Syringic acid alleviates cisplatin-induced ovarian injury through modulating endoplasmic reticulum stress, inflammation and Nrf2 pathway.

BACKGROUND: Reproductive toxicity is one of the most important side effects of cisplatin (CIS) and leading to discontinuation of treatment. Syringic acid (SA) is a phenolic acid whose industrial use has increased in recent years due to its antioxidant properties. Recent reports highlight the importance of the supressed Nrf2 pathway in the molecular pathogenesis of CIS toxicity. Therefore, this study aimed to evaluate the therapeutic effect of SA on CIS-induced ovotoxicity through the Nrf2 pathway for the first time. MATERIAL AND METHODS: Thirty female rats were divided into 5 groups: control, CIS, CIS+SA (5 and 10 mg/kg) and only SA (per se, 10 mg/kg). CIS was administered intraperitoneally at a dose of 5 mg/kg on the 1st day, injections of SA followed by three consecutive days in the rats. Serum anti-mullerian hormone (AMH) levels and ovarian oxidative stress (OS), inflammation, endoplasmic reticulum stress (ERS), apoptosis and Nrf2 pathway markers were determined colorimetrically. Histopathological examinations of the ovaries with hematoxylin and eosin staining were also used to evaluate CIS-induced ovotoxicity. RESULTS: The CIS treatment depleted serum AMH levels, caused histopathological findings and increased OS, inflammation, ERS and apoptosis levels in ovarian tissue. However, treatments with SA significantly ameliorated CIS-induced biochemical and histopathological changes by activating Nrf2 pathway. CONCLUSION: The promising adjuvant potential of SA to alleviate CIS-related ovarian damage should be supported by more comprehensive studies.

Alpha-pinene neutralizes cisplatin-induced reproductive toxicity in male rats through activation of Nrf2 pathway.

PURPOSE: Testicular toxicity is one of the most important side effects of cisplatin (CP) therapy. Alpha-pinene (AP) is a naturally occurring monoterpene with antioxidant character in plants. Here, we aimed to evaluate the therapeutic activity of AP against CP-induced testicular toxicity by including the nuclear factor erythroid 2-associated factor 2 (Nrf2) pathway in rats. METHODS: Thirty male rats were divided into 5 groups: control, CP, CP + AP (5 and 10 mg/kg) and only AP (10 mg/kg). CP was administered intraperitoneally at a dose of 5 mg/kg on the first day, followed by three consecutive injections of AP. Serum reproductive hormone levels were evaluated using ELISA kits. Oxidative stress (OS), inflammation, endoplasmic reticulum stress (ERS) and apoptosis markers in testicular tissue were also determined colorimetrically. In addition, how CP affects Nrf2 pathway and the effect of AP on this situation were also addressed. RESULTS: Treatment with CP significantly increased OS, inflammation, ERS and apoptosis in testicular tissue. Administrations of AP resulted in an amelioration of these altered parameters. The mechanism of therapeutic effect of AP appeared to involve induction of Nrf2. Furthermore, these results were also confirmed by histological data. CONCLUSION: Results suggest that AP can exhibit therapeutic effects against CP-induced testicular toxicity. It can be concluded that AP may be a potential molecule to abolish reproductive toxicity after chemotherapy.

Evaluation of the therapeutic effects of arbutin on cisplatin-induced ovarian toxicity in rats through endoplasmic reticulum stress and Nrf2 pathway.

Arbutin (ARB) is a glycosylated hydroquinone with potent antioxidant effects. Although cisplatin (CP) is widely used in chemotherapy, its toxicity in healthy tissues, including ovotoxicity, is an insurmountable problem. This study aimed to evaluate the therapeutic effect of ARB against CP-related ovototoxicity by including nuclear factor erythroid 2-related factor 2 (Nrf2) pathway in rats for the first time. Rats treated one dose of CP (5 mg/kg) on the first day, followed by ARB (5 and 10 mg/kg) for three days. Serum reproductive hormone levels were determined using ELISA kits. Oxidative stress (OS), inflammation, endoplasmic reticulum stress (ERS) and apoptosis markers in ovarian tissue were also determined colorimetrically. In addition, how CP affects Nrf2 pathway and the effect of ARB on this situation were also addressed. ARB treatment reduced the levels of markers of OS, inflammation, ERS and apoptosis in ovarian tissue of CP-stimulated animals. ARB regenerated the depleted antioxidant system by triggering Nrf2 pathway in the ovarian tissues of animals stimulated by CP. Histological findings also supported the therapeutic efficacy of ARB. The results indicate that ARB may have therapeutic effects against CP-induced reproductive toxicity with its Nrf2 activator potential. ARB should be tested in more extensive studies as a new generation chemopreventive candidate molecule.

Gentisic acid ameliorates cisplatin-induced reprotoxicity through suppressing endoplasmic reticulum stress and upregulating Nrf2 pathway.

Reproductive toxicity is a serious side effect of cisplatin (CP) chemotherapy. Gentisic acid (GTA) is a phenolic acid with strong antioxidant properties. Here, we aimed to determine therapeutic effect of GTA against CP-induced testicular toxicity in rats for the first time. Male Sprague-Dawley rats received a single dose of CP (5 mg/kg; intraperitoneal) and treated with GTA (1.5 and 3 mg/kg; intraperitoneal; 3 consecutive days). The levels of oxidative stress (OS), inflammation, endoplasmic reticulum stress (ERS) and apoptosis biomarkers were assessed in the testicular tissue of rats. In addition, how CP affects the nuclear factor erythroid-2-related factor 2 (Nrf2) pathway and the effect of GTA on this situation were also addressed in the testicular tissue. CP administration induced histopathological changes in testicular tissue of rats with a significant increase in OS, inflammation, ERS and apoptosis biomarkers and a decrease in antioxidant capacity and Nrf2 expression levels. Administrations of GTA resulted in an amelioration of these altered parameters. These data suggest that GTA may be a potential therapeutic agent against CP-induced testicular toxicity. Activation of the Nrf2 pathway plays a key role of this therapeutic effect of GTA.

Propolis ameliorates ischemia/reperfusion-induced testicular damage by reducing oxidative stress / El propóleo mejora el daño testicular inducido por isquemia/reperfusión al reducir el estrés oxidativo

Purpose: This study was performed to evaluate the effect of ethanolic extract of Turkish propolis (EEP) on testicular ischemia/reperfusion (I/R) damage in rats in terms of biochemistry and histopathology, for the first time. Methods: A total of 18 male Sprague-Dawley rats were divided into three groups with six rats in each group: control, torsion/detorsion (T/D), and T/D+EEP (100mg/kg). Testicular torsion was performed by 720° rotating the left testicle in a clockwise direction. The duration of ischemia was 4h and orchiectomy was performed after 2h of detorsion. EEP was applied only once 30min before detorsion. Tissue malondialdehyde (MDA), total oxidant status (TOS) and total antioxidant status (TAS) levels were determined using colorimetric methods. Oxidative stress index (OSI) was calculated by proportioning tissue TOS and TAS values to each other. Tissue glutathione (GSH) and glutathione peroxidase (GPx) levels were determined using enzyme-linked immunosorbent assay (ELISA) kits. Johnsen's testicle scoring system was used for histological evaluation. Results: In the T/D group, it was determined that statistically significant decreasing in TAS, GSH, GPx levels and Johnsen score, and increasing in TOS, OSI and MDA levels (p<0.05) compared with control group. EEP administration statistically significantly restored this I/R damage (p<0.05). Conclusion: This is the first study to show that propolis prevent I/R-induced testicular damage through its antioxidant activity. More comprehensive studies are needed to see the underlying mechanisms. (AU)

Objetivo: Este estudio se realizó para evaluar por primera vez el efecto del extracto etanólico de propóleo turco (EEP) sobre el daño por isquemia/reperfusión (I/R) testicular en ratas en términos de bioquímica e histopatología. Métodos: Un total de 18 ratas macho Sprague-Dawley se dividieron en 3 grupos con 6 ratas en cada grupo: control, torsión/detorsión (T/D) y T/D+EEP (100mg/kg). La torsión testicular se realizó con una rotación de 720° del testículo izquierdo en el sentido de las agujas del reloj. La duración de la isquemia fue de 4h y la orquiectomía se realizó a las 2h de la detorsión. EEP se aplicó solo una vez 30min antes de la detorsión. Los niveles de malondialdehído tisular (MDA), estado oxidante total (TOS) y estado antioxidante total (TAS) se determinaron mediante métodos colorimétricos. El índice de estrés oxidativo (OSI) se calculó proporcionando los valores de TOS y TAS del tejido entre sí. Los niveles de glutatión tisular (GSH) y glutatión peroxidasa (GPx) se determinaron utilizando kits de ensayo inmunoabsorbente ligado a enzimas (ELISA). Se utilizó el sistema de puntuación de testículos de Johnsen para la evaluación histológica. Resultados: En el grupo T/D, se determina una disminución estadísticamente significativa en los niveles de TAS, GSH, GPx y puntuación de Johnsen y un aumento en los niveles de TOS, OSI y MDA (p<0,05) en comparación con el grupo control. La administración de EEP restauró de forma estadísticamente significativa este daño I/R (p<0,05). Conclusión: Este es el primer estudio que demuestra que el propóleo previene el daño testicular inducido por I/R a través de su actividad antioxidante. Se necesitan estudios más completos para ver los mecanismos subyacentes. (AU)

Vanillic acid abrogates cisplatin-induced ovotoxicity through activating Nrf2 pathway.

Although cisplatin (CDDP) is an effective anticancer agent, the ovotoxicity that can occur in female patients limits its use. Oxidative stress (OS) and inflammation are known to contribute to CDDP-induced ovotoxicity. Vanillic acid (VA) is a dietary herbal secondary metabolite with high free radical scavenging activity. It was aimed to evaluate the therapeutic effects of VA against CDDP-induced ovotoxicity in rats in this study for the first time. Ovotoxicity was achieved with a single dose of CDDP (5 mg/kg) in female rats. The therapeutic effect of VA was evaluated with 3-day administration of two different doses (5 and 10 mg/kg). While OS, inflammation, endoplasmic reticulum stress (ERS) and apoptosis markers were measured in tissue samples, the levels of reproductive hormones were determined in serum samples using colorimetric methods. The results showed that CDDP-induced nuclear factor erythroid 2-associated factor 2 (Nrf2) inhibition combined with increased OS, inflammation, ERS and apoptosis increased ovarian damage. VA treatments reversed these changes via activating Nrf2 pathway dose-dependently. In addition, histopathological findings also supported the biochemical results. VA may be a good therapeutic molecule candidate for CDDP-induced ovarian damage due to strong antioxidant and Nrf2 activator properties.

Propolis ameliorates ischemia/reperfusion-induced testicular damage by reducing oxidative stress.

PURPOSE: This study was performed to evaluate the effect of ethanolic extract of Turkish propolis (EEP) on testicular ischemia/reperfusion (I/R) damage in rats in terms of biochemistry and histopathology, for the first time. METHODS: A total of 18 male Sprague-Dawley rats were divided into three groups with six rats in each group: control, torsion/detorsion (T/D), and T/D+EEP (100mg/kg). Testicular torsion was performed by 720° rotating the left testicle in a clockwise direction. The duration of ischemia was 4h and orchiectomy was performed after 2h of detorsion. EEP was applied only once 30min before detorsion. Tissue malondialdehyde (MDA), total oxidant status (TOS) and total antioxidant status (TAS) levels were determined using colorimetric methods. Oxidative stress index (OSI) was calculated by proportioning tissue TOS and TAS values to each other. Tissue glutathione (GSH) and glutathione peroxidase (GPx) levels were determined using enzyme-linked immunosorbent assay (ELISA) kits. Johnsen's testicle scoring system was used for histological evaluation. RESULTS: In the T/D group, it was determined that statistically significant decreasing in TAS, GSH, GPx levels and Johnsen score, and increasing in TOS, OSI and MDA levels (p<0.05) compared with control group. EEP administration statistically significantly restored this I/R damage (p<0.05). CONCLUSION: This is the first study to show that propolis prevent I/R-induced testicular damage through its antioxidant activity. More comprehensive studies are needed to see the underlying mechanisms.

Arbutin abrogates testicular ischemia/reperfusion injury in rats through repression of inflammation and ER stress.

The aim of this study was to investigate the effects of arbutin (ARB) administration on oxidative stress, inflammation, endoplasmic reticulum (ER) stress and apoptosis in an experimental testicular torsion/detorsion (T/D)-induced testicular injury model for the first time. A total of 24 male Sprague-Dawley rats were divided into four groups with six rats in each group: sham control, T/D, T/D+ARB (50 mg/kg) and T/D+ARB (100 mg/kg). Torsion and detorsion times were applied as 4 h and 2 h, respectively. The levels of lipid peroxidation [malondialdehyde (MDA)] and oxidative stress [total oxidant status (TOS) and total antioxidant status (TAS)] in testicular tissues were determined using colorimetric methods. The levels of DNA damage [8-hydroxy-2'-deoxyguanosine (8-OHdG)], antioxidant system [superoxide dismutase (SOD) and catalase (CAT)], pro-inflammatory cytokines [high mobility group box 1 (HMGB1), nuclear factor kappa B protein 65 (NF-κB p65), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and myeloperoxidase (MPO)], ER stress [78-kDa glucose-regulated protein (GRP78), activating transcription factor 6 (ATF6) and CCAAT-enhancer-binding protein homologous protein (CHOP)] and apoptosis (caspase-3) markers in testicular tissues were determined using commercial enzyme-linked immunosorbent assay (ELISA) kits. Johnsen's testicle scoring system was used for histological evaluation. In the T/D group, it was determined that statistically significant increasing in the levels of oxidative stress, inflammation, ER stress and apoptosis compared with sham control group (p < 0.05). ARB administrations statistically significantly restored testicular I/R damage in a dose dependent manner (p < 0.05). In addition, it was determined that the data of histological examinations supported the biochemical results. Our findings support the hypothesis that ARB may be used as a protective agent against T/D-induced testicular damage.

Syringic acid ameliorates ischemia/reperfusion-induced testicular injury in rats via suppressing of HMGB1/NF-κB axis and endoplasmic reticulum stress.

PURPOSE: To investigate the possible protective role of syringic acid on torsion/detorsion-induced testicular injury using biochemical and histopathological approaches for the first time. METHODS: A total of 24 rats were divided into 4 groups: sham control, torsion/detorsion, torsion/detorsion + syringic acid (50 mg/kg and 100 mg/kg). Tissue malondialdehyde, total oxidant status and total antioxidant status levels were determined using colorimetric methods. Tissue 8-hydroxy-2'-deoxyguanosine, superoxide dismutase, catalase, high mobility group box 1, nuclear factor kappa B protein 65, tumor necrosis factor-alpha, interleukin-6, myeloperoxidase, 78-kDa glucose-regulated protein, activating transcription factor-6, C/EBP homologous protein and caspase-3 levels were determined using commercial enzyme-linked immunosorbent assay kits. Johnsen's testicle scoring system was used for histological evaluation. RESULTS: Compared with the control group, the levels of oxidative stress, inflammation, endoplasmic reticulum stress and apoptosis were significantly increased in the torsion/detorsion group (p < 0.05). Syringic acid administrations statistically significantly restored these damage in a dose dependent manner (p < 0.05). Moreover, it was found that the results of histological examinations supported the biochemical results to a statistically significant extent. CONCLUSION: The overall results suggest that syringic acid emerges as a potential compound for the treatment of testicular torsion and may be subject to clinical trials.