The Middle Part of the Plucked Hair Follicle Outer Root Sheath Is Identified as an Area Rich in Lineage-Specific Stem Cell Markers

Hair follicle outer root sheath (ORS) is a putative source of stem cells with therapeutic capacity. ORS contains several multipotent stem cell populations, primarily in the distal compartment of the bulge region. However, the bulge is routinely obtained using invasive isolation methods, which require human scalp tissue ex vivo. Non-invasive sampling has been standardized by means of the plucking procedure, enabling to reproducibly obtain the mid-ORS part. The mid-ORS shows potential for giving rise to multiple stem cell populations in vitro. To demonstrate the phenotypic features of distal, middle, and proximal ORS parts, gene and protein expression profiles were studied in physically separated portions. The mid-part of the ORS showed a comparable or higher NGFR, nestin/NES, CD34, CD73, CD44, CD133, CK5, PAX3, MITF, and PMEL expression on both protein and gene levels, when compared to the distal ORS part. Distinct subpopulations of cells exhibiting small and round morphology were characterized with flow cytometry as simultaneously expressing CD73/CD271, CD49f/CD105, nestin, and not CK10. Potentially, these distinct subpopulations can give rise to cultured neuroectodermal and mesenchymal stem cell populations in vitro. In conclusion, the mid part of the ORS holds the potential for yielding multiple stem cells, in particular mesenchymal stem cells

Roles of the Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways in controlling growth and sensitivity to therapy-implications for cancer and aging

Dysregulated signaling through the Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways is often the result of genetic alterations in critical components in these pathways or upstream activators. Unrestricted cellular proliferation and decreased sensitivity to apoptotic-inducing agents are typically associated with activation of these pro-survival pathways. This review discusses the functions these pathways have in normal and neoplastic tissue growth and how they contribute to resistance to apoptotic stimuli. Crosstalk and commonly identified mutations that occur within these pathways that contribute to abnormal activation and cancer growth will also be addressed. Finally the recently described roles of these pathways in cancer stem cells, cellular senescence and aging will be evaluated. Controlling the expression of these pathways could ameliorate human health

Advances in Targeting Signal Transduction Pathways

Over the past few years, significant advances have occurred in both our understanding of the complexity of signal transduction pathways as well as the isolation of specific inhibitors which target key components in those pathways. Furthermore critical information is being accrued regarding how genetic mutations can affect the sensitivity of various types of patients to targeted therapy. Finally, genetic mechanisms responsible for the development of resistance after targeted therapy are being discovered which may allow the creation of alternative therapies to overcome resistance. This review will discuss some of the highlights over the past few years on the roles of key signaling pathways in various diseases, the targeting of signal transduction pathways and the genetic mechanisms governing sensitivity and resistance to targeted therapies

Synthesis, X-ray structure and strong in vitro cytotoxicity of novel organoruthenium complexes

Two p-cymene ruthenium chlorido complexes containing isobutyl (C1) and isoamyl (C2) esters of (S,S)ethylenediamine-N,N'-di-2-(3-cyclohexyl) propanoic acid as ligands were prepared from p-cymene ruthenium dichloride dimer and corresponding ester. All compounds have been characterized by elemental analysis, IR, ESI-MS, H-1 and C-13 NMR spectroscopy. Single crystal X-ray structure diffraction analysis of C1 shows the usual piano-stool geometry of complexes, with coordination of ester ligand via nitrogen donor atoms. Ligands exhibit moderate anticancer activity (IC50 gt 50 mu M), while the complexes were significantly more cytotoxic towards various cancer cell lines, including B16, A375, HCT116, A549 and MCF7 cells (IC50 min.-max. 2.9-8.0 mu M). We stress that cisplatin resistant HCT116 cell line was highly sensitive to the treatment with C1 and C2 (IC50 values: 4.4 and 5.5 mu M versus IC50 gt 120 mu M for cisplatin). In parallel, primary fibroblasts-MRC-5 were remarkably less affected by these compounds. (C) 2013 Elsevier B. V. All rights reserved

Aloe emodin inhibits the cytotoxic action of tumor necrosis factor

We demonstrate the capacity of an herbal anthraquinone aloe emodin to reduce the cytotoxicity of the proinflammatory cytokine tumor necrosis factor (TNF) towards L929 mouse fibrosarcoma and U251 human glioma cell lines. Aloe emodin inhibited both TNF-induced cell necrosis and apoptosis, but it did not reduce cell death induced by UV radiation or hydrogen peroxide. Aloe emodin inhibited both basal and TNF-triggered activation of extracellular signal-regulated kinase (ERK), and a selective blockade of ERK activation mimicked the cytoprotective action of the drug. On the other hand, aloe emodin did not affect TNF-induced activation of p38 mitogen-activated protein kinase or generation of reactive oxygen species. The combination of aloe emodin and TNF caused an intracellular appearance of acidified autophagic vesicles, and the inhibition of autophagy with bafilomycin or 3-methyladenine efficiently blocked the cytoprotective action of aloe emodin. These data indicate that aloe emodin could prevent TNF-triggered cell death through mechanisms involving induction of autophagy and blockade of ERK activation. (C) 2007 Elsevier B.V. All rights reserved

Melanoma tumor inhibition by tetrachlorido(O,O '-dibutyl-ethylenediamine-N,N '-di-3-propionate)platinum(IV) complex: in vitro and in vivo investigations

Tetrachlorido(O,O'-dibutyl-ethylenediamine-N,N'-di-3-propionate)-platinum(IV) complex, [PtCl4(n-Bu(2)eddp)], was previously found to be effective against fibrosarcoma and glioma cell lines. Here we presented that [PtCl4(n-Bu(2)eddp)] strongly reduced the growth of B16 melanoma cells in vitro. Inhibition of cell viability was accompanied with induction of both necrotic and apoptotic cell death. In addition, [PtCl4(n-Bu(2)eddp)] concealed the expansion of tumors induced in syngeneic C57BI/6 mice without visible signs of nephrotoxicity

Carboranyl Analogues of Ketoprofen with Cytostatic Activity against Human Melanoma and Colon Cancer Cell Lines

Ketoprofen is a widely used nonsteroidal anti-inflammatory drug (NSAID) that also exhibits cytotoxic activity against various cancers. This makes ketoprofen an attractive structural lead for the development of new NSAIDs and cytotoxic agents. Recently, the incorporation of carboranes as phenyl mimetics in structures of established drugs has emerged as an attractive strategy in drug design. Herein, we report the synthesis and evaluation of four novel carborane-containing derivatives of ketoprofen, two of which are prodrug esters with an nitric oxide-releasing moiety. One of these prodrug esters exhibited high cytostatic activity against melanoma and colon cancer cell lines. The most pronounced activity was found in cell lines that are sensitive to oxidative stress, which was apparently induced by the ketoprofen analogue

In Vitro Assessment of Ni-Cr and Co-Cr Dental Alloys Upon Recasting: Cellular Compatibility

The aim of this study was to evaluate the effect of recasting of commercially available Ni-Cr (Wiron 99) and Co-Cr (Dentalit C) dental alloys on physiology of microenvironmental cells. The viability of fibrosarcoma (L929) cells, human embrional fibroblasts (MRC-5) and isolated peripheral blood mononuclear cells (PBMC) was measured by MTT and acidic phosphatase tests. Presence of dying cells was estimated by Annexin/PI staining while the production of intracellular nitric oxide (NO), reactive oxygen (ROS) and nitrogen (RNS) species was determined by DAF-FM diacetate and DHR staining. Recasting of Ni-Cr alloy intensified its cytotoxicity manifested through enhanced free radicals production, induction of cell death and permamently diminished cell proliferation. On the other hand, after initial toxic effect cells adapted to the presence of Co-Cr alloys. Independently of recasting, Co-Cr alloys are more compatible with microenvironment then Ni-Cr alloy. Oppositely, recasting of Ni-Cr alloy promoted its toxicity

In Vitro Assessment of Ni-Cr and Co-Cr Dental Alloys Upon Recasting: Cellular Compatibility

The aim of this study was to evaluate the effect of recasting of commercially available Ni-Cr (Wiron 99) and Co-Cr (Dentalit C) dental alloys on physiology of microenvironmental cells. The viability of fibrosarcoma (L929) cells, human embrional fibroblasts (MRC-5) and isolated peripheral blood mononuclear cells (PBMC) was measured by MTT and acidic phosphatase tests. Presence of dying cells was estimated by Annexin/PI staining while the production of intracellular nitric oxide (NO), reactive oxygen (ROS) and nitrogen (RNS) species was determined by DAF-FM diacetate and DHR staining. Recasting of Ni-Cr alloy intensified its cytotoxicity manifested through enhanced free radicals production, induction of cell death and permamently diminished cell proliferation. On the other hand, after initial toxic effect cells adapted to the presence of Co-Cr alloys. Independently of recasting, Co-Cr alloys are more compatible with microenvironment then Ni-Cr alloy. Oppositely, recasting of Ni-Cr alloy promoted its toxicity

Anticancer and Differentiation Properties of the Nitric Oxide Derivative of Lopinavir in Human Glioblastoma Cells

Glioblastoma (GBM) is the most frequent and deadly form of primary malignant brain tumor among adults. A promising emerging approach for GBM treatment may be offered from HIV protease inhibitors (HIV-PIs). In fact, in addition to their primary pharmacological activity in the treatment of HIV infection, they possess important anti-neoplastic effects. According to previous studies, the addition of a nitric oxide (NO) donating group to parental compounds can reduce their toxicity and enhance the anticancer action of various compounds, including HIV-PIs. In this study we compared the effects of the HIV-PI Lopinavir (Lopi) and of its NO-derivative Lopinavir-NO (Lopi-NO) on the in vitro growth of LN-229 and U-251 human GBM cell lines. Lopi-NO reduced the viability of LN-229 and U-251 cells at significantly lower concentrations than the parental drug. In particular, Lopi-NO inhibited tumor cell proliferation and induced the differentiation of U-251 cells toward an astrocyte-like phenotype without triggering significant cell death in both cell types. The anticancer effect of Lopi-NO was persistent even upon drug removal. Furthermore, Lopi-NO induced strong autophagy that did not appear to be related to its chemotherapeutic action. Overall, our results suggest that Lopi-NO could be a potential effective anticancer drug for GBM treatment