Atherosclerosis is an inflammatory disease of high lethality associated with endothelial dysfunction. Due to the pathophysiological complexity and our incomplete understanding of the mechanisms for ...the development and progression of atherosclerosis, effective means for the prevention and treatment of atherosclerosis still need further exploration. This study was designed to investigate the potential effects and underlying mechanisms of aloe-emodin derivative (AED) on atherosclerosis. High fat diet (HFD) treated ApoE−/− mice were used as an animal model of atherosclerosis. Intragastric administration of aloe-emodin (AE) or AED for 12 weeks markedly reduced the atherosclerotic plaque in aorta with decreased plaque area, lipid accumulation, macrophage infiltration, collagen content and metabolic abnormalities. By comparison, AED produced more potent anti-atherosclerosis effects than AE at the same dose. AED enhanced production of autophagy flux in cultured human aortic endothelial cells (HAECs). Moreover, AED increased the expression of activating molecule in Beclin1-regulated autophagy 1 (AMBRA1), a key protein involved in autophagosome formation. Furthermore, knockdown of AMBRA1 blocked the promotion effect of AED on autophagy in HAECs. Taken together, AED facilitates endothelial autophagy via AMBRA1 during the progression of atherosclerosis, suggesting the potential application of this compound for atherosclerosis treatment.
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•AED produces anti-atherosclerosis effect in ApoE−/- mice.•AED normalizes the abnormal downregulation of endothelial AMBRA1 in atherosclerosis.•AED promotes AMBRA1-mediated autophagy to yield its anti-atherosclerosis effects.
Polygonum multiflorum Thunb. (PM) is a common traditional Chinese medicine with diverse biological activities of resolving toxins, nourishing livers and promoting hairs. Nevertheless, in recent years ...hepatotoxic adverse reactions caused by the administration of PM have raised worldwide concerns. In our previous study, we found that emodin dianthrones showed hepatotoxicity and may be potential toxicity markers. However, the metabolic transformation and pharmacokinetic behavior of emodin dianthrones in vivo have still not been elucidated.
Taking trans-emodin dianthrones (TED) as an example, the present study was conducted to investigate the pharmacokinetics and bioavailability of TED in rats and characterized its metabolic transformation in the plasma, urine and feces of rats.
A rapid and sensitive UPLC-qqq-MS/MS method was developed for accurate quantification of TED in plasma and successfully applied to the pharmacokinetic evaluation of TED in rats after intravenous and oral administration. A reliable UFLC-Q-TOF-MS high resolution mass spectrometry combined with a scientific metabolite identification strategy was used to comprehensively characterize the metabolic transformation of TED in plasma, urine and feces in rats.
The established UPLC-qqq-MS/MS method had a linear range of 1–500 ng/mL, and the method was accurate and reliable to meet the quantitative requirements. When 20 mg/kg TED was given by gavage rats, it was rapidly absorbed into the circulatory system and had a long half-life time of 6.44 h and wide tissue distribution in vivo. While intravenous injection of 0.4 mg/kg TED in rats, it was rapidly metabolized and eliminated with a half-life time of 1.82 h. The oral absorption bioavailability of TED was only 2.83%. Furthermore with a sensitive UFLC-Q-TOF-MS technique and metabolite identification strategy, 21 metabolites were successfully identified, including 11 in plasma, 12 in urine and 18 in feces. The main Ⅰ and Ⅱ phase metabolic processes involved glucuronidation, oxidation, carbonylation, (de)methylation, sulfation and hydrogenation.
TED could be rapidly absorbed into the blood circulation and widely distributed and slowly metabolized in the body and underwent extensive cleavage and metabolic transformation in vivo. The study provided a basis for in-depth elucidation of the toxicology and mechanism research of TED, but also laid the foundation for further research on the material basis of hepatotoxicity of PM.
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•Study the pharmacokinetics and bioavailability of the potential toxic marker TED in Polygonum multiflorum for the first time•A sensitive UPLC-MS/MS method was successfully constructed to determine the content of TED in plasma with the LOD of 1 ng/ml•First comprehensively elucidate the metabolic transformation of TED in plasma, urine and feces in rats•Twenty-one Ⅰ and Ⅱ phase metabolites were revealed by UFLC-Q-TOF-MS and a stepwise identification strategy
Aberrant cellular metabolism drives cancer proliferation and metastasis. ATP citrate lyase (ACL) plays a critical role in generating cytosolic acetyl CoA, a key building block for de novo fatty acid ...and cholesterol biosynthesis. ACL is overexpressed in cancer cells, and siRNA knockdown of ACL limits cancer cell proliferation and reduces cancer stemness. We characterized a new class of ACL inhibitors bearing the key structural feature of the natural product emodin. Structure-activity relationship (SAR) study led to the identification of 1d as a potent lead that demonstrated dose-dependent inhibition of proliferation and cancer stemness of the A549 lung cancer cell line. Computational modeling indicates this class of inhibitors occupies an allosteric binding site and blocks the entrance of the substrate citrate to its binding site.
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•Emodin anthraquinones inhibited the enzymatic activity ATP-citrate lyase (ACL), a key player in cancer cell metabolism.•Lead compound 1d inhibited A549 lung cancer cell proliferation and reduced the stemness of A549 cells.•Docking suggested that anthraquinone inhibitors occupied an allosteric site adjacent to the citrate-binding domain of ACL.
Nonalcoholic steatohepatitis (NASH) is a subtype of nonalcoholic fatty liver disease (NAFLD) characterized by hepatic steatosis and evidence of hepatocyte injury (ballooning) and inflammation, with ...or without liver fibrosis. In this study, after 12 weeks of induction, the mice were treated with emodin succinyl ethyl ester (ESEE) for four weeks at doses of 10/30/90 mg/kg/d. The blood analysis of experimental endpoints showed that ESEE exhibited significant therapeutic effects on the progression of disorders of glycolipid metabolism and the induced liver injury in the model animals. Histopathological diagnosis of the liver and total triglyceride measurements revealed that ESEE had a significant therapeutic effect on the histopathological features of nonalcoholic fatty liver disease/hepatitis, such as cellular steatosis and activation of intrahepatic inflammation. Additionally, ESEE was able to improve hepatocyte fat deposition, steatosis, and the course of intrahepatic inflammatory activity. Furthermore, it showed some inhibitory effect on liver fibrosis in the model animals. In summary, this study confirms the therapeutic effects of ESEE on the NAFLD/NASH model in C57BL/6J mice induced by a high-fat, high cholesterol, and fructose diet. These effects were observed through improvements in liver function, inhibition of fibrosis, and inflammatory responses. Changes in blood glucose levels, blood lipid metabolism, liver histopathological staining, liver fibrosis staining, and related pathological scores further supported the therapeutic effects of ESEE. Therefore, this study has important implications for the exploration of novel drugs for nonalcoholic fatty liver disease.
Aloe‐emodin is a naturally anthraquinone derivative and an active ingredient of Chinese herbs, such as Cassia occidentalis, Rheum palmatum L., Aloe vera, and Polygonum multiflorum Thunb. Emerging ...evidence suggests that aloe‐emodin exhibits many pharmacological effects, including anticancer, antivirus, anti‐inflammatory, antibacterial, antiparasitic, neuroprotective, and hepatoprotective activities. These pharmacological properties lay the foundation for the treatment of various diseases, including influenza virus, inflammation, sepsis, Alzheimer's disease, glaucoma, malaria, liver fibrosis, psoriasis, Type 2 diabetes, growth disorders, and several types of cancers. However, an increasing number of published studies have reported adverse effects of aloe‐emodin. The primary toxicity among these reports is hepatotoxicity and nephrotoxicity, which are of wide concern worldwide. Pharmacokinetic studies have demonstrated that aloe‐emodin has a poor intestinal absorption, short elimination half‐life, and low bioavailability. This review aims to provide a comprehensive summary of the pharmacology, toxicity, and pharmacokinetics of aloe‐emodin reported to date with an emphasis on its biological properties and mechanisms of action.
•Emodin reduces HIBD in neonatal mice.•Emodin improves neurologic recovery of neonatal mice after HIBD.•Emodin can exert neuroprotective effects on HIBD by inhibiting neuronal apoptosis.
Neonatal ...hypoxic-ischemic brain damage (HIBD) can lead to mortality and severe neurological dysfunction. Emodin is a natural anthraquinone derivative that is easy to obtain and has good neuroprotective effects. This study aimed to investigate the neuroprotective effect of emodin on neonatal mouse HIBD. The modified Rice–Vannucci method was used to induce HIBD in mouse pups. Eighty postnatal 7-day (P7) C57BL/6 neonatal mice were randomly divided into the sham group (sham), vehicle group (vehicle), and emodin group (emodin). TTC staining and whole-brain morphology were used to evaluate the infarct volume and morphology of the brain tissue. The condition of the neurons was observed through Nissl staining, HE staining, FJC staining, immunofluorescence and Western blot for NeuN, IBA-1, and GFAP. The physiological status of the mice was evaluated using weight measurements. The neural function of the mice was assessed using the negative geotaxis test, righting reflex test, and grip test. TUNEL staining was used to detect apoptosis in brain cells. Finally, Western blot and immunofluorescence were used to detect the expression levels of apoptosis-related proteins, such as P53, cleaved caspase-3, Bax and Bcl-2, in the brain. Experiments have shown that emodin can reduce the cerebral infarct volume, brain oedema, neuronal apoptosis, and degeneration and improve the reconstruction of brain tissue morphology, neuronal morphology, physiological conditions, and neural function. Additionally, emodin inhibited the expression of proapoptotic proteins such as P53, Bax and cleaved caspase-3 and promoted the expression of the antiapoptotic protein Bcl-2. Emodin attenuates HIBD by inhibiting neuronal apoptosis in neonatal mice.
•Six isolated known compounds and novel semi-synthetic anthraquinones were obtained.•Novel bioactive semi-synthetic anthraquinones were obtained from emodin and aloe-emodin.•Antioxidant, ...antiproliferative and human serum albumin activities were assayed.•Two semi-synthetic derivatives exhibited excellent antiproliferative activities.•The most activesemi-synthetic compoundwasAE-1 on HeLa and PC-3 cell lines.
Rheum ribes L. (Rhubarb) is one of the most important edible medicinal plants in the Eastern Anatolia region and is called “Işkın” by local people. Resveratrol and 6-O-methylalaternin were isolated from the Rhubarb for the first time in addition to well-known secondary metabolites including emodin, aloe-emodin, β-sitosterol and rutin. The new semi-synthetic anthraquinone derivatives with the NαFmoc-l-Lys and ethynyl group were synthesized from the isolated anthraquinones emodin and aloe-emodin of Rhubarb to increase the bioactivities. Aloe-emodin derivative with NαFmoc-l-Lys shows the highest inhibition values by 94.11 ± 0.12 and 82.38 ± 0.00% against HT-29 and HeLa cell lines, respectively, at 25 µg/mL. Further, modification of the aloe-emodin with both the ethynyl and the NαFmoc-l-Lys groups showed an antioxidant activity-enhancing effect. From molecular docking studies, the relative binding energies of the emodin and aloe-emodin derivatives to human serum albumin ranged from −7.30 and −10.62 kcal/mol.
Aloe-emodin, known as a 3-hydroxymethyl-chrysazin, is one of anthraquinones mainly found in Rheum officinale Baill, Rheum palmatum L and Rheum tanguticum Maxim. Ex BALF. In recent studies, ...aloe-emodin possesses many pharmacological effects, including antitumor, antibacterial, antiviral, anti-inflammatory, cardiovascular protection, liver protection, immune regulation, estrogenic activity as a phytoestrogen, and so on. Cytochrome P450 (CYP) 1B1 (CYP1B1), as a major estrogen metabolizing enzyme, can metabolize 17β-estradiol (E2) to 4-hydroxy-E2 (4-OH-E2), which cause DNA damage and lead to tumor. Few studies have found that anthraquinones possess inhibitory activity against CYP1B1 enzyme. In this study, compared with emodin (3-Hydroxy-6-methyl-chrysazin, C
H
O
), the inhibition of aloe-emodin (3-hydroxymethyl-chrysazin, C
H
O
) on the activity of CYP1B1 was studied. The molecular mechanism of inhibition and the structure-activity relationship were also discussed. Although isomeric, the IC50 values of aloe-emodin and emodin were 0.192± 0.015 nM and 0.067± 0.003 µM, indicating the inhibition of aloe-emodin was about 350times stronger than that of emodin. Through structure-activity relationship analyses, it revealed the difference of inhibitory activity only due to different hydroxyl positions. When the hydroxyl group is transferred from the chrysazin skeleton to the methyl group, the hydrogen bond formed by this structure with the CYP1B1 protein can change the protein conformation, which may interfere with the binding of the substrate to CYP1B1 protein active site pocket and inhibit the catalytic activity of the CYP1B1 protein. Although the hydroxyl position changed, the inhibition mechanism did not change, all of which were mixed inhibition. This study reveals an anti-tumor mechanism of the anthraquinone compound aloe-emodin.
Cassia mimosoides Linn (CMD) is a traditional Chinese herb that clears liver heat and dampness. It has been widely administered in clinical practice to treat jaundice associated with damp-heat ...pathogen and obesity. Emodin (EMO) is a major bioactive constituent of CMD that has apparent therapeutic efficacy against obesity and fatty liver. Here, we investigated the protective effects and underlying mechanisms of EMO against high-fat diet (HFD)-induced nonalcoholic fatty liver disease (NAFLD).
We aimed to investigate whether EMO activates farnesoid X receptor (FXR) signaling to alleviate HFD-induced NAFLD.
In vivo assays included serum biochemical indices tests, histopathology, western blotting, and qRT-PCR to evaluate the effects of EMO on glucose and lipid metabolism disorders in wild type (WT) and FXR knockout mice maintained on an HFD. In vitro experiments included intracellular triglyceride (TG) level measurement and Oil Red O staining to assess the capacity of EMO to remove lipids induced by oleic acid and palmitic acid in WT and FXR knockout mouse primary hepatocytes (MPHs). We also detected mRNA expression of FXR signaling genes in MPHs.
After HFD administration, body weight and serum lipid and inflammation levels were dramatically increased in the WT mice. The animals also presented with impaired glucose tolerance, insulin resistance, and antioxidant capacity, liver tissue attenuation, and pathological injury. EMO remarkably reversed the foregoing changes in HFD-induced mice. EMO improved HFD-induced lipid accumulation, insulin resistance, inflammation, and oxidative stress in a dose-dependent manner in WT mice by inhibiting FXR expression. EMO also significantly repressed TG hyperaccumulation by upregulating FXR expression in MPHs. However, it did not improve lipid accumulation, insulin sensitivity, or glucose tolerance in HFD-fed FXR knockout mice.
The present study demonstrated that EMO alleviates HFD-induced NAFLD by activating FXR signaling which improves lipid accumulation, insulin resistance, inflammation, and oxidative stress.
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