No abstract

Hepatocellular carcinoma (HCC) is one of the most serious cancers, with rapid progression and high mortality. However, chemotherapy of HCC is hindered by multi-drug resistance (MDR). It is urgent, therefore, to explore new approaches for overcoming MDR of HCC cells. Ubenimex, an inhibitor of CD13, has been used as an immuno-enhancer for treating hematological neoplasms and other solid tumors. Here, we demonstrate that Ubenimex can also reverse MDR in the HCC cell lines HepG2/5-FU and Bel7402/5-FU. Ubenimex inhibits the expression of the proto-oncogene, Pim-3, which is accompanied by decreased expression of BCL-2 and BCL-XL, decreased phosphorylation of Bad, and increased tumor apoptosis.Moreover, Ubenimex decreases expression of the MDR-associated proteins P-gp, MRP3 and MRP2 to enhance intracellular accumulation of Cisplatin, for which down-regulation of Pim-3 is essential. Our results reveal a previously uncharacterized function of Ubenimex in mediating drug resistance in HCC, which suggests that Ubenimex may provide a new strategy to reverse MDR and improve HCC sensitivity to chemotherapeutic drugs via its effects on Pim-3.

Epimedium brevicornu Maxim has been used as a traditional herbal drug in China. In this study, the anti-inflammatory effects of E. brevicornu Maxim ethanol extract (EBME) were investigated in RAW264.7 macrophages and mice challenged with lipopolysaccharide (LPS). Results showed that EBME attenuated inflammation by decreasing the production of several proinflammatory mediators, such as nitric oxide (NO), prostaglandin (PG) E, inducible nitric oxide synthase, and cyclooxygenase-2, in LPS-stimulated RAW264.7 macrophages. EBME increased the expression of heme oxygenase-1 (HO-1) and promoted the nuclear translocation of nuclear factor erythroid 2-related factor 2. The inhibitory effects of EBME on LPS-stimulated NO and PGE expression were partially reversed by HO-1 inhibitor. EBME also elicited an anti-inflammatory effect by inhibiting the production of tumor necrosis factor-α, interleukin (IL)-1β, and IL-6 in LPS-induced peritonitis. Therefore, EBME exhibited anti-inflammatory effects in vitro and in vivo.

Context: Salvianolic acid A (Sal A) is a hydrophilic bioactive compound isolated from Salvia miltiorrhiza Bunge (Lamiaceae). It exerts beneficial effects after oral administration on diabetic complications.Objective: To systematically study the absorption, distribution and excretion of Sal A after single-dose oral administration.Materials and methods: Animal experiments were conducted in Sprague-Dawley rats. Plasma was sampled at designated times after oral doses of 5, 10 and 20 mg/kg, and an intravenous dose of 50 μg/kg. Tissues were harvested at 10, 60 and 120 min postdosing. Bile, urine and feces were collected at specified intervals before and after dosing. Absorption and distribution characteristics were analyzed by LC–MS, and excretion characteristics were analyzed by UPLC–MS/MS. The Caco-2 cell model was applied to investigate potential mechanisms.Results: The Cmax (5 mg/kg: 31.53 μg/L; 10 mg/kg: 57.39 μg/L; 20 mg/kg: 111.91 μg/L) of Sal A increased linearly with doses (r> 0.99). The calculated absolute bioavailability was 0.39–0.52%. Transport experiment showed poor permeability and the ratio of PB–A to PA–B was 3.13–3.97. The highest concentration of Sal A was achieved in stomach followed by small intestine and liver, and it could also be detected in brain homogenate. Approximately 0.775% of its administered dose was excreted via feces, followed by bile (0.00373%) and urine (0.00252%).Discussion and conclusions: These results support the future development of Sal A as an oral drug for the treatment of diabetic complications. Future research should be conducted to investigate the reason for its poor bioavailability and improve this situation.

Rhamnella gilgitica Mansf. et Melch, which belongs to the rhamnus family (Rhamnaceae), is traditionally used to treat rheumatism, swelling and pain in China. However, little is known about the pharmacological activities of this plant. The anti-inflammatory activities of the 70% ethanol extract of R. gilgitica (RG) in RAW264.7 macrophages and complete Freund's adjuvant (CFA)-induced arthritic rats are investigated in this study for the first time. The effects of RG on cell viability were determined by a MTT assay, and the effects of RG on pro-inflammatory mediators were analyzed by ELISA and Western blot. The effects of RG on paw thickness, thymus and spleen index were also examined in CFA-induced arthritic rats. RG suppressed the induction of proinflammatory mediators, including iNOS (inducible nitric oxide synthase), NO (nitric oxide), COX-2 (cyclooxygenase-2) and PG (prostaglandin) E2 in LPS stimulated RAW264.7 macrophages. RG also inhibited the phosphorylation and degradation of I[Formula: see text]B-[Formula: see text], as well as the nuclear translocation of nuclear factor kappa B (NF-[Formula: see text]B) p65. In addition, RG treatment significantly reduced the paw thickness in CFA-induced arthritic rats. Oral administration of RG led to a significant decrease of both the thymus and spleen index at a concentration of 100[Formula: see text]mg/mL. Taken together, these findings suggest that RG might be an agent for further development in the treatment of a variety of inflammatory diseases.