p16ink4a Positivity of Melanocytes in Non-Segmental Vitiligo

Cellular senescence is induced in response to cellular stressors such as increased levels of reactive oxygen species. The chronic accumulation of senescent cells is currently recognized as a contributor to the pathologic processes of diverse degenerative diseases. Vitiligo is characterized by the disappearance of melanocytes driven by cellular stress within melanocytes and autoimmune processes. In this study, we examined p16INK4A positivity in the lesional and perilesional skin of 54 non-segmental vitiligo patients to explore cellular senescence in vitiligo. There were more p16INK4A-positive melanocytes in the perilesional vitiligo skin samples than in control samples. It was also found that p16INK4A immunoreactivity was not restricted to melanocytes but also existed in fibroblasts; the number of p16INK4A-positive fibroblasts was significantly increased in lesional skin compared to perilesional skin and normal controls. However, in the subgroup analysis of sun-exposed and non-exposed samples, this outcome was only found at sun-exposed sites, suggesting that fibroblast senescence is an epiphenomenon related to the loss of pigment in skin with vitiligo. In summary, exploring p16INK4A positivity in vitiligo revealed melanocyte senescence in perilesional skin, which may play a role in vitiligo pathogenesis.

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THU0010 GENES ASSOCIATED WITH NUCLEOTIDE OLIGOMERIZATION DOMAIN-LIKE RECEPTOR SIGNALING PATHWAY ARE UPREGULATED IN CUTANEOUS LUPUS ERYTHEMATOSUS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.6159 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 217.3-217

Author(s):

I. Calderon ◽

R. Mina

Keyword(s):

Immune System ◽

Signaling Pathway ◽

Lupus Erythematosus ◽

Innate Immune System ◽

Cutaneous Lupus Erythematosus ◽

Skin Lesions ◽

Innate Immune ◽

Normal Controls ◽

Cutaneous Lupus ◽

Skin Samples

Background:Cutaneous Lupus Erythematosus (CLE) is a disfiguring autoimmune skin disorder with several subtypes: discoid lupus, subacute cutaneous lupus, and acute cutaneous lupus. CLE is associated with defects in the adaptive immune system, and, at times, systemic involvement. The innate immune system is likely involved as seen in the presence of interface dermatitis, which is observed in viral exanthems, and improvement of CLE using inhibitors to membrane-bound Pattern Recognition Receptors.Objectives:Compare the expression of genes associated with the innate immune system in active CLE skin lesions of different subtypes compared to normal skin controls.Methods:Five datasets selected from the Gene Expression Omnibus (GEO) were analyzed using GEO2R to compare the gene expressions between different subtypes of CLE. Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database, Gene Card, and Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway analysis were used to identify the interaction and function of specific genes.Results:There were a total of 147 CLE skin samples and 52 normal controls. Genes associated with the Nucleotide-Binding Oligomerization Domain-Like Receptor (NLR) signaling pathway were upregulated in CLE skin samples (adjusted p-value < 0.001). Five genes associated with the NLR signaling pathway, STAT1, OAS1, OAS2, OAS3, and AIM2, were found to be upregulated in skin samples of CLE patients in all datasets, regardless of type, compared to normal controls in all datasets. These five genes are associated with transcription activation, regulation of viral infection, and interferon response.Conclusion:Genes associated with the NLR signaling pathway are upregulated in the skin lesions of CLE patients compared to normal controls, supporting the role of the innate immune system in CLE. Further validation studies using experimental methods are needed.References:[1]Enhanced inflammasome activity in systemic lupus erythematosus is mediated via type I interferon upregulation of interferon regulatory factor 1. Liu J, et al. Arth Rheum. 2017; 69(9): 1840-1849.Disclosure of Interests:None declared

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Towards a Consensus on Alzheimer’s Disease Comorbidity?

Journal of Clinical Medicine ◽

10.3390/jcm10194360 ◽

2021 ◽

Vol 10 (19) ◽

pp. 4360

Author(s):

Iska Avitan ◽

Yudit Halperin ◽

Trishna Saha ◽

Naamah Bloch ◽

Dana Atrahimovich ◽

...

Keyword(s):

Risk Factors ◽

Heart Failure ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Potential Role ◽

Oxygen Species ◽

Degenerative Diseases ◽

Comorbid Diseases

Alzheimer’s disease (AD) is often comorbid with other pathologies. First, we review shortly the diseases most associated with AD in the clinic. Then we query PubMed citations for the co-occurrence of AD with other diseases, using a list of 400 common pathologies. Significantly, AD is found to be associated with schizophrenia and psychosis, sleep insomnia and apnea, type 2 diabetes, atherosclerosis, hypertension, cardiovascular diseases, obesity, fibrillation, osteoporosis, arthritis, glaucoma, metabolic syndrome, pain, herpes, HIV, alcoholism, heart failure, migraine, pneumonia, dyslipidemia, COPD and asthma, hearing loss, and tobacco smoking. Trivially, AD is also found to be associated with several neurodegenerative diseases, which are disregarded. Notably, our predicted results are consistent with the previously published clinical data and correlate nicely with individual publications. Our results emphasize risk factors and promulgate diseases often associated with AD. Interestingly, the comorbid diseases are often degenerative diseases exacerbated by reactive oxygen species, thus underlining the potential role of antioxidants in the treatment of AD and comorbid diseases.

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Rejuvenation of mesenchymal stem cells by extracellular vesicles inhibits the elevation of reactive oxygen species

Scientific Reports ◽

10.1038/s41598-020-74444-8 ◽

2020 ◽

Vol 10 (1) ◽

Cited By ~ 1

Author(s):

Vuong Cat Khanh ◽

Toshiharu Yamashita ◽

Kinuko Ohneda ◽

Chiho Tokunaga ◽

Hideyuki Kato ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Stem Cells ◽

Mesenchymal Stem Cells ◽

Extracellular Vesicles ◽

Cellular Senescence ◽

Skin Flap ◽

Reactive Oxygen ◽

Oxygen Species

Abstract Aging induces numerous cellular disorders, such as the elevation of reactive oxygen species (ROS), in a number type of cells, including mesenchymal stem cells (MSCs). However, the correlation of ROS and impaired healing abilities as well as whether or not the inhibition of elevating ROS results in the rejuvenation of elderly MSCs is unclear. The rejuvenation of aged MSCs has thus recently received attention in the field of regenerative medicine. Specifically, extracellular vesicles (EVs) act as a novel tool for stem cell rejuvenation due to their gene transfer ability with systemic effects and safety. In the present study, we examined the roles of aging-associated ROS in the function and rejuvenation of elderly MSCs by infant EVs. The data clearly showed that elderly MSCs exhibited the downregulation of superoxide dismutase (SOD)1 and SOD3, which resulted in the elevation of ROS and downregulation of the MEK/ERK pathways, which are involved in the impairment of the MSCs’ ability to decrease necrotic area in the skin flap model. Furthermore, treatment with the antioxidant Edaravone or co-overexpression of SOD1 and SOD3 rescued elderly MSCs from the elevation of ROS and cellular senescence, thereby improving their functions. Of note, infant MSC-derived EVs rejuvenated elderly MSCs by inhibiting ROS production and the acceleration of cellular senescence and promoting the proliferation and in vivo functions in both type 1 and type 2 diabetic mice.

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Expression of miR-135b in Psoriatic Skin and Its Association with Disease Improvement

Cells ◽

10.3390/cells9071603 ◽

2020 ◽

Vol 9 (7) ◽

pp. 1603 ◽

Cited By ~ 1

Author(s):

Pablo Chicharro ◽

Pedro Rodríguez-Jiménez ◽

Mar Llamas-Velasco ◽

Nuria Montes ◽

Ancor Sanz-García ◽

...

Keyword(s):

Severity Index ◽

Psoriatic Skin ◽

Local Inflammatory Response ◽

Lesional Skin ◽

Basal Expression ◽

Severity Index Score ◽

Residual Lesions ◽

Generation Sequencing ◽

Additional Sample ◽

Skin Samples

miRNAs have been associated with psoriasis since just over a decade. However, we are far from a complete understanding of their role during the development of this disease. Our objective was to characterize the cutaneous expression of miRNAs not previously described in psoriasis, the changes induced following the treatment with biologicals and their association with disease improvement. Next generation sequencing was performed from five skin samples from psoriasis patients (lesional and non-lesional skin) and five controls, and from this cohort, 12 microRNAs were selected to be analyzed in skin samples from 44 patients with plaque psoriasis. In 15 patients, an additional sample was obtained after three months of biological treatment. MiR-9-5p, miR-133a-3p and miR-375 were downregulated in the lesional skin of psoriasis patients. After treatment, expression of miR-133a-3p, miR-375, miR-378a and miR-135b in residual lesions returned towards the levels observed in non-lesional skin. The decrease in miR-135b levels after treatment with biologics was associated with both the improvement of patients evaluated through Psoriasis Area and Severity Index score and the decrease in local inflammatory response. Moreover, basal expression of miR-135b along with age was associated with the improvement of psoriasis, suggesting its possible usefulness as a prognostic biomarker.

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Melanogenic Properties and Expression Profiles of Melanogenic Paracrine Molecules in Riehl’s Melanosis

International Journal of Molecular Sciences ◽

10.3390/ijms21051695 ◽

2020 ◽

Vol 21 (5) ◽

pp. 1695

Author(s):

Yu Woo ◽

Hyo Park ◽

Seo-Won Jeong ◽

Hyun Park

Keyword(s):

Stem Cell Factor ◽

Immunohistochemical Staining ◽

Expression Profiles ◽

Pathogenetic Mechanism ◽

Lesional Skin ◽

Vascular Proliferation ◽

The Face ◽

Skin Biopsies ◽

Perilesional Skin

Riehl’s melanosis is a hyperpigmentary disorder that occurs predominantly on the face and neck. To date, the pathogenesis of Riehl’s melanosis with regards to the melanogenic properties and paracrine melanogenic molecules has not well been studied. This study was aimed to provide a novel perspective on the pathogenesis of Riehl’s melanosis by identifying the relevant paracrine melanogenic molecules in Riehl’s melanosis. Skin biopsies were performed on lesional and normal-appearing perilesional skin of 12 patients with Riehl’s melanosis and 12 age- and sex-matched healthy controls. Histopathological and immunohistochemical staining for paracrine melanogenic molecules was analyzed. The major histopathological findings of Riehl’s melanosis were basal hyperpigmentation, melanocyte proliferation, interface change, dermal pigmentary incontinence, vascular proliferation, and dermal inflammation. Dermal expression intensities of stem cell factor (SCF) and c-kit were increased in the lesional skin of Riehl’s melanosis. In addition, increased expression of epidermal and dermal ET-1 was also observed in the lesional skin of Riehl’s melanosis. Increased tissue expressions of SCF, c-kit, and ET-1 in Riehl’s melanosis support the role of these paracrine melanogenic molecules in the pathogenesis of Riehl’s melanosis. The findings from this study might present useful information on the pathogenetic mechanism of Riehl’s melanosis.

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Differential Expression of Estrogen-Responsive Genes in Women with Psoriasis

Journal of Personalized Medicine ◽

10.3390/jpm11090925 ◽

2021 ◽

Vol 11 (9) ◽

pp. 925

Author(s):

Vladimir Sobolev ◽

Anna Soboleva ◽

Elena Denisova ◽

Malika Denieva ◽

Eugenia Dvoryankova ◽

...

Keyword(s):

Healthy Volunteers ◽

Differential Expression ◽

Biological Effects ◽

Differentially Expressed ◽

Lesional Skin ◽

Female Patients ◽

Genes Encoding ◽

Liquid Chromatography Tandem Mass ◽

Severity Of The Disease ◽

Skin Samples

In women, the flow of psoriasis is influenced by each phase of a woman’s life cycle. According to previous findings, significant changes in the levels of sex hormones affect the severity of the disease. Aim: The aim of this study was to identify the estrogen-responsive genes that could be responsible for the exacerbation of psoriasis in menopausal women. Methods: Skin samples of lesional skin donated by psoriasis patients (n = 5) were compared with skin samples of healthy volunteers (n = 5) using liquid chromatography–tandem mass spectrometry (LC–MS/MS). The set of differentially expressed proteins was subjected to protein ontology analysis to identify differentially expressed estrogen-responsive proteins. The expression of discovered proteins was validated by qPCR and ELISA on four groups of female participants. The first group included ten psoriasis patients without menopause; the second included eleven postmenopausal patients; the third included five healthy volunteers without menopause; and the fourth included six postmenopausal volunteers. Moreover, the participants’ blood samples were used to assess the levels of estradiol, progesterone, and testosterone. Results: We found that the levels of estradiol and progesterone were significantly lower and the levels of testosterone were significantly higher in the blood of patients compared to the control. The protein ontology analysis of LC–MS/MS data identified six proteins, namely HMOX1, KRT19, LDHA, HSPD1, MAPK1, and CA2, differentially expressed in the lesional skin of female patients compared to male patients. ELISA and qPCR experiments confirmed differential expression of the named proteins and their mRNA. The genes encoding the named proteins were differentially expressed in patients compared to volunteers. However, KRT19 and LDHA were not differentially expressed when we compared patients with and without menopause. All genes, except MAPK1, were differentially expressed in patients with menopause compared to the volunteers with menopause. HMOX1, KRT19, HSPD1, and LDHA were differentially expressed in patients without menopause compared to the volunteers without menopause. However, no significant changes were found when we compared healthy volunteers with and without menopause. Conclusion: Our experiments discovered a differential expression of six estrogen-controlled genes in the skin of female patients. Identification of these genes and assessment of the changes in their expression provide insight into the biological effects of estrogen in lesional skin. The results of proteomic analysis are available via ProteomeXchange with identifier PXD021673.

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d-amino acid oxidase promotes cellular senescence via the production of reactive oxygen species

Life Science Alliance ◽

10.26508/lsa.201800045 ◽

2019 ◽

Vol 2 (1) ◽

pp. e201800045 ◽

Cited By ~ 3

Author(s):

Taiki Nagano ◽

Shunsuke Yamao ◽

Anju Terachi ◽

Hidetora Yarimizu ◽

Haruki Itoh ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Amino Acids ◽

Dna Damage ◽

Amino Acid ◽

Cellular Senescence ◽

Reactive Oxygen ◽

Acid Oxidase ◽

Dependent Manner ◽

Oxygen Species ◽

Amino Acid Oxidase

d-amino acid oxidase (DAO) is a flavin adenine dinucleotide (FAD)–dependent oxidase metabolizing neutral and polard-amino acids. Unlikel-amino acids, the amounts ofd-amino acids in mammalian tissues are extremely low, and therefore, little has been investigated regarding the physiological role of DAO. We have recently identifiedDAOto be up-regulated in cellular senescence, a permanent cell cycle arrest induced by various stresses, such as persistent DNA damage and oxidative stress. Because DAO produces reactive oxygen species (ROS) as byproducts of substrate oxidation and the accumulation of ROS mediates the senescence induction, we explored the relationship between DAO and senescence. We found that inhibition of DAO impaired senescence induced by DNA damage, and ectopic expression of wild-type DAO, but not enzymatically inactive mutant, enhanced it in an ROS-dependent manner. Furthermore, addition ofd-amino acids and riboflavin, a metabolic precursor of FAD, to the medium potentiated the senescence-promoting effect of DAO. These results indicate that DAO promotes senescence through the enzymatic ROS generation, and its activity is regulated by the availability of its substrate and coenzyme.

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