Panax ginseng (C.A. Mey.) has been traditionally employed in Korea and China to alleviate fatigue and digestive disorders. In particular, Korean red ginseng (KRG), derived from streamed and dried P. ginseng, is known for its anti-aging and anti-inflammatory properties. However, its effects on benign prostatic hyperplasia (BPH), a representative aging-related disease, and the underlying mechanisms remain unclear. This study aims to elucidate the therapeutic effects of KRG on BPH, with a particular focus on mitochondrial dynamics, including fission and fusion processes. The effects of KRG on cell proliferation, apoptosis, and mitochondrial dynamics and morphology were evaluated in a rat model of testosterone propionate (TP)-induced BPH and TP-treated LNCaP cells, with mdivi-1 as a control. The results revealed that KRG treatment reduced the levels of androgen receptors (AR) and prostate-specific antigens in the BPH group. KRG inhibited cell proliferation by downregulating cyclin D and proliferating cell nuclear antigen (PCNA) levels, and it promoted apoptosis by increasing the ratio of B-cell lymphoma protein 2 (Bcl-2)-associated X protein (Bax) to Bcl-2 expression. Notably, KRG treatment enhanced the phosphorylation of dynamin-related protein 1 (DRP-1, serine 637) compared with that in the BPH group, which inhibited mitochondrial fission and led to mitochondrial elongation. This modulation of mitochondrial dynamics was associated with decreased cell proliferation and increased apoptosis. By dysregulating AR signaling and inhibiting mitochondrial fission through enhanced DRP-1 (ser637) phosphorylation, KRG effectively reduced cell proliferation and induced apoptosis. These findings suggest that KRG’s regulation of mitochondrial dynamics offers a promising clinical approach for the treatment of BPH.
| [1] |
Berry SJ, Coffey DS, Walsh PC, et al. The development of human benign prostatic hyperplasia with age[J]. J Urol, 1984, 132(3): 474-479.
|
| [2] |
Lee KL, Peehl DM. Molecular and cellular pathogenesis of benign prostatic hyperplasia[J]. J Urol, 2004, 172(5 Pt)1: 1784-1791.
|
| [3] |
Carson C, Rittmaster R. The role of dihydrotestosterone in benign prostatic hyperplasia[J]. Urology, 2003, 61(4Suppl 1): 2-7.
|
| [4] |
Kyprianou N, Tu H, Jacobs SC. Apoptotic versus proliferative activities in human benign prostatic hyperplasia[J]. Hum Pathol, 1996, 27(7): 668-675.
|
| [5] |
Li Y, Wang Q, Li J, et al. SIRT3 affects mitochondrial metabolic reprogramming via the AMPK-PGC-1alpha axis in the development of benign prostatic hyperplasia[J]. Prostate, 2021, 81(15): 1135-1148.
|
| [6] |
Archer SL. Mitochondrial dynamics: mitochondrial fission and fusion in human diseases[J]. N Engl J Med, 2013, 369(23): 2236-2251.
|
| [7] |
Hall AR, Burke N, Dongworth RK, et al. Mitochondrial fusion and fission proteins: novel therapeutic targets for combating cardiovascular disease[J]. Br J Pharmacol, 2014, 171(8): 1890-1906.
|
| [8] |
Tilokani L, Nagashima S, Paupe V, et al. Mitochondrial dynamics: overview of molecular mechanisms[J]. Essays Biochem, 2018, 62(3): 341-360.
|
| [9] |
Yu R, Lendahl U, Nistér M, et al. Regulation of mammalian mitochondrial dynamics: opportunities and challenges[J]. Front Endocrinol (Lausanne), 2020, 11: 374.
|
| [10] |
Lee HC, Wei YH. Mitochondria and aging[J]. Adv Exp Med Biol, 2012, 942: 311-327.
|
| [11] |
Jun H. Donguibogam[M]. Jinhan M&B: 2020.
|
| [12] |
Liu CX, Xiao PG. Recent advances on ginseng research in China[J]. J Ethnopharmacol, 1992, 36(1): 27-38.
|
| [13] |
Jeong YA, Kim BR, Kim DY, et al. Korean red ginseng extract increases apoptosis by activation of the noxa pathway in colorectal cancer[J]. Nutrients, 2019, 11(9): 2026.
|
| [14] |
Baek KS, Yi YS, Son YJ, et al. In vitro and in vivo anti-inflammatory activities of Korean red ginseng-derived components[J]. J Ginseng Res, 2016, 40(4): 437-444.
|
| [15] |
Shin KK, Yi YS, Kim JK, et al. Korean red ginseng plays an anti-aging role by modulating expression of aging-related genes and immune cell subsets[J]. Molecules, 2020, 25(7): 1492.
|
| [16] |
Shin SJ, Nam Y, Park YH, et al. Therapeutic effects of non-saponin fraction with rich polysaccharide from Korean red ginseng on aging and Alzheimer’s disease[J]. Free Radic Biol Med, 2021, 164: 233-248.
|
| [17] |
Park HK, Kim SK, Lee SW, et al. A herbal formula, comprising Panax ginseng and bee-pollen, inhibits development of testosterone-induced benign prostatic hyperplasia in male Wistar rats[J]. Saudi J Biol Sci, 2017, 24(7): 1555-1561.
|
| [18] |
Kim SK, Chung JH, Lee BC, et al. Influence of Panax ginseng on alpha-adrenergic receptor of benign prostatic hyperplasia[J]. Int Neurourol J, 2014, 18(4): 179-186.
|
| [19] |
Bae BS, Lee MW, Lee JS, et al. Comparison of the constituents of processed Korean and American ginseng grown in Korea siz years[J]. Korean J Med Crop Sci, 2021, 29(1): 35-44.
|
| [20] |
Hong GL, Park SR, Jung DY, et al. The therapeutic effects of Stauntonia hexaphylla in benign prostate hyperplasia are mediated by the regulation of androgen receptors and 5 alpha-reductase type 2[J]. J Ethnopharmacol, 2020, 250: 112446.
|
| [21] |
Smith G, Gallo G. To mdivi-1 or not to mdivi-1: is that the question[J]. Dev Neurobiol, 2017, 77(11): 1260-1268.
|
| [22] |
Manczak M, Kandimalla R, Yin X, et al. Mitochondrial division inhibitor 1 reduces dynamin-related protein 1 and mitochondrial fission activity[J]. Hum Mol Genet, 2019, 28(2): 177-199.
|
| [23] |
Schleiff E, Turnbull JL. Functional and structural properties of the mitochondrial outer membrane receptor Tom20[J]. Biochemistry, 1998, 37(38): 13043-13051.
|
| [24] |
Yin J, Zhang H, Ye J. Traditional Chinese medicine in treatment of metabolic syndrome[J]. Endocr Metab Immune Disord Drug Targets, 2008, 8(2): 99-111.
|
| [25] |
Lee JY, Kim S, Kim S, et al. Effects of red ginseng oil (KGC11o) on testosterone-propionate-induced benign prostatic hyperplasia[J]. J Ginseng Res, 2022, 46(3): 473-480.
|
| [26] |
Bae JS, Park HS, Park JW, et al. Red ginseng and 20(S)-Rg 3 control testosterone-induced prostate hyperplasia by deregulating androgen receptor signaling [J]. J Nat Med, 2012, 66( 3): 476-485.
|
| [27] |
Cornu JN, Oelke M, Parsons KF. Benign prostatic hyperplasia and lower urinary tract symptoms[J]. N Engl J Med, 2012, 367(17): 1668.
|
| [28] |
Isaacs JT, Isaacs WB. Androgen receptor outwits prostate cancer drugs[J]. Nat Med, 2004, 10(1): 26-27.
|
| [29] |
Youle RJ, van-der Bliek AM. Mitochondrial fission, fusion, and stress[J]. Science, 2012, 337(6098): 1062-1065.
|
| [30] |
Chen H, Chomyn A, Chan DC. Disruption of fusion results in mitochondrial heterogeneity and dysfunction[J]. J Biol Chem, 2005, 280(28): 26185-26192.
|
| [31] |
Hu C, Huang Y, Li L. Drp1-dependent mitochondrial fission plays critical roles in physiological and pathological progresses in mammals[J]. Int J Mol Sci, 2017, 18(1): 144.
|
| [32] |
Dal YF, Kim SH, Ding Z, et al. Mitochondrial dynamic alterations regulate melanoma cell progression[J]. J Cell Biochem, 2019, 120(2): 2098-2108.
|
| [33] |
Lennon FE, Salgia R. Mitochondrial dynamics: biology and therapy in lung cancer[J]. Expert Opin Investig Drugs, 2014, 23(5): 675-692.
|
| [34] |
Bastian P, Dulski J, Roszmann A, et al. Regulation of mitochondrial dynamics in Parkinson’s disease: is 2-methoxyestradiol a missing piece[J]. Antioxidants (Basel), 2021, 10(2): 248.
|
| [35] |
Smirnova E, Griparic L, Shurland DL, et al. Dynamin-related protein Drp1 is required for mitochondrial division in mammalian cells[J]. Mol Biol Cell, 2001, 12(8): 2245-2256.
|
| [36] |
Lee YG, Nam Y, Shin KJ, et al. Androgen-induced expression of DRP1 regulates mitochondrial metabolic reprogramming in prostate cancer[J]. Cancer Lett, 2020, 471: 72-87.
|
| [37] |
Prieto J, León M, Ponsoda X, et al. Early ERK1/2 activation promotes DRP1-dependent mitochondrial fission necessary for cell reprogramming[J]. Nat Commun, 2016, 7: 11124.
|
| [38] |
Cribbs JT, Strack S. Reversible phosphorylation of Drp1 by cyclic AMP-dependent protein kinase and calcineurin regulates mitochondrial fission and cell death[J]. EMBO Rep, 2007, 8(10): 939-944.
|
| [39] |
Youle RJ, Karbowski M. Mitochondrial fission in apoptosis[J]. Nat Rev Mol Cell Biol, 2005, 6(8): 657-663.
|
| [40] |
Traish AM. Negative impact of testosterone deficiency and 5alpha-reductase inhibitors therapy on metabolic and sexual function in men[J]. Adv Exp Med Biol, 2017, 1043: 473-526.
|
Funding
2021 Grant from the Korean Society of Ginseng(2022YFC3502100)
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