Biomedical subjects

Jochen Seufert

Publications and source records attributed to Jochen Seufert.

14 recordsLinked to original sources

PubMed2006

Single-frequency Sb-based distributed-feedback lasers emitting at 2.3 microm above room temperature for application in tunable diode laser absorption spectroscopy.

GaInAsSb/GaAlAsSb/GaSb distributed-feedback (DFB) laser diodes based on a type I active region were fabricated by molecular beam epitaxy at the Centre d'Electronique et de Micro-Optoélectronique de Montpellier (CEM2). The DFB processing was done by Nanoplus Nanosystems and Technologies GmbH. The devices work in the continuous-wave regime above room temperature around an emission wavelength of 2.3 microm with a side-mode suppression ratio greater than 25 dB and as great as 10 mW of output power. The laser devices are fully characterized in terms of optical and electrical properties. Their tuning properties made them adaptable to tunable diode laser absorption spectroscopy because they exhibit more than 220 GHz of continuous tuning by temperature or current. The direct absorption of CH4 is demonstrated to be possible with high spectral selectivity.

Journal Article↗

PubMed2006

Glucose-dependent expansion of pancreatic beta-cells by the protein p8 in vitro and in vivo.

p8 protein expression is known to be upregulated in the exocrine pancreas during acute pancreatitis. Own previous work revealed glucose-dependent p8 expression also in endocrine pancreatic beta-cells. Here we demonstrate that glucose-induced INS-1 beta-cell expansion is preceded by p8 protein expression. Moreover, isopropylthiogalactoside (IPTG)-induced p8 overexpression in INS-1 beta-cells (p8-INS-1) enhances cell proliferation and expansion in the presence of glucose only. Although beta-cell-related gene expression (PDX-1, proinsulin I, GLUT2, glucokinase, amylin) and function (insulin content and secretion) are slightly reduced during p8 overexpression, removal of IPTG reverses beta-cell function within 24 h to normal levels. In addition, insulin secretion of p8-INS-1 beta-cells in response to 0-25 mM glucose is not altered by preceding p8-induced beta-cell expansion. Adenovirally transduced p8 overexpression in primary human pancreatic islets increases proliferation, expansion, and cumulative insulin secretion in vitro. Transplantation of mock-transduced control islets under the kidney capsule of immunosuppressed streptozotocin-diabetic mice reduces blood glucose and increases human C-peptide serum concentrations to stable levels after 3 days. In contrast, transplantation of equal numbers of p8-transduced islets results in a continuous decrease of blood glucose and increase of human C-peptide beyond 3 days, indicating p8-induced expansion of transplanted human beta-cells in vivo. This is underlined by a doubling of insulin content in kidneys containing p8-transduced islet grafts explanted on day 9. These results establish p8 as a novel molecular mediator of glucose-induced pancreatic beta-cell expansion in vitro and in vivo and support the notion of existing beta-cell replication in the adult organism.

Adenoviridae↗

PubMed2006

A fixed-dose combination of pioglitazone and metformin: A promising alternative in metabolic control.

BACKGROUND: When type 2 diabetes is managed with glucose-lowering monotherapy, glycemic control ultimately deteriorates due to the inability of the beta-cell to overcome insulin resistance. Combining drugs with different complementary mechanisms of action improves long-term glycemic control and may lower the risk of vascular complications. A fixed-dose combination of pioglitazone (a thiazolidinedione) and metformin has been approved for use in the US (Actoplus met) and in Europe (Competact). SCOPE: This review (based upon MEDLINE and EMBASE searches from January 1990 to April 2006) discusses the potential benefits of co-formulating metformin and pioglitazone with respect to compliance and targeting glycemia, as well as other metabolic parameters. FINDINGS: Pioglitazone increases insulin sensitivity, while metformin reduces hepatic gluconeogenesis and improves peripheral glucose uptake. Both agents reduce hyperglycemia and hyperinsulinemia, and appear to protect beta-cell function. Their similar pharmacokinetic time profiles have facilitated a co-formulation bioequivalent to their separate administration. In randomized studies, pioglitazone and metformin administered separately provided significantly better glycemic control than metformin monotherapy or metformin plus gliclazide. Pioglitazone and metformin have complimentary benefits on diabetic dyslipidemia; pioglitazone primarily improves high-density lipoprotein cholesterol and triglyceride levels (to a greater extent than rosiglitazone does), while metformin mainly improves total cholesterol. Pioglitazone and metformin also modulate other atherosclerosis biomarkers, including inflammatory mediators, coagulation thrombosis components, and carotid intima media thickness. Together, these pleiotropic effects have the potential to confer a reduced risk of cardiovascular disease in patients with type 2 diabetes. Pioglitazone and metformin are well tolerated in combination, with low rates of hypoglycemia, and the convenience of a single tablet may be expected to aid dosing compliance. CONCLUSION: The co-formulation of pioglitazone and metformin is a rational approach that maximizes the established, complimentary benefits of these agents, while potentially improving compliance.

Cardiovascular Diseases↗

PubMed2006

Parathyroid-hormone-related-protein-associated hypercalcemia in a patient with CLL-type low-grade leukemic B-cell lymphoma.

Humoral hypercalcemia of malignancy is a common metabolic disturbance associated with solid tumors, but it also occurs in lymphoma patients. Among these, low grade B-cell lymphoma accounts for only few cases, in which secretion of parathyroid hormone-related protein (PTHrP) remains even exceptional. We report the very rare case of a patient with a CLL type low grade leukemic B-cell lymphoma showing PTHrP-related hypercalcemia without evidence of bone lesions. Using immunohistochemistry, we demonstrate the cytoplasmic expression of PTHrP by the lymphoma cells in the bone marrow obtained at the onset of hypercalcemia. We postulate a pathogenetic role of leukemic cell production and secretion of PTHrP in hypercalcemia in low grade leukemic B-cell lymphoma.

Aged↗

PubMed2005

Activation of NF-kappaB signalling and TNFalpha-expression in THP-1 macrophages by TiAlV- and polyethylene-wear particles.

Wear particles are believed to induce periprosthetic inflammation which contributes to periprosthetic osteolysis. TNFalpha plays a pivotal role in the pathogenesis of this process. The molecular mechanisms leading to the development of periprosthetic inflammation with upregulated TNFalpha expression in monocytic cells in response to different wear particles have yet to be defined. In this study we evaluated the effects of polyethylene- and TiAlV-particles on activation of NF-kappaB signalling pathways and TNFalpha biosynthesis and release in monocytic cells with respect to periprosthetic osteoclastogenesis. THP-1 monocytic cells were differentiated to macrophage-like cells and exposed to LPS-detoxified polyethylene and prosthesis-derived TiAlV-particles. TNFalpha release was analyzed in culture supernatant by ELISA. NF-kappaB activation was examined by electrophoretic mobility shift assay (EMSA), and NF-kappaB target promoter activities including transactivation of the TNFalpha promoter were determined by luciferase reporter gene assays. Differentiated THP-1 macrophages were exposed to increasing numbers of particles for 0, 60, 180 and 360 min. Both, polyethylene- and TiAlV-particles induced a significant activation of both NF-kappaB and TNFalpha promoters at 180 min. A significant TNFalpha release was detected after 360 min exposure to polyethylene- and TiAlV-particles in a dose dependent manner. In comparison, LPS induced a much greater activation of NF-kappaB and TNFalpha promoters, and TNFalpha secretion into the supernatant was strongly induced. These results provide evidence that induction of the NF-kappaB signal transduction pathway in macrophages plays a major role in initiating and mediating the inflammatory response leading to periprosthetic osteolysis.

Alloys↗

PubMed2005

Inhibition of preproinsulin gene expression by leptin induction of suppressor of cytokine signaling 3 in pancreatic beta-cells.

Leptin inhibits insulin secretion and preproinsulin gene expression in pancreatic beta-cells, but signal transduction pathways and molecular mechanisms underlying this effect are poorly characterized. In this study, we analyzed leptin-mediated signal transduction and preproinsulin gene regulation at the molecular level in pancreatic beta-cells. Leptin stimulation led to janus kinase (JAK)2-dependent phosphorylation and nuclear translocation of the transcription factors signal transducer and activator of transcription (STAT)3 and STAT5b in INS-1 beta-cells. Leptin also induced mRNA expression of the JAK-STAT inhibitor suppressor of cytokine signaling (SOCS)3 in INS-1 beta-cells and human pancreatic islets in vitro and in pancreatic islets of ob/ob mice in vivo. Transcriptional activation of the rat SOCS3 promoter by leptin was observed with concomitant leptin-induced STAT3 and STAT5b DNA binding to specific promoter regions. Unexpectedly, SOCS3 inhibited both basal and STAT3/5b-dependent rat preproinsulin 1 gene promoter activity in INS-1 cells. These results suggest that SOCS3 represents a transcriptional inhibitor of preproinsulin gene expression, which is induced by leptin through JAK-STAT3/5b signaling in pancreatic beta-cells. In conclusion, although SOCS3 is believed to be a negative feedback regulator of JAK-STAT signaling, our findings suggest involvement of SOCS3 in a direct gene regulatory pathway downstream of leptin-activated JAK-STAT signaling in pancreatic beta-cells.

Animals↗

PubMed2004

A comparison of the effects of thiazolidinediones and metformin on metabolic control in patients with type 2 diabetes mellitus.

BACKGROUND: Type 2 diabetes mellitus is a condition characterized by impaired insulin secretion and resistance to insulin-mediated glucose uptake and utilization. A number of oral antidiabetic medication are available for its treatment, including metformin and the thiazolidinediones (TZDs). The TZDs have been shown to improve insulin resistance, and it has been suggested that metformin has similar effects. Although both types of agents improve glycemic control, their mechanisms of action and effects on metabolic processes differ. OBJECTIVE: The goal of this review was to compare the effects of TZDs and metformin on metabolic control in patients with type 2 diabetes. METHODS: A search of MEDLINE to March 2004 using the terms metformin and biguanides, and thiazolidinediones and glitazones was conducted to identify preclinical and clinical studies focusing on the mechanisms of action and comparative effects of TZDs and metformin. Also searched were published abstracts from recent major diabetes and endocrinology conferences. RESULTS: In the studies reviewed, both TZDs and metformin demonstrated the ability to improve glycemic control, although long-term monotherapy with TZDs appeared to be more effective than metformin. There continues to be debate about whether metformin is more effective than TZDs in terms of inhibition of hepatic glucose production. However, various studies have found TZDs to be more effective in promoting an increase in whole-body insulin sensitivity. With respect to lipid metabolism, patients who received TZDs had a greater reduction in concentrations of both plasma triglycerides and free fatty acids. Metformin was more effective in promoting weight loss in patients with type 2 diabetes, although TZDs may decrease visceral fat levels. Treatment with either metformin or TZDs was associated with a reduction in the risk of cardiovascular disease, although the mechanisms by which they accomplished this seem to differ. CONCLUSIONS: The evidence suggests that the predominant effect of metformin is inhibition of hepatic glucose production, whereas the primary effects of TZDs is reduction of insulin resistance and promotion of peripheral glucose uptake. TZDs appear to have more positive effects on other metabolic processes and to be associated with greater improvements in cardiovascular risk factors compared with metformin.

Animals↗

PubMed2004

Effects of polyethylene and TiAlV wear particles on expression of RANK, RANKL and OPG mRNA.

BACKGROUND: Wear debris has been associated with periprosthetic osteolysis and loosening of total joint arthroplasties. RANKL (receptor activator of NF-kappaB ligand), RANK (receptor activator of NF-kappaB) and OPG (osteoprotegerin) are three key molecules which regulate differentiation, survival, fusion, and activation of osteoclasts. MATERIAL AND METHODS: We evaluated the effect of TiAIV and polyethylene particles on expression of RANK, RANKL and OPG mRNA. We used a human monocytic leukemic cell line (THP-1) in this in vitro study. THP-1 monocytes were differentiated into macrophage-like cells and exposed to polyethylene particles and prosthesis-derived TiAIV particles. The supernantant was used for measurement of TNFalpha protein and total RNA was extracted from the cells. Expression of the genes coding for OPG, RANKL and RANK was analysed at the mRNA level using a semiquantitative RT-PCR method. RESULTS: Both polyethylene and TiAIV particles induced a significant release of TNFalpha after 6 h of exposure and a significant upregulation of RANK mRNA. OPG mRNA expression was transiently upregulated after exposure to polyethylene and TiAIV particles. These effects were dependent on particle dose. RANKL mRNA was not detectable in our THP-1 model. In contrast, LPS exhibited a different pattern of RANK/ RANKL/OPG mRNA expression. INTERPRETATION: Our findings provide evidence that both polyethylene and TiAIV particles induce upregulation of RANK expression in cells of the monocytic lineage, which may be important for periprosthetic osteoclastogenesis.

Alloys↗

PubMed2004

Leptin effects on pancreatic beta-cell gene expression and function.

The hormone leptin is secreted from white adipocytes, and serum levels of leptin correlate with adipose tissue mass. Leptin was first described to act on the satiety center in the hypothalamus through specific receptors (leptin receptor [ObR]) to restrict food intake and enhance energy expenditure. Important peripheral actions of leptin involve inhibition of insulin biosynthesis and secretion in pancreatic beta-cells. In turn, insulin stimulates leptin secretion from adipose tissue, establishing a hormonal regulatory feedback loop-the so-called "adipo-insular axis." Multiple signal transduction pathways are involved in leptin signaling in pancreatic beta-cells. We have identified the proinsulin gene and protein phosphatase 1 gene as leptin repressed genes and the gene for the suppressor of cytokine signaling 3 protein as a leptin-induced gene in pancreatic beta-cells. The molecular effects of leptin culminate to restrict insulin secretion and biosynthesis to adapt glucose homeostasis to the amount of body fat. In most overweight individuals, however, physiological regulation of body weight by leptin seems to be disturbed, representing "leptin resistance." This leptin resistance at the level of the pancreatic beta-cell may contribute to dysregulation of the adipo-insular axis and promote the development of hyperinsulinemia and manifest type 2 diabetes in overweight patients.

Animals↗

PubMed2004

Nuclear protein p8 is associated with glucose-induced pancreatic beta-cell growth.

On its own, glucose is a major factor for proliferation of pancreatic beta-cells and is also an essential prerequisite for IGF-I and growth hormone-induced growth of these cells. p8 was originally identified as an emergency gene product upregulated in pancreatic acinar cells in response to acute pancreatitis. p8 was further shown to be involved in a broad range of biological functions, including cell growth, growth arrest, apoptosis, and tumor development. These in part opposite actions may be related to distinct stimuli and pathways in certain conditions and cell types. Here we demonstrate that p8 is widely expressed in human pancreatic islets in vivo and in several beta-cell lines in vitro. Based on this observation, we tested the hypothesis that p8 production in pancreatic beta-cells is regulated by glucose. Incubation of rat INS-1 beta-cells with 25 mmol/l glucose resulted in a continuous increase of proliferating cell numbers. This was accompanied by a strong upregulation of p8 mRNA and protein expression, indicating that p8 is a physiological mediator of glucose-induced pancreatic beta-cell growth. Binding of glucose-activated protein kinase C (PKC) to two PKC sites within a highly conserved region of the p8 protein may be a possible mechanism linking glucose and p8 pathways leading to proliferation.

Animals↗

PubMed2003

[Current status and perspectives of stem cell therapy for the treatment of diabetes mellitus].

Due to autoimmune destruction of insulin-producing pancreatic beta-cells, type 1 diabetic patients, and also patients with type 2 diabetes suffering from defective insulin secretion rely on lifelong substitution with insulin. A clinically established alternative therapy for diabetics with exogenous insulin substitution, the transplantation of human islets of Langerhans, is limited by the lack of donor organs. The intensive search for new sources of pancreatic beta-cells now focuses on human stem cells. Insulin-producing cells for transplantation can be generated from both embryonic and adult pancreatic stem cells. Both types of stem cells, however, differ with respect to availability, in vitro expansion, potential for differentiation, and tumorigenicity, which is elucidated by the authors. Before stem cell therapeutic strategies for diabetes mellitus can be transferred to clinical application in humans, aspects of functional effectiveness, safety, and cost-effectiveness have to be solved. Considering these prerequisites in the light of currently available therapeutic options, however, it can be estimated, that stem cell therapy for diabetes mellitus may be cost-effectively introduced into clinical routine in the future.

Adult↗

PubMed2003

Selenium supplementation enhances low selenium levels and stimulates glutathione peroxidase activity in peripheral blood and distal colon mucosa in past and present carriers of colon adenomas.

Selenoproteins such as glutathione peroxidases (GPx), thioredoxin reductases (TrxR), and selenoprotein P (SePP) contain molecular selenium in form of selenocysteines within their active center. They are involved in the defense of reactive oxygen species, which otherwise may cause DNA damage and alterations of protein function. Selenium intake has been linked to colon carcinogenesis in epidemiological and interventional studies. In a double-blinded, placebo-controlled trial, we demonstrate that carriers of colon adenomas present with low basal serum levels of selenium and plasma glutathione peroxidase (pGPx) activity before treatment, but both parameters can be normalized by interventional selenium supplementation. GPx activity in colon mucosa was enhanced in the verum group, albeit this had only borderline significance. No change of activity was observed for mucosal TrxR activity on selenium supplementation. In summary, our results confirm the existence of low selenium levels in patients prone to colon adenomas and show that by selenium supplementation this can be normalized. If prospective trials confirm that selenium supplementation reduces colon cancer incidence rates, it may be concluded that selenium supplementation should be recommended for patients at risk.

Adenoma↗

PubMed2002

A complex DNA-repeat structure within the Selenoprotein P promoter contains a functionally relevant polymorphism and is genetically unstable under conditions of mismatch repair deficiency.

Epidemiological data, animal studies and interventional studies provide evidence for a potential chemopreventive effect of selenium during development of colorectal cancer. The human glycoprotein Selenoprotein P (SeP) contains up to 50% of plasma selenium content. SeP is expressed in the gastrointestinal tract and the liver, where its expression is downregulated by various proinflammatory cytokines (Il1beta, TGFbeta, IFNgamma). Previously, we have demonstrated dramatically reduced SeP expression in human colon adenomas. Here, we have identified a complex (A)4-C-(A)4-GG-(A)8-GCT-(TC)5-(T)17 (bp -429 to bp - 477) repeat structure within the SeP promoter and we have analysed this regulatory DNA sequence with respect to polymorphisms, genomic instability and functional relevance to promoter activity. As opposed to the (TC)5 variant we identified a novel (TC)3 polymorphism within this repeat in the general population, which conferred significantly reduced basal promoter activity to reporter gene constructs in HepG2 cells. Allelic distribution of this (TC)(n) element was similar in colon carcinoma patients and healthy controls. Additionally, we observed genetic instability within the (T)17 repeat motif in colon cancers of the mutator phenotype. This instability of the (T)17 repeat had no effect on basal promoter activity in reporter gene assays. In conclusion, we characterised a complex repeat structure within the SeP promoter that may be of functional relevance to SeP gene expression. Further studies on the effect of different SeP promoter genotypes on SeP protein expression and disease susceptibility are needed.

Base Pair Mismatch↗

PubMedDate not supplied

Three-dimensional in vitro model of adipogenesis: comparison of culture conditions.

In vivo and in vitro studies have demonstrated both promise and current limitations in tissue engineering of fat. Herein, we report the establishment of a well-defined three-dimensional (3-D) in vitro model useful for systematic investigations of 3-D adipogenesis. Polyglycolic acid fiber meshes were dynamically seeded with 3T3-L1 preadipocytes; subsequently, cell-polymer constructs were hormonally induced and cultivation under three different conditions was evaluated. Regarding tissue coherence and intracellular lipid content, culture of cell-polymer constructs either dynamically in well plates or in stirred bioreactors yielded similar results, which were distinctly improved compared with static conditions in well plates. At the protein and mRNA levels, significantly increased expression of genes characteristic for a mature adipose phenotype was demonstrated for constructs dynamically cultured in well plates, as compared with static conditions. Furthermore, investigation of lipolysis under stimulating and inhibiting conditions demonstrated functionality of the dynamically differentiated constructs. Using dynamic culture conditions, the presented in vitro model system is suggested as a valuable tool serving both fat tissue engineering and basic research by facilitating investigations of tissue-inherent features not possible under conventional 2-D culture conditions.

3T3-L1 Cells↗