Nanoparticles Coated with Brain Microvascular Endothelial Cell Membranes can Target and Cross the Blood-Brain Barrier to Deliver Drugs to Brain Tumors.

The blood-brain barrier (BBB) contains tightly connected brain microvascular endothelial cells (BMECs) that hinder drug delivery to the brain, which makes brain tumors difficult to treat. Previous studies have shown that nanoparticles coated with tumor cell membranes selectively target their homologous tumors. Therefore, this study investigated whether bEnd.3-line BMEC membrane-coated nanoparticles with poly(lactide-co-glycolide)-poly(ethylene glycol)-based doxorubicin-loaded cores (BM-PDs) can be used to target BMECs and cross the BBB. In vitro, the BM-PDs effectively target BMECs and cross a BBB model. The BM-PDs enter the BMECs via macropinocytosis, clathrin-mediated endocytosis, caveolin-mediated endocytosis, and membrane fusion, which result in excellent cellular uptake. The BM-PDs also show excellent cellular uptake in brain tumor cells. In vivo, the BM-PDs target BMECs, cross the BBB, accumulate in brain tumors, and efficiently kill tumor cells. Therefore, the proposed strategy has great therapeutic potential owing to its ability to cross the BBB to reach brain tumors.

Comprehensive exercise reduces traumatic brain injury deficits via improving the neural network function of hippocampal CA1 and medial entorhinal cortex.

The present study aimed to investigate the alterations in functional interaction between hippocampal CA1 and medial entorhinal cortex (MEC) after moderate traumatic brain injury (TBI) in C57BL/6J mice, and the possible beneficial effects of comprehensive exercise (CE). Following TBI, two microelectrodes were implanted into CA1 and MEC for extracellular recording. We found a clear synchronization of neuronal firing in CA1 and MEC, particularly within 100 Hz and peaked at 20-30 Hz range. TBI induced a significant reduction (P < 0.001) of the coherences of firing between 20-40 Hz frequency band. The mean power spectral densities (PSD) of all group mice in MEC were steadily larger than the values in CA1 in both 20-40 Hz and 56-100 Hz ranges. TBI induced significant and consistent increases of averaged 20-40 Hz or 56-100 Hz PSD (P < 0.001 or P < 0.01) in both CA1 and MEC. Injured mice displayed more varied firing patterns, and showed increased burst frequency (BF), burst duration (BD), inter-spike intervals (ISI) and inter-burst interval (IBI). Injured mice also showed worsened neurological function, sleep, gait performance, and working memory. CE facilitated the restoration of aforementioned electrophysiological characteristics and functional deficits in TBI mice. These results suggest that the beneficial effects of CE on TBI functional deficits may be partly attributed to improved neuronal network interaction between CA1 and MEC.

Modified mouse model of repeated mild traumatic brain injury through a thinned-skull window and fluid percussion.

Mild traumatic brain injury (mTBI) is a clinically highly heterogeneous neurological disorder, none of the existing animal models can replicate the entire sequelae. This study aimed to develop a modified closed head injury (CHI) model of repeated mTBI (rmTBI) for investigating Ca2+ fluctuations of the affected neural network, the alternations of electrophysiology, and behavioral dysfunctions. The transcranial Ca2+ study protocol includes AAV-GCaMP6s infection in the right motor cortex, thinned-skull preparation, and two-photon laser scanning microscopy (TPLSM) imaging. The CHI rmTBI model is fabricated using the thinned-skull site and applying 2.0 atm fluid percussion with 48-h interval. The neurological dysfunction, minor motor performance, evident mood, spatial working, and reference deficits we found in this study mimic the clinically relevant syndromes after mTBI. Besides, our study revealed that there was a trend of transition from Ca2+ singlepeak to multipeak and plateau, and the total Ca2+ activities of multipeaks and plateaus (p < .001 vs. pre-rmTBI value) were significantly increased in ipsilateral layer 2/3 motor neurons after rm TBI. In parallel, there is a low-frequency power shift from delta to theta band (p < .01 vs. control) in the ipsilateral layer 2/3 of motor cortex of the rmTBI mice, and the overall firing rates significantly increased (p < .01 vs. control). Moreover, rmTBI causes slight cortical and hippocampal neuron damage and possibly induces neurogenesis in the dentate gyrus (DG). The alternations of Ca2+ and electrophysiological characteristics in layer 2/3 neuronal network, histopathological changes, and possible neurogenesis may play concertedly and partially contribute to the functional outcome post-rmTBI.

Triazine-Porphyrin-Based Hyperconjugated Covalent Organic Framework for High-Performance Photocatalysis.

Covalent organic frameworks (COFs) with porphyrins as structural units are a new kind of porous organic polymers, which have a regular and ordered structure, abundant porosity, and good stability. In the past, the construction of porphyrin COFs was generally synthesized by routes such as a Schiff base reaction. Here, we report a new COF structure by linking the porphyrin with the triazine ring. Using a cyano group-terminated porphyrin as a structural unit precursor, a new triazine-porphyrin hyperconjugated COF (TA-Por-sp2-COF) was constructed through the cyano group's self-polymerization. The extension of porphyrin units in two directions that stemmed from the cyano group at para-positions accounts for the establishment of a highly ordered two-dimensional topological structure. Attributing to the collaboration of electron-donating and withdrawing blocks for photo-induced carrier separation and adequate porosity for mass diffusion, this hyperconjugated system showed high photocatalytic performance in organic reactions such as the aerobic coupling reaction of benzylamine and thioanisole selective oxidation.

Gold Nanoparticle-Decorated Drug Nanocrystals for Enhancing Anticancer Efficacy and Reversing Drug Resistance Through Chemo-/Photothermal Therapy.

Limited chemotherapeutic efficiency, drug resistance, and side effects are primary obstacles for cancer treatment. The development of co-delivery systems with synergistic treatment modes should be a promising strategy. Here, we fabricated a multifunctionalized nanocarrier with a combination of chemotherapeutic agents and gold nanoparticles (AuNPs), which could integrate chemo-photothermal therapy, thus enhancing overall anticancer efficacy, sensitizing drug-resistant cancer cells, and diminishing cancer stem cells (CSCs). To be specific, camptothecin nanocrystals (CPT NCs) were prepared as a platform, on the surface of which AuNPs were decorated and a hyaluronic acid layer acted as capping, stabilizing, targeting, and hydrophilic agents for CPT NCs, and reducing agents for AuNPs, providing a bridge connecting AuNPs to CPT. These AuNP-decorated CPT NCs exhibited good physico-chemical properties such as optimal sizes, payload, stability, and photothermal efficiency. Compared to other CPT formulations, they displayed considerably improved biocompatibility, selectivity, intracellular uptake, cytotoxicity, apoptosis induction activity, Pgp inhibitory capability, and anti-CSC activity, owing to a synergistic/cooperative effect from AuNPs, CPT, near-infrared treatment, pH/photothermal-triggered drug release, and nanoscaled structure. A mitochondrial-mediated signaling pathway is the underlying mechanism for cytotoxic and apoptotic effects from AuNP-decorated CPT NCs, in terms of mitochondrial dysfunction, intensified oxidative stress, DNA fragmentation, caspase 3 activation, upregulation of proapoptotic genes such as p53, Bax, and caspase 3, and lower levels of antiapoptotic Bcl-2.

The arachidonic acid and its metabolism pathway play important roles for Apostichopus japonicus infected by Vibrio splendens.

Improving the immune ability and guiding healthy culture for sea cucumber by purposefully screening the significant differential metabolites when Apostichopus japonicus (A. japonicus) is infected by pathogens is important. In this study, 35 types of significant differential metabolites appeared when A. japonicus were infected by Vibrio splendens (VSI group) compared with the control A. japonicus group (CK group) by using liquid chromatography-mass spectrometry (LC-MS/MS)-based untargeted metabolomics. Based on that finding, the 10 types of key metabolic pathways were analyzed by MetPA. The "arachidonic acid (ARA) metabolism" pathway, which was screened by three elevated biomarkers: ARA, prostaglandin F2α and 2-arachidonoyl glycerol, had an important impact on immune stress in A. japonicus. Due to the similar changes in several metabolites in its metabolic pathway, the ARA metabolic pathway was selected for further study. The activities of ACP, AKP and lysozyme, which are important innate immune-related enzymes, the survival rates of A. japonicus infected with V. splendidus and the relative content of ARA in the body wall detected by GC-MS were all upregulated significantly by exogenous daily 0.60% and 1.09% ARA consumption over a short period of approximately 7 days. These results demonstrated that ARA and its metabolic pathway indeed played important roles in the immunity of A. japonicus infected by the pathogen. The findings also provide novel insights for the effects of metabolites in A. japonicum healthy culture.

Effects of dietary arachidonic acid (ARA) on immunity, growth and fatty acids of Apostichopus japonicus.

As an important aquaculture species, improving the immunity of cultured Apostichopus japonicus (A. japonicus) is vital for its health in aquaculture farming. It has been shown that ARA is an important metabolite for A. japonicus infected by Vibrio splendidus. In this study, we aimed to determine the effects of dietary exogenous ARA on healthy sea cucumber cultures, including assessments of immunity, growth, and fatty acid content. Five experimental diets containing 0.01%, 0.29%, 0.46%, 0.70%, and 1.09% ARA were tested. The specific growth rate (SGR) of sea cucumbers did not be significantly affected by exogenous ARA diet groups. The results showed that dietary ARA between 0.49 and 1.09% notably improved the survival rate of sea cucumbers infected by Vibrio splendidus compared with the control group without exogenous ARA. The results also showed the effects of dietary ARA on immune-related genes, enzymes, and oxidation indices; most of the exogenous ARA significantly upregulated the mRNA expression of the genes NFκB, TLR, TLR3, TRAF6, Toll, and MyD88. The activities of ACP, AKP, and lysozyme increased in the 0.49-1.09% ARA groups, especially the dietary 0.49% ARA group. The SOD1 and NOS activities were enhanced by dietary ARA between 0.29 and 0.70%. Compared with the control, the MDA content increased, but the 0.49% ARA-diet group had a lower MDA content. Based on these data, 0.49-0.70% ARA significantly enhanced immunity in cultured A. japonicus. Exogenous 0.49% and 0.70% ARA also elevated the ARA, total PUFA and n-6 PUFA in the body walls. In conclusion, the appropriate exogenous ARA (0.49%-0.70%) in diets could improve immunity and fatty acid content considerably. The results provide basic evidence that ARA can serve a useful immune enhancer for A. japonicus aquaculture.

Gibberellic acid-induced fatty acid metabolism and ABC transporters promote astaxanthin production in Phaffia rhodozyma.

AIMS: Astaxanthin is an important natural antioxidant with various biological functions; however, the production of astaxanthin does not meet the requirements for industrialization. The aim of the present study was to identify an inducer that increases astaxanthin yield and to evaluate the regulatory mechanism of the induction of astaxanthin synthesis in Phaffia rhodozyma. METHODS AND RESULTS: The effects of indole-3-acetic acid (IAA), jasmonic acid (JA) and gibberellic acid (GA) on astaxanthin synthesis were studied by fermentation kinetics analysis. Then, combined transcriptomics and metabolomics approaches were used to analyse differential metabolites and expressed genes involved in astaxanthin synthesis induced by GA. The results indicated that GA significantly increased astaxanthin production; however, IAA and JA had no significant effect on astaxanthin synthesis. The induction by GA significantly enhanced fatty acid metabolism and ABC transporters, increased the expression of fatty acid desaturase and ABC transporter genes, and elevated the contents of unsaturated fatty acids. CONCLUSIONS: These results suggested that fatty acid saturation plays an important role in astaxanthin accumulation and that ABC transporters may be the efflux pumps for astaxanthin. SIGNIFICANCE AND IMPACT OF THE STUDY: The present study reveals metabolic mechanism of GA-induced astaxanthin synthesis and proposes a new strategy of transporter engineering to improve astaxanthin production.

High production of d-psicose from d-fructose by immobilized whole recombinant Bacillus subtilis cells expressing d-psicose 3-epimerase from Agrobacterium tumefaciens.

d-Psicose 3-epimerase (DPEase) can catalyze the isomerization of d-fructose to be rare sugar d-psicose, which has wide application prospects in the food and medical fields. In this study, the DPEase gene from Agrobacterium tumefaciens was constructed into plasmid pMA5, and was successfully expressed in the host Bacillus subtilis WB600 (B. subtilis). After optimization of the fermentation conditions, whole recombinant B. subtilis WB600/pMA5-At-DEPase(O) cells produced d-psicose from d-fructose with a conversion rate of 29.01 ± 0.19%, which could be used for the efficient synthesis of d-psicose. To further improve the whole recombinant B. subtilis application, B. subtilis cells were immobilized onto a gel bead biocatalyst by Ca-alginate. After optimization of the biotransformation conditions, the conversion rate of the immobilized biocatalyst reached 20.74 ± 0.39%, which was lower than the free cells. However, the results showed that the immobilized biocatalyst had higher thermal/pH stability and storability, and the gel beads could be recycled for at least six batches. The results showed that the amount of d-psicose generated reached 32.83 ± 2.56 g/L with the immobilized biocatalyst after six times biotransformation, whereas the free cells produced only approximately 10.44 ± 0.07 g/L. The results showed that immobilized recombinant B. subtilis cells are promising to use for the efficient synthesis of d-psicose.

Antioxidative Effect of Chlorella Pyrenoidosa Protein Hydrolysates and Their Application in Krill Oil-in-Water Emulsions.

Chlorella pyrenoidosa is an excellent source of protein, and in this research, we assessed the antioxidant and emulsifying effects of Chlorella protein hydrolysate (CPH) using neutral proteases and alkaline proteases, as well as the properties of CPH-derived krill oil-in-water (O/W) emulsions. The CPHs exhibited the ability to scavenge several kinds of free radicals, including 1,1-diphenyl-2-picrylhydrazyl (DPPH), O2-, hydroxyl, and ABTS. Additionally, the CPHs (5 mg/mL) scavenged approximately 100% of the DPPH and ABTS. The CPHs showed similar emulsifying activities to Tween 20 and excellent foaming activities (max FS 74%), which helped to stabilize the krill oil-in-water emulsion. Less than 10 mg/mL CPHs was able to form fresh krill oil-in-water emulsions; moreover, the CPHs (5 mg/mL) in a krill O/W emulsion were homogenous, opaque, and stable for at least 30 days. Based on their inhibitory effects on the peroxide value (POV) and thiobarbituric acid reactive substances (TRABS), the CPHs were found to be able to inhibit lipid oxidation in both emulsifying systems and krill O/W emulsions. Thus, the CPHs could improve superoxide dismutase (SOD) activities by 5- or 10-fold and decrease the high reactive oxygen species (ROS) level caused by the addition of H2O2 in vitro. In conclusion, health-promoting CPHs could be applied in krill oil-in-water emulsions as both emulsifiers and antioxidants, which could help to improve the oxidative and physical stability of emulsions.

Neuroprotective effects of voluntary exercise and Yisaipu after traumatic brain injury in mice.

The mechanisms underlying exercise-induced neuroprotective effects after traumatic brain injury (TBI) remained elusive, and there is a lack of effective treatments for TBI. In this study, we investigated the effects of an integrative approach of exercise and Yisaipu (TNFR-IgG fusion protein, TNF inhibitor) in a mouse TBI model. Male C57BL/6J mice were randomly assigned to a sedentary group or a group that followed a voluntary exercise regimen. The effects of 6-week prophylactic preconditioning exercise (PE) alone or in combination with post-TBI Yisaipu treatment on moderate TBI associated deficits were examined. The results showed that combined treatments of PE and post-TBI Yisaipu were superior to single treatments on reducing sensorimotor and gait dysfunctions in mice. These functional improvements were accompanied by reduced systemic inflammation largely via decreased serum TNF-α, boosted autophagic flux, and mitigated lesion volume after TBI. Given these neuroprotective effects, composite approaches such as a combination of exercise and TNF inhibitor may be a promising strategy for facilitating functional recovery from TBI and are worth further investigation.

Antimicrobial mechanism of 4-hydroxyphenylacetic acid on Listeria monocytogenes membrane and virulence.

4-Hydroxyphenylacetic acid (4-HPCA) is the major intestinal metabolite of kaempferol and polymeric proanthocyanidins whereas the effect of 4-HPCA on Listeria monocytogenes remains unknown. In this study, we investigated the effect and mechanism of action of 4-HPCA on the highly lethal foodborne pathogen Listeria monocytogenes. Our results indicated that 4-HPCA inhibited L. monocytogenes growth and proliferation in a dose-dependent manner. In particular, L. monocytogenes displayed negligible growth or proliferation after 4-HPCA treatment (15.61 mM) for 24 h. The impact of 4-HPCA on cell membrane structure and function was investigated in terms of fluorometric cell membrane integrity, zeta potential and relative electrical conductivity. We observed an approximately 15 % fluorescence reduction in the cell membrane after MIC treatment. The zeta potential of the bacteria shifted significantly from -49.74 to -43.70 mV, -36.65 mV and -37.97 mV after treatment with 4-HPCA at the MIC for 0 h, 3 h and 12 h, respectively. The absolute value of the relative electrical conductivities increased significantly following 3 h, 6 h, 9 h and 15 h of 4-HPCA treatment at the MIC level. The results of scanning electron microscopy (SEM) showed that cells treated with 4-HPCA displayed a wrinkled morphology and irregular shapes. Moreover, 4-HPCA obviously decreased the expression of three virulence genes (hlyA, prfA, and inlA) in L. monocytogenes after 12 h of treatment. All these results verified that 4-HPCA, as an effective antibacterial compound against L. monocytogenes, could cause cell death through cell membrane damage and decrease the expression of three virulence factors.

Left ventricular ejection fraction and right atrial diameter are associated with deep regional CBF in arteriosclerotic cerebral small vessel disease.

BACKGROUND: Systemic cardiac hypoperfusion is a well-acknowledged contributor to ischemic leukoencephalopathy. However, it has remained elusive how atherosclerosis-mediated cardiac remodelling modifies cerebral perfusion homeostasis as well as neuroimaging burden in cerebral small vessel disease (CSVD) development. METHODS: This retrospective study identified 103 arteriosclerotic CSVD (aCSVD) patients (CSVD burdenlow 0 ~ 1, n = 61 and CSVD burdenhigh 2 ~ 4, n = 42) from Sep. 2017 to Dec. 2019 who underwent transthoracic echocardiography(n = 81), structural magnetic resonance imaging and arterial spin labelling (ASL). Total CSVD burden was graded according to the ordinal "small vessel disease" rating score (0-4). We investigated the univariate and multivariate linear regression of mean deep regional cerebral blood flow (CBF) as well as logistic regression analysis of CSVD burdenhigh. RESULTS: Right atrial diameter (B coefficient, - 0.289; 95% CI, - 0.578 to - 0.001; P = 0.049) and left ventricular ejection fraction (B coefficient, 32.555; 95% CI, 7.399 to 57.711; P = 0.012) were independently associated with deep regional CBF in aCSVD patients. Binary logistic regression analysis demonstrated decreased deep regional CBF (OR 0.894; 95% CI 0.811-0.985; P = 0.024) was independently associated with higher CSVD burden after adjusted for clinical confounders. Multivariate receiver operating characteristics curve integrating clinical risk factors, mean deep CBF and echocardiographic parameters showed predictive significance for CSVD burdenhigh diagnosis (area under curve = 84.25, 95% CI 74.86-93.65%, P < 0.0001). CONCLUSION: The interrelationship of "cardiac -deep regional CBF-neuroimaging burden" reinforces the importance and prognostic significance of echocardiographic and cerebral hemodynamic assessment in CSVD early-warning.

Silver nanoparticles functionalized Paclitaxel nanocrystals enhance overall anti-cancer effect on human cancer cells.

For chemotherapeutic drugs, precise tumor-targeting and high anti-cancer efficiency is equally important in order to enhance chemotherapy and reverse drug resistance. The combination of multifunctional agents to achieve synergy should be a promising strategy. In our study, we have successfully developed novel multifunctionalized drug nanocrystals to realize co-delivery of the organic drug Paclitaxel (PTX), inorganic silver nanoparticles (AgNPs) and a tumor targeting agent. To be specific, PTX nanocrystals were first prepared as a template, then coated with polydopamine (PDA). The PDA layer was utilized as the connection bridge to produce and deposit AgNPs in situ, and provide sites for tumor-targeting peptide NR1 (RGDARF) grafting. As a result, these NR1/AgNP-decorated drug nanocrystals exhibited dramatically improved cellular uptake efficiency, in vitro anti-cancer activity and an anti-migratory effect against a variety of cancer cells, which was attributable to the synergistic, or at least additive, effect of the AgNPs and PTX, enhanced cellular uptake efficiency through NR1-receptor interaction, pH-responsive drug release and the nanoscaled nature. In particular, high anti-cancer activity and low side effects from these NR1/AgNP-decorated PTX nanocrystals were well balanced in terms of good selectivity and biocompatibility. Moreover, these novel drug nanocrystals displayed strong apoptotic-inducing potency, resulting in cell membrane lysis, nuclear damage, mitochondria dysfunction, excessive ROS release and double-stranded DNA breakage. The potential acting mechanism and molecular basis of these novel drug nanocrystals is relevant to the regulation of mitochondria-mediated apoptosis with a greater Bax-to-Bcl-2 ratio and the activation of pro-apoptotic P53 and caspase 3.

Hyaluronic Acid-Coated Camptothecin Nanocrystals for Targeted Drug Delivery to Enhance Anticancer Efficacy.

Tumor-targeted drug delivery via chemotherapy is very effective on cancer treatment. For potential anticancer agent such as Camptothecin (CPT), high chemotherapeutic efficacy and accurate tumor targeting are equally crucial. Inspired by special CD44 binding capability from hyaluronic acid (HA), in this study, novel HA-coated CPT nanocrystals were successfully prepared by an antisolvent precipitation method for tumor-targeted delivery of hydrophobic drug CPT. These HA-coated CPT nanocrystals demonstrated high drug loading efficiency, improved aqueous dispersion, prolonged circulation, and enhanced stability resulting from their nanoscaled sizes and hydrophilic HA layer. Moreover, as compared to crude CPT and naked CPT nanocrystals, HA-coated CPT nanocrystals displayed dramatically enhanced in vitro anticancer activity, apoptosis-inducing potency against CD44 overexpressed cancer cells, and lower toxic effect toward normal cells due to pH-responsive drug release behavior and specific HA-CD44 mediated endocytosis. Additionally, HA-coated CPT nanocrystals performed fairly better antimigration activity and biocompatibility. The possible molecular mechanism regarding this novel drug formulation might be linked to intrinsic mitochondria-mediated apoptosis by an increase of Bax to Bcl-2 ratio and upregulation of P53. Consequently, HA-coated CPT nanocrystals are expected to be an effective nanoplatform in drug delivery for cancer therapy.

Bacillus baekryungensis MS1 regulates the growth, non-specific immune parameters and gut microbiota of the sea cucumber Apostichopus japonicus.

Winter is a high incidence period of skin ulceration syndrome in the sea cucumber Apostichopus japonicus. Disease control during the overwintering of sea cucumber can help increase yield and reduce losses. The purpose of this study was to study the effect of the low temperature-resistant probiotic Bacillus baekryungensis MS1 on the growth and immune parameters of sea cucumbers and preliminarily investigate the molecular mechanism of the effects. A low temperature-resistant bacterium, B. baekryungensis MS1, was isolated from a sea cucumber pond in winter and used for culture experiments. After 10 days of prefeeding, the experiment was divided into the control group (fed with commercial diet) and the MS1 group (fed with diet containing B. baekryungensis MS1 at 107 cfu g-1) for a total of 60 days. The specific growth rate was measured at the end of the culture period to evaluate the growth performance of the sea cucumber. Samples were taken on days 30 and 60 to determine the immune parameters (including superoxide dismutase activity, catalase activity, alkaline phosphatase activity, acid phosphatase activity, nitric oxide synthetase activity, phagocytosis and respiratory burst), aquaculture water microbiota and gut microbiota of the sea cucumber. Finally, transcriptome sequencing and qRT-PCR verification of the two groups of sea cucumbers were performed to study the mechanism of B. baekryungensis MS1 to improve the immunity of the sea cucumber. The results showed that after 60 days of feeding, B. baekryungensis MS1 significantly improved the growth performance and immune enzyme activity and formed a healthier structure of the gut microbiota in the sea cucumber. The challenge test showed that B. baekryungensis MS1 significantly reduced the mortality of sea cucumbers infected with Vibrio splendidus. Transcriptome and gene expression analysis indicated that B. baekryungensis MS1 activated the ubiquitin-mediated proteolysis pathway and inhibited the mTOR signaling pathway to regulate the immunity of the sea cucumber. In summary, the low temperature-resistant bacterium B. baekryungensis MS1 could be applied for the aquiculture of sea cucumber in winter to improve health status and resist pathogenic bacteria such as V. splendidus.

Non breathing-related sleep fragmentation and imaging markers in patients with atherosclerotic cerebral small vessel disease (CSVD): a cross-sectional case-control study.

BACKGROUND: Sleep fragmentation was shown to be positively associated with cognitive impairment in patients with cerebral small vessel disease (CSVD); however, the underlying mechanisms are not well characterized. In this study, we sought to clarify this issue by investigating the relationship between non breathing-related sleep fragmentation and brain imaging markers in patients with CSVD. METHODS: Eighty-four CSVD patients and 24 age- and sex-matched healthy controls were prospectively recruited. All subjects underwent 3.0 T superconducting magnetic resonance imaging and overnight polysomnography. Polysomnography parameters including sleep onset latency (SOL), total sleep time (TST); sleep efficiency (SE), wake after sleep onset (WASO), percentage of each sleep stage (N1, N2, N3 and rapid eye movement [REM]), arousal index (ArI), periodic limb movement in sleep index (PLSMI), and periodic limb movement related arousal index (PLMAI) were compared between CSVD patients and healthy controls. The relationship between arousal index and CSVD markers was explored in the CSVD group. RESULTS: On polysomnography, CSVD patients showed significantly higher ArI, WASO, PLSMI, and PLMAI, and lower sleep efficiency and N- 3 ratio compared to healthy controls (p < 0.05). On ordinal logistic regression, higher ArI showed a positive association with the severity of periventricular white matter hyperintensity (odds ratio [OR] 1.121, 95% confidence interval [CI] 0.138-2.185) and perivascular space (OR 2.108, 95% CI 1.032-4.017) in CSVD patients, after adjusting for potential confounding variables. CONCLUSIONS: These preliminary results indicate that non breathing-related sleep fragmentation is common and related to the pathological markers of CSVD patients. Future prospective research is required to determine the causal relationship between sleep parameters and CSVD pathology.

Lytic peptide-grafted beta-cyclodextrin polymer based nano-scaled drug delivery system with enhanced camptothecin anti-cancer efficacy.

The aqueous solubility of drug molecules is closely related to its bioactivity like bioavailability and subsequent therapeutic index, especially in the case of hydrophobic drugs like camptothecin (CPT), a potential broad-spectrum anti-cancer agent. Enhanced anti-cancer activity and selectivity of CPT are equally important. Inspired by host-guest effect and drug combination regimen, we developed a novel tumor lytic peptide incorporated drug delivery system by forming beta-cyclodextrin polymer (BCDp) based inclusion complex in nano-scaled size. In this study, BCDp formed inclusion complex with CPT and then a lytic-type peptide (ZH) was grafted. The resulting combinational formulation of BCDp, CPT and ZH, named as ZH-BCDp-CPT inclusion complex, demonstrated greater solubility resulting from its nano-scaled size, amorphous solid state and inclusion structure. Moreover, ZH facilitated quick internalization of conjugated drug via cell membrane lysis, leading to efficient intracellular drug delivery. This novel drug formulation was featured with prolonged circulation, enhanced anti-cancer efficacy, selectivity, anti-cell migration activity and better biocompatibility in comparison with crude CPT and binary BCDp-CPT inclusion complex, all of which were attributed to a cooperative action between ZH and BCDp-CPT inclusion complex. Our results suggested ZH-BCDp-CPT inclusion complex induced cell apoptosis by up-regulation of Bax and P53 and down-regulation of Bcl-2, primarily involved in the mitochondrial pathways.

Decreased visible deep medullary veins is a novel imaging marker for cerebral small vessel disease.

PURPOSE: Visibility of deep medullary veins (DMVs) seen at SWI is predictive of poor prognosis in ischemic stroke. Few attentions have been paid to DMVs in atherosclerotic cerebral small vessel disease (aCSVD) which is attributed to long-term imbalanced microhemodynamics. We conducted this retrospective study to explore the association between DMVs profiles and aCSVD risk factors, neuroimaging markers. METHODS: Two hundred and two patients identified as aCSVD from January 2017 to March 2019 were included in the study. Their demographic, clinical, laboratory, and neuroimaging data were reviewed. The quantity and morphology of DMVs were assessed with a 5-grade (range 0~4) visual rating scale. Total CSVD burden was calculated with an ordinal "SVD score" (range 0~4). Spearman rank correlation and multivariable logistic regression analysis were performed to determine the association between DMV scale and CSVD markers. RESULTS: DMV scale showed strong positive correlation with CSVD burden (rs = 0.629, P < 0.001). Age (OR 1.078, 95% CI 1.015-1.145, P = 0.015) and hypertension (OR 2.629, 95% CI 1.024-6.749, P = 0.045) were two demographic risk factors for high DMV scale. Among CSVD neuroimaging markers, periventricular WMH (OR 2.925, 95% CI 1.464-5.845, P = 0.002), deep WMH (OR 2.872, 95% CI 1.174-7.022, P = 0.021), lacunae (OR 1.961, 95% CI 1.181-3.254, P = 0.009), and cerebral atrophy (OR 2.046, 95% CI 1.079-3.880, P = 0.028) were associated with high DMV scale after adjusting for clinical and metabolic confounders. CONCLUSION: Multifactorial association between DMV scale and epidemiological, radiological contributors of aCSVD suggests DMV's involved pathomechanism may participate in aCSVD development. Attach importance to DMV radiological profile in aCSVD will provide more neuroimaging information for diagnosis and prognosis.

The glucagon-like peptide-1 receptor agonist reduces inflammation and blood-brain barrier breakdown in an astrocyte-dependent manner in experimental stroke.

BACKGROUND: Preserving the integrity of the blood-brain barrier (BBB) is beneficial to avoid further brain damage after acute ischemic stroke (AIS). Astrocytes, an important component of the BBB, promote BBB breakdown in subjects with AIS by secreting inflammatory factors. The glucagon-like peptide-1 receptor (GLP-1R) agonist exendin-4 (Ex-4) protects the BBB and reduces brain inflammation from cerebral ischemia, and GLP-1R is expressed on astrocytes. However, the effect of Ex-4 on astrocytes in subjects with AIS remains unclear. METHODS: In the present study, we investigated the effect of Ex-4 on astrocytes cultured under oxygen-glucose deprivation (OGD) plus reoxygenation conditions and determined whether the effect influences bEnd.3 cells. We used various methods, including permeability assays, western blotting, immunofluorescence staining, and gelatin zymography, in vitro and in vivo. RESULTS: Ex-4 reduced OGD-induced astrocyte-derived vascular endothelial growth factor (VEGF-A), matrix metalloproteinase-9 (MMP-9), chemokine monocyte chemoattractant protein-1 (MCP-1), and chemokine C-X-C motif ligand 1 (CXCL-1). The reduction in astrocyte-derived VEGF-A and MMP-9 was related to the increased expression of tight junction proteins (TJPs) in bEnd.3 cells. Ex-4 improved neurologic deficit scores, reduced the infarct area, and ameliorated BBB breakdown as well as decreased astrocyte-derived VEGF-A, MMP-9, CXCL-1, and MCP-1 levels in ischemic brain tissues from rats subjected to middle cerebral artery occlusion. Ex-4 reduced the activation of the JAK2/STAT3 signaling pathway in astrocytes following OGD. CONCLUSION: Based on these findings, ischemia-induced inflammation and BBB breakdown can be improved by Ex-4 through an astrocyte-dependent manner.