Aloe emodin promotes mucosal healing by modifying the differentiation fate of enteroendocrine cells via regulating cellular free fatty acid sensitivity.

The proper differentiation and reorganization of the intestinal epithelial cell population is critical to mucosal regeneration post injury. Label retaining cells (LRCs) expressing SRY-box transcription factor 9 (SOX9) promote epithelial repair by replenishing LGR5+ intestinal stem cells (ISCs). While, LRCs are also considered precursor cells for enteroendocrine cells (EECs) which exacerbate mucosal damage in inflammatory bowel disease (IBD). The factors that determine LRC-EEC differentiation and the effect of intervening in LRC-EEC differentiation on IBD remain unclear. In this study, we investigated the effects of a natural anthraquinone called aloe emodin (derived from the Chinese herb rhubarb) on mucosal healing in IBD models. Our findings demonstrated that aloe emodin effectively interfered with the differentiation to EECs and preserved a higher number of SOX9+ LRCs, thereby promoting mucosal healing. Furthermore, we discovered that aloe emodin acted as an antagonist of free fatty acid receptors (FFAR1), suppressing the FFAR1-mediated Gßγ/serine/threonine-protein kinase (AKT) pathway and promoting the translocation of forkhead box protein O1 (FOXO1) into the nucleus, ultimately resulting in the intervention of differentiation fate. These findings reveal the effect of free fatty acid accessibility on EEC differentiation and introduce a strategy for promoting mucosal healing in IBD by regulating the FFAR1/AKT/FOXO1 signaling pathway.

Aloe-emodin alleviates inflammatory bowel disease in mice by modulating intestinal microbiome homeostasis via the IL-4/IL-13 axis.

Introduction: Inflammatory bowel disease (IBD) is a global health concern. Aloe-emodin (AE) has diverse pharmacological benefits, including anti-inflammatory effects. However, its role in IBD remains unclear, prompting our investigation of its regulatory effects and mechanisms in an IBD mouse model. Methods: We studied the therapeutic efficacy of AE in alleviating symptoms and modulating cytokine secretion in a murine model of dextran sulfate sodium (DSS)-induced colitis. BALB/c mice were administered DSS to induce colitis and were subsequently treated with varying doses of AE. Changes in body weight, fecal lipocalin-2 (LCN2) levels, colon tissue histology, and serum cytokine concentrations were evaluated to assess the effects of AE treatment. Additionally, 16 S rRNA sequencing was used to analyze alterations in the composition of the gut microbiota following AE intervention. Finally, the database was used to analyze the signaling pathways associated with IBD in AE and to detect the expression levels of interleukin (IL)-4 pathway using real-time quantitative reverse transcription PCR. Exogenous IL-4 was used in rescue experiments to observe its effects on the disease process of IBD under AE regulation. Results: AE treatment resulted in a dose-dependent mitigation of weight loss, reduction in fecal LCN2 levels, and amelioration of histological damage in DSS-induced colitis in mice. The levels of superoxide dismutase and catalase increased, whereas malondialdehyde decreased following AE treatment, indicating a dose-dependent alleviation of colitis symptoms. Furthermore, AE administration attenuated the secretion of pro-inflammatory cytokines, including IL-17, tumor necrosis factor-alpha (TNF-α), and chemokine ligand 1, while promoting the expression of anti-inflammatory cytokines IL-4 and IL-13. Analysis of the gut microbiota revealed that AE effectively suppressed the overgrowth of colitis-associated bacterial species and restored microbial homeostasis. Finally, we found that overexpression of IL-4 was able to reverse the therapeutic effect of AE for DSS-induced IBD. Conclusion: AE shows promise in alleviating colitis severity, influencing inflammatory cytokines, and modulating the gut microbiota in an IBD mouse model via the IL-4/IL-13 pathway, suggesting its potential as a natural IBD remedy.

Natural redox mediator anthraquinone aloe-emodin facilitated the in-situ mineralized γ-FeO(OH) membrane for the removal of tannic acid through photocatalytic-PMS activation.

The growing utilization of Traditional Chinese Medicine (TCM) has resulted in an increase in wastewater. Herein, a new kind of organic-inorganic redox mediator membrane by immobilizing γ-FeO(OH) and aloe-emodin(AE) with the characteristic large π-conjugation anthraquinone structure on PVDF membrane was innovatively achieved. AE exhibiting both electron deficiency and redox activity possesses a co-catalyst role in degradation of tannic acid (TA), aiding in the separation of charge carriers through the sequential hydrogenation and dehydrogenation of AE. The removal rates of TA were 92.8 % in the tannic acid solution and 60.3 % in the simulated rhubarb wastewater by the AE-γ-FeO(OH) membrane under PMS+Vis conditions in 45 min. Also, they show a higher recovery of pure water flux and owning good fouling performance. Overall, this current work presents a novel approach for the design and preparation of organic-inorganic photocatalytic composite membrane using readily available natural products for the purification TCM wastewater.

Aloe-emodin relieves allergic contact dermatitis pruritus by inhibiting mast cell degranulation.

Urushiol-induced allergic contact dermatitis (ACD) is a chronic inflammatory skin disease in which skin barrier dysfunction leads to pruritus and eczematous lesions. ACD is triggered by immune imbalance. Aloe emodin is an anthraquinone derivative extracted from rhubarb, aloe and other traditional Chinese medicines. It has a wide range of pharmacological effects, including anti-inflammatory, anti-tumor, and anti-allergic effects. The purpose of our study was to demonstrate the effectiveness of aloe-emodin on urushiol-induced acute pruritus and allergic contact dermatitis. The results showed that urushiol could stimulate keratinocytes to release chemokines CXCL1, CXCL2, CCL2, TSLP, and TNF-α, which recruit or activate mast cells. Aloe-emodin treatment inhibited inflammatory-response-induced mast cell degranulation in skin lesions and suppressed the expression of inflammatory cytokines, such as interleukin-4, and interleukin-6. Therefore, the results indicate that aloe-emodin can improve urushiol-induced acute pruritus and allergic contact dermatitis in mice by inhibiting mast cell degranulation.

Potential preventative impact of aloe-emodin nanoparticles on cerebral stroke-associated myocardial injury by targeting myeloperoxidase: In supporting with In silico and In vivo studies.

The present study examined the potential neuroprotective effects of aloe-emodin (AE) nanoparticles on the cerebral stroke-associated target protein myeloperoxidase (MPO). We investigated the binding interactions between AE and MPO through molecular docking and molecular dynamics simulations. Molecular docking results indicated that AE exhibited a binding energy of -6.9 kcal/mol, whereas it was -7.7 kcal/mol for 2-{[3,5-bis(trifluoromethyl)benzyl]amino}-n-hydroxy-6-oxo-1,6-dihydropyrimidine-5-carboxamide (CCl). Furthermore, molecular dynamics studies demonstrated that AE possesses a stronger binding affinity (-57.137 ± 13.198 kJ/mol) than does CCl (-22.793 ± 30.727 kJ/mol), suggesting that AE has a more substantial inhibitory effect on MPO than does CCl. Despite the therapeutic potential of AE for neurodegenerative disorders, its bioavailability is limited within the body. A proposed hypothesis to enhance the bioavailability of AE is its conversion into aloe-emodin nanoparticles (AENP). The AENPs synthesized through a fabrication method were spherical with a consistent diameter of 104.4 ± 7.9 nm and a polydispersity index ranging from 0.525 to 0.586. In rats experiencing cerebral stroke, there was a notable increase in cerebral infarction size; abnormalities in electrocardiogram (ECG) and electroencephalogram (EEG) patterns; a decrease in brain and cardiac antioxidant activities; and an increase in myeloperoxidase levels compared to those in normal rats. Compared with AE treatment, AENP treatment significantly ameliorated cerebral infarction, normalized ECG and EEG patterns, enhanced brain and cardiac antioxidant activities, and reduced MPO levels in stroke rats. Histopathological evaluations revealed pronounced alterations in the rat hippocampus, with pyknotic nuclei, disarray and loosely packed cells, deterioration of cardiac muscle fibers, and extensive damage to cardiac myocytes, in contrast to those in normal rats. AENP treatment mitigated these pathological changes more effectively than AE treatment in both brain and cardiac cells. These findings support that AENP provides considerable protection against stroke-associated myocardial infarction.

Aloe vera: capacidad antioxidante y uso potencial como agente terapéutico en el tratamiento del Alzheimer mediante evaluación in silico / Aloe vera: antioxidant capacity and potential use as therapeutic agent in the treatment of Alzheimer's through in silico evaluation

Resumen: El gel de Aloe vera es considerado una fuente natural de múltiples beneficios, originados por la acción combinada de vitaminas, aminoácidos, compuestos fenólicos, enzimas, minerales, ácidos orgánicos, lípidos y carbohidratos, que se relacionan con la mejora de enfermedades neuro-degenerativas como Alzheimer. Los ensayos in vitro e in silico permiten confirmar e identificar posibles beneficios de esta planta y sus compuestos en enfermedades. El objetivo del presente trabajo fue evaluar la actividad antioxidante del gel de A. vera y mediante análisis in silico, establecer el potencial terapéutico de sus compuestos bioactivos en la enfermedad de Alzheimer. Se obtuvieron hojas de A. vera, de las que se extrajo el gel, retirando el exocarpio, se liofilizó y almacenó hasta su uso. Se caracterizó la capacidad antioxidante, se cuantificaron los compuestos fenólicos y flavonoides y se analizó la relación que existe entre los parámetros mediante correlación de Pearson. Mediante análisis in silico se evaluó el potencial de interacción de 8 compuestos del gel con la proteína gamma secretasa. El gel de A. vera obtuvo alta capacidad antioxidante por ABTS, DPPH, radical OH y poder reductor, usando bajas concentraciones para inhibir el 50 % de los radicales, y correlaciones positivas con fenoles totales y flavonoides. En el estudio in silico el compuesto que presentó mejor unión con gamma secretasa fue aloe-emodina, con menor energía libre de unión y menor concentración de constante de inhibición, sugiriendo su potencial uso como coadyuvante en el tratamiento de la enfermedad de Alzheimer.

Abstract: Aloe vera gel is considered a natural source of multiple benefits, originated by the combined action of vitamins, amino acids, phenolic compounds, enzymes, minerals, organic acids, lipids and carbohydrates, which are related to the improvement of neuro-degenerative diseases such as Alzheimer's. In vitro and in silico tests allow us to confirm and identify possible benefits of this plant and its compounds in diseases. The objective of the present study was to evaluate the antioxidant activity of A. vera gel and, through in silico analysis, to establish the therapeutic potential of its bioactive compounds in Alzheimer's disease. A. vera leaves were obtained, from which the gel was extracted, removing the exocarp, lyophilized and stored until use. The antioxidant capacity was characterized, the phenolic compounds and flavonoids were quantified, and the relationship between the parameters was analyzed using Pearson correlation. The interaction potential of 8 compounds in the gel with the gamma secretase protein was evaluated through in silico analysis. The A. vera gel obtained high antioxidant capacity due to ABTS, DPPH, OH radical and reducing power, using low concentrations to inhibit 50 % of the radicals, and positive correlations with total phenols and flavonoids. In the in silico study, the compound that showed the best binding with gamma secretase was aloe-emodin, with lower binding free energy and lower inhibition constant concentration, suggesting its potential use as an adjuvant in the treatment of Alzheimer's disease.

Aloe-emodin: Progress in Pharmacological Activity, Safety, and Pharmaceutical Formulation Applications.

Aloe-emodin (AE) is an anthraquinone derivative and a biologically active component sourced from various plants, including Rheum palmatum L. and Aloe vera. Known chemically as 1,8-dihydroxy-3-hydroxymethyl-anthraquinone, AE has a rich history in traditional medicine and is esteemed for its accessibility, safety, affordability, and effectiveness. AE boasts multiple biochemical and pharmacological properties, such as strong antibacterial, antioxidant, and antitumor effects. Despite its array of benefits, AE's identity as an anthraquinone derivative raises concerns about its potential for liver and kidney toxicity. Nevertheless, AE is considered a promising drug candidate due to its significant bioactivities and cost efficiency. Recent research has highlighted that nanoformulated AE may enhance drug delivery, biocompatibility, and pharmacological benefits, offering a novel approach to drug design. This review delves into AE's pharmacological impacts, mechanisms, pharmacokinetics, and safety profile, incorporating insights from studies on its nanoformulations. The goal is to outline the burgeoning research in this area and to support the ongoing development and utilization of AE-based therapies.

Aloe-emodin alleviates cerebral ischemia-reperfusion injury by regulating microglial polarization and pyroptosis through inhibition of NLRP3 inflammasome activation.

BACKGROUND: Microglial activation plays a crucial role in injury and repair after cerebral ischemia, and microglial pyroptosis exacerbates ischemic injury. NOD-like receptor protein 3 (NLRP3) inflammasome activation has an important role in microglial polarization and pyroptosis. Aloe-emodin (AE) is a natural anthraquinone compound originated from rhubarb and aloe. It exerts antioxidative and anti-apoptotic effects during cerebral ischemia/reperfusion (I/R) injury. However, whether AE affects microglial polarization, pyroptosis, and NLRP3 inflammasome activation remains unknown. PURPOSE: This study aimed to explore the effects of AE on microglial polarization, pyroptosis, and NLRP3 inflammasome activation in the cerebral infarction area after I/R. METHODS: The transient middle cerebral artery occlusion (tMCAO) and oxygen-glucose deprivation/re-oxygenation (OGD/R) methods were used to create cerebral I/R models in vivo and in vitro, respectively. Neurological scores and triphenyl tetrazolium chloride and Nissl staining were used to assess the neuroprotective effects of AE. Immunofluorescence staining, quantitative polymerase chain reaction and western blot were applied to detect NLRP3 inflammasome activation and microglial polarization and pyroptosis levels after tMCAO or OGD/R. Cell viability and levels of interleukin (IL)-18 and IL-1ß were measured. Finally, MCC950 (an NLRP3-specific inhibitor) was used to evaluate whether AE affected microglial polarization and pyroptosis by regulating the activation of the NLRP3 inflammasome. RESULTS: AE improved neurological function scores and reduced the infarct area, brain edema rate, and Nissl-positive cell rate following I/R injury. It also showed a protective effect on BV-2 cells after OGD/R. AE inhibited microglial pyroptosis and induced M1 to M2 phenotype transformation and suppressed microglial NLRP3 inflammasome activation after tMCAO or OGD/R. The combined administration of AE and MCC950 had a synergistic effect on the inhibition of tMCAO- or OGD/R-induced NLRP3 inflammasome activation, which subsequently suppressed microglial pyroptosis and induced microglial phenotype transformation. CONCLUSION: AE exerts neuroprotective effects by regulating microglial polarization and pyroptosis through the inhibition of NLRP3 inflammasome activation after tMCAO or OGD/R. These findings provide new evidence of the molecular mechanisms underlying the neuroprotective effects of AE and may support the exploration of novel therapeutic strategies for cerebral ischemia.

Microbial responses and changes in metabolic products in bovine uteri infected with Staphylococcus aureus.

There is mounting evidence that the uterine microbiota has an important role in the pathogenesis of endometritis, with invasion of pathogenic bacteria being a main cause of uterine microbial imbalance. However, mechanisms of uterine microbiota resistance to pathogen invasion remain unclear. In this study, an intrauterine infusion of Staphylococcus aureus was used as a bovine endometritis model; it significantly increased abundance of pathogenic bacteria (Streptococcus, Helccoccus, Fusobacterium, and Escherichia-Shigella) and significantly decreased abundance of probiotics (Allstipes, Bacteroides, Phascolarctobacterium, Romboutsia, and Prevotella). In addition, the metabolite aloe-emodin was positively correlated with Prevotella and based on combined analyses of omics and probiotics, the presence of its metabolite aloe-emodin in the uterus at least partially resisted Staphylococcus aureus invasion. Therefore, Aloe-emodin has potential for regulating microbial structure and preventing endometritis.

Photodynamic Inactivation of Staphylococcus aureus Using Aloe-emodin as Photosensitizer.

Aloe-emodin (AE) is a natural compound with photodynamic properties. The aim of this study was to investigate the inhibitory effect of AE-mediated photodynamic inactivation (PDI) on Staphylococcus aureus (S. aureus). The bacteriostatic efficiency under different photodynamic conditions and photosensitizing mechanism was studied in detail. The results showed that AE-mediated PDI exhibited a typical concentration and time-dependent characteristics. In terms of bactericidal mechanism, disruption of membrane integrity and increase of cell membrane permeability was observed. Type II reaction was assumed as the main photochemical reaction involved in AE-mediated PDI as evidenced by the action of different ROS quenching agents. Furthermore, AE-mediated PDI decreased the bacterial survival in freshly squeezed apple juice and maintained its quality. The combination of blue light and AE enlarged the application of AE as an effective natural photosensitizer suitable for a food system.

Formulation, characterization and and evaluation of aloe-emodin-loaded solid dispersions for dissolution enhancement.

OBJECTIVE: To prepare aloe-emodin solid dispersion (AE-SD) and determine the metabolic process of AE and AE-SD in vivo. METHODS: AE-SD was prepared viasolvent evaporation or solvent melting using PEG-6000 and PVP-K30 as carriers. Thermogravimetric analysis, X-ray diffraction spectroscopy, differential scanning calorimetry, Fourier transform infrared spectroscopy and scanning electron microscopy were used to identify the physical state of AE-SD. Optimal prescriptions were screened viathe dissolution degree determination method. Using Phoenix software, AE suspension and AE-SD were subjected to a pharmacokinetic comparison study analyzing the alteration of behavior in vivo after AE was prepared as a solid dispersion. Acute toxicity was assessed in mice, and the physiological toxicity was used as the determination criterion for toxicity. RESULTS: AE-SD showed that AE existed in the carrier in an amorphous state. Compared with polyethylene glycol, polyvinylpyrrolidone (PVP) inhibited AE crystallization, causing the drug to transform from a dense crystalline state to an amorphous form and increasing the degree of drug dispersion. Therefore, it was more suitable as a carrier material for AE-SD. The addition of poloxamer (POL) was more beneficial to the stability of solid dispersions and could reduce the amount of PVP. The dissolution test confirmed that the optimal ratio of AE to the composite vector AE-PVP-POL was 1：2：2, and its dissolution effect was also optimal. Based on the pharmacokinetic comparison, the drug absorption was faster and quickly reached the peak of blood drug concentration in AE-SD compared to AE, the Cmax of AE-SD was greater than that of AE, and t1/2 and mean residence time of AE-SD were less than AE. The results showed that the drug metabolism in AE-SD was better, and the residence time was shorter. The toxicology study showed that both AE and AE-SD had no toxicity. CONCLUSION: This paper established that the solubility of the drug could be increased after preparing a solid dispersion, as demonstrated by in vitro dissolution experiments. In vivo pharmacokinetics studies confirmed that AE-SD could improve the bioavailability of AE in vivo, providing a new concept for the research and development of AE preparations.

Antimicrobial efficacy of aloe-emodin mediated photodynamic therapy against antibiotic-resistant Pseudomonas aeruginosa in vitro.

Multidrug-resistant Pseudomonas aeruginosa is a common pathogen that causes topical infections following burn injuries. Antimicrobial photodynamic therapy (aPDT) has emerged as a promising approach for treating antibiotic-resistant bacterial infections. The objective of this study was to evaluate the aPDT efficacy of aloe-emodin (AE), which is a photosensitizer extracted from traditional Chinese herbs, on antibiotic-sensitive and antibiotic-resistant P. aeruginosa in vitro. In this study, we confirmed the effectiveness of AE-mediated aPDT against both standard and MDR P. aeruginosa, explored the effects of irradiation time and AE concentration on bacterial survival in AE-mediated aPDT, and observed the structural damage of P. aeruginosa by using transmission electron microscope. Our results showed that neither AE nor light irradiation alone caused cytotoxic effects on P. aeruginosa. However, AE-mediated aPDT effectively inactivated both antibiotic-sensitive and antibiotic-resistant P. aeruginosa. The transmission electron microscope investigation showed that aPDT mediated by AE primarily caused damage to the cytoplasm and cell membrane. Our findings suggest that AE is a photosensitizer in the aPDT of MDR P. aeruginosa-caused topical infections following burn injuries. Future investigations will concentrate on the safety and efficacy of AE-mediated aPDT in animal models and clinical trials.

Aloe-Emodin Isolated from Rheum Undulatum L. Regulates Cell Cycle Distribution and Cellular Senescence in Human Prostate Cancer LNCaP Cells.

Senescence can promote hyperplastic pathologies, such as cancer. Prostate cancer is the second most common type of cancer in men. The p21-mediate cellular senescence, facilitated through the tumor suppressor p53-dependent pathway, is considered the primary mechanism for cancer treatment. Aloe-emodin, has been reported to exert anticancer effects in various types of cancers. This study aimed to investigate the bioactivity of aloe-emodin in LNCaP cells via the activation of p21-mediated cellular senescence. Aloe-emodin treatment increased the percentage of cells in the G1 phase while decreasing the percentage in the S phase. This effect was reflected in the expression levels of proteins associated with cell cycle progression, such as p21CIP, retinoblastoma protein, and cyclin-dependent kinase2/4 in LNCaP cells. However, aloe-emodin-treated LNCaP cells did not induce cell cycle arrest at G2/M checkpoint. Moreover, increased senescence-associated-galactosidase activity was observed in a dose-dependent manner following treatment with aloe-emodin. Aloe-emodin also induced DNA damage by modulating the expression of histone H2AX and lamin B1. Furthermore, aloe-emodin inhibited the proliferation of LNCaP cells, contrasting with the exponential growth observed in the nontreated cells. Importantly, this inhibition did not impact the immune system, as evidenced by the increased proliferation of splenocytes isolated from mice. These findings provide preliminary evidence of the anticancer effect of aloe-emodin in LNCaP cells, necessitating further investigations into the underlying mechanisms in vivo and human subjects.

Aloe-emodin from Sanhua Decoction inhibits neuroinflammation by regulating microglia polarization after subarachnoid hemorrhage.

ETHNOPHARMACOLOGICAL RELEVANCE: Subarachnoid hemorrhage (SAH) triggers a cascade of events that lead to early brain injury (EBI), which contributes to poor outcomes and appears within 3 days after SAH initiation. EBI involves multiple process including neuronal death, blood-brain barrier (BBB) injury and inflammation response. Microglia are cluster of immune cells originating in the brain which respond to SAH by changing their states and releasing inflammatory molecules through various signaling pathways. M0, M1, M2 are three states of microglia represent resting state, promoting inflammation state, and anti-inflammation state respectively, which can be modulated by pharmacological strategies. AIM OF THE STUDY: After identified potential active ingredients and targets of Sanhua Decoction (SHD) for SAH, we selected aloe-emodin (AE) as a potential ingredient modulating microglia activation states. MATERIALS AND METHODS: Molecular mechanisms, targets and pathways of SHD were reveal by network pharmacology technique. The effects of AE on SAH were evaluated in vivo by assessing neurological deficits, neuronal apoptosis and BBB integrity in a mouse SAH model. Furthermore, BV-2 cells were used to examine the effects of AE on microglial polarization. The influence of AE on microglia transformation was measured by Iba-1, TNF-α, CD68, Arg-1 and CD206 staining. The signal pathways of neuronal apoptosis and microglia polarization was measured by Western blot. RESULTS: Network pharmacology identified potential active ingredients and targets of SHD for SAH. And AE is one of the active ingredients. We also confirmed that AE via NF-κB and PKA/CREB pathway inhibited the microglia activation and promoted transformation from M1 phenotype to M2 at EBI stage after SAH. CONCLUSIONS: AE, as one ingredient of SHD, can alleviate the inflammatory response and protecting neurons from SAH-induced injury. AE has potential value for treating SAH-induced nerve injury and is expected to be applied in clinical practice.

Therapeutic Potential of 1,8-Dihydroanthraquinone Derivatives for Breast Cancer.

Breast cancer (BC) is the most common malignancy among women worldwide. In recent years, significant progress has been made in BC therapy. However, serious side effects resulting from the use of standard chemotherapeutic drugs, as well as the phenomenon of multidrug resistance (MDR), limit the effectiveness of approved therapies. Advanced research in the BC area is necessary to create more effective and safer forms of therapy to improve the outlook for individuals diagnosed with this aggressive neoplasm. For decades, plants and natural products with anticancer properties have been successfully utilized in treating various medical conditions. Anthraquinone derivatives are tricyclic secondary metabolites of natural origin that have been identified in plants, lichens, and fungi. They represent a few botanical families, e.g., Rhamnaceae, Rubiaceae, Fabaceae, Polygonaceae, and others. The review comprehensively covers and analyzes the most recent advances in the anticancer activity of 1,8-dihydroanthraquinone derivatives (emodin, aloe-emodin, hypericin, chrysophanol, rhein, and physcion) applied both individually, or in combination with other chemotherapeutic agents, in in vitro and in vivo BC models. The application of nanoparticles for in vitro and in vivo evidence in the context of 1,8-dihydroanthraquinone derivatives was also described.

Exploring the mechanism of aloe-emodin in the treatment of liver cancer through network pharmacology and cell experiments.

Objective: Aloe-emodin (AE) is an anthraquinone compound extracted from the rhizome of the natural plant rhubarb. Initially, it was shown that AE exerts an anti-inflammatory effect. Further studies revealed its antitumor activity against various types of cancer. However, the mechanisms underlying these properties remain unclear. Based on network pharmacology and molecular docking, this study investigated the molecular mechanism of AE in the treatment of hepatocellular carcinoma (HCC), and evaluated its therapeutic effect through in vitro experiments. Methods: CTD, Pharmmapper, SuperPred and TargetNet were the databases to obtain potential drug-related targets. DisGenet, GeneCards, OMIM and TTD were used to identify potential disease-related targets. Intersection genes for drugs and diseases were obtained through the Venn diagram. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses of intersecting genes were conducted by the website of Bioinformatics. Intersection genes were introduced into STRING to construct a protein-protein interaction network, while the Cytoscape3.9.1 software was used to visualize and analyze the core targets. AutoDock4.2.6 was utilized to achieve molecular docking between drug and core targets. In vitro experiments investigated the therapeutic effects and related mechanisms of AE. Results: 63 overlapped genes were obtained and GO analysis generated 3,646 entries by these 63 intersecting genes. KEGG analysis mainly involved apoptosis, proteoglycans in cancer, TNF signaling pathway, TP53 signaling pathway, PI3K-AKT signaling pathway, etc. AKT1, EGFR, ESR1, TP53, and SRC have been identified as core targets because the binding energies of them between aloe-emodin were less than -5 kcal/Mol.The mRNA and protein expression, prognosis, mutation status, and immune infiltration related to core targets were further revealed. The involvement of AKT1 and EGFR, as well as the key target of the PI3K-AKT signaling pathway, indicated the importance of this signaling pathway in the treatment of HCC using AE. The results of the Cell Counting Kit-8 assay and flow analysis demonstrated the therapeutic effect of AE. The downregulation of EGFR, PI3KR1, AKT1, and BCL2 in mRNA expression and PI3KR1, AKT,p-AKT in protein expression confirmed our hypothesis. Conclusion: Based on network pharmacology and molecular docking, our study initially showed that AE exerted a therapeutic effect on HCC by modulating multiple signaling pathways. Various analyses confirmed the antiproliferative activity and pro-apoptotic effect of AE on HCC through the PI3K-AKT signaling pathway. This study revealed the therapeutic mechanism of AE in the treatment of HCC through a novel approach, providing a theoretical basis for the clinical application of AE.

Antagonism of androgen receptor signaling by aloe-emodin.

Over the past decades, androgen receptor (AR) signaling has been a key driver of both primary and recurrent prostate cancer. In this work, aloe-emodin was identified as a novel AR antagonist, effectively inhibiting AR signaling. Firstly, aloe-emodin can inhibit LNCaP cell growth by promoting apoptosis. Then, the results of Western blot and quantitative real-time PCR further confirmed that aloe-emodin modulated AR protein levels by promoting AR proteasomal degradation, and also inhibited the transcription of the AR downstream target genes, including PSA, KLK2, and TMPRSS2. Furthermore, the result of immunofluorescence showed that aloe-emodin prevented the nuclear translocation of AR. Molecular docking and molecular dynamics simulation suggested that aloe-emodin combined with AR to form stable complexes, which might explain that aloe-emodin prevented the translocation of AR from the cytoplasm to the nucleus by affecting the ligand binding of AR. Therefore, aloe-emodin as a novel AR antagonist may play a crucial role in promoting cancer prevention or complementing pharmacological therapies in the treatment of prostate cancer.

Fucoxanthin Ameliorates Sepsis via Modulating Microbiota by Targeting IRF3 Activation.

To improve patient survival in sepsis, it is necessary to curtail exaggerated inflammatory responses. Fucoxanthin (FX), a carotenoid derived from brown algae, efficiently suppresses pro-inflammatory cytokine expression via IRF3 activation, thereby reducing mortality in a mouse model of sepsis. However, the effects of FX-targeted IRF3 on the bacterial flora (which is disrupted in sepsis) and the mechanisms by which it impacts sepsis development remain unclear. This study aims to elucidate how FX-targeted IRF3 modulates intestinal microbiota compositions, influencing sepsis development. FX significantly reduced the bacterial load in the abdominal cavity of mice with cecal ligation and puncture (CLP)-induced sepsis via IRF3 activation and increased short-chain fatty acids, like acetic and propionic acids, with respect to their intestines. FX also altered the structure of the intestinal flora, notably elevating beneficial Verrucomicrobiota and Akkermansia spp. while reducing harmful Morganella spp. Investigating the inflammation-flora link, we found positive correlations between the abundances of Morganella spp., Proteus spp., Escherichia spp., and Klebsiella spp. and pro-inflammatory cytokines (IL-6, IL-1ß, and TNF-α) induced by CLP. These bacteria were negatively correlated with acetic and propionic acid production. FX alters microbial diversity and promotes short-chain fatty acid production in mice with CLP-induced sepsis, reshaping gut homeostasis. These findings support the value of FX for the treatment of sepsis.

Aloe-Emodin Derivative, an Anthraquinone Compound, Attenuates Pyroptosis by Targeting NLRP3 Inflammasome in Diabetic Cardiomyopathy.

Diabetic cardiomyopathy (DCM) is widely recognized as a major contributing factor to the development of heart failure in patients with diabetes. Previous studies have demonstrated the potential benefits of traditional herbal medicine for alleviating the symptoms of cardiomyopathy. We have chemically designed and synthesized a novel compound called aloe-emodin derivative (AED), which belongs to the aloe-emodin (AE) family of compounds. AED was formed by covalent binding of monomethyl succinate to the anthraquinone mother nucleus of AE using chemical synthesis techniques. The purpose of this study was to investigate the effects and mechanisms of AED in treating DCM. We induced type 2 diabetes in Sprague-Dawley (SD) rats by administering a high-fat diet and streptozotocin (STZ) injections. The rats were randomly divided into six groups: control, DCM, AED low concentration (50 mg/kg/day), AED high concentration (100 mg/kg/day), AE (100 mg/kg/day), and positive control (glyburide, 2 mg/kg/day) groups. There were eight rats in each group. The rats that attained fasting blood glucose of ˃16.7 mmol/L were considered successful models. We observed significant improvements in cardiac function in the DCM rats with both AED and AE following four weeks of intragastric treatment. However, AED had a more pronounced therapeutic effect on DCM compared to AE. AED exhibited an inhibitory effect on the inflammatory response in the hearts of DCM rats and high-glucose-treated H9C2 cells by suppressing the pyroptosis pathway mediated by the nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain 3 (NLRP3) inflammasome. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of differentially expressed genes showed a significant enrichment in the NOD-like receptor signaling pathway compared to the high-glucose group. Furthermore, overexpression of NLRP3 effectively reversed the anti-pyroptosis effects of AED in high-glucose-treated H9C2 cells. This study is the first to demonstrate that AED possesses the ability to inhibit myocardial pyroptosis in DCM. Targeting the pyroptosis pathway mediated by the NLRP3 inflammasome could provide a promising therapeutic strategy to enhance our understanding and treatment of DCM.

Targeting TRPV1 and TRPA1: A feasible strategy for natural herbal medicines to combat postoperative ileus.

Under physiological or pathological conditions, transient receptor potential (TRP) channel vanilloid type 1 (TRPV1) and TRP ankyrin 1 (TRPA1) possess the ability to detect a vast array of stimuli and execute diverse functions. Interestingly, increasing works have reported that activation of TRPV1 and TRPA1 could also be beneficial for ameliorating postoperative ileus (POI). Increasing research has revealed that the gastrointestinal (GI) tract is rich in TRPV1/TRPA1, which can be stimulated by capsaicin, allicin and other compounds. This activation stimulates a variety of neurotransmitters, leading to increased intestinal motility and providing protective effects against GI injury. POI is the most common emergent complication following abdominal and pelvic surgery, and is characterized by postoperative bowel dysfunction, pain, and inflammatory responses. It is noteworthy that natural herbs are gradually gaining recognition as a potential therapeutic option for POI due to the lack of effective pharmacological interventions. Therefore, the focus of this paper is on the TRPV1/TRPA1 channel, and an analysis and summary of the processes and mechanism by which natural herbs activate TRPV1/TRPA1 to enhance GI motility and relieve pain are provided, which will lay the foundation for the development of natural herb treatments for this disease.