Promotion of remyelination is an important therapeutic strategy to facilitate functional recovery after traumatic spinal cord injury (SCI).Transplantation of neural stem cells (NSCs) or oligodendrocyte precursor cells (OPCs) has been used to enhance remyelination after SCI. However, the microenvironment in the injured spinal cord is inhibitory for oligodendrocyte (OL) differentiation of NSCs or OPCs. Identifying the signaling pathways that inhibit OL differentiation in the injured spinal cord could lead to new therapeutic strategies to enhance remyelination and functional recovery after SCI. In the present study, we show that reactive astrocytes from the injured rat spinal cord or their conditioned media inhibit OL differentiation of adult OPCs with concurrent promotion of astrocyte differentiation. The expression of bone morphogenetic proteins (BMP) is dramatically increased in the reactive astrocytes and their conditioned media. Importantly, blocking BMP activity by BMP receptor antagonist, noggin, reverse the effects of active astrocytes on OPC differentiation by increasing the differentiation of OL from OPCs while decreasing the generation of astrocytes. These data indicate that the upregulated bone morphogenetic proteins in the reactive astrocytes are major factors to inhibit OL differentiation of OPCs and to promote its astrocyte differentiation. These data suggest that manipulation of BMP signaling in the endogenous or grafted NSCs or OPCs may be a useful therapeutic strategy to increase their OL differentiation and remyelination and enhance functional recovery after SCI.
Promotion of remyelination is an important therapeutic strategy for the treatment of the demyelinating neurological disorders. Adult oligodendrocyte precursor cells (OPCs), which normally reside quiescently in the adult central nervous system (CNS), become activated and proliferative after demyelinating lesions. However, the extent of endogenous remyelination is limited because of the failure of adult OPCs to mature into myelinating oligodendrocytes (OLs) in the demyelinated CNS. Understanding the molecular mechanisms that regulate the differentiation of adult OPCs could lead to new therapeutic strategies to treat these disorders. In this study, we established a stable culture of adult spinal cord OPCs and developed a reliable in vitro protocol to induce their sequential differentiation. Adult OPCs expressed bone morphogenetic protein (BMP) type Ia, Ib, and II receptor subunits, which are required for BMP signal transduction. BMP2 and 4 promoted dose-dependent astrocyte differentiation of adult OPCs with concurrent suppression of OL differentiation. Treatment of OPCs with BMP2 and 4 increased ID4 expression and decreased the expression of olig1 and olig2. Overexpression of olig1 or olig2 blocked the astrocyte differentiation of adult OPCs induced by BMP2 and 4. Furthermore, overexpression of both olig1 and olig2, but not olig1 or olig2 alone, rescued OL differentiation from inhibition by BMP2 and 4. Our results demonstrated that downregulation of olig1 and olig2 is an important mechanism by which BMP2 and 4 inhibit OL differentiation of adult OPCs. These data suggest that blocking BMP signaling combined with olig1/2 overexpression could be a useful therapeutic strategy to enhance endogenous remyelination and facilitate functional recovery in CNS demyelinated disorders.
UCA1 (urothelial carcinoma associated 1) is a long non-coding RNA (lncRNA) that was found overexpressed in various human cancers including prostate cancer (PCa). However, the aspect of UCA1-miRNA-mRNA interaction in PCa remains unclear. In this study, we confirmed the role of UCA1 in PCa and found that UCA1 downregulation inhibited cell proliferation of PCa cells. Then we demonstrated that repressed UCA1 promoted the microRNA-143 (miR-143) expression and miR-143 could bind to the predicted binding site of UCA1. We then proved the anti-tumor role of miR-143 in PCa. Furthermore, we found that miR-143 displays its role in PCa via modulating the MYO6 expression. In summary, our study demonstrated that UCA1 exerts oncogenes activity in PCa, acting mechanistically by upregulating MYO6 expression through "sponging" miR-143.
Artemisinin-based therapies are the only effective treatment for malaria, which reached to 219 million cases and killed 435,000 people in 2017. To meet the growing demand for artemisinin and make it accessible to the poorest, genetic engineering of Artemisia annua becomes one of the most promising approaches to improve artemisinin yield. In this work, AabZIP9 transcription factor has been identified and characterized. The expression profile of AabZIP9 revealed that it was clustered with the artemisinin specific biosynthetic pathway genes ADS, CYP71AV1, DBR2, and ALDH1. Furthermore, the transiently dual-LUC analysis showed that the activation of ADS promoter was enhanced by AabZIP9. Meanwhile, yeast one-hybrid assay showed that AabZIP9 was able to bind to the “ACGT” cis-element present in both ADS and CYP71AV1 promoters. AabZIP9 gene was driven by the constitutive CaMV35S promoter and the glandular trichome specific CYP71AV1 promoter and stably transformed into A. annua plants. The transcript level of AabZIP9 was increased in both of the 35S and CYP71AV1 driven transgenic plants compared with the wild type or GUS control plants. All the transgenic A. annua plants overexpressing AabZIP9 showed elevated transcript level of ADS, but the transcription levels of CYP71AV1, DBR2, and ALDH1 have no significant change in both types of transgenic plants. The significantly upregulated ADS promoted the accumulation of artemisinin, dihydroartemisinic acid, and artemisinic acid biosynthesis in the transgenic A. annua plants. These results suggest that AabZIP9 can positively regulate the biosynthesis of artemisinin.
Artemisinin, a sesquiterpenoid endoperoxide, isolated from the plant Artemisia annua L., is widely used in the treatment of malaria. Another sesquiterpenoid, β-caryophyllene having antibiotic, antioxidant, anticarcinogenic and local anesthetic activities, is also presented in A. annua. The role played by sesquiterpene transporters in trichomes and accumulation of these metabolites is poorly understood in A. annua and in trichomes of other plant species. We identified AaPDR3, encoding a pleiotropic drug resistance (PDR) transporter located to the plasma membrane from A. annua. Expression of AaPDR3 is tissue-specifically and developmentally regulated in A. annua. GUS activity is primarily restricted to T-shaped trichomes of old leaves and roots of transgenic A. annua plants expressing proAaPDR3: GUS. The level of β-caryophyllene was decreased in transgenic A. annua plants expressing AaPDR3-RNAi while transgenic A. annua plants expressing increased levels of AaPDR3 accumulated higher levels of β-caryophyllene. When AaPDR3 was expressed in transformed yeast, yeasts expressing AaPDR3 accumulated more β-caryophyllene, rather than germacrene D and β-farnesene, compared to the non-expressing control.
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