Lifespan extension and increased resistance to environmental stressors by N-Acetyl-L-Cysteine in <i>Caenorhabditis elegans</i>

Oh, Seung-Il,Park, Jin-Kook,Park, Sang-Kyu Hospital das Clínicas da Faculdade de Medic 2015 Clinics Vol.70 No.5

<P><B>OBJECTIVE:</B></P><P>This study was performed to determine the effect of N-acetyl-L-cysteine, a modified sulfur-containing amino acid that acts as a strong cellular antioxidant, on the response to environmental stressors and on aging in <I>C. elegans</I>.</P><P><B>METHOD:</B></P><P>The survival of worms under oxidative stress conditions induced by paraquat was evaluated with and without <I>in vivo</I> N-acetyl-L-cysteine treatment. The effect of N-acetyl-L-cysteine on the response to other environmental stressors, including heat stress and ultraviolet irradiation (UV), was also monitored. To investigate the effect on aging, we examined changes in lifespan, fertility, and expression of age-related biomarkers in <I>C. elegans</I> after N-acetyl-L-cysteine treatment.</P><P><B>RESULTS:</B></P><P>Dietary N-acetyl-L-cysteine supplementation significantly increased resistance to oxidative stress, heat stress, and UV irradiation in <I>C. elegans</I>. In addition, N-acetyl-L-cysteine supplementation significantly extended both the mean and maximum lifespan of <I>C. elegans</I>. The mean lifespan was extended by up to 30.5% with 5 mM N-acetyl-L-cysteine treatment, and the maximum lifespan was increased by 8 days. N-acetyl-L-cysteine supplementation also increased the total number of progeny produced and extended the gravid period of <I>C. elegans</I>. The green fluorescent protein reporter assay revealed that expression of the stress-responsive genes, <I>sod-3</I> and <I>hsp-16.2</I>, increased significantly following N-acetyl-L-cysteine treatment.</P><P><B>CONCLUSION:</B></P><P>N-acetyl-L-cysteine supplementation confers a longevity phenotype in <I>C. elegans</I>, possibly through increased resistance to environmental stressors.</P>

N-Acetyl-L-Cysteine에 의한 생쥐 골수유래 가지세포의 기능적 활성화 저해

정영주(Young-joo Jeong),맹형건(Hyung Gun Maeng),김민규(Min Kyu Kim),강재승(Jae Seung Kang),이왕재(Wang Jae Lee),황영일(Young-il Hwang) 대한해부학회 2008 Anatomy & Cell Biology Vol.41 No.2

N-acetyl-L-cysteine (NAC)은 thiol기를 포함하는 화합물로서, glutathione (GSH)의 전구체로 작용하여 포유류 세포 내에서 항산화제로 작용한다. 또한 항염기능이 있으며 호산구나 B세포, 가지세포 (dendritic cell, DC)와 같은 면역세포 들에 여러 가지 영향을 미치는 것으로 알려져 있다. 특히 가지세포에 작용하여 활성화를 억제하거나 가지세포에 의한 Th2 반응 유도에 관여한다고 알려져 있다. 그러나 이들 연구는 세부적인 사항에 있어서 그 결과가 서로 상치하는바가 많으며, 또한 조절T세포의 관점에서는 연구된 바가 없다. 따라서 본 연구에서는 NAC 처리가 가지세포 활성화에 미치는 영향을 재확인하였고, NAC 처리된 가지세포의 T세포 활성 능력 저하, 또는 Th2 반응 유도 여부를 알아보았다. 활성화 시 가지세포에서 증가하는 활성산소기 (reactive oxygen species)는 NAC 처리로 낮아져서, NAC이 가지세포에 항산화작용을 나타냄을 확인하였다. NAC 처리로 가지세포에서 보조자극인자인 CD40과 CD86의 발현이 저해되었으며, 활성화 시 정상적으로 낮아지는 포식기능은 처리된 NAC의 농도에 비례하게 보존되었다. 활성화 시 분비되는 IL-6, IL-10, IL-12는 모두 감소하였다. 이러한 NAC-DC와 함께 배양한 T세포의 증식이나 Th1 cytokine인 IFN-γ, Th2 cytokine인 IL-5의 분비가 모두 저하되어 Th1/Th2의 편중 없이 가지세포의 T세포 자극능력이 전반적으로 감소하였음을 나타내었다. 또한 T세포 배양액에서 IL-10과 TGF-β의 농도 역시 NAC-DC로 자극된 경우에 현저히 줄어서, NAC-DC에 의한 T세포 증식 감소 등은 조절T세포 유도에 의한 것이 아니라 T세포 무반응이 유도된 때문임을 나타내 주었다. N-acetyl-L-cysteine (NAC) is a thiol-containing compound and acts as a precursor for glutathione (GSH). It behaves as an antioxidant in mammalian cells and also exerts anti-inflammatory effects. NAC is also known to affect several immune cells including eosinophils, B cells, T cells, and dendritic cells (DC) in many aspects. Even though it has been reported that NAC inhibits DC activation and shifts the immune response to Th2, these studies exhibit some contradictory results in detail and do not give any information with respect to the induction of regulatory T cells. In this study, we re-analyzed the effects of NAC on DC during their activation. We also evaluated whether it induced T cell anergy, Th1/Th2 shift, or regulatory T cells. NAC suppressed the elevation of intracellular reactive oxygen species during DC activation. In parallel, it down-regulated surface expression of CD40 and CD86, suppressed the decrease of phagocytic function, lowered the secretion of cytokines such as IL-6, IL-10, and IL-12. All these effects showed dose-dependency. Thus, it seems likely that NAC inhibited DC activation with regard to their phenotype and cytokine secretion. When we evaluated the T cell-stimulating capacity of these NAC-DC, T cell proliferation and secretion of both Th1 (IFN-γ) and Th2 cytokine (IL-5) were decreased. This implies that the T cell-stimulating activity of NAC-DC decreased without any shift to Th1 or Th2 cytokine (IL-5). The secretion of IL-10 and TGF-β in the supernatants were also decreased, which suggests that the decrease of T cell proliferation and cytokine secretion is due to the induction of T cell anergy, rather than regulatory T cells.

Saccharomyces cerevisiae에서 이온화 방사선과 N-acetyl-L-cysteine 처리에 따른 세포 생존과 Superoxide Dismutase와 Catalase 유전자 발현

박지영 ( Ji Young Park ),백동원 ( Dong Won Baek ),모하마드닐리 ( Mohammad Nili ),김진규 ( Jin Kyu Kim ) 한국환경생물학회 2011 환경생물 : 환경생물학회지 Vol.29 No.1

N-acetyl-L-cysteine (NAC) having a thiol, a precursor for glutathione (GSH), is known as one of the antioxidants. NAC used as a radioprotector against ionizing radiation (IR)-induced injury and damage. The aim of this study was to evaluate the radioprotective effects of NAC against IR-induced cell damage in Saccharomyces cerevisiae and the antioxidative effect of NAC on transcriptional level of yeast antioxidant enzyme genes such as superoxide dismutase (SOD) and catalase. In the present study, yeast cells were pretreated with various concentrations of NAC and/or irradiated with various doses of gamma rays. The cell viability was measured by counting the cell forming unit (CFU). The quantitative real-time PCR was performed for analysis of gene expression of SOD and catalase. The viability of irradiated cells was not improved by pretreatment with NAC. Ionizing radiation with 100 Gy highly induced the gene expression of antioxidant enzymes. In the irradiated group with NAC pretreatment, the gene expression of SOD and catalase was gradually reduced with the increased concentrations of NAC. These results indicate that NAC can act as a useful antioxidant to scavenge reactive oxygen species in vivo, but does not protect cells against IR-induced cell death in S. cerevisiae.

Synthesis, Antioxidative and Whitening Effects of Novel Cysteine Derivatives

하지훈,김경미,정윤주,박영민,이재영,박진오,박수남 대한화학회 2017 Bulletin of the Korean Chemical Society Vol.38 No.1

Recently, development of biocompatibility functional cosmetic agents as antioxidant or whitening agent has increased. In this study, synthetic cysteine derivatives (DBLS-21, -24, and -33) were developed containing syringic acid and cysteine moieties (l-cysteine ethyl ester, N-acetyl cysteine methyl ester, and N-acetyl cysteine ethyl ester), and their antioxidative and whitening activities were evaluated. The cellular protective effect (τ50) of DBLS-21 was 51.1 min at 50 μM on1O2 -induced hemolysis of erythrocytes. This activity was slightly higher than that of α-tocopherol (43.6 min) as a lipophilic antioxidant. In the melanogenesis inhibitory effect, DBLS-21, -24, and -33 was 1.6-, 1.8-, and 2.5-fold higher than arbutin, respectively. In particular, DBLS-21 and -33 was 112.8- and 6.1-fold higher than arbutin, respectively (293.4 μM) on tyrosinase inhibition activity (IC50 ). But DBLS-24 had no tyrosinase inhibitory activity. These results suggest that cysteine derivatives possess potential for use as an antioxidant agent (DBLS-21) and whitening agents (all derivatives) in cosmetics.

Metabolism and Pharmacokinetics of S-(N,N-Diethyldithiocar-bamoyul)-N-acetyl-L-cysteine in Rats

Lee, Byung-Hoon,Song, Yun-Seon,Park, Jongsei,Ryu, Jae-Chun The Pharmaceutical Society of Korea 1994 Archives of Pharmacal Research Vol.17 No.6

The methabolism and phamacokinetics of a mixed disulfide S-(N, N-diethyldithiocarbamoyl)-N-acetyl-L-cysteine (AC-DDTC) were studied in rats. Two metabolites of AC-DDTC following iv and po administration were indentified in plasma and liver by HPLC and GC, namely N, N-diethyldithiocarbamate (DDTC) and the methyl ester of DDTC (Me-DDTC). AC-DDTC was very unstable in vivo and could not be detected neither in plasma nor in urine. Pharmacokinetic parameters of DDTC following intravenous administration of AC-DDTC (20 mg/kg) were calculated. DDTC has a low affinity to rat tissue and the body clearance was $9.0{\pm}3.4mkl/mim/kg$. The mean residence time (MRT) was $11.5{\pm}16.3 min$. After oral administration of 20 mg/kg AC-DDTC, maximal plasma concenttion ($C_{max}$) was $3.8{\pm}0.2 nmol/ml$ and the bioavailability was 7.04%. $C_{max}$ for DDTC at a dose of 120 mg/kg. AC-DDTC was $40.1{\pm}2.2 nmol/ml$. ART was $47.1{\pm}2.8min$.at a dose of 20 mg/kg and $110.5{\pm}6.0 min$ at 120 mg/kg.

Glutathione-Mediated Intracellular Release of Anti-Inflammatory N-Acetyl-L-Cysteine from Mesoporous Silica Nanoparticles

구안나,임화평,박동진,김종호,정서영,이상천 한국고분자학회 2013 Macromolecular Research Vol.21 No.7

We report on a smart mesoporous silica nanoparticle (MSN) that can trigger the release of anti-inflammatory N-acetyl-L-cysteine (NAC) within the intracellular environment. NAC was conjugated to the pore surfaces of MSNs through glutathione (GSH)-cleavable disulfide linkages. Solid-state nuclear magnetic resonance (NMR),Fourier-transform infrared (FTIR) spectroscopy, and Brunauer-Emmett-Teller (BET) analyses confirmed the successful NAC conjugation to the pore walls. The release of NAC from the NAC-conjugated MSN (MSN-NAC) could be controlled by adjusting the concentration of GSH regarding the release media. At an extracellular level of GSH (10 μM), the NAC release was greatly inhibited, whereas, at an intracellular level of GSH (2 mM), MSN-NAC facilitated the release of NAC. Confocal laser scanning microscopy (CLSM) studies showed that the NAC release was effectively triggered by intracellular GSH after uptake by BV-2 microglial cells. The MSN developed in this work may serve as the efficient intracellular carriers of NAC for the treatment of neuroinflammation.

The Protective Effects of N-Acetyl-L-cysteine on Cadmium-induced Cell Apoptosis in Rat Testis

Ji-Sun Kim,Jaemog Soh 대한의생명과학회 2019 Biomedical Science Letters Vol.25 No.4

Cadmium (Cd) generates reactive oxygen species (ROS), which in turn cause the apoptosis of various cell types including developing germ cells in rodent testis. Ascorbic acids (AA), one of the ROS scavengers, had been reported to protect against Cd-induced apoptosis. N-Acetyl-L-cysteine (NAC), another ROS scavenger, is known to remove ROS and alleviate the Cd-induced apoptosis in various cell types. In this study we tried to elucidate how NAC affected on Cd-induced cell apoptosis in rat testis. Rats were administered with NAC before and after Cd treatment and then testicular cell apoptosis was examined. NAC treatment resulted in the reduction of Cd-induced chromosomal DNA fragmentation in agarose gel electrophoresis. Terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) assay showed that treatment of NAC reduced the Cd-induced apoptosis of germ cells. The administration of NAC showed that the translocation of apoptosis inducing factor (AIF) from mitochondria to nucleus was prevented, which indicated that the mechanism of Cd-induced testicular apoptosis is mediated through the release of AIF in caspase-independent manner. Taken together, the NAC may remove Cd-induced ROS and protect ROS-induced cell apoptosis in rat testis.

동충하초에서 분리된 acetyepoxyltrichothecenediol에 의한 인간 백혈병 HL-60 세포의 세포고사 연구

김태현 ( Tae Hyeun Kim ),송호준 ( Ho Joon Song ),신민교 ( Min Kyo Shin ) 대한본초학회 2004 大韓本草學會誌 Vol.19 No.2

N/A Objectives : It has been reported that the trichothecene mycotoxin 4-acetyl-12,13-epoxyl-9-trichothecene-3,15-diol (AETD) from the fruiting bodies of Isaria japonica Yasuda is a potent inducer of apoptosis in human promyelocytic HL-60 cells. Methods : The present study aims to characterize the molecular events leading to AETD-induced apoptosis in HL-60 cells. Results : The percentage of apoptotic cells (annexin V-positive cell population) increased dose- and time-dependently after AETD exposure. Apoptosis of HL-60 cells by AETD was associated with the formation of intracellular reactive oxygen species (ROS), the depletion of intracellular glutathione (GSH), and the activation of caspase-3. Pre-treating the cells with the antioxidant N-acetyl-L- cystein (NAC) and the caspase-3 inhibitor Z-DEVD-fmk abrogated AETD-induced apoptosis and caspase-3 activation. NAC blocked intracellular ROS formation and GSH depletion, but Z-DEVD-fmk did not. Conclusions : These results indicate that AETD induces apoptosis in HL-60 cells by causing intracellular ROS formation and GSH depletion followed by the downstream event of caspase-3 activation.

N-acetyl-L-cysteine mimics the effect of dietary restriction on lifespan and reduces amyloid beta-induced toxicity in Caenorhabditis elegans

오승일,박상규 한국식품과학회 2017 Food Science and Biotechnology Vol.26 No.3

The effects of antioxidants on lifespan have been widely studied. Our previous study showed supplementation with N-acetyl-L-cysteine (NAC) extends the lifespan of Caenorhabditis elegans. Here we aimed to determine the lifespan-extending mechanism involved with NAC and the effect of NAC on Alzheimer’s disease (AD). NAC further increased the lifespan of age-1 and clk-1 mutants, which have increased lifespan owing to reduced insulin/IGF-1- like signaling and mitochondrial function, respectively. There was no additional lifespan extension in eat-2 background, a genetic model of dietary restriction (DR), by NAC. Gene knockdown experiments revealed that the effect of NAC is not dependent on SKN-1, a proteinsensing DR status, whereas DAF-16, a transcription factor regulating stress-responsive genes, is required for lifespan extension by NAC. NAC delayed paralysis caused by amyloid beta. Our results show that NAC mimics the effect of DR on lifespan, possibly through the induction of DAF- 16 nuclear localization and may retard the incidence of AD.

효모에서 N-acetyl-L-cysteine 처리와 감마선 조사에 따른 Superoxide Dismutase 활성변화 측정

박지영,Mohammad Nili,김진규 대한방사선방어학회 2011 대한방사선방어학회 학술발표회 논문요약집 Vol.2011 No.11