Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Sotos Syndrome. Core disease mechanisms, molecular and cellular pathways,...

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

• Papers retrieved: 20
• Snippets retrieved: 20

Relevant Papers

[1] Sotos syndrome.

• Authors: T. McLellan, Bryan Rotella, Stephanie Grote-Garcia, Steven L. Proctor, Daniel Patanella et al.
• Year: 2011
• Venue: Journal of the Indian Society of Pedodontics and Preventive Dentistry
• URL: https://www.semanticscholar.org/paper/cf89215b6e9de5fc180c3ecb401d94116937c3e5
• DOI: 10.4103/0970-4388.90741
• PMID: 22169837
• Citations: 4
• Summary: A case of Sotos syndrome is presented in a 5½-year-old child with typical facial gestalt including macrodolichocephaly with frontal bossing, frontoparietal sparseness of hair, apparent hypertelorism, downslanting palpebral fissures, and facial flushing.
• Evidence snippets:
• Snippet 1 (score: 0.413) > Sotos syndrome.

[2] Histone Lysine Methylation and Neurodevelopmental Disorders

• Authors: Jeong-Hoon Kim, J. Lee, Im-Soon Lee, Sung Bae Lee, K. Cho
• Year: 2017
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/89be0a35498be6fa3fb43ece6485a32a2a783a41
• DOI: 10.3390/ijms18071404
• PMID: 28665350
• PMCID: 5535897
• Citations: 60
• Influential citations: 4
• Summary: The latest studies that revealed the pathological implications of alterations in histone methylation status in the context of various neurodevelopmental disorders are reviewed and possible therapeutic application of epigenetic compounds regulating histonemethylation status for the treatment of these diseases are proposed.
• Evidence snippets:
• Snippet 1 (score: 0.400) > Recent studies demonstrated that disrupted levels or patterns of H3K36 methylation can cause a range of human diseases, including neurodevelopmental disorders. Among them, Sotos syndrome 1 (SOTOS1; OMIM 117550) represents an important human model system for studying the neurodevelopmental outcome of epigenetic dysregulation, which is caused by mutations in NSD1 [117]. SOTOS1 is an autosomal dominant disorder characterized by pre-and postnatal overgrowth, facial dysmorphism, macrocephaly, and non-progressive neurological delay [118]. Interestingly, amplified genomic events of NSD1 resulted in the opposite phenotypic outcome of SOTOS1, so that duplication in NSD1 led to reversed clinical phenotypes of SOTOS1 with microcephaly, as well as delayed bone age, indicating the importance of proper NSD1 expression during brain development [119]. In addition, it was shown that neuroblastoma and glioma may occur in human in the absence of NSD1 function [120]. Although the MAPK/ERK pathway was mapped as a downstream signaling pathway of NSD1-related overgrowth of stature in SOTOS1 [121], until recently, the molecular mechanisms how dysregulated NSD1 affects the mental retardation in SOTOS1 patients remains elusive. To date, two Sotos-like overgrowth syndromes called as Sotos syndrome 2 (SOTOS2; OMIM 614753) and 3 (SOTOS3; OMIM 617169) have been reported, which are caused by mutations in the NFIX and APC2 genes, respectively [122,123]. Among the products of the two genes, APC2, a WNT signaling pathway regulator, has recently been suggested as a crucial target of NSD1, of which defects may cause the intellectual disability associated with SOTOS [123]. In the mouse model system, Apc2 deficiency caused impaired learning and memory abilities along with an abnormal head shape.

[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: 0.391) > 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] 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: 0.375) > 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.

[5] Nasopharyngeal Carcinoma Signaling Pathway: An Update on Molecular Biomarkers

• Authors: W. Tulalamba, T. Janvilisri
• Year: 2012
• Venue: International Journal of Cell Biology
• URL: https://www.semanticscholar.org/paper/307cb9186444d9dad6e2e3b53763be0de76de186
• DOI: 10.1155/2012/594681
• PMID: 22500174
• PMCID: 3303613
• Citations: 96
• Influential citations: 5
• Summary: The molecular signaling pathways in the NPC are discussed for the holistic view of NPC development and progression and the important insights toward NPC pathogenesis may offer strategies for identification of novel biomarkers for diagnosis and prognosis.
• Evidence snippets:
• Snippet 1 (score: 0.367) > In the pregenomic eras, highly integrated and complex circuitry of molecular signaling in NPC pathogenesis was only partially understood. Over the past decade, the knowledge of the molecular mechanisms in NPC carcinogenesis has been rapidly accumulated. Dysregulation and abnormal protein expression of molecules in certain signaling pathways involved in cellular functions including proliferation, adhesion, survival, and apoptosis has been demonstrated in the NPC cells. Detailed information on the complex network in signaling pathway leading to a coordinated pattern of gene expression and regulation in NPC will undoubtedly provide important clues to develop novel prognostic and therapeutic strategies for this cancer. Refining molecular markers into clinically relevant assays may assist in the detection of NPC in asymptomatic patients, as well as stage classification and monitoring disease progression and treatments. Furthermore, selective regulation of particular proteins targeting cancer cell proliferation, invasion, and apoptosis is a hopeful prospect for future anticancer therapy that slow disease progression and improve survival.

[6] Phenotypic categorization of genetic skin diseases reveals new relations between phenotypes, genes and pathways

• Authors: R. Sadreyev, J. Feramisco, H. Tsao, N. Grishin
• Year: 2009
• Venue: Bioinformatics
• URL: https://www.semanticscholar.org/paper/c53babf10fe6c28338852adee48cf41949958e14
• DOI: 10.1093/bioinformatics/btp538
• PMID: 19744994
• PMCID: 2773259
• Citations: 7
• Summary: Analysis of genetic skin disorders and a manually designed set of elementary phenotypes whose combinations define diseases as points in a multidimensional space reveals new patterns that suggest previously unknown functional links between proteins, signaling pathways and disease phenotypes.
• Evidence snippets:
• Snippet 1 (score: 0.363) > Rigorous quantitative analysis of disease phenotypes is a key problem on our way to understanding systemic effects of human gene mutations. Such understanding would enable statistical prediction of clinical manifestations for genome abnormalities, inference of causative genes from complex disease phenotypes, as well as deeper insights into molecular mechanisms of pathophysiology. This tremendous task requires the development of new approaches to link the rapidly growing dataset of gene-disease associations with the many complex and overlapping phenotypes of human disease. > Previously reported approaches to this problem ranged from considering diseases as individual entities connected through shared causative genes (Goh et al., 2007) or co-occurrence in the same patient (Rzhetsky et al., 2007), to more detailed classifications involving the comparison of disease phenotypes, usually based on ontologies of phenotypic terms derived from natural-language phenotype descriptions through automated or semi-automated text analysis (Robinson et al., 2008;van Driel et al., 2006). These analyses may include additional high-throughput data on protein associations (Lage et al., 2007;Wu et al., 2008), improving prediction of new connections between diseases and proteins involved. Here we suggest a different approach to quantitative gene-phenotype analysis. By focusing on the set of genetic skin disorders, we are able to manually analyze the corresponding descriptions of phenotypic manifestations and design a set of elementary phenotypic features whose combinations define any given disease as a point in a multidimensional space. Placing the known gene-disease associations in the context of this space reveals new patterns that suggest previously unknown functional links between disease phenotypes, proteins and signaling pathways. In particular, analysis of telangiectasias (spider vein diseases), reveals a previously unrecognized interplay between the TGF-β signaling cascade and pentose phosphate pathway (PPP), which may mediate glucose-dependent regulation of TGF-β signaling in diabetes.

[7] Clinical Manifestations of Sotos Syndrome

• Authors: J. Millichap
• Year: 2009
• Venue: Pediatric Neurology Briefs
• URL: https://www.semanticscholar.org/paper/faa8082caac14db3f99d6ee4d94e2baee0a0a214
• DOI: 10.15844/PEDNEURBRIEFS-23-6-1
• Summary: The major clinical criteria for the diagnosis of Sotos syndrome were evaluated by geneticists in a retrospective analysis of patients examined at the Children’s Hospital, Goudi, Athens, Greece.
• Evidence snippets:
• Snippet 1 (score: 0.361) > Clinical Manifestations of Sotos Syndrome

[8] 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

[9] Precision Therapeutics in Lennox–Gastaut Syndrome: Targeting Molecular Pathophysiology in a Developmental and Epileptic Encephalopathy

• Authors: Debopam Samanta
• Year: 2025
• Venue: Children
• URL: https://www.semanticscholar.org/paper/455479c1bfbea7b90b73c109228f67c813d13888
• DOI: 10.3390/children12040481
• PMID: 40310132
• PMCID: 12025602
• Citations: 23
• Influential citations: 1
• Summary: A narrative review explores precision therapeutic strategies for LGS based on molecular pathophysiology, including channelopathies, receptor and ligand dysfunction, receptor and ligand dysfunction, cell signaling abnormalities, cell signaling abnormalities, synaptopathies, and the repurposing of existing medications with mechanism-specific effects.
• Evidence snippets:
• Snippet 1 (score: 0.358) > Lennox–Gastaut syndrome (LGS) is a severe childhood-onset developmental and epileptic encephalopathy characterized by multiple drug-resistant seizure types, cognitive impairment, and distinctive electroencephalographic patterns. Current treatments primarily focus on symptom management through antiseizure medications (ASMs), dietary therapy, epilepsy surgery, and neuromodulation, but often fail to address the underlying pathophysiology or improve cognitive outcomes. As genetic causes are identified in 30–40% of LGS cases, precision therapeutics targeting specific molecular mechanisms are emerging as promising disease-modifying approaches. This narrative review explores precision therapeutic strategies for LGS based on molecular pathophysiology, including channelopathies (SCN2A, SCN8A, KCNQ2, KCNA2, KCNT1, CACNA1A), receptor and ligand dysfunction (GABA/glutamate systems), cell signaling abnormalities (mTOR pathway), synaptopathies (STXBP1, IQSEC2, DNM1), epigenetic dysregulation (CHD2), and CDKL5 deficiency disorder. Treatment modalities discussed include traditional ASMs, dietary therapy, targeted pharmacotherapy, antisense oligonucleotides, gene therapy, and the repurposing of existing medications with mechanism-specific effects. Early intervention with precision therapeutics may not only improve seizure control but could also potentially prevent progression to LGS in susceptible populations. Future directions include developing computable phenotypes for accurate diagnosis, refining molecular subgrouping, enhancing drug development, advancing gene-based therapies, personalizing neuromodulation, implementing adaptive clinical trial designs, and ensuring equitable access to precision therapeutic approaches. While significant challenges remain, integrating biological insights with innovative clinical strategies offers new hope for transforming LGS treatment from symptomatic management to targeted disease modification.

[10] 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: 0.357) > 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.

[11] Investigating the role of NPR1 in dilated cardiomyopathy and its potential as a therapeutic target for glucocorticoid therapy

• Authors: Yaomeng Huang, Tongxin Li, Shichao Gao, Shuyu Li, Xiaoran Zhu et al.
• Year: 2023
• Venue: Frontiers in Pharmacology
• URL: https://www.semanticscholar.org/paper/be229f6f2059faab4c97ec0a04bd055adab9dfe1
• DOI: 10.3389/fphar.2023.1290253
• PMID: 38026943
• PMCID: 10662320
• Citations: 4
• Summary: Natriuretic peptide receptor 1 (NPR1) was identified as a core gene associated with DCM through bioinformatics analysis and led to substantial improvements in cardiac and renal function, accompanied by an upregulation of NPR1 expression.
• Evidence snippets:
• Snippet 1 (score: 0.352) > Multiple pathways and molecules are involved in this process; however, the detailed underlying mechanisms remain unclear. In recent years, with the development of high-throughput sequencing and gene chip technologies, the use of bioinformatics technology to explore the occurrence, development, and prognosis of diseases has become a hot topic for scholars worldwide (Hwang et al., 2018;Nayor et al., 2019;Rinschen et al., 2019;Sturm et al., 2019;Montaner et al., 2020). > The present study aimed to use bioinformatics technology to screen for DCM-related genes and investigate their mechanisms, with the purpose of revealing the pathogenesis of DCM and seeking treatment methods. The GSE3586 dataset, containing expression profiles related to DCM, was selected from the Gene Expression Omnibus (GEO) database. This study aimed to predict the core genes that may play crucial roles in disease progression at the molecular level through the enrichment of relevant molecular pathways associated with DCM. Furthermore, the phenotype of the core genes was validated to further support the results of the bioinformatics analysis through basic and clinical experiments. Additionally, the role of glucocorticoids in DCM treatment is discussed in this article with the purpose of providing a theoretical and experimental basis for exploring the pathogenesis of DCM and elucidating therapeutic methods. This study also provides a theoretical reference for the interpretation, early diagnosis, and treatment of DCM.

[12] 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: 0.352) > 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.

[13] 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: 0.349) > 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].

[14] 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: 0.346) > 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

[15] DNA-damage-associated protein co-expression network in cardiomyocytes informs on tolerance to genetic variation and disease

• Authors: Omar D. Johnson, Sayan Paul, Jose A. Gutierrez, William K. Russell, M. C. Ward
• Year: 2025
• Venue: iScience
• URL: https://www.semanticscholar.org/paper/c060d4fbd3241deb2252e8d80ec52a5a539fd99b
• DOI: 10.1016/j.isci.2025.112474
• PMID: 40469117
• PMCID: 12135479
• Citations: 1
• Summary: It is demonstrated that protein connectivity in DNA-damage-associated modules influences the tolerance to genetic variation and supports the use of dynamic networks to explore complex traits.
• Evidence snippets:
• Snippet 1 (score: 0.345) > While DOX can lead to cellular effects through mechanisms including the generation of ROS, at clinically tolerated sub-micromolar doses, DSBs induced through interactions with TOP2B are the main contributors to DOXinduced cardiotoxicity. 10 Clinically, DOX-induced cardiac dysfunction is not a unique pathology but shares characteristics of multiple CVDs. 6 For example, 9% of individuals receiving DOX exhibit reductions in their left ventricular ejection fractions within values that would constitute heart failure. 11,12 Similarly, treatment with DOX increases the risk for electrophysiologic dysfunction and atrial fibrillation by 10-fold and is associated with other related clinically measurable phenotypes, such as an increased QT-interval. 13,14 These pathologies overlap with those influenced by DNA damage and are impacted by genetic risk. 4,15 enome-wide association studies (GWASs) have identified hundreds of risk loci associated with complex CVDs including ll OPEN ACCESS atrial fibrillation, heart failure, and clinical cardiovascular phenotypes, highlighting the genetic component of CVD. 15 Although GWASs identify genetic risk loci that can be mapped to genes that implicate putative regulatory effects, they do not explain the molecular mechanisms of the diseases that they associate with. 16,17 This ultimately impedes our understanding of the effect of genetic variation on CVD and its applicability to identify potential drug targets. 17 ne approach to understand a complex disease phenotype is to construct networks based on molecular phenotypes such as global mRNA or protein expression levels. 0][21] Targeted studies investigating the protein interactomes of proteins encoded in GWAS loci have identified convergent points in the interaction network for autism spectrum disorder and coronary artery disease, highlighting disease-relevant biology. 22,23 Complex disease networks are likely to exert tissue-and cell-typespecific effects. Indeed, proteins relevant to late onset Alzheimer disease are localized within glial cells in the brain. 21 Similarly, the appropriate cellular context, such as cell type and state, is important for understanding the basis of CVD.

[16] Computational modelling of TNFα related pathways regulated by neuroinflammation, oxidative stress and insulin resistance in neurodegeneration

• Authors: Hemalatha Sasidharakurup, Shyam Diwakar
• Year: 2020
• Venue: Applied Network Science
• URL: https://www.semanticscholar.org/paper/aea95bfe3c4303f1361a8ea72828d2926ea0d03e
• DOI: 10.1007/s41109-020-00307-w
• Citations: 9
• Summary: Simulations suggest insulin may be an important factor identifying neurodegeneration in AD and PD, through its action along with the neuroinflammation and oxidative stress.
• Evidence snippets:
• Snippet 1 (score: 0.344) > Modelling complex biological pathway networks including their cellular and molecular components, and interactions (Ji et al. 2017) can help connect critical factors statistically relevant as common signaling mechanisms or phentotypic functions to both disorders. Developing computational models can aid reproducing disease pathways and predicting dynamical behaviours essential for approprite protocol design and experimental testing and to map clinical symptoms to molecular processes going through cellular and circuit functions (Conradi et al. 2007;Bartocci and Lió 2016). Using biochemical systems theory (BST), sub-cellular reactions and biochemical pathways were modeled using ordinary differential equations (ODE) for reconstructing signalling dynamics in this study (Savageau et al. 1987). All biochemical reactions involved in disease-related signalling pathways were expressed mathematically using ODE and rate equations were computed using computational tools (Bartocci and Lió 2016). > The objective of this modeling exercise was to map major genes or proteins involved in disease mechanism, the reactions affected by the mutation of these genes and the difference in reactions when compared with healthy controls, action ofpotential drugs. In literature, BST models on oxidative stress and inflammation in insulin resistance were already available for PD condition (Braatz and Coleman 2015). These models explore some of the important pathways involved in PD and the treatment options. Most of the initial conditions for the model parameters were assigned as relative values rather than real data. With the need to model crosstalk and critical networks relevant to neurodegeneration identified by more recent studies, we have incorporated the crosstalk between insulin resistance, oxidative stress and neuroinflammation related to TNFα signalling in normal, AD and PD conditions (Fallahi-Sichani et al. 2011;Sasidharakurup et al. 2020;Su and Wu 2020). The parameteric values relating to biological states and initial conditions for this model were manually extracted from literature on disease models. In a previous study, we had modelled the role of TNFα mediated glutamate excitotoxicity and neuroinflammation (Sasidharakurup et al. 2020) and the variations in TNFα levels during both healthy and diseased conditions were analyzed.

[17] Role of Transcriptomics in Precision Oncology

• Authors: Ruby Srivastava
• Year: 2024
• Venue: Reports of Radiotherapy and Oncology
• URL: https://www.semanticscholar.org/paper/0bd862558bbb7286336111d9dfd232b5f905d3d9
• DOI: 10.5812/rro-142195
• Citations: 5
• Summary: : Transcriptome profiling is one of the most widely used approaches in the field of multiomics research. It plays a crucial role in the prognostic, diagnostic, and predictive treatment of cancer patients. Novel next-generation sequencing (NGS) technologies permit the identification of cancer biomarkers, gene signatures, and their abnormal expression, affecting oncogenic and molecular targets and novel biomarkers for cancer therapies. Multiomics studies have changed the overall understanding o...
• Evidence snippets:
• Snippet 1 (score: 0.341) > : Transcriptome profiling is one of the most widely used approaches in the field of multiomics research. It plays a crucial role in the prognostic, diagnostic, and predictive treatment of cancer patients. Novel next-generation sequencing (NGS) technologies permit the identification of cancer biomarkers, gene signatures, and their abnormal expression, affecting oncogenic and molecular targets and novel biomarkers for cancer therapies. Multiomics studies have changed the overall understanding of cancer and opened a precise perspective for tumor diagnostics and therapy. The use of these approaches has strengthened our understanding of disease pathophysiology and classifications at the molecular level, including specific interference with drug mechanisms of action. Still, it has limited added value in the clinical setting. The omics data on precision medicine include the application of data from genes, transcripts, and proteins for diagnosis, monitoring of diseases, risk factor determination, counseling, and development of novel therapeutics. Bioinformatics applications have expanded statistics-based analysis toward deriving molecular pathways and process models for characterizing phenotypes and drug action mechanisms. In this review, we will discuss transcriptomics and interference analysis that allows the identification of predictive biomarkers at the molecular level to test drug response and analyze the molecular process interface of disease progression-relevant pathophysiology and mechanism of action to propose predictive biomarkers.

[18] ‘Breast Cancer Resistance Likelihood and Personalized Treatment Through Integrated Multiomics’

• Authors: S. Mehmood, M. Faheem, Hammad Ismail, Syeda Mehpara Farhat, Mahwish Ali et al.
• Year: 2022
• Venue: Frontiers in Molecular Biosciences
• URL: https://www.semanticscholar.org/paper/c542ec176c594aeddb3790bb3d10767598b86ae4
• DOI: 10.3389/fmolb.2022.783494
• PMID: 35495618
• PMCID: 9048735
• Citations: 21
• Influential citations: 2
• Summary: This review has summarized therapeutic resistance associated with BC and the techniques used for its management, and identifies the biomarkers of disease progression and treatment progress by collective characterization and quantification of pools of biological molecules within and among the cancerous cells.
• Evidence snippets:
• Snippet 1 (score: 0.341) > Breast cancer is a very complex and heterogeneous disorder with unique molecular and morphological features relative to a disease which involves only a single gene or protein in a simple signaling pathway contributing toward the progression of disease in an independent and autonomous manner (Organization 2019). Various studies had represented BC heterogeneity through the differential response of the same type of BC patients to treatment and risk of developing side effects. One of the major clinical complications in the treatment of breast carcinoma patients is the development of therapeutic resistance (Luque-Bolivar et al., 2020). Recently drug resistance in BC treatment is not properly addressed, rather to focus on molecular pathways deeply; an alternative strategy of using a different drug is commonly applied. In order to reduce the adverse effects of BC treatment including drug resistance, a profound understanding of the molecular mechanism of the disease and the response to the drug is needed. Multidrug resistance (MDR) and consequent relapse on therapy are prevalent issues related to breast carcinoma as our understanding is incomplete related to the molecular mechanism of breast carcinoma disease (Waks and Winer, 2019a). Therefore, elucidating the molecular mechanisms involved in drug resistance is critical. For the management of breast cancers, the treatment decision not only depends on the Treatment with exemestane alone or in combination with an mTOR inhibitor such as everolimus (Carlini et al., 2007Chin et al., 2007Geisler et al., 2008Bahrami et al. (2020) ER+/ HER2- assessment of prognosis factors but also on the evaluation of pathological and clinical factors. Integrated data assessments of these multiple factors of breast carcinoma through multiomics can provide significant insight and hope for making therapeutic decisions (Parsons and Francavilla 2020). Major BC treatment strategies rely on the tumor subtype, immunohistochemical evaluation of prognostic elements, and seek new genetic markers to improve the diagnostic strategies and to enhance treatment outcomes with minimal side effects.

[19] Mitochondrial Dysfunction in Diabetes: Shedding Light on a Widespread Oversight

• Authors: F. Iheagwam, A. J. Joseph, E. D. Adedoyin, Olawumi Toyin Iheagwam, Samuel Akpoyowvare Ejoh
• Year: 2025
• Venue: Pathophysiology
• URL: https://www.semanticscholar.org/paper/dbf8042761c1a5fc50f8cd894cc498505abac7cb
• DOI: 10.3390/pathophysiology32010009
• PMID: 39982365
• PMCID: 12077258
• Citations: 43
• Influential citations: 1
• Summary: This review aims to elucidate the complex link between mitochondrial dysfunction and diabetes, covering the spectrum of diabetes types, the role of mitochondria in insulin resistance, highlighting pathophysiological mechanisms, mitochondrial DNA damage, and altered mitochondrial biogenesis and dynamics.
• Evidence snippets:
• Snippet 1 (score: 0.341) > The landscape of DM research is continuously evolving, with emerging technologies and approaches offering new insights into the pathophysiology of the disease and potential therapeutic targets. Advancements in omics technologies, encompassing genomes, transcriptomics, proteomics, and metabolomics, have transformed the molecular mechanisms underlying DM [134]. High-throughput sequencing techniques enable comprehensive analysis of genetic variants, gene expression profiles, protein abundance, and metabolite levels associated with DM and its complications [135]. Single-cell omics approaches provide unprecedented resolution and granularity, allowing researchers to dissect cellular heterogeneity and identify novel cell types, subpopulations, and signalling pathways involved in DM pathogenesis. Integrating multi-omics data sets offers a systems-level perspective of DM, unravelling complex networks of molecular interactions and regulatory circuits underlying disease progression [136]. > In addition to omics technologies, advances in imaging modalities, such as MRI, PET, and optical imaging, enable non-invasive visualisation and quantification of metabolic, functional, and structural changes. Molecular imaging probes targeting specific biomarkers and metabolic pathways provide valuable insights into disease mechanisms and treatment responses in preclinical and clinical settings [85]. Despite significant progress in DM research, numerous unanswered questions and knowledge gaps persist, hindering the ability to develop effective prevention and treatment strategies. Key areas requiring further investigation include the role of epigenetics, environmental factors, and the microbiome in DM susceptibility and progression. Moreover, the interaction between environmental cues and genetic predisposition remains incompletely understood, highlighting the need for comprehensive multi-omics studies and large-scale epidemiological analyses to identify gene-environment interactions and modifiable risk factors for DM [137]. Furthermore, the heterogeneity of DM phenotypes and clinical outcomes poses a challenge for personalised medicine approaches, necessitating robust biomarkers and predictive models to stratify patients based on disease subtypes, prognosis, and treatment response [138].

[20] 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: 0.340) > 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.

Notes

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

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References that may not be about this subject

These identifiers resolve, so they are not fabrications, but the records they resolve to share almost none of this report's vocabulary. That is a clue and not a verdict - a paper can be relevant in ways its title and abstract do not spell out - so read them before deciding:

• PMID:22169837 (1 mention) - Sotos syndrome.
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• GEO:GSE3586 (1 mention) - Dilated Cardiomyopathy and Non Failing Septal Biopsies
• shared terms: disease

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