Publications by authors named "Abbas Jafari"

46 Publications

Potential Antioxidative, Anti-inflammatory and Immunomodulatory Effects of Ghrelin, an Endogenous Peptide from the Stomach in SARS-CoV2 Infection.

Int J Pept Res Ther 2021 Apr 16:1-9. Epub 2021 Apr 16.

Department of Pharmacology and Toxicology, School of Pharmacy, Urmia University of Medical Sciences, PO Box 5715799313, Urmia, Iran.

The current COVID-19 pandemic is one of the most devastating events in recent history. The respiratory effects of this disease include acute respiratory distress syndrome, systemic inflammation, cytokine storm, and pulmonary fibrosis. Ghrelin, an endogenous ligand for the growth hormone secretagogue receptor, is a peptide hormone secreted mainly by the stomach. Interestingly, ghrelin possesses promising antioxidant, anti-and inflammatory effects, making it an attractive agent to reduce the complications of the SARS-CoV-2. In addition, ghrelin exerts a wide range of immunomodulatory and anti-inflammatory effects and can mitigate the uncontrolled cytokine production responsible for acute lung injury by upregulating PPARγ and down-regulating NF-κB expression. Ghrelin has also been reported to enhance Nrf2 expression in inflammatory conditions which led to the suppression of oxidative stress. The current opinion summarizes the evidence for the possible pharmacological benefits of ghrelin in the therapeutic management of SARS-CoV-2 infection.
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http://dx.doi.org/10.1007/s10989-021-10217-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8050636PMC
April 2021

Myeloma-bone marrow adipocyte axis in tumour survival and treatment response.

Br J Cancer 2021 Apr 15. Epub 2021 Apr 15.

Maine Medical Center Research Institute, Scarborough, ME, USA.

Multiple myeloma is an incurable cancer of the bone marrow that is dependent on its microenvironment, including bone marrow adipocytes (BMAds). Here, we discuss our findings that the reciprocal interaction of myeloma cells and BMAds, leads to myeloma cell survival and induces metabolic dysfunction and senescence-associated secretory phenotype in BMAds.
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http://dx.doi.org/10.1038/s41416-021-01371-4DOI Listing
April 2021

The Antiresorptive Effect of GIP, But Not GLP-2, Is Preserved in Patients With Hypoparathyroidism-A Randomized Crossover Study.

J Bone Miner Res 2021 Apr 14. Epub 2021 Apr 14.

Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-2 (GLP-2) are gut hormones secreted postprandially. In healthy humans, both hormones decrease bone resorption accompanied by a rapid reduction in parathyroid hormone (PTH). The aim of this study was to investigate whether the changes in bone turnover after meal intake and after GIP- and GLP-2 injections, respectively, are mediated via a reduction in PTH secretion. This was tested in female patients with hypoparathyroidism given a standardized liquid mixed-meal test (n = 7) followed by a peptide injection test (n = 4) using a randomized crossover design. We observed that the meal- and GIP- but not the GLP-2-induced changes in bone turnover markers were preserved in the patients with hypoparathyroidism. To understand the underlying mechanisms, we examined the expression of the GIP receptor (GIPR) and the GLP-2 receptor (GLP-2R) in human osteoblasts and osteoclasts as well as in parathyroid tissue. The GIPR was expressed in both human osteoclasts and osteoblasts, whereas the GLP-2R was absent or only weakly expressed in osteoclasts. Furthermore, both GIPR and GLP-2R were expressed in parathyroid tissue. Our findings suggest that the GIP-induced effect on bone turnover may be mediated directly via GIPR expressed in osteoblasts and osteoclasts and that this may occur independent of PTH. In contrast, the effect of GLP-2 on bone turnover seems to depend on changes in PTH and may be mediated through GLP-2R in the parathyroid gland. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
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http://dx.doi.org/10.1002/jbmr.4308DOI Listing
April 2021

Endectocides as a complementary intervention in the malaria control program: a systematic review.

Syst Rev 2021 Jan 18;10(1):30. Epub 2021 Jan 18.

Social Determinants of Health Research Center, Clinical Research Institute, Urmia University of Medical Sciences, Urmia, Iran.

Background: Malaria is the most common vector-borne disease transmitted to humans by Anopheles mosquitoes. Endectocides and especially ivermectin will be available as a vector control tool soon. The current review could be valuable for trial design and clinical studies to control malaria transmission.

Methods: PubMed/MEDLINE, Scopus, Web of Science, and Science Direct were searched for original English published papers on ("Malaria chemical control" OR "Malaria elimination" OR "Anopheles vector control" OR "Malaria zooprophylaxis") AND ("Systemic insecticides" OR "Endectocides" OR "Ivermectin"). The last search was from 19 June 2019 to 31 December 2019. It was updated on 17 November 2020. Two reviewers (SG and FGK) independently reviewed abstracts and full-text articles. Data were extracted by one person and checked by another. As meta-analyses were not possible, a qualitative summary of results was performed.

Results: Thirty-six published papers have used systemic insecticides/endectocides for mosquito control. Most of the studies (56.75%) were done on Anopheles gambiae complex species on doses from 150 μg/kg to 400 μg/kg in several studies. Target hosts for employing systemic insecticides/drugs were animals (44.2%, including rabbit, cattle, pig, and livestock) and humans (32.35%).

Conclusions: Laboratory and field studies have highlighted the potential of endectocides in malaria control. Ivermectin and other endectocides could soon serve as novel malaria transmission control tools by reducing the longevity of Anopheles mosquitoes that feed on treated hosts, potentially decreasing Plasmodium parasite transmission when used as mass drug administration (MDA).
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http://dx.doi.org/10.1186/s13643-021-01578-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812718PMC
January 2021

Myeloma-Modified Adipocytes Exhibit Metabolic Dysfunction and a Senescence-Associated Secretory Phenotype.

Cancer Res 2021 02 20;81(3):634-647. Epub 2020 Nov 20.

Maine Medical Center Research Institute, Scarborough, Maine.

Bone marrow adipocytes (BMAd) have recently been implicated in accelerating bone metastatic cancers, such as acute myelogenous leukemia and breast cancer. Importantly, bone marrow adipose tissue (BMAT) expands with aging and obesity, two key risk factors in multiple myeloma disease prevalence, suggesting that BMAds may influence and be influenced by myeloma cells in the marrow. Here, we provide evidence that reciprocal interactions and cross-regulation of myeloma cells and BMAds play a role in multiple myeloma pathogenesis and treatment response. Bone marrow biopsies from patients with multiple myeloma revealed significant loss of BMAT with myeloma cell infiltration of the marrow, whereas BMAT was restored after treatment for multiple myeloma. Myeloma cells reduced BMAT in different preclinical murine models of multiple myeloma and using myeloma cell-adipocyte cocultures. In addition, multiple myeloma cells altered adipocyte gene expression and cytokine secretory profiles, which were also associated with bioenergetic changes and induction of a senescent-like phenotype. , senescence markers were also increased in the bone marrow of tumor-burdened mice. BMAds, in turn, provided resistance to dexamethasone-induced cell-cycle arrest and apoptosis, illuminating a new possible driver of myeloma cell evolution in a drug-resistant clone. Our findings reveal that bidirectional interactions between BMAds and myeloma cells have significant implications for the pathogenesis and treatment of multiple myeloma. Targeting senescence in the BMAd or other bone marrow cells may represent a novel therapeutic approach for treatment of multiple myeloma. SIGNIFICANCE: This study changes the foundational understanding of how cancer cells hijack the bone marrow microenvironment and demonstrates that tumor cells induce senescence and metabolic changes in adipocytes, potentially driving new therapeutic directions.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-1088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7854508PMC
February 2021

Innate and adaptive immune responses against coronavirus.

Biomed Pharmacother 2020 Dec 22;132:110859. Epub 2020 Oct 22.

Department of Toxicology and Cellular and Molecular Research Center, School of Public Health, Urmia University of Medical Sciences, Urmia, Iran. Electronic address:

Coronaviruses (CoVs) are a member of the Coronaviridae family with positive-sense single- stranded RNA. In recent years, the CoVs have become a global problem to public health. The immune responses (innate and adaptive immunity) are essential for elimination and clearance of CoVs infections, however, uncontrolled immune responses can result in aggravating acute lung injury and significant immunopathology. Gaining profound understanding about the interaction between CoVs and the innate and adaptive immune systems could be a critical step in the field of treatment. In this review, we present an update on the host innate and adaptive immune responses against SARS-CoV, MERS-CoV and newly appeared SARS-CoV-2.
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http://dx.doi.org/10.1016/j.biopha.2020.110859DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7580677PMC
December 2020

Neurological effects of long-term exposure to low doses of pesticides mixtures in male rats: Biochemical, histological, and neurobehavioral evaluations.

Chemosphere 2021 Feb 30;264(Pt 2):128464. Epub 2020 Sep 30.

Department of Toxicology and Neurophysiology Research Center, Faculty of Health, Urmia University of Medical Sciences, Urmia, Iran. Electronic address:

Humans are usually exposed to multiple pesticides in real life, but little is known as yet about the safety of low-dose pesticides mixtures. This study was conducted to evaluate the effects of long-term exposure to very low doses of pesticide mixtures on biochemical, histological, and neurobehavioral alterations in the rat model. For 90 days, four groups of male Wistar rats were given a mixture of five pesticides (in drinking water) in doses of 0, 0.25, 1 and 5 times the legally permitted levels (mg/kg body weight/day). After three-month exposure, the neurobehavioral effects of pesticide mixtures were evaluated by the Morris water maze, elevated plus maze and the open field tests. Then the biochemical and histopathological alterations in the hippocampus of studied animals were evaluated. Results showed that long-term exposure to a combination of five pesticides affected the nervous system in dose-dependent manner. As expected, nearly all of the parameters determined in this study were adversely changed in the high dose group. Exposure to medium dose (permitted level of pesticides mixture) was also able to induce oxidative stress and impaired memory and learning ability, although not all parameters were significantly changed in this group. It means that pesticides may behave differently when mixed. Interestingly, the administration of low doses of these chemicals induced an adaptive response by stimulating the redox system. In conclusion, it seems that the prolonged exposure to pesticide mixtures may cause adverse neurobehavioral effects, even at permitted levels.
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http://dx.doi.org/10.1016/j.chemosphere.2020.128464DOI Listing
February 2021

Fibroblasts direct differentiation of human breast epithelial progenitors.

Breast Cancer Res 2020 09 29;22(1):102. Epub 2020 Sep 29.

Section for Cell Biology and Physiology, Department of Biology, University of Copenhagen, Copenhagen, Denmark.

Background: Breast cancer arises within specific regions in the human breast referred to as the terminal duct lobular units (TDLUs). These are relatively dynamic structures characterized by sex hormone driven cyclic epithelial turnover. TDLUs consist of unique parenchymal entities embedded within a fibroblast-rich lobular stroma. Here, we established and characterized a new human breast lobular fibroblast cell line against its interlobular counterpart with a view to assessing the role of region-specific stromal cues in the control of TDLU dynamics.

Methods: Primary lobular and interlobular fibroblasts were transduced to express human telomerase reverse transcriptase (hTERT). Differentiation of the established cell lines along lobular and interlobular pathways was determined by immunocytochemical staining and genome-wide RNA sequencing. Their functional properties were further characterized by analysis of mesenchymal stem cell (MSC) differentiation repertoire in culture and in vivo. The cells' physiological relevance for parenchymal differentiation was examined in heterotypic co-culture with fluorescence-activated cell sorting (FACS)-purified normal breast primary luminal or myoepithelial progenitors. The co-cultures were immunostained for quantitative assessment of epithelial branching morphogenesis, polarization, growth, and luminal epithelial maturation. In extension, myoepithelial progenitors were tested for luminal differentiation capacity in culture and in mouse xenografts. To unravel the significance of transforming growth factor-beta (TGF-β)-mediated crosstalk in TDLU-like morphogenesis and differentiation, fibroblasts were incubated with the TGF-β signaling inhibitor, SB431542, prior to heterotypic co-culture with luminal cells.

Results: hTERT immortalized fibroblast cell lines retained critical phenotypic traits in culture and linked to primary fibroblasts. Cell culture assays and transplantation to mice showed that the origin of fibroblasts determines TDLU-like and ductal-like differentiation of epithelial progenitors. Whereas lobular fibroblasts supported a high level of branching morphogenesis by luminal cells, interlobular fibroblasts supported ductal-like myoepithelial characteristics. TDLU-like morphogenesis, at least in part, relied on intact TGF-β signaling.

Conclusions: The significance of the most prominent cell type in normal breast stroma, the fibroblast, in directing epithelial differentiation is largely unknown. Through establishment of lobular and interlobular fibroblast cell lines, we here demonstrate that epithelial progenitors are submitted to stromal cues for site-specific differentiation. Our findings lend credence to considering stromal subtleties of crucial importance in the development of normal breast and, in turn, breast cancer.
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http://dx.doi.org/10.1186/s13058-020-01344-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526135PMC
September 2020

Delta-like 1 (DLK1) is a possible mediator of vitamin D effects on bone and energy metabolism.

Bone 2020 09 1;138:115510. Epub 2020 Jul 1.

Calcium Metabolism and Osteoporosis Program, Division of Endocrinology and Metabolism, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon. Electronic address:

Vitamin D effects on bone and mineral metabolism are well recognized, and its anti-inflammatory actions are gaining particular interest. Delta-like 1 (DLK1) is a protein, expressed by progenitor cells of different tissues, and increases the size of progenitor cell population during the inflammatory phase of tissue regeneration. DLK1 also plays a role in energy metabolism as it antagonizes insulin signaling in bone. In this one-year randomized clinical trial of overweight elderly individuals that received either 600 or 3750 IU daily cholecalciferol we assessed the effect of vitamin D supplementation on pre-specified secondary outcomes: DLK1, leptin, adiponectin, C-Reactive Protein (CRP) and Vascular Cell Adhesion Molecule (VCAM). We also examined correlations between DLK1 and bone (BMD, bone markers), fat (adipokines, body composition), insulin sensitivity and inflammatory markers. Multivariate analyses were conducted to further explore these associations. Overall, there was a significant increase in serum DLK1 and leptin and a decrease in VCAM, but no change in CRP, after 12 months of vitamin D supplementation. DLK1 was negatively correlated with BMD and positively correlated with bone markers, associations that persisted after adjusting for age, gender and BMI. DLK1 was also positively associated with indices of insulin resistance and negatively with indices of insulin sensitivity. Correlations between DLK1 and fat parameters, such as adipokines, and DXA derived fat mass were less consistent. There were no correlations between DLK1 and inflammatory markers. In conclusion, twelve months supplementation of vitamin D3 increased serum DLK1. DLK1 was negatively associated with indices of bone health and fuel metabolism, and with 1,25(OH)D levels. Similar to the role of DLK1 in animal models, our findings support the hypothesis that DLK1 can be targeted to regulate bone and energy metabolism and develop drugs to improve BMD and insulin sensitivity. However, further studies are needed to explore the role of DLK1 and its relationship to vitamin D metabolites in vivo.
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http://dx.doi.org/10.1016/j.bone.2020.115510DOI Listing
September 2020

The effects of exposure to fluoxetine during lactation on testicular tissue and sperm parameters in mice offspring.

Vet Res Forum 2020 15;11(1):35-42. Epub 2020 Mar 15.

Department of Anatomy and Histology, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran.

Fluoxetine is a selective serotonin reuptake inhibitor is commonly prescribed to treat maternal depression in pregnancy and lactation. This study aimed to investigate the effects of maternal exposure to fluoxetine via lactation on testicular tissue, sperm parameters including count, motility, viability, and normal morphology and testicular oxidative stress status in male mice offspring. Ten mice dams were divided into control and experimental groups. The control group received water and the experimental group received fluoxetine (20.00 mg kg) by gavage daily from postnatal days of 0-21. Histology of testis, sperm parameters and oxidative stress in the testicular tissue were analyzed at 80 days after birth in their male offspring (n = 8). Significant reductions in the body and testes weights were observed in animals exposed to fluoxetine. Additionally, fluoxetine exposure significantly reduced all sperm parameters, tubular diameter and epithelial height of the seminiferous tubules as well as Leydig cells number. Significant increases in the testicular malondialdehyde levels and percentage of sperm with chromatin/DNA damage were observed in mice exposed to fluoxetine compared to control. These findings suggest that maternal exposure to fluoxetine during lactation in mice has a negative effect on the testicular tissue of their offspring and impairs the spermatogenesis process which in turn can induce infertility.
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http://dx.doi.org/10.30466/vrf.2018.82090.2082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7282220PMC
March 2020

Topiramate: A novel protective agent against ischemia reperfusion-induced oxidative injury after testicular torsion/detorsion.

Am J Emerg Med 2020 Apr 1. Epub 2020 Apr 1.

Department of Pharmacology and Toxicology, School of Pharmacy, Urmia University of Medical Sciences, Urmia, Iran. Electronic address:

Testicular torsion is a common urologic emergency and one of the causes of genital injury in males. Hence, early diagnosis and treatment are necessary to prevent testicular damage and infertility. It has been proved that topiramate (TPM) a medication used to treat epilepsy and prevent migraines has anti-inflammatory and anti-oxidative effects. Therefore, this study was designed to determine the influence of TPM on ischemia/reperfusion injury following testicular torsion/detorsion (T/D). Thirty-six male Wistar rats were divided into three groups (n = 12 for each group) including sham operated, T/D + vehicle, T/D + TPM(100 mg/kg, 30 min before detorsion). Testicular torsion was induced for 1 h by rotating right testis 720 in the clockwise direction. After 5 h of reperfusion the testis was removed and histological changes and biochemical markers such as superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT) and levels of malondialdehyde (MDA) and reduced glutathione (GSH) were evaluated. MDA level significantly increased and GSH level significantly decreased after T/D compared to the sham group (p < 0.001). Moreover, after inducing testicular T/D, GPx, CAT and SOD activity were decreased, whereas administration of TPM significantly increased GSH level and GPx, CAT and SOD activities and decreased MDA level in testis tissue as compared to T/D group. After induction of T/D, histopathological evaluations also revealed severe testicular damages which were improved by TPM administration. Our results indicate that TPM had an ameliorating impact on ischemia/reperfusion injury in the rat model of testicular T/D. This protective effect was most likely induced by anti-oxidative properties of this drug.
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http://dx.doi.org/10.1016/j.ajem.2020.03.060DOI Listing
April 2020

Phosphoproteomic profiling reveals a defined genetic program for osteoblastic lineage commitment of human bone marrow-derived stromal stem cells.

Genome Res 2020 01 12;30(1):127-137. Epub 2019 Dec 12.

Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark.

Bone marrow-derived mesenchymal stem cells (MSCs) differentiate into osteoblasts upon stimulation by signals present in their niche. Because the global signaling cascades involved in the early phases of MSCs osteoblast (OB) differentiation are not well-defined, we used quantitative mass spectrometry to delineate changes in human MSCs proteome and phosphoproteome during the first 24 h of their OB lineage commitment. The temporal profiles of 6252 proteins and 15,059 phosphorylation sites suggested at least two distinct signaling waves: one peaking within 30 to 60 min after stimulation and a second upsurge after 24 h. In addition to providing a comprehensive view of the proteome and phosphoproteome dynamics during early MSCs differentiation, our analyses identified a key role of serine/threonine protein kinase D1 (PRKD1) in OB commitment. At the onset of OB differentiation, PRKD1 initiates activation of the pro-osteogenic transcription factor RUNX2 by triggering phosphorylation and nuclear exclusion of the histone deacetylase HDAC7.
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http://dx.doi.org/10.1101/gr.248286.119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6961576PMC
January 2020

Protective effects of orally administered thymol against titanium dioxide nanoparticle-induced testicular damage.

Environ Sci Pollut Res Int 2020 Jan 28;27(2):2353-2360. Epub 2019 Nov 28.

Department of Pharmacology and Toxicology, School of Pharmacy, Urmia University of Medical Sciences, PO Box 5715799313, Urmia, Iran.

In this study, we investigated the potential of thymol and its mode of action to protect against the titanium dioxide (TiO) nanoparticle-induced testicular damage. Twenty-four rats were randomly divided into four groups: control group, TiO (100 mg/kg BW/day) group, TiO + thymol (10 mg/kg BW/day) group, and TiO + thymol (30 mg/kg BW/day) group. With the exception of the control group, all animals received orally TiO nanoparticles for 60 days. In treatment groups, animals were given orally thymol 1 h before TiO nanoparticles. Epididymal sperm parameters, testicular histopathology, and spermatogenesis assessments were performed for evaluation of the TiO and thymol effects on the testis. Furthermore, antioxidative enzyme activities such as catalase (CAT), glutathione peroxidase (GPx) and superoxide dismutase (SOD), and malondialdehyde (MDA), glutathione (GSH) levels and ferric-reducing antioxidant power (FRAP) value were measured. Intragastric administration of TiO for 60 consecutive days caused a significant decrease in sperm quality, widespread histopathological alteration, and significantly induced oxidative stress as manifested by elevated MDA levels and a remarkable decline in antioxidant enzyme activities such as CAT, SOD, and GPx, and also FRAP and GSH levels in testis tissue. Nearly all of these alterations were significantly ameliorated in the groups that orally received thymol before TiO nanoparticles administration. The results of this study demonstrated that thymol improved the spermatogenesis defects induced by TiO nanoparticles in rats in a dose-dependent manner by protecting the testes against the testicular toxicity. Reduction in TiO nanoparticle-induced oxidative stress may have a major role in this protective effect.
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http://dx.doi.org/10.1007/s11356-019-06937-7DOI Listing
January 2020

Aging and lineage allocation changes of bone marrow skeletal (stromal) stem cells.

Bone 2019 06 1;123:265-273. Epub 2019 Apr 1.

The Molecular Endocrinology & Stem Cell Research Unit (KMEB), Department of Endocrinology, Odense University Hospital & University of Southern Denmark, Odense, Denmark; Department of Cellular and Molecular Medicine, The Novo Nordisk Foundation Center for Stem Cell Biology (DanStem), Panum Institute, University of Copenhagen, Copenhagen, Denmark; Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University, Riyadh, Saudi Arabia. Electronic address:

Aging is associated with decreased bone mass and accumulation of bone marrow adipocytes. Both bone forming osteoblastic cells and bone marrow adipocytes are derived from a stem cell population within the bone marrow stroma called bone marrow stromal (skeletal or mesenchymal) stem cells (BMSC). In the present review, we provide an overview, based on the current literature, regarding the physiological aging processes that cause changes in BMSC lineage allocation, enhancement of adipocyte and defective osteoblast differentiation, leading to gradual exhaustion of stem cell regenerative potential and defects in bone tissue homeostasis and metabolism. We discuss strategies to preserve the "youthful" state of BMSC, to reduce bone marrow age-associated adiposity, and to counteract the overall negative effects of aging on bone tissues with the aim of decreasing bone fragility and risk of fractures.
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http://dx.doi.org/10.1016/j.bone.2019.03.041DOI Listing
June 2019

Lansoprazole inhibits the cysteine protease legumain by binding to the active site.

Basic Clin Pharmacol Toxicol 2019 Aug 11;125(2):89-99. Epub 2019 Apr 11.

Section for Pharmacology and Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Oslo, Norway.

Proton pump inhibitors (PPIs) are prodrugs used in the treatment of peptic ulcer diseases. Once activated by acidic pH, the PPIs subsequently inhibit the secretion of gastric acid by covalently forming disulphide bonds with the SH groups of the parietal proton pump, that is the H /K -ATPase. Long-term use of PPIs has been associated with numerous adverse effects, including bone fractures. Considering the mechanism of activation, PPIs could also be active in acidic micro-environments such as in lysosomes, tumours and bone resorption sites. We suggested that the SH group in the active site of cysteine proteases could be susceptible for inhibition by PPIs. In this study, the inhibition by lansoprazole was shown on the cysteine proteases legumain and cathepsin B by incubating purified proteases or cell lysates with lansoprazole at different concentrations and pH conditions. The mechanism of legumain inhibition was shown to be a direct interaction of lansoprazole with the SH group in the active site, and thus blocking binding of the legumain-selective activity-based probe MP-L01. Lansoprazole was also shown to inhibit both legumain and cathepsin B in various cell models like HEK293, monoclonal legumain over-expressing HEK293 cells (M38L) and RAW264.7 macrophages, but not in human bone marrow-derived skeletal (mesenchymal) stem cells (hBMSC-TERT). During hBMSC-TERT differentiation to osteoblasts, lansoprazole inhibited legumain secretion, alkaline phosphatase activity, but had no effects on in vitro mineralization capacity. In conclusion, lansoprazole acts as a direct covalent inhibitor of cysteine proteases via disulphide bonds with the SH group in the protease active site. Such inhibition of cysteine proteases could explain some of the off-target effects of PPIs.
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http://dx.doi.org/10.1111/bcpt.13230DOI Listing
August 2019

Shift Work Effects and Pregnancy Outcome: A Historical Cohort Study.

J Family Reprod Health 2018 Jun;12(2):84-88

Industrial Disease Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.

Employed mothers face considerable amount of hazards. Especially shift work can impact pregnant women by affecting some hormones. This study was conducted to assess the adverse effects of shift work on pregnancy outcomes. This historical cohort study was conducted in 2017 in order to assess the effect of shift work on pregnancy outcomes. The subjects were consecutively selected from pregnant women, which referred to Al Zahra and Shahid Beheshti hospitals, Isfahan, Iran for their pregnancy care. The effect of shift work on pregnancy and labor complications (low birth weight, small for gestational age, pre-eclampsia and eclampsia, intra-uterine growth retardation, spontaneous abortion, preterm delivery, excessive bleeding during labor, and type of labor) was assessed. The effect was adjusted for occupation and number of children as well. Data were analyzed by SPSS (ver. 17) usingT-test, chi-Square test and logistic regression analysis. Totally, 429 pregnant women entered the study. There was not a statistically significant difference between morning and shift workers regarding age. It was found that shift work probably increases the incidence of small for gestational age, pre-eclampsia and eclampsia, intra-uterine growth retardation, spontaneous abortion, and preterm delivery, but after adjustment for job and number of children the effect was observed only on preterm delivery. Working in a rapid cycling schedule of shift work may cause an increase in the incidence of preterm delivery in pregnant mothers.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391306PMC
June 2018

TAFA2 Induces Skeletal (Stromal) Stem Cell Migration Through Activation of Rac1-p38 Signaling.

Stem Cells 2019 03 17;37(3):407-416. Epub 2018 Dec 17.

Department of Cellular and Molecular Medicine, Novo Nordisk Foundation Center for Stem Cell Biology (DanStem), University of Copenhagen, Copenhagen, Denmark.

Understanding the mechanisms regulating recruitment of human skeletal (stromal or mesenchymal) stem cells (hMSC) to sites of tissue injury is a prerequisite for their successful use in cell replacement therapy. Chemokine-like protein TAFA2 is a recently discovered neurokine involved in neuronal cell migration and neurite outgrowth. Here, we demonstrate a possible role for TAFA2 in regulating recruitment of hMSC to bone fracture sites. TAFA2 increased the in vitro trans-well migration and motility of hMSC in a dose-dependent fashion and induced significant morphological changes including formation of lamellipodia as revealed by high-content-image analysis at single-cell level. Mechanistic studies revealed that TAFA2 enhanced hMSC migration through activation of the Rac1-p38 pathway. In addition, TAFA2 enhanced hMSC proliferation, whereas differentiation of hMSC toward osteoblast and adipocyte lineages was not altered. in vivo studies demonstrated transient upregulation of TAFA2 gene expression during the inflammatory phase of fracture healing in a closed femoral fracture model in mice, and a similar pattern was observed in serum levels of TAFA2 in patients after hip fracture. Finally, interleukin-1β was found as an upstream regulator of TAFA2 expression. Our findings demonstrate that TAFA2 enhances hMSC migration and recruitment and thus is relevant for regenerative medicine applications. Stem Cells 2019;37:407-416.
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http://dx.doi.org/10.1002/stem.2955DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7379704PMC
March 2019

Low Frequency of Knockdown Resistance Mutations in Musca domestica (Muscidae: Diptera) Collected From Northwestern Iran.

J Med Entomol 2019 02;56(2):501-505

Cellular and Molecular Research Center, Urmia University of Medical Sciences, Urmia, Iran.

Musca domestica L., the common housefly, is a very important mechanical vector of pathogens. Continuous exposure to pyrethroid insecticides has led to insecticide resistance in houseflies. Some mutations in the voltage-gated sodium channel gene (vgsc) reduce the binding affinity of pyrethroids target site insensitivity. We collected houseflies from the Urmia district of Northwestern Iran. Following DNA extraction, 580 bp regions of the vgsc known to contain knockdown resistance (kdr) mutations were amplified and sequenced using specific primers. The amplified region contained two exons (211-bp and 248-bp) and three introns. There were eight polymorphic sites between M. domestica insecticide-susceptible (MDU38813), super-kdr (NW_004774263) and aabys (KT897924) strains from GenBank in comparison with our sequences. Two amino acid substitutions were detected, N967Y (% polymorphism = 9.5%) and L1014H (% polymorphism = 4.7%) that can be associated with resistance. The common and previously reported mutations L1014F and M918T+L1014F were not detected. Diagnosis based on sequence analysis is useful for monitoring the frequency of pyrethroid resistance mutations, which will be helpful in avoiding overuse of this class of insecticides in house fly control.
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http://dx.doi.org/10.1093/jme/tjy177DOI Listing
February 2019

Oral administration of titanium dioxide nanoparticle through ovarian tissue alterations impairs mice embryonic development.

Int J Reprod Biomed 2018 Jun;16(6):397-404

Department of Occupational Health, School of Health, Urmia University of Medical Sciences, Urmia, Iran.

Background: Titanium dioxide nanoparticle (TiONP) is commonly used in industrial products including food colorant, cosmetics, and drugs. Previous studies have shown that oral administration of TiONP can be toxic to the reproductive system, but little is known if TiONP could be able to affect the functions of the female reproductive system, in particular fertility.

Objective: The objective was to evaluate the effects of oral administration of TiONP on histological changes in ovaries, pregnancy rate and in vitro fertility in mice.

Materials And Methods: In this experimental study, 54 adult female NMRI mice were randomly assigned to two groups: control group (received vehicle orally) and TiONP group (received 100 mg/kg/daily TiONP solution orally). After 5 wk, pregnancy and in vitro fertilization rates, histological changes in ovaries, malondyaldehyde and estrogen hormone levels in the blood serum were investigated and compared between groups.

Results: Our results revealed that TiONP administration induced histological alterations in ovary including, degenerating and reduction of ovarian follicles, ovarian cyst formation and disturbance of follicular development. Compared to control, animals in TiONP group have shown significant reduction of pregnancy rates and number of giving birth (p=0.04). TiONP caused significant reduction in oocyte number, fertilization rate, and pre-implantation embryo development (p<0.001). Furthermore, malondyaldehyde and estrogen hormone levels were significantly (p<0.01) increased in mice received TiONP.

Conclusion: Our findings suggest that TiONP exposure induces alterations on mice ovary resulting in a decrease in the rate of embryo development and fertility.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6079309PMC
June 2018

Synergistic effect of rapamycin and metformin against germ cell apoptosis and oxidative stress after testicular torsion/detorsion-induced ischemia/reperfusion in rats.

Biomed Pharmacother 2018 Sep 11;105:645-651. Epub 2018 Jun 11.

Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. Electronic address:

The aim of this study was to investigate the effects of rapamycin (rapa) and metformin (met), combined administration on testicular torsion-detorsion (T/D) injury. A total of 108 male rats were divided randomly into six groups (n = 18), control, sham-operated, T/D, T/D + met (100 mg/kg), T/D + rapa (0.25 mg/kg) and T/D + met (100 mg/kg)+rapa (0.25 mg/kg). Except for the control and sham groups, torsion was created by rotating the right testis 720° in a clockwise direction for 1 h. Treatment groups received drug intraperitoneally, 30 min before detorsion. The right testis of 6 animals from each group was excised 4 h after detorsion for the measurement of lipid peroxidation, caspase-3, and antioxidant enzyme activities. Histopathological changes and germ cell apoptosis were determined by measuring mean of seminiferous tubules diameters (MSTD) and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labeling (TUNEL) test in rest of animals, 24 h after detorsion. In T/D group tissue malondialdehyde (MDA) level and caspase-3 activity increased and the activities of catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx) decreased in comparison with the control group after detorsion. Met and rapa separately pre-treatment reduced MDA and caspase-3 levels, normalized antioxidant enzyme activities, reduced germ cell apoptosis and improved the MSTD in comparison with T/D group. However combined administration of met and rapa indicated a significant augmented effect as compared to the individual drug interventions on the reversal of T/D induced oxidative stress, apoptosis, and histologic changes, suggesting a synergistic response. Thus, this study shows that rapa and met combination have significant synergistic effects against oxidative stress and apoptosis and opens up further possibilities for the design of new combinatorial therapies to prevent tissue damage after ischemia-reperfusion (I/R).
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http://dx.doi.org/10.1016/j.biopha.2018.06.012DOI Listing
September 2018

Hepatoprotective effect of thymol against subchronic toxicity of titanium dioxide nanoparticles: Biochemical and histological evidences.

Environ Toxicol Pharmacol 2018 Mar 17;58:29-36. Epub 2017 Dec 17.

Department of Anatomy and Histology, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran. Electronic address:

The study was aimed to investigate the protective action of thymol against nano titanium dioxide (nano-TiO) induced hepatotoxicity in rats. To achieve this purpose, the rats were divided into four groups (n = 6) including control, nano-TiO (100 mg/kg), nano-TiO + thymol (10 mg/kg) and nano-TiO + thymol (30 mg/kg). Intragastric (IG) administration of nano-TiO for 60 consecutive days caused widespread histological changes and significantly induced oxidative stress in the liver tissues as manifested by the rise in serum transaminase activities accompanied by marked decline of enzymatic (catalase, superoxide dismutase and glutathione peroxidase) and non-enzymatic (ferric reducing antioxidant power and glutathione) antioxidant levels, and rise of malondialdehyde levels in liver tissue. Pretreatment with thymol (IG) prior to nano-TiO administration significantly ameliorated all of biochemical and histopathological alterations in a dose-dependent manner. In conclusion, thymol effectively protects against nano-TiO-induced hepatotoxicity in rats by its antioxidant properties.
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http://dx.doi.org/10.1016/j.etap.2017.12.010DOI Listing
March 2018

Environmental and biological measurements of isoflurane and sevoflurane in operating room personnel.

Int Arch Occup Environ Health 2018 Apr 15;91(3):349-359. Epub 2017 Dec 15.

Department of Occupational Health, Health Faculty, Urmia University of Medical Sciences, Pardis-e Nazloo, Serow Rd Km 11, Urmia, Iran.

Purpose: The present study aimed to compare the concentration of isoflurane and sevoflurane in the individual's breathing zone and ambient air of operating rooms (ORs), to investigate the correlation between breathing zone levels and urinary concentrations, and to evaluate the ORs pollution in the different working hours and weeks.

Methods: Environmental and biological concentrations of isoflurane and sevoflurane were evaluated at 9ORs. Air samples were collected by active sampling method and urine samples were collected from each subject at the end of the work shift. All samples were analyzed using gas chromatography.

Results: The geometric mean ± GSD concentration of isoflurane and sevoflurane in breathing zone air were 1.41 ± 2.27 and 0.005 ± 1.74 ppm, respectively, while in post-shift urine were 2.42 ± 2.86 and 0.006 ± 3.83 µg/l, respectively. A significant positive correlation was found between the urinary and environmental concentration of isoflurane (r  = 0.724, P < 0.0001). The geometric mean ± GSD values of isoflurane and sevoflurane in ambient air were 2.30 ± 2.43 and 0.004 ± 1.56 ppm, respectively. The isoflurane concentration was different for three studied weeks and significantly increased over time in the ambient air of ORs.

Conclusions: The occupational exposure of OR personnel to isoflurane and sevoflurane was lower than national recommended exposure limits. The urinary isoflurane could be a good internal dose biomarker for monitoring of occupational isoflurane exposure. Considering the accumulation of anesthetic waste gases in the studied ORs, real-time air monitoring is better to be done at the end of the work shift.
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http://dx.doi.org/10.1007/s00420-017-1287-yDOI Listing
April 2018

Green cellulose-based nanocomposite catalyst: Design and facile performance in aqueous synthesis of pyranopyrimidines and pyrazolopyranopyrimidines.

Carbohydr Polym 2017 Nov 5;175:409-416. Epub 2017 Aug 5.

Catalysts and Organic Synthesis Research Laboratory, Department of Chemistry, Iran University of Science and Technology, Tehran 16846-13114, Iran; Department of Chemistry, Faculty of Science, Yazd University, Yazd 89195.741, Iran.

A cellulose-based nanobiocomposite decorated with FeO nanoparticles was prepared, characterized and applied as an easily recoverable and reusable green nanocatalyst in the synthesis of pyrano[2,3-d]pyrimidine derivatives in water at room temperature. The characterization was performed by using a variety of conventional analytical instruments such as Fourier transform infrared spectra (FT-IR), field emission scanning electron microscopy (FE-SEM), transmission electron microscopy (TEM), energy dispersive X-ray (EDX), vibrating sample magnetometer (VSM), thermal analysis (TGA/DTA) and inductively coupled plasma atomic emission spectroscopy (ICP-AES) analyses. Two series of pyranopyrimidine and pyrazolopyranopyrimidines derivatives were synthesized by using the present cellulose-based nanocomposite. This protocol has valuable features like high yield of the products, short reaction times, mild conditions and easy work-up procedure. In addition, the catalyst can be prepared easily with cheap and green starting materials.
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http://dx.doi.org/10.1016/j.carbpol.2017.08.019DOI Listing
November 2017

On the mechanisms of melatonin in protection of aluminum phosphide cardiotoxicity.

Arch Toxicol 2017 Sep 27;91(9):3109-3120. Epub 2017 May 27.

Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.

Aluminum phosphide (AlP), one of the most commonly used pesticides worldwide, has been the leading cause of self-poisoning mortalities among many Asian countries. The heart is the main organ affected in AlP poisoning. Melatonin has been previously shown to be beneficial in reversing toxic changes in the heart. The present study reveals evidence on the probable protective effects of melatonin on AlP-induced cardiotoxicity in rats. The study groups included a control (almond oil only), ethanol 5% (solvent), sole melatonin (50 mg/kg), AlP (16.7 mg/kg), and 4 AlP + melatonin groups which received 20, 30, 40 and 50 mg/kg of melatonin by intraperitoneal injections following AlP treatment. An electronic cardiovascular monitoring device was used to record the electrocardiographic (ECG) parameters. Heart tissues were studied in terms of oxidative stress biomarkers, mitochondrial complexes activities, ADP/ATP ratio and apoptosis. Abnormal ECG records as well as declined heart rate and blood pressure were found to be related to AlP administration. Based on the results, melatonin was highly effective in controlling AlP-induced changes in the study groups. Significant improvements were observed in the activities of mitochondrial complexes, oxidative stress biomarkers, the activities of caspases 3 and 9, and ADP/ATP ratio following treatment with melatonin at doses of 40 and 50 mg/kg. Our results indicate that melatonin can counteract the AlP-induced oxidative damage in the heart. This is mainly done by maintaining the normal balance of intracellular ATP as well as the prevention of oxidative damage. Further research is warranted to evaluate the possibility of using melatonin as an antidote in AlP poisoning.
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http://dx.doi.org/10.1007/s00204-017-1998-6DOI Listing
September 2017

Legumain Regulates Differentiation Fate of Human Bone Marrow Stromal Cells and Is Altered in Postmenopausal Osteoporosis.

Stem Cell Reports 2017 02 2;8(2):373-386. Epub 2017 Feb 2.

Department of Cellular and Molecular Medicine, Danish Stem Cell Center (DanStem), University of Copenhagen, 2200 Copenhagen, Denmark; Molecular Endocrinology & Stem Cell Research Unit (KMEB), Department of Endocrinology and Metabolism, Odense University Hospital & University of Southern Denmark, J.B. Winsloewsvej 25, 1st Floor, 5000 Odense C, Denmark; Stem Cell Unit, Department of Anatomy, Faculty of Medicine, King Saud University, Riyadh 12372, Saudi Arabia. Electronic address:

Secreted factors are a key component of stem cell niche and their dysregulation compromises stem cell function. Legumain is a secreted cysteine protease involved in diverse biological processes. Here, we demonstrate that legumain regulates lineage commitment of human bone marrow stromal cells and that its expression level and cellular localization are altered in postmenopausal osteoporotic patients. As shown by genetic and pharmacological manipulation, legumain inhibited osteoblast (OB) differentiation and in vivo bone formation through degradation of the bone matrix protein fibronectin. In addition, genetic ablation or pharmacological inhibition of legumain activity led to precocious OB differentiation and increased vertebral mineralization in zebrafish. Finally, we show that localized increased expression of legumain in bone marrow adipocytes was inversely correlated with adjacent trabecular bone mass in a cohort of patients with postmenopausal osteoporosis. Our data suggest that altered proteolytic activity of legumain in the bone microenvironment contributes to decreased bone mass in postmenopausal osteoporosis.
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http://dx.doi.org/10.1016/j.stemcr.2017.01.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5312427PMC
February 2017

CRMP4 Inhibits Bone Formation by Negatively Regulating BMP and RhoA Signaling.

J Bone Miner Res 2017 May 2;32(5):913-926. Epub 2017 Feb 2.

Molecular Endocrinology Laboratory (KMEB), Department of Endocrinology, Odense University Hospital & University of Southern Denmark, Odense, Denmark.

We identified the neuroprotein collapsing response mediator protein-4 (CRMP4) as a noncanonical osteogenic factor that regulates the differentiation of mouse bone marrow skeletal stem cells (bone marrow stromal stem cells [mBMSCs]) into osteoblastic cells. CRMP4 is the only member of the CRMP1-CRMP5 family to be expressed by mBMSCs and in osteoprogenitors of both adult mouse and human bones. In vitro gain-of-function and loss-of-function of CRMP4 in murine stromal cells revealed its inhibitory effect on osteoblast differentiation. In addition, Crmp4-deficient mice (Crmp4 ) displayed a 40% increase in bone mass, increased mineral apposition rate, and bone formation rate, compared to wild-type controls. Increased bone mass in Crmp4 mice was associated with enhanced BMP2 signaling and BMP2-induced osteoblast differentiation in Crmp4 osteoblasts (OBs). Furthermore, Crmp4 OBs exhibited enhanced activation of RhoA/focal adhesion kinase (FAK) signaling that led to cytoskeletal changes with increased cell spreading. In addition, Crmp4 OBs exhibited increased cell proliferation that was mediated via inhibiting cyclin-dependent kinase inhibitor 1B, p27 and upregulating cyclin D1 expression which are targets of RhoA signaling pathway. Our findings identify CRMP4 as a novel negative regulator of osteoblast differentiation. © 2016 American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbmr.3069DOI Listing
May 2017

Evidence of two distinct functionally specialized fibroblast lineages in breast stroma.

Breast Cancer Res 2016 11 3;18(1):108. Epub 2016 Nov 3.

Department of Biology, University of Copenhagen, Copenhagen, Denmark.

Background: The terminal duct lobular unit (TDLU) is the most dynamic structure in the human breast and the putative site of origin of human breast cancer. Although stromal cells contribute to a specialized microenvironment in many organs, this component remains largely understudied in the human breast. We here demonstrate the impact on epithelium of two lineages of breast stromal fibroblasts, one of which accumulates in the TDLU while the other resides outside the TDLU in the interlobular stroma.

Methods: The two lineages are prospectively isolated by fluorescence activated cell sorting (FACS) based on different expression levels of CD105 and CD26. The characteristics of the two fibroblast lineages are assessed by immunocytochemical staining and gene expression analysis. The differentiation capacity of the two fibroblast populations is determined by exposure to specific differentiating conditions followed by analysis of adipogenic and osteogenic differentiation. To test whether the two fibroblast lineages are functionally imprinted by their site of origin, single cell sorted CD271/MUC1 normal breast luminal epithelial cells are plated on fibroblast feeders for the observation of morphological development. Epithelial structure formation and polarization is shown by immunofluorescence and digitalized quantification of immunoperoxidase-stained cultures.

Results: Lobular fibroblasts are CD105/CD26 while interlobular fibroblasts are CD105/CD26. Once isolated the two lineages remain phenotypically stable and functionally distinct in culture. Lobular fibroblasts have properties in common with bone marrow derived mesenchymal stem cells and they specifically convey growth and branching morphogenesis of epithelial progenitors.

Conclusions: Two distinct functionally specialized fibroblast lineages exist in the normal human breast, of which the lobular fibroblasts have properties in common with mesenchymal stem cells and support epithelial growth and morphogenesis. We propose that lobular fibroblasts constitute a specialized microenvironment for human breast luminal epithelial progenitors, i.e. the putative precursors of breast cancer.
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http://dx.doi.org/10.1186/s13058-016-0769-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5093959PMC
November 2016

Molecular and biochemical evidence on the protection of cardiomyocytes from phosphine-induced oxidative stress, mitochondrial dysfunction and apoptosis by acetyl-L-carnitine.

Environ Toxicol Pharmacol 2016 Mar 2;42:30-7. Epub 2016 Jan 2.

Department of Toxicology and Pharmacology, Faculty of Pharmacy; and Pharmaceutical Sciences Research Center; and Poisoning & Toxicology Research Center; and Endocrinology & Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran 1417614411, Iran. Electronic address:

The aim of the present study was to investigate the efficacy of acetyl-L-carnitine (ALCAR) on pathologic changes of mitochondrial respiratory chain activity, ATP production, oxidative stress, and cellular apoptosis/necrosis induced by aluminum phosphide (AlP) poisoning. The study groups included: the Sham that received almond oil only; the AlP that received oral LD50 dose of aluminum; the AC-100, AC-200, and AC-300 which received concurrent oral LD50 dose of AlP and single 100, 200, and 300 mg/kg of ALCAR by intraperitoneal injection. After 24 h, the rats were sacrificed; the heart and blood sample were taken for measurement of biochemical and mitochondrial factors. The results specified that ALCAR significantly attenuated the oxidative stress (elevated ROS and plasma iron levels) caused by AlP poisoning. ALCAR also increased the activity of cytochrome oxidase, which in turn amplified ATP production. Furthermore, flow cytometric assays and caspase activity indicated that ALCAR prohibited AlP-induced apoptosis in cardiomyocytes.
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http://dx.doi.org/10.1016/j.etap.2015.12.019DOI Listing
March 2016

Molecular and biochemical evidences on the protective effects of triiodothyronine against phosphine-induced cardiac and mitochondrial toxicity.

Life Sci 2015 Oct 1;139:30-9. Epub 2015 Aug 1.

Department of Toxicology and Pharmacology, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran 1417614411, Iran; International Campus, Tehran University of Medical Sciences, Tehran 1417614411, Iran; Endocrinology & Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran. Electronic address:

Aim: Aluminum phosphide (AlP) is a widely used fumigant and rodenticide. While AlP ingestion leads to high mortality, its exact mechanism of action is unclear. There are ample evidences suggesting cardioprotective effects of triiodothyronine (T3). In this study, we aimed to examine the potential of T3 in the protection of a rat model of AlP induced cardiotoxicity.

Main Methods: In order to induce AlP intoxication animals were intoxicated with AlP (12 mg/kg; LD50) by gavage. In treatment groups, T3 (1, 2 and 3 μg/kg) was administered intra-peritoneally 30 min after AlP administration. Animals were connected to the electronic cardiovascular monitoring device simultaneously after T3 administration. Then, electrocardiogram (ECG), blood pressure (BP), and heart rate (HR) were monitored for 180 min. Additionally, 24h after AlP intoxication, rats were deceased and the hearts were dissected out for evaluation of oxidative stress, cardiac mitochondrial function (complexes I, II and IV), ATP/ADP ratio, caspases 3 & 9, and apoptosis by flow cytometry.

Key Findings: The results demonstrated that AlP intoxication causes cardiac toxicity presenting with changes in ECG patterns such as decrement of HR, BP and abnormal QRS complexes, QTc and ST height. T3 at a dose of 3 μg/kg significantly improved ECG and also oxidative stress parameters. Furthermore, T3 administration could increase mitochondrial function and ATP levels within the cardiac cells. In addition, administration of T3 showed a reduction in apoptosis through diminishing the caspase activities and improving cell viability.

Significance: Overall, the present data demonstrate the beneficial effects of T3 in cardiotoxicity of AlP.
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http://dx.doi.org/10.1016/j.lfs.2015.07.026DOI Listing
October 2015

Molecular characterisation of stromal populations derived from human embryonic stem cells: Similarities to immortalised bone marrow derived stromal stem cells.

Bone Rep 2015 Dec 4;3:32-39. Epub 2015 Aug 4.

Molecular Endocrinology Laboratory, Odense University Hospital, University of Southern Denmark, Odense, Denmark; Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University, Riyadh, Saudi Arabia; Danish Stem Cell Centre (DanStem), Institute of Cellular and Molecular Medicine, University of Copenhagen, Denmark.

Human bone marrow-derived stromal (skeletal) stem cells (BM-hMSC) are being employed in an increasing number of clinical trials for tissue regeneration. A limiting factor for their clinical use is the inability to obtain sufficient cell numbers. Human embryonic stem cells (hESC) can provide an unlimited source of clinical grade cells for therapy. We have generated MSC-like cells from hESC (called here hESC-stromal) that exhibit surface markers and differentiate to osteoblasts and adipocytes, similar to BM-hMSC. In the present study, we used microarray analysis to compare the molecular phenotype of hESC-stromal and immortalised BM-hMSC cells (hMSC-TERT). Of the 7379 genes expressed above baseline, only 9.3% of genes were differentially expressed between undifferentiated hESC-stromal and BM-hMSC. Following ex vivo osteoblast induction, 665 and 695 genes exhibited ≥ 2-fold change (FC) in hESC-stromal and BM-hMSC, respectively with 172 genes common to both cell types. Functional annotation of significantly changing genes revealed similarities in gene ontology between the two cell types. Interestingly, genes in categories of cell adhesion/motility and epithelial-mesenchymal transition (EMT) were highly enriched in hESC-stromal whereas genes associated with cell cycle processes were enriched in hMSC-TERT. This data suggests that while hESC-stromal cells exhibit a similar molecular phenotype to hMSC-TERT, differences exist that can be explained by ontological differences between these two cell types. hESC-stromal cells can thus be considered as a possible alternative candidate cells for hMSC, to be employed in regenerative medicine protocols.
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http://dx.doi.org/10.1016/j.bonr.2015.07.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5365211PMC
December 2015