5-alpha-reductase

2012年12月24日星期一

Clinical application of development of nonantibiotic macrolides that correct inflammation-driven immune dysfunction in inflammatory skin diseases.

Clinical application of development of nonantibiotic macrolides that correct inflammation-driven immune dysfunction in inflammatory skin diseases.

Mediators Inflamm. 2012;2012:563709

Authors: Rodriguez-Cerdeira C, Sanchez-Blanco E, Molares-Vila A

Abstract
Background. Inflammation-driven immune dysfunction supports the development of several chronic human disorders including skin diseases. Nonantibiotic macrolides have anti-inflammatory and/or immunomodulatory activity that suggests the exploitation of these in the treatment of skin diseases characterized by inflammatory disorders. Materials and Methods. We performed an extensive review of the nonantibiotic macrolide literature published between 2005 and 2012, including cross-references of any retrieved articles. We also included some data from our own experience. Results. Calcineurin antagonists such as tacrolimus and ascomycins (e.g., pimecrolimus) act by inhibiting the activation of the nuclear factor for activated T cells (NFAT). There are new applications for these macrolides that have been available for several years and have been applied to skin and hair disorders such as atopic dermatitis, oral lichen planus, vitiligo, chronic autoimmune urticaria, rosacea, alopecia areata, pyoderma gangrenosum, Behcet's disease, neutrophilic dermatosis, and lupus erythematosus. We also reviewed new macrolides, like rapamycin, everolimus, and temsirolimus. In addition to the literature review, we report a novel class of nonantibiotic 14-member macrocycle with anti-inflammatory and immunomodulatory effects. Conclusions. This paper summarizes the most important clinical studies and case reports dealing with the potential benefits of nonantibiotic macrolides which have opened new avenues in the development of anti-inflammatory strategies in the treatment of cutaneous disorders.

PMID: 23258954 [PubMed - in process]

coxinhibitors c-met inhibitors zm-447439

Improvement of pest resistance in transgenic tobacco plants expressing dsRNA of an insect-associated gene EcR.

Improvement of pest resistance in transgenic tobacco plants expressing dsRNA of an insect-associated gene EcR.

PLoS One. 2012;7(6):e38572

Authors: Zhu JQ, Liu S, Ma Y, Zhang JQ, Qi HS, Wei ZJ, Yao Q, Zhang WQ, Li S

Abstract
The adoption of pest-resistant transgenic plants to reduce yield loss and pesticide utilization has been successful in the past three decades. Recently, transgenic plant expressing double-stranded RNA (dsRNA) targeting pest genes emerges as a promising strategy for improving pest resistance in crops. The steroid hormone, 20-hydroxyecdysone (20E), predominately controls insect molting via its nuclear receptor complex, EcR-USP. Here we report that pest resistance is improved in transgenic tobacco plants expressing dsRNA of EcR from the cotton bollworm, Helicoverpa armigera, a serious lepidopteran pest for a variety of crops. When H. armigera larvae were fed with the whole transgenic tobacco plants expressing EcR dsRNA, resistance to H. armigera was significantly improved in transgenic plants. Meanwhile, when H. armigera larvae were fed with leaves of transgenic tobacco plants expressing EcR dsRNA, its EcR mRNA level was dramatically decreased causing molting defects and larval lethality. In addition, the transgenic tobacco plants expressing H. armigera EcR dsRNA were also resistant to another lepidopteran pest, the beet armyworm, Spodoptera exigua, due to the high similarity in the nucleotide sequences of their EcR genes. This study provides additional evidence that transgenic plant expressing dsRNA targeting insect-associated genes is able to improve pest resistance.

PMID: 22685585 [PubMed - indexed for MEDLINE]

dovitinib dna-pk coxinhibitors

2012年12月23日星期日

A validated tumorgraft model reveals activity of dovitinib against renal cell carcinoma.

A validated tumorgraft model reveals activity of dovitinib against renal cell carcinoma.

Sci Transl Med. 2012 Jun 6;4(137):137ra75

Authors: Sivanand S, Pe�a-Llopis S, Zhao H, Kucejova B, Spence P, Pavia-Jimenez A, Yamasaki T, McBride DJ, Gillen J, Wolff NC, Morlock L, Lotan Y, Raj GV, Sagalowsky A, Margulis V, Cadeddu JA, Ross MT, Bentley DR, Kabbani W, Xie XJ, Kapur P, Williams NS, Brugarolas J

Abstract
Most anticancer drugs entering clinical trials fail to achieve approval from the U.S. Food and Drug Administration. Drug development is hampered by the lack of preclinical models with therapeutic predictive value. Herein, we report the development and validation of a tumorgraft model of renal cell carcinoma (RCC) and its application to the evaluation of an experimental drug. Tumor samples from 94 patients were implanted in the kidneys of mice without additives or disaggregation. Tumors from 35 of these patients formed tumorgrafts, and 16 stable lines were established. Samples from metastatic sites engrafted at higher frequency than those from primary tumors, and stable engraftment of primary tumors in mice correlated with decreased patient survival. Tumorgrafts retained the histology, gene expression, DNA copy number alterations, and more than 90% of the protein-coding gene mutations of the corresponding tumors. As determined by the induction of hypercalcemia in tumorgraft-bearing mice, tumorgrafts retained the ability to induce paraneoplastic syndromes. In studies simulating drug exposures in patients, RCC tumorgraft growth was inhibited by sunitinib and sirolimus (the active metabolite of temsirolimus in humans), but not by erlotinib, which was used as a control. Dovitinib, a drug in clinical development, showed greater activity than sunitinib and sirolimus. The routine incorporation of models recapitulating the molecular genetics and drug sensitivities of human tumors into preclinical programs has the potential to improve oncology drug development.

PMID: 22674553 [PubMed - indexed for MEDLINE]

chir-258 dovitinib dna-pk

New insights into the roles of ATM and DNA-PKcs in the cellular response to oxidative stress.

New insights into the roles of ATM and DNA-PKcs in the cellular response to oxidative stress.

Cancer Lett. 2012 Dec 31;327(1-2):103-10

Authors: Chen BP, Li M, Asaithamby A

Abstract
Reactive oxygen species (ROS) are induced by a variety of endogenous and exogenous sources. At pathologically high levels, ROS cause damage to biological molecules, including DNA. The damage sustained by DNA likely plays a key role in the pathogenesis of aging and carcinogenesis. Extensive research has established in detail the mechanism of cellular response to oxidative stress. Attention is now focused on identifying the molecular contributions of the key DNA damage response kinases ataxia telangiectasia mutated (ATM), DNA-dependent protein kinase catalytic subunit (DNA-PKcs), and ATM- and Rad3-related (ATR) in the oxidative stress response. In this review, we will provide an update of the current evidence regarding the involvement of these related DNA damage response kinases in oxidative DNA lesion repair and signaling responses. The growing understanding of the involvement of ATM, DNA-PKcs, and ATR in the oxidative stress response will offer new possibilities for the treatment of ROS-related diseases.

PMID: 22155347 [PubMed - indexed for MEDLINE]

zm-447439 rad001 ecdysone

Improvement of pest resistance in transgenic tobacco plants expressing dsRNA of an insect-associated gene EcR.

Improvement of pest resistance in transgenic tobacco plants expressing dsRNA of an insect-associated gene EcR.

PLoS One. 2012;7(6):e38572

Authors: Zhu JQ, Liu S, Ma Y, Zhang JQ, Qi HS, Wei ZJ, Yao Q, Zhang WQ, Li S

PMID: 22685585 [PubMed - indexed for MEDLINE]

chir-258 dovitinib dna-pk

Licofelone inhibits interleukin-18-induced pro-inflammatory cytokine release and cellular proliferation in human mesangial cells.

Licofelone inhibits interleukin-18-induced pro-inflammatory cytokine release and cellular proliferation in human mesangial cells.

Basic Clin Pharmacol Toxicol. 2012 Sep;111(3):166-72

Authors: Wu YJ, Xue M, Chen H

Abstract
Licofelone, a novel dual anti-inflammatory drug that inhibits 5-lipoxygenase (5-LOX) and cyclooxygenase (COX), has recently been defined to have therapeutic effects in osteoarthritis. Both 5-LOX and COX play functional roles in the pathogenesis of glomerulonephritis in children as well. Interleukin-18 is a pro-inflammatory cytokine. It remains unclear whether licofelone can ameliorate inflammatory response of human mesangial cells (HMC) exposed to interleukin-18. In this study, HMC were cultured and exposed to interleukin-18 with or without pre-treatment of licofelone. COX-2 and 5-LOX enzyme activities in mesangial cells were determined with chromometry or high-performance liquid chromatography. Prostaglandin E2, cysteinyl leukotriene, monocyte chemotactic protein-1 and interferon-? concentrations in culture medium were measured using an enzyme-linked immunosorbent assay. Western blotting was employed to detect phosphorylated mitogen-activated protein kinases ERK1/2, p38 and JNK1/2 in HMC. It was found that licofelone attenuated interleukin-18-induced COX-2 enzyme activity in HMC and prostaglandin E2 release in a dose-dependent manner. Similarly, licofelone inhibited interleukin-18-induced 5-LOX enzyme activity and leukotriene release. Licofelone reduced interleukin-18-induced phosphorylation of p38 mitogen-activated protein kinase and suppressed monocyte chemotactic protein-1 and interferon-? synthesis. Moreover, licofelone inhibited IL-18-induced proliferation of mesangial cells. We conclude that licofelone inhibits interleukin-18-induced pro-inflammatory cytokine release and cellular proliferation in HMC, which may represent a really interesting therapeutic approach for glomerulonephritis in children.

PMID: 22433003 [PubMed - indexed for MEDLINE]