Search PubMed⌕ Search

Biomedical subjects

Sheng-Di Chen

Publications and source records attributed to Sheng-Di Chen.

15 recordsLinked to original sources
PubMed2006

Lmx1b is essential for Fgf8 and Wnt1 expression in the isthmic organizer during tectum and cerebellum development in mice.

Secreted factors FGF8 and WNT1 are essential either for the inductive activity of the isthmus organizer or for the regionalization of the midbrain-hindbrain boundary (MHB). However, transcriptional regulation of these secreted factors during development remains to be elucidated. Here we show that the LIM homeobox gene Lmx1b is expressed in the anterior embryo as early as E7.5 and its expression becomes progressively restricted to the isthmus at E9.0. Analysis of gene expression in the MHB of the mutant embryos showed that many genes were lost by E9.5. In the MHB of Lmx1b-/- embryos, the expression of Fgf8, which normally occurs at the 4-somite stage, was completely absent, whereas Wnt1 was downregulated before the 4-somite stage. Moreover, transcription factors En1 and Pax2 were also downregulated prior to the 4-somite stage, whereas Gbx2 downregulation occurred at the 4-somite stage. By contrast, Otx2 and Pax6 expression was not affected in Lmx1b-/- embryos. The requirement of specific Lmx1b expression in the MHB was further confirmed by Wnt1-Cre-mediated region-specific conditional knockout of Lmx1b. As a result of these molecular defects, the development of the tectum and cerebellum was severely impaired in Lmx1b-/- mice. Taken together, our results indicate that Lmx1b plays an essential role in the development of the tectum and cerebellum by regulating expression of Fgf8, Wnt1 and several isthmus-related transcription factors in the MHB, and is a crucial component of a cross-regulatory network required for the induction activity of the isthmic organizer in the MHB.

Animals↗
PubMed2006

Therapeutic effects of differentiated bone marrow stromal cell transplantation on rat models of Parkinson's disease.

This study was to explore curative effect of bone marrow stromal cells (BMSCs) differentiated into nestin-positive cells transplantation on rat Parkinson's disease (PD) model. The PD rats were selected and allocated randomly into three groups. BMSCs with differentiation, BMSCs without differentiation and physiological saline were injected into right striatum of PD rat. The rotation test and immunofluorescence double staining were done. Frequency of rotation was significantly less in differentiated or non-differentiated BMSCs groups than that in normal saline group. Brdu/GFAP- and Brdu/NSE-positive cells appeared except BrdU/TH-positive cells. BMSCs differentiated had better effect than that of BMSCs without differentiated and physiological saline group.

Animals↗
PubMed2006

Parkinson disease IgG and C5a-induced synergistic dopaminergic neurotoxicity: role of microglia.

Increasing evidence suggests the involvement of immune/inflammatory system in Parkinson's disease (PD). Many immune/inflammatory factors may synergistically participate in PD. In this study, we demonstrated that immunoglobulin G from the serum of 4/11 PD patients (PDIgG, 60microg/ml) and recombinant human C5a (0.1nM) synergistically induced selective dopaminergic neurodegeneration in rat mesencephalic neuron-glia cultures, while that PDIgG alone or C5a alone was minimally toxic or nontoxic. IgG from 17 disease controls and from 7 normal controls did not significantly induce dopaminergic neurotoxicity in the cultures even in the presence of C5a. Using mesencephalic neuron-enriched cultures, we found that the synergistic dopaminergic neurotoxicity was mediated by glia. The results from microglia-supplemented neuronal cultures, astroglia-supplemented neuronal cultures and neuron-astroglia cocultures indicated that microglia, not astroglia, played a pivotal role in the neurotoxicity. Through immunocytochemistry analysis and assay of proinflammatory factors, we observed that each of the four PDIgGs (60microg/ml) and C5a (0.1nM) synergistically induced microglia activation and production of superoxide and nitric oxide (NO) in neuron-glia cultures. Further investigations indicated that superoxide and NO were both responsible for the synergistic neurotoxicity. Finally, using F(ab')(2) fragments of PDIgG, we demonstrated that microglial Fc receptors may play an important role in the neurotoxicity. Our work provides new evidence for the involvement of the immune/inflammatory system in PD and helpful clues for studying the combined effect of antibody and complement on microglia.

Animals↗
PubMed2006

Mitogen activated protein kinase and protein kinase C activation mediate promotion of sAPPalpha secretion by deprenyl.

The beta amyloid cascade plays a crucial role in the pathogenesis of Alzheimer's disease (AD). Therefore, drugs that regulate amyloid precursor protein (APP) processing toward the nonamyloidgenic pathway may have therapeutic potential. Many anti-dementia drugs can regulate APP processing in addition to their pharmacological properties. Deprenyl is a neuroprotective agent used to treat some neurodegenerative diseases, including AD. In the present study, the effects of deprenyl on APP processing were investigated. Using SK-N-SH and PC12 cells, it was demonstrated that deprenyl stimulated the release of the nonamyloidogenic alpha-secretase form of soluble APP (sAPPalpha) in a dose-dependent manner without affecting cellular APP expression. The increase of sAPPalpha secretion by deprenyl was blocked by the mitogen activated protein (MAP) kinase inhibitor U0126 and PD98059, and by the protein kinase C (PKC) inhibitor GF109203X and staurosporine, suggesting the involvement of these signal transduction pathways. Deprenyl induced phosphorylation of p42/44 MAP kinase, which was abolished by specific inhibitors of MAP kinase and PKC. Deprenyl also phosphorylated PKC and its major substrate, and myristoylated alanine-rich C kinase (MARCKS) at specific amino acid residues. The data also indicated that 10microM deprenyl successfully induced two PKC isoforms involved in the pathogenesis of AD, PKCalpha and PKCepsilon, to translocate from the cytosolic to the membrane fraction. This phenomenon was substantiated by immunocytochemistry staining. These data suggest a novel pharmacological mechanism in which deprenyl regulates the processing of APP via activation of the MAP kinase and PKC pathways, and that this mechanism may underlie the clinical efficacy of the drug in some AD patients.

Amyloid beta-Protein Precursor↗
PubMed2006

Dopaminergic neuroprotection by neurturin-expressing c17.2 neural stem cells in a rat model of Parkinson's disease.

Genetically engineered neural stem cell (NSC) lines are promising vectors for the treatment of regenerative diseases, especially Parkinson's disease (PD). Neurturin (NTN), a member of the glial cell line-derived neurotrophic factor-family, has been demonstrated to act specifically on mesencephalic dopaminergic neurons, suggesting its therapeutic potential for PD. Here, we have generated a NTN-secreting c17.2 NSC line and investigated the protective effect of NTN-c17.2 on PD rat models. These NTN-releasing NSCs engrafted and integrated in the host striatum with good success, gave rise to neurons, astrocytes and oligodendrocytes, and maintained stable, high-level NTN expression. In addition, inverse transfer of NTN protein into the substantia nigra (SN) was able to protect dopaminergic neurons from 6-OHDA toxicity. Observation of rotational behavior showed that the NTN group performed significantly better than the Mock group, and the protective effect of NTN lasted for at least 4 months. HPLC tests indicated that the contents of neurotransmitters (e.g. dopamine) in the corpus striatum area of the NTN-c17.2 group and the Mock-c17.2 group were significantly higher than in the PBS group, but there was no significant difference between expression in the NTN-c17.2 and Mock-c17.2 groups. Taken together, our results suggest that transplantation of NTN-secreting NSCs exerted protective on PD rat models.

Adrenergic Agents↗
PubMed2006

Heat shock proteins reduce alpha-synuclein aggregation induced by MPP+ in SK-N-SH cells.

Alpha-synuclein has been implicated in the pathogenesis of Parkinson's disease (PD). Heat shock proteins (HSPs) can reduce protein misfolding and accelerate the degradation of misfolded proteins. 1-methyl-4-phenylpyridinium ion (MPP+) is the compound responsible for the PD-like neurodegeneration caused by MPTP. In this study, we found that MPP+ could increase the expression of alpha-synuclein mRNA but could not elevate proteasome activity sufficiently, leading to alpha-synuclein protein accumulation followed by aggregation. Both HSPs and HDJ-1, a homologue of human Hsp40, can inhibit MPP+-induced alpha-synuclein mRNA expression, promote ubiquitination and elevate proteasome activity. These findings suggest that HSPs may inhibit the MPP+-induced alpha-synuclein expression, accelerate alpha-synuclein degradation, thereby reducing the amount of alpha-synuclein protein and accordingly preventing its aggregation.

1-Methyl-4-phenylpyridinium↗
PubMed2006

Economic burden of Parkinson's disease in a developing country: a retrospective cost analysis in Shanghai, China.

We investigated economic costs from patients with Parkinson's disease (PD) in Shanghai, China, which could be used as a baseline for future evaluations. Data were collected from 190 patients by interview during 1-year period. Direct medical care costs averaged approximately Chinese yuan, renminbi (RMB) 4,305 (USD 519, or EUR 410) per year per patient, of which drugs (RMB 2,677) accounted for the major costly component. Nonmedical direct costs were much less than direct health care costs, averaging approximately RMB 3,301 (USD 398, or EUR 314). Costs due to loss of productivity averaged approximately RMB 73 (USD 8.8, or EUR 7.0) per patient per year. Taken together, the overall mean annual cost for PD in our series was approximately RMB 7,679 (USD 925, or EUR 731), and these costs accounted for around half of the mean annual income. Total cost was significantly associated with the disease severity and the frequency of outpatient visits. In addition, levodopa equivalent dose (LED) and the number of drugs being taken were also closely related with the drug cost. The results indicate that the economic burden of Chinese PD patients is heavy.

Adult↗
PubMed2005

Heat shock proteins reduce toxicity of 1-methyl-4-phenylpyridinium ion in SK-N-SH cells.

The pathology of Parkinson's disease (PD) is characterized by the progressive loss of dopaminergic (DA) neurons in the substantia nigra. However, the pathogenesis of PD remains unclear. Heat shock proteins (HSPs) have many functions, including inhibition of apoptosis and necrosis, protection from oxidative stress, and maintenance of the mitochondrial membrane potential, that are related to neurodegenerative diseases. 1-Methyl-4-phenylpyridinium ion (MPP(+)) is a neurotoxin that selectively inhibits the mitochondrial functions of DA neurons in the substantia nigra. MPP(+) administration is accepted as a model for PD. In the present study, we found that MPP(+) induced a concentration- and time-dependent decrease in cell viability. Lower concentrations of MPP(+) induced mainly early apoptosis, and, as the concentration increased, the number of late apoptotic and necrotic cells significantly increased. However, treated by heat shock preconditioning or transfection with HDJ-1, a homologue of human Hsp40, cells showed marked improvement in viability after exposure to the same concentrations of MPP(+). Compared with heat shock, HDJ-1 appeared to improve cell viability obviously. Similarly, HDJ-1 elicited significantly stronger protective effects against apoptosis and necrosis. In addition, HDJ-1 transfection maintained more injured cells in early apoptotic stages and inhibited the occurrence of late apoptotic/necrotic events. Heat shock and HDJ-1 both ameliorated MPP(+)-induced cytotoxicity by maintaining the mitochondrial membrane potential and reducing reactive oxygen species (ROS). Therefore, the effects of HSPs, such as reducing apoptosis and necrosis, preserving mitochondrial functions and decreasing oxidative stress, may bring a novel approach for PD therapy.

1-Methyl-4-phenylpyridinium↗
PubMed2005

PACAP protects neuronal differentiated PC12 cells against the neurotoxicity induced by a mitochondrial complex I inhibitor, rotenone.

In vivo and in vitro studies have suggested a neuroprotective role for Pituitary adenylate cyclase activating polypeptide (PACAP) against neuronal insults. Here, we showed that PACAP27 protects against neurotoxicity induced by rotenone, a mitochondrial complex I inhibitor that has been implicated in the pathogenesis of Parkinson's disease (PD). The neuroprotective effect of PACAP27 was dose-dependent and blocked by its specific receptor antagonist, PACAP6-27. The effects of PACAP27 on rotenone-induced cell death were mimicked by dibutyryl-cAMP (db-cAMP), forskolin and prevented by the PKA inhibitor H89, the ERK inhibitor PD98059 and the p38 inhibitor SB203580. PACAP27 administration blocked rotenone-induced increases in the level of caspase-3-like activity, whereas could not restore mitochondrial activity damaged by rotenone. Thus, our results demonstrate that PACAP27 has a neuroprotective role against rotenone-induced neurotoxicity in neuronal differentiated PC12 cells and the neuroprotective effects of PACAP are associated with activation of MAP kinase pathways by PKA and with inhibition of caspase-3 activity; the signaling mechanism appears to be mediated through mitochondrial-independent pathways.

Animals↗
PubMed2005

Neuroprotection of Parkin against apoptosis is independent of inclusion body formation.

Loss-of-function mutations in the parkin gene are known to result in autosomal recessive juvenile parkinsonism, which causes selective degeneration of nigrostriatal dopaminergic neurons in the absence of Lewy bodies. Here, we show that overexpression of parkin protects PC12 cells from neurotoxin of the proteasome inhibitor lactacystin and increases the accumulation of ubiquitin-protein conjugates and the formation of ubiquitin-positive inclusions induced by lactacystin. However, the protective effect of parkin against lactacystin-induced apoptosis is not associated with its ability to promote the formation of ubiquitinated inclusions. It is likely that Lewy body formation may be only a compensatory mechanism of dopaminergic neurons attempting to counteract toxicity, and not the ultimate cause of neuronal death.

Animals↗
PubMed2004

Neuroprotection by pergolide against levodopa-induced cytotoxicity of neural stem cells.

Neural stem cells (NSCs) are currently considered very hopeful candidates for cell replacement therapy in neurodegenerative pathologies such as Parkinson's disease (PD), but like embryonic neural tissue transplantation, levodopa medication may still be required to improve symptoms even after cell transplantation. The issues of whether levodopa induces cytotoxicity and apoptosis of NSCs following transplantation, as well as the means to prevent these processes from occurring remain to be elucidated. In this study, the possible cytotoxicity of levodopa at different doses on C17.2 neural stem cells and subsequent neuroprotection by pergolide were investigated. The cell viability was determined by the MTT assay. Cell proliferation was assayed by BrdU labeling, while apoptosis was detected by Annexin-V-FLUOS staining and flow cytometry. Levels of p53, Bax, Bcl-2, NFkB, cytochrome c, caspase-3 as well as cleavage of caspase-3 were measured by western blotting. We found levodopa induced a concentration- and time-dependent decrease in cell viability and proliferation. Apoptotic cells were observed at different stages, specifically 12 and 24 h following exposure to levodopa (200 microM). Elevated p53, Bax, cytochrome c, caspase-3 and active fragments of caspase-3 protein were observed in the cells exposed to levodopa. These alterations were partly inhibited by pergolide, a dopamine receptor agonist, while Bcl-2 and NFkB p65 levels remained constant at the various time-points in all the groups examined. These observations indicate that levodopa at high concentrations (> or = 200 microM) was neurotoxic to C17.2 neural stem cells via inhibition of DNA synthesis and cell proliferation. Activation of the mitochondria-dependent pathway and caspase-3 protease may contribute to the mechanism by which levodopa induces apoptosis. Pergolide, an anti-Parkinson drug, has a neuroprotective effect and partly blocks levodopa-induced cytotoxicity.

Animals↗
PubMed2001

Treatment of Parkinson's Disease by Genetically Modified Immortalized Fibroblasts.

Primary rat fibroblast cells were immortalized by genetic modification of SV40 large T antigen (LT(Ag)) gene and called RFLT. This cell line was non-tumorigenic after grafting into nud-mouse and rat. The LT(Ag)gene stopped expression when the cells were transplanted in rat striatum, but it resumed the expression ability after the transplanted cells were recovered from striatum and cultured in vitro.TH gene and GCH gene were transfected into RFLT, respectively, and two types of transfected cells, RFLT-TH and RFLT-GCH, were obtained. In mixed culture with these two cell lines, DA was detected with HPLC-ECD. Implanting mixture of those cells into the striatum of PD rats significantly decreased their rotational asymmetry for up to 12 weeks. The expression of TH gene was proved by TH immunohistochemical staining in the sections of rat brain. The establishment of the genetically modified immortalized cells may play role in the gene therapy of PD.

Journal Article↗
PubMed1999

Preliminary Study on Gene Therapy of PD Monkey Using Microcapsulated Rat Transgenetic Myoblasts.

Rat myoblast cells transfected with tyrosine hydroxylase gene were microcapsulated using the ALG/PLL system. These microcapsulated cells could survive grow and produce tyrosine hydroxylase(TH)for at least two months in vitro. After the implantation of these microcapsules into monkey striatum microcapsulated cells still survived one month more. No obvious gliosis was seen around implanted microcapsules. Then the microcapsules were transplanted into the striatum of PD monkeys and their typical PD rotation numbers were significantly decreased.

Journal Article↗