EBioMedicine最新文献

Background: Reduced mitochondrial respiratory function has been implicated in metabolic disorders like type 2 diabetes (T2D), obesity, and metabolic dysfunction-associated steatotic liver disease (MASLD), which are tightly linked to insulin resistance and impaired metabolic flexibility. However, the contribution of the ketone bodies (KBs) β-hydroxybutyrate (HBA) and acetoacetate (ACA) as substrates for mitochondrial oxidative phosphorylation (OXPHOS) in these insulin resistant states remains unclear.

Methods: Targeted high-resolution respirometry protocols were applied to detect the differential contribution of HBA and ACA to OXPHOS capacity in heart, skeletal muscle, kidney, and liver of distinct human or murine cohorts with T2D, obesity, and MASLD.

Findings: In humans with T2D, KB-driven mitochondrial OXPHOS capacity was ∼30% lower in the heart (p < 0.05) and skeletal muscle (p < 0.05) compared to non-diabetic controls. The relative contribution of KBs to maximal OXPHOS capacity in T2D was also lower in both the heart (∼25%, p < 0.05) and skeletal muscle (∼50%, p < 0.05). Similarly, in kidney cortex from high-fat diet-induced obese mice, both the absolute and relative contribution of KBs to OXPHOS capacity was ∼15% lower (p < 0.05). Finally, hepatic HBA-driven mitochondrial OXPHOS capacity was 29% lower (p < 0.05) in obese humans with hepatic steatosis compared to humans without.

Interpretation: Mitochondrial KB-driven OXPHOS capacity is impaired in insulin resistant states in various organs in absolute and relative terms, likely reflecting impaired mitochondrial metabolic flexibility. Our data suggest that KB respirometry can provide a sensitive readout of impaired mitochondrial function in diabetes, obesity, and MASLD.

Funding: German Research Foundation, German Diabetes Center, German Federal Ministry of Health, Ministry of Culture and Science of the state of North Rhine-Westphalia, German Federal Ministry of Education and Research, German Center for Diabetes Research, German Heart Foundation, German Diabetes Society, Christiane-and-Claudia Hempel Foundation, European Community and Schmutzler Stiftung.

Background: The human lung is a highly complex organ characterised by extensive cellular heterogeneity, making it susceptible to a broad range of diseases. Single-cell transcriptomics has shed light on disease-specific cellular features, but previous studies have been fragmented, limiting a unified understanding of cellular mechanisms across various lung diseases. Furthermore, high-resolution reference atlases for lung cells are lacking, impeding the effective integration of spatial omics data and the exploration of shared pathogenic mechanisms.

Methods: We constructed uniLUNG, the most comprehensive single-cell RNA sequencing atlas of the human lung, by integrating 62 published datasets comprising 9.2 million cells from 1807 donors across health and 17 disease conditions. We leveraged this high-resolution cell atlas to seek distinct cell types across diverse lung pathologies. By integrating spatial transcriptomics, we also identified transitional cell populations in lung cancer, and provided new insights into tumour evolution and the associated microenvironment.

Findings: We present a comprehensive lung cell atlas, encompassing cellular data across major lung diseases and health states. Using this resource, we identified distinct cell populations, such as Lym-monocytes and T-like B cells, which are specifically enriched in certain lung diseases and linked to immune dysregulation. Furthermore, our spatially resolved multi-omics analysis revealed a transitional malignant subpopulation, NSCLC-like SCLC, which plays a key role in the transformation from non-small cell lung cancer (NSCLC) to small cell lung cancer (SCLC), driving tumour microenvironment remodelling.

Interpretation: We offered a high-resolution, cross-disease lung cell reference that uncovers distinct cell types and cellular transitions critical to disease progression and therapeutic resistance. This resource provides essential insights into lung disease mechanisms and has important implications for the development of targeted therapeutic strategies, particularly in the context of lung cancer.

Funding: This work was supported by the grants of National Key R&D Program of China (2021YFF1200900 and 2021YFF1200903), National Natural Science Foundation of China (92474107), Guangdong Basic and Applied Basic Research Foundation of China (2022B1515120077), Major Project of Guangzhou National Laboratory of China (GZNL2024A01003), and Support Scheme of Guangzhou for Leading Talents in Innovation and Entrepreneurship of China (2020007).

Iron oxide nanoparticles (IONPs) demonstrate substantial translational potential in precision medicine, leveraging their favourable biocompatibility and distinctive magnetic properties. This comprehensive review systematically analyses their established clinical applications including magnetic resonance imaging (MRI) contrast enhancement, oncological interventions, and iron deficiency therapies. It further examines the critical design parameters governing the performance, safety, and metabolic fate of IONPs from a clinical-translational perspective. It addresses pivotal challenges in their clinical application and translation, including synthetic reproducibility, scalable manufacturing, and long-term biosafety, while also reviewing recent promising advances aimed at overcoming these hurdles. Furthermore, the translational potential of emerging preclinical innovations, including magnetic particle imaging (MPI), stem cell tracking modalities, and novel oral iron supplementation approaches, was critically evaluated. When integrated with multimodal imaging platforms and personalized therapeutic regimens, these advancements would pave the way for IONPs to become transformative agents in next-generation precision medicine.

Background: Inflammatory bowel disease (IBD) has been suggested to be associated with neuropsychiatric disorders, but the underlying mechanisms remain poorly understood.

Methods: We employed Cell-Stratified Mendelian Randomisation (csMR) to analyse genetic variants associated with IBD and their effects on neuropsychiatric disorders. We conducted two-sample MR analyses using the partitioned genetic variants and performed SuSiE co-localisation analysis to identify shared causal variants between GWAS traits and the single-cell eQTL data. We also examined the imaging-derived phenotypes (IDPs) to understand the structural changes in the brain.

Findings: We identified specific cell types and IDPs associated with the interplay between IBD and neuropsychiatric disorders. Importantly, the oligodendrocytes (ODC)-stratified variants associated with IBD were linked to multiple sclerosis and schizophrenia, astrocytes-stratified variants associated with ulcerative colitis (UC) were connected to obsessive-compulsive disorder and schizophrenia, and inhibitory neurons -stratified variants associated with Crohn's disease (CD) were linked to multiple sclerosis. Moreover, mediation analysis suggested that 31.4% of the association from UC to schizophrenia was mediated by alterations in mean diffusivity in the left tapetum, while structural changes in the right inferior temporal region associated with CD accounted for a 37.5% increased risk of cerebral aneurysm.

Interpretation: Our findings may facilitate understanding of the molecular mechanisms involved in diseases modulated by the gut-brain axis and develop novel therapeutic strategies for IBD and neuropsychiatric disorders.

Funding: CZ was supported by National Key Research and Development Program of China (2023YFC2705700), and operational funds from The First Affiliated Hospital of Nanchang University (500021010). LZ was supported by National Natural Science Foundation of China (82160155).

Background: Obesity and chronic inflammation are associated with an elevated risk of diverticulitis. However, the underlying mechanisms, particularly the role of circulating metabolites are not well understood.

Methods: We derived metabolomic signatures of metabolic dysfunction (body mass index, waist circumference, C-peptide, and adiponectin) and inflammation (C-reactive protein, interleukin 6, and tumor necrosis factor receptor superfamily 1B). We then predicted metabolomic signatures among 7888 participants who were free of diverticulitis at blood collection in Nurses' Health Study (NHS), NHSII, and Health Professional Follow-up Study (HPFS) and evaluated their association with risk of diverticulitis incidence, recurrence, and surgery.

Findings: Metabolomic signatures explained 32% of the variation in the metabolic dysfunction markers and 29% of the variation in inflammation markers. Both signatures were significantly associated with an increased risk of diverticulitis. The multivariable-adjusted hazard ratio (HR) for incident diverticulitis comparing participants in the highest quartile to those in the lowest was 1.97 (95% confidence interval [CI]: 1.52-2.54; P-trend<0.0001) for the metabolic dysfunction signature and 1.40 (95% CI: 1.08-1.81; P-trend = 0.02) for the inflammation signature. Metabolic dysfunction signature was additionally associated with an increased risk of diverticulitis recurrence (extreme-quartile HR: 1.80; 95% CI: 1.10-2.96; P-trend = 0.004) and surgery requirement (HR: 2.99; 95% CI: 1.56-5.70; P-trend = 0.005).

Interpretation: Both metabolomic signatures of metabolic dysfunction and inflammation were significantly associated with incident diverticulitis. The metabolic dysfunction signature showed a more robust association with diverticulitis recurrence and surgery requirement. Our results suggest a role of circulating metabolites in metabolic and inflammatory pathways in diverticulitis pathogenesis.

Funding: This study was supported by grants from the National Institutes of Health (UM1 CA186107, R01 CA49449, U01CA176726, R01 CA67262, U01 CA167552). ATC is an American Cancer Society Research Professor. WM is supported by the National Institutes of Health (K01DK135854-01A1), American Gastroenterological Association (AGA2021-13-01), and MGH Claflin Distinguished Scholar Award. ATC, ELG, and LLS are supported by National Institutes of Health (R01 DK101495). MD is supported by the National Institutes of Health/National Cancer Institute (NIH/NCI K00CA274714, K99CA297022). LLS is supported by National Institute of Health (NIDDK 1 R01DK131694). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Background: To investigate efficacy, safety, and tolerance of high-intensity interval training (HIIT) vs. clinical standard low-moderate intensity home-based exercise (CON) to improve aerobic capacity, muscle endurance, and mitochondrial function in patients with recent onset, idiopathic inflammatory myopathies (IIM).

Methods: Twenty-three patients with recent onset IIM were randomised into HIIT or CON groups. Both groups underwent 12 weeks of exercise training. The HIIT did 3 sessions/week, always supervised during the first three weeks. Then, training was supervised 1-3 session per week based on an individual assessment of the participants' preference and ability to perform HIIT in the clinic. The CON received one supervised session and then exercised five days per week at home, following clinical standard. Primary outcome was maximal exercise test (VO_2peak l/min and ml/kg x min, peak power (Watt), time-to-exhaustion TTE min/sec), with secondary outcomes mitochondrial protein expression in muscle. Safety was assessed by disease activity (serum levels of muscle enzymes, muscle strength (MMT8), Physician Global Assessment, pain, and fatigue (VAS, 0-100).

Findings: HIIT resulted in a 16% increase in VO_2peak L/min, significantly higher than the 1.8% change in CON (95% CI 0.1; 0.47). Peak power and TTE improved significantly more in HIIT, 18% and 23%, respectively, compared to CON, 8% and 12% (95% CI 3.9; 30.8 and 00:06; 03:18, respectively). Muscle biopsies (HIIT n = 7, CON n = 6) showed increases (p < 0.05) in central mitochondrial protein expression in HIIT but not CON, suggesting enhanced mitochondrial function. Both groups maintained stable serum muscle enzymes indicating no increase in disease activity from the intervention. Muscle disease activity remained low and unchanged in both groups (95% CI -1.2; 1.0), physician global activity and MMT8 significantly improved within CON (95% CI -1.7; -0.26 and 0.1; 3.9, respectively) but not in the HIIT group.

Interpretation: HIIT is an effective and safe exercise intervention to improve aerobic fitness, muscle endurance, and mitochondrial function in patients with recent onset IIM. This approach should be considered an adjuvant treatment in managing IIM, potentially health-enhancing for these patients.

Funding: Swedish Research Council, the Swedish Rheumatism Association, Stockholm County Research Grant (ALF), King Gustaf V 80-year Foundation, the Swedish Heart and Lung Foundation, Promobilia Foundation, and Stig Thune Foundation.

Background: Cellular senescence is involved in the pathogenesis of osteoarthritis (OA). This study aimed to identify prodrug SSK1 as a senolytic strategy for alleviating OA.

Methods: An oxidative stress-induced cellular senescence model was established to evaluate cell viability, replication, and genotoxicity after SSK1 treatment. Human OA chondrocytes and explants were collected to evaluate the therapeutic effect of prodrug SSK1 in vitro. In vivo evaluation was performed in young and aged male murine models. SSK1 (intra-articular injection every 3 days) was administrated 2 weeks after anterior cruciate ligament transection (ACLT) surgery. Animals were sacrificed 8 weeks after surgery. OA phenotype was analysed by micro-computerised tomography (μCT), histology and pain-related behaviour tests.

Findings: SSK1 showed precise, efficient, and broad-spectrum elimination of senescent chondrocytes. When co-cultured with human osteoarthritic chondrocytes and cartilage explants, the senolytic SSK1 prevented the generation of senescence-associated secretory phenotype factors, enhanced production of extracellular matrix (ECM) molecules, and promoted a regenerative chondral environment. Intra-articular administration of SSK1 showed improved pain response, enhanced retention of ECM, and remodelled subchondral bone homeostasis in both young and aged ACLT-induced OA murine model.

Interpretation: SSK1 is an effective candidate for senolytics in alleviating OA. The anti-ageing therapeutic effect of SSK1 lies in restoring a regenerative phenotype by improving the proliferation microenvironment, and reducing the accumulation of apoptotic signals in the joint microenvironment.

Funding: Funded by the Regional Innovation Joint Fund of the National Natural Science Foundation of China (Integrated Project) (U23A6009), the National Natural Science Foundation of China (82202687, 82172420, and 82072486), the Beijing Municipal Natural Science Foundation (7222213), and the Capital's Funds for Health Improvement and Research (2022-4-20511), and Beijing Tongren Hospital Seed Funds (2021-YJJ-ZZL-008).

Background: Periodontitis is linked to metabolic dysfunction-associated steatotic liver disease (MASLD); however, the underlying mechanisms remain unclear.

Methods: Periodontitis was investigated in male mice with high-fat diet (HFD)-induced MASLD. Gut microbiome and metabolomic profiling were conducted using16S rRNA gene sequencing, along with both untargeted and targeted metabolomic profiling via liquid chromatography-tandem mass spectrometry. Intestinal barrier integrity was evaluated by histopathological analysis. Faecal microbiota transplantation was conducted and the vital role of the aryl hydrocarbon receptor (AHR) was confirmed using Ahr gene knockout (Ahr^-/-) mice. The protective roles of tryptophan derivative indole-3-propionic acid (IPA) and the tryptophan-metabolising probiotic Limosilactobacillus reuteri were assessed following their administration via oral gavage. The impact of endotoxin-mediated hyperinflammation on hepatic mitochondrial dynamics was examined in vitro.

Findings: Periodontitis promoted MASLD, gut microbiota dysbiosis, and tryptophan metabolism depletion, leading to intestinal barrier dysfunction, systemic inflammation, and endotoxin overexpression in HFD-fed mice. Periodontitis-accelerated MASLD was attenuated in HFD-fed Ahr^-/- mice. In an AHR-dependent manner, IPA or L. reuteri alleviated the detrimental effects of periodontitis on MASLD progression, intestinal barrier impairment, systemic inflammation, and endotoxin translocation to the liver. Conditioned medium from endotoxin-stimulated THP-1 cells promoted mitochondrial fission in HepG2 cells by upregulating Drp1 expression.

Interpretation: Periodontitis exacerbates MASLD by disrupting the gut microbiota-tryptophan metabolism-AHR axis, leading to intestinal barrier dysfunction, systemic inflammation, and endotoxin translocation. Endotoxin plays a pivotal role in promoting hepatic mitochondrial fission during the exacerbation of MASLD by periodontitis. AHR agonists offer a novel intervention strategy for patients with comorbid MASLD and periodontitis.

Funding: This work was supported by the Jiangsu Province Key Research and Development Program [No. BE2022670]; National Natural Science Foundation of China [No. 82270979]; Jiangsu Provincial Medical Key Discipline Cultivation Unit [No. JSDW202246]; and High-Level Hospital Construction Project of Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Institute of Stomatology, Nanjing University [No. 0224C001].

Background: Inflammatory bowel disease (IBD) remains a therapeutic challenge due to its chronic relapsing nature and limited long-term remission strategies. Here, we propose a therapy using stem cells from human exfoliated deciduous teeth (SHEDs).

Methods: We evaluated SHEDs in murine colitis models (DSS/TNBS) and human IBD tissues. Single-cell RNA sequencing (scRNA-seq) and organoid cocultures were used to characterise SHED differentiation and therapeutic mechanisms.

Findings: SHEDs migrate to inflamed intestines, differentiate into TGM2⁺TFPI2⁺ quiescent fibroblast-like synovial cells (QFLSs) via a β-catenin-independent Wnt/JNK pathway, and significantly ameliorate colitis in preclinical models. Mechanistically, QFLSs exhibit dual therapeutic actions: (1) IL-6 secretion promoted Paneth cell proliferation to restore crypt homoeostasis; and (2) LIF-driven expansion of immunosuppressive Treg cells reshaped the inflammatory microenvironment. Crucially, we validated the presence of QFLSs in human IBD tissues, where their abundance correlated with reduced disease severity and improved prognosis.

Interpretation: Our study identified SHED-derived QFLSs as multifunctional mediators that concurrently addressed epithelial damage and immune dysregulation in IBD. This cell-based strategy overcame spatial limitations of traditional therapies by leveraging endogenous repair pathways, offering a translatable blueprint for chronic inflammatory diseases.

Funding: Supported by Beijing Natural Science Foundation (7242034, 7242092, L232077), National Natural Science Foundation of China (81870393, 81970500, 82473154, 81970500, and 82203559), and Jiangsu Province Basic Research Special Fund (BK20240117).