Protective effect of gomisin N on benzyl butyl phthalate-induced dysfunction of testosterone production in TM3 Leydig cells.

BACKGROUND: Exposure to benzyl butyl phthalate (BBP) may induce disorders in the male reproductive system. However, the molecular mechanisms remain unknown. Here we investigated the effect of BBP on testosterone production and its molecular mechanisms. Furthermore, we also investigated the role of gomisin N (GN) from Schisandra chinensis (S. chinensis) in testosterone synthesis in TM3 Leydig cells. METHOD AND RESULTS: First, we examined the effects of BBP on expression levels of testosterone biosynthesis-related genes (StAR, CYP11α1, CYP17α1, 3ßHSD, and 17ßHSD) and attenuation-related genes (CYP1ß1, CYP19α1, and Srd5α1-3). Although testosterone biosynthesis-related genes did not change, attenuation-related genes such as CYP1ß1 and CYP19α1 were upregulated with ROS generation and testosterone level attenuation in the presence of 50 µM of BBP. However, the compound with the highest ROS and ONOO- scavenging activity from S. chinensis, GN, significantly reversed the expression of BBP-induced testosterone attenuation-related gene to normal levels. Subsequently, GN improved the testosterone production levels in TM3 Leydig cells. These events may be regulated by the antioxidant effect of GN. CONCLUSIONS: On conclusion, our study suggests, for the first time, that BBP impairs testosterone synthesis by the modulation of CYP1ß1 and CYP19α1 expression in TM3 cells; GN could potentially minimize the BBP-induced dysfunction of TM3 cells to produce testosterone by suppressing CYP19α1 expression.

Nudging Public Health Behaviors to Prevent COVID-19: A Systematic Review.

Many countries have implemented strict preventive measures and mandatory policies to curb virus transmission during the COVID-19 pandemic. Some have adopted softer approaches, such as nudge-based intervention, to influence public health behavior. This systematic review, conducted following Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) 2020 guidelines, aims to determine if the nudge-based intervention can effectively influence people's preventive behavior during the early period of the COVID-19 pandemic. The review indicated an overall positive outcome, but results were mixed as nudge-based interventions substantially depended on the situational context. While the review found that the nudging technique that presents and conveys decision-related information was essential to nudging people, a secondary nudge would often applied to deliver the interventions. In addition, there was no indication of an ideal nudge technique that would be effective in most situations. Conversely, our findings indicate that the nudge would likely suffer from habituation after repeated intervention or backfire due to inappropriate use of nudges. Also, the ceiling effect would inhibit any nudge influences regardless of the technique(s) used. In sum, the results and the applicability of nudge-based interventions were mixed, highlighting the need for further research to advance the theory and practical developments.

Crisis and Emergency Risk Communication and Emotional Appeals in COVID-19 Public Health Messaging: Quantitative Content Analysis.

BACKGROUND: Although COVID-19 is no longer a global health emergency, it remains pervasive in Singapore, a city-state situated in Southeast Asia, with periodic waves of infection. In addition to disease management, strong communication strategies are critical in the government's response to the pandemic to keep the public updated and equip them in protecting themselves. OBJECTIVE: Grounded in the crisis and emergency risk communication (CERC) framework and emotional appeals, this study aimed to analyze public health communication strategies in Singapore during the COVID-19 pandemic. METHODS: Quantitative content analysis was conducted on 696 Facebook (Meta Platforms Inc) posts and 83 website articles published by Singapore-based public health institutions between January 2020 and September 2022. RESULTS: The results showed that increasing communication on message themes, such as inquisitive messaging and clarification, can enhance communication strategies. The use of emotional appeals also varies with time and should be carefully used as they are context-specific. CONCLUSIONS: Theoretically, this study contributes to advancements in the CERC framework and concepts of emotional appeals by exploring the applications and changes of CERC message types and emotional appeals at different phases. The findings can provide practical guidance for authorities and communication practitioners in developing effective communication strategies.

Schisandrin C: an active compound from the fruit of Schisandra chinensis in anti-inflammation and anti-oxidation.

Inflammatory responses are involved in various diseases, such as insulin resistance, atherosclerosis, and hypogonadism. This study investigates the effects of SCE on anti-inflammation and molecular mechanisms in LPS-induced macrophages. RAW 264.7 macrophage cells were treated with LPS for 24 hr, followed by SCE, schisandrin C (Sch C) (1, 10, and 100 µM), and gomisin N (GN) (1, 10, and 100 µM) for 24 hr. Gene expression levels of pro-inflammatory cytokines were measured by qPCR. Protein expression of NLPR3 inflammasome was examined by western blot analysis. The expression levels of pro-inflammatory cytokines, including IL-1ß, IL-6, and TNFα, were significantly reduced after SCE treatment. Sch C significantly inhibits these pro-inflammatory cytokines, while GN suppresses only IL6. Furthermore, Sch C significantly prevented the activation of NLRP3 inflammasome complexes such as NLRP3 and caspase-1. Sch C is the major active compound of SCE on anti-inflammation through attenuation of NLRP3 inflammasome.

Can Press Freedom Enhance the Effect of News Exposure on COVID-19 Health Beliefs? A Health Belief Model Perspective.

News media can influence citizens' health beliefs about COVID-19 and eventually their vaccination intention. However, existing literature has rarely investigated how such effect is contingent upon a country-level factor: press freedom. Situated in the Health Belief Model, this study draws upon a multi-national survey (N = 3,599), involving 10 major cities in Asia to address the research gap. Results showed that news exposure has a positive effect on personal health beliefs on COVID-19, affecting their vaccination intention. More interestingly, the relationship between news exposure and personal health beliefs about COVID-19 was negatively moderated by level of press freedom - that is, the relationship between news exposure and personal health beliefs is stronger in cities that belong to countries with low levels of press freedom.

Biological Activity and Component Analyses of Chamaecyparis obtusa Leaf Extract: Evaluation of Antiwrinkle and Cell Protection Effects in UVA-Irradiated Cells.

Background and Objectives: Chamaecyparis obtusa (C. obtuse) extract has been used as a folk medicinal remedy in East Asian countries to alleviate inflammation and prevent allergies. Active oxygen causes skin aging and leads to skin cell and tissue damage. Extensive research has been conducted to control active oxygen generation to prevent skin aging. We evaluated the antioxidant activity and antiwrinkle effect of C. obtusa extract to determine its potential as a cosmetic material. Materials and Methods: The antioxidant activity of a 70% ethanol extract of C. obtusa (COE 70) and a water extract of C. obtusa (COW) was determined using 2,2-diphenyl-1-picrylhydrazy (DPPH) scavenging, 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS+) scavenging, superoxide dismutase-like activity, xanthine oxidase inhibition, and ferric-reducing antioxidant power assays. The effective concentration of the extracts was determined using the methyl thiazolyl tetrazolium assay to evaluate their toxicity. The effects of COE 70 on the production of matrix metalloproteinases (MMPs) and procollagen, and expression of activated cytokines, interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α), in UVA-irradiated fibroblasts were determined using quantitative real-time PCR. Additionally, quercitrin, amentoflavone, hinokiflavone, and myricetin concentrations in COE 70 were determined using high-pressure high-performance liquid chromatography. Results: COE 70 had higher polyphenol and flavonoid concentrations than COW and exhibited an excellent antioxidant effect. COE 70 suppressed UVA-induced fibroblast death by 21.3% at 25 µg/mL. It also increased MMP-1, MMP-3, TNF-α, and IL-6 mRNA levels at 5-25 µg/mL compared with those in control UVA-irradiated fibroblasts. Moreover, mRNA levels of collagen type I and superoxide dismutase significantly increased, indicating the antiwrinkle and anti-inflammatory effects of the extract. Among the COE 70 components, quercitrin concentration was the highest; hence, quercitrin could be an active ingredient. Conclusions: COE 70 could be used as a natural antioxidant and antiwrinkle agent.

The Abundance and Availability of Cytokine Receptor IL-2Rß (CD122) Constrain the Lymphopenia-Induced Homeostatic Proliferation of Naive CD4 T Cells.

Lymphopenia-induced homeostatic proliferation (LIP) is a critical mechanism for restoring T cell immunity upon lymphodepleting insults or infections. LIP is primarily driven by homeostatic cytokines, such as IL-7 and IL-15, but not all T cells respond with the same efficiency to homeostatic proliferative cues. Although CD8 T cells vigorously proliferate under lymphopenic conditions, naive CD4 T cells are substantially impaired in their response to homeostatic cytokines, and they fail to fully expand. In this study, we show that the availability of IL-2Rß (CD122), which is a receptor subunit shared by IL-2 and IL-15, affects both the cytokine responsiveness and the LIP of naive CD4 T cells in the mouse. The enumeration of surface IL-2Rß molecules on murine naive CD4 and naive CD8 T cells revealed a 5-fold difference in IL-2Rß abundance. Notably, it was the limited availability of IL-2Rß that impaired CD4 T cell responsiveness to IL-15 and suppressed their LIP. As such, forced IL-2Rß expression on CD4 T cells by transgenesis bestowed IL-15 responsiveness onto naive CD4 T cells, which thus acquired the ability to undergo robust LIP. Collectively, these results identify IL-2Rß availability as a new regulatory mechanism to control cytokine responsiveness and the homeostatic proliferation of murine CD4 T cells.

Gender-Specific Pictorial Health Warnings: Moderation Effects of the Threat Level and Gender.

This study examined the effects of gender-specific pictorial health warning labels contingent on their intended gender and threat levels (for females) in forming anti-smoking intentions. We conducted a within-subject design experiment with smokers and nonsmokers in Singapore (N = 100, 50% men). Each participant viewed 10 warning labels-four female-specific (high and low threat), four gender-neutral (high and low threat), and two male-specific (only low threat)-in a random order, evaluating each label on personal relevance, attention, cognitive elaboration, reactance, and intentions to purchase or avoid smoking. The findings showed that females reported greater relevance, attention, elaboration, and intentions to avoid smoking for low threat female-specific warning labels than male-specific or gender-neutral counterparts. Males reported less attention, elaboration, and relevance for low threat male-specific warning labels than female-specific or gender-neutral counterparts. Under high threat conditions, female-specific and gender-neutral warning labels were equally effective for both genders. No differences were observed by smoking status. Overall, gender-specific warning labels are potentially more effective than gender-neutral ones for deterring smoking in women contingent on low threat levels. By providing a deeper understanding of persuasive mechanisms and boundary conditions for the effects of gender specificity, findings can aid health policymakers in developing better gender-responsive interventions.

Wear or Not to Wear a Mask? Recommendation Inconsistency, Government Trust and the Adoption of Protection Behaviors in Cross-Lagged TPB Models.

This study examined how exposure to government health advisories on face mask-wearing and trust in government influenced people's compliance with the advisory overtime. We conducted a three-wave panel survey (N = 1,024; T1 in February, T2 in March, T3 in April 2020) in Singapore, where the government initially enforced wearing a face mask conditional on feeling sick, and then later revised its advisory to make mask-wearing mandatory regardless of sickness. Exposure to the initial advisory at T1 had cross-lagged effects on forming positive expectancy, normative, and self-efficacy beliefs on conditional face mask-wearing at T2. Government trust at T1 also had a cross-lagged effect on increasing supportive perceived norm for conditional mask-wearing, while reducing positive expectancy of nonconditional mask-wearing at T2. Exposure to the revised advisory and government trust at T3 were positively associated with outcome expectancy, perceived norm, and self-efficacy regardless of behavior type. Regarding nonconditional mask-wearing, the autoregressive links from T2 to T3 were insignificant for perceived norm and self-efficacy and even negatively significant for intention and behavior. This study offers theoretical and practical insights by documenting the complex and dynamic processes involved in health decision-making during a novel disease pandemic.

Multilevel causal attributions on transboundary risk: Effects on attributions of responsibility, psychological distance, and policy support.

This study used two randomized experiments in a prospective design (Study 1 N = 297, Study 2 N = 296) to examine how multilevel causal attribution dimensions (internal vs. external to an individual or a country) shape domestic and foreign policy support to counter transboundary risk. Results from Study 1 and 2 showed that external-country (vs. internal-country) causal attribution reduced perceptions of internal-country attributions of responsibility, which had a cross-lagged effect on support for domestic-industry policies to mitigate the risk. In contrast, perceptions of external-country attributions of responsibility increased support for foreign policies in a 2-week follow up. This study offers theoretical insights into the demarcation of multilevel causal attribution dimensions in studying media framing effects. It also highlights some important causal mechanisms of how media frames shape public support for policies aimed at transboundary risk mitigation.

The Impact of Emotion and Government Trust on Individuals' Risk Information Seeking and Avoidance during the COVID-19 Pandemic: A Cross-country Comparison.

This study examines the emotional mechanisms of how public trust in the governments' actions to address the COVID-19 pandemic shapes individuals' risk information-seeking and avoidance. To make cross-cultural comparisons, we conducted a multi-country survey early in the pandemic in South Korea, the United States (US) and Singapore. The results suggest that trust was negatively related to fear, anger, sadness and anxiety, and positively related to hope. These emotions were significant mediators of the effect of trust on information seeking and avoidance, except for anger on avoidance. Importantly, the indirect effects of trust in government varied by country. Fear was a stronger mediator between trust and information seeking in South Korea than in the US. In contrast, sadness and anger played more prominent mediating roles in Singapore than in South Korea. This study offers theoretical insights into better understanding the roles of discrete emotions in forming information behaviors. The findings of this study also inform communication strategies that seek to navigate trust in managing pandemics that impact multiple nations.

Cultural Determinants of Cancer Fatalism and Cancer Prevention Behaviors among Asians in Singapore.

This research aims to better understand cultural disparities in cancer prevention behaviors. To do this, we investigate how four cultural beliefs - optimism, pessimism, naïve dialecticism, and superstition - associate with cancer fatalism, which has been recognized as a major barrier to cancer prevention behaviors. Based on an online survey of 1,021 Singapore residents, the results reveal that cancer fatalism is positively associated with pessimism, naïve dialecticism and superstitions, and associated negatively with optimism. Mediation analyses further reveal that cancer fatalism is a significant mediator between these four cultural beliefs and four cancer prevention behaviors including fruit and vegetable intake, regular exercise, avoidance of smoking, and sunscreen use. This study offers theoretical insights into the understanding of how people develop cancer fatalism and practical guidance on the promotion of cancer prevention behaviors, particularly among Asian populations.

Coronavirus Disease Outbreak in Call Center, South Korea.

We describe the epidemiology of a coronavirus disease (COVID-19) outbreak in a call center in South Korea. We obtained information on demographic characteristics by using standardized epidemiologic investigation forms. We performed descriptive analyses and reported the results as frequencies and proportions for categoric variables. Of 1,143 persons who were tested for COVID-19, a total of 97 (8.5%, 95% CI 7.0%-10.3%) had confirmed cases. Of these, 94 were working in an 11th-floor call center with 216 employees, translating to an attack rate of 43.5% (95% CI 36.9%-50.4%). The household secondary attack rate among symptomatic case-patients was 16.2% (95% CI 11.6%- 22.0%). Of the 97 persons with confirmed COVID-19, only 4 (1.9%) remained asymptomatic within 14 days of quarantine, and none of their household contacts acquired secondary infections. Extensive contact tracing, testing all contacts, and early quarantine blocked further transmission and might be effective for containing rapid outbreaks in crowded work settings.

Integrating Risk Perception Attitude Framework and the Theory of Planned Behavior to Predict Mental Health Promotion Behaviors among Young Adults.

Mental disorder is a pressing public health issue in Singapore, especially among young adults. By integrating the risk perception attitude (RPA) framework and the theory of planned behavior (TPB), this study examines psychosocial factors underlying two mental health promotion behaviors - seeking counseling and employing self-help methods - among young Singaporeans. The results of an online survey (n = 232) showed that, as predicted by RPA framework, perceived risk interacted with self-efficacy to affect behavioral intention to seek counseling. However, this interaction existed only among individuals with favorable attitudes toward counseling-seeking behavior and not among those with unfavorable attitudes. In addition, the interaction between perceived risk and self-efficacy was not significant for the intention to perform self-help methods. The current findings demonstrated that the nature of focal behavior and attitudes are boundary conditions of the interaction effect between perceived risk and efficacy, which is the core premise of the RPA framework. These findings offer practical implications for developing campaign strategies to promote mental well-being among young adults in Singapore.

The Interplay between Framing and Regulatory Focus in Processing Narratives about HPV Vaccination in Singapore.

This study examined whether regulatory focus changes the effects of gain- and loss-framed narratives on promoting Human Papillomavirus (HPV) vaccination among young females in Singapore. We conducted a quasi-experiment in which participants reported their regulatory focus and then read either a gain- or loss-framed narrative about HPV vaccination. The results showed an overall advantage of a loss frame over a gain frame in producing transportation and self-referent emotions, which in turn led to increased vaccination intentions. This pattern was more pronounced among those high in prevention or promotion focus, with self-referent emotions being the primary mediator transferring the interactive effects onto vaccination intentions. This study contributes to the extant literature on narrative persuasion by addressing the specific mechanisms of the effect of framing employed in narratives.

The Importance of Mandatory COVID-19 Diagnostic Testing Prior to Release from Quarantine.

A 14-day quarantine is implemented in many countries in response to the coronavirus disease pandemic. Korea implemented a mandatory quarantine for those who had close contact with infected patients and those returning from abroad. The present study explored the implications of mandatory coronavirus disease 2019 testing before releasing individuals from the 14-day quarantine in Incheon, Korea. From February 11 to July 5, 2020, 19,296 people were self-quarantined, and 56 (0.3%) of them were confirmed cases of COVID-19. Twenty (35.7%) were identified through the reporting of symptoms during quarantine, and 32 (57.1%) were identified using mandatory pre-release RT-PCR tests. Among the 32, 14 (25%) individuals reported mild symptoms and 18 (32.1%) were asymptomatic. It is suggested that mandatory diagnostic testing prior to release and the symptom-based surveillance after the 14-day quarantine may help control delayed or asymptomatic COVID-19 cases.

Gui-A-Gra Attenuates Testicular Dysfunction in Varicocele-Induced Rats via Oxidative Stress, ER Stress and Mitochondrial Apoptosis Pathway.

Gui-A-Gra, a commercial insect powder from Gryllus bimaculatus, is registered as an edible insect by the Korean food and drug administration. The aim of this study was to investigate the effect of Gui-A-Gra on testicular damage induced by experimental left varicocele in male Sprague Dawley rats. A total of 72 rats were randomly divided into the following six groups (12 rats in each group): a normal control group (CTR), a group administrated with Gui-A-Gra 1.63 gm/kg (G1.63), a group administrated with Gui-A-Gra 6.5 gm/kg (G6.5), a varicocele (VC)-induced control group (VC), a VC-induced group administrated with Gui-A-Gra 1.63 gm/kg (VC + G1.63), and a VC-induced group administrated with Gui-A-Gra 6.5 gm/kg (VC + G6.5). Rats were administrated 1.63 or 6.5 gm/kg Gui-A-Gra once daily for 42 days. Indicators of sperm parameters, histopathology, reproductive hormones, oxidative stress, endoplasmic reticulum (ER) stress, inflammation, and mitochondrial apoptosis were analyzed to evaluate effects of Gui-A-Gra on VC-induced testicular dysfunction. Gui-A-Gra administration to VC-induced rats significantly (p < 0.05) increased sperm count and sperm motility, Johnsen score, spermatogenic cell density, serum testosterone, testicular superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase, GPx4, and steroidogenic acute regulatory protein (StAR) level. Moreover, pretreatment with Gui-A-Gra significantly (p < 0.05) decreased terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) positive cells/tubules, serum luteinizing hormone (LH), serum follicle-stimulating hormone (FSH), testicular tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), malondialdehyde (MDA), reactive oxygen species (ROS)/reactive nitrogen species (RNS) level, glucose-regulated protein-78 (Grp-78), phosphorylated c-Jun-N-terminal kinase (p-JNK), phosphorylated inositol-requiring transmembrane kinase/endoribonuclease 1α (p-IRE1α), cleaved caspase-3, and BCL2 associated X protein: B-cell lymphoma 2 (Bax: Bcl2) ratio in VC rats. These results suggest that protective effects of Gui-A-Gra on VC-induced testicular injury might be due to its antioxidant, anti-inflammatory, and androgenic activities that might be mediated via crosstalk of oxidative stress, ER stress, and mitochondrial apoptosis pathway.

MOTILIPERM Ameliorates Immobilization Stress-Induced Testicular Dysfunction via Inhibition of Oxidative Stress and Modulation of the Nrf2/HO-1 Pathway in SD Rats.

It is well established that physiological stress has an adverse effect on the male reproductive system. Experimental studies have demonstrated the promising effects of MOTILIPERM in male infertility. MOTILIPERM extract is composed of three crude medicinal herbs: Morinda officinalis How (Rubiaceae) roots, Allium cepa L. (Liliaceae) outer scales, and Cuscuta chinensis Lamark (convolvulaceae) seeds. The present study aimed to investigate the possible mechanisms responsible for the effects of MOTILIPERM on testicular dysfunction induced by immobilization stress. Fifty male Sprague Dawley rats were divided into five groups (10 rats each): a normal control group (CTR), a control group administered MOTILIPERM 200 mg/kg (M 200), an immobilization-induced stress control group (S), an immobilization-induced stress group administered MOTILIPERM 100 mg/kg (S + M 100), and MOTILIPERM 200 mg/kg (S + M 200). Stressed rats (n = 30) were subjected to stress by immobilization for 6 h by placing them in a Perspex restraint cage, while controls (n = 20) were maintained without disturbance. Rats were administrated 100 or 200 mg/kg MOTILIPERM once daily for 30 days 1 h prior to immobilization. At the end of the treatment period, we measured body and reproductive organ weight; sperm parameters; histopathological damage; reproductive hormone levels; steroidogenic acute regulatory protein (StAR); biomarkers of oxidative stress; and apoptosis markers. MOTILIPERM treatment improved testicular dysfunction by up-regulating (p < 0.05) sperm count, sperm motility, serum testosterone level, StAR protein level, Johnsen score, and spermatogenic cell density in stressed rats. MOTILIPERM decreased oxidative stress by increasing (p < 0.05) testicular superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione peroxidase-4 (GPx 4), catalase, nuclear factor erythroid 2-related factor 2 (Nrf2), and heme oxygenase 1 (HO-1) levels and decreasing (p < 0.05) malondialdehyde (MDA) and reactive oxygen species/reactive nitrogen species (ROS/RNS) levels. Furthermore, MOTILIPERM down-regulated (p < 0.05) cleaved caspase 3 and BCL2 associated X protein (Bax) levels; increased pro caspase-3 and B-cell lymphoma 2 (Bcl-2) levels; and upregulated testicular germ cell proliferation in stressed rats. The number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive cells and serum luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels also significantly (p < 0.05) decreased after pretreatment with MOTILIPERM in stressed rats. Collectively, our results suggest that, in immobilization-mediated stress-induced testicular dysfunction, MOTILIPERM sustains normal spermatogenesis via antioxidant and anti-apoptotic activities by activating the NRF/HO-1 signaling pathway.

Effects of COVID-19 Misinformation on Information Seeking, Avoidance, and Processing: A Multicountry Comparative Study.

We examined the implications of exposure to misinformation about COVID-19 in the United States, South Korea, and Singapore in the early stages of the global pandemic. The online survey results showed that misinformation exposure reduced information insufficiency, which subsequently led to greater information avoidance and heuristic processing, as well as less systematic processing of COVID-19 information. Indirect effects differ by country and were stronger in the U.S. sample than in the Singapore sample. This study highlights negative consequences of misinformation during a global pandemic and addresses possible cultural and situational differences in how people interpret and respond to misinformation.

Cross-talk between ER stress and mitochondrial pathway mediated adriamycin-induced testicular toxicity and DA-9401 modulate adriamycin-induced apoptosis in Sprague-Dawley rats.

BACKGROUND: DA-9401 was prepared as a mixture of Chinese medicinal herb extracts from roots of Morinda officinalis How (Rubiaceae), outer scales of Allium cepa L. (Liliceae) and seeds of Cuscuta chinensis Lamark (Convolvulaceae). The present study was designed to investigate the possible protective role of DA-9401 in adriamycin (ADR)-induced testicular toxicity associated with oxidative stress, endoplasmic reticulum (ER) stress, and apoptosis. METHODS: Fifty healthy 8-week-old male Sprague-Dawley rats were equally divided into five groups. The first CTR group was treated with normal saline 2 ml/day by gavage. The second was treated with DA-100 (DA-9401 100 mg/kg/day). The third (ADR) group received ADR (2 mg/kg/once a week) intraperitoneally, while the combination of ADR and DA-9401 was given to the fourth ADR + DA-100 (100 mg/kg/day p.o) group and fifth ADR + DA-200 (200 mg/kg/day p.o) group. At the end of the 8-week treatment period, body weight, reproductive organ weights, fertility rate, pups per female were recorded, and serum were assayed for hormone concentrations. Tissues were subjected to semen analysis, histopathological changes, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), oxidative stress markers and expression levels of endoplasmic reticulum (ER) stress markers, apoptosis markers, tight junction protein markers, steroidogenic acute regulatory protein (StAR), cation channel of sperm (CatSper) and glycogen synthase kinase-3 (GSK-3) by western blot. RESULTS: DA-9401 administration to ADR-treated rats significantly decreased serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels, interleukin-6, TNF-α, MDA level, ROS/RNS level, ER stress response protein levels, tunnel positive cells, cleaved caspase-3, and Bax/Bcl2 ratio. Moreover, pretreatment with DA-9401 significantly increased body weight, reproductive organ weights, fertility rate, pups per female, Johnsen's score, spermatogenic cell density, sperm count and sperm motility, serum testosterone concentration, testicular superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), tight junction protein markers, star protein level, CatSper, and GSK-3 level. CONCLUSIONS: ADR treatment can markedly impair testicular function and induce testicular cell death presumably by causing significant changes in oxidative stress, ER stress, and mitochondrial pathway. DA-9401 exerts beneficial effects against oxidative stress, ER stress, and mitochondria-mediated cell death pathway in testis tissue by up-regulating expression levels of tight junction protein markers, steroidogenic acute regulatory protein, GSK-3 alpha, and cation channels of sperm.