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1.
J Autoimmun ; 124: 102713, 2021 11.
Article in English | MEDLINE | ID: mdl-34390919

ABSTRACT

Despite the existence of potent anti-inflammatory biological drugs e.g., anti-TNF and anti IL-6 receptor antibodies, for treating chronic inflammatory and autoimmune diseases, these are costly and not specific. Cheaper oral available drugs remain an unmet need. Expression of the acute phase protein Serum Amyloid A (SAA) is dependent on release of pro-inflammatory cytokines IL-1, IL-6 and TNF-α during inflammation. Conversely, SAA induces pro-inflammatory cytokine secretion, including Th17, leading to a pathogenic vicious cycle and chronic inflammation. 5- MER peptide (5-MP) MTADV (methionine-threonine-alanine-aspartic acid-valine), also called Amilo-5MER, was originally derived from a sequence of a pro-inflammatory CD44 variant isolated from synovial fluid of a Rheumatoid Arthritis (RA) patient. This human peptide displays an efficient anti-inflammatory effects to ameliorate pathology and clinical symptoms in mouse models of RA, Inflammatory Bowel Disease (IBD) and Multiple Sclerosis (MS). Bioinformatics and qRT-PCR revealed that 5-MP, administrated to encephalomyelytic mice, up-regulates genes contributing to chronic inflammation resistance. Mass spectrometry of proteins that were pulled down from an RA synovial cell extract with biotinylated 5-MP, showed that it binds SAA. 5-MP disrupted SAA assembly, which is correlated with its pro-inflammatory activity. The peptide MTADV (but not scrambled TMVAD) significantly inhibited the release of pro-inflammatory cytokines IL-6 and IL-1ß from SAA-activated human fibroblasts, THP-1 monocytes and peripheral blood mononuclear cells. 5-MP suppresses the pro-inflammatory IL-6 release from SAA-activated cells, but not from non-activated cells. 5-MP could not display therapeutic activity in rats, which are SAA deficient, but does inhibit inflammations in animal models of IBD and MS, both are SAA-dependent, as shown by others in SAA knockout mice. In conclusion, 5-MP suppresses chronic inflammation in animal models of RA, IBD and MS, which are SAA-dependent, but not in animal models, which are SAA-independent.


Subject(s)
Arthritis, Rheumatoid/immunology , Hyaluronan Receptors/genetics , Inflammation/immunology , Inflammatory Bowel Diseases/immunology , Multiple Sclerosis/immunology , Peptides/genetics , Serum Amyloid A Protein/immunology , Animals , Anti-Inflammatory Agents/therapeutic use , Autoimmunity , Cells, Cultured , Computational Biology , Cytokines/metabolism , Disease Models, Animal , Humans , Inflammation Mediators/metabolism , Mice , Mice, Knockout , Peptides/therapeutic use , Serum Amyloid A Protein/genetics
2.
FASEB J ; 35(1): e21202, 2021 01.
Article in English | MEDLINE | ID: mdl-33368638

ABSTRACT

Among the fascinating adaptations to limiting oxygen conditions (hypoxia) is the suppression of food intake and weight loss. In humans, this phenomenon is called high-altitude anorexia and is observed in people suffering from acute mountain syndrome. The high-altitude anorexia appears to be conserved in evolution and has been seen in species across the animal kingdom. However, the mechanism underlying the recovery of eating behavior after hypoxia is still not known. Here, we show that the phosphatidylinositol transfer protein PITP-1 is essential for the fast recovery of eating behavior after hypoxia in the nematode Caenorhabditis elegans. Unlike the neuroglobin GLB-5 that accelerates the recovery of eating behavior through its function in the oxygen (O2 )-sensing neurons, PITP-1 appears to act downstream, in neurons that express the mod-1 serotonin receptor. Indeed, pitp-1 mutants display wild-type-like O2 -evoked-calcium responses in the URX O2 -sensing neuron. Intriguingly, loss-of-function of protein kinase C 1 (PKC-1) rescues pitp-1 mutants' recovery after hypoxia. Increased diacylglycerol (DAG), which activates PKC-1, attenuates the recovery of wild-type worms. Together, these data suggest that PITP-1 enables rapid recovery of eating behavior after hypoxia by limiting DAG's availability, thereby limiting PKC activity in mod-1-expressing neurons.


Subject(s)
Caenorhabditis elegans Proteins/metabolism , Caenorhabditis elegans/metabolism , Hypoxia/metabolism , Phospholipid Transfer Proteins/metabolism , Animals , Caenorhabditis elegans/genetics , Caenorhabditis elegans Proteins/genetics , Hypoxia/genetics , Phospholipid Transfer Proteins/genetics
3.
Redox Biol ; 28: 101359, 2020 01.
Article in English | MEDLINE | ID: mdl-31677552

ABSTRACT

Iron is vital for the life of most organisms. However, when dysregulated, iron can catalyze the formation of oxygen (O2) radicals that can destroy any biological molecule and thus lead to oxidative injury and death. Therefore, iron metabolism must be tightly regulated at all times, as well as coordinated with the metabolism of O2. However, how is this achieved at the whole animal level is not well understood. Here, we explore this question using the nematode Caenorhabditis elegans. Exposure of worms to O2 starvation conditions (i.e. hypoxia) induces a major upregulation in levels of the conserved iron-cage protein ferritin 1 (ftn-1) in the intestine, while exposure to 21% O2 decreases ftn-1 level. This O2-dependent inhibition is mediated by O2-sensing neurons that communicate with the intestine through neurotransmitter and neuropeptide signalling, and requires the activity of hydroxylated HIF-1. By contrast, the induction of ftn-1 in hypoxia appears to be HIF-1-independent. This upregulation provides protection against Pseudomonas aeruginosa bacteria and oxidative injury. Taken together, our studies uncover a neuro-intestine axis that coordinates O2 and iron responses at the whole animal level.


Subject(s)
Caenorhabditis elegans/metabolism , Ferritins/metabolism , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Neuropeptides/metabolism , Animals , Caenorhabditis elegans Proteins/metabolism , Cell Hypoxia , Gene Expression Regulation/drug effects , Intestinal Mucosa/metabolism , Iron/metabolism , Nervous System/metabolism , Oxygen/pharmacology
4.
Aging Cell ; 16(2): 401-413, 2017 04.
Article in English | MEDLINE | ID: mdl-28054425

ABSTRACT

Oxygen (O2 ) homeostasis is important for all aerobic animals. However, the manner by which O2 sensing and homeostasis contribute to lifespan regulation is poorly understood. Here, we use the nematode Caenorhabditis elegans to address this question. We demonstrate that a loss-of-function mutation in the neuropeptide receptor gene npr-1 and a deletion mutation in the atypical soluble guanylate cyclase gcy-35 O2 sensor interact synergistically to extend worm lifespan. The function of npr-1 and gcy-35 in the O2 -sensing neurons AQR, PQR, and URX shortens the lifespan of the worm. By contrast, the activity of the atypical soluble guanylate cyclase O2 sensor gcy-33 in these neurons is crucial for lifespan extension. In addition to AQR, PQR, and URX, we show that the O2 -sensing neuron BAG and the interneuron RIA are also important for the lifespan lengthening. Neuropeptide processing by the proprotein convertase EGL-3 is essential for lifespan extension, suggesting that the synergistic effect of joint loss of function of gcy-35 and npr-1 is mediated through neuropeptide signal transduction. The extended lifespan is regulated by hypoxia and insulin signaling pathways, mediated by the transcription factors HIF-1 and DAF-16. Moreover, reactive oxygen species (ROS) appear to play an important function in lifespan lengthening. As HIF-1 and DAF-16 activities are modulated by ROS, we speculate that joint loss of function of gcy-35 and npr-1 extends lifespan through ROS signaling.


Subject(s)
Caenorhabditis elegans Proteins/metabolism , Caenorhabditis elegans/physiology , Guanylate Cyclase/metabolism , Longevity/physiology , Neuropeptides/metabolism , Signal Transduction , Animals , Caenorhabditis elegans/drug effects , Caenorhabditis elegans/genetics , Food , Gene Expression Regulation/drug effects , Immunity, Innate/drug effects , Immunity, Innate/genetics , Interneurons/drug effects , Interneurons/metabolism , Longevity/drug effects , Mutation/genetics , Neurotransmitter Agents/metabolism , Oxidation-Reduction/drug effects , Oxygen/metabolism , Paraquat/toxicity , Reactive Oxygen Species/metabolism , Receptors, Neuropeptide Y/metabolism , Signal Transduction/drug effects , Stress, Physiological/drug effects , Temperature , Transcription, Genetic/drug effects
5.
PLoS One ; 6(12): e28804, 2011.
Article in English | MEDLINE | ID: mdl-22194917

ABSTRACT

Thioredoxin-interacting protein (TXNIP) regulates critical biological processes including inflammation, stress and apoptosis. TXNIP is upregulated by glucose and is a critical mediator of hyperglycemia-induced beta-cell apoptosis in diabetes. In contrast, the saturated long-chain fatty acid palmitate, although toxic to the beta-cell, inhibits TXNIP expression. The mechanisms involved in the opposing effects of glucose and fatty acids on TXNIP expression are unknown. We found that both palmitate and oleate inhibited TXNIP in a rat beta-cell line and islets. Palmitate inhibition of TXNIP was independent of fatty acid beta-oxidation or esterification. AMP-activated protein kinase (AMPK) has an important role in cellular energy sensing and control of metabolic homeostasis; therefore we investigated its involvement in nutrient regulation of TXNIP. As expected, glucose inhibited whereas palmitate stimulated AMPK. Pharmacologic activators of AMPK mimicked fatty acids by inhibiting TXNIP. AMPK knockdown increased TXNIP expression in presence of high glucose with and without palmitate, indicating that nutrient (glucose and fatty acids) effects on TXNIP are mediated in part via modulation of AMPK activity. TXNIP is transcriptionally regulated by carbohydrate response element-binding protein (ChREBP). Palmitate inhibited glucose-stimulated ChREBP nuclear entry and recruitment to the Txnip promoter, thereby inhibiting Txnip transcription. We conclude that AMPK is an important regulator of Txnip transcription via modulation of ChREBP activity. The divergent effects of glucose and fatty acids on TXNIP expression result in part from their opposing effects on AMPK activity. In light of the important role of TXNIP in beta-cell apoptosis, its inhibition by fatty acids can be regarded as an adaptive/protective response to glucolipotoxicity. The finding that AMPK mediates nutrient regulation of TXNIP may have important implications for the pathophysiology and treatment of diabetes.


Subject(s)
AMP-Activated Protein Kinases/metabolism , Carrier Proteins/metabolism , Insulin-Secreting Cells/drug effects , Insulin-Secreting Cells/enzymology , Oleic Acid/pharmacology , Palmitic Acid/pharmacology , AMP-Activated Protein Kinases/antagonists & inhibitors , Animals , Apoptosis/drug effects , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism , Cell Cycle Proteins , Cell Nucleus/drug effects , Cell Nucleus/metabolism , Deoxyglucose/pharmacology , Enzyme Activation/drug effects , Enzyme Activators/pharmacology , Gene Knockdown Techniques , Glucose/pharmacology , Humans , Insulin-Secreting Cells/cytology , Isoenzymes/metabolism , Metformin/pharmacology , Protein Transport/drug effects , Rats , Rats, Wistar
6.
Diabetes ; 60(7): 1872-81, 2011 Jul.
Article in English | MEDLINE | ID: mdl-21602511

ABSTRACT

OBJECTIVE: Overactivity of the Forkhead transcription factor FoxO1 promotes diabetic hyperglycemia, dyslipidemia, and acute-phase response, whereas suppression of FoxO1 activity by insulin may alleviate diabetes. The reported efficacy of long-chain fatty acyl (LCFA) analogs of the MEDICA series in activating AMP-activated protein kinase (AMPK) and in treating animal models of diabesity may indicate suppression of FoxO1 activity. RESEARCH DESIGN AND METHODS: The insulin-sensitizing and anti-inflammatory efficacy of a MEDICA analog has been verified in guinea pig and in human C-reactive protein (hCRP) transgenic mice, respectively. Suppression of FoxO1 transcriptional activity has been verified in the context of FoxO1- and STAT3-responsive genes and compared with suppression of FoxO1 activity by insulin and metformin. RESULTS: Treatment with MEDICA analog resulted in total body sensitization to insulin, suppression of lipopolysaccharide-induced hCRP and interleukin-6-induced acute phase reactants and robust decrease in FoxO1 transcriptional activity and in coactivation of STAT3. Suppression of FoxO1 activity was accounted for by its nuclear export by MEDICA-activated AMPK, complemented by inhibition of nuclear FoxO1 transcriptional activity by MEDICA-induced C/EBPß isoforms. Similarly, insulin treatment resulted in nuclear exclusion of FoxO1 and further suppression of its nuclear activity by insulin-induced C/EBPß isoforms. In contrast, FoxO1 suppression by metformin was essentially accounted for by its nuclear export by metformin-activated AMPK. CONCLUSIONS: Suppression of FoxO1 activity by MEDICA analogs may partly account for their antidiabetic anti-inflammatory efficacy. FoxO1 suppression by LCFA analogs may provide a molecular rational for the beneficial efficacy of carbohydrate-restricted ketogenic diets in treating diabetes.


Subject(s)
AMP-Activated Protein Kinases/metabolism , Dicarboxylic Acids/pharmacology , Forkhead Transcription Factors/metabolism , Acute-Phase Reaction/drug therapy , Acute-Phase Reaction/metabolism , Animals , C-Reactive Protein/metabolism , CCAAT-Enhancer-Binding Protein-beta/physiology , COS Cells , Chlorocebus aethiops , Forkhead Transcription Factors/drug effects , Guinea Pigs , Hep G2 Cells , Humans , Insulin/pharmacology , Male , Metformin/pharmacology , Mice , Mice, Transgenic , STAT3 Transcription Factor/pharmacology
7.
Int J Cancer ; 126(10): 2268-81, 2010 May 15.
Article in English | MEDLINE | ID: mdl-19998334

ABSTRACT

In neuroblastoma LAN-1 cells harboring an amplified MycN gene, disruption of cooperation between Ras and MycN proteins by the Ras inhibitor farnesylthiosalicylic acid (FTS, Salirasib) reportedly arrests cell growth. Our aim was to establish whether this is a general phenomenon. We examined the effects of FTS on gene-expression profiles, growth and death of NCIH929 myeloma cells and K562 leukemia cells, which-like LAN-1 cells-exhibit Myc gene amplification and harbor active Ras. Under specified conditions, FTS reduced Ras and Myc and induced cell growth arrest and death in all Myc-amplified cell lines but not in SHEP, a neuroblastoma cell line without Myc gene amplification. Gene-expression analysis revealed a common pattern of FTS-induced endoplasmic reticulum (ER) stress, known as the unfolded protein response (UPR), in Myc-amplified cells, but not in SHEP. Thus, Ras negatively regulates ER stress in cells with amplified Myc. ER stress was also inducible by dominant-negative (DN)-Ras or shRNA to Ras isoforms, all of which induced an increase in BIP (the master regulator of ER stress) and its downstream targets Nrf2 and eIF2alpha, both regulated by active p-PERK. FTS also induced an increase in p-PERK, while small interfering RNA to PERK reduced Nrf2 and ATF4 and rescued cells from FTS-induced death. BIP and its downstream targets were also increased by inhibitors of MAPK p38 and MEK. Ras, acting through MAPK p38 and MEK, negatively regulates the ER stress cascades BIP/PERK/Nrf2 and eIF2alpha/ATF4/ATF3. These findings can explain the Ras-dependent protection of Myc-amplified cells from ER stress-associated death.


Subject(s)
Antineoplastic Agents/pharmacology , Endoplasmic Reticulum/drug effects , Endoplasmic Reticulum/metabolism , Enzyme Inhibitors/pharmacology , Farnesol/analogs & derivatives , Gene Amplification , Nuclear Proteins/genetics , Oncogene Proteins/genetics , Salicylates/pharmacology , Unfolded Protein Response , ras Proteins/metabolism , Cell Line, Tumor , Cell Proliferation/drug effects , Endoplasmic Reticulum/genetics , Farnesol/pharmacology , Gene Expression Profiling , Gene Expression Regulation, Neoplastic/drug effects , Humans , K562 Cells , Mitogen-Activated Protein Kinase Kinases/metabolism , N-Myc Proto-Oncogene Protein , NF-E2-Related Factor 2/metabolism , Neuroblastoma , RNA, Small Interfering/metabolism , Transcription Factors/metabolism , Unfolded Protein Response/drug effects , Unfolded Protein Response/genetics , eIF-2 Kinase/metabolism , ras Proteins/antagonists & inhibitors
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