作者: Barrett, Anthony G. M. ; Cochran, Lauren E. ; Trivedi, Evan R. ; Hoffman, Brian M. ; Kandela, Irawati K. ; Mazar, Andrew P. ; McAuliffe, Katherine J.

A series of porphyrazines (Pzs) with chiral bis-acetal moieties in the β-pyrrole positions ((2R,3R)-2,3-dimethyl-2,3-dimethoxy-1,4-diox-2-ene) have been synthesized and screened as antitumor agents in MDA-MB-231 breast tumor cells in vitro. The lead Pz 285 was further tested in a mouse tumor xenograft model with Td-tomato-luc2 fluorescent breast tumor cells (MDA-MB-231 LM24 Her2+) that are highly metastatic to the lungs. Pz 285 shows marked antitumor effects in vivo, with treated mice exhibiting longer median survival that we attribute to smaller primary tumor regrowth after resection and less occurrence of metastasis when compared to vehicle control groups. Pz 285 is further compared to the clinically approved chemotherapeutic doxorubicin (Dox). This report lays the groundwork for development of an understudied class of compounds for classical chemotherapy.

2012-12-01·Cellular Signalling3区 · 生物学

Nerve growth factor stimulation of ERK1/2 phosphorylation requires both p75NTR and α9β1 integrin and confers myoprotection towards ischemia in C2C12 skeletal muscle cell model

3区 · 生物学

Article

作者: Shimon Lecht ; Shlomit Aga-Mizrachi ; Gadi Cohen ; Nurit Yanay ; Keren Ettinger ; Philip Lazarovici ; Hinyu Nedev ; Yoram Nevo ; Hadar Arien-Zakay ; H. Uri Saragovi ; Cezary Marcinkiewicz

The functions of nerve growth factor (NGF) in skeletal muscles physiology and pathology are not clear and call for an updated investigation. To achieve this goal we sought to investigate NGF-induced ERK1/2 phosphorylation and its role in the C2C12 skeletal muscle myoblasts and myotubes. RT-PCR and western blotting experiments demonstrated expression of p75(NTR), α9β1 integrin, and its regulator ADAM12, but not trkA in the cells, as also found in gastrocnemius and quadriceps mice muscles. Both proNGF and βNGF induced ERK1/2 phosphorylation, a process blocked by (a) the specific MEK inhibitor, PD98059; (b) VLO5, a MLD-disintegrin with relative selectivity towards α9β1 integrin; and (c) p75(NTR) antagonists Thx-B and LM-24, but not the inactive control molecule backbone Thx. Upon treatment for 4 days with either anti-NGF antibody or VLO5 or Thx-B, the proliferation of myoblasts was decreased by 60-70%, 85-90% and 60-80% respectively, indicative of trophic effect of NGF which was autocrinically released by the cells. Exposure of myotubes to ischemic insult in the presence of βNGF, added either 1h before oxygen-glucose-deprivation or concomitant with reoxygenation insults, resulted with about 20% and 33% myoprotection, an effect antagonized by VLO5 and Thx-B, further supporting the trophic role of NGF in C2C12 cells. Cumulatively, the present findings propose that proNGF and βNGF-induced ERK1/2 phosphorylation in C2C12 cells by functional cooperation between p75(NTR) and α9β1 integrin, which are involved in myoprotective effects of autocrine released NGF. Furthermore, the present study establishes an important trophic role of α9β1 in NGF-induced signaling in skeletal muscle model, resembling the role of trkA in neurons. Future molecular characterization of the interactions between NGF receptors in the skeletal muscle will contribute to the understanding of NGF mechanism of action and may provide novel therapeutic targets.

International Journal of Environmental Research and Public Health

Metabolic Mechanism of Bacillus sp. LM24 under Abamectin Stress

Article

作者: Xie, Wenyu ; Wang, Ruzhen ; Li, Dehao ; Xie, Qilai ; Yin, Xudong ; Zhu, Yueping ; Ye, Jinshao

Abamectin (ABM) has been recently widely used in aquaculture. However, few studies have examined its metabolic mechanism and ecotoxicity in microorganisms. This study investigated the molecular metabolic mechanism and ecotoxicity of Bacillus sp. LM24 (B. sp LM24) under ABM stress using intracellular metabolomics. The differential metabolites most affected by the bacteria were lipids and lipid metabolites. The main significant metabolic pathways of B. sp LM24 in response to ABM stress were glycerolipid; glycine, serine, and threonine; and glycerophospholipid, and sphingolipid. The bacteria improved cell membrane fluidity and maintained cellular activity by enhancing the interconversion pathway of certain phospholipids and sn-3-phosphoglycerol. It obtained more extracellular oxygen and nutrients to adjust the lipid metabolism pathway, mitigate the impact of sugar metabolism, produce acetyl coenzyme A to enter the tricarboxylic acid (TCA) cycle, maintain sufficient anabolic energy, and use some amino acid precursors produced during the TCA cycle to express ABM efflux protein and degradative enzymes. It produced antioxidants, including hydroxyanigorufone, D-erythroascorbic acid 1′-a-D-xylopyranoside, and 3-methylcyclopentadecanone, to alleviate ABM-induced cellular and oxidative damage. However, prolonged stress can cause metabolic disturbances in the metabolic pathways of glycine, serine, threonine, and sphingolipid; reduce acetylcholine production; and increase quinolinic acid synthesis.

100 项与 LM-024 相关的药物交易

登录后查看更多信息