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Mutation in nAChR Beta Subunit Is Associated with Imidacloprid Resistance in the Aphis gossypii
Ju Il Kim,Min Kwon,Sangeun Park,Jeong-Jin Ahn,Young-Uk Park,Seonwoo Lee,Hyun-Na Koo,Gil-Hah Kim,Si Young Kim,Si Hyeock Lee 한국응용곤충학회 2013 한국응용곤충학회 학술대회논문집 Vol.2013 No.04
The cotton aphid, Aphis gossypii (Glover), is one of the most serious pests in various vegetable crops. In Korea, some field populations of A. gossypii especially in greenhouse showed high resistance against neonicotinoids. The imidaclopridresistant strain (IR) selected from one of the greenhouse strains was found to be about 3,800 folds more resistant to imidacloprid, compared to the susceptible strain (S), as judged by LC50 values. To identify differentially expressed genes in IR, an isogenic strain, reverse susceptible strain (IRS) was generated from IR and comparative transcriptome analyses based on GS-FLX were conducted using total RNAs extracted from both IR and IRS. Also we confirmed protein expression patterns by 2DE and detoxification enzyme over-expression by synergist test. However there was no significant variation among IR, IRS and S. Comparison of the nucleotide sequence of seven nicotinic acetylcholine receptor (nAChR) subunit (alpha 1-5,7 and beta 1) genes from S and IR strain revealed a point mutation causing an arginine to threonine substitution (R81T) in the loop D region of the nAChR beta 1 subunit of the IR. These mechanisms were also reported in M. persicae and this amino acid change confers a vertebrate-like character to the insect nAChR and results in reduced sensitivity to neonicotinoids. Moreover an extra point mutation, L80S (leucine to serine substitution) was also detected nearby R81T mutation in nAChR beta 1 subunit variant. These mutations can be an additive factor in imidacloprid resistance in A. gossypii. This is the first report of imidacloprid resistance mechanism in A.gossypii. Further, this would be helpful in managing A. gossypii resistant populations in field.
만성적 니코틴 처치에 의한 행동적 민감화에서 NMDA 수용체와 산화질소의 역할
김영호,심인섭,김상은,김현택 한국심리학회 한국심리학회지 생물 및 생리 Vol.11 No.1
일반적으로 니코틴이나 코카인, 그리고 암페타민을 비롯한 중독성 약물을 반복적, 간헐적으로 투여하면 동물의 보행성 활동과 상동적 행동이 점진적으로 증가하는 ‘행동적 민감화’ 현상이 나타난다. 니코틴의 반복적 투여에 의한 ‘행동적 민감화’ 현상의 신경 기전을 규명하기 위하여, 본 연구는 NMDA 수용체 길항제인 MK-801(0.3㎎/㎏, i.p.)과 산화질소 합성효소 억제제인 L-NAME(75㎎/㎏, i.p.)을 사전 처치하고 니코틴(0.4㎎/㎏, s.c.)의 반복적 투여에 의한 ‘행동적 민감화’ 현상을 관찰함으로써 이 현상에서의 NMDA 수용체와 산화질소의 역할을 알아보고자 하였다. 수컷 sprague dawley 흰쥐에게 니코틴(0.4㎎/㎏)을 7일 동안 하루에 두 번씩 피하 주사하여 행동적 민감화의 발달을 유도하고(score 707), 3일간의 약물 철회 기간을 거친 후 실험 11일째 날에 동일 용량의 니코틴을 피하 주사한 후 보행성 활동량을 측정함으로써 행동적 민감화의 발현을 설립하였다(score 741). 이러한, 행동적 민감화의 발달과 발현, 각각의 단계에서 NMDA 수용체와 산화질소의 역할을 규명하기 위하여 MK-801과 L-NAME을 7일간의 민감화 발달 기간중 니코틴 투여 30분전에, 또는 약물 철회 기간에 하루에 두 번씩 사전 처치하였다. 실험 결과, 니코틴에 의한 행동적 민감화의 발달은 MK-801과 L-NAME, 모두에 의해 통계적으로 유의미하게 억제되었으나(각각, 니코틴 처치 통제군의 40.5%, 56.7%), 행동적 민감화의 발현은 MK-801에 의해서만 통계적으로 유의미하게 억제되었다(니코틴 처치 통제군의 41.8%). 이러한 연구 결과는 NMDA 수용체와 산화질소가 니코틴에 의한 행동적 민감화의 생성 또는 발달에 결정적인 역할을 담당하나, 민감화의 발현, 또는 유지에는 NMDA 수용체만이 결정적 역할을 담당하고 있음을 시사한다. Repeated intermittent administration of psychostimulants produces an enhancement of the subsequent behavioral effects of these drugs. This behavioral sensitization has been implicated in maintenance of and relapse to drug-taking, there has been great interest in elucidating the mechanisms underlying both the development and expression of behavioral sensitization. An accumulation of data from studies of stimulant-induced locomotor activity and stereotypy has implicated excitory amino acids and nitric oxide(NO) in the development and expression of behavioral sensitization. The present study examined the effects of non-competitive NMDA receptor antagonist, MK-801 and nitric oxide synthase inhibitor, N^(G)-nitro-L-arginine methyl ester(L-NAME) on behavioral sensitization induced by repeated administration of nicotine. Repeated administration of nicotine(0.4㎎/㎏, s.c.) twice daily for consecutive days result in an augmentation of the locomotor and stereotypy activating effect of nicotine(0.4㎎/㎏, s.c.) challenged 3 days after last injection. Administration of the NMDA receptor antagonist, MK-801(0.3㎎/㎏, i.p.) and nitric oxide inhibitor, L-NAME(75㎎/㎏, i.p.), before daily nicotine injections attenuated the development of behavioral sensitization to subsequent nicotine challenge. Whereas, administration of MK-801(0.3㎎/㎏, i.p.) and L-NAME (75㎎/㎏, i.p.) twice daily for withdrawal periods of 3 days ensuing after chronic nicotine treatment periods of 7 days results in different consequences. MK-801 attenuated the expression of behavioral sensitization to nicotine, but L-NAME did not significantly reduce activity scores. These results suggest that NMDA receptor is involved in the expression as well as development of behavioral sensitization to nicotine, and that nitric oxide synthesis is involved in the development of behavioral sensitization to nicotine but not critically involved in expression of behavioral sensitization to nicotine. However, nitric oxide synthesis may have a modulatory role in expression of behavioral sensitization to nicotine. In addition, behavioral sensitization is thought to be mediated by changes in central dopaminergic systems. Accordingly, NMDA receptor and nitric oxide may influence on these changes similar to proposed role of nitric oxide and NMDA receptor in cellular adaptation and learning.
Kim Tai Young,Jeon Sangeun,Jang Youngho,Gotina Lizaveta,Won Joungha,Ju Yeon Ha,Kim Sunpil,Jang Minwoo Wendy,Won Woojin,Park Mingu Gordon,Pae Ae Nim,Han Sunkyu,Kim Seungtaek,Lee C. Justin 생화학분자생물학회 2021 Experimental and molecular medicine Vol.53 No.-
An ongoing pandemic of coronavirus disease 2019 (COVID-19) is now the greatest threat to global public health. Herbal medicines and their derived natural products have drawn much attention in the treatment of COVID-19, but the detailed mechanisms by which natural products inhibit SARS-CoV-2 have not been elucidated. Here, we show that platycodin D (PD), a triterpenoid saponin abundant in Platycodon grandiflorum (PG), a dietary and medicinal herb commonly used in East Asia, effectively blocks the two main SARS-CoV-2 infection routes via lysosome- and transmembrane protease serine 2 (TMPRSS2)-driven entry. Mechanistically, PD prevents host entry of SARS-CoV-2 by redistributing membrane cholesterol to prevent membrane fusion, which can be reinstated by treatment with a PD-encapsulating agent. Furthermore, the inhibitory effects of PD are recapitulated by the pharmacological inhibition or gene silencing of NPC1 , which is mutated in patients with Niemann–Pick type C (NPC) displaying disrupted membrane cholesterol distribution. Finally, readily available local foods or herbal medicines containing PG root show similar inhibitory effects against SARS-CoV-2 infection. Our study proposes that PD is a potent natural product for preventing or treating COVID-19 and that briefly disrupting the distribution of membrane cholesterol is a potential novel therapeutic strategy for SARS-CoV-2 infection.
Targeting mutant <i>KRAS</i> with CRISPR-Cas9 controls tumor growth
Kim, Wonjoo,Lee, Sangeun,Kim, Han Sang,Song, Minjung,Cha, Yong Hoon,Kim, Young-Hoon,Shin, Jeonghong,Lee, Eun-Seo,Joo, Yeonsoo,Song, Jae J.,Choi, Eun Ju,Choi, Jae W.,Lee, Jinu,Kang, Moonkyung,Yook, Jon Cold Spring Harbor Laboratory Press 2018 Genome Research Vol.28 No.3
<P>KRAS is the most frequently mutated oncogene in human tumors, and its activating mutations represent important therapeutic targets. The combination of Cas9 and guide RNA from the CRISPR-Cas system recognizes a specific DNA sequence and makes a double-strand break, which enables editing of the relevant genes. Here, we harnessed CRISPR to specifically target mutant KRAS alleles in cancer cells. We screened guide RNAs using a reporter system and validated them in cancer cells after lentiviral delivery of Cas9 and guide RNA. The survival, proliferation, and tumorigenicity of cancer cells in vitro and the growth of tumors in vivo were determined after delivery of Cas9 and guide RNA. We identified guide RNAs that efficiently target mutant OAS without significant alterations of the wild-type allele. Doxycycline-inducible expression of this guide RNA in KRAS-mutant cancer cells transduced with a lentiviral vector encoding Cas9 disrupted the mutant KRAS gene, leading to inhibition of cancer cell proliferation both in vitro and in vivo. Intra-tumoral injection of lentivirus and adeno-associated virus expressing Cas9 and sgRNA suppressed tumor growth in vivo, albeit incompletely, in immunodeficient mice. Expression of Cas9 and the guide RNA in cells containing wild-type KIZAS did not alter cell survival or proliferation either in vitro and in vivo. Our study provides a proof-of-concept that CRISPR can be utilized to target driver mutations of cancers in vitro and in vivo.</P>