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Fenvalerate (FEN), a mainstream pyrethroid pesticide, was initially recommended as a low-toxicity agent for controlling agricultural and domestic pests. Despite the widespread use of FEN worldwide, little data are available on FEN-induced hepatic lesions and molecular mechanisms. In the present study, we first performed an occupational cross-sectional study on FEN factory workers and found that the levels of serum alanine aminotransferase (ALT) and total antioxidant capacity increased, whereas malondialdehyde decreased in laborers in the working areas where the levels of airborne FEN were much higher compared with the office area. The results were then confirmed by animal experiments that abnormal hepatic histology, increased ALT level, and compromised hepatic oxidative capability were observed in rats exposed to a high concentration of FEN. Furthermore, the bioinformatics analysis of gene microarray in rat liver tissue showed that FEN significantly changed the expressions of genes related to the regulation of intracellular calcium ion homeostasis and the calcium signal pathway. Finally, the functional experiments in Buffalo rat liver (BRL) cells demonstrated that FEN first activated ERK MAPK, followed by IKK and NF-κB, which triggered the transcription of genes responsible for accelerating an overload of intracellular calcium ions, prompted reactive oxygen species generation in the mitochondria, and finally, induced hepatic cellular apoptosis. The calcium signaling pathway and in particular, an overload of intracellular calcium play a critical role in this pathophysiological process via the ERK/IKK/NF-κB pathway. Our study furthers the understanding of the mechanism of FEN-induced hepatic injuries and may have implications in the prevention and control of liver diseases induced by environmental pesticides.-Qiu, L.-L., Wang, C., Yao, S., Li, N., Hu, Y., Yu, Y., Xia, R., Zhu, J., Ji, M., Zhang, Z., Wang S.-L. Fenvalerate induces oxidative hepatic lesions through an overload of intracellular calcium triggered by the ERK/IKK/NF-κB pathway.

New and practical synthetic route of ivacaftor is described on a grams scale. An electrophilic addition of two t-butyl groups to the aromatic ring is adopted to prepare 5-amino-2,4-di-t-butylphenol in 61% yield over three steps with 98.1% purity (high-performance liquid chromatography). An intramolecular cyclization of ethyl 3-(2-aminophenyl)-3-oxo-propanoate with dimethylformamide-dynamic mechanical analysis is used to prepare 4-oxo-1,4-dihydroquinoline-3-carboxylic acid in 54% yield over four steps. Ivacaftor is obtained by condensation of the two parts in 71% yield with 99.1% purity (high-performance liquid chromatography).

Stimuli-responsive poly(N-isopropylacrylamide) nanogel with covalently labeled rhodamine B urea derivatives (P(NIPAM-co-RhBUA)) is utilized as a sensitive fluorescent probe for Cr(3+) in aqueous solution, and its thermo-induced tunable detection capacity is investigated. At 20 °C, non-fluorescent nanogel can selectively bind with Cr(3+) over some other metal ions, leading to prominent fluorescence OFF-ON switching due to the recognition of RhBUA with Cr(3+) . Upon heating above the phase transition temperature, enhanced fluorescence intensity is observed (≈61-fold increase at 45 °C) for the nanogel in the presence of Cr(3+) , accompanied with an improved detection sensitivity, which suggest that hydrophobic microenvironment generated in the collapsed nanogel plays an active role for their detection performance.

Nandrolone, an anabolic steroid, slows denervation atrophy of rat muscle, prevents denervation-induced nuclear accumulation of intracellular domain of the Notch receptor, and elevates expression of Numb. Numb acts as an inhibitor of Notch signaling and promotes myogenic differentiation of satellite cells. Turnover of Numb is regulated by mdm2, an E3 ubiquitin ligase. With these considerations in mind, we investigated the effects of nandrolone on the expression of Numb and mdm2 proteins and determined the effect of mdm2 on nandrolone-induced alterations in Numb protein in C2C12 myoblasts. When C2C12 cells were cultured in a medium favoring differentiation (Dulbecco modified Eagle medium containing 2% horse serum), nandrolone up-regulated Numb protein levels in a time-dependent manner and prolonged Numb protein half-life from 10 to 18 hours. In contrast, nandrolone reduced the expression of mdm2 protein. To determine whether the decreased mdm2 expression induced by nandrolone was responsible for the increased levels and prolonged half-life of Numb protein in this cell line, mdm2-small interfering RNA (siRNA) was employed to inhibit mdm2 expression. Compared to cells transfected with scrambled siRNA (negative control), transfection with mdm2-siRNA increased basal Numb protein expression but abolished the further increase in Numb protein levels by nandrolone. In addition, transfection of mdm2-siRNA mimicked the effect of nandrolone to prolong the half-life of Numb protein. Moreover, when C2C12 cells were forced to overexpress mdm2, there was a significant decline in the expression of both basal and inducible Numb protein. Our data suggest that nandrolone, by a novel mechanism for this agent in a muscle cell type, increases Numb protein levels in C2C12 myoblasts by stabilizing Numb protein against degradation, at least in part, via suppression of mdm2 expression.

Prostate cancer (PCa) bone metastases are a major cause of morbidity and mortality. There are no effective therapies for PCa bone metastases that prolong survival. Prostatic acid phosphatase (PAP) is a secretory protein expressed by PCa cells. We demonstrate that PAP is strongly expressed in PCa bone metastases in 7/7 patients, while prostate-specific antigen (PSA) is only weakly expressed. The human PCa cell line VCaP secretes PAP and induces an osteoblastic reaction in bone similar to that seen in human PCa bone metastases. Coculture of MC3T3 mouse preosteoblast cells with VCaP cells induces MC3T3 cell growth and differentiation as measured by alkaline phosphatase secretion, and this effect is inhibited by addition of the PAP-inhibitor, l-tartrate. Taken together, these data indicate that PAP is expressed in PCa bone metastases and may play a causal role in the osteoblastic phase of the disease.

Epidemiologic evidence suggests that a diet rich in fruits and vegetables is associated with a reduced risk of prostate cancer (PCa) development. Although several dietary compounds have been tested in preclinical PCa prevention models, no agents have been identified that either prevent the progression of premalignant lesions or treat advanced disease. Momordica charantia, known as bitter melon in English, is a plant that grows in tropical areas worldwide and is both eaten as a vegetable and used for medicinal purposes. We have isolated a protein, designated as MCP30, from bitter melon seeds. The purified fraction was verified by SDS-PAGE and mass spectrometry to contain only 2 highly related single chain Type I ribosome-inactivating proteins (RIPs), alpha-momorcharin and beta-momorcharin. MCP30 induces apoptosis in PIN and PCa cell lines in vitro and suppresses PC-3 growth in vivo with no effect on normal prostate cells. Mechanistically, MCP30 inhibits histone deacetylase-1 (HDAC-1) activity and promotes histone-3 and -4 protein acetylation. Treatment with MCP30 induces PTEN expression in a prostatic intraepithelial neoplasia (PIN) and PCa cell lines resulting in inhibition of Akt phosphorylation. In addition, MCP30 inhibits Wnt signaling activity through reduction of nuclear accumulation of beta-catenin and decreased levels of c-Myc and Cyclin-D1. Our data indicate that MCP30 selectively induces PIN and PCa apoptosis and inhibits HDAC-1 activity. These results suggest that Type I RIPs derived from plants are HDAC inhibitors that can be utilized in the prevention and treatment of prostate cancer.

To explore the mechanism of diabetic erectile dysfunction, we studied the distribution of neurotrophins in the penises of diabetic rats, including nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4). Male Sprague-Dawley rats were injected with 65 mg/kg streptozotocin to induce diabetes mellitus (DM). The control rats were raised as age-matched control. Eight weeks later, the intercavernous pressure (ICP) of the rats was measured after electrostimulation and before sacrifice. Each peeled penis was divided into 2 parts, one for immunohistochemistry and the other for Western blot analysis. The ICP of the DM group rats was significantly decreased as compared to the vehicle control rats. There were significantly more NGF-positive neurons in the penises of the diabetic rats than in those of the control rats, while the opposite results were observed for BDNF-positive neurons. In the Western blot analysis, the proteins of NGF, NT-3, and NT-4 were all increased, while that of BDNF was decreased in diabetic rats. This is the first study revealing the expression of NT-4 protein in cavernous tissue. The abnormal level of these 4 neurotrophins in cavernous tissue may be one of the factors of the pathogenesis of diabetic ED. The increase of neurotrophins may reflect the degree of cavernous tissue denervation and may represent a compensatory mechanism. The lesion of the retrograde axonal transport of the nerves caused by hyperglycemia may be related to this phenomenon.