A synthetic diosgenin primary amine derivative attenuates LPS-stimulated inflammation via inhibition of NF-κB and JNK MAPK signaling in microglial BV2 cells

Cai, Bangrong,Seong, Kyung-Joo,Bae, Sun-Woong,Chun, Changju,Kim, Won-Jae,Jung, Ji-Yeon Elsevier 2018 INTERNATIONAL IMMUNOPHARMACOLOGY Vol.61 No.-

<P><B>Abstract</B></P> <P>Diosgenin, a precursor of steroid hormones in plants, is known to exhibit diverse pharmacological activities including anti-inflammatory properties. In this study, (3β, 25<I>R</I>)‑spirost‑5‑en‑3‑oxyl (2‑((2((2‑aminoethyl)amino)ethyl)amino)ethyl) carbamate (DGP), a new synthetic diosgenin derivative incorporating primary amine was used to investigate its anti-inflammatory effects and underlying mechanisms of action in lipopolysaccharide (LPS)-stimulated microglial BV2 cells. Pretreatment with DGP resulted in significant inhibition of nitric oxide (NO) synthesis, and down-regulation of nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in LPS-stimulated microglial BV2 cells. In addition, DGP decreased the production of reactive oxygen species (ROS) and pro-inflammatory cytokines such as interleukin (IL)-6, IL-1β, and tumor necrosis factor alpha (TNF-α). The inhibitory effects of DGP on these inflammatory mediators in LPS-stimulated microglial BV2 cells were regulated by NF-κB signaling through blocking p65 nuclear translocation and NF-κB p65/DNA binding activity. DGP also blocked the phosphorylation of c-Jun amino-terminal kinase (JNK), but not p38 kinase or extracellular signal-regulated kinases (ERK). The NF-κB inhibitor JSH-23 and JNK-specific inhibitor SP600125 significantly decreased NO production and IL-6 release in LPS-stimulated BV2 cells, respectively. The overall results demonstrate that DGP has anti-inflammatory effects on LPS-stimulated BV2 cells via inhibition of NF-κB and JNK activation, suggesting that DGP is a potential prophylactic agent in various neurodegenerative disorders.</P> <P><B>Highlights</B></P> <P> <UL> <LI> A new synthetic diosgenin derivative incorporating primary amine (DGP) was prepared. </LI> <LI> DGP suppresses LPS-stimulated inflammatory responses in microglial BV2 cells. </LI> <LI> DGP exerts anti-inflammatory effect via inhibition of NF-κB and JNK MAPK signaling. </LI> <LI> DGP has potential to prevent various neurodegenerative disorders as a therapeutic agent. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Design, synthesis of methotrexate-diosgenin conjugates and biological evaluation of their effect on methotrexate transport-resistant cells

( Bangrong Cai ),( Aimei Liao ),( Kyung-ku Lee ),( Jae-sam Ban ),( Hyun-sam Yang ),( Young Jun Im ),( Changju Chun ) 전남대학교 약품개발연구소 2016 약품개발연구지 Vol.25 No.-

A series of methotrexate-diosgenin conjugates was designed and synthesized to enhance the passive internalization of methotrexate (MTX) in to transport-resistant cells. The inhibitory effects of these con-jugates on dihydrofolate reductase (DHFR), and their anti-proliferation behaviors against a transport-resistant breast cancer cell line, MDA-MB-231, were investigated. All of the synthesized conjugates retained an ability to inhibit DHFR after the diosgenin substitution. The MTX conjugates were much more potent against methotrexate-resistant MDA-MB-231 cells than MTX. Conjugate 18, containing a disulfide bond, exhibited the most potent anti-proliferative and DHFR inhibitory effects (IC₅₀=4.1 μM and 17.21 nM, respectively). Anti-proliferative activity was higher in the conjugate with a longer space linker (conjugate 21) than those with shorter linkers (conjugates 19 and 20). These results suggest that dios-genin conjugation of MTX may be an effective way to overcome its transport resistance in cancer cells. ⓒ 2016 Elsevier Inc. All rights reserved.

Design, synthesis and evaluation of 5-substituted 1-H-tetrazoles as potent anticonvulsant agents

Aimei LIAO,Tiantian Wang,Bangrong Cai,Yi Jin,천승훈,ChangJu Chun,Zengtao Wang 대한약학회 2017 Archives of Pharmacal Research Vol.40 No.4

A series of 5-substituted 1-H-tetrazoles weredesigned and synthesized as potent anticonvulsant agents. Their preliminary anticonvulsant activities were evaluatedusing maximal electroshock and subcutaneouspentylenetetrazole (scPTZ) seizure tests. Neurotoxicity wasdetermined using rotarod test. The results indicated that thecompound 2j in scPTZ model exhibited the ED50 values of83.3 mg/kg, superior to the standard drug ethosuximidewith the maximum activity. In addition, compound 2kshowed the most potent activity in MES model with ED50value of 9.6 mg/kg and TD50 value of 189.5 mg/kg afterintraperitoneal injection in mice, and displayed a highprotective index (TD50/ED50) of 19.7 compared to referenceantiepileptic drugs.

Toll-like receptor 2 promotes neurogenesis from the dentate gyrus after photothrombotic cerebral ischemia in mice

Seong, Kyung-Joo,Kim, Hyeong-Jun,Cai, Bangrong,Kook, Min-Suk,Jung, Ji-Yeon,Kim, Won-Jae The Korean Society of Pharmacology 2018 The Korean Journal of Physiology & Pharmacology Vol.22 No.2

The subgranular zone (SGZ) of hippocampal dentate gyrus (HDG) is a primary site of adult neurogenesis. Toll-like receptors (TLRs), are involved in neural system development of Drosophila and innate immune response of mammals. TLR2 is expressed abundantly in neurogenic niches such as adult mammalian hippocampus. It regulates adult hippocampal neurogenesis. However, the role of TLR2 in adult neurogenesis is not well studied in global or focal cerebral ischemia. Therefore, this study aimed to investigate the role of TLR2 in adult neurogenesis after photochemically induced cerebral ischemia. At 7 days after photothrombotic ischemic injury, the number of bromodeoxyuridine (BrdU)-positive cells was increased in both TLR2 knock-out (KO) mice and wild-type (WT) mice. However, the increment rate of BrdU-positive cells was lower in TLR2 KO mice compared to that in WT mice. The number of doublecortin (DCX) and neuronal nuclei (NeuN)-positive cells in HDG was decreased after photothrombotic ischemia in TLR2 KO mice compared to that in WT mice. The survival rate of cells in HDG was decreased in TLR2 KO mice compared to that in WT mice. In contrast, the number of cleaved-caspase 3 (apoptotic marker) and the number of GFAP (glia marker)/BrdU double-positive cells in TLR2 KO mice were higher than that in WT mice. These results suggest that TLR2 can promote adult neurogenesis from neural stem cell of hippocampal dentate gyrus through increasing proliferation, differentiation, and survival from neural stem cells after ischemic injury of the brain.

Toll-like receptor 2 promotes neurogenesis from the dentate gyrus after photothrombotic cerebral ischemia in mice

Kyung-Joo Seong,Hyeong-Jun Kim,Bangrong Cai,Min-Suk Kook,Ji-Yeon Jung,Won-Jae Kim 대한생리학회-대한약리학회 2018 The Korean Journal of Physiology & Pharmacology Vol.22 No.2

The subgranular zone (SGZ) of hippocampal dentate gyrus (HDG) is a primary site of adult neurogenesis. Toll-like receptors (TLRs), are involved in neural system development of Drosophila and innate immune response of mammals. TLR2 is expressed abundantly in neurogenic niches such as adult mammalian hippocampus. It regulates adult hippocampal neurogenesis. However, the role of TLR2 in adult neurogenesis is not well studied in global or focal cerebral ischemia. Therefore, this study aimed to investigate the role of TLR2 in adult neurogenesis after photochemically induced cerebral ischemia. At 7 days after photothrombotic ischemic injury,the number of bromodeoxyuridine (BrdU)-positive cells was increased in both TLR2 knock-out (KO) mice and wild-type (WT) mice. However, the increment rate of BrdUpositive cells was lower in TLR2 KO mice compared to that in WT mice. The number of doublecortin (DCX) and neuronal nuclei (NeuN)-positive cells in HDG was decreased after photothrombotic ischemia in TLR2 KO mice compared to that in WT mice. The survival rate of cells in HDG was decreased in TLR2 KO mice compared to that in WT mice. In contrast, the number of cleaved-caspase 3 (apoptotic marker) and the number of GFAP (glia marker)/BrdU double-positive cells in TLR2 KO mice were higher than that in WT mice. These results suggest that TLR2 can promote adult neurogenesis from neural stem cell of hippocampal dentate gyrus through increasing proliferation, differentiation, and survival from neural stem cells after ischemic injury of the brain.

Green tea polyphenol (-)-epigallocatechin-3-gallate prevents ultraviolet-induced apoptosis in PC12 cells

Woo, Su-Mi,Kim, Yoon-Jung,Cai, Bangrong,Park, Sam-Young,Kim, Young,Kim, Ok Joon,Kang, In-Chol,Kim, Won-Jae,Jung, Ji-Yeon The Korean Academy of Oral Biology 2020 International Journal of Oral Biology Vol.45 No.4

Green tea polyphenol (-)-epigallocatechin-3-gallate (EGCG) is a potent antioxidant with protective effects against neurotoxicity. However, it is currently unclear whether EGCG protects neuronal cells against radiation-induced damage. Therefore, the objective of this study was to investigate the effects of EGCG on ultraviolet (UV)-induced oxidative stress and apoptosis in PC12 cells. The effects of UV irradiation included apoptotic cell death, which was associated with DNA fragmentation, reactive oxygen species (ROS) production, enhanced caspase-3 and caspase-9 activity, and poly (ADP-ribose) polymerase cleavage. UV irradiation also increased the Bax/Bcl-2 ratio and mitochondrial pathway-associated cytochrome c expression. However, pretreatment with EGCG before UV exposure markedly decreased UV-induced DNA fragmentation and ROS production. Furthermore, the UV irradiation-induced increase in Bax/Bcl-2 ratio, cytochrome c upregulation, and caspase-3 and caspase-9 activation were each ameliorated by EGCG pretreatment. Additionally, EGCG suppressed UV-induced phosphorylation of p38 and rescued UV-downregulated phosphorylation of ERK. Taken together, these results suggest that EGCG prevents UV irradiation-induced apoptosis in PC12 cells by scavenging ROS and inhibiting the mitochondrial pathways known to play a crucial role in apoptosis. In addition, EGCG inhibits UV-induced apoptosis via JNK inactivation and ERK activation in PC12 cells. Thus, EGCG represents a potential neuroprotective agent that could be applied to prevent neuronal cell death induced by UV irradiation.