NAD(P)H:quinone oxidoreductase 1 (NQO1) is a two-electron reductase responsible for detoxification of quinones and also bioactivation of certain quinones. It is abnormally overexpressed in many tumors and intimately linked with multiple carcinogenic processes. NQO1 is considered to be a cancer-specific target for therapy but currently available NQO1 inhibitors have not yet led to chemotherapeutic success. Utilization of NOQ1's ability to bioactivate chemotherapeutic quinones, however, has emerged as a promising selective anticancer therapy. On the basis of the different levels of NQO1 between cancer and normal cells, the catalytic property of NQO1 has recently been exploited to develop effective probes for cancer detection. This article summarizes the most significant advances concerning the discovery and development of NQO1 inhibitors, NQO1-directed chemotherapeutic quinones, and NQO1-activated optical probes, along with the prospects and potential obstacles in this research area.
BackgroundHuman endometrial mesenchymal stem cells (EnSCs) derived from menstrual blood have mesenchymal stem/stromal cells (MSCs) characteristics and can differentiate into cell types that arise from all three germ layers. We hypothesized that EnSCs may offer promise for restoration of ovarian dysfunction associated with premature ovarian failure/insufficiency (POF/POI).MethodsMouse ovaries were injured with busulfan and cyclophosphamide (B/C) to create a damaged ovary mouse model. Transplanted EnSCs were injected into the tail vein of sterilized mice (Chemoablated with EnSCs group; n = 80), or culture medium was injected into the sterilized mice via the tail vein as chemoablated group (n = 80). Non-sterilized mice were untreated controls (n = 80). Overall ovarian function was measured using vaginal smears, live imaging, mating trials and immunohistochemical techniques.ResultsEnSCs transplantation increased body weight and improved estrous cyclicity as well as restored fertility in sterilized mice. Migration and localization of GFP-labeled EnSCs as measured by live imaging and immunofluorescent methods indicated that GFP-labeled cells were undetectable 48 h after cell transplantation, but were later detected in and localized to the ovarian stroma. 5’-bromodeoxyuridine (BrdU) and mouse vasa homologue (MVH) protein double-positive cells were immunohistochemically detected in mouse ovaries, and EnSC transplantation reduced depletion of the germline stem cell (GSCs) pool induced by chemotherapy.ConclusionEnSCs derived from menstrual blood, as autologous stem cells, may restore damaged ovarian function and offer a suitable clinical strategy for regenerative medicine.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-015-0516-y) contains supplementary material, which is available to authorized users.
Mesenchymal stem cells (MSCs) may have potential applications in regenerative medicine for the treatment of chronic liver diseases (CLDs). Human menstrual blood is a novel source of MSCs, termed menstrual blood‐derived stem cells (MenSCs). Compared with bone marrow MSCs, MenSCs exhibit a higher proliferation rate and they can be obtained through a simple, safe, painless procedure without ethical concerns. Although the therapeutic efficacy of MenSCs has been explored in some diseases, their effects on liver fibrosis are still unclear. In the present study, we investigated the therapeutic effects of MenSC transplantation in a carbon tetrachloride‐induced mouse model of liver fibrosis. These results revealed that MenSCs markedly improved liver function, attenuated collagen deposition, and inhibited activated hepatic stellate cells up to 2 weeks after transplantation. Moreover, tracking of green fluorescent protein‐expressing MenSCs demonstrated that transplanted cells migrated to the sites of injury, but few differentiated into functional hepatocyte‐like cells. Transwell coculturing experiments also showed that MenSCs suppressed proliferation of LX‐2 cells (an immortalized hepatic stellate cell line) through secretion of monocyte chemoattractant protein‐1, interleukin‐6, hepatocyte growth factor, growth‐related oncogene, interleukin‐8, and osteoprotegerin. Collectively, our results provided preliminary evidence for the antifibrotic capacity of MenSCs in liver fibrosis and suggested that these cells may be an alternative therapeutic approach for the treatment of CLDs. Stem Cells Translational Medicine 2017;6:272–284
Recently, a unique population of progenitor cells was isolated from human menstrual blood. The human menstrual blood progenitor cells (MBPCs) possess many advantages, such as the noninvasive acquisition procedure, broad multipotency, a higher proliferative rate, and low immunogenicity, and have attracted extensive attention in regenerative medicine. Preclinical studies to test the safety and efficacy of MBPCs have been underway in several animal models. However, relevant studies in type 1 diabetes mellitus (T1DM) have not yet been proceeded. Herein, we studied the therapeutic effect of MBPCs and the mechanism of b-cell regeneration after MBPC transplantation in the T1DM model. Intravenous injection of MBPCs can reverse hyperglycemia and weight loss, prolong lifespan, and increase insulin production in diabetic mice. Histological and immunohistochemistry analyses indicated that T1DM mice with MBPC transplantation recovered islet structures and increased the b-cell number. We further analyzed in vivo distribution of MBPCs and discovered that a majority of MBPCs migrated into damaged pancreas and located at the islet, duct, and exocrine tissue. MBPCs did not differentiate into insulin-producing cells, but enhanced neurogenin3 (ngn3) expression, which represented endocrine progenitors that were activated. Ngn3+ cells were not only in the ductal epithelium, but also in the islet and exocrine tissue. We analyzed a series of genes associated with the embryonic mode of b-cell development by real-time polymerase chain reaction and the results showed that the levels of those gene expressions all increased after cell transplantation. According to the results, we concluded that MBPCs stimulated b-cell regeneration through promoting differentiation of endogenous progenitor cells.
An efficient, general palladium catalyst for C–O bond-forming reactions of secondary and primary alcohols with a range of aryl halides has been developed. Use of a catalyst based on a single bulky biarylphosphine ligand L4 (RockPhos, soon to be commercially available) has expanded this chemistry to allow the transformation of a variety of heteroaryl halides, and for the first time, allows for the coupling of electron-rich aryl halides with secondary alcohols. Additionally, this new catalyst system provides the ability to effect these reactions with a diverse set of substrate combinations, while employing a single ligand. Thus the need to survey mutiple ligands, as was previously the case, is obviated.
The clinical success of inhibitors targeting the PD-1/PD-L1 pathway has made this an active field in cancer immunotherapy. Currently, most drugs targeting this pathway are monoclonal antibodies. Small-molecule inhibitors as the alternative to monoclonal antibodies are expected to overcome the disadvantages of mAbs which include production difficulties and their long half-life. Recently, progress has been reported on anti-PD-1/PD-L1 small-molecule inhibitors. In this paper, we review the development of inhibitors targeting the PD-1/PD-L1 pathway, focusing mainly on peptide-based and nonpeptidic small-molecule inhibitors. The structures and the preclinical and clinical studies of several peptide-based small-molecule candidate compounds in clinical trials are discussed. We also illustrate the design strategies underlying reported nonpeptidic small-molecule inhibitors and provide insight into possible future exploration. Development of small-molecule drugs for anti-PD-1/PD-L1 activity with specific cancer applications is a promising and challenging prospect.
An extremophilic challenge: Stereospecific condensation of a fully functionalized ketal aldehyde and a 2,6-dihydroxybenzoic acid is the key step in the synthesis of (-)-berkelic acid confirming Fürstner's reassignment of the stereochemistry at C18 and C19, establishing the absolute stereochemistry, and tentatively assigning the stereochemistry at C22.
Orthotopic liver transplantation (OLT) is the only proven effective treatment for both end-stage and metabolic liver diseases. Hepatocyte transplantation is a promising alternative for OLT, but the lack of available donor livers has hampered its clinical application. Hepatocyte-like cells (HLCs) differentiated from many multi-potential stem cells can help repair damaged liver tissue. Yet almost suitable cells currently identified for human use are difficult to harvest and involve invasive procedures. Recently, a novel mesenchymal stem cell derived from human menstrual blood (MenSC) has been discovered and obtained easily and repeatedly. In this study, we examined whether the MenSCs are able to differentiate into functional HLCs in vitro. After three weeks of incubation in hepatogenic differentiation medium containing hepatocyte growth factor (HGF), fibroblast growth factor-4 (FGF-4), and oncostain M (OSM), cuboidal HLCs were observed, and cells also expressed hepatocyte-specific marker genes including albumin (ALB), α-fetoprotein (AFP), cytokeratin 18/19 (CK18/19), and cytochrome P450 1A1/3A4 (CYP1A1/3A4). Differentiated cells further demonstrated in vitro mature hepatocyte functions such as urea synthesis, glycogen storage, and indocyanine green (ICG) uptake. After intrasplenic transplantation into mice with 2/3 partial hepatectomy, the MenSC-derived HLCs were detected in recipient livers and expressed human ALB protein. We also showed that MenSC-derived HLC transplantation could restore the serum ALB level and significantly suppressed transaminase activity of liver injury animals. In conclusion, MenSCs may serve as an ideal, easily accessible source of material for tissue engineering and cell therapy of liver tissues.
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