In Search for Multi-Target Ligands as Potential Agents for Diabetes Mellitus and Its Complications - A Structure-Activity Relationship Study on Inhibitors of Aldose Reductase and Protein Tyrosine Phosphatase 1B

Diabetes mellitus (DM) is a complex disease which currently affects more than 460 million people and is one of the leading cause of death worldwide. Its development implies numerous metabolic dysfunctions and the onset of hyperglycaemia-induced chronic complications. Multiple ligands can be rationally designed for the treatment of multifactorial diseases, such as DM, with the precise aim of simultaneously controlling multiple pathogenic mechanisms related to the disease and providing a more effective and safer therapeutic treatment compared to combinations of selective drugs. Starting from our previous findings that highlighted the possibility to target both aldose reductase (AR) and protein tyrosine phosphatase 1B (PTP1B), two enzymes strictly implicated in the development of DM and its complications, we synthesised 3-(5-arylidene-4-oxothiazolidin-3-yl)propanoic acids and analogous 2-butenoic acid derivatives, with the aim of balancing the effectiveness of dual AR/PTP1B inhibitors which we had identified as designed multiple ligands (DMLs). Out of the tested compounds, 4f exhibited well-balanced AR/PTP1B inhibitory effects at low micromolar concentrations, along with interesting insulin-sensitizing activity in murine C2C12 cell cultures. The SARs here highlighted along with their rationalization by in silico docking experiments into both target enzymes provide further insights into this class of inhibitors for their development as potential DML antidiabetic candidates

Identification and Characterization of ADNT1, a Novel Mitochondrial Adenine Nucleotide Transporter from Arabidopsis1[OA]

Despite the fundamental importance and high level of compartmentation of mitochondrial nucleotide metabolism in plants, our knowledge concerning the transport of nucleotides across intracellular membranes remains far from complete. Study of a previously uncharacterized Arabidopsis (Arabidopsis thaliana) gene (At4g01100) revealed it to be a novel adenine nucleotide transporter, designated ADNT1, belonging to the mitochondrial carrier family. The ADNT1 gene shows broad expression at the organ level. Green fluorescent protein-based cell biological analysis demonstrated targeting of ADNT1 to mitochondria. While analysis of the expression of β-glucuronidase fusion proteins suggested that it was expressed across a broad range of tissue types, it was most highly expressed in root tips. Direct transport assays with recombinant and reconstituted ADNT1 were utilized to demonstrate that this protein displays a relatively narrow substrate specificity largely confined to adenylates and their closest analogs. ATP uptake was markedly inhibited by the presence of other adenylates and general inhibitors of mitochondrial transport but not by bongkrekate or carboxyatractyloside, inhibitors of the previously characterized ADP/ATP carrier. Furthermore, the kinetics are substantially different from those of this carrier, with ADNT1 preferring AMP to ADP. Finally, isolation and characterization of a T-DNA insertional knockout mutant of ADNT1, alongside complementation and antisense approaches, demonstrated that although deficiency of this transporter did not seem to greatly alter photosynthetic metabolism, it did result in reduced root growth and respiration. These findings are discussed in the context of a potential function for ADNT1 in the provision of the energy required to support growth in heterotrophic plant tissues

In Search for Multi-Target Ligands as Potential Agents for Diabetes Mellitus and Its Complications—A Structure-Activity Relationship Study on Inhibitors of Aldose Reductase and Protein Tyrosine Phosphatase 1B

Diabetes mellitus (DM) is a complex disease which currently affects more than 460 million people and is one of the leading cause of death worldwide. Its development implies numerous metabolic dysfunctions and the onset of hyperglycaemia-induced chronic complications. Multiple ligands can be rationally designed for the treatment of multifactorial diseases, such as DM, with the precise aim of simultaneously controlling multiple pathogenic mechanisms related to the disease and providing a more effective and safer therapeutic treatment compared to combinations of selective drugs. Starting from our previous findings that highlighted the possibility to target both aldose reductase (AR) and protein tyrosine phosphatase 1B (PTP1B), two enzymes strictly implicated in the development of DM and its complications, we synthesised 3-(5-arylidene-4-oxothiazolidin-3-yl)propanoic acids and analogous 2-butenoic acid derivatives, with the aim of balancing the effectiveness of dual AR/PTP1B inhibitors which we had identified as designed multiple ligands (DMLs). Out of the tested compounds, 4f exhibited well-balanced AR/PTP1B inhibitory effects at low micromolar concentrations, along with interesting insulin-sensitizing activity in murine C2C12 cell cultures. The SARs here highlighted along with their rationalization by in silico docking experiments into both target enzymes provide further insights into this class of inhibitors for their development as potential DML antidiabetic candidates

Il pubblico di Palazzo Davanzati nei libri dei visitatori. 1910-1924

A pochi mesi dall\u2019apertura di Palazzo Davanzati, Elia Volpi ebbe l\u2019idea di mettere a disposizione dei visitatori del suo museo privato un libro, dalle pagine bianche, sul quale ognuno avrebbe potuto lasciare la propria firma e un commento, seguendo forse l\u2019esempio di altri musei privati come quello di Frederick Stibbert o il milanese Bagatti Valsecchi. I due libri con le firme dei visitatori dal 1910 al 1924 furono poi donati, per volont\ue0 della moglie Marina Volpi, da Mario Vannini Parenti, genero dell\u2019antiquario e sono oggi conservati nel museo. Lo spoglio sistematico dei dati contenuti in questi straordinari documenti ha fatto emergere aspetti molto significativi riguardanti il numero e la provenienza dei visitatori di Palazzo Davanzati, cos\uec come i riflessi della societ\ue0 del tempo e del contesto storico, rappresentando un interessante caso di studio sul pubblico dei musei in un\u2019epoca precedente all\u2019affermazione del turismo di massa. \uc8 il museo visto dalla parte dei suoi visitatori, studenti, educande, persone comuni o aristocratici d\u2019alto lignaggio, turisti stranieri e non con la passione per Firenze e la sua storia, molti dei quali lasciano un commento, una battuta, anche una poesia, o semplicemente la traccia della loro visita. Davvero numerosi, poi, sono i nomi dei personaggi celebri: storici dell\u2019arte (Adolfo e Lionello Venturi, Roberto Longhi), artisti, letterati e intellettuali (Giovanni Boldini, Sibilla Aleramo, Benedetto Croce), mercanti e collezionisti (Salvatore Romano, Georges Wildenstein, Peggy Guggenheim) o personaggi dello spettacolo (Ettore Petrolini, Rodolfo Valentino). La loro presenza, cos\uec come quella di moltissimi architetti e decoratori stranieri e dei tanti visitatori meno noti, restituiscono un feedback importante a tutte quelle iniziative di promozione del museo che Elia Volpi aveva intrapreso sin dal giorno della sua inaugurazione, attraverso campagne fotografiche, pubblicazioni, cartoline illustrate ed eventi a tema

Discovery of Entrectinib: A New 3‑Aminoindazole As a Potent Anaplastic Lymphoma Kinase (ALK), c‑ros Oncogene 1 Kinase (ROS1), and Pan-Tropomyosin Receptor Kinases (Pan-TRKs) inhibitor

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase responsible for the development of different tumor types. Despite the remarkable clinical activity of crizotinib (Xalkori), the first ALK inhibitor approved in 2011, the emergence of resistance mutations and of brain metastases frequently causes relapse in patients. Within our ALK drug discovery program, we identified compound <b>1</b>, a novel 3-aminoindazole active on ALK in biochemical and in cellular assays. Its optimization led to compound <b>2</b> (entrectinib), a potent orally available ALK inhibitor active on ALK-dependent cell lines, efficiently penetrant the blood–brain barrier (BBB) in different animal species and highly efficacious in in vivo xenograft models. Moreover, entrectinib resulted to be strictly potent on the closely related tyrosine kinases ROS1 and TRKs recently found constitutively activated in several tumor types. Entrectinib is currently undergoing phase I/II clinical trial for the treatment of patients affected by ALK-, ROS1-, and TRK-positive tumors

Italian pediatric nutrition survey

Introduction the prevalence of malnutrition in children and its impact on clinical outcomes is underrecognized by clinicians in Italy as well as worldwide. A novel definition of pediatric malnutrition has been recently proposed by a working group of the Academy of Nutrition and Dietetics and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.), based on the correlation between illness and the use of zscores of anthropometric measurements. Aim to investigate the prevalence of malnutrition and related nutritional support among hospitalized children in Italy, in a nationwide survey performed in a single day (16/4/2015). Methods an open access website (http://nday.biomedia.net) was used to collected data from 73 hospitals and 101 wards in 14 Italian regions (1994 patients). Anonymous information was collected on hospitals' characteristics, patient's anthropometry, admission diagnosis, presence of chronic diseases and use of nutritional support: oral nutritional supplements (ONS), enteral nutrition (EN) or parenteral nutrition (PN). Z-scores of anthropometric measurements, calculated with Epi Info 7.1.5, defined nutritional status: wasting was identified by BMI or Weight-for-Length z-score (<−1 mild, <−2 moderate, <−3 severe), stunting by Height-for-Age Z-score <−2. WHO 2006 and CDC 2000 growth charts were used respectively for children younger and older than 2 years old. Results 1790 complete records were obtained for hospitalized patients aged 0–20 years, with median age 6.16 (0.1–20 years and 53.3% males). 52.9% were aged 0–6 years and 58.8% of children suffered from chronic diseases. Wasting was detected in 28.7% of the total sample with higher occurrence observed in age ranges 0–6 and 14–20 years, while 17.3% of patients showed stunting; surprisingly almost 27% of them were aged 0–2. A ranking of the admission diagnosis with the highest rate of malnutrition was complied. The prevalence of wasting was significantly (p < 0.005) higher amongst children with chronic diseases (34.1% vs. 27.1%); stunting prevalence tripled in patients with chronic disease (24.5% vs. 8.3%). Only 23.5% of malnourished children (17%, 25.6% and 36.7%, respectively mild, moderate and severe malnutrition) received nutritional support: 11.7% received oral nutrition supplements (ONS, modular or complete), 11.5% enteral nutrition (EN, 6.4% via nasogastric tube, 5.1% via gastrostomy) and 6.8 % received parenteral nutrition (PN); in some patients a combination of two. Nutritional support is more commonly used among stunting patients, 39.5% of children under treatment. Conclusion Malnutrition of any grade was observed in nearly 1/3 and stunting in 17% of the reported hospitalized children, and it is likely to be underrecognized as the nutritional support reached only a small part of the malnourished children

Italian pediatric nutrition survey

Introduction the prevalence of malnutrition in children and its impact on clinical outcomes is underrecognized by clinicians in Italy as well as worldwide. A novel definition of pediatric malnutrition has been recently proposed by a working group of the Academy of Nutrition and Dietetics and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.), based on the correlation between illness and the use of zscores of anthropometric measurements. Aim to investigate the prevalence of malnutrition and related nutritional support among hospitalized children in Italy, in a nationwide survey performed in a single day (16/4/2015). Methods an open access website (http://nday.biomedia.net) was used to collected data from 73 hospitals and 101 wards in 14 Italian regions (1994 patients). Anonymous information was collected on hospitals' characteristics, patient's anthropometry, admission diagnosis, presence of chronic diseases and use of nutritional support: oral nutritional supplements (ONS), enteral nutrition (EN) or parenteral nutrition (PN). Z-scores of anthropometric measurements, calculated with Epi Info 7.1.5, defined nutritional status: wasting was identified by BMI or Weight-for-Length z-score (<â\u88\u921 mild, <â\u88\u922 moderate, <â\u88\u923 severe), stunting by Height-for-Age Z-score <â\u88\u922. WHO 2006 and CDC 2000 growth charts were used respectively for children younger and older than 2 years old. Results 1790 complete records were obtained for hospitalized patients aged 0â\u80\u9320 years, with median age 6.16 (0.1â\u80\u9320 years and 53.3% males). 52.9% were aged 0â\u80\u936 years and 58.8% of children suffered from chronic diseases. Wasting was detected in 28.7% of the total sample with higher occurrence observed in age ranges 0â\u80\u936 and 14â\u80\u9320 years, while 17.3% of patients showed stunting; surprisingly almost 27% of them were aged 0â\u80\u932. A ranking of the admission diagnosis with the highest rate of malnutrition was complied. The prevalence of wasting was significantly (p < 0.005) higher amongst children with chronic diseases (34.1% vs. 27.1%); stunting prevalence tripled in patients with chronic disease (24.5% vs. 8.3%). Only 23.5% of malnourished children (17%, 25.6% and 36.7%, respectively mild, moderate and severe malnutrition) received nutritional support: 11.7% received oral nutrition supplements (ONS, modular or complete), 11.5% enteral nutrition (EN, 6.4% via nasogastric tube, 5.1% via gastrostomy) and 6.8 % received parenteral nutrition (PN); in some patients a combination of two. Nutritional support is more commonly used among stunting patients, 39.5% of children under treatment. Conclusion Malnutrition of any grade was observed in nearly 1/3 and stunting in 17% of the reported hospitalized children, and it is likely to be underrecognized as the nutritional support reached only a small part of the malnourished children