Impinging Flow Mediates Vascular Endothelial Cell Injury through the PKCα/ERK/PPARγ Pathway in vitro.

INTRODUCTION: This study aimed to elucidate the mechanisms underlying endothelial injury in the context of intracranial aneurysm formation and development, which are associated with vascular endothelial injury caused by hemodynamic abnormalities. Specifically, we focus on the involvement of PKCα, an intracellular signaling transmitter closely linked to vascular diseases, and its role in activating MAPK. Additionally, we investigate the protective effects of PPARγ, a vasculoprotective factor known to attenuate vascular injury by mitigating the inflammatory response in the vessel wall. METHODS: The study employs a modified T-chamber to replicate fluid flow conditions at the artery bifurcation, allowing us to assess wall shear stress effects on human umbilical vein endothelial cells in vitro. Through experimental manipulations involving PKCα knockdown and Ca2+ and MAPK inhibitors, we evaluated the phosphorylation status of PKCα, NF-κB, ERK5, ERK1/2, JNK1/2/3, and P38, as well as the expression levels of PPARγ, NF-κB, and MMP2 via Western blot analysis. The cellular localization of phosphorylated NF-κB was determined using immunofluorescence. RESULTS: Our results showed that impinging flow resulted in the activation of PKCα, followed by the phosphorylation of ERK5, ERK1/2, and JNK1/2/3, leading to a decrease in PPARγ expression, an increase in the expression of NF-κB and MMP2, and the induction of apoptotic injury. Inhibition of PKCα activation or knockdown of PKCα using shRNA leads to a suppression of ERK5, ERK1/2, JNK1/2/3, and P38 phosphorylation, an elevation in PPARγ expression, and a reduction in NF-κB and MMP2 expression, alleviated apoptotic injury. Furthermore, we observe that the regulation of PPARγ, NF-κB, and MMP2 expression is influenced by ERK5 and ERK1/2 phosphorylation, and activation of PPARγ effectively counteracts the elevated expression of NF-κB and MMP2. CONCLUSION: Our findings suggest that the PKCα/ERK/PPARγ pathway plays a crucial role in mediating endothelial injury under conditions of impinging flow, with potential implications for vascular diseases and intracranial aneurysm development.

Histomorphological and ultrastructural cadmium-induced kidney injuries and precancerous lesions in rats and screening for biomarkers.

Long-term exposure to cadmium (Cd) can severely damage the kidney, where orally absorbed Cd accumulates. However, the molecular mechanisms of Cd-induced kidney damage, especially the early biomarkers of Cd-induced renal carcinogenesis, are unclear. In the present study, we established a rat kidney injury model by intragastric administration of Cd to evaluate the morphological and biochemical aspects of kidney injury. We randomly divided Sprague-Dawley rats into control, low Cd (3 mg/kg), and high Cd (6 mg/kg) groups and measured biochemical indices associated with renal toxicity after 2, 4, and 8 weeks of treatment. The Cd-exposed mice had significantly higher Cd concentrations in blood and renal tissues as well as blood urea nitrogen (BUN), ß2-microglobulin (ß2-MG), urinary protein excretion, and tumor necrosis factor-α (TNF-α) levels. Furthermore, histopathological and transmission electron microscopy (TEM) observations revealed structural disruption of renal tubules and glomeruli after 8 weeks of exposure to the high Cd regimen. Besides, microarray technology experiments showed that Cd increased the expression of genes related to the chemical carcinogenesis pathway in kidney tissue. Finally, combining the protein-protein interaction (PPI) network of the Cd carcinogenesis pathway genes with the microarray and Comparative Toxicogenomics Database (CTD) results revealed two overlapping genes, CYP1B1 and UGT2B. Therefore, the combined molecular and bioinformatics experiments' results suggest that CYP1B1 and UGT2B are biomarkers of Cd-induced kidney injury with precancerous lesions.

Impinging Flow Induces Expression of Monocyte Chemoattractant Protein-1 in Endothelial Cells Through Activation of the c-Jun N-terminal Kinase/c-Jun/p38/c-Fos Pathway.

OBJECTIVE: Monocyte chemoattractant protein-1 (MCP-1) is an important regulator of the formation and development of intracranial aneurysms. This study explored the molecular mechanisms underlying the induction of MCP-1 and related inflammatory factors in human umbilical vein endothelial cells (HUVECs) under hemodynamic conditions. METHODS: A modified T chamber was used to simulate fluid flow at the bifurcation of the artery and wall shear stress on HUVECs in vitro. Changes in HUVECs were analyzed in response to impinging flow. And HUVECs without impinging flow were used as the control group. Protein expression levels of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), p38, activator protein-1, and MCP-1 were detected by Western blot, and the messenger RNA expression levels of MCP-1, interleukin (IL)-1ß, and IL-6 were determined by quantitative reverse transcription polymerase chain reaction. RESULTS: Under impinging flow, the phosphorylation levels of ERK, JNK, and p38, as well as the protein levels of MCP-1, c-Jun, and c-Fos, increased. The messenger RNA expression of MCP-1, IL-1ß, and IL-6 also increased in HUVECs. Pretreatment of the HUVECs with inhibitors of JNK and p38 significantly attenuated the increased expression of MCP-1, IL-1ß, and IL-6, while ERK inhibitors had no obvious effect. CONCLUSIONS: Under impinging flow, MCP-1 and inflammatory factors are regulated through the JNK/c-Jun/p38/c-Fos pathway and participate in EC inflammation.

The Notch Signaling Pathway Regulates Differentiation of NG2 Cells into Oligodendrocytes in Demyelinating Diseases.

NG2 cells are highly proliferative glial cells that can self-renew or differentiate into oligodendrocytes, promoting remyelination. Following demyelination, the proliferative and differentiation potentials of NG2 cells increase rapidly, enhancing their differentiation into functional myelinating cells. Levels of the transcription factors Olig1 and Olig2 increase during the differentiation of NG2 cells and play important roles in the development and repair of oligodendrocytes. However, the ability to generate new oligodendrocytes is hampered by injury-related factors (e.g., myelin fragments, Wnt and Notch signaling components), leading to failed differentiation and maturation of NG2 cells into oligodendrocytes. Here, we review Notch signaling as a negative regulator of oligodendrocyte differentiation and discuss the extracellular ligands, intracellular pathways, and key transcription factors involved.

Relationship Between Serum Fibrinogen Level and Depressive Symptoms in an Adult Population with Spinal Cord Injury: A Cross-Sectional Study.

PURPOSE: Depression is associated with an inflammatory immune response. There are minimal data regarding the association of inflammatory markers with depression in patients with spinal cord injury (SCI). We aimed to investigate the association of inflammatory markers with depression in middle-aged and elderly SCI patients. METHODS: Data were obtained from the Midlife in the United States (MIDUS) study, a longitudinal study of a representative sample of the adult population. We analyzed the associations of serum levels of fibrinogen, interleukin-6, tumor necrosis factor-ɑ, and C-reactive protein with depressive symptoms. RESULTS: The median participant age was 52.5 years; 44.9% of participants were men. Multivariate linear regression analyses showed that an increased serum fibrinogen level (Sß = 0.114, p = 0.005) was associated with higher Centre for Epidemiological Studies-Depression (CES-D) scores after adjustment for age, sex, body mass index (BMI), ethnicity, education, marital status, smoking, alcohol use, exercise, perceived stress score, and cardiovascular disease (CVD). Multivariate logistic regression analysis showed that an increased serum fibrinogen level was independently associated with a history of depression (odds ratio [OR] = 1.240, 95% confidence interval [CI] = 1.103-1.997, p = 0.012) and depressive symptoms (OR = 1.884, 95% CI = 1.165-2.499, p < 0.001; CES-D score ≥ 16) after adjustment for confounding factors. Stratified analysis revealed that the association between serum fibrinogen level and depressive symptoms was affected by antidepressant use. CONCLUSION: Serum fibrinogen level had a significantly positive association with depressive symptoms in middle-aged and elderly patients with SCI. Future longitudinal cohort studies should evaluate the possible use of serum fibrinogen for diagnosis of depression in SCI patients.

Potential Correlation Between Depression-like Behavior and the Mitogen-Activated Protein Kinase Pathway in the Rat Hippocampus Following Spinal Cord Injury.

BACKGROUND: Depression induced by spinal cord injury (SCI) has been demonstrated in clinical and experimental studies; it significantly impacts patients' lives and may be associated with changes in the hippocampus. However, the biological mechanisms underlying depression after SCI are unknown. The mitogen-activated protein kinase (MAPK) signaling pathway participates in potential mechanisms of depression; it is unknown whether this pathway plays a role in SCI-induced depression. METHODS: We applied an animal model of depression induced by SCI, established using an aneurysm clip, to determine whether MAPK activation in the hippocampus is associated with depression-like behavior. RESULTS: SCI led to depression-like behavior, such as anhedonia in the sucrose preference test, decreased number of crossings in the open field test, decreased body weight, and decreased immobility time in the forced swim test. Western blot analysis further showed that SCI significantly increased the levels of phosphorylated p38 MAPK and cleaved caspase-3 in the hippocampus and inhibited the phosphorylation of extracellular signal-related kinase 1/2 and c-Jun N-terminal kinase 1/2. In addition, there were significant negative correlations between depression-like behavior and phosphorylated extracellular signal-related kinase 1/2 and positive correlations between depression-like behavior and phosphorylated p38 MAPK and cleaved caspase-3. CONCLUSIONS: These findings suggest that the MAPK pathway in the rat hippocampus may be involved in the pathophysiology of depression induced by SCI.

Driving effect of BDNF in the spinal dorsal horn on neuropathic pain.

Neuropathic pain (NP) is caused by direct or indirect damage to the nervous system and is a common symptom of many diseases. The mechanisms underlying the onset and persistence of NP are unclear. Therefore, research concerning these mechanisms has become an important focus in the medical field. Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophic factor family of signaling molecules. BDNF is an important regulator of neuronal development, synaptic transmission, and cellular and synaptic plasticity, which are essential for nerve maintenance and repair. However, BDNF is upregulated in the spinal dorsal horn and can promote NP by activating glial cells, reducing inhibitory functions and enhancing excitement after nociceptive stimulation. This review considers the relationship between NP and BDNF signaling in the spinal dorsal horn and discusses potentially related pathological mechanisms.

Au Nanoparticles Modified with Pt, Ru and SnO2 as Electrocatalysts for Ethanol Oxidation Reaction in Acids.

The anodic reaction in direct ethanol fuel cells (DEFCs), ethanol oxidation reaction (EOR) faces challenges, such as incomplete electrooxidation of ethanol and high cost of the most efficient electrocatalyst, Pt in acidic media at low temperature. In this study, core-shell electrocatalysts with an Au core and Pt-based shell (Au@Pt) are developed. The Au core size and Pt shell thickness play an important role in the EOR activity. The Au size of 2.8 nm and one layer of Pt provide the most optimized performance, having 6 times higher peak current density in contrast to commercial Pt/C. SnO2 as a support also enhances the EOR activity of Au@Pt by 1.73 times. Further modifying the Pt shell with Ru atoms achieve the highest EOR current density that is 15 and 2.5 times of Pt/C and Au@Pt. Our results suggest the importance of surface modification in rational design of advanced electrocatalysts.

Clinical nomogram for predicting the survival of patients with cerebral anaplastic gliomas.

The present study aimed to develop an effective nomogram for predicting the overall survival (OS) of patients with cerebral anaplastic glioma (AG).This study included 1939 patients diagnosed with AG between 1973 and 2013 who were identified using the Surveillance, Epidemiology, and End Results database. A multivariate Cox regression analysis revealed that age, histology, tumor site, marital status, radiotherapy, and surgery were independent prognostic factors and, thus, these factors were selected to build a clinical nomogram. Harrell's concordance index (C-index) and a calibration curve were formulated to evaluate the discrimination and calibration of the nomogram using bootstrapping.A nomogram was developed to predict 5- and 9-year OS rates based on 6 independent prognostic factors identified in the training set: age, tumor site, marital status, histology, radiotherapy, and surgery (P < .05). The Harrell's concordance index values of the training and validation sets were 0.776 (0.759-0.793) and 0.766 (0.739-0.792), respectively. The calibration curve exhibited good consistency with the actual observation curve in both sets.Although the prognostic value of the World Health Organization (WHO) classification has been validated, we developed a novel nomogram based on readily available clinical variables in terms of demographic data, therapeutic modalities, and tumor characteristics to predict the survival of AG patients. When used in combination with the WHO classification system, this clinical nomogram can aid clinicians in making individualized predictions of AG patient survival and improving treatment strategies.

The Role of Circular RNAs in Brain Injury.

Circular RNAs are an increasingly important topic in non-coding RNA biology, drawing considerable attention in recent years. Accumulating evidence suggests a critical role for circular RNAs in both early and latent stages of disease pathogenesis. Circular RNAs are abundantly expressed in brain tissue, with significant implications for neural development and disease progression. Disruption of these processes, including those seen in response to brain injury, can have serious consequences such as hemiplegia, aphasia, coma, and death. In this review, we describe the role of circular RNAs in the context of brain injury and explore the potential connection between circular RNAs, brain hypoxic ischemic injury, ischemia-reperfusion injury, and traumatic injury.

Fluid Shear Stress Induces Endothelial Cell Injury via Protein Kinase C Alpha-Mediated Repression of p120-Catenin and Vascular Endothelial Cadherin In Vitro.

OBJECTIVE: The present study aimed to characterize the mechanism of fluid shear stress (FSS)-induced endothelial cell (EC) injury via protein kinase C alpha (PKCα)-mediated vascular endothelial cadherin (VE-cadherin) and p120-catenin (p120ctn) expression. METHODS: We designed a T chamber system that produced stable FSS on ECs in vitro. Human umbilical vein endothelial cells (HUVECs) in which PKCα was knocked down and normal HUVECs were cultured on the coverslips. FSS was impinged on these 2 types of ECs for 0 hours and 6 hours. The morphology and density of HUVECs were evaluated, and expression levels of phosphorylated PKCα, p120-catenin (p120ctn), VE-cadherin, phosphorylated p120ctn at S879 (p-S879p120ctn), and nuclear factor kappa B (NF-κB) were analyzed by Western blot. RESULTS: HUVECs exposed to FSS were characterized by a polygonal shape and decreased cell density. The phosphorylated PKCα level was increased under FSS at 6 hours (P < 0.05). In normal HUVECs during FSS, p120ctn and VE-cadherin were decreased, whereas p-S879p120ctn and NF-κB were increased, at 6 hours (P < 0.05). In HUVECs after PKCα knockdown, p120ctn and VE-cadherin were not significantly changed (P > 0.05), p-S879p120ctn was undetectable, but NF-κB was decreased (P < 0.05) at 6 hours. CONCLUSIONS: The possible mechanism of FSS-induced EC injury may be as follows: 1) PKCα induces low expression of p120ctn, which leads to activation of NF-κB and degradation of VE-cadherin; 2) PKCα-mediated phosphorylation of p120ctn at S879 disrupts p120ctn binding to VE-cadherin.

A Nomogram for Predicting Individual Prognosis of Patients with Low-Grade Glioma.

OBJECTIVE: The present study aimed to develop and evaluate a nomogram for predicting the overall survival (OS) of patients with low-grade glioma (LGG). METHODS: Patients with LGG diagnosed from 1973 to 2013 were identified using the Surveillance, Epidemiology, and End Results (SEER) database. A total of 3732 patients were randomly divided into a training set (n = 2612) and a validation set (n = 1120). Univariate and multivariate Cox regression analyses of the clinical variables were performed to screen for significant prognostic factors. Next, a nomogram that included significant prognostic variables was formulated to predict for LGG. Harrell's concordance index (C-index) and calibration plots were formulated to evaluate the reliability and accuracy of the nomogram using bootstrapping according to the internal (training set) and external (validation set) validity. RESULTS: A nomogram was developed to predict the 5- and 9-year OS rates using 7 variables in the training set: age, tumor site, sex, marital status, histological type, tumor size, and surgery (P < 0.05). The C-index for internal validation, which the nomogram used to predict OS according to the training set, was 0.777 (range, 0.763-0.791), and the C-index for external validation (validation set) was 0.776 (range, 0.754-0.797). The results of the calibration plots showed that the actual observation and prediction values obtained by the nomogram had good consistency between the 2 sets. CONCLUSIONS: We have developed a ready-to-use nomogram model that includes clinical characteristics to predict OS. The nomogram might provide consultation and risk assessments for subsequent treatment of patients with LGG.