ABSTRACT
Inorganic mercury (IHg) is hazardous to marine organisms especially resulting in neurotoxicity, bivalves are sensitive to pollutants as "ocean sentinel", but data on the neurotoxicity of IHg in bivalves are sparse. So we chosed M. chinensis philippi with typical neural structures in bivalves to investigate the neurotoxicity of IHg, which could be helpful to understand the specificity of neural regulation and the response characteristics of bivalves. After acute exposed to IHg (HgCl2) for 24 h, the metabolites of ganglion tissues in M. chinensis philippi were evaluated using 1H-nuclear magnetic resonance based metabolomics; Ca2+, neurotransmitters (nitric oxide, glutamate, acetylcholine) and related enzymes (calcineurin, nitric oxide synthase and acetylcholinesterase) were measured using biochemical detection. Compared to the control group, the levels of the nitric oxide (81.04 ± 12.84 µmol/g prot) and acetylcholine (30.93 ± 12.57 µg/mg prot) in M. chinensis philippi of IHg-treated were decreased, while glutamate (2.11 ± 0.61 mmol/L) increased significantly; the activity of nitric oxide synthase (679.34 ± 135.33 U/mg prot) was increased, while acetylcholinesterase (1.39 ± 0.44 U/mg prot) decreased significantly, and the activity of calcineurin (0.52 ± 0.02 U/mg prot) had a statistically insignificant increasing tendency. The concentration of Ca2+ (0.92 ± 0.46 mmol/g prot) in the IHg-treated group was significantly higher than that in the control group. OPLS-DA was performed to reveal the difference in metabolites between the control and IHg-challenged groups, the metabolites of glucose, glutamine, inosine, succinate, glutamate, homarine, and alanine were sensitive to IHg, subsequently metabolic pathways that were affected including glucose metabolism, glutamine metabolism, nucleotide metabolism, Krebs cycle, amino acid metabolism and osmotic regulation. In our study, IHg interfered with metabolites in M. chinensis philippi, thus the corresponding metabolic pathways were changed, which influenced the neurotransmitters subsequently. Furthermore, Ca2+overload affected the synthesis or degradation of the neurotransmitters, and then the altered neurotransmitters involved in changes in metabolic pathways again. Overall, we hypothesized that the neurotoxic effects of IHg on bivalve were in close contact with metabolism, neurotransmitters, related enzymes and Ca2+, which could be effective neurotoxic biomarkers for marine environmental quality assessment, and also provide effective data for the study of the regulatory mechanism of the nervous system in response to IHg in bivalves.
Subject(s)
Bivalvia , Mercury , Methylmercury Compounds , Water Pollutants, Chemical , Animals , Mercury/toxicity , Mercury/metabolism , Acetylcholinesterase , Nitric Oxide , Acetylcholine , Calcineurin , Glutamine , Water Pollutants, Chemical/toxicity , Bivalvia/metabolism , Glutamates , Neurotransmitter Agents , Nitric Oxide Synthase , Methylmercury Compounds/toxicityABSTRACT
Multi-drug resistance (MDR) in advanced breast cancer (ABC) is triggered by the high expression of P-glycoprotein (P-gp), which reduces intracellular concentration of anti-tumor drugs, in turn preventing oxidative stress damage to cytoplasmic and mitochondrial membranes. It is therefore of clinical relevance to develop P-gp-specific targeted nanocarriers for the treatment of drug resistant ABC. Herein, a drug carrier targeting CD44 and mitochondria was synthesised for the delivery of encequidar (ER, P-gp inhibitor) and paclitaxel (PTX). HT@ER/PTX nanoparticles (ER:PTX molar ratio 1:1) had excellent P-gp inhibition ability and targeted mitochondria to induce apoptosis in MCF-7/PTX cells in vitro. Furthermore, HT@ER/PTX nanocarriers showed more anti-tumor efficacy than PTX (Taxol®) in a xenograft mouse model of MCF-7/PTX cells; the tumor inhibitory rates of HT@ER/PTX nanoparticles and Taxol® were 72.64% ± 4.41% and 32.36% ± 4.09%, respectively. The survival of tumor-bearing mice administered HT@ER/PTX nanoparticles was prolonged compared to that of the mice treated with Taxol®. In addition, HT@ER/PTX not only inhibited P-gp-mediated removal of toxic lipid peroxidation byproducts resulting from anti-tumor drugs but also upregulated the expression of mitochondrial dynamics-related protein, fostering oxidative stress damage, which induced activation of the Caspase-3 apoptosis pathway. Our findings indicate that mitochondria targeted co-delivery of anti-tumor drugs and P-gp inhibitors could be a practical approach in treating multi-drug resistance in ABC.
ABSTRACT
Pulmonary emphysema is a fatal lung disease caused by the progressive thinning, enlargement and destruction of alveoli that is closely related to inflammation and oxidative stress. Oxymatrine (OMT), as a bioactive constituent of traditional Chinese herbal Sophora flavescens, has great potential to alleviate pulmonary emphysema via its anti-inflammatory and antioxidative activities. Pulmonary administration is the most preferable way for the treatment of lung diseases. To improve the in vivo stability and pulmonary retention of OMT, OMT-loaded liposome with carboxymethyl chitosan (CMCS) modification was developed. The CMCS was modified on the surface of OMT liposomes via electrostatic attraction and covalent conjugation to obtain Lipo/OMT@CMCS and CMCS-Lipo/OMT, respectively. A porcine pancreatic elastase (PPE)-induced emphysema mice model was established to evaluate the alleviation effects of OMT on alveolar expansion and destruction. CMCS-modified liposomal OMT exhibited superior ameliorative effects on emphysema regardless of the preparation methods, and higher sedimentation and longer retention in the lung were observed in the CMCS-Lipo group. The mechanisms of OMT on emphysema were related to the downregulation of inflammatory cytokines and the rebalancing of antioxidant/oxidation via the Nrf2/HO-1 and NF-κB/IκB-α signaling pathways, leading to reduced cell apoptosis. Moreover, the OMT liposomal preparations further enhanced its anti-inflammatory and antioxidative effects. In conclusion, pulmonary administration of OMT is a potential strategy for the treatment of emphysema and the therapeutic effects can be further improved by CMCS-modified liposomes.
Subject(s)
Anti-Inflammatory Agents/pharmacology , Chitosan , Emphysema , Liposomes/pharmacology , Pulmonary Emphysema , Alkaloids/chemistry , Animals , Anti-Inflammatory Agents/chemistry , Antioxidants/chemistry , Antioxidants/pharmacology , Liposomes/chemistry , Mice , Quinolizines , SwineABSTRACT
1,8-Cineole (also known as eucalyptol) is mostly extracted from the essential oils of plants, which showed extensively pharmacological properties including anti-inflammatory and antioxidant mainly via the regulation on NF-κB and Nrf2, and was used for the treatment of respiratory diseases and cardiovascular, etc. Although various administration routes have been used in the application of 1.8-cineole, few formulations have been developed to improve its stability and bioavailability. This review retrospects the researches on the source, biological activities, mechanisms, and application of 1,8-cineole since 2000, which provides a view for the further studies on the application and formulations of 1,8-cineole.
Subject(s)
Cyclohexanols , Monoterpenes , Anti-Inflammatory Agents , Cyclohexanols/pharmacology , Eucalyptol , Molecular Structure , Monoterpenes/pharmacologyABSTRACT
Hyperglycaemia is responsible for the major pathophysiological factor of diabetes-associated vascular endothelial injury, which mainly resulted from the disturbance of equilibrium between ROS generation and elimination. Eucalyptol was verified with exact anti-oxidation effects via stimulating the secretion of endogenous antioxidant enzymes against ROS. However, the volatility, instability and poor water solubility of eucalyptol limited its pharmacological activities in vivo. In this study, we developed carboxymethyl chitosan-coated lipid nanoparticles for eucalyptol (CMC/ELN) to facilitate oral administration. A thin lipid film dispersion method was used to prepare the ELN. After CMC coating, the diameter of ELN increased from 166 nm to 177 nm and charge reversal was observed. The nanocarrier enhanced the protective effects of eucalyptol both in the high level of glucose (HG)-damaged HUVECs and endothelial injury in type I diabetes mellitus (T1DM) rat model. Furthermore, the mechanism of eucalyptol on the promotion of Nrf2 and HO-1 and reduction on Keap1 expression have been verified both in the in vitro and in vivo model. Besides, the pharmacokinetics data were verified the promotion of the oral eucalyptol absorption by the nanocarrier. Taken together, we established an optimal oral delivery system that promoted oral administration of eucalyptol to exert protective effects on hyperglycaemia-induced vascular endothelial injury.
Subject(s)
Chitosan/analogs & derivatives , Endothelium, Vascular/drug effects , Eucalyptol/administration & dosage , Hyperglycemia/drug therapy , Liposomes/administration & dosage , Nanoparticles/administration & dosage , Administration, Oral , Animals , Chitosan/administration & dosage , Chitosan/chemical synthesis , Endothelium, Vascular/metabolism , Eucalyptol/chemical synthesis , Human Umbilical Vein Endothelial Cells/drug effects , Human Umbilical Vein Endothelial Cells/metabolism , Humans , Hyperglycemia/metabolism , Liposomes/chemical synthesis , Male , Rats , Rats, Sprague-DawleyABSTRACT
Reinforcement learning (RL)-based traffic signal control has been proven to have great potential in alleviating traffic congestion. The state definition, which is a key element in RL-based traffic signal control, plays a vital role. However, the data used for state definition in the literature are either coarse or difficult to measure directly using the prevailing detection systems for signal control. This paper proposes a deep reinforcement learning-based traffic signal control method which uses high-resolution event-based data, aiming to achieve cost-effective and efficient adaptive traffic signal control. High-resolution event-based data, which records the time when each vehicle-detector actuation/de-actuation event occurs, is informative and can be collected directly from vehicle-actuated detectors (e.g., inductive loops) with current technologies. Given the event-based data, deep learning techniques are employed to automatically extract useful features for traffic signal control. The proposed method is benchmarked with two commonly used traffic signal control strategies, i.e., the fixed-time control strategy and the actuated control strategy, and experimental results reveal that the proposed method significantly outperforms the commonly used control strategies.