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.

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.

The ameliorative effect of monotropein, astragalin, and spiraeoside on oxidative stress, endoplasmic reticulum stress, and mitochondrial signaling pathway in varicocelized rats.

BACKGROUND: Monotropein, astragalin, and spiraeoside (MAS) are active compounds extracted from medicinal herbs; monotropein from Morinda officinalis How (Rubiaceae), astragalin (kaempferol 3-O-glucoside) from Cuscuta chinensis Lamark (Convolvulaceae) and spiraeoside from the outer scales of Allium cepa L. (Liliceae) in a ratio of 6.69:0.41:3.61. Monotropein, astragalin, and spiraeoside are well-known antioxidants, anti-inflammatory, and antinociceptive agents. The current investigation aims to study the molecular mechanism of varicocele-induced male infertility and the underlying pharmacological mechanisms of MAS. METHODS: Four groups were included: control (CTR), MAS 200 group (MAS 200 mg/kg), varicocele group (VC), and VC + MAS 200 group (MAS 200 mg/kg). Sprague-Dawley (SD) rats were treated with 200 mg/kg MAS or vehicle once daily for 28 days. The possible signaling mechanism and effects of MAS were measured via histological staining, immunohistochemistry, western blot, and biochemical assays. RESULTS: Parameters such as sperm motility and count, Johnsen's scores, spermatogenic cell density, serum testosterone, testicular superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx) and expression of the steroidogenic acute regulatory protein (StAR) improved significantly in the VC + MAS 200 group compared with the VC group. MAS treatment of varicocele-induced group significantly decreased the levels of serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH), as well as testicular interleukin-6 (IL6), tumor necrosis factor-α (TNF-α), ROS/RNS, and malondialdehyde (MDA). It also decreased the apoptotic index and reduced the expression of endoplasmic reticulum (ER) protein levels (Grp78, p-IRE1α, and p-JNK) and apoptotic markers such as cleaved caspase-3 and Bax/Bcl2 ratio. CONCLUSION: This study suggests that the crosstalk between oxidative stress, ER stress, and mitochondrial pathway mediates varicocele-induced testicular germ cell apoptosis. MAS promotes spermatogenesis in varicocele-induced SD rat, probably by decreasing cytokines (IL-6, TNF-α) levels, regulating abnormal sex hormones, and decreasing oxidative stress, ER stress, and apoptosis.

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.

CONTEXT: MOTILIPERM was prepared as a mixture of extracts of three medicinal herbs [roots of Morinda officinalis How (Rubiaceae), outer scales of Allium cepa L. (Liliaceae) and seeds of Cuscuta chinensis Lamark (Convolvulaceae)]. OBJECTIVE: 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. MATERIALS AND METHODS: 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). RESULTS: 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. DISCUSSION AND CONCLUSIONS: 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.

The relationship between serum total testosterone and free testosterone levels with serum hemoglobin and hematocrit levels: a study in 1221 men.

OBJECTIVE: To investigate the relationship between serum total testosterone (TT) and free testosterone (FT) levels in men with anemia. METHODS: We reviewed the records of 1221 subjects between March 2009 and December 2014. All the subjects' blood samples were drawn for TT and FT assays. Their serum hemoglobin (Hb) and serum hematocrit (Hct) levels were measured. The primary objective of our study was to investigate the association between TT and FT levels with Hb and Hct levels. RESULTS: The mean age was 59.82 ± 12.71 years. The mean TT and FT levels were 4.54 ± 2.02 ng/mL and 10.63 ± 3.69 pg/mL, respectively. The mean Hb and Hct levels were 14.72 ± 1.34 g/dL and 43.11 ± 3.75%, respectively. Subjects with low TT (<2.35 ng/mL) had low Hb and Hct levels (p < 0.001, p < 0.001, respectively). TT was positively associated with FT, Hb, and Hct. TT and FT levels were significantly lower in older men. CONCLUSIONS: Subjects with low TT and FT levels had low Hb and Hct levels. This suggests that TT and FT play a significant role in erythropoiesis. Testosterone replacement therapy may be effective in men with hypogonadism to reduce the incidence of anemia.

The effects of MOTILIPERM on cisplatin induced testicular toxicity in Sprague-Dawley rats.

BACKGROUND: Cisplatin causes male infertility but the exact mechanism have not been clarified, yet. MOTILIPERM has been implicated in alleviation of infertility in Sprague-Dawley rats caused by cisplatin. We evaluated recovery effect of MOTILIPERM on cisplatin (CIS)-induced testicular toxicity in Sprague-Dawley rats. METHODS: Five groups were included. The groups are control (CTR), CTR + MOTILIPERM 200 mg/kg/day per oral, CIS 10 mg/kg i.v., CIS 10 mg/kg + MOTILIPERM 100 mg/kg/day, CIS 10 mg/kg + MOTILIPERM 200 mg/kg/day. CIS 10 mg/kg i.v. single dose was given before 100 mg/kg, or 200 mg/kg MOTILIPERM per oral daily for 28 days. Body and genital organs weight, epididymis sperm count, sperm motility, sperm apoptosis, testosterone level, MDA of testis tissue, spermatogenic cell density, and Johnsen's score were evaluated. Steroidogenic acute regulatory (StAR) protein, and Glucose-regulated protein-78 (GRP-78), phosphorylated Inositol-Requiring Transmembrane Kinase/Endoribonuclease 1 (IRE1) and phosphorylated c-jun-N-terminal kinase (p-JNK) were quantitated by western blot to show its signaling pathway. RESULTS: The body weight was decreased significantly in CIS 10 mg/kg, CIS 10 mg/kg + MOTILIPERM 100 mg/kg/day, CIS 10 mg/kg + MOTILIPERM 200 mg/kg/day compared with CTR (p < 0.001) however, it was increased in CIS 10 mg/kg + MOTILIPERM 100 mg/kg/day, CIS 10 mg/kg + MOTILIPERM 200 mg/kg/day compared with CIS 10 mg/kg. The decreased weight of epididymis and prostate were increased significantly in CIS 10 mg/kg + MOTILIPERM 100 mg/kg/day compared with CIS 10 mg/kg. Sperm count, sperm motility, sperm apoptosis, MDA of testis tissue, spermatogenic cell density, Johnsen's score, and total testosterone were also significantly improved by MOTILIPERM treatment. The levels of decreased StAR protein was significantly improved by MOTILIPERM administration, increased GRP-78 protein p-IRE1and p-JNK was also significantly decreased with MOTILIPREM treatment. CONCLUSION: The MOTILIPERM could be an effective medicine to reduce the toxic effect caused ER stress by CIS in the testis.

Endobronchial Metastasis of Renal Cancer Presented as Atelectasis.

The most common primary tumors associated with endobronchial metastasis (EBM) are colorectal, breast, and renal. When EBM is present, respiratory symptoms such as shortness of breath or hemoptysis accompanied by coughing usually appear. Herein, we report a case of atelectasis caused by EBM of renal cell carcinoma (RCC) in a 53-year-old man who underwent laparoscopic radical nephrectomy for RCC 5 years ago. The patient's primary RCC stage was pT1b, and the histological cell type was clear cell RCC with Fuhrman nuclear grade 3/4. At the time of EBM diagnosis, the patient was classified as "favorable" according to IMDC (International mRCC Database Consortium) risk calculator. The patient refused surgical treatment and received targeted therapy with sunitinib. A tumor mass spontaneously detached and came out through the airway during targeted therapy. Subsequently, the patient's respiratory symptoms were alleviated, and his atelectasis disappeared. This case shows that when there is atelectasis due to EBM of RCC, the obstructed bronchus may be reopened with targeted therapy without any interventional treatment.

Effects of Unripe Black Raspberry Extract Supplementation on Male Climacteric Syndrome and Voiding Dysfunction: A Pilot, Randomized, Double-Blind, Placebo-Controlled Trial.

Male climacteric syndrome (MCS) is a medical condition that can affect middle-aged men whose testosterone levels begin to decline considerably. These symptoms may include fatigue, decreased libido, mood swings, and disturbed sleep. MCS can be managed with lifestyle modifications and testosterone replacement. However, testosterone therapy may cause number of side effects, including an increased risk of cardiovascular issues. This study aims to evaluate the efficacy and safety of unripe black raspberry extract (BRE) against MCS and voiding dysfunction in men with andropause symptoms. A total of 30 subjects were enrolled and randomly assigned to the BRE group (n = 15) or the placebo group (n = 15). Participants were supplemented with 4800 mg BRE or placebo twice daily for 12 weeks. The impact of BRE was assessed using the Aging Male's Symptoms (AMS scale), International Prostate Symptom Score (IPSS) and the IPSS quality of life index (IPSS-QoL). Additionally, male sex hormones, lipid profiles, and anthropometric indices were assessed 6 and 12 weeks after treatment. The AMS scores did not differ significantly between the two groups. In the BRE group, the total IPSS and IPSS-QoL scores decreased significantly after 12 weeks compared to baseline (p < 0.05), but there was no significant difference compared to the placebo group. However, a significant difference was observed in the IPSS voiding symptoms sub-score compared to the placebo group. Furthermore, LDL-C and TC levels were also significantly lower in the BRE group than in the placebo group (p < 0.05). Collectively, the study provides strong evidence supporting the safety of BRE as a functional food and its supplementation potentially enhances lipid metabolism and alleviates MCS and dysuria symptoms, limiting the development of BPH.

Friction underwear for ease of pulling down in elderly patients with overactive bladder: A prospective randomized control trial.

Purpose: Friction underwear was developed by adding small silicon dots in front of the underwear to decrease the time for pulling down underwear in elderly patients with urge incontinence. We studied about the effects of the friction underwear for elderly overactive bladder (OAB) patients. Materials and Methods: Male patients over 60 years of age diagnosed with OAB were prospectively enrolled and randomized to either the friction underwear first group (measuring for the time taken to pull down the friction underwear first and the non-friction underwear second) or the friction underwear later group (non-friction underwear first and the friction underwear second). An investigator measured the time to pulling down the underwear. And we measured the coefficient of friction of underwear. Results: A total of 56 male patients were randomly divided into two groups using a random number table envelope method. There were no significant differences in demographics and clinical characteristics between the two groups. Of the total 56 patients, the time taken to pull down underwear for the friction underwear (3.79±0.15 seconds) was found significantly shorter than that for the non-friction underwear (4.10±0.17 seconds) (p=0.03). The static and dynamic coefficients of friction of the friction were 4.21 and 2.88, respectively, while those of the non-friction underwear were 0.64 and 0.45, respectively. Conclusions: Our study demonstrates that friction underwear significantly shortened the time to pull down underwear. This functional underwear may be effective in preventing the underwear from getting wet in patients who suffer from urge incontinence.