Angiotensin-converting enzyme 2 (ACE2) is related to ACE but turned out to counteract several pathophysiological actions of ACE. ACE2 exerts antihypertensive and cardioprotective effects and reduces lung inflammation. ACE2 is subjected to extensive transcriptional and post-transcriptional modulation by epigenetic mechanisms and microRNAs. Also, ACE2 expression is regulated post-translationally by glycosylation, phosphorylation, and shedding from the plasma membrane. ACE2 protein is ubiquitous across mammalian tissues, prominently in the cardiovascular system, kidney, and intestine. ACE2 expression in the respiratory tract is of particular interest, in light of the discovery that ACE2 serves as the initial cellular target of severe acute respiratory syndrome (SARS)-coronaviruses, including the recent SARS-CoV2, responsible of the COronaVIrus Disease 2019 (COVID-19). Since the onset of the COVID-19 pandemic, an intense effort has been made to elucidate the biochemical determinants of SARS-CoV2-ACE2 interaction. It has been determined that SARS-CoV2 engages with ACE2 through its spike (S) protein, which consists of two subunits: S1, that mediates binding to the host receptor; S2, that induces fusion of the viral envelope with the host cell membrane and delivery of the viral genome. Owing to the role of ACE2 in SARS-CoV2 pathogenicity, it has been speculated that medical conditions, i.e., hypertension, and/or drugs, i.e., ACE inhibitors and angiotensin receptor blockers, known to influence ACE2 density could alter the fate of SARS-CoV-2 infection. The debate is still open and will only be solved when results of properly designed experimental and clinical investigations will be made public. An interesting observation is, however that, upon infection, ACE2 activity is reduced either by downregulation or by shedding. These events might precipitate the so-called "cytokine storm" that characterizes the most severe COVID-19 forms. As evidence accumulates, ACE2 appears a druggable target in the attempt to limit virus entry and replication. Strategies aimed at blocking ACE2 with antibodies, small molecules or peptides, or at neutralizing the virus by competitive binding with exogenously administered ACE2, are currently under investigations. In this review, we will present an overview of the state-of-the-art knowledge on ACE2 biochemistry and pathophysiology, outlining open issues in the context of COVID-19 disease and potential experimental and clinical developments.

Background. A novel branch of thyroid hormone (TH) signaling is represented by 3iodothyronamine (T 1 AM), an endogenous TH derivative that interacts with specific molecular targets, including trace amine associated receptor-1 (TAAR 1 ), and induces pro-learning and antiamnestic effects in mice. Dysregulation of TH signaling has long been hypothesized to play a role in Alzheimer's disease (AD). In the present investigation, we explored the neuroprotective role of T 1 AM in beta amyloid (Aβ)-induced synaptic and behavioral impairment, focusing our study on the entorhinal cortex (EC), an area which is early affected by AD pathology.Methods. Field potentials were evoked in EC layer II and long-term potentiation (LTP) was elicited by high frequency stimulation (HFS). T 1 AM (5 µM) and/or Aβ 142 (200 nM), were administered for 10 minutes, starting 5 minutes before HFS. Selective TAAR 1 agonist RO5166017 (250 nM) and TAAR 1 antagonist EPPTB (5 nM) were also used. The electrophysiological experiments were repeated in EC-slices taken from a mouse model of AD (mhAPP, J20 line). We also assessed the in vivo effects of T 1 AM on EC-dependent associative memory deficits, that were detected in mhAPP mice by behavioral evaluations based on the novel-object recognition paradigm. TAAR 1 expression was determined by Western blot, while T 1 AM and its metabolite 3-iodothyroacetic acid (TA 1

In the two decades since its discovery, a large body of evidence has amassed to highlight the potential of 3-iodothyronamine (T1AM) as an antiobesity drug, whose pleiotropic signaling actions profoundly impact energy metabolism. In the present review, we recapitulate the most relevant properties of T1AM, including its structural and functional relationship to thyroid hormone, its endogenous levels, molecular targets, as well as its genomic and non-genomic effects on metabolism elicited in experimental models after exogenous administration. The physiological and pathophysiological relevance of T1AM in the regulation of energy homeostasis and metabolism is also discussed, along with its potential therapeutic applications in metabolic disturbances. Finally, we examine a number of T1AM analogs that have been recently developed with the aim of designing novel pharmacological agents for the treatment of interlinked diseases, such as metabolic and neurodegenerative disorders, as well as additional synthetic tools that can be exploited to further explore T1AM-dependent mechanisms and the physiological roles of trace amine-associated receptor 1 (TAAR1)-mediated effects.

Recent reports highlighted the significant neuroprotective effects of thyronamines (TAMs), a class of endogenous thyroid hormone derivatives. In particular, 3-iodothyronamine (T1AM) has been shown to play a pleiotropic role in neurodegeneration by modulating energy metabolism and neurological functions in mice. However, the pharmacological response to T1AM might be influenced by tissue metabolism, which is known to convert T1AM into its catabolite 3-iodothyroacetic acid (TA1). Currently, several research groups are investigating the pharmacological effects of T1AM systemic administration in the search of novel therapeutic approaches for the treatment of interlinked pathologies, such as metabolic and neurodegenerative diseases (NDDs). A critical aspect in the development of new drugs for NDDs is to know their distribution in the brain, which is fundamentally related to their ability to cross the blood–brain barrier (BBB). To this end, in the present study we used the immortalized mouse brain endothelial cell line bEnd.3 to develop an in vitro model of BBB and evaluate T1AM and TA1 permeability. Both drugs, administered at 1 µM dose, were assayed by high-performance liquid chromatography coupled to mass spectrometry. Our results indicate that T1AM is able to efficiently cross the BBB, whereas TA1 is almost completely devoid of this property.

Background3-Iodothyronamine (T1AM) is an endogenous messenger chemically related to thyroid hormone. Recent results indicate significant transcriptional effects of chronic T1AM administration involving the protein family of sirtuins, which regulate important metabolic pathways and tumor progression. Therefore, the aim of this work was to compare the effect of exogenous T1AM and 3,5,3′-triiodo-L-thyronine (T3) chronic treatment on mammalian sirtuin expression in hepatocellular carcinoma cells (HepG2) and in primary rat hepatocytes at micromolar concentrations.Materials and methodsSirtuin (SIRT) activity and expression were determined using a colorimetric assay and Western blot analysis, respectively, in cells treated for 24 h with 1–20 μM T1AM or T3. In addition, cell viability was evaluated by the MTTtest upon 24 h of treatment with 0.1–20 μM T1AM or T3.ResultsIn HepG2, T1AM significantly reduced SIRT 1 (20 μM) and SIRT4 (10–20 μM) protein expression, while T3 strongly decreased the expression of SIRT1 (20 μM) and SIRT2 (any tested concentration). In primary rat hepatocytes, T3 decreased SIRT2 expression and cellular nicotinamide adenine dinucleotide (NAD) concentration, while on sirtuin activity it showed opposite effects, depending on the evaluated cell fraction. The extent of MTT staining was moderately but significantly reduced by T1AM, particularly in HepG2 cells, whereas T3 reduced cell viability only in the tumor cell line.ConclusionsT1AM and T3 downregulated the expression of sirtuins, mainly SIRT1, in hepatocytes, albeit in different ways. Differences in mechanisms are only observational, and further investigations are required to highlight the potential role of T1AM and T3 in modulating sirtuin expression and, therefore, in regulating cell cycle or tumorigenesis.