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1.
Zygote ; 32(1): 66-70, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38099429

ABSTRACT

At this time, with advances in medical science, many cancers and chronic diseases are treatable, but one of their side effects is infertility. Some women also want to delay pregnancy for personal reasons. There has been some evidence that kisspeptin activates broad signals by binding to its receptor, suggesting that the role of kisspeptin in direct control of ovarian function includes follicle growth and steroid production. In this study, the effect of kisspeptin on improving the quality and results for human ovarian follicles was investigated. A section of ovary was removed laparoscopically from women between 20 and 35 years of age (n = 12). Pieces were divided randomly into two groups, control and treatment (with 1 µM kisspeptin). Real-time PCR was performed for GDF9, BMP15 and mTOR gene expression assessments. Western blotting was carried out to measure AKT and FOXO3a protein expression. Data were analyzed using one-way analysis of variance (ANOVA) and Tukey's test; means were considered significantly different at a P-value < 0.05. During treatment with the kisspeptin group, maturity genes are expressed. Therefore, kisspeptin is an effective substance to improve the quality of the human ovarian medium as it increases the maturity of follicles.


Subject(s)
Kisspeptins , Ovary , Pregnancy , Humans , Female , Kisspeptins/genetics , Kisspeptins/pharmacology , Kisspeptins/metabolism , Ovarian Follicle/physiology
2.
J Diabetes Metab Disord ; 22(2): 1039-1052, 2023 Dec.
Article in English | MEDLINE | ID: mdl-37975135

ABSTRACT

Objectives: Diabetes mellitus (DM) is a complex metabolic disease that results from impaired insulin secreting pancreatic ß-cells or insulin resistance. Although available medications help control the disease, patients suffer from its complications. Therefore, finding effective therapeutic approaches to treat DM is a priority. Adipose Derived Stem Cells (ADSCs) based therapy is a promising strategy in various regenerative medicine applications, but its systematic translational use is still somewhat out of reach. This review is aimed at clarifying achievements as well as challenges facing the application of ADSCs for the treatment of DM, with a special focus on the mechanisms involved. Methods: Literature searches were carried out on "Scopus", "PubMed" and "Google Scholar" up to September 2022 to find relevant articles in the English language for the scope of this review. Results: Recent evidence showed a significant role of ADSC therapies in DM by ameliorating insulin resistance and hyperglycemia, regulating hepatic glucose metabolism, promoting ß cell function and regeneration, and functioning as a gene delivery tool. In addition, ADSCs could improve diabetic wound healing by promoting collagen deposition, inhibiting inflammation, and enhancing angiogenesis. Conclusion: Overall, this literature review revealed the great clinical implications of ADSCs for translating into the clinical setting for the treatment of diabetes. However, further large-scale and controlled studies are needed to overcome challenges and confirm the safety and optimal therapeutic scheme before daily clinical application. Supplementary Information: The online version contains supplementary material available at 10.1007/s40200-023-01280-8.

4.
BMC Pharmacol Toxicol ; 24(1): 44, 2023 09 05.
Article in English | MEDLINE | ID: mdl-37670365

ABSTRACT

BACKGROUND: Deferoxamine (DFO) angiogenesis induction potential has been demonstrated in earlier studies, but not in the osteonecrosis of the femoral head (ONFH). In this study, we evaluated the outcome of ONFH treated with combined core decompression and local DFO administration loaded on Polylactic Glycolic Acid (PLGA). PATIENTS AND METHODS: In a pilot experimental study, six patients (10 hips) with early-stage non-traumatic ONFH were treated by core decompression, and concurrent injection of local DFO loaded on PLGA scaffold into the subchondral femoral head. Outcome measures were evaluated before the surgery and 12 and 24 months after the surgery and included visual analog scale (VAS) for pain, modified Merle d'Aubigné-Postel (MAP) score for hip function by MRI, and rate of osteonecrosis assessed by the modified. RESULTS: The mean MPA score was 14.7 ± 1.16 before the surgery and 16.7 ± 1.41 one year after the surgery (P = 0.004). The mean VAS for pain was 4.7 ± 1.25 before the surgery and 1.8 ± 1.03 one year after the surgery (P = 0.005). The mean Kerboul angle was 219 ± 58.64 before the operation and 164.6 ± 41.82 one year after the operation (P < 0.001). Osteonecrosis progression or collapse was not seen in any of the patients at the final follow-up. No postoperative side effect attributed to the DFO was noticed, as well. CONCLUSION: In short-term follow-up, combined core decompression and local DFO administration not only prevent the progression of ONFH but also reduces the rate of osteonecrosis significantly. However, future controlled studies are required to confirm the present results. TRIAL REGISTRATION: IRCT20161121031003N3, 16/04/2019.


Subject(s)
Glycols , Osteonecrosis , Humans , Pilot Projects , Femur Head , Decompression
5.
Adv Pharm Bull ; 13(2): 350-360, 2023 Mar.
Article in English | MEDLINE | ID: mdl-37342375

ABSTRACT

Purpose: Insufficient angiogenesis is associated with serious diabetic complications. Recently, adipose-derived mesenchymal stem cells (ADScs) are known to be a promising tool causing therapeutic neovascularization. However, the overall therapeutic efficacy of these cells is impaired by diabetes. This study aims to investigate whether in vitro pharmacological priming with deferoxamine, a hypoxia mimetic agent, could restore the angiogenic potential of diabetic human ADSCs. Methods: Diabetic human ADSCs were treated with deferoxamine and compared to normal and nontreated diabetic ADSCs for the expression of hypoxia inducible factor 1-alpha (HIF-1α), vascular endothelial growth factor (VEGF), fibroblast growth factor-2 (FGF-2) and stromal cell-derived factor-1α (SDF-1α), at mRNA and protein levels, using qRT-PCR, western blotting and ELISA assay. Activities of matrix metalloproteinases (MMPs)-2 and -9 were measured using a gelatin zymography assay. Angiogenic potentials of conditioned media derived from normal, Deferoxamine treated, and non-treated ADSCs were determined by in vitro scratch assay and also three-dimensional tube formation assay. Results: It is demonstrated that deferoxamine (150 and 300 µM) stabilized HIF-1α in primed diabetic ADSCs. At the concentrations used, deferoxamine did not show any cytotoxic effects. In deferoxamine treated ADSCs, expression of VEGF, SDF-1α, FGF-2 and the activity of MMP-2 and MMP-9 were significantly increased compared to nontreated ADSCs. Moreover, deferoxamine increased the paracrine effects of diabetic ADSCs in promoting endothelial cell migration and tube formation. Conclusion: Deferoxamine might be an effective drug for pharmacological priming of diabetic ADSCs to enhance the expression of proangiogenic factors noted via HIF-1α accumulation. In addition, impaired angiogenic potential of conditioned medium derived from diabetic ADSCs was restored by deferoxamine.

6.
Macromol Biosci ; 23(9): e2200574, 2023 09.
Article in English | MEDLINE | ID: mdl-37116215

ABSTRACT

In vitro production of sperm is a desirable idea for fertility preservation in azoospermic men and prepubertal boys suffering from cancer. In this study, a biocompatible porous scaffold based on a triad mixture of silk fibroin (SF), alginate (Alg), and laminin (LM) is developed to facilitate the differentiation of mouse spermatogonia stem cells (SSCs). Following SF extraction, the content is analyzed by SDS-PAGE and stable porous 3D scaffolds are successfully prepared by merely Alg, SF, and a combination of Alg-SF, or Alg-SF-LM through freeze-drying. Then, the biomimetic scaffolds are characterized regarding the structural and biological properties, water absorption capacity, biocompatibility, biodegradability, and mechanical behavior. Neonatal mice testicular cells are seeded on three-dimensional scaffolds and their differentiation efficiency is evaluated using real-time PCR, flow cytometry, immunohistochemistry. Blend matrices showed uniform porous microstructures with interconnected networks, which maintained long-term stability and mechanical properties better than homogenous structures. Molecular analysis of the cells after 21 days of culture showed that the expression of differentiation-related proteins in cells that are developed in composite scaffolds is significantly higher than in other groups. The application of a composite system can lead to the differentiation of SSCs, paving the way for a novel infertility treatment landscape in the future.


Subject(s)
Fibroins , Mice , Animals , Male , Fibroins/chemistry , Tissue Scaffolds/chemistry , Laminin , Porosity , Spermatids/metabolism , Alginates , Haploidy , Semen/metabolism , Tissue Engineering/methods , Silk/chemistry
7.
Adv Pharm Bull ; 12(3): 632-640, 2022 May.
Article in English | MEDLINE | ID: mdl-35935054

ABSTRACT

Purpose: The aim of this study was to evaluate the protective effect of conditioned medium derived from human adipose mesenchymal stem cells (CM-hADSCs) on C28I2 chondrocytes against oxidative stress and mitochondrial apoptosis induced by high glucose (HG). Methods: C28I2 cells were pre-treated with CM-hADSCs for 24 hours followed by HG exposure (75 mM) for 48 hours. MTT assay was used to assess the cell viability. Reactive oxygen species (ROS) and lipid peroxidation were determined by 2,7-dichlorofluorescein diacetate (DCFHDA) and thiobarbituric acid reactive substances (TBARS) assays, respectively. Expressions of glutathione peroxidase 3 (GPX 3), heme oxygenase-1 (HO-1), and NAD(P)H quinone dehydrogenase 1 (NQO1) were analyzed by RT-PCR. Finally, western blot analysis was used to measure Bax, Bcl-2, cleaved caspase-3, and Nrf-2 expression at protein levels. Results: CM-hADSCs pretreatment mitigated the cytotoxic effect of HG on C28I2 viability. Treatment also markedly reduced the levels of ROS, lipid peroxidation, and augmented the expression of HO-1, NQO1, and GPx3 genes in HG-exposed group. CM-ADSCs enhanced Nrf-2 protein expression and reduced mitochondrial apoptosis through reducing Bax/Bcl-2 ratio and Caspase-3 activation. Conclusion: MSCs, probably through its paracrine effects, declined the deleterious effect of HG on chondrocytes. Hence, therapies based on MSCs secretomes appear to be a promising therapeutic approaches to prevent joint complications in diabetic patients.

8.
ACS Biomater Sci Eng ; 8(8): 3485-3497, 2022 08 08.
Article in English | MEDLINE | ID: mdl-35786844

ABSTRACT

Owing to the noticeable increase in the number of patients with impaired wound healing capabilities, developing bioactive wound dressings with supportive physicomechanical and biological properties for clinical wound management has attracted much more attention nowadays. In this regard, engineered dressings with angiogenesis potential are vital for accelerated tissue regeneration. In the current study, nanoniosomal deferoxamine (DFO)-loaded transparent films of egg white-poly(vinyl alcohol) (PVA/EW/ND) were successfully fabricated at three different PVA/EW ratios (1:0, 1:1, and 1:1.5 wt/wt %) through the thin film hydration and solvent casting methods. The developed films' characterizations were carried out using scanning electron microscopy, Fourier transform infrared spectroscopy analysis, uniaxial tensile strength, water uptake, water vapor transmission rate, in vitro degradation, and drug release. The results demonstrated that the various weight ratios of PVA/EW have a significant effect on the microscopic morphology, equilibrium swelling, degradation, and mechanical properties of the films. The drug release profile exhibited a sustained release of DFO with controlled burst-lag phases resembling the Korsmeyer-Peppas pattern. The cytotoxicity and adhesion analysis using human dermal fibroblasts displays the biocompatibility of the developed PVA/EW/ND films and the formation of cellular colonies on the surface. The in vitro angiogenic capability of the developed films evaluated by the scratch wound assay and microbead-assisted tube formation study showed a significant increase in the rate of migration of human umbilical vein endothelial cells and in the number of tube-like structures. Therefore, the achieved results suggest that the presented PVA/EW/ND film has promising potential for effective wound healing applications.


Subject(s)
Deferoxamine , Polyvinyl Alcohol , Bandages , Deferoxamine/pharmacology , Egg White , Endothelial Cells/metabolism , Humans , Polyvinyl Alcohol/chemistry , Polyvinyl Alcohol/metabolism , Polyvinyl Alcohol/pharmacology
9.
J Biomed Mater Res B Appl Biomater ; 110(9): 2089-2099, 2022 09.
Article in English | MEDLINE | ID: mdl-35383398

ABSTRACT

This study aimed to investigate the regenerative effect of decellularized osteochondral ECM xenograft in combination with various biological products in an osteochondral (OC) defect. OC tissue from the sheep femur were obtained and decellularized. The decellularized ECM (dECM) was combined with either platelet-rich fibrin (PRF), amniotic membrane extract (AME), or rabbit bone marrow-derived mesenchymal stromal cells (rBMSCs). The hybrid dECM-biological products were then utilized for the treatment of rabbit OC critical size defects. The regenerative potential of different groups was compared using; MRI, macroscopic assessment, histopathology, and histomorphometry. All characterizations analysis verified successful decellularization. Three months post-surgery, macroscopic findings indicated that dECM was better compared to controls. Also, dECM in combination with AME, PRF, and rBMSCs showed enhanced OC regeneration compared to only dECM (AME: +100%, PRF: +61%, rBMSCs: +28%). In particular, the dECM+AME group results in the best integration of new cartilage into surrounding cartilage tissue. The histomorphometric evaluations demonstrated enhancement in new cartilage formation and bone tissue (86.5 ± 5.9% and 90 ± 7.7%, respectively) for the dECM+AME group compared to other groups. Furthermore, histological results for the dECM+AME elucidated a mature hyaline cartilage tissue that covered the new and symmetrically formed subchondral bone, exhibiting a significantly higher regenerative effect compared to all other treated groups. This finding was also confirmed with MRI images. The current study revealed that in addition to the benefits of dECM alone, its combination with AME indicated to have a superior regenerative effect on OC regeneration. Overall, dECM+AME may be considered a suitable construct for treating knee OC injuries.


Subject(s)
Biological Products , Cartilage, Articular , Knee Injuries , Mesenchymal Stem Cells , Platelet-Rich Fibrin , Amnion/pathology , Animals , Cartilage, Articular/injuries , Decellularized Extracellular Matrix , Extracellular Matrix , Heterografts , Humans , Hyaline Cartilage , Mesenchymal Stem Cells/pathology , Rabbits , Sheep , Tissue Engineering , Tissue Scaffolds
10.
Mol Pharm ; 18(9): 3302-3325, 2021 09 06.
Article in English | MEDLINE | ID: mdl-34297586

ABSTRACT

Microvascular complications are among the major outcomes of patients with type II diabetes mellitus, which are the consequences of impaired physiological functioning of small blood vessels and angiogenic responses in these patients. Overproduction and accumulation of methylglyoxal (MGO), a highly reactive dicarbonyl byproduct of glycolysis pathway, has been acclaimed as the main inducer of impaired angiogenic responses and microvascular dysfunction in diabetic patients with uncontrolled hyperglycemia. Hence, an effective approach to overcome diabetes-associated microvascular complications is to neutralize the deleterious activity of enhanced the concentration of MGO in the body. Owing to the glycation inhibitory activity of Aloe vera whole extract, and capability of l-carnosine, an endogenous dipeptide, in attenuating MGO's destructive activity, we examined whether application of a combination of l-carnosine and A. vera could be an effective way of synergistically weakening this reactive dicarbonyl's impaired angiogenic effects. Additionally, overcoming the poor cellular uptake and internalization of l-carnosine and A. vera, a nanophytosomal formulation of the physical mixture of two compounds was also established. Although l-carnosine and A. vera at whole studied combination ratios could synergistically enhance viability of human umbilical vein endothelial cells (HUVECs) treated with MGO, the 25:1 w/w ratio was the most effective one among the others (27 ± 0.5% compared to 12 ± 0.3 to 18 ± 0.4%; F (4, 15) = 183.9, P < 0.0001). Developing dual nanophytosomes of l-carnosine/A. vera (25:1) combination ratio, we demonstrated superiority of the nanophytosomal formulation in protecting HUVECs against MGO-induced toxicity following a 24-72 h incubation period (17.3, 15.8, and 12.4% respectively). Moreover, 500 µg/mL concentration of dual l-carnosine/A. vera nanophytosomes exhibited a superior free radical scavenging potency (63 ± 4 RFU vs 83 ± 5 RFU; F (5, 12) = 54.81, P < 0.0001) and nitric oxide synthesizing capacity (26.11 ± 0.19 vs 5.1 ± 0.33; F (5, 12) = 2537, P < 0.0001) compared to their physical combination counterpart. Similarly, 500 µg/mL dual l-carnosine/A. vera nanophytosome-treated HUVECs demonstrated a superior tube formation capacity (15 ± 3 vs 2 ± 0.3; F (5, 12) = 30.87, P < 0.001), wound scratch healing capability (4.92 ± 0.3 vs 3.07 ± 0.3 mm/h; F (5, 12) = 39.21, P < 0.0001), and transwell migration (586 ± 32 vs 394 ± 18; F (5, 12) = 231.8, P < 0.001) and invasion (172 ± 9 vs 115 ± 5; F (5, 12) = 581.1, P < 0.0001) activities compared to the physical combination treated ones. Further confirming the proangiogenic activity of the dual l-carnosine/A. vera nanophytosomes, a significant shift toward expression of proangiogenic genes including HIF-1α, VEGFA, bFGF, KDR, and Ang II was reported in treated HUVECs. Overall, dual l-carnosine/A. vera nanophytosomes could be a potential candidate for attenuating type II DM-associated microvascular complications with an impaired angiogenesis background.


Subject(s)
Carnosine/pharmacology , Diabetic Angiopathies/drug therapy , Nanoparticles/therapeutic use , Neovascularization, Physiologic/drug effects , Plant Extracts/pharmacology , Aloe/chemistry , Carnosine/therapeutic use , Diabetic Angiopathies/metabolism , Diabetic Angiopathies/pathology , Drug Synergism , Human Umbilical Vein Endothelial Cells , Humans , Microvessels/drug effects , Plant Extracts/therapeutic use , Pyruvaldehyde/metabolism , Pyruvaldehyde/toxicity
11.
Regen Ther ; 18: 12-20, 2021 Dec.
Article in English | MEDLINE | ID: mdl-33816722

ABSTRACT

BACKGROUND: The present study focused on burning as one of the main causes of mortality with detrimental economic and social effects in the world. The purpose of this study was to investigate the impact of collagen-chitosan gel extracted from Scomberomorus guttatus and shrimp skin in the treatment of second degree burn healing among rats. MATERIALS & METHOD: To fulfill the purpose of the study, chitosan and collagen were extracted respectively from shrimp and Scomberomorus guttatus skin waste by the acid-based method and were evaluated by using Pico Tag, SDS-PAGE. The burn wound healing efficiency of marine collagen-chitosan gel was examined in vivo using rats. Three different ratios of collagen and chitosan blend (Col-CH, 1:3, 1:1 and 3:1) were prepared to obtain the most effective Col-CH gel for burn wound healing and were compared to the animals treated with silver sulfadiazine ointment. Healing burn wound was studied by measuring wound surface area with Image J and histopathologic examination was carried out based on the mean of epithelialization, fibroblastic cells, acute and chronic inflammatory cells, angiogenesis, structure collagen and the amount of collagen on days 15 and 25 post-burn. RESULTS: The results of SDS-PAGE indicated that the extracted collagen was type I and it was composed of two α (α1 and α2) chains. Amino acid analysis showed a much higher glaycin content in extracted collagen which amounted to one-third of the total amino. The wound surface measurement showed a significant reduction in wound size in the group treated with Col-CH (3:1) compared to silver-sulfadiazine treated group on 15th and 25th days. Histopathological findings represented a high score in epithelialization, collagen, collagen structure, fibroblast cell and a decrease in inflammatory cells infiltration in Col-CH (3:1) treated group on 25th day. The most obvious finding of the present study is that chitosan-collagen gel (3:1) represented a better efficacy compared to sulfadiazine in burn wound healing on day 25 post-burn.

12.
J Mater Chem B ; 9(10): 2547, 2021 Mar 17.
Article in English | MEDLINE | ID: mdl-33687050

ABSTRACT

Correction for 'Synergistic effects of magnetic drug targeting using a newly developed nanocapsule and tumor irradiation by ultrasound on CT26 tumors in BALB/c mice' by Ali Shakeri-Zadeh et al., J. Mater. Chem. B, 2015, 3, 1879-1887, DOI: 10.1039/C4TB01708K.

13.
Int J Pharm ; 596: 120213, 2021 Mar 01.
Article in English | MEDLINE | ID: mdl-33493599

ABSTRACT

Wound healing is a complicated process that takes a long time to complete. The three-layer nanofiber wound dressing containing melatonin is highly expected to show remarkable wound repair by reducing the wound healing time. In this study, chitosan (Cs)-polycaprolactone (PCL)/ polyvinylalcohol (PVA)-melatonin (MEL)/ chitosan-polycaprolactone three-layer nanofiber wound dressing was prepared by electrospinning for melatonin sustained release. The characteristics of the wound dressing were further evaluated. The wound dressing had a high water uptake after 24 h (401%), and the water contact angle results showed that it had hydrophilicity effect that supported the cell attachment. The wound healing effect of wound dressing was examined using a full-thickness excisional model of rat skin by the local administration of MEL. The gene expressions of transforming growth factor-beta (TGF-ß1), alpha-smooth muscle actin (α-SMA), collagen type I (COL1A1), and collagen type III (COL3A1) were further studied. The histopathological evaluation showed the complete regeneration of the epithelial layer, remodeling of wounds, collagen synthesis, and reduction in inflammatory cells. The NF + 20% MEL significantly increased TGF-ß1, COL1A1, COL3A1, and α-SMA mRNA expressions. This wound dressing may have a considerable potential as a wound dressing to accelerate the wound healing.


Subject(s)
Chitosan , Melatonin , Nanofibers , Animals , Bandages , Polyvinyl Alcohol , Rats , Wound Healing
14.
J Biomed Mater Res A ; 109(4): 453-478, 2021 04.
Article in English | MEDLINE | ID: mdl-32985051

ABSTRACT

Skin injuries and in particular, chronic wounds, are one of the major prevalent medical problems, worldwide. Due to the pivotal role of angiogenesis in tissue regeneration, impaired angiogenesis can cause several complications during the wound healing process and skin regeneration. Therefore, induction or promotion of angiogenesis can be considered as a promising approach to accelerate wound healing. This article presents a comprehensive overview of current and emerging angiogenesis induction methods applied in several studies for skin regeneration, which are classified into the cell, growth factor, scaffold, and biological/chemical compound-based strategies. In addition, the advantages and disadvantages of these angiogenic strategies along with related research examples are discussed in order to demonstrate their potential in the treatment of wounds.


Subject(s)
Neovascularization, Physiologic , Skin/blood supply , Tissue Engineering/methods , Wound Healing , Angiogenesis Inducing Agents/therapeutic use , Animals , Biocompatible Materials/therapeutic use , Humans , Neovascularization, Physiologic/drug effects , Regeneration/drug effects , Skin/drug effects , Skin Physiological Phenomena/drug effects , Wound Healing/drug effects
15.
Cell J ; 22(Suppl 1): 38-48, 2020 Jul.
Article in English | MEDLINE | ID: mdl-32779432

ABSTRACT

OBJECTIVE: This study aimed to investigate the reliability of diabetic adipose-derived stem cells (ADSCs) for autologous cell-based therapies by exploring the functionality of signalling pathways involved in regulating oxidative stress and apoptosis. MATERIALS AND METHODS: In this experimental study, ADSCs were isolated from streptozotocin (STZ)-induced diabetic rats (dADSCs) and normal rats (nADSCs). The colonies derived from dADSCs and nADSCs were compared by colony-forming unit (CFU) assay. Reactive oxygen species (ROS) formation and total antioxidant power (TAP) were also measured. Furthermore, the expression of antioxidant enzymes, including catalase (Cat), superoxide dismutase (Sod)-1 and -3, glutathione peroxidase (Gpx)-1, -3 and -4 was measured at mRNA level by semi-quantitative reverse transcriptase polymerase chain reaction assay. The expression of Bax, Bcl2, caspase-3, total and phosphorylated c-Jun N-terminal kinase (JNK) and P38 Mitogen-Activated Protein Kinase (MAPK) at protein level was analyzed by western blotting. RESULTS: The results of this study indicated that viability and plating efficiency of dADSCs were significantly lower than those of nADSCs. ROS generation and TAP level were respectively higher and lower in dADSCs. The gene expression of antioxidant enzymes, including Cat, Sod-1, Gpx-3 and Gpx-4 in dADSCs was significantly greater than that in nADSCs. However, Sod-3 and Gpx-1 mRNA levels were decreased in dADSCs. Moreover, Bax/Bcl-2 protein ratio, caspase-3 protein expression and phosphorylation of JNK and P38 proteins were increased in dADSCs compared to nADSCs. CONCLUSION: Taken together, diabetes might impair the cellular functions of dADSCs as candidates for autologous cellbased therapies. This impairment seems to be mediated by JNK, P38 MAPKs, and mitochondria pathway of apoptosis and partly by disruption of antioxidant capacity.

16.
Cells Tissues Organs ; 209(1): 13-25, 2020.
Article in English | MEDLINE | ID: mdl-32634811

ABSTRACT

Due to their ability in self-renewing and differentiation into a wide variety of tissues, mesenchymal stem cells (MSCs) exhibit outstanding potential for regenerative medicine. This study was aimed at investigating different aspects of MSC therapy in controlling hyperglycemia in streptozotocin-induced diabetes rats. Using an islet cell differentiation protocol, bone marrow (BM) MSCs were differentiated into insulin-producing cells (IPCs). The differentiation process was evaluated by immunocytochemistry, reverse transcriptase PCR, and dithizone staining. Diabetic animals in 4 diabetic individual groups received normal saline, BM-MSCs, coadministration of BM-MSCs with supernatant, and IPCs. Blood glucose and insulin levels were monitored during the experiment. Immunohistochemical analysis of the pancreas was performed at the end of the experiment. Administration of BM-MSCs could not reverse glucose and insulin levels in experimental animals as efficiently as cotransplantation of BM-MSCs with supernatant. The effect of coadministration of BM-MSCs with supernatant and transplantation of IPCs on controlling hyperglycemia is comparable. Immunohistochemical analysis showed that number and size of islets per section were significantly increased in groups receiving IPCs and BM-MSC-supernatant compared to the MSC group of animals. In conclusion, coadministration of BM-MSCs with supernatant could be used as efficiently as IPC transplantation in controlling hyperglycemia in diabetic rats.


Subject(s)
Diabetes Mellitus, Type 1/therapy , Hyperglycemia/therapy , Mesenchymal Stem Cells/metabolism , Animals , Cell Differentiation , Male , Mesenchymal Stem Cells/cytology , Rats , Rats, Wistar
17.
Acta Biomater ; 113: 144-163, 2020 09 01.
Article in English | MEDLINE | ID: mdl-32590170

ABSTRACT

Abnormal wound healing caused by the over-expression of collagen and fibronectin leads to fibrosis, the major complication of all treatment modalities. A three-layer nanofiber scaffold was designed, optimized, and fabricated. This scaffold comprised two supportive polycaprolactone (PCL)-chitosan layers on the sides and a polyvinyl alcohol (PVA)-metformin hydrochloride (metformin-HCl) in the middle. The physico-chemical properties of scaffold, such as mechanical characteristics, degradation, swelling, and in-vitro drug release, were evaluated. The biological tests, including cell viability in response to metformin-HCl and Tween 80, scaffold biocompatibility, cell attachment, and antibacterial activity, were further conducted. The wound healing effect of scaffold loaded with metformin-HCl (MSc+Met) was assessed in donut-shaped silicone splints in rats. Histopathological and immunohistochemical evaluation as well as mRNA expression levels of fibrosis markers were also studied. SEM images indicated a uniform, bead-less morphology and high porosity. Surface modification of scaffold by Tween 80 improved the surface hydrophilicity and enhanced the adhesion and proliferation of fibroblasts. The scar area on day 15 in MSc+Met was significantly lower than that of other groups. Histopathological and immunohistochemical evaluation revealed that group MSc+Met was the best, having significantly lower inflammation, higher angiogenesis, the smallest scar width and depth, maximum epitheliogenesis score, and the most optimal modulation of collagen density. Local administration of metformin-HCl substantially down-regulated the expression of fibrosis-involved genes: transforming growth factor (TGF-ß1), collagen type 1 (Col-I), fibronectin, collagen type 3 (Col-III), and alpha-smooth muscle actin (α-SMA). Inhibiting these genes alleviates scar formation but delays wound healing; thus, an engineered scaffold was used to prevent delay in wound healing. These results provided evidence for the first time to introduce an anti-fibrogenic slow-releasing scaffold, which acts in a dual role, both alleviating fibrosis and accelerating wound healing.


Subject(s)
Delayed-Action Preparations , Hypoglycemic Agents , Metformin , Nanofibers , Animals , Collagen , Delayed-Action Preparations/pharmacology , Hypoglycemic Agents/administration & dosage , Metformin/pharmacology , Rats , Tissue Scaffolds , Wound Healing
18.
Biochem Cell Biol ; 98(3): 405-414, 2020 06.
Article in English | MEDLINE | ID: mdl-31940231

ABSTRACT

Parkinson's disease (PD) is a neurodegenerative disease accompanied by a low expression level of cerebral hypoxia-inducible factor (HIF-1α). Hence, activating the hypoxia-signaling pathway may be a favorable therapeutic approach for curing PD. This study explored the efficacy of hydralazine, a well-known antihypertensive agent, for restoring the impaired HIF-1 signaling in PD, with the aid of 6-hydroxydopamine (6-OHDA)-exposed SH-SY5Y cells. The cytotoxicity of hydralazine and 6-OHDA on the SH-SY5Y cells were evaluated by MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] and apoptosis detection assays. The activities of malondialdehyde, nitric oxide (NO), ferric reducing antioxidant power (FRAP), and superoxide dismutase (SOD) were also measured. Expression levels of HIF-1α and its downstream genes at the protein level were assessed by Western blotting. Hydralazine showed no toxic effects on SH-SY5Y cells, at the concentration of ≤50 µmol/L. Hydralazine decreased the levels of apoptosis, malondialdehyde, and NO, and increased the activities of FRAP and SOD in cells exposed to 6-OHDA. Furthermore, hydralazine up-regulated the protein expression levels of HIF-1α, vascular endothelial growth factor, tyrosine hydroxylase, and dopamine transporter in the cells also exposed to 6-OHDA, by comparison with the cells exposed to 6-OHDA alone. In summary, hydralazine priming could attenuate the deleterious effects of 6-OHDA on SH-SY5Y cells by increasing cellular antioxidant capacity, as well as the protein levels of HIF-1α and its downstream target genes.


Subject(s)
Hydralazine/pharmacology , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Oxidopamine/pharmacology , Parkinson Disease/drug therapy , Parkinson Disease/metabolism , Antioxidants/metabolism , Apoptosis , Cell Hypoxia , Cell Line, Tumor , Cell Survival , Dopamine/metabolism , Humans , Malondialdehyde/metabolism , Nitric Oxide/metabolism , Superoxide Dismutase/metabolism
19.
J Recept Signal Transduct Res ; 39(1): 1-8, 2019 Feb.
Article in English | MEDLINE | ID: mdl-31237181

ABSTRACT

Aims: A number of epidemiological and experimental documents emphasizes a close relation between type 2 diabetes mellitus (T2DM) and the progression of osteoarthritis (OA). In order to understand the underlying mechanisms of atorvastatin (ATO) in OA, we sought to explore the effect of ATO on high glucose (HG)-mediated NF-κB activation in cultured C28I2 chondrocytes. Methods: The effects of various concentrations of ATO on C28I2 human chondrocytes viability were assessed to obtain the non-cytotoxic concentrations of drug by MTT-assay. The cells were pretreated with 0.01 and 0.1 µM ATO for 6 h, followed by incubation with HG (75 mM) for 72 h. The protein expressions of IκBα (np), IκBα (p), NF-κB (p), and NF-κB (np) were analyzed by western blotting. The effects of ATO on the mRNA expressions of chondrogenic specific markers including SOX9, aggrecan, collagen type 2, and COMP were evaluated by reverse transcription-polymerase chain reaction. Results: ATO in determined concentrations had no cytotoxic effect on C28I2 cells after 72 h. ATO pretreatment exerted remarkable protective effects against HG-induced cytotoxicity. Moreover, ATO decreased IκBα phosphorylation and NF-κB nuclear translocation. It was also able to improve the gene expression of chondrogenic-specific markers in C28I2 cells compared to the control group. Conclusion: ATO could significantly decrease HG-induced inflammation in the cultured C28I2 chondrocytes through the activation of canonical NF-κB signaling pathway. These beneficial effects of ATO may be owing to its anti-inflammatory properties. Therefore, treatment with ATO may provide an effective approach to prevent HG-induced cartilage destruction in clinical setting.


Subject(s)
Apoptosis/drug effects , Atorvastatin/pharmacology , Cell Proliferation/drug effects , Chondrocytes/drug effects , Glucose/pharmacology , NF-kappa B/metabolism , Protective Agents/pharmacology , Cells, Cultured , Chondrocytes/metabolism , Chondrocytes/pathology , Gene Expression Regulation/drug effects , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , NF-kappa B/genetics , Signal Transduction , Sweetening Agents/pharmacology
20.
J Physiol Biochem ; 75(2): 153-162, 2019 Jun.
Article in English | MEDLINE | ID: mdl-30796627

ABSTRACT

The high glucose concentration is able to disturb chondrocyte homeostasis and contribute to OA pathogenesis. This study was designed to investigate the protective effects of atorvastatin (ATO) on high glucose (HG)-mediated oxidative stress and mitochondrial apoptosis in C28I2 human chondrocytes. The protective effect of ATO (0.01 and 0.1 µM) on HG (75 mM)-induced oxidative stress and apoptosis was evaluated in C28I2 cells. The effects of ATO on HG-induced intracellular ROS production and lipid peroxidation were detected and the protein expression levels of Bax, Bcl-2, caspase-3, total and phosphorylated JNK and P38 MAPKs were analyzed by Western blotting. The mRNA expression levels of antioxidant enzymes including heme oxygenase-1, NAD(P)H quinine oxidoreductase, glutathione S-transferase-P1, catalase, superoxide dismutase-1, glutathione peroxidase-1, -3, -4 were evaluated by reverse transcription-polymerase chain reaction. Pretreatment with ATO remarkably increased the gene expression levels of antioxidant enzymes and reduced HG-induced elevation of ROS, lipid peroxidation, Bax/Bcl-2 ratio, caspase-3 activation, and JNK and P38 phosphorylation. Atorvastatin could considerably reduce HG-induced oxidative stress and mitochondrial apoptosis through increasing the expression of antioxidant enzymes. Atorvastatin may be considered as a promising agent to prevent high glucose-induced cartilage degradation in OA patients.


Subject(s)
Apoptosis/drug effects , Atorvastatin/pharmacology , Glucose/toxicity , Mitochondria/metabolism , Oxidative Stress/drug effects , Caspase 3/metabolism , Cell Line , Chondrocytes/drug effects , Chondrocytes/metabolism , Humans , Lipid Peroxidation/drug effects , MAP Kinase Kinase 4/metabolism , Oxidoreductases/metabolism , Proto-Oncogene Proteins c-bcl-2/metabolism , Reactive Oxygen Species/metabolism , Signal Transduction/drug effects , bcl-2-Associated X Protein/metabolism , p38 Mitogen-Activated Protein Kinases/metabolism
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