Annexin A2 combined with TTK accelerates esophageal cancer progression via the Akt/mTOR signaling pathway.

Annexin A2 (ANXA2) is a widely reported oncogene. However, the mechanism of ANXA2 in esophageal cancer is not fully understood. In this study, we provided evidence that ANXA2 promotes the progression of esophageal squamous cell carcinoma (ESCC) through the downstream target threonine tyrosine kinase (TTK). These results are consistent with the up-regulation of ANXA2 and TTK in ESCC. In vitro experiments by knockdown and overexpression of ANXA2 revealed that ANXA2 promotes the progression of ESCC by enhancing cancer cell proliferation, migration, and invasion. Subsequently, animal models also confirmed the role of ANXA2 in promoting the proliferation and metastasis of ESCC. Mechanistically, the ANXA2/TTK complex activates the Akt/mTOR signaling pathway and accelerates epithelial-mesenchymal transition (EMT), thereby promoting the invasion and metastasis of ESCC. Furthermore, we identified that TTK overexpression can reverse the inhibition of ESCC invasion after ANXA2 knockdown. Overall, these data indicate that the combination of ANXA2 and TTK regulates the activation of the Akt/mTOR pathway and accelerates the progression of ESCC. Therefore, the ANXA2/TTK/Akt/mTOR axis is a potential therapeutic target for ESCC.

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.

Role of Non-Receptor-Type Tyrosine Phosphatases in Brain-Related Diseases.

The non-receptor protein tyrosine phosphatase is a class of enzymes that catalyze the dephosphorylation of phosphotyrosines in protein molecules. They are involved in cellular signaling by regulating the phosphorylation status of a variety of receptors and signaling molecules within the cell, thereby influencing cellular physiological and pathological processes. In this article, we detail multiple non-receptor tyrosine phosphatase and non-receptor tyrosine phosphatase genes involved in the pathological process of brain disease. These include PTPN6, PTPN11, and PTPN13, which are involved in glioma signaling; PTPN1, PTPN5, and PTPN13, which are involved in the pathogenesis of Alzheimer's disease Tau protein lesions, PTPN23, which may be involved in the pathogenesis of Epilepsy and PTPN1, which is involved in the pathogenesis of Parkinson's disease. The role of mitochondrial tyrosine phosphatase in brain diseases was also discussed. Non-receptor tyrosine phosphatases have great potential for targeted therapies in brain diseases and are highly promising research areas.

Construction of lung cancer serum markers based on ReliefF feature selection.

Serum miRNAs are available clinical samples for cancer screening. Identifying early serum markers in lung cancer (LC) is essential for patients' early diagnosis and clinical treatment. Expression data of serum miRNAs of lung adenocarcinoma (LUAD) patients and healthy individuals were downloaded from the Gene Expression Omnibus (GEO). These data were normalized and subjected to differential expression analysis to obtain differentially expressed miRNAs (DEmiRNAs). The DEmiRNAs were subsequently subjected to ReliefF feature selection, and subsets closely related to cancer were screened as candidate feature miRNAs. Thereafter, a Gaussian Naive Bayes (NB), Support Vector Machine (SVM), and Random Forest (RF) classifier were constructed based on these candidate feature miRNAs. Then the best diagnostic signature was constructed through NB combined with incremental feature selection (IFS). Thereafter, these samples were subjected to principal component analysis (PCA) based on miRNAs with optimal predictive performance. Finally, the peripheral serum miRNAs of 64 LUAD patients and 59 normal individuals were extracted for qRT-PCR analysis to validate the performance of the diagnostic model in respect of clinical detection. Finally, according to area under the curve (AUC) and accuracy values, the NB classifier composed of miR-5100 and miR-663a manifested the most outstanding diagnostic performance. The PCA results also revealed that the 2-miRNA diagnostic signature could effectively distinguish cancer patients from healthy individuals. Finally, qRT-PCR results of clinical serum samples revealed that miR-5100 and miR-663a expression in tumor samples was remarkably higher than that in normal samples. The AUC of the 2-miRNA diagnostic signature was 0.968. In summary, we identified markers (miR-5100 and miR-663a) in serum for early LUAD screening, providing ideas for developing early LUAD diagnostic models.

SNHG15 enhances cisplatin resistance in lung adenocarcinoma by affecting the DNA repair capacity of cancer cells.

BACKGROUND: Lung adenocarcinoma (LUAD) is a prevalent malignancy. SNHG15 has been demonstrated to be oncogenic in many kinds of cancers, however the mechanism of SNHG15 in LUAD cisplatin (DDP) resistance remains unclear. In this study, we demonstrated the effect of SNHG15 on DDP resistance in LUAD and its related mechanism. METHODS: Bioinformatics analysis was adopted to assess SNHG15 expression in LUAD tissues and predict the downstream genes of SNHG15. The binding relationship between SNHG15 and downstream regulatory genes was proved through RNA immunoprecipitation, chromatin immunoprecipitation and dual-luciferase reporter assays. Cell counting kit-8 assay was adopted to evaluate LUAD cell viability, and gene expression was determined by Western blot and quantitative real-time polymerase chain reaction. We then performed comet assay to assess DNA damage. Cell apoptosis was detected by Tunnel assay. Xenograft animal models were created to test the function of SNHG15 in vivo. RESULTS: SNHG15 was up-regulated in LUAD cells. Moreover, SNHG15 was also highly expressed in drug-resistant LUAD cells. Down-regulated SNHG15 strengthened the sensitivity of LUAD cells to DDP and induced DNA damage. SNHG15 could elevate ECE2 expression through binding with E2F1, and it could induce DDP resistance by modulating the E2F1/ECE2 axis. In vivo experiments verified that the SNHG15 could enhance DDP resistance in LUAD tissue. CONCLUSION: The results suggested that SNHG15 could up-regulate ECE2 expression by recruiting E2F1, thereby enhancing the DDP resistance of LUAD.

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.

Connexin43 promotes angiogenesis through activating the HIF-1α/VEGF signaling pathway under chronic cerebral hypoperfusion.

Chronic cerebral hypoperfusion, a major vascular contributor to vascular cognitive impairment and dementia, can exacerbate small vessel pathology. Connexin43, the most abundant gap junction protein in brain tissue, has been found to be critically involved in the pathological changes of vascular cognitive impairment and dementia caused by chronic cerebral hypoperfusion. However, the precise mechanisms underpinning its role are unclear. We established a mouse model via bilateral common carotid arteries stenosis on connexin43 heterozygous male mice and demonstrated that connexin43 improves brain blood flow recovery by mediating reparative angiogenesis under chronic cerebral hypoperfusion, which subsequently reduces the characteristic pathologies of vascular cognitive impairment and dementia including white matter lesions and irreversible neuronal injury. We additionally found that connexin43 mediates hypoxia inducible factor-1α expression and then activates the PKA signaling pathway to regulate vascular endothelial growth factor-induced angiogenesis. All the above findings were replicated in bEnd.3 cells treated with 375 µM CoCl2in vitro. These results suggest that connexin 43 could be instrumental in developing potential therapies for vascular cognitive impairment and dementia caused by chronic cerebral hypoperfusion.

The effect of different atmosphere absolute hyperbaric oxygen on the expression of extracellular histones after traumatic brain injury in rats.

By observing the dynamic changes of extracellular histones H1, H2A, H4, and NF-κB expression in brain tissues after brain injury in rats, we explore the association among the expression of extracellular histones H1, H2A, H4, and NF-κB following traumatic brain injury (TBI), as well as the effect of different atmospheres absolute hyperbaric oxygen (HBO) intervention on the expression and possible mechanisms. A total of 120 SD rats were randomly divided into 4 groups: Sham-operated (SH), TBI (traumatic brain injury) group, traumatic brain injury and hyperbaric oxygen treatment 1.6ATA (TBI + HBO1) group, and traumatic brain injury and hyperbaric oxygen treatment2.2ATA (TBI + HBO2) group, with 30 rats in each group. The rats in each group were then randomly divided into five smaller time-specific sub-groups: 3 h, 6 h, 12 h, 24 h, and 48 h after surgery. TBI models were established, and the brain tissue around the lesion was taken at different time points. On the one hand,we detected the level of local histones H1, H2A, H4, and NF-κB by RT-PCR and Western Blot. On the other hand, we used immunohistochemical methods to detect the expression of NF-κB, while using the TUNEL method to observe the cell apoptosis in experimental groups after brain injury. Extracellular histones H1, H2A, H4, and NF-κB proteins were highly expressed at 3 h, then with a slight fluctuation, reached to peak at 48 h after the injury. HBO can affect the expression of histones H1, H2A, H4, and NF-κB. The decline of each indicator in the 1.6ATA group was significantly lower than that in the 2.2ATA group, especially within 6 h (P < 0. 05). In addition, NF-κB expression was consistent with the pathological changes of apoptosis in experimental groups. Hyperbaric oxygen therapy with relatively low pressure (1.6ATA) at the early stage can significantly inhibit the expression of extracellular histones H1, H2A, H4, and NF-κB around the lesion, reduce the apoptosis of nerve cells, and thus play an important role in alleviating secondary brain injury.

The Role of T Follicular Helper Cells and T Follicular Regulatory Cells in the Pathogenesis of Autoimmune Hemolytic Anemia.

Autoimmune hemolytic anemia (AIHA) is an acquired autoimmune disease mediated by antibodies against the patient's red blood cells. However, the underlying mechanisms for antibody production are not fully understood. Previous studies of etiology and pathogenesis of AIHA mainly focus on autoreactive B cells that have escaped tolerance mechanisms. Few studies have reported the function of TFH and TFR cells in the process of AIHA. The present study aimed to explore the potential mechanism of TFH and TFR cells in the pathogenesis of AIHA. With the model of murine AIHA, increased ratios of TFH:TFR, elevated serum IL-21 and IL-6 levels, and upregulated Bcl-6 and c-Maf expression were reported. Also, adoptive transfer of purified CD4+CXCR5+CD25- T cells from immunized mice promoted the induction of autoantibody in the AIHA mouse model. Altogether, our data demonstrate the important role of TFH cells for control and induction of AIHA. In the light of the key contributions of TFH cells to the immune response in AIHA, strategies aimed at inhibiting the TFH development or function should be emphasized.

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.

Neuromyelitis optica spectrum disorder coincident with renal clear cell carcinoma: A case report.

RATIONALE: Detection of aquaporin-4 (AQP4) antibody in cerebrospinal fluid (CSF) was not suggested for the diagnosis of neuromyelitis opica spectrum disorders (NMOSD). However, some patients with NMOSD have only AQP4 antibody positive in CSF but not in serum with unknown cause. Besides, it is rarely reported that NMOSD complicated with renal clear cell carcinoma. So, the relationship between AQP4-Ab, NMOSD and malignant tumors warrants an investigation. PATIENTS CONCERNS: A 31-year-old female presented in our hospital with chief complaints of urinary retention and weakness in bilateral lower extremities for more than 10 days. DIAGNOSES: The patient was diagnosed as NMOSD by neuroimaging and laboratory examination, with AQP4 antibody positive only in CSF. Besides, asymptomatic clear cell carcinoma was also found in left kidney. INTERVENTIONS: The patient underwent 2-month immunosuppressive therapy for NMOSD at first, including intravenous administration of immunoglobulin (IVIG) and methylprednisone, with oral drugs of predisone and tacrolimus. After that, Partial nephrectomy of left kidney was performed. OUTCOMES: The patient demonstrated almost complete remission for NMOSD after immunosuppressive therapy, and the renal tumor was cured by partial nephrectomy. LESSON: This case indicates that neuromyelitis optica (NMO)-IgG positive only in CSF could have potential association with the etiology of NMOSD, and renal clear cell carcinoma could be found complicated with NMOSD coincidently. Besides, it is necessary to examine NMO-IgG in CSF for patients suspicious with NMOSD, even when the serum test is negative, especially for those with complicated malignant tumors.

A near-infrared fluorescent probe for rapid detection of carbon monoxide in living cells.

A near-infrared (NIR) and colorimetric fluorescent probe system was developed for Carbon Monoxide (CO) via a Pd0-mediated Tsuji-Trost reaction. In this probe, phenoxide anion formation (DPCO-) was acted as the signal unit and an allyl carbonate group was used as the recognition unit. This non-fluorescent probe molecule can release the relevant fluorophore after conversion of Pd2+ to Pd0 by CO. The probe system including probe 1 and Pd2+ can be used for "naked-eye" detection of CO, and exhibited high selectivity to CO over various other sensing objects. More importantly, the probe system has great potential for fluorescence imaging of intracellular CO in living cells.

An optical sensing composite for cysteine detection using up-conversion nanoparticles and a rhodamine-derived chemosensor: Construction, characterization, photophysical feature and sensing performance.

In this paper, we reported an optical sensing composite for cysteine detection. A chemosensor derived from rhodamine 6G was synthesized and characterized. To minimize its photobleaching, up-conversion nanocrystals ß-NaYF4:Yb(3+)/Er(3+) were prepared and modified with α-cyclodextrin, serving as excitation host. Under 980nm laser excitation, emission of these up-conversion nanocrystals overlapped well with the absorption of our chemosensor. Energy transfer between them was analyzed and confirmed by emission decay analysis. Job's analysis suggested that the complexation equilibrium between our chemosensor and cysteine was a simple one with binding stoichiometry of 1:1. A sensing system was constructed with up-conversion nanocrystals (modified with α-cyclodextrin) and this chemosensor. Emission "turn-on" effect was observed only for cysteine but immune to other competing amino acids and thiols, showing a good selectivity.

Modeled microgravity suppressed invasion and migration of human glioblastoma U87 cells through downregulating store-operated calcium entry.

Glioblastoma is the most common brain tumor and is characterized with robust invasion and migration potential resulting in poor prognosis. Previous investigations have demonstrated that modeled microgravity (MMG) could decline the cell proliferation and attenuate the metastasis potential in several cell lines. In this study, we studied the effects of MMG on the invasion and migration potentials of glioblastoma in human glioblastoma U87 cells. We found that MMG stimulation significantly attenuated the invasion and migration potentials, decreased thapsigargin (TG) induced store-operated calcium entry (SOCE) and downregulated the expression of Orai1 in U87 cells. Inhibition of SOCE by 2-APB or stromal interaction molecule 1 (STIM1) downregulation both mimicked the effects of MMG on the invasion and migration potentials in U87 cells. Furthermore, upregulation of Orai1 significantly weakened the effects of MMG on the invasion and migration potentials in U87 cells. Therefore, these findings indicated that MMG stimulation inhibited the invasion and migration potentials of U87 cells by downregulating the expression of Orai1 and sequentially decreasing the SOCE, suggesting that MMG might be a new potential therapeutic strategy in glioblastoma treatment in the future.