Network Pharmacology Analysis of the Therapeutic Potential of Colchicine in Acute Lung Injury.

Background: This study employed integrated network pharmacology approach to explore the mechanisms underlying the protective effect of colchicine against acute lung injury (ALI). Methods: We analyzed the expression profiles from 13 patients with sepsis-related ALI and 21 controls to identify differentially expressed genes and key modules. ALI-related genes were curated using databases such as DisGeNET, Therapeutic Target, and Comparative Toxicogenomics Database to curate ALI-related genes. Drug target fishing for colchicine was conducted using the DrugBank, BATMAN-TCM, STITCH, and SwissTargetPrediction. Potential drug-disease interactions were determined by intersecting ALI-associated genes with colchicine target genes. We performed comprehensive pathway and process enrichment analyses on these genes. A protein-protein interaction network was constructed, and topological analysis was executed. Additionally, an ALI mouse model was established to evaluate the effect of colchicine on CXCL12 and CXCR4 levels through western blot analysis. Results: Analysis revealed 23 potential colchicine-ALI interaction genes from the intersection of 253 ALI-associated genes and 389 colchicine targets. Functional enrichment analysis highlighted several inflammation-related pathways, such as cytokine-mediated signaling pathway, CXCR chemokine receptor binding, NF-kappa B signaling pathway, TNF signaling pathway, and IL-17 signaling pathway. The protein-protein interaction network demonstrated complex interactions for CXCL12 and CXCR4 among other candidate genes, with significant topological interaction degrees. In vivo studies showed that colchicine significantly reduced elevated CXCL12 and CXCR4 levels in ALI mice. Conclusion: Our findings suggest that colchicine's therapeutic effect on ALI might derive from its anti-inflammatory properties. Further research is needed to explore the specific mechanisms of colchicine's interaction with sepsis-induced ALI.

Low-dose curcumin stimulates proliferation of rat embryonic neural stem cells through glucocorticoid receptor and STAT3.

AIMS: This study was to determine whether curcumin had any effect on the proliferation of neural stem cell (NSC), analyze the expression of glucocorticoid receptor (GR), signal transducer and activator of transcription 3 (STAT3), and Notch1 at transcription and protein level, and discuss the related mechanisms. METHODS AND RESULTS: NSCs were harvested from E15 SD rat brain and cultured. All experiments were performed at the second passage. Cell cytotoxicity, cell viability, and proliferation assays were used to figure out the optimal concentration of curcumin, which can be used for the protein and mRNA studies. The results showed that by downregulation of GR and STAT3 expression, 0.5 µmol L-1 curcumin exhibited the most pronounced effect in promoting the proliferation of NSCs, which were also induced by antagonists of GR and STAT3, but was inhibited by GR agonist. CONCLUSION: This study shows that low-dose curcumin stimulates the proliferation of NSCs, which is probably by inhibiting the mRNA and protein expressions of GR and directly or indirectly regulating the STAT3 via the synergistic effect of GR and STAT3 pathways and its related signal pathways.

Isoflurane anesthesia in aged mice and effects of A1 adenosine receptors on cognitive impairment.

AIMS: Isoflurane may not only accelerate the process of Alzheimer's disease (AD), but increase the risk of incidence of postoperative cognitive dysfunction (POCD). However, the underlying mechanisms remain unknown. This study was designed to investigate whether isoflurane contributed to the POCD occurrence through A1 adenosine receptor (A1AR) in aged mice. METHODS: We assessed cognitive function of mice with Morris water maze (MWM) and then measured expression level of two AD biomarkers (P-tau and Aß) and a subtype of the NMDA receptor (NR2B) in aged wild-type (WT) and homozygous A1 adenosine receptor (A1AR) knockout (KO) mice at baseline and after they were exposed to isoflurane (1.4% for 2 hours). RESULTS: For cognitive test, WT mice with isoflurane exposure performed worse than the WT mice without isoflurane exposure. However, A1AR KO mice with isoflurane exposure performed better than WT mice with isoflurane exposure. WT mice exposed to isoflurane had increased levels of Aß and phosphorylated tau (P-tau). Levels of Aß and P-tau were decreased in A1AR KO mice, whereas no differences were noted between KO mice with and without isoflurane exposure. NR2B expression was inversely related to that of P-tau, with no differences found between KO mice with and without isoflurane exposure. CONCLUSIONS: We found an association between isoflurane exposure, impairment of spatial memory, decreasing level of NR2B, and increasing levels of A-beta and P-tau, presumably via the activation of the A1A receptor.