Trends Mol Med
· 2025 May · PMID 39741011
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Most patients with Hutchinson-Gilford progeria syndrome (HGPS) succumb to cardiovascular disease. Recent studies by Barettino et al., Cardoso et al., and Vakili et al. utilized progeria mouse models to elucidate novel me...Most patients with Hutchinson-Gilford progeria syndrome (HGPS) succumb to cardiovascular disease. Recent studies by Barettino et al., Cardoso et al., and Vakili et al. utilized progeria mouse models to elucidate novel mechanisms by which vascular smooth muscle cell (VSMC) and endothelial cell (EC) dysfunction accelerate the progress of the disease, thus providing directions for the development of new targeted pharmaco-therapies.
Arrizabalaga L, García-Torralba E, Galluzzi L
… +1 more, Buqué A
Trends Mol Med
· 2025 Jun · PMID 39732571
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Genetic and epigenetic defects of the p53 system have previously been associated with resistance to CDK4/6 inhibitors in women with HR breast cancer. Recent data from Kudo et al. demonstrate that CDK2-targeting agents ma...Genetic and epigenetic defects of the p53 system have previously been associated with resistance to CDK4/6 inhibitors in women with HR breast cancer. Recent data from Kudo et al. demonstrate that CDK2-targeting agents may offer an effective strategy to circumvent such resistance by enforcing cellular senescence downstream of RBL2 dephosphorylation.
Short-chain fatty acids (SCFAs), primarily derived from gut microbiota, play a role in regulating fetal development; however, the mechanism remains unclear. Fetal SCFAs levels depends on maternal SCFAs transported via th...Short-chain fatty acids (SCFAs), primarily derived from gut microbiota, play a role in regulating fetal development; however, the mechanism remains unclear. Fetal SCFAs levels depends on maternal SCFAs transported via the placenta. Metabolic stress, particularly from diabetes and obesity, can disrupt maternal SCFAs levels, impairing fetal metabolic reprogramming. Dysregulated SCFAs may negatively impact the development of the fetal cardiovascular, nervous, and immune systems, potentially contributing to adverse outcomes in adulthood. This review focuses on recent advances regarding the role of maternal SCFAs in shaping the metabolic profile of offspring, especially in the context of various maternal metabolic disorders. Given that SCFAs may influence fetal development through the placenta-embryo axis, targeted SCFAs supplementation could be a promising strategy against developmental diseases associated with intrauterine risk factors.
Trends Mol Med
· 2025 May · PMID 39690058
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Galectin-3 (Gal3), a β-galactoside-binding lectin, is expressed predominantly in immunological and inflammatory cells. Gal3 expression is elevated in metabolic diseases, including obesity, diabetes, and metabolic dysfunc...Galectin-3 (Gal3), a β-galactoside-binding lectin, is expressed predominantly in immunological and inflammatory cells. Gal3 expression is elevated in metabolic diseases, including obesity, diabetes, and metabolic dysfunction-associated steatotic liver disease (MASLD), and plays an important role in the progression of these diseases. In this review, we summarize the structure and post-translational modifications of Gal3 and the cellular functions of Gal3 according to its subcellular localization. We focused on the pathological functions and molecular mechanisms of Gal3 in various cell types. In particular, extracellular Gal3 and intracellular Gal3 may have different physiological and pathological functions. We also discuss promising Gal3 inhibitors or antibodies that are currently in clinical trials and outstanding questions and challenges for future pursuit.
Trends Mol Med
· 2025 Jul · PMID 39690057
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Idiopathic pulmonary fibrosis (IPF) is a progressive and debilitating lung disease characterized by excessive extracellular matrix deposition and tissue scarring. The median survival of patients with IPF is only 4.5 year...Idiopathic pulmonary fibrosis (IPF) is a progressive and debilitating lung disease characterized by excessive extracellular matrix deposition and tissue scarring. The median survival of patients with IPF is only 4.5 years following diagnosis, and effective treatment options are scarce. Recent studies found aberrant translation of specific mRNAs in various fibrosing diseases, highlighting the role of key translational regulators, including RNA binding proteins (RBPs), microRNAs, long noncoding RNAs, and transcript modifications. Notably, when inhibited, 10 profibrotic RBPs cause a significant attenuation of fibrosis, illuminating potential therapeutic targets. In this review, we describe translational regulation in fibrosis and highlight a model where a conserved evolutionary mechanism may explain this regulation.
Trends Mol Med
· 2025 Feb · PMID 39668101
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The Yamanaka factors (YFs), a set of four transcription factors, are widely studied for their ability to dedifferentiate somatic cells into a pluripotent state. In a recent study, Shen and colleagues show that transient...The Yamanaka factors (YFs), a set of four transcription factors, are widely studied for their ability to dedifferentiate somatic cells into a pluripotent state. In a recent study, Shen and colleagues show that transient expression of YFs in the mouse brain expands the developing cortex and prevents cognitive decline in an Alzheimer's disease (AD) model.
Trends Mol Med
· 2025 Jun · PMID 39665958
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Deep learning has revolutionized cancer diagnostics, shifting from pixel-based image analysis to more comprehensive, patient-centric care. This opinion article explores recent advancements in neural network architectures...Deep learning has revolutionized cancer diagnostics, shifting from pixel-based image analysis to more comprehensive, patient-centric care. This opinion article explores recent advancements in neural network architectures, highlighting their evolution in biomedical research and their impact on medical imaging interpretation and multimodal data integration. We emphasize the need for domain-specific artificial intelligence (AI) systems capable of handling complex clinical tasks, advocating for the development of multimodal large language models that can integrate diverse data sources. These models have the potential to significantly enhance the precision and efficiency of cancer diagnostics, transforming AI from a supplementary tool into a core component of clinical decision-making, ultimately improving patient outcomes and advancing cancer care.
Cresto N, Givalois L, Badaut J
… +5 more, Janvier A, Genin A, Audinat E, Brewster AL, Marchi N
Trends Mol Med
· 2025 Jun · PMID 39665957
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Hypersynchronous and exaggerated neuronal firing, exemplified by epileptiform activity and seizures, are disruptors of brain function across acute and chronic neuropathological conditions. Here, we focus on how seizure a...Hypersynchronous and exaggerated neuronal firing, exemplified by epileptiform activity and seizures, are disruptors of brain function across acute and chronic neuropathological conditions. Here, we focus on how seizure activity, whether as a primary symptom or a secondary comorbid event within a complex pathological setting, adversely impacts neurological trajectories. We discuss experimental and clinical evidence illustrating the participation of neurodegenerative and senescence-like adaptations. Paroxysmal neuronal events, through bidirectional causality, are linked with immune and microvascular changes, disrupting cellular homeostasis and creating a feed-forward loop that intertwines with age-related frailty to deteriorate mental health. We emphasize the clinical significance of early detection of these brain vulnerabilities through biomarkers, monitoring neurodevelopmental risks in children, and tracking neurodegenerative disease progression in aging populations.
Chen Y, Mao W, Shen Y
… +5 more, Huang H, Chang HM, Dong X, Jiang J, Mu L
Trends Mol Med
· 2025 Jun · PMID 39648053
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Recent research highlights that Lon protease 1 (LONP1) regulates steroidogenesis in the ovary and plays a role in oocyte development and quality control. Dysregulation of LONP1 has been observed in polycystic ovary syndr...Recent research highlights that Lon protease 1 (LONP1) regulates steroidogenesis in the ovary and plays a role in oocyte development and quality control. Dysregulation of LONP1 has been observed in polycystic ovary syndrome and ovarian aging. This forum article explores the role of LONP1 in the ovary and its therapeutic potential.
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer characterized by dismal prognosis. Late diagnosis, resistance to chemotherapy, and lack of efficacious targeted therapies render PDAC almost untreatable. Dy...Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer characterized by dismal prognosis. Late diagnosis, resistance to chemotherapy, and lack of efficacious targeted therapies render PDAC almost untreatable. Dysregulation of splicing, the process that excises the introns from nascent transcripts, is emerging as a hallmark of PDAC and a possible vulnerability of this devastating cancer. Splicing factors are deregulated in PDAC and contribute to all steps of tumorigenesis, from inflammation-related early events to metastasis and acquisition of chemoresistance. At the same time, splicing dysregulation offers a therapeutic opportunity to target cancer-specific vulnerabilities. We discuss mounting evidence that splicing plays a key role in PDAC and the opportunities that this essential process offers for developing new targeted therapies.
Trends Mol Med
· 2025 May · PMID 39643521
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A milestone in sickle cell disease (SCD) therapeutics was achieved in December 2023 with the FDA-approved gene therapy for patients aged 12 years and older. However, these therapies may only suit a fraction of patients b...A milestone in sickle cell disease (SCD) therapeutics was achieved in December 2023 with the FDA-approved gene therapy for patients aged 12 years and older. However, these therapies may only suit a fraction of patients because of cost or health risks. A better understanding of SCD outcome heterogeneity is needed to propose patient-specific pharmacological interventions. To achieve this, humanized and genetically diverse mouse models are essential for associating candidate genotypes with specific hematological traits, organ function, and disease resilience. Here, we discuss the challenges and opportunities in developing genetically diverse sickle cell mice (GDS mice). These models are expected to complement current approaches in SCD research and enhance our understanding of SCD heterogeneity and anemia.
Inflammatory bowel diseases (IBDs) involve relapsing-remitting immune activation and inflammation. Both immune system activity and digestive tract function exhibit diurnal variations, regulated by the circadian clock. Di...Inflammatory bowel diseases (IBDs) involve relapsing-remitting immune activation and inflammation. Both immune system activity and digestive tract function exhibit diurnal variations, regulated by the circadian clock. Disruption of this clock is linked to inflammation, suggesting that circadian regulators may play a pivotal role in the inflammatory process of IBD.
Kosmara D, Neofotistou-Themeli E, Semitekolou M
… +1 more, Bertsias G
Trends Mol Med
· 2025 May · PMID 39627079
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Most people affected by systemic lupus erythematosus (SLE) are women. Although the role of sex hormones has been appreciated, we discuss emerging evidence that links X-linked genes escaping from dosage compensation to fe...Most people affected by systemic lupus erythematosus (SLE) are women. Although the role of sex hormones has been appreciated, we discuss emerging evidence that links X-linked genes escaping from dosage compensation to female predisposition to lupus. This is exemplified by TLR7 and CXorf21 whose female-biased expression may converge to enhance interferon responses and promote autoantibody-producing B cells, which are hallmarks of SLE. Notably, autosomal transcription factors with female overexpression may regulate molecular programs in the skin that are sufficient to induce lupus. These findings indicate a multifactorial basis for female vulnerability; however, several areas remain elusive, including the epigenetic landscape of X-chromosome inactivation (XCI) in SLE, the interplay with environmental factors, and the role of male-specific factors such as Y-linked genes.