Comparative Molecular Mechanisms of Biosynthesis of Naringenin and Related Chalcones in Actinobacteria and Plants: Relevance for the Obtention of Potent Bioactive Metabolites

Naringenin and its glycosylated derivative naringin are flavonoids that are synthesized by the phenylpropanoid pathway in plants. We found that naringenin is also formed by the actinobacterium Streptomyces clavuligerus, a well-known microorganism used to industrially produce clavulanic acid. The production of naringenin in S. clavuligerus involves a chalcone synthase that uses p-coumaric as a starter unit and a P450 monoxygenase, encoded by two adjacent genes (ncs-ncyP). The p-coumaric acid starter unit is formed by a tyrosine ammonia lyase encoded by an unlinked, tal, gene. Deletion and complementation studies demonstrate that these three genes are required for biosynthesis of naringenin in S. clavuligerus. Other actinobacteria chalcone synthases use caffeic acid, ferulic acid, sinapic acid or benzoic acid as starter units in the formation of different antibiotics and antitumor agents. The biosynthesis of naringenin is restricted to a few Streptomycess species and the encoding gene cluster is present also in some Saccharotrix and Kitasatospora species. Phylogenetic comparison of S. clavuligerus naringenin chalcone synthase with homologous proteins of other actinobacteria reveal that this protein is closely related to chalcone synthases that use malonyl-CoA as a starter unit for the formation of red-brown pigment. The function of the core enzymes in the pathway, such as the chalcone synthase and the tyrosine ammonia lyase, is conserved in plants and actinobacteria. However, S. clavuligerus use a P450 monooxygenase proposed to complete the cyclization step of the naringenin chalcone, whereas this reaction in plants is performed by a chalcone isomerase. Comparison of the plant and S. clavuligerus chalcone synthases indicates that they have not been transmitted between these organisms by a recent horizontal gene transfer phenomenon. We provide a comprehensive view of the molecular genetics and biochemistry of chalcone synthases and their impact on the development of antibacterial and antitumor compounds. These advances allow new bioactive compounds to be obtained using combinatorial strategies. In addition, processes of heterologous expression and bioconversion for the production of naringenin and naringenin-derived compounds in yeasts are described.

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Fishing for Targets of Alien Metabolites: A Novel Peroxisome Proliferator-Activated Receptor (PPAR) Agonist from a Marine Pest

Marine Drugs ◽

10.3390/md16110431 ◽

2018 ◽

Vol 16 (11) ◽

pp. 431 ◽

Cited By ~ 12

Author(s):

Rosa Vitale ◽

Enrico D'Aniello ◽

Stefania Gorbi ◽

Andrea Martella ◽

Cristoforo Silvestri ◽

...

Keyword(s):

Native Species ◽

Molecular Mechanisms ◽

Ex Vivo ◽

Invasion Biology ◽

In Vitro Assays ◽

Bioactive Metabolites ◽

Peroxisome Proliferator ◽

Invasive Pests

Although the chemical warfare between invasive and native species has become a central problem in invasion biology, the molecular mechanisms by which bioactive metabolites from invasive pests influence local communities remain poorly characterized. This study demonstrates that the alkaloid caulerpin (CAU)—a bioactive component of the green alga Caulerpa cylindracea that has invaded the entire Mediterranean basin—is an agonist of peroxisome proliferator-activated receptors (PPARs). Our interdisciplinary study started with the in silico prediction of the ligand-protein interaction, which was then validated by in vivo, ex vivo and in vitro assays. On the basis of these results, we candidate CAU as a causal factor of the metabolic and behavioural disorders observed in Diplodus sargus, a native edible fish of high ecological and commercial relevance, feeding on C. cylindracea. Moreover, given the considerable interest in PPAR activators for the treatment of relevant human diseases, our findings are also discussed in terms of a possible nutraceutical/pharmacological valorisation of the invasive algal biomasses, supporting an innovative strategy for conserving biodiversity as an alternative to unrealistic campaigns for the eradication of invasive pests.

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New Insights on the Effects of Dietary Omega-3 Fatty Acids on Impaired Skin Healing in Diabetes and Chronic Venous Leg Ulcers

Foods ◽

10.3390/foods10102306 ◽

2021 ◽

Vol 10 (10) ◽

pp. 2306

Author(s):

Simona Serini ◽

Gabriella Calviello

Keyword(s):

Fatty Acids ◽

Molecular Mechanisms ◽

Current Knowledge ◽

Healing Process ◽

Vascular Diseases ◽

Lower Limbs ◽

Bioactive Metabolites ◽

Omega 3 ◽

Patients With Diabetes ◽

Skin Healing

Long-chain Omega-3 polyunsaturated fatty acids (Omega-3 PUFAs) are widely recognized as powerful negative regulators of acute inflammation. However, the precise role exerted by these dietary compounds during the healing process is still largely unknown, and there is increasing interest in understanding their specific effects on the implicated cells/molecular factors. Particular attention is being focused also on their potential clinical application in chronic pathologies characterized by delayed and impaired healing, such as diabetes and vascular diseases in lower limbs. On these bases, we firstly summarized the current knowledge on wound healing (WH) in skin, both in normal conditions and in the setting of these two pathologies, with particular attention to the cellular and molecular mechanisms involved. Then, we critically reviewed the outcomes of recent research papers investigating the activity exerted by Omega-3 PUFAs and their bioactive metabolites in the regulation of WH in patients with diabetes or venous insufficiency and showing chronic recalcitrant ulcers. We especially focused on recent studies investigating the mechanisms through which these compounds may act. Considerations on the optimal dietary doses are also reported, and, finally, possible future perspectives in this area are suggested.

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The Genetic Regulation of Secondary Metabolic Pathways in Response to Salinity and Drought as Abiotic Stresses

Applied Sciences ◽

10.3390/app11156668 ◽

2021 ◽

Vol 11 (15) ◽

pp. 6668

Author(s):

Sameer Hasan Qari ◽

Ibrahim Tarbiyyah

Keyword(s):

Complex System ◽

Secondary Metabolite ◽

Abiotic Stresses ◽

Molecular Mechanisms ◽

Secondary Metabolite Production ◽

Bioactive Metabolites ◽

Biosynthetic Pathways ◽

Plant Genomics ◽

Metabolite Production ◽

The Relationship

Global development has generated a plethora of unfavorable and adverse environmental factors for the living organisms in the ecosystem. Plants are sessile organisms, and they are crucial to sustain life on earth. Since plants are sessile, they face a great number of environmental challenges related to abiotic stresses, such as temperature fluctuation, drought, salinity, flood and metal contamination. Salinity and drought are considered major abiotic stresses that negatively affect the plants’ growth and production of useful content. However, plants have evolved various molecular mechanisms to increase their tolerance to these environmental stresses. There is a whole complex system of communication (cross-talk) through massive signaling cascades that are activated and modulated in response to salinity and drought. Secondary metabolites are believed to play significant roles in the plant’s response and resistance to salinity and drought stress. Until recently, attempts to unravel the biosynthetic pathways were limited mainly due to the inadequate plant genomics resources. However, recent advancements in generating high-throughput “omics” datasets, computational tools and functional genomics approach integration have aided in the elucidation of biosynthetic pathways of many plant bioactive metabolites. This review gathers comprehensive knowledge of plants’ complex system that is involved in the response and resistance to salinity and water deficit stresses as abiotic stress. Additionally, it offers clues in determining the genes involved in this complex and measures its activity. It covers basic information regarding the signaling molecules involved in salinity and drought resistance and how plant hormones regulate the cross-talking mechanism with emphasis on transcriptional activity. Moreover, it discusses many studies that illustrate the relationship between salinity and drought and secondary metabolite production. Furthermore, several transcriptome analysis research papers of medicinal plants are illustrated. The aim of this review is to be a key for any researcher that is aspiring to study the relationship between salinity and drought stresses and secondary metabolite production at the transcriptome and transcription level.

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Anticancer and Antioxidant Activities of Some Algae from Western Libyan Coast

10.20944/preprints201609.0018.v1 ◽

2016 ◽

Author(s):

Rabia Alghazeer ◽

Mahboba Enaeli ◽

Nazlin K. Howell

Keyword(s):

Cell Cycle ◽

Cell Proliferation ◽

Antioxidant Activity ◽

Molecular Mechanisms ◽

Antioxidant Activities ◽

Morphological Changes ◽

Reducing Power ◽

Bioactive Metabolites ◽

Anticancer Activities ◽

Hypnea Musciformis

Seaweeds are considered as one of the largest biomass producers in marine environment that is rich in bioactive metabolites and a source of natural ingredients for functional foods. The potential antioxidant activity and the potential inhibition of Caco2 cell proliferation, of crude extracts of: Chlorophyta (Ulva lactuca, and Codium tomentosum), Phaeophyta (Cystoseira crinita, Cystoseira stricta, and Sargassum vulgare), and Rhodophyta (Gelidium latifolium, Hypnea musciformis, and Jania rubens) collected from western Libyan coast were evaluated in vitro. The antioxidant activity was determined by reducing power and DPPH assays while cell proliferation, morphological changes and the cell cycle arrest were assessed by MTT, inverted light microscope and flow cytometry methods respectively. The polyphenols and flavonoids rich extracts showed remarkable reducing power and antiradical properties. After exposure of Caco2 cells to; various concentrations of extracts (50, 100,150 and 200 µg/mL) especially from brown algae for 72 h, significantly reduced cell proliferation. The antiproliferative effect of algae extracts was correlated with their polyphenol and flavonoid contents. Cell cycle analysis further showed that cells were arrested in G phases along with an increment in sub-diploidal cell population (sub-G) after extract application. These results imply that seaweeds which are rich in bioactive compounds may be in anticancer drug research programs. However, further investigations are essential to reveal the molecular mechanisms of the anticancer activities of these algae.

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Marine Natural Products: A Source of Novel Anticancer Drugs

Marine Drugs ◽

10.3390/md17090491 ◽

2019 ◽

Vol 17 (9) ◽

pp. 491 ◽

Cited By ~ 46

Author(s):

Shaden A. M. Khalifa ◽

Nizar Elias ◽

Mohamed A. Farag ◽

Lei Chen ◽

Aamer Saeed ◽

...

Keyword(s):

Natural Products ◽

Anticancer Drugs ◽

Marine Natural Products ◽

Molecular Mechanisms ◽

Biological Effects ◽

Marine Organisms ◽

New Drugs ◽

Bioactive Metabolites ◽

Chemical Structures ◽

The Impact

Cancer remains one of the most lethal diseases worldwide. There is an urgent need for new drugs with novel modes of action and thus considerable research has been conducted for new anticancer drugs from natural sources, especially plants, microbes and marine organisms. Marine populations represent reservoirs of novel bioactive metabolites with diverse groups of chemical structures. This review highlights the impact of marine organisms, with particular emphasis on marine plants, algae, bacteria, actinomycetes, fungi, sponges and soft corals. Anti-cancer effects of marine natural products in in vitro and in vivo studies were first introduced; their activity in the prevention of tumor formation and the related compound-induced apoptosis and cytotoxicities were tackled. The possible molecular mechanisms behind the biological effects are also presented. The review highlights the diversity of marine organisms, novel chemical structures, and chemical property space. Finally, therapeutic strategies and the present use of marine-derived components, its future direction and limitations are discussed.

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Isolation and Characterization of Three Chalcone Synthase Genes in Pecan (Carya illinoinensis)

Biomolecules ◽

10.3390/biom9060236 ◽

2019 ◽

Vol 9 (6) ◽

pp. 236 ◽

Cited By ~ 3

Author(s):

Zhang ◽

Yao ◽

Ren ◽

Wang ◽

Chang

Keyword(s):

Molecular Mechanisms ◽

Chalcone Synthase ◽

Phenolic Content ◽

Plant Secondary Metabolites ◽

Resistance Breeding ◽

Carya Illinoinensis ◽

Total Phenolic ◽

Phenolic Metabolism ◽

Isolation And Characterization ◽

Phenolic Components

Phenolics are a group of important plant secondary metabolites that have been proven to possess remarkable antioxidant activity and to be beneficial for human health. Pecan nuts are an excellent source of dietary phenolics. In recent years, many studies have focused on the separation and biochemical analysis of pecan phenolics, but the molecular mechanisms of phenolic metabolism in pecans have not been fully elucidated, which significantly hinders quality breeding research for this plant. Chalcone synthase (CHS) plays crucial roles in phenolic biosynthesis. In this study, three Carya illinoinensis CHSs (CiCHS1, CiCHS2, and CiCHS3), were isolated and analyzed. CiCHS2 and CiCHS3 present high expression levels in different tissues, and they are also highly expressed at the initial developmental stages of kernels in three pecan genotypes. A correlation analysis was performed between the phenolic content and CHSs expression values during kernel development. The results indicated that the expression variations of CiCHS2 and CiCHS3 are significantly related to changes in total phenolic content. Therefore, CiCHSs play crucial roles in phenolic components synthesis in pecan. We believe that the isolation of CiCHSs is helpful for understanding phenolic metabolism in C. illinoinensis, which will improve quality breeding and resistance breeding studies in this plant.

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The Circadian Protein PER1 Modulates the Cellular Response to Anticancer Treatments

International Journal of Molecular Sciences ◽

10.3390/ijms22062974 ◽

2021 ◽

Vol 22 (6) ◽

pp. 2974

Author(s):

Marina Maria Bellet ◽

Claudia Stincardini ◽

Claudio Costantini ◽

Marco Gargaro ◽

Stefania Pieroni ◽

...

Keyword(s):

Circadian Rhythms ◽

Circadian Clock ◽

Cancer Cells ◽

Cellular Response ◽

Molecular Mechanisms ◽

Antitumor Agents ◽

Pharmacological Therapy ◽

Drug Induced

The circadian clock driven by the daily light–dark and temperature cycles of the environment regulates fundamental physiological processes and perturbations of these sophisticated mechanisms may result in pathological conditions, including cancer. While experimental evidence is building up to unravel the link between circadian rhythms and tumorigenesis, it is becoming increasingly apparent that the response to antitumor agents is similarly dependent on the circadian clock, given the dependence of each drug on the circadian regulation of cell cycle, DNA repair and apoptosis. However, the molecular mechanisms that link the circadian machinery to the action of anticancer treatments is still poorly understood, thus limiting the application of circadian rhythms-driven pharmacological therapy, or chronotherapy, in the clinical practice. Herein, we demonstrate the circadian protein period 1 (PER1) and the tumor suppressor p53 negatively cross-regulate each other’s expression and activity to modulate the sensitivity of cancer cells to anticancer treatments. Specifically, PER1 physically interacts with p53 to reduce its stability and impair its transcriptional activity, while p53 represses the transcription of PER1. Functionally, we could show that PER1 reduced the sensitivity of cancer cells to drug-induced apoptosis, both in vitro and in vivo in NOD scid gamma (NSG) mice xenotransplanted with a lung cancer cell line. Therefore, our results emphasize the importance of understanding the relationship between the circadian clock and tumor regulatory proteins as the basis for the future development of cancer chronotherapy.

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New Drugs from the Sea: Pro-Apoptotic Activity of Sponges and Algae Derived Compounds

Marine Drugs ◽

10.3390/md17010031 ◽

2019 ◽

Vol 17 (1) ◽

pp. 31 ◽

Cited By ~ 19

Author(s):

Giuseppe Ercolano ◽

Paola De Cicco ◽

Angela Ianaro

Keyword(s):

Molecular Mechanisms ◽

Human Cancer ◽

Biological Activities ◽

Mitochondrial Pathway ◽

Marine Organisms ◽

New Drugs ◽

Bioactive Molecules ◽

Bioactive Metabolites ◽

Apoptotic Activity

Natural compounds derived from marine organisms exhibit a wide variety of biological activities. Over the last decades, a great interest has been focused on the anti-tumour role of sponges and algae that constitute the major source of these bioactive metabolites. A substantial number of chemically different structures from different species have demonstrated inhibition of tumour growth and progression by inducing apoptosis in several types of human cancer. The molecular mechanisms by which marine natural products activate apoptosis mainly include (1) a dysregulation of the mitochondrial pathway; (2) the activation of caspases; and/or (3) increase of death signals through transmembrane death receptors. This great variety of mechanisms of action may help to overcome the multitude of resistances exhibited by different tumour specimens. Therefore, products from marine organisms and their synthetic derivates might represent promising sources for new anticancer drugs, both as single agents or as co-adjuvants with other chemotherapeutics. This review will focus on some selected bioactive molecules from sponges and algae with pro-apoptotic potential in tumour cells.

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Extremophilic Fungi from Marine Environments: Underexplored Sources of Antitumor, Anti-Infective and Other Biologically Active Agents

Marine Drugs ◽

10.3390/md20010062 ◽

2022 ◽

Vol 20 (1) ◽

pp. 62

Author(s):

Lesley-Ann Giddings ◽

David J. Newman

Keyword(s):

Natural Products ◽

Antitumor Agents ◽

Marine Fungi ◽

Gene Clusters ◽

Biologically Active ◽

Bioactive Metabolites ◽

Marine Environments ◽

Environmental Pressures ◽

Symbiotic Associations ◽

Extremophilic Fungi

Marine environments are underexplored terrains containing fungi that produce a diversity of natural products given unique environmental pressures and nutrients. While bacteria are commonly the most studied microorganism for natural products in the marine world, marine fungi are also abundant but remain an untapped source of bioactive metabolites. Given that their terrestrial counterparts have been a source of many blockbuster antitumor agents and anti-infectives, including camptothecin, the penicillins, and cyclosporin A, marine fungi also have the potential to produce new chemical scaffolds as leads to potential drugs. Fungi are more phylogenetically diverse than bacteria and have larger genomes that contain many silent biosynthetic gene clusters involved in making bioactive compounds. However, less than 5% of all known fungi have been cultivated under standard laboratory conditions. While the number of reported natural products from marine fungi is steadily increasing, their number is still significantly lower compared to those reported from their bacterial counterparts. Herein, we discuss many varied cytotoxic and anti-infective fungal metabolites isolated from extreme marine environments, including symbiotic associations as well as extreme pressures, temperatures, salinity, and light. We also discuss cultivation strategies that can be used to produce new bioactive metabolites or increase their production. This review presents a large number of reported structures though, at times, only a few of a large number of related structures are shown.

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Gossypol Suppresses Growth of Temozolomide-Resistant Glioblastoma Tumor Spheres

Biomolecules ◽

10.3390/biom9100595 ◽

2019 ◽

Vol 9 (10) ◽

pp. 595 ◽

Cited By ~ 7

Author(s):

Kim ◽

Lee ◽

Jeon ◽

Kim ◽

Kang ◽

...

Keyword(s):

Molecular Mechanisms ◽

Antitumor Agents ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Culture Conditions ◽

First Line ◽

Tumor Sphere ◽

Adherent Culture ◽

Binding Energy Calculations ◽

Similar Affinity

Temozolomide is the current first-line treatment for glioblastoma patients but, because many patients are resistant to it, there is an urgent need to develop antitumor agents to treat temozolomide-resistant glioblastoma. Gossypol, a natural polyphenolic compound, has been studied as a monotherapy or combination therapy for the treatment of glioblastoma. The combination of gossypol and temozolomide has been shown to inhibit glioblastoma, but it is not clear yet whether gossypol alone can suppress temozolomide-resistant glioblastoma. We find that gossypol suppresses the growth of temozolomide-resistant glioblastoma cells in both tumor sphere and adherent culture conditions, with tumor spheres showing the greatest sensitivity. Molecular docking and binding energy calculations show that gossypol has a similar affinity to the Bcl2 (B-cell lymphoma 2) family of proteins and several dehydrogenases. Gossypol reduces mitochondrial membrane potential and cellular ATP levels before cell death, which suggests that gossypol inhibits several dehydrogenases in the cell’s metabolic pathway. Treatment with a Bcl2 inhibitor does not fully explain the effect of gossypol on glioblastoma. Overall, this study demonstrates that gossypol can suppress temozolomide-resistant glioblastoma and will be helpful for the refinement of gossypol treatments by elucidating some of the molecular mechanisms of gossypol in glioblastoma.

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