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A novel nickel complex works as a proteasomal deubiquitinase inhibitor for cancer therapy.

Based on the central role of the ubiquitin-proteasome system (UPS) in the degradation of cellular proteins, proteasome inhibition has been considered an attractive approach for anticancer therapy. Deubiquitinases (DUBs) remove ubiquitin conjugates from diverse substrates; therefore, they are essential regulators of the UPS. DUB inhibitors, especially the inhibitors of proteasomal DUBs are becoming a research hotspot in targeted cancer therapy. Previous studies have shown that metal complexes, such as copper and zinc complexes, can induce cancer cell apoptosis through inhibiting UPS function. Moreover, we have found that copper pyrithione inhibits both 19S proteasome-associated DUBs and 20S proteasome activity with a mechanism distinct from that of the classical 20S proteasome inhibitor bortezomib. In the present study, we reveal that (i) nickel pyrithione complex (NiPT) potently inhibits the UPS via targeting the 19S proteasome-associated DUBs (UCHL5 and USP14), without effecting on the 20S proteasome; (ii) NiPT selectively induces proteasome inhibition and apoptosis in cultured tumor cells and cancer cells from acute myeloid leukemia human patients; and (iii) NiPT inhibits proteasome function and tumor growth in nude mice. This study, for the first time, uncovers a nickel complex as an effective inhibitor of the 19S proteasomal DUBs and suggests a potentially new strategy for cancer treatment.Oncogene advance online publication, 18 April 2016; doi:10.1038/onc.2016.114.

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12-Oxo-phytodienoic acid, a plant-derived oxylipin, attenuates lipopolysaccharide-induced inflammation in microglia.

Jasmonates are plant lipid-derived oxylipins that act as key signaling compounds in plant immunity, germination, and development. Although some physiological activities of natural jasmonates in mammalian cells have been investigated, their anti-inflammatory actions in mammalian cells remain unclear. Here, we investigated whether jasmonates protect mouse microglial MG5 cells against lipopolysaccharide (LPS)-induced inflammation. Among the jasmonates tested, only 12-oxo-phytodienoic acid (OPDA) suppressed LPS-induced expression of the typical inflammatory cytokines interleukin-6 and tumor necrosis factor α. In addition, only OPDA reduced LPS-induced nitric oxide production through a decrease in the level of inducible nitric oxide synthase. Further mechanistic studies showed that OPDA suppressed neuroinflammation by inhibiting nuclear factor κB and p38 mitogen-activated protein kinase signaling in LPS-activated MG5 cells. In addition, OPDA induced expression of suppressor of cytokine signaling-1, a negative regulator of inflammation, in MG5 cells. Finally, we found that the nuclear factor erythroid 2-related factor 2 signaling cascade induced by OPDA is not involved in the anti-inflammatory effects of OPDA. These results demonstrate that OPDA inhibited LPS-induced cell inflammation in mouse microglial cells via multiple pathways, including suppression of nuclear factor κB, inhibition of p38, and activation of SOCS-1 signaling.
Copyright © 2016. Published by Elsevier Inc.

Adolescent endogenous sex hormones and breast density in early adulthood.

During adolescence the breasts undergo rapid growth and development under the influence of sex hormones. Although the hormonal etiology of breast cancer is hypothesized, it remains unknown whether adolescent sex hormones are associated with adult breast density, which is a strong risk factor for breast cancer.
Percentage of dense breast volume (%DBV) was measured in 2006 by magnetic resonance imaging in 177 women aged 25-29 years who had participated in the Dietary Intervention Study in Children from 1988 to 1997. They had sex hormones and sex hormone-binding globulin (SHBG) measured in serum collected on one to five occasions between 8 and 17 years of age. Multivariable linear mixed-effect regression models were used to evaluate the associations of adolescent sex hormones and SHBG with %DBV.
Dehydroepiandrosterone sulfate (DHEAS) and SHBG measured in premenarche serum samples were significantly positively associated with %DBV (all P trend ≤0.03) but not when measured in postmenarche samples (all P trend ≥0.42). The multivariable geometric mean of %DBV across quartiles of premenarcheal DHEAS and SHBG increased from 16.7 to 22.1 % and from 14.1 to 24.3 %, respectively. Estrogens, progesterone, androstenedione, and testosterone in pre- or postmenarche serum samples were not associated with %DBV (all P trend ≥0.16).
Our results suggest that higher premenarcheal DHEAS and SHBG levels are associated with higher %DBV in young women. Whether this association translates into an increased risk of breast cancer later in life is currently unknown.
ClinicalTrials.gov Identifier, NCT00458588 April 9, 2007; NCT00000459 October 27, 1999.

ADCT-402

ADCT-402 is being developed for the treatment of CD19-expressing non-Hodgkin’s lymphoma and B-cell leukemia (Company Pipeline, ADC Therapeutics, APR 19, 2016, View Source [SID:1234511064]). ADCT-402 is composed of a humanized antibody directed against human CD19, conjugated to a potent PBD dimer toxin. We have reported preclinical data demonstrating potent antitumor activity of ADCT-402 against CD19-expressing B-cell malignancies.1
CD19 expression has been demonstrated in many types of Non-Hodgkin lymphoma2 including Burkitt’s Lymphoma, Follicular Lymphoma and Diffuse Large B-cell Lymphoma.

Evaluation of established human iPSC-derived neurons to model neurodegenerative diseases.

Neurodegenerative diseases are difficult to study due to unavailability of human neurons. Cell culture systems and primary rodent cultures have shown to be indispensable to clarify disease mechanisms and provide insights into gene functions. Nevertheless, it is hard to translate new findings into new medicines. The discovery of human induced pluripotent stem cells (iPSC) might partially overcome this problem. Commercially available human iPSC-derived neurons, when thoroughly characterized and suitable for viral transduction, might represent a faster model for drugs screening than the time-consuming derivation and differentiation of iPSC from patient samples. In this study we show that iCell neurons are primarily immature GABAergic neurons within the tested time frame. Addition of C6 glioma conditioned medium improved the bursting frequency of cells without further maturation or evidence for glutamatergic responses. Furthermore, cells were suitable for lentiviral transduction within the tested time frame. Altogether, iCell neurons might be useful to model neurodegenerative diseases in which young GABAergic subtypes are affected.
Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.