Gabor Viczjan

The risk behaviors underlying the most prevalent chronic noncommunicable diseases (NCDs) encompass alcohol misuse, unhealthy diets, smoking and sedentary lifestyle behaviors. These are all linked to the altered function of the mesocorticolimbic (MCL) system. As the mesocorticolimbic circuit is central to the reward pathway and is involved in risk behaviors and mental disorders, we set out to test the hypothesis that these pathologies may be approached therapeutically as a group. To address these questions, the identification of novel targets by exploiting knowledge-based, network-based and disease similarity algorithms in two major Thomson Reuters databases (MetaBase™, a database of manually annotated protein interactions and biological pathways, and Integrity^SM, a unique knowledge solution integrating biological, chemical and pharmacological data) was performed. Each approach scored proteins from a particular approach-specific standpoint, followed by integration of the scores by machine learning techniques yielding an integrated score for final target prioritization. Machine learning identified characteristic patterns of the already known targets (control targets) with high accuracy (area under curve of the receiver operator curve was ~93%). The analysis resulted in a prioritized list of 250 targets for MCL disorders, many of which are well established targets for the mesocorticolimbic circuit e.g., dopamine receptors, monoamino oxidases and serotonin receptors, whereas emerging targets included DPP4, PPARG, NOS1, ACE, ARB1, CREB1, POMC and diverse voltage-gated Ca²⁺ channels. Our findings support the hypothesis that disorders involving the mesocorticolimbic circuit may share key molecular pathology aspects and may be causally linked to NCDs, yielding novel targets for drug repurposing and personalized medicine.

Cannabidiol (CBD), the most extensively studied non-intoxicating phytocannabinoid, has been attracting a lot of interest worldwide owing to its numerous beneficial effects. The aim of this review is to describe the various effects of CBD, since it seems to have several molecular targets, acting at which CBD can modify several pathological conditions. CBD has anti-inflammatory, anti-cancer, neuroprotective, anticonvulsant, anxiolytic, antipsychotic, antidepressant, antidiabetic and anti-obesity effects, furthermore it can affect the functions of the adenosinergic system as well. Regarding myocardial adenosinergic system, CBD is thought to influence two important targets: the A1 adenosine receptor and the equilibrative and nitrobenzylthioinosine-sensitive nucleoside transporter (ENT1 or SLC29A1). ENT1 is a main equilibrative adenosine transporter capable of regulating the interstitial level of adenosine, while the A1 adenosine receptor is a chief protective receptor of the myocardium. A kannabidiol (CBD) a legjobban tanulmányozott, nem bódító hatású fitokannabinoid, ami számos kedvező hatása miatt világszerte nagy érdeklődés tárgyát képezi. Összefoglalónk célja a CBD sokrétű hatásainak jellemzése, mivel az emberi szervezetben számos molekuláris célpontját tárták már fel, melyeken hatva igen sokféle kórállapotot képes módosítani. A CBD gyulladáscsökkentő, daganatellenes, neuroprotektív, görcsoldó, anxiolitikus, antipszichotikus, antidepresszív, antidiabetikus, elhízás elleni, valamint az adenozinerg rendszert érintő hatásokkal is rendelkezik. A szív adenozinerg rendszere szempontjából a CBD esetében két fontos molekuláris célpontról lehet adatokat találni: az ENT1 típusú nukleozid transzporter (ENT1 vagy SLC29A1), melyet több vizsgálat is igazolt, és az A1 adenozin receptor, amelyet szintén gyanúba hoztak. Az ENT1 a szív egyik fő adenozin transzportere, melyen keresztül befolyásolni lehet a szív interszticiális adenozin szintjét, míg az A1 adenozin receptor a szívizom védelmében szerepet játszó egyik legfontosabb adenozin receptortípus.

In previous studies using isolated, paced guinea pig left atria, we observed that FSCPX, known as a selective A₁ adenosine receptor antagonist, paradoxically increased the direct negative inotropic response to A₁ adenosine receptor agonists (determined using concentration/effect (E/c) curves) if NBTI, a nucleoside transport inhibitor, was present. Based on mathematical modeling, we hypothesized that FSCPX blunted the cardiac interstitial adenosine accumulation in response to nucleoside transport blockade, probably by inhibiting CD39 and/or CD73, which are the two main enzymes of the interstitial adenosine production in the heart. The goal of the present study was to test this hypothesis. In vitro CD39 and CD73 inhibitor assays were carried out; furthermore, E/c curves were constructed in isolated, paced rat and guinea pig left atria using adenosine, CHA and CPA (two A₁ adenosine receptor agonists), FSCPX, NBTI and NBMPR (two nucleoside transport inhibitors), and PSB-12379 (a CD73 inhibitor), measuring the contractile force. We found that FSCPX did not show any inhibitory effect during the in vitro enzyme assays. However, we successfully reproduced the paradox effect of FSCPX in the rat model, mimicked the “paradox” effect of FSCPX with PSB-12379, and demonstrated the lipophilia of FSCPX, which could explain the negative outcome of inhibitor assays with CD39 and CD73 dissolved in a water-based solution. Taken together, these three pieces of indirect evidence are strong enough to indicate that FSCPX possesses an additional action besides the A₁ adenosine receptor antagonism, which action may be the inhibition of an ectonucleotidase. Incidentally, we found that POM-1 inhibited CD73, in addition to CD39.