Microglial IL-1RA ameliorates brain injury after ischemic stroke by inhibiting astrocytic CXCL1-mediated neutrophil recruitment and microvessel occlusion.

Acute ischemic stroke (AIS), one of the leading causes of mortality worldwide, is characterized by a rapid inflammatory cascade resulting in exacerbation of ischemic brain injury. Microglia are the first immune responders. However, the role of postischemic microglial activity in ischemic brain injury remains far from being fully understood. Here, using the transgenic mouse line CX3 CR1creER :R26iDTR to genetically ablate microglia, we showed that microglial deletion exaggerated ischemic brain injury. Associated with this worse outcome, there were increased neutrophil recruitment, microvessel blockade and blood flow stagnation in the acute phase, accompanied by transcriptional upregulation of chemokine (C-X-C motif) ligand 1 (CXCL1). Our study showed that microglial interleukin-1 receptor antagonist (IL-1RA) suppressed astrocytic CXCL1 expression induced by oxygen and glucose deprivation and inhibited neutrophil migration. Furthermore, neutralizing antibody therapy against CXCL1 or the administration of recombinant IL-1RA protein reduced brain infarct volume and improved motor coordination performance of mice after ischemic stroke. Our study suggests that microglia protect against acute ischemic brain injury by secreting IL-1RA to inhibit astrocytic CXCL1 expression, which reduces neutrophil recruitment and neutrophil-derived microvessel occlusion.

Dexmedetomidine Ameliorates Postoperative Cognitive Dysfunction in Aged Mice.

Neuroinflammation and oxidative stress coexist and interact in the progression of postoperative cognitive dysfunction (POCD) and other neurodegenerative disease. Mounting studies reveal that Dexmedetomidine (Dex) possesses anti-inflammatory and antioxidant properties. Nevertheless, whether Dex exerts neuroprotective effect on the cognitive sequelae of oxidative stress and inflammatory process remains unclear. A mouse model of abdominal exploratory laparotomy-induced cognitive dysfunction was employed to explore the underlying mechanism of neuroprotective effects exerted by Dex in POCD. Aged mice were treated with Dex (20 µg/kg) 20 min prior to surgery. Open field test (OFT) and Morris water maze (MWM) were employed to examine the cognitive function on postoperative day 3 (POD 3) or POD 7. In the present study, mice underwent surgery exhibited cognitive impairment without altering spontaneous locomotor activity, while the surgery-induced cognitive impairment could be alleviated by Dex pretreatment. Dex inhibited surgery-induced pro-inflammatory cytokines accumulation and microglial activation in the hippocampi of mice. Furthermore, Dex decreased MDA levels, enhanced SOD activity, modulated CDK5 activity and increased BDNF expression in the hippocampus. In addition, Dex remarkably reduced the surgery-induced increased ratio of Bax/Bcl-2 and apoptotic neurons in the hippocampi of aged mice. Collectively, our study provides evidence that Dex may exert neuroprotective effects against surgery-induced cognitive impairment through mechanisms involving its anti-inflammatory and antioxidant properties, as well as the suppression on the mitochondrial permeability transition pore and apoptosis-related pathway.

Light grazing facilitates carbon accumulation in subsoil in Chinese grasslands: A meta-analysis.

Grazing by livestock greatly affects the soil carbon (C) cycle in grassland ecosystems. However, the effects of grazing at different intensities and durations on the dynamics of soil C in its subsoil layers are not clearly understood. Here, we compiled data from 78 sites (in total 122 published studies) to examine the effects of varying grazing intensities and durations on soil C content at different depths for grasslands in China. Our meta-analysis revealed that grazing led to an overall decrease in soil C content and productivity of above-ground vegetation (e.g., above-ground biomass and litter) but an increase in below-ground biomass. Specifically, the effects of grazing on soil C content became less negative or even positive with increasing soil depths. An increase of soil C content was consequently found under light grazing (LG), although soil C content still decreased under moderate and heavy grazing. The increase in soil C content under LG could be largely attributed to the increase of soil C content in subsoil layers (>20 cm), despite that soil C content in surface soil layer (0-20 cm) decreased. Moreover, the magnitude of increase in soil C content under LG in subsoil layers increased with grazing duration. A possible reason of the increase in soil C content in the subsoil layers was due to the increases in below-ground biomass. Our study highlights that LG may modify the allocation of C input and promote its accumulation in subsoil layers, thus offsetting the negative impact of grazing on surface soil C content, a finding that has significant implications for C sequestration in grasslands.

Using sternal angle as anatomic landmark for right internal jugular vein catheterization in pediatrics.

BACKGROUND: Many formulas based on the patient's height, weight and/or age exist to determine central venous catheter (CVC) depth in children. However, this information is unavailable in some emergency conditions. Therefore, direct methods should be developed to guide catheter position in children. METHODS: Eighty patients aged 1-10 y were enrolled from July 2015 to August 2016 and seventy-five were completed; fifty were male, and twenty-five were female. The exclusion criteria were inability to identify the sternal angle or failure to use the right internal jugular vein approach. The catheter was inserted using the right internal jugular vein approach, the distance from the skin puncture point to the midpoint of the sternal angle plane was measured, and the catheter tip was positioned to this distance minus 1 cm. Chest radiography were performed for those children after catheter insertion. The relative position between the catheter tip and carina was confirmed and the longitudinal distance from the catheter tip to the carina was calculated on radiographic images, and related complications were recorded. RESULTS: All catheter tips were above the carina, and the average distance from the catheter tip to the carina was 9.8 mm. No patients experienced serious complications. CONCLUSION: The sternal angle is a useful and reliable anatomic landmark for guiding CVC position in children. Using this landmark, the catheter can be quickly and conveniently placed at a safety position in right internal jugular vein, especially in some emergency conditions.

Adjuvant radiotherapy and chemotherapy for patients with breast phyllodes tumors: a systematic review and meta-analysis.

BACKGROUND: As the efficacy of radiotherapy and chemotherapy for treatment of phyllodes tumors (PTs) remains unclear, this study aimed to review all available data and evaluate the roles of radiotherapy and chemotherapy in PT treatment. METHODS: We performed a comprehensive search of databases, including PubMed, Web of Science and the Cochrane Library. The outcomes of interest included the local recurrence (LR) rate, metastasis rate, disease-free survival rate and overall survival rate. RESULTS: Seventeen studies enrolling 696 patients were included in this random effect meta-analysis. Subgroup analysis and meta-regression were also conducted to determine study heterogeneity. A pooled local recurrence rate of 8% (95% CI: 1-22%) was observed with a statistical heterogeneity of I2 = 86.6% (p < 0.01) for radiotherapy. This was lower than the recurrence rate of 12% for simple surgical treatment (95% CI: 7-18%). Meta-regression analysis found that surgical margin status was the main source of heterogeneity (p = 0.04). The metastasis rate of 4% (95% CI: 0-11%) for patients receiving radiotherapy without significant heterogeneity was also lower than the rate for the simple surgery group (8, 95% CI: 3-15%). The available data for chemotherapy were too limited to support meta-analysis. Accordingly, we offer a pure review of these data. CONCLUSION: Our findings suggest that radiotherapy is effective in achieving local disease control and preventing metastasis.

Lidocaine Attenuates Cognitive Impairment After Isoflurane Anesthesia by Reducing Mitochondrial Damage.

Mitochondrial dysfunction has been proposed to be one of the earliest triggering events in isoflurane-induced neuronal damage. Lidocaine has been demonstrated to attenuate the impairment of cognition in aged rats induced by isoflurane in our previous study. In this study, we hypothesized that lidocaine could attenuate isoflurane anesthesia-induced cognitive impairment by reducing mitochondrial damage. H4 human neuroglioma cells and 18-month-old male Fischer 344 rats were exposed to isoflurane or isoflurane plus lidocaine. Cognitive function was tested at 14 days after treatment by the Barnes Maze test in male Fischer 344 rats. Morphology was observed under electron microscope, and mitochondrial transmembrane potential, electron transfer chain (ETC) enzyme activity, complex-I-IV activity, immunofluorescence and flow cytometry of annexin V-FITC binding, TUNEL assay, and Western blot analyses were applied. Lidocaine attenuated cognitive impairment caused by isoflurane in aged Fischer 344 rat. Lidocaine was effective in reducing mitochondrial damage, mitigating the decrease in mitochondrial membrane potential (ΔΨm), reversing isoflurane-induced changes in complex activity in the mitochondrial electron transfer chain and inhibiting the apoptotic activities induced by isoflurane in H4 cells and Fischer 344 rats. Additionally, lidocaine suppressed the ratio of Bax (the apoptosis-promoting protein) to Bcl-2 (the apoptosis-inhibiting protein) caused by isoflurane in H4 cells. Lidocaine proved effective in attenuating isoflurane-induced POCD by reducing mitochondrial damage.

Morphine Promotes the Angiogenesis of Postoperative Recurrent Tumors and Metastasis of Dormant Breast Cancer Cells.

BACKGROUND: Surgery plays a significant role in the comprehensive treatment of breast cancer, and opioids are often the first-choice analgesics in the perioperative period. However, recent studies showed that opioids may enhance the angiogenesis of breast cancer and the recurrence and metastasis of tumor cells. OBJECTIVES: We aim to investigate the influence of opioids on recurrence and metastasis of breast cancer in nude mice. METHODS: Forty female nude mice with breast tumor were randomly divided into 4 groups (n = 10). They were treated with (i) normal saline (10 mL/kg), (ii) morphine (10 mg/kg), (iii) morphine plus naloxone (10 + 4 mg/kg), and (iv) naloxone (4 mg/kg) for 2 weeks. Four groups of MDA-MB-231 cells were administered (i) Dulbecco's Modified Eagle's Medium, (ii) morphine (10 µmol/mL), (iii) morphine plus naloxone (10 + 10 µmol/mL), and (iv) naloxone (10 µmol/mL). The influence of morphine in each treated group was evaluated by immunocytochemistry and Western blotting. RESULTS: Mice in the morphine group had higher rates of Ki67-positive cells, lower rates of apoptotic index, and a significant increase in the microvessels density of the tumor as evidenced by CD31 staining (p < 0.05). Furthermore, the MDA-MB-231 cells in the morphine group showed an increase in p-Akt, c-Myc, and thrombosponin-1 expression. CONCLUSION: In the current study, we found that morphine promotes the angiogenesis of the recurrent postoperative tumors of nude mice with breast cancer and the proliferation of tumor cells and such promotion may be related to the PI3K-c-Myc signaling pathway.

Identification of Independent Risk Factors for Complications: A Retrospective Analysis of 163 Fibular Free Flaps for Mandibulofacial Reconstruction.

PURPOSE: Fibular free flap transfer is a powerful tool available to the reconstructive surgeon when treating oral and maxillofacial defects, but complications still occasionally occur and predictive analysis focusing on this specific flap is limited in terms of risk factors for complication. The purpose of this study was to identify key variables associated with complications in patients undergoing fibular free flap transfer. PATIENTS AND METHODS: The data of 163 consecutive patients who underwent fibular free flap surgery at the Department of Oral and Maxillofacial Surgery, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, between 2012 and 2015 were reviewed retrospectively. Patient demographic data, laboratory data, surgical data, and fluid infusion-related data that may have an influence on free flap outcomes were recorded. Univariate and multivariate logistic regression analyses were used to identify relevant risk factors. RESULTS: A total of 163 fibular free flaps were transferred for mandibulofacial reconstruction in 163 patients with a mean age of 50.9 years. Postoperative complications developed in 33 (20.2%). Multivariate analysis showed that free flap complications were significantly associated with radiotherapy history (odds ratio [OR], 5.12; P = .001), postoperative anemia (OR, 1.048; P = .041), postoperative hypoalbuminemia (OR, 0.844; P = .002), and prolonged operative time (OR, 1.005; P = .004). CONCLUSIONS: Radiotherapy history, decreased postoperative hemoglobin and albumin levels, and prolonged operative time are potential predictors of postoperative complications after fibular free flap reconstruction for mandibulofacial defects.

The Postoperative Immunosuppressive Phenotypes of Peripheral T Helper Cells Are Associated with Poor Prognosis of Breast Cancer Patients.

PURPOSE: T helper cells play essential roles in anti-tumor immune response. However, the postoperative changes of peripheral T cell subsets and their clinical significance in breast cancer patients remain largely unknown. METHODS: We evaluated the perioperative changes of T lymphocyte subsets in invasive breast cancer (IBC) patients and breast fibroadenoma (BF) patients preoperatively (preop) and 6, 24, 72 hours postoperatively (POH6, POH24, and POH72). Proportions of CD3, CD4, CD8, T helper (Th) 1, Th2, Th17 cells, regulatory T cells (Treg), and CD4+/CD8+, Th1/Th2 ratio were detected by flow cytometry. Changes in T helper cell quantity were correlated to clinicopathological parameters. Furthermore, we explored the association between the perioperative variations of T cell subsets and disease-free survival (DFS) of IBC patients. RESULTS: In IBC patients, Th1 cells diminished while Tregs elevated in postoperative 72 hours in the peripheral blood. In contrast, no significant perioperative changes of T cell subsets were observed in BF patients. Postoperative lower Th1 cells at POH 72 of IBC patients were correlated with greater tumor burden, HER2 positive and Ki67 positive. The increased Tregs at POH 72 of IBC patients were correlated with larger tumor size and HER2 positive. Th1 cell decline and Treg increment were both associated with shorter DFS in IBC patients. CONCLUSIONS: The variations of peripheral T helper cell subsets showed postoperative immunosuppression and were associated with poor prognosis in IBC patients.

Familiar observers attenuate surgery-induced neuroinflammation and cognitive dysfunction in mice.

AIMS: Postoperative cognitive dysfunction (POCD) is a common complication associated with poor outcome. Our previous study has shown that living with familiar observers in the same cage reduces anxiety of mice with surgery. Anxiety can impair learning and memory. Thus, this study was designed to determine whether living with familiar observers attenuated the dysfunction of learning and memory of mice with surgery. METHODS: Six- to eight-week-old CD-1 male mice or 18-month-old C57BL/6 male mice had left carotid artery exposure under isoflurane anesthesia. They lived with non-surgery male mice at 2 (number of surgery mice) to 3 (number of non-surgery mice) ratio or with other surgery mice. Mice were subjected to light and dark box test 3 days after surgery to measure their anxiety levels and novel object recognition and fear conditioning tests from 5 days after surgery to measure their learning and memory. Blood and brain were harvested for biochemical analysis. RESULTS: Living with familiar observers that lived with surgery mice for at least 2 weeks before the surgery and then after surgery reduced the anxiety and dysfunction of learning and memory in young adult male mice. Living with unfamiliar observers that lived with surgery mice after the surgery but not before the surgery did not have those effects on the mice with surgery. Living with familiar observers attenuated learning and memory dysfunction after surgery also in old male mice. Living with familiar observers attenuated inflammatory response in the blood and brain and the activation of the lateral habenula (LHb)-ventral tegmental area (VTA) neural circuitry, which has been shown to be important for POCD. Wound infiltration with bupivacaine attenuated the activation of LHb-VTA. CONCLUSION: These results suggest that living with familiar observers attenuates POCD and neuroinflammation, possibly via inhibiting the activation of the LHb-VTA neural circuitry.

An empirical analysis of the factors driving customers' purchase intention of green smart home products.

With the improvement of consumers' environmental awareness and the popularity of the Internet of Things, green smart home products (GSHPs) are becoming the dominant trend of future home life. This shift not only makes tedious home life easier and more convenient but also helps families save energy and reduce carbon emissions. However, given the impact of the current technological level, the proportion of users who actually purchase GSHPs remains small. Thus, seeking ways to promote the consumption of GSHPs has become an urgent issue. Hence, this study seeks to fill the gap in the existing research on green consumption behavior and obtain a full understanding of the factors influencing the purchase intention of GSHPs. To do so, this work uses task-technology fit theory and considers the actual situation of green smart home consumption to add social-technology fit into the original theoretical basis. In particular, this research focuses on middle- and high-end Chinese consumers who have experience in purchasing GSHPs. Moreover, it aims for an in-depth exploration of the formation mechanism of Chinese consumers' purchase intention for GSHPs through structural equation modeling. Using survey data collected from 331 green smart home product users in China, the study empirically examines the relationships among autonomy, environmental agility, sense of belonging, and self-actualization, and both task-technology fit and social-technology fit, which are expected to shape the purchase intention of GSHP users. The empirical results provide broad support for our hypotheses. The results of this study offer important contributions to the increasing research on GSHPs consumption and shed light on the importance of both technology characteristics and the needs of users in achieving both task-technology fit and social-technology fit and, ultimately enhancing the users' intention to purchase GSHPs.

Gas Dispersion Coefficient Test System and Dimensionless Inversion Method for Porous Media.

Due to the complex porous media structure of the longwall gob area, it has been difficult to determine the gas dispersion coefficient of oxygen when studying spontaneous coal combustion in the gob area. In this work, we first designed an experimental device for testing the gas diffusion coefficient of porous media. Then, the distribution law of gas concentration in porous media under different particle size conditions was obtained by experiments. Subsequently, we established a dimensionless mathematical model of gas dispersion in porous media and developed a corresponding numerical simulator based on the finite volume method (FVM). The influence of the dimensionless gas dispersion coefficient on the gas concentration distribution was analyzed, and then a dimensionless inversion method of the gas dispersion coefficient was summarized and put forward. Finally, we obtained the values of the gas dispersion coefficient in the experimental device under different particle size conditions by inversion and discussed its effect on the gas dispersion behavior in porous media. The results show that (1) the distribution of gas concentration obtained from the experimental test and numerical simulation is consistent, which verifies the reliability of our work; (2) the dimensionless gas concentration is the highest near the injection point and gradually decreases along the depth and both sides of the test container; (3) with the increase of the dimensionless gas dispersion coefficient, the distance required for uniform gas mixing in the test container is gradually shortened and the gas dispersion coverage is wider; and (4) the larger pore space facilitates the dispersion behavior of the gas, and the gas dispersion coefficient shows a parabolic trend with the increase of porous medium particle size.

Numerical simulation and investigation of methane gas distribution and extraction in goaf with U-type ventilation of working face.

The accumulated methane in goaf during coal mining may leak into the working face under the airflow influence, which is possibly causing disasters such as methane gas excessive at the working face and seriously threatening the mine safety. This paper first established a three-dimensional numerical model of the mining area under U-shaped ventilation, introducing the gas state equation, continuity equation, momentum equation, porosity evolution equation, and permeability evolution equation to simulate the airflow field and gas concentration field in the mining area under the natural state. The reliability of the numerical simulations is then verified by the measured air volumes at the working face. The areas in the mining area where gas is likely to accumulate are also delineated. Subsequently, the gas concentration field in goaf under the gas extraction state was theoretically simulated for different locations of large-diameter borehole. The maximum gas concentration in goaf and the gas concentration trend in the upper corner were analyzed in detail, and the critical borehole location (17.8 m from the working face) was determined as the optimum location for gas extraction from the upper corner. Finally, a gas extraction test was carried out on-site to evaluate the application effect. The results show that the measured airflow rate has a small error with the simulated results. The gas concentration in the area without gas extraction is high, with the gas concentration in the upper corner being over 1.2%, which is greater than the critical value of 0.5%. The maximum reduction in gas concentration was 43.9%, effectively reducing the gas concentration in the extraction area after employing a large borehole to extract methane gas. The gas concentration in the upper corner and the distance of the borehole from the working face are expressed as a positive exponential function. The field engineering results show that the implementation of the large borehole at a distance of less than 17.8 m from the working face can control the gas in the upper corner to less than 0.5%, effectively reducing the risk of gas in the upper corner. The numerical simulation work in this paper can provide some basic support for the design of an on-site borehole to extract gas from the mining void and reduce the gas hazard in coal mines.

Bioactive lipid-nanoparticles with inherent self-therapeutic and anti-angiogenic properties for cancer therapy.

Angiogenesis inhibition has become a promising therapeutical strategy for cancer treatment. Current clinical anti-angiogenesis treatment includes antibodies against vascular endothelial growth factor (VEGF) or VEGF receptor, fusion proteins with high affinity to VEGF receptor, and tyrosine kinase inhibitors of VEGF receptor. However, current treatments are prone to systemic toxicity or acquiring drug resistance. A natural bioactive lipid 1,2-dipalmitoyl-sn­glycero-3-phosphate (dipalmitoyl phosphatidic acid, DPPA) was reported to exhibit anti-angiogenic and anti-tumoral activity. However, the hydrophobic property of DPPA largely restricted its clinical use, while systemic infusion of free DPPA could result in undesirable side effects. Herein, we successfully developed DPPA-based lipid-nanoparticles (DPPA-LNPs) which turns the "therapeutic payload into nanocarrier". This strategy could improve on DPPA's hydrophiliciy, thereby facilitating its systemic administration. . DPPA-LNPs not only retained the therapeutic anti-angiogenic and anti-tumoral bioactivity of parental DPPA, but also greatly improved its tumor targeting ability via enhanced permeability and retention (EPR) effect. This strategy not only eliminates the limitation of drug encapsulation rate, toxicity of the delivery vehicle; but also enhances DPPA bioacvtity in vitro and in vivo. Systemic administration of DPPA-LNPs significantly suppressed the blood vessel formation and tumor growth of triple negative breast cancer and liver cancer growth on both xenograft tumor models. STATEMENT OF SIGNIFICANCE: This is the first-in-kind self-therapeutic inherent lipid to be made into a nanocarrier, with inherent anti-angiogenic and anti-tumor properties. DPPA nanocarrier is fully natural, fully compatible with minimal systemic toxicity. DPPA nanocarrier can accumulate at high concentration at tumor via EPR effect, exerting both anti-angiogenic and anti-tumor effects in vivo. DPPA nanocarrier could be used to encapsulate biologics or small molecules for synergistic anti-cancer therapy.

CD146 promotes malignant progression of breast phyllodes tumor through suppressing DCBLD2 degradation and activating the AKT pathway.

BACKGROUND: As a rapid-progressing tumor, breast malignant phyllodes tumors (PTs) are challenged by the lack of effective therapeutic strategies and suitable prognostic markers. This study aimed to clarify the role and mechanism of CD146 on promoting PTs malignant progression, and to identify a novel prognosis marker and treatment target of breast malignant PTs. METHODS: The expression and prognostic significance of CD146 in PTs was detected through single-cell RNA-sequencing (scRNA-seq), immunostaining, real-time PCR and other methodologies. Functional experiments including proliferation assay, colony formation assay, transwell assay, and collagen contraction assay were conducted to validate the role of CD146 in malignant progression of PTs. The efficacy of anti-CD146 monoclonal antibody AA98 against malignant PTs was corroborated by a malignant PT organoid model and a PT patient-derived xenograft (PDX) model. Transcriptome sequencing, proteomic analysis, co-immunoprecipitation, and pull-down assay was employed to identify the modulating pathway and additional molecular mechanism. RESULTS: In this study, the scRNA-seq analysis of PTs disclosed a CD146-positive characteristic in the α-SMA+ fibroblast subset. Furthermore, a progressive elevation in the level of CD146 was observed with the malignant progression of PTs. More importantly, CD146 was found to serve as an independent predictor for recurrence in PT patients. Furthermore, CD146 was found to augment the viability and invasion of PTs. Mechanistically, CD146 acted as a protective "shield" to prevent the degradation of Discoidin, CUB, and LCCL domain-containing protein 2 (DCBLD2), thereby activating the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway and enhancing malignant behaviors of PT cells. In the malignant PT organoid and PDX model, a significant suppression of malignant PT growth was observed after the application of AA98. CONCLUSIONS: These findings suggested that CD146 served as an efficacious marker for predicting PT malignant progression and showed promise as a prognosis marker and treatment target of breast malignant PTs. The study further unveiled the essential role of the CD146-DCBLD2/PI3K/AKT axis in the malignant progression of PTs.

Concurrent silencing of TBCE and drug delivery to overcome platinum-based resistance in liver cancer.

Platinum-based chemotherapy resistance is a key factor of poor prognosis and recurrence in hepatocellular carcinoma (HCC). Herein, RNAseq analysis revealed that elevated tubulin folding cofactor E (TBCE) expression is associated with platinum-based chemotherapy resistance. High expression of TBCE contributes to worse prognoses and earlier recurrence among liver cancer patients. Mechanistically, TBCE silencing significantly affects cytoskeleton rearrangement, which in turn increases cisplatin-induced cycle arrest and apoptosis. To develop these findings into potential therapeutic drugs, endosomal pH-responsive nanoparticles (NPs) were developed to simultaneously encapsulate TBCE siRNA and cisplatin (DDP) to reverse this phenomena. NPs (siTBCE + DDP) concurrently silenced TBCE expression, increased cell sensitivity to platinum treatment, and subsequently resulted in superior anti-tumor effects both in vitro and in vivo in orthotopic and patient-derived xenograft (PDX) models. Taken together, NP-mediated delivery and the co-treatment of siTBCE + DDP proved to be effective in reversing chemotherapy resistance of DDP in multiple tumor models.

Fully Natural Lecithin Encapsulated Nano-Resveratrol for Anti-Cancer Therapy.

Introduction: Chemotherapeutics are known to have undesirable side effects (i.e. nausea, weight loss, hair loss, weakened immune system, etc.) due to the non-specificity of the drugs. Encapsulation of these chemotherapeutics inside nanoparticles significantly improves the bioavailability and half-life of drugs, while increasing their tumor penetration and localization. However, most, if not all, nanoparticles in clinics or research are synthetic, with no long-term studies on the effect of these nanoparticles in vivo. Herein, we developed a synergistic resveratrol nanoparticle system by using lecithin encapsulation. Lecithin, being a fully natural phospholipid derived from soybean, possesses inherent anti-tumor activity. Methods: Lec(RSV) was successfully prepared using the nanoprecipitation method, and characterized by particle size and zeta potential analysis, and transmission electron microscopy (TEM). The in vitro cellular uptake and cytotoxic effects of Lec(RSV) were investigated in human breast cancer cell line BT474. Finally, the in vivo tumoral uptake of Lec(RSV) was carried out in the BT474 orthotopic model. Results: Lec(RSV) showed a uniform distribution of ~120 nm, with prolonged stability. Lec(RSV) showed high cellular uptake and anti-cancer properties in vitro. Time-dependent uptake in the BT474 xenograft model indicated an increased tumoral uptake and apoptosis rate at 4 hours after tail vein injection of Lec(RSV). Conclusion: Taken together, we successfully developed a fully natural Lec(RSV) that possesses potent anti-cancer activity in vitro, with good tumoral uptake in vivo. We hypothesize that Lec(RSV) could be a safe anti-cancer therapeutic that could be easily translated into clinical application.

Transforming Tea Catechins into Potent Anticancer Compound: Analysis of Three Boronated-PEG Delivery System.

Chemotherapy has led to many undesirable side effects, as these are toxic drugs that are unable to differentiate between cancer and normal cells. Polyphenols (tea catechins) are an ideal option as alternative chemotherapeutics owing to their inherent anticancer properties, antioxidant properties and being naturally occurring compounds, are deemed safe for consumption. However, without proper administration, the bioavailability of these compounds is low and inefficient. Therefore, proper delivery of these phenolic compounds is vital for cancer therapy. Herein, we analyzed three potential solutions to creating nanoparticle drugs using naturally occurring phenolic compounds (piceatannol (PIC), epigallocatechin gallate hydrophilic (EGCG) and l-epicatechin (EPI)). By using a simple pi-pi stacking mechanism, we utilized boronated PEG (PEG-Br) as an anchor to efficiently load EPI, PIC and EGCG, respectively, to produce three effective phenolic compound-based nanoparticles, which could be delivered safely in systemic circulation, yet detach from its cargo intracellularly to exert its anticancer effect for effective cancer therapy.

Galectin-1 ameliorates perioperative neurocognitive disorders in aged mice.

INTRODUCTION: The incidence of perioperative neurocognitive disorders (PND) is higher in the elderly patients undergoing surgery. Microglia activation-mediated neuroinflammation is one of the hallmarks of PND. Galectin-1 has been identified as a pivotal modulator in the central nervous system (CNS), while the role of galectin-1 in PND induced by microglia-mediated neuroinflammation is still undetermined. METHODS: An exploratory laparotomy model anesthetized with isoflurane was employed to investigate the role of galectin-1 on PND in aged mice. Open field test and Morris water maze were used to test the cognitive function 3- or 7-days post-surgery. The activation of microglia in the hippocampus of aged mice was tested by immunohistochemistry. Western blot, enzyme-linked immunosorbent assay (ELISA), and quantitative real-time polymerase chain reaction (qRT-PCR) were employed to elucidate the underlying mechanisms. RESULTS: Galectin-1 attenuated the cognitive dysfunction induced by surgery in aged mice and inhibited microglial activity. Moreover, galectin-1 decreased the expression level of inflammatory proteins (interleukin-1ß, interleukin-6, and tumor necrosis factor-α), and prevented neuronal loss in the hippocampus. Galectin-1 inhibited the inflammation of BV2 microglial cells induced by lipopolysaccharide via decreasing the translocation of NF-κB p65 and c-Jun, while this kind of inhibition was rescued when overexpressing IRAK1. CONCLUSION: Our findings provide evidence that galectin-1 may inhibit IRAK1 expression, thus suppressing inflammatory response, inhibiting neuroinflammation, and improving ensuing cognitive dysfunction. Collectively, these findings unveil that galectin-1 may elicit protective effects on surgery-induced neuroinflammation and neurocognitive disorders.

BDNF Participates in Chronic Constriction Injury-Induced Neuropathic Pain via Transcriptionally Activating P2X7 in Primary Sensory Neurons.

Neuropathic pain, resulting from the pathological changes of the somatosensory nervous system, remains a severe public health problem worldwide. The effect of treatment targeting neuropathic pain is very limited, as the underlying mechanism of neuropathic pain is largely unknown. In this study, we demonstrated that the expression level of brain-derived neurotrophic factor (BDNF) was remarkably and time-dependently increased in dorsal root ganglion (DRG) neurons. DRG microinjection of BDNF siRNA in DRG ameliorated chronic constriction injury (CCI) induced mechanical, thermal, and cold nociceptive hypersensitivities. Overexpressing BDNF through microinjection of the AAV5-BDNF in DRG caused enhanced responses to basal mechanical, thermal, and cold stimuli in mice exposed to CCI. Mechanically, the P2X7 promoter activity was enhanced by CCI-induced increase of DRG BDNF protein and was involved in the CCI-induced upregulation of DRG P2X7 protein. The overexpression of BDNF also increased P2X7 expression in DRG neurons, which was validated in in vivo and in vitro experiments. BDNF may exert crucial effect via transcriptionally activating the P2X7 gene in primary sensory neurons, since P2X7 acts as a role of endogenous agitator in neuropathic pain and BDNF largely co-expresses with P2X7 in DRG neurons. Therefore, our data provide evidence that BDNF may be a promising therapeutic target for neuropathic pain.