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FEMS Microbiology Reviews Jul 2010Bacteria can utilize signal molecules to coordinate their behavior to survive in dynamic multispecies communities. Indole is widespread in the natural environment, as a... (Review)
Review
Bacteria can utilize signal molecules to coordinate their behavior to survive in dynamic multispecies communities. Indole is widespread in the natural environment, as a variety of both Gram-positive and Gram-negative bacteria (to date, 85 species) produce large quantities of indole. Although it has been known for over 100 years that many bacteria produce indole, the real biological roles of this molecule are only now beginning to be unveiled. As an intercellular signal molecule, indole controls diverse aspects of bacterial physiology, such as spore formation, plasmid stability, drug resistance, biofilm formation, and virulence in indole-producing bacteria. In contrast, many non-indole-producing bacteria, plants and animals produce diverse oxygenases which may interfere with indole signaling. It appears indole plays an important role in bacterial physiology, ecological balance, and possibly human health. Here we discuss our current knowledge and perspectives on indole signaling.
Topics: Bacteria; Bacterial Physiological Phenomena; Biofilms; Drug Resistance, Bacterial; Gene Expression Regulation, Bacterial; Indoles; Plasmids; Quorum Sensing; Signal Transduction; Virulence
PubMed: 20070374
DOI: 10.1111/j.1574-6976.2009.00204.x -
Gut Microbes Nov 2020Commensal microbiota-dependent tryptophan catabolism within the gastrointestinal tract is known to exert profound effects upon host physiology, including the maintenance...
Commensal microbiota-dependent tryptophan catabolism within the gastrointestinal tract is known to exert profound effects upon host physiology, including the maintenance of epithelial barrier and immune function. A number of abundant microbiota-derived tryptophan metabolites exhibit activation potential for the aryl hydrocarbon receptor (AHR). Gene expression facilitated by AHR activation through the presence of dietary or microbiota-generated metabolites can influence gastrointestinal homeostasis and confer protection from intestinal challenges. Utilizing untargeted mass spectrometry-based metabolomics profiling, combined with AHR activity screening assays, we identify four previously unrecognized tryptophan metabolites, present in mouse cecal contents and human stool, with the capacity to activate AHR. Using GC/MS and LC/MS platforms, quantification of these novel AHR activators, along with previously established AHR-activating tryptophan metabolites, was achieved, providing a relative order of abundance. Using physiologically relevant concentrations and quantitative gene expression analyses, the relative efficacy of these tryptophan metabolites with regard to mouse or human AHR activation potential is examined. These data reveal indole, 2-oxindole, indole-3-acetic acid and kynurenic acid as the dominant AHR activators in mouse cecal contents and human stool from participants on a controlled diet. Here we provide the first documentation of the relative abundance and AHR activation potential of a panel of microbiota-derived tryptophan metabolites. Furthermore, these data reveal the human AHR to be more sensitive, at physiologically relevant concentrations, to tryptophan metabolite activation than mouse AHR. Additionally, correlation analyses indicate a relationship linking major tryptophan metabolite abundance with AHR activity, suggesting these cecal/fecal metabolites represent biomarkers of intestinal AHR activity.
Topics: Animals; Basic Helix-Loop-Helix Transcription Factors; Cecum; Diet; Feces; Gastrointestinal Microbiome; Gastrointestinal Tract; Humans; Indoleacetic Acids; Indoles; Kynurenic Acid; Mice; Mice, Inbred C57BL; Receptors, Aryl Hydrocarbon; Signal Transduction; Tryptophan
PubMed: 32783770
DOI: 10.1080/19490976.2020.1788899 -
Cell Reports Jul 2023Cryptosporidiosis is a leading cause of life-threatening diarrhea in young children in resource-poor settings. To explore microbial influences on susceptibility, we...
Cryptosporidiosis is a leading cause of life-threatening diarrhea in young children in resource-poor settings. To explore microbial influences on susceptibility, we screened 85 microbiota-associated metabolites for their effects on Cryptosporidium parvum growth in vitro. We identify eight inhibitory metabolites in three main classes: secondary bile salts/acids, a vitamin B precursor, and indoles. Growth restriction of C. parvum by indoles does not depend on the host aryl hydrocarbon receptor (AhR) pathway. Instead, treatment impairs host mitochondrial function and reduces total cellular ATP, as well as directly reducing the membrane potential in the parasite mitosome, a degenerate mitochondria. Oral administration of indoles, or reconstitution of the gut microbiota with indole-producing bacteria, delays life cycle progression of the parasite in vitro and reduces the severity of C. parvum infection in mice. Collectively, these findings indicate that microbiota metabolites impair mitochondrial function and contribute to colonization resistance to Cryptosporidium infection.
Topics: Animals; Mice; Cryptosporidium parvum; Cryptosporidiosis; Cryptosporidium; Microbiota; Mitochondria; Indoles
PubMed: 37384526
DOI: 10.1016/j.celrep.2023.112680 -
Molecules (Basel, Switzerland) Nov 2016Indole phytoalexins from crucifers have been shown to exhibit significant anti-cancer, chemopreventive, and antiproliferative activity. Phytoalexins are natural low... (Review)
Review
Indole phytoalexins from crucifers have been shown to exhibit significant anti-cancer, chemopreventive, and antiproliferative activity. Phytoalexins are natural low molecular antimicrobial compounds that are synthesized and accumulated in plants after their exposure to pathogenic microorganisms. Most interestingly, crucifers appear to be the only plant family producing sulfur-containing indole phytoalexins. The mechanisms underlying its anti-cancer properties are unknown. Isolation from cruciferous plants does not provide sufficient quantities of indole phytoalexins and, for biological screening, they are usually obtainable through synthesis. Understanding the molecular mechanism of the action of these substances and their structure-activity relationships is quite important in the development of new analogs with a more favorable profile of biological activities. In this review, we present the key features of indole phytoalexins, mainly their antiproliferative ativities.
Topics: Brassicaceae; Cell Proliferation; Humans; Indoles; Molecular Structure; Sesquiterpenes; Tumor Cells, Cultured; Phytoalexins
PubMed: 27898039
DOI: 10.3390/molecules21121626 -
Molecules (Basel, Switzerland) Mar 2022Considering the potential bioactivities of natural product and natural product-like compounds with highly complex and diverse structures, the screening of collections... (Review)
Review
Considering the potential bioactivities of natural product and natural product-like compounds with highly complex and diverse structures, the screening of collections and small-molecule libraries for high-throughput screening (HTS) and high-content screening (HCS) has emerged as a powerful tool in the development of novel therapeutic agents. Herein, we review the recent advances in divergent synthetic approaches such as complexity-to-diversity (Ctd) and biomimetic strategies for the generation of structurally complex and diverse indole-based natural product and natural product-like small-molecule libraries.
Topics: Biological Products; Indoles; Small Molecule Libraries
PubMed: 35408569
DOI: 10.3390/molecules27072171 -
Organic & Biomolecular Chemistry Apr 2013Indole is a heterocycle of great importance to biological systems and materials applications. Synthesis of indole and its derivatives has been a major focus of research... (Review)
Review
Indole is a heterocycle of great importance to biological systems and materials applications. Synthesis of indole and its derivatives has been a major focus of research for over a century. BN/CC isosterism is an emerging strategy for expanding the structural diversity of indole-based compounds. Two classes of BN indoles have been reported to date: the well-studied "external" BN indoles (or 1,3,2-benzodiazaborolines), and the recently reported "fused" BN indoles. This perspective presents the history of both classes of indole isosteres, with a general overview of their synthesis, functionalization, and properties.
Topics: Indoles; Models, Molecular; Molecular Structure; Stereoisomerism
PubMed: 23403937
DOI: 10.1039/c3ob27436e -
Frontiers in Endocrinology 2022The increasing prevalence of metabolic syndrome has become a serious public health problem. Certain bacteria-derived metabolites play a key role in maintaining human... (Review)
Review
The increasing prevalence of metabolic syndrome has become a serious public health problem. Certain bacteria-derived metabolites play a key role in maintaining human health by regulating the host metabolism. Recent evidence shows that indole-3-propionic acid content can be used to predict the occurrence and development of metabolic diseases. Supplementing indole-3-propionic acid can effectively improve metabolic disorders and is considered a promising metabolite. Therefore, this article systematically reviews the latest research on indole-3-propionic acid and elaborates its source of metabolism and its association with metabolic diseases. Indole-3-propionic acid can improve blood glucose and increase insulin sensitivity, inhibit liver lipid synthesis and inflammatory factors, correct intestinal microbial disorders, maintain the intestinal barrier, and suppress the intestinal immune response. The study of the mechanism of the metabolic benefits of indole-3-propionic acid is expected to be a potential compound for treating metabolic syndrome.
Topics: Humans; Indoles; Insulin Resistance; Intestines; Propionates
PubMed: 35370963
DOI: 10.3389/fendo.2022.841703 -
Molecules (Basel, Switzerland) Feb 2023The ocean has always been one of the important sources of natural products. In recent years, many natural products with different structures and biological activities... (Review)
Review
The ocean has always been one of the important sources of natural products. In recent years, many natural products with different structures and biological activities have been obtained, and their value has been clearly recognized. Researchers have been deeply engaged in the field of separation and extraction, derivative synthesis, structural studies, biological evaluation, and other fields of research for marine natural products. Thus, a series of marine indole natural products which have structural and biological prospect have caught our eyes. In this review, we summarize some of these marine indole natural products with relatively good pharmacological activity and research value, and discuss issues concerning chemistry, pharmacological activity, biological evaluation, and synthesis, including monomeric indoles, indole peptides, bis-indoles, and annelated indoles. Most of the compounds have cytotoxic, antiviral, antifungal, or anti-inflammatory activities.
Topics: Biological Products; Indoles; Antiviral Agents; Antineoplastic Agents
PubMed: 36903451
DOI: 10.3390/molecules28052204 -
Molecules (Basel, Switzerland) May 2024Neurodegeneration is a gradual decay process leading to the depletion of neurons in both the central and peripheral nervous systems, ultimately resulting in cognitive... (Review)
Review
Neurodegeneration is a gradual decay process leading to the depletion of neurons in both the central and peripheral nervous systems, ultimately resulting in cognitive dysfunctions and the deterioration of brain functions, alongside a decline in motor skills and behavioral capabilities. Neurodegenerative disorders (NDs) impose a substantial socio-economic strain on society, aggravated by the advancing age of the world population and the absence of effective remedies, predicting a negative future. In this context, the urgency of discovering viable therapies is critical and, despite significant efforts by medicinal chemists in developing potential drug candidates and exploring various small molecules as therapeutics, regrettably, a truly effective treatment is yet to be found. Nitrogen heterocyclic compounds, and particularly those containing the indole nucleus, which has emerged as privileged scaffold, have attracted particular attention for a variety of pharmacological applications. This review analyzes the rational design strategy adopted by different research groups for the development of anti-neurodegenerative indole-based compounds which have the potential to modulate various molecular targets involved in NDs, with reference to the most recent advances between 2018 and 2023.
Topics: Humans; Indoles; Neurodegenerative Diseases; Animals; Neuroprotective Agents
PubMed: 38731618
DOI: 10.3390/molecules29092127 -
Drug Design, Development and Therapy 2020Malaria remains a global public health problem due to the uphill fight against the causative parasites that are relentless in developing resistance. Indole-based... (Review)
Review
Malaria remains a global public health problem due to the uphill fight against the causative parasites that are relentless in developing resistance. Indole-based antiplasmodial compounds are endowed with multiple modes of action, of which inhibition of hemozoin formation is the major mechanism of action reported for compounds such as cryptolepine, flinderoles, and isosungucine. Indole-based compounds exert their potent activity against chloroquine-resistant strains by inhibiting hemozoin formation in a mode of action different from that of chloroquine or through a novel mechanism of action. For example, dysregulating the sodium and osmotic homeostasis of through inhibition of PfATP4 is the novel mechanism of cipargamin. The potential of developing multi-targeted compounds through molecular hybridization ensures the existence of indole-based compounds in the antimalarial pipeline.
Topics: Antimalarials; Calcium-Transporting ATPases; Enzyme Inhibitors; Humans; Indoles; Malaria, Falciparum; Parasitic Sensitivity Tests; Plasmodium falciparum
PubMed: 33204071
DOI: 10.2147/DDDT.S278588