Long-circulating siRNA nanoparticles for validating Prohibitin1-targeted non-small cell lung cancer treatment

Zhu, Xi,Xu, Yingjie,Solis, Luisa M.,Tao, Wei,Wang, Liangzhe,Behrens, Carmen,Xu, Xiaoyang,Zhao, Lili,Liu, Danny,Wu, Jun,Zhang, Ning,Wistuba, Ignacio I.,Farokhzad, Omid C.,Zetter, Bruce R.,Shi, Jinjun National Academy of Sciences 2015 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF Vol.112 No.25

<P><B>Significance</B></P><P>This study developed a new generation lipid–polymer hybrid nanoparticle platform for effective systemic delivery of small interfering RNA (siRNA) to tumors, which represents a challenging hurdle for the widespread application of RNA interference (RNAi) in cancer research and therapy. With promising in vivo features such as long blood circulation, high tumor accumulation, and effective gene silencing, the hybrid siRNA nanoparticles were successfully used to reveal and validate a putative therapeutic target, Prohibitin1 (PHB1), in non-small cell lung cancer treatment. In vivo antitumor efficacy results and human tissue microarray analysis further suggested the feasibility of utilizing PHB1 siRNA nanoparticles as a novel therapeutic agent. This hybrid RNAi nanoparticle platform may serve as a valuable tool for validating potential cancer targets and developing new cancer therapies.</P><P>RNA interference (RNAi) represents a promising strategy for identification and validation of putative therapeutic targets and for treatment of a myriad of important human diseases including cancer. However, the effective systemic in vivo delivery of small interfering RNA (siRNA) to tumors remains a formidable challenge. Using a robust self-assembly strategy, we develop a unique nanoparticle (NP) platform composed of a solid polymer/cationic lipid hybrid core and a lipid-poly(ethylene glycol) (lipid-PEG) shell for systemic siRNA delivery. The new generation lipid–polymer hybrid NPs are small and uniform, and can efficiently encapsulate siRNA and control its sustained release. They exhibit long blood circulation (<I>t</I><SUB>1/2</SUB> ∼8 h), high tumor accumulation, effective gene silencing, and negligible in vivo side effects. With this RNAi NP, we delineate and validate the therapeutic role of Prohibitin1 (PHB1), a target protein that has not been systemically evaluated in vivo due to the lack of specific and effective inhibitors, in treating non-small cell lung cancer (NSCLC) as evidenced by the drastic inhibition of tumor growth upon PHB1 silencing. Human tissue microarray analysis also reveals that high PHB1 tumor expression is associated with poorer overall survival in patients with NSCLC, further suggesting PHB1 as a therapeutic target. We expect this long-circulating RNAi NP platform to be of high interest for validating potential cancer targets in vivo and for the development of new cancer therapies.</P>

Charge Transport and Separation Dynamics at the C₆₀/GaAs(001) Interface

Kim, Jeong Won,Park, Heungman,Zhu, Xiaoyang American Chemical Society 2014 The Journal of Physical Chemistry Part C Vol.118 No.6

<P>We probe charge separation dynamics at a model hybrid organic/inorganic semiconductor heterojunction, C<SUB>60</SUB>/GaAs(001), using time-resolved two-photon photoemission spectroscopy (TR-2PPE). For a p-type GaAs(001) surface with downward band bending, TR-2PPE allows us to directly follow the subpicosecond drift of photoexcited electrons toward the surface by the space charge field. Upon C<SUB>60</SUB> adsorption, we find that electron transfer from the GaAs conduction band to C<SUB>60</SUB> occurs on the faster time scale of ≤0.1 ps. We discuss the role of the space charge field in assisting electron transfer at the hybrid organic/inorganic semiconductor interface.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/jpccck/2014/jpccck.2014.118.issue-6/jp412180t/production/images/medium/jp-2013-12180t_0006.gif'></P>

Identifying natural genotypes of grain number per panicle in rice (Oryza sativa L.) by association mapping

Jianyin Xie,Fengmei Li,Najeeb Ullah Khan,Xiaoyang Zhu,Xueqiang Wang,Zhifang Zhang,Xiaoqian Ma,Yan Zhao,Quan Zhang,Shuyang Zhang,Zhanying Zhang,Jinjie Li,Zichao Li,Hongliang Zhang 한국유전학회 2019 Genes & Genomics Vol.41 No.3

Introduction As one of the main yield components, grain number per panicle (GNP) played critical role in the rice yield improvement. The identification of natural advantageous variations under different situations will promote the sustainable genetic improvement in rice yield. Objectives This study was designed to identify natural genotypes in a rice mini-core collection, to examine the genotypic effects across the indica and japonica genetic background in different environments, and excavating the superior genotypes that had drove the modern genetic improvement. Methods The association mapping of GNP was carried out using a mini-core collection including 154 indica and 119 japonica accessions in seven different environments. Genotypic effects of each genotype for each QTL were calculated and genotype frequency distortion between the commercial rice cultivars and landraces was screened by χ2-test. Results In total, 74 QTLs containing stable and sensitive QTLs in various environments were detected. Within them, 20 positive and 24 negative genotypes in indica, and 24 positive and 16 negative genotypes in japonica were identified. When checking the accumulation of positive genotypes identified in indica across cultivars in each of the two subspecies, it indicated that increased number of positive genotypes identified in indica results in the substantially increased GNP in both indica and japonica across all of the environments, while this trend was not obvious for the positive genotypes identified in japonica especially in short day environments. Moreover, the positive and negative genotype frequency distortion between the landraces and commercial rice cultivars indicated that both positive selection of positive genotypes and negative selection of negative genotypes had driven the genetic improvement on GNP. Conclusion Our findings suggested that the accumulation of positive genotypes and purifying negative genotypes played equivalently important roles in the improvement of rice yield, but the efficient use for some QTLs or genotypes depends on the comprehensive evaluation of their effect under diverse genetic backgrounds and environments.

Transplantation of Wnt5a-modified NSCs promotes tissue repair and locomotor functional recovery after spinal cord injury

Li Xiang,Peng Zhiming,Long Lingli,Lu Xiaofang,Zhu Kai,Tuo Ying,Chen Ningning,Zhao Xiaoyang,Wang Le,Wan Yong 생화학분자생물학회 2020 Experimental and molecular medicine Vol.52 No.-

Traditional therapeutic strategies for spinal cord injury (SCI) are insufficient to repair locomotor function because of the failure of axonal reconnection and neuronal regeneration in the injured central nervous system (CNS). Neural stem cell (NSC) transplantation has been considered a potential strategy and is generally feasible for repairing the neural circuit after SCI; however, the most formidable problem is that the neuronal differentiation rate of NSCs is quite limited. Therefore, it is essential to induce the neuronal differentiation of NSCs and improve the differentiation rate of NSCs in spinal cord repair. Our results demonstrate that both Wnt5a and miRNA200b-3p could promote NSC differentiation into neurons and that Wnt5a upregulated miRNA200b-3p expression through MAPK/JNK signaling to promote NSC differentiation into neurons. Wnt5a could reduce RhoA expression by upregulating miRNA200b-3p expression to inhibit activation of the RhoA/Rock signaling pathway, which has been reported to suppress neuronal differentiation. Overexpression of RhoA abolished the neurogenic capacity of Wnt5a and miRNA200b-3p. In vivo, miRNA200b-3p was critical for Wnt5a-induced NSC differentiation into neurons to promote motor functional and histological recovery after SCI by suppressing RhoA/Rock signaling. These findings provide more insight into SCI and help with the identification of novel treatment strategies.

A Novel Human BTB-kelch Protein KLHL31, Strongly Expressed in Muscle and Heart, Inhibits Transcriptional Activities of TRE and SRE

Weishi Yu,Yuequn Wang,Yongqing Li,Yun Deng,Zequn Wang,Wuzhou Yuan,Dali Li,Chuanbing Zhu,Xueying Zhao,Xiaoyang Mo,Wen Huang,Na Luo,Yan Yan,Karen Ocorr,Rolf Bodmer,Xiushan Wu 한국분자세포생물학회 2008 Molecules and cells Vol.26 No.5

The Bric-a-brac, Tramtrack, Broad-complex (BTB) domain is a protein-protein interaction domain that is found in many zinc finger transcription factors. BTB containing proteins play important roles in a variety of cellular functions including regulation of transcription, regulation of the cytoskeleton, protein ubiquitination, angiogenesis, and apoptosis. Here, we report the cloning and characterization of a novel human gene, KLHL31, from a human embryonic heart cDNA library. The cDNA of KLHL31 is 5743 bp long, encoding a protein product of 634 amino acids containing a BTB domain. The protein is highly conserved across different species. Western blot analysis indicates that the KLHL31 protein is abundantly expressed in both embryonic skeletal and heart tissue. In COS-7 cells, KLHL31 proteins are localized to both the nucleus and the cytoplasm. In primary cultures of nascent mouse cardiomyocytes, the majority of endogenous KLHL31 proteins are localized to the cytoplasm. KLHL31 acts as a transcription repressor when fused to GAL4 DNA-binding domain and deletion analysis indicates that the BTB domain is the main region responsible for this repression. Overexpression of KLHL31 in COS-7 cells inhibits the transcriptional activities of both the TPA-response element (TRE) and serum response element (SRE). KLHL31 also significantly reduces JNK activation leading to decreased phosphorylation and protein levels of the JNK target c-Jun in both COS-7 and Hela cells. These results suggest that KLHL31 protein may act as a new transcriptional repressor in MAPK/JNK signaling pathway to regulate cellular functions.

An Analytical Model of Chip Heat-Carrying Capacity for High-Speed Dry Hobbing Based on 3D Chip Geometry

Xiao Yang,Huajun Cao,Yong-peng Chen,Li-Bin Zhu,Ben-jie Li 한국정밀공학회 2017 International Journal of Precision Engineering and Vol.18 No.2

High-speed dry hobbing is the dominating green technique for gear hobbing owing to its high productivity and environmental friendliness. However, a large amount of cutting heat is generated during the machining process due to the absence of metalworking fluids and the adoption of high cutting speed. A better understanding of chip heat-carrying capacity for high-speed dry hobbing is quite necessary when aiming to reduce the influence of cutting heat on machining precision. In this paper, an analytical model is established to quantitatively determine the chip heat-carrying capacity of high-speed dry hobbing. According to the progressive heat transfer characteristic of high-speed dry hobbing, cutting heat generation and transmission are analyzed. 3D chip geometry is numerically calculated by modeling the complex hob geometry and the interrelated kinematic relations of high-speed dry hobbing. Based on the 3D chip geometry and the specific cutting energy, chip heat-carrying capacity model is developed considering three heat sources. In this model, chip heat partition is experimentally determined by calorimetric method. With the help of the developed model, chip heat-carrying quantity and chip heat-carrying efficiency are discussed by investigating their influence factors (hob rotation speed, axial feed, feed method, chip removal time and hob geometry).