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The Role of Free Radicals in the Aging Brain and Parkinson’s Disease: Convergence and Parallelism
Kumar, Hemant,Lim, Hyung-Woo,More, Sandeep Vasant,Kim, Byung-Wook,Koppula, Sushruta,Kim, In Su,Choi, Dong-Kug Molecular Diversity Preservation International (MD 2012 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Vol.13 No.8
<P>Free radical production and their targeted action on biomolecules have roles in aging and age-related disorders such as Parkinson’s disease (PD). There is an age-associated increase in oxidative damage to the brain, and aging is considered a risk factor for PD. Dopaminergic neurons show linear fallout of 5–10% per decade with aging; however, the rate and intensity of neuronal loss in patients with PD is more marked than that of aging. Here, we enumerate the common link between aging and PD at the cellular level with special reference to oxidative damage caused by free radicals. Oxidative damage includes mitochondrial dysfunction, dopamine auto-oxidation, α-synuclein aggregation, glial cell activation, alterations in calcium signaling, and excess free iron. Moreover, neurons encounter more oxidative stress as a counteracting mechanism with advancing age does not function properly. Alterations in transcriptional activity of various pathways, including nuclear factor erythroid 2-related factor 2, glycogen synthase kinase 3β, mitogen activated protein kinase, nuclear factor kappa B, and reduced activity of superoxide dismutase, catalase and glutathione with aging might be correlated with the increased incidence of PD.</P>
MORE KUNAL NANDKUMAR,장동조,Jun-Young Lee,Jeong-Hoon Park 대한방사성의약품학회 2019 Journal of radiopharmaceuticals and molecular prob Vol.5 No.1
Hypoxia-inducible factor-1 (HIF-1α) is a transcription factor activated in response to low oxygen level, and ishighly expressed in many solid tumors. Moreover, HIF-1α is a representative biomarker of hypoxia and alsohelps to maintain cell homeostasis under hypoxic condition. Most solid tumors show hypoxia, which inducespoor prognosis and resistance to conventional cancer therapies. Thus, early diagnosis of hypoxia with positronemission tomography (PET) radiotracer would be highly beneficial for management of malignant solid tumorswith effective cancer therapy. YC-1 is a most promising candidate among several HIF-1α inhibitors. As an effortto develop a hypoxia imaging tool as a PET radiotracer, we designed and synthesized [18F]DFYC based onpotent derivative of YC-1 and performed preliminary in vitro cell uptake study. [18F]DFYC showed a significantaccumulation in SKBR-3 cells among other cancer cells, proving as a good lead to develop a hypoxic solidtumor such as breast cancer.
More, Kunal N.,Lim, Tae-Hwan,Kim, So-Young,Kang, Julie,Inn, Kyung-Soo,Chang, Dong-Jo Applied Science Publishers 2018 Dyes and pigments Vol.151 No.-
<P><B>Abstract</B></P> <P>Hypoxia is a common feature of many solid tumors and is known to cause the resistance to chemotherapy and radiotherapy. Nitroreductase (NTR), a common biomarker of hypoxia, is an attractive target for the design of therapeutics and imaging agents targeting hypoxia. Under hypoxic condition, nitroreductase can reduce an aromatic nitro group conjugated to a drug or fluorophore to amine, which leads to release a free drug or fluorophore through the subsequent 1,6-rearrangment elimination. This type of 1,6-rearrangement elimination to release a drug or fluorophore has been widely used in the development of activity-based “turn on” fluorescent probes as well as targeted therapeutics such as antibody-drug conjugates (ADCs) and small molecule-drug conjugates (SMDCs). In this paper, novel “turn on” NTR-responsive fluorescent probes diversely linked to a 4-nitrobenzyl moiety via ether, carbonate, amine and carbamate linkages have been developed. The effect of variation in linkage on the release of fluorophore has been studied by the analysis of spectroscopic properties, temperature and pH stability, kinetics and concentration-dependency of the probes during NTR reaction. Fluorescent probes with an ether (<B>10</B>) or a carbamate (<B>16</B>) linkage showed biocompatible nature, high sensitivity (working below 1 μM of concentration) and strong fluorescence emission in the presence of NTR whereas they showed very low quantum yields in the absence of NTR. Finally, the probes (<B>10, 16)</B> were successfully applied to <I>in vitro</I> imaging of hypoxic cancer cells.</P> <P><B>Highlights</B></P> <P> <UL> <LI> “Turn on” fluorescent probes linked to NTR-sensing moiety via ether, carbonate, amines and carbamate linkages were prepared. </LI> <LI> The Effect of variation in the linkage between fluorophore and NTR-responsive moiety was evaluated by NTR reaction. </LI> <LI> The probes with an ether or carbamate linkage exhibited fast responses to NTR and strong fluorescent images in hypoxic cells. </LI> <LI> This study can be applied to not only activity-based fluorescent probes but also therapeutics to release a drug such as ADCs. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>
More, Kunal N.,Lee, Jun Young,Park, Jeong-Hoon,Chang, Dong-Jo Korean Society of Radiopharmaceuticals and Molecul 2019 Journal of radiopharmaceuticals and molecular prob Vol.5 No.1
Hypoxia-inducible factor-1 ($HIF-1{\alpha}$) is a transcription factor activated in response to low oxygen level, and is highly expressed in many solid tumors. Moreover, $HIF-1{\alpha}$ is a representative biomarker of hypoxia and also helps to maintain cell homeostasis under hypoxic condition. Most solid tumors show hypoxia, which induces poor prognosis and resistance to conventional cancer therapies. Thus, early diagnosis of hypoxia with positron emission tomography (PET) radiotracer would be highly beneficial for management of malignant solid tumors with effective cancer therapy. YC-1 is a most promising candidate among several $HIF-1{\alpha}$ inhibitors. As an effort to develop a hypoxia imaging tool as a PET radiotracer, we designed and synthesized [$^{18}F$]DFYC based on potent derivative of YC-1 and performed preliminary in vitro cell uptake study. [$^{18}F$]DFYC showed a significant accumulation in SKBR-3 cells among other cancer cells, proving as a good lead to develop a hypoxic solid tumor such as breast cancer.
More, Kunal N.,Lee, Jun Young,Kim, Dong-Yeon,Cho, Nam-Chul,Pyo, Ayoung,Yun, Misun,Kim, Hyeon Sik,Kim, Hangun,Ko, Kwangseok,Park, Jeong-Hoon,Chang, Dong-Jo Elsevier 2018 Bioorganic & medicinal chemistry letters Vol.28 No.5
<P><B>Abstract</B></P> <P>Carbonic anhydrase IX is overexpressed in many solid tumors including hypoxic tumors and is a potential target for cancer therapy and diagnosis. Reported imaging agents targeting CA-IX are successful mostly in clear cell renal carcinoma as SKRC-52 and no candidate was approved yet in clinical trials for imaging of CA-IX. To validate CA-IX as a valid target for imaging of hypoxic tumor, we designed and synthesized novel [<SUP>18</SUP>F]-PET tracer (<B>1</B>) based on acetazolamide which is one of the well-known CA-IX inhibitors and performed imaging study in CA-IX expressing hypoxic tumor model as 4T1 and HT-29 <I>in vivo</I> models other than SKRC-52. [<SUP>18</SUP>F]-acetazolamide (<B>1</B>) was found to be insufficient for the specific accumulation in CA-IX expressing tumor. This study might be useful to understand <I>in vivo</I> behavior of acetazolamide PET tracer and can contribute to the development of successful PET imaging agents targeting CA-IX in future. Additional study is needed to understand the mechanism of poor targeting of CA-IX, as if CA-IX is not reliable as a sole target for imaging of CA-IX expressing hypoxic solid tumors.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>
Discovery and evaluation of 3,5-disubstituted indole derivatives as Pim kinase inhibitors
More, Kunal N.,Hong, Victor S.,Lee, Ahyeon,Park, Jongsung,Kim, Shin,Lee, Jinho Elsevier 2018 Bioorganic & medicinal chemistry letters Vol.28 No.14
<P><B>Abstract</B></P> <P>Pim kinases are promising therapeutic targets for the treatment of hematological cancers. A potent Pim kinase inhibitor <B>7f,</B> derived from meridianin C, was further optimized by the replacement of 2-aminopyrimidine with substituted benzene. The optimization of the C-3 and C-5 positions of indole yielded compound <B>43</B> with improved cellular potency and high selectivity against a panel of 14 different kinases.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Pim-1 and Pim-3 kinase inhibitors were prepared using indole as the core structure. </LI> <LI> 2-Aminopyrimidine of meridianin C derivative was replaced by substituted benzene. </LI> <LI> Cellular potency of inhibitor was improved by the optimization process. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>
The Impact of Greenwashing on Green Brand Trust from an Indian Perspective
More, Praful Vijay Asian Society for Innovation and Policy 2019 Asian Journal of Innovation and Policy Vol.8 No.1
Purpose: Companies in haste for higher consumers' preference tend to appear as 'green' and mislead about environmental concerns, which are termed as "Greenwashing." The purpose of the study is to investigate the consumer perception on greenwashing activities and analyze its impact on green brand image, green brand loyalty and green brand trust among Indian consumers. Design/methodology: The study makes use of a written questionnaire method to collect survey data from approximately 500 consumers all over India. The study uses Structural Equation Modeling (SEM) to study the hypothesized relationship between constructs affected by greenwashing based on consumer perspective in the Indian context. Findings: The study shows that Indian consumers are becoming aware of greenwashing activities, which have a negative impact on green brand trust and undermines green brand image and green brand loyalty. Implications: The study results are beneficial to policy-makers, researchers, practitioners, and managers to create awareness among Indian consumers on greenwashing activities.