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OBJECTIVE: To evaluate the rate of supraventricular tachycardia (SVT) termination between 6 mg and 12 mg initial adenosine doses. METHODS: This multi-center, retrospective cohort study evaluated patients presenting to the emergency department (ED) from January 1, 2020 to June 30, 2022 in SVT and received adenosine. The primary objective of the study is to compare the rate of SVT termination between adenosine 6 mg and 12 mg as documented on a formal electrocardiogram. Secondary endpoints include termination of SVT with subsequent adenosine dose, time to ED disposition, adverse effects, and subgroup analyses of patients with a body mass index greater than or equal to 40 kg/m2 and a history of SVT. RESULTS: Of 213 patients included, a 6 mg initial adenosine dose was administered to 117 patients (54.9 %) and a 12 mg initial adenosine dose was administered to 96 patients (45.1 %). SVT termination following the initial dose of 6 mg or 12 mg was 56.4 % and 79.1 %, respectively (p < 0.001). Among the 46 patients who failed to terminate SVT with an initial 6 mg dose, 33 converted to sinus rhythm with a subsequent adenosine dose in comparison to 1 of the 7 patients receiving an initial dose of 12 mg (71.7 % vs 14.3 %, p = 0.007). Median time to ED disposition, either inpatient admission or discharge, was 209 and 161 min, respectively (p = 0.104). There was no statistical difference in either subgroup analyses. CONCLUSION: A higher rate of SVT termination was observed with an initial adenosine dose of 12 mg in the ED in comparison to the guideline recommended dose of 6 mg. There were no significant differences in adverse effects observed.
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BACKGROUND AND PURPOSE: Adenosine receptor activation induces delayed, sustained cardioprotection against ischaemia-reperfusion (IR) injury (24-72 h), but the mechanisms underlying extended cardioprotection duration remain unresolved. We hypothesized that a positive feedback loop involving adenosine receptor-induced proteasomal degradation of adenosine kinase (ADK) and decreased myocardial adenosine metabolism extends the duration of cardioprotection. EXPERIMENTAL APPROACH: Mice were administered an ADK inhibitor, ABT-702, to induce endogenous adenosine signalling. Cardiac ADK protein and mRNA levels were analysed 24-120 h later. Theophylline or bortezomib was administered 24 h after ABT-702 to examine the late roles of adenosine receptors or proteasomal activity, respectively, in ADK expression and cardioprotection at 72 h. Coronary flow and IR tolerance were analysed by Langendorff technique. The potential for continuous adenosinergic cardioprotection was examined using heterozygous, cardiac-specific ADK KO (cADK+/-) mice. Cardiac ADK expression was also examined after A1 or A3 receptor agonist, phenylephrine, lipopolysaccharide or sildenafil administration. KEY RESULTS: ABT-702 treatment decreased ADK protein content and provided cardioprotection from 24 to 72 h. ADK mRNA upregulation restored ADK protein after 96-120 h. Adenosine receptor or proteasome inhibition at 24 h reversed ABT-702-induced ADK protein deficit and cardioprotection at 72 h. cADK+/- hearts exhibited continuous cardioprotection. Diverse preconditioning agents also diminished cardiac ADK protein expression. CONCLUSION AND IMPLICATIONS: A positive feedback loop driven by adenosine receptor-induced ADK degradation and renewed adenosine signalling extends the duration of cardioprotection by ABT-702 and possibly other preconditioning agents. The therapeutic potential of continuous adenosinergic cardioprotection is demonstrated in cADK+/- hearts.
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BACKGROUND AND AIMS: Adenosine is a widely used potent cardioprotective drug, but the effect of an adenosine bolus in initial cardioplegia on cardioprotection in aortic valve replacement (AVR) patients has not been demonstrated. The aim of this double-blind randomized clinical trial was to compare intra-aortic adenosine bolus with saline on the postoperative myocardial function in patients undergoing AVR. METHODS: Aortic valve stenosis patients scheduled for elective or urgent AVR surgery were randomized to receive either a 20 mg (4 mL) single dose of adenosine or a saline into the ascending aorta during the first cardioplegia infusion. The primary outcome was cardiac index (CI (L/min/m2) at four timepoints (before incision, after weaning from cardiopulmonary bypass (CPB), at 7 p.m. on the operation day, and at 6 a.m. the next morning). Secondary outcomes included left ventricular stroke work index, right ventricular stroke work index, and myocardial biomarkers at the same timepoints. RESULTS: Between November 2015 and March 2018, 45 patients were recruited, 23 in the adenosine group and 22 in the placebo group. The last follow-up date was 17 March 2018. There were no statistically significant differences in CI (mean differences with 95% confidence interval (95% CI): 0.09 L/min/m2 at baseline (-0.20 to 0.38), -1.39 L/min/m2 (-3.47 to 0.70) at post-CPB, -0.39 L/min/m2 (-0.78 to 0.004) at 7 p.m., and -0.32 L/min/m2 (-0.68 to 0.05) at 6 a.m., (p = 0.066)), right ventricular stroke work index, (p = 0.24), or cardiac biomarkers between the groups. Left ventricular stroke work index was lower in the adenosine group (-3.66 gm/m2 (-11.13 to 3.81) at baseline, -17.42 gm/m2 (-37.81 to 2.98) at post-CPB, -3.36 gm/m2 (-11.10 to 4.38) at 7 p.m., and -3.77 gm/m2 (-10.19 to 2.66) at 6 a.m. (p = 0.021)). CONCLUSIONS: There were no differences between 20 mg adenosine bolus and saline in the first cardioplegia infusion in CI improvement in AVR surgery for aortic valve stenosis.EudraCT number: 2014-001382-26.
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Introduction and importance: Deficiency of adenosine deaminase 2 (DADA2) is a rare autosomal recessive genetic disorder caused by loss-of-function mutations in the adenosine deaminase 2 (ADA2) gene. This condition primarily manifests in pediatric cases before the age of 10 years, with sporadic cases reported in adults. ADA2 is a critical enzyme involved in macrophage differentiation and immune homeostasis. The clinical manifestations of DADA2 vary widely and can affect multiple organ systems. Our case uniquely highlights an infrequent DADA2 manifestation. Case presentation: An 18-year-old female presented with right flank pain, fever, and a history of joint pain, Raynaud's phenomenon, livedo-like rash, and chronic abdominal pain. Physical examination revealed subcapsular hematoma in the right kidney. Further evaluation showed positive serologic tests for rheumatoid factor and antinuclear antibody (ANA). Genetic testing confirmed DADA2 homozygosity. The patient was discharged on the appropriate medications. Clinical discussion: DADA2 is associated with vascular dysfunction and systemic vasculopathy. The clinical manifestations of DADA2 encompass a spectrum of organ involvement, including the skin, nervous system, gastrointestinal system, renal system, and the cardiovascular system. Early recognition and diagnosis are crucial for appropriate management. Conclusion: This case report highlights the diverse clinical presentations of ADA2 deficiency, specifically focusing on bilateral renal subcapsular hematoma. This finding emphasizes the importance of considering DADA2 as a differential diagnosis in patients presenting with unexplained renal manifestations. Increased awareness of the varied clinical presentations of DADA2 will contribute to earlier diagnosis, appropriate management, and improved outcomes in patients affected by this rare genetic disorder.
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Mitochondria are central to cellular metabolism; hence, their dysfunction contributes to a wide array of human diseases. Cardiolipin, the signature phospholipid of the mitochondrion, affects proper cristae morphology, bioenergetic functions, and metabolic reactions carried out in mitochondrial membranes. To match tissue-specific metabolic demands, cardiolipin typically undergoes an acyl tail remodeling process with the final step carried out by the phospholipid-lysophospholipid transacylase tafazzin. Mutations in tafazzin are the primary cause of Barth syndrome. Here, we investigated how defects in cardiolipin biosynthesis and remodeling impacts metabolic flux through the TCA cycle and associated yeast pathways. Nuclear magnetic resonance was used to monitor in real-time the metabolic fate of 13C3-pyruvate in isolated mitochondria from three isogenic yeast strains. We compared mitochondria from a wild-type strain to mitochondria from a Δtaz1 strain that lacks tafazzin and contains lower amounts of unremodeled cardiolipin, and mitochondria from a Δcrd1 strain that lacks cardiolipin synthase and cannot synthesize cardiolipin. We found that the 13C-label from the pyruvate substrate was distributed through twelve metabolites. Several of the metabolites were specific to yeast pathways including branched chain amino acids and fusel alcohol synthesis. While most metabolites showed similar kinetics amongst the different strains, mevalonate concentrations were significantly increased in Δtaz1 mitochondria. Additionally, the kinetic profiles of α-ketoglutarate, as well as NAD+ and NADH measured in separate experiments, displayed significantly lower concentrations for Δtaz1 and Δcrd1 mitochondria at most time points. Taken together, the results show how cardiolipin remodeling influences pyruvate metabolism, tricarboxylic acid cycle flux, and the levels of mitochondrial nucleotides.
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Recently a novel genetically modified mouse strain with serum carboxylesterase knocked-out and the human acetylcholinesterase gene knocked-in (KIKO) was created to simulate human responses to nerve agent (NA) exposure and its standard medical treatment. A1 adenosine receptor (A1AR) agonist N-bicyclo-(2.2.1)-hept-2-yl-5'-chloro-5'-deoxyadenosine (ENBA) alone is a potent anticonvulsant and neuroprotectant (A/N) in both rat and KIKO mouse soman (GD) seizure models. In this study we utilized the KIKO mouse to evaluate further the basic pharmacologic A/N effects of ENBA as an adjunct to standard NA medical treatments (i.e., atropine sulfate, pralidoxime chloride [2-PAM], and midazolam). Male mice, implanted with cortical electroencephalographic (EEG) electrodes, were pretreated with asoxime (HI-6) and exposed to an epileptogenic dose of GD (33 µg/kg, s.c.) or saline (sham exposure) and then treated 15 min after seizure onset with ENBA at 15 mg/kg, i.p. (a minimum efficacy dose in suppressing NA-induced seizure) alone or as an adjunct to standard medical treatments. We collected EEG activity, seizure suppression outcomes, daily body temperature and weight, heart rate, toxic signs, neuropathology, and lethality data for up to 14 days. Without ENBA, death from NA exposure was 45%, while with ENBA, either alone or in combination with midazolam, the survival improved to 80% and 90%, respectively. Additionally, seizure was suppressed quickly and permanently, toxic signs, hypothermia, and bradycardia recovered by 48 h, and no neuropathology was evident. Our findings confirmed that ENBA is a potent A/N adjunct for delayed medical treatments of NA exposure.
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Acetilcolinesterasa , Agonistas del Receptor de Adenosina A1 , Modelos Animales de Enfermedad , Convulsiones , Soman , Animales , Soman/toxicidad , Convulsiones/inducido químicamente , Convulsiones/tratamiento farmacológico , Masculino , Agonistas del Receptor de Adenosina A1/farmacología , Humanos , Ratones , Acetilcolinesterasa/metabolismo , Electroencefalografía , Adenosina/análogos & derivados , Adenosina/farmacología , Ratones Noqueados , Anticonvulsivantes/farmacología , Anticonvulsivantes/toxicidadRESUMEN
Background: Parkinson's disease (PD) is a complex neurodegenerative disorder characterized by dopamine depletion and severe motor impairments. Preladenant, an adenosine A2 receptor antagonist, is an investigational treatment for PD. This systematic review and meta-analysis aimed to critically evaluate the efficacy of Preladenant in improving motor symptoms in patients with PD. Methods: A comprehensive literature search was conducted in PubMed, Embase, and Cochrane Central Register of Controlled Trials from inception to March 2023, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Randomized controlled trials (RCTs) comparing Preladenant with placebo in PD patients were included. The primary outcome was the change in daily ON time without troublesome dyskinesia. Secondary outcomes included the change in daily OFF time and adverse events. The risk of bias was assessed using the Cochrane Risk of Bias tool. Results: Four RCTs with a total of 2097 PD patients were included. Pooled analysis showed that Preladenant could generally increase daily ON time (pooled effect 0.15 and 95â¯% CI: -0.19-0.48) and reduce daily OFF time (pooled effect -0.04 and 95â¯% CI: -0.43-0.36) compared to placebo, however it was not significant. The included studies had moderate to high heterogeneity. No significant differences in adverse events were observed between Preladenant and placebo. Conclusion: This meta-analysis suggests that Preladenant may improve motor fluctuations in PD patients by increasing ON time and reducing OFF time. However, the high heterogeneity among studies warrants further large-scale, high-quality RCTs to confirm these findings and establish the long-term safety and efficacy of Preladenant in PD management.
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Humans can flexibly switch between two primary metabolic modes, usually distinguished by whether substrate supply from glucose can meet energy demands or not. However, it is often overlooked that when glucose use is limited, the remainder of energy needs may still be met more or less effectively with fat and ketone bodies. Hence a fat-based metabolism marked by ketosis is often conflated with starvation and contexts of inadequate energy (including at the cellular level), even when energy itself is in ample supply. Sleep and satiation are regulated by common pathways reflecting energy metabolism. A conceptual analysis that distinguishes signals of inadequate energy in a glucose-dominant metabolism from signals of a fat-based metabolism that may well be energy sufficient allows a reexamination of experimental results in the study of sleep that may shed light on species differences and explain why ketogenic diets have beneficial effects simultaneously in the brain and the periphery. It may also help to distinguish clinically when a failure of a ketogenic diet to resolve symptoms is due to inadequate energy rather than the metabolic state itself.
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BACKGROUND: Phosphodiesterases (PDEs) are enzymes that catalyze the hydrolysis of cyclic adenosine monophosphate AMP (cAMP) and/or cyclic guanosine monophosphate (cGMP). PDE inhibitors can mitigate chronic pain and depression when these disorders occur individually; however, there is limited understanding of their role in concurrent chronic pain and depression. We aimed to evaluate the mechanisms of action of PDE using two mouse models of concurrent chronic pain and depression. METHODS: C57BL/6J mice were subjected to partial sciatic nerve ligation (PSNL) to induce chronic neuropathic pain or injected with complete Freund's adjuvant (CFA) to induce inflammatory pain, and both animals showed depression-like behavior. First, we determined the change in PDE expression in both animal models. Next, we determined the effect of PDE7 inhibitor BRL50481 or hippocampal PDE7A knockdown on PSNL- or CFA-induced chronic pain and depression-like behavior. We also investigated the role of cAMP-protein kinase A (PKA)-cAMP response element binding protein (CREB)-brain-derived neurotrophic factor (BDNF) signaling and neuroinflammation in the effect of PDE7A inhibition on PSNL- or CFA-induced chronic pain and depression-like behavior. RESULTS: This induction of chronic pain and depression in the two animal models upregulated hippocampal PDE7A. Oral administration of PDE7 inhibitor, BRL50481, or hippocampal PDE7A knockdown significantly reduced mechanical hypersensitivity and depression-like behavior. Hippocampal PDE7 inhibition reversed PSNL- or CFA-induced downregulation of cAMP and BDNF and the phosphorylation of PKA, CREB and p65. cAMP agonist forskolin, reversed these changes and caused milder behavioral symptoms of pain and depression. BRL50481 reversed neuroinflammation in the hippocampus in PSNL mice. CONCLUSIONS: Hippocampal PDE7A mediated concurrent chronic pain and depression in both mouse models by inhibiting cAMP-PKA-CREB-BDNF signaling Inhibiting PDE7A or activating cAMP-PKA-CREB-BDNF signaling are potential strategies to treat concurrent chronic pain and depression.
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The fields of allostery and amyloid-related pathologies, such as Parkinson's disease (PD), have been extensively explored individually, but less is known about how amyloids control allostery. Recent advancements have revealed that amyloids can drive allosteric effects in both intrinsically disordered proteins, such as alpha-synuclein (αS), and multi-domain signaling proteins, such as protein kinase A (PKA). Amyloid-driven allostery plays a central role in explaining the mechanisms of gain-of-pathological-function mutations in αS (e.g. E46K, which causes early PD onset) and loss-of-physiological-function mutations in PKA (e.g. A211D, which predisposes to tumors). This review highlights allosteric effects of disease-related mutations and how they can cause exposure of amyloidogenic regions, leading to amyloids that are either toxic or cause aberrant signaling. We also discuss multiple potential modulators of these allosteric effects, such as MgATP and kinase substrates, opening future opportunities to improve current pharmacological interventions against αS and PKA-related pathologies. Overall, we show that amyloid-driven allosteric models are useful to explain the mechanisms underlying disease-related mutations.
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BACKGROUND: Pleural effusion indicates an imbalance between pleural fluid formation and removal. Classified into exudative and transudative, with common symptoms of dry cough, dyspnea and pleuritic chest pain. Confirmed etiology has to be established for effective treatment. OBJECTIVE: Correlate clinical and biochemical profile of various etiologies of pleural effusion. MATERIALS & METHODS: Retrospective observational study of 2 years in the department of respiratory medicine, GMC Bhopal on 280 cases of pleural effusion. RESULTS: Most common etiology was tubercular 202 (72.4%) followed by malignant in 36 (12.8%). With respect to tubercular, malignant pleural effusion has relative risk (RR) of 0.138 (p value < 0.05) in the age group of 51-60 years, which is statistically significant. Patients of tuberculosis complained of fever 158 (78.2%) whereas with malignancy complained of chest pain 16 (44.4%) followed by hemoptysis 12 (33.3%). For hemoptysis, with respect to tubercular, malignant effusion has RR of 5.68 (p value < 0.05) which is significant. History of smoking was significant in malignant effusion with RR of 2.57 (p value < 0.05) as compared to tubercular. Pleural fluid ADA was >70 in 83.7% in tubercular effusion, glucose was <60 mg/dl in 79% tubercular, malignant and bacteriological cause, LDH was >1000 in 88.4% in bacteriological and 72.3% in malignant effusion. CONCLUSION: Lack of tools for confirming diagnosis leads to diagnostic dilemma and delay in treatment initiation, leading to deterioration and untoward fatality in some cases. Our goal is early diagnosis by correlating clinical symptoms with biochemical profile and help initiate rapid treatment.
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Derrame Pleural , Centros de Atención Terciaria , Humanos , Estudios Retrospectivos , Persona de Mediana Edad , India/epidemiología , Masculino , Femenino , Derrame Pleural/etiología , Derrame Pleural/diagnóstico , Derrame Pleural/epidemiología , Derrame Pleural/metabolismo , Adulto , Anciano , Derrame Pleural Maligno/diagnóstico , Derrame Pleural Maligno/etiología , Derrame Pleural Maligno/metabolismo , Tuberculosis Pleural/diagnóstico , Tuberculosis Pleural/epidemiología , Adulto Joven , Hemoptisis/etiología , Hemoptisis/epidemiología , Dolor en el Pecho/etiología , Adolescente , Adenosina Desaminasa/análisis , Fumar/epidemiología , Fiebre/etiologíaRESUMEN
OBJECTIVE: Glucocorticoid (GC)-induced adverse reactions (ARs) have been extensively studied due to their potential impact on patients' health. This study aimed to examine the potential correlation between two polymorphisms [adenosine triphosphate-binding cassette B1 (ABCB1) C3435T and plasminogen activator inhibitor-1 (PAI-1) 4G/5G] and various GC-induced ARs in nephrotic syndrome (NS) patients. METHODS: In this study, 513 NS patients who underwent GC treatment were enrolled. Then, the patients were divided into two groups based on ABCB1 C3435T and PAI-1 4G/5G genotyping, and intergroup comparisons of clinicopathological data and GC-induced ARs were performed. Univariate and multivariate logistic analyses were subsequently conducted to identify potential risk factors for GC-induced ARs, and a nomogram was subsequently established and validated via the area under the ROC curve (AUC), calibration curve and decision curve analysis (DCA). RESULTS: We identified ABCB1 C3435T as an independent risk factor for the development of steroid-associated avascular necrosis of the femoral head (SANFH) (OR: 2.191, 95% CI: 1.258-3.813, P=0.006) but not as a risk factor for the occurrence of steroid diabetes mellitus (S-DM). On the other hand, PAI-1 4G/5G was identified as an independent risk factor for the development of both SANFH (OR: 2.198, 95% CI: 1.267-3.812, P=0.005) and S-DM (OR: 2.080, 95% CI: 1.166-3.711, P=0.013). Notably, no significant correlation was found between the two gene polymorphisms and other GC-induced ARs. In addition, two nomograms were established and validated to demonstrate strong calibration capability and clinical utility. CONCLUSION: Assessing ABCB1 C3435T and PAI-1 4G/5G before steroid treatment in NS patients could be useful for identifying patients at a high risk of developing SANFH and S-DM.
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Ectophosphatases catalyse the hydrolysis of phosphorylated molecules, such as phospho-amino acids, in the extracellular environment. Nevertheless, the hydrolysis of nucleotides in the extracellular environment is typically catalysed by ectonucleotidases. Studies have shown that acid ectophosphatase, or transmembrane-prostatic acid phosphatase (TM-PAP), a membrane-bound splice variant of prostatic acid phosphatase, has ecto-5'-nucleotidase activity. Furthermore, it was demonstrated that ectophosphatase cannot hydrolyse ATP, ADP, or AMP in triple-negative breast cancer cells. In contrast to previous findings in MDA-MB-231 cells, the ectophosphatase studied in the present work displayed a remarkable capacity to hydrolyse AMP in luminal A breast cancer cells (MCF-7). We showed that AMP dose-dependently inhibited p-nitrophenylphosphate (p-NPP) hydrolysis. The p-NPP and AMP hydrolysis showed similar biochemical behaviours, such as increased hydrolysis under acidic conditions and comparable inhibition by NiCl2, ammonium molybdate, and sodium orthovanadate. In addition, this ectophosphatase with ectonucleotidase activity was essential for the release of adenosine and inorganic phosphate from phosphorylated molecules available in the extracellular microenvironment. This is the first study to show that prostatic acid phosphatase on the membrane surface of breast cancer cells (MCF-7) is correlated with cell adhesion and migration.
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Human dental tissue mesenchymal stem cells (DT-MSCs) constitute an attractive alternative to bone marrow-derived mesenchymal stem cells (BM-MSCs) for potential clinical applications because of their accessibility and anti-inflammatory capacity. We previously demonstrated that DT-MSCs from dental pulp (DP-MSCs), periodontal ligaments (PDL-MSCs), and gingival tissue (G-MSCs) show immunosuppressive effects similar to those of BM, but to date, the DT-MSC-mediated immunoregulation of T lymphocytes through the purinergic pathway remains unknown. In the present study, we compared DP-MSCs, PDL-MSCs, and G-MSCs in terms of CD26, CD39, and CD73 expression; their ability to generate adenosine (ADO) from ATP and AMP; and whether the concentrations of ADO that they generate induce an immunomodulatory effect on T lymphocytes. BM-MSCs were included as the gold standard. Our results show that DT-MSCs present similar characteristics among the different sources analyzed in terms of the properties evaluated; however, interestingly, they express more CD39 than BM-MSCs; therefore, they generate more ADO from ATP. In contrast to those produced by BM-MSCs, the concentrations of ADO produced by DT-MSCs from ATP inhibited the proliferation of CD3+ T cells and promoted the generation of CD4+CD25+FoxP3+CD39+CD73+ Tregs and Th17+CD39+ lymphocytes. Our data suggest that DT-MSCs utilize the adenosinergic pathway as an immunomodulatory mechanism and that this mechanism is more efficient than that of BM-MSCs.
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5'-Nucleotidasa , Adenosina , Apirasa , Pulpa Dental , Células Madre Mesenquimatosas , Ligamento Periodontal , Linfocitos T , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/inmunología , Humanos , Adenosina/metabolismo , Pulpa Dental/citología , Pulpa Dental/inmunología , Pulpa Dental/metabolismo , Linfocitos T/inmunología , Linfocitos T/metabolismo , 5'-Nucleotidasa/metabolismo , Apirasa/metabolismo , Ligamento Periodontal/citología , Ligamento Periodontal/metabolismo , Adenosina Trifosfato/metabolismo , Células Cultivadas , Encía/citología , Encía/metabolismo , Encía/inmunología , Antígenos CD/metabolismo , Inmunomodulación , Diferenciación Celular , Proliferación Celular , Dipeptidil Peptidasa 4/metabolismo , Transducción de Señal , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Proteínas Ligadas a GPIRESUMEN
Coffee intake is increasingly recognized as a life-style factor associated with the preservation of health, but there is still a debate on the relative effects of caffeinated and decaffeinated coffee. We now tested how the regular drinking of caffeinated and decaffeinated coffee for 3 weeks impacted on the behavior of male and female adult mice. Males drinking caffeinated coffee displayed statistically significant lower weight gain, increased sensorimotor coordination, greater motivation in the splash test, more struggling in the forced swimming test, faster onset of nest building, more marble burying and greater sociability. Females drinking caffeinated coffee displayed statistically significant increased hierarchy fighting, greater self-care and motivation in the splash test and faster onset of nest building. A post-hoc two-way ANOVA revealed sex-differences in the effects of caffeinated coffee (p values for interaction between the effect of caffeinated coffee and sex) on the hierarchy in the tube test (p = 0.044; dominance), in the time socializing (p = 0.044) and in the latency to grooming (p = 0.048; selfcare), but not in the marble burying test (p = 0.089). Intake of decaffeinated coffee was devoid of effects in males and females. Since caffeine targets adenosine receptors, we verified that caffeinated but not decaffeinated coffee intake increased the density of adenosine A1 receptors (A1R) and increased A1R-mediated tonic inhibition of synaptic transmission in the dorsolateral striatum and ventral but not dorsal hippocampus, the effects being more evident in the ventral hippocampus of females and striatum of males. In contrast, caffeinated and decaffeinated coffee both ameliorated the antioxidant status in the frontal cortex. It is concluded that caffeinated coffee increases A1R-mediated inhibition in mood-related areas bolstering wellbeing of both males and females, with increased sociability in males and hierarchy struggling and self-care in females.
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Conducta Animal , Cafeína , Café , Animales , Masculino , Femenino , Cafeína/farmacología , Ratones , Conducta Animal/efectos de los fármacos , Receptor de Adenosina A1/metabolismo , Factores Sexuales , Ratones Endogámicos C57BLRESUMEN
Damage-associated molecular patterns (DAMPs) are endogenous molecules released in tissues upon cellular damage and necrosis, acting to initiate sterile inflammation. Constitutive DAMPs (cDAMPs) have the particularity to be present within the intracellular compartments of healthy cells, where they exert diverse functions such as regulation of gene expression and cellular homeostasis. However, after injury to the central nervous system (CNS), cDAMPs are rapidly released by stressed, damaged or dying neuronal, glial and endothelial cells, and can trigger inflammation without undergoing structural modifications. Several cDAMPs have been described in the injured CNS, such as interleukin (IL)-1α, IL-33, nucleotides (e.g. ATP), and high-mobility group box protein 1. Once in the extracellular milieu, these molecules are recognized by the remaining surviving cells through specific DAMP-sensing receptors, thereby inducing a cascade of molecular events leading to the production and release of proinflammatory cytokines and chemokines, as well as cell adhesion molecules. The ensuing immune response is necessary to eliminate cellular debris caused by the injury, allowing for damage containment. However, seeing as some molecules associated with the inflammatory response are toxic to surviving resident CNS cells, secondary damage occurs, aggravating injury and exacerbating neurological and behavioral deficits. Thus, a better understanding of these cDAMPs, as well as their receptors and downstream signaling pathways, could lead to identification of novel therapeutic targets for treating CNS injuries such as SCI, TBI, and stroke. In this review, we summarize the recent literature on cDAMPs, their specific functions, and the therapeutic potential of interfering with cDAMPs or their signaling pathways.
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Alarminas , Sistema Nervioso Central , Humanos , Alarminas/metabolismo , Animales , Sistema Nervioso Central/metabolismo , Sistema Nervioso Central/lesiones , Inflamación/metabolismo , Citocinas/metabolismo , Proteína HMGB1/metabolismo , Interleucina-33/metabolismo , Interleucina-1alfa/metabolismo , Transducción de Señal/fisiologíaRESUMEN
The biological clocks of the circadian timing system coordinate cellular and physiological processes and synchronize them with daily cycles. While the central clock in the suprachiasmatic nucleus (SCN) is mainly synchronized by the light/dark cycles, the peripheral clocks react to other stimuli, including the feeding/fasting state, nutrients, sleep-wake cycles, and physical activity. During the disruption of circadian rhythms due to genetic mutations or social and occupational obligations, incorrect arrangement between the internal clock system and environmental rhythms leads to the development of obesity. Desynchronization between the central and peripheral clocks by altered timing of food intake and diet composition leads to uncoupling of the peripheral clocks from the central pacemaker and to the development of metabolic disorders. The strong coupling of the SCN to the light-dark cycle creates a situation of misalignment when food is ingested during the "wrong" time of day. Food-anticipatory activity is mediated by a self-sustained circadian timing, and its principal component is a food-entrainable oscillator. Modifying the time of feeding alone greatly affects body weight, whereas ketogenic diet (KD) influences circadian biology, through the modulation of clock gene expression. Night-eating behavior is one of the causes of circadian disruption, and night eaters have compulsive and uncontrolled eating with severe obesity. By contrast, time-restricted eating (TRE) restores circadian rhythms through maintaining an appropriate daily rhythm of the eating-fasting cycle. The hypothalamus has a crucial role in the regulation of energy balance rather than food intake. While circadian locomotor output cycles kaput (CLOCK) expression levels increase with high-fat diet-induced obesity, peroxisome proliferator-activated receptor-alpha (PPARα) increases the transcriptional level of brain and muscle aryl hydrocarbon receptor nuclear translocator (ARNT)-like 1 (BMAL1) in obese subjects. In this context, effective timing of chronotherapies aiming to correct SCN-driven rhythms depends on an accurate assessment of the SCN phase. In fact, in a multi-oscillator system, local rhythmicity and its disruption reflects the disruption of either local clocks or central clocks, thus imposing rhythmicity on those local tissues, whereas misalignment of peripheral oscillators is due to exosome-based intercellular communication.Consequently, disruption of clock genes results in dyslipidemia, insulin resistance, and obesity, while light exposure during the daytime, food intake during the daytime, and sleeping during the biological night promote circadian alignment between the central and peripheral clocks. Thus, shift work is associated with an increased risk of obesity, diabetes, and cardiovascular diseases because of unusual eating times as well as unusual light exposure and disruption of the circadian rhythm.
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Ritmo Circadiano , Conducta Alimentaria , Obesidad , Obesidad/fisiopatología , Obesidad/metabolismo , Obesidad/etiología , Ritmo Circadiano/fisiología , Humanos , Animales , Conducta Alimentaria/fisiología , Núcleo Supraquiasmático/metabolismo , Núcleo Supraquiasmático/fisiología , Núcleo Supraquiasmático/fisiopatología , Dieta Cetogénica/efectos adversos , Relojes Circadianos/fisiología , Relojes Circadianos/genéticaRESUMEN
Obesity-related co-morbidities decrease life quality, reduce working ability, and lead to early death. In the adult population, eating addiction manifests with excessive food consumption and the unrestrained overeating behavior, which is associated with increased risk of morbidity and mortality and defined as the binge eating disorder (BED). This hedonic intake is correlated with fat preference and the total amount of dietary fat consumption is the most potent risk factor for weight gain. Long-term BED leads to greater sensitivity to the rewarding effects of palatable foods and results in obesity fatefully. Increased plasma concentrations of non-esterified free fatty acids and lipid-overloaded hypertrophic adipocytes may cause insulin resistance. In addition to dietary intake of high-fat diet, sedentary lifestyle leads to increased storage of triglycerides not only in adipose tissue but also ectopically in other tissues. Lipid-induced apoptosis, ceramide accumulation, reactive oxygen species overproduction, endoplasmic reticulum stress, and mitochondrial dysfunction play role in the pathogenesis of lipotoxicity. Food addiction and BED originate from complex action of dopaminergic, opioid, and cannabinoid systems. BED may also be associated with both obesity and major depressive disorder. For preventing morbidity and mortality, as well as decreasing the impact of obesity-related comorbidities in appropriately selected patients, opiate receptor antagonists and antidepressant combination are recommended. Pharmacotherapy alongside behavioral management improves quality of life and reduces the obesity risk; however, the number of licensed drugs is very few. Thus, stereotactic treatment is recommended to break down the refractory obesity and binge eating in obese patient. As recent applications in the field of non-invasive neuromodulation, transcranial magnetic stimulation and transcranial direct current stimulation are thought to be important in image-guided deep brain stimulation in humans. Chronic overnutrition most likely provides repetitive and persistent signals that up-regulate inhibitor of nuclear factor kappa B (NF-κB) kinase beta subunit/NF-κB (IKKß/NF-κB) in the hypothalamus before the onset of obesity. However, how the mechanisms of high-fat diet-induced peripheral signals affect the hypothalamic arcuate nucleus remain largely unknown.
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Hiperfagia , Obesidad , Humanos , Hiperfagia/fisiopatología , Hiperfagia/psicología , Obesidad/metabolismo , Obesidad/fisiopatología , Trastorno por Atracón/terapia , Trastorno por Atracón/psicología , Trastorno por Atracón/fisiopatología , Animales , Conducta Alimentaria/fisiologíaRESUMEN
The action of protein kinases and protein phosphatases is essential for multiple physiological responses. Each protein kinase displays its own unique substrate specificity and a regulatory mechanism that may be modulated by association with other proteins. Protein kinases are classified as dual-specificity kinases and dual-specificity phosphatases. Dual-specificity phosphatases are important signal transduction enzymes that regulate various cellular processes in coordination with protein kinases and play an important role in obesity. Impairment of insulin signaling in obesity is largely mediated by the activation of the inhibitor of kappa B-kinase beta and the c-Jun N-terminal kinase (JNK). Oxidative stress and endoplasmic reticulum (ER) stress activate the JNK pathway which suppresses insulin biosynthesis. Adenosine monophosphate (AMP)-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) are important for proper regulation of glucose metabolism in mammals at both the hormonal and cellular levels. Additionally, obesity-activated calcium/calmodulin dependent-protein kinase II/p38 suppresses insulin-induced protein kinase B phosphorylation by activating the ER stress effector, activating transcription factor-4. To alleviate lipotoxicity and insulin resistance, promising targets are pharmacologically inhibited. Nifedipine, calcium channel blocker, stimulates lipogenesis and adipogenesis by downregulating AMPK and upregulating mTOR, which thereby enhances lipid storage. Contrary to the nifedipine, metformin activates AMPK, increases fatty acid oxidation, suppresses fatty acid synthesis and deposition, and thus alleviates lipotoxicity. Obese adults with vascular endothelial dysfunction have greater endothelial cells activation of unfolded protein response stress sensors, RNA-dependent protein kinase-like ER eukaryotic initiation factor-2 alpha kinase (PERK), and activating transcription factor-6. The transcriptional regulation of adipogenesis in obesity is influenced by AGC (protein kinase A (PKA), PKG, PKC) family signaling kinases. Obesity may induce systemic oxidative stress and increase reactive oxygen species in adipocytes. An increase in intracellular oxidative stress can promote PKC-ß activation. Activated PKC-ß induces growth factor adapter Shc phosphorylation. Shc-generated peroxides reduce mitochondrial oxygen consumption and enhance triglyceride accumulation and lipotoxicity. Liraglutide attenuates mitochondrial dysfunction and reactive oxygen species generation. Co-treatment of antiobesity and antidiabetic herbal compound, berberine with antipsychotic drug olanzapine decreases the accumulation of triglyceride. While low-dose rapamycin, metformin, amlexanox, thiazolidinediones, and saroglitazar protect against insulin resistance, glucagon-like peptide-1 analog liraglutide inhibits palmitate-induced inflammation by suppressing mTOR complex 1 (mTORC1) activity and protects against lipotoxicity.
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Obesidad , Humanos , Obesidad/metabolismo , Obesidad/tratamiento farmacológico , Animales , Proteínas Quinasas/metabolismo , Transducción de Señal/efectos de los fármacos , Terapia Molecular Dirigida , Resistencia a la Insulina , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéuticoRESUMEN
The adiponectin (APN) levels in obesity are negatively correlated with chronic subclinical inflammation markers. The hypertrophic adipocytes cause obesity-linked insulin resistance and metabolic syndrome. Furthermore, macrophage polarization is a key determinant regulating adiponectin receptor (AdipoR1/R2) expression and differential adiponectin-mediated macrophage inflammatory responses in obese individuals. In addition to decrease in adiponectin concentrations, the decline in AdipoR1/R2 messenger ribonucleic acid (mRNA) expression leads to a decrement in adiponectin binding to cell membrane, and this turns into attenuation in the adiponectin effects. This is defined as APN resistance, and it is linked with insulin resistance in high-fat diet-fed subjects. The insulin-resistant group has a significantly higher leptin-to-APN ratio. The leptin-to-APN ratio is more than twofold higher in obese individuals. An increase in expression of AdipoRs restores insulin sensitivity and ß-oxidation of fatty acids via triggering intracellular signal cascades. The ratio of high molecular weight to total APN is defined as the APN sensitivity index (ASI). This index is correlated to insulin sensitivity. Homeostasis model of assessment (HOMA)-APN and HOMA-estimated insulin resistance (HOMA-IR) are the most suitable methods to estimate the metabolic risk in metabolic syndrome. While morbidly obese patients display a significantly higher plasma leptin and soluble (s)E-selectin concentrations, leptin-to-APN ratio, there is a significant negative correlation between leptin-to-APN ratio and sP-selectin in obese patients. When comparing the metabolic dysregulated obese group with the metabolically healthy obese group, postprandial triglyceride clearance, insulin resistance, and leptin resistance are significantly delayed following the oral fat tolerance test in the first group. A neuropeptide, Spexin (SPX), is positively correlated with the quantitative insulin sensitivity check index (QUICKI) and APN. APN resistance together with insulin resistance forms a vicious cycle. Despite normal or high APN levels, an impaired post-receptor signaling due to adaptor protein-containing pleckstrin homology domain, phosphotyrosine-binding domain, and leucine zipper motif 1 (APPL1)/APPL2 may alter APN efficiency and activity. However, APPL2 blocks adiponectin signaling through AdipoR1 and AdipoR2 because of the competitive inhibition of APPL1. APPL1, the intracellular binding partner of AdipoRs, is also an important mediator of adiponectin-dependent insulin sensitization. The elevated adiponectin levels with adiponectin resistance are compensatory responses in the condition of an unusual discordance between insulin resistance and APN unresponsiveness. Hypothalamic recombinant adeno-associated virus (rAAV)-leptin (Lep) gene therapy reduces serum APN levels, and it is a more efficient strategy for long-term weight maintenance.