A far-ultraviolet-driven photoevaporation flow observed in a protoplanetary disk.

Most low-mass stars form in stellar clusters that also contain massive stars, which are sources of far-ultraviolet (FUV) radiation. Theoretical models predict that this FUV radiation produces photodissociation regions (PDRs) on the surfaces of protoplanetary disks around low-mass stars, which affects planet formation within the disks. We report James Webb Space Telescope and Atacama Large Millimeter Array observations of a FUV-irradiated protoplanetary disk in the Orion Nebula. Emission lines are detected from the PDR; modeling their kinematics and excitation allowed us to constrain the physical conditions within the gas. We quantified the mass-loss rate induced by the FUV irradiation and found that it is sufficient to remove gas from the disk in less than a million years. This is rapid enough to affect giant planet formation in the disk.

Retrospective Quality by Design (rQbD) applied to the optimization of orodispersible films.

The study demonstrates the application of QbD based on historical data for a product at a later development stage - retrospective QbD (rQbD). More specifically, it is investigated the root-cause for the observed slower drug release in Orodispersible Films (ODFs) during storage. Risk assessment tools were used to identify parameters affecting ODFs critical quality attributes, namely percent drug release and residual water content. The parameters room temperature, room relative humidity, drying temperature and mixing equipment were used in the statistical modeling of the available data. The estimated models were then used to define the feasible working region. Statistical modeling indicates that initial residual water content of the ODFs is mainly affected by 2nd order interactions of room temperature, room relative humidity and drying temperature, while the stability of drug release profile is mostly influenced by room temperature and an interaction between room relative humidity and drying temperature. Depending on the drying temperature employed the effect of room temperature and room relative humidity change significantly. This work shows that it is possible to apply rQbD to achieve a greater understanding of the manufacturing process of ODFs and to define a proper design space.

Insulin-mimetic compound hexaquis (benzylammonium) decavanadate is antilipolytic in human fat cells.

AIM: To assess in rodent and human adipocytes the antilipolytic capacity of hexaquis(benzylammonium) decavanadate (B6V10), previously shown to exert antidiabetic effects in rodent models, such as lowering free fatty acids (FFA) and glucose circulating levels. METHODS: Adipose tissue (AT) samples were obtained after informed consent from overweight women undergoing plastic surgery. Comparison of the effects of B6V10 and reference antilipolytic agents (insulin, benzylamine, vanadate) on the lipolytic activity was performed on adipocytes freshly isolated from rat, mouse and human AT. Glycerol release was measured using colorimetric assay as an index of lipolytic activity. The influence of B6V10 and reference agents on glucose transport into human fat cells was determined using the radiolabelled 2-deoxyglucose uptake assay. RESULTS: In all the species studied, B6V10 exhibited a dose-dependent inhibition of adipocyte lipolysis when triglyceride breakdown was moderately enhanced by ß-adrenergic receptor stimulation. B6V10 exerted on human adipocyte a maximal lipolysis inhibition of glycerol release that was stronger than that elicited by insulin. However, B6V10 did not inhibit basal and maximally stimulated lipolysis. When incubated at dose ≥ 10 µmol/L, B6V10 stimulated by twofold the glucose uptake in human fat cells, but - similarly to benzylamine - without reaching the maximal effect of insulin, while it reproduced one-half of the insulin-stimulation of lipogenesis in mouse fat cells. CONCLUSION: B6V10 exerts insulin-like actions in adipocytes, including lipolysis inhibition and glucose transport activation. B6V10 may be useful in limiting lipotoxicity related to obesity and insulin resistance.

Accelerated telomere attrition in children and teenagers with α1-antitrypsin deficiency.

Numerous studies have shown that oxidative stress accelerates telomere shortening in several lung pathologies. Since oxidative stress is involved in the pathophysiology of α1-antitrypsin deficiency (AATD), we hypothesised that telomere shortening would be accelerated in AATD patients. This study aimed to assess telomere length in AATD patients and to study its association with α1-antitrypsin phenotypes.Telomere length, telomerase activity, telomerase reverse transcriptase (hTERT) expression and biomarkers of oxidative stress were measured in 62 children and teenagers (aged 2-18 years) diagnosed with AATD and 18 controls (aged 3-16 years).Our results show that intermediate-risk (MZ; SZ) and high-risk (ZZ) AATD patients have significantly shorter telomeres and increased oxidative stress than controls. Correlation studies indicate that telomere length was related to oxidative stress markers in AATD patients. Multiple hypothesis testing revealed an association between telomere length, telomerase activity, hTERT expression and AATD phenotypes; high-risk patients showed shorter telomeres, lower hTERT expression and decreased telomerase activity than intermediate-risk and low-risk patients.AATD patients show evidence of increased oxidative stress leading to telomere attrition. An association between telomere and α1-antitrypsin phenotypes is observed suggesting that telomere length could be a promising biomarker for AATD disease progression.

Arylalkylamine vanadium salts as new anti-diabetic compounds.

Vanadium compounds show insulin-like effects in vivo and in vitro. Several clinical studies have shown the efficacy of vanadium compounds in type 2 diabetic subjects. However, a major concern is safety, which calls for the development of more potent vanadium compounds. For that reason different laboratories develop strategies to decrease the therapeutic dose of vanadate. One of these strategies use substrates of semicarbazide-sensitive amine oxidase (SSAO)/vascular adhesion protein-1 (VAP-1), a bifunctional protein with amine oxidase activity and adhesive properties implicated in lymphocyte homing at inflammation sites. Substrates of SSAO combined with low concentrations of vanadate strongly stimulate glucose transport and GLUT4 glucose transporter recruitment to the plasma membrane in 3T3-L1 adipocytes and in rat adipocytes. This combination also shows anti-diabetic effects in various animal models of type 1 and type 2 diabetes. Benzylamine/vanadate administration generates peroxovanadium locally in pancreatic islets, which stimulates insulin secretion, and also produces peroxovanadium in adipose tissue, thereby activating glucose metabolism in adipocytes and in neighboring muscle. This opens up the possibility of using the SSAO/VAP-1 activity as a local generator of protein tyrosine phosphatase inhibitors in anti-diabetic therapy. More recently a novel class of arylalkylaminevanadium salts have shown potent insulin-mimetic effects downstream of the insulin receptor. Administration of these compounds lowers glycemia and normalizes the plasma lipid profile in type 1 and type 2 models of diabetes. The combination of different approaches to decrease vanadium doses, among them chelating agents and SSAO substrates, should permit to develop safe and efficient vanadium based agents safe for diabetes treatment.

Understanding the mechanism of action of the novel SSAO substrate (C7NH10)6(V10O28).2H2O, a prodrug of peroxovanadate insulin mimetics.

A new vanadium salt, hexakis(benzylammonium) decavanadate (V) dihydrate (C(7)NH(10))(6)(V(10)O(28)).2H(2)O (1), has been synthesized as well as characterized chemically and biologically. An in vitro enzyme assay revealed that compound 1 is oxidized to the same extent as a combination of benzylamine and vanadate by the enzyme semicarbazide-sensitive amine oxidase (SSAO), and therefore can be considered an SSAO substrate. It also stimulates glucose uptake in isolated rat adipocytes in a dose-dependent manner. We describe here the results of (51)V-NMR experiments that, combined with the in vitro results, corroborate that compound 1 could act as a prodrug of di-peroxovanadate ([V(OH)(2)(OO)(2)(OH)(2)](2-)) insulin mimetics.

Oral insulin-mimetic compounds that act independently of insulin.

The hallmarks of insulin action are the stimulation and suppression of anabolic and catabolic responses, respectively. These responses are orchestrated by the insulin pathway and are initiated by the binding of insulin to the insulin receptor, which leads to activation of the receptor's intrinsic tyrosine kinase. Severe defects in the insulin pathway, such as in types A and B and advanced type 1 and 2 diabetes lead to severe insulin resistance, resulting in a partial or complete absence of response to exogenous insulin and other known classes of antidiabetes therapies. We have characterized a novel class of arylalkylamine vanadium salts that exert potent insulin-mimetic effects downstream of the insulin receptor in adipocytes. These compounds trigger insulin signaling, which is characterized by rapid activation of insulin receptor substrate-1, Akt, and glycogen synthase kinase-3 independent of insulin receptor phosphorylation. Administration of these compounds to animal models of diabetes lowered glycemia and normalized the plasma lipid profile. Arylalkylamine vanadium compounds also showed antidiabetic effects in severely diabetic rats with undetectable circulating insulin. These results demonstrate the feasibility of insulin-like regulation in the complete absence of insulin and downstream of the insulin receptor. This represents a novel therapeutic approach for diabetic patients with severe insulin resistance.

New efficient substrates for semicarbazide-sensitive amine oxidase/VAP-1 enzyme: analysis by SARs and computational docking.

Structure activity relationships for semicarbazide-sensitive amine oxidase/vascular adhesion protein-1 (SSAO/VAP-1) were studied using a library of arylalkylamine substrates, with the aim of contributing to the discovery of more efficient SSAO substrates. Experimental data were contrasted with computational docking studies, thereby allowing us to examine the mechanism and substrate-binding affinity of SSAO and thus contribute to the discovery of more efficient SSAO substrates and provide a structural basis for their interactions. We also built a model of the mouse SSAO structure, which provides several structural rationales for interspecies differences in SSAO substrate selectivity and reveals new trends in SSAO substrate recognition. In this context, we identified novel efficient substrates for human SSAO that can be used as a lead for the discovery of antidiabetic agents.

Exploring the binding mode of semicarbazide-sensitive amine oxidase/VAP-1: identification of novel substrates with insulin-like activity.

We previously reported that substrates of semicarbazide-sensitive amine oxidase in combination with low concentrations of vanadate exert potent insulin-like effects. Here we performed homology modeling of the catalytic domain of mouse SSAO/VAP-1 and searched through chemical databases to identify novel SSAO substrates. The modeling of the catalytic domain revealed that aromatic residues Tyr384, Phe389, and Tyr394 define a pocket of stable size that may participate in the binding of apolar substrates. We identified a number of amines as substrates of human, rat, and mouse SSAO. The compounds PD0119035, 2,3-dimethoxy-benzylamine, and C-naphthalen-1-yl-methylamine showed high affinity as substrates of rat SSAO. C-Naphthalen-1-yl-methylamine was the only substrate that showed high affinity for human SSAO. C-Naphthalen-1-yl-methylamine and 4-aminomethyl-benzenesulfonamide showed the highest capacity to stimulate glucose transport in isolated rat adipocytes. The impact of these findings on the development of new treatments for diabetes is discussed.