Journal of ethnopharmacology · 2025
Cistanche total glycoside capsule promotes sperm maturation and fertility by activating the NELL2 Lumicrine pathway in a male reproductive impairment model.
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Guo Li, Xu Panyu, Li Zehui, Li Yuan, Li Jiashan, Li Siqi, Lin Na, Xu Ying
Аннотация
ETHNOPHARMACOLOGICAL RELEVANCE: Cistanche deserticola Ma is a traditional Chinese herb for reproductive health. Cistanche total glycoside capsule (CTGC), derived from Cistanche deserticola, is clinically used for the treatment of vascular dementia, yet its potential for treating male reproductive impairment (MRImp) remains uninvestigated.
AIM OF THE STUDY: This study investigates the efficacy of CTGC in enhancing sperm maturation and fertility potential, as well as its underlying mechanisms.
MATERIALS AND METHODS: Sixty male Sprague-Dawley rats were randomized into six groups: control, model, low (90 mg/kg), medium (180 mg/kg), high (360 mg/kg) CTGC, and L-carnitine (100 mg/kg, positive control). Sperm parameters, fertilization capacity, testis/epididymis histopathology, hypothalamic-pituitary-gonadal (HPG) axis hormones, and NELL2 Lumicrine system (NELL2-ROS1-OVCH2-ADAM3) were analyzed. Serum metabolomics and bio-network analyses explored the correlations between metabolites and MRImp. In vitro, GC-2spd cells were treated with CTGC, verbascoside (VB), and echinacoside (ECH) to assess NELL2 secretion. Co-culture of GC-2spd and MPC-1 cells verified the effects of Cistanche total glycoside (CTG), VB, and ECH on the NELL2 system.
RESULTS: CTGC significantly improved sperm count (P < 0.01), viability (P < 0.001), fertilization rate (P < 0.05), and reduced malformation rate (P < 0.05) compared with the model group. It also alleviated testicular/epididymal damage, normalized HPG axis hormone levels, and significantly upregulated NELL2, ROS1, OVCH2, and ADAM3 proteins in testis/epididymis tissues (CTGC vs. model, P < 0.001). Moreover, metabolomics and network pharmacology identified differential metabolites in phenylalanine, cofactor, and carbon metabolism pathways, which are associated with HPG axis hormones and the NELL2 system. In vitro, VB and ECH strongly bound to NELL2. CTGC, VB, and ECH treatment increased NELL2 secretion in GC-2spd cells and upregulated ROS1/OVCH2 expression in MPC-1 cells (vs. adenine-treated control, P < 0.05).
CONCLUSION: CTGC promotes fertility by activating the NELL2 signaling pathway, offering a non-hormonal strategy for addressing male infertility.
AIM OF THE STUDY: This study investigates the efficacy of CTGC in enhancing sperm maturation and fertility potential, as well as its underlying mechanisms.
MATERIALS AND METHODS: Sixty male Sprague-Dawley rats were randomized into six groups: control, model, low (90 mg/kg), medium (180 mg/kg), high (360 mg/kg) CTGC, and L-carnitine (100 mg/kg, positive control). Sperm parameters, fertilization capacity, testis/epididymis histopathology, hypothalamic-pituitary-gonadal (HPG) axis hormones, and NELL2 Lumicrine system (NELL2-ROS1-OVCH2-ADAM3) were analyzed. Serum metabolomics and bio-network analyses explored the correlations between metabolites and MRImp. In vitro, GC-2spd cells were treated with CTGC, verbascoside (VB), and echinacoside (ECH) to assess NELL2 secretion. Co-culture of GC-2spd and MPC-1 cells verified the effects of Cistanche total glycoside (CTG), VB, and ECH on the NELL2 system.
RESULTS: CTGC significantly improved sperm count (P < 0.01), viability (P < 0.001), fertilization rate (P < 0.05), and reduced malformation rate (P < 0.05) compared with the model group. It also alleviated testicular/epididymal damage, normalized HPG axis hormone levels, and significantly upregulated NELL2, ROS1, OVCH2, and ADAM3 proteins in testis/epididymis tissues (CTGC vs. model, P < 0.001). Moreover, metabolomics and network pharmacology identified differential metabolites in phenylalanine, cofactor, and carbon metabolism pathways, which are associated with HPG axis hormones and the NELL2 system. In vitro, VB and ECH strongly bound to NELL2. CTGC, VB, and ECH treatment increased NELL2 secretion in GC-2spd cells and upregulated ROS1/OVCH2 expression in MPC-1 cells (vs. adenine-treated control, P < 0.05).
CONCLUSION: CTGC promotes fertility by activating the NELL2 signaling pathway, offering a non-hormonal strategy for addressing male infertility.