The antiprotozoal drug nitazoxanide improves experimental liver fibrosis in mice.

Nitazoxanide is an FDA-approved antiprotozoal drug. Our previous studies find that nitazoxanide and its metabolite tizoxanide affect AMPK, STAT3, and Smad2/3 signals which are involved in the pathogenesis of liver fibrosis, therefore, in the present study, we examined the effect of nitazoxanide on experimental liver fibrosis and elucidated the potential mechanisms. The in vivo experiment results showed that oral nitazoxanide (75, 100 mg·kg-1) significantly improved CCl4- and bile duct ligation-induced liver fibrosis in mice. Oral nitazoxanide activated the inhibited AMPK and inhibited the activated STAT3 in liver tissues from liver fibrosis mice. The in vitro experiment results showed that nitazoxanide and its metabolite tizoxanide activated AMPK and inhibited STAT3 signals in LX-2 cells (human hepatic stellate cells). Nitazoxanide and tizoxanide inhibited cell proliferation and collagen I expression and secretion of LX-2 cells. Nitazoxanide and tizoxanide inhibited transforming growth factor-ß1 (TGF-ß1)- and IL-6-induced increases of cell proliferation, collagen I expression and secretion, inhibited TGF-ß1- and IL-6-induced STAT3 and Smad2/3 activation in LX-2 cells. In mouse primary hepatic stellate cells, nitazoxanide and tizoxanide also activated AMPK, inhibited STAT3 and Smad2/3 activation, inhibited cell proliferation, collagen I expression and secretion. In conclusion, nitazoxanide inhibits liver fibrosis and the underlying mechanisms involve AMPK activation, and STAT3 and Smad2/3 inhibition.

Designing Benzodithiophene-Based Small Molecule Donors for Organic Solar Cells by Regulation of Halogenation Effects.

The donors are key components of organic solar cells (OSCs) and play crucial roles in their photovoltaic performance. Herein, we designed two new donors (BTR-γ-Cl and BTR-γ-F) by finely optimizing small molecule donors (BTR-Cl and BTR-F) with a high performance. The optoelectronic properties of the four donors and their interfacial properties with the well-known acceptor Y6 were studied by density functional theory and time-dependent density functional theory. Our calculations show that the studied four donors have large hole mobility and strong interactions with Y6, where the BTR-γ-Cl/Y6 has the largest binding energy. Importantly, the proportion of charge transfer (CT) states increases at the BTR-γ-Cl/Y6 (50%) and BTR-γ-F/Y6 (45%) interfaces. The newly designed donors are more likely to achieve CT states through intermolecular electric field (IEF) and hot exciton mechanisms than the parent molecules; meanwhile, donors containing Cl atoms are more inclined to produce CT states through the direct excitation mechanism than those containing F atoms. Our results not only provided two promising donors but also shed light on the halogenation effects on donors in OSCs, which might be important to design efficient photovoltaic materials.

D-Optimal Design and Development of a Koumine-Loaded Microemulsion for Rheumatoid Arthritis Treatment: In vivo and in vitro Evaluation.

Introduction: Koumine (KME) is the most abundant active ingredient separated from Gelsemium elegans Benth and exhibits a significant therapeutic effect on rheumatoid arthritis (RA). It is a lipophilic compound with poor aqueous solubility, and there is an urgent need to develop novel dosage forms of KME and promote its clinical application for the treatment of RA. The aim of this study was to design and develop KME-loaded microemulsions (KME-MEs) for the effective management of RA. Methods: The composition of the microemulsion was selected by carrying out a solubility study and generating pseudoternary phase diagrams, and further optimized by D-Optimal design. The optimized KME-MEs was evaluated for particle size, viscosity, drug release, storage stability, cytotoxicity, cellular uptake, Caco-2 cell transport and everted gut sac investigations. In vivo fluorescence imaging and the therapeutic effects of KME and KME-MEs on collagen-induced arthritis (CIA) rats were also evaluated. Results: The optimized microemulsion contained 8% oil, 32% Smix (surfactant/cosurfactant) and 60% water and was used for in vivo and in vitro studies. The optimal KME-MEs exhibited a small globule size of 18.5 ± 0.14 nm and good stability over 3 months, and the release kinetics followed a first-order model. These KME-MEs had no toxic effect on Caco-2 cells but were efficiently internalized into the cytoplasm. Compared to KME, the KME-MEs displayed significantly increased permeability and absorption in Caco-2 cell monolayer assay and ex vivo everted gut sac experiment. As expected, the KME-MEs attenuated the progression of RA in CIA rats and were more effective than free KME with a reduced frequency of administration. Conclusion: The KME-MEs improved the solubility and therapeutic efficacy of KME by employing formulation technology. These results provide a promising vehicle for the oral delivery of KME to treat RA and have attractive potential for clinical translation.

Okicamelliaside targets the N-terminal chaperone pocket of HSP90 disrupts the chaperone protein interaction of HSP90-CDC37 and exerts antitumor activity.

Heat shock protein 90 (HSP90) has been recognized as a crucial target in cancer cells. However, various toxic reactions targeting the ATP binding site of HSP90 may not be the best choice for HSP90 inhibitors. In this paper, an ellagic acid derivative, namely, okicamelliaside (OCS), with antitumor effects was found. To identify potential anti-cancer mechanisms, an OCS photosensitive probe was applied to target fishing and tracing. Chemical proteomics and protein-drug interaction experiments have shown that HSP90 is a key target for OCS, with a strong binding affinity (KD = 6.45 µM). Mutation analysis of the target protein and molecular dynamics simulation revealed that OCS could competitively act on the key Glu-47 site at the N-terminal chaperone pocket of HSP90, where the co-chaperone CDC37 binds to HSP90, affect its stability and reduce the ∆Gbind of HSP90-CDC37. It was demonstrated that OCS destroys the protein-protein interactions of HSP90-CDC37; selectively affects downstream kinase client proteins of HSP90, including CDK4, P-AKT473, and P-ERK1/2; and exerts antitumor effects on A549 cells. Furthermore, tumor xenograft experiments demonstrated high antitumor activity and low toxicity of OCS in the same way. Our findings identified a novel N-terminal chaperone pocket natural inhibitor of HSP90, that is, OCS, which selectively inhibits the formation of the HSP90-CDC37 protein complex, and provided further insight into HSP90 inhibitors for anti-cancer candidate drugs.

Populeuphrines A and B, two new cembrane diterpenoids from the resins of Populus euphratica.

Two new cembrane diterpenoids, named populeuphrines A and B (1 and 2), together with three known analogues (3-5) were isolated from the resins of Populus euphratica. The planar structures and relative configurations of 1 and 2 were elucidated by detailed 1 D and 2 D NMR spectroscopic analyses. The absolute configurations of 1 and 2 were determined by X-ray diffraction analysis and quantum chemical computation. Biological activities of all the isolates against proliferation of human cancer cells and umbilical cord mesenchymal stem cells were evaluated.

Discovery of Populusone, a Skeletal Stimulator of Umbilical Cord Mesenchymal Stem Cells from Populus euphratica Exudates.

Populusone (1), a cembrane-type macrocyclic trinorditerpenoid, was isolated from the exudates of Populus euphratica and shown to have an unprecedented carbon skeleton, The structure was identified using spectroscopic methods and X-ray crystallography. A possible pathway for the biosynthesis of 1 was proposed. Populusone (10 µM) was found to promote proliferation and differentiation of umbilical cord derived mesenchymal stem cells into keratinocyte like cells.