Platelets play an important role in the development of endometriosis. Scutellarin is a flavonoid isolated from a medicinal herb traditionally used as a potent antiplatelet agent. In this study, we sought to evaluate its potential therapeutic effect, if any, in mice with induced endometriosis. Endometriosis was induced in 27 female Balb/c mice by intraperitoneal injection of uterine fragments. Two weeks after the induction, the 27 mice were randomly divided in equal sizes into 3 groups: untreated, which received only vehicle, and low-dose and high-dose groups, which received low- and high dose of scutellarin treatment. Hotplate test was administrated to all mice before endometriosis induction, and before and after the scutellarin treatment. Two weeks after the treatment, a blood sample was drawn before sacrifice and all lesions were harvested. The peripheral platelet activation rate and total lesion weight were assessed, and immunohistochemistry and histochemistry analyses were performed to evaluate the extent of proliferation, angiogenesis, fibroblast-to-myofibroblast transdifferentiation (FMT), and fibrosis in lesions. Compared with untreated mice, mice in both low-dose and high-dose groups had significantly reduced lesion weight and improved hyperalgesia. Scutellarin also reduced the peripheral-activated platelets rate and resulted in significantly reduced platelet aggregation, cellular proliferation, angiogenesis, the extent of FMT, and the extent of fibrosis in lesions. Thus, we conclude that scutellarin is efficacious in treating endometriosis in vivo by suppressing platelet aggregation, inhibiting proliferation, angiogenesis, and fibrogenesis, resulting in reduced lesion size and improved pain behavior. As such, scutellarin may be a potentially promising therapeutics for the treatment of endometriosis.

Despite the demonstrated efficacy of surgical treatment of endometriosis, recurrence after surgery still remains a formidable challenge. Surgery, especially when performed repeatedly, decreases ovarian reserve. Clearly, control of recurrence is an unmet medical need. So far nearly all efforts to control recurrence have been devoted to the identification of risk factors, biomarkers, and postoperative medication. One area that has been completely overlooked is the possibility of perioperative intervention. In this study, we tested the hypothesis that perioperative use of a nonspecific b-blocker and/or a nuclear factor-kB (NF-kB) inhibitor can retard the growth of residual endometriotic lesions that are left intact in the primary surgery. We established a mouse model of recurrence due to incomplete lesion removal by deliberately leaving residual lesions intact in the primary excision surgery. One hour before and 24 hours after the surgery, mice were either untreated or treated with andrographolide, propranolol, or both. Two weeks after the primary surgery, all mice were sacrificed and all lesions were excised and evaluated for immunohistochemistry analysis. We found that perioperative use of andrographolide and/or propranolol significantly decelerated the growth of residual lesions that were intentionally left out during the primary surgery. The perioperative intervention also significantly attenuated the generalized hyperalgesia resulting from the presence of residual lesions. It also inhibited the activation of the adrenergic receptor b2 signaling, resulting in reduced angiogenesis, epithelial-mesenchymal transition, fibroblast-tomyofibroblast transdifferentiation as well as NF-kB suppression and progesterone receptor isoform B induction. These data strongly suggest that perioperative use of b-blockers and/or NF-kB inhibitors may reduce the risk of recurrence in endometriosis.

PurposeThe aim of this study was to evaluate the dynamic change in staining of Class I HDACs and Hdac6 in lesions harvested serially from different time points in mice with induced endometriosis. In addition, the effect of Hdac8 activation as well as Hdac8 and Hdac6 inhibition on lesional progression and fibrogenesis was evaluated.MethodsImmunohistochemistry analysis of Class I HDACs and Hdac6 in serially harvested lesion samples in mouse. Hdac8 activation, as well as Hdac6/8 inhibition, was evaluated in mice with induced endometriosis.ResultsWe found a progressive increase in lesional staining of Hdac1, Hdac8, and Hdac6 and gradual decrease in Hdac2 staining and consistently reduced staining of Hdac3 during the course of lesional progression. The stromal Hdac8 staining correlated most prominently with all markers of lesional fibrosis. Hdac8 activation significantly accelerated the progression and fibrogenesis of endometriotic lesions. In contrast, specific inhibition of Hdac8 or Hdac6, especially of Hdac8, significantly hindered lesional progression and fibrogenesis.ConclusionsHdac8 is progressively and aberrantly overexpressed as endometriotic lesions progress. This, along with the documented HDAC1 upregulation in endometriosis and the overwhelming evidence for the therapeutic potentials of HDACIs, calls for further and in‐depth investigation of epigenetic aberrations of endometriosis in general and of HDACs in particular.

PurposeTo screen Zn2+‐dependent histone deacetylase (HDAC) 1‐11 in endometriotic cells and then evaluated the HDACs identified from the screening in ovarian endometrioma (OE) and deep endometriotic (DE) lesions, and to evaluate the therapeutic potential of HDAC8 inhibition in mice.MethodsQuantification of gene and protein expression levels of HDAC1‐11 in endometriotic cells stimulated by TGF‐β1, and immunohistochemistry analysis of Class I HDACs and HDAC6 in OE/DE lesion samples. The therapeutic potential of HDAC8 inhibition was evaluated by a mouse model of deep endometriosis.ResultsThe screening identified Class I HDACs and HDAC6 as targets of interest. Immunohistochemistry analysis found a significant elevation in HDAC8 immunostaining in both OE and DE lesions, which was corroborated by gene and protein expression quantification. For other Class I HDACs and HDAC6, their lesional expression was more subtle and nuanced. HDAC1 and HDAC6 staining was significantly elevated in DE lesions while HDAC2 and HDAC3 staining was reduced in DE lesions. Treatment of mice with induced deep endometriosis with an HDAC8 inhibitor resulted in significantly longer hotplate latency, a reduction of lesion weight by nearly two‐thirds, and significantly reduced lesional fibrosis.ConclusionsThese findings highlight the progression‐dependent nature of specific HDAC aberrations in endometriosis, and demonstrate, for the first titme, the therapeutic potential of suppressing HDAC8.