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1.
Biomed Pharmacother ; 179: 117303, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-39153437

RESUMEN

The role of peroxisome proliferator-activated receptor (PPAR)ß/δ in hepatic fibrosis remains a subject of debate. Here, we examined the effects of a PPARß/δ agonist on the pathogenesis of liver fibrosis and the activation of hepatic stellate cells (HSCs), the main effector cells in liver fibrosis, in response to the pro-fibrotic stimulus transforming growth factor-ß (TGF-ß). The PPARß/δ agonist GW501516 completely prevented glucose intolerance and peripheral insulin resistance, blocked the accumulation of collagen in the liver, and attenuated the expression of inflammatory and fibrogenic genes in mice fed a choline-deficient high-fat diet (CD-HFD). The antifibrogenic effect of GW501516 observed in the livers CD-HFD-fed mice could occur through an action on HSCs since primary HSCs isolated from Ppard-/- mice showed increased mRNA levels of the profibrotic gene Col1a1. Moreover, PPARß/δ activation abrogated TGF-ß1-mediated cell migration (an indicator of cell activation) in LX-2 cells (immortalized activated human HSCs). Likewise, GW501516 attenuated the phosphorylation of the main downstream intracellular protein target of TGF-ß1, suppressor of mothers against decapentaplegic (SMAD)3, as well as the levels of the SMAD3 co-activator p300 via the activation of AMP-activated protein kinase (AMPK) and the subsequent inhibition of extracellular signal-regulated kinase-1/2 (ERK1/2) in LX-2 cells. Overall, these findings uncover a new mechanism by which the activation of AMPK by a PPARß/δ agonist reduces TGF-ß1-mediated activation of HSCs and fibrosis via the reduction of both SMAD3 phosphorylation and p300 levels.


Asunto(s)
Proteínas Quinasas Activadas por AMP , Proteína p300 Asociada a E1A , Células Estrelladas Hepáticas , Cirrosis Hepática , Ratones Endogámicos C57BL , PPAR delta , PPAR-beta , Proteína smad3 , Células Estrelladas Hepáticas/metabolismo , Células Estrelladas Hepáticas/efectos de los fármacos , Células Estrelladas Hepáticas/patología , Animales , Fosforilación/efectos de los fármacos , PPAR-beta/agonistas , PPAR-beta/metabolismo , PPAR-beta/genética , Cirrosis Hepática/metabolismo , Cirrosis Hepática/patología , PPAR delta/metabolismo , PPAR delta/agonistas , PPAR delta/genética , Proteína smad3/metabolismo , Proteínas Quinasas Activadas por AMP/metabolismo , Proteína p300 Asociada a E1A/metabolismo , Masculino , Ratones , Humanos , Tiazoles/farmacología , Dieta Alta en Grasa/efectos adversos , Ratones Noqueados , Resistencia a la Insulina , Línea Celular , Factor de Crecimiento Transformador beta1/metabolismo
2.
Microbiol Spectr ; 12(6): e0007124, 2024 Jun 04.
Artículo en Inglés | MEDLINE | ID: mdl-38700321

RESUMEN

Novel antimicrobial agents are needed to combat antimicrobial resistance. This study tested novel pentafluorosulfanyl-containing triclocarban analogs for their potential antibacterial efficacy. Standard procedures were used to produce pentafluorosulfanyl-containing triclocarban analogs. Twenty new compounds were tested against seven Gram-positive and Gram-negative indicator strains as well as 10 clinical isolates for their antibacterial and antibiofilm activity. Mechanistic investigations focused on damage to cell membrane, oxidizing reduced thiols, iron-sulfur clusters, and oxidative stress to explain the compounds' activity. Safety profiles were assessed using cytotoxicity experiments in eukaryotic cell lines. Following screening, selected components had significantly better antibacterial and antibiofilm activity against Gram-positive bacteria in lower concentrations in comparison to ciprofloxacin and gentamycin. For instance, one compound had a minimum inhibitory concentration of <0.0003 mM, but ciprofloxacin had 0.08 mM. Mechanistic studies show that these novel compounds do not affect reduced thiol content, iron-sulfur clusters, or hydrogen peroxide pathways. Their impact comes from Gram-positive bacterial cell membrane damage. Tests on cell culture toxicity and host component safety showed promise. Novel diarylurea compounds show promise as Gram-positive antimicrobials. These compounds offer prospects for study and optimization. IMPORTANCE: The rise of antibiotic resistance among bacterial pathogens poses a significant threat to global health, underscoring the urgent need for novel antimicrobial agents. This study presents research on a promising class of novel compounds with potent antibacterial properties against Gram-positive bacteria, notably Staphylococcus aureus and MRSA. What sets these novel analogs apart is their superior efficacy at substantially lower concentrations compared with commonly used antibiotics like ciprofloxacin and gentamycin. Importantly, these compounds act by disrupting the bacterial cell membrane, offering a unique mechanism that could potentially circumvent existing resistance mechanisms. Preliminary safety assessments also highlight their potential for therapeutic use. This study not only opens new avenues for combating antibiotic-resistant infections but also underscores the importance of innovative chemical approaches in addressing the global antimicrobial resistance crisis.


Asunto(s)
Antibacterianos , Carbanilidas , Bacterias Grampositivas , Pruebas de Sensibilidad Microbiana , Carbanilidas/farmacología , Carbanilidas/química , Antibacterianos/farmacología , Antibacterianos/química , Bacterias Grampositivas/efectos de los fármacos , Humanos , Biopelículas/efectos de los fármacos , Bacterias Gramnegativas/efectos de los fármacos , Ciprofloxacina/farmacología
3.
Artículo en Inglés | MEDLINE | ID: mdl-38816269

RESUMEN

Abnormally increased hepatic gluconeogenesis is a significant contributor to hyperglycemia in the fasting state in patients with type 2 diabetes mellitus (T2DM) due to insulin resistance. Metformin, the most prescribed drug for the treatment of T2DM, is believed to exert its effect mainly by reducing hepatic gluconeogenesis. Here, we discuss how increased hepatic gluconeogenesis contributes to T2DM and we review newly revealed mechanisms underlying the attenuation of gluconeogenesis by metformin. In addition, we analyze the recent findings on new determinants involved in the regulation of gluconeogenesis, which might ultimately lead to the identification of novel and targeted treatment strategies for T2DM.

4.
Cell Commun Signal ; 22(1): 297, 2024 May 28.
Artículo en Inglés | MEDLINE | ID: mdl-38807218

RESUMEN

BACKGROUND: Endoplasmic reticulum (ER) stress-mediated increases in the hepatic levels of the very low-density lipoprotein (VLDL) receptor (VLDLR) promote hepatic steatosis by increasing the delivery of triglyceride-rich lipoproteins to the liver. Here, we examined whether the NAD(+)-dependent deacetylase sirtuin 1 (SIRT1) regulates hepatic lipid accumulation by modulating VLDLR levels and the subsequent uptake of triglyceride-rich lipoproteins. METHODS: Rats fed with fructose in drinking water, Sirt1-/- mice, mice treated with the ER stressor tunicamycin with or without a SIRT1 activator, and human Huh-7 hepatoma cells transfected with siRNA or exposed to tunicamycin or different inhibitors were used. RESULTS: Hepatic SIRT1 protein levels were reduced, while those of VLDLR were upregulated in the rat model of metabolic dysfunction-associated steatotic liver disease (MASLD) induced by fructose-drinking water. Moreover, Sirt1-/- mice displayed increased hepatic VLDLR levels that were not associated with ER stress, but were accompanied by an increased expression of hypoxia-inducible factor 1α (HIF-1α)-target genes. The pharmacological inhibition or gene knockdown of SIRT1 upregulated VLDLR protein levels in the human Huh-7 hepatoma cell line, with this increase abolished by the pharmacological inhibition of HIF-1α. Finally, SIRT1 activation prevented the increase in hepatic VLDLR protein levels in mice treated with the ER stressor tunicamycin. CONCLUSIONS: Overall, these findings suggest that SIRT1 attenuates fatty liver development by modulating hepatic VLDLR levels.


Asunto(s)
Hígado , Receptores de LDL , Sirtuina 1 , Animales , Sirtuina 1/metabolismo , Sirtuina 1/genética , Humanos , Hígado/metabolismo , Hígado/efectos de los fármacos , Receptores de LDL/metabolismo , Receptores de LDL/genética , Ratones , Masculino , Estrés del Retículo Endoplásmico/efectos de los fármacos , Ratas , Línea Celular Tumoral , Ratones Noqueados , Hígado Graso/metabolismo , Hígado Graso/genética , Hígado Graso/patología , Ratones Endogámicos C57BL , Tunicamicina/farmacología , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Ratas Sprague-Dawley
5.
Int J Mol Sci ; 25(8)2024 Apr 18.
Artículo en Inglés | MEDLINE | ID: mdl-38674052

RESUMEN

The metabolic and immune systems are complex networks of organs, cells, and proteins that are involved in the extraction of energy from food; this is to run complex cellular processes and defend the body against infections while protecting its own tissues, respectively [...].


Asunto(s)
Inflamación , Receptores Activados del Proliferador del Peroxisoma , Humanos , Inflamación/metabolismo , Inflamación/genética , Animales , Receptores Activados del Proliferador del Peroxisoma/metabolismo , Receptores Activados del Proliferador del Peroxisoma/genética , Regulación de la Expresión Génica
6.
Int J Mol Sci ; 25(5)2024 Feb 23.
Artículo en Inglés | MEDLINE | ID: mdl-38473843

RESUMEN

Gadd45 genes have been implicated in survival mechanisms, including apoptosis, autophagy, cell cycle arrest, and DNA repair, which are processes related to aging and life span. Here, we analyzed if the deletion of Gadd45a activates pathways involved in neurodegenerative disorders such as Alzheimer's Disease (AD). This study used wild-type (WT) and Gadd45a knockout (Gadd45a-/-) mice to evaluate AD progression. Behavioral tests showed that Gadd45a-/- mice presented lower working and spatial memory, pointing out an apparent cognitive impairment compared with WT animals, accompanied by an increase in Tau hyperphosphorylation and the levels of kinases involved in its phosphorylation in the hippocampus. Moreover, Gadd45a-/- animals significantly increased the brain's pro-inflammatory cytokines and modified autophagy markers. Notably, neurotrophins and the dendritic spine length of the neurons were reduced in Gadd45a-/- mice, which could contribute to the cognitive alterations observed in these animals. Overall, these findings demonstrate that the lack of the Gadd45a gene activates several pathways that exacerbate AD pathology, suggesting that promoting this protein's expression or function might be a promising therapeutic strategy to slow down AD progression.


Asunto(s)
Enfermedad de Alzheimer , Disfunción Cognitiva , Ratones , Animales , Enfermedad de Alzheimer/metabolismo , Ratones Transgénicos , Proteínas tau/metabolismo , Disfunción Cognitiva/metabolismo , Hipocampo/metabolismo , Cognición , Modelos Animales de Enfermedad
7.
Clin Investig Arterioscler ; 36(2): 78-79, 2024.
Artículo en Inglés, Español | MEDLINE | ID: mdl-38402024
8.
Metabolism ; 152: 155772, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38176644

RESUMEN

INTRODUCTION: The levels of the cellular energy sensor AMP-activated protein kinase (AMPK) have been reported to be decreased via unknown mechanisms in the liver of mice deficient in growth differentiation factor 15 (GDF15). This stress response cytokine regulates energy metabolism mainly by reducing food intake through its hindbrain receptor GFRAL. OBJECTIVE: To examine how GDF15 regulates AMPK. METHODS: Wild-type and Gdf15-/- mice, mouse primary hepatocytes and the human hepatic cell line Huh-7 were used. RESULTS: Gdf15-/- mice showed glucose intolerance, reduced hepatic phosphorylated AMPK levels, increased levels of phosphorylated mothers against decapentaplegic homolog 3 (SMAD3; a mediator of the fibrotic response), elevated serum levels of transforming growth factor (TGF)-ß1, as well as upregulated gluconeogenesis and fibrosis. In line with these observations, recombinant (r)GDF15 promoted AMPK activation and reduced the levels of phosphorylated SMAD3 and the markers of gluconeogenesis and fibrosis in the liver of mice and in mouse primary hepatocytes, suggesting that these effects may be independent of GFRAL. Pharmacological inhibition of SMAD3 phosphorylation in Gdf15-/- mice prevented glucose intolerance, the deactivation of AMPK and the increase in the levels of proteins involved in gluconeogenesis and fibrosis, suggesting that overactivation of the TGF-ß1/SMAD3 pathway is responsible for the metabolic alterations in Gdf15-/- mice. CONCLUSIONS: Overall, these findings indicate that GDF15 activates AMPK and inhibits gluconeogenesis and fibrosis by lowering the activity of the TGF-ß1/SMAD3 pathway.


Asunto(s)
Intolerancia a la Glucosa , Factor de Crecimiento Transformador beta1 , Humanos , Proteínas Quinasas Activadas por AMP/metabolismo , Fibrosis , Gluconeogénesis , Intolerancia a la Glucosa/metabolismo , Factor 15 de Diferenciación de Crecimiento/genética , Hígado/metabolismo , Transducción de Señal , Proteína smad3 , Factor de Crecimiento Transformador beta1/metabolismo
9.
Med Res Rev ; 44(4): 1375-1403, 2024 07.
Artículo en Inglés | MEDLINE | ID: mdl-38264852

RESUMEN

The growth arrest and DNA damage inducible (GADD)45 family includes three small and ubiquitously distributed proteins (GADD45A, GADD45B, and GADD45G) that regulate numerous cellular processes associated with stress signaling and injury response. Here, we provide a comprehensive review of the current literature investigating GADD45A, the first discovered member of the family. We first depict how its levels are regulated by a myriad of genotoxic and non-genotoxic stressors, and through the combined action of intricate transcriptional, posttranscriptional, and even, posttranslational mechanisms. GADD45A is a recognized tumor suppressor and, for this reason, we next summarize its role in cancer, as well as the different mechanisms by which it regulates cell cycle, DNA repair, and apoptosis. Beyond these most well-known actions, GADD45A may also influence catabolic and anabolic pathways in the liver, adipose tissue and skeletal muscle, among others. Not surprisingly, GADD45A may trigger AMP-activated protein kinase activity, a master regulator of metabolism, and is known to act as a transcriptional coregulator of numerous nuclear receptors. GADD45A has also been reported to display a cytoprotective role by regulating inflammation, fibrosis and oxidative stress in several organs and tissues, and is regarded an important contributor for the development of heart failure. Overall data point to that GADD45A may play an important role in metabolic, neurodegenerative and cardiovascular diseases, and also autoimmune-related disorders. Thus, the potential mechanisms by which dysregulation of GADD45A activity may contribute to the progression of these diseases are also reviewed below.


Asunto(s)
Proteínas de Ciclo Celular , Humanos , Animales , Proteínas de Ciclo Celular/metabolismo , Neoplasias/metabolismo , Proteínas Nucleares/metabolismo , Apoptosis , Proteinas GADD45
10.
Cell Commun Signal ; 21(1): 326, 2023 11 13.
Artículo en Inglés | MEDLINE | ID: mdl-37957724

RESUMEN

BACKGROUND: The placentas from newborns that are small for gestational age (SGA; birth weight < -2 SD for gestational age) may display multiple pathological characteristics. A key determinant of fetal growth and, therefore, birth weight is placental amino acid transport, which is under the control of the serine/threonine kinase mechanistic target of rapamycin (mTOR). The effects of endoplasmic reticulum (ER) stress on the mTOR pathway and the levels of amino acid transporters are not well established. METHODS: Placentas from SGA and appropriate for gestational age (AGA) newborns and the human placental BeWo cell line exposed to the ER stressor tunicamycin were used. RESULTS: We detected a significant increase in the levels of C/EBP homologous protein (CHOP) in the placentas from SGA newborns compared with those from AGA newborns, while the levels of other ER stress markers were barely affected. In addition, placental mTOR Complex 1 (mTORC1) activity and the levels of the mature form of the amino acid transporter sodium-coupled neutral amino acid transporter 2 (SNAT2) were also reduced in the SGA group. Interestingly, CHOP has been reported to upregulate growth arrest and DNA damage-inducible protein 34 (GADD34), which in turn suppresses mTORC1 activity. The GADD34 inhibitor guanabenz attenuated the increase in CHOP protein levels and the reduction in mTORC1 activity caused by the ER stressor tunicamycin in the human placental cell line BeWo, but it did not recover mature SNAT2 protein levels, which might be reduced as a result of defective glycosylation. CONCLUSIONS: Collectively, these data reveal that GADD34A activity and glycosylation are key factors controlling mTORC1 signaling and mature SNAT2 levels in trophoblasts, respectively, and might contribute to the SGA condition. Video Abstract.


Asunto(s)
Sistema de Transporte de Aminoácidos A , Placenta , Serina-Treonina Quinasas TOR , Factor de Transcripción CHOP , Femenino , Humanos , Recién Nacido , Embarazo , Peso al Nacer , Retardo del Crecimiento Fetal/genética , Retardo del Crecimiento Fetal/metabolismo , Edad Gestacional , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Placenta/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Tunicamicina/farmacología , Regulación hacia Arriba , Factor de Transcripción CHOP/genética , Sistema de Transporte de Aminoácidos A/genética
11.
Biomed Pharmacother ; 168: 115667, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-37826940

RESUMEN

Soluble epoxide hydrolase (sEH) is a drug target with the potential for therapeutic utility in the areas of inflammation, neurodegenerative disease, chronic pain, and diabetes, among others. Proteolysis-targeting chimeras (PROTACs) molecules offer new opportunities for targeting sEH, due to its capacity to induce its degradation. Here, we describe that the new ALT-PG2, a PROTAC that degrades sEH protein in the human hepatic Huh-7 cell line, in isolated mouse primary hepatocytes, and in the liver of mice. Remarkably, sEH degradation caused by ALT-PG2 was accompanied by an increase in the phosphorylated levels of AMP-activated protein kinase (AMPK), while phosphorylated extracellular-signal-regulated kinase 1/2 (ERK1/2) was reduced. Consistent with the key role of these kinases on endoplasmic reticulum (ER) stress, ALT-PG2 attenuated the levels of ER stress and inflammatory markers. Overall, the findings of this study indicate that targeting sEH with degraders is a promising pharmacological strategy to promote AMPK activation and to reduce ER stress and inflammation.


Asunto(s)
Epóxido Hidrolasas , Enfermedades Neurodegenerativas , Humanos , Animales , Ratones , Proteínas Quinasas Activadas por AMP/metabolismo , Inflamación , Estrés del Retículo Endoplásmico/fisiología
12.
Biomed Pharmacother ; 167: 115623, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-37783154

RESUMEN

Elafibranor is a dual peroxisome proliferator-activated receptor (PPAR)α and ß/δ agonist that has reached a phase III clinical trial for the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we examined the effects of elafibranor in mice fed a choline-deficient high-fat diet (CD-HFD), a model of metabolic dysfunction-associated steatohepatitis (MASH) that presents obesity and insulin resistance. Our findings revealed that elafibranor treatment ameliorated steatosis, inflammation, and fibrogenesis in the livers of CD-HFD-fed mice. Unexpectedly, elafibranor also increased the levels of the epithelial-mesenchymal transition (EMT)-promoting protein S100A4 via PPARß/δ activation. The increase in S100A4 protein levels caused by elafibranor was accompanied by changes in the levels of markers associated with the EMT program. The S100A4 induction caused by elafibranor was confirmed in the BRL-3A rat liver cells and a mouse primary hepatocyte culture. Furthermore, elafibranor reduced the levels of ASB2, a protein that promotes S100A4 degradation, while ASB2 overexpression prevented the stimulating effect of elafibranor on S100A4. Collectively, these findings reveal an unexpected hepatic effect of elafibranor on increasing S100A4 and promoting the EMT program.


Asunto(s)
Enfermedad del Hígado Graso no Alcohólico , PPAR delta , PPAR-beta , Animales , Ratones , Ratas , Dieta Alta en Grasa , Transición Epitelial-Mesenquimal , Hígado , Enfermedad del Hígado Graso no Alcohólico/metabolismo , PPAR delta/metabolismo , PPAR-beta/agonistas , PPAR-beta/metabolismo , PPAR-beta/uso terapéutico
13.
Molecules ; 28(14)2023 Jul 17.
Artículo en Inglés | MEDLINE | ID: mdl-37513338

RESUMEN

Targeting growth differentiation factor 15 (GDF15) is a recent strategy for the treatment of obesity and type 2 diabetes mellitus (T2DM). Here, we designed, synthesized, and pharmacologically evaluated in vitro a novel series of AMPK activators to upregulate GDF15 levels. These compounds were structurally based on the (1-dibenzylamino-3-phenoxy)propan-2-ol structure of the orphan ubiquitin E3 ligase subunit protein Fbxo48 inhibitor, BC1618. This molecule showed a better potency than metformin, increasing GDF15 mRNA levels in human Huh-7 hepatic cells. Based on BC1618, structural modifications have been performed to create a collection of diversely substituted new molecules. Of the thirty-five new compounds evaluated, compound 21 showed a higher increase in GDF15 mRNA levels compared with BC1618. Metformin, BC1618, and compound 21 increased phosphorylated AMPK, but only 21 increased GDF15 protein levels. Overall, these findings indicate that 21 has a unique capacity to increase GDF15 protein levels in human hepatic cells compared with metformin and BC1618.


Asunto(s)
Diabetes Mellitus Tipo 2 , Metformina , Humanos , Proteínas Quinasas Activadas por AMP , Factor 15 de Diferenciación de Crecimiento/genética , Factor 15 de Diferenciación de Crecimiento/metabolismo , Metformina/farmacología , ARN Mensajero
14.
Trends Pharmacol Sci ; 44(7): 457-473, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-37188578

RESUMEN

Metformin is the most prescribed drug for the treatment of type 2 diabetes mellitus (T2DM), but its mechanism of action has not yet been completely elucidated. Classically, the liver has been considered the major site of action of metformin. However, over the past few years, advances have unveiled the gut as an additional important target of metformin, which contributes to its glucose-lowering effect through new mechanisms of action. A better understanding of the mechanistic details of metformin action in the gut and the liver and its relevance in patients remains the challenge of present and future research and may impact drug development for the treatment of T2DM. Here, we offer a critical analysis of the current status of metformin-driven multiorgan glucose-lowering effects.


Asunto(s)
Diabetes Mellitus Tipo 2 , Metformina , Humanos , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Metformina/farmacología , Metformina/uso terapéutico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hígado , Glucosa
15.
Pharmacol Res ; 187: 106578, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-36435271

RESUMEN

BACKGROUND AND AIMS: Metformin, the most prescribed drug for the treatment of type 2 diabetes mellitus, has been recently reported to promote weight loss by upregulating the anorectic cytokine growth differentiation factor 15 (GDF15). Since the antidiabetic effects of metformin are mostly mediated by the activation of AMPK, a key metabolic sensor in energy homeostasis, we examined whether the activation of this kinase by metformin was dependent on GDF15. METHODS: Cultured hepatocytes and myotubes, and wild-type and Gdf15-/- mice were utilized in a series of studies to investigate the involvement of GDF15 in the activation of AMPK by metformin. RESULTS: A low dose of metformin increased GDF15 levels without significantly reducing body weight or food intake, but it ameliorated glucose intolerance and activated AMPK in the liver and skeletal muscle of wild-type mice but not Gdf15-/- mice fed a high-fat diet. Cultured hepatocytes and myotubes treated with metformin showed AMPK-mediated increases in GDF15 levels independently of its central receptor GFRAL, while Gdf15 knockdown blunted the effect of metformin on AMPK activation, suggesting that AMPK is required for the metformin-mediated increase in GDF15, which in turn is needed to sustain the full activation of this kinase independently of the CNS. CONCLUSION: Overall, these findings uncover a novel mechanism through which GDF15 upregulation by metformin is involved in achieving and sustaining full AMPK activation by this drug independently of the CNS.


Asunto(s)
Proteínas Quinasas Activadas por AMP , Diabetes Mellitus Tipo 2 , Factor 15 de Diferenciación de Crecimiento , Hipoglucemiantes , Metformina , Animales , Ratones , Proteínas Quinasas Activadas por AMP/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Factor 15 de Diferenciación de Crecimiento/genética , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Metformina/farmacología , Metformina/uso terapéutico , Retroalimentación Fisiológica
16.
Life Sci ; 311(Pt A): 121136, 2022 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-36349603

RESUMEN

AIMS: Endoplasmic reticulum (ER) stress poses a new pathological mechanism for metabolic-associated fatty liver disease (MAFLD). MAFLD treatment has encompassed renin-angiotensin system (RAS) blockers and aerobic exercise training, but their association with hepatic ER stress is not well known. Therefore, we aimed to compare the effects of hepatic RAS modulation by enalapril and/or aerobic exercise training over ER stress in MAFLD caused by a diet-induced obesity model. MAIN METHODS: C57BL/6 mice were fed a standard-chow (CON, n = 10) or a high-fat (HF, n = 40) diet for 8 weeks. HF group was then randomly divided into: HF (n = 10), HF + Enalapril (EN, n = 10), HF + Aerobic exercise training (AET, n = 10), and HF + Enalapril+Aerobic exercise training (EN + AET, n = 10) for 8 more weeks. Body mass (BM) and glucose profile were evaluated. In the liver, ACE and ACE2 activity, morphology, lipid profile, and protein expression of ER stress and metabolic markers were assessed. KEY FINDINGS: Both enalapril and aerobic exercise training provided comparable efficacy in improving diet-induced MAFLD through modulation of RAS and ER stress, but the latter was more efficient in improving ER stress, liver damage and metabolism. SIGNIFICANCE: This is the first study to evaluate pharmacological (enalapril) and non-pharmacological (aerobic exercise training) RAS modulators associated with ER stress in a diet-induced MAFLD model.


Asunto(s)
Enalapril , Estrés del Retículo Endoplásmico , Animales , Ratones , Biomarcadores/metabolismo , Dieta , Enalapril/farmacología , Ratones Endogámicos C57BL
17.
Trends Endocrinol Metab ; 33(11): 741-754, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-36151002

RESUMEN

Although a large number of drugs are available for the treatment of type 2 diabetes mellitus (T2DM), many patients do not achieve adequate disease control despite adhering to medication. Recent findings indicate that the pharmacological modulation of the stress-induced cytokine growth differentiation factor 15 (GDF15) shows promise for the treatment of T2DM. GDF15 suppresses appetite and reduces inflammation, increases thermogenesis and lipid catabolism, sustains AMP-activated protein kinase (AMPK) activity, and ameliorates insulin resistance and hepatic steatosis. In addition, circulating GDF15 levels are elevated in response to several antidiabetic drugs, including metformin, with GDF15 mediating some of their effects. Here, we review the mechanistic insights into the beneficial effects of recently explored therapeutic approaches that target GDF15 for the treatment of T2DM.


Asunto(s)
Diabetes Mellitus Tipo 2 , Metformina , Humanos , Factor 15 de Diferenciación de Crecimiento/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Proteínas Quinasas Activadas por AMP/metabolismo , Hipoglucemiantes/uso terapéutico , Metformina/farmacología , Metformina/uso terapéutico , Lípidos
18.
Front Pharmacol ; 13: 902047, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35899125

RESUMEN

Peroxisome proliferator-activated receptor ß/δ (PPARß/δ), the most PPAR abundant isotype in the central nervous system, is involved in microglial homeostasis and metabolism, whose disturbances have been demonstrated to play a key role in memory impairment. Although PPARß/δ function is well-established in metabolism, its contribution to neuronal and specifically memory process is underexplored. Therefore, the aim of the study is to determine the role of PPARß/δ in the neuropathological pathways involved in memory impairment and as to whether a risk factor implicated in memory loss such as obesity modulates neuropathological markers. To carry out this study, 6-month-old total knock-out for the Ppard gene male mice with C57BL/6X129/SV background (PPARß/δ-/-) and wild-type (WT) littermates with the same genetic background were used. Animals were fed, after the weaning (at 21 days old), and throughout their growth, either conventional chow (CT) or a palmitic acid-enriched diet (HFD). Thus, four groups were defined: WT CT, WT HFD, PPARß/δ-/- CT, and PPARß/δ-/- HFD. Before sacrifice, novel object recognition test (NORT) and glucose and insulin tolerance tests were performed. After that, animals were sacrificed by intracardiac perfusion or cervical dislocation. Different techniques, such as GolgiStain kit or immunofluorescence, were used to evaluate the role of PPARß/δ in memory dysfunction. Our results showed a decrease in dendritic spine density and synaptic markers in PPARß/δ-/- mice, which were corroborated in the NORT. Likewise, our study demonstrated that the lack of PPARß/δ receptor enhances gliosis in the hippocampus, contributing to astrocyte and microglial activation and to the increase in neuroinflammatory biomarkers. Additionally, alterations in the hippocampal insulin receptor pathway were found. Interestingly, while some of the disturbances caused by the lack of PPARß/δ were not affected by feeding the HFD, others were exacerbated or required the combination of both factors. Taken together, the loss of PPARß/δ-/- affects neuronal and synaptic structure, contributing to memory dysfunction, and they also present this receptor as a possible new target for the treatment of memory impairment.

19.
20.
Cell Commun Signal ; 20(1): 53, 2022 04 15.
Artículo en Inglés | MEDLINE | ID: mdl-35428325

RESUMEN

BACKGROUND: Peroxisome proliferator-activated receptor γ (PPARγ) coactivator 1α (PGC-1α) downregulation in skeletal muscle contributes to insulin resistance and type 2 diabetes mellitus. Here, we examined the effects of endoplasmic reticulum (ER) stress on PGC-1α levels in muscle and the potential mechanisms involved. METHODS: The human skeletal muscle cell line LHCN-M2 and mice exposed to different inducers of ER stress were used. RESULTS: Palmitate- or tunicamycin-induced ER stress resulted in PGC-1α downregulation and enhanced expression of activating transcription factor 4 (ATF4) in human myotubes and mouse skeletal muscle. Overexpression of ATF4 decreased basal PCG-1α expression, whereas ATF4 knockdown abrogated the reduction of PCG-1α caused by tunicamycin in myotubes. ER stress induction also activated mammalian target of rapamycin (mTOR) in myotubes and reduced the nuclear levels of cAMP response element-binding protein (CREB)-regulated transcription co-activator 2 (CRTC2), a positive modulator of PGC-1α transcription. The mTOR inhibitor torin 1 restored PCG-1α and CRTC2 protein levels. Moreover, siRNA against S6 kinase, an mTORC1 downstream target, prevented the reduction in the expression of CRTC2 and PGC-1α caused by the ER stressor tunicamycin. CONCLUSIONS: Collectively, these findings demonstrate that ATF4 and the mTOR-CRTC2 axis regulates PGC-1α transcription under ER stress conditions in skeletal muscle, suggesting that its inhibition might be a therapeutic target for insulin resistant states. Video Abstract.


Asunto(s)
Factor de Transcripción Activador 4 , Diabetes Mellitus Tipo 2 , Estrés del Retículo Endoplásmico , Músculo Esquelético , Serina-Treonina Quinasas TOR , Factores de Transcripción , Factor de Transcripción Activador 4/metabolismo , Animales , Diabetes Mellitus Tipo 2/metabolismo , Regulación hacia Abajo , Ratones , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Factores de Transcripción/metabolismo , Tunicamicina/metabolismo , Tunicamicina/farmacología
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