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Introduction Endoscopic retrograde cholangiopancreatography (ERCP) is considered to be a challenge in patients with surgically altered anatomy. We aimed to identify the risk factors of ERCP-related adverse events in patients with surgically altered anatomy in our center. Methods We included patients with surgically altered anatomy who underwent ERCP between April 2017 and December 2020 at our center. Clinical characteristics and outcomes were analyzed in univariate and multivariate methods to identify the risk factors for adverse events. Results A total of 121 ERCP procedures were performed in 93 patients. The papilla or surgical anastomosis was successfully reached in 113 cases (93.4%). Diagnostic success was achieved in 106 cases (93.8%) and subsequent therapeutic success was achieved in 102 cases (96.2%). ERCP-related adverse events occurred in 31 cases (25.6%). In univariate analysis, not first time ERCP attempt, a CBD stone diameter ≥ 15 mm, multiple cannulation attempts, endoscopic papillary balloon dilation, endoscopic papillary large balloon dilation, endoscopic retrograde biliary drainage, biopsy in the bile duct or papilla, mechanical lithotripsy use, and stone retrieval basket were associated with ERCP-related adverse events. In multivariate analysis, multiple cannulation attempts (OR 5.283; 95% CI 1.088–25.659; p = 0.039), endoscopic papillary balloon dilation (OR 4.381; 95% CI 1.191–16.114; p = 0.026), and biopsy in the bile duct or papilla (OR 35.432; 95% CI 2.693–466.104; p = 0.007) were independently associated with ERCP-related adverse events. Conclusions ERCP in patients with surgically altered anatomy was feasible and safe. Interventions including multiple cannulation attempts, endoscopic papillary balloon dilation, and biopsy in the bile duct or papilla were independent risk factors for ERCP-related adverse events.

There has been an exponential increase in the rate of incidence of Parkinson's disease (PD) with aging in the global population. PD, the second most common neurodegenerative disorder, results from damaged dopamine neurons in the substantia nigra pars compacta (SNpc), along with the deposition of abnormal α-synuclein (α-Syn), and the progressive degeneration of neurons in striatal regions. Despite extensive investigations to understand the pathophysiology of PD to develop effective therapies to restrict its progression, there is currently no cure for PD. Puerarin (Pue) is a natural compound with remarkable anti-PD properties. However, its poor pharmacological properties, including poor water solubility, inadequate bioavailability, and incomplete penetration of the blood-brain barrier (BBB) have restricted its use for the treatment of PD. Nevertheless, advancements in nanotechnology have revealed the potential advantages of targeted drug delivery into the brain to treat PD. Here, we used Pue-loaded graphene oxide (GO) nanosheets, which have an excellent drug-loading ability, modifiable surface functional groups, and good biocompatibility. Then, Pue was transported across the BBB into the brain using lactoferrin (Lf) as the targeting ligand, which could bind to the vascular endothelial receptor on the BBB. In vivo and in vitro results indicated that this multifunctional brain targeted drug delivery system (Lf-GO-Pue) was an effective and safe therapy for PD.

Background: Fibroblast growth factor receptors (FGFRs) are key targets for nerve regeneration and repair. The therapeutic effect of exogenous recombinant FGFs in vivo is limited due to their high molecular weight. Small peptides with low molecular weight, easy diffusion, low immunogenicity, and nontoxic metabolite formation are potential candidates. The present study aimed to develop a novel low-molecular-weight peptide agonist of FGFR to promote nerve injury repair. Methods: Phage display technology was employed to screen peptide ligands targeting FGFR2. The peptide ligand affinity for FGFRs was detected by isothermal titration calorimetry. Structural biology-based computer virtual analysis was used to characterize the interaction between the peptide ligand and FGFR2. The peptide ligand effect on axon growth, regeneration, and behavioral recovery of sensory neurons was determined in the primary culture of sensory neurons and dorsal root ganglia (DRG) explants in vitro and a rat spinal dorsal root injury (DRI) model in vivo. The peptide ligand binding to other membrane receptors was characterized by surface plasmon resonance (SPR) and liquid chromatography-mass spectrometry (LC-MS)/MS. Intracellular signaling pathways primarily affected by the peptide ligand were characterized by phosphoproteomics, and related pathways were verified using specific inhibitors. Results: We identified a novel FGFR-targeting small peptide, CH02, with seven amino acid residues. CH02 activated FGFR signaling through high-affinity binding with the extracellular segment of FGFRs and also had an affinity for several receptor tyrosine kinase (RTK) family members, including VEGFR2. In sensory neurons cultured in vitro, CH02 maintained the survival of neurons and promoted axon growth. Simultaneously, CH02 robustly enhanced nerve regeneration and sensory-motor behavioral recovery after DRI in rats. CH02-induced activation of FGFR signaling promoted nerve regeneration primarily via AKT and ERK signaling downstream of FGFRs. Activation of mTOR downstream of AKT signaling augmented axon growth potential in response to CH02. Conclusion: Our study revealed the significant therapeutic effect of CH02 on strengthening nerve regeneration and suggested a strategy for treating peripheral and central nervous system injuries.

Carbon dots (CDs) exhibit a wide range of desirable properties including excellent photoluminescence, photostability, and water solubility, making them ideally suitable for use in the context of drug delivery, bioimaging, and related biomedical applications. Before these CDs can be translated for use in humans, however, further research regarding their in vivo toxicity is required. Owing to their low cost, rapid growth, and significant homology to humans, zebrafish (Danio rerio) are commonly employed as in vivo model systems in the toxicity studies of nanomaterials. In the present report, our group employed a hydrothermal approach to synthesize CDs and then assessed their toxicity in zebrafish. The resultant CDs were roughly 2.4 nm spheroid particles that emitted strong blue fluorescence in response to the excitation at 365 nm. These CDs did not induce any evident embryonic toxicity or did cause any apparent teratogenic effects during hatching or development when dosed at 150 μg/mL. However, significant effects were observed in zebrafish embryos at CD concentrations >200 μg/mL, including pericardial and yolk sac edema, delayed growth, spinal cord flexure, and death. These high CD concentrations were further associated with the reduction in zebrafish larval locomotor activity and decreased dopamine levels, reduced frequencies of tyrosine hydroxylase-positive dopaminergic neurons, and multiple organ damage. Further studies will be required to fully understand the mechanistic basis for CD-mediated neurotoxicity, with such studies being essential to fully understand the translational potential of these unique nanomaterials.

Traditional Chinese medicine (TCM) are becoming more and more popular all over the world. However, quality issues of TCM may lead to medical incidents in practice and therefore quality control is essential to TCM. In this review, the state of TCM in European Pharmacopoeia are compared with that in Chinese Pharmacopoeia, and herbal drugs that are not considered as TCM and not elaborated by TCM working party at European Directorate for the Quality of Medicines & Health Care (EDQM) but present in both European Pharmacopoeia and Chinese Pharmacopoeias are also discussed. Different aspects in quality control of TCM including origins, identification, tests and assays, as well as sample preparation, marker selection and TCM processing are covered to address the importance of establishing comprehensive quality standard of TCM. Furthermore, advanced analytical techniques for quality control and standard establishment of TCM are also reviewed. Electronic supplementary material The online version of this article (10.1186/s13020-020-00357-3) contains supplementary material, which is available to authorized users.

Resveratrol (RES), a non-flavonoid polyphenol extracted from a wide variety of plants, exhibits neuroprotective activities against Parkinson's disease (PD). However, undesirable water solubility of RES reduces its oral bioavailability and demonstrates low efficacy in blood and brain, thus limiting its application. In present study, a nanocrystal formulation of RES (RES-NCs) was developed to enhance its oral bioavailability and delivery into brain for PD treatment. RES-NCs were fabricated with hydroxypropyl methylcellulose (HPMC) stabilizer via antisolvent precipitation approach. The obtained RES-NCs displayed the particle size of 222.54 ± 1.66 nm, the PDI of 0.125 ± 0.035, the zeta potential of −9.41 ± 0.37 mV, and a rapid in vitro dissolution rate. Molecular dynamics simulation of RES and HPMC revealed an interaction energy of −68.09 kJ/mol and a binding energy of −30.98 ± 0.388 kJ/mol, indicating that the spontaneous binding between the two molecules is through van der Waals forces. RES-NCs conferred enhanced cellular uptake as well as improved permeability relative to pure RES. In addition, RES-NCs were able to protect neurons against cytotoxicity induced by MPP+. Meanwhile, RES-NCs exerted no significant toxic effects on zebrafish embryos and larvae, and did not influence their survival and hatching rates. When orally administered to rats, RES-NCs exhibited more favorable pharmacokinetics than pure RES, with higher plasma and brain concentrations. More importantly, MPTP-induced PD mice showed notable improvements in behavior, attenuated dopamine deficiency, and elevated levels of dopamine and its metabolites after the treatment with RES-NCs. Furthermore, immunoblot analysis revealed that the neuroprotective role of RES-NCs may be at least partially mediated by Akt/Gsk3β signaling pathway. Taken altogether, RES-NCs can serve as a potential treatment modality for PD, offering means of improving RES oral bioavailability and brain accumulation., Graphical abstract Resveratrol nanocrystals improve the oral bioavailability of resveratrol and enhance its delivery into the brain to treat Parkinson's disease. Image, graphical abstract

Handheld robotic laparoscopic instruments fill the gap between robotic and conventional instruments, combining the advantages of degrees of freedom and low price. The difficulty and value in learning these new instruments require detailed investigation. Forty novice surgeons with no laparoscopic experience were randomly assigned to two groups: conventional instrument group (Group Conv) and robotic instrument group (Group Rob). The same training protocol was used in both groups: after viewing a standard operation film, laparoscopic suture training was administered using the corresponding instruments. After each training period, surgeons were tested using a force-sensing test platform. Maximum force (MF) and impulse (IMP) of operators through each ring were recorded. Learning curves based on MF and IMP for both instruments were compared. Institutional review board approval is not needed for this study. MF and IMP of both groups decreased with increased training time; the learning curve of Group Conv decreased faster than that of Group Rob. When training time reached 13 h, the MF of Group Rob was significantly lower than that of Group Conv (P

Iron and steel industry emission is an important industrial source of air pollution. However, little is known about the relationship between volatile organic compounds (VOCs) emitted and regional air pollution. In this study, VOCs emissions from a typical iron and steel plant in Yangtze River Delta (YRD, China) were monitored from April 2018 to March 2019. The ozone formation potential (OFP) and secondary organic aerosol (SOA) formation of VOCs were calculated to reveal the influence of VOCs emissions on regional ozone and particulate pollution, and the sensitivity analysis approach was performed to explore the qualitative and quantitative relationships between VOCs and O3, as well as VOCs and PM2.5. The VOCs concentration was 93.76 ± 266.97 ppbv during the study. The OFP was 760.08 ± 2391.90 μg m−3, and aromatics were the predominant precursors, contributing 54.05% of the total OFP. Furthermore, the SOA estimated by fractional aerosol coefficient (FAC) and time-resolved (TR) methods were 6.032 ± 13.347 μg m−3 and 0.971 ± 4.650 μg m−3, accounting for 8.65–26.39% (13.78 ± 7.46%) and 1.55–4.20% (2.22 ± 1.23%) of the PM2.5 concentrations, respectively. The results indicated that VOCs were more sensitive to O3 pollution in high pollution domains, whereas VOCs were more sensitive to PM2.5 pollution in low pollution domains. We concluded that reducing VOCs emissions might be effective in alleviating photochemical pollution episodes in areas around iron and steel industry, and the haze pollution occurred in these regions may be caused by the primary emission of PM, and the contribution of SOA was relatively small.

Despite the relative severity of Parkinson's disease (PD), to date, there has been only limited success in preventing or treating this condition owing to the low permeability of the blood-brain barrier (BBB), which makes the cerebral delivery of pharmaceutical agents very challenging. In the present study, we explored an approach to increasing BBB permeability via the use of mesoporous silica-encapsulated gold nanorods (MSNs-AuNRs) that could reliably achieve a robust photothermal effect in response to second near-infrared (NIR-II) irradiation. To test the potential anti-Parkinsonian activity, we loaded MSNs-AuNRs with the frequently utilized anti-PD agent quercetin (QCT) to yield MSNs-AuNRs@QCT. Following NIR-II irradiation, we observed a dramatical increase in QCT transfer through the BBB, indicating that MSNs-AuNRs may enhance BBB permeability via the photothermal effect. These findings were further supported by rat pharmacokinetic studies, which clearly revealed that the combination of MSNs-AuNRs and NIR-II irradiation was associated with significantly improved brain accumulation. In a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced murine model of PD, we also found that intravenous MSNs-AuNRs@QCT delivery and subsequent NIR-II irradiation was sufficient to markedly reduce the neurological abnormalities in these mice. Together, this combination offers promising potential as a nanoplatform for neuroprotective drug delivery and treatment of PD.

Highlights The recent progress on using cell membrane-coated nanoparticles for drug delivery, cancer treatment, vascular disease, immune modulation, and detoxification are summarized in this review.The patent applications related to the cell membrane coating technology from the past 10 years are collected, the future challenges and trends pertaining to this technology are comprehensively discussed.Unique properties of cell membrane-coated nanoparticles make it a promising strategy for biomedical applications and will make outstanding contributions to human health., Cell membrane coating technology is an approach to the biomimetic replication of cell membrane properties, and is an active area of ongoing research readily applicable to nanoscale biomedicine. Nanoparticles (NPs) coated with cell membranes offer an opportunity to unite natural cell membrane properties with those of the artificial inner core material. The coated NPs not only increase their biocompatibility but also achieve effective and extended circulation in vivo, allowing for the execution of targeted functions. Although cell membrane-coated NPs offer clear advantages, much work remains before they can be applied in clinical practice. In this review, we first provide a comprehensive overview of the theory of cell membrane coating technology, followed by a summary of the existing preparation and characterization techniques. Next, we focus on the functions and applications of various cell membrane types. In addition, we collate model drugs used in cell membrane coating technology, and review the patent applications related to this technology from the past 10 years. Finally, we survey future challenges and trends pertaining to this technology in an effort to provide a comprehensive overview of the future development of cell membrane coating technology.

Mitochondrial dysfunction is commonly detected in individuals suffering from Parkinson’s disease (PD), presenting within the form of excessive reactive oxygen species (ROS) generation as well as energy metabolism. Overcoming this dysfunction within brain tissues is an effective approach to treat PD, while unluckily, the blood-brain barrier (BBB) substantially impedes intracerebral drug delivery. In an effort to improve the delivery of efficacious therapeutic drugs to the brain, a drug delivery platform hydrogel (MAG-NCs@Gel) was designed by complexing magnolol (MAG)-nanocrystals (MAG-NCs) into the noninvasive thermosensitive poly( N -isopropylacrylamide) (PNIPAM) with self-gelation. The as-prepared MAG-NCs@Gel exhibited obvious improvements in drug solubility, the duration of residence with the nasal cavity, and the efficiency of brain targeting, respectively. Above all, continuous intranasal MAG-NCs@Gel delivery enabled MAG to cross the BBB and enter dopaminergic neurons, thereby effectively alleviating the symptoms of MPTP-induced PD. Taking advantage of the lower critical solution temperature (LCST) behavior of this delivery platform increases its viscoelasticity in nasal cavity, thus improving the efficiency of MAG-NCs transit across the BBB. As such, MAG-NCs@Gel represented an effective delivery platform capable of normalizing ROS and adenosine triphosphate (ATP) in the mitochondria of dopaminergic neurons, consequently reversing the mitochondrial dysfunction and enhancing the behavioral skills of PD mice without adversely affecting normal tissues.

Exosomes are composed of a lipid bilayer membrane, containing proteins, nucleic acids, DNA, RNA, etc., derived from donor cells. They have a size range of approximately 30-150 nm. The intrinsic characteristics of exosomes, including efficient cellular uptake, low immunogenicity, low toxicity, intrinsic ability to traverse biological barriers, and inherent targeting ability, facilitate their application to the drug delivery system. Here, we review the generation, uptake, separation, and purification methods of exosomes, focusing on their application as carriers in tumor diagnosis and treatment, especially in brain tumors, as well as the patent applications of exosomes in recent years.

Mitochondrial dysfunction, which is directly involved in Parkinson's disease (PD), is characterized by the production of reactive oxygen species (ROS) and aberrant energy metabolism. Thus, regulating mitochondrial function might be an effective strategy to treat PD. However, the blood-brain barrier (BBB) presents a significant challenge for the intracerebral delivery of drugs. Here, we synthesized a zeolitic imidazolate framework 8-coated Prussian blue nanocomposite (ZIF-8@PB), which was encapsulated with quercetin (QCT), a natural antioxidant, to treat PD. ZIF-8@PB-QCT exhibited superior near-infrared radiation (NIR) response and penetrated through the BBB to the site of mitochondrial damage guided by the photothermal effect. In the mice model of PD, the QCT released from ZIF-8@PB-QCT significantly increased the adenosine triphosphate levels, reduced the oxidative stress levels, and reversed dopaminergic neuronal damage as well as PD-related behavioral deficits without any damage to the normal tissues. Furthermore, we explored the underlying neuroprotective mechanism of ZIF-8@PB-QCT that was mediated by activating the PI3K/Akt signaling pathway. Thus, combined with noninvasive NIR radiation, the biocompatible ZIF-8@PB-QCT nanocomposite could be used to treat neurodegenerative diseases.

A maytansin derivative, DM1, is a promising therapeutic compound for treating tumors, but is also a highly poisonous substance with various side effects. For clinical expansion, we tried to develop novel peptide–drug conjugates (PDCs) with DM1. In the study, a one-bead one-compound (OBOC) platform was used to screen and identify a novel, highly stable, non-natural amino acid peptide targeting the tyrosine receptor FGFR2. Then, the identified peptide, named LLC2B, was conjugated with the cytotoxin DM1. Our results show that LLC2B has high affinity for the FGFR2 protein according to an isothermal titration calorimetry (ITC) test. LLC2B-Cy5.5 binding to FGFR2-positive cancer cells was confirmed by fluorescent microscopic imaging and flow cytometry in vitro. Using xenografted nude mouse models established with breast cancer MCF-7 cells and esophageal squamous cell carcinoma KYSE180 cells, respectively, LLC2B-Cy5.5 was observed to specifically target tumor tissues 24 h after tail vein injection. Incubation assays, both in aqueous solution at room temperature and in human plasma at 37 °C, suggested that LLC2B has high stability and strong anti-proteolytic ability. Then, we used two different linkers, one of molecular disulfide bonds and another of a maleimide group, to couple LLC2B to the toxin DM1. The novel peptide–drug conjugates (PDCs) inhibited tumor growth and significantly increased the maximum tolerated dose of DM1 in xenografted mice. In brief, our results suggest that LLC2B–DM1 can be developed into a potential PDC for tumor treatment in the future.

Recent work has highlighted the potential of puerarin (PU) as a valuable compound to treat Parkinson's disease (PD), but its undesirable water solubility and bioavailability have constrained its utility. In this study, we sought to develop nanoparticles (NPs) that could be used to encapsulate PU, thereby extending its in vivo half-life and improving its bioavailability and accumulation in the brain to treat the symptoms of PD. We prepared spherical NPs (88.36 ± 1.67 nm) from six-armed star-shaped poly(lactide-co-glycolide) (6-s-PLGA) NPs that were used to encapsulate PU (PU-NPs) with 89.52 ± 1.74% encapsulation efficiency, 42.97 ± 1.58% drug loading, and a 48 h sustained drug release. NP formation and drug loading were largely mediated by hydrophobic interactions, while changes in the external environment led these NPs to become increasingly hydrophilic, thereby leading to drug release. Relative to PU alone, PU-NPs exhibited significantly improved cellular internalization, permeation, and neuroprotective effects. Upon the basis of Forster resonance energy transfer (FRET) of NPs-administered zebrafish, we were able to determine that these NPs were rapidly absorbed into circulation whereupon they were able to access the brain. We further conducted oral PU-NPs administration to rats, revealing significant improvements in PU accumulation within the plasma and brain relative to rats administered free PU. In MPTP-mediated neurotoxicity in mice, we found that PU-NPs treatment improved disease-associated behavioral deficits and depletion of dopamine and its metabolites. These findings indicated that PU-NPs represent a potentially viable approach to enhancing PU oral absorption, thus improving its delivery to the brain wherein it can aid in the treatment of PD.

Background Mesenchymal stem cells (MSCs) exert positive effects in chronic wounds. However, critical parameters, such as the most effective administration routes, remain unclear. Accordingly, the purpose of this study was to compare the effects of topical and systemic transplantation MSCs on diabetic ischemic wound healing and explored the underlying mechanisms. Method A diabetic ischemic wound model was created on the dorsal foot of type 2 diabetes mellitus (T2DM) rat. Bone marrow-derived mesenchymal stem cells (BM-MSCs) were administered via two routes: topical injection and intravenous (IV) infusion. Wound healing outcomes and blood glucose level were assessed dynamically. Meanwhile, blood flow recovery was evaluated in ischemic gastrocnemius muscles. The homing and transdifferentiation of mKate2-labeled BM-MSCs were assessed by fluorescence imaging and immunohistochemistry (IHC) analysis. Result Both topical and systemic treatments had a positive effect on the diabetic ischemic wound showing a significant reduction in wound area at day 14. Histological results showed an increase in the length of epithelial edges, collagen content, microvessel density in the wound bed, and a higher expression of vascular endothelial growth factor (VEGF). Meanwhile, systemic administration can ameliorate hyperglycemia and improve the blood perfusion of the ischemic hindlimb. BM-MSCs administered systemically were found distributed in wounded tissue and transdifferentiated into endothelial cells. Furthermore, BM-MSCs stimulated angiogenesis at wound sites by downregulating phosphatase and tensin homolog (PTEN) and activation of AKT signaling pathway. Conclusions The results demonstrated that both transplantation delivery method (topical and systemic) of BM-MSCs accelerated wound healing remarkably under pathological conditions. Nevertheless, systemic administration has the potential to ameliorate hyperglycemia and repair the damaged tissue.

Intracerebral hemorrhage (ICH) is a neurological disorder resulting from the nontraumatic rupture of blood vessels in the brain. Ferroptosis is a newly identified form of programmed cell death, which is an important pathological feature of ICH injury. At present, the therapeutic efficacy of ICH treatment is far from satisfactory, so it is urgent to develop a safer and more effective method to treat ICH injury. Resveratrol (Res), a widely used nonflavonoid polyphenol compound, plays a neuroprotective role in many diseases. However, its poor oral bioavailability limits its clinical application in ICH. Polymer nanoparticles (NPs) are a commonly used drug delivery matrix material with good biocompatibility. To improve its bioavailability and accumulation in the brain, we used NPs to encapsulate Res. These spherical Res nanoparticles (Res-NPs) had a particle size of 297.57 ± 7.07 nm, a PDI of 0.23 ± 0.02 and a zeta potential of -5.45 ± 0.27 mV. They could be taken up by Madin-Darby canine kidney (MDCK) cells through a variety of nonspecific endocytosis mechanisms, mainly mediated by clathrin and plasma membrane microcapsules. After entering the cell, Res-NPs tend to accumulate in the endoplasmic reticulum and lysosomes. In a zebrafish model, we observed that Res-NPs could transport across physiological barriers. In a Sprague-Dawley (SD) rat model, we found that Res-NPs had more desirable improvements in Res accumulation within the plasma and brain. Moreover, we demonstrated that Res-NPs were able to inhibit ferroptosis induced by erastin in HT22 mouse hippocampal cells, which are commonly used in in vitro studies to examine neuronal differentiation and neurotoxicity implicated in brain injuries or neurological diseases. Finally, in an ICH mouse model, we confirmed that Res-NPs are a safer and effective treatment for ICH injury. Collectively, Res-NPs are effective to improve Res brain delivery and its therapeutic efficacy in ICH treatment.

Yuying Zhao,1 Sha Xiong,1 Piaoxue Liu,1 Wei Liu,1 Qun Wang,1 Yao Liu,1 Hanxu Tan,2 Xiaojia Chen,3 Xuguang Shi,4 Qi Wang,1 Tongkai Chen1 1Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, People’s Republic of China; 2Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, People’s Republic of China; 3State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau 999078, People’s Republic of China; 4School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, People’s Republic of ChinaCorrespondence: Tongkai Chen; Qi WangScience and Technology Innovation Center, Guangzhou University of Chinese Medicine, 12 Jichang Road, Guangzhou 510405, People’s Republic of ChinaEmail chentongkai@gzucm.edu.cn; wangqi@gzucm.edu.cnPurpose: Ginkgolide B (GB) is a terpene lactone derivative of Ginkgo biloba that is believed to function in a neuroprotective manner ideal for treating Parkinson’s disease (PD). Despite its promising therapeutic properties, GB has poor bioavailability following oral administration and cannot readily achieve sufficient exposure in treated patients, limiting its clinical application for the treatment of PD. In an effort to improve its efficacy, we utilized poly(ethylene glycol)-co-poly(ϵ-caprolactone) (PEG-PCL) nanoparticles as a means of encapsulating GB (GB-NPs). These NPs facilitated the sustained release of GB into the blood, thereby improving its ability to accumulate in the brain and to treat PD.Methods and Results: Using Madin-Darby canine kidney (MDCK) cells, we were able to confirm that these NPs could be taken into cells via multiple nonspecific mechanisms including micropinocytosis, clathrin-dependent endocytosis, and lipid raft/caveolae-mediated endocytosis. Once internalized, these NPs tended to accumulate in the endoplasmic reticulum and lysosomes. In zebrafish, we determined that these NPs were readily able to undergo transport across the chorion, gastrointestinal, blood–brain, and blood-retinal barriers. In a 1-methyl-4-phenylpyridinium ion (MPP+)-induced neuronal damage model system, we confirmed the neuroprotective potential of these NPs. Following oral administration to rats, GB-NPs exhibited more desirable pharmacokinetics than did free GB, achieving higher GB concentrations in both the brain and the blood. Using a murine PD model, we demonstrated that these GB-NPs achieved superior therapeutic efficacy and reduced toxicity relative to free GB.Conclusion: In conclusion, these results indicate that NPs encapsulation of GB can significantly improve its oral bioavailability, cerebral accumulation, and bioactivity via mediating its sustained release in vivo.Keywords: drug delivery system, blood–brain barrier, endocytosis, zebrafish, PD treatment

3CLpro is the main protease of the novel coronavirus (SARS-CoV-2) responsible for their intracellular duplication. Based on virtual screening technology, we found 23 approved clinical drugs such as Carfilzomib, Saquinavir, Thymopentin and etc., which showed high affinity with the 3CLpro active sites. These findings suggest that 3CLpro inhibitors might be potential candidates for further activity detection and molecular modification.

Midazolam has been successfully used for sedation, which the tablets, injections and oral solutions were available in market. However, the oral bioavailability of midazolam is less due to the first effect, while injection formulation has a low patient compliance. The purpose of this study was to obtain midazolam rectal gel to meet the production and market requirements. We evaluated the in vitro release behavior of midazolam powder, a physical mixture of midazolam and HPMC, and midazolam gel. The results showed that the midazolam gel has superior release degree compared to the other. Correspondingly, midazolam gel produced relevant plasma concentrations result in the rats. At the same dose (1 mg/kg), the Cmax and AUC (0-t) of midazolam after administration of the midazolam rectal gel were 8-10 times higher than that of the oral solution. The midazolam rectal gel was evaluated for physico-chemical tests including pH, viscosity, drug content at 40°C /75%RH (relative humidity) for 180 days (6 months). It provides information about the shelf lives of medicine, as well as the conditions for their storage. Rectum irritation test demonstrated that frequent application of midazolam rectal gel did not induce rectal mucosal damage. In conclusion, midazolam rectal gel was a potential new dosage form, which could alleviate the feeling of alien, discomfort and refusal during application of the patients. It was likely to be a more convenient and effective sedative medicine form specifically for infants and children.

Fibroblast growth factors (FGFs) and their receptors (FGFRs) modulate a wide range of biological functions, especially tumor genesis. The aim of this study was to investigate the possible association of FGFR expression with the susceptibility of digestive system and reproductive system cancers in Chinese population. In total, 343 patients with digestive or reproductive system cancers were enrolled in this study. The expression levels of four highly-conserved FGFRs including FGFR1, FGFR2, FGFR3 and FGFR4 were measured by immunohistochemistry (IHC). The expression levels of FGFRs were compared between carcinoma and para-carcinoma tissues. FGFR1 expression significantly differed between carcinoma and para-carcinoma tissues in colon and gastric cancers. FGFR2 expression significantly differed between carcinoma and para-carcinoma tissues in esophageal cancer. FGFR3 expression was significantly different between carcinoma and para-carcinoma tissues in liver and gastric cancers. FGFR2 showed the highest expression probability in all the selected cancers and FGFR4 showed the lowest expression probability. FGFR1 and FGFR3 showed comparable moderate expression probabilities. Our findings have demonstrated significant differences regarding FGFR expression levels between carcinoma and para-carcinoma cells in digestive or reproductive system cancer patients. The data also implicated that FGFR2 and FGFR4 could serve as two prominent factors closely related to the susceptibility of digestive and reproductive system cancers.

In the present study, we successfully developed a preferable doxorubicin (Dox) loaded drug delivery system based on Cetuximab and silica nanoparticles (Cet-SLN/Dox). By employing the tumor homing property of Cetuximab and the drug-loading capability of silica nanoparticles, the prepared Cet-SLN/Dox was able to load Dox to achieve the co-delivery of two drugs (Cetuximab and Dox). In vitro analysis revealed that Cet-SLN/Dox was nano-sized particles with decent drug loading capabilities and smart drug release profile. Further studies demonstrated that Cet-SLN/Dox was superior in tumor-homing and anti-cancer efficiency than Cetuximab free SLN/Dox and free Dox, possibly due to EGFR mediated endocytosis and the combined anti-cancer effects of Cetuximab and Dox within Cet-SLN/Dox.

Cancer-associated fibroblasts (CAFs) are believed to influence tumor behavior and clinical outcomes. We previously showed that conditioned medium (CM) from CAFs induces proliferation and motility of esophageal squamous cell carcinoma (ESCC) cells. Here, we investigated the molecular mechanisms by which the CAF-secreted proteins induce ESCC development and progression. Using antibody arrays, we identified urokinase plasminogen activator (uPA) as one of the main proteins whose release was increased in CAFs compared to normal fibroblasts (NFs). Immunohistochemical analysis of pathological sections showed that uPA-positive cells were localized at the boundaries of tumor and stroma tissues, in stroma between tumor nests, and within the tumors. Increased stromal uPA levels (132/146 cases) correlated with tumor invasion (p < 0.05) and overall survival of ESCC patients (p < 0.05). In vitro assays showed that uPA promotes ESCC cell proliferation, migration, and invasion via PI3K/AKT and ERK signaling pathways. In vivo, anti-uPA antibody suppressed tumor growth in ESCC xenografts. These results suggest that uPA released from stroma, and especially from CAFs, might be a predictive marker for ESCC diagnosis and prognosis, as well as an effective therapeutic target.

The human Fibroblast Growth Factor Receptor (FGFR) family comprises four members, namely, FGFR1, FGFR2, FGFR3, and FGFR4, that are involved in various biological activities including cell proliferation, survival, migration and differentiation. Several aberrations in the FGFR signaling pathway, owing to mutations or gene amplification events, have been identified in various types of cancers. Hence, recent research has focused on developing strategies involving therapeutic targeting of FGFRs. Current FGFR inhibitors at various stages of pre-clinical and clinical development include either small molecule inhibitors of tyrosine kinases or monoclonal antibodies, with only a few peptide- based inhibitors in the pipeline. Here, we provide a protocol using phage display technology to screen small peptides as antagonists of FGFR2. Briefly, a library of phage-displayed peptides was incubated in a plate coated with FGFR2. Subsequently, unbound phage was washed off by TBST (TBS + 0.1% [v/v] Tween-20), and bound phage was eluted with 0.2 M glycine-HCl buffer (pH 2.2). The eluted phage was further amplified and used as input for the next round of biopanning. Following three rounds of biopanning, the peptide sequences of individual phage clones were identified by DNA sequencing. Finally, the screened peptides were synthesized and analyzed for affinity and biological activity.

Resistance to platinum-based combination chemotherapy is the main cause of poor prognosis in patients with advanced esophageal squamous cell carcinoma (ESCC). Previously, we showed that CACNA2D3 (voltage-dependent subunit alpha 2 delta 3 of a calcium channel complex) was significantly downregulated and functioned as a tumor suppressor in ESCC, but its role in the chemosensitivity of ESCC to cisplatin remained unknown. Here, we found that the expression of CACNA2D3 was significantly associated with poor platinum response in ESCC patients from the Gene Expression Omnibus database. Overexpression of CACNA2D3 increased sensitivity to cisplatin in ESCC in vitro, whereas knockdown of CACNA2D3 increased cisplatin resistance. CACNA2D3 promoted cisplatin-induced apoptosis by modulating intracellular Ca2+ stores. In vivo experiments further showed that overexpression of CACNA2D3 enhanced cisplatin anti-tumor effects in a xenograft mouse model. CACNA2D3 overexpression also resulted in the attenuation of PI3K and Akt phosphorylation. Treatment with the PI3K/Akt inhibitor LY294002 restored the chemosensitivity of CACAN2D3-knockdown cells to cisplatin. In conclusion, the results of the current study indicate that CACAN2D3 enhances the chemosensitivity of ESCC to cisplatin via inducing Ca2+-mediated apoptosis and suppressing PI3K/Akt pathways. Therefore, regulating the expression of CACNA2D3 is a potential new strategy to increase the efficacy of cisplatin in ESCC patients.

Esophageal cancer is the eighth most common malignant tumor worldwide, of which esophageal squamous cell carcinoma (ESCC) is the dominant histological subtype. A drug shortage for ESCC therapy triggered us to explore the roles of fibroblast growth factor receptor 2 (FGFR2) and its upstream regulator miR-671-5p in ESCC progression. We compared the levels of FGFR2 and miR-671-5p between human ESCC tissues and their matched normal esophageal tissues and found an association between higher levels of FGFR2 and lower levels of miR-671-5p in ESCC tissues. High levels of FGFR2 resulted in the activation of the ERK and AKT pathways and a promotion of ESCC progression. High levels of miR-671-5p specifically reduced the expression of FGFR2 and suppressed ESCC progression in both in vitro and in vivo models. Therefore, suppressing FGFR2 and enhancing miR-671-5p expression may be the right approaches for ESCC therapy.

Handheld laparoscopic robotized instruments have been developed to combine the advantages of a robotic operation system and conventional laparoscopic instruments. Direct objective standards are needed to quantify surgeons' skill level and validate the advantages of new instruments. This study describes and objectively evaluates the use of a robotized instrument using a force-sensing test platform.The test platform consists of 12 rings on a hypersensitive force sensor. Forty volunteers were recruited: the expert group included 20 laparoscopic experts and the novice group included 20 medical students in their 4th year without laparoscopic skills. The baseline of the two groups was identified using a conventional needle holder. Participants then repeated the test with the robotized needle holder after training. The maximum force and impulse of each ring were analyzed for each group. Institutional review board approval is not needed for this study.Significantly lower maximum force and impulse were observed in the expert group than in the novice group during the baseline test (all P 0.05). After training, a significant difference remained in maximum force and impulse between the two groups using the robotized needle holder (all P 0.05). Within each group, there was no difference in maximum force or impulse using the robotized needle holder after training compared to that on using the conventional needle holder (all P 0.05).The maximum force and impulse recorded by a test platform can accurately identify participants' laparoscopic skill level. Six hours' training can ensure that experts master the use of the robotized needle holder, but this training session is too short for novices to improve their performance with a new instrument. The force-sensing test platform can reflect the suturing characteristics of users based on the skill level and is useful for laparoscopic suture training.

Concentrations of fine particulate mercury (PHg), particulate matter ≤2.5 μm (PM 2.5 ), and particulate matter ≤10 μm (PM 10 ) were monitored for the whole year of 2013 in Shanghai, China. The average concentrations of PHg were 1270 ± 716 pg/m 3 and 341 ± 187 pg/m 3 during haze and non-haze days respectively. The average PHg concentration throughout the whole year 2013 was 642 ± 616 pg/m 3 . It was observed that PHg concentrations on haze days were 3 times higher than on non-haze days. The concentration of PHg on non-haze days in 2013 varied from 0.25 to 0.48 ng/m 3 . The mean monthly PHg concentration was highest in December (1.92 ng/m 3 ), while the minimum mean concentration was observed in February and August (0.80 ng/m 3 ), and there was a clear seasonal variation: winter (1.67 ng/m 3 ), autumn (1.08 ng/m 3 ), spring (1.02 ng/m 3 ), and summer (1.00 ng/m 3 ) during haze days. The correlation between PHg and PM 2.5 was strong (r = 0.96 on haze days; r = 0.90 on non-haze days), while the correlation between PHg and PM 10 was weaker (r = 0.85 on haze days; r = 0.57 on non-haze days). The PHg concentration on haze days was always higher than on non-haze days, indicating that haze conditions were accelerating the formation of PHg. The result also indicated that PHg was inclined to combine with fine particles. The existence of strong correlations between the concentrations of PM 2.5 , PM 10 , and PHg indicated the commonality of the contributing sources, such as traffic, industrial emissions, and the combustion of coal.

Carthamus tinctorius L. is a multifunctional cash crop. Its flowers and seeds are extensively used in traditional herbal medicine in China, Korea, Japan, and other Asian countries, for treating various ailments such as gynecological, cardiovascular, and cerebrovascular diseases as well as blood stasis and osteoporosis. More than 100 compounds have been isolated and identified from C. tinctorius. Flavonoids and alkaloids, especially the quinochalcone c-glycoside hydroxysafflor yellow A, N-(p-Coumaroyl)serotonin, and N-feruloylserotonin, are responsible for most of the pharmacological activities of C. tinctorius. In this paper, comprehensive and up-to-date information on the phytochemistry and pharmacology of C. tinctorius is presented. This information will be helpful for further explorations of the therapeutic potential of C. tinctorius and may provide future research opportunities.

A one-year campaign was conducted to collected PM2.5 samples in the rural area of Guangzhou, the largest megacity in South China, from March 2012 to February 2013. Mass concentration of PM2.5, carbonaceous fractions (i.e., organic carbon (OC) and elemental carbon (EC)) and 6 water-soluble ions were analyzed. Light extinction coefficient (bext) of fine particulate matter was reconstructed using the revised IMPROVE formula at the site. The reconstructed bext was compared with the measured bext converted from visibility. A good correlation was obtained between the two sets of bext with a coefficient of determination (R2) of 0.61 and a slope of 0.99. The average reconstructed bext in the study was 253.7 ± 162.9 Mm–1. The seasonal reconstructed bext was in the order of autumn (319.4 ± 207.2 Mm–1) > winter (269.6 ± 175.5 Mm–1) > summer (219.0 ± 129.3 Mm–1) > spring (193.3 ± 94.9 Mm–1). (NH4)2SO4 (AS) made a dominant contribution to the light extinction budget, accounting for 61.3% (155.6 ± 108.5 Mm–1) annually, with highest in autumn (68.0%) and lowest in winter (55.2%). Organic matter (OM) was the second largest contributor accounting for 20.5% (52.2 ± 42.7 Mm–1) with highest in winter (23.4%) and lowest in spring (18.0%). The relationship between reconstructed bext and measured bext was investigated under the influence of seasonality, visibility and PM2.5 concentration. We found that bext could be reconstructed using revised IMPROVE formula in high PM2.5 days (threshold value of ~60 µg m–3). On other hand, the performance of formula was unsatisfactory for bext reconstruction of in low PM2.5 days, when meteorological conditions could have significant impact on visibility.

Purpose: The majority of patients with prostate cancer who are treated with androgen-deprivation therapy (ADT) will eventually develop fatal metastatic castration-resistant prostate cancer (mCRPC). Currently, there are no effective durable therapies for patients with mCRPC. High expression of galectin-1 (Gal-1) is associated with prostate cancer progression and poor clinical outcome. The role of Gal-1 in tumor progression is largely unknown. Here, we characterized Gal-1 functions and evaluated the therapeutic effects of a newly developed Gal-1 inhibitor, LLS30, in mCRPC.Experimental Design: Cell viability, colony formation, migration, and invasion assays were performed to examine the effects of inhibition of Gal-1 in CRPC cells. We used two human CRPC xenograft models to assess growth-inhibitory effects of LLS30. Genome-wide gene expression analysis was conducted to elucidate the effects of LLS30 on metastatic PC3 cells.Results: Gal-1 was highly expressed in CRPC cells, but not in androgen-sensitive cells. Gal-1 knockdown significantly inhibited CRPC cells' growth, anchorage-independent growth, migration, and invasion through the suppression of androgen receptor (AR) and Akt signaling. LLS30 targets Gal-1 as an allosteric inhibitor and decreases Gal-1–binding affinity to its binding partners. LLS30 showed in vivo efficacy in both AR-positive and AR-negative xenograft models. LLS30 not only can potentiate the antitumor effect of docetaxel to cause complete regression of tumors, but can also effectively inhibit the invasion and metastasis of prostate cancer cells in vivo.Conclusions: Our study provides evidence that Gal-1 is an important target for mCRPC therapy, and LLS30 is a promising small-molecule compound that can potentially overcome mCRPC. Clin Cancer Res; 24(17); 4319–31. ©2018 AACR.

Sepsis is a leading cause of death in intensive care units that can result in acute hepatic damage. Animal experiments and clinical trials have shown that mesenchymal stem cell (MSC) therapy has some beneficial in several liver diseases. However, the protective effects of MSC therapy on sepsis-induced hepatic damage and associated mechanisms are not completely understood. The aim of the present study was to investigate the effects of MSCs on sepsis-induced liver injury and underlying mechanisms. A rat model of sepsis-induced liver injury was established by cecal ligation and puncture, and serum alanine aminotransferase and aspartate transaminase activities as well as liver histological changes were measured. Inflammatory cytokines, Kupffer cell M1 phenotype markers, and associated signal molecules were also determined in septic rats and in lipopolysaccharide (LPS)-treated Kupffer cells. Our results showed that injection of MSCs attenuated sepsis-induced liver injury. Treatment with MSCs inhibited activation of Kupffer cells towards M1 phenotype, attenuated TNF-α and IL-6 expression, and promoted IL-4 and IL-10 expression in septic rats and LPS-treated Kupffer cells. Furthermore, MSCs also inhibited the nuclear translocation of nuclear factor-kappa B in LPS-challenged Kupffer cells and the liver of septic rats. These results indicated that MSCs attenuated sepsis-induced liver injury through suppressing M1 polarization of Kupffer cells.

Background: Exosome plays an important role in cell communication and cell environment. But the mechanism of how exosome derived from cancer-associated fibroblast (CAF) influent esophageal squamous cell carcinoma (ESCC) progression is not clear. In this work, compared with normal fibroblast-derived exosomes (NDEs), we found that CAF derived exosomes (CDEs) can enhance the growth, migration, and invasion of ESCC cells obviously. Therefore, we would like to clarify the role of CDEs in ESCC progression. Methods and Results: Using microRNA array to analyze the different miRNAs in the CDEs and NDEs, we got a series of up-regulation miRNAs and two down-regulation miRNAs in CDEs. Among them, miR-3656 shows a significantly highest level. Then, we transfected miR-3656 mimics to the ESCC cells and found the mimics increased the growth, migration, and invasion of ESCC cells in cell proliferation assay. cell scratch tests and chamber invasion experiments. We established recombinant ESCC cells with miR-3656 high expression by the lentiviral system. The cells were injected into mice to form the xenograft tumor. The results showed the miR-3656 can enhance the tumor formation. After that, aided by TargetScan software, we found ACAP2, one of miR3656 targets, was significantly down-regulating in ESCC cells at the high level of miR-3656. When ACAP2 expression was knocked-down by siRNA, the proliferation and migration of ESCC cells was increased, which indicated ACAP2 a potential anti-tumor factor. Furthermore, we detected the different proteins between ESCC cells with high expression miR-3656 and normal ESCC cells through LC_MS; the results were analyzed by Integrate Pathway Analysis (IPA) system and many differential proteins were found to be involved of PI3K/AKT and Wnt pathways. Conclusions: In this study, we found the CDEs promote the progression of their sounding ESCC cells in vitro and in vivo. The main reason is that CDEs carry some tumor-promoting miRNAs that influent the target ESCC cells. Especially, miR-3656 expresses the highest level of miRNAs in CDEs. It not only decreases the expression of ACAP2 but also impacts the expression of proteins involved PI3K/AKT and Wnt pathways in ESCC cells. The results indicate the CDEs playing a very important role in ESCC progression. Citation Format: Xiaojia Chen, Yuan Jin, Bihui Zhang, Xiaocen LI, Baoqing Tian, Qiang Wang, An Hong. Exosome from CAF-ESCC aggravates tumor progression by its containing molecular miR-3656 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1987.

Accumulating evidence shows the disruption of hippocampal neurotrophins secretion leads to memory deficits in Alzheimer's disease (AD) animal models. Invasive injection of exogenous neurotrophins into hippocampus reverses spatial memory deficits, but its clinical application is limited by traumatic brain injury during the injection procedure. Notably, recent studies have demonstrated that noninvasive repetitive transcranial magnetic stimulation (rTMS) increases endogenous neurotrophins contents in the brain of normal rats. Whether low-frequency rTMS can reverse Aβ(1-42)-mediated decrease in hippocampal neurotrophins contents and spatial memory impairment is still unclear. Here, we reported that severe deficit in long-term potentiation (LTP) and spatial memory were observed in an Aβ(1-42)-induced toxicity rat model. Furthermore, neurotrophins (NGF and BDNF) and NMDA-receptor levels were decreased after Aβ injection. However, low-frequency rTMS markedly reversed the decrease in neurotrophins contents. And the rTMS-induced increment of neurotrophins up-regulated hippocampal NMDA-receptor expression. Moreover, low-frequency rTMS rescued deficits in LTP and spatial memory of rats with Aβ-injection. These results indicate that low-frequency rTMS noninvasively and effectively increases hippocampal neurotrophins and NMDA-receptor contents in Aβ(1-42)-induced toxicity model rats, which helps to enhance hippocampal LTP and reverses Aβ(1-42)-mediated memory deficits.

Repetitive transcranial magnetic stimulation (rTMS) is able to induce alteration in cortical activity and excitability that outlast the period of stimulation, which is long-term depre-ssion (LTD) or long-term potentiation (LTP)-like. Accumulating evidence shows that Na(+), Ca(2+) and K(+) channels are important for the regulation of neuronal excitability. To investigate the possible mechanisms of rTMS on regulation of intrinsic excitability in hippocampal neurons, the male or female Sprague-Dawley rats aged 2-3 d or 7-8 d were treated with 14 or 7-d's low frequency (1 Hz) rTMS (400 stimuli/d), respectively. After that, the effects of rTMS on ion channels such as Na(+)-channel, A-type K(+)-channel and Ca(2+)-channel in rat hippocampal CA1 pyramidal neurons were performed by standard whole-cell patch-clamp technique. The results showed that the peak amplitude and maximal rise slope of evoked single action potential (AP) were significantly increased after 14-d's rTMS treatment. Meanwhile, the AP threshold was significantly more depolarized in neurons after 14-d's rTMS treatment than neurons in control group that without rTMS treatment. The spontaneous excitatory post-synaptic currents (sEPSCs) frequency and amplitude of CA1 pyramidal neurons in groups with rTMS treatment (both 7 d and 14 d) were obviously increased compared with the age-matched control group. Furthermore, we found that electrophysiological properties of Na(+)-channel were markedly changed after rTMS treatment, including negative-shifted activation and inactivation curves, as well as fasten recovery rate. After rTMS application, the IA amplitude of K(+)-channel was reduced; the activation and inactivation curves of K(+)-channel were significantly shifted to right. Time constant of recovery from inactivation was also more rapid. Moreover, rTMS induced an obvious increment in the maximal current peak amplitude of Ca(2+)-channel. At the same time, there was a significant rightward shift in the activation curve and inactivation curves of Ca(2+)-channel. These data suggest that rTMS can enhance the AP and sEPSCs of hippocampal CA1 neurons. Altered electrophysiological properties of Na(+)-channel, A-type K(+) channels and Ca(2+) channels contribute to the underling mechanisms of rTMS-induced up-regulation of neural excitability.

Anti-angiogenesis is an effective strategy for cancer treatment because uncontrolled tumor growth depends on tumor angiogenesis and sufficient blood supply. Thus, blocking angiogenesis could be a strategy to arrest tumor growth. The function and mechanism of luminescent ruthenium-modified selenium nanoparticles (Ru-SeNPs) in angiogenesis have not been elucidated to date. Here, we found that Ru-SeNPs significantly inhibited human umbilical vascular endothelial cell (HUVEC) proliferation, migration and tube formation. Ru-SeNPs was also tested in vivo in the chicken chorioallantoic membrane (CAM) assay and found to inhibit bFGF-treated CAMs development like suramin. Moreover, we showed that Ru-SeNPs inhibited the activations of FGFR1 and its downstream protein kinases, such ErK and AKT. Furthermore, by using fluorescence confocal microscopy and TEM imaging studies, we have demonstrated their cellular uptake and localization within the cytoplasm of HepG2 and HUVEC cells. These findings indicate that Ru-SeNPs inhibits angiogenesis and may be a viable drug candidate in anti-angiogenesis and anticancer therapies.

Small interfering RNAs (siRNA)/microRNAs (miRNA) have promising therapeutic potential, yet their clinical application has been hampered by the lack of appropriate delivery systems. Herein, we employed extracellular vesicles (EVs) as a targeted delivery system for small RNAs. EVs are cell-derived small vesicles that participate in cell-to-cell communication for protein and RNA delivery. We used the aptamer AS1411-modified EVs for targeted delivery of siRNA/microRNA to breast cancer tissues. Tumor targeting was facilitated via AS1411 binding to nucleolin, which is highly expressed on the surface membrane of breast cancer cells. This delivery vesicle targeted let-7 miRNA delivery to MDA-MB-231 cells in vitro as confirmed with fluorescent microscopic imaging and flow cytometry. Also, intravenously delivered AS1411-EVs loaded with miRNA let-7 labeled with the fluorescent marker, Cy5, selectively targeted tumor tissues in tumor-bearing mice and inhibited tumor growth. Importantly, the modified EVs were well tolerated and showed no evidence of nonspecific side effects or immune response. Thus, the RNAi nanoplatform is versatile and can deliver siRNA or miRNA to breast cancer cells both in vitro and in vivo. Our results suggest that the AS1411-EVs have a great potential as drug delivery vehicles to treat cancers.

Recently, most anticancer drugs are derived from natural resources such as marine, microbial, and botanical sources, but the low success rates of chemotherapies and the development of multidrug resistance emphasize the importance of discovering new compounds that are both safe and effective against cancer. Ginseng types, including Asian ginseng, American ginseng, and notoginseng, have been used traditionally to treat various diseases, due to their immunomodulatory, neuroprotective, antioxidative, and antitumor activities. Accumulating reports have shown that ginsenosides, the major active component of ginseng, were helpful for tumor treatment. 20(S)-Protopanaxadiol (PDS) and 20(S)-protopanaxatriol saponins (PTS) are two characteristic types of triterpenoid saponins in ginsenosides. PTS holds capacity to interfere with crucial metabolism, while PDS could affect cell cycle distribution and prodeath signaling. This review aims at providing an overview of PTS and PDS, as well as their metabolites, regarding their different anticancer effects with the proposal that these compounds might be potent additions to the current chemotherapeutic strategy against cancer.

Licorice (Gancao in Chinese) has been used worldwide as a botanical source in medicine and as a sweetening agent in food products for thousands of years. Triterpene saponins and flavonoids are its main ingredients that exhibit a variety of biological activities, including hepatoprotective, antiulcer, anti-inflammatory, antiviral and anticancer effects among others. This review attempts to summarize the current knowledge on the anticancer properties and mechanisms of the compounds isolated from licorice and obtain new insights for further research and development of licorice. A broad spectrum of in vitro and in vivo studies have recently demonstrated that the mixed extracts and purified compounds from licorice exhibit evident anticancer properties by inhibition of proliferation, induction of cell cycle arrest, apoptosis, autophagy, differentiation, suppression of metastasis, angiogenesis, and sensitization of chemotherapy or radiotherapy. A combined treatment of licorice compounds and clinical chemotherapy drugs remarkably enhances anticancer effects and reduces the side effects of chemotherapeutics. Furthermore, glycyrrhizic acid and glycyrrhetinic acid in licorice have been indicated to present obvious liver-targeting effects in targeted drug delivery systems for hepatocellular carcinoma treatment.

Esophageal cancer is the world's tenth common malignant tumor. Esophageal cancer is divided into esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (ECA). ESCC is the dominant histological subtype. The overall 5-year survival rate for people with advanced-stage of ESCC is only about 10%-20%, but ESCC is still not well-studied. Therefore, it is very important to study the mechanism of cancer progression in ESCC in order to develop new therapies for this deadly disease. Fibroblast growth factor receptor2 (FGFR2) is one of the RTK members and generally regarded as an oncogene, but little is known about its function in ESCC. In our study, we proved FGFR2 played the key role in ESCC progression. From In vitro studies, overexpression of FGFR2 promoted the ESCC cells' migration, invasion, and proliferation, which was confirmed through knocking down FGFR2 in ESCC cells. In vivo xenograft tumor mouse model studies showed the tumor size from ESCC cells with FGFR2 over-expression larger than that of the control group. Conversely, the tumor size from ESCC cells with FGFR2 knock-down was significantly smaller compared with the control group. Molecular mechanism studies showed that overexpression of FGFR2 activated the ERK and AKT signal pathways and altered the cell cycle in ESCC. In addition, decreased expression of miR-671-5p was identified by microRNA array and QPCR verify assay in ESCC–FGFR2+ tissue. Using a dual influence report system, we confirmed miR-671-5p could regulate expression of FGFR2. It was also found that FGFR2 was highly expressed whereas miR-671-5p was expressed at a low level in most of the FGFR2-positive ESCC clinic samples. Furthermore, we demonstrated that miR-671-5p could inhibit the proliferation and metastasis of ESCC cells in vitro and it could suppress growth of ESCC in vivo. The miR-671-5p suppressed MAPK and PI3K signal pathways through down-regulation of phosphorylation of FGFR2. Therefore, miR-671-5p was seen as a tumor suppressor in ESCC. Our results demonstrated that FGFR2 and miR-671-5p are potential therapeutic targets in ESCC. They both participate in the progression of ESCC, but also play the contrasting roles. Antagonists of FGFR2 or activators of miR-671-5p could be therapeutics against ESCC. Citation Format: Xiaojia Chen, Xiaoyan Li, Baoqing Tian, Xuan Tan, Wei Han, Jiakang Wang, An Hong. FGFR2 and miR-671-5p as key participants involved in the progression of human esophageal squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2520.

Ovarian cancer ranks fifth in cancer deaths among women in America. The standard treatment for advanced stages ovarian cancer consists of primary debulking surgery followed by i.v. and i.p. chemotherapy. DM1, or mertansine, is a thiol-containing maytansinoid, that inhibits microtubule assembly and kills various cancer cells at low nM concentration. However, its application in the clinic has been hampered by severe toxic side effects1. Its trastuzumab conjugate (T-DM1), which was approved by the FDA in 2013, is a promising therapeutic agent for patients harboring ovarian cancers with high Her-2 expression2. However, the general limitation for antibody drug conjugates (ADCs) is low drug content, high clearance by the reticuloendothelial, and high manufacturing cost. To overcome this, we designed and synthesized a novel PEG-based, cholic acid/ DM1 hybrid telodendrimer (PEG5k-CA4-DM1) comprised of one DM1 molecule and three molecules of maleimide per telodendrimer, which self-assembled into 25nm nanomicelles for targeted therapy against ovarian cancer. To enhance the stability of this nanoparticle, PEG5k-Cys4-CA8, which contain 4 thiol groups per telodendrimer is formulated together with PEG5k-CA4-DM1 at a ratio of 2:5, to generate thiol/maleimide crosslinked DM1 micellar prodrug (DM1-nano). To further enhance its tumor-targeting ability, the surface of DM1-nano was decorated with LXY30 via a hydrophilic “stealth” linker (EK)3, using copper-free ‘Click' chemistry. LXY30 is a potent and specific ligand against α3β1 integrin which is overexpressed on the surface of many epithelial cancer cells including a panel of ovarian cancer cell lines (e.g. SKOV-3). Compared with free DM1 and non-targeted DM1-nano, LXY30-EK-DM1-nano not only prevented premature drug release, but also further enhanced tumor targeting ability, drug solubility and in vivo circulation time in blood. When loaded with a fluorescent dye (DiD), LXY30-EK-DM1-nano was found to (i) internalize inside SKOV-3 cells in vitro, (ii) significantly accumulated at the tumor site of SKOV-3 xenograft mice, and (iii) exhibit potent anti-cancer activity in vitro (IC50=26nM with SKOV-3 cells) and in vivo (SKOV-3 xenograft model). In addition, LXY30-EK-DM1-nano was found to be significantly more efficacious and less toxic than free DM1 and non-targeted DM1-nano. In conclusion, the LXY30-DM1-nano offers a promising novel nanotherapeutic agent against ovarian cancer. Citation Format: Xiaocen Li, Wenwu Xiao, Yayu Wang, Xiaojia Chen, Ruiwu Liu, Kit S. Lam. α3β1-Integrin targeted DM1 micellar prodrug for targeted therapy against ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3717.

Dietary nucleosides and nucleotides play an important role in the maintenance of functions of bone marrow hematopoietic cells, intestinal mucosa, and brain. Therefore, analysis of those compounds in food is very important for improving and assuring food quality. This review summarized the application of CE and CEC in the analysis of nucleosides and nucleotides in food. The sample preparation and detection are also discussed.

Ethnopharmacological relevance Ophiopogonis Radix (Maidong in Chinese), the root of Ophiopogon japonicus , is widely used in local medicines of China, Japan and some south-eastern Asian countries. According to the traditional Chinese medicine (TCM) principle, Ophiopogonis Radix nourishes the yin , promotes body fluid production, moistens the lung, eases the mind and clears away heart fire. This review summarizes the achievements of the investigations in botany, phytochemistry, quality control, traditional uses, pharmacological activities and clinical studies on O. japonicus ; this review also describes the shortcomings of studies on this herbal drug and thus serves as the basis of further scientific research and development of this traditional herbal drug. Materials and methods O. japonicus -related information was collected from various resources, including books on Chinese herbs and the Internet databases, such as Google Scholar, SciFinder, Web of Science, Elsevier, ACS, PubMed and China Knowledge Resource Integrated (CNKI). Results O. japonicus is widely distributed in East Asia, especially in China. Numerous compounds were identified from this plant. The main components of O. japonicus include steroidal saponins, homoisoflavonoids and polysaccharides, which exhibited various pharmacological activities, such as cardiovascular protection, anti-inflammation, anticancer, anti-oxidation, immunomodulation, cough relief, antimicrobial, and anti-diabetes. Conclusions O. japonicus is a common traditional Chinese herbal drug used as the main ingredient in many prescriptions. Modern researches verified that O. japonicus can be used either as a healthy food or a therapeutic agent for disease prevention and treatment. The molecular mechanisms and chemical principles of this herbal medicine should be further explored.

Fetuses and infants are vulnerable to perchlorate toxicity. We assessed fetal and infantile exposure to perchlorate in two Chinese cities (Nanchang and Tianjin). Perchlorate was widely found (82%-100%) in breast milk, dissolved infant formula, infants' urine, maternal and cord blood samples. Perchlorate levels in infants' urine (mean ± standard deviation: 22.4 ± 35.6 ng mL(-1)), breast milk (36.6 ± 48.1 ng mL(-1)), and cord blood (3.18 ± 3.83 ng mL(-1)) samples collected from Nanchang and Tianjin were approximately an order of magnitude higher than those reported for the U.S. Perchlorate concentrations in cord blood were comparable to that in maternal blood, indicating that perchlorate is transferred from mother to fetus through placenta. Among all infants providing urine samples, the average daily intake of perchlorate (DOSEU) was estimated to be 1.17 ± 1.57 μg kg(-1) bw d(-1), and 40% of these infants had DOSEU exceeding the RfD (0.7 μg kg(-1) bw d(-1)) recommended by U.S. EPA. However, approximately 70% of exclusively breast-fed infants had perchlorate exposure dose via breast milk exceeding the RfD. For breast-fed infants, breast milk was the overwhelmingly predominant exposure pathway; while infant formula and indoor dust ingestion were major perchlorate exposure sources for formula-fed infants. To our knowledge, this is the first report to assess the fetal and infantile exposure to perchlorate in China.

Perchlorate is used in fireworks and China is the largest fireworks producer and consumer in the world. Information regarding human exposure to perchlorate is scarce in China, and exposure via indoor dust ingestion (EDI indoor dust) has rarely been evaluated. In this study, perchlorate was found in indoor dust (detection rate: 100%, median: 47.4 μg/g), human urine (99%, 26.2 ng/mL), drinking water (100%, 3.99 ng/mL), and dairy milk (100%, 12.3 ng/mL) collected from cities that have fireworks manufacturing areas (Yueyang and Nanchang) and in cities that do not have fireworks manufacturing industries (Tianjin, Shijiazhuang, Yuxi and Guilin) in China. In comparison with perchlorate levels reported for other countries, perchlorate levels in urine samples from fireworks sites and nonfireworks sites in China were higher. Median indoor dust perchlorate concentrations were positively correlated (r = 0.964, p < 0.001) with outdoor dust perchlorate levels reported previously. The total daily intake (EDI total) of perchlorate, estimated based on urinary levels, ranged from 0.090 to 27.72 μg/kg body weight (bw)/day for all studied participants; the percentage of donors who had EDI total exceeding the reference dose (RfD) recommended by the United States Environmental Protection Agency (US EPA) was 79%, 48%, and 25% for toddlers (median: 1.829 μg/kg bw/day), adults (0.669 μg/kg bw/day), and children (median: 0.373 μg/kg bw/day), respectively. Toddlers (0.258 μg/kg bw/day) had the highest median EDI indoor dust, which was 2 to 5 times greater than the EDI indoor dust calculated for other age groups (the range of median values: 0.044 to 0.127 μg/kg bw/day). Contribution of indoor dust to EDItotal was 26%, 28%, and 7% for toddlers, children, and adults, respectively. Indoor dust contributed higher percentage to EDI total than that by dairy milk (0.5-5%).

By comparing the target proteins (TPs) of classic traditional Chinese medicine (TCM) herbal formulas and modern drugs used for treating coronary artery disease (CAD), this study aimed to identify potential therapeutic TPs for treating CAD. Based on the theory of TCM, the Xuefu-Zhuyu decoction (XZD) and Gualou-Xiebai-Banxia decoction (GXBD), both of which are classic herbal formulas, were selected for treating CAD. Data on the chemical ingredients and corresponding TPs of the herbs in these two formulas and data on modern drugs approved for treating CAD and related TPs were retrieved from professional TCM and bioinformatics databases. Based on the associations between the drugs or ingredients and their TPs, the TP networks of XZD, GXBD, and modern drugs approved for treating CAD were constructed separately and then integrated to create a complex master network in which the vertices represent the TPs and the edges, the ingredients or drugs that are linked to the TPs. The reliability of this master network was validated through statistical tests. The common TPs of the two herbal formulas have a higher possibility of being targeted by modern drugs in comparison with the formula-specific TPs. A total of 114 common XZD and GXBD TPs that are not yet the target of modern drugs used for treating CAD should be experimentally investigated as potential therapeutic targets for treating CAD. Among these TPs, the top 10 are NOS3, PTPN1, GABRA1, PRKACA, CDK2, MAOB, ESR1, ADH1C, ADH1B, and AKR1B1. The results of this study provide a valuable reference for further experimental investigations of therapeutic targets for CAD. The established method shows promise for searching for potential therapeutic TPs based on herbal formulas. It is crucial for this work to select beneficial therapeutic targets of TCM, typical TCM syndromes, and corresponding classic formulas.