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In the present retrospective, assessor-blinded cross-sectional study, we compared the diagnostic efficacy of the relaxation-enhanced angiography without contrast and triggering (REACT) protocol for magnetic resonance venography (MRV) and intravascular ultrasound (IVUS).All patients without prior lower limb vascular stenting who had undergone MRV with the REACT protocol and IVUS at our institution from January 2018 to May 2020 were included. The REACT protocol for MRV comprises three main phases: the adiabatic-based T2-preparation module, the non-volume-selective short tau inversion recovery pulse sequence, and the three-dimensional, modified two-point chemical-shift water-fat separated turbo-field echo pulse sequence. The IVUS findings served as the reference standard for stenosis and were used in the diagnostic efficacy analysis of the REACT protocol for MRV. The REACT protocol MRV images were reviewed by three board-certified interventional radiologists, and an interrater analysis was performed.A total of 33 patients (110 segments with IVUS correlation; 18 men [54.5%] and 15 women [45.5%]) were included. Most patients were Chinese (63.6%), and 24 had had bilateral deep venous disease (72.7%). The mean patient age was 59.0 years (range, 26.0-79.5 years). Moderate agreement was found between the three radiologists' diagnoses of iliac vein pathology using the REACT protocol for MRV (κ = 0.524; 95% confidence interval [CI], 0.426-0.623; P .001). Compared with IVUS, REACT protocol MRV achieved a sensitivity of 96.10% (95% CI, 89.03%-99.19%), specificity of 78.79% (95% CI, 61.09%-91.02%), positive predictive value of 91.36% (95% CI, 84.54%-95.33%), and negative predictive value of 89.66% (95% CI, 73.81%-96.38%). Overall, 78.5% agreement was noted between the REACT protocol MRV and IVUS findings. Good agreement between the index test and reference standard was noted (κ = 0.779; 95% CI, 0.645-0.907; P ≤ .05).REACT protocol MRV has the potential to be a highly sensitive and specific screening tool to diagnose deep venous disease.

To retrospectively compare efficacy and safety of computed tomography (CT)-guided percutaneous ablation of metastatic lymph nodes (LN) between cryoablation (CA) and radiofrequency ablation (RFA).A bi-central institutional database research identified 28 patients (42 metastatic LNs) who underwent percutaneous CT-guided ablation. RFA group included 18 patients/26 tumors; CA group included 10 patients/16 tumors. Contrast-enhanced CT or MRI was used for post-ablation follow-up. Patient and tumor characteristics, technical and clinical success on a per tumor and a per patient basis and complication rates were recorded, evaluated and compared between the 2 groups.Both RFA and CA groups had the same median tumor size (2.00 vs. 2.20 cm, p = 0.257), the same median follow-up time (20.50 vs. 20.00 months, p = 0.923) and the same median length of hospital stay (1.00 vs. 1.00 days, p = 0.283). CA group had a higher median procedure time (110.50 vs. 52.00 min, p = 0.001). On a per lesion basis, the overall complete response post-ablation was 88.46% (23/26 lesions) in the RFA and 93.75% (15/16 lesions) in the CA group; no association was revealed between local tumor control and ablation technique (p = 0.709). No complications were recorded in both Groups. On a per patient basis, CA had a longer disease-free interval (24.00 vs. 14.50, p = 0.012) which, however, did not affect the overall survival between the two techniques (26.0 vs. 22.0, p = 0.099 for CA and RFA respectively).Our limited data suggest that CT-guided RFA and CA are equally effective on terms of efficacy and safety for the treatment of metastatic lymph nodes.

Reconstruction of severe acetabular deficiency is extremely challenging in total hip arthroplasty (THA) revisions. Novel bispherical augments were designed to fill acetabular bone loss and facilitate restoration of hip center of rotation (HCOR). Current study aims to compare the outcomes of bispherical augments and tantalum augments. Between July 2017 and December 2018, bispherical augments (BA group) were implanted in 25 patients (25 hips) and 22 patients (22 hips) underwent porous tantalum augments (TA group) reconstruction in revision THA. Clinical and radiographic results were evaluated for 25 hips in BA group and 20 hips in TA group at the final follow-up. The mean duration of follow-up was 2.9 years (range, 2.2 ~ 3.7) in BA group and 2.9 years (range, 2.3 ~ 3.8) in TA group. Harris hip scores, HCOR, and leg length discrepancy (LLD) correction did not differ between the treatment groups. The bispherical augments were located more closer to the medial-superior part (zone II) of acetabular shell while the majority of tantalum augments were located at the lateral-superior part (zone I) (P = 0.010). More screws were used in the BA group for augment fixation (mean 2.1 vs. 1.3) (P = 0.000). There was no evidence of loosening or migration in all hips. Only one dislocation occurred in BA group and treated with closed reduction, no recurrence of instability up to the final follow-up. The clinical and radiological outcomes of bispherical augments were comparable with tantalum augments; this technique was a reliable alternative method in severe acetabular deficiency reconstruction.

Stroke patients with diabetes have worse neurological outcomes than non-diabetic stroke patients, and treatments beneficial for non-diabetic stroke patients are not necessarily effective for diabetic stroke patients. While stem cell-derived extracellular vesicles (EVs) show potential for treating stroke, the results remain unsatisfactory due to the lack of approaches for retaining and controlling EVs released into the brain. Herein, a glucose/reactive oxygen species dual-responsive hydrogel showing excellent injectability, biocompatibility, and self-healing capability is introduced as an EVs-loading vehicle and an intelligent EVs sustained releasing system in the brain. These EVs-hydrogels are developed via crosslinking of phenylboronic acid-modified hyaluronic acid and Poly vinyl alcohol, and fusion with neural stem cell-derived EVs. The results show EVs are stably incorporated into the hydrogels and can be controllably released in response to the brain microenvironment after stroke in type 2 diabetic mice. The EVs-hydrogels exert an excellent angiogenic effect, increasing the migration and tube formation of human umbilical vein endothelial cells. In addition, injection of EVs-hydrogels into the ischemic mouse brain enhances EVs retention and facilitates sustained release, promotes angiogenesis, and improves neurobehavioral recovery. These results suggest such a microenvironment responsive and sustained release EVs-hydrogel system offers a safe, and efficient therapy for diabetic stroke.

Lung cancer is the leading cause of cancer-related death worldwide. The development of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and immune checkpoint inhibitors (ICIs) has brought favorable survival benefits to patients with non-small-cell lung cancer (NSCLC); unfortunately, acquired drug resistance remains a major barrier to the treatment of NSCLC. Recent studies have demonstrated that the transcriptional co-activator with a PDZ-binding motif (TAZ, also called WWTR1) induces tumor immune evasion by directly modulating the expression of programmed death ligand 1 (PD-L1), a key therapeutic target for checkpoint immunotherapy. Moreover, aberrant activation of TAZ is also a major mechanism of acquired resistance to EGFR-TKIs in NSCLC. Therefore, TAZ signaling blockade might be an effective strategy to overcome resistance to ICIs and EGFR-TKIs in NSCLC. In this study, we showed for the first time that artesunate effectively reduced TAZ and PD-L1 expression in NSCLC. We further demonstrated that artesunate suppressed TAZ/PD-L1-induced T-cell growth inhibition in vitro and enhanced anti-tumor immunity by recruiting infiltrating CD8 + T-cells in syngeneic mouse models. Artesunate also inhibited the stem cell-like properties of NSCLC cells and suppressed tumor growth in xenografts bearing gefitinib-resistant tumors. In addition, our results of molecular docking and cellular thermal shift assay analysis suggested that artesunate might directly target the TAZ-TEAD complex and induce proteasome-dependent TAZ degradation in NSCLC cells. These results suggest that artesunate enhanced anti-tumor immunity and overcame EGFR-TKI resistance in NSCLC at least in part by suppressing TAZ/PD-L1 signaling.

Ursolic acid (UA), found widely in nature, exerts effective anti-tumoral activity against various malignant tumors. However, the low water solubility and poor bioavailability of UA have greatly hindered its translation to the clinic. To overcome these drawbacks, a simple redox-sensitive UA polymeric prodrug was synthesized by conjugating UA to polyethylene glycol using a disulfide bond. This formulation can self-assemble into micelles (U-SS-M) in aqueous solutions to produce small size micelles (∼62.5 nm in diameter) with high drug loading efficiency (∼16.7%) that exhibit pH and reduction dual-sensitivity. The cell and animal studies performed using the osteosarcoma MG-63 cell line and MG-63 cancer xenograft mice as the model systems consistently confirmed that the U-SS-M formulation could significantly prolong the circulation in blood and favor accumulation in tumor tissue. Targeted accumulation allows the U-SS-M to be effectively internalized by cancer cells, where the rapid release of UA is favored by a glutathione-rich and acidic intracellular environment, and ultimately achieves potent antitumor efficacy.

Somatic mutations are a large category of genetic variations, which play an essential role in tumorigenesis. Detection of somatic single nucleotide variants (SNVs) could facilitate downstream analysis of tumorigenesis. Many computational methods have been developed to detect SNVs, but most require normal matched samples to differentiate somatic SNVs from the normal state, which can be difficult to obtain. Therefore, developing new approaches for detecting somatic SNVs without matched samples are crucial. In this work, we detected somatic mutations from individual tumor samples based on a novel machine learning approach, svmSomatic, using next-generation sequencing (NGS) data. In addition, as somatic SNV detection can be impacted by multiple mutations, with germline mutations and co-occurrence of copy number variations (CNVs) common in organisms, we used the novel approach to distinguish somatic and germline mutations based on the NGS data from individual tumor samples. In summary, svmSomatic: (1) considers the influence of CNV co-occurrence in detecting somatic mutations; and (2) trains a support vector machine algorithm to distinguish between somatic and germline mutations, without requiring normal matched samples. We further tested and compared svmSomatic with other common methods. Results showed that svmSomatic performance, as measured by F1-score, was significantly better than that of others using both simulation and real NGS data.体细胞突变是癌症基因组中一种主要的变异类型，它与肿瘤的产生与发展有密切联系。单核苷酸变异（SNVs）的检测可以促进肿瘤研究的下游分析。目前已经有许多方法来检测SNVs，但大多数方法都需要癌症样本有与之匹配正常样本才能将体细胞变异检测出来，但与之配对的正常样本通常不容易获得。因此，发展新的方法对肿瘤单样本数据进行体细胞变异的检测至关重要。在这项工作中，我们发展了一个新的机器学习方法用于精确检测单个肿瘤样本的新一代测序数据中的体细胞突变。在体细胞变异检测中要考虑的另一点是多种变异同时存在的情形，即肿瘤细胞内拷贝数变异（CNV）和SNV的共同出现是很常见。因此，我们提出了一种新的机器学习模型svmSomatic，该方法可以根把单个肿瘤样本的基因组数据中的体细胞突变与种系突变区分开。svmSomatic的新特点包括：1）考虑了CNV的对检测体细胞变异的影响；2）在单肿瘤样本数据中，采用支持向量机（SVM）的训练结果作为分类器来区分体细胞变异和种系变异。我们在基因组的模拟数据和真实数据中测试了svmSomatic，并将其与其它同类方法进行了比较。这些模拟和比较结果表明，在F1-score的综合评价下，svmSomatic与其它方法相比在模拟数据和真实数据中都表现出了较好的性能。.

Ischaemic stroke is a leading cause of long-term disability in the world, with limited effective treatments. Increasing evidence demonstrates that exosomes are involved in ischaemic pathology and exhibit restorative therapeutic effects by mediating cell–cell communication. The potential of exosome therapy for ischaemic stroke has been actively investigated in the past decade. In this review, we mainly discuss the current knowledge of therapeutic applications of exosomes from different cell types, different exosomal administration routes, and current advances of exosome tracking and targeting in ischaemic stroke. We also briefly summarised the pathology of ischaemic stroke, exosome biogenesis, exosome profile changes after stroke as well as registered clinical trials of exosome-based therapy.

Background Our previous studies suggest that human fat extract (FE) contains a variety of angiogenic factors and may provide an alternative treatment option for stroke. However, the therapeutic effect is largely limited due to its short half-life, and inaccurate targeting. Results Herein, we leverage the targeting abilities of platelets (PLTs) to the lesion area of stroke and Arg-Gly-Asp (RGD) peptides to the angiogenic blood vessels to develop a biomimetic nanocarrier that capable of delivering FE precisely to treat stroke. The biomimetic nanocarriers are comprised of FE-encapsulated PLGA (poly(lactic-co-glycolic acid)) core enclosed by RGD peptides decorated plasma membrane of PLTs, namely RGD-PLT@PLGA-FE. We found that RGD-PLT@PLGA-FE not only targeted damaged and inflamed blood vessels but also achieved rapid accumulation in the lesion area of ischemic brain. In addition, RGD-PLT@PLGA-FE kept a sustained release behavior of FE at the lesion site, effectively increased its half-life and promoted angiogenesis and neurogenesis with delivering neurotrophic factors including BDNF, GDNF and bFGF to the brain, that ultimately resulted in blood flow increase and neurobehavioral recovery. Conclusions In conclusion, our study provides a new strategy to design a biomimetic system for FE delivery and it is a promising modality for stroke therapy. Graphical Abstract

As a characteristic transcription factor in solid tumors, hypoxia inducible factor-1 (HIF-1) acts as a master regulator in breast cancer progression. Cryptolepine, as a natural alkaloid, noticeably inhibited HIF-1 transcriptional activity and decreased the protein expression of hypoxia-induced HIF-1α in breast cancer cells. Further study showed that cryptolepine blocked HIF-1-mediated glycolysis and suppressed the expression of multiple glycolysis enzymes, resulting in a decrease in ATP production in hypoxic T47D and 4T1 cells. Meanwhile, cryptolepine displayed potent suppressive effect on tumor growth in a dose-dependent manner. In 4T1 tumor xenografts, cryptolepine reduced HIF-1α protein expression, and thus decreased the levels of both lactate acid and ATP productions. The mechanistic study revealed that cryptolepine could effectively suppress the process of HIF-1α mRNA translation rather than transcription, which was attributed to the inhibition on the phosphorylation of eIF4E regulated by both MAPK and mTOR signaling pathways. Collectively, current findings suggested that cryptolepine possesses the potential to treat breast cancers by modulating HIF-1 both in vitro and in vivo.

(±)-Decumicorine A (1) and (±)-epi-decumicorine A (2), two pairs of enantiomeric isoquinoline alkaloids featuring a novel phenylpropanoid-conjugated protoberberine skeleton, were isolated and purified from the rhizomes of Corydalis decumbens. The separation of (±)-1 and (±)-2 was achieved by chiral HPLC to produce four optically pure enantiomers. The structures and absolute configurations of compounds (-)-1, (+)-1, (-)-2, and (+)-2 were elucidated by spectroscopic analysis, ECD calculations, and X-ray crystallographic analyses. The two racemates were generated from a Diels-Alder [4 + 2] cycloaddition between jatrorrhizine and ferulic acid in the proposed biosynthetic pathways, which were fully verified by a biomimetic synthesis. Moreover, compound (+)-1 exhibited an antiviral entry effect on SARS-CoV-2 pseudovirus by blocking spike binding to the ACE2 receptor on HEK-293T-ACE2

To investigate the changes in proinflammatory cytokines and chemokines, namely, C-C motif ligand (CCL) 2 and CCL7, in postmenopausal osteoporosis (PMOP) and to develop a new drug, bindarit (Bnd), for PMOP in an ovariectomized (OVX) mouse model.Bone marrow macrophages (BMMs) from the femurs of five women with PMOP and five premenopausal women without osteoporosis were detected by RNA sequencing. BMMs from mice were differentiated into osteoclasts and treated with a synthetic inhibitor of CCL2 and CCL7, Bnd, or 17 beta estradiol (ECCL2, CCL7 and their receptor of C-C chemokine receptor-2 (CCR2), and the NF-κB signaling pathway, were significantly increased in women with PMOP. CCL2 and CCL7 protein and mRNA expression was increased in OVX mice and aged female mice, but the increases were attenuated by EThe proinflammatory cytokines and chemokines CCL2, CCL7 and CCR2 were correlated with PMOP. Bnd attenuated the increases in CCL2 and CCL7 levels to affect osteoporosis in OVX mice via the NFκB signaling pathway. Thus, Bnd may be useful as a new therapeutic for the prevention of PMOP.

Objective: We aimed to perform a systematic review and meta-analysis to compare the treatment effects of unstable shoes and flat shoes on lower back pain patients. Data sources: Literature databases, including PubMed, Web of Science, and EMBASE (up to June 2019), were searched systematically. Review methods: Two authors independently screened the retrieved records and identified the randomized controlled trials where patients with lower back pain who wore unstable shoes as intervention and wore flat shoes as a control. Relevant data were extracted for meta-analysis using Review Manager 5.3 software. The Grading of Recommendations Assessment, Development and Evaluation approach was used to assess the pooled outcome evidence levels. Results: Five randomized controlled trials and 251 patients were included in the analysis. The meta-analysis results showed that there was a tendency toward a reduction in the Roland–Morris disability questionnaire score (mean difference (MD) –2.16, 95% confidence interval (CI) –4.28 to −0.03, I2 = 53%) and pain score (MD −0.84, 95% CI −1.66 to −0.02, I2 = 84%) in patients wearing unstable shoes compared to those wearing flat shoes. There was no significant difference in the life quality scores between the unstable shoe and flat shoe groups (MD −0.59, 95% CI −6.18 to 5.01, I2 = 0%). Functional disability and pain scores were determined to have very low-quality evidence, and life quality scores were determined to have low-quality evidence according to the Grading of Recommendations Assessment, Development and Evaluation analysis. Conclusion: Unstable shoes may be effective in treating lower back pain in the clinic, but the conclusion was limited by the current low-quality studies.

Summary Introduction Dl‐3‐N‐butylphthalide (NBP), a small molecule drug used clinically in the acute phase of ischemic stroke, has been shown to improve functional recovery and promote angiogenesis and collateral vessel circulation after experimental cerebral ischemia. However, the underlying molecular mechanism is unknown. Aims To explore the potential molecular mechanism of angiogenesis induced by NBP after cerebral ischemia. Results NBP treatment attenuated body weight loss, reduced brain infarct volume, and improved neurobehavioral outcomes during focal ischemia compared to the control rats (P

Alzheimer's disease (AD) is one of the fastest growing cognitive decline-related neurological diseases. To date, effective curative strategies have remained elusive. A growing body of evidence indicates that dietary patterns have significant effects on cognitive function and the risk of developing AD. Previous studies on the association between diet and AD risk have mainly focused on individual food components and specific nutrients, and the mechanisms responsible for the beneficial effects of dietary patterns on AD are not well understood. This article provides a comprehensive overview of the effects of dietary patterns, including the Mediterranean diet (MedDiet), dietary approaches to stop hypertension (DASH) diet, Mediterranean-DASH diet intervention for neurological delay (MIND), ketogenic diet, caloric restriction, intermittent fasting, methionine restriction, and low-protein and high-carbohydrate diet, on cognitive impairment and summarizes the underlying mechanisms by which dietary patterns attenuate cognitive impairment, especially highlighting the modulation of dietary patterns on cognitive impairment through gut microbiota. Furthermore, considering the variability in individual metabolic responses to dietary intake, we put forward a framework to develop personalized dietary patterns for people with cognitive disorders or AD based on individual gut microbiome compositions.

Graphene oxide–silver nanoparticle (GO-AgNPs) nanocomposites have drawn much attention for their potential in biomedical uses. However, the potential toxicity of GO-AgNPs in animals and humans remains unknown, particularly in the developing fetus. Here, we reported the GO-AgNP-mediated cytotoxicity and epigenetic alteration status in caprine fetal fibroblast cells (CFFCs). In brief, the proliferation and apoptosis rate of GO-AgNP-treated CFFCs (4 and 8 µg/mL of GO-AgNPs) were measured using the cell-counting kit (CCK-8) assay and the annexin V/propidium iodide (PI) assay, respectively. In addition, the oxidative stress induced by GO-AgNPs and detailed mechanisms were studied by evaluating the generation of reactive oxygen species (ROS), superoxide dismutase (SOD), lactate dehydrogenase (LDH), malondialdehyde (MDA), and caspase-3 and abnormal methylation. The expression of pro- and anti-apoptotic genes and DNA methyltransferases was measured using reverse transcription followed by RT-qPCR. Our data indicated that GO-AgNPs cause cytotoxicity in a dose-dependent manner. GO-AgNPs induced significant cytotoxicity by the loss of cell viability, production of ROS, increasing leakage of LDH and level of MDA, increasing expression of pro-apoptotic genes, and decreasing expression of anti-apoptotic genes. GO-AgNPs incited DNA hypomethylation and the decreased expression of DNMT3A. Taken together, this study showed that GO-AgNPs increase the generation of ROS and cause apoptosis and DNA hypomethylation in CFFCs. Therefore, the potential applications of GO-AgNPs in biomedicine should be re-evaluated.

The pathological role of reactive gliosis in CNS repair remains controversial. In this study, using murine ischemic and hemorrhagic stroke models, we demonstrated that microglia/macrophages and astrocytes are differentially involved in engulfing synapses in the reactive gliosis region. By specifically deleting MEGF10 and MERTK phagocytic receptors, we determined that inhibiting phagocytosis of microglia/macrophages or astrocytes in ischemic stroke improved neurobehavioral outcomes and attenuated brain damage. In hemorrhagic stroke, inhibiting phagocytosis of microglia/macrophages but not astrocytes improved neurobehavioral outcomes. Single-cell RNA sequencing revealed that phagocytosis related biological processes and pathways were downregulated in astrocytes of the hemorrhagic brain compared to the ischemic brain. Together, these findings suggest that reactive microgliosis and astrogliosis play individual roles in mediating synapse engulfment in pathologically distinct murine stroke models and preventing this process could rescue synapse loss., Microglia and astrocytes clear neuronal debris after stroke, whether glia remain phagocytic and cause synapse loss at the subacute stage remains unknown. Here, the authors show in a murine model of ischemic stroke that inhibition of phagocytosis by MEGF10 and MERTK deletion in microglia and astrocytes attenuated damage and improved neurological outcomes by preventing synapse loss.

Fourteen new monoterpene-flavonoid conjugates including four monoterpene-conjugated chalcones (glabratins A–D, 1–4), seven monoterpene-conjugated dihydrochalcones (glabratins E–K, 5–11), and three monoterpene-conjugated flavanones (glabratins L–N, 12–14), together with four known analogues (15–18) were isolated from the aerial parts of Sarcandra glabra. The structures and the absolute configurations of these compounds were elucidated by the spectroscopic data, single-crystal X-ray diffraction, and electronic circular dichroism (ECD) calculations. Compounds 1, 4–6, 9–14, and 18 showed obvious cell autophagy-inducing activities at 25 μM in HEK293 cells. Furthermore, the bioassay results also showed that 18 induced cell autophagy in a dose dependent manner. Our findings revealed a rare class of monoterpene-flavonoid conjugates in nature and firstly reported their autophagy-inducing activities.

Ribosomal proteins (RPs) are mostly derived from the energy-consuming enzyme families such as ATP-dependent RNA helicases, AAA-ATPases, GTPases and kinases, and are important structural components of the ribosome, which is a supramolecular ribonucleoprotein complex, composed of Ribosomal RNA (rRNA) and RPs, coordinates the translation and synthesis of proteins with the help of transfer RNA (tRNA) and other factors. Not all RPs are indispensable; in other words, the ribosome could be functional and could continue the translation of proteins instead of lacking in some of the RPs. However, the lack of many RPs could result in severe defects in the biogenesis of ribosomes, which could directly influence the overall translation processes and global expression of the proteins leading to the emergence of different diseases including cancer. While microRNAs (miRNAs) are small non-coding RNAs and one of the potent regulators of the post-transcriptional gene expression, miRNAs regulate gene expression by targeting the 3′ untranslated region and/or coding region of the messenger RNAs (mRNAs), and by interacting with the 5′ untranslated region, and eventually finetune the expression of approximately one-third of all mammalian genes. Herein, we highlighted the significance of miRNAs mediated regulation of RPs coding mRNAs in the global protein translation.

Intracerebral hemorrhage- (ICH-) induced secondary brain injury (SBI) is a very complex pathophysiological process. However, the molecular mechanisms and drug targets of SBI are highly intricate and still elusive, yet a clear understanding is crucial for the treatment of SBI. In the current study, we aimed to confirm that nuclear factor-E2-related factor 2 (Nrf2)/Optineurin- (OPTN-) mediated mitophagy alleviated SBI by inhibiting nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3 (NLRP3) inflammasome activation based on the isobaric tag for relative and absolute quantization (iTRAQ) quantification proteomics. Human ICH brain specimens were collected for iTRAQ-based proteomics analysis. Male Nrf2 wild-type (WT) and knockout (KO) mice were employed to establish ICH murine models. The survival rate, hematoma volume, neurofunctional outcomes, blood-brain barrier (BBB) permeability, brain edema, spatial neuronal death, NLRP3 inflammasome, inflammatory response, mitochondrial function, and mitophagy level were evaluated after ICH. The iTRAQ quantification analysis showed that the differentially expressed proteins (DEPs), Nrf2 and NLRP3, were closely associated with the initiation and development of SBI after ICH. The Nrf2 KO mice had a significantly lower survival rate, bigger hematoma volume, worse neurological deficits, and increased BBB disruption, brain edema, and neuronal death when compared with the Nrf2 WT mice after ICH. Furthermore, Nrf2 KO enhanced NLRP3 inflammasome activation and neuroinflammation as evidenced by the NF-κB activation and various proinflammatory cytokine releases following ICH. Moreover, Nrf2 could interact with and modulate the mitophagy receptor OPTN, further mediating mitophagy to remove dysfunctional mitochondria after ICH. Furthermore, OPTN small interfering RNA (siRNA) increased the NLRP3 inflammasome activation by downregulating mitophagy level and enhancing mitochondrial damage in the Nrf2 WT mice after ICH. Together, our data indicated that Nrf2/OPTN inhibited NLRP3 inflammasome activation, possibly via modulating mitophagy, therefore alleviating SBI after ICH.

To investigate the effects of different plasma target concentrations of remifentanil on the minimum alveolar concentration (MAC) for blocking adrenergic response (BAR) of sevoflurane in children with laparoscopic herniorrhaphy.Seventy-five children with 3-7 years old scheduled for laparoscopic herniorrhaphy were randomly divided into group RA total of 52 child patients were used among the anticipated 75 patients. In groups RRemifentanil by target-controlled infusion can effectively reduce the MACThe trial was registered at http://www.chictr.org.cn ( ChiCTR1800019393 , 8, Nov, 2018).

Benign giant renal schwannoma is rarely found and the diagnosis difficulty only depends on physical and imagological examination. Pathological examination is essential to confirm the diagnosis of renal schwannoma. Nephrectomy and tumorectomy are primary treatments for renal schwannoma. Although most of the reported patients present satisfactory outcome, however, there is still not sufficient evidence to reveal the biological characteristics and post-operation recurrence rate of renal schwannoma. Herein, we report a rare case of giant and complicated renal schwannoma. A 56-years-old female patient was admitted to the urology department due to left lower back pain for approximately 5 days. No positive signs and other special abnormalities were found. CT scan presented a soft tissue tumor with inhomogeneous enhanced in the renal hilum. Surgery was performed to excise the tumor and left renal. Renal schwannoma was confirmed by pathological examination. At the 6-month follow-up, no evidence of recurrence was found. Our present report could provide more material for further study.

Background Low-dose amitriptyline (AMT) is an effective treatment for diarrhea-dominant irritable bowel syndrome (IBS-D). Its efficacy depends upon its serum concentration and the patient's CYP2C19 genotype. Aims To identify the association between serum AMT and nortriptyline (NT) concentration and CYP2C19 polymorphism and the clinical response in IBS-D patients. Methods Ninety IBS-D patients were treated of AMT for 6 weeks. Efficacy was evaluated by the results of the Adequate Relief question each week and an IBS severity scoring system (IBS-SSS) at 0, 3, and 6 weeks. CYP2C19 genotyping was performed by direct sequencing. AMT and NT steady-state serum concentrations were detected by high-performance liquid chromatography. Results The CYP2C19 polymorphism exhibited a significant influence on the NT serum concentration but did not predict the clinical efficacy of AMT for treating IBS-D. The NT steady-state and dose-corrected serum concentrations were significantly correlated with an improvement in the IBS-SSS score after 6 weeks, whereas the AMT serum concentration was not correlated with clinical improvement. The cut-off NT steady-state serum concentration of 2.91 ng/ml may help distinguish responders from non-responders. Conclusions NT serum concentration but not CYP2C19 polymorphism may be correlated with the clinical efficacy of AMT for treating IBS-D, and such a response may occur at the upper NT threshold of 2.91 ng/ml.

Triple-negative breast cancer (TNBC) is a highly lethal subtype of breast cancer associated with early relapse and metastasis. Epithelial to mesenchymal transition (EMT) plays pivotal roles in the progression of TNBC, including inducing cancer stem cell (CSC) properties, chemoresistance, tumor metastasis, and recurrence. Abnormally activated YAP/TAZ induces EMT in TNBC, making it a promising target for drug development. Our goal is to identify potential YAP/TAZ inhibitors from naturally derivative molecules and further study its effects on inhibiting EMT and metastasis of TNBC. In the current study, we demonstrate that luteolin significantly inhibits YAP/TAZ activity by promoting YAP/TAZ degradation in TNBC cells. Luteolin treatment leads to a decrease of mesenchymal markers and an increase of epithelial markers in both TNBC cells and TAZ-induced mesenchymal cells. Consistently, luteolin treatment inhibits cell migration in TNBC cells. Additionally, luteolin inhibits tumor growth in mice xenografted with TNBC cells. Collectively, our results support luteolin as a novel YAP/TAZ inhibitor for development as a new agent for the treatment of TNBC.

BACKGROUND The modified buried vertical mattress suture (MBVMS) is believed to provide excellent outcomes by relieving the tension on wound edges. However, clinical data on the topic remain sparse and inadequate. OBJECTIVE To compare the cosmetic results of the MBVMS and the buried intradermal suture (BIS) in chest wounds using a split-scar model. MATERIALS AND METHODS Twenty patients participated in the study. One randomly selected half of each chest wound was closed with the MBVMS; the other half was closed with the BIS. Immediately, postoperatively, the maximum degree of wound eversion was obtained. After 3 months, the wound complication rates were recorded, and the aesthetic appearance of each scar was evaluated by the Patient and Observer Scar Assessment Scale (POSAS), the Vancouver Scar Scale (VSS), the visual analog scale (VAS), and scar width. RESULTS The MBVMS yielded a greater mean postoperative eversion height and width (p < .05); lower POSAS, VSS, and VAS scores (p < .05); and a narrower scar width (p < .05) than did the BIS. CONCLUSION Compared with the BIS, the MBVMS provided significantly increased wound eversion immediately, postoperatively, and improved aesthetic outcomes at the end of the 3-month follow-up period.

Background This study aims to observe the effects of different target controlled plasma sufentanil concentrations on the minimum alveolar concentration (MAC) of sevoflurane for blocking adrenergic response (BAR) in patients undergoing laparoscopic cholecystectomy with carbon dioxide pneumoperitoneum stimulation. Methods Eighty-five patients undergoing laparoscopic cholecystectomy, aged 30–65 years, with American Society of Anesthesiologists physical status I-II, were enrolled in this study. All the patients were randomly divided into 5 groups (S0, S1, S2, S3, S4) with different sufentanil plasma target concentration (0.0, 0.1, 0.3, 0.5, 0.7 ng ml− 1). Anesthesia was induced by inhalation of 8% sevoflurane in 100% oxygen, and 0.6 mg kg− 1 of rocuronium was intravenously injected to facilitate the insertion of a laryngeal mask airway. The end-tidal sevoflurane concentration and sufentanil plasma target concentration were adjusted according to respective preset value in each group. The hemodynamic response to pneumoperitoneum stimulus was observed after the end-tidal sevoflurane concentration had been maintained stable at least for 15 min. The MACBAR of sevoflurane was measured by a sequential method. Meanwhile, epinephrine (E) and norepinephrine (NE) concentrations in the blood were also determined before and after pneumoperitoneum stimulus in each group. Results When the method of independent paired reversals was used, the MACBAR of sevoflurane in groups S0, S1, S2, S3, S4 was 5.333% (confidence interval [CI] 95%: 5.197–5.469%), 4.533% (95% CI: 4.451–4.616%), 2.861% (95% CI: 2.752–2.981%), 2.233% (95% CI: 2.142–2.324%) and 2.139% (95% CI: 2.057–2.219%), respectively. Meanwhile, when the isotonic regression analysis was used, the MACBAR of sevoflurane in groups S0, S1, S2, S3, S4 was 5.329% (95% CI: 5.321–5.343%), 4.557% (95% CI: 4.552–4.568%), 2.900% (95% CI: 2.894–2.911%), 2.216% (95% CI: 2.173–2.223%) and 2.171% (95% CI: 2.165–2.183%), respectively. The MACBAR was not significantly different between groups S3 and S4 when using 0.5 and 0.7 ng ml− 1 of sufentanil plasma target concentrations. No significant difference was found in the change of E or NE concentration between before and after pneumoperitoneum stimulation in each group. Conclusions The MACBAR of sevoflurane can be decreased with increasing sufentanil plasma target concentrations. A ceiling effect of the decrease occurred at a sufentanil plasma target concentration of 0.5 ng ml− 1. When the sympathetic adrenergic response was inhibited in half of the patients to pneumoperitoneum stimulation in each group, the changes of E and NE concentrations showed no significant differences. Trial registration The study was registered at http://www.chictr.org.cn (ChiCTR1800015819, 23, April, 2018).

A girl, aged 4 years and 3 months, presented with cyanosis of the lips shortly after birth. She then experienced shortness of breath after activity 1 year ago and acrocyanosis 3 months ago, with obvious acropachy and toe deformity. Laboratory examinations revealed an increase in hemoglobin (178 g/L) and a reduction in arterial partial pressure of oxygen (37.7 mm Hg). Plain and contrast-enhanced CT scans of the lungs showed a large area of dense shadow and multiple nodules with clear boundaries in the right lower lung, as well as thickening of the arteries and dilatation of the veins in the right lower lung. Magnetic resonance angiography of the pulmonary artery showed large arteriovenous malformation in the lung. The child was diagnosed with congenital pulmonary arteriovenous fistula and was given interventional embolization of the pulmonary arterial fistula. The child was followed up at 3 months after surgery. The symptoms of shortness of breath and cyanosis disappeared, and activity tolerance, heart rate, hemoglobin, red blood cell count, and transcutaneous oxygen saturation all returned to normal.

Rationale: The capsular warning syndrome (CWS) is a rare and special type of transient ischemic attacks (TIAs) syndrome. The pathophysiology of CWS is very complicate, and intracranial atherosclerotic stenosis (ICAS) is rare cause. Moreover, the effective and standard therapy has not yet been established. Patient concerns: A 47-year-old man experienced repeated and exacerbated TIAs of right hemiparesis and dysarthria. Fourteen hours after the first episode of TIAs, he developed more severe right hemiparesis and dysarthria, the National Institute of Health Stroke Scale (NIHSS) score was 12 points, and did not recover in a long time. Diagnosis: The computed tomography (CT) angiography displayed high stenosis in the M1 segment of the left middle cerebral artery. The patient was diagnosed as CWS with ICAS. Interventions: Loading dose of clopidogrel and aspirin were started but were ineffective, then we used recombinant tissue plasminogen (r-tPA) for thrombolysis therapy after repeat CT scan that showed small acute infarcts in the right putamen and no bleeding. Outcomes: The patient was successfully treated by r-tPA intravenous thrombolysis after loading dose of dual-anti-platelet. He recovered rapidly, and the NIHSS score was 0 point, modified Rankin Scale score was 0 point, and Barthel Index score was 100 points at 3-month follow-up. Lessons: r-tPA combined with loading dose of dual antiplatelet appears safe and effective in carefully selected CWS patients with ICAS. The collection of similar cases and further randomized controlled trial research would be desirable.

Accurate models that describe temporal-spatial parameters are desirable in gait estimation and rehabilitation. This study aimed to explore simple but relatively accurate models to describe stride length (SL), speed (SP) and walk ratio (WR) at various cadences. Twenty-four able-bodied participants (16 in a test group and 8 in a validation group) walked at seven cadence ratios (CRs). The individual and group mean SL, SP and WR were studied. Suitable temporal-spatial model structures were proposed and used to approximate the individual SL, SP and WR at various CRs. After the temporal-spatial model structures were found to be feasible, the general temporal-spatial models were analysed using the test group mean SL, SP and WR. Accuracy was assessed using the validation group mean values. Individual approximation accuracies showed that the proposed model structure deduced from the linear SL model was suitable for WR approximation. The linear, deduced quadratic and power functions approximated the individual SL, SP and WR, respectively, with high accuracy. Based on the test group mean SL, SP and WR, the general temporal-spatial models were obtained and produced comparable approximation accuracies in the validation group. The general temporal-spatial models predicted well the individual gait parameters with similar individual errors for both groups. These temporal-spatial models clearly describe SL, SP and especially WR at various cadences. They provide accurate reference data for gait estimation and have potential to guide speed modulation in robot-assisted gait rehabilitation. Graphical abstractTwenty-four able-bodied participants (16 in test group and 8 in validation group) walked at seven cadence ratios (CRs), with the individual and group mean stride length (SL), speed (SP) and walk ratio (WR) studied. This work selected the cadence ratio as the independent variable and yielded general temporal-spatial models based on the test group data, which were a linear model for SL, a quadratic function for SP and a power function for WR. The general temporal-spatial model produced comparable approximation accuracies in the validation group. Clearly describing SL, SP and especially WR at various cadences, these temporal-spatial models provide accurate references for gait estimation and have the potential to guide speed modulation in robot-assisted gait rehabilitation. Approximation of the group mean temporal-spatial parameters at seven cadences. Solid lines in parts (a, b): the general linear SL model. Solid lines in (c, d): the general quadratic SP model. Solid lines in (e, f): the general WR model. Dots and stars in (a, c, e): the individual and group mean values for the test group. Dots and stars in (b, d, f): the individual and group mean values for the validation group. Electronic supplementary material The online version of this article (10.1007/s11517-018-1919-8) contains supplementary material, which is available to authorized users.

Seven new α,β-diphenyl-γ-butyrolactones (1-7), three new lignans (8-10), five new neolignans (11-15), two new 1,3-biphenylpropanoids (16 and 17), and a new flavonol galactoside-lignan ester (18), together with 43 known compounds (19-61), were isolated from the twigs of Cinnamomum cassia. Their structures were elucidated by spectroscopic data analysis as well as chemical methods. The α,β-diphenyl-γ-butyrolactones are a class of unique natural compounds that have only been isolated from C. cassia. Compounds 11 and 12 are rare examples of neolignans possessing a 1,2-dioxetane moiety. Compound 13 is a new oxyneolignan possessing a unique C-9-O-C-9' linkage between the benzopyran and cinnamyl alcohol moieties. Compound 15 is the first example of a natural neolignan possessing a 2-styryl-3-phenyltetrahydrofuran skeleton. The isolated compounds were evaluated for their neuroprotective activities against tunicamycin-induced cytotoxicity in SH-SY5Y cells. Compounds 3, 5, 10, 11, 12, 20, 36, and 56 showed statistically significant neuroprotective activity with EC

Background Ischemic stroke causes a multitude of brain damage. Neurovascular injury and myelin sheath degradation are two manifestations of ischemic brain damage. Therapeutic strategies aiming only at repairing the neural components or the vessels cannot efficiently restore neurological function. Endothelial progenitor cells (EPCs) have the advantages of both promoting angiogenesis and secreting trophic factors that would promote neurogenesis. Chemokine cxcl12 gene therapy has also been shown to promote angiogenesis, neurogenesis, and remyelination, attracting EPCs, neural progenitor cells, and oligodendrocyte progenitor cells (OPCs) to the injured sites of the brain. In this work, we tested whether these two therapeutics can be combined by genetically engineering the EPCs with cxcl12 to harness the synergistic effects of these two interventions. Methods We used lentivirus (LV) to deliver cxcl12 gene into human umbilical cord blood EPCs to generate the engineered CXCL12-EPCs, which were then delivered into the perifocal region at 1 week after permanent middle cerebral artery occlusion to investigate the effects of CXCL12-EPCs on the functional recovery and angiogenesis, neurogenesis, and remyelination in ischemic stroke mice. Green fluorescent protein (gfp) gene-modified EPCs and LV-CXCL12 gene therapy were used as controls. Results CXCL12-EPC treatment significantly reduced brain atrophy and improved neurobehavioral function at 5 weeks after brain ischemia. The treatment resulted in increased blood vessel density and myelin sheath integrity, and promoted neurogenesis, angiogenesis, and the proliferation and migration of OPCs. In-vitro data showed that CXCL12-EPCs performed better in proliferation and tube formation assays and expressed a higher level of vascular endothelial growth factor compared to GFP-EPCs. Conclusions The synergistic treatment of CXCL12-EPCs outperformed the single therapies of GFP-EPCs or LV-CXCL12 gene therapy in various aspects related to post-ischemic brain repair. cxcl12-engineered EPCs hold great potential in the treatment of ischemic stroke.

Background/Aims: Cerebral aneurysm growth is characterized by continuous structural weakness of local smooth muscle cells, though the mechanism is unclear. In this study, we examine protein changes in cerebral aneurysm and human brain vascular smooth muscle cells after cyclic mechanical stretch. We further explore the relationship between the smooth muscle cell changes and reductions in the levels of collagen types IV and VI. Methods: Saccular cerebral aneurysms (n=10) were collected, and temporal artery samples were used as controls. Quantitative proteomics were analyzed and histopathological changes were examined. Smooth muscle cells were cultured in a flexible silicone chamber and subjected to 15% cyclic mechanical stretch. The effect of stretch on the cell viability, function, gene and protein expression were further studied for the understanding the molecular mechanism of aneurysm development. Results: Proteomics analysis revealed 92 proteins with increased expression and 88 proteins with decreased expression compared to the controls (p

Aortic dissection (AD) is a catastrophic disease with high mortality and morbidity, characterized with fragmentation of elastin and loss of smooth muscle cells. Although AD has been largely attributable to polymorphisms defect in the elastin-coding gene, tropoelastin (TE), other undermined factors also appear to play roles in AD onset. Here, we investigated the effects of post-transcriptional control of TE by microRNAs (miRNAs) on elastin levels in aortic smooth muscle cells (ASMC). We found that miR-144-3p is a miRNA that targets TE mRNA in both human and mouse. Bioinformatics analyses and dual luciferase reporter assay showed that miR-144-3p inhibited protein translation of TE, through binding to the 3'-UTR of the TE mRNA. Interestingly, higher miR-144-3p levels and lower TE were detected in the ASMC obtained from AD patients, compared to those from non-AD controls. In a mouse model for human AD, infusion of adeno-associated viruses (serotype 6) carrying antisense for miR-144-3p (as-miR-144-3p) under CAG promoter significantly reduced the incidence and severity of AD, seemingly through enhancement of TE levels in ASMC. Thus, our data suggest an essential role of miR-144-3p on the pathogenesis of AD.

(±)-Sativamides A (1) and B (2), two pairs of nor-lignanamide enantiomers featuring a unique benzo-angular triquinane skeleton, were isolated from the fruits of Cannabis sativa (hemp seed). Their structures were elucidated by detailed spectroscopic analysis and ECD calculations. The resolution of (+)- and (-)-sativamides A and B were achieved by chiral HPLC. Pretreatment of neuroblastoma cells with 1 and 2 significantly reduced the endoplasmic reticulum (ER) stress-induced cytotoxicity.

Four new monoterpenoid indole alkaloids (MIAs), scholarisines P-S (1-4), and 14 known MIAs (5-18) were isolated from the leaves of Alstonia scholaris (L) R. Br. (Apocynaceae). Their structures were elucidated by analyzing their HRESIMS data and NMR spectroscopic data. All of the isolated MIAs were evaluated for their Nuclear Factor-kappa B (NF-κB) inhibitory activity in HepG2-NF-κB-Luc cells. Among them, five compounds (4, 7, 8, 13 and 16) exhibited significant NF-κB inhibitory activity.

Endothelial progenitor cells have been shown to differentiate into endothelial cells and to play a pivotal role in vascular homeostasis. Adiponectin has anti-atherogenic and anti-inflammatory properties via directly acting on vascular cells. The aim of the present study is to explore the effect of adiponectin on major functions involved in survival, migration, and tube formation of endothelial progenitor cells and to explore the underlying mechanism. In this study, we transferred adiponectin gene into endothelial progenitor cells via lentiviral vectors and investigated the proliferation, migration and tube formation of these transfected cells. We found that adiponectin is highly expressed in endothelial progenitor cells and promotes their proliferation, migration and tube formation. Western blot data showed that the former two processes were mediated through the AMPK/Akt/eNOS pathway, the latter via the AMPK/eNOS pathway. Use of the AMPK inhibitor (Compound C) or Akt inhibitor (MK-2206) reduced eNOS phosphorylation and attenuated adiponectin-induced endothelial progenitor cell proliferation, migration and tube formation compared to the controls (p < 0.05). Taken together, these data indicated that adiponectin promotes endothelial progenitor cell proliferation and migration via AMPK/Akt/eNOS signaling pathway and promotes tube formation through AMPK/eNOS, suggesting that adiponectin-transduced endothelial progenitor cell transplantation is a potential therapeutic target for vascular disease.

Microglia are brain resident macrophages originated from primitive progenitor cells in the yolk sac. Microglia can be activated within hours and recruited to the lesion site. Traditionally, microglia activation is considered to play a deleterious role in ischemic stroke, as inhibition of microglia activation attenuates ischemia induced brain injury. However, increasing evidence show that microglia activation is critical for attenuating neuronal apoptosis, enhancing neurogenesis, and promoting functional recovery after cerebral ischemia. Differential polarization of microglia could likely explain the biphasic role of microglia in ischemia. We comprehensively reviewed the mechanisms involved in regulating microglia activation and polarization. The latest discoveries of microRNAs in modulating microglia function are discussed. In addition, the interaction between microglia and other cells including neurons, astrocytes, oligodendrocytes, and stem cells were also reviewed. Future therapies targeting microglia may not exclusively aim at suppressing microglia activation, but also at modulating microglia polarization at different stages of ischemic stroke. More work is needed to elucidate the cellular and molecular mechanisms of microglia polarization under ischemic environment. The roles of microRNAs and transplanted stem cells in mediating microglia activation and polarization during brain ischemia also need to be further studied.

Yu-Guo Yuan,1 Qiu-Ling Peng,2 Sangiliyandi Gurunathan3 1College of Veterinary Medicine/Animal Science and Technology/Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, Jiangsu, People’s Republic of China; 2College of Chemistry and Bioengineering, Yichun University, Yichun, Jiangxi, People’s Republic of China; 3Department of Stem cell and Regenerative Biotechnology, Konkuk University, Seoul, Republic of Korea Background: Gemcitabine (GEM) is widely used as an anticancer agent in several types of solid tumors. Silver nanoparticles (AgNPs) possess unique cytotoxic features and can induce apoptosis in a variety of cancer cells. In this study, we investigated whether the combination of GEM and AgNPs can exert synergistic cytotoxic effects in the human ovarian cancer cell line A2780.Methods: We synthesized AgNPs using resveratrol as a reducing and stabilizing agent. The synthesized nanomaterials were characterized using various analytical techniques. The anticancer effects of a combined treatment with GEM and AgNPs were evaluated using a series of cellular assays. The expression of pro- and antiapoptotic genes was measured using real-time reverse transcription polymerase chain reaction. Apoptosis was confirmed by TUNEL assay.Results: In this study, combined treatment with GEM and AgNPs significantly inhibited viability and proliferation in A2780 cells. Moreover, the levels of apoptosis in cells treated with a combination of GEM and AgNPs were significantly higher compared with those in cells treated with GEM or AgNPs alone. Our data suggest that GEM and AgNPs exhibit potent apoptotic activity in human ovarian cancer cells. Combined treatment with GEM and AgNPs showed a significantly higher cytotoxic effect in ovarian cancer cells compared with that induced by either of these agents alone.Conclusion: Our study demonstrated that the interaction between GEM and AgNPs was cytotoxic in ovarian cancer cells. Combined treatment with GEM and AgNPs caused increased cytotoxicity and apoptosis in A2780 cells. This treatment may have therapeutic potential as targeted therapy for the treatment of ovarian cancer. To our knowledge, this study could provide evidence that AgNPs can enhance responsiveness to GEM in ovarian cancer cells and that AgNPs can potentially be used as chemosensitizing agents in ovarian cancer therapy. Keywords: cell viability, proliferation, cytotoxicity, apoptosis, gemcitabine, silver nanoparticles

Yu-Guo Yuan,1 Yan-Hong Wang,1 Hui-Hui Xing,1 Sangiliyandi Gurunathan2 1Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonosis, College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu, People’s Republic of China; 2Department of Stem Cell and Regenerative Biotechnology, Konkuk University, Seoul, Republic of Korea Background: Graphene and graphene-related materials have gained substantial interest from both academia and industry for the development of unique nanomaterials for biomedical applications. Graphene oxide (GO) and silver nanoparticles (AgNPs) are a valuable platform for the development of nanocomposites, permitting the combination of nanomaterials with different physical and chemical properties to generate novel materials with improved and effective functionalities in a single platform. Therefore, this study was conducted to synthesize a graphene oxide–silver nanoparticle (GO-AgNPs) nanocomposite using the biomolecule quercetin and evaluate the potential cytotoxicity and mechanism of GO-AgNPs in human neuroblastoma cancer cells (SH-SY5Y).Methods: The synthesized GO-AgNPs were characterized using various analytical techniques. The potential toxicities of GO-AgNPs were evaluated using a series of biochemical and cellular assays. The expression of apoptotic and anti-apoptotic genes was measured by quantitative real-time reverse transcription polymerase chain reaction. Further, apoptosis was confirmed by caspase-9/3 activity and a terminal deoxynucleotidyl transferase dUTP nick end labeling assay, and GO-AgNPs-induced autophagy was also confirmed by transmission electron microscopy.Results: The prepared GO-AgNPs exhibited significantly higher cytotoxicity toward SH-SY5Y cells than GO. GO-AgNPs induced significant cytotoxicity in SH-SY5Y cells by the loss of cell viability, inhibition of cell proliferation, increased leakage of lactate dehydrogenase, decreased level of mitochondrial membrane potential, reduced numbers of mitochondria, enhanced level of reactive oxygen species generation, increased expression of pro-apoptotic genes, and decreased expression of anti-apoptotic genes. GO-AgNPs induced caspase-9/3-dependent apoptosis via DNA fragmentation. Finally, GO-AgNPs induced accumulation of autophagosomes and autophagic vacuoles.Conclusion: In this study, we developed an environmentally friendly, facile, dependable, and simple method for the synthesis of GO-AgNPs nanocomposites using quercetin. The synthesized GO-AgNPs exhibited enhanced cytotoxicity compared with that of GO at very low concentrations. This study not only elucidates the potential cytotoxicity against neuroblastoma cancer cells, but also reveals the molecular mechanism of toxicity. Keywords: neuroblastoma, cell viability, cytotoxicity, graphene oxide–silver nanoparticles nanocomposite, apoptosis, autophagy

Stroke is the second leading cause of mortality and morbidity worldwide. Early intervention is of great importance in reducing disease burden. Since the conventional risk factors cannot fully account for the pathogenesis of stroke, it is extremely important to detect useful biomarkers of the vascular disorder for appropriate intervention. Arterial stiffness, a newly recognised reliable feature of arterial structure and function, is demonstrated to be associated with stroke onset and serve as an independent predictor of stroke incidence and poststroke functional outcomes. In this review article, different measurements of arterial stiffness, especially pressure wave velocity, were discussed. We explained the association between arterial stiffness and stroke occurrence by discussing the secondary haemodynamic changes. We reviewed clinical data that support the prediction role of arterial stiffness on stroke. Despite the lack of long-term randomised double-blind controlled therapeutic trials, it is high potential to reduce stroke prevalence through a significant reduction of arterial stiffness (which is called de-stiffening therapy). Pharmacological interventions or lifestyle modification that can influence blood pressure, arterial function or structure in either the short or long term are promising de-stiffening therapies. Here, we summarised different de-stiffening strategies including antihypertension drugs, antihyperlipidaemic agents, chemicals that target arterial remodelling and exercise training. Large and well-designed clinical trials on de-stiffening strategy are needed to testify the prevention effect for stroke. Novel techniques such as modern microscopic imaging and reliable animal models would facilitate the mechanistic analyses in pathophysiology, pharmacology and therapeutics.

Ethnopharmacological relevance Calotropis gigantea (L.) Dryand (Apocynaceae) is a medicinal plant native to southern China, India and Southeast Asia. It has been traditionally used for the treatment of several diseases including cancers in these countries. Aim of the study This study aimed to isolate bioactive cardenolides from C. gigantea , to screen their hypoxia-inducible factor (HIF-) 1 inhibitory activity, and to analyze the structure-activity relationship (SAR). Materials and methods Isolation and purification of cardenolides from the latex and the fruits of C. gigantea were performed by using a series of separation techniques. Their structures were fully characterized by elucidating their NMR and HRMS data. The HIF-1 inhibitory activities of cardenolides were evaluated by using a T47D cell-based dual-luciferase reporter assay. The potent cardenolides were selected to further evaluate their dose-response manner. Cytotoxic effects of selected cardenolides were also examined against breast cancer cell line (MCF-7) and normal mammary epithelial cell line (MCF-10A) by MTT assay. Results Among twenty isolated cardenolides, compounds 1 , 3 , 4 , 6–8 , 14 and 17 exhibited stronger HIF-1 inhibitory activities than that of digoxin, a well-known HIF-1 inhibitor ( P 50 values in nanomolar potency (21.8–64.9 nM). An analysis of SAR revealed the great contributions of a β -configuration of the substituents at positions of C-2′ and C-3′, an aldehydic moiety on C-19, and the dioxane moiety between the aglycone and sugar parts of cardenolides to the HIF-1 inhibitory activity. In contrast, a hydroxyl group at any positions of C-15, C-16 and C-4′ of cardenolides showed negative effects on suppressing HIF-1 transcriptional activity. In addition, these eight cardenolides also exhibited potent cytotoxic effects against human breast cancer cell MCF-7 (IC 50 values ranged from 30.5 to 68.8 nM), but less toxic effects to human normal mammary epithelial cell MCF-10A (IC 50 values >20 µM). Conclusions This is the first report of a comprehensive study of SAR on cardenolides from C. gigantea as HIF-1 inhibitors. Eight cardenolides ( 1 , 3 , 4 , 6–8 , 14 and 17 ) showed both potent HIF-1 inhibitory activity and strong cytotoxic effect against MCF-7 cancer cells in nanomolar level. The findings of these cardenolides provided important insights into the development of these potent HIF-1 inhibitors as anticancer drug.

A girl was diagnosed with intravenous immunoglobulin (IVIG)-resistant Kawasaki disease (KD) due to pyrexia and hemoptysis for eight days. The girl was a school-age child with major clinical manifestations of pyrexia, skin rash, enlargement of bilateral cervical lymph nodes, conjunctival hyperaemia, red and cracked lips and strawberry-like tongue, followed by swelling of both hands and feet. Laboratory examination showed significant increases in white blood cell count, platelet count, C-reactive protein, erythrocyte sedimentation rate and liver enzymes, a significant reduction in albumin, and the presence of aseptic pyuria. After the first course of IVIG treatment, the girl still had recurrent pyrexia, with hemoptysis on day 2 after admission, and lung CT showed uneven luminance and patchy shadow. The symptoms were quickly alleviated after the second course of IVIG treatment combined with methylprednisolone and aspirin treatment. KD is a febrile disease characterized by multiple systemic vasculitis in childhood and can involve various organ systems such as the heart, lungs, kidneys and the nervous system. Therefore, it is necessary to carefully monitor and recognize the rare symptoms of KD, and early recognition of pulmonary complications of KD can avoid delay in diagnosis, prevent the development of more serious complications, and help with early treatment and disease recovery.

Stroke is the second most common cause of death in the world especially in the ageing population.1 Thrombolysis and intravascular embolectomy are the main treatment and populated rapidly.2 3 However, the beneficiary is still limited because the mechanistic studies are behind. The basic research on stroke is improved because of new devices, novel techniques and the development of other disciplines.4 The update of a broad range of topics related to stroke is a widely appreciated feature. In order to improve the understanding of cellular and molecular mechanisms of stroke, the 2nd Summit of Chinese Basic Science Research on Stroke 2018 has been held in Beijing, China. Total of 60 basic stroke researchers from China and abroad attended this meeting. The meeting focused on six fields: (1) neuroprotection in acute ischaemic stroke; (2) neurorepair and regeneration; (3) neuroinflammation and neuroimmunology; (4) cognitive disorder in stroke; (5) drug/small molecule therapy for stroke; and (6) advances in optical imaging. Although 95% of published preclinical studies on ‘neuroprotective agents’ (1990–2018) reported positive outcomes in animal models of ischaemic stroke, none translated to successful phase III trials.5 Studies are therefore focusing other approaches. For example, preconditioning and postconditioning induced neuroprotection are advancements in our understanding of the neurochemical basis for their neuroprotective role.6 Some of these studies are trying to transfer these techniques …