Key Takeaways & Executive Findings
- •• Chlorella peptides exert multi-target synergistic regulatory effects on key pathological links of rheumatoid arthritis, including oxidative stress, macrophage polarization, synovial fibroblast invasion, and vascular endothelial dysfunction. • An optimized extraction process using bromelain enzymatic hydrolysis combined with phosphomolybdic acid precipitation was established, achieving high peptide yield with low cost and scalability. • Chlorella peptides exhibit concentration-dependent antioxidant activity and good biocompatibility in the effective concentration range (1-10 μg/mL), supporting their safety for potential clinical translation. • Chlorella peptides promote M2 macrophage polarization, inhibit fibroblast-like synoviocyte migration, proliferation, and invasion, and suppress endothelial cell migration and tube formation, highlighting their therapeutic potential in rheumatoid arthritis.
Abstract
BACKGROUND: Recent studies have shown that Chlorella possesses potential value in treating rheumatoid arthritis. The pathological progression of rheumatoid arthritis is closely associated with an imbalance in oxidative stress, abnormal macrophage polarization, aggressive activation of fibroblast-like synoviocytes, and disturbances in the vascular endothelial system. However, the optimization of extraction processes for peptides derived from Chlorella and their regulatory effects on key pathological links of rheumatoid arthritis remain to be systematically validated. OBJECTIVE: To optimize the extraction process of antioxidant peptides from Chlorella, clarify their antioxidant activity and biosafety, and explore their regulatory effects on pathological phenotypes of rheumatoid arthritis-related cells (RAW 264.7 mouse monocyte macrophage leukemia cells, fibroblast-like synoviocytes, and human umbilical vein endothelial cells), providing experimental evidence for the treatment of rheumatoid arthritis with Chlorella peptides. METHODS: (1) Chlorella peptide extract was prepared by bromelain enzymatic hydrolysis combined with phosphomolybdic acid precipitation. Using peptide yield as the evaluation index, the extraction process parameters were optimized by single-factor experiments, including solid-liquid ratio, enzymatic hydrolysis time, and reaction system pH. (2) The peptide content was determined by BCA method, antioxidant capacity was detected by ABTS method, and biosafety of peptides on RAW 264.7 cells, fibroblast-like synoviocytes, and human umbilical vein endothelial cells was evaluated by CCK-8 method. (3) An inflammatory model of RAW 264.7 cells induced by lipopolysaccharide was established. The effects of peptides on intracellular reactive oxygen species levels and M1/M2 polarization phenotypes were detected by DCFH-DA staining, flow cytometry, and real-time fluorescence quantitative reverse transcription polymerase chain reaction. (4) An activation model of fibroblast-like synoviocytes induced by tumor necrosis factor-alpha was established. The effects of peptides on migration, proliferation, invasion, and related gene expression of fibroblast-like synoviocytes were detected by wound healing assay, EdU proliferation assay, Transwell invasion assay, and real-time fluorescence quantitative reverse transcription polymerase chain reaction. (5) An abnormal activation model of human umbilical vein endothelial cells induced by vascular endothelial growth factor A was established. The effects of peptides on migration, tube formation, and expression of hypoxia-inducible factor 1 alpha and vascular endothelial growth factor A genes were detected by wound healing assay, Transwell assay, tube formation assay, and real-time fluorescence quantitative reverse transcription polymerase chain reaction. RESULTS AND CONCLUSION: (1) The optimal extraction process for Chlorella peptides was solid-liquid ratio of 2:1 (g:100 mL), enzymatic hydrolysis time of 60 minutes, and reaction system pH of 6.5, yielding the highest peptide yield. (2) Chlorella peptides exhibited concentration-dependent antioxidant activity and showed no obvious toxicity to RAW 264.7 cells, fibroblast-like synoviocytes, and human umbilical vein endothelial cells in the concentration range of 1-10 μg/mL, indicating good biocompatibility. (3) Chlorella peptides dose-dependently inhibited lipopolysaccharide-induced reactive oxygen species generation in RAW 264.7 cells, downregulated M1 pro-inflammatory genes such as interleukin-1 beta and tumor necrosis factor-alpha, upregulated M2 anti-inflammatory genes such as interleukin-10 and arginase 1, and promoted macrophage polarization from M1 to M2 phenotype. (4) Chlorella peptides significantly inhibited tumor necrosis factor-alpha-induced migration, proliferation, and invasion of fibroblast-like synoviocytes, and downregulated the expression of interleukin-6, matrix metalloproteinase 13, tumor necrosis factor receptor superfamily member 11A, and C-X-C motif chemokine ligand 12. (5) Chlorella peptides effectively inhibited vascular endothelial growth factor A-induced migration and tube formation of human umbilical vein endothelial cells, and reduced the expression of hypoxia-inducible factor 1 alpha and vascular endothelial growth factor A genes. These results indicate that Chlorella peptides regulate multiple pathological links of rheumatoid arthritis through anti-oxidative stress, regulation of macrophage polarization, inhibition of aggressive phenotype of fibroblast-like synoviocytes, and improvement of vascular endothelial disorders, suggesting potential therapeutic value for rheumatoid arthritis.
1. Introduction
Rheumatoid arthritis is a chronic systemic autoimmune disease characterized by abnormal proliferation of synovial tissue that invades and destroys articular cartilage. The pathological process involves multiple key links, including oxidative stress imbalance, abnormal macrophage polarization, aggressive proliferation of fibroblast-like synoviocytes, and disordered angiogenesis. These pathological events interact synergistically, forming a vicious cycle that exacerbates joint damage.
Current therapeutic agents for rheumatoid arthritis mainly include nonsteroidal anti-inflammatory drugs, corticosteroids, disease-modifying antirheumatic drugs, and biological agents. Although these drugs can alleviate symptoms to some extent, they are often associated with significant side effects, high costs, or limited efficacy in some patients. Therefore, there is an urgent need to develop novel, safe, and effective therapeutic strategies targeting multiple pathological pathways.
Chlorella, a unicellular freshwater green alga, is rich in proteins, vitamins, and other nutrients, and has been reported to possess significant anti-inflammatory and antioxidant properties. However, the potential of Chlorella-derived peptides in the treatment of rheumatoid arthritis has not been systematically investigated. This study aims to optimize the extraction process of Chlorella peptides, evaluate their antioxidant activity and biosafety, and explore their regulatory effects on key pathological cells involved in rheumatoid arthritis, providing experimental evidence for their therapeutic application.
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ZHANG Yiwei, FANG Ya, SUN Xin, YANG Han, LIN Haiyang, CHEN Zhouhao, ZHENG Yue, FU Jingke, WANG Jinwu (2026). Regulatory effects of optimized extraction processes for chlorella-derived peptides on key pathological links in rheumatoid arthritis. Chinese Journal of Tissue Engineering Research. https://doi.org/10.12307/2026.21577
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Frequently Asked Questions
What is the optimal extraction process for Chlorella peptides?
The optimal extraction process for Chlorella peptides was determined as follows: solid-liquid ratio of 2:1 (g:100 mL), enzymatic hydrolysis time of 60 minutes, and reaction system pH of 6.5, yielding the highest peptide yield.
What are the key pathological links of rheumatoid arthritis targeted by Chlorella peptides?
Chlorella peptides target multiple key pathological links of rheumatoid arthritis, including oxidative stress, macrophage polarization, aggressive activation of fibroblast-like synoviocytes, and vascular endothelial dysfunction.
Are Chlorella peptides safe for use in rheumatoid arthritis treatment?
Chlorella peptides showed good biocompatibility in the effective concentration range of 1-10 μg/mL, with no obvious toxicity to RAW 264.7 cells, fibroblast-like synoviocytes, and human umbilical vein endothelial cells, indicating their potential safety for clinical application.
How do Chlorella peptides regulate macrophage polarization in rheumatoid arthritis?
Chlorella peptides dose-dependently inhibit lipopolysaccharide-induced reactive oxygen species generation in RAW 264.7 cells, downregulate M1 pro-inflammatory genes (e.g., IL-1β, TNF-α), and upregulate M2 anti-inflammatory genes (e.g., IL-10, Arg-1), thereby promoting macrophage polarization from M1 to M2 phenotype.
What are the effects of Chlorella peptides on fibroblast-like synoviocytes and endothelial cells?
Chlorella peptides significantly inhibit TNF-α-induced migration, proliferation, and invasion of fibroblast-like synoviocytes, and downregulate the expression of IL-6, MMP-13, RANKL, and CXCL12. They also inhibit VEGF-A-induced migration and tube formation of human umbilical vein endothelial cells, and reduce HIF-1α and VEGF-A gene expression.
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