The Janus of a disease: Diabetes and metabolic dysfunction-associated fatty liver disease.

Metabolic Dysfunction-Associated Fatty Liver Disease and Diabetes Mellitus are two prevalent metabolic disorders that often coexist and synergistically contribute to the progression of each other. Several pathophysiological pathways are involved in the association, including insulin resistance, inflammation, and lipotoxicity, providing a foundation for understanding the complex interrelationships between these conditions. The presence of MASLD has a significant impact on diabetes risk and the development of microvascular and macrovascular complications, and diabetes significantly contributes to an increased risk of liver fibrosis progression in MASLD and the development of hepatocellular carcinoma. Moreover, both pathologies have a synergistic effect on cardiovascular events and mortality. Therapeutic interventions targeting MASLD and diabetes are discussed, considering lifestyle modifications, pharmacological agents, and emerging treatment modalities. The review also addresses the challenges in managing these comorbidities, such as the need for personalized approaches and the potential impact on cardiovascular health. The insights gleaned from this analysis can inform clinicians, researchers, and policymakers in developing integrated strategies for preventing, diagnosing, and managing these metabolic disorders.

Enforced dimerization between XBP1s and ATF6f enhances the protective effects of the UPR in models of neurodegeneration.

Alteration to endoplasmic reticulum (ER) proteostasis is observed in a variety of neurodegenerative diseases associated with abnormal protein aggregation. Activation of the unfolded protein response (UPR) enables an adaptive reaction to recover ER proteostasis and cell function. The UPR is initiated by specialized stress sensors that engage gene expression programs through the concerted action of the transcription factors ATF4, ATF6f, and XBP1s. Although UPR signaling is generally studied as unique linear signaling branches, correlative evidence suggests that ATF6f and XBP1s may physically interact to regulate a subset of UPR target genes. In this study, we designed an ATF6f/XBP1s fusion protein termed UPRplus that behaves as a heterodimer in terms of its selective transcriptional activity. Cell-based studies demonstrated that UPRplus has a stronger effect in reducing the abnormal aggregation of mutant huntingtin and α-synuclein when compared to XBP1s or ATF6 alone. We developed a gene transfer approach to deliver UPRplus into the brain using adeno-associated viruses (AAVs) and demonstrated potent neuroprotection in vivo in preclinical models of Parkinson's disease and Huntington's disease. These results support the concept in which directing UPR-mediated gene expression toward specific adaptive programs may serve as a possible strategy to optimize the beneficial effects of the pathway in different disease conditions.

Insulin-like growth factor 2 (IGF2) protects against Huntington's disease through the extracellular disposal of protein aggregates.

Impaired neuronal proteostasis is a salient feature of many neurodegenerative diseases, highlighting alterations in the function of the endoplasmic reticulum (ER). We previously reported that targeting the transcription factor XBP1, a key mediator of the ER stress response, delays disease progression and reduces protein aggregation in various models of neurodegeneration. To identify disease modifier genes that may explain the neuroprotective effects of XBP1 deficiency, we performed gene expression profiling of brain cortex and striatum of these animals and uncovered insulin-like growth factor 2 (Igf2) as the major upregulated gene. Here, we studied the impact of IGF2 signaling on protein aggregation in models of Huntington's disease (HD) as proof of concept. Cell culture studies revealed that IGF2 treatment decreases the load of intracellular aggregates of mutant huntingtin and a polyglutamine peptide. These results were validated using induced pluripotent stem cells (iPSC)-derived medium spiny neurons from HD patients and spinocerebellar ataxia cases. The reduction in the levels of mutant huntingtin was associated with a decrease in the half-life of the intracellular protein. The decrease in the levels of abnormal protein aggregation triggered by IGF2 was independent of the activity of autophagy and the proteasome pathways, the two main routes for mutant huntingtin clearance. Conversely, IGF2 signaling enhanced the secretion of soluble mutant huntingtin species through exosomes and microvesicles involving changes in actin dynamics. Administration of IGF2 into the brain of HD mice using gene therapy led to a significant decrease in the levels of mutant huntingtin in three different animal models. Moreover, analysis of human postmortem brain tissue and blood samples from HD patients showed a reduction in IGF2 level. This study identifies IGF2 as a relevant factor deregulated in HD, operating as a disease modifier that buffers the accumulation of abnormal protein species.

The specificity protein factor Sp1 mediates transcriptional regulation of P2X7 receptors in the nervous system.

P2X7 receptors are involved not only in physiological functions but also in pathological brain processes. Although an increasing number of findings indicate that altered receptor expression has a causative role in neurodegenerative diseases and cancer, little is known about how expression of P2rx7 gene is controlled. Here we reported the first molecular and functional evidence that Specificity protein 1 (Sp1) transcription factor plays a pivotal role in the transcriptional regulation of P2X7 receptor. We delimited a minimal region in the murine P2rx7 promoter containing four SP1 sites, two of them being highly conserved in mammals. The functionality of these SP1 sites was confirmed by site-directed mutagenesis and Sp1 overexpression/down-regulation in neuroblastoma cells. Inhibition of Sp1-mediated transcriptional activation by mithramycin A reduced endogenous P2X7 receptor levels in primary cultures of cortical neurons and astrocytes. Using P2rx7-EGFP transgenic mice that express enhanced green fluorescent protein under the control of P2rx7 promoter, we found a high correlation between reporter expression and Sp1 levels in the brain, demonstrating that Sp1 is a key element in the transcriptional regulation of P2X7 receptor in the nervous system. Finally, we found that Sp1 mediates P2X7 receptor up-regulation in neuroblastoma cells cultured in the absence of serum, a condition that enhances chromatin accessibility and facilitates the exposure of SP1 binding sites.

Seizure suppression and neuroprotection by targeting the purinergic P2X7 receptor during status epilepticus in mice.

Prolonged seizures [status epilepticus (SE)] constitute a neurological emergency that can permanently damage the brain. SE results from a failure of the normal mechanisms to terminate seizures; in particular, γ-amino butyric acid-mediated inhibition, and benzodiazepine anticonvulsants are often incompletely effective. ATP acts as a fast neurotransmitter via ionotropic ligand-gated P2X receptors. Here we report that SE induced by intra-amygdala kainic acid in mice selectively increased hippocampal levels of P2X7 receptors relative to other P2X receptors. Using transgenic P2X7 reporter mice expressing enhanced green fluorescent protein, we identify dentate granule neurons as the major cell population transcribing the P2X7 receptor after SE. Pretreatment of mice with an intracerebroventricular microinjection of 1.75 nmol A438079, a P2X7 receptor antagonist, reduced seizure duration by 58% and reduced seizure-induced neuronal death by 61%. Injection of brilliant blue G (1 pmol), another selective antagonist, reduced seizure duration by 48% and was also neuroprotective. A438079 was seizure-suppressive when injected shortly after induction of SE, and coinjection of A438079 with lorazepam 60 min after triggering SE, when electrographic seizure-responsiveness to lorazepam had decreased, also terminated SE. Our results suggest that P2X7 receptor antagonists may be a promising class of drug for seizure abrogation and neuroprotection in SE.

Corrigendum: Parental psychological control: Maternal, adolescent, and contextual predictors.

[This corrects the article DOI: 10.3389/fpsyg.2021.712087.].

Up-regulation of the ATPase inhibitory factor 1 (IF1) of the mitochondrial H+-ATP synthase in human tumors mediates the metabolic shift of cancer cells to a Warburg phenotype.

The H(+)-ATP synthase is a reversible engine of mitochondria that synthesizes or hydrolyzes ATP upon changes in cell physiology. ATP synthase dysfunction is involved in the onset and progression of diverse human pathologies. During ischemia, the ATP hydrolytic activity of the enzyme is inhibited by the ATPase inhibitory factor 1 (IF1). The expression of IF1 in human tissues and its participation in the development of human pathology are unknown. Here, we have developed monoclonal antibodies against human IF1 and determined its expression in paired normal and tumor biopsies of human carcinomas. We show that the relative mitochondrial content of IF1 increases significantly in carcinomas, suggesting the participation of IF1 in oncogenesis. The expression of IF1 varies significantly in cancer cell lines. To investigate the functional activity of IF1 in cancer, we have manipulated its cellular content. Overexpression of IF1 or of its pH-insensitive H49K mutant in cells that express low levels of IF1 triggers the up-regulation of aerobic glycolysis and the inhibition of oxidative phosphorylation with concurrent mitochondrial hyperpolarization. Treatment of the cells with the H(+)-ATP synthase inhibitor oligomycin mimicked the effects of IF1 overexpression. Conversely, small interfering RNA-mediated silencing of IF1 in cells that express high levels of IF1 promotes the down-regulation of aerobic glycolysis and the increase in oxidative phosphorylation. Overall, these findings support that the mitochondrial content of IF1 controls the activity of oxidative phosphorylation mediating the shift of cancer cells to an enhanced aerobic glycolysis, thus supporting an oncogenic role for the de-regulated expression of IF1 in cancer.

Parental Psychological Control: Maternal, Adolescent, and Contextual Predictors.

Parental psychological control (PC) hinders the development of autonomy, identity formation, and the attainment of self-determination and individuation of adolescents. The aim of this study was to deepen the understanding of which conditions increase the risk of the use of maternal PC by simultaneously considering the contribution of adolescent temperament, maternal separation anxiety, and adolescents' perception of interparental conflict. A correlational study involving a sample of 106 Chilean adolescent-mother dyads was done. Adolescents were, on average, 15.42 years old (SD = 1.09) and 77% male. Mothers were, on average, 45.46 years old (SD = 6.39). We administered self-report questionnaires to the adolescent measuring effortful control and frustration as temperamental dimensions, along with the perception of interparental conflict. Mothers reported on their separation anxiety. Both the adolescents and their mothers reported on the use of maternal PC. Adolescents reported higher levels of maternal PC than their mothers did. All predictors were associated with PC reports. Higher levels of maternal anxiety about adolescent distancing, inter-parental conflict, and adolescent frustration were associated with higher reported levels of PC. In contrast, higher levels of adolescent effortful control were associated with lower levels of maternal PC. Finally, when maternal separation anxiety and inter-parental conflict were high there was a higher use of maternal PC. The present findings inform on how adolescent's self-regulatory skills could reduce the risk of being exposed to maternal PC. And highlight the importance of using a systemic and interactional conceptualization when trying to understand their use.

[Undiagnosed (corrected) cases of obstructive sleep apnoea syndrome: a new reason for involvement of otorhinolaryngologists]. / Casos no diagnosticados de síndrome de apnea obstructiva del sueño: un nuevo motivo de implicación para el otorrinolaringólogo.

INTRODUCTION: In Spain there are around 2 million people with obstructive sleep apnoea syndrome who should be treated. However, less than 10 % have been diagnosed and treated. Untreated patients are associated with a higher risk of cardiovascular and neurological complications, higher accident rates, reduced quality of life and greater health-care consumption. It is necessary, therefore, to reduce these consequences through early diagnosis and treatment. OBJECTIVE: To demonstrate the usefulness of a simple series of questions and examination as a mechanism to detect patients with undiagnosed obstructive sleep apnoea syndrome, in a consultation with a general otorhinolaryngologist. MATERIAL AND METHOD: Five hundred two consecutive patients coming to an otorhinolaryngological consultation for reasons other than sleep pathology were submitted to a series of questions and an examination of upper aerodigestive tract, to search for indications of suspected sleep apnoea. For the different clinical and anatomical comparisons, a control group of 178 consecutive already-diagnosed patients was used. RESULTS: Of the 502 cases, 74 (14.7%) fulfilled the requirements for suspicion and 35 of them agreed to take a polysomnograph test (47.29%). Of this group, an apnoea/ hypopnoea index greater than 5 was found in 24 of the 35 cases (4.78%). CONCLUSIONS: The prevalence of obstructive sleep apnoea in the group of patients studied is greater than that of the general population. With a simple interview and physical examination, a high rate of success can be obtained in the detection of undiagnosed sleep apnoea cases.

ER chaperones in neurodegenerative disease: Folding and beyond.

Proteins along the secretory pathway are co-translationally translocated into the lumen of the endoplasmic reticulum (ER) as unfolded polypeptide chains. Afterwards, they are usually modified with N-linked glycans, correctly folded and stabilized by disulfide bonds. ER chaperones and folding enzymes control these processes. The accumulation of unfolded proteins in the ER activates a signaling response, termed the unfolded protein response (UPR). The hallmark of this response is the coordinated transcriptional up-regulation of ER chaperones and folding enzymes. In order to discuss the importance of the proper folding of certain substrates we will address the role of ER chaperones in normal physiological conditions and examine different aspects of its contribution in neurodegenerative disease. This article is part of a Special Issue entitled SI:ER stress.

The intersection between growth factors, autophagy and ER stress: A new target to treat neurodegenerative diseases?

One of the salient features of most neurodegenerative diseases is the aggregation of specific proteins in the brain. This proteostasis imbalance is proposed as a key event triggering the neurodegenerative cascade. The unfolded protein response (UPR) and autophagy pathways are emerging as critical processes implicated in handling disease-related misfolded proteins. However, in some conditions, perturbations in the buffering capacity of the proteostasis network may be part of the etiology of the disease. Thus, pharmacological or gene therapy strategies to enhance autophagy or UPR responses are becoming an attractive target for disease intervention. Here, we discuss current evidence depicting the complex involvement of autophagy and ER stress in brain diseases. Novel pathways to modulate protein misfolding are discussed including the relation between aging and growth factor signaling. This article is part of a Special Issue entitled SI:Autophagy.

PI3K/Akt signaling pathway triggers P2X7 receptor expression as a pro-survival factor of neuroblastoma cells under limiting growth conditions.

The expression of purinergic P2X7 receptor (P2X7R) in neuroblastoma cells is associated to accelerated growth rate, angiogenesis, metastasis and poor prognosis. Noticeably, P2X7R allows the survival of neuroblastoma cells under restrictive conditions, including serum and glucose deprivation. Previously we identified specificity protein 1 (Sp1) as the main factor involved in the transcriptional regulation of P2rx7 gene, reporting that serum withdrawal triggers the expression of P2X7R in Neuro-2a (N2a) neuroblastoma cell line. Here we demonstrate that PI3K/Akt pathway is crucial for the upregulation of P2X7R expression in serum-deprived neuroblastoma cells, circumstance that facilitates cell proliferation in the absence of trophic support. The effect exerted by PI3K/Akt is independent of both mTOR and GSK3, but requires the activation of EGF receptor (EGFR). Nuclear levels of Sp1 are strongly reduced by inhibition of PI3K/Akt pathway, and blockade of Sp1-dependent transcription with mithramycin A prevents upregulation of P2rx7 gene expression following serum withdrawal. Furthermore, atypical PKCζ plays a key role in the regulation of P2X7R expression by preventing phosphorylation and, consequently, activation of Akt. Altogether, these data indicate that activation of EGFR enhanced the expression of P2X7R in neuroblastoma cells lacking trophic support, being PI3K/Akt/PKCζ signaling pathway and Sp1 mediating this pro-survival outcome.

Ca2+/calmodulin-dependent kinase II signalling cascade mediates P2X7 receptor-dependent inhibition of neuritogenesis in neuroblastoma cells.

ATP, via purinergic P2X receptors, acts as a neurotransmitter and modulator in both the central and peripheral nervous systems, and is also involved in many biological processes, including cell proliferation, differentiation and apoptosis. Previously, we have reported that P2X7 receptor inhibition promotes axonal growth and branching in cultured hippocampal neurons. In this article, we demonstrate that the P2X7 receptor negatively regulates neurite formation in mouse Neuro-2a neuroblastoma cells through a Ca2+/calmodulin-dependent kinase II-related mechanism. Using both molecular and immunocytochemical techniques, we characterized the presence of endogenous P2X1, P2X3, P2X4 and P2X7 subunits in these cells. Of these, the P2X7 receptor was the only functional receptor, as its activation induced intracellular calcium increments similar to those observed in primary neuronal cultures, exhibiting pharmacological properties characteristic of homomeric P2X7 receptors. Patch-clamp experiments were also conducted to fully demonstrate that ionotropic P2X7 receptors mediate nonselective cation currents in this cell line. Pharmacological inhibition of the P2X7 receptor and its knockdown by small hairpin RNA interference resulted in increased neuritogenesis in cells cultured in low serum-containing medium, whereas P2X7 overexpression significantly reduced the formation of neurites. Interestingly, P2X7 receptor inhibition also modified the phosphorylation state of focal adhesion kinase, Akt and glycogen synthase kinase 3, protein kinases that participate in the Ca2+/calmodulin-dependent kinase II signalling cascade and that have been related to neuronal differentiation and axonal growth. Taken together, our results provide the first mechanistic insight into P2X7 receptor-triggered signalling pathways that regulate neurite formation in neuroblastoma cells.

Voice quality after CO2 laser cordectomy--what can we really expect?

BACKGROUND: Endoscopic management of laryngeal carcinoma has gained popularity among laryngologists based on the good oncologic and functional results. We evaluated the voice quality after laser cordectomy for early glottic cancer in a variety of vocal situations and its relation with the extension of resection and the age. METHODS: We conducted a cross-sectional study of voice quality in 42 consecutive male patients treated for T1 glottic carcinoma with laser cordectomy. Patients were compared with 21 controls. Voice quality was self-assessed by the patients. Perceptual analysis was done by a speech pathologist on a running speech sample [GRBAS (grade, roughness, breathiness, asthenicity, strain)]. Acoustic analysis included fundamental frequency (F0), jitter, shimmer, noise to harmonic ratio (N/H), and maximum phonation time (MPT) on the sustained vowels /a/ and /i/, and on various running speech voice samples. RESULTS: Distribution of the patients included in the study by T classification was as follows: Tis, n = 2 (4.8%); T1a, n = 35 (83.3%); and T1b, n = 5 (11.9%). Cordectomy types were: (I), 14%; (II), 26%; (III), 21%; and (V), 38%. Voice improved in almost 60% of patients, returning to normal in 45%. GRBAS showed significant differences between patients and controls and correlated with type of cordectomy. Acoustic analysis showed significant differences in F0, and jitter, with smaller differences in shimmer, N/H, and MPT. CONCLUSION: Voice quality after laser cordectomy differs from controls, but improves in a majority of patients after the surgery, with almost 50% of patients with subjective normal or near normal voice. Voice quality depends on type of cordectomy.

Casos no diagnosticados de síndrome de apnea obstructiva del sueño: un nuevo motivo de implicación para el otorrinolaringólogo / Diagnosed cases of obstructive sleep apnoea syndrome: a new reason for involvement of otorhinolaryngologists

Introducción: En España hay alrededor de 2 millones de sujetos portadores de un síndrome de apnea obstructiva del sueño subsidiarios de tratamiento. Sin embargo, tan sólo se ha diagnosticado y tratado menos del 10 %. Los pacientes no tratados tienen un riesgo superior de complicaciones cardiovasculares y neurológicas, mayor accidentabilidad, reducción en calidad de vida y mayores consumos sanitarios. Es necesario, por tanto, reducir estas consecuencias mediante un diagnóstico y un tratamiento precoces. Objetivo: Demostrar la utilidad de un interrogatorio y una exploración sencillos, como mecanismo de detección de pacientes con síndrome de apnea obstructiva del sueño no diagnosticado, en una consulta de otorrinolaringología general. Material y metodo: A 502 pacientes consecutivos, que acuden a la consulta de otorrinolaringología por un motivo diferente de patología de sueño, se los somete a un interrogatorio y la exloración de vías aerodigestivas altas en busca de criterios de sospecha de apnea del sueño. Los casos con sospecha clínica son invitados a realizar una polisomnografía nocturna. Para las diferentes comparaciones clínicas y anatómicas se ha utilizado un grupo control de 178 pacientes consecutivos ya diagnosticados. Resultados: De los 502 casos, 74 (14,7 %) cumplen los requisitos de sospecha y 35 (47,29 %) de ellos acceden a la práctica de la polisomnografía. En este último grupo se obtuvo un índice de apnea/hipopnea (IAH) superior a 5, en 24 de los 35 casos (4,78 %). Conclusiones: La prevalencia de apnea obstructiva del sueño en el grupo de pacientes analizados es superior a la de la población general. Con un sencillo interrogatorio y la exploración física, se puede obtener un alto rendimiento en la detección de casos no diagnosticados de apnea del sueño (AU)

Introduction: In Spain there are around 2 million people with obstructive sleep apnoea syndrome who should be treated. However, less than 10 % have been diagnosed and treated. Untreated patients are associated with a higher risk of cardiovascular and neurological complications, higher accident rates, reduced quality of life and greater health-care consumption. It is necessary, therefore, to reduce these consequences through early diagnosis and treatment. Objective: To demonstrate the usefulness of a simple series of questions and examination as a mechanism to detect patients with undiagnosed obstructive sleep apnoea syndrome, in a consultation with a general otorhinolaryngologist. Material and method: Five hundred two consecutive patients coming to an otorhinolaryngological consultation for reasons other than sleep pathology were submitted to a series of questions and an examination of upper aerodigestive tract, to search for indications of suspected sleep apnoea. For the different clinical and anatomical comparisons, a control group of 178 consecutive already-diagnosed patients was used. Results: Of the 502 cases, 74 (14.7 %) fulfilled the requirements for suspicion and 35 of them agreed to take a polysomnograph test (47.29 %). Of this group, an apnoea/ hypopnoea index greater than 5 was found in 24 of the 35 cases (4.78 %). Conclusions: The prevalence of obstructive sleep apnoea in the group of patients studied is greater than that of the general population. With a simple interview and physical examination, a high rate of success can be obtained in the detection of undiagnosed sleep apnoea cases (AU)