Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Buschke-Ollendorff Syndrome. Core disease mechanisms, molecular and cellul...

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

• Papers retrieved: 20
• Snippets retrieved: 20

Relevant Papers

[1] 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
• Citations: 1
• 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: 0.393) > 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.

[2] 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: 39
• 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: 0.390) > 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.

[3] Molecular Genetics of Bartter Syndrome: Bridging Genotype–Phenotype Correlations and Precision Therapeutics

• Authors: Lina Zhu, Yang Li, Yiyao Bao
• Year: 2026
• Venue: Current Issues in Molecular Biology
• URL: https://www.semanticscholar.org/paper/a5e1ddccfa7d333834c4d32be123c71bfd573f83
• DOI: 10.3390/cimb48040422
• PMID: 42042082
• PMCID: 13114623
• Summary: A comprehensive framework to provide a comprehensive framework to facilitate precise diagnosis and individualized treatment strategies, ultimately advancing precision medicine in the management of Bartter syndrome is provided.
• Evidence snippets:
• Snippet 1 (score: 0.387) > Molecular genetic research on Bartter syndrome has made remarkable strides, elucidating the principal BS genes SLC12A1, KCNJ1, CLCNKB, BSND, and MAGED2 and their corresponding protein defects, thereby refining the molecular framework of disease classification while separating CaSR-associated Bartter-like disease from the core canonical BS spectrum. This progress has significantly deepened our understanding of the underlying pathophysiology and provided an essential framework for correlating genotypes with clinical phenotypes. However, the intricate relationship between genetic mutations and clinical manifestations remains complex and multifaceted, reflecting the profound heterogeneity of the syndrome. Addressing these diagnostic challenges and refining disease classification beyond traditional clinical criteria requires an integrative approach that seamlessly balances high-throughput sequencing technologies with rigorous functional studies. > The mechanisms by which these genetic mutations lead to protein dysfunction are diverse, encompassing critical defects in protein expression, impaired membrane localization, and direct functional impairments. Notably, aberrant protein folding, endoplasmic reticulum-associated degradation (ERAD), and splicing abnormalities have emerged as critical pathogenic pathways. These mechanistic insights not only enhance our fundamental understanding of the disease but also highlight highly promising therapeutic targets. While current treatments remain predominantly symptomatic, focusing primarily on managing electrolyte imbalances and associated complications, they inherently fail to address the underlying molecular defects driving the disease. > The precise identification of specific molecular defects opens innovative avenues for the development of targeted interventions aimed at correcting or compensating for specific protein abnormalities. For instance, molecular chaperones that assist in protein folding, agents that modulate aberrant splicing, and future gene-based strategies represent important experimental directions for mechanism-based therapy. Consequently, the future of Bartter syndrome management may increasingly move toward precision medicine tailored to the molecular pathology of individual patients. However, the transition from concept to clinical implementation will require substantial additional functional, translational, and trial-level evidence. Such mechanism-based strategies promise not only to alleviate clinical symptoms but to fundamentally modify disease progression, thereby drastically improving long-term prognosis and quality of life for patients.

[4] Tubular Aggregate Myopathies: Genetic Heterogeneity and Diverse Clinical Features Converging on Calcium Dysregulation

• Authors: Matteo Serano, F. Fiore, Vincenzo Sorrentino, Daniela Rossi
• Year: 2026
• Venue: Cells
• URL: https://www.semanticscholar.org/paper/c53accfaacb913a69aeeb832222593ca90afabeb
• DOI: 10.3390/cells15070635
• PMID: 41972723
• PMCID: 13072200
• Citations: 2
• Summary: Highlights TAM is an inherited muscle disorder caused by STIM1 and ORAI1 mutations that disrupt calcium entry, leading to tubular aggregates and muscle dysfunction. Its overlap with Stormorken syndrome suggests a disease continuum. Although the genetics are known, mechanisms behind aggregate formation and multisystem features remain unclear, highlighting the need for deeper insight and targeted therapies. What are the main findings? Genetics and Pathogenesis: Tubular aggregate myopathy (TAM)...
• Evidence snippets:
• Snippet 1 (score: 0.380) > , hypocalcemia, hyposplenism, and ichthyosis, thereby resulting in a clinical picture that overlaps with symptoms of Stormorken (STRMK) syndrome. Considerable heterogeneity exists in age of onset, severity, and extra-muscular involvement, suggesting that TAM and STRMK represent a continuum rather than distinct entities. Histopathological hallmarks include TAs staining positive for SR proteins and displaying a honeycomb-like ultrastructure, consistent with aberrant SR remodeling. Mutations in genes encoding key regulators of store-operated calcium entry (SOCE), including STIM1 and ORAI1 have been identified as major contributors to TAM and its broader clinical spectrum, which encompasses STRMK syndrome, whereas mutations in CASQ1 and RYR1, have been described in only a minority of patients. Despite advances in delineating the genetic and molecular basis of TAM, key questions remain regarding the mechanisms that drive TAs formation and translate Ca2+ dysregulation into muscle dysfunction and multisystem disease. Understanding the molecular mechanisms underlying TAM and STRMK syndrome is crucial for developing targeted therapies. Moreover, further research is needed to elucidate additional pathways involved in disease progression and to refine genotype–phenotype correlations. This review summarizes current knowledge on the genetics, pathophysiology, clinical features, and diagnostic hallmarks of TAM, with particular emphasis on the role of Ca2+ homeostasis.

[5] Ellis–van Creveld syndrome with facial dysmorphic features in an Egyptian child

• Authors: R. Shawky, D. I. Sadik, N. Seifeldin
• Year: 2010
• Venue: Egyptian Journal of Medical Human Genetics
• URL: https://www.semanticscholar.org/paper/fb61ac8ae2dfea28141342fc3fb585d728f37b0d
• DOI: 10.1016/J.EJMHG.2010.05.001
• Citations: 6
• Summary: A patient with the typical features of the syndrome but with facial dysmorphic features (upward slant of eyes, megalocornea and high forehead), for the first time in the literature are reported.
• Evidence snippets:
• Snippet 1 (score: 0.378) > [11][12][13]. Disruption of either of these non-homologous genes results in an indistinguishable heart-hand phenotype, but the role of EVC and LBN in development and disease pathogenesis remains largely unknown. > However, EvC syndrome is considered part of an emerging class of diseases called ciliopathies. The underlying cause may be a dysfunctional molecular mechanism in the primary cilia structures of the cell, organelles which are present in many cellular types throughout the human body. The cilia defects adversely affect ''numerous critical developmental signaling pathways'' essential to cellular development and thus offer a plausible hypothesis for the often multi-symptom nature of a large set of syndromes and diseases. Known ciliopathies include primary ciliary dyskinesia, Bardet-Biedl syndrome, polycystic kidney and liver disease, nephronophthisis, Alstrom syndrome, Meckel-Gruber syndrome and some forms of retinal degeneration [14]. > We present here a clinical analysis of a male child manifesting many of the specific features of EvC, but with facial dysmorphic features for the first time in the literature.

[6] Molecular genetic basis of epidermolysis bullosa

• Authors: Y. Kotalevskaya, V. Stepanov
• Year: 2023
• Venue: Vavilov Journal of Genetics and Breeding
• URL: https://www.semanticscholar.org/paper/720cbefbd0435504a6ed670ccf4f491dfbd3f143
• DOI: 10.18699/VJGB-23-04
• PMID: 36923479
• PMCID: 10009482
• Citations: 9
• Influential citations: 3
• Summary: The study of clinical, genetic and ultrastructural changes in EB has significantly expanded the understanding of the natural history of the disease and supplemented the data on genotype-phenotype correlations, promotes the search and study of epigenetic and non-genetic disease modifier factors, and also allows developing approaches to radical treatment of the Disease.
• Evidence snippets:
• Snippet 1 (score: 0.374) > Epidermolysis bullosa (EB) is an inherited disorder of skin fragility, caused by mutations in a large number of genes associated with skin integrity and dermal-epidermal adhesion. Skin fragility is manifested by a decrease in resistance to external mechanical influences, the clinical signs of which are the formation of blisters, erosions and wounds on the skin and mucous membranes. EB is a multisystemic disease and characterized by a wide phenotypic spectrum with extracutaneous complications in severe types, besides the skin and mucous membranes, with high mortality. More than 30 clinical subtypes have been identified, which are grouped into four main types: simplex EB, junctional EB, dystrophic EB and Kindler syndrome. To date, pathogenic variants in 16 different genes are associated with EB and encode proteins that are part of the skin anchoring structures or are signaling proteins. Genetic mutations cause dysfunction of cellular structures, differentiation, proliferation and apoptosis of cells, leading to mechanical instability of the skin. The formation of reduced proteins or decrease in their level leads mainly to functional disorders, forming mild or intermediate severe phenotypes. Absent protein expression is a result of null genetic variants and leads to structural abnormalities, causing a severe clinical phenotype. For most of the genes involved in the pathogenesis of EB, certain relationships have been established between the type and position of genetic variant and the severity of the clinical manifestations of the disease. Establishing an accurate diagnosis depends on the correlation of clinical, genealogical and immunohistological data in combination with molecular genetic testing. In general, the study of clinical, genetic and ultrastructural changes in EB has significantly expanded the understanding of the natural history of the disease and supplemented the data on genotype-phenotype correlations, promotes the search and study of epigenetic and non-genetic disease modifier factors, and also allows developing approaches to radical treatment of the disease. New advances of sequencing technologies have made it possible to describe new phenotypes and study their genetic and molecular mechanisms. This article describes the pathogenetic aspects and genes that cause main and rare syndromic subtypes of EB.

[7] Improving Drug Trial Success Rates in Systemic Lupus Erythematosus: Endotyping-based Patient Stratification Could be the way Forward

• Authors: Anand N. Malaviya, Neeraj Jain
• Year: 2024
• Venue: Indian Journal of Rheumatology
• URL: https://www.semanticscholar.org/paper/d023e00e1b518c7089cb3d310e78b3b6cb5bd895
• DOI: 10.1177/09733698241229780
• Summary: Using a 2-pronged approach of defining theratypes of pre-endotyped patients could fast-track drug discovery of drugs for SLE treatment and pave the way for more effective treatments for SLE.
• Evidence snippets:
• Snippet 1 (score: 0.373) > Over the years, it has been observed that the different phenotypes do not offer insight into the underlying pathobiological mechanism; these may or may not have the same underlying abnormalities in disease-causing biological pathways.For an appropriate understanding of that, a much deeper analysis of the biological mechanisms involved in causing the pathobiology, is required.The evolving understanding of the physiology of the biological systems has discovered a variety of biochemical, metabolic, inflammatory, immunological cells and subcellular milieu that can be exploited to understand their role in health and disease.Studying the heterogeneity in type-1 diabetes, it was demonstrated that traits are often linked (e.g., age and HLA-specific autoimmunity) in such a thrombocytopaenia and/or leukopenia/ lymphopenia, Evan's syndrome, often associated with antiphospholipid syndrome).5. 'Thromboembolic lupus' associated with anti-phospholipid syndrome (APS).6. 'Obstetric complications of lupus' (usually with recurrent pregnancy loss associated with secondary anti-phospholipid syndrome).7. Others-uncommon presentations (recalcitrant dermatological manifestations, others).way that suggests associations, which could be built into distinct pathobiological entities. 33Using molecular and omics techniques, these abnormalities can be characterised with high precision.Using these techniques, a particular clinically diagnosable disease, especially those with protean manifestations, can be further categorised in clearly defined subsets.This approach of precisely subtyping such diseases is called 'Endotyping' 33,34 that further stratifies any clinical disease into different 'endotypes'.As endotypes characterise the disease at subcellular/biochemical/molecular level, it becomes possible to correct that abnormality with targeted treatment.The current popular term for such a treatment approach is called 'precision medicine'.

[8] 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
• Citations: 2
• 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: 0.372) > 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.

[9] Diagnostic and referral pathways in patients with rare lipodystrophy and insulin-resistance syndromes: key milestones assessed from a national reference center

• Authors: B. Donadille, S. Janmaat, H. Mosbah, Inès Belalem, Sophie Lamothe et al.
• Year: 2024
• Venue: Orphanet Journal of Rare Diseases
• URL: https://www.semanticscholar.org/paper/823da349ccd35ba745c9241586d2fa0cb443118a
• DOI: 10.1186/s13023-024-03173-2
• PMID: 38678257
• PMCID: 11056061
• Citations: 5
• Summary: The national rare disease database provides an important tool for assessment of care pathways in patients with lipodystrophy and rare insulin-resistance syndromes in France and improving knowledge to reduce diagnostic delay is an important objective of the PRISIS reference center.
• Evidence snippets:
• Snippet 1 (score: 0.371) > Lipodystrophy syndromes are heterogeneous chronic rare diseases, characterized by anatomical and functional defects of adipose tissue resulting from genetic or acquired causes. Lipodystrophy syndromes present as systemic diseases with progressive metabolic alterations associated with insulin-resistance, such as diabetes, hypertriglyceridemia, non-alcoholic fatty liver disease, and ovarian dysfunction in women, with multi-tissue involvement depending on the underlying cause. Besides different clinical presentations with generalized or partial lipoatrophy, with or without fat overgrowth in body areas without lipoatrophy, these syndromes are highly heterogeneous diseases. The onset of lipodystrophy may be precocious, from birth or early infancy, or delayed in late childhood or adulthood. Some subtypes of lipodystrophy are associated with specific clinical signs and complications, such as cardiovascular and/or neurological involvement [1][2][3]. Acquired forms of lipodystrophies generally result from autoimmune mechanisms and/or iatrogenic therapies. The identification of causative pathogenic variants in more than 20 genes leading to monogenic forms of lipodystrophies has highlighted several determinants in adipose tissue pathophysiology. Molecular and cellular bases of monogenic lipodystrophy syndromes involve, among others, altered adipocyte differentiation, structure and/or regulation of the adipocyte lipid droplet and/ or premature cellular senescence. This field of research, still highly productive, indicates adipose tissue as a major actor to ensure proper whole-body insulin sensitivity [4]. Other rare conditions characterized by severe insulinresistance without primary adipose tissue dysfunction result from direct defects in insulin signaling pathways, due to specific genetic or dysimmune disorders [5]. The four main forms of Congenital Generalized Lipodystrophy, referred to as CGL1 to CGL4, are due to pathogenic variants in AGPAT2, BSCL2, CAV1, and CAVIN1/PTRF genes, respectively.

[10] Modelling Mitochondrial Disease in Human Pluripotent Stem Cells: What Have We Learned?

• Authors: Cameron L. McKnight, Y. C. Low, D. Elliott, D. Thorburn, A. E. Frazier
• Year: 2021
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/bf41f9d980522896fcd2284bd630fbb418e55941
• DOI: 10.3390/ijms22147730
• PMID: 34299348
• PMCID: 8306397
• Citations: 21
• Summary: Mitochondrial diseases disrupt cellular energy production and are among the most complex group of inherited genetic disorders. Affecting approximately 1 in 5000 live births, they are both clinically and genetically heterogeneous, and can be highly tissue specific, but most often affect cell types with high energy demands in the brain, heart, and kidneys. There are currently no clinically validated treatment options available, despite several agents showing therapeutic promise. However, modell...
• Evidence snippets:
• Snippet 1 (score: 0.370) > Mitochondrial disease hPSC models provide a system to study disease gene-or mutation-related pathomechanisms in tissues relevant to the clinical phenotype. Ultimately, the long-term goal of these models would be to identify a phenotype in a clinically relevant cell type that could be used to validate efficacy of targeted treatments, or for use in highthroughput treatment trials [94][95][96] (Figure 2). > There are now a wide range of endpoints that have been validated in terminally differentiated cell types to investigate the underlying cellular mechanisms of disease and efficiently identify targetable pathways. Many of these approaches can also be adapted to suit different cell types and even organoids at scale. The tissue specific nature of mitochondrial diseases means that mitochondrial function post-differentiation can be distinct to that from the undifferentiated stem cells or original fibroblast line, often greatly exaggerating any underlying defects [97]. Additionally, detailed transcriptomic and proteomic analyses can elucidate cellular compensation mechanisms and potential target pathways to inform downstream treatment studies [98,99]. Other approaches include microscopic visualization of key cellular features to determine a mutation's impact on cell structure or function [100]. For cardiomyocytes and neurons, electrophysiology can provide highly sensitive data to identify even subtle functional changes [101]. Calcium imaging can be particularly informative in the context of mitochondrial diseases, since calcium handling is a key role of mitochondria [102,103].

[11] Molecular mechanisms and phenotypic diversity in Bardet-Biedl syndrome

• Authors: Carlos Lopez Solarat
• Year: Unknown
• Venue: Unknown venue
• URL: https://www.semanticscholar.org/paper/a574e514383f0a43ed35aa91418e699308c97629
• DOI: 10.35869/11093/8876
• Summary: This thesis primarily aims to identify and elucidate common and fundamental cellular metabolic mechanisms that could account for the considerable phenotypic diversity observed in BBS.
• Evidence snippets:
• Snippet 1 (score: 0.368) > Ciliopathies are a group of rare diseases characterized by a wrong function or structure of the cilia. One of them is Bardet-Biedl syndrome, a multisystemic disease whose main symptoms are retinal degeneration, obesity, polydactyly, cognitive impairment, cryptorchidism and wrong renal structure and function, as well as other less common but of great clinical relevance symptoms such as liver fibrosis, diabetes and hypertension. Ciliopathies are a group of diseases characterized by an alteration in the function or structure of the primary cilium, a cellular organelle responsible for signal transduction. One of these diseases is Bardet-Biedl syndrome (BBS MIM # 209900), which is characterized by mutations in genes that code for a series of proteins that interact to form a protein complex, the BBSome. The precise molecular process underlying BBS manifestation remains unclear. The positioning and involvement of BBSome in ciliary signal transduction suggest a specific disruption of particular metabolic pathways. Nevertheless, the extensive phenotypic variability in this syndrome coincides with distinct tissue alterations, indicating that BBSome likely affects cell signalling through a shared mechanism influencing a majority of receptors within the cell. Numerous ciliopathies exhibit a pathological phenotype that significantly overlaps not only with other ciliopathies but also with different disease types. This is exemplified by BBS and mitochondrial diseases, where both entail multiple tissues and present symptoms such as optic atrophy, neurological involvement, and metabolic irregularities. Consequently, mitochondrial dysfunction could be viewed as a potential novel mechanism contributing to specific BBS symptoms. Building upon the aforementioned points, this thesis primarily aims to identify and elucidate common and fundamental cellular metabolic mechanisms that could account for the considerable phenotypic diversity observed in BBS.

[12] Investigating the Transition of Pre-Symptomatic to Symptomatic Huntington’s Disease Status Based on Omics Data

• Authors: Christiana C. Christodoulou, M. Zachariou, M. Tomazou, E. Karatzas, C. Demetriou et al.
• Year: 2020
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/04a48e68a0a0ad9eca22aeffdb8c22c7fb41ed86
• DOI: 10.3390/ijms21197414
• PMID: 33049985
• PMCID: 7582902
• Citations: 28
• Influential citations: 2
• Summary: The genes, pathways and metabolites identified for each HD stage can provide a better understanding of the mechanisms that become altered in each disease stage, leading to an improvement in clinical symptoms and hopefully a delay in the age of onset.
• Evidence snippets:
• Snippet 1 (score: 0.367) > HD is a monogenetic and incurable disease and at the same time its molecular manifestations remain highly complex and involve multiple cellular processes, genes, and metabolites, which needs to be investigated to understand HD pathology. Systems bioinformatics (SB) allows the integration of different biological omics data to better understand the biological pathways, mechanisms, genes and metabolites involved in HD and lead to possible therapeutic treatments and biomarker discovery. > SB is an interdisciplinary field which combines the research fields of systems biology and bioinformatics. SB allows the integration of biological data across the omics categories such a genomics, transcriptomics, proteomics, metabolomics, lipidomics, epigenomics and several types of omics data [7]. > A major approach in this direction is the generation and construction of biological networks representing each level of omics data and their integration in a layered network that permits the exchange of information between and within the layers. The goal is to reveal synergistic relationships among numerous factors rather than explore each entity individually. This data integration approach results in the construction of highly complex molecular interaction networks. The biological data, obtained through large-scale omics analysis can provide a better understanding into biological mechanisms and pathways and how a dysfunction in these mechanisms and pathways can cause the disease [7]. Furthermore, the emerging importance of biological network-based approaches, allows for potential biological and clinical applications by suggesting an intuitive and trustworthy approach to explore the biological and molecular complexity of a disease of interest [8]. > The metabolome is defined as the complete set of small chemical molecules found within a biological samples (urine, cerebrospinal fluid (CSF), serum, plasma), tissues and cells. Changes and interactions in gene and protein expression and the environment are directly revealed in the metabolome making it more chemically and physically complex than the genome, transcriptome and proteome. Metabolites are affected by the upstream influence of the genome, proteome, environmental and lifestyle factors, as well as medication and underlying diseases [9]. > Metabolomics is an omics category focused in the study of metabolites. Metabolites are defined as small biological and low molecular weight (<1500 Da) compounds, they are the end-products of metabolism [10].

[13] A Lifelike guided journey through the pathophysiology of pulmonary hypertension—from measured metabolites to the mechanism of action of drugs

• Authors: Nathan Weinstein, Jørn Carlsen, S. Schulz, T. Stapleton, H. H. Henriksen et al.
• Year: 2023
• Venue: Frontiers in Cardiovascular Medicine
• URL: https://www.semanticscholar.org/paper/0b2dc837dea11add7e2f67f06acf6280ac96a019
• DOI: 10.1101/2023.11.21.23298782
• PMID: 38845688
• PMCID: 11153715
• Citations: 6
• Summary: The present study shows the power of mining knowledge graphs using Lifelike's diverse set of data analytics functionalities for developing knowledge-driven hypotheses on PH pathophysiological and drug mechanisms and their interactions.
• Evidence snippets:
• Snippet 1 (score: 0.365) > Despite substantial progress in the understanding of PH pathophysiology over the last years, the detailed mechanisms underlying PH remain elusive due to the complex interplay of dysregulated biological processes.Also, although the mechanisms of action of some drugs that have been successfully used for the treatment of PH have been proposed, certain drugs may show additional mechanisms of action that are yet to be identified.Understanding these additional mechanisms of action is crucial for the personalized and thus more effective treatment of PH patients.In this study, we aimed to generate detailed mechanistic hypotheses of pathophysiological processes in PH using our in-house developed software platform Lifelike.Importantly, we have focused our analyses on the potential effects of blood plasma metabolites from PH patients on pulmonary endothelial and smooth muscle cells.Moreover, we used Lifelike to investigate the mechanisms of action of existing and new drugs used for the treatment of PH in more detail.We have achieved this by analyzing metabolite data and receptor ligands on the curated database Reactome using graph algorithms, and by combining our software's additional data analytics functionalities, including statistical enrichment and semantic analysis of textual information from Lifelike's knowledge graph.Additionally, we validated, interpreted, and extended our results based on relevant existing literature.This entire process allowed us to explore the pathophysiology of PH and to propose the model shown in figure 3 and summarized in figure 6.Further, Lifelike allowed us to generate the hypotheses discussed in the following sections and shown in Tables 2 and 3. > Lifelike also enables the reader of a biology article to quickly find the molecules, diseases, and phenotypes that are discussed in the manuscript or included in the figures through entity recognition.For instance, genes detected in articles by Lifelike's entity recognition system can be used to create an enrichment table where the genes can be associated with biological processes, molecular functions, and cell structures by GO enrichment.This allows the reader to find context-specific information quickly, and to extend the knowledge beyond what is described in the article with other sources of information (Table 1 row 21) We encourage the reader to upload this manuscript in PDF format into Lifelike for improved reading and knowledge extraction capabilities.

[14] Serum metabolomics identified specific lipid compounds which may serve as markers of disease progression in patients with Alström and Bardet-Biedl syndromes

• Authors: Krzysztof Jeziorny, Karolina Pietrowska, Julia Siemińska, E. Zmysłowska-Polakowska, A. Kretowski et al.
• Year: 2023
• Venue: Frontiers in Molecular Biosciences
• URL: https://www.semanticscholar.org/paper/1a1d29801c10582356f9813c445fa88ea892e855
• DOI: 10.3389/fmolb.2023.1251905
• PMID: 38028552
• PMCID: 10657895
• Citations: 5
• Summary: Patients with ALMS/BBS have altered lipid metabolism compared to controls or obese subjects, and as the disease progresses, they show elevated levels of lipid oxidation products, which may suggest increased oxidative stress.
• Evidence snippets:
• Snippet 1 (score: 0.362) > To date, no precise therapy has been found to inhibit the development of all components of both syndromes, and treatment is only symptomatic or targeted at particular disorders, including those of a central origin (Haws et al., 2020;Haws et al., 2021). > Due to the progressive nature of the observed symptoms, leading to shortened life expectancy of patients, it seems reasonable to look for markers of progression of ALMS and BBS syndromes. One of the promising methods may be metabolomics. > Metabolomics is a relatively new technology that enables the evaluation of metabolites-small molecules formed during metabolism, the precise identification of which provides insight into biological processes. This allows a better understanding of cellular mechanisms and links them to the phenotype of patients. > Metabolomics is gaining popularity and there are more and more attempts to demonstrate its usefulness in understanding the pathophysiology of diseases, especially rare diseases (Zmyslowska et al., 2017;Zacchia et al., 2020). > The aim of the study was to identify serum metabolites characteristic to ALMS and BBS and to correlate the identified compounds with clinical parameters and diseases progression.

[15] Investigating the impact of gut microbiota-derived metabolites on benign prostatic hyperplasia using network pharmacology approaches

• Authors: Yuanzhao Xu, Lingyue An, Jiling Xie, Chenggong Luo, Heng Zhang et al.
• Year: 2026
• Venue: BMC Pharmacology & Toxicology
• URL: https://www.semanticscholar.org/paper/197e46477cdeb6884c734497d818f92cac74e67f
• DOI: 10.1186/s40360-025-01059-y
• PMID: 41535879
• PMCID: 12888338
• Citations: 1
• Summary: A network pharmacology approach is employed to elucidate the intricate “Microbiota-Substrate-Metabolite-Target” (M-S-M-T) network in Benign Prostatic Hyperplasia (BPH), identifying key hub genes (AKT1, IL-6, IL-1B), signaling pathways, and gut microbiota-derived metabolites (butyrate, propionate, TMAO) as central regulators.
• Evidence snippets:
• Snippet 1 (score: 0.361) > KEGG analysis serves as a powerful tool for delineating well-characterized biological pathways and predicting the functions of currently uncharacterized genes or proteins. This methodology provides critical insights into the regulatory mechanisms governing biological processes, thereby enhancing our comprehensive understanding of them. The results of the KEGG enrichment analysis could be systematically categorized into three major groups (Fig. 5A, 5B, and 5C): 1) Human Diseases, such as "Pathways in cancer" and "Inflammatory bowel disease". This does not imply that BPH is a type of cancer or intestinal disease, but rather reveals that BPH shares many key regulatory mechanisms of cell proliferation and inflammation with these diseases. Gut microbial metabolites influence the development and progression of both BPH and its comorbidities (e.g., diabetes, cardiovascular diseases) by regulating these pathways. 2) Organismal Systems, which are primarily enriched in the "Immune system". This again highlights the central role of immune dysregulation in BPH, and the intervention effect of gut microbial metabolites on BPH through regulating immune-related pathways. 3) Signal Transduction, which is the focus of our attention. Among these, the five major pathways-AGE-RAGE, Toll-like receptor, HIF-1, C-type lectin receptor, and PI3K/Akt-serve as critical bridges linking GM metabolites, core targets, and BPH pathophysiology. Figure 5D presents the pathway-target

[16] 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: 5
• 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: 0.361) > 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.

[17] Human Dermal Fibroblast: A Promising Cellular Model to Study Biological Mechanisms of Major Depression and Antidepressant Drug Response

• Authors: P. Mesdom, R. Colle, É. Lebigot, S. Trabado, Eric Deflesselle et al.
• Year: 2020
• Venue: Current Neuropharmacology
• URL: https://www.semanticscholar.org/paper/79368e365458486de96794333613c12a6063bf54
• DOI: 10.2174/1570159X17666191021141057
• PMID: 31631822
• PMCID: 7327943
• Citations: 16
• Summary: This review highlights the great and still underused potential of HDF, which stands out as a very promising tool in the understanding of MDD and AD mechanisms of action.
• Evidence snippets:
• Snippet 1 (score: 0.360) > Background: Human dermal fibroblasts (HDF) can be used as a cellular model relatively easily and without genetic engineering. Therefore, HDF represent an interesting tool to study several human diseases including psychiatric disorders. Despite major depressive disorder (MDD) being the second cause of disability in the world, the efficacy of antidepressant drug (AD) treatment is not sufficient and the underlying mechanisms of MDD and the mechanisms of action of AD are poorly understood. Objective The aim of this review is to highlight the potential of HDF in the study of cellular mechanisms involved in MDD pathophysiology and in the action of AD response. Methods The first part is a systematic review following PRISMA guidelines on the use of HDF in MDD research. The second part reports the mechanisms and molecules both present in HDF and relevant regarding MDD pathophysiology and AD mechanisms of action. Results HDFs from MDD patients have been investigated in a relatively small number of works and most of them focused on the adrenergic pathway and metabolism-related gene expression as compared to HDF from healthy controls. The second part listed an important number of papers demonstrating the presence of many molecular processes in HDF, involved in MDD and AD mechanisms of action. Conclusion The imbalance in the number of papers between the two parts highlights the great and still underused potential of HDF, which stands out as a very promising tool in our understanding of MDD and AD mechanisms of action

[18] The Lamin Proteins in Nuclear Structure, Functions, and Laminopathies

• Authors: Gan Zhao, Zi-Heng Chen, Caifeng Yang, Mingzheng Liu, Weiyong Wang et al.
• Year: 2026
• Venue: Cells
• URL: https://www.semanticscholar.org/paper/9db8088d893cc5c3de80d3afda68b52e1cf501fc
• DOI: 10.3390/cells15121051
• PMID: 42346079
• PMCID: 13296569
• Citations: 1
• Summary: Collectively, studies of lamin protein function reveal how the nucleus maintains its structures and functions, while studies of laminopathies demonstrate how nuclear dysfunction drives systemic disease and points toward mechanism-based therapies.
• Evidence snippets:
• Snippet 1 (score: 0.359) > Laminopathies represent a clinically diverse class of human diseases caused by mutations in genes encoding components of the nuclear lamina and associated nuclear envelope proteins. Here, we summarize the mutation sites, phenotypes, and underlying molecular mechanisms of laminopathies (Table 1). Although mutations in LMNA account for the majority of reported cases, disease-causing alterations in B-type lamins, particularly LMNB1, as well as mutations in other nuclear envelope proteins, also give rise to distinct laminopathy phenotypes [13,77]. The pathogenesis of laminopathies is explained through several interconnected mechanistic frameworks. The classical structural hypothesis attributes disease to compromised nuclear integrity and impaired mechanical signaling, leading to stress-induced cellular damage, particularly in striated muscle tissues [23]. In contrast, the "gene expression hypothesis" emphasizes that lamin mutations disrupt chromatin organization and intracellular signaling pathways, thereby altering transcriptional programs [12,119]. More recently, these perspectives have been integrated with models highlighting cellular senescence, stem cell exhaustion, and chronic inflammation as additional pathogenic contributors, especially in progeroid syndromes [112]. Current evidence suggests that these mechanisms are not mutually exclusive but operate within an interconnected and synergistic network that drives disease progression [120]. > In laminopathies, mutations affect structural components present in nearly all nucleated cells. Nevertheless, laminopathies exhibit marked tissue-specific vulnerability, predominantly affecting striated muscle, adipose tissue, peripheral nerves, or, in some cases, causing systemic premature aging [12,15]. This tissue selectivity likely arises from the interaction between a specific lamin mutation and the distinct mechanical demands, transcriptional programs, and developmental context of individual tissues [15,119]. Consequently, although laminopathies share common molecular roots, their clinical manifestations are highly system-oriented. > For this reason, laminopathies are conventionally classified according to the primary tissue or organ system affected, despite substantial phenotypic overlap among categories [14]. This classification provides a clinically practical framework while acknowledging that shared pathogenic mechanisms underlie seemingly distinct disease entities. > Striated muscle laminopathies represent a major disease category.

[19] Modeling psychiatric disorders: from genomic findings to cellular phenotypes

• Authors: Anna Falk, Vivi M. Heine, A. Harwood, Patrick F. Sullivan, M. Peitz et al.
• Year: 2016
• Venue: Molecular Psychiatry
• URL: https://www.semanticscholar.org/paper/235b41240d78140de7ab06a3ad8a7d0b1bdff1a5
• DOI: 10.1038/mp.2016.89
• PMID: 27240529
• PMCID: 4995546
• Citations: 83
• Influential citations: 2
• Summary: The challenges for modeling of psychiatric disorders, potential solutions and how iPSC technology can be used to develop an analytical framework for the evaluation and therapeutic manipulation of fundamental disease processes are critically reviewed.
• Evidence snippets:
• Snippet 1 (score: 0.359) > The key challenge for iPSC-based disease modeling is to identify one or more relevant cellular phenotypes that accurately represent the disease pathophysiology. Increasing numbers of reports have demonstrated that for many diseases specific pathophysiology can be captured in human iPSC-based disease models. These range from cardiovascular disease, 44,45 cancer, 46,47 ocular disease, 48,49 diabetes mellitus 50,51 and neurological disorders of the brain. 52,53 Can the same approach be applied to complex psychiatric disorders? > The problem is that almost all psychiatric disorders are characterized by clinical signs and symptoms, but lack independent verification from objective biomarkers. Thus, how might these clinical phenotypes manifest themselves in terms of cell behavior? The identity of robust cellular 'readouts', which typify any psychiatric disorder, is a crucial unsolved problem and an area of intense study 54 (Table 2). When satisfactorily answered, this will herald a new degree of biological objectivity and quantification for the study of psychiatric disorders. > The aim is to find a single or small number of cell phenotypes or parameters that strongly associate with psychiatric disorders, and establish a cellular profile characteristic of cells derived from the general patient population. Although a consensus set of cellular phenotypes for psychiatric disorder is yet to be established, we can define some of their desired characteristics. First, cellular phenotypes have to relate to the biological pathways identified by genetics. Second, although there are many risk genes in disparate biological pathways, at some level, phenotypes should converge onto a much smaller grouping. Third, phenotypes need to be quantifiable. Finally, to be useful for drug development cellular phenotypes should be reversed by pharmacological treatment, although not necessarily by drugs in current use. > Although human iPSC-based approaches underrepresent the complexity of the human central nervous system, cellular phenotypes are likely to lie more proximal to molecular disease mechanisms than phenotypes seen at the level of a tissue or organism, 55 and thus may bypass compensatory homeostatic (2) Gene expression profiles of SCZ human iPSC neurons identified altered expression of many components of the cyclic AMP and WNT signaling pathways.

[20] Clinical Phenotypes of Cardiovascular and Heart Failure Diseases Can Be Reversed? The Holistic Principle of Systems Biology in Multifaceted Heart Diseases

• Authors: K. Lourida, G. Louridas
• Year: 2022
• Venue: Cardiogenetics
• URL: https://www.semanticscholar.org/paper/3960806730c4c1115f527e22d6d0a76536570ec5
• DOI: 10.3390/cardiogenetics12020015
• Citations: 4
• Influential citations: 1
• Summary: Only by understanding the complexity of chronic heart diseases and explaining the interrelationship between different interconnected biological networks can the probability for clinical phenotypes reversal be increased.
• Evidence snippets:
• Snippet 1 (score: 0.358) > Treatment with ACEIs, ARBs, and β-blockers impedes deterioration of myocardial function as well as clinical deterioration caused by the deleterious impact of the compensatory systems [58,59]. Therefore, the therapy with ACEIs, ARBs, and β-blockers is the appropriate therapy to block LV remodeling and HF progression and reduce symptoms and/or mortality [55]. > In general, the HF syndrome demonstrates a modular construction with predictable behavior of functional clinical phenotypes having a strong impact on biological networks from epigenetic, cellular to regulatory systems [18]. The importance of individual genes for the pathogenesis and clinical progression of the HF syndrome is restricted to the hypertrophic and dilated cardiomyopathies. It seems that some HF patients have a complex multigenic inheritance, but the importance of individual genes is limited. In contrast, the significant role of epigenetics, proteomics, and metabolomics is increased; but, the complete genetic network system and the interactions between multiomics systems are still uncertain [60]. Multimodal systems that include genetic networks, multiomics, metabolic pathways, environmental factors, and sophisticated disease-related clinical networks are required to be integrated and provide a new holistic and realistic picture. > Significant breakthroughs have been made to understand many of the pathophysiological mechanisms of HFrEF but the natural pathophysiological history and clinical progression of HFpEF still remains inadequately defined [39]. The subclinical progression of pre-clinical diastolic dysfunction (PDD) of LV "to clinical phenotype of HFpEF and the further clinical progression to some more complex clinical models with multi-organ involvement . . . continue to be poorly understood" [40]. Prospective studies are expected to clarify the natural history and clinical progression of HFpEF and define the LV remodeling mechanisms involved. The pathophysiology of LV systolic dysfunction is different to the diastolic dysfunction, as systolic dysfunction is considered a disease of calcium handling and diastolic dysfunction is regarded as a disease of increased myofilament sensitivity to calcium [61][62][63].

Notes

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

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