Dem-Aging: autophagy-related pathologies and the "two faces of dementia".

Neuronal ceroid lipofuscinosis (NCL) is an umbrella term referring to the most frequent childhood-onset neurodegenerative diseases, which are also the main cause of childhood dementia. Although the molecular mechanisms underlying the NCLs remain elusive, evidence is increasingly pointing to shared disease pathways and common clinical features across the disease forms. The characterization of pathological mechanisms, disease modifiers, and biomarkers might facilitate the development of treatment strategies.The DEM-AGING project aims to define molecular signatures in NCL and expedite biomarker discovery with a view to identifying novel targets for monitoring disease status and progression and accelerating clinical trial readiness in this field. In this study, we fused multiomic assessments in established NCL models with similar data on the more common late-onset neurodegenerative conditions in order to test the hypothesis of shared molecular fingerprints critical to the underlying pathological mechanisms. Our aim, ultimately, is to combine data analysis, cell models, and omic strategies in an effort to trace new routes to therapies that might readily be applied in the most common forms of dementia.

Mitochondrial potassium channels as pharmacological target for cardioprotective drugs.

Brief periods of ischemia are known to confer to the myocardium an increased resistance to the injury due to a later and more prolonged ischemic episode. This phenomenon, known as ischemic preconditioning (IPreC), is ensured by different biological mechanisms. Although an exhaustive comprehension of them has not been reached yet, it is widely accepted that mitochondria are pivotally involved in controlling cell life and death, and thus in IPreC. Among the several signaling pathways involved, as triggers and/or end effectors, in the mitochondrial mechanisms of cardioprotection, an important role is played by the activation of potassium channels located in the mitochondrial inner membrane (mitoK) of cardiomyocytes. Presently, different types of mitoK channels have been recognized in the heart, such as ATP-sensitive (mitoKATP) and calcium-activated (mitoBK(Ca) and mitoSK(Ca)) potassium channels. Consistently, drugs modulating mitoK, on one hand, have been employed as useful experimental tools for early basic studies on IPreC. On the other hand, activators of mitoK are promising and innovative therapeutic agents for limiting the myocardial injury due to ischemic episodes. In this review, we report the experimental evidence supporting the role of mitoK in signaling pathways in the mechanisms of cardioprotection and an overview on the most important molecules acting as modulators of these channels, with their profiles of selectivity. Some innovative pharmaceutical strategies for mitochondriotropic drugs have been also reported. Finally, an appendix describing the main experimental approaches usually employed to study mitoK in isolated mitochondria or in intact cells has been added.

New emerging prospects in the pharmacotherapy of hypertension.

One of the main approaches to the treatment of cardiovascular diseases is to block pathways and enzymes within the Renin-Angiotensin System (RAS) involved in the modulation of Angiotensin II. Besides this complex system, many other alternative strategies may represent interesting targets for new and more effective cardiovascular therapies. Many different approaches have led medicinal chemists to develop new molecules with the aim of improving current antihypertensive therapies. The development of these new compounds is based on different strategies which include the synthesis of new hybrid compounds in which two or more pharmacophore groups are combined together to give a new entity with better pharmacodynamic properties and fewer side effects, and the development of new molecules with targets such as renin, angiotensin (1-7) and urotensin-II. The aim of this review is to present various approaches used to improve antihypertensive therapy, developing both original molecules with new mechanisms of action (such as renin inhibitors, or Mas-agonists) and new hybrid cardiovascular drugs targeting multiple factors involved in hypertensive disease (NO-ACE inhibitors, NO-sartans, AT1/ETA antagonists).

Cardiac ATP-sensitive potassium channels: a potential target for an anti-ischaemic pharmacological strategy.

Brief periods of ischaemia induce in the myocardium an increased resistance to the injury due to a subsequent, more prolonged ischaemic episode. This phenomenon, known as ischaemic pre-conditioning (IPC), articulated in two distinct phases (an early and a delayed one), is ensured by different biological mechanisms. Although an exhaustive comprehension of these mechanisms has not yet been reached, it is widely accepted that among the various signals involved as triggers and/or end-effectors, an important role is undoubtedly played by the activation of cardiac ATP-sensitive potassium channels (K(ATP)). In the myocardial cells, K(ATP) channels have been identified both in the sarcolemmal membrane (sarc-K(ATP)) and in the mitochondrial inner membrane (mito-K(ATP)). Although many experimental findings suggest that a role of sarc-K(ATP) channel activation in IPC cannot be excluded, in the last few years, many authors have indicated that this phenomenon could be attributed to the exclusive (or at least prevalent) activation of the mito-K(ATP) channels. Conversely, drugs modulating the K(ATP) channels (as activators or blockers), on one hand, have been employed as useful experimental tools for basic studies on IPC. On the other hand, K(ATP)-openers have been viewed as promising possible therapeutic agents for limiting the myocardial injury due to ischaemic episodes. In particular, those molecules exhibiting a good degree of selectivity towards the mito-K(ATP) channels have been indicated as potential anti-ischaemic cardio-protective pharmacological tools, devoid of other biological effects (such as negative inotropic activity, hypotension or hyperglycaemia) linked to the activation of cardiac and non-cardiac sarcK(ATP) channels. In this paper, we wish to report the experimental evidence supporting the role of sarc- and mito-K(ATP) channels in IPC, the relative signalling pathways potentially involved in the mechanisms of cardio-protection and, finally, an overview of the most important molecules acting as activators or blockers of K(ATP) channels, with their selectivity profiles.

NO-releasing hybrids of cardiovascular drugs.

Nitric oxide (NO) is an endogenous compound, which plays a fundamental role in the modulation of the function of the cardiovascular system, where it induces vasorelaxing and antiplatelet responses, mainly through the stimulation of guanylate cyclase and the increase of cGMP. Many drugs of common, time-honoured clinical use (for example, glycerol trinitrate and all the vasodilator nitrites and nitrates) act via the release of exogenous NO, thus mimicking the effects of the endogenous factor. In the last few years, a revision of the "one-compound-one-target" paradigm has led pharmacologists and pharmaceutical chemists to develop new classes of molecules which combine different pharmacodynamic properties. This innovative pharmacological/pharmaceutical strategy has produced hybrid drugs, with a dual mechanism of action: a) the slow release of nitric oxide and b) another fundamental pharmacodynamic profile. These drugs have been obtained by inserting appropriate NO-donor chemical groups (i.e. nitrate esters, nitrosothiols, etc.), linked to a known drug, by means of a variable spacer moiety. These new pharmacodynamic hybrids present the advantage of combining a basic mechanism of action (for example, cyclooxygenase inhibition, beta-antagonism or ACE inhibition) with a slow release of NO, which may be useful either to reduce adverse side effects (for example, the gastrotoxicity of NSAIDs), or to improve the effectiveness of the drug (for example, conferring direct vasorelaxing and antiplatelet effects on an ACE-inhibitor). The aim of this review is to present the chemical features of NO-releasing hybrids of cardiovascular drugs, and to explain the pharmacological improvements obtained by the addition of the NO-donor properties.

Enantiopure 3-(arylmethylidene)aminoxy-2-methylpropionic acids: synthesis and antiinflammatory properties.

Some optically active 3-(arylmethylidene)aminoxy- (3a-g, 4a-g) and fluorenylideneaminoxy-2-methylpropionic acids (5, 6), were prepared as analogues of the antiinflammatory arylpropionic acids of type B, in which the aromatic group is substituted by an MAOM moiety. Some of the new compounds, tested in vivo for their antiinflammatory properties by means of the carrageenan-induced paw edema method in rats, exhibited activity indices similar to that shown in the same test by ibuprofen. Compounds 3a,b and 4a,b, for which at least one of the two enantiomers had shown an inhibition value higher than 40% in the in vivo test, were assayed for their in vitro enzymatic inhibitory activity, showing percentage inhibition values between 40 and 50% at a concentration of 10 microM against COX-2; at the same concentration, they appeared to be devoid of any activity towards COX-1. Compounds 3a,b and 4a,b also proved to possess a similar toxicity. The lack of enantioselectivity shown by compounds 3-6 was tentatively explained in terms of a conformational freedom of the enantiomers which allows their quasi-superimposition.

Synthesis and inhibitory activity towards human leukocyte elastase of new 7alpha-methoxy and 7alpha-chloro (2-acyloxymethyl) cephem derivatives.

Some new cephem derivatives of types 4 and 5, viewed as analogues of type I esters in which the atomic sequence of the C-2 ester group is formally inverted, were synthesised and tested in vitro for their inhibitory activity towards human leukocyte elastase and porcine pancreatic elastase. An examination of the inhibition data obtained for the new type 4 and 5 derivatives, while exhibiting a considerable reduction in their activity against porcine pancreatic elastase, indicated that these compounds still maintain an appreciable inhibitory activity against human leukocyte elastase. On this basis the new type of C-2 substitution appears to contribute to the research of new, potentially interesting, cephalosporinic human leukocyte elastase inhibitors.