Sintering phenomena, densification, and grain growth are crucial for proper control of the microstructure for good mechanical strength. Here, materials and processing parameters, the addition of ...La2O3, and two‐step sintering (TSS) were combined to lead to higher strength in the porous alumina prepared by freeze‐casting. Based on grain growth and densification behaviors with the La2O3 doping, a beneficial thermal profile was designed for the TSS. As a result, higher relative density levels and smaller grain size were obtained compared with the results with conventional sintering (CS): 38.56% and 0.82 µm at 1500°C by CS; 40.78% and 1.78 µm at 1600°C by CS; 41.43% and 0.87 µm by TSS. The microstructural benefits provided ∼1.4 times higher compressive strength (5.46 MPa) from TSS than from the CS sample (3.92 MPa), highlighting the synergetic effect of La2O3 doping and the TSS strategy.
Lipocalin‐2 (LCN2) has diverse functions in multiple pathophysiological conditions; however, its pathogenic role in vascular dementia (VaD) is unknown. Here, we investigated the role of LCN2 in VaD ...using rodent models of global cerebral ischemia and hypoperfusion with cognitive impairment and neuroinflammation. Mice subjected to transient bilateral common carotid artery occlusion (tBCCAo) for 50 min showed neuronal death and gliosis in the hippocampus at 7 days post‐tBCCAo. LCN2 expression was observed predominantly in the hippocampal astrocytes, whereas its receptor was mainly detected in neurons, microglia, and astrocytes. Furthermore, Lcn2‐deficient mice, compared with wild‐type animals, showed significantly weaker CA1 neuronal loss, cognitive decline, white matter damage, blood–brain barrier permeability, glial activation, and proinflammatory cytokine production in the hippocampus after tBCCAo. Lcn2 deficiency also attenuated hippocampal neuronal death and cognitive decline at 30 days after unilateral common carotid artery occlusion (UCCAo). Furthermore, intracerebroventricular (i.c.v) injection of recombinant LCN2 protein elicited CA1‐neuronal death and a cognitive deficit. Our studies using cultured glia and hippocampal neurons supported the decisive role of LCN2 in hippocampal neurotoxicity and microglial activation, and the role of the HIF‐1α–LCN2–VEGFA axis of astrocytes in vascular injury. Additionally, plasma levels of LCN2 were significantly higher in patients with VaD than in the healthy control subjects. These results indicate that hippocampal damage and cognitive impairment are mediated by LCN2 secreted from reactive astrocytes in VaD.
Main Points
Astrocyte‐derived LCN2 mediates hippocampal damage in rodent models of vascular dementia, with higher plasma levels of LCN2 protein in patients with vascular dementia, suggesting the possibility of effective glia‐based treatment for vascular dementia.
Externally stimuli‐triggered spatially and temporally controlled gene delivery can play a pivotal role in achieving targeted gene delivery with maximized therapeutic efficacy. In this study, a ...photothermally controlled gene delivery carrier is developed by conjugating low molecular‐weight branched polyethylenimine (BPEI) and reduced graphene oxide (rGO) via a hydrophilic polyethylene glycol (PEG) spacer. This PEG–BPEI–rGO nanocomposite forms a stable nano‐sized complex with plasmid DNA (pDNA), as confirmed by physicochemical studies. For the in vitro gene transfection study, PEG–BPEI–rGO shows a higher gene transfection efficiency without observable cytotoxicity compared to unmodified controls in PC‐3 and NIH/3T3 cells. Moreover, the PEG–BPEI–rGO nanocomposite demonstrates an enhanced gene transfection efficiency upon NIR irradiation, which is attributed to accelerated endosomal escape of polyplexes augmented by locally induced heat. The endosomal escaping effect of the nanocomposite is investigated using Bafilomycin A1, a proton sponge effect inhibitor. The developed photothermally controlled gene carrier has the potential for spatial and temporal site‐specific gene delivery.
Phototriggered gene transfection is enabled by a novel nano‐sized PEG–BPEI–rGO nanocomposite, developed by conjugating polymers with reduced graphene oxide (rGO) for photothermal gene transfection. This new concept of an NIR‐responsive nanocomposite could provide significant insight to design the gene carriers endowed with controlled and advanced target‐specific gene delivery.
Stimuli‐responsive gene delivery systems maximize therapeutic efficacy by controlling the cytosolic conveyance and rate of effective gene release. We present herein a hybrid nanocomposite composed of ...a 2D nanomaterial, MoS2, modified by attaching two polymers (polyethylenimine (PEI) and polyethylenglycol (PEG)) via disulfide bonds. This MoS2–PEI–PEG nanocomposite interacts with DNA by electrostatic interaction, and accordingly forms a nanosized complex with high stability. Photothermal conversion of MoS2 nanosheet is employed in order to induce photothermally triggered endosomal escape upon the near infrared light irradiation. After endosomal escape, polymers are detached from the MoS2 nanosheet by the intracellular reducing agent, glutathione (GSH), resulting in effective gene release from the nanocomposite. This sequential process initiated by external and internal stimuli remarkably enhances gene delivery efficiency by effective endosomal escape and gene release without severe cytotoxicity. Our rationally designed MoS2 nanocomposite provides a spatiotemporally controllable platform to deliver genetic material into cells.
Single‐layered MoS2–PEI–PEG nanocomposites provide an externally and internally controllable platform for effective gene transfection. Local heat generated from MoS2 enables the endosomal escape of polyplexes, and sequentially intracellular redox environment governed by GSH triggers the effective DNA release, leading to high gene transfection.
Oxidative stress and its associated lipid peroxidation play a key role in nonalcoholic steatohepatitis (NASH). Ferroptosis is a recently recognized type of cell death characterized by an ...iron-dependent and lipid peroxidation–mediated nonapoptotic cell death. We demonstrate the impact of ferroptosis on the progression of NASH induced by methionine/choline-deficient diet (MCD) feeding for 10 days. RSL-3 (a ferroptosis inducer) treatment showed decreased hepatic expression of glutathione peroxidase 4 (GPX4) and conversely increased 12/15-lipoxygenase, and apoptosis-inducing factor, indicating that ferroptosis plays a key role in NASH-related lipid peroxidation and its associated cell death. Consistently, levels of serum biochemical, hepatic steatosis, inflammation, and apoptosis in MCD-fed mice were exacerbated with RSL-3 treatment. However, MCD-fed mice treated with sodium selenite (a GPX4 activator) showed increase of hepatic GPX4, accompanied by reduced NASH severity. To chelate iron, deferoxamine mesylate salt was used. Administration of deferoxamine mesylate salt significantly reduced NASH severity and abolished the harmful effects of RSL-3 in MCD-fed mice. Finally, treatment with liproxstatin-1 (a ferroptosis inhibitor) repressed hepatic lipid peroxidation and its associated cell death, resulting in decreased NASH severity. Consistent with the in vivo findings, modulation of ferroptosis/GPX4 affected hepatocellular death in palmitic acid–induced in vitro NASH milieu. We conclude that GPX4 and its related ferroptosis might play a major role in the development of NASH.
Synthetic scaffolds, as bone grafts, provide a favorable environment for the repair and growth of new bone tissue at defect sites. However, the lack of angio‐ and osteo‐induction limits the ...usefulness of artificial scaffolds for bone regeneration. Nitric oxide (NO) performs essential roles in healing processes, such as regulating inflammation and addressing incomplete revascularization. In this study, a polymer capable of controlled NO release is developed to promote the osteogenic capacity in artificial scaffolds. The biological efficiency of the NO compound is assessed by its effect on pre‐osteoblasts and macrophages in vitro and the extent of vascularization and bone formation in the calvaria defect model in vivo. The compound does not inhibit cell adhesion or proliferation. NO treatment significantly increases both alkaline phosphatase activity and mineralization in pre‐osteoblasts. Macrophages treated with NO secrete high levels of anti‐inflammatory factors and adopt the pro‐regenerative phenotype. In the critical‐sized defect model, the collagen scaffold containing the NO compound enhances neovascularization and bone formation. The developed NO‐releasing system promotes osteogenesis and regeneration of damaged bone tissue. As the multiple functions of NO involve macrophage modulation and angiogenesis, such release systems may be valuable for guiding bone regeneration in critical‐sized defects.
A nitric oxide (NO)‐releasing vehicle is developed for application in the promotion of bone regeneration with the guided bone regeneration method. Cell toxicity and osteogenic differentiation are assessed to evaluate the effect of NO. The NO‐efficiency in an animal is evaluated in the mice's calvarial defect. The novel NO‐system may be useful in various applications to accelerate bone regeneration.
Although numerous studies have suggested that canonical IκB kinases (IKK) play a key role in the progression of liver fibrosis, the role of non‐canonical IKKε and TANK‐binding kinase 1 (TBK1) on the ...development and progression of liver fibrosis remains unclear. To demonstrate such issue, repeated injection of CCl4 was used to induce hepatotoxin‐mediated chronic liver injury and biliary fibrosis was induced by 0.1% diethoxycarbonyl‐1, 4‐dihydrocollidine diet feeding for 4 weeks. Mice were orally administered with amlexanox (25, 50, and 100 mg/kg) during experimental period. Significantly increased levels of TBK1 and IKKε were observed in fibrotic livers or hepatic stellate cells (HSCs) isolated from fibrotic livers. Interestingly, amlexanox treatment significantly inhibited the phosphorylation of TBK1 and IKKε accompanied by reduced liver injury as confirmed by histopathologic analysis, decreased serum biochemical levels and fibro‐inflammatory responses. Additionally, treatment of amlexanox promoted the fibrosis resolution. In accordance with these findings, amlexanox treatment suppressed HSC activation and its related fibrogenic responses by partially inhibiting signal transducer and activator of transcription 3. Furthermore, amlexanox decreased the activation and inflammatory responses in Kupffer cells. Collectively, we found that inhibition of the TBK1 and IKKε by amlexanox is a promising therapeutic strategy to cure liver fibrosis.
We aimed to develop a novel prediction model for early neurological deterioration (END) based on an interpretable machine learning (ML) algorithm for atrial fibrillation (AF)-related stroke and to ...evaluate the prediction accuracy and feature importance of ML models. Data from multicenter prospective stroke registries in South Korea were collected. After stepwise data preprocessing, we utilized logistic regression, support vector machine, extreme gradient boosting, light gradient boosting machine (LightGBM), and multilayer perceptron models. We used the Shapley additive explanation (SHAP) method to evaluate feature importance. Of the 3,213 stroke patients, the 2,363 who had arrived at the hospital within 24 h of symptom onset and had available information regarding END were included. Of these, 318 (13.5%) had END. The LightGBM model showed the highest area under the receiver operating characteristic curve (0.772; 95% confidence interval, 0.715-0.829). The feature importance analysis revealed that fasting glucose level and the National Institute of Health Stroke Scale score were the most influential factors. Among ML algorithms, the LightGBM model was particularly useful for predicting END, as it revealed new and diverse predictors. Additionally, the effects of the features on the predictive power of the model were individualized using the SHAP method.
To test whether autologous modified mesenchymal stem cells (MSCs) improve recovery in patients with chronic major stroke.
In this prospective, open-label, randomized controlled trial with blinded ...outcome evaluation, patients with severe middle cerebral artery territory infarct within 90 days of symptom onset were assigned, in a 2:1 ratio, to receive preconditioned autologous MSC injections (MSC group) or standard treatment alone (control group). The primary outcome was the score on the modified Rankin Scale (mRS) at 3 months. The secondary outcome was to further demonstrate motor recovery.
A total of 39 and 15 patients were included in the MSC and control groups, respectively, for the final intention-to-treat analysis. Mean age of patients was 68 (range 28-83) years, and mean interval between stroke onset to randomization was 20.2 (range 5-89) days. Baseline characteristics were not different between groups. There was no significant difference between the groups in the mRS score shift at 3 months (
= 0.732). However, secondary analyses showed significant improvements in lower extremity motor function in the MSC group compared to the control group (change in the leg score of the Motricity Index,
= 0.023), which was notable among patients with low predicted recovery potential. There were no serious treatment-related adverse events.
IV application of preconditioned, autologous MSCs with autologous serum was feasible and safe in patients with chronic major stroke. MSC treatment was not associated with improvements in the 3-month mRS score, but we did observe leg motor improvement in detailed functional analyses.
This study provides Class III evidence that autologous MSCs do not improve 90-day outcomes in patients with chronic stroke.
NCT01716481.
This study was performed to investigate the prevalence, clinical characteristics, and treatment response according to BRCA1 and BRCA2 (BRCA) mutations in Korean patients with epithelial ovarian ...cancer (EOC). Two‐hundred and ninety‐eight Korean women diagnosed with high‐grade serous and/or endometrioid EOC from 2010 to 2015 were tested for germline and 86 specimens for somatic BRCA mutations, regardless of the family history. Clinical characteristics including survival outcomes were compared in patients with and without BRCA mutations (NCT02963688). A total of 43 different germline BRCA mutations were identified in 78 patients among 298 patients (26.2%). Somatic BRCA mutations were identified in 11 (12.8%) patients among patients without germline BRCA mutations. Haplotype analysis demonstrated no founder mutations in our Korean patient cohort. Insignificant differences in age at diagnosis, primary site, and residual disease after surgery were observed between patients with and without BRCA mutations. In multivariate analysis for overall survival (OS), the presence of BRCA mutation was significantly associated with OS (P = .049) in addition to platinum sensitivity (P < .001), indicating it is an independent prognostic factor for survival regardless of platinum sensitivity to first‐line chemotherapy. In addition, a higher response rate to subsequent chemotherapy after recurrence was observed in EOC patients with BRCA mutations resulting in better OS. In the current study, the prevalence of BRCA mutations in Korean patients with EOC was higher than previously reported in other ethnic groups. We demonstrated characteristics and treatment response in Korean EOC patients with BRCA mutations. These findings may provide valuable information to be considered in future clinical trials including Asian patients.
A total of 43 different germline BRCA mutations were identified in 78 patients among 298 patients (26.2%). Somatic BRCA mutations were identified in 11 (12.8%) patients among patients without germline BRCA mutations. BRCA mutation is an independent prognostic factor for survival regardless of platinum sensitivity to first‐line chemotherapy. A higher response rate to subsequent chemotherapy after recurrence was observed in patients with BRCA mutation, resulting in better overall survival in these patients.
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