Circ_0004851 regulates the molecular mechanism of miR-296-3p/FGF11 in the influence of high iodine on PTC.

The prevalence of papillary thyroid cancer (PTC) has been rising in recent years. Despite its relatively low mortality, PTC frequently metastasizes to lymph nodes and often recurs, posing significant health and economic burdens. The role of iodine in the pathogenesis and advancement of thyroid cancer remains poorly understood. Circular RNAs (circRNAs) are recognized to function as competing endogenous RNAs (ceRNAs) that modulate gene expression and play a role in various cancer stages. Consequently, this research aimed to elucidate the mechanism by which circRNA influences the impact of iodine on PTC. Our research indicates that high iodine levels can exacerbate the malignancy of PTC via the circ_0004851/miR-296-3p/FGF11 axis. These insights into iodine's biological role in PTC and the association of circRNA with the disease could pave the way for novel biomarkers and potentially effective therapeutic strategies to mitigate PTC progression.

Study on the risk assessment of Pedestrian-Vehicle conflicts in channelized Right-Turn lanes based on the Hierarchical-Grey Entropy-Cloud model.

Channelized right-turn lanes (CRTLs) in urban areas have been effective in improving the efficiency of right-turning vehicles but have also presented negative impacts on pedestrian movement. Pedestrians experience confusion regarding the allocation of road space when crossing crosswalks within these areas, leading to frequent conflicts between pedestrians and motor vehicles. In this paper, considering the characteristics of pedestrian-vehicle conflicts at channelized right-turn lanes as well as the ambiguity and uncertainty of the causes, a comprehensive assignment combined with a cloud model is proposed as a risk evaluation model for pedestrian-vehicle conflicts. The study established a risk indicator system based on three aspects of the transportation system: pedestrians, motor vehicles, and the road environment. Combining the analytic hierarchy process (AHP), grey relational analysis (GRA), and entropy weighting method (EWM) to get the weights of indicator combinations, and then using the cloud model to realize quantitative and qualitative language transformation to complete the risk evaluation. This study employs specific road segments in Qingdao as a validation case for model analysis. The results indicate that the model's evaluation outcomes exhibited a significant level of agreement with the findings from field investigations during both peak and off-peak periods. It is demonstrated that the model has good performance for the safety assessment of pedestrian-vehicle conflicts at CRTL, and it also reflects the ability of the model to assess fuzzy randomness problems. It provides participation value for urban pedestrian-vehicle safety problems as well as applications in other fields.

Nucleotide at position 66 of NS2A in Japanese encephalitis virus is associated with the virulence and proliferation of virus.

Most wild strains of Japanese encephalitis virus (JEV) produce NS1' protein, which plays an important role in viral infection and immune escape. The G66A nucleotide mutation in NS2A gene of the wild strain SA14 prevented the ribosomal frameshift that prevented the production of NS1' protein, thus reduced the virulence. In this study, the 66th nucleotide of the NS2A gene of SA14 was mutated into A, U or C, respectively. Both the G66U and G66C mutations cause the E22D mutation of the NS2A protein. Subsequently, the expression of NS1' protein, plaque size, replication ability, and virulence to mice of the three mutant strains were examined. The results showed that the three mutant viruses could not express NS1' protein, and their proliferation ability in nerve cells and virulence to mice were significantly reduced. In addition, the SA14(G66C) was less virulent than the other two mutated viruses. Our results indicate that only when G is the 66th nucleotide of NS2A, the JEV can produce NS1' protein, which affects the virulence.

Neutrophil extracellular traps promote gastric cancer cell metastasis via the NAT10-mediated N4-acetylcytidine modification of SMYD2.

It has been reported that the formation of neutrophil extracellular traps (NETs) is associated with cancer metastasis. The current study aimed to explore the effects of NETs on gastric cancer (GC) cell metastasis and uncover their underlying mechanism. NETs were measured in the plasma of patients with GC. Then, GC cells were treated with NETs to assess cell viability, migration, and invasion using cell counting kit 8 and Transwell assay, The liver metastasis and xenograft tumor mouse models were established to assess tumor growth and metastasis. The N4-acetylcytidine (ac4C) modification of SET and MYND domain containing 2 (SMYD2) mediated by NAT10 was evaluated using acetylated RNA immunoprecipitation. The results showed that the level of NETs was increased in the plasma of patients with GC, particularly in those with metastatic GC. In addition, GC cell co-treatment with NETs promoted cell viability, migration and invasion, while NAT10 or SMYD2 knockdown abrogated this effect. NAT10 also promoted the ac4C modification of SMYD2, thus increasing SMYD2 stability. Furthermore, NETs promoted the metastasis of GC cells in the liver in vivo. Overall, the results of the present study demonstrated that NETs promoted GC cell metastasis via the NAT10-mediated ac4C modification of SMYD2. These findings suggested that inhibiting the formation of NETs could be an effective approach for attenuating GC progression.

EGFR ligand shifts the role of EGFR from oncogene to tumour suppressor in EGFR-amplified glioblastoma by suppressing invasion through BIN3 upregulation.

The epidermal growth factor receptor (EGFR) is a prime oncogene that is frequently amplified in glioblastomas. Here we demonstrate a new tumour-suppressive function of EGFR in EGFR-amplified glioblastomas regulated by EGFR ligands. Constitutive EGFR signalling promotes invasion via activation of a TAB1-TAK1-NF-κB-EMP1 pathway, resulting in large tumours and decreased survival in orthotopic models. Ligand-activated EGFR promotes proliferation and surprisingly suppresses invasion by upregulating BIN3, which inhibits a DOCK7-regulated Rho GTPase pathway, resulting in small hyperproliferating non-invasive tumours and improved survival. Data from The Cancer Genome Atlas reveal that in EGFR-amplified glioblastomas, a low level of EGFR ligands confers a worse prognosis, whereas a high level of EGFR ligands confers an improved prognosis. Thus, increased EGFR ligand levels shift the role of EGFR from oncogene to tumour suppressor in EGFR-amplified glioblastomas by suppressing invasion. The tumour-suppressive function of EGFR can be activated therapeutically using tofacitinib, which suppresses invasion by increasing EGFR ligand levels and upregulating BIN3.

Proteolytic Activities of Enterovirus 2A Do Not Depend on Its Interaction with SETD3.

Enterovirus 2Apro is a protease that proteolytically processes the viral polyprotein and cleaves several host proteins to antagonize host responses during enteroviral infection. Recently, the host protein actin histidine methyltransferase SET domain containing 3 (SETD3) was identified to interact with 2Apro and to be essential for virus replication. The role of SETD3 and its interaction with 2Apro remain unclear. In this study, we investigated the potential involvement of SETD3 in several functions of 2Apro. For this, we introduced the 2Apro from coxsackievirus B3 (CVB3) in a mutant of encephalomyocarditis virus (EMCV) containing an inactivated Leader protein (EMCV-Lzn) that is unable to shut down host mRNA translation, to trigger nucleocytoplasmic transport disorder (NCTD), and to suppress stress granule (SG) formation and type I interferon (IFN) induction. Both in wt HeLa cells and in HeLa SETD3 knockout (SETD3KO) cells, the virus containing active 2Apro (EMCV-2Apro) efficiently cleaved eukaryotic translation initiation factor 4 gamma (eIF4G) to shut off host mRNA translation, cleaved nucleoporins to trigger NCTD, and actively suppressed SG formation and IFN gene transcription, arguing against a role of SETD3 in these 2Apro-mediated functions. Surprisingly, we observed that the catalytic activity of enteroviral 2A is not crucial for triggering NCTD, as a virus containing an inactive 2Apro (EMCV-2Am) induced NCTD in both wt and SETD3KO cells, albeit delayed, challenging the idea that the NCTD critically depends on nucleoporin cleavage by this protease. Taken together, our results do not support a role of SETD3 in the proteolytic activities of enterovirus 2Apro.

Comprehensive targeting of resistance to inhibition of RTK signaling pathways by using glucocorticoids.

Inhibition of RTK pathways in cancer triggers an adaptive response that promotes therapeutic resistance. Because the adaptive response is multifaceted, the optimal approach to blunting it remains undetermined. TNF upregulation is a biologically significant response to EGFR inhibition in NSCLC. Here, we compared a specific TNF inhibitor (etanercept) to thalidomide and prednisone, two drugs that block TNF and also other inflammatory pathways. Prednisone is significantly more effective in suppressing EGFR inhibition-induced inflammatory signals. Remarkably, prednisone induces a shutdown of bypass RTK signaling and inhibits key resistance signals such as STAT3, YAP and TNF-NF-κB. Combined with EGFR inhibition, prednisone is significantly superior to etanercept or thalidomide in durably suppressing tumor growth in multiple mouse models, indicating that a broad suppression of adaptive signals is more effective than blocking a single component. We identify prednisone as a drug that can effectively inhibit adaptive resistance with acceptable toxicity in NSCLC and other cancers.

Tumor necrosis factor in lung cancer: Complex roles in biology and resistance to treatment.

Tumor necrosis factor (TNF) and its receptors are widely expressed in non-small cell lung cancer (NSCLC). TNF has an established role in inflammation and also plays a key role in inflammation-induced cancer. TNF can induce cell death in cancer cells and has been used as a treatment in certain types of cancer. However, TNF is likely to play an oncogenic role in multiple types of cancer, including NSCLC. TNF is a key activator of the transcription factor NF-κB. NF-κB, in turn, is a key effector of TNF in inflammation-induced cancer. Data from The Cancer Genome Atlas database suggest that TNF could be a biomarker in NSCLC and indicate a complex role for TNF and its receptors in NSCLC. Recent studies have reported that TNF is rapidly upregulated in NSCLC in response to targeted treatment with epidermal growth factor receptor (EGFR) inhibition, and this upregulation leads to NF-κB activation. The TNF upregulation and consequent NF-κB activation play a key role in mediating both primary and secondary resistance to EGFR inhibition in NSCLC, and a combined inhibition of EGFR and TNF can overcome therapeutic resistance in experimental models. TNF may mediate the toxic side effects of immunotherapy and may also modulate resistance to immune checkpoint inhibitors. Drugs inhibiting TNF are widely used for the treatment of various inflammatory and rheumatologic diseases and could be quite useful in combination with targeted therapy of NSCLC and other cancers.

Apoptosis and Autophagy in Picornavirus Infection.

Cell death is a fundamental process in maintaining cellular homeostasis, which can be either accidental or programed. Programed cell death depends on the specific signaling pathways, resulting in either lytic or non-lytic morphology. It exists in two primary forms: apoptosis and autophagic cell death. Apoptosis is a non-lytic and selective cell death program, which is executed by caspases in response to non-self or external stimuli. In contrast, autophagy is crucial for maintaining cellular homeostasis via the degradation and recycling of cellular components. These two mechanisms also function in the defense against pathogen attack. However, picornaviruses have evolved to utilize diverse strategies and target critical components to regulate the apoptotic and autophagic processes for optimal replication and the release from the host cell. Although an increasing number of investigations have shown that the apoptosis and autophagy are altered in picornavirus infection, the mechanism by which viruses take advantage of these two processes remains unknown. In this review, we discuss the mechanisms of picornavirus executes cellular apoptosis and autophagy at the molecular level and the relationship between these interactions and viral pathogenesis.

Effects of Huangkui Capsule on the Expression of SPARC in the Kidney Tissue of a Rat Model with Diabetic Nephropathy.

OBJECTIVE: The objective of the research is to investigate the effects of Huangkui capsule on the expression of SPARC in the kidney tissues of diabetic nephropathy. METHODS: SD rats were divided into three groups: normal control group, untreated DN group and HKC-treated DN group. The therapeutic effects and underlying molecular mechanism of HKC on DN rats induced by streptozotocin were evaluated by the levels of serum creatinine, blood urea nitrogen, 24-hour urinary protein and the expression of SPARC. Pathological changes in kidney tissues were observed through hematoxylin-eosin (HE) staining. Moreover, western blot and quantitative real-time polymerase chain reaction (qRT-PCR) were applied to detect the variation of SPARC. RESULTS: This study was performed to investigate the effects of HKC on DN in SD rats model and its molecular mechanism. Our results showed that the rats treated with HKC had an improved general state and reduced creatinine, blood urea nitrogen and 24-hour urinary protein levels. The deterioration of renal function was delayed due to treatment with HKC. HE staining was utilized to observe that HKC can improve histopathological findings in the kidney tissues of DN rats, including kidney fibrosis. Results of western blot and qRT-PCR showed that HKC can inhibit the expressions of SPARC in the rat model of DN. CONCLUSION: The present findings demonstrated that HKC inhibited SPARC level and had significant therapeutic effects on DN.

Iodine promotes thyroid cancer development via SPANXA1 through the PI3K/AKT signalling pathway.

The aim of this study was to examine the impact of iodine on the development of thyroid cancer cells and to detect the underlying mechanisms. It was observed that proliferation was promoted and apoptosis was inhibited in cells treated with iodine at a specific concentration. This treatment group was then selected for further analysis, to investigate how iodine affects the development of thyroid cancer cells. It was reported that sperm protein associated with the nucleus, X-linked, family member A1 (SPANXA1) expression in iodine-treated cells was significantly upregulated. Furthermore, downregulation of SPANXA1 inhibited cell proliferation, migration and invasion, and promoted cell apoptosis. These results suggested that SPANXA1 played an important role in iodine-treated thyroid cancer cells. Novel associations between SPANXA1 and thyroid cancer were described in the current study. In addition, SPANXA1 gene silencing resulted in the downregulation of PI3K and phosphorylated (p)AKT expression in iodine-treated thyroid cancer cells, whereas iodine treatment alone resulted in upregulated PI3K and p-AKT expression. Inhibiting PI3K further suppressed cell proliferation and contributed to apoptosis, even in the presence of SPANXA1 at high levels. As a consequence, PI3K/AKT may be one of the key signalling pathways by which iodine promotes thyroid cancer development in association with SPANXA1. In addition, our results further suggested that patients with thyroid cancer may need to avoid high-iodine intake.

DHAV-1 2A1 Peptide - A Newly Discovered Co-expression Tool That Mediates the Ribosomal "Skipping" Function.

Duck hepatitis A virus 1 (DHAV-1) belongs to the genus Avihepatovirus in the family Picornaviridae. Little research has been carried out on the non-structural proteins of this virus. This study reports that 2A1 protein, the first non-structural protein on the DHAV-1 genome, has a ribosomal "skipping" function mediated by a "-GxExNPGP-" motif. In addition, we prove that when the sequence is extended 10aa to VP1 from the N-terminal of 2A1, the ribosome "skips" completely. However, as the N-terminus of 2A is shortened, the efficiency of ribosomal "skipping" reduces. When 2A1 is shortened to 10aa, it does not function. In addition, we demonstrate that N18, P19 G20, and P21 have vital roles in this function. We find that the expression of upstream and downstream proteins linked by 2A1 is different, and the expression of the upstream protein is much greater than that of the downstream protein. In addition, we demonstrate that it is the nature of 2A1 that is responsible for the expression imbalance. We also shows that the protein "cleavage" is not due to RNA "cleavage" or RNA transcription abnormalities, and the expressed protein level is independent of RNA transcriptional level. This study provides a systematic analysis of the activity of the DHAV-1 2A1 sequence and, therefore, adds to the "tool-box" that can be deployed for the co-expression applications. It provides a reference for how to apply 2A1 as a co-expression tool.

Autophagy-Src Regulates Connexin43-Mediated Gap Junction Intercellular Communication in Irradiated HepG2 Cells.

Connexin molecules are an important component of the gap junction, with connexin43 (Cx43) being the most abundantly expressed type. Src is a nonreceptor tyrosine-protein kinase that affects Cx43 activity by multiple mechanisms. However, it is not clear how Src regulates Cx43 to influence radiation-induced bystander effects (RIBEs). In this study, we demonstrated that Cx43 on Tyr265 was phosphorylated by activated Src in α-irradiated HepG2 cells, with the total expression of Cx43 unchanged. After inhibition of Cx43 phosphorylation in irradiated cells, the frequency of γ-H2AX foci formation in adjacent nonirradiated bystander cells was significantly enhanced. Furthermore, this study showed that autophagy regulated the activity of Src and phosphorylation of Cx43, and the level of autophagy was correlated with the radiation-induced reactive oxygen species (ROS). These results suggest that ROS and autophagy play an important role in regulating the Src-Cx43 axis to affect the RIBEs. Our findings provide new insights into the Cx43-mediated gap junction intercellular communication, as well as the underlying mechanism of RIBEs.

Cyclooxygenase­2­mediated upregulation of heme oxygenase 1 mitigates the toxicity of deuterium­tritium fusion radiation.

Utilizing the energy released from the nuclear fusion of deuterium with tritium (D­T) may be an important method of supplying energy in the future. The ionizing radiation emitted from nuclear fusion is a potential health risk to humans, including scientists who are currently performing nuclear fusion experiments and the employees of fusion nuclear plants, in the future. However, there have been few reports on the biological effects of fusion radiation. In the present study, using the High Intensity D­T Fusion Neutron Generator, the DNA damage and its regulation in normal human fibroblasts exposed to fusion radiation were investigated. Heme oxygenase 1 (HO­1), which is reported to induce anti­inflammatory activity, was upregulated in the irradiated cells. Pretreatment with the HO­1 inhibitor, protoporphyrin IX zinc (II), exacerbated double strand break formation following exposure to fusion radiation. The expression of cyclooxygenase­2 (COX­2) contributed to the upregulation of HO­1, as demonstrated by the result that its inhibitor, NS­398, inhibited the induction of HO­1 in irradiated cells. It was further clarified that the ataxia telangiectasia mutated DNA damage response was activated and it stimulated the phosphorylation of p38 mitogen­activated protein kinase, which was responsible for the upregulation of COX­2 and HO­1. These results provide novel information on fusion radiation­induced biological effects and potential targets for decreasing the associated health risks.

Structures and Corresponding Functions of Five Types of Picornaviral 2A Proteins.

Among the few non-structural proteins encoded by the picornaviral genome, the 2A protein is particularly special, irrespective of structure or function. During the evolution of the Picornaviridae family, the 2A protein has been highly non-conserved. We believe that the 2A protein in this family can be classified into at least five distinct types according to previous studies. These five types are (A) chymotrypsin-like 2A, (B) Parechovirus-like 2A, (C) hepatitis-A-virus-like 2A, (D) Aphthovirus-like 2A, and (E) 2A sequence of the genus Cardiovirus. We carried out a phylogenetic analysis and found that there was almost no homology between each type. Subsequently, we aligned the sequences within each type and found that the functional motifs in each type are highly conserved. These different motifs perform different functions. Therefore, in this review, we introduce the structures and functions of these five types of 2As separately. Based on the structures and functions, we provide suggestions to combat picornaviruses. The complexity and diversity of the 2A protein has caused great difficulties in functional and antiviral research. In this review, researchers can find useful information on the 2A protein and thus conduct improved antiviral research.

Graphene Oxide Modulates B Cell Surface Phenotype and Impairs Immunoglobulin Secretion in Plasma Cell.

Since discovery, graphene oxide (GO) has been used in all aspects of human life and revealed promising applications in biomedicine. Nevertheless, the potential risks of GO were always being revealed. Although GO was found to induce immune cell death and innate immune response, little is known regarding its toxicity to the specific adaptive immune system that is crucial for protecting against exotic invasion. The B-cell mediated adaptive immune system, which composed of highly specialized cells (B and plasma cell) and specific immune response (antibody response) is the focus in our present study. Using diverse standard immunological techniques, we found that GO modulated B cell surface phenotype, both costimulatory molecules (CD80, CD86 and especially CD40) and antigen presenting molecules (both classical and nonclassical) under the condition without causing cell death. Meanwhile, the terminal differentiated immunoglobulin (Ig) secreting plasma cell was affected by GO, which displayed a less secretion of Ig and more severe ER stress caused by the retention of the secreted form of Ig in cell compartment. The combined data reveal that GO has a particular adverse effect to B cell and the humoral immunity, directly demonstrating the potential risk of GO to the specific adaptive immunity.