J.G.S. Won

Taipei Veterans General Hospital, T’ai-pei, Taipei, Taiwan

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Publications (13)28.86 Total impact

  • Source
    V S Fang · C C Juan · YP Hsu · J.G.S. Won · L T Ho
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    ABSTRACT: The effect of vasoactive intestinal peptide (VIP) on cortisol production was studied in a primary culture enriched with guinea pig Zona Fasciculata (ZF) cells. In ZF cells, VIP stimulates cortisol secretion and enhances the steroidogenic action of ACTH. Compared to ACTH on an equal molar basis, the cortisol-stimulatory effect of VIP is at least 10-fold less potent. As VIP exhibits a wide range of biological actions with widespread distribution in the body, the steroidogenic action of VIP on the adrenal glands is not tissue-specific. There are VIP receptors in ZF cells. With the aid of a VIP receptor antagonist, we found that ACTH and VIP mutually bind each other's receptors with an affinity-ranking order of ACTH > VIP receptor antagonist > VIP. VIP stimulates cortisol production most likely through the cyclic AMP (cAMP) signaling pathway. Both ACTH receptors and the VIP receptors bind VIP receptor antagonist more avidly than VIP, but the bindings do not lead to a consequential effect on cAMP production and cortisol secretion. However, the VIP receptor antagonist counteracted ACTH and VIP to lower both cAMP and cortisol production. In addition, ASIF and BNP-32, which are the proven ACTH receptor antagonists, reduced the cortisol-stimulatory effect of ACTH and VIP. These results suggest that besides ACTH, VIP be an important factor in regulating the cortisol secretion from the adrenal cortex at the site of ACTH receptors. In cases with hypercortisolemia being detected concomitantly with normal or low ACTH levels, we may need to investigate the influential role of VIP.
    Full-text · Article · Jun 2001 · The Chinese journal of physiology
  • Source
    V S Fang · C C Juan · J. G. S. Won · L T Ho
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    ABSTRACT: The suppressive effect of aldosterone secretion-inhibitory factor (ASIF) and brain natriuretic peptide (BNP-32) on the basal and ACTH-stimulated cortisol production in a primary culture enriched with guinea pig Zona Fasciculata (ZF) cells was further studied. The binding of 125I-labeled ACTH(1-24) and ASIF to ZF cells was found to be displaced by ACTH(1-24), [Phe2, Nle4 and Ala24]-ACTH(1-24), ASIF, and BNP in a concentration-dependent manner. The binding of 125I-labeled [Phe2, Nle4 and Ala24]-ACTH(1-24) to two transformed clones of mammalian cells expressing the guinea pig ACTH receptor was also competitively inhibited by ASIF and BNP. ASIF and BNP significantly suppressed ACTH-stimulated cAMP production in ZF cells. The 10- and 30-min cellular changes in cAMP induced by ASIF and BNP did not correlate in the rank order with the ultimate magnitude of cortisol suppression observed in ZF cells after a 24-hour treatment with these peptides. Nevertheless, the results did conform to the signaling mechanism of their action. Overall, the findings clearly demonstrated that ASIF and BNP suppressed the adrenocortical function and inhibited ACTH for their antagonistic action against ACTH primarily at the ACTH receptor site. These results support the notion that a physiological role of adrenal medulla in regulating the adrenocortical function may be mediated by the neuropeptides through a paracrine pathway.
    Full-text · Article · Jan 2001 · The Chinese journal of physiology
  • S Y Lin · T Kao · J.G.-S. Won · K T Tang · H D Lin
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    ABSTRACT: Hürthle cell neoplasm of the thyroid gland is rarely associated with tumor necrosis. We report a case of Hürthle cell carcinoma of the thyroid gland with extensive necrosis. An 82-year-old man had had a right neck mass for more than 10 years. Approximately two to three weeks before he was hospitalized, this neck mass became progressively enlarged. An 131I scan could not demonstrate the right lobe of the thyroid gland, while the contralateral lobe was unremarkable. A 99mTc-sestamibi scan showed increased uptake on the lesion side. Fine needle aspiration cytology showed necrosis with macrophages in the initial aspirate, and the secondary aspirate appeared suspicious for a Hürthle cell tumor. The patient had a total thyroidectomy, and the pathology proved to be Hürthle cell carcinoma with tumor necrosis.
    No preview · Article · Mar 1999 · Zhonghua yi xue za zhi = Chinese medical journal; Free China ed
  • S Y Lin · C L Chang · T S Jap · H D Lin · J.G.-S. Won
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    ABSTRACT: Genitourinary tuberculosis (TB) rarely involves the adrenal gland. A 67-year-old man presented with progressively hyperpigmented skin and an enlarged mass over both testes. Early morning plasma cortisol concentration was low and adrenocorticotropic hormone (ACTH) concentration was high. A rapid ACTH stimulation test revealed the absence of plasma cortisol response and confirmed a diagnosis of primary adrenocortical insufficiency. An abdomen computed tomography (CT) scan disclosed enlargement of the right adrenal gland and punctuate calcification over the left one. This is compatible with tuberculous adrenalitis. Currettage biopsy of the prostate demonstrated chronic granulomatous inflammation with Langerhan's giant cells, but without TB bacilli. Anti-TB treatment, in addition to glucocorticoid and mineralocorticoid replacement, was administered. The testicular mass decreased progressively though the results of a subsequent ACTH stimulation test, six months later, disclosed no significant change. A follow-up CT scan, one and a half years later, showed a decrease in the size of the right adrenal mass.
    No preview · Article · Apr 1998 · Zhonghua yi xue za zhi = Chinese medical journal; Free China ed
  • W L Lee · J.G.S. Won · J H Chiang · J I Hwang · C H Lee · S H Tsay
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    ABSTRACT: A 69-year-old man with recurrent hypoglycaemia had inappropriately elevated plasma insulin level during a symptomatic hypoglycaemia, but had a negative prolonged fast. Computerized tomography (CT) of the abdomen revealed a nodular lesion over the body of pancreas, whereas pancreatic arteriography failed to show tumour blush. Hence, arterial stimulation (with calcium) and venous sampling (ASVS) was performed and a brisk response of plasma insulin level was found when calcium was injected both into the splenic and the superior mesenteric arteries. Since no tumour was found during the operation, the patient received subtotal distal pancreatectomy. Pathological examination of the resected tissue disclosed a typical finding of nesidioblastosis. We suggest that selective intra-arterial calcium injection with hepatic venous sampling for insulin gradients is useful for the diagnosis of adult nesidioblastosis.
    No preview · Article · Nov 1997 · Diabetic Medicine
  • J. G. S. Won · D N Orth
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    ABSTRACT: Intracellular Ca2+ (Cai2+) stores contribute significantly to Ca2+ signaling in many types of cells. We studied the role of inositol trisphosphate (InsP3)-sensitive Ca2+ stores, a principal Cai2+ store that presumably is within the endoplasmic reticulum (ER), in cell signaling by examining the effect of thapsigargin (Tg), an ER Ca2+ pump inhibitor that depletes the ER Ca2+ pool, on ACTH secretion. Preincubation for 6-24 h with 2-20 nM Tg had no effect on the resting cytosolic free Ca2+ concentrations ([Cai2+]) but inhibited the ionomycin-stimulated spike-type increase in [Cai2+], which is mediated by InsP3-independent Cai2+ release from the ER, in a dose-dependent (IC50, 4 nM) and time-dependent manner. In ER Cai(2+)-depleted cells, the spike phase (initial 5 min) of the ACTH secretory response to arginine vasopressin (AVP), which is mediated by InsP3-induced Cai2+ release, was also attenuated (IC50, 7.3 nM). However, the spike phase of the ACTH secretory response to AVP was inhibited to a much greater degree than the spike-type response to ionomycin, suggesting that ER Cai2+ stores might have functions other than simply providing Ca2+ for InsP3-stimulated Cai2+ release. Tg pretreatment (IC50, 12 nM) also markedly inhibited the sustained plateau (final 15-min) phase of the ACTH secretory response to AVP, which is mediated by diacylglycerol-induced activation of protein kinase C and subsequent influx of extracellular Ca2+ via L-type voltage-sensitive Ca2+ channels (VSCC), but had no effect on the sustained (full 20 min) response to dioctanoylglycerol that directly activates protein kinase C. Tg had no effect on specific cell binding of [125I]AVP or on specific cell binding of [3H]phorbol 12,13-dibutyrate (except at 20 nM Tg), an index of protein kinase C concentration, or on protein kinase C activity. AVP significantly stimulated inositol trisphosphate accumulation, but pretreatment with Tg completely abolished this effect of AVP, whereas [3H]myoinositol incorporation into membrane-associated inositol lipids and inositol phosphates was unaffected. Thus, Tg-induced depletion of ER Cai2+ stores inhibited both the spike and plateau phases of the ACTH secretory response to AVP, presumably by inhibiting phospholipase C activity and the resulting generation of InsP3 and diacylglycerol. Preincubation with Tg inhibited, in a dose-dependent (IC50, 13 nM) and time-dependent manner, the sustained ACTH secretory response to corticotropin-releasing hormone (CRH) that is mediated by cAMP-induced activation of protein kinase A and Cae2+ influx via L-type VSCC, and the sustained response to forskolin, which directly activates adenylate cyclase.(ABSTRACT TRUNCATED AT 400 WORDS)
    No preview · Article · Mar 1996 · Endocrinology
  • J.G.S. Won · D N Orth
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    ABSTRACT: Arachidonic acid metabolites have been implicated in the regulation of ACTH secretion. To define further which eicosanoid(s) is primarily involved, we examined the effects of both inhibitors of the three arachidonate metabolic pathways (cyclooxygenase, lipoxygenase, and epoxygenase) and specific eicosanoid products on ACTH secretion by rat pituitary corticotrophs in a microperifusion system. CRF stimulates sustained ACTH release that is mediated by protein kinase-A-induced extracellular Ca2+ (Cae2+) influx via L-type voltage-sensitive calcium channels (VSCC). Arginine vasopressin (AVP) stimulates an initial spike phase of ACTH release that presumably is mediated by inositol 1,4,5-trisphosphate-induced intracellular Ca2+ (Cai2+) release, followed by a sustained plateau phase of ACTH release that is mediated by protein kinase-C-induced Cae2+ influx via L-type VSCC. Pretreatment for 15 min with the lipoxygenase inhibitor nordihydroguaiaretic acid (NDGA; 50 microM), but not the cyclooxygenase inhibitor indomethacin (10 microM) or the epoxygenase inhibitor SKF525A (100 microM) inhibited the sustained response to CRF by 48% and the initial spike response to AVP by 38%. NDGA-induced inhibition was not reversed by indomethacin or SKF525A, alone or in combination, precluding arachidonate shunting into other pathways. However, the results suggested that epoxygenase metabolites may have a minor stimulatory and cyclooxygenase metabolites may have a minor inhibitory effect on ACTH secretion. Preexposure to NDGA suppressed by 43% the sustained response to 8-bromo-cAMP, which directly activates protein kinase-A; by 57% the sustained response to dioctanolglycerol, which directly activates protein kinase-C; and by 59% the spike-type response to ionomycin, which releases Cai2+ by an inositol 1,4,5-trisphosphate-independent mechanism. These results suggest that NDGA either inhibits the production of a lipoxygenase metabolite involved in Cae2+ influx and/or Cai2+ release or acts other than by inhibiting lipoxygenase, such as by directly blocking membrane transport of Cae2+. The three major lipoxygenase metabolites tested, 5(S)-, 12(S)-, and 15(S)-hydroxyeicosatetraenoic acid (HETE), all stimulated sustained ACTH release in a dose-dependent manner. At a concentration of 2 microM, 12(S)-HETE was 4.7 and 2.5 times more potent than 5(S)- and 15(S)-HETE, respectively, and completely reversed NDGA inhibition of both CRF- and AVP-stimulated ACTH secretion. The ACTH-releasing activity of 12(S)-HETE was inhibited 26% by removing Cae2+ and 54% by both removing Cae2+ and depleting Cai2+, indicating either that 12(S)-HETE facilitates transmembrane Ca2+ transfer or that increased cytosolic Ca2+ is necessary for 12(S)-HETE's action.(ABSTRACT TRUNCATED AT 400 WORDS)
    No preview · Article · Nov 1994 · Endocrinology
  • J.G.S. Won · W E Nicholson · K N Ching · D N Orth
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    ABSTRACT: We studied the effect of Ca2+/phospholipid-dependent protein kinase-C (protein kinase-C) down-regulation by chronic exposure to phorbol 12-myristate 13-acetate (PMA) on ACTH secretion by dispersed male rat anterior pituitary cells in a microperifusion system. Preincubation for 24 h and preperifusion for 3 h with 0.1 and 1 microM PMA significantly inhibited (by 85% and 91%, respectively) the specific cell binding of [3H]phorbol 12,13-dibutyrate, an index of protein kinase-C concentration, and significantly reduced (by 101% and 20%, respectively) the sustained plateau (final 15-min) phase of the ACTH response to arginine vasopressin (AVP) and (by 56% and 54%, respectively) the sustained (full 20-min) response to dioctanoylglycerol (DOG), both of which are mediated by protein kinase-C activation. In contrast, the spike (initial 5-min) phase of the response to AVP, which is mediated by intracellular Ca2+ release from inositol 1,4,5-trisphosphate (InsP3)-sensitive stores, was significantly increased (by 112% and 99%, respectively), but the spike-type response to ionomycin, which releases intracellular Ca2+ by an InsP3-independent mechanism, was unaffected. AVP significantly stimulated inositol bisphosphate and InsP3, but not inositol monophosphate, accumulation, and PMA pretreatment significantly enhanced their AVP-stimulated accumulation (by 86%, 34%, and 78%, respectively), an effect that was abolished by simultaneous preperifusion with PMA and cycloheximide to inhibit new protein synthesis. Enhancement of the spike phase response to AVP and AVP-stimulated InsP3 accumulation were lost within 1 h of PMA removal, but [3H]phorbol 12,13-dibutyrate binding and the sustained responses to AVP and DOG remained suppressed after 3 h. Pretreatment with 0.1 and 1 microM PMA slightly reduced the sustained responses to CRF (by 29% and 16%, respectively) and 8-bromo-cAMP (by 8% and 12%, respectively), which are mediated by protein kinase-A activation and extracellular Ca2+ influx via L-type voltage-sensitive Ca2+ channels, but not the response to KCl, which is mediated by extracellular Ca2+ influx via all types of voltage-sensitive Ca2+ channels. The sustained response to CRF was still suppressed 1 h after PMA removal, but returned to the control level by 3 h. When new protein synthesis was inhibited by preperifusion with cycloheximide alone for 3 h after 24-h PMA pretreatment, recovery from the effects of PMA was abolished. Three-hour exposure to cycloheximide without PMA pretreatment inhibited the sustained responses to CRF, AVP, and DOG, but not the spite response to AVP.(ABSTRACT TRUNCATED AT 400 WORDS)
    No preview · Article · Oct 1993 · Endocrinology
  • T C Chang · T S Jap · C F Kwok · J.G.S. Won · L T Ho
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    ABSTRACT: To examine the effect of steroid therapy on insulin antibody titer in insulin-dependent diabetes mellitus, we studied a 58 year-old gentleman with recurrent diabetic ketoacidosis. No any overt precipitating factors could be accounted for, except limited pancreatic beta cell reserve and high titers of anti insulin antibodies. Despite the persistence of high titers of plasma antiinsulin antibodies, the clinical manifestations of diabetic ketoacidosis improved greatly by the administration of steroid. Nevertheless, the patient still showed the great excursion of plasma glucose concentration.
    No preview · Article · Mar 1990 · Zhonghua yi xue za zhi = Chinese medical journal; Free China ed
  • T S Jap · L T Ho · J. G. S. Won
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    ABSTRACT: To examine the effect of hyperthyroidism on carbohydrate metabolism, we studied glucose-stimulated insulin secretion and glucose utilization in 8 subjects with Graves' disease before and after treatment for hyperthyroidism and 8 age-, sex- and weight-matched normal subjects. Subjects with Graves' disease had significant elevated serum levels of thyroxine (24.81 +/- 2.44 micrograms/dl, mean +/- SEM) and triiodothyronine (459 +/- 5.5 ng/dl, mean +/- SEM). Simultaneous measurement of plasma glucose, serum insulin and C-peptide levels during fasting and every 30 minutes up to 180 minutes after 75 g oral glucose loading was determined. In addition, plasma glucose, serum insulin and serum C-peptide were measured during euglycemic glucose clamp with insulin infusion of 40 mU/m2 min-1. Mean fasting plasma glucose (P less than 0.05, serum insulin (P less than 0.005) and serum C-peptide (P less than 0.005) levels were significantly higher in the hyperthyroid patients. After glucose loading, the plasma glucose (P less than 0.05), serum insulin (P less than 0.05) and C-peptide (P less than 0.05) responses were significantly higher in hyperthyroid patients at all times up to 180 minutes. During euglycemic clamp studies, the steady-state serum insulin levels were identical in the two groups. The glucose disposal rate was lower in hyperthyroid patients before treatment (P less than 0.01) than in normal subjects. After thyroid function had been normalized for 2 to 4 weeks, the glucose disposal rate increased significantly (P less than 0.05), but was still significantly lower than those of normal subjects (P less than 0.05). Our data show that patients with Graves' hyperthyroidism manifest glucose intolerance, hyperinsulinemia and insulin resistance.
    No preview · Article · Jun 1989 · Hormone and Metabolic Research
  • Justin G.S. Won · T.S. Jap · K.N. Ching · Benjamin N. Chiang
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    ABSTRACT: We recently demonstrated the presence of a delayed phase of glucocorticoid feedback on nonstress-induced ACTH secretion in normal volunteers. In this study, we investigate the effects of corticotropin-releasing factor (CRF) on that delayed feedback pathway with an attempt to determine the sites on which glucocorticoid exerts its delayed feedback effects. Thirty normal subjects were subjected to study and each subject received a single midnight dosage of 30 mg/kg BW metyrapone before each test. The whole experiment was divided into two studies. In study I, we found that ovine CRF (oCRF) 1 microgram/kg BW alone as an IV bolus injection caused an increase in the plasma ACTH level, which persisted for at least 120 minutes. Continuous infusion of cortisol 25 mg/h alone for two hours produced a significant decrease in the plasma ACTH level; this fall of ACTH began 30 minutes after the onset of cortisol administration. When IV bolus injection of oCRF 1 microgram/kg BW and the continuous infusion of cortisol 25 mg/h for two hours were both given, the plasma ACTH level increased firstly and then decreased 60 minutes after the onset of cortisol administration, progressing thereafter to the end of the study. Study II showed in those who received the IV bolus injection of human CRF (hCRF) 100 micrograms and the continuous infusion of cortisol 25 mg/h for two hours, the plasma ACTH level increased firstly and began to decline 45 minutes after the onset of cortisol administration, progressing thereafter to the end of the test.(ABSTRACT TRUNCATED AT 250 WORDS)
    No preview · Article · Nov 1987 · Metabolism
  • F Y Lee · J G Won · K J Hsiao · K N Ching

    No preview · Article · May 1987 · Taiwan yi xue hui za zhi. Journal of the Formosan Medical Association
  • Justin G.S. Won · T.S. Jap · S.C. Chang · K.N. Ching · Benjamin N. Chiang
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    ABSTRACT: To investigate the mechanisms responsible for glucocorticoid feedback on nonstress-induced ACTH secretion in normal subjects, 24 volunteer subjects (14 males and 10 females, 21 to 43 years) were divided into six groups in a randomized fashion and studied. Each subject received a single midnight dose of 30 mg/kg per body weight of metyrapone and then cortisol was administered according to different protocols in the next morning to provide extreme variations of the input signal. It was found that no obvious inhibition in plasma ACTH levels was shown during the first 15 min despite the fact that cortisol was given at rather larger doses and short time intervals. However, a significant suppression in plasma ACTH levels began to manifest approximately 30 min after cortisol administration in each study group and it became apparent that the degree of inhibition of ACTH level at 75 min correlated with the plasma cortisol concentrations at the same moment (r = 0.97, P less than 0.01) as well as with the dosage of cortisol during this time, whatever administered (r = 0.99, P less than 0.01). In summary, our data provided evidence for a delayed, proportional, and integral phase of glucocorticoid feedback on nonstress-induced ACTH secretion in normal human volunteers.
    No preview · Article · Apr 1986 · Metabolism

Publication Stats

121 Citations
28.86 Total Impact Points

Institutions

  • 1986-2001
    • Taipei Veterans General Hospital
      • Department of Medicine
      T’ai-pei, Taipei, Taiwan
  • 1997
    • National Yang Ming University
      • School of Medicine
      T’ai-pei, Taipei, Taiwan
  • 1996
    • Vanderbilt University
      • Department of Medicine
      Нашвилл, Michigan, United States