Traumatic brain injury (TBI) is a well-established risk factor for Alzheimer’s disease-related tauopathy. However, whether maternal TBI can lead to transgenerational transmission of pathogenic tau to offspring remains unknown. This study examines whether maternal Traumatic brain injury (TBI) induces pathogenic tau transfer to offspring, impairing fetal brain development. TBI was induced in pregnant Balb/C mice prior to pregnancy using a weight-drop model, while the sham group underwent anesthesia without injury, and the fetal brains were analyzed for cis p-tau using immunofluorescence (IF) and Western blotting (WB). Maternal anxiety post-TBI was assessed via the Elevated Plus Maze (EPM). Compared with the sham group, maternal TBI resulted in 4.25 and 5.81-fold increase in cis p-tau aggregation in embryonic and fetal brains, respectively (F(2,12) = 68.45, p < 0.001; F(2,12) = 102.34, p < 0.0001), and protein levels showed 3.13- and 6.79-fold increases (F(2,12) = 45.12, p < 0.001; F(2,12) = 89.67, p < 0.0001). This was accompanied by a significant increase in apparent transfer efficiency of p-tau to fetal brains (t(8) = 12.50, p < 0.0001). EPM assessment revealed that TBI-induced dams spent significantly more time in the open arms compared with sham (t(8) = 2.65, p = 0.029), suggesting reduced anxiety-like behavior or increased risk-taking. Maternal serum p-tau181 and fetal cis p-tau showed a positive but non-significant correlation (r(3) = 0.78, p = 0.120). These changes were associated with IL-6 and TNF increased by 2.8-fold (t(8) = 4.22, p = 0.003) and 1.8-fold (t(8) = 2.45, p = 0.040), respectively. These findings demonstrate a significant increase in apparent p-tau transfer efficiency from maternal serum to fetal brain following maternal TBI, although the correlation between maternal serum p-tau181 and fetal brain cis p-tau did not reach statistical significance.

Introduction: Traumatic brain injury (TBI) encompasses a wide range of brain lesions caused by a blow to or severe impact on the head. Traumatic brain injuries are divided into four categories based on their symptoms and consequences: mild, moderate, severe, and very severe. Studies in animal models have shown that TBI leads to neurodegeneration, progressive brain atrophy, and changes in cerebrospinal fluid (CSF) composition. The aim of this study was to investigate the effect of CSF isolated from TBI victims on neurodegeneration and the differentiation of neural progenitor cells (NPCs). Methods: To achieve this goal, the expression of genes involved in NPC differentiation and the induction of tauopathy in these cells were examined. First, an animal model of craniocerebral trauma was created in rats, and CSF was collected. The collected CSF was then added to the NPC culture medium to study its effect on cell behavior. The cells were divided into three groups: NPC, NPC + EGF/bFGF, and NPC + EGF/bFGF + CSF. After seven days, the expression of Nestin, Pax6, Map2, and Tubb3 genes was measured by real-time PCR, and TAU expression was evaluated by immunocytochemistry. Results: A significant decrease in Nestin and Pax6 expression (P = 0.0001 for both) was observed in the experimental group. Map2 and Tubb3 expression increased (P = 0.0001 and P = 0.0002, respectively), indicating NPC differentiation. In addition, immunocytochemistry revealed elevated TAU protein levels (P = 0.05), consistent with tauopathy induction. Conclusion: We conclude that CSF obtained from TBI rats promotes neuronal differentiation but simultaneously exerts neurotoxic effects through tauopathy induction.

Endometriosis is a benign yet chronic gynecological disorder characterized by dysregulation of processes such as inflammation, angiogenesis, migration, apoptosis, and proliferation. Menstrual blood-derived endometrial stem cells play a crucial role in the retrograde development and progression of endometriotic lesions. To evaluate the therapeutic potential of exosomes derived from menstrual blood-derived stem cells, exosomes from non-endometriotic MenSCs (NE-MenSCs), both unmodified (Exo) and transfected with miR-4289, were applied as treatments to MenSCs from the endometriosis cell line (E-MenSCs). Publicly available databases were used to identify key genes and signaling pathways implicated in endometriosis, from which miR-4289 was selected as an effective regulatory microRNA. Following treatment, cellular migration was assessed by scratch assays; gene expression was evaluated via real-time PCR; protein levels of ROS, IL-10, and IL-1β were measured by ELISA; and ESR1, CTNNB1, and Ki67 levels were determined by Western blotting. The results indicate that treatments significantly reduced the expression of genes associated with inflammation, proliferation, migration, and the Wnt/β-catenin pathway. Scratch assays and reductions in MMP9 expression suggest decreased migration in the Exo and miR-Exo groups. The expression of CTNNB1, IL-1β, and IL-10 was significantly downregulated in treated groups compared to E-MenSCs. In addition, KRAS and IDO1 expression levels were significantly decreased following treatment, and Ki67 protein levels were notably reduced in the miR and miR-Exo groups. These findings highlight the therapeutic potential of MenSC-derived exosomes loaded with miR-4289 as a promising and novel strategy for treating endometriosis.

Background: Neural progenitor cells (NPCs) in specific regions of the adult brain hold promise for treating central nervous system (CNS) disorders and degenerative diseases, such as Parkinson's and Alzheimer's. Rosa damascena, enriched with flavonoids, offers restorative, inhibitory, and protective advantages against nerve damage. Objectives: This study investigates the neuroprotective effects of R. damascena essential oil (ESO) on NPCs exposed to ethanol (ETH)-induced toxicity. Methods: The study involved two phases: The NPCs were isolated from the brains of young Wistar rats and cultured following standard protocols. Differentiation into mature neural cells (NCs) was induced by withdrawing supportive factors. MTT assays were used to determine effective ETH and ESO doses, followed by assessments of their impact on NPCs and NCs. Gene expression analysis of neuroepithelial stem cell protein (Nestin), Sex determining region Y-box 2 (Sox2), and Paired Box 6 (Pax6) was conducted using real-time PCR during the NPC phase, while class III β-tubulin (Tuj1) and microtubule associated protein 2 (Map2) were evaluated during the NC stage. TAU protein expression was analyzed via immunocytochemistry (ICC). Results: The ETH exposure significantly reduced cell viability in a dose- and time-dependent manner (24, 48, 72 hours), while treatment with 200 µM ESO significantly improved survival in NPCs and NCs (P < 0.001). Additionally, ESO reduced TAU protein expression in NCs exposed to ETH. The NPCs treated with ETH + ESO showed increased expression of Nestin, Sox2, and Pax6 compared to the ETH-only group (P < 0.01). Similarly, Tuj1 and Map2 expression levels were significantly higher in the ETH + ESO group compared to ETH-treated NCs (P < 0.01). Conclusions: The ESO demonstrates significant neuroprotective properties, mitigating ETH-induced toxicity in NPCs and NCs. These findings highlight its potential as a therapeutic agent for reducing neurodegenerative damage and supporting nervous system function.

Objective(s): Endometriosis carries remarkable social, public health, and financial consequences. Based on two theories of retrograde menstruation and stem cells, menstrual blood-derived stem cells (MenSCs) play a significant role in endometriosis since key genes of critical cellular processes are differentially expressed in the MenSCs of endometriosis and non-endometriosis women (E- and NE-MenSCs, respectively). In this study, E-MenSCs were isolated from the menstrual blood of women with various endometriosis subtypes. We tried to find the proper microRNA (miRNA) and assayed the effects of exosome-encapsulated miRNA on modulating the gene expression profile and functional pattern of E-MenSCs.Materials and Methods: After in silico selection of miR-149-3p using publicly accessible algorithm-based databases, E- and NE-MenSCs were cultured as controls, and the other experimental groups were as follows: E-MenSCs transfected with empty and miRNA vectors (E-MenSC+BB and E-MenSC+miR), and E-MenSCs treated with exosomes derived from non-transfected and miRNA-transfected NE-MenSCs (E-MenSC+Exo and E-MenSC+T-Exo). Then, the expression level of selected genes, the level of interleukins (ILs) and oxygen reactive species (ROS), the protein level of β-catenin and Ki-67, and the migratory ability were assessed through real-time PCR, ELISA, western blot, and scratching tests, respectively.Results: Although both E-MenSCs+T-Exo and E-MenSC+miR showed down-regulation of IL-6, -8, and -10, neither had decreased IL-1β, vascular endothelial growth factor, IDO1, and KRAS levels. Furthermore, only the IL-6 protein level was significantly decreased in the E-MenSC+miR group, but the levels of IL-6, IL-8, ROS, β-catenin, and Ki67 were significantly lower in the E-MenSCs+T-Exo group compared to the E-MenSCs.Conclusion: The potential of exosomes as miRNA carriers could be considered in developing novel endometriosis therapies.

Introduction: Many studies have shown that asthma is characterized by inflammation of the airway and infiltration of eosinophil cells (EOSCs). It has also shown that during pregnancy, the level leptin, as a regulator of immune responses, increases with the progression of the pregnancy process. In this study, the effect of asthma on inflammatory factors was evaluated in the lung and uterine tissues of asthmatic pregnant or non-pregnant mice. Methods: In this experimental study, 40 female Balb/c mice (8 weeks old) were classified into groups, and asthma by ovalbumin (OVA) at a concentration of 20 mu g/100 mu l was induced. Lung and uterus tissues were histopathologically evaluated for the presence of inflammation. The level of leptin hormone in blood serum was investigated using an indirect enzyme-linked immunosorbent assay (ELISA). Also, Interleukin-8 (IL-8 ), forkhead box protein 3 ( Foxp3 ), eosinophil chemotactic protein ( eotaxin ), and mucin 5AC ( Muc5ac ) gene expression were measured in respiratory and uterine cells by Real-Time Quantitative Reverse Transcription PCR (qRT-PCR) assay (P<0.05, P <0.01 and P <0.001). Results: Morphological assessment of inflammation in lung tissue showed a significant increase asthmatic groups compared to healthy groups. Hormone measurement revealed a significant rise leptin levels in pregnant groups compared to non-pregnant groups. Also, the expression level of IL-8 Foxp3, eotaxin, and Muc5ac genes increased in pregnancy compared to negative control. Conclusion: n asthma, inflammation rate increases at the cellular and molecular levels, and the leptin increment might have an influence on the inflammation.

IntroductionAcute kidney injury (AKI) is a common health problem that leads to high morbidity and potential mortality. The failure of conventional treatments to improve forms of this condition highlights the need for innovative and effective treatment approaches. Regenerative therapies with Renal Progenitor Cells (RPCs) have been proposed as a promising new strategy. A growing body of evidence suggests that progenitor cells differentiated from different sources, including human embryonic stem cells (hESCs), can effectively treat AKI.MethodsHere, we describe a method for generating RPCs and directed human Embryoid Bodies (EBs) towards CD133+CD24+ renal progenitor cells and evaluate their functional activity in alleviating AKI.ResultsThe obtained results show that hESCs-derived CD133+CD24+ RPCs can engraft into damaged renal tubules and restore renal function and structure in mice with gentamicin-induced kidney injury, and significantly decrease blood urea nitrogen levels, suppress oxidative stress and inflammation, and attenuate histopathological disturbances, including tubular necrosis, tubular dilation, urinary casts, and interstitial fibrosis.ConclusionThe results suggest that RPCs have a promising regenerative potential in improving renal disease and can lay the foundation for future cell therapy and disease modeling.

Spinal cord injury (SCI) can result in significant neurological impairment and functional and cognitive deficits. It is well established that SCI results in focal neurodegeneration that gradually spreads to other cord areas. On the other hand, traumatic brain injury (TBI) is strongly associated with tau protein pathology and neurodegeneration that can spread in areas throughout the brain. Tau is a microtubule-associated protein abundant in neurons and whose abnormalities result in neuronal cell death. While SCI and TBI have been extensively studied, there is limited research on the relationship between SCI and brain tau pathology. As a result, in this study, we examined tau pathology in spinal cord and brain samples obtained from severe SCI mouse models at various time points. The effects of severe SCI on locomotor function, spatial memory, anxiety/risk-taking behavior were investigated. Immunostaining and immunoblotting confirmed a progressive increase in tau pathology in the spinal cord and brain areas. Moreover, we used electron microscopy to examine brain samples and observed disrupted mitochondria and microtubule structure following SCI. SCI resulted in motor dysfunction, memory impairment, and abnormal risk-taking behavior. Notably, eliminating pathogenic cis P-tau via systemic administration of appropriate monoclonal antibodies restored SCI’s pathological and functional consequences. Thus, our findings suggest that SCI causes severe tauopathy that spreads to brain areas, indicating brain dysfunction. Additionally, tau immunotherapy with an anti-cis P-tau antibody could suppress pathogenic outcomes in SCI mouse models, with significant clinical implications for SCI patients. SCI induces profound pathogenic cis p-tau, which diffuses into the brain through CSF, resulting in brain neurodegeneration and cognitive decline.

OBJECTIVE:In the present study, we examined the tolerance-inducing effects of human adipose-derived mesenchymal stem cells (hAD-MSCs) and bone marrow-derived MSCs (hBM-MSCs) on a nonhuman primate model of skin transplantation. MATERIALS AND METHODS:In this experimental study, allogenic and xenogeneic of immunomodulatory properties of human AD-MSCs and BM-MSCs were evaluated by mixed lymphocyte reaction (MLR) assays. Human MSCs were obtained from BM or AD tissues (from individuals of either sex with an age range of 35 to 65 years) and intravenously injected (2×106 MSCs/kg) after allogeneic skin grafting in a nonhuman primate model. The skin sections were evaluated by H and E staining for histopathological evaluations, particularly inflammation and rejection reaction of grafts after 96 hours of cell injection. At the mRNA and protein levels, cellular mediators of inflammation, such as CD4+IL-17+ (T helper 17; Th17) and CD4+INF-γ+ (T helper 1, Th1) cells, along with CD4+FoxP3+ cells (Treg), as the mediators of immunomodulation, were measured by RT-PCR and flow cytometry analyses. RESULTS:A significant Treg cells expansion was observed in MSCs-treated animals which reached the zenith at 24 hours and remained at a high concentration for 96 hours; however, Th1 and Th17 cells were significantly decreased. Our results showed that human MSCs significantly decrease Th1 and Th17 cell proliferation by decreasing interleukin-17 (IL-17) and interferon-γ (INF-γ) production and significantly increase Treg cell proliferation by increasing FoxP3 production. They also extend the allogenic skin graft survival in nonhuman primates. Histological evaluations showed no obvious presence of inflammatory cells or skin redness or even bulging after MSCs injection up to 96 hours, compared to the group without MSCs. There were no significant differences between hBM-MSCs and hAD-MSCs in terms of histopathological scores and inflammatory responses (P<0.05). CONCLUSION:It seems that MSCs could be regarded as a valuable immunomodulatory tool to reduce the use of immunosuppressive agents.

Purpose: Mesenchymal stem cells (MSCs) have immunomodulatory traits making them a promising choice in the treatment of inflammatory diseases such as graft-versus-host disease (GVHD). Tumor necrosis factor-alpha (TNFα) is a major player of inflammatory disease which is blocked by infliximab to reduce the inflammation. The present study aims to assess the infliximab effects on the anti-inflammatory properties of MSCs. Methods: In this study, bone marrow mesenchymal stem cells (BMMSCs) were co-cultured with peripheral blood mononuclear cells (PBMCs) of GVHD patients in the presence of 10, 20 and 30 µg/mL of infliximab for 48 and 72 hours. The mRNA expression of indoleamine-2,3- dioxygenase (IDO) and inducible nitric oxide synthase (iNOS), as well as the secreted amount of prostaglandin E2 (PGE2) in the culture supernatant, were examined. Results: The results of this study show that the expression of IDO and iNOS genes, as well as the secretion amount of PGE2 in co-cultured groups raised dramatically, compared to the culture of BMMSCs or PBMCs alone. In co-culture groups containing infliximab, the expression of IDO and iNOS and also the amount of released PGE2 was significantly decreased compared to the control group without infliximab. However, no difference was found in the expression of assayed factors between 48 and 72 hours of treatments. Conclusion: As an anti-TNFα agent, infliximab can decrease the inflammation in the microenvironment of MSCs, which might mitigate the immunomodulatory effects of MSCs. These effects of anti-inflammatory agents on the immunomodulatory capacity of MSCs should be considered in MSC therapy.

End-stage renal disease (ESRD) is a major global public health issue. In the past decade, regenerative medicine and cell-based therapies were recommended for treatment of devastating diseases like ESRD. Renal progenitor (RP) cells are essential players in such treatment approaches. The major practical difficulties in application of RP cells are generation of these cells and preservation of their self-renewal capacity; also, they should lack identified appropriate cell surface markers. To identify and isolate RP cells, two cell surface markers namely, CD133 and CD24 were recently used. In this study, we used these markers to facilitate selection and purification of RP cells from embryoid bodies (EBs), and assessed the impact of the use of bFGF on frequency of CD133(+)CD24(+) expression in cells presented in EBs. Moreover, following isolation of CD133(+)CD24(+) cells from EBs, we evaluated the effect of embryonic, neonatal and adult mouse kidney-derived mesenchymal stem cells (E-KMSC, N-KMSC and A-KMSC respectively) and fibronectin on further differentiation of the sorted cells. Hence, we cultured undifferentiated human embryonic stem cells (hESCs) in suspension state in the presence or absence of bFGF and determined maximum number of CD133(+)CD24(+) cells in bFGF-treated EBs on day 7. Then, we tested the effect of E-KMSC co-culture and seeding on fibronectin-coated plated on differentiation of the sorted cells into renal epithelial cells. Results revealed down-regulation of several RP cells, markers in CD133(+)CD24(+) cells. In contrast, renal epithelial marker gene expressions were up-regulated after 7 days of co-culture with E-KMSC. Furthermore, fibronectin resulted in higher expression of renal epithelial markers compared to the E-KMSC co-cultured cells. All in all, bFGF could enhance the number of RP cells expressing CD133 and CD24 markers, in human EBs. We suggest E-KMSC and fibronectin as a promising supplementary factor to further induce differentiation of RP cells into renal epithelial cells.

Herein, the interaction of CeO2 NPs with HSA was explored by fluorescence, CD, UV-vis and molecular docking studies. Afterwards, the antioxidant activity of CeO2 NPs against H2O2-induced oxidative stress in BM-MSCs were explored by MTT, ROS and apoptosis assays. Antibacterial assay was also done on two Gram-positive and Gram-negative bacterial strains. Fluorescence study showed that the interaction of CeO2 NPs with HSA occurs through static quenching and hydrophilic interactions are involved in the spontaneous complex formation. The theoretical study also revealed that the distribution of hydrophilic residues of HSA is dominant in the binding site. CD and UV-vis techniques also revealed that the ellipticity changes and Tm of HSA, respectively did not alter significantly in the presence of CeO2 NPs. Cellular assays depicted that CeO2 NPs did not induce cytotoxicity against BM-MSC up to 50 mu g/ml for 24 h and pretreatment of cells with CeO2 NPs can reduce the cell mortality, ROS production and apoptosis in BM-MSC exposed to oxidative stress. The antibacterial assay revealed that CeO2 NPs have a significant antibacterial effect against all studied bacterial strains. This study may provide useful details about the biomedical applications of CeO2 NPs. (C) 2019 Elsevier B.V. All rights reserved.

Bipolar disorder is a complex neuropsychiatric disorder, characterized by intermittent episodes of mania and depression. Recent studies have indicated argyrophilic grains, composed of hyperphosphorylated tau, are observable in postmortem brains of bipolar patients. It remains uncertain how tau hyperphosphorylation results in neurodegeneration upon the disease. Recent studies have demonstrated that phosphorylated tau at Thr231 exists in two distinct cis and trans conformations, in which cis pT231-tau is highly neurotoxic and acts as an early driver of tauopathy in several neurodegenerative diseases. We herein employed an in vitro model, which resembles some aspects of bipolar disorder, to study the cis p-tau mediatory role. We established GSK3β overexpressing SH-SY5Y cells and examined cell viability, cis p-tau formation, and lithium effects by immunofluorescence and flow cytometry. We found an increase in cis p-tau levels as well as viability decrease in the cell model. Furthermore, we discovered that lithium treatment inhibits cis p-tau formation, resulting in diminished cell death. We also examined BD and healthy human brain samples and detected cis p-tau in the patients' brains. Our results show that tauopathy, observed in bipolar disorder, is being mediated through cis p-tau and that a conformer could be the cause of neurodegeneration upon the disease. Our findings would suggest novel therapeutic target to fight the devastating disorder.

Alzheimer’s disease (AD) is the sixth leading cause of death globally and the main reason for dementia in elderly people. AD is a long-term and progressive neurodegenerative disorder that steadily worsens memory and communicating skills eventually leads to a disabled person of performing simple daily tasks. Unfortunately, numerous clinical trials exploring new therapeutic drugs have encountered disappointing outcomes in terms of improved cognitive performance since they are not capable of halting or stimulating the regeneration of already-damaged neural cells, and merely provide symptomatic relief. Therefore, a deeper understanding of the mechanism of action of stem cell may contribute to the development of novel and effective therapies. The revolutionary discovery of stem cells has cast a new hope for the development of disease-modifying treatments for AD, in terms of their potency in the replenishment of lost cells via differentiating towards specific lineages, stimulating in situ neurogenesis, and delivering the therapeutic agents to the brain. Herein, firstly, we explore the pathophysiology of AD. Next, we summarize the most recent preclinical stem cell reports designed for AD treatment, their benefits and outcomes according to cell type. We briefly review relevant clinical trials and their potential clinical applications in order to find a unique solution to effectively relieve the patients’ pain.

This paper investigates a multi-objective project management problem where the goals of the decision maker are fuzzy. Prior research on this topic has considered linear membership functions to model uncertain project goals. Linear membership functions, however, are not much flexible to model uncertain information of projects in many situations, and therefore, fuzzy models with linear membership functions are not suitable to be applied in many practical situations. Hence, the purpose of this paper is to apply nonlinear membership functions in order to develop a better representation of fuzzy project planning in practice. This approach supports managers in examining different solution strategies and in planning projects more realistically. In doing so, a fuzzy mathematical project planning model with exponential fuzzy goals is developed first which takes account of (a) the time between events, (b) the crashing time for activities, and (c) the available budget. Following, a weighted max---min model is applied for solving the multi-objective project management problem. The performance of the developed solution procedure is compared with the literature that applied linear membership functions to this problem, and it is shown that the model developed in this paper outperforms the existing solution.

This paper studies a multi-objective supplier selection and order allocation problem with fuzzy objectives. The problem is formulated as a linear programming model, and three interactive and non-interactive approaches are suggested for solving the problem, namely interactive fuzzy multi-objective linear programming (i-FMOLP), interactive fuzzy goal programming (IFGP) and a standard fuzzy programming approach. The objective of the paper is to efficiently obtain solutions that are close to the aspiration levels and the decision maker's satisfaction degree. The performance of the suggested approaches and the weighted max-min approach of an earlier study are evaluated by using a set of metric distance functions. The results obtained illustrate that the solutions of the approaches applied in this paper are closer to the ideal solution as compared to the compromise solution of the weighted max-min method used in an earlier study.

This paper extends a recent work that investigated a single-stage production-inventory model with reworks and planned backorders by fuzzifying its input parameters. The graded mean integration representation (GMIR) method, a useful and effective defuzzification method, is employed to develop a fuzzified total inventory cost function of model of interest. Triangular and trapezoidal fuzzy numbers are used to examine the developed fuzzy model. Later, the optimal policy, including the batch size, the backordering level and total cost, is determined using the classical approach. Furthermore, the derived optimal policies are tested using arbitrary fuzzy numbers.