Kidney Diseases in the Treatise "Dynameron" of Aelius Promotus (2nd Century AD). A Comparison with Dioscorides and Nikolaos Myrepsos

Dynameron is a medical treatise from the 2nd century AD, written in Greek by an Alexandrian physician named Aelius Promotus. A copy made in Sicily during the 16th century is kept in the Marciana Library of Venice (Codex gr. Ζ. 295). In 130 chapters, Dynameron contains 870 recipes for the treatment of various diseases. Regarding the kidneys, Aelius describes 32 recipes with herbal (59), animal (6) and mineral (1) ingredients, with diuretic, spasmolytic, analgesic, or antiseptic properties, suitable for treating nephrolithiasis, strangury, dysuria and renal inflammations. Several diuretics of Aelius Promotus are similar to those found in De Materia Medica of Dioscorides (1st century AD). On the other hand, all of them are also included in the treatise Dynameron of Nikolaos Myrepsos, written in the 13th century AD. When the recipes are evaluated as a whole, it is evident that Aelius Promotus was a competent practising physician in a city with a glorious tradition in medicine and sciences

D-2-dopaminergic receptor-linked pathways: critical regulators of CYP3A, CYP2C, and CYP2D

Various hormonal and monoaminergic systems play determinant roles in the regulation of several cytochromes P450 (P450s) in the liver. Growth hormone (GH), prolactin, and insulin are involved in P450 regulation, and their release is under dopaminergic control. This study focused on the role of D -dopaminergic systems in the regulation of the major drug-metabolizing P450s, i.e., CYP3A, CYP2C, and CYP2D. Blockade of D -dopaminergic receptors with either sulpiride (SULP) or 4-(4-chlorophenyl)-1-(1H-indol-3-ylmethyl)piperidin-4-ol (L-741,626) markedly down-regulated CYP3A1/2, CYP2C11, and CYP2D1 expression in rat liver. This suppressive effect appeared to be mediated by the insulin/phosphatidylinositol 3-kinase/Akt/FOXO1 signaling pathway. Furthermore, inactivation of the GH/STAT5b signaling pathway appeared to play a role in D-dopaminergic receptor-mediated down-regulating effects on these P450s. SULP suppressed plasma GH levels, with subsequently reduced activation of STAT5b, which is the major GH pulse-activated transcription factor and has up-regulating effects on various P450s in hepatic tissue. Levels of prolactin, which exerts down-regulating control on P450s, were increased by SULP, which may contribute to SULP-mediated effects. Finally, it appears that SULP-induced inactivation of the cAMP/protein kinase A/cAMP-response element-binding protein signaling pathway, which is a critical regulator of pregnane X receptor and hepatocyte nuclear factor 1α, and inactivation of the c-Jun N-terminal kinase contribute to SULP-induced down-regulation of the aforementioned P450s. Taken together, the present data provide evidence that drugs acting as D-dopaminergic receptor antagonists might interfere with several major signaling pathways involved in the regulation of CYP3A, CYP2C, and CYP2D, which are critical enzymes in drug metabolism, thus affecting the effectiveness of the majority of prescribed drugs and the toxicity and carcinogenic potency of a plethora of toxicants and carcinogens

D-2-receptor-linked signaling pathways regulate the expression of hepatic CYP2E1

This study investigated the role of catecholamine-related signaling pathways in the regulation of hepatic cytochrome P450 (CYP2E1). Central and peripheral catecholamine depletion with reserpine down-regulated CYP2E1. On the other hand, selective peripheral catecholamine depletion with guanethidine increased CYP2E1 apoprotein levels. Enrichment of peripheral catecholamines with adrenaline suppressed p-nitrophenol hydroxylase activity (PNP). PNP activity was also markedly suppressed by l-DOPA. Stimulation of D2-receptors with bromocriptine up-regulated CYP2E1, as assessed by enzyme activity and protein levels, whereas blockade of D2-dopaminergic receptors with sulpiride down-regulated this isozyme. These findings indicate that central and peripheral catecholamines have different effects on CYP2E1. Central catecholamines appear related to the up-regulation, whereas the role of peripheral catecholamines is clearly related to the type and location of adrenoceptors involved. D2-receptor-linked signaling pathways have an up-regulating effect on CYP2E1, while D1-receptor pathways may down-regulate this isozyme. It is worth noting that the widespread environmental pollutant benzo(α)pyrene (B(α)P) altered the modulating effect of catecholaminergic systems on CYP2E1 regulation. In particular, whereas stimulation or blockade of adrenoceptors had no effect on constitutive PNP activity, exposure to B(α)P modified the impact of central and peripheral catecholamines and α2-adrenoceptors on CYP2E1 expression. It appears that under the influence of B(α)P, α2-adrenergic receptor-linked signaling pathways increased CYP2E1 apoprotein levels. Given that a wide range of xenobiotics and clinically used drugs are activated by CYP2E1 to toxic metabolites, including the production of reactive oxygen species (ROS), it is possible that therapies challenging dopaminergic receptor- and/or alpha2-adrenoceptor-linked signaling pathways may alter the expression of CYP2E1, thus affecting the progress and development of several pathologies

Benzo(alpha)pyrene-induced up-regulation of CYP1A2 gene expression: Role of adrenoceptor-linked signaling pathways

CYP1A2, a principal catalyst for metabolism of various therapeutic drugs and carcinogens, among others, is in part regulated by the stress response. This study was designed to assess whether catecholamines and in particular adrenergic receptor-dependent pathways, modulate benzo(α)pyrene (B(α)P)-induced hepatic CYP1A2. To distinguish between the role of central and peripheral catecholamines in the regulation of CYP1A2 induction, the effect of central and peripheral catecholamine depletion using reserpine was compared to that of peripheral catecholamine depletion using guanethidine. The effects of peripheral adrenaline and L-DOPA administration were also assessed. The results suggest that alterations in central catecholamines modulate 7-methoxyresorufin O-demethylase activity (MROD), CYP1A2 mRNA and protein levels in the B(α)P-induced state. In particular, central catecholamine depletion, dexmedetomidine-induced inhibition of noradrenaline release and blockade of α1-adrenoceptors with prazosin, up-regulated CYP1A2 expression. Phenylephrine and dexmedetomidine-induced up-regulation may be mediated, in part, via peripheral α1- and α2-adrenoceptors, respectively. On the other hand, the L-DOPA-induced increase in central dopaminergic activity was not followed by any change in the up-regulation of CYP1A2 expression by B(α)P. Central noradrenergic systems appeared to counteract up-regulating factors, most likely via α1- and α2-adrenoceptors. In contrast, peripheral alpha- and beta-adrenoceptor-related signaling pathways are linked to up-regulating processes. The findings suggest that drugs that bind to adrenoceptors or affect central noradrenergic neurotransmission, as well as factors that challenge the adrenoceptor-linked signaling pathways may deregulate CYP1A2 induction. This, in turn, may result in drug-therapy and drug-toxicity complications

Box plots for mRNA levels of different metabolizing genes of meningiomas and astrocytomas.

<p>The line represents the median; boxes, 25% and 75% percentiles; whiskers, 1.5 times the box size. Outliers are indicated by open circle. The numbers of biologic replicates were: meningiomas, n = 20; astrocytomas, n = 15. For VEGFA the numbers of biologic replicates were: meningiomas, n = 14; astrocytomas, n = 11. The significant <i>p</i> values in each case were less than 0.05.</p