Metabolic profiling reveals reprogramming of lipid metabolic pathways in treatment of polycystic ovary syndrome with 3-iodothyronamine

Complex diseases such as polycystic ovary syndrome (PCOS) are associated with intricate pathophysiological, hormonal, and metabolic feedbacks that make their early diagnosis challenging, thus increasing the prevalence risks for obesity, cardiovascular, and fatty liver diseases. To explore the crosstalk between endocrine and lipid metabolic pathways, we administered 3-iodothyronamine (T1AM), a natural analog of thyroid hormone, in a mouse model of PCOS and analyzed plasma and tissue extracts using multidisciplinary omics and biochemical approaches. T1AM administration induces a profound tissue-specific antilipogenic effect in liver and muscle by lowering gene expression of key regulators of lipid metabolism, PTP1B and PLIN2, significantly increasing metabolites (glucogenic, amino acids, carnitine, and citrate) levels, while enhancing protection against oxidative stress. In contrast, T1AM has an opposing effect on the regulation of estrogenic pathways in the ovary by upregulating STAR, CYP11A1, and CYP17A1. Biochemical measurements provide further evidence of significant reduction in liver cholesterol and triglycerides in post-T1AM treatment. Our results shed light onto tissue-specific metabolic vs. hormonal pathway interactions, thus illuminating the intricacies within the pathophysiology of PCOS. This study opens up new avenues to design drugs for targeted therapeutics to improve quality of life in complex metabolic diseases

New Insights into the Potential Roles of 3-Iodothyronamine (T1AM) and Newly Developed Thyronamine-Like TAAR1 Agonists in Neuroprotection

3-Iodothyronamine (T1AM) is an endogenous high-affinity ligand of the trace amine-associated receptor 1 (TAAR1), detected in mammals in many organs, including the brain. Recent evidence indicates that pharmacological TAAR1 activation may offer a novel therapeutic option for the treatment of a wide range of neuropsychiatric and metabolic disorders. To assess potential neuroprotection by TAAR1 agonists, in the present work, we initially investigated whether T1AM and its corresponding 3-methylbiaryl-methane analog SG-2 can improve learning and memory when systemically administered to mice at submicromolar doses, and whether these effects are modified under conditions of MAO inhibition by clorgyline. Our results revealed that when i.p. injected to mice, both T1AM and SG-2 produced memory-enhancing and hyperalgesic effects, while increasing ERK1/2 phosphorylation and expression of transcription factor c-fos. Notably, both compounds appeared to rely on the action of ubiquitous enzymes MAO to produce the corresponding oxidative metabolites that were then able to activate the histaminergic system. Since autophagy is key for neuronal plasticity, in a second line of experiments we explored whether T1AM and synthetic TAAR1 agonists SG1 and SG2 were able to induce autophagy in human glioblastoma cell lines (U-87MG). After treatment of U-87MG cells with 1 μM T1AM, SG-1, SG-2 transmission electron microscopy (TEM) and immunofluorescence (IF) showed a significant time-dependent increase of autophagy vacuoles and microtubule-associated protein 1 light chain 3 (LC3). Consistently, Western blot analysis revealed a significant increase of the LC3II/LC3I ratio, with T1AM and SG-1 being the most effective agents. A decreased level of the p62 protein was also observed after treatment with T1AM and SG-1, which confirms the efficacy of these compounds as autophagy inducers in U-87MG cells. In the process to dissect which pathway induces ATG, the effects of these compounds were evaluated on the PI3K-AKT-mTOR pathway. We found that 1 μM T1AM, SG-1 and SG-2 decreased pAKT/AKT ratio at 0.5 and 4 h after treatment, suggesting that autophagy is induced by inhibiting mTOR phosphorylation by PI3K-AKT-mTOR pathway. In conclusion, our study shows that T1AM and thyronamine-like derivatives SG-1 and SG-2 might represent valuable tools to therapeutically intervene with neurological disorder

Metabolic reprogramming by 3-Iodothyronamine (T1AM): a new perspective to reverse obesity through co-regulation of sirtuin 4 and 6 expression

Obesity is a complex disease associated with environmental and genetic factors. 3-Iodothyronamine (T1AM) has revealed great potential as an effective weight loss drug. We used metabolomics and associated transcriptional gene and protein expression analysis to investigate the tissue specific metabolic reprogramming effects of subchronic T1AM treatment at two pharmacological daily doses (10 and 25 mg/kg) on targeted metabolic pathways. Multi-analytical results indicated that T1AM at 25 mg/kg can act as a novel master regulator of both glucose and lipid metabolism in mice through sirtuin-mediated pathways. In liver, we observed an increased gene and protein expression of Sirt6 (a master gene regulator of glucose) and Gck (glucose kinase) and a decreased expression of Sirt4 (a negative regulator of fatty acids oxidation (FAO)), whereas in white adipose tissue only Sirt6 was increased. Metabolomics analysis supported physiological changes at both doses with most increases in FAO, glycolysis indicators and the mitochondrial substrate, at the highest dose of T1AM. Together our results suggest that T1AM acts through sirtuin-mediated pathways to metabolically reprogram fatty acid and glucose metabolism possibly through small molecules signaling. Our novel mechanistic findings indicate that T1AM has a great potential as a drug for the treatment of obesity and possibly diabetes

B-TURP versus HoLEP. Peri-operative outcomes and complications in frail elderly (>75 y.o.) patients. A prospective randomized study

Background: The aim of this study was to compare the peri-operative and functional results between trans-urethral resection of the prostate (TURP) and holmium laser enucleation of the prostate (HoLEP) in the treatment of benign prostatic hyperplasia (BPH) associated with lower urinary tract symptoms (LUTS) in middle-old patients. Materials and methods: This prospective single-center study included patients over 75 years old treated with B-TURP or HoLEP for BPH associated with LUTS with prostate volume (PV) <100 mL. Primary endpoints were the intra-operative blood loss, percentage of loss of hemoglobin, blood transfusion, complications, and the comparison of functional outcomes. All patients were evaluated at 1, 3, 6, and 12 months of follow-up. Results: Overall, 96 patients undergoing HoLEP and 104 B-TURP were eligible and enrolled for the study. Post-operative results showed statistically significant differences between the two groups, all in favor of HoLEP group, specifically in terms of removed prostate tissue, PV reduction rate, hemoglobin values at 24 h, hemoglobin loss, operative time, length of hospitalization, days of catheterization, and urinary flow rates. There was no significant difference in terms of postvoid residual urine volume, perioperative complication, blood transfusion, International Prostate Symptom Score (IPSS), and IPSS quality of life scores. Conclusions: In middle-old patients, the HoLEP technique represents a prostate size-independent treatment option with a more favorable safety profile defined by less bleeding, lower blood transfusions, and a significantly lower hemoglobin drop than B-TURP

Hit-to-Lead Optimization of Mouse Trace Amine Associated Receptor 1 (mTAAR1) Agonists with a Diphenylmethane-Scaffold: Design, Synthesis, and Biological Study

The trace amine-associated receptor 1 (TAAR1) is a G-protein-coupled receptors (GPCR) potently activated by a variety of molecules besides trace amines (TAs), including thyroid hormone-derivatives like 3-iodothyronamine (T1AM), catechol-O-methyltransferase products like 3-methoxytyramine, and amphetamine-related compounds. Accordingly, TAAR1 is considered a promising target for medicinal development. To gain more insights into TAAR1 physiological functions and validation of its therapeutic potential we recently developed a new class of thyronamine-like derivatives. Among them compound SG2 showed high affinity and potent agonist activity at mouse TAAR1. In the present work we describe design, the synthesis and SAR study of a new series of compounds (1-16) obtained by introducing specific structural changes at key points of our lead-compound SG2 skeleton. Five of the newly synthesized compounds displayed mTAAR1 agonist activity higher than both SG2 and T1AM. Selected diphenylmethane analogs, namely 1 and 2, showed potent functional activity in in vitro and in vivo models

Management of pregnancy in autoimmune rheumatic diseases: maternal disease course, gestational and neonatal outcomes and use of medications in the prospectiveItalian P-RHEUM.it study

Objectives To investigate pregnancy outcomes in women with autoimmune rheumatic diseases (ARD) in the Italian prospective cohort study P-RHEUM.it. Methods Pregnant women with different ARD were enrolled for up to 20 gestational weeks in 29 Rheumatology Centres for 5 years (2018-2023). Maternal and infant information were collected in a web-based database. Results We analysed 866 pregnancies in 851 patients (systemic lupus erythematosus was the most represented disease, 19.6%). Maternal disease flares were observed in 135 (15.6%) pregnancies. 53 (6.1%) pregnancies were induced by assisted reproduction techniques, 61 (7%) ended in miscarriage and 11 (1.3%) underwent elective termination. Obstetrical complications occurred in 261 (30.1%) pregnancies, including 2.3% pre-eclampsia. Two cases of congenital heart block were observed out of 157 pregnancies (1.3%) with anti-Ro/SSA. Regarding treatments, 244 (28.2%) pregnancies were treated with glucocorticoids, 388 (44.8%) with hydroxychloroquine, 85 (9.8%) with conventional synthetic disease-modifying anti-rheumatic drugs and 122 (14.1%) with biological disease-modifying anti-rheumatic drugs. Live births were 794 (91.7%), mostly at term (84.9%); four perinatal deaths (0.5%) occurred. Among 790 newborns, 31 (3.9%) were small-for-gestational-age and 169 (21.4%) had perinatal complications. Exclusive maternal breast feeding was received by 404 (46.7%) neonates. The Edinburgh Postnatal Depression Scale was compiled by 414 women (52.4%); 89 (21.5%) scored positive for emotional distress. Conclusions Multiple factors including preconception counselling and treat-to-target with pregnancy-compatible medications may have contributed to mitigate disease-related risk factors, yielding limited disease flares, good pregnancy outcomes and frequency of complications which were similar to the Italian general obstetric population. Disease-specific issues need to be further addressed to plan preventative measures

A genome-wide association study for survival from a multi-centre European study identified variants associated with COVID-19 risk of death

: The clinical manifestations of SARS-CoV-2 infection vary widely among patients, from asymptomatic to life-threatening. Host genetics is one of the factors that contributes to this variability as previously reported by the COVID-19 Host Genetics Initiative (HGI), which identified sixteen loci associated with COVID-19 severity. Herein, we investigated the genetic determinants of COVID-19 mortality, by performing a case-only genome-wide survival analysis, 60 days after infection, of 3904 COVID-19 patients from the GEN-COVID and other European series (EGAS00001005304 study of the COVID-19 HGI). Using imputed genotype data, we carried out a survival analysis using the Cox model adjusted for age, age2, sex, series, time of infection, and the first ten principal components. We observed a genome-wide significant (P-value < 5.0 × 10-8) association of the rs117011822 variant, on chromosome 11, of rs7208524 on chromosome 17, approaching the genome-wide threshold (P-value = 5.19 × 10-8). A total of 113 variants were associated with survival at P-value < 1.0 × 10-5 and most of them regulated the expression of genes involved in immune response (e.g., CD300 and KLR genes), or in lung repair and function (e.g., FGF19 and CDH13). Overall, our results suggest that germline variants may modulate COVID-19 risk of death, possibly through the regulation of gene expression in immune response and lung function pathways

Host genetics and COVID-19 severity: increasing the accuracy of latest severity scores by Boolean quantum features

The impact of common and rare variants in COVID-19 host genetics has been widely studied. In particular, in Fallerini et al. (Human genetics, 2022, 141, 147–173), common and rare variants were used to define an interpretable machine learning model for predicting COVID-19 severity. First, variants were converted into sets of Boolean features, depending on the absence or the presence of variants in each gene. An ensemble of LASSO logistic regression models was used to identify the most informative Boolean features with respect to the genetic bases of severity. After that, the Boolean features, selected by these logistic models, were combined into an Integrated PolyGenic Score (IPGS), which offers a very simple description of the contribution of host genetics in COVID-19 severity.. IPGS leads to an accuracy of 55%–60% on different cohorts, and, after a logistic regression with both IPGS and age as inputs, it leads to an accuracy of 75%. The goal of this paper is to improve the previous results, using not only the most informative Boolean features with respect to the genetic bases of severity but also the information on host organs involved in the disease. In this study, we generalize the IPGS adding a statistical weight for each organ, through the transformation of Boolean features into “Boolean quantum features,” inspired by quantum mechanics. The organ coefficients were set via the application of the genetic algorithm PyGAD, and, after that, we defined two new integrated polygenic scores (IPGSph1 and IPGSph2). By applying a logistic regression with both IPGS, (IPGSph2 (or indifferently IPGSph1) and age as inputs, we reached an accuracy of 84%–86%, thus improving the results previously shown in Fallerini et al. (Human genetics, 2022, 141, 147–173) by a factor of 10%

Influenza del biofilm marino sul reclutamento della macroalga Ericaria amentacea

Nel Mar Mediterraneo le foreste di Cystoseira rivestono un ruolo fondamentale come specie fondatrici. Attualmente, però, gran parte di queste sono andate perdute lungo le coste della Toscana e dove presenti, soprattutto nelle isole dell’Arcipelago toscano, sono minacciate dagli impatti antropici e dai cambiamenti climatici. Vengono, perciò, incoraggiate attività di ripristino ambientale per prevenire la perdita definitiva di tali habitat e proteggere la biodiversità associata. La presente tesi ha lo scopo di valutare se il reclutamento della specie Ericaria amentacea sia influenzato dalle caratteristiche del film microbico presente sul substrato dove avviene l’insediamento dei suoi zigoti. Per testare l’interazione tra il biofilm e i primi stadi vitali di E. amentacea, attività sul campo sono state affiancate da esperimenti in mesocosmi. Lo studio è stato condotto in tre siti diversi nel Mar Mediterraneo, caratterizzati da diversi livelli di impatto antropico: 1) L’ Isola di Capraia, 2) L’AMP delle Secche della Meloria, 3) La costa urbana del litorale livornese. Nei siti sono stati posizionati, ad una profondità tra i 5 e i 7m, supporti con sopra mattonelle di terracotta, le quali sono servite come substrati artificiali per la colonizzazione del biofilm. I supporti colonizzati sono stati disposti in vasche da 5L dove è stato fatto avvenire il reclutamento di E. amentacea tramite il posizionamento di apici fertili sopra i substrati. Dalla quantificazione degli zigoti, l’insediamento è risultato maggiore sui substrati provenienti dall’’Isola di Capraia, rispetto a quelli dislocati lungo la costa di Livorno o presso le Secche della Meloria. In conclusione, il film microbico che ha colonizzato le mattonelle in mare potrebbe avere una diversa composizione in base ai siti di provenienza, dal momento che le comunità microbiche possono variare a scale spaziali e temporali diverse e in base ai diversi livelli di impatto antropico, andando così a promuovere o ridurre l’insediamento degli zigoti di E. amentacea. In the Mediterranean Sea, the algal forests of Cystoseira play a key role in community structure and functioning on rocky bottoms. They are dominant habitat-forming species in rocky intertidal and subtidal shores and are recognized as hotspots for biodiversity in marine environments, by providing food, habitat and shelters to diverse assemblages of understory species. A drastic reduction in cover of canopy-forming algae is caused by various anthropogenic disturbances, as well as by climate change. Therefore, increasing concerns about biodiversity loss have promoted international efforts to restore degraded habitats, by implementing ecosystem restoration actions. The aim of the present thesis is to evaluate if the recruitment of the seaweed Ericaria amentacea is influenced by biofilm assemblages that pre colonize the substrate. Indeed, microbial communities affect settlement of spores and larvae of some macrofouling species. In order to show the interactions between microorganisms and early life stages of E. amentacea, field activities and mesocosms experiments were combined. The research was conducted in three different sites in the Mediterranean Sea, with different human impact levels: 1) Capraia Island, 2) The MPA of Meloria 3) Livorno. Within each of the sites substrates with clay tiles (5x5 cm) were placed at 5-7 meters depth, then the tiles were colonized by marine microorganisms after a period of time. After the colonization period, tiles were placed in tanks and apices of E. amentacea with mature receptacles were placed on each substratum in separate acquaria per condition. After the recruitment, the number of settled zygotes was assessed and it was higher on tiles of Capraia Island, than on tiles of Livorno or Meloria. Our findings show that environmental conditions as well as anthropogenic disturbances may affect the settlement of early life stages of the seaweed E. amentacea, probably due to the presence of specific microbial communities on the substrates