Sung Hee Hwang - Academia.edu (original) (raw)

Papers by Sung Hee Hwang

Earth and Planetary Science Letters, 2006

Nanometer-size P/K-rich silica glass (former melt) inclusions were identified within metamorphic ... more Nanometer-size P/K-rich silica glass (former melt) inclusions were identified within metamorphic microdiamonds from garnets of ultrahigh-pressure (UHP) gneisses of the Kokchetav and the Erzgebirge massifs by analytical electron microscopy (AEM). The chemical characteristics of these inclusions within microdiamonds are surprisingly similar among various gneissic rocks from both Kokchetav and Erzgebirge, but are significantly different from the Si-poor ultrapotassic fluid inclusions within microdiamonds from garnets of the Kokchetav UHP marble. These contrasting findings not only provide constraints on the characteristics/ compositions of the formation media of metamorphic microdiamonds, but also imply that the formation media must have been buffered by the hosting rocks, resulting in the observed diversities as reported here. In addition, depending on the rock types and thus on the nature of the formation media from which metamorphic microdiamonds were formed, the respective characteristic morphologies of the microdiamonds differ. The P/K-rich silica melt tends to form octahedral or cubo-octahedral microdiamonds within garnet in gneissic rocks, whereas the Si-poor ultrapotassic fluid tends to form spheroids/cuboid microdiamonds with rugged surfaces within garnet in marble. Consequently, the buffered media in hosting rocks played a decisive role in determining the different morphologies and growth rates/mechanisms of metamorphic microdiamonds in general.

Bioorganic & Medicinal Chemistry Letters, 2006

A 192-member library of N,N 0 -disubstituted urea inhibitors was synthesized by a solid-phase met... more A 192-member library of N,N 0 -disubstituted urea inhibitors was synthesized by a solid-phase method. The ureas were tested for their inhibitory activities against recombinant human soluble epoxide hydrolase. Simple carbocyclic or para/meta-substituted phenyl groups showed inhibition potencies that were equal to or greater than adamantane-based sEH inhibitors, while the presence of bulky or ionizable groups close to the urea group dramatically decreased their activities.

Angewandte Chemie International Edition, 2000

Ethylene is not only a substrate, but also a solvent: Catalytic intermolecular Pauson - Khand rea... more Ethylene is not only a substrate, but also a solvent: Catalytic intermolecular Pauson - Khand reactions of terminal alkynes were carried out in supercritical ethylene to provide 2-substituted cyclopentenones in moderate to high yields [Eq. (1)]. Under these conditions, even a low pressure of CO (5 atm) is sufficient for the reaction to take place.

American Journal of Respiratory Cell and Molecular Biology, 2015

Rationale: Control of airway inflammation is critical in asthma treatment. The soluble epoxide hy... more Rationale: Control of airway inflammation is critical in asthma treatment. The soluble epoxide hydrolase (sEH) has recently been demonstrated as a novel therapeutic target for treating inflammation, including lung inflammation. Here, we hypothesize that pharmacological inhibition of sEH can modulate the inflammatory response in a murine ovalbumin (OVA) model of asthma. Methods: BALB/c mice were sensitized and exposed to OVA over 6 weeks. The sEH inhibitor (sEHI) was administrated for two weeks. Respiratory system compliance, resistance and forced exhale nitric oxide were measured. Lung lavage cell counts were performed and a selected panel of cytokines and chemokines in the lung lavage fluid were measured by a Multiplex immunoassay kit. A liquid chromatography tandem mass spectrometry method was used to measure 87 regulatory lipids mediators in plasma, lung tissue homogenates, and lung lavage fluid. Results: The pharmacological inhibition of sEH increased the concentrations of the antiinflammatory epoxy eicosatrienoic acids (EETs) and simultaneously decreased the concentrations of the pro-inflammatory dihydroxyeicosatrienoic acids (DHETs) and dihydroxyoctadecenoic acids (DHOMEs). All monitored inflammatory markers, which including FeNO levels, and total cell and eosinophil numbers in the lung lavage of OVAexposed mice were reduced by sEHI. The Th2 cytokines (IL-4, IL-5) and chemokines (Eotaxin and RANTES) were dramatically reduced after administration of sEHI. Moreover, the resistance and dynamic lung compliance were also improved by sEHI.

Journal of medicinal chemistry, Jan 28, 2014

Diabetes is affecting the life of millions of people. A large proportion of diabetic patients suf... more Diabetes is affecting the life of millions of people. A large proportion of diabetic patients suffer from severe complications such as neuropathic pain, and current treatments for these complications have deleterious side effects. Thus, alternate therapeutic strategies are needed. Recently, the elevation of epoxy-fatty acids through inhibition of soluble epoxide hydrolase (sEH) was shown to reduce diabetic neuropathic pain in rodents. In this report, we describe a series of newly synthesized sEH inhibitors with at least 5-fold higher potency and doubled residence time inside both the human and rodent sEH enzyme than previously reported inhibitors. These inhibitors also have better physical properties and optimized pharmacokinetic profiles. The optimized inhibitor selected from this new series displayed improved efficacy of almost 10-fold in relieving pain perception in diabetic neuropathic rats as compared to the approved drug, gabapentin, and previously published sEH inhibitors. Th...

The Journal of Physiology, 2011

Arachidonic acid metabolites called epoxyeicosatrienoic acids (EETs) influence vascular tone and ... more Arachidonic acid metabolites called epoxyeicosatrienoic acids (EETs) influence vascular tone and renal tubular sodium and water transport and thus have been implicated in the control of blood pressure. Inhibition of the enzyme soluble epoxide hydrolase (sEH), which reduces EET degradation to the corresponding diols, leads to substantial attenuation of malignant hypertension in a transgenic rat strain harbouring the mouse renin gene particularly via an improvement of renal function. The observed antihypertensive and renoprotective effects of this novel pharmacological approach provide a potentially new direction in antihypertensive therapy.

Proceedings of the National Academy of Sciences, 2014

Soluble epoxide hydrolase (sEH) is an emerging therapeutic target in a number of diseases that ha... more Soluble epoxide hydrolase (sEH) is an emerging therapeutic target in a number of diseases that have inflammation as a common underlying cause. sEH limits tissue levels of cytochrome P450 (CYP) epoxides derived from omega-6 and omega-3 polyunsaturated fatty acids (PUFA) by converting these antiinflammatory mediators into their less active diols. Here, we explored the metabolic effects of a sEH inhibitor (t-TUCB) in fat-1 mice with transgenic expression of an omega-3 desaturase capable of enriching tissues with endogenous omega-3 PUFA. These mice exhibited increased CYP1A1, CYP2E1, and CYP2U1 expression and abundant levels of the omega-3-derived epoxides 17,18-epoxyeicosatetraenoic acid in insulinsensitive tissues, especially liver, as determined by LC-ESI-MS/MS. In obese fat-1 mice, t-TUCB raised hepatic 17,18-EEQ and 19,20-EDP levels and reinforced the omega-3-dependent reduction observed in tissue inflammation and lipid peroxidation. t-TUCB also produced a more intense antisteatotic action in obese fat-1 mice, as revealed by magnetic resonance spectroscopy. Notably, t-TUCB skewed macrophage polarization toward an antiinflammatory M2 phenotype and expanded the interscapular brown adipose tissue volume. Moreover, t-TUCB restored hepatic levels of Atg12-Atg5 and LC3-II conjugates and reduced p62 expression, indicating up-regulation of hepatic autophagy. t-TUCB consistently reduced endoplasmic reticulum stress demonstrated by the attenuation of IRE-1α and eIF2α phosphorylation. These actions were recapitulated in vitro in palmitate-primed hepatocytes and adipocytes incubated with 19,20-EDP or 17,18-EEQ. Relatively similar but less pronounced actions were observed with the omega-6 epoxide, 14,15-EET, and nonoxidized DHA. Together, these findings identify omega-3 epoxides as important regulators of inflammation and autophagy in insulin-sensitive tissues and postulate sEH as a druggable target in metabolic diseases. obesity | inflammation | autophagy | omega-3-derived epoxides | soluble epoxide hydrolase C ytochrome P450 (CYP) epoxygenases represent the third branch of polyunsaturated fatty acid (PUFA) metabolism (1). CYP epoxygenases add oxygen across one of the four double bonds of PUFA to generate three-membered ethers known as epoxides (1). In the case of arachidonic acid, CYP epoxygenases convert this omega-6 PUFA into epoxyeicosatrienoic acids (EETs), which act as autocrine or paracrine factors in the regulation of vascular tone, inflammation, hyperalgesia, and organ and tissue regeneration (2, 3). In addition to omega-6s, CYP epoxygenases also convert the omega-3 PUFA eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) into novel epoxyeicosatetraenoic (EEQs) and epoxydocosapentaenoic (EDPs) acids, respectively (4, 5). These omega-3-derived epoxides also exert salutary actions and are even more effective and potent than omega-6-derived EETs (4-8).

PLoS ONE, 2010

Epoxyeicotrienoic acids (EETs) are cytochrome P450-dependent anti-hypertensive and anti-inflammat... more Epoxyeicotrienoic acids (EETs) are cytochrome P450-dependent anti-hypertensive and anti-inflammatory derivatives of arachidonic acid, which are highly abundant in the kidney and considered reno-protective. EETs are degraded by the enzyme soluble epoxide hydrolase (sEH) and sEH inhibitors are considered treatment for chronic renal failure (CRF). We determined whether sEH inhibition attenuates the progression of CRF in the 5/6-nephrectomy model (5/6-Nx) in mice. 5/6-Nx mice were treated with a placebo, an ACE-inhibitor (Ramipril, 40 mg/kg), the sEH-inhibitor cAUCB or the CYP-inhibitor fenbendazole for 8 weeks. 5/6-Nx induced hypertension, albuminuria, glomerulosclerosis and tubulo-interstitial damage and these effects were attenuated by Ramipril. In contrast, cAUCB failed to lower the blood pressure and albuminuria was more severe as compared to placebo. Plasma EET-levels were doubled in 5/6 Nx-mice as compared to sham mice receiving placebo. Renal sEH expression was attenuated in 5/6-Nx mice but cAUCB in these animals still further increased the EET-level. cAUCB also increased 5-HETE and 15-HETE, which derive from peroxidation or lipoxygenases. Similar to cAUCB, CYP450 inhibition increased HETEs and promoted albuminuria. Thus, sEH-inhibition failed to elicit protective effects in the 5/6-Nx model and showed a tendency to aggravate the disease. These effects might be consequence of a shift of arachidonic acid metabolism into the lipoxygenase pathway.

Proceedings of the National Academy of Sciences of the United States of America, Jan 29, 2014

Tumor suppressor p53 plays an important role in mediating growth inhibition upon telomere dysfunc... more Tumor suppressor p53 plays an important role in mediating growth inhibition upon telomere dysfunction. Here, we show that loss of the p53 target gene cyclin-dependent kinase inhibitor 1A (CDKN1A, also known as p21(WAF1/CIP1)) increases apoptosis induction following telomerase inhibition in a variety of cancer cell lines and mouse xenografts. This effect is highly specific to p21, as loss of other checkpoint proteins and CDK inhibitors did not affect apoptosis. In telomerase, inhibited cell loss of p21 leads to E2F1- and p53-mediated transcriptional activation of p53-upregulated modulator of apoptosis, resulting in increased apoptosis. Combined genetic or pharmacological inhibition of telomerase and p21 synergistically suppresses tumor growth. Furthermore, we demonstrate that simultaneous inhibition of telomerase and p21 also suppresses growth of tumors containing mutant p53 following pharmacological restoration of p53 activity. Collectively, our results establish that inactivation o...

Bioorganic & Medicinal Chemistry Letters, 2013

To reduce the pro-angiogenic effects of sEH inhibition, a structure-activity relationship (SAR) s... more To reduce the pro-angiogenic effects of sEH inhibition, a structure-activity relationship (SAR) study was performed by incorporating structural features of the anti-angiogenic multi-kinase inhibitor sorafenib into soluble epoxide hydrolase (sEH) inhibitors. The structural modifications of this series of molecules enabled the altering of selectivity towards the pro-angiogenic kinases C-RAF and vascular endothelial growth factor receptor-2 (VEGFR-2), while retaining their sEH inhibition. As a result, sEH inhibitors with greater potency against C-RAF and VEGFR-2 were obtained. Compound 4 (t-CUPM) possesses inhibition potency higher than sorafenib towards sEH but similar against C-RAF and VEGFR-2. Compound 7 (t-CUCB) selectively inhibits sEH, while inhibiting HUVEC cell proliferation, a potential anti-angiogenic property, without liver cancer cell cytotoxicity. The data presented suggest a potential rational approach to control the angiogenic responses stemming from sEH inhibition.

Biochemical Pharmacology, 2010