Publications by authors named "Jongki Hong"

164 Publications

Alterations in Pattern Baldness According to Sex: Hair Metabolomics Approach.

Metabolites 2021 Mar 18;11(3). Epub 2021 Mar 18.

Molecular Recognition Research Center, Korea Institute of Science and Technology, Seoul 02792, Korea.

Pattern baldness has been associated with the male hormone, dihydrotestosterone. In this study, we tried to determine how the overall metabolic pathways of pattern baldness differ in patients and in normal controls. Our study aimed to identify alterations in hair metabolomic profiles in order to identify possible markers of pattern baldness according to sex. Untargeted metabolomics profiling in pattern baldness patients and control subjects was conducted using ultra-performance liquid chromatography-mass spectrometry. To identify significantly altered metabolic pathways, partial least squares discriminant analysis was performed. Our analysis indicated differences in steroid biosynthesis pathway in both males and females. However, there was a remarkable difference in the androgen metabolic pathway in males, and the estrogen metabolic and arachidonic acid pathways in females. For the first time, we were able to confirm the metabolic pathway in pattern baldness patients using hair samples. Our finding improves understanding of pattern baldness and highlights the need to link pattern baldness and sex-related differences.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/metabo11030178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8003215PMC
March 2021

Aromatic and Aliphatic Apiuronides from the Bark of .

J Nat Prod 2021 Mar 8;84(3):553-561. Epub 2021 Mar 8.

Department of Life and Nanopharmaceutical Science, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea.

Presl (Cinnamon) has been widely cultivated in the tropical or subtropical areas, such as Yunnan, Fujian, Guandong, and Hainan in China, as well as India, Vietnam, Thailand, and Malaysia. Four new glycosides bearing apiuronic acid (, , , and ) and their sodium or potassium salts (, , and ), together with 31 known compounds, were isolated from a hot water extract of the bark of via repeated chromatography. The structures of the new compounds (-) were determined by NMR, IR, MS, and ICP-AES data and by acid hydrolysis and sugar analysis. This is the first report of the presence of apiuronic acid glycosides. Some of the isolates were evaluated for their analgesic effects on a neuropathic pain animal model induced by paclitaxel. Cinnzeylanol (), cinnacaside (), kelampayoside A (), and syringaresinol () showed analgesic effects against paclitaxel-induced cold allodynia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jnatprod.0c01062DOI Listing
March 2021

Simultaneous Determination of Polyamines and Steroids in Human Serum from Breast Cancer Patients Using Liquid Chromatography-Tandem Mass Spectrometry.

Molecules 2021 Feb 21;26(4). Epub 2021 Feb 21.

Molecular Recognition Research Center, Korea Institute of Science and Technology, Seoul 02792, Korea.

A simultaneous quantitative profiling method for polyamines and steroids using liquid chromatography-tandem mass spectrometry was developed and validated. We applied this method to human serum samples to simultaneously evaluate polyamine and steroid levels. Chemical derivatization was performed using isobutyl chloroformate to increase the sensitivity of polyamines. The method was validated, and the matrix effects were in the range of 78.7-126.3% and recoveries were in the range of 87.8-123.6%. Moreover, the intra-day accuracy and precision were in the ranges of 86.5-116.2% and 0.6-21.8%, respectively, whereas the inter-day accuracy and precision were in the ranges of 82.0-119.3% and 0.3-20.2%, respectively. The linearity was greater than 0.99. The validated method was used to investigate the differences in polyamine and steroid levels between treated breast cancer patients and normal controls. In our results, -acetyl putrescine, -acetyl spermidine, cadaverine, 1,3-diaminopropane, and epitestosterone were significantly higher in the breast cancer patient group. Through receiver operating characteristic curve analysis, all metabolites that were significantly increased in patient groups with areas under the curve >0.8 were shown. This mass spectrometry-based quantitative profiling method, used for the investigation of breast cancer, is also applicable to androgen-dependent diseases and polyamine-related diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/molecules26041153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7926538PMC
February 2021

Profiling of Steroid Metabolic Pathways in Human Plasma by GC-MS/MS Combined with Microwave-Assisted Derivatization for Diagnosis of Gastric Disorders.

Int J Mol Sci 2021 Feb 13;22(4). Epub 2021 Feb 13.

Department of Pharmacy, College of Pharmacy, Kyung Hee University, Seoul 02447, Korea.

Steroid hormones are associated in depth to cellular signaling, inflammatory immune responses, and reproductive functions, and their metabolism alterations incur various diseases. In particular, quantitative profiling of steroids in plasma of patients with gastric cancer can provide a vast information to understand development of gastric cancer, since both sex hormones and glucocorticoids might be correlated with the pathological mechanisms of gastric cancer. Here, we developed a gas chromatography-tandem mass spectrometry-dynamic multiple reaction monitoring (GC-MS/MS-dMRM) method combined with solid-phase extraction (SPE) and microwave-assisted derivatization (MAD) to determine 20 endogenous steroids in human plasma. In this study, MAD conditions were optimized with respect to irradiation power and time. The SPE enabled effective cleanup and extraction for profiling of steroid hormones in human plasma samples. The MAD could improve laborious and time-consuming derivatization procedure, since dielectric heating using microwave directly increase molecular energy of reactants by penetrating through medium. Furthermore, dMRM method provided more sensitive determination of 20 steroids, compared to traditional MRM detection. The limits of quantification of steroids were below 1.125 ng/mL and determination coefficients of calibration curves were higher than 0.9925. Overall precision and accuracy results were below 19.93% and within ±17.04%, respectively. The developed method provided sufficient detection sensitivities and reliable quantification results. The established method was successfully applied to profile steroid metabolism pathways in plasma of patients with chronic superficial gastritis (CSG), intestinal metaplasia (IM), and gastric cancer. Statistical significances of steroid plasma levels between gastric disorder groups were investigated. In conclusion, this method provided comprehensive profiling of 20 steroids in human plasma samples and will be helpful to discover potential biomarkers for the development of gastric cancer and to further understand metabolic syndrome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms22041872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918215PMC
February 2021

Artemisiae Iwayomogii Herba inhibits lipopolysaccharide-induced neuroinflammation by regulating NF-κB and MAPK signaling pathways.

Phytomedicine 2021 Apr 10;84:153501. Epub 2021 Feb 10.

Department of Life and Nanopharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; Department of Oriental Pharmaceutical Science, College of Pharmacy and Kyung Hee East-West Pharmaceutical Research Institute, Kyung Hee University, Seoul 02447, Republic of Korea. Electronic address:

Background: Neuroinflammation plays a major role in the development of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. The regulation of microglia is an efficient therapeutic approach to controlling neuroinflammation.

Purpose: In this study, we aimed to determine whether Artemisiae Iwayomogii Herba (AIH), which is herbal medicine traditionally used for inflammation-related disorders, controls neuroinflammatory responses by regulating the microglia-mediated signaling pathway.

Methods: BV-2 microglial cells were treated with AIH and lipopolysaccharides (LPS), then various pro-inflammatory mediators were analyzed using griess reaction, quantitative reverse-transcription polymerase chain reaction, or western blotting. C57BL/6 J mice were orally administered by AIH for 17 days and intraperitoneally injected with LPS for the last 14 days. The brains were collected and the microglial activation and nucleotide-binding oligomerization domain-, leucine-rich repeat-, and pyrin domain-containing 3 (NLRP3) expression in the cortex and hippocampus were analyzed using immunohistochemistry or western blotting.

Results: In BV-2 microglial cells, we found that AIH inhibited nitric oxide (NO) production induced by LPS. AIH also suppressed the expressions of pro-inflammatory mediators, including inducible NO synthase, cyclooxygenase-2, tumor necrosis factor-α, and interleukin-6. The study also revealed that the effects of AIH are related to the regulation of the nuclear factor kappa B (NF-κB) and the mitogen-activated protein kinase (MAPK) signaling pathway. Additionally, we found that AIH prevented the formation of NLRP3 inflammasomes. Consistent with the results of in vitro studies on the brains of LPS-injected mice, we observed that AIH suppressed microglial activation and NLRP3 expression.

Conclusion: Taken together, these results suggest that AIH attenuates neuroinflammation by regulating the NF-κB and MAPK pathways, and it may be used for treating neurological diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.phymed.2021.153501DOI Listing
April 2021

Untargeted Metabolomics and Polyamine Profiling in Serum before and after Surgery in Colorectal Cancer Patients.

Metabolites 2020 Nov 27;10(12). Epub 2020 Nov 27.

Molecular Recognition Research Center, Korea Institute of Science and Technology, Seoul 02792, Korea.

Colorectal cancer is one of the most prevalent cancers in Korea and globally. In this study, we aimed to characterize the differential serum metabolomic profiles between pre-operative and post-operative patients with colorectal cancer. To investigate the significant metabolites and metabolic pathways associated with colorectal cancer, we analyzed serum samples from 68 patients (aged 20-71, mean 57.57 years). Untargeted and targeted metabolomics profiling in patients with colorectal cancer were performed using liquid chromatography-mass spectrometry. Untargeted analysis identified differences in sphingolipid metabolism, steroid biosynthesis, and arginine and proline metabolism in pre- and post-operative patients with colorectal cancer. We then performed quantitative target profiling of polyamines, synthesized from arginine and proline metabolism, to identify potential polyamines that may serve as effective biomarkers for colorectal cancer. Results indicate a significantly reduced serum concentration of putrescine in post-operative patients compared to pre-operative patients. Our metabolomics approach provided insights into the physiological alterations in patients with colorectal cancer after surgery.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/metabo10120487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7760053PMC
November 2020

Recent advances in nanoscale materials for antibody-based cancer theranostics.

Biosens Bioelectron 2020 Nov 6;173:112787. Epub 2020 Nov 6.

Central Scientific Instruments Organization (CSIR-CSIO), Sector 30 C, Chandigarh, 160030, India. Electronic address:

The quest for advanced management tools or options of various cancers has been on the rise to efficiently reduce their risks of mortality without the demerits of conventional treatments (e.g., undesirable side effects of the medications on non-target tissues, non-targeted distribution, slow clearance of the administered drugs, and the development of drug resistance over the duration of therapy). In this context, nanomaterials-antibody conjugates can offer numerous advantages in the development of cancer theranostics over conventional delivery systems (e.g., highly specific and enhanced biodistribution of the drug in targeted tissues, prolonged systemic circulation, low toxicity, and minimally invasive molecular imaging). This review comprehensively discusses and evaluates recent advances in the application of nanomaterial-antibody bioconjugates for cancer theranostics for the further advancement in the control of diverse cancerous diseases. Further, discussion is expanded to cover the various challenges and limitations associated with the design and development of nanomaterial-antibody conjugates applicable towards better management of cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bios.2020.112787DOI Listing
November 2020

Insights into the Vastly Different Effects of Eutectic Solvents on the Stability of Phenolic Compounds.

J Phys Chem Lett 2020 Jul 18;11(13):5268-5272. Epub 2020 Jun 18.

School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi 16419, Republic of Korea.

Eutectic solvents (ESs) have shown stabilizing effects on several molecules. Due to the potential applicability of bioactive compounds, understanding how ESs stabilize them is of great interest in pharmaceutical and related fields. Here, among various ESs, CTU, which comprise thiourea and choline chloride (ChCl), exerted remarkably high stabilizing effects on various phenolic compounds, whereas CU consisting of urea and ChCl exhibited the opposite effects. Using a potent polyphenol, (-)-epigallocatechin gallate (EGCG), as a model compound, we conducted experimental and studies to unravel the underlying mechanisms of the two very similar ESs for the contrasting effects. The results suggest that ESs can affect with great diversity the stability of EGCG by complicated interactions arising from the unique properties of both ESs and their components.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jpclett.0c00610DOI Listing
July 2020

Reliable screening and classification of phosphodiesterase type 5 inhibitors in dietary supplements using gas chromatography / mass spectrometry combined with specific common ions.

J Chromatogr A 2020 Jul 12;1623:461210. Epub 2020 May 12.

College of Pharmacy, Kyung Hee University, Seoul, 26, Kyungheedae-ro, Dongdaemun-gu, 02447, Republic of Korea. Electronic address:

Illegal dietary supplements adulterated with phosphodiesterase type 5 inhibitors (PDE-5i) are increasingly widely distributed through internet markets and underground routes. For this reason, it demands development of reliable screening methods to determine a wide range of PDE-5i drugs in various types of dietary supplements. Herein, we developed a screening method using gas chromatography-mass spectrometry (GC-MS) for simultaneous detection of 53 PDE-5i drugs in supplements. Common formulations (such as capsule, powder, pill, and tablet) of supplements with complicated matrices were treated by simple liquid-liquid extraction and trimethylsilyl (TMS) derivatization. With the aid of TMS derivatization, 53 PDE-5i drugs could be successfully separated and detected within 15 min, using a short microbore GC column (15 m). Moreover, owing to enhanced detection sensitivity and selectivity of PDE-5i TMS derivatives, 0.5 mg of sample was sufficient to screen and confirm targeted PDE-5i drugs. In this study, specific common ions according to structural characteristics of PDE-5i drugs were found under the electron ionization (EI) of their TMS derivatives. These specific common fragments could reflect the common pharmacophores for 4 classes of PDE-5i drugs (sildenafil, other sildenafil, vardenafil, and tadalafil analogues). Based on characteristic EI fragment ions, extracted common ion chromatograms (ECICs) and discriminant analysis (DA) were effectively used for reliable screening and classification of various types of PDE-5i drugs. Specific ECICs and DA using characteristic EI fragments here will aid in identification of newly emerging PDE-5i counterfeits in supplements. This study will be helpful to supervise illegal adulteration of PDE-5i drugs in dietary supplements to protect public health and consumer safety.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.chroma.2020.461210DOI Listing
July 2020

Untargeted Metabolomics and Steroid Signatures in Urine of Male Pattern Baldness Patients after Finasteride Treatment for a Year.

Metabolites 2020 Mar 30;10(4). Epub 2020 Mar 30.

Molecular Recognition Research Center, Korea Institute of Science and Technology, Seoul 02792, Korea.

Male pattern baldness (MPB) has been associated with dihydrotestosterone (DHT) expression. Finasteride treats MPB by inhibiting 5-alpha reductase and blocking DHT production. In this study, we aimed to identify metabolic differences in urinary metabolomics profiles between MPB patients after a one-year treatment with finasteride and healthy controls. Untargeted and targeted metabolomics profiling was performed using liquid chromatography-mass spectrometry (LC-MS). We hypothesized that there would be changes in overall metabolite concentrations, especially steroids, in the urine of hair loss patients treated with finasteride and normal subjects. Untargeted analysis indicated differences in steroid hormone biosynthesis. Therefore, we conducted targeted profiling for steroid hormone biosynthesis to identify potential biomarkers, especially androgens and estrogens. Our study confirmed the differences in the concentration of urinary androgens and estrogens between healthy controls and MPB patients. Moreover, the effect of finasteride was confirmed by the DHT/T ratio in urine samples of MPB patients. Our metabolomics approach provided insight into the physiological alterations in MPB patients who have been treated with finasteride for a year and provided evidence for the association of finasteride and estrogen levels. Through a targeted approach, our results suggest that urinary estrogens must be studied in relation to MPB and post-finasteride syndrome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/metabo10040131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7241081PMC
March 2020

Neuroprotective effects of Suhexiang Wan on the in vitro and in vivo models of Parkinson's disease.

J Tradit Chin Med 2019 12;39(6):800-808

Department of Oriental Medicine, Dongguk University, Gyeogju, 38066, Republic of Korea.

Objective: To examine the role of KSOP1009 (a modified formulation of Suhexiang Wan essential oil) in an animal model of Parkinson's disease (PD) induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) injection.

Methods: Cell toxicity, apoptosis, and reactive oxygen species (ROS) levels were analyzed in the human neuroblastoma cell line SH-SY5Y. After that, changes in animal behavior and tyrosine hydroxylase (TH) protein levels in the substantia nigra (SN) of MPTP-injected mice were examined. Three different doses of KSOP1009 (30, 100, and 300 mg/kg, n = 8 for each group) were administered daily for 7 d before MPTP injection and 14 d after MPTP injection, totaling 21 d.

Results: MPP+, the active metabolite of MPTP, decreased the viability of SH-SY5Y cells, whereas KSOP1009 alleviated MPP+-induced cytotoxicity. KSOP1009 (10 and 50 mg/mL) reduced MPP+-induced ROS generation compared with the control group. Treatment with 1 mM MPP+ increased the percentage of depolarized/live cells, whereas KSOP1009 intake at a dose of 10 mg/mL decreased the percentage of these cells. The mean latency to fall in the rotarod test was reduced in mice treated with MPTP compared with the control group. However, mice receiving three different doses of KSOP1009 performed better than MPTP-treated animals. MPTP-treated mice were more hesitant and took longer to traverse the balance beam than the control animals. In contrast, KSOP1009-treated mice performed significantly better than MPTP- treated mice. Furthermore, the KSOP1009-treated groups had a significantly higher number of TH-positive neurons in the lesioned SN and significantly higher expression of TH in the striatum than the MPTP-treated group. MPTP treatment strongly induced Jun-N-terminal kinase (JNK) activation, whereas KSOP1009 suppressed MPTP-induced JNK activation. In addition, KSOP1009 intake reversed the decrease in the phosphorylation levels of cAMP-response element-binding protein in the brain of MPTP-treated mice. KSOP1009 also restored the decrease in dopaminergic neurons and dopamine levels in the brain of MPTP-treated mice.

Conclusion: KSOP1009 protected mice against MPTP-induced toxicity by decreasing ROS formation and restoring mitochondrial function.
View Article and Find Full Text PDF

Download full-text PDF

Source
December 2019

Anti-inflammatory effects of an optimized PPAR-γ agonist via NF-κB pathway inhibition.

Bioorg Chem 2020 03 22;96:103611. Epub 2020 Jan 22.

College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea. Electronic address:

In our previous study, a PPAR-γ agonist (+)-(R,E)-6a1 was elaborated as an anti-inflammatory lead. However, in silico analysis showed that (+)-(R,E)-6a1 lacks key hydrogen bonding with Tyr of PPAR-γ LBD (ligand binding domain). To facilitate additional hydrogen bonding with Tyr, a more polar head group was introduced to the structure of (+)-(R,E)-6a1, and we also attempted to synthesize enzymatically stable derivatives. Of the synthetic derivatives, compound (+)-(R,E)-5f showed highest PPAR-γ transcriptional activity and reasonable metabolic stability. Compound (+)-(R,E)-5f suppressed the expression of pro-inflammatory mediators such as inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin 6 (IL-6), and tumor necrosis factor-α (TNF-α). Reduction of nitric oxide (NO), and ROS was also observed. Compound (+)-(R,E)-5f was found to suppress the NF-κB pathway by inhibiting phosphorylation of IKK (IκB kinase), and this may lead to subsequent inhibition of IκBα (inhibitor of NF-κBα) phosphorylation and inhibition of NF-κB activation. These results indicate that (+)-(R,E)-5f exerts anti-inflammatory activity via NF-κB pathway inhibition, and may serve as a potential anti-inflammatory lead.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bioorg.2020.103611DOI Listing
March 2020

Sex-related differences in urinary immune-related metabolic profiling of alopecia areata patients.

Metabolomics 2020 01 16;16(2):15. Epub 2020 Jan 16.

Molecular Recognition Research Center, Korea Institute of Science and Technology, Seoul, 02792, Korea.

Introduction: Alopecia areata is a well-known autoimmune disease affecting humans. Polyamines are closely associated with proliferation and inflammation, and steroid hormones are involved in immune responses. Additionally, bile acids play roles in immune homeostasis by activating various signaling pathways; however, the roles of these substances and their metabolites in alopecia areata remain unclear.

Objectives: In this study, we aimed to identify differences in metabolite levels in urine samples from patients with alopecia areata and healthy controls.

Methods: To assess polyamine, androgen, and bile acid concentrations, we performed high-performance liquid chromatography-tandem mass spectrometry.

Results: Our results showed that spermine and dehydroepiandrosterone levels differed significantly between male patients and controls, whereas ursodeoxycholic acid levels were significantly higher in female patients with alopecia areata than in controls.

Conclusion: Our findings suggested different urinary polyamine, androgen, and bile acid concentrations between alopecia areata patients and normal controls. Additionally, levels of endogenous substances varied according to sex, and this should be considered when developing appropriate treatments and diagnostic techniques. Our findings improve our understanding of polyamine, androgen, and bile acid profiles in patients with alopecia areata and highlight the need to consider sex-related differences.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11306-020-1634-yDOI Listing
January 2020

Effects of Combined Treatment with Acupuncture and Chunggan Formula in a Mouse Model of Parkinson's Disease.

Evid Based Complement Alternat Med 2019 21;2019:3612587. Epub 2019 Nov 21.

Acupuncture and Meridian Science Research Center, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea.

Parkinson's disease is the second most common neurodegenerative disease. Patients with Parkinson's disease can be treated with a combination of acupuncture and herbal medicine, but studies on the synergistic effects of the combined treatment have not yet been conducted. Thus, we subjected an MPTP-induced Parkinson's disease mouse model to the combined treatment. We used acupoint GB34 for acupuncture and modified Chunggantang (KD5040) as the herbal medicine, as they have been reported to be effective in Parkinson's disease. We investigated the suboptimal dose of KD5040 and then used this dose in the combined treatment. The results showed that the combined treatment had a synergistic effect on improvements in abnormal motor function and neurodegeneration compared with the use of acupuncture or herbal medicine alone. The combined treatment also had a neuroprotective effect via the PI3K/AKT and MAPK/ERK signaling pathways. These findings suggest that the combined treatment with acupuncture and KD5040 can help improve the symptoms of Parkinson's disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2019/3612587DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6907061PMC
November 2019

Graphene oxide-induced neurotoxicity on neurotransmitters, AFD neurons and locomotive behavior in Caenorhabditis elegans.

Neurotoxicology 2020 03 17;77:30-39. Epub 2019 Dec 17.

School of Environmental Engineering, University of Seoul, 163 Siripdaero, Dongdaemun-gu, Seoul 02504, South Korea. Electronic address:

Graphene oxide (GO) and graphene-based nanomaterials have been widely applied in recent years, but their potential health risk and neurotoxic potentials remain poorly understood. In this study, neurotoxic potential of GO and its underlying molecular and cellular mechanism were investigated using the nematode, Caenorhabditis elegans. Deposition of GO in the head region and increased reactive oxygen species (ROS) was observed in C. elegans after exposure to GO. The neurotoxic potential of GO was then investigated, focusing on neurotransmitters contents and neuronal activity using AFD sensory neurons. The contents of all neurotransmitters, such as, tyrosine, tryptophan, dopamine, tyramine, and GABA, decreased significantly by GO exposure. Decreased fluorescence of Pgcy-8:GFP, a marker of AFD sensory neuron, by GO exposure suggested GO could cause neuronal damage on AFD neuron. GO exposure led decreased expression of ttx-1 and ceh-14, genes required for the function of AFD neurons also confirmed possible detrimental effect of GO to AFD neuron. To understand physiological meaning of AFD neuronal damage by GO exposure, locomotive behavior was then investigated in wild-type as well as in loss-of-function mutants of ttx-1 and ceh-14. GO exposure significantly altered locomotor behavior markers, such as, speed, acceleration, stop time, etc., in wild-type C. elegans, which were mostly rescued in AFD neuron mutants. The present study suggested the GO possesses neurotoxic potential, especially on neurotransmitters and AFD neuron in C. elegans. These findings provide useful information to understand the neurotoxic potential of GO and other graphene-based nanomaterials, which will guide their safe application.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neuro.2019.12.011DOI Listing
March 2020

Assessing the progression of gastric cancer via profiling of histamine, histidine, and bile acids in gastric juice using LC-MS/MS.

J Steroid Biochem Mol Biol 2020 03 12;197:105539. Epub 2019 Nov 12.

College of Pharmacy, Kyung Hee University, Seoul, 02447, Republic of Korea. Electronic address:

Bile acid (BA) imbalance may be directly associated with gastric cancer and indirectly influence stomach carcinogenesis via overexpression of histidine decarboxylase (HDC), which converts histidine (His) into histamine (HIST). Moreover, the progression of gastric cancer, could change the gut microbiome, including bacteria spp. that produce secondary BAs. Gastric juice has various metabolites that could indicate gastric cancer-related stomach conditions. Therefore, profiling of HIST, His, and BAs in gastric juice is crucial for understanding the etiological mechanisms of gastric cancer. We used a profiling method to simultaneously determine targeted metabolites in gastric juice using liquid chromatography-tandem mass spectrometry (LC-MS/MS). We successfully analyzed 70 human gastric juice samples from patients with chronic superficial gastritis (CSG, n = 20), intestinal metaplasia (IM, n = 12), and gastric cancer (n = 38). Furthermore, we investigated the relevance between BA metabolism and gastric cancer. There were statistical differences in the metabolism of cholic acid (CA) into deoxycholic acid (DCA) based on the progression of CSG into IM and gastric cancer. Hence, the progression of gastric cancer might be related to the alterations in gut microbiome composition. We provide insight into the etiological mechanisms of the progression of gastric cancer and biomarkers to diagnose and treat gastric cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jsbmb.2019.105539DOI Listing
March 2020

iTRAQ-Based Quantitative Proteomic Comparison of 2D and 3D Adipocyte Cell Models Co-cultured with Macrophages Using Online 2D-nanoLC-ESI-MS/MS.

Sci Rep 2019 11 14;9(1):16746. Epub 2019 Nov 14.

Center for Bioanalysis, Division of Chemical and Medical metrology, Korea Research Institute of Standards and Science, Daejeon, 34113, Republic of Korea.

The demand for novel three-dimensional (3D) cell culture models of adipose tissue has been increasing, and proteomic investigations are important for determining the underlying causes of obesity, type II diabetes, and metabolic disorders. In this study, we performed global quantitative proteomic profiling of three 3D-cultured 3T3-L1 cells (preadipocytes, adipocytes and co-cultured adipocytes with macrophages) and their 2D-cultured counterparts using 2D-nanoLC-ESI-MS/MS with iTRAQ labelling. A total of 2,885 shared proteins from six types of adipose cells were identified and quantified in four replicates. Among them, 48 proteins involved in carbohydrate metabolism (e.g., PDHα, MDH1/2, FH) and the mitochondrial fatty acid beta oxidation pathway (e.g., VLCAD, ACADM, ECHDC1, ALDH6A1) were relatively up-regulated in the 3D co-culture model compared to those in 2D and 3D mono-cultured cells. Conversely, 12 proteins implicated in cellular component organisation (e.g., ANXA1, ANXA2) and the cell cycle (e.g., MCM family proteins) were down-regulated. These quantitative assessments showed that the 3D co-culture system of adipocytes and macrophages led to the development of insulin resistance, thereby providing a promising in vitro obesity model that is more equivalent to the in vivo conditions with respect to the mechanisms underpinning metabolic syndromes and the effect of new medical treatments for metabolic disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-019-53196-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6856061PMC
November 2019

β-Caryophyllene in the Essential Oil from Induces G Phase Cell Cycle Arrest in Human Lung Cancer Cells.

Molecules 2019 Oct 18;24(20). Epub 2019 Oct 18.

College of Pharmacy, Kyung Hee University, Seoul 02447, Korea.

is a plant widespread in East Asia, used in folk medicine to treat various disorders, such as pneumonia, colitis, stomatitis, and carbuncle. Whether the essential oil from (ECB) and its active constituents have anti-proliferative activities in lung cancer is unknown. Therefore, we investigated the cytotoxic effects of ECB in A549 and NCI-H358 human lung cancer cells. Culture of A549 and NCI-H358 cells with ECB induced apoptotic cell death, as revealed by an increase in annexin V staining. ECB treatment reduced mitochondrial membrane potential (MMP), disrupted the balance between pro-apoptotic and anti-apoptotic Bcl-2 proteins, and activated caspase-8, -9, and -3, as assessed by western blot analysis. Interestingly, pretreatment with a broad-spectrum caspase inhibitor (z-VAD-fmk) significantly attenuated ECB-induced apoptosis. Furthermore, gas chromatography-mass spectrometry (GC/MS) analysis of ECB identified six compounds. Among them, β-caryophyllene exhibited a potent anti-proliferative effect, and thus was identified as the major active compound. β- Caryophyllene induced G cell cycle arrest by downregulating cyclin D1, cyclin E, cyclin-dependent protein kinase (CDK) -2, -4, and -6, and RB phosphorylation, and by upregulating p21 and p27. These results indicate that β-caryophyllene exerts cytotoxic activity in lung cancer cells through induction of cell cycle arrest.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/molecules24203754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6832734PMC
October 2019

Altered polyamine profiling in the hair of patients with androgenic alopecia and alopecia areata.

J Dermatol 2019 Nov 28;46(11):985-992. Epub 2019 Aug 28.

Molecular Recognition Research Center, Korea Institute of Science and Technology, Seoul, Korea.

Hair follicles are among the most highly proliferative tissues. Polyamines are associated with proliferation, and several polyamines including spermidine and spermine play anti-inflammatory roles. Androgenic alopecia results from increased dihydrotestosterone metabolism, and alopecia areata is an autoimmune disease. This study aimed to investigate differences in polyamine profiles in hair samples between patients with androgenic alopecia and alopecia areata. Polyamine concentrations were determined through high-performance liquid chromatography-mass spectrometry. Hair samples were derivatized with isobutyl chloroformate. Differences in polyamine levels were observed between androgenic alopecia and alopecia areata compared with normal controls. In particular, polyamine levels were higher in alopecia areata patients than in normal controls. Certain polyamines displayed different concentrations between the androgenic alopecia and alopecia areata groups, suggesting that some polyamines, particularly N-acetyl putrescine (P = 0.007) and N-acetyl cadaverine (P = 0.0021), are significantly different in androgenic alopecia. Furthermore, spermidine (P = 0.021) was significantly different in alopecia areata. Our findings suggest that non-invasive quantification of hair polyamines may help distinguish between androgenic alopecia and alopecia areata. Our study provides novel insights into physiological alterations in patients with androgenic alopecia and those with alopecia areata and reveals some differences in polyamine levels in hair loss diseases with two different modes of action.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/1346-8138.15063DOI Listing
November 2019

Design of balanced COX inhibitors based on anti-inflammatory and/or COX-2 inhibitory ascidian metabolites.

Eur J Med Chem 2019 Oct 6;180:86-98. Epub 2019 Jul 6.

College of Pharmacy, Pusan National University, Busan, 46241, Republic of Korea. Electronic address:

The aim of this study was to design and synthesize COX-1/COX-2 balanced inhibitors incorporating the structural motifs of anti-inflammatory ascidian metabolites. We designed a series of substituted indole analogs that incorporate the key structures of the ascidian metabolites, herdmanines C and D. The synthesized analogs were tested for their inhibitory activity against COX-1 and COX-2, and compound 5m, which displayed balanced inhibition, was further evaluated for in vitro anti-inflammatory activity. Compound 5m suppressed the expression of pro-inflammatory factors, including iNOS, COX-2, TNF-α, and IL-6 in LPS-stimulated murine RAW264.7 macrophages. The reduction of PGE, NO, and ROS was also observed, together with the suppression of NF-κB, IKK, and IκBα phosphorylation. Our results characterized 5m as a COX-1/COX-2 balanced inhibitor that subsequently caused ROS inhibition and NF-κB suppression, and culminated in the suppression of iNOS, COX-2, TNF-α, and IL-6 expression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejmech.2019.07.016DOI Listing
October 2019

LC-MS/MS Software for Screening Unknown Erectile Dysfunction Drugs and Analogues: Artificial Neural Network Classification, Peak-Count Scoring, Simple Similarity Search, and Hybrid Similarity Search Algorithms.

Anal Chem 2019 07 1;91(14):9119-9128. Epub 2019 Jul 1.

Department of Chemistry , Sogang University , Seoul 04107 , Republic of Korea.

Screening and identifying unknown erectile dysfunction (ED) drugs and analogues, which are often illicitly added to health supplements, is a challenging analytical task. The analytical technique most commonly used for this purpose, liquid chromatography-tandem mass spectrometry (LC-MS/MS), is based on the strategy of searching the LC-MS/MS spectra of target compounds against database spectra. However, such a strategy cannot be applied to unknown ED drugs and analogues. To overcome this dilemma, we have constructed a standalone software named AI-SIDA (artificial intelligence screener of illicit drugs and analogues). AI-SIDA consists of three layers: , , and . In the second AI classifier layer, an artificial neural network (ANN) classification model, which was constructed by training 149 LC-MS/MS spectra (including 27 sildenafil-type, 6 vardenafil-type, 11 tadalafil-type ED drugs/analogues and other 105 compounds), is included to classify the LC-MS/MS spectra of the query compound into four categories: i.e., sildenafil, vardenafil, and tadalafil families and non-ED compounds. This ANN model was found to show 100% classification accuracy for the 187 LC-MS/MS modeling and test data sets. In the third Identifier layer, three search algorithms (pick-count scoring, simple similarity search, and hybrid similarity search) are implemented. In particular, the hybrid similarity search was found to be very powerful in identifying unknown ED drugs/analogues with a single modification from the library ED drugs/analogues. Altogether, the AI-SIDA software provides a very useful and powerful platform for screening unknown ED drugs and analogues.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.analchem.9b01643DOI Listing
July 2019

Distribution of polyamines may be altered in different scalp regions of patients with hair loss.

Exp Dermatol 2019 09 19;28(9):1083-1086. Epub 2019 Aug 19.

Molecular Recognition Research Center, Korea Institute of Science and Technology, Seoul, Korea.

Hair loss, from the vertex or front of the head, generally occurs due to increased androgenic steroid levels. Androgenic steroids, particularly testosterone and dihydrotestosterone, are distributed differently across the vertex and occipital regions and are involved in inducing ornithine decarboxylase expression. Therefore, we hypothesized that the distribution of polyamines may be altered in different scalp regions. For the overall metabolic profiling of polyamines in patients with hair loss, a liquid chromatography-mass spectrometry was used. We investigated the differential polyamine levels in different regions of the hair of patients with male pattern baldness and those with female pattern hair loss. The levels of most polyamines were higher in the vertex region than in the occipital region, and N-acetyl polyamine levels differed significantly. We proposed to test our hypothesis by profiling polyamines in human hair fibre to evaluate the distribution of metabolites in various regions of the scalp.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/exd.13998DOI Listing
September 2019

An Algal Metabolite-Based PPAR-γ Agonist Displayed Anti-Inflammatory Effect via Inhibition of the NF-κB Pathway.

Mar Drugs 2019 May 30;17(6). Epub 2019 May 30.

College of Pharmacy, Pusan National University, Busan 46241, Korea.

In our previous study, a synthetic compound, (+)-(,)-, that incorporated the key structures of anti-inflammatory algal metabolites and the endogenous peroxisome proliferator-activated receptor γ (PPAR-γ) ligand 15-deoxy-∆-prostaglandin J (15d-PGJ), exerted significant PPAR-γ transcriptional activity. Because PPAR-γ expressed in macrophages has been postulated as a negative regulator of inflammation, this study was designed to investigate the anti-inflammatory effect of the PPAR-γ agonist, (+)-(,)-. Compound (+)-(,)- displayed in vitro anti-inflammatory activity in lipopolysaccharides (LPS)-stimulated murine RAW264.7 macrophages. Compound (+)-(,)- suppressed the expression of proinflammatory factors, such as nitric oxide (NO), inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), possibly by the inhibition of the nuclear factor-κB (NF-κB) pathway. In macrophages, (+)-(,)- suppressed LPS-induced phosphorylation of NF-κB, inhibitor of NF-κB α (IκBα), and IκB kinase (IKK). These results indicated that PPAR-γ agonist, (+)-(,)- exerts anti-inflammatory activity via inhibition of the NF-κB pathway.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/md17060321DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627743PMC
May 2019

Rapid screening of sulfonamides in dietary supplements based on extracted common ion chromatogram and neutral loss scan by LC-Q/TOF-mass spectrometry.

J Food Drug Anal 2019 01 28;27(1):164-174. Epub 2018 Sep 28.

College of Pharmacy, Kyung Hee University, Seoul 02447, South Korea. Electronic address:

There is an increasing amount of dietary supplements that are adulterated with diuretics and anti-diabetic drugs; this has become a global problem due to the wide distribution of dietary supplements and the serious negative health effects of the adulterants. In this study, a rapid screening method was developed for detection and confirmation of 35 sulfonamides in supplements by ultra-high performance liquid chromatography quadrupole/time of flight mass spectrometry. For effective extraction of sulfonamides from dietary supplements, four extraction protocols including HLB and WAX solid-phase extraction, Quick Easy Cheap Effective Rugged and Safe method, and pH-controlled liquid-liquid extraction were evaluated, and pH-controlled liquid-liquid extraction method was shown to be the most effective with high recovery efficiency and low matrix effect. Rapid separation of 35 sulfonamides was achieved with the UHPLC C18 column (150 × 2.1 mm, 1.7 um) within 7 min using ammonium acetate aqueous solution (pH 8) and acetonitrile as the mobile phase. From the MS/MS spectra of sulfonamides, common ions (m/z 77.9650 [SON] and m/z 79.9812 [SONH]) and neutral molecule loss fragments (HCl and SO) were observed according to their structural characteristics. Extracted common ion chromatograms and neutral loss scan of these characteristic fragments could effectively apply for rapid screening of sulfonamides in various types of supplements. A reduced mass tolerance window of ±5 ppm was useful for detecting targeted and untargeted sulfonamides and could avoid false positive and false negative results. Overall calibration curves within dynamic range for all targets were shown to be linear with a correlation coefficient R > 0.995 and limits of detection ranged from 0.04 to 11.18 ng/g for all sulfonamides. The established method was successfully applied for screening and confirmation of sulfonamides in various supplements. The developed method will be helpful for the identification of sulfonamide diuretics and anti-diabetics in dietary supplements, promoting public health and consumer safety.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jfda.2018.08.006DOI Listing
January 2019

Development of in vitro three-dimensional co-culture system for metabolic syndrome therapeutic agents.

Diabetes Obes Metab 2019 05 18;21(5):1146-1157. Epub 2019 Feb 18.

Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon, Republic of Korea.

Aims: There are many obstacles to overcome in the development of new drugs for metabolic diseases, including efficacy and toxicity problems in later stages of drug development. To overcome these problems and predict efficacy and toxicity in early stages, we constructed a new model of insulin resistance in terms of communication between 3T3-L1 adipocytes and RAW264.7 macrophages by three-dimensional (3D) culture.

Results: In this study, results focused on the functional resemblance between 3D co-culture of adipocytes and macrophages and adipose tissue in diabetic mice. The 3D mono-culture preadipocytes showed good cell viability and induced cell differentiation to adipocytes, without cell confluence or cell-cell contact and interaction. The 3D co-cultured preadipocytes with RAW264.7 macrophages induced greater insulin resistance than two-dimensional and 3D mono-cultured adipocytes. Additionally, we demonstrated that 3D co-culture model had functional metabolic similarity to adipose tissue in diabetic mice. We utilized this 3D co-culture system to screen PPARγ antagonists that might have potential as therapeutic agents for diabetes as demonstrated by an in vivo assay.

Conclusion: This in vitro 3D co-culture system could serve as a next-generation platform to accelerate the development of therapeutics for metabolic diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/dom.13628DOI Listing
May 2019

Design, synthesis and cytotoxicity of chimeric erlotinib-alkylphospholipid hybrids.

Bioorg Chem 2019 03 19;84:51-62. Epub 2018 Nov 19.

Department of Life and Nanopharmaceutical Sciences, Kyung Hee University, Seoul 02447, Republic of Korea; Department of Pharmacy, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea; KHU-KIST Department of Converging Science and Technology, Kyung Hee University, Seoul 02447, Republic of Korea. Electronic address:

Two series of erlotinib-alkylphospholipid hybrids were prepared and evaluated for their antiproliferative activities against a panel of four cell lines representing lung, breast, liver and skin cancers using erlotinib and miltefosine as reference standards. Amide analogs elicited more enhanced cytotoxic activity than analogous esters. Amide derivatives 8d and 8e exhibited promising broad-spectrum antiproliferative activity and higher efficacy than reference erlotinib and miltefosine. Their cellular GI values was in the ranges of 24.7-46.9 μM and 26.8-43.1 μM for 8e and 8d respectively. Assay results of the inhibitory activity of the prepared compounds on EGFR kinase reaction and Akt phosphorylation in conjugation with statistical correlation analysis indicated that other mechanisms might contribute to their elicited cytotoxicities. In addition, statistical correlation analysis revealed that mechanisms of elicited cytotoxicities for amide series might be different from ester series. In addition, correlation analysis indicated variations in the mechanisms according to the types of cell line.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bioorg.2018.11.021DOI Listing
March 2019

Development of a parallel microbore hollow fiber enzyme reactor platform for online O-labeling: Application to lectin-specific lung cancer N-glycoproteome.

J Chromatogr B Analyt Technol Biomed Life Sci 2018 Nov 2;1100-1101:58-64. Epub 2018 Oct 2.

Center for Bioanalysis, Division of Chemical and Medical Metrology, Korea Research Institute of Standards and Science, Daejeon, 34113, Republic of Korea. Electronic address:

We introduce a simple online O-labeling protocol for protein samples that uses a parallelizing microbore hollow fiber enzyme reactor (mHFER) as an alternative tool for online proteolytic digestion. Online O-labeling is performed by separately attaching two mHFERs in parallel to a 10-port switching valve with a high-pressure syringe pump and two syringes containing O- or O-water. O-/O-labeled peptides are formed in this manner and simultaneously analyzed online using nanoflow liquid chromatography-tandem mass spectrometry (nLC-MS/MS) without any residual trypsin activity. The usefulness of a parallel mHFER platform (P-mHFER) in O-labeling was tested using both cytochrome C and alpha-1-acid-glycoprotein to verify the incorporation level of two O atoms into tryptic peptides and to provide a quantitative assessment with varied mixing ratios. Additionally, our O-labeling approach was used to study the serum N-glycoproteome from lung cancer patients and controls to evaluate the applicability of lectin-based quantitative N-glycoproteomics. We successfully quantified 76 peptides (from 62 N-glycoproteins). Nineteen of these peptides from lung cancer serum were up-/down-regulated at least 2.5-fold compared to controls. As a result, the P-mHFER-based online O-labeling platform presented here can be a simple and reproducible way to allow quantitative proteomic analysis of diverse proteome samples.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jchromb.2018.09.041DOI Listing
November 2018

Graphene oxide nano-bio interaction induces inhibition of spermatogenesis and disturbance of fatty acid metabolism in the nematode Caenorhabditis elegans.

Toxicology 2018 12 13;410:83-95. Epub 2018 Sep 13.

School of Environmental Engineering, University of Seoul, 163 Seoulsiripdaero, Dongdaemun-gu, Seoul 02504, Republic of Korea. Electronic address:

Graphene oxide (GO) has the potential for wide applications, which necessitates an intensive investigation of its potential hazard on human and environmental health. Even if previous studies show reproductive toxicity in the nematode Caenorhabditis elegans, the mechanisms of reproductive toxicity by GO are poorly understood. To understand the underlying mechanisms of GO-induced reproductive toxicity, we investigated the interaction between GO and C. elegans using Raman spectroscopy, sperm counts produced by spermatogenesis, progeny and analyzed the fatty acid metabolism using molecular techniques. GO-characteristic Raman spectral bands measured throughout C. elegans, brood size and Hoecst staining of dissected gonads clearly showed GO accumulation in the reproductive organs, reduced progeny and low sperm counts, which are possibly direct results of the reproductive toxicity from GO exposure. Interestingly, reduced fatty acid metabolites, such as stearic, oleic, palmitoleic, and palmitic acids, were found with GO exposure. We found that GO increased intestinal fat accumulation in wild type N2, fat-5(tm420), and fat-7(wa36) mutants, whereas it decreased fat storage in the fat-6(tm331) and nhr-49(nr2041) mutants. GO exposure affected C. elegans fat accumulation and consumption, which was possibly regulated by daf-16 and nhr-80 gene activity. Also, GO exposure suppressed the survival of long-lived fat-5(tm420) mutants, whereas it increased the survival of short-lived nhr-49(nr2041) mutants. Hence, our studies collectively indicated that GO accumulation in reproductive organs, suppression of spermatogenesis, and the alteration of fatty acid metabolism play critical roles in understanding mechanisms of toxicity in C. elegans.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.tox.2018.09.006DOI Listing
December 2018

Design of PPAR-γ agonist based on algal metabolites and the endogenous ligand 15-deoxy-Δ-prostaglandin J.

Eur J Med Chem 2018 Sep 30;157:1192-1201. Epub 2018 Aug 30.

College of Pharmacy, Pusan National University, Busan, 46241, Republic of Korea. Electronic address:

In a previous study, we synthesized endocyclic enone jasmonate derivatives that function as anti-inflammatory and PPAR-γ-activating entities by using key functional moieties of anti-inflammatory algal metabolites. Herein, we designed additional derivatives containing an exocyclic enone moiety that resembles the key structure of the natural PPAR-γ ligand, 15-deoxy-Δ-prostaglandin J (15 d-PGJ). The exocyclic enone moiety of 15 d-PGJ is essential for covalent bonding with the Cys residue in the PPAR-γ ligand-binding domain (LBD). In silico analysis of the designed compounds indicated that they may form hydrogen bonds with key amino acid residues in the PPAR-γ LBD, and thus, secure a position in the bioactive cavity in a similar fashion as does rosiglitazone and 15 d-PGJ. By a luciferase reporter assay on rat liver Ac2F cells, the synthesized compounds were evaluated for PPAR-γ transcriptional activity. The differential PPAR-γ transcriptional activities of the geometric and enantiomeric isomers of the selected analog were also evaluated; based on our results, the enantiopure compound (+)-(R,E)-6a1 was suggested as a potential PPAR-γ ligand.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejmech.2018.08.090DOI Listing
September 2018

Quantitative Proteomic Analysis of 2D and 3D Cultured Colorectal Cancer Cells: Profiling of Tankyrase Inhibitor XAV939-Induced Proteome.

Sci Rep 2018 09 5;8(1):13255. Epub 2018 Sep 5.

Center for Bioanalysis, Division of Chemical and Medical Metrology, Korea Research Institute of Standards and Science, Daejeon, 34113, Korea.

Recently there has been a growing interest in three-dimensional (3D) cell culture systems for drug discovery and development. These 3D culture systems better represent the in vivo cellular environment compared to two-dimensional (2D) cell culture, thereby providing more physiologically reliable information on drug screening and testing. Here we present the quantitative profiling of a drug-induced proteome in 2D- and 3D-cultured colorectal cancer SW480 cells using 2D nanoflow liquid chromatography-tandem mass spectrometry (2D-nLC-MS/MS) integrated with isobaric tags for relative and absolute quantitation (iTRAQ). We identified a total of 4854 shared proteins between 2D- and 3D-cultured SW480 cells and 136/247 differentially expressed proteins (up/down-regulated in 3D compared to 2D). These up/down-regulated proteins were mainly involved in energy metabolism, cell growth, and cell-cell interactions. We also investigated the XAV939 (tankyrase inhibitor)-induced proteome to reveal factors involved in the 3D culture-selective growth inhibitory effect of XAV939 on SW480 cells. We identified novel XAV939-induced proteins, including gelsolin (a possible tumor suppressor) and lactate dehydrogenase A (a key enzyme of glycolysis), which were differentially expressed between 2D- and 3D-cultured SW480 cells. These results provide a promising informative protein dataset to determine the effect of XAV939 on the expression levels of proteins involved in SW480 cell growth.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-018-31564-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6125324PMC
September 2018