Lack of kinase-independent activity of PI3Kγ in locus coeruleus induces ADHD symptoms through increased CREB signaling.

Although PI3Kγ has been extensively investigated in inflammatory and cardiovascular diseases, the exploration of its functions in the brain is just at dawning. It is known that PI3Kγ is present in neurons and that the lack of PI3Kγ in mice leads to impaired synaptic plasticity, suggestive of a role in behavioral flexibility. Several neuropsychiatric disorders, such as attention-deficit/hyperactivity disorder (ADHD), involve an impairment of behavioral flexibility. Here, we found a previously unreported expression of PI3Kγ throughout the noradrenergic neurons of the locus coeruleus (LC) in the brainstem, serving as a mechanism that regulates its activity of control on attention, locomotion and sociality. In particular, we show an unprecedented phenotype of PI3Kγ KO mice resembling ADHD symptoms. PI3Kγ KO mice exhibit deficits in the attentive and mnemonic domains, typical hyperactivity, as well as social dysfunctions. Moreover, we demonstrate that the ADHD phenotype depends on a dysregulation of CREB signaling exerted by a kinase-independent PI3Kγ-PDE4D interaction in the noradrenergic neurons of the locus coeruleus, thus uncovering new tools for mechanistic and therapeutic research in ADHD

Protection from angiotensin II–mediated vasculotoxic and hypertensive response in mice lacking PI3Kγ

Hypertension affects nearly 20% of the population in Western countries and strongly increases the risk for cardiovascular diseases. In the pathogenesis of hypertension, the vasoactive peptide of the renin-angiotensin system, angiotensin II and its G protein–coupled receptors (GPCRs), play a crucial role by eliciting reactive oxygen species (ROS) and mediating vessel contractility. Here we show that mice lacking the GPCR-activated phosphoinositide 3-kinase (PI3K)γ are protected from hypertension that is induced by administration of angiotensin II in vivo. PI3Kγ was found to play a role in angiotensin II–evoked smooth muscle contraction in two crucial, distinct signaling pathways. In response to angiotensin II, PI3Kγ was required for the activation of Rac and the subsequent triggering of ROS production. Conversely, PI3Kγ was necessary to activate protein kinase B/Akt, which, in turn, enhanced L-type Ca2+ channel–mediated extracellular Ca2+ entry. These data indicate that PI3Kγ is a key transducer of the intracellular signals that are evoked by angiotensin II and suggest that blocking PI3Kγ function might be exploited to improve therapeutic intervention on hypertension

Effect of aliskiren on post-discharge outcomes among diabetic and non-diabetic patients hospitalized for heart failure: insights from the ASTRONAUT trial

Aims The objective of the Aliskiren Trial on Acute Heart Failure Outcomes (ASTRONAUT) was to determine whether aliskiren, a direct renin inhibitor, would improve post-discharge outcomes in patients with hospitalization for heart failure (HHF) with reduced ejection fraction. Pre-specified subgroup analyses suggested potential heterogeneity in post-discharge outcomes with aliskiren in patients with and without baseline diabetes mellitus (DM). Methods and results ASTRONAUT included 953 patients without DM (aliskiren 489; placebo 464) and 662 patients with DM (aliskiren 319; placebo 343) (as reported by study investigators). Study endpoints included the first occurrence of cardiovascular death or HHF within 6 and 12 months, all-cause death within 6 and 12 months, and change from baseline in N-terminal pro-B-type natriuretic peptide (NT-proBNP) at 1, 6, and 12 months. Data regarding risk of hyperkalaemia, renal impairment, and hypotension, and changes in additional serum biomarkers were collected. The effect of aliskiren on cardiovascular death or HHF within 6 months (primary endpoint) did not significantly differ by baseline DM status (P = 0.08 for interaction), but reached statistical significance at 12 months (non-DM: HR: 0.80, 95% CI: 0.64-0.99; DM: HR: 1.16, 95% CI: 0.91-1.47; P = 0.03 for interaction). Risk of 12-month all-cause death with aliskiren significantly differed by the presence of baseline DM (non-DM: HR: 0.69, 95% CI: 0.50-0.94; DM: HR: 1.64, 95% CI: 1.15-2.33; P < 0.01 for interaction). Among non-diabetics, aliskiren significantly reduced NT-proBNP through 6 months and plasma troponin I and aldosterone through 12 months, as compared to placebo. Among diabetic patients, aliskiren reduced plasma troponin I and aldosterone relative to placebo through 1 month only. There was a trend towards differing risk of post-baseline potassium ≥6 mmol/L with aliskiren by underlying DM status (non-DM: HR: 1.17, 95% CI: 0.71-1.93; DM: HR: 2.39, 95% CI: 1.30-4.42; P = 0.07 for interaction). Conclusion This pre-specified subgroup analysis from the ASTRONAUT trial generates the hypothesis that the addition of aliskiren to standard HHF therapy in non-diabetic patients is generally well-tolerated and improves post-discharge outcomes and biomarker profiles. In contrast, diabetic patients receiving aliskiren appear to have worse post-discharge outcomes. Future prospective investigations are needed to confirm potential benefits of renin inhibition in a large cohort of HHF patients without D

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Synthesis and characterization of new porphyrin- fullerene architectures and their potential applications for photocurrent generation

In questo lavoro verranno presentate nuove diadi porfirina-fullerene, questi nuovi composti sono stati sviluppati prendendo spunto dalle possibili diverse tipologie di interazione tra i due sopraindicati cromofori, riportate in letteratura. In particolare la mia attenzione è stata focalizzata sulla sintesi e caratterizzazione di nuovi composti porfirina-fullerene, contenenti una molecola “linker” direttamente legata nelle posizioni β-pirroliche della porfirina stessa, allo scopo di verificare come questo tipo di connessione, alterando le proprietà chimico-fisiche del macrociclo tetrapirrolico, influenzasse i processi di trasferimento energetico ed elettronico. Come subunità base spaziatrice tra porfirina e fullerene è stata scelta l’unità etinilenefenilenica; per le sue proprietà elettroniche questo tipo di “ponte molecolare” dovrebbe garantire un accoppiamento elettronico abbastanza buono tra i cromofori in questione. Alla luce di queste considerazioni sono stati sintetizzati nuovi sistemi porfirina-fullerene recanti “ponti molecolari” di diversa lunghezza interposti tra i due cromofori. Tali composti sono stati caratterizzati e studiati attraverso misure di spettrometria di massa (MALDI-TOF e FAB), risonanza magnetica (1H e 13C NMR), fluorescenza e voltammetria ciclica. Inoltre, nuovi bis addotti ciclici porfirina-fullerene sono stati sintetizzati e parzialmente caratterizzati e diversi sforzi sono stati fatti per introdurre un gruppo coordinante nei nuovi sistemi porfirina-fullerene, allo scopo di ottenere fili molecolari “auto assemblanti” contenenti unità già attive da un punto di vista fotochimico. La presenza di un gruppo coordinante, come appunto un piridile, ha offerto la possibilità di funzionalizzare ulteriormente i sistemi porfirina-fullerene, con il proposito di suggerire un potenziale campo di applicazione dei nuovi sistemi sintetizzati: la produzione di dispositivi molecolari per la generazione di corrente fotoindotta.In this work new porphyrin-fullerene architectures will be presented, these new porphyrinfullerene compounds are developed taking in consideration the main typologies of interaction between the two chromophores reported in literature. In particular my attention was focused in the synthesis and characterization of new β-modified porphyrin-fullerene compounds in order to evaluate how such type of connection, altering the chemico-physical properties of the porphyrin moiety, can influence energy and electron-transfer processes. Ethynylenephenylene subunit was chosen as molecular spacer between porphyrin and fullerene. Due to its electronic properties these type of molecular bridges should offer quite good electronic coupling between the two chromophores. Under the light of these considerations different porphyrin-wirefullerene systems bearing a molecular bridge of different length, their corresponding zinc complexes and reference compounds were synthesized and characterized (MALDI-TOF and FAB mass spectra, 1H and 13C NMR, Fluorescence, Cyclic Voltammetry). New cyclic porphyrin-fullerene bis-adducts are also synthesized and partially characterized and several efforts are dedicated to introduce coordinating groups into porphyrin-fullerene systems in order to have self-assembling molecular wires, containing already photoactive units, able to give energy and electron-transfer. The presence of a coordinating group such as pyridyl group has offered the possibility to further functionalize the porphyrin-fullerene systems with the aim to suggest potential applications to build up molecular devices useful for photocurrent generation

Synthesis and characterization of new porphyrin- fullerene architectures and their potential applications for photocurrent generation

In questo lavoro verranno presentate nuove diadi porfirina-fullerene, questi nuovi composti sono stati sviluppati prendendo spunto dalle possibili diverse tipologie di interazione tra i due sopraindicati cromofori, riportate in letteratura. In particolare la mia attenzione è stata focalizzata sulla sintesi e caratterizzazione di nuovi composti porfirina-fullerene, contenenti una molecola “linker” direttamente legata nelle posizioni β-pirroliche della porfirina stessa, allo scopo di verificare come questo tipo di connessione, alterando le proprietà chimico-fisiche del macrociclo tetrapirrolico, influenzasse i processi di trasferimento energetico ed elettronico. Come subunità base spaziatrice tra porfirina e fullerene è stata scelta l’unità etinilenefenilenica; per le sue proprietà elettroniche questo tipo di “ponte molecolare” dovrebbe garantire un accoppiamento elettronico abbastanza buono tra i cromofori in questione. Alla luce di queste considerazioni sono stati sintetizzati nuovi sistemi porfirina-fullerene recanti “ponti molecolari” di diversa lunghezza interposti tra i due cromofori. Tali composti sono stati caratterizzati e studiati attraverso misure di spettrometria di massa (MALDI-TOF e FAB), risonanza magnetica (1H e 13C NMR), fluorescenza e voltammetria ciclica. Inoltre, nuovi bis addotti ciclici porfirina-fullerene sono stati sintetizzati e parzialmente caratterizzati e diversi sforzi sono stati fatti per introdurre un gruppo coordinante nei nuovi sistemi porfirina-fullerene, allo scopo di ottenere fili molecolari “auto assemblanti” contenenti unità già attive da un punto di vista fotochimico. La presenza di un gruppo coordinante, come appunto un piridile, ha offerto la possibilità di funzionalizzare ulteriormente i sistemi porfirina-fullerene, con il proposito di suggerire un potenziale campo di applicazione dei nuovi sistemi sintetizzati: la produzione di dispositivi molecolari per la generazione di corrente fotoindotta.In this work new porphyrin-fullerene architectures will be presented, these new porphyrinfullerene compounds are developed taking in consideration the main typologies of interaction between the two chromophores reported in literature. In particular my attention was focused in the synthesis and characterization of new β-modified porphyrin-fullerene compounds in order to evaluate how such type of connection, altering the chemico-physical properties of the porphyrin moiety, can influence energy and electron-transfer processes. Ethynylenephenylene subunit was chosen as molecular spacer between porphyrin and fullerene. Due to its electronic properties these type of molecular bridges should offer quite good electronic coupling between the two chromophores. Under the light of these considerations different porphyrin-wirefullerene systems bearing a molecular bridge of different length, their corresponding zinc complexes and reference compounds were synthesized and characterized (MALDI-TOF and FAB mass spectra, 1H and 13C NMR, Fluorescence, Cyclic Voltammetry). New cyclic porphyrin-fullerene bis-adducts are also synthesized and partially characterized and several efforts are dedicated to introduce coordinating groups into porphyrin-fullerene systems in order to have self-assembling molecular wires, containing already photoactive units, able to give energy and electron-transfer. The presence of a coordinating group such as pyridyl group has offered the possibility to further functionalize the porphyrin-fullerene systems with the aim to suggest potential applications to build up molecular devices useful for photocurrent generation

Fatty acids are the best fuel for overloaded hearts

This editorial refers to ‘Glucose is preferentially utilized for biomass synthesis in pressure-overloaded hearts: evidence from fatty acid-binding protein-4 and -5 knockout mice’ by Y. Umbarawan et al., pp. 1132–1144