The question of the reasons for the extreme variation in morbidity among the gene carriers of acute porphyria and the great diversity of the precipitating factors are approached by the aid of a model of interacting genomic circuits. It is based on the current paradigm of the acute porphyric attack as a result of a toxic proximal overload of the enzyme-
deficient heme-biosynthetic patway. Porphyrogenic influx of precursors is seen as a consequence of uncontrolled induction of its gate-keeping enzyme, ubiquitous 5-aminolevulinate synthase (ALAS1), due to attenuated post-translational control of the enzyme combined with activated gene transcription. Focus is directed on the genomic
control of the master-regulator of ALAS1-transcription, the nuclear receptor pair constitutively active receptor (CAR) and pregnane xenobiotic receptor (PXR). On activation by their ligands, i.e. lipophilic drugs, solvents, alcohols, hormonal steroids and biocides, these DNA-binding proteins transform xenobiotic or steroid stimuli to coordinated
activations of gene transcription-programs for ALAS1 and apo-cytochromes P450 (apo-CYPs), thus effecting the formation of xenobiotic-metabolizing cytochrome P450 enzymes. The potency of the CAR/PXR-transduction axis is enhanced by co-activators generated in
at least four other genomic circuits, each triggered by different external and internal stimuli clinically experienced to be porphyroge
nic, and each controlled by co-activating and co-repressing modulators. The expressions of the genes for CAR and PXR are thus augmented by binding glucocorticoid receptor (GR) activated by a steroid hormone, e.g, cortisol generated in fasting, infection or different forms of stress. The promotor regions of ALAS1 and apoCYPs contain binding sites for at least three co-activating transcription factors enhancing CAR/PXR transduction: i.e. the ligand-independent growth hormone (GH)-pulse controlled hepatocyte nuclear factor 4 (HNF4), the insulin-responsive forkhead box class O-(FOXO) protein pathway activated in stress and infection, and the proliferator-activated receptor gamma co-activator 1 al
pha (PGC-1alpha) circuit responding to glucagon liberated in fasting. Many interactions and cross-talk take place within the tangle of genomic circuits that control ALAS1-transcription, which may explain the extreme inter- and intra-individual variability in morbidity in acute porphyria. Reasons for gender-differences are found in sex-dependent control of HPA- and GH-activity as well as in direct, or GR-mediated effects on CAR/PCR activation. Constitutional differences in individual porphyric morbidity may be discussed along lines of mutations or duplications of genes for co-activating or co-repressing nuclear proteins active at different levels within the circuits.
In the course of cytogenetic studies on Alegoria castelnaui Fleutiaux & Sallé 1889 (Coleoptera: Tenebrionidae: Tenebrioninae: Ulomini) from Guadeloupe, a number of adult specimens were dissected. A larva was found in the abdomens of almost all of the females. The karyotype, 20,XX / 20,Xyp, and the presence of heterochromatin at multiple chromosomal locations, of the larvae and adults were similar, which excludes parasitism and indicates viviparous reproduction. The adverse habitat of the adults, i.e., putrid and fermenting pseudo-stems of banana trees rather than geo-climatic conditions, may explain the occurrence of viviparity in this species. This is the first example of (ovo-)viviparity in the Ulomini tribe and among New World Tenebrionidae. A. castelnaui is regularly collected on banana trees infested with the weevil Cosmopolites sordidus Germar, 1824, a major pest of banana trees around the word. The coexistence of these two species on banana trees may be coincidental but another Ulomini species, Eutochia pulla Erichson 1843, is described as an egg predator of C. sordidus in Africa and therefore, A. castelnaui could also be a predator of this pest.
(Pro)renin receptor (PRR) contributes to regulating many physiological and pathological processes; however, the role of PRR-mediated signaling pathways in myocardial ischemia/reperfusion injury (IRI) remains unclear. In this study, we used an in vitro model of hypoxia/reoxygenation (H/R) to mimic IRI and carried out PRR knockdown by siRNA and PRR overexpression using cDNA in H9c2 cells. Cell proliferation activity was examined by MTT and Cell Counting Kit-8 (CCK-8) assays. Apoptosis-related factors, autophagy markers and β-catenin pathway activity were assessed by real-time PCR and western blotting. After 24 h of hypoxia followed by 2 h of reoxygenation, the expression levels of PRR, LC3B-I/II, Beclin1, cleaved caspase-3, cleaved caspase-9 and Bax were upregulated, suggesting that apoptosis and autophagy were increased in H9c2 cells. Contrary to the effects of PRR downregulation, the overexpression of PRR inhibited proliferation, induced apoptosis, increased the expression of pro-apoptotic factors and autophagy markers, and promoted activation of the β-catenin pathway. Furthermore, all these effects were reversed by treatment with the β-catenin antagonist DKK-1. Thus, we concluded that PRR activation can trigger H/R-induced apoptosis and autophagy in H9c2 cells through the β-catenin signaling pathway, which may provide new therapeutic targets for the prevention and treatment of myocardial IRI.