Dieckol Attenuates Microglia-mediated Neuronal Cell Death via ERK, Akt and NADPH Oxidase-mediated Pathways

Yanji Cui,Jee-Yun Park,Jinji Wu,Ji Hyung Lee,Yoon-Sil Yang,Moon-Seok Kang,Sung-Cherl Jung,Joo Min Park,Eun-Sook Yoo,Seong-Ho Kim,Sangmee Ahn Jo,Kyoungho Suk,Su-Yong Eun 대한생리학회-대한약리학회 2015 The Korean Journal of Physiology & Pharmacology Vol.19 No.3

Excessive microglial activation and subsequent neuroinflammation lead to synaptic loss and dysfunction as well as neuronal cell death, which are involved in the pathogenesis and progression of several neurodegenerative diseases. Thus, the regulation of microglial activation has been evaluated as effective therapeutic strategies. Although dieckol (DEK), one of the phlorotannins isolated from marine brown alga <em>Ecklonia cava</em>, has been previously reported to inhibit microglial activation, the molecular mechanism is still unclear. Therefore, we investigated here molecular mechanism of DEK via extracellular signal-regulated kinase (ERK), Akt and nicotinamide adenine dinuclelotide phosphate (NADPH) oxidase-mediated pathways. In addition, the neuroprotective mechanism of DEK was investigated in microglia-mediated neurotoxicity models such as neuron-microglia co-culture and microglial conditioned media system. Our results demonstrated that treatment of anti-oxidant DEK potently suppressed phosphorylation of ERK in lipopolysaccharide (LPS, 1 μg/ml)-stimulated BV-2 microglia. In addition, DEK markedly attenuated Akt phosphorylation and increased expression of gp91^phox, which is the catalytic component of NADPH oxidase complex responsible for microglial reactive oxygen species (ROS) generation. Finally, DEK significantly attenuated neuronal cell death that is induced by treatment of microglial conditioned media containing neurotoxic secretary molecules. These neuroprotective effects of DEK were also confirmed in a neuron-microglia co-culture system using enhanced green fluorescent protein (EGFP)-transfected B35 neuroblastoma cell line. Taken together, these results suggest that DEK suppresses excessive microglial activation and microglia-mediated neuronal cell death via downregulation of ERK, Akt and NADPH oxidase-mediated pathways.

Neuroprotective mechanisms of dieckol against glutamate toxicity through reactive oxygen species scavenging and nuclear factor-like 2/heme oxygenase-1 pathway

Cui, Yanji,Amarsanaa, Khulan,Lee, Ji Hyung,Rhim, Jong-Kook,Kwon, Jung Mi,Kim, Seong-Ho,Park, Joo Min,Jung, Sung-Cherl,Eun, Su-Yong The Korean Society of Pharmacology 2019 The Korean Journal of Physiology & Pharmacology Vol.23 No.2

Glutamate toxicity-mediated mitochondrial dysfunction and neuronal cell death are involved in the pathogenesis of several neurodegenerative diseases as well as acute brain ischemia/stroke. In this study, we investigated the neuroprotective mechanism of dieckol (DEK), one of the phlorotannins isolated from the marine brown alga Ecklonia cava, against glutamate toxicity. Primary cortical neurons ($100{\mu}M$, 24 h) and HT22 neurons (5 mM, 12 h) were stimulated with glutamate to induce glutamate toxic condition. The results demonstrated that DEK treatment significantly increased cell viability in a dose-dependent manner ($1-50{\mu}M$) and recovered morphological deterioration in glutamate-stimulated neurons. In addition, DEK strongly attenuated intracellular reactive oxygen species (ROS) levels, mitochondrial overload of $Ca^{2+}$ and ROS, mitochondrial membrane potential (${\Delta}{\Psi}_m$) disruption, adenine triphosphate depletion. DEK showed free radical scavenging activity in the cell-free system. Furthermore, DEK enhanced protein expression of heme oxygenase-1 (HO-1), an important anti-oxidant enzyme, via the nuclear translocation of nuclear factor-like 2 (Nrf2). Taken together, we conclude that DEK exerts neuroprotective activities against glutamate toxicity through its direct free radical scavenging property and the Nrf-2/HO-1 pathway activation.

Dieckol Attenuates Microglia-mediated Neuronal Cell Death via ERK, Akt and NADPH Oxidase-mediated Pathways

Cui, Yanji,Park, Jee-Yun,Wu, Jinji,Lee, Ji Hyung,Yang, Yoon-Sil,Kang, Moon-Seok,Jung, Sung-Cherl,Park, Joo Min,Yoo, Eun-Sook,Kim, Seong-Ho,Ahn Jo, Sangmee,Suk, Kyoungho,Eun, Su-Yong The Korean Society of Pharmacology 2015 The Korean Journal of Physiology & Pharmacology Vol.19 No.3

Excessive microglial activation and subsequent neuroinflammation lead to synaptic loss and dysfunction as well as neuronal cell death, which are involved in the pathogenesis and progression of several neurodegenerative diseases. Thus, the regulation of microglial activation has been evaluated as effective therapeutic strategies. Although dieckol (DEK), one of the phlorotannins isolated from marine brown alga Ecklonia cava, has been previously reported to inhibit microglial activation, the molecular mechanism is still unclear. Therefore, we investigated here molecular mechanism of DEK via extracellular signal-regulated kinase (ERK), Akt and nicotinamide adenine dinuclelotide phosphate (NADPH) oxidase-mediated pathways. In addition, the neuroprotective mechanism of DEK was investigated in microglia-mediated neurotoxicity models such as neuron-microglia co-culture and microglial conditioned media system. Our results demonstrated that treatment of anti-oxidant DEK potently suppressed phosphorylation of ERK in lipopolysaccharide (LPS, $1{\mu}g/ml$)-stimulated BV-2 microglia. In addition, DEK markedly attenuated Akt phosphorylation and increased expression of $gp91^{phox}$, which is the catalytic component of NADPH oxidase complex responsible for microglial reactive oxygen species (ROS) generation. Finally, DEK significantly attenuated neuronal cell death that is induced by treatment of microglial conditioned media containing neurotoxic secretary molecules. These neuroprotective effects of DEK were also confirmed in a neuron-microglia co-culture system using enhanced green fluorescent protein (EGFP)-transfected B35 neuroblastoma cell line. Taken together, these results suggest that DEK suppresses excessive microglial activation and microglia-mediated neuronal cell death via downregulation of ERK, Akt and NADPH oxidase-mediated pathways.

Anti-neuroinflammatory Activity of Nobiletin on Suppression of Microglial Activation

Cui, Yanji,Wu, Jinji,Jung, Sung-Cherl,Park, Deok-Bae,Maeng, Young-Hee,Hong, Jeong Yun,Kim, Se-Jae,Lee, Sun-Ryung,Kim, Soon-Jong,Kim, Sang Jeong,Eun, Su-Yong Pharmaceutical Society of Japan 2010 BIOLOGICAL & PHARMACEUTICAL BULLETIN Vol.33 No.11

<P>A growing body of evidence suggests that nobiletin (5,6,7,8,3′,4′-hexamethoxy flavone) from the peel of citrus fruits, enhances the damaged cognitive function in disease animal models. However, the neuroprotective mechanism has not been clearly elucidated. Since nobiletin has shown anti-inflammatory effects in several tissues, we investigated whether nobiletin suppresses excessive microglial activation implicated in neurotoxicity in lipopolysaccharide (LPS)-stimulated BV-2 microglia cell culture models. Release of nitric oxide (NO), the major inflammatory mediator in microglia, was markedly suppressed in a dose-dependent manner following nobiletin treatment (1—50 μ<SMALL>M</SMALL>) in LPS-stimulated BV-2 microglia cells. The inhibitory effect of nobiletin was similar to that of minocycline, a well-known microglial inactivator. Nobiletin significantly inhibited the release of the pro-inflammatory cytokine tumor necrosis factor (TNF-α) and interleukin-1β (IL-1β). LPS-induced phosphorylations of extracellular signal-regulated kinase (ERK), c-Jun NH<SUB>2</SUB>-terminal kinase (JNK), and p38 mitogen-activated protein kinases (MAPKs) were also significantly inhibited by nobiletin treatment. In addition, nobiletin markedly inhibited the LPS-induced pro-inflammatory transcription factor nuclear factor κB (NF-κB) signaling pathway by suppressing nuclear NF-κB translocation from the cytoplasm and subsequent expression of NF-κB in the nucleus. Taken together, these results may contribute to further exploration of the therapeutic potential and molecular mechanism of nobiletin in relation to neuroinflammation and neurodegenerative diseases.</P>

Privacy Analysis and Comparison of Pandemic Contact Tracing Apps

( Yanji Piao ),( Dongyue Cui ) 한국인터넷정보학회 2021 KSII Transactions on Internet and Information Syst Vol.15 No.11

During the period of epidemic prevention and control, contact tracing systems are developed in many countries, to stop or slow down the progression of COVID-19 contamination. However, the privacy issues involved in the use of contact tracing apps have also attracted people’s attention. First, we divide contact tracing techniques into two types: Bluetooth Low Energy (BLE) based and Global Positioning System (GPS) based techniques. In order to clear understand the system structure and its elements, we create data flow diagram (DFD) of each types. Second, we analyze the possible privacy threats contained in various types of contact tracing apps by applying LINDDUN, which is a threat modeling technique for personal information protection. Third, we make a comparison and analysis of various contact tracing techniques from privacy point of view. These studies can facilitate improve tracing and security performance to contact tracing apps through comparisons between different types.

Sensitive detection of levofloxacin and copper (II) based on fluorescence ‘‘turn on-off” of biomass carbonized polymer dots

Jiasheng Lin,Shuliang Yang,Yanjie Wang,Yahan Cui,Qiaoyan Li,Yanhua Chen,Lan Ding 한국공업화학회 2022 Journal of Industrial and Engineering Chemistry Vol.114 No.-

A novel type of biomass carbonized polymer dots (CS-CPDs) with green fluorescence emission were synthesizedvia a one-step microwave-assisted method, using chitosan and maleic acid as the precursors. The fluorescence intensity of CS-CPDs was selectively enhanced (turn on) with increasing levofloxacin(LEV) concentration based on Aggregation Induced Emission Enhancement. The linear range of thismethod was 1–35 lmol/L, with the limit of detection of 0.20 lmol/L. Furthermore, we demonstrated thatthe fluorescence intensity of CS-CPDs/LEV was restored (turn on-off) due to the addition of copper (II),which could assemble a more stable Cu2+/LEV complex through coordination. For the first time, CSCPDswere utilized as a selective fluorescent ‘‘turn on-off” probe for the continuous detection of LEVand Cu2+. Excellent results were also obtained in environmental water samples analysis with recoveriesranging of 91.3–99.6% and 97.7–113.4%, respectively. Moreover, the prepared CS-CPDs exhibited excellentoptical stability and large Stokes shift (139 nm), which predicted broad application prospects inthe field of fluorescence sensing.

Nobiletin attenuates neurotoxic mitochondrial calcium overload through K⁺ influx and ∆Ψ_m across mitochondrial inner membrane

Lee, Ji Hyung,Amarsanaa, Khulan,Wu, Jinji,Jeon, Sang-Chan,Cui, Yanji,Jung, Sung-Cherl,Park, Deok-Bae,Kim, Se-Jae,Han, Sang-Heon,Kim, Hyun-Wook,Rhyu, Im Joo,Eun, Su-Yong The Korean Society of Pharmacology 2018 The Korean Journal of Physiology & Pharmacology Vol.22 No.3

Mitochondrial calcium overload is a crucial event in determining the fate of neuronal cell survival and death, implicated in pathogenesis of neurodegenerative diseases. One of the driving forces of calcium influx into mitochondria is mitochondria membrane potential (${\Delta}{\psi}_m$). Therefore, pharmacological manipulation of ${\Delta}{\psi}_m$ can be a promising strategy to prevent neuronal cell death against brain insults. Based on these issues, we investigated here whether nobiletin, a Citrus polymethoxylated flavone, prevents neurotoxic neuronal calcium overload and cell death via regulating basal ${\Delta}{\psi}_m$ against neuronal insult in primary cortical neurons and pure brain mitochondria isolated from rat cortices. Results demonstrated that nobiletin treatment significantly increased cell viability against glutamate toxicity ($100{\mu}M$, 20 min) in primary cortical neurons. Real-time imaging-based fluorometry data reveal that nobiletin evokes partial mitochondrial depolarization in these neurons. Nobiletin markedly attenuated mitochondrial calcium overload and reactive oxygen species (ROS) generation in glutamate ($100{\mu}M$)-stimulated cortical neurons and isolated pure mitochondria exposed to high concentration of $Ca^{2+}$ ($5{\mu}M$). Nobiletin-induced partial mitochondrial depolarization in intact neurons was confirmed in isolated brain mitochondria using a fluorescence microplate reader. Nobiletin effects on basal ${\Delta}{\psi}_m$ were completely abolished in $K^+-free$ medium on pure isolated mitochondria. Taken together, results demonstrate that $K^+$ influx into mitochondria is critically involved in partial mitochondrial depolarization-related neuroprotective effect of nobiletin. Nobiletin-induced mitochondrial $K^+$ influx is probably mediated, at least in part, by activation of mitochondrial $K^+$ channels. However, further detailed studies should be conducted to determine exact molecular targets of nobiletin in mitochondria.

Nobiletin attenuates neurotoxic mitochondrial calcium overload through K+ influx and ΔΨm across mitochondrial inner membrane

Ji Hyung Lee,Khulan Amarsanaa,Jinji Wu,Sang-Chan Jeon,Yanji Cui,Sung-Cherl Jung,Deok-Bae Park,Se-Jae Kim,Sang-Heon Han,Hyun-Wook Kim,Im Joo Rhyu,Su-Yong Eun 대한생리학회-대한약리학회 2018 The Korean Journal of Physiology & Pharmacology Vol.22 No.3

Mitochondrial calcium overload is a crucial event in determining the fate of neuronal cell survival and death, implicated in pathogenesis of neurodegenerative diseases. One of the driving forces of calcium influx into mitochondria is mitochondria membrane potential (ΔΨm). Therefore, pharmacological manipulation of ΔΨm can be a promising strategy to prevent neuronal cell death against brain insults. Based on these issues, we investigated here whether nobiletin, a Citrus polymethoxylated flavone, prevents neurotoxic neuronal calcium overload and cell death via regulating basal ΔΨm against neuronal insult in primary cortical neurons and pure brain mitochondria isolated from rat cortices. Results demonstrated that nobiletin treatment significantly increased cell viability against glutamate toxicity (100 μM,20 min) in primary cortical neurons. Real-time imaging-based fluorometry data reveal that nobiletin evokes partial mitochondrial depolarization in these neurons. Nobiletin markedly attenuated mitochondrial calcium overload and reactive oxygen species (ROS) generation in glutamate (100 μM)-stimulated cortical neurons and isolated pure mitochondria exposed to high concentration of Ca2+ (5 μM). Nobiletininduced partial mitochondrial depolarization in intact neurons was confirmed in isolated brain mitochondria using a fluorescence microplate reader. Nobiletin effects on basal ΔΨm were completely abolished in K+-free medium on pure isolated mitochondria. Taken together, results demonstrate that K+ influx into mitochondria is critically involved in partial mitochondrial depolarization–related neuroprotective effect of nobiletin. Nobiletin-induced mitochondrial K+ influx is probably mediated, at least in part, by activation of mitochondrial K+ channels. However, further detailed studies should be conducted to determine exact molecular targets of nobiletin in mitochondria.

Identification of quantitative trait loci associated with drought tolerance traits in rice (Oryza sativa L.) under PEG and field drought stress

Han, Bing,Wang, Jiao,Li, Yafei,Ma, Xiaoding,Jo, Sumin,Cui, Di,Wang, Yanjie,Park, Dongsoo,Song, Youchun,Cao, Guilan,Wang, Xingsheng,Sun, Jianchang,Shin, Dongjin,Han, Longzhi Springer Netherlands 2018 Euphytica Vol.214 No.4