Genistein Enhances or Reduces Glycosaminoglycan Quantity in a Cell Type-Specific Manner

Lan, Ying; Li, Xiulian; Liu, Xuebo; Song, Ning; Ren, Sumei; Wang, Wei; Feng, Nan; Zhang, Lijuan

doi:10.1159/000490985

Cited by 6 publications

(3 citation statements)

References 46 publications

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“…Genistein has been demonstrated by various groups to slow the production of GAG in cultured fibroblasts [43,45], and some studies showed an increase in GAG synthesis in chondrocytes [50]. The discrepancy among studies has been suggested to be due to different effects of genistein on GAG levels in different types of cells [51]. Nevertheless, experiments with animal models of MPS II and MPS IIIB demonstrated the efficacy of this isoflavone in reducing GAG levels and attenuating abnormal behavior [46,52], but these benefits have not been observed in MPS I mice [53].…”

Section: Discussionmentioning

confidence: 99%

Activities of (Poly)phenolic Antioxidants and Other Natural Autophagy Modulators in the Treatment of Sanfilippo Disease: Remarkable Efficacy of Resveratrol in Cellular and Animal Models

et al. 2023

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Sanfilippo disease, caused by mutations in the genes encoding heparan sulfate (HS) (a glycosaminoglycan; GAG) degradation enzymes, is a mucopolysaccharidosis (MPS), which is also known as MPS type III, and is characterized by subtypes A, B, C, and D, depending on identity of the dysfunctional enzyme. The lack of activity or low residual activity of an HS-degrading enzyme leads to excess HS in the cells, impairing the functions of different types of cells, including neurons. The disease usually leads to serious psychomotor dysfunction and death before adulthood. In this work, we show that the use of molecules known as dietary (poly)phenolic antioxidants and other natural compounds known as autophagy activators (genistein, capsaicin, curcumin, resveratrol, trehalose, and calcitriol) leads to accelerated degradation of accumulated HS in the fibroblasts of all subtypes of MPS III. Both the cytotoxicity tests we performed and the available literature data indicated that the use of selected autophagy inducers was safe. Since it showed the highest effectivity in cellular models, resveratrol efficacy was tested in experiments with a mouse model of MPS IIIB. Urinary GAG levels were normalized in MPS IIIB mice treated with 50 mg/kg/day resveratrol for 12 weeks or longer. Behavioral tests indicated complete correction of hyperactivity and anxiety in these animals. Biochemical analyses indicated that administration of resveratrol caused autophagy stimulation through an mTOR-independent pathway in the brains and livers of the MPS IIIB mice. These results indicate the potential use of resveratrol (and possibly other autophagy stimulators) in the treatment of Sanfilippo disease.

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Section: Discussionmentioning

confidence: 99%

Activities of (Poly)phenolic Antioxidants and Other Natural Autophagy Modulators in the Treatment of Sanfilippo Disease: Remarkable Efficacy of Resveratrol in Cellular and Animal Models

et al. 2023

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“…58 A selective peptide, called synstatin (SSTN92-119) inhibits the complex formation between syndecan-1, IGF1R, and integrin αvβ3 and reduce the activation of the angiogenic growth factors, vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF/FGF-2), inhibits angiogenic and decreasing tumor growth in mammary carcinoma in mouse and hepatocellular carcinoma in rats. 39,40 NT4 is a tetra-branched peptide specifically binds to sulfated glycosaminoglycans on cancer cell membranes, such as colorectal cancer, pancreas adenocarcinoma, and urinary bladder cancer and can efficiently and selectively deliver drugs or liposomes for cancer cell imaging or therapy. NT4 inhibits cancer cell adhesion and migration on different proteins, 4,38 however, the exact mechanism of action is still unclear.…”

Section: Mimetic Peptidementioning

confidence: 99%

Heparan sulfate proteoglycans as targets for cancer therapy: a review

Onyeisi

Ferreira

Nader

et al. 2020

Cancer Biology & Therapy

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Heparan sulfate proteoglycans (HSPGs) play important roles in cancer initiation and progression, by interacting with the signaling pathways that affect proliferation, adhesion, invasion and angiogenesis. These roles suggest the possibility of various strategies of regulation of these molecules. In this review, we demonstrated that the anticancer drugs can regulate the heparan sulfate proteoglycans activity in different ways: some act directly in core protein, and can bind to a specific type of HSPG. Others drugs interact with glycosaminoglycans chains, and others can act directly in enzymes that regulate HSPGs levels. We also demonstrated that the HSPGs drug targets can be divided into four groups: monoclonal antibodies, antitumor antibiotic, natural products, and mimetics peptide. Interestingly, many drugs demonstrated in this review are approved by FDA and is used in cancer therapy (Food and Drug Administration) like trastuzumab, panitumumab, bleomycin and bisphosphonate zoledronic acid (ASCO) or are in clinical trials like codrituzumab and genistein. This review should help researchers to understand the mechanism of action of anticancer drugs existing and also may inspire the discovery of new drugs that regulate the heparan sulfate proteoglycans activity.

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“…Genistein has also been found to partially correct cell cycle disturbances in MPS cells [15,16], suggesting a potential mechanism of action. However, SRT with genistein has shown variable effects on glycan and glycosaminoglycan levels, with changes observed in a cell-type-dependent manner [17]. Although genistein has shown promise in reducing GAG synthesis and improving cell cycle disturbances in MPS, its clinical efficacy and effects on specific disease outcomes require further investigation.…”

Section: Introductionmentioning

confidence: 99%

Efficacy of a Combination Therapy with Laronidase and Genistein in Treating Mucopolysaccharidosis Type I in a Mouse Model

Malinowska,

Nowicka,

Kloska

et al. 2024

IJMS

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Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disorder caused by α-L-iduronidase deficiency. The standard treatment, enzyme replacement therapy with laronidase, has limited effectiveness in treating neurological symptoms due to poor blood–brain barrier penetration. An alternative is substrate reduction therapy using molecules, such as genistein, which crosses this barrier. This study evaluated the effectiveness of a combination of laronidase and genistein in a mouse model of MPS I. Over 12 weeks, MPS I and wild-type mice received laronidase, genistein, or both. Glycosaminoglycan (GAG) storage in visceral organs and the brain, its excretion in urine, and the serum level of the heparin cofactor II–thrombin (HCII-T) complex, along with behavior, were assessed. The combination therapy resulted in reduced GAG storage in the heart and liver, whereas genistein alone reduced the brain GAG storage. Laronidase and combination therapy decreased liver and spleen weights and significantly reduced GAG excretion in the urine. However, this therapy negated some laronidase benefits in the HCII-T levels. Importantly, the combination therapy improved the behavior of female mice with MPS I. These findings offer valuable insights for future research to optimize MPS I treatments.

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Genistein Enhances or Reduces Glycosaminoglycan Quantity in a Cell Type-Specific Manner

Cited by 6 publications

References 46 publications

Activities of (Poly)phenolic Antioxidants and Other Natural Autophagy Modulators in the Treatment of Sanfilippo Disease: Remarkable Efficacy of Resveratrol in Cellular and Animal Models

Activities of (Poly)phenolic Antioxidants and Other Natural Autophagy Modulators in the Treatment of Sanfilippo Disease: Remarkable Efficacy of Resveratrol in Cellular and Animal Models

Heparan sulfate proteoglycans as targets for cancer therapy: a review

Efficacy of a Combination Therapy with Laronidase and Genistein in Treating Mucopolysaccharidosis Type I in a Mouse Model

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