查找使用阿拉丁产品的科研文献

Pinosylvin and Sanguinarine Combination to Enhance Antifungal Activity against Candida albicans

Yaxuan Yue,Jing Liu,Chen Li,Fengfeng Chen,Cheng Yang,Bingtian Zhao

Candida albicans is one of the major sources of fungal infections that can lead to life-threatening systemic infections. However, effective control of C. albicans remains a great challenge. Herein, this study aimed at investigating the antifungal effect of a combination of two natural compounds, pinosylvin (PIN) and sanguinarine (SAN), against C. albicans . In order to investigate the antifungal effect and mechanism of the combination of PIN and SAN, antimicrobial assay, time-kill assay, biofilm formation assay, cell membrane integrity assay, and reactive oxygen species (ROS) assay were performed. The results showed that the combination of PIN and SAN was more effective against C. albicans than PIN or SAN alone. PIN and SAN could jointly inhibit biofilm formation and thus attenuate C. albicans adhesion and colonization ability. PIN mainly targeting the cell membrane while SAN mainly inducing the cell to produce large amounts of ROS. Besides, PIN promoted the entry of SAN into C. albicans . Finally, the hemolysis experiment demonstrated that the combination of PIN and SAN is biocompatible. Taken together, the combination of PIN and SAN enhanced the antifungal effect against C. albicans , which has a broad application prospect in the control of C. albicans .

Simple Analogues of Quaternary Benzo[c]phenanthridine Alkaloids: Discovery of a Novel Antifungal 2-Phenylphthalazin-2-ium Scaffold with Excellent Potency against Phytopathogenic Fungi

Zhi-Ming Cui,Bo-Hang Zhou,Chao Fu,Liu Chen,Juan Fu,Fang-Jun Cao,Xin-Juan Yang,Le Zhou

Inspired by sanguinarine and chelerythrine, a novel antifungal 2-phenylphthalazin-2-ium scaffold as a simple analogue was designed. Most of the 30 compounds showed excellent inhibition activity against almost all eight phytopathogenic fungi, far superior to sanguinarine and chelerythrine. A third of the compounds were more active than azoxystrobin in most cases. Compounds 26 and 27 showed the highest total activity against all the fungi with EC50 means of ca. 4.6 μg/mL. Fusarium solani showed the highest susceptibility with an EC50 mean of 3.62 μg/mL to 19 compounds. A concentration of 25.0 μg/mL 27 can fully control the Colletotrichum gloeosporioides infection in apples over 9 days. Electron microscopic observations showed that 27 was able to damage the structures of the hypha and cell membrane. The structure–activity relationship showed that the presence of electron-withdrawing groups on the C-ring increases the activity against most of the fungi. Thus, 2-phenylphthalazin-2-ium compounds represent promising leads for the development of novel fungicides.

Sanguinarine synergistically potentiates aminoglycoside-mediated bacterial killing

Chang Lu,Nian Zhang,Sihoi Kou,Liangliang Gao,Bo Peng,Yunlu Dai,Jun Zheng

Summary Aminoglycosides are one of the oldest classes of antimicrobials that are being used in current clinical practice, especially on multi-drug resistant Gram-negative pathogenic bacteria. However, the serious side effects at high dosage such as ototoxicity, neuropathy and nephrotoxicity limit their applications in clinical practice. Approaches that potentiate aminoglycoside killing could lower down their effective concentrations to a non-toxic dosage for clinical treatment. In this research, we screened a compound library and identified sanguinarine that acts synergistically with various aminoglycosides. By checkerboard and dynamical killing assay, we found that sanguinarine effectively potentiated aminoglycoside killing on diverse bacterial pathogens, including Escherichia coli, Acinetobacter baumannii, Klebsiella pneumonia and Pseudomonas aeruginosa . The mechanistic studies showed an elevated intracellular ROS and DNA oxidative level in the bacterial cells treated by a combination of sanguinarine with aminoglycosides. Furthermore, an enhanced level of sanguinarine was observed in bacteria in the presence of aminoglycosides, suggesting that aminoglycosides promote the uptake of sanguinarine. Importantly, sanguinarine was shown to promote the elimination of persister cells and established biofilm cells both in vivo and in vitro . Our study provides a novel insight for approaches to lower down the clinical dosages of aminoglycosides.

Sanguinarine Rapidly Relaxes Rat Airway Smooth Muscle Cells Dependent on TAS2R Signaling

Mingzhi Luo,Peili Yu,Kai Ni,Yang Jin,Lei Liu,Jingjing Li,Yan Pan,Linhong Deng

Excessive contraction of airway smooth muscle cells (ASMCs) is a hallmark feature of asthma. Intriguing, the activation of bitter taste receptor (TAS2R) in ASMCs can relax ASMCs. However, there is a lack of potent TAS2R agonists that can be used in asthma therapies since those tested agonists cannot relax ASMCs at the dose below a few hundred micromolar. Considering that sanguinarine (SA) is a bitter substance often used in small doses for the treatment of asthma in folk medicine, the present study was to determine the rapid relaxation effect of SA on ASMCs and to reveal the underlying mechanisms associated with TAS2R signaling. Here, cell stiffness, traction force, calcium signaling, cAMP levels, and the mRNA expression were evaluated by using optical magnetic twisting cytometry, traction force microscopy, Fluo-4/AM labeling, enzyme-linked immunosorbent assay (ELISA), and quantitative (q)RT-PCR, respectively. We found that 0.5 µM SA immediately decreased cell stiffness and traction force, which is comparable with the effect of 5 µM isoproterenol. In addition, 0.5 µM SA immediately increased intracellular free calcium concentration ([Ca2+]i) and decreased the mRNA expression of contractile proteins such as calponin and α-smooth muscle actin after the treatment for 24 h. Furthermore, SA-mediated decrease in cell stiffness/traction force and increase in [Ca2+]i were significantly blunted by inhibiting the TAS2Rs signaling. These findings establish the rapid relaxation effect of SA at low concentration (<1 µM) on cultured ASMCs depending on TAS2R signaling, indicating that SA might be developed as a useful bronchodilator in asthma therapy.

Microchip electrophoretic separation and fluorescence detection of chelerythrine and sanguinarine in medicinal plants

Yue Sun,Yuanyuan Li,Jiajian Zeng,Qixian Lu,Paul C.H. Li

A new method has been developed for separation of chelerythrine and sanguinarine in medicinal plants used in traditional Chinese medicine (TCM). The separation is achieved by microchip electrophoresis (CE) using laser-induced fluorescence detection. The CE separation is achieved by using a hydro-organic medium as the electrolyte buffer. The experimental results are consistent with the prediction by theory in terms of resolution and migration speed because of the low Joule heat generated in microchip CE . In addition, formamide was found to have a potential for separation of molecules with similar chemical structures. Based on these findings, a run buffer containing 50% formamide was used to separate chelerythrine (CHE) and sanguinarine (SAN). The influencing factors, such as solvent of run buffer, pH of buffer, separation distance, and separation voltage, were optimized. Baseline separation of chelerythrine and sanguinarine was achieved within 120   s under an electrical voltage of 1.8   kV. Good linearity was observed in the concentration range of 0.15–550   μg   mL −1 ( r =0.9993) for CHE and in the range of 0.3–600   μg   mL −1 ( r =0.9998) for SAN. A low limit of detection (LOD) was achieved because of the high sensitivity achieved by laser-induced fluorescence detection (i.e. 5.0   ng   mL −1 and 2.0   ng   mL −1 for CHE and SAN, respectively). The contents of CHE are found to be 641.8±7.5 and 134.0±2.3   mg/kg in extracts of Macleaya cordata and Chelidonium majus , respectively, with good recovery of above 99%. The corresponding values for SAN found in these Chinese herbal extracts are 681.8±7.9   mg/kg and 890.5±8.9   mg/kg, respectively.

Targeting membrane integrity and imidazoleglycerol-phosphate dehydratase: Sanguinarine multifaceted approach against Staphylococcus aureus biofilms

Qianwei Qu,Xingyu Huang,Zhenxin Zhu,Jun Wang,Mengmeng Zhao,Wenqiang Cui,Yadan Zheng,Yanyan Liu,Xueying Chen,Zhiyun Zhang,Na Dong,Chunliu Dong,Yanhua Li

Background Staphylococcus aureus is an opportunistic pathogen capable of readily forming biofilms, which can result in life-threatening infections involving different organs. Sanguinarine are benzo[c]phenanthridine alkaloids extracted from the Sanguinaria canadensis L. (Papaveraceae), which have a wide range of biological activities. Previous reports have shown that sanguinarine is able to induce an elevation of ROS to exert an anti- S. aureus effect. Nevertheless, the specific mechanism of action of sanguinarine against S. aureus biofilms remains unexplored. Purpose The objective of this study was to elucidate the target site of sanguinarine in S. aureus , as well as to investigate its mechanism of antimicrobial action and its interference with biofilm formation. Additionally, the study aimed to provide further evidence supporting the use of sanguinarine as an alternative to traditional antibiotics. Methods Initially, we assessed the in vitro anti- S. aureus properties of sanguinarine through a series of methodologies, including MIC assays, time-dependent assays, and resistance development studies. Secondly, we explored the antimicrobial mechanism of sanguinarine using TEM, membrane permeability assays, and membrane fluidity assays. Subsequently, the mechanism by which sanguinarine interferes with S. aureus biofilm formation was preliminarily analyzed in vitro . Additionally, the interaction between sanguinarine and imidazoleglycerol-phosphate dehydratase (IGPD) was investigated using bio-layer interferometry assays, circular dichroism spectroscopy, molecular docking, and site-directed mutagenesis to further elucidate the role of sanguinarine in biofilm disruption. Finally, the therapeutic efficacy of sanguinarine was evaluated in vivo using mouse models of biofilm and bacteremia. Results Herein, sanguinarine demonstrated notable antimicrobial properties and interfering effects on biofilm formation. Mechanistic investigations revealed that sanguinarine exerts its antimicrobial action by dissipating the proton motive force in bacteria and compromising the integrity and functionality of the cytoplasmic membrane. Furthermore, sanguinarine was found to regulate IGPD expression and inhibit L-histidine synthesis, thereby interfering S. aureus biofilm formation. Consequently, due to its polypharmacological effect, sanguinarine significantly reduced the S. aureus load in mouse organs and the formation of biofilm on the surface of implants in vivo without any resistance. Conclusions In this study, we demonstrated that sanguinarine can exert antibacterial and interfere with biofilm formation by disrupting the cell membrane of S. aureus and targeting IGPD. These findings suggest that sanguinarine holds potential for further development as a novel antibiotic to combat biofilm-associated infections.

Sanguinarine triggers apoptosis and ferroptosis synchronously by directly binding BiP in lung squamous cell carcinoma

Weidan Tan,Xinyu Wei,Changsheng Li,Huilan Wei,Fei Yu,Xiaoju Shen,Xiaoxiang Mo,Meifen Wei,Shangping Xing,Zhuo Luo,Jie Yang

Lung squamous cell carcinoma (LUSC) is a prevalent and aggressive form of lung cancer with limited therapeutic options. Sanguinarine (SAG), a prominent benzophenanthridine alkaloid derived from Zanthoxylum nitidum (Roxb.) DC, exhibits established anti-tumor activity; however, its molecular mechanisms in LUSC remain incompletely defined. In this study, the anti-cancer effects and underlying mechanisms of SAG were systematically investigated in vitro and in vivo . Cell viability and death were evaluated using methyl thiazolyl tetrazolium (MTT) assays, colony formation assays, flow cytometry, transmission electron microscopy (TEM), and Western blotting (WB). Drug affinity responsive target stability (DARTS) combined with liquid chromatography–tandem mass spectrometry (LC-MS/MS), molecular docking, cellular thermal shift assay (CETSA), and surface plasmon resonance (SPR) were employed to identify and validate molecular targets of SAG. The results demonstrated that SAG simultaneously induces apoptosis and ferroptosis in LUSC cells by directly targeting the endoplasmic reticulum (ER) chaperone binding immunoglobulin protein (BiP). Silencing of BiP markedly attenuated SAG-induced apoptosis and ferroptosis, confirming its essential role in this process. Mechanistically, SAG up-regulates BiP expression and activates the protein kinase R-like endoplasmic reticulum kinase (PERK)/eIF2α/C/EBP homologous protein (CHOP)/GADD34 signaling axis of ER stress (ERS), ultimately leading to dual induction of apoptosis and ferroptosis in vitro and in vivo .

Enhanced healing activity of burn wound infection by a dextran-HA hydrogel enriched with sanguinarine

Qiyu Zhu,Ming Jiang,Qiang Liu,Shina Yan,Longbao Feng,Yong Lan,Guiqiu Shan,Wei Xue,Rui Guo

Burn wounds are associated with a series of risks, such as infection and pathologic scar tissue formation, which significantly delay wound healing and lead to complications. In this study, we successfully fabricated a dextran-hyaluronic acid (Dex-HA) hydrogel enriched with sanguinarine (SA) incorporated into gelatin microspheres (GMs), which had high porosity, good swelling ratio, enhanced NIH-3T3 fibroblast cell proliferation, and sustained SA release profile. The in vitro degradation results indicate that the SA/GMs/Dex-HA hydrogel can be degraded. The in vitro antibacterial tests showed that the SA/GMs/Dex-HA hydrogel can inhibit methicillin-resistant Staphylococcus aureus (MRSA) and Escherichia coli (E. coli). We evaluated the wound-healing effects and antibacterial properties of SA/GMs/Dex-HA hydrogels in a rat full-thickness burn infection model. The hematoxylin–eosin (H&E) and Masson's trichrome staining results of the SA/GMs/Dex-HA hydrogel showed that it improved re-epithelialization and enhanced extracellular matrix remodeling, and immunohistochemistry results showed that the expression of TGF-β1 and TNF-α was decreased, while the TGF-β3 expression was increased. Our findings suggest that the SA/GMs/Dex-HA hydrogel provides a potential way for infected burn treatment with high-quality and efficient scar inhibition.

The induced and intrinsic resistance of Escherichia coli to sanguinarine is mediated by AcrB efflux pump

Jian-Sheng Dai,Jian Xu,Hao-Jie Shen,Ni-Pi Chen,Bing-Qi Zhu,Zheng-Jie Xue,Hao-Han Chen,Zhi-Shan Ding,Rui Ding,Chao-Dong Qian

Natural Product Library Screens Identify Sanguinarine Chloride as a Potent Inhibitor of Telomerase Expression and Activity

Siyu Yan,Song Lin,Kexin Chen,Shanshan Yin,Haoyue Peng,Nanshuo Cai,Wenbin Ma,Zhou Songyang,Yan Huang

Reverse transcriptase hTERT is essential to telomerase function in stem cells, as well as in 85–90% of human cancers. Its high expression in stem cells or cancer cells has made telomerase/hTERT an attractive therapeutic target for anti-aging and anti-tumor applications. In this study, we screened a natural product library containing 800 compounds using an endogenous hTERT reporter. Eight candidates have been identified, in which sanguinarine chloride (SC) and brazilin (Braz) were selected due to their leading inhibition. SC could induce an acute and strong suppressive effect on the expression ofhTERTand telomerase activity in multiple cancer cells, whereas Braz selectively inhibited telomerase in certain types of cancer cells. Remarkably, SC long-term treatment could cause telomere attrition and cell growth retardation, which lead to senescence features in cancer cells, such as the accumulation of senescence-associated β-galactosidase (SA-β-gal)-positive cells, the upregulation of p16/p21/p53 pathways and telomere dysfunction-induced foci (TIFs). Additionally, SC exhibited excellent capabilities of anti-tumorigenesis, both in vitro and in vivo. In the mechanism, the compound down-regulated several active transcription factors including p65, a subunit of NF-κB complex, and reintroducing p65 could alleviate its suppression of the hTERT/telomerase. Moreover, SC could directly bind hTERT and inhibit telomerase activity in vitro. In conclusion, we identified that SC not only down-regulates thehTERTgene’s expression, but also directly affects telomerase/hTERT. The dual function makes this compound an attractive drug candidate for anti-tumor therapy.Keywords:telomerase/hTERT;anti-cancer;sanguinarine chloride;cellular senescence

Studies on pharmacokinetic properties and intestinal absorption mechanism of sanguinarine chloride: in vivo and in situ

Wenqing Sun,Yufeng Xu,Zhiqin Liu,Wei Liu,Hongting Wang,Guanyu Chang,Zihui Yang,Zhen Dong,Jianguo Zeng

Sanguinarine (SAN) is an alkaloid with multiple biological activities, mainly extracted from Sanguinaria canadensis or Macleaya cordata. The low bioavailability of SAN limits its utilization. At present, the nature and mechanism of SAN intestinal absorption are still unclear. The pharmacokinetics, single-pass intestinal perfusion test (SPIP), and equilibrium solubility test of SAN in rats were studied. The absorption of SAN at 20, 40, and 80 mg/L in different intestinal segments was investigated, and verapamil hydrochloride (P-gp inhibitor), celecoxib (MPR2 inhibitor), and ko143 (BCRP inhibitor) were further used to determine the effect of efflux transporter proteins on SAN absorption. The equilibrium solubility of SAN in three buffer solutions (pH 1.2, 4.5 and 6.8) was investigated. The oral pharmacokinetic results in rats showed that SAN was rapidly absorbed (Tmax=0.5 h), widely distributed (Vz/F = 134 L/kg), rapidly metabolized (CL = 30 L/h/kg), and had bimodal phenomena. SPIP experiments showed that P-gp protein could significantly affect the effective permeability coefficient (Peff) and apparent absorption rate constant (Ka) of SAN. Equilibrium solubility test results show that SAN has the best solubility at pH 4.5. In conclusion, SAN is a substrate of P-gp, and its transport modes include efflux protein transport, passive transport and active transport.

EefR mutations drive sanguinarine resistance by activating cryptic multidrug efflux pumps in AcrB-Null Escherichia coli

Hao-Jie Shen,Jun-Feng Wang,Zheng-Jie Xue,Jia-Qi Shi,Bing Chen,Dong-Min Chen,Ni-Pi Chen,Yu-Dong Li,Chao-Dong Qian

Antimicrobial resistance is one of the greatest threats to global health. A thorough comprehension of the underlying processes through which bacteria evolve the ability to withstand diverse stressors is vital for the development of efficacious strategies to address this challenge. This study aimed to elucidate the mechanisms underlying the adaptation of an acrB-deficient strain of Escherichia coli ATCC 35218 (35218m) to sanguinarine (SAN), the main component of phytobiotic derived from Macleaya cordata. Analysis of the in vitro-selected SAN-resistant clones of strain 35218m led to the identification of a functionally uncharacterized TetR regulator, EefR. The regulator represses its own expression and that of four neighboring genes forming the eefRABCD operon, encoding components of a tripartite RND-efflux pump (EefABC) and a putative MFS-type exporter (EefD). Overexpression of these pumps reduces the susceptibility of acrB-deficient E. coli to SAN and structurally diverse antibiotics. The eefR-eefABC-eefD cluster, widely distributed across Enterobacteriaceae genomes, is also found on plasmids in several E. coli isolates, indicating a significant risk for the rapid spread of this multidrug resistance mechanism.