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Biochemical Pharmacology (v.84, #10)

Editorial Board (pp. iii).

Redox regulation – Natural compound as regulators of inflammation signaling by Cristina Florean; Marc Diederich (pp. 1223-1224).

Traditional West African pharmacopeia, plants and derived compounds for cancer therapy by Wamtinga Richard Sawadogo; Marc Schumacher; Marie-Hélène Teiten; Mario Dicato; Marc Diederich (pp. 1225-1240).

Traditional pharmacopeia is strongly involved in the continuous search for the well being of African populations. The World Health Organization (WHO) estimates that 80% of the population of developing countries relies on traditional medicine for their primary care needs. Medicinal plants are the major resource of this folk medicine where several species are used for the treatment of diseases with an inflammatory and/or infectious component as it is the case of old wounds, skin diseases and malfunctions affecting internal organs such as liver, lung, prostate and kidney. Many of these pathologies described by practitioners of traditional medicine have similarities with certain cancers, but the lack of training of many of these healers does not allow them to establish a link with cancer. However, ethnobotanical and ethnopharmacological surveys conducted by several researchers allowed to identify plants of interest for cancer treatment. Most scientific investigations on these plants demonstrated an anti-inflammatory or antioxidant effect, and sometimes, antiproliferative and cytotoxic activities against cancer cells were reported as well. The emergence of resistance to cancer chemotherapy has forced researchers to turn to natural products of plant and marine origin. In the West African sub-region, research on natural anti-cancer molecules is still in its infancy stage because of very limited financial resources and the scarcity of adequate technical facilities. However, several plants were investigated for their anticancer properties through north–south or south–south partnerships. In this review, we will review the role of West African traditional pharmacopeia in cancer treatment as well as medicinal plants with anti-cancer properties.

Keywords: Abbreviations; CDC2; cell division control protein 2 homolog; CDC25C; M-phase inducer phosphatase 3; DMBA; dimethylbenzen(α)anthracene; DLD1; human colorectal carcinoma; EBV-EA; Epstein-Bar Virus Early Antigen in Raji cell line; GST; glutathione; S; transferase; GSH; glutathione; JNK; Jun N-terminal kinases; MDR; multidrug resistance; NAD(P)H; nicotinamide adenine dinucleotide phosphate-oxidase; PARP; poly(ADP-ribose) polymerase; P-gp; P-glycoprotein; P12; cyclin-dependent kinase inhibitor 1; PI3 kinase/Akt; phosphoinositol-3-kinase; PKC; protein kinase C; PP2A; protein phosphatase 2; p38 MAP kinases; p38 mitogen-activated protein kinases; P450CYP3A2; hepatic expression of cytochrome P450; P450CYP2C11; male-specific P450; TPA; 12-O-tetradecanoylphorbol-13-acetate; TPM4-ALK; tropomyosin alpha-4 chain-anaplastic lymphoma kinase; UDP-GT; glucuronosyl S-transferase; VEGF; vascular endothelial growth factorWest Africa; Medicinal plants; Anticancer; Traditional medicine; Natural compounds

Diallyl trisulfide induces apoptosis in human breast cancer cells through ROS-mediated activation of JNK and AP-1 by Hye-Kyung Na; Eun-Hee Kim; Min-Ah Choi; Jong-Min Park; Do-Hee Kim; Young-Joon Surh (pp. 1241-1250).

Multiple lines of evidence support an inverse association between consumption of garlic and the risk of cancer. Chemopreventive effects of garlic have been attributed to its oil-soluble sulfur ingredients, such as diallyl sulfide (DAS), diallyl disulfide (DADS), and diallyl trisulfide (DATS), but their underlying molecular mechanisms remain largely unresolved. In the present study, we found that DATS showed the most potent anti-proliferative effects in human breast cancer MCF-7 cells. MCF-7 cells treated with DATS underwent apoptotic death as revealed by a progressive increase in the proportion of the sub-G0/G1 cell population and a typical pattern of annexin V/propidium iodide staining. DATS induced phosphorylation of the antiapoptotic Bcl-2 and proteolytic cleavage of poly(ADP-ribose)polymerase (PARP) in MCF-7 cells. DATS treatment activated c-Jun N-terminal kinase (JNK). DATS-induced apoptosis was blunted in MCF-7 cells treated with a specific JNK inhibitor SP600125 or transiently transfected with dominant negative JNK. DATS treatment resulted in accumulation of reactive oxygen species (ROS). DATS-induced apoptosis as well as activation of JNK was abrogated by N-acetyl-l-cysteine (NAC). Furthermore, DATS induced phosphorylation and expression of c-Jun, which were attenuated by NAC. MCF-7 cells treated with DATS also exhibited increased DNA binding activity of AP-1, which was blocked by NAC and the JNK inhibitor. Proteolytic cleavage of PARP induced by DATS was abrogated in the cells transfected with c- jun siRNA. Oral administration of 5μmol/kg DATS to female Balb/c mice inhibited the growth of human MCF-7 cell tumor xenografts. These results suggest that DATS-induced apoptosis is mediated through ROS generation and subsequent activation of JNK and AP-1.

Keywords: Diallyl trisulfide; Apoptosis; ROS; JNK; AP-1; MCF-7 cells

Resveratrol initiates differentiation of mouse skeletal muscle-derived C2C12 myoblasts by Jacques Kaminski; Allan Lançon; Virginie Aires; Emeric Limagne; Esmerina Tili; Jean-Jacques Michaille; Norbert Latruffe (pp. 1251-1259).

Resveratrol initiates early differentiation of myoblasts to myotubes in C2C12 mouse cell line.Resveratrol is one of the most widely studied bio-active plant polyphenols. While its effect on endothelial blood vessel cells, cancer cells, inflammatory processes and neurodegenerative events is well documented, little is known about the implication of this phytophenol in differentiating processes, particularly in skeletal muscle cells. Here, we report the effects of resveratrol on mouse skeletal muscle-derived cells (C2C12) in either a nondifferentiated (myoblasts) or differentiated state (myotubes) by evaluating resveratrol uptake, cell proliferation, changes in cell shape, and the expression of genes encoding muscle-specific transcription factors or contractile proteins. Resveratrol: (1) rapidly accumulates within cells through passive and facilitated processes; (2) does not strongly affect cell viability, cell cycle and apoptosis; (3) behaves as a pro-differentiating agent as shown by the lengthening of cells, leading to a myotube phenotype; (4) upregulates muscular pro-differentiation markers and transcription factors (myogenin, Scrp3) starting after 12h of exposure and strongly increases heavy chain myosin content after 18h of exposure to resveratrol; (5) increases the Srf transcription factor's transcript level, a target mRNA of the miRNA-133b, which is itself downregulated by this polyphenol. These results put forward new pro-differentiating regulatory properties of resveratrol on skeletal muscles at least partly via modulation of specific miRNAs.

Keywords: Resveratrol; Differentiation transcription factors; C2C12 skeletal muscle cells; Myoblasts; Myotubes; MicroRNAs

Berberine: New perspectives for old remedies by Micol Tillhon; Luis M. Guamán Ortiz; Paolo Lombardi; A. Ivana Scovassi (pp. 1260-1267).

Chemical compounds derived from plants have been used since the origin of human beings to counteract a number of diseases. Among them, the natural isoquinoline alkaloid berberine has been employed in Ayurvedic and Chinese Medicine for hundreds of years with a wide range of pharmacological and biochemical effects. More recently, a growing body of reports supports the evidence that berberine has anticancer effects, being able to block the proliferation of and to kill cancer cells. This review addresses the properties and therapeutic use of berberine and focuses on the recent advances as promising anticancer drug lead.

Keywords: Apoptosis; Autophagy; Berberine; Cancer; Isoquinoline alkaloid

Berberine: New perspectives for old remedies by Micol Tillhon; Luis M. Guamán Ortiz; Paolo Lombardi; A. Ivana Scovassi (pp. 1260-1267).

Keywords: Apoptosis; Autophagy; Berberine; Cancer; Isoquinoline alkaloid

Key cell signaling pathways modulated by zerumbone: Role in the prevention and treatment of cancer by Remya Prasannan; Karunakaran A. Kalesh; Muthu K. Shanmugam; Alamelu Nachiyappan; Lalitha Ramachandran; An H. Nguyen; Alan Prem Kumar; Manikandan Lakshmanan; Kwang Seok Ahn; Gautam Sethi (pp. 1268-1276).

Phytochemicals and their synthetic derivatives are making a significant contribution in modern drug discovery programs by targeting several human diseases, including cancer. Most of these natural compounds are often multitargeted in nature, which is generally a very desirable property for cancer therapy, as carcinomas typically involve dysregulation of multiple genes and associated cell-signaling pathways at various stages of initiation, progression and metastasis. Additionally, these natural agents generally have lower side-effects, are readily available and hence are cost effective. One such natural compound is zerumbone, a cyclic eleven-membered sesquiterpene, isolated from the tropical plant Zingiber zerumbet Smith that has attracted great attention recently for its potent anticancer activities in several tumor models. This review summarizes the data based on various in vitro and in vivo studies related to the effects of zerumbone on numerous pivotal molecular targets in cancer and its reported chemopreventive/therapeutic effects in different models of cancer.

Keywords: Apoptosis; Cancer; NF-κB; TRAIL; Zerumbone

Dietary flavonoid fisetin: A novel dual inhibitor of PI3K/Akt and mTOR for prostate cancer management by Vaqar Mustafa Adhami; Deeba Nadeem Syed; Naghma Khan; Hasan Mukhtar (pp. 1277-1281).

Epidemiologic and case control population based studies over the past few decades have identified diet as an important determinant of cancer risk. This evidence has kindled interest into research on bioactive food components and has till date resulted in the identification of many compounds with cancer preventive and therapeutic potential. Among such compounds has been fisetin (3,7,3′,4′-tetrahydroxyflavone), a flavonol and a member of the flavonoid polyphenols that also include quercetin, myricetin and kaempferol. Fisetin is commonly found in many fruits and vegetables such as apples, persimmons, grapes, kiwis, strawberries, onions and cucumbers. We evaluated the effects of fisetin against melanoma and cancers of the prostate, pancreas and the lungs. Using prostate and lung adenocarcinoma cells, we demonstrated that fisetin acts as a dual inhibitor of the PI3K/Akt and the mTOR pathways. This is a significant finding considering the fact that mTOR is phosphorylated and its activation is more frequent in tumors with overexpression of PI3K/Akt. Dual inhibitors of PI3K/Akt and mTOR signaling have been suggested as valuable agents for treating such cancers. Here, we summarize our findings on the dietary flavonoid fisetin and its effects on cancer with particular focus on prostate cancer. Our observations and findings from other laboratories suggest that fisetin could be a useful chemotherapeutic agent that could be used either alone or as an adjuvant with conventional chemotherapeutic drugs for the management of prostate and other cancers.

Keywords: Fisetin; Prostate; Cancer; mTOR; PI3K/Akt

Dietary flavonoid fisetin: A novel dual inhibitor of PI3K/Akt and mTOR for prostate cancer management by Vaqar Mustafa Adhami; Deeba Nadeem Syed; Naghma Khan; Hasan Mukhtar (pp. 1277-1281).

Keywords: Fisetin; Prostate; Cancer; mTOR; PI3K/Akt

Molecular insight in the multifunctional activities of Withaferin A by Wim Vanden Berghe; Linde Sabbe; Mary Kaileh; Guy Haegeman; Karen Heyninck (pp. 1282-1291).

Herbal medicine which involves the use of plants for their medicinal value, dates as far back as the origin of mankind and demonstrates an array of applications including cardiovascular protection and anti-cancer activities, via antioxidant, anti-inflammatory and metabolic activities. Even today the popularity of medicinal herbs is still growing like in traditional medicines such as the Indian medicine, Ayurveda. One of the Ayurvedic medicinal plants is Withania somnifera Dunal, of which the important constituents are the withanolides. Among them, Withaferin A is one of the most bioactive compounds, exerting anti-inflammatory, pro-apoptotic but also anti-invasive and anti-angiogenic effects. In the context of modern pharmacology, a better insight in the underlying mechanism of the broad range of bioactivities exerted by Withaferin A is compulsory. Therefore, a lot of effort was made to explore the intracellular effects of Withaferin A and to characterize its target proteins. This review provides a decisive insight on the molecular basis of the health-promoting potential of Withaferin A.

Keywords: Withaferin A; Carcinogenesis; Inflammation; Angiogenesis; Therapy

Molecular insight in the multifunctional activities of Withaferin A by Wim Vanden Berghe; Linde Sabbe; Mary Kaileh; Guy Haegeman; Karen Heyninck (pp. 1282-1291).

Keywords: Withaferin A; Carcinogenesis; Inflammation; Angiogenesis; Therapy

Redox modulation of the DNA damage response by Fanny Caputo; Rolando Vegliante; Lina Ghibelli (pp. 1292-1306).

Lesions to DNA trigger the DNA-damage response (DDR), a complex, multi-branched cell-intrinsic process targeted to DNA repair, or elimination of the damaged cells by apoptosis. DDR aims at reducing permanence of mutated cells, decreasing the risk of tumor development: the more stringent the response, the lower the likelihood that sub-lethally damaged, unrepaired cells survive and proliferate. Accordingly, leakage often occurs in tumor cells with compromised DDR, accumulating mutations and accelerating tumor progression. Oxidations mediate DNA damage upon different insults such as UV, X and γ radiation, pollutants, poisons, or endogenous disequilibria, producing different types of lesions that trigger DDR, which can be alleviated by antioxidants. But reactive oxygen species (ROS), and the enzymes involved in their production or scavenging, also participate in DDR signaling, modulating the activity of key enzymes, and regulating the stringency of DDR. Accordingly, antioxidant enzymes such as superoxide dismutase play intimate and complex roles in tumor development, exceeding the basal roles of preventing the initial DNA damage. Likewise, it is emerging that dietary antioxidants help controlling tumor onset and progression by preventing DNA damage and by acting on cell cycle checkpoints, opening a novel and promising frontier to anticancer therapy.

Keywords: DNA damage response; Redox modulation; Tumor progression; Superoxide dismutase; Natural compounds

Redox modulation of the DNA damage response by Fanny Caputo; Rolando Vegliante; Lina Ghibelli (pp. 1292-1306).

Keywords: DNA damage response; Redox modulation; Tumor progression; Superoxide dismutase; Natural compounds

Reactive oxygen species (ROS) and sensitization to TRAIL-induced apoptosis, in Bayesian network modelling of HeLa cell response to LY303511 by Lisa Tucker-Kellogg; Yuan Shi; Jacob K. White; Shazib Pervaiz (pp. 1307-1317).

The compound LY303511 (LY30) has been proven to induce production of ROS and to sensitize cancer cells to TRAIL-induced apoptosis, but the mechanisms and mediators of LY30-induced effects are potentially complex. Bayesian networks are a modelling technique for making probabilistic inferences about complex networks of uncertain causality.Fluorescent indicators for ROS, reactive nitrogen species (RNS), and free calcium were measured in time-series after LY30 treatment. This “correlative” dataset was used as input for Bayesian modelling to predict the causal dependencies among the measured species. Predictions were compared against a separate “causal” dataset, in which cells had been treated with FeTPPS to scavenge peroxynitrite, EGTA-am to chelate calcium, and Tiron to scavenge O₂⁻. Finally, cell viability measurements were integrated into an extended model of LY30 effects.LY30 treatment caused a rapid increase of ROS (measured by DCFDA) as well as a significant increase in RNS and calcium. Bayesian modelling predicted that Ca²⁺was a partial cause of the ROS induced by short incubations with LY30, and that RNS was strongly responsible for the ROS induced by long incubations with LY30. Validation experiments confirmed the predicted roles of RNS and calcium, and also demonstrated a causal role for O₂⁻. In cell viability experiments, the additive effects of calcium and peroxynitrite were responsible for 90% of LY30-mediated sensitization to TRAIL-induced apoptosis.We conclude that LY30 induces interdependent pathways of reactive species and stress signalling, with peroxynitrite and calcium contributing most significantly to apoptosis sensitization.

Keywords: Reactive oxygen species; Combination therapy; Systems biology; Cancer apoptosis; Computational models

PARP inhibition potentiates the cytotoxic activity of C-1305, a selective inhibitor of topoisomerase II, in human BRCA1-positive breast cancer cells by Józefa Węsierska-Gądek; Nora Zulehner; Franziska Ferk; Andrzej Składanowski; Oxana Komina; Margarita Maurer (pp. 1318-1331).

Two cellular proteins encoded by the breast and ovarian cancer type 1 susceptibility ( BRCA1 and BRCA2) tumor suppressor genes are essential for DNA integrity and the maintenance of genomic stability. Approximately 5–10% of breast and ovarian cancers result from inherited alterations or mutations in these genes.Remarkably, BRCA1/BRCA2-deficient cells are hypersensitive to selective inhibition of poly(ADP-ribose)polymerase 1 (PARP-1), whose primary functions are related to DNA base excision repair; PARP-1 inhibition significantly potentiates the cytotoxicity of various anti-cancer drugs, including inhibitors of topoisomerase I and II.In the present study, we examined the anti-proliferative and pro-apoptotic effects of C-1305, a selective inhibitor of topoisomerase II, on human breast cancer cell lines with different BRCA1 and p53 statuses. BRCA1-competent breast cancer cell lines exhibited different responses to topoisomerase II inhibition. BT-20 cells that express high levels of BRCA1 levels were most resistant to C-1305 than other tested cells. Surprisingly, pharmacological interference with PARP-1 activity strongly inhibited their proliferation and potentiated the efficacy of C-1305 treatment. In contrast, PARP-1 inhibition only weakly affected the proliferation of BRCA1-deficient SKBr-3 cells and was not synergistic with the effects of C-1305. Further experiments revealed that the inhibition of PARP-1 in BT-20 cells caused the accumulation of DNA strand breaks and induced caspase-3 dependent apoptosis. These results seem to indicate that PARP-1 inhibition can potentiate the cytotoxicity of anti-cancer drugs in cancer cells with functional BRCA1 and suggest that mutations in other DNA repair proteins may render cancer cells more sensitive to interference with PARP-1 activity.

Keywords: Abbreviations; BER; base excision repair; BRCA1; breast cancer type 1 susceptibility protein; HMC; Hoffman modulation contrast; HR; homologous recombination; NER; nucleotide excision repair; NHEJ; non-homologous end joining; MMP; mitochondrial membrane potential; PARP-1; poly(ADP-ribose)polymerase-1; PD; Petri dish; PVDF; polyvinylidene difluoride; TOPO; topoisomerase; WCL; whole cell lysate; WT; wild-typeDNA strand breaks; Caspase-3 activation; Apoptosis; Cell cycle; G; ₂; arrest; Potential of mitochondrial membrane

Perspectives on translational and therapeutic aspects of SIRT1 in inflammaging and senescence by Hongwei Yao; Irfan Rahman (pp. 1332-1339).

Sirtuin1 (SIRT1), a type III protein deacetylase, is considered as a novel anti-aging protein involved in regulation of cellular senescence/aging and inflammation. SIRT1 level and activity are decreased during lung inflammaging caused by oxidative stress. The mechanism of SIRT1-mediated protection against inflammaging is associated with the regulation of inflammation, premature senescence, telomere attrition, senescence associated secretory phenotype, and DNA damage response. A variety of dietary polyphenols and pharmacological activators are shown to regulate SIRT1 so as to intervene the progression of type 2 diabetes, cancer, cardiovascular diseases, and chronic obstructive pulmonary disease associated with inflammaging. However, recent studies have shown the non-specific regulation of SIRT1 by the aforementioned pharmacological activators and polyphenols. In this perspective, we have briefly discussed the role of SIRT1 in regulation of cellular senescence and its associated secretory phenotype, DNA damage response, particularly in lung inflammaging and during the development of chronic obstructive pulmonary diseases. We have also discussed the potential directions for future translational therapeutic avenues for SIRT1 in modulating lung inflammaging associated with senescence in chronic lung diseases associated with increased oxidative stress.

Keywords: SIRT1; Inflammation; Cellular senescence; Telomere attrition; Senescence associated secretory phenotype; DNA damage and repair

Perspectives on translational and therapeutic aspects of SIRT1 in inflammaging and senescence by Hongwei Yao; Irfan Rahman (pp. 1332-1339).

Keywords: SIRT1; Inflammation; Cellular senescence; Telomere attrition; Senescence associated secretory phenotype; DNA damage and repair

Therapeutic potential of resolvins in the prevention and treatment of inflammatory disorders by Ha-Na Lee; Young-Joon Surh (pp. 1340-1350).

Acute inflammation, the primary response to harmful infection and injury, can be successfully completed through effective resolution and tissue repair. Resolution of inflammation requires the elimination of key inflammatory cells and the downregulation of pro-inflammatory mediators in the inflamed sites. This coordinated process is actively regulated by biochemical mediators which possess anti-inflammatory and/or pro-resolving effects. Resolvins, endogenous lipid mediators generated from omega-3 fatty acids, have emerged as a novel class of potent molecules that counteract excessive inflammatory responses and stimulate pro-resolving mechanisms; regulating the trafficking of leukocytes and stimulating non-phlogistic phagocytosis of apoptotic neutrophils by macrophages. The disruption of these anti-inflammatory and pro-resolving mechanisms can not only cause the initiation of unnecessary inflammation, but also lead to the persistence of inflammation which contributes to the pathogenesis and progression of chronic inflammatory diseases. Since inflammation can have the beneficial effect on host defense, the timely resolution of inflammation is better to avoid chronic inflammatory situation, rather than merely blocking inflammation at the beginning. In this regards, understanding of the mechanism underlying resolution of inflammation provides a novel therapeutic approach to prevent and treat chronic inflammatory disorders. This review will address therapeutic potential of resolvins for the successful management of inflammatory ailments.

Keywords: Resolution of inflammation; Chronic inflammatory disease; Lipid mediator class switching; Resolvin; Macrophage

Therapeutic potential of resolvins in the prevention and treatment of inflammatory disorders by Ha-Na Lee; Young-Joon Surh (pp. 1340-1350).

Keywords: Resolution of inflammation; Chronic inflammatory disease; Lipid mediator class switching; Resolvin; Macrophage

Development of chemical inhibitors of the SARS coronavirus: Viral helicase as a potential target by Young-Sam Keum; Yong-Joo Jeong (pp. 1351-1358).

Severe acute respiratory syndrome (SARS) was the first pandemic in the 21st century to claim more than 700 lives worldwide. However, effective anti-SARS vaccines or medications are currently unavailable despite being desperately needed to adequately prepare for a possible SARS outbreak. SARS is caused by a novel coronavirus, and one of its components, a viral helicase, is emerging as a promising target for the development of chemical SARS inhibitors. In the following review, we describe the characterization, family classification, and kinetic movement mechanisms of the SARS coronavirus (SCV) helicase—nsP13. We also discuss the recent progress in the identification of novel chemical inhibitors of nsP13 in the context of our recent discovery of the strong inhibition of the SARS helicase by natural flavonoids, myricetin and scutellarein. These compounds will serve as important resources for the future development of anti-SARS medications.

Keywords: Severe acute respiratory syndrome (SARS); Coronavirus; nsP13; Myricetin; Scutellarein

Development of chemical inhibitors of the SARS coronavirus: Viral helicase as a potential target by Young-Sam Keum; Yong-Joo Jeong (pp. 1351-1358).

Keywords: Severe acute respiratory syndrome (SARS); Coronavirus; nsP13; Myricetin; Scutellarein

Endogenously synthesized n-3 polyunsaturated fatty acids in fat-1 mice ameliorate high-fat diet-induced non-alcoholic fatty liver disease by Eun-Hee Kim; Jin-Sik Bae; Ki Baik Hahm; Ji-Young Cha (pp. 1359-1365).

Dietary n-3 polyunsaturated fatty acids (n-3 PUFAs) have well-documented protective effects against obesity-induced insulin resistance and hepatic steatosis. Here, we investigated the effects of endogenous n-3 PUFAs on diet-induced fatty liver disease using fat-1 transgenic mice ( fat-1) capable of converting n-6 to n-3 PUFAs. Wild-type (WT) and fat-1 mice were maintained on a high-fat diet (HFD) for 5months. HFD-induced weight gain and fatty liver were more prominent in WT mice than fat-1 mice. Histological analysis indicated that WT mice fed the HFD developed moderate-to-severe macrovesicular steatosis, whereas fat-1 mice developed very mild steatosis. In addition, HFD-induced hepatocyte ballooning and fibrosis were ameliorated in fat-1 mice. Serum alanine transaminase (ALT) and aspartate transaminase (AST) levels were within the respective normal ranges in HFD-fed fat-1 mice, whereas both were significantly elevated in HFD-fed WT mice. The fat-1 mice showed significantly decreased serum lipid levels, including triglycerides, total cholesterol (TC), HDL-C, and LDL-C, compared to WT mice regardless of diet. Specifically, the increases in very low-density lipoprotein cholesterol (VLDL-C) and chylomicrons detected in HFD-fed WT mice were completely blunted in HFD-fed fat-1 mice. Gene expression analysis showed that hepatic Cyp7a1 mRNA and protein expression levels were markedly increased in HFD-fed fat-1 mice. In addition, genes involved in cholesterol uptake ( Ldlr) and bile acid excretion ( Abcg5 and Abcg8) were increased in the livers of fat-1 mice. These data suggest that n-3 PUFAs ameliorate diet-induced hyperlipidemia and fatty liver through induction of CYP7A1 expression and activation of cholesterol catabolism to bile acid.

Keywords: Abbreviations; NAFLD; non-alcoholic fatty liver disease; PUFAs; polyunsaturated fatty acids; HFD; high-fat diet; ALT; alanine transaminase; AST; aspartate transaminase; HDL; high density lipoprotein; LDL; low density lipoprotein; CYP7A1; cholesterol 7α-hydroxylaseomega-3 PUFAs; NAFLD; CYP7A1; fat-1; transgenic mouse

Function, diversity and therapeutic potential of the N-terminal domain of human chemokine receptors by Martyna Szpakowska; Virginie Fievez; Karthik Arumugan; Nico van Nuland; Jean-Claude Schmit; Andy Chevigné (pp. 1366-1380).

Putative two-site mechanism for the interactions between chemokines and their receptors.Chemokines and their receptors play fundamental roles in many physiological and pathological processes such as leukocyte trafficking, inflammation, cancer and HIV-1 infection. Chemokine-receptor interactions are particularly intricate and therefore require precise orchestration. The flexible N-terminal domain of human chemokine receptors has regularly been demonstrated to hold a crucial role in the initial recognition and selective binding of the receptor ligands. The length and the amino acid sequences of the N-termini vary considerably among different receptors but they all show a high content of negatively charged residues and are subject to post-translational modifications such as O-sulfation and N- or O-glycosylation. In addition, a conserved cysteine that is most likely engaged in a receptor-stabilizing disulfide bond delimits two functionally distinct parts in the N-terminus, characterized by specific molecular signatures. Structural analyses have shown that the N-terminus of chemokine receptors recognizes a groove on the chemokine surface and that this interaction is stabilized by high-affinity binding to a conserved sulfotyrosine-binding pocket. Altogether, these data provide new insights on the chemokine-receptor molecular interplay and identify the receptor N-terminus-binding site as a new target for the development of therapeutic molecules. This review presents and discusses the diversity and function of human chemokine receptor N-terminal domains and provides a comprehensive annotated inventory of their sequences, laying special emphasis on the presence of post-translational modifications and functional features. Finally, it identifies new molecular signatures and proposes a computational model for the positioning and the conformation of the CXCR4 N-terminus grafted on the first chemokine receptor X-ray structure.

Keywords: Chemokine receptor; Receptor N-terminus; Chemokine; CXCR4; Sulfotyrosine

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Biochemical Pharmacology (v.84, #10)

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Biochemical Pharmacology (v.84, #10)