第3卷，第3期

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1161

While CRISPR/Cas9-mediated genome editing technology has been experiencing a rapid transformation during the past few years, a recent report on NgAgo-mediated singlestranded DNA-guided genome editing may offer an attractive alternative for genome manipulation. While it's too early to predict whether NgAgo will be able to compete with or be superior to CRISPR/Cas9, the scientific community is anxiously waiting for further optimization and broader applications of the NgAgo genome editing technology.

1180

The intervertebral disc (IVD) comprises a gelatinous inner core (nucleus pulposus; NP) and concentric rings (annulus fibrosus; AF). The NP, an important structure for shock absorption in the vertebrate spinal motion segment, can be traced back to the notochord in ontogenetic lineage. In vertebrates, the notochord undergoes mucinoid changes, and had been considered vestigial until recently. However, observed correlations between IVD degeneration and back pain in humans have renewed interest in the IVD in biomedical fields.Beyond its mechanical contribution to development, the notochord is also an essential signaling center, which coordinates formation of the neural tube and somites. The pertinent signaling molecules, particularly TGF-β and bone morphogenetic proteins (BMPs), continue to play roles in the adult tissues and have been utilized for tissue regeneration. Genetic factors are major determinants of who will develop IVD degeneration and related back pain, and seem to correlate better with disc degeneration and back pain than do external forces on the spine.In summary, the spinal column is a landmark development in evolution. Genes directing the development of the IVD may also contribute to its maintenance, degeneration, and regeneration. Likewise, structural genes as well as genes responsible for maintenance of the structure are related to IVD degeneration. Finally, genes responsible for inflammation may play a dual role in exacerbating degeneration or facilitating repair responses depending on the context.

1153

Low back pain (LBP) is a major cause of disability and imposes huge economic burdens on human society worldwide. Among many factors responsible for LBP, intervertebral disc degeneration (IDD) is the most common disorder and is a target for intervention. The etiology of IDD is complex and its mechanism is still not completely understood. Many factors such as aging, spine deformities and diseases, spine injuries, and genetic factors are involved in the pathogenesis of IDD. In this review, we will focus on the recent advances in studies on the most promising and extensively examined genetic factors associated with IDD in humans. A number of genetic defects have been correlated with structural and functional changes within the intervertebral disc (IVD), which may compromise the disc's mechanical properties and metabolic activities. These genetic and proteomic studies have begun to shed light on the molecular basis of IDD, suggesting that genetic factors are important contributors to the onset and progression of IDD. By continuing to improve our understanding of the molecular mechanisms of IDD, specific early diagnosis and more effective treatments for this disabling disease will be possible in the future.

1255

Endothelial damage and dysfunction are implicated in cardiovascular pathological changes and the development of vascular diseases. In view of the fact that the spontaneous endothelial cell (EC) regeneration is a slow and insufficient process, it is of great significance to explore alternative cell sources capable of generating functional ECs to repair damaged endothelium. Indeed, recent achievements of cell reprogramming to convert somatic cells to other cell types provide new powerful approaches to study endothelial regeneration. Based on progress in the research field, the present review aims to summarize the strategies and mechanisms of generating endothelial cells through reprogramming from somatic cells, and to examine what this means for the potential application of cell therapy in the clinic.

1190

Temozolomide (TMZ) is an oral alkylating agent used to treat glioblastoma multiforme (GBM) and astrocytomas. However, at least 50% of TMZ treated patients do not respond to TMZ. This is due primarily to the over-expression of O⁶-methylguanine methyltransferase (MGMT) and/or lack of a DNA repair pathway in GBM cells. Multiple GBM cell lines are known to contain TMZ resistant cells and several acquired TMZ resistant GBM cell lines have been developed for use in experiments designed to define the mechanism of TMZ resistance and the testing of potential therapeutics. However, the characteristics of intrinsic and adaptive TMZ resistant GBM cells have not been systemically compared. This article reviews the characteristics and mechanisms of TMZ resistance in natural and adapted TMZ resistant GBM cell lines. It also summarizes potential treatment options for TMZ resistant GBMs.

1152

The prevalence of diabetes and its complications is increasing at an alarming rate in both developed and deve1oping nations. The emerging evidences highlighted that both genetic and epigenetic mechanisms including histone modifications play a significant role in the pathogenesis of diabetic nephropathy (DN). Histone deacetylases (HDACs) and acetylation are involved in the regulation of autophagy as well as pathogenesis of DN. Both HDACs and histone acetyltransferases (HATs) play a key role in chromatin remodeling and affect the transcription of various genes involved in the cellular homeostasis, apoptosis, immunity and angiogenesis. Further, HDAC inhibitors are exert the renoprotective effects in DN and other diabetic complications. Thus, the cellular acetylation plays a crucial role in the regulation of autophagy and can be explored as a new therapeutic target for the treatment of DN. This review aimed to delineate the role of HDACs and associated molecular signaling/pathways in the regulation of autophagy with an emphasis on promising targets for the treatment of DN.

1205

Alzheimer's disease (AD) remains the most common neurodegenerative disease characterized by β-amyloid protein (Aβ) deposition and memory loss. Studies have shown that mitochondrial dysfunction plays a crucial role in AD, which involves oxidative stress-induced respiratory chain dysfunction, loss of mitochondrial biogenesis, defects of mitochondrial dynamics and mtDNA mutations. Thus mitochondria might serve as drug therapy target for AD. In this article, we first briefly discussed mitochondrial theory in the development of AD, and then we summarized recent advances of mitochondrial abnormalities in AD pathology and introduced a series of drugs and techniques targeting mitochondria. We think that maintaining mitochondrial function may provide a new way of thinking in the treatment of AD.

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Protein kinases play an important role in the incidence of neurodegenerative diseases. However their incidence in non-human primates is found to be very low. Small differences among the genomes might influence the disease susceptibilities. The present study deals with finding the genetic differences of protein kinases in humans and their three closest evolutionary partners chimpanzee, gorilla and orangutan for three neurodegenerative diseases namely, Alzheimer's, Parkinson's and Huntington's diseases. In total 47 human protein kinases associated with three neurodegenerative diseases and their orthologs from other three nonhuman primates were identified and analyzed for any possible susceptibility factors in humans. Multiple sequence alignment and pairwise sequence alignment revealed that, 18 human protein kinases including DYRK1A, RPS6KB1, and GRK6 contained significant indels and substitutions. Further phosphorylation site analysis revealed that eight kinases including MARK2 and LTK contained sites of phosphorylation exclusive to human genomes which could be particular candidates in determining disease susceptibility between human and non-human primates. Final pathway analysis of these eight kinases and their targets revealed that these kinases could have long range consequences in important signaling pathways which are associated with neurodegenerative diseases.

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