Nanomaterial-Based Drug Delivery Systems for Ischemic Stroke.

Ischemic stroke is a leading cause of death and disability in the world. At present, reperfusion therapy and neuroprotective therapy, as guidelines for identifying effective and adjuvant treatment methods, are limited by treatment time windows, drug bioavailability, and side effects. Nanomaterial-based drug delivery systems have the characteristics of extending half-life, increasing bioavailability, targeting drug delivery, controllable drug release, and low toxicity, thus being used in the treatment of ischemic stroke to increase the therapeutic effects of drugs. Therefore, this review provides a comprehensive overview of nanomaterial-based drug delivery systems from nanocarriers, targeting ligands and stimulus factors of drug release, aiming to find the best combination of nanomaterial-based drug delivery systems for ischemic stroke. Finally, future research areas on nanomaterial-based drug delivery systems in ischemic stroke and the implications of the current knowledge for the development of novel treatment for ischemic stroke were identified.

Risk factors associated with the failure of initial treatment for cesarean scar pregnancy.

OBJECTIVE: To explore the factors related to cesarean scar pregnancy (CSP) treatment failure under different treatment strategies. METHODS: This is a cohort study that consecutively included 1637 patients with CSP. Characteristics including age, gravidity, parity, previous uterine curettages, time since the last cesarean section, gestational age, mean sac diameter, initial serum ß-human chorionic gonadotropin, distance between gestational sac and serosal layer, CSP subtype, classification of blood flow abundance, fetal heartbeat presence, and intraoperative bleeding were recorded. Four strategies were performed separately on these patients. Binary logistic regression analysis was used to analyze the risk factors for initial treatment failure (ITF) under the different treatment strategies. RESULTS: The treatment methods failed in 75 CSP patients, and succeeded in 1298 patients. The analysis found that the presence of a fetal heartbeat was significantly associated with ITF of strategy 1, 2 and 4 (P < 0.05); sac diameter was associated with ITF of strategy 1 and 2 (P < 0.05); gestational age was associated with initial treatment failure of strategy 2 (P < 0.05). CONCLUSION: There was no difference of the failure rate between ultrasound-guided evacuation and hysteroscopy-guided evacuation for CSP treatment with or without uterine artery embolization pretreatment. Sac diameter, fetal heartbeat presence, and gestational age were all associated with CSP initial treatment failure.

[Response of Topsoil Fungal Community Structure to Soil Improvement Measures in Degraded Forest of Red Soil Region].

Soil fungal community structure and diversity are highly sensitive to variations in the external environment, as well as soil improvement measures. In order to clarify the effects of soil improvement measures on topsoil fertility or quality, a field experiment was conducted in eroded forest of a red soil region. Organic fertilizer, biochar, and lime+microbial fertilizer were added to the topsoil, respectively. After four years, the chemistry properties and nutrients in the topsoil were measured, and the diversity and composition of fungi were analyzed. The results showed that the additions of organic fertilizer, biochar, and lime+microbial fertilizer reduced fungal richness in topsoil, compared to that with no fertilizer addition (CK). Among them, lime+microbial fertilizer had the most negative effect on fungal richness. The three soil improvement measures also affected the diversity of topsoil fungi, but the impacts were not significant. The dominant fungal phyla in the topsoil were Ascomycota (31.29%-46.55%) and Basidiomycota (30.07%-70.71%), and the dominant fungal genera were Amphinema and Archaeorhizomyces. The effects of soil improvement measures on fungal community structure in the topsoil were different; organic fertilizer increased the relative abundance of Ascomycetes and Archaeopteroides, and biochar enhanced the relative abundance of Basidiomycetes and Archaeopteroides, whereas lime+microbial fertilizer improved the relative abundance of Basidiomycetes and Archaeopteroides. Fungal diversity and community structure in the topsoil was affected by edaphic factors, and fungal richness was regulated by pH value, whereas fungal community structure was influenced by pH, total nitrogen, and organic carbon. This study provides scientific guidance for soil improvement and ecological restoration below the canopy in eroded forests of red soil regions.

A glutathione-sensitive drug delivery system based on carboxymethyl chitosan co-deliver Rose Bengal and oxymatrine for combined cancer treatment.

At present, monotherapy of tumor has not met the clinical needs, due to high doses, poor efficacy, and the emergence of drug resistance. Combination therapy can effectively solve these problems, which is a better option for tumor suppression. Based on this, we developed a novel glutathione-sensitive drug delivery nanoparticle system (OMT/CMCS-CYS-RB NPs) for oral cancer treatment. Briefly, carboxymethyl chitosan (CMCS) was used as a carrier to simultaneously load Rose Bengal (RB) and oxymatrine (OMT). The OMT/CMCS-CYS-RB NPs prepared by ion crosslinking were spheres with a stable structure. In addition, the nanoparticles can be excited in vitro to generate a large amount of singlet oxygen, which has a good photodynamic effect. In vitro anti-tumor activity study showed that the nanoparticles after the laser enhanced therapeutic efficacy on tumor cells compared with the free drug and exhibited well security. Furthermore, OMT/CMCS-CYS-RB NPs could inhibit the PI3K/AKT signaling pathway in oxidative stress, and realize tumor apoptosis through mitochondria-related pathways. In conclusion, this combination delivery system for delivering RB and OMT is a safe and effective strategy, which may provide a new avenue for the tumor treatment.

The Spouses of Stroke Patients Have a Similar Oral Microbiome to Their Partners with an Elevated Risk of Stroke.

Spousal members who share no genetic relatedness show similar oral microbiomes. Whether a shared microbiome increases the risk of cerebrovascular disease is challenging to investigate. The aim of this study was to compare the oral microbiota composition of poststroke patients, their partners, and controls and to compare the risk of stroke between partners of poststroke patients and controls. Forty-seven pairs of spouses and 34 control subjects were recruited for the study. Alcohol use, smoking, metabolic disease history, clinical test results, and oral health were documented. Oral microbiome samples were measured by 16S rRNA gene sequencing. The risk of stroke was measured by risk factor assessment (RFA) and the Framingham Stroke Profile (FSP). Poststroke patients and their partners exhibited higher alpha diversity than controls. Principal-coordinate analysis (PCoA) showed that poststroke patients share a more similar microbiota composition with their partners than controls. The differentially abundant microbial taxa among the 3 groups were identified by linear discriminant analysis effect size (LEfSe) analysis. The risk factor assessment indicated that partners of poststroke patients had a higher risk of stroke than controls. Spearman correlation analysis showed that Prevotellaceae was negatively associated with RFA. Lactobacillales was negatively associated with FSP, while Campilobacterota and [Eubacterium]_nodatum_group were positively associated with FSP. These results suggest that stroke risk may be transmissible between spouses through the oral microbiome, in which several bacteria might be involved in the pathogenesis of stroke.

Long-Term Pregnancy Outcomes of Patients with Diffuse Adenomyosis after Double-Flap Adenomyomectomy.

Although many studies show that patients with diffuse adenomyosis who underwent fertility-sparing surgery can have a successful pregnancy, their pregnancy outcomes are still controversial. The objective of this study was to determine long-term pregnancy outcomes and possible influencing factors after double-flap adenomyomectomy for patients with diffuse adenomyosis. A total of 137 patients with diffuse adenomyosis who underwent double-flap adenomyomectomy between January 2011 and December 2019 were studied, and correlations between pregnancy outcomes and clinical data, including age and junctional zone measured by magnetic resonance imaging (JZmax-A), were analyzed. The results show that 56 patients (40.9%, 56/137) had 62 pregnancies, including 35 natural pregnancies and 27 assisted reproduction pregnancies, after operation. A univariate regression analysis showed that the pregnancy outcomes were related to age at surgery, visual analog scale (VAS) score of preoperative dysmenorrhea, parity experience, length of infertility, and postoperative JZmax-A. A multivariate regression analysis showed that age at surgery, VAS score of preoperative dysmenorrhea, and postoperative JZmax-A were the independent indicators correlated with pregnancy outcomes. A receiver operating characteristic curve analysis showed that postoperative JZmax-A was the most valuable indicator for predicting pregnancy outcomes. Cumulative pregnancy rates during the first 3 years were 70.1% and 20.9% in the postoperative JZmax-A ≤ 8.5 mm and the postoperative JZmax-A > 8.5 mm groups, respectively. In conclusion, double-flap adenomyomectomy could improve fertility for diffuse adenomyosis, and postoperative JZmax-A might be a promising indicator for predicting pregnancy outcomes.

Gut microbiota is causally associated with poststroke cognitive impairment through lipopolysaccharide and butyrate.

BACKGROUND: Poststroke cognitive impairment (PSCI) is prevalent in stroke patients. The etiology of PSCI remains largely unknown. We previously found that stroke induces gut microbiota dysbiosis which affects brain injury. Hereby, we aimed to investigate whether the gut microbiota contributes to the pathogenesis of PSCI. METHODS: 83 stroke patients were recruited and their cognitive function were measured by Montreal Cognitive Assessment (MoCA) scores 3 months after stroke onset. The peripheral inflammatory factor levels and gut microbiota compositions of the patients were analyzed. Fecal microbiota transplantation from patients to stroke mice was performed to examine the causal relationship between the gut microbiota and PSCI. The cognitive function of mice was evaluated by Morris water maze test. RESULTS: 34 and 49 stroke patients were classified as PSCI and non-PSCI, respectively. Compared with non-PSCI patients, PSCI patients showed significantly higher levels of gut Enterobacteriaceae, lipopolysaccharide (LPS) and peripheral inflammation markers. Consistently, stroke mice that received microbiota from PSCI patients (PSCI mice) presented a higher level of Enterobacteriaceae, intestinal Toll-like receptor-4 (TLR4) expression, circulating LPS, LPS-binding protein (LBP) and inflammatory cytokines, and a lower level of fecal butyrate, severer intestine destruction and cognitive impairment than mice that received microbiota from nPSCI patients (nPSCI mice). In addition, we observed exacerbations in blood-brain barrier (BBB) integrity, microglial activation, neuronal apoptosis in the CA1 region of the hippocampus, and Aß deposition in the thalamus of PSCI mice in comparison with nPSCI mice. Intraperitoneal injection of LPS after stroke caused similar pathology to those seen in PSCI mice. Supplementation with sodium butyrate (NaB) via drinking water rescued these detrimental changes in PSCI mice. CONCLUSIONS: Our data indicate a cause-effect relationship between gut microbiota and PSCI for the first time, which is likely mediated by inflammation-regulating metabolites including LPS and butyrate.

Effect of enteral nutrition on the intestinal microbiome and risk of death in ischemic stroke patients.

BACKGROUND: Studies have shown that the intestinal microbiome of stroke patients is significantly altered and that the degree of microbiota disturbance correlates with prognosis. Enteral nutrition (EN) can reshape the intestinal microbiome and is important for stroke patients with dysphagia. We aimed to describe the intestinal microbiome in patients with ischemic cerebral infarction receiving standard EN. METHODS: First, 17 healthy controls (HCs), 54 stroke patients with oral feeding (ON), and 50 stroke patients with EN were matched to investigate the changes in the intestinal microbiota with EN in the first week after admission and dynamic changes in the EN group in the second week. Second, we investigated the relationship between the intestinal microbiome and clinical characteristics in a larger sample of participants receiving EN (n = 147). Survival analysis was performed using Cox proportional hazards regression. The composition and structure of the intestinal microbiota were analyzed by 16S rRNA sequencing. RESULTS: Compared with the HC and ON groups, patients with EN exhibited significantly different compositions of the intestinal microbiota in the first week, including enrichment of the opportunistic pathogen Enterococcus and depletion of bacteria such as Lachnospiraceae, and Ruminococcus, which were further depleted in the second week. An increase in Parvimonas and Comamonas abundances was associated with an increased risk of 180-day mortality. CONCLUSIONS: The intestinal microbiota in ischemic stroke patients receiving EN is significantly altered, and specific strains of bacteria may be associated with prognosis and clinical indicators.

Low Serum Superoxide Dismutase Is Associated With a High Risk of Cognitive Impairment After Mild Acute Ischemic Stroke.

Background: Post-stroke cognitive impairment (PSCI) is a common complication after stroke, but effective therapy is limited. Identifying potential risk factors for effective intervention is warranted. We investigated whether serum superoxide dismutase (SOD) levels were related to cognitive impairment after mild acute ischemic stroke (AIS) by using a prospective cohort design. Methods: A total of 187 patients diagnosed with mild AIS (National Institutes of Health Stroke Scale ≤ 8) were recruited. Serum SOD, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and interleukin-6 (IL-6) levels were measured, and cognitive assessments (Mini-Mental State Examination, MMSE; Montreal Cognitive Assessment, MoCA) were performed in the early phase (within 2 weeks). These indexes and assessments were repeated at 3 months after onset. MoCA < 22 was defined as early cognitive impairment (CI-E) within 2 weeks and late cognitive impairment (CI-L) at 3 months after stroke. Results: In a survey, 105 of 187 (56.1%) patients were identified as CI-E after mild AIS. Lower serum SOD associated with higher inflammatory biomarkers (ESR, CRP, and IL-6) and worse cognitive scores was observed in CI-E patients. In a survey, 39 of 103 (37.9%) stroke patients who completed the 3-month follow-up were identified as CI-L. Serum SOD was consistently lower in CI-L patients at baseline and 3 months and positively associated with cognitive scores. In adjusted analyses, low serum SOD at baseline was independently associated with high risks of CI-E and CI-L, with odds ratios (ORs) of 0.64 and 0.33 per standard deviation increase in serum SOD, respectively. Multiple-adjusted spline regression models showed linear associations between serum SOD and CI-E (P = 0.044 for linearity) and CI-L (P = 0.006 for linearity). Moreover, 35.2% (19/54) of CI-E patients cognitively recovered during the 3-month follow-up. In multivariable analysis, SOD was identified as a protective factor for cognitive recovery after stroke (OR 1.04, 95% CI: 1.01-1.08, P = 0.024). Conclusion: We demonstrate that low serum SOD is associated with a high risk of cognitive impairment after mild AIS, indicating SOD may be a potential modifiable factor for PSCI.

Glutathione-sensitive IPI-549 nanoparticles synergized with photodynamic Chlorin e6 for the treatment of breast cancer.

We combined phosphoinositol-3-kinin inhibitor IPI-549 and photodynamic Chlorin e6 (Ce6) on carboxymethyl chitosan to develop a novel drug delivery nanoparticle (NP) system (Ce6/CMCS-DSP-IPI549) and evaluate its glutathione (GSH) sensitivity and targeting ability for breast cancer treatment. The NPs were spherical with a uniform size of 218.8 nm, a stable structure over 7 days. The maximum encapsulation efficiency was 64.42%, and NPs drug loading was 8.05%. The NPs released drugs within tumor cells due to their high GSH concentration, while they maintained structural integrity in normal cells, which have low GSH concentration. The cumulative release rates of IPI-549 and Ce6 at 108 h were 70.67% and 40.35% (at GSH 10 mM) and 8.11% and 2.71% (at GSH 2µM), respectively. The NPs showed a strong inhibitory effect on 4T1 cells yet did not affect human umbilical vein endothelial cells (HUVECs). After irradiation by a 660 nm infrared laser for 72 h, the survival rate of 4T1 cells was 15.51%. Cellular uptake studies indicated that the NPs could accurately release drugs into tumor cells. In addition, the NPs had a good photodynamic effect and promoted the release of reactive oxygen species to damage tumor cells. Overall, the combination therapy of IPI-549 and Ce6 is safe and effective, and may provide a new avenue for the treatment of breast cancer.

Glycyrrhetinic acid remodels the tumor microenvironment and synergizes with doxorubicin for breast cancer treatment in a murine model.

We aimed to combine glycyrrhetinic acid with doxorubicin to prepare, characterize and evaluate a drug delivery nano-system with REDOX sensitivity for the treatment of breast cancer. M-DOX-GA NPs prepared by nano sedimentation were spherical, with a particle size of 181 nm. And the maximum encapsulation efficiency and drug loading in M-DOX-GA NPs were 89.28% and 18.22%, respectively. Cytotoxicity and cellular uptake experiments of nanoparticles to KC cells, Cal-27 cells and 4T1 cells were studied by the CCK-8 method. The result indicated that M-DOX-GA NPs could accurately release the drug into the tumor cells, thus achieving the targeted release of the drug. Comparing the survival rate of the above three cells, it was found that M-DOX-GA NPs had a good tumor selectivity and had a more significant therapeutic effect on breast cancer. A 4T1-bearing mouse model was established, and the tumor inhibition rate was 77.37% after injection of nanoparticle solution for 14 d. Normal tissue H&E stained sections and TUNEL assay were verified M-DOX-GA NPs have excellent tumor suppressive effect, and can efficiently reduce the toxic side effects on normal organisms, and effectively avoided 4T1 cells metastasis. Immunofluorescence detection and Western-blot analysis figured a decline in both CUGBP1 and α-SMA, which verifying the TME remodeling induced by glycyrrhetinic acid. Collectively, the combination of doxorubicin and glycyrrhetinic acid is an effective and safe strategy for remodeling fibrotic TME by improving the therapeutic outcome for breast cancer.

Tuning mPEG-PLA/vitamin E-TPGS-based mixed micelles for combined celecoxib/honokiol therapy for breast cancer.

This study aimed to develop, evaluate, and optimize the mPEG-PLA/vitamin E-TPGS mixed micelle drug delivery system to encapsulate celecoxib (CXB) and honokiol (HNK) for intravenous treatment of breast cancer. To this end, we formulated CXB-loaded mPEG-PLA/vitamin E-TPGS (PV-CXB) and HNK-loaded mPEG-PLA/vitamin E-TPGS (PV-HNK) mixed micelles and analyzed their characteristics. The 4T1 cell line was used for cytotoxicity determination and cellular uptake experiments, and for establishing a 4T1-bearing mouse model for histopathology, immunofluorescence, terminal deoxynucleotidyl transferase-mediated nick end labeling, and Western blot analysis. The synergistic effects of PV-CXB and PV-HNK combination therapy were investigated in vitro and in vivo using the coefficient of drug interaction values. The mean size of PV-CXB and PV-HNK prepared with optimal formulation was approximately 50 nm, with a spherical shape. PV-CXB and PV-HNK combination therapy exhibited cytotoxicity in 4T1 cells in vitro. However, the toxicity of PV-CXB and PV-HNK combination therapy was not apparent in normal tissues (heart, liver, spleen, lung, and kidney) in vivo and reduced the expression of collagen fibers in tumor tissues. Moreover, the combination therapy reduced the expression of tumor growth biomarkers (Foxp3, CD4, Gr-1, CD11b, CD31, Ki67, FoxM1, and VEGF). In addition, the tumor cell apoptosis rate reached 45.71 ± 0.62%. The combined treatment with PV-CXB and PV-HNK showed synergistic effect both in vitro and in vivo. Thus, the PV-CXB and PV-HNK drug delivery system could be used as a potential combination therapy for breast cancer .

α-Fe2 O3 Nanoparticles Decorated C@MoS2 Nanosheet Arrays with Expanded Spacing of (002) Plane for Ultrafast and High Li/Na-Ion Storage.

MoS2 nanosheets as a promising 2D nanomaterial have extensive applications in energy storage and conversion, but their electrochemical performance is still unsatisfactory as an anode for efficient Li+ /Na+ storage. In this work, the design and synthesis of vertically grown MoS2 nanosheet arrays, decorated with graphite carbon and Fe2 O3 nanoparticles, on flexible carbon fiber cloth (denoted as Fe2 O3 @C@MoS2 /CFC) is reported. When evaluated as an anode for lithium-ion batteries, the Fe2 O3 @C@MoS2 /CFC electrode manifests an outstanding electrochemical performance with a high discharge capacity of 1541.2 mAh g-1 at 0.1 A g-1 and a good capacity retention of 80.1% at 1.0 A g-1 after 500 cycles. As for sodium-ion batteries, it retains a high reversible capacity of 889.4 mAh g-1 at 0.5 A g-1 over 200 cycles. The superior electrochemical performance mainly results from the unique 3D ordered Fe2 O3 @C@MoS2 array-type nanostructures and the synergistic effect between the C@MoS2 nanosheet arrays and Fe2 O3 nanoparticles. The Fe2 O3 nanoparticles act as spacers to steady the structure, and the graphite carbon could be incorporated into MoS2 nanosheets to improve the conductivity of the whole electrode and strengthen the integration of MoS2 nanosheets and CFC by the adhesive role, together ensuring high conductivity and mechanical stability.

Effect of photoperiod change on chronobiology of cercarial emergence of Schistosoma japonicum derived from hilly and marshy regions of China.

The chronobiology of cercarial emergence appeared to be a genetically controlled behavior, adapted to definitive host species, for schistosome. However, a few physiological and ecological factors, for example the change of photoperiod, were reported to affect the rhythmic emergence of cercariae. Therefore, the effect of photoperiod change on cercarial emergence of two Schistosoma japonicum isolates, the hilly and the marshland, was investigated. Four shedding experiments each under a different photoperiod were conducted. Under a natural photoperiod, two distinct shedding modes, one from the hilly region and one from the marshland, were observed. Under a reversed photoperiod, the regular pattern (i.e. under a natural photoperiod) of S. japonicum cercarial emergence was reversed for the marshland isolate and disappeared for the hilly isolate. With an input of a 2 h darkness from 7am to 9am, the cercarial emergence peak were delayed for the two isolates; whereas with an input of a 2 h darkness from 5pm to 7pm, neither effect on the cercarial emergence rhythm was observed. The total cercariae emerged for both parasite isolates varied with a different photoperiod. The results indicate that the change of photoperiod could affect the chronobiology of S japonicum cercarial emergence.

Insight into the interactions between novel isoquinolin-1,3-dione derivatives and cyclin-dependent kinase 4 combining QSAR and molecular docking.

Several small-molecule CDK inhibitors have been identified, but none have been approved for clinical use in the past few years. A new series of 4-[(3-hydroxybenzylamino)-methylene]-4H-isoquinoline-1,3-diones were reported as highly potent and selective CDK4 inhibitors. In order to find more potent CDK4 inhibitors, the interactions between these novel isoquinoline-1,3-diones and cyclin-dependent kinase 4 was explored via in silico methodologies such as 3D-QSAR and docking on eighty-one compounds displaying potent selective activities against cyclin-dependent kinase 4. Internal and external cross-validation techniques were investigated as well as region focusing, bootstraping and leave-group-out. A training set of 66 compounds gave the satisfactory CoMFA model (q2 = 0.695, r2 = 0.947) and CoMSIA model (q2 = 0.641, r2 = 0.933). The remaining 15 compounds as a test set also gave good external predictive abilities with r2pred values of 0.875 and 0.769 for CoMFA and CoMSIA, respectively. The 3D-QSAR models generated here predicted that all five parameters are important for activity toward CDK4. Surflex-dock results, coincident with CoMFA/CoMSIA contour maps, gave the path for binding mode exploration between the inhibitors and CDK4 protein. Based on the QSAR and docking models, twenty new potent molecules have been designed and predicted better than the most active compound 12 in the literatures. The QSAR, docking and interactions analysis expand the structure-activity relationships of constrained isoquinoline-1,3-diones and contribute towards the development of more active CDK4 subtype-selective inhibitors.

[Cloning, expression and antigenic analysis of merozoite surface protein MSPDBL2-DBL2 domain from Plasmodium falciparum].

OBJECTIVE: To clone and express the DBL domain of Plasmodium falciparum merozoite surface protein MSPDBL2(DBL2), and investigate its antigenicity. METHODS: The DBL2 fragment was amplified by PCR and cloned into pET28a vector. The recombinant pET28a-DBL2 plasmid was transformed into E. coli BL21 (DE3) and protein expression was induced by IPTG. The expressed product was purified by Ni-NTA affinity chromatography, and analyzed by SDS-PAGE and Western blotting. RESULTS: DBL2 gene fragment of Plasmodium falciparum merozoite surface protein MSPDBL2 (950 bp) was obtained by PCR. The recombinant pET28a-DBL2 plasmid was identified by PCR, double enzyme digestion, and DNA sequencing. The recombinant DBL2 protein was expressed in an inclusion body form with Mr 340,000 after being induced with IPTG. Moreover, the purified recombinant DBL2 protein was recognized by sera from patients with falciparum malaria. CONCLUSION: The recombinant pET28a-DBL2 plasmid has been constructed. The purified rDBL2 protein shows adequate antigenicity.