The role of ADAM17 in metabolic inflammation

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The PAAD/PYRIN-Family Protein ASC Is a Dual Regulator of a Conserved Step in Nuclear Factor κB Activation Pathways

Apoptosis-associated speck-like protein containing a Caspase recruitment domain (ASC) belongs to a large family of proteins that contain a Pyrin, AIM, ASC, and death domain-like (PAAD) domain (also known as PYRIN, DAPIN, Pyk). Recent data have suggested that ASC functions as an adaptor protein linking various PAAD-family proteins to pathways involved in nuclear factor (NF)-κB and pro-Caspase-1 activation. We present evidence here that the role of ASC in modulating NF-κB activation pathways is much broader than previously suspected, as it can either inhibit or activate NF-κB, depending on cellular context. While coexpression of ASC with certain PAAD-family proteins such as Pyrin and Cryopyrin increases NF-κB activity, ASC has an inhibitory influence on NF-κB activation by various proinflammatory stimuli, including tumor necrosis factor (TNF)α, interleukin 1β, and lipopolysaccharide (LPS). Elevations in ASC protein levels or of the PAAD domain of ASC suppressed activation of IκB kinases in cells exposed to pro-inflammatory stimuli. Conversely, reducing endogenous levels of ASC using siRNA enhanced TNF- and LPS-induced degradation of the IKK substrate, IκBα. Our findings suggest that ASC modulates diverse NF-κB induction pathways by acting upon the IKK complex, implying a broad role for this and similar proteins containing PAAD domains in regulation of inflammatory responses

IL-21 is a major negative regulator of IRF4-dependent lipolysis affecting Tregs in adipose tissue and systemic insulin sensitivity.

Obesity elicits immune cell infiltration of adipose tissue provoking chronic low-grade inflammation. Regulatory T cells (Tregs) are specifically reduced in adipose tissue of obese animals. Since interleukin (IL)-21 plays an important role in inducing and maintaining immune-mediated chronic inflammatory processes and negatively regulates Treg differentiation/activity, we hypothesized that it could play a role in obesity-induced insulin resistance. We found IL-21 and IL-21R mRNA expression upregulated in adipose tissue of high-fat diet (HFD) wild-type (WT) mice and in stromal vascular fraction from human obese subjects in parallel to macrophage and inflammatory markers. Interestingly, a larger infiltration of Treg cells was seen in the adipose tissue of IL-21 knockout (KO) mice compared with WT animals fed both normal diet and HFD. In a context of diet-induced obesity, IL-21 KO mice, compared with WT animals, exhibited lower body weight, improved insulin sensitivity, and decreased adipose and hepatic inflammation. This metabolic phenotype is accompanied by a higher induction of interferon regulatory factor 4 (IRF4), a transcriptional regulator of fasting lipolysis in adipose tissue. Our data suggest that IL-21 exerts negative regulation on IRF4 and Treg activity, developing and maintaining adipose tissue inflammation in the obesity state

Bridging therapeutic opportunities: a survey by the Italian molecular tumor board workgroup of Alliance Against Cancer

Background: Molecular tumor boards (MTBs) match molecular alterations with targeted anticancer drugs upon failure of the available therapeutic options. Special and local needs are most likely to emerge through the comparative analysis of MTB networks, but these are rarely reported. This manuscript summarizes the state-of-art of 16 active Italian MTBs, as it emerges from an online survey curated by Alliance Against Cancer (ACC).Main text: Most MTBs (13/16) are exclusively supported through local Institutional grants and meet regularly. All but one adopts a fully virtual or a mixed face-to-face/virtual calling/attendance meeting model. It appears that the ACC MTB initiative is shaping a hub-and-spoke virtual MTB network reminiscent of non-redundant, cost-effective health-care organization models. Unfortunately, public awareness of MTB opportunities presently remains insufficient. Only one center has a website. Dedicated e-mail addresses are for the exclusive use of the MTB staff. More than half of ACC members consider a miscellanea of most or all solid and hematological malignancies, and more than one-third consider neoplasms arising at any anatomical location. The average number of Staff Members in MTBs is 9. More than 10 staff members simultaneously attend MTB meetings in 13 MTBs. A medical oncologist is invariably present and is in charge of introducing the clinical case either with (45%) or without previous discussion in organ-specific multidisciplinary Boards. All but two MTBs take charge of not only patients with no standard-of-care (SoC) therapy option, but also cases receiving NGS profiling in SoC settings, implying a larger number of yearly cases. All MTBs run targeted NGS panels. Three run whole-exome and/or RNAseq approaches. ESCAT-ESMO and/or Onco-KB levels of evidence are similarly used for diagnostic reporting. Most MTBs (11) provide a written diagnostic report within 15 days. Conclusions are invariably communicated to the patient by the medical oncologist.Conclusions: MTB networking is crucial not only for molecular diagnosis and therapy assignment, but also for healthcare governance. Survey results show that MTBs review therapeutic opportunities at the crossover between standard-of-care with off-label, the former task being much beyond their scope. Societal and scientific implications of this beyond-the-scope MTB function may be relevant for healthcare in Italy and abroad

Where Is More Important Than How in Coastal and Marine Ecosystems Restoration

Restoration is considered an effective strategy to accelerate the recovery of biological communities at local scale. However, the effects of restoration actions in the marine ecosystems are still unpredictable.We performed a global analysis of published literature to identify the factors increasing the probability of restoration success in coastal and marine systems. Our results confirm that the majority of active restoration initiatives are still concentrated in the northern hemisphere and that most of information gathered from restoration efforts derives from a relatively small subset of species. The analysis also indicates that many studies are still experimental in nature, covering small spatial and temporal scales. Despite the limits of assessing restoration effectiveness in absence of a standardized definition of success, the context (degree of human impact, ecosystem type, habitat) of where the restoration activity is undertaken is of greater relevance to a successful outcome than how (method) the restoration is carried out. Contrary to expectations, we found that restoration is not necessarily more successful closer to protected areas (PA) and in areas of moderate human impact. This result can be motivated by the limits in assessing the success of interventions and by the tendency of selecting areas in more obvious need of restoration, where the potential of actively restoring a degraded site is more evident. Restoration sites prioritization considering human uses and conservation status present in the region is of vital importance to obtain the intended outcomes and galvanize further actions

Genetic determinants in a critical domain of ns5a correlate with hepatocellular carcinoma in cirrhotic patients infected with hcv genotype 1b

HCV is an important cause of hepatocellular carcinoma (HCC). HCV NS5A domain‐1 interacts with cellular proteins inducing pro‐oncogenic pathways. Thus, we explore genetic variations in NS5A domain‐1 and their association with HCC, by analyzing 188 NS5A sequences from HCV genotype‐1b infected DAA‐naïve cirrhotic patients: 34 with HCC and 154 without HCC. Specific NS5A mutations significantly correlate with HCC: S3T (8.8% vs. 1.3%, p = 0.01), T122M (8.8% vs. 0.0%, p < 0.001), M133I (20.6% vs. 3.9%, p < 0.001), and Q181E (11.8% vs. 0.6%, p < 0.001). By multivariable analysis, the presence of >1 of them independently correlates with HCC (OR (95%CI): 21.8 (5.7–82.3); p < 0.001). Focusing on HCC‐group, the presence of these mutations correlates with higher viremia (median (IQR): 5.7 (5.4–6.2) log IU/mL vs. 5.3 (4.4–5.6) log IU/mL, p = 0.02) and lower ALT (35 (30–71) vs. 83 (48–108) U/L, p = 0.004), suggesting a role in enhancing viral fitness without affecting necroinflammation. Notably, these mutations reside in NS5A regions known to interact with cellular proteins crucial for cell‐cycle regulation (p53, p85‐PIK3, and β‐ catenin), and introduce additional phosphorylation sites, a phenomenon known to ameliorate NS5A interaction with cellular proteins. Overall, these results provide a focus for further investigations on molecular bases of HCV‐mediated oncogenesis. The role of these NS5A domain‐1 mutations in triggering pro‐oncogenic stimuli that can persist also despite achievement of sustained virological response deserves further investigation

Ruolo della diade TACE/Timp3 nell'insulino-resistenza e nella steatosi epatica

Nel nostro laboratorio è stato recentemente dimostrato che l’enzima TACE (TNFa-converting enzyme) e il suo inibitore fisiologico Timp-3 sono coinvolti nella patogenesi dell’insulino-resistenza e conseguentemente nell’omeostasi metabolica. Nel presente lavoro sono stati effettuati studi metabolici su topi sottoposti ad un regime alimentare ricco in grassi ed è stato osservato un aumento dell’attività di TACE nel fegato di tali animali e, in misura minore, anche nel muscolo e nel tessuto adiposo, rispetto a topi di controllo nutriti con una dieta normale. E’ stato anche dimostrato che l’attività di TACE può essere indotta in diversi sistemi cellulari da numerosi stimoli metabolici, come l’acido palmitico, il lipopolisaccaride, alte concentrazioni di glucosio o di insulina, e questa attivazione è in grado di interferire con la via di trasduzione del segnale insulinico, determinando una diminuzione nella fosforilazione di Akt, GSK3 e FoxO1. Per studiare in vivo il ruolo dell’attività di TACE sono stati utilizzati dei topi knockout per Timp-3 (Timp-3-/-) che, mancando dell’inibitore dell’enzima, hanno di base un’aumentata attività di TACE. I topi Timp-3-/- sottoposti a dieta grassa sono caratterizzati da una ridotta tolleranza al glucosio e da steatosi epatica. Allo scopo di individuare i meccanismi molecolari responsabili del fenotipo osservato, è stato analizzato mediante spettrometria di massa il proteoma epatico di topi wild type (WT) e Timp-3-/- sottoposti a dieta grassa per 20 settimane e i dati ottenuti sono stati interpretati e integrati mediante programmi di bioinformatica. Sono state così identificate alcune proteine che presentano livelli di espressione diversi nei due genotipi; tra queste l’adenosina-chinasi (ADK), la metionina adenosil-trasferasi I/III (MATI/III) e la glicina N-metiltrasferasi (GNMT) risultano meno espresse, mentre l’espressione di FABP-1 (fatty acid binding protein 1) risulta aumentata nei topi Timp3-/- rispetto ai topi WT. Le stesse variazioni nei livelli di espressione di tali molecole sono state riscontrate anche in epatociti in vitro in cui l’espressione di TACE è stata aumentata mediante infezione retrovirale. Tutte queste proteine svolgono un ruolo importante nel metabolismo degli acidi grassi e della metionina. Queste alterazioni hanno contribuito a chiarire il meccanismo molecolare che è alla base dell’aumentata insulino-resistenza e della steatosi epatica che caratterizza i topi Timp-3-/-, fornendo così un’evidenza del ruolo importante che la diade TACE-Timp-3 assume nella risposta dell’organismo ad una dieta ricca di grassi.  Tumor necrosis factor a–converting enzyme (TACE) and its physiological inhibitor Timp-3 were recently involved in the pathogenesis of insulin resistance. We observed that TACE activity was significantly higher in mice fed a high fat diet, particularly in livers but also in muscle and adipose tissue, compared to littermates fed a regular diet. In mouse hepatocytes, myocytes and adipocytes TACE activity was triggered by several metabolic stimuli, such as palmitic acid, lipopolysaccharide, high glucose and high insulin. TACE overexpression significantly impaired insulin-dependent phosphorylation of Akt, GSK3 and FoxO1, the major controllers of gluconeogenesis and lipogenesis. To test the role of TACE activation in vivo, we used Timp3 null mice which have higher TACE activity compared with wild type (WT) mice. Timp3-/- mice fed a high fat diet for 20 weeks were glucose-intolerant and insulin-resistant; they showed macrovescicular steatosis and ballooning degeneration compared to WT mice, which presented only microvescicular steatosis. Shotgun proteomic analysis revealed that Timp3-/- liver has a significant differential expression of 38 proteins, including lower levels of adenosine kinase (ADK), methionine adenosyltransferase I/III (MATI/III) and glycine N-methyltransferase (GNMT), and higher levels of liver fatty acid-binding protein 1 (FABP-1). These changes in protein levels were also observed in hepatocytes infected with an adenovirus encoding TACE. All these proteins play a role in fatty acid uptake, trygliceride synthesis and methionine metabolism, providing a molecular explanation for the increased hepatosteatosis observed in Timp3-/- compared to WT mice. So we have identified novel mechanisms governed by the TACE/ Timp3 dyad involved in the determination of insulin resistance and liver steatosis during overfeeding in mice.

Italian Geological mapping of submerged areas and its contribution to EMODnet – European Marine Observation and Data Network

Il Progetto di Cartografia Geologica Italiana (CARG) include la rappresentazione delle aree sommerse, per le quali sono state elaborate dal Servizio Geologico d'Italia – ISPRA linee guida dedicate che seguono, per quanto possibile, gli stessi criteri adottati per le aree emerse. La rappresentazione cartografica delle aree sommerse si concentra sulla stratigrafia (sequenza deposizionale post-glaciale), sull'interpretazione dei processi sedimentari in un quadro ambientale e evolutivo, sulla morfologia e sulla sedimentologia dei fondali marini. Tutte le informazioni raccolte nel corso dei rilevamenti sono archiviate in una banca dati nazionale in continuo aggiornamento, realizzata alla scala 1:25.000. I dati resi disponibili dalla Cartografia Geologica Italiana stanno contribuendo costruttivamente alla realizzazione di una cartografia geologica digitale armonizzata a livello europeo, nella quale vengono convogliate tutte le conoscenze geologiche dei diversi paesi. Tale cartografia è uno degli obiettivi del Progetto EMODnet – European Marine Observation and Data Network, finalizzato alla costruzione di una infrastruttura contenente tutte le informazioni relative alle aree sommerse e accessibile liberamente.The Italian Geological Mapping Project (CARG) includes the representation of submerged areas. For this purpose the Geological Survey of Italy - ISPRA has elaborated specific guidelines harmonized, as much as possible, with those applied on land. The cartographic representation of outcropping units focuses on stratigraphy (post-glacial depositional sequence), on the interpretation of sedimentary processes within an environmental and evolutionary framework, on the morphology and sedimentology of the seafloor. All information collected during surveys is stored in a constantly updated national database, realized at the 1: 25,000 scale. Data available from the Italian Geological Mapping Project are constructively contributing to the production of digital geological maps harmonized at European level, in which all of the geological knowledge of several countries is conveyed. These maps are one of the goals of the EMODnet - European Marine Observation and Data Network Project, aimed at building a freely accessible infrastructure containing all information related to submerged areas