Epidermal Hyperproliferation Research Articles

The Essential Role of Herbal-based Therapies in Combatting Acne Vulgaris

Inflammation, follicular epidermal hyperproliferation, and Propionibacterium acnes (P. acnes) are the primary causes of acne vulgaris, a prevalent skin condition that affects millions of young adults and adolescents. This intricate pathophysiology leads to various acne symptoms, such as whiteheads and blackheads, inflammatory nodules, and scarring. Among the many traditional allopathic acne therapies that often have serious side effects include hormone therapy, hydroxy acids, oral and topical antibiotics, retinoic acid derivatives, and acne medications. Herbal extracts are becoming more and more well-liked as more holistic, kinder substitutes with fewer side effects. Herbal extracts with antibacterial, anti-inflammatory, and antioxidant qualities include Eucalyptus Globulus, Thymus vulgaris (thyme), Melaleuca alternifolia (tea tree), Lavandula angustifolia (lavender), Origanum vulgare (oregano), and Curcuma longa (turmeric). Because of these qualities, they are considered to be viable candidates for treating different elements of acne etiology, including wound healing, inflammation reduction, and P. acnes growth inhibition. Developing herbal remedies is a viable approach to developing efficient and minimally invasive acne treatments. Medicinal plants and essential oils have a long history of traditional use and the potential to attenuate harmful exposures and lessen drug-induced side effects. Their use in dermatological treatments demonstrates their ability to offer comprehensive and natural solutions for the treatment of acne vulgaris, a common and frequently upsetting skin condition.

Vitamin D Supplementation in Congenital Ichthyosis: A Case Series.

Ichthyosis is a group of genetic keratinization disorders characterized by excessive scaling that is associated with hyperproliferative epidermis and/or cellular retention. Whereas normal outer epidermis thickness is 25 μm, it can be 10-fold greater in patients with ichthyosis. As a result, photoactivation of 7-dehydrocholesterol is impaired, causing systemic vitamin D deficiency.In this case series, 25 patients with congenital ichthyosis with vitamin D deficiency (<10 ng/mL) were supplemented with 60,000 IU of vitamin D3 for 10 days followed by daily allowance of 400 to 600 IU of vitamin D3 and 40 mg/kg per day of elemental calcium. The authors assessed improvement in cutaneous scaling and body and tested patients' blood and urine samples at day 1, day 10, 1 month, and 3 months. They also documented patients' Dermatology Life Quality Index score before and after treatment.All patients had normal vitamin D levels; supplementation was discontinued for two patients who reached a level of 100 ng/mL within 10 days. Subjective improvement of symptoms (dryness of the skin, allergic rhinitis, tightness of the skin, and scaling) was observed by both the provider and the patients. There was remarkable improvement in symptoms of severe ichthyosis such as lamellar ichthyosis (tightness of the skin and scaling). Marked improvement in Dermatology Life Quality Index score was also noted.This case series demonstrated remarkable symptomatic relief with vitamin D supplementation in patients with congenital ichthyosis; however, additional research should be conducted with larger sample sizes to support these findings.

Defactinib inhibits FAK phosphorylation and regulates psoriasis via attenuating hyperproliferation of keratinocytes.

Excessive proliferation of keratinocytes is a crucial pathological risk feature of psoriasis. Focal adhesion kinase (FAK) is a non-receptor protein that primarily regulates cell proliferation and migration. However, the expression and regulatory mechanism of FAK in psoriasis remains unclear. This study aimed to investigate the regulation of FAK in psoriasis and examined the potential impact of FAK inhibitor on psoriasis. A small molecular selective FAK inhibitor, defactinib, was used to evaluate the effect of FAK on psoriasis in invitro and invivo functional assays. In our experiments, imiquimod (IMQ)-induced psoriasis mice and human keratinocytes cells were used to study the potential roles and mechanisms of FAK in psoriasis. FAK phosphorylation has been weakly detected in normal intact skin and is markedly elevated upon IMQ treatment. By reducing FAK phosphorylation (p-FAK),defactinib treatment could attenuate psoriasiform inflammation and epidermal hyperplasia in IMQ-treated mice compared with IMQ-induced mice treated with the vehicle. In invitro studies, resiquimod (R848) increased (p-FAK) and promoted cell proliferation in human keratinocytes cells, while defactinib reversed this effect. Mechanistically, defactinib can alleviate the proliferation via JNK/YB1 pathway invitro and invivo. Defactinib significantly attenuates psoriasiform inflammation and epidermal hyperproliferation through the inhibition of the FAK-mediated axis. The downregulation of phosphorylated FAK then suppressed the activation of JNK/YB1 protein signaling pathway in psoriasis. Our work highlights targeting FAK as a potentially effective strategy for the treatment of psoriasis.

Influence of peripheral nerve system on proliferation and migration of keratinocytes on site of the wound edges

AIM: to assess proliferation and migration of keratinocytes at the nonhealing edges of neuropathic wounds.MATERIALS AND METHODS: 25 patients with neuropathic ulcers and 5 patients without diabetes with decubitus were enrolled. Diabetic foot (DF) patients were underwent to standard treatment including debridement, atraumatic dressing, offloading, antibacterial therapy if it needs. Severity of peripheral neuropathy was assessed according to the NDS scale. Histo­logical (hematoxylin and eosin) and immunohistochemical (Ki-67 , α7nAChR markers) examination of wound edge were done during treatment (0, 10, 24 days).RESULTS: All patients have severe neuropathy according to NDSm (&gt;8). The average size of DF ulcers before and on 10th day of treatment was of 4 cm2 and 2,5 cm2, respectively (p&lt;0,004). Neuropathic ulcers were characterized by hyperproliferative epidermis. Mitotically active keratinocytes reside throughout the suprabasal layers. Ki-67 expressed all layers of the epidermis, but a greater staining density was detected in the basal layer. The density of a7nAChR-positive cells increased from 0 to 24 days (p=0,031).THE CONCLUSION: The data shows that neuropathy is one of the possible mechanisms of keratinocyte cell cycle disruption: proliferative activity and ability to migrate. Identification of new signaling pathways regulating the physiological repair of tissues and the study of their disorders in diabetes mellitus opens the prospect of developing an optimal therapeutic strategy.

Embryonic NIPP1 Depletion in Keratinocytes Triggers a Cell Cycle Arrest and Premature Senescence in Adult Mice

NIPP1 is a ubiquitously expressed regulatory subunit of protein phosphatase-1. Its embryonic deletion in keratinocytes causes chronic sterile skin inflammation, epidermal hyperproliferation and resistance to mutagens in adult mice. To explore the primary effects of NIPP1 deletion, we first examined hair-cycle progression of NIPP1 skin knockouts (SKOs). The entry of the 1st hair cycle in the SKOs was delayed due to prolonged quiescence of hair-follicle stem cells (HFSCs). In contrast, the entry of the 2nd hair cycle in the SKOs was advanced as a result of precocious activation of HFSCs. The epidermis of SKOs progressively accumulated senescent cells and this cell-fate switch was accelerated by DNA damage. Primary keratinocytes from SKO neonates and human NIPP1-depleted HaCaT keratinocytes failed to proliferate and showed an increase in the expression of cell-cycle inhibitors (p21, p16/Ink4a and/or p19/Arf) and senescence-associated-secretory-phenotype (SASP) factors as well as in DNA damage (γH2AX and 53bp1). Our data demonstrate that the primary effect of NIPP1 deletion in keratinocytes is a cell-cycle arrest and premature senescence that gradually progresses to chronic senescence and likely contributes to the decreased sensitivity of SKOs to mutagens.

Ginsenoside Compound K Reduces Psoriasis-related Inflammation by Activation of the Glucocorticoid Receptor in Keratinocytes.

To investigate the effects and mechanism of Ginsenoside Compound K (GCK) on psoriasis, focusing on the glucocorticoid receptor (GR) in keratinocytes. An imiquimod (IMQ)-induced psoriasis-like dermatitis mouse model was generated to evaluate the anti-inflammatory effect of GCK. Hematoxylin and eosin (H&E) staining was used to assess skin pathological changes. Protein expression of K17 and p-p65 in mice skin was assayed by immunohistochemical. Protein expression and phosphorylation of p65 IκB were assayed by Western blot. Protein expression of K1, K6, K10, K16, K17, and GR were assayed by Western blot and immunofluorescence. Enzyme-linked immunosorbent assay (ELISA) was used to determine cytokine levels of TNF-α, IL-6, CXCL-8, and ICAM-1. Real-time polymerase chain reaction (RT-PCR) was used to quantify TNF-α, IL-6, IL-8, and ICAM-1 mRNA expression. Cell viability was determined by Cell Counting Kit-8(CCK-8) assay. A high-content cell-imaging system was used to assay cell proliferation. Nuclear translocation of p65 and GR was assayed by imaging flow cytometry and immunofluorescence microscopy. Small interfering RNA was used to confirm the role of GR in the anti-inflammatory and immunoregulatory effect of GCK in normal human epidermal keratinecytes (NHEKs). GCK reduced the psoriasis area, severity index, and epidermal thickening in IMQ-induced mice. GCK significantly attenuated the mRNA levels of IL-6, IL-8, TNF-α, and ICAM-1 and reduced epidermal hyperproliferation in the skin of IMQ-induced mice. GCK inhibited in vitro activation of NF-κB, leading to attenuated release of inflammatory mediators (IL-6, IL-8, TNF-α, and ICAM-1) and suppression of NHEK hyperproliferation and abnormal differentiation. These inhibitory effects of GCK were diminished by GR silencing in NHEKs. GCK suppressed psoriasis-related inflammation by suppressing keratinocyte activation, which may be related to promoting GR nuclear translocation and inhibiting NF-κB activation. In summary, GCK appears to be a GR activator and a promising therapeutic candidate for antipsoriatic agents.

Mechanistic Investigation of WWOX Function in NF-kB-Induced Skin Inflammation in Psoriasis.

Psoriasis is a chronic inflammatory skin disease characterized by epidermal hyperproliferation, aberrant differentiation of keratinocytes, and dysregulated immune responses. WW domain-containing oxidoreductase (WWOX) is a non-classical tumor suppressor gene that regulates multiple cellular processes, including proliferation, apoptosis, and migration. This study aimed to explore the possible role of WWOX in the pathogenesis of psoriasis. Immunohistochemical analysis showed that the expression of WWOX was increased in epidermal keratinocytes of both human psoriatic lesions and imiquimod-induced mice psoriatic model. Immortalized human epidermal keratinocytes were transduced with a recombinant adenovirus expressing microRNA specific for WWOX to downregulate its expression. Inflammatory responses were detected using Western blotting, real-time quantitative reverse transcription polymerase chain reaction (PCR), and enzyme-linked immunosorbent assay. In human epidermal keratinocytes, WWOX knockdown reduced nuclear factor-kappa B signaling and levels of proinflammatory cytokines induced by polyinosinic: polycytidylic acid [(poly(I:C)] in vitro. Furthermore, calcium chelator and protein kinase C (PKC) inhibitors significantly reduced poly(I:C)-induced inflammatory reactions. WWOX plays a role in the inflammatory reaction of epidermal keratinocytes by regulating calcium and PKC signaling. Targeting WWOX could be a novel therapeutic approach for psoriasis in the future.

Expression of hornerin in skin lesions of atopic dermatitis and skin diseases.

We have previously identified the filaggrin (FLG)-like protein, hornerin (HRNR). Recently, there have been several reports regarding the relationship between HRNR and atopic dermatitis (AD). In the present study, we examined HRNR expression in the skin lesions of seven unrelated patients with AD to clarify the role of HRNR in the pathogenesis of AD. HRNR was detected in chronic AD lesions (n = 4), whereas no HRNR signals were observed in acute AD lesions (n = 3). HRNR was detected in the cytokeratin 6-expressing epidermis, and Ki67-positive keratinocytes were more abundant in the HRNR-positive epidermis. These findings suggest that HRNR may be associated with epidermal hyperproliferation in AD lesions. Next, we examined HRNR expression in skin diseases associated with hyperkeratosis. HRNR signals were irregularly observed in different cells from those expressing FLG in epidermolytic ichthyosis and actinic keratosis. Therefore, HRNR may play a unique role in the molecular process of cornification.

Epigenetic switch reshapes epithelial progenitor cell signatures and drives inflammatory pathogenesis in hidradenitis suppurativa.

Hidradenitis suppurativa (HS) is a complex inflammatory skin disease with undefined mechanistic underpinnings. Here, we investigated HS epithelial cells and demonstrated that HS basal progenitors modulate their lineage restriction and give rise to pathogenic keratinocyte clones, resulting in epidermal hyperproliferation and dysregulated inflammation in HS. When comparing to healthy epithelial stem/progenitor cells, in HS, we identified changes in gene signatures that revolve around the mitotic cell cycle, DNA damage response and repair, as well as cell-cell adhesion and chromatin remodeling. By reconstructing cell differentiation trajectory and CellChat modeling, we identified a keratinocyte population specific to HS. This population is marked by S100A7/8/9 and KRT6 family members, triggering IL1, IL10, and complement inflammatory cascades. These signals, along with HS-specific proinflammatory cytokines and chemokines, contribute to the recruitment of certain immune cells during the disease progression. Furthermore, we revealed a previously uncharacterized role of S100A8 in regulating the local chromatin environment of target loci in HS keratinocytes. Through the integration of genomic and epigenomic datasets, we identified genome-wide chromatin rewiring alongside the switch of transcription factors (TFs), which mediated HS transcriptional profiles. Importantly, we identified numerous clinically relevant inflammatory enhancers and their coordinated TFs in HS basal CD49fhigh cells. The disruption of the S100A enhancer using the CRISPR/Cas9-mediated approach or the pharmacological inhibition of the interferon regulatory transcription factor 3 (IRF3) efficiently reduced the production of HS-associated inflammatory regulators. Our study not only uncovers the plasticity of epidermal progenitor cells in HS but also elucidates the epigenetic mechanisms underlying HS pathogenesis.

Dietary Fiber Inulin Improves Murine Imiquimod-Induced Psoriasis-like Dermatitis.

Psoriasis is a chronic skin disease with interleukin (IL)-17-dominated inflammation and hyperproliferation of epidermis. Dietary fiber is fermented by the gut microbiome into short-chain fatty acids (SCFAs) that manifest anti-inflammatory effects. We examined if feeding with an inulin-enriched high-fiber diet (HFD) might improve topical imiquimod-induced psoriasis-like dermatitis in mice. HFD reduced thickening and total severity scores of imiquimod-induced dermatitis and reduced epidermal thickness, inflammatory infiltrates, including Ly6G+ neutrophils, and epidermal Ki67+ proliferating cells. HFD reduced mRNA levels of IL-17A, IL-17F, IL-22, IL-1β, tumor necrosis factor (TNF)-α, CXCL1, CXCL2, and keratin 16 and increased those of transforming growth factor (TGF)-β1 and cyclin-dependent kinase inhibitor 1A in imiquimod-induced dermatitis. In 16S rRNA sequencing of the gut microbiome, imiquimod increased relative abundance of phylum Firmicutes, while HFD increased that of phylum Bacteroidota and genus Bacteroides. HFD increased serum and fecal concentrations of SCFA propionate. Oral propionate reduced inflammatory infiltrates and epidermal Ki67+ cells and reduced mRNA levels of IL-17A, IL-17F, IL-17C, IL-22, IL-1β, IL-6, TNF-α, CXCL1, CCL20 and increased those of TGF-β1and IL-10 in imiquimod-indued dermatitis. Dietary inulin supplementation improves imiquimod-induced psoriasis-like dermatitis partially via propionate, and may be a promising adjunctive therapy for psoriasis.

Hyaluronic acid engineered gallic acid embedded chitosan nanoparticle as an effective delivery system for treatment of psoriasis

Psoriasis is a deleterious auto-immune disorder which seriously harms the patients physical and mental health. CD44 are found to be over-expressed on psoriatic lesions which are highly responsible for epidermal hyperproliferation and inflammation. Gallic acid (GA), a phenolic acid natural compound has potential inhibitory impact on pro-inflammatory transcription factors. However, the penetration across skin and availability is low when applied topically, making the treatment extremely challenging. Considering such factors, we developed GA loaded chitosan nanoparticles and modified with hyaluronic acid (HA) (HA@CS-GA NP) to assess the therapeutic potential against psoriasis. The formulations were characterized by DSC, zetasizer and TEM for assuring the development of nanosystems. GA loaded CS NP had a particle size of 207.2 ± 0.08 nm while after coating with HA, the size increased to 220.1 ± 0.18 nm. The entrapment efficiency was 93.24 ± 0.132% and drug loading of 73.17 ± 0.23%. The in vitro cell viability assessment study confirmed enhanced anti-proliferative effect of HA@CS-GA NP over plain GA which is due to high sensitivity towards HaCaT cell. The in vivo results on imiquimod induced psoriasis model indicated that CD44 receptor mediated targeted approach of HA@CS-GA NP gel had great potential in restricting the keratinocyte hyperproliferation and circumventing psoriasis. For the therapy of further skin-related conditions, HA modified nanoparticles should be investigated extensively employing genes, antibodies, chemotherapeutics, or natural substances.

Inducible Keratinocyte Specific FGFR2 Deficiency Inhibits UVB-Induced Signaling, Proliferation, Inflammation, and Skin Carcinogenesis

A potential role for fibroblast growth factor receptor 2 (FGFR2) in cutaneous squamous cell carcinoma (cSCC) has been reported. To demonstrate the specific role of FGFR2 in UVB-induced skin carcinogenesis and development of cSCC, we generated a keratinocyte specific, tamoxifen inducible mouse model of FGFR2 deficiency. In this mouse model, topical application of 4-hydroxy tamoxifen led to the induction of Cre recombinase to delete FGFR2 in epidermal keratinocytes of both male and female transgenic mice. Analysis of epidermal protein lysates isolated from FGFR2 deficient mice exposed to UVB showed significant reductions of phospho-FGFR (pFGFR; Y653/654) and phospho-fibroblast growth factor receptor substrate 2α as well as downstream effectors of mTORC1 signaling. Phosphorylation of signal transducer and activators of transcription 1/3 was significantly reduced as well as levels of IRF-1, DUSP6, early growth response 1, and PD-L1 compared to the control groups. Keratinocyte-specific ablation of FGFR2 also significantly inhibited epidermal hyperproliferation, hyperplasia, and inflammation after exposure to UVB. Finally, keratinocyte-specific deletion of FGFR2 significantly inhibited UVB-induced cSCC formation. Collectively, the current data demonstrate an important role of FGFR2 in UVB-induced oncogenic signaling as well as development of cSCC. In addition, the current preclinical findings suggest that inhibition of FGFR2 signaling may provide a previously unreported strategy to prevent and/or treat UVB-induced cSCC.

SIRT6 pharmacological inhibition delays skin cancer progression in the squamous cell carcinoma

Sirtuin 6 (SIRT6) has a critical role in cutaneous Squamous Cell Carcinoma (cSCC): SIRT6 silencing in skin SCC cells has pro-differentiating effects and SIRT6 deletion abrogated DMBA-TPA-induced skin tumorigenesis in mice. On the other hand, SIRT6 acts as tumor suppressor in SCC by enhancing glycolysis in tumor propagating cells. Herein, pharmacological modulation of SIRT6 deacetylase activity was investigated in cSCC, with S6 (inhibitor) or MDL-800 (activator). In cSCC cells, S6 recreated the pro-differentiating effects of SIRT6 silencing, as the levels of Keratin 1, Keratin 10 and Loricrin were upregulated compared to controls. Next, the effects of SIRT6 pharmacological modulation were evaluated in a DMBA-TPA-induced skin cancer mouse model. Mice treated with the inhibitor S6 in a preventive approach, i.e. at the beginning of the promotion stage, presented reduced number and size of papillomas, compared to the controls. The epidermal hyperproliferation marker Keratin 6 and the cSCC marker Keratin 8 were less abundant when SIRT6 was inhibited. In S6-treated lesions, the Epithelial-Mesenchymal Transition (EMT) markers Zeb1 and Vimentin were less expressed compared to untreated lesions. In a therapeutic approach, i.e. treatment starting after papilloma appearance, the S6 group presented reduced papillomas (number and size), whereas MDL-800-treated mice displayed an opposite trend. In S6-treated lesions, Keratin 6 and Keratin 8 were less expressed, EMT was less advanced, with a higher E-cadherin/Vimentin ratio, indicating a delayed carcinogenesis when SIRT6 was inhibited. Our results confirm that SIRT6 plays a role in skin carcinogenesis and suggest SIRT6 pharmacological inhibition as a promising strategy in cSCC.

Epidermal Loss of RORα Enhances Skin Inflammation in a MC903-Induced Mouse Model of Atopic Dermatitis.

Atopic dermatitis (AD) is a chronic inflammatory skin disease featuring skin barrier dysfunction and immune dysregulation. Previously, we reported that the retinoid-related orphan nuclear receptor RORα was highly expressed in the epidermis of normal skin. We also found that it positively regulated the expression of differentiation markers and skin barrier-related genes in human keratinocytes. In contrast, epidermal RORα expression was downregulated in the skin lesions of several inflammatory skin diseases, including AD. In this study, we generated mouse strains with epidermis-specific Rora ablation to understand the roles of epidermal RORα in regulating AD pathogenesis. Although Rora deficiency did not cause overt macroscopic skin abnormalities at the steady state, it greatly amplified MC903-elicited AD-like symptoms by intensifying skin scaliness, increasing epidermal hyperproliferation and barrier impairment, and elevating dermal immune infiltrates, proinflammatory cytokines, and chemokines. Despite the normal appearance at the steady state, Rora-deficient skin showed microscopic abnormalities, including mild epidermal hyperplasia, increased TEWL, and elevated mRNA expression of Krt16, Sprr2a, and Tslp genes, indicating subclinical impairment of epidermal barrier functions. Our results substantiate the importance of epidermal RORα in partially suppressing AD development by maintaining normal keratinocyte differentiation and skin barrier function.

Breakthroughs and bottlenecks of psoriasis therapy: Emerging trends and advances in lipid based nano-drug delivery platforms for dermal and transdermal drug delivery

Psoriasis is a chronic autoimmune skin disease characterised by abnormal epidermal keratinocytes, hyperproliferation, and inflammatory infiltration. The main challenges that make treating psoriasis difficult are the complex aetiology, frequency of administration, and multiple side effects of traditional therapeutics. Clinicians often face difficulties while treating serious wounds caused by psoriasis. The therapeutic advantages of existing molecules can be maximised by administering them at the correct place for an extended period. Over the past two to three decades, there has been an increase in the availability of lipid-based nanocarriers for cosmetic and skin-care applications. However, there is still significant room for the development of additional lipid-based nanocarriers that are both highly biocompatible and capable of stimulating skin regeneration processes. This review discusses the contemporary trends and latest progress in research on various lipid-based nanodrug delivery systems employed for the effective management of psoriasis. Here, we first recapitulated skin structure and its function. Second, we discussed an overview of pathophysiology of psoriasis and challenges of existing therapies in psoriasis treatment. We outlined skin delivery through various lipid-based nano-drug delivery systems like liposomes, transferosomes, niosomes, ethosomes, transethosomes, phytosomes, solid lipid nanoparticles, cerosomes, glyceroethosomes, and spanlastics for the effective management of psoriasis. Finally, we outlined in vitro assays and models for anti-psoriatic activity assessment. It will assist clinicians and formulation scientists in treating skin diseases, particularly psoriasis.

AHNAK, regulated by the OSM/OSMR signaling, involved in the development of primary localized cutaneous amyloidosis

BackgroundPrimary localized cutaneous amyloidosis (PLCA) is a chronic skin disease characterized by aberrant keratinocyte differentiation, epidermal hyperproliferation, and amyloid deposits. Previously, we demonstrated OSMR loss-function mutants enhanced basal keratinocyte differentiation through the OSMR/STAT5/KLF7 signaling in PLCA patients. ObjectiveTo investigate the underlying mechanisms involved in basal keratinocyte proliferation in PLCA patients that remain unclear. MethodsPatients with pathologically confirmed PLCA visiting the dermatologic outpatient clinic were involved in the study. Laser capture microdissection and mass spectrometry analysis, gene-edited mice, 3D human epidermis culture, flow cytometry, western blot, qRT-PCR and RNA sequencing were used to explore the underlying molecular mechanisms. ResultsIn this study, we found that AHNAK peptide fragments were enriched in the lesions of PLCA patients, as detected by laser capture microdissection and mass spectrometry analysis. The upregulated expression of AHNAK was further confirmed using immunohistochemical staining. qRT-PCR and flow cytometry revealed that pre-treatment with OSM can inhibit AHNAK expression in HaCaT cells, NHEKs, and 3D human skin models, but OSMR knockout or OSMR mutations abolished this down-regulation trend. Similar results were obtained in wild-type and OSMR knockout mice. More importantly, EdU incorporation and FACS assays demonstrated the knockdown of AHNAK could induce G1 phase cell cycle arrest and inhibit keratinocyte proliferation. Furthermore, RNA sequencing revealed that AHNAK knockdown regulated keratinocyte differentiation. ConclusionTaken together, these data indicated that the elevated expression of AHNAK by OSMR mutations led to hyperproliferation and overdifferentiation of keratinocytes, and the discovered mechanism might provide insights into potential therapeutic targets for PLCA.

Nutritional Modulation of Guinea Pig Skin Hyperproliferation by Essential Fatty Acid Deficiency is Associated with Selective Down Regulation of Protein Kinase C-β

In a previous study we demonstrated that 13-hydroxyoctadecadienoic acid (13-HODE), a 15-lipoxygenase metabolite of linoleic acid is incorporated into epidermal phosphatidyl 4,5-bisphosphate (PtdIns 4,5-P2) and released as 13-HODE-containing-diacylglycerol (13-HODE-DAG). In vitro, 13-HODE-DAG was shown to selectively inhibit epidermal total protein kinase C (PKC-β) activity. To determine whether these observations are relevant in vivo, guinea pigs were made essential fatty acid deficient (EFAD) by feeding them a basal diet supplemented with 4% hydrogenated coconut oil for 8 wk. Tissue levels of putative 13-HODE-DAG, protein kinase C (PKC) isozymes and tissue hyperproliferation were determined in the epidermal preparations from skin of control safflower oil-fed guinea pigs, those fed EFAD diet and those fed EFAD diet followed by the control diet for 2 wk. Our data revealed that cutaneous 13-HODE and 13-HODE-DAG were significantly lower in EFAD animals than in safflower-fed controls. These reductions were associated with both elevated epidermal hyperproliferation and elevated expressions and activities of PKC-α and β-isozymes. Refeeding the animals with safflower oil for 2 wk replenished tissue levels of 13-HODE-DAG, which inversely correlated with the selective down regulation of PKC-β expression and activity and the reversal of hyperproliferation. In contrast, although the expression and activity of PKC-α was elevated in the epidermis of the EFAD guinea pigs, this elevated PKC-α expression was not down regulated after refeeding the safflower oil diet to the animals. These results suggest that the epidermal level of 13-HODE plays a role in vivo in modulating cutaneous hyperproliferation via the generation of 13-HODE-DAG via signal transduction and its selective suppression of PKC-β isozyme.

Two for two: Dual therapy with erlotinib and acitretin for twins with severe keratoderma in Olmsted syndrome.

Olmsted syndrome (OS) is a rare genetic disorder, characterized by painful palmoplantar keratoderma (PPK), periorificial and intertriginous hyperkeratoses, and alopecia. Fewer than 75 cases have been described. Variants in TRPV3 result in constitutive activation of transient receptor potential vanilloid 3, leading to increased epidermal growth factor receptor (EGFR) signaling, palmoplantar epidermal hyperproliferation, and exquisite lesional pain. We describe pre-school aged twins with OS with partial improvement from oral erlotinib, an EGFR inhibitor, but dramatic reduction of their persistent palmoplantar thickening and pain from adding acitretin.

The Long Noncoding RNA LINC00958 Is Induced in Psoriasis Epidermis and Modulates Epidermal Proliferation

Psoriasis is a common, immune-mediated skin disease characterized by epidermal hyperproliferation and chronic skin inflammation. Long noncoding RNAs are >200 nucleotide-long transcripts that possess important regulatory functions. To date, little is known about the contribution of long noncoding RNAs to psoriasis. In this study, we identify LINC00958 as a long noncoding RNA overexpressed in keratinocytes (KCs) from psoriasis skin lesions, in a transcriptomic screen performed on KCs sorted from psoriasis and healthy skin. Increased levels of LINC00958 in psoriasis KCs were confirmed by RT-qPCR and single-molecule in situ hybridization. Confocal microscopy and analysis of subcellular fractions showed that LINC00958 is mainly localized in the cytoplasm of KCs. IL-17A, a key psoriasis cytokine, induced LINC00958 in KCs through C/EBP-β and the p38 pathway. The inhibition of LINC00958 led to decreased proliferation as measured by Ki-67 expression, live cell analysis imaging, and 5-ethynyl-2-deoxyuridine assays. Transcriptomic analysis of LINC00958-depleted KCs revealed enrichment of proliferation- and cell cycle‒related genes among differentially expressed transcripts. Moreover, LINC00958 depletion led to decreased basal and IL-17A‒induced phosphorylation of p38. Furthermore, IL-17A‒induced KC proliferation was counteracted by the inhibition of LINC00958. In summary, our data support a role for the IL-17A‒induced long noncoding RNA, LINC00958, in the pathological circuits of psoriasis by reinforcing IL-17A‒induced epidermal hyperproliferation.

Effect of Oral Drug Apremilast on Histopathological Changes in Patients of Plaque Psoriasis: A Prospective Observational Study

Introduction: Psoriasis is a chronic non infectious recurrent papulosquamous inflammatory disorder characterised by vascular alterations such as angiogenesis, dilatation, increased endothelial venule generation, epidermal keratinocyte hyperproliferation, and aberrant differentiation, and lymphocytic invasion of T-cells. The aetiopathogenesis of disease is influenced by both hereditary and environmental factors. Pathogenesis is significantly influenced by immune dysregulation, which affects both innate and acquired immunity. A relatively recent medication for the management of moderate to severe plaque psoriasis is apremilast, an oral phosphodiesterase-4 inhibitor. Compared to other immune-suppressing drugs used in psoriasis apremilast causes no reactivation of tuberculosis or opportunistic infections, does not need dose adjustment in elderly or patients with hepatic impairment, and is not contraindicated in diabetes, ischaemic heart disease, or congestive cardiac failure. Due to its advantage of the absence of the need for laboratory monitoring, the patients on long-term methotrexate can also be switched to apremilast. Aim: To evaluate the histopathological changes in the skin of all plaque psoriatic patients treated with oral drug apremilast. Materials and Methods: This hospital-based prospective study was done in the Department of Pathology at the Rajasthan University of Health Sciences (RUHS), Jaipur, India for a period of one year from February 2020 to January 2021 comparing the efficacy of Apremilast clinically by evaluating plaque psoriasis patients’ by Psoriasis Area and Severity Index (PASI) scores. Patients of all age groups with a clinical diagnosis of psoriasis were subjected to a punch biopsy from an active lesion by a dermatologist. For histopathological examination, biopsy was taken from the lesion before starting treatment with apremilast and after four weeks of apremilast therapy. The subsequent changes in the form of histopathological score and PASI score were analysed and compared with the previous score to study the effect of oral drug apremilast. Results: Total of 100 patients enrolled in the study with the mean age 39.14 years including 59% males and 41% females. Main site of lesion was back, hand and leg. The PASI score at the first visit was 11.28 and at the second visit were 7.27 with the improvement 35.54% which was statistically significant from first visit (p-value&lt;0.001). The histopathological score at the first visit was 15.98 and at the second visit were 10.06 with the improvement 37.1%. Conclusion: Apremilast was found to be a safe and effective treatment for psoriasis patients, and this impact was unaffected by confounding variables.