title: Combination of mesenchymal stem cell injection with icariin for the treatment of diabetes-associated erectile dysfunction.
abstract: The present study was aimed to examine whether icariin, a traditional Chinese medicine, could improve therapeutic effects of adipose derived mesenchymal stem cells (ADSCs) for diabetes-associated erectile dysfunction (DMED). DMED were induced in rats by intraperitoneal injection of streptozotocin and confirmed by erectile function measurement. Then, rats of diabetic ED were randomly divided to receive the treatment of saline, ADSCs, icariin or ADSCs combined with icariin respectively. Compared with the treatment by ADSCs or icariin alone, intracavernosum injection of ADSCs combined with the following daily gastric gavage of icariin significantly augmented the value of ICP and ICP/MAP (p<0.01). Meanwhile, the survival of transplanted ADSCs was much improved due to the application of icariin. Similarly, immunofluorescent staining analysis demonstrated that the improved erectile tissue structure by combination of ADSCs and icariin was significantly associated with the increased expression of endothelial markers (vWF) (p<0.01) and smooth muscle markers (α-SMA) (p<0.01). Furthermore, the structure changes in corpus cavernosum were further confirmed by the Masson's trichrome staining. To explore the possible mechanism underlying icariin-enhanced therapeutic efficacy of MSCs, we employed an in vitro testing system by introducing H2O2 to imitate oxidative stress condition considering the oxidative environment faced by engrafted ADSCs and anti-oxidative capacity of icariin. In vitro, we found that the addition of icariin considerably reduced the apoptosis of ADSCs, and attenuated the intracellular reactive oxygen species (ROS), the superoxidase dismutase (SOD) activity and the lactate dehydrogenase (LDH). Subsequently, we examined the expression of apoptosis-related proteins and explored the potential signaling pathway through which icariin promoted the survival of ADSCs against oxidative stress. It was demonstrated that icariin significantly inhibited the upregulation of apoptosis-related proteins under oxidative condition, including Bax and cleaved caspase-3, while promoted the expression of anti-apoptotic factor BCL2. These effects were accompanied with the activation of signal molecules, PI3K/Akt and STAT3. The further signal protein inhibition assays exhibited that the suppression of STAT3 abrogated the icariin-mediated anti-apoptotic effects observed above, while did not influence the expression of PI3K/Akt. However, PI3K inhibition could abrogate icariin-mediated STAT3 activation and achieved a similar effect as STAT3 inhibition. Our results suggested that icariin was an effective adjuvant for enhancing ADSC-based therapy of DMEM, which may be ascribed to their protection of ADSCs against oxidative stress via the regulation of PI3K/Akt-STAT3 signal pathway.
authors.affiliation: Department of Urology, PLA Navy General Hospital, Hai dian District, Beijing, People's Republic of China.
authors.forename: Xiyou
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Urology, The Second Artillery General Hospital of Chinese People's Liberation Army, Xicheng District, Beijing, People's Republic of China.
authors.forename: Chuanhai
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Urology, PLA General Hospital, Hai dian District, Beijing, People's Republic of China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Urology, PLA Navy General Hospital, Hai dian District, Beijing, People's Republic of China.
authors.forename: Ping
authors.initials: P
authors.lastname: Chen
authors.affiliation: Department of Urology, PLA Navy General Hospital, Hai dian District, Beijing, People's Republic of China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Department of Urology, PLA Navy General Hospital, Hai dian District, Beijing, People's Republic of China.
authors.forename: Yansheng
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Urology, PLA Navy General Hospital, Hai dian District, Beijing, People's Republic of China.
authors.forename: Yubo
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Urology, PLA Navy General Hospital, Hai dian District, Beijing, People's Republic of China.
authors.forename: Weihao
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Urology, PLA Navy General Hospital, Hai dian District, Beijing, People's Republic of China.
authors.forename: Xinyu
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Urology, PLA Navy General Hospital, Hai dian District, Beijing, People's Republic of China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Ouyang
authors.affiliation: Department of Urology, PLA Navy General Hospital, Hai dian District, Beijing, People's Republic of China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Urology, PLA Navy General Hospital, Hai dian District, Beijing, People's Republic of China.
authors.forename: Changliang
authors.initials: C
authors.lastname: Xie
authors.affiliation: Department of Urology, PLA Navy General Hospital, Hai dian District, Beijing, People's Republic of China.
authors.forename: Maojun
authors.initials: M
authors.lastname: Zhou
authors.affiliation: Department of Urology, PLA Navy General Hospital, Hai dian District, Beijing, People's Republic of China.
authors.forename: Cuilong
authors.initials: C
authors.lastname: Liu
mesh_terms: D000273:Adipose Tissue / Q000166:cytology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003131:Combined Modality Therapy; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D004365:Drugs, Chinese Herbal / Q000494:pharmacology; D007172:Erectile Dysfunction / Q000150:complications / Q000628:therapy*; D005419:Flavonoids / Q000494:pharmacology*; D006085:Graft Survival / Q000187:drug effects; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007274:Injections, Intraperitoneal; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016877:Oxidants / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D004365:Drugs, Chinese Herbal; D005419:Flavonoids; D016877:Oxidants; D050796:STAT3 Transcription Factor; D006861:Hydrogen Peroxide; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C056599:icariin