Biomedical subjects

Haiyan Xu

Publications and source records attributed to Haiyan Xu.

36 records · Page 2Linked to original sources

PubMed2005

[Development and applications of dendrimers in biomedicine].

Dendrimers are new macromolecules synthesized in recent years, which are of great interests in many fields where they have potential important applications because of their hyperbranched, well defined and monodisperse structures. In this paper, the unique structures, general synthesis routes and basic physical and chemical properties of dendrimers are introduced in brief, and the progress in the research of dendrimers in drug (gene) delivery, contrast agents, cancer therapy were reviewed, as well as the perspective in research and applications.

Contrast Media↗

PubMed2005

[Developments in understanding of interactions between blood and biomaterials at molecular and cellular levels].

Blood compatibility is one of the most important factors for biomaterials applied in blood-contacting environment, which is determined by a series of complicated interactions of biomaterials surfaces with both soluble and cellular components in blood. As the development of molecular biology technology and emergence of new characterization methods for changes of protein conformation structure and function, more and more researchers are making intensive efforts to understand hemocompatibility of biomaterials at molecular and cellular levels. In this paper, developments in understanding of interactions between blood and materials surfaces, especially the changes of plasma protein conformation structure and activation of platelets induced by biomaterials surfaces, are reviewed.

Biocompatible Materials↗

PubMed2004

Simultaneous determination of albendazole and its major active metabolite in human plasma using a sensitive and specific liquid chromatographic-tandem mass spectrometric method.

A method for the simultaneous determination of albendazole (ABZ) and its major active metabolite albendazole sulfoxide (ABZ-SO) was developed and validated. The analytes were extracted from plasma samples by liquid-liquid extraction and analyzed using liquid chromatography-tandem mass spectrometry with an electrospray ionization interface. Estazolam was used as the internal standard. The assay was linear in the concentration range 0.4-200 ng/ml for ABZ and 4.0-2000 ng/ml for ABZ-SO. The intra- and inter-run precision (R.S.D.), calculated from quality control (QC) samples was less than 7.1 and 9.4% for ABZ and ABZ-SO, respectively. The accuracy as determined from QC samples was within +/- 3% for the analytes. Recoveries of ABZ and ABZ-SO were greater than 77 and 53%, respectively, over the calibration curve range. The method developed was successfully applied to pharmacokinetic studies of ABZ and ABZ-SO after an oral dose of 400 mg albendazole to healthy volunteers.

Albendazole↗

PubMed2004

Pulmonary toxicity of polyvinyl chloride particles after repeated intratracheal instillations in rats. Elevated CD4/CD8 lymphocyte ratio in bronchoalveolar lavage.

Occupational exposure to polyvinyl chloride (PVC) particles has been associated with interstitial lung disease. Our previous study showed that a single intratracheal instillation of emulsion PVC particles, with or without residual additives, induces acute but transient alveolitis in a dose-dependent manner in rats. The aim of the present study was to investigate the pulmonary response after the administration of the same PVC particles (PVC-E3 and PVC-W3) given in the same cumulative doses (10 and 50 mg/kg BW), but fractionated as seven intratracheal instillations (7 x 1.4 and 7 x 7.1 mg/kg BW) in the course of 3 weeks (day 0 to day 21). Pulmonary response was characterized by analysis of lung weight, bronchoalveolar lavage (BAL) fluid for lactate dehydrogenase (LDH), total protein, and cell cytology, and a microscopic evaluation of lung tissue. BAL T lymphocyte phenotypes (CD3 + CD4 +, CD3 + CD8+) were analyzed by flow cytometry. On day 28, lung weights, BAL-LDH, cell numbers in BAL, and CD4/CD8 ratios in BAL T lymphocytes were higher in rats that had received the high dose of PVC-E3 or PVC-W3 than in rats that had received the low dose of PVC particles and control rats. On day 90, the pulmonary response had partially regressed towards control values, but there were still microscopically evident lesions in the lungs and greater CD4/CD8 ratio in the high dose groups. There were significant positive correlations between the CD4/CD8 ratio and a histopathology score of the lung (r = 0.36, P = 0.038 on day 28, and r = 0.46, P = 0.006 on day 90). In conclusion, repeated intratracheal instillations of PVC particles yielded similar results as single instillations. The examined PVC particles have the potential of inducing a limited and transient acute inflammatory reaction in the lung, and possibly a more persistent alteration of pulmonary T lymphocyte subsets towards a high CD4/CD8 ratio.

Animals↗

PubMed2004

Pulmonary toxicity of polyvinyl chloride particles after a single intratracheal instillation in rats. Time course and comparison with silica.

Our previous in vitro studies indicated that emulsion polyvinyl chloride (PVC) particles (PVC-E3), with a mean diameter of 2 microm, exhibited a moderate toxicity in different pulmonary cell cultures. The in vitro cytotoxicity and pro-inflammatory potential of PVC-E3 particles were reduced when the additives had been "washed off" (PVC-W3), indicating that PVC-particle associated toxicity is probably related to the residual additives. In the present study, male Wistar rats (230 +/- 18 g) received a single intratracheal instillation of vehicle, crystalline silica particles [Min-U-Sil, 10 mg/kg body weight (BW)], PVC-E3 (10 or 50 mg/kg BW), or PVC-W3 (10 or 50 mg/kg BW). After 2, 7, 28, or 90 days, the rats were sacrificed (n = 6) and pulmonary injury and inflammation were determined by measuring lung weight, lactate dehydrogenase (LDH) activity and protein concentrations in bronchoalveolar lavage fluid (BALF), differential BALF cell count, and histopathology. Silica exposure resulted in pulmonary inflammation and damage at all time points with a progressive deterioration. Exposure to high concentrations of PVC particles caused pulmonary inflammation and damage, which were similar to the silica-exposed group at 2 days, but at 90 days, most parameters had returned to the control level, except for minor histopathological lesions. PVC-E3 did not induce more damage than PVC-W3. Two days after exposure, PVC-W3 caused less neutrophil but more eosinophil influx than PVC-E3. Although the pulmonary toxicity of both PVC-E3 and PVC-W3 appeared limited, this in vivo study has not confirmed the conclusion from the in vitro toxicity tests that removal of residual additives reduces the toxicity of PVC-E3 particles.

Animals↗

PubMed2004

New oligodendrocytes are generated after neonatal hypoxic-ischemic brain injury in rodents.

Neonatal hypoxic-ischemic (HI) white matter injury is a major contributor to chronic neurological dysfunction. Immature oligodendrocytes (OLGs) are highly vulnerable to HI injury. As little is known about in vivo OLG repair mechanisms in neonates, we studied whether new OLGs are generated after HI injury in P7 rats. Rats received daily BrdU injections at P12-14 or P21-22 and sacrificed at P14 to study the level of cell proliferation or at P35 to permit dividing OLG precursors to differentiate. In P14 HI-injured animals, the number of BrdU+ cells in the injured hemisphere is consistently greater than controls. At P35, sections were double-labeled for BrdU and markers for OLGs, astrocytes, and microglia. Double-labeled BrdU+/myelin basic protein+ and BrdU+/carbonic anhydrase+ OLGs are abundant in the injured striatum, corpus callosum, and the infarct core. Quantitative studies show four times as many OLGs are generated from P21-35 in HI corpora callosa than controls. Surprisingly, the infarct core contains many newly generated OLGs in addition to hypertrophied astrocytes and activated microglia. These glia and non-CNS cells may stimulate OLG progenitor proliferation or induce their migration. At P35, astrogliosis and microgliosis are dramatic ipsilaterally but only a few microglia and some astrocytes are BrdU+. This finding indicates microglial and astrocytic hyperplasia occurs shortly after HI but before the P21 BrdU injections. Although the neonatal brain undergoes massive cell death and atrophy the first week after injury, it retains the potential to generate new OLGs up to 4 weeks after injury within and surrounding the infarct.

Animals↗

PubMed2003

Validity of methods to predict the respiratory sensitizing potential of chemicals: A study with a piperidinyl chlorotriazine derivative that caused an outbreak of occupational asthma.

A piperidinyl chlorotriazine (PCT) derivative, used as a plastic UV-stabilizer, caused an outbreak of occupational asthma. We verified, in BALB/c mice, the sensitizing potential of PCT in comparison to a known respiratory sensitizer (toluene diisocyanate [TDI]) and a known dermal sensitizer (oxazolone), using three different methods in order to evaluate the validity of current models of sensitization. These included the local lymph node assay (LLNA) and the mouse IgE test. In addition, respiratory hyper-reactivity was assessed following a novel protocol involving dermal sensitization (20 microl of a 3% solution on each ear for three days) and intranasal challenge (0.1% or 1%, 10 microl per nostril on day 10), followed, after 24 h, by a methacholine challenge (using whole-body plethysmography), bronchoalveolar lavage, and histology. PCT was also used for structure-activity relationship (SAR) models for (respiratory) sensitization. High concentrations of PCT (10 and 20%) resulted in significant responses in the local lymph node assay (LLNA; stimulation indices (SI) of 2.7 +/- 0.9 and 3.2 +/- 0.6, respectively). The mouse IgE test was positive with 20% PCT only. Methacholine responsiveness was increased only in previously sensitized mice receiving a challenge with TDI or PCT. However, there was no evidence for pulmonary inflammation. The SAR studies indicated that PCT could be a respiratory sensitizer. Based on an approved test protocol such as the LLNA and the mouse IgE test, PCT proved to be a weak sensitizer when compared to TDI and oxazolone. However, in a protocol involving an intranasal challenge, PCT appeared to be a respiratory sensitizer of similar potency to TDI.

Adjuvants, Immunologic↗

PubMed2003

Dual specificity mitogen-activated protein (MAP) kinase phosphatase-4 plays a potential role in insulin resistance.

Insulin is the key hormone that controls glucose homeostasis. Dysregulation of insulin function causes diabetes mellitus. Among the two major forms of diabetes, type 2 diabetes accounts for over 90% of the affected population. The incidence of type 2 diabetes is highly related to obesity. To find novel proteins potentially involved in obesity-related insulin resistance and type 2 diabetes, a functional expression screen was performed to search for genes that negatively regulate insulin signaling. Specifically, a reporter system comprised of the PEPCK promoter upstream of alkaline phosphatase was used in a hepatocyte cell-based assay to screen an expression cDNA library for genes that reverse insulin-induced repression of PEPCK transcription. The cDNA library used in this study was derived from the white adipose tissue of ob/ob mice, which are highly insulin-resistant. The mitogen-activated dual specificity protein kinase phosphatase 4 (MKP-4) was identified as a candidate gene in this screen. Here we show that MKP-4 is expressed in insulin-responsive tissues and that the expression levels are up-regulated in obese insulin-resistant rodent models. Heterologous expression of MKP-4 in preadipocytes significantly blocked insulin-induced adipogenesis, and overexpression of MKP-4 in adipocytes inhibited insulin-stimulated glucose uptake. Our data suggest that MKP-4 negatively regulates insulin signaling and, consequently, may contribute to the pathogenesis of insulin resistance.

3T3 Cells↗

PubMed2003

Role of residual additives in the cytotoxicity and cytokine release caused by polyvinyl chloride particles in pulmonary cell cultures.

Occupational exposure to polyvinyl chloride (PVC) dust has been linked to pulmonary disease. The aim of the present study was to investigate, in vitro, the role of additives in the cytotoxicity and the release of inflammatory mediators caused by PVC particles in different cells. We compared two types of emulsion PVC particles (E3 and E8) with their washed (hence, "additive-free") counterparts (W3 and W8). A positive control (crystalline SiO2, Min-U-Sil) and the pure additives, sodium lauryl sulfate (A3) and sodium alkylbenzenesulfonate (A8), were tested concurrently. Cytotoxicity (MTT assay) was assessed in primary cultures of rat alveolar macrophages, rat type II pneumocytes, and human alveolar macrophages (h-AM), and cultures of the A549 cell line (type II cell-derived) and the differentiated THP-1 cell line (macrophage-like). Hemolytic potential was assessed after a 2-h incubation with human erythrocytes. Cytokine release (IL-8, IL-6, and TNF-alpha) by A549 cells, THP-1 cells, and h-AM, was measured by ELISA after 4, 16, 24 and/or 48 h of exposure. Cytotoxicity and hemolytic activity of the washed particles were abolished or markedly decreased compared with their nonwashed forms. In A549 cells, E3 and E8 (2.5 mg/ml) caused a 3-fold increase in IL-8 release and a more than 10-fold increase in IL-6 release, whereas W3 and W8 did not elicit any significant response at similar concentrations. Compared with Min-U-Sil (0.1, 0.5, and 2.5 mg/ml), the response to E3 and E8 occurred later and was slightly lower (IL-8) or much more pronounced (IL-6). A3 and A8 exhibited similar responses to E3 and E8, at concentrations corresponding to those present in the particles. In conclusion, the in vitro cytotoxicity and inflammatory potential of some PVC particles appear to be mostly due to their residual additives.

Animals↗

PubMed2003

Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance.

Insulin resistance arises from the inability of insulin to act normally in regulating nutrient metabolism in peripheral tissues. Increasing evidence from human population studies and animal research has established correlative as well as causative links between chronic inflammation and insulin resistance. However, the underlying molecular pathways are largely unknown. In this report, we show that many inflammation and macrophage-specific genes are dramatically upregulated in white adipose tissue (WAT) in mouse models of genetic and high-fat diet-induced obesity (DIO). The upregulation is progressively increased in WAT of mice with DIO and precedes a dramatic increase in circulating-insulin level. Upon treatment with rosiglitazone, an insulin-sensitizing drug, these macrophage-originated genes are downregulated. Histologically, there is evidence of significant infiltration of macrophages, but not neutrophils and lymphocytes, into WAT of obese mice, with signs of adipocyte lipolysis and formation of multinucleate giant cells. These data suggest that macrophages in WAT play an active role in morbid obesity and that macrophage-related inflammatory activities may contribute to the pathogenesis of obesity-induced insulin resistance. We propose that obesity-related insulin resistance is, at least in part, a chronic inflammatory disease initiated in adipose tissue.

Adipocytes↗

PubMed2002

Black cohosh (Cimicifuga racemosa L.) protects against menadione-induced DNA damage through scavenging of reactive oxygen species: bioassay-directed isolation and characterization of active principles.

The roots/rhizomes of Cimicifuga racemosa L. (Nutt.) (black cohosh) have traditionally been used to treat menopausal symptoms through an unknown mechanism of action. In an effort to determine if black cohosh had additional health benefits, methanol extracts were investigated for their potential to scavenge reactive oxygen species and to protect against menadione-induced DNA damage. These extracts effectively scavenged 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radicals. In addition, the extracts showed dose-dependent decreases in DNA single-strand breaks and oxidized bases induced by the quinone menadione using the comet (single-cell gel electrophoresis assay) and fragment length associated repair enzyme assays, respectively. Bioassay-directed fractionation of the methanolic extracts using the DPPH assay as a monitor led to the isolation of nine antioxidant active compounds: caffeic acid (1), methyl caffeate (2), ferulic acid (3), isoferulic acid (4), fukinolic acid (5), cimicifugic acid A (6), cimicifugic acid B (7), cimicifugic acid F (8), cimiracemate A (9), and cimiracemate B (10). Six of these antioxidants were found to reduce menadione-induced DNA damage in cultured S30 breast cancer cells with the following order of potency: methyl caffeate (2) > caffeic acid (1) > ferulic acid (3) > cimiracemate A (9) > cimiracemate B (10) > fukinolic acid (5). These data suggest that black cohosh can protect against cellular DNA damage caused by reactive oxygen species by acting as antioxidants.

Antioxidants↗

PubMed2002

Ultrafine particles affect experimental thrombosis in an in vivo hamster model.

Particulate air pollution is associated with cardiovascular morbidity and mortality. To investigate this association, we studied the effect of ultrafine (60 nm) polystyrene particles on thrombus formation in a hamster model after intravenous and intratracheal administration of unmodified, carboxylate-polystyrene, or amine-polystyrene particles. Unmodified particles had no effect on thrombosis up to 5 mg/kg. Carboxylate-polystyrene particles significantly inhibited thrombus formation at 500 and 100 microg/kg body weight but not at 50 microg/kg body weight. In contrast, amine-polystyrene particles significantly enhanced thrombosis at 500 and 50 microg/kg body weight but not at 5 microg/kg body weight. Similarly, the intratracheal instillation of 5,000 microg of amine-polystyrene particles significantly increased thrombus formation. The unmodified particles and carboxylate-polystyrene particles had no effect. During platelet aggregation in human platelet-rich plasma, induced with 1.25 microM ADP, unmodified particles had no effect up to 100 microg/ml, and carboxylate-polystyrene particles weakly enhanced platelet aggregation at 25 to 100 microg/ml. However, amine-polystyrene particles (50 and 100 microg/ml) induced platelet aggregation themselves and strongly increased the ADP-induced aggregation. We conclude that the presence of (ultrafine) particles in the circulation may affect hemostasis. The observed in vivo prothrombotic tendency results, at least in part, from platelet activation by positively charged amine-polystyrene particles.

Adenosine Diphosphate↗

PubMed2002

In vitro toxicity assessment of polyvinyl chloride particles and comparison of six cellular systems.

Occupational exposure to polyvinyl chloride (PVC) dust has been occasionally associated with lung disease. Our aim was to evaluate the in vitro toxicity of various types of PVC particles in relevant cell culture systems. Six samples from the normal industrial suspension process (PVC-S) and eight samples from the emulsion process (PVC-E) were studied. Cytotoxicity was assessed, using the MTT assay, after 20 h of incubation in A549 cells and in primary cultures of alveolar macrophages (AM) and type II pneumocytes (TII) obtained from rats (r-AM, r-TII) or from human surgical specimens (h-AM, h-TII). Hemolysis was assessed after 2 h of incubation with human erythrocytes (h-RBC). A positive control (crystalline SiO(2), Min-U-Sil) and relevant additives of these PVC particles were tested concurrently. No toxicity of PVC-S particles could be established up to 5 mg/ml in the hemolysis test and 2.5 mg/ml in the MTT assay. In contrast, 4 out of 8 PVC-E particles induced significant toxicity, with EC50 values ranging from 0.7 to 3.7 mg/ml in the hemolysis test and from 0.2 to 1.2 mg/ml in primary cells. The most toxic particles were those that contained the additives with the highest in vitro cytotoxicity. There was a good correlation between EC50 values obtained in relevant bioassays. The sensitivity order of the cell systems was A549 < h-RBC approximately h-TII < or = h-AM < r-TII < or = r-AM for the particles. In conclusion, PVC-E particles produced a moderate in vitro toxicity for primary rat and human pulmonary cells, probably because of the residual presence of additives.

Aged↗

PubMed2002

Sensitive and specific liquid chromatographic-tandem mass spectrometric assay for dihydroergotamine and its major metabolite in human plasma.

A sensitive and specific procedure for the simultaneous determination of dihydroergotamine (DHE) and its 8'-hydroxylated metabolite (8'-OH-DHE) in human plasma was developed and validated. The analytes were extracted from plasma samples by liquid-liquid extraction, separated through a Zorbax C18 column (50x2.1 mm I.D.) and detected by tandem mass spectrometry with an electrospray ionization interface. Caroverine was used as the internal standard. The method has a lower limit of quantitation (LOQ) of 10.0 and 11.0 pg/ml for DHE and 8'-OH-DHE, respectively. The intra- and inter-run precision was measured to be below 9.1% for both DHE and 8'-OH-DHE. The inter-run accuracy was within 4% for the analytes. The overall extraction recoveries of DHE and 8'-OH-DHE were determined to be about 58 and 52% on average, respectively. The chromatographic run time was approximately 2.5 min. More than 120 samples could be assayed daily with this method, including sample preparation, data acquisition and processing. The method developed was successfully used to investigate plasma concentrations of DHE and 8'-OH-DHE in a pharmacokinetic study of volunteers who received DHE orally.

Chromatography, Liquid↗

PubMed2002

Obesity modulates the expression of haptoglobin in the white adipose tissue via TNFalpha.

Increase in adipose mass results in obesity and modulation of several factors in white adipose tissue (WAT). Two important examples are tumor necrosis factor alpha (TNFalpha) and leptin, both of which are upregulated in adipose tissue in obesity. In order to isolate genes differentially expressed in the WAT of genetically obese db/db mice compared to their lean littermates, we performed RNA fingerprinting and identified haptoglobin (Hp), which is significantly upregulated in the obese animals. Hp is a glycoprotein induced by a number of cytokines, LPS (Lipopolysaccharide), and more generally by inflammation. A significant upregulation of WAT Hp expression was also evident in several experimental obese models including the yellow agouti (/) A(y), ob/ob and goldthioglucose-treated mice (10-, 8-, and 7-fold, respectively). To identify the potential signals for an increase in Hp expression in obesity, we examined leptin and TNFalpha in vivo. Wild type animals treated with recombinant leptin did not show any alteration in WAT Hp expression compared to controls that were food restricted to the level of intake of the treated animals. On the other hand, Hp expression was induced in mice transgenically expressing TNFalpha in adipose tissue. Finally, a significant downregulation of WAT Hp mRNA was observed in ob/ob mice deficient in TNFalpha function, when compared to the ob/ob controls. These results demonstrate that haptoglobin expression in WAT is increased in obesity in rodents and TNFalpha is an important signal for this regulation.

Adipocytes↗

PubMed2002

Hypoxic-ischemic injury induces macrophage inflammatory protein-1alpha expression in immature rat brain.

BACKGROUND AND PURPOSE: Macrophage inflammatory protein (MIP)-1alpha is a well-characterized monocyte chemoattractant; its role in regulating monocyte and microglial recruitment and activation in the injured neonatal brain is unknown. We evaluated the impact of acute hypoxic-ischemic (HI) brain injury on the expression of MIP-1alpha in neonatal rat brain. METHODS: To elicit forebrain ischemic injury, 7-day-old (P7) rats underwent right carotid ligation, followed by 2.5 hours of 8% oxygen exposure. We used an enzyme-linked immunosorbent assay and immunohistochemistry to detect MIP-1alpha; double-labeling immunofluorescence assays were analyzed with confocal microscopy to identify cellular sources of MIP-1alpha. Immunocytochemistry assays were also used to detect 2 MIP-1alpha receptors, CCR1 and CCR5. RESULTS: We found marked increases in tissue concentrations of MIP-1alpha in the HI cerebral hemisphere, peaking from 8 to 72 hours after lesioning. Immunocytochemistry assays revealed that MIP-1alpha was constitutively expressed in physiologically activated microglia; from 8 to 120 hours after lesioning, MIP-1alpha immunoreactive monocytes and microglia accumulated in the lesion territory. In immunoreactive cells, MIP-1alpha was diffusely distributed throughout the cytoplasm at early post-HI time intervals; by 72 hours, MIP-1alpha immunoreactivity was typically concentrated adjacent to the nucleus, a pattern indicative of active MIP-1alpha production. In P7 to P12 brain, many cells expressed MIP-1alpha receptors; both CCR1 and CCR5 immunoreactivity were localized to endothelium and ependyma; CCR1-immunoreactive astrocytes and neurons and CCR5-immunoreactive microglia were also identified. CONCLUSIONS: These data implicate MIP-1alpha as a mediator of the complex and sustained inflammatory response initiated by perinatal HI braininjury.

Animals↗

PubMed2002

Exclusive action of transmembrane TNF alpha in adipose tissue leads to reduced adipose mass and local but not systemic insulin resistance.

Aberrant TNF alpha expression in adipocytes is a molecular mechanism by which insulin action is modulated in adipose tissue. While this might be a compensatory response to limit adipose expansion, neither the mechanisms underlying this local effect nor its systemic biological consequences have been studied. It is also not clear whether TNF alpha-induced insulin resistance in adipocyte alone is responsible for systemic insulin resistance in the absence of obesity. In a transgenic mouse model deficient in endogenous TNF alpha, we demonstrate that specific expression of the transmembrane TNF alpha (mTNF alpha) in adipocytes leads to decreased whole body adipose mass, and local, but not systemic insulin resistance. These data demonstrate that exclusive action of TNF alpha in adipose tissue strongly inhibits insulin action at this site and leads to reduced adiposity in mice. However, this isolated adipocyte insulin resistance in the context of reduced fat mass and/or the absence of obesity is insufficient to alter systemic glucose homeostasis.

Adipocytes↗

PubMed2002

Altered tumor necrosis factor-alpha (TNF-alpha) processing in adipocytes and increased expression of transmembrane TNF-alpha in obesity.

Tumor necrosis factor-alpha (TNF-alpha) is synthesized as a 26-kDa transmembrane protein (mTNF-alpha), which may present on the cell surface or be processed to release the 17-kDa soluble form (sTNF-alpha). Because regulation of this ectodomain shedding might be critical in the generation of systemic versus local cytokine responses, we examined the rate of mTNF-alpha processing in adipocytes and its regulation in obesity. Here, we demonstrate that the 26-kDa mTNF-alpha is present in adipose tissue and that its production is significantly increased in different rodent obesity models as well as in obese humans. There was no apparent deficiency in the level of the major TNF-alpha converting enzyme in adipose tissue to account for the excess amount of mTNF-alpha produced in obesity. However, experiments in cultured fat cells stably expressing TNF-alpha demonstrated a significantly decreased rate of TNF-alpha cleavage in differentiated adipocytes compared with preadipocytes. Thus, a decreased processing rate of mTNF-alpha in mature adipocytes combined with an increase in TNF-alpha production may be a potential mechanism resulting in elevated membrane-associated TNF-alpha in adipose tissue in obesity.

3T3 Cells↗