Testicular torsion or torsion of the spermatic cord is one of the most serious urological conditions. It causes testicular injury, which potentially leads to male subfertility. The turning of the spermatic cord and spermatic structures around themselves results in biochemical and histological changes; however, following testicular detorsion, tissues undergo reperfusion that causes more severe damage than that induced by ischemia. Since the primary causes of testicular damage are reactive oxygen species production, an increase in intra-mitochondrial calcium concentration and an increased rate of cellular apoptosis, different medications may potentially be effective. It seems that several medications, experimentally and sometimes clinically, serve an adjuvant role in the cellular damage that occurs following ischemia-reperfusion. Antioxidants, calcium channel blockers, phytotherapeutical medicinals, anaesthetics, hormones and platelet inhibitors may potentially create a solid basis for an adjuvant restoring therapy and ameliorate testicular function following torsion. The current study aimed to review the relevant literature and discuss the actions of a number of molecules that may protect the testes during ischemia/reperfusion injury.

BACKGROUND AND PURPOSE: Inflammation plays a key role in the development of benign prostatic hyperplasia (BPH). Eicosanoids derived from the COX and 5‐lipoxygenase (5‐LOX) pathways are elevated in the enlarging prostate. Flavocoxid is a novel flavonoid–based ‘dual inhibitor’ of the COX and 5‐LOX enzymes. This study evaluated the effects of flavocoxid in experimental BPH.EXPERIMENTAL APPROACH: Rats were treated daily with testosterone propionate (3 mg·kg⁻¹ s.c.) or its vehicle for 14 days to induce BPH. Animals receiving testosterone were randomized to receive vehicle (1 mL·kg⁻¹, i.p.) or flavocoxid (20 mg·kg⁻¹, i.p.) for 14 days. Histological changes, eicosanoid content and mRNA and protein levels for apoptosis‐related proteins and growth factors were assayed in prostate tissue. The effects of flavocoxid were also tested on human prostate carcinoma PC3 cells.KEY RESULTS: Flavocoxid reduced prostate weight and hyperplasia, blunted inducible expression of COX‐2 and 5‐LOX as well as the increased production of PGE₂ and leukotriene B₄ (LTB₄), enhanced pro‐apoptotic Bax and caspase‐9 and decreased the anti‐apoptotic Bcl‐2 mRNA. Flavocoxid also reduced EGF and VEGF expression. In PC3 cells, flavocoxid stimulated apoptosis and inhibited growth factor expression. Flavocoxid‐mediated induction of apoptosis was inhibited by the pan‐caspase inhibitor, Z‐VAD‐FMK, in PC3 cells, suggesting an essential role of caspases in flavocoxid‐mediated apoptosis during prostatic growth.CONCLUSION AND IMPLICATIONS: Our results show that a ‘dual inhibitor’ of the COX and 5‐LOX enzymes, such as flavocoxid, might represent a rational approach to reduce BPH through modulation of eicosanoid production and a caspase‐induced apoptotic mechanism.

Cadmium (Cd) causes male infertility. There is the need to identify safe treatments counteracting this toxicity. Flavocoxid is a flavonoid that induces a balanced inhibition of cyclooxygenase (COX)-1 and COX-2 peroxidase moieties and of 5-lipoxygenase (LOX) and has efficacy in the male genitourinary system. We investigated flavocoxid effects on Cd-induced testicular toxicity in mice. Swiss mice were divided into 4 groups: 2 control groups received 0.9% NaCl (vehicle; 1 ml/kg/day) or flavocoxid (20 mg/kg/day ip); 2 groups were challenged with cadmium chloride (CdCl₂; 2 mg/kg/day ip) and administered with vehicle or flavocoxid. The treatment lasted for 1 or 2 weeks. The testes were processed for biochemical and morphological studies. CdCl₂ increased phosphorylated extracellular signal-regulated kinase (p-ERK) 1/2, tumor necrosis factor (TNF)-α, COX-2, 5-LOX, malondialdehyde (MDA), B-cell-lymphoma (Bcl)-2-associated X protein (Bax), follicle-stimulating hormone (FSH), luteinizing hormone (LH), transforming growth factor (TGF) -β3, decreased Bcl-2, testosterone, inhibin-B, occludin, N-Cadherin, induced structural damages in the testis and disrupted the blood-testis barrier. Many TUNEL-positive germ cells and changes in claudin-11, occludin, and N-cadherin localization were present. Flavocoxid administration reduced, in a time-dependent way, p-ERK 1/2, TNF-α, COX-2, 5-LOX, MDA, Bax, FSH, LH, TGF-β3, augmented Bcl-2, testosterone, inhibin B, occludin, N-Cadherin, and improved the structural organization of the testis and the blood-testis barrier. Few TUNEL-positive germ cells were present and a morphological retrieval of the intercellular junctions was observed. In conclusion, flavocoxid has a protective anti-inflammatory, antioxidant, and antiapoptotic function against Cd-induced toxicity in mice testis. We suggest that flavocoxid may play a relevant positive role against environmental levels of Cd, otherwise deleterious to gametogenesis and tubular integrity.

Background: The apoptosis machinery is a promising target against benign prostatic hyperplasia (BPH). Inhibitors of apoptosis proteins (IAPs) modulate apoptosis by direct inhibition of caspases. Serenoa Repens (SeR) may be combined with other natural compounds such as Lycopene (Ly) and Selenium (Se) to maximize its therapeutic activity in BPH. We investigated the effects of SeR, Se and Ly, alone or in association, on the expression of four IAPs, cIAP-1, cIAP-2, NAIP and survivin in rats with experimental testosterone-dependent BPH. Moreover, caspase-3, interleukin-6 (IL-6) and prostate specific membrane antigen (PSMA) have been evaluated. Rats were administered, daily, with testosterone propionate (3 mg/kg/sc) or its vehicle for 14 days. Testosterone injected animals (BPH) were randomized to receive vehicle, SeR (25 mg/kg/sc), Se (3 mg/kg/sc), Ly (1 mg/kg/sc) or the SeR-Se-Ly association for 14 days. Animals were sacrificed and prostate removed for analysis. Results: BPH animals treated with vehicle showed unchanged expression of cIAP-1 and cIAP-2 and increased expression of NAIP, survivin, caspase-3, IL-6 and PSMA levels when compared with sham animals. Immunofluorescence studies confirmed the enhanced expression of NAIP and survivin with a characteristic pattern of cellular localization. SeR-Se-Ly association showed the highest efficacy in reawakening apoptosis; additionally, this therapeutic cocktail significantly reduced IL-6 and PSMA levels. The administration of SeR, Se and Ly significantly blunted prostate overweight and growth; moreover, the SeR-Se-Ly association was most effective in reducing prostate enlargement and growth by 43.3% in treated animals. Conclusions: The results indicate that IAPs may represent interesting targets for drug therapy of BPH.