Palbociclib blocks neutrophilic phosphatidylinositol 3-kinase activity to alleviate psoriasiform dermatitis.

BACKGROUND AND PURPOSE: Neutrophilic inflammation is a critical pathogenic factor in psoriasis. The therapeutic applicability of palbociclib, a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor clinically used to treat cancer, in the treatment of neutrophil-associated psoriasis remains undefined. In this study, we evaluated the therapeutic potential and pharmacological effect of palbociclib on neutrophil-associated psoriasiform dermatitis. EXPERIMENTAL APPROACH: The anti-inflammatory effects of palbociclib were determined in activated human neutrophils. The therapeutic feasibility of palbociclib in psoriasis was demonstrated in a mouse model of imiquimod-induced psoriasiform dermatitis. The in vitro enzymatic assays and in silico analyses were used to identify the underlying pharmacological mechanisms. KEY RESULTS: This study found that palbociclib inhibited neutrophilic inflammation, including superoxide anion generation, reactive oxygen species (ROS) formation, elastase degranulation and chemotactic responses. The mechanistic studies identified that the anti-inflammatory effects of palbociclib involved the targeting of phosphatidylinositol 3-kinase (PI3K) but not CDK4/6 in human neutrophils. Palbociclib preferentially targeted the p110δ catalytic subunit of PI3K and thereby blocked signalling via the PI3K/protein kinase B (Akt) pathway. Furthermore, topical application of palbociclib significantly ameliorated imiquimod-induced psoriasiform dermatitis in mice, including psoriatic symptoms, neutrophil infiltration, Akt activation and cytokine up-regulation. CONCLUSIONS AND IMPLICATIONS: This is the first study to demonstrate that palbociclib can potentially be used to treat neutrophil-associated psoriasiform dermatitis through the targeting of neutrophilic PI3K activity. Our findings prompt further research to explore the potential of palbociclib and PI3K in psoriasis and other inflammatory diseases.

Anti-Obesity Effect of Nostoc commune Ethanol Extract In Vitro and In Vivo.

Nostoc commune is an edible terrestrial blue-green alga. It has shown many beneficial effects on human health. This study aimed to investigate the phytochemical assay of N. commune ethanol extract (NEE) and its anti-obesity effects. The effect of a high-calorie diet on lipid accumulation in 3T3-L1 preadipocytes is investigated, and a Wistar rat model is used to demonstrate the anti-obesity effect of NEE and its mechanism. The results showed that the NEE has phytochemical compounds, such as total polyphenol, total flavonoids, and total terpenoids. NEE was also shown to suppress cell proliferation and lipid accumulation (26.9%) in 3T3-L1 preadipocytes. Furthermore, NEE reduced the body weight (13.5%), fat tissue weight (13.3%), and the serum FFA (19.4%), TG (14.2%), TC (11.8%), and LDL-C (16.4%) of rats. In histopathology, NEE was shown to diminish the size of adipocytes and hepatic lipid droplets. The NEE downregulated the mRNA expression of adipogenesis (PPAR-γ, SREBP-1c) and lipid lysis-related genes (ATGL, HSL) in epididymal adipose tissue. The NEE also upregulated the mRNA expression of ß-oxidation related genes (AMPK, CPT-1, PPAR-α) in the liver. Overall, this study suggests NEE has the potential to be developed as a functional food for anti-obesity.