Asta Literature Retrieval: Pathophysiology and clinical mechanisms of angioosteohypertrophic syndrome. Core disease mechanisms, molecular and ce...

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: 0.486) > 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] Systems pharmacology-based integration of human and mouse data for drug repurposing to treat thoracic aneurysms.

• Authors: J. Hansen, J. Galatioto, Cristina I. Caescu, P. Arnaud, R. C. Calizo et al.
• Year: 2019
• Venue: JCI insight
• URL: https://www.semanticscholar.org/paper/261628418de4c8b21daeb694301dc1b8759b622d
• DOI: 10.1172/jci.insight.127652
• PMID: 31167969
• Citations: 20
• Summary: System pharmacology approaches that compare patient- and mouse-derived transcriptomic data for subcellular pathway-based drug repurposing represent an effective strategy to identify potential new treatments of human diseases.
• Evidence snippets:
• Snippet 1 (score: 0.445) > TAA with ensuing dissection and rupture of the vessel wall is the clinical hallmark of Marfan syndrome (MFS), a relatively common connective tissue disease associated with mutations in the gene that codes for the multifunctional ECM glycoprotein fibrillin-1 (4,5). Fibrillin-1 assemblies (microfibrils and elastic fibers) impart specific physical properties to tissues, distribute mechanical forces within and across them, communicate to multiple types of vessel wall cells through integrin receptors, and modulate local bioavailability of ECM-bound latent TGF-β complexes (5). In spite of significant research effort, the molecular pathogenesis of arterial disease in MFS remains unresolved, therefore hindering advances in drug therapy. Earlier studies of MFS mice with nondissecting TAA (Fbn1 C1039G/+ mice) have correlated aneurysm onset and progression with increased TGF-β signaling in the media stimulated by improper angiotensin II (AngII) type I receptor (AT1r) activity (6,7). More recent findings indicate a more complex disease mechanism involving the gradual stratification of stress-stimulated interactions among different cell types and multiple regulatory pathways, of which the AT1r and TGF-β signaling pathways are a critical subset (8)(9)(10)(11)(12)(13)(14). > An overview of regulatory pathways and networks associated with a given pathology can often be obtained by examining changes in gene expression during disease progression. Systems pharmacology approaches that consider drug targets as nodes within cellular regulatory networks can use differentially expressed genes (DEGs) to predict dysregulated SCPs that underlie cell-level mechanisms (1,3). Further, computational analyses of the pharmacologically induced perturbations of gene expression listed in the Connectivity Map (CMap) database can predict drugs to be repurposed to normalize dysregulated SCPs (15).

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

• Authors: K. Lourida, G. Louridas
• Year: 2022
• Venue: Cardiogenetics
• URL: https://www.semanticscholar.org/paper/3960806730c4c1115f527e22d6d0a76536570ec5
• DOI: 10.3390/cardiogenetics12020015
• Citations: 4
• Influential citations: 1
• Summary: Only by understanding the complexity of chronic heart diseases and explaining the interrelationship between different interconnected biological networks can the probability for clinical phenotypes reversal be increased.
• Evidence snippets:
• Snippet 1 (score: 0.443) > Treatment with ACEIs, ARBs, and β-blockers impedes deterioration of myocardial function as well as clinical deterioration caused by the deleterious impact of the compensatory systems [58,59]. Therefore, the therapy with ACEIs, ARBs, and β-blockers is the appropriate therapy to block LV remodeling and HF progression and reduce symptoms and/or mortality [55]. > In general, the HF syndrome demonstrates a modular construction with predictable behavior of functional clinical phenotypes having a strong impact on biological networks from epigenetic, cellular to regulatory systems [18]. The importance of individual genes for the pathogenesis and clinical progression of the HF syndrome is restricted to the hypertrophic and dilated cardiomyopathies. It seems that some HF patients have a complex multigenic inheritance, but the importance of individual genes is limited. In contrast, the significant role of epigenetics, proteomics, and metabolomics is increased; but, the complete genetic network system and the interactions between multiomics systems are still uncertain [60]. Multimodal systems that include genetic networks, multiomics, metabolic pathways, environmental factors, and sophisticated disease-related clinical networks are required to be integrated and provide a new holistic and realistic picture. > Significant breakthroughs have been made to understand many of the pathophysiological mechanisms of HFrEF but the natural pathophysiological history and clinical progression of HFpEF still remains inadequately defined [39]. The subclinical progression of pre-clinical diastolic dysfunction (PDD) of LV "to clinical phenotype of HFpEF and the further clinical progression to some more complex clinical models with multi-organ involvement . . . continue to be poorly understood" [40]. Prospective studies are expected to clarify the natural history and clinical progression of HFpEF and define the LV remodeling mechanisms involved. The pathophysiology of LV systolic dysfunction is different to the diastolic dysfunction, as systolic dysfunction is considered a disease of calcium handling and diastolic dysfunction is regarded as a disease of increased myofilament sensitivity to calcium [61][62][63].

[4] 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: 0.425) > 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.

[5] From molecular signatures to predictive biomarkers: modeling disease pathophysiology and drug mechanism of action

• Authors: A. Heinzel, P. Perco, G. Mayer, R. Oberbauer, A. Lukas et al.
• Year: 2014
• Venue: Frontiers in Cell and Developmental Biology
• URL: https://www.semanticscholar.org/paper/36d6c03a528c1358c0ae5b667cca5ce73b2fbee5
• DOI: 10.3389/fcell.2014.00037
• PMID: 25364744
• PMCID: 4207010
• Citations: 23
• Summary: This work exemplifies a computational workflow for expanding from statistics-based association analysis toward deriving molecular pathway and process models for characterizing phenotypes and drug mechanism of action, in turn providing precision medicine hypotheses utilizing predictive biomarkers.
• Evidence snippets:
• Snippet 1 (score: 0.422) > In such scenario a biomarker needs to serve as proxy of key mechanistic factors characterizing and driving a disease on a patient-specific level, combined with educating on the specific interference of disease mechanism with drug mechanism of action. For capturing these constraints a detailed molecular map of a clinical phenotype and its interference with a drug mechanism of action is needed, and here integration of Omics profiling adds to identifying such mechanisms (Fechete et al., 2011;Mühlberger et al., 2012). > An a priori stratification of patients based on an appropriately chosen biomarker panel reflecting the pathophysiology of a given patient (group) allowing to determine a match with a specific drug's mechanism of action appears as promising approach. As recently discussed by Himmelfarb et al. fresh approaches are critical in finding therapies to kidney disease benefiting patients, outlining the importance of improving the translational aspect in clinical research (Himmelfarb and Tuttle, 2013). Here, omics technologies have added significantly to the data landscape characterizing chronic kidney disease, however, in a first instance mainly expanding the candidate set of apparently relevant processes and pathways, going in hand with a large number of biomarker candidates, which individually hamper clinically relevant assessment on disease progression (Fechete et al., 2011;Hellemons et al., 2012). > Integrative approaches in the realm of Systems Biology have been proposed for reaching a consensus description of chronic kidney disease pathophysiology, including molecular models of DN as well as of the reno-cardial axis (He et al., 2012;Komorowsky et al., 2012;Mayer et al., 2012;Heinzel et al., 2013). Still, a translation process needs to be followed, joining disease pathophysiology, stratification markers allowing enrichment strategies, combined with on a molecular mechanistic level matching drugs for allowing precision medicine (Mirnezami et al., 2012). In this work we exemplify such procedure on DN being the major clinical presentation leading to end stage renal disease.

[6] 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: 0.421) > 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.

[7] Macrophage Paired Immunoglobulin-Like Receptor B Deficiency Promotes Peripheral Atherosclerosis in Apolipoprotein E–Deficient Mice

• Authors: Wenhua Su, Liwen Liang, Liang Zhou, Yu Cao, Xiuli Zhou et al.
• Year: 2022
• Venue: Frontiers in Cell and Developmental Biology
• URL: https://www.semanticscholar.org/paper/369e03a3bc199af07a690f7aee3155c98a720f0e
• DOI: 10.3389/fcell.2021.783954
• PMID: 35321392
• PMCID: 8936951
• Citations: 2
• Summary: A myeloid-specific PirB-knockout Apoe −/− murine model of PAD (PirB MΦKO) is created to analyze femoral atherosclerotic burden, plaque features of vulnerability, and monocyte recruitment to femoral atheism lesions to explore the role of the murine LILRB2 homologue PirB in vivo.
• Evidence snippets:
• Snippet 1 (score: 0.420) > The narrowing or blockage of arteries that supply blood to the lower limbs is known as peripheral atherosclerotic disease (PAD). The principal cause of PAD is the atherosclerotic occlusion of arteries supplying the affected limbs. Although the disease is mostly asymptomatic, a commonplace clinical presentation is intermittent claudication (i.e., pain on walking). More severe clinical manifestations include critical limb ischemia (CLI), which presents as pain even during rest as well as tissue loss due to ulceration or gangrene (Morley et al., 2018). PAD is estimated to affect about 13% in adults of the Western population aged 50 or above (Morley et al., 2018). Mortality due to cardiovascular disease is seen in 10-15% of patients with intermittent claudication within 5 years of diagnosis (Norgren et al., 2007). Based on this evidence, it is important to identify the pathophysiological mechanism(s) underlying PAD progression, which can provide guidance towards more effective management of PAD patients. > However, the molecular pathophysiology underlying PAD is complicated, as there are a number of pathways, proteins, and cell types involved in PAD progression (Scholz et al., 2002;Coats and Wadsworth, 2005;Kuang et al., 2008). The primary cells implicated in the development of PAD include macrophages, vascular endothelial cells (ECs), resident stem cells, platelets, vascular smooth muscle cells (SMCs), fibroblasts, and pericytes (Scholz et al., 2002;Coats and Wadsworth, 2005;Kuang et al., 2008). In an otherwise healthy individual, tissue damage due to progressive limb ischemia progresses along a continuum. Initially, the body attempts to homeostatically restore blood supply to the affected limb(s) by angiogenic and arteriogenic pathways. To further resolve limb ischemia and tissue damage, inflammatory, vascular remodeling, and apoptotic pathways are activated. However, in patients diagnosed with CLI, such compensatory mechanisms are inefficient to restore sufficient blood flow.

[8] Clinical metabolomics in type 2 diabetes mellitus: from pathogenesis to biomarkers

• Authors: Chuanxin Liu, Hetao Chen, Yujin Ma, Lei Zhang, Lulu Chen et al.
• Year: 2025
• Venue: Frontiers in Endocrinology
• URL: https://www.semanticscholar.org/paper/36f8d26a208b7b96763df2e9aa3211e440031c0e
• DOI: 10.3389/fendo.2025.1501305
• PMID: 40070584
• PMCID: 11893406
• Citations: 11
• Summary: The results facilitate understanding the pathophysiology and mechanism of type 2 diabetes mellitus and supports research in accurate diagnosis, risk prediction, curative effect, distinct stages, and prognosis judgment of T2DM.
• Evidence snippets:
• Snippet 1 (score: 0.419) > The metabolome is sensitive to a variety of genetic and environmental stimuli and susceptible to genetic, environmental, and gut microbiome pressures, so subtle differences between individuals can lead to large perturbations in metabolite concentrations and fluxes (15, 24). At present, cystatin C has become an ideal endogenous marker for evaluating glomerular filtration function because it is not affected by sex, age or muscle mass (25). In addition, more and more evidence shows that serum CysC is involved in the pathological process of vascular remodeling and neovascularization, which is closely related to the occurrence and development of diabetic microangiopathy (26). > Eighty-four papers were included in this review and obtained through database searches, namely, PubMed, Cochrane Library, China national knowledge internet(CNKI), General Purpose, and VIP Database. The keywords for the searches were "metabolomics" and "type 2 diabetes mellitus" and its complications. The papers were incorporated by reading and summarizing the literature according to the classification standards (27). The profound analysis of clinical differential metabolites identified in type 2 diabetes and its complications were conducted concerning composition, frequency of category, sample type, and pathways to explore the pathological mechanism of type 2 diabetes and its complications to provide a systematic basis for clinical diagnosis, risk stratification, comprehending disease progression, prognosis assessment, and drug efficacy. Our goal is to apply metabolomics to clinical diagnostic biomarkers, metabolic mechanisms, and prognostic observations, and early diagnosis can be made through metabolites to avoid progression to more serious complications.

[9] 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: 0.414) > 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.

[10] Hutchinson–Gilford progeria syndrome: unraveling the genetic basis, symptoms, and advancements in therapeutic approaches

• Authors: Akhil Arun, A. R. Nath, Bonny Thankachan, M. K. Unnikrishnan
• Year: 2024
• Venue: Therapeutic Advances in Rare Disease
• URL: https://www.semanticscholar.org/paper/c8779a55f2e2a90033c9ae94b822691bdee9d829
• DOI: 10.1177/26330040241305144
• PMID: 39691184
• PMCID: 11650505
• Citations: 3
• Summary: From the genetic underpinnings involving the LMNA gene to the myriad of symptoms affecting various organ systems, the article illuminates the pathophysiology and disease progression of HGPS.
• Evidence snippets:
• Snippet 1 (score: 0.412) > HGPS is a rare and devastating genetic disorder that accelerates aging and significantly shortens life expectancy. This article has explored the clinical manifestations, genetic basis, and complications of HGPS, highlighting the profound impact of LMNA gene mutations on multiple physiological systems. The core learning from this exploration is the complex interplay of genetic, cellular, and molecular mechanisms that contribute to the premature aging phenotype observed in progeria. Despite the severe limitations imposed by the disease, advances in genetic testing and early diagnosis provide a glimmer of hope for affected individuals and their families. > The future of HGPS treatment lies in ongoing research efforts aimed at targeting the underlying molecular defects. Emerging therapies, such as FTIs and gene editing techniques, show promise in mitigating some of the disease's symptoms and slowing its progression. However, these approaches remain experimental and require further clinical validation. Additionally, the focus on cardiovascular health, given the high mortality associated with heart-related complications, will be crucial in improving patient outcomes. Despite significant progress in understanding the pathophysiology of HGPS, several limitations remain. The rarity of the condition poses challenges in conducting large-scale clinical trials, and the current treatments only provide symptomatic relief without addressing the root cause of the disease. Moreover, the ethical considerations surrounding gene editing and its long-term effects need careful deliberation. Further research is essential to develop more effective and targeted therapies that can not only extend the lifespan but also enhance the quality of life for individuals with HGPS.

[11] 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: 0.408) > 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.

[12] ECHS1 as a Lipid Metabolism Biomarker for Pediatric Focal Segmental Glomerulosclerosis

• Authors: Chao He, Wei Peng, Sheng Li, Can Xu, Xiuping Chen et al.
• Year: 2025
• Venue: PLOS One
• URL: https://www.semanticscholar.org/paper/088a4669a745352aabcbaf6afabee831bcf826dd
• DOI: 10.1371/journal.pone.0319049
• PMID: 40063869
• PMCID: 11893130
• Citations: 2
• Summary: This study highlights ECHS1 as a potential biomarker for pediatric FSGS, suggesting a potential role in early diagnosis or personalized treatment, and offering insights into its pathogenesis and paving the way for targeted therapeutic strategies.
• Evidence snippets:
• Snippet 1 (score: 0.404) > Currently, treatment options for FSGS, such as immunosuppressants and renal transplantation, often yield variable results, highlighting the need for a deeper understanding of the underlying pathophysiological mechanisms that contribute to disease progression [11,12]. > The dysregulation of lipid metabolism plays a pivotal role in the pathogenesis of various kidney diseases, including FSGS [13]. Alterations in lipid homeostasis can lead to cellular damage and inflammation, thereby exacerbating glomerular injury and sclerosis [14]. Specific lipid metabolic pathways may be involved in the development of glomerulosclerosis, but the precise mechanisms remain to be elucidated [15,16]. > Although progress has been made in our understanding of lipid metabolism in kidney diseases, there is still a considerable gap in the identification of specific lipid-related biomarkers linked to FSGS. This gap suggests an urgent need for comprehensive research aimed at exploring the relationship between differentially expressed lipid metabolism genes and their contributions to FSGS pathogenesis. These studies may reveal potential biomarkers that can improve the diagnosis and prognosis of patients with FSGS [17]. > To address this research gap, we employed a multi-faceted approach that included differential gene expression analysis, functional enrichment analysis, and protein-protein interaction (PPI) network construction. Using bioinformatics tools and experimental validation, we aimed to identify important genes related to lipid metabolism that are significantly altered in FSGS. This methodology allows systematic exploration of the role of lipid metabolism in FSGS, providing insights that could lead to the discovery of novel therapeutic targets and biomarkers for clinical use [18,19]. > The primary goal of this study was to elucidate the relationship between lipid metabolism and FSGS pathophysiology. By identifying the differentially expressed genes(DEGs) involved in lipid metabolism, we hope to establish a clearer understanding of their roles in kidney function and disease progression. Our findings are expected to help develop effective diagnostic tools and targeted treatments for patients with FSGS to improve their clinical outcomes and quality of life [20].

[13] Molecular insights into the premature aging disease progeria

• Authors: Sandra Vidak, R. Foisner
• Year: 2016
• Venue: Histochemistry and Cell Biology
• URL: https://www.semanticscholar.org/paper/60fb3b46bb7e42d5d08cc3b7cbc783b118300c31
• DOI: 10.1007/s00418-016-1411-1
• PMID: 26847180
• PMCID: 4796323
• Citations: 105
• Influential citations: 3
• Summary: Changes in mechanosignaling, altered chromatin organization and impaired genome stability, and changes in signaling pathways, leading to impaired regulation of adult stem cells, defective extracellular matrix production and premature cell senescence are discussed.
• Evidence snippets:
• Snippet 1 (score: 0.403) > The number of molecular biological studies aiming at the identification of lamin-mediated molecular disease mechanisms involved in HGPS increased tremendously following the surprising discovery that LMNA is causally linked to the premature aging disease HGPS in 2003. Despite numerous cellular pathways that were identified to be affected by the expression of the mutant lamin A protein (Fig. 2), the mechanistic details behind these effects are still unclear in most cases. Knowledge based on what was already known on lamin biology before the protein was linked to HGPS and findings on novel roles of lamins in diverse pathways in recent years allowed the launch of translational studies and the efficient search for drug targets and therapeutic approaches within a short time period. The results of the first clinical trials taught us that some improvements of the disease phenotypes can be achieved by FTI treatment, but they also made clear that we need a much better understanding of the underlying disease mechanisms to be able to tackle specific aspects of the disease in a more focused approach. It will also be important to elucidate which of the numerous pathways found to be impaired in HGPS are most relevant for and causally involved in the pathologies, and which ones are just bystanders.

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

• Authors: P. Brownjohn, A. Zoufir, Daniel J O’Donovan, Saatviga Sudhahar, A. Syme et al.
• Year: 2024
• Venue: Frontiers in Pharmacology
• URL: https://www.semanticscholar.org/paper/a595e78572ca02b8cb2897bfc4a989a2b021b279
• DOI: 10.3389/fphar.2024.1397864
• PMID: 38846086
• PMCID: 11154008
• Citations: 3
• Summary: It is determined that the anthelmintic mebendazole was a potent anti-cystic agent in human cellular and in vivo models of ADPKD, and is likely acting through the inhibition of microtubule polymerisation and protein kinase activity.
• Evidence snippets:
• Snippet 1 (score: 0.403) > Targets and molecules were ultimately filtered for validation based on biological and chemical insights, and the potential for clinical translation.Earlier this year, Wilk et al., 2023 applied a similar transcriptomic approach to us, in that case making use of publicly available transcriptomic datasets to create Pkd2-specific ADPKD disease signatures, from which signature reversion was sought from the Library of Integrated Network-based Cellular Signatures (LINCs) drug signature database in order to identify drug repurposing candidates.While one group has previously made use of a knowledge graph-based approach to prioritise preclinically active compounds with the highest chance of clinical translation (Malas et al., 2019), to our knowledge, the current study provides the first combined application of transcriptomic and machine-learning approaches to identify and prioritise putative treatments for ADPKD, and further deconvolute potential mechanisms of action for experimental validation. > In summary we report, using computational, in vitro and in vivo approaches, that the anthelmintic drug mebendazole ameliorates disease-relevant phenotypes in cellular and animal models of ADPKD.We further show that this effect is likely primarily due to the inhibitory effect of mebendazole on the polymerisation of microtubules, which underlie cellular processes important in ADPKD, including cell proliferation, transport, and cilia signalling, and extends previous work linking the importance of the microtubule network to ADPKD pathophysiology.We also describe the inhibitory profile of mebendazole on known and novel protein kinase targets, some of which have previously been implicated in ADPKD, suggesting mebendazole may be acting via polypharmacology to impact disease mechanisms.We acknowledge that further experimental efforts will be required to confirm the actions of mebendazole on these putative targets in relevant disease model systems.It would be particularly informative to investigate these mechanisms in dedicated in vivo studies, where the effects of mebendazole on a wider range of ADPKD-relevant cell types and phenotypes could be evaluated.

[15] Hallmarks of progeroid syndromes: lessons from mice and reprogrammed cells

• Authors: Dido Carrero, C. Soria-Valles, C. López-Otín
• Year: 2016
• Venue: Disease Models & Mechanisms
• URL: https://www.semanticscholar.org/paper/ec1ed5c2e45d4aeb1fcd088517438dc345058b88
• DOI: 10.1242/dmm.024711
• PMID: 27482812
• PMCID: 4958309
• Citations: 137
• Influential citations: 8
• Summary: A series of molecular and cellular hallmarks that characterize progeroid syndromes and parallel physiological ageing are defined and the therapeutic strategies developed to date are discussed.
• Evidence snippets:
• Snippet 1 (score: 0.403) > The physiological deterioration that accompanies ageing constitutes a major risk factor for the development of human pathologies, such as cancer, cardiovascular disorders and neurodegenerative diseases . Key molecular hallmarks of the ageing phenotype include telomere attrition, genomic instability, loss of proteostasis, epigenetic alterations, mitochondrial dysfunction, deregulated nutrient sensing, stem cell exhaustion, cellular senescence and altered intercellular communication . At the macromolecular level, ageing is characterized by the development of wrinkles, greying and loss of hair, presbyopia, osteoarthritis and osteoporosis, progressive loss of fertility, loss of muscle mass and mobility, decreased cognitive ability, hearing loss, and a higher risk for the development of cancer and heart diseases, among other features (López-Otín et al., 2013). > Progeroid syndromes are a group of very rare genetic disorders that are characterized by clinical features that mimic physiological ageing, such as hair loss, short stature, skin tightness, cardiovascular diseases and osteoporosis. Consequently, they constitute a relevant source of information to understand the molecular mechanisms involved in normal ageing. Progeroid disorders do not show differences in prevalence depending on sex or ethnic origin, and appear at an early age, mainly due to defects in the nuclear envelope and DNA repair mechanisms (Gordon et al., 2014). Affected individuals die at a young age, usually as a consequence of cardiovascular problems and musculoskeletal degeneration. > In this Review, we classify human progeroid syndromes into two main groups according to the mechanisms that underlie the disease. Next, we discuss recent findings in the study of progeroid syndromes, achieved through the use of cellular and animal models. On the basis of these findings, we propose nine candidate hallmarks of premature ageing, and highlight their similarities with those described for physiological ageing. These proposed hallmarks recapitulate the most remarkable characteristics of progeroid syndromes and define the mechanisms underlying their pathogenesis, which could provide ideas for future studies on both physiological and pathological ageing. Finally, we review different therapeutic strategies developed for the treatment of these rare but devastating diseases. > A classification system for human progeroid syndromes All progeroid

[16] Atherosclerosis: From Molecular Biology to Therapeutic Perspective 2.0

• Authors: I. Perrotta
• Year: 2022
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/f736c87623efb99ce939fe552dcf44f2d916597d
• DOI: 10.3390/ijms232315158
• PMID: 36499481
• PMCID: 9740737
• Citations: 7
• Summary: Atherosclerosis is a chronic inflammatory disease of large- and medium-sized arteries involving aberrant immune-inflammatory responses, dysfunctional molecular pathways, and impaired tissue repair mechanisms [...].
• Evidence snippets:
• Snippet 1 (score: 0.402) > Atherosclerosis is a chronic inflammatory disease of large-and medium-sized arteries involving aberrant immune-inflammatory responses, dysfunctional molecular pathways, and impaired tissue repair mechanisms [1]. Atherosclerosis begins with endothelial damage, proceeds with the subendothelial retention of modified low-density lipoproteins (LDL) and the phenotypic switching of the smooth muscle cells (SMCs), and culminates with plaque instability and eventually with plaque rupture with its often-fatal sequelae [2][3][4]. Over recent years, the rapidly evolving field of cellular and molecular biology has improved our ability to characterize the lesions beyond their anatomical structure, revealing new insights into the signaling axes that typify vascular behavior and regulate multiple critical steps in the pathogenesis of atherosclerosis. These include previously unknown biochemical signals and molecular pathways whose activities and interactions with their surrounding environment could contribute to atherosclerosis by initiating the lesion and participating in its progression. There has also been an important recognition of the role of exosomes and their miRNAs in different processes that appear to significantly contribute to the pathophysiology of the disease [5]. Substantial progress continues to be made toward understanding the complex interplay between various genetic, epigenetic, and environmental risk factors implicated in the pathogenesis of atherosclerosis [6,7]. Finally, there have been some exciting discoveries in the therapeutic arena with tangible improvements in patient outcomes. > This Special Issue contains research articles and reviews written by experts in the field and focused on the cellular and molecular mechanisms of atherosclerosis and their pivotal roles in the development and progression of the plaque. This Special Issue also explores the classic and more recently defined clinical risk factors for atherosclerotic cardiovascular disease, outlines new promising approaches for its early detection and treatment, and highlights areas where more research activities could usefully be directed. > Vascular SMCs are key participants in both early atherogenesis and advanced plaque progression. SMCs are not terminally differentiated and can modulate their phenotype in response to environmental cues, such as growth factors, inflammatory mediators, mechanical forces, cell-cell and cell-matrix interactions, extracellular lipids, and lipoproteins.

[17] 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: 0.401) > 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.

[18] 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: 0.399) > 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.

[19] 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: 12
• 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: 0.398) > 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

[20] 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: 0.397) > 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.

Notes

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