Cyclophosphamide (CP) is widely used as chemotherapy in various cancers; however, testicular atrophy has been encountered as an associated adverse effect. Oxidative stress, enhanced endoplasmic reticulum (ER) stress, and subsequent apoptosis are involved in the molecular mechanisms of CP-induced testicular toxicity. In addition to the cardiovascular benefits of LCZ696 (sacubitril/valsartan (VAL)), neprilysin inhibition was shown to mediate Ca2+ sequestration inside the ER. Furthermore, long noncoding RNA taurine-upregulated gene 1 (lncRNA TUG1) was shown to ameliorate apoptosis in various diseases. This tempted us to investigate the possible benefit of LCZ696 against CP-induced testicular dysfunction in rats through neprilysin inhibition axis, and the downstream apoptotic cascade, with highlighting the impact of lncRNA TUG1 in regulating testicular toxicity. Sixty adult male Wistar rats were randomly allocated as control, LCZ696, VAL, CP, CP + LCZ696, and CP + VAL. Testicular atrophy was induced by single-dose injection of CP (200 mg/kg; i.p.). LCZ696 treated group received LCZ696 (30 mg/kg; p.o.) for 6 days, with CP (200 mg/kg; i.p.) single-dose on day 5. LCZ696 increased lncRNA TUG1 expression, improved sperm characteristics, hormonal profile, testicular function, antioxidant defences, and Bcl-2. The histopathological picture and reduced oxidative and ER stress markers, aligned with declined Bax, caspase-3 and the expression of CHOP, PUMA, Noxa, Bim, and p53, with a subtle superior effect over VAL-treated group. In conclusion, the current study highlights the promising impact of LCZ696 in ameliorating chemotherapy-induced testicular atrophy; yet, further investigation regarding longer duration and different doses of LCZ696 is warranted.

中文翻译：

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LCZ696（沙屈比特/缬沙坦）保护大鼠免受环磷酰胺诱导的睾丸毒性：中性溶酶抑制作用和lncRNA TUG1在改善细胞凋亡中的作用。

环磷酰胺（CP）在各种癌症中被广泛用作化学疗法。然而，睾丸萎缩已引起相关的不良反应。氧化应激，内质网（ER）增强和随后的细胞凋亡均与CP诱导的睾丸毒性的分子机制有关。除了LCZ696的心血管益处（屈比特尔/缬沙坦（VAL））外，抑制脑啡肽酶还可以介导ER内的Ca2 +隔离。此外，长的非编码牛磺酸RNA上调的长基因1（lncRNA TUG1）被证明可以改善各种疾病中的细胞凋亡。这促使我们通过中性溶酶抑制轴和下游的凋亡级联研究LCZ696对CP诱导的大鼠睾丸功能障碍的可能益处，强调了lncRNA TUG1在调节睾丸毒性中的作用。将60只成年雄性Wistar大鼠随机分配为对照组，LCZ696，VAL，CP，CP + LCZ696和CP + VAL。通过单剂量注射CP（200 mg / kg; ip）诱导睾丸萎缩。LCZ696治疗组接受LCZ696（30 mg / kg;口服）治疗6天，第5天给予CP（200 mg / kg; ip）单剂量。LCZ696增加lncRNA TUG1表达，改善精子特性，激素状况，睾丸功能，抗氧化剂防御和Bcl-2。组织病理学图片和氧化和ER应激标志物减少，与Bax，caspase-3下降以及CHOP，PUMA，Noxa，Bim和p53的表达一致，与VAL治疗组相比有微妙的优越性。结论，当前的研究强调了LCZ696在改善化学疗法引起的睾丸萎缩方面的有希望的影响。然而，需要对更长的持续时间和不同剂量的LCZ696进行进一步研究。