine expression. Further, SAC was found to inhibit TNF‐α‐induced activation of p38, JNK and NF‐κB pathways. Interestingly, SAC was found to differentially regulate ERK MAP kinase in cells. TNF‐α‐induced transient ERK activation and SAC treatment resulted in sustained ERK activation both in the presence and absence of TNF‐α. Additionally, SAC failed to inhibit the TNF‐α‐induced expression of the pro‐inflammatory cytokines TNF‐α and IL‐1β when cells were treated with the MEK inhibitor PD98059, suggesting that the anti‐inflammatory effect of SAC is via sustained activation of the ERK pathway. Since ERK activation has been reported to negatively regulate NF‐κB‐driven gene expression and we find that SAC activates ERK and negatively regulates NF‐κB, we investigated whether there existed any crosstalk between the ERK and the NF‐κB pathways. NF‐κB‐dependent reporter assay, visualization of the nuclear translocation of NF‐κB‐p65 subunit and determination of the cellular levels of I‐κB, the inhibitor of NF‐κB, revealed that SAC inhibited TNF‐α‐induced NF‐κB activation, and PD98059 treatment reversed this effect. These results collectively suggest that SAC inhibits TNF‐α‐induced inflammation in HaCaT cells via a combined effect entailing the inhibition of the p38 and the JNK pathways and NF‐κB pathway via the sustained activation of ERK.     

Efficacy and safety of topical clascoterone cream for treatment of acne vulgaris: A systematic review and meta‐analysis of randomized placebo‐controlled trials

To systematically and meta‐analytically pool evidence from randomized placebo‐controlled trials that examined the efficacy and safety of topical clascoterone cream in patients with acne vulgaris. Four databases were screened from inception to 10 October 2020. Included studies were assessed for risk of bias. Efficacy outcomes included investigator's global assessment (IGA) treatment success and absolute change in inflammatory lesion counts (ILCs) and noninflammatory lesion counts (NILCs). Safety outcomes included the proportion of patients with any treatment‐emergent adverse event (TEAE) as well as incidence of any TEAE, serious adverse events (AEs), AEs related to study drug, AEs leading to study drug discontinuation, nasopharyngitis, headache, oropharyngeal pain, and vomiting. Dichotomous data were analyzed using the risk ratio (RR) and 95% confidence interval (95% CI) whereas continuous data were analyzed using the mean difference (MD) and 95% CI. Review Manager Software version 5.4.1 was used for statistical analysis. Five clinical trials, comprising 2457 patients (1357 and 1100 patients received clascoterone and placebo, respectively) were included. Studies revealed an overall low risk of bias. Clascoterone significantly increased IGA success rates (RR = 2.87, 95% CI [2.11, 3.89], P < .001) and decreased NILCs (MD = ?5.64, 95% CI [?8.41, ?2.87], P < .01) without substantially impacting the ILCs (MD = ?1.82, 95% CI [?5.06, 1.43], P = .27). No significant differences were noted between both groups for all safety outcomes, except for nasopharyngitis which was significantly lower in the clascoterone group (RR = 0.47, 95% CI [0.27, 0.83], P = .01). Topical clascorterone cream is safe and effective in the treatment of acne vulgaris.     

Mutually enhancing anti‐inflammatory activities of dimethyl fumarate and NF‐κB inhibitors – implications for dose‐sparing combination therapies

Fumaric acid esters, dimethyl fumarate (DMF) in particular, have been established for the therapy of psoriasis and, more recently, multiple sclerosis. In the light of therapy‐limiting dose‐dependent side effects, such as gastrointestinal irritation, reducing the effective doses of FAE is a worthwhile goal. In search of strategies to maintain the anti‐inflammatory activity of DMF at reduced concentrations, we found that NF‐κB inhibition augmented key anti‐inflammatory effects of DMF in two complementary experimental settings in vitro. At non‐toxic concentrations, both proteasome inhibition with bortezomib as well as blocking NF‐κB activation through KINK‐1, a small molecule inhibitor of IKKβ‐profoundly enhanced DMF‐dependent inhibition of nuclear NF‐κB translocation in TNFα‐stimulated human endothelial cells. This resulted in significant and selective co‐operative down‐regulation of endothelial adhesion molecules crucial for leucocyte extravasation, namely E‐selectin (CD62E), VCAM‐1 (CD106) and ICAM‐1 (CD54), on both mRNA and protein levels. Functionally, these molecular changes led to synergistically decreased rolling and firm adhesion of human lymphocytes on TNF‐activated endothelial cells, as demonstrated in a dynamic flow chamber system. If our in vitro findings can be translated into clinical settings, it is conceivable that anti‐inflammatory effects of DMF can be achieved with lower doses than currently used, thus potentially reducing unwanted side effects.     

Z‐ligustilide ameliorated ultraviolet B‐induced oxidative stress and inflammatory cytokine production in human keratinocytes through upregulation of Nrf2/HO‐1 and suppression of NF‐κB pathway

Ultraviolet B (UVB), a harmful environmental factor, is responsible for a variety of skin disorders including skin inflammation through reactive oxygen species (ROS) and inflammatory mediator production. Here, we investigated the effect of Z‐ligustilide (Z‐lig), an active ingredient isolated from the medicinal plants Cnidium officinale and Angelica acutiloba, on UVB‐induced ROS generation and inflammatory mediator production in normal human epidermal keratinocytes (NHEKs) as well as its underlying mechanisms. Z‐lig significantly rescued UVB‐induced NHEKs damage in a dosage‐dependent manner. Pretreatment of NHEKs with Z‐lig inhibited UVB‐induced ROS production in NHEKs. Both silencing the nuclear factor E2‐related factor 2 (Nrf2) and the supplement of tin protoporphyrin IX (SnPP), a haeme oxygenase‐1 (HO‐1) inhibitor, cancelled the inhibitory effect of Z‐lig on UVB‐induced ROS upregulation in NHEKs. Moreover, pretreatment of NHEKs with Z‐lig reduced UVB‐induced nuclear factor kappa B (NF‐κB)‐dependent inflammatory mediators (IL‐6, IL‐8 and MCP‐1) production at both mRNA and protein level. In the presence of Z‐lig, UVB‐induced NF‐κB subunit p65 nuclear translocation was abolished, and the IκBα degradation was suppressed. Taken together, these findings suggest that Z‐lig can suppress UVB‐induced ROS generation through Nrf2/HO‐1 upregulation and inflammation by suppressing the NF‐κB pathway, suggesting that Z‐lig may be beneficial in protecting skin from UVB exposure.     

FGFR2 signaling and the pathogenesis of acne

Acne in Apert syndrome and unilateral segmental acneiform nevus are associated with mutations of fibroblast growth factor receptor 2 (FGFR2), which are likely to be involved in the pathogenesis of acne. Translational animal and cellular models, developmental biology studies and clinical observations have contributed to our understanding of FGF‐FGFR2 signaling in the pilosebaceous follicle. The importance of FGF‐FGFR2 signaling in mesenchymal‐epithelial interaction for skin appendage formation, pilosebaceous follicle homeostasis, come‐dogenesis and sebaceous gland proliferation is explored. Overstimulation of FGFR2 signaling with increased expression of interleukin‐1α explains acne in Apert syndrome und nevus comedonicus. Androgen‐mediated up‐regulation of FGFR2 signaling could be the initiating signal in the pathogenesis of acne. The gain of function FGFR2 mutations in Apert syndrome and unilateral acneiform nevus are most helpful model diseases for uncovering the fundamental process of androgen‐dependent mesenchymal‐epithelial FGF‐FGFR2 signaling in acne in Apert syndrome, nevus comedonicus and acne vulgaris.     

Fatty acid compositions of triglycerides and free fatty acids in sebum depend on amount of triglycerides,and do not differ in presence or absence of acne vulgaris

To clarify the influence of the fatty acid composition of sebum in acne vulgaris, we investigated the amounts and fatty acid compositions of triglycerides (TG) and free fatty acids (FFA), and the amounts of cutaneous superficial Propionibacterium acnes in acne patients and healthy subjects. The foreheads of 18 female patients, 10 male patients, 10 healthy females and 10 healthy males were studied in a Japanese population. There were significant differences in the amounts of sebum, TG and cutaneous superficial P. acnes, as well as the fatty acid compositions of TG and FFA between acne patients and healthy subjects in females. Their fatty acid compositions were correlated with the amount of TG with or without acne. It was clarified that the fatty acid compositions of TG and FFA depended on the amount of TG, and there were no differences in the fatty acid composition in the presence and absence of acne.     

IL‐17F regulates psoriasis‐associated genes through IκBζ

Psoriasis is a common chronic inflammatory and immune‐mediated skin disease. Antagonists of TNF‐α and, recently, IL‐17 have proven to be highly effective in the treatment for psoriasis; however, the molecular mechanisms involved in the pathogenesis of psoriasis are poorly understood. Recently, we presented evidence that IκBζ is a key regulator in the development of psoriasis through its role in mediating IL‐17A‐driven effects. Like IL‐17A, IL‐17F is produced by a variety of immune cells, and the expression of IL‐17F is increased in psoriatic skin. The purpose of this study was to characterize the role of IL‐17F in the regulation of IκBζ expression and to investigate whether IL‐17F regulates psoriasis‐associated genes in human keratinocytes through IκBζ. Here, we demonstrate that IL‐17F stimulation induces IκBζ expression at both the mRNA and the protein levels in normal human keratinocytes. Moreover, silencing IκBζ by siRNA revealed that IκBζ is a key regulator of specific IL‐17F‐inducible psoriasis‐associated genes and proteins, including DEFB4/hBD2, S100A7, CCL20, IL‐8 and CHI3L1. In addition, IL‐17F‐induced IκBζ expression is mediated by a mechanism involving the p38 MAPK and NF‐κB signalling pathways, as shown by the clear reduction in IL‐17F‐mediated expression of IκBζ during chemical inhibition of these two signalling pathways. In summary, we present IκBζ as a novel key regulator of IL‐17F‐driven effects in psoriasis. Thus, antagonists to IκBζ could potentially provide a more targeted approach for treating psoriasis as well as for treating the other inflammatory and immune‐mediated diseases for which IL‐17‐targeting drugs have recently been approved.     

Intercellular pathway through hyaluronic acid in UVB‐induced inflammation

Ultraviolet B (UVB) radiation induces inflammation in the skin specifically at the site of exposure. We unexpectedly found that UVB‐induced inflammation was not induced in gp91phox‐depleted mice. To test whether gp91phox is directly involved in UVB‐induced inflammation, neutrophil‐ and hyaluronic acid–depleted mice were also irradiated and examined for their response. Hyaluronic acid–depleted mice showed strongly inhibited UVB‐induced inflammation, but the neutrophil‐depleted mice did not exhibit any suppressed UVB‐induced inflammation. To elucidate the pathway by which UVB irradiation induced inflammation, we examined the expression of nucleotide‐binding domain, leucine‐rich‐containing family, pyrin domain‐containing‐3 (NLRP3) and caspase‐1 in the mouse skin. An increase in the expression of NLRP3 and caspase‐1 was seen following the UVB irradiation of C57BL mice; however, the UVB‐irradiated gp91phox‐knockout (gp91phox^?/?) mice did not have this increase in expression. Furthermore, the plasma IL‐1β level increased after the UVB irradiation in C57BL mice, but there was no change in the gp91phox^?/? mice. These results clearly indicate that nicotinamide adenine dinucleotide phosphate oxidase is activated by gp91phox, which is expressed on the surface in response to the increased expression of hyaluronic acid induced by UVB irradiation, and as result, the generation of reactive oxygen species (ROS) increases. This ROS activate NLRP3, and NLRP3 leads to the production of caspase‐1, which subsequently increases IL‐1β, thereby finally inducing inflammation. It is thought that this system may play an important role in the damage and ageing of skin, and further studies are necessary to confirm these finding.     

NF‐κB is involved in inhibition of lipoxin A4 on dermal inflammation and hyperplasia induced by mezerein

Please cite this paper as: NF‐κB is involved in inhibition of lipoxin A₄ on dermal inflammation and hyperplasia induced by mezerein. Experimental Dermatology 2010; 19 : e286–e288. Abstract: The mechanisms by which lipoxin A₄ (LXA₄) inhibit skin inflammation remain unclear. In the present studies, the ear inflammatory model was induced by topical application of mezerein. Treatment of the mouse ear with LXA₄ exhibited the inhibitory effects on oedema, neutrophil infiltration, vascular permeability, expressions of interleukin (IL)‐1, IL‐6 and IL‐8 mRNA, DNA‐binding activity of nuclear factor‐κB (NF‐κB), and on dermal hyperplasia. NF‐κB reporter activities and nuclear translocations of NF‐κB p65 in cultured keratinocytes stimulated by mezerein were inhibited by pretreatment of the cells with LXA₄. LXA₄ reduced degradation, but not phosphorylation of IκBα in cultured keratinocytes stimulated by mezerein, suggesting that LXA₄‐attenuated IκBα degradation may restore the mezerein‐blocked inhibitory effects of IκB on nuclear translocation and DNA‐binding activity of NF‐κB. Our results demonstrated that LXA₄ displays the anti‐inflammatory and anti‐proliferative role on ear inflammatory model induced by mezerein and these effects were related with downregulation of DNA‐binding activity of NF‐κB.