hernan concha - Academia.edu (original) (raw)

Papers by hernan concha

Research paper thumbnail of Lentiviral-Mediated HoxB4 Expression in Human Embryonic Stem Cells Initiates Early Hematopoiesis in a Dose-Dependent Manner but Does Not Promote Myeloid Differentiation

Stem Cells, 2008

The variation of HoxB4 expression levels might be a key regulatory mechanism in the differentiati... more The variation of HoxB4 expression levels might be a key regulatory mechanism in the differentiation of human embryonic stem cell (hESC)-derived hematopoietic stem cells (HSCs). In this study, hESCs ectopically expressing high and low levels of HoxB4 were obtained using lentiviral gene transfer. Quantification throughout differentiation revealed a steady increase in transcription levels from our constructs. The effects of the two expression levels of HoxB4 were compared regarding the differentiation potential into HSCs. High levels of HoxB4 expression correlated to an improved yield of cells expressing CD34, CD38, the stem cell leukemia gene, and vascular epithelium-cadherin. However, no improvement in myeloid cell maturation was observed, as determined by colony formation assays. In contrast, hESCs with low HoxB4 levels did not show any elevated hematopoietic development. In addition, we found that the total population of HoxB4-expressing cells, on both levels, decreased in developi...

Research paper thumbnail of PP226-SUN Fish Oil Does Not Modulate the Response of in Vivo Protein Synthesis in Immune Cells to Endotoxin in Healthy Volunteers

Clinical Nutrition Supplements, 2011

Research paper thumbnail of Flow cytometry as a method for studying effects of stressors on primary rat neurons

Journal of Neuroscience Research, 2005

The mechanisms associated with cell death have been an important focus for neurobiology research.... more The mechanisms associated with cell death have been an important focus for neurobiology research. In the present study, the methodology of flow cytometry was used to optimize quantification of the toxic effects of tumor necrosis factor-alpha (TNF-alpha), trans-4-hydroxy-2-nonenal (4-HNE), and aged amyloid-beta (Abeta1-42) on rat primary cortical neurons. The fluorescent dyes annexin V-FITC and propidium iodide (PI) were used to identify populations of viable, early apoptotic, necrotic and late apoptotic cells by flow cytometry. Prior to exposure, the primary cultures showed 83% cell viability. Flow cytometry following labeling of cells with a specific neuronal marker, TUJ-1, revealed 82% pure neuronal populations, whereas approximately 7% were astrocytic as shown by glial fibrillary acidic protein positivity. Exposure of primary cultures to TNF-alpha, 4-HNE, and aged Abeta1-42 gave an increased number of early apoptotic cells. We show that flow cytometry is a suitable method for quantifying effects of different stressors on neurons in primary cultures. This technique could be useful for screening and testing of pharmacological compounds relevant to neurodegenerative disorders.

Research paper thumbnail of Kainic acid-induced excitotoxic hippocampal neurodegeneration in C57BL/6 mice: B cell and T cell subsets may contribute differently to the pathogenesis

Brain Behavior and Immunity, Mar 1, 2004

The roles of T cells and B cells in kainic acid (KA)-induced hippocampal lesions were studied in ... more The roles of T cells and B cells in kainic acid (KA)-induced hippocampal lesions were studied in C57BL/6 mice lacking specific T cell populations (CD4, CD8, and CD4/CD8 cells) and B cells [Igh-6()/))]. At 48 mg/kg of KA administrated intranasally, KA-induced convulsions were seen in all groups. However, CD4/CD8()/)) mice exhibited the mildest seizures; the responses of CD8()/)), Igh-6()/)) and wild-type mice were intermediate, whereas CD4()/)) mice displayed much more severe clinical signs and 100% early mortality, indicating that a deficiency of CD4 T cells obviously increased susceptibility to KA-induced brain damage. Histopathological analysis of the mice that survived 7 days after KA administration revealed that CD4/CD8()/)) mice had the fewest pathologic changes but Igh-6()/)) mice showed more severe lesions in area CA3 of the hippocampus than CD8()/)) and wild-type mice. Reactive astrogliosis were prominent in all KA-treated mice. Locomotor activity as assessed by open-field test increased after KA administration in Igh-6()/)) and wild-type mice only. These results denote the influence of the adaptive immune response on KAinduced hippocampal neurodegeneration and suggest that B cell and T cell subsets may contribute differently to the pathogenesis.

Research paper thumbnail of Small heat shock proteins Hsp27 or αB-crystallin and the protein components of neurofibrillary tangles: Tau and neurofilaments

Journal of Neuroscience Research, 2008

Background and aims: Among those afflicted with dementia more than half suffer from Alzheimer's d... more Background and aims: Among those afflicted with dementia more than half suffer from Alzheimer's disease (AD). Pathological hallmarks of the disease include aggregates of A, so called amyloid plaques, and neurofibrillary tangles (NFTs) made up of hyperphosphorylated cytoskeletal proteins. So far, no single pathological lesion has proven to be the sole cause of this slowly progressive disorder, with declining memory and cognitive deficits. No curative treatment exists for AD, even though some clinical symptoms can be alleviated. If this disease is to be defeated, probably the treatment must be directed against the disease-causing proteins, rather than downstream clinical manifestations. To find out more about the disease mechanisms, the studies included in this thesis focused on regulation of tau and neurofilament proteins (NFs), both part of the NFTs. Both tau and NFs are hyperphosphorylated in NFTs and the abnormal phosphorylation is dependent on dysregulated kinase and phosphatase activities found in AD. For example, the activity of the kinases GSK-3 and p70S6K have been found to be increased in AD, and their effects on tau and NFs were investigated in the studies in this thesis. Kinase activity may be regulated by other kinases or by AD pathology in the form of A, increased zinc concentrations or the reoccurrence of cell cycle markers to name a few, and this was also investigated in these studies. Results and discussion: In Study I, sequential accumulation of A variants and phosphorylated tau epitopes were demonstrated in AD brains. The levels of A showed good correlation with phosphorylated tau; the strength of the correlation depending on the specific tau phosphorylation epitopes. Both A and tau correlated well with different stages of the Braak or CERAD staging systems, which suggests that tau antibodies can be used selectively in AD diagnosis as a complement to morphological evaluations. In Study II, zinc treatment led to increased kinase activities, among them p70S6K and GSK-3, and a subsequent increase in tau phosphorylation. Tau translation was also increased through the activation of p70S6K, in accordance with increased tau levels in AD brains. These results indicate that p70S6K can regulate tau on both translational and post-translational levels, while the main effect of other kinases, such as GSK-3, is on tau phosphorylation. Many tau kinases are also capable of NF phosphorylation and when N2a cells were treated with zinc, in Study III, an increase in p70S6K activity was observed, together with a concomitant increase in NF phosphorylation. However, when p70S6K activity was blocked with rapamycin, the NF phosphorylation remained unchanged, despite the fact that the p70S6K activity was significantly decreased. Thus, zinc must induce NF phosphorylation in the N2a cells through other kinases. Other factors, such as small heat shock proteins, may influence tau and NF regulation. In Study IV, both Hsp27 and B-crystallin were up-regulated in AD brains, and this correlated with increased tau and NF phosphorylation. Hsp27 overexpression in N2a cells led to increased pSer262-tau levels, probably regulated by p70S6K, while B-crystallin overexpression actually resulted in decreased tau and NF phosphorylation. These differences reflect the complexity behind cellular regulation, and the picture gets even more complicated in the human brain, where the surrounding environment also has an effect. Since many pathways intertwine and affect each other, both directly and indirectly, sHSPs, for example, may be activated by tau hyperphosphorylation or the cell cycle. And they may in turn have reciprocal effects on tau regulation or the cell cycle, and so the circle continues. This complexity will affect the choice of possible future treatment strategies for AD since it is difficult to isolate one specific part of one pathway, without affecting any of the others detrimentally.

Research paper thumbnail of Inhibition of microsomal prostaglandin E synthase‐1 by aminothiazoles decreases prostaglandin E <sub>2</sub> synthesis <i>in vitro</i> and ameliorates experimental periodontitis <i>in vivo</i>

The FASEB Journal, Feb 27, 2013

Inhibition of mPGES-1 as therapeutic strategy in inflammation and cancer THESIS FOR DOCTORAL DEGR... more Inhibition of mPGES-1 as therapeutic strategy in inflammation and cancer THESIS FOR DOCTORAL DEGREE (Ph.D.) that is publicly defended for doctoral degree at Karolinska Institutet in Lecture Hall Germinal Center, CMM L8:00 on

Research paper thumbnail of Research Article Circulating Th17, Th22, and Th1 Cells Are Elevated in the Guillain-Barré Syndrome and Downregulated by IVIg Treatments

which permits unrestricted use, distribution, and reproduction in any medium, provided the origin... more which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Guillain-Barre ́ syndrome (GBS) is considered a T helper 1 (Th1) cells-mediated acute inflammatory peripheral neuropathy. However, some changes in GBS could not be explained completely by Th1 cells pathogenic role. Recently, Th17 cells have been identified and canmediate tissue inflammation and autoimmune response.Therefore, a study on the role ofTh17 andTh22 cells and their cytokines in GBS is necessary for exploring the pathogenesis of GBS. Here, we detected the frequency of Th1, Th17, andTh22 cells by using 4-color flow cytometry and we detected the plasma levels of IL-17 and IL-22 by ELISA in GBS patients, relapsing-remitting multiple sclerosis patients at the acute phase of relapse, viral encephalitis or meningitis patients and healthy controls. Our data showed that the frequency of circulatingTh1,Th17, andTh22 cells was significantly increased in GBS ...

Research paper thumbnail of Small Heat Shock Proteins Hsp27 or aB-Crystallin and the Protein Components of Neurofibrillary Tangles : Tau and Neurofilaments

Journal of Neuroscience Research, 2008

Research paper thumbnail of Effects of Novel mPGES-1 Inhibitors on PGE2 Production

Objective: Prostaglandin E2 (PGE2) has a central role in the pathogenesis of inflammatory conditi... more Objective: Prostaglandin E2 (PGE2) has a central role in the pathogenesis of inflammatory conditions including periodontitis. The final step of the PGE2 biosynthesis is catalyzed by the PGE synthases, where the inducible isoform, mPGES-1, is an attractive target for selective PGE2 inhibition. The objective of this study was to investigate the effects of thiazole compounds as potential mPGES-1 inhibitors of IL1β-induced PGE2 synthesis in gingival fibroblasts. Method: Several compounds were identified as mPGES-1 inhibitors by docking models using a modeling program. The two most potent of the compounds, TH-644 and TH-848, were used alone or in combination with the pro-inflammatory cytokine IL-1β on gingival fibroblasts. After stimulation, PGE2 levels were measured in the culture medium using EIA, and RNA and protein expression of PGE synthases and COX-2 was analyzed by RT-PCR, flow cytometry and western blot. In vitro mPGES-1 activity, with or without TH-644 or TH-848, was investigate...

Research paper thumbnail of IL-12p35 deficiency alleviates kainic acid-induced hippocampal neurodegeneration in C57BL/6 mice

Neurobiology of Disease, 2004

The role of IL-12 in excitotoxic neurodegeneration of brain is largely unknown. To address this i... more The role of IL-12 in excitotoxic neurodegeneration of brain is largely unknown. To address this issue, we used the model of kainic acid (KA)induced hippocampal injury in IL-12p35 knockout (KO) mice, a wellcharacterized model for human neurodegenerative diseases. After KA treatment, hippocampal neurodegeneration was significantly less severe in the IL-12p35 KO mice than in wild-type mice as demonstrated by reduced pathological changes and astrogliosis. One day after KA treatment, levels of F4/80 and CD86 expression on microglia were significantly lower in IL-12p35 KO mice than in wild-type mice analyzed by flow cytometry, indicating that IL-12p35 deficiency resulted in lower levels of microglial activation. Five days after KA treatment, CD86 expression on microglia of wild-type mice was still higher, whereas F4/80 expression in wild-type mice decreased and was similar to that in IL-12p35 KO mice. Because microglial activation is necessary for KA-induced neurodegeneration, the lower level of microglial activation in the absence of IL-12p35 may alleviate hippocampal injury in KO mice. In summary, this study indicates that IL-12 may play a critical role in excitotoxin-induced brain injury.

Research paper thumbnail of Small heat shock proteins Hsp27 or αB‐crystallin and the protein components of neurofibrillary tangles: Tau and neurofilaments

Journal of Neuroscience Research, 2008

The heat‐shock proteins (HSPs) Hsp27 and αB‐crystallin are up‐regulated in Alzheimer's diseas... more The heat‐shock proteins (HSPs) Hsp27 and αB‐crystallin are up‐regulated in Alzheimer's disease (AD), but the extent of this and the consequences are still largely unknown. The HSPs are involved in protein degradation and protection against protein aggregation, and they interact with several cytoskeletal components such as microtubules (MT) and neurofilaments (NF). AD pathology includes aggregated proteins (tau, NF), decreased protein degradation, and cytoskeletal disruption. It is thus of interest to investigate more closely the possible roles of the HSPs in AD pathology. The expressions of Hsp27 and αB‐crystallin in AD brain samples were significantly increased (by ∼20% and ∼30%, respectively) and correlated significantly with phosphorylated tau and NF proteins. To investigate the consequences of increased HSP levels on tau and NF regulation, N2a cells were transfected with Hsp27 or αB‐crystallin constructs, and overexpression of the HSPs was confirmed in the cells. Increased t...

Research paper thumbnail of Flow cytometry as a method for studying effects of stressors on primary rat neurons

Journal of Neuroscience Research, 2005

The mechanisms associated with cell death have been an important focus for neurobiology research.... more The mechanisms associated with cell death have been an important focus for neurobiology research. In the present study, the methodology of flow cytometry was used to optimize quantification of the toxic effects of tumor necrosis factor-alpha (TNF-alpha), trans-4-hydroxy-2-nonenal (4-HNE), and aged amyloid-beta (Abeta1-42) on rat primary cortical neurons. The fluorescent dyes annexin V-FITC and propidium iodide (PI) were used to identify populations of viable, early apoptotic, necrotic and late apoptotic cells by flow cytometry. Prior to exposure, the primary cultures showed 83% cell viability. Flow cytometry following labeling of cells with a specific neuronal marker, TUJ-1, revealed 82% pure neuronal populations, whereas approximately 7% were astrocytic as shown by glial fibrillary acidic protein positivity. Exposure of primary cultures to TNF-alpha, 4-HNE, and aged Abeta1-42 gave an increased number of early apoptotic cells. We show that flow cytometry is a suitable method for quantifying effects of different stressors on neurons in primary cultures. This technique could be useful for screening and testing of pharmacological compounds relevant to neurodegenerative disorders.

Research paper thumbnail of Differential role of presenilin‐1 and ‐2 on mitochondrial membrane potential and oxygen consumption in mouse embryonic fibroblasts

Journal of Neuroscience Research, 2006

Increasing evidence indicates that mitochondrial alterations contribute to the neuronal death in ... more Increasing evidence indicates that mitochondrial alterations contribute to the neuronal death in Alzheimer's disease (AD). Presenilin 1 (PS1) and Presenilin 2 (PS2) mutations have been shown to sensitize cells to apoptosis by mechanisms suggested to involve impaired mitochondrial function. We have previously detected active γ‐secretase complexes in mitochondria. We investigated the impact of PS/γ‐secretase on mitochondrial function using mouse embryonal fibroblasts derived from wild‐type, PS1−/−, PS2−/− and PS double knock‐out (PSKO) embryos. Measurements of mitochondrial membrane potential (ΔΨm) showed a higher percentage of fully functional mitochondria in PS1−/− and PSwt as compared to PS2−/− and PSKO cells. This result was evident both in whole cell preparations and in isolated mitochondria. Interestingly, pre‐treatment of isolated mitochondria with the γ‐secretase inhibitor L‐685,458 resulted in a decreased population of mitochondria with high ΔΨm in PSwt and PS1−/− cells, ...

Research paper thumbnail of Myeloablative and immunosuppressive properties of treosulfan in mice

Experimental Hematology, 2006

Allogeneic stem cell transplantation (SCT) is a curative treatment for malignant and non-malignan... more Allogeneic stem cell transplantation (SCT) is a curative treatment for malignant and non-malignant diseases. However, transplantation related morbidity and mortality are major drawbacks affecting the survival and life quality of the patients. The major complications of SCT are infections, hemorrhagic cystitis, liver toxicity, interstitial pneumonia and GVHD. Busulphan (Bu), treosulfan (Tr) and cyclophosphamide (Cy) are alkylating agents. They are currently used in high doses as preparative regimen before SCT. Pharmacokinetics and pharmacodynamics of these drugs have been intensively studied with the aim of defining a therapeutic window to achieve a satisfactory myeloablation and immunosuppression with less treatment related toxicity. Study I: We administered N-acetyl-L-cysteine (NAC) during conditioning to patients at risk of Sinusoidal obstructive Syndrome (SOS) due to pretransplant liver disorders or elevated liver enzymes. No side effects related to the NAC administration were observed and Bu-kinetics was not affected. All patients became pancytopenic and engrafted with100% donor cells. None of the patients developed SOS or liver failure. Increased liver enzymes during conditioning decreased or normalized in all patients. We suggested that NAC therapy is safe and does not impair the myeloablative effect of Bu during conditioning prior to SCT and hence NAC may be an effective prophylactic treatment against SOS and hepatic toxicity during conditioning. Study II In a preclinical study, myeloablative as well as immunosuppressive properties of Tr were compared with those of Bu and Cy in a mouse model. The animals were treated with Tr, Cy, or Bu at sublethal doses that maintained survival without bone marrow support. The myeloablative effect was evaluated using colony-forming unit granulocyte macrophages (CFU-GM), while the immunological effect was performed using spleen cells. We found that Tr and Bu induced a high and persistent myeloablation compared to Cy. Moreover, Tr was more effective in depletion splenic B and T cells compared to Bu and Cy. T-cells isolated from the spleens of Tr-or Bu-treated mice were not responsive to allogeneic cells compared with those observed in Cy treated mice. Our findings suggested that Tr possesses both myeloablative and immunosuppressive properties and may be used as a single agent for conditioning prior to SCT. Study III. Therapeutic drug monitoring (TDM) of Bu-iv was performed in 34 pediatric SCT patients. Buiv was administered twice daily according to recommended weight-based doses. Bu levels were measured and pharmacokinetic analysis was performed. The targeted Bu exposure was aimed to range between areas under the curve (AUC) of 9000-12000 ng/mLxh. In 23/34 patients (68%) Bu dose had to be adjusted at least once. In 16/23 patients the dose had to be increased in a range of 7-33%, while in 7/23 patients (30%) the dose had to be decreased by 7-20%. The need of dose adjustment was not related to weight, age or underlying disease. SOS was observed in 21% of the patients in spite of total AUC's within the target AUC. We concluded that TDM of iv Bu is essential to increase the efficacy and safety of Bubased conditioning protocols in pediatric HSCT recipients. Study IV. Limited sampling models for use in TDM of Bu in patients treated for hematologic malignancies. 23 patients were sampled according to standard protocol (8 samples). AUC calculated from three limited sampling models were compared with WinNonLin compartment modeling. Combining a curve fitting model and a compartment model, using the average AUC estimate, gave a concordance correlation coefficient of 0.85 with the described standard sampling protocol. Using Bland-Altman plots it was evident that most patients would have been treated the same regarding dose adjustment using the combined method as well as standard rich sampling. The results support the use of limited sampling in clinical therapeutic drug monitoring, provided adequate algorithms are used for evaluation. Both models included in the combined method utilized four concentrations points. The model is reliable, solid and user friendly providing the clinician with a graph and a numeric AUC estimate. These four studies taken together may provide a step forward in treatment optimization and dose individualization to the benefit of SCT patients.

Research paper thumbnail of Signaling pathways involved in the regulation of TNFα-induced toll-like receptor 2 expression in human gingival fibroblasts

Cytokine, 2012

Periodontitis is a chronic inflammatory disease characterized by a host inflammatory response aga... more Periodontitis is a chronic inflammatory disease characterized by a host inflammatory response against bacteria that leads to destruction of the supporting structures of the teeth. Bacterial components of pathogens in the periodontal pocket are recognized by toll-like receptors (TLRs) that trigger an inflammatory response. In this study, we investigated the effects of the pro-inflammatory cytokine tumor necrosis factor α (TNFα) on TLR2 expression in human gingival fibroblasts. In addition, we examined the signaling pathways involved in the regulation of TNFα-induced TLR2 expression. Our results showed that TNFα increased TLR2 mRNA and protein expression. Microarray analysis and the inhibition of specific signaling pathways demonstrated that c-Jun N-terminal kinases (JNK) and nuclear factor kappa B (NF-κB) were involved in the regulation of TNFα-induced TLR2 expression in gingival fibroblasts. Furthermore, the prostaglandin E(2) (PGE(2)) regulatory enzyme cytosolic phospholipase A(2) (cPLA(2)) and the anti-inflammatory prostaglandin 15-deoxy-Δ(12,14)-prostaglandin J(2) (15d-PGJ(2)), were found to regulate TLR2 mRNA expression stimulated by TNFα. Our findings suggest that these pathways and mediators, through the regulation of TLR2 expression in gingival fibroblasts, may be involved in the pathogenesis of periodontitis. The study provides new insights into the molecular mechanisms underlying the regulation of TLR2, implicated in the chronic inflammatory disease periodontitis.

Research paper thumbnail of Expansion and Activation Kinetics of Immune Cells during Early Phase of GVHD in Mouse Model Based on Chemotherapy Conditioning

Clinical and Developmental Immunology, 2010

In the present paper, we have investigated early pathophysiological events in graft-versus-host d... more In the present paper, we have investigated early pathophysiological events in graft-versus-host disease (GVHD), a major complication to hematopoietic stem cell transplantation (HSCT). BLLB/c female mice conditioned with busulfan/cyclophosphamide (Bu-Cy) were transplanted with allogeneic male C57BL/6. Control group consisted of syngeneic transplanted Balb/c mice. In allogeneic settings, significant expansion and maturation of donor dendritic cells (DCs) were observed at day +3, while donor T-cells CD8+ were increased at day +5 (230%) compared to syngeneic HSCT. Highest levels of inflammatory cytokines IL-2, IFN-gamma, and TNF-alfa at day +5 matched T-cell activation. Concomitantly naïve T-cells gain effecr-memory phenotype and migrated from spleen to peripheral lymphoid organs. Thus, in the very early phase of GHVD following Bu-Cy conditioning donor, DCs play an important role in the activation of donor T cells. Subsequently, donor naïve T-cells gain effector-memory phenotype and ini...

Research paper thumbnail of Kainic acid-induced excitotoxic hippocampal neurodegeneration in C57BL/6 mice: B cell and T cell subsets may contribute differently to the pathogenesis

Brain, Behavior, and Immunity, 2004

The roles of T cells and B cells in kainic acid (KA)-induced hippocampal lesions were studied in ... more The roles of T cells and B cells in kainic acid (KA)-induced hippocampal lesions were studied in C57BL/6 mice lacking specific T cell populations (CD4, CD8, and CD4/CD8 cells) and B cells [Igh-6()/))]. At 48 mg/kg of KA administrated intranasally, KA-induced convulsions were seen in all groups. However, CD4/CD8()/)) mice exhibited the mildest seizures; the responses of CD8()/)), Igh-6()/)) and wild-type mice were intermediate, whereas CD4()/)) mice displayed much more severe clinical signs and 100% early mortality, indicating that a deficiency of CD4 T cells obviously increased susceptibility to KA-induced brain damage. Histopathological analysis of the mice that survived 7 days after KA administration revealed that CD4/CD8()/)) mice had the fewest pathologic changes but Igh-6()/)) mice showed more severe lesions in area CA3 of the hippocampus than CD8()/)) and wild-type mice. Reactive astrogliosis were prominent in all KA-treated mice. Locomotor activity as assessed by open-field test increased after KA administration in Igh-6()/)) and wild-type mice only. These results denote the influence of the adaptive immune response on KAinduced hippocampal neurodegeneration and suggest that B cell and T cell subsets may contribute differently to the pathogenesis.

Research paper thumbnail of Dynamics of Adipocyte Turnover in Humans

Nature, vol. 453, na, …, 2007

Research paper thumbnail of Correction to: Defined serum- and xeno-free cryopreservation of mesenchymal stem cells

Cell and Tissue Banking, 2019

In the original article, Fig. 1A was by mistakenly duplicated. The corrected image is provided in... more In the original article, Fig. 1A was by mistakenly duplicated. The corrected image is provided in this correction article.

Research paper thumbnail of Aminothiazoles inhibit RANKL- and LPS-mediated osteoclastogenesis and PGE2 production in RAW 264.7 cells

Journal of cellular and molecular medicine, Jun 14, 2016

Periodontitis is characterized by chronic inflammation and osteoclast-mediated bone loss regulate... more Periodontitis is characterized by chronic inflammation and osteoclast-mediated bone loss regulated by the receptor activator of nuclear factor-κB (RANK), RANK ligand (RANKL) and osteoprotegerin (OPG). The aim of this study was to investigate the effect of aminothiazoles targeting prostaglandin E synthase-1 (mPGES-1) on RANKL- and lipopolysaccharide (LPS)-mediated osteoclastogenesis and prostaglandin E2 (PGE2 ) production in vitro using the osteoclast precursor RAW 264.7 cells. RAW 264.7 cells were treated with RANKL or LPS alone or in combination with the aminothiazoles 4-([4-(2-naphthyl)-1,3-thiazol-2-yl]amino)phenol (TH-848) or 4-(3-fluoro-4-methoxyphenyl)-N-(4-phenoxyphenyl)-1,3-thiazol-2-amine (TH-644). Aminothiazoles significantly decreased the number of multinucleated tartrate-resistant acid phosphatase (TRAP)-positive osteoclast-like cells in cultures of RANKL- and LPS-stimulated RAW 264.7 cells, as well as reduced the production of PGE2 in culture supernatants. LPS-treatment...

Research paper thumbnail of Lentiviral-Mediated HoxB4 Expression in Human Embryonic Stem Cells Initiates Early Hematopoiesis in a Dose-Dependent Manner but Does Not Promote Myeloid Differentiation

Stem Cells, 2008

The variation of HoxB4 expression levels might be a key regulatory mechanism in the differentiati... more The variation of HoxB4 expression levels might be a key regulatory mechanism in the differentiation of human embryonic stem cell (hESC)-derived hematopoietic stem cells (HSCs). In this study, hESCs ectopically expressing high and low levels of HoxB4 were obtained using lentiviral gene transfer. Quantification throughout differentiation revealed a steady increase in transcription levels from our constructs. The effects of the two expression levels of HoxB4 were compared regarding the differentiation potential into HSCs. High levels of HoxB4 expression correlated to an improved yield of cells expressing CD34, CD38, the stem cell leukemia gene, and vascular epithelium-cadherin. However, no improvement in myeloid cell maturation was observed, as determined by colony formation assays. In contrast, hESCs with low HoxB4 levels did not show any elevated hematopoietic development. In addition, we found that the total population of HoxB4-expressing cells, on both levels, decreased in developi...

Research paper thumbnail of PP226-SUN Fish Oil Does Not Modulate the Response of in Vivo Protein Synthesis in Immune Cells to Endotoxin in Healthy Volunteers

Clinical Nutrition Supplements, 2011

Research paper thumbnail of Flow cytometry as a method for studying effects of stressors on primary rat neurons

Journal of Neuroscience Research, 2005

The mechanisms associated with cell death have been an important focus for neurobiology research.... more The mechanisms associated with cell death have been an important focus for neurobiology research. In the present study, the methodology of flow cytometry was used to optimize quantification of the toxic effects of tumor necrosis factor-alpha (TNF-alpha), trans-4-hydroxy-2-nonenal (4-HNE), and aged amyloid-beta (Abeta1-42) on rat primary cortical neurons. The fluorescent dyes annexin V-FITC and propidium iodide (PI) were used to identify populations of viable, early apoptotic, necrotic and late apoptotic cells by flow cytometry. Prior to exposure, the primary cultures showed 83% cell viability. Flow cytometry following labeling of cells with a specific neuronal marker, TUJ-1, revealed 82% pure neuronal populations, whereas approximately 7% were astrocytic as shown by glial fibrillary acidic protein positivity. Exposure of primary cultures to TNF-alpha, 4-HNE, and aged Abeta1-42 gave an increased number of early apoptotic cells. We show that flow cytometry is a suitable method for quantifying effects of different stressors on neurons in primary cultures. This technique could be useful for screening and testing of pharmacological compounds relevant to neurodegenerative disorders.

Research paper thumbnail of Kainic acid-induced excitotoxic hippocampal neurodegeneration in C57BL/6 mice: B cell and T cell subsets may contribute differently to the pathogenesis

Brain Behavior and Immunity, Mar 1, 2004

The roles of T cells and B cells in kainic acid (KA)-induced hippocampal lesions were studied in ... more The roles of T cells and B cells in kainic acid (KA)-induced hippocampal lesions were studied in C57BL/6 mice lacking specific T cell populations (CD4, CD8, and CD4/CD8 cells) and B cells [Igh-6()/))]. At 48 mg/kg of KA administrated intranasally, KA-induced convulsions were seen in all groups. However, CD4/CD8()/)) mice exhibited the mildest seizures; the responses of CD8()/)), Igh-6()/)) and wild-type mice were intermediate, whereas CD4()/)) mice displayed much more severe clinical signs and 100% early mortality, indicating that a deficiency of CD4 T cells obviously increased susceptibility to KA-induced brain damage. Histopathological analysis of the mice that survived 7 days after KA administration revealed that CD4/CD8()/)) mice had the fewest pathologic changes but Igh-6()/)) mice showed more severe lesions in area CA3 of the hippocampus than CD8()/)) and wild-type mice. Reactive astrogliosis were prominent in all KA-treated mice. Locomotor activity as assessed by open-field test increased after KA administration in Igh-6()/)) and wild-type mice only. These results denote the influence of the adaptive immune response on KAinduced hippocampal neurodegeneration and suggest that B cell and T cell subsets may contribute differently to the pathogenesis.

Research paper thumbnail of Small heat shock proteins Hsp27 or αB-crystallin and the protein components of neurofibrillary tangles: Tau and neurofilaments

Journal of Neuroscience Research, 2008

Background and aims: Among those afflicted with dementia more than half suffer from Alzheimer's d... more Background and aims: Among those afflicted with dementia more than half suffer from Alzheimer's disease (AD). Pathological hallmarks of the disease include aggregates of A, so called amyloid plaques, and neurofibrillary tangles (NFTs) made up of hyperphosphorylated cytoskeletal proteins. So far, no single pathological lesion has proven to be the sole cause of this slowly progressive disorder, with declining memory and cognitive deficits. No curative treatment exists for AD, even though some clinical symptoms can be alleviated. If this disease is to be defeated, probably the treatment must be directed against the disease-causing proteins, rather than downstream clinical manifestations. To find out more about the disease mechanisms, the studies included in this thesis focused on regulation of tau and neurofilament proteins (NFs), both part of the NFTs. Both tau and NFs are hyperphosphorylated in NFTs and the abnormal phosphorylation is dependent on dysregulated kinase and phosphatase activities found in AD. For example, the activity of the kinases GSK-3 and p70S6K have been found to be increased in AD, and their effects on tau and NFs were investigated in the studies in this thesis. Kinase activity may be regulated by other kinases or by AD pathology in the form of A, increased zinc concentrations or the reoccurrence of cell cycle markers to name a few, and this was also investigated in these studies. Results and discussion: In Study I, sequential accumulation of A variants and phosphorylated tau epitopes were demonstrated in AD brains. The levels of A showed good correlation with phosphorylated tau; the strength of the correlation depending on the specific tau phosphorylation epitopes. Both A and tau correlated well with different stages of the Braak or CERAD staging systems, which suggests that tau antibodies can be used selectively in AD diagnosis as a complement to morphological evaluations. In Study II, zinc treatment led to increased kinase activities, among them p70S6K and GSK-3, and a subsequent increase in tau phosphorylation. Tau translation was also increased through the activation of p70S6K, in accordance with increased tau levels in AD brains. These results indicate that p70S6K can regulate tau on both translational and post-translational levels, while the main effect of other kinases, such as GSK-3, is on tau phosphorylation. Many tau kinases are also capable of NF phosphorylation and when N2a cells were treated with zinc, in Study III, an increase in p70S6K activity was observed, together with a concomitant increase in NF phosphorylation. However, when p70S6K activity was blocked with rapamycin, the NF phosphorylation remained unchanged, despite the fact that the p70S6K activity was significantly decreased. Thus, zinc must induce NF phosphorylation in the N2a cells through other kinases. Other factors, such as small heat shock proteins, may influence tau and NF regulation. In Study IV, both Hsp27 and B-crystallin were up-regulated in AD brains, and this correlated with increased tau and NF phosphorylation. Hsp27 overexpression in N2a cells led to increased pSer262-tau levels, probably regulated by p70S6K, while B-crystallin overexpression actually resulted in decreased tau and NF phosphorylation. These differences reflect the complexity behind cellular regulation, and the picture gets even more complicated in the human brain, where the surrounding environment also has an effect. Since many pathways intertwine and affect each other, both directly and indirectly, sHSPs, for example, may be activated by tau hyperphosphorylation or the cell cycle. And they may in turn have reciprocal effects on tau regulation or the cell cycle, and so the circle continues. This complexity will affect the choice of possible future treatment strategies for AD since it is difficult to isolate one specific part of one pathway, without affecting any of the others detrimentally.

Research paper thumbnail of Inhibition of microsomal prostaglandin E synthase‐1 by aminothiazoles decreases prostaglandin E <sub>2</sub> synthesis <i>in vitro</i> and ameliorates experimental periodontitis <i>in vivo</i>

The FASEB Journal, Feb 27, 2013

Inhibition of mPGES-1 as therapeutic strategy in inflammation and cancer THESIS FOR DOCTORAL DEGR... more Inhibition of mPGES-1 as therapeutic strategy in inflammation and cancer THESIS FOR DOCTORAL DEGREE (Ph.D.) that is publicly defended for doctoral degree at Karolinska Institutet in Lecture Hall Germinal Center, CMM L8:00 on

Research paper thumbnail of Research Article Circulating Th17, Th22, and Th1 Cells Are Elevated in the Guillain-Barré Syndrome and Downregulated by IVIg Treatments

which permits unrestricted use, distribution, and reproduction in any medium, provided the origin... more which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Guillain-Barre ́ syndrome (GBS) is considered a T helper 1 (Th1) cells-mediated acute inflammatory peripheral neuropathy. However, some changes in GBS could not be explained completely by Th1 cells pathogenic role. Recently, Th17 cells have been identified and canmediate tissue inflammation and autoimmune response.Therefore, a study on the role ofTh17 andTh22 cells and their cytokines in GBS is necessary for exploring the pathogenesis of GBS. Here, we detected the frequency of Th1, Th17, andTh22 cells by using 4-color flow cytometry and we detected the plasma levels of IL-17 and IL-22 by ELISA in GBS patients, relapsing-remitting multiple sclerosis patients at the acute phase of relapse, viral encephalitis or meningitis patients and healthy controls. Our data showed that the frequency of circulatingTh1,Th17, andTh22 cells was significantly increased in GBS ...

Research paper thumbnail of Small Heat Shock Proteins Hsp27 or aB-Crystallin and the Protein Components of Neurofibrillary Tangles : Tau and Neurofilaments

Journal of Neuroscience Research, 2008

Research paper thumbnail of Effects of Novel mPGES-1 Inhibitors on PGE2 Production

Objective: Prostaglandin E2 (PGE2) has a central role in the pathogenesis of inflammatory conditi... more Objective: Prostaglandin E2 (PGE2) has a central role in the pathogenesis of inflammatory conditions including periodontitis. The final step of the PGE2 biosynthesis is catalyzed by the PGE synthases, where the inducible isoform, mPGES-1, is an attractive target for selective PGE2 inhibition. The objective of this study was to investigate the effects of thiazole compounds as potential mPGES-1 inhibitors of IL1β-induced PGE2 synthesis in gingival fibroblasts. Method: Several compounds were identified as mPGES-1 inhibitors by docking models using a modeling program. The two most potent of the compounds, TH-644 and TH-848, were used alone or in combination with the pro-inflammatory cytokine IL-1β on gingival fibroblasts. After stimulation, PGE2 levels were measured in the culture medium using EIA, and RNA and protein expression of PGE synthases and COX-2 was analyzed by RT-PCR, flow cytometry and western blot. In vitro mPGES-1 activity, with or without TH-644 or TH-848, was investigate...

Research paper thumbnail of IL-12p35 deficiency alleviates kainic acid-induced hippocampal neurodegeneration in C57BL/6 mice

Neurobiology of Disease, 2004

The role of IL-12 in excitotoxic neurodegeneration of brain is largely unknown. To address this i... more The role of IL-12 in excitotoxic neurodegeneration of brain is largely unknown. To address this issue, we used the model of kainic acid (KA)induced hippocampal injury in IL-12p35 knockout (KO) mice, a wellcharacterized model for human neurodegenerative diseases. After KA treatment, hippocampal neurodegeneration was significantly less severe in the IL-12p35 KO mice than in wild-type mice as demonstrated by reduced pathological changes and astrogliosis. One day after KA treatment, levels of F4/80 and CD86 expression on microglia were significantly lower in IL-12p35 KO mice than in wild-type mice analyzed by flow cytometry, indicating that IL-12p35 deficiency resulted in lower levels of microglial activation. Five days after KA treatment, CD86 expression on microglia of wild-type mice was still higher, whereas F4/80 expression in wild-type mice decreased and was similar to that in IL-12p35 KO mice. Because microglial activation is necessary for KA-induced neurodegeneration, the lower level of microglial activation in the absence of IL-12p35 may alleviate hippocampal injury in KO mice. In summary, this study indicates that IL-12 may play a critical role in excitotoxin-induced brain injury.

Research paper thumbnail of Small heat shock proteins Hsp27 or αB‐crystallin and the protein components of neurofibrillary tangles: Tau and neurofilaments

Journal of Neuroscience Research, 2008

The heat‐shock proteins (HSPs) Hsp27 and αB‐crystallin are up‐regulated in Alzheimer's diseas... more The heat‐shock proteins (HSPs) Hsp27 and αB‐crystallin are up‐regulated in Alzheimer's disease (AD), but the extent of this and the consequences are still largely unknown. The HSPs are involved in protein degradation and protection against protein aggregation, and they interact with several cytoskeletal components such as microtubules (MT) and neurofilaments (NF). AD pathology includes aggregated proteins (tau, NF), decreased protein degradation, and cytoskeletal disruption. It is thus of interest to investigate more closely the possible roles of the HSPs in AD pathology. The expressions of Hsp27 and αB‐crystallin in AD brain samples were significantly increased (by ∼20% and ∼30%, respectively) and correlated significantly with phosphorylated tau and NF proteins. To investigate the consequences of increased HSP levels on tau and NF regulation, N2a cells were transfected with Hsp27 or αB‐crystallin constructs, and overexpression of the HSPs was confirmed in the cells. Increased t...

Research paper thumbnail of Flow cytometry as a method for studying effects of stressors on primary rat neurons

Journal of Neuroscience Research, 2005

The mechanisms associated with cell death have been an important focus for neurobiology research.... more The mechanisms associated with cell death have been an important focus for neurobiology research. In the present study, the methodology of flow cytometry was used to optimize quantification of the toxic effects of tumor necrosis factor-alpha (TNF-alpha), trans-4-hydroxy-2-nonenal (4-HNE), and aged amyloid-beta (Abeta1-42) on rat primary cortical neurons. The fluorescent dyes annexin V-FITC and propidium iodide (PI) were used to identify populations of viable, early apoptotic, necrotic and late apoptotic cells by flow cytometry. Prior to exposure, the primary cultures showed 83% cell viability. Flow cytometry following labeling of cells with a specific neuronal marker, TUJ-1, revealed 82% pure neuronal populations, whereas approximately 7% were astrocytic as shown by glial fibrillary acidic protein positivity. Exposure of primary cultures to TNF-alpha, 4-HNE, and aged Abeta1-42 gave an increased number of early apoptotic cells. We show that flow cytometry is a suitable method for quantifying effects of different stressors on neurons in primary cultures. This technique could be useful for screening and testing of pharmacological compounds relevant to neurodegenerative disorders.

Research paper thumbnail of Differential role of presenilin‐1 and ‐2 on mitochondrial membrane potential and oxygen consumption in mouse embryonic fibroblasts

Journal of Neuroscience Research, 2006

Increasing evidence indicates that mitochondrial alterations contribute to the neuronal death in ... more Increasing evidence indicates that mitochondrial alterations contribute to the neuronal death in Alzheimer's disease (AD). Presenilin 1 (PS1) and Presenilin 2 (PS2) mutations have been shown to sensitize cells to apoptosis by mechanisms suggested to involve impaired mitochondrial function. We have previously detected active γ‐secretase complexes in mitochondria. We investigated the impact of PS/γ‐secretase on mitochondrial function using mouse embryonal fibroblasts derived from wild‐type, PS1−/−, PS2−/− and PS double knock‐out (PSKO) embryos. Measurements of mitochondrial membrane potential (ΔΨm) showed a higher percentage of fully functional mitochondria in PS1−/− and PSwt as compared to PS2−/− and PSKO cells. This result was evident both in whole cell preparations and in isolated mitochondria. Interestingly, pre‐treatment of isolated mitochondria with the γ‐secretase inhibitor L‐685,458 resulted in a decreased population of mitochondria with high ΔΨm in PSwt and PS1−/− cells, ...

Research paper thumbnail of Myeloablative and immunosuppressive properties of treosulfan in mice

Experimental Hematology, 2006

Allogeneic stem cell transplantation (SCT) is a curative treatment for malignant and non-malignan... more Allogeneic stem cell transplantation (SCT) is a curative treatment for malignant and non-malignant diseases. However, transplantation related morbidity and mortality are major drawbacks affecting the survival and life quality of the patients. The major complications of SCT are infections, hemorrhagic cystitis, liver toxicity, interstitial pneumonia and GVHD. Busulphan (Bu), treosulfan (Tr) and cyclophosphamide (Cy) are alkylating agents. They are currently used in high doses as preparative regimen before SCT. Pharmacokinetics and pharmacodynamics of these drugs have been intensively studied with the aim of defining a therapeutic window to achieve a satisfactory myeloablation and immunosuppression with less treatment related toxicity. Study I: We administered N-acetyl-L-cysteine (NAC) during conditioning to patients at risk of Sinusoidal obstructive Syndrome (SOS) due to pretransplant liver disorders or elevated liver enzymes. No side effects related to the NAC administration were observed and Bu-kinetics was not affected. All patients became pancytopenic and engrafted with100% donor cells. None of the patients developed SOS or liver failure. Increased liver enzymes during conditioning decreased or normalized in all patients. We suggested that NAC therapy is safe and does not impair the myeloablative effect of Bu during conditioning prior to SCT and hence NAC may be an effective prophylactic treatment against SOS and hepatic toxicity during conditioning. Study II In a preclinical study, myeloablative as well as immunosuppressive properties of Tr were compared with those of Bu and Cy in a mouse model. The animals were treated with Tr, Cy, or Bu at sublethal doses that maintained survival without bone marrow support. The myeloablative effect was evaluated using colony-forming unit granulocyte macrophages (CFU-GM), while the immunological effect was performed using spleen cells. We found that Tr and Bu induced a high and persistent myeloablation compared to Cy. Moreover, Tr was more effective in depletion splenic B and T cells compared to Bu and Cy. T-cells isolated from the spleens of Tr-or Bu-treated mice were not responsive to allogeneic cells compared with those observed in Cy treated mice. Our findings suggested that Tr possesses both myeloablative and immunosuppressive properties and may be used as a single agent for conditioning prior to SCT. Study III. Therapeutic drug monitoring (TDM) of Bu-iv was performed in 34 pediatric SCT patients. Buiv was administered twice daily according to recommended weight-based doses. Bu levels were measured and pharmacokinetic analysis was performed. The targeted Bu exposure was aimed to range between areas under the curve (AUC) of 9000-12000 ng/mLxh. In 23/34 patients (68%) Bu dose had to be adjusted at least once. In 16/23 patients the dose had to be increased in a range of 7-33%, while in 7/23 patients (30%) the dose had to be decreased by 7-20%. The need of dose adjustment was not related to weight, age or underlying disease. SOS was observed in 21% of the patients in spite of total AUC's within the target AUC. We concluded that TDM of iv Bu is essential to increase the efficacy and safety of Bubased conditioning protocols in pediatric HSCT recipients. Study IV. Limited sampling models for use in TDM of Bu in patients treated for hematologic malignancies. 23 patients were sampled according to standard protocol (8 samples). AUC calculated from three limited sampling models were compared with WinNonLin compartment modeling. Combining a curve fitting model and a compartment model, using the average AUC estimate, gave a concordance correlation coefficient of 0.85 with the described standard sampling protocol. Using Bland-Altman plots it was evident that most patients would have been treated the same regarding dose adjustment using the combined method as well as standard rich sampling. The results support the use of limited sampling in clinical therapeutic drug monitoring, provided adequate algorithms are used for evaluation. Both models included in the combined method utilized four concentrations points. The model is reliable, solid and user friendly providing the clinician with a graph and a numeric AUC estimate. These four studies taken together may provide a step forward in treatment optimization and dose individualization to the benefit of SCT patients.

Research paper thumbnail of Signaling pathways involved in the regulation of TNFα-induced toll-like receptor 2 expression in human gingival fibroblasts

Cytokine, 2012

Periodontitis is a chronic inflammatory disease characterized by a host inflammatory response aga... more Periodontitis is a chronic inflammatory disease characterized by a host inflammatory response against bacteria that leads to destruction of the supporting structures of the teeth. Bacterial components of pathogens in the periodontal pocket are recognized by toll-like receptors (TLRs) that trigger an inflammatory response. In this study, we investigated the effects of the pro-inflammatory cytokine tumor necrosis factor α (TNFα) on TLR2 expression in human gingival fibroblasts. In addition, we examined the signaling pathways involved in the regulation of TNFα-induced TLR2 expression. Our results showed that TNFα increased TLR2 mRNA and protein expression. Microarray analysis and the inhibition of specific signaling pathways demonstrated that c-Jun N-terminal kinases (JNK) and nuclear factor kappa B (NF-κB) were involved in the regulation of TNFα-induced TLR2 expression in gingival fibroblasts. Furthermore, the prostaglandin E(2) (PGE(2)) regulatory enzyme cytosolic phospholipase A(2) (cPLA(2)) and the anti-inflammatory prostaglandin 15-deoxy-Δ(12,14)-prostaglandin J(2) (15d-PGJ(2)), were found to regulate TLR2 mRNA expression stimulated by TNFα. Our findings suggest that these pathways and mediators, through the regulation of TLR2 expression in gingival fibroblasts, may be involved in the pathogenesis of periodontitis. The study provides new insights into the molecular mechanisms underlying the regulation of TLR2, implicated in the chronic inflammatory disease periodontitis.

Research paper thumbnail of Expansion and Activation Kinetics of Immune Cells during Early Phase of GVHD in Mouse Model Based on Chemotherapy Conditioning

Clinical and Developmental Immunology, 2010

In the present paper, we have investigated early pathophysiological events in graft-versus-host d... more In the present paper, we have investigated early pathophysiological events in graft-versus-host disease (GVHD), a major complication to hematopoietic stem cell transplantation (HSCT). BLLB/c female mice conditioned with busulfan/cyclophosphamide (Bu-Cy) were transplanted with allogeneic male C57BL/6. Control group consisted of syngeneic transplanted Balb/c mice. In allogeneic settings, significant expansion and maturation of donor dendritic cells (DCs) were observed at day +3, while donor T-cells CD8+ were increased at day +5 (230%) compared to syngeneic HSCT. Highest levels of inflammatory cytokines IL-2, IFN-gamma, and TNF-alfa at day +5 matched T-cell activation. Concomitantly naïve T-cells gain effecr-memory phenotype and migrated from spleen to peripheral lymphoid organs. Thus, in the very early phase of GHVD following Bu-Cy conditioning donor, DCs play an important role in the activation of donor T cells. Subsequently, donor naïve T-cells gain effector-memory phenotype and ini...

Research paper thumbnail of Kainic acid-induced excitotoxic hippocampal neurodegeneration in C57BL/6 mice: B cell and T cell subsets may contribute differently to the pathogenesis

Brain, Behavior, and Immunity, 2004

The roles of T cells and B cells in kainic acid (KA)-induced hippocampal lesions were studied in ... more The roles of T cells and B cells in kainic acid (KA)-induced hippocampal lesions were studied in C57BL/6 mice lacking specific T cell populations (CD4, CD8, and CD4/CD8 cells) and B cells [Igh-6()/))]. At 48 mg/kg of KA administrated intranasally, KA-induced convulsions were seen in all groups. However, CD4/CD8()/)) mice exhibited the mildest seizures; the responses of CD8()/)), Igh-6()/)) and wild-type mice were intermediate, whereas CD4()/)) mice displayed much more severe clinical signs and 100% early mortality, indicating that a deficiency of CD4 T cells obviously increased susceptibility to KA-induced brain damage. Histopathological analysis of the mice that survived 7 days after KA administration revealed that CD4/CD8()/)) mice had the fewest pathologic changes but Igh-6()/)) mice showed more severe lesions in area CA3 of the hippocampus than CD8()/)) and wild-type mice. Reactive astrogliosis were prominent in all KA-treated mice. Locomotor activity as assessed by open-field test increased after KA administration in Igh-6()/)) and wild-type mice only. These results denote the influence of the adaptive immune response on KAinduced hippocampal neurodegeneration and suggest that B cell and T cell subsets may contribute differently to the pathogenesis.

Research paper thumbnail of Dynamics of Adipocyte Turnover in Humans

Nature, vol. 453, na, …, 2007

Research paper thumbnail of Correction to: Defined serum- and xeno-free cryopreservation of mesenchymal stem cells

Cell and Tissue Banking, 2019

In the original article, Fig. 1A was by mistakenly duplicated. The corrected image is provided in... more In the original article, Fig. 1A was by mistakenly duplicated. The corrected image is provided in this correction article.

Research paper thumbnail of Aminothiazoles inhibit RANKL- and LPS-mediated osteoclastogenesis and PGE2 production in RAW 264.7 cells

Journal of cellular and molecular medicine, Jun 14, 2016

Periodontitis is characterized by chronic inflammation and osteoclast-mediated bone loss regulate... more Periodontitis is characterized by chronic inflammation and osteoclast-mediated bone loss regulated by the receptor activator of nuclear factor-κB (RANK), RANK ligand (RANKL) and osteoprotegerin (OPG). The aim of this study was to investigate the effect of aminothiazoles targeting prostaglandin E synthase-1 (mPGES-1) on RANKL- and lipopolysaccharide (LPS)-mediated osteoclastogenesis and prostaglandin E2 (PGE2 ) production in vitro using the osteoclast precursor RAW 264.7 cells. RAW 264.7 cells were treated with RANKL or LPS alone or in combination with the aminothiazoles 4-([4-(2-naphthyl)-1,3-thiazol-2-yl]amino)phenol (TH-848) or 4-(3-fluoro-4-methoxyphenyl)-N-(4-phenoxyphenyl)-1,3-thiazol-2-amine (TH-644). Aminothiazoles significantly decreased the number of multinucleated tartrate-resistant acid phosphatase (TRAP)-positive osteoclast-like cells in cultures of RANKL- and LPS-stimulated RAW 264.7 cells, as well as reduced the production of PGE2 in culture supernatants. LPS-treatment...