Hub genes and their key effects on prognosis of Burkitt lymphoma.

BACKGROUND: Burkitt lymphoma (BL) is an exceptionally aggressive malignant neoplasm that arises from either the germinal center or post-germinal center B cells. Patients with BL often present with rapid tumor growth and require high-intensity multi-drug therapy combined with adequate intrathecal chemotherapy prophylaxis, however, a standard treatment program for BL has not yet been established. It is important to identify biomarkers for predicting the prognosis of BLs and discriminating patients who might benefit from the therapy. Microarray data and sequencing information from public databases could offer opportunities for the discovery of new diagnostic or therapeutic targets. AIM: To identify hub genes and perform gene ontology (GO) and survival analysis in BL. METHODS: Gene expression profiles and clinical traits of BL patients were collected from the Gene Expression Omnibus database. Weighted gene co-expression network analysis (WGCNA) was applied to construct gene co-expression modules, and the cytoHubba tool was used to find the hub genes. Then, the hub genes were analyzed using GO and Kyoto Encyclopedia of Genes and Genomes analysis. Additionally, a Protein-Protein Interaction network and a Genetic Interaction network were constructed. Prognostic candidate genes were identified through overall survival analysis. Finally, a nomogram was established to assess the predictive value of hub genes, and drug-gene interactions were also constructed. RESULTS: In this study, we obtained 8 modules through WGCNA analysis, and there was a significant correlation between the yellow module and age. Then we identified 10 hub genes (SRC, TLR4, CD40, STAT3, SELL, CXCL10, IL2RA, IL10RA, CCR7 and FCGR2B) by cytoHubba tool. Within these hubs, two genes were found to be associated with OS (CXCL10, P = 0.029 and IL2RA, P = 0.0066) by survival analysis. Additionally, we combined these two hub genes and age to build a nomogram. Moreover, the drugs related to IL2RA and CXCL10 might have a potential therapeutic role in relapsed and refractory BL. CONCLUSION: From WGCNA and survival analysis, we identified CXCL10 and IL2RA that might be prognostic markers for BL.

Network pharmacological analysis of corosolic acid reveals P4HA2 inhibits hepatocellular carcinoma progression.

BACKGROUND: Corosolic acid is a pentacyclic triterpene acid with hypoglycemic, anti-inflammatory, and anti-cancer effects. However, its potential targets in hepatocellular carcinoma (HCC) are unknown, hindering clinical utilization. METHODS: Differentially expressed proteins of the Bel-7404 cell line were identified with tandem mass tag analysis and differentially expressed genes (DEGs) of an HCC TCGA dataset using bioinformatics. Gene functions and pathways were inferred using the DAVID database. Online databases were used to establish P4HA2 expression in HCC (GEPIA2) and its relationship with patient survival (UALCAN and The Human Protein Atlas), the association between P4HA2 expression and immune cell infiltration (TIMER2), and DNA methylation of the P4HA2 gene (MethSurv). Cell proliferation, cell cycle, and cell death were assessed with PI and SYTOX-Green staining, CCK-8, and colony formation assays. Protein expression levels were detected by Western blotting. RESULTS: A total of 44 differentially expressed proteins and 4498 DEGs were identified. Four genes whose proteins were also found in the differential protein profile but with opposing expressions were selected as candidate targets. The candidate gene prolyl 4-hydroxylase subunit alpha 2 (P4HA2) was recognized as the only potential target due to its high expression in public datasets, association with poor patient survival, and relation to immune cell infiltration in HCC tissues. Moreover, the DNA methylation status in 4 CpG islands of the P4HA2 gene correlated with a poor prognosis. Furthermore, corosolic acid treatment inhibited the proliferation of HCC cell lines Bel-7404 and HepG2 in a dose-dependent manner, caused G2/M phase cell cycle arrest, and promoted cell death. In addition, the treatment reduced P4HA2 protein levels. CONCLUSION: Our results indicate that P4HA2 is a potential target of corosolic acid. Thus, they contribute to understanding molecular changes in HCC after corosolic acid treatment and facilitate finding new treatment regimens.

Coronary computed tomography angiography study on the relationship between the Ramus Intermedius and Atherosclerosis in the bifurcation of the left main coronary artery.

OBJECTIVE: This study aimed to explore the relationship between the ramus intermedius (RI) and atherosclerosis in the bifurcation of the left coronary artery (LCA). METHODS: Screening patients who underwent CCTA from January to September 2021, 100 patients with RI (RI group) and 100 patients without RI (no-RI group) were randomly enrolled, Evaluation of RI distribution characteristics and left main coronary artery(LM),Left anterior descending branch(LAD),left circumflex branch(LCX) proximal segment plaque distribution, measurement of LAD-LCX bifurcation angle(∠LAD-LCX),Comparison of the three distribution characteristics with the incidence of plaques in the left main trunk bifurcation area (LM, LAD, LCX) between groups and within the RI group. RESULTS: The difference in the incidence of plaques in the proximal LCX and the LM between the RI group and the no-RI group were not statistically significant (P > 0.05). The incidence of plaques in the proximal LAD in the RI group was significantly higher than that in the non-RI group (77% versus 53%, P < 0.05). However, there was no statistically significant difference between the two groups after PSM. A univariate logistic regression analysis revealed that an RI was a risk factor for plaque formation in the proximal LAD (P < 0.001), and a multivariate logistic regression analysis revealed that an RI was not an independent risk factor for plaque formation in the proximal LAD (P > 0.05). When compared within the RI group, the difference in the incidence of plaques in the proximal segment of LAD, the proximal segment of LCX, and the LM among the different distribution groups of RI was not statistically significant, respectively (P > 0.05). CONCLUSION: RI is not an independent risk factor for atherosclerosis in the left coronary artery bifurcation zone, but it may indirectly increase the risk of atherosclerosis in the proximal segment of the LAD.

Study on the correlation between false-positive filling defect in LAA CT and LAA structure in patients with atrial fibrillation based on TEE.

OBJECTIVE: This study aims to explore the actual meaning of "false positive filling defect" in left atrial appendage (LAA) computed tomography (CT) in patients with atrial fibrillation (AF), with transesophageal echocardiography (TEE) as the gold standard. METHODS: Patients with AF undergoing cardiac CT angiography and TEE examinations for proposed radiofrequency catheter ablation between October 2020 and October 2021 were selected as the study subjects. Transesophageal echocardiography was taken as the "gold standard," and spontaneous echocardiographic contrast (SEC) and thrombus events were defined as positive events. The CT manifestations were classified into three groups (true positive, false positive, and true negative) to evaluate the differences in left atrium (LA) anterior-posterior diameter (LAAP), LA anterior wall thickness, and LAA orifice long diameter and short diameter, area, and depth between the three groups. RESULTS: (1) There was no statistical difference in LA anterior wall thickness between the three groups (p > .05); there was a statistical difference in LAAP (only) between the true-positive group and the true-negative group (p < .05). (2) There was a statistical difference in LAA orifice long diameter, short diameter, and area between the true-positive group and the true-negative group as well as between the false-positive group and the true-negative group (p < .05). (3) There was a statistical difference in LAA depth between the true-positive group and the false-positive group as well as between the true-positive group and the true-negative group (p < .05). (4) The area under the receiver operator characteristic curve (AUC) of LAA depth affecting the LAA thrombus and SEC was 0.863 (confidence interval = 0.718-1.000), the sensitivity was 77.8%, and the specificity was 90.6% for predicting the occurrence of LAA thrombus and SEC in patients with nonvalvular AF (NVAF) and an LAA depth of ≥50.84 mm. CONCLUSIONS: There was a difference in LAA diameter between the TEE-based CT false-positive group and the other groups. A "CT false positive" is an objectively existing state, and CT might be able to identify the LAA hemodynamic disorder earlier than TEE. Furthermore, a CT + TEE combined application could more accurately evaluate LAA hemodynamics in patients with AF.

Roles of F-18-Fluoro-2-Deoxy-Glucose PET/Computed Tomography Scans in the Management of Post-Transplant Lymphoproliferative Disease in Pediatric Patient.

Post-transplant lymphoproliferative disease is a well-known complication in transplant recipients. Evaluating the extent and stage of disease is important for management and follow-up. As a combination of anatomic and functional imaging, PET/CT is a sensitive and specific tool to stage and detect occult disease compared with conventional imaging. PET/CT also has a role in monitoring treatment response. Although PET/CT has been shown to be potentially useful in adults, evidence in children is insufficient. This review provides an overview of the use of PET/CT in post-transplant lymphoproliferative disease, especially in pediatric patients.

Establishment of BALB/C mouse models of influenza A H1N1 aerosol inhalation.

Influenza A (H1N1) is a rapidly spreading acute respiratory illness that remains a worldwide burden on public health. To simulate natural infection routes, BALB/C mice were challenged with the H1N1 virus by aerosol and intranasal instillation routes. We compared the weight change and survival of the mice for 14 consecutive days after infection. The infected mice were euthanized at days 3, 5, 7, and 9 to perform necropsies, lung pathological analyses, viral titers measurement, and lung cytokines examination. The aerosol-treated mice showed clinical symptoms on day 4, obvious lung lesions on day 5, rapid weight loss on day 7, peak virus replication in the lungs on days 7 to 9, and bronchial epithelial hyperplasia on day 9. However, after intranasal instillation, the mice exhibited clinical signs on day 2, rapid weight loss and obvious lung lesions on day 3, and peak virus replication in the lungs on days 3 to 5; no bronchial epithelial hyperplasia was detected. High levels of proinflammatory cytokines and chemokines were detected in the lungs of infected mice by both two routes. Disease and lung lesion progressions were slower in the mice that inhaled H1N1-containing aerosols than in those treated by intranasal instillation, and lung lesions were homogeneous in the aerosol group and heterogeneous in the intranasal group. In this study, BALB/C mouse models of H1N1 virus aerosol inhalation were successfully established and compared with mouse models of intranasal inoculation, aerosol mouse models had an infection route and lung pathology characteristics that more closely resembled those observed in humans.

The characteristics of hDPP4 transgenic mice subjected to aerosol MERS coronavirus infection via an animal nose-only exposure device.

BACKGROUND: Middle East respiratory syndrome coronavirus (MERS-CoV), which is not fully understood in regard to certain transmission routes and pathogenesis and lacks specific therapeutics and vaccines, poses a global threat to public health. METHODS: To simulate the clinical aerosol transmission route, hDPP4 transgenic mice were infected with MERS-CoV by an animal nose-only exposure device and compared with instillation-inoculated mice. The challenged mice were observed for 14 consecutive days and necropsied on days 3, 5, 7, and 9 to analyze viral load, histopathology, viral antigen distribution, and cytokines in tissues. RESULTS: MERS-CoV aerosol-infected mice with an incubation period of 5-7 days showed weight loss on days 7-11, obvious lung lesions on day 7, high viral loads in the lungs on days 3-9 and in the brain on days 7-9, and 60% survival. MERS-CoV instillation-inoculated mice exhibited clinical signs on day 1, obvious lung lesions on days 3-5, continuous weight loss, 0% survival by day 5, and high viral loads in the lungs and brain on days 3-5. Viral antigen and high levels of proinflammatory cytokines and chemokines were detected in the aerosol and instillation groups. Disease, lung lesion, and viral replication progressions were slower in the MERS-CoV aerosol-infected mice than in the MERS-CoV instillation-inoculated mice. CONCLUSION: hDPP4 transgenic mice were successfully infected with MERS-CoV aerosols via an animal nose-only exposure device, and aerosol- and instillation-infected mice simulated the clinical symptoms of moderate diffuse interstitial pneumonia. However, the transgenic mice exposed to aerosol MERS-CoV developed disease and lung pathology progressions that more closely resembled those observed in humans.

The impact of adaptive iterative dose reduction 3D on the improvement of shoulder image quality in head and neck CTA.

OBJECTIVE: The aim of this study was to determine the impact of adaptive iterative dose reduction 3 D (AIDR3D) on the improvement of shoulder image quality in low-radiographic dose head and neck CT angiography (CTA). MATERIALS AND METHODS: Ninety patients who underwent CTA examination were randomly divided into two groups, namely group A (n = 45) and B (n = 45). Patients in group A were scanned under 120 kV and 300 mA, with images reconstructed by filtered back projection (FBP), and patients in group B were scanned under 80 kV and auto mA with images reconstructed by AIDR3D. Image quality was accessed by two experienced radiologists. The noise, signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) of common carotid artery (CCA) at C7 level, and radiation dosage were compared between the two groups. RESULTS: The score of CCA in group B was significantly higher than group A (p < 0.05), and there were no significant differences in the scores of carotid sinus and internal carotid artery between the two groups (p > 0.05). The score of intracranial artery in group B was lower than that of group A, however, the image quality in group B can meet the requirement of clinical diagnosis. The noise value of CCA at C7 level in group B was significantly lower than that of group A (p < 0.05). SNR and CNR values of CCA at C7 level in group B were significantly higher than those of group A (p < 0.05). Effective radiation dose in group B was significantly decreased compared with group A (p < 0.05). CONCLUSION: AIDR3D remarkably improved image quality in low-radiographic dose head and neck CTA over FBP, which made the low-dose CTA images meet the requirement of clinical diagnosis.

Altered Gut Microbiota in a Mouse Model of Alzheimer's Disease.

The topic of gut microbiota is currently attracting considerable interest as a potential factor in Alzheimer's disease (AD). However, the extent and time course of alterations in the gut microbiota, and their effects on AD pathology remain uncertain. Herein, we compared the fecal microbiomes and fecal short chain fatty acid composition (SCFAs) between wild-type and AD model mice at different ages under strictly controlled specific pathogen free conditions, and also conducted microscopic investigations of intestinal structures. Our results showed that the microbiota composition and diversity were perturbed and the level of SCFAs was reduced in AD mice, predicting alterations in more than 30 metabolic pathways, which may be associated with amyloid deposition and ultrastructural abnormalities in AD mouse intestine. These findings indicate that AD pathology might not only affect brain function directly, but also exacerbate cognitive deficits through reducing the level of SCFAs via alterations of gut microbiota induced by intestinal amyloid deposition. Our data may support a role of gut microbiota, and suggest a novel route for therapeutic intervention in AD.

Pathological Changes in APP/PS-1 Transgenic Mouse Models of Alzheimer's Disease Treated with Ganoderma Lucidum Preparation.

Objective To explore the efficacy of ganoderma lucidum preparation(Ling Zhi) in treating APP/PS-1 transgenic mouse models of Alzheimer's disease(AD).Methods APP/PS-1 transgenic mice of 4 months were randomly divided into model group,ganoderma lucidum treatment groups,including high [2250 mg/(kg·d)] and middle [750 mg/(kg·d)] dose groups,i.e.LZ-H and LZ-M groups,and the positive control group(treated with donepezil hydrochloride [2 mg/(kg·d)]).In addition,C57BL/6J wild mice were selected as normal group.The animals were administered for 4 months.Histopathological examinations including hematoxylin-eosin(HE) staining,immunohistochemistry,special staining,and electron microscopy were applied,and then the pathological morphology and structures in different groups were compared. Results The senile plaques and neurofibrillar tangles in the cerebrum and cerebellum were dissolved or disappeared in LZ-H and LZ-M groups.Decrease of amyloid angiopathy was found in LZ-H and LZ-M groups.The immature neurons appeared more in hippocampus and dentate nucleus of LZ-H and LZ-M groups than those in AD model and donepezil hydrochloride groups(hippcampus:F=1.738,P=0.016;dentate nucleus:F=1.924,P=0.026),and these immature neurons differentiated to be neurons.More Purkinje cells loss occurred in AD model mice than that in LZ-H and LZ-M groups(F=9.46,P=0.007;F=9.46,P=0.010).The LZ-H and LZ-M groups had more new neuron stem cells grown up in cerebellum.Electromicroscopic examination showed the hippocampal neurons in LZ-H and LZ-M group were integrated,the nuclear membrane was intact,and the mitochondria in the cytoplasm,endoplasmic reticulum,Golgi bodies,microtubules,and synapses were also complete.The microglial cell showed no abnormality.No toxicity appeared in the pathological specimens of mice treated with ganoderma lucidum preparation.Conclusion The ganoderma lucidum preparation can dissolve and decline or dismiss the senile plaques and neurofibrillar tangles in the brain of AD mice and also reduce the amyloid angiopathy.

Effective expression of Drebrin in hippocampus improves cognitive function and alleviates lesions of Alzheimer's disease in APP (swe)/PS1 (ΔE9) mice.

AIMS: Alzheimer's disease (AD), a progressive development dementia, is increasingly impacting patients' living conditions worldwide. Despite medical care and funding support, there are still no highly individualized drugs and practical strategies for clinical prevention and treatment. Developmentally regulated brain protein (abbreviated as Drebrin or Dbn, also known as Dbn1 in mouse) exists in neurons, especially in dendrites, and is an actin-binding protein that modulates synaptic morphology and long-term memory. However, the majority of previous studies have focused on its upstream proteins and neglected the impact Drebrin has on behavior and AD in vivo. METHODS: Here, we tracked the behavioral performances of 4-, 8-, 12-, and 16-month-old AD mice and investigated the expression level of Drebrin in their hippocampi. A Pearson correlation analysis between Drebrin levels and behavioral data was performed. Subsequently, 2-month-old AD mice were injected with rAAV-zsGreen-Dbn1 vector, composing the APP/PS1-Dbn1 group, and sex- and age-matched AD mice were injected with rAAV-tdTomato vector to serve as the control group. All mice were conducted behavioral tests and molecular detection 6 months later. RESULTS: (i) The expression of Drebrin is decreased in the hippocampus of aged AD mice compared with that of age-matched WT and young adult AD mice; (ii) cognitive ability of APP/PS1 mice decreases with age; (iii) Drebrin protein expression in the hippocampus correlates with behavioral performance in different aged AD mice; (iv) cognitive ability improved significantly in APP/PS1-Dbn1 mice; (v) the expression level of Drebrin in APP/PS1-Dbn1 mouse hippocampus was significantly increased; (vi) the pathological lesion of AD was alleviated in APP/PS1-Dbn1 mice; (vii) the filamentous actin (F-actin) and microtubule-associated protein 2(MAP-2) in APP/PS1-Dbn1 mice were notably more than control mice. CONCLUSION: In this study, an effective expression of Drebrin improves cognitive abilities and alleviates lesions in an AD mouse model. These results may provide some valid resources for therapy and research of AD.

Histone deacetylase-2 is involved in stress-induced cognitive impairment via histone deacetylation and PI3K/AKT signaling pathway modification.

Exposure to chronic stress upregulates blood glucocorticoid levels and impairs cognition via diverse epigenetic mechanisms, such as histone deacetylation. Histone deacetylation can lead to transcriptional silencing of many proteins involved in cognition and may also cause learning and memory dysfunction. Histone deacetylase­2 (HDAC2) has been demonstrated to epigenetically block cognition via a reduction in the histone acetylation level; however, it is unknown whether HDAC2 is involved in the cognitive decline induced by chronic stress. To the best of authors' knowledge, this is the first study to demonstrate that the stress hormone corticosteroid upregulate HDAC2 protein levels in neuro­2a cells and cause cell injuries. HDAC2 knockdown resulted in a significant amelioration of the pathological changes in N2a cells via the upregulation of histone acetylation and modifications in the phosphoinositide 3­kinase/protein kinase B signaling pathway. In addition, the HDAC2 protein levels were upregulated in 12­month­old female C57BL/6J mice under chronic stress in vivo. Taken together, these findings suggested that HDAC2 may be an important negative regulator involved in chronic stress­induced cognitive impairment.

Effect of Polysaccharide from Cordyceps militaris (Ascomycetes) on Physical Fatigue Induced by Forced Swimming.

Cordyceps militaris is the one of the most important medicinal mushrooms, widely used in East Asian countries. Polysaccharide is considered to be the principal active component in C. militaris and has a wide range of biological and pharmacological properties. This study was undertaken to investigate the effect of polysaccharide from C. militaris (PCM) on physical fatigue induced in animals through a forced swimming test. The mice were divided into 4 groups receiving 28 days' treatment with drinking water (exercise control) or low-, medium-, and high-dose PCM (40, 80, and 160 mg/kg/day, respectively). After 28 days, the mice were subjected to the forced swimming test; the exhaustive swimming time was measured and fatigue-related biochemical parameters, including serum lactic acid, urea nitrogen, creatine kinase, alanine aminotransferase, aspartate aminotransferase, superoxide dismutase, glutathi- one peroxidase, catalase, malondialdehyde, liver glycogen, and muscle glycogen, were analyzed. The results showed that PCM could significantly prolong the exhaustive swimming time of mice; decrease concentrations of serum lactic acid, urea nitrogen, creatine kinase, aspartate aminotransferase, alanine aminotransferase, and malondialdehyde; and increase liver and muscle glycogen contents and the concentrations of serum superoxide dismutase, glutathione per- oxidase, and catalase. The data suggest that PCM has an antifatigue effect, and it might become a new functional food or medicine for fatigue resistance.

Multiple myeloma with intracranial extension and bilateral renal infiltration: A case report and review of the literature.

Multiple myeloma (MM) is a rare hematological malignancy, characterized by uncontrolled proliferation of plasma cells in the bone marrow. MM is usually confined to the bone marrow, however, it may occasionally infiltrate other tissues, which is known as extramedullary plasmacytoma (EMP). The majority of EMPs involve the head and neck region, although different anatomical sites, including the gastrointestinal tract, central nervous system, thyroid gland and breast may also be affected. The simultaneous presentation of EMP in the kidney and head is rare, presenting diagnostic challenges due to its unusual location and non-specific or absent symptoms. To the best of our knowledge, no case of extramedullary plasmacytoma presenting with simultaneous renal and intracranial infiltration has been reported in the literature thus far. However, the present study reports a case of primary renal and intracranial extramedullary plasmacytoma in a 76-year-old male patient. The patient presented with a swelling over the right side of the forehead, which had slowly increased in size prior to hospital admission. The swelling was associated with dizziness and weakness, without bone pain. Contrast magnetic resonance imaging suggested an osteolytic skull lesion with intracranial extension. Abdominal enhanced computed tomography scanning revealed a large tumor mass extending around and into the kidneys. Immunohistochemical examination of the renal tumor biopsy, and blood and serum samples, as well as immunoelectrophoresis of serum proteins, resulted in a diagnosis of EMP being proposed. Therefore, the patient was administered with two cycles of cyclophosphamide and thalidomide in combination with dexamethasone. Follow-up imaging performed 4 months later revealed almost complete disappearance of the intracranial tumor mass and renal infiltration. The current study also presented a review of the literature. This study revealed that EMPs may co-exist with MM or present as the main symptom of MM. The diagnosis of an EMP is complex and requires radiological, hematological, biochemical and histological investigation. At present, no guidelines for EMP treatment have been established and thus, treatment options include surgery, chemotherapy and radiotherapy, either alone or in combination. We hypothesize that combined treatment may provide the best patient outcome.

[Dynamic Changes of the Quantitative Distribution,Apoptosis and Proliferation of T and B Cells in the Skin of KM Mutant Mice].

OBJECTIVE: To observe the change of quantitative distribution,apoptosis and proliferation of T and B cells in the skin of KM mutant mice. METHODS: We chose 1-,3-,6-,9-,22-day,3-,6-month-old KM mutant and wild-type mice to detect the changes of T and B lymphocytes using blood routine tests and immunohistochemical staining. Apoptosis was detected by TUNEL staining and proliferation by proliferating cell nuclear antigen (PCNA) staining. RESULTS: T cells on KM mutant mice skin were mainly seen in epidermis and dermis. They increased on the first day to 6(th) day after birth and decreased on the 9(th) and 22(nd) day,but after 3-month-old,their number began to increase;at the time of 6 months,the number of B cells also increased. The apoptosis of the skin hair follicle and sebaceous gland cells were more obvious in KM mutant mice than in wild-type mice,with the maximal apoptosis occurred at the age of 22-day-old in both groups. The proliferation of epidermal basal cells in KM mutant mice between 1 to 9-day-old was not significantly different from that in the wild-type mice,but decreasing on the 22(nd) day and 3(rd) month and increasing in the 6(th) month. The proliferation in hair follicle and sebaceous glands decreased on 9(th) day,increased on 22(nd) day,and deceased on the 3(rd) month again. CONCLUSIONS: The quantitative distribution,apoptosis,and proliferation of T and B lymphocytes abnormally change in the skin tissue of KM spontaneous mutant mice. They may lead to immune and hair growth disorders and promote the inflammatory responses.

Tubastatin A/ACY-1215 improves cognition in Alzheimer's disease transgenic mice.

Histone deacetylase 6 (HDAC6) is currently being discussed as a promising therapeutic target for the treatment of Alzheimer's disease (AD). Mounting evidence indicates that increased HDAC6 expression may contribute to AD-associated neurodegeneration, although beneficial effects have also been identified. In the present study, we tested the potential of two selective HDAC6 inhibitors, tubastatin A and ACY-1215, to rescue cognitive deficits in a mouse model of AD. We found that both tubastatin A and ACY-1215 alleviated behavioral deficits, altered amyloid-ß (Aß) load, and reduced tau hyperphosphorylation in AD mice without obvious adverse effects. Our data suggested that tubastatin A and ACY-1215 not only promoted tubulin acetylation, but also reduced production and facilitated autophagic clearance of Aß and hyperphosphorylated tau. Further, the decreased hyperphosphorylated tau and increased tubulin acetylation may account for the improved microtubule stability in AD mice after tubastatin A/ACY-1215 treatment. These preclinical results support the detrimental role of HDAC6 in AD, and offer prospective approaches for using tubastatin A/ACY-1215 as potential therapeutic strategy for AD.

Necrotizing myositis causes restrictive hypoventilation in a mouse model for human enterovirus 71 infection.

BACKGROUND: Enterovirus 71 (EV71) infections are associated with a high prevalence of hand, foot and mouth disease (HFMD) in children and occasionally cause lethal complications. Most infections are self-limiting. However, resulting complications, including aseptic meningitis, encephalitis, poliomyelitis-like acute flaccid paralysis, and neurological pulmonary edema or hemorrhage, are responsible for the lethal symptoms of EV71 infection, the pathogenesis of which remain to be clarified. RESULTS: In the present study, 2-week-old Institute of Cancer Research (ICR) mice were infected with a mouse-adapted EV71 strain. These infected mice demonstrated progressive paralysis and died within 12 days post infection (d.p.i.). EV71, which mainly replicates in skeletal muscle tissues, caused severe necrotizing myositis. Lesions in the central nervous system (CNS) and other tissues were not observed. CONCLUSIONS: Necrotizing myositis of respiratory-related muscles caused severe restrictive hypoventilation and subsequent hypoxia, which could explain the fatality of EV71-infected mice. This finding suggests that, in addition to CNS injury, necrotic myositis may also be responsible for the paralysis and death observed in EV71-infected mice.

Co-location of HDAC2 and insulin signaling components in the adult mouse hippocampus.

As one part of epigenetics, histone deacetylases (HDACs) have been demonstrated to get into the neural events, including neurogenesis, synaptic plasticity, and neurodegeneration through regulating acetylation status of target proteins to influence protein function and gene expression. However, the recent studies indicated that HDAC2, a member of HDACs family, played a role in insulin signaling pathway and synaptic plasticity. Here, we are concerned about whether HDAC2 was co-located with insulin signaling components in postsynaptic glutamatergic neurons (PSGNs) of the adult mouse hippocampus using double immunofluorescence staining. The results displayed that HDAC2 was present in PSGNs marked by N-methyl-D-aspartate receptor subunit 2B, in which major components of insulin signaling pathway such as insulin receptor alpha and beta and insulin receptor substrate-1 were also involved. Accordingly, we speculate that the interaction of HDAC2 and insulin signaling system in PSGNs observed in the present study may serve as a potential mechanism in memory formation. We hope this could provide a valuable basis for understanding the roles of HDAC2 and insulin on cognitive impairment of diabetes mellitus, involved Alzheimer's disease, which is also called type 3 diabetes recently. And this will also benefit to the treatment of insulin-related diseases in the central nervous system.

Total saponin from root of Actinidia valvata Dunn prevents the metastasis of human hepatocellular carcinoma cells.

OBJECTIVE: To extract the active component from the root of Actinidia valvata Dunn and to investigate the effects on hepatocellular carcinoma (HCC) cells in vitro. METHODS: Total saponin was extracted from the root of A. valvata (TSAVD). HCC cells, such as BEL-7402, HepG2, PLC, SMMC-7721, MHCC-97-H, and MHCC-97-L, were treated with TSAVD in 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenytetrazolium bromide (MTT) assay. BEL-7402 and MHCC-97-H cells were also treated respectively with TSAVD at different concentrations for 24 h in wound healing and adhesion assays, and the effects of TSAVD on BEL-7402 and MHCC-97-H cells mobility and adhesion abilities were observed. Meanwhile, the effects of TSAVD on invasion and migration of BEL-7402 and MHCC-97-H cells were also investigated by transwell chamber in invasion and migration assays. RESULTS: TSAVD at 1.5 mg/mL inhibited BEL-7402 cell proliferation with inhibition ratios (IRs) of 61.08%, 74.12%, 84.55% at 24, 48, and 72 h, respectively. Meanwhile, TSAVD inhibited MHCC-97-H proliferation in a concentration-dependent manner from 1.5 to 0.5 mg/mL, with the IR of 36% at 1.5 mg/mL at 24 h. For SMMC-7721, PLC, and HepG2, the IR was lower than 30% at 1.5 mg/mL at 24 h. In the wound healing assay, mobility abilities of BEL-7402 and MHCC-97-H cells in TSAVD treated groups were significantly weaker than those of the control group. After pretreatment for 24 h with TSAVD, adhesion abilities were reduced in both MHCC-97-H and BEL-7402 cells, with IRs of 48.50%±4.86% and 49.85%±5.25% at 200 µg/mL. The IRs of MHCC-97-H and BEL-7402 cells in the migration assay were 49.13%±2.91% and 79.37%±0.09% at 200 µg/mL. In the invasion assay, IRs were 69.78%±4.88% and 82.48%±0.25% at 200 µg/mL. CONCLUSIONS: Of all HCC cells, the highest inhibition by TSAVD was seen for BEL-7402 proliferation. TSAVD could restrain adhesion, invasion, mobility, and migration abilities of BEL-7402 and MHCC-97-H cells in vitro.

Fascin promotes the motility and invasiveness of pancreatic cancer cells.

AIM: To explore the role of actin-bundling protein, fascin during the progression of pancreatic cancer. METHODS: The plasmid expressing human fascin-1 was stably transfected into the pancreatic cancer cell line MIA PaCa-2. The proliferation, cell cycle, motility, scattering, invasiveness and organization of the actin filament system in fascin-transfected MIA PaCa-2 cells and control non-transfected cells were determined. RESULTS: Heterogeneous overexpression of fascin markedly enhanced the motility, scattering, and invasiveness of MIA PaCa-2 cells. However, overexpression of fascin had minimal effect on MIA PaCa-2 cell proliferation and cell cycle. In addition, cell morphology and organization of the actin filament system were distinctly altered in fascin overexpressed cells. When transplanted into BALB/c-nu mice, fascin-transfected pancreatic cancer cells developed solid tumors at a slightly slower rate, but these tumors displayed more aggressive behavior in comparison with control tumors. CONCLUSION: Fascin promotes pancreatic cancer cell migration, invasion and scattering, thus contributes to the aggressive behavior of pancreatic cancer cells.