Search Results (2,351)

Triple-negative breast cancer (TNBC), characterized by the lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression, is a highly aggressive molecular subtype with high recurrence and metastasis rates. Due to the absence of reliable molecular targets, surgery combined with chemotherapy remains the mainstay of clinical treatment. In recent years, immunotherapy has provided new strategies for TNBC management. Immune checkpoints are key regulatory molecules that maintain immune homeostasis, and blocking these checkpoints can restore T cell activity and enhance tumor cell killing. Immune checkpoint inhibitors (ICIs) have demonstrated clinical benefit, particularly in combination with chemotherapy for patients with locally advanced or metastatic TNBC. This review focuses on immune checkpoint–based immunotherapy in TNBC, providing an overview from mechanistic insights to clinical applications and emerging therapeutic strategies. In addition to ICIs, we discuss alternative approaches, such as bispecific antibodies, antibody–drug conjugates (ADCs), chimeric antigen receptor T cell (CAR-T) therapy, tumor vaccines, and oncolytic viruses (OVs), highlighting their current research progress and clinical applications in TNBC treatment. Full article

Adolescence is a developmental stage marked by dynamic interactions between diet, the gut microbiome and endocrine maturation, creating a physiological environment in which early metabolic disturbances can rapidly translate into long-term cardiovascular vulnerability. This narrative review summarises the latest research on the diet–microbiome–hormone axis in adolescents, focusing on the metabolic pathways through which microbial metabolites influence host physiology. Short-chain fatty acids (SCFAs), microbially transformed bile acids and postbiotic signalling molecules regulate enteroendocrine communication, insulin sensitivity, vascular function and inflammatory tone, thereby linking dietary exposures to early cardiometabolic alterations. Dysbiosis, driven by ultra-processed dietary patterns, low fibre intake and reduced microbial diversity, promotes metabolic endotoxemia, neuroendocrine imbalance and endothelial impairment, all of which are recognised as early indicators of cardiovascular disease. A distinctive contribution of this review is the integration of PF into the adolescent cardiometabolic framework. This emerging biotechnological process enables the controlled production of structurally defined bioactive compounds, including angiotensin-converting enzyme (ACE) inhibitory peptides, targeted prebiotic oligosaccharides, fermentable substrates that promote SCFA formation, microbially derived eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), phytosterols and purified postbiotics. These compounds modulate several regulatory pathways, such as the renin–angiotensin–aldosterone system, lipid and bile acid metabolism, gut barrier stability, inflammatory signalling and endocrine axes involving glucagon-like peptide-1 (GLP-1), peptide YY (PYY), leptin, insulin sensitivity and growth hormone/insulin-like growth factor-1 (GH/IGF-1) dynamics. By situating precision fermentation within the broader context of adolescent metabolic susceptibility, this review highlights its potential to support microbiome resilience, stabilise hormonal regulation and mitigate early cardiovascular risk. However, further adolescent-specific clinical trials and long-term safety assessments are required to translate these advances into effective public health strategies. Full article

Bacterial outer membrane vesicles (OMVs) are spherical structures made up of a double layer, they are each nanostructured (20–300 nm), and they are released from all populations of Gram-negative bacteria. The purpose of this review is to synthesize a comprehensive summary of the current state of knowledge about OMV biogenesis, function in biology, and application to biomedical engineering. Using these three known biogenesis mechanisms as a basis for this review, we discuss the mechanisms of OMV biogenesis that have been described as conserved: (1) disruption of outer membrane–peptidoglycan links. (2) periplasmic stress-driven adaptive release is associated with bilayer lipid asymmetry and the use of signaling molecules. OMVs are considered to be “public goods” for the microbe, allowing for nutrient acquisition, resistance to antibiotics, and the potential for horizontal gene transfer between microbes. OMVs exhibit a different duality at the interface of the pathogen host, where the pathogenic OMV is the delivery vehicle for virulence factors and pathogen-associated molecular patterns (PAMPs) leading to host immune response, while the symbiotic OMV (e.g., those produced by Bacteroides fragilis (Bact. fragilis)) promote regulatory T cell differentiation and mucosal tolerance. The review also addresses the various techniques currently available to isolate OMVs (e.g., ultracentrifugation and size-exclusion chromatographic techniques) and presents engineered/alloying strategies (e.g., genetic modifications to tolR/msbB and surface functionalization) to enhance the viability, safety, and specificity of OMVs for biomedical delivery. Finally, the review addresses significant obstacles related to standardization, batch variation, and in vivo safety associated with synthetic or personalized therapeutics based on OMVs, providing some recommendations for future research in this area. Full article

Skeletal myogenesis is an extremely complex process that mononuclear myoblasts undergo proliferation, differentiation, and fusion to form multinucleated contractile muscle fibers, involving a balance between synthesis and degradation metabolism. Skeletal muscle requires an effective mechanism to balance rapid proliferation by degrading supernumerary or damaged organelles/proteins, or by activating cellular signals to regulate subsequent muscle differentiation. In recent years, three important cellular processes—apoptosis, ubiquitin–proteasome system (UPS), and autophagy—have received extensive attention in skeletal myogenesis. The UPS supports the early differentiation process and initiates apoptosis, and the increase in apoptosis activates autophagy to clear damaged organelles and proteins, which in turn inhibits apoptosis, preventing excessive cell death and maintaining cellular stability. The coordination among apoptosis, UPS, and autophagy is more intricate, as they interact through a dynamic balancing mechanism, determining the balance between cell death and survival, and enabling proper muscle differentiation. Here, we explore the molecular signals that mediate apoptosis, UPS, and autophagy, with a focus on analyzing their interrelationship in skeletal myogenesis. Studying the regulatory mechanisms of these molecules will help in understanding the role of cell death in skeletal muscle development, especially how they affect muscle cell differentiation, providing new insights into mammalian skeletal myogenesis. Full article

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide, characterized by a multi-step carcinogenesis process involving genetic mutations and epigenetic alterations. Despite advances in screening and therapy, challenges such as treatment resistance, recurrence, and metastasis persist. Emerging evidence highlights the critical role of epigenetic modifications, particularly N7-methylguanosine (m7G), in post-transcriptional regulation. This ubiquitous RNA modification participates extensively in tumor biological behaviors by regulating RNA stability, processing, and translation. Studies have shown that dysregulation of m7G modification is closely associated with adverse clinical outcomes in CRC. This review systematically summarizes the biological functions of m7G modification and its key regulatory proteins (such as METTL1/WDR4, eIF4E, etc.), with a focus on their roles in the pathogenesis, progression, prognosis, and diagnosis of, as well as therapy for, colorectal cancer. m7G modification and related molecules hold potential as novel biomarkers and therapeutic targets, thereby providing new strategies for the precision diagnosis and treatment of colorectal cancer. Full article

Quantitative ¹H NMR (qNMR) is a versatile analytical tool that provides simultaneous structural and quantitative information without the need for analyte-specific standards. This review summarizes its key methodological fundamentals and broad applications in both pharmaceutical and biomedical analysis. In drug analysis, qNMR enables content determination and purity assessment of small molecules, polysaccharides and glycoconjugates, synthetic polymers, and complex herbal medicines. In biomedical analysis, it serves as a powerful platform for metabolomics profiling, real-time monitoring of cellular processes, and absolute quantification of metabolites in biofluids and tissues. Recent and emerging technological advancements, including hyperpolarization, quantum mechanical spectral analysis, artificial intelligence, and deep learning, hold great promise for further enhancing sensitivity, resolving power, and automation. With ongoing integration into pharmacopoeial standards and regulatory frameworks, qNMR is poised to expand its role in both routine quality control and cutting-edge biomedical research. Full article

Long non-coding RNAs (lncRNAs) have emerged as important regulatory molecules in plants, but their potential roles during modern maize breeding remain largely unexplored. This study systematically characterized lncRNA expression dynamics using transcriptome data from 137 maize inbred lines from different breeding eras in China. We identified 18,023 lncRNAs transcripts, grouped by expression trends across historical breeding eras. Comparative analysis revealed 2228 differentially expressed lncRNAs transcripts (DElncRNAs) between modern (CN2000&10s) and early (CN1960&70s) accessions. By integrating WGCNA and cis-target analysis, we identified candidate lncRNAs and putative lncRNA-PCG associations that may be associated with maize plant architecture-related processes. Further, 771 DElncRNAs were predicted to be associated with 810 protein-coding genes, and these associated genes were significantly enriched in plant hormone signal transduction. Dual-luciferase reporter assays provided preliminary experimental support that lncrna.33063 and lncrna.33068 can repress the promoter activity of ZmPIF5.2 in a heterologous transient expression system. Furthermore, we constructed a putative ceRNA-related candidate interaction network consisting of lncRNA–miRNA–mRNA triplets that include 317 candidate miRNA-lncRNA pairs and 8325 candidate miRNA-mRNA pairs, with the associated mRNAs enriched in biological processes such as morphogenesis, stimulus response, and hormone metabolism. These findings provide a set of candidate lncRNAs and lncRNA-PCG associations for future functional validation and may offer useful clues for understanding the possible roles of lncRNAs in agronomic trait-related biological processes and maize molecular breeding. Overall, this study provides candidate genetic resources and a framework for future investigation of lncRNA-associated relationships potentially related to agronomic trait variation in maize. Full article

The potential for the use of antimicrobial peptides (AMPs) as anticancer agents has garnered much interest because of their selective cytotoxicity to tumor cells and ability to evade multidrug resistance mechanisms. AMPs are shorter cationic amphiphilic molecules, part of our innate immune system, with direct membrane-disruptive activity and immunomodulatory effects. Anticancer peptides (ACPs) can be derived from natural biophysical sources or synthetically engineered, taking advantage of the unique biophysical properties of cancer cell membranes to exert their anti-tumor activities rapidly and often without significant effects on normal tissues. Advances in peptide engineering, such as D-amino acid substitution, cyclization, and PEGylation, combined with nanocarrier systems, have provided opportunities to improve peptide stability, bioavailability, and delivery to targeted sites. Studies in preclinical and clinical models show promise, indicating that AMPs and ACPs can induce immunogenic cell death, modify tumor microenvironments, and be used in combination with more conventional therapies. While the promise of AMPs and ACPs as relatively novel cancer therapeutics is substantial, challenges such as proteolytic degradation, dose-dependent toxicity, costs for production, and regulatory hurdles are notable. This review organizes the current literature on classification, mechanism(s) of action, delivery strategies, preclinical and clinical data, and provides areas for future work to improve and help speed their clinical translation as new cancer therapies. Full article

Expression of the mevalonate (MVA) pathway in yeast mitochondria is deployed at commercial scale for production of squalene, because mitochondria contain abundant acetyl-CoA, the starting molecule of the MVA pathway. However, it is still unknown whether this strategy is effective in boosting the post-squalene pathway. Here the potential of this strategy is explored for production of the post-squalene chemical cholesterol, a precursor of many valuable steroidal drugs. A cholesterol-producing yeast strain, named CEN-Cho, was constructed by expressing the biosynthetic genes leading to cholesterol, accompanied by the augmentation of the cytosolic MVA pathway. The CEN-Cho strain produced 60.17 ng/mg fresh weight (FW) of squalene and 121.75 ng/mg FW of cholesterol in shake flask cultivation. When the complete MVA pathway was introduced into the mitochondria of CEN-Cho, yielding CEN-Cho-mMVA, the squalene level was increased to 325.24 ng/mg FW. Unexpectedly, the yield of cholesterol produced by CEN-Cho-mMVA was decreased to 1.5 ng/mg FW, demonstrating significant suppression on the post-squalene pathway due to the mitochondrial engineering. Comparative transcriptomic and proteomic analyses of the engineered cells provide insights into the metabolic and regulatory bottlenecks underlying this inhibition. This work reveals that the introduction of the MVA pathway into mitochondria generally inhibits the post-squalene pathway in yeast. Full article

Fatty acid amide hydrolase (FAAH) is a critical metabolic enzyme in the endocannabinoid system. Through regulating the metabolism of lipid signaling molecules, FAAH is involved in a variety of physiological and pathological processes, including cell proliferation, inflammatory responses, and metabolic homeostasis. Polycystic ovary syndrome (PCOS), one of the most common endocrine and metabolic disorders affecting women of reproductive age, is closely associated with abnormal follicular development, dysregulated hormone secretion, insulin resistance, dyslipidemia, and inflammatory imbalance. Emerging evidence suggests that FAAH-mediated dysregulation of endocannabinoid metabolism is associated with the pathogenesis of PCOS through the modulation of inflammatory pathways, insulin sensitivity, and hormone secretion. This review systematically summarizes the structure, biological functions, and regulatory mechanisms of FAAH, with particular emphasis on its roles in PCOS-associated pathological processes, including reproductive dysfunction, hormonal dysregulation, metabolic imbalance, and inflammatory responses. This review aims to provide a theoretical foundation for elucidating the molecular mechanisms underlying PCOS and for the development of novel therapeutic strategies. Full article

Tuberculosis (TB) remains a major global public health burden. This study aimed to identify differentially expressed messenger RNAs (mRNAs) and circulating microRNAs (miRNAs) associated with TB and to validate their potential roles in the disease. We performed RNA sequencing (RNA-Seq) on peripheral blood samples from 10 patients with active pulmonary TB and 10 healthy controls, using peripheral blood mononuclear cells (PBMCs) for mRNA sequencing and plasma for miRNA sequencing. Given the exploratory nature of the plasma miRNA data and the limitations of the U6 normalization method, the results for circulating miRNAs will need to be validated using alternative methods in subsequent experiments. A total of 1323 differentially expressed mRNAs and 49 differentially expressed miRNAs were identified. Functional annotation of differentially expressed genes was conducted using the Database for Annotation, Visualization and Integrated Discovery (DAVID), followed by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, which revealed two TB-associated pathways: “MicroRNAs in cancer” and “Small cell lung cancer.” Two key mRNAs—tumor protein p53 (TP53) and forkhead box protein P1 (FOXP1)—and one key miRNA (hsa-miR-29b-3p) were identified as potential core regulatory factors. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) validation confirmed that the expression patterns of these candidate molecules were consistent with the RNA-Seq results. Three potential candidate molecules associated with TB were ultimately identified, although their disease specificity remains to be determined. Full article

Background/Objectives: As important post-transcriptional and epigenetic regulators of gene expression, miRNAs play a pivotal role in modulating host–virus interactions. While prior reviews have addressed either direct miRNA–HIV genome interactions or miRNA-mediated immune modulation in isolation, the integrated dual functionality of these molecules has not been systematically characterized. This review aimed to comprehensively explore how miRNAs that target the HIV-1 genome simultaneously modulate key innate and adaptive host immune signaling pathways. The conceptual novelty of this study is determined not by the identification of previously unknown miRNA-target gene pairs, but by the systemic integration of two regulatory levels (direct inhibition of the viral genome and modulation of the host cell immune signaling pathways) within a unified analytical framework. Such an integrated approach reveals a proviral regulatory network that remains non-obvious when each of these levels is examined separately. Methods: A narrative review was conducted using PubMed, Scopus, Web of Science, and Google Scholar (all years through 2025). In Stage 1, publications reporting experimentally confirmed interactions between host miRNAs and the HIV-1 genome were identified, yielding a curated set of 15 miRNAs. In Stage 2, target genes for each miRNA were retrieved from miRTarBase, TarBase (experimentally validated) and TargetScan 8.0 (in silico predicted). In Stage 3, target genes were manually mapped to key immune signaling pathways (TLR, NF-κB, JAK-STAT). In Stage 4, targeted literature searches were performed for each miRNA–target gene pair to identify direct experimental evidence of interaction. All stages were performed by two independent researchers, with discrepancies resolved by a third. Results: Fifteen host miRNAs with experimentally confirmed binding to the HIV-1 genome were identified, targeting viral genes including nef, pol, vpr, gag, env, vif, and the 3′-UTR. Thirteen of these miRNAs were found to regulate components of major immune pathways. miR-92a-3p, miR-29a/b-3p, miR-150-5p, and miR-125b-5p emerged as the most pleiotropic regulators, simultaneously suppressing TLR signaling (TLR3, TLR7, TLR8, MyD88, TRAF3/6, IRAK1/4), NF-κB components (REL, RELA, NFKB1), JAK-STAT effectors (STAT1–3, STAT5A/B, JAK2), and negative regulators of cytokine signaling (SOCS and PIAS family proteins). miR-133b and miR-196b-5p were found to selectively regulate SOCS/PIAS proteins without involvement in other analyzed pathways, suggesting potential for selective therapeutic targeting. Conclusions: The analyzed miRNAs exhibit functional dualism, acting as direct post-transcriptional suppressors of the HIV-1 genome while simultaneously functioning as epigenetic modulators of host immune signaling. These two modes of action are not independent but together form a conceptual framework of a self-reinforcing proviral regulatory network that, based on the synthesis of published evidence, is proposed to promote viral latency and immune evasion. The identified miRNAs represent promising, albeit complex, targets for novel therapeutic strategies aimed at eliminating latent HIV reservoirs. Full article

Background: Programmed cell death protein-1 (PD-1) and its ligands, PD-L1 and PD-L2, constitute a central immune checkpoint pathway that regulates T-cell activity and tumor immune escape, while their relationship with STAT signaling remains incompletely understood in ccRCC. Methods: We analyzed 27 paired ccRCC and adjacent non-tumorous human kidney tissue samples. mRNA levels of PD-1, PD-L1, PD-L2, STAT1, and STAT3 were quantified by RT-qPCR. In addition, representative human ccRCC cell lines (CAKI-2 and A-498) were treated with IFN-γ to assess the time-dependent modulation of immune checkpoint molecules and STAT pathway activation. Results: PD-L1 and PD-L2 were significantly upregulated in tumor tissues compared with adjacent normal kidney tissue. Exploratory observation suggests grade dependent increase. Whereas PD-1 was predominantly downregulated, IFN-γ treatment induced a rapid transcriptional upregulation of PD-L1 and PD-L2 in RCC cell lines, with maximal protein accumulation observed at 72 h. STAT1, but not STAT3, exhibited dynamic induction following IFN-γ stimulation, showing temporal association with PD-L1 and PD-L2 upregulation, indicating cell-line-specific regulatory effects. Correlation analyses confirmed a strong correlation between PD-1 and its ligands, whereas STAT1 and STAT3 expression showed no direct association with PD-L1 or PD-L2 levels in cancer samples. Conclusions: Our findings demonstrate that PD-L1 and PD-L2 are frequently upregulated in ccRCC and dynamically regulated by IFN-γ/STAT1-dependent signaling. Our results provide additional insight into the mechanisms of immune escape and underscore the potential of integrated profiling of PD-1 ligands and STAT signaling to guide personalized immunotherapeutic strategies in ccRCC. Full article

Vibrio splendidus is an important opportunistic pathogen that causes diseases in aquatic animals, and its persisters increase the difficulty of aquaculture disease control. The stringent response is a central pathway in bacteria for coping with environmental stress, and the signaling molecule (p)ppGpp, synthesized under the regulation of RelA/SpoT homologs, is closely associated with persister formation and virulence modulation. However, the regulatory mechanisms linking the stringent response to persister formation and virulence in V. splendidus remain unclear. In this study, the core gene deletion strains ΔrelA and ΔrelAΔspoT were constructed via homologous recombination. Combined with D₂O single-cell Raman spectroscopy, transcriptomics, and phenotypic assays, we systematically characterized the biological effects of stringent response inactivation. The results showed that the loss of relA and spoT significantly reduced persister formation and key virulence traits while enhancing biofilm formation. Single-cell Raman spectroscopy analysis indicated that persisters remained metabolically active, accompanied by changes in different cellular components. Transcriptome analysis revealed that the absence of stringent response affected multiple pathways, including ribosomal function, energy metabolism, two-component systems, and quorum sensing. Additionally, the sigma factor RpoS may potentially exert a compensatory function in ΔrelAΔspoT strain, but this requires further validation. In conclusion, the stringent response positively regulates persister formation and virulence in V. splendidus, despite the existence of complex regulatory mechanisms. This study provides a theoretical basis for the development of anti-infective strategies targeting stringent response in aquatic pathogens. Full article

Background/Objectives: Trauma triggers complex early immune responses. However, the relationship among trauma severity, changes in immune cell survival, and circulating inflammatory mediators remains unclear. This study compared early cell viability and death patterns in CD66b⁺ granulocytes, total T lymphocytes, and CD4⁺ and CD8⁺ T-cell subsets as well as inflammatory mediator levels between patients with non-severe and severe trauma. Methods: This single-center prospective observational study included 67 adult patients with trauma who were classified into non-severe and severe trauma groups according to the Injury Severity Score (ISS < 15 vs. ISS ≥ 15). Blood samples were obtained within 1 h of arrival at the emergency department. Flow cytometry was used to assess the viability, early apoptosis, late apoptosis, and necrosis in the leukocyte subsets. Serum concentrations of intercellular adhesion molecule-1 (ICAM-1), macrophage migration inhibitory factor (MIF), CD40 ligand (CD40L), and interleukin-1 receptor antagonist (IL-1ra) were measured using enzyme-linked immunosorbent assays. Results: The severe trauma group had a significantly lower proportion of early apoptotic CD66b⁺ granulocytes than the non-severe trauma group (2.9% [1.4–6.7] vs. 6.3% [3.7–10.9], p = 0.001), whereas the live, late apoptotic, and necrotic CD66b⁺ granulocyte fractions did not differ significantly between the two groups. Most T-cell death parameters were similar between the groups, although an exploratory increase in necrotic CD4⁺ T lymphocyte abundance was observed in the severe trauma group. IL-1ra levels were significantly higher in the severe trauma group than in the non-severe trauma group and were associated with ISS in both mediator-only and adjusted sensitivity regression analyses. Conclusions: Severe trauma was associated with reduced early apoptosis in the CD66b⁺ granulocyte compartment and elevated IL-1ra levels shortly after injury compared with non-severe trauma. These findings suggest that early immune alterations after severe trauma may involve compartment-specific granulocyte death patterns and counter-regulatory inflammatory responses rather than generalized changes across leukocyte populations. Full article