Predominant Role of mTOR Signaling in Skin Diseases with Therapeutic Potential

International Journal of Molecular Sciences, Год журнала: 2022, Номер 23(3), С. 1693 - 1693

Опубликована: Фев. 1, 2022

The serine/threonine kinase mechanistic target of rapamycin (mTOR) plays a pivotal role in the regulation cell proliferation, survival, and motility response to availability energy nutrients as well mitogens. mTOR signaling axis regulates important biological processes, including cellular growth, metabolism, survival many tissues. In skin, dysregulation PI3K/AKT/mTOR pathway may lead severe pathological conditions characterized by uncontrolled proliferation inflammation, skin hyperproliferative malignant diseases. Herein, we provide an update on current knowledge regarding pathogenic implication diseases with inflammatory features (such psoriasis, atopic dermatitis, pemphigus, acne) characteristics cutaneous T lymphoma melanoma) while critically discuss future perspectives for therapeutic targeting clinical practice.

Язык: Английский

---

Pathogenesis, multi-omics research, and clinical treatment of psoriasis

Journal of Autoimmunity, Год журнала: 2022, Номер 133, С. 102916 - 102916

Опубликована: Окт. 6, 2022

Язык: Английский

---

Dual targeting of mTOR/IL-17A and autophagy by fisetin alleviates psoriasis-like skin inflammation

Frontiers in Immunology, Год журнала: 2023, Номер 13

Опубликована: Янв. 18, 2023

Psoriasis is a chronic autoimmune inflammatory skin disorder characterized by epidermal hyperplasia and aberrant immune response. In addition to cytokine production, psoriasis associated with activation of the Akt/mTOR pathway. mTOR/S6K1 regulates T-lymphocyte migration, keratinocytes proliferation upregulated in psoriatic lesions. Several drugs that target Th1/Th17 cytokines or their receptors have been approved for treating humans variable results necessitating improved therapies. Fisetin, natural dietary polyphenol anti-oxidant anti-proliferative properties, covalently binds mTOR/S6K1. The effects fisetin on its underlying mechanisms not clearly defined. Here, we evaluated immunomodulatory Th1/Th17-cytokine-activated adult human (HEKa) anti-CD3/CD28-stimulated CD4 + T cells compared these activities those rapamycin (an mTOR inhibitor). Transcriptomic analysis HEKa revealed 12,713 differentially expressed genes (DEGs) fisetin-treated group 7,374 DEGs rapamycin-treated group, both individually treated group. Gene ontology enriched functional groups related PI3K/Akt/mTOR signaling pathways, psoriasis, development. Using silico molecular modeling, observed high binding affinity IL-17A. vitro , significantly inhibited activity, increased expression autophagy markers LC3A/B Atg5 suppressed secretion IL-17A activated lymphocytes co-cultured HEKa. Topical administration an imiquimod (IMQ)-induced mouse model exhibited better effect than reducing psoriasis-like inflammation phosphorylation promoting keratinocyte differentiation mice Fisetin also T-lymphocytes F4/80 macrophage infiltration into skin. We conclude potently inhibits pathway promotes alleviate IMQ-induced disease mice. Altogether, our findings suggest as potential treatment possibly other diseases.

Язык: Английский

---

Application of Luteolin in Neoplasms and Nonneoplastic Diseases

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(21), С. 15995 - 15995

Опубликована: Ноя. 6, 2023

Researchers are amazed at the multitude of biological effects 3′,4′,5,7-tetrahydroxyflavone, more commonly known as luteolin, it simultaneously has antioxidant and pro-oxidant, well antimicrobial, anti-inflammatory, cancer-preventive, properties. The anticancer properties luteolin constitute a mosaic pathways due to which this flavonoid influences cancer cells. Not only is able induce apoptosis inhibit cell proliferation, but also suppresses angiogenesis metastasis. Moreover, succeeds in sensitization therapeutically induced cytotoxicity. Nevertheless, apart from its promising role chemoprevention, exhibits numerous potential utilizations patients with conditions other than neoplasms, include inflammatory skin diseases, diabetes mellitus, COVID-19. This review aims present multidimensionality luteolin’s impact on both neoplastic nonneoplastic diseases. When comes we intend describe complexity molecular mechanisms that underlay effectiveness, prove usefulness integrating therapy via analysis recent research breast, colon, lung cancer. Regarding emphasize importance researching areas such diabetology, virology, dermatology summarizes most important discoveries those fields regarding application.

Язык: Английский

---

Nobiletin and Eriodictyol Suppress Release of IL-1β, CXCL8, IL-6, and MMP-9 from LPS, SARS-CoV-2 Spike Protein, and Ochratoxin A-Stimulated Human Microglia

International Journal of Molecular Sciences, Год журнала: 2025, Номер 26(2), С. 636 - 636

Опубликована: Янв. 14, 2025

Neuroinflammation is involved in various neurological and neurodegenerative disorders which the activation of microglia one key factors. In this study, we examined anti-inflammatory effects flavonoids nobiletin (5,6,7,8,3′,4′-hexamethoxyflavone) eriodictyol (3′,4′,5,7-tetraxydroxyflavanone) on human cell line stimulated by either lipopolysaccharide (LPS), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) full-length Spike protein (FL-Spike), or mycotoxin ochratoxin A (OTA). Human were preincubated with (10, 50, 100 µM) for h, following which, they 24 h. The inflammatory mediators interleukin-1 beta (IL-1β), chemokine (C-X-C motif) ligand 8 (CXCL8), IL-6, matrix metalloproteinase-9 (MMP-9) quantified culture supernatant enzyme-linked immunosorbent assay (ELISA). Both significantly inhibited LPS, FL-Spike, OTA-stimulated release IL-1β, CXCL8, MMP-9 at 50 µM, while, most cases, was also effective 10 pronounced reductions µM. These findings suggest that both are potent inhibitors pathogen-stimulated microglial mediators, highlighting their potential therapeutic application neuroinflammatory diseases, such as long COVID.

Язык: Английский

---

miR-16-5p, miR-21-5p, and miR-155-5p in circulating vesicles as psoriasis biomarkers

Scientific Reports, Год журнала: 2025, Номер 15(1)

Опубликована: Фев. 26, 2025

Abstract Psoriasis is a chronic skin disorder marked by fast cell growth, leading to thick, red, scaly patches. MicroRNAs are small, non-coding RNA molecules that play crucial role in post-transcriptional gene regulation. This study investigates miR-16-5p, miR-21-5p, and miR-155-5p expression psoriasis EVs assesses their biomarker potential, exploring associated target genes pathways via bioinformatics. A cross-sectional case-control included 40 patients, with blood samples collected EDTA tubes. from extracellular vesicles was isolated using Qiagen kits, miRNAs were quantified RT-qPCR. Bioinformatic analysis predicted databases like miRDB TargetScan. Gene data GEO processed, differentially expressed identified. assessed patients’ circulating versus controls, finding significantly lower levels patients. ROC confirmed diagnostic potential. positive correlation of miR-16-5p the Area Severity Index (PASI) suggests severity marker Bioinformatics identified 378 common dysregulated genes, revealing key interactions psoriasis. heat map miRNA-mediated suppression disease. identifies as potential biomarkers, addition significant involved pathophysiology.

Язык: Английский

---

Metabolic Syndrome and Skin Diseases

Frontiers in Endocrinology, Год журнала: 2019, Номер 10

Опубликована: Ноя. 20, 2019

The increasing prevalence Metabolic syndrome (MetS) is a worldwide health problem, and the association between MetS skin diseases has recently attracted growing attention. In this review, we summarize associations diseases, such as psoriasis, acne vulgaris, hidradenitis suppurativa, androgenetic alopecia, acanthosis nigricans, atopic dermatitis. To discuss potential common mechanisms underlying focus on insulin signaling resistance, well chronic inflammation including adipokines proinflammatory cytokines related to molecular mechanisms. A better understanding of relationship contributes early diagnosis prevention, providing clues for developing novel therapeutic strategies.

Язык: Английский

---

IL-33 stimulates human mast cell release of CCL5 and CCL2 via MAPK and NF-κB, inhibited by methoxyluteolin

European Journal of Pharmacology, Год журнала: 2019, Номер 865, С. 172760 - 172760

Опубликована: Окт. 26, 2019

Mast Cells (MCs) are critical for allergic reactions but also play important roles in inflammation, following stimulation by non-allergic triggers such as cytokines. Upon stimulation, MCs secrete numerous newly synthesized mediators, the mechanism of release chemokines, which pathogenesis and inflammatory diseases, remains unknown. IL-33 is an "alarmin", known to augment MCs, its effect on chemokines not known. The present work investigated action CCL5 CCL2 from human well inhibitory flavonoid 3′,4′,5,7-tetramethoxyflavone (methoxyluteolin). Stimulation cultured (LAD2) primary (hCBMCs) (1–100 ng/ml) increased gene expression ( P < 0.0001) 0.01). with (10 activated MAPK components, shown phosphorylation p38α MAPK, JNK, c-Jun using Western blot analysis. Inhibition these responses inhibitors confirmed that stimulated activation IκB-α. were significantly inhibited 2 h pre-treatment methoxyluteolin (10, 50, 100 μM). inhibition (50 μM) was mediated via phosphorylated JNK affected. In conclusion, plays role chemokine more than one signaling pathway. may indicate it can be developed a novel treatment diseases. Diagrammatic Representation stimulates Proposed Points Methoxyluteolin. binds ST2 IL-1 receptor accessory protein (IL-1RAcP) receptors leading recruitment MyD88 TRAF6, leads NF-κB CCL2. Inhibitors p38 or IκB-α reduces Pre-treatment inhibits release. However, does occur pathway rather previous our laboratory has Iκβ-α induction at both transcriptional translational levels LAD2.

Язык: Английский

---

Interleukin (IL)-17/IL-36 axis participates to the crosstalk between endothelial cells and keratinocytes during inflammatory skin responses

PLoS ONE, Год журнала: 2020, Номер 15(4), С. e0222969 - e0222969

Опубликована: Апрель 30, 2020

In inflammatory skin conditions, such as psoriasis, vascular enlargement is associated with endothelial cell proliferation, release of cytokines and adhesion molecule expression. Interleukin (IL)-17A a pro-inflammatory cytokine mainly secreted by T helper-17 cells that critically involved in psoriasis pathogenesis. IL-36α, IL-36β IL-36γ are also up-regulated induced various stimuli, including IL-17A. this study, we found human keratinocytes the main source IL-36, particular IL-36γ. This was strongly IL-17A and, together IL-17A, efficiently activated dermal microvascular (HDMECs), which expressed both IL-17 IL-36 receptors. Both proliferation through specific molecular cascades involving ERK1/2 only or ERK1/2, STAT3 NF-κB, respectively. We highlighted intense IL-17A- -dependent interplay between HDMECs, likely active psoriatic lesions leading to establishment network responsible for development maintenance inflamed state. showed HDMECs synergic activity TNF-α potently inducing cytokine/chemokine ICAM-1 investigated involvement VEGF-A, substantially reduced lesional patients pharmacologically treated anti-IL-17A antibody Secukinumab. Importantly, keratinocyte-derived represented an additional pro-angiogenic mediator observed VEGF-A influenced but did not act on expression molecules HDMECs. On other hand, inhibition released IL-17A-treated impaired either vivo murine model psoriasis. Taken together, our data demonstrated highly cells/keratinocytes crosstalk conditions.

Язык: Английский

---

Psoriasis immunometabolism: progress on metabolic biomarkers and targeted therapy

Frontiers in Molecular Biosciences, Год журнала: 2023, Номер 10

Опубликована: Июнь 19, 2023

Psoriasis is a common inflammatory disease that affects mainly the skin. However, moderate to severe forms have been associated with several comorbidities, such as psoriatic arthritis, Crohn’s disease, metabolic syndrome and cardiovascular disease. Keratinocytes T helper cells are dominant cell types involved in psoriasis development via complex crosstalk between epithelial cells, peripheral immune residing Immunometabolism has emerged potent mechanism elucidating aetiopathogenesis of psoriasis, offering novel specific targets diagnose treat early. The present article discusses reprogramming activated tissue-resident memory keratinocytes skin, presenting biomarkers therapeutic targets. In phenotype, glycolysis dependent characterized by disruptions TCA cycle, amino acid metabolism fatty metabolism. Upregulation mammalian target rapamycin (mTOR) results hyperproliferation cytokine secretion keratinocytes. Metabolic through inhibition affected pathways dietary restoration imbalances may thus opportunity achieve long-term management improved quality life minimum adverse effects.

Язык: Английский

---