EBioMedicine最新文献

Background: Neuronal intranuclear inclusion disease (NIID), caused by GGC repeat expansions in NOTCH2NLC, is a neurodegenerative disease frequently involved with cognitive impairment. Limited studies have focused on the biomarkers alteration in patients with NIID and presymptomatic NIID (preNIID) individuals. The clinical overlap between NIID and AD drives the exploration of plasma biomarker alterations in NIID and preNIID.

Methods: Cohorts 1 (87 patients with NIID, 147 individuals with Alzheimer's disease [AD], and 110 healthy controls [HCs]) and 2 (26 individuals with preNIID and 26 HCs) were included. Eight plasma biomarkers including amyloid-β (Aβ) 40, Aβ42, neurofilament light (NfL), α-synuclein (α-syn), phosphorylated tau protein 181 (p-tau181), p-tau217, p-tau231, and glial fibrillary acidic protein (GFAP) were detected. Neuropsychological scores, magnetic resonance imaging measures, Aβ positron emission tomography (Aβ-PET), and tau-PET were analysed.

Findings: P-tau217, p-tau231, p-tau181, α-syn, NfL, and GFAP levels were elevated in patients with NIID compared with HCs; p-tau species and GFAP were also upregulated in preNIID. P-tau species, particularly p-tau217, effectively distinguished NIID/preNIID from HCs (AUC 0.814/0.848), but failed to differentiate NIID from AD. The level of p-tau217 was associated with MMSE and FAB scores in dementia-dominant subtype, and the level of GFAP correlated to white matter volume. A tau-PET study revealed distinct tau deposition on the occipital lobe and temporal pole in NIID without Aβ pathology.

Interpretation: The significant changes of p-tau levels and prominent tau deposition highlight tau pathology involvement in NIID. Elevated plasma p-tau species in preNIID/NIID indicate their potential as biomarkers for NIID.

Funding: This study was supported by the National Natural Science Foundation of China (82394421, 82394420, 82371866, 82371434); the National Key R&D Program of China (2022ZD0213700); Natural Science Foundation of Hunan Province (2023JJ10097, 2025JJ40089, 2023JJ40948).

Background: The oral delivery of native glucagon like peptide-1 (GLP-1) using recombinant probiotics has shown hypoglycaemic effects and glucose tolerance improvement in diabetic mice. However, the pharmacological mechanisms remain incompletely understood. This study aimed to clarify whether GLP-1 analogues cross the intestinal mucosal barrier and exert systemic hypoglycaemic effects.

Methods: The recombinant Lactococcus lactis (L. lactis) was constructed for oral delivery of long-duration GLP-1 (LGLP) or exendin-4 (EX4). The hypoglycemic effects in vivo were investigated in db/db mice. The pancreatic islet structure and DNA replication were studied with BrdU-labelled double immunofluorescence. The peptide absorptions in vitro and in vivo were traced with tetramethylrhodamine (TMR) labelled LGLP or EX4. The Ussing Chamber test with rat intestinal mucosa and the absorption test in the ligated loops of intestinal tube were used to verify the absorption of GLP-1 analogues.

Findings: The supernatant of recombinant L. lactis expressing LGLP or EX4 stimulated proliferation and insulin secretion in rat insulinoma cell INS-1 in vitro. The LGLP-recombinant L. lactis significantly reduced fasting blood glucose, improved oral glucose tolerance, especially increased the number and size of pancreatic islets after oral administration for 4 weeks in diabetic mice. TMR-labelled LGLP or EX4 peptides were internalized by intestinal epithelial cells in vitro. LGLP and EX4 peptides crossed the rat intestinal mucosa and entered the opposite chamber in a receptor-mediated endocytosis manner in the Ussing Chamber test. Following injection into the ligated intestinal loops, a small amount of TMR-labelled LGLP or EX4 was observed in the lamina propria of intestinal villi, pancreas and other tissues through mucosal absorption.

Interpretation: Oral delivery of GLP-1 analogues by recombinant L. lactis restored the structure of pancreatic islets and exerted systemic hypoglycaemic effects through receptor-mediated intestinal mucosa absorption.

Funding: The study was supported by the National Natural Science Foundation of China, the Science and Technology Program Key Projects of Guangdong Province (China), the Science and Technology Planning Project of Guangdong Province (China), and the Biomedical Innovation Foundation of China Pharmaceutical Association &Yiling Pharmaceutical Company.

Background: Prostate cancer (PC) is a leading cause of cancer-related deaths in men, with advanced cases exhibiting resistance to androgen deprivation therapy. Dysregulated lipid metabolism has emerged as a hallmark of aggressive PC. This study investigates the biological underpinnings of a circulating three-lipid signature (3LS) previously validated as a prognostic biomarker in patients with metastatic castration-resistant prostate cancer (mCRPC).

Methods: Using plasma samples from 16 mCRPC patients (8 positive and 8 negative for the 3LS), we assessed the impact of 3LS-positive plasma on three prostate cancer cell lines representative of disease progression. We investigated changes in cell viability and intracellular lipid metabolism associated with plasma from the two patient cohorts.

Findings: Exposure to 3LS-positive plasma improved cell viability across AR-positive (LNCaP, C4-2B) and AR-negative (PC3) cell lines compared to exposure to 3LS-negative plasma. Lipidomic profiling revealed elevated sphingolipids and glycosphingolipids in 3LS-positive plasma-treated cells, accompanied by metabolic shifts characterised by increased monounsaturated and reduced polyunsaturated fatty acid levels. Inhibition of sphingosine kinase 1 abrogated the 3LS-positive plasma-treatment phenotype consistent with ceramide/sphingosine 1 phosphate (S1P) signalling being the mechanism of action.

Interpretation: These findings suggest that the circulating 3LS is not just a prognostic biomarker, but an actionable signature reflecting changes in PC biology. The plasma lipid milieu identified by the 3LS drives a pro-survival phenotype by modifying lipid metabolism and upregulating ceramide/S1P signalling. The study provides the biological rationale to target ceramide-S1P signalling in patients, who are 3LS-positive.

Funding: National Health and Medical Research Council of Australia Investigator grants (1196225; 2009965; 1197190); Cancer Institute New South Wales Translational Program Grant (TPG172146); Victorian Government Operational Infrastructure Support Program; Australian Government Research Training Program; University of Sydney merit award.

Background: Human genetic analyses have identified numerous single-nucleotide polymorphism (SNP) loci in noncoding regions associated with obesity-related traits; however, the functional contributions of such SNP loci to obesity are largely unknown. The noncoding variant rs713586, with its risk allele C, is linked to two candidate genes, DNAJC27 and ADCY3, potentially implicated in obesity. However, whether rs713586 primary targets ADCY3 or DNAJC27 gene to regulate body weight and what molecular mechanisms underlie this process remain unclear.

Methods: We conducted bioinformatics analyses using BMI data from the UK biobank and GIANT consortium, and prioritised functional variants on chromosome 2 linked to ADCY3 gene for experimental validation. The variant rs713586 was identified as a functional regulator of ADCY3 and DNAJC27 expression. We investigated the molecular mechanisms by which rs713586 participates in obesity through epigenetic regulation. Dual-luciferase reporter assay and genome-editing in cell lines were conducted to assess the impacts of the rs713586-C risk allele or a proximal enhancer (Enh) on ADCY3 and DNAJC27 promoter activity and expression levels. CRISPR/Cas9-mediated knockout of Dnajc27 was performed in mice to evaluate its role in obesity. Mechanistic studies examined the interactions between the rs713586-T or -C alleles and the transcription factor ZFP42. Additionally, we assessed the DNA methylation patterns within the Enh and promoter regions of ADCY3 to evaluate their impact on ADCY3 expression.

Findings: First, the rs713586-C risk allele significantly reduced the promoter activity of ADCY3 and DNAJC27 and thus reduced their expression levels. However, Dnajc27 knockout mice did not develop obesity, thereby excluding DNAJC27 as the target gene through which rs713586 mediates obesity. Further, we demonstrate that the rs713586-C allele impaired ZFP42 binding, leading to decreased TET1 recruitment and increased DNA methylation in the Enh and promoter regions of ADCY3, ultimately suppressing its expression. Given that ADCY3 is a well-established gene involved in obesity, we conclude that the rs713586-C risk allele may associated with obesity susceptibility, concomitant with downregulated ADCY3 expression.

Interpretation: Our findings establish the rs713586-ZFP42-TET1-ADCY3 epigenetic regulatory axis, providing insights into the mechanism of rs713586-mediated obesity pathogenesis.

Funding: National Natural Science Foundation of China and Natural Science Foundation of Hebei Province of China (32470645, 32070567, 32202840), and Priority-Funded Postdoctoral Research Project, Zhejiang Province (ZJ2025118). Full funding details are provided in the Acknowledgements.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infected over 26 million individuals in Italy, resulting in ∼200,000 COVID-19-related deaths. Unravelling host genetic factors underlying disease severity is key to understanding progression mechanisms.

Methods: We applied multi-omics approaches to investigate genetic susceptibility to COVID-19 severity in the Italian population. We combined an exome-wide case-control study of rare germline variants (215 severe/critically ill patients vs 1755 controls) with transcriptomic (differential gene expression and alternative splicing) analyses of 59 hospitalised patients to identify signatures associated with severe respiratory outcomes (ICU admission).

Findings: Rare variant analysis revealed significant associations with genes implicated in oxidative stress and mitochondrial dysfunction, including MTERF1 (FDR = 7.69 × 10^-5), TDP1 (FDR = 3.23 × 10^-7), and LPO (FDR = 1.58 × 10^-2). Pathway analyses confirmed enrichment in "reactive oxygen species", "oxidative phosphorylation", and "inflammatory response" pathways. Transcriptomics showed a proinflammatory profile in hospitalised patients (N = 24) and a prothrombotic signature in ICU-admitted individuals (N = 35), reflecting disease progression. Genomic and transcriptomic data integration highlighted LPO, encoding the antimicrobial enzyme lactoperoxidase, as the only gene both significantly enriched for damaging variants and upregulated in ICU-admitted cases (log₂FC = 0.57, FDR = 0.028). Notably, we confirmed the genetic association with severity in independent cohorts (1873 cases vs 508,532 controls; meta-analysis p = 0.0050, OR = 3.44, 95% CI = 1.71-6.89). We propose that LPO haploinsufficiency may impair host capacity to neutralise ROS, contributing to COVID-19 progression.

Interpretation: In conclusion, our multi-omics analysis implicates oxidative stress and mitochondrial dysfunction as central to COVID-19 severity, identifying LPO as a candidate susceptibility gene.

Funding: Banca Intesa San Paolo, EU Next-Generation EU-MUR-PNRR (INF-ACT, PE00000007), Dolce & Gabbana.

Background: The global burden of malaria remains substantial, and increasing parasite resistance to current antimalarials necessitates the development of drugs with unique mechanisms of action. This study aimed to develop and characterise a new antimalarial compound targeting Plasmodium aspartic proteases.

Methods: We conducted high-throughput screening, medicinal chemistry optimisation, and extensive in vitro and in vivo testing to develop and evaluate MK-7602, a dual inhibitor of plasmepsins IX and X.

Findings: MK-7602, a clinical candidate, acts as a dual sub-nanomolar inhibitor of plasmepsins IX and X in multiple Plasmodium species. It exhibits favourable pharmacokinetic properties and a promising safety profile. MK-7602 demonstrates activity against liver and blood life-cycle stages of the parasite and blocks transmission to mosquitoes. Importantly, it shows a high barrier to resistance development and lacks cross-resistance with Plasmodium falciparum strains resistant to other antimalarials. MK-7602 effectively inhibits both wild-type parasites and those with increased plasmepsin expression, highlighting its potential to overcome existing resistance mechanisms.

Interpretation: MK-7602 represents a new class of antimalarial for treating uncomplicated malaria with a new mechanism of action and the potential to address drug-resistant malaria. Clinical evaluation of MK-7602's activity against P. falciparum is ongoing.

Funding: This work was funded by The Wellcome Trust (109662/Z/15/Z, 202749/Z/16/Z, 219658/Z/19/Z), NHMRC (GNT1176955, GNT637406, GNT1173049), the Human Frontiers Science Program (LT0001/2022-L, JMD), Drakensberg Trust, the Victorian State Government Operational Infrastructure Support grant, and the Australian Government NHMRC IRIISS. JPo was supported by the NIH/NIAID (R01AI173171, R01AI175134 and R61AI187100) and the Pasteur International Unit PvESMEE.

Henipaviruses, particularly the species Nipah (NiV) and Hendra (HeV), are emerging viral threats with potential to cause a public health emergency of international concern due to their high virulence and absence of approved preventative and therapeutical countermeasures. Consequently, research of NiV and HeV is restricted to high-containment laboratories and relies heavily on in vitro models. Despite NiV and HeV initial characterisation >25 years ago, significant gaps remain in the knowledge of the host-pathogen interactions, which are an important research focus for design of therapeutics and supportive care modalities. This review summarises current knowledge in the host-pathogen interactions of henipaviruses and critically assesses the current and emerging in vivo and in vitro models for henipavirus research.