Search

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.

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

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.

Multifunctional magnetic nanoagents (MMNs) have drawn increasing attention in cancer precision therapy, attributed to their good biocompatibility and the potential applications for multimodal imaging and multidisciplinary therapy. The noble metal or isotopes contained in MMNs could not only perform superparamagnetism, providing an outstanding magnetic targeting property for drug delivery, but also endow the MMNs with a magnetocaloric effect, photothermal performance, and radiotherapy sensitization, arriving at a multimode combination therapy for cancer. Also, the composite component can endow MMNs with various imaging performance, such as magnetic resonance imaging (MRI), computed tomography (CT), positron emission tomography (PET), and single-photon emission computed tomography (SPECT), thereby achieving accurate image-guided therapy for cancer. However, the joint function of MMNs is closely correlated with their functional nanocomponents and nanostructures. In this article, we will systematically discuss the design, synthesis, and structure optimization of MMNs, as well as their potential in multimodal diagnosis and therapy, scientifically providing an integrated diagnosis and treatment of nanomedicine for the future cancer therapy.

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.

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.

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.

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide.1 Inducing tumour cells apoptosis by chemotherapy is a common treatment modality for inoperable tumour.2 Some studies have shown that amyloid protein precursor (APP), which plays an important role in neuronal cells owing to their linkage with Alzheimer's disease,3 aberrantly altered in many types of cancers. However, the regulation of APP in tumour cells and its role in tumour cells remains unknown.‐Epigallocatechin‐3‐gallate (EGCG) has been shown to possess a wide range of pharmacological properties, including anti‐inflammatory and neuroprotective effects, which have been linked to the antioxidant/pro‐oxidant properties of its polyphenol constituents.4 Some studies have shown that EGCG inhibited hepatocellular carcinoma growth and induced apoptosis.5 We previously also found that EGCG induced neuroblastoma apoptosis via inhibition of amyloid precursor protein.6 However, little is known about the mechanism of EGCG on APP regulation in tumour. The RNA‐binding proteins (RBPs) interact with other proteins and RNAs to form different ribonucleoprotein (RNP) complexes, which participate in the post‐transcriptional regulation of RNAs and which orchestrate the fate of those RNAs.7 Human antigen R (HuR, also known as ELAVL1) is an important RNA‐binding protein. Some studies reported that HuR correlated with patient outcome in liver cancer and interacted with lncRNA‐{"type":"entrez-nucleotide","attrs":{"text":"AK058003","term_id":"16554001","term_text":"AK058003"}}AK058003 to regulate proliferation and metastasis of hepatocellular carcinoma.7 Furthermore, in neurons, studies showed that HuD interacted with the 3’ UTRs of APP mRNA (encoding amyloid precursor protein) and BACE1 mRNA (encoding β‐site APP‐cleaving enzyme 1) and increased the half‐lives of these mRNAs.8 However, the role of HuR in APP expression and EGCG‐regulated APP expression in tumour is not clear. In this study, we first indicate that the role of EGCG in APP and ADAM10 regulation is mediated by HuR, result in tumour cells apoptosis via HuR‐Erk1/2‐APP/ADAM10 pathway, adding a new dimension to EGCG‐mediated regulation of APP and ADAM10 in cancer cell apoptosis.

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

Photodynamic Therapy (PDT), as a clinically approved modality for the treatment of various disordered diseases including cancer, has received great advances in recent years. By preferentially accumulating non-toxic Photosensitizers (PSs) in the pathological area, and in situ generation of cytotoxic reactive oxygen species (ROS) under local irradiation by a light source with appropriate wavelength, PDT works in a dual-selective manner. Over the past decades, numerous studies and reviews on PDT mainly focused on activable PSs and the newly emerging PSs in PDT. However, to the best of our knowledge, there are few articles on the systematic introduction of light sources and limited reports about targeted strategies in PDT. This review comprehensively summarizes various light sources applied in PDT together with typical enhanced targeting strategies, and outlines their advantages and disadvantages, respectively. The clinical applications and future perspectives in light sources are also partly presented and discussed.

In traditional Chinese medicine, dihydroartemisinin (DHA) is the focus of extensive attention because of its unique activity with Fe2+ to produce reactive oxygen species (ROS) and promote apoptosis. In this work, we designed a newfangled ink@hydrogel containing FeCl3, traditional Chinese ink (Hu Kaiwen ink), and agarose hydrogel to create a synergistic activity with DHA in the treatment of cancer. When the system is irradiated under 1,064 nm for a few minutes, the ink in the ink@hydrogel converts the light to heat and hyperthermia causes the reversible hydrolysis of hydrogel. Then, Fe3+ quickly diffuses from the hydrogel to the tumor microenvironment and is reduced to Fe2+ to break the endoperoxide bridge in pre-injected DHA, which results in the release of free radicals for a potent anticancer action. To our knowledge, this is the first report of a hydrogel tumor therapy system that induces a photo-thermal response in the second near infrared window (NIR-II). in vivo experiments also showed a significant effect of DHA-Fe2+ in chemodynamic therapy (CDT) and in photo-thermal therapy. This hydrogel platform provided an encouraging idea for synergistic tumor therapy.

In Chinese traditional medicine, quercetin (QT) plays a fundamental role in the treatment of asthma, as an anti-allergen and to lower blood pressure. Recent evidence suggests that QT can improve tumor radiosensitivity through multiple mechanisms. However, poor tumor tissue targeting ability and low water solubility of QT limit its usefulness in the treatment of cancers. Herein, we designed a novel drug delivery system (CQM) consisting of inner QT loaded mesoporous silica nanoparticles (MSNs) and outer cancer cell membranes (CM). The developed nanoplatform had strong anti-cancer effects under X-ray irradiation and good QT loading characteristics. In addition, CQM effectively targeted tumor tissues. Results of in vitro and in vivo experiments demonstrated that the developed CQM drug delivery system has excellent tumor targeting ability and effectively inhibited tumor growth. Therefore, the CQM platform realized targeted drug delivery and radiotherapy sensitization, which provided a newfangled idea of cancer treatment.

With the wide application of nanotechnology to drug delivery systems, a simple, dynamic and visual in vivo model for high-throughput screening of novel formulations with fluorescence markers across biological barriers is desperately needed. In vitro cell culture models have been widely used, although they are far from a complimentary in vivo system. Mammalian animal models are common predictive models to study transport, but they are costly and time consuming. Zebrafish (Danio rerio), a small vertebrate model, have the potential to be developed as an "intermediate" model for quick evaluations. Based on our previously established coumarin 6 nanocrystals (C6-NCs), which have two different sizes, the present study investigates the transportation of C6-NCs across four biological barriers, including the chorion, blood brain barrier (BBB), blood retinal barrier (BRB) and gastrointestinal (GI) barrier, using zebrafish embryos and larvae as in vivo models. The biodistribution and elimination of C6 from different organs were quantified in adult zebrafish. The results showed that compared to 200nm C6-NCs, 70nm C6-NCs showed better permeability across these biological barriers. A FRET study suggested that intact C6-NCs together with the free dissolved form of C6 were absorbed into the larval zebrafish. More C6 was accumulated in different organs after incubation with small sized NCs via lipid raft-mediated endocytosis in adult zebrafish, which is consistent with the findings from in vitro cell monolayers and the zebrafish larvae model. C6-NCs could be gradually eliminated in each organ over time. This study demonstrated the successful application of zebrafish as a simple and dynamic model to simultaneously assess the transport of nanosized drug delivery systems across several biological barriers and biodistribution in different organs, especially in the brain, which could be used for central nervous system (CNS) drug and delivery system screening.

A novel sensitive and selective probe for the important antibiotic vancomycin (Van) has been synthesized by integrating a coumarin and a fluorescein as dual fluorescence reporters and a Van binding peptide D-Ala-D-Ala. Only weak green fluorescence was initially observed, which was mostly attributed to fluorescence self-quenching induced by fluorophore stacking. Upon the binding of Van with the D-Ala-D-Ala peptide, the fluorescence turned on, probably due the disaggregation of fluorophores. The intensity ratio of the dual emission bands I519/I446 exhibited an excellent linear relationship with the concentration of Van increasing from 0-20 μM in synthetic urine. The lowest detection limit was calculated to be 92.8 nM in urine, which made the probe applicable in clinically relevant concentration ranges. The synthetic probe has also shown the potential for Van detection in human serum. More interestingly, this probe has been successfully applied for in vivo imaging of Van in zebrafish. Graphical Abstract.

Microglia-mediated neuroinflammatory responses are inevitable and important pathological processes in several kinds of disorder of the central nervous system (CNS). Therefore, alleviating activated microglia-induced inflammatory process might be a valuable therapeutic approach to neuroinflammation-related diseases. In the present study, we investigated BHDPC, a novel neuroprotectant discovered in our previous study that had anti-inflammatory effects under neuroinflammatory conditions. First, we found that BHDPC could inhibit neuroinflammatory responses and promote microglial M2 phenotype polarization in both lipopolysaccharide (LPS)-activated BV-2 microglia l cells. Furthermore, BHDPC provided protective actions against neuroinflammation-induced neurotoxicity in HT22 mouse hippocampal cells co-cultured with activated BV-2 microglia. Further experiments demonstrated that BHDPC could suppress LPS-induced activation of transcription factor nuclear factor kappa B (NF-κB) via interfering with the degradation of the inhibitor of kappa B (IκB) and phosphorylation of IκB, the IκB kinase (IKK). Moreover, we also found that BHDPC could induce phosphorylation of cAMP-dependent protein kinase A (PKA) and cAMP-response element-binding protein (CREB) in BV-2 microglial cells. Also, using the PKA-specific inhibitor, we found that BHDPC-induced CREB phosphorylation was dependent on PKA, which also contributed to BHDPC-mediated anti-inflammation and neuroprotection.

The blood brain barrier (BBB) is the network of capillaries that controls the passage of substances from the blood into the brain and other parts of the central nervous system (CNS). As this barrier is the major obstacle for drug delivery into CNS, a credible BBB model is very necessary to assess the BBB permeability of novel neuroactive compounds including thousands of bioactive compounds which have been extracted from medicinal plants and have the potential for the treatment of CNS diseases. Increasing reports indicated that zebrafish has emerged as a timely, reproducible model for BBB permeability assessment. In this review, the development and functions of the BBB in zebrafish, such as its anatomical morphology, tight junctions, drug transporters and enzyme expression, are compared with those in mammals. The studies outlined in this review describe the utilization of the zebrafish as a BBB model to investigate the permeability and distribution of fluorescent dyes and drugs. Particularly, this review focuses on the use of zebrafish to evaluate the delivery of natural products and nanosized drug delivery systems across the BBB. Due to the highly conserved nature of both the structure and function of the BBB between zebrafish and mammals, zebrafish has the potential to be developed as a model for assessing and predicting the permeability of BBB to novel compounds.