Antibacterial Activity of Plants in Cirsium: A Comprehensive Review.

As ethnic medicine, the whole grass of plants in Cirsium was used as antimicrobial. This review focuses on the antimicrobial activity of plants in Cirsium, including antimicrobial components, against different types of microbes and bacteriostatic mechanism. The results showed that the main antimicrobial activity components in Cirsium plants were flavonoids, triterpenoids and phenolic acids, and the antimicrobial ability varied according to the species and the content of chemicals. Among them, phenolic acids showed a strong antibacterial ability against Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterococcus faecium. The antibacterial mechanisms include: (1) damaging the cell membrane, cell walls, mitochondria and nucleus of bacteria; (2) inhibiting the synthesis of proteins and nucleic acids; (3) suppressing the synthesis of enzymes for tricarboxylic acid cycle pathways and glycolysis, and then killing the bacteria via inhibition of energy production. Totally, most research results on antimicrobial activity of Cirsium plants are reported based on in vitro assays. The evidence from clinical data and comprehensive evaluation are needed.

Inhibitory Mechanism of Prenylated Flavonoids Isolated from Mulberry Leaves on α-Glucosidase by Multi-Spectroscopy and Molecular Dynamics Simulation.

Flavonoids have always been considered as the chemical basis for the hypoglycemic effect of mulberry leaves. In the course of our search for hypoglycemic effect agents from natural sources, a systematic study was launched to explore prenylated flavonoids from mulberry leaves. Herein, chemical investigation led to the isolation of 10 characteristic prenylated flavonoids, including two new compounds (1 and 3). Their structures were elucidated based on spectroscopic data. All compounds exhibited good α-glucosidase inhibitory activity in vitro, among which compound 2 had the best activity (IC50 = 2.6 µM), better than acarbose (IC50 = 19.6 µM). Additional in vivo tests have further demonstrated compound that compound 2 has a good ability to reduce postprandial blood glucose. Then, multi-spectroscopic methods and molecular simulation studies were used to study the inhibition mechanism. The results showed that compound 2 was a mixed inhibition of α-glucosidase and the binding process was spontaneous, with van der Waals forces as the main driving force, followed by hydrogen bonding and electrostatic forces. The above studies enriched the chemical basis of mulberry leaves, and the application of computational chemistry also provided a reference for future research on such structures.

Synergistic Effects of Combined Anthocyanin and Metformin Treatment for Hyperglycemia In Vitro and In Vivo.

The mechanism underlying the hypoglycemic effect of the simultaneous use of metformin and anthocyanin-rich foods is not yet clear. Hence, the effects and possible mechanisms of action of these substances, alone and in combination, were evaluated in insulin-resistant HepG2 cells and a diabetic mouse model. The results indicated that anthocyanin and metformin had a significant synergistic effect on glucose consumption (CI < 0.9) compared with metformin alone in HepG2 cells. In the mouse model, combined treatment (50 and 100 mg/kg metformin + anthocyanin groups) demonstrated synergistic restorative effects on the blood glucose level, insulin resistance, and organ damage in the liver, pancreas, and ileum. Additionally, combined metformin and anthocyanin treatment suppressed protein tyrosine phosphatase 1B expression and regulated the PI3K/AKT/GSK3ß pathway. Combined treatment also altered the gut microbial composition and structure by increasing the relative abundance of beneficial bacteria and the short-chain fatty acid content. These results suggest that the use of anthocyanins can enhance the efficacy of metformin treatment for hyperglycemia and provide a reference for further clinical research regarding nutrition and supplementary treatment.

Traditional uses, phytochemistry, pharmacology and clinical applications of Cortex Juglandis Mandshuricae: A comprehensive review.

ETHNOPHARMALOGICAL RELEVANCE: Cortex Juglandis Mandshuricae (CJM) is the dry branch or stem bark of the Juglans mandshurica Maxim. and is widely used as a traditional Chinese medicine in Asia and Africa. Its use was first recorded in Kaibao Bencao. AIM OF THE STUDY: The present review provides a deeper insight, better awareness and detailed knowledge of phytochemistry, pharmacology, quality control, along with clinical applications of Cortex Juglandis Mandshuricae. METHODS: The relevant information of Cortex Juglandis Mandshuricae was obtained from several databases including Web of Science, PubMed, and CNKI. The medical books, PhD and MSc dissertations in Chinese were also used to perform this work. RESULTS: CJM has been traditionally used against a wide range of diseases, including dysentery, acute conjunctivitis, bacterial infections, and cancer. A total of 249 compounds have been isolated from CJM; they mainly include quinones and their derivatives, flavonoids, tannins, diarylheptanoids, triterpenoids, coumarins, phenylpropanoids, and volatile oils. These compounds exert anti-tumor, anti-oxidant, anti-inflammatory, bacteriostatic, anti-complement, immunomodulatory, anti-parasitic activities. Specifically, the effects of juglone, alkaloids and unsaturated fatty acid CJM components against hepatic cancer occur through exertion of apoptosis through a mitochondria-dependent pathway. In addition, taxifolin and several tannins have been found to have anti-HIV activity, and (±)-juglanaloid A and (±)-juglanaloid B target Alzheimer disease. Quality control is monitored through identification of juglone, quercetin, and volatile oils. A clinical preparation of CJM, Compound Muji Granules, is used in the treatment of various liver diseases with good therapeutic effect. CONCLUSION: While CJM has been used extensively as a folk medicine, the relationships between structure and activity remain unclear. More in vivo models are needed to study the pharmacological mechanisms of action and to assess potential toxic components, in addition to which the evidence used to demonstrate the quality standards of medicinal materials is clearly inadequate. Therefore, more in-depth research is needed to provide a reasonable scientific basis improve its clinical utilization.

Prenylated isoflavones from the roots of Flemingia philippinensis as potential inhibitors of ß-amyloid aggregation.

In our efforts to find potential agents for the treatment of Alzheimer's disease in naturally occurring compounds, a systematic investigation for the active constituents of Flemingia philippinensis was carried out. Four new prenylated isoflavones, philippinone A-D (1-4), together with six known analogues (5-10), were obtained from the roots of Flemingia philippinensis. Their structures were established through extensive physical and spectroscopic data analysis. All the isolates were evaluated for their inhibitory effect of self-induced Aß aggregation among which compound 5 showed significant Aß aggregation inhibitory ability with the inhibitory rate of 70.56%. The results of molecular docking experiment for compounds 1 and 6 corresponded to that of the thioflavin-T assay. Moreover, the results further clarified the effects of different substituent group of tested compounds on the Aß aggregation inhibition. A preliminary structure-activity relationship is further discussed. Our results suggested that the isoflavonoids may mitigate the progression of AD and compounds 2 and 5 may be a candidate in the treatment of AD.

Current progress on the mechanisms of hyperhomocysteinemia-induced vascular injury and use of natural polyphenol compounds.

Cardiovascular disease is one of the most common diseases in the elderly population, and its incidence has rapidly increased with the prolongation of life expectancy. Hyperhomocysteinemia is an independent risk factor for various cardiovascular diseases, including atherosclerosis, and damage to vascular function plays an initial role in its pathogenesis. This review presents the latest knowledge on the mechanisms of vascular injury caused by hyperhomocysteinemia, including oxidative stress, endoplasmic reticulum stress, protein N-homocysteinization, and epigenetic modification, and discusses the therapeutic targets of natural polyphenols. Studies have shown that natural polyphenols in plants can reduce homocysteine levels and regulate DNA methylation by acting on oxidative stress and endoplasmic reticulum stress-related signaling pathways, thus improving hyperhomocysteinemia-induced vascular injury. Natural polyphenols obtained via daily diet are safer and have more practical significance in the prevention and treatment of chronic diseases than traditional drugs.

Bioactive flavonoids from Rubus corchorifolius inhibit α-glucosidase and α-amylase to improve postprandial hyperglycemia.

This research established an optimized method for the extraction and enrichment of flavonoids from R. corchorifolius fruit. Under the optimized extraction conditions, 12 flavonoids (1-12) were isolated, of which six (2-4, 9-10, 12) were obtained from R. corchorifolius for the first time. Compound 4 showed significant α-glucosidase (4.96 µM) and α-amylase (8.04 µM) inhibitory effects. Molecular modeling revealed that compound 4 exhibits strong binding with the active sites of α-glucosidase and α-amylase. Lineweaver-Burk plot analysis and surface plasmon resonance revealed the possible dynamic binding mechanism of the flavonoids with α-glucosidase and α-amylase. The enriched flavonoids and compound 4 showed significant hypoglycemic effects in mice administered a high dose of glucose. In this study, a variety of flavonoids with hypoglycemic activity were found for the first time, revealing the rich chemical composition of R. corchorifolius fruit and highlighting the potential value of R. corchorifolius fruit flavonoids as dietary supplements.

Novel Protein Tyrosine Phosphatase 1B Inhibitor-Geranylated Flavonoid from Mulberry Leaves Ameliorates Insulin Resistance.

Mulberry leaf is a common vegetable with a variety of beneficial effects, such as hypoglycemic activity. However, the underlying mechanism of its hypoglycemic effect have not been fully revealed. In this study, two flavonoid derivatives were isolated from mulberry leaves, a new geranylated flavonoid compound (1) and its structural analogue (2). The structures of compounds 1 and 2 were elucidated using spectroscopic analysis. To study the potential hypoglycemic properties of these compounds, their regulatory effects on protein tyrosine phosphatase 1B (PTP1B) were investigated. In comparison to oleanolic acid, compounds 1 and 2 showed significant inhibitory activities (IC50 = 4.53 ± 0.31 and 10.53 ± 1.76 µM) against PTP1B, the positive control (IC50 = 7.94 ± 0.76 µM). Molecular docking predicted the binding sites of compound 1 to PTP1B. In insulin-resistance HepG2 cell, compound 1 promoted glucose consumption in a dose-dependent manner. Furthermore, western blot and polymerase chain reaction analyses indicated that compound 1 might regulate glucose consumption through the PTP1B/IRS/PI3K/AKT pathway. In conclusion, geranylated flavonoids in mulberry leaves inhibite PTP1B and increase the glucose consumption in insulin-resistant cells. These findings provide an important basis for the use of mulberry leaf flavonoids as a dietary supplement to regulate glucose metabolism.

Identification of Cyanidin-3-arabinoside Extracted from Blueberry as a Selective Protein Tyrosine Phosphatase 1B Inhibitor.

Protein tyrosine phosphatase 1B (PTP1B) is an important target for type 2 diabetes. PTP1B inhibitors can reduce blood glucose levels by increasing insulin sensitivity. Anthocyanins often play a hypoglycemic effect, but the research about them have mainly focused on glucosidase. At present, the research about protein tyrosine phosphatase 1B (PTP1B) target is less, and the corresponding molecular mechanism is still unclear. Therefore, in this present study, anthocyanins isolated from blueberry were used to study the inhibitory activity on PTP1B. The isolated cyanidin-3-arabinoside (Cya-3-Ara) exhibited a better inhibitory activity with IC50 = 8.91 ± 0.63 µM, which was higher than the positive control (oleanolic acid, IC50 = 13.9 ± 1.01 µM), and the mechanism of PTP1B inhibition was reversible mixed pattern. The structure-activity relationship (SAR) between anthocyanins and PTP1B inhibition was investigated. The enzyme activity inhibition and molecular docking showed that anthocyanins had high selectivity for PTP1B inhibition. Further study showed that Cya-3-Ara could promote glycogen synthesis through ameliorating PTP1B-involved IRS-1/PI3K/Akt/GSK3ß pathways. Cya-3-Ara could also be regarded as a synergistic inhibitor (CI ≤ 0.54) of oleanolic acid to obtain a better inhibitory effect on PTP1B. Taken together, our study clearly illustrates the SAR between anthocyanins and PTP1B inhibition and the mechanism of Cya-3-Ara in the insulin signaling pathway.

A "Green" Homogenate Extraction Coupled with UHPLC-MS for the Rapid Determination of Diterpenoids in Croton Crassifolius.

Clerodane diterpenoids are the main bioactive constituents of Croton crassifolius and are proved to have multiple biological activities. However, quality control (QC) research on the constituents are rare. Thus, the major research purpose of the current study was to establish an efficient homogenate extraction (HGE) process combined with a sensitive and specific ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC⁻MS) technique together for the rapid extraction and determination of clerodane diterpenoids in C. crassifolius. All calibration curves showed good linearity (r > 0.9943) within the test ranges and the intra- and inter-day precisions and repeatability were all within required limits. This modified HGE⁻UHPLC⁻MS method only took 5 min to extract nine clerodane diterpenoids in C. crassifolius and another 12 min to quantify these components. The results indicated that the quantitative analysis based on UHPLC⁻MS was a feasible method for QC of clerodane diterpenoids in C. crassifolius, and the findings outlined in the current study also inferred the potential of the method in the QC of clerodane diterpenoids in other complex species of plants.

Sesquiterpenoids from the roots of Croton crassifolius.

Phytochemical investigation of Croton crassifolius roots afforded five sesquiterpenes (1-5), including two new sesquiterpenes 6S-hydroxy-cyperenoic acid (1) and crassifterpenoid A (5), together with three known compounds (2-4). The structures of the new compounds were determined by comprehensive spectroscopic methods, and their absolute configurations were determined by quantum chemical ECD calculation. Crassifterpenoid A (5) is the first germacrane-type sesquiterpene isolated from C. crassifolius, which enriched the diversity of chemical constituents in Croton crassifolius. In addition, the cytotoxicities of all compounds against human liver cancer lines HepG2 and Hep3B were determined, but none showed significant activity.

Pyran-2-one derivatives from Croton crassifolius as potent apoptosis inducers in HepG2 cells via p53-mediated Ras/Raf/ERK pathway.

Chemical investigation of the roots of Croton crassifolius led to the isolation of five pyran-2-one derivatives, including two brand new compounds (1-2), one new natural product (3) and two known compounds (4-5). Their structures and absolute configurations were established by spectroscopic analyses as well as comparison between the calculated optical rotation (OR) values with the experimental data. Interestingly, the new compound 1 showed an unusual negative chemical shift at H-11. It is well known that negative chemical shift values of 1H NMR spectrum are extremely rare in natural products. Such a negative chemical shift of 1H NMR spectrum was reproduced by density functional theory (DFT) calculations and explained by the shielding effect from the pyran-2-one ring over the hydrogen atom in the 3D conformations. Then, MTT assay was applied to evaluate the cytotoxicity of the isolated compounds (1-5) against two liver cancer cell lines (HepG2 and MHCC97H). The results suggested that compound 1 displayed the highest cytotoxicity with an IC50 value of 9.8 µM against HepG2 cells. Moreover, there was no obvious cytotoxicity of compounds 1-5 on normal liver cell line LO2. Furthermore, the mechanism of apoptosis induction in compound 1-treated HepG2 cells was investigated. The results showed that compound 1 could induce apoptosis via p53-mediated Ras/Raf/ERK suppression in HepG2 cells.

Biotransfomation of cyperenoic acid by Cunninghamella elegans AS 3.2028 and the potent anti-angiogenic activities of its metabolites.

Cyperenoic acid (1) is one of the major sesquiterpenes isolated from Croton crassifolius, which exhibited potent anti-angiogenic activity. Traditional structural modification of 1 is difficult to perform by chemical technology due to the remarkable stability of the patchoulane skeleton. In order to overcome chemical synthesis difficulties and obtain structurally diverse derivations, microbial transformation of 1 by using Cunninghamella elegans AS 3.2028 was studied for the first time. Five new hydroxylated products 2-6 were obtained. Furthermore, cytotoxicity and anti-angiogenic activities of all the biotransformation products were evaluated by MTT assay and ELISA in HepG2 and MCF-7 cells. These results indicated that hydroxylated modification products 2-4 significantly inhibited VEGF release, which suggest the potential use of hydroxylated modification products for cancer therapy.

Cytotoxic clerodane diterpenoids from Croton crassifolius.

Hepatocellular carcinoma (HCC) is the most common type of liver cancer, and treatment options for HCC are limited. In addition, the discovery of new natural compounds with anti-hepatocarcinoma activity is attracting increasing attention. For this reason, phytochemical investigation of Croton crassifolius led to the isolation of 17 diterpenoids, including three new clerodane diterpenoids, named crassifolius A-C (1-3), along with 14 known ones (4-17). Their structures were established by 1D, 2D NMR, HR-ESI-MS, detailed calculated electronic circular dichroism (ECD) spectra and the assistance of quantum chemical predictions (QCP) of 13C NMR chemical shifts. The cytotoxicities of all these compounds against human liver cancer lines (HepG2 and Hep3B) were determined. Among them, compound 1 exhibited good cytotoxicity with IC50 value of 17.91µM against human liver tumor cells Hep3B. Following further studies of the anti-tumor mechanism of compound 1-induced cell growth inhibition, we found that compound 1 caused apoptotic cell death in Hep3B cells by detecting morphologic changes and Western blotting analysis.

Two new alkaloids from Portulaca oleracea and their cytotoxic activities.

Two new alkaloids named (3R)-3,5-bis(3-methoxy-4-hydroxyphenyl)-2,3-dihydro-2(1H)-pyridinone (1) and 1,5-dimethyl-6-phenyl-1,2-dihydro-1,2,4-triazin-3(2H)-one (2), together with two known compounds (7'R)-N-feruloyl normetanephrine (3) and N-trans-feruloyl tyramine (4) were isolated from the air-dried aerial parts of Portulaca oleracea L. Their structures and configurations were elucidated by spectroscopic methods including 1D NMR, 2D NMR, and HR-MS techniques. In addition, compounds 1-4 were tested for in vitro cytotoxic activities against human lung (K562 and A549) and breast (MCF-7 and MDA-MB-435) cancer cell lines.