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Ryu, Ji-Kan,Tumurbaatar, Munkhbayar,Jin, Hai-Rong,Kim, Woo Jean,Kwon, Mi-Hye,Piao, Shuguang,Choi, Min Ji,Yin, Guo Nan,Song, Kang-Moon,Kang, Yong-Jin,Koh, Young Jun,Koh, Gou Young,Suh, Jun-Kyu Blackwell Pub 2012 JOURNAL OF SEXUAL MEDICINE Vol.9 No.12
<P>Men with diabetic erectile dysfunction (ED) often have severe endothelial dysfunction and respond poorly to oral phosphodiesterase-5 inhibitors.</P>
Yin, Jun,Kwon, Younghee,Kim, Dabin,Lee, Dayoung,Kim, Gyoungmi,Hu, Ying,Ryu, Ji-Hwan,Yoon, Juyoung American Chemical Society 2014 JOURNAL OF THE AMERICAN CHEMICAL SOCIETY - Vol.136 No.14
<P>Glutathione (GSH) plays a crucial role in human pathologies. Near-infrared fluorescence-based sensors capable of detecting intracellular GSH in vivo would be useful tools to understand the mechanisms of diseases. In this work, two cyanine-based fluorescent probes, <B>1</B> and <B>2</B>, containing sulfonamide groups were prepared. Evaluation of the fluorescence changes displayed by probe <B>1</B>, which contains a 2,4-dinitrobenzenesulfonamide group, shows that it is cell-membrane-permeable and can selectively detect thiols such as GSH, cysteine (Cys), and homocysteine (Hcy) in living cells. The response of <B>1</B> to thiols can be reversed by treatment with <I>N</I>-methylmaleimide (NMM). Probe <B>2</B>, which possesses a 5-(dimethylamino)naphthalenesulfonamide group, displays high selectivity for GSH over Cys and Hcy, and its response can be reversed using NMM. The potential biological utility of <B>2</B> was shown by its use in fluorescence imaging of GSH in living cells. Furthermore, probe <B>2</B> can determine changes in the intracellular levels of GSH modualated by H<SUB>2</SUB>O<SUB>2</SUB>. The properties of <B>2</B> enable its use in monitoring GSH in vivo in a mouse model. The results showed that intravenous injection of <B>2</B> into a mouse generates a dramatic image in which strong fluorescence is emitted from various tissues, including the liver, kidney, lung, and spleen. Importantly, <B>2</B> can be utilized to monitor the depletion of GSH in mouse tissue cells promoted by excessive administration of the painkiller acetaminophen. The combined results coming from this effort suggest that the new probe will serve as an efficient tool for detecting cellular GSH in animals.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/jacsat/2014/jacsat.2014.136.issue-14/ja412628z/production/images/medium/ja-2013-12628z_0013.gif'></P><P><A href='http://pubs.acs.org/doi/suppl/10.1021/ja412628z'>ACS Electronic Supporting Info</A></P>
Yin, Guo Nan,Jin, Hai-Rong,Choi, Min-Ji,Limanjaya, Anita,Ghatak, Kalyan,Minh, Nguyen Nhat,Ock, Jiyeon,Kwon, Mi-Hye,Song, Kang-Moon,Park, Heon Joo,Kim, Ho Min,Kwon, Young-Guen,Ryu, Ji-Kan,Suh, Jun-Kyu American Diabetes Association 2018 Diabetes Vol.67 No.6
<P>Penile erection requires well-coordinated interactions between vascular and nervous systems. Penile neurovascular dysfunction is amajor cause of erectile dysfunction (ED) in patients with diabetes, which causes poor response to oral phosphodiesterase-5 inhibitors. Dickkopf2 (DKK2), a Wnt antagonist, is known to promote angiogenesis. Here, using DKK2-Tg mice or DKK2 protein administration, we demonstrate that the overexpression of DKK2 in diabetic mice enhances penile angiogenesis and neural regeneration and restores erectile function. Transcriptome analysis revealed that angiopoietin-1 and angiopoietin-2 are target genes for DKK2. Using an endothelial cell-pericyte co-culture system and ex vivo neurite sprouting assay, we found that DKK2-mediated juxtacrine signaling in pericyte-endothelial cell interactions promotes angiogenesis and neural regeneration through an angiopoietin-1-Tie2 pathway, rescuing erectile function in diabetic mice. The dual angiogenic and neurotrophic effects of DKK2, especially as a therapeutic protein, will open new avenues to treating diabetic ED.</P>
Yin, Guo Nan,Kim, Woo Jean,Jin, Hai-Rong,Kwon, Mi-Hye,Song, Kang-Moon,Choi, Min Ji,Park, Jin-Mi,Das, Nando Dulal,Kwon, Ki-Dong,Batbold, Dulguun,Kim, Kyu-Won,Ryu, Ji-Kan,Suh, Jun-Kyu Blackwell Pub 2013 The journal of sexual medicine Vol.10 No.6
<P>Radical prostatectomy for prostate cancer can not only induce cavernous nerve injury (CNI) but also result in structural changes in the cavernous tissues. Nerve injury-induced protein 1, Ninjurin-1 (Ninj1), is known to be involved in neuroinflammatory processes and to be related to vascular regression during the embryonic period.</P>
Yin, Jun,Kwon, Younghee,Kim, Dabin,Lee, Dayoung,Kim, Gyoungmi,Hu, Ying,Ryu, Ji-Hwan,Yoon, Juyoung Nature Publishing Group 2015 NATURE PROTOCOLS -ELECTRONIC EDITION- Vol.10 No.11
Glutathione (GSH) is a major endogenous antioxidant that has a central role in cellular defense against toxins and free radicals. This protocol describes the preparation of CPDSA, a cyanine-based near-infrared (NIR) fluorescent probe for the detection of GSH in cells and in vivo. CPDSA is prepared with high yield through a simple two-step process. The first step is to react commercially available IR-780 iodide with excess anhydrous piperazine in anhydrous N,N-dimethyl formamide at 85 °C to form cyanine-piperazine (CP). The second step is the sulfonylation of CP with dansyl chloride in anhydrous dichloromethane. CPDSA selectively detects GSH in cells, and it has been shown to not react with other biothiols such as cysteine (Cys) and homocysteine (Hcy). This probe can also be used to monitor the GSH level of mouse bone marrow–derived neutrophils (BMDNs). The preparation of probe CPDSA takes 2 d, and experiments in cells and mice take 12–13 d.
Heat Shock Protein 70 in Penile Neurovascular Regeneration Requires Cystathionine Gamma-Lyase
Ghatak Kalyan,Yin Guo Nan,Hong Soon-Sun,Kang Ju-Hee,Suh Jun-Kyu,Ryu Ji-Kan 대한남성과학회 2022 The World Journal of Men's Health Vol.40 No.4
Purpose: Diabetes mellitus, one of the major causes of erectile dysfunction, leads to a poor response to phosphodiesterase-5 inhibitors. Heat shock protein 70 (Hsp70), a ubiquitous molecular chaperone, is known to play a role in cell survival and neuroprotection. Here, we aimed to assess whether and how Hsp70 improves erectile function in diabetic mice. Materials and Methods: Eight-week-old male C57BL/6 mice and Hsp70-Tg mice were used in this study. We injected Hsp70 protein into the penis of streptozotocin (STZ)-induced diabetic mice. Detailed mechanisms were evaluated in WT or Hsp70- Tg mice under normal and diabetic conditions. Primary MCECs, and MPG and DRG tissues were cultivated under normalglucose and high-glucose conditions. Results: Using Hsp70-Tg mice or Hsp70 protein administration, we demonstrate that elevated levels of Hsp70 restores erectile function in diabetic mice. We found that cystathionine gamma-lyase (Cse) is a novel target of Hsp70 in this process, showing that Hsp70-Cse acts through the SDF1/HO-1/PI3K/Akt/eNOS/NF-κB p65 pathway to exert its neurovascular regeneration- promoting effects. Coimmunoprecipitation and pull-down assays using mouse cavernous endothelial cells treated with Hsp70 demonstrated physical interactions between Hsp70 and Cse with a dissociation constant of 1.8 nmol/L. Conclusions: Our findings provide novel and solid evidence that Hsp70 acts through a Cse-dependent mechanism to mediate neurovascular regeneration and restoration of erectile function under diabetic conditions.
Crystal structure of LRG1 and the functional significance of LRG1 glycan for LPHN2 activation
Yang Jimin,Yin Guo Nan,Kim Do-Kyun,Han Ah-reum,Lee Dong Sun,Min Kwang Wook,Fu Yaoyao,Yun Jeongwon,Suh Jun-Kyu,Ryu Ji-Kan,Kim Ho Min 생화학분자생물학회 2023 Experimental and molecular medicine Vol.55 No.-
The serum glycoprotein leucine-rich ɑ-2-glycoprotein 1 (LRG1), primarily produced by hepatocytes and neutrophils, is a multifunctional protein that modulates various signaling cascades, mainly TGFβ signaling. Serum LRG1 and neutrophil-derived LRG1 have different molecular weights due to differences in glycosylation, but the impact of the differential glycan composition in LRG1 on its cellular function is largely unknown. We previously reported that LRG1 can promote both angiogenic and neurotrophic processes under hyperglycemic conditions by interacting with LPHN2. Here, we determined the crystal structure of LRG1, identifying the horseshoe-like solenoid structure of LRG1 and its four N-glycosylation sites. In addition, our biochemical and cell-biological analyses found that the deglycosylation of LRG1, particularly the removal of glycans on N325, is critical for the high-affinity binding of LRG1 to LPHN2 and thus promotes LRG1/LPHN2-mediated angiogenic and neurotrophic processes in mouse tissue explants, even under normal glucose conditions. Moreover, the intracavernous administration of deglycosylated LRG1 in a diabetic mouse model ameliorated vascular and neurological abnormalities and restored erectile function. Collectively, these data indicate a novel role of LRG1 glycans as molecular switches that can tune the range of LRG1’s cellular functions, particularly the LRG1/LPHN2 signaling axis.
Kang, Dong Hyuk,Yin, Guo Nan,Choi, Min-Ji,Song, Kang-Moon,Ghatak, Kalyan,Minh, Nguyen Nhat,Kwon, Mi-Hye,Seong, Do-Hwan,Ryu, Ji-Kan,Suh, Jun-Kyu Korean Society for Sexual Medicine and Andrology 2018 The World Journal of Men's Health Vol.36 No.2
<P><B>Purpose</B></P><P>Epigenetic modifications, such as histone acetylation/deacetylation and DNA methylation, play a crucial role in the pathogenesis of inflammatory disorders and fibrotic diseases. The aim of this study was to study the differential gene expression of histone deacetylases (HDACs) in fibroblasts isolated from plaque tissue of Peyronie's disease (PD) or normal tunica albuginea (TA) and to examine the anti-fibrotic effect of small interfering RNA (siRNA)-mediated silencing of HDAC7 in fibroblasts derived from human PD plaque.</P><P><B>Materials and Methods</B></P><P>For differential gene expression study, we performed reverse-transcriptase polymerase chain reaction for HDAC isoforms (1–11) in fibroblasts isolated from PD plaque or normal TA. Fibroblasts isolated from PD plaque were pretreated with HDAC7 siRNA (100 pmol) and then stimulated with transforming growth factor-β1 (TGF-β1, 10 ng/mL). Protein was extracted from treated fibroblasts for Western blotting. We also performed immunocytochemistry to detect the expression of extracellular matrix proteins and to examine the effect of HDAC2 siRNA on the TGF-β1-induced nuclear translocation of Smad2/3 and myofibroblastic differentiation.</P><P><B>Results</B></P><P>The mRNA expression of HDAC2, 3, 4, 5, 7, 8, 10, and 11 was higher in fibroblasts isolated from PD plaque than in fibroblasts isolated from normal TA tissue. Knockdown of HDAC7 in PD fibroblasts inhibited TGF-β1-induced nuclear shuttle of Smad2 and Smad3, transdifferentiation of fibroblasts into myofibroblasts, and abrogated TGF-β1-induced production of extracellular matrix protein.</P><P><B>Conclusions</B></P><P>These findings suggest that specific inhibition of HDAC7 with RNA interference may represent a promising epigenetic therapy for PD.</P>