Department of Human Pathology of Adult and Childhood, University of Messina,98125 Messina, Italy.
Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy.
Nutrients. 2021 Feb 25;13(3):734. doi: 10.3390/nu13030734.
Varicocele is an age-related disease with no current medical treatments positively impacting infertility. Toll-like receptor 4 (TLR4) expression is present in normal testis with an involvement in the immunological reactions. The role of peroxisome proliferator-activated receptor-α (PPAR-α), a nuclear receptor, in fertility is still unclear. N-Palmitoylethanolamide (PEA), an emerging nutraceutical compound present in plants and animal foods, is an endogenous PPAR-α agonist with well-demonstrated anti-inflammatory and analgesics characteristics. In this model of mice varicocele, PPAR-α and TLR4 receptors' roles were investigated through the administration of ultra-micronized PEA (PEA-um). Male wild-type (WT), PPAR-α knockout (KO), and TLR4 KO mice were used. A group underwent sham operation and administration of vehicle or PEA-um (10 mg/kg i.p.) for 21 days. Another group (WT, PPAR-α KO, and TLR4 KO) underwent surgical varicocele and was treated with vehicle or PEA-um (10 mg/kg i.p.) for 21 days. At the end of treatments, all animals were euthanized. Both operated and contralateral testes were processed for histological and morphometric assessment, for PPAR-α, TLR4, occludin, and claudin-11 immunohistochemistry and for PPAR-α, TLR4, transforming growth factor-beta3 (TGF-β3), phospho-extracellular signal-Regulated-Kinase (p-ERK) 1/2, and nucleotide-binding oligomerization domain-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) Western blot analysis. Collectively, our data showed that administration of PEA-um revealed a key role of PPAR-α and TLR4 in varicocele pathophysiology, unmasking new nutraceutical therapeutic targets for future varicocele research and supporting surgical management of male infertility.
精索静脉曲张是一种与年龄相关的疾病，目前尚无任何医学治疗方法能有效改善不育症。Toll 样受体 4（TLR4）在正常睾丸中表达，并参与免疫反应。核受体过氧化物酶体增殖物激活受体-α（PPAR-α）在生育中的作用尚不清楚。N-棕榈酰乙醇酰胺（PEA）是一种存在于植物和动物食品中的新兴营养化合物，是一种内源性 PPAR-α激动剂，具有良好的抗炎和镇痛特性。在这种精索静脉曲张小鼠模型中，通过给予超微化 PEA（PEA-um）来研究 PPAR-α 和 TLR4 受体的作用。使用野生型（WT）、PPAR-α 敲除（KO）和 TLR4 KO 雄性小鼠。一组进行假手术并给予载体或 PEA-um（10mg/kg 腹腔注射）治疗 21 天。另一组（WT、PPAR-α KO 和 TLR4 KO）进行手术精索静脉曲张，并给予载体或 PEA-um（10mg/kg 腹腔注射）治疗 21 天。治疗结束时，所有动物均被安乐死。对手术和对侧睾丸进行组织学和形态计量评估，进行 PPAR-α、TLR4、occludin 和 claudin-11 的免疫组织化学分析，以及 PPAR-α、TLR4、转化生长因子-β3（TGF-β3）、磷酸细胞外信号调节激酶（p-ERK）1/2 和核苷酸结合寡聚结构域样受体（NLR）家族吡喃结构域包含 3（NLRP3）Western blot 分析。总的来说，我们的数据表明，PEA-um 的给药揭示了 PPAR-α 和 TLR4 在精索静脉曲张病理生理学中的关键作用，为未来的精索静脉曲张研究和支持男性不育症的手术治疗提供了新的营养治疗靶点。
