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Coffin-Lowry syndrome

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Coffin-Lowry syndrome. Core disease mechanisms, molecular and cellular pat...

2026-04-11
Asta MONDO:0010561 Model: Asta Scientific Corpus Retrieval 20 citations

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Coffin-Lowry syndrome. Core disease mechanisms, molecular and cellular pat...

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

  • Papers retrieved: 20
  • Snippets retrieved: 20

Relevant Papers

[1] New therapeutic targets in rare genetic skeletal diseases

  • Authors: M. Briggs, Peter A. Bell, M. Wright, K. A. Pirog
  • Year: 2015
  • Venue: Expert Opinion on Orphan Drugs
  • URL: https://www.semanticscholar.org/paper/1363107f71ae6d2d60abca471cddf3da5d13644b
  • DOI: 10.1517/21678707.2015.1083853
  • PMID: 26635999
  • PMCID: 4643203
  • Citations: 37
  • Influential citations: 1
  • Summary: An overview of disease mechanisms that are shared amongst groups of different GSDs and potential therapeutic approaches that are under investigation are described to generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.
  • Evidence snippets:
  • Snippet 1 (score: 0.377) > proteins of the cartilage ECM such as type II collagen [50]. However, emerging knowledge suggests that the primary genetic defect may be less important than the cells' response to the expression of the mutant gene product [107]. Moreover, the largely overlooked response of a cell (i.e. chondrocyte) to the abnormal extracellular environment is also important for disease progression as illustrated by several GSDs discussed in this review. > It is important that 'omics'-based approaches and technologies are systematically applied to the study of rare GSDs so that definitive reference profiles and disease signatures are generated for each phenotype. These can then be used in a Systems Biology approach to identify both common and dissimilar pathological signatures and disease mechanisms. This approach is entirely dependent upon relevant in vitro and in vivo models (and also novel 'disease-mechanism phenocopies' [107]) for testing new diagnostic and prognostic tools and for determining the molecular mechanisms that underpin the pathophysiology so that effective therapeutic treatments can be developed and validated. This approach will eventually lead to personalized treatments and care strategies centred on shared disease mechanisms with the use of relevant biomarkers to monitor the efficacy of treatment and disease progression. > It is vital that all relevant stakeholders are involved from the outset in defining the appropriate outcomes of any potential therapeutic regime. The perceptions of a successful therapy can differ widely between the clinical academic community and the relevant patient-support groups and it is vital that there is engagement on all these issues. > In summary, the identification of causative genes and mutations for GSDs over the last 20 years, coupled with the generation and in-depth analysis of a plethora of relevant cell and mouse models, has derived new knowledge on disease mechanisms and suggested potential therapeutic targets. The fast-evolving hypothesis that clinically disparate diseases can share common disease mechanisms is a powerful concept that will generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.

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

  • Authors: Sandra Vidak, Sohyoung Kim, Tom Misteli
  • Year: 2026
  • Venue: Nucleus
  • URL: https://www.semanticscholar.org/paper/4bd99b0875508364d8672b6da5a50d024d485a53
  • DOI: 10.1080/19491034.2025.2611484
  • PMID: 41489464
  • PMCID: 12773485
  • Summary: To probe the clinical relevance of previously implicated cellular pathways and to address the extent of gene expression heterogeneity between patients, transcriptomic analysis of a comprehensive set of HGPS patients finds misexpression of several cellular pathways, including multiple signaling pathways, the UPR and mesodermal cell fate specification.
  • Evidence snippets:
  • Snippet 1 (score: 0.373) > 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.

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

  • Authors: Hao Xiong, Jinsheng Guo
  • Year: 2025
  • Venue: Pharmaceuticals
  • URL: https://www.semanticscholar.org/paper/76e92127053136900f7e3f10e2c9278251ced5d2
  • DOI: 10.3390/ph18040507
  • PMID: 40283943
  • PMCID: 12030350
  • Citations: 8
  • Summary: HSC-targeted approaches using specific surface markers and receptors may enable the selective delivery of drugs, oligonucleotides, and therapeutic peptides that exert optimized anti-fibrotic and anti-HCC effects.
  • Evidence snippets:
  • Snippet 1 (score: 0.364) > Significant progress has been made in elucidating the cellular and molecular mechanisms of liver fibrosis; however, only a few findings have been successfully translated into clinical applications. Firstly, the high cost of drug development and target validation necessitates prolonged timelines and substantial financial investment. Secondly, as regulatory requirements become more stringent, there is an increasing demand for drugs with well-defined clinical efficacy and safety profiles. Moreover, the efficacy observed in animal models often fails to fully translate to clinical settings due to differences in pharmacokinetics, extracellular matrix (ECM) cross-linking, and disease pathophysiology. Despite advancements in anti-fibrotic drug development, accurately identifying ideal noninvasive biomarkers for fibrotic activity and establishing consensus on optimal clinical endpoints remain significant challenges [113,114]. > Currently, addressing the underlying cause remains the only proven strategy to halt or reverse liver fibrosis progression, while the development of effective anti-fibrotic therapies continues to pose a major challenge in liver disease management. Over the past few decades, substantial progress has been made in elucidating the cellular and molecular mechanisms underlying liver fibrosis. Liver fibrosis is a complex pathological change involving multiple cells, factors, and pathways, and the study of the cellular and molecular mechanisms of its occurrence and development provides an important theoretical basis and therapeutic target for clinical drug development. It is anticipated that improved animal models and well-designed clinical trials will facilitate the successful translation of anti-fibrotic research into effective clinical treatments in the near future.

[4] 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: 93
  • 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: 0.363) > 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.

[5] 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: 3
  • 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: 0.357) > 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.

[6] Diet, ageing and genetic factors in the pathogenesis of diverticular disease.

  • Authors: D. Commane, Ramesh P. Arasaradnam, Sarah C Mills, J. Mathers, M. Bradburn
  • Year: 2009
  • Venue: World journal of gastroenterology
  • URL: https://www.semanticscholar.org/paper/883d2787f282e3eab29382e53699c35fb19dc620
  • DOI: 10.3748/WJG.15.2479
  • PMID: 19468998
  • Citations: 142
  • Influential citations: 4
  • Summary: It is argued that the evidence supporting the barotrauma hypothesis is largely anecdotal and several gaps in the knowledge base need to be filled before a model for the etiology of diverticular disease can be completed.
  • Evidence snippets:
  • Snippet 1 (score: 0.357) > Clinical observations associate a number of rare genetic disorders with a strong predisposition towards diverticula for mation. Notably, patients with Ehlers-Danlos syndrome [84,85] , Williams-Beuren syndrome [86] , polycystic kidney disease [87] and Coffin-Lowry syndrome [88] are often afflicted with diverticula of the colon and other internal organs. The etiology of diverticula formation in these syndromes may be unrelated to sporadic age-related DD, but they may offer insight into mechanisms of disease in that at least three of these syndromes are associated with a connective tissue disorder. Ehlers-Danlos syndrome is an inherited connective tissue disorder arising through mutations in either the COL5A1 or COL5A2 genes encoding part of the type V collagen protein or through mutations in the gene for the extra cellular matrix (ECM) protein, tenascin-X [89] . Williams-Beuren syndrome affects 1:10 000 of the population and is due to a deletion of about 20 genes on chromosome 7. Although the genetic basis of this syndrome has not been elucidated fully, it appears to result in elastin haplo-insufficiency [90] . Coffin-Lowry syndrome is a maternally inheritable disorder that may also be related to disrupted collagen metabolism [88] . Scheff et al [91] observed colonic diverticulae in 83% of patients with end stage polycystic kidney disease (PKD). PKD is due to mutations in the PKD1 or PKD2 genes coding for the cell membrane-bound polycystin proteins. Whilst the function of these proteins is uncertain, it has been suggested that they interact with the ECM and with extra-cellular signaling pathways regulating cell migration and differentiation [92] . Collectively, these syndromes linked by an ECM defect might suggest that the accumulation of collagen and elastin in the smooth muscle of sporadic DD specimens [20,21] is a prerequisite to diverticula formation. > Separately, clinical observations of poor colonic motility also feature in a significant subset of individuals with mitochondrial diseases [93] .

[7] The Classification of Autosomal Recessive Cerebellar Ataxias: a Consensus Statement from the Society for Research on the Cerebellum and Ataxias Task Force

  • Authors: M. Beaudin, A. Matilla-Dueñas, B. Soong, J. Pedroso, O. Barsottini et al.
  • Year: 2019
  • Venue: Cerebellum (London, England)
  • URL: https://www.semanticscholar.org/paper/8be333265c4faffaeb605213aa48cb23b33981c1
  • DOI: 10.1007/s12311-019-01052-2
  • PMID: 31267374
  • PMCID: 6867988
  • Citations: 49
  • Summary: A consensus is built on the classification of autosomal recessive ataxias in order to develop a general approach to a patient presenting with ataxia, organize disorders according to clinical presentation, and define this field of research by identifying common pathogenic molecular mechanisms in these disorders.
  • Evidence snippets:
  • Snippet 1 (score: 0.356) > The importance of a proper recessive ataxia classification goes beyond the clinical diagnosis perspective. Autosomal recessive ataxias can be regrouped according to the deficient cellular and metabolic pathways involved, which provide a better understanding of cerebellar physiology and of its selective vulnerability to certain metabolic defects. This is also essential from a therapeutic perspective, as disorders that belong to the same metabolic pathway may to the same treatment options, indicating potential for drug repurposing. Figure 3 presents a pathophysiological classification of autosomal recessive ataxias. Certain genes are presented more than once since some proteins are involved in several metabolic pathways or may interfere with other cellular processes as they accumulate in neurons or glial cells. Table 3 presents a more detailed listing of the pathogenic pathways involved along with relevant references. Certain pathways are predominantly involved, notably mitochondrial dysfunction, which may result from abnormal mitochondrial DNA maintenance with progressive mutagenesis, defective mitochondrial protein synthesis and quality control, increased levels of reactive oxygen species and oxidative stress, deficient coenzyme Q10 metabolism, altered mitochondrial dynamics, defective mitochondrial chain assembly, or abnormal mitochondrial RNA maturation and processing (Table 3). Interestingly, many of the disorders caused by mitochondrial dysfunction also present with a mitochondrial clinical syndrome as shown in Fig. 1. Disorders of DNA repair mechanisms are also common, with double-strand break repair pathway or single-strand break repair complexes predominantly involved. Pathogenic mutations in these genes are also associated with a susceptibility to ionizing radiations and predisposition for cancers, but the neurological syndrome is characterized by cerebellar involvement and extrapyramidal movement disorders. It remains debated whether defective DNA repair is the main pathogenic mechanism causing the neurological phenotype [230], but the fact that several interacting genes in this pathway are involved in degenerative cerebellar ataxias suggests that the cerebellum has a peculiar susceptibility to DNA damage for which the underlying mechanism is not understood. Finally, altered synaptic morphology or synaptic dysfunction of Purkinje cells (PC) is frequently involved in recessive ataxias and is associated with aberrant Fig. 1 Clinical classification of autosomal recessive ataxias.

[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
  • 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: 0.356) > 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] Pulmonary fibrosis: pathogenesis and therapeutic strategies

  • Authors: Jianhai Wang, Kuan Li, De Hao, Xue Li, Yu Zhu et al.
  • Year: 2024
  • Venue: MedComm
  • URL: https://www.semanticscholar.org/paper/27d52cce107cbf87fe7b61df145de94a94bc4167
  • DOI: 10.1002/mco2.744
  • PMID: 39314887
  • PMCID: 11417429
  • Citations: 56
  • Summary: This review thoroughly examines the diverse etiological factors, cellular and molecular mechanisms, and key signaling pathways involved in PF, such as TGF‐β, WNT/β‐catenin, and PI3K/Akt/mTOR and discusses current therapeutic strategies.
  • Evidence snippets:
  • Snippet 1 (score: 0.353) > This review highlights that PF involves multiple factors, including epithelial cells, mesenchymal cells, immune responses, and microorganisms. These elements interact with and modify various pathways simultaneously, necessitating a systematic and integrative research approach. Future research on the mechanisms, diagnostics, and therapies should incorporate advanced technologies, such as single-cell sequencing, organoid cultures, and metabolomics (Figure 3). Single-cell sequencing can be used to identify the unique contributions of specific cell types to the lung microenvironment. Organoid cultures replicate the three-dimensional structure and function of the lung tissue, providing a more physiologically relevant model for studying disease mechanisms and testing treatments. Metabolomics can reveal changes in metabolic pathways that contribute to disease progression, whereas microbiology can elucidate the role of microorganisms in PF. These studies should be integrated within a systems biology framework to capture the intricate interactions and regulatory networks involved in PF. > Early and accurate diagnosis is crucial for effective management of PF. Future efforts should focus on the discovery and clinical application of new biomarkers to detect this disease in its early stages. Advanced imaging techniques and molecular diagnostics can be used to monitor disease progression and evaluate treatment responses. Reliable biomarkers can facilitate personalized treatment strategies, allowing timely and targeted interventions to slow or halt disease progression. > Because of the multifactorial nature of PF, a single therapeutic approach is often inadequate. Therefore, a combination of treatments that target multiple pathways and cellular interactions should be considered. Combining antifibrotic drugs with cell and gene therapies, as well as leveraging nanoparticles and gene-editing technologies, can enhance treatment precision and efficacy. Exploring the synergistic effects of various therapies can improve therapeutic outcomes and reduce adverse effects. Supportive measures such as lifestyle modifications, pulmonary rehabilitation, and oxygen therapy should be incorporated to improve the overall quality of life of patients. > In summary, the pathogenic mechanisms underlying PF are complex and involve numerous cellular interactions and pathways. Future research should adopt a systematic and integrative approach to uncover the intricate details of PF pathogenesis. Early diagnosis using novel biomarkers and advanced imaging techniques coupled with multimodal treatment strategies holds promise for significantly improving patient outcomes.

[10] 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: 4
  • 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: 0.349) > : 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.

[11] The hyperornithinemia–hyperammonemia-homocitrullinuria syndrome

  • Authors: D. Martinelli, D. Diodato, Emanuela Ponzi, M. Monné, S. Boenzi et al.
  • Year: 2015
  • Venue: Orphanet Journal of Rare Diseases
  • URL: https://www.semanticscholar.org/paper/ed033868ee677da141e5c926bc7c93cac242ea06
  • DOI: 10.1186/s13023-015-0242-9
  • PMID: 25874378
  • PMCID: 4358699
  • Citations: 92
  • Influential citations: 5
  • Summary: The clinical phenotype of HHH syndrome is extremely variable and its severity does not correlate with the genotype or with recorded ammonium/ornithine plasma levels, suggesting the need for a better understanding of the still unsolved pathophysiology of the disease.
  • Evidence snippets:
  • Snippet 1 (score: 0.349) > Although the disease responds well to treatment with low risk of relapse of hyperammonemia [38], slowly progressive pyramidal signs characterize the chronic course, as also seen in argininemia [89]. However, the mechanism(s) of pyramidal dysfunction in HHH syndrome still remains to be elucidated. Creatine deficiency may contribute to the pathogenetic mechanism of the syndrome, as creatine is relevant for mitochondrial energy metabolism, regulation of glycolysis, proteins synthesis, membrane stabilization and neuromodulation [77,78,85]. This could be in line with the finding of abnormally shaped mitochondria at electron microscopy studies in skin fibroblasts, hepatocytes and muscle biopsy from HHH syndrome patients [11,23,82]. Furthermore, a mitochondrial dysfunction has been recently related to the effects of ornithine and homocitrulline in causing oxidative stress and disturbed mitochondrial homeostasis [79,80]. > A further mechanism that can be involved in the pathophysiology of HHH syndrome is related to polyamines metabolism. Shimizu and colleagues reported increased total and fractional (putrescine, cadaverine, spermine, spermidine) polyamines in one HHH syndrome patient [30]. Indeed, the clinical similarities between HHH syndrome and argininemia, which has been associated to an abnormal polyamine metabolism [91,92], may suggest a common pathogenetic mechanism causing pyramidal dysfunction. > Overall, the pathogenesis of HHH syndrome is complex and not completely understood. It is likely that different mechanisms, including the impact of low mitochondrial ornithine on UC flux, the presence of hyperammonemic crises and the disturbance of other pathways in major organs play a role in determining the heterogeneous clinical presentation of ORC1 deficiency. > In addition, as molecular studies failed to disclose a correlation between type of mutations or ornithine transport capacity and disease severity, an effect of genetic modifiers, such as ORC genes redundancy, seems to be likely, but further studies are certainly needed to clarify this point.

[12] Role of the Microbiome and Its Metabolites in Primary Sjögren’s Syndrome

  • Authors: Jazz Alan Corona-Angeles, Roxana Lizbeth Martínez-Pulido, E. Oregón-Romero, C. Palafox-Sánchez
  • Year: 2025
  • Venue: Microorganisms
  • URL: https://www.semanticscholar.org/paper/664b0d112cb22153ebf90460ce675eed5b0c6851
  • DOI: 10.3390/microorganisms13091979
  • PMID: 41011312
  • PMCID: 12472975
  • Citations: 1
  • Summary: This review aims to explore the mechanisms through which microbiota-derived metabolites contribute to the pathophysiology of primary Sjögren’s syndrome.
  • Evidence snippets:
  • Snippet 1 (score: 0.348) > However, the specific role of microbiome in the development and progression of pSS remains largely unresolved [5]. > The microbiome is now recognized as a key producer of bioactive metabolites, including short-chain fatty acids (SCFAs), bile acids, tryptophan, choline metabolites, gases, and vitamins. These compounds are involved in essential physiological processes ranging from metabolic regulation and gene expression to immune modulation and cellular homeostasis [6]. > Given these insights, this review aims to investigate the potential contributions of microbiota-derived metabolites from different anatomical niches to the pathogenesis of pSS, with particular emphasis on the molecular mechanisms through which they may exert pathogenic or regulatory effects. This is a narrative review based on the guiding question, What is the effect of microbiotaderived metabolites on the progression of primary Sjögren's syndrome (pSS)? It considers all relevant information available to date, using the keywords 'primary Sjögren's syndrome', 'dysbiosis', 'autoimmunity', and 'microbiota-derived metabolites'. The literature was retrieved from major databases such as PubMed and ResearchGate. The aim is to provide a comprehensive overview of the effects of these compounds on the disease, with the purpose of fostering reader interest and encouraging further research in this field.

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

  • Authors: Carly S. Pontifex, Mashiat Zaman, R. Fanganiello, T. Shutt, G. Pfeffer
  • Year: 2024
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/a0717d977acc61d9c08343d1ac6aed94c33f2138
  • DOI: 10.3390/ijms25115633
  • PMID: 38891822
  • PMCID: 11172259
  • Citations: 14
  • Summary: In this review we examine the functionally diverse ATPase associated with various cellular activities (AAA-ATPase), valosin-containing protein (VCP/p97), its molecular functions, the mutational landscape of VCP and the phenotypic manifestation of VCP disease. VCP is crucial to a multitude of cellular functions including protein quality control, endoplasmic reticulum-associated degradation (ERAD), autophagy, mitophagy, lysophagy, stress granule formation and clearance, DNA replication and mito...
  • Evidence snippets:
  • Snippet 1 (score: 0.346) > Although the major roles of VCP in protein quality control are presumed to be the major mechanisms implicated in MSP, the incredible functional diversity and pleiotropic effects of VCP also imply that other mechanisms may be relevant and require further study.VCP cooperates with the 26S proteasome, the main pathway for protein degradation, to manage the protein quality control system.In the nucleus, VCP regulates cell cycle control and the DNA damage response by coordinating proteins at DNA damage sites.In the cytosol, VCP regulates responses to cellular stress by forming and clearing stress granules, facilitating ERAD, autophagy, mitophagy and lysophagy, and VCP may also be involved in apoptosis.The complexity of VCP's diverse molecular functions is also mirrored by the variability in clinical dysfunction caused by pathogenic variants in VCP.The relationship between specific molecular functions of VCP and the spectrum of clinical presentations remains poorly understood, and, in general, genotype-phenotype correlation is still difficult to demonstrate.Certainly, VCP plays many yet-to-be-identified roles in different cellular systems.Given that the role of VCP extends to so many cellular systems, it makes it difficult to ascertain which dysfunction leads to which clinical phenotype.The majority of MSP cases are related to variants at positions 155 and 159, but the phenotypic variability is extensive, suggesting that other genetic or epigenetic factors and/or environmental factors may interact.To better narrow down a causative mechanism in a given tissue, we advise that, when possible, experiments should include one or two other MSP genes such as SQSTM1 or HNRNPA2B1, as this may help identify common mechanisms of dysfunction in MSP.Studies of large cohorts of patients who have common variants in VCP may allow for the identification of genetic modifiers or other factors that contribute to phenotypic variability.Even though pathogenic variants in VCP typically lead to multisystem disease, in general, the affected systems predictably include certain tissue types (primarily skeletal muscle, the cerebrum, motor neurons and osteoclasts).Even though VCP is ubiquitously expressed and participates in numerous crucial cellular functions, pan-systemic disease is not observed.

[14] Homocysteine thiolactone and N-homocysteinylated protein induce pro-atherogenic changes in gene expression in human vascular endothelial cells

  • Authors: D. Gurda, L. Handschuh, Weronika Kotkowiak, H. Jakubowski
  • Year: 2015
  • Venue: Amino Acids
  • URL: https://www.semanticscholar.org/paper/0e9ac31119ab67e72fdaa6e9cc442fa7ed2f4642
  • DOI: 10.1007/s00726-015-1956-7
  • PMID: 25802182
  • PMCID: 4458266
  • Citations: 93
  • Influential citations: 3
  • Summary: It is found that each Hcy metabolite uniquely modulates gene expression in pathways important for vascular homeostasis and identify new genes and pathways that are linked to HHcy-induced endothelial dysfunction and vascular disease.
  • Evidence snippets:
  • Snippet 1 (score: 0.345) > lead to the accumulation of Hcy and its metabolites in the blood-hyperhomocysteinemia (HHcy)-which is an independent risk factor for cardiovascular disease (CVD) and causes endothelial dysfunction, a hallmark of atherosclerosis (Dayal and Lentz 2008). However, molecular mechanisms underlying the pathophysiology of HHcy are not fully understood (Jakubowski 2011(Jakubowski , 2013;;Perla-Kajan et al. 2007). One hypothesis states that metabolic conversion of Hcy to Hcythiolactone initiates a pathway that leads to pathologies associated with HHcy (Jakubowski 1997a(Jakubowski , 1999(Jakubowski , 2007)). Hcy-thiolactone is chemically reactive and modifies ε-amino groups of protein lysine residues, which generates immunogenic and toxic N-homocysteinylated protein (N-Hcy-protein) (Jakubowski 2008(Jakubowski , 2013;;Jakubowski et al. 2000). > In humans and mice, HHcy leads to the accumulation of Hcy-thiolactone and N-Hcy-protein, in addition to Hcy (Chwatko et al. 2007;Jakubowski et al. 2008Jakubowski et al. , 2009)). We and other investigators have shown that HHcy induces changes in gene expression in mouse models that are associated with atherothrombotic disease (Devlin et al. 2005;DiBello et al. 2010;Ingrosso et al. 2003;Kim et al. 2011;Pogribny et al. 2008;Sharma et al. 2006;Suszynska-Zajczyk et al. 2014a, b, c, d). However, it is not known what mechanism(s) are involved and which metabolite-Hcy itself, Hcy-thiolactone, or N-Hcy-protein-is responsible for changes in gene expression. > The key to understanding mechanisms by which HHcy disrupts normal cellular function and ultimately causes disease is to identify genes whose expression is affected by individual Hcy metabolites.

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

  • Authors: Esmeralda Alonso-Barroso, B. Pérez, L. Desviat, E. Richard
  • Year: 2021
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/da649a0f04477c53b448c5ac5f873f8762235290
  • DOI: 10.3390/ijms22031161
  • PMID: 33503868
  • PMCID: 7865492
  • Citations: 16
  • Influential citations: 1
  • Summary: The novel results show that PA iPSC-cardiomyocytes represent a promising model for investigating the pathological mechanisms underlying PA cardiomyopathies, also serving as an ex vivo platform for therapeutic evaluation.
  • Evidence snippets:
  • Snippet 1 (score: 0.344) > The study of the mechanisms involved in disease physiopathology has been mainly performed using the hypomorphic PA mouse model that mimics the biochemical and clinical phenotype [5]. Using this model, bioenergetic failure, oxidative damage and deregulation of miRNAs induced by accumulating propionyl-CoA have been described as potential mechanisms contributing to PA physiopathology [6][7][8]. The limitations of animal models for the study of cardiac energy metabolism [9] and of the commonly available cellular human models such as fibroblasts, underline the importance of generating new relevant cell models to provide deeper insight into the underlying mechanisms of disease. The use of in vitro models with human cellular context is highly recommended and, in this sense, induced pluripotent stem cells (iPSCs) have certain advantages since they provide the genetic background of the patient and represent an unlimited source of biological material for the study of pathophysiology and treatment effectiveness [10]. We have previously generated an iPSC line from a PA patient with defects in the PCCA gene that showed full pluripotency, differentiation capacity and genetic stability [11]. > In the present study, we aimed to establish a platform that served as a disease model to study the cellular and molecular alterations operating in cardiac tissue affected by PA disease. We described the characterization of cardiomyocytes derived from the PCCA iPSC line (PCCA iPSC-CMs) and the analysis of specific pathways potentially involved in cardiac PA physiopathology.

[16] Cardiac Phenotype and Gene Mutations in RASopathies

  • Authors: M. Faienza, G. Meliota, D. Mentino, R. Ficarella, Mattia Gentile et al.
  • Year: 2024
  • Venue: Genes
  • URL: https://www.semanticscholar.org/paper/a4087d3b73d20a6e2f46b7fb87eed4017ec9a9be
  • DOI: 10.3390/genes15081015
  • PMID: 39202376
  • PMCID: 11353738
  • Citations: 9
  • Influential citations: 1
  • Summary: The molecular mechanisms underlying the development of cardiac diseases associated particularly with NS are clarified, and the main morphological and clinical characteristics of the two most frequent cardiac disorders, namely pulmonary valve stenosis (PVS) and HCM are discussed.
  • Evidence snippets:
  • Snippet 1 (score: 0.343) > Cardiac involvement is a major feature of RASopathies, a group of phenotypically overlapping syndromes caused by germline mutations in genes encoding components of the RAS/MAPK (mitogen-activated protein kinase) signaling pathway. In particular, Noonan syndrome (NS) is associated with a wide spectrum of cardiac pathologies ranging from congenital heart disease (CHD), present in approximately 80% of patients, to hypertrophic cardiomyopathy (HCM), observed in approximately 20% of patients. Genotype–cardiac phenotype correlations are frequently described, and they are useful indicators in predicting the prognosis concerning cardiac disease over the lifetime. The aim of this review is to clarify the molecular mechanisms underlying the development of cardiac diseases associated particularly with NS, and to discuss the main morphological and clinical characteristics of the two most frequent cardiac disorders, namely pulmonary valve stenosis (PVS) and HCM. We will also report the genotype–phenotype correlation and its implications for prognosis and treatment. Knowing the molecular mechanisms responsible for the genotype–phenotype correlation is key to developing possible targeted therapies. We will briefly address the first experiences of targeted HCM treatment using RAS/MAPK pathway inhibitors.

[17] 18O-assisted dynamic metabolomics for individualized diagnostics and treatment of human diseases

  • Authors: E. Nemutlu, Song Zhang, N. Juranic, A. Terzic, S. Macura et al.
  • Year: 2012
  • Venue: Croatian Medical Journal
  • URL: https://www.semanticscholar.org/paper/880f053c7f060db4b990e447d0a22c4b69372ddb
  • DOI: 10.3325/cmj.2012.53.529
  • PMID: 23275318
  • PMCID: 3541579
  • Citations: 28
  • Summary: The potential use of dynamic phosphometabolomic platform for disease diagnostics currently under development at Mayo Clinic is described and discussed briefly.
  • Evidence snippets:
  • Snippet 1 (score: 0.342) > Living cells represent an integrated and interacting network of genes, transcripts, proteins, small signaling molecules, and metabolites that define cellular phenotype and function. Traditionally the focus of biomedical research was on individual genes, single protein targets, single metabolites, and metabolic or signaling pathways. This "molecular reductionist" paradigm was based on the assumption that identifying genetic variations and molecular components would lead to discovery of cures for human diseases. However, most of diseases are complex and multi-factorial and the disease phenotype is determined by the alterations of multiple genes, pathways, proteins and metabolites (at cellular, tissue, and organismal levels). Therefore, an integrated "omics" approach is more viable direction for uncovering alterations in metabolic networks, disease mechanisms, and mechanisms of drug effects. > Recent advent of large-scale metabolomics and fluxomic (metabolite dynamics and metabolic flux analysis) completed the "omics revolution" (Figure 1), where genomics, transcriptomics, proteomics, metabolomics, and fluxomics all together complement phenotype determination of living organism. Such integrated "omics" cascades provide a framework for advances in system and network biology, integrative physiology, and system medicine as well as system pharmacology and regenerative medicine. Noteworthy is the "reverse omic" approach or "metabolomicsinformed pharmacogenomics, " where discovery of specific metabolite changes have led to discovery of genetic alterations (2). Therefore, bringing new "omics" technologies to clinical practice will improve disease diagnostics and treatment by targeting drugs and procedures for each unique transcriptomic and metabolomic profiles.

[18] Effects of SARS-CoV-2 Spike S1 Subunit on the Interplay Between Hepatitis B and Hepatocellular Carcinoma Related Molecular Processes in Human Liver

  • Authors: Giovanni Colonna
  • Year: 2024
  • Venue: Livers
  • URL: https://www.semanticscholar.org/paper/2f31a9d4b1e7e8e8c18f5b714e724960c624f61d
  • DOI: 10.3390/livers5010001
  • Summary: The interactome tells us that genes involved in HCC and HVB-related pathways have the potential to activate disease processes and can be considered as a gold standard for personalized molecular medicine diagnoses.
  • Evidence snippets:
  • Snippet 1 (score: 0.342) > The interactions we studied derive from controlled in vivo studies in different cellular models without direct links to specific clinical phenotypes. Model cell systems mimic an organism but are not the organism [93][94][95][96]. This reinforces the idea that molecular interactions potentially reflect mechanistic processes rather than direct clinical outcomes. The multi-to-one or multi-multi correlations between molecular mechanisms and phenotypic expressions further complicate the assumption that molecular evidence can directly explain macroscopic disease processes like the progression from hepatitis to HCC. > In short, the SARS-CoV-2 S1 protein may induce microscopic conditions that develop differently based on individual phenotypic states, which is in line with the complexity of viral pathogenesis. This reflects the non-deterministic nature of interactome data-capturing potentialities rather than predicting phenotypic outcomes. We propose an approach to interpreting molecular data that avoids overgeneralization in linking it to clinical disease progression. We could use our molecular results as a gold standard against molecular data from specific patients to identify whether the metabolic system of the infected patient is implementing the mechanisms driving the progression of HBV infection. These processes should not be present in a healthy person. However, they could also be a clinically useful signal of the level of severity reached by the viral infection in a patient with previous morbidity. > We can now discuss in more detail some aspects of our results through our interpretation of the interactomics approach used by exploring the different levels at which molecular variability could influence the results. > 1. Phenotypic Heterogeneity in Liver Cells. Even without pre-existing liver diseases, subtle variations in liver cell signaling pathways or receptor expression could lead to diverse responses to the S1 protein. For instance, different tissues and even liver cell types variably express ACE2, a key receptor involved in SARS-CoV-2 entry [97]. If liver cells from two individuals express ACE2 at differing levels, the downstream signaling pathways activated by S1 binding will differ, leading to heterogeneity in the subsequent cellular response (e.g., stress, apoptosis, or immune modulation); > 2. S1's Influence on Liver-Specific Signaling Pathways. The S1 protein might activate or inhibit liver-specific pathways [98].

[19] Human 45,X Fibroblast Transcriptome Reveals Distinct Differentially Expressed Genes Including Long Noncoding RNAs Potentially Associated with the Pathophysiology of Turner Syndrome

  • Authors: Shriram N. Rajpathak, S. Vellarikkal, A. Patowary, V. Scaria, S. Sivasubbu et al.
  • Year: 2014
  • Venue: PLoS ONE
  • URL: https://www.semanticscholar.org/paper/5ae975136b3a4bb370421d9084dff7037ab4a740
  • DOI: 10.1371/journal.pone.0100076
  • PMID: 24932682
  • PMCID: 4059722
  • Citations: 48
  • Influential citations: 3
  • Summary: Analysis of transcriptome profiles of human untransformed 45,X and 46,XX fibroblast cells and identified differential expression of genes in these two karyotypes revealed that these differentially expressing genes are associated with bone differentiation, glucose metabolism and gonadal development pathways.
  • Evidence snippets:
  • Snippet 1 (score: 0.341) > Turner syndrome is a chromosomal abnormality characterized by the absence of whole or part of the X chromosome in females. This X aneuploidy condition is associated with a diverse set of clinical phenotypes such as gonadal dysfunction, short stature, osteoporosis and Type II diabetes mellitus, among others. These phenotypes differ in their severity and penetrance among the affected individuals. Haploinsufficiency for a few X linked genes has been associated with some of these disease phenotypes. RNA sequencing can provide valuable insights to understand molecular mechanism of disease process. In the current study, we have analysed the transcriptome profiles of human untransformed 45,X and 46,XX fibroblast cells and identified differential expression of genes in these two karyotypes. Functional analysis revealed that these differentially expressing genes are associated with bone differentiation, glucose metabolism and gonadal development pathways. We also report differential expression of lincRNAs in X monosomic cells. Our observations provide a basis for evaluation of cellular and molecular mechanism(s) in the establishment of Turner syndrome phenotypes.

[20] Non-Invasive Prenatal Screening for Down Syndrome: A Review of Mass-Spectrometry-Based Approaches

  • Authors: Răzvan Lucian Jurca, I. Pralea, M. Iacobescu, I. Rus, C. Iuga et al.
  • Year: 2025
  • Venue: Life
  • URL: https://www.semanticscholar.org/paper/77585fbeddaee796b0d9030dfccee9713f2d3e52
  • DOI: 10.3390/life15050695
  • PMID: 40430124
  • PMCID: 12112985
  • Citations: 1
  • Summary: A comprehensive examination of the differentially expressed proteins (DEPs) and metabolites (DEMs) reported in the literature in T21 prenatal screening aims to guide future research in the field and foster the development of more advanced, less invasive prenatal screening techniques for T21.
  • Evidence snippets:
  • Snippet 1 (score: 0.341) > Additionally, CS and DS are commonly associated with atherosclerosis, nerve development and repair, inflammation, tumor growth, and metastasis [80]. Modifications of the enzymes involved in the biosynthesis of glycosaminoglycans are important in Ehlers-Danlos syndrome, joint dislocations, short stature, spondyloepiphyseal dysplasia with congenital joint dislocations, spondyloepimetaphyseal dysplasia with joint laxity type 1, congenital heart defects, and Temtamy preaxial brachydactyly syndrome. While congenital heart defects and joint laxity are common in T21 patients, the co-occurrence of T21 and Ehlers-Danlos syndrome is rare, and no established correlation exists between the two conditions [104]. > Pathways associated with diseases of hemostasis were predominantly observed in maternal plasma, along with pathways related to signal transduction mediated by growth factors and second messengers-specifically, oncogenic MAPK signaling. MAPKs are protein kinases that control intracellular processes, such as gene expression, metabolism, proliferation, differentiation, and apoptosis, as part of normal physiology, being mainly studied in the context of oncogenesis, tumor progression, and drug resistance [105]. MAPK pathways in T21 patients have been primarily studied to enhance antitumor treatment efficacy in patients with B cell acute lymphoblastic leukemia [106] or to assess MAPK activity in the brains of T21 and Alzheimer's disease patients [107]. > Table 2 summarizes the key molecular pathways implicated in Down syndrome (T21), emphasizing their normal biological functions and the observed or potential alterations in T21. While direct evidence for some pathways remains limited, numerous pathways-particularly those involved in signaling, immune functions, extracellular matrix organization, and metabolic processes-show promising associations with the clinical features of T21. Regarding the metabolomic pathways of significant differentially expressed metabolites (DEMs) in T21, brief discussions on this topic are included in the description of each metabolomic study outlined in the previous section.

Notes

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