PMID: 

Food Chem Toxicol. 2010 Jun ;48(6):1741-5. Epub 2010 Apr 9. PMID: 20385192

Abstract Title: 

Astaxanthin improves the proliferative capacity as well as the osteogenic and adipogenic differentiation potential in neural stem cells.

Abstract: 

In the present study, the effect of astaxanthin on improvement of the proliferative capacity as well as the osteogenic and adipogenic differentiation potential in neural stem cells (NSCs) was evaluated. Treatment of astaxanthin-induced actives cell growth in a dose-dependent and time-dependent manner. Results from a clonogenic assay clearly indicated that astaxanthin can actively stimulate proliferation of NSCs. Astaxanthin-induced improvement in the proliferative capacity of NSCs resulted in overexpression of several proliferation-related proteins. Astaxanthin-induced activation of PI3K and its downstream mediators, p-MEK, p-ERK, and p-Stat3 in NSCs resulted in subsequent induction of expression of proliferation-related transcription factors (Rex1, CDK1, and CDK2) and stemness genes (OCT4, SOX2, Nanog, and KLF4). Astaxanthin also improved the osteogenic and adipogenic differentiation potential of NSCs. Astaxanthin-treated NSCs showed prominent calcium deposits and fat formation. These results were consistent with overexpression of osteogenesis-related genes (osteonectin, RXR, and osteopontin) and adipogenesis-related genes (AP and PPAR-gamma) after astaxanthin treatment. These findings clearly demonstrated that astaxanthin acts synergistically on the regulatory circuitry that controls proliferation and differentiation of NSCs.

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PMID: 

Avicenna J Med Biotechnol. 2018 Apr-Jun;10(2):69-74. PMID: 29849982

Abstract Title: 

The Evaluation of Astaxanthin Effects on Differentiation of Human Adipose Derived Stem Cells into Oligodendrocyte Precursor Cells.

Abstract: 

Background: Multiple Sclerosis (MS) has been explained as an autoimmune mediated disorder in central nerve system. Since conventional therapies for MS are not able to stop or reverse the destruction of nerve tissue, stem cell-based therapy has been proposed for the treatment of MS. Astaxanthin (AST) is a red fat-soluble xanthophyll with neuroprotection activity. The aim of this study was evaluation of pre-inducer function of AST on differentiation of human Adipose-Derived Stem Cells (hADSCs) into oligodendrocyte precursor cells.Methods: After stem cell isolation, culture and characterization by flow cytometry, hanging drop technique was done for embryoid body formation. In the following, hADSCs were differentiated into oligodendrocyte cells in the presence of AST at various concentrations (1, 5, and 10). Finally, immunocytochemistry and real-time PCR techniques were used for assessment of oligodendrocyte differentiation.Results: Flow cytometry results indicated that hADSCs were CD44, CD49-positive, but were negative for CD14, CD45 markers. In addition, immunocytochemistry results revealed that, in AST treated groups, the mean percentage of Olig 2 and A2B5 positive cells increased especially in 5AST treated group compared to control group (p

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PMID: 

PLoS One. 2019 ;14(5):e0216755. Epub 2019 May 20. PMID: 31107886

Abstract Title: 

Enhanced proliferation and differentiation of mesenchymal stem cells by astaxanthin-encapsulated polymeric micelles.

Abstract: 

Astaxanthin is a highly potent antioxidant which can be extracted from Haematococcus pluvialis when cultivated and induced at high stress conditions. Due to astaxanthin's hydrophobicity, methoxypolyethylene glycol-polycaprolactone (mPEG-PCL) copolymer was synthesized to form polymeric micelles for the encapsulation of astaxanthin. Astaxanthin-loaded polymeric micelles were then used to examine the effects on the proliferation and differentiation of human mesenchymal stem cells (MSCs). Dynamic light scattering (DLS) and Fourier transform infrared spectroscopy (FT-IR) confirmed astaxanthin was encapsulated into mPEG-PCL micelles. Astaxanthin loading and encapsulation efficiency, determined by UV/Vis spectroscopy, were 3.27% and 96.67%, respectively. After 48 h, a total of 87.31% of astaxanthin was released from the polymeric micelles. The drug release profile was better fit by the Michaelis-Menten type model than the power law model. The MSC culture results showed that culture medium supplemented with 0.5μg/mL astaxanthin-encapsulated polymeric micelles led to a 26.3% increase in MSC proliferation over an 8-day culture period. MSC differentiation results showed that 20 ng/mL astaxanthin-encapsulated polymeric micelles enhanced adipogenesis, chondrogenesis, and osteogenesis of MSCs by 52%, 106%, and182%, respectively.

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PMID: 

Materials (Basel). 2019 Jul 29 ;12(15). Epub 2019 Jul 29. PMID: 31362414

Abstract Title: 

The Influence of Astaxanthin on the Proliferation of Adipose-derived Mesenchymal Stem Cells in Gelatin-Methacryloyl (GelMA) Hydrogels.

Abstract: 

Recently, astaxanthin, a red lipophilic pigment belonging to the xanthophyllic family of carotenoids, has shown the feasibility of its uses in tissue engineering and regenerative medicine, due to its excellent antioxidant activities and its abilities to enhance the self-renewal potency of stem cells. In this study, we demonstrate the influence of astaxanthin on the proliferation of adipose-derived mesenchymal stem cells in tissue-engineered constructs. The tissue engineered scaffolds were fabricated using photopolymerizable gelatin methacryloyl (GelMA) with different concentrations of astaxanthin. The effects of astaxanthin on cellular proliferation in two-dimensional environments were assessed using alamar blue assay and reverse transcription polymerase chain reaction (RT-PCR). Then, rheological properties, chemical structures and the water absorption of the fabricated astaxanthin-incorporated GelMA hydrogels were characterized using NMR analysis, rheological analysis and a swelling ratio test. Finally, the influence in three-dimensional environments of astaxanthin-incorporated GelMA hydrogels on the proliferative potentials of adipose-derived stem cells was assessed using alamar blue assay and the confocal imaging with Live/dead staining. The experimental results of the study indicate that an addition of astaxanthin promises to induce stem cell potency via proliferation, and that it can be a useful tool for a three-dimensional culture system and various tissue engineering applications.

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PMID: 

Int J Mol Med. 2019 Dec ;44(6):2234-2244. Epub 2019 Sep 27. PMID: 31573052

Abstract Title: 

Biological effects of melatonin on human adipose‑derived mesenchymal stem cells.

Abstract: 

Mesenchymal stem cells (MSCs) are capable of differentiating into other cell types and exhibit immunomodulatory effects. MSCs are affected by several intrinsic and extrinsic signaling modulators, including growth factors, cytokines, extracellular matrix and hormones. Melatonin, produced by the pineal gland, is a hormone that regulates sleep cycles. Recent studies have shown that melatonin improves the therapeutic effects of stem cells. The present study aimed to investigate whether melatonin enhances the biological activities of human adipose‑derived MSCs. The results demonstrated that treatment with melatonin promoted cell proliferation by inducing SRY‑box transcription factor 2 gene expression and preventing replicative senescence. In addition, melatonin exerted anti‑adipogenic effects on MSCs. PCR analysis revealed that the expression of the CCAAT enhancer binding protein a gene, a key transcription factor in adipogenesis, was decreased following melatonin treatment, resulting in reduced adipogenic differentiation in an in vitro assay. The present study also examined the effect of melatonin on the immunomodulatory response using a co‑culture system of human peripheral blood mononuclear cells and MSCs. Activated T cells were strongly inhibited following melatonin exposure compared with those in the control group. Finally, the favorable effects of melatonin on MSCs were confirmed using luzindole, a selective melatonin receptor antagonist. The proliferation‑promoting, anti‑inflammatory effects of melatonin suggested that melatonin‑treated MSCs may be used for effective cell therapy.

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PMID: 

Stem Cell Res Ther. 2019 10 17 ;10(1):306. Epub 2019 Oct 17. PMID: 31623678

Abstract Title: 

Antioxidants inhibit cell senescence and preserve stemness of adipose tissue-derived stem cells by reducing ROS generation during long-term in vitro expansion.

Abstract: 

BACKGROUND: Adipose tissue-derived mesenchymal stem cells (ADSCs) are promising candidates for regenerative medicine. However, long-term in vitro passaging leads to stemness loss and cell senescence of ADSCs, resulting in failure of ADSC-based therapy.METHODS: In this study, ADSCs were treated with low dose of antioxidants (reduced glutathione and melatonin) with anti-aging and stem cell protection properties in the in vitro passaging, and the cell functions including stem cell senescence, cell migration, cell multidirectional differentiation potential, and ROS content were carefully analyzed.RESULTS: We found that GSH and melatonin could maintain ADSC cell functions through reducing cell senescence and promoting cell migration, as well as by preserving stemness and multidirectional differentiation potential, through inhibiting ROS generation during long-term expansion of ADSCs.CONCLUSIONS: Our results suggested that antioxidant treatment could efficiently prevent the dysfunction and preserve cell functions of ADSCs after long-term passaging, providing a practical strategy to facilitate ADSC-based therapy.

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PMID: 

Stem Cell Res Ther. 2019 Dec 21 ;10(1):408. Epub 2019 Dec 21. PMID: 31864412

Abstract Title: 

Melatonin promotes the BMP9-induced osteogenic differentiation of mesenchymal stem cells by activating the AMPK/β-catenin signalling pathway.

Abstract: 

BACKGROUND: Mesenchymal stem cells (MSCs) play a crucial role in maintaining the dynamic balance of bone metabolism. Melatonin may have a regulatory effect on bone metabolism by regulating the lineage commitment and differentiation signalling pathways of MSCs. Among the BMP families, the osteogenesis of BMP9 is considered to be one of the strongest in MSCs. Here, we explored whether melatonin and BMP9 act synergistically on MSC osteogenic differentiation.METHODS: The C3H10T1/2 osteogenic differentiation function induced by melatonin synergizes with BMP9, as detected by the expression of osteogenic markers at different periods. The result was further confirmed by foetal limb explant culture and in vivo stem cell implantation experiments. The effects of the AMPK/β-catenin pathway on the osteogenic differentiation of C3H10T1/2 cells were evaluated by Western blotting.RESULTS: Melatonin combined with BMP9 significantly enhanced the expression of osteogenic markers at different periods in C3H10T1/2 cells, effectively enhancing BMP9-induced bone formation in cultured foetal explants and ectopic bone formation in vivo in stem cell transplantation experiments. Melatonin increases the expression of BMP9 in C3H10T1/2 cells and induces Smad1/5/8 translocation from the cytoplasm to the nucleus. In addition, melatonin and BMP9 synergistically promote AMPK andβ-catenin phosphorylation, which can be largely eliminated by AMPK siRNA pretreatment.CONCLUSIONS: Melatonin and BMP9 in C3H10T1/2 cells synergistically promote osteogenic differentiation at least in part by activating the AMPK/β-catenin signalling pathway.

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PMID: 

Stem Cells Int. 2019 ;2019:6568394. Epub 2019 Dec 30. PMID: 32082385

Abstract Title: 

Melatonin Reverses the Loss of Stemness Induced by TNF-in Human Bone Marrow Mesenchymal Stem Cells through Upregulation of YAP Expression.

Abstract: 

Mesenchymal stem cells (MSCs) are promising candidates for tissue regeneration and disease treatment. However, long-termculture results in loss of MSC stemness. The inflammation that occurs at stem cell transplant sites (such as that resulting from TNF-) is a contributing factor for stem cell treatment failure. Currently, there is little evidence regarding the protective role of melatonin with regard to the negative effects of TNF-on the stemness of MSCs. In this study, we report a melatonin-based method to reduce the inflammatory effects on the stemness of bone marrow mesenchymal stem cells (BMMSCs). The results of colony formation assays, Alizarin red staining, western blotting, and reverse transcription-polymerase chain reactions suggest that melatonin can reverse the inflammatory damage caused by TNF-treatment in the third, seventh, and tenth generations of primary BMMSCs (vs. control and the TNF–treated group). Meanwhile, a detailed analysis of the molecular mechanisms showed that the melatonin receptor and YAP signaling pathway are closely related to the role that melatonin plays in negative inflammatory effects against BMMSCs. In addition,experiments showed that melatonin could reverse the damage caused by TNF-on bone regeneration by BMMSCs in nude mice. Overall, our results suggest that melatonin can reverse the loss of stemness caused by inflammatory factor TNF-in BMMSCs. Our results also provide a practical strategy for the application of BMMSCs in tissue engineering and cell therapy.

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PMID: 

Toxicol Appl Pharmacol. 2020 Jan 15 ;387:114851. Epub 2019 Dec 5. PMID: 31812774

Abstract Title: 

Thymoquinone promotes mouse mesenchymal stem cells migration in vitro and induces their immunogenicity in vivo.

Abstract: 

Mesenchymal stem cells (MSCs) have unique potentials, including migration and immunomodulation. Identification of the factors that enhance these activities can improve clinical applications of MSCs. This study aimed to investigate total antioxidant capacity (TAC) and migration potential of mouse MSCs exposed to thymoquinone (TQ) in vitro, and to examine the effect of TQ-treated MSCs on the expression of mouse immune cell markers. The results of total antioxidant capacity and wound healing assays showed that TQ increased the rate of MSCs TAC and migration in a dose- and time-dependent manner. The maximum TAC and migration were detected at 600 and 250 ng/ml of TQ, respectively. Functionally, the real-time PCR data analysis indicated that TQ induced c-Met and Cxcr4 expression and therefore, there may be a correlation between upregulation of these genes and increased MSCs migration. TQ also enhanced the up and down regulating impact of MSCs on Rorγt and Plzf expression and the expression of Tcf4 in mouse immune cells, respectively. Overall, this study declares that TQ increases the TAC of MSCs. It also proposes that TQ may, through activation of c-MET and CXCR4 signalling pathways, promote MSCs migration. TQ may also augment MSCs immunogenicity through its influence on the expression of genes involved in commitment of mouse immune system cells in vivo.

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PMID: 

World J Stem Cells. 2019 Dec 26 ;11(12):1045-1064. PMID: 31875868

Abstract Title: 

Influence of olive oil and its components on mesenchymal stem cell biology.

Abstract: 

Extra virgin olive oil is characterized by its high content of unsaturated fatty acid residues in triglycerides, mainly oleic acid, and the presence of bioactive and antioxidant compounds. Its consumption is associated with lower risk of suffering chronic diseases and unwanted processes linked to aging, due to the antioxidant capacity and capability of its components to modulate cellular signaling pathways. Consumption of olive oil can alter the physiology of mesenchymal stem cells (MSCs). This may explain part of the healthy effects of olive oil consumption, such as prevention of unwanted aging processes. To date, there are no specific studies on the action of olive oil on MSCs, but effects of many components of such food on cell viability and differentiation have been evaluated. The objective of this article is to review existing literature on how different compounds of extra virgin olive oil, including residues of fatty acids, vitamins, squalene, triterpenes, pigments and phenols, affect MSC maintenance and differentiation, in order to provide a better understanding of the healthy effects of this food. Interestingly, most studies have shown a positive effect of these compounds on MSCs. The collective findings support the hypothesis that at least part of the beneficial effects of extra virgin olive oil consumption on health may be mediated by its effects on MSCs.

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