Aquaporin 4 Mediates the Effect of Iron Overload on Hydrocephalus After Intraventricular Hemorrhage.

BACKGROUND: Iron overload plays an important role in hydrocephalus development following intraventricular hemorrhage (IVH). Aquaporin 4 (AQP4) participates in the balance of cerebrospinal fluid secretion and absorption. The current study investigated the role of AQP4 in the formation of hydrocephalus caused by iron overload after IVH. METHODS: There were three parts to this study. First, Sprague-Dawley rats received an intraventricular injection of 100 µl autologous blood or saline control. Second, rats had IVH and were treated with deferoxamine (DFX), an iron chelator, or vehicle. Third, rats had IVH and were treated with 2-(nicotinamide)-1,3,4-thiadiazole (TGN-020), a specific AQP4 inhibitor, or vehicle. Rats underwent T2-weighted and T2* gradient-echo magnetic resonance imaging to assess lateral ventricular volume and intraventricular iron deposition at 7, 14, and 28 days after intraventricular injection and were then euthanized. Real-time quantitative polymerase chain reaction, western blot analysis, and immunofluorescence analyses were conducted on the rat brains to evaluate the expression of AQP4 at different time points. Hematoxylin and eosin-stained brain sections were obtained to assess the ventricular wall damage on day 28. RESULTS: Intraventricular injection of autologous blood caused a significant ventricular dilatation, iron deposition, and ventricular wall damage. There was increased AQP4 mRNA and protein expression in the periventricular tissue in IVH rats through day 7 to day 28. The DFX treatment group had a lower lateral ventricular volume and less intraventricular iron deposition and ventricular wall damage than the vehicle-treated group after IVH. The expression of AQP4 protein in periventricular tissue was also inhibited by DFX on days 14 and 28 after IVH. The use of TGN-020 attenuated hydrocephalus development after IVH and inhibited the expression of AQP4 protein in the periventricular tissue between day 14 and day 28 without a significant effect on intraventricular iron deposition or ventricular wall damage. CONCLUSIONS: AQP4 located in the periventricular area mediated the effect of iron overload on hydrocephalus after IVH.

An Anthocyanin-Based Eco-Friendly Triboelectric Nanogenerator for pH Monitoring and Energy Harvesting.

In recent years, renewable and sustainable triboelectric nanogenerators have attracted attention due to their high energy conversion rate, and enhancing their functionality further contributes to their applicability across various fields. A pH-sensitive triboelectric nanogenerator (pH-TENG) has been prepared by electrostatic spinning technology, with anthocyanin as the pH indicator and environmentally friendly polyvinyl alcohol (PVA) as the substrate. Among many friction-negative materials, the pH-TENG exhibits the best combination with fluorinated ethylene propylene (FEP) and yields an open-circuit voltage of 62 V, a short-circuit current of 370 nA, and a transferred charge of 21.8 nC. At a frequency of 3 Hz, it can charge a 4.7 µF capacitor to 2 V within 45 s, effectively powering a thermometer. Furthermore, the presence of anthocyanin does not affect the pH-TENG's power generation performance and enables the monitoring of a wide range of environmental pH changes, with an ΔE change of 28.8 ± 7.6. Therefore, pH-TENG prepared with environmentally friendly materials can bring new available materials to the biological and medical fields.

Microcirculation No-Reflow Phenomenon after Acute Ischemic Stroke.

BACKGROUND: The no-reflow phenomenon refers to a failure to restore normal cerebral microcirculation despite brain large artery recanalization after acute ischemic stroke, which was observed over 50 years ago. SUMMARY: Different mechanisms contributing to no-reflow extend across the endovascular, vascular wall, and extravascular factors. There are some clinical tools to evaluate cerebral microvascular hemodynamics and represent biomarkers of the no-reflow phenomenon. As substantial experimental and clinical data showed that clinical outcome was better correlated with reperfusion status rather than recanalization in patients with ischemic stroke, how to address the no-reflow phenomenon is critical. But effective treatments for restoring cerebral microcirculation have not been well established until now, so there is an urgent need for novel therapeutic perspectives to improve outcomes after recanalization therapies. CONCLUSION: Here, we review the occurrence of the no-reflow phenomenon after ischemic stroke and discuss its impact, detection method, and therapeutic strategies on the course of ischemic stroke, from basic science to clinical findings.

Proteomic and bioinformatic analysis of human endometrium from polycystic ovarian syndrome with and without insulin resistance.

Objective: The aim of this study was to investigate the endometrial proteomic profiles of patients with polycystic ovary syndrome (PCOS) with and without insulin resistance (IR). Method of Study: We collected 40 endometrial samples, including PCOS-IR (n = 21), PCOS-non-IR (n = 12), and control (n = 7). Data-independent acquisition (DIA)-based proteomics method is used to identify the expressed proteins among the three groups. The correlation between pregnancy outcomes and identified proteins was analyzed by Lasso regression. Results: A total of 5331 proteins were identified, while 275 proteins were differentially expressed in the PCOS vs. control group and 215 proteins were differentially expressed in the PCOS-IR vs. PCOS-non-IR group. Platelet degranulation, neutrophil degranulation, and very long-chain fatty acid catabolic processes have been found to play important roles in the endometrium of patients with PCOS-IR. Lasso regression analysis found that ACTR1A, TSC22D2, CKB, ABRAXAS2, and TAGLN2 were associated with miscarriage in patients with PCOS. ACTR1A and CKB were higher in the PCOS-IR group and were positively correlated with HOMA-IR (p < .05). Conclusion: In this study, a panel of proteins was found to be differently expressed in the endometrium. ACTR1A and CKB may be considered as PCOS-IR candidate biomarkers.

Effect of ß2-microglobulin in evaluating the severity and prognosis of brain injury: a clinical study.

BACKGROUND: ß2-microglobulin has been showing to be vital that associated with brain function and neurological diseases. This study aimed to explore the expressions of ß2-microglobulin in blood and urine of the patients with brain injury, and the effect of hyperbaric oxygen therapy on the content of ß2-microglobulin. METHODS: This prospective study included 54 patients with brain injury and 11 healthy controls. The patients were further assigned to two groups: the conscious disturbance group (n = 32) and the non-conscious disturbance group (n = 22) depending on the Glasgow Coma Scale (GCS). The patients received routine treatment and two courses of hyperbaric oxygen therapy (2.0ATA, 60 min, once a day, 10 days for a course). In the brain injury group, blood ß2-microglobulin (ß2MG) and urine ß2-microglobulin (ß2MU) were detected respectively before and after hyperbaric oxygen therapy (HBOT). Consciousness and cognitive scores were performed, correspondingly. RESULTS: Compared with those of the control group, levels of ß2MG and ß2MU in the brain injury group were significantly increased before HBOT (P < 0.05). Whether it was before or after HBOT, ß2MG's content in the conscious disturbance group was higher than that in the non-conscious disturbance group, while ß2MU's content was obviously higher than that of the non-conscious disturbance group only before HBOT (P < 0.05). Besides, the ß2MU's content in the conscious disturbance group was negatively correlated with GCS score (R = -0.351, P < 0.05) and ß2MG's content in the non-conscious disturbance group was positively correlated with the MMSE score grade (R = 0.598, P < 0.05). The ROC curve was used to assess the evaluation of ß2MG and ß2MU for patients with impaired consciousness with the area under the curve (AUC) of ß2MG and ß2MU were 0.775 and 0.796, respectively. CONCLUSION: The concentrations of blood ß2-microglobulin and urinary ß2-microglobulin were significantly increased in patients with brain injury. The concentrations of ß2-microglobulin were correlated with the degree of consciousness and cognitive function. The changes tendency of ß2-microglobulin may be considered as clinical monitoring index to evaluate the patient's disturbance of consciousness and cognitive degree, and provide a basis for early assessment of prognosis.

Exploring the impact of urban form on urban land use efficiency under low-carbon emission constraints: A case study in China's Yellow River Basin.

In the Urban Anthropocene, how to meet the demands of growing urban populations on limited urban land is a key global challenge. Unreasonable urban planning and land use has brought about undesirable consequences including huge carbon emissions. However, research on the spatial impact of urban form on urban land use efficiency (ULUE) under low-carbon emission constraints is limited. This study analyzes 91 cities located in China's Yellow River Basin (YRB). First, we define a new comprehensive indicator system to measure ULUE under low-carbon constraints using the SBM-UN model. We then select nine landscape indicators to quantify the sprawl, complexity, and aggregation of urban form. Finally, we use Spatial Durbin Model to reveal the relationship between urban form and ULUE. We find that carbon emissions in the YRB increased steadily during the study period. The average value of ULUE increased from 0.469 in 1994 to 0.772 in 2018. Efficiency improved most in the provinces of Shaanxi, Henan, Ningxia, and Shandong, with growth rates of 234.15%, 102.40%, 93.09%, and 66.24%, respectively. Positive global Moran's I indices suggest that the spatial distribution of ULUE is positively correlated at basin level. Moreover, urban form metrics in the YRB demonstrated significant regional differences from 1994 to 2018. The regression results showed irregular urban form can negatively impact ULUE while compact and aggregated urban forms can improve ULUE under low carbon constrains. In addition, there are both positive and negative correlations between urban sprawl and ULUE in different regions. Today's choices on urban form can restrict the development pattern of cities and lock in pathways of carbon emissions in the future. Based on the findings in this study, the government should pursue optimal city sizes, avoid scattered patterns and aim for compact urban form.

New insights into targeting mitochondria in ischemic injury.

Stroke is the leading cause of adult disability and death worldwide. Mitochondrial dysfunction has been recognized as a marker of neuronal death during ischemic stroke. Maintaining the function of mitochondria is important for improving the survival of neurons and maintaining neuronal function. Damaged mitochondria induce neuronal cell apoptosis by releasing reactive oxygen species (ROS) and pro-apoptotic factors. Mitochondrial fission and fusion processes and mitophagy are of great importance to mitochondrial quality control. This paper reviews the dynamic changes in mitochondria, the roles of mitochondria in different cell types, and related signaling pathways in ischemic stroke. This review describes in detail the role of mitochondria in the process of neuronal injury and protection in cerebral ischemia, and integrates neuroprotective drugs targeting mitochondria in recent years, which may provide a theoretical basis for the progress of treatment of ischemic stroke. The potential of mitochondrial-targeted therapy is also emphasized, which provides valuable insights for clinical research.

A novel SPAST gene mutation identified in a Chinese family with hereditary spastic paraplegia.

BACKGROUND: Hereditary spastic paraplegia is a heterogeneous group of clinically and genetically neurodegenerative diseases characterized by progressive gait disorder. Hereditary spastic paraplegia can be inherited in various ways, and all modes of inheritance are associated with multiple genes or loci. At present, more than 76 disease-causing loci have been identified in hereditary spastic paraplegia patients. Here, we report a novel mutation in SPAST gene associated with hereditary spastic paraplegia in a Chinese family, further enriching the hereditary spastic paraplegia spectrum. METHODS: Whole genomic DNA was extracted from peripheral blood of the 15 subjects from a Chinese family using DNA Isolation Kit. The Whole Exome Sequencing of the proband was analyzed and the result was identified in the rest individuals. RaptorX prediction tool and Protein Variation Effect Analyzer were used to predict the effects of the mutation on protein tertiary structure and function. RESULTS: Spastic paraplegia has been inherited across at least four generations in this family, during which only four HSP patients were alive. The results obtained by analyzing the Whole Exome Sequencing of the proband exhibited a novel disease-associated in-frame deletion in the SPAST gene, and this mutation also existed in the rest three HSP patients in this family. This in-frame deletion consists of three nucleotides deletion (c.1710_1712delGAA) within the exon 16, resulting in lysine deficiency at the position 570 of the protein (p.K570del). This novel mutation was also predicted to result in the synthesis of misfolded SPAST protein and have the deleterious effect on the function of SPAST protein. CONCLUSION: In this case, we reported a novel mutation in the known SPAST gene that segregated with HSP disease, which can be inherited in each generation. Simultaneously, this novel discovery significantly enriches the mutation spectrum, which provides an opportunity for further investigation of genetic pathogenesis of HSP.

Myriocin and d-PDMP ameliorate atherosclerosis in ApoE-/- mice via reducing lipid uptake and vascular inflammation.

Sphingolipids have been implicated in the etiology of atherosclerosis. The commonly used sphingolipid inhibitors, myriocin (a ceramide inhibitor) and d-PDMP (d-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol, a glycosphingolipid inhibitor), have shown therapeutic potential but their efficacy and their underlying mechanisms remain unclear. Here, apolipoprotein E-deficient (apoE-/-) mice were fed a high-fat diet (HFD) and treated with a control, myriocin, d-PDMP, or atorvastatin for 12 weeks. We analyzed the effects of these drugs on the size and detailed composition of atherosclerotic plaques. Molecular biological approaches were used to explore how the inhibitors affect lipid metabolism and foam-cell formation. Treatment with myriocin or d-PDMP led to smaller and less vulnerable atherosclerotic lesions and was almost as effective as atorvastatin. Sphingolipid inhibitors down-regulated the expression of monocyte chemotactic protein 1 (MCP-1) and its receptor chemoattractant cytokine receptor 2 (CCR2), which play a key role in monocyte recruitment. They also decreased pro-inflammatory Ly-6chigh monocytes and influenced the uptake of modified LDL by down-regulating the expression of cluster of differentiation 36 (CD36) and lectin-like oxidized LDL (ox-LDL) receptor-1 (LOX-1). The inhibitors exhibited the advantage of maintaining normal glucose homeostasis compared with atorvastatin. These findings reveal for the first time that the modulation of sphingolipid synthesis can effectively alleviate atherosclerosis progression by preventing lipid uptake and reducing inflammatory responses in the arterial walls.

Cilostazol ameliorates ischemia/reperfusion-induced tight junction disruption in brain endothelial cells by inhibiting endoplasmic reticulum stress.

Endoplasmic reticulum (ER) stress is essential for brain ischemia/reperfusion (I/R) injury. However, whether it contributes to I/R-induced blood-brain barrier (BBB) injury remains unclear. cilostazol exerts protective effects toward I/R-induced BBB injury, with unclear mechanisms. This study explored the potential role of ER stress in I/R-induced endothelial cell damage and determined whether the therapeutic potential of cilostazol, with respect to I/R-induced endothelial cell damage, is related to inhibition of ER stress. We found that exposing brain endothelial cells (bEnd.3) to oxygen-glucose deprivation/reoxygenation (OGD/R) significantly activated ER stress and diminished the barrier function of cell monolayers; treatment with the ER stress inhibitor 4-phenylbutyric acid (4-PBA) or cilostazol prevented OGD/R-induced ER stress and preserved barrier function. Furthermore, OGD/R induced the expression and secretion of matrix metalloproteinase-9 and nuclear translocation of phosphorylated NF-κB. These changes were partially reversed by 4-PBA or cilostazol treatment. In vivo, 4-PBA or cilostazol significantly attenuated I/R-induced ER stress and ameliorated Evans blue leakage and tight junction loss. These results demonstrate that I/R-induced ER stress participates in BBB disruption. Targeting ER stress could be a useful strategy to protect the BBB from ischemic stroke, and cilostazol is a promising therapeutic agent for this process.-Nan, D., Jin, H., Deng, J., Yu, W., Liu, R., Sun, W., Huang, Y. Cilostazol ameliorates ischemia/reperfusion-induced tight junction disruption in brain endothelial cells by inhibiting endoplasmic reticulum stress.