Yang Wang,Zhimin Chen,Fang You,Jing Sun,Hongyi Yang
Premature ovarian insufficiency (POI) is a female reproductive disorder characterized by impaired ovarian function. Protein tyrosine kinase 2 beta (PTK2B), a non-receptor tyrosine kinase, has been implicated in folliculogenesis, but its role in POI remains unknown. In this study, a rat POI model was established by intraperitoneal injection of cyclophosphamide (Cy) for 14 days. Electroacupuncture (EA) has been elicited to effectively improve ovarian function in POI. Here, mRNA sequencing (mRNA-seq) analysis found that PTK2B expression in ovarian tissues was upregulated by Cy treatment but downregulated by EA. To investigate PTK2B's role, primary rat ovarian granulosa cells (GCs) were co-treated with Cy (250 μM) and a PTK2B inhibitor PF-431396 (10 μM) for 48 h. PF-431396 inhibited Cy-induced inflammatory response and apoptosis in GCs. Further, PTK2B binds to AKT1 in GCs. PF-431396 facilitated AKT1 phosphorylation, and the inhibitory effects of PF-431396 on GC inflammatory response and apoptosis were reversed by an AKT1 inhibitor LY294002. In vivo , rats were given PF-431396 (10 mg/kg/d) by gavage for 7 days following Cy induction for 14 days. Treatment with PF-431396 increased ovarian weight, serum E2, and AMH levels, while decreased FSH and LH levels. Additionally, it could improve Cy-induced ovarian tissue injury, inhibit inflammation and apoptosis, and elevate p-AKT1 level in ovarian tissues. Together, our results unveil that PF-431396, a PTK2B inhibitor, ameliorates ovarian dysfunction in POI through promoting AKT1 phosphorylation, suggesting that PTK2B may be a therapeutic target for POI.
The aim of this study was to investigate the effects of histone deacetylase-6 (HDAC6) on the functional and pathological changes of the amyloid beta (Aβ)-induced cognitive dysfunction rats by regulating protein tyrosine kinase 2 beta (PTK2B). Ninety Sprague Dawley rats were randomly
divided into nine groups, consisting of five experimental groups and four control groups. In five experimental groups, Aβ1–42 was infused intracerebroventricularly and 3 days later, rats in each group were infused intracerebroventricularly with tubastatin A hydrochloride
(TSA), the HDAC6-specific inhibitor (Aβ + TSA group), theophylline, the HDACs agonist (Aβ + Theo group), PF431396 (PF), the PTK2B inhibitor (Aβ + PF group), the combination of PF and theophylline (Aβ + PF + Theo
group), and normal saline (Aβ + normal saline group), respectively. Rats in four control groups took normal saline that was equivalent to the volume of Aβ1–42, and 3 days later, TSA (TSA group), theophylline (Theo group), (PF group, or normal
saline group) was given at a volume of 5 µL for rats in each group. Our results showed that HDAC6 may not only lead to the deterioration of learning and memory abilities but also elevate the levels of Aβo and Tau phosphorylation in Aβ-induced cognitive dysfunction rats
via upregulating PTK2B.
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