TRA2A Binds With LncRNA MALAT1 To Promote Esophageal Cancer Progression By Regulating EZH2/beta-catenin Pathway

The RNA binding protein TRA2A, a member of the transformer 2 homolog family, plays a crucial role in the alternative splicing of pre-mRNA. However, it remains unclear whether TRA2A is involved in non-coding RNA regulation and, if so, what are the functional consequences. By analyzing expression profiling data, we found that TRA2A is highly expressed in esophageal cancer and is associated with disease-free survival and overall survival time. Subsequent gain- and loss-of-function studies demonstrated that TRA2A promotes proliferation and migration of esophageal squamous cell carcinoma and adenocarcinoma cells. RNA immunoprecipitation and RNA pull-down assay indicated that TRA2A can directly bind specific sites on MALAT1 in cells. In addition, ectopic expression or depletion of TRA2A leads to MALAT expression changes accordingly, thus modulates EZH2/β-catenin pathway. Together, these findings elucidated that TRA2A triggers carcinogenesis via MALAT1 mediated EZH2/β-catenin axis in esophageal cancer cells

Enhanced excitability of small dorsal root ganglion neurons in rats with bone cancer pain

<p>Abstract</p> <p>Background</p> <p>Primary and metastatic cancers that affect bone are frequently associated with severe and intractable pain. The mechanisms underlying the development of bone cancer pain are largely unknown. The aim of this study was to determine whether enhanced excitability of primary sensory neurons contributed to peripheral sensitization and tumor-induced hyperalgesia during cancer condition. In this study, using techniques of whole-cell patch-clamp recording associated with immunofluorescent staining, single-cell reverse-transcriptase PCR and behavioral test, we investigated whether the intrinsic membrane properties and the excitability of small-sized dorsal root ganglion (DRG) neurons altered in a rat model of bone cancer pain, and whether suppression of DRG neurons activity inhibited the bone cancer-induced pain.</p> <p>Results</p> <p>Our present study showed that implantation of MRMT-1 tumor cells into the tibial canal in rats produced significant mechanical and thermal hyperalgesia in the ipsilateral hind paw. Moreover, implantation of tumor cells provoked spontaneous discharges and tonic excitatory discharges evoked by a depolarizing current pulse in small-sized DRG neurons. In line with these findings, alterations in intrinsic membrane properties that reflect the enhanced neuronal excitability were observed in small DRG neurons in bone cancer rats, of which including: 1) depolarized resting membrane potential (RMP); 2) decreased input resistance (R_in); 3) a marked reduction in current threshold (CT) and voltage threshold (TP) of action potential (AP); 4) a dramatic decrease in amplitude, overshot, and duration of evoked action potentials as well as in amplitude and duration of afterhyperpolarization (AHP); and 5) a significant increase in the firing frequency of evoked action potentials. Here, the decreased AP threshold and increased firing frequency of evoked action potentials implicate the occurrence of hyperexcitability in small-sized DRG neurons in bone cancer rats. In addiotion, immunofluorescent staining and single-cell reverse-transcriptase PCR revealed that in isolated small DRG neurons, most neurons were IB4-positive, or expressed TRPV1 or CGRP, indicating that most recorded small DRG neurons were nociceptive neurons. Finally, using in vivo behavioral test, we found that blockade of DRG neurons activity by TTX inhibited the tumor-evoked mechanical allodynia and thermal hyperalgesia in bone cancer rats, implicating that the enhanced excitability of primary sensory neurons underlied the development of bone cancer pain.</p> <p>Conclusions</p> <p>Our present results suggest that implantation of tumor cells into the tibial canal in rats induces an enhanced excitability of small-sized DRG neurons that is probably as results of alterations in intrinsic electrogenic properties of these neurons. Therefore, alterations in intrinsic membrane properties associated with the hyperexcitability of primary sensory neurons likely contribute to the peripheral sensitization and tumor-induced hyperalgesia under cancer condition.</p

Dahuang Fuzi Decoction Attenuates Renal Fibrosis and Ameliorates Mitochondrial Dysfunction in Chronic Aristolochic Acid Nephropathy

Objectives. The effects of the traditional formula Dahuang Fuzi Decoction (DFD) on chronic aristolochic acid nephropathy (AAN) in mice and its underlying mechanisms were studied. Methods. Mice were randomly divided into the following six groups: the control group, the model group (AAN), the saline-treated group (AAN + vehicle), the normal dose DFD-treated group (AAN + NDFD), the high dose DFD-treated group (AAN + HDFD), and the rosiglitazone treated group (AAN + Rosi). After treating for 8 weeks, 24 h urine and blood samples were collected and the mice sacrificed to study the biochemical parameters associated with renal function. The samples were analyzed for renal fibrosis and mitochondrial dysfunction (MtD) markers. To achieve that, collagen III, collagen I, mitochondrial DNA copy numbers (mtDNA), mitochondrial membrane potential (MMP), ATP content, and ROS production were evaluated. Results. Our results showed that proteinuria, kidney function, and the renal pathological characteristics were improved by DFD and rosiglitazone. The expression of collagen III and collagen I decreased after treating with either DFD or rosiglitazone. Mitochondrial dysfunction based on the increase in ROS production, decrease in mitochondrial DNA copy numbers, and reduction of MMP and ATP content was improved by DFD and rosiglitazone. Conclusions. DFD could protect against renal impairments and ameliorate mitochondrial dysfunction in chronic AAN mice

Splicing factor TRA2A contributes to esophageal cancer progression via a noncanonical role in lncRNA m⁶A methylation

Transformer 2 alpha homolog (TRA2A), a member of the serine/arginine-rich splicing factor family, has been shown to control mRNA splicing in development and cancers. However, it remains unclear whether TRA2A is involved in lncRNA regulation. In the present study, we found that TRA2A was upregulated and correlated with poor prognosis in esophageal cancer. Downregulation of TRA2A suppressed the tumor growth in xenograft nude mice. Epitranscriptomic microarray showed that depletion of TRA2A affected global lncRNA methylation similarly to the key m6A methyltransferase, METTL3, by silencing. MeRIP-qPCR, RNA pull-down, CLIP analyses, and stability assays indicated that ablation of TRA2A reduced m6A-modification of the oncogenic lncRNA MALAT1, thus inducing structural alterations and reduced stability. Furthermore, Co-IP experiments showed TRA2A directly interacted with METTL3 and RBMX, which also affected the writer KIAA1429 expression. Knockdown of TRA2A inhibited cell proliferation in a manner restored by RBMX/KIAA1429 overexpression. Clinically, MALAT1, RBMX, and KIAA1429 were prognostic factors of worse survival in ESCA patients. Structural similarity-based virtual screening in FDA-approved drugs repurposed nebivolol, a β1-adrenergic receptor antagonist, as a potent compound to suppress the proliferation of esophageal cancer cells. Cellular thermal shift and RIP assay indicated that nebivolol may compete with MALAT1 to bind TRA2A. In conclusion, our study revealed the noncanonical function of TRA2A, which coordinates with multiple methylation proteins to promote oncogenic MALAT1 during ESCA carcinogenesis.</p

Logistic regression analysis of clinical and computed tomography features of pulmonary abscesses and risk factors for pulmonary abscess-related empyema

OBJECTIVES: This study was conducted to investigate the risk factors for pulmonary abscess-related empyema by investigating the clinical characteristics and chest computed tomography imaging features of patients with pulmonary abscesses. METHODS: We retrospectively analyzed the chest computed tomography findings and clinical features of 101 cases of pulmonary abscess, including 25 cases with empyema (the experimental group) and 76 cases with no empyema (the control group). The potential risk factors for pulmonary abscess-related empyema were compared between the groups by using univariate and multivariate logistic regression analyses. RESULTS: The incidence of pulmonary abscess-related empyema was 24.8% (25/101). Univariate analysis showed that male gender, diabetes, pleuritic symptoms, white blood cells 410 109 /L, albumin level o25 g/L, and positive sputum cultures were potential clinical-related risk factors and that an abscess 45 cm in diameter and transpulmonary fissure abscesses were potential computed tomography imaging-related risk factors for pulmonary abscess-related empyema. Multivariate logistic regression analysis showed that transpulmonary fissure abscesses (odds ratio=9.102, p=0.003), diabetes (odds ratio=9.066, p=0.003), an abscess 45 cm in diameter (odds ratio=8.998, p=0.002), and pleuritic symptoms (odds ratio=5.395, p=0.015) were independent risk factors for pulmonary abscess-related empyema. CONCLUSIONS: Transpulmonary fissure abscesses, diabetes, giant pulmonary abscesses, and pleuritic symptoms increased the risk of empyema among patients with pulmonary abscesses

Cyclic threshold shear strain for pore water pressure generation and stiffness degradation in marine clays at Yangtze estuary

Cyclic threshold shear strain is a fundamental property of saturated soils under cyclic loading. To investigate the cyclic threshold shear strain for pore water pressure generation (γtp) and stiffness degradation (γtd), a series of strain-controlled multistage undrained cyclic triaxial tests were carried out on in-situ saturated marine clay in the Yangtze estuary with different plasticity index Ip. The test results show that both γtp and γtd increase with increasing Ip, and γtp is larger than γtd for the same marine clay tested under the same conditions, with γtp = 0.017 ~ 0.019%, γtd = 0.008 ~ 0.012% for Ip of 17, γtp = 0.033 ~ 0.039%, γtd = 0.020 ~ 0.025% for Ip of 32, and γtp = 0.040 ~ 0.048%, γtd = 0.031 ~ 0.036% for Ip of 40. Moreover, the development of stiffness degradation may not necessarily require the generation of pore water pressure but can be aggravated by it. Furthermore, the γtp and γtd of marine clay are compared with terrestrial soils and marine clays cited from the published literature, the results indicate that the special marine sedimentary environment and the combined action of flow and tidal wave system cause the γtp and γtd of marine clay in the Yangtze estuary to be smaller than that of the terrestrial clays and marine clays in other sea areas