Cho HJ

References (9)

Title : Azo-Stilbene and Pyridine-Amine Hybrid Multifunctional Molecules to Target Metal-Mediated Neurotoxicity and Amyloid-beta Aggregation in Alzheimer's Disease - Rana_2022_Inorg.Chem__
Author(s) : Rana M , Cho HJ , Arya H , Bhatt TK , Bhar K , Bhatt S , Mirica LM , Sharma AK
Ref : Inorg Chem , : , 2022
Abstract : Neurodegenerative diseases such as Alzheimer's disease (AD) are associated with progressive neuronal cell death, and they are commonly correlated with aberrant protein misfolding and aggregation of Abeta peptides. Transition metal ions (Cu, Fe, and Zn) have been shown to promote aggregation and oxidative stress through formation of Abeta-metal complexes. In this context, integrating molecular scaffolds rationally is used here to generate multifunctional molecules as modulators for metal-induced abnormalities. This work encompasses two azo-stilbene (AS)-derived compounds (AS-HL1 and AS-HL2), the rationale behind the design, their synthesis, characterization, and metal chelation ability [Cu(II) and Zn(II)]. The molecular frameworks of the designed compounds consist of stilbene as an Abeta-interacting moiety, whereas N,N,O and N,N,N,O donor atoms are linked to generate the metal chelation moiety. Furthermore, we went on exploring their multifunctionality with respect to (w.r.t.) (i) their metal chelating capacities and (ii) their utility to modulate the aggregation pathways of both metal-free and metal-bound amyloid-beta, (iii) scavenge free radicals, and (iv) inhibit the activity of acetylcholinesterase and (v) cytotoxicity. Moreover, the compounds were able to sequester Cu(2+) from the Abeta-Cu complex as studied by the UV-visible spectroscopic assay. Molecular docking studies were also performed with Abeta and acetylcholinesterase enzyme. Overall, the studies presented here qualify these molecules as promising candidates for further investigation in the quest for finding a treatment for Alzheimer's disease.
ESTHER : Rana_2022_Inorg.Chem__
PubMedSearch : Rana_2022_Inorg.Chem__
PubMedID: 35768324

Title : Subcutaneously Injectable Hyaluronic Acid Hydrogel for Sustained Release of Donepezil with Reduced Initial Burst Release: Effect of Hybridization of Microstructured Lipid Carriers and Albumin - Kang_2021_Pharmaceutics_13_2
Author(s) : Kang NW , Yoon SY , Kim S , Yu NY , Park JH , Lee JY , Cho HJ , Kim DD
Ref : Pharmaceutics , 13 : , 2021
Abstract : The daily oral administration of acetylcholinesterase (AChE) inhibitors for Alzheimer's disease features low patient compliance and can lead to low efficacy or high toxicity owing to irregular intake. Herein, we developed a subcutaneously injectable hyaluronic acid hydrogel (MLC/HSA hydrogel) hybridized with microstructured lipid carriers (MLCs) and human serum albumin (HSA) for the sustained release of donepezil (DNP) with reduced initial burst release. The lipid carrier was designed to have a microsized mean diameter (32.6 +/- 12.8 microm) to be well-localized in the hydrogel. The hybridization of MLCs and HSA enhanced the structural integrity of the HA hydrogel, as demonstrated by the measurements of storage modulus (G'), loss modulus (G''), and viscosity. In the pharmacokinetic study, subcutaneous administration of MLC/HSA hydrogel in rats prolonged the release of DNP for up to seven days and reduced the initial plasma concentration, where the C(max) value was 0.3-fold lower than that of the control hydrogel without a significant change in the AUC(last) value. Histological analyses of the hydrogels supported their biocompatibility for subcutaneous injection. These results suggest that a new hybrid MLC/HSA hydrogel could be promising as a subcutaneously injectable controlled drug delivery system for the treatment of Alzheimer's disease.
ESTHER : Kang_2021_Pharmaceutics_13_2
PubMedSearch : Kang_2021_Pharmaceutics_13_2
PubMedID: 34208289

Title : Complex interrelationships between nitro-alkene-dependent inhibition of soluble epoxide hydrolase, inflammation and tumor growth - Cho_2020_Redox.Biol_29_101405
Author(s) : Cho HJ , Switzer CH , Kamynina A , Charles R , Rudyk O , Ng T , Burgoyne JR , Eaton P
Ref : Redox Biol , 29 :101405 , 2020
Abstract : Nitro-oleate (10-nitro-octadec-9-enoic acid), which inhibits soluble epoxide hydrolase (sEH) by covalently adducting to C521, increases the abundance of epoxyeicosatrienoic acids (EETs) that can be health promoting, for example by lowering blood pressure or their anti-inflammatory actions. However, perhaps consistent with their impact on angiogenesis, increases in EETs may exacerbate progression of some cancers. To assess this, Lewis lung carcinoma (LLc1) cells were exposed to oleate or nitro-oleate, with the latter inhibiting the hydrolase and increasing their proliferation and migration in vitro. The enhanced proliferation induced by nitro-oleate was EET-dependent, being attenuated by the ETT-receptor antagonist 14,15-EE-5(Z)-E. LLc1 cells were engineered to stably overexpress wild-type or C521S sEH, with the latter exhibiting resistance to nitro-oleate-dependent hydrolase inhibition and the associated stimulation of tumor growth in vitro or in vivo. Nitro-oleate also increased migration in endothelial cells isolated from wild-type (WT) mice, but not those from C521S sEH knock-in (KI) transgenic mice genetically modified to render the hydrolase electrophile-resistant. These observations were consistent with nitro-oleate promoting cancer progression, and so the impact of this electrophile was examined in vivo again, but this time comparing growth of LLc1 cells expressing constitutive levels of wild-type hydrolase when implanted into WT or KI mice. Nitro-oleate inhibited tumor sEH (P < 0.05), with a trend for elevated plasma 11(12)-EET/DHET and 8(9)EET/DHET (dihydroxyeicosatrienoic acid) ratios when administered to WT, but not KI, mice. Although in vitro studies with LLc1 cells supported a role for nitro-oleate in cancer cell proliferation, it failed to significantly stimulate tumor growth in WT mice implanted with the same LLc1 cells in vivo, perhaps due to its well-established anti-inflammatory actions. Indeed, pro-inflammatory cytokines were significantly down-regulated in nitro-oleate treated WT mice, potentially countering any impact of the concomitant inhibition of sEH.
ESTHER : Cho_2020_Redox.Biol_29_101405
PubMedSearch : Cho_2020_Redox.Biol_29_101405
PubMedID: 31926628

Title : Esterase-sensitive cleavable histone deacetylase inhibitor-coupled hyaluronic acid nanoparticles for boosting anticancer activities against lung adenocarcinoma - Lee_2019_Biomater.Sci_7_4624
Author(s) : Lee SY , Hong EH , Jeong JY , Cho J , Seo JH , Ko HJ , Cho HJ
Ref : Biomater Sci , 7 :4624 , 2019
Abstract : 4-Phenylbutyric acid (PBA)-installed hyaluronic acid (HA)-based nanoparticles (NPs) were developed for amplifying the anticancer potential of curcumin (CUR) for lung cancer therapy. PBA was introduced to the HA backbone as a hydrophobic segment of a nanoassembled structure and as a histone deacetylase (HDAC) inhibitor for cancer therapy. PBA was released from the HA-PBA conjugate (HAPBA) via an esterase-responsive cleavage of ester bonds in cancer cells and may affect the dissociation of NP structure. CUR-entrapped HAPBA-based NPs, with 265 nm hydrodynamic size, unimodal size distribution, negative zeta potential, and sustained drug release, were fabricated. Co-treatment of A549 cells by PBA and CUR elevated the antiproliferation efficiency compared with CUR-treatment. CUR-loaded HAPBA NPs also exhibited a significantly lower IC50 value compared with the CUR and HAPBA10 + CUR groups (p < 0.05). Cy5.5-labeled HAPBA NPs containing CUR group displayed higher accumulation in tumor tissue and less distribution in liver and spleen after intravenous injection compared with the Cy5.5-injected group in A549 tumor-bearing mouse model. Multiple dosing of CUR-loaded HAPBA NPs in A549 tumor-bearing mouse model exhibited efficient tumor growth suppression and apoptosis-inducing effects. CD44 receptor targeting and HDAC inhibiting HAPBA NPs can be used to boost the anticancer potentials of drug cargo for the therapy of CD44 receptor-expressed cancers.
ESTHER : Lee_2019_Biomater.Sci_7_4624
PubMedSearch : Lee_2019_Biomater.Sci_7_4624
PubMedID: 31451819

Title : Physostigmine-loaded liposomes for extended prophylaxis against nerve agent poisoning - Park_2018_Int.J.Pharm_553_467
Author(s) : Park JH , Lee JY , Kim KT , Joe HE , Cho HJ , Shin YK , Kim DD
Ref : Int J Pharm , 553 :467 , 2018
Abstract : Pre-administration of physostigmine can prevent poisoning against nerve agent exposure by reversibly binding to cholinesterase. However, its cholinesterase protection-based prophylactic effect can be eliminated rapidly due to short biological half-life. Liposomes are useful for encapsulating hydrophilic drugs like physostigmine, and can be used for sustained release after parenteral injection. Thus, physostigmine liposomes were prepared by the pH-gradient condition-based remote-loading method for subcutaneous injection. In addition, polyethylene glycol (PEG)-lipid was applied to further extend the release of physostigmine and its prophylactic action. In vitro release of physostigmine, pharmacokinetics and duration of prophylactic effect were then evaluated. Physostigmine was dissolved in distilled water and used as a solution group for comparison. The prepared liposomes showed spherical shape and their particle size was around 130mum. Addition of PEG-lipid in liposomes significantly increased the entrapment efficiency of physostigmine. Both control and PEG liposomes exhibited sustained release pattern compared to the solution. Moreover, the release of PEG liposomes was relatively slower than that of the control liposomes. Pharmacokinetic study in rats revealed that physostigmine liposomes exhibited lower maximum plasma concentration and longer half-life compared to the solution. Plasma cholinesterase inhibition ratio in the liposomal group decreased more gradually compared to the solution. Moreover, PEG liposomes showed higher plasma concentration of physostigmine and cholinesterase inhibition ratio compared to the control liposomes. These results suggest that PEG liposomes have potential to enhance the duration of cholinesterase-protecting effect of physostigmine.
ESTHER : Park_2018_Int.J.Pharm_553_467
PubMedSearch : Park_2018_Int.J.Pharm_553_467
PubMedID: 30389473

Title : A Little CFTR Goes a Long Way: CFTR-Dependent Sweat Secretion from G551D and R117H-5T Cystic Fibrosis Subjects Taking Ivacaftor - Char_2014_PLoS.One_9_e88564
Author(s) : Char JE , Wolfe MH , Cho HJ , Park IH , Jeong JH , Frisbee E , Dunn C , Davies Z , Milla C , Moss RB , Thomas EA , Wine JJ
Ref : PLoS ONE , 9 :e88564 , 2014
Abstract : To determine if oral dosing with the CFTR-potentiator ivacaftor (VX-770, Kalydeco) improves CFTR-dependent sweating in CF subjects carrying G551D or R117H-5T mutations, we optically measured sweat secretion from 32-143 individually identified glands in each of 8 CF subjects; 6 F508del/G551D, one G551D/R117H-5T, and one I507del/R117H-5T. Two subjects were tested only (-) ivacaftor, 3 only (+) ivacaftor and 3 (+/-) ivacaftor (1-5 tests per condition). The total number of gland measurements was 852 (-) ivacaftor and 906 (+) ivacaftor. A healthy control was tested 4 times (51 glands). For each gland we measured both CFTR-independent (M-sweat) and CFTR-dependent (C-sweat); C-sweat was stimulated with a beta-adrenergic cocktail that elevated [cAMP]i while blocking muscarinic receptors. Absent ivacaftor, almost all CF glands produced M-sweat on all tests, but only 1/593 glands produced C-sweat (10 tests, 5 subjects). By contrast, 6/6 subjects (113/342 glands) produced C-sweat in the (+) ivacaftor condition, but with large inter-subject differences; 3-74% of glands responded with C/M sweat ratios 0.04%-2.57% of the average WT ratio of 0.265. Sweat volume losses cause proportionally larger underestimates of CFTR function at lower sweat rates. The losses were reduced by measuring C/M ratios in 12 glands from each subject that had the highest M-sweat rates. Remaining losses were estimated from single channel data and used to correct the C/M ratios, giving estimates of CFTR function (+) ivacaftor = 1.6%-7.7% of the WT average. These estimates are in accord with single channel data and transcript analysis, and suggest that significant clinical benefit can be produced by low levels of CFTR function.
ESTHER : Char_2014_PLoS.One_9_e88564
PubMedSearch : Char_2014_PLoS.One_9_e88564
PubMedID: 24520399

Title : In vivo readout of CFTR function: ratiometric measurement of CFTR-dependent secretion by individual, identifiable human sweat glands - Wine_2013_PLoS.One_8_e77114
Author(s) : Wine JJ , Char JE , Chen J , Cho HJ , Dunn C , Frisbee E , Joo NS , Milla C , Modlin SE , Park IH , Thomas EA , Tran KV , Verma R , Wolfe MH
Ref : PLoS ONE , 8 :e77114 , 2013
Abstract : To assess CFTR function in vivo, we developed a bioassay that monitors and compares CFTR-dependent and CFTR-independent sweat secretion in parallel for multiple (~50) individual, identified glands in each subject. Sweating was stimulated by intradermally injected agonists and quantified by optically measuring spherical sweat bubbles in an oil-layer that contained dispersed, water soluble dye particles that partitioned into the sweat bubbles, making them highly visible. CFTR-independent secretion (M-sweat) was stimulated with methacholine, which binds to muscarinic receptors and elevates cytosolic calcium. CFTR-dependent secretion (C-sweat) was stimulated with a beta-adrenergic cocktail that elevates cytosolic cAMP while blocking muscarinic receptors. A C-sweat/M-sweat ratio was determined on a gland-by-gland basis to compensate for differences unrelated to CFTR function, such as gland size. The average ratio provides an approximately linear readout of CFTR function: the heterozygote ratio is ~0.5 the control ratio and for CF subjects the ratio is zero. During assay development, we measured C/M ratios in 6 healthy controls, 4 CF heterozygotes, 18 CF subjects and 4 subjects with 'CFTR-related' conditions. The assay discriminated all groups clearly. It also revealed consistent differences in the C/M ratio among subjects within groups. We hypothesize that these differences reflect, at least in part, levels of CFTR expression, which are known to vary widely. When C-sweat rates become very low the C/M ratio also tended to decrease; we hypothesize that this nonlinearity reflects ductal fluid absorption. We also discovered that M-sweating potentiates the subsequent C-sweat response. We then used potentiation as a surrogate for drugs that can increase CFTR-dependent secretion. This bioassay provides an additional method for assessing CFTR function in vivo, and is well suited for within-subject tests of systemic, CFTR-directed therapeutics.
ESTHER : Wine_2013_PLoS.One_8_e77114
PubMedSearch : Wine_2013_PLoS.One_8_e77114
PubMedID: 24204751

Title : Carriage of the V279F null allele within the gene encoding Lp-PLA(2) is protective from coronary artery disease in South Korean males - Jang_2011_PLoS.One_6_e18208
Author(s) : Jang Y , Waterworth D , Lee JE , Song K , Kim S , Kim HS , Park KW , Cho HJ , Oh IY , Park JE , Lee BS , Ku HJ , Shin DJ , Lee JH , Jee SH , Han BG , Jang HY , Cho EY , Vallance P , Whittaker J , Cardon L , Mooser V
Ref : PLoS ONE , 6 :e18208 , 2011
Abstract : BACKGROUND: The Asia-specific PLA2G7 994G-T transversion leads to V279F substitution within the lipoprotein-associated phospholipase-A2 (Lp-PLA(2)) and to absence of enzyme activity in plasma. This variant offers a unique natural experiment to assess the role of Lp-PLA(2) in the pathogenesis of coronary artery disease (CAD) in humans. Given conflicting results from mostly small studies, a large two-stage case-control study was warranted. METHODOLOGY/PRINCIPAL FINDINGS: PLA2G7 V279F genotypes were initially compared in 2890 male cases diagnosed with CAD before age 60 with 3128 male controls without CAD at age 50 and above and subsequently in a second independent male dataset of 877 CAD cases and 1230 controls. In the first dataset, the prevalence of the 279F null allele was 11.5% in cases and 12.8% in controls. After adjustment for age, body mass index, diabetes, smoking, glucose and lipid levels, the OR (95% CI) for CAD for this allele was 0.80 (0.66-0.97, p = 0.02). The results were very similar in the second dataset, despite lower power, with an allele frequency of 11.2% in cases and 12.5% in controls, leading to a combined OR of 0.80 (0.69-0.92), p = 0.002. The magnitude and direction of this genetic effect were fully consistent with large epidemiological studies on plasma Lp-PLA(2) activity and CAD risk.
CONCLUSIONS: Natural deficiency in Lp-PLA(2) activity due to carriage of PLA2G7 279F allele protects from CAD in Korean men. These results provide evidence for a causal relationship between Lp-PLA(2) and CAD, and support pharmacological inhibition of this enzyme as an innovative way to prevent CAD.
ESTHER : Jang_2011_PLoS.One_6_e18208
PubMedSearch : Jang_2011_PLoS.One_6_e18208
PubMedID: 21490708
Gene_locus related to this paper: human-PLA2G7

Title : Hepatic lipase C514T polymorphism and its relationship with plasma HDL-C levels and coronary artery disease in Koreans - Park_2003_J.Biochem.Mol.Biol_36_237
Author(s) : Park KW , Choi JH , Chae IH , Cho HJ , Oh S , Kim HS , Lee MM , Park YB , Choi YS
Ref : J Biochem Mol Biol , 36 :237 , 2003
Abstract : Hepatic lipase is a key enzyme that is involved in HDL-C metabolism. The goal of this study was to find out the frequency of the hepatic lipase C514T polymorphism, and evaluate its relationship with plasma HDL-C levels and coronary artery disease (CAD) in Koreans. Two hundred and twenty four subjects with no previous history of lipid-lowering therapy, 118 patients with significant CAD, and 106 controls were examined with respect to their genotypes, lipid profiles, and other risk factors for CAD. The frequency of the -514T allele was 0.37 in men and 0.35 in women, which were higher than the frequency that was reported in Caucasians, but lower than the frequency that was reported in African-Americans. The -514T allele was associated with significantly higher HDL-C levels in women. After controlling for age, gender, BMI, DM, and smoking, the non-CC genotype was significantly associated with HDL-C levels, and explained 6% of the HDL-C variation in this study. When the genotypes-distribution was compared between the CAD and non-CAD patients, the hepatic lipase C-514T polymorphism was not associated with the presence of CAD. Koreans have a higher frequency of the hepatic lipase gene 514T allele than Caucasians, and the -514T allele is associated with higher plasma HDL-C levels in Korean women, and perhaps non-smoking men. However, our data does not suggest an association between the polymorphism and an increased risk of CAD.
ESTHER : Park_2003_J.Biochem.Mol.Biol_36_237
PubMedSearch : Park_2003_J.Biochem.Mol.Biol_36_237
PubMedID: 12689525