The Src-homology 2 domain-containing phosphatase 2 (SHP2), which is encoded by PTPN11, participates in many cellular signaling pathways and is closely related to various tumorigenesis. Inhibition of the abnormal activity of SHP2 by small molecules is an important part of cancer treatment. Here, three abietane diterpenoids, named compounds 1–3, were isolated from Ajuga ovalifolia var. calantha. Spectroscopic analysis was used to identify the exact structure of the compounds. The enzymatic kinetic experiment and the cellular thermal shift assay showed compound 2 selectively inhibited SHP2 activity in vitro. Molecular docking indicated compound 2 targeted the SHP2 catalytic domain. The predicted pharmacokinetic properties by SwissADME revealed that compound 2 passed the majority of the parameters of common drug discovery rules. Compound 2 restrained A549 proliferation (IC₅₀ = 8.68 ± 0.96 μM), invasion and caused A549 cell apoptosis by inhibiting the SHP2–ERK/AKT signaling pathway. Finally, compound 2 (Ajuforrestin A) is a potent and efficacious SHP2 inhibitor and may be a promising compound for human lung epithelial cancer treatment.

Background: In recent years, more and more attention has been paid to the role of skin microcirculation in the pathogenesis of psoriasis. The vascular network of the skin is mainly distributed in the dermis and the subcutaneous fat layer join. The microvessels are composed of terminal arterioles, arteriovenous capillaries, and postcapillary venules. Vascular endothelial growth factor (VEGF) plays an important role in the pathogenesis of psoriasis by promoting angiogenesis. The purpose of this study is to evaluate the relationship between serum VEGF and psoriasis vulgaris. Methods: Embase, CENTRAL, PubMed, China Biology Medicine Database, China National Knowledge Database, Wan Fang Database, and Chong Qing VIP Database will be searched to collect case-control studies and cohort studies and evaluate the relationship between serum VEGF and psoriasis vulgaris. The search time limits will be from the establishment of the database to December 2020. Two researchers will independently screen the studies, extract data, and evaluate the risk of bias of the studies. The Meta-analysis will be carried out with the RevMan5.3 software. The quality of all included studies will be evaluated by the Newcastle-Ottawa scale. Results: This study will evaluate the relationship between serum VEGF and the pathogenesis of psoriasis vulgaris. Conclusion: This study will provide a theoretical basis for the pathogenesis of psoriasis vulgaris. OSF registration number: DOI 10.17605/OSF.IO/6DV8P

Background: During psoriasis initiation and development, deregulations in signaling pathways and gene expression are observed. Methods: Herein, we downloaded seven sets of microarray mRNA expression profiles showing differentially-expressed genes in psoriasis lesion skin and non-lesion skin tissues and three sets of RNA-seq data and analyzed these online data attempting to screen for crucial genes related to keratinocyte differentiation and psoriasis development. Results: The expression of catenin beta interacting protein 1 (CTNNBIP1) was remarkably downregulated within psoriasis lesion skin tissue samples compared to that within non-lesion skin tissues based on both online data and experimental results. In response to a period of different therapies, respectively, CTNNBIP1 expression could be rescued in lesion skin tissues. Within IMQ-induced psoriasis-like dermatitis in mice, CTNNBIP1 silence further aggravated psoriatic phenotypes. In human immortalized keratinocytes, HaCaT cells, CTNNBIP1 silence significantly inhibited cell apoptosis and promoted cell proliferation. Regarding the molecular mechanism, CTNNBIP1 silence in HaCaT cells promoted β-catenin nucleus translocation, enhanced the transcriptional activity of TCF4, and increased β-catenin/TCF-complex downstream c-Myc and cyclin D1 proteins while decreased the late differentiation marker filaggrin. In contrast to CTNNBIP1, the expression of c-Myc and cyclin D1 showed to be dramatically upregulated within psoriasis lesion tissue samples than that within non-lesion tissue samples. Within tissues, c-Myc and cyclin D1 showed to be negatively correlated with CTNNBIP1, respectively. Conclusions: We identify CTNNBIP1 as an abnormally downregulated gene in psoriasis. CTNNBIP1 silence significantly disturbs the differentiation of keratinocytes through promoting the transcription of β-catenin/TCF-complex downstream genes.

Background: Psoriasis vulgaris (PV) is one of the most common chronic inflammatory skin diseases, but its exact etiology and pathological mechanism are not fully understood. The regulation of tryptophan metabolism by gut microbiota-host co-metabolism has been confirmed to significantly affect the pathogenesis of various chronic inflammatory and autoimmune diseases. Tryptophan and its main metabolites are partly involved in the pathogenesis and progression of psoriasis, but its specific regulatory mechanism has not yet been clarified. The purpose of this study is to explore the changes in the intestinal flora and its metabolic characteristics in PV patients. Methods: 16S rRNA sequencing combined with metabolomics was used to explore changes in gut microbiota and its metabolic characteristics. Alpha, Beta diversity and LEfSe (Linear Discriminant Analysis Effect Size) analyses were used to analyze the changes in the intestinal flora and to screen biomarkers. PCA (Principal Component Analysis) and OPLS-DA (Orthogonal Partial Least Squares-Discriminant Analysis) methods were used to analyze the differences in metabolite composition. PICRUS (Phylogenetic Investigation of Communities by Reconstruction of Unobserved States) software was used to predict metabolic function. Results: The result revealed differences in the tract microbiota composition between normal and psoriasis patients, suggesting that microbial populations may mediate the development of psoriasis. Fecal metabolite profiles revealed distinct metabolites associated with the psoriasis samples group (PSG). These products of metabolism primarily participated in metabolic pathways including amino acid biosynthesis, carbohydrate degradation and glycolysis. There is a positive/negative correlation between these gut microbes and metabolites. Conclusions: The results suggest that the gut microbiota and its metabolites may play a crucial role in the development of PSG, which may provide a potential biomarker for the treatment of PSG.

Psoriasis is a chronic inflammatory skin disorder characterized by excessive keratinocyte proliferation, immune dysregulation, and systemic inflammation. Emerging evidences highlight the gut-skin axis as a key regulatory mechanism linking gut microbiota dysbiosis to psoriasis pathogenesis. This study investigates the therapeutic effects of Zhuhuang Granules (ZH) on psoriasis, focusing on cutaneous inflammation, intestinal barrier integrity, and gut microbiota homeostasis. Using an imiquimod (IMQ)-induced psoriasis-like dermatitis mouse model, ZH treatment significantly reduced Psoriasis Area and Severity Index (PASI) scores, epidermal hyperplasia, and inflammatory infiltration, with marked improvements observed following medium- and high-dose ZH treatment. ZH also suppressed systemic immune activation by decreasing spleen weight, inhibiting keratinocyte proliferation, and downregulating pro-inflammatory cytokines, including IL-22, IL-1β, TNF-α and CCL20. Additionally, ZH enhanced intestinal barrier function through the upregulation of essential tight junction proteins (TJP1, Occludin, and Claudin-1), leading to reduced intestinal permeability and systemic endotoxemia. 16S rRNA sequencing revealed that ZH partially reversed IMQ-induced gut dysbiosis, with partial restoration of several IMQ-associated microbial taxa, including Lachnospiraceae FCS020 group, Lachnospiraceae UCG-001, and Bacteroides. Functional prediction analysis indicated that ZH altered the predicted abundance of microbial functional pathways related to immune regulation and lipid metabolism. Importantly, antibiotic-mediated gut microbiota depletion attenuated the protective effects of ZH against IMQ-induced psoriasis-like inflammation, providing functional evidence for a contribution of the gut microbiota to the therapeutic effects of ZH. These findings suggest that ZH alleviates psoriasis-like inflammation through suppressing systemic inflammation, improved intestinal barrier functions, and microbiota restoration, supporting its therapeutic potential in psoriasis management.