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1.
Lipids ; 57(6): 313-325, 2022 Nov.
Article in English | MEDLINE | ID: mdl-36098349

ABSTRACT

Although it is well established that glucocorticoids inactivate thermogenesis and promote lipid accumulation in interscapular brown adipose tissue (IBAT), the underlying mechanisms remain unknown. We found that dexamethasone treatment (1 mg/kg) for 7 days in rats decreased the IBAT thermogenic activity, evidenced by its lower responsiveness to noradrenaline injection associated with reduced content of mitochondrial proteins, respiratory chain protein complexes, noradrenaline, and the ß3 -adrenergic receptor. In parallel, to understand better how dexamethasone increases IBAT lipid content, we also investigated the activity of the ATP citrate lyase (ACL), a key enzyme of de novo fatty acid synthesis, glucose-6-phosphate dehydrogenase (G6PD), a rate-limiting enzyme of the pentose phosphate pathway, and the three glycerol-3-P generating pathways: (1) glycolysis, estimated by 2-deoxyglucose uptake, (2) glyceroneogenesis, evaluated by phosphoenolpyruvate carboxykinase activity and pyruvate incorporation into triacylglycerol-glycerol, and (3) direct phosphorylation of glycerol, investigated by the content and activity of glycerokinase. Dexamethasone increased the mass and the lipid content of IBAT as well as plasma levels of glucose, insulin, non-esterified fatty acid, and glycerol. Furthermore, dexamethasone increased ACL and G6PD activities (79% and 48%, respectively). Despite promoting a decrease in the incorporation of U-[14 C]-glycerol into triacylglycerol (~54%), dexamethasone increased the content (~55%) and activity (~41%) of glycerokinase without affecting glucose uptake or glyceroneogenesis. Our data suggest that glucocorticoid administration reduces IBAT thermogenesis through sympathetic inactivation and stimulates glycerokinase activity and content, contributing to increased generation of glycerol-3-P, which is mostly used to esterify fatty acid and increase triacylglycerol content promoting IBAT whitening.


Subject(s)
Adipose Tissue, Brown , Glycerol Kinase , Animals , Rats , Adipose Tissue, Brown/metabolism , Glycerol Kinase/metabolism , Glucocorticoids , Glycerol , Rats, Wistar , Thermogenesis , Triglycerides/metabolism , Fatty Acids/metabolism , Dexamethasone/metabolism , Norepinephrine , Adipose Tissue/metabolism
2.
Life Sci ; 279: 119665, 2021 Aug 15.
Article in English | MEDLINE | ID: mdl-34087281

ABSTRACT

AIMS: Although it is well established that skeletal muscle contains oxytocin (OT) receptors and OT-knockout mice show premature development of sarcopenia, the role of OT in controlling skeletal muscle mass is still unknown. Therefore, the present work aimed to determine OT's effects on skeletal muscle protein metabolism. MAIN METHODS: Total proteolysis, proteolytic system activities and protein synthesis were assessed in isolated soleus muscle from prepubertal female rats. Through in vivo experiments, rats received 3-day OT treatment (3UI.kg-1.day-1, i.p.) or saline, and muscles were harvested for mass-gain assessment. KEY FINDINGS: In vitro OT receptor stimulation reduced total proteolysis, specifically through attenuation of the lysosomal and proteasomal proteolytic systems, and in parallel activated the Akt/FoxO1 signaling and suppressed atrogenes (e.g., MuRF-1 and atrogin-1) expression induced by motor denervation. On the other hand, the protein synthesis was not altered by in vitro treatment with the OT receptor-selective agonist. Although short-term OT treatment did not change the atrogene mRNA levels, the protein synthesis was stimulated, resulting in soleus mass gain, probably through an indirect effect. SIGNIFICANCE: Taken together, these data show for the first time that OT directly inhibits the proteolytic activities of the lysosomal and proteasomal systems in rat oxidative skeletal muscle by suppressing atrogene expression via stimulation of Akt/FoxO signaling. Moreover, the data obtained from in vivo experiments suggest OT's ability to control rat oxidative skeletal muscle mass.


Subject(s)
Anabolic Agents/pharmacology , Lysosomes/metabolism , Muscle, Skeletal/metabolism , Oxytocin/pharmacology , Protein Biosynthesis , Proteolysis , Animals , Female , Lysosomes/drug effects , Lysosomes/pathology , Muscle, Skeletal/drug effects , Muscle, Skeletal/pathology , Oxidative Stress , Oxytocics/pharmacology , Rats , Rats, Wistar , Signal Transduction
3.
Life Sci ; 278: 119563, 2021 Aug 01.
Article in English | MEDLINE | ID: mdl-33930364

ABSTRACT

AIM: There is growing evidence about the ability of cyclic adenosine monophosphate (cAMP) signaling and nonselective phosphodiesterase (PDE) inhibitors on mitigate muscle atrophy. PDE4 accounts for the major cAMP hydrolyzing activity in skeletal muscles, therefore advances are necessary about the consequences of treatment with PDE4 inhibitors on protein breakdown in atrophied muscles. We postulated that rolipram (selective PDE4 inhibitor) may activate cAMP downstream effectors, inhibiting proteolytic systems in skeletal muscles of diabetic rats. MAIN METHODS: Streptozotocin-induced diabetic rats were treated with 2 mg/kg rolipram for 3 days. Changes in the levels of components belonging to the proteolytic machineries in soleus and extensor digitorum longus (EDL) muscles were investigated, as well as cAMP effectors. KEY FINDINGS: Treatment of diabetic rats with rolipram decreased the levels of atrogin-1 and MuRF-1 in soleus and EDL, and reduced the activities of calpains and caspase-3; these findings partially explains the low ubiquitin conjugates levels and the decreased proteasome activity. The inhibition of muscle proteolysis may be occurring due to phosphorylation and inhibition of forkhead box O (FoxO) factors, probably as a consequence of the increased cAMP levels, followed by the activation of PKA and Akt effectors. Akt activation may be associated with the increased levels of exchange protein directly activated by cAMP (EPAC). As a result, rolipram treatment spared muscle mass in diabetic rats. SIGNIFICANCE: The antiproteolytic responses associated with PDE4 inhibition may be helpful to motivate future investigations about the repositioning of PDE4 inhibitors for the treatment of muscle wasting conditions.


Subject(s)
3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors , Cyclic AMP-Dependent Protein Kinases/metabolism , Diabetes Mellitus, Experimental/metabolism , Muscle, Skeletal/metabolism , Nerve Tissue Proteins/antagonists & inhibitors , Phosphodiesterase 4 Inhibitors/pharmacology , Proto-Oncogene Proteins c-akt/metabolism , Animals , Calpain/metabolism , Caspase 3/metabolism , Cyclic AMP/metabolism , Male , Muscular Atrophy/metabolism , Phosphorylation , Proteasome Endopeptidase Complex/metabolism , Rats , Rats, Wistar , Rolipram/pharmacology , Signal Transduction/drug effects
4.
J Appl Physiol (1985) ; 124(3): 704-716, 2018 03 01.
Article in English | MEDLINE | ID: mdl-29357512

ABSTRACT

Advances in the knowledge of the mechanisms controlling protein breakdown in skeletal muscles have allowed the exploration of new options for treating muscle-wasting conditions. Pentoxifylline (PTX), a nonselective phosphodiesterase (PDE) inhibitor, attenuates the loss of muscle mass during catabolic conditions, mainly via inhibiting protein breakdown. The aim of this study was to explore the mechanisms by which PTX inhibits proteolysis in the soleus and extensor digitorum longus (EDL) muscles of streptozotocin-induced diabetic rats. The levels of atrogin-1 and muscle RING finger-1 were decreased, as were the activities of caspase-3 (EDL) and calpains (soleus and EDL), in diabetic rats treated with PTX, which at least partly explains the drop in the ubiquitin conjugate (EDL) levels and in proteasome activity (soleus and EDL). Treatment with PTX decreased PDE activity and increased cAMP content in muscles of diabetic rats; moreover, it also increased both the protein levels of exchange protein directly activated by cAMP (EPAC, a cAMP effector) and the phosphorylation of Akt. The loss of muscle mass was practically prevented in diabetic rats treated with PTX. These findings advance our understanding of the mechanisms underlying the antiproteolytic effects of PTX and suggest the use of PDE inhibitors as a strategy to activate cAMP signaling, which is emerging as a promising target for treating muscle mass loss during atrophic conditions. NEW & NOTEWORTHY cAMP signaling has been explored as a strategy to attenuate skeletal muscle atrophies. Therefore, in addition to ß2AR agonists, phosphodiesterase inhibitors such as pentoxifylline (PTX) can be an interesting option. This study advances the understanding of the mechanisms related to the antiproteolytic effects of PTX on skeletal muscles of diabetic rats, which involve the activation of both exchange protein directly activated by cAMP and Akt effectors, inhibiting the expression of atrogenes and calpain/caspase-3-proteolytic machinery.


Subject(s)
Diabetes Mellitus, Experimental/complications , Muscle, Skeletal/drug effects , Muscular Atrophy/prevention & control , Pentoxifylline/therapeutic use , Phosphodiesterase Inhibitors/therapeutic use , Proteolysis/drug effects , Animals , Blood Glucose/drug effects , Body Weight/drug effects , Cyclic AMP/metabolism , Drug Evaluation, Preclinical , Guanine Nucleotide Exchange Factors/metabolism , Male , Muscle, Skeletal/metabolism , Muscular Atrophy/etiology , Muscular Atrophy/metabolism , Pentoxifylline/pharmacology , Phosphodiesterase Inhibitors/pharmacology , Proto-Oncogene Proteins c-akt/metabolism , Rats, Wistar , Signal Transduction/drug effects , Tumor Necrosis Factor-alpha/blood
5.
Endocrine ; 57(2): 287-297, 2017 Aug.
Article in English | MEDLINE | ID: mdl-28555305

ABSTRACT

PURPOSE: Investigate the glycerol-3-phosphate generation pathways in epididymal (EPI) and retroperitoneal (RETRO) adipose tissues from dexamethasone-treated rats. METHODS: Rats were treated with dexamethasone for 7 days. Glycerol-3-phosphate generation pathways via glycolysis, glyceroneogenesis and direct phosphorylation of glycerol were evaluated, respectively, by 2-deoxyglucose uptake, phosphoenolpyruvate carboxykinase (PEPCK-C) activity and pyruvate incorporation into triacylglycerol (TAG)-glycerol, and glycerokinase activity and glycerol incorporation into TAG-glycerol. RESULTS: Dexamethasone treatment markedly decreased the body weight, but increased the weight and lipid content of EPI and RETRO and plasma insulin, glucose, non-esterified fatty acid and TAG levels. EPI and RETRO from dexamethasone-treated rats showed increased rates of de novo fatty acid synthesis (80 and 100%) and basal lipolysis (20%). In EPI, dexamethasone decreased the 2-deoxyglucose uptake (50%), as well as glyceroneogenesis, evidenced by a decrease of PEPCK-C activity (39%) and TAG-glycerol synthesis from pyruvate (66%), but increased the glycerokinase activity (50%) and TAG-glycerol synthesis from glycerol (72%) in this tissue. In spite of a similar reduction in 2-deoxyglucose uptake in RETRO, dexamethasone treatment increased glyceroneogenesis, evidenced by PEPCK activity (96%), and TAG-glycerol synthesis from pyruvate (110%), accompanied by a decrease in glycerokinase activity (50%) and TAG-glycerol synthesis from glycerol (50%). Dexamethasone effects on RETRO were accompanied by a decrease in p-Akt content and by lower insulin effects on the rates of glycerol release in the presence of isoproterenol and on the rates of glucose uptake in isolated adipocytes. CONCLUSION: Our data demonstrated differential regulation of glyceroneogenesis and direct phosphorylation of glycerol by glucocorticoids in EPI and RETRO from rats.


Subject(s)
Adipose Tissue, White/metabolism , Adipose Tissue/drug effects , Adipose Tissue/metabolism , Dexamethasone/pharmacology , Epididymis/metabolism , Glucocorticoids/pharmacology , Glycerol/metabolism , Intra-Abdominal Fat/drug effects , Intra-Abdominal Fat/metabolism , Adipocytes/drug effects , Adipocytes/metabolism , Adipose Tissue, White/drug effects , Adiposity/drug effects , Animals , Body Weight/drug effects , Epididymis/drug effects , Glycerol Kinase/biosynthesis , Intracellular Signaling Peptides and Proteins/biosynthesis , Intracellular Signaling Peptides and Proteins/genetics , Lipolysis/drug effects , Male , Organ Size/drug effects , Phosphoenolpyruvate Carboxykinase (GTP)/biosynthesis , Phosphoenolpyruvate Carboxykinase (GTP)/genetics , Rats , Rats, Wistar , Retroperitoneal Space , Triglycerides/biosynthesis
6.
J Nutr Biochem ; 34: 89-98, 2016 08.
Article in English | MEDLINE | ID: mdl-27239756

ABSTRACT

Compared with the extensor digitorum longus (EDL) muscle of control rats (C), the EDL muscle of rats fed a low-protein, high-carbohydrate diet (LPHC) showed a 36% reduction in mass. Muscle mass is determined by the balance between protein synthesis and proteolysis; thus, the aim of this work was to evaluate the components involved in these processes. Compared with the muscle from C rats, the EDL muscle from LPHC diet-fed rats showed a reduction (34%) in the in vitro basal protein synthesis and a 22% reduction in the in vitro basal proteolysis suggesting that the reduction in the mass can be associated with a change in the rate of the two processes. Soon after euthanasia, in the EDL muscles of the rats fed the LPHC diet for 15days, the activity of caspase-3 and that of components of the ubiquitin-proteasome system (atrogin-1 content and chymotrypsin-like activity) were decreased. The phosphorylation of p70(S6K) and 4E-BP1, proteins involved in protein synthesis, was also decreased. We observed an increase in the insulin-stimulated protein content of p-Akt. Thus, the higher insulin sensitivity in the EDL muscle of LPHC rats seemed to contribute to the lower proteolysis in LPHC rats. However, even with the higher insulin sensitivity, the reduction in p-E4-BP1 and p70(S6K) indicates a reduction in protein synthesis, showing that factors other than insulin can have a greater effect on the control of protein synthesis.


Subject(s)
Caspase 3/metabolism , Diet, Carbohydrate Loading/adverse effects , Diet, Protein-Restricted/adverse effects , Down-Regulation , Insulin Resistance , Muscle, Skeletal/metabolism , Proteasome Endopeptidase Complex/metabolism , Animals , Carrier Proteins/genetics , Carrier Proteins/metabolism , Foot , Intracellular Signaling Peptides and Proteins , Male , Muscle Development , Muscle, Skeletal/enzymology , Phosphoproteins/genetics , Phosphoproteins/metabolism , Phosphorylation , Protein Biosynthesis , Protein Processing, Post-Translational , Protein Tyrosine Phosphatases/genetics , Protein Tyrosine Phosphatases/metabolism , Proteolysis , Random Allocation , Rats, Wistar , Ribosomal Protein S6 Kinases, 70-kDa/genetics , Ribosomal Protein S6 Kinases, 70-kDa/metabolism , Ubiquitination
7.
Can J Physiol Pharmacol ; 92(6): 445-54, 2014 Jun.
Article in English | MEDLINE | ID: mdl-24826789

ABSTRACT

The aim of this study was to investigate the changes in the rates of both protein synthesis and breakdown, and the activation of intracellular effectors that control these processes in soleus muscles from growing rats fed a low-protein, high-carbohydrate (LPHC) diet for 15 days. The mass and the protein content, as well as the rate of protein synthesis, were decreased in the soleus from LPHC-fed rats. The availability of amino acids was diminished, since the levels of various essential amino acids were decreased in the plasma of LPHC-fed rats. Overall rate of proteolysis was also decreased, explained by reductions in the mRNA levels of atrogin-1 and MuRF-1, ubiquitin conjugates, proteasome activity, and in the activity of caspase-3. Soleus muscles from LPHC-fed rats showed increased insulin sensitivity, with increased levels of insulin receptor and phosphorylation levels of AKT, which probably explains the inhibition of both the caspase-3 activity and the ubiquitin-proteasome system. The fall of muscle proteolysis seems to represent an adaptive response that contributes to spare proteins in a condition of diminished availability of dietary amino acids. Furthermore, the decreased rate of protein synthesis may be the driving factor to the lower muscle mass gain in growing rats fed the LPHC diet.


Subject(s)
Caspase 3/metabolism , Diet, Protein-Restricted , Dietary Carbohydrates/pharmacology , Muscle, Skeletal/drug effects , Proteasome Endopeptidase Complex/metabolism , Protein Biosynthesis/drug effects , Proteolysis/drug effects , Ubiquitin/metabolism , Amino Acids/blood , Animals , Cathepsin B/metabolism , Dietary Proteins/administration & dosage , Dietary Proteins/pharmacology , Insulin Resistance , Male , Muscle Proteins/biosynthesis , Muscle, Skeletal/enzymology , Muscle, Skeletal/metabolism , Phosphorylation , Proto-Oncogene Proteins c-akt/metabolism , Rats , Receptor, Insulin/metabolism , SKP Cullin F-Box Protein Ligases/biosynthesis , Tripartite Motif Proteins , Ubiquitin-Protein Ligases/biosynthesis
8.
Mol Cell Endocrinol ; 315(1-2): 104-12, 2010 Feb 05.
Article in English | MEDLINE | ID: mdl-19804812

ABSTRACT

Very little is known about the signaling pathways by which catecholamines exert anabolic effects on muscle protein metabolism, stimulating protein synthesis and suppressing proteolysis. The present work tested the hypothesis that epinephrine-induced inhibition of muscle proteolysis is mediated through the cAMP/Epac/PI3K-dependent pathway with the involvement of AKT and Foxo. The incubation of extensor digitorum longus (EDL) muscles from rats with epinephrine and/or insulin increased the phosphorylation of AKT and its downstream target Foxo3a, a well-known effect that prevents Foxo translocation to the nucleus and the activation of proteolysis. Similar effects on AKT/Foxo signaling were observed in muscles incubated with DBcAMP (cAMP analog). The stimulatory effect of epinephrine on AKT phosphorylation was completely blocked by wortmannin (selective PI3K inhibitor), suggesting that the epinephrine-induced activation of AKT is mediated through PI3K. As for epinephrine and DBcAMP, the incubation of muscles with 8CPT-2Me-cAMP (selective Epac agonist) reduced rates of proteolysis and increased phosphorylation levels of AKT and Foxo3a. The specific PKA agonist (N6BZ-cAMP) inhibited proteolysis and abolished the epinephrine-induced AKT and Foxo3a phosphorylation. On the other hand, inhibition of PKA by H89 further increased the phosphorylation levels of AKT and Foxo3a induced by epinephrine, DBcAMP or 8CPT-2Me-cAMP. These findings suggest that the antiproteolytic effect of the epinephrine on isolated skeletal muscle may occur through a cAMP/Epac/PI3K-dependent pathway, which leads to the phosphorylation of AKT and Foxo3a. The parallel activation of PKA-dependent pathway also inhibits proteolysis and seems to limit the stimulatory effect of cAMP on AKT/Foxo3a signaling.


Subject(s)
Cyclic AMP/metabolism , Epinephrine/pharmacology , Guanine Nucleotide Exchange Factors/metabolism , Muscle, Skeletal , Phosphatidylinositol 3-Kinases/metabolism , Signal Transduction/physiology , Androstadienes/metabolism , Animals , Bucladesine/metabolism , Cyclic AMP/analogs & derivatives , Forkhead Box Protein O3 , Forkhead Transcription Factors/genetics , Forkhead Transcription Factors/metabolism , Guanine Nucleotide Exchange Factors/genetics , Humans , Insulin/metabolism , Male , Muscle, Skeletal/drug effects , Muscle, Skeletal/physiology , Phosphoinositide-3 Kinase Inhibitors , Protein Kinase Inhibitors/metabolism , Rats , Rats, Wistar , Ribonucleosides/metabolism , Wortmannin
9.
Muscle Nerve ; 38(2): 1027-35, 2008 Aug.
Article in English | MEDLINE | ID: mdl-18663737

ABSTRACT

The present work investigated the role of the sympathetic nervous system (SNS) in the control of protein degradation in skeletal muscles from rats with streptozotocin (STZ)-induced diabetes. Diabetes (1, 3, and 5 days after STZ) induced a significant increase in the norepinephrine content of soleus and EDL muscles, but it did not affect plasma catecholamine levels. Chemical sympathectomy induced by guanethidine (100 mg/kg body weight, for 1 or 2 days) reduced muscle norepinephrine content to negligible levels (less than 5%), decreased plasma epinephrine concentration, and further increased the high rate of protein degradation in muscles from acutely diabetic rats. The rise in the rate of proteolysis (nmol.mg wet wt(-1).2h(-1)) in soleus from 1-day diabetic sympathectomized rats was associated with increased activities of lysosomal (0.127 +/- 0.008 vs. 0.086 +/- 0.013 in diabetic control) and ubiquitin (Ub)-proteasome-dependent proteolytic pathways (0.154 +/- 0.007 vs. 0.121 +/- 0.006 in diabetic control). Increases in Ca2+-dependent (0.180 +/- 0.007 vs. 0.121 +/- 0.011 in diabetic control) and Ub-proteasome-dependent proteolytic systems (0.092 +/- 0.003 vs. 0.060 +/- 0.002 in diabetic control) were observed in EDL from 1-day diabetic sympathectomized rats. The lower phosphorylation levels of AKT and Foxo3a in EDL muscles from 3-day diabetic rats were further decreased by sympathectomy. The data suggest that the SNS exerts acute inhibitory control of skeletal muscle proteolysis during the early stages of diabetes in rats, probably involving the AKT/Foxo signaling pathway.


Subject(s)
Diabetes Mellitus, Experimental/metabolism , Muscle Proteins/metabolism , Muscle, Skeletal/metabolism , Sympathectomy, Chemical , Animals , Blood Glucose/drug effects , Body Weight/drug effects , Body Weight/physiology , Calcium/metabolism , Diabetes Mellitus, Experimental/pathology , Disease Models, Animal , Epinephrine/blood , Forkhead Box Protein O3 , Forkhead Transcription Factors/metabolism , Guanethidine/toxicity , Lysosomes/metabolism , Male , Muscle, Skeletal/drug effects , Norepinephrine/metabolism , Oncogene Protein v-akt/metabolism , Proteasome Endopeptidase Complex/metabolism , Rats , Rats, Wistar , Time Factors , Ubiquitin/metabolism
10.
Am J Physiol Endocrinol Metab ; 292(3): E702-8, 2007 Mar.
Article in English | MEDLINE | ID: mdl-17077345

ABSTRACT

Previous studies from this laboratory have shown that catecholamines exert an inhibitory effect on muscle protein degradation through a pathway involving the cAMP cascade. The present work investigated the systemic effect of pentoxifylline (PTX; cAMP-phosphodiesterase inhibitor) treatment on the rate of overall proteolysis, the activity of proteolytic systems, and the process of protein synthesis in extensor digitorum longus muscles from normal and acutely diabetic rats. The direct in vitro effect of this drug on the rates of muscle protein degradation was also investigated. Muscles from diabetic rats treated with PTX showed an increase (22%) in the cAMP content and reduction in total rates of protein breakdown and in activity of Ca2+-dependent (47%) and ATP proteasome-dependent (23%) proteolytic pathways. The high content of m-calpain observed in muscles from diabetic rats was abolished by PTX treatment. The addition of PTX (10(-3) M) to the incubation medium increased the cAMP content in muscles from normal (22%) and diabetic (51%) rats and induced a reduction in the rates of overall proteolysis that was accompanied by decreased activity of the Ca2+-dependent and ATP proteasome-dependent proteolytic systems, in both groups. The in vitro addition of H-89, an inhibitor of protein kinase A (PKA), completely blocked the effect of PTX on the reduction of proteolysis in muscles from normal and diabetic rats. The present data suggest that PTX exerts a direct inhibitory effect on protein degradative systems in muscles from acutely diabetic rats, probably involving the participation of cAMP intracellular pathways and activation of PKA, independently of tumor necrosis factor-alpha inhibition.


Subject(s)
Adenosine Triphosphate/physiology , Calcium/physiology , Diabetes Mellitus, Experimental/metabolism , Muscle, Skeletal/drug effects , Pentoxifylline/pharmacology , Proteasome Endopeptidase Complex/drug effects , Protein Processing, Post-Translational/drug effects , Animals , Calcium-Binding Proteins/metabolism , Calpain/metabolism , Cyclic AMP/metabolism , Diabetes Mellitus, Experimental/blood , Male , Muscle Proteins/metabolism , Muscle, Skeletal/metabolism , Proteasome Endopeptidase Complex/physiology , Rats , Rats, Wistar , Tumor Necrosis Factor-alpha/blood
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