Differential Effector Engagement by Oncogenic KRAS

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A novel porcupine inhibitor blocks WNT pathways and attenuates cardiac hypertrophy

WNT pathways are critically involved in the cardiac hypertrophy growth. Porcupine, an acyltransferase that specifically enables secretion of all WNT ligands, became a highly druggable target for inhibiting WNT pathways. Here we test if a novel small-molecule porcupine inhibitor CGX1321, which has entered human clinical trials as an anti-cancer agent, exerts an anti-hypertrophic effect. Transverse aortic constriction (TAC) was performed to induce cardiac hypertrophy on four-month-old male C57 mice. Cardiac function was measured with echocardiography. Histological analysis was performed to detect cardiomyocyte size and molecular expressions. CGX1321 was administrated daily for 4?weeks post TAC injury. As a result, CGX1321 improved cardiac function and animal survival of post-TAC mice. CGX1321 significantly reduced cardiomyocyte hypertrophy, cardiomyocyte apoptosis and fibrosis induced by TAC injury. CGX1321 significantly inhibited TAC induced nuclear translocation of β-catenin and the elevation of Frizzled-2, cyclin-D1 and c-myc expression, indicating its inhibitory effect on canonical WNT pathway. Furthermore, CGX1321 inhibited TAC induced nuclear translocation of nuclear factor of activated T-cells and the elevation of phosphorylated c-Jun expression, suggesting its inhibitory function on non-canonical WNT pathway. We conclude that CGX1321 inhibits both canonical and non-canonical WNT pathways, and attenuates cardiac hypertrophy. Our findings support the porcupine inhibitors as a class of new drugs to be potentially used for treating patients with cardiac hypertrophy.     

RNAi targeting STMN alleviates the resistance to taxol and collectively contributes to down regulate the malignancy of NSCLC cells in vitro and in vivo

Stathmin (STMN) plays a vital role in maintaining the malignant behavior of cancer through directly regulating microtubule dynamics equilibrium. Taxol, an effective chemotherapeutics mainly acting to promote microtubule polymerization, has been commercially applied in treating solid tumors, which results in serious drug resistance. Our study demonstrated that STMN RNA interference (RNAi) enlarged taxol-induced inhibitions in cellular proliferation, colony formation, and multidimensional spaces of cell immigration and decreased half maximal inhibitory concentration (IC₅₀) of taxol in nonsmall cell lung cancer (NSCLC) NCI-H1299 cells; STMN RNAi and taxol jointly attenuated the expressions of extracellular regulated kinase (ERK), nuclear factor kappa B (NF-κB) and B cell lymphoma-2 (Bcl-2), but up regulated Bax expression and initiated intrinsic cell death pathway by activating caspase-3 and caspase-9, while inhibited interleukin 10 (IL-10) autocrine from cell culture supernatant and xenografted mouse serum, as well as intracellular expressions of IL-10 protein and mRNA in vitro; additionally, neutralizing IL-10 alone would incur cell apoptosis to some degree; the further study confirmed that RNAi targeting STMN promoted the sensitivity of taxol in different NSCLC cells. In vivo animal experiments proved that STMN RNAi and taxol cooperatively inhibited the tumorigenicity of NCI-H1299 cells and histological atypia and Ki-67 proliferative index of xenografted tumors and promoted cell differentiation to a higher grade with well-differentiated indicators of glandular lumen-like structure and proliferative fibroblasts. These findings suggest that silencing STMN alleviates the resistance to taxol and collectively contributes to induce the dysfunction of multiple signals and down regulate the malignancy of tumors; thus, STMN is a promising target in treating refractory tumors.     

Silencing of <Emphasis Type="Italic">GbANS</Emphasis> reduces cotton resistance to <Emphasis Type="Italic">Verticillium dahliae</Emphasis> through decreased ROS scavenging during the pathogen invasion process

Anthocyanins are secondary metabolites that play important roles in plant adaption to adverse environments. The anthocyanin biosynthetic pathway is conserved in high plants. Previous studies revealed the significant role of anthocyanins in natural-colorized cotton. However, little is known about the involvement of anthocyanins in the interaction of cotton and pathogen. In this study, a pathogen-induced gene was isolated from Gossypium barbadense that encodes an anthocyanidin synthase protein (GbANS) with dioxygenase structures. GbANS was preferentially expressed in colored tissue. Silencing of GbANS significantly reduced the production of anthocyanins, as well as the cotton’s resistance to Verticillium dahliae. Biochemical studies revealed that GbANS-silenced cotton accumulated more hydrogen peroxide compared to control plants during the V. dahliae invasion process. This accumulation of hydrogen peroxide corresponded with increased cell death around the invasion sites, which in turn accelerated the V. dahliae infection. Taken together, we found that GbANS contributes to the biosynthesis of anthocyanins in cotton and anthocyanins positively regulate cotton’s resistance to V. dahliae.     

CD10+GPR77+ Cancer-Associated Fibroblasts Promote Cancer Formation and Chemoresistance by Sustaining Cancer Stemness

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TBK1 at the Crossroads of Inflammation and Energy Homeostasis in Adipose Tissue

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Angelica muliensis sp. nov. (Apiaceae) from Sichuan,southwest China

Angelica muliensis (Apiaceae), a new species from Sichuan Province, southwest China, is described and illustrated. The new species resembles A. biserrata, but differs in the shapes of the leaflets and sheaths, umbel number and size and especially mericarp features. The diagnostic characters of these two species are presented and compared.     

中国人肥胖基因克隆及其原核表达载体的构建

为了探讨人肥胖（obesity,OB）基因的生理和病理意义,利用逆转录-聚合酶链式．反应（RT-PCR）方法,从中国汉族成人腹膜后脂肪组织总RNA中扩增出肥胖基因编码区序列（cDNA）．定向亚克隆pUC19质粒,克隆的OBcDNA不含信号肽序列并加入了新的起始密码子ATG,序列分析表明,与日本报道的人OBcDNA相比,多出一个谷氨酸密码子CAG．将OBcDNA定向克隆至原核表达载体pBV220,构建了重组OB基因表达质粒pBV220-OB．SDS-PAGE证实pBV220-OB在大肠杆菌中可表达分子量为16.7KD的特异蛋白带．