Elevated Blood S100B Levels in Patients With Migraine: A Systematic Review and Meta-Analysis.

Background: In recent years, a growing number of researches indicate that S100B may act in migraine, but the relationship between S100B and migraine remains controversial. Therefore, the current study aimed to perform a meta-analysis to quantitatively summarize S100B levels in migraine patients. Methods: We used Stata 12.0 software to summarize eligible studies from PubMed, EMBASE, Web of Science, Cochrane Library, China National Knowledge Infrastructure (CNKI), and Wanfang databases. We applied standardized mean differences (SMDs) with 95% confidence intervals (95%CIs) to appraise the association between S100B and migraine. Results: The combined results of nine case-control studies indicated that compared with healthy controls, overall migraine patients had significantly increased S100B levels in peripheral blood (SMD = 0.688, 95%CI: 0.341-1.036, P < 0.001). The S100B levels in migraineurs during ictal periods (SMD =1.123, 95%CI: 0.409-1.836, P = 0.002) and interictal periods (SMD = 0.487, 95%CI: 0313-0.661, P < 0.001), aura (SMD = 0.999, 95%CI: 0.598-1.400, P < 0.001) and without aura (SMD = 0.534, 95%CI: 0.286-0.783, P < 0.001) were significantly higher than those in the controls. The subgroup analyses by age, country, migraine assessment, and assay method of S100B also illustrated a statistically obvious association between S100B levels and migraine, indicating that age may be the most important source of heterogeneity. Sensitivity analysis showed that no individual study has a significant influence on the overall association between S100B and migraine. Conclusion: This meta-analysis demonstrates that the level of S100B in peripheral blood of patients with migraine was significantly increased. Migraine may be associated with pathological reactions involving S100B, which is instrumental for the clinical diagnosis of migraine and therapy that considers S100B as a potential target.

Side effects of long-term oral anti-seizure drugs on thyroid hormones in patients with epilepsy: a systematic review and network meta-analysis.

INTRODUCTION: Anti-seizure drugs have long been known to affect thyroid hormone levels in epilepsy patients. The current study is a network meta-analysis designed to produce a systematic review and comprehensive evaluation of thyroid hormone changes to inform future research and clinical treatment. METHOD: A systematic search of databases, PubMed, EMBASE, Web of Science, and the Cochrane Library, was conducted and all observational studies reporting thyroid hormone levels in epilepsy patients receiving monotherapy and controls were included. Stata MP.14 was used for analysis. RESULTS: A total of 35 studies, including 4135 participants and 8 anti-seizure drugs, were analyzed. TSH levels were elevated following use of topiramate [mean = 1.86; 95%CI: 0.83 to 2.90], levetiracetam [mean = 1.08; 95%CI: 0.07 to 2.09], and valproic acid [mean = 1.54; 95%CI: 0.58 to 2.50]. FT4 levels may be lowered by oxcarbazepine [mean = - 6.13; 95%CI: - 8.25 to - 4.02] and T4 was lowered by carbamazepine [mean = - 1.55; 95%CI: - 2.05 to - 1.05] and phenytoin [mean = - 1.33; 95%CI: - 1.80 to - 0.85]. No significant changes were reported for FT3, although use of phenobarbital resulted in a non-significant decrease [mean = - 0.31; 95%CI: - 0.99 to 0.37]. T3 levels were lowered by carbamazepine [mean = - 0.52; 95%CI: - 0.81 to - 0.24]. Lamotrigine had no significant effect on thyroid hormone levels. CONCLUSION: Carbamazepine and phenytoin were the drugs most strongly associated with decreases in T4 and T3 levels while topiramate had the greatest elevating effect on TSH. Oxcarbazepine may lead to decreased serum FT4 and FT3, an effect relevant to central hypothyroidism. Phenobarbital appeared to significantly lower FT3. Use of levetiracetam and valproic acid may result in subclinical hypothyroidism. The anti-seizure drug with the least disruptive effect on thyroid hormone levels was found to be lamotrigine.

The Function of NF-Kappa B During Epilepsy, a Potential Therapeutic Target.

The transcriptional regulator nuclear factor kappa B (NF-κB) modulates cellular biological activity by binding to promoter regions in the nucleus and transcribing various protein-coding genes. The NF-κB pathway plays a major role in the expressing genes related to inflammation, including chemokines, interleukins, and tumor necrosis factor. It also transcribes genes that can promote neuronal survival or apoptosis. Epilepsy is one of the most common brain disorders and it not only causes death worldwide but also affects the day-to-day life of affected individuals. While epilepsy has diverse treatment options, there remain patients who are not sensitive to the existing treatment methods. Recent studies have implicated the critical role of NF-κB in epilepsy. It is upregulated in neurons, glial cells, and endothelial cells, due to neuronal loss, glial cell proliferation, blood-brain barrier dysfunction, and hippocampal sclerosis through the glutamate and γ-aminobutyric acid imbalance, ion concentration changes, and other mechanisms. In this review, we summarize the functional changes caused by the upregulation of NF-κB in the central nervous system during different periods after seizures. This review is the first to deconvolute the complicated functions of NF-κB, and speculate that the regulation of NF-κB can be a safe and effective treatment strategy for epilepsy.

Bioinspired mimics: Self-assembly of redox-activated phosphorylcholine-based biodegradable copolymers for enhancing antitumor efficiency.

With the purpose of reducing side effects in anticancer therapy, the micelles of a novel reduction-activated copolymer with biomimicking phosphorylcholine, poly(ε-caprolactone)-ss-b-poly(2-methacryloyloxyethyl phosphorylcholine) (PCL-ss-PMPC) are developed. The well-suitable nanosize of micelles with good physiological stability (approximately 50 nm, 2.5 µg/mL) can be quickly internalized into cells due to bioinspired phosphorylcholine property and mainly located in endo/lysosomes. The reduction response of micelles is confirmed by size change and accelerated drug release under reducing environment, proved as better anticancer efficacy in comparison to insensitive micelles. Pharmacokinetics and in vivo studies demonstrate that redox-activated polymeric micelles can prolong blood transportation, facilitate passive target and accumulate in tumor site, and prompt drug release in cytoplasmic redox environment, behaving as much better antitumor efficiency than control and positive DOX·HCl groups. More importantly, the DOX-loaded micelles considerably reduce side effects and systematic toxicity. Therefore, this work fabricated an innovative bioinspired nanosystem via a facile strategy to achieve effective anticancer therapy.

In vitro and in vivo anti-tumor efficiency comparison of phosphorylcholine micelles with PEG micelles.

Polymer micelles for anticancer drug delivery have shown many advantages. In this study, poly(ε-caprolactone)-b-poly(2-methacryloyloxyethyl phosphorylcholine) (PCL-PMPC) with bio-inspired structure self-assembled into small and uniform micelles as traditional poly(ε-caprolactone)-b-poly(ethylene glycol) (PCL-PEG). The in vitro and in vivo anti-tumor efficiency of PCL-PMPC and PCL-PEG micelles were detailedly evaluated. The both micelles were able to load DOX with high efficiency. PCL-PMPC micelles exhibited faster drug release at pH 5.5 than that of PCL-PEG micelles. Confocal laser scanning microscopy and flow cytometry results showed that PCL-PMPC micelles were more effectively internalized by tumor cells. DOX-loaded PCL-PMPC micelles presented higher cytotoxicity to tumor cells. PCL-PMPC micelles displayed not only longer circulation time in pharmacokinetics investigation, but also higher accumulation at the tumor site in in vivo imaging study in comparison with PCL-PEG micelles. More importantly, in a tumor model DOX-loaded PCL-PMPC micelles showed better therapeutic efficacy than DOX-loaded PCL-PEG micelles along with mild side effects. Therefore, PCL-PMPC micelles are deemed to be promising drug carriers for cancer therapy.

pH responsive micelles based on copolymers mPEG-PCL-PDEA: The relationship between composition and properties.

Polymeric micelles with pH response are considered as promising drug carriers for cancer therapy. In this study, copolymers methoxy-poly (ethylene glycol)-b-poly (ε-caprolactone)-b-poly (diethylaminoethyl methacrylate) (mPEG-PCL-PDEA) were designed and synthesized to investigate the relationship between number of pH responsive units and micelle properties. The structures of these copolymers were characterized by nuclear magnetic resonance, Fourier transform infrared, gel permeation chromatograph, differential scanning calorimetry and water contact angle. The micelles of the copolymers were obtained, the micelle properties were studied by critical micellization concentration, micelle size, morphology, pH response, cytotoxicity and drug loading/release. Moreover, dissipative particle dynamics (DPD) was used to investigate the structure of the micelles under different pH. The results showed that the micelle properties including pH sensitivity, cytotoxicity and drug loading/releasing performance, were related to PDEA units in copolymers. So, mPEG-PCL-PDEA micelles with suitable composition are promising as drug carriers due to their high pH sensitivity, low cytotoxicity and good drug loading/releasing performance.

Effects of copolymer component on the properties of phosphorylcholine micelles.

Zwitterionic polymers have unique features, such as good compatibility, and show promise in the application of drug delivery. In this study, the zwitterionic copolymers, poly(ε-caprolactone)-b-poly(2-methacryloyloxyethyl phosphorylcholine) with disulfide (PCL-ss-PMPC) or poly(ε-caprolactone)-b-poly(2-methacryloyloxyethyl phosphorylcholine) or without disulfide (PCL-PMPC) and with different block lengths in PCL-ss-PMPC, were designed. The designed copolymers were obtained by a combination of ring-opening polymerization and atom transferring radical polymerization. The crystallization properties of these polymers were investigated. The micelles were prepared based on the obtained copolymers with zwitterionic phosphorylcholine as the hydrophilic shell and PCL as the hydrophobic core. The size distributions of the blank micelles and the doxorubicin (DOX)-loaded micelles were uniform, and the micelle diameters were <100 nm. In vitro drug release and intracellular drug release results showed that DOX-loaded PCL-ss-PMPC micelles could release drugs faster responding to the reduction condition and the intracellular microenvironment in contrast to PCL-PMPC micelles. Moreover, in vitro cytotoxicity evaluation revealed that the designed copolymers possessed low cell toxicity, and the inhibiting effect of DOX-loaded phosphorylcholine micelles to tumor cells was related to the components of these copolymers. These results reveal that the reduction-responsive phosphorylcholine micelles with a suitable ratio of hydrophilic/hydrophobic units can serve as promising drug carriers.

The anti-bacterial poly(caprolactone)-poly(quaternary ammonium salt) as drug delivery carriers.

Anti-bacterial materials play significant role in biomedical field. Researches and applications of new anti-bacterial materials are necessary. Novel linear and star-shaped copolymers of poly(caprolactone)-poly(quaternary ammonium salt) (PCL-PJDMA) were synthesized by a combination of ring-opening polymerization and atom transfer radical polymerization. The structures of the copolymers were confirmed by nuclear magnetic resonance ((1)H-NMR) and Fourier transform infrared spectroscopy. The copolymers self-assembled into ball-shaped micelles with low critical micelle concentration (10(-4) ∼ 10(-3) mg/ml). An anti-bacterial drug, triclosan, was chosen as a model drug to investigate the potential application of the copolymers in drug-controlled release. The anti-bacterial experiments against Escherichia coli indicated that all the copolymer micelles had anti-bacterial ability and drug-loaded star-shaped PCL-PJDMA micelles were the best. The slow release of the drug from the drug-loaded micelles prolonged anti-bacterial effect. Therefore, PCL-PJDMA themselves have not only anti-bacterial ability but also the copolymer micelles can be used as carriers for anti-bacterial drugs.

Characteristic of core materials in polymeric micelles effect on their micellar properties studied by experimental and dpd simulation methods.

Polymeric micelles are one important class of nanoparticles for anticancer drug delivery, but the impact of hydrophobic segments on drug encapsulation and release is unclear, which deters the rationalization of drug encapsulation into polymeric micelles. This paper focused on studying the correlation between the characteristics of hydrophobic segments and encapsulation of structurally different drugs (DOX and ß-carotene). Poly(ϵ-caprolactone) (PCL) or poly(l-lactide) (PLLA) were used as hydrophobic segments to synthesize micelle-forming amphiphilic block copolymers with the hydrophilic methoxy-poly(ethylene glycol) (mPEG). Both blank and drug loaded micelles were spherical in shape with sizes lower than 50 nm. PCL-based micelles exhibited higher drug loading capacity than their PLLA-based counterparts. Higher encapsulation efficiency of ß-carotene was achieved compared with DOX. In addition, both doxorubicin and ß-carotene were released much faster from PCL-based polymeric micelles. Dissipative particle dynamics (DPD) simulation revealed that the two drugs tended to aggregate in the core of the PCL-based micelles but disperse in the core of PLLA based micelles. In vitro cytotoxicity investigation of DOX loaded micelles demonstrated that a faster drug release warranted a more efficient cancer-killing effect. This research could serve as a guideline for the rational design of polymeric micelles for drug delivery.

Synthesis of amphiphilic copolymers containing zwitterionic sulfobetaine as pH and redox responsive drug carriers.

Amphiphilic poly(ɛ-caprolactone)-SS-poly(N,N-diethylaminoethyl methacrylate)-r-poly(N-(3-sulfopropyl)-N-methacrylate-N,N-diethylammonium-betaine) (PCL-SS-PDEASB) was designed and synthesized successfully. pH and redox dually responsive micelles were prepared based on the obtained copolymers, with zwitterionic sulfobetaines as hydrophilic shell, DEA as pH sensitive content and disulfide as redox responsive linkage. The micelle diameters were all less than 200 nm and the micelle diameter distributions were narrow. These micelles could be triggered by pH and redox condition. The drug release from the drug-loaded micelles displayed fastest under simultaneously acidic and reductive conditions. Results of in vitro cell toxicity evaluation showed that introduction of sulfobetaines could greatly decrease the toxicity of poly(ɛ-caprolactone)-SS-poly(N,N-diethylaminoethyl methacrylate) (PCL-SS-PDEA) micelles. DOX-loaded PCL-SS-PDEASB micelles showed higher efficiency to kill HeLa cells than DOX-loaded PCL-PDEASB micelles. Half inhibitory concentration (IC50) of DOX-loaded PCL-SS-PDEASB micelles decreased with the content of sulfobetaines increasing and was even closer to that of DOX·HCl. Thus, the pH and redox dually responsive biodegradable micelles generated by PCL-SS-PDEASB may be potential smart drug carriers for tumor targeted delivery.

Framework effect of amphiphilic polyesters on their molecular movement and protein adsorption-resistance properties.

Surface chemical characteristics of biomedical polymers, which are determined by the migration and rearrangement of polymeric chains, play an important role in the protein adsorption. In this work, the relationship between the architectures of amphiphilic polyesters and their protein adsorption resistance was investigated. Three poly (ɛ-caprolactone)s containing sulfobetaines (PCL-b-PDEAS) segments with linear, four arms and six arms star-shaped architectures were synthesized with the combination of ring-opening polymerization (ROP) and atom transfer radical polymerization (ATRP). The structures of the amphiphiles were confirmed by (1)H NMR and FTIR. Water contact angles (WCA) and X-ray photoelectron spectroscopy (XPS) were used to study the surface properties of the amphiphilic copolymer films. The water contact angles were decreased due to the surface migration of hydrophilic segments. Transmission electron microscopy (TEM) displayed the occurrence of microphase separation phenomena for PCL-b-PDEAS above glass transition temperature (Tg). The results showed that the hydrophilic segments in the copolymers would migrate to the surface of the films, which resulted in the surface more hydrophilic to resist protein adsorption. The adsorption of both fibrinogen (Fg) and bovine serum albumin (BSA) were studied. The results showed that protein adsorption was depended on not only the hydrophilic chain migration but also the shape of proteins.

Uptake enhancement of curcumin encapsulated into phosphatidylcholine-shielding micelles by cancer cells.

Internalization of drugs by cancer cells is a crucial factor to impact cancer treatment effect. Curcumin, having inhibitory effect on a variety of cancers, was encapsulated into micelles of six-arm star-shape poly(ε-caprolactone)-b-poly(2-methacryloyloxyethylphosphorylcholine) (6sPCL-PMPC) in order to enhance its concentration in blood and cellular uptake. Micelles and curcumin-loaded micelles were prepared by the solvent-evaporation method. Drug-loading content and drug-loading efficiency could be achieved as high as 18.9 and 98%. MTT results showed that these curcumin-loaded micelles displayed significant cell cytotoxicity, while these blank micelles were noncytotoxic. The curcumin-loaded 6sPCL-PMPC micelles showed higher efficiency to kill HeLa cells than that of curcumin-loaded PCL-PEG micelles. The cellular uptake study indicated that the curcumin encapsulated into 6sPCL-PMPC micelles was ingested more by HeLa cells than the curcumin encapsulated into PCL-PEG micelles. In conclusion, the micelles with phosphatidylcholine (PC) groups as their exterior can greatly enhance the uptake by HeLa cells and the cytotoxicity of curcumin due to excellent internalization by cancer cells.

pH and redox-responsive mixed micelles for enhanced intracellular drug release.

In order to prepare pH and redox sensitive micelles, amphiphilic copolymers of poly (epsilon-caprolactone)-b-poly(2-(diethylamino) ethyl methacrylate) (PCL-PDEA) and disulfide-linked poly(ethyl glycol)-poly(epsilon-caprolactone) (mPEG-SS-PCL) were synthesized. The double-sensitive micelles were prepared simply by solvent-evaporating method with the mixed two copolymers. The pH sensitivity of the mixed micelles was confirmed by the change of micelle diameter/diameter distribution measured by dynamic lighting scattering (DLS) and the redox sensitivity of the mixed micelles was testified by the change of micellar morphous observed by scanning electron microscope (SEM). In vitro drug release showed that drug-loaded mixed micelles (mass ratio 5:5) could achieve above 90% of drug release under low pH and reducing condition within 10h. Moreover, the drug-loaded mixed micelles (mass ratio 5:5) showed the largest cellular toxicity compared with other drug-loaded micelles, while blank mixed micelles exhibited no toxicity. These results meant that the mixed micelles composed by the two amphiphilic copolymers can enhance intracellular drug release. It is concluded that the newly developed mixed micelles can serve as a potential drug delivery system for anticancer drugs.

Effect of architecture on the micellar properties of poly (ɛ-caprolactone) containing sulfobetaines.

Linear and star-shape poly(ɛ-caprolactone)-b-poly(N-(3-sulfopropyl)-N-methacryloxyethyl-N,N-diethylammoniumbetaine) (L/sPCL-b-PDEAS) with 4 and 6 arms were synthesized with the combination of Ring Opening Polymerization (ROP) and Atom Transfer Radical Polymerization (ATRP). These copolymers self-assembled into micelles via solvent evaporation method. The critical micelle concentration (CMC), determined by fluorescence spectroscopy using pyrene as a probe, was lower than 10(-3)mg/mL and decreased with increasing arm numbers. Atom force microscopy (AFM) images showed that the micelles were spherical in shape with narrow size distribution. The hydrophobic drug model carotene was efficiently loaded in the polymeric micelles. The sizes and drug loading content (DLC) of the carotene-loaded micelles increased with increasing drug content in feed. In vitro drug release experiment demonstrated that the release rate of carotene from the micelles was closely related to the arm numbers and drug loading content. Linear copolymer micelles showed the fastest release rate, 4-arm star shape copolymer micelles exhibited the lowest release rate. The micelles with higher drug loading content showed lower release rate. The release kinetics of carotene from micelles fitted the Ritger-Peppas equation.