Deciphering the mechanism of Fang-Ji-Di-Huang-Decoction in ameliorating psoriasis-like skin inflammation via the inhibition of IL-23/Th17 cell axis.

ETHNOPHARMACOLOGICAL RELEVANCE: In the theory of traditional Chinese medicine (TCM), the etiology of psoriasis is assigned to damp-heat internal depression, blood poisoning, Yin deficiency and loss of nourishment. Fang-Ji-Di-Huang-Decoction (FJDH), a well-known Chinese traditional formula, is recorded in Synopsis of the Golden Chamber (in the Eastern Han Dynasty). This decoction is composed of dried roots of Rehmannia glutinosa (Gaertn.) DC., dried roots of Stephania tetrandra S. Moore, roots of Saposhnikovia divaricata (Turcz.) Schischk., dried twigs of Cinnamomum cassia (L.) J. Presl and dry roots and rhizomes of Glycyrrhiza uralensis Fisch. FJDH has the function of clearing heat, removing dampness, and nourishing blood. Therefore, in modern medical theory, FJDH can regulate the infiltration of inflammatory cells and the secretion of inflammatory cytokines in the process of psoriasis. AIM OF THE STUDY: This study evaluated whether FJDH treated psoriasis and its specific mechanism for the efficacy in mice. At the same time, it clarified s what important role of the copperware played s in the curative effect of FJDH. METHODS AND MATERIALS: We used imiquimod (IMQ) to induce psoriasis-like skin inflammation in mice. Mice were treated with imiquimod for one week, and FJDH was given by intragastric administration one week in advance. Record the weight change and psoriasis Area and Severity Index (PASI) score of the mouse during the whole process to assess the severity of psoriasis were recored mouse. Hematoxylin-eosin staining was used to evaluate skin tissue structure change. Immunohistochemistry was performed to observe the expressions of Ki67 and proliferating cell nuclear antigen (PCNA) in skin tissue. In order to further explore the mechanism of FJDH in the treatment of psoriasis, we used network pharmacology to predict the therapeutic target. TCMSP and Uniprot were used to collect compounds and genes of FJDH. Genecards was used for obtaining genes of psoriasis. String was used to analyze the relationship between genes. Metascape was used for gene enrichment and pathway prediction. Using molecular biological detection methods, we verified whether FJDH could regulate Interleukin 17 signaling pathway and T helper cell 17 (Th17) cell differentiation. Flow cytometry was used to detect Th17 cell differentiation in mouse spleen. Quantitative Real-time PCR was used to detect mRNA expression of IL-17 signaling pathway-related inflammatory factors in mouse skin tissues. UPLC-Triple TOF-MS/MS and Phenol-Sulphate colorimetry were used to explore the main components of FJDH, and further elaborate the mechanism of FJDH in the treatment of psoriasis. RESULTS: FJDH with copper was found to improve psoriasis-related pathological symptoms in a dose-dependent manner, possibly by inhibiting IL-23/Th17 cell axis and reducing inflammatory cytokines such as IL-17A, IL-17F, IL-22 and TNF-α. Furthermore, R. glutinosa polysaccharide in FJDH was the main substance that exerted the drug effect and it work by forming a complex with copper. Experimental data proved that Rehmannia glutinosa polysaccharide and copper complex had the same pharmacological activity and therapeutic effect as FJDH. CONCLUSIONS: FJDH may attenulated imiquimod-induced psoriasis-like skin inflammation in mice by inhibiting IL-23/Th17 cell axis. The material basis for the therapeutic effect may be the formation of complexes between the polysaccharides of R. glutinosa and copper in FJDH to produce the effect. These findings suggest that FJDH can be used as an effective Chinese medicine to treat psoriasis.

Harnessing affinity-based protein profiling to reveal a novel target of nintedanib.

Nintedanib (BIBF1120), a triple angiokinase inhibitor, was first approved for idiopathic pulmonary fibrosis (IPF) therapy and is also efficacious for lung carcinoma, and interstitial lung diseases, far beyond its inhibition of VEGFR/PDGFR/FGFR. We identified tripeptidyl-peptidase 1 (TPP1) as one of the direct targets of nintedanib employing the affinity-based protein profiling (AfBPP) technique. This may be a new mechanism for nintedanib's role different from tyrosine kinase inhibition.

Andrographolide potentiates PD-1 blockade immunotherapy by inhibiting COX2-mediated PGE2 release.

Cancer immunotherapy has now become a first line therapy for several kinds of tumors. However, the clinical performance of immnuocheckpoint blockade therapy is usually limited by low response rate or side effects including cytokine storm. Andrographolide, a natural diterpenoid from Andrographis paniculata, has been used in Asia for treatment of bronchitis, paristhmitis and bacillary dysentery for its unique anti-inflammatory effect. However, its effect on anti-tumor immunity remains elusive. In this study, we found that andrographolide in combination with anti-PD-1 antibody showed a higher therapeutic benefit than individual therapy in murine xenograft model of CT26 colon cancer. Consequently, andrographolide and anti-PD-1 antibody co-treatment boosted the function of CD4+ and CD8+ T cells evidenced by considerable tissue infiltration, elevated IFN-γ secretion and enhanced expression of cytotoxic T-cell related molecules including FasL, perforin and Granzyme B, which significantly decreases the tumor load. Mechanistically, andrographolide treatment inhibited COX2 activity and PGE2 release both in vivo and in vitro, which augments anti-tumor efficiency of anti-PD-1 therapy. Finally, we confirmed that COX2 level in human colon cancer sample positively correlated with tumor-promoting factors. Our study here provides a potential combination strategy for immunotherapy against colorectal cancer.