Upc2p, a transcription factor of the zinc cluster family, is an important regulator of sterol biosynthesis and azole drug resistance in Candida albicans. To better understand Upc2p function in C. albicans, we used genomewide location profiling to identify the transcriptional targets of Upc2p in vivo. A triple hemagglutinin epitope, introduced at the C terminus of Upc2p, conferred a gain-of-function effect on the fusion protein.Location profiling identified 202 bound promoters (P < 0.05). Overrepresented functional groups of genes whose promoters were bound by Upc2p included 12 genes involved in ergosterol biosynthesis (NCP1, ERG11, ERG2, and others), 18 genes encoding ribosomal subunits (RPS30, RPL32, RPL12, and others), 3 genes encoding drug transporters (CDR1, MDR1, and YOR1), 4 genes encoding transcription factors (INO2, ACE2, SUT1, and UPC2), and 6 genes involved in sulfur amino acid metabolism (MET6, SAM2, SAH1, and others). Bioinformatic analyses suggested that Upc2p binds to the DNA motif 5-VNCGBDTR that includes the previously characterized Upc2p binding site 5-TCGTATA. Northern blot analysis showed that increased binding correlates with increased expression for the analyzed Upc2p targets (ERG11, MDR1, CDR1, YOR1, SUT1, SMF12, and CBP1). The analysis of ERG11, MDR1, and CDR1 transcripts in wild-type and upc2⌬/upc2⌬ strains grown under Upc2p-activating conditions (lovastatin treatment and hypoxia) showed that Upc2p regulates its targets in a complex manner, acting as an activator or as a repressor depending upon the target and the activating condition. Taken together, our results indicate that Upc2p is a key regulator of ergosterol metabolism. They also suggest that Upc2p may contribute to azole resistance by regulating the expression of drug efflux pump-encoding genes in addition to ergosterol biosynthesis genes.Candida albicans is an important human fungal pathogen, in terms of both its clinical significance and its use as an experimental model for scientific investigation. This opportunistic pathogen is a natural component of the human flora, colonizing skin and the gastrointestinal and genitourinary tracts (4). Although many infections involve the colonization of surface mucosal membranes (oral thrush and vaginal candidiasis, for example), immunosuppressed patients can be subject to potentially lethal systemic infections (45).Many antifungal drugs used to treat C. albicans infections function by targeting ergosterol, the analogue of cholesterol in mammalian cells and the major sterol of fungal cell membranes. Polyenes, such as amphotericin B, bind directly to ergosterol and perturb general membrane functions, resulting in low selectivity and high toxicity (2, 35). Azoles, including fluconazole and voriconazole, are more widely used and target the enzyme lanosterol demethylase (Erg11p) in the ergosterol biosynthesis pathway, with the consequence that ergosterol is depleted and replaced by unusual sterols, altering the fluidity of the membrane and the activities of membrane-bound proteins (e.g., enzymes...
BackgroundEpidemiological studies have shown that the offspring of mothers who experience diabetes mellitus during pregnancy are seven times more likely to develop health complications than the offspring of mothers who do not suffer from diabetes during pregnancy. The present study was designed to investigate whether supplementation of streptozotocin (STZ)-induced diabetic pregnant mice with thymoquinone (TQ) during pregnancy and lactation improves the risk of developing diabetic complications acquired by their offspring.MethodsThree groups of pregnant female mice were used: non-diabetic control dams (CD), diabetic dams (DD), and diabetic dams supplemented with TQ (DD + TQ) during pregnancy and lactation (n = 10 female mice in each group).ResultsOur data demonstrated a marked decrease in the number of neonates born to DD, and these neonates showed a marked increase in their mean body weight (macrosomic pups) compared to those born to CD and DD + TQ. The induction of diabetes during pregnancy and lactation resulted in macrosomic pups with several postpartum complications, such as a marked increase in their levels of blood glucose, free radicals, plasma pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α), and lipids, and a tendency toward abnormal obesity compared to the offspring of CD. By contrast, macrosomic offspring born to DD exhibited a marked reduction in plasma cytokine levels (IL-2, -4 and -7), an obvious reduction in the number of circulating lymphocytes, decreased proliferation of superantigen (SEB)-stimulated lymphocytes and aberrant AKT phosphorylation. Interestingly, the supplementation of DD with TQ during pregnancy and lactation had an obvious and significant effect on the number and mean body weight of neonates. Furthermore, TQ significantly restored the levels of blood glucose, insulin, free radicals, plasma cytokines, and lipids as well as lymphocyte proliferation in the offspring.ConclusionsOur data suggest that the nutritional supplementation of DD with the natural antioxidant TQ during pregnancy and lactation protects their offspring from developing diabetic complications and preserves an efficient lymphocyte immune response later in life.
This review evaluated prostate cancer studies from around the world and investigated the causes of differences among them. Prostate cancer incidence and mortality rates showed significant discrepancies between countries and ethnicities. In North America as well as in other western countries, the most common cancer was found to be prostate cancer; however, it appears to be not as prevalent among men in the Middle East and North Africa. Statistics show that screening of prostate-specific antigen levels should be applied depending on ethnicity and age. Other environmental aspects such as dietary and androgenic factors are believed to have caused these differences.
These findings suggest that the cytokines, particularly IL-6, whose levels were elevated in the chemotherapy-treated patients may be involved in the pathophysiology of CIP, and that they might be potential new targets for pain control in cancer patients receiving chemotherapy.
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