Effects of butyltin compounds on follicular steroidogenesis in the bullfrog(<i>Rana catesbeiana</i>)

Ahn, Ryun Sup,Han, Seong-Jeong,Kim, Seung Chang,Kwon, Hyuk Bang Elsevier 2007 Environmental toxicology and pharmacology Vol.24 No.2

<P><B>Abstract</B></P><P>The effects of butyltin compounds on follicular steroidogenesis in amphibians were examined using ovarian follicles of <I>Rana catesbeiana</I>. Isolated follicles were cultured for 18h in the presence and absence of frog pituitary homogenate (FPH) or various steroid precursors, and the steroid levels in the follicles or culture media were measured by radioimmunoassay (RIA). Among the butyltin compounds, tributyltin (TBT) strongly inhibited the FPH-induced synthesis of pregnenolone (P<SUB>5</SUB>), progesterone (P<SUB>4</SUB>) and testosterone (T). It also inhibited the conversion of P<SUB>5</SUB>–P<SUB>4</SUB> and T to estradiol-17β(E<SUB>2</SUB>) and it partially suppressed the conversion of androstenedione (AD) to T, but not P<SUB>4</SUB> to 17α-hydroxyprogesterone (17α-OHP<SUB>4</SUB>). A high concentration of dibutyltin (DBT) also inhibited steroidogenesis by the follicles while monobutyltin (MBT) and tetrabutylin (TeBT) had no effect. These results suggest that the initial step of steroidogenesis (P<SUB>5</SUB> synthesis) and enzymes such as 3β-HSD, 17β-HSD and aromatase are inhibited by TBT or DBT. However, 17α-hydroxylase was not suppressed by TBT or the other butyltin compounds.</P>

Phosphoenolpyruvate Carboxykinase and Glucose-6-phosphatase Are Required for Steroidogenesis in Testicular Leydig Cells

Ahn, Seung Won,Gang, Gil-Tae,Tadi, Surendar,Nedumaran, Balachandar,Kim, Yong Deuk,Park, Ji Hoon,Kweon, Gi Ryang,Koo, Seung-Hoi,Lee, Keesook,Ahn, Ryun-Sup,Yim, Yong-Hyeon,Lee, Chul-Ho,Harris, Robert A. American Society for Biochemistry and Molecular Bi 2012 The Journal of biological chemistry Vol.287 No.50

Comprehensive analysis of the characteristics and treatment outcomes of patients with non-small cell lung cancer treated with anti-PD-1 therapy in real-world practice

Ahn, Beung-Chul,Pyo, Kyoung-Ho,Xin, Chun-Feng,Jung, Dongmin,Shim, Hyo Sup,Lee, Chang Young,Park, Seong Yong,Yoon, Hong In,Hong, Min Hee,Cho, Byoung Chul,Kim, Hye Ryun Springer; 1999 2019 Journal of Cancer Research and Clinical Oncology Vol.145 No.6

<P><B>Purpose</B></P><P>Immune checkpoint inhibitors (ICI) have shown marked responses in patients with non-small cell lung cancer (NSCLC) in clinical trials. However, because such trials comprise cohorts selected based on specific criteria, it is unclear if their results represent routine clinical practice.</P><P><B>Methods</B></P><P>We examined 155 patients with advanced NSCLC who were administered either nivolumab or pembrolizumab at Yonsei Cancer Center, Korea between March 2014 and January 2019. Patient characteristics, <I>EGFR</I>/<I>ALK</I> mutation status, metastatic locations, response to ICIs, and adverse events were retrospectively analyzed.</P><P><B>Results</B></P><P>The median age was 64 years and 72.9% of patients were male; former or current smokers constituted 67.1% of the subjects. Adenocarcinoma was predominant (67.7%), and 50.3% of the patients underwent ≥ 2 previous treatments. Twenty-three patients (14.8%) were <I>EGFR</I> mutation- or <I>ALK</I> rearrangement-positive. The objective response rate (ORR) was 23.9% [95% confidence interval (CI) 17.4–31.4%]; the median progression-free survival (PFS) and overall survival (OS) were 3.06 (95% CI 1.893–4.21) and 10.25 (95% CI 5.39–15.11) months, respectively. Multivariate analysis identified ECOG performance status, <I>EGFR</I> mutation/<I>ALK</I> rearrangement status, liver metastasis and PD-L1 proportion as independent predictors of OS. Furthermore, 61.9% of the patients had adverse events of any grade; 38.1% had immune-related adverse events that were associated with PFS and OS on multivariate analysis.</P><P><B>Conclusions</B></P><P>The real-world ORR, PFS, OS, and adverse event profiles were comparable to previous clinical trials despite the patients’ different baseline characteristics. Our findings can aid in establishing effective immunotherapeutic management of NSCLC in routine clinical practice.</P><P><B>Electronic supplementary material</B></P><P>The online version of this article (10.1007/s00432-019-02899-y) contains supplementary material, which is available to authorized users.</P>

Effect of 6-Hydroxydopamine (6-OHDA) on the Expression of Testicular Steroidogenic Genes in Adult Rats

Heo Hyun-Jin,Ahn Ryun-Sup,Lee Sung-Ho 한국발생생물학회 2010 발생과 생식 Vol.14 No.3

A neurotoxin, 6-hydroxydopamine (6-OHDA) has been widely used to create animal model for Parkinson's disease (PD). The present study was undertaken to examine whether depletion of brain dopamine (DA) stores with 6-OHDA can make alteration in the activities of the testicular steroidogenesis in adult rats. Young adult male rats (3 months old) were received a single dose of 6-OHDA (200 in 10 /animal) by intracerebroventricular (icv) injection, and sacrificed after two weeks. The mRNA levels of steroidogenesis-related enzymes were measured by qRT-PCRs. Serum testosterone levels were measured by radioimmunoassay. Single icv infusion of 6-OHDA significantly decreased the mRNA levels of CYP11A1 (control:6-OHDA group= AU, p<0.05), CYP17 (control:6-OHDA group= AU, p<0.05). There were no changes in the mRNA levels of -HSD (control:6-OHDA group= AU) and -HSD (control: 6-OHDA group= AU), though the levels tended to be decreased in the 6-OHDA treated group. Administration of 6-OHDA decreased significantly the mRNA level of StAR when compared to the level of saline-injected control animals (control:6-OHDA group= AU, p<0.05). Treatment with single dose of 6-OHDA remarkably lowered serum testosterone levels compared to the levels of control group (control:6-OHDA group=, p<0.05). Taken together with our previous study, the present study demonstrated that the activities of hypothalamus-pituitary-testis hormonal axis could be negatively affected by blockade of brain DA biosynthesis, and suggested the reduced reproductive potential might be resulted in the animals. More precise information on the testicular steroidogenic activities in PD patients and PD-like animals should be required prior to the generalization of the sex steroid hormone therapy to meet the highest standards for safety and efficacy.

Effects of Heavy Metals on the in vitro Follicular Steroidogenesis in Amphibians

Choi, Mee-Jeong,Ahn, Ryun-Sup,Kwon, Hyuk-Bang The Korean Society for Integrative Biology 2006 Integrative biosciences Vol.10 No.4

Heavy metals are well known as important environmental pollutants and also considered as endocrine disrupters. This study was performed to evaluate the direct effects of heavy metals such as cadmium (Cd), zinc (Zn), mercury (Hg), lead (Pb), cobalt (Co), and arsenic (As) on the various steroidogenic enzymes in frog ovarian follicles. Ovarian follicles from Rana catesbeiana were isolated and cultured for 18 hours in the presence of frog pituitary homogenate (FPH, 0.05 gland/ml) or various steroid precursors with or without heavy metals (0.01-100 ${\mu}M$), and steroid levels in the follicle or culture medium were measured by radioimmunoassay (RIA). Thus, the steroidogenic enzyme activities were indirectly evaluated by measuring the converted steroid levels from the added precursor steroid. Among heavy metals, Hg, Cd and Zn significantly inhibited FPH-induced pregnenolone ($P_5$) production by the follicles ($EC_{50},\;4.0{\mu}M,\;25.6{\mu}M\;and\;5.7{\mu}M$, respectively ), and also suppressed the conversion of testosterone (T) to estradiol $17{beta}\;(E_2)\;(EC_{50},\;4.2{\mu}M,\;7.5{\mu}M\;and\;80.0{\mu}M) while Pb, Co and As are not or less effective in the inhibition. Other enzymes such as $C_{17-20}$ lyase and $17{\beta}$-hydroxysteroid dehydrogenase ($17{\beta}$-HSD) were suppressed only in the high concentration of Hg, Cd and Zn. Taken together, these data demonstrate that cytochrome P450 side chain cleavage (P450scc) and aromatase are much more sensitive to heavy metals than other steroidogenic enzymes and Hg, Cd and Zn show stronger toxicity to follicles than other heavy metals examined.

Effects of Organotin Compounds on Follicular Steroidogenesis in Frogs

Kwon Hyuk-Bang,Kim Seung-Chang,Kim An-Na,Lee Sung-Ho,Ahn Ryun-Sup 한국발생생물학회 2009 발생과 생식 Vol.13 No.3

Some organotin compounds such as butyltins and phenyltins are known to induce impo-sex in various marine animals and are considered to be endocrine disruptors. In this study, the effect of organotins on follicular steroidogenesis in amphibians was examined using ovarian follicles of Rana dybowskii and Rana catesbeiana. Isolated follicles were cultured for 6 or 18 h in the presence and absence of frog pituitary homogenate (FPH) or various steroid precursors, and the levels of product steroids in the culture media oassay. Among the butyltin compounds, tributyltin (TBT) strongly and dose-dependently inhibited the FPH-induced synthesis of pregnenolone () and progesterone () by the follicles. TBT also strongly suppressed the conversion of cholesterol to and partially suppressed the conversion of to . A high concentration of dibutyltin (DBT) also inhibited steroidogenesis by the follicles while monobutyltin and tetrabutyltin had negligible effects. The toxic effect of TBT or DBT was irreversible and a short time of exposure (30 min) was enough to suppress steroidogenesis. All the phenyltin compounds significantly inhibited FPH-induced synthesis by the follicles. The effective dose of 50% inhibition by diphenyltin was and those of monophenyltin and triphenyltin were and , respectively. However, none of the phenyltin compounds significantly suppressed the conversion of to -hydroxyprogesterone (-OHP) (by -hydroxylase), -OHP to androstenedione (AD) (by lyase), or AD to testosterone by the follicles. Taken together, the data show that among the steroidogenic enzymes, P450scc in the follicles is the most sensitive to organotin compounds and that an amphibian follicle culture system can be a useful screening model for endocrine disruptors.

Effect of Endocrine Disruptors on the Oocyte Maturation and Ovulation in Amphibians, Rana dybowskii

Choi, Mee-Jeong,Kim, Seung-Chang,Kim, An-Na,Kwon, Hyuk-Bang,Ahn, Ryun-Sup The Korean Society for Integrative Biology 2007 Integrative biosciences Vol.11 No.1

Recently, we have shown that some endocrine disruptors, heavy metals, organotins and azoles suppressed steroidogenic enzymes such as P450 side-chain cleavage enzyme (P450scc) and aromatase in bullfrog ovarian follicles. In the present study, by using an amphibian ovarian follicle culture system, we examined the effects of these endocrine disruptors on maturation and ovulation of oocytes from Rana dybowskii in vitro. Ovarian fragments or isolated follicles were cultured for 24 h in a medium containing frog pituitary homogenate (FPH) or progesterone ($P_{4}$) with or without endocrine disruptors, and oocyte maturation (germinal vesicle breakdown, GVBD) and ovulation were examined. Among the organotins, tributyltin (TBT) strongly inhibited both FPH-and $P_{4}-induced$ oocyte maturation ($ED_{50}$:0.6 and 0.7 ${\mu}M$, respectively); however, tetrabutyltin (TTBT) and dibutyltin (DBT) showed only partial suppression, while monobutyltin (MBT) showed no inhibitory effect. All of the organotins suppressed $P_{4}-induced$ oocyte ovulation very effectively at a low concentration, and TBT and DBT exerted an inhibitory effect on FPH-induced ovulation. Among the heavy metals, mercury (Hg), cadmium (Cd) and cobalt (Co) were very effective in inhibiting FPH-induced oocyte maturation and ovulation, while lead (Pb), arsenite (As) and zinc (Zn) were less effective. However, all of the heavy metals suppressed FPH-induced oocyte ovulation at a high dose ($100{\mu}M$). Among the azoles, itraconazole (ICZ), ketoconazole (KCZ) and clotrimazole (CTZ) effectively inhibited FPH-induced oocyte maturation and ovulation, while econazole (ECZ), miconazole (MCZ) and fluconazole (FCZ) were considerably less effective. These results demonstrated that the abovementioned endocrine disruptors exhibited differential effects on oocyte maturation and ovulation in amphibian follicles and that the frog ovarian culture system could be used as an effective experimental tool to screen and evaluate the toxicity of various endocrine disruptors in vitro.

전기 침 자극의 기억 조절 효과

이상관(Sang Kwan Lee),김민수(Min Soo Kim),안련섭(Ryun Sup Ahn),김문수(Moon Soo Kim),성강경(Kang Keyng Sung) 한의병리학회 2007 동의생리병리학회지 Vol.21 No.6