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Aggregation-induced emission (AIE) materials are attracting great attention in biomedical fields such as sensors, bioimaging, and cancer treatment, et al. due to their strong fluorescence emission in the aggregated state. In this contribution, a series of tetraphenylene-acetonitrile AIE compounds with D-A-D' structures were synthesized by Suzuki coupling reaction and Knoevenagel condensation, and their relationship of chemical structure and fluorescence properties was investigated in detail, among which TPPA compound was selected as the monomer owing to the longest emission wavelength at about 530â¯nm with low energy band gap ΔE 3.09â¯eV of neutral TPPA and 1.43â¯eV of protonated TPPA. Novel amphiphilic AIE PEG-TA copolymers were prepared by RAFT polymerization of TPPA and PEGMA with about 1.44×104 Mw and narrow PDI, and the molar ratio of TPPA in the PEG-TA1 and PEG-TA2 copolymers was about 23.4â¯% and 29.6â¯%. The as-prepared PEG-TA copolymers would self-assembled in aqueous solution to form core-shell structures with a diameter of 150-200â¯nm, and their emission wavelength could reversibly convert from 545â¯nm to 650â¯nm with excellent pH sensitivity. The CLSM images showed that the PEG-TA FONs and PTX drugs-loaded PTX-TA FONs could be endocytosed by cells and mainly enriched in the cytoplasm, and CCK-8 results showed that the PEG-TA FONs had excellent biocompatibility but PTX-TA FONs had high inhibition ratio for A549 cells, moreover, the flow cytometry also showed that PTX-TA FONs could result in the apoptosis of A549 cells with some extent anti-tumor effect.
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ETHNOPHARMACOLOGICAL RELEVANCE: 2,3,5,4'-tetrahydroxy-stilbene-2-O-ß-D-glucoside (TSG) is the principal bioactive compound contained in Polygonum multiflorum Thunb. (PMT), which is traditionally recorded to possess tonic and anti-aging efficacy. AIM OF THE STUDY: To identify the TSG-provided promotion on liver regeneration (LR) following partial hepatectomy (PHx) in mice and to explicate its involved mechanism. MATERIALS AND METHODS: The promotion of TSG on LR was evaluated by hematoxylin and eosin (H&E), 5-bromodeoxyuridinc (BrdU) and Ki-67 staining, and measuring the level of proliferating cell nuclear antigen (PCNA) and Cyclin D1 in mice with PHx at different time points. Gene Expression Omnibus (GEO, GSE15239) database and the label-free quantitative proteomics from liver of mice at 24 h after PHx were integrated to identify potential involved critical proteins, which were verified by Western-blot, Real-time polymerase chain reaction (RT-PCR), molecular docking and luciferase activity assay. Primary hepatocytes isolated from mice were used to investigate the TSG-provided promotion on proliferation in vitro. RESULTS: TSG (20 mg/kg) promoted LR in mice after PHx. Results from RNA expression data from clinical samples and proteomic analysis from liver tissues indicated that peroxisome proliferator-activated receptor α (PPARα)-mediated fatty acid metabolism pathway were crucially associated with the TSG-provided promotion on LR. TSG enhanced the nuclear translocation of PPARα and the mRNA expression of a series of PPARα-regulated downstream genes. In addition, TSG lowered hepatic triglyceride (TG) and non-esterified fatty acid (NEFA) amounts and increased hepatic adenosine triphosphate (ATP) level in mice after PHx. TSG up-regulated the transcriptional activity of PPARα in vitro. Next results displayed that TSG promoted cell proliferation as well as ATP level in mice primary hepatocytes, which were abolished when PPARα was suppressed. Meanwhile, the cell viability was also elevated in mice primary hepatocytes treated with ATP. CONCLUSION: Activating PPARα-mediated fatty acid ß-oxidation (FAO) pathway led to the production of ATP, which contributed to the TSG-provided promotion on LR after PHx in mice.
Subject(s)
Fatty Acids , Glucosides , Hepatectomy , Liver Regeneration , PPAR alpha , Stilbenes , Animals , PPAR alpha/metabolism , PPAR alpha/genetics , Glucosides/pharmacology , Male , Liver Regeneration/drug effects , Mice , Stilbenes/pharmacology , Fatty Acids/metabolism , Cell Proliferation/drug effects , Liver/drug effects , Liver/metabolism , Mice, Inbred C57BL , Hepatocytes/drug effects , Hepatocytes/metabolismABSTRACT
In this contribution, a novel AIE monomers 2-(4-styrylphenyl)- 1,2-diphenylvinyl)styryl)pyridine (SDVPY) with smart fluorescent pH-sensitivity basing on tetraphenylethylene-pyridine were successfully synthesized for the first time, subsequently, a series of amphiphilic copolymers PEG-PY were achieved by reversible addition-fragmentation chain transfer (RAFT) polymerization of SDVPY and poly(ethylene glycol) methacrylate (PEGMA), which would self-assemble in water solution to form core-shell nanoparticles (PEG-PY FONs) with about 150 nm diameter. The PEG-PY FONs showed obvious fluorescence response to Fe3+, HCO3- and CO32- ions in aqueous solution owing to their smart pH-sensitivity and AIE characteristics, and their maximum emission wavelength could reversibly change from 525 nm to 624 nm. The as-prepared PEG-PY FONs showed also prospective application in cells imaging with the variable fluorescence for different pH cells micro-environment. When PEG-PY copolymers self-assembled with the anti-tumor drug paclitaxel (PTX), the obtained PY-PTX FONs could effectively deliver and release PTX with pH-sensitivity, and could be easily internalized by A549 cells and located at the cytoplasm with high cytotoxicity, which was further confirmed by the Calcein-AM/PI staining of dead and alive A549 cells. Moreover, the flow cytometry results indicated that the PY-PTX FONs could obviously induce the apoptosis of A549 cells, which further showed the great potential of PY-PTX FONs in the application of tumors therapy.
Subject(s)
Methacrylates , Nanoparticles , Neoplasms , Stilbenes , Humans , Polyethylene Glycols , Polymers , Coloring Agents , Paclitaxel/pharmacology , Hydrogen-Ion Concentration , Pyridines/pharmacology , Tumor MicroenvironmentABSTRACT
Low molecular weight heparins (LMWHs) are derived from heparin through chemical or enzymatic cleavage with an average molecular weight (Mw) of 2000-8000 Da. They exhibit more selective activities and advantages over heparin, causing fewer side effects, such as bleeding and heparin-induced thrombocytopenia. Due to different preparation methods, LMWHs have diverse structures and extensive biological activities. In this review, we describe the basic preparation methods in this field and compare the main principles and advantages of these specific methods in detail. Importantly, we focus on the non-anticoagulant pharmacological effects of LMWHs and their conjugates, such as preventing glycocalyx shedding, anti-inflammatory, antiviral infection, anti-fibrosis, inhibiting angiogenesis, inhibiting cell adhesion and improving endothelial function. LMWHs are effective in various diseases at the animal level, including cancer, some viral diseases, fibrotic diseases, and obstetric diseases. Finally, we briefly summarize their usage and potential applications in the clinic to promote the development and utilization of LMWHs.
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BACKGROUND: Liver diseases have a negative impact on global health and are a leading cause of death worldwide. Chlorogenic acids (CGAs), a family of esters formed between certain trans-cinnamic acids and quinic acid, are natural polyphenols abundant in coffee, tea, and a variety of traditional Chinese medicines (TCMs). They are reported to have good hepatoprotective effects against various liver diseases. PURPOSE: This review aims to analyze the available literature on the hepatoprotective effect of CGAs, with particular emphasis on their mechanisms. METHODS: Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. PubMed and Web of Science databases were adopted to retrieve all relevant literature on CGAs for liver disease from 2013 to March 2023. RESULTS: Research has indicated that CGAs play a crucial role in improving different types of liver diseases, including drug-induced liver injury (DILI), alcoholic liver disease (ALD), metabolic (dysfunction)-associated fatty liver disease (MAFLD), cholestatic liver disease (CLD), liver fibrosis, and liver cancer. CGAs display remarkable antioxidant and anti-inflammatory effects by activating erythroid 2-related factor 2 (Nrf2) and inhibiting toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) signaling pathways. Some important molecules such as AMP-activated protein kinase (AMPK) and extracellular signal-regulated kinases 1 and 2 (ERK1/2), and other key physiological processes like intestinal barrier and gut microbiota have also been discovered to participate in CGAs-provided amelioration on various liver diseases. CONCLUSION: In this review, different studies indicate that CGAs have an excellent protective effect against various liver diseases associated with various signaling pathways.
Subject(s)
Chlorogenic Acid , Liver Diseases, Alcoholic , Humans , Chlorogenic Acid/pharmacology , Polyphenols/pharmacology , Antioxidants/pharmacology , Antioxidants/metabolism , Liver Diseases, Alcoholic/metabolism , Nucleotidyltransferases/metabolism , Nucleotidyltransferases/pharmacology , LiverABSTRACT
HDAC6, a member of the histone deacetylase family, mainly is a cytosolic protein and regulates cell growth by acting on non-histone substrates, such as α -tubulin, cortactin, heat shock protein HSP90, programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1), that are closely related to the proliferation, invasion, immune escape and angiogenesis of cancer tissues. The approved drugs targeting the HDACs are all pan-inhibitors and have many side effects due to their lack of selectivity. Therefore, development of selective inhibitors of HDAC6 has attracted much attention in the field of cancer therapy. In this review, we will summarize the relationship between HDAC6 and cancer, and discuss the design strategies of HDAC6 inhibitors for cancer treatment in recent years.
Subject(s)
Antineoplastic Agents , Neoplasms , Humans , Histone Deacetylase 6/metabolism , Histone Deacetylase Inhibitors/chemistry , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Neoplasms/drug therapy , Histone Deacetylases/metabolismABSTRACT
Temperature is one of the important factors affecting the growth, development, and metamorphosis of amphibians. Endochondral ossification during metamorphosis plays a crucial role in amphibian survival and adaptation on land. In this study, we explored the effects of different temperature treatments on the growth, development, and endochondral ossification of Rana chensinensis tadpoles during metamorphosis. The results showed that high temperature exposure may affect the skeletal development of tadpoles during metamorphosis, such as reduction of bone length and ossification of limbs, thyroid gland damage and change of ossification-related genes expression levelsï¼and ultimately affect the movement and survival of tadpoles in the terrestrial environment. These results provide an experimental reference for further research on the effects of temperature on amphibian growth and development and provide an important theoretical basis for the decline of the amphibian population caused by temperature.
Subject(s)
Osteogenesis , Ranidae , Animals , Larva , Osteogenesis/genetics , Temperature , Thyroid Gland/metabolism , Metamorphosis, BiologicalABSTRACT
The cathode materials work as the host framework for both Li+ diffusion and electron transport in Li-ion batteries. The Li+ diffusion property is always the research focus, while the electron transport property is less studied. Herein, we propose a unique strategy to elevate the rate performance through promoting the surface electric conductivity. Specifically, a disordered rock-salt phase was coherently constructed at the surface of LiCoO2 , promoting the surface electric conductivity by over one magnitude. It increased the effective voltage (Veff ) imposed in the bulk, thus driving more Li+ extraction/insertion and making LiCoO2 exhibit superior rate capability (154â mAh g-1 at 10â C), and excellent cycling performance (93 % after 1000 cycles at 10â C). The universality of this strategy was confirmed by another surface design and a simulation. Our findings provide a new angle for developing high-rate cathode materials by tuning the surface electron transport property.
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As a potential substitute for lithium-ion battery, sodium-ion batteries (SIBs) have attracted a tremendous amount of attention due to their advantages in terms of cost, safety and sustainability. Nevertheless, further improvement of the energy density of cathode materials in SIBs remains challenging and requires the activation of anion redox reaction (ARR) activity to provide additional capacity. Herein, we report a high-performance Mn-based sodium oxide cathode material, Na0.67Mg0.1Zn0.1Mn0.8O2 (NMZMO), with synergistic activation of ARR by cosubstitution. This material can deliver an ultra-high capacity of â¼233 mAh/g at 0.1 C, which is significantly higher than their single-cation-substituted counterparts and among the best in as-reported MgMn or ZnMn-based cathodes. Various spectroscopic techniques were comprehensively employed and it was demonstrated that the higher capacity of NMZMO originated from the enhanced ARR activity. Neutron pair distribution function and resonant inelastic X-ray scattering experiments revealed that out-of-plane migration of Mg/Zn occurred upon charging and oxygen anions in the form of molecular O2 were trapped in vacancy clusters in the fully-charged-state. In NMZMO, Mg and Zn mutually interacted with each other to migrate toward tetrahedral sites, which provided a prerequisite for further ARR activity enhancement to form more trapped molecular O2. These findings provide unique insight into the ARR mechanism and can guide the development of high-performance cathode materials through ARR enhancement strategies.
Subject(s)
Electric Power Supplies , Oxides , Oxidation-Reduction , Ions , Electrodes , OxygenABSTRACT
Climate change such as global warming is considered a major threat to amphibians. The guts of amphibians are home to trillions of microbes, which are key regulators of gastrointestinal digestion and play a crucial role in lipid metabolites. The aim of this study was to evaluate the effect of temperature change on intestinal microbiota and lipid metabolism in Rana chensinensis tadpoles. Morphological and intestinal microbiota data of R. chensinensis larvae exposed to different temperatures (15 °C, 21 °C, and 26 °C) were measured. The results show that the warm temperature causes histological damage to the intestinal epithelium. In addition, temperature treatments alter the diversity and composition of gut microbes in R. chensinensis tadpoles. At the phylum level of intestinal microbial community, Campilobacterota was detected only in the warm group. At the genera level, unclassified_f__Enterobacteriaceae was markedly declined in the warm group but was notably enriched in the cold group. For lipid metabolism-related genes, the expression levels of GPR109A, HDAC1, and APOA-I decreased significantly in both warm and cold treatment groups, while the expression levels of CLPS and LIPASE increased significantly. Collectively, these observations demonstrated that warm and cold temperatures may reduce the immune capacity of tadpoles by changing the composition of intestinal microorganisms and the expression of genes related to lipid metabolism, affecting the survival of tadpoles.
Subject(s)
Gastrointestinal Microbiome , Animals , Larva , Temperature , Lipid Metabolism , RanidaeABSTRACT
Gardenia jasminoides Ellis is a well-known herbal medicine. In this study, the effect of G. jasminoides Ellis polysaccharide (GPS) on liver injury in an alpha-naphthylisothiocyanate (ANIT)-induced cholestatic mouse model and the associated molecular mechanisms were investigated. GPS administration dose-dependently ameliorated impaired hepatic function, including a 2-7-fold decrease in aminotransferase levels, ameliorating tissue damage, upregulating the expression of farnesoid X receptor (FXR) and pregnane X receptor (PXR) and their downstream efflux transporters, and decreasing the levels of 12 bile acids (BAs), in cholestatic mice. Furthermore, GPS ameliorated gut microbiota dysbiosis, improved intestinal barrier function, and reduced serum and hepatic lipopolysaccharide levels 1.5-fold. GPS also inhibited the Toll-like receptor 4 (TLR4)/nuclear factor kappa-B (NF-κB) signaling, decreased the expression of inflammatory factor genes, and ameliorated hepatic inflammation. Notably, fecal microbiota transplantation from GPS-fed mice also increased the hepatic expression of FXR, PXR, and efflux transporters; decreased the levels of 12 BAs; restored intestinal barrier function; and decreased hepatic inflammation mediated by the TLR4/NF-κB pathway. In conclusion, GPS has a protective effect against cholestatic liver injury through modulation of gut microbiota and inhibition of the TLR4/NF-κB pathway. Regulating gut microbiota using herbal medicine polysaccharides may hold unique therapeutic promise for cholestatic liver diseases.
Subject(s)
Gardenia , Gastrointestinal Microbiome , Animals , Dysbiosis/drug therapy , Liver , Mice , Mice, Inbred C57BL , NF-kappa B/genetics , Polysaccharides/pharmacology , Polysaccharides/therapeutic use , Signal Transduction , Toll-Like Receptor 4/geneticsABSTRACT
Da-Huang-Xiao-Shi decoction (DHXSD) is a traditional Chinese medicine formula and is used to treat cholestasis. In this study, we developed a reliable and comprehensive HPLC coupled with a linear ion trap-Orbitrap mass spectrometry method for the separation and determination of 21 components including six alkaloids, five anthraquinones, three tannins, three terpenes, two iridoid glycosides, one organic acid and one flavonoid in DHXSD. A C18 column was eluted using a gradient mobile phase at a flow rate of 1 ml/min. Detection was operated with an electrospray ionization source in positive and negative ion modes using selective ion monitoring. The calibration curves for all analytes showed good linearity (r > 0.9901), and the inter- and intra-day precision did not exceed 4.98%. The recovery, repeatability and stability were also within the acceptable limits. The method was successfully applied to determine multiple active constituents in DHXSD and its constituent herbs. Compared with Da Huang, the total contents of the five anthraquinones were significantly higher in DHXSD. However, the changes in the components from Zhi Zi/Huang Bo were complicated in DHXSD. The study could serve as a fundamental reference for establishing comprehensive DHXSD quality control measures and be helpful to understand some compatibility laws of DHXSD.
Subject(s)
Drugs, Chinese Herbal , Anthraquinones/chemistry , Chromatography, High Pressure Liquid/methods , Drugs, Chinese Herbal/chemistry , Mass Spectrometry/methodsABSTRACT
Macrophages play a key role in inflammation, infection, cancer, and repairing damaged tissues. Thus, modulating macrophages with engineered nanomaterials is an important therapeutic strategy for healing chronic inflammatory injuries. However, designing and manufacturing therapeutic nanomaterials remains challenging. Therefore, in this study, apoptotic-cell-inspired deformable phosphatidylserine (PS)- containing nanoliposomes (D-PSLs) with a Young's modulus (E) of approximately 0.5 kPa were constructed via a facile and scalable method. Compared with similar-sized conventional PSLs with an E of approximately 80 kPa, the d-PSLs had a lower uptake efficacy, a much longer binding time to the cell surface, and induced enhanced anti-inflammatory and pro-healing effects via the synergistic effects of their mechanical stimulus and PS-receptor mediation after recognition by macrophages. In particular, chronic wound healing in diabetic rats showed that d-PSLs can efficiently promote M2-like macrophage polarization, increase the expression of the vascular endothelial marker CD31 and accelerate wound closure. Our findings suggest that soft d-PSLs represent a promising biomimetic nano-therapeutic approach for macrophage immunotherapy for chronic inflammatory injury, and that the mechanical stimulus of nanomaterials significantly affects the receptor-mediated biological responses, which will inspire the design of engineered nanomaterials for biomedical applications. STATEMENT OF SIGNIFICANCE: Macrophages play a significant role in restoring tissue homeostasis by modulating inflammation and wound healing. Specifically, an M1/M2 macrophage imbalance contributes to various inflammatory disorders. However, modulating macrophages with engineered nanomaterials remains a challenge. In this study, apoptotic-cell-inspired deformable phosphatidylserine (PS)- containing nanoliposomes (D-PSLs) were constructed to explore their interactions with macrophages, and evaluate their anti-inflammatory and pro-healing effects on chronic wounds in diabetic rats. We found that soft d-PSLs can persistently bind to macrophage membranes and enhance the anti-inflammatory and pro-healing responses of macrophages, which not only sheds new light on the design of therapeutic biomaterials based on regulating macrophages but also provide a promising biomimetic nano-therapeutic approach for chronic inflammatory injury.
Subject(s)
Diabetes Mellitus, Experimental , Nanoparticles , Animals , Anti-Inflammatory Agents , Macrophage Activation , Macrophages , RatsABSTRACT
Alkali metals have low potentials and high capacities, making them ideal anodes for next-generation batteries, but they suffer major problems, including dendrite growth and low Coulombic efficiency (CE). Achieving uniform metal deposition and having a reliable solid electrolyte interphase (SEI) are the basic requirements for overcoming these problems. Here, a general remedy is reported for various alkali-metal anodes by the supramolecularization of alkali-metal cations with crown ethers that follows a size-matching rule. The positively charged supramolecular complex provides electrostatic shielding layers to regulate metal deposition and suppress dendrite formation. More promisingly, it reforms electric double layers and drives the production of organic-dominated SEIs with improved flexibility that can accommodate large volume changes. The high flexibility of SEIs during metal deposition and dissolution reduces the amount of dead metal and improves CE and cycling stability. Specifically, a 200% excess Li-based full cell has a capacity retention of ≈100% after 100 cycles. This crown-like supramolecularization strategy is a new chemistry that may be used for the production of dendrite-free metal-anode-based batteries not limited to the cases with alkali metal. It is also expected as a practical technology to improve the uniformity of coatings produced in the electrodeposition industry.
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Cholestasis is characterized by obstruction of bile flow and can lead to serious liver injury. With sustained damage, cholestasis can progress to cholestatic liver fibrosis (CLF), and cirrhosis. Non-invasive, predictive, and reliable metabolites based on the early and progressive stages of CLF are urgently needed. Based on the 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induced CLF mouse model, serum metabolic profiling via a time-series strategy with ultra-performance liquid chromatography-LTQ-Orbitrap-based metabolomics, combined with histological progression, was used to find CLF-specific metabolites, and explore their dynamic changes in progressive stages of CLF. Compared to those in the control group, DDC-induced groups showed a substantial elevation in cholestatic liver injury and fibrosis indices. Next, 21 differential serum metabolites were selected and identified between the normal (control) and DDC groups, and 12 of them were greatly altered over time. Among these, taurocholic acid, tauromuricholic acid, LysoPE (20:2), sulfoglycolithocholic acid, and taurohyodeoxycholic acid were associated with the progression of the hepatocyte injury index, alanine aminotransferase. More importantly, docosahexaenoic acid, arachidonic acid, proline, leucine, and linoleic acid were associated with the progression of liver fibrosis index, liver hydroxyproline. Moreover, the differential metabolites that were related to hepatocyte injury and liver fibrosis were further validated in DDC-induced mice at weeks 4 and 8. Overall, this work provides data on differential metabolites for the progressive pathology of CLF.
Subject(s)
Cholestasis , Animals , Cholestasis/pathology , Disease Models, Animal , Liver/pathology , Liver Cirrhosis/chemically induced , Liver Cirrhosis/pathology , Metabolomics , Mice , Mice, Inbred C57BL , PyridinesABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: Chronic cholestasis is a usual clinical pathological process in hepatopathy and has few treatment options; it is classified under the category of jaundice in Chinese medicine. Da-Huang-Xiao-Shi decoction (DHXSD) is a classic Chinese prescription which is used to treat jaundice. AIM OF THE STUDY: We aimed to examine the protective effect of DHXSD on liver and its potential mechanism of action against chronic cholestasis. MATERIALS AND METHODS: Chronic cholestasis was induced using 3, 5-diethoxycarbonyl-1,4-dihydroxychollidine (DDC) in mice. Mice were then administered DHXSD intragastrically at doses of 3.68, 7.35, and 14.70 g/kg for four weeks followed by further analyses. Serum biochemical indices and liver pathology were explored. Eighteen individual bile acids (BAs) in mice serum and liver were quantified using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The expression of BA related metabolic enzymes, transporters, along with nuclear receptor farnesoid X receptor (FXR) was detected by real-time qPCR and Western blot. RESULTS: DHXSD treatment reduced the serum biochemical indices, ameliorated pathological injury, and improved the disordered BA homeostasis. Mice treated with DHXSD showed significantly upregulated expression of the metabolic enzymes, cytochrome P450 2b10 (Cyp2b10), Cyp3a11, and UDP-glucuronosyltransferase 1a1 (Ugt1a1); and the bile acid transporters, multidrug resistance protein 2 (Mdr2), bile salt export pump (Bsep), and multidrug resistance-associated protein 3 (Mrp3). DHXSD treatment also significantly upregulated FXR expression in mice with DDC-induced chronic cholestasis. CONCLUSIONS: DHXSD exerted protective effects on chronic cholestasis in DDC-treated mice by alleviating the disordered homeostasis of BAs through increased expression of BA related metabolic enzymes and efflux transporters.
Subject(s)
Bile Acids and Salts/metabolism , Cholestasis/drug therapy , Drugs, Chinese Herbal/pharmacology , Enzymes/genetics , Protective Agents/pharmacology , ATP Binding Cassette Transporter, Subfamily B/genetics , ATP Binding Cassette Transporter, Subfamily B/metabolism , ATP Binding Cassette Transporter, Subfamily B, Member 11/genetics , ATP Binding Cassette Transporter, Subfamily B, Member 11/metabolism , Angiogenic Proteins/genetics , Angiogenic Proteins/metabolism , Animals , Bile Acids and Salts/analysis , Bile Acids and Salts/chemistry , Chemical and Drug Induced Liver Injury/drug therapy , Chemical and Drug Induced Liver Injury/pathology , Cholestasis/chemically induced , Chromatography, Liquid , Chronic Disease/drug therapy , Drugs, Chinese Herbal/therapeutic use , Enzymes/metabolism , Ethnopharmacology , Homeostasis/drug effects , Liver/drug effects , Male , Mice, Inbred C57BL , Protective Agents/therapeutic use , Pyridines/toxicity , Receptors, Cytoplasmic and Nuclear/genetics , Receptors, Cytoplasmic and Nuclear/metabolism , Tandem Mass Spectrometry , Up-Regulation/drug effects , ATP-Binding Cassette Sub-Family B Member 4ABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: Natural bear bile powder (NBBP) has been used to treat seizures for thousands of years, but its application is greatly restricted due to ethical reasons. Cultured bear bile powder (CBBP), which is produced by biotransformation, may be an appropriate substitute for NBBP. However, the anti-convulsant effects of CBBP and its mechanisms remain unclear. AIM OF THE STUDY: This study aimed to investigate the anti-convulsant effects and possible mechanisms of CBBP in a febrile seizure (FS) rat model. MATERIALS AND METHODS: FS was induced by placing the rats in a warm water bath (45.5 °C). The incidence rate and latency of FS, and hematoxylin-eosin staining (HE) were conducted for neurological damage. The levels of 4 bile acids and 8 main neurotransmitters in vivo were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The expression of bile acid related transports, neurotransmitter receptors, inflammatory factors, neurotrophic factors and glial fibrillary acidic protein (GFAP) in hippocampal tissues were detected by real-time PCR, western blotting, and immunohistochemistry. RESULTS: Pre-treatments with CBBP and similarly, NBBP, significantly reduced the incidence rate and prolonged the latency of FS. Additionally, CBBP alleviated the histological injury induced by FS in the rat hippocampus tissue. LC-MS/MS analyses revealed that CBBP markedly increased the levels of tauroursodeoxycholic acid (TUDCA), taurochenodeoxycholic acid (TCDCA), ursodeoxycholic acid (UDCA), and chenodeoxycholic acid (CDCA) in FS rats. Furthermore, the content of gamma-aminobutyric acid (GABA) was up-regulated in rats pre-treated with CBBP whereas GFAP was down-regulated. CBBP also significantly suppressed the expression of interleukin -1ß (IL-1ß), tumor necrosis factor α (TNF-α), nuclear factor kappa B (NF-κB), and brain-derived neurotrophic factor (BDNF) and its TrkB receptors, and improved the expression of GABA type A receptors (GABAAR) and farnesoid X receptors (FXR). CONCLUSIONS: The present study demonstrated that CBBP had anti-convulsant effects in a FS rat model. CBBP may protect rats against FS, probably by up-regulating FXR, which was activated by increasing brain bile acids, up-regulating GABAergic transmission by inhibiting BDNF-TrkB signaling, and suppressing neuroinflammation by inhibiting the NF-κB pathway.
Subject(s)
Anticonvulsants/therapeutic use , Biological Factors/therapeutic use , Brain/drug effects , Inflammation Mediators/antagonists & inhibitors , Seizures, Febrile/drug therapy , Synaptic Transmission/drug effects , Animals , Anticonvulsants/isolation & purification , Anticonvulsants/pharmacology , Bile , Biological Factors/isolation & purification , Biological Factors/pharmacology , Brain/metabolism , Inflammation Mediators/metabolism , Male , Powders , Random Allocation , Rats , Rats, Sprague-Dawley , Seizures, Febrile/metabolism , Synaptic Transmission/physiology , UrsidaeABSTRACT
Da-Huang-Xiao-Shi decoction (DHXSD), a traditional Chinese medicinal formula, has been used mainly to treat jaundice for more than 1700 years in China. In this study, we developed a rapid, sensitive, and accurate LC-MS/MS method to simultaneously determine multiple, potentially bioactive compounds of DHXSD, including five alkaloids (berberine, phellodendrine, palmatine, jatrorrhizine, and magnoflorine), five anthraquinones (rhein, aloe-emodin, emodin, chrysophanol, and physcion), two iridoid glycosides (geniposide and genipin 1-gentiobioside), and one iridoid aglycone (genipin) in rat plasma. Plasma samples collected from rats were treated immediately with 5% acetic acid to avoid the degradation of genipin. After protein precipitation with acetonitrile containing 5% acetic acid, the compounds were reconstituted in acetonitrile-water (50:50, v/v) solution containing 6.5% formic acid and separated on the ACQUITY™ UPLC BEH C18 column (2.1â¯×â¯100â¯mm; 1.7⯵m) using a mobile phase composed of 2â¯mM ammonium formate in water (solvent A) and acetonitrile (solvent B) at a flow rate of 0.3â¯mL/min. Quantitation was performed on a Triple Quand 5500 tandem mass spectrometer coupled with an electrospray ionization (ESI) source. Multiple reaction monitoring (MRM) was used to quantify compounds in positive and negative ion modes. The method validation results showed that the specificity, linearity, precision and accuracy, recovery, matrix effect, and stability of the 13 compounds met the requirements for their quantitation in biological samples. This newly established method was successfully used in a pharmacokinetic study on rats orally treated with DHXSD. Besides, glucuronide and sulfate metabolites were also determined in rat plasma after hydrolysis. This is the first method developed for the simultaneous quantification of multiple compounds of DHXSD in vivo. Our study provides relevant information on the pharmacokinetics of DHXSD and the relationship between the compounds of DHXSD and their therapeutic effects.
Subject(s)
Drugs, Chinese Herbal/pharmacokinetics , Rheum/chemistry , Administration, Oral , Animals , Anthraquinones/blood , Chromatography, Liquid , Flavonoids/pharmacokinetics , Glucuronides/blood , Glucuronides/chemistry , Hydrolysis , Linear Models , Quality Control , Quinolizines/blood , Rats , Reproducibility of Results , Sensitivity and Specificity , Solvents , Sulfates/blood , Sulfates/chemistry , Tandem Mass SpectrometryABSTRACT
Zwitterionic polymer is a new generation of anti-fouling materials with its good resistance to protein and bacterial adhesion. Constructing the anti-fouling surfaces with zwitterionic polymer has been regarded as an effective approach for improving the biocompatibility and biofunctionality of clinic devices. Herein, we reported a facile approach to construct a biodegradable anti-biofouling and functionalizable hydrogel coating via photo-immobilization using commercial polyethylene terephthalate (PET) films as the substrate, based on zwitterionic glycidyl methacrylate-phosphorylcholine-chitosan (PCCs-GMA). The surface structure and physicochemical properties of zwitterionic PCCs-GMA hydrogel coating were investigated by X-ray photoelectron spectroscopy (XPS), atomic force microscope (AFM) and static water contact angle measurement, and its functionalizable sites were detected by fluorescence labeling. Compared with the pristine PET and cationic chitosan - GMA and hydroxypropyltrimethyl ammonium chloride chitosan (HTCC) - GMA hydrogel coatings, zwitterionic PCCs-GMA hydrogel coating exhibited excellent biocompatibility, and significantly reduced protein adsorption for three model proteins of fibrinogen, immunoglobulin and lysozyme, repelled platelet adhesion, as well as showed a high resistance to bacterial attachment of Escherichia coli and Staphylococcus aureus and superior anti-fouling properties to MRC-5 cells. The results indicated that photo-immobilized zwitterionic PCCs-GMA hydrogel coating has perspective as a dual functional platform with integrated antifouling and further biofunctional properties for various biomedical applications.