Chemical Properties, Preparation, and Pharmaceutical Effects of Cyclic Peptides from Pseudostellaria heterophylla
Abstract
:1. Introduction
2. Chemical Features of Cyclic Peptides from P. heterophylla
No. | Compound | Ring Size (aa) | Structure | Mw (m/z) | Ref. |
---|---|---|---|---|---|
1 | Heterophyllin A | 7 | Cyclo(Thr-Pro-Val-Ile-Phe-Gly-Ile) | 727.9 | [16] |
2 | Heterophyllin B | 8 | Cyclo(Gly-Gly-Leu-Pro-Pro-Pro-Ile-Phe) | 778.9 | [16] |
3 | Heterophyllin C | 7 | Cyclo(Gly-Pro-Ile-Ile-Pro-Ile-Leu) | 703.9 | [17] |
4 | Heterophyllin D | 6 | Cyclo(Gly-Phe-Ile-Thr-Val-Phe) | 664.8 | [23] |
5 | Heterophyllin E | 10 | Cyclo(Val-Tyr-Ala-Gly-Pro-Tyr-Leu-Ala-Gly-Pro) | 989.1 | [23] |
6 | Heterophyllin F | 6 | Cyclo(Ile-Ile-Leu-Leu-Leu-Gly) | 622.8 | [23] |
7 | Heterophyllin G | 7 | Cyclo(Pro-Val-Ile-Phe-Gly-Ile-[Thr-O(CH2)4CH3]) | 798.0 | [23] |
8 | Heterophyllin H | 2 | Cyclo(Tyr-Pro) | 260.3 | [23] |
9 | Heterophyllin J | 5 | Cyclo(Ala-Gly-Pro-Val-Tyr) | 487.6 | [18] |
10 | Pseudostellarin A | 5 | Cyclo(Gly-Pro-Tyr-Leu-Ala) | 501.6 | [19] |
11 | Pseudostellarin B | 8 | Cyclo(Gly-Ile-Gly-Gly-Gly-Pro-Pro-Phe) | 682.8 | [19] |
12 | Pseudostellarin C | 8 | Cyclo(Gly-Thr-Leu-Pro-Ser-Pro-Phe-Leu) | 812.9 | [19] |
13 | Pseudostellarin D | 7 | Cyclo(Gly-Gly-Tyr-Pro-Leu-Ile-Leu) | 713.9 | [20] |
14 | Pseudostellarin E | 9 | Cyclo(Gly-Pro-Pro-Leu-Gly-Pro-Val-Ile-Phe) | 878.1 | [20] |
15 | Pseudostellarin F | 8 | Cyclo(Gly-Gly-Tyr-Leu-Pro-Pro-Leu-Ala-Pro) | 784.9 | [20] |
16 | Pseudostellarin G | 8 | Cyclo(Phe-Ser-Phe-Gly-Pro-Leu-Ala-Pro) | 816.9 | [21] |
17 | Pseudostellarin H | 8 | Cyclo(Gly-Thr-Pro-Thr-Pro-Leu-Phe-Phe) | 861.0 | [21] |
18 | Pseudostellarin K | 6 | Cyclo(Ile-Phe-Gly-Thr-Val-Phe) | 664.8 | [3] |
19 | Pseudostellarin L | 5 | Cyclo(Pro-Gly-Tyr-Phe-Val) | 563.7 | [22] |
3. Preparation for Cyclic Peptides from P. heterophylla
3.1. Direct Extraction and Separation
3.2. Biosynthesis
3.3. Chemical Synthesis
4. Pharmacokinetic Characteristics
5. Biological Activities of Cyclic Peptides from P. heterophylla
5.1. Anti-Tumor Activity
5.2. Anti-Inflammatory Activity
5.3. Antioxidant Activity
5.4. Anti-Tussive Activity
5.5. Hypoglycemic Activity
5.6. Promoting Angiogenic Activity
5.7. Modulating Gut Microbiota
5.8. Enhancing Cognitive Function
5.9. Inhibiting Tyrosinase Activity
5.10. Anti-Fibrotic Effects
6. Conclusions and Prospectives
Author Contributions
Funding
Conflicts of Interest
References
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Parameters | 2.08 mg/kg [39] | 4.16 mg/kg [39] | 8.32 mg/kg [39] | 20 mg/kg [40] |
---|---|---|---|---|
Cmax (ng/mL) | 1372 ± 148 | 2446 ± 242 | 4666 ± 192 | 4082.76 ± 892.20 |
Tmax (min) | 5 | 5 | 10 | 3.0 ± 1.8 |
T1/2 (min) | 39.9 ± 14.6 | 48.6 ± 11.2 | 64.8 ± 14.5 | 574.2 ± 160.2 |
MRT0–t (min) | 23.1 ± 3.5 21 | 23.3 ± 3.7 | 21.8 ± 2.2 | 54.0 ± 16.2 |
MRT0–∞ (min) | 26.5 ± 3.6 | 24.6 ± 4.3 | 22.6 ± 2.6 | 92.4 ± 25.8 |
AUC0–t (ng·min/mL) | 29,043 ± 5221 | 48,312 ± 2747 | 116,838 ± 12,018 | 42,100 ± 1170 |
AUC0–∞ (ng·min/mL) | 29,451 ± 5033 | 48,489 ± 2811 | 117,006 ± 11,947 | 718.02 ± 19.77 |
Vd (L/kg) | 4.38 ± 2.35 | 5.99 ± 1.18 | 6.79 ± 1.94 | 383,460.70 ± 1003.09 |
CL (L/min/kg) | 0.072 ± 0.013 | 0.086 ± 0.005 | 0.071 ± 0.007 | 464.48 ± 12.99 |
Ke (1/h) | 0.08 ± 0.02 |
Compound | Types | Testing Subjects | Doses/Duration/Route | Effects | Mechanism | Ref. |
---|---|---|---|---|---|---|
HB | In vitro | OVCAR-8 andSKOV3 cells | 0, 25, 50, 75, 100 μM for 24 h | Cell proliferation ↓; Colony formation↓; Apoptosis ↑; | NRF2 and HO-1 expression ↓; Involved in apoptosis induction. | [43] |
MKN-4 and BGC-823 cells | 0, 10, 25, and 50 μM for 24–48 h | Cell proliferation ↓; Apoptosis ↑; Arrested cell cycle at G0/G1 phase; | Activates ER stress by upregulating IRE1, CHOP, GRP78, downregulating Bcl-2, and facilitating caspase-3 expression. | [44] | ||
ECA-109 cells | 10, 25, 50 μM, 24 h | Adhesion and invasion ↓; Cell proliferation ↓; E-cadherin expression ↑; | PI3K/AKT/β-catenin pathway ↓; Snail, Vimentin, MMP-2/9 ↓; E-cadherin ↑; | [45] | ||
HGC-27 and AGS cells | 0, 10, 20, 40, 60, 80, 100 μM for 24 h | Cell viability, colony formation, migration, and invasion ↓; | Binds to CXCR4, PI3K/AKT signaling pathway; PD-L1 expression, metastasis ↓; | [46] | ||
In vivo | OVCAR8 xenografted nude mice | 20 mg/kg/day, i.p., 35 days | Tumor growth ↓; Tumor volume ↓; Ki67 expression ↑; | Tumor proliferation via NRF2/HO-1 inhibition; Apoptosis in tumor tissues ↑; | [43] | |
MKN-45 cells-induced tumor model in nude mice | 10, 15 mg/kg/2 days, i.p., 28 days | Tumor growth, tumor weight ↓; IRE1, CHOP, GRP78 ↑; Bcl-2 ↓; | ER stress activation through IRE1, CHOP, GRP78, Bcl-2 suppression, leading to apoptosis and inhibited tumor growth. | [44] | ||
HGC-27 cells-induced tumor metastasis model in nude mice | 500 mg/kg/day, i.g., 14 days | Tumor metastasis ↓; Lung metastatic nodules ↓; | Targets CXCR4 and modulates PI3K/AKT signaling; PD-L1 expression, tumor cell migration/invasion ↓; | [46] |
Compound | Types | Testing Subjects | Doses/Duration/Route | Effects | Mechanism | Ref. |
---|---|---|---|---|---|---|
HB | In vitro | LPS-stimulated RAW 264.7 cells | 25, 50, 100 μM, 1 h | LPS-induced NO, IL-6, and IL-1β production ↓; ROS generation ↓; Apoptosis ↓; | Suppression of inflammation and oxidative stress through the PI3K/Akt pathway; p-AKT/AKT and p-PI3K/PI3K ratios ↑; | [47] |
In vivo | SCI contusion model in C57BL/6J mice | 20 mg/kg/day, i.p., 3 days | Motor function ↑; Axonal regeneration ↑; Bladder recovery ↑; | Activates autophagy by enhancing TFEB translocation; Suppresses oxidative stress and pyroptosis by the AMPK-TRPML1-calcineurin pathway. | [48] | |
DSS (4% Dextran Sulfate Sodium)-induced colitis in C57BL/6J mice | 20, 80 mg/kg/day, i.g., 7 days | Disease activity index↓; Colon length ↑; Histological damage, and inflammation ↓; | Restored the intestinal mucosal barrier, improved microbiota composition, and reduced inflammatory cytokines. | [49] |
Extract | Types | Testing Subjects | Doses/Duration/Route | Effects | Mechanism | Ref. |
---|---|---|---|---|---|---|
CPE | In vitro | Alveolar macrophages | 50, 100, 200, 500, 1000, and 2000 μg/mL for 12, 24, and 48 h | TNF-α release ↓; IL-10 release ↑; Inflammation ↓; | TLR4, MyD88, and AP-1 mRNA levels ↓; JNK/p38 signaling pathways ↓; Pro-inflammatory cytokine release ↑; | [55] |
In vivo | Smoky environment + Papain aerosol to induce LQIS-COPD rats | 100, 200, 400 mg/kg/d, i.g., 30 days | Cough, shortness of breath, wheezing ↓; RL ↓; Balanced Cdyn; | Improved lung function by reducing RL and enhancing Cdyn; effects may be due to the restoration of lung qi and inhibition of inflammation. | [54] | |
SCS-induced COPD model rats | 200, 400, 500 mg/kg/day, p.o., 15 days | Lung function ↑; Alveolar destruction ↓; Alveolar space ↑; | TLR4-MyD88 signaling pathway ↓; Inflammatory cytokines (TNF-α, IL-10) ↓; Lung tissue morphology and function ↑; | [55] |
Compound | Types | Testing Subjects | Doses/Duration/Route | Effects | Mechanism | Ref. |
---|---|---|---|---|---|---|
HB | In vitro | HUVEC cells | 0–200 μg/mL for 48 h | Cell proliferation ↑ (0–100 μg/mL HB); Cell proliferation ↓ (150–200 μg/mL HB); | Promoted cell proliferation through increased VEGF expression and activation of the MAPK signaling pathway (Ras/Raf/Mek/Erk). | [58] |
HB | In vivo | CAM | 0–10 mg/mL/day, 3 days | Vascular proliferation (5 mg/mL/day) ↓; Blood vessel growth (10 mg/mL/da) ↑; | Promoted angiogenesis by influencing growth factors (e.g., VEGF) and their signaling pathways. | [58] |
Compound | Types | Testing Subjects | Doses/Duration/Route | Effects | Mechanism | Ref. |
---|---|---|---|---|---|---|
HB | In vitro | NCM460 cells | 0.1–10 μM, 24 h | Occludin and ZO-1 expression ↑; Disruption of the epithelial barrier induced by TNF-α ↓; | AMPK signaling ↑; Maintain intestinal epithelial barrier function. | [49] |
HB | In vivo | DSS-induced colitis in mice. | 20, 80 mg/kg/day, i.g., 7 days | Colon length ↑; Inflammation ↓; Deterioration of the intestinal mucosal barrier. | Protects beneficial intestinal bacteria, restores gut health, and protects against colitis. | [49] |
Compound | Types | Testing Subjects | Doses/Duration/Route | Effects | Mechanism | Ref. |
---|---|---|---|---|---|---|
HB | In vitro | Aβ25-35-induced primary cortical neurons | 1, 10 μM, 4 days | Neuron death ↓; | Apoptosis markers (Bax) ↓; Anti-apoptotic markers (Bcl-2) ↑; Synaptic protein levels were preserved; | [61] |
SH-SY5Y cells | 0.1–10 μM, 1–3 days | Aβ-induced cell damage ↓; | Aβ-induced neuronal apoptosis ↓; Synaptic regeneration↑; | [61] | ||
Aβ25-35-induced primary cortical neurons | 1–100 μM | Neuronal survival rate ↑; Aβ25-35-induced cell damage ↓; | Expression of apoptosis-related genes (P53 and Caspase3) ↓; β3-tubulin and MAP2-positive neurite density ↑; Synaptic plasticity ↑; | [62] | ||
Primary cortical neurons | 0.011 μM, 4 days | β3-tubulin-positive neurite density ↑; Neurite outgrowth ↑; | Promotes cognitive enhancement and neuroprotection through neuronal growth. | [63] | ||
In vivo | Aβ1-42 i.c.v.-induced AD mice | 1, 10 μM/kg/day, i.p., 16 days | Memory deficits ↓; Cognitive performance ↑; Neuroinflammation. ↓; | Microglial activation ↓; Axonal regeneration ↑; Modulation of inflammatory cytokines. | [61] | |
APP/PS1 transgenic mice | 10 μM/kg/day, i.p., 60 days | Novel object recognition and spatial memory ↑; Exploration of new locations; | Expression of apoptosis-related genes (P53 and Caspase3) ↓; Neuronal survival rate, neurite density, neural connectivity ↑; | [62] | ||
ICR mice | 1 and 10 μM/kg, i.p., 10 days | Object recognition and location memory ↑; Neurite outgrowth ↑; | Penetrates the blood–brain barrier and regulates dopamine turnover, leading to cognitive improvements and enhanced memory function. | [63] |
Compounds | Type | Testing Subjects | Effects | Ref. |
---|---|---|---|---|
PA | In vitro | Tyrosinase solution | IC50: 187 μM | [20] |
PB | Tyrosinase solution | 43% tyrosinase inhibition at 4.98 μg/mL | [65] | |
PB | Tyrosinase solution | IC50: 187 μM | [20] | |
PC | Tyrosinase solution | IC50: 63 μM | [20] | |
PC | Mouse B16 melanoma cells | IC50: 134 μM | [20] | |
PD | Tyrosinase solution | IC50: 100 μM | [21] | |
PD | Mouse B16 melanoma cells | IC50: 49 μM | [21] | |
PE | Tyrosinase solution | IC50: 175 μM | [21] | |
PF | Tyrosinase solution | IC50: 50 μM | [21] | |
PG | Tyrosinase solution | IC50: 75 μM | [3] | |
PH | Tyrosinase solution | 15% tyrosinase inhibition at 800 μM | [66] |
Compound | Types | Testing Subjects | Doses/Duration/Route | Effects | Mechanism | Ref. |
---|---|---|---|---|---|---|
HB | In vitro | MLE-12 cells | 0.5 mg/mL, 1 day | ROS ↓; Ferroptosis ↓; Preserved mitochondrial mass; | Suppressed ferroptosis via IDO1-mediated Fe2+ accumulation and oxidative stress reduction. | [60] |
A549 cells | 0.5 mg/mL, 1 day | Lung fibrosis ↓; ROS and collagen deposition ↓; | IDO1-mediated ferroptosis suppression. | [60] | ||
NCM460 cells | 0.5 mg/mL, 1 day | Restored colonic epithelial integrity; Oxidative damage ↓; | Modulated ferroptosis and re-established intestinal mucosal barrier. | [60] | ||
MLE-12 cells | 1, 10, 20, 50, 100 μM, 1 day | Inhibited TGF-β1-induced EMT in alveolar cells; | Inhibited the expression of Vimentin and promoted E-cadherin expression; AMPK activation reduced STING expression. | [66] | ||
Primary lung fibroblasts | 1, 10, 20, 50, 100 μM, 2 days | Fibroblast transdifferentiation ↓; ECM deposition ↓; | AMPK pathway ↑; STING expression ↓; TGF-β1 signaling in fibroblasts ↓; | [66] | ||
In vivo | BLM-induced PF in mice | 20 mg/kg/day, i.g., 21 days | Collagen I deposition ↓; Restored intestinal barrier; | Enriched M. intestinale and promoted the production of 3-HA, which modulates IDO1-mediated ferroptosis. | [60] | |
Antibiotic-induced microbiota depletion in mice | 20 mg/kg/day, i.g., 7 days | Restored intestinal mucosal barrier; PF symptoms↓; | Increased 3-HA production and reprogramed the intestinal ecosystem to modulate the gut microbiota and alleviate PF. | [60] | ||
C57BL/6 Mice (PF model induced by BLM): | 5 and 20 mg/kg/day, p.o., 14 days | Fibrosis and collagen deposition in lungs ↓; | AMPK ↑; STING expression ↓; TGF-β1/Smad2/3 signaling ↓; ECM deposition and fibroblast accumulation ↓. | [66] |
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Yang, Y.; Wen, L.; Jiang, Z.-Z.; Chan, B.C.-L.; Leung, P.-C.; Wong, C.-K.; Tan, N.-H. Chemical Properties, Preparation, and Pharmaceutical Effects of Cyclic Peptides from Pseudostellaria heterophylla. Molecules 2025, 30, 2521. https://doi.org/10.3390/molecules30122521
Yang Y, Wen L, Jiang Z-Z, Chan BC-L, Leung P-C, Wong C-K, Tan N-H. Chemical Properties, Preparation, and Pharmaceutical Effects of Cyclic Peptides from Pseudostellaria heterophylla. Molecules. 2025; 30(12):2521. https://doi.org/10.3390/molecules30122521
Chicago/Turabian StyleYang, Yue, Luan Wen, Zhuang-Zhuang Jiang, Ben Chung-Lap Chan, Ping-Chung Leung, Chun-Kwok Wong, and Ning-Hua Tan. 2025. "Chemical Properties, Preparation, and Pharmaceutical Effects of Cyclic Peptides from Pseudostellaria heterophylla" Molecules 30, no. 12: 2521. https://doi.org/10.3390/molecules30122521
APA StyleYang, Y., Wen, L., Jiang, Z.-Z., Chan, B. C.-L., Leung, P.-C., Wong, C.-K., & Tan, N.-H. (2025). Chemical Properties, Preparation, and Pharmaceutical Effects of Cyclic Peptides from Pseudostellaria heterophylla. Molecules, 30(12), 2521. https://doi.org/10.3390/molecules30122521