Thyroid Hormone and Heart Failure: Charting Known Pathways for Cardiac Repair/Regeneration.

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.

PDIA3 Expression Is Altered in the Limbic Brain Regions of Triple-Transgenic Mouse Model of Alzheimer's Disease.

In the present study, we used a mouse model of Alzheimer's disease (AD) (3×Tg-AD mice) to longitudinally analyse the expression level of PDIA3, a protein disulfide isomerase and endoplasmic reticulum (ER) chaperone, in selected brain limbic areas strongly affected by AD-pathology (amygdala, entorhinal cortex, dorsal and ventral hippocampus). Our results suggest that, while in Non-Tg mice PDIA3 levels gradually reduce with aging in all brain regions analyzed, 3×Tg-AD mice showed an age-dependent increase in PDIA3 levels in the amygdala, entorhinal cortex, and ventral hippocampus. A significant reduction of PDIA3 was observed in 3×Tg-AD mice already at 6 months of age, as compared to age-matched Non-Tg mice. A comparative immunohistochemistry analysis performed on 3×Tg-AD mice at 6 (mild AD-like pathology) and 18 (severe AD-like pathology) months of age showed a direct correlation between the cellular level of Aß and PDIA3 proteins in all the brain regions analysed, even if with different magnitudes. Additionally, an immunohistochemistry analysis showed the presence of PDIA3 in all post-mitotic neurons and astrocytes. Overall, altered PDIA3 levels appear to be age- and/or pathology-dependent, corroborating the ER chaperone's involvement in AD pathology, and supporting the PDIA3 protein as a potential novel therapeutic target for the treatment of AD.

A protocol for the generation of EPO - Producing neural crest cells from human induced pluripotent stem cells.

Insufficient production of erythropoietin (EPO) leads to anaemia. Developing methods for the generation and transplantation of EPO-producing cells would allow scientists to design personalised therapeutic solutions. Here we present a simple and highly reproducible protocol for the generation of neural crest cells (NCCs) that can produce and secrete erythropoiesis-competent EPO in response to hypoxia.

Cell Hypertrophy: A "Biophysical Roadblock" to Reversing Kidney Injury.

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 Signalling in Human Evolution and Disease: A Novel Hypothesis.

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.

Thyroid Hormone Signalling Alteration in Diabetic Nephropathy and Cardiomyopathy: a "Switch" to the Foetal Gene Programme.

PURPOSE OF THE REVIEW: In this study, we will analyse how diabetes induces the reactivation of organs' developmental programmes and growth, discuss how thyroid hormone (TH) signalling orchestrates these processes, and suggest novel strategies for exploiting TH-mediated reparative and regenerative properties. RECENT FINDINGS: Diabetes is a global pandemic that poses an enormous threat to human health. The kidney and the heart are among the organs that are the most severely damaged by diabetes over time. They undergo profound metabolic, structural, and functional changes that may be due (at least partially) to a recapitulation of their early developmental programmes. There is growing evidence to suggest that this foetal reprogramming is controlled by the TH/TH receptor alpha 1 (TRα1) axis. We introduce the hypothesis that in diabetes-and probably in other diseases-TH signalling acts in an antagonistic manner: it recapitulates a foetal profile that is necessary to coordinate metabolic and structural adaptations to sustain energy preservation and growth, but in the long term the persistent changes in these pathways are detrimental.

Thyroid Hormone Signalling: From the Dawn of Life to the Bedside.

Thyroid hormone (TH) signalling is a key modulator of fundamental biological processes that has been evolutionarily conserved in both vertebrate and invertebrate species. TH may have initially emerged as a nutrient signal to convey environmental information to organisms to induce morpho-anatomical changes that could maximise the exploitation of environmental resources, and eventually integrated into the machinery of gene regulation and energy production to become a key regulator of development and metabolism. As such, TH signalling is particularly sensitive to environmental stimuli, and its alterations result in fundamental changes in homeostasis and physiology. Stressful stimuli of various origins lead to changes in the TH-TH receptor (TR) axis in different adult mammalian organs that are associated with phenotypical changes in terminally differentiated cells, the reactivation of foetal development programmes, structural remodelling and pathological growth. Here, we discuss the evolution of TH signalling, review evolutionarily conserved functions of THs in essential biological processes, such as metamorphosis and perinatal development, and analyse the role of TH signalling in the phenotypical and morphological changes that occur after injury, repair and regeneration in adult mammalian organs. Finally, we examine the potential of TH treatment as a therapeutic strategy for improving organ structure and functions following injury.

Alteration of thyroid hormone signaling triggers the diabetes-induced pathological growth, remodeling, and dedifferentiation of podocytes.

Thyroid hormone (TH) signaling is a universal regulator of metabolism, growth, and development. Here, we show that TH-TH receptor (TH-TR) axis alterations are critically involved in diabetic nephropathy-associated (DN-associated) podocyte pathology, and we identify TRα1 as a key regulator of the pathogenesis of DN. In ZSF1 diabetic rats, T3 levels progressively decreased during DN, and this was inversely correlated with metabolic and renal disease worsening. These phenomena were associated with the reexpression of the fetal isoform TRα1 in podocytes and parietal cells of both rats and patients with DN and with the increased glomerular expression of the TH-inactivating enzyme deiodinase 3 (DIO3). In diabetic rats, TRα1-positive cells also reexpressed several fetal mesenchymal and damage-related podocyte markers, while glomerular and podocyte hypertrophy was evident. In vitro, exposing human podocytes to diabetes milieu typical components markedly increased TRα1 and DIO3 expression and induced cytoskeleton rearrangements, adult podocyte marker downregulation and fetal kidney marker upregulation, the maladaptive cell cycle induction/arrest, and TRα1-ERK1/2-mediated hypertrophy. Strikingly, T3 treatment reduced TRα1 and DIO3 expression and completely reversed all these alterations. Our data show that diabetic stress induces the TH-TRα1 axis to adopt a fetal ligand/receptor relationship pattern that triggers the recapitulation of the fetal podocyte phenotype and subsequent pathological alterations.

Engineering kidney tissues for polycystic kidney disease modeling and drug discovery.

Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent, potentially lethal monogenic human disorder. There is currently no cure for ADPKD. The mechanistic complexity of the disease, the absence of animal models that can faithfully mimic the disease, as well as the lack of functional human in vitro assays for compound testing, have made drug discovery for PKD very difficult. We recently developed an engineering platform that allowed us to generate polycystic tubules using patients' own cells to test drug efficacy and discover potential new pharmacological treatments for PKD. Here we describe an engineering platform that enables the generation of custom-made polycystic tubules using patients' own cells for modeling PKD and testing drug efficacy.

Glutamate and Mitochondria: Two Prominent Players in the Oxidative Stress-Induced Neurodegeneration.

The aetiology of major neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD) is still unknown, but increasing evidences suggest that glutamate and mitochondria are two prominent players in the oxidative stress (OS) process that underlie these illnesses. Although AD and PD have distinct pathological and clinical features, OS is a common mechanism contributing to neuronal damage. Glutamate is an important neurotransmitter in neurons and glial cells and is strongly dependent on calcium homeostasis and on mitochondrial function. In the present work we focused on glutamate- induced calcium signaling and its relation to the mitochondrial dysfunction with cell death processes. In addition, we have discussed how alterations in this pathway may lead or aggravate the neurodegenerative diseases. Finally, this review aims to stimulate further studies on this issue and thereby engage a new perspective regarding the design of possible therapeutic agents or the identification of biomarkers.

The Role of Brain Cholesterol and its Oxidized Products in Alzheimer's Disease.

The human brain is the most cholesterol-rich organ harboring 25% of the total cholesterol pool of the whole body. Cholesterol present in the central nervous system (CNS) comes, almost entirely, from the endogenous synthesis, being circulating cholesterol unable to cross the blood-brain barrier (BBB). Astrocytes seem to be more active than neurons in this process. Neurons mostly depend on cholesterol delivery from nearby cells for axonal regeneration, neurite extension and synaptogenesis. Within the brain, cholesterol is transported by HDL-like lipoproteins associated to apoE which represents the main apolipoprotein in the CNS. Although CNS cholesterol content is largely independent of dietary intake or hepatic synthesis, a relationship between plasma cholesterol level and neurodegenerative disorders, such as Alzheimer's disease (AD), has often been reported. To this regard, alterations of cholesterol metabolism were suggested to be implicated in the etiology of AD and amyloid production in the brain. Therefore a special attention was dedicated to the study of the main factors controlling cholesterol metabolism in the brain. Brain cholesterol levels are tightly controlled: its excessive amount can be reduced through the conversion into the oxidized form of 24-S-hydroxycholesetrol (24-OH-C), which can reach the blood stream. In fact, the BBB is permeable to 24-OH-C as well as to 27-OH-C, another oxidized form of cholesterol mainly synthesized by non- neural cells. In this review, we summarize the main mechanisms regulating cholesterol homeostasis and review the recent advances on the role played by cholesterol and cholesterol oxidized products in AD. Moreover, we delineate possible pharmacological strategies to control AD progression by affecting cholesterol homeostasis.

Depressive-like behavior is paired to monoaminergic alteration in a murine model of Alzheimer's disease.

BACKGROUND: Neuropsychiatric signs are critical in primary caregiving of Alzheimer patients and have not yet been fully investigated in murine models. METHODS: 18-month-old 3×Tg-AD male mice and their wild-type male littermates (non-Tg) were used. The open field test and the elevated plus maze test were used to evaluate anxiety-like behaviors, whereas the Porsolt forced swim test, the tail suspension test, and the sucrose preference test for antidepressant/depression-coping behaviors. Neurochemical study was conducted by microdialysis in freely-moving mice, analyzing the basal and K(+)-stimulated monoamine output in the frontal cortex and ventral hippocampus. Moreover by immunohistochemistry, we analysed the expression of Tyrosin hydroxylase and Tryptophan hydroxylase, which play a key role in the synthesis of monoamines. RESULTS: Aged 3×Tg-AD mice exhibited a higher duration of immobility in the forced swim and tail suspension tests (predictors of depression-like behavior) which was not attenuated by a noradrenaline reuptake inhibitor, desipramine. In the sucrose preference test, 3×Tg-AD mice showed a significantly lower sucrose preference compared to the non-Tg group, without any difference in total fluid intake. In contrast, the motor functions and anxiety-related emotional responses of 3×Tg-AD mice were normal, as detected by the open-field and elevated plus-maze tests. To strengthen these results, we then evaluated the monoaminergic neurotransmissions by in vivo microdialysis and immunohistochemistry. In particular, with the exception of the basal hippocampal dopamine levels, 3×Tg-AD mice exhibited a lower basal extracellular output of amines in the frontal cortex and ventral hippocampus and also a decreased extracellular response to K(+) stimulation. Such alterations occur with obvious local amyloid-ß and tau pathologies and without gross alterations in the expression of Tyrosin and Tryptophan hydroxylase. CONCLUSIONS: These results suggest that 3×Tg-AD mice exhibit changes in depression-related behavior involving aminergic neurotrasmitters and provide an animal model for investigating AD with depression.