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Hong Lin

Publications and source records attributed to Hong Lin.

70 records · Page 4Linked to original sources
PubMed2003

Evaluation of the combination of multiple subpial transection and other techniques for treatment of intractable epilepsy.

OBJECTIVE: Multiple subpial transection (MST) is one approach to the surgical treatment of intractable epilepsy with epileptogenic lesion located in functional areas. To verify the effect of MST, an experimental study was performed first, followed by clinical application. METHODS: On the basis of the experimental study, MST was performed in 200 intractable epileptic patients from 1991 to 2000. Of them, 80 cases underwent MST only while 120 others underwent MST combined with other techniques, such as corpus callosotomy, temporal lobectomy and focus resection. A series of modifications of the surgical techniques were made. RESULTS: The results of the experimental study indicated that MST could inhibit the formation and spreading of epileptic discharge and limit the damage to neurons in a minimal area on the epileptogenic agent injected cortex. MST does not impair major functions of the cortex. After the clinical application and modifications, 160 patients were followed up for 1 to 8 years. Complete control of seizure was obtained in 100 cases (62.5%), significant reduction (more than 75%) in 32, reduction (more than 50%) in 20 and no change in 8. The total rate of effectiveness was 95.0%, and the significant rate of effectiveness was 82.5%. No functional defects were found in any patients. CONCLUSIONS: The results indicate that MST is an effective approach to the surgical treatment of intractable epilepsy. MST can be combined with other approaches. The outcome of the subdivision of the MST only group indicates that MST on local epileptogenic lesion without structural changes is as effective as that of the combined operation group. To evade hemispheric disturbance, MST should be done first to avoid severe complications. Hemispherectomy should be performed only on poor effected cases of MST.

Adolescent↗
PubMed2002

Activation of JNK by vanadate induces a Fas-associated death domain (FADD)-dependent death of cerebellar granule progenitors in vitro.

Apoptosis is a highly regulated process that plays a critical role in neuronal development as well as the homeostasis of the adult nervous system. Vanadate, an environmental toxicant, causes developmental defects in the central nervous system. Here, we demonstrated that vanadate induced apoptosis in cultured cerebellar granule progenitors (CGPs). Treatment of cultured CGPs with vanadate activated ERKs and JNKs but not p38 MAPK and also induced c-Jun phosphorylation. In addition, vanadate induced FasL production, Fas (CD95) aggregation, and its association with the Fas-associated death domain (FADD), as well as the activation of caspase-8. Furthermore, vanadate generated reactive oxygen species (ROS) in CGPs; however, ROS was not involved in vanadate-mediated MAPK activation. Vanadate-induced FasL expression was ROS-dependent but JNK-independent. In contrast, vanadate-elicited Fas aggregation and Fas-FADD association, as well as caspase-8 activation, were dependent on JNK activation but were minimally regulated by ROS generation. The hydrogen peroxide scavenger, catalase, blocked vanadate-induced FasL expression and partially mitigated vanadate-induced cell death. On the other hand, dominant negative FADD and caspase-8 inhibitor completely eliminated vanadate-induced apoptosis. Thus, JNK signaling plays a major role in vanadate-mediated activation of the Fas-FADD-caspase-8 pathway that accounts for vanadate-induced apoptosis of CGPs.

Adaptor Proteins, Signal Transducing↗
PubMed2002

Epidermal growth factor up-regulates the transcription of mouse lon homology ATP-dependent protease through extracellular signal-regulated protein kinase- and phosphatidylinositol-3-kinase-dependent pathways.

Epidermal growth factor (EGF) induces tumorigenic transformation of mouse epidermal cells (JB6 P(+)). We cloned a full-length EGF-responsive cDNA in JB6P(+) cells; EGF up-regulated mRNA expression of this gene 5- to 6-fold. The deduced amino acid sequence of this cDNA exhibited 84 and 96% homology with human and rat Lon homology ATP-dependent protease, respectively, and all conserved domains of Lon, such as ATPase/protease domains, are present in the mouse gene, indicating that this gene is mouse Lon. EGF increased the transcriptional rate without affecting the mRNA stability of m-Lon. The level of m-Lon in irreversibly transformed mouse epidermal cells (JB7) was 3.4-fold higher than that in parental JB6 P(+) cells. Similarly, human mammary epithelial cells overexpressing the proto-oncogene ErbB2 expressed significantly higher levels of Lon than normal mammary epithelial cells. EGF failed to regulate Lon expression in ERK-deficient JB6 P(-) cells or cells that expressed the dominant-negative p85 P13-K regulatory unit. Furthermore, selective chemical blockers for MEK1 and P13-K (PD98059 and LY294002) inhibited EGF-mediated induction. Mitochondria-localized Lon protease plays a critical role in the regulation of mitochondrial gene expression and genome integrity. Disruption of mitochondrial homeostasis is a general characteristic of tumorigenic transformation. Thus, the role of Lon in tumor promotion warrants further study.

ATP-Dependent Proteases↗
PubMed2002

Nitric oxide-containing pyramidal neurons of the subiculum innervate the CA1 area.

Neurons and axon terminals containing neuron-specific nitric oxide synthase (nNOS) were examined in the rat subiculum and CA1 area of Ammon's horn. In the subiculum, a large subpopulation of the pyramidal neurons and non-pyramidal cells are immunoreactive for nNOS, whereas in the neighbouring CA1 area of Ammon's horn only non-pyramidal neurons are labelled with the antibody against nNOS. In the pyramidal layer of the subiculum, nNOS-positive axon terminals form both asymmetric and symmetric synapses. In the adjacent CA1 area the nNOS-positive terminals that form symmetric synapses are found in all layers, whereas those terminals that form asymmetric synapses are only in strata radiatum and oriens, but not in stratum lacunosum-moleculare. In both the subiculum and CA1 area, labelled terminals make symmetric synapses only on dendritic shafts, whereas asymmetric synapses are exclusively on dendritic spines. Previous observations demonstrated that all nNOS-positive non-pyramidal cells are GABAergic local circuit neurons, which form exclusively symmetric synapses. We suggest that nNOS-immunoreactive pyramidal cells of the subiculum may innervate neighbouring subicular pyramidal cells and, to a smaller extent, pyramidal cells of the adjacent CA1 area, forming a backward projection between the subicular and hippocampal principal neurons.

Animals↗
PubMed2002

Binding of p190RhoGEF to a destabilizing element on the light neurofilament mRNA is competed by BC1 RNA.

The enhancement of RNA-mediated motor neuron degeneration in transgenic mice by mutating a major mRNA instability determinant in a light neurofilament (NF-L) transgene implicates cognate RNA binding factors in the pathogenesis of motor neuron degeneration. p190RhoGEF is a neuron-enriched guanine exchange factor (GEF) that binds to the NF-L-destabilizing element, to c-Jun N-terminal kinase-interactive protein-1 (JIP-1), and to 14-3-3 and may link neurofilament expression to pathways affecting neuronal homeostasis. This study was undertaken to identify additional RNA species that bind p190RhoGEF and could affect interactions of the exchange factor with NF-L transcripts. The C-terminal domain of p190RhoGEF, containing the RNA-binding site, was expressed as a glutathione S-transferase fusion protein and was used as an affinity probe to isolate interactive RNAs in rat brain extracts. As expected, NF-L mRNA was identified as an RNA specie eluted from the affinity column. In addition, BC1 RNA was also found enriched in the bound RNA fraction. BC1 is a 152-nucleotide RNA that is highly expressed but untranslated in differentiated neurons. We show that BC1 and NF-L mRNA bind to a similar site in the C-terminal domain of p190RhoGEF, and their bindings to p190RhoGEF are readily cross-competed. Moreover, we identify a novel binding site in BC1 to account for its interaction with p190RhoGEF. The findings suggest a novel role of BC1 in differentiated neurons involving RNA-protein interactions of p190RhoGEF.

Animals↗
PubMed2002

Untranslated element in neurofilament mRNA has neuropathic effect on motor neurons of transgenic mice.

Studies of experimental motor neuron degeneration attributable to expression of neurofilament light chain (NF-L) transgenes have raised the possibility that the neuropathic effects result from overexpression of NF-L mRNA, independent of NF-L protein effects (Cañete-Soler et al., 1999). The present study was undertaken to test for an RNA-mediated pathogenesis. Transgenic mice were derived using either an enhanced green fluorescent protein reporter construct or modified chimeric constructs that differ only in their 3' untranslated regions (UTRs). Motor function and spinal cord histology were normal in mice expressing the unmodified reporter transgene. In mice expressing a chimeric transgene in which sequence of NF-L 3' UTR was inserted into the 3' UTR of the reporter transgene, we observed growth retardation and reduced kinetic activity during postnatal development. Older mice developed impairment of motor function and atrophy of nerve fibers in the ventral roots. A similar but more severe phenotype was observed when the chimeric transgene contained a 36 bp c-myc insert in an mRNA destabilizing element of the NF-L sequence. Our results suggest that neuropathic effects of overexpressing NF-L can occur at the level of transgene RNA and are mediated by sequences in the NF-L 3' UTR.

3' Untranslated Regions↗
PubMed2002

Explorations in organic chemistry leading to the total synthesis of (+/-)-gelsemine.

The total synthesis of (+/-)-gelsemine (1) is described. A defining phase of the effort involved recourse to a strategic oxetane ring (see compound 25). It was constructed anticipating an intramolecular displacement of the carbon (C17)-oxygen (O4) bond (see product 48). A key intermediate in the stereospecific elaboration of the oxetane linkage was enone 22, which was susceptible to two beta-face attacks leading to 24 and, thence, 25. Three sigmatropic rearrangements were employed in building the bridgehead (C20) and the spiroanilide (C7) quaternary centers en route to gelsemine.

Alkaloids↗
PubMed2002

Highly concise routes to epothilones: the total synthesis and evaluation of epothilone 490.

A concise modular laboratory construction of the epothilone class of promising antitumor agents has been accomplished. For the first time in the epothilone area, the new synthesis exploits the power of ring-closing olefin metathesis (RCM) in a stereospecific way. Previous attempts at applying RCM to epothilone syntheses have been repeatedly plagued by complete lack of stereocontrol in the generation of the desired 12,13-olefin geometry in the products. The isolation of epothilone 490 (3) prompted us to reevaluate the utility of the RCM procedure for fashioning the 10,11-olefin, with the Z-12,13-olefin geometry already in place. Olefin metathesis of the triene substrate 12 afforded the product diene macrolide in stereoselective fashion. For purposes of greater synthetic convergency, the C3-(S)-alcohol was fashioned late in the synthesis, using chiral titanium-mediated aldol conditions with the entire O-alkyl fragment as a C15 acetate as the enolate component. Examination of the effects of protecting groups on the RCM process showed that deprotection of the C7 alcohol has a beneficial effect on the reaction yield. Performing the RCM as the last synthetic step in the sequence afforded a 64% yield of only the desired E-olefin. Selective diimide reduction of the new 10,11-olefin yielded 12,13-desoxyepothilone B, our current clinical candidate, demonstrating the utility of this new RCM-reduction protocol in efficiently generating the epothilone framework. Furthermore, the new olefin was selectively funtionalized to demonstrate the advantage conferred by this route for the construction of new analogues for SAR studies, in cytoxicity and microtubule affinity screens. Also described is the surprisingly poor in vivo performance of epothilone 490 in xenografts in the light of very promising in vitro data. This disappointing outcome was traced to unfavorable pharmacokinetic features of the drug in murine plasma. By the pharmacokinetic criteria, the prognosis for the effectiveness of 3 in humans is, in principle, much more promising.

Animals↗
PubMed2002

Progression of systolic abnormalities in patients with "isolated" diastolic heart failure and diastolic dysfunction.

BACKGROUND: The definition of diastolic heart failure (DHF) relies on the use of sensitive tools to exclude the presence of systolic dysfunction. The use of ejection fraction (EF) of 50% as the cutoff point may not be adequate to address such a task. We believe that systolic dysfunction is common in DHF. METHODS AND RESULTS: Echocardiography with tissue Doppler imaging was performed in 339 subjects, of whom 92 had systolic heart failure (SHF) (EF<50%), 73 had DHF (EF > or = 50% with diastolic abnormalities on Doppler echocardiography), and 68 had isolated diastolic dysfunction (DD); 106 were normal control subjects. Regional myocardial velocity curves were constructed off-line with the use of a 6-basal, 6-midsegmental model. The peak regional myocardial sustained systolic (S(M)) and early diastolic (E(M)) velocities were significantly lower in patients with SHF, DHF, and DD than in control subjects in almost all the myocardial segments. Likewise, the mean S(M) (SHF<DHF<DD<control subjects; 3.3 plus/minus 1.0 < 4.6 plus/minus 1.3 < 5.4 plus/minus 1.0 < 6.3 plus/minus 1.0 cm/s; all P less-than-or-equal 0.001) and mean E(M) (SHF=DHF<DD<control subjects; 3.6 plus/minus 1.2 =3.9 plus/minus 1.3 < 5.3 plus/minus 1.6 < 7.2 plus/minus 1.7 cm/s; all P<0.001) from the six basal segments were decreased in all the disease groups. A mean S(M) of 4.4 cm/s (-2 SD of control subjects) predicted the presence of systolic dysfunction in 92% of patients with SHF, 52% with DHF, and 14% with DD. CONCLUSIONS: Through the use of tissue Doppler imaging, systolic abnormalities were evident in patients previously labeled as DHF and to a much lesser extent, isolated DD. This indicates the common coexistence of systolic and diastolic dysfunction in a spectrum of different severity in the pathophysiological process of heart failure.

Aged↗
PubMed2002

Tissue Doppler echocardiographic evidence of reverse remodeling and improved synchronicity by simultaneously delaying regional contraction after biventricular pacing therapy in heart failure.

BACKGROUND: Biventricular pacing has been proposed to improve symptoms and exercise capacity in patients with advanced heart failure and wide electrocardiographic wave complexes. This study investigated the effect of biventricular pacing on reverse remodeling and the underlying mechanisms. METHODS AND RESULTS: Twenty-five patients with NYHA class III to IV heart failure and electrocardiographic wave complex duration >140 ms receiving biventricular pacing therapy were assessed serially up to 3 months after pacing and when pacing was withheld for 4 weeks. Tissue Doppler echocardiography was performed using a 6-basal, 6-mid segmental model to assess the time to peak sustained systolic contraction (T(S)). There was significant improvement of ejection fraction, dP/dt, and myocardial performance index; decrease in mitral regurgitation, left ventricular (LV) end-diastolic (205+/-68 versus 168+/-67 mL, P<0.01) and end-systolic volume (162+/-54 versus 122+/-42 mL, P<0.01); and improved 6-minute hall-walk distance and quality of life score after pacing for 3 months. The mechanisms of benefits were as follows: (1) improved LV synchrony, as evident by homogeneous delay of T(S) to a timing close to the latest (usually the lateral) segment abolishing the intersegmental difference in T(S) and decreasing the standard deviation of T(S) within the left ventricle (37.7+/-10.9 versus 29.3+/-8.3 ms, P<0.05); (2) improved interventricular synchrony; and (3) shortened isovolumic contraction time (122+/-57 versus 82+/-36 ms, P<0.05) but increased diastolic filling time. These benefits are pacing dependent, because withholding the pacing resulted in varying speeds in the loss of cardiac improvements. CONCLUSIONS: Biventricular pacing reverses LV remodeling and improves cardiac function. Improvement of LV mechanical synchrony seems to be the predominant mechanism.

Aged↗
PubMed2002

XK469, a novel antitumor agent, inhibits signaling by the MEK/MAPK signaling pathway.

PURPOSE: XK469 (NSC 697887) is a novel antitumor agent with broad activity against a variety of tumors including drug-resistant tumors. Previous studies have indicated that XK469 is an antiproliferative agent with a low cytotoxic effect in human H116 tumor cells. In this study, we sought to determine the signaling pathways involved in mediating its antiproliferative activity. METHODS: The antiproliferative activity of XK469 was tested using human U-937 leukemia cells in culture. XK469-induced cell cycle arrest was determined using flow cytometric analysis. Phosphorylation/activation of MEK and MAPK was analyzed using immunoblot analyses with specific antibodies against p-MEK and p-MAPK. RESULTS: Cell cycle analysis revealed that XK469 arrested U-937 cells at the G(2)/M phase. Compared with conventional anticancer agents, XK469 showed very low, if any, cytotoxic or proapoptotic effect against U-937 cells. In contrast, treatment of U-937 cells with vinblastine, doxorubicin and m-AMSA resulted in extensive cell death through apoptotic pathways. XK469, but not other agents, potently inhibited the phosphorylation/activation of MEK in U-937 cells cultured in serum-containing medium. XK469 was also able to block the activation of MEK by serum addition in starved U-937 cells. Exposure of cells to XK469 for 1 h was sufficient to inhibit the activation of MEK and its downstream kinase, MAPK. The antiproliferative response to XK469 was correlated with a steady accumulation of cyclins B1 and A, which appeared to be a direct result of G(2)/M arrest. CONCLUSIONS: Our findings suggest that the antiproliferative effect of XK469 is mediated by inhibiting the MEK/MAPK signaling pathways in U-937 human leukemia cells.

Antineoplastic Agents↗
PubMed2002

Activation of the MEK/MAPK pathway is involved in bryostatin1-induced monocytic differenciation and up-regulation of X-linked inhibitor of apoptosis protein.

Induction of monocytic differentiation by bryostatin1 (bryo1) conferred on THP-1 leukemia cells the ability to resist Z-LLL-CHO-induced apoptosis. The mechanism of resistance developed during this process was investigated. Apoptosis resistance was associated with an enhanced expression of X-linked inhibitor of apoptosis protein (XIAP), an endogenous caspase inhibitor, in differentiated THP-1 cells. Bryo1 also increased the level of c-IAP-1, yet decreased the level of c-IAP-2 in THP-1 cells, indicating that distinct regulatory mechanisms are operative. In addition, treatment of THP-1 cells with bryo1 induced a rapid and sustained activation of MEK, prior to the upregulation of XIAP and monocytic differentiation. Pretreatment of THP-1 cells with MEK inhibitors (U0126 and PD98059) prior to bryo1 induction blocked the expression of both XIAP and the c-fms product (M-CSF receptor), a hallmark of monocytic differentiation, but not Bcl-2. In addition, the expression of XIAP in bryo1-treated cells was inhibited by CAPE, a NF-kappaB-specific inhibitor, indicating that its expression is under the transcriptional regulation of NF-kappaB downstream of the MEK/MAPK pathway. The importance of XIAP in mediating apoptosis resistance was illustrated in cells transiently transfected with XIAP, which conferred on THP-1 cells the ability to resist Z-LLL-CHO-induced apoptosis. These findings suggest that the expression of XIAP is linked to monocytic differentiation in bryo1-treated THP-1 cells and represents one of the potential antiapoptotic mechanisms acquired during this process.

Apoptosis↗
PubMed2002

Mitotic arrest induced by XK469, a novel antitumor agent, is correlated with the inhibition of cyclin B1 ubiquitination.

XK469 (NSC 697887) is a novel antitumor agent with broad activity against a variety of tumors. Previous studies suggest that XK469 is a topoisomerase II beta poison with functional activity similar to that of 4'-(9-acridinylamino) methanesulfon-m-anisidide (m-AMSA). The goal of our study was to investigate its mechanism of action further using a human HCT-116 (H116) colon tumor cell model. Concentration-survival curves with continuous exposure indicated that XK469 had low cytotoxic activity against H116 cells. Cell cycle analysis revealed that XK469 is a phase-specific cell cycle blocker that is associated with increased levels of cyclin B1, cyclin A and p53 but not CDK1 (cdc2) or cyclin E. In contrast, treatment of H116 cells with m-AMSA caused a total degradation of both cyclin A and B1 but enhanced expression of cyclin E and p53. Accumulation of cyclin B1 in XK469-treated cells was correlated with the inhibition of cyclin B1 ubiquitination, a metabolic process mandatory for proteasome-mediated protein turnover. However, no inhibition of cyclin B1 ubiquitination was detected in cells treated with m-AMSA or colchicine, a known mitotic inhibitor. Furthermore, unlike m-AMSA, XK469 did not induce caspase activation or apoptotic cell death in H116 cells. Our results suggest that XK469 is a phase-specific cell cycle inhibitor with a unique mechanism of action that is correlated with the inhibition of cyclin B1 ubiquitination and its accumulation at early M phase.

Amsacrine↗
PubMed2002

Induction or suppression of expression of cytochrome C oxidase subunit II by heregulin beta 1 in human mammary epithelial cells is dependent on the levels of ErbB2 expression.

The ErbB family of receptor kinases is composed of four members: epidermal growth factor receptor (EGFR/ErbB1), ErbB2/neu, ErbB3, and ErbB4. Amplification of the ErbB2/neu is found in about 30% of breast cancer patients and is associated with a poor prognosis. Heregulin (HRG) activates the ErbB2 via induction of heterodimerization with ErbB3 and ErbB4 receptors. With suppression subtractive hybridization, we demonstrated that the expression of cytochrome c oxidase subunit II (COXII) is HRG-responsive. Two nontransformed human mammary epithelial cell lines, the HB2 and the HB2(ErbB2) (the HB2 engineered to overexpress ErbB2), displayed an opposite response to HRG-mediated regulation. HRG upregulated mRNA expression of COXII in the HB2 cells, but suppressed COXII expression in the HB2(ErbB2) cells. A human breast cancer cell line (T47D), which expresses ErbB2 at a level similar to that of the HB2 cells, also responded to HRG by increasing COXII mRNA levels. Therefore, HRG regulation of COXII expression depends on the levels of ErbB2 expression. Furthermore, the expression of COXII was inversely correlated to the levels of ErbB2, i.e., the cells overexpressing ErbB2 exhibited lower COXII levels. HRG-evoked signal transduction differed between the cells with normal ErbB expression and the cells overexpressing ErbB2. The activation of both ERK and PI3-K was essential for HRG regulation of COXII, i.e., blockage of either pathway eliminated HRG-mediated alteration. This is the first report demonstrating that the expression of mitochondria-encoded COXII is HRG-responsive. The levels of ErbB2 expression are decisive for the diverse biological activities of HRG.

Breast Neoplasms↗
PubMed2002

[Changes of protein tyrosine phosphorylation in erythrocyte band 3 glucose-6-phosphate dehydrogenase deficiency].

OBJECTIVE: To explore the hemolytic mechanism of glucose-6-phosphate dehydrogenase (G6PD) deficient erythrocytes in the view of phosphorylation of membrane protein. METHODS: The alternation of membrane protein phosphorylation and the effect of dithiothreitol (DTT) on protein phosphorylation were analysed by Western blot technique. The activity of phosphotyrosine phosphatase (PTPs) was determined by using p-nitrophenyl phosphate as substrate. RESULTS: Tyrosine phosphorylation of band 3 protein was obviously enhanced in G6PD-deficient erythrocytes. The activity of PTPs was low compared to the normal erythrocytes. The level of phosphotyrosine in G6PD-deficient erythrocytes incubated with DTT was almost the same as in those without DTT. The results were consistent with the activity of PTPs. CONCLUSIONS: PTPs activity reduction and tyrosine phosphorylation enhancement induced by oxidation in G6PD deficiency play an important role in erythrocytes hemolysis. However, the alternation of thiol group is not the only factor affecting the activity of PTPs in G6PD-deficient erythrocytes.

Anion Exchange Protein 1, Erythrocyte↗