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. 2020 Apr;9(2):416-427.
doi: 10.21037/tau.2020.01.23.

Combined treatment with extracorporeal shockwaves therapy and an herbal formulation for activation of penile progenitor cells and antioxidant activity in diabetic erectile dysfunction

Seung Hwan Jeon  1   2 , Woong Jin Bae  1   2 , Guan Qun Zhu  1   2 , Wenjie Tian  1   2 , Eun Bi Kwon  1   2 , Ga Eun Kim  1   2 , Sung Yeoun Hwang  3 , Kyu Won Lee  1   2 , Hyuk Jin Cho  1 , U-Syn Ha  1 , Sung-Hoo Hong  1 , Ji Youl Lee  1 , Sae Woong Kim  1   2
Affiliations

Combined treatment with extracorporeal shockwaves therapy and an herbal formulation for activation of penile progenitor cells and antioxidant activity in diabetic erectile dysfunction

Seung Hwan Jeon et al. Transl Androl Urol. 2020 Apr.

Abstract

Background: A Korean herbal formulation named KH-204 was reported to have an antioxidant effect in our previous study. We hypothesized that Low-intensity extracorporeal shockwave therapy (Li-ESWT) combined with KH-204 would accelerate the treatment of erectile dysfunction (ED) by enhancing antioxidant. We investigated the synergistic effect of Li-ESWT and KH-204 for ED and explored the mechanism.

Methods: Human umbilical vein endothelial cells (HUVEC) were treated with KH-204 and LI-ESWT in vitro. Fifty 5-week-old male Sprague Dawley rats received an intraperitoneal injection of 5-ethynyl-20-deoxyuridine (EdU) which can label live cells, and were randomly divided into five groups: (I) normal; (II) diabetes mellitus-associated erectile dysfunction (DMED); (III) DMED + KH-204; (IV) DMED + Li-ESWT; and (V) DMED + KH-204/Li-ESWT. Li-ESWT treatment was repeated three times a week every other day for four weeks in group 4 and 5. Meanwhile, rats in group 3 and 5 were orally fed 400 mg/kg of KH-204 daily for 1 month. Following a 1-week washout period, penile tissues were evaluated by immunostaining and Western blotting.

Results: KH-204 combined with Li-ESWT improved intracavernosal pressure (ICP) in DMED rats. Li-ESWT/KH-204 stimulated HUVEC tube formation and promoted proliferation. Li-ESWT drove progenitor cells to migrate to penile tissue and KH-204 protected penile progenitor cells in the corpus cavernosum. Oxidative stress was relieved by KH-204/Li-ESWT. Treatment with KH-204/Li-ESWT protected penile progenitor cells, which were recruited to the corpus cavernosum by Li-ESWT, from apoptosis via its antioxidant activity. KH-204/Li-ESWT protected penile tissue from oxidative stress by improving the expression of nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1), increasing superoxide dismutase (SOD), decreasing 8-hydroxy-20-deoxyguanosine (8-OHdG), and reducing apoptosis. KH-204/Li-ESWT promoted stromal derived factor-1 (SDF-1) and platelet endothelial cell adhesion molecule-1 (PECAM-1) in DMED rats.

Conclusions: KH-204 protected penile progenitor cells, which were recruited to the corpus cavernosum by Li-ESWT, from apoptosis via its antioxidant activity. The combination of Li-ESWT and KH-204 as a synergy therapy could be a potential and effective treatment for DMED.

Keywords: Low-intensity extracorporeal shockwave therapy; antioxidant; diabetes mellitus; erectile dysfunction (ED); herbal formulation; progenitor cells.

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Conflict of interest statement

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tau.2020.01.23). The authors have no conflicts of interest to declare.

Figures

Figure 1
Figure 1
Erectile function of each group. (A) Representative images of intracavernous pressure (ICP) in response to electrical stimulation of the cavernosal nerve; (B) results of the ratio of ICP to the mean MAP of each group. Each bar shows the mean values (standard deviation). *, P<0.01 compared with DMED rats; **, P<0.05 compared with DM + ESWT and DM + MSCT groups.
Figure 2
Figure 2
KH-204/Li-ESWT promotes tube formation in vitro and stimulated proliferation in vivo. (A) Representative images of IB4 and H3P. After KH-204 and Li-ESWT treatment, the expression of H3P and IB4 was increased. Original magnification: ×200. (B) Fluorescence microscopy images showing formation of tube network. Original magnification: ×50. (C) Quantitative results of the total meshes in each group. *, P<0.05 compared with DMED group; **, P<0.01 compared with DMED group.
Figure 3
Figure 3
KH-204 maintains penile progenitor cells survival after Li-ESWT homed them to the corpus cavernosum. (A) Representative images of corpus cavernosum. Original magnification: ×200. (B) Quantitative results of EdU-labelled cells. *, P<0.05 compared with DMED group; **, P<0.01 compared with DMED group.
Figure 4
Figure 4
Oxidative stress is relieved by KH-204/Li-ESWT through the Nrf2/HO-1 pathway. (A) and (B) are representative results of 8-OHdG and SOD analyzed by ELISA in each group. #, &, P<0.05 compared to DMED group. (C) Western blot results of each group in the corpus cavernosum. (D) Relative band densities of Western blot results in each group. *, P<0.05 compared to DMED group; **, P<0.01 compared to DMED group.
Figure 5
Figure 5
KH-204/Li-ESWT decreases apoptosis in DMED rats. (A) Representative images of TUNEL in the corpus cavernosum. Apoptotic cells are red, blue are DAPI-labelled cells. Original magnification: ×200. (B) Apoptosis index. *, P<0.05 compared to DMED group; **, P<0.01 compared to DMED group.
Figure 6
Figure 6
Li-ESWT increases nNOS expression in the corpus cavernosum. (A) Representative images of nNOS staining in the corpus cavernosum; (B) the ratio of positive nNOS in each group. Each bar shows the mean values (standard deviation). Original magnification: ×400. *, P<0.01 compared with DMED control group.
Figure 7
Figure 7
KH-204/Li-ESWT promotes SDF-1 and PECAM-1 expression in vivo. (A) Western blot results of each group in the corpus cavernosum; (B) relative band densitities of the Western blot results in each group. *, P<0.05 compared to DMED group; **, P<0.01 compared to DMED group.
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