2019) Shikonin induces apoptosis and prosurvival autophagy in human melanoma A375 cells via ROS-mediated ER stress and p38 pathways, Artificial Cells, Nanomedicine, and Biotechnology, 47:1, 626-635, ABSTRACT Shikonin, a botanical drug extracted from Lithospermum erythrorhizon, exhibits anti-cancer effects in various cancer cell lines. However, the mechanisms underlying these effects have not been completely elucidated yet. Here, we showed that Shikonin induces apoptosis and autophagy in A375 cells and inhibits their proliferation. Shikonin caused G2/M phase arrest through upregulation of p21 and downregulation of cyclin B1. Shikonin significantly triggered ER stress-mediated apoptosis by upregulating the expression of p-eIF2a, CHOP, and cleaved caspase-3. It also induced protective autophagy by activating the p38 pathway, followed by an increase in the levels of p-p38, LC3B-II, and Beclin 1. Upon suppression of autophagy by 3-methyladenine, Shikonin-induced apoptosis was enhanced in A375 cells. Moreover, after pretreatment with N-acetyl-cysteine, Shikonin increased the production of reactive oxygen species that are involved in regulating ER stress-mediated apoptosis and p38-activated autophagy, as evidenced by the reversion of cell viability and apoptosis and a decrease in p-eIF2a, CHOP, p-p38, LC3B-II, and Beclin 1 levels. Thus, we demonstrated that Shikonin induced apoptosis and autophagy in A375 cells via the activation of ROS-mediated ER stress and p38 pathways, indicating that Shikonin can serve as a potential agent for human melanoma therapy. ARTICLE HISTORY

The effects of polymerized porcine hemoglobin (pPolyHb) on hemodynamic stability and maintenance of mesenteric microvascular function were explored in a rat model of hemorrhagic shock (HS). Following controlled hemorrhage, rats were infused with equal volumes of either pPolyHb, hetastarch (HES), or red blood cell (RBC). The results showed that pPolyHb was superior to HES and RBC in restoring hemodynamic stability and reversing anaerobic metabolism. We observed a reduction in the diameter of mesenteric microvasculature after HS. Resuscitation with pPolyHb and RBC was able to restore the diameters of the venules and arterioles, whereas HES failed to restore the diameters during the observation period.

We investigated the allele frequencies of drug absorption, distribution, metabolism and elimination (ADME)-related drug-metabolizing enzymes and transporters (DMET) genes in the Northwestern Han, Tibetan and Uyghur populations and compared the related genes in these three populations with those in eleven 1000 Genome populations. We examined 1936 single nucleotide polymorphisms of 225 DMET genes involved in ADME processes and found 732, 679 and 804 sites were polymorphic in Han, Tibetan and Uyghur. Tibetan differed from Han in only four sites (p < .05), whereas Uyghur differed from Han and Tibetan in 24 and 21 sites, respectively (p < .05). The distributions of 1058 genotyping data of 245 individuals from Han, Tibetan and Uyghur were compared with 1207 other individuals from the eleven 1000 Genomes populations. The top four populations in Han that exhibited the smallest pairwise Fst values were CHB, Tibetan, CHD and JPT; those in Tibetan were Han, CHB, Uyghur and CHD; and those in Uyghur were Han, Tibetan, GIH and CEU. MEGA results revealed that CHB, CHD, JPT, Han, Tibetan and Uyghur were grouped in cluster 1. GIH, MEX, CEU and TSI were grouped in cluster 2. MKK, ASW, LWK and YRI were grouped in cluster 3.

Polymerized porcine hemoglobin (pPolyHb), a kind of glutaraldehyde-polymerized haemoglobin-based oxygen carrier, was developed as a potential red blood substitute for clinical applications. Assessment of its absorption, distribution, and metabolism is a major determinant of its safety and efficacy. In this study, a series of pharmacokinetic parameters of pPolyHb were measured and calculated in different animal models, such as the top-load model, the 50% exchange transfusion model and the haemorrhagic shock model. The results showed that the kinetic process of pPolyHb in rats conforms to the laws of linear pharmacokinetics in vivo. The half-life of pPolyHb was superior and more stable under non-pathological conditions, but in clinical situations such as trauma and anaemia, the half-life of pPolyHb may decline. The study of clearance (CL) and the apparent volume of distribution (Vd) of pPolyHb in these three different animal models demonstrated longer residence and a predominant, targeted role of pPolyHb with little accumulation in tissues. Through this study, the superior pharmacokinetic characteristics of pPolyHb have been proved and will aid in the determination of a reasonable dosing regimen and administration interval in clinical situations.