Neuroprotective and Anti-Inflammatory Activities of Allyl Isothiocyanate through Attenuation of JNK/NF-κB/TNF-α Signaling

Subedi, Lalita,Venkatesan, Ramu,Kim, Sun Yeou MDPI 2017 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Vol.18 No.7

<P>Allyl isothiocyanate (AITC), present in <I>Wasabia japonica</I> (wasabi), is an aliphatic isothiocyanate derived from the precursor sinigrin, which is a glucosinolate present in vegetables of the Brassica family. Traditionally, it has been used to treat rheumatic arthralgia, blood circulation, and pain. This study focuses on its anti-apoptotic activity through the regulation of lipopolysaccharide (LPS)-induced neuroinflammation. Furthermore, we assessed its neuroprotective efficacy, which it achieves through the upregulation of nerve growth factor (NGF) production. Pretreatment with AITC significantly inhibited inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression, decreased tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), prostaglandin E2 (PGE2), and nitric oxide (NO) production in activated microglia, and increased the nerve growth factor (NGF) and neurite outgrowth in neuroblastoma cells. AITC inhibited the nuclear factor (NF-κB-mediated transcription by modulating mitogen activated protein kinase (MAPK) signaling, particularly downregulating c-Jun N-terminal kinase (JNK) phosphorylation, which was followed by a reduction in the TNF-α expression in activated microglia. This promising effect of AITC in controlling JNK/NF-κB/TNF-α cross-linking maintains the <I>Bcl-2</I> gene family and protects neuroblastoma cells from activated microglia-induced toxicity. These findings provide novel insights into the anti-neuroinflammatory effects of AITC on microglial cells, which may have clinical significance in neurodegeneration.</P>

Resveratrol-Enriched Rice Attenuates UVB-ROS-Induced Skin Aging via Downregulation of Inflammatory Cascades

Subedi, Lalita,Lee, Taek Hwan,Wahedi, Hussain Mustatab,Baek, So-Hyeon,Kim, Sun Yeou Hindawi 2017 Oxidative medicine and cellular longevity Vol.2017 No.-

<P>The skin is the outermost protective barrier between the internal and external environments in humans. Chronic exposure to ultraviolet (UV) radiation is a major cause of skin aging. UVB radiation penetrates the skin and induces ROS production that activates three major skin aging cascades: matrix metalloproteinase- (MMP-) 1-mediated aging; MAPK-AP-1/NF-<I>κ</I>B-TNF-<I>α</I>/IL-6, iNOS, and COX-2-mediated inflammation-induced aging; and p53-Bax-cleaved caspase-3-cytochrome C-mediated apoptosis-induced aging. These mechanisms are collectively responsible for the wrinkling and photoaging characteristic of UVB-induced skin aging. There is an urgent requirement for a treatment that not only controls these pathways to prevent skin aging but also avoids the adverse effects often encountered when applying bioactive compounds in concentrated doses. In this study, we investigated the efficacy of genetically modified normal edible rice (NR) that produces the antiaging compound resveratrol (R) as a treatment for skin aging. This resveratrol-enriched rice (RR) overcomes the drawbacks of R and enhances its antiaging potential by controlling the abovementioned three major pathways of skin aging. RR does not exhibit the toxicity of R alone and promisingly downregulates the pathways underlying UVB-ROS-induced skin aging. These findings advocate the use of RR as a nutraceutical for antiaging purposes.</P>

Genetically Engineered Resveratrol-Enriched Rice Inhibits Neuroinflammation in Lipopolysaccharide-Activated BV2 Microglia Via Downregulating Mitogen-Activated Protein Kinase-Nuclear Factor Kappa B Signaling Pathway

Subedi, Lalita,Baek, So-Hyeon,Kim, Sun Yeou Hindawi 2018 Oxidative medicine and cellular longevity Vol.2018 No.-

<P>Resveratrol, a natural stilbenoid, is produced by several plants, especially grape vines. Its strong potency against obesity, metabolic disorders, vascular disease, inflammation, and various cancers has already been reported. Large amounts of wine or grapes need to be consumed to obtain the amount of resveratrol required for biological activity. Pure resveratrol at concentrations as low as 10 <I>μ</I>M induces cytotoxicity to normal cells. To overcome these limitations, we prepared genetically modified resveratrol-enriched rice (RR). We previously reported the strong antiaging potential of RR against ultraviolet B/reactive oxygen species-induced toxicity in normal human dermal fibroblasts (NHDF). As aging is characterized by neuroinflammation and neurodegeneration, we further evaluated the role of RR against LPS-induced neuroinflammation. RR inhibited nitric oxide production and the expression of inflammatory proteins such as iNOS and COX-2. RR significantly modulated mitogen-activated protein kinase signaling, activator protein AP-1 signaling, and nuclear factor kappa B (NF-<I>κ</I>B) mediated transcription of inflammatory proteins via inhibition of NF-<I>κ</I>B translocation, IkB phosphorylation, and proinflammatory cytokine productions such as interleukin IL-6, IL-1<I>β</I>, tumor necrosis factor alpha (TNF-<I>α</I>), and prostaglandin E2 (PGE2). These findings show that the strong antineuroinflammatory effects of RR can be beneficial for aging-mediated neurodegenerative conditions as well as disorders of the central nervous system caused by neuroinflammation.</P>

Sulforaphane-Enriched Broccoli Sprouts Pretreated by Pulsed Electric Fields Reduces Neuroinflammation and Ameliorates Scopolamine-Induced Amnesia in Mouse Brain through Its Antioxidant Ability via Nrf2-HO-1 Activation

Subedi, Lalita,Cho, KyoHee,Park, Yong Un,Choi, Hyuk Joon,Kim, Sun Yeou Hindawi 2019 Oxidative medicine and cellular longevity Vol.2019 No.-

<P>Activated microglia-mediated neuroinflammation plays a key pathogenic role in neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, and ischemia. Sulforaphane is an active compound produced after conversion of glucoraphanin by the myrosinase enzyme in broccoli (<I>Brassica oleracea</I> var) sprouts. Dietary broccoli extract as well as sulforaphane has previously known to mitigate inflammatory conditions in aged models involving microglial activation. Here, we produced sulforaphane-enriched broccoli sprouts through the pretreatment of pulsed electric fields in order to trigger the biological role of normal broccoli against lipopolysaccharide-activated microglia. The sulforaphane-enriched broccoli sprouts showed excellent potency against neuroinflammation conditions, as evidenced by its protective effects in both 6 and 24 h of microglial activation <I>in vitro</I>. We further postulated the underlying mechanism of action of sulforaphane in broccoli sprouts, which was the inhibition of an inflammatory cascade <I>via</I> the downregulation of mitogen-activated protein kinase (MAPK) signaling. Simultaneously, sulforaphane-enriched broccoli sprouts inhibited the LPS-induced activation of the NF-<I>κ</I>B signaling pathway and the secretions of inflammatory proteins (iNOS, COX-2, TNF-<I>α</I>, IL-6, IL-1<I>β</I>, PGE2, etc.), which are responsible for the inflammatory cascades in both acute and chronic inflammation. It also upregulated the expression of Nrf2 and HO-1 in normal and activated microglia followed by the lowered neuronal apoptosis induced by activated microglia. Based on these results, it may exhibit anti-inflammatory effects via the NF-<I>κ</I>B and Nrf2 pathways. Interestingly, sulforaphane-enriched broccoli sprouts improved the scopolamine-induced memory impairment in mice through Nrf2 activation, inhibiting neuronal apoptosis particularly through inhibition of caspase-3 activation which could lead to the neuroprotection against neurodegenerative disorders. The present study suggests that sulforaphane-enriched broccoli sprouts might be a potential nutraceutical with antineuroinflammatory and neuroprotective activities.</P>

Corrigendum to “Resveratrol-Enriched Rice Attenuates UVB-ROS-Induced Skin Aging via Downregulation of Inflammatory Cascades”

Subedi, Lalita,Lee, Taek Hwan,Wahedi, Hussain Mustatab,Baek, So-Hyeon,Kim, Sun Yeou Hindawi 2018 Oxidative medicine and cellular longevity Vol.2018 No.-

A New Neolignan Derivative, Balanophonin Isolated from Firmiana simplex Delays the Progress of Neuronal Cell Death by Inhibiting Microglial Activation

임수영,Lalita Subedi,신동윤,김충섭,이강노,김선여 한국응용약물학회 2017 Biomolecules & Therapeutics(구 응용약물학회지) Vol.25 No.5

Excessive activation of microglia causes the continuous production of neurotoxic mediators, which further causes neuron degeneration. Therefore, inhibition of microglial activation is a possible target for the treatment of neurodegenerative disorders. Balanophonin, a natural neolignoid from Firmiana simplex, has been reported to have anti-inflammatory and anti-cancer effects. In this study, we aimed to evaluate the anti-neuroinflammatory effects and mechanism of balanophonin in lipopolysaccharide (LPS)- stimulated BV2 microglia cells. BV2 microglia cells were stimulated with LPS in the presence or absence of balanophonin. The results indicated that balanophonin reduced not only the LPS-mediated TLR4 activation but also the production of inflammatory mediators, such as nitric oxide (NO), prostaglandin E2 (PGE2), Interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α), in BV2 cells. Balanophonin also inhibited LPS-induced inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX2) protein expression and mitogen activated protein kinases (MAPKs), including extracellular signal-regulated kinase (ERK1/2), c-Jun Nterminal kinase (JNK), and p38 MAPK. Interestingly, it also inhibited neuronal cell death resulting from LPS-activated microglia by regulating cleaved caspase-3 and poly ADP ribose polymerase (PARP) cleavage in N2a cells. In conclusion, our data indicated that balanophonin may delay the progression of neuronal cell death by inhibiting microglial activation.

Chemical Constituents of Impatiens balsamina Stems and Their Biological Activities

김동현,이태현,Lalita Subedi,김선연,이강노 한국생약학회 2019 Natural Product Sciences Vol.25 No.2

The purification of the MeOH extract from Impatiens basamina by repeated column chromatography led to the isolation of one new tetrahydronaphthalene (1), together with eleven known compounds (2 - 12). The structure of the new compound (1) was determined by spectral data analysis (1H and 13C-NMR, 1H-1H COSY, HSQC, HMBC, NOESY, and HR-ESI-MS). Isolated compounds (1 - 12) were evaluated for their inhibitory effects on NO production in LPS-activated murine microglial BV-2 cells and their effects on NGF secretion from C6 glioma cells. Compounds 3, 7, and 10 reduced NO levels in LPS-activated murine microglial cells with IC50 values of 26.89, 25.59, and 44.21 μM, respectively. Compounds 1, 5, and 9 upregulated NGF secretion to 153.09 ± 4.66, 156.88 ± 8.86, and 157.34 ± 3.30%, respectively.

Anti-inflammatory and Neurotrophic 2H-1-Benzopyran Derivatives of Chaenomeles sinensis

하영준,이태현,Lalita Subedi,김혜령,문규리,Sun Yeou Kim,김충섭 한국생약학회 2022 Natural Product Sciences Vol.28 No.1

Two 2H-1-benzopyran derivatives, methyl 8-hydroxy-2,2-dimethyl-2H-1-benzopyran-5-carboxylate (1) and methyl 8-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carboxylate (2), including a new compound (1) were isolated from the twigs of Chaenomeles sinensis. Their chemical structures were characterized based on analysis of NMR data including 1H and 13C, COSY, HSQC, and HMBC and HRMS data. The isolated compounds (1 and 2) were assessed for their anti-neuroinflammatory activity by measuring inhibition levels of nitric oxide (NO) production in lipopolysaccharide (LPS)-activated BV-2 cells and for their neurotrophic activity by the secretion of nerve growth factor (NGF) in C6 cells. Compounds 1 and 2 exhibited powerful anti-neuroinflammatory effects with IC50 values of 17.14 and 19.30 μM, respectively, without cell toxicity, and also showed moderate effects on the stimulation of NGF secretion levels with 113.15 ± 3.54 and 130.20 ± 8.03%, respectively. The biosynthetic pathway of 1 and 2 was proposed that they would be derived from a protocatechuic acid and an isoprenyl unit.

Gomisin N Inhibits Melanogenesis through Regulating the PI3K/Akt and MAPK/ERK Signaling Pathways in Melanocytes

Chae, Jae Kyoung,Subedi, Lalita,Jeong, Minsun,Park, Yong Un,Kim, Chul Young,Kim, Hakwon,Kim, Sun Yeou MDPI 2017 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Vol.18 No.2

<P>Gomisin N, one of the lignan compounds found in <I>Schisandra chinensis</I> has been shown to possess anti-oxidative, anti-tumorigenic, and anti-inflammatory activities in various studies. Here we report, for the first time, the anti-melenogenic efficacy of Gomisin N in mammalian cells as well as in zebrafish embryos. Gomisin N significantly reduced the melanin content without cellular toxicity. Although it was not capable of modulating the catalytic activity of mushroom tyrosinase in vitro, Gomisin N downregulated the expression levels of key proteins that function in melanogenesis. Gomisin N downregulated melanocortin 1 receptor (MC1R), adenylyl cyclase 2, microphthalmia-associated transcription factor (MITF), tyrosinase, tyrosinase-related protein-1 (TRP-1), and tyrosinase-related protein-2 (TRP-2). In addition, Gomisin N-treated Melan-A cells exhibited increased p-Akt and p-ERK levels, which implies that the activation of the PI3K/Akt and MAPK/ERK pathways may function to inhibit melanogenesis. We also validated that Gomisin N reduced melanin production by repressing the expression of MITF, tyrosinase, TRP-1, and TRP-2 in mouse and human cells as well as in developing zebrafish embryos. Collectively, we conclude that Gomisin N inhibits melanin synthesis by repressing the expression of MITF and melanogenic enzymes, probably through modulating the PI3K/Akt and MAPK/ERK pathways.</P>

Lignan Glycosides from the Twigs of <i>Chaenomeles sinensis</i> and Their Biological Activities

Kim, Chung Sub,Subedi, Lalita,Kim, Sun Yeou,Choi, Sang Un,Kim, Ki Hyun,Lee, Kang Ro American Chemical Society and American Society of 2015 Journal of natural products Vol.78 No.5

<P>Phytochemical investigation of the twigs of <I>Chaenomeles sinensis</I> led to the isolation and identification of six new lignan glycosides, chaenomiside A–F (<B>1</B>–<B>6</B>), along with five known ones (<B>7</B>–<B>11</B>). Their chemical structures were determined by spectroscopic methods, including NMR, MS, ECD, and GC/MS analyses. All the isolated compounds (<B>1</B>–<B>11</B>) were tested for their inhibitory effects on nitric oxide (NO) production in lipopolysaccharide-activated murine microglial cells and the secretion of nerve growth factor (NGF) in a C6 rat glioma cell line. Compound <B>6</B> significantly reduced NO levels in the murine microglia BV2 cells with an IC<SUB>50</SUB> value of 21.3 μM, and compounds <B>1</B>, <B>3</B>, and <B>6</B> were potent stimulants of NGF release with stimulation levels of 151.74 ± 6.77%, 144.31 ± 7.49%, and 167.61 ± 18.5%, respectively.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/jnprdf/2015/jnprdf.2015.78.issue-5/acs.jnatprod.5b00090/production/images/medium/np-2015-00090g_0003.gif'></P><P><A href='http://pubs.acs.org/doi/suppl/10.1021/np5b00090'>ACS Electronic Supporting Info</A></P>