The mechanism of Croci stigma in the treatment of melasma based on network pharmacology and molecular docking.

PURPOSE: To investigate the molecular mechanism of Croci stigma (CS) in the treatment of melasma by network pharmacology and molecular docking. METHODS: TCMSP, CTD, STITCH, SymMap, GeneCard, GenBank, OMIM and DrugBank databases were used to obtain the components and targets of CS and the targets of chloasma. STRING was used to build a protein-protein interaction (PPI) network of intersecting targets between drugs and diseases. Cytoscape was used to establish drug-compounds-targets-disease network and analyze PPI network. R was used for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis and visualization. AutoDock was used for molecular docking and R was used to visualize docking results. RESULTS: Four active compounds were screened out from CS, and 31 target genes intersecting with melasma were found after further analysis. The top 10 hub genes were found after analysis of the PPI network, including TYR, TYRP1, DCT, CREB1, KITLG, MITF, ESR1, EDNRB, CD4, and PTGS2. In the enrichment analysis, melanogenesis was considered as the core pathway through which CS exerts its therapeutic effect on melasma. Molecular docking results showed that the core genes in the regulatory network had high binding activity with related active components, especially crocetin. CONCLUSION: CS may treat melasma by regulating core targets, such as TYR, TYRP1, DCT, CREB1, KITLG, MITF, EDNRB, and PTGS2, and acting on melanogenesis. And crocetin may be the core compound worthy of further study.

Formulation of the novel structure curcumin derivative-loaded solid lipid nanoparticles: synthesis, optimization, characterization and anti-tumor activity screening in vitro.

This study investigated the effect of structural modification of Curcumin (CU) combined with the solid lipid nanoparticles (SLN) drug delivery system on anti-tumor activity in vitro. A new structure of Curcumin derivative (CU1) was successfully synthesized by modifying the phenolic hydroxyl group of CU. CU1 was two times more stable than CU at 45 °C or constant light. The SLN containing CU1 (CU1-SLN) was prepared, and the particle size, polydispersity index, entrapment efficiency, drug loading, and zeta potential of CU1-SLN were (104.1 ± 2.43) nm, 0.22 ± 0.008, (95.1 ± 0.38) %, (4.28 ± 0.02) %, and (28.3 ± 1.60) mV, respectively. X-ray diffraction (XRD) and Differential scanning calorimetry (DSC) showed that CU1 is amorphous in SLN. CU1-SLN released the drug slowly for 48 h, while CU and CU1 were released rapidly within 8 h. In terms of cytotoxicity, CU1 exhibited a 1.5-fold higher inhibition than CU against A549 and SMMC-7721 cells, while CU1-SLN showed 2-fold higher inhibition than CU1. Both CU1 and CU1-SLN reduced the toxicity in normal hepatocytes compared with CU (2.6-fold and 12.9-fold, respectively). CU1-SLN showed a significant apoptotic effect (p < 0.05). In summary, CU1 retained the inhibitory effect of CU against tumor cells, while improving stability and safety. Additionally, CU1-SLN presents a promising strategy for the treatment of liver and lung cancer.

The Effects of a Novel Curcumin Derivative Loaded Long-Circulating Solid Lipid Nanoparticle on the MHCC-97H Liver Cancer Cells and Pharmacokinetic Behavior.

Purpose: The objective of this study was to develop long-circulating solid lipid nanoparticles (LSLN) containing a novel curcumin (CU) derivative (CU1), to improve CU1's pharmacokinetic behavior and its anti-cancer effects in MHCC-97H liver cancer cells. Methods: LSLN loaded with CU1 (CU1-LSLN) was optimized and characterized. The cell biological properties and the anti-cancer mechanism of CU1-LSLN on MHCC-97H cells were evaluated by MTT, flow cytometry, Transwell, and Western blot. CU1-LSLN was further evaluated for pharmacokinetic behavior, biodistribution, and liver toxicity in SD rats. Results: The optimized CU1-LSLN formulation showed the ideal particle size (PS), polydispersity index (PDI), zeta potential (ZP), encapsulation efficiency (EE%), and drug loading (DL%) of 122.10 ± 6.63 nm, 0.19 ± 0.02, -36.30 ± 1.25 mV, 94.98 ± 0.90% and 4.53 ± 0.69%, respectively. X-ray powder diffraction (XRD), differential scanning calorimetry (DSC), and Fourier transform infrared spectrometry (FTIR) indicated that CU1 was well encapsulated by LSLN and existed in amorphous form. Storage stability of CU1-LSLN was up to 180 days with a sustained-release of drug over 96 h. The uptake efficiency of CU1-LSLN to MHCC-97H cells was 3.24 and 2.98 times higher than that of CU and CU1 after treatment for 3 h, which helped to enhance the inhibitive effect of CU1-LSLN on the proliferation, migration, and invasion potential of MHCC-97H cells and increased its ability to promote apoptosis. Meanwhile, the expression levels of NF-κB, COX-2, MMP-2, MMP-9, and uPA decreased significantly. In vivo, CU1-LSLN prolonged the retention time of the drug, the area under the curve (AUC) increased significantly (CU: 69.9-fold, CU1: 85.9-fold), and no significant liver toxicity was observed. Conclusion: CU1-LSLN is a novel preparation with great potential for treating liver cancer.

Enhanced Oral Bioavailability of Felodipine from Solid Lipid Nanoparticles Prepared Through Effervescent Dispersion Technique.

Felodipine (FLD), a dihydropyridine calcium channel blocker with excellent antihypertensive effect, is poorly soluble and undergoes extensive hepatic metabolism, which lead to poor oral bioavailability (about 15%) and limit its clinic application. The goal of this study was to develop solid lipid nanoparticles (SLNs) loading FLD to improve the oral bioavailability. The FLD loaded solid lipid nanoparticles (FLD-SLNs) were prepared by the effervescent dispersion technique developed by our laboratory, which might have some advantages over traditional methods. The FLD-SLNs showed desired particle characteristics with particle size (198.15 ± 1.82 nm), poly dispersity index (0.26 ± 0.02), zeta-potential (- 25.53 ± 0.60 mV), entrapment efficiency (95.65 ± 0.70%), drug loading (2.33 ± 0.10%), and a spherical appearance. Pharmacokinetic results showed that the FLD-SLNs presented 3.17-fold increase in area under the curve (AUC(0-t)) compared with free FLD after oral administration in beagle dogs, which indicated that SLNs prepared using the effervescent dispersion technique can improve the bioavailability of lipophilic drugs like felodipine by enhancement of absorption and reduction first-pass metabolism.

Synergistic Effects of Curcumin and 5-Fluorouracil on the Hepatocellular Carcinoma In vivo and vitro through regulating the expression of COX-2 and NF-κB.

Curcumin (CU) has shown broad anti-cancer effects. 5-fluorouracil (5-FU) has been a conventional chemotherapeutic agent for hepatocellular carcinoma. Unfortunately, the nonspecific cytotoxicity and multidrug resistance caused by long-term use limited the clinical efficacy of 5-FU. This study was aimed to investigate whether the combination of CU and 5-FU could generate synergistic effect in inhibiting the human hepatocellular carcinoma. The results of cytotoxicity test showed that compared with applying single drugs, the combination of CU and 5-FU (1:1, 1:2, 1:4, 2:1 and 4:1, mol/mol) presented stronger cytotoxicity in SMMC-7721, Bel-7402, HepG-2 and MHCC97H cells, while the combination groups are relatively insensitive to normal hepatocytes (L02). Among them, the molar ratio of 2:1 combination group showed strong synergistic effect in SMMC-7721cells. Then, western blotting assay further verified that the mechanism of the synergistic effect may be related to the inhibition of the expression of NF-κB (overall) and COX-2 protein. In addition, the synergistic effect was also validated in the xenograft mice in vivo. This research not only provides a novel and effective combination strategy for the therapy of hepatocellular carcinoma but also provides an experimental basis for the development of CU and 5-FU compound preparation.

Application of curcumin and its derivatives in tumor multidrug resistance.

Malignant tumor endangers seriously the health of all mankind. Multidrug resistance (MDR) is one of the main causes of clinical tumor chemotherapy failure. Curcumin (CUR) has not only antitumor activity but also reversing tumor MDR effect. CUR reverses tumor MDR via regulating related signal pathways or corresponding expressed proteins or gene. When combined with chemotherapeutic agents, CUR can be a chemotherapeutic sensitive agent to enhance chemotherapy efficacy and weaken tumor MDR. On the other hand, to improve the MDR reversal effect of CUR, its derivatives have been extensively studied. Therefore, this article mainly focuses on reviewing the application of CUR and its derivatives in MDR and its mechanism of reversing MDR.

Co-delivery system of chemotherapy drugs and active ingredients from natural plants: a brief overview of preclinical research for cancer treatment.

Introduction: Many active ingredients from natural plants (AINPs) have been revealed to possess remarkable anticancer properties. Combination chemotherapy of chemo-drugs and AINPs has also proven to be more advantageous than individual chemo-drug treatment with respect to enhancing efficiency, alleviating toxicity, and controlling the development of multidrug resistance (MDR). Co-delivery is considered a promising method to effectively achieve and manage combination chemotherapy of chemo-drugs and AINPs, and various distinctive and functional co-delivery systems have been designed for these purposes to date.Areas covered: This review focuses on recent preclinical investigations of co-delivery systems for chemo-drugs and AINPs as new cancer treatment modalities. We particularly emphasize the apparent treatment advantages of these approaches, including augmenting efficiency, reducing toxicity, and controlling MDR.Expert opinion: There has already been notable progress in the application of combination chemotherapy with co-delivery systems loaded with chemo-drugs and AINPs based on results with cellular and animal models. The main challenge is to translate these successes into new anticancer compound preparations and promote their clinical application in practice. Nevertheless, continuous efforts with new designs of co-delivery systems remain essential, providing a foundation for future clinical research and development of new anticancer drugs.