Thalidomide Attenuates Skin Lesions and Inflammation in Rosacea-Like Mice Induced by Long-Term Exposure of LL-37

Kang

et al. 2023

CIMB

Self Cite

Rosacea is a chronic inflammatory skin disease whose late manifestations have not yet been clearly reported in animal models. The objective of this study is to describe the skin lesions and major histopathological changes in a rosacea-like phenotype in mice induced by prolonged LL-37 administration and furthermore, to assess the potential of long-term LL-37 administration in inducing irreversible rosacea-like skin lesion models. Balb/c mice were continuously injected intradermally with LL-37 every 12 h to induce a rosacea-like phenotype. After LL-37 injections were administered for 20 consecutive days, the area of rosacea-like lesions gradually expanded in the first 13 days, then entered a stable phase. Haematoxylin and eosin (H&E) and Van Gieson’s staining showed a high degree of inflammatory cell aggregation, thickening of the epidermis and dermis, and collagen deposition in large quantities. The results of immunofluorescence staining and Western blotting showed that the expression of α-SMA, TNF-α, vimentin, and COL1 in the skin of mice was significantly upregulated. Short-term LL-37 administration induced rosacea-like lesions that only featured the aggregation of inflammatory factors and thickening of the epidermis, whereas no collagen hyperplasia was observed, and a full recovery was noticed. However, rosacea-like skin lesions induced by long-term LL-37 administration did not completely recover. Our study compares rosacea-like lesions induced by short-term versus long-term LL-37 administration, and the results suggest that irreversible rosacea-like lesions can be induced by long-term LL-37 administration.

Section: Discussionsupporting

confidence: 84%

Long-Term Administration of LL-37 Can Induce Irreversible Rosacea-like Lesion

Kang

et al. 2023

CIMB

Self Cite

“…The drug functions by inhibiting the Ca 2+ -CaMKII-dependent mTOR-NF-kβ signaling pathway ( 97 ). Continuing the theme of LL-37 modulation for treatment of rosacea, thalidomide has been shown to alleviate rosacea phenotypes in a mouse model by reducing the production of cytokines and chemokines induced through LL-37 ( 98 , 99 ). Another medication with therapeutic potential around the cathelicidin pathway is supramolecular salicylic acid (SSA).…”

Section: Future Therapies and Rational Targetsmentioning

confidence: 99%

Rosacea pathogenesis and therapeutics: current treatments and a look at future targets

Fisher,

Travers,

Rohan

2023

Front. Med.

Rosacea is a chronic inflammatory skin condition associated with a significant health and economic burden from costs and loss of productivity due to seeking medical treatment. The disease encompasses multiple phenotypic manifestations involving a complex and multi-variate pathogenesis. Although the pathophysiology of rosacea is not completely understood, ongoing research is continually elucidating its mechanisms. In this review, current concepts of rosacea pathogenesis will be addressed which involve skin barrier and permeability dysfunction, the innate and adaptive immune systems, and the neurovascular system. More specifically, the cathelicidin pathway, transient potential receptor channels, mast cells, and the NLRP3 inflammasome pathway are various targets of current pharmacologic regimens. Future therapies may seek different mechanisms to act on current treatment targets, like the potential use of JAK/STAT inhibitors in ameliorating skin barrier dysfunction or TLR antagonists in alleviating cathelicidin mediated inflammation. Other potential treatments aim for entirely different molecular targets such as microvesicle particle mediated local and systemic inflammation. Ultimately rosacea is associated with a significant health and economic burden which warrants deeper research into its pathogenesis and resultant new treatment discovery.

“…Silicosis is a common form of pulmonary fibrosis in China (Li et al 2022b ) 39 Thalidomide derivative CC-885 was found to be a Basonuclin 2 (BNC2) inhibitor. The transcript BCN2 is responsible for simulating fibrosis signalling in tissues (Bobowski-Gerard et al 2022 ) 40 Thalidomide effectively lowered skin lesions, inflammation and fibrosis related factors in rosacea mice model (Kang et al 2022 ) …”

Section: Introductionmentioning

confidence: 99%

Thalidomide interaction with inflammation in idiopathic pulmonary fibrosis

et al. 2023

The “Thalidomide tragedy” is a landmark in the history of the pharmaceutical industry. Despite limited clinical trials, there is a continuous effort to investigate thalidomide as a drug for cancer and inflammatory diseases such as rheumatoid arthritis, lepromatous leprosy, and COVID-19. This review focuses on the possibilities of targeting inflammation by repurposing thalidomide for the treatment of idiopathic pulmonary fibrosis (IPF). Articles were searched from the Scopus database, sorted, and selected articles were reviewed. The content includes the proven mechanisms of action of thalidomide relevant to IPF. Inflammation, oxidative stress, and epigenetic mechanisms are major pathogenic factors in IPF. Transforming growth factor-β (TGF-β) is the major biomarker of IPF. Thalidomide is an effective anti-inflammatory drug in inhibiting TGF-β, interleukins (IL-6 and IL-1β), and tumour necrosis factor-α (TNF-α). Thalidomide binds cereblon, a process that is involved in the proposed mechanism in specific cancers such as breast cancer, colon cancer, multiple myeloma, and lung cancer. Cereblon is involved in activating AMP-activated protein kinase (AMPK)-TGF-β/Smad signalling, thereby attenuating fibrosis. The past few years have witnessed an improvement in the identification of biomarkers and diagnostic technologies in respiratory diseases, partly because of the COVID-19 pandemic. Hence, investment in clinical trials with a systematic plan can help repurpose thalidomide for pulmonary fibrosis. Graphical Abstract