Deep analysis of skin molecular heterogeneities and their significance on the precise treatment of patients with psoriasis.

Background: Psoriasis is a highly heterogeneous autoinflammatory disease. At present, heterogeneity in disease has not been adequately translated into concrete treatment options. Our aim was to develop and verify a new stratification scheme that identifies the heterogeneity of psoriasis by the integration of large-scale transcriptomic profiles, thereby identifying patient subtypes and providing personalized treatment options whenever possible. Methods: We performed functional enrichment and network analysis of upregulated differentially expressed genes using microarray datasets of lesional and non-lesional skin samples from 250 psoriatic patients. Unsupervised clustering methods were used to identify the skin subtypes. Finally, an Xgboost classifier was utilized to predict the effects of methotrexate and commonly prescribed biologics on skin subtypes. Results: Based on the 163 upregulated differentially expressed genes, psoriasis patients were categorized into three subtypes (subtypes A-C). Immune cells and proinflammatory-related pathways were markedly activated in subtype A, named immune activation. Contrastingly, subtype C, named stroma proliferation, was enriched in integrated stroma cells and tissue proliferation-related signaling pathways. Subtype B was modestly activated in all the signaling pathways. Notably, subtypes A and B presented good responses to methotrexate and interleukin-12/23 inhibitors (ustekinumab) but inadequate responses to tumor necrosis factor-α inhibitors and interleukin-17A receptor inhibitors. Contrastly, subtype C exhibited excellent responses to tumor necrosis factor-α inhibitors (etanercept) and interleukin-17A receptor inhibitors (brodalumab) but not methotrexate and interleukin-12/23 inhibitors. Conclusions: Psoriasis patients can be assorted into three subtypes with different molecular and cellular characteristics based on the heterogeneity of the skin's immune cells and the stroma, determining the clinical responses of conventional therapies.

Polystyrene Microplastics Postpone APAP-Induced Liver Injury through Impeding Macrophage Polarization.

Polystyrene microplastics (PS MPs) are micrometer-scale items degraded from plastics and have been detected in various organisms. PS MPs have been identified as causing cognitive, cardiac, intestinal, and hepatic damage. However, their role in liver regeneration under drug-induced liver injury remains unknown. Thus, the current study aims to evaluate the impact of PS MPs on liver repair during APAP hepatotoxicity. PS MPs pretreatment exacerbates mice mortality and hepatocyte apoptosis, suppresses hepatic cell proliferation, and disturbs the inflammatory response in the APAP-induced damage model. Further mechanism exploration uncovers that prior PS MPs administration is sufficient to recruit neutrophils and macrophages, which are necessary for tissue recovery in the acute liver injury model. However, the polarization capacity of macrophages to anti-inflammatory sub-type is significantly delayed in PS MPs plus APAP group compared to the single APAP group, which is the leading cause of tissue repair suppression. Overall, the current study supports a new insight to realize the toxicity of PS MPs in acute liver injury, which should be considered in health risk assessment.