imd-0354 and Disease-Models--Animal

Development of chemoresistance in breast cancer patients greatly increases mortality. Thus, understanding mechanisms underlying breast cancer resistance to chemotherapy is of paramount importance to overcome this clinical challenge. Although activated Notch receptors have been associated with chemoresistance in cancer, the specific Notch ligands and their molecular mechanisms leading to chemoresistance in breast cancer remain elusive. Using conditional knockout and reporter mouse models, we demonstrate that tumor cells expressing the Notch ligand Dll1 is important for tumor growth and metastasis and bear similarities to tumor-initiating cancer cells (TICs) in breast cancer. RNA-seq and ATAC-seq using reporter models and patient data demonstrated that NF-κB activation is downstream of Dll1 and is associated with a chemoresistant phenotype. Finally, pharmacological blocking of Dll1 or NF-κB pathway completely sensitizes Dll1

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Breast; Breast Neoplasms; Calcium-Binding Proteins; Cell Line, Tumor; Cell Proliferation; Cell Survival; Datasets as Topic; Disease Models, Animal; Doxorubicin; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Neoplastic; Humans; Membrane Proteins; Mice; Mice, Knockout; Neoplastic Stem Cells; NF-kappa B p50 Subunit; Receptors, Notch; RNA-Seq; Signal Transduction

When Zika virus emerged as a public health emergency there were no drugs or vaccines approved for its prevention or treatment. We used a high-throughput screen for Zika virus protease inhibitors to identify several inhibitors of Zika virus infection. We expressed the NS2B-NS3 Zika virus protease and conducted a biochemical screen for small-molecule inhibitors. A quantitative structure-activity relationship model was employed to virtually screen ∼138,000 compounds, which increased the identification of active compounds, while decreasing screening time and resources. Candidate inhibitors were validated in several viral infection assays. Small molecules with favorable clinical profiles, especially the five-lipoxygenase-activating protein inhibitor, MK-591, inhibited the Zika virus protease and infection in neural stem cells. Members of the tetracycline family of antibiotics were more potent inhibitors of Zika virus infection than the protease, suggesting they may have multiple mechanisms of action. The most potent tetracycline, methacycline, reduced the amount of Zika virus present in the brain and the severity of Zika virus-induced motor deficits in an immunocompetent mouse model. As Food and Drug Administration-approved drugs, the tetracyclines could be quickly translated to the clinic. The compounds identified through our screening paradigm have the potential to be used as prophylactics for patients traveling to endemic regions or for the treatment of the neurological complications of Zika virus infection.

Topics: Animals; Antiviral Agents; Artificial Intelligence; Chlorocebus aethiops; Disease Models, Animal; Drug Evaluation, Preclinical; High-Throughput Screening Assays; Immunocompetence; Inhibitory Concentration 50; Methacycline; Mice, Inbred C57BL; Protease Inhibitors; Quantitative Structure-Activity Relationship; Small Molecule Libraries; Vero Cells; Zika Virus; Zika Virus Infection

IMD-0354 is a novel I kappa-B kinase (IKK) inhibitor, which regulates inflammation. The purpose of this study was to examine the effect of the reagent on bone loss for ligature-induced periodontitis.. We ligated around the upper right second molars of 8-week-old C57BL/6J mice in the split-mouth model. The test mice were injected intraperitoneally with IMD-0354 before the placement of the ligature. The control mice were injected intraperitoneally with 0.5% carboxymethylcellulose (CMC) as vehicle before the placement of the ligature. To determine the optimum concentration of the reagent on ligature-induced periodontitis in the mice, we examined the effect of three types of concentration, which were 1, 5, and 10 mg/kg of IMD-0354, as a preliminary experiment. After we determined 10 mg/kg as the optimum concentration for the IMD group by micro-CT analysis, both the IMD and CMC groups (n = 15 each in total, including all the analyses) were subdivided into two small groups, respectively, for further analyses: I group (unligated side of IMD group), IL group (ligated side of IMD group), C group (unligated side of CMC group) and CL group (ligated side of CMC group). The mice in the IMD and CMC groups were treated with each reagent daily and sacrificed 8 days after the ligation. For assessment of bone resorption, we performed micro-CT and histological analyses. We also carried out real-time PCR to investigate proinflammatory and bone metabolic markers.. There were significant differences for linear bone loss and volumetric parameter in the test (IMD) group compared to the control (CMC) group 8 days after ligation. In terms of the mRNA expression level of gingival tissue, the level of RANKL was significantly suppressed in the IMD group compared to the CMC group. IMD-0354 also tended to suppress the levels of interleukin-1 beta, tumor necrosis factor-alpha, and osteoprotegerin. For histological analysis, the relative numbers of TRAP-positive multinucleated cells decreased significantly in the IMD group compared to the CMC group.. IMD-0354 regulated bone resorption by ligature-induced periodontitis, and it is suggested that the inhibition of IKK via down-regulation of NF kappa-B may provide periodontal patients with an effective approach to prevent or suppress the disease.

Topics: Alveolar Bone Loss; Animals; Benzamides; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Inhibitors; Gene Expression; Gingiva; I-kappa B Kinase; Injections, Intraperitoneal; Interleukin-1beta; Ligation; Mice, Inbred C57BL; Osteoprotegerin; Periodontitis; RANK Ligand; RNA, Messenger; Tumor Necrosis Factor-alpha; X-Ray Microtomography

IκB kinase (IKK) is important for nuclear factor (NF)-κB activation under inflammatory conditions. It has been demonstrated that IMD-0354, i.e. a selective inhibitor of IKKβ, inhibited allergic inflammation in a mouse model of ovalbumin (OVA)-induced asthma. The present study attempts to shed light on the involvement of CD4(+) effector (Teff) and regulatory (Treg) T cells in the anti-asthmatic action of IMD-0354. The animals were divided into three groups: vehicle treated, PBS-sensitized/challenged mice (PBS group); vehicle treated, OVA-sensitized/challenged mice (OVA group); and IMD-0354-treated, OVA-sensitized/challenged mice. The analyzed parameters included the absolute counts of Treg cells (Foxp3(+)CD25(+)CD4(+)), activated Teff cells (Foxp3(-)CD25(+)CD4(+)) and resting T cells (CD25(-)CD4(+)) in the mediastinal lymph nodes (MLNs), lungs and peripheral blood. Moreover, lung histopathology was performed to evaluate lung inflammation. It was found that the absolute number of cells in all studied subsets was considerably increased in the MLNs and lungs of mice from OVA group as compared to PBS group. All of these effects were fully prevented by treatment with IMD-0354. Histopathological examination showed that treatment with IMD-0354 protected the lungs from OVA-induced allergic airway inflammation. Our results indicate that IMD-0354 exerts anti-asthmatic action, at least partially, by blocking the activation and clonal expansion of CD4(+) Teff cells in the MLNs, which, consequently, prevents infiltration of the lungs with activated CD4(+) Teff cells. The beneficial effects of IMD-0354 in a mouse model of asthma are not mediated through increased recruitment of Treg cells into the MLNs and lungs and/or local generation of inducible Treg cells.

Topics: Allergens; Animals; Anti-Asthmatic Agents; Asthma; Benzamides; CD4-Positive T-Lymphocytes; Disease Models, Animal; I-kappa B Kinase; Lung; Lymph Nodes; Mice, Inbred BALB C; Ovalbumin

The prolongation of progression-free survival (PFS) in patients with advanced ovarian cancer by antiangiogenic therapy has been shown in several clinical trials. However, although an anti-VEGF antibody (bevacizumab) is the only option currently available, its efficacy is limited and it is not cost effective for use in all patients. Therefore, the development of a novel antiangiogenic drug, especially composed of small-molecule compounds, could be a powerful armament for ovarian cancer treatment. As NF-κB signaling has the potential to regulate VEGF expression, we determined to identify whether VEGF expression is associated with NF-κB activation and to investigate the possibility of a novel IKKβ inhibitor, IMD-0354 (IMMD Inc.), as an antiangiogenic drug. Tissue microarrays from 94 ovarian cancer tissues were constructed and immunohistochemical analyses performed. We revealed that IKK phosphorylation is an independent prognostic factor (PFS: 26.1 vs. 49.8 months, P = 0.011), and is positively correlated with high VEGF expression. In in vitro analyses, IMD-0354 robustly inhibited adhesive and invasive activities of ovarian cancer cells without impairing cell viabilities. IMD-0354 significantly suppressed VEGF production from cancer cells, which led to the inhibition of angiogenesis. In a xenograft model, the treatment of IMD-0354 significantly inhibited peritoneal dissemination with a marked reduction of intratumoral blood vessel formation followed by the inhibition of VEGF expression from cancer cells. IMD-0354 is a stable small-molecule drug and has already been administered safely to humans in other trials. Antiangiogenic therapy targeting IKKβ is a potential future option to treat ovarian cancer.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Benzamides; Cell Adhesion; Cell Line, Tumor; Cell Movement; Disease Models, Animal; Enzyme Activation; Female; Gene Expression Regulation, Neoplastic; Humans; I-kappa B Kinase; Immunohistochemistry; Mice; Molecular Targeted Therapy; Neoplasm Metastasis; Neovascularization, Pathologic; Ovarian Neoplasms; Phosphorylation; Prognosis; Vascular Endothelial Growth Factors; Xenograft Model Antitumor Assays

Prior experimental and epidemiologic data support a link between exposure to fine ambient particulate matter (<2.5 μm in aerodynamic diameter, PM2.5) and development of insulin resistance/Type II diabetes mellitus (Type II DM). We investigated the role of hypothalamic inflammation in PM2.5-mediated diabetes development.. KKay mice, a genetically susceptible model of Type II DM, were assigned to either concentrated PM2.5 or filtered air (FA) for 4-8 weeks via a versatile aerosol concentrator and exposure system, or administered intra-cerebroventricular with either IKKβ inhibitor (IMD-0354) or TNFα antibody (infliximab) for 4-5 weeks simultaneously with PM2.5 exposure. Glucose tolerance, insulin sensitivity, oxygen consumption and heat production were evaluated. At euthanasia, blood, spleen, visceral adipose tissue and hypothalamus were collected to measure inflammatory cells using flow cytometry. Standard immunohistochemical methods and quantitative PCR were used to assess targets of interest.. PM2.5 exposure led to hyperglycemia and insulin resistance, which was accompanied by increased hypothalamic IL-6, TNFα, and IKKβ mRNA expression and microglial/astrocyte reactivity. Targeting the NFκB pathway with intra-cerebroventricular administration of an IKKβ inhibitor [IMD-0354, n = 8 for each group)], but not TNFα blockade with infliximab [(n = 6 for each group], improved glucose tolerance, insulin sensitivity, rectified energy homeostasis (O2 consumption, CO2 production, respiratory exchange ratio and heat generation) and reduced peripheral inflammation in response to PM2.5.. Central inhibition of IKKβ prevents PM2.5 mediated peripheral inflammation and exaggeration of type II diabetes. These results provide novel insights into how air pollution may mediate susceptibility to insulin resistance and Type II DM.

Topics: Animals; Anti-Inflammatory Agents; Antibodies, Monoclonal; Benzamides; Blood Glucose; Diabetes Mellitus, Type 2; Disease Models, Animal; Energy Metabolism; Hypothalamus; I-kappa B Kinase; Inflammation; Infliximab; Inhalation Exposure; Injections, Intraventricular; Insulin; Insulin Resistance; Interleukin-6; Mice; Oxygen Consumption; Particulate Matter; Protein Kinase Inhibitors; Risk Assessment; RNA, Messenger; Thermogenesis; Time Factors; Tumor Necrosis Factor-alpha

Proliferation of pulmonary arterial smooth muscle cells (PASMCs) is one histological sign of pulmonary arterial hypertension (PAH). We hypothesized that a signalling cascade from fibroblast growth factor 2 (FGF₂) to plasminogen activator inhibitor 1 (PAI-1) and monocyte chemotactic protein-1 (MCP-1) via nuclear transcription factor nuclear factor kappaB (NF-kB) play a critical role in progression of PAH, and tested this hypothesis both in vivo and in vitro using a synthetic selective NF-kB inhibitor, N-(3,5-Bis-trifluoromethyl-phenyl)-5-chloro-2-hydroxy-benzamide (IMD-0354).. Monocrotaline (MCT) was injected into 75 Sprague-Dawley rats. Starting at day 14 after MCT injection, we administered IMD-0354 (MCT + IMD group) or vehicle (MCT group) daily. At day 32, 65% of the MCT + IMD group were alive compared with 0% of the MCT group. IMD-0354 prevented increase of right ventricular pressure, and suppressed proliferation and induced apoptosis of PASMCs. mRNA transcript levels of FGF₂, PAI-1, and tissue plasminogen activator (t-PA) were lower in MCT + IMD compared with MCT. In in vitro experiments, IMD-0354 inhibited p65 translocation to the nucleus promoted by FGF₂ in PASMCs. Furthermore, the time courses of extracellular signal-regulated kinase (Erk) 1/2, MCP-1, and PAI-1 stimulated with FGF₂ were each markedly shortened by IMD-0354.. We speculate that the positive-feedback loop (Erk1/2-NF-kB-MCP-1-Erk1/2) is associated with progression of PAH by causing FGF₂-induced inflammation in MCT rats. IMD-0354 has potential as a new therapeutic tool for PAH.

Topics: Animals; Antihypertensive Agents; Apoptosis; Benzamides; Cell Proliferation; Cells, Cultured; Chemokine CCL2; Disease Models, Animal; Familial Primary Pulmonary Hypertension; Feedback, Physiological; Fibroblast Growth Factor 2; Hypertension, Pulmonary; Male; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Monocrotaline; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; NF-kappa B; Pulmonary Artery; Rats; Rats, Sprague-Dawley; RNA, Messenger; Signal Transduction; Time Factors; Tissue Plasminogen Activator; Transcription Factor RelA; Ventricular Function, Right; Ventricular Pressure

NF-κB, which is activated by the inhibitor of NF-κB kinase (IKK), is involved in the progression of inflammatory disease. However, the effect of IKK inhibition on the progression of myocarditis is unknown. We examined the effect of IKK inhibition on the progression of myocarditis. Lewis rats were immunized with porcine cardiac myosin to induce experimental autoimmune myocarditis (EAM). We administered the IKK inhibitor (IMD-0354; 15 mg·kg(-1)·day(-1)) or vehicle to EAM rats daily. Hearts were harvested 21 days after immunization. Although the untreated EAM group showed increased heart weight-to-body weight ratio, and severe myocardial damage, these changes were attenuated in the IKK inhibitor-treated group. Moreover, IKK inhibitor administration significantly reduced NF-κB activation and mRNA expression of IFN-γ, IL-2, and monocyte chemoattractant protein-1 in myocardium compared with vehicle administration. In vitro study showed that the IKK inhibitor treatment inhibited T-cell proliferation and Th1 cytokines production induced by myosin stimulation. The IKK inhibitor ameliorated EAM by suppressing inflammatory reactions via suppression of T-cell activation.

Topics: Animals; Autoimmune Diseases; Benzamides; Disease Models, Animal; Male; Myocarditis; NF-kappa B; NF-kappaB-Inducing Kinase; Protein Serine-Threonine Kinases; Rats; Rats, Inbred Lew; Severity of Illness Index; T-Lymphocytes

Restenosis after percutaneous coronary intervention (PCI) is still a clinically serious problem. We examined the treatment efficacy of IMD-0354, a novel IKK inhibitor, on arteriopathy. Using C57BL/6J mice, a wire-injury model was prepared and the mice were intraperitoneally injected with IMD-0354 or vehicle twice a day. The vehicle-treated injured arteries showed significantly thickened intima (3.77 ± 0.59, n = 8), however, IMD-0354 suppressed its progression (1.62 ± 0.22, n = 10, P < 0.05) on day 28. While enhanced expression of PCNA and NF-κB was observed in the untreated injured arteries, IMD-0354 significantly suppressed their expressions. Quantitative RT-PCR revealed that the expression of several inflammatory factors was reduced in the arteries from mice which received IMD-0354 treatment compared with the control animals. Thus, this drug may effectively prevent restenosis after coronary intervention and other cardiovascular diseases.

Topics: Angioplasty, Balloon, Coronary; Animals; Benzamides; Blotting, Western; Cell Proliferation; Cytokines; Disease Models, Animal; Disease Progression; Femoral Artery; Fluorescent Antibody Technique; Graft Occlusion, Vascular; I-kappa B Kinase; Immunohistochemistry; Injections, Intraperitoneal; Male; Mice; Mice, Inbred C57BL; Postoperative Complications; Proliferating Cell Nuclear Antigen; Real-Time Polymerase Chain Reaction; Treatment Outcome; Tunica Intima; Vascular System Injuries

Nuclear factor (NF)-κB is a transcription factor that regulates cytokine and chemokine production in various inflammatory diseases, including bronchial asthma. IκB kinase (IKK) β is important for NF-κB activation in inflammatory conditions, and is possibly related to airway remodelling. Thus, inhibition of the IKKβ-NF-κB pathway may be an ideal strategy for the management of airway remodelling.. We examined the effects of a newly synthesized IKKβ inhibitor, IMD-0354, in a chronic allergen exposure model of bronchial asthma in mice.. A chronic mouse model was generated by challenge with house dust mite antigen (Dermatophagoides pteronyssinus). IMD-0354 was administrated intraperitoneally in therapeutic groups. Lung histopathology, hyperresponsiveness and the concentrations of mediators and molecules in supernatants of lung homogenates were determined.. NF-κB activation was inhibited by prolonged periods of IMD-0354 administration. IMD-0354 reduced the numbers of bronchial eosinophils. IMD-0354 also inhibited the pathological features of airway remodelling, including goblet cell hyperplasia, subepithelial fibrosis, collagen deposition and smooth muscle hypertrophy. Inhibition of these structural changes by IMD-0354 was the result of the suppressing the production and activation of remodelling-related mediators, such as TGF-β, via inhibition of IKKβ. IMD-0354 inhibited IL-13 and IL-1β production, and it restored the production of IFN-γ. It also ameliorated airway hyperresponsiveness.. IKKβ plays crucial roles in airway inflammation and remodelling in a chronic mouse model of asthma. A specific IKKβ inhibitor, IMD-0354, may be therapeutically beneficial for treating airway inflammation and remodelling in chronic asthma.

Topics: Airway Remodeling; Animals; Antigens, Dermatophagoides; Asthma; Benzamides; Chronic Disease; Disease Models, Animal; Female; I-kappa B Kinase; Mice; Mice, Inbred BALB C; Molecular Structure

To investigate the anti-fibrosis effect of IκB kinase-beta inhibitor (IKK2 inhibitor IMD0354) in liver fibrosis.. Twenty male C57BL6 mice were divided into four groups. Five high-fat fed mice were injected with lipopolysaccharide (LPS, 10 mg/kg) intraperitoneally and five high-fat fed mice were without LPS injection to build models of liver injury, and the intervention group (five mice) was injected intraperitoneally with IKK2 inhibitor (IMD 30 mg/kg for 14 d), while the remaining five mice received a normal diet as controls. Hepatic function, pathological evaluation and liver interleukin-6 (IL-6) expression were examined. Western blotting and real-time polymerase chain reaction were used to detect the expressions of nuclear factor-κB (NF-κB), alpha-smooth muscle actin (α-SMA), tumor growth factor-beta1 (TGF-β1), tumor necrosis factor-alpha (TNF-α), typeIand type III collagen proteins and mRNA.. A mouse model of liver injury was successfully established, and IMD decreased nuclear translocation of NF-κB p65 in liver cells. In the IMD-treated group, the levels of alanine aminotransferase (103 ± 9.77 μ/L vs 62.4 ± 7.90 μ/L, P < 0.05) and aminotransferase (295.8 ± 38.56 μ/L vs 212 ± 25.10 μ/L, P < 0.05) were significantly decreased when compared with the model groups. The histological changes were significantly ameliorated. After treatment, the expressions of IL-6 (681 ± 45.96 vs 77 ± 7.79, P < 0.05), TGF-β1 (Western blotting 5.65% ± 0.017% vs 2.73% ± 0.005%, P < 0.05), TNF-α (11.58% ± 0.0063% vs 8.86% ± 0.0050%, P < 0.05), typeIcollagen (4.49% ± 0.014% vs 1.90% ± 0.0006%, P < 0.05) and type III collagen (3.46% ± 0.008% vs 2.29% ± 0.0035%, P < 0.05) as well as α-SMA (6.19 ± 0.0036 μ/L vs 2.16 ± 0.0023 μ/L, P < 0.05) protein and mRNA were downregulated in the IMD group compared to the fibrosis control groups (P < 0.05).. IKK2 inhibitor IMD markedly improved non-alcoholic fatty liver disease in mice by lowering NF-κB activation, which could become a remedial target for liver fibrosis.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Benzamides; Collagen Type I; Collagen Type III; Disease Models, Animal; Fatty Liver; I-kappa B Kinase; Interleukin-6; Lipopolysaccharides; Liver Cirrhosis; Male; Mice; Mice, Inbred C57BL; NF-kappa B; Non-alcoholic Fatty Liver Disease; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha

Nuclear factor (NF)-kappaB is a transcription factor known to regulate allergy-associated cytokine and chemokine production related to the induction of inflammation. I kappaB kinase beta (IKK beta), which is responsible for activation of the NF-kappaB pathway, may be an ideal molecular target to inhibit this process. IMD-0354 [N-(3,5-bis-trifluoromethyl-phenyl)-5-chloro-2-hydroxy-benzamide] is an attractive novel IKK beta inhibitor that prevents the production of inflammatory cytokines in various diseases, although it is not known if IMD-0354 is effective against allergic inflammation. This study aimed to elucidate the antiallergic effects of a newly synthesized IKK beta inhibitor, IMD-0354, in a mouse model of allergic inflammation.. We generated ovalbumin (OVA)-sensitized mice which were then challenged with OVA. IMD-0354 was administered intraperitoneally to therapeutic groups. Lung histopathology and the concentrations of cytokines and chemokines in bronchoalveolar lavage fluid (BALF) and supernatants of lung homogenates were determined.. Administration of IMD-0354 ameliorated airway hyperresponsiveness and reduced the numbers of bronchial eosinophils and mucus-producing cells in OVA-sensitized mice. The total numbers of cells and eosinophils in BALF were also reduced by treatment with IMD-0354. Treatment with IMD-0354 inhibited the production of Th2 cytokines such as interleukin (IL)-5 and IL-13 and eotaxin in the airways and/or lungs of OVA-sensitized mice, but it did not affect the restoration of Th1 cytokines such as IL-12 and interferon-gamma under the same experimental conditions. IgE production was also inhibited by IMD-0354.. A specific IKK beta inhibitor, IMD-0354, improved allergic airway inflammation and hyperresponsiveness in mice. IMD-0354 may have therapeutic potential for bronchial asthma.

Topics: Airway Resistance; Animals; Anti-Allergic Agents; Anti-Inflammatory Agents; Benzamides; Body Weight; Bronchoalveolar Lavage Fluid; Cell Count; Chemokines; Cytokines; Disease Models, Animal; Eosinophils; Female; I-kappa B Kinase; Immunoglobulin E; Lung; Lymphocytes; Macrophages; Mice; Mice, Inbred BALB C; Ovalbumin; Respiratory Hypersensitivity

Adiponectin is an anti-diabetic and anti-atherogenic hormone that is exclusively secreted from fat cells. Serum adiponectin levels are reduced in obese patients and obese model mice, despite increased adipose tissue mass. Elucidation of the mechanism(s) by which plasma adiponectin levels are decreased in obese and diabetic patients would provide insight into the cause of obesity-induced diabetes and the development of therapeutic advances. In the present study, the regulation of adiponectin secretion was investigated using 3T3-L1 adipocytes and a diabetic-/obese-mouse model. A novel insulin sensitizer, IkappaB kinase beta (IKKbeta) inhibitor, ameliorated insulin resistance and up-regulated plasma levels of adiponectin without producing a significant change in body weight in KKAy mice that were fed a high-fat diet. The IKKbeta inhibitor cancelled the TNFalpha-mediated down-regulation of adiponectin secretion and simultaneously up-regulated the phosphorylation of Akt in 3T3-L1 adipocytes. Using dominant-negative mutants of Akt or PKClambda (downstream effectors of phosphoinositide 3-kinase), insulin-stimulated Akt activity was found to be important in the regulation of adiponectin secretion by insulin in 3T3-L1 adipocytes. These observations suggest that "insulin-stimulated Akt activity in adipocytes" may play an important role in the regulation of adiponectin secretion.

Topics: 3T3-L1 Cells; Adipocytes; Adiponectin; Animals; Benzamides; Blood Glucose; Body Weight; Chromones; Diabetes Mellitus; Disease Models, Animal; Dose-Response Relationship, Drug; Down-Regulation; Enzyme Inhibitors; Gene Expression Regulation; Genes, Dominant; Glucose; I-kappa B Kinase; Insulin; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Leptin; Mice; Mice, Obese; Models, Biological; Morpholines; Obesity; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Time Factors; Up-Regulation