Frontiers in molecular medicine最新文献

Interstitial cystitis/bladder pain syndrome (IC/BPS) with Hunner Lesions (Hunner Type Interstitial Cystitis or HIC) is characterized by lesions on the bladder wall. Previous work on these lesions identified B cells and monocytes within the lesion. However, the overall role of the adaptive immune system in the disorder remains uncertain. In this study, we performed HLA sequencing on 12 IC/BPS patients with HIC and 7 Non Hunner Type IC (NHIC) patients, and identified HLA-DQB1*02:02 and HLA-DRB1*07:01:01 have a significant association with HIC. This pilot study provides genetic evidence supporting a potential autoimmune component in HIC and may help define the pathogenesis of at least one subtype of IC/BPS, and lay the groundwork for identifying the etiology of IC/BPS as a disease complex. Identifying the mechanisms can also open new approaches to treatment. Identifying an HLA haplotype associated with HIC would indicate that it is autoimmune.

Adeno-Associated Virus (AAV) vectors are at the forefront of gene therapy, offering transformative therapeutic potential for many genetic disorders. However, the translation of this promise into accessible treatments is constrained by manufacturing challenges, including process variability, low yields, and scalability challenges. This review provides a comprehensive framework for establishing robust AAV-based gene therapy manufacturing processes by evaluating industry challenges and recent technological innovations. We studied the end-to-end AAV-based gene therapy manufacturing process, from upstream unit operations such as cell culture and transfection to downstream purification and fill-finish operations. Key upstream innovations highlighted include high-density perfusion cultures, advanced single- and dual-plasmid systems, and next-generation transfection reagents that collectively enhance the overall process quality and viral vector productivity. In the realm of downstream processing, recent advancements in serotype-agnostic affinity chromatography and ion-exchange chromatographic purifications have enhanced the critical separation of full capsids from empty capsids. The implementation of a quality-by-design framework is the heart of the AAV-based gene therapy manufacturing process. We emphasize the necessity of a rigorous process characterization, utilizing validated scale-down models and design of experiments, as a prerequisite for establishing a robust control strategy with defined proven and normal operating ranges. This data-driven approach not only mitigates process inconsistency, but it also serves as the foundation for an effective process validation and regulatory compliance. Looking ahead, the integration of artificial intelligence and continuous manufacturing methodologies will be pivotal in expediting the development of safer, more efficacious, and personalized AAV-based gene therapies.

MYC is a transcription factor crucial for a host of cellular functions from proliferation to metabolism, and MYC dysregulation contributes to disease pathogenesis. A growing body of evidence suggests that MYC signaling is regulated by the caspase activation and recruitment domain-coiled-coil (CARD-CC) proteins: a family of immunological signaling mediators that canonically drive NF-κB signaling across nearly all tissues. MYC regulation coordinated by the CARD-CC proteins occurs by multiple mechanisms, including transcription, physical binding, and subcellular localization. Herein, we highlight the hallmark studies that collectively broaden the sphere of influence of CBM complexes beyond NF-κB to include MYC, which has functional impact on cells within and likely beyond the immune system. The studies reviewed herein provide rationale for future studies that examine non-canonical CBM-MYC signaling, its relationship with canonical NF-κB signaling, and its contribution to human health and disease.

The classical cadherin (CDH), claudin (CLDN) and nectin families of transmembrane-type adhesion molecules are located at adherens or tight junctions in epithelial cells but diffuse to the nonjunctional cell surface in solid tumors with epithelial-mesenchymal plasticity. Human/humanized antibody-drug conjugates (ADCs) with chemical linkers and cytotoxic payloads have been developed for the treatment of malignancies. Here, the clinical development of ADCs that target CDH6, CDH17, CLDN6, CLDN18.2 and NECTIN4 is reviewed. Enfortumab vedotin is an NECTIN4-targeting antibody-drug conjugate that is approved for the treatment of urothelial cancer, whereas other ADCs or derivatives that target NECTIN4, such as bulumtatug fuvedotin, SHR-A2102 and zelenectide pevedotin, are being studied in randomized phase III clinical trials. In contrast, arcotatug tavatecan, garetatug rezetecan, sonesitatug vedotin and tecotabart vedotin are anti-CLDN18.2 ADCs in phase III clinical trials for the treatment of CLDN18.2-positive gastric or gastroesophageal junction adenocarcinomas, and raludotatug deruxtecan is an anti-CDH6 ADC in a phase II/III clinical trial for the treatment of platinum-resistant ovarian cancer. ADCs that target cell-cell adhesion molecules are a rapidly emerging class of cancer therapeutics, and bispecific ADCs and longitudinal companion diagnostics are emerging to further improve the clinical benefits of conventional ADCs.

One development in the growing field of Alzheimer's Disease and related neurological disorders (ADRD) is the consideration of brain resilience, the ability to respond to and recover from adversity, which builds on a growing literature on the role of lifestyle behaviours in ADRD prevention and response. This paper reviews definitions of 'brain health' and integrates these with innovations in resilience system models applied to ADRD. Based on a socio-ecological framework that links physiological, behavioral, economic, and social determinants of mental health, we propose a unified model of resilience and aging in this field. We contend that applications of a resilience analytical approach to brain health require innovation in Artificial Intelligence (AI) to harness the full potential of immense interdisciplinary data mining opportunities. These include: development of digital twins, precision health analytics, AI sensors, and Multimodal Large Language Models (MLLM), knowledge graph technologies, and cognitive/decision science modeling. We apply this model to research and clinical examples to elucidate its potential value, requirements, risks, and challenges in developing new research agendas.

Coronavirus disease 2019 (COVID-19), caused by the betacoronavirus SARS-CoV-2, emerged in Wuhan, China, and rapidly evolved into a global health crisis. Recent evidence highlights the activation of the aryl hydrocarbon receptor (AHR) pathway following SARS-CoV-2 infection, implicating AHR in facilitating viral replication and impairing antiviral immunity. As a ligand-dependent transcription factor, AHR regulates immune responses, cellular differentiation, and proliferation, and is frequently exploited by viruses to evade host defences. In relation to COVID-19, AHR activation drives immune suppression, systemic inflammation, and metabolic disturbances, intensifying disease severity. Notably, in individuals with comorbidities such as obesity and diabetes, AHR overactivity exacerbates insulin resistance, oxidative stress, endothelial dysfunction, and thrombotic risk, contributing to cardiovascular complications. AHR also promotes airway remodelling and mucus hypersecretion, fostering respiratory dysfunction and fibrotic progression. This review synthesizes current insights into the mechanistic role of AHR signalling in SARS-CoV-2 pathogenesis and discusses its potential as a target for host-directed therapeutic interventions.

N6-methyladenosine (m6A) is the best-studied post-transcriptional RNA modification. It refers to the methylation in the N6 position. M6A exists universally from viruses to mammalian cells and is highly abundant in RNA polymerase II-transcribed, protein-coding transcripts and various non-coding RNAs. M6A RNA modification influences multiple physiological and pathological processes. This RNA methylation plays a role in the pathogenesis of many human diseases, including but not limited to hematopoietic, central nervous, and reproductive systems. One of the m6A-modified non-coding RNAs is the circular form of RNA. Circular RNA (circRNA) refers to a single-stranded RNA molecule with a circular structure that exists across a wide range of organisms, including eukaryotes and prokaryotes. Its unique circular structure is formed by the covalent closure between the 3'and 5'ends of the RNA molecule. This closed-loop structure prevents the circRNA from being degraded readily by the exonucleases, resulting in more stability compared to its linear RNA counterparts. CircRNAs have been reported to regulate gene expression, protein interaction, and RNA sponging. They play important roles in many human diseases. M6A modifications of the host gene mRNAs regulate the circRNA biogenesis. Furthermore, m6A modification of circRNA itself adds additional regulation of these complicated processes. This mini-review elaborates on recent advances in m6A modification on circRNA biogenesis and function, focusing on the role of circRNA m6A modification in the development of inflammatory responses.

The idea of ​​using stem cell therapy to treat neurodegenerative diseases has undergone significant change over the years and has made significant progress recently. Neurotrophins, growth factors, and transcription factors regulate neural stem cell proliferation and differentiation. Disruption of these regulatory mechanisms, including negative feedback, can contribute to neurodegenerative diseases. Contemporary research highlights a growing global concern regarding diverse neurodegenerative disorders affecting both humans and animals. These conditions arise from neuronal cell death, axonal regeneration failure, and impairment of neuronal structure. Current pharmacological treatments primarily offer symptomatic relief without altering disease progression. Consequently, researchers are investigating innovative therapeutic strategies, with neural stem cell therapy emerging as a promising avenue. Adult neural stem cells, embryonic neural stem cells, and induced pluripotent stem cells represent potential cell sources, although challenges such as ethical considerations and technical limitations remain. The therapeutic application of neural stem cells holds significant promise for addressing neurodegenerative diseases, including Alzheimer's disease, stroke, amyotrophic lateral sclerosis, spinal cord injury, and multiple sclerosis. Neural stem cell therapy aims to replenish lost neurons and promote neural regeneration in these conditions. While clinical trials have demonstrated some success in improving cognitive and motor functions in individuals with neurodegenerative impairments, challenges such as immunological rejection, the identification of compatible cell sources, ethical concerns, treatment efficacy, and potential side effects necessitate thorough investigation before widespread clinical implementation. Despite these challenges, neural stem cell-based therapy offers substantial potential for revolutionizing the treatment of neurodegenerative diseases and central nervous system injuries. This paper, therefore, explores adult neurogenesis and the therapeutic potential of neural stem cells within the dynamic field of neurodegenerative disorders.