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INTRODUCTION: Septic shock, a life-threatening condition, can result in cerebral dysfunction and heightened mortality rates. In these patients, disturbances in cerebral hemodynamics, as reflected by impairment of myogenic cerebral autoregulation (CA), metabolic regulation, expressed by critical closing pressure (CrCP) and reductions in intracranial compliance (ICC), can adversely impact septic shock outcomes. The general recommendation is to maintain a target mean arterial pressure (MAP) of 65 mmHg but the effect of different MAP targets on cerebral hemodynamics in these patients is not clear and optimal targets might be dependent on the status of CA. This protocol aims to assess the cerebral hemodynamics profile at different pressure targets in septic shock patients. METHODS: Prospective, non-randomized, single-center trial, which will study cerebral hemodynamics in patients with septic shock within 48 hours of its onset. Patients will be studied at their baseline MAP and at three MAP targets (T1: 65, T2: 75, T3: 85 mmHg). Cerebral hemodynamics will be assessed by transcranial Doppler (TCD) and a skull micro-deformation sensor (B4C). Dynamic CA will be expressed by the autoregulation index (ARI), calculated by transfer function analysis, using fluctuations of MAP as input and corresponding oscillations in cerebral blood velocity (CBv). The instantaneous relationship between arterial blood pressure and CBv will be used to estimate CrCP and resistance-area product (RAP) for each cardiac cycle using the first harmonic method. The B4C will access ICC by intracranial pressure waveforms (P2/P1). The primary aim is to assess cerebral hemodynamics (ARI, CrCP, RAP, and P2/P1) at different targets of MAP in septic shock patients. Our secondary objective is to assess cerebral hemodynamics at 65mmHg (target recommended by guidelines). In addition, we will assess the correlation between markers of organ dysfunction (such as lactate levels, vasoactive drugs usage, SOFA score, and delirium) and CA. ETHICS AND DISSEMINATION: The results of this study may help to understand the effect of the recommended MAP and variations in blood pressure in patients with septic shock and impaired CA and ICC. Furthermore, the results can assist large trials in establishing new hypotheses about neurological management in this group of patients. Approval was obtained from the local Ethics Committee (28134720.1.0000.0048). It is anticipated that the results of this study will be presented at national and international conferences and will be published in peer-reviewed journals in 2024 and 2025. TRIAL REGISTRATION: Trial registration number: NCT05833607. https://clinicaltrials.gov/study/NCT05833607.

Asunto(s)

Circulación Cerebrovascular , Hemodinámica , Choque Séptico , Humanos , Choque Séptico/fisiopatología , Estudios Prospectivos , Proyectos Piloto , Circulación Cerebrovascular/fisiología , Presión Sanguínea , Encéfalo/fisiopatología , Encéfalo/diagnóstico por imagen , Homeostasis , Masculino , Presión Arterial , Ultrasonografía Doppler Transcraneal/métodos , Femenino

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Copper homeostasis in fungi is a tightly regulated process crucial for cellular functions. Fungi acquire copper from their environment, with transporters facilitating its uptake into the cell. Once inside, copper is utilized in various metabolic pathways, including respiration and antioxidant defense. However, excessive copper can be toxic by promoting cell damage mainly due to oxidative stress and metal displacements. Fungi employ intricate regulatory mechanisms to maintain optimal copper levels. These involve transcription factors that control the expression of genes involved in copper transport, storage, and detoxification. Additionally, chaperone proteins assist in copper trafficking within the cell, ensuring its delivery to specific targets. Furthermore, efflux pumps help remove excess copper from the cell. Altogether, these mechanisms enable fungi to balance copper levels, ensuring proper cellular function while preventing toxicity. Understanding copper homeostasis in fungi is not only essential for fungal biology but also holds implications for various applications, including biotechnology and antifungal drug development.

Asunto(s)

Cobre , Hongos , Homeostasis , Cobre/metabolismo , Hongos/metabolismo , Hongos/genética , Regulación Fúngica de la Expresión Génica , Proteínas Fúngicas/metabolismo , Proteínas Fúngicas/genética , Transporte Biológico , Chaperonas Moleculares/metabolismo , Chaperonas Moleculares/genética , Factores de Transcripción/metabolismo , Factores de Transcripción/genética

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Microglia are highly dynamic cells that have been mainly studied under pathological conditions. The present review discusses the possible implication of microglia as modulators of neuronal electrical responses in physiological conditions and hypothesizes how these cells might modulate hypothalamic circuits in health and during obesity. Microglial cells studied under physiological conditions are highly diverse, depending on the developmental stage and brain region. The evidence also suggests that neuronal electrical activity modulates microglial motility to control neuronal excitability. Additionally, we show that the expression of genes associated with neuron-microglia interaction is down-regulated in obese mice compared to control-fed mice, suggesting an alteration in the contact-dependent mechanisms that sustain hypothalamic arcuate-median eminence neuronal function. We also discuss the possible implication of microglial-derived signals for the excitability of hypothalamic neurons during homeostasis and obesity. This review emphasizes the importance of studying the physiological interplay between microglia and neurons to maintain proper neuronal circuit function. It aims to elucidate how disruptions in the normal activities of microglia can adversely affect neuronal health.

Asunto(s)

Núcleo Arqueado del Hipotálamo , Homeostasis , Microglía , Neuronas , Microglía/metabolismo , Animales , Núcleo Arqueado del Hipotálamo/metabolismo , Humanos , Neuronas/metabolismo , Neuronas/fisiología , Obesidad/metabolismo , Obesidad/fisiopatología , Ratones

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Interleukin (IL) 17 is a proinflammatory cytokine belonging to a structurally related group of cytokines known as the IL-17 family. It has been profoundly studied for its contribution to the pathology of autoimmune diseases. However, it also plays an important role in homeostasis and the defense against extracellular bacteria and fungi. IL-17 is important for epithelial barriers, including the skin, where some of its cellular targets reside. Most of the research work on IL-17 has focused on its effects in the skin within the context of autoimmune diseases or sterile inflammation, despite also having impact on other skin conditions. In recent years, studies on the role of IL-17 in the defense against skin pathogens and in the maintenance of skin homeostasis mediated by the microbiota have grown in importance. Here we review and discuss the cumulative evidence regarding the main contribution of IL-17 in the maintenance of skin integrity as well as its protective or pathogenic effects during some skin infections.

Asunto(s)

Interleucina-17 , Piel , Animales , Humanos , Homeostasis , Interleucina-17/inmunología , Interleucina-17/metabolismo , Piel/inmunología , Piel/microbiología , Piel/patología , Enfermedades Cutáneas Infecciosas/inmunología , Enfermedades Cutáneas Infecciosas/microbiología , Enfermedades Autoinmunes/inmunología

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Environmental factors in the early life stages can lead the descendant to adaptations in gene expression, permanently impacting several structures and organs. The amount and quality of fatty acids in the maternal diet in pregnancy and lactation were found to impact offspring metabolism. So, maternal diet and insulin resistance can affect the male and female descendants through distinct pathways and at different time points. We hypothesized that maternal high-fat diet (HFD) intake before conception and an adequate amount of different fatty acids intake during pregnancy and lactation could influence the energy homeostasis system of 21-day-old offspring. Female rats received control diet (C) or HFD (HF) for 8 weeks before pregnancy. During pregnancy and lactation C group remained with same diet (C-C), HF group were distributed into 4 groups and received C diet (HF-C), normolipidic diet based on saturated fatty acids (HF-S) or based on polyunsaturated fatty acids n-3 (HF-P) or remained in same diet (HF-HF). Maternal HFD in preconception, pregnancy, and lactation (HF-HF) led to lower glucagon-like peptide-1 levels in male (HF-HF21) compared to other groups (C-C21, HF-C21, and HF-P21) and compared to HF-HF21 females. Neuropeptide YY levels were higher in the HF-HF21, HF-C21, and HF-S21 male offspring compared to HF-P21. HF-P21 was similar to C-C21. Positive correlations were found among the energy homeostasis markers genes expressed in the offspring hypothalamus. Maternal diet changes to adequate quantities of fatty acids during pregnancy and lactation showed less impaired results but was not entirely avoided. A maternal diet based on PUFA n-3 during pregnancy and lactation seems to reverse the damage of an HFD in preconception. These results of homeostasis energy system disturbance in the offspring at weaning give us clues about changes that precede the onset of the disease in adult life - adding notes to the knowledge for future investigations of prevention and treatment of chronic diseases.

Asunto(s)

Dieta Alta en Grasa , Metabolismo Energético , Ácidos Grasos , Intolerancia a la Glucosa , Homeostasis , Lactancia , Fenómenos Fisiologicos Nutricionales Maternos , Destete , Femenino , Animales , Masculino , Embarazo , Ácidos Grasos/metabolismo , Ácidos Grasos/administración & dosificación , Dieta Alta en Grasa/efectos adversos , Ratas , Lactancia/fisiología , Ratas Wistar , Efectos Tardíos de la Exposición Prenatal , Resistencia a la Insulina

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Over the last few decades, scientists have recognized the critical role that various components of the extracellular matrix (ECM) play in maintaining homeostatic immunity. Besides, dysregulation in the synthesis or degradation levels of these components directly impacts the mechanisms of immune response during tissue injury caused by tumor processes or the regeneration of the tissue itself in the event of damage. ECM is a complex network of protein compounds, proteoglycans and glycosaminoglycans (GAGs). Hyaluronic acid (HA) is one of the major GAGs of this network, whose metabolism is strictly physiologically regulated and quickly altered in injury processes, affecting the behavior of different cells, from stem cells to differentiated immune cells. In this revision we discuss how the native or chemically modified HA interacts with its specific receptors and modulates intra and intercellular communication of immune cells, focusing on cancer and tissue regeneration conditions.

Asunto(s)

Homeostasis , Ácido Hialurónico , Neoplasias , Regeneración , Humanos , Ácido Hialurónico/metabolismo , Ácido Hialurónico/química , Neoplasias/metabolismo , Neoplasias/inmunología , Neoplasias/patología , Animales , Matriz Extracelular/metabolismo , Inmunidad

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OBJECTIVES: To determine how age affects insulin resistance during the menstrual cycle and insulin resistance-associated indices: the Triglyceride-glucose and Triglyceride-glucose-BMI indexes. METHODS: This prospective observational study used fasting plasma glucose, fasting insulin, triglycerides, body mass index (BMI), and days since the start of the menstrual period collected from the NHANES dataset (1999-2006). Insulin resistance was determined using the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR). The participants were categorized as young (16-34 years) or older (>35 years). Rhythmicity during the menstrual cycle was analyzed using the Cosinor and Cosinor2 packages for R. MAIN OUTCOME MEASURES: Cosine fit curves for insulin resistance during the menstrual cycle and age-associated effects on rhythmicity. RESULTS: Using 1256 participants, rhythmicity was observed for fasting insulin and HOMA-IR (p < 0.05) but not for fasting plasma glucose, the Triglyceride-glucose index, or the Triglyceride-glucose-BMI index. Significant amplitudes for fasting insulin and HOMA-IR were observed when age was considered. Acrophases for fasting insulin and HOMA-IR were significant only for the younger group, and the differences between these groups were significant, suggesting that the changes in scores for insulin resistance for the younger and older groups occur at different times of their menstrual cycle. CONCLUSIONS: Insulin resistance does fluctuate during the menstrual cycle, and it is at a maximum at different times for younger and older women. Since these results are unadjusted, this study is preliminary and further investigation is required.

Asunto(s)

Glucemia , Índice de Masa Corporal , Resistencia a la Insulina , Insulina , Ciclo Menstrual , Triglicéridos , Humanos , Femenino , Adulto , Triglicéridos/sangre , Ciclo Menstrual/sangre , Glucemia/metabolismo , Adulto Joven , Adolescente , Insulina/sangre , Estudios Transversales , Estudios Prospectivos , Factores de Edad , Encuestas Nutricionales , Ayuno/sangre , Persona de Mediana Edad , Homeostasis

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A T-cell-independent (TI) pathway activated by microbiota results in the generation of low-affinity homeostatic IgA with a critical role in intestinal homeostasis. Moderate aerobic exercise (MAE) provides a beneficial impact on intestinal immunity, but the action of MAE on TI-IgA generation under senescence conditions is unknown. This study aimed to determine the effects of long-term MAE on TI-IgA production in young (3 month old) BALB/c mice exercised until adulthood (6 months) or aging (24 months). Lamina propria (LP) from the small intestine was obtained to determine B cell and plasma cell sub-populations by flow cytometry and molecular factors related to class switch recombination [Thymic Stromal Lymphopoietin (TSLP), A Proliferation-Inducing Ligand (APRIL), B Cell Activating Factor (BAFF), inducible nitric oxide synthase (iNOS), and retinal dehydrogenase (RDH)] and the synthesis of IgA [α-chain, interleukin (IL)-6, IL-21, and Growth Factor-ß (TGF-ß)]; and epithelial cells evaluated IgA transitosis [polymeric immunoglobulin receptor (pIgR), tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), IL-4] by the RT-qPCR technique. The results were compared with data obtained from sedentary age-matched mice. Statistical analysis was computed with ANOVA, and p < 0.05 was considered to be a statistically significant difference. Under senescence conditions, MAE promoted the B cell and IgA+ B cells and APRIL, which may improve the intestinal response and ameliorate the inflammatory environment associated presumably with the downmodulation of pro-inflammatory mediators involved in the upmodulation of pIgR expression. Data suggested that MAE improved IgA and downmodulate the cytokine pro-inflammatory expression favoring homeostatic conditions in aging.

Asunto(s)

Envejecimiento , Homeostasis , Inmunoglobulina A , Ratones Endogámicos BALB C , Condicionamiento Físico Animal , Animales , Inmunoglobulina A/metabolismo , Inmunoglobulina A/inmunología , Ratones , Envejecimiento/inmunología , Citocinas/metabolismo , Linfocitos B/inmunología , Linfocitos B/metabolismo , Factor Activador de Células B/metabolismo , Factor Activador de Células B/genética , Mucosa Intestinal/metabolismo , Mucosa Intestinal/inmunología , Intestino Delgado/inmunología , Intestino Delgado/metabolismo , Masculino , Células Plasmáticas/inmunología , Células Plasmáticas/metabolismo , Miembro 13 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/metabolismo , Miembro 13 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/genética

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Astrocytes provide metabolic support to neurons, maintain ionic and water homeostasis, and uptake and recycle neurotransmitters. After exposure to the prototypical PAMP lipopolysaccharide (LPS), reactive astrocytes increase the expression of pro-inflammatory genes, facilitating neurodegeneration. In this study, we analyzed the expression of homeostatic genes in astrocytes exposed to LPS and identified the epigenetic factors contributing to the suppression of homeostatic genes in reactive astrocytes. Primary astrocytic cultures were acutely exposed to LPS and allowed to recover for 24, 72 h, and 7 days. As expected, LPS exposure induced reactive astrogliosis and increased the expression of pro-inflammatory IL-1B and IL-6. Interestingly, the acute exposure resulted in persistent hypermethylation of astroglial DNA. Similar hypermethylation was observed in highly reactive astrocytes from the traumatic brain injury (TBI) penumbra in vivo. Hypermethylation was accompanied by decreased expression of homeostatic genes including LDHA and Scl16a1 (MCT1) both involved in the lactate shuttle to neurons; glutamine synthase (GS) responsible for glutamate processing; Kcnj10 (Kir4.1) important for K+ homeostasis, and the water channel aquaporin-4 (Aqp4). Furthermore, the master regulator of DNA methylation, MAFG-1, as well as DNA methyl transferases DNMT1 and DNMT3a were overexpressed. The downregulation of homeostatic genes correlated with increased methylation of CpG islands in their promoters, as assessed by methylation-sensitive PCR and increased DNMT3a binding to the GS promoter. Treatment with decitabine, a DNMT inhibitor, prevented the LPS- and the HMGB-1-induced downregulation of homeostatic genes. Decitabine treatment also prevented the neurotoxic effects of these astrocytes in primary cortical cultures. In summary, our findings reveal that the pathological remodeling of reactive astrocytes encompasses not only the pro-inflammatory response but, significantly, also entails a long-term suppression of homeostatic gene expression with methylation of crucial CpG islands within their promoters.

Asunto(s)

Astrocitos , Metilación de ADN , Regulación hacia Abajo , Homeostasis , Astrocitos/metabolismo , Astrocitos/efectos de los fármacos , Astrocitos/patología , Metilación de ADN/efectos de los fármacos , Animales , Homeostasis/efectos de los fármacos , Regulación hacia Abajo/efectos de los fármacos , Células Cultivadas , Lipopolisacáridos/farmacología , Masculino , Ratones , Lesiones Traumáticas del Encéfalo/patología , Lesiones Traumáticas del Encéfalo/metabolismo , Lesiones Traumáticas del Encéfalo/genética , Ratas , Ratones Endogámicos C57BL

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Successful heart development depends on the careful orchestration of a network of transcription factors and signaling pathways. In recent years, in vitro cardiac differentiation using human pluripotent stem cells (hPSCs) has been used to uncover the intricate gene-network regulation involved in the proper formation and function of the human heart. Here, we searched for uncharacterized cardiac-development genes by combining a temporal evaluation of human cardiac specification in vitro with an analysis of gene expression in fetal and adult heart tissue. We discovered that CARDEL (CARdiac DEvelopment Long non-coding RNA; LINC00890; SERTM2) expression coincides with the commitment to the cardiac lineage. CARDEL knockout hPSCs differentiated poorly into cardiac cells, and hPSC-derived cardiomyocytes showed faster beating rates after controlled overexpression of CARDEL during differentiation. Altogether, we provide physiological and molecular evidence that CARDEL expression contributes to sculpting the cardiac program during cell-fate commitment.

Asunto(s)

Diferenciación Celular , Corazón , Homeostasis , Miocitos Cardíacos , ARN Largo no Codificante , Humanos , Diferenciación Celular/genética , Linaje de la Célula/genética , Regulación del Desarrollo de la Expresión Génica , Corazón/embriología , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/citología , Organogénesis/genética , Células Madre Pluripotentes/metabolismo , Células Madre Pluripotentes/citología , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo

RESUMEN

This chapter (part one of a trilogy) summarizes the neurobiological foundations of endogenous opioids in the regulation of energy balance and eating behavior, dysregulation of which translates to maladaptive dietary responses in individuals with obesity and eating disorders, including anorexia, bulimia, and binge eating disorder. Knowledge of these neurobiological foundations is vital to researchers' and clinicians' understanding of pathophysiology as well as the science-based development of multidisciplinary diagnoses and treatments for obesity and eating disorders. We highlight mechanisms of endogenous opioids in both homeostatic and hedonic feeding behavior, review research on the dysregulation of food reward that plays a role in a wide array of obesity and disordered eating, and the clinical implications of neurobiological responses to food for current science-based treatments for obesity and eating disorders.

Asunto(s)

Conducta Alimentaria , Homeostasis , Hambre , Obesidad , Péptidos Opioides , Humanos , Homeostasis/fisiología , Hambre/fisiología , Péptidos Opioides/metabolismo , Obesidad/metabolismo , Obesidad/fisiopatología , Conducta Alimentaria/fisiología , Trastornos de Alimentación y de la Ingestión de Alimentos/metabolismo , Trastornos de Alimentación y de la Ingestión de Alimentos/fisiopatología , Saciedad/fisiología , Recompensa , Metabolismo Energético/fisiología , Ingestión de Alimentos/fisiología , Animales

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Introduction: TAM receptor-mediated efferocytosis plays an important function in immune regulation and may contribute to antigen tolerance in the lungs, a site with continuous cellular turnover and generation of apoptotic cells. Some studies have identified failures in efferocytosis as a common driver of inflammation and tissue destruction in lung diseases. Our study is the first to characterize the in vivo function of the TAM receptors, Axl and MerTk, in the innate immune cell compartment, cytokine and chemokine production, as well as the alveolar macrophage (AM) phenotype in different settings in the airways and lung parenchyma. Methods: We employed MerTk and Axl defective mice to induce acute silicosis by a single exposure to crystalline silica particles (20 mg/50 µL). Although both mRNA levels of Axl and MerTk receptors were constitutively expressed by lung cells and isolated AMs, we found that MerTk was critical for maintaining lung homeostasis, whereas Axl played a role in the regulation of silica-induced inflammation. Our findings imply that MerTk and Axl differently modulated inflammatory tone via AM and neutrophil recruitment, phenotype and function by flow cytometry, and TGF-ß and CXCL1 protein levels, respectively. Finally, Axl expression was upregulated in both MerTk-/- and WT AMs, confirming its importance during inflammation. Conclusion: This study provides strong evidence that MerTk and Axl are specialized to orchestrate apoptotic cell clearance across different circumstances and may have important implications for the understanding of pulmonary inflammatory disorders as well as for the development of new approaches to therapy.

Asunto(s)

Tirosina Quinasa del Receptor Axl , Homeostasis , Pulmón , Macrófagos Alveolares , Ratones Noqueados , Proteínas Proto-Oncogénicas , Proteínas Tirosina Quinasas Receptoras , Silicosis , Tirosina Quinasa c-Mer , Animales , Ratones , Tirosina Quinasa c-Mer/metabolismo , Tirosina Quinasa c-Mer/genética , Citocinas/metabolismo , Modelos Animales de Enfermedad , Pulmón/inmunología , Pulmón/metabolismo , Pulmón/patología , Macrófagos Alveolares/inmunología , Macrófagos Alveolares/metabolismo , Ratones Endogámicos C57BL , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas/genética , Proteínas Tirosina Quinasas Receptoras/metabolismo , Proteínas Tirosina Quinasas Receptoras/genética , Silicosis/metabolismo , Silicosis/inmunología , Silicosis/patología , Masculino

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Transient or partial synchronization can be used to do computations, although a fully synchronized network is sometimes related to the onset of epileptic seizures. Here, we propose a homeostatic mechanism that is capable of maintaining a neuronal network at the edge of a synchronization transition, thereby avoiding the harmful consequences of a fully synchronized network. We model neurons by maps since they are dynamically richer than integrate-and-fire models and more computationally efficient than conductance-based approaches. We first describe the synchronization phase transition of a dense network of neurons with different tonic spiking frequencies coupled by gap junctions. We show that at the transition critical point, inputs optimally reverberate through the network activity through transient synchronization. Then, we introduce a local homeostatic dynamic in the synaptic coupling and show that it produces a robust self-organization toward the edge of this phase transition. We discuss the potential biological consequences of this self-organization process, such as its relation to the Brain Criticality hypothesis, its input processing capacity, and how its malfunction could lead to pathological synchronization and the onset of seizure-like activity.

Asunto(s)

Homeostasis , Modelos Neurológicos , Red Nerviosa , Neuronas , Homeostasis/fisiología , Neuronas/fisiología , Red Nerviosa/fisiología , Humanos , Potenciales de Acción/fisiología , Animales , Simulación por Computador , Encéfalo/fisiología , Transmisión Sináptica/fisiología

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The immune system is traditionally classified as a defense system that can discriminate between self and non-self or dangerous and non-dangerous situations, unleashing a tolerogenic reaction or immune response. These activities are mainly coordinated by the interaction between innate and adaptive cells that act together to eliminate harmful stimuli and keep tissue healthy. However, healthy tissue is not always the end point of an immune response. Much evidence has been accumulated over the years, showing that the immune system has complex, diversified, and integrated functions that converge to maintaining tissue homeostasis, even in the absence of aggression, interacting with the tissue cells and allowing the functional maintenance of that tissue. One of the main cells known for their function in helping the immune response through the production of cytokines is CD4+ T lymphocytes. The cytokines produced by the different subtypes act not only on immune cells but also on tissue cells. Considering that tissues have specific mediators in their architecture, it is plausible that the presence and frequency of CD4+ T lymphocytes of specific subtypes (Th1, Th2, Th17, and others) maintain tissue homeostasis. In situations where homeostasis is disrupted, such as infections, allergies, inflammatory processes, and cancer, local CD4+ T lymphocytes respond to this disruption and, as in the healthy tissue, towards the equilibrium of tissue dynamics. CD4+ T lymphocytes can be manipulated by tumor cells to promote tumor development and metastasis, making them a prognostic factor in various types of cancer. Therefore, understanding the function of tissue-specific CD4+ T lymphocytes is essential in developing new strategies for treating tissue-specific diseases, as occurs in cancer. In this context, this article reviews the evidence for this hypothesis regarding the phenotypes and functions of CD4+ T lymphocytes and compares their contribution to maintaining tissue homeostasis in different organs in a steady state and during tumor progression.

Asunto(s)

Linfocitos T CD4-Positivos , Homeostasis , Neoplasias , Animales , Humanos , Adaptación Fisiológica/inmunología , Linfocitos T CD4-Positivos/inmunología , Citocinas/metabolismo , Citocinas/inmunología , Homeostasis/inmunología , Neoplasias/inmunología , Neoplasias/patología , Microambiente Tumoral/inmunología

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UNASSIGNED: Excess body weight has become a global epidemic and a significant risk factor for developing chronic diseases, which are the leading causes of worldwide morbidities. Adipose tissue (AT), primarily composed of adipocytes, stores substantial amounts of energy and plays a crucial role in maintaining whole-body glucose and lipid metabolism. This helps prevent excessive body fat accumulation and lipotoxicity in peripheral tissues. In addition, AT contains endothelial cells and a substantial population of immune cells (constituting 60-70% of non-adipocyte cells), including macrophages, T and B lymphocytes, and natural killer cells. These resident immune cells engage in crosstalk with adipocytes, contributing to the maintenance of metabolic and immune homeostasis in AT. An exacerbated inflammatory response or inadequate immune resolution can lead to chronic systemic low-grade inflammation, triggering the development of metabolic alterations and the onset of chronic diseases. This review aims to elucidate the regulatory mechanisms through which immune cells influence AT function and energy homeostasis. We also focus on the interactions and functional dynamics of immune cell populations, highlighting their role in maintaining the delicate balance between metabolic health and obesity-related inflammation. Finally, understanding immunometabolism is crucial for unraveling the pathogenesis of metabolic diseases and developing targeted immunotherapeutic strategies. These strategies may offer innovative avenues in the rapidly evolving field of immunometabolism. (Rev Invest Clin. 2024;76(2):65-79).

Asunto(s)

Tejido Adiposo , Inflamación , Enfermedades Metabólicas , Obesidad , Humanos , Tejido Adiposo/metabolismo , Tejido Adiposo/inmunología , Obesidad/inmunología , Obesidad/metabolismo , Inflamación/inmunología , Inflamación/metabolismo , Enfermedades Metabólicas/inmunología , Enfermedades Metabólicas/metabolismo , Enfermedades Metabólicas/etiología , Metabolismo Energético/fisiología , Adipocitos/metabolismo , Adipocitos/inmunología , Metabolismo de los Lípidos/fisiología , Animales , Homeostasis

RESUMEN

STUDY OBJECTIVES: Sleep deprivation is a potential risk factor for metabolic diseases, including obesity and type 2 diabetes. We evaluated the impacts of moderate chronic sleep deprivation on glucose and lipid homeostasis in adult rats. METHODS: Wistar rats (both sexes) were sleep-perturbed daily for 2 hours at the early (06:00-08:00) and the late light cycle (16:00-18:00) five days a week (except weekends) for 4 weeks. RESULTS: Sleep perturbation (SP) resulted in reduced body weight gain in both sexes, associated with altered food intake and reduced adiposity. SP did not alter the short- or long-term memories or cause anxiogenic behavior. No major changes were observed in the plasma insulin, leptin, triacylglycerol, non-esterified fatty acids, and blood glucose upon SP. After SP, females exhibited a transitory glucose intolerance, while males became glucose intolerant at the end of the experimental period. Male rats also developed higher insulin sensitivity at the end of the SP protocol. Morphometric analyses revealed no changes in hepatic glycogen deposition, pancreatic islet mass, islet-cell distribution, or adrenal cortex thickness in SP rats from both sexes, except for lower adipocyte size compared with controls. We did not find homogeneous changes in the relative expression of circadian and metabolic genes in muscle or hepatic tissues from the SP rats. CONCLUSIONS: Moderate chronic SP reduces visceral adiposity and causes glucose intolerance with a more pronounced impact on male rats, reinforcing the metabolic risks of exposure to sleep disturbances.

Asunto(s)

Glucemia , Homeostasis , Resistencia a la Insulina , Ratas Wistar , Privación de Sueño , Animales , Privación de Sueño/fisiopatología , Privación de Sueño/complicaciones , Privación de Sueño/metabolismo , Masculino , Femenino , Ratas , Homeostasis/fisiología , Resistencia a la Insulina/fisiología , Glucemia/metabolismo , Metabolismo de los Lípidos , Insulina/metabolismo , Insulina/sangre , Intolerancia a la Glucosa/fisiopatología , Adiposidad/fisiología , Ingestión de Alimentos/fisiología , Leptina/sangre

RESUMEN

Type II pneumocytes are the target of the SARS-CoV-2 virus, which alters their redox homeostasis to increase reactive oxygen species (ROS). Melatonin (MT) has antioxidant proprieties and protects mitochondrial function. In this study, we evaluated whether treatment with MT compensated for the redox homeostasis alteration in serum from COVID-19 patients. We determined oxidative stress (OS) markers such as carbonyls, glutathione (GSH), total antioxidant capacity (TAC), thiols, nitrites (NO2-), lipid peroxidation (LPO), and thiol groups in serum. We also studied the enzymatic activities of glutathione peroxidase (GPx), glutathione-S-transferase (GST), reductase (GR), thioredoxin reductase (TrxR), extracellular superoxide dismutase (ecSOD) and peroxidases. There were significant increases in LPO and carbonyl quantities (p ≤ 0.03) and decreases in TAC and the quantities of NO2-, thiols, and GSH (p < 0.001) in COVID-19 patients. The activities of the antioxidant enzymes such as ecSOD, TrxR, GPx, GST, GR, and peroxidases were decreased (p ≤ 0.04) after the MT treatment. The treatment with MT favored the activity of the antioxidant enzymes that contributed to an increase in TAC and restored the lost redox homeostasis. MT also modulated glucose homeostasis, functioning as a glycolytic agent, and inhibited the Warburg effect. Thus, MT restores the redox homeostasis that is altered in COVID-19 patients and can be used as adjuvant therapy in SARS-CoV-2 infection.

Asunto(s)

Antioxidantes , Tratamiento Farmacológico de COVID-19 , COVID-19 , Homeostasis , Melatonina , Oxidación-Reducción , Estrés Oxidativo , SARS-CoV-2 , Melatonina/uso terapéutico , Melatonina/farmacología , Humanos , Oxidación-Reducción/efectos de los fármacos , COVID-19/metabolismo , COVID-19/virología , COVID-19/sangre , Homeostasis/efectos de los fármacos , Antioxidantes/metabolismo , Antioxidantes/uso terapéutico , Estrés Oxidativo/efectos de los fármacos , Masculino , Femenino , Persona de Mediana Edad , SARS-CoV-2/efectos de los fármacos , Peroxidación de Lípido/efectos de los fármacos , Anciano , Adulto , Especies Reactivas de Oxígeno/metabolismo , Glutatión/metabolismo , Glutatión/sangre

RESUMEN

The prevalence and socioeconomic impact of metabolic diseases is rapidly growing. The limited availability of effective and affordable treatments has fuelled interest in the therapeutic potential of natural compounds as they occur in selected food sources. These compounds might help to better manage the current problems of treatment availability, affordability, and adverse effects that, in combination, limit treatment duration and efficacy at present. Specifically, berries garnered interest given a strong epidemiological link between their consumption and improved metabolic functions, making the analysis of their phytochemical composition and the identification and characterization of biologically active ingredients an emerging area of research. In this regard, the present review focuses on the South American maqui berry Aristotelia chilensis, which has been extensively used by the indigenous Mapuche population for generations to treat a variety of disease conditions. An overview of the maqui plant composition precedes a review of pre-clinical and clinical studies that investigated the effects of maqui berries and their major components on metabolic homeostasis. The final part of the review highlights possible technologies to conserve maqui berry structural and functional integrity during passage through the small intestine, ultimately aiming to augment their systemic and luminal bioavailability and biological effects. The integration of the various aspects discussed herein can assist in the development of effective maqui-based therapies to benefit the growing population of metabolically compromised patients.

Asunto(s)

Frutas , Homeostasis , Frutas/química , Frutas/metabolismo , Humanos , Animales , Elaeocarpaceae/química , Extractos Vegetales/farmacología

RESUMEN

Originally developed as a chemotherapeutic agent, miltefosine (hexadecylphosphocholine) is an inhibitor of phosphatidylcholine synthesis with proven antiparasitic effects. It is the only oral drug approved for the treatment of Leishmaniasis and American Trypanosomiasis (Chagas disease). Although its precise mechanisms are not yet fully understood, miltefosine exhibits broad-spectrum anti-parasitic effects primarily by disrupting the intracellular Ca2+ homeostasis of the parasites while sparing the human hosts. In addition to its inhibitory effects on phosphatidylcholine synthesis and cytochrome c oxidase, miltefosine has been found to affect the unique giant mitochondria and the acidocalcisomes of parasites. Both of these crucial organelles are involved in Ca2+ regulation. Furthermore, miltefosine has the ability to activate a specific parasite Ca2+ channel that responds to sphingosine, which is different to its L-type VGCC human ortholog. Here, we aimed to provide an overview of recent advancements of the anti-parasitic mechanisms of miltefosine. We also explored its multiple molecular targets and investigated how its pleiotropic effects translate into a rational therapeutic approach for patients afflicted by Leishmaniasis and American Trypanosomiasis. Notably, miltefosine's therapeutic effect extends beyond its impact on the parasite to also positively affect the host's immune system. These findings enhance our understanding on its multi-targeted mechanism of action. Overall, this review sheds light on the intricate molecular actions of miltefosine, highlighting its potential as a promising therapeutic option against these debilitating parasitic diseases.

Asunto(s)

Calcio , Enfermedad de Chagas , Homeostasis , Leishmaniasis , Fosforilcolina , Fosforilcolina/análogos & derivados , Humanos , Fosforilcolina/farmacología , Fosforilcolina/uso terapéutico , Enfermedad de Chagas/tratamiento farmacológico , Enfermedad de Chagas/parasitología , Enfermedad de Chagas/metabolismo , Calcio/metabolismo , Leishmaniasis/tratamiento farmacológico , Leishmaniasis/metabolismo , Leishmaniasis/parasitología , Homeostasis/efectos de los fármacos , Animales , Antiprotozoarios/farmacología , Antiprotozoarios/uso terapéutico , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Leishmania/efectos de los fármacos , Leishmania/metabolismo , Trypanosoma cruzi/efectos de los fármacos , Trypanosoma cruzi/metabolismo

RESUMEN

Sex differences in metabolic dysfunction-associated steatotic liver disease (MASLD) have been reported. Oxidative stress and inflammation are involved in the progression of MASLD. Thus, we aimed to evaluate liver redox homeostasis and inflammation in male and female rats fed a high-fat diet (HFD). Male and female Wistar rats were divided into the following groups: standard chow diet (SCD) or HFD during 12 weeks. HFD groups of both sexes had higher hepatocyte injury, with no differences between the sexes. Portal space liver inflammation was higher in females-HFD compared to females-SCD, whereas no differences were observed in males. Lobular inflammation and overall liver inflammation were higher in HFD groups, regardless of sex. TNF-α, IL-6, and IL-1ß levels were higher in males-HFD compared to males-SCD, but no differences were observed in females. Catalase activity was higher in males compared to females, with no differences between the SCD and HFD groups of both sexes. Glutathione peroxidase activity was higher in females compared to males, with no differences between the SCD and HFD groups in both sexes. Lipid peroxidation was higher in female-SCD when compared to male-SCD, and in both male- and female-HFD compared to SCD groups. Furthermore, both cytoplasmic and nuclear NRF2 staining were lower in the HFD group compared to the SCD group in males. However, female-HFD exhibited reduced nuclear NRF2 staining compared to the female-SCD group. In conclusion, our study demonstrated that while both male and female rats developed metabolic dysfunction-associated steatohepatitis after 12 weeks of HFD, the alterations in inflammatory cytokines and redox balance were sexually dimorphic.

Asunto(s)

Citocinas , Dieta Alta en Grasa , Homeostasis , Hígado , Oxidación-Reducción , Estrés Oxidativo , Ratas Wistar , Animales , Masculino , Femenino , Dieta Alta en Grasa/efectos adversos , Citocinas/metabolismo , Hígado/metabolismo , Peroxidación de Lípido , Ratas , Factores Sexuales , Factor 2 Relacionado con NF-E2/metabolismo , Caracteres Sexuales