ObjectiveTo analyze the clinical features, laboratory findings, and treatment outcomes of febrile hospitalized children with herpes simplex virus (HSV) detected by serological and/or molecular biological tests, and to provide an evidence-based basis for the early clinical screening, differential diagnosis and targeted intervention of HSV in pediatric febrile cases.MethodsA retrospective analysis was performed on the clinical data of 100 febrile children with positive HSV test results who were admitted to Jinan Children's Hospital from January 2018 to October 2024. The collected data included demographic characteristics, clinical manifestations, confirmed clinical diagnoses, co-detected pathogen status(diagnosed by a combination of serology, PCR and microbial culture), laboratory examination indicators, treatment regimens(including individualized acyclovir course), and prognostic outcomes. HSV detection was conducted by serum HSV-IgM antibody assay and/or HSV-DNA detection in pharyngeal swab/blood samples, and the number of cases with single positive and double positive results of the two tests was statistically analyzed separately. All statistical analyses were performed using SPSS 26.0 software, with measurement data described as median [interquartile range (IQR)] and compared by Mann–Whitney U test. A two-sided P < 0.05 was considered statistically significant.ResultsAmong the 100 children, 62 were male and 38 were female, with a male-to-female ratio of 1.6:1. The age ranged from 1 month to 8 years, with a median age of 2.1 years, and the 1 to <3 years age group accounted for the highest proportion (56.0%, 56/100). Fever was the primary admission symptom in all cases, with 72.0% (72/100) presenting with high fever (≥39 °C). The most common local manifestation was oral mucosal lesions (19.0%, 19/100). Physical examination showed cervical lymphadenopathy in 85.0% (85/100) and pharyngeal mucosal congestion/redness in 92.0% (92/100) of the children. Of the 100 HSV-positive cases, 65 (65.0%) were double positive for HSV-IgM and HSV-DNA, 23 (23.0%) were single positive for HSV-IgM, and 12 (12.0%) were single positive for HSV-DNA. Other pathogens were co-detected in 52.0% (52/100) of the cases, with Epstein–Barr virus (EBV) being the most common (27.0%, 27/100). Abnormal liver function (elevated alanine aminotransferase [ALT] and/or aspartate aminotransferase [AST]) was found in 30.0% (30/100) of the children. Ninety-two children received intravenous acyclovir for antiviral treatment, with a median time to defervescence of 2.5 days (IQR: 2.0–3.0) and a median hospital stay of 7.0 days (IQR: 6.0–8.0). All children were cured and discharged. Statistical analysis showed that children who received early acyclovir treatment (within 24 h of admission) had significantly shorter time to defervescence and hospital stay compared with those in the delayed treatment group (>24 h) (Z = −3.874 and −4.125, respectively, both P < 0.001). Co-detection of EBV and abnormal liver function were associated with a significant prolongation of hospital stay (Z = −3.987 and −4.563, respectively, both P < 0.001).ConclusionHSV is a frequently isolated pathogen in febrile infants and young children with herpetic gingivostomatitis as the core clinical diagnosis and diverse clinical manifestations dominated by non-specific systemic and oropharyngeal symptoms (cutaneous herpes with low incidence). HSV infection is often accompanied by co-detection of other pathogens such as EBV and Bordetella pertussis (diagnosed by standardized serological, PCR and microbial culture methods) and abnormal liver function in some cases. Early HSV-PCR detection combined with serological testing, timely and individualized acyclovir treatment (with clear course standards) based on comprehensive clinical judgment can significantly improve the clinical outcomes of febrile children with HSV detected. Comprehensive intervention targeting co-detected pathogens and complications is equally important for the clinical management of such cases.

[This retracts the article DOI: 10.1016/j.omtn.2017.12.014.].

BACKGROUND:Peripheral nerve injury frequently causes refractory neuropathic pain and muscle atrophy. While clinical care focuses on analgesia, effective therapies for muscle wasting are lacking. Angelica dahurica (BZ) is known for its analgesic properties, but whether it also ameliorates muscle atrophy remains unclear. PURPOSE:This study evaluates the dual analgesic and anti‑atrophic effects of BZ, with a focus on determining whether its muscle‑protective action is separable from pain relief and elucidating the underlying mechanism. METHODS:Following sciatic nerve chronic constriction injury (CCI), rats were treated with BZ extract or Pregabalin (Pre), a positive analgesic control. Nociceptive behaviors and motor function were assessed via behavioral tests and gait analysis. Muscle atrophy was evaluated by wet weight, histology, and transmission electron microscopy. RNA‑seq was performed to profile transcriptomic changes in muscle. High‑resolution mass spectrometry was used to identify BZ‑derived components in plasma and muscle. RESULTS:Post-CCI muscle atrophy and pain showed distinct temporal trajectories, with atrophy transitioning from an acute phase of rapid mass loss (days 1-10) to a later phase of progressive fibrosis (days 14-21). BZ administration significantly alleviated mechanical, cold, and thermal hypersensitivity, while concurrently increasing muscle mass and partially improving myofiber morphology and sarcomere ultrastructure. Notably, while Pre provided equivalent analgesia, it failed to mitigate muscle atrophy, demonstrating that the anti-atrophic effect of BZ is largely independent of its analgesic activity. Mechanistically, BZ-mediated recovery was associated with the modulation of the intramuscular Phlpp2‑Akt‑ FoxO3α signaling axis, as indicated by suppressed Phlpp2 expression and enhanced Akt phosphorylation. Seven muscle-distributed components were identified as potential contributors to these therapeutic effects. CONCLUSIONS:BZ exerts potential anti-atrophic effects that correlated with modulation of the Phlpp2‑Akt‑FoxO3α axis, largely independent of its analgesic activity. These findings identify BZ as a promising dual-action therapeutic candidate for addressing both neuropathic pain and muscle wasting following peripheral nerve injury.

A common hypoxic scenario in tumors involves unresolved acute hypoxia that eventually leads to sustained (chronic) hypoxia. This shift drives a characteristic "HIF switch", where the key hypoxia-responsive factors change from HIF-1α to HIF-2α over time, and importantly, this switch is closely linked to stemness regulation. However, the mechanisms underlying this switch and its impact on stemness regulation are not yet fully understood. Here, we developed a mechanistic network model integrating the HIF-1/HIF-2 signaling axis with the stemness regulators OCT4 and SOX2. We found that the duration and intensity of hypoxia jointly shape the dynamics of HIF-1α and HIF-2α, ultimately regulating OCT4-mediated stemness. Under physioxia, HIF-2α-mTORC2 positive feedback supports the gradual accumulation of HIF-2α toward a modest steady level and low OCT4 expression, corresponding to a primed state. Under prolonged mild hypoxia, the concurrent induction of HIF-1α, albeit at low levels, and accelerated accumulation of HIF-2α elevate OCT4 to intermediate levels, promoting stem-like traits. Under moderate hypoxia, PHD-2-mediated negative feedback triggers pulsatile HIF-1α dynamics, driving a shift toward HIF-2α dominance. Ultimately, cooperative HIF-1α/HIF-2α signaling induces REDD1 and suppresses mTORC1-dependent protein synthesis, pushing OCT4 into a high-expression state associated with differentiation. This work presents a unified framework for understanding how the HIF signaling hierarchy coordinates metabolic and transcriptional programs to direct cell fate across varying hypoxic landscapes.

[This retracts the article DOI: 10.1016/j.omtn.2017.12.020.].

Tumour cell dormancy is a reversible, non-proliferative state in which cancer cells arrest in the G0 phase of the cell cycle. Increasingly recognized as a critical survival strategy, dormancy enables cancer cells to withstand therapeutic insult, escape immune surveillance, and endure hostile microenvironments. Clinically, dormant cells underlie extended asymptomatic intervals following primary treatment and are notably implicated in estrogen receptor-positive (ER+) breast cancer, prostate cancer, and clear cell renal cell carcinoma. In this review, we synthesize recent insights into hypoxia-mediated dormancy and, using breast cancer bone metastasis as an archetypal model, delineate how spatiotemporally heterogeneous hypoxia shapes the metastatic cascade. Specifically, we show that graded hypoxia in the primary tumour initiates dormancy traits, while persistent hypoxia within metastatic niches - such as the bone marrow - reinforces and deepens quiescence. These transitions are orchestrated by stage-specific activation of hypoxia-inducible factor 1α (HIF-1α) and its dynamic transcriptional outputs. We further argue that a mechanistic understanding of dormancy requires integrative frameworks that bridge single-cell level regulatory programs - including cell-cycle arrest, translational inhibition, and metabolic reprogramming - with systems-level networks capturing the dynamic, multistage nature of metastasis. Such integration may uncover actionable vulnerabilities within dormant cell populations and guide the development of precision therapies targeting minimal residual disease.

Increasing evidence shows that RNA-binding proteins play crucial roles in modulating the blood-tumor barrier (BTB) permeability in glioblastoma (GB). In this study, we identified elevated expression of Musashi RNA-binding protein 2 (MSI2) and Long intergenic nonprotein coding RNA 667 (LINC00667) in glioma co-cultured endothelial cells. MSI2 enhanced the stability of LINC00667, and its knockdown elevated the BTB permeability. In contrast, transcription factor interferon regulatory factor 6 (IRF6) exhibited reduced expression in glioma co-cultured endothelial cells, and its over-expression elevated the BTB permeability. Mechanistically, LINC00667 facilitated IRF6 mRNA degradation through Staufen1-mediated mRNA decay pathway. IRF6 inhibited the transcriptions of key tight junction associated proteins (ZO-1, occludin, and claudin-5) through promoter binding. That is, MSI2 knockdown down-regulated the expression of LINC00667, thereby diminishing its ability to degrade IRF6 through the Staufen1-mediated mRNA decay pathway. This led to IRF6 accumulation, which transcriptionally suppressed ZO-1, occludin and claudin-5 expression, ultimately increasing BTB permeability. Furthermore, both individual and combined modulation of MSI2 knockdown, LINC00667 knockdown and IRF6 over-expression enhanced BTB permeability to doxorubicin, thereby increasing the apoptosis rate of GB cells. Collectively, the MSI2/LINC00667/IRF6 pathway plays an important role in modulating BTB permeability, offering potential targets for new molecular therapies in GB.

BACKGROUND:Heterozygous PURA (Purine-rich element-binding protein A) variants cause PURA syndrome, a neurodevelopmental disorder characterised by hypotonia, seizures and intellectual disability. Previous studies have focused on the effect of the PURA variant in the cytoplasmic location, but nuclear mislocalisation remains to be explored. METHODS:We identified a de novo heterozygous frameshift variant (c.442del, p.L148Wfs*77) via trio whole-exome sequencing in one child suspected of PURA syndrome due to intellectual disability. Functional analyses included structural modelling, subcellular localisation assays, RNA-seq, CUT&Tag and DNA unwinding assays. RESULTS:The variant disrupts PURA repeats II-III, causing aberrant nuclear mislocalisation. RNA-seq revealed 688 differentially expressed genes enriched in neurodevelopmental pathways. CUT&Tag analysis revealed that PURA and Pol II exhibit enhanced binding at transcription start sites in cells expressing the variant, indicating dysregulated transcriptional engagement. Despite retained nucleic acid binding, the variant impaired DNA unwinding partly due to disrupted repeat III-mediated homodimerisation. CONCLUSIONS:Nuclear mislocalisation of the PURA variant dysregulates transcriptional balance and impairs DNA unwinding, linking PURA's structural integrity to neurodevelopmental deficits. This highlights PURA's dual roles in cytoplasmic RNA regulation and nuclear transcription, providing mechanistic insights into PURA syndrome pathogenesis.

The journal retracts the article titled “Shikonin Inhibits the Migration and Invasion of Human Glioblastoma Cells by Targeting Phosphorylated β-Catenin and Phosphorylated PI3K/Akt: A Potential Mechanism for the Anti-Glioma Efficacy of a Traditional Chinese Herbal Medicine” [...]

Graded hypoxia is a common microenvironment in malignant solid tumors. As a central regulator in the hypoxic response, hypoxia-inducible factor-1 (HIF-1) can induce multiple cellular processes including glycolysis, angiogenesis, and necroptosis. How cells exploit the HIF-1 pathway to coordinate different processes to survive hypoxia remains unclear. We developed an integrated model of the HIF-1α network to elucidate the mechanism of cellular adaptation to hypoxia. By numerical simulations and bifurcation analysis, we found that HIF-1α is progressively activated with worsening hypoxia due to the sequential deactivation of the hydroxylases prolyl hydroxylase domain enzymes and factor inhibiting HIF (FIH). Bistable switches control the activation and deactivation processes. As a result, glycolysis, immunosuppression, angiogenesis, and necroptosis are orderly elicited in aggravating hypoxia. To avoid the excessive accumulation of lactic acid during glycolysis, HIF-1α induces monocarboxylate transporter and carbonic anhydrase 9 sequentially to export intracellular hydrogen ions, facilitating tumor cell survival. HIF-1α-induced miR-182 facilitates vascular endothelial growth factor production to promote angiogenesis under moderate hypoxia. The imbalance between accumulation and removal of lactic acid in severe hypoxia may result in acidosis and induce cell necroptosis. In addition, the deactivation of FIH results in the destabilization of HIF-1α in anoxia. Collectively, HIF-1α orchestrates the adaptation of tumor cells to hypoxia by selectively inducing its targets according to the severity of hypoxia. Our work may provide clues for tumor therapy by targeting the HIF-1 pathway.

BACKGROUND:Glioblastoma multiforme (GBM) is a highly aggressive brain tumor, characterized by its poor prognosis. Glycolipid metabolism is strongly associated with GBM development and malignant behavior. However, the precise functions of snoRNAs and ADARs in glycolipid metabolism within GBM cells remain elusive. The objective of the present study is to delve into the underlying mechanisms through which snoRNAs and ADARs exert regulatory effects on glycolipid metabolism in GBM cells. METHODS:RNA immunoprecipitation and RNA pull-down experiments were conducted to verify the homodimerization of ADAR2 by SNORD113-3, and Sanger sequencing and Western blot experiments were used to detect the A-to-I RNA editing of PHKA2 mRNA by ADAR2. Furthermore, the phosphorylation of EBF1 was measured by in vitro kinase assay. Finally, in vivo studies using nude mice confirmed that SNORD113-3 and ADAR2 overexpression, along with PHKA2 knockdown, could suppress the formation of subcutaneous xenograft tumors and improve the outcome of tumor-bearing nude mice. RESULTS:We found that PHKA2 in GBM significantly promoted glycolipid metabolism, while SNORD113-3, ADAR2, and EBF1 significantly inhibited glycolipid metabolism. SNORD113-3 promotes ADAR2 protein expression by promoting ADAR2 homodimer formation. ADAR2 mediates the A-to-I RNA editing of PHKA2 mRNA. Mass spectrometry analysis and in vitro kinase testing revealed that PHKA2 phosphorylates EBF1 on Y256, reducing the stability and expression of EBF1. Furthermore, direct binding of EBF1 to PKM2 and ACLY promoters was observed, suggesting the inhibition of their expression by EBF1. These findings suggest the existence of a SNORD113-3/ADAR2/PHKA2/EBF1 pathway that collectively regulates the metabolism of glycolipid and the growth of GBM cells. Finally, in vivo studies using nude mice confirmed that knockdown of PHKA2, along with overexpression of SNORD113-3 and ADAR2, could obviously suppress GBM subcutaneous xenograft tumor formation and improve the outcome of those tumor-bearing nude mice. CONCLUSIONS:Herein, we clarified the underlying mechanism involving the SNORD113-3/ADAR2/PHKA2/EBF1 pathway in the regulation of GBM cell growth and glycolipid metabolism. Our results provide a framework for the development of innovative therapeutic interventions to improve the prognosis of patients with GBM.

Graded hypoxia is a common microenvironment in malignant solid tumors. As a central regulator in the hypoxic response, hypoxia-inducible factor-1 (HIF-1) can induce multiple cellular processes including glycolysis, angiogenesis, and necroptosis. How cells exploit the HIF-1 pathway to coordinate different processes to survive hypoxia remains unclear. We developed an integrated model of the HIF-1α network to elucidate the mechanism of cellular adaptation to hypoxia. By numerical simulations and bifurcation analysis, we found that HIF-1α is progressively activated with worsening hypoxia due to the sequential deactivation of the hydroxylases prolyl hydroxylase domain enzymes and factor inhibiting HIF (FIH). Bistable switches control the activation and deactivation processes. As a result, glycolysis, immunosuppression, angiogenesis, and necroptosis are orderly elicited in aggravating hypoxia. To avoid the excessive accumulation of lactic acid during glycolysis, HIF-1α induces monocarboxylate transporter and carbonic anhydrase 9 sequentially to export intracellular hydrogen ions, facilitating tumor cell survival. HIF-1α-induced miR-182 facilitates vascular endothelial growth factor production to promote angiogenesis under moderate hypoxia. The imbalance between accumulation and removal of lactic acid in severe hypoxia may result in acidosis and induce cell necroptosis. In addition, the deactivation of FIH results in the destabilization of HIF-1α in anoxia. Collectively, HIF-1α orchestrates the adaptation of tumor cells to hypoxia by selectively inducing its targets according to the severity of hypoxia. Our work may provide clues for tumor therapy by targeting the HIF-1 pathway.

Glioma is the most common type of primary intracranial malignancy. The average survival time of patients with malignant glioma is less than 15 months. Vasculogenic mimicry (VM) is a tubular structure independent of vascular endothelial cells formed by malignant tumor cell. VM is closely related to the pathological grade and cell malignant biological behavior of glioma. Inhibition of vasculogenic mimicry in glioma cells can be used as one of the main steps of anti-angiogenesis therapy. The study revealed that long non-coding RNA ST7 antisense RNA 2 (lncRNA ST7-AS2) changes RNA binding motif protein 22 (RBM22) nucleoplasmic distribution by promoting small ubiquitin like modifier (SUMO) modification of RBM22. RBM22 upregulates the transcription activity of vascular endothelial growth factor recptor 2 (VEGFR2) promotor by binding SRY-box transcription factor 2 (SOX2). The results of xenograft tumor model in nude mice showed that combined knockdown of RBM22 and lncRNA ST7-AS2 was the most effective in inhibiting tumor formation in vivo, with the least formation of vasculogenic mimicry and the longest survival time in nude mice. The lncRNA ST7-AS2/RBM22/SOX2 axis play a crucial part in the process of VM formation in gliomas and could provide potential alternative strategies for the combined anti-tumor therapy.

Glioblastoma multiforme (GBM) is the most common and aggressive primary central nervous system tumor. The formation of vasculogenic mimicry (VM) in GBM is closely related to poor patient prognosis. Therefore, it is urgently necessary to explore the mechanisms that promote VM formation in GBM and identify therapeutic targets. CGGA data analysis revealed that TRMT10A expression is significantly downregulated in WHO grade IV primary glioma samples compared to grade II samples, consistent with the protein expression levels. Additionally, GBM patients with low TRMT10A expression have poorer prognoses. In human glioma cells, TRMT10A expression is significantly lower than in human astrocytes. Knockdown of TRMT10A reduces m1G9 modification of tRNA-ArgCCT, upregulates tRF-22 expression, and promotes glioma cell proliferation, migration, invasion, and tube formation. Overexpression of tRF-22 in glioma cells significantly downregulates MXD1 expression. tRF-22 negatively regulates MXD1 expression by binding to its 3’UTR, reducing MXD1’s transcriptional inhibition of HIF1A, thereby promoting glioma cell proliferation, migration, invasion, and tube formation. Overexpression of TRMT10A combined with tRF-22 inhibition significantly reduces the number of VM channels and inhibits tumor growth in xenograft models in nude mice. This study elucidates the mechanism by which TRMT10A affects VM formation in glioma and provides a novel therapeutic target for GBM.

BACKGROUND:H1N1 influenza virus can cause diffuse alveolar damage, such as pneumonia and pulmonary fibrosis, when it infects the respiratory tract. Metformin not only improves chronic inflammation but also has direct anti-inflammatory effects. Therefore, the focus of this study was on the molecular mechanism and regulatory mechanism of metformin against influenza virus in alleviating lung disease. METHODS:An animal model of H1N1 infection was constructed by injecting H1N1 virus into mice. The lung tissues of H1N1-infected mice treated with metformin were subjected to miRNA-seq, and the data were analyzed. The weights and lung indices of the mice were evaluated. The pathological tissues were stained with HE and Masson's trichrome. H1N1-infected A549 cells were used to construct a model of H1N1 infection. Western blotting was used to detect virus-, apoptosis-, PI3K/AKT signaling pathway-, and inflammation-related proteins. The expression of miR-130a-5p was detected by RT‒qPCR. IF was used to detect virus replication. TUNEL and flow cytometry were used to detect apoptosis. ELISA was used to detect inflammatory factors. Cell proliferation was detected using CCK-8 and EDU assays. RESULTS:Metformin effectively alleviated H1N1-induced fibrosis, inflammation and apoptosis. Bioinformatics analysis revealed that miR-130a-5p was the only miRNA that was differentially expressed in both groups (normal vs. H1N1 group; H1N1 vs. metformin group). In H1N1-induced A549 cell experiments, metformin promoted the upregulation of miR-130a-5p, thereby inhibiting PI3K/AKT signaling pathway activation. However, the miR-130a-5p inhibitor and PI3K/AKT agonist weakened the protective effects of metformin on A549 cell proliferation, anti-apoptosis and viral inhibition to some extent. CONCLUSION:Metformin alleviates H1N1-induced fibrosis, inflammation, and apoptosis by inhibiting the aberrant activation of PI3K/AKT by the promotion of miR-130a-5p expression.

The most common primary malignant tumor of the central nervous system is glioma. One of the key features of malignant tumors is energy reprogramming, which involves changes in lipid metabolism. The objective of our study was to investigate the role of SRSF10, SNORD46, FTSJ3, and FOXO4 in regulating lipid metabolism and proliferation of glioma cells. Our findings revealed a significant increase in the expression of SRSF10, SNORD46, and FTSJ3 in glioma tissues and cells. Knockdown of SRSF10 and SNORD46 led to a reduction in both glioma cell proliferation and lipid metabolism. Furthermore, we discovered that SRSF10 enhanced the stability of SNORD46 by directly binding to it. The study revealed that FTSJ3 functions as a 2'-O-methylation transferase, while SNORD46 downregulated FOXO4 expression by promoting its 2'-O-methylation via FTSJ3. Additionally, FOXO4 suppressed lipid metabolism and cell proliferation in glioma cells by binding to the promoter regions of target genes ACLY and FASN and inhibiting transcription. Furthermore, SRSF10 stabilized SNORD46, which enhanced the SRSF10/SNORD46/FTSJ3/FOXO4 signaling pathway's role as a crucial regulator of glioma cell proliferation and lipid metabolism, presenting potential therapeutic targets for glioma treatment.

Chronic cerebral ischemia (CCI) is a clinical syndrome characterised by brain dysfunction due to decreased chronic cerebral perfusion. CCI initiates several inflammatory pathways, including pyroptosis. RNA-binding proteins (RBPs) play important roles in CCI. This study aimed to explore whether the interaction between RBP-Cpeb4 and Dclk2 affected Ehf phosphorylation to regulate neuronal pyroptosis. HT22 cells and mice were used to construct oxygen glucose deprivation (OGD)/CCI models. We found that Cpeb4 and Dclk2 were upregulated in OGD-treated HT22 cells and CCI-induced hippocampal CA1 tissues. Cpeb4 upregulated Dclk2 expression by increasing Dclk2 mRNA stability. Knockdown of Cpeb4 or Dclk2 inhibited neuronal pyroptosis in OGD-treated HT22 cells and CCI-induced hippocampal CA1 tissues. By binding to the promoter regions of Caspase1 and Caspase3, the transcription factor Ehf reduced their promoter activities and inhibited the transcription. Dclk2 phosphorylated Ehf and changed its nucleoplasmic distribution, resulting in the exit of p-Ehf from the nucleus and decreased Ehf levels. It promoted the expression of Caspase1 and Caspase3 and stimulated neuronal pyroptosis of HT22 cells induced by OGD. Cpeb4/Dclk2/Ehf pathway plays an important role in the regulation of cerebral ischemia-induced neuronal pyroptosis.