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The phenotypic switch of vascular smooth cells (VSMCs) from a contractile to a synthetic state is associated with the development and progression of aortic aneurysm (AA). However, the mechanism underlying this process remains unclear. In this issue of the JCI, Song et al. identified SLC44A2 as a regulator of the phenotypic switch in VSMCs. Inhibition of SLC44A2 facilitated the switch to the synthetic state, contributing to the development of AA. Mechanistically, SLC44A2 interacted with NRP1 and ITGB3 to activate the TGF-[beta]/SMAD signaling pathway, resulting in VSMCs with a contractile phenotype. Furthermore, VSMC-specific SLC44A2 overexpression by genetic or pharmacological manipulation reduced AA in mouse models. These findings suggest the potential of targeting the SLC44A2 signaling pathway for AA prevention and treatment., Aortic aneurysm and the phenotypic switch of VSMCs Aortic aneurysm (AA) is characterized by a permanently localized enlargement or expansion of the aorta, involving vascular inflammation and damage to the [...]

There remains a critical need to define molecular pathways underlying sarcopenia to identify putative therapeutic targets. Research in the mechanisms of aging and sarcopenia relies heavily on preclinical rodent models. In this issue of the JCI, Kerr et al. implemented a clinically-relevant sarcopenia classification system of aged C57BL/6J mice, capturing sarcopenia prevalence across both sexes. The authors performed detailed physiological, molecular, and energetic analyses and demonstrated that mitochondrial biogenesis, oxidative capacity, and AMPK-autophagy signaling decreased as sarcopenia progressed in male mice. Sarcopenia was less prevalent in female mice with fewer alterations compared with the male-affected processes. The findings highlight factors beyond age as necessary for classifying the sarcopenic phenotype in rodent models, reveal sexual dimorphism across the trajectory of age-related declines in muscle mass and function in a commonly used rodent model, and provide insight into sex-dependent molecular alterations associated with sarcopenia progression., Establishing a mouse sarcopenia designation Conserved across a majority of mammalian species, sarcopenia is the age-related loss of skeletal muscle mass and function, which is strongly predictive of mortality (1). [...]

A disturbed balance between excitation and inhibition (E/I balance) is increasingly recognized as a key driver of neurodegeneration in multiple sclerosis (MS), a chronic inflammatory disease of the central nervous system. To understand how chronic hyperexcitability contributes to neuronal loss in MS, we transcriptionally profiled neurons from mice lacking inhibitory metabotropic glutamate signaling with shifted E/I balance and increased vulnerability to inflammation- induced neurodegeneration. This revealed a prominent induction of the nuclear receptor NR4A2 in neurons. Mechanistically, NR4A2 increased susceptibility to excitotoxicity by stimulating continuous VGF secretion leading to glycolysis-dependent neuronal cell death. Extending these findings to people with MS (pwMS), we observed increased VGF levels in serum and brain biopsies. Notably, neuron-specific deletion of Vgf in a mouse model of MS ameliorated neurodegeneration. These findings underscore the detrimental effect of a persistent metabolic shift driven by excitatory activity as a fundamental mechanism in inflammation-induced neurodegeneration., Introduction Inflammation-induced neurodegeneration is the principal driver of disease progression and the accumulation of neurological disabilities in people with multiple sclerosis (pwMS) (1, 2), the most prevalent inflammatory disease of [...]

T cells rewire their metabolic activities to meet the demand of immune responses, but how to coordinate the immune response by metabolic regulators in activated T cells is unknown. Here, we identified autocrine VEGF-B as a metabolic regulator to control lipid synthesis and maintain the integrity of the mitochondrial inner membrane for the survival of activated T cells. Disruption of autocrine VEGF-B signaling in T cells reduced cardiolipin mass, resulting in mitochondrial damage, with increased apoptosis and reduced memory development. The addition of cardiolipin or modulating VEGF-B signaling improved T cell mitochondrial fitness and survival. Autocrine VEGF-B signaling through GA-binding protein [alpha] (GABP[alpha]) induced sentrin/SUMO-specific protease 2 (SENP2) expression, which further de-SUMOylated PPAR[gamma] and enhanced phospholipid synthesis, leading to a cardiolipin increase in activated T cells. These data suggest that autocrine VEGF-B mediates a signal to coordinate lipid synthesis and mitochondrial fitness with T cell activation for survival and immune response. Moreover, autocrine VEGF-B signaling in T cells provides a therapeutic target against infection and tumors as well as an avenue for the treatment of autoimmune diseases., Introduction T cells rewire metabolic activity to meet their own activation demand in response to antigens (1-4). Glucose metabolism in T cells, which increases glucose anabolic metabolism and biomass accumulation [...]

Tissue fibrosis remains unamenable to meaningful therapeutic interventions and is the primary cause of chronic graft failure after organ transplantation. Eukaryotic translation initiation factor (eIF4E), a key translational regulator, serves as convergent target of multiple upstream profibrotic signaling pathways that contribute to mesenchymal cell (MC) activation. Here, we investigate the role of MAP kinase-interacting serine/threonine kinase-induced (MNK-induced) direct phosphorylation of eIF4E at serine 209 (Ser209) in maintaining fibrotic transformation of MCs and determine the contribution of the MNK/ eIF4E pathway to the pathogenesis of chronic lung allograft dysfunction (CLAD). MCs from patients with CLAD demonstrated constitutively higher eIF4E phosphorylation at Ser209, and eIF4E phospho-Ser209 was found to be critical in regulating key fibrogenic protein autotaxin, leading to sustained p-catenin activation and profibrotic functions of CLAD MCs. MNK1 signaling was upregulated in CLAD MCs, and genetic or pharmacologic targeting of MNK1 activity inhibited eIF4E phospho- Ser209 and profibrotic functions of CLAD MCs in vitro. Treatment with an MNK1/2 inhibitor (eFT-508) abrogated allograft fibrosis in an orthotopic murine lung-transplant model. Together these studies identify what we believe is a previously unrecognized MNK/ eIF4E/ATX/[beta]-catenin signaling pathway of fibrotic transformation of MCs and present the first evidence, to our knowledge, for the utility of MNK inhibitors in fibrosis., Introduction Lung transplantation has the worst long-term prognosis among all solid-organ transplantations, with a 10-year survival of only 20% (1). The major cause of these poor long-term outcomes is progressive [...]

Methotrexate (MTX) is an antineoplastic and anti-inflammatory agent, which is used in severe diseases. Its use should be limited due to side effects such as nephrotoxicity, myelotoxicity, and hepatotoxicity. Nebivolol (NBV), which is a beta-blocker used in the treatment of hypertension, also contributes to vasodilation in tissues by activating the endothelial nitric oxide synthase (eNOS) enzyme. The purpose of this study is to research the effect of NBV on MTX- induced nephrotoxicity through the AKT1/hypoxia-inducible factor 1-alpha (Hif-1[alpha])/eNOS signaling pathway. The rats were randomly divided into three groups of eight each. The groups were control, MTX, and MTX + NBV. A single dose of 20 mg/kg MTX was given intraperitoneally to the rats on the first day of the study and 10 mg/kg NBV was given orally to the treatment group for 7 days. At the end of the study, rats' blood and kidney tissues were taken for histopathological, immunohistochemical, and biochemical examinations. MTX administration significantly decreased the expression levels of AKT1, eNOS, and Hif-1[alpha] compared with the control group (p < 0.001 for all), and NBV treatment increased these values compared with the MTX group (p < 0.001 for all). In conclusion, NBV treatment ameliorated the MTX-induced nephrotoxicity via AKT1/Hif-1[alpha]/eNOS signaling pathway. Keywords: AKT1/Hif-1[alpha]/eNOS, inflammation, methotrexate, nebivolol, nephrotoxicity, oxidative stress, Introduction Methotrexate (MTX) is an agent with a dose-dependent effect used as an antineoplastic and anti-inflammatory drug in serious diseases (Cronstein and Aune 2020). Its use should be limited due [...]

Obesity is a metabolic syndrome characterized by abnormal lipid deposition and energy imbalance. CD38 is a single-chain transmembrane glycoprotein widely expressed in a variety of cell types. The roles of skeletal muscle and brown fat in CD38 deficiency under HFD-induced obesity remain unknown. In this study, we established obesity model with HFD and examined the changes in metabolites with metabonomics. Our results showed that CD38 expression was increased in muscle and brown fat after HFD treatment. Moreover, the results of metabonomics showed that CD38 deficiency significantly altered the metabolites in energy metabolism, cofactor generation, and redox homeostasis. Furthermore, CD38 deficiency reduced the expressions of NADPH oxidase 2 and FASN in mRNA level. We found that the expressions of Sirt1, Sirt3, and PGC1[alpha] were upregulated in CD38-deficient muscle tissue. In brown fat, the Sirt1-3, cell death inducing DFFA-like effector A, ELOVL3, and Di[O.sub.2] expressions were increased in CD38-deficient mice. Our results showed the uncoupling protein 1 expression was upregulated. And [NAD.sup.+] supplementation increased the expression of Sirt1 and PGC1[alpha] after palmitic acid treatment. Taken together, our results demonstrated that the protection of CD38 deficiency on HFD-induced obesity was related to the inhibition of oxidative stress and increasing energy expenditure via activating [NAD.sup.+]/Sirtuins signaling pathways in muscle and brown fat. Keywords: CD38, Sirt1, energy expenditure, PGC1[alpha], Introduction Obesity is a chronic metabolic disease caused by the interaction of genetic and environmental factors. Over the past ~40 years, the prevalence of obesity has increased in pandemic dimensions [...]

Prostate cancer (PC) is a clinically and biologically heterogeneous disease that lacks effective treatment. Heat shock protein B8 (HSPB8) is an important factor in the progression of various types of cancer. However, the clinical significance and biological role of HSPB8 in PC are still unclear. In this study, we determined HSPB8 expression in PC tissues by immunohistochemical staining and explored the in vitro functions of HSPB8 using HSPB8 knockdown DU145 and LNcap PC cell lines. The in vivo effect of HSPB8 was explored by a subcutaneous xenograft mice model. The human phospho-kinase array and signal transducer and activator of transcription (STAT) 3 activator were utilized to explore the potential mechanism of HSPB8-induced PC progression. As a result, we found that HSPB8 was abundantly expressed in PC tissues and cell lines. HSPB8 knockdown inhibited cell proliferation and migration, promoted apoptosis and cycle repression, as well as weakened tumorigenesis ability. Mechanistically, we demonstrated that HSPB8 facilitates the malignant phenotypes of PC by activating the Janus kinase/STAT3 signaling pathway. These results proposed that HSPB8 seems to be an attractive therapeutic target for PC patients. Key words: PC, HSPB8, malignant phenotype, JAK/STAT3 signaling pathway, Introduction Prostate cancer (PC) is an epithelial malignancy of the prostate gland, which is the second leading cause of cancerrelated death in men (Siegel et al. 2020). At present, patients [...]

Chronic kidney disease (CKD) is associated with a higher risk of atrial fibrillation (AF). The mechanistic link between CKD and AF remains elusive. IL-1[beta], a main effector of NLR family pyrin domain-containing 3 (NLRP3) inflammasome activation, is a key modulator of conditions associated with inflammation, such as AF and CKD. Circulating IL-1[beta] levels were elevated patients with CKD who had AF (versus patients with CKD in sinus rhythm). Moreover, NLRP3 activity was enhanced in atria of patients with CKD. To elucidate the role of NLRP3/IL- 1[beta] signaling in the pathogenesis of CKD-induced AF, [Nlrp3.sup.-/-] and WT mice were subjected to a 2-stage subtotal nephrectomy protocol to induce CKD. Four weeks after surgery, IL-1[beta] levels in serum and atrial tissue were increased in WT CKD (WT-CKD) mice versus sham-operated WT (WT-sham) mice. The increased susceptibility to pacing-induced AF and the longer AF duration in WT-CKD mice were associated with an abbreviated atrial effective refractory period, enlarged atria, and atrial fibrosis. Genetic inhibition of NLRP3 in [Nlrp3.sup.-/-] mice or neutralizing anti-IL- 1[beta] antibodies effectively reduced IL- 1[beta] levels, normalized left atrial dimensions, and reduced fibrosis and the incidence of AF. These data suggest that CKD creates a substrate for AF development by activating the NLRP3 inflammasome in atria, which is associated with structural and electrical remodeling. Neutralizing IL-1[beta] antibodies may be beneficial in preventing CKD-induced AF., Introduction Atrial fibrillation (AF) is the most commonly diagnosed cardiac arrhythmia, with a high prevalence worldwide (1, 2). AF significantly affects the quality of life, as it is associated with [...]

Pulmonary arterial hypertension (PAH) is characterized by abnormal outgrowth of pulmonary artery smooth muscle cells (PASMCs) of the media. Abundant expression of endothelin-1 (ET-1) and activated p38 mitogen-activated protein kinase (p38MAPK) has been observed in PAH patients. p38MAPK has been implicated in cell proliferation. An unspecified disturbance in bone morphogenetic protein (BMP) signaling may be involved in the development of PAH. Type I receptors (BMPR1A and BMPR1B) and type II receptor (BMPR2) transduce signals via two distinct pathways, i.e., canonical and non-canonical pathways, activating Smad1/5/8 and p38MAPK, respectively. BMPR1B expression was previously reported to be enhanced in the PASMCs of patients with idiopathic PAH. BMP15 binds specifically to BMPR1B. We assessed the effects of ET-1 on BMP receptor expression and cell proliferation. BMP2 increased BMPR1B expression in human PASMCs after pretreatment with ET-1 in vitro. Although BMP2 alone did not affect PASMC proliferation, BMP2 treatment after ET-1 pretreatment significantly accelerated PASMC proliferation. PH-797804, a selective p38MAPK inhibitor, abrogated this proliferation. Similarly, after ET-1 pretreatment, BMP15 significantly accelerated the proliferation of PASMCs, whereas stimulation with BMP15 alone did not. In conclusion, in PASMCs, ET-1 exposure under pathological conditions alters BMP signaling to activate p38MAPK, resulting in cell proliferation. Key words: BMPR1B, BMP15, endothelin, p38MAPK, pulmonary artery smooth muscle cells L'hypertension arterielle pulmonaire (HAP) se caracterise par l'excroissance anormale de cellules musculaires lisses de la media de l'artere pulmonaire (CMLAP). On a observe une expression de l'endotheline 1 (ET-1) et de la MAPKp38 (pour << p38 mitogen-activated protein kinase >>) abondante chez les patients atteints d'HAP. La MAPKp38 a ete mise en cause dans la proliferation cellulaire. Des perturbations non specifiees de la voie de signalisation de la BMP (pour << bone morphogenetic protein >>) pourraient jouer un role dans l'apparition de l'HAP. Les recepteurs de type I (BMPR1A et BMPR1B) et de type II (BMPR2) permettent la transduction du signal par l'intermediaire de deux voies de signalisation distinctes : canonique et non canonique, activant la Smad1/5/8 et la MAPKp38, respectivement. On a rapporte precedemment que l'expression des BMPR1B est amplifiee dans les CMLAP de patients atteints d'HAP idiopathique. La BMP15 se lie au BMPR1B de maniere specifique. Nous avons evalue l'effet de l'ET-1 sur l'expression des recepteurs du BMP et la proliferation des cellules. Avec l'administration prealable d'ET-1 in vitro, le BMP2 entrainait une augmentation de l'expression des BMPR1B dans les CMLAP humaines. Meme si le BMP2 seul n'a pas affecte la proliferation des CMLAP, l'administration d'ET-1 prealablement a celle du BMP2 entrainait une acceleration marquee de la proliferation des CMLAP. Le PH-797804, un inhibiteur selectif de la MAPKp38, permettait d'abolir cette proliferation. De maniere analogue, l'administration d'ET-1 prealablement a celle du BMP15 entrainait une acceleration marquee de la proliferation des CMLAP, mais pas la stimulation a l'aide de BMP15 seul. En conclusion, dans les CMLAP, l'exposition a l'ET-1 en situation pathologique entraine des perturbations dans la voie de signalisation de BMP pour activer la MAPKp38, ce qui entraine une proliferation cellulaire. [Traduit par la Redaction] Mots-cles : BMPR1B, BMP15; endotheline, MAPKp38, cellules musculaires lisses d'artere pulmonaire, Introduction Pulmonary arterial hypertension (PAH) is a progressive disease that presents as persistently elevated pulmonary vascular resistance and increased pulmonary arterial pressure (Frazier and Burke 2012). Only limited treatments for [...]

Background: The efficacy of repetitive transcranial magnetic stimulation (rTMS) to the left dorsolateral prefrontal cortex (dIPFC) has been established in patients with treatment-resistant depression (TRD), suggesting that alterations in signal propagation from the left dIPFC to other brain regions may be linked to the pathophysiology of TRD. Alterations at the cellular level, including dysfunction of oligodendrocytes, may contribute to these network abnormalities. The objectives of the present study were to compare signal propagation from the left dIPFC to other neural networks in patients with TRD and healthy controls. We used TMS combined with electroencephalography to explore links between cell-specific gene expression and signal propagation in TRD using a virtual-histology approach. Methods: We examined source-level estimated signal propagation from the left dIPFC to the 7 neural networks in 60 patients with TRD and 30 healthy controls. We also calculated correlations between the interregional profiles of altered signal propagation and gene expression for 9 neural cell types derived from the Allen Human Brain Atlas data set. Results: Signal propagation from the left dIPFC to the salience network was reduced in the 0 and a bands in patients with TRD (p = 0.0055). Furthermore, this decreased signal propagation was correlated with cell-specific gene expression of oligodendrocytes (p < 0.000001). Limitations: These results show only part of the pathophysiology of TRD, because stimulation was limited to the left dIPFC. Conclusion: Reduced signal propagation from the left dIPFC to the salience network may represent a pathophysiological endophenotype of TRD; this finding may be associated with reduced expression of oligodendrocytes., Introduction Major depressive disorder (MDD) is one of the most prevalent mental disorders. (1) However, nearly one-third of patients with MDD show little or no response to 2 or more [...]

Acute pancreatitis (AP), a disorder of global importance, has a growing incidence and prevalence, particularly in the Western world. Its complications include pseudocysts and chronic pancreatitis. Pramipexole (PMX), a D2/3 receptor selecting agonist used in Parkinsonism, was reported to have anti-inflammatory effects. This study explored the potential curative role of PMX in an L-arginine-induced acute pancreatitis rat model in addition to a possible mechanistic pathway. Rats were divided randomly into three groups: control, L-arginine, and L-arginine + PMX. Seven days after AP induction, rats were decapitated and estimated for serum amylase, lipase, glucose, pancreatic inflammatory mediators toll-like receptor-4, nuclear factor [kappa] B p65, serum tumor necrosis factor-[alpha], NOD-, LRR and pyrin domain-containing protein 3 (NLRP3) inflammasome, caspase-1, interleukin 1[beta], oxidative biomarkers malondialdehyde, myeloperoxidase, nitrite/nitrate, reduced glutathione, and the apoptotic marker caspase-3, with pancreatic histopathological changes. L-arginine-mediated AP was proved by elevated serum lipase and amylase and pancreatic inflammatory, oxidative, and apoptotic markers with infiltration of inflammatory cells using hematoxylin and eosin stain. PMX improved all these adverse signs of AP greatly. PMX might be considered an innovative therapy for AP due to its remarkable antioxidant, antiapoptotic, and anti-inflammatory effects, which are attributed to the suppression of the NLRP3 inflammasome and its downstream inflammatory cytokines. Key words: L-arginine, acute pancreatitis, pramipexole, NLRP3 inflammasome, TLR4 La pancreatite aigue (PA), maladie d'importance mondiale, a une incidence et une prevalence croissantes, particulierement en Occident. On compte parmi ses complications les pseudokystes et la pancreatite chronique. Dernierement, on a rapporte que le pramipexole (PMX), agoniste selectif des recepteurs D2/3 utilise dans le parkinsonisme, est dote de proprietes antiinflammatoires. Cette etude avait pour but d'explorer le role curatif eventuel du PMX dans un modele de PA engendree par la l-arginine chez le rat, de meme qu'un possible mode d'action sequentiel. Nous avons reparti aleatoirement des rats dans trois groupes : temoin, l-arginine et << l-arginine + PMX >>. Sept jours apres la production d'une PA, les rats ont ete decapites et nous avons estime dans le serum l'amylase, la lipase, le glucose, des mediateurs de l'inflammation pancreatique (le recepteur de type << toll-like >> 4 [TLR 4], la sous-unite p65 du facteur nucleaire [kappa] B, le facteur de necrose tumorale [alpha], l'inflammasome NLRP3, la caspase 1, l'interleukine 1[beta]), des biomarqueurs de l'oxydation (le malondialdehyde, la myeloperoxydase, les nitrites/nitrates, le glutathion), de meme qu'un marqueur de l'apoptose (la caspase 3), et etudie les variations histopathologiques dans le pancreas. La PA engendree par la l-arginine s'est manifestee par une hausse de la lipase et de l'amylase seriques, ainsi que des marqueurs de l'inflammation, de l'oxydation et de l'apoptose dans le pancreas, avec l'observation d'une infiltration de cellules inflammatoires a l'aide de la coloration a l'hematoxyline-eosine. Le PMX a permis d'attenuer de facon marquee tous ces signes defavorables. En conclusion, on pourrait considerer que le PMX constitue un nouvel element dans le traitement de la PA en raison de ses effets antioxydants, anti-apoptotiques, anti-inflammatoires remarquables, attribuables a l'inhibition de l'inflammasome NLRP3, ainsi que de ses cytokines inflammatoires en aval. [Traduit par la Redaction] Mots-cles : L-arginine, pancreatite aigue, pramipexole, inflammasome NLRP3, TLR-4, Introduction Acute pancreatitis (AP) is an acute inflammatory pancreatic process that commonly includes peripancreatic tissues and even remote organs (Besselink et al. 2013). It is clinically specified by abdominal pain [...]

The effect of oxaprozin (OXP) on an experimental model of seizures in rats was investigated in this study. Seizures in Wistar rats (200-250 g) were induced by pentylenetetrazole (PTZ, 60 mg/kg). The anticonvulsant effect of OXP (100, 200, and 400 mg/kg, intraperitoneally) was evaluated in a seizure model. After behavioral tests, the animals underwent deep anesthesia and were put down painlessly. Animal serum was isolated for antioxidant assays (nitric oxide (NO) and glutathione (GSH)). The animals' brains were also isolated to gauge the relative expression of genes in the oxidative stress pathway (sirtuin 1 (Sirt1) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Pgc1[alpha])). Intraperitoneal injection of OXP increased the mean latency of myoclonic jerks and generalized tonic-clonic seizure (GTCS) and decreased the number of myoclonic jerks and GTCS duration compared with the PTZ group. Biochemical tests showed that pretreatment with OXP was able to restore GSH serum levels and reverse the augmented NO serum levels caused by PTZ induction to the normal level. The quantitative polymerase chain reaction results also revealed that OXP counteracts the negative effects of PTZ by affecting the expression of the Sirt1 and Pgc1[alpha] genes. Overall, this study suggests the potential neuroprotective effects of the nonsteroidal, anti- inflammatory OXP drug in a model of neural impairment caused by seizures via the mechanism of inhibition of the oxidative stress pathway. Key words: nonsteroidal anti-inflammatory drug, tonic-clonic epilepsy, antioxidant, behavior, gene expression La presente etude porte sur l'effet de l'oxaprozine (OXP) dans un modele experimental de convulsions chez le rat. A l'aide de pentylenetetrazole (PTZ, 60 mg/kg), nous avons provoque des convulsions chez des rats Wistar (200-250 g). Nous avons evalue l'effet anticonvulsivant de l'OXP (100, 200 et 400 mg/kg, par voie intraperitoneale) dans un modele de convulsions. Apres des tests comportementaux, les rats ont ete places sous anesthesie profonde et euthanasies sans douleur. Nous avons isole du serum des animaux en vue d'epreuves d'antioxydation (NO et GSH). Nous avons aussi isole le cerveau des animaux en vue de sonder les expressions relatives des genes dans l'axe du stress oxydatif (Sirt1 et Pgc1[alpha]). L'injection d'OXP par voie intraperitoneale entrainait une augmentation de la latence moyenne des secousses myocloniques et des convulsions tonicocloniques generalisees (CTCG) avec une diminution du nombre de secousses myocloniques et de la duree des CTCG par rapport au groupe PTZ. Les tests biochimiques ont montre que l'administration prealable d'OXP permettait aux taux seriques de GSH de se retablir et d'inverser l'augmentation des taux seriques de NO entrainee par l'administration de PTZ avec des taux normaux. Les resultats de PCR quantitatif ont aussi revele que l'OXP permet de contrecarrer les effets negatifs de la PTZ par la modification de l'expression des genes Sirt1 et Pgc1[alpha]. Dans l'ensemble, notre etude laisse entendre que l'OXP, un anti- inflammatoire non steroidien, pourrait avoir des effets neuroprotecteurs dans un modele de defaillance neuronale causee par des convulsions par l'intermediaire d'un mode d'action d'inhibition de la voie de signalisation du stress oxydatif. [Traduit par la Redaction] Mots-cles : anti-inflammatoire non steroidien, convulsions tonicocloniques, antioxydant, comportement, expression genique, Introduction Seizure is a condition in which nerve cells make sudden and simultaneous nerve discharges, and it is often accompanied by changes in the neural network and function. Epilepsy, which [...]

Dexamethasone is a synthetic glucocorticoid that has been associated with oxidative stress in central and peripheral tissues. p-Chloro-diphenyl diselenide ([(p-ClPhSe).sub.2]) is an antioxidant organoselenium compound. The present study evaluated whether nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap-1) signaling contributes to the [(p-ClPhSe).sub.2] antioxidant effects in the kidney of mice exposed to dexamethasone. Adult Swiss mice received dexamethasone (intraperitoneal) at a dose of 2 mg/kg or its vehicle for 21 days. After that, mice were treated with [(p- ClPhSe).sub.2] (intragastric) (1, 5, or 10 mg/kg) for 7 days. Samples of kidneys were collected for biochemical assays. [(p-ClPhSe).sub.2] at a dose of 1 mg/kg reversed the renal reactive oxygen species (ROS) and carbonyl protein (CP) levels increased by dexamethasone. [(p-ClPhSe).sub.2] at doses of 5 and 10 mg/kg was effective against the increase of thiobarbituric acid reactive substances, ROS, and CP, as well as the decrease of [delta]-aminolevulinic acid dehydratase activity and nonprotein sulfhydryl levels induced by dexamethasone. At 5 mg/kg, [(p-ClPhSe).sub.2] reduced the renal levels of 4-OH-2-HNE and heme oxygenase (HO-1), as well as modulated the Nrf2/Keap-1 signaling in mice exposed to dexamethasone. The present findings revealed that [(p-ClPhSe).sub.2] antioxidant effects were associated with the modulation of Nrf2/Keap-1 signaling pathway in the kidney of mice exposed to dexamethasone. Key words: glucocorticoid, kidney, antioxidant, organoselenium, Nrf2/Keap-1 La dexamethasone est un glucocorticoide synthetique que l'on a associe au stress oxydatif dans les tissus centraux et peripheriques. Le p-chlorodiphenyle diselenide [(p-ClPhSe).sub.2] est un compose d'organoselenium antioxydant. La presente etude visait a evaluer si la voie de signalisation Nrf2/Keap-1 participe aux effets antioxydants du [(p-ClPhSe).sub.2] dans les reins de souris exposes a la dexamethasone. Nous avons administre de la dexamethasone a 2 mg/kg par voie i.p. ou son vehicule pendant 21 jours a des souris suisses adultes. Ensuite, nous avons administre aux souris du [(p-ClPhSe).sub.2] par voie i.g. a 1, 5 ou 10 mg/kg pendant 7 jours. Nous avons preleve des echantillons renaux en vue d'etudes biochimiques. Le [(p-ClPhSe).sub.2] a 1 mg/kg permettait d'inverser l'augmentation des taux renaux de derives reactifs de l'oxygene (ou ROS pour << reactive oxygen species >>) et de proteine carbonyl (PC) entrainee par la dexamethasone. Le [(p-ClPhSe).sub.2] a 5 et a 10 mg/kg etait efficace contre la hausse des derives reactifs de l'acide thiobarbiturique, des ROS et de la PC, de meme que contre l'abaissement de l'activite de l'acide [delta]-aminolevulinique deshydratase ([delta]-ALA-D) et des taux de thiols (SH) non-proteiques (NPSH) entraines par la dexamethasone. Le [(p-ClPhSe).sub.2] a raison de 5 mg/kg entrainait une diminution des taux renaux de 4-OH-2-HNE et de HO-1 de meme qu'une modulation de la voie de signalisation Nrf2/Keap-1 chez les souris exposees a la dexamethasone. Les presents resultats ont montre que les effets antioxydants du [(p-ClPhSe).sub.2] etaient associes avec la modulation de la voie de signalisation Nrf2/Keap-1 dans les reins de souris exposes a la dexamethasone.[Traduit par la Redaction] Mots-cles : glucocorticoide, rein, antioxydant, organoselenium, Nrf2/Keap-1, Introduction Glucocorticoids (GCs) are adrenal hormones synthesized by the adrenal glands and involved in lipid, carbohydrate, and protein metabolism, as well as in immune and stress response (Liberman et al. [...]

The complexity of hepatocellular carcinoma (HCC) signaling and the failure of pharmacological therapeutics reveal the significance of establishing new anti-cancer strategies. Interferon alpha (IFN-[alpha]) has been used as adjuvant therapy for reducing HCC recurrence and improving survival. Delta-tocotrienol ([delta]-tocotrienol), a natural unsaturated isoform of vitamin E, is a promising candidate for cancer treatment. In this study, we evaluated whether the combination of [delta]- tocotrienol with IFN-[alpha] displays significant advantages in the treatment of HCC cells. Results showed that the combination significantly decreased cell viability, migration and invasion of HCC cells compared with single therapies. Combining [delta]-tocotrienol and IFN-[alpha] enhanced the decrease in proliferating cell nuclear antigen (PCNA) and matrix metalloproteinase (MMP) 7 and MMP-9. The combination also produced an enhancement of apoptosis together with increased Bax/Bcl-xL ratio and reactive oxygen species (ROS) generation. [delta]-tocotrienol induced Notchl activation and changes in Erk and p38 MAPK signaling status. Blocking experiments confirmed that ROS and Erk are involved, at least in part, in the anti-cancer effects of the combined treatment. In conclusion, the combination of [delta]-tocotrienol with IFN-[alpha] therapy showed promising results for HCC cell treatment, which makes the combination of cytokine-based immunotherapy with natural products a potential strategy against liver cancer. Key words: hepatocellular carcinoma, interferon, tocotrienol, apoptosis, Notchl, p38 MAPK, Erk. La complexite des voies de signalisation dans le carcinome hepatocellulaire (CHH) et l'echec des traitements pharmacologiques revelent l'importance d'etablir de nouvelles strategies anticancereuses. L'interferon alpha (IFN [alpha]) a ete utilise comme medicament adjuvant dans le but de reduire la recidive des CHH et d'ameliorer la survie. Le delta-tocotrienol ([delta]-tocotrienol), une isoforme insaturee de la vitamine E, est un candidat prometteur dans le traitement du cancer. Dans cette etude, nous avons evalue si l'association du [delta]-tocotrienol avec l'IFN [alpha] apporte de nets avantages dans le traitement des cellules de CHH. Les resultats ont montre que le traitement d'association entrainait une diminution nettement plus marquee de la vitalite, de la migration et de l'invasion des cellules de CHH que les monotherapies. L'association du [delta]- tocotrienol avec l'IFN [alpha] a permis d'amplifier la diminution des taux de PCNA (pour << proliferating cell nuclear antigen >>) et des metalloproteinases matricielles MMP-7 et MMP-9. Le traitement d'association a aussi permis d'accentuer l'apoptose, de meme que de faire augmenter le ratio Bax/Bcl-xL et la production de derives reactifs de l'oxygene. Le [delta]-tocotrienol a entraine l'activation de Notchl et des variations dans l'etat de la signalisation par Erk et p38 MAPK. Des experiences d'inhibition ont permis de confirmer que les derives reactifs de l'oxygene et Erk jouent un role au moins partiel dans les effets anticancereux du traitement d'association. En conclusion, l'association du [delta]-tocotrienol avec l'IFN [alpha] donne des resultats prometteurs dans le traitement des cellules de CHH, ce qui fait de l'association d'une immunotherapie a base de cytokines avec des produits naturels une strategie eventuelle dans le traitement contre le cancer du foie. [Traduit par la Redaction] Mots-cles : carcinome hepatocellulaire, interferon, tocotrienol, apoptose, Notchl, p38 MAPK, Erk., Introduction Liver cancer ranks sixth in incidence and it is the third most common cause of death from cancer worldwide (Forner et al. 2018). The most common type of primary [...]

Persistent hyperglycemia in type 1 diabetes triggers numerous signaling pathways, which may prove deleterious to the endothelium. As hyperglycemia damages the endothelial layer via multiple signaling pathways, including enhanced oxidative stress, downregulation of angiotensin-converting enzyme 2 signaling, and exacerbation of endoplasmic reticulum (ER) stress, it becomes difficult to prevent injury using monotherapy. Thus, the present study was conceived to evaluate the combined effect of ER stress inhibition along with angiotensin-converting enzyme 2 activation, two major contributors to hyperglycemia-induced endothelial dysfunction, in preventing endothelial dysfunction associated with type 1 diabetes. Streptozotocin-induced diabetic animals were treated with either diminazene aceturate (5 mg * [kg.sup.-1] per day, p.o.) or tauroursodeoxycholic acid, sodium salt (200 mg * [kg.sup.-1] per day i.p.), or both for 4 weeks. Endothelial dysfunction was evaluated using vasoreactivity assay, where acetylcholine-induced relaxation was assessed in phenylephrine pre-contracted rings. Combination therapy significantly improved vascular relaxation when compared with diabetic control as well as monotherapy. Restoration of nitrite levels along with prevention of collagen led to improved vasodilatation. Moreover, there was an overall reduction in aortic oxidative stress. We conclude that by simultaneously inhibiting ER stress and activating angiotensin converting enzyme 2 deleterious effects of hyperglycemia on endothelium were significantly alleviated. This could serve as a novel strategy for the prevention of endothelial dysfunction. Key words: endothelial dysfunction, endoplasmic reticulum stress, angiotensin-converting enzyme 2, type 1 diabetes. Dans le diabete de type 1, l'hyperglycemie persistante entraine le declenchement de nombreuses voies de signalisation, ce qui pourrait avoir des effets resolument deleteres sur l'endothelium. Puisque l'hyperglycemie entraine des dommages dans la couche endotheliale par l'intermediaire de nombreuses voies de signalisation, y compris l'augmentation du stress oxydatif, la regulation a la baisse de la signalisation par l'enzyme de conversion de l'angiotensine de type 2, de meme que l'exacerbation du stress du reticulum endoplasmique, etc., il devient difficile de prevenir la production de lesions a l'aide d'une monotherapie. Par consequent, nous avons concu la presente etude en vue d'evaluer l'effet combine de l'inhibition du stress du reticulum endoplasmique et de l'activation de l'enzyme de conversion de l'angiotensine de type 2, deux voies de signalisation contribuant de maniere tres importante au dysfonctionnement endothelial engendre par l'hyperglycemie, dans la prevention du dysfonctionnement endothelial associe avec le diabete de type 1. Pendant quatre semaines, nous avons administre de l'aceturate de diminazene (5 mg * [kg.sup.-1] par jour, p.o.) ou le sel de sodium de l'acide tauroursodeoxycholique (200 mg * [kg.sup.-1] par jour, i.p.), ou encore les deux chez des animaux devenus diabetiques par l'administration de streptozotocine. Nous avons evalue le dysfonctionnement endothelial a l'aide d'une epreuve de vasoreactivite, ou nous avons evalue la relaxation provoquee par l'acetylcholine dans des anneaux precontractes par la phenylephrine. Le traitement d'association permettait d'ameliorer la relaxation vasculaire par rapport aux temoins diabetiques, et la monotherapie aussi. La vasodilatation s'est amelioree avec le retablissement des taux de nitrite et la prevention du depot de collagene. En outre, nous avons observe une diminution globale du stress oxydatif aortique. Nous en arrivons a la conclusion qu'en inhibant simultanement le stress du reticulum endoplasmique et l'activation de l'enzyme de conversion de l'angiotensine de type 2, les effets deleteres de l'hyperglycemie sur l'endothelium s'attenuaient de facon marquee, ce qui pourrait servir de nouvelle strategie dans la prevention du dysfonctionnement endothelial. [Traduit par la Redaction] Mots-cles : dysfonctionnement endothelial, stress du reticulum endoplasmique, enzyme de conversion de l'angiotensine de type 2, diabete de type 1., Introduction Diabetes mellitus leads to different macrovascular complications, which are the major contributors to the morbidity and mortality associated with diabetes (Bjornstad et al. 2018; Varma et al. 2005). This [...]

Microglia are the major cell type expressing complement C3a receptor (C3aR) in the brain. Using a knockin mouse line in which a Td-tomato reporter is incorporated into the endogenous C3ar1 locus, we identified 2 major subpopulations of microglia with differential C3aR expression. Expressing the Td-tomato reporter on the [APP.sup.NL-G-F]-knockin (APP-KI) background revealed a significant shift of microglia to a high-C3aR-expressing subpopulation and they were enriched around amyloid [beta] (A[beta]) plaques. Transcriptomic analysis of C3aR-positive microglia documented dysfunctional metabolic signatures, including upregulation of hypoxia-inducible factor 1 (HIF-1) signaling and abnormal lipid metabolism in APP-KI mice compared with wild-type controls. Using primary microglial cultures, we found that C3ar1-null microglia had lower HIF-1[alpha] expression and were resistant to hypoxia mimetic-induced metabolic changes and lipid droplet accumulation. These were associated with improved receptor recycling and A[beta] phagocytosis. Crossing C3ar1-knockout mice with the APP-KI mice showed that C3aR ablation rescued the dysregulated lipid profiles and improved microglial phagocytic and clustering abilities. These were associated with ameliorated A[beta] pathology and restored synaptic and cognitive function. Our studies identify a heightened C3aR/HIF-1[alpha] signaling axis that influences microglial metabolic and lipid homeostasis in Alzheimer disease, suggesting that targeting this pathway may offer therapeutic benefit., Introduction Alzheimer disease (AD), the leading cause of dementia in the elderly, is pathologically characterized by the accumulation of amyloid [beta] (A[beta]) plaques and intracellular tau tangles and accompanying neuroinflammation [...]

Patients with severe COVID-19 develop acute respiratory distress syndrome (ARDS) that may progress to cytokine storm syndrome, organ dysfunction, and death. Considering that complement component 5a (C5a), through its cellular receptor C5aR1, has potent proinflammatory actions and plays immunopathological roles in inflammatory diseases, we investigated whether the C5a/C5aR1 pathway could be involved in COVID-19 pathophysiology. C5a/C5aR1 signaling increased locally in the lung, especially in neutrophils of critically ill patients with COVID-19 compared with patients with influenza infection, as well as in the lung tissue of K18-hACE2 Tg mice (Tg mice) infected with SARS-CoV-2. Genetic and pharmacological inhibition of C5aR1 signaling ameliorated lung immunopathology in Tg-infected mice. Mechanistically, we found that C5aR1 signaling drives neutrophil extracellular traps-dependent (NETs-dependent) immunopathology. These data confirm the immunopathological role of C5a/C5aR1 signaling in COVID-19 and indicate that antagonists of C5aR1 could be useful for COVID-19 treatment., Introduction COVID-19 is the major acute global public health issue in this century. Patients with severe COVID-19 develop acute respiratory distress syndrome (ARDS), which may progress to organ dysfunction and [...]

While the rapid advancement of immunotherapies has revolutionized cancer treatment, only a small fraction of patients derive clinical benefit. Eradication of large, established tumors appears to depend on engaging and activating both innate and adaptive immune system components to mount a rigorous and comprehensive immune response. Identifying such agents is a high unmet medical need, because they are sparse in the therapeutic landscape of cancer treatment. Here, we report that IL-36 cytokine can engage both innate and adaptive immunity to remodel an immune-suppressive tumor microenvironment (TME) and mediate potent antitumor immune responses via signaling in host hematopoietic cells. Mechanistically, IL-36 signaling modulates neutrophils in a cell-intrinsic manner to greatly enhance not only their ability to directly kill tumor cells but also promote T and NK cell responses. Thus, while poor prognostic outcomes are typically associated with neutrophil enrichment in the TME, our results highlight the pleiotropic effects of IL-36 and its therapeutic potential to modify tumor-infiltrating neutrophils into potent effector cells and engage both the innate and adaptive immune system to achieve durable antitumor responses in solid tumors., Introduction Immunotherapy, particularly checkpoint inhibitors such as anti-PD(L)1, has revolutionized treatment options for patients with cancer. However, responses are limited to only subsets of patients and indications (1-3). Intratumoral T [...]

Despite advances in acute care, ischemic stroke remains a major cause of long-term disability. Approaches targeting both neuronal and glial responses are needed to enhance recovery and improve long-term outcome. The complement C3a receptor (C3aR) is a regulator of inflammation with roles in neurodevelopment, neural plasticity, and neurodegeneration. Using mice lacking C3aR ([C3aR.sup.-/-]) and mice overexpressing C3a in the brain, we uncovered 2 opposing effects of C3aR signaling on functional recovery after ischemic stroke: inhibition in the acute phase and facilitation in the later phase. Peri-infarct astrocyte reactivity was increased and density of microglia reduced in [C3aR.sup.-/-] mice; C3a overexpression led to the opposite effects. Pharmacological treatment of wild-type mice with intranasal C3a starting 7 days after stroke accelerated recovery of motor function and attenuated astrocyte reactivity without enhancing microgliosis. C3a treatment stimulated global white matter reorganization, increased peri-infarct structural connectivity, and upregulated Igf1 and Thbs4 in the peri-infarct cortex. Thus, C3a treatment from day 7 after stroke exerts positive effects on astrocytes and neuronal connectivity while avoiding the deleterious consequences of C3aR signaling during the acute phase. Intranasal administration of C3aR agonists within a convenient time window holds translational promise to improve outcome after ischemic stroke., Introduction Ischemic stroke affects around 7.6 million people each year with global prevalence of over 77 million (1). Despite the major advances in acute stroke treatment and care, more than [...]

The renal actions of parathyroid hormone (PTH) promote 1,25-vitamin D generation; however, the signaling mechanisms that control PTH-dependent vitamin D activation remain unknown. Here, we demonstrated that salt-inducible kinases (SIKs) orchestrated renal 1,25-vitamin D production downstream of PTH signaling. PTH inhibited SIK cellular activity by cAMP-dependent PKA phosphorylation. Whole-tissue and single-cell transcriptomics demonstrated that both PTH and pharmacologic SIK inhibitors regulated a vitamin D gene module in the proximal tubule. SIK inhibitors increased 1,25-vitamin D production and renal Cyp27b1 mRNA expression in mice and in human embryonic stem cell-derived kidney organoids. Global- and kidney-specific Sik2/Sik3 mutant mice showed Cyp27b1 upregulation, elevated serum 1,25- vitamin D, and PTH-independent hypercalcemia. The SIK substrate CRTC2 showed PTH and SIK inhibitor-inducible binding to key Cyp27b1 regulatory enhancers in the kidney, which were also required for SIK inhibitors to increase Cyp27b1 in vivo. Finally, in a podocyte injury model of chronic kidney disease-mineral bone disorder (CKD-MBD), SIK inhibitor treatment stimulated renal Cyp27b1 expression and 1,25-vitamin D production. Together, these results demonstrated a PTH/SIK/CRTC signaling axis in the kidney that controls Cyp27b1 expression and 1,25-vitamin D synthesis. These findings indicate that SIK inhibitors might be helpful for stimulation of 1,25-vitamin D production in CKD-MBD., Introduction Vitamin D plays a critical role in bone and mineral metabolism and also controls other physiologic and pathophysiologic processes, including skeletal muscle function, reproductive health, cancer risk and progression, [...]

Chronic glucocorticoids therapy is commonly complicated by steroid diabetes, although the underlying mechanisms are still elusive. Liraglutide, a glucagon-like peptide-1, was initially found to induce glycemic control and recently it was found to have many pleotropic effects; however, its role in pancreas remains unknown. The present study aims to estimate the protective role of liraglutide on dexamethasone-induced pancreatic cytotoxicity and hyperglycemia, highlighting the possible underlying biochemical, molecular, and cellular mechanisms. Twenty-eight male Wistar rats were involved in this study and were randomly divided into four groups. Group III and IV were treated with 1 mg/kg dexamethasone daily for 10 days. Group II and IV were treated with liraglutide in a dose of 0.8 mg/kg per day for 2 weeks. Pancreatic caspase-9, nuclear factor erythroid 2-related factor 2 (Nrf2), phospho-protein kinase-B (pAkt), and sequestrome 1 (p62) levels were assessed by immunoassay. Moreover, phosphoinositide 3-kinase (PI3K) expression by real-time PCR, microtubule-associated protein light chain 3 (LC3B) expression by immunohistochemistry, glycemic status, [beta]-cell function by homoeostasis model assessment (HOMA) [beta] index, and pancreatic redox status were assessed. Liraglutide improved blood glucose level, [beta]-cell function, pancreatic caspase-9 level, redox status, and autophagy. Additionally, it increased pancreatic PI3K, pAkt, and Nrf2 levels. Moreover, preservation of pancreatic histological and the ultrastructural morphological features of [beta]- and [alpha]-cells were observed. In conclusion, liraglutide protected against dexamethasone-induced pancreatic injury and hyperglycemia and decelerated the progression towards steroid diabetes via activating PI3K/Akt/Nrf2 signaling and autophagy flux pathways. Key words: glucagon-like peptide-1, nuclear factor erythroid 2-related factor 2, microtubule-associated protein light chain 3, caspase-9, protein kinase-B, sequestrosome 1. L'administration de glucocorticoides a long terme se complique frequemment de diabete steroidien, tandis que les modes d'action sous-jacents continuent a echapper a notre comprehension. Au depart, on a montre que le liraglutide, un peptide 1 s'apparentant au glucagon, permet d'obtenir une maitrise glycemique et, recemment, qu'il a de nombreux effets pleiotropiques. En revanche, son role dans le pancreas demeure inconnu. La presente etude vise donc a estimer le role protecteur du liraglutide contre la cytotoxicite pancreatique et l'hyperglycemie provoquees par la dexamethasone, en soulignant les modes d'action biochimiques, moleculaires et cellulaires sous-jacents eventuels. Dans le cadre de cette etude, nous avons reparti aleatoirement 28 rats Wistar males dans quatre groupes, dont les groupes III et IV avec administration de dexamethasone a 1 mg/kg quotidiennement pendant 10 jours et les groupes II et IV avec administration d'une dose quotidienne de liraglutide a 0,8 mg/kg pendant 2 semaines. A l'aide d'immunoessais, nous avons evalue les taux de caspase-9, de Nrf2, de pAkt et de sequestrome 1 (p62) pancreatiques. En outre, nous avons evalue l'expression de la phosphoinositide 3-kinase (PI3K) a l'aide de techniques de PCR en temps reesl, l'expression de LC3B a l'aide de l'immunohistochimie, l'etat glycemique, le fonctionnement des cellules [beta] a l'aide de l'indice HOMA-[beta] ainsi l'etat redox du pancreas. Le liraglutide permettait d'obtenir des ameliorations quant a la glycemie et au fonctionnement des cellules [beta] de meme qu'aux taux de caspase 9, qu'a l'etat redox et qu'a l'autophagie pancreatiques. De plus, il entrainait une augmentation des taux de PI3K, de pAkt et de Nrf2 pancreatiques. Par ailleurs, nous avons observe les caracteristiques morphologiques histologiques et ultrastructurelles des cellules [beta] et [alpha]. En conclusion, le liraglutide assure une protection contre les lesions pancreatiques engendrees par la dexamethasone et l'hyperglycemie, avec un ralentissement de Revolution vers un diabete steroidien par l'intermediaire de l'activation de la voie de signalisation PI3K/Akt/Nrf2 et de l'autophagie dynamique. [Traduit par la Redaction] Mots-cles : GLP-1 (glucagon-like peptide 1), Nrf2 (nuclear factor erythroid 2-related factor 2), proteine LC3 (light chain 3) associee aux microtubules, caspase 9, proteine kinase B, sequestrosome 1., Introduction Glucocorticoids (GCs) are used to treat variety of inflammatory and immunological diseases; however, they encourage the induction of oxidative stress, apoptosis, impairment of insulin secretion, and peripheral insulin resistance [...]

Theobromine, a methylxanthine present in cocoa, has been shown to possess many beneficial pharmacological properties such as anti-oxidative stress, anti-inflammatory property, and anti-microbial activity. In this study, we investigated the effects of theobromine on nonalcoholic fatty liver disease (NAFLD) and the possible underlying mechanisms in vivo and in vitro. The results showed that theobromine reduced body weight and fat mass and improved dyslipidemia. Theobromine mitigated liver injury and significantly reduced hepatic triglyceride level in mice with obesity. Histological examinations also showed hepatic steatosis was alleviated after theobromine treatment. Furthermore, theobromine reversed the elevated mRNA and protein expression of SREBP-1c, FASN, CD36, FABP4, and the suppressed expression of PPAR[alpha] and CPT1a in the liver of mice with obesity, which were responsible for lipogenesis, fatty acid uptake, and fatty acid oxidation respectively. In vitro, theobromine also downregulated SREBP-1c, FASN, CD36, FABP4 and upregulated PPAR[alpha] and CPT1a mRNA and protein levels in hepatocytes in a dose-dependent manner, while these changes were reversed by L-leucine, a mammalian target of rapamycin (mTOR) agonist. The present study demonstrated that theobromine improved NAFLD by inhibiting lipogenesis and fatty acid uptake and promoting fatty acid oxidation in the liver and hepatocytes, which might be associated with its suppression of mTOR signaling pathway. Novelty: * Theobromine protects against high-fat diet--induced NAFLD. * Theobromine inhibits lipogenesis and fatty acid uptake and promotes fatty acid oxidation in the liver and hepatocytes via inhibiting mTOR signaling pathway. Key words: nonalcoholic fatty liver disease, theobromine, mTOR, lipogenesis, fatty acid uptake, fatty acid oxidation. On a montre que la theobromine, une methylxanthine presente dans le cacao, est dotee de nombreuses proprietes pharmacologiques avantageuses entre autres contre le stress oxydatif et l'inflammation, avec une activite antimicrobienne. Cette etude porte sur les effets de la theobromine sur la steatose hepatique non alcoolique (SHNA) et les modes d'action in vivo et in vitro sous-jacents eventuels. Les resultats ont montre que la theobromine permet de faire diminuer la masse corporelle et la masse adipeuse, ainsi que d'attenuer la dyslipidemie. La theobromine permettait d'attenuer les lesions hepatiques et de faire diminuer les taux hepatiques de TG de facon marquee chez la souris obese. L'examen histologique a aussi montre que la steatose hepatique s'attenuait a la suite de l'administration de theobromine. En outre, la theobromine permettait d'inverser la hausse de l'expression en ARNm et en proteines de SREBP-1c, de FASN, de CD36 et de FABP4 ainsi que d'inhiber completement l'expression des PPAR[alpha] et de CPT1a dans le foie des souris obeses, expressions qui etaient responsables de la lipogenese, de la mobilisation des acides gras et de leur oxydation, respectivement. Dans les hepatocytes in vitro, la theobromine a aussi entraine une regulation a la baisse de SREBP-1c, de FASN, de CD36 et de FABP4 ainsi qu'une regulation a la hausse des PPAR[alpha] et de CPT1a en ARNm et en proteines de maniere proportionnelle a la dose, tandis que ces variations s'inversaient avec la L-leucine, un agoniste de mTOR. La presente etude a montre que la theobromine permettait d'attenuer la SHNA par l'intermediaire de l'inhibition de la lipogenese, de la mobilisation des acides gras et a la faveur de leur oxydation dans le foie et les hepatocytes, ce qui pourrait etre associe avec son inhibition complete de la voie de signalisation de mTOR. [Traduit par la Redaction] Nouveaute: * La theobromine assure une protection contre la SHNA provoquee par un regime alimentaire a teneur elevee en matieres grasses. * La theobromine permet d'inhiber la lipogenese et la mobilisation des acides gras ainsi que de favoriser l'oxydation des acides gras dans le foie et les hepatocytes par l'intermediaire de l'inhibition de la voie de signalisation de mTOR. Mots-cles: steatose hepatique non alcoolique, theobromine, mTOR, lipogenese, mobilisation des acides gras, oxydation des acides gras., Introduction Nonalcoholic fatty liver disease (NAFLD) is rapidly increasing and gradually becoming the most common chronic liver disease due to its strong relationship with obesity, type 2 diabetes mellitus (T2DM), [...]

Physical exercise is essential for the amelioration of insulin resistance (IR). The mechanisms in charge of improved IR, regulated by exercise, are insufficiently studied. Previous research revealed that Sirtuin 6 (SIRT6)--mediated insulin signaling acts a crucial element in hepatic IR. The objective of our research was to determine the effects of exercise on SIRT6-mediated insulin signaling in liver of IR rats. Forty male Sprague Dawley rats were randomly assigned to four groups (n = 10 rats each): control rats fed with standard chow (Lean group); sedentary rats fed with a high-fat diet (HFD-SED); rats fed with HFD and submitted to 8 week chronic swimming exercise training (HFD-CE); and rats fed HFD and submitted to one acute swimming exercise training (HFD-AE). HFD feeding lead to increased body weight, accumulation of hepatic triglyceride and serum free fatty acids, and enhanced gluconeogenesis. Besides, HFD feeding decreased body insulin sensitivity. Hepatic USP10 and SIRT6 protein levels decreased under obese status. Both chronic and acute exercise intervention alleviated physiological and metabolic status, increased hepatic USP10 and SIRT6 levels, improved insulin signaling transduction, and inhibited gluconeogenesis. These results showed that exercise intervention regulated SIRT6-mediated insulin signaling, which contributes to our understanding of the molecular mechanisms behind IR, in that a regular exercise can mitigate the effects of IR. Key words: exercise, insulin resistance, SIRT6, insulin signaling transduction, gluconeogenesis. L'exercice physique est essentiel pour permettre d'attenuer la resistance a l'insuline. Les modes d'action en jeu dans l'attenuation de la resistance a l'insuline par un exercice physique regule ont ete trop peu etudies. Des recherches anterieures ont revele que la voie de signalisation de l'insuline mediee par SIRT6 est une caracteristique cruciale de l'ischemie-reperfusion (IR) hepatique. Notre recherche portait sur les effets de l'exercice physique sur la voie de signalisation de l'insuline mediee par SIRT6 dans le foie de rat soumis a une IR. Nous avons reparti aleatoirement 40 rats Sprague Dawley males dans quatre groupes (n = 10 rats chacun) : rats temoins avec administration d'une moulee standard (groupe maigre); rats sedentaires avec administration d'un regime alimentaire a haute teneur en matieres grasses (RHMG-SED); rats avec administration d'un RHMG et d'un entrainement physique a long terme (nage sur 8 semaines--RHMG-ELT) et avec exercice physique a court terme (nage ponctuelle--RHMD-ECT). L'administration d'un RHMG menait a une augmentation de la masse corporelle, a l'accumulation de triglycerides dans le foie et d'acides gras libres dans le serum, ainsi qu'a une augmentation de la gluconeogenese. Par ailleurs, l'administration du RHMG entrainait une diminution de la sensibilite de l'organisme a l'insuline. Les taux hepatiques d'USP10 et de SIRT6 en proteines diminuaient a l'etat obese. Tant a long terme qu'a court terme, l'administration de l'exercice physique permettait d'ameliorer l'etat physiologique et metabolique, d'augmenter les taux hepatiques d'USP10 et de SIRT6, d'ameliorer la transduction dans les voies de signalisation de l'insuline, ainsi que d'inhiber la gluconeogenese. Ces consequences revelaient que l'administration d'un exercice physique entraine une regulation de la voie de signalisation de l'insuline mediee par SIRT6, ce qui permet d'obtenir des progres notables dans l'accomplissement des modes d'action moleculaires latents, ce qui liait l'administration d'un exercice physique a l'attenuation des effets de l'IR. Mots-cles : exercice physique, resistance a l'insuline, SIRT6, transduction dans les voies de signalisation de l'insuline, gluconeogenese., Introduction Insulin primarily controls blood glucose via promoting glucose ingestion in insulin-sensitive tissue containing skeletal muscle, adipose tissues, and liver. It also suppresses glucose production in related tissues and organ. [...]

Various liver diseases caused by liver damage seriously affect people's health. The purpose of this study was to clarify the effects and the mechanisms of carnitine palmitoyltransferase 1 (Cpt1a) on oxidative stress and inflammation in liver injury. It was found that the expression of Cpt1a mRNA was upregulated in a model of liver injury in mice. Thus, overexpression of Cpt1a increased reactive oxygen species (ROS) production and malondialdehyde (MDA) levels and reduced superoxide dismutase (SOD), glutathione (GSH), and glutathione peroxidase (GSH- px) levels in an in vitro model of liver injury. It was also shown that overexpression of Cpt1a suppressed the nuclear factor erythroid-2-related factor 2 (Nrf2)/ heme oxygenase-1 (HO-1) signaling pathway. In summary, these data indicate that Cpt1a promotes ROS-induced oxidative stress in liver injury via the Nrf2/HO-1 and nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome signaling pathway. Key words: Cpt1a, ROS, oxidative stress, liver injury, Nrf2/HO-1, inflammasome. Diverses maladies du foie causees par des dommages hepatiques affectent gravement la sante des gens. Cette etude avait pour but de clarifier les effets et les modes d'action de la carnitine palmitoyltransferase 1 (Cpt1a) sur le stress oxydatif et l'inflammation dans les lesions hepatiques. Nous avons observe que l'expression de la Cpt1a en ARNm etait regulee a la hausse dans un modele de lesions hepatiques chez la souris. Ainsi, la surexpression de la Cpt1a entrainait une augmentation de la production de derives reactifs de l'oxygene (DRO) et des taux de malondialdehyde (MDA), avec une diminution des taux de superoxyde dismutase (SOD), de glutathion (GSH) et de glutathion peroxydase (GSH-px) dans un modele in vitro de lesions hepatiques. Nous avons aussi montre que la surexpression de la Cpt1a entrainait une inhibition de la voie de signalisation Nrf2/HO-1 (pour<<< nuclear factor erythroid-2- related factor 2 >>et heme oxygenase-1). En resume, ces donnees montrent que la Cpt1a favorise le stress oxydatif engendre par les DRO dans les lesions hepatiques par l'intermediaire de l'axe Nrf2/HO-1 et inflammasome NLRP3 (pour <<< nucleotide-binding oligomerization domain-like receptor protein 3 >>). Mots-cles : carnitine palmitoyltransferase 1, derives reactifs de l'oxygene, stress oxydatif, lesions hepatiques, axe Nrf2/HO-1, inflammasome., Introduction The body can produce reactive oxygen species (ROS) during the oxidation process of life activities under normal circumstances (Zuo et al. 2016). ROS is the intermediate product produced by [...]

Background: Bipolar disorder is characterized by cyclical alternation between mania and depression, often comorbid with psychosis and suicide. Compared with other medications, the mood stabilizer lithium is the most effective treatment for the prevention of manic and depressive episodes. However, the pathophysiology of bipolar disorder and lithium's mode of action are yet to be fully understood. Evidence suggests a change in the balance of excitatory and inhibitory activity, favouring excitation in bipolar disorder. In the present study, we sought to establish a holistic understanding of the neuronal consequences of lithium exposure in mouse cortical neurons, and to identify underlying mechanisms of action. Methods: We used a range of technical approaches to determine the effects of acute and chronic lithium treatment on mature mouse cortical neurons. We combined RNA screening and biochemical and electrophysiological approaches with confocal immunofluorescence and live-cell calcium imaging. Results: We found that only chronic lithium treatment significantly reduced intracellular calcium flux, specifically by activating metabotropic glutamatergic receptor 5. This was associated with altered phosphorylation of protein kinase C and glycogen synthase kinase 3, reduced neuronal excitability and several alterations to synapse function. Consequently, lithium treatment shifts the excitatory-inhibitory balance toward inhibition. Limitations: The mechanisms we identified should be validated in future by similar experiments in whole animals and human neurons. Conclusion: Together, the results revealed how lithium dampens neuronal excitability and the activity of the glutamatergic network, both of which are predicted to be overactive in the manic phase of bipolar disorder. Our working model of lithium action enables the development of targeted strategies to restore the balance of overactive networks, mimicking the therapeutic benefits of lithium but with reduced toxicity., Introduction Bipolar disorder is a major psychiatric illness that affects 1% to 3% of the population worldwide, and it is 1 of the top 10 causes of disability. (1,2) Bipolar [...]