Classification and clinical significance of immunogenic cell death-related genes in Plasmodium falciparum infection determined by integrated bioinformatics analysis and machine learning.

BACKGROUND: Immunogenic cell death (ICD) is a type of regulated cell death that plays a crucial role in activating the immune system in response to various stressors, including cancer cells and pathogens. However, the involvement of ICD in the human immune response against malaria remains to be defined. METHODS: In this study, data from Plasmodium falciparum infection cohorts, derived from cross-sectional studies, were analysed to identify ICD subtypes and their correlation with parasitaemia and immune responses. Using consensus clustering, ICD subtypes were identified, and their association with the immune landscape was assessed by employing ssGSEA. Differentially expressed genes (DEGs) analysis, functional enrichment, protein-protein interaction networks, and machine learning (least absolute shrinkage and selection operator (LASSO) regression and random forest) were used to identify ICD-associated hub genes linked with high parasitaemia. A nomogram visualizing these genes' correlation with parasitaemia levels was developed, and its performance was evaluated using receiver operating characteristic (ROC) curves. RESULTS: In the P. falciparum infection cohort, two ICD-associated subtypes were identified, with subtype 1 showing better adaptive immune responses and lower parasitaemia compared to subtype 2. DEGs analysis revealed upregulation of proliferative signalling pathways, T-cell receptor signalling pathways and T-cell activation and differentiation in subtype 1, while subtype 2 exhibited elevated cytokine signalling and inflammatory responses. PPI network construction and machine learning identified CD3E and FCGR1A as candidate hub genes. A constructed nomogram integrating these genes demonstrated significant classification performance of high parasitaemia, which was evidenced by AUC values ranging from 0.695 to 0.737 in the training set and 0.911 to 0.933 and 0.759 to 0.849 in two validation sets, respectively. Additionally, significant correlations between the expressions of these genes and the clinical manifestation of P. falciparum infection were observed. CONCLUSION: This study reveals the existence of two ICD subtypes in the human immune response against P. falciparum infection. Two ICD-associated candidate hub genes were identified, and a nomogram was constructed for the classification of high parasitaemia. This study can deepen the understanding of the human immune response to P. falciparum infection and provide new targets for the prevention and control of malaria.

Astrocyte-derived lactoferrin reduces ß-amyloid burden by promoting the interaction between p38 kinase and PP2A phosphatase in male APP/PS1 transgenic mice.

BACKGROUND AND PURPOSE: Overexpression of astrocytic lactoferrin (Lf) was observed in the brain of Alzheimer's disease (AD) patients, whereas the role of astrocytic Lf in AD progression remains unexplored. In this study, we aimed to evaluate the effects of astrocytic Lf on AD progression. EXPERIMENTAL APPROACH: Male APP/PS1 mice with astrocytes overexpressing human Lf were developed to evaluate the effects of astrocytic Lf on AD progression. N2a-sw cells also were employed to further uncover the mechanism of astrocytic Lf on ß-amyloid (Aß) production. KEY RESULTS: Astrocytic Lf overexpression increased protein phosphatase 2A (PP2A) activity and reduced amyloid precursor protein (APP) phosphorylation, Aß burden and tau hyperphosphorylation in APP/PS1 mice. Mechanistically, astrocytic Lf overexpression promoted the uptake of astrocytic Lf into neurons in APP/PS1 mice, and conditional medium from astrocytes overexpressing Lf inhibited p-APP (Thr668) expression in N2a-sw cells. Furthermore, recombinant human Lf (hLf) significantly enhanced PP2A activity and inhibited p-APP expression, whereas inhibition of p38 or PP2A activities abrogated the hLf-induced p-APP down-regulation in N2a-sw cells. Additionally, hLf promoted the interaction of p38 and PP2A via p38 activation, thereby enhancing PP2A activity, and low-density lipoprotein receptor-related protein 1 (LRP1) knockdown significantly reversed the hLf-induced p38 activation and p-APP down-regulation. CONCLUSIONS AND IMPLICATIONS: Our data suggested that astrocytic Lf promoted neuronal p38 activation, via targeting to LRP1, subsequently promoting p38 binding to PP2A to enhance PP2A enzyme activity, which finally inhibited Aß production via APP dephosphorylation. In conclusion, promoting astrocytic Lf expression may be a potential strategy against AD. LINKED ARTICLES: This article is part of a themed issue From Alzheimer's Disease to Vascular Dementia: Different Roads Leading to Cognitive Decline. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.6/issuetoc.

Enzastaurin cardiotoxicity: QT interval prolongation, negative inotropic responses and negative chronotropic action.

Several clinical trials observed that enzastaurin prolonged QT interval in cancer patients. However, the mechanism of enzastaurin-induced QT interval prolongation is unclear. Therefore, this study aimed to assess the effect and mechanism of enzastaurin on QT interval and cardiac function. The Langendorff and Ion-Optix MyoCam systems were used to assess the effects of enzastaurin on QT interval, cardiac systolic function and intracellular Ca2+ transient in guinea pig hearts and ventricular myocytes. The effects of enzastaurin on the rapid delayed rectifier (IKr), the slow delayed rectifier K+ current (IKs), transient outward potassium current (Ito), action potentials, Ryanodine Receptor 2 (RyR2) and the sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a (SERCA2a) expression and activity in HEK 293 cell system and primary cardiomyocytes were investigated using whole-cell recording technique and western blotting. We found that enzastaurin significantly prolonged QT interval in guinea pig hearts and increased the action potential duration (APD) in guinea pig cardiomyocytes in a dose-dependent manner. Enzastaurin potently inhibited IKr by binding to the human Ether-à-go-go-Related gene (hERG) channel in both open and closed states, and hERG mutant channels, including S636A, S631A, and F656V attenuated the inhibitory effect of enzastaurin. Enzastaurin also moderately decreased IKs. Additionally, enzastaurin also induced negative chronotropic action. Moreover, enzastaurin impaired cardiac systolic function and reduced intracellular Ca2+ transient via inhibition of RyR2 phosphorylation. Taken together, we found that enzastaurin prolongs QT, reduces heart rate and impairs cardiac systolic function. Therefore, we recommend that electrocardiogram (ECG) and cardiac function should be continuously monitored when enzastaurin is administered to cancer patients.

Multicohort transcriptome analysis of whole blood identifies robust human response signatures in Plasmodium falciparum infections.

BACKGROUND: To understand how Plasmodium falciparum malaria is controlled, it is essential to elucidate the transcriptomic responses of the human host in naturally-exposed populations. Various individual studies of the human transcriptomic responses to naturally transmitted P. falciparum infections have been reported with varying results. Multicohort gene expression analysis by aggregating data from diverse populations into a single analysis will increase the reproducibility and reliability of the results. METHODS: In this study, discovery cohorts GSE1124-GPL96, GSE34404, GSE117613, and validation cohort GSE35858 were obtained from the Gene Expression Omnibus. A meta-analysis using data from the multicohort studies was performed to identify the differentially expressed genes (DEGs) between malaria-infected and noninfected individuals using the MetaIntegrator R package. Subsequently, the protein-protein interaction (PPI) networks of the DEGs were constructed using Cytoscape software. Significant modules were selected, and the hub genes were identified using the CytoHubba and MCODE plug-ins. Multicohort WGCNA was conducted to find a correlation between modules and malaria infection. Furthermore, the immune cell profile of the peripheral blood in different groups was identified using ssGSEA. RESULTS: These analyses reveal that neutrophil activation, neutrophil-mediated immunity, and neutrophil degranulation are involved in the human response to natural malaria infection. However, neutrophil cell enrichment and activation were not significantly different between mild malaria and severe malaria groups. Malaria infection also downregulates host genes in ribosome synthesis and protein translation and upregulates host cell division-related genes. Furthermore, immune cell profiling analysis shows that activated dendritic cells and type 2 T helper cells are upregulated, while activated B cells, immature B cells, and monocytes are downregulated in the malaria-infected patients relative to the noninfected individuals. Significantly higher enrichment of activated dendritic cell-related genes and significantly lower enrichment of monocyte-related genes are also observed in the peripheral blood of the severe malaria group than in the mild malaria group. CONCLUSION: These results reveal important molecular signatures of host responses to malaria infections, providing some bases for developing malaria control strategies and protective vaccines.

Toripalimab combined with targeted therapy and chemotherapy achieves pathologic complete response in gastric carcinoma: A case report.

BACKGROUND: Neoadjuvant or perioperative chemotherapy combined with surgery can reduce postoperative recurrence and improve the long-term survival rate of patients with locally advanced resectable gastric carcinoma. Nivolumab combined with chemotherapy has been recommended by the National Comprehensive Cancer Network guidelines as a first-line therapy for advanced gastric carcinoma/ adenocarcinoma of the gastroesophageal junction and serves as the basis for immunotherapy combined with chemotherapy to become a neoadjuvant therapy. Herein, we report a case in which pathologic complete response was achieved by neoadjuvant administration of toripalimab, Herceptin, and docetaxel, oxaliplatin, calcium folinate, and fluorouracil (FLOT) chemotherapy followed by surgery for human epidermal growth factor receptor 2 (HER2)- and programmed death-ligand 1 (PD-L1)-positive locally advanced gastric carcinoma. We hope that this case will shed some light on neoadjuvant therapy for gastric carcinoma. CASE SUMMARY: The patient was diagnosed with locally advanced adenocarcinoma of the cardia. Immunohistochemistry of the baseline tissues suggested that the tissues were HER2- (fluorescent in situ hybridization) and PD-L1-positive (combined positive score = 1). The patient underwent surgery following a four-cycle neoadjuvant therapy comprising Herceptin, toripalimab, and FLOT chemotherapy. The postoperative pathological findings showed mild atypical hyperplasia of the local glands with chronic mucosal inflammation (proximal stomach), no clear residual tumor (tumor regression grade 0), no regional lymph node metastasis, and negative upper and lower cut ends. The levels of tumor markers were reduced to normal levels after re-examination. With good postoperative recovery, the four-cycle preoperative chemotherapy was continued at the same dosage as that previously administered. After the treatment, the patient was monitored every 3 mo with a follow-up of 12 mo (4 times). As of February 27, 2022, he was in a good condition without disease progression. The clinical trial registration number is E2019401. CONCLUSION: There are many ongoing studies on neoadjuvant immunotherapy combined with chemotherapy or radiotherapy; however, most of these studies are phase II studies with small cohorts. According to the results of some current studies, these combined regimens have shown promising results in terms of efficacy and safety. However, the clinical efficacy and safety of the neoadjuvant therapies used in these combined regimens need to be confirmed by additional prospective phase III clinical trials, and further exploration of molecular markers for effective populations is required.

Astrocyte-specific loss of lactoferrin influences neuronal structure and function by interfering with cholesterol synthesis.

Growing evidence indicates that circulating lactoferrin (Lf) is implicated in peripheral cholesterol metabolism disorders. It has emerged that the distribution of Lf changes in astrocytes of aging brains and those exhibiting neurodegeneration; however, its physiological and/or pathological role remains unknown. Here, we demonstrate that astrocyte-specific knockout of Lf (designated cKO) led to decreased body weight and cognitive abnormalities during early life in mice. Accordingly, there was a reduction in neuronal outgrowth and synaptic structure in cKO mice. Importantly, Lf deficiency in the primary astrocytes led to decreased sterol regulatory element binding protein 2 (Srebp2) activation and cholesterol production, and cholesterol content in cKO mice and/or in astrocytes was restored by exogenous Lf or a Srebp2 agonist. Moreover, neuronal dendritic complexity and total dendritic length were decreased after culture with the culture medium of the primary astrocytes derived from cKO mice and that this decrease was reversed after cholesterol supplementation. Alternatively, these alterations were associated with an activation of AMP-activated protein kinase (AMPK) and inhibition of SREBP2 nuclear translocation. These data suggest that astrocytic Lf might directly or indirectly control in situ cholesterol synthesis, which may be implicated in neurodevelopment and several neurological diseases.

Kai-Xin-San Inhibits Tau Pathology and Neuronal Apoptosis in Aged SAMP8 Mice.

Alzheimer's disease (AD) is an age-related neurological disorder. Currently, there is no effective cure for AD due to its complexity in pathogenesis. In light of the complex pathogenesis of AD, the traditional Chinese medicine (TCM) formula Kai-Xin-San (KXS), which was used for amnesia treatment, has been proved to improve cognitive function in AD animal models. However, the active ingredients and the mechanism of KXS have not yet been clearly elucidated. In this study, network pharmacology analysis predicts that KXS yields 168 candidate compounds acting on 863 potential targets, 30 of which are associated with AD. Enrichment analysis revealed that the therapeutic mechanisms of KXS for AD are associated with the inhibition of Tau protein hyperphosphorylation, inflammation, and apoptosis. Therefore, we chose 7-month-old senescence-accelerated mouse prone 8 (SAMP8) mice as AD mouse model, which harbors the behavioral and pathological hallmarks of AD. Subsequently, the potential underlying action mechanisms of KXS on AD predicted by the network pharmacology analyses were experimentally validated in SAMP8 mice after intragastric administration of KXS for 3 months. We observed that KXS upregulated AKT phosphorylation, suppressed GSK3ß and CDK5 activation, and inhibited the TLR4/MyD88/NF-κB signaling pathway to attenuate Tau hyperphosphorylation and neuroinflammation, thus suppressing neuronal apoptosis and improving the cognitive impairment of aged SAMP8 mice. Taken together, our findings reveal a multi-component and multi-target therapeutic mechanism of KXS for attenuating the progression of AD, contributing to the future development of TCM modernization, including KXS, and broader clinical application.

Differences in transcriptomic and metabolomic analyses of metabolites of shoots on tea plants of different ages and relevant regulatory network.

To investigate differences in fresh leaves of tea plants at different ages in gene expression, metabolism, and dried tea quality, and to provide references to a deep exploration on metabolite differential accumulation of fresh leaves of tea plants at different ages as well as the regulation mechanism, two groups of fresh leaves from tea plants at different ages (group JP: 20-, 200-, and 1,200-year tea plants; group YX: 50-, 100-, and 400-year tea plants) were chosen as materials, and their differences in gene expression, metabolites, and metabolic regulatory network were investigated by transcriptomics and metabolomics. A total of 12,706 differentially expressed genes (DEGs) were screened from the fresh tea leaves in the JP group, of which tea-20 vs. tea-200 had the largest number of DEGs, up to 9,041 (4,459 down-regulated genes, 4,582 up-regulated genes). A total of 644 common genes in the fresh leaves of three different ages of tea plants in the JP group were differentially expressed. A total of 8,971 DEGs were screened from the fresh leaf samples of tea plants in the YX group, of which the number of DEGs obtained in the tea-50 vs. tea-400 comparison combination was the largest with a total of 3,723 (1,722 up-regulated genes and 2,001 down-regulated genes). A total of 147 common genes were differentially expressed in the fresh leaves of three different tree ages in the YX group. The pathway enrichment analysis showed that most up-regulated DEGs and their related metabolic pathways were similar in the two groups, and that the metabolic pathways of common significant enrichment included flavonoid biosynthesis, phenylpropane biosynthesis, carbon metabolism, amino acid biosynthesis, and plant pathogen interaction. The metabolomics results showed that 72 and 117 different metabolites were screened from the JP and YX groups, respectively. Most of the different metabolites in the two groups were flavonoids, phenolic acids, amino acids, and their derivatives. Among them, the number of down-regulated flavonoids in older tea plants is generally higher than the number of up-regulated flavonoids. Moreover, according to the sensory evaluation results of dried tea of fresh leaves from tea plants of different ages, tea-1200 and tea-400 showed the highest sensory evaluation scores in their groups. With increase in plant age, the fragrance of the tea was more elegant, and it changed from a dense scent to a faint scent; the tea tasted sweet and its freshness increased, while the sense of astringency was weakened and the concentration declined. Therefore, the quality difference of tea of different tree ages is mainly related to secondary metabolic pathways such as the flavonoid biosynthesis pathway. With increase in tea age, a large number of gene expression in the flavonoid biosynthesis pathway is down-regulated, which reduces the content of bitter flavonoid substances in fresh leaves and makes tea soup more mellow.

Knowledge mapping of alternative splicing of cancer from 2012 to 2021: A bibliometric analysis.

Background: As a processing method of RNA precursors, alternative splicing (AS) is critical to normal cellular activities. Aberrant AS events are associated with cancer development and can be promising targets to treat cancer. However, no detailed and unbiased study describes the current state of AS of cancer research. We aim to measure and recognize the current state and trends of AS cancer research in this study. Methods: The Web of Science Core Collection was used to acquire the articles. Utilizing three bibliometric tools (CiteSpace, VOSviewer, R-bibliometrix), we were able to measure and recognize the influence and collaboration data of individual articles, journals, and co-citations. Analysis of co-occurrence and burst information helped us identify the trending research areas related to AS of cancer. Results: From 2012 to 2021, the total number of papers on AS of cancer published in 766 academic journals was 3,507, authored by 20,406 researchers in 405 institutions from 80 countries/regions. Research involving AS of cancer genes was primarily conducted in the United States and China; simultaneously, the Chinese Academy of Sciences, Fudan University, and National Cancer Institute were the institutions with strong research capabilities. Scorilas Andreas is the scholar with the most publications, while the most co-citations were generated by Wang, Eric T. Plos One published the most papers on AS of cancer, while J Biol Chem was the most co-cited academic journal in this field. The results of keyword co-occurrence analysis can be divided into three types: molecular (P53, CD44, androgen receptor, srsf3, esrp1), pathological process (apoptosis, EMT, metastasis, angiogenesis, proliferation), and disease (breast cancer, colorectal cancer, prostate cancer, hepatocellular carcinoma, gastric cancer). Conclusion: Research on AS of cancer has been increasing in intensity over the past decade. Current AS of cancer studies focused on the hallmarks of AS in cancer and AS signatures including diagnostic and therapeutic targets. Among them, the current trends are splicing factors regulating epithelial-mesenchymal transition and other hallmarks, aberrant splicing events in tumors, and further mechanisms. These might give researchers interested in this field a forward-looking perspective and inform further research.

Interleukin-17A in Alzheimer's Disease: Recent Advances and Controversies.

Alzheimer's disease (AD) is a progressive neurodegenerative disease that mainly affects older adults. Although the global burden of AD is increasing year by year, the causes of AD remain largely unknown. Numerous basic and clinical studies have shown that interleukin-17A (IL-17A) may play a significant role in the pathogenesis of AD. A comprehensive assessment of the role of IL-17A in AD would benefit the diagnosis, understanding of etiology and treatment. However, over the past decade, controversies remain regarding the expression level and role of IL-17A in AD. We have incorporated newly published researches and point out that IL-17A expression levels may vary along with the development of AD, exercising different roles at different stages of AD, although much more work remains to be done to support the potential role of IL-17A in AD-related pathology. Here, it is our intention to review the underlying mechanisms of IL-17A in AD and address the current controversies in an effort to clarify the results of existing research and suggest future studies.

Activation of vitamin D receptor inhibits Tau phosphorylation is associated with reduction of iron accumulation in APP/PS1 transgenic mice.

Vitamin D deficiency and iron accumulation are prevalent in the brains of Alzheimer's disease (AD) patients, however, whether Vitamin D has a role in the regulations of iron metabolism in the condition of AD remains unknown. Our previous studies revealed that vitamin D deficiency promotes ß-amyloid (Aß) deposition in the APP/PS1 mouse brains, while supplemented with a specific agonist of vitamin D receptor (VDR), paricalcitol (PAL), significantly reduced Aß production via promoting the lysosomal degradation of ß-site APP cleavage enzyme 1 (BACE1). In this study, our data suggested that activation of VDR by PAL significantly reduced the iron accumulation in the cortex and hippocampus of APP/PS1 mice through downregulation of Transferrin receptor (TFR) by reducing iron-regulatory protein 2 (IRP2) expression. Furthermore, activation of VDR effectively reduced the phosphorylations of Tau at Ser396 and Thr181 sites via inhibiting the GSK3ß phosphorylation (Tyr216). Taken together, our data suggest that activation of VDR could inhibit the phosphorylations of Tau possibly by repressing the iron accumulation-induced upregulation of GSK3ß activity in the brains of APP/PS1 mice. Thus, activation of VDR may be an effective strategy for treating AD.

Solitary hyoid plasmacytoma with unicentric Castleman disease: A case report and review of literature.

BACKGROUND: Solitary plasmacytoma and unicentric Castleman disease (UCD) are rare lymphoproliferative disorders characterized by monoclonal plasma cells and a single set of locally enlarged lymph nodes, respectively. CASE SUMMARY: A 48-year-old Han Chinese man presented to our department with a neck mass and progressive foreign body sensation in his throat. 18F-FDG positron emission tomography revealed focally increased radioactivity centered around the hyoid, and computed tomography (CT) revealed osteolytic lesions. Histopathology revealed Castleman-like features and CD138/CD38-positive mature plasma cells. Systemic work-up ruled out the possibility of POEMS syndrome, lymphoma, and multiple myeloma, leading to a final diagnosis of solitary hyoid plasmacytoma with UCD. The patient underwent partial hyoid resection and selective neck dissection, followed by intensity-modulated radiotherapy. 99mTc-MDP single-photon emission computed tomography/CT reevaluation showed neither local recurrence nor distant bone metastasis at the 40-mo follow-up. CONCLUSION: The diagnostic process and differential diagnosis of this rare case provided valuable educational information to clinicians.

Mechanisms of gefitinib-induced QT prolongation.

Gefitinib, a tyrosine kinase inhibitor, was the first targeted therapy for non-small cell lung cancer (NSCLC). Gefitinib could block human Ether-à-go-go-Related Gene (hERG) channel, an important target in drug-induced long QT syndrome. However, it is unclear whether gefitinib could induce QT interval prolongation. Here, whole-cell patch-clamp technique was used for evaluating the effect of gefitinib on rapidly-activating delayed rectifier K+ current (IKr), slowly-activating delayed rectifier K+ current (IKs), transient outward potassium current (Ito), inward rectifier K+ current (IK1) and on action potentials in guinea pig ventricular myocytes. The Langendorff heart perfusion technique was used to determine drug effect on the ECG. Gefitinib depressed IKr by binding to open and closed hERG channels in a concentration-dependent way (IC50: 1.91 µM). The inhibitory effect of gefitinib on wildtype hERG channels was reduced at the hERG mutants Y652A, S636A, F656V and S631A (IC50: 8.51, 13.97, 18.86, 32.99 µM), indicating that gefitinib is a pore inhibitor of hERG channels. In addition, gefitinib accelerated hERG channel inactivation and decreased channel steady-state inactivation. Gefitinib also decreased IKs with IC50 of 23.8 µM. Moreover, gefitinib increased action potential duration (APD) in guinea pig ventricular myocytes and the corrected QT interval (QTc) in isolated perfused guinea pig hearts in a concentration-dependent way (1-30 µM). These findings indicate that gefitinib could prolong QTc interval by potently blocking hERG channel, modulating kinetic properties of hERG channel. Partial block of KCNQ1/KCNE1 could also contribute to delayed repolarization and prolonged QT interval. Thus, caution should be taken when gefitinib is used for NSCLC treatment.

Expression and significance of aquaporin-4 in thyroid carcinoma.

OBJECTIVE: To investigate the expression of aquaporin-4 (AQP4) in thyroid carcinoma (TC) and explore its clinical significance. MATERIALS AND METHODS: The formalin-fixed paraffin-embedded specimens including 275 TC cancer tissues, 258 corresponding paracancerous thyroid tissues and their clinicopathologic data were retrospectively analyzed. Immunohistochemical EnVision two-step method was used to detect the expression of AQP4 in the cancer tissues and adjacent thyroid tissues, and its clinical significance was analyzed. RESULTS: AQP4 could be expressed in both TC cancer tissues and paracancerous thyroid tissues. In TC cancer tissues, the positive expression rate was 99.3% (273/275), and the positive expression rate was 86.4% (223/258) in paracancerous thyroid tissues. The expression level of AQP4 in cancer tissues was significantly higher than that in paracancerous thyroid tissues, and the difference was statistically significant (P < 0.05). The positive expression rates of AQP4 in papillary thyroid carcinoma (PTC), follicular thyroid carcinoma (FTC), medullary thyroid carcinoma (MTC) and undifferentiated thyroid carcinoma (UTC) were 99.2% (258/260), 100.0% (6/6), 100.0% (6/6) and 100.0% (3/3), respectively and there was little difference in different types of TC. Analysis of relationship between expression level of AQP4 in 275 TC cancer tissues and 260 PTC cancer tissues and clinicopathologic characteristics of patients was not significant correlation (P > 0.05). Among the 275 patients, one (0.4%, 1/275) was diagnosed as neuromyelitis optica spectrum disorder (NMOSD) associated with TC. CONCLUSIONS: AQP4 is generally expressed in TC cancer tissues and paracancerous thyroid tissues. Expression level of AQP4 in cancer tissues was significantly higher than that in paracancerous thyroid tissue. Expression level of AQP4 in TC cancer tissues is not related to the clinicopathological characteristics of the patients. Paraneoplastic NMOSD caused by TC is rare, and whether its specific pathogenesis is related to the expression of AQP4 in TC still needs further study.

SIK2 represses AKT/GSK3ß/ß-catenin signaling and suppresses gastric cancer by inhibiting autophagic degradation of protein phosphatases.

Salt-inducible kinase 2 (SIK2) is an important regulator in various intracellular signaling pathways related to apoptosis, tumorigenesis and metastasis. However, the involvement of SIK2 in gastric tumorigenesis and the functional linkage with gastric cancer (GC) progression remain to be defined. Here, we report that SIK2 was significantly downregulated in human GC tissues, and reduced SIK2 expression was associated with poor prognosis of patients. Overexpression of SIK2 suppressed the migration and invasion of GC cells, whereas knockdown of SIK2 enhanced cell migratory and invasive capability as well as metastatic potential. These changes in the malignant phenotype resulted from the ability of SIK2 to suppress epithelial-mesenchymal transition via inhibition of AKT/GSK3ß/ß-catenin signaling. The inhibitory effect of SIK2 on AKT/GSK3ß/ß-catenin signaling was mediated primarily through inactivation of AKT, due to its enhanced dephosphorylation by the upregulated protein phosphatases PHLPP2 and PP2A. The upregulation of PHLPP2 and PP2A was attributable to SIK2 phosphorylation and activation of mTORC1, which inhibited autophagic degradation of these two phosphatases. These results suggest that SIK2 acts as a tumor suppressor in GC and may serve as a novel prognostic biomarker and therapeutic target for this tumor.

Vitamin D deficiency exacerbates Alzheimer-like pathologies by reducing antioxidant capacity.

Vitamin D (VD) deficiency is prevalent among aging people and Alzheimer's disease (AD) patients. However, the roles of VD deficiency in the pathology of AD remain largely unexplored. In this study, APP/PS1 mice were fed a VD-deficient diet for 13 weeks to evaluate the effects of VD deficiency on the learning and memory functions and the neuropathological characteristics of the mice. Our study revealed that VD deficiency accelerated cognitive impairment in the APP/PS1 mice. Mechanistic studies revealed that VD deficiency promoted glial activation and increased inflammatory factor secretion. Furthermore, VD deficiency increased the production and deposition of Aß by elevating the expression levels of amyloid precursor protein (APP) and ß-site APP cleavage enzyme 1 (BACE1). In addition, VD deficiency increased the phosphorylation of Tau at Thr181, Thr205 and Ser396 by increasing the activities of cyclin-dependent kinase 5 (CDK5) and glycogen synthase kinase 3α/ß (GSK3α/ß) and promoted synaptic dystrophy and neuronal loss. All these effects of VD deficiency may be ascribed to enhanced oxidative stress via the downregulation of superoxide dismutase 1 (SOD1), glutathione peroxidase 4 (GPx4) and cystine/glutamate exchanger (xCT). Taken together, our data suggest that VD deficiency exacerbates Alzheimer-like pathologies via promoting inflammatory stress, increasing Aß production and elevating Tau phosphorylation by decreasing antioxidant capacity in the brains of APP/PS1 mice. Hence, rescuing the VD status of AD patients should be taken into consideration during the treatment of AD.

α-Lipoic Acid Maintains Brain Glucose Metabolism via BDNF/TrkB/HIF-1α Signaling Pathway in P301S Mice.

The microtubule-associated protein tau is closely correlated with hypometabolism in Alzheimer's disease (AD). α-lipoic acid (LA), which is a naturally occurring cofactor in mitochondrial, has been shown to have properties that can inhibit the tau pathology and neuronal damage in our previous research. However, if LA affects glucose metabolism when it reverses tau pathology remains unclear, especially concerning the potential mechanism. Therefore, we make a further study using the P301S mouse model (a tauopathy and AD mouse model which overexpressing fibrillary tau) to gain a clear idea of the aforementioned problems. Here, we found chronic LA administration significantly increased glucose availability by elevating glucose transporter 3 (GLUT3), GLUT4, vascular endothelial growth factor (VEGF) protein and mRNA level, and heme oxygenase-1 (HO-1) protein level in P301S mouse brains. Meanwhile, we found that LA also promoted glycolysis by directly upregulating hexokinase (HK) activity, indirectly by increasing proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and DNA repair enzymes (OGG1/2 and MTH1). Further, we found the underlying mechanism of restored glucose metabolism might involve in the activation of brain-derived neurotrophic factor (BDNF)/tyrosine Kinase receptor B (TrkB)/hypoxia-inducible factor-1α (HIF-1α) signaling pathway by LA treatment.

Effect of ciRS-7 expression on clear cell renal cell carcinoma progression.

BACKGROUND: Circular RNA ciRS-7 has been reported to be involved in the progression of various cancers. However, ciRS-7 expression and its role in clear cell renal cell carcinoma (ccRCC) progression remains unclear. This study aimed to investigate the effect of ciRS-7 expression on ccRCC and the related signaling pathway. METHODS: ciRS-7 expression was analyzed using quantitative reverse transcription polymerase chain reaction in 87 pairs of ccRCC and matched adjacent normal tissues. The role of ciRS-7 in ccRCC cell proliferation and invasion was determined using the cell counting kit-8 and invasion assays, respectively. Potential mechanisms underlying the role of ciRS-7 in promoting ccRCC progression were explored by Western blotting. The relationship between the expression of ciRS-7 and features of ccRCC was analyzed by the Chi-square test and progression-free survival was determined using a Kaplan-Meier plot. RESULTS: ciRS-7 was overexpressed in ccRCC tissues compared with that in matched adjacent normal tissues. In addition, ciRS-7 up-regulation was closely associated with tumor diameter (P = 0.050), clinical stage (P = 0.009), and distant metastasis (P = 0.007). ciRS-7 knockdown in 786O and 769P cells markedly inhibited their proliferative and invasive abilities. In addition, ciRS-7 inhibition reduced phosphorylated epidermal growth factor receptor (p-EGFR) and phosphorylated serine/threonine kinase (p-Akt) levels. CONCLUSIONS: ciRS-7 up-regulation could promote ccRCC cell proliferation and invasion, which may be related with the EGFR/Akt signaling pathway. ciRS-7 might be a potential ccRCC therapeutic target.

Endoscopic closure of large colonic perforations with a novel endoscopic clip device: An animal study (with videos).

BACKGROUND AND AIM: An endoscopic clip device was newly designed to accomplish the closure of large gastrointestinal defects. The aim of this study was to determine the feasibility and efficacy of this device in an ex vivo experimental setting. METHODS: This prospective study was conducted in porcine colons (n = 5). A large (3-4 cm) linear full-thickness incision was created using a scalpel externally. The device was used for endoscopic closure. The procedure time, number of clips, and success rate of closure were determined. RESULTS: Ten defects were created in five porcine colons (two incisions in each specimen). Successful closure was achieved in all defects. The mean procedure time was 24.30 ± 4.42 min, the mean leak pressure is 28.30 ± 9.49 mmHg, and the mean number of additional conventional hemostatic clips used was 5.10 ± 0.99. CONCLUSIONS: The results indicated that this clip achieved the convenient and reliable closure of large defects in the colon wall in an ex vivo porcine model and seems to be a promising option for closing large gastrointestinal perforations.

Supersensitive Photoelectrochemical Aptasensor Based on Br,N-Codoped TiO2 Sensitized by Quantum Dots.

Here, we fabricated a novel photoelectrochemical (PEC) aptasensor based on Br,N-codoped TiO2/CdS quantum dots (QDs) sensitization structure with excellent energy level arrangement for supersensitive detection of carcinoembryonic antigen (CEA). The prepared Br,N-codoped TiO2 could reduce the energy bandwidth of TiO2 from 3.2 to 2.88 eV, which could dramatically reduce the basic signal and obviously broaden the absorption of light (400-700 nm). In addition, the energy bandwidth of Br,N-codoped TiO2 (2.88 eV) matched well with that of CdS QDs (2.4 eV), making CdS QDs an ideal signal enhancer for amplifying the photocurrent signal of Br,N-codoped TiO2. More importantly, the constructed Br,N-codoped TiO2/CdS QDs sensitization structure with narrow energy level gradient enabled the effective promotion of electron-transfer capability and dramatic improvement of photoelectric conversion efficiency. Simultaneously, a small amount of the CEA was transformed into substantial single-chain DNA (T-DNA) via exonuclease III (Exo-III)-assisted cycle strategy. Under optimum conditions, the designed PEC aptasensor demonstrated a wide detection range from 1 fg/mL to 1 ng/mL and a low detection limit as 0.46 fg/mL for CEA assay. This strategy prepared a new photoactive material to markedly improve photoelectric conversion efficiency and initiated a new way to realize the highly sensitive PEC biomolecules detection.