Table 3. ICA /ICA derivatives repair injured penile tissue and modulate tissue endogenous stem cells.
| ICA and ICA derivative | Year of publication | Study design | Study type | Stem cell type | Treatment results | Molecular Mechanisms | Effective dose | STAIR list score (full 7 points) | Key reference |
|---|---|---|---|---|---|---|---|---|---|
| ICAII | 2013 | Streptozotocin-induced diabetic ED rats | In vivo | SMCs | Increased SMC proliferation and decreased the numbers of autophagosomes | Up-regulated NO-cGMP and downregulated mTOR pathway | 10 mg/kg/day | 4 | (24) |
| ICA | 2017 | Male rats with bilateral cavernous nerves injury | In vivo | NSCs | Repaired the damaged neural pathway for erection; Promoted differentiation of endogenous stem cells to Schwann cells | – | 1.5 mg/kg/day | 5 | (25) |
| ICA | 2011 | Streptozotocin-induced diabetic ED rats | In vivo | – | Promoted smooth muscle/collagen ratio and endothelial cell content in the corpora cavernosa | up-regulated vWF and PECAM; down-regulated TGFβ1/Smad2 signaling pathway | 1, 5, and 10 mg/kg/day | 5 | (26) |
| ICAII | 2018 | Zucker Fatty (ZUC-Leprfa 185; ZF) male rats | In vivo | – | Prevented penile smooth muscle atrophy, endothelial dysfunction, and lipid accumulation | – | 1.5 mg/kg/day | 4 | (38) |
| Activated more penile stem cells to proliferate and differentiate | |||||||||
| ICAII | 2014 | Male rats with bilateral cavernous nerves injury | In vivo | – | Prevented distortion of normal neural anatomy, smooth muscle atrophy, and collagen deposition of penile | – | 0.5, 1.5 or 4.5 mg/kg/day | 4 | (39) |
| Promoted differentiation of penile endogenous stem cells | |||||||||
| ICAII | 2016 | Streptozotocin-induced diabetic ED rats | In vivo | – | Increased density of dorsal nerve bundle of penile | Increased NGF expression | 5 mg/kg/day | 5 | (40) |
| YS 10 | 2021 | Male rats with bilateral cavernous nerves injury | In vivo | – | Repaired corpora cavernous nerves injury | Increased β-Catenin and cyclin D1 expression | 2.5 mg/kg/day | 5 | (41) |
| ICA | 2018 | NSCs isolated from rats and EdU labeled | In vitro | NSCs | Increased the number of stem cell spheres | Increased mRNA and protein expression of cell cycle genes cyclin D1 and p21 | 50 & 100 μmol/L | – | (42) |
| ICA | 2014 | NSCs isolated from mice embryos and EdU labeled | In vitro | NSCs | Increased neurosphere formation and NSCs with EdU | Activated ERK/MAPK pathway | 100 μmol/L | – | (43) |
| ICA | 2016 | NSCs isolated from 16‑20‑week human fetuses | In vitro | NSCs | Enhanced NSCs proliferation and neurosphere formation | Upregulated Frizzled 7, DVL3, FGFR1 and down-regulated GSK-3β | 10 μmol/L | – | (44) |
| ICA | 2020 | Aβ25-35-treated hippocampal neural stem cells of rats | In vitro | NSCs | promoted the viability and differentiation into neurons and astrocytes | Activated BDNF-TrkB-ERK/Akt signaling pathway | 20, 40, 80 μmol/L | – | (45) |
| ICA | 2022 | Chronic unpredictable mild stress for depression rat; Corticosterone treated NSCs from rats embryonic hippocampi | In vivo & In vitro | NSCs | Alleviated dysfunctional neurogenesis and neuronal loss | Down-regulated Rps4x, Rps12, Rps14, Rps19, Hsp90b1, and Hsp90aa1 and up-regulated HtrA1 | 120 mg/kg/day in vivo and 20 μmol/L s in vitro | 5 | (46) |
| Promoted neuronal proliferation and differentiation | |||||||||
| ICAII | 2012 | Streptozotocin-induceddiabetic ED rats | In vivo | – | Promoted corpus cavernosum smooth muscle/collagen ratio and endothelial cell content | Down-regulated TGFβ1/Smad2/CTGF and up-regulated NO-cGMP | 1, 5, and 10 mg/kg/day | 4 | (47) |
| ICA | 2019 | High glucose-induced rats bone marrow derived EPCs | In vitro | EPCs | Partially restored EPCs migration and tube formation | Inhibited p38/CREB pathway and activated Akt/eNOS/NO pathway | 1μmol/L | – | (48) |
| ICA | 2015 | H2O2-induced rats bone marrow derived EPCs | In vitro | EPCs | Promoted cell migration and capillary tube formation, abrogated apoptotic and autophagic programmed cell death | Reduced ROS levels and restored ΔΨm; activated rapamycin /p70S6K/4EBP1 and increased ATF2 and ERK1/2 protein levels | 7.5, 15, and 30 µM | – | (49) |
| ICAII | 2020 | Streptozotocin-induced diabetic ED rats | In vivo | SMCs | Increased smooth muscle cell/collagen fibril proportions, decreased mitochondrial autophagy, and AGE concentrations | – | 10 mg/kg/day | 4 | (50) |
| ICA | 2020 | Monocrotaline-Induced Pulmonary Arterial rats | In vivo | – | Decreased right ventricular systolic pressure (RVSP) and the right ventricular hypertrophy index (RI) | Inhibited TGF-β1, Smad2/3, P-Smad2/3, and MMP2 expressions | 50 or 100 mg/kg/day | 4 | (51) |
| ICAII | 2018 | Hemorrhage injection model of subarachnoid hemorrhage rats | In vivo | – | Inhibited subarachnoid fibrosis, attenuated ventriculomegaly, and chronic hydrocephalus | Inhibited TGF-β1/Smad/CTGF signaling pathway | 1, 5, 10 mg/kg/day | 4 | (52) |
ICA, icariin; ICAII, icariside II; NSCs, neural stem cell; EPCs, endothelial progenitor cells; SMCs, smooth muscle cells; TGF-β1, transforming growth factor β1; Smad2, SMAD family member 2; CREB, cAMP response element binding protein; AGE, advanced glycation end products; ERK, extracellular signal-regulated kinase; Akt, protein kinase B; MAPK, mitogen-activated protein kinase; NO, nitric oxide; eNOS, nitric oxide synthase; Frizzled 7, frizzled class receptor 7; DVL3, dishevelled segment polarity protein 3; FGFR1, fibroblast growth factor receptor 1; GSK-3β, Glycogen synthase kinase-3β; ΔΨm, mitochondrial membrane potential; ox-LDL, oxidized low‑density lipoprotein; EdU, 5-ethynyl-2-deoxyuridine; STAIR list, initial stroke therapy academic industry roundtable (evaluation tools commonly used in quality assessment of animal experiments); BDNF, brain-derived neurotrophic factor; cGMP, cyclic guanosine monophosphate; vWF, von Willebrand factor; PECAM, platelet endothelial cell adhesion molecule; NGF, nerve growth factor; ERK, extracellular regulated protein kinases; BDNF, brain derived neurotrophicfactor; TrkB, tyrosine kinase receptor B;CTGF, connective tissue growth factor; p70S6K, ribosomal protein S6 kinase, 70kDa; 4EBP1, 4E-binding protein 1; ATF2, activating transcription factor-2; MMP2, matrix metalloproteinase; Rps4x, ribosomal protein S4 X; Rps12, ribosomal protein 12; Rps14, ribosomal protein 14; Rps19, ribosomal protein 19; Hsp90b1, heat shock protein 90 beta family member 1; and Hsp90aa1, heat shock protein 90 alpha family class A member 1; HtrA1, high-temperature requirement protein A1.