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1.
Mol Immunol ; 152: 215-223, 2022 12.
Article in English | MEDLINE | ID: mdl-36379129

ABSTRACT

Identification of immunologic epitopes against SARS-CoV-2 is crucial for the discovery of diagnostic, therapeutic, and preventive targets. In this study, we used a pan-coronavirus peptide microarray to screen for potential B-cell epitopes and validated the results with peptide-based ELISA. Specifically, we identified three linear B-cell epitopes on the SARS-CoV-2 proteome, which were recognized by convalescent plasma from COVID-19 patients. Interestingly, two epitopes (S 809-823 and R1ab 909-923) strongly reacted to convalescent plasma collected at the early phase (< 90 days) of COVID-19 symptom onset, whereas one epitope (M 5-19) reacted to convalescent plasma collected > 90 days after COVID-19 symptom onset. Neutralization assays using antibody depletion with the identified spike (S) peptides revealed that three S epitopes (S 557-571, S 789-803, and S 809-823) elicited neutralizing antibodies in COVID-19 patients. However, the levels of virus-specific antibody targeting S 789-803 only positively correlated with the neutralizing rates at the early phase (<60 days) after disease onset, and the antibody titers diminished quickly with no correlation to the neutralizing activity beyond two months after recovery from COVID-19. Importantly, stimulation of peripheral blood mononuclear cells from COVID-19-recovered patients with these SARS-CoV-2 S peptides resulted in poor virus-specific B cell activation, proliferation, differentiation into memory B cells, and production of immunoglobulin G (IgG) antibodies, despite the B-cells being functionally competent as demonstrated by their response to non-specific stimulation. Taken together, these findings indicate that these newly identified SARS-CoV-2-specific B-cell epitopes can elicit neutralizing antibodies, with titers and/or neutralizing activities declining significantly within 2-3 months in the convalescent plasma of COVID-19 patients.


Subject(s)
COVID-19 , Humans , COVID-19/therapy , SARS-CoV-2 , Epitopes, B-Lymphocyte , Spike Glycoprotein, Coronavirus , Leukocytes, Mononuclear , Antibodies, Viral , Antibodies, Neutralizing , COVID-19 Serotherapy
2.
Proteomics Clin Appl ; 16(5): e2200031, 2022 09.
Article in English | MEDLINE | ID: mdl-35929818

ABSTRACT

BACKGROUND: While the majority of COVID-19 patients fully recover from the infection and become asymptomatic, a significant proportion of COVID-19 survivors experience a broad spectrum of symptoms lasting weeks to months post-infection, a phenomenon termed "post-acute sequelae of COVID-19 (PASC)." The aim of this study is to determine whether inflammatory proteins are dysregulated and can serve as potential biomarkers for systemic inflammation in COVID-19 survivors. METHODS: We determined the levels of inflammatory proteins in plasma from 22 coronavirus disease 2019 (COVID-19) long haulers (COV-LH), 22 COVID-19 asymptomatic survivors (COV-AS), and 22 healthy subjects (HS) using an Olink proteomics assay and assessed the results by a beads-based multiplex immunoassay. RESULTS: Compared to HS, we found that COVID-19 survivors still exhibited systemic inflammation, as evidenced by significant changes in the levels of multiple inflammatory proteins in plasma from both COV-LH and COV-AS. CXCL10 was the only protein that significantly upregulated in COV-LH compared with COV-AS and HS. CONCLUSIONS: Our results indicate that several inflammatory proteins remain aberrantly dysregulated in COVID-19 survivors and CXCL10 might serve as a potential biomarker to typify COV-LH. Further characterization of these signature inflammatory molecules might improve the understanding of the long-term impacts of COVID-19 and provide new targets for the diagnosis and treatment of COVID-19 survivors with PASC.


Subject(s)
COVID-19 , Biomarkers , COVID-19/complications , Humans , Inflammation , SARS-CoV-2 , Survivors
3.
Virus Res ; 304: 198508, 2021 10 15.
Article in English | MEDLINE | ID: mdl-34329696

ABSTRACT

The COVID-19 pandemic caused by SARS-CoV-2 infection poses a serious threat to public health. An explicit investigation of COVID-19 immune responses, particularly the host immunity in recovered subjects, will lay a foundation for the rational design of therapeutics and/or vaccines against future coronaviral outbreaks. Here, we examined virus-specific T cell responses and identified T cell epitopes using peptides spanning SARS-CoV-2 structural proteins. These peptides were used to stimulate peripheral blood mononuclear cells (PBMCs) derived from COVID-19-recovered subjects, followed by an analysis of IFN-γ-secreting T cells by enzyme-linked immunosorbent spot (ELISpot). We also evaluated virus-specific CD4 or CD8 T cell activation by flow cytometry assay. By screening 52 matrix pools (comprised of 315 peptides) of the spike (S) glycoprotein and 21 matrix pools (comprised of 102 peptides) spanning the nucleocapsid (N) protein, we identified 28 peptides from S protein and 5 peptides from N protein as immunodominant epitopes. The immunogenicity of these epitopes was confirmed by a second ELISpot using single peptide stimulation in memory T cells, and they were mapped by HLA restrictions. Notably, SARS-CoV-2 specific T cell responses positively correlated with B cell IgG and neutralizing antibody responses to the receptor-binding domain (RBD) of the S protein. Our results demonstrate that defined levels of SARS-CoV-2 specific T cell responses are generated in some, but not all, COVID-19-recovered subjects, fostering hope for the protection of a proportion of COVID-19-exposed individuals against reinfection. These results also suggest that these virus-specific T cell responses may induce protective immunity in unexposed individuals upon vaccination, using vaccines generated based on the immune epitopes identified in this study. However, SARS-CoV-2 S and N peptides are not potently immunogenic, and none of the single peptides could universally induce robust T cell responses, suggesting the necessity of using a multi-epitope strategy for COVID-19 vaccine design.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , Epitopes, T-Lymphocyte/immunology , Pandemics , Spike Glycoprotein, Coronavirus/immunology , Adult , CD8-Positive T-Lymphocytes/cytology , COVID-19/epidemiology , Female , Humans , Immunodominant Epitopes/immunology , Male , Middle Aged , SARS-CoV-2/immunology , Young Adult
4.
J Immunol ; 206(9): 2052-2060, 2021 05 01.
Article in English | MEDLINE | ID: mdl-33820854

ABSTRACT

RUNX1 overlapping RNA (RUNXOR) is a long noncoding RNA and a key regulator of myeloid-derived suppressor cells (MDSCs) via targeting runt-related transcription factor 1 (RUNX1). We and others have previously reported MDSC expansion and inhibition of host immune responses during viral infections; however, the mechanisms regulating MDSC differentiation and suppressive functions, especially the role of RUNXOR-RUNX1 in the regulation of MDSCs in people living with HIV (PLHIV), remain unknown. In this study, we demonstrate that RUNXOR and RUNX1 expressions are upregulated in MDSCs that expand and accumulate in human PBMCs derived from PLHIV. We found that the upregulation of RUNXOR and RUNX1 is associated with the expressions of several key immunosuppressive molecules, including arginase 1, inducible NO synthase, STAT3, IL-6, and reactive oxygen species. RUNXOR and RUNX1 could positively regulate each other's expression and control the expressions of these suppressive mediators. Specifically, silencing RUNXOR or RUNX1 expression in MDSCs from PLHIV attenuated MDSC expansion and immunosuppressive mediator expressions, whereas overexpressing RUNXOR in CD33+ myeloid precursors from healthy subjects promoted their differentiation into MDSCs and enhanced the expression of these mediators. Moreover, loss of RUNXOR-RUNX1 function in MDSCs improved IFN-γ production from cocultured autologous CD4 T cells derived from PLHIV. These results suggest that the RUNXOR-RUNX1 axis promotes the differentiation and suppressive functions of MDSCs via regulating multiple immunosuppressive signaling molecules and may represent a potential target for immunotherapy in conjunction with antiviral therapy in PLHIV.


Subject(s)
Core Binding Factor Alpha 2 Subunit/genetics , Gene Expression Regulation , HIV Infections/genetics , Myeloid-Derived Suppressor Cells/metabolism , RNA, Long Noncoding/genetics , Arginase/genetics , Arginase/metabolism , Cell Differentiation/genetics , Cell Proliferation/genetics , Cells, Cultured , Core Binding Factor Alpha 2 Subunit/metabolism , HIV Infections/drug therapy , HIV Infections/metabolism , Humans , Myeloid-Derived Suppressor Cells/cytology , RNA Interference , Reverse Transcriptase Polymerase Chain Reaction , STAT3 Transcription Factor/genetics , STAT3 Transcription Factor/metabolism , Signal Transduction/genetics , Up-Regulation
5.
Sci Rep ; 11(1): 5558, 2021 03 10.
Article in English | MEDLINE | ID: mdl-33692386

ABSTRACT

The recent COVID-19 pandemic poses a serious threat to global public health, thus there is an urgent need to define the molecular mechanisms involved in SARS-CoV-2 spike (S) protein-mediated virus entry that is essential for preventing and/or treating this emerging infectious disease. In this study, we examined the blocking activity of human COVID-19 convalescent plasma by cell-cell fusion assays using SARS-CoV-2-S-transfected 293 T as effector cells and ACE2-expressing 293 T as target cells. We demonstrate that the SARS-CoV-2 S protein exhibits a very high capacity for membrane fusion and is efficient in mediating virus fusion and entry into target cells. Importantly, we find that COVID-19 convalescent plasma with high titers of IgG neutralizing antibodies can block cell-cell fusion and virus entry by interfering with the SARS-CoV-2-S/ACE2 or SARS-CoV-S/ACE2 interactions. These findings suggest that COVID-19 convalescent plasma may not only inhibit SARS-CoV-2-S but also cross-neutralize SARS-CoV-S-mediated membrane fusion and virus entry, supporting its potential as a preventive and/or therapeutic agent against SARS-CoV-2 as well as other SARS-CoV infections.


Subject(s)
COVID-19/immunology , COVID-19/therapy , Spike Glycoprotein, Coronavirus/immunology , Adult , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/prevention & control , Cell Fusion/methods , Female , Humans , Immunization, Passive/methods , Male , Membrane Fusion/drug effects , Middle Aged , Pandemics/prevention & control , Plasma/chemistry , Receptors, Virus/metabolism , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/metabolism , Virus Internalization/drug effects , COVID-19 Serotherapy
6.
Sci Rep ; 10(1): 22033, 2020 12 16.
Article in English | MEDLINE | ID: mdl-33328510

ABSTRACT

HOXA transcript antisense RNA myeloid-specific 1 (HOTAIRM1) is a long non-coding RNA (lncRNA) that plays a pivotal role in regulating myeloid cell development via targeting HOXA1 gene expression. We and others have previously shown that myeloid-derived suppressor cells (MDSCs), a heterogeneous population of immature myeloid cells, expand during chronic viral (HCV, HIV) infections. However, the role of HOTAIRM1 in the development and suppression of MDSCs during viral infection remains unknown. In this study, we demonstrate that the expressions of HOTAIRM1 and its target HOXA1 are substantially upregulated to promote the expressions of immunosuppressive molecules, including arginase 1, inducible nitric oxide synthase, signal transducer and activator of transcription 3, and reactive oxygen species, in CD33+ myeloid cells derived from hepatitis C virus (HCV)-infected patients. We show that HCV-associated exosomes (HCV-Exo) can modulate HOTAIRM1, HOXA1, and miR124 expressions to regulate MDSC development. Importantly, overexpression of HOTAIRM1 or HOXA1 in healthy CD33+ myeloid cells promoted the MDSC differentiation and suppressive functions; conversely, silencing of HOTAIRM1 or HOXA1 expression in MDSCs from HCV patients significantly reduced the MDSC frequency and their suppressive functions. In essence, these results indicate that the HOTAIRM1-HOXA1-miR124 axis enhances the differentiation and suppressive functions of MDSCs and may be a potential target for immunomodulation in conjunction with antiviral therapy during chronic viral infection.


Subject(s)
Hepacivirus/physiology , Hepatitis C, Chronic/genetics , Hepatitis C, Chronic/pathology , Homeodomain Proteins/metabolism , MicroRNAs/metabolism , Myeloid-Derived Suppressor Cells/metabolism , Transcription Factors/metabolism , CD4-Positive T-Lymphocytes/metabolism , Cell Differentiation , Cell Proliferation , Gene Silencing , Homeodomain Proteins/genetics , Humans , Immunosuppression Therapy , MicroRNAs/genetics , RNA, Messenger/genetics , RNA, Messenger/metabolism , Transcription Factors/genetics , Up-Regulation/genetics
7.
Cells ; 9(12)2020 12 18.
Article in English | MEDLINE | ID: mdl-33353065

ABSTRACT

RUNX1 overlapping RNA (RUNXOR) is a long non-coding RNA and plays a pivotal role in the differentiation of myeloid cells via targeting runt-related transcription factor 1 (RUNX1). We and others have previously reported that myeloid-derived suppressor cells (MDSCs) expand and inhibit host immune responses during chronic viral infections; however, the mechanisms responsible for MDSC differentiation and suppressive functions, in particular the role of RUNXOR-RUNX1, remain unclear. Here, we demonstrated that RUNXOR and RUNX1 expressions are significantly upregulated and associated with elevated levels of immunosuppressive molecules, such as arginase 1 (Arg1), inducible nitric oxide synthase (iNOS), signal transducer and activator of transcription 3 (STAT3), and reactive oxygen species (ROS) in MDSCs during chronic hepatitis C virus (HCV) infection. Mechanistically, we discovered that HCV-associated exosomes (HCV-Exo) can induce the expressions of RUNXOR and RUNX1, which in turn regulates miR-124 expression via STAT3 signaling, thereby promoting MDSC differentiation and suppressive functions. Importantly, overexpression of RUNXOR in healthy CD33+ myeloid cells promoted differentiation and suppressive functions of MDSCs. Conversely, silencing RUNXOR or RUNX1 expression in HCV-derived CD33+ myeloid cells significantly inhibited their differentiation and expressions of suppressive molecules and improved the function of co-cultured autologous CD4 T cells. Taken together, these results indicate that the RUNXOR-RUNX1-STAT3-miR124 axis enhances the differentiation and suppressive functions of MDSCs and could be a potential target for immunomodulation in conjunction with antiviral therapy during chronic HCV infection.


Subject(s)
Core Binding Factor Alpha 2 Subunit/metabolism , Exosomes/virology , Hepacivirus , MicroRNAs/metabolism , Myeloid-Derived Suppressor Cells/cytology , RNA, Long Noncoding , STAT3 Transcription Factor/metabolism , Adult , Aged , Arginase/metabolism , CD4-Positive T-Lymphocytes/cytology , Cell Differentiation , Cell Proliferation , Female , Gene Expression Regulation, Viral , Genotype , Hepatitis C, Chronic/metabolism , Hepatitis C, Chronic/virology , Humans , Immunosuppressive Agents , Interferon-gamma/metabolism , Male , Middle Aged , Myeloid-Derived Suppressor Cells/metabolism , Reactive Oxygen Species/metabolism , Sialic Acid Binding Ig-like Lectin 3/metabolism , Up-Regulation , Viral Load
8.
AIDS ; 34(15): 2211-2221, 2020 12 01.
Article in English | MEDLINE | ID: mdl-33048872

ABSTRACT

OBJECTIVE: Myeloid-derived suppressor cells (MDSCs) contribute to HIV progression by impairing antiviral immunity; however, the mechanisms responsible for MDSC development during HIV infection are incompletely understood. HOX antisense intergenic RNA myeloid 1 (HOTAIRM1) is a long noncoding RNA (lncRNA) that plays a pivotal role in regulating myeloid cell development via targeting HOXA1. The role of HOTAIRM1--HOXA1 in the differentiation and functions of MDSCs during HIV infection remains unclear. METHODS: In this study, we measured MDSC induction and suppressive functions by flow cytometry, RT-PCR, and co-culture experiments using CD33 myeloid cells derived from people living with HIV (PLHIV) on antiretroviral therapy (ART). We also manipulated the HOTAIRM1--HOXA1 axis in myeloid cells using knockdown and overexpression approaches. RESULTS: We demonstrate that HOTAIRM1 and HOXA1 expressions are reciprocally upregulated and are responsible for increased levels of immunosuppressive molecules, such as arginase 1 (Arg1), inducible nitric oxide synthase (iNOS), signal transducer and activator of transcription 3 (STAT3), and reactive oxygen species (ROS), in CD33 myeloid cells derived from PLHIV on ART. We found that overexpression of HOTAIRM1 or HOXA1 in CD33 cells isolated from healthy individuals promoted the differentiation and suppressive functions of MDSCs, whereas silencing of HOTAIRM1 or HOXA1 expression in MDSCs derived from PLHIV significantly inhibited the frequency of MDSCs and expressions of the immunosuppressive molecules and reduced their immunosuppressive effects on T cells. CONCLUSION: These results indicate that the HOTAIRM1--HOXA1 axis enhances differentiation and suppressive functions of MDSCs and could be a potential therapeutic target for immunomodulation during latent HIV infection.


Subject(s)
HIV Infections , Homeodomain Proteins , MicroRNAs , Myeloid-Derived Suppressor Cells , Transcription Factors , Anti-HIV Agents/therapeutic use , Cell Differentiation/physiology , Cell Proliferation/physiology , HIV Infections/drug therapy , HIV Infections/genetics , HIV Infections/immunology , HIV Infections/pathology , Homeodomain Proteins/genetics , Homeodomain Proteins/metabolism , Humans , MicroRNAs/genetics , MicroRNAs/metabolism , Myeloid-Derived Suppressor Cells/immunology , Myeloid-Derived Suppressor Cells/pathology , Transcription Factors/genetics , Transcription Factors/metabolism , Up-Regulation
9.
Front Immunol ; 10: 1152, 2019.
Article in English | MEDLINE | ID: mdl-31191531

ABSTRACT

T cells in chronic viral infections are featured by premature aging with accelerated telomere erosion, but the mechanisms underlying telomere attrition remain unclear. Here, we employed human CD4 T cells treated with KML001 (a telomere-targeting drug) as a model to investigate the role of telomere integrity in remodeling T cell senescence. We demonstrated that KML001 could inhibit cell proliferation, cytokine production, and promote apoptosis via disrupting telomere integrity and DNA repair machineries. Specifically, KML001-treated T cells increased dysfunctional telomere-induced foci (TIF), DNA damage marker γH2AX, and topoisomerase cleavage complex (TOPcc) accumulation, leading to telomere attrition. Mechanistically, KML001 compromised telomere integrity by inhibiting telomeric repeat binding factor 2 (TRF2), telomerase, topoisomerase I and II alpha (Top1/2a), and ataxia telangiectasia mutated (ATM) kinase activities. Importantly, these KML001-induced telomeric DNA damage and T cell senescent phenotype and machineries recapitulated our findings in patients with clinical HCV or HIV infection in that their T cells were also senescent with short telomeres and thus more vulnerable to KML001-induced apoptosis. These results shed new insights on the T cell aging network that is critical and essential in protecting chromosomal telomeres from unwanted DNA damage and securing T cell survival during cell crisis upon genomic insult.


Subject(s)
Arsenites/pharmacology , CD4-Positive T-Lymphocytes/drug effects , DNA Repair/drug effects , Sodium Compounds/pharmacology , Telomere/drug effects , Adult , Aged , Apoptosis/drug effects , CD4-Positive T-Lymphocytes/physiology , Cell Proliferation/drug effects , Cells, Cultured , Cellular Senescence/drug effects , Coculture Techniques , Cytokines/immunology , DNA Damage , Female , HIV Infections/immunology , Hepatitis C/immunology , Humans , Male , Middle Aged
10.
Eur J Clin Nutr ; 61(9): 1075-80, 2007 Sep.
Article in English | MEDLINE | ID: mdl-17268415

ABSTRACT

OBJECTIVE: To evaluate the FAO/WHO/UNU equations for predicting resting metabolic rate (RMR) in Vietnamese adolescents. DESIGN: A cross-sectional study involving healthy subjects was carried out at the Basic Nutrition Department, National Institute of Nutrition, Vietnam. The RMR was measured by indirect calorimetry and anthropometric indices were recorded. Equations derived by linear regression of RMR and body weight were compared to the FAO/WHO/UNU (1985) predictive equations. SUBJECTS: A total of 110 subjects who had normal body mass index (5-85 percentile) and divided into two groups by sex. RESULTS: Mean RMRs (MJ/kg/day) were 0.1146+/-0.0054 for males and 0.1062+/-0.0103 for females. Compared to the FAO/WHO/UNU equation, our findings were 7.8% and 11.7% lower in the two groups, respectively (P<0.001). CONCLUSION: Our findings suggest that the FAO/WHO/UNU equations may overestimate RMR in Vietnamese adolescents. Further studies on establishing reference of daily energy needs for Vietnamese adolescents should be carried out.


Subject(s)
Basal Metabolism/physiology , Calorimetry, Indirect/methods , Mathematics , Adolescent , Anthropometry , Body Mass Index , Body Weight/physiology , Calorimetry, Indirect/standards , Cross-Sectional Studies , Energy Metabolism/physiology , Female , Humans , Linear Models , Male , Predictive Value of Tests , Reference Values , Vietnam
11.
J Vasc Res ; 44(2): 110-8, 2007.
Article in English | MEDLINE | ID: mdl-17215582

ABSTRACT

BACKGROUND: Consumption of high-glycemic index foods contributes to the development of hypertension in some patients. Likewise, in spontaneously hypertensive rats (SHR), high sucrose promotes a secondary rise in systolic blood pressure (SBP). Chromium (III) (Cr(3+)) prevents sucrose-induced hypertension, but leaves the basal hypertension that characterizes SHR intact. METHODS: Since hypertension entails increased peripheral resistance, we compared effects of Cr(3+) on resistance arteries from SHR fed low-glycemic (starch) versus high-glycemic (sucrose) index diets. Subgroups of SHR also received Cr(3+). Structure, stiffness, and vasodilation of mesenteric resistance arteries were studied using pressurized myography. RESULTS: Sucrose increased SBP in SHR and, exclusively in sucrose-fed SHR, Cr(3+) reduced SBP and augmented acetylcholine or nitroprusside-dependent vasodilation. Neither sucrose nor Cr(3+) affected artery structure or stiffness. Since Cr(3+) enhanced vasodilation, we assessed endothelial NO synthase (eNOS), guanylate cyclase, cGMP-dependent protein kinase (PKG-1alpha and 1beta), and PKG activity by immunoblotting. Sucrose reduced eNOS, PKG-1beta, and PKG activity. Cr(3+) prevented the effects of sucrose on NO signaling. CONCLUSION: In hypertension exacerbated by high-glycemic index diet, Cr(3+) reduces SBP. The BP-lowering effect of Cr(3+), selectively on sucrose-induced but not basal hypertension in SHR, involves at least in part, improving vasodilatory function vis-à-vis restoration of NO signaling in resistance arteries.


Subject(s)
Chromium/pharmacology , Hypertension/drug therapy , Nitric Oxide/metabolism , Signal Transduction/physiology , Vascular Resistance/drug effects , Vasodilation/drug effects , Animal Feed , Animals , Cyclic GMP/metabolism , Dietary Sucrose/pharmacology , Hypertension/metabolism , Male , Nitric Oxide Synthase Type III/metabolism , Rats , Rats, Inbred SHR , Starch/pharmacology
12.
J Mol Endocrinol ; 36(1): 163-74, 2006 Feb.
Article in English | MEDLINE | ID: mdl-16461936

ABSTRACT

Obesity is typically associated with resistance to leptin, yet the mechanism by which leptin signaling becomes impaired is poorly understood. Here we sought to determine if the development of obesity and leptin resistance correlates with increased expression of protein tyrosine phosphatase 1B (PTP1B) in peripheral tissues and whether over-expression of this phosphatase, specifically in liver, could alter the leptin-mediated effects on feeding and glucose metabolism. Obesity was induced in mice through a high-fat diet that resulted in hyperglycemia, hyperinsulinemia and hyperleptinemia. Resistance to leptin was confirmed as exogenous leptin administration reduced food intake in animals on low-fat, but not high-fat diets. Diet-induced resistance to leptin and insulin was associated with increased hepatic levels of PTP1B. Intriguingly, hepatic adenoviral over-expression of PTP1B in ob/ob mice attenuated the ability of exogenous leptin to reduce both plasma glucose levels and food intake. These findings suggest that leptin reduces both plasma glucose and food intake in part through actions on the liver, and hepatic leptin resistance resulting from over-expression of PTP1B may contribute to the development of both diabetes and obesity.


Subject(s)
Leptin/physiology , Liver/enzymology , Protein Tyrosine Phosphatases/metabolism , Adenoviridae/genetics , Animals , Base Sequence , Blood Glucose/analysis , CHO Cells , Cricetinae , DNA Primers , Dietary Fats/administration & dosage , Feeding Behavior , Genetic Vectors , Hyperglycemia/etiology , Hyperinsulinism/etiology , Leptin/blood , Male , Mice , Mice, Inbred BALB C , Polymerase Chain Reaction , Protein Tyrosine Phosphatase, Non-Receptor Type 1
13.
J Mol Endocrinol ; 32(2): 415-24, 2004 Apr.
Article in English | MEDLINE | ID: mdl-15072548

ABSTRACT

Leptin suppresses insulin secretion by opening ATP-sensitive K(+) (K(ATP)) channels and hyperpolarizing beta-cells. We measured the intracellular concentration of ATP ([ATP](i)) in tumor-derived beta-cells, INS-1, and found that leptin reduced [ATP](i) by approximately 30%, suggesting that the opening of K(ATP) channels by leptin is mediated by decreased [ATP](i). A reduction in glucose availability for metabolism may explain the decreased [ATP](i), since leptin (30 min) reduced glucose transport into INS-1 cells by approximately 35%, compared to vehicle-treated cells. The twofold induction of GLUT2 phosphorylation by GLP-1, an insulin secretagogue, was abolished by leptin. Therefore, the acute effect of leptin could involve covalent modification of GLUT2. These findings suggest that leptin may inhibit insulin secretion by reducing [ATP](i) as a result of reduced glucose availability for the metabolic pathway. In addition, leptin reduced glucose transport by 35% in isolated rat hepatocytes that also express GLUT2, suggesting that glucose transport may also be altered by leptin in other glucose-responsive tissues such as the liver.


Subject(s)
Adenosine Triphosphate/metabolism , Glucose/metabolism , Islets of Langerhans/metabolism , Leptin/pharmacology , Animals , Biological Transport/drug effects , Cells, Cultured , Glucagon/drug effects , Glucagon/metabolism , Glucagon-Like Peptide 1 , Glucose Transporter Type 2 , Hepatocytes/drug effects , Hepatocytes/metabolism , Humans , Islets of Langerhans/drug effects , Male , Monosaccharide Transport Proteins/drug effects , Monosaccharide Transport Proteins/metabolism , Peptide Fragments/drug effects , Peptide Fragments/metabolism , Phosphorylation , Potassium Channels/drug effects , Potassium Channels/metabolism , Protein Precursors/drug effects , Protein Precursors/metabolism , Rats , Rats, Sprague-Dawley
14.
Minerva Endocrinol ; 27(2): 79-93, 2002 Jun.
Article in English | MEDLINE | ID: mdl-11961501

ABSTRACT

Glucagon-like peptide-1 (GLP-1), an intestinal gut hormone, is rapidly emerging as a new therapeutic agent for the treatment of diabetes mellitus. GLP-1, released from intestinal L-cells, is renowned for its potent stimulation of insulin biosynthesis and release from pancreatic b-cells. Exogenous administration of GLP-1 to subjects with type 2 diabetes results in the normalization of plasma glucose concentrations, in part, as a result of augmented glucose-stimulated insulin secretion. However, it is now recognized that GLP-1 has several other anti-diabetic actions that collectively improve the type 2 diabetic phenotype, and may also prove beneficial in the treatment of type 1 diabetes. These effects include the deceleration of gastric emptying and promotion of satiety, thereby reducing the availability of nutrients for absorption and reducing the requirement for insulin secretion. GLP-1 also reduces plasma glucose levels by suppressing glucagon secretion from pancreatic a-cells and potentially by improving insulin sensitivity in peripheral tissues. Further-more, GLP-1 upregulates expression of b-cell genes (GLUT2, glucokinase, insulin, and PDX-1) and promotes b-cell neogenesis and differentiation of ductal cells into insulin secreting cells. Although initial clinical trials indicate GLP-1 has excellent therapeutic potential, its relatively short-lived biological activity and delivery difficulties limit its appeal. Several approaches that are currently being explored to overcome these limitations include mobilizing endogenous GLP-1 release, preserving the biological activity of the native peptide, and developing GLP-1 analogues with extended durations of action.


Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Glucagon/therapeutic use , Hypoglycemic Agents/therapeutic use , Peptide Fragments/therapeutic use , Protein Precursors/therapeutic use , Animals , Blood Glucose/analysis , Clinical Trials as Topic , Diabetes Mellitus, Experimental/drug therapy , Drug Administration Routes , Gastric Emptying/drug effects , Gene Expression Regulation/drug effects , Glucagon/metabolism , Glucagon/pharmacokinetics , Glucagon/pharmacology , Glucagon-Like Peptide 1 , Glucagon-Like Peptide-1 Receptor , Humans , Hypoglycemic Agents/pharmacokinetics , Hypoglycemic Agents/pharmacology , Insulin/biosynthesis , Insulin/metabolism , Insulin Resistance , Insulin Secretion , Intestine, Small/metabolism , Islets of Langerhans/drug effects , Islets of Langerhans/metabolism , Peptide Fragments/pharmacokinetics , Peptide Fragments/pharmacology , Protein Precursors/pharmacokinetics , Protein Precursors/pharmacology , Rats , Receptors, Glucagon/drug effects , Receptors, Glucagon/physiology , Satiety Response/drug effects , Signal Transduction/drug effects , Signal Transduction/physiology
15.
Phytomedicine ; 5(1): 29-34, 1998 Mar.
Article in English | MEDLINE | ID: mdl-23195696

ABSTRACT

In a joint Vietnam-Sweden prospective double-blind two-center study, the herbal remedy of Curcuma longa (turmeric) - in a dosage of 6 g daily as suggested in the Vietnamese pharmacopoeia - was compared with an equal amount of placebo in 118 patients, suffering from duodenal ulcer. The patients in the two groups were well matched prior to treatment. Clinical assessments were carried out weekly, while laboratory investigations were carried out before beginning of the treatment and after four and eight weeks: Only patients, having one duodenal ulcer with a minimum diameter of 5 mm verified by endoscopy (Uong Bi General Hospital, UBGH) and/or radiography (UBGH and Viet Due University Hospital, VDUH) not more than 4 days prior the study were included in the study. No treatment with H(2)-receptor antagonists, anticholinergics or other drugs used in the treatment of ulcer disease during the preceding week were allowed. Follow-up endoscopy and/or radiography were performed after 28 ± 4 days and 56 ± 4 days. Turmeric was not superior to placebo in healing duodenal ulcer either after four or eight weeks of treatment. After eight weeks the ulcer-healing rate of turmeric was 27% while placebo had healed 29%. Both drugs were well tolerated.

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