Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Thomsen and Becker disease. Core disease mechanisms, molecular and cellula...

This report is retrieval-only and is generated directly from Asta results.

• Papers retrieved: 20
• Snippets retrieved: 20

Relevant Papers

[1] New therapeutic targets in rare genetic skeletal diseases

• Authors: M. Briggs, Peter A. Bell, M. Wright, K. A. Pirog
• Year: 2015
• Venue: Expert Opinion on Orphan Drugs
• URL: https://www.semanticscholar.org/paper/1363107f71ae6d2d60abca471cddf3da5d13644b
• DOI: 10.1517/21678707.2015.1083853
• PMID: 26635999
• PMCID: 4643203
• Citations: 37
• Influential citations: 1
• Summary: An overview of disease mechanisms that are shared amongst groups of different GSDs and potential therapeutic approaches that are under investigation are described to generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.
• Evidence snippets:
• Snippet 1 (score: 0.483) > proteins of the cartilage ECM such as type II collagen [50]. However, emerging knowledge suggests that the primary genetic defect may be less important than the cells' response to the expression of the mutant gene product [107]. Moreover, the largely overlooked response of a cell (i.e. chondrocyte) to the abnormal extracellular environment is also important for disease progression as illustrated by several GSDs discussed in this review. > It is important that 'omics'-based approaches and technologies are systematically applied to the study of rare GSDs so that definitive reference profiles and disease signatures are generated for each phenotype. These can then be used in a Systems Biology approach to identify both common and dissimilar pathological signatures and disease mechanisms. This approach is entirely dependent upon relevant in vitro and in vivo models (and also novel 'disease-mechanism phenocopies' [107]) for testing new diagnostic and prognostic tools and for determining the molecular mechanisms that underpin the pathophysiology so that effective therapeutic treatments can be developed and validated. This approach will eventually lead to personalized treatments and care strategies centred on shared disease mechanisms with the use of relevant biomarkers to monitor the efficacy of treatment and disease progression. > It is vital that all relevant stakeholders are involved from the outset in defining the appropriate outcomes of any potential therapeutic regime. The perceptions of a successful therapy can differ widely between the clinical academic community and the relevant patient-support groups and it is vital that there is engagement on all these issues. > In summary, the identification of causative genes and mutations for GSDs over the last 20 years, coupled with the generation and in-depth analysis of a plethora of relevant cell and mouse models, has derived new knowledge on disease mechanisms and suggested potential therapeutic targets. The fast-evolving hypothesis that clinically disparate diseases can share common disease mechanisms is a powerful concept that will generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.

[2] Changes in Serum Proteomic Profiles at Different Stages of Pregnancy Toxemia in Goats

• Authors: M. Uzti̇mür, C. N. Ünal, Gurler Akpinar
• Year: 2025
• Venue: Journal of Veterinary Internal Medicine
• URL: https://www.semanticscholar.org/paper/4b9c488b5dbd65d7b26fd2ad9aed70e8c4b59942
• DOI: 10.1111/jvim.70139
• PMID: 40492724
• PMCID: 12150350
• Summary: Understanding the serum proteome profiles of goats with pregnancy toxemia might help identify the proteomes and pathways responsible for the development of this disease and improve diagnosis and treatment.
• Evidence snippets:
• Snippet 1 (score: 0.482) > The pathophysiology and progression of this disease are not fully understood. > Traditional biomedical research has focused on the analysis of single genes, proteins, metabolites, or metabolic pathways in diseases. This molecular reductionist approach is based on the assumption that identifying genetic variations and molecular components will lead to new treatments for diseases [13][14][15][16]. However, many diseases are complex and multifactorial, and in order to determine the phenotype of such diseases, it is necessary to understand the changes that occur in more than one gene, pathway, protein, or metabolite at the cellular, tissue, and organismal levels [17][18][19]. Therefore, in recent years, proteomics, as one field of multi-omics technologies, has helped in evaluating the complex pathogenetic mechanisms of different diseases from a broad perspective and has made substantial contributions [20,21]. In veterinary medicine, proteomic analysis of metabolic diseases such as ketosis [16], hypocalcemia [22], and fatty liver [23] in dairy cows has contributed valuable insights for the definition of new pathophysiological pathways and new diagnosis and treatment protocols for these diseases. The proteomic approach can contribute importantly to a broad and detailed understanding of the changes that occur at the organismal level associated with the increase in BHBA concentration in goats with pregnancy toxemia. Our aim was to evaluate the serum protein profiles of goats with SPT or CPT using proteomic techniques to determine the proteomic profiles of these animals and to identify the relevant pathophysiological mechanisms.

[3] Organoids in gastrointestinal diseases: from bench to clinic

• Authors: Qinying Wang, Fanying Guo, Qinyuan Zhang, Tingting Hu, Yutao Jin et al.
• Year: 2024
• Venue: MedComm
• URL: https://www.semanticscholar.org/paper/9b8880d8b9d45670da950197d7e353794f51d09e
• DOI: 10.1002/mco2.574
• PMID: 38948115
• PMCID: 11214594
• Citations: 12
• Summary: A comprehensive and systematical depiction of organoids models is drawn, providing a novel insight into the utilization of organoids models from bench to clinic and clinical adhibition.
• Evidence snippets:
• Snippet 1 (score: 0.475) > Organoids models offer a robust platform for investigating the potential mechanisms of GI diseases and evaluating potential therapeutic interventions.By culturing organoids derived from patients' tissues or stem cells, researchers can delve into disease-specific cellular and molecular pathways, encompassing aberrant cell signaling, perturbed immune responses, and dysfunctional metabolic processes.These disease-specific phenotypes enable the study of disease progression, screening of prospective therapeutics, as well as identification of novel drug targets and mechanisms of action for GI diseases in a clinically relevant context.

[4] The Notch signaling pathway in skeletal muscle health and disease

• Authors: D. Vargas-Franco, R. Kalra, Isabelle Draper, C. A. Pacak, A. Asakura et al.
• Year: 2022
• Venue: Muscle & Nerve
• URL: https://www.semanticscholar.org/paper/2bc32ef6a1acc95f1c31b7e3ef5a268aadda4024
• DOI: 10.1002/mus.27684
• PMID: 35968817
• PMCID: 9804383
• Citations: 37
• Summary: The clinical syndromes associated with pathogenic variants in each of these genes, known molecular and cellular functions of their protein products with a particular focus on the Notch signaling pathway, and potential novel therapeutic targets that may emerge from further investigations of these diseases are reviewed.
• Evidence snippets:
• Snippet 1 (score: 0.442) > Since the landmark discovery in 1986 of DMD (dystrophin), 1 the causative gene for Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD), dozens of additional genes have been associated with various phenotypic subtypes of muscular dystrophy. > Common disease mechanisms across multiple subtypes have, however, been more difficult to identify, with only a few major clusters such as the dystroglycanopathies identified to date. Given the common phenotypic features within muscular dystrophy categories, such as limb-girdle muscular dystrophy (LGMD), there is a high likelihood that convergent disease mechanisms exist across more muscular dystrophy subtypes than is currently recognized. > There are therapeutic implications of identifying deeper biological ties between muscular dystrophy subtypes. In recent years, the US Food and Drug Administration (FDA) has approved several molecular and genetic therapies for neuromuscular disorders that target specific genes and even specific mutation types within those genes. These approaches are being applied to ever rarer forms of muscular dystrophies. However, proceeding through the preclinical and clinical research studies needed to attain FDA approval for a new therapy is lengthy and costly, and on the current trajectory it will be decades before molecular and genetic therapies are available for all known subtypes of muscular dystrophy. > The identification and characterization of disease mechanisms that are shared by multiple muscular dystrophy subtypes could pave the way for new pathway-based treatments that have therapeutic effects for multiple disease subtypes. 2 This has the potential to accelerate the timeline for broader therapeutic coverage of patients with muscular dystrophy, with a greater impact on the entire muscular dystrophy population. > One disease mechanism that bears further analysis is the Notch signaling pathway, which is known to maintain muscle stem cell (MuSC, also known as satellite cell) quiescence. Recently, three different muscle disease genes that are known to interact with the Notch signaling pathway have been identified: MEGF10, POGLUT1, and most recently JAG2.

[5] Cellular reprogramming and inherited peripheral neuropathies: perspectives and challenges

• Authors: M. Saporta
• Year: 2015
• Venue: Neural Regeneration Research
• URL: https://www.semanticscholar.org/paper/8c3dabb1b4abf93506e2026564b8a329c0ec37c6
• DOI: 10.4103/1673-5374.158345
• PMID: 26199602
• PMCID: 4498347
• Citations: 4
• Summary: iPSC-based models of neuromuscular disorders, including amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA) and inherited peripheral neuropathies, have successfully reproduced pathophysiological findings from previous animal and cellular models and have also identified new disease mechanisms with potential therapeutical implications.
• Evidence snippets:
• Snippet 1 (score: 0.424) > Inherited peripheral neuropathies (or Charcot-Marie-Tooth disease, CMT) are a phenotypically and genetically heterogeneous group of disorders, which are currently untreatable. They are the most common inherited neuromuscular disorder, affecting around 1 in every 2,500 people (over 120,000 people in the US). Based on clinical neurophysiological and histopathological features, inherited neuropathies can be divided into two major forms: demyelinating (type 1) and axonal (type 2) CMT (Saporta, 2014). From a biological standpoint, these two major forms of CMT are associated with mutations in different sets of genes, affecting Schwann cell development and myelination (type 1) or peripheral axon physiology (type 2), although some overlap does exist (Figure 1). To date, over 70 genes have been associated with a CMT phenotype, making CMT an attractive natural model to study peripheral nervous system biology. Despite significant advances made in our knowledge of disease mechanisms in CMT, findings from animal models have so far translated poorly in clinical trials, underscoring the need for innovative methods to investigate the pathophysiology of these human disorders. Induced pluripotent stem cells (iPSCs) offer an unlimited source of patient specific, disease-relevant cell lines that can be used as a platform for identification of disease mechanisms, discovery of molecular targets and development of phenotypic screens for drug discovery (Saporta et al., 2011). iPSC-based models of neuromuscular disorders, including amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA) and inherited peripheral neuropathies, have successfully reproduced pathophysiological findings from previous animal and cellular models and have also identified new disease mechanisms with potential therapeutical implications.

[6] Heat Shock Proteins in Oxidative Stress and Ischemia/Reperfusion Injury and Benefits from Physical Exercises: A Review to the Current Knowledge

• Authors: Jakub Szyller, I. Bil-Lula
• Year: 2021
• Venue: Oxidative Medicine and Cellular Longevity
• URL: https://www.semanticscholar.org/paper/4ec4bee9f1b89cdf5a3c513d847990f3cfc18bb8
• DOI: 10.1155/2021/6678457
• PMID: 33603951
• PMCID: 7868165
• Citations: 112
• Influential citations: 2
• Summary: The latest research focuses on determining the role of H SPs in OS, their antioxidant activity, and the possibility of using HSPs in the treatment of I/R consequences, where reactive oxygen species play a major role.
• Evidence snippets:
• Snippet 1 (score: 0.421) > Heat shock proteins play a cytoprotective role under pathological conditions such as cardiovascular diseases. The knowledge about cellular and molecular mechanisms underlying ROS-mediated modulation of HSP expression can help to better understand the pathophysiology of OS, which is associated with the development of many diseases (cardiovascular, neurodegenerative, etc.). I/R injury is considered a major contributor to tissue damage in multiple clinical situations such as myocardial infarction, stroke, and organ transplantation. Oxidative damage is a key factor in the initiation of I/R. HSP expression is highly sensitive to I/R injury. > Understanding the exact mechanisms of HSP and the structure of the protein interaction network can help to better understand the pathophysiology and treatment of many diseases, as well as to develop new drugs. There is a need to understand the relationship between cell pathways-signaling, metabolism, etc. The relationships between HSP and OS discussed in this work seem to be very complicated and not yet fully understood. Data showed that modulation of HSP expression in reperfusion injuries may result in better treatment of myocardial infarction. This can also help to prepare organs for the transplantation.

[7] Chapter 15: Disease Gene Prioritization

• Authors: Y. Bromberg
• Year: 2013
• Venue: PLoS Computational Biology
• URL: https://www.semanticscholar.org/paper/2c8913d03b29b4facfc3737a24d8b91a93e5ad41
• DOI: 10.1371/journal.pcbi.1002902
• PMID: 23633938
• PMCID: 3635969
• Citations: 69
• Influential citations: 3
• Summary: Comprehensive prioritization of candidate genes prior to experimental testing drastically reduces the associated costs and faster and more reliable techniques that account for novel data types are necessary for the development of new diagnostics, treatments, and cure for many diseases.
• Evidence snippets:
• Snippet 1 (score: 0.416) > Changes in gene expression in diseaseaffected tissues are associated with many complex diseases [65]. Tissue specificity is also important for choosing correct protein-protein interaction networks, as some proteins interact in some tissues, but rarely in others [66]. Disease-associated cellular pathways (e.g. ion channels or endocytic membrane transport) and compartments (e.g. membrane or nucleus) implicate pathway/compartment-specific gene-products in disease as well. For example, autosomal recessive generalized myotonia (Becker's disease) (GM) and autosomal dominant myotoniacongenita (Thomsen's disease, MC) are characterized by skeletal muscle stiffness [67]. This phenotype is the result of muscle membrane hyperexcitability and, in conjunction with observed alterations in muscle chloride and sodium currents, points to possible involvement of deficiencies of the muscle chloride channel. In fact, studies point to the mutations in the transmembrane region of CLC-1, the muscle chloride channel coding gene, as the culprit [67]. Another example is that of the multiple storage diseases, such as Tay-Sachs, Gaucher, Niemann-Pick and Pompe disease, which are caused by the impairment of the degradation pathways of the intracellular vesicular transport. In fact, many of the genes implicated in these diseases encode for proteins localized to endosomes (e.g. NPC1 in Neimann-Pick [68]) or lysosomes (e.g. GBA [69] in Gaucher, GAA in Pompe [70] and HEXA in Tay Sachs [71]).

[8] Therapies for Mitochondrial Disease: Past, Present, and Future

• Authors: Megan Ball, Nicole J. Van Bergen, A. Compton, David R Thorburn, S. Rahman et al.
• Year: 2025
• Venue: Journal of Inherited Metabolic Disease
• URL: https://www.semanticscholar.org/paper/196ee50a950f29bc4134cfb8fe6bdfa9a3a1468b
• DOI: 10.1002/jimd.70065
• PMID: 40714961
• PMCID: 12301291
• Citations: 2
• Summary: The latest developments in the pursuit to identify effective treatments for mitochondrial disease are examined and the barriers impeding their success in translation to clinical practice are discussed.
• Evidence snippets:
• Snippet 1 (score: 0.414) > Mitochondrial disease is a diverse group of clinically and genetically complex disorders caused by pathogenic variants in nuclear or mitochondrial DNA‐encoded genes that disrupt mitochondrial energy production or other important mitochondrial pathways. Mitochondrial disease can present with a wide spectrum of clinical features and can often be difficult to recognize. These conditions can be devastating; however, for the majority, there is no targeted treatment. In the last 60 years, mitochondrial medicine has experienced significant evolution, moving from the pre‐molecular era to the Age of Genomics in which considerable gene discovery and advancement in our understanding of the pathophysiology of mitochondrial disease have been made. In the last decade, in response to the urgent need for effective treatments, a wide range of emerging therapies have been developed, driven by innovative approaches addressing both the genetic and cellular mechanisms underpinning the diseases. Emerging therapies include dietary intervention, small molecule therapies aimed to restore mitochondrial function, stem cell or liver transplantation, and gene or RNA‐based therapies. However, despite these advances, translation to clinical practice is complicated by the sheer genetic and clinical complexity of mitochondrial disease, difficulty in efficient and precise delivery of therapies to affected tissues, rarity of individual genetic conditions, lack of reliable biomarkers and clinically relevant outcome measures, and the dearth of natural history data. This review examines the latest developments in the pursuit to identify effective treatments for mitochondrial disease and discusses the barriers impeding their success in translation to clinical practice. While treatment for mitochondrial disease may be on the horizon, many challenges must be addressed before it can become a reality.

[9] Aberrant NLRP3 Inflammasome Activation Ignites the Fire of Inflammation in Neuromuscular Diseases

• Authors: Christine Péladeau, J. Sandhu
• Year: 2021
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/763a36db080236fca8cde89b2afcdf056f3584d0
• DOI: 10.3390/ijms22116068
• PMID: 34199845
• PMCID: 8200055
• Citations: 18
• Influential citations: 1
• Summary: Whether therapeutic targeting of the NLRP3 inflammasome components is a viable approach to alleviating the detrimental phenotype of neuromuscular diseases and improving clinical outcomes is examined.
• Evidence snippets:
• Snippet 1 (score: 0.410) > Despite a large number of mechanisms that have been identified in muscle degeneration and nerve cell loss, none have proven to be the primary cause of the disease. There is much need for a deeper understanding of the biology of the pathogeneses and the molecular mechanisms that are activated early in the diseases in order to identify "druggable" targets and disease-modifying treatments for these devastating diseases. > Human iPSC technologies are emerging as useful platforms for disease modeling to study pathogenic mechanisms and discover novel therapeutics for neuromuscular diseases [211,237]. Indeed, patient-derived iPSCs are being used to create a "patient-in-adish" disease model to derive relevant cell types for testing potential therapeutics, paving the way towards personalized medicine. This approach allows drug screening in a dish prior to administration to patients and "bench-to-bedside" translation of potential therapies. Additionally, iPSCs may also be used to stratify patients with various phenotypes and guide future clinical trials for bringing improved therapies to patients. Since multiple cell types are involved in disease pathogenesis, future research efforts need to be focused on deciphering "disease-specific signatures" at single-cell resolution, and not only in neuronal cells but also in non-neuronal cells. The application of modern technologies, including single-cell RNA sequencing and spatial transcriptomics, to neuromuscular diseases, will allow to ascertain cellular vulnerability and cell-specific mechanisms during various stages of disease progression. > The vital roles of the NLRP3 inflammasome in neuromuscular diseases such as DMD, LGMD and ALS, reveal that targeting this pathway is indeed a promising therapeutic strategy. Dysregulation of the NLRP3 inflammasome in muscle tissues by muscle damage, membrane instability, extracellular ATP and Ca 2+ ions or signals from infiltrating immune cells, clearly impacts the progression of neuromuscular and neurodegenerative disorders. Thus, modulation of these pathways involved with activation and assembly of NLRP3 inflammasome could be truly beneficial.

[10] New Insights into Mitochondria in Health and Diseases

• Authors: Ya Li, Huhu Zhang, Chunjuan Yu, Xiaolei Dong, Fanghao Yang et al.
• Year: 2024
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/23002a4ffabfd043f52c664f4d5acab85b8dcac0
• DOI: 10.3390/ijms25189975
• PMID: 39337461
• PMCID: 11432609
• Citations: 38
• Summary: This overview outlines the various mechanisms by which mitochondria are involved in numerous illnesses and cellular physiological activities and provides new discoveries regarding the involvement of mitochondria in both disorders and the maintenance of good health.
• Evidence snippets:
• Snippet 1 (score: 0.409) > Mitochondria are essential organelles within cells, playing critical roles not only in energy metabolism but also in various cellular activities, such as cell differentiation, signal transduction, and apoptosis. Mitochondrial dysfunction is implicated in a range of diseases, including but not limited to diabetes and its complications, neurodegenerative disorders, myocardial ischemia-reperfusion injury, and heart failure. Therefore, investigating the structure and function of mitochondria as well as the mechanisms underlying mitochondrial dysfunction in disease contexts holds significant scientific and clinical importance. > Basic scientific research: Diseases manifest systemically and exhibit complexity; thus, it is imperative to understand mitochondrial structure at the molecular level along with known pathways while characterizing novel pathways that influence mitochondrial behavior and functionality. For instance, mapping genetic interactions among genes encoding mitochondrial proteins can elucidate interrelations between different aspects of mitochondrial function. The first focused map of mitochondria has been constructed in yeast models, revealing dense and significant connections among localization pathways distributed across various mitochondrial compartments [126]. > Disease diagnosis: A comprehensive understanding of the mechanisms governing mitochondrial dysfunction can facilitate the development of innovative diagnostic tools. By monitoring specific indicators related to mitochondrial function, earlier diagnosis of diseases associated with mitochondrial impairment becomes feasible. Employing nextgeneration sequencing technologies for analyzing the mitochondrial proteome aids in identifying novel proteins and pathways linked to mitochondria while enabling streamlined diagnostics alongside genetic counseling opportunities for patients with mitochondrial diseases [127]. > Drug development: Advancements in our comprehension of how mitochondria contribute to disease processes may promote targeted therapeutic strategies. For example, metformin-a widely used antidiabetic agent-has recently been repurposed as an anticancer drug; its combination with standard epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) significantly improves progression-free survival rates and overall survival outcomes for patients with advanced lung adenocarcinoma [125]. > Personalized medicine: Given that manifestations of mitochondrial dysfunction may vary among individuals, research into mitochondria provides a theoretical foundation for personalized medicine by allowing tailored treatment plans based on individual states of mitochondrial functionality [127].

[11] Novel Approaches to Studying SLC13A5 Disease

• Authors: Adriana S. Beltran
• Year: 2024
• Venue: Metabolites
• URL: https://www.semanticscholar.org/paper/8469c534cd81d96f84b61e2d963dead12088feb7
• DOI: 10.3390/metabo14020084
• PMID: 38392976
• PMCID: 10890222
• Citations: 2
• Summary: Current technologies for generating patient-specific induced pluripotent stem cells (iPSCs) and their inherent advantages and limitations are discussed, followed by a summary of the methods for differentiating iPSCs into neurons, hepatocytes, and organoids.
• Evidence snippets:
• Snippet 1 (score: 0.405) > The precise pathophysiology underlying how SLC13A5 loss-of-function results in epilepsy refractory to treatment is a subject of open and ongoing research. Several hypotheses suggest SLC13A5 alters metabolic pathways, leading to neuronal dysfunction. Conversely, therapeutic inhibition of NaCT in the liver is a target to improve metabolic diseases, including non-alcoholic fatty liver disease, obesity, and insulin resistance. Thus, functionally accurate modeling and characterization of the mechanisms involved in citrate transport disruption are critical for understanding its role in human disease. > IPSC-derived cellular systems are a powerful tool for modeling rare human genetic diseases, such as SLC13A5 (Figure 5). IPSCs derived from patients containing the genetic information of the disease can overcome the limitations of animal models, providing access to relevant human cell types that recapitulate the disease phenotype. For instance, patient-derived iPSCs differentiated into neurons or hepatocytes can be used to investigate molecular and cellular mechanisms, including citrate transport and accumulation, energy metabolism, oxidative stress, and other cellular processes. They can also be used to define the spectrum of the disease and how different mutations might lead to various disease severities, screen for potential therapeutic compounds that can restore the transporter function or ameliorate the symptoms, and enable personalized medicine approaches that can tailor treatments to individual patients based on their genetic background and disease severity. > transport disruption are critical for understanding its role in human disease. > IPSC-derived cellular systems are a powerful tool for modeling rare human genetic diseases, such as SLC13A5 (Figure 5). IPSCs derived from patients containing the genetic information of the disease can overcome the limitations of animal models, providing access to relevant human cell types that recapitulate the disease phenotype. For instance, patient-derived iPSCs differentiated into neurons or hepatocytes can be used to investigate molecular and cellular mechanisms, including citrate transport and accumulation, energy metabolism, oxidative stress, and other cellular processes.

[12] Transcriptional profiling of Hutchinson-Gilford progeria patients identifies primary target pathways of progerin

• Authors: Sandra Vidak, Sohyoung Kim, Tom Misteli
• Year: 2026
• Venue: Nucleus
• URL: https://www.semanticscholar.org/paper/4bd99b0875508364d8672b6da5a50d024d485a53
• DOI: 10.1080/19491034.2025.2611484
• PMID: 41489464
• PMCID: 12773485
• Summary: To probe the clinical relevance of previously implicated cellular pathways and to address the extent of gene expression heterogeneity between patients, transcriptomic analysis of a comprehensive set of HGPS patients finds misexpression of several cellular pathways, including multiple signaling pathways, the UPR and mesodermal cell fate specification.
• Evidence snippets:
• Snippet 1 (score: 0.404) > Oxidative stress represents another key pathogenic mechanism in HGPS, as impaired NRF2 activity or increased reactive oxygen species (ROS) levels are sufficient to recapitulate HGPSassociated phenotypes [17,32,60]. Collectively, these findings underscore the multifactorial nature of HGPS pathogenesis, implicating interconnected signaling cascades involved in inflammation, oxidative stress, proteostasis, and vascular remodeling. Reassuringly, our findings indicate that many of the major pathways that have been described to contribute to HGPS phenotypes in mouse and cellular disease models are also misregulated in progeria patients, and targeting these pathways may provide therapeutic avenues to mitigate disease severity and improve outcomes in HGPS. > Although individuals with HGPS typically exhibit a characteristic set of clinical features, such as craniofacial abnormalities, growth retardation, and cardiovascular complications, there is notable variability in the age of onset, severity, and progression of symptoms between patients [7,9]. At the cellular level, HGPS is associated with several hallmark abnormalities, including nuclear envelope defects, decreased expression of several nuclear proteins and epigenetic marks, mitochondrial dysfunction, and increased cellular senescence [1,11,30,31,61]. These cellular phenotypes also exhibit considerable variation between patients, possibly contributing to differences in clinical outcomes. Our results indicate that even though some degree of transcriptional heterogeneity between the individual patients exists, the majority of patients exhibit misregulation of a set of shared pathways, suggesting that these pathways are universal driver mechanisms in HGPS. Further work is needed to understand the molecular and genetic factors that underlie inter-individual variability in disease expression and progression. > A limitation of pathway analysis of HGPS patient samples is to distinguish the pathways which are directly targeted by the disease-causing progerin protein and the emergence of adaptive secondary response pathways during progression of the disease in patients during their lifetime. The same caveat applies to the use of cell-based models used in the study of HGPS disease mechanisms.

[13] Cardiomyocytes Derived from Induced Pluripotent Stem Cells as a Disease Model for Propionic Acidemia

• Authors: Esmeralda Alonso-Barroso, B. Pérez, L. Desviat, E. Richard
• Year: 2021
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/da649a0f04477c53b448c5ac5f873f8762235290
• DOI: 10.3390/ijms22031161
• PMID: 33503868
• PMCID: 7865492
• Citations: 16
• Influential citations: 1
• Summary: The novel results show that PA iPSC-cardiomyocytes represent a promising model for investigating the pathological mechanisms underlying PA cardiomyopathies, also serving as an ex vivo platform for therapeutic evaluation.
• Evidence snippets:
• Snippet 1 (score: 0.399) > The study of the mechanisms involved in disease physiopathology has been mainly performed using the hypomorphic PA mouse model that mimics the biochemical and clinical phenotype [5]. Using this model, bioenergetic failure, oxidative damage and deregulation of miRNAs induced by accumulating propionyl-CoA have been described as potential mechanisms contributing to PA physiopathology [6][7][8]. The limitations of animal models for the study of cardiac energy metabolism [9] and of the commonly available cellular human models such as fibroblasts, underline the importance of generating new relevant cell models to provide deeper insight into the underlying mechanisms of disease. The use of in vitro models with human cellular context is highly recommended and, in this sense, induced pluripotent stem cells (iPSCs) have certain advantages since they provide the genetic background of the patient and represent an unlimited source of biological material for the study of pathophysiology and treatment effectiveness [10]. We have previously generated an iPSC line from a PA patient with defects in the PCCA gene that showed full pluripotency, differentiation capacity and genetic stability [11]. > In the present study, we aimed to establish a platform that served as a disease model to study the cellular and molecular alterations operating in cardiac tissue affected by PA disease. We described the characterization of cardiomyocytes derived from the PCCA iPSC line (PCCA iPSC-CMs) and the analysis of specific pathways potentially involved in cardiac PA physiopathology.

[14] Mitochondrial transplantation as a promising therapy for mitochondrial diseases

• Authors: Tian-Guang Zhang, Chaoyu Miao
• Year: 2022
• Venue: Acta Pharmaceutica Sinica. B
• URL: https://www.semanticscholar.org/paper/72802097939b0bffc319c93d05128d7e3160e0eb
• DOI: 10.1016/j.apsb.2022.10.008
• PMID: 36970208
• PMCID: 10031255
• Citations: 84
• Influential citations: 1
• Summary: Different techniques used in mitochondrial isolation and delivery, mechanisms of mitochondrial internalization and consequences of mitochondrial transplantation, along with challenges for clinical application are presented.
• Evidence snippets:
• Snippet 1 (score: 0.396) > Mitochondria, the vital organelles of eukaryotic cells, are integrators of various cellular metabolic pathways, including oxidative phosphorylation, fatty acid oxidation, urea cycle, Krebs cycle, ketogenesis and gluconeogenesis 1 . Mitochondria are also important in many other essential cellular processes such as calcium homeostasis, lipid metabolism, amino acid metabolism, biosynthesis of heme, and thermogenesis 2 . However, they also have important roles in many pathways which can cause both apoptosis and necrosis 3 . Therefore, the importance of the mitochondrion in the maintenance of cellular homeostasis is well established, meanwhile a large amount of evidence shows that mitochondrial dysfunction is deleterious 4 . > Due to the essential function of mitochondria in the human body, mitochondrial dysfunction causes a great variety of mitochondrial diseases, which can affect almost all the organs in the body and present at any age 4,5 . Mitochondrial diseases are a group of metabolic disorders characterized by energy metabolism dysfunction. The pathophysiology is further complicated by the involvement of genetic mutations in nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) which encode mitochondrial proteins. This means that mitochondrial diseases may result from inheritance for nDNA mutations and maternal inheritance for mtDNA mutations. The estimated minimum prevalence of mitochondrial diseases is 1 in 5000, whereas it could be higher 6 . > As advances in molecular and biochemical methodologies led to a better understanding of the mechanisms of mitochondrial disorders for various diseases, mitochondria have become a major target for research institutions and pharma companies. Pharmacological approaches include dietary supplements such as agents increasing respiratory chain function (coenzyme Q10 and riboflavin), agents inducing mitochondrial biogenesis (AICAR and bezafibrate), antioxidants (vitamin C and vitamin E), mitochondrial substrates (L-carnitine) and so on 7,8 . However, these agents fail to significantly alleviate disease symptoms or effectively slow disease progressions, there has therefore been no satisfactory therapeutic strategy available for mitochondrial diseases so far 9 . In addition, all new drugs under clinical trials for treatment of mitochondrial diseases are unable to cure these diseases permanently 9 .

[15] Molecular insights into the premature aging disease progeria

• Authors: Sandra Vidak, R. Foisner
• Year: 2016
• Venue: Histochemistry and Cell Biology
• URL: https://www.semanticscholar.org/paper/60fb3b46bb7e42d5d08cc3b7cbc783b118300c31
• DOI: 10.1007/s00418-016-1411-1
• PMID: 26847180
• PMCID: 4796323
• Citations: 105
• Influential citations: 3
• Summary: Changes in mechanosignaling, altered chromatin organization and impaired genome stability, and changes in signaling pathways, leading to impaired regulation of adult stem cells, defective extracellular matrix production and premature cell senescence are discussed.
• Evidence snippets:
• Snippet 1 (score: 0.395) > The number of molecular biological studies aiming at the identification of lamin-mediated molecular disease mechanisms involved in HGPS increased tremendously following the surprising discovery that LMNA is causally linked to the premature aging disease HGPS in 2003. Despite numerous cellular pathways that were identified to be affected by the expression of the mutant lamin A protein (Fig. 2), the mechanistic details behind these effects are still unclear in most cases. Knowledge based on what was already known on lamin biology before the protein was linked to HGPS and findings on novel roles of lamins in diverse pathways in recent years allowed the launch of translational studies and the efficient search for drug targets and therapeutic approaches within a short time period. The results of the first clinical trials taught us that some improvements of the disease phenotypes can be achieved by FTI treatment, but they also made clear that we need a much better understanding of the underlying disease mechanisms to be able to tackle specific aspects of the disease in a more focused approach. It will also be important to elucidate which of the numerous pathways found to be impaired in HGPS are most relevant for and causally involved in the pathologies, and which ones are just bystanders.

[16] 18O-assisted dynamic metabolomics for individualized diagnostics and treatment of human diseases

• Authors: E. Nemutlu, Song Zhang, N. Juranic, A. Terzic, S. Macura et al.
• Year: 2012
• Venue: Croatian Medical Journal
• URL: https://www.semanticscholar.org/paper/880f053c7f060db4b990e447d0a22c4b69372ddb
• DOI: 10.3325/cmj.2012.53.529
• PMID: 23275318
• PMCID: 3541579
• Citations: 28
• Summary: The potential use of dynamic phosphometabolomic platform for disease diagnostics currently under development at Mayo Clinic is described and discussed briefly.
• Evidence snippets:
• Snippet 1 (score: 0.395) > Living cells represent an integrated and interacting network of genes, transcripts, proteins, small signaling molecules, and metabolites that define cellular phenotype and function. Traditionally the focus of biomedical research was on individual genes, single protein targets, single metabolites, and metabolic or signaling pathways. This "molecular reductionist" paradigm was based on the assumption that identifying genetic variations and molecular components would lead to discovery of cures for human diseases. However, most of diseases are complex and multi-factorial and the disease phenotype is determined by the alterations of multiple genes, pathways, proteins and metabolites (at cellular, tissue, and organismal levels). Therefore, an integrated "omics" approach is more viable direction for uncovering alterations in metabolic networks, disease mechanisms, and mechanisms of drug effects. > Recent advent of large-scale metabolomics and fluxomic (metabolite dynamics and metabolic flux analysis) completed the "omics revolution" (Figure 1), where genomics, transcriptomics, proteomics, metabolomics, and fluxomics all together complement phenotype determination of living organism. Such integrated "omics" cascades provide a framework for advances in system and network biology, integrative physiology, and system medicine as well as system pharmacology and regenerative medicine. Noteworthy is the "reverse omic" approach or "metabolomicsinformed pharmacogenomics, " where discovery of specific metabolite changes have led to discovery of genetic alterations (2). Therefore, bringing new "omics" technologies to clinical practice will improve disease diagnostics and treatment by targeting drugs and procedures for each unique transcriptomic and metabolomic profiles.

[17] Computational drug discovery approaches identify mebendazole as a candidate treatment for autosomal dominant polycystic kidney disease

• Authors: P. Brownjohn, A. Zoufir, Daniel J O’Donovan, Saatviga Sudhahar, A. Syme et al.
• Year: 2024
• Venue: Frontiers in Pharmacology
• URL: https://www.semanticscholar.org/paper/a595e78572ca02b8cb2897bfc4a989a2b021b279
• DOI: 10.3389/fphar.2024.1397864
• PMID: 38846086
• PMCID: 11154008
• Citations: 3
• Summary: It is determined that the anthelmintic mebendazole was a potent anti-cystic agent in human cellular and in vivo models of ADPKD, and is likely acting through the inhibition of microtubule polymerisation and protein kinase activity.
• Evidence snippets:
• Snippet 1 (score: 0.393) > Targets and molecules were ultimately filtered for validation based on biological and chemical insights, and the potential for clinical translation.Earlier this year, Wilk et al., 2023 applied a similar transcriptomic approach to us, in that case making use of publicly available transcriptomic datasets to create Pkd2-specific ADPKD disease signatures, from which signature reversion was sought from the Library of Integrated Network-based Cellular Signatures (LINCs) drug signature database in order to identify drug repurposing candidates.While one group has previously made use of a knowledge graph-based approach to prioritise preclinically active compounds with the highest chance of clinical translation (Malas et al., 2019), to our knowledge, the current study provides the first combined application of transcriptomic and machine-learning approaches to identify and prioritise putative treatments for ADPKD, and further deconvolute potential mechanisms of action for experimental validation. > In summary we report, using computational, in vitro and in vivo approaches, that the anthelmintic drug mebendazole ameliorates disease-relevant phenotypes in cellular and animal models of ADPKD.We further show that this effect is likely primarily due to the inhibitory effect of mebendazole on the polymerisation of microtubules, which underlie cellular processes important in ADPKD, including cell proliferation, transport, and cilia signalling, and extends previous work linking the importance of the microtubule network to ADPKD pathophysiology.We also describe the inhibitory profile of mebendazole on known and novel protein kinase targets, some of which have previously been implicated in ADPKD, suggesting mebendazole may be acting via polypharmacology to impact disease mechanisms.We acknowledge that further experimental efforts will be required to confirm the actions of mebendazole on these putative targets in relevant disease model systems.It would be particularly informative to investigate these mechanisms in dedicated in vivo studies, where the effects of mebendazole on a wider range of ADPKD-relevant cell types and phenotypes could be evaluated.

[18] Valosin-Containing Protein (VCP): A Review of Its Diverse Molecular Functions and Clinical Phenotypes

• Authors: Carly S. Pontifex, Mashiat Zaman, R. Fanganiello, T. Shutt, G. Pfeffer
• Year: 2024
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/a0717d977acc61d9c08343d1ac6aed94c33f2138
• DOI: 10.3390/ijms25115633
• PMID: 38891822
• PMCID: 11172259
• Citations: 14
• Summary: In this review we examine the functionally diverse ATPase associated with various cellular activities (AAA-ATPase), valosin-containing protein (VCP/p97), its molecular functions, the mutational landscape of VCP and the phenotypic manifestation of VCP disease. VCP is crucial to a multitude of cellular functions including protein quality control, endoplasmic reticulum-associated degradation (ERAD), autophagy, mitophagy, lysophagy, stress granule formation and clearance, DNA replication and mito...
• Evidence snippets:
• Snippet 1 (score: 0.393) > Although the major roles of VCP in protein quality control are presumed to be the major mechanisms implicated in MSP, the incredible functional diversity and pleiotropic effects of VCP also imply that other mechanisms may be relevant and require further study.VCP cooperates with the 26S proteasome, the main pathway for protein degradation, to manage the protein quality control system.In the nucleus, VCP regulates cell cycle control and the DNA damage response by coordinating proteins at DNA damage sites.In the cytosol, VCP regulates responses to cellular stress by forming and clearing stress granules, facilitating ERAD, autophagy, mitophagy and lysophagy, and VCP may also be involved in apoptosis.The complexity of VCP's diverse molecular functions is also mirrored by the variability in clinical dysfunction caused by pathogenic variants in VCP.The relationship between specific molecular functions of VCP and the spectrum of clinical presentations remains poorly understood, and, in general, genotype-phenotype correlation is still difficult to demonstrate.Certainly, VCP plays many yet-to-be-identified roles in different cellular systems.Given that the role of VCP extends to so many cellular systems, it makes it difficult to ascertain which dysfunction leads to which clinical phenotype.The majority of MSP cases are related to variants at positions 155 and 159, but the phenotypic variability is extensive, suggesting that other genetic or epigenetic factors and/or environmental factors may interact.To better narrow down a causative mechanism in a given tissue, we advise that, when possible, experiments should include one or two other MSP genes such as SQSTM1 or HNRNPA2B1, as this may help identify common mechanisms of dysfunction in MSP.Studies of large cohorts of patients who have common variants in VCP may allow for the identification of genetic modifiers or other factors that contribute to phenotypic variability.Even though pathogenic variants in VCP typically lead to multisystem disease, in general, the affected systems predictably include certain tissue types (primarily skeletal muscle, the cerebrum, motor neurons and osteoclasts).Even though VCP is ubiquitously expressed and participates in numerous crucial cellular functions, pan-systemic disease is not observed.

[19] Targeting Hepatic Stellate Cells for the Prevention and Treatment of Liver Cirrhosis and Hepatocellular Carcinoma: Strategies and Clinical Translation

• Authors: Hao Xiong, Jinsheng Guo
• Year: 2025
• Venue: Pharmaceuticals
• URL: https://www.semanticscholar.org/paper/76e92127053136900f7e3f10e2c9278251ced5d2
• DOI: 10.3390/ph18040507
• PMID: 40283943
• PMCID: 12030350
• Citations: 8
• Summary: HSC-targeted approaches using specific surface markers and receptors may enable the selective delivery of drugs, oligonucleotides, and therapeutic peptides that exert optimized anti-fibrotic and anti-HCC effects.
• Evidence snippets:
• Snippet 1 (score: 0.388) > Significant progress has been made in elucidating the cellular and molecular mechanisms of liver fibrosis; however, only a few findings have been successfully translated into clinical applications. Firstly, the high cost of drug development and target validation necessitates prolonged timelines and substantial financial investment. Secondly, as regulatory requirements become more stringent, there is an increasing demand for drugs with well-defined clinical efficacy and safety profiles. Moreover, the efficacy observed in animal models often fails to fully translate to clinical settings due to differences in pharmacokinetics, extracellular matrix (ECM) cross-linking, and disease pathophysiology. Despite advancements in anti-fibrotic drug development, accurately identifying ideal noninvasive biomarkers for fibrotic activity and establishing consensus on optimal clinical endpoints remain significant challenges [113,114]. > Currently, addressing the underlying cause remains the only proven strategy to halt or reverse liver fibrosis progression, while the development of effective anti-fibrotic therapies continues to pose a major challenge in liver disease management. Over the past few decades, substantial progress has been made in elucidating the cellular and molecular mechanisms underlying liver fibrosis. Liver fibrosis is a complex pathological change involving multiple cells, factors, and pathways, and the study of the cellular and molecular mechanisms of its occurrence and development provides an important theoretical basis and therapeutic target for clinical drug development. It is anticipated that improved animal models and well-designed clinical trials will facilitate the successful translation of anti-fibrotic research into effective clinical treatments in the near future.

[20] New clinical insight in amyotrophic lateral sclerosis and innovative clinical development from the non-profit repurposing trial of the old drug guanabenz

• Authors: A. Ambrosini, E. Dalla Bella, M. Ravasi, M. Melazzini, Giuseppe Lauria
• Year: 2024
• Venue: Frontiers in Medicine
• URL: https://www.semanticscholar.org/paper/983d5185beeab23e247e3c66b1992ec068a74cb4
• DOI: 10.3389/fmed.2024.1407912
• PMID: 38915767
• PMCID: 11194437
• Summary: The case of an academic multicentre study that considered the repurposing of the old drug guanabenz as a therapeutic strategy in amyotrophic lateral sclerosis is presented, finding that even a repurposing study with an old product has the potential to generate innovation and interest from industry partners.
• Evidence snippets:
• Snippet 1 (score: 0.388) > Amyotrophic lateral sclerosis (ALS) is a severe neurological disease characterized by the degeneration of motor neurons.Although the ultimate cause of death derives from respiratory muscles failure, clinical manifestations are very heterogeneous, with anatomical distinction between bulbar versus spinal onset and speed of disease progression (1). > Biological studies suggested the pathophysiological involvement of various cellular pathways (2,3).However, whether an impaired/dysfunctional mechanism is causative or a downstream effect that ultimately contributes to neuronal cell death remains challenging.Familial forms have been identified, implying a genetic origin of the disease in a small percentage (10%) of ALS cases, while the etiology of the disease is unknown in most patients and the interplay between dysfunctional pathways and exogenous risk factors may play a role.Close collaboration between basic and clinical researchers is encouraged to clarify the relationship between genetic and sporadic forms, correlate clinical heterogeneity with underlying disease mechanisms, develop informative preclinical models, and identify therapeutic targets. 1iven the large number of cellular pathways possibly involved in ALS, it is not surprising that several studies, both at preclinical and clinical level, have focused on known molecular targets to investigate the efficacy of new or existing drugs and to accelerate the development of therapies for ALS.However, despite much effort of academia and industry, most randomized clinical trials (RCTs) conducted over the last three decades have failed to demonstrate efficacy (4).Currently, only one drug -riluzole -has been approved by regulatory authorities worldwide, and few others are in advanced stages of development (3).The ALS scientific community has put a lot of effort into understanding the reasons for failure and improving the design of RCTs to ensure that any sign of efficacy of the putative drug is captured (2,5,6). > A white paper was recently published by an international group of experts including academics, industry, and patient representatives, to learn from experience and facilitate the translation of drug discovery into clinical development (7).The document proposed a framework of guiding principles, ranging from understanding the molecular basis of the disease, through drug discovery, to experimental medicine.

Notes

• This provider combines search_papers_by_relevance with snippet_search.
• No synthesis or second-stage model call is performed.