Porcine reproductive and respiratory syndrome (PRRS), caused by PRRSV, remains a major threat to the global swine industry, and current control relies mainly on vaccination. GP5a, encoded by ORF5a, is a newly identified non-glycosylated envelope structural protein of PRRSV. This review summarizes published studies on the discovery, molecular characteristics, genetic evolution, biological functions, and applications of GP5a, with emphasis on its sequence variation, interactions with host and viral proteins, roles in replication and virulence, and co-evolution with GP5. GP5a is approximately 5–6 kDa and is the smallest PRRSV structural protein. Although relatively conserved, it shows amino acid variations mainly in transmembrane and intramembrane domains. GP5a interacts with host proteins and viral nonstructural proteins, participates in replication and transcription, regulates virulence, and influences immune responses. Silencing GP5a markedly reduces viral titers, and GP5a mutations are associated with attenuation and virulence reversion. GP5a co-evolves with GP5 through overlapping ORF5a/ORF5 and codon usage balance. Its immunogenicity and conserved epitopes make it a potential target for vaccines, diagnostics, and antiviral drugs, although neutralizing antibodies induced by GP5a are limited. Its structure, interactome, and precise molecular mechanisms should be clarified in further studies.
Major depressive disorder (MDD) is a leading cause of disability worldwide, and one-third to two-thirds of patients do not reach remission after successive monoaminergic treatments. Impaired brain bioenergetics, including mitochondrial dysfunction and altered brain high-energy phosphate levels, has been proposed to contribute to the anergic, cognitive, and fatigue-related symptoms of MDD. Through the creatine kinase-phosphocreatine (CK-PCr) system, creatine buffers ATP in time and space and supports the fluctuating energy demands of synaptic transmission and plasticity. In this narrative review, we summarize creatine metabolism and critically appraise the preclinical evidence implicating monoaminergic, purinergic, NMDA receptor and nitric oxide, PI3K/Akt/mTORC1, GSK-3β/Nrf2, and BDNF signaling, redox and neuroinflammatory control, and hippocampal neurogenesis in the antidepressant-like effects of creatine. We then review the human evidence, including phosphorus-31 magnetic resonance spectroscopy (31P-MRS) studies of brain high-energy phosphates and randomized trials of adjunctive creatine, and we discuss why the clinical findings remain inconsistent. Human evidence suggests that oral creatine could reach the brain and increase total creatine, yet clinical efficacy has not been established, and existing trials were not designed to test the bioenergetic mechanism. We therefore propose trials that select the dose by 31P-MRS target engagement and stratify patients by bioenergetic markers.
Background: Serous ovarian tumors comprise biologically distinct entities ranging from benign and borderline tumors to low-grade (LGSC) and high-grade serous carcinoma (HGSC). EBP50/NHERF1 and Merlin/NF2 regulate epithelial polarity, membrane–cytoskeletal organization, and signaling. We evaluated EBP50 and Merlin expression across the spectrum of serous ovarian tumors, explored their clinicopathological and diagnostic associations, and compared these findings with Ki67 and mitotic activity in serous carcinomas. Methods: EBP50 and Merlin immunoreactivity was evaluated in serous cystadenomas, serous borderline tumors (SBTs), LGSCs, and HGSCs. Ki67 and mitotic activity were assessed in malignant tumors. Exploratory discriminatory performance was evaluated by receiver operating characteristic analysis, and overall survival by Kaplan–Meier and Cox proportional hazards analyses. Results: EBP50 expression differed significantly among tumor groups (p < 0.001), with the lowest expression and most frequent complete loss in HGSC. EBP50 showed moderate discrimination between carcinomas and non-carcinoma tumors (AUC = 0.790) and lower expression was associated with more advanced disease, including higher FIGO stage. Merlin expression also differed among groups (p = 0.003) but showed limited discriminatory performance (AUC = 0.605). Ki67 and mitotic activity strongly distinguished LGSC from HGSC (AUC = 0.992 for both). Although Ki67 was associated with poorer overall survival in univariable analysis, none of the biomarkers independently predicted survival after adjustment for age and FIGO stage. Conclusions: EBP50 showed potentially useful differences in expression across serous ovarian tumor categories and may provide adjunctive information in selected diagnostic settings, whereas the diagnostic contribution of Merlin appeared limited. Ki67 and mitotic activity confirm the established proliferative distinction between LGSC and HGSC. Further validation of EBP50 and Merlin in independent cohorts is warranted.
Alzheimer’s disease (AD) presents a severe global public health challenge. The gut microbiota influences the physiological and pathological processes of AD. Although extensive research has been conducted to elucidate these effects, the roles of gut microbiota and microbial metabolites in AD remain to be further explored. This study adopted an integrated network pharmacology approach coupled with multiple database mining to dissect the molecular associations among gut microbiota, microbial metabolites and AD. Gut microbiota and microbial metabolites regulate the AD mainly through the core targets MAOB, MAOA, APP, DRD2, HTR1A, SLC6A4 and IL-1β. KEGG pathway analysis revealed that neuroactive ligand–receptor interaction, Alzheimer’s disease, dopaminergic synapse and neuroactive ligand signaling were the key signaling pathways underlying the regulation of AD by gut microbiota metabolites. In addition, 33 gut microbial metabolites and numerous gut bacterial species that regulate AD were identified. Molecular docking verified the favorable binding affinity and stability between microbial metabolites and core targets. Strains from the genera Bifidobacterium, Eubacterium, Bacteroides, Clostridium, Roseburia, Enterococcus, Blautia and Escherichia sp. exhibited significant regulatory effects in AD. These findings offer scientific support for further research on the molecular mechanisms by which gut microbiota and microbial metabolites regulate AD, and also provide insights for the development of probiotics and metabolite-based interventions.
TP53 mutations frequently co-occur with HER2 amplification in breast cancer, yet how mutant p53 influences HER2-positive (HER2+) tumor biology remains incompletely understood, as does whether distinct hotspot mutations exert allele-specific effects. Here, we investigated the effects of p53R172H and p53R245W in genetically engineered HER2+ mammary tumor models. Tumor latency, incidence, growth, and histopathology were comparable between HER2-only tumors and those with mutant p53; unexpectedly, lung metastases occurred less frequently in tumors with mutant p53. HER2+ tumors with p53R172H exhibited greater Trp53 loss of heterozygosity than those with p53R245W. Transcriptomic analyses revealed mutant p53-associated activation of cell-cycle, DNA-replication and -repair, chromatin, RNA-processing, and immune pathways, whereas HER2-only tumors showed enrichment of metabolic and nuclear receptor programs. The two alleles shared proliferative programs but displayed distinct metabolic, stress-response, cell-communication, cytoskeletal, and microenvironmental signatures. Metastatic status revealed state-dependent reprogramming: non-metastatic HER2+ tumors with mutant p53 showed suppression of metastasis-associated pathways, whereas their metastatic counterparts activated these programs. Allele-specific differences were more pronounced in non-metastatic tumors. Whole-exome sequencing identified candidate alterations in tumor-suppressive and oncogenic regulators. Collectively, these findings demonstrate allele- and metastatic-state-dependent molecular reprogramming by p53R172H and p53R245W in HER2+ breast cancer, highlighting a complex relationship between mutant p53 and metastatic progression.
