Christodoulos Xinaris

Objective: Elevated body temperature may increase seizure risk, yet the relationship between thermoregulation and seizures, as well as the underlying mechanisms, remains poorly understood. We investigated whether thermoregulatory control is altered in experimental temporal lobe epilepsy (TLE), as such impairment could reduce the ability of affected individuals to adapt to environmental temperature changes. Methods: Using an adult mouse model of temporal lobe epilepsy (TLE), we longitudinally measured brain temperature before and after epilepsy onset using 7 T ¹ H‐magnetic resonance spectroscopy thermometry. The temporal relationship between spontaneous seizures and body temperature fluctuations was assessed using electroencephalographic recordings combined with implanted temperature probes under controlled environmental conditions. Neuronal density, glial reactivity, and transcriptomic profiles were examined in hypothalamic temperature‐sensing regions (ventromedial preoptic nucleus [VMPO] and dorsomedial nucleus [DMD]) in epileptic mice and sham mice. Hypothalamic volume was assessed by magnetic resonance imaging (MRI) in both mice and people with epilepsy (PWE). Serum thyroid‐stimulating hormone (TSH), T3, and T4 concentrations were measured as indices of hypothalamic–pituitary–thyroid (HPT) axis activity and metabolic thermogenesis. Results: Hippocampal temperature increased by ~.5–1.5°C prior to epilepsy onset (3 days postkainate) and remained elevated during chronic epilepsy (1.5 months postkainate). Acutely, body temperature rose from 15 min before to 15 min after spontaneous seizures. Serum T3 and T4 levels were reduced by ~50% without compensatory TSH elevation, indicating HPT axis dysregulation in epileptic mice. Neuronal density in VMPO and DMD decreased by ~20% in chronic epileptic mice versus sham mice ( p < .05), accompanied by induction of FosB, immune/inflammatory pathways, and glia reactivity. MRI revealed reduced hypothalamic volume in epileptic mice ( p < .05), paralleling findings in PWE. Significance: Thermoregulatory control is impaired in experimental TLE and is associated with neuronal loss and inflammation in hypothalamic temperature‐sensing regions. These findings reveal a link between thermoregulatory dysfunction and epilepsy and highlight that alterations in temperature homeostasis may interact with mechanisms underlying seizure generation.

Background: Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder characterized by progressive cyst development and renal dysfunction. While thyroid hormones (THs) are known to regulate key pathways in various kidney diseases, their role in ADPKD pathobiology and therapeutic potential remains unexplored. Here, we aimed to elucidate the role of THs in ADPKD and evaluate whether their pharmacological modulation could serve as a therapeutic strategy. Methods: Patient-derived renal epithelial cells were used to engineer 3D polycystic tubules and to test the anti-cystogenic effects of THs and their analogs. The therapeutic efficacy of thyroxine (T4) in reducing cyst formation and delaying disease progression was assessed in vivo using PCK rats, an animal model of ADPKD. Lastly, serum THs levels were measured in 90 ADPKD patients enrolled in the REORIENTED clinical study and correlated with estimated glomerular filtration rate to explore their clinical relevance (Clinical Trial Gov NCT 05646420). Results: Mechanistically, thyroxine inhibits cyst growth by modulating proliferative, metabolic and ferroptotic pathways through αvβ3 integrin binding. In PCK rats, an animal model of ADPKD, T4 administration decreased kidney weight and significantly reduced macrocystic area (%, Vehicle 9.255 ± 2.654 vs. T4 1.945 ± 0.850, p < 0.05). Clinical data from ADPKD patients showed that altered TH serum levels correlate with disease severity: in the overall population of the study reverse triiodothyronine (rT3, a T3′s metabolite) levels inversely correlate with renal function ( R ² = 0.159, r = −0.397, p < 0.001), while free triiodothyronine (fT3) levels show a positive correlation ( R ² = 0.110, r = 0.332, p < 0.01). Conclusions: This study reveals that THs contribute to ADPKD progression and identifies them as potential prognostic and therapeutic agents. By modulating multiple pathogenic pathways, THs may offer a novel, multi-targeted approach to reduce cyst growth and preserve renal function. These findings further support the development of personalized, hormone-based treatments and more refined stratification in the clinical management of ADPKD.

Myocardial infarction (MI) is a leading cause of heart failure, with thyroid hormone (TH) signaling playing a key role in heart function and postinfarct recovery. Despite evidence of TH administration's safety in cardiac patients, inconsistent therapeutic outcomes and limited understanding of its mechanisms hinder clinical translation. This study aims to investigate the long-term effect of acute triiodothyronine (T3) administration following MI and to elucidate the mechanisms of its cardioprotective actions. To this end, two doses (40 μg/kg) of T3 were administered immediately after injury and 24 h later in a cryoinjury mouse model of left ventricle (LV) infarction. Remarkably T3 administration significantly reduced scar expansion. Echocardiographic analysis conducted 28 days post-injury revealed that T3 administration improved LV remodeling and prevented LV hypertrophy. At molecular level, T3 administration strongly reduced apoptosis in the peri-infarcted area, without inducing cardiac cell proliferation. Furthermore, T3 prevented the accumulation of long-chain acylcarnitines and the subsequent mitochondrial damage. These findings demonstrate that acute T3 treatment following MI improves long-term LV function and reduces LV remodeling by limiting apoptosis in the peri-infarct region and by preserving mitochondrial function and structural integrity.

Autosomal dominant polycystic kidney disease (ADPKD) is a monogenic, rare disease, characterized by the formation of multiple cysts that grow out of the renal tubules. Despite intensive attempts to develop new drugs or repurpose existing ones, there is currently no definitive cure for ADPKD. This is primarily due to the complex and variable pathogenesis of the disease and the lack of models that can faithfully reproduce the human phenotype. Therefore, the development of models that allow automated detection of cysts’ growth directly on human kidney tissue is a crucial step in the search for efficient therapeutic solutions. Artificial Intelligence methods, and deep learning algorithms in particular, can provide powerful and effective solutions to such tasks, and indeed various architectures have been proposed in the literature in recent years. Here, we comparatively review state-of-the-art deep learning segmentation models, using as a testbed a set of sequential RGB immunofluorescence images from 4 in vitro experiments with 32 engineered polycystic kidney tubules. To gain a deeper understanding of the detection process, we implemented both pixel-wise and cyst-wise performance metrics to evaluate the algorithms. Overall, two models stand out as the best performing, namely UNet++ and UACANet: the latter uses a self-attention mechanism introducing some explainability aspects that can be further exploited in future developments, thus making it the most promising algorithm to build upon towards a more refined cyst-detection platform. UACANet model achieves a cyst-wise Intersection over Union of 0.83, 0.91 for Recall, and 0.92 for Precision when applied to detect large-size cysts. On all-size cysts, UACANet averages at 0.624 pixel-wise Intersection over Union. The code to reproduce all results is freely available in a public GitHub repository.

Heart failure affects more than 64 million people worldwide, having a serious impact on their survival and quality of life. Exploring its pathophysiology and molecular bases is an urgent need in order to develop new therapeutic approaches. Thyroid hormone signaling, evolutionarily conserved, controls fundamental biological processes and has a crucial role in development and metabolism. Its active form is L-triiodothyronine, which not only regulates important gene expression by binding to its nuclear receptors, but also has nongenomic actions, controlling crucial intracellular signalings. Stressful stimuli, such as acute myocardial infarction, lead to changes in thyroid hormone signaling, and especially in the relation of the thyroid hormone and its nuclear receptor, which are associated with the reactivation of fetal development programmes, with structural remodeling and phenotypical changes in the cardiomyocytes. The recapitulation of fetal-like features of the signaling may be partially an incomplete effort of the myocardium to recapitulate its developmental program and enable cardiomyocytes to proliferate and finally to regenerate. In this review, we will discuss the experimental and clinical evidence about the role of the thyroid hormone in the recovery of the myocardium in the setting of heart failure with reduced and preserved ejection fraction and its future therapeutic implications.

In anamniotes cell loss can typically be compensated for through proliferation, but in amniotes, this capacity has been significantly diminished to accommodate tissue complexity. In order to cope with the increased workload that results from cell death, instead of proliferation highly specialised post-mitotic cells undergo polyploidisation and hypertrophy. Although compensatory hypertrophy is the main strategy of repair/regeneration in various parenchymal tissues, the long-term benefits and its capacity to sustain complete recovery of the kidney has not been addressed sufficiently. In this perspective article we integrate basic principles from biophysics and biology to examine whether renal cell hypertrophy is a sustainable adaptation that can efficiently regenerate tissue mass and restore organ function, or a maladaptive detrimental response.

Thyroid hormone (TH) signalling is a universally conserved pathway with pleiotropic actions that is able to control the development, metabolism, and homeostasis of organisms. Using evidence from paleoecology/palaeoanthropology and data from the physiology of modern humans, we try to assess the natural history of TH signalling and its role in human evolution. Our net thesis is that TH signalling has likely played a critical role in human evolution by facilitating the adaptive responses of early hominids to unprecedently challenging and continuously changing environments. These ancient roles have been conserved in modern humans, in whom TH signalling still responds to and regulates adaptations to present-day environmental and pathophysiological stresses, thus making it a promising therapeutic target.