Trifolirhizin: A Phytochemical with Multiple Pharmacological Properties
Abstract
:1. Introduction
2. Electronic Literature Search Strategy
3. Toxicity Studies
4. Pharmacokinetics Studies
5. Pharmacological Activities of Trifolirhizin
5.1. Antibacterial Activity of Trifolirhizin
5.2. Hepatoprotective Activity of Trifolirhizin
5.3. Antiplatelet Aggregation Effect of Trifolirhizin
5.4. Estrogenic Effect of Trifolirhizin
5.5. Antiasthma Activity of Trifolirhizin
5.6. Anti-Inflammatory Effect of Trifolirhizin
5.6.1. In Vitro Anti-Inflammatory Effect of Trifolirhizin
5.6.2. In Vivo Anti-Inflammatory Effect of Trifolirhizin
5.7. Anti-Ulcerative Colitis Activity of Trifolirhizin
5.8. Protective Effect of Trifolirhizin on Bone
5.8.1. In Vitro Protective Effect of Trifolirhizin on Bone
5.8.2. In Vivo Protective Effect of Trifolirhizin on Bone
5.9. Skin-Whitening and Tyrosinase Inhibition Activity
5.10. Anti-Diabetic Nephropathy
5.11. Anticancer Effects of Trifolirhizin
5.11.1. In Vitro Anticancer Activities of Trifolirhizin
5.11.2. In Vivo Anticancer Activities of Trifolirhizin
5.12. Wound-Healing Effects of Trifolirhizin
6. Gaps and Future Direction
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Sr. No. | Activity | Model and Dose | Method | Result | Ref |
---|---|---|---|---|---|
1 | Anti-inflammatory activity | LPS-induced inflammation in the J774A.1 macrophage of the mouse | QRTPCR to study the mRNA expression of tumor necrosis factor (TNF-α) and interleukin-6 (IL-6) | TNF-α ↓ and IL-6 ↓ | [8] |
ELISAQRTPCR to study the mRNA expression of tumor necrosis factor (TNF-α) | TNF-α ↓ | ||||
WB to study the protein expression of COX-2 | COX-2 ↓ | ||||
2 | Wound-healing | Inhibition assay of enzymes at 50 and 100 μg/mL | Enzymes hyaluronidase, collagenase, and elastase enzymes | Percentage inhibition (at 100 μg/mL) was 28.45 ± 1.96, 27.84 ± 0.72, and 21.53 ± 1.66 for hyaluronidase ↓, collagenase ↓, and elastase enzymes ↓, respectively | [21] |
3 | Skin-whitening | Treated with different concentrations (1–500 μg/mL) | Tyrosinase inhibition activity | IC50: 506.77 ± 4.94 μM | [20] |
B16 melanoma cells treated with different concentrations (12.5, 25, and 50 μM) | B16 cells induced with IBMX | IC50: 36 μM | |||
4 | Protect bone loss | MC3T3-E1 cells were used to study osteogenesis in the study | ALP activity and staining assays | ALP ↑ | [15] |
RT-qPCR | ColI ↑, bone sialoprotein Bsp ↑, and Alp ↑ | ||||
Detection of F-actin polymerization in the cells; phalloidin staining | F-actin polymerization ↑ | ||||
Cell migration through Matrigel-coated membranes | Cell migration ↑ | ||||
ARS staining to study mineralization by calcium deposition | Mineralization ↑ | ||||
WB | RUNX2 ↑, β-catenin ↑, p-Smad1/5/8 ↑, p-JNK ↑, p-GSK3β ↑, and p-β-catenin ↓ | ||||
Marker in the immunofluorescence assay | The accumulation of RUNX2 ↑ (in the nucleus) | ||||
BMM extracted from the bone marrow cavity of the femur and tibia of C57BL/6J and RANKL used as a stimulator Dose: 10, 20, and 40 μM | Cell staining to detect TRAP activity | Significant reduction in the formation of multinucleated osteoclasts was observed at all doses (10, 20, and 40 μM) used in the study | [14] | ||
Western blot analysis | NFATc1 ↓ | ||||
RT-qPCR | ACP5 ↓, ATc1 ↓, DC-STAMP ↓, MMP9 ↓, V-ATPase-D2 ↓, and CTSK ↓ were found to be downregulated in a dose-dependent manner in the treatment groups | ||||
Bone resorption assay | In the bone resorption analysis, trifolirhizin treatment (at 20 and 40 μM) significantly decreased absorption area | ||||
5 | Anticancer | Human leukemia cells (HL-60 cells) | Viable cell number estimated by the trypan blue dye exclusion method | Proliferation of HL-60 cells ↓ | [5] |
Analysis of morphological changes through microscopic observation | Apoptotic bodies and fragmentation of genomic DNA were observed in the treated cells | ||||
A2780 ovarian cancer cells (5–250 μM) | MTT assay | Proliferation of A2780 ovarian cancer cells ↓ (at 50 μM or more) | [8] | ||
H23 lung cancer cells (5–250 μM) | MTT assay | Proliferation of H23 lung cancer cells ↓ (at 250 μM) | |||
MKN45 cells was 20, 30, and 40 μg/mL | MTT assay | Proliferation of MKN45 cells ↓ (IC50: 33.27 ± 2.06 μg/mL) | [6] | ||
Flow cytometry Hoechst staining TUNEL staining and Annexin V/PI assay | Increased the number of apoptotic cells, cell shrinkage, nuclear fragmentation, and chromatin compaction of apoptosis accumulation in the G2/M phase in MKN45 cells | ||||
The JC-10 assay | Normal cells ↓ and apoptotic cells ↑ (20–40 μg/mL trifolirhizin treatment) | ||||
Western blot analysis | p-EGFR levels ↓, cyclin B ↓, Cdc2 ↓, p-ERC ↓, p-MEK ↓, p-P38 ↑, P53 ↑, c-Myc ↑, caspase-9 ↑, and caspase-3 ↑ | ||||
HCT116 and SW620 cells | Immuno-blotting assay of two autophagy marker proteins, LC-3 and p62/SQSTM-1 | LC-3B-I ↑ and LC-3B-II ↑ | [7] | ||
CCK-8 assay | Cell viability ↓ | ||||
Transmission electron microscopy | Autophagic vacuole ↑ | ||||
AdmCherry-GFP-LC3B fluorescent assay | Autophagosomes ↑ and autophagolysosomes ↑ | ||||
Flow cytometry analysis and TUNEL staining | Long-term growth of both cell lines ↓ | ||||
Western blot | Cleaved caspase-3 ↑, cleaved caspase-8 ↑, cleaved poly ADP-ribose polymerase ↑, p-AMPK ↑, and p-mTOR ↓ | ||||
Human nasopharyngeal carcinoma cell lines (6–10 B and HK1) | CCK-8 assays | Cell viability of 6–10 B cells ↓ (IC50: 83.67 ± 1.70 μmol/L at 72 h) Cell viability of HK1cells ↓ (IC50: 33.21 ± 1.40 μmol/L at 72 h) | [10] | ||
Flow cytometry analysis through PI staining | Nasopharyngeal cancer cells at G0/G1 phase | ||||
Scratch assay to study cell migration | 6–10 B and HK1 cell migration ↓ | ||||
Transwell assays | Invaded cell numbers ↓ in both 6–10 B and HK1 cells | ||||
RNA-seq analysis followed by volcano plot and KEGG pathway analysis | The PI/Akt pathway was among the enriched pathways by the differentially expressed genes | ||||
WB | Phosphorylation of both PI3K and Akt proteins ↓ (in both 6–10 B and HK1 cells) | ||||
MHCC97H, MHCC97L, and HepG2 cells (12.5, 25, 50, and 100 μg/mL) | MTT assay | IC50: 143.1 μg/mL (alone) IC50: 1.5 ± 0.06 0.7 ± 0.17 μg/M (in combination with SF (100 μg/mL)) IC50: 104.2 μg/mL (alone) IC50: 0.7 ± 0.17 μg/M (in combination with SF (100 μg/mL)) IC50: >60 μg/mL (alone) IC50: 8.4 ± 0.54 μg/M (in combination with SF (100 μg/mL)) | [9] | ||
Microscopy using DAPI Annexin-V FITC/PI analysis using flow cytometry (50.0 μg/mL, 22.4 μM) and SF (2.0 μM) | Nucleus fragmentation ↑ and apoptotic body formation ↑ Percentage of apoptotic cells significantly increased by 5.0-fold for SF-induced apoptosis in comparison to the single treatment of SF | ||||
Cell cycle assay | Similarly, the combination of compound 17 with SF arrested MHCC97H cells in the G1 phase | ||||
JC-1 assay | ΔΨm ↓ | ||||
WB | Cyclin D1 ↓ and cyclin B1 ↓, leaved- caspase-3 ↑ cleaved caspase-9 ↑, Bax/Bcl2 ↑, JNK ↓, P38 ↓, p-ERK1/2 ↓, and p-AKT ↓ | ||||
Nasopharyngeal carcinoma cell lines (C666-1) (0, 0.005, 0.01, 0.02, 0.04, 0.08, 0.16, 0.4, 0.8, and 2 mg/mL) | CCK-8 assay and EdU staining | Viability of C666-1 cells ↓ | [22] | ||
TUNEL staining | Apoptosis of C666-1 cells ↑ | ||||
WB | PTK6 ↓, LC3-II/I ↑, Beclin1 ↑, p62 ↓, Ki67 ↓, and PCNA ↓ | ||||
RT-qPCR | PTK6 ↓ | ||||
Immunofluorescence (IF) | LC3 accumulation ↑, levels of LC3-II/I ↑, and Beclin1 ↑ |
Sr. No. | Activity | Animal Model and Dose | Method | Results | Reference |
---|---|---|---|---|---|
1 | Hepatoprotective activity | Wistar rats and 7.5 mg/kg (20.7 μmol/kg) 5 days before CCl4 administration and continued until the end of the experiment. | Carbon tetrachloride (CCl4)-induced liver toxicity, and the levels of liver enzymes in serum were studied | SGOT ↓, SGPT ↓, ALP ↓, and total bilirubin ↓ | [31] |
Non-protein sulfhydryl groups in the liver (wet weight) | Non-protein sulfhydryl groups ↑ | ||||
2 | Antiplatelet aggregation activity | Blood was collected from Wistar rats via cardiac puncture; 400 and 800 μg/mL concentrations were used in the study. | Aggregation of platelets was caused by ADP | Aggregation of platelets ↓ | [31] |
3 | Estrogenic activity | Female Wistar rat model; 20 mg/kg body weight. | Weights of the uteri in control and treated animals to the whole animal weight were also calculated (positive control 17β-estradiol) | Uterine weight ↑ | [31] |
4 | Anti-inflammatory activity | Wistar rat paw edema as a model and 4.5 mg/kg dose. | Carrageenan was used to induce edema; indomethacin was used as a positive drug | Paw edema ↓ # (35%) | [31] |
5 | Protect against bone loss | Wild-type (WT) C57BL/6J mice; ovariectomy was executed 10 and 20 mg/kg by intraperitoneal injection for 6 weeks. | μCT scanning analysis of tibia and histological assessments | Bone loss ↓ Number of TRAP-positive osteoclasts ↓ | [14] |
Male C57BL/6J mice; 5 and 10 mg/kg injected periosteum in the midline of the skull on days 2, 4, 6, and 8. | LPS-induced osteolysis of cranial cap bone analyzed through μCT scanning | Bone loss ↓, BV/TV ↑, and bone destruction area ↓ | [13] | ||
Histological analysis | Number of TRAP-positive osteoclasts ↓, IL-1β-positive area in of cranial cap bone ↓ | ||||
6 | Anticancer | BALB/C nude mice; dose: 1–3 mg/kg for 21 days of treatment. | Intraperitoneal injection of MKN45 cells to induce tumors in mice | Tumor weight ↓ | [32] |
Immunohistochemistry | Ki67-positive cells ↓ and cleaved caspase-3-positive cells ↑ | ||||
BALB/C mice; dose: 10 mg/kg once every three days for 21 days. | Xenograft tumor studies | Size of tumor ↓ | [7] | ||
Hematoxylin and eosin (H&E) and TUNEL staining | Tumor tissue showed the damage of tumor cells | ||||
WB to study expression | Cleaved caspase-3 ↑, cleaved caspase-8 ↑, p-AMPK ↑, p-mTOR ↓, Atg5 ↑, and Atg7 ↑ | ||||
Male nude mice; dose: administered every other day for 14 days at a dose of 40 mg/kg. | Xenograft tumor model 6–10 B and HK1 cells injected subcutaneously into the right axilla of nude mice | Tumor size and weight ↓ | [10] | ||
HE staining | Tumor tissue showed damage to tumor cells | ||||
7 | Anti-UC | C57BL/6 mice; dose: intraperitoneally injected trifolirhizin (12.5, 25, 50 mg/kg) for one time. | Mice received DSS treatment for 7 days with 1.5% DSS in the drinking water | Body weight ↑ and length of the colon ↑ | [33] |
Quantitative reverse transcription (qRT)-polymerase chain reaction (PCR). | TNF-α ↓, IL-6 ↓, IL-1β ↓, NLRP3 ↓, caspase 1 ↓, and ASC ↓ | ||||
ELISA | The protein expression of TNF-α ↓, IL-6 ↓, IL-1β ↓, IL-17 ↓, IL-10 ↑, IgM ↑, IgA ↓, and IgG ↓ (colon tissue) | ||||
WB | p-nuclear factor (NF)-κB/NF-κB ↓, RORγt protein ↓, Foxp3 ↑, NLRP3 ↓, caspase 1 ↓ and ASC ↓, IL-1β ↓, p-AMPK/AMPK ↓, and TXNIP ↑ | ||||
Flow cytometry analysis of cells from mesenteric lymph nodes and the spleen | Th17 (CD4+ IL17+) cells ↓ Treg (CD4+ CD25+ Foxp3+) cells ↑ | ||||
Immunofluorescence staining | NLRP3 expression ↓ | ||||
8 | Anti-diabetic nephropathy | Male db/db mice; trifolirhizin (0, 12.5, 25 and 50 mg/kg); 3 weeks. | Histological analysis of renal tissues was performed by H & E staining | Body and renal weight ↓, fasting blood glucose ↓, renal injury ↓ | [16] |
TUNEL staining of renal tissues | Apoptosis ↓ | ||||
ELISA | BUN ↓, creatinine ↓ MDA ↓, and SOD ↑ | ||||
WB of renal tissues | LC3II ↑, Beclin1 ↑, p62 ↓, p-PI3K/PI3K ↓, p-AKT/AKT ↓, and p-mTOR/mTOR ↓ | ||||
DHE staining of renal tissues | ROS ↓ | ||||
9 | Antiasthma | Six-week-old BALB/c asthmatic mouse model induced by albumin sensitization and challenge. | ASM contraction in tracheal rings was induced by acetylcholine | ASM contraction ↓ | [4] |
Neonatal pups of SD rats; asthmatic mouse model induced by albumin sensitization. | Histopathology | Tissue damage ↓, aggregation of inflammatory cells ↓, edema in pulmonary tissues ↓, and histological scores ↓ | [34] | ||
Immunohistochemistry | Muc5AC ↓ and Muc5B ↓ genes (the lungs) TNF-α ↓ and ICAM-1 ↓, IL-4 ↓, IL-5 ↓, and IL-13 ↓ (in BALF) | ||||
WB | IκBα protein expression ↑ |
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Jaiswal, V.; Lee, H.-J. Trifolirhizin: A Phytochemical with Multiple Pharmacological Properties. Molecules 2025, 30, 383. https://doi.org/10.3390/molecules30020383
Jaiswal V, Lee H-J. Trifolirhizin: A Phytochemical with Multiple Pharmacological Properties. Molecules. 2025; 30(2):383. https://doi.org/10.3390/molecules30020383
Chicago/Turabian StyleJaiswal, Varun, and Hae-Jeung Lee. 2025. "Trifolirhizin: A Phytochemical with Multiple Pharmacological Properties" Molecules 30, no. 2: 383. https://doi.org/10.3390/molecules30020383
APA StyleJaiswal, V., & Lee, H.-J. (2025). Trifolirhizin: A Phytochemical with Multiple Pharmacological Properties. Molecules, 30(2), 383. https://doi.org/10.3390/molecules30020383