Euphorbia Pekinensis Research Articles

Deciphering the mechanisms underlying the neuroprotective potential of kaempferol: a comprehensive investigation.

Neurodegenerative disorders are characterized by neuronal degradation, dysfunction, or death within the CNS. Oxidative and inflammatory stress play crucial roles in the pathogenesis of various neurodegenerative diseases. The interplay between these stressors and dysregulated cellular signaling pathways contributes to neurodegeneration. Downregulation of NRF-2 compromises antioxidant defense, exacerbating neuronal damage, while increased TLR-4/MAPK and TLR-4/NF-κB signaling promotes neuroinflammation. Excessive ROS production by NADPH oxidase leads to oxidative damage and neuronal apoptosis. The strategies targeting NRF-2, TLR-4-mediated inflammatory stress, and NADPH oxidase activity promise to mitigate neuronal damage and halt the progression of the disease. Kaempferol is a flavonoid polyphenol antioxidant found abundantly in various fruits and vegetables, including apples, grapes, tomatoes, and broccoli. It is widely found in medicinal plants including Equisetum spp., Sophora japonica, Ginkgo biloba, and Euphorbia pekinensis (Rupr.). A substantial body of in vitro and in vivo evidences have demonstrated the neuroprotective potential of kaempferol against neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Kaempferol demonstrates multifaceted potential in mitigating neuroinflammation, apoptosis, and oxidative stress in different neurodegenerative diseases through the modulation of various pathways including NRF-2, NADPH oxidase, TLR-4/MAPK, and TLR-4/NF-κB. This review article was developed through a comprehensive analysis and interpretation of research published between 2009 and 2024, sourced from multiple scientific databases, including PubMed, Scopus, ScienceDirect, and Web of Science. This review aims to provide an in-depth overview of the neuroprotective effects of kaempferol, focusing on its underlying molecular mechanisms. A total of 24 research evidence were included to elucidate the molecular pathways by which kaempferol exerts its protective effects against neurodegenerative diseases.

Euphorbia Pekinensis Rupr. sensitizes colorectal cancer to PD-1 blockade by remodeling the tumor microenvironment and enhancing peripheral immunity

BackgroundImmune checkpoint blockade, such as monoclonal antibodies targeting programmed cell death protein 1 (PD-1), has been a major breakthrough in the treatment of several cancers, but has limited effect in colorectal cancer (CRC), which is a highly prevalent cancer worldwide. Current chemotherapy-based strategies to boost PD-1 response have many limitations. And the role of peripheral immunity in boosting PD-1 response continues to attract attention. Therefore, candidate combinations of PD-1 blockade need to be drugs with multi-targets and multi-modulatory functions. However, it is still unknown whether traditional Chinese medicines with such property can enhance the applicability and efficacy of PD-1 blockade in colorectal cancer. MethodsEuphorbia Pekinensis extract (EP) was prepared and the constituents were analyzed by HPLC. CRC cells were used for in vitro experiments, including cell viability assay, colony formation assay, flow cytometry for 7-AAD staining, western blotting for caspase 3 and caspase 7, HMGB1 and ATP detection. An orthotopic CT26 mouse model was subsequently used to investigate the combination of EP and PD-1 blockade therapy. Tumor volume and tumor weight were assessed, tumor tissues were subjected to histopathological HE staining and TUNEL staining, and tumor-infiltrating immune cells were evaluated by immunofluorescence staining. RNA-sequencing, target prediction and pathway analysis were further employed to explore the mechanism. Molecular docking and cellular thermal shift assay (CETSA) were utilized to verify the direct target of the core component of EP. And, loss-of-function analysis was carried to confirm the upstream-downstream relationship. Flow cytometry was employed to analyze CD8+ T cells in the peripheral blood and spleen. ResultsThe main constituents of EP are diterpenoids and flavonoids. EP dramatically suppresses CRC cell growth and exerts its cytotoxic effect by triggering immunogenic cell death in vitro. Moreover, EP synergizes with PD-1 blockade to inhibit tumorigenesis in tumor-bearing mice. Disruption of ISX nuclear localization by helioscopinolide E is a central mechanism of EP-induced apoptosis in CRC cell. Meanwhile, EP activates immune response by upregulating Phox2b to reshape the immune microenvironment. In addition, EP regulates peripheral immunity by regulating the T cell activation and proliferation, and the ratio of CD8+ T cells in peripheral blood is drastically increased, thereby enhancing the therapeutic efficacy of anti-PD1 immunotherapy. ConclusionEP triggers intra-tumor immunogenic cell death and modulates the immunoregulatory signaling to elicit the tumor immunogenicity. Moreover, EP participates in transcriptional activation of immune response-related pathways. Consequently, multiple stimulating functions of EP on macro- and micro-immune potentiates the anti-tumor effect of PD-1 blockade in CRC.

Fructus Jujubae cooperated with water-expelling members in Shizao decoction alleviated intestinal injury and malignant ascites by modulating gut microbiota and metabolic homeostasis

BackgroundShizao decoction (SZD) consisted of Euphorbia kansui (EK), Euphorbia pekinensis (EP), Daphne genkwa (DG), and Fructus Jujubae (FJ) is a classic Chinese herbal medicine formula for treating malignant ascites, which is closely related to the modulation of gut microbiota by our previous study. For water-expelling members (WEM) including EK, EP, and DG may have side effects on the intestine, FJ is employed for detoxification and effectivity enhancement of WEM. However, the underlying mechanism for the compatibility of WEM and FJ is still unknown. PurposeTo investigate the effect of the compatibility of WEM with FJ in SZD on malignant ascites and elucidate the potential mechanism from the perspective of the modulation of gut microbiota and related metabolic function. MethodsQualitative and quantitative evaluation of main components was conducted for comprehensive characterization of SZD and WEM. The effect of WEM and SZD was compared on malignant ascites effusion (MAE) rats. The intestinal injury was evaluated by HE staining and oxidative damage. Ascites weight, urine amount, fecal water content, the expression of aquaporins, and cytokines in ascites (IL-6, VEGF, and TNF-α) were measured to estimate the water-expelling activity. The intestinal flora was detected by 16S rDNA sequencing and the content of fecal short-chain fatty acids (SCFAs) was analyzed using gas chromatography-mass spectrometry. Pseudo-germ-free (PGF) and fecal bacteria transplantation animal experiments were subsequently employed to validate this finding. The fecal metabolomics and correlation analysis were finally conducted to explore the related metabolic changes. Results51 and 33 components were identified in SZD and WEM, respectively. Compared to WEM alone, the compatibility with FJ remarkably reduced intestinal oxidative damage in MAE rats. Ascites was also relieved by downregulating the expression of AQP3 in the colon and decreasing the levels of IL-6, TNF-α and VEGF in ascites. The diversity of gut microbiota was reversed with an increase in Lactobacillus and Clostridia_UCG-014 while a decrease in Colidextribacter. Under the PGF condition, compatibility of WEM with FJ failed to reduce intestinal injury and alleviate MA significantly, but this effect was further enhanced after FMT. 23 potential fecal metabolites were finally identified. Correlation analysis further showed that Lactobacillus and Clostridia_UCG-014 were positively correlated with SCFAs and l-tryptophan. Colidextribacter was negatively correlated with thymidine but positively correlated with ursodeoxycholic acid and deoxycholic acid. ConclusionFJ cooperated with WEM reduced intestinal injury and alleviated malignant ascites by modulating gut microbiota, short-chain fatty and tryptophan metabolism. These findings provide a scientific basis for the clinical application of FJ from SZD and the safe usage of SZD.

Two new ketene derivatives from the endophytic fungus Daldinia eschscholtzii J11

Two new secondary metabolites, including a new cyclopentenone derivative (1) and a new pyrone derivative (2), together with seventeen known compounds (3–19), were isolated from the fermentation of the endophytic fungus Daldinia eschscholtzii J11 in the stems of Euphorbia pekinensis. Their structures were elucidated by using NMR and HRESIMS data and by comparing the information with literature data. Compounds 3, 4, and 18 possessed moderate ABTS+ radical scavenging activity, and Compound 12 exhibited a potential neuroprotective effect against 6-OHDA-induced injury in PC12 cells. In addition, all compounds were evaluated for their tyrosinase inhibitory activities.

Metabolomics-based investigation of the chemical composition changes in Mongolian medicinal plant Euphorbia pekinensis before and after processing with Chebulae Fructus

Euphorbia pekinensis (EP), known for its diuretic properties, is clinically utilized for treating conditions such as edema and malignant tumors. However, in its raw form, Euphorbia pekinensis is toxic, and oral administration of this crude medicine can lead to gastrointestinal stimulation, resulting in abdominal pain and diarrhea. In Mongolian medicine's ethnomedicinal system, a distinctive processing method called “Chebulae Fructus processing” is employed. Chebulae Fructus is used to mitigate the toxicity of EP and alleviate its purgative effects. Nevertheless, the detoxification mechanism associated with this processing method remains unexplored. It is hypothesized that processing with Chebulae Fructus may alter the chemical composition of EP, and the residual components of Chebulae Fructus within processed Chinese medicine might exhibit pharmacological antagonistic effects, thereby achieving the purpose of processing and reducing toxicity. To investigate this further, a combination of UPLC-QTOF-MS-based metabolomics technology and multivariate statistical analysis was employed to analyze and compare the chemical composition of raw and processed EP. Differential variables contributing to group separation were identified based on specific criteria, including VIP (Variable Importance in Projection) values of ≥ 1 in PLS-DA models, p-values < 0.05, and fold changes (FC) > 1.2 or < 0.8. The resulting differentially expressed features were then identified through database matching, literature review, or manual annotation. In total, 47 components were identified from the PEP samples in both positive and negative ionization modes, primarily belonging to flavonoids, terpenoids, organic acids, glycosides, and fatty acids. Among the raw EP group and PEP S4 group, 10 differential compounds were identified. Notably, one toxic terpene and one phenylpropanoid from EP were downregulated, while two bioactive components from Chebulae Fructus were upregulated in the processed group. The possible conversion reactions of these two processing Q-markers were also elucidated. The characteristic processing with Chebulae Fructus resulted in a change in the composition of this Mongolian medicine EP. Furthermore, this study provides a scientific foundation for optimizing the processing technology of EP and offers insights into the processing of other ethnomedicines with toxic properties.

Integrated gut microbiota and serum metabolomics reveal the protective effect of oleanolic acid on liver and kidney-injured rats induced by Euphorbia pekinensis.

Euphorbia pekinensis (EP) is a commonly used Chinese medicine treating edema with potential hepatorenal toxicity. However, its toxic mechanism and prevention are remained to be explored. Oleanolic acid (OA) is a triterpene acid with potential hepatorenal protective activities. We investigated the protective effect and potential mechanism of OA on EP-induced hepatorenal toxicity. In this study, rats were given total diterpenes from EP (TDEP, 16 mg/kg) combined with OA (10, 20, 40 mg/kg) by gavage for 4 weeks. The results showed that TDEP administration could lead to a 3-4-fold increasement in hepatorenal biochemical parameters with histopathological injuries, while OA treatment could ameliorate them in a dose-dependent manner. At microbial and metabolic levels, intestinal flora and host metabolism were perturbed after TDEP administration. The disturbance of bile acid metabolism was the most significant metabolic pathway, with secondary bile acids increasing while conjugated bile acids decreased. OA treatment can improve the disorder of intestinal flora and metabolic bile acid spectrum. Further correlation analysis screened out that Escherichia-Shigella, Phascolarctobacterium, Acetatifactor, and Akkermansia were closely related to the bile acid metabolic disorder. In conclusion, oleanolic acid could prevent hepatorenal toxicity induced by EP by regulating bile acids metabolic disorder via intestinal flora improvement.

A three-dimensional integration strategy for Q-markers identification: Taken Euphorbia Pekinensis Radix as an example

Euphorbia Pekinensis Radix (EPR) is an important antitumor medicinal resource. However, quality control of EPR has not been well established due to the lack of quality markers (Q-markers) research. In this study, a three-dimensional integration strategy was developed to systematically characterize Q-markers and this method was successfully applied to identify Q-markers of EPR. Firstly, three core quality attributes-effectiveness, testability and specificity-were considered as three dimensions, and the weights of each dimension were calculated by analytical hierarch process. Then, the values of each dimension were evaluated by multi-indicators. For EPR with antitumor activity, cytotoxic assay and network pharmacology, UPLC analysis and literature search, compound belonging search were employed to calculate the values of effectiveness, testability and specificity, respectively. Finally, the weights and values were multiplied as the scores of each component on that dimension, and the total scores of the three dimensions were further integrated based on the radar plot and expressed as regression area, by which Q-markers were quantified and visualized. Five components were identified as Q-markers of EPR due to their high-ranked antitumor capacity, ease of measurement and excellent specificity, which laid an important foundation for the quality control improvement of EPR. Furthermore, the integrated strategy summarized here is helpful for the quantitative identification of Q-markers and promote the quality standard of traditional Chinese medicine.

Characterization of the complete chloroplast genome of Euphorbia pekinensis Rupr. (Euphorbiaceae)

Euphorbia pekinensis Rupr. 1859 is a medicinal herb endemic to China and distributed throughout the country, particularly across the northern part of the mainland. However, the systematic classification of Euphorbiaceae remains controversial. Therefore, studying the chloroplast genome of E. pekinensis is crucial for the resolution of this taxonomic dispute, clarification of the systematic status of Euphorbia, and establishment of an accurate classification system for Euphorbiaceae. In this study, we sequenced the complete chloroplast genome of E. pekinensis using Illumina sequencing technology and annotated it using GeSeq. The complete chloroplast genome was 162,002-bp-long with a guanine–cytosine (GC) content of 35.7%. It included one large single-copy (LSC), one small single-copy (SSC), and two inverted repeat sequence regions (IRa and IRb), which were 90,225 bp, 18,067 bp, and 26,855 bp in length, respectively, and are indicative of a typical tetrad structure. The genome encoded 129 functional genes, comprising 85 protein-coding genes, 36 tRNA genes, and eight rRNA genes. According to the maximum-likelihood phylogenetic tree that was constructed using 16 complete chloroplast genomes, E. pekinensis was found to be closely related to E. ebracteolata. Therefore, the complete chloroplast genome of E. pekinensis provides a better understanding of Euphorbia genetics.

Complete chloroplast genome of Euphorbia micractina Boiss (Euphorbiaceae: Euphorbia)

Euphorbia micractina Boiss is a plant with high medicinal value. Yet, its molecular biology is not fully understood. In this study, we sequenced the whole chloroplast genome (CP) sequence of E. micractina to study its phylogenetic relationship in Euphorbiaceae. The total length of the chloroplast genome of E. micractina is 162,056 bp, including a large single-copy (LSC) region of 89,936bp bp, a small single-copy (SSC) region of 18,376 bp, and a pair of identical inverted repeat regions (IRs) of 11,367 bp. The genome has 128 genes, including 84 protein-coding genes, 36 transfer RNA (tRNA) genes, and 8 ribosomal RNA (rRNA) genes. The overall GC content of the plastome is 35.7%. The phylogenetic analysis of E. micractina with 30 related species suggested a closest taxonomical relationship with Euphorbia pekinensis in the Euphorbiaceae family.

Pimarane, abietane, and labdane diterpenoids from Euphorbia pekinensis Rupr. and their anti-tumor activities

Chemical investigation of the roots of Euphorbia pekinensis Rupr. led to the isolation of five undescribed labdane diterpenoids “(4S, 5S, 9R, 10S, 13R)-18-O-galloyl-labda-8(17), 14(15)-dien-13-ol; (4S, 5S, 9R, 10S, 13R)-13-hydroxy-labda-8(17), 14(15)-dien-18-one; (4S, 5S, 9R, 10S, 13R)-18-O-acetyl-labda-8(17), 14(15)-dien-13-ol; (4S, 5S, 9R, 10S)-labda-8(17), 13(16), 14(15)-trien-18-ol; (5R, 6R, 9R, 10S, 13R)-labda-8(17), 14(15)-dien-6,13-diol”, two undescribed pimarane diterpenoids “(2R, 5S, 9R, 10S, 12R, 13R)-2,12-dihydroxy-isopimara-7,15-dien-3-one; (5S, 9R, 10S, 12R, 13R)-2, 12-dihydroxy-isopimara-1, 7, 15-trien-3-one)”, together with nine known diterpenoids, including three pimarane-type “(3β,11α,13α)-3,11-dihydroxypimara-7,15-diene-2,12-dione; (11R, 12S)-2,11,12-trihydroxy-ent-isopimara-1,7,15-trien-3-one; isopimara-7,15-dien-3β-ol)”, five abietane-type “helioscopinolide A-C; helioscopinolide E; helioscopinolide I″, and one lathyrane-type “jolkinol B”. The structures of these compounds were elucidated by analysis of HRESIMS, 1D NMR, 2D NMR, and X-ray diffraction. These sixteen compounds were evaluated for cytotoxic activity in vitro against three human cancer cell lines, U-937, LOVO, and K-562. Jolkinol B exhibited IC50 of 3.60 μM and 8.44 μM against U-937 and LOVO cell lines, (4S, 5S, 9R, 10S, 13R)-18-O-galloyl-labda-8(17), 14(15)-dien-13-ol displayed IC50 of 5.92 μM against U-937 cell lines, isopimara-7,15-dien-3β-ol showed IC50 of 0.87 μM against K-562 cell lines.

Screening and identification of Euphorbiae pekinensis Rupr. anti-angiogenic multi-components with UPLC-QTOF-MS in zebrafish

Euphorbia pekinensis Rupr. (EP) (Euphorbiaceae), as Traditional Chinese Medicine (TCM), exhibits therapeutic effects on tumors in clinical practice. Anti-angiogenesis may be an underlying molecular mechanism of EP’s actions. However, the anti-angiogenic active ingredients of EP remain unclear. The screening and analysis of anti-angiogenic agents were essential for the sufficient utilization and development of EP. Thus, we established a UPLC-QTOF-MS method based on a transgenic zebrafish model to screen anti-angiogenesis activity components in EP. UPLC-QTOF-MS was used to characterize compounds from EP and in vivo compounds in Tg (flk1: mCherry) zebrafish larvae treated with EP. Based on the identification results, five components were selected, and their anti-angiogenesis activity were investigated via assessment of intersegmental blood vessels during the development of the transgenic zebrafish. Three of these components (3,3′-O-dimethoxy ellagic acid, quercetin, and ingenol) are active components of EP with anti-angiogenic effects. Among them, 3, 3′-O-dimethoxy ellagic acid and ingenol were first demonstrated with anti-angiogenesis effects. UPLC-PDA analysis was performed on EP water extracts to determine anti-angiogenesis active ingredients quantitatively. In the concentration range of 100–200 μg/mL, EP and the active ingredient compositions, mixed according to the content of EP, had equivalent anti-angiogenesis activities. These experimental results indicate that the UPLC-QTOF-MS method, combined with a transgenic zebrafish model, is rapid, sensitive and reliable. The combination in TCM offers the potential to achieve certain effect levels with lower concentrations of the individual compound.

Gut microbiota disorder caused by diterpenoids extracted from Euphorbia pekinensis aggravates intestinal mucosal damage.

Gut microbiota disorder will lead to intestinal damage. This study evaluated the influence of total diterpenoids extracted from Euphorbia pekinensis (TDEP) on gut microbiota and intestinal mucosal barrier after long‐term administration, and the correlations between gut microbiota and intestinal mucosal barrier were analysed by Spearman correlation analysis. Mice were randomly divided to control group, TDEP groups (4, 8, 16 mg/kg), TDEP (16 mg/kg) + antibiotic group. Two weeks after intragastric administration, inflammatory factors (TNF‐α, IL‐6, IL‐1β) and LPS in serum, short chain fatty acids (SCFAs) in feces were tested by Enzyme‐linked immunosorbent assay (ELISA) and high‐performance liquid chromatography (HPLC), respectively. The expression of tight junction (TJ) protein in colon was measured by western blotting. Furthermore, the effects of TDEP on gut microbiota community in mice have been investigated by 16SrDNA high‐throughput sequencing. The results showed TDEP significantly increased the levels of inflammatory factors in dose‐dependent manners, and decreased the expression of TJ protein and SCFAs, and the composition of gut microbiota of mice in TDEP group was significantly different from that of control group. When antibiotics were added, the diversity of gut microbiota was significantly reduced, and the colon injury was more serious. Finally, through correlation analysis, we have found nine key bacteria (Barnesiella, Muribaculaceae_unclassified, Alloprevotella, Candidatus_Arthromitus, Enterorhabdus, Alistipes, Bilophila, Mucispirillum, Ruminiclostridium) that may be related to colon injury caused by TDEP. Taken together, the disturbance of gut microbiota caused by TDEP may aggravate the colon injury, and its possible mechanism may be related to the decrease of SCFAs in feces, disrupted the expression of TJ protein in colon and increasing the contents of inflammatory factors.

Antioxidant Role of Kaempferol in Prevention of Hepatocellular Carcinoma.

Reactive oxygen species (ROS) are noxious to cells because their increased level interacts with the body’s defense mechanism. These species also cause mutations and uncontrolled cell division, resulting in oxidative stress (OS). Prolonged oxidative stress is responsible for incorrect protein folding in the endoplasmic reticulum (ER), causing a stressful condition, ER stress. These cellular stresses (oxidative stress and ER stress) are well-recognized biological factors that play a prominent role in the progression of hepatocellular carcinoma (HCC). HCC is a critical global health problem and the third leading cause of cancer-related mortality. The application of anti-oxidants from herbal sources significantly reduces oxidative stress. Kaempferol (KP) is a naturally occurring, aglycone dietary flavonoid that is present in various plants (Crocus sativus, Coccinia grandis, Euphorbia pekinensis, varieties of Aloe vera, etc.) It is capable of interacting with pleiotropic proteins of the human body. Efforts are in progress to develop KP as a potential candidate to prevent HCC with no adverse effects. This review emphasizes the molecular mechanism of KP for treating HCC, targeting oxidative stress.

Toxicity reduction and water expelling effect preservation of Shizaotang after its toxic members processing with vinegar on rats with malignant pleural effusions

Ethnopharmacological relevanceShizaotang (SZT), consisted of Euphorbia kansui S.L.Liou ex S.B.Ho (EK), Euphorbia pekinensis Rupr. (EP), Daphne genkwa Sieb. et Zucc. (DG，fried) and Ziziphus jujuba Mill. (ZJ), is usually used for treating malignant pleural effusions (MPE), but the toxicity of EK and EP limits its clinical safe application. It was reported that vinegar processing can reduce the toxicity of EK and EP. Whether EK and EP processing with vinegar can cause the reduced toxicity and retained pharmacological effects of SZT, it still remains unknown.Aim of the study: We aimed to evaluate whether using vinegar processed EK and EP would reduce toxicity and preserve water expelling effect of SZT. Materials and methodsNetwork pharmacology and qualitative analysis of SZT/VSZT were used to construct compound-target-pathway network of their effects and toxicity. Pleural fluid weight, urine volume, uric electrolyte, pH, pro-inflammatory cytokines in pleural fluid, serum Renin-Angiotensin-Aldosterone System (RAAS), anti-diuretic hormone (ADH) and intestinal aquaporin 8 (AQP8) protein were used to evaluate the effect mechanisms involved in rats experiments. And liver damage, oxidative damage and HE staining (liver, stomach, and intestine) were used to determine the toxicity. ResultsNetwork pharmacology analysis reviewed inflammation-related pathways of the effect and toxicity of SZT/VSZT: VEGF-PI3K-AKT pathway inhibited MPE by changing the vasopermeability; PI3K-Akt/Mitogen-activated protein kinase (MAPK)/TNF-NF-κB signaling pathway inhibited MPE by up-regulating expression of AQP8 protein. In vivo experiments displayed that SZT/VSZT could reduce pleural fluid, increase urine volume, lower pro-inflammatory cytokines levels and up-regulate AQP8 protein expression significantly (P < 0.05, P < 0.01). In addition, disorders on electrolyte (Na+, K+ and Cl−) and pH were ameliorated (P < 0.05, P < 0.01). The levels of RAAS and ADH were significantly dose-dependently called back (P < 0.01). These findings were partly consistent with the results of network pharmacology analysis. Results of toxicity experiments demonstrated that SZT and VSZT exhibited certain toxicity on normal rats, and VSZT had lower toxicity than that of SZT. Interestingly, SZT and VSZT exerted alleviation effect to the liver damage and oxidative damage on model rats. ConclusionSZT/VSZT improved MPE by regulating associated inflammation pathways. Besides, compared to SZT, VSZT showed lower toxicity and equivalent expelling MPE effect. This study may provide scientific basis for guiding the clinical application of SZT.

Euphopanes A–C, three new diterpenoids from Euphorbia pekinensis

Three new diterpenoids, euphopanes A–C (1–3), including one ent-isopimarane (1), one ent-abietane (2) and one cembrane (3), along with five known compounds (4–8) were isolated from the roots of Euphorbia pekinensis. Their structures were elucidated by extensive spectroscopic analysis, and the absolute configurations of compounds 1–3 were determined by ECD calculations. All the isolates were screened for the cytotoxicity against three cancer cell lines (C4-2B, C42B/ENZR, and MDA-MB-231), and compounds 1, 2, and 4 showed significant cytotoxicity against human prostate cancer cells C4-2B with IC50 values of 14.3, 16.9, and 15.3 μM, respectively.

Diterpene pekinenal from euphorbia pekinensis radix induced IEC-6 cells apoptosis mediated by mitochondria and death receptors

Pekinenal, a diterpenoid from the roots of Euphorbia pekinensis Rupr., can cause serious intestinal toxicity. However, its toxic mechanism hasn't been comprehensively understood. This present study aims to clarify its toxic effects and investigate the potential mechanism. In vitro effects of pekinenal on cell proliferation, cell cycle and apoptosis were examined by performing experiments on rat intestinal crypt epithelial cells (IEC-6). Proteins and enzymes involved in cell apoptotic pathways were detected by Western blot and enzyme-linked immunosorbent assay (ELISA), and related mRNAs were detected by RT-PCR. The results showed that the cell cycle was arrested in G0/G1 phase, and apoptotic morphology changes in pekinenal-treated cells. Furthermore, pekinenal up-regulated the expression level of apoptotic protein including Bax, AIF, Apaf-1 and the expression level of mRNA such as Fas, FasL, TNFR1 and NF-κB, while down-regulated the expression level of Bcl-2, ultimately triggering the apoptosis of caspase dependence. In conclusion, the above data confirmed that pekinenal inhibited the proliferation of IEC-6 cells and induced cells apoptosis by modulating mitochondrial and death receptor pathways.

Selective oncolytic effect in Epstein-Barr virus (EBV)-associated gastric carcinoma through efficient lytic induction by Euphorbia extracts

Lytic induction of latent Epstein-Barr virus (EBV) has been considered as a therapeutic approach for efficient treatment of EBV-associated malignancies. Here, we established a robust assay system quantitatively measuring EBV lytic induction and identified three Euphorbia extracts as strong inducers from a screen of Korean medicinal plant extracts library. Expression of lytic genes were efficiently induced by each Euphorbia extract in SNU-719 (EBV-positive gastric carcinoma cells). Euphorbia pekinensis, out of three extracts, exhibited the most potent lytic-inducing activity. Importantly, treatment with E. pekinensis extract led to an obvious cytotoxic effect on SNU-719 cells, but little on MKN-74 cells (EBV-negative gastric carcinoma cells), indicating the selective oncolytic effect on EBV-positive gastric carcinoma. We further revealed that lytic-inducing activity of E. pekinensis was mediated by PKC/MEK signal. Moreover, we defined two structural analogs of PMA with strong lytic-inducing activity, suggesting their therapeutic applicability for the treatment of EBV-associated gastric carcinoma.

Metabolomic evaluation of Euphorbia pekinensis induced nephrotoxicity in rats

Context: Euphorbia pekinensis Rupr. (Euphorbiaceae) has long been used in the Orient, while its clinical use was limited due to its nephrotoxic effect.Objective: The possible mechanism of nephrotoxicity of Euphorbia pekinensis (EPR) and its related constituents were investigated.Materials and methods: Petroleum ether (PE), acetic ether (AE) and n-butanol (BUT) extracted sections of EPR were separately given to Wistar rats by gavage at the dose of 3 g/kg/day for 10 weeks to determine the nephrotoxic section of EPR. Then, renal metabolic profiling of EPR after oral administration of nephrotoxic section was investigated and its related constituents were identified by LC/Q-TOF-MS method.Results: The average values of creatinine (CREA) in PE, AE, BUT and control groups were 76.54 ± 9.52, 54.12 ± 10.34, 51.33 ± 5.19 and 48.23 ± 6.67 μmol/L. The average values of blood urea nitrogen (BUN) in PE, AE, BUT and control groups were 15.25 ± 3.37, 8.32 ± 0.89, 9.22 ± 1.78 and 8.47 ± 1.33 mmol/L, respectively. Only kidney section of rats in PE group showed that glomeruli had cellular or fibrocellular crescents. Renal metabolic profiling showed disturbed metabolic pathways of purine, amino acid, phospholipids and sphingolipids in EPR nephrotoxicity. A total of 25 compounds [(–)-(1S)-15-hydroxy-18-carboxycembrene is a new compound] in PE section and 10 compounds in rat serum after administration of PE section were identified.Conclusions: This is the first time that the toxic compounds of PER and action mechanism of EPR nephrotoxicity were explored to provide a new reference for studying the toxic components of Traditional Chinese Medicine (TCM).

Polyphenols from Euphorbia pekinensis Inhibit AGEs Formation In Vitro and Vessel Dilation in Larval Zebrafish In Vivo.

To identify active compounds in the roots of Euphorbia pekinensis for treatment of diabetic complications, an active column fraction from a 70% EtOH extract of E. pekinensis root was purified by preparative reversed-phase high-performance liquid chromatography, leading to the isolation of a new ellagic acid derivative, 3,3'-di-O-methylellagic acid 4-O-(6"-O-galloyl)-β-D-galactopyranoside (1: ), along with three known compounds, geraniin (2: ), 3,3'-di-O-methylellagic acid 4-O-β-D-xylopyranoside (3: ), and ellagic acid 3,3'-dimethyl ether (4: ). The structure of the new compound was established by extensive spectroscopic studies and chemical evidence. The inhibitory effects of isolated compounds 1: -4: on advanced glycation end-products (AGEs) formation were examined. All compounds exhibited considerable inhibition of AGEs formation and IC50 values of 0.41 - 12.33 µM, compared with those of the positive controls aminoguanidine (IC50 = 1122.34 µM) and quercetin (IC50 = 27.80 µM). In addition, the effects of 2: and 4: on the dilation of hyaloid-retinal vessels induced by high glucose (HG) in larval zebrafish were investigated; both compounds significantly reduced the HG-induced dilation of hyaloid-retinal vessels relative to the HG-treated control group.

Upregulation of aquaporin 3 expression by diterpenoids in Euphorbia pekinensis is associated with activation of the NF-κB signaling pathway in the co-culture system of HT-29 and RAW 264.7 cells

This study was designed to evaluate the toxic effects of diterpenoids separated from the roots of Euphorbia pekinensis, a type of widely used traditional Chinese medicine. This herb has intestinal toxicity associated with its complex diterpenoids. In this study, the diterpenoids (pekinenin A, pekinenin C, pekinenin F, pekinenin G, yuexiandajisu A, (−)-(1S)-15-hydroxy-18-carboxycembrene) elevated the expression of interleukin 1 beta and tumor necrosis factor alpha in a dose-dependent manner at doses of 6.25, 12.5, and 25 μM in RAW264.7 monocultures. Pekinenin C increased the expression of phosphorylated IκB and phosphorylated p65 in RAW264.7 monocultures, indicating that it stimulated a substantial inflammatory response and activated the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway. A co-culture model of RAW 264.7 mouse macrophage cells and HT-29 human intestinal epithelial cells was established to study the correlation between inflammation and aquaporin (AQP) expression and to evaluate the toxicity of different diterpenoids from E. pekinensis. Pekinenin C (6.25, 12.5, and 25 μM) increased AQP3 mRNA and protein expression of HT-29 cells in the co-culture system in a dose-dependent manner but not in HT-29 monocultures. AQP3 mRNA and protein expression peaked at 2 and 3 h of HT-29 cells in the co-culture system, respectively. In contrast, their expression peaked more slowly in the monoculture system. After the specific NF-κB inhibitor BAY11-7082 (5, 10, and 20 μM) was added to the co-culture system, the release of cytokines and increased AQP3 expression caused by pekinenin C were inhibited. Comparisons of the representative monomeric compound pekinenin C, diterpenoid monomer mixtures, and total diterpenoids from E. pekinensis showed that the monomer mixtures had the most toxicity. In conclusion, this study demonstrated that E. pekinensis induces inflammation and increases the expression of AQP3, causing disorders of water metabolism, which may lead to gastrointestinal side effects such as diarrhea.