Exploring the potential of Aspergillus wentii: secondary metabolites and biological properties.

Fungi are of considerable importance due to their capacity to biosynthesize various secondary metabolites with bioactive properties that draw high attention in new drug discovery with beneficial uses for improving human well-being and life quality. Aspergillus genus members are widespread and cosmopolitan species with varying economic significance in the fields of industry, medicine, and agriculture. Its species are renowned for their biosynthesis of secondary metabolites, characterized by both potent biological activity and structural novelty, making them a substantial reservoir for the development of new pharmaceuticals. The current work aimed at focusing on one species of this genus, Aspergillus wentii Wehmer, including its reported secondary metabolites in the period from 1951 to November 2023. A total of 97 compounds, including nitro-compounds, terpenoids, anthraquinones, xanthones, benzamides, and glucans. A summary of their bioactivities, as well as their biosynthesis was highlighted. Additionally, the reported applications of this fungus and its enzymes have been discussed. This review offers a useful reference that can direct future research into this fungus and its active metabolites, as well as their possible pharmacological and biotechnological applications.

Novel Anthraquinone-Based Benzenesulfonamide Derivatives and Their Analogues as Potent Human Carbonic Anhydrase Inhibitors with Antitumor Activity: Synthesis, Biological Evaluation, and In Silico Analysis.

In this study, we designed two series of novel anthraquinone-based benzenesulfonamide derivatives and their analogues as potential carbonic anhydrase inhibitors (CAIs) and evaluated their inhibitory activities against off-target human carbonic anhydrase II (hCA II) isoform and tumor-associated human carbonic anhydrase IX (hCA IX) isoform. Most of these compounds exhibited good inhibitory activities against hCA II and IX. The compounds that exhibited the best hCA inhibition were further studied against the MDA-MB-231, MCF-7, and HepG2 cell lines under hypoxic and normoxic conditions. Additionally, the compounds exhibiting the best antitumor activity were subjected to apoptosis and mitochondrial membrane potential assays, which revealed a significant increase in the percentage of apoptotic cells and a notable decrease in cell viability. Molecular docking studies were performed to demonstrate the presence of numerous hydrogen bonds and hydrophobic interactions between the compounds and the active site of hCA. Absorption, distribution, metabolism, excretion (ADME) predictions showed that all of the compounds had good pharmacokinetic and physicochemical properties.

Anthraquinones against Cryptococcus neoformans sensu stricto: antifungal interaction, biofilm inhibition and pathogenicity in the Caenorhabditis elegans model.

Introduction. Cryptococcal biofilms have been associated with persistent infections and antifungal resistance. Therefore, strategies, such as the association of natural compounds and antifungal drugs, have been applied for the prevention of biofilm growth. Moreover, the Caenorhabditis elegans pathogenicity model has been used to investigate the capacity to inhibit the pathogenicity of Cryptococcus neoformans sensu stricto.Hypothesis. Anthraquinones and antifungals are associated with preventing C. neoformans sensu stricto biofilm formation and disrupting these communities. Antraquinones reduced the C. neoformans sensu stricto pathogenicity in the C. elegans model.Aim. This study aimed to evaluate the in vitro interaction between aloe emodin, barbaloin or chrysophanol and itraconazole or amphotericin B against growing and mature biofilms of C. neoformans sensu stricto.Methodology. Compounds and antifungal drugs were added during biofilm formation or after 72 h of growth. Then, the metabolic activity was evaluated by the MTT reduction assay, the biomass by crystal-violet staining and the biofilm morphology by confocal laser scanning microscopy. C. neoformans sensu stricto's pathogenicity was investigated using the nematode C. elegans. Finally, pathogenicity inhibition by aloe emodin, barbarloin and chrysophanol was investigated using this model.Results. Anthraquinone-antifungal combinations affected the development of biofilms with a reduction of over 60 % in metabolic activity and above 50 % in biomass. Aloe emodin and barbaloin increased the anti-biofilm activity of antifungal drugs. Chrysophanol potentiated the effect of itraconazole against C. neoformans sensu stricto biofilms. The C. elegans mortality rate reached 76.7 % after the worms were exposed to C. neoformans sensu stricto for 96 h. Aloe emodin, barbaloin and chrysophanol reduced the C. elegans pathogenicity with mortality rates of 61.12 %, 65 % and 53.34 %, respectively, after the worms were exposed for 96 h to C. neoformans sensu stricto and these compounds at same time.Conclusion. These results highlight the potential activity of anthraquinones to increase the effectiveness of antifungal drugs against cryptococcal biofilms.

Biosynthesis of copper nanoparticles using Alstonia scholaris leaves and its antimicrobial studies.

The utilization of plants for the production of metallic nanoparticles is gaining significant attention in research. In this study, we conducted phytochemical screening of Alstonia scholaris (A. scholaris) leaves extracts using various solvents, including chloroform, ethyl acetate, n-hexane, methanol, and water. Our findings revealed higher proportions of flavonoids and alkaloids in both solvents compared to other phytochemical species. In the methanol, extract proteins, anthraquinone and reducing sugar were not detected. On the other hand, the aqueous extract demonstrated the presence of amino acids, reducing sugar, phenolic compounds, anthraquinone, and saponins. Notably, ethyl acetate and chloroform extracts displayed the highest levels of bioactive compounds among all solvents. Intrigued by these results, we proceeded to investigate the antibacterial properties of the leaf extracts against two major bacterial strains, Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). All extracts exhibited significant zones of inhibition against both bacterial isolates, with S. aureus showing higher susceptibility compared to E. coli. Notably, the methanol extract displayed the most potent I hibitory effect against all organisms. Inspired by the bioactivity of the methanol extract, we employed it as a plant-based material for the green synthesis of copper nanoparticles (Cu-NPs). The synthesized Cu-NPs were characterized using Fourier infrared spectroscopy (FT-IR), UV-visible spectroscopic analysis, and scanning electron microscopy (SEM). The observed color changes confirmed the successful formation of Cu-NPs, while the FTIR analysis matched previously reported peaks, further verifying the synthesis. The SEM micrographs indicated the irregular shapes of the surface particles. From the result obtained by energy dispersive X-ray spectroscopic analysis, Cu has the highest relative abundance of 67.41 wt%. Confirming the purity of the Cu-NPs colloid. These findings contribute to the growing field of eco-friendly nanotechnology and emphasize the significance of plant-mediated approaches in nanomaterial synthesis and biomedical applications.

Synthesis of a New Series of Anthraquinone-Linked Cyclopentanone Derivatives: Investigating the Antioxidant, Antibacterial, Cytotoxic and Tyrosinase Inhibitory Activities of the Mushroom Tyrosinase Enzyme Using Molecular Docking.

Purpose: New bioactive anthraquinone derivatives are investigated for antibacterial, tyrosinase inhibitory, antioxidant cytotoxic activity, and molecular docking. Methods: The compounds were produced using the grindstone method, yielding 69 to 89%. These compounds were analyzed using IR, 1H, and 13C NMR and elemental and mass spectral methods. Additionally, the antibacterial, antioxidant, and tyrosinase inhibitory activities of all the synthesised compounds were evaluated. Results: Compound 2 showed remarkable tyrosinase inhibition activity, with an (IC50: 13.45 µg/mL), compared to kojic acid (IC50: 19.40 µg/mL). It also exhibited moderate antioxidant and antibacterial activities with respect to the references BHT and ampicillin, respectively. Kinetic analysis revealed that the tyrosinase inhibitory activity of compound 2 was non-competitive and competitive, whereas that of compound 1 was low. All compounds (1-8) were significantly less active than doxorubicin (LC50: 0.74±0.01µg/mL). However, compound 2 affinity for the 2Y9X protein was lower than kojic acid, with a lower docking score (-8.6 kcal/mol compared to (-4.7 kcal/mol), making it more effective. Conclusion: All synthesized compounds displayed remarkable antibacterial, tyrosinase inhibitory, antioxidant, and cytotoxic activities, with compound 2 showing exceptional potency as a multitarget agent. Anthraquinone substituent groups may offer the potential for the development of treatments. The derivatives were synthesized using the grindstone method, and their antibacterial, antioxidant, tyrosinase inhibitory, and cytotoxic activities were inspected. Molecular docking and molecular dynamics simulations were performed using compound 2 and kojic acid to validate the results and confirm the stability of the compounds.

Antiprotozoal potential of Vismia species (Hypericaceae), medicinal plants used to fight cutaneous leishmaniasis.

ETHNOPHARMACOLOGICAL RELEVANCE: Species of Vismia (Hypericaceae), known in Brazil as "lacre", are commonly used in traditional Amazonian medicine for the treatment of skin lesions, including those caused by Leishmania infection. AIM OF THE STUDY: Hexane extracts from the leaves of Vismia cayennensis, V. gracilis, V. sandwithii and V. guianensis, as well as from the fruits of the latter, in addition to the anthraquinones vismiaquinone, physcion and chrysophanol isolated from these species were explored for their anti-promastigote and anti-amastigote activity on Leishmania amazonensis. MATERIALS AND METHODS: Extracts were prepared by static maceration with n-hexane. The compounds, isolated by chromatographic techniques, were identified by spectroscopic methods (1H and 13C NMR). Promastigotes of L.amazonensis were incubated with hexane extracts (1-50 µg/mL) or anthraquinones (1-50 µM) and the parasite survival analyzed. The action of compounds on reactive oxygen species (ROS) production, mitochondrial membrane potential, and membrane integrity of promastigotes were evaluated by flow cytometer, and the cytotoxicity on mammalian cells using MTT assay. Furthermore, the activity of compounds against amastigotes and nitric oxide production were also investigated. RESULTS: Vismiaquinone and physcion were obtained from the leaves of V. guianensis. Physcion, as well as chrysophanol, were isolated from V. sandwithii. Vismia cayennensis and V. gracilis also showed vismiaquinone, compound detected in lower quantity in the fruits of V. guianensis. All extracts were active against the parasite, corroborating the popular use. The greatest activity against promastigotes was achieved with V. guianensis extract (IC50 4.3 µg/mL), precisely the most used Vismia species for treating cutaneous leishmaniasis. Vismiaquinone and physcion exhibited relevant activity with IC50 12.6 and 2.6 µM, respectively. Moreover, all extracts and anthraquinones tested induced ROS production, mitochondrial dysfunction, membrane disruption and were able to kill intracellular amastigote forms, being worthy of further in vivo studies as potential antileishmanial drugs. CONCLUSIONS: The overall data achieved in the current investigation scientifically validate the traditional use of Vismia species, mainly V. guianensis, as an anti-Leishmania agent. Furthermore, the promising results presented here indicate species of Vismia as potentially useful resources of Brazilian flora for the discovery of therapeutic solutions for neglected diseases.

In silico and in vivo study of anti-inflammatory activity of Morinda longissima (Rubiaceae) extract and phytochemicals for treatment of inflammation-mediated diseases.

ETHNOPHARMACOLOGICAL RELEVANCE: Traditionally, the plant Morinda longissima Y.Z.Ruan (Rubiaceae) is used by ethnic people in Vietnam for the treatment of liver diseases and hepatitis. AIM OF THE STUDY: The study was designed to assess the efficacy of the 95% ethanolic extract of Morinda longissima roots (MLE) in experimental immune inflammation. The phytochemical variation of root extract and the chemical structures of natural compounds were also investigated using HPLC-DAD-HR-MS analysis. MATERIALS AND METHODS: Three different doses (100, 200, and 300 mg/kg b.w.) of MLE were chosen to determine anti-inflammatory activity. The mice were given orally extracts and monitored their behavior and mortality for 14 days to evaluate acute toxicity. The volume of the paw and the histopathological evaluation were carried out. The polyphenolic phytoconstituents of MLE extract were identified using LC/MS analysis. The anti-inflammatory efficacy in silico and molecular docking simulations of these natural products were evaluated based on their cyclooxygenase (COX)-1 and 2 inhibitory effects. RESULTS: This investigation showed the 95% ethanolic extract of Morinda longissima roots was found non-toxic up to 2000 mg/kg dose level in an acute study, neither showed mortality nor treatment-related signs of toxicity in mice. Eight anthraquinones and anthraquinone glycosides of Morinda longissima roots were identified by HPLC-DAD-HR-MS analysis. In the in vivo experiments, MLE was found to possess powerful anti-inflammatory activities in comparison with diclofenac sodium. The highest anti-inflammatory activity of MLE in mice was observed at a dose of 300 mg/kg body weight. The in silico analysis showed that seven out the eight anthraquinones and anthraquinone glycosides possess a selectivity index RCOX-2/COX-1 lower than 1, indicating that these compounds are selective against the COX-2 enzyme in the following the order: rubiadin-3-methyl ether < morindone morindone-6-methyl ether < morindone-5-methyl ether < damnacanthol < rubiadin < damnacanthol-3-O-ß-primeveroside. The natural compounds with the best selectivity against the COX-2 enzyme are quercetin (9), rubiadin-3-methyl ether (7), and morindone (4), with RCOX2/COX1 ratios of 0.02, 0.03, and 0.19, respectively. When combined with the COX-2 protein in the MD research, quercetin and rubiadin-3-methyl ether greatly stabilized the backbone proteins and ligands. CONCLUSION: In conclusion, the anthraquinones and ethanolic extract of Morinda longissima roots may help fight COX-2 inflammation. To develop novel treatments for inflammatory disorders linked to this one, these chemicals should be investigated more in the future.

Morindone as a potential therapeutic compound targeting TP53 and KRAS mutations in colorectal cancer cells.

There is an increasing demand for anticancer agent in treating colorectal cancer (CRC) with frequently mutated TP53 and KRAS genes. Phytochemical compounds are suitable as chemoprevention for CRC since dietary factor is a major risk factor. Anthraquinones from Morinda citrifolia L. were previously reported with various pharmacological properties. Various in vitro experiments were conducted to investigate the effects of two anthraquinones: damnacanthal and morindone on the cell proliferation, cell cycle, apoptosis, gene expression and protein expression in two CRC cells: HCT116 and HT29. Real-time monitoring of CRC cells showed that both anthraquinones exerted significant anti-proliferative effects in a dose- and time-dependent manner. Next, cell cycle analysis revealed an increase in the percentage of CRC cells in the G1 phase under anthraquinones treatment. Fluorescence microscopy also showed an increment of apoptotic cells under anthraquinones' treatment. siRNA transfection was conducted to evaluate the mediating effect of gene knockdown on mutated TP53 and KRAS in CRC cells. Before transfection, qRT-PCR analysis showed that only morindone downregulated the gene expression of mutated TP53 and KRAS and then further downregulated them after transfection. Both damnacanthal and morindone treatments further downregulated the expression of these two genes but upregulated at the protein expression level. Furthermore, gene knockdown also sensitised CRC cells to both damnacanthal and morindone treatments, resulting in lowered IC50 values. The accumulation of cells at the G1 phase was reduced after gene knockdown but increased after damnacanthal and morindone treatments. In addition, gene knockdown has increased the number of apoptotic cells in both cell lines and further increment was observed after anthraquinone treatment. In conclusion, morindone could be a competitive therapeutic agent in CRC by exhibiting multiple mechanism of anti-cancer actions.

Free total rhubarb anthraquinones protect intestinal mucosal barrier of SAP rats via inhibiting the NLRP3/caspase-1/GSDMD pyroptotic pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Rhubarb is the peeled and dried roots of Rheum palmatum L. and Rheum tanguticum Maxim. ex Balf. or Rheum officinale Baill. Free total rhubarb anthraquinones (FTRAs) were isolated and extracted from rhubarb. Previous studies have revealed that the early administration of FTRAs protects the intestinal mucosal barrier in rats with severe acute pancreatitis (SAP), the mechanism of which is not yet clear. However, we observed an enhanced expression of intestinal pyroptotic factors in rats treated with SAP, which may be related to the mechanism of intestinal barrier protection by FTRAs. AIM OF THE STUDY: The main objective of this study was to investigate the mechanism by which FTRAs protect the intestinal mucosal barrier in SAP rats, focusing on the classical pyroptosis pathway. MATERIALS AND METHODS: SAP was induced in rats through retrograde injection of sodium taurocholate via the pancreaticobiliary duct. Subsequently, FTRAs (22.5, 45, and 90 mg/kg), rhubarb (900 mg/kg, positive control), and saline (control) were administered at 0 h (immediately), 12 h, and 24 h post-surgery. Pancreatic and intestinal tissue injury, positive PI staining rate, and expression levels of various factors in intestinal tissues were compared across different groups. These factors include diamine oxidase (DAO), lactate dehydrogenase (LDH), high mobility group box chromosomal protein 1(HMGB1) and pro-inflammatory factors in intestinal and serum, pyroptosis-associated factors, toll-like receptor 4 (TLR-4), nuclear factor kappa-B (NF-kB), apoptosis-associated speck-like protein (ASC), NOD-like receptor protein 3 (NLRP3), cysteine protease-1 (caspase-1) and Gasdermin (GSDMD). RESULTS: The findings indicated that FTRAs protected the damaged intestine and pancreas and restored the expression of intestinal epithelial junction proteins in SAP rats. Additionally, it reduced intestinal and serum levels of DAO, interleukin 1, interleukin 18, HMGB1, and LDH, attenuated intestinal Positive PI staining rate, and significantly decreased the expressions of TLR-4, NF-kB, ASC, NLRP3, caspase-1 and GSDMD in SAP rats. CONCLUSIONS: The results suggest that FTRAs inhibited pyroptosis through down-regulation of the NLRP3-Caspase-1-GSDMD and TLR-4- NF-kB signaling pathways of intestinal tissues., thereby protecting the intestinal barrier of SAP rats.

Neuroprotective effect of chrysophanol in Alzheimer disease via modulating the Ca2+/EGFR-PLCγ pathway.

Chrysophanol (CHR) is an anthraquinone compound found in rhubarb, and it possesses neuroprotective properties. The purpose of this study was to gain a better understanding of its role in Alzheimer's disease (AD). In vivo study, D-galactose combined with intracerebral injection of ß-protein 25-35(Aß25-35) were used to establish AD model rats. In vitro study, Aß25-35 was used to induce AD model cells. Our results indicated that CHR improves learning and memory in AD model rats and provides protection against neuronal damage in both AD model rats and cells. Additionally, we observed that CHR suppressed the protein expression of p-tau, EGFR, PLCγ, IP3R, and CAM, as well as the mRNA levels of tau, EGFR, PLCγ, IP3R, and CAM. Furthermore, we have confirmed that CHR inhibited the fluorescence expression of calcium ions (Ca2+). In conclusion, the CHR may exert neuroprotective effects in AD by reducing tau phosphorylation through the Ca2+/EGFR-PLCγ pathway.

Cholesterol-lowering effects of rhubarb free anthraquinones and their mechanism of action.

Rhubarb free anthraquinones (RhA) have significant lipid-regulating activity. However, whether RhA monomers have a role in lipid-regulating and their mechanism of action remains unclear. Based on the cholesterol accumulated HepG2 cell model, the cholesterol-regulating effect of RhA monomers and their combinations was investigated. The expression of sterol-regulatory element binding protein 2 (SREBP2), 3-hydroxy-3-methyl glutaryl coenzyme A reductase (HMGCR) and squalene monooxygenase (SQLE) of the model cells was analyzed to preliminarily explore the mechanism of action. After that, the liposomes of each active RhA monomer were separately prepared with the same lipid materials and the same preparation method so that each monomer has similar or equal bioavailability after oral administration to rats. Finally, the hypercholesterolemic rat model was established, and the effect of active RhA monomers loaded liposomes as well as their combinations on cholesterol-regulating was investigated and their mechanism of action was analyzed. The results showed that aloe-emodin, rhein and emodin were the main cholesterol-regulating components of RhA, and the combination of rhein and emodin showed significant cholesterol-lowering effect, which may be related to the expression of SREBP2, HMGCR and SQLE in the rat liver.

Antitumoral photoinduced effects of crude extract, fractions, and naphthoquinones from Sinningia magnifica (Otto & A. Dietr.) Wiehler (Gesneriaceae) in a bioguided study.

Photodynamic therapy (PDT) has been used for various purposes, including as an antitumor resource in a noninvasive therapy with minimal side effects. Sinningia magnifica (Otto & A. Dietr.) Wiehler is a rupicolous plant found in rock crevices in Brazilian tropical forests. Initial studies indicate the presence of phenolic glycosides and anthraquinones in species of the genus Sinningia (Generiaceae family). It is known that anthraquinones are natural photosensitizers with potential PDT applications. This led us to investigate the potential compounds of S. magnifica for use as a natural photosensitizer against the melanoma (SK-MEL-103) and the prostate cancer (PC-3) cell lines in a bioguided study. Our results showed that singlet oxygen production by the 1,3-DPBF photodegradation assay greatly increased in the presence of crude extract and fractions. The biological activity evaluation showed photodynamic action against melanoma cell line SK-MEL-103 and prostate cell line PC-3. These results suggest the presence of potential photosensitizing substances, as demonstrated in this in vitro antitumor PDT study by the naphthoquinones Dunniol and 7-hydroxy-6-methoxy-α-dunnione for the first time. Naphthoquinones, anthraquinones and phenolic compounds were identified in the crude extract by UHPLC-MS/MS analysis, motivating us to continue with the bioguided phytochemical study aiming to discover more photochemically bioactive substances in Gesneriaceae plants.

Anthraquinones from Rhamnus alaternus L.: A Phytocosmetic Ingredient with Photoprotective and Antimelanogenesis Properties.

The purpose of the present work was to develop a phytocosmetic sunscreen emulsion with antioxidant activity and an anti-melanogenic effect, containing an anthraquinone-enriched extract of Rhamnus alaternus (A.E.). Our findings demonstrated that A.E. decreased the levels of reactive oxygen species, DNA damage, and malondialdehyde induced by UVA in human keratinocytes and melanocytes. Furthermore, the calculated SPF value in vitro of the cream containing A.E. was 14.26±0.152. Later, it was shown that A.E. extract had an inhibitory effect on the amount of melanin. This extract could also reduce B16F10 intracellular tyrosinase activity. Besides, docking studies were carried out to provide a logical justification for the anti-tyrosinase potential. The findings showed that, A.E. may provide protection against UVA-induced oxidative stress and could be thought of as a viable treatment for hyperpigmentation disorders.

1,8-Dihydroxy-3-methoxy-anthraquinone inhibits tumor angiogenesis through HIF-1α downregulation.

Photorhabdus luminescens is a gram-negative bioluminescent bacterium known as an intestinal bacterium that coexists in the digestive tract of insect-pathogenic nematodes. As part of our ongoing exploration to identify bioactive compounds from diverse natural resources, the chemical analysis of the cultures of P. luminescens KACC 12254 via LC/MS and TLC-based analyses enabled the isolation and identification of a major fluorescent compound. Its chemical structure was elucidated as 1,8-dihydroxy-3-methoxyanthraquinone (DMA) using HR-ESI-MS and NMR analysis. In this study, we conducted comprehensive investigations utilizing human colorectal cancer HCT116 cells, human umbilical cord vascular endothelial cells (HUVECs), and zebrafish embryos to assess the potential benefits of DMA in suppressing tumor angiogenesis. Our results convincingly demonstrate that DMA effectively suppresses the stability of hypoxia-inducible factor-1α (HIF-1α) protein and its target genes without inducing any cytotoxic effects. Furthermore, DMA demonstrates the ability to inhibit HIF-1α transcriptional activation and mitigate the production of reactive oxygen species (ROS). In our in vitro experiments, DMA exhibits notable inhibitory effects on VEGF-mediated tube formation, migration, and invasion in HUVECs. Additionally, in vivo investigations using zebrafish embryos confirm the antiangiogenic properties of DMA. Notably, DMA does not exhibit any adverse developmental or cardiotoxic effects in the in vivo setting. Moreover, we observe DMA's capability to restrain tumor growth through the downregulation of PI3K/AKT and c-RAF/ERK pathway. Collectively, these compelling findings underscore DMA's potential as a promising therapeutic candidate for targeted intervention against HIF-1α and angiogenesis in cancer treatment.

9,10-Dioxoanthracenyldithiocarbamates effectively inhibit the proliferation of non-small cell lung cancer by targeting multiple protein tyrosine kinases.

Anthraquinones have attracted considerable interest in the realm of cancer treatment owing to their potent anticancer properties. This study evaluates the potential of a series of new anthraquinone derivatives as anticancer agents for non-small-cell lung cancer (NSCLC). The compounds were subjected to a range of tests to assess their cytotoxic and apoptotic properties, ability to inhibit colony formation, pro-DNA damage functions, and capacity to inhibit the activity of tyrosine kinase proteins (PTKs). Based on the research findings, it has been discovered that most active derivatives (i84, i87, and i90) possess a substantial capability to impede the viability of NSCLC while having mostly a negligible effect on the human kidney cell line. Moreover, the anthraquinones displayed pro-apoptotic and genotoxic attributes while blocking the phosphorylation of multiple PTKs. Collectively, our findings indicate that these derivatives may demonstrate promising potential as effective anticancer agents for lung cancer treatment.

The potential of Rhein's aromatic amines for Parkinson's disease prevention and treatment: α-Synuclein aggregation inhibition and disaggregation of preformed fibers.

The aggregation of α-Syn is a pivotal mechanism in Parkinson's disease (PD). Effectively maintaining α-Syn proteostasis involves both inhibiting its aggregation and promoting disaggregation. In this study, we developed a series of aromatic amide derivatives based on Rhein. Two of these compounds, 4,5-dihydroxy-N-(3-hydroxyphenyl)-9,10-dioxo-9,10-dihydroanthracene-2-carboxamide (a5) and 4,5-dihydroxy-N-(2-hydroxy-4-chlorophenyl)-9,10-dioxo-9,10-dihydroanthracene-2-carboxamide (a8), exhibited good binding affinities to α-Syn residues, demonstrating promising inhibitory activity against α-Syn aggregation in vitro, with low IC50 values (1.35 and 1.08 µM, respectivly). These inhibitors acted throughout the entire aggregation process by stabilizing α-Syn's conformation and preventing the formation of ß-sheet aggregates. They also effectively disassembled preformed α-Syn oligomers and fibrils. Preliminary mechanistic insights indicated that they bound to the specific domain within fibrils, inducing fibril instability, collapse, and the formation of smaller aggregates and monomeric α-Syn units. This research underscores the therapeutic potential of Rhein's aromatic amides in targeting α-Syn aggregation for PD treatment and suggests broader applications in managing and preventing neurodegenerative diseases.

Exploring natural anthraquinones as potential MMP2 inhibitors: A computational study.

OBJECTIVE: Matrix metalloproteinase-2 (MMP2) plays a significant role in cleaving extracellular matrix components, leading to many cancer cells' progression and invasion behavior. Therefore, MMP2 inhibition may hold promise for cancer treatment. Anthraquinones have shown antineoplastic effects, some of which have been used in clinical practice as anticancer drugs. This study used a computational drug discovery approach to assess the possible inhibitory effects of selected anthraquinones on MMP2. The results were then compared with that of Captopril, which was considered a standard drug. METHODS: This study used the AutoDock 4.0 tool to evaluate the binding affinity of 21 anthraquinones to the MMP2 catalytic domain. The most favorable scores based on the Gibbs free binding energy scores were given to the highest-ranked ligands. The Discovery Studio Visualizer tool illustrated interactions between MMP2 residues and top-ranked anthraquinones. RESULTS: A total of 12 anthraquinones were identified with ΔGbinding scores less than - 10 kcal/mol. Pulmatin (Chrysophanol-8-glucoside) was the most potent MMP2 inhibitor, with a ΔGbinding score of - 12.91 kcal/mol. This anthraquinone was able to restrict MMP2 activity within a picomolar range. CONCLUSION: MMP2 inhibition by anthraquinones, notably Pulmatin, may be a useful therapeutic approach for cancer treatment.

Stool-softening effect and action mechanism of free anthraquinones extracted from Rheum palmatum L. on water deficit-induced constipation in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: In traditional Chinese herbal medicine, rhubarb is said to remove accumulation with purgation, clearing heat, and discharging fire. Modern pharmacology has shown that rhubarb extract has a purgative effect when given to experimental animals in an appropriate dose. However, the active components and their mechanism of action are still not clearly defined. AIM OF THE STUDY: The current research aimed to evaluate the synergistic stool-softening effects and explore the action mechanism of rhubarb free anthraquinones (RhA) and their monomers on constipation in rats. MATERIALS AND METHODS: A rat model of water deficit-induced constipation was established to induce constipation, and these rats were treated with RhA and its monomers. ELISA, histopathology, immunohistochemistry, qPCR and Western blotting based on network pharmacology and molecular docking were conducted to explore the possible mechanism of action of RhA and its monomers. RESULTS: RhA, aloe-emodin, rhein, and chrysophanol showed stool-softening activity, and the combination of aloe-emodin and rhein had the strongest softening effect on faecal pellets. Aloe-emodin, rhein, and chrysophanol significantly increased the serum levels of vasoactive intestinal peptide (VIP), motilin (MTL), and substance P (SP), upregulated the expression of VIP, cyclase-associated protein 1 (CAP1), protein kinase A (PKA), cystic fibrosis transmembrane conductance regulator (CFTR), aquaporin 3 (AQP3), aquaporin 4 (AQP4), and aquaporin 8 (AQP8), decreased the expression of epithelial sodium channel (ENaC) and Na+/H+ exchanger 3 (NHE3), and reduced the colonic tissue concentration of Na+-K+-ATPase in the constipated rats. Osmolality of colonic fluid in model rats treated by RhA, aloe-emodin, rhein, and chrysophanol was increased. CONCLUSION: Aloe-emodin, rhein, and chrysophanol were the stool-softening components of the RhA extract, and there were certain drug-interactions between the components. RhA upregulated VIP expression, activated the cyclic adenosine monophosphate protein kinase A (cAMP/PKA) pathway, and further stimulated CFTR expression while inhibiting NHE3 and ENaC expression, resulting in a hypertonic state in the colonic lumen. Water transport could then be driven by an osmotic gradient, which in turn led to the upregulation of AQP3, AQP4, and AQP8 expression. In addition, RhA likely improved gastrointestinal motility by increasing serum VIP, SP, and MTL concentrations, thus promoting faecal excretion.

Anthraquinones from the roots of Morinda scabrida Craib exhibit antiproliferative activity against A549 lung cancer cells and antitubulin polymerization.

Six anthraquinones were isolated from Morinda scabrida Craib, an unexplored species of Morinda found in the tropical forest of Thailand. All six anthraquinones showed cytotoxicity against A549 lung cancer cells, with the most active compound, nordamnacanthal (MS01), exhibiting the IC50 value of 16.3 ± 2.5 µM. The cytotoxic effect was dose-dependent and led to cell morphological changes characteristic of apoptosis. In addition, flow cytometric analysis showed dose-dependent apoptosis induction and the G2/M phase cell cycle arrest, which was in agreement with the tubulin polymerization inhibitory activity of MS01. Molecular docking analysis illustrated the binding between MS01 and the α/ß-tubulin heterodimer at the colchicine binding site, and UV-visible absorption spectroscopy revealed the DNA binding capacity of MS01.

A Review on Bioactive Anthraquinone and Derivatives as the Regulators for ROS.

Anthraquinones are bioactive natural products, which are often found in medicinal herbs. These compounds exert antioxidant-related pharmacological actions including neuroprotective effects, anti-inflammation, anticancer, hepatoprotective effects and anti-aging, etc. Considering the benefits from their pharmacological use, recently, there was an upsurge in the development and utilization of anthraquinones as reactive oxygen species (ROS) regulators. In this review, a deep discussion was carried out on their antioxidant activities and the structure-activity relationships. The antioxidant mechanisms and the chemistry behind the antioxidant activities of both natural and synthesized compounds were furtherly explored and demonstrated. Due to the specific chemical activity of ROS, antioxidants are essential for human health. Therefore, the development of reagents that regulate the imbalance between ROS formation and elimination should be more extensive and rational, and the exploration of antioxidant mechanisms of anthraquinones may provide new therapeutic tools and ideas for various diseases mediated by ROS.