The Role of Endoplasmic Reticulum Stress Response in Male Reproductive Physiology and Pathology: A Review

Keshab Kumar Karna,신유섭,최보람,김혜경,박종관 대한남성과학회 2020 The World Journal of Men's Health Vol.38 No.4

Endoplasmic reticulum (ER) stress, defined as prolonged disturbances in protein folding and accumulation of unfolded proteins in the ER. Perturbation of the ER, such as distribution of oxidative stress, iron imbalance, Ca2+ leakage, protein overload, and hypoxia, can cause ER stress. The cell reacts to ER stress by activating protective pathways, called the unfolded protein response (UPR), which is comprised of cellular mechanisms aimed for maintaining cellular homeostasis or, in case of excessively severe stress, at the initiation of cellular apoptosis. The three UPR signaling pathways from the ER stress sensors are initiated by activating transcription factor 6, inositol requiring enzyme 1, and protein kinase RNA-activated-like ER kinase. A number of physiological and pathological conditions, environmental toxicants and variety of pharmacological agents showed disruption of proper ER functions and thereby cause ER stress in male reproductive organ in rat model. The present review summarizes the existing data concerning the molecular and biological mechanism of ER stress in male reproduction and male infertility. ER stress initiated cell death pathway has been related to several diseases, including hypoxia, heath disease, diabetes, and Parkinson’s disease. Although there is not enough evidence to prove the relationship between ER stress and male infertility in human, most studies in this review found that ER stress was correlated with male reproduction and infertility in animal models. The ER stress could be novel signaling pathway of regulating male reproductive cellular apoptosis. Infertility might be a result of disturbing the ER stress response during the process of male reproduction.

Protective effect of DA-9401 in finasteride-induced apoptosis in rat testis: inositol requiring kinase 1 and c-Jun N-terminal kinase pathway

Soni, Kiran Kumar,Shin, Yu Seob,Choi, Bo Ram,Karna, Keshab Kumar,Kim, Hye Kyung,Lee, Sung Won,Kim, Chul Young,Park, Jong Kwan Dove Medical Press 2017 Drug design, development and therapy Vol.11 No.-

<P>Finasteride is used to treat male pattern baldness and benign prostatic hyperplasia. This study investigated the toxicity of finasteride and recovery by DA-9401 using Sprague Dawley (SD) rats. Forty adult male SD rats were assigned to four groups: control (CTR), finasteride 1 mg/kg/day (F), finasteride 1 mg/kg + DA-9401 100 mg/kg/day (F + DA 100) and finasteride 1 mg/kg + DA-9401 200 mg/kg/day (F + DA 200). Treatments were by oral delivery once daily for 90 consecutive days. The gross anatomical parameters assessed included: genital organ weight; vas deferens sperm count and sperm motility; testosterone, dihydrotestosterone (DHT) and malondialdehyde levels; and histological and terminal deoxynucleotidyl transferase enzyme mediated dUTP nick-end labeling (TUNEL) staining of testis for spermatogenic cell density, Johnsen’s score and apoptosis. Testicular tissue was also used for evaluating endoplasmic reticulum (ER) stress and apoptotic proteins. Epididymis weight, seminal vesicle weight, prostate weight, penile weight and vas deferens sperm motility showed significant differences between the F group and the CTR, F + DA 100 and F + DA 200 groups. There was no significant change in the testosterone level. DHT level decreased significantly in the F group compared with the CTR group. Testis tissue revealed significant changes in spermatogenic cell density, Johnsen’s score and apoptotic index. Western blot showed significant changes in the ER stress and apoptotic markers. Finasteride resulted in reduced fertility and increased ER stress and apoptotic markers, which were recovered by administration of DA-9401 in the SD rats.</P>

Protective effect of MOTILIPERM in varicocele-induced oxidative injury in rat testis by activating phosphorylated inositol requiring kinase 1α (p-IRE1α) and phosphorylated c-Jun N-terminal kinase (p-JNK) pathways

Soni, Kiran Kumar,Zhang, Li Tao,Choi, Bo Ram,Karna, Keshab Kumar,You, Jae Hyung,Shin, Yu Seob,Lee, Sung Won,Kim, Chul Young,Zhao, Chen,Chae, Han-Jung,Kim, Hye Kyung,Park, Jong Kwan TaylorFrancis 2018 Pharmaceutical biology Vol.56 No.1

<P><B>Abstract</B></P><P><B>Context:</B> MOTILIPERM was prepared as a mixture of extracts of three medicinal herbs [roots of <I>Morinda officinalis</I> How (Rubiaceae), outer scales of <I>Allium cepa</I> L. (Liliaceae) and seeds of C<I>uscuta chinensis</I> Lamark (Convolvulaceae)].</P><P><B>Objective:</B> To investigate the role of reactive oxygen species (ROS)-based endoplasmic reticulum (ER) stress in a rat model of varicocele and the therapeutic efficacy of MOTILIPERM in this model.</P><P><B>Materials and methods:</B> Sixty male rats were divided into five experimental groups: a normal control group (CTR + vehicle), a control group administered MOTILIPERM 200 mg/kg (CTR + M 200), a varicocele-induced control group (VC + vehicle) and two varicocele-induced groups administered MOTILIPERM 100 (VC + M 100) or 200 (VC + M 200) mg/kg for 4 weeks. Testis weights were recorded and serums were assayed for hormone concentrations. Tissues were subjected to semen analysis, histopathology, analyses of ER response protein expression levels and oxidative stress were assessed by measuring ROS, reactive nitrogen species (RNS), malondialdehyde (MDA) level and ratios of total glutathione (GSH)/oxidized GSH (GSSG).</P><P><B>Results:</B> MOTILIPERM treatment of varicocele-induced groups significantly increased left testis weight, testosterone level, sperm motility, count and spermatogenic cell density. ER-response protein expression levels were dose-dependently decreased in VC + M 200 group compared with VC + vehicle group. MOTILIPERM treatment also decreased MDA and ROS/RNS level but increased GSH/GSSG ratio.</P><P><B>Discussion and conclusions:</B> This study suggests that ROS-related ER stress may play a major role in varicocele-induced infertility and MOTILIPERM, a novel compound targeting ROS-based ER stress, may be therapeutically useful in treatment of varicocele, or as a supplement for the treatment of infertility.</P>

Finasteride and Erectile Dysfunction in Patients with Benign Prostatic Hyperplasia or Male Androgenetic Alopecia

Yu Seob Shin,Keshab Kumar Karna,Bo Ram Choi,Jong Kwan Park 대한남성과학회 2019 The World Journal of Men's Health Vol.37 No.2

Finasteride is primarily used to treat benign prostatic hyperplasia (BPH) and male androgenetic alopecia (MAA). Five-alpha reductase inhibitors (5α-RIs) could induce male sexual dysfunction due to their effects on testosterone and dihydrotestos-terone. There is evidence suggesting that 5α-RIs may independently increase the risk of erectile dysfunction (ED). However, many investigators believe that side effects of 5α-RIs will disappear with continuous treatment. Considerable controversy exists regarding the severity and persistence of side effects of finasteride on ED. The aim of this review was to summarize current research studies on finasteride associated with ED. The search strategy used each term of finasteride and ED against PubMed database to identify related studies. ED data reported from available trials for finasteride were summarized and reviewed. Although there is not enough evidence to prove the relationship between finasteride and ED, most studies in this review found that finasteride for BPH was correlated with ED. However, most studies included in this review revealed that finasteride for MAA was not correlated with ED. On the other hand, some studies reported side effects of finasteride associ-ated with sexual dysfunction, including ED, male infertility, ejaculation problem, and loss of libido, even in MAA patients. Well-designed randomized controlled trials are needed to further determine the mechanism and effects of finasteride on ED. However, physicians should discuss with their patients possible long-term effects of finasteride on sexual function, although we do not have evidence showing that adverse events of sexual dysfunction are absolutely associated with 5α-RIs.

Pharmacokinetic properties of monotropein, kaempferol 3-O-glucoside and quercetin 4"-O-glucoside after oral and intravenous gavage of MOTILIPERM in rats

Bo Ram Choi,Keshab Kumar Karna,Yu Seob Shin,Sung Won Lee,Chul Young Kim,Hye Kyung Kim,Jong Kwan Park 한국실험동물학회 2019 한국실험동물학회 학술발표대회 논문집 Vol.2019 No.7

Additive effect of oral LDD175 to tamsulosin and finasteride in a benign prostate hyperplasia rat model

Choi, Bo Ram,Kim, Hye Kyung,Soni, Kiran Kumar,Karna, Keshab Kumar,Lee, Sung Won,So, Insuk,Park, Jong Kwan Dove Medical Press 2018 Drug design, development and therapy Vol.12 No.-

<P><B>Objective</B></P><P>We investigated the benefits of the BK<SUB>Ca</SUB> agonist 4-chloro-7-trifluoromethyl-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid (LDD175) combined with tamsulosin and finasteride, in a benign prostatic hyperplasia (BPH) rat model.</P><P><B>Materials and methods</B></P><P>Castration was performed by bilateral orchiectomy under ketamine anesthesia. A rat model of BPH was established by daily intramuscular administration of testosterone propionate plus 17β-estradiol for 8 weeks. Model rats were administered combinations of 20 mg/kg LDD175, 0.01 mg/kg tamsulosin and 1 mg/kg finasteride once daily by oral gavage for 4 weeks from week 6 to 9 post-surgery. Intraurethral pressure induced by electrostimulation of the hypogastric nerve was measured at the end of administration. Body and genitourinary organ weights were recorded, serums were assayed for hormone concentrations, and tissues were subjected to histopathology, and analyses of α1-adrenoceptor mRNA and protein expression levels after treatment.</P><P><B>Results</B></P><P>Combined LDD175, tamsulosin, and finasteride significantly decreased prostatic index, serum hormone levels, epithelial thickness, and prostate expression of α1-adrenoceptors in BPH model rats. The 3-drug combination was more effective than any other combination or LDD175 alone.</P><P><B>Conclusion</B></P><P>These results suggest that LDD175 addition to tamsulosin and finasteride may be beneficial for the treatment of BPH patients who do not respond to tamsulosin plus finasteride.</P>