scholarly journals Therapeutic Potential of Dietary Polyphenols

2021 ◽  
Author(s):  
Amy L. Stockert ◽  
Seth Hall
Keyword(s):  
Transcription Factors ◽  
Oxidative Damage ◽  
Efflux Pump ◽  
Therapeutic Potential ◽  
Inflammatory Diseases ◽  
Epigenetic Modifications ◽  
Inflammatory Factors ◽  
Multidrug Efflux Pump ◽  
Disease States ◽  
Regulatory Enzymes

The chapter summarizes available research on polyphenols and the potential for polyphenol based therapeutics. Polyphenols have the potential to be used in a multi-target fashion therapeutically. The majority of the polyphenol benefits appear to share positive effects across multiple disease states including inflammatory diseases, diseases of metabolic dysregulation and cancer. The reviewed literature includes human, animal and cell culture based studies. Selected mechanisms within each disease state are highlighted including interleukin inflammatory markers, NF-κB, acetyl-CoA concentration regulation of metabolism, and p-glycoprotein multidrug efflux pump associated with cancer treatment failures. Reviewed studies discuss polyphenols inhibiting transcription factors that control expression on inflammatory factors as well as activating other transcription factors that increase expression of enzymes protective of oxidative damage. Levels of metabolic regulatory enzymes are also affected positively by polyphenol addition through epigenetic modifications. Epigenetic modifications affecting cancer development and progression appear positively affected by polyphenol treatment. Additionally, oxidative damage protection of normal cells can be achieved by polyphenol treatment thus limiting chemotherapeutic damage. Upon review of the available literature, a strong case for the potential use of polyphenols in therapeutic situations stands out. Potential risks included are that the purity and specific concentrations required to achieve therapeutic benefits without potential side effects need to be examined prior to the adoption of therapeutics.

scholarly journals Differential Requirement of the Transcription Factor Mcm1 for Activation of the Candida albicans Multidrug Efflux PumpMDR1by Its Regulators Mrr1 and Cap1

2011 ◽  
Vol 55 (5) ◽  
pp. 2061-2066 ◽  
Author(s):  
Selene Mogavero ◽  
Arianna Tavanti ◽  
Sonia Senesi ◽  
P. David Rogers ◽  
Joachim Morschhäuser
Keyword(s):  
Transcription Factor ◽  
Candida Albicans ◽  
Transcription Factors ◽  
Molecular Mechanisms ◽  
Efflux Pump ◽  
Multidrug Efflux ◽  
Multidrug Efflux Pump ◽  
Gain Of Function ◽  
Pathogenic Yeast ◽  
Content Type

ABSTRACTOverexpression of the multidrug efflux pump Mdr1 causes increased fluconazole resistance in the pathogenic yeastCandida albicans. The transcription factors Mrr1 and Cap1 mediateMDR1upregulation in response to inducing stimuli, and gain-of-function mutations in Mrr1 or Cap1, which render the transcription factors hyperactive, result in constitutiveMDR1overexpression. The essential MADS box transcription factor Mcm1 also binds to theMDR1promoter, but its role in inducible or constitutiveMDR1upregulation is unknown. Using a conditional mutant in which Mcm1 can be depleted from the cells, we investigated the importance of Mcm1 forMDR1expression. We found that Mcm1 was dispensable forMDR1upregulation by H2O2but was required for fullMDR1induction by benomyl. A C-terminally truncated, hyperactive Cap1 could upregulateMDR1expression both in the presence and in the absence of Mcm1. In contrast, a hyperactive Mrr1 containing a gain-of-function mutation depended on Mcm1 to causeMDR1overexpression. These results demonstrate a differential requirement for the coregulator Mcm1 for Cap1- and Mrr1-mediatedMDR1upregulation. When activated by oxidative stress or a gain-of-function mutation, Cap1 can induceMDR1expression independently of Mcm1, whereas Mrr1 requires either Mcm1 or an active Cap1 to cause overexpression of theMDR1efflux pump. Our findings provide more detailed insight into the molecular mechanisms of drug resistance in this important human fungal pathogen.

scholarly journals Candida albicans Zn Cluster Transcription Factors Tac1 and Znc1 Are Activated by Farnesol To Upregulate a Transcriptional Program Including the Multidrug Efflux Pump CDR1

2018 ◽  
Vol 62 (11) ◽  
Author(s):  
Zhongle Liu ◽  
John M. Rossi ◽  
Lawrence C. Myers
Keyword(s):  
Candida Albicans ◽  
Transcription Factors ◽  
Quorum Sensing ◽  
Efflux Pump ◽  
Close Relative ◽  
Multidrug Efflux ◽  
Multidrug Efflux Pump ◽  
Content Type ◽  
Dna Binding Specificity ◽  
Hyphal Formation

ABSTRACT Farnesol, a quorum-sensing molecule, inhibits Candida albicans hyphal formation, affects its biofilm formation and dispersal, and impacts its stress response. Several aspects of farnesol's mechanism of action remain incompletely uncharacterized. Among these are a thorough accounting of the cellular receptors and transporters for farnesol. This work suggests these processes are linked through the Zn cluster transcription factors Tac1 and Znc1 and their induction of the multidrug efflux pump Cdr1. Specifically, we have demonstrated that Tac1 and Znc1 are functionally activated by farnesol through a mechanism that mimics other means of hyperactivation of Zn cluster transcription factors. This is consistent with our observation that many genes acutely induced by farnesol are dependent on TAC1, ZNC1, or both. A related molecule, 1-dodecanol, invokes a similar TAC1-ZNC1 response, while several other proposed C. albicans quorum-sensing molecules do not. Tac1 and Znc1 both bind to and upregulate the CDR1 promoter in response to farnesol. Differences in inducer and DNA binding specificity lead to Tac1 and Znc1 having overlapping, but nonidentical, regulons. Induction of genes by farnesol via Tac1 and Znc1 was inversely related to the level of CDR1 present in the cell, suggesting a model in which induction of CDR1 by Tac1 and Znc1 leads to an increase in farnesol efflux. Consistent with this premise, our results show that CDR1 expression, and its regulation by TAC1 and ZNC1, facilitates growth in the presence of high farnesol concentrations in C. albicans and in certain strains of its close relative, C. dubliniensis.

scholarly journals Targeting NF-κB-Inducing Kinase (NIK) in Immunity, Inflammation, and Cancer

2020 ◽  
Vol 21 (22) ◽  
pp. 8470
Author(s):  
Kathryn M. Pflug ◽  
Raquel Sitcheran
Keyword(s):  
Cell Survival ◽  
Metabolic Disorders ◽  
Therapeutic Potential ◽  
Inflammatory Diseases ◽  
Aberrant Expression ◽  
Cellular Processes ◽  
Disease States ◽  
Upstream Kinase ◽  
Immune Defects

NF-κB-inducing kinase (NIK), the essential upstream kinase, which regulates activation of the noncanonical NF-κB pathway, has important roles in regulating immunity and inflammation. In addition, NIK is vital for maintaining cellular health through its control of fundamental cellular processes, including differentiation, growth, and cell survival. As such aberrant expression or regulation of NIK is associated with several disease states. For example, loss of NIK leads to severe immune defects, while the overexpression of NIK is observed in inflammatory diseases, metabolic disorders, and the development and progression of cancer. This review discusses recent studies investigating the therapeutic potential of NIK inhibitors in various diseases.

scholarly journals Inducible and Constitutive Activation of Two Polymorphic Promoter Alleles of the Candida albicans Multidrug Efflux PumpMDR1

2012 ◽  
Vol 56 (8) ◽  
pp. 4490-4494 ◽  
Author(s):  
Christoph Sasse ◽  
Rebecca Schillig ◽  
Alexandra Reimund ◽  
Julia Merk ◽  
Joachim Morschhäuser
Keyword(s):  
Candida Albicans ◽  
Transcription Factors ◽  
Loss Of Heterozygosity ◽  
Efflux Pump ◽  
Multidrug Efflux ◽  
Multidrug Efflux Pump ◽  
Fluconazole Resistance ◽  
Content Type ◽  
Constitutive Activation ◽  
Strain Sc5314

ABSTRACTOverexpression of the multidrug efflux pumpMDR1confers resistance to the antifungal drug fluconazole onCandida albicans. It has been reported that two types ofMDR1promoters exist inC. albicansand that homozygosity for the allele with higher activity may promote fluconazole resistance. We found that the twoMDR1promoter alleles in strain SC5314 were equally well activated by inducing chemicals or hyperactive forms of the transcription factors Mrr1 and Cap1, which controlMDR1expression. In addition, no loss of heterozygosity at theMDR1locus was observed inMDR1-overexpressing clinicalC. albicansstrains that developed fluconazole resistance during therapy.

scholarly journals An Efficient Synthesis Towards the Core of Crinipellin and Alliacol-B Along With Their Docking Studies

2020 ◽  
Author(s):  
Raghaba Sahu ◽  
Ranjan Kumar Mohapatra ◽  
Saud I. Al-Resayes ◽  
Debadutta Das ◽  
Pankaj K. Parhi ◽  
...  
Keyword(s):  
Estrogen Receptor Alpha ◽  
Efflux Pump ◽  
Therapeutic Potential ◽  
Docking Study ◽  
Docking Studies ◽  
Alder Reaction ◽  
Multidrug Efflux Pump ◽  
Prostaglandin Synthase ◽  
Human Estrogen Receptor ◽  
Tetracyclic Core

In this present work, we are reporting a novel route for the synthesis of the tetracyclic ring systems, which is a common core of crinipellin via oxidative dearomatization, cycloaddition and oxa- di-pi-methane rearrangement. We considered to exploring a route to tetracyclic core (1e) of Crinipellin and tricyclic core (1g) of Allicaol B through intermolecular diels alder reaction and photochemically 1,2 acyl shift. Moreover, docking study of compound 13 and 16has been investigated against AcrB multidrug efflux pump of Escherichia coli (PDB ID: 1T9U), main protease of SARS COV-2 (PDB ID: 6W63), DNA gyrase of Streptococcus pneumonia (PDB ID: 4Z2C), human estrogen receptor alpha (PDB ID: 3ERT), human lanosterol 14-alpha-demethylase (CYP51)(PDB ID: 3JUS) and cyclooxygenase-2 (Prostaglandin Synthase-2) (PDB ID: 1CX2). The obtained results herein are important for the exploitation of the therapeutic potential of these derivatives as antimicrobial, antiviral, anticancer, antifungal or anti-inflammatory agents.

scholarly journals Multiple cis-Acting Sequences Mediate Upregulation of the MDR1 Efflux Pump in a Fluconazole-Resistant Clinical Candida albicans Isolate

2006 ◽  
Vol 50 (7) ◽  
pp. 2300-2308 ◽  
Author(s):  
Davina Hiller ◽  
Stephanie Stahl ◽  
Joachim Morschhäuser
Keyword(s):  
Candida Albicans ◽  
Transcription Factors ◽  
Efflux Pump ◽  
Regulatory Region ◽  
Laboratory Strain ◽  
Major Facilitator Superfamily ◽  
Metabolic Inhibitors ◽  
Multidrug Efflux Pump ◽  
Promoter Deletion Analysis ◽  
Major Facilitator

ABSTRACT Overexpression of the MDR1 gene, which encodes a multidrug efflux pump of the major facilitator superfamily, is a frequent cause of resistance to the antimycotic agent fluconazole and other metabolic inhibitors in clinical Candida albicans strains. Constitutive MDR1 overexpression in such strains is caused by mutations in as yet unknown trans-regulatory factors. In order to identify the cis-acting sequences in the MDR1 regulatory region that mediate constitutive MDR1 upregulation, we performed a promoter deletion analysis in the genetic background of an MDR1-overexpressing clinical C. albicans isolate. We found that several different regions in the MDR1 promoter can mediate MDR1 overexpression in this isolate. In contrast, deletion of one of these regions abolished benomyl-induced MDR1 expression in a C. albicans laboratory strain. These results suggest that multiple transcription factors control expression of the MDR1 efflux pump in C. albicans and that the mutation(s) that causes constitutive MDR1 overexpression and drug resistance in clinical C. albicans isolates affects the activities of several of these transcription factors.

scholarly journals Regulatory Regions of smeDEF in Stenotrophomonas maltophilia Strains Expressing Different Amounts of the Multidrug Efflux Pump SmeDEF

2004 ◽  
Vol 48 (6) ◽  
pp. 2274-2276 ◽  
Author(s):  
Patricia Sanchez ◽  
Ana Alonso ◽  
Jose L. Martinez
Keyword(s):  
Transcription Factors ◽  
Stenotrophomonas Maltophilia ◽  
Efflux Pump ◽  
Multidrug Efflux ◽  
Multidrug Efflux Pump ◽  
Regulatory Regions

ABSTRACT The smeT-smeDEF region and the smeT gene, which encodes the smeDEF repressor, are highly polymorphic. Few changes in smeT might be associated with smeDEF overexpression. The results obtained with cellular extracts suggest that mutant SmeT proteins cannot bind to the operator and that other transcription factors besides SmeT are involved in the regulation of smeDEF expression.

scholarly journals Nuclear receptors: from molecular mechanisms to therapeutics

2021 ◽  
Vol 65 (6) ◽  
pp. 847-856
Author(s):  
Daniel E. Frigo ◽  
Maria Bondesson ◽  
Cecilia Williams
Keyword(s):  
Transcription Factors ◽  
Nuclear Receptors ◽  
Molecular Mechanisms ◽  
Hormone Receptors ◽  
Inflammatory Diseases ◽  
Deep Understanding ◽  
Standard Of Care ◽  
Aging Brain ◽  
Disease States ◽  
Prostate Cancers

Abstract Nuclear receptors are classically defined as ligand-activated transcription factors that regulate key functions in reproduction, development, and physiology. Humans have 48 nuclear receptors, which when dysregulated are often linked to diseases. Because most nuclear receptors can be selectively activated or inactivated by small molecules, they are prominent therapeutic targets. The basic understanding of this family of transcription factors was accelerated in the 1980s upon the cloning of the first hormone receptors. During the next 20 years, a deep understanding of hormone signaling was achieved that has translated to numerous clinical applications, such as the development of standard-of-care endocrine therapies for hormonally driven breast and prostate cancers. A 2004 issue of this journal reviewed progress on elucidating the structures of nuclear receptors and their mechanisms of action. In the current issue, we focus on the broad application of new knowledge in this field for therapy across diverse disease states including cancer, cardiovascular disease, various inflammatory diseases, the aging brain, and COVID-19.

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