Keratinocyte Apoptosis Research Articles

Particulate Matters Induce Apoptosis in Human Hair Follicular Keratinocytes.

BackgroundParticulate matters (PM) comprise a heterogeneous mixture of particles suspended in air. A recent study found that urban PMs may penetrate into hair follicles via transfollicular and transdermal routes in dorsal skin.ObjectiveTo investigate the effects of PM on ex vivo cultured human scalp hair follicles and hair follicular keratinocytes in vitro.MethodsTUNEL staining was employed to check cells undergoing apoptosis in cultured hair follicles after PM treatment. MTT assay was employed to check cell viability after PM treatment. Quantitative real-time PCR analysis was employed to quantitate the expression of inflammatory genes, matrix metalloproteinases (MMPs), and Duox1. Inflammatory cytokine levels were measured by ELISA after PM treatment. The level of reactive oxygen species (ROS) production was measured using a chemical fluorescent probe by a fluorescence plate reader.ResultsAbundant TUNEL-positive cells were observed in the keratinocyte region of hair including the epidermis, sebaceous gland, outer root sheath (ORS), inner root sheath (IRS), and bulb region. The viability of follicular cells, including the ORS, was found to be decreased upon PM exposure. mRNA expression and protein levels of inflammatory response genes and MMPs were upregulated in a dose-dependent manner by PM treatment. ROS levels were also increased by PM.ConclusionThese data strongly suggest that penetrated PMs from air pollution may cause apoptotic cell death to follicular keratinocytes by increased production of ROS and inflammatory cytokines, which could impair hair growth.

Role of autophagy and apoptosis in atrophic epithelium in oral submucous fibrosis.

Oral submucous fibrosis (OSF) is a serious, potentially malignant oral disorder. It is histopathologically characterized by chronic inflammation and atrophic epithelium accompanied by the accumulation of collagen fibers in the lamina propria. The molecular mechanisms leading to atrophic epithelium remain poorly understood. Therefore, the present study investigated the role of autophagy and apoptosis in atrophic epithelium in OSF. The expression of Caspase-3 and autophagy-related proteins (LC3 and P62) in OSF epithelial tissues was quantified by immunohistochemistry. The analysis demonstrated that, compared with normal oral mucosal tissues, autophagy and apoptosis increased with the progression of OSF. Flow cytometry and Western blotting showed that arecoline induces apoptosis in human oral keratinocytes (HOKs) in a time-dependent manner in vitro. Arecoline-induced autophagy was confirmed by transmission electron microscopy and Western blotting. When chloroquine was used as an inhibitor of autophagy, the apoptosis rate and Caspase-3 expression decreased compared with the use of arecoline alone. Thus, autophagy and apoptosis may be involved in atrophic epithelium in OSF, and arecoline-induced autophagy promotes apoptosis in HOKs.

Enzymatically synthesized glycogen prevents ultraviolet B-induced cell damage in normal human epidermal keratinocytes.

Enzymatically synthesized glycogen is a product from starch. Enzymatically synthesized glycogen has been reported to possess various health beneficial effects such as anti-oxidative and anti-inflammatory effects. In this study, we investigated the effect of enzymatically synthesized glycogen on ultraviolet B-induced oxidative stress and apoptosis in normal human epidermal keratinocytes. Treatment with enzymatically synthesized glycogen suppressed ultraviolet B-induced reactive oxygen species, caspase-3 activity, and DNA fragmentation in normal human epidermal keratinocytes. Furthermore, enzymatically synthesized glycogen increased in the expression level of heme oxygenase-1, NAD(P)H: quinone oxidoreductase 1, and NF-E2-related factor 2, a transcriptional factor for heme oxygenase-1 and NAD(P)H: quinone oxidoreductase 1. Although enzymatically synthesized glycogen did not increase in its mRNA expression level of NF-E2-related factor 2, enzymatically synthesized glycogen retained its protein degradation. Knockdown of heme oxygenase-1 and NAD(P)H: quinone oxidoreductase 1 canceled enzymatically synthesized glycogen-suppressed reactive oxygen species accumulation in normal human epidermal keratinocytes. It is, therefore, concluded that enzymatically synthesized glycogen inhibited ultraviolet B-induced oxidative stress through increasing the expression level of heme oxygenase-1 and NAD(P)H: quinone oxidoreductase 1 through the NF-E2-related factor 2 pathway in normal human epidermal keratinocytes.

Expression of pigment epithelium-derived factor in psoriasis, verrucae, squamous cell carcinoma and normal skin: An immunohistochemical study.

Preservation of homeostasis status in the skin needs an equilibrium of keratinocyte proliferation, differentiation, necrosis and apoptosis. Disturbance of these regulatory mechanisms may lead to keratinocyte neoplastic and hyperproliferative diseases. Pigment epithelium-derived factor is a glycoprotein that is endogenously produced in different tissues and has a variety of biological effects in different diseases. To evaluate the keratinocyte expression of pigment epithelium-derived factor in normal skin and three epidermal hyperproliferative diseases, namely, psoriasis, verrucae and squamous cell carcinoma. This study included skin biopsy samples from 80 participants who were divided into four equal groups; each containing 20 samples. The first group included skin biopsies from normal skin, the second group from psoriatic lesions, the third group from verruca vulgaris and the fourth group from squamous cell carcinoma. All tissue samples were stained with hematoxylin and eosin stain and later immunohistochemically for pigment epithelium-derived factor expression. Scores of pigment epithelium-derived factor expression were lower in squamous cell carcinoma and verruca and psoriasis than normal skin with a significant difference (P = 0.04). In addition, the pattern of pigment epithelium-derived factor expression was mainly cytoplasmic in normal skin with a significant difference with that seen in psoriasis, squamous cell carcinoma and verruca vulgaris (P = 0.001). Pigment epithelium-derived factor may play a role in keratinocyte differentiation.

Piperlongumine regulates epigenetic modulation and alleviates psoriasis-like skin inflammation via inhibition of hyperproliferation and inflammation

Psoriasis is an autoimmune skin disease, where chronic immune responses due to exaggerated cytokine signaling, abnormal differentiation, and evasion of keratinocytes apoptosis plays a crucial role in mediating abnormal keratinocytes hyperproliferation. From the therapeutic perspective, the molecules with strong anti-proliferative and anti-inflammatory properties could have tremendous relevance. In this study, we demonstrated that piperlongumine (PPL) treatment effectively abrogated the hyperproliferation and differentiation of keratinocytes by inducing ROS-mediated late apoptosis with loss of mitochondrial membrane potential. Besides, the arrest of cell cycle was found at Sub-G1 phase as a result of DNA fragmentation. Molecularly, inhibition of STAT3 and Akt signaling was observed with a decrease in proliferative markers such as PCNA, ki67, and Cyclin D1 along with anti-apoptotic Bcl-2 protein expression. Keratin 17 is a critical regulator of keratinocyte differentiation, and it was found to be downregulated with PPL significantly. Furthermore, prominent anti-inflammatory effects were observed by inhibition of lipopolysaccharide (LPS)/Imiquimod (IMQ)-induced p65 NF-κB signaling cascade and strongly inhibited the production of cytokine storm involved in psoriasis-like skin inflammation, thus led to the restoration of normal epidermal architecture with reduction of epidermal hyperplasia and splenomegaly. In addition, PPL epigenetically inhibited histone-modifying enzymes, which include histone deacetylases (HDACs) of class I (HDAC1–4) and class II (HDAC6) evaluated by immunoblotting and HDAC enzyme assay kit. In addition, our results show that PPL effectively inhibits the nuclear translocation of p65 and a histone modulator HDAC3, thus sequestered in the cytoplasm of macrophages. Furthermore, PPL effectively enhanced the protein–protein interactions of HDAC3 and p65 with IκBα, which was disrupted by LPS stimulation and were evaluated by Co-IP and molecular modeling. Collectively, our findings indicate that piperlongumine may serve as an anti-proliferative and anti-inflammatory agent and could serve as a potential therapeutic option in treating psoriasis.

Expression of Fas Receptor and Fas Ligand in Eczematous Dermatitis

Background: The principal role of epidermal keratinocytes (KCs) in inducing and maintaining eczematous dermatitis has been rather neglected. Objectives: The study aimed to assess the expression of Fas receptor (FasR) and Fas ligand (FasL) in the skin of eczematous dermatitis patients to examine T-cell mediated KC apoptosis. Methods: The population included 35 patients with eczematous dermatitis, as well as 15 age- and sex-matched healthy controls. The cases group included 13 eczema, five atopic dermatitis (AD) and 17 contact dermatitis (CD) patients. Tissue levels of FasR and FasL were estimated using a quantitative real time-polymerase chain reaction. Results: FasR and FasL were upregulated in the cases group compared to the control group (P < 0.001). Moreover, FasR and FasL were upregulated in the eczema cases compared to the cases with CD and AD (P = 0.001). On the contrary, there was downregulation of FasR and FasL in the CD cases in comparison to the cases having eczema and AD (P = 0.001). Conclusions: The study concluded that the upregulation of FasR and FasL may be involved in the pathogenesis of eczema through induction of KC apoptosis. This might help in the future use of anti-apoptotic therapy for prevention and treatment of eczematous dermatitis.

Mechanism of danshensu-induced inhibition of abnormal epidermal proliferation in psoriasis

Psoriasis is a chronic, inflammatory skin disease with high incidence and high rates of relapse, for which no satisfactory treatments are currently available. Yes-associated protein (YAP) is highly expressed in psoriasis and may regulate the proliferation and apoptosis of keratinocytes. Danshen is a traditional Chinese medicine, commonly used in the treatment of psoriasis. Danshensu is the most abundant water-soluble component of Danshen, but its therapeutic mechanism is still unclear. In this study, MTT was used to detect the effects of different danshensu concentrations (0.125, 0.25, 0.5 mmol/l) on the proliferation of an M5-based psoriasis cell model. The effects of danshensu on cell cycle and apoptosis were detected by flow cytometry. Cyclins and apoptosis-related proteins were evaluated by Western blot. Danshensu (20, 40, 80 mg/kg/day) was administered intraperitoneally to the imiquimod (IMQ) psoriasis mouse model. After 7 days, the expression of YAP in the lesions was detected by immunohistochemistry and Western blot. We found that danshensu reduced the expression of YAP in the M5 psoriasis cell model, inhibited cell proliferation, induced cell cycle arrest in G0/G1 phase, and promoted cell apoptosis. All these effects were partly reverted by YAP overexpression. The skin lesions of IMQ mice were thinned and the scales reduced after intragastric administration of danshensu, which also resulted in dose-dependent inhibition of YAP expression. We concluded that danshensu prevents abnormal epidermis proliferation in psoriasis possibly by modulating YAP expression. Our work can provide a theoretical basis for the clinical application of Danshen in the treatment of psoriasis.

Theophylline exerts complex anti-ageing and anti-cytotoxicity effects in human skin ex vivo.

Theophylline is a phosphodiesterase inhibitor that is being used clinically for asthma therapy. In addition, it is recognized as a cosmetic agent with possible anti-ageing and anti-oxidative properties. Nevertheless, how it affects human skin is still poorly examined. Theophylline (10 or 100µM) was administered to the culture medium of full-thickness human skin ex vivo for 24 or 72h. Theophylline stimulated protein expression of the anti-oxidant metallothionein-1 and mRNA levels of collagen I and III. Assessment of fibrillin-1 immunohistology revealed enhanced structural stability of dermal microfibrils. Theophylline also exerted extracellular matrix-protective effects by decreasing MMP-2 and MMP-9 mRNA levels, partially antagonizing the effects of menadione, the potent, toxic ROS donor. In addition, it decreased menadione-stimulated epidermal keratinocytes apoptosis. Interestingly, theophylline also increased the level of intracutaneously produced melatonin, that is the most potent ROS-protective and DNA damage repair neuromediator, and tendentially increased protein expression of MT1, the melatonin receptor. Theophylline also increased the expression of keratin 15, the stem cell marker, in the epidermal basal layer but did not change mitochondrial activity or epidermal pigmentation. This ex vivo pilot study in human skin shows that theophylline possesses several interesting complex skin-protective properties. It encourages further examination of theophylline as a topical candidate for anti-ageing treatment.

High glucose augments ROS generation regulates mitochondrial dysfunction and apoptosis via stress signalling cascades in keratinocytes

Mitochondria are fascinating structures of the cellular compartments that generate energy to run the cells. However, inherent disorders of mitochondria due to diabetes can cause major disruption of metabolism that produces huge amount of reactive oxygen species (ROS). Here we study the elevated level of ROS provoked by high glucose (HG) environment triggered mitochondrial dysfunction, inflammatory response and apoptosis via stress signalling pathway in keratinocytes. Our results demonstrated that elevated glucose level in keratinoctes, increase the accumulations of ROS and decrease in cellular antioxidant capacities. Moreover, excess production of ROS was associated with mitochondrial dysfunction, characterized by loss of mitochondrial membrane potential (ΔΨm), increase in mitochondrial mass, alteration of mitochondrial respiratory complexes, cytochrome c (Cyt c) release, decrease in mitochondrial transcription factor A (TFAM) and increase in mitochondrial DNA (mtDNA) fragmentation. Damaged mtDNA escaped into the cytosol, where it engaged the activation of ERK1/2, PI3K/Akt, tuberin and mTOR via cGAS-STING leading to IRF3 activation. Pre-treatment of pharmacological inhibitors, ERK1/2 or PI3K/Akt suppressed the IRF3 activation. Furthermore, our results demonstrated that activation of IRF3 in HG environment coinciding with increased expression of inflammatory mediators. Excess production of ROS interfered with decreased in cell viability, increased lysosomal content and expression of FoxOs, leading to cell cycle deregulation and apoptosis. Pre-treatment of N-acetyl-l-cysteine (NAC) significantly reduced the HG-induced cell cycle deregulation and apoptosis in keratinocytes. In conclusion, increased oxidative stress underlies the decrease in antioxidant capacities and mitochondrial dysfunction in HG environment correlate with inflammation response and apoptosis via ERK1/2-PI3K/Akt-IRF3 pathway in keratinoctes.

Tumor Necrosis Factor (TNF) Receptor Expression Determines Keratinocyte Fate upon Stimulation with TNF-Like Weak Inducer of Apoptosis.

The interaction between tumor necrosis factor- (TNF-) like weak inducer of apoptosis (TWEAK) and fibroblast growth factor-inducible 14 (Fn14) regulates the fate of keratinocytes, depending on the relative expression of TNF receptor (TNFR) 1 or TNFR2. However, the precise mechanism underlying this TWEAK-mediated regulation remains unclear. The aim of this study was to provide comprehensive insight into the roles of Fn14, TNFR1/2, and other relevant molecules in the fate of keratinocytes. Further, we sought to elucidate the structural basis for the interaction of TWEAK and Fn14 in regulating cellular outcomes. Normal keratinocytes (mainly expressing TNFR1) and TNFR2-overexpressing keratinocytes were stimulated with TWEAK. Through immunoprecipitation and Western blotting of keratinocyte lysates, we elucidated the associations between Fn14, TNFR-associated factor 2 (TRAF2), cellular inhibitor of apoptosis protein 1 (cIAP1), and TNFR1/2 molecules. Additionally, we found that TRAF2 exhibited binding to Fn14, cIAP1, and TNFR1/2. Our data suggest that TWEAK induces apoptosis in normal keratinocytes and proliferation in TNFR2-overexpressing keratinocytes in a TNF-α-independent manner; however, inhibition of TRAF2 appears to reverse this effect. Interestingly, the interaction between TWEAK and Fn14 increased TNFR1-associated death domain protein and caspase-8 expression in normal keratinocytes and promoted cytoplasmic import of cIAP1 in TNFR2-overexpressing keratinocytes. In conclusion, we found that the Fn14-TRAF2-TNFR signaling axis mediates TWEAK's regulation of the fate of keratinocytes, possibly in a manner involving the TNF-α-independent TNFR signal transduction.

Post-translational Modification of OTULIN Regulates Ubiquitin Dynamics and Cell Death

Linear ubiquitination has emerged as an important post-translational modification that regulates NF-κB activation, inflammation, and cell death in both immune and non-immune compartments, including the skin. The deubiquitinase OTULIN specifically disassembles linear ubiquitin chains generated by the linear ubiquitin assembly complex (LUBAC) and is necessary to prevent embryonic lethality and autoinflammatory disease. Here, we dissect the direct role of OTULIN in cell death andfind that OTULIN limits apoptosis and necroptosis in keratinocytes. During apoptosis, OTULIN is cleaved by capase-3 at Asp-31 into a C-terminal fragment that restricts caspase activation and cell death. During necroptosis, OTULIN is hyper-phosphorylated at Tyr-56, which modulates RIPK1 ubiquitin dynamics and promotes cell death. OTULIN Tyr-56 phosphorylation is counteracted by the activity of dual-specificity phosphatase 14 (DUSP14), which we identify as an OTULIN phosphatase that limits necroptosis. Our data provide evidence of dynamic post-translational modifications of OTULIN and highlight their importance in cell death outcome.

Keratinocytes apoptosis contributes to crizotinib induced-erythroderma

Crizotinib is a multi-target receptor tyrosine kinase inhibitor which is of great importance for the management of ALK-rearranged non-small cell lung cancer (NSCLC) patients. Serious erythroderma and toxic epidermal necrolysis have been reported associated with crizotinib treatment. The underlying mechanisms have not been examined. In this study, we tested the toxicity of crizotinib on immortal human keratinocytes (HaCaT) and human primary keratinocytes. We found that crizotinib directly cause cytotoxic on these two cells, which could be the explanation of the clinical characteristic of pathology. Apoptosis was observed and Z-VAD-FMK, a pan-caspase inhibitor can almost totally reverse the apoptosis induction effect of crizotinib. However, mitochondrial dysfunction and DNA damage were not involved in crizotinib-induced apoptosis, indicating the intrinsic apoptosis pathway have no connection with this cutaneous toxicity. Further studies showed that crizotinib significantly increased cleaved-caspase-8, a signaling protein of extrinsic apoptosis pathway, in a concentration and time-dependent manner. Moreover, we found the targets of crizotinib were not involved in HaCaT cells apoptosis. Collectively, our findings first report keratinocytes apoptosis is the key cause of crizotinib-induced cutaneous toxicity. We also reveal crizotinib induce apoptosis through the extrinsic apoptosis pathway due to detected up-regulated cleaved-caspase-8. Meanwhile, the apoptosis is independent of mitochondrial dysfunction, DNA damage and related drug targets inhibition.

Juxtaposition of IL-1β and IFN-γ expression and apoptosis of keratinocytes in adult-onset Still’s disease

ABSTRACTBackgroud: Recently, atypical persistent skin eruptions (APSEs) have been documented as a new manifestation of adult-onset Still’s disease (AOSD), with a unique pathological feature of necrotic keratinocytes in the upper third of the epidermis, but the mechanism has not been elucidated. The aim of this study was to explore the potential mechanism of the unique pathological phenomenon of APSEs.Methods: Clinical and pathological data from 26 AOSD patients with APSEs and 6 with evanescent skin eruptions (ESEs) were reviewed. Fourteen APSE biopsies and 6 ESE biopsies were selected for multi-spectrum immunohistochemistry with 5 disease controls and 5 healthy controls.Results: The unique pathological manifestation was present in all APSE patients but was hardly found in ESE patients. There were more CD4 + T-cells infiltrated in the dermis of APSEs than in the dermis of ESEs. IL-1β and IFN-γ were specifically expressed in the upper third of the epidermis and were juxtaposed to the loci of the necrotic keratinocytes.Conclusion: Our findings showed important cellular and molecular derangements related to the APSE-specific pathological phenomena and helped to understand the pathogenesis of dyskeratosis in the epidermis. The findings could also pave a way to explore an effective intervention to this potentially life-threatening disorder.

LncRNA MEG3 influences the proliferation and apoptosis of psoriasis epidermal cells by targeting miR-21/caspase-8

BackgroundIt was reported that microRNA-21(miR-21) was differentially expressed in the keratinocytes of psoriasis patients, and it may influence the apoptosis and proliferation of cells. The role of lncRNA maternally expressed gene3 (MEG3), a competing endogenous RNAs of miR-21, in the progression of psoriasis remains unclear. We aimed to unfold the influence of MEG3 and miR-21 on the proliferation and apoptosis of psoriasis epidermal cells.Methods50μg/L TNF-α was used to treat HaCaTs and NHEKs cells for 24 h, and then different experiments were conducted. qRT-PCR were applied for measuring the mRNA level of MEG3, miR-2, and caspase-8, and the protein expression of caspase-8 was measured with western blotting. Flow cytometry was used for assessing apoptosis. Cell proliferation was detected using MTT and colony formation assays. Dual luciferase reporter assay was applied for confirming the binding site between MEG3 and miR-21, miR-21 and Caspase-8.ResultsA cell model for in vitro studying the role of MEG3 in psoriasis pathophysiology was established using HaCaT and HHEKs. MEG3 was significantly down-regulated in HaCaT, HHEKs, and psoriatic skin samples. MEG3 inhibits proliferation and promotes apoptosis of Activated-HaCaT (Act-HaCaT) and Activated-HHEKs (Act- HHEK) by regulating miR-21, and the binding site between MEG3 and miR-21 was identified. We also found that miR-21 could inhibit the level of caspase-8 and identified the binding site between caspase-8 and miR-21. Some down-stream proteins of caspase-8, Cleaved caspase-8, cytc, and apaf-1 were regulated by miR-21 and MEG3.ConclusionMEG3/miR-21 axis may regulate the expression of caspase-8, and further influence the proliferation and apoptosis of psoriasis keratinocyte, Act-HaCaT and Act- HHEK. Therefore, our findings may provide a new thought for the study of pathogenesis and treatment of psoriasis.

Mutant GNLY is linked to Stevens-Johnson syndrome and toxic epidermal necrolysis.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare severe cutaneous adverse reactions to drugs. Granulysin (GNLY) plays a key role in keratinocyte apoptosis during SJS/TEN pathophysiology. To determine if GNLY-encoding mutations might be related to the protein's functional disturbances, contributing to SJS/TEN pathogenesis, we performed direct sequencing of GNLY's coding region in a group of 19 Colombian SJS/TEN patients. A GNLY genetic screening was implemented in a group of 249 healthy individuals. We identified the c.11G > A heterozygous sequence variant in a TEN case, which creates a premature termination codon (PTC) (p.Trp4Ter). We show that a mutant protein is synthesised, possibly due to a PTC-readthrough mechanism. Functional assays demonstrated that the mutant protein was abnormally located in the nuclear compartment, potentially leading to a toxic effect. Our results argue in favour of GNLY non-synonymous sequence variants contributing to SJS/TEN pathophysiology, thereby constituting a promising, clinically useful molecular biomarker.

IFN-γ enhances cell-mediated cytotoxicity against keratinocytes via JAK2/STAT1 in lichen planus.

Lichen planus (LP) is a chronic debilitating inflammatory disease of unknown etiology affecting the skin, nails, and mucosa with no current FDA-approved treatments. It is histologically characterized by dense infiltration of T cells and epidermal keratinocyte apoptosis. Using global transcriptomic profiling of patient skin samples, we demonstrate that LP is characterized by a type II interferon (IFN) inflammatory response. The type II IFN, IFN-γ, is demonstrated to prime keratinocytes and increase their susceptibility to CD8+ T cell-mediated cytotoxic responses through MHC class I induction in a coculture model. We show that this process is dependent on Janus kinase 2 (JAK2) and signal transducer and activator of transcription 1 (STAT1), but not JAK1 or STAT2 signaling. Last, using drug prediction algorithms, we identify JAK inhibitors as promising therapeutic agents in LP and demonstrate that the JAK1/2 inhibitor baricitinib fully protects keratinocytes against cell-mediated cytotoxic responses in vitro. In summary, this work elucidates the role and mechanisms of IFN-γ in LP pathogenesis and provides evidence for the therapeutic use of JAK inhibitors to limit cell-mediated cytotoxicity in patients with LP.

Allopurinol-Induced Toxic Epidermal Necrolysis

Toxic epidermal necrolysis (TEN) is an extremely rare condition characterized by separation of dermoepidermal junctions, necrosis, and subsequent detachment of the epidermis over large cutaneous areas. TEN can emerge after exposure to certain medications such as allopurinol, aromatic anticonvulsants, NSAIDs, nevirapine, and antibacterial sulfonamides. There is no standard protocol for TEN, and the therapy of choice varies from one patient to another. Some of these therapies include silver-releasing wraps/dressings, glucocorticoids, antibodies to inhibit Fas-mediated keratinocyte apoptosis, and cyclosporine A. A 35-year-old male with an allergy to antibacterial sulfonamides who was being treated for arterial hypertension and hyperuricemia with captopril and allopurinol, respectively, was admitted to hospital. The patient showed skin detachment affecting approximately 95% of his surface area, including his face, upper and lower extremities, trunk, back, oropharyngeal mucosa, anal mucosa, ocular mucosa, and genital mucosa. Intravenous methylprednisolone at a dosage of 40 mg/day for 7 days along with abrasive cures was found to be an appropriate treatment in this case.

Experimental atopic dermatitis is dependent on the TWEAK/Fn14 signaling pathway.

Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) acts through its receptor fibroblast growth factor inducible 14 (Fn14), and participates in skin inflammation. Both TWEAK and Fn14 are highly expressed in skin lesions of patients with atopic dermatitis. The purpose of this study was to further explore the effect of Fn14 inhibition on experimental atopic dermatitis. Experimental atopic dermatitis was induced in the wild-type and Fn14 knock-out BALB/c mice. The effect of TWEAK/Fn14 interaction on keratinocytes was studied in an in-vitro model of atopic dermatitis. Fn14 deficiency ameliorates skin lesions in the mice model, accompanied by less infiltration of inflammatory cells and lower local levels of proinflammatory cytokines, including TWEAK, TNF-α and interleukin (IL)-17. Fn14 deficiency also attenuates the up-regulation of TNFR1 in skin lesions of atopic dermatitis. Moreover, topical TWEAK exacerbates skin lesion in the wild-type but not in the Fn14 knock-out mice. In vitro, TWEAK enhances the expressions of IL-17, IL-18 and IFN-γ in keratinocytes under atopic dermatitis-like inflammation. These results suggest that Fn14 deficiency protects mice from experimental atopic dermatitis, involving the attenuation of inflammatory responses and keratinocyte apoptosis. In the context of atopic dermatitis-like inflammation, TWEAK modulates keratinocytes via a TNFR1-mediated pathway.

CDK4/6 inhibition mitigates stem cell damage in a novel model for taxane‐induced alopecia

Taxanes are a leading cause of severe and often permanent chemotherapy‐induced alopecia. As the underlying pathobiology of taxane chemotherapy‐induced alopecia remains poorly understood, we investigated how paclitaxel and docetaxel damage human scalp hair follicles in a clinically relevant ex vivo organ culture model. Paclitaxel and docetaxel induced massive mitotic defects and apoptosis in transit amplifying hair matrix keratinocytes and within epithelial stem/progenitor cell‐rich outer root sheath compartments, including within Keratin 15+ cell populations, thus implicating direct damage to stem/progenitor cells as an explanation for the severity and permanence of taxane chemotherapy‐induced alopecia. Moreover, by administering the CDK4/6 inhibitor palbociclib, we show that transit amplifying and stem/progenitor cells can be protected from paclitaxel cytotoxicity through G1 arrest, without premature catagen induction and additional hair follicle damage. Thus, the current study elucidates the pathobiology of taxane chemotherapy‐induced alopecia, highlights the paramount importance of epithelial stem/progenitor cell‐protective therapy in taxane‐based oncotherapy, and provides preclinical proof‐of‐principle in a healthy human (mini‐) organ that G1 arrest therapy can limit taxane‐induced tissue damage.

Magnoflorine from Coptis chinese has the potential to treat DNCB-induced Atopic dermatits by inhibiting apoptosis of keratinocyte

AimsIn Sheng Nong’s herbal classic in China, Rhizoma coptidisaRC: Rhizoma coptidisa(RC) could be used to treat Atopic dermatitsbAD: Atopic dermatitsb(AD), but its core ingredient(s) and mechanism remains unknown. The present study aimed to find out the ingredients against AD and expound its mechanisms. Materials and methodsSeven alkaloids were isolated from RC to compare the inhibition against HaCaT cells by MTT assays and apoptosis of cells stimulated with TNF-α/IFN-γ by flow cytometry. The effects of target alkaloids against AD were evaluated on DNCBcDNCB: 2,4-dinitrochlorobenzenec (2,4-dinitrochlorobenzene)-induced atopic dermatitis in mice. Key findingsSeven alkaloids were isolated from RC successfully. The results from MTT and flow cytometry indicated that among these alkaloids, only magnoflorine dMAG: magnoflorined(MAG) had no obvious toxicity on cells, but could inhibit the apoptosis of the cells stimulated with TNF-α/IFN-γ. Further animal experiments confirmed that MAG significantly attenuated the AD-like symptom and inhibited the AD-induced increases in IgE/IL-4, as compared with control (P < 0.01). Moreover, MAG reduced the low ΔψmeΔψm: mitochondrial membrane potentiale(mitochondrial membrane potential) in HaCaT cells. The results of western blotting proved that MAG inhibited apoptosis of keratinocytes through decreasing the expressions of CTSBfCTSB: cathepsin Bf (cathepsin B), Cyte CgCyte C: cytochrome Cg (cytochrome C), Bid and caspase-3/7/8/9. SignificanceOverall, MAG inhibited apoptosis by decreasing the expression of apoptotic pathway-related proteins, and laid a foundation for the study of AD mechanisms.