microRNA-25 as a novel modulator of circadian Period2 gene oscillation

Inah Park,김도연,김정아,Sangwon Jang,Mijung Choi,최한경,최영식,김경진 생화학분자생물학회 2020 Experimental and molecular medicine Vol.52 No.-

Circadian clock controls an organism’s biological rhythm and regulates its physiological processes in response to external time cues. Most living organisms have their own time-keeping mechanism that is maintained by transcriptional–translational autoregulatory feedback loops involving several core clock genes, such as Period. Recent studies have found the relevance between the modulation of circadian oscillation and posttranscriptional modifications by microRNAs (miRNAs). However, there are limited studies on candidate miRNAs that regulate circadian oscillation. Here, we characterize the functions of novel miRNA-25 regulating circadian Period2 (Per2) expression. Using several in silico algorithms, we identified novel miR-25-3p that, together with miR-24-3p, targets the Per2 gene. Luciferase reporter assays validated that miR-25-3p and miR-24-3p repressed Per2 expression and confirmed their predicted binding sites in the 3′-untranslated region (UTR) of Per2 mRNA. Real-time bioluminescence analyses using Per2::Luc mouse embryonic fibroblasts confirmed that PER2 protein oscillation patterns were responsive to miR-25-3p and miR-24-3. The overexpression of miR-25-3p or miR-24-3p resulted in the dampening and period shortening of the PER2::LUC oscillation, while inhibition of either miRNA increased the relative amplitude of the PER2::LUC oscillation. Notably, endogenous miR-25-3p expression in the suprachiasmatic nucleus (SCN) showed no circadian rhythmicity, but the expression levels differed in various brain regions and peripheral tissues. These results suggest that the posttranscriptional regulation of miR-25-3p and miR-24-3p may differ according to Per2 gene expression in different tissue regions. In summary, we found that novel miR-25-3p was involved in fine-tuning circadian rhythmicity by regulating Per2 oscillation at the posttranscriptional level and that it functioned synergistically with miR-24-3p to affect Per2 oscillation.

Atypical Dysphagia in an Anti-Hu Positive Non-Small-Cell Lung Cancer Patient

Kim Inah,Kim Jeana,Lee Hee Yeon,Park Geun Young,Jeong Sang Ah,Hwang Hyemi,Im Sun 대한연하장애학회 2022 대한연하장애학회지 Vol.12 No.1

Anti-Hu antibodies usually present in small cell lung cancer are associated with encephalomyelitis, encephalitis, cer-ebellitis, and neuropathies. However, to our knowledge, non-small-cell lung cancer (NSCLC) related anti-Hu syn-drome presenting acute exacerbation of dysphagia has not been reported. Herein, we report a rare case of atypical dysphagia in an anti-Hu positive NSCLC patient resulting in a fatal outcome. A 73-year-old Korean male went through surgical interventions for recurrent tongue cancer and NSCLC. After the surgery, he resumed full oral feed-ing with a regular diet. However, four weeks later, he developed a sudden difficulty in swallowing. Neck computed tomography angiography, brain magnetic resonance imaging, brain positron emission tomography, computed tomog-raphy and electromyography all showed nonspecific findings. A paraneoplastic antibody test was positive for an-ti-Hu antibodies. His dysphagia worsened and eventually, he expired due to malignant pleural effusion. Our case shows that anti-Hu antibodies can be expressed in NSCLC and when associated with dysphagia, the outcome can be fatal.

Catalase Deficiency Accelerates Diabetic Renal Injury Through Peroxisomal Dysfunction

Hwang, Inah,Lee, Jiyoun,Huh, Joo Young,Park, Jehyun,Lee, Hi Bahl,Ho, Ye-Shih,Ha, Hunjoo American Diabetes Association 2012 Diabetes Vol.61 No.3

<P><B/></P><P>Mitochondrial reactive oxygen species (ROS) play an important role in diabetes complications, including diabetic nephropathy (DN). Plasma free fatty acids (FFAs) as well as glucose are increased in diabetes, and peroxisomes and mitochondria participate in FFA oxidation in an interconnected fashion. Therefore, we investigated whether deficiency of catalase, a major peroxisomal antioxidant, accelerates DN through peroxisomal dysfunction and abnormal renal FFA metabolism. Diabetes was induced by multiple injections of low-dose streptozotocin into catalase knock-out (CKO) and wild-type (WT) C57BL/6 mice. Murine mesangial cells (MMCs) transfected with catalase small interfering RNA followed by catalase overexpression were used to further elucidate the role of endogenous catalase. Despite equivalent hyperglycemia, parameters of DN, along with markers of oxidative stress, were more accelerated in diabetic CKO mice than in diabetic WT mice up to 10 weeks of diabetes. CKO mice and MMCs showed impaired peroxisomal/mitochondrial biogenesis and FFA oxidation. Catalase deficiency increased mitochondrial ROS and fibronectin expression in response to FFAs, which were effectively restored by catalase overexpression or <I>N</I>-acetylcysteine. These data provide unprecedented evidence that FFA-induced peroxisomal dysfunction exacerbates DN and that endogenous catalase plays an important role in protecting the kidney from diabetic stress through maintaining peroxisomal and mitochondrial fitness.</P>

A case of acute organic solvent poisoning during epoxy coating

Sujin Lee,Inah Kim,Dooyong Park,Jaechul Song,Sang Gil Lee 대한직업환경의학회 2019 대한직업환경의학회지 Vol.31 No.-

Background: In the construction industry, maintaining health and safety of workers often challenging. Among the workers at construction sites, painters are at particular risk of respiratory diseases and neurotoxicity. However, in Korea there is weak enforcement of workers" health and safety practices in the construction industry in Korea. Poisonings frequently occur at (semi)closed construction sites. In this study, we report a case of acute organic solvent poisoning during construction site painting. Case presentation: A 71-year-old man was found unconscious at a construction site and immediately transferred to the emergency room. The consciousness level was "stupor state" and the body temperature was hypothermic, at 32 degrees (Celsius). There were no acute brain or cardiac lesions that would have accounted for the faintness. In addition, blood and urine tests did not indicate a cause of loss of consciousness. He had been painting epoxy to waterproof the basement floor before fainting. According to exposure simulation, the patient was overexposed to various organic solvents, such as approximately 316–624 ppm toluene during the work before fainting. Considering the ventilation status of the workplace and the status of no protection, it is considered that exposure through the respiratory tract was considerable. Conclusions: The patient in this case lost consciousness during the epoxy coating in a semi-enclosed space. It can be judged as a result of acute poisoning caused by organic solvent exposure and considered to be highly related to work environment.

Effects of ethanol exposure during early pregnancy in hyperactive, inattentive and impulsive behaviors and MeCP2 expression in rodent offspring.

Kim, Pitna,Park, Jin Hee,Choi, Chang Soon,Choi, Inah,Joo, So Hyun,Kim, Min Kyoung,Kim, Soo Young,Kim, Ki Chan,Park, Seung Hwa,Kwon, Kyoung Ja,Lee, Jongmin,Han, Seol-Heui,Ryu, Jong Hoon,Cheong, Jae Hoo Kluwer Academic/Plenum Publishers 2013 Neurochem Res Vol.38 No.3

<P>Prenatal exposure to alcohol has consistently been associated with adverse effects on neurodevelopment, which is collectively called fetal alcohol spectrum disorder (FASD). Increasing evidence suggest that prenatal exposure to alcohol increases the risk of developing attention deficit/hyperactivity disorder-like behavior in human. In this study, we investigated the behavioral effects of prenatal exposure to EtOH in offspring mice and rats focusing on hyperactivity and impulsivity. We also examined changes in dopamine transporter and MeCP2 expression, which may underlie as a key neurobiological and epigenetic determinant in FASD and hyperactive, inattentive and impulsive behaviors. Mouse or rat offspring born from dam exposed to alcohol during pregnancy (EtOH group) showed hyper locomotive activity, attention deficit and impulsivity. EtOH group also showed increased dopamine transporter and norepinephrine transporter level compared to control group in the prefrontal cortex and striatum. Prenatal exposure to EtOH also significantly decreased the expression of MeCP2 in both prefrontal cortex and striatum. These results suggest that prenatal exposure to EtOH induces hyperactive, inattentive and impulsive behaviors in rodent offspring that might be related to global epigenetic changes as well as aberration in catecholamine neurotransmitter transporter system.</P>

Impact of the circadian nuclear receptor REV-ERBα in dorsal raphe 5-HT neurons on social interaction behavior, especially social preference

Jang Sangwon,Park Inah,Choi Mijung,Kim Jihoon,Yeo Seungeun,Huh Sung-Oh,Choi Ji-Woong,Moon Cheil,Choe Han Kyoung,Choe Youngshik,Kim Kyungjin 생화학분자생물학회 2023 Experimental and molecular medicine Vol.55 No.-

Social interaction among conspecifics is essential for maintaining adaptive, cooperative, and social behaviors, along with survival among mammals. The 5-hydroxytryptamine (5-HT) neuronal system is an important neurotransmitter system for regulating social behaviors; however, the circadian role of 5-HT in social interaction behaviors is unclear. To investigate whether the circadian nuclear receptor REV-ERBα, a transcriptional repressor of the rate-limiting enzyme tryptophan hydroxylase 2 (Tph2) gene in 5-HT biosynthesis, may affect social interaction behaviors, we generated a conditional knockout (cKO) mouse by targeting Rev-Erbα in dorsal raphe (DR) 5-HT neurons (5-HTDR-specific REV-ERBα cKO) using the CRISPR/Cas9 gene editing system and assayed social behaviors, including social preference and social recognition, with a three-chamber social interaction test at two circadian time (CT) points, i.e., at dawn (CT00) and dusk (CT12). The genetic ablation of Rev-Erbα in DR 5-HTergic neurons caused impaired social interaction behaviors, particularly social preference but not social recognition, with no difference between the two CT points. This deficit of social preference induced by Rev-Erbα in 5-HTDR-specific mice is functionally associated with real-time elevated neuron activity and 5-HT levels at dusk, as determined by fiber-photometry imaging sensors. Moreover, optogenetic inhibition of DR to nucleus accumbens (NAc) 5-HTergic circuit restored the impairment of social preference in 5-HTDR-specific REV-ERBα cKO mice. These results suggest the significance of the circadian regulation of 5-HT levels by REV-ERBα in regulating social interaction behaviors.

Stereoselective Synthesis of 1,4,5-Tri-<i>cis</i>-guaiane Sesquiterpene: First Total Synthesis of (−)-Dendroside C Aglycon

Sim, Jaehoon,Park, Hyunkyung,Lim, Juhee,Yoon, Inah,Lim, Changjin,An, Hongchan,Yun, Hwayoung,Choi, Hyun Jin,Suh, Young-Ger American Chemical Society 2018 Organic letters Vol.20 No.3

<P>The first total synthesis of (−)-dendroside C aglycon, consisting of a 1,4,5-tri-<I>cis</I>-guaiane skeleton, from a versatile hydroazulene intermediate has been accomplished. The key features of the syntheses include the stereoselective preparation of the unusual <I>cis</I>-hydroazulene core via a sequence of a unique Dieckmann condensation of the bicyclic lactone system, which was concisely prepared by the tandem conjugate addition and intramolecular allylic alkylation of a butenolide precursor, and construction of the characteristic tricyclic skeleton by a carbene-mediated cyclopropanation.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/orlef7/2018/orlef7.2018.20.issue-3/acs.orglett.7b03701/production/images/medium/ol-2017-03701r_0008.gif'></P><P><A href='http://pubs.acs.org/doi/suppl/10.1021/ol7b03701'>ACS Electronic Supporting Info</A></P>

Gut Microbial Metabolites Induce Changes in Circadian Oscillation of Clock Gene Expression in the Mouse Embryonic Fibroblasts

Ku, Kyojin,Park, Inah,Kim, Doyeon,Kim, Jeongah,Jang, Sangwon,Choi, Mijung,Choe, Han Kyoung,Kim, Kyungjin Korean Society for Molecular and Cellular Biology 2020 Molecules and cells Vol.43 No.3

Circadian rhythm is an endogenous oscillation of about 24-h period in many physiological processes and behaviors. This daily oscillation is maintained by the molecular clock machinery with transcriptional-translational feedback loops mediated by clock genes including Period2 (Per2) and Bmal1. Recently, it was revealed that gut microbiome exerts a significant impact on the circadian physiology and behavior of its host; however, the mechanism through which it regulates the molecular clock has remained elusive. 3-(4-hydroxyphenyl)propionic acid (4-OH-PPA) and 3-phenylpropionic acid (PPA) are major metabolites exclusively produced by Clostridium sporogenes and may function as unique chemical messengers communicating with its host. In the present study, we examined if two C. sporogenes-derived metabolites can modulate the oscillation of mammalian molecular clock. Interestingly, 4-OH-PPA and PPA increased the amplitude of both PER2 and Bmal1 oscillation in a dose-dependent manner following their administration immediately after the nadir or the peak of their rhythm. The phase of PER2 oscillation responded differently depending on the mode of administration of the metabolites. In addition, using an organotypic slice culture ex vivo, treatment with 4-OH-PPA increased the amplitude and lengthened the period of PER2 oscillation in the suprachiasmatic nucleus and other tissues. In summary, two C. sporogenes-derived metabolites are involved in the regulation of circadian oscillation of Per2 and Bmal1 clock genes in the host's peripheral and central clock machineries.

Allergic Diseases and Multiple Chemical Sensitivity in Korean Adults

Inchul Jeong,Inah Kim,Hye Jung Park,Jaehoon Roh,Jung-Won Park,Jae-Hyun Lee 대한직업환경의학회 2013 대한직업환경의학회 학술대회 논문집 Vol.2013 No.11

Development of Korean CARcinogen EXposure: Assessment of the Exposure Intensity of Carcinogens by Industry

Koh, Dong-Hee,Park, Ju-Hyun,Lee, Sang-Gil,Kim, Hwan-Cheol,Jung, Hyejung,Kim, Inah,Choi, Sangjun,Park, Donguk Occupational Safety and Health Research Institute 2022 Safety and health at work Vol.13 No.3

Background: Occupational cancer is a global health issue. The Korean CARcinogen EXposure (K-CAREX), a database of CARcinogen EXposure, was developed for the Korean labor force to estimate the number of workers exposed to carcinogens by industry. The present study aimed to estimate the intensity of exposure to carcinogens by industry, in order to supply complementary information about CARcinogen EXposure intensity to the K-CAREX. Methods: We used nationwide workplace monitoring data from 2014 to 2016 and selected target carcinogens based on the K-CAREX list. We computed the 95th percentile levels of measurements for each industry by carcinogens. Based on the 95th percentile level relative to the occupational exposure limit, we classified the CARcinogen EXposure intensity into five exposure ratings (1-5) for each industry. Results: The exposure ratings were estimated for 21 carcinogenic agents in each of the 228 minor industry groups. For example, 3,058 samples were measured for benzene in the manufacturing industry of basic chemicals. This industry was assigned a benzene exposure rating of 3. Conclusions: We evaluated the CARcinogen EXposure ratings across industries in Korean workers. The results will provide information on the exposure intensity to carcinogens for integration into the K-CAREX. Furthermore, it will aid in prioritizing control efforts and identifying industries of concern.