Chronic Skin Research Articles

Immune cell activity during anti-TNF treatment in patients with psoriasis and psoriatic arthritis.

Psoriasis is a chronic, inflammatory skin disease characterized by a dysregulated immune response and systemic inflammation. Up to one-third of patients with psoriasis have psoriatic arthritis (PsA). Targeted treatment with antibodies neutralizing tumor necrosis factor (TNF) can ameliorate both diseases. We here explored the impact of long-term infliximab treatment on the composition and activity status of circulating immune cells involved in chronic skin and joint inflammation. Immune cells were analyzed by multicolor flow cytometry. We measured markers of immune activation in peripheral blood mononuclear cell (PBMC) populations in 24 infliximab-treated patients with psoriasis/psoriatic arthritis compared to 32 healthy controls. We observed a significant decrease in the frequency of both peripheral natural killer (NK) cells and their subset CD56dimCD16+ NK cells in PsA compared to healthy controls and patients with psoriasis. The latter had a strong positive correlation with PASI in these patients, while CD56brightCD16- NK cells were negatively correlated with PASI. In addition, we observed an upregulation of CD69+ intermediate CD14+CD16+ and CD69+ classical CD14+CD16- monocytes in PsA and increased activity of CD38+ intermediate CD14+CD16+ monocytes in patients with psoriasis. Compared to healthy controls, psoriasis patients demonstrated shifts of the three B cell subsets with a decrease in transitional CD27-CD38high B cells. Our exploratory study indicates a preserved pathophysiological process including continuous systemic inflammation despite clinical stability of the patients treated with infliximab.

Top weapons in skin aging and actives to target the consequences of skin cell senescence.

Skin aging has long been considered a purely cosmetic problem. However, as life expectancy increases, skin aging is taking on a functional dimension that goes beyond cosmetics and appearance. Preventive or therapeutic strategies are needed to target cellular senescence, a key process underlying the alterations in skin function and appearance that occur with aging, as well as to address the age-related skin changes associated with 'dermatoporosis' and chronic skin insufficiency/fragility syndrome. Thus, given the need for effective anti-aging products that improve both the appearance and function of the skin, it is essential to distinguish active ingredients that have been proven to be effective, among the large number of available over-the-counter cosmeceuticals. This brief review focuses on a core group of topical actives, describing their clinical effects on senescence and aging, and their molecular mechanisms of action. These actives include hyaluronic acid, which has hydrating and viscoelastic properties and has been shown to reduce skin atrophy; retinaldehyde, which activates retinoid receptors and increases cutaneous elasticity; vitamins C and E, which provide stable oxidative protection; and niacinamide, which reduces inflammation and mitigates the effects of senescence.

Elevated serum vasohibin-1 levels in atopic dermatitis: Implications for disease chronicity.

Atopic dermatitis (AD) is often characterized by chronic skin changes of dermal fibrosis, typically regulated by inflammatory and angiogenic factors. However, the significance of angiogenesis inhibitory factors in the development of AD is poorly understood. The present study investigated the potential role of an angiogenesis inhibitory factor, vasohibin-1 (VASH1), in AD by evaluating serum and skin VASH1 levels and their correlation with clinical features. The results showed that VASH1 expression levels in both the serum and skin of patients with AD were significantly elevated compared to healthy controls. Immunohistochemical staining of AD skin showed increased VASH1 expression in dermal vascular endothelial cells. Notably, there was a significant correlation between serum VASH1 levels and disease duration as well as VASH1 and vascular endothelial growth factor A expression levels in the skin tissue of patients with AD. These results may suggest a pathogenesis of increased angiogenesis and associated elevated inhibitory processes accompanying inflammation in the chronic phase of AD.

Blepharochalasis and Lichen Planus Pigmentosus: A Very Rare Association

Abstract Blepharochalasis syndrome is a condition of the eyelids consisting of episodic inflammation and chronic skin changes. It is usually bilateral and tends to manifest in the upper eyelids. But, there are cases of unilateral presentation also which exclusively affects the lower eyelids. There are multiple theories regarding the etiology of blepharochalasis. Blepharochalasis is believed to be a manifestation of angioneurotic edema. Hormonal changes may play an important role in the disease process. Immunohistochemical analysis of excised eyelid skin has demonstrated the presence of IgA in several studies. These findings suggest that there may be a concomitant inflammatory process accompanying the extravasations’ of fluid and localized edema occurring at the capillary level. Blepharochalasis might also present as part of systemic disease. The disease, lichen planus pigmentosus, is a variant of lichen planus and has also been noted the presence of IgA and IgG along with complement C3 in the epidermal cells in several studies.

Lichen planus: A Systematic Review

Lichen planus (LP) is a chronic skin, mucous membrane, and nail disease. Lichen planus is a rare skin condition occurring in less than 1% of the general population, affecting both children and adults. Oral lichen planus (OLP) involvement is much more common. It is an autoimmune disease caused by T lymphocytes, with epigenetic factors playing a significant role in the development of autoimmune skin diseases. MicroRNAs (miRNAs), a group of non-coding RNAs, play a substantial role in regulating the immune response.1 The etiology of lichen planus in not fully understood. It can be triggered by antihypertensive drugs, beta-blockers, infections, viral hepatitis, psychological stress, and others. Cases of lichen planus appearing after recovering from COVID-19 have been reported, as well as a significant increase in cases after COVID-19 vaccination.2–5 Diagnosis is based on clinical presenstation and characteristic histopathological findings. The disease is often self-limiting, accompanied by persistent itching and painful erosions of the mucous membrane, affecting the patient’s quality of life and mental well-being. First-line treatments inculde topical corticosteroids and/or oral corticosteroids. There are reports of new potential treatments, such as biologic drugs (anti-IL12/13, anti-IL17) and Janus kinase inhibitors. Consequently, a dramatic change in lichen planus treatment can be expected in the near future. The majority of patients suffering from lichen planus develop metabolic syndrome which is the cause of other diseases. This article provides a comprehensive overview of current knowledge about lichen planus and its variants.

Mycobacterium marinum: A Case-Based Narrative Review of Diagnosis and Management.

Skin and soft tissue infections caused by non-tuberculous mycobacteria are occurring more frequently in recent years. However, chronic skin and soft tissue lesions present a challenge for clinicians, as the diagnostic work-up and definitive diagnosis require knowledge and available laboratory resources. We present here the case of a 66-year-old male patient who presented with painful abscess-like nodules on his right hand and forearm, which worsened after treatment with an anti-TNF-a agent. The fluid specimen taken from the lesion was positive for mycobacteria according to the acid-fast stain. Mycobacterium marinum was identified, first by next-generation sequencing and finally grown on culture, after eight weeks. Acknowledging the complexity of diagnosing and managing infections by non-tuberculous mycobacteria, and especially Mycobacterium marinum, we provide a review of the current epidemiology, clinical characteristics, diagnosis and management of Mycobacterium marinum infection.

The Presence and Impact of Bacteria and Biofilms in Chronic Skin and Systemic Diseases

This will be an overview of our studies on biofilms and the diseases with which they are associated. Where possible, it will include the microbes that create these biofilms, their locations in the body, and their impact on the innate and adaptive immune systems. It will include all the diseases which we have recently classified as eczema in addition to those previously considered as such. It will also include psoriasis, tinea versicolor, leprosy, tertiary Lyme disease and Alzheimer’s disease, the deposition diseases (arteriosclerosis, gout pretibial myxedema), the necrobiotic granulomas (granuloma annulare, rheumatoid nodules, and necrobiosis lipoidica), molluscum contagiosum and squamous cell carcinoma in situ in pigmented transplant patients. Consequently, many chronic skin and systemic diseases have been shown to be biofilm diseases. This implies that these disorders have a large, often determinative microbiological component. Where known, the mechanism whereby these biofilms interact with the immune system will be discussed

Contrasting between Atopic Dermatitis and Psoriasis in the Quality of Life Impact and the Prevalence of Psychiatric Disorders

As chronic inflammatory skin conditions, psoriasis and atopic dermatitis have both been associated with significant psychosocial comorbidities. However, the similarities and differences between the two in the manifestation of psychologic/psychiatric sequalae have not been reviewed. We reviewed the current literature comparing these two skin conditions and determined that there are potentially notable differences in psychiatric impact between psoriasis and atopic dermatitis patients. For example, patients with atopic dermatitis appears to have more issues with attention deficit hyperactive disorder (ADHD) and conduct disorder while psoriasis is associated more with suicidal acts. We propose that these may stem from the different ages of onset, which subsequently influences how the psychological impact manifests within the individual.

Stigma, psychosocial and economic effects of yaws in the Philippines: an exploratory, qualitative study

BackgroundYaws is a chronic, non-venereal, highly contagious skin and bone infection affecting children living in impoverished, remote communities and caused by Treponema pallidum subspecie pertenue. Social stigma and economic losses due to yaws have been reported anecdotally in the Southern Philippines but have not been well-documented.ObjectiveTo describe and compare the psychological, social, and economic effects of yaws from the perspective of patients, contacts, and key informants in two areas of the Philippines.Materials and methodsYaws and contacts were identified through clinicoseroprevalence surveys conducted in the Liguasan Marsh area, Mindanao, Southern Philippines in 2017 and among the Aetas, an indigenous people community in Quezon province, Luzon region in 2020. Skin examinations and serologic tests confirmed the diagnosis of active, latent, or past yaws among the children and adults. Trained health personnel conducted in-depth interviews of those affected by yaws and their guardians, household contacts, and key informants, such as health workers regarding their perceptions, feelings, health-seeking behaviors, and effects of yaws on their lives.ResultsA total of 26 participants were interviewed: 17 from Mindanao and 9 from Luzon. Aside from the physical discomforts and embarrassment, yaws was considered stigmatizing in Mindanao, because positive non-treponemal tests or treponemal antibody tests were associated with syphilis and promiscuity. These have led to loss of employment and income opportunities for adults with latent or past yaws. In contrast, the Aetas of Luzon did not perceive yaws as stigmatizing, because it was a common skin problem. Plantar yaws interfered with the Aeta’s gold panning livelihood due to the pain of wounds.ConclusionsYaws is not merely a chronic skin and bone disease. It can lead to significant psychosocial and economic problems as well. Yaws is a generally forgotten disease in the Philippines. There is no yaws surveillance and control program. Treatments are not readily available for the populations affected, thus perpetuating the infection and negative effects.Significance of studyThis is the first study to document the psychosocial and economic effects of yaws among Filipinos. Information campaigns about yaws and a yaws control program are needed to reduce stigma and discrimination.

Study protocol: assessing SleeP IN infants with early-onset atopic Dermatitis by Longitudinal Evaluation (The SPINDLE study)

BackgroundAtopic dermatitis (AD) is the most common chronic inflammatory skin condition in childhood. Most (50-60%) children with AD report sleep disturbance, which is secondary to itch, dry skin, inflammation, and abnormal circadian rhythm. Sleep is essential for brain development, learning, and growth. Sleep disruption in early life is associated with cognitive and psychological dysfunction in later life. The aim of this study is to describe in detail the sleep architecture of infants with early-onset atopic dermatitis (AD), compared to controls, by using EEG polysomnography, sleep actigraphy, and parental reporting.MethodsThis observational study will recruit six- to eight-month old infants with moderate to severe AD and age-matched control infants who do not have AD. At six-eight months diurnal sleep electroencephalography and polysomnography will be performed in our research center. Nocturnal sleep actigraphy will be performed at home for five consecutive nights at six-eight months and 12 months. Between six and 12 months, monthly questionnaires will capture data on quantitative sleep and parental sleep. Skin barrier and immune profiles will be captured at six-eight and 12 months. AD will be assessed using standardized severity assessment tools and treated according to protocol. A neurodevelopmental assessment will be performed at 18 months to assess cognition and behaviour. An estimated sample size of 50 participants in each group is required to power the primary outcome of disturbed macrostructure of sleep and secondary outcomes of disturbed microstructure of sleep, and disturbed parental sleep, assuming an attrition rate of 60%. Potential confounding factors which will be controlled for in the data analysis will include parental educational level, parental depression, feeding practice, and number of siblings.DiscussionThis study will provide a rich analysis of sleep in infants with AD in the first year of life using detailed electroencephalography, novel actigraphy techniques, and longitudinal parent-reported data. It may provide guidance on the optimal treatment of AD to prevent or reduce sleep disruption.Trial registrationclinicaltrials.govNCT05031754, retrospectively registered on September 2nd, 2021.

Antipsoriatic Potential of Quebecol and Its Derivatives.

Psoriasis is a chronic inflammatory skin disease mainly characterized by the hyperproliferation and abnormal differentiation of the epidermal keratinocytes. An interesting phenolic compound, namely quebecol (2,3,3-tri-(3-methoxy-4-hydroxyphenyl)-1-propanol) (compound 1, CPD1), was isolated from maple syrup in 2011 and was recently synthesized. Quebecol and its derivatives ethyl 2,3,3-tris(3-hydroxy-4-methoxyphenyl)propenoate (compound 2, CPD2) and bis(4-hydroxy-3-methoxyphenyl)methane (compound 3, CPD3) have shown antiproliferative and anti-inflammatory potential, making them promising candidates for the treatment of psoriasis. This study aimed to evaluate the antipsoriatic potential of quebecol and its derivatives on psoriatic skin substitutes produced according to the self-assembly method. A sulforhodamine B (SRB) assay determining the concentration that inhibits 20% of cell growth (IC20) was performed for CPD1, CPD2 and CPD3, and their IC20 values were 400, 150 and 350 μM, respectively. At these concentrations, cell viability was 97%, 94% and 97%, respectively. The comparative control methotrexate (MTX) had a cell viability of 85% at a concentration of 734 μM. Histological analyses of psoriatic skin substitutes treated with CPD1, CPD2 and CPD3 exhibited significantly reduced epidermal thickness compared with untreated psoriatic substitutes, which agreed with a decrease in keratinocyte proliferation as shown by Ki67 immunofluorescence staining. The immunofluorescence staining of differentiation markers (keratin 14, involucrin and loricrin) showed improved epidermal differentiation. Taken together, these results highlight the promising potential of quebecol and its derivatives for the treatment of psoriasis.

Exploration of the Potential Mechanism of the Common Differentially Expressed Genes in Psoriasis and Atopic Dermatitis.

Backgrounds Psoriasis and atopic dermatitis are two common chronic inflammatory skin diseases that enormously deteriorate the psycho-physical and socio-economic condition of the patients. Although differential immune responses have been found to operate in the pathomechanisms of atopic dermatitis and psoriasis, the epidermal keratinocytes are the major targets in both diseases, and sometimes, they show similar clinical presentations. The skin barrier, itching, and inflammation are current and future treatment targets for both of them, but the relevant shared mechanisms of the two diseases are far from understood. Methods The differential analyses of GSE14905 (psoriasis) and GSE32924 (atopic dermatitis) deposited in GEO database were conducted and obtained their differential expressed genes. Moreover, PPI, functional modules, GO, and KEGG enrichment analyses were used for the further analysis. The mouse models of psoriasis and atopic dermatitis were established, and then, RT-qPCR and Western blotting assay were performed to check the abundant changes of hub genes. Results There are 732 differentially expressed genes in psoriasis versus nonlesional skin samples. Besides, 611 differentially expressed genes were identified in atopic dermatitis versus nonlesional skin data sets. Based on these differentially expressed genes, we predicted their joint and individual protein-protein interaction networks and functional modules in both psoriasis and atopic dermatitis. Through the PPI network of genes, we calculated the hub nodes and do the GO and KEGG enrichment analysis of overlapped genes of psoriasis and atopic dermatitis, which suggested there were some terms like “positive regulation of interleukin-12 production,” “centromeric region,” and “TNF signaling pathway.” Conclusion We constructed the predicted PPI networks and functional modules related to psoriasis and atopic dermatitis and distinguished the key candidate target genes CXCL8, STAT1, and MMP9 in the diagnosis and therapy of similar pathogenesis.

The efficacy and safety of Longmu Tang granule for the treatment of atopic dermatitis: study protocol for a single-centred, double-blinded, randomised, placebo-controlled trial

BackgroundAtopic dermatitis (AD) is a chronic relapsing skin disease that has long-term physical and mental health impacts on children with this condition. Current treatments mainly include anti-inflammatory, antibacterial, and anti-allergic interventions, systemic therapy, and recently emerging target-focused agents. However, these treatments have limited effectiveness and unwanted side effects. The use of traditional Chinese medicine (TCM) in the treatment of AD has a long history, with promising efficacies, low toxicity, and improvements in the quality of life of patients with AD. Longmu Tang granule, a TCM, has been used to effectively treat AD since 2008 through doctors’ prescriptions. To scientifically evaluate the clinical efficacy and safety of Longmu Tang granule, we proposed to launch a single-centred, double-blinded, randomised, placebo-controlled trial.MethodsIn this single-centred, double-blinded, randomised, placebo-controlled clinical trial conducted at Xiyuan Hospital of China Academy of Chinese Medical Sciences, a total of 60 participants will be randomly assigned (1:1) to receive the Longmu Tang granule or placebo granule for 8 weeks. The primary outcome will be evaluated using the index of Scoring Atopic Dermatitis. The secondary outcomes will be evaluated using the Children’s Dermatology Life Quality Index and the number cancellation test. The mechanistic evidence will be the serum levels of inflammatory cytokines, including immunoglobulin E, tumour necrosis factor-α, interleukin-1, and interleukin-6.DiscussionThe results of this trial will provide evidence of the efficacy and safety of the Longmu Tang granule and prove its anti-inflammatory action in patients with AD.Trial registrationChinese Clinical Trial Registry Chictr.org ID: ChiCTR2100041591. Registered on 1 January 2021

Treatment of Moderate to Severe Psoriasis during the COVID-19 Pandemic: Lessons Learned and Opportunities.

Since the beginning of the coronavirus disease 2019 (COVID-19) pandemic, clinicians have been overwhelmed by questions beyond the SARS-CoV-2 infection itself. In dermatology practice, clinicians have been facing difficulties concerning therapeutic management of chronic immune-mediated skin disease, above all psoriasis. Major challenges arisen were to understand the role of immunosuppression or immunomodulation on COVID-19 evolution, the benefit/risk ratio related to discontinuation or modification of ongoing treatment, and the appropriateness of initiating new treatments, the optimization of timing in vaccination administration to patients under immunomodulatory treatments, and finally how to find new strategy of patients’ management through remote assistance. In this comprehensive review, we present the current evidence about the course and management of psoriasis during the COVID-19 pandemic. The general message from dermatologists was that data did not suggest that having PSO or its treatment significantly increased risk of SARS-CoV-2 infection or more severe COVID-19 course, the vaccination is highly recommended in all psoriatic patients, beyond ongoing treatment, and that the telehealth experience was a success overall.

Is psoriasis therapy an art based on experience?

Psoriasis is a chronic immune-associated skin disease of a multifactorial nature with phenotypic diversity in the general population, as well as a large number of comorbid diseases in patients. The generalized pustular psoriasis, historically was considered one of the variants of the course of psoriasis. Today some authors classify it as a genetically different condition combined with a plaque psoriasis. The selected tactics of psoriasis therapy can become a trigger for the manifestation of a pustular form. Despite the availability of modern data on the immunopathogenesis of the disease, there are no standardized methods of treatment that can take into account the individual characteristics of patients, which is doubly important in pediatric practice, since the arsenal of drugs approved for use is limited. We demonstrate the clinical case of a patient with progressive plaque psoriasis, earlier getting systemic and topical corticosteroids for a long time. This therapy did not allowed to take the course of the disease under control, even more it caused appearance of complications. Our clinical example from practice allows us to focus on the problem of complications of classical therapy for psoriasis and the intricacies of prescribing both topical and systemic drugs. Systemic therapy requires the development of algorithms based on objective diagnostic criteria and the results of studies on the effectiveness and safety of modern drugs in pediatric practice.

Analysis of the Vulvar Skin Microbiota in Asymptomatic Women and Patients With Vulvar Lichen Sclerosus Based on 16S rRNA Sequencing

Vulvar lichen sclerosus (VLS) is a chronic inflammatory skin disease that brings life-long and psychological distress to patients. It remains unclear whether this condition is related to changes in the skin microbial community. The aim of this study was to evaluate the compositional characteristics of the vulvar skin microbiota between VLS patients and asymptomatic postmenopausal women. We included 60 cases of postmenopausal patients in the outpatient vulvar clinic of Peking University First Hospital from August 2020 to October 2020. Thirty-one patients were diagnosed with VLS by vulvar skin biopsy (VLS group), while 29 women were asymptomatic volunteers (control group). DNA was extracted from vulvar skin swabs of the VLS and control groups. The V3-V4 fragments of 16S rRNA were targeted for high-throughput sequencing and gene sequence analysis. The sequencing results were analysed by α diversity, β diversity, species composition, LEfSe analysis to compare the compositional differences of the vulvar skin microbiota between the two groups. Our study revealed that at the phylum level, patients with VLS had a lower relative abundance of Firmicutes (p < 0.0001) and a higher relative abundance of Proteobacteria than the control group (p < 0.0001). At the genus level, Lactobacillus spp. accounted for the largest proportion of the microflora in the asymptomatic controls, while the proportion of Prevotella spp. in the VLS group was the highest. In the VLS group, the relative abundance of Finegoldia spp., Ralstonia spp., Peptoniphilus spp., Anaerococcus spp., Campylobacter spp., Providencia spp. Kelbsiella spp., Ezakiella spp., and Escherichia-Shigella spp. was significantly increased compared with the control group. Although there was no significant difference in the α diversity of the vulvar skin microbiota, the β diversity differed significantly between the two groups.

Effective Primary Prevention of Atopic Dermatitis in High-Risk Neonates via Moisturizer Application: Protocol for a Randomized, Blinded, Parallel, Three-Group, Phase II Trial (PAF Study)

BackgroundAtopic dermatitis (AD) is a chronic and inflammatory skin disease that causes health-related burdens associated with pruritus and poor quality of life. Our previous study demonstrated that moisturizer (2e) application has a primary preventive effect on AD. However, this effect was not observed in recent randomized control trials. Thus, the ideal moisturizer type and application frequency for preventing AD development in infants remains unclear. We hypothesize that twice daily application of moisturizer is more effective than once daily application. We predict that applying sufficient amounts of high-quality moisturizer may be effective for preventing AD development in neonates and infants. Here, we describe a protocol for comparing the efficacy of twice daily and once daily application of Fam's Baby™ moisturizer and once daily application of 2e moisturizer for preventing AD in neonates.MethodsThis study is a single-center, three-parallel group, assessor-blind, superiority, individually randomized, controlled, phase II trial. Sixty newborns with at least one parent or sibling who has had AD is randomly assigned to application of Fam's Baby twice daily, Fam's Baby once daily, or 2e once daily in a 1:1:1 ratio until 32 weeks old. The primary outcome is the time to the first onset of AD during administration of the moisturizer.DiscussionThis is the first phase II randomized, controlled trial in Japan to estimate how effective the twice daily or once daily application of Fam's Baby moisturizer is in preventing AD compared to the once daily application of 2e moisturizer. In this study, we will use 2e once daily as a control to confirm the efficacy for primary prevention of AD as found in our previous trial. Based on the results of this study, we hope to conduct a phase III study to determine the optimal method for preventing AD via moisturizer application. Evaluation of application of moisturizers for preventing AD in this study is expected to contribute to a reduction in the prevalence of AD and a reduction in health care costs.Trial registrationJapan Registry of Clinical Trials (jRCT); ID: jRCTs031200070.

Searching for new therapeutic options for the uncommon pathogen Mycobacterium chimaera: an open drug discovery approach

SummaryBackgroundMycobacterium chimaera is a slowly growing non-tuberculous mycobacterium associated with outbreaks of fatal infections in patients after cardiac surgery, and it is increasingly being detected in patients with chronic lung conditions. M chimaera can cause disseminated disease, osteomyelitis, and chronic skin or soft-tissue infections. We aimed to find new inhibitory compounds and drug repurposing opportunities for M chimaera, as current therapeutic options often result in poor outcomes.MethodsIn an open drug discovery approach, we screened the Medicines for Malaria Venture (MMV) Pathogen Box to assess the in-vitro antimicrobial drug susceptibility of M chimaera compared with the antimicrobial drug susceptibility of the slowly growing, major human pathogen Mycobacterium tuberculosis, and the rapidly growing Mycobacterium abscessus reference strains. Compounds identified from an initial resazurin microtitre cell viability assay screen were further characterised by determining the minimum inhibitory concentration (MIC) of MMV Pathogen Box compounds against M chimaera; and the MICs of a panel of 20 drugs commonly used to treat mycobacterial infections against M tuberculosis, M abscessus, and M chimaera. We also assessed the time-kill kinetics of doxycycline, clarithromycin, ethambutol, and rifabutin against M chimaera.FindingsM chimaera was inhibited by 21 (5%) of 400 compounds in the Pathogen Box. Ten compounds were active against all three mycobacteria. MMV675968, with activity against slowly growing mycobacteria that probably targets folate metabolism, had a mean MIC of 2·22 μM (0·80 μg/mL) against M chimaera. Antimicrobial susceptibility testing showed that oxazolidinones such as linezolid (mean MIC 3·13 μg/mL) were active against M chimaera and that bedaquiline was the most potent compound (mean MIC 0·02 μg/mL). Doxycycline, a broad-spectrum antimicrobial drug with excellent tissue penetration properties, also inhibited M chimaera with a mean MIC of 6·25 μg/mL.InterpretationMolecular diagnostics present an opportunity for more effective, targeted drug therapies—treating bacterial infections at the species level. Using an open drug discovery platform, we identified compounds that inhibit the newly recognised pathogen M chimaera. The existing evidence base is poor and the option for expensive drug discovery is improbable; therefore, we have also found options for drug repurposing. Future in-vivo efficacy studies will reveal whether these findings result in new, targeted treatment regimens for M chimaera.FundingWellcome Trust, National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs), and the University of Sussex Junior Research Associate scheme.

A multifunctional composite hydrogel as an intrinsic and extrinsic coregulator for enhanced therapeutic efficacy for psoriasis

BackgroundPsoriasis is a chronic relapsing immunological skin disease characterized by multiple cross-talk inflammatory circuits which are relevantly associated with abnormal cross-reactivity between immune cells and keratinocytes (KCs). It may be inadequate to eradicate complicated pathogenesis only via single-mode therapy. To provide optimal combinatory therapeutics, a nanocomposite-based hydrogel was constructed by loading methotrexate (MTX) into ZnO/Ag to realize combined multiple target therapy of psoriasis.ResultsIn this composite hydrogel, ZnO hybrid mesoporous microspheres were utilized both as drug carriers and reactive oxygen species (ROS)-scavenging nanoparticles. A proper amount of Ag nanoparticle-anchored ZnO nanoparticles (ZnO/Ag) was functionalized with inherent immunoregulatory property. The experiments showed that ZnO/Ag nanoparticles could exhibit a self-therapeutic effect that was attributed to reducing innate cytokine profiles by inactivating p65 in proinflammatory macrophages and abrogating secretion of adaptive cytokines in KCs by downregulating ROS-mediated STAT3-cyclin D1 signaling. A preferable antipsoriatic efficacy was achieved via topical administration of this hydrogel on the imiquimod (IMQ)-induced psoriasis mice model, demonstrating the superior transdermal delivery and combined enhancement of therapeutic efficacy caused by intrinsic nanoparticles and extrinsic MTX.ConclusionThis composite hydrogel could serve as a multifunctional, nonirritating, noninvasive and effective transcutaneous nanoagent against psoriasis.Graphical

Circ_0060531 knockdown ameliorates IL-22-induced keratinocyte damage by binding to miR-330-5p to decrease GAB1 expression

Background Psoriasis is a chronic immune-mediated skin disease. Recent studies showed its pathogenesis involved circular RNA (circRNA). However, the role of circ_0060531 in psoriasis development and the behind mechanism remain to be explored. Methods Psoriasis cell model was constructed by treating keratinocytes (HaCaT cells) using interleukin 22 (IL-22). Expression of circ_0060531, microRNA-330-5p (miR-330-5p) and GRB2 associated binder 1 (GAB1) was determined by quantitative real-time polymerase chain reaction. The functional effects of circ_0060531 on IL-22-caused cell injury were investigated by 3-(4,5-Dimethylthazol-2-yl)-2,5-diphenyltetrazolium bromide, 5-Ethynyl-29-deoxyuridine, wound-healing and enzyme-linked immunosorbent assays. Protein expression was analysed by Western blot. The interactions among circ_0060531, miR-330-5p and GAB1 were identified by dual-luciferase reporter or RNA immunoprecipitation assay. Results Circ_0060531 and GAB1 expression were significantly increased, while miR-330-5p was decreased in psoriatic skin biopsies and IL-22-stimulated HaCaT cells in comparison with controls. In function, circ_0060531 knockdown assuaged IL-22-induced cell proliferation, cell migration and inflammation. Besides, circ_0060531 acted as a miR-330-5p sponge, and regulated the processes of IL-22-treated HaCaT cells by binding to the miRNA. Under the treatment of IL-22, miR-330-5p mediated HaCaT cell damage by targeting GAB1. Importantly, circ_0060531 modulated GAB1 production by interacting with miR-330-5p. Conclusion Circ_0060531 knockdown assuaged IL-22-induced keratinocyte dysfunction through miR-330-5p/GAB1 pathway, proving a novel target for the therapy of psoriasis.