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Article: The Effect of Rosmarinic Acid on Neural Differentiation of Wartons Jelly-derived Mesenchymal Stem Cells in Two-dimensional and Three-dimensional Cultures using Chitosan-based Hydrogel.

Salmanvandi, Mohsen / Haramshahi, Seyed Mohammad Amin / Mansouri, Elahe / Alizadeh, Akram

2023 Volume 14, Issue 1, Page(s) 117–128

Abstract: Introduction: Numerous studies have shown the positive effects of rosmarinic acid on the nervous system. Rosmarinic acid as a herbal compound with anti-inflammatory effects can prevent thedestructive effect of inflammation on the nervous system. ... ...

Abstract	Introduction: Numerous studies have shown the positive effects of rosmarinic acid on the nervous system. Rosmarinic acid as a herbal compound with anti-inflammatory effects can prevent thedestructive effect of inflammation on the nervous system. Furthermore, various studies haveemphasized the advantages of three-dimensional (3D) culture over the two-dimensional (2D) culture of cells. Methods: In this study, thermosensitive chitosan (CH)-based hydrogel as a 3D scaffoldwith the combination of chitosan, beta-glycerol phosphate and hydroxyl ethyl cellulose (CH-GP-HEC) loaded with rosmarinic acid was used to induce neuronal differentiation in humanWharton jelly stem cells. Also, cells were divided into eight groups to evaluate the effect of 3Dcell culture and to compare gene expression in different induction conditions. Results: The results ofgene expression analysis showed the highest expression of neuronal markers in Whartons jelly derived mesenchymal stem cells (WJMSCs) cultured in chitosan, beta-glycerol phosphate and hydroxyl ethyl cellulose (ch-gp-hec) loaded with differentiation medium androsmarinic acid. According to the results of gene expression, rosmarinic acid alone has a positiveeffect on the induction of expression of neural markers. This positive effect is enhanced by cellculture in 3D conditions. Conclusion: This study shows that rosmarinic acid can be considered an inexpensiveand available compound for use in neural tissue engineering. The results of this study indicatethat rosmarinic acid can be considered a cheap and available compound for use in neural tissueengineering.
Language	English
Publishing date	2023-01-01
Publishing country	Iran
Document type	Journal Article
ZDB-ID	2652444-2
ISSN	2228-7442 ; 2008-126X
ISSN (online)	2228-7442
ISSN	2008-126X
DOI	10.32598/bcn.2021.2596.1
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Article ; Online: A comparative study of the effects of crab derived exosomes and doxorubicin in 2 & 3-dimensional in vivo models of breast cancer.

Rezakhani, Leila / Rahmati, Shima / Ghasemi, Sorayya / Alizadeh, Morteza / Alizadeh, Akram

Chemistry and physics of lipids

2022 Volume 243, Page(s) 105179

Abstract: Introduction: Using tissue engineering and modifying the tumor microenvironment, three-dimensional (3D) in vitro and in vivo cancer modeling can be performed with appropriate similarity to native. Exosomes derived from different sources have recently ... ...

Abstract	Introduction: Using tissue engineering and modifying the tumor microenvironment, three-dimensional (3D) in vitro and in vivo cancer modeling can be performed with appropriate similarity to native. Exosomes derived from different sources have recently been used in cancer studies due to their anticancer effects. In this study, the effect of crab derived exosomes in 2 & 3-dimensional (2& 3D) in vivo models of breast cancer (BC) were investigated and compared with the doxorubicin (DOX). Methods: 2D and 3D models of BC were induced using the chitosan/β-glycerol phosphate hydrogel (Ch/β-GP) and 1 × 10 Results and conclusion: Based on the results, the size and weight of tumors in treated groups with exosomes and DOX were reduced significantly (P ≤ 0.001, P ≤ 0.002, P ≤ 0.02) in 2D and 3D models. Changes in VEGF, Bcl2 and P53 gene expression levels were less in the 3D model than in the 2D model. Drug delivery with hydrogel increased tumor inhibition compared to drug injection without hydrogel. Decreased NO secretion was observed in all treatment groups compared to the control group (untreated). Crab exosomes showed anti cancer effects on 2&3D models of BC. 3D model of BC showed greater drug resistance than the 2D model after treating with crab derived exosomes and DOX. 3D model of BC mimics native tumor better than 2D and can be used in cancer studies and for drug screening with greater confidence than 2D model. Also, the use of slow release drug delivery system reduced drug resistance in both models.
MeSH term(s)	Animals ; Brachyura ; Breast Neoplasms/metabolism ; Cell Line, Tumor ; Doxorubicin/pharmacology ; Doxorubicin/therapeutic use ; Exosomes/metabolism ; Female ; Humans ; Hydrogels/metabolism ; Mice ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Proto-Oncogene Proteins c-bcl-2/therapeutic use ; Tumor Microenvironment ; Vascular Endothelial Growth Factor A/metabolism ; Vascular Endothelial Growth Factor A/therapeutic use
Chemical Substances	Hydrogels ; Proto-Oncogene Proteins c-bcl-2 ; Vascular Endothelial Growth Factor A ; Doxorubicin (80168379AG)
Language	English
Publishing date	2022-02-09
Publishing country	Ireland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	213869-4
ISSN	1873-2941 ; 0009-3084
ISSN (online)	1873-2941
ISSN	0009-3084
DOI	10.1016/j.chemphyslip.2022.105179
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Article ; Online: Tumor-resident adenosine-producing mesenchymal stem cells as a potential target for cancer treatment.

Arab, Samaneh / Alizadeh, Akram / Asgharzade, Samira

Clinical and experimental medicine

2021 Volume 21, Issue 2, Page(s) 205–213

Abstract: The development of new therapies based on tumor biology is one of the main topics in cancer treatment. In this regard, investigating the microenvironment and cellular composition of the tumor is of particular interest. Mesenchymal stem cells (MSCs) are a ...

Abstract	The development of new therapies based on tumor biology is one of the main topics in cancer treatment. In this regard, investigating the microenvironment and cellular composition of the tumor is of particular interest. Mesenchymal stem cells (MSCs) are a major group of cells in the tumor tissue and play a critical role in tumor growth and development. Investigating the mechanisms by which MSCs influence tumor growth and progression is very useful in establishing new therapeutic approaches. MSCs have some immunological capacities, including anti-inflammatory, immune-regulatory, and immune-suppressive abilities, which help the tumor growth in the inflammatory condition. They can suppress the proliferation and activation of CD4 + T cells and direct them toward the regulatory phenotype through the release of some factors such as indoleamine 2,3-dioxygenase, prostaglandin E2, and HO-1, PD-1 ligands (PD-L1 and PD-L2) and promote tolerance and apoptosis. Besides, these cells are able to produce adenosine. Adenosine has a key role in controlling the immune system by signaling through receptors located on the surface of immune cells. It plays a very essential role in tumor growth and progression. In the present review, we investigate and introduce adenosine-producing mesenchymal stem cells as a potential target for cancer treatment.
MeSH term(s)	5'-Nucleotidase/antagonists & inhibitors ; Adenosine/physiology ; Humans ; Mesenchymal Stem Cells/drug effects ; Mesenchymal Stem Cells/physiology ; Neoplasms/drug therapy ; Neoplasms/etiology ; Tumor Microenvironment
Chemical Substances	5'-Nucleotidase (EC 3.1.3.5) ; Adenosine (K72T3FS567)
Language	English
Publishing date	2021-01-23
Publishing country	Italy
Document type	Journal Article ; Review
ZDB-ID	2053018-3
ISSN	1591-9528 ; 1591-8890
ISSN (online)	1591-9528
ISSN	1591-8890
DOI	10.1007/s10238-020-00674-9
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Article ; Online: Regenerative Medicine Approaches in COVID-19 Pneumonia.

Asgharzade, Samira / Alizadeh, Akram / Arab, Samaneh

Current stem cell research & therapy

2021 Volume 16, Issue 6, Page(s) 647–655

Abstract: Regenerative medicine (RM) is an interdisciplinary field that uses different approaches to accelerate the repair and regeneration or replace damaged or diseased human cells or tissues to achieve normal tissue function. These approaches include the ... ...

Abstract	Regenerative medicine (RM) is an interdisciplinary field that uses different approaches to accelerate the repair and regeneration or replace damaged or diseased human cells or tissues to achieve normal tissue function. These approaches include the stimulation of the body's own repair processes, transplantation of progenitor cells, stem cells, or tissues, as well as the use of cells and exosomes as delivery-vehicles for cytokines, genes, or other therapeutic agents. COVID-19 pneumonia is a specific disease consistent with diffuse alveolar damage resulting in severe hypoxemia. Therefore, the most serious cause of death from COVID-19 is lung dysfunction. Here, we consider RM approaches to cure COVID-19 pneumonia based on what RM has so far used to treat lung diseases, injuries, or pneumonia induced by other pathogens. These approaches include stem and progenitor cell transplantation, stem cell-derived exosomes, and microRNAs therapy.
MeSH term(s)	COVID-19/therapy ; Exosomes ; Humans ; Mesenchymal Stem Cells ; MicroRNAs/therapeutic use ; Pneumonia/therapy ; Regenerative Medicine ; SARS-CoV-2 ; Stem Cell Transplantation
Chemical Substances	MicroRNAs
Language	English
Publishing date	2021-01-12
Publishing country	United Arab Emirates
Document type	Journal Article
ZDB-ID	2251937-3
ISSN	2212-3946 ; 1574-888X
ISSN (online)	2212-3946
ISSN	1574-888X
DOI	10.2174/1574888X16999210112205826
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Article: A Decrease in CD44 on Cell Surfaces (MKN-45 cell line) After RELA Knockout Using CRISPR/Cas9.

Karimi, Saeid / Salmani, Sima / Alizadeh, Akram / Rezakhani, Leila / Saltanatpour, Zohreh / Ghasemi, Sorayya

International journal of molecular and cellular medicine

2023 Volume 11, Issue 2, Page(s) 117–126

Abstract: The NF-kB signaling pathway was introduced as a key pathway in carcinogenesis that is induced by inflammation in gastrointestinal malignancies. The RelA transcription factor is an important component of this signaling pathway. Furthermore, CD44 is ... ...

Abstract	The NF-kB signaling pathway was introduced as a key pathway in carcinogenesis that is induced by inflammation in gastrointestinal malignancies. The RelA transcription factor is an important component of this signaling pathway. Furthermore, CD44 is implicated in the tumorigenesis and metastasis of gastric cancer. The aim of this study was to assay the effect of RELA knockout on CD44 expression in MKN45 cells. CRISPR/Cas9 was used to knock out RELA in MKN-45. The median fluorescence intensity (MFI) of CD44 before and after RELA knockout is analyzed in MKN45. The CRISPR/Cas9 vector pSpCas9 (BB)-2A-Puro (PX459) was used for gRNA cloning (two guides). The MKN-45 cell line was co-transfected. The purified co-transfected cells with puromycin were cultured and used for the RELA gene expression assay by real-time PCR. Flow cytometry was used for the analysis of the MFI of CD44+ in MKN45. The results showed that 180 nucleotide sequences between exon 2 and exon 3 of RELA were deleted in MKN45. RELA expression significantly (P<0.001) decreased after CRISPR/Cas9 knockout. Compared to the control group, the MFI of CD44 in transfected cells significantly decreased (P <0.001). Knockout of RELA significantly decreased CD44 expression in MKN45 cells. It can be concluded that the NF-kB signaling pathway via RELA is related to CD44 expression and consequently the tumorigenesis of gastric cancer. More studies about this relationship are recommended.
Language	English
Publishing date	2023-03-01
Publishing country	Iran
Document type	Journal Article
ZDB-ID	2697015-6
ISSN	2251-9645 ; 2251-9637
ISSN (online)	2251-9645
ISSN	2251-9637
DOI	10.22088/IJMCM.BUMS.11.2.117
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Article: A comparative study of the effects of crab derived exosomes and doxorubicin in 2 & 3-dimensional in vivo models of breast cancer

Rezakhani, Leila / Rahmati, Shima / Ghasemi, Sorayya / Alizadeh, Morteza / Alizadeh, Akram

Chemistry and physics of lipids. 2022 Mar., v. 243

2022

Abstract: Using tissue engineering and modifying the tumor microenvironment, three-dimensional (3D) in vitro and in vivo cancer modeling can be performed with appropriate similarity to native. Exosomes derived from different sources have recently been used in ... ...

Abstract	Using tissue engineering and modifying the tumor microenvironment, three-dimensional (3D) in vitro and in vivo cancer modeling can be performed with appropriate similarity to native. Exosomes derived from different sources have recently been used in cancer studies due to their anticancer effects. In this study, the effect of crab derived exosomes in 2 & 3-dimensional (2& 3D) in vivo models of breast cancer (BC) were investigated and compared with the doxorubicin (DOX). 2D and 3D models of BC were induced using the chitosan/β-glycerol phosphate hydrogel (Ch/β-GP) and 1 × 10⁶ 4T1 cells in the female mice aged 6–8 weeks. 1 mg/ml exosome and 5 mg/kg DOX were injected by intratumoral (IT), intravenous (IV), and intraperitoneal (IP) methods into mice on day 9, 13, and 17 with and without hydrogel as a drug delivery system. After 21 days, the mice were sacrificed, and the tissues (lung, liver, and tumor) were removed. The weight and size of the tumor were measured. Real-time PCR assessed changes of VEGF, Bcl2, and P53 genes expression levels. Nitric oxide (NO) secretion from the cancer 3D model was evaluated by Griess assay. Based on the results, the size and weight of tumors in treated groups with exosomes and DOX were reduced significantly (P ≤ 0.001, P ≤ 0.002, P ≤ 0.02) in 2D and 3D models. Changes in VEGF, Bcl2 and P53 gene expression levels were less in the 3D model than in the 2D model. Drug delivery with hydrogel increased tumor inhibition compared to drug injection without hydrogel. Decreased NO secretion was observed in all treatment groups compared to the control group (untreated). Crab exosomes showed anti cancer effects on 2&3D models of BC. 3D model of BC showed greater drug resistance than the 2D model after treating with crab derived exosomes and DOX. 3D model of BC mimics native tumor better than 2D and can be used in cancer studies and for drug screening with greater confidence than 2D model. Also, the use of slow release drug delivery system reduced drug resistance in both models.
Keywords	breast neoplasms ; comparative study ; crabs ; doxorubicin ; drug injection ; drug resistance ; exosomes ; females ; gene expression ; hydrogels ; intravenous injection ; liver ; lungs ; models ; nitric oxide ; phosphates ; physics ; quantitative polymerase chain reaction ; secretion
Language	English
Dates of publication	2022-03
Publishing place	Elsevier B.V.
Document type	Article
ZDB-ID	213869-4
ISSN	1873-2941 ; 0009-3084
ISSN (online)	1873-2941
ISSN	0009-3084
DOI	10.1016/j.chemphyslip.2022.105179
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Article: Development of meniscus cartilage using polycaprolactone and decellularized meniscus surface modified by gelatin, hyaluronic acid biomacromolecules: A rabbit model

Abpeikar, Zahra / Javdani, Moosa / Alizadeh, Akram / Khosravian, Pegah / Tayebi, Lobat / Asadpour, Shiva

International journal of biological macromolecules. 2022 May 19,

2022

Abstract: The lack of vascularization in the white-red and white zone of the meniscus causes these zones of tissue to have low self-healing capacity in case of injury and accelerate osteoarthritis (OA). In this study, we have developed hybrid constructs using ... ...

Abstract	The lack of vascularization in the white-red and white zone of the meniscus causes these zones of tissue to have low self-healing capacity in case of injury and accelerate osteoarthritis (OA). In this study, we have developed hybrid constructs using polycaprolactone (PCL) and decellularized meniscus extracellular matrix (DMECM) surface modified by gelatin (G), hyaluronic acid (HU) and selenium (Se) nanoparticles (PCL/DMECM/G/HU/Se), following by the cross-linking of the bio-polymeric surface. Material characterization has been performed on the fabricated scaffold using scanning electron microscopy (SEM), Fourier transforms infrared (FTIR) spectroscopy, swelling and degradation analyses, and mechanical tests. In Vitro, investigations have been conducted by C28/I2 human chondrocyte culture into the scaffold and evaluated the cytotoxicity and cell/scaffold interaction. For the in vivo study, the scaffolds were transplanted into the defect sites of female New Zealand white rabbits. Good regeneration was observed after two months. We have concluded that the designed PCL/DMECM/G/HU construct can be a promising candidate as a meniscus tissue engineering scaffold to facilitate healing.
Keywords	cartilage ; crosslinking ; cytotoxicity ; electron microscopy ; extracellular matrix ; females ; gelatin ; humans ; hyaluronic acid ; osteoarthritis ; rabbits
Language	English
Dates of publication	2022-0519
Publishing place	Elsevier B.V.
Document type	Article
Note	Pre-press version
ZDB-ID	282732-3
ISSN	1879-0003 ; 0141-8130
ISSN (online)	1879-0003
ISSN	0141-8130
DOI	10.1016/j.ijbiomac.2022.05.140
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Article ; Online: A three dimensional in vivo model of breast cancer using a thermosensitive chitosan-based hydrogel and 4 T1 cell line in Balb/c.

Rezakhani, Leila / Alizadeh, Morteza / Alizadeh, Akram

Journal of biomedical materials research. Part A

2020 Volume 109, Issue 7, Page(s) 1275–1285

Abstract: The two-dimensional (2D) models of breast cancer still exhibit a limited success. Whereas, three-dimensional (3D) models provide more similar conditions to the tumor for growth of cancer cells. In this regard, a 3D in vivo model of breast cancer using 4 ... ...

Abstract	The two-dimensional (2D) models of breast cancer still exhibit a limited success. Whereas, three-dimensional (3D) models provide more similar conditions to the tumor for growth of cancer cells. In this regard, a 3D in vivo model of breast cancer using 4 T1 cells and chitosan-based thermosensitive hydrogel were designed. Chitosan/β-glycerol phosphate hydrogel (Ch/β-GP) was prepared with a final ratio of 2% and 10%. The hydrogel properties were examined by Fourier transformed infrared spectroscopy, MTT assay, pH, scanning electron microscopy, and biodegradability assay. 3D model of breast cancer was induced by injection of 1 × 10
MeSH term(s)	Animals ; Breast Neoplasms/pathology ; Cell Line, Tumor ; Chitosan/chemistry ; Female ; Glycerophosphates/chemistry ; Humans ; Hydrogels/chemistry ; Mammary Neoplasms, Animal/pathology ; Mice, Inbred BALB C ; Neoplastic Stem Cells/pathology ; Temperature ; Tissue Scaffolds/chemistry ; Mice
Chemical Substances	Glycerophosphates ; Hydrogels ; Chitosan (9012-76-4) ; beta-glycerophosphoric acid (WWH06G87W6)
Language	English
Publishing date	2020-10-24
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2099989-6
ISSN	1552-4965 ; 1549-3296 ; 0021-9304
ISSN (online)	1552-4965
ISSN	1549-3296 ; 0021-9304
DOI	10.1002/jbm.a.37121
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Article: Isolation and Characterization of Crab Haemolymph Exosomes and Its Effects on Breast Cancer Cells (4T1).

Rezakhani, Leila / Alizadeh, Morteza / Sharifi, Esmaeel / Soleimannejad, Mostafa / Alizadeh, Akram

Cell journal

2021 Volume 23, Issue 6, Page(s) 658–664

Abstract: Objective: The use of animal or plant exosomes in cancer treatment is promising because of their easy access and low cost. Freshwater crabs are used in traditional Iranian medicine to treat cancer. This study aims to determine the anti-cancer properties ...

Abstract	Objective: The use of animal or plant exosomes in cancer treatment is promising because of their easy access and low cost. Freshwater crabs are used in traditional Iranian medicine to treat cancer. This study aims to determine the anti-cancer properties of exosomes removed from freshwater crabs on a breast cancer cell line (4T1) compared to bone marrow mesenchymal stem cells (BMSCs). Materials and methods: In this experimental study, crab haemolymph exosomes were isolated via the precipitation method and characterised by electron microscopy, dynamic light scattering (DLS), and Western blot analysis. The protein concentration and total antioxidant capacity of these exosomes were determined by bicinchoninic acid (BCA) and cupric reducing antioxidant capacity (CUPRAC). The 4T1 cells and BMSCs were treated with exosomes and we assessed the cell survival by the resazurin and MTT assays. The level of nitric oxide (NO) secretion from the 4T1 cells was determined after treatment with the exosomes. Results: Electron microscopy, DLS and Western blot for CD63 confirmed that the isolated exosomes were <100 nm in size and expressed CD63. The total antioxidant capacity in these exosomes was 1.003 μM/ml and the protein concentration was 650 mg/ml. Resazurin and MTT assay results showed a decrease in survival of the 4T1 cells (P≤0.001) after treatment with the exosomes compared to cell growth in the exosome-treated BMSCs. Conclusion: Crab haemolymph contains protein-rich exosomes with antioxidant activities that can have anti-cancer effects on 4T1 cells. These exosomes may be proposed for breast cancer therapeutics.
Language	English
Publishing date	2021-11-23
Publishing country	Iran
Document type	Journal Article
ZDB-ID	2647430-X
ISSN	2228-5814 ; 2228-5806
ISSN (online)	2228-5814
ISSN	2228-5806
DOI	10.22074/cellj.2021.7595
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Article ; Online: The effect of Scrophularia striata on cell attachment and biocompatibility of decellularized bovine pericardia.

Alizadeh, Morteza / Rezakhani, Leila / Taghdiri Nooshabadi, Vajihe / Alizadeh, Akram

Cell and tissue banking

2021 Volume 23, Issue 2, Page(s) 261–269

Abstract: Since using tissue transplantation has faced limitations all over the world, regenerative medicine has introduced decellularized tissues as natural scaffolds and researchers are trying to improve their efficiency and function. In this study, to increase ... ...

Abstract	Since using tissue transplantation has faced limitations all over the world, regenerative medicine has introduced decellularized tissues as natural scaffolds and researchers are trying to improve their efficiency and function. In this study, to increase cell attachment and ultimately cell proliferation on decellularized bovine pericardia, scrophularia striata extract was used. Scrophularia striata is an Iranian traditional medicinal plant. For this aim after decellularization of bovine pericardium and analysis of its morphology, it was incubated in scrophularia striata solution. Next, isolated human adipose-derived mesenchymal stem cells were cultured on the tissue. Finally, MTT assay, nitric oxide assay, and scanning electron microscopy observation were performed. MTT showed an increase in cell survival after treating the tissue with the plant extract after 48 h in a dose dependent manner significantly. The survival of cells in 0.5%, 2.5%, and 5% groups was about 5, 10 and 15 folds higher in comparison to control groups, respectively. Additionally, nitric oxide secretion in 2.5% and 5% samples was three and five folds higher than that in control group, respectively. Moreover, SEM observation indicated an impressive and dose-dependent effect of using Scrophularia striata on tissue biocompatibility. The results of this study showed that using Scrophularia striata increased cell viability and cell attachment on decellularized pericardia which could pave the way for the use of natural extracts of medicinal plants to reduce unwanted effects and make desired changes in decellularized tissues.
MeSH term(s)	Animals ; Cattle ; Humans ; Iran ; Nitric Oxide ; Pericardium ; Plant Extracts/pharmacology ; Scrophularia ; Tissue Engineering ; Tissue Scaffolds
Chemical Substances	Plant Extracts ; Nitric Oxide (31C4KY9ESH)
Language	English
Publishing date	2021-06-26
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2170897-6
ISSN	1573-6814 ; 1389-9333
ISSN (online)	1573-6814
ISSN	1389-9333
DOI	10.1007/s10561-021-09939-3
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