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author:("Zhu, wensu")
1.  A positive autoregulatory loop of Jak-STAT signaling controls the onset of astrogliogenesis 
Nature neuroscience  2005;8(5):616-625.
During development of the CNS, neurons and glia are generated in a sequential manner. The mechanism underlying the later onset of gliogenesis is poorly understood, although the cytokine-induced Jak-STAT pathway has been postulated to regulate astrogliogenesis. Here, we report that the overall activity of Jak-STAT signaling is dynamically regulated in mouse cortical germinal zone during development. As such, activated STAT1/3 and STAT-mediated transcription are negligible at early, neurogenic stages, when neurogenic factors are highly expressed. At later, gliogenic periods, decreased expression of neurogenic factors causes robust elevation of STAT activity. Our data demonstrate a positive autoregulatory loop whereby STAT1/3 directly induces the expression of various components of the Jak-STAT pathway to strengthen STAT signaling and trigger astrogliogenesis. Forced activation of Jak-STAT signaling leads to precocious astrogliogenesis, and inhibition of this pathway blocks astrocyte differentiation. These observations suggest that autoregulation of the Jak-STAT pathway controls the onset of astrogliogenesis.
doi:10.1038/nn1440
PMCID: PMC4222251  PMID: 15852015
2.  Sulforaphane synergizes with quercetin to inhibit self-renewal capacity of pancreatic cancer stem cells 
According to the cancer stem cell hypothesis, the aggressive growth and early metastasis of cancer may arise through dysregulation of self-renewal of stem cells. The objectives of this study were to examine the molecular mechanisms by which sulforaphane (SFN, an active compound in cruciferous vegetables) inhibits self-renewal capacity of pancreatic cancer stem cells (CSCs), and synergizes with quercetin, a major polyphenol and flavonoid commonly detected in many fruits and vegetables. Our data demonstrated that SFN inhibited self-renewal capacity of pancreatic CSCs. Inhibition of Nanog by lentiviral-mediated shRNA expression enhanced the inhibitory effects of sulforaphane on self-renewal capacity of CSCs. SFN induced apoptosis by inhibiting the expression of Bcl-2 and XIAP, phosphorylation of FKFR, and activating caspase-3. Moreover, SFN inhibited expression of proteins involved in the epithelial-mesenchymal transition (β-catenin, vimentin, twist-1, and ZEB1), suggesting the blockade of signaling involved in early metastasis. Furthermore, the combination of quercetin with SFN had synergistic effects on self-renewal capacity of pancreatic CSCs. These data suggest that SFN either alone or in combination with quercetin can eliminate cancer stem cell-characteristics.
PMCID: PMC4080794  PMID: 21196331
Stem cells; pancreatic cancer; sulforaphane; quercetin; Nanog
3.  Impaired Osteoblast Function in GPRC6A Null Mice 
Journal of Bone and Mineral Research  2009;25(5):1092-1102.
GPRC6A is a widely expressed orphan G protein–coupled receptor that senses extracellular amino acids, osteocalcin, and divalent cations in vitro. GPRC6A null (GPRC6A−/−) mice exhibit multiple metabolic abnormalities including osteopenia. To investigate whether the osseous abnormalities are a direct function of GPRC6A in osteoblasts, we examined the function of primary osteoblasts and bone marrow stromal cell cultures (BMSCs) in GPRC6A−/− mice. We confirmed that GPRC6A−/− mice exhibited a decrease in bone mineral density (BMD) associated with reduced expression of osteocalcin, ALP, osteoprotegerin, and Runx2-II transcripts in bone. Osteoblasts and BMSCs derived from GPRC6A−/− mice exhibited an attenuated response to extracellular calcium-stimulated extracellular signal-related kinase (ERK) activation, diminished alkaline phosphatase (ALP) expression, and impaired mineralization ex vivo. In addition, siRNA-mediated knockdown of GPRC6A in MC3T3 osteoblasts also resulted in a reduction in extracellular calcium-stimulated ERK activity. To explore the potential relevance of GPRC6A function in humans, we looked for an association between GPRC6A gene polymorphisms and BMD in a sample of 1000 unrelated American Caucasians. We found that GPRC6A gene polymorphisms were significantly associated with human spine BMD. These data indicate that GRPC6A directly participates in the regulation of osteoblast-mediated bone mineralization and may mediate the anabolic effects of extracellular amino acids, osteocalcin, and divalent cations in bone. © 2010 American Society for Bone and Mineral Research.
doi:10.1359/jbmr.091037
PMCID: PMC3153369  PMID: 19874200
GPRC6A; G protein–coupled receptor (GPCR); osteoblast; bone mineral density; gene polymorphisms
4.  Spongipyran Synthetic Studies. Evolution of a Scalable Total Synthesis of (+)-Spongistatin 1 
Tetrahedron  2009;65(33):6489-6509.
Three syntheses of the architecturally complex, cytotoxic marine macrolide (+)-spongistatin 1 (1) are reported. Highlights of the first-generation synthesis include: use of a dithiane multicomponent linchpin coupling tactic for construction of the AB and CD spiroketals, and their union via a highly selective Evans boron-mediated aldol reaction en route to an ABCD aldehyde; introduction of the C(44)–C(51) side chain via a Lewis acid-mediated ring opening of a glucal epoxide with an allylstannane to assemble the EF subunit; and final fragment union via Wittig coupling of the ABCD and EF subunits to form the C(28)–C(29) olefin, followed by regioselective Yamaguchi macrolactonization and global deprotection. The second- and third- generation syntheses, designed with the goal of accessing one gram of (+)-spongistatin 1 (1), maintain both the first-generation strategy for the ABCD aldehyde and final fragment union, while incorporating two more efficient approaches for construction of the EF Wittig salt. The latter combine the original chelation-controlled dithiane union of the E- and F-ring progenitors with application of a highly efficient cyanohydrin alkylation to append the F-ring side chain, in conjunction with two independent tactics to access the F-ring pyran. The first F-ring synthesis showcases a Petasis-Ferrier union/rearrangement protocol to access tetrahydropyrans, permitting the preparation of 750 mgs of the EF Wittig salt, which in turn was converted to 80 mg of (+)-spongistatin 1, while the second F-ring strategy, incorporates an organocatalytic aldol reaction as the key construct, permitting completion of 1.009 g of totally synthetic (+)-spongistatin 1 (1). A brief analysis of the three syntheses alongside our earlier synthesis of (+)-spongistatin 2 is also presented.
doi:10.1016/j.tet.2009.04.003
PMCID: PMC2902791  PMID: 20640040
5.  GPRC6A Null Mice Exhibit Osteopenia, Feminization and Metabolic Syndrome 
PLoS ONE  2008;3(12):e3858.
Background
GPRC6A is a widely expressed orphan G-protein coupled receptor that senses extracellular amino acids, osteocalcin and divalent cations in vitro. The physiological functions of GPRC6A are unknown.
Methods/Principal Findings
In this study, we created and characterized the phenotype of GPRC6A−/− mice. We observed complex metabolic abnormalities in GPRC6A−/− mice involving multiple organ systems that express GPRC6A, including bone, kidney, testes, and liver. GPRC6A−/− mice exhibited hepatic steatosis, hyperglycemia, glucose intolerance, and insulin resistance. In addition, we observed high expression of GPRC6A in Leydig cells in the testis. Ablation of GPRC6A resulted in feminization of male GPRC6A−/− mice in association with decreased lean body mass, increased fat mass, increased circulating levels of estradiol, and reduced levels of testosterone. GPRC6A was also highly expressed in kidney proximal and distal tubules, and GPRC6A−/− mice exhibited increments in urine Ca/Cr and PO4/Cr ratios as well as low molecular weight proteinuria. Finally, GPRC6A−/− mice exhibited a decrease in bone mineral density (BMD) in association with impaired mineralization of bone.
Conclusions/Significance
GPRC6A−/− mice have a metabolic syndrome characterized by defective osteoblast-mediated bone mineralization, abnormal renal handling of calcium and phosphorus, fatty liver, glucose intolerance and disordered steroidogenesis. These findings suggest the overall function of GPRC6A may be to coordinate the anabolic responses of multiple tissues through the sensing of extracellular amino acids, osteocalcin and divalent cations.
doi:10.1371/journal.pone.0003858
PMCID: PMC2585477  PMID: 19050760

Results 1-5 (5)