Distinct molecular targets of ProEGCG from EGCG and superior inhibition of angiogenesis signaling pathways for treatment of endometriosis

Endometriosis is a common chronic gynecological disease with endometrial cell implantation outside the uterus.Angiogenesis is a major pathophysiology in endometriosis.Our previous studies have demonstrated that the prodrug of epigallocatechin gallate(ProEGCG)exhibits superior anti-endometriotic and anti-angiogenic effects compared to epigallocatechin gallate(EGCG).However,their direct binding targets and underlying mechanisms for the differential effects remain unknown.In this study,we demonstrated that oral ProEGCG can be effective in preventing and treating endometriosis.Additionally,1D and 2D Proteome Integral Solubility Alteration assay-based chemical proteomics identified metadherin(MTDH)and PX domain containing serine/threonine kinase-like(PXK)as novel binding targets of EGCG and ProEGCG,respectively.Computational simulation and BioLayer interferometry were used to confirm their binding affinity.Our results showed that MTDH-EGCG inhibited protein kinase B(Akt)-mediated angiogenesis,while PXK-ProEGCG inhibited epidermal growth factor(EGF)-mediated angiogenesis via the EGF/hypoxia-inducible factor(HIF-1a)/vascular endothelial growth factor(VEGF)pathway.In vitro and in vivo knockdown assays and microvascular network imaging further confirmed the involvement of these signaling pathways.Moreover,our study demonstrated that ProEGCG has superior therapeutic effects than EGCG by targeting distinct signal transduction pathways and may act as a novel antiangiogenic therapy for endometriosis.

Unique anti-angiogenic effects,pharmacological targets and therapeutic mechanisms of Chinese herbal medicines for endometriosis

Endometriosis is a common and benign angiogenesisdependent gynecological disorder,which refers to the proliferation and growth of endometrium-like tissues with neovasculature formation outside of the uterus.1 Available medical treatments for endometriosis containing hormonal and non-hormonal treatments had been limited for longterm usage by their side effects.2 Ideal medical treatment for endometriosis with efficacy to relieve symptoms and suppress endometriotic lesion growth and minimal side effects has been longing for decades.3 Angiogenesis is a promising therapeutic target for endometriosis.

Histone demethylase Kdm5c regulates osteogenesis and bone formation via PI3K/Akt/HIF1α and Wnt/β-catenin signaling pathways

Fractures have an extraordinarily negative impact on individuals'quality of life and functional status.Nonunion or disability of fracture is a major health issue with important clinical,social,and economic implications.1 Mesenchymal stem cells(MSCs)play an indispensable role in the initiation of the fracture repair process including the formation of a callus which is replaced by new bone.The use of MSCs in the treatment of fractures is very attractive as they can reduce the time of healing and occurrence of nonunion.

Avascular necrosis of the first metatarsal head in a young female adult:A case report and review of literature

BACKGROUND This case study describes an atypical presentation of avascular necrosis(AVN)of the first metatarsal head,which is largely unfounded in the literature.CASE SUMMARY A healthy 24-year-old female initially presented with pain at the first metatarsophalangeal joint(MTPJ)and was diagnosed with AVN by physical examination and magnetic resonance imaging.The patient demonstrated atypically poor progress in recovery,despite being in otherwise good health and being of young age,with no history of corticosteroid or alcohol use.The patient also did not have any history or clinical features of autoimmune disease or vasculitis,such as systemic lupus erythematosus.The patient was managed with conservative treatment for 18 mo,which allowed for gradual return of full range of motion of the first MTPJ and subsiding pain,permitting the patient to return to highintensity sports training and full weight-bearing.Throughout her recovery,many differential diagnoses were ruled out through specific investigations leading to further reinforcement of the diagnosis of AVN of the 1st metatarsal head.CONCLUSION Atypical AVN may occur with no predisposing risk factors.Treatment is mainly conservative,with unclear guidelines in literature on management.