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ABSTRACT: Misfolding of exportable proteins can trigger endocrinopathies. For example, misfolding of insulin can result in autosomal dominant mutant INS gene-induced diabetes of youth, and misfolding of thyroglobulin can result in autosomal recessive congenital hypothyroidism with deficient thyroglobulin. Both proinsulin and thyroglobulin normally form homodimers; the mutant versions of both proteins misfold in the ER, triggering ER stress, and, in both cases, heterozygosity creates potential for cross-dimerization between mutant and WT gene products. Here, we investigated these two ER-retained mutant secretory proteins and the selectivity of their interactions with their respective WT counterparts. In both cases and in animal models of these diseases, we found that conditions favoring an increased stoichiometry of mutant gene product dominantly inhibited export of the WT partner, while increased relative level of the WT gene product helped to rescue secretion of the mutant partner. Surprisingly, the bidirectional consequences of secretory blockade and rescue occur simultaneously in the same cells. Thus, in the context of heterozygosity, expression level and stability of WT subunits may be a critical factor influencing the effect of protein misfolding on clinical phenotype. These results offer new insight into dominant as well as recessive inheritance of conformational diseases and offer opportunities for the development of new therapies.
The Journal of clinical investigation 06/2013; · 15.39 Impact Factor
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ABSTRACT: Targeted molecular imaging with hyaluronic acid (HA) has been highlighted in the diagnosis and treatment of CD44-overexpressing cancer. CD44, a receptor for HA, is closely related to the growth of cancer including proliferation, metastasis, invasion, and angiogenesis. For the efficient detection of CD44, we fabricated a few kinds of HA-modified MnFe2O4 nanocrystals (MNCs) to serve as specific magnetic resonance (MR) contrast agents (HA-MRCAs) and compared physicochemical properties, biocompatibility, and the CD44 targeting efficiency. Hydrophobic MNCs were efficiently phase-transferred using aminated polysorbate 80 (P80) synthesized by introducing spermine molecules on the hydroxyl groups of P80. Subsequently, a few kinds of HA-MRCAs were fabricated, conjugating different ratios of HA on the equal amount of phase-transferred MNCs. The optimized conjugation ratio of HA against magnetic content was identified to exhibit not only effective CD44 finding ability but also high cell viability through in vitro experiments. The results of this study demonstrate that the suggested HA-MRCA shows strong potential to be used for accurate tumor diagnosis.
Nanoscale Research Letters 04/2013; 8(1):149. · 2.73 Impact Factor
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ABSTRACT: Purpose: Levodopa is the most effective anti-Parkinsonian agent. It has also been known to exhibit analgesic properties in laboratory and clinical settings. However, studies evaluating its effects on neuropathic pain are limited. The aim of the present study was to examine the anti-allodynic effects of levodopa in neuropathic rats. Materials and Methods: Sprague-Dawley male rats underwent the surgical procedure for L5 and L6 spinal nerves ligation. Sixty neuropathic rats were randomly divided into 6 groups for the oral administration of distilled water and levodopa at 10, 30, 50, 70, and 100 mg/kg, respectively. We co-administered carbidopa with levodopa to prevent peripheral synthesis of dopamine from levodopa, and observed tactile, cold, and heat allodynia pre-administration, and at 15, 30, 60, 90, 120, 150, 180, and 240 min after drug administration. We also measured locomotor function of neuropathic rats using rotarod test to examine whether levodopa caused side effects or not. Results: Distilled water group didn't show any difference in all allodynia. For the levodopa groups (10-100 mg/kg), tactile and heat withdrawal thresholds were increased, and cold withdrawal frequency was decreased dose-dependently (p<0.01). In addition, levodopa induced biphasic analgesia. Different dosage of levodopa did not impact on the rotarod time (p>0.05). Conclusion: Levodopa reversed tactile, cold and heat allodynia in neuropathic rat without any side effects.
Yonsei medical journal 03/2013; 54(2):330-5. · 0.77 Impact Factor
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ABSTRACT: The immune system releases cytokines during the stress response, and the balance between proinflammatory and anti-inflammatory cytokines is important. This prospective study was done to determine which cytokines are responsible for maintaining cytokine balance during live-donor liver transplant surgery.
Recipients undergoing live-donor liver transplant surgery due to cirrhotic hepatitis were allocated to a recipient group (n=44), and healthy donors were placed in the donor group (n=45). In donors, blood sampling for cytokine level analysis was performed after anesthetic induction (before the start of surgery, time point 1). In recipients, blood samples were collected before the start of surgery (time point 1), 60 minutes after the start of the anhepatic period (time point 2), and 60 minutes after reperfusion (time point 3). The proinflammatory cytokines measured were interleukin-1 β, interleukin-6, and tumor necrosis factor-α; the anti-inflammatory cytokines were interleukin-10 and interleukin-4. Cytokines were quantified using sandwich enzyme-linked immunoassays. The time course of proinflammatory and anti-inflammatory cytokine concentrations during surgery in the recipient group was evaluated.
Interleukin-6, interleukin-10 and tumor necrosis factor-α showed significant changes in concentration during surgery, with interleukin-6 reaching levels 40 times higher than the preoperative value at the anhepatic stage. Interleukin-10 reached a peak at the neohepatic phase, with values 60 times higher than the preoperative value. The preoperative concentrations of interleukin-6 and interleukin-10 in the recipient group were higher than those in the donor group with a median of 4.48 vs 1.98 pg/mL (P < .001) and 2.98 vs 1.22 (P = .026).
Interleukin-6 and interleukin-10 play a major role in cytokine balance before and during live-donor liver transplant surgery.
Experimental and clinical transplantation : official journal of the Middle East Society for Organ Transplantation. 02/2013; 11(1):39-43.
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ABSTRACT: STUDY OBJECTIVE: To investigate whether a continuous infusion of low-dose esmolol results in an opioid-sparing effect during surgery. DESIGN: Randomized, double-blinded, placebo-controlled clinical comparison study. SETTING: Operating room of a university hospital. PATIENTS: 56 ASA physical status 1 and 2 patients, aged 20 to 60 years, undergoing laparoscopic gynecologic surgery of less than two hours' duration. INTERVENTIONS: The esmolol group (n = 28) received a 0.5 mg/kgloading dose of esmolol followed by an infusion of esmolol30 μg/kg/min; the saline group (n = 28) received equivalent volumes of normal saline. MEASUREMENTS: The effect-site concentration of remifentanil (ng/mL) to maintain adequate anesthetic depth before infusion of the study drug (before-concentration) was measured. During infusion of study drug, the effect-site concentration of remifentanil was adjusted every 5 minutes to maintain systolic blood pressure within 15% of baseline and a Bispectral Index value between 50-60. The average of these adjusted concentrations (after-concentration) was measured and compared to the before-concentration.The quality of postoperativey recovery was assessed. MAIN RESULTS: In the esmolol group, the after-concentration of remifentanilwas decreased by 33.3% compared with the before-concentration. The total dose of remifentanil infused was also lower in the esmolol group (0.09 ± 0.1 vs 0.14 ± 0.03 μg/kg/min;P = 0.031). The esmolol group had lower scores on a pain numerical rating scale and required less fentanyl in the Postanesthesia Care Unit. CONCLUSIONS: Intraoperative esmololinfusion decreases both the requirement for remifentanil and postoperative administration of rescue analgesics.
Journal of clinical anesthesia 11/2012; · 1.32 Impact Factor
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ABSTRACT: Body posture, as a gravitational factor, has a clear impact on pulmonary ventilation and perfusion. In lung units with mismatched ventilation and perfusion, gas exchange and/or elimination of carbon dioxide can be impaired. In this situation, differences in the value of arterial and end-tidal carbon dioxide tension [Δ(PaCO(2) - P(ET)CO(2))] are expected to increase. This study was conducted to observe how Δ(PaCO(2) - P(ET)CO(2)) changed according to the 3 different surgical positions, and to determine whether Δ(PaCO(2) - P(ET)CO(2)) is a reliable predictor of ventilation/perfusion mismatch when a patient is in different postural positions.
Fifty-nine patients were divided into either the chronic obstructive pulmonary disease (COPD) group (n = 29) or the non-COPD group (n = 30). PaCO(2) and P(ET)CO(2) were measured during surgery in the supine, prone, and lateral decubitus positions after a 10 minute stabilization period. The Δ(PaCO(2) - P(ET)CO(2)) were calculated and compared among positions.
The Δ(PaCO(2) - P(ET)CO(2)) decreased slightly in the prone position and increased significantly in the lateral decubitus position compared with the supine position in both groups. These patterns almost corresponded with the degree of ventilation/perfusion mismatch from the results of the radiological studies. The Δ(PaCO(2) - P(ET)CO(2)) in the COPD group was significantly greater than that in the non-COPD group at all surgical positions.
Lateral decubitus position is associated with marked increase in Δ(PaCO(2) - P(ET)CO(2)), especially in patients with COPD. The Δ(PaCO(2) - P(ET)CO(2)) is a simple and reliable indicator to predict ventilation/perfusion mismatch at different surgical positions in patients with or without COPD.
Korean journal of anesthesiology 09/2012; 63(3):216-20.
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ABSTRACT: Purpose: Epidural morphine is associated with decreased bowel motility and increased transit time. Low doses of intravenous
naloxone reduce morphine-induced pruritus without reversing analgesia, but the effect of epidural naloxone on bowel motility
has not been studied. Therefore we evaluated bowel motility and analgesia when naloxone was co-administered with morphine
into the epidural space.
Methods: Forty-three patients having combined thoracic epidural and general anesthesia for subtotal gastrectomy were randomly
assigned to one of two study groups. All received a bolus dose of 3 mg epidural morphine at the beginning of surgery, followed
by a continuous epidural infusion containing 3 mg morphine in 100 ml bupivacaine 0.125% with either no naloxone (control group,
n=18) or a calculated dose of 0.208 µg·kg−1·hr−1 of naloxone (experimental group, n=25) for 48 hr. We measured the time to the first postoperative passage of flatus and feces
to evaluate the restoration of bowel function, and visual analog scales (VAS) for pain during rest and movement. Scores were
assessed at 2, 4, 8, 16, 24, 36 and 48 hr postoperatively.
Results: The experimental group had a shorter time to the first postoperative passage of flatus (51.9±16.6 hrvs 87.0±19.5 hr,P<0.001) and feces (95.3±25.0 hrvs 132.9±29.4 hr,P<0.001). No differences were found in either resting or active VAS between the two groups.
Conclusion: Epidural naloxone reduces epidural morphine-induced intestinal hypomotility without reversing its analgesic effects.
Objectif: L’administration péridurale de morphine est associée à une baisse de la motilité intestinale et à une augmentation
de la durée du transit. De faibles doses de naloxone intraveineuse réduisent le prurit induit par la morphine sans renverser
l’analgésie, mais l’effet de l’administration péridurale de naloxone sur la motilité intestinale n’a pas encore été étudié.
C’est pourquoi nous avons évalué cette action et l’analgésie de la naloxone administrée avec de la morphine dans l’espace
péridural.
Méthode: Quarante-trois patients qui recevaient une anesthésie péridurale thoracique et générale combinée, pour une gastrectomie
partielle, ont été répartis au hasard en deux groupes. Tous ont reçu un bolus de 3 mg de morphine péridurale au début de l’intervention,
suivi d’une perfusion péridurale continue de 3 mg de morphine dans 100 ml de bupivacaïne à 0,125 % sans naloxone (groupe témoin,
n=18) ou avec une dose calculée de 0,208 µg·kg−1·h−1 de naloxone (groupe expérimental, n=25) pendant 48 h. Nous avons mesuré le temps écoulé avant la première expulsion des gaz
intestinaux et des selles afin d’évaluer la restauration de la fonction intestinale et mesuré les scores de douleur à l’aide
de l’échelle visuelle analogique (EVA), au repos et pendant le mouvement. Les scores postopératoires ont été relevés à 2,
4, 8, 16, 24, 36 et à 48 h.
Résultats: Dans le groupe expérimental, le temps précédant le premier passage postopératoire des gaz (51,9±16,6 hvs 87,0±19,5 h,P<0,001) et des selles (95,3 ±25,0 h) a été plus court comparé au groupe témoin (132,9±29,4 h,P<0,001). Aucune différence intergroupe n’a été observée aux scores de l’EVA obtenus au repos ou pendant le mouvement.
Conclusion: La naloxone péridurale réduit l’hypomotilité intestinale induite par la morphine péridurale sans renverser ses
effets analgésiques.
Canadian Journal of Anaesthesia 04/2012; 48(1):54-58. · 2.35 Impact Factor
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ABSTRACT: The aim of this study was to evaluate and compare the Child-Turcotte-Pugh (CTP) classification system and the model for end-stage liver disease (MELD) score in predicting the severity of the systemic inflammatory response in living-donor liver transplantation patients. Recipients of liver graft were allocated to a recipient group (n = 39) and healthy donors to a donor group (n = 42). The association between the CTP classification, the MELD scores and perioperative cytokine concentrations in the recipient group was evaluated. The pro-inflammatory cytokines measured included interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α; the anti-inflammatory cytokines measured included IL-10 and IL-4. Cytokine concentrations were quantified using sandwich enzyme-linked immunoassays. The IL-6, TNF-α, and IL-10 concentrations in the recipient group were significantly higher than those in healthy donor group patients. All preoperative cytokine levels, except IL-6, increased in relation to the severity of liver disease, as measured by the CTP classification. Additionally, all cytokine levels, except IL-6, were significantly correlated preoperatively with MELD scores. However, the correlations diminished during the intraoperative period. The CTP classification and the MELD score are equally reliable in predicting the severity of the systemic inflammatory response, but only during the preoperative period.
Journal of Korean medical science 10/2011; 26(10):1333-8. · 0.84 Impact Factor
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ABSTRACT: In vertebrates, the thyroglobulin (Tg) gene product must be exported to the lumen of thyroid follicles for thyroid hormone synthesis. In toto, Tg is composed of multiple type-1 repeats connected by linker and hinge (altogether considered as "region I," nearly 1,200 residues); regions II-III (~720 residues); and cholinesterase-like (ChEL) domain (~570 residues). Regions II-III and ChEL rapidly acquire competence for secretion, yet regions I-II-III require 20 min to become a partially mature disulfide isomer; stabilization of a fully oxidized form requires ChEL. Transition from partially mature to mature Tg occurs as a discrete "jump" in mobility by nonreducing SDS-PAGE, suggesting formation of at most a few final pairings of Cys residues that may be separated by significant intervening primary sequence. Using two independent approaches, we have investigated which portion of Tg is engaged in this late stage of its maturation. First, we demonstrate that this event is linked to oxidation involving region I. Introduction of the Tg-C1245R mutation in the hinge (identical to that causing human goitrous hypothyroidism) inhibits this maturation, although the Cys-1245 partner remains unidentified. Second, we find that Tg truncated after its fourth type-1 repeat is a fully independent secretory protein. Together, the data indicate that final acquisition of secretory competence includes conformational maturation in the interval between linker and hinge segments of region I.
Journal of Biological Chemistry 08/2011; 286(38):33045-52. · 4.77 Impact Factor
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ABSTRACT: To determine the optimal dose of esmolol in combination with nicardipine in effectively blocking undesirable cardiovascular responses during rapid-sequence induction.
Prospective, randomized clinical comparison study.
Operating room of a university hospital.
200 ASA physical status 1 and 2 patients requiring general anesthesia with endotracheal tube placement.
Patients were randomly allocated into one of 4 groups: Group E0 (no esmolol; control), Group E0.25 (esmolol 0.25 mg/kg), Group E0.5 (esmolol 0.5 mg/kg), and Group E1.0 (esmolol 1.0 mg/kg). All patients received 20 μg/kg of nicardipine, and esmolol was then given according to group allocation. Ninety seconds later, thiopental sodium 5 mg/kg and succinylcholine 1.0 mg/kg were injected. Endotracheal intubation was performed 60 seconds after injection of the anesthetic agents.
Systolic (SBP), diastolic (DBP), and mean arterial (MAP) pressures; heart rate (HR), and rate-pressure product (RPP) were measured 30 seconds before and after intubation, and at 1, 3, 5, and 10 minutes after intubation. Rate changes using baseline values as the standard [rate changes = measured value/baseline value × 100 (%)] were calculated.
Significant attenuations in SBP, MAP, HR, and RPP after intubation were noted in the experimental groups as compared with the control group (P < 0.05). Rate changes in HR in Groups E0.5 and E1.0 were significantly lower than those in Group E0.25 immediately and one minute after intubation (P < 0.05). No difference in rate changes in HR were noted between the E0.5 and E1.0 groups.
The combination of nicardipine 20 μg/kg and esmolol 0.5 mg/kg most effectively attenuates the cardiovascular responses during rapid-sequence induction.
Journal of clinical anesthesia 06/2011; 24(1):8-13. · 1.32 Impact Factor
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ABSTRACT: Thyroglobulin (precursor for thyroid hormone synthesis) is a large secreted glycoprotein comprising contiguous region I (multiple type-1 repeating units engaging the first ∼1,191 residues, followed by a ∼245-residue hinge region), regions II-III (multiple type-2 and 3 repeating units, comprising ∼720 residues), and the C-terminal cholinesterase-like (ChEL) domain (∼570 residues). A signal peptide attached to ChEL makes an independent secretory protein that binds to I-II-III, stabilizing it and rescuing the secretion of I-II-III that would otherwise be trapped in the endoplasmic reticulum (ER). In this study, we found that a signal peptide attached to regions II-III also makes for an efficient secretory protein that neither demonstrably interacts nor has its secretion enhanced by the presence of secretory ChEL. By contrast, region I, either with or without the hinge region, cannot be secreted on its own and remains in the ER where it is bound to ER chaperones BiP and GRP94. Whereas ChEL can rescue secretion of I-II-III, it can rescue I-II only very weakly, and region I not at all. Yet, ChEL begins to rescue region I in cells that also co-express secretory II-III. The data suggest that conformational maturation of region I is a limiting step in the thyroglobulin maturation process, and this step is facilitated by the presence of both regions II-III and ChEL. Mutations causing hypothyroidism might induce solely local/regional misfolding or may interfere more globally by impeding interactions between regions that are required for thyroglobulin secretion.
Journal of Biological Chemistry 06/2011; 286(30):26327-33. · 4.77 Impact Factor
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ABSTRACT: Although intravenous acetaminophen is commonly used for the management of postoperative pain, very limited evidence supports the usefulness of preoperative administration. The aim of this study was to determine the analgesic effect of preoperative acetaminophen on opioid consumption, pain scores, and side effects in patients receiving an elective abdominal hysterectomy.
A randomized, double-blinded, placebo-controlled clinical trial was performed in 76 women undergoing abdominal hysterectomy. Patients received either acetaminophen 2 g (group A) or placebo (group C) intravenously 30 min before surgery under general anesthesia. Postoperative pain was treated with patient-controlled intravenous hydromorphone 0.2 mg bolus. Hydromorphone consumption, pain scores during rest and movement, and any adverse effects were recorded at 1, 2, 6, 12, and 24 h after the operation.
Overall hydromorphone consumption was significantly lower in group A compared with group C at all the time points (P = 0.013). The total 24-h hydromorphone consumption was reduced by 30% in group A. There was no significant difference in pain scores. The incidence of postoperative nausea and vomiting after the operation were significantly lower in group A than in group C (P < 0.05).
Premedication with acetaminophen reduced hydromorphone consumption and opioid-related side effect in patients undergoing abdominal hysterectomy, but did not significantly reduce pain intensity.
Archives of Gynecology 02/2011; 284(6):1455-60. · 0.91 Impact Factor
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Jaemin Lee
Korean journal of anesthesiology 01/2011; 60(1):1-2.
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ABSTRACT: Thyroglobulin (Tg, precursor for thyroid hormone synthesis) is a large secreted glycoprotein composed of upstream regions
I-II-III, followed by the ∼570 residue cholinesterase-like (ChEL) domain. ChEL has two identified functions: 1) homodimerization,
and 2) binding to I-II-III that facilitates I-II-III oxidative maturation required for intracellular protein transport. Like
its homologs in the acetylcholinesterase (AChE) family, ChEL possesses two carboxyl-terminal α-helices. We find that a Tg-AChE
chimera (swapping AChE in place of ChEL) allows for dimerization with monomeric AChE, proving exposure of the carboxyl-terminal
helices within the larger context of Tg. Further, we establish that perturbing trans-helical interaction blocks homodimerization of the Tg ChEL domain. Additionally, ChEL can associate with neuroligins (a related
family of cholinesterase-like proteins), demonstrating potential for Tg cross-dimerization between non-identical partners.
Indeed, when mutant rdw-Tg (Tg-G2298R, defective for protein secretion) is co-expressed with wild-type Tg, the two proteins
cross-dimerize and secretion of rdw-Tg is partially restored. Moreover, we find that AChE and soluble neuroligins also can
bind to the upstream Tg regions I-II-III; however, they cannot rescue secretion, because they cannot facilitate oxidative
maturation of I-II-III. These data suggest that specific properties of distinct Tg ChEL mutants may result in distinct patterns
of Tg monomer folding, cross-dimerization with wild-type Tg, and variable secretion behavior in heterozygous patients.
Journal of Biological Chemistry 06/2010; 285(23):17564-17573. · 4.77 Impact Factor
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ABSTRACT: Thyroglobulin (Tg, precursor for thyroid hormone synthesis) is a large secreted glycoprotein composed of upstream regions I-II-III, followed by the approximately 570 residue cholinesterase-like (ChEL) domain. ChEL has two identified functions: 1) homodimerization, and 2) binding to I-II-III that facilitates I-II-III oxidative maturation required for intracellular protein transport. Like its homologs in the acetylcholinesterase (AChE) family, ChEL possesses two carboxyl-terminal alpha-helices. We find that a Tg-AChE chimera (swapping AChE in place of ChEL) allows for dimerization with monomeric AChE, proving exposure of the carboxyl-terminal helices within the larger context of Tg. Further, we establish that perturbing trans-helical interaction blocks homodimerization of the Tg ChEL domain. Additionally, ChEL can associate with neuroligins (a related family of cholinesterase-like proteins), demonstrating potential for Tg cross-dimerization between non-identical partners. Indeed, when mutant rdw-Tg (Tg-G2298R, defective for protein secretion) is co-expressed with wild-type Tg, the two proteins cross-dimerize and secretion of rdw-Tg is partially restored. Moreover, we find that AChE and soluble neuroligins also can bind to the upstream Tg regions I-II-III; however, they cannot rescue secretion, because they cannot facilitate oxidative maturation of I-II-III. These data suggest that specific properties of distinct Tg ChEL mutants may result in distinct patterns of Tg monomer folding, cross-dimerization with wild-type Tg, and variable secretion behavior in heterozygous patients.
Journal of Biological Chemistry 03/2010; 285(23):17564-73. · 4.77 Impact Factor
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ABSTRACT: To facilitate combined doxorubicin and photothermal treatments, we developed doxorubicin-loaded poly(lactic-co-glycolic acid)-gold half-shell nanoparticles (DOX-loaded PLGA-Au H-S NPs) by depositing Au films on DOX-loaded PLGA NPs. As the PLGA NPs biodegraded, DOX was released, and heat was locally generated upon near-infrared (NIR) irradiation due to NIR resonance of DOX-loaded PLGA H-S NPs. Compared with chemotherapy or photothermal treatment alone, the combined treatment demonstrated a synergistic effect, resulting in higher therapeutic efficacy and shorter treatment times. Since our NPs selectively deliver both heat and drug to tumorigenic regions, they may improve the therapeutic effectiveness with minimal side effects.
ACS Nano 09/2009; 3(10):2919-26. · 10.77 Impact Factor
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ABSTRACT: Novel bifunctional fluorescent magneto polymeric nanoprobes (FMPNs) were synthesized to provide simultaneous diagnostic information via magnetic resonance imaging (MRI) and optical imaging. FMPNs consist of ultra-sensitive magnetic nanocrystals that function as MR probes combined with Nile Red, which functions as a fluorescent probe. FMPNs were encapsulated by a nano-emulsion method in polyvinyl alcohol (PVA, 87-89% hydrolyzed) through a matrix of polymethyl methacrylate (PMMA). FMPNs exhibited excellent colloidal stability and monodispersity. The production of MR and optical images demonstrated that FMPNs have potential as dual-mode imaging agents.
Journal of Colloid and Interface Science 08/2009; 340(2):176-81. · 3.07 Impact Factor
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ABSTRACT: The carboxyl-terminal cholinesterase-like (ChEL) domain of thyroglobulin (Tg) has been identified as critically important in Tg export from the endoplasmic reticulum. In a number of human kindreds suffering from congenital hypothyroidism, and in the cog congenital goiter mouse and rdw rat dwarf models, thyroid hormone synthesis is inhibited because of mutations in the ChEL domain that block protein export from the endoplasmic reticulum. We hypothesize that Tg forms homodimers through noncovalent interactions involving two predicted alpha-helices in each ChEL domain that are homologous to the dimerization helices of acetylcholinesterase. This has been explored through selective epitope tagging of dimerization partners and by inserting an extra, unpaired Cys residue to create an opportunity for intermolecular disulfide pairing. We show that the ChEL domain is necessary and sufficient for Tg dimerization; specifically, the isolated ChEL domain can dimerize with full-length Tg or with itself. Insertion of an N-linked glycan into the putative upstream dimerization helix inhibits homodimerization of the isolated ChEL domain. However, interestingly, co-expression of upstream Tg domains, either in cis or in trans, overrides the dimerization defect of such a mutant. Thus, although the ChEL domain provides a nidus for Tg dimerization, interactions of upstream Tg regions with the ChEL domain actively stabilizes the Tg dimer complex for intracellular transport.
Journal of Biological Chemistry 04/2009; 284(19):12752-61. · 4.77 Impact Factor
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ABSTRACT: Antibody-conjugated hydrophilic magnetic nanocrystals for use as smart nanoprobes were developed for ultrasensitive detection of breast cancer via magnetic resonance (MR) imaging. MnFe(2)O(4) nanocrystals (MNCs) for use as MR imaging contrast agents were synthesized by thermal decomposition to take advantage of their MR signal enhancement effect. The MNC surfaces were then modified with amphiphilic tri-block copolymers (dicarboxy poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol)), not only allowing the MNCs to transfer from the organic to the aqueous phase, but also increasing the colloidal stability of the MNCs by masking poly(ethylene glycol). The physicochemical properties of the synthesized hydrophilic magnetic nanocrystals (HMNCs) were fully investigated. Trastuzumab (TZ), a monoclonal antibody against human epidermal growth factor receptor (HER2/neu), was further conjugated on the surface of HMNCs to specifically target HER2/neu over-expressed breast cancer cells. MR imaging analysis of target cells treated with TZ-conjugated HMNCs (TZ-HMNCs) clearly demonstrated their potential as high-performance nanoprobes for selective imaging.
Nanotechnology 12/2008; 19(48):485101. · 3.98 Impact Factor
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ABSTRACT: Thyroid hormonogenesis requires secretion of thyroglobulin, a protein comprising Cys-rich regions I, II, and III (referred to collectively as region I-II-III) followed by a cholinesterase-like (ChEL) domain. Secretion of mature thyroglobulin requires extensive folding and glycosylation in the ER. Multiple reports have linked mutations in the ChEL domain to congenital hypothyroidism in humans and rodents; these mutations block thyroglobulin from exiting the ER and induce ER stress. We report that, in a cell-based system, mutations in the ChEL domain impaired folding of thyroglobulin region I-II-III. Truncated thyroglobulin devoid of the ChEL domain was incompetent for cellular export; however, a recombinant ChEL protein ("secretory ChEL") was secreted efficiently. Coexpression of secretory ChEL with truncated thyroglobulin increased intracellular folding, promoted oxidative maturation, and facilitated secretion of region I-II-III, indicating that the ChEL domain may function as an intramolecular chaperone. Additionally, we found that the I-II-III peptide was cosecreted and physically associated with secretory ChEL. A functional ChEL domain engineered to be retained intracellularly triggered oxidative maturation of I-II-III but coretained I-II-III, indicating that the ChEL domain may also function as a molecular escort. These insights into the role of the ChEL domain may represent potential therapeutic targets in the treatment of congenital hypothyroidism.
Journal of Clinical Investigation 08/2008; 118(8):2950-8. · 15.39 Impact Factor
