The Protective Effects of Nutraceutical Components in Methotrexate-Induced Toxicity Models—An Overview
Abstract
:1. Introduction
2. MTX as a Disease-Modifying Agent
3. Gut Microbiota-Related Changes following Treatment with MTX
3.1. Involvement of Gut Microbiota in Health and Disease
3.2. The Role and Protective Effects Exhibited by Microbiota
3.3. The Role of Microbiota for Promoting an Intact Epithelial Cell Barrier
3.4. The Influence of MTX on Gut Microbiota
4. Nutraceuticals Use to Counteract MTX Toxicity in Experimental Models
4.1. Hepatotoxicity
4.2. Nephrotoxicity
4.3. Gastrointestinal Toxicity
4.4. Pulmonary Toxicity
5. Conclusions and Future Perspectives
Author Contributions
Funding
Data Availability Statement
Conflicts of Interest
References
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Disease | End-Organ Effect | Molecular Mechanism | Efficient Dose Indicated | Most Common Adverse Effects |
---|---|---|---|---|
Acute lymphoblastic leukemia | Neoplastic cells, abnormally fast-dividing cells | DHFR inhibition, disruption of de novo nucleotide biosynthesis and DNA replication, resulting in cell death | Induction 3.3 mg/m2 Maintenance 30 mg/m2/week |
|
Acute promyelocytic leukemia | ||||
Meningeal leukemia | 12 mg/m2/every 2–5 days until the cell count of the CSF returns to normal | |||
Burkitt’s lymphoma and other non-Hodgkin’s lymphomas | 10–25 mg/day 4–8 days | |||
Mycosis Fungoides | 2.5–10 mg/day orally or 50 mg/week i.m. | |||
Epidermoid cancers of the head and neck | 30–40 mg/m2/week i.v | |||
Early-stage breast cancer | ||||
Squamous cell carcinoma | ||||
Small cell carcinoma | ||||
Osteosarcoma | 12 g/m2 i.v. | |||
Chorioadenoma destruens | 15–30 mg/day 5 day course | |||
Hydatidiform mole | ||||
Severe psoriasis | T cells B cells | Adenosine accumulation, inhibition of T-cell activation, downregulation of B cells | Single dose 10–25 mg/week | |
Rheumatoid arthritis | Single dose 7.5 mg/week | |||
Polyarticular course juvenile rheumatoid arthritis | Single dose 10 mg/m2/week |
Gut Microbiota Changes in Subjects Exposed to MTX | Intestinal Epithelial Changes | Samples | Technique | References |
---|---|---|---|---|
↑ Peptostreptococcaceae and Porphyromonadaceae ↓ Ruminococcaceae, Erysipelotrichaceae | NR | 22 Male Sprague Dawley rats 7 to 8 weeks old | Fecal DNA extraction and sequencing | [26] |
↓ Lactobacillus ↑ Muribaculaceae | ↓ ZO-1, claudin-1, and E-cadherin | 8-week-old male mice (6 per group) | Fecal DNA extraction and sequencing | [32] |
↓ H. filiformis and Bacteroides sp. ↑ P. intermedia | NR | 21 RA patients at pre and post-MTX + tripterygium glycosides | Metagenomic shotgun sequencing | [121] |
↑ Subdoligranulum ↓ Rikenellaceae, Veillonellaceae, Bacteroidales_S24-7_group, Alistipes Prevotellaceae_NK3B31_group | NR | Fecal samples from 29 children with JIA treated with MTX | DNA extraction, amplification, and sequencing | [122] |
↓ Enterobateriales | NR | 11 patients with RA receiving MTX | DNA extraction and metagenomic sequencing | [124] |
Name | Model | Class | Source | Therapeutic Effects | Ref. |
---|---|---|---|---|---|
Choline | In vivo liver toxicity rat model | Vitamin/nutrient | Multiple sources in meat and plants | ↑ PCho, GroPCho, and betaine | [155] |
Gossypin/gossypentin | In vivo liver toixicity rat model | Flavonoid/plant extract | Hibiscus sabdariffa | ↓BAX, TGF-β, caspase 3, and NF-κB ↓hepatic fibrosis | [161] |
Epicatechin/Catechin | In vivo liver toxicity mice model | Flavonoid/plant extract | Mimosa catechu | ↓ IL-1β, TNF-α, and NO ↓ MDA GSH level and activity level of catalase, SOD, and GPx ↑ | [30] |
Thiamine and thiamine pyrophosphate | In vivo liver toixicity rat model | Vitamin | Whole grains, legumes, and some meats and fish | Thiamine no protective effects reported TPP effects on: MDA and MPO ↓ GSH and SOD ↑ | [178] |
Thymoquinone | In vivo liver toixicity rat model | Plant extract | Nigella sativa | ↓TNF-α, NF-κB COX-2 expressions ↓MDA ↑glutathione and catalase | [158] |
Ferulic acid | In vivo liver toxicity mice model | Plant extract | Ferula communis | ↓MDA, IL-6, and TNF-α ↓accumulation of inflammatory cells ↓nuclear pyknosis ↑GSH, CAT, TAC | [159] |
Rhein/cassic acid | In vivo liver toxicity rat model In vitro normal human hepatocyte (L02 cells) model | Plant extract | Rheum undulatum, Rheum palmatum, Cassia reticulata | ↑cell survival rate ↓apoptosis ↑Nrf2, Bcl-2, HO-1 and GCLC ↓Bax ↓NF-κB, TNF-α and caspase-3 | [160] |
Berberine | In vivo liver toixicity rat model | Plant extract | Berberis vulgaris, Berberis aristata, Mahonia aquifolium, Hydrastis canadensis, Xanthorhiza simplicissima, Phellodendron amurense | ↓MDA, PC, NO levels and MPO activity ↑GSH level, SOD, GPx and CAT activities | [162] |
Resveratrol | In vivo liver toixicity rat model | Plant extract | Skin of grapes, blueberries, raspberries, mulberries, and peanuts | ↓MDA levels, MPO and TF activities and collagen contents ↑GSH ↓TNF-α ↓TBARS, CAT, and GST | [152,163] |
Ginko biloba | In silico bio computational model In vivo liver toxicity rat model | Plant extract | Ginko biloba tree | ↓caspase-3, JNK and TNF-α ↓apoptosis ↑GSH and GST in silico: drug-receptor interactions stabilized by a low energy value and with a good number of hydrogen bonds | [166] |
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Marin, G.-E.; Neag, M.-A.; Burlacu, C.-C.; Buzoianu, A.-D. The Protective Effects of Nutraceutical Components in Methotrexate-Induced Toxicity Models—An Overview. Microorganisms 2022, 10, 2053. https://doi.org/10.3390/microorganisms10102053
Marin G-E, Neag M-A, Burlacu C-C, Buzoianu A-D. The Protective Effects of Nutraceutical Components in Methotrexate-Induced Toxicity Models—An Overview. Microorganisms. 2022; 10(10):2053. https://doi.org/10.3390/microorganisms10102053
Chicago/Turabian StyleMarin, Gheorghe-Eduard, Maria-Adriana Neag, Codrin-Constantin Burlacu, and Anca-Dana Buzoianu. 2022. "The Protective Effects of Nutraceutical Components in Methotrexate-Induced Toxicity Models—An Overview" Microorganisms 10, no. 10: 2053. https://doi.org/10.3390/microorganisms10102053