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Articles by H. J Park
Total Records ( 8 ) for H. J Park
  Y. S Kim , H. J Park , T. K Kim , D. E Moon and H. J. Lee

BACKGROUND: Neuropathic pain is chronic pain that is caused by an injury to the peripheral or central nervous system. The symptoms of neuropathic pain are continuing pain, hyperalgesia, and allodynia. Ginkgo biloba extract is an oriental herbal medicine that has various pharmacological actions. We examined the effect of Ginkgo biloba extract, EGb 761, on the mechanical and cold allodynia in a rat model of neuropathic pain.

METHODS: Male Sprague-Dawley rats were prepared by tightly ligating the left L5 and L6 spinal nerves. All the rats developed mechanical and cold allodynia 7 days after surgery. Fifty neuropathic rats were assigned into five groups for the intraperitoneal administration of drugs. The study was double-blind and the order of the treatments was randomized. Normal saline and EGb 761 (50, 100, 150, and 200 mg/kg) were administered, respectively, to the individual groups. We examined mechanical and cold allodynia at preadministration and at 15, 30, 60, 90, 120, 150, and 180 min after intraperitoneal drug administration. Mechanical allodynia was quantified by measuring the paw withdrawal threshold to stimuli with von Frey filaments of 1.0, 1.4, 2.0, 4.0, 6.0, 8.0, 10.0, 12.0, 15.0, and 26.0 g. Cold allodynia was quantified by measuring the frequency of foot lift with applying 100% acetone. We measured the locomotor function of the neuropathic rats by using the rotarod test to reveal if EGb 761 has side effects, such as sedation or reduced motor coordination.

RESULTS: The control group showed no differences for mechanical and cold allodynia. For the EGb 761 groups, the paw withdrawal thresholds to mechanical stimuli and withdrawal frequencies to cold stimuli were significantly reduced versus the preadministration values and versus the control group. The duration of antiallodynic effects increased in a dose-dependent fashion, and these were maintained for 120 min at the highest dose (P < 0.05). Only at the highest dose (200 mg/kg) did EGb 761 reduce the rotarod performance time.

CONCLUSION: We conclude that Ginkgo biloba extract, EGb 761, attenuates mechanical and cold allodynia in a rat model of neuropathic pain, and it may be useful for the management of neuropathic pain.

  S. K Park , Y. S Hwang , K. K Park , H. J Park , J. Y Seo and W. Y. Chung

Induction of matrix metalloproteinase (MMP)-9 is particularly important for the invasiveness of breast cancers. We investigated the inhibitory effect of kalopanaxsaponin A (KPS-A) on cell invasion and MMP-9 activation in phorbol 12-myristate 13-acetate (PMA)-treated MCF-7 human breast cancer cells. KPS-A inhibited PMA-induced cell proliferation and invasion. PMA-induced cell invasion was blocked in the presence of a primary antibody of MMP-9, and KPS-A suppressed the increased expression and/or secretion of MMP-9 and tissue inhibitor of metalloproteinase (TIMP)-1. Using specific inhibitors, we confirmed that PMA-induced cell invasion and MMP-9 expression is primarily regulated by nuclear factor-kappa B (NF-B) activation via phosphatidylinositol 3-kinase (PI3K)/Akt and activator protein-1 (AP-1) activation via extracellular signal-regulated kinase (ERK)1/2. KPS-A decreased PMA-induced transcriptional activation of NF-B and AP-1 and inhibited PMA-induced phosphorylation of ERK1/2 and Akt. Treatment with the protein kinase C (PKC) inhibitor rottlerin caused a marked decrease in PMA-induced MMP-9 secretion and cell invasion, as well as ERK/AP-1 activation, and KPS-A reduced PMA-induced membrane localization of PKC. Furthermore, oral administration of KPS-A led to a substantial decrease in tumor volume and expression of proliferating cell nuclear antigen, MMP-9, TIMP-1 and PKC in mice with MCF-7 breast cancer xenografts in the presence of 17β-estradiol. These results suggest that KPS-A inhibits PMA-induced invasion by reducing MMP-9 activation, mainly via the PI3K/Akt/NF-B and PKC/ERK/AP-1 pathways in MCF-7 cells and blocks tumor growth and MMP-9-mediated invasiveness in mice with breast carcinoma. Therefore, KPS-A may be a promising anti-invasive agent with the advantage of oral dosing.

  H. J Park , Y Zhang , C Du , C. M Welzig , C Madias , M. J Aronovitz , S. P Georgescu , I Naggar , B Wang , Y. B Kim , R. O Blaustein , R. H Karas , R Liao , C. E Mathews and J. B. Galper

Rationale: Diabetic autonomic neuropathy (DAN), a major complication of diabetes mellitus, is characterized, in part, by impaired cardiac parasympathetic responsiveness. Parasympathetic stimulation of the heart involves activation of an acetylcholine-gated K+ current, IKAch, via a (GIRK1)2/(GIRK4)2 K+ channel. Sterol regulatory element binding protein-1 (SREBP-1) is a lipid-sensitive transcription factor.

Objective: We describe a unique SREBP-1–dependent mechanism for insulin regulation of cardiac parasympathetic response in a mouse model for DAN.

Methods and Results: Using implantable EKG transmitters, we demonstrated that compared with wild-type, Ins2Akita type I diabetic mice demonstrated a decrease in the negative chronotropic response to carbamylcholine characterized by a 2.4-fold decrease in the duration of bradycardia, a 52±8% decrease in atrial expression of GIRK1 (P<0.01), and a 31.3±2.1% decrease in SREBP-1 (P<0.05). Whole-cell patch-clamp studies of atrial myocytes from Akita mice exhibited a markedly decreased carbamylcholine stimulation of IKAch with a peak value of –181±31 pA/pF compared with –451±62 pA/pF (P<0.01) in cells from wild-type mice. Western blot analysis of extracts of Akita mice demonstrated that insulin treatment increased the expression of GIRK1, SREBP-1, and IKAch activity in atrial myocytes from these mice to levels in wild-type mice. Insulin treatment of cultured atrial myocytes stimulated GIRK1 expression 2.68±0.12-fold (P<0.01), which was reversed by overexpression of dominant negative SREBP-1. Finally, adenoviral expression of SREBP-1 in Akita atrial myocytes reversed the impaired IKAch to levels in cells from wild-type mice.

Conclusions: These results support a unique molecular mechanism for insulin regulation of GIRK1 expression and parasympathetic response via SREBP-1, which might play a role in the pathogenesis of DAN in response to insulin deficiency in the diabetic heart.

  H. K Lee , M. H Song , M Kang , J. T Lee , K. A Kong , S. J Choi , K. Y Lee , H Venselaar , G Vriend , W. S Lee , H. J Park , T. K Kwon , J Bok and U. K. Kim

X-linked deafness type 3 (DFN3), the most prevalent X-linked form of hereditary deafness, is caused by mutations in the POU3F4 locus, which encodes a member of the POU family of transcription factors. Despite numerous reports on clinical evaluations and genetic analyses describing novel POU3F4 mutations, little is known about how such mutations affect normal functions of the POU3F4 protein and cause inner ear malformations and deafness. Here we describe three novel mutations of the POU3F4 gene and their clinical characterizations in three Korean families carrying deafness segregating at the DFN3 locus. The three mutations cause a substitution (p.Arg329Pro) or a deletion (p.Ser310del) of highly conserved amino acid residues in the POU homeodomain or a truncation that eliminates both DNA-binding domains (p.Ala116fs). In an attempt to better understand the molecular mechanisms underlying their inner ear defects, we examined the behavior of the normal and mutant forms of the POU3F4 protein in C3H/10T1/2 mesodermal cells. Protein modeling as well as in vitro assays demonstrated that these mutations are detrimental to the tertiary structure of the POU3F4 protein and severely affect its ability to bind DNA. All three mutated POU3F4 proteins failed to transactivate expression of a reporter gene. In addition, all three failed to inhibit the transcriptional activity of wild-type proteins when both wild-type and mutant proteins were coexpressed. Since most of the mutations reported for DFN3 thus far are associated with regions that encode the DNA binding domains of POU3F4, our results strongly suggest that the deafness in DFN3 patients is largely due to the null function of POU3F4.

  M Endale , S. D Kim , W. M Lee , S Kim , K Suk , J. Y Cho , H. J Park , Y Wagley , J. W Oh and M. H. Rhee

Regulator of G protein signaling (RGS) family members, such as RGS2, interact with G subunits of heterotrimeric G proteins, accelerating the rate of GTP hydrolysis and attenuating the intracellular signaling triggered by the G protein-coupled receptor-ligand interaction. They are also reported to regulate G protein-effector interactions and form multiprotein signaling complexes. Ischemic stress-induced changes in RGS2 expression have been described in astrocytes, and these changes are associated with intracellular signaling cascades, suggesting that RGS2 upregulation may be an important mechanism by which astrocytes may regulate RGS2 function in response to physiological stress. However, information on the functional roles of stress-induced modulation of RGS2 protein expression in astrocyte function is limited. We report the role of ischemic stress in RGS2 protein expression in rat C6 astrocytoma cells and primary mouse astrocytes. A marked increase in RGS2 occurred after ischemic stress induced by chemicals (sodium azide and 2-deoxyglucose) or oxygen-glucose deprivation (OGD, real ischemia). RGS2 mRNA expression was markedly enhanced by 1 h of exposure to chemical ischemia or 6 h of OGD followed by 2 or 6 h of recovery, respectively. This enhanced expression in primary astrocytes and C6 cells was restored to baseline levels after 12 h of recovery from chemically induced ischemic stress or 4–6 h of recovery from OGD. RGS2 protein was also significantly expressed at 12–24 h of recovery from ischemic insult. Ischemia-induced RGS2 upregulation was associated with enhanced apoptosis. It significantly increased annexin V-positive cells, cleaved caspase-3, and enhanced DNA ladder formation and cell cycle arrest. However, a small interfering RNA (siRNA)-mediated RGS2 knockdown reversed the apoptotic cell death associated with ischemia-induced RGS2 upregulation. Upregulated RGS2 was significantly inhibited by SB-203580, a p38 MAPK inhibitor. Rottlerin, a potent inhibitor of PKC, completely abrogated the increased RGS2 expression. We also examine whether ischemia-induced RGS2-mediated apoptosis is affected by siRNA-targeted endogenous PKC downregulation or its phosphorylation. Although RGS2 upregulation was not affected, siRNA transfection significantly suppressed endogenous PKC mRNA and protein expressions. Ischemia-induced PKC phosphorylation and caspase-3 cleavage were dose dependently inhibited by PKC knockdown, and this endogenous PKC suppression reversed ischemia-induced annexin V-positive cells. This study suggests that ischemic stress increases RGS2 expression and that this condition contributes to enhanced apoptosis in C6 cells and primary astrocytes. The signaling it follows may involve PKC and p38 MAPK pathways.

  H. J Park , I Rajbhandari , H. S Yang , S Lee , D Cucoranu , D. S Cooper , J. D Klein , J. M Sands and I. Choi

The sodium-bicarbonate cotransporter NBCn1 (SLC4A7) is an acid-base transporter that normally moves Na+ and HCO3 into the cell. This membrane protein is sensitive to cellular and systemic pH changes. We examined NBCn1 expression and localization in the brain and its response to chronic metabolic acidosis. Two new NBCn1 antibodies were generated by immunizing a rabbit and a guinea pig. The antibodies stained neurons in a variety of rat brain regions, including hippocampal pyramidal neurons, dentate gyrus granular neurons, posterior cortical neurons, and cerebellar Purkinje neurons. Choroid plexus epithelia were also stained. Double immunofluorescence labeling showed that NBCn1 and the postsynaptic density protein PSD-95 were found in the same hippocampal CA3 neurons and partially colocalized in dendrites. PSD-95 was pulled down from rat brain lysates with the GST/NBCn1 fusion protein and was also coimmunoprecipitated with NBCn1. Chronic metabolic acidosis was induced by feeding rats with normal chow or 0.4 M HCl-containing chow for 7 days. Real-time PCR and immunoblot showed upregulation of NBCn1 mRNA and protein in the hippocampus of acidotic rats. NBCn1 immunostaining was enhanced in CA3 neurons, posterior cortical neurons, and cerebellar granular cells. Intraperitoneal administration of N-methyl-d-aspartate caused neuronal death determined by caspase-3 activity, and this effect was more severe in acidotic rats. Administering N-methyl-d-aspartate also inhibited NBCn1 upregulation in acidotic rats. We conclude that NBCn1 in neurons is upregulated by chronic acid loads, and this upregulation is associated with glutamate excitotoxicity.

  H. S Yang , E Kim , S Lee , H. J Park , D. S Cooper , I Rajbhandari and I. Choi

To understand the mechanism for ion transport through the sodium/bicarbonate transporter SLC4A4 (NBCe1), we examined amino acid residues, within transmembrane domains, that are conserved among electrogenic Na/HCO3 transporters but are substituted with residues at the corresponding site of all electroneutral Na/HCO3 transporters. Point mutants were constructed and expressed in Xenopus oocytes to assess function using two-electrode voltage clamp. Among the mutants, D555E (charge-conserved substitution of the aspartate at position 555 with a glutamate) produced decreasing HCO3 currents at more positive membrane voltages. Immunohistochemistry showed D555E protein expression in oocyte membranes. D555E induced Na/HCO3-dependent pH recovery from a CO2-induced acidification. Current-voltage relationships revealed that D555E produced an outwardly rectifying current in the nominally CO2/HCO3-free solution that was abolished by Cl removal from the bath. In the presence of CO2/HCO3, however, the outward current produced by D555E decreased only slightly after Cl removal. Starting from a Cl-free condition, D555E produced dose-dependent outward currents in response to a series of chloride additions. The D555E-mediated chloride current decreased by 70% in the presence of CO2/HCO3. The substitution of Asp555 with an asparagine also produced a Cl current. Anion selectivity experiments revealed that D555E was broadly permissive to other anions including NO3. Fluorescence measurements of chloride transport were done with human embryonic kidney HEK 293 cells expressing NBCe1 and D555E. A marked increase in chloride transport was detected in cells expressing D555E. We conclude that Asp555 plays a role in HCO3 selectivity.

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