Frontiers in bioscience (Landmark edition)最新文献

Background: The activation of adenosine-monophosphate-activated protein kinase (AMPK) by berberine (BBR) benefits various inflammatory diseases. Conversely, high mobility group box-1 (HMGB1), a prototypical damage-associated molecular pattern (DAMP), typically exerts opposing effects. This research aims to investigate the relationship between AMPK and HMGB1, elucidating the functions and underlying mechanisms by which BBR alleviates acute lung injury (ALI) caused by lipopolysaccharide (LPS).

Methods: Male C57BL/6J mice were intragastrically administered BBR twice daily for three days with a total of 25 and 100 mg/kg/day. On day four, an intraperitoneal injection of 10 mg/kg LPS was administered, and BBR was given two hours before and six hours after this injection, respectively. Eighteen hours post-LPS administration, lung tissues and serum samples were collected to assess indicators of lung tissue injury, inflammation, oxidative stress, and apoptosis. The relationship between AMPK activation, HMGB1 release, and inflammatory activation was investigated in both mice and RAW264.7 cells using protein expression analysis, AMPK silencing, and exogenous HMGB1 introduction.

Results: Our findings demonstrate that BBR activates AMPK and inhibits HMGB1 expression, translocation, and release in LPS-induced ALI, resulting in reduced histopathological lung injuries, decreased expression of inflammatory cytokine genes, and diminished oxidative stress and apoptosis. Mechanistic studies revealed that BBR decreases extracellular HMGB1 in LPS-stimulated RAW264.7 cells and inhibits HMGB1-stimulated nuclear factor Kappa B (NF-κB) activation. Concurrently, silencing the activation of AMPK by siRNA and compound C reversed the BBR-reduced extracellular HMGB1 level in LPS-stimulated RAW264.7 cells.

Conclusions: Based on these findings, we conclude that BBR effectively inhibits inflammation, oxidative stress, and apoptosis in LPS-induced ALI by modulating the AMPK-HMGB1-NF-κB axis. Consequently, BBR and other AMPK activators may represent promising therapeutic options for managing systemic inflammation and injury during sepsis.

Background: Triple-negative breast cancer (TNBC) is an aggressive malignancy that lacks effective treatment. Immune infiltration plays an important role in anti-tumor responses. Serpin family G1 (SERPING1), a biomarker associated with immune infiltration, has been implicated in multiple cancers, but its role in TNBC remains unclear.

Methods: RNA sequencing and clinical data for TNBC were obtained from the Gene Expression Omnibus, the Cancer Genome Atlas, and the Molecular Taxonomy of Breast Cancer International Consortium databases. First, the expression, prognostic value, and biological functions of SERPING1 were analyzed. Then, the tumor microenvironment (TME) was comprehensively characterized, and the relationship between SERPING1 expression and immunotherapy response was assessed. Immunohistochemical staining was performed to confirm SERPING1 expression and the abundance of CD4+ T cells and CD8+ T cells in clinical specimens. Finally, single-cell analysis was conducted to investigate the role of SERPING1 in immune cell activation.

Results: SERPING1 was downregulated in TNBC and was an independent predictor of survival. Functionally, SERPING1 activated the immune response in TNBC patients. Mechanistically, elevated SERPING1 levels lead to increased immune cell infiltration, particularly of CD4+ and CD8+ T cells, in the TME. Moreover, SERPING1 was primarily localized in cancer-associated fibroblasts (CAFs), with SERPING1+ apCAFs exhibiting increased communications with anti-tumor immune cells at the single-cell level.

Conclusions: SERPING1 contributes to enhanced immune cell infiltration, desirable immunotherapy response, and improved prognosis. It thus can be utilized as a promising biomarker for immune infiltration and prognosis. These findings provide novel insights into TME-related immune regulation and may inform strategies to enhance immunotherapy efficacy in TNBC.

Background: N6-methyladenosine (m6A) RNA methylation is a crucial epigenetic modification that plays an essential role in regulating diverse biological processes. Accurate identification of m6A sites is therefore fundamental to understanding its regulatory mechanisms. In this study, we proposed DT-m6A, a novel deep learning framework that integrates DenseNet and Transformer architectures for accurate m6A site identification across diverse cell lines and tissues.

Methods: RNA sequences are first encoded using nucleotide chemical properties (NCP) for initial features extraction, after which DenseNet captures and reuses local sequence features through dense connections. The Transformer module then models long-range dependencies and extracts nonlinear representations, in which Batch Normalization replaces the conventional Layer Normalization in both sublayers to enhance training stability. Finally, a fully connected layer predicts m6A modification sites.

Results: Evaluated on 11 independent test sets spanning eight cell lines and three tissue types, DT-m6A demonstrated robust performance, achieving average accuracy (ACC) of 76.97%, Matthews correlation coefficient (MCC) of 54.27%, precision (PRE) of 75.18%, recall (REC) of 79.76%, and F1 score of 77.26%.

Conclusions: DT-m6A surpassed the state-of-the-art method MST-m6A by 0.63% in average accuracy (p = 0.0023) and 1.4% in mean MCC (p = 0.0012) across 11 independent test sets. Although its performance on the CD8T and MOLM13 cell lines was comparable to MST-m6A, DT-m6A consistently achieved superior results across all other cell lines and tissues. Overall, DT-m6A effectively captures both local patterns and global dependencies in RNA sequences, improving prediction performance across diverse biological contexts.

Introduction: Epithelial-mesenchymal transition (EMT) is a fundamental biological process. During EMT, epithelial cells transition to a mesenchymal phenotype, thereby contributing to embryonic development, tissue renewal, and cancer progression. EMT is a well-recognized key driver of tumor invasion and metastasis. However, the transcriptional differences between the physiological and cancer-associated EMT remain incompletely understood.

Methods: In the present study, we applied an integrative framework that combined transcriptomic profiling, functional enrichment analysis, and machine learning. The analysis was performed on 89 RNA-sequencing datasets derived from mouse cell lines and tissues, encompassing both normal and malignant contexts. This approach aimed to identify and prioritize genes systematically and signaling pathways associated with EMT.

Results: Differential gene expression and pathway enrichment analyses revealed an over-representation of shared core biological processes related to cell adhesion, cytoskeletal remodeling, and morphogenesis, in both normal and cancer-associated EMT. Nonetheless, cancer-associated EMT exhibited additional enrichment for developmental and neural-related programs, including neurogenesis and gliogenesis. Machine learning models consistently prioritized candidate EMT biomarkers, with greater transcriptional heterogeneity observed in cancer samples.

Conclusion: Collectively, this integrative analysis delineates distinct transcriptional profiles between malignant and physiological EMT. The enrichment of neural-related programs in cancer-associated EMT highlights potential mechanisms that contribute to malignant cellular plasticity. In addition, the analysis identifies candidate biomarkers for future investigation of EMT heterogeneity.

The mammalian tongue is an intricate skeletal muscle organ. From its initial formation to maturation, tongue muscle development involves precisely coordinated processes during embryonic and fetal phases of myogenesis. Extensive research on the regulatory pathways involved in tongue epithelial taste organ development has shown that the Hedgehog (HH) signaling pathway is vital to the formation and epithelial patterning of the tongue and taste organs. Emerging evidence also points to its involvement in the initial formation and spatial patterning of the tongue muscle. HH signaling is a well-established regulator of skeletal muscle development, particularly in limb myogenesis. However, structural and functional differences between limb and tongue muscles, as well as variations in their HH signaling regions, prevent the direct application of findings from limb muscles to the tongue. Consequently, a comprehensive comparative analysis is essential to establish the conserved and divergent mechanisms by which HH signaling operates in these distinct muscle systems. A detailed mechanistic understanding of HH signaling during lingual muscle formation and maturation is vital for fully elucidating its role in tongue function. Further, lingual myogenesis studies pave the way for potential regenerative therapeutic strategies for congenital anomalies and acquired conditions affecting the tongue. Thus, understanding the regulatory mechanisms of tongue muscle development has both biological and clinical importance. This review explores the role of HH signaling throughout the key stages of embryonic tongue muscle development (including myoblast determination, proliferation, differentiation, patterning, and maturation) and compares its role in limb myogenesis.

Stroke is a leading cause of long-term disability, and many patients fail to achieve complete recovery following cerebral injury. Therefore, post-stroke rehabilitation is essential to restore impaired function. Transcranial electrical stimulation (tES), transcranial direct current stimulation (tDCS), and transcranial alternating current stimulation (tACS) have emerged as promising neuromodulation approaches to enhance post-stroke recovery. These treatments have therapeutic effects to restore impaired function by modulating cortical excitability and reorganizing brain tissue through electrical stimulation. However, the fundamental mechanisms underlying these therapeutic effects remain poorly understood. This review focused on the neurobiological mechanisms underlying tES that extend beyond cortical excitability and encompass long-term neuroplasticity, cerebral blood flow, neurometabolism, and neuroinflammatory modulation. Our summary provides a comprehensive understanding of tES processes and plays a vital role in the advancement of improved treatments. Additionally, our review promotes enhanced clinical outcomes through interactions with various stroke rehabilitation strategies.

Background: Acupuncture has been shown to promote gastrointestinal motility. This study explores whether cutaneous transient receptor potential vanilloid 1 (TRPV1)⁺ fibers at Zusanli (ST36) acupoint can mediate the multimodal effects of acupuncture on colorectal motility, as well as examining their mechanistic role.

Methods: C57BL/6 mice were subjected to electroacupuncture (EA), manual acupuncture (MA), 46 °C thermal stimulation, and 1% capsaicin at the ST36 acupoint. Colon motility was quantified via the area under the curve (AUC) and contraction amplitude. Immunofluorescent co-localization of TRPV1 with CGRP, NF200, peripherin, and tyrosine hydroxylase (TH) was conducted in TrpV1^Cre mice to determine neural phenotypic subtypes. Furthermore, TrpV1^ChR2-eYFP and TrpV1^NpHR-eYFP transgenic mice that underwent optogenetic activation or silencing of local TRPV1⁺ fibers at ST36 were evaluated for acupuncture-like stimulation effects on colorectal AUC and amplitude.

Results: All applied stimuli in C57BL/6 mice significantly increased colorectal motility parameters (AUC and amplitude, p < 0.05) compared to baseline. TRPV1⁺ somatosensory neurons in the dorsal root ganglion (DRG) predominantly co-expressed with peripherin (46.76%) and CGRP (27%), which are markers of unmyelinated peptidergic fibers, but rarely with NF200 (6%) or TH (< 1%). Optogenetic activation (30 mW blue light) of TRPV1⁺ fibers in TrpV1^ChR2-eYFP mice mimicked acupuncture-like stimuli, with significantly enhanced colorectal AUC and amplitude (p < 0.05). In contrast, optogenetic silencing of TRPV1⁺ fibers with yellow light abolished acupuncture-like stimulation of colorectal motility in TrpV1^NpHR-eYFP mice (p < 0.05).

Conclusion: Through the use of spatiotemporally precise optogenetic control, our study revealed that TRPV1⁺ sensory fibers at ST36 are the major convergent pathway for multimodal (electrical/mechanical/thermal/chemical) enhancement of colorectal motility by acupuncture.

Background: Identifying oncogenic drivers with broad relevance across multiple cancer types is critical for developing novel therapeutic strategies. Kinesin family member 18B (KIF18B) is involved in mitotic regulation, but its comprehensive role and clinical significance across human malignancies remain poorly understood. This study performed a comprehensive pan-cancer analysis of KIF18B and experimentally validated its role in lung adenocarcinoma (LUAD).

Methods: We conducted a comprehensive bioinformatic analysis using public databases to evaluate the expression profile, prognostic value, and potential biological functions of KIF18B across various human cancers. Based on these findings, LUAD was selected for further investigation. We evaluated KIF18B protein levels in LUAD cell lines (A549, HCC827, H1975) and compared them to a normal bronchial epithelial cell line (BEAS-2B). Subsequently, KIF18B was silenced in A549 cells using small interfering RNA (siRNA), and its effects on cell proliferation, migration, and invasion were examined using colony formation, wound-healing, and Transwell assays.

Results: Our analysis across various cancers revealed that KIF18B is markedly overexpressed, including in LUAD, and this high expression correlates with poor prognosis in patients across different cancer types. In line with these bioinformatic results, our experiments confirmed that KIF18B protein levels were elevated in LUAD cell lines compared with normal controls. Functional assays demonstrated that knockdown of KIF18B in A549 cells significantly suppressed colony-forming ability and impaired migratory and invasive capacities.

Conclusions: This study, integrating pan-cancer bioinformatic analysis with experimental validation, establishes KIF18B as a widely expressed oncogene with significant prognostic value. Our findings in LUAD confirm its crucial role in promoting key malignant phenotypes. Thus, KIF18B emerges as a valuable prognostic biomarker and a potential therapeutic target, not only for LUAD but potentially for a wider array of cancers.

Objective: Emerging evidence indicates that Akkermansia muciniphila (A. muciniphila or AKK) regulates host glucose metabolism through multiple pathways. In this study, we examined the therapeutic effects of A. muciniphila on chronic sleep deprivation (CSD)-induced glucose dysregulation and the underlying mechanisms.

Methods: A modified multiplatform water environment method was used to generate a mouse model of CSD. The mice were divided into three groups: the control (CON) group (ad libitum sleep), the CSD group (subjected to sleep deprivation), and the CSD+AKK group (CSD mice were supplemented with A. muciniphila at 3 × 10⁸ CFU per mouse, three times per week). After an 8-week intervention, glucose metabolism was assessed. Serum concentrations of lipopolysaccharide (LPS), interleukin-6 (IL-6), interleukin-1β (IL-1β) and tumor necrosis factor α (TNF-α) were measured. The mRNA expression and protein expression of mucin 2 (MUC2) and zonula occludens-1 (ZO-1) in the colon tissue were analyzed. Goblet cells in colon tissues were quantified using Alcian Blue-Periodic Acid-Schiff (AB-PAS) staining. Additionally, changes in gut microbiome diversity and composition among groups were compared.

Results: CSD induced significant glucose intolerance and insulin resistance, evidenced by increased area under the curve (AUC) of the oral glucose tolerance test (OGTT), homeostatic model assessment of insulin resistance (HOMA-IR), and fasting insulin levels compared to the CON group (all p < 0.05). This was accompanied by a marked impairment of the colonic mucosal barrier, characterized by a profound loss of goblet cells and downregulation of key barrier components, MUC2 and ZO-1, at both the mRNA and protein levels (all p < 0.05). Intervention with A. muciniphila significantly ameliorated CSD-induced glucose intolerance, insulin resistance and colonic barrier damage. Furthermore, CSD elevated serum levels of LPS, IL-6, TNF-α, and IL-1β (all p < 0.05), which were effectively mitigated by A. muciniphila intervention. 16S rDNA sequencing confirmed the successful colonization of A. muciniphila, as its absolute abundance was significantly greater in the CSD+AKK group than in the CSD group. In addition, A. muciniphila intervention affected the abundance of Burkholderiales bacterium, Lactococcus garvieae, and other bacterial strains in the intestine.

Conclusion: A. muciniphila supplementation effectively ameliorated CSD-induced glucose intolerance, reduced the serum levels of LPS and proinflammatory cytokines (IL-6, TNF-α, and IL-1β), and restored intestinal barrier integrity by upregulating MUC2 and ZO-1 expression in colon tissues.

People with autism spectrum disorders (ASD) show a relative suppression of the melatonergic pathway across CNS and systemic cells. The differential regulation of the mitochondrial melatonergic pathway may therefore be an important core aspect of ASD pathophysiology in all its manifestations. Recent data across diverse human cells show that the melatonergic pathway is powerfully regulated by interactions between signal transducer and activator of transcription 3 (STAT3) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), with the composition of the NF-κB dimer determining whether the melatonergic pathway is upregulated or downregulated. Diverse aspects of ASD pathoetiology and pathophysiology, including the aryl hydrocarbon receptor (AhR), microRNAs, suboptimal mitochondrial function, pro-inflammatory cytokines, glucocorticoid receptor, vagal nerve, and oxytocin, are all intimately linked to pineal and/or local melatonin regulation, indicating the relevance of the mitochondrial melatonergic pathway regulation in the pathoetiology and pathophysiology of ASD. This article reviews and integrates diverse aspects of ASD pathoetiology and pathophysiology, with implications for future research and treatment.