ABSTRACT
Rhein, a component derived from rhubarb, has been proven to possess anti-inflammatory properties. Here, we show that rhein mitigates obesity by promoting adipose tissue thermogenesis in diet-induced obese mice. We construct a macrophage-adipocyte co-culture system and demonstrate that rhein promotes adipocyte thermogenesis through inhibiting NLRP3 inflammasome activation in macrophages. Moreover, clues from acetylome analysis identify SIRT2 as a potential drug target of rhein. We further verify that rhein directly interacts with SIRT2 and inhibits NLRP3 inflammasome activation in a SIRT2-dependent way. Myeloid knockdown of SIRT2 abrogates adipose tissue thermogenesis and metabolic benefits in obese mice induced by rhein. Together, our findings elucidate that rhein inhibits NLRP3 inflammasome activation in macrophages by regulating SIRT2, and thus promotes white adipose tissue thermogenesis during obesity. These findings uncover the molecular mechanism underlying the anti-inflammatory and anti-obesity effects of rhein, and suggest that rhein may become a potential drug for treating obesity.
Subject(s)
Anthraquinones , Macrophages , Obesity , Sirtuin 2 , Thermogenesis , Animals , Male , Mice , Adipocytes/drug effects , Adipocytes/metabolism , Adipose Tissue/metabolism , Adipose Tissue/drug effects , Anthraquinones/pharmacology , Inflammasomes/metabolism , Inflammasomes/drug effects , Macrophages/drug effects , Macrophages/metabolism , Mice, Inbred C57BL , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , Obesity/metabolism , Obesity/drug therapy , Sirtuin 2/metabolism , Sirtuin 2/genetics , Thermogenesis/drug effectsABSTRACT
Dye-decolorizing peroxidases (DyPs) belong to a novel superfamily of heme peroxidases that can oxidize recalcitrant compounds. In the current study, the GlDyP2 gene from Ganoderma lucidum was heterologously expressed in Escherichia coli, and the enzymatic properties of the recombinant GlDyP2 protein were investigated. The GlDyP2 protein could oxidize not only the typical peroxidase substrate ABTS but also two lignin substrates, namely guaiacol and 2,6-dimethoxy phenol (DMP). For the ABTS substrate, the optimum pH and temperature of GlDyP2 were 4.0 and 35 °C, respectively. The pH stability and thermal stability of GlDyP2 were also measured; the results showed that GlDyP2 could function normally in the acidic environment, with a T50 value of 51 °C. Moreover, compared to untreated controls, the activity of GlDyP2 was inhibited by 1.60 mM of Mg2+, Ni2+, Mn2+, and ethanol; 0.16 mM of Cu2+, Zn2+, methanol, isopropyl alcohol, and Na2EDTA·2H2O; and 0.016 mM of Fe2+ and SDS. The kinetic constants of recombinant GlDyP2 for oxidizing ABTS, Reactive Blue 19, guaiacol, and DMP were determined; the results showed that the recombination GlDyP2 exhibited the strongest affinity and the most remarkable catalytic efficiency towards guaiacol in the selected substrates. GlDyP2 also exhibited decolorization and detoxification capabilities towards several dyes, including Reactive Blue 19, Reactive Brilliant Blue X-BR, Reactive Black 5, Methyl Orange, Trypan Blue, and Malachite Green. In conclusion, GlDyP2 has good application potential for treating dye wastewater.
Subject(s)
Coloring Agents , Enzyme Stability , Escherichia coli , Guaiacol , Recombinant Proteins , Reishi , Temperature , Coloring Agents/metabolism , Coloring Agents/chemistry , Reishi/genetics , Reishi/enzymology , Reishi/metabolism , Hydrogen-Ion Concentration , Escherichia coli/genetics , Escherichia coli/metabolism , Recombinant Proteins/metabolism , Recombinant Proteins/genetics , Recombinant Proteins/chemistry , Guaiacol/metabolism , Guaiacol/analogs & derivatives , Biodegradation, Environmental , Kinetics , Benzothiazoles/metabolism , Substrate Specificity , Lignin/metabolism , Oxidation-Reduction , Peroxidase/genetics , Peroxidase/metabolism , Peroxidase/chemistry , Fungal Proteins/genetics , Fungal Proteins/metabolism , Fungal Proteins/chemistry , Peroxidases/genetics , Peroxidases/metabolism , Peroxidases/chemistry , Water Pollutants, Chemical/metabolism , Azo Compounds/metabolism , Wastewater/microbiology , Wastewater/chemistry , Sulfonic Acids/metabolism , Anthraquinones , Rosaniline DyesABSTRACT
The biosynthetic pathway of actinorhodin in Streptomyces coelicolor A3(2) has been studied for decades as a model system of type II polyketide biosynthesis. The actinorhodin biosynthetic gene cluster includes a gene, actVI-orfA, that encodes a protein that belongs to the nuclear transport factor-2-like (NTF-2-like) superfamily. The function of this ActVI-ORFA protein has been a long-standing question in this field. Several hypothetical functions, including pyran ring cyclase, enzyme complex stability enhancer, and gene transcription regulator, have been proposed for ActVI-ORFA in previous studies. However, although the recent structural analysis of ActVI-ORFA revealed a solvent-accessible cavity, the protein displayed structural differences to the well-characterized cyclase SnoaL and did not possess a DNA-binding domain. The obtained crystal structure facilitates an inspection of the previous hypotheses regarding the function of ActVI-ORFA. In the present study, we investigated the effects of a series of actVI-orfA test plasmids with different mutations in an established vector/host system. Time-course analysis of dynamic metabolism profiles demonstrated that ActVI-ORFA prevented formation of shunt metabolites and may have a metabolic flux directing function, which shepherds the flux of unstable intermediates towards actinorhodin. The expression studies resulted in the isolation and structure elucidation of two new shunt metabolites from the actinorhodin pathway. Next, we utilized computational modeling to probe the active site of ActVI-ORFA and confirmed the importance of residues R76 and H78 in the flux directing functionality by expression studies. This is the first time such a function has been observed for a member of NTF-2-like superfamily in Streptomyces secondary metabolism.
Subject(s)
Anthraquinones , Bacterial Proteins , Streptomyces coelicolor , Anthraquinones/metabolism , Streptomyces coelicolor/metabolism , Streptomyces coelicolor/genetics , Bacterial Proteins/metabolism , Bacterial Proteins/genetics , Multigene Family , Mutation , BenzoisochromanequinonesABSTRACT
An electrochemical sensor based on an electroactive nanocomposite was designed for the first time consisting of electrochemically reduced graphene oxide (ERGO), polyaniline (PANI), and poly(alizarin red S) (PARS) for ciprofloxacin (CIPF) detection. The ERGO/PANI/PARS-modified screen-printed carbon electrode (SPCE) was constructed through a three-step electrochemical protocol and characterized using FTIR, UV-visible spectroscopy, FESEM, CV, LSV, and EIS. The new electrochemical CIPF sensor demonstrated a low detection limit of 0.0021 µM, a broad linear range of 0.01 to 69.8 µM, a high sensitivity of 5.09 µA/µM/cm2, and reasonable selectivity and reproducibility. Moreover, the ERGO/PANI/PARS/SPCE was successfully utilized to determine CIPF in milk with good recoveries and relative standard deviation (< 5%), which were close to those with HPLC analysis.
Subject(s)
Aniline Compounds , Anthraquinones , Carbon , Ciprofloxacin , Electrochemical Techniques , Electrodes , Graphite , Limit of Detection , Milk , Graphite/chemistry , Milk/chemistry , Aniline Compounds/chemistry , Electrochemical Techniques/methods , Electrochemical Techniques/instrumentation , Animals , Ciprofloxacin/analysis , Carbon/chemistry , Anthraquinones/chemistry , Reproducibility of Results , Food Contamination/analysis , Anti-Bacterial Agents/analysisABSTRACT
The present study explored the potential of leaf litter as a source of fungi able to produce ligninolytic enzymes for the biodegradation of anthraquinone dyes. Within the colonies isolated from the leaf litter, only three colonies of two species Trametes were selected based on the detection of oxidation and decolorization halos in Petri dishes with PDA (potato-dextrose-agar) + Guaicol and PDA + RBBR (Remazol Brilliant Blue R). The identification of the colonies was done through sequencing of the ITS region. The enzymatic activity of Lac (lacase), MnP (manganês peroxidase) and LiP (lignina peroxidase) was analyzed by spectrophotometry during fermentation in PD+RBBR imedium. Isolates A1SSI01 and A1SSI02 were identified as Trametes flavida, while A5SS01 was identified as Trametes sp. Laccase showed the highest enzymatic activity, reaching 452.13 IU.L-1 (A1SSI01, 0.05% RBBR) after 96h. Isolate A1SSI02 reached the highest percentage of decolorization, achieving 89.28% in seven days. The results imply that these Trametes isolates can be highly effective in waste treatment systems containing toxic anthraquinone dyes. Keywords: laccase, peroxidases, basidiomycete, litter and biodecolorization.
Subject(s)
Biodegradation, Environmental , Laccase , Peroxidases , Plant Leaves , Trametes , Plant Leaves/chemistry , Plant Leaves/microbiology , Trametes/enzymology , Peroxidases/metabolism , Laccase/metabolism , Forests , Anthraquinones/metabolism , Coloring Agents , Lignin/metabolism , BrazilABSTRACT
Carrier-free self-assembly has gradually shifted the focus of research on natural products, which effectively improve the bioavailability and the drug-loading rate. However, in spite of the existing studies, the development of self-assembled natural phytochemicals that possess pharmacological effects still has scope for further exploration and enhancement. Herein, a nano-delivery system was fabricated through the direct self-assembly of Rhein and Matrine and was identified as a self-assembled Rhein-Matrine nanoparticles (RM NPs). The morphology of RM NPs was characterized by TEM. The molecular mechanisms of self-assembly were explored using FT-IR, 1H NMR, and molecular dynamics simulation analysis. Gelatin methacryloyl (GelMA) hydrogel was used as a drug carrier for controlled release and targeted delivery of RM NPs. The potential wound repair properties of RM NPs were evaluated on a skin wound-healing model. TEM and dynamic light scattering study demonstrated that the RM NPs were close to spherical, and the average size was approximately 75 nm. 1H NMR of RM NPs demonstrated strong and weak changes in the interaction energies during self-assembly. Further molecular dynamics simulation analysis predicted the self-assembly behavior. An in vivo skin wound-healing model demonstrated that RM NPs present better protection effect against skin damages. Taken together, RM NPs are a new self-assembly system; this may provide new directions for natural product applications.
Subject(s)
Alkaloids , Anthraquinones , Matrines , Molecular Dynamics Simulation , Nanoparticles , Quinolizines , Wound Healing , Alkaloids/chemistry , Alkaloids/pharmacology , Wound Healing/drug effects , Quinolizines/chemistry , Quinolizines/pharmacology , Nanoparticles/chemistry , Anthraquinones/chemistry , Anthraquinones/pharmacology , Animals , Drug Carriers/chemistry , Mice , Hydrogels/chemistry , HumansABSTRACT
The presented study was focused on the simple, eco-friendly synthesis of composite hydrogels of crosslinked carboxymethyl cellulose (CMC)/alginate (SA) with encapsulated g-C3N4 nanoparticles. The structural, textural, morphological, optical, and mechanical properties were determined using different methods. The encapsulation of g-C3N4 into CMC/SA copolymer resulted in the formation of composite hydrogels with a coherent structure, enhanced porosity, excellent photostability, and good adhesion. The ability of composite hydrogels to eliminate structurally different dyes with the same or opposite charge properties (cationic Methylene Blue and anionic Orange G and Remazol Brilliant Blue R) in both single- and binary-dye systems was examined through adsorption and photocatalytic reactions. The interactions between the dyes and g-C3N4 and the negatively charged CMC/SA copolymers had a notable influence on both the adsorption capacity and photodegradation efficiency of the prepared composites. Scavenger studies and leaching tests were conducted to gain insights into the primary reactive species and to assess the stability and long-term performance of the g-C3N4/CMC/SA beads. The commendable photocatalytic activity and excellent recyclability, coupled with the elimination of costly catalyst separation requirements, render the g-C3N4/CMC/SA composite hydrogels cost-effective and environmentally friendly materials, and strongly support their selection for tackling environmental pollution issues.
Subject(s)
Alginates , Carboxymethylcellulose Sodium , Coloring Agents , Hydrogels , Water Pollutants, Chemical , Carboxymethylcellulose Sodium/chemistry , Hydrogels/chemistry , Alginates/chemistry , Coloring Agents/chemistry , Catalysis , Water Pollutants, Chemical/chemistry , Methylene Blue/chemistry , Azo Compounds/chemistry , Nitriles/chemistry , Nitrogen Compounds/chemistry , Photolysis , Adsorption , Green Chemistry Technology/methods , Anthraquinones , GraphiteABSTRACT
Chrysophanol and hesperidin are natural nutraceuticals that exhibit synergistic bioactivities, but their hydrophobicity limits their applications, and it is unclear whether coencapsulation can improve their solubility and release behaviors. The objective of this work was to coencapsulate chrysophanol and hesperidin by octenylsuccinated ß-glucan aggregates (OSßG-Agg) and to reveal how coencapsulation improves their release and bioaccessibility. Mechanisms underlying the hypothesis of beneficial effects in coloading, corelease and bioaccessibility were revealed. The solubilization of OSßG-Agg was due to hydrogen-bonding among ß-glucan moieties of OSßG and hydroxyl groups of chrysophanol and hesperidin and hydrophobic interactions among octenyl chains of OSßG and hydrophobic moieties of chrysophanol and hesperidin. Structural analyses confirmed the hypothesis that chrysophanol molecules were nearly embedded deeper into the interior of hydrophobic domains, and most of hesperidin molecules were incorporated into the exterior of the hydrophobic domains of OSßG-Agg due to the strength of these interactions, but they interacted in OSßG-Agg with a dense and compact structure rather than existing in isolation. The combined effects delayed their release and enhanced their bioaccessibility because of dynamic equilibrium between the favorable interactions and unfavorable structural erosion and relaxation of OSßG-Agg. Overall, OSßG-Agg is effective at codelivering hydrophobic phenolics for functional foods and pharmaceuticals.
Subject(s)
Anthraquinones , Hesperidin , beta-Glucans , Hesperidin/chemistry , beta-Glucans/chemistry , Anthraquinones/chemistry , Solubility , Hydrophobic and Hydrophilic Interactions , Biological Availability , Hydrogen BondingABSTRACT
The bioreduction of toxic chromium(VI) to sparingly soluble chromium(III) represents an environmentally friendly and cost-effective method for remediating Cr contamination. Usually, this bioreduction process is slow and requires the addition of quinone compounds as electron shuttles to enhance the reaction rate. However, the dissolved quinone compounds are susceptible to loss with water flow, thereby limiting their effectiveness. To address this challenge, this study loaded anthraquinone-2,6-disulfonate (AQDS), a typical quinone compound, onto biochar (BC) to create a novel solid-phase electron mediator (BC-AQDS) that can sustainably promote Cr(VI) bioreduction. The experimental results demonstrated that BC-AQDS significantly promoted the bioreduction of Cr(VI), where the reaction rate constant increased by 4.81 times, and the reduction extent increased by 38.31%. X-ray photoelectron spectroscopy and Fourier-Transform Infrared Spectroscopy analysis revealed that AQDS replaced the -OH functional groups on the BC surface to form BC-AQDS. Upon receiving electrons from Shewanella putrefaciens CN32, BC-AQDS was reduced to BC-AH2DS, which subsequently facilitated the reduction of Cr(VI) to Cr(III). This redox cycle between BC-AQDS and BC-AH2DS effectively enhanced the bioreduction rate of Cr(VI). Our study also found that a lower carbonization temperature of BC resulted in a higher surface -OH functional group content, enabling a greater load of AQDS and a more pronounced enhancement effect on the bioreduction of Cr(VI). Additionally, a smaller particle size of BC and a higher dosage of BC-AQDS further contributed to the enhancement of Cr(VI) bioreduction. The preparation of BC-AQDS in this study effectively improve the utilization of quinone compounds and offer a promising approach for enhancing the bioreduction of Cr(VI). It provides a more comprehensive reference for understanding and solving the problem of Cr pollution in groundwater.
Subject(s)
Anthraquinones , Biodegradation, Environmental , Charcoal , Chromium , Oxidation-Reduction , Shewanella putrefaciens , Chromium/metabolism , Chromium/chemistry , Charcoal/chemistry , Anthraquinones/metabolism , Anthraquinones/chemistry , Shewanella putrefaciens/metabolism , Water Pollutants, Chemical/metabolismABSTRACT
Periodontitis causes an increase in several bioactive agents such as interleukins (IL), tumor necrosis factor (TNF)-α and receptor activator of NF-kB ligand (RANKL), which induce the osteoclast formation and activity. Since diacerein exerts anti-TNF-α and anti-IL-1 effects, alleviating bone destruction in osteoarthritis, we investigated whether this drug inhibits the formation and survival of osteoclast in the periodontitis. Rats were distributed into 3 groups: 1) group with periodontitis treated with 100â¯mg/kg diacerein (PDG), 2) group with periodontitis treated with saline (PSG) and group control (CG) without any treatment. After 7, 15 and 30 days, the maxillae were collected for light and transmission electron microscopy analyses. Gingiva samples were collected to evaluate the mRNA levels for Tnf, Il1b, Tnfsf11 and Tnfrsf11b by RT-qPCR. In PDG, the expression of Tnf and Il1b genes reduced significantly compared to PSG, except for Tnf expression at 7 days. The number of osteoclasts reduced significantly in the PDG in comparison with PSG at 7 and 15 days. In all periods, the IL-6 immunoexpression, RANKL/OPG immunoexpression and mRNA levels of Tnfsf11/Tnfrsf11b ratio were significantly lower in PDG than in PSG. PDG exhibited significantly higher frequency of TUNEL-positive osteoclasts than in PSG and CG at all time points. Osteoclasts with caspase-3-immunolabelled cytoplasm and nuclei with masses of condensed chromatin were observed in PDG, confirming osteoclast apoptosis. Diacerein inhibits osteoclastogenesis by decreasing Tnf and Il1b mRNA levels, resulting in decreased RANKL/OPG ratio, and induces apoptosis in osteoclasts of alveolar process of rat molars with periodontitis.
Subject(s)
Anthraquinones , Cytokines , Osteoclasts , Periodontitis , Animals , Osteoclasts/drug effects , Osteoclasts/metabolism , Periodontitis/drug therapy , Periodontitis/pathology , Periodontitis/metabolism , Anthraquinones/pharmacology , Male , Cytokines/metabolism , Rats, Wistar , Rats , RANK Ligand/metabolism , Cell Survival/drug effects , Tumor Necrosis Factor-alpha/metabolism , Gingiva/metabolism , Gingiva/pathology , Gingiva/drug effects , Apoptosis/drug effects , RNA, Messenger/metabolism , RNA, Messenger/geneticsABSTRACT
Triple-negative breast cancer (TNBC) is the most lethal subtype of breast cancer. Hypoxia-activated prodrugs (HAPs) have shown promise as potential therapeutic agents for TNBC. While increasing hypoxia levels may promote the HAP activation, it raises concerns regarding HIF1α-dependent drug resistance. It is desirable to develop a targeted approach that enhances tumor hypoxia for HAP activation without promoting HIF1α-dependent drug resistance in TNBC treatment. Herein, we proposed a multi-responsive carrier-free self-assembled nanomedicine named AQ4N@CA4T1ASO. This nanomedicine first targeted tumors by the TNBC-targeting aptamers (T1), and then disassembled in the reductive and acidic conditions within tumors. The released Combretastatin 4 (CA4) could exacerbate hypoxia, thereby promoting the conversion of inactive Banoxantrone (AQ4N) to its active form, AQ4. Simultaneously, the released antisense oligonucleotide (ASO) could attenuate hypoxia-induced HIF1α mRNA expression, thereby sensitizing the tumor to chemotherapy. Overall, this smart nanomedicine represents a profound targeted therapy strategy, combining "hypoxia-potentiating, hypoxia-activated, chemo-sensitization" approaches for TNBC treatment. In vivo study demonstrated significant suppression of tumor growth, highlighting the promising potential of this nanomedicine for future clinical translation.
Subject(s)
Aptamers, Nucleotide , Hypoxia-Inducible Factor 1, alpha Subunit , Prodrugs , Triple Negative Breast Neoplasms , Prodrugs/pharmacology , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/metabolism , Triple Negative Breast Neoplasms/pathology , Animals , Humans , Aptamers, Nucleotide/pharmacology , Female , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Hypoxia-Inducible Factor 1, alpha Subunit/antagonists & inhibitors , Mice , Cell Line, Tumor , Xenograft Model Antitumor Assays , Mice, Nude , Mice, Inbred BALB C , AnthraquinonesSubject(s)
Anthraquinones , Atherosclerosis , Vascular Calcification , Humans , Vascular Calcification/metabolism , Vascular Calcification/pathology , Atherosclerosis/metabolism , Atherosclerosis/pathology , Silver Nitrate , Renal Insufficiency, Chronic/metabolism , Staining and Labeling/methods , Aortic Aneurysm/metabolism , Aortic Aneurysm/pathology , Calcium/metabolism , Silver StainingABSTRACT
Lichens are symbiotic organisms that effectively survive in harsh environments, including arid regions. Maintaining viability with an almost complete loss of water and the rapid restoration of metabolism during rehydration distinguishes lichens from most eukaryotic organisms. The lichen Xanthoria parietina is known to have high stress tolerance, possessing diverse defense mechanisms, including the presence of the bright-orange pigment parietin. While several studies have demonstrated the photoprotective and antioxidant properties of this anthraquinone, the role of parietin in the tolerance of lichens to desiccation is not clear yet. Thalli, which are exposed to solar radiation and become bright orange, may require enhanced desiccation tolerance. Here, we showed differences in the anatomy of naturally pale and bright-orange thalli of X. parietina and visualized parietin crystals on the surface of the upper cortex. Parietin was extracted from bright-orange thalli by acetone rinsing and quantified using HPLC. Although acetone rinsing did not affect PSII activity, thalli without parietin had higher levels of lipid peroxidation and a lower membrane stability index in response to desiccation. Furthermore, highly pigmented thalli possess thicker cell walls and, according to thermogravimetric analysis, higher water-holding capacities than pale thalli. Thus, parietin may play a role in desiccation tolerance by stabilizing mycobiont membranes, providing an antioxidative defense, and changing the morphology of the upper cortex of X. parietina.
Subject(s)
Desiccation , Lichens , Lichens/metabolism , Emodin/analogs & derivatives , Emodin/metabolism , Anthraquinones/metabolism , Anthraquinones/chemistryABSTRACT
BACKGROUND: This study aimed to explore the impact of Diacerein (DIC) on endocrine and cardio-metabolic changes in polycystic ovarian syndrome (PCOS) mouse model. METHODS: A total of 18 adult female mice (Parkes strain), aged 4-5 weeks, were randomly assigned to three groups, each comprising 6 animals, as follows: Group I (control), received normal diet and normal saline as vehicle for 51 days; Group II received Letrozole (LET; 6 mg/kg bw) for 21 days to induce PCOS; Group III received LET, followed by daily oral gavage administration of DIC (35 mg/kg bw) for 30 days. RESULTS: This study indicates that treatment with LET resulted in PCOS with characteristics such as polycystic ovaries, elevated testosterone, weight gain, visceral adiposity, high levels of insulin as well as fasting blood glucose in addition to insulin resistance, improper handling of ovarian lipids, atherogenic dyslipidemia, impaired Na + /K + -ATPase activity and serum, cardiac, and ovarian oxidative stress. Serum/ovarian adiponectin levels were lowered in LET-treated mice. In mice treated with LET, we also discovered a reduction in cardiac and serum paraoxonase 1 (PON1). Interestingly, DIC restored ovarian andcardio-metabolic abnormalities in LET-induced PCOS mice. DIC prevented the endocrine and cardio-metabolic changes brought on by letrozole-induced PCOS in mice. CONCLUSION: The ameliorative effects of DIC on letrozole-induced PCOS with concurrent oxidative stress, abdominal fat deposition, cardiac and ovarian substrate mishandling, glucometabolic dysfunction, and adiponectin/PON1 activation support the idea that DIC perhaps, restore compromised endocrine and cardio-metabolic regulators in PCOS.
Subject(s)
Anthraquinones , Aryldialkylphosphatase , Disease Models, Animal , Insulin Resistance , Polycystic Ovary Syndrome , Animals , Polycystic Ovary Syndrome/drug therapy , Polycystic Ovary Syndrome/chemically induced , Polycystic Ovary Syndrome/metabolism , Female , Mice , Anthraquinones/pharmacology , Anthraquinones/therapeutic use , Aryldialkylphosphatase/metabolism , Letrozole , Receptors, Adiponectin/metabolism , Oxidative Stress/drug effects , Adiponectin/metabolismABSTRACT
Aspergillus flavus and its carcinogenic secondary metabolites, aflatoxins, not only cause serious losses in the agricultural economy, but also endanger human health. Rhein, a compound extracted from the Chinese herbal medicine Rheum palmatum L. (Dahuang), exhibits good anti-inflammatory, anti-tumor, and anti-oxidative effects. However, its effect and underlying mechanisms against Aspergillus flavus have not yet been fully illustrated. In this study, we characterized the inhibition effect of rhein on A. flavus mycelial growth, sporulation, and aflatoxin B1 (AFB1) biosynthesis and the potential mechanism using RNA-seq analysis. The results indicate that A. flavus mycelial growth and AFB1 biosynthesis were significantly inhibited by 50 µM rhein, with a 43.83% reduction in colony diameter and 87.2% reduction in AFB1 production. The RNA-seq findings demonstrated that the differentially expressed genes primarily participated in processes such as spore formation and development, the maintenance of cell wall and membrane integrity, management of oxidative stress, the regulation of the citric acid cycle, and the biosynthesis of aflatoxin. Biochemical verification experiments further confirmed that 50 µM rhein effectively disrupted cell wall and membrane integrity and caused mitochondrial dysfunction through disrupting energy metabolism pathways, leading to decreased ATP synthesis and ROS accumulation, resulting in impaired aflatoxin biosynthesis. In addition, a pathogenicity test showed that 50 µM rhein inhibited A. flavus spore growth in peanut and maize seeds by 34.1% and 90.4%, while AFB1 biosynthesis was inhibited by 60.52% and 99.43%, respectively. In conclusion, this research expands the knowledge regarding the antifungal activity of rhein and provides a new strategy to mitigate A. flavus contamination.
Subject(s)
Aflatoxin B1 , Anthraquinones , Aspergillus flavus , Reactive Oxygen Species , Aspergillus flavus/drug effects , Aspergillus flavus/metabolism , Aspergillus flavus/growth & development , Anthraquinones/pharmacology , Reactive Oxygen Species/metabolism , Aflatoxin B1/biosynthesis , Aflatoxin B1/toxicity , Energy Metabolism/drug effects , Spores, Fungal/drug effects , Spores, Fungal/growth & development , Mycelium/drug effects , Mycelium/growth & development , Antifungal Agents/pharmacologyABSTRACT
Aloe-emodin, a natural hydroxyanthraquinone, exerts both adverse and protective effects. This study aimed at investigating these potential effects of aloe-emodin in humans upon the use of food supplements and herbal medicines using a physiologically based kinetic (PBK) modeling-facilitated quantitative in vitro to in vivo extrapolation (QIVIVE) approach. For this, PBK models in rats and humans were established for aloe-emodin including its active metabolite rhein and used to convert in vitro data on hepatotoxicity, nephrotoxicity, reactive oxidative species (ROS) generation, and Nrf2 induction to corresponding in vivo dose-response curves, from which points of departure (PODs) were derived by BMD analysis. The derived PODs were subsequently compared to the estimated daily intakes (EDIs) resulting from the use of food supplements or herbal medicines. It is concluded that the dose levels of aloe-emodin from food supplements or herbal medicines are unlikely to induce toxicity, ROS generation, or Nrf2 activation in liver and kidney.
Subject(s)
Anthraquinones , Kidney , Liver , Animals , Humans , Rats , Kidney/metabolism , Kidney/drug effects , Anthraquinones/chemistry , Anthraquinones/metabolism , Liver/metabolism , Liver/drug effects , Kinetics , Male , Models, Biological , Reactive Oxygen Species/metabolism , NF-E2-Related Factor 2/metabolism , NF-E2-Related Factor 2/genetics , Dietary Supplements/analysis , Aloe/chemistry , Aloe/metabolism , Rats, Sprague-Dawley , FemaleABSTRACT
BACKGROUND: Microbial genome sequencing and analysis revealed the presence of abundant silent secondary metabolites biosynthetic gene clusters (BGCs) in streptomycetes. Activating these BGCs has great significance for discovering new compounds and novel biosynthetic pathways. RESULTS: In this study, we found that ovmZ and ovmW homologs, a pair of interdependent transcriptional regulators coding genes, are widespread in actinobacteria and closely associated with the biosynthesis of secondary metabolites. Through co-overexpression of native ovmZ and ovmW in Streptomyces neyagawaensis NRRL B-3092, a silent type II polyketide synthase (PKS) gene cluster was activated to produce gephyromycin A, tetrangomycin and fridamycin E with the yields of 22.3 ± 8.0 mg/L, 4.8 ± 0.5 mg/L and 20.3 ± 4.1 mg/L respectively in the recombinant strain of S.ne/pZnWn. However, expression of either ovmZ or ovmW failed to activate this gene cluster. Interestingly, overexpression of the heterologous ovmZ and ovmW pair from oviedomycin BGC of S. ansochromogenes 7100 also led to awakening of this silent angucyclinone BGC in S. neyagawaensis. CONCLUSION: A silent angucyclinone BGC was activated by overexpressing both ovmZ and ovmW in S. neyagawaensis. Due to the wide distribution of ovmZ and ovmW in the BGCs of actinobacteria, co-overexpression of ovmZ and ovmW could be a strategy for activating silent BGCs, thus stimulating the biosynthesis of secondary metabolites.
Subject(s)
Anthraquinones , Anti-Bacterial Agents , Multigene Family , Streptomyces , Streptomyces/genetics , Streptomyces/metabolism , Anti-Bacterial Agents/biosynthesis , Anthraquinones/metabolism , Gene Expression Regulation, Bacterial , Bacterial Proteins/genetics , Bacterial Proteins/metabolism , Biosynthetic Pathways/genetics , Polyketide Synthases/genetics , Polyketide Synthases/metabolism , Secondary Metabolism/genetics , Angucyclines and AngucyclinonesABSTRACT
BACKGROUND: The search for new bioactive natural compounds with anticancer activity is still of great importance. Even though their potential for diagnostics and treatment of cancer has already been proved, the availability is still limited. Hypericin, a naphthodianthrone isolated essentially from plant source Hypericum perforatum L. along with other related anthraquinones and bisanthraquinones belongs to this group of compounds. Although it has been proven that hypericin is synthesized by the polyketide pathway in plants, none of the candidate genes coding for key enzymes has been experimentally validated yet. Despite the rare occurrence of anthraquinones in plants, their presence in microorganisms, including endophytic fungi, is quite common. Unlike plants, several biosynthetic genes grouped into clusters (BGCs) in fungal endophytes have already been characterized. RESULTS: The aim of this work was to predict, identify and characterize the anthraquinone BGCs in de novo assembled and functionally annotated genomes of selected endophytic fungal isolates (Fusarium oxysporum, Plectosphaerella cucumerina, Scedosporium apiospermum, Diaporthe eres, Canariomyces subthermophilus) obtained from different tissues of Hypericum spp. The number of predicted type I polyketide synthase (PKS) BGCs in the studied genomes varied. The non-reducing type I PKS lacking thioesterase domain and adjacent discrete gene encoding protein with product release function were identified only in the genomes of C. subthermophilus and D. eres. A candidate bisanthraquinone BGC was predicted in C. subthermophilus genome and comprised genes coding the enzymes that catalyze formation of the basic anthraquinone skeleton (PKS, metallo-beta-lactamase, decarboxylase, anthrone oxygenase), putative dimerization enzyme (cytochrome P450 monooxygenase), other tailoring enzymes (oxidoreductase, dehydrogenase/reductase), and non-catalytic proteins (fungal transcription factor, transporter protein). CONCLUSIONS: The results provide an insight into genetic background of anthraquinone biosynthesis in Hypericum-borne endophytes. The predicted bisanthraquinone gene cluster represents a basis for functional validation of the candidate biosynthetic genes in a simple eukaryotic system as a prospective biotechnological alternative for production of hypericin and related bioactive anthraquinones.
Subject(s)
Anthraquinones , Endophytes , Hypericum , Multigene Family , Polyketides , Hypericum/microbiology , Hypericum/genetics , Hypericum/metabolism , Polyketides/metabolism , Endophytes/genetics , Endophytes/metabolism , Anthraquinones/metabolism , Fungi/genetics , Genome, Fungal , Computer Simulation , Polyketide Synthases/genetics , Perylene/analogs & derivatives , Perylene/metabolism , Anthracenes/metabolism , Genomics , PhylogenyABSTRACT
Association behavior between quinizarin (1,4-dihydroxyanthraquinone), an analogue of the chromophore of anthracycline anticancer drugs and sodium dodecyl sulfate (SDS) micelles in the presence of glucose, NaCl and urea additives was studied using absorption spectroscopy and conductometric techniques. The spectral results indicate an increase of binding constant and partition coefficient values in the presence of glucose and NaCl whereas the addition of urea leads to a decrease of binding strength and quinizarin partitioning into SDS micelles. Thus, the rise of NaCl and glucose concentrations is favorable for the quinizarin distribution into SDS micelles. From electrical conductivity measurements it was found that the critical micelle concentration (CMC) of SDS/quinizarin system decreases by adding NaCl and glucose whereas urea has not influence on the micelization process at the concentrations used in the present study. Since biologically compounds like glucose, NaCl and urea are found in the human body, the attained outcomes can be important in finding of effective drug delivery systems.
Subject(s)
Anthraquinones , Glucose , Micelles , Sodium Chloride , Sodium Dodecyl Sulfate , Urea , Anthraquinones/chemistry , Sodium Chloride/chemistry , Glucose/chemistry , Sodium Dodecyl Sulfate/chemistry , Urea/chemistryABSTRACT
BACKGROUND: Hypoxia-activated prodrugs present new opportunities for safe and effective tumor drug resistance therapy due to their high selectivity for hypoxic cells. However, the uneven distribution of oxygen in solid tumor and insufficient hypoxia in the tumor microenvironment greatly limit its therapeutic efficacy. RESULTS: In this paper, a novel AQ4N-Mn(II)@PDA coordination nanoplatform was designed and functionalized with GMBP1 to target drug-resistant tumor cells. Its excellent photothermal conversion efficiency could achieve local high-temperature photothermal therapy in tumors, which could not only effectively exacerbate tumor hypoxia and thus improve the efficacy of hypoxia-activated chemotherapy of AQ4N but also significantly accelerate Mn2+-mediated Fenton-like activity to enhance chemodynamic therapy. Moreover, real-time monitoring of blood oxygen saturation through photoacoustic imaging could reflect the hypoxic status of tumors during treatment. Furthermore, synergistic treatment effectively inhibited tumor growth and improved the survival rate of mice bearing orthotopic drug-resistant tumors. CONCLUSIONS: This study not only provided a new idea for PTT combined with hypoxia-activated chemotherapy and CDT for drug-resistant tumors but also explored a vital theory for real-time monitoring of hypoxia during treatment.