Strictosamide promotes wound healing through activation of the PI3K/AKT pathway.

Nauclea officinalis, as a Chinese medicine in Hainan province, had the effect of treating lower limb ulcers, burn infections. In this paper, we studied the effect of Strictosamide (STR), the main bioactive compound in Nauclea officinals, on wound healing and explored its internal mechanism. Firstly, the wound healing potential of STR was evaluated in a rat model, demonstrating its ability to expedite wound healing, mitigate inflammatory infiltration, and enhance collagen deposition. Additionally, immunofluorescence analysis revealed that STR up-regulated the expression of CD31 and PCNA. Subsequently, target prediction, protein-protein interaction (PPI), gene ontology (GO), and pathway enrichment analyses were used to obtain potential targets, specific biological processes, and molecular mechanisms of STR for the potential treatment of wound healing. Furthermore, molecular docking was conducted to predict the binding affinity between STR and its associated targets. Additionally, in vivo and in vitro experiments confirmed that STR could increase the expression of P-PI3K, P-AKT and P-mTOR by activating the PI3K/AKT signaling pathway. In summary, this study provided a new explanation for the mechanism by which STR promotes wound healing through network pharmacology, suggesting that STR may be a new candidate for treating wound.

Strictosamide alleviates acute lung injury via regulating T helper 17 cells, regulatory T cells, and gut microbiota.

BACKGROUND: Nauclea officinalis (Pierre ex Pit.) Merr. & Chun (Rubiaceae) is widely used to treat respiratory diseases in China. Strictosamide is its main active component and has significant anti-inflammatory activity. However, the effects and molecular mechanisms of strictosamide in the treatment of acute lung injury (ALI) remain largely unknown. PURPOSE: This study aimed to examine the regulatory effects of strictosamide on T helper 17 cells (Th17 cells)/Regulatory T cells (Treg cells) and gut microbiota in ALI-affected mice. MATERIALS AND METHODS: The ALI model was induced using lipopolysaccharide (LPS) intraperitoneal injection. Hematoxylin-eosin (H&E) staining, the number of inflammatory cells in broncho-alveolar lavage fluid (BALF), the Wet/Dry (W/D) ratio, and myeloperoxidase (MPO) activity were utilized as evaluation indices for the therapeutic efficacy of strictosamide on ALI. Flow cytometry (FCM), enzyme-linked immune sorbent assay (ELISA), quantitative reverse transcription polymerase chain reaction (qRT-PCR), and western blotting were used to determine the regulation of strictosamide on the Th17/Treg cells and the STAT3/STAT5 signaling pathway. The analysis of gut microbiota was conducted using 16S rDNA sequencing. The verification of the relationship between the gut microbiome and immune function was conducted using Spearman analysis. RESULTS: Strictosamide attenuated inflammation on ALI induced by LPS, which reduced the levels of Th17-related factors interleukin (IL)-6 and IL-17 and increased Treg-related factors IL-10 and transforming growth factor (TGF)-ß. In the spleens and whole blood, strictosamide reduced the proportion of Th17 cells and increased the proportion of Treg cells. Furthermore, strictosamide increased Forkhead/winged helix transcription factor 3 (Foxp3) and p-STAT5 protein expression while inhibiting Retinoid-related orphan nuclear receptors-γt (RORγt) and p-STAT3 expression. Moreover, strictosamide reshaped the diversity and structure of the gut microbiota, and influence the associations between immune parameters and gut microbiota in ALI mice. CONCLUSIONS: In summary, the results of the current investigation showed that strictosamide has a therapeutic impact on LPS-induced ALI. The mechanism of action of this effect may be associated with the modulation of Th17 and Treg cells differentiation via the SATA signaling pathway, as well as the impact of the gut microbiota.

Measurement of Pharmacokinetics and Tissue Distribution of Four Compounds from Nauclea officinalis in Rat Plasma and Tissues through HPLC-MS/MS.

A rapid, sensitive, selective, and accurate HPLC-MS/MS method was developed and validated for the simultaneous determination of chlorogenic acid, naucleactonin C, khaephuoside A 3,4-dimethoxyphenyl-1-O-ß-apiofuroseyl(1 ⟶ 2)-ß-D-glucopyranoside in rat plasma and tissues after oral administration of Nauclea officinalis extracts. Chloramphenicol was used as an internal standard (IS). The plasma and tissue samples were extracted by protein precipitation with methanol-ethyl acetate (1 : 1, v/v) including 0.1% (v/v) formic acid. The chromatographic separation was achieved by using an C18 column with gradient elution using mobile phase, which consisted of 0.1% formic acid water (A) and acetonitrile (B) and the flow rate of 0.8 mL/min. Mass spectrometric detection was performed in multiple reaction monitoring (MRM) mode utilizing electrospray ionization (ESI) in negative mode. The developed method exhibited good linearity (determination coefficients, R 2 ≥ 0.9849), and the lower limits of quantification were 2, 5, 5, and 25 ng/mL for chlorogenic acid, naucleactonin C, khaephuoside A, and 3,4-dimethoxyphenyl-1-O-ß-apiofuroseyl(1 ⟶ 2)-ß-D-glucopyranoside. The intraday and interday precisions (relative standard deviation, RSD) were less than 12.65%, while the accuracy was ranged from 86.31 to 114.17%. The recovery rate were 51.85-97.06%, 75.99-106.68%, 77.46-105.35%, and 68.36-103.75% for chlorogenic acid, naucleactonin C, khaephuoside A, and 3,4-dimethoxyphenyl-1-O-ß-apiofuroseyl(1 ⟶ 2)-ß-D-glucopyranoside the matrix effects were 50.17-116.62%, 86.75-115.99%, 45.79-87.44%, and 51.60-92.34% for chlorogenic acid, naucleactonin C, khaephuoside A, and 3,4-dimethoxyphenyl-1-O-ß-apiofuroseyl(1 ⟶ 2)-ß-D-glucopyranoside in different matrix. The developed method was successfully applied to a pharmacokinetic study and tissue distribution of four compounds in rats after oral administration of Nauclea officinalis extracts.

Excellent antitumor and antimetastatic activities based on novel coumarin/pyrazole oxime hybrids.

A series of hybrids 10a-v based on coumarin/pyrazole oxime have been synthesized, and exhibit good to excellent antitumor activities. Compound 10n has shown remarkable anticancer effect on SMMC-7721 cells (IC50 = 2.08 µM), which is considerably lower than 5-FU (IC50 = 37.8 µM) and similar to ADM (IC50 = 2.67 µM), with little effect on normal hepatic cells LO2. Notably, the suppression experiments of metastatic activities reveal that 10n also displays significant anti-metastasis effects through inhibiting cell migration and invasion in highly metastatic SMMC-7721 cell line, and dose-dependently reverses TGF-ß1-induced epithelial-mesenchymal transition (EMT) procedure better than ADM. Finally, 10n also possesses low acute toxicity and potent tumor growth inhibitory property against SMMC-7721 cell lines in vivo. Our findings suggest that novel coumarin/pyrazole oxime hybrids are promising therapeutic agent candidates for further research.