Katrin Sak

The nucleotide receptor P2Y13 is a key regulator of hepatic High-Density Lipoprotein (HDL) endocytosis

Abstract.Cell surface receptors for high-density lipoprotein (HDL) on hepatocytes are major partners in the regulation of cholesterol homeostasis. We recently identified a cell surface ATP synthase as a high-affinity receptor for HDL apolipoprotein A-I (apoA-I) on human hepatocytes. Stimulation of this ectopic ATP synthase by apoA-I triggered a low-affinity-receptor-dependent HDL endocytosis by a mechanism strictly related to the generation of ADP. This suggests that nucleotide G-protein- coupled receptors of the P2Y family are molecular components in this pathway. Only P2Y1 and P2Y13 are present on the membrane of hepatocytes. Using both a pharmacological approach and small interference RNA, we identified P2Y13 as the main partner in hepatic HDL endocytosis, in cultured cells as well as in situ in perfused mouse livers. We also found a new important action of the antithrombotic agent AR-C69931MX as a strong activator of P2Y13-mediated HDL endocytosis.

Molecular mechanisms underlying chemopreventive potential of curcumin: Current challenges and future perspectives.

In recent years, natural compounds have received considerable attention in preventing and curing most dreadful diseases including cancer. The reason behind the use of natural compounds in chemoprevention is associated with fewer numbers of side effects than conventional chemotherapeutics. Curcumin (diferuloylmethane, PubMed CID: 969516), a naturally occurring polyphenol, is derived from turmeric, which is used as a common Indian spice. It governs numerous intracellular targets, including proteins involved in antioxidant response, immune response, apoptosis, cell cycle regulation and tumor progression. A huge mass of available studies strongly supports the use of Curcumin as a chemopreventive drug. However, the main challenge encountered is the low bioavailability of Curcumin. This extensive review covers various therapeutic interactions of Curcumin with its recognized cellular targets involved in cancer treatment, strategies to overcome the bioavailability issue and adverse effects associated with Curcumin consumption.

Involvement of P2Y receptors in the differentiation of haematopoietic cells.

The effects of extracellular nucleotides are mediated by multiple P2X ionotropic receptors and G protein‐coupled P2Y receptors. These receptors are ubiquitous, but few physiological roles have been firmly identified. In this review article, we present a survey of the functional expression of P2Y receptors in the different haematopoietic lineages by analyzing the selectivity of these cells for the various adenine and uracil nucleotides as well as the second messenger signaling pathways involved. The pharmacological profiles of metabotropic nucleotide receptors are different among myeloid, megakaryoid, erythroid, and lymphoid cells and change during differentiation. A role of P2Y receptors in the differentiation and maturation of blood cells has been proposed: In particular the P2Y11receptor seems to be involved in the granulocytic differentiation of promyelocytes and in the maturation of monocyte‐derived dendritic cells. It is suggested that the role of P2Y receptors in the maturation of blood cells may be more important than believed so far.

Nongenomic effects of 17β-estradiol-diversity of membrane binding sites

The classical model of the action of 17beta-estradiol comprises binding of this gonadal steroid hormone to nuclear estrogen receptors leading to the modulation of gene transcription and protein synthesis. However, in the last few years several evidences about the rapid nongenomic action of 17beta-estradiol via the stimulation of putative receptors located in the cell membrane have also been reported. These nongenomic responses occur within a few minutes and are insensitive to the inhibitors of transcription and translation; however, no such membrane receptors have been cloned so far. In this review article, we present a survey showing that such membrane binding sites of 17beta-estradiol have rather different ligand specificity properties than that of classical genomic estrogen receptors concerning the potential activity of different estrogens and other steroid hormones, supporting the conception of structurally distinct receptors for genomic and nongenomic pathways. The fact that rapid responses to 17beta-estradiol could be induced by a wide concentration range from some picomolar to high micromolar doses points to the diversity of these nongenomic membrane binding sites as well as the complexity of their functioning.

Molecular mechanisms of action of quercetin in cancer: recent advances.

In the last few decades, the scientific community has discovered an immense potential of natural compounds in the treatment of dreadful diseases such as cancer. Besides the availability of a variety of natural bioactive molecules, efficacious cancer therapy still needs to be developed. So, to design an efficacious cancer treatment strategy, it is essential to understand the interactions of natural molecules with their respective cellular targets. Quercetin (Quer) is a naturally occurring flavonol present in many commonly consumed food items. It governs numerous intracellular targets, including the proteins involved in apoptosis, cell cycle, detoxification, antioxidant replication, and angiogenesis. The weight of available synergistic studies vigorously fortifies the utilization of Quer as a chemoprevention drug. This extensive review covers various therapeutic interactions of Quer with their recognized cellular targets involved in cancer treatment.

Kaempferol – A dietary anticancer molecule with multiple mechanisms of action: Recent trends and advancements

Abstract The consumption of diet-based naturally bioactive metabolites is preferred to synthetic material in order to avert health-associated disorders. Among the plant-derived polyphenols, kaempferol (KMF) is considered as a valuable functional food ingredient with a broad range of therapeutic applications such as anti-cancer, antioxidant and anti-inflammatory uses. KMF acts on a range of intracellular as well as extracellular targets involved in the cell signaling pathways that in turn are known to regulate the hallmarks of cancer growth progressions like apoptosis, cell cycle, invasion or metastasis, angiogenesis and inflammation. Importantly, the understanding of mechanisms of action of KMF-mediated therapeutic effects may help the scientific community to design novel strategies for the treatment of dreadful diseases. The current review summarizes the various types of molecular targets of KMF in cancer cells as well as other health-associated disorders. In addition, this review also highlights the absorption, metabolism and epidemiological findings.

Role of Flavonoids in Future Anticancer Therapy by Eliminating the Cancer Stem Cells

Despite the numerous recent advances made in conventional anticancer therapies, metastasis and recurrence still remain the major problems in cancer management. The current treatment modalities kill the bulk of the tumor, leaving cancer stem cells behind and therefore, the agents specifically targeting this cancer initiating cell population may have important clinical implications. In this review article, the data about the inhibitory action of flavonoids, both natural as well as their synthetic derivatives, on the self-renewal capacity and survival of cancer stem cells of different origins are compiled and analyzed. These data indicate that several plant secondary metabolites, including soy isoflavone genistein, green tea catechins and a widely distributed flavonol quercetin, have the potential to suppress the stemness markers and properties, traits of the epithelial-to-mesenchymal transition and migratory characteristics, being also able to sensitize these cells to the standard chemotherapeutic drugs. These polyphenolic compounds act through multiple signal transduction pathways, providing thus the maximal therapeutic response and offering some promise to be included in the future cancer treatment schemes in combination with the conventional therapies. Such approach may give an important contribution to the shift of cancer management from palliative to curative mode, likely leading to the disease-free survival. Thus, flavonoids can serve as attractive candidates for novel anticancer agents by eliminating the roots of cancer.

Mechanistic insight into carnosol-mediated pharmacological effects: Recent trends and advancements

&NA; For several decades, bioactive phytochemicals have been appreciated to prevent and cure various lethal diseases. Many studies have proven the ability of dietary phytochemicals to avoid and retard tumor initiation and progression. Among the pharmacologically active moieties, terpenoids are considered one of the most important classes. Carnosol, is also a kind of diterpenoid, which known to possess a range of therapeutic effects such as anti‐cancer, anti‐inflammatory, and anti‐oxidant activities. All these effects are mediated via modulating different signaling cascades, including apoptosis regulating molecules (Bax/Bcl2), prosurvival‐proproliferative molecules (Akt/mTOR, MAPK), transcription factors like NF‐kappaB, STAT3‐6, and steroid receptors, such as androgen and estrogen receptors. The present review highlights the recent trends and advancements have been done in the field of research by using carnosol. Graphical abstract Figure. No caption available.

Adenosine triphosphate is full antagonist at human P2Y1 purinoceptors

Both agonistic and antagonistic effects have been reported for ATP at P2Y(1) purinoceptors at micromolar ligand concentrations. These conflicting data hamper specification of the true pharmacological profile as well as structural requirements for antagonistic ligands of this receptor. In this report the type of ATP activity at human P2Y(1) receptors in hP2Y(1)-1321N1 cells was revisited. In parallel, kinetics of degradation of ATP in the assay mixture was analysed. It was found that transformation of this ligand to ADP was responsible for initiation of synthesis of inositol phosphates, observed in the presence of ATP in hP2Y(1)-1321N1 cells. This agonistic effect was abolished in the presence of the triphosphate regeneration system (CP/CPK). On the other hand, if the agonistic effect caused by degradation product of ATP was taken into consideration, this ligand behaved as a full antagonist at P2Y(1) receptors and was characterized by the apparent inhibitory constant 5 microM.

Fisetin: A bioactive phytochemical with potential for cancer prevention and pharmacotherapy

&NA; A wide variety of chronic diseases, such as neurodegenerative and cardiovascular disorders, diabetes mellitus, osteoarthtitis, obesity and various cancers, are now being treated with cost effective phytomedicines. Since synthetic medicines are very expensive, concerted efforts are being made in developing and poor countries to discover cost effective medicines for the treatment of non‐communicable diseases (NCDs). Understanding the underlying mechanisms of bioactive medicines from natural sources would not only open incipient avenues for the scientific community and pharmaceutical industry to discover new drug molecules for the therapy of NCDs, but also help to garner knowledge for alternative therapeutic approaches for the management of chronic diseases. Fisetin is a polyphenolic molecule of flavonoids class, and belongs to the bioactive phytochemicals that have potential to block multiple signaling pathways associated with NCDs such as cell division, angiogenesis, metastasis, oxidative stress, and inflammation. The emerging evidence suggests that fisetin may be useful for the prevention and management of several types of human malignancies. Efforts are being made to enhance the bioavailability of fisetin after oral administration to prevent and/or treat cancer of the liver, breast, ovary and other organs. The intent of this review is to highlight the in vitro and in vivo activities of fisetin and to provide up‐to‐date information about the molecular interactions of fisetin with its cellular targets involved in cancer initiation, promotion and progression as well as to focus on strategies underway to increase the bioavailability and reduce the risk of deleterious effects, if any, associated with fisetin administration. Graphical abstract: Figure. No caption available.