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Benign prostate hyperplasia (BPH) is a common disease in old-age males, accounting for approximately 77% of morbidity within the age range of 40 to 70 years. It has been shown that morbidity increases with social graying. Quisqualis indica linn (QI) has been used to treat inflammation, stomach pain, and digestion problems. In this study, we evaluated the symptom-regulating effects of QI extract on a testosterone-induced BPH rat model. After inducing BPH in rats using testosterone propionate (TP) injection, we assessed basal intraurethral pressure (IUP) and increments of IUP elicited by electrical field stimulation (5 V, 5, 10, or 20 Hz) or phenylephrine (Phe) (0.01, 0.03, 0.1 mg/kg IV). To induce BPH, 8-week-old rats were subjected to a daily subcutaneous TP (3 mg/kg) injection for 4 weeks. Finasteride (Fina) (10 mg/kg PO) was administered to the rats in the first treatment, while QI (150 mg/kg PO) was administered to those in the second group. Blood pressure was measured together with IUP, after which low urinary tract (LUT), ventral prostate (VP), testicle, and corpus spongiosum were isolated and weighed. Basal IUPs for the Fina- and QI-treated groups were 87.6 and 86.8%, respectively. LUT and VP organ weights in the QI group were lower than those in the Fina group. However, the QI group showed significantly reduced electrical stimulated or Phe-induced IUP increment compared to the Fina and BPH groups. These results proved that QI can be beneficial for BPH symptoms by inhibiting 5α-reductase and consequently decreasing prostate and releasing urinary pressure.
Dae-Geon Kim; Hyo-Jeong Kwon; Jong-Hwan Lim; Joo-Heon Kim; Kyu Pil Lee. Quisqualis indica extract ameliorates low urinary tract symptoms in testosterone propionate-induced benign prostatic hyperplasia rats. Laboratory Animal Research 2020, 36, 1 -10.
AMA StyleDae-Geon Kim, Hyo-Jeong Kwon, Jong-Hwan Lim, Joo-Heon Kim, Kyu Pil Lee. Quisqualis indica extract ameliorates low urinary tract symptoms in testosterone propionate-induced benign prostatic hyperplasia rats. Laboratory Animal Research. 2020; 36 (1):1-10.
Chicago/Turabian StyleDae-Geon Kim; Hyo-Jeong Kwon; Jong-Hwan Lim; Joo-Heon Kim; Kyu Pil Lee. 2020. "Quisqualis indica extract ameliorates low urinary tract symptoms in testosterone propionate-induced benign prostatic hyperplasia rats." Laboratory Animal Research 36, no. 1: 1-10.
Bacteriocins are functionally diverse toxins produced by most microbes and are potent antimicrobial peptides (AMPs) for bacterial ghosts as next generation vaccines. Here, we first report that the AMPs secreted from Lactobacillus taiwanensis effectively form ghosts of pathogenic bacteria and are identified as diverse bacteriocins, including novel ones. In detail, a cell-free supernatant from L. taiwanensis exhibited antimicrobial activities against pathogenic bacteria and was observed to effectively cause cellular lysis through pore formation in the bacterial membrane using scanning electron microscopy (SEM). The treatment of the cell-free supernatant with proteinase K or EDTA proved that the antimicrobial activity is mediated by AMPs, and the purification of AMPs using Sep-Pak columns indicated that the cell-free supernatant includes various amphipathic peptides responsible for the antimicrobial activity. Furthermore, the whole-genome sequencing of L. taiwanensis revealed that the strain has diverse bacteriocins, confirmed experimentally to function as AMPs, and among them are three novel bacteriocins, designated as Tan 1, Tan 2, and Tan 3. We also confirmed, using SEM, that Tan 2 effectively produces bacterial ghosts. Therefore, our data suggest that the bacteriocins from L. taiwanensis are potentially useful as a critical component for the preparation of bacterial ghosts.
Sam Kim; Yeon Ha; Kyu Bang; Seungki Lee; Joo-Hong Yeo; Hee-Sun Yang; Tae-Won Kim; Kyu Lee; Woo Bang. Potential of Bacteriocins from Lactobacillus taiwanensis for Producing Bacterial Ghosts as a Next Generation Vaccine. Toxins 2020, 12, 432 .
AMA StyleSam Kim, Yeon Ha, Kyu Bang, Seungki Lee, Joo-Hong Yeo, Hee-Sun Yang, Tae-Won Kim, Kyu Lee, Woo Bang. Potential of Bacteriocins from Lactobacillus taiwanensis for Producing Bacterial Ghosts as a Next Generation Vaccine. Toxins. 2020; 12 (7):432.
Chicago/Turabian StyleSam Kim; Yeon Ha; Kyu Bang; Seungki Lee; Joo-Hong Yeo; Hee-Sun Yang; Tae-Won Kim; Kyu Lee; Woo Bang. 2020. "Potential of Bacteriocins from Lactobacillus taiwanensis for Producing Bacterial Ghosts as a Next Generation Vaccine." Toxins 12, no. 7: 432.
Sperm function and male fertility are closely related to pH dependent K+ current (KSper) in human sperm, which is most likely composed of Slo3 and its auxiliary subunit leucine-rich repeat-containing protein 52 (LRRC52). Onion peel extract (OPE) and its major active ingredient quercetin are widely used as fertility enhancers; however, the effect of OPE and quercetin on Slo3 has not been elucidated. The purpose of this study is to investigate the effect of quercetin on human Slo3 channels. Human Slo3 and LRRC52 were co-transfected into HEK293 cells and pharmacological properties were studied with the whole cell patch clamp technique. We successfully expressed and measured pH sensitive and calcium insensitive Slo3 currents in HEK293 cells. We found that OPE and its key ingredient quercetin inhibit Slo3 currents. Inhibition by quercetin is dose dependent and this degree of inhibition decreases with elevating internal alkalization and internal free calcium concentrations. Functional moieties in the quercetin polyphenolic ring govern the degree of inhibition of Slo3 by quercetin, and the composition of such functional moieties are sensitive to the pH of the medium. These results suggest that quercetin inhibits Slo3 in a pH and calcium dependent manner. Therefore, we surmise that quercetin induced depolarization in spermatozoa may enhance the voltage gated proton channel (Hv1), and activate non-selective cation channels of sperm (CatSper) dependent calcium influx to trigger sperm capacitation and acrosome reaction.
Tharaka Darshana Wijerathne; Ji Hyun Kim; Min Ji Kim; Chul Young Kim; Mee Ree Chae; Sung Won Lee; Kyu Pil Lee. Onion peel extract and its constituent, quercetin inhibits human Slo3 in a pH and calcium dependent manner. The Korean Journal of Physiology & Pharmacology 2019, 23, 381 -392.
AMA StyleTharaka Darshana Wijerathne, Ji Hyun Kim, Min Ji Kim, Chul Young Kim, Mee Ree Chae, Sung Won Lee, Kyu Pil Lee. Onion peel extract and its constituent, quercetin inhibits human Slo3 in a pH and calcium dependent manner. The Korean Journal of Physiology & Pharmacology. 2019; 23 (5):381-392.
Chicago/Turabian StyleTharaka Darshana Wijerathne; Ji Hyun Kim; Min Ji Kim; Chul Young Kim; Mee Ree Chae; Sung Won Lee; Kyu Pil Lee. 2019. "Onion peel extract and its constituent, quercetin inhibits human Slo3 in a pH and calcium dependent manner." The Korean Journal of Physiology & Pharmacology 23, no. 5: 381-392.
Store-operated calcium entry (SOCE), an important mechanism of Ca2+ signaling in a wide range of cell types, is mediated by stromal interaction molecule (STIM), which senses the depletion of endoplasmic reticulum Ca2+ stores and binds and activates Orai channels in the plasma membrane. This inside-out mechanism of Ca2+ signaling raises an interesting question about the evolution of SOCE: How did these two proteins existing in different cellular compartments evolve to interact with each other? We investigated the gating mechanism of Caenorhabditis elegans Orai channels. Our analysis revealed a mechanism of Orai gating by STIM binding to the intracellular 2–3 loop of Orai in C. elegans that is radically different from Orai gating by STIM binding to the N and C termini of Orai in mammals. In addition, we found that the conserved hydrophobic amino acids in the 2–3 loop of Orai1 are important for the oligomerization and gating of channels and are regulated via an intramolecular interaction mechanism mediated by the N and C termini of Orai1. This study identifies a previously unknown SOCE mechanism in C. elegans and suggests that, while the STIM–Orai interaction is conserved between invertebrates and mammals, the gating mechanism for Orai channels differs considerably.
Kyu Min Kim; Tharaka Wijerathne; Jin-Hoe Hur; Uk Jung Kang; Ihn Hyeong Kim; Yeong Cheon Kweon; Ah Reum Lee; Su Ji Jeong; Sang Kwon Lee; Yoon Young Lee; Bo-Woong Sim; Jong-Hee Lee; Chunggi Baig; Sun-Uk Kim; Kyu-Tae Chang; Kyu Pil Lee; Chan Young Park. Distinct gating mechanism of SOC channel involving STIM–Orai coupling and an intramolecular interaction of Orai in Caenorhabditis elegans. Proceedings of the National Academy of Sciences 2018, 115, E4623 -E4632.
AMA StyleKyu Min Kim, Tharaka Wijerathne, Jin-Hoe Hur, Uk Jung Kang, Ihn Hyeong Kim, Yeong Cheon Kweon, Ah Reum Lee, Su Ji Jeong, Sang Kwon Lee, Yoon Young Lee, Bo-Woong Sim, Jong-Hee Lee, Chunggi Baig, Sun-Uk Kim, Kyu-Tae Chang, Kyu Pil Lee, Chan Young Park. Distinct gating mechanism of SOC channel involving STIM–Orai coupling and an intramolecular interaction of Orai in Caenorhabditis elegans. Proceedings of the National Academy of Sciences. 2018; 115 (20):E4623-E4632.
Chicago/Turabian StyleKyu Min Kim; Tharaka Wijerathne; Jin-Hoe Hur; Uk Jung Kang; Ihn Hyeong Kim; Yeong Cheon Kweon; Ah Reum Lee; Su Ji Jeong; Sang Kwon Lee; Yoon Young Lee; Bo-Woong Sim; Jong-Hee Lee; Chunggi Baig; Sun-Uk Kim; Kyu-Tae Chang; Kyu Pil Lee; Chan Young Park. 2018. "Distinct gating mechanism of SOC channel involving STIM–Orai coupling and an intramolecular interaction of Orai in Caenorhabditis elegans." Proceedings of the National Academy of Sciences 115, no. 20: E4623-E4632.
To evaluate nafamostat mesilate (NM) as an alternative anticoagulant agent for intermittent hemodialysis (IHD). Prospective randomized study. University teaching hospital. Eighteen healthy Beagle dogs. In group 1 (n = 6), NM was administered at a dose of 0.5 mg/kg/h during IHD for 5 hours. In group 2 (n = 6), NM was administered at a low dose of 0.25 mg/kg/h during IHD. In group 3 (n = 6), which was the control group, unfractionated heparin (UFH) was administered during IHD. The evaluated parameters included: the amount of residual blood clots in the blood chamber and arterial side of the dialyzer; the levels of hemoglobin, hematocrit, and platelets; and the prothrombin time (PT), activated partial thromboplastin time (aPTT), and activated clotting time (ACT). Groups 1 and 2 successfully completed IHD without serious coagulation in the extracorporeal circulation. The residual blood clotting in the blood chamber and arterial side of the dialyzer did not significantly differ in groups 1 and 2 compared to group 3 (group 1 vs group 3, P = 1.000; and group 2 vs group 3, P = 1.000). No significant differences were observed between pre- and posttreatment PTs in groups 1 (P = 0.476) and 2 (P = 0.597), between pre- and posttreatment aPTTs in groups 1 (P = 0.983) and 2 (P = 0.977), and between pre- and posttreatment ACT in groups 1 (P = 0.282) and 2 (P = 0.401). In group 3, a significant elevation of ACT was observed at the posttest (P < 0.001). The results of this study in healthy Beagle dogs suggest that NM at 0.25 mg/kg/h may be a valid alternative to UFH for IHD. Further studies are needed in patients at high risk of bleeding.
Joon-Hyuk Choi; Seok-Yeong Byun; Aryung Nam; Sei-Myoung Han; Kyu-Pil Lee; Kun-Ho Song; Hwa-Young Youn; Kyoung-Won Seo. Evaluation of nafamostat mesilate as an alternative anticoagulant during intermittent hemodialysis in healthy Beagle dogs. Journal of Veterinary Emergency and Critical Care 2018, 28, 122 -129.
AMA StyleJoon-Hyuk Choi, Seok-Yeong Byun, Aryung Nam, Sei-Myoung Han, Kyu-Pil Lee, Kun-Ho Song, Hwa-Young Youn, Kyoung-Won Seo. Evaluation of nafamostat mesilate as an alternative anticoagulant during intermittent hemodialysis in healthy Beagle dogs. Journal of Veterinary Emergency and Critical Care. 2018; 28 (2):122-129.
Chicago/Turabian StyleJoon-Hyuk Choi; Seok-Yeong Byun; Aryung Nam; Sei-Myoung Han; Kyu-Pil Lee; Kun-Ho Song; Hwa-Young Youn; Kyoung-Won Seo. 2018. "Evaluation of nafamostat mesilate as an alternative anticoagulant during intermittent hemodialysis in healthy Beagle dogs." Journal of Veterinary Emergency and Critical Care 28, no. 2: 122-129.
Protein phosphatase 1 (PP1) is involved in various signal transduction mechanisms as an extensive regulator. The PP1 catalytic subunit (PP1c) recognizes and binds to PP1-binding consensus residues (FxxR/KxR/K) in NBCe1-B. Consequently, we focused on identifying the function of the PP1-binding consensus residue, FMDRLK, in NBCe1-B. Using site-directed mutagenesis and co-immunoprecipitation assays, we revealed that in cases where the residues were substituted (F922A, R925A, and K927A) or deleted (deletion of amino acids 922-927), NBCe1-B mutants inhibited PP1 binding to NBCe1-B. Additionally, by recording the intracellular pH, we found that PP1-binding consensus residues in NBCe1-B were not only critical for NBCe1-B activity, but also relevant to its surface expression level. Therefore, we reported that NBCe1-B, as a substrate of PP1, contains these residues in the C-terminal region and that the direct interaction between NBCe1-B and PP1 is functionally critical in controlling the regulation of the HCO transport. These results suggested that like IRBIT, PP1 was another novel regulator of HCO secretion in several types of epithelia.
Kyu Pil Lee; Hyun Jin Kim; Ngki Yang. Functional identification of protein phosphatase 1-binding consensus residues in NBCe1-B. The Korean Journal of Physiology & Pharmacology 2018, 22, 91 -99.
AMA StyleKyu Pil Lee, Hyun Jin Kim, Ngki Yang. Functional identification of protein phosphatase 1-binding consensus residues in NBCe1-B. The Korean Journal of Physiology & Pharmacology. 2018; 22 (1):91-99.
Chicago/Turabian StyleKyu Pil Lee; Hyun Jin Kim; Ngki Yang. 2018. "Functional identification of protein phosphatase 1-binding consensus residues in NBCe1-B." The Korean Journal of Physiology & Pharmacology 22, no. 1: 91-99.
Onion (Allium cepa L.) and quercetin protect against oxidative damage and have positive effects on multiple functional parameters of spermatozoa, including viability and motility. However, the associated underlying mechanisms of action have not yet been identified. The aim of this study was to investigate the effect of onion peel extract (OPE) on voltage‐gated proton (Hv1) channels, which play a critical role in rapid proton extrusion. This process underlies a wide range of physiological processes, particularly male fertility. The whole‐cell patch‐clamp technique was used to record the changes in Hv1 currents in HEK293 cells transiently transfected with human Hv1 (HVCN1). The effects of OPE on human sperm motility were also analyzed. OPE significantly activated the outward‐rectifying proton currents in a concentration‐dependent manner, with an EC50 value of 30 μg/mL. This effect was largely reversible upon washout. Moreover, OPE induced an increase in the proton current amplitude and decreased the time constant of activation at 0 mV from 4.9 ± 1.7 to 0.6 ± 0.1 sec (n = 6). In the presence of OPE, the half‐activation voltage (V1/2) shifted in the negative direction, from 20.1 ± 5.8 to 5.2 ± 8.7 mV (n = 6), but the slope was not significantly altered. The OPE‐induced current was profoundly inhibited by 10 μm Zn2+, the most potent Hv1 channel inhibitor, and was also inhibited by treatment with GF109203X, a specific protein kinase C (PKC) inhibitor. Furthermore, sperm motility was significantly increased in the OPE‐treated groups. OPE exhibits protective effects on sperm motility, at least partially via regulation of the proton channel. Moreover, similar effects were exerted by quercetin, the major flavonoid in OPE. These results suggest OPE, which is rich in the potent Hv1 channel activator quercetin, as a possible new candidate treatment for human infertility.
M. R. Chae; S. J. Kang; K. P. Lee; B. R. Choi; H. K. Kim; J. K. Park; C. Y. Kim; S. W. Lee. Onion (Allium cepa L.) peel extract (OPE) regulates human sperm motility via protein kinase C-mediated activation of the human voltage-gated proton channel. Andrology 2017, 5, 979 -989.
AMA StyleM. R. Chae, S. J. Kang, K. P. Lee, B. R. Choi, H. K. Kim, J. K. Park, C. Y. Kim, S. W. Lee. Onion (Allium cepa L.) peel extract (OPE) regulates human sperm motility via protein kinase C-mediated activation of the human voltage-gated proton channel. Andrology. 2017; 5 (5):979-989.
Chicago/Turabian StyleM. R. Chae; S. J. Kang; K. P. Lee; B. R. Choi; H. K. Kim; J. K. Park; C. Y. Kim; S. W. Lee. 2017. "Onion (Allium cepa L.) peel extract (OPE) regulates human sperm motility via protein kinase C-mediated activation of the human voltage-gated proton channel." Andrology 5, no. 5: 979-989.
Ja-Won Kim; Aryung Nam; Kyu-Pil Lee; Kun-Ho Song; Hwa-Young Youn; Kyoung-Won Seo. Evaluation of Hemostatic Function with Thromboelastography in Dogs with Hypercoagulable Diseases. Journal of Veterinary Clinics 2017, 34, 65 .
AMA StyleJa-Won Kim, Aryung Nam, Kyu-Pil Lee, Kun-Ho Song, Hwa-Young Youn, Kyoung-Won Seo. Evaluation of Hemostatic Function with Thromboelastography in Dogs with Hypercoagulable Diseases. Journal of Veterinary Clinics. 2017; 34 (2):65.
Chicago/Turabian StyleJa-Won Kim; Aryung Nam; Kyu-Pil Lee; Kun-Ho Song; Hwa-Young Youn; Kyoung-Won Seo. 2017. "Evaluation of Hemostatic Function with Thromboelastography in Dogs with Hypercoagulable Diseases." Journal of Veterinary Clinics 34, no. 2: 65.
Plasma membrane hyperpolarization associated with activation of Ca-activated K channels plays an important role in sperm capacitation during fertilization. Although Slo3 (slowpoke homologue 3), together with the auxiliary γ2-subunit, LRRC52 (leucine-rich-repeat-containing 52), is known to mediate the pH-sensitive, sperm-specific K current KSper in mice, the molecular identity of this channel in human sperm remains controversial. In this study, we tested the classical BKCa activators, NS1619 and LDD175, on human Slo3, heterologously expressed in HEK293 cells together with its functional interacting γ2 subunit, hLRRC52. As previously reported, Slo3 K current was unaffected by iberiotoxin or 4-aminopyridine, but was inhibited by ~50% by 20 mM TEA. Extracellular alkalinization potentiated hSlo3 K+ current, and internal alkalinization and Ca elevation induced a leftward shift its activation voltage. NS1619, which acts intracellularly to modulate hSlo1 gating, attenuated hSlo3 K currents, whereas LDD175 increased this current and induced membrane potential hyperpolarization. LDD175-induced potentiation was not associated with a change in the half-activation voltage at different intracellular pHs (pH 7.3 and pH 8.0) in the absence of intracellular Ca. In contrast, elevation of intracellular Ca dramatically enhanced the LDD175-induced leftward shift in the half-activation potential of hSlo3. Therefore, the mechanism of action does not involve pH-dependent modulation of hSlo3 gating; instead, LDD175 may modulate Ca-dependent activation of hSlo3. Thus, LDD175 potentially activates native KSper and may induce membrane hyperpolarization-associated hyperactivation in human sperm.
Tharaka Wijerathne; Jihyun Kim; Dongki Yang; Kyu Pil Lee. Intracellular calcium-dependent regulation of the sperm-specific calcium-activated potassium channel, hSlo3, by the BKCaactivator LDD175. The Korean Journal of Physiology & Pharmacology 2017, 21, 241 -249.
AMA StyleTharaka Wijerathne, Jihyun Kim, Dongki Yang, Kyu Pil Lee. Intracellular calcium-dependent regulation of the sperm-specific calcium-activated potassium channel, hSlo3, by the BKCaactivator LDD175. The Korean Journal of Physiology & Pharmacology. 2017; 21 (2):241-249.
Chicago/Turabian StyleTharaka Wijerathne; Jihyun Kim; Dongki Yang; Kyu Pil Lee. 2017. "Intracellular calcium-dependent regulation of the sperm-specific calcium-activated potassium channel, hSlo3, by the BKCaactivator LDD175." The Korean Journal of Physiology & Pharmacology 21, no. 2: 241-249.
Context: Fructus Psoralea, Psoralea corylifolia L. (Leguminosae), has been widely used in traditional medicines for the treatment of dermatitis, leukoderma, asthma and osteoporosis. Objectives: In this study, we sought to study mechanisms underlying the vasoactive properties of Psoralea corylifolia extract (PCE) and its active ingredients. Materials and methods: To study mechanisms underlying the vasoactive properties of PCE prepared by extracting dried seeds of Psoralea corylifolia with 70% ethanol, isometric tension recordings of rat aortic rings and the ionic currents through TRPC3 (transient receptor potential canonical 3) channels were measured with the cumulative concentration (10–600 μg/mL) of PCE or its constituents. Results: Cumulative treatment with PCE caused the relaxation of pre-contracted aortic rings in the presence and absence of endothelium with EC50 values of 61.27 ± 3.11 and 211.13 ± 18.74 μg/mL, respectively. Pretreatment with inhibitors of nitric oxide (NO) synthase, guanylate cyclase, or cyclooxygenase and pyrazole 3, a selective TRPC3 channel blocker, significantly decreased PCE-induced vasorelaxation (p < 0.01). The PCE constituents, bakuchiol, isobavachalcone, isopsoralen and psoralen, inhibited hTRPC3 currents (inhibited by 40.6 ± 2.7, 27.1 ± 7.9, 35.1 ± 4.8 and 47.4 ± 3.9%, respectively). Furthermore, these constituents significantly relaxed pre-contracted aortic rings (EC50 128.9, 4.5, 32.1 and 114.9 μg/mL, respectively). Discussion and conclusions: Taken together, our data indicate that the vasodilatory actions of PCE are dependent on endothelial NO/cGMP and also involved in prostaglandin production. PCE and its active constituents, bakuchiol, isobavachalcone, isopsoralen and psoralen, caused dose-dependent inhibition of TRPC3 channels, indicating that those ingredients attenuate Phe-induced vasoconstriction.
Addis Kassahun Gebremeskel; Tharaka Wijerathne; Ji Hyun Kim; Min Ji Kim; Chang-Seob Seo; Hyeun-Kyoo Shin; Kyu Pil Lee. Psoralea corylifolia extract induces vasodilation in rat arteries through both endothelium-dependent and -independent mechanisms involving inhibition of TRPC3 channel activity and elaboration of prostaglandin. Pharmaceutical Biology 2017, 55, 2136 -2144.
AMA StyleAddis Kassahun Gebremeskel, Tharaka Wijerathne, Ji Hyun Kim, Min Ji Kim, Chang-Seob Seo, Hyeun-Kyoo Shin, Kyu Pil Lee. Psoralea corylifolia extract induces vasodilation in rat arteries through both endothelium-dependent and -independent mechanisms involving inhibition of TRPC3 channel activity and elaboration of prostaglandin. Pharmaceutical Biology. 2017; 55 (1):2136-2144.
Chicago/Turabian StyleAddis Kassahun Gebremeskel; Tharaka Wijerathne; Ji Hyun Kim; Min Ji Kim; Chang-Seob Seo; Hyeun-Kyoo Shin; Kyu Pil Lee. 2017. "Psoralea corylifolia extract induces vasodilation in rat arteries through both endothelium-dependent and -independent mechanisms involving inhibition of TRPC3 channel activity and elaboration of prostaglandin." Pharmaceutical Biology 55, no. 1: 2136-2144.
Meropenem, a second carbapenem antimicrobial agent with a broad spectrum of activity, is used to treat sepsis and resistant‐bacterial infections in veterinary medicine. The objective of this study was to identify the pharmacokinetics of meropenem in dogs receiving intermittent hemodialysis (IHD) and to determine the proper dosing in renal failure patients receiving IHD. Five healthy beagle dogs were given a single i.v. dose of 24 mg/kg of meropenem and received IHD. The blood flow rate, dialysate flow, and ultrafiltration rate were maintained at 40 mL/min, 300 mL/min, and 40 mL/h, respectively. Blood samples were collected for 24 h from the jugular vein and from the extracorporeal arterial and venous line. Urine samples and dialysate were also collected. The concentrations of meropenem were assayed using HPLC/MS/MS determination. The peak plasma concentration was 116 ± 37 μg/mL at 15 min. The systemic clearance was 347 ± 117 mL/h/kg, and the steady‐state volume of distribution was 223 ± 67 mL/kg. Dialysis clearance was 71.1 ± 34.3 mL/h/kg, and the extraction ratio by hemodialysis was 0.455 ± 0.150. The half‐life (T1/2) in dogs with IHD decreased compared with those without IHD, and the reduction in T1/2 was greater in renal failure patients than in normal patients. Sixty‐nine percent and 21% of the administered drug were recovered by urine and dialysate in the unchanged form, respectively. In conclusion, additional dosing of 24 mg/kg of meropenem after dialysis could be necessary according to the residual renal function of the patient based on the simulated data.
S. Y. Byun; J. W. Jeong; J. H. Choi; K. P. Lee; H. Y. Youn; H. J. Maeng; K. H. Song; T. S. Koo; K. W. Seo. Pharmacokinetic study of meropenem in healthy beagle dogs receiving intermittent hemodialysis. Journal of Veterinary Pharmacology and Therapeutics 2016, 39, 560 -565.
AMA StyleS. Y. Byun, J. W. Jeong, J. H. Choi, K. P. Lee, H. Y. Youn, H. J. Maeng, K. H. Song, T. S. Koo, K. W. Seo. Pharmacokinetic study of meropenem in healthy beagle dogs receiving intermittent hemodialysis. Journal of Veterinary Pharmacology and Therapeutics. 2016; 39 (6):560-565.
Chicago/Turabian StyleS. Y. Byun; J. W. Jeong; J. H. Choi; K. P. Lee; H. Y. Youn; H. J. Maeng; K. H. Song; T. S. Koo; K. W. Seo. 2016. "Pharmacokinetic study of meropenem in healthy beagle dogs receiving intermittent hemodialysis." Journal of Veterinary Pharmacology and Therapeutics 39, no. 6: 560-565.
Transient receptor potential canonical (TRPC) family contains a non-selective cation channel, and four TRPC subunits form a functional tetrameric channel. TRPC4/5 channels form not only the homotetrameric channel but also a heterotetrameric channel with TRPC1. We investigated the interaction domain required for TRPC1/4 or TRPC1/5 heteromultimeric channels using FRET and the patch-clamp technique. TRPC1 only localized at the plasma membrane (PM) when it was coexpressed with TRPC4 or TRPC5. The TRPC1/4 or TRPC1/5 heteromultimeric showed the typical outward rectifying I/V curve. When TRPC1 and TRPC4 form a heteromeric channel, the N-terminal coiled-coil domain (CCD) and C-terminal 725–745 region of TRPC1 interact with the N-terminal CCD and C-terminal 700–728 region of TRPC4. However, when TRPC1 and TRPC5 form a heteromeric channel, the N-terminal CCD and C-terminal 673–725 region of TRPC1 interact with the N-terminal CCD and C-terminal 707–735 region of TRPC5. In conclusion, the N-terminal CCD of TRPC channels is essential for the heteromultimeric structure of TRPC channels, whereas specific C-terminal regions are required for unique heteromerization between subgroups of TRPC channels.
Jongyun Myeong; Juyeon Ko; Chansik Hong; Dongki Yang; Kyu Pil Lee; Ju-Hong Jeon; InSuk So. The interaction domains of transient receptor potential canonical (TRPC)1/4 and TRPC1/5 heteromultimeric channels. Biochemical and Biophysical Research Communications 2016, 474, 476 -481.
AMA StyleJongyun Myeong, Juyeon Ko, Chansik Hong, Dongki Yang, Kyu Pil Lee, Ju-Hong Jeon, InSuk So. The interaction domains of transient receptor potential canonical (TRPC)1/4 and TRPC1/5 heteromultimeric channels. Biochemical and Biophysical Research Communications. 2016; 474 (3):476-481.
Chicago/Turabian StyleJongyun Myeong; Juyeon Ko; Chansik Hong; Dongki Yang; Kyu Pil Lee; Ju-Hong Jeon; InSuk So. 2016. "The interaction domains of transient receptor potential canonical (TRPC)1/4 and TRPC1/5 heteromultimeric channels." Biochemical and Biophysical Research Communications 474, no. 3: 476-481.
Jinsung Kim; Sang Hui Moon; Young-Cheul Shin; Ju-Hong Jeon; Kyu Joo Park; Kyu Pil Lee; InSuk So. Erratum to: Intracellular spermine blocks TRPC4 channel via electrostatic interaction with C-terminal negative amino acids. Pflügers Archiv - European Journal of Physiology 2016, 468, 1297 -1297.
AMA StyleJinsung Kim, Sang Hui Moon, Young-Cheul Shin, Ju-Hong Jeon, Kyu Joo Park, Kyu Pil Lee, InSuk So. Erratum to: Intracellular spermine blocks TRPC4 channel via electrostatic interaction with C-terminal negative amino acids. Pflügers Archiv - European Journal of Physiology. 2016; 468 (7):1297-1297.
Chicago/Turabian StyleJinsung Kim; Sang Hui Moon; Young-Cheul Shin; Ju-Hong Jeon; Kyu Joo Park; Kyu Pil Lee; InSuk So. 2016. "Erratum to: Intracellular spermine blocks TRPC4 channel via electrostatic interaction with C-terminal negative amino acids." Pflügers Archiv - European Journal of Physiology 468, no. 7: 1297-1297.
Transient receptor potential canonical (TRPC) 4 channels are calcium-permeable, nonselective cation channels and are widely expressed in mammalian tissue, especially in the GI tract and brain. TRPC4 channels are known to be involved in neurogenic contraction of ileal smooth muscle cells via generating cationic current after muscarinic stimulation (muscarinic cationic current (mIcat)). Polyamines exist in numerous tissues and are believed to be involved in cell proliferation, differentiation, scar formation, wound healing, and carcinogenesis. Besides, physiological polyamines are essential to maintain inward rectification of cardiac potassium channels (Kir2.1). At membrane potentials more positive than equilibrium potential, intracellular polyamines plug the cytosolic surface of the Kir2.1 so that potassium ions cannot pass through the pore. Recently, it was reported that polyamines inhibit not only cardiac potassium channels but also nonselective cation channels that mediate the generation of mIcat. Here, we report that TRPC4, a definite mIcat mediator, is inhibited by intracellular spermine with great extent. The inhibition was specific to TRPC4 and TRPC5 channels but was not effective to TRPC1/4, TRPC1/5, and TRPC3 channels. For this inhibition to occur, we found that glutamates at 728th and 729th position of TRPC4 channels are essential whereby we conclude that spermine blocks the TRPC4 channel with electrostatic interaction between negative amino acids at the C-terminus of the channel.
Jinsung Kim; Sang Hui Moon; Young-Cheul Shin; Ju-Hong Jeon; Kyu Joo Park; Kyu Pil Lee; InSuk So. Intracellular spermine blocks TRPC4 channel via electrostatic interaction with C-terminal negative amino acids. Pflügers Archiv - European Journal of Physiology 2015, 468, 551 -561.
AMA StyleJinsung Kim, Sang Hui Moon, Young-Cheul Shin, Ju-Hong Jeon, Kyu Joo Park, Kyu Pil Lee, InSuk So. Intracellular spermine blocks TRPC4 channel via electrostatic interaction with C-terminal negative amino acids. Pflügers Archiv - European Journal of Physiology. 2015; 468 (4):551-561.
Chicago/Turabian StyleJinsung Kim; Sang Hui Moon; Young-Cheul Shin; Ju-Hong Jeon; Kyu Joo Park; Kyu Pil Lee; InSuk So. 2015. "Intracellular spermine blocks TRPC4 channel via electrostatic interaction with C-terminal negative amino acids." Pflügers Archiv - European Journal of Physiology 468, no. 4: 551-561.
Aberrant glutathione or Ca2+ homeostasis due to oxidative stress is associated with the pathogenesis of neurodegenerative disorders. The Ca2+-permeable transient receptor potential cation (TRPC) channel is predominantly expressed in the brain, which is sensitive to oxidative stress. However, the role of the TRPC channel in neurodegeneration is not known. Here, we report a mechanism of TRPC5 activation by oxidants and the effect of glutathionylated TRPC5 on striatal neurons in Huntington’s disease. Intracellular oxidized glutathione leads to TRPC5 activation via TRPC5 S-glutathionylation at Cys176/Cys178 residues. The oxidized glutathione-activated TRPC5-like current results in a sustained increase in cytosolic Ca2+, activated calmodulin-dependent protein kinase and the calpain-caspase pathway, ultimately inducing striatal neuronal cell death. We observed an abnormal glutathione pool indicative of an oxidized state in the striatum of Huntington’s disease transgenic (YAC128) mice. Increased levels of endogenous TRPC5 S-glutathionylation were observed in the striatum in both transgenic mice and patients with Huntington’s disease. Both knockdown and inhibition of TRPC5 significantly attenuated oxidation-induced striatal neuronal cell death. Moreover, a TRPC5 blocker improved rearing behaviour in Huntington’s disease transgenic mice and motor behavioural symptoms in littermate control mice by increasing striatal neuron survival. Notably, low levels of TRPC1 increased the formation of TRPC5 homotetramer, a highly Ca2+-permeable channel, and stimulated Ca2+-dependent apoptosis in Huntington’s disease cells (STHdhQ111/111). Taken together, these novel findings indicate that increased TRPC5 S-glutathionylation by oxidative stress and decreased TRPC1 expression contribute to neuronal damage in the striatum and may underlie neurodegeneration in Huntington’s disease.
Chansik Hong; Hyemyung Seo; Misun Kwak; Jeha Jeon; Jihoon Jang; Eui Man Jeong; Jongyun Myeong; Yu Jin Hwang; Kotdaji Ha; Min Jueng Kang; Kyu Pil Lee; Eugene C. Yi; In-Gyu Kim; Ju-Hong Jeon; Hoon Ryu; InSuk So. Increased TRPC5 glutathionylation contributes to striatal neuron loss in Huntington’s disease. Brain 2015, 138, 3030 -3047.
AMA StyleChansik Hong, Hyemyung Seo, Misun Kwak, Jeha Jeon, Jihoon Jang, Eui Man Jeong, Jongyun Myeong, Yu Jin Hwang, Kotdaji Ha, Min Jueng Kang, Kyu Pil Lee, Eugene C. Yi, In-Gyu Kim, Ju-Hong Jeon, Hoon Ryu, InSuk So. Increased TRPC5 glutathionylation contributes to striatal neuron loss in Huntington’s disease. Brain. 2015; 138 (10):3030-3047.
Chicago/Turabian StyleChansik Hong; Hyemyung Seo; Misun Kwak; Jeha Jeon; Jihoon Jang; Eui Man Jeong; Jongyun Myeong; Yu Jin Hwang; Kotdaji Ha; Min Jueng Kang; Kyu Pil Lee; Eugene C. Yi; In-Gyu Kim; Ju-Hong Jeon; Hoon Ryu; InSuk So. 2015. "Increased TRPC5 glutathionylation contributes to striatal neuron loss in Huntington’s disease." Brain 138, no. 10: 3030-3047.
Ca2+ signaling entails receptor-stimulated Ca2+ release from the ER stores that serves as a signal to activate Ca2+ influx channels present at the plasma membrane, the store-operated Ca2+ channels (SOCs). The two known SOCs are the Orai and TRPC channels. The SOC-dependent Ca2+ influx mediates and sustains virtually all Ca2+-dependent regulatory functions. The signal that transmits the Ca2+ content of the ER stores to the plasma membrane is the ER resident, Ca2+-binding protein STIM1. STIM1 is a multidomain protein that clusters and dimerizes in response to Ca2+ store depletion leading to activation of Orai and TRPC channels. Activation of the Orais by STIM1 is obligatory for their function as SOCs, while TRPC channels can function as both STIM1-dependent and STIM1-independent channels. Here we discuss the different mechanisms by which STIM1 activates the Orai and TRPC channels, the emerging specific and non-overlapping physiological functions of Ca2+ influx mediated by the two channel types, and argue that the TRPC channels should be the preferred therapeutic target to control the toxic effect of excess Ca2+ influx.
Seok Choi; József Maléth; Archana Jha; Kyu Pil Lee; Min Seuk Kim; InSuk So; Malini Ahuja; Shmuel Muallem. The TRPCs–STIM1–Orai Interaction. Organotypic Models in Drug Development 2014, 223, 1035 -1054.
AMA StyleSeok Choi, József Maléth, Archana Jha, Kyu Pil Lee, Min Seuk Kim, InSuk So, Malini Ahuja, Shmuel Muallem. The TRPCs–STIM1–Orai Interaction. Organotypic Models in Drug Development. 2014; 223 ():1035-1054.
Chicago/Turabian StyleSeok Choi; József Maléth; Archana Jha; Kyu Pil Lee; Min Seuk Kim; InSuk So; Malini Ahuja; Shmuel Muallem. 2014. "The TRPCs–STIM1–Orai Interaction." Organotypic Models in Drug Development 223, no. : 1035-1054.
Transient receptor potential canonical (TRPC) channels mediate a critical part of the receptor-evoked Ca(2+) influx. TRPCs are gated open by the endoplasmic reticulum Ca(2+) sensor STIM1. Here we asked which stromal interaction molecule 1 (STIM1) and TRPC domains mediate the interaction between them and how this interaction is used to open the channels. We report that the STIM1 Orai1-activating region domain of STIM1 interacts with the TRPC channel coiled coil domains (CCDs) and that this interaction is essential for opening the channels by STIM1. Thus, disruption of the N-terminal (NT) CCDs by triple mutations eliminated TRPC surface localization and reduced binding of STIM1 to TRPC1 and TRPC5 while increasing binding to TRPC3 and TRPC6. Single mutations in TRPC1 NT or C-terminal (CT) CCDs reduced interaction and activation of TRPC1 by STIM1. Remarkably, single mutations in the TRPC3 NT CCD enhanced interaction and regulation by STIM1. Disruption in the TRPC3 CT CCD eliminated regulation by STIM1 and the enhanced interaction caused by NT CCD mutations. The NT CCD mutations converted TRPC3 from a TRPC1-dependent to a TRPC1-independent, STIM1-regulated channel. TRPC1 reduced the FRET between BFP-TRPC3 and TRPC3-YFP and between CFP-TRPC3-YFP upon stimulation. Accordingly, knockdown of TRPC1 made TRPC3 STIM1-independent. STIM1 dependence of TRPC3 was reconstituted by the TRPC1 CT CCD alone. Knockout of Trpc1 and Trpc3 similarly inhibited Ca(2+) influx, and inhibition of Trpc3 had no further effect on Ca(2+) influx in Trpc1(-/-) cells. Cell stimulation enhanced the formation of Trpc1-Stim1-Trpc3 complexes. These findings support a model in which the TRPC3 NT and CT CCDs interact to shield the CT CCD from interaction with STIM1. The TRPC1 CT CCD dissociates this interaction to allow the STIM1 Orai1-activating region within STIM1 access to the TRPC3 CT CCD and regulation of TRPC3 by STIM1. These studies provide evidence that the TRPC channel CCDs participate in channel gating.
Kyu Pil Lee; Seok Choi; Jeong Hee Hong; Malini Ahuja; Sarabeth Graham; Rong Ma; InSuk So; Dong Min Shin; Shmuel Muallem; Joseph P. Yuan. Molecular Determinants Mediating Gating of Transient Receptor Potential Canonical (TRPC) Channels by Stromal Interaction Molecule 1 (STIM1). Journal of Biological Chemistry 2014, 289, 6372 -6382.
AMA StyleKyu Pil Lee, Seok Choi, Jeong Hee Hong, Malini Ahuja, Sarabeth Graham, Rong Ma, InSuk So, Dong Min Shin, Shmuel Muallem, Joseph P. Yuan. Molecular Determinants Mediating Gating of Transient Receptor Potential Canonical (TRPC) Channels by Stromal Interaction Molecule 1 (STIM1). Journal of Biological Chemistry. 2014; 289 (10):6372-6382.
Chicago/Turabian StyleKyu Pil Lee; Seok Choi; Jeong Hee Hong; Malini Ahuja; Sarabeth Graham; Rong Ma; InSuk So; Dong Min Shin; Shmuel Muallem; Joseph P. Yuan. 2014. "Molecular Determinants Mediating Gating of Transient Receptor Potential Canonical (TRPC) Channels by Stromal Interaction Molecule 1 (STIM1)." Journal of Biological Chemistry 289, no. 10: 6372-6382.
The ubiquitous transient receptor potential canonical (TRPC) channels function as non-selective, Ca(2+)-permeable channels. TRPC channels are activated by stimulation of Gαq-PLC-coupled receptors. Here, we report that TRPC4/TRPC5 can be activated by Gαi. We studied the essential role of Gαi subunits in TRPC4 activation and investigated changes in ion selectivity and pore dilation of the TRPC4 channel elicited by the Gαi2 subunit. Activation of TRPC4 by Gαi2 increased Ca2+ permeability and Ca2+ influx through TRPC4 channels. Co-expression of the muscarinic receptor (M2) and TRPC4 in HEK293 cells induced TRPC4-mediated Ca2+ influx. Moreover, both TRPC4β and the TRPC4β-Gαi2 signaling complex induced inhibition of neurite growth and arborization in cultured hippocampal neurons. Cells treated with KN-93, a CaMKII inhibitor, prevented TRPC4- and TRPC4-Gαi2(Q205L)-mediated inhibition of neurite branching and growth. These findings indicate an essential role of Gαi proteins in TRPC4 activation and extend our knowledge of the functional role of TRPC4 in hippocampal neurons.
Jae-Pyo Jeon; Seung-Eon Roh; Jinhong Wie; Jinsung Kim; Hana Kim; Kyu Pil Lee; Dongki Yang; Ju-Hong Jeon; Nam-Hyuk Cho; In-Gyu Kim; David E. Kang; Hyun Jin Kim; InSuk So. Activation of TRPC4β by Gαi subunit increases Ca2+ selectivity and controls neurite morphogenesis in cultured hippocampal neuron. Cell Calcium 2013, 54, 307 -319.
AMA StyleJae-Pyo Jeon, Seung-Eon Roh, Jinhong Wie, Jinsung Kim, Hana Kim, Kyu Pil Lee, Dongki Yang, Ju-Hong Jeon, Nam-Hyuk Cho, In-Gyu Kim, David E. Kang, Hyun Jin Kim, InSuk So. Activation of TRPC4β by Gαi subunit increases Ca2+ selectivity and controls neurite morphogenesis in cultured hippocampal neuron. Cell Calcium. 2013; 54 (4):307-319.
Chicago/Turabian StyleJae-Pyo Jeon; Seung-Eon Roh; Jinhong Wie; Jinsung Kim; Hana Kim; Kyu Pil Lee; Dongki Yang; Ju-Hong Jeon; Nam-Hyuk Cho; In-Gyu Kim; David E. Kang; Hyun Jin Kim; InSuk So. 2013. "Activation of TRPC4β by Gαi subunit increases Ca2+ selectivity and controls neurite morphogenesis in cultured hippocampal neuron." Cell Calcium 54, no. 4: 307-319.
Ca(2+) is a critical factor in the regulation of signal transduction and Ca(2+) homeostasis is altered in different human diseases. The level of Ca(2+) in cells is highly regulated through a diverse class of regulators. Among them is the transient receptor potential vanilloid 6 (TRPV6), which is a Ca(2+) selective channel that absorbs Ca(2+) in the small intestine. TRPV6 is overexpressed in some cancers and exhibits oncogenic potential, but its exact mechanism is still poorly understood. The Numb protein is a cell fate determinant that functions in endocytosis and as a tumor suppressor via the stabilization of p53. Numb protein consisted of four isoforms. Here, we showed a novel function of Numb1, which negatively regulates TRPV6 activity. The expression of Numb1 decreased cytosolic Ca(2+) concentrations in TRPV6-transfected HEK293 cells. When all the isoforms of Numb were depleted using siRNA in a TRPV6 stable cell line, the levels of cytosolic Ca(2+) increased. We observed an interaction between Numb1 and TRPV6 using co-immunoprecipitation. We confirmed this interaction using Fluorescence Resolution Energy Transfer (FRET). We identified the TRPV6 and Numb1 binding site using TRPV6 C-terminal truncation mutants and Numb1 deletion mutants. The binding site in TRPV6 was an aspartic acid at amino acid residue 716, and that binding site in Numb1 was arginine at amino acid residue 434. A Numb1 mutant, lacking TRPV6 binding activity, failed to inhibit TRPV6 activity. Every isoform of Numb knockdown, using an siRNA-based approach in MCF-7 breast cancer cells, not only showed enhanced TRPV6 expression but also both the cytosolic Ca(2+) concentration and cell proliferation were increased. The down-regulated expression of TRPV6 using siRNA increased Numb protein expression; however, the cytosolic influx of Ca(2+) and proliferation of the cell were decreased. To examine downstream signaling during Ca(2+) influx, we performed Western blotting analysis on TRPV6 upregulated cancer cells (MCF-7, PC-3). Taken together, these results demonstrated that Numb1 interacts with TRPV6 through charged residues and inhibits its activity via the regulation of protein expression. Moreover, we provided evidence for a Ca(2+)-regulated cancer cell signaling pathway and that the Ca(2+) channel is a target of cancer cells.
Sung-Young Kim; Dongki Yang; Jongyoun Myeong; Kotdaji Ha; Su-Hwa Kim; Eun-Jung Park; In-Gyu Kim; Nam-Hyuk Cho; Kyu Pil Lee; Ju-Hong Jeon; InSuk So. Regulation of calcium influx and signaling pathway in cancer cells via TRPV6–Numb1 interaction. Cell Calcium 2013, 53, 102 -111.
AMA StyleSung-Young Kim, Dongki Yang, Jongyoun Myeong, Kotdaji Ha, Su-Hwa Kim, Eun-Jung Park, In-Gyu Kim, Nam-Hyuk Cho, Kyu Pil Lee, Ju-Hong Jeon, InSuk So. Regulation of calcium influx and signaling pathway in cancer cells via TRPV6–Numb1 interaction. Cell Calcium. 2013; 53 (2):102-111.
Chicago/Turabian StyleSung-Young Kim; Dongki Yang; Jongyoun Myeong; Kotdaji Ha; Su-Hwa Kim; Eun-Jung Park; In-Gyu Kim; Nam-Hyuk Cho; Kyu Pil Lee; Ju-Hong Jeon; InSuk So. 2013. "Regulation of calcium influx and signaling pathway in cancer cells via TRPV6–Numb1 interaction." Cell Calcium 53, no. 2: 102-111.
Jeong Hee Hong; Min Seuk Kim; Kyu Pil Lee; Joseph P. Yuan; Shmuel Muallem. STIM-TRP Pathways. Store-operated Ca2+ entry (SOCE) pathways 2011, 57 -72.
AMA StyleJeong Hee Hong, Min Seuk Kim, Kyu Pil Lee, Joseph P. Yuan, Shmuel Muallem. STIM-TRP Pathways. Store-operated Ca2+ entry (SOCE) pathways. 2011; ():57-72.
Chicago/Turabian StyleJeong Hee Hong; Min Seuk Kim; Kyu Pil Lee; Joseph P. Yuan; Shmuel Muallem. 2011. "STIM-TRP Pathways." Store-operated Ca2+ entry (SOCE) pathways , no. : 57-72.