GDF11: An emerging therapeutic target for liver diseases and fibrosis.

Growth differentiation factor 11 (GDF11), also known as bone morphogenetic protein 11 (BMP11), has been identified as a key player in various biological processes, including embryonic development, aging, metabolic disorders and cancers. GDF11 has also emerged as a critical component in liver development, injury and fibrosis. However, the effects of GDF11 on liver physiology and pathology have been a subject of debate among researchers due to conflicting reported outcomes. While some studies suggest that GDF11 has anti-aging properties, others have documented its senescence-inducing effects. Similarly, while GDF11 has been implicated in exacerbating liver injury, it has also been shown to have the potential to reduce liver fibrosis. In this narrative review, we present a comprehensive report of recent evidence elucidating the diverse roles of GDF11 in liver development, hepatic injury, regeneration and associated diseases such as non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), liver fibrosis and hepatocellular carcinoma. We also explore the therapeutic potential of GDF11 in managing various liver pathologies.

The effects of simvastatin-loaded nanoliposomes on human multilineage liver fibrosis microtissue.

In this in vitro study, for the first time, we evaluate the effects of simvastatin-loaded liposome nanoparticles (SIM-LipoNPs) treatment on fibrosis-induced liver microtissues, as simvastatin (SIM) has shown potential benefits in the non-alcoholic fatty liver disease process. We developed multicellular liver microtissues composed of hepatic stellate cells, hepatoblastoma cells and human umbilical vein endothelial cells. The microtissues were supplemented with a combination of palmitic acid and oleic acid to develop fibrosis models. Subsequently, various groups of microtissues were exposed to SIM and SIM-LipoNPs at doses of 5 and 10 mg/mL. The effectiveness of the treatments was evaluated by analysing cell viability, production of reactive oxygen species (ROS) and nitric oxide (NO), the expression of Kruppel-like factor (KLF) 2, and pro-inflammatory cytokines (interleukin(IL)-1 α, IL-1 ß, IL-6 and tumour necrosis factor-α), and the expression of collagen I. Our results indicated that SIM-LipoNPs application showed promising results. SIM-LipoNPs effectively amplified the SIM-klf2-NO pathway at a lower dosage compatible with a high dosage of free SIM, which also led to reduced oxidative stress by decreasing ROS levels. SIM-LipoNPs administration also resulted in a significant reduction in pro-inflammatory cytokines and Collagen I mRNA levels, as a marker of fibrosis. In conclusion, our study highlights the considerable therapeutic potential of using SIM-LipoNPs to prevent liver fibrosis progress, underscoring the remarkable properties of SIM-LipoNPs in activating the KLF2-NO pathway and anti-oxidative and anti-inflammatory response.

Droplet-based microfluidics: an efficient high-throughput portable system for cell encapsulation.

One of the goals of tissue engineering and regenerative medicine is restoring primary living tissue function by manufacturing a 3D microenvironment. One of the main challenges is protecting implanted non-autologous cells or tissues from the host immune system. Cell encapsulation has emerged as a promising technique for this purpose. It involves entrapping cells in biocompatible and semi-permeable microcarriers made from natural or synthetic polymers that regulate the release of cellular secretions. In recent years, droplet-based microfluidic systems have emerged as powerful tools for cell encapsulation in tissue engineering and regenerative medicine. These systems offer precise control over droplet size, composition, and functionality, allowing for creating of microenvironments that closely mimic native tissue. Droplet-based microfluidic systems have extensive applications in biotechnology, medical diagnosis, and drug discovery. This review summarises the recent developments in droplet-based microfluidic systems and cell encapsulation techniques, as well as their applications, advantages, and challenges in biology and medicine. The integration of these technologies has the potential to revolutionise tissue engineering and regenerative medicine by providing a precise and controlled microenvironment for cell growth and differentiation. By overcoming the immune system's challenges and enabling the release of cellular secretions, these technologies hold great promise for the future of regenerative medicine.

Expression of miR-let7b and miR-19b in progressive familial intrahepatic cholestasis (PFIC) children.

BACKGROUND: MicroRNAs (miRNAs) are a group of small non-coding RNAs that bind to the target mRNA and regulate gene expression. Recently circulating microRNAs were investigated as markers of diseases and therapeutic targets. Although various studies analyze the miRNA expression in liver disease, these studies on PFIC are few. Progressive familial intrahepatic cholestasis (PFIC) is a rare liver disease with autosomal recessive inheritance. Most children with PFIC progress to cirrhosis and liver failure and consequently need to have a liver transplant. The aim of this study is the investigation of the miR-19b and miR-let7b expression levels in Iranian PFIC children. METHODS: 25 PFIC patients, 25 healthy children and 25 Biliary Atresia patients were considered as case and two control groups respectively. Blood samples were obtained and Liver function tests (LFTs) were measured. After RNA extraction and cDNA synthesis, quantitative PCR was performed using specific primers for miR-19b and miR-let7b. The U6 gene is used as an internal control. RESULTS: qPCR on PFIC patients' samples demonstrated that the miR-19b and the miR-let7b expression were significantly decreased in patients compared to the control groups, with a p-value<0.0001 and p-value=0.0006 receptively. CONCLUSION: In conclusion, circulating micro-RNA like miR-19b and miR-let7b have a potential opportunity to be a non-invasive diagnostic marker or therapeutic target for PFIC in the future.

Indirect co-culture of islet cells in 3D biocompatible collagen/laminin scaffold with angiomiRs transfected mesenchymal stem cells.

Diabetes is an autoimmune disease in which the pancreatic islets produce insufficient insulin. One of the treatment strategies is islet isolation, which may damage these cells as they lack vasculature. Biocompatible scaffolds are one of the efficient techniques for dealing with this issue. The current study is aimed to determine the effect of transfected BM-MSCS with angiomiR-126 and -210 on the survival and functionality of islets loaded into a 3D scaffold via laminin (LMN). AngiomiRs/Poly Ethylenimine polyplexes were transfected into bone marrow-mesenchymal stem cells (BM-MSCs), followed by 3-day indirect co-culturing with islets laden in collagen (Col)-based hydrogel scaffolds containing LMN. Islet proliferation and viability were significantly increased in LMN-containing scaffolds, particularly in the miRNA-126 treated group. Insulin gene expression was superior in Col scaffolds, especially, in the BM-MSCs/miRNA-126 treated group. VEGF was upregulated in the LMN-containing scaffolds in both miRNA-treated groups, specifically in the miRNA-210, leading to VEGF secretion. MiRNAs' target genes showed no downregulation in LMN-free scaffolds; while a drastic downregulation was seen in the LMN-containing scaffolds. The highest insulin secretion was recorded in the Oxidized dextran (Odex)/ColLMN+ group with miRNA-126. LMN-containing biocompatible scaffolds, once combined with angiomiRs and their downstream effectors, promote islets survival and restore function, leading to enhanced angiogenesis and glycemic status.

Cholestasis-Associated Pulmonary Inflammation, Oxidative Stress, and Tissue Fibrosis: The Protective Role of the Biogenic Amine Agmatine.

INTRODUCTION: Cholestasis is the stoppage of bile flow, leading to the accumulation of potentially cytotoxic bile components in the liver. These cytotoxic molecules affect many organs. Cholestasis-induced lung injury is a severe complication that could lead to tissue fibrosis and respiratory distress. Substantial evidence indicates the role of oxidative stress and inflammatory response in the pathogenesis of cholestasis-associated pulmonary damage. Agmatine (AGM; 1-amino-4-guanidinobutane) is a biogenic amine endogenously synthesized in the human body. This amine provides potent anti-inflammatory and antioxidant properties. METHODS: In the current study, a series (six C57BL/6J male mice/group) of bile duct-ligated (BDL) animals were monitored at scheduled intervals (7, 14, and 28 days after the BDL operation) to ensure inflammatory response in their lung tissue (by analyzing their bronchoalveolar lavage fluid [BALF]). It was found that the level of inflammatory cells, pro-inflammatory cytokines, and IgG in the BALF reached their maximum level on day 28 after the BDL surgery. Therefore, other research groups were selected as follows: 1) Sham-operated (2.5 mL/kg normal saline, i.p., for 28 consecutive days), 2) BDL, 3) BDL + AGM (1 mg/kg/day, i.p., for 28 consecutive days), and 4) BDL + AGM (10 mg/kg/day, i.p., for 28 consecutive days). Then, the BALF was monitored at scheduled time intervals (7, 14, and 28 days post-BDL). RESULTS: It was found that pro-inflammatory cytokines (TNF-α, IL-6, and IL-1ß), bile acids, bilirubin, and inflammatory cells (monocytes, neutrophils, and lymphocytes) were significantly increased in the BALF of BDL mice. Moreover, biomarkers of oxidative stress were significantly increased in the pulmonary tissue of cholestatic animals. Lung tissue histopathological changes, tissue collagen deposition, and increased TGF-ß were also detected. It was found that AGM significantly ameliorated cholestasis-induced lung injury. CONCLUSION: The effects of AGM on inflammatory indicators, oxidative stress biomarkers, and tissue fibrosis seem to play a pivotal role in its protective properties.

Osteoprotective effects of kefir fortified with omega-3 and vitamin C in ovariectomized rats.

Nutritional interventions can be valuable for the prevention of postmenopausal osteoporosis. This study aimed to investigate the effects of kefir fortified with omega-3 and vitamin C on the bone and uterus parameters of ovariectomized rats. Seventy-seven female Sprague-Dawley rats were ovariectomized or sham-operated. The ovariectomized rats were assigned to six groups and received 1 ml/day of distilled water (OVX group), milk, kefir, kefir fortified with omega-3 fatty acids (kefir+ω3), kefir fortified with vitamin C (kefir+vit-C) or kefir fortified with omega-3 and vitamin C (kefir+ω3+vit-C) for 12 weeks. The sham group also received 1ml/day of distilled water. Subsequently, bone mineral content (BMC) and bone mineral density (BMD) of various bones were assessed. Femurs and uteri were harvested for bone ash analysis and histopathological examinations, respectively. Sera were analyzed for carboxy-terminal cross-linked telopeptide of type 1 collagen, procollagen type 1 amino-terminal propeptide, calcium, phosphorous, tumor necrosis factor-α (TNF-α) and total antioxidant capacity levels. Ovariectomy resulted in significant reduction in bone density (P<0.05). Kefir+ω3+vit-C significantly improved BMC of lumbar spine (0.699±0.027 g compared with 0.580±0.018 in the OVX group), and kefir, kefir+vit-C and kefir+ω3+vit-C significantly increased BMD of tibia (0.118±0.003 g/cm2, 0.119±0.001 and 0.120±0.004 compared with 0.102±0.005 in the OVX group). Moreover, ovariectomy markedly elevated TNF-α level, which was significantly reversed by kefir+ω3+vit-C. Significant atrophy of the uterus was observed following ovariectomy, although the uterus parameters did not change by any of the interventions. In conclusion, kefir fortified with omega-3 fatty acids and vitamin C may have protective effects against bone loss through suppressing inflammation.

Short-term beneficial effects of human dental pulp stem cells and their secretome in a rat model of mild ischemic stroke.

Although cell therapy has been applied in regenerative medicine for decades, recent years have seen greatly increased attention being given to the use of stem cell-based derivatives such as cell-free secretome. Dental pulp stem cells (DPSCs) are widely available, easily accessible, and have high neuroprotective and angiogenic properties. In addition, DPSC-derived secretome contains a rich mixture of trophic factors. The current investigation evaluated the short-term therapeutic effects of human DPSCs and their secretome in a rat model of mild ischemic stroke. Mild ischemic stroke was induced by 30 min middle cerebral artery occlusion, and hDPSCs or their secretome was administered intra-arterially and intranasally. Neurological function, infarct size, spatial working memory, and relative expression of seven target genes in two categories of neurotrophic and angiogenic factors were assessed three days after stroke. In the short-term, all treatments reduced the severity of neurological and histological deficits caused by ischemic stroke. Moreover, transient middle cerebral artery occlusion led to the striatal and cortical over-expression of BDNF, NT-3, and angiogenin, while NGF and VEGF expression was reduced. Almost all interventions were able to modulate the expression of target genes after stroke. The obtained data revealed that single intra-arterial administration of hDPSCs or their secretome, single intranasal transplantation of hDPSCs, or repeated intranasal administration of hDPSC-derived secretome was able to ameliorate the devastating effects of a mild stroke, at least in the short-term.

microRNAs Alterations of Myocardium and Brain Ischemia-Reperfusion Injury: Insight to Improve Infarction.

Heart and cerebral infarctions, as two important ischemic diseases, lead to the death of tissues due to inadequate blood supply and high mortality worldwide. These statuses are started via blockage of vessels and depletion of oxygen and nutrients which affected these areas. After reperfusion and restoration of oxygen supply, more severe injury was mediated by multifaceted cascades of inflammation and oxidative stress. microRNAs (miRNAs) as the regulator of biological and pathological pathways can adjust these conditions by interaction with their targets. Also, miRNAs can be modulated by preconditioning and external agents that may improve the functional outcome after IRI. miRNAs might be considered as therapeutic approaches to improve the symptoms of patients after myocardial infarction and cerebral ischemic stroke.

Vesicles of yeast cell wall-sitagliptin to alleviate neuroinflammation in Alzheimer's disease.

A cell-based drug delivery system based on yeast-cell wall loaded with sitagliptin, a drug with an anti-inflammatory effect, was developed to control neuroinflammation associated with Alzheimer's disease. The optimized nanoparticles had a spherical shape with a negative surface charge, and were shown to be less toxic than the carrier and sitagliptin. Moreover, the nanoparticles caused anti-inflammatory effects against tumor necrosis factor-alpha in mice model of neuroinflammation. The pharmacokinetics study showed the brain concentration of drug in the nanoparticles group was much higher than in the control group. To evaluate the effect of P-glycoprotein on brain entry of sitagliptin, the experiment was repeated with verapamil, as a P-glycoprotein inhibitor. Brain concentration of the nanoparticles group remained approximately unchanged, proving the "Trojan Horse" effect of the developed nanocarriers. The results are promising for using yeast-cell wall as a carrier for targeted delivery to immune cells for the management of inflammation.

Stem cells and common biomaterials in dentistry: a review study.

Stem cells exist as normal cells in embryonic and adult tissues. In recent years, scientists have spared efforts to determine the role of stem cells in treating many diseases. Stem cells can self-regenerate and transform into some somatic cells. They would also have a special position in the future in various clinical fields, drug discovery, and other scientific research. Accordingly, the detection of safe and low-cost methods to obtain such cells is one of the main objectives of research. Jaw, face, and mouth tissues are the rich sources of stem cells, which more accessible than other stem cells, so stem cell and tissue engineering treatments in dentistry have received much clinical attention in recent years. This review study examines three essential elements of tissue engineering in dentistry and clinical practice, including stem cells derived from the intra- and extra-oral sources, growth factors, and scaffolds.

Glycine protects the male reproductive system against lead toxicity via alleviating oxidative stress, preventing sperm mitochondrial impairment, improving kinematics of sperm, and blunting the downregulation of enzymes involved in the steroidogenesis.

Lead (Pb) is a highly toxic heavy metal widely dispersed in the environment because of human industrial activities. Many studies revealed that Pb could adversely affect several organs, including the male reproductive system. Pb-induced reproductive toxicity could lead to infertility. Thus, finding safe and clinically applicable protective agents against this complication is important. It has been found that oxidative stress plays a fundamental role in the pathogenesis of Pb-induced reprotoxicity. Glycine is the simplest amino acid with a wide range of pharmacological activities. It has been found that glycine could attenuate oxidative stress and mitochondrial impairment in various experimental models. The current study was designed to evaluate the role of glycine in Pb-induced reproductive toxicity in male mice. Male BALB/c mice received Pb (20 mg/kg/day; gavage; 35 consecutive days) and treated with glycine (250 and 500 mg/kg/day; gavage; 35 consecutive days). Then, reproductive system weight indices, biomarkers of oxidative stress in the testis and isolated sperm, sperm kinetic, sperm mitochondrial indices, and testis histopathological alterations were monitored. A significant change in testis, epididymis, and Vas deferens weight was evident in Pb-treated animals. Markers of oxidative stress were also significantly increased in the testis and isolated sperm of the Pb-treated group. A significant disruption in sperm kinetic was also evident when mice received Pb. Moreover, Pb exposure caused significant deterioration in sperm mitochondrial indices. Tubular injury, tubular desquamation, and decreased spermatogenic index were histopathological alterations detected in Pb-treated mice. It was found that glycine significantly blunted oxidative stress markers in testis and sperm, improved sperm mitochondrial parameters, causing considerable higher velocity-related indices (VSL, VCL, and VAP) and percentages of progressively motile sperm, and decreased testis histopathological changes in Pb-exposed animals. These data suggest glycine as a potential protective agent against Pb-induced reproductive toxicity. The effects of glycine on oxidative stress markers and mitochondrial function play a key role in its protective mechanism.

Immunity to hepatitis A virus in liver transplant recipients: A population-based study in Iran.

BACKGROUND: Acute hepatitis A is usually a self-limited viral disease but can be severe and even fatal in special groups of patients including those with chronic liver disease and recipients of liver transplantation. To take appropriate preventive measures, it is important to determine the immune status against the hepatitis A virus in patients at risk of grave clinical outcomes following infection. To assess the need for immunization against hepatitis A, we aimed to determine the immune status against hepatitis A in a population of liver transplant recipients. We also investigated the association between hepatitis A immune status and demographic factors such as age and sex, underlying liver disease, source of drinking water, geographical area of residence and socioeconomic status. METHODS: This cross-sectional study was performed on 242 recipients of allogenic liver transplants at Abu Ali Sina Organ Transplant Hospital in Shiraz, Iran, between January 2017 and April 2017. The level of immunity was assessed using hepatitis A antibody detection kits. RESULTS: The rate of immunity against hepatitis A was detected as 88.8% in our study population. In the multivariable logistic regression model, younger age (OR=1.175, P<0.001) and higher education level (OR=2.142, P=0.040) were the main determinants of non-immune status. However, hepatitis A immunity was independent of gender, monthly family income, water supply source, residential area and underlying liver disorder. CONCLUSION: Although a significant proportion of liver transplant recipients in this study showed evidence of natural immunity to hepatitis A, a considerable proportion of younger patients and those with a higher level of education were non-immune. The results of this study signify the importance of screening for hepatitis A immunity in this at-risk population of patients and the need for vaccinating non-immune patients.

Use of Magnetic Resonance Imaging to Assess the Regenerative Effects of Adipose Tissue-Derived Mesenchymal Stem Cells in a Rabbit Cartilaginous Laryngeal Defect Model.

Background: Stenosis and scar formation after repair of laryngeal tissue defects are serious problems that can significantly influence a patient's quality of life. Objective: In this study, we evaluated the use of magnetic resonance imaging to assess the efficacy of adipose tissue-derived mesenchymal stem cells (ASCs) on cartilaginous regeneration in an experimental rabbit model. Methods: Ten male white Dutch rabbits each had a 5 mm cartilaginous defect created surgically in the right and left thyroid lamina. On the right side, ASCs labeled with iron oxide particles were infused. As a control, the left side was left untreated. Repair of the defects were then evaluated by direct observation, histological evaluation, and magnetic resonance imaging monitoring done on days 1, 7, 14, and 28. Results: Histological examination revealed that compared with control, transplanted ASCs significantly increased cartilage regeneration (P ˂ 0.001), reduced inflammation (P ˂ 0.001), and fibrosis (P = 0.050). Magnetic resonance imaging tracking showed accurate placement and viability of the infused ASCs, as evidenced by low signal intensity onT2 weighted images at the level of the right thyroid cartilage. Conclusions: Infusion of ASCs improved laryngeal regeneration of surgically induced cartilaginous defects while decreasing fibrous tissue formation in this in vivo rabbit model. Furthermore, magnetic resonance imaging was shown to be a useful, noninvasive method to track correct ASCs placement and viability in cartilage regeneration in this animal model.

Evaluation of morphology and angiogenesis of breast cancer in BALB/c mice using trypsin inhibitor from Cucumis melo seeds. In vitro and in vivo study.

Introduction: Melon seeds, as an excellent source of protease inhibitors, may have a protective role against tumor progression and angiogenesis. However, their effects on angiogenesis and the mechanism of their action against cancer progression remain elusive. This study aimed to investigate the effect of bioactive compounds of melon seed on the expression of angiogenesis genes in BALB/c mice with breast cancer. Material and methods: Trypsin inhibitor (TI) was purified from the seed powder of Cucumis melo. Half- maximal inhibitory concentration was determined for TI, extract of melon seed powder (EXT), and tamoxifen (TAM) by the (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) test. Also, breast tumor was induced by subcutaneous injection of MC4-L2 cells in BALB/c inbred mice breast tissue. After tumor growth, mice were treated with TI, EXT, and TAM to examine their effects on the tumor characteristics and expression of angiogenesis-related genes including MMP-2, MMP-9, and vascular endothelial growth factor (VEGF) using the reverse transcription polymerase chain reaction method. Results: Trypsin inhibitor, EXT, TAM, and adjuvant treatment of TI + TAM resulted a reduction in expression of MMP-2, MMP-9, and VEGF. All treatments improved the breast tumor characteristics and the necrosis. The real-time polymerase chain reaction method verified the positive effects of the treatments on the breast cancer cell line and tumors. Conclusions: The results indicated that treatments with TI purified from Cucumis melo seeds and also combination therapy of TI and TAM can be considered as an alternative therapy in breast cancer patients. Further studies are warranted.

N-acetyl cysteine treatment mitigates biomarkers of oxidative stress in different tissues of bile duct ligated rats.

Cholestasis is a multifaceted clinical complication. Obstructive jaundice induced by bile duct ligation (BDL) is known as an animal model to investigate cholestasis and its associated complications. N-acetyl cysteine (NAC) is an antioxidant, radical scavenger, and thiol reductant widely investigated for its cytoprotective properties. The current investigation was designed to evaluate the role of NAC treatment on biomarkers of oxidative stress and organ histopathological alterations in a rat model of cholestasis/cirrhosis. BDL animals were supplemented with NAC (100 and 300 mg/kg, i.p, 42 consecutive days). Biomarkers of oxidative stress in the liver, brain, heart, skeletal muscle, lung, serum, and kidney tissue, as well as organ histopathological changes, were monitored. A significant increase in reactive oxygen species, lipid peroxidation, and protein carbonylation were detected in different tissues of BDL rats. Moreover, tissue antioxidant capacity was hampered, glutathione (GSH) reservoirs were depleted, and oxidized glutathione (GSSG) levels were significantly increased in the BDL group. Significant tissue histopathological alterations were evident in cirrhotic animals. It was found that NAC treatment (100 and 300 mg/kg, i.p) significantly mitigated biomarkers of oxidative stress and alleviated tissue histopathological changes in cirrhotic rats. These data represent NAC as a potential protective agent with therapeutic capability in cirrhosis and its associated complications.HIGHLIGHTSCholestasis is a multifaceted clinical complication that affects different organsOxidative stress plays a pivotal role in cholestasis-associated complicationsTissue antioxidant capacity is hampered in different tissues of cholestatic animalsAntioxidant therapy might play a role in the management of cholestasis-induced organ injuryNAC alleviated biomarkers of oxidative stress in cholestatic animalsNAC significantly improved tissues histopathological alterations in cholestatic rats.

Structural, mechanical, and biological characterization of hierarchical nanofibrous Fmoc-phenylalanine-valine hydrogels for 3D culture of differentiated and mesenchymal stem cells.

Fmoc-dipeptides are a class of short aromatic peptides featuring eminent supramolecular self-assembly, which is due to the aromaticity of the Fmoc group, which improves the association of peptide building blocks. This study aimed to introduce a new dipeptide hydrogel scaffold, Fmoc-phenylalanine-valine (Fmoc-FV), for 3D culture of various cells. Peptide hydrogel scaffolds were prepared by the pH-titration method in various concentrations and temperatures, and characterized by spectroscopic methods, including circular dichroism, attenuated total reflection FT-IR and fluorimetry. Mechanical behaviors such as thixotropy and temperature-sensitivity were investigated by oscillatory rheology. The Fmoc-FV hydrogels were then applied in 3D-culture of WJ-MSCs (mesenchymal stem cells), HUVECs (normal endothelial cells), and MDA-MB231 (tumor cell line) by live-dead fluorescence microscopy and Alamar blue viability assay experiments. The results confirmed that the ß-sheet structure is principally interlocked by π-π stacking of the Fmoc groups and entangled nanofibrous morphologies as revealed by FE-SEM. Fmoc-FV self-assembly in physiologic conditions resulted in a thermo-sensitive and shear-thinning hydrogel. Notably, the Fmoc-FV hydrogel exhibited cell type-dependent biological activity, so higher cell proliferation was attained in HUVEC or MDA-MB231 cells than WJ-MSCs, indicating a possible need for incorporating cell-adhesion ligands in the Fmoc-FV hydrogel matrix. Therefore, the structural and biological properties of the Fmoc-dipeptide hydrogels are inter-related and can affect their applications in 3D cell culture and regenerative medicine.

Variations in TM6SF2, PCSK9 and PCSK7 genes and risk of hepatic steatosis after liver transplantation: a cross-sectional study.

BACKGROUND: Genetic abnormalities might have important role in pathogenesis of hepatic steatosis after liver transplantation. We aimed to investigate association between genetic variations in transmembrane 6 superfamily member 2 (TM6SF2) rs58542926, proprotein convertase subtilisin/kexin type 9 (PCSK9) rs505151 and proprotein convertase subtilisin/kexin type 7 (PCSK7) rs2277287 with hepatic steatosis in liver transplant recipients. METHODS: In a cross-sectional study, adult (> 18 years) liver transplant recipients who were referred for their routine post-transplant follow-up between June 2018 and September 2018 were included in the study. Hepatic steatosis in transplant recipients was assessed by controlled attenuation parameter (CAP). Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to study TM6SF2 rs58542926, PCSK7 rs2277287 and PCSK9 rs505151 genotypes. RESULTS: 107 liver transplant recipients were included. There was no association between different genotypes of PCSK9 rs505151 and PCSK7 rs2277287 with hepatic steatosis in liver transplant recipients (P value > 0.05). The presence of TT genotype of TM6SF2 rs58542926 was higher in patients with hepatic steatosis measured by CAP after liver transplantation. In patients with moderate and severe hepatic steatosis (grade 2 and 3 steatosis), AG + GG genotypes of PCSK9 rs505151 were more prevalent than AA genotype (OR 8.667; 95% CI 1.841-40.879; P value = 0.004) compared to patients with mild steatosis (grade 1). In multivariate regression model, AG + GG genotypes of PCSK9 rs505151 were associated with moderate and severe steatosis in liver transplant recipients (OR 5.747; 95% CI 1.086-30.303; P value = 0.040). CONCLUSIONS: Genetic variations in TM6SF2 rs58542926 and PCSK9 rs505151 might be associated with hepatic steatosis in liver transplant recipients.

Effects of labeling human mesenchymal stem cells with superparamagnetic zinc-nickel ferrite nanoparticles on cellular characteristics and adipogenesis/osteogenesis differentiation.

OBJECTIVE: An attractive cell source for stem cell-based therapy are WJ-MSCs. Hence, tracking WJ-MSCs using non-invasive imaging procedures (such as MRI) and contrast agents (Zn0.5Ni0.5Fe2O4, NFNPs) are required to evaluate cell distribution, migration, and differentiation. RESULTS: Results showed that the bare and dextrin-coated NFNPs were internalized inside the WJ-MSCs and had no effect on the cell viability, proliferation, apoptosis, karyotyping, and morphology of WJ-MSCs up to 125 µg/mL. Besides, treated WJ-MSCs were differentiated into osteo/adipocyte-like cells. The expression of RUNX 2, SPP 1 (P < 0.05), and OCN (P > 0.05) genes in the WJ-MSCs treated with dextrin-coated NFNPs was higher than the untreated WJ-MSCs; and the expression of CFD, LPL, and PPAR-γ genes was reduced in WJ-MSCs treated with both NFNPs in comparison with the untreated WJ-MSCs (P > 0.05). CONCLUSION: Overall, results showed that dextrin-coated NFNPs had no adverse effect on the cellular characteristics, proliferation, and differentiation of WJ-MSCs, and suggesting their potential clinical efficacy.

Synergic effects of decellularized bone matrix, hydroxyapatite, and extracellular vesicles on repairing of the rabbit mandibular bone defect model.

BACKGROUND: Extracellular vesicles (ECV) and bone extracellular matrix (ECM) have beneficial effects on the treatment of some pathological conditions. The purpose of this study was to find the synergic effects of decellularized bone (DB) ECM and ECVs on the repair of rabbit. METHODS: The quality of decellularized sheep bones was confirmed by H&E, Hoechst, DNA quantification, immunohistochemistry, histochemical staining, and scanning electron microscopy (SEM). Osteoblast-derived ECVs were evaluated by internalization test, Transmission electron microscopy, Dynamic light scattering, and flow cytometry for CD9, CD63, CD81 markers. The hydrogel containing DB and hydroxyapatite (HA) with or without ECVs was evaluated for osteoblast functions and bone repair both in vitro and in vivo. RESULTS: The data indicated ECM preservation after decellularization as well as cell depletion. In vitro assessments revealed that mineralization and alkaline phosphatase activity did not improve after treatment of MG63 cells by ECVs, while in vivo morphomatrical estimations showed synergic effects of ECVs and DB + HA hydrogels on increasing the number of bone-specific cells and vessel and bone area compared to the control, DB + HA and ECV-treated groups. CONCLUSIONS: The DB enriched with ECVs can be an ideal scaffold for bone tissue engineering and may provide a suitable niche for bone cell migration and differentiation.