Trends in molecular medicine最新文献

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic debilitating condition with no cure that shares commonality with long-COVID. This review examines current understanding of long-COVID symptoms, characteristics of the affected population, the connection with ME/CFS, and the potential for salubrinal, an agent known for its influence on cellular stress pathways, to mitigate these disorders It also describes the historical development and mechanism of action of salubrinal, to mitigate endoplasmic reticulum (ER)/cellular stress responses, that could potentially contribute to symptom improvement in both ME/CFS and long-COVID patients. Further research and clinical trials are warranted to advance our understanding of the potential role of salubrinal in improving the quality of life for individuals with long-COVID-related ME/CFS symptoms as well as ME/CFS patients.

Osteoarthritis (OA) is a prevalent articular disorder characterized by joint degeneration and persistent pain; it imposes a significant burden on both individuals and society. While OA has traditionally been viewed as a localized peripheral disorder, recent preclinical and clinical studies have revealed the crucial interconnections between the bone and the brain, highlighting the systemic nature of OA. The neuronal pathway, molecular signaling, circadian rhythms, and genetic underpinnings within the bone-brain axis play vital roles in the complex interplay that contributes to OA initiation and progression. This review explores emerging evidence of the crosstalk between the bone and brain in OA progression, and discusses the potential contributions of the bone-brain axis to the development of effective interventions for managing OA.

The increasing prevalence and poor prognosis of central nervous system (CNS) metastases pose a significant challenge in oncology, necessitating improved therapeutic strategies. Recent research has shed light on the complex genomic landscape of brain metastases, identifying unique and potentially actionable genetic alterations. These insights offer new avenues for targeted therapy, highlighting the potential of precision medicine approaches in treating CNS metastases. However, translating these discoveries into clinical practice requires overcoming challenges such as availability of tissue for characterization, access to molecular testing, drug delivery across the blood-brain barrier (BBB) and addressing intra- and intertumoral genetic heterogeneity. This review explores novel insights into the evolution of CNS metastases, the molecular mechanisms underlying their development, and implications for therapeutic interventions.

Duchenne muscular dystrophy (DMD) is caused by mutations in the X-linked DMD gene, resulting in the absence of dystrophin, progressive muscle degeneration, and heart failure. Genetically tailored pig models resembling human DMD mutations recapitulate the biochemical, clinical, and pathological hallmarks of DMD with an accelerated disease progression compared to human patients. DMD pigs have been used to evaluate therapeutic concepts such as gene editing to reframe a disrupted DMD reading frame or the delivery of artificial chromosome vectors carrying the complete DMD gene. Moreover, DMD pigs have been instrumental in validating new diagnostic modalities such as multispectral optoacoustic tomography (MSOT) for non-invasive monitoring of disease progression. DMD pigs may thus help to bridge the gap between proof-of-concept studies in cellular or rodent models and clinical studies in patients.

In this opinion article, we discuss potential connections between sleep disturbances observed in Alzheimer's disease (AD) and Parkinson's disease (PD) and the dysregulation of lipids in the brain. Research using Drosophila has highlighted the role of glial-mediated lipid metabolism in sleep and diurnal rhythms. Relevant to AD, the formation of lipid droplets in glia, which occurs in response to elevated neuronal reactive oxygen species (ROS), is required for sleep. In disease models, this process is disrupted, arguing a connection to sleep dysregulation. Relevant to PD, the degradation of neuronally synthesized glucosylceramides by glia requires glucocerebrosidase (GBA, a PD-associated risk factor) and this regulates sleep. Loss of GBA in glia causes an accumulation of glucosylceramides and neurodegeneration. Overall, research primarily using Drosophila has highlighted how dysregulation of glial lipid metabolism may underlie sleep disturbances in neurodegenerative diseases.

Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common causes of Parkinson's disease (PD) to date. Dysfunction in LRRK2 enzymatic activities and elevated protein levels are associated with the disease. How is LRRK2 activated, and what downstream molecular and cellular processes does LRRK2 regulate? Addressing these questions is crucial to decipher the disease mechanisms. In this review we focus on the upstream regulations and briefly discuss downstream substrates of LRRK2 as well as the cellular consequences caused by these regulations. Building on these basic findings, we discuss therapeutic strategies targeting LRRK2 and highlight the challenges in clinical trials. We further highlight the important questions that remains to be answered in the LRRK2 field.

Faulkes et al. recently showed that naked mole-rats (NMRs) have a very distinctive cardiac gene expression profile among other African mole-rats, as well as metabolic variations that result from their chronic exposure to a hypoxic environment. These adaptations might underlie their resistance to cardiac ischemic injuries.

Glioma, the most common primary malignant tumor in the central nervous system (CNS), lacks effective treatments, and >60% of cases are glioblastoma (GBM), the most aggressive form. Despite advances in immunotherapy, GBM remains highly resistant. Approaches that target tumor antigens expedite the development of immunotherapies, including personalized tumor-specific vaccines, patient-specific target selection, dendritic cell (DC) vaccines, and chimeric antigen receptor (CAR) and T cell receptor (TCR) T cells. Recent studies show promising results in treating GBM and lower-grade glioma (LGG), fostering hope for future immunotherapy. This review discusses tumor vaccines against glioma, preclinical models in immunological research, and the role of CD4⁺ T cells in vaccine-induced antitumor immunity. We also summarize clinical approaches, challenges, and future research for creating more effective vaccines.

An effective HIV-1 vaccine is still not available, and most vaccine efficacy trials conducted over the years resulted in no significant overall protection. Here we highlight several insights gained from these trials as well as emerging questions that may be important for further guidance to advance current research directions.

Historical reasons resulted in the almost exclusive use of a few species, most prominently Mus musculus, as the mainstream models in biomedical research. This selection was not based on Mus's distinctive relevance to human disease but rather to the pre-existing availability of resources and tools for the species that were used as models, which has enabled their adoption for research in health sciences. Unless the utilization and range of nontraditional research models expand considerably, progress in biomedical research will remain restricted within the trajectory that has been set by the existing models and their ability to provide clinically relevant information.