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Biomedical subjects

M S Su

Publications and source records attributed to M S Su.

At least 55 records · Page 3Linked to original sources
PubMed1997

The hepatitis C virus NS4A protein: interactions with the NS4B and NS5A proteins.

Hepatitis C virus encodes a large polyprotein precursor that is proteolytically processed into at least 10 distinct products, in the order NH2-C-E1-E2-p7-NS2-NS3-NS4A-NS4B-NS5A-NS5B -COOH. A serine proteinase encoded in the N-terminal 181 residues of the NS3 nonstructural protein is responsible for cleavage at four sites (3/4A, 4A/4B, 4B/5A, and 5A/5B) in the nonstructural region. NS4A, a 54-residue nonstructural protein which forms a stable complex with the NS3 proteinase, is required as a cofactor for cleavage at the 3/4A and 4B/5A sites and enhances processing at the 4A/4B and 5A/5B sites. Recently reported crystal structures demonstrated that NS4A forms an integral part of the NS3 serine proteinase. In this report, we present evidence that NS4A forms a nonionic-detergent-stable complex with the NS4B5A polyprotein substrate, which may explain the requirement of NS4A for the 4B/5A cleavage. Isoleucine-29 of NS4A, which has been previously shown to be essential for its proteinase cofactor activity and formation of the NS3 complex, was found to be important for the interaction between NS4A and the NS4B5A substrate. In addition, two more hydrophobic residues in the NS4A central region (valine-23 and isoleucine-25) were also shown to be essential for the cofactor activity and for the interaction with either the NS3 proteinase or the NS4B5A polyprotein substrate. Finally, the possible mechanisms by which these viral proteins interact with each other are discussed.

Animals↗
PubMed1997

Role of p38 and JNK mitogen-activated protein kinases in the activation of ternary complex factors.

The transcription factors Elk-1 and SAP-1 bind together with serum response factor to the serum response element present in the c-fos promoter and mediate increased gene expression. The ERK, JNK, and p38 groups of mitogen-activated protein (MAP) kinases phosphorylate and activate Elk-1 in response to a variety of extracellular stimuli. In contrast, SAP-1 is activated by ERK and p38 MAP kinases but not by JNK. The proinflammatory cytokine interleukin-1 (IL-1) activates JNK and p38 MAP kinases and induces the transcriptional activity of Elk-1 and SAP-1. These effects of IL-1 appear to be mediated by Rho family GTPases. To examine the relative roles of the JNK and p38 MAP kinase pathways, we examined the effects of IL-1 on CHO and NIH 3T3 cells. Studies of NIH 3T3 cells demonstrated that both the JNK and p38 MAP kinases are required for IL-1-stimulated Elk-1 transcriptional activity, while only p38 MAP kinase contributes to IL-1-induced activation of SAP-1. In contrast, studies of CHO cells demonstrated that JNK (but not the p38 MAP kinase) is required for IL-1-stimulated Elk-1-dependent gene expression and that neither JNK nor p38 MAP kinase is required for IL-1 signaling to SAP-1. We conclude that (i) distinct MAP kinase signal transduction pathways mediate IL-1 signaling to ternary complex transcription factors (TCFs) in different cell types and (ii) individual TCFs show different responses to the JNK and p38 signaling pathways. The differential utilization of TCF proteins and MAP kinase signaling pathways represents a potential mechanism for the determination of cell-type-specific responses to extracellular stimuli.

3T3 Cells↗
PubMed1997

Relationship between mesial temporal seizure focus and elevated serum prolactin in temporal lobe epilepsy.

We evaluated the relationship between mesial temporal seizure focus and serum prolactin (PRL) in patients before and after they underwent anterior temporal lobectomy (ATL) for medically intractable temporal lobe epilepsy (TLE). These patients had a confirmed unilateral epileptogenic focus in mesial temporal structures, a postictal rise in serum PRL 15 to 20 minutes after onset of complex partial seizures, and were refractory for more than 2 years to antiepileptic drugs. Presurgical interictal serum PRL levels were significantly elevated (16.47 +/- 0.85 ng/mL, n = 62) and declined after ATL to normal values (patients, 9.63 +/- 0.55 ng/mL, n = 54; normal subjects, 8.99 +/- 0.57 ng/mL, n = 52). Serial evaluations indicated that normalization was seen 3 months after surgery (9.42 +/- 1.22 ng/mL, n = 9). The postsurgical reduction in serum PRL was similar in men and women, in patients with epileptogenic focus on either side of mesial temporal structures, and was unaffected by antiepileptic medication. We conclude that PRL is elevated following seizures and that a seizure focus in mesial temporal structures may exert a sustained excitatory influence on PRL release in patients with medically intractable TLE.

Adolescent↗
PubMed1997

Lamotrigine as add-on therapy in adult patients with refractory epilepsy.

BACKGROUND: Lamotrigine (LTG), one of the newly developed antiepileptic drugs, is efficacious in treating both partial and generalized seizure disorders including Lennox-Gastaut syndrome. Its effect as an add-on therapy was evaluated in 41 adult Chinese patients with refractory epilepsy. Five of the patients were Lennox-Gastaut syndrome and 36 patients had partial epilepsy. METHODS: We started LTG at 25 mg or 50 mg per day, respectively, depending on whether the patients were simultaneously taking valproate (VPA) or not. Then, LTG was increased in steps to maximal dosage (200 mg or 400 mg per day) within seven weeks and maintained for three months while pre-existing antiepileptic drugs remained unchanged. The efficacy of LTG therapy was assessed by the reduction in the overall seizure frequency. Hematological and biochemical parameters were checked before and after the trial in all patients. RESULTS: In all, 38 patients completed the trial. Twenty-two patients (57.9%) had > or = 50% reduction in seizure frequency, including four patients with Lennox-Gastaut syndrome and 18 patients with partial seizures. Among the patients with partial epilepsy, there was no significant difference in the efficacy of LTG whether the seizures were of temporal or extra-temporal origin (p = 0.577). In addition, the efficacy was not determined by the concomitant use of VPA (p = 0.189). Thirteen patients (31.7%) complained of adverse experiences, usually mild and dose-dependent. LTG had to be discontinued in only two patients (4.9%) due to severe side effects. The change in blood cell counts and biochemistry profiles was not significant in any of the patients. CONCLUSIONS: We conclude that LTG is an efficacious and safe antiepileptic drug for add-on therapy in adult patients with refractory epilepsy.

Adolescent↗
PubMed1996

Crystal structure of p38 mitogen-activated protein kinase.

p38 mitogen-activated protein kinase is activated by environmental stress and cytokines and plays a role in transcriptional regulation and inflammatory responses. The crystal structure of the apo, unphosphorylated form of p38 kinase has been solved at 2.3 A resolution. The fold and topology of p38 is similar to ERK2 (Zhang, F., Strand, A., Robbins, D., Cobb, M. H., and Goldsmith, E. J. (1994) Nature 367, 704-711). The relative orientation of the two domains of p38 kinase is different from that observed in the active form of cAMP-dependent protein kinase. The twist results in a misalignment of the active site of p38, suggesting that the orientation of the domains would have to change before catalysis could proceed. The residues that are phosphorylated upon activation of p38 are located on a surface loop that occupies the peptide binding channel. Occlusion of the active site by the loop, and misalignment of catalytic residues, may account for the low enzymatic activity of unphosphorylated p38 kinase.

Amino Acid Sequence↗
PubMed1996

Processing and activation of CMH-1 by granzyme B.

Granzyme B plays an essential role in cytotoxic T lymphocyte (CTL)-mediated cell killing. Recent studies suggest that granzyme B may exert its effect by cleaving and activating CPP32, a member of the interleukin-1 beta-converting enzyme/Ced-3 family of cysteine proteases. We have examined the processing and activation of CMH-1, a close homologue of CPP32, by granzyme B in vitro. We have found that granzyme B specifically cleaves CMH-1 at Asp198-Ser199 between the p20 and p12 and activates the cysteine protease. Cleavage between p20 and the prosequence of CMH-1 at Asp23-Ala24 is autocatalytic and is not required for CMH-1 activity in vitro. The cleavage and activation of CMH-1 by granzyme B in vitro sugge st that, in addition to CPP32, CMH-1 may also play a role in CTL-mediated cell killing.

Amino Acid Sequence↗
PubMed1996

Identification and characterization of CPP32/Mch2 homolog 1, a novel cysteine protease similar to CPP32.

We have identified and characterized a novel cysteine protease named CMH-1 that is a new member of the interleukin 1 beta converting enzyme (ICE) family of proteases with substrate specificity for Asp-X. CMH-1 has the highest similarity to CPP32 (52% amino acid identity) and MCH2 (31% identical). CMH-1 shares conserved amino acid residues that form the core structure of ICE as well as those residues involved in catalysis and in the P1 aspartate binding. Overexpression of CMH-1 in COS cells resulted in the processing of CMH-1 and the induction of apoptosis of transfected cells. Coexpression of CMH-1 with poly(ADP-ribose) polymerase (PARP) also resulted in a specific cleavage of PARP. Purified recombinant CMH-1 cleaved PARP but not interleukin 1 beta precursor in vitro.

Amino Acid Sequence↗
PubMed1996

Dynamic NMR studies of ligand-receptor interactions: design and analysis of a rapidly exchanging complex of FKBP-12/FK506 with a 24 kDa calcineurin fragment.

Dynamic NMR methods, such as differential line broadening and transferred NOE spectroscopy, are normally reserved for the study of small molecule ligand interactions with large protein receptors. Using a combination of isotope labeling and isotope edited NMR, we have extended these techniques to characterize interactions of a much larger protein/drug complex, FKBP-12/ FK506 with its receptor protein, calcineurin. In order to examine this multicomponent system by dynamic NMR methods, the 93 kDa, tightly bound FKBP-12/FK506/Cn complex was replaced with a lower affinity, rapidly exchanging system consisting of FKBP-12/FK506 (13 kDa), recombinant calcineurin subunit B (CnB) (20 kDa), and a synthetic peptide (4 kDa) corresponding to the B binding domain (BBD) of calcineurin catalytic subunit A (CnA). Analysis of 1H-13C HSQC data acquired for the FKBP-12/ 13C-FK506 and FKBP-12/13C-FK506/CnB/BBD complexes indicates that FKBP-12/FK506 and CnB/BBD are in fast exchange in the quaternary complex. Comparison of proton line widths shows significant broadening of resonances along the macrocycle backbone at 13-CH, 13-OMe, 15-OMe, 18-CH2, 20-CH, 21-CH, and 25-Me, as well as moderate broadening on the macrocycle backbone at 17-Me, 24-CH, and the pyranose 12-CH2 protons. The tri-substituted olefin and cyclohexyl groups also show moderate broadening at the 27-Me, 28-CH, and 30-CH2 positions, respectively. Unexpectedly, little line broadening was observed for the allyl resonances of FK506 in the quaternary complex, although 13C longitudinal relaxation measurements suggest this group also makes contacts with calcineurin. In addition, intermolecular transfer NOE peaks were observed for the allyl 37-CH2, 21-CH, 30-CH2, 13-OMe, 15-OMe, 17-Me, 25-Me, and 27-Me groups, indicating that these are potential sites on the FK506 molecule that interact with calcineurin.

Amino Acid Sequence↗
PubMed1996

Ictal speech manifestations in temporal lobe epilepsy: a video-EEG study.

To evaluate ictal speech manifestations in complex partial seizures (C PS), we reviewed videotapes of 68 consecutive patients who underwent anterior temporal lobectomy (ATL) for treatment of intractable epilepsy in Taiwan. In all, 261 CPS were collected from their video-EEG (VEEG) recordings. Cerebral speech dominance was determined by intracarotid injection of sodium amobarbital (Wada test) in all cases. Ictal speech manifestations, classified as verbalization or vocalization, occurred in 32 patients (47.1%) with 96 seizures (36.8%). Ictal verbalization occurred in 10 patients (14.7%). Ictal vocalization was observed in 28 patients (41.2%); including 6 patients who also had ictal verbalization. Thirty-six patients (52.9%) had no seizure with ictal speech manifestations. Ictal verbalization had significant lateralization value: 90% of patients with this manifestation had seizure focus in the nondominant temporal lobe (p = 0.049). Seizures of patients with ictal vocalization were not more likely to arise from either temporal lobe. We also observed bilingual patients who exclusively spoke in their mother tongue (Taiwanese) rather than the acquired language (Mandarin) in 72.2% of seizures with verbalization. This finding is significant and contrary to a commonly held notion that the acquired language is used in seizures associated with speech behaviors.

Adolescent↗
PubMed1995

Cleavage of poly(ADP-ribose) polymerase by interleukin-1 beta converting enzyme and its homologs TX and Nedd-2.

The proteolytic cleavage of poly(ADP-ribose) polymerase (PARP) is an early biochemical event, which occurs during apoptosis. A recent study suggested that PARP cleavage can be mediated by a novel cytosolic protease (prICE) that resembles interleukin-1 beta converting enzyme (ICE), but cannot be mediated by ICE itself (Lazebnik, Y.A., Kaufmann, S.H., Desnoyers, S., Poirier, G.G., and Earnshaw, W.C. (1994) Nature 371, 346-347). We have used a COS cell co-transfection assay to investigate if ICE or any known ICE-like protease is active in PARP cleavage within the cell. Here we report that co-expression of human PARP with human ICE, or the ICE homologs TX and Nedd-2, resulted in a cleavage of PARP identical to that observed in apoptotic cells. Experiments with purified recombinant human ICE indicated that PARP polypeptide can be specifically cleaved in vitro by ICE in a time- and enzyme concentration-dependent manner. PARP cleavage, however, requires a 50-100-fold higher ICE concentration than does processing of the interleukin-1 beta precursor at an equivalent substrate concentration. The abilities of ICE, TX, and Nedd-2, when expressed at high intracellular concentrations, to cleave PARP are consistent with their induction of apoptosis in transfected cells.

Amino Acid Sequence↗
PubMed1995

Interaction of FKBP12-FK506 with calcineurin A at the B subunit-binding domain.

Calcineurin is a calcium-dependent protein phosphatase that plays a pivotal role in antigen-stimulated T cell activation. The complexes formed between the immunosuppressants cyclosporin A and FK506 and their respective intracellular binding proteins (immunophilins) block T cell activation by binding to calcineurin. Recent studies have shown that the immunophilin-immunosuppressant complexes interact with the latch region of the calcineurin B subunit (Milan, D., Griffith, J., Su, M., Price, E. R., and McKeon, F. (1994) Cell 79, 437-447). Mutations in the B subunit-binding domain of the calcineurin A subunit result in a reduction of calcineurin activity that correlates with B binding affinity. Calcineurin A subunit mutants D348A, F350A, W352A, S353A, and E359A lost greater than 90% of their activity to activate the transcription factor NF kappa B in Jurkat T cells. Furthermore, calcineurin A subunit mutants of residues Thr351, Leu354, and Lys360 showed NF kappa B transactivation activity and phosphatase activity with increased resistance to FKBP12-FK506 but displayed no or minimal increase in resistance for cyclosporin A inhibition. Together, these results strongly suggest that the B subunit-binding domain is required for calcineurin activity intracellulary and interacts with the FKBP12-FK506 complex.

Amino Acid Sequence↗
PubMed1995

Interleukin-1 beta converting enzyme requires oligomerization for activity of processed forms in vivo.

Interleukin-1 beta converting enzyme (ICE) is composed of 10' (p10) and 20 kDa (p20) subunits, which are derived from a common 45 kDa precursor. Recent crystallographic studies have shown that ICE exists as a tetramer (p20/p10)2 in the crystal lattice. We provide evidence that the p10 and p20 subunits of ICE associate as oligomers in transfected COS cells. Using intragenic complementation, we show that the activity of a p10/p10 interface mutant defective in autoprocessing can be restored by co-expression with active site ICE mutants. Different active site mutants can also complement each other by oligomerization to form active ICE. These studies indicate that ICE precursor polypeptides may associate in different quaternary structures and that oligomerization is required for autoprocessing. Furthermore, integenic complementation of active site mutants of ICE and an ICE homolog restores autoprocessing activity, suggesting that hetero-oligomerization occurs between ICE homologs.

Amino Acid Sequence↗
PubMed1995

Altered cytokine export and apoptosis in mice deficient in interleukin-1 beta converting enzyme.

The interleukin-1 beta (IL-1 beta) converting enzyme (ICE) processes the inactive IL-1 beta precursor to the proinflammatory cytokine. Adherent monocytes from mice harboring a disrupted ICE gene (ICE-/-) did not export IL-1 beta or interleukin-1 alpha (IL-1 alpha) after stimulation with lipopolysaccharide. Export of tumor necrosis factor-alpha and interleukin-6 (IL-6) from these cells was also diminished. Thymocytes from ICE-/- mice were sensitive to apoptosis induced by dexamethasone or ionizing radiation, but were resistant to apoptosis induced by Fas antibody. Despite this defect in apoptosis, ICE-/- mice proceed normally through development.

Amino Acid Sequence↗
PubMed1995

Effect of postischemic reperfusion on microcirculation and lipid metabolism of skeletal muscle.

To study the effect of ischemia reperfusion injury on microvascular reactivity and tissue metabolism in skeletal muscle, a Sprague-Dawley rat cremaster muscle was prepared as a tourniquet ischemia model and subjected to 2 hr ischemia followed by 1 hr reperfusion to simulate the timing of ischemia during microvascular surgery. The dose-response curve of arteriolar reactivity to norepinephrine, lipid peroxidation, and ultrastructure of capillaries was determined in both the control and postischemic reperfusion stages. Judging from the results, we summarize our observations as follows: (1) Postischemic reperfusion significantly increased arteriolar reactivity to norepinephrine, in which the EC50 for vasoconstriction decreased in all three orders of arterioles. These results suggest that reperfusion could have impaired the vasodilation control mechanism, possibly being endothelium dependent. (2) Lipid peroxidation increased sixfold in the reperfusion group, suggesting that oxygen free radicals have produced significant tissue damage under the created conditions. (3) Significant endothelial damage in the capillaries shown by electron microscope observation supports these studies, indicating that ischemia/reperfusion in clinically transplanted skeletal muscles could cause significant damage to the tissue microcirculation both physiologically and metabolically.

Animals↗
PubMed1995

Hypothalamic hamartoma and gelastic epilepsy: a case report.

We studied a 6-year-old girl who presented with inappropriate and uncontrollable laughing episodes since age 3. Physical examination revealed a precocious puberty. The luteinizing hormone-releasing hormone (LH-RH) stimulation test showed an increased level of follicle-stimulating hormone (FSH). The interictal electroencephalogram (EEG) was normal. Several laughing fits were documented during video/EEG monitoring. During laughing, the ictal EEG showed a diffuse suppression of background rhythm, prominent over the left mesial temporal region. A mass lesion about 2 x 2 cm in size was found over the suprasellar cistern with a broad base attached to the hypothalamus, which was isodense on a computed tomography (CT) scan, isointense to gray matter on T1-weighted magnetic resonance (MR) imaging and hyperintense on T2-weighted MR imaging. The findings were suggestive of a hypothalamic hamartoma. A variety of anticonvulsants had been used with little or no response to the frequency or duration of the laughing seizures.

Child↗
PubMed1995

Startle epilepsy presenting as drop attacks: a case report.

A case of startle epilepsy, induced by an unexpected touch on the left shoulder of a 3.5 year old boy, was investigated. The startle epilepsy manifested as an atonic drop attack. Neurological examination revealed a mild hemiparesis on the left side. Computed tomography (CT) scanning demonstrated an enhancement over the right parieto-frontal region, suggesting a hemangioma. Interictal electroencephalography (EEG) showed diffuse slowing and asymmetry of background activities with lower amplitude over the right centro-parieto-temporal region. The ictal EEG showed a paroxysmal bilaterally synchronized high amplitude single spike followed by a few slow waves lasting about one second over the bilateral centro-parieto-temporal regions. The seizure resisted anticonvulsant therapy and no significant responses were observed despite the use of combined therapy with valproic acid, phenytoin, primidone and clonazepam.

Child, Preschool↗
PubMed1994

Frequency and characteristics of early seizures in Chinese acute stroke.

We retrospectively studied 1200 hospitalized acute strokes of all etiologies between July 1990 and August 1992. Ninety-six % of all strokes underwent computed tomography of the head. Fifty-eight percent of the 1200 strokes were brain infarction, 32% brain hemorrhage, 6% subarachnoid hemorrhage and 4% were other stroke subtypes. Thirty (2.5%) of all strokes suffered from early seizures. The incidences of early seizures were 2.8% in brain hemorrhage, 2.3% in brain infarction, 2.7% in subarachnoid hemorrhage and 2% in other stroke subtypes. Early seizures were documented in 6% of the patients with carotid territory cortical infarctions and 12% of the patients with lobar hemorrhage, whereas only 0.6% of the patients without carotid territory cortical infarctions and 0.6% of the patients without lobar hemorrhage were affected. Sixty-six percent of 30 early seizures were partial seizures, 24% generalized and status epilepticus were seen only in 10%. In conclusion, we found the early seizure incidence was 2.5% in Chinese patients hospitalized with acute strokes. There was no correlation between seizure occurrence and stroke subtypes. Early seizure developed significantly higher in acute stroke patients with lesions of the cortex than those patients without cortical involvement. The partial seizures were the most frequent type occurring in 66% of all acute stroke patients with early seizures.

Acute Disease↗