Recent advances in isolation, identification, and culture of mammalian spermatogonial stem cells.

Continuous spermatogenesis depends on the self-renewal and differentiation of spermatogonial stem cells (SSCs). SSCs, the only male reproductive stem cells that transmit genetic material to subsequent generations, possess an inherent self-renewal ability, which allows the maintenance of a steady stem cell pool. SSCs eventually differentiate to produce sperm. However, in an in vitro culture system, SSCs can be induced to differentiate into various types of germ cells. Rodent SSCs are well defined, and a culture system has been successfully established for them. In contrast, available information on the biomolecular markers and a culture system for livestock SSCs is limited. This review summarizes the existing knowledge and research progress regarding mammalian SSCs to determine the mammalian spermatogenic process, the biology and niche of SSCs, the isolation and culture systems of SSCs, and the biomolecular markers and identification of SSCs. This information can be used for the effective utilization of SSCs in reproductive technologies for large livestock animals, enhancement of human male fertility, reproductive medicine, and protection of endangered species.

Silencing of NAC1 Expression Induces Cancer Cells Oxidative Stress in Hypoxia and Potentiates the Therapeutic Activity of Elesclomol.

In order to survive under conditions of low oxygen, cancer cells can undergo a metabolic switch to glycolysis and suppress mitochondrial respiration in order to reduce oxygen consumption and prevent excessive amounts of reactive oxygen species (ROS) production. Nucleus accumbens-1 (NAC1), a nuclear protein of the BTB/POZ gene family, has pivotal roles in cancer development. Here, we identified that NAC1-PDK3 axis as necessary for suppression of mitochondrial function, oxygen consumption, and more harmful ROS generation and protects cancer cells from apoptosis in hypoxia. We show that NAC1 mediates suppression of mitochondrial function in hypoxia through inducing expression of pyruvate dehydrogenase kinase 3 (PDK3) by HIF-1α at the transcriptional level, thereby inactivating pyruvate dehydrogenase and attenuating mitochondrial respiration. Re-expression of PDK3 in NAC1 absent cells rescued cells from hypoxia-induced metabolic stress and restored the activity of glycolysis in a xenograft mouse model, and demonstrated that silencing of NAC1 expression can enhance the antitumor efficacy of elesclomol, a pro-oxidative agent. Our findings reveal a novel mechanism by which NAC1 facilitates oxidative stress resistance during cancer progression, and chemo-resistance in cancer therapy.

[Network pharmacology-based study on mechanism of Yuanhu Zhitong Dropping Pills in the treatment of primary dysmenorrhea].

This study was designed to explore the mechanism of Yuanhu Zhitong Dropping Pills(YHZT) in the treatment of primary dysmenorrhea by pharmacological network technology and establish a research approach of "Compound-Target-Pathway-Disease" network. Twenty-eight compounds absorbed into blood including 22 prototype and 6 metabolites of YHZT were submitted to Pharm Mapper and Kyoto Encyclopedia of Genes and Genomes(KEGG) bioinformatics softwares to predict the target proteins and related pathways respectively. The network of "Compound-Target-Pathway-Disease" was constructed and analyzed using Cytoscape software. The in silico prediction results showed that the 28 constituents of YHZT affected 111 pathways through 109 target proteins. Among them, a total of 52 proteins and 31 pathways were related to the primary dysmenorrhea. The effect of YHZT on primary dysmenorrhea may be dependent on regulation of the proteins and pathways related with hormonal regulation, central analgesia, spasmolysis, inflammation and immunoregulation.

An update on RNA interference-mediated gene silencing in cancer therapy.

INTRODUCTION: Based on our previous review, this article presents the new progress in RNA interference (RNAi)-mediated gene silencing in cancer therapy, and reviews the hurdles and how they might be overcome. AREAS COVERED: RNAi-mediated gene silencing approaches have been demonstrated in humans, and ongoing clinical trials hold promise for treating cancer or providing alternatives to traditional chemotherapies. Here we describe the broad range of approaches to achieve targeted gene silencing for cancer therapy, discuss the progress made in developing RNAi as therapeutics for cancer and highlight challenges and emerging solutions associated with its clinical development. EXPERT OPINION: Although the field of RNAi-based cancer therapy is still an emerging one, we have yet to get solutions for overcoming all obstacles associated with its clinical development. The current rapid advances in development of new targeted delivery strategies and noninvasive imaging methods will be big steps to explore RNAi as a new and potent clinical modality in humans.

Inhibition of elongation factor-2 kinase augments the antitumor activity of Temozolomide against glioma.

BACKGROUND: Glioblastoma multiforme (GBM), the most common form of brain cancer with an average survival of less than 12 months, is a highly aggressive and fatal disease characterized by survival of glioma cells following initial treatment, invasion through the brain parenchyma and destruction of normal brain tissues, and ultimately resistance to current treatments. Temozolomide (TMZ) is commonly used chemotherapy for treatment of primary and recurrent high-grade gliomas. Nevertheless, the therapeutic outcome of TMZ is often unsatisfactory. In this study, we sought to determine whether eEF-2 kinase affected the sensitivity of glioma cells to treatment with TMZ. METHODOLOGY/PRINCIPAL FINDINGS: Using RNA interference approach, a small molecule inhibitor of eEF-2 kinase, and in vitro and in vivo glioma models, we observed that inhibition of eEF-2 kinase could enhance sensitivity of glioma cells to TMZ, and that this sensitizing effect was associated with blockade of autophagy and augmentation of apoptosis caused by TMZ. CONCLUSIONS/SIGNIFICANCE: These findings demonstrated that targeting eEF-2 kinase can enhance the anti-glioma activity of TMZ, and inhibitors of this kinase may be exploited as chemo-sensitizers for TMZ in treatment of malignant glioma.