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Stiff Person Syndrome

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Stiff Person Syndrome. Core disease mechanisms, molecular and cellular pat...

2026-05-08
Asta MONDO:0008491 Model: Asta Scientific Corpus Retrieval 20 citations

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Stiff Person 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] 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: 0.410) > Oxidative stress represents another key pathogenic mechanism in HGPS, as impaired NRF2 activity or increased reactive oxygen species (ROS) levels are sufficient to recapitulate HGPSassociated phenotypes [17,32,60]. Collectively, these findings underscore the multifactorial nature of HGPS pathogenesis, implicating interconnected signaling cascades involved in inflammation, oxidative stress, proteostasis, and vascular remodeling. Reassuringly, our findings indicate that many of the major pathways that have been described to contribute to HGPS phenotypes in mouse and cellular disease models are also misregulated in progeria patients, and targeting these pathways may provide therapeutic avenues to mitigate disease severity and improve outcomes in HGPS. > Although individuals with HGPS typically exhibit a characteristic set of clinical features, such as craniofacial abnormalities, growth retardation, and cardiovascular complications, there is notable variability in the age of onset, severity, and progression of symptoms between patients [7,9]. At the cellular level, HGPS is associated with several hallmark abnormalities, including nuclear envelope defects, decreased expression of several nuclear proteins and epigenetic marks, mitochondrial dysfunction, and increased cellular senescence [1,11,30,31,61]. These cellular phenotypes also exhibit considerable variation between patients, possibly contributing to differences in clinical outcomes. Our results indicate that even though some degree of transcriptional heterogeneity between the individual patients exists, the majority of patients exhibit misregulation of a set of shared pathways, suggesting that these pathways are universal driver mechanisms in HGPS. Further work is needed to understand the molecular and genetic factors that underlie inter-individual variability in disease expression and progression. > A limitation of pathway analysis of HGPS patient samples is to distinguish the pathways which are directly targeted by the disease-causing progerin protein and the emergence of adaptive secondary response pathways during progression of the disease in patients during their lifetime. The same caveat applies to the use of cell-based models used in the study of HGPS disease mechanisms.

[2] New therapeutic targets in rare genetic skeletal diseases

  • Authors: M. Briggs, Peter A. Bell, M. Wright, K. A. Pirog
  • Year: 2015
  • Venue: Expert Opinion on Orphan Drugs
  • URL: https://www.semanticscholar.org/paper/1363107f71ae6d2d60abca471cddf3da5d13644b
  • DOI: 10.1517/21678707.2015.1083853
  • PMID: 26635999
  • PMCID: 4643203
  • Citations: 38
  • 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: 0.404) > 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.

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

  • Authors: Yaomeng Huang, Tongxin Li, Shichao Gao, Shuyu Li, Xiaoran Zhu et al.
  • Year: 2023
  • Venue: Frontiers in Pharmacology
  • URL: https://www.semanticscholar.org/paper/be229f6f2059faab4c97ec0a04bd055adab9dfe1
  • DOI: 10.3389/fphar.2023.1290253
  • PMID: 38026943
  • PMCID: 10662320
  • Citations: 4
  • Summary: Natriuretic peptide receptor 1 (NPR1) was identified as a core gene associated with DCM through bioinformatics analysis and led to substantial improvements in cardiac and renal function, accompanied by an upregulation of NPR1 expression.
  • Evidence snippets:
  • Snippet 1 (score: 0.394) > 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.

[4] 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: 10
  • 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: 0.391) > 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.

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

  • Authors: Anna Falk, Vivi M. Heine, A. Harwood, Patrick F. Sullivan, M. Peitz et al.
  • Year: 2016
  • Venue: Molecular Psychiatry
  • URL: https://www.semanticscholar.org/paper/235b41240d78140de7ab06a3ad8a7d0b1bdff1a5
  • DOI: 10.1038/mp.2016.89
  • PMID: 27240529
  • PMCID: 4995546
  • Citations: 77
  • Influential citations: 2
  • Summary: The challenges for modeling of psychiatric disorders, potential solutions and how iPSC technology can be used to develop an analytical framework for the evaluation and therapeutic manipulation of fundamental disease processes are critically reviewed.
  • Evidence snippets:
  • Snippet 1 (score: 0.390) > The key challenge for iPSC-based disease modeling is to identify one or more relevant cellular phenotypes that accurately represent the disease pathophysiology. Increasing numbers of reports have demonstrated that for many diseases specific pathophysiology can be captured in human iPSC-based disease models. These range from cardiovascular disease, 44,45 cancer, 46,47 ocular disease, 48,49 diabetes mellitus 50,51 and neurological disorders of the brain. 52,53 Can the same approach be applied to complex psychiatric disorders? > The problem is that almost all psychiatric disorders are characterized by clinical signs and symptoms, but lack independent verification from objective biomarkers. Thus, how might these clinical phenotypes manifest themselves in terms of cell behavior? The identity of robust cellular 'readouts', which typify any psychiatric disorder, is a crucial unsolved problem and an area of intense study 54 (Table 2). When satisfactorily answered, this will herald a new degree of biological objectivity and quantification for the study of psychiatric disorders. > The aim is to find a single or small number of cell phenotypes or parameters that strongly associate with psychiatric disorders, and establish a cellular profile characteristic of cells derived from the general patient population. Although a consensus set of cellular phenotypes for psychiatric disorder is yet to be established, we can define some of their desired characteristics. First, cellular phenotypes have to relate to the biological pathways identified by genetics. Second, although there are many risk genes in disparate biological pathways, at some level, phenotypes should converge onto a much smaller grouping. Third, phenotypes need to be quantifiable. Finally, to be useful for drug development cellular phenotypes should be reversed by pharmacological treatment, although not necessarily by drugs in current use. > Although human iPSC-based approaches underrepresent the complexity of the human central nervous system, cellular phenotypes are likely to lie more proximal to molecular disease mechanisms than phenotypes seen at the level of a tissue or organism, 55 and thus may bypass compensatory homeostatic (2) Gene expression profiles of SCZ human iPSC neurons identified altered expression of many components of the cyclic AMP and WNT signaling pathways. > (3

[6] 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: 14
  • 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: 0.389) > 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

[7] Direct Sarcomere Modulators Are Promising New Treatments for Cardiomyopathies

  • Authors: O. Tsukamoto
  • Year: 2019
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/07467943fe92ce135b52ded5e5dea2bfc2ddf179
  • DOI: 10.3390/ijms21010226
  • PMID: 31905684
  • PMCID: 6982115
  • Citations: 16
  • Summary: The direct inhibition of sarcomere contractility may be able to suppress the development and progression of HCM with hypercontractile mutations and improve clinical parameters in patients with HCM, and direct activation of sar COMs modulators that can positively influence the natural history of cardiomyopathies represent promising treatment options.
  • Evidence snippets:
  • Snippet 1 (score: 0.382) > Hereditary DCM can be caused by single point mutations in sarcomere proteins. However, the link between point mutations and clinical phenotypes in DCM is not thoroughly understood in most cases. Recent advances in biochemical, biophysical, stem cell, and gene editing technologies have provided a better understanding of the molecular mechanisms through which the initial insult in DCM (i.e., mutations in a sarcomere protein) induces alterations in cellular organization and contractility, resulting in disease phenotypes. In particular, hiPSC-CMs and genetically modified animals are excellent models because they can capture the initial molecular phenotype that occurs before major compensatory mechanisms mask it.

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

  • Authors: Christine Péladeau, J. Sandhu
  • Year: 2021
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/763a36db080236fca8cde89b2afcdf056f3584d0
  • DOI: 10.3390/ijms22116068
  • PMID: 34199845
  • PMCID: 8200055
  • Citations: 18
  • Influential citations: 1
  • Summary: Whether therapeutic targeting of the NLRP3 inflammasome components is a viable approach to alleviating the detrimental phenotype of neuromuscular diseases and improving clinical outcomes is examined.
  • Evidence snippets:
  • Snippet 1 (score: 0.382) > Despite a large number of mechanisms that have been identified in muscle degeneration and nerve cell loss, none have proven to be the primary cause of the disease. There is much need for a deeper understanding of the biology of the pathogeneses and the molecular mechanisms that are activated early in the diseases in order to identify "druggable" targets and disease-modifying treatments for these devastating diseases. > Human iPSC technologies are emerging as useful platforms for disease modeling to study pathogenic mechanisms and discover novel therapeutics for neuromuscular diseases [211,237]. Indeed, patient-derived iPSCs are being used to create a "patient-in-adish" disease model to derive relevant cell types for testing potential therapeutics, paving the way towards personalized medicine. This approach allows drug screening in a dish prior to administration to patients and "bench-to-bedside" translation of potential therapies. Additionally, iPSCs may also be used to stratify patients with various phenotypes and guide future clinical trials for bringing improved therapies to patients. Since multiple cell types are involved in disease pathogenesis, future research efforts need to be focused on deciphering "disease-specific signatures" at single-cell resolution, and not only in neuronal cells but also in non-neuronal cells. The application of modern technologies, including single-cell RNA sequencing and spatial transcriptomics, to neuromuscular diseases, will allow to ascertain cellular vulnerability and cell-specific mechanisms during various stages of disease progression. > The vital roles of the NLRP3 inflammasome in neuromuscular diseases such as DMD, LGMD and ALS, reveal that targeting this pathway is indeed a promising therapeutic strategy. Dysregulation of the NLRP3 inflammasome in muscle tissues by muscle damage, membrane instability, extracellular ATP and Ca 2+ ions or signals from infiltrating immune cells, clearly impacts the progression of neuromuscular and neurodegenerative disorders. Thus, modulation of these pathways involved with activation and assembly of NLRP3 inflammasome could be truly beneficial.

[9] Gene expression profiles and protein-protein interaction networks in amyotrophic lateral sclerosis patients with C9orf72 mutation

  • Authors: M. Kotni, Mingzhu Zhao, Dongqing Wei
  • Year: 2016
  • Venue: Orphanet Journal of Rare Diseases
  • URL: https://www.semanticscholar.org/paper/02c62f8684ad7d39193758203a4298e2ea826a9e
  • DOI: 10.1186/s13023-016-0531-y
  • PMID: 27814735
  • PMCID: 5097384
  • Citations: 39
  • Influential citations: 2
  • Summary: Tumor necrosis factor (TNF), Endothelin 1 (EDN1), Angiotensin (AGT) and many cell adhesion molecules (CAM) were detected as hub genes that can be targeted as novel therapeutic targets for ALS disease.
  • Evidence snippets:
  • Snippet 1 (score: 0.376) > Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that involves the death of neurons [1,2]. ALS is often called Lou Gehrig's disease, after the famous baseball player who was diagnosed with it. The occurrence of ALS is two per 100,000 people, and it is estimated that more than 20,000 Americans may be living with ALS at any given time. It is worldwide with no racial, ethnic or socioeconomic boundaries and can affect anyone. It affects the nerve cells in the brain and the spinal cord and is characterized by stiff muscles, muscle twitching and gradually worsening weakness due to muscles decreasing in size. Despite intensive research, the clinical and pathophysiological mechanisms of ALS still remain unclear. There are two types of ALS, sporadic (SALS) and familial (FALS). 90-95 % of ALS cases are sporadic for which the cause is unknown and 5-10 % are familial, which are inherited [3]. Findings on ALS patients have drawn in numerous genes related to ALS pathogenesis and have identified diverse processes, such as excitotoxicity, oxidative stress, cytoskeletol abnormalities, impaired axonal transport, mitochondrial dysfunction and protein aggregation. Presently, ten genes such as SOD1, ALSIN, SETX, SPG11, FUS, VAPB, TARDBP, OPTN, ATXN2 and C9orf72 were found to affect the pathogenesis of ALS [4]. Though SALS and FALS are clinically and pathophysiologically similar, there is a requirement of finding the genes involved in FALS and the molecular mechanism pathways involved in the mutation of these genes. Till date studies were done to know the molecular mechanisms and underlying pathogenesis of ALS disease related to SALS with Superoxide dismutase 1 (SOD1) mutation [5,6]. As the study of SOD1 has led to great advances in proper illustration of molecular mechanisms underlying in ALS disease, identifying the mutations in other genes and the pathways involved in these mechanisms is utmost important. Till date there is no cure for ALS, however the drug riluzolethe only prescribed drug approved by Food and Drug Administration (FDA) to treat ALS which prolong

[10] Solving the Evidence Interpretability Crisis in Health Technology Assessment: A Role for Mechanistic Models?

  • Authors: E. Courcelles, J. Boissel, J. Massol, I. Klingmann, R. Kahoul et al.
  • Year: 2022
  • Venue: Frontiers in Medical Technology
  • URL: https://www.semanticscholar.org/paper/877d5b1b75599745f704a9c8371f74601ff17e2f
  • DOI: 10.3389/fmedt.2022.810315
  • PMID: 35281671
  • PMCID: 8907708
  • Citations: 6
  • Summary: Light is shed on different stakeholder's contributions and needs in the appraisal phase and how mechanistic modeling strategies and reporting can contribute to this effort to implement mechanistic models central in the evidence generation, synthesis, and appraisal of HTA so that the totality of mechanistic and clinical evidence can be leveraged by all relevant stakeholders.
  • Evidence snippets:
  • Snippet 1 (score: 0.375) > A second limitation in HTA is the fact that currently population (and sometimes stratified) medicine is pursued during clinical Uncertainty not completely addressed in competent authority assessment report Example use of MIDD relevant to address uncertainty potentially also during HTA What is the optimal dosage in the clinical context? > Physiologically based pharmacokinetic models can investigate dosing-regimens relevant for regulatory review and product labels (9) and can also mimic real-life adherence to prescribed treatment regimens (see also below) or pharmacology-relevant characteristics of special populations as well as drug-drug interactions. > What is the duration of the effectiveness, especially with chronic use of a treatment? > Mechanistic models can predict the long-term disease progression by extrapolation of shorter-term findings under the constraints of how the components of the system function (and these constraints convey biological plausibility by design). An example is the use of a mechanism-based disease progression model for comparison of long-term effects of pioglitazone, metformin, and gliclazide on disease processes underlying Type 2 Diabetes Mellitus (10). Another example is prediction of long-term outcomes by short-term marker data as demonstrated by a semi-mechanistic approach in context of osteoporosis treatment (11). > What is the efficacy for relevant clinical outcomes? > Mechanistic models combined with pharmacometric approaches can translate findings for one outcome to a range of other outcomes. An example of survival modeling on the back of a mechanistic description is the modeling framework for CD19-Specific CAR-T cell immunotherapy using a quantitative systems pharmacology model (12). > What is the size of the clinical effect dependent on patient characteristics and extrinsic factors? > Data-driven modeling techniques can capture correlation within clinical data. Describing the clinical effect of a drug can also be based on mechanistic considerations. Such models either (a) link disease phenotypes to increasingly granular mathematical representations of pathophysiologic processes (top-down approach) or (b) derive functional, computable cellular networks from the molecular building blocks of genes and proteins to elucidate the impact of pathologic or therapeutic alterations on network operating states and hence clinical phenotype (bottom-up) [

[11] Probing disorders of the nervous system using reprogramming approaches

  • Authors: J. Ichida, E. Kiskinis
  • Year: 2015
  • Venue: The EMBO Journal
  • URL: https://www.semanticscholar.org/paper/07c84453351dfc9065d2f4870f5c534a96e63282
  • DOI: 10.15252/embj.201591267
  • PMID: 25925386
  • PMCID: 4474524
  • Citations: 4
  • Summary: Tables listing the various human neural cell types that can be generated and the neurological disease modeling studies that have been reported are presented, the current state of the field is described, important breakthroughs are highlighted and the next steps and future challenges are discussed.
  • Evidence snippets:
  • Snippet 1 (score: 0.374) > Neurological disorders including schizophrenia, ALS, PD, FTD and epilepsy are often characterized by a profound clinical and genetic heterogeneity, suggesting that they might represent a syndrome rather than a single nosological entity (Fanous & Kendler, 2005;Tremblay et al, 2013;Jeste & Geschwind, 2014). The variable combination of positive and negative symptoms in schizophrenia, the variable degree of upper and lower motor neuron dysfunction in ALS, the heterogeneity of cognitive symptoms in PD, the variable rate of progression in FTD and the differential response to anti-epileptic treatments in epileptic syndromes are some examples of the clinical diversity in neurological disorders. In addition, genetic studies in ALS, for example, have demonstrated that the disease can be caused by mutations in genes that encode proteins involved in diverse cellular functions ranging from RNA metabolism, vesicle transport, cytoskeletal homeostasis and the processing of unfolded proteins (Cleveland & Rothstein, 2001;Pasinelli & Brown, 2006;Sreedharan & Brown, 2013). While progress has been achieved in terms of genetic taxonomy, pathological stratification and the classification of patients based on their clinical presentation, little is known about how similar or different patients are, in terms of the molecular pathways that mediate their disease processes. Reprogramming technologies can be used to develop in vitro models of genetic and sporadic disease cases and effectively stratify patients, based on (i) the neuronal subtype that exhibits a disease-associated phenotype and (ii) the pathway that leads to this phenotype in each case (Fig 3). This approach may lead to the identification of overlapping disease mechanisms that will be broadly relevant and represent the best therapeutic opportunities, or toward a personalized approach to clinical trials and therapeutic treatments.

[12] 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: 0.373) > 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.

[13] The ties that bind: functional clusters in limb-girdle muscular dystrophy

  • Authors: E. Barton, C. A. Pacak, Whitney L. Stoppel, P. Kang
  • Year: 2020
  • Venue: Skeletal Muscle
  • URL: https://www.semanticscholar.org/paper/653422e1a9dc9cc7f16758b10f3f203155bc68c9
  • DOI: 10.1186/s13395-020-00240-7
  • PMID: 32727611
  • PMCID: 7389686
  • Citations: 24
  • Summary: A deeper understanding of these disease pathways could yield a new generation of precision therapies that would each be expected to treat a broader range of LGMD patients than a single subtype, thus expanding the scope of the molecular medicines that may be developed for this complex array of muscular dystrophies.
  • Evidence snippets:
  • Snippet 1 (score: 0.372) > Pyridine nucleotide-disulfide reductase [55] Many of the protein functions listed require further confirmation or are disputed these methodologies. Those patients with moderate disease phenotypes regardless of the underlying causative gene mutation would likely fall into a category where there may be interest in testing a pharmacological treatment (that could be halted) but reduced interest in a more permanent experimental strategy. For all of the above-mentioned reasons, the identification of unifying therapeutic targets applicable to multiple subtypes of > LGMDs is highly desirable. > To identify such targets, we should first consider the question: What binds all of these LGMDs together? The two core phenotypic features are progressive proximal muscle weakness, along with characteristic signs of muscle fiber destruction on biopsy, referred to as "dystrophic" features. Nuances in clinical presentation have helped to distinguish some of the LGMDs, such as the frequent occurrence of difficulty walking on tiptoes in LGMD R2 (LGMD2B), caused by dysferlin deficiency. However, heterogeneity associated with variable ages of onset and ranges of severity makes it generally difficult to distinguish and diagnose LGMD subtypes based on clinical presentation alone. A change in perspective is in order to aid in understanding disease pathways responsible for clinical features even when the genetic mutation is unknown. Further, given the large number of genespecific LGMD subtypes, it could very well be that several major disease mechanisms may be shared across the family of diseases. Yet despite careful studies that have collectively determined the cellular localization of most proteins associated with LGMD (Fig. 1), there is limited knowledge of potentially unifying molecular disease mechanisms. We assert that the identification of functional clusters of these proteins, grouped by such common mechanisms, will streamline our understanding of the disease processes and identify therapeutic targets relevant to individuals in multiple disease subgroups, including individuals whose pathogenic mutations have not been found. By extension, this approach may serve as a tool to not only find common mechanisms, but may also help to distinguish LGMD subtypes that do not share similar functional patterns, and afford further refinement of potential treatments.

[14] The ties that bind: functional clusters in limb-girdle muscular dystrophy

  • Authors: E. Barton, C. A. Pacak, Whitney L. Stoppel, Peter B. Kang
  • Year: 2020
  • Venue: Skeletal Muscle
  • URL: https://www.semanticscholar.org/paper/3493c658bb8716d789a05ddf292162832e064e47
  • DOI: 10.1186/s13395-020-00240-7
  • Summary: A deeper understanding of these disease pathways could yield a new generation of precision therapies that would each be expected to treat a broader range of LGMD patients than a single subtype, thus expanding the scope of the molecular medicines that may be developed for this complex array of muscular dystrophies.
  • Evidence snippets:
  • Snippet 1 (score: 0.372) > Pyridine nucleotide-disulfide reductase [55] Many of the protein functions listed require further confirmation or are disputed these methodologies. Those patients with moderate disease phenotypes regardless of the underlying causative gene mutation would likely fall into a category where there may be interest in testing a pharmacological treatment (that could be halted) but reduced interest in a more permanent experimental strategy. For all of the above-mentioned reasons, the identification of unifying therapeutic targets applicable to multiple subtypes of > LGMDs is highly desirable. > To identify such targets, we should first consider the question: What binds all of these LGMDs together? The two core phenotypic features are progressive proximal muscle weakness, along with characteristic signs of muscle fiber destruction on biopsy, referred to as "dystrophic" features. Nuances in clinical presentation have helped to distinguish some of the LGMDs, such as the frequent occurrence of difficulty walking on tiptoes in LGMD R2 (LGMD2B), caused by dysferlin deficiency. However, heterogeneity associated with variable ages of onset and ranges of severity makes it generally difficult to distinguish and diagnose LGMD subtypes based on clinical presentation alone. A change in perspective is in order to aid in understanding disease pathways responsible for clinical features even when the genetic mutation is unknown. Further, given the large number of genespecific LGMD subtypes, it could very well be that several major disease mechanisms may be shared across the family of diseases. Yet despite careful studies that have collectively determined the cellular localization of most proteins associated with LGMD (Fig. 1), there is limited knowledge of potentially unifying molecular disease mechanisms. We assert that the identification of functional clusters of these proteins, grouped by such common mechanisms, will streamline our understanding of the disease processes and identify therapeutic targets relevant to individuals in multiple disease subgroups, including individuals whose pathogenic mutations have not been found. By extension, this approach may serve as a tool to not only find common mechanisms, but may also help to distinguish LGMD subtypes that do not share similar functional patterns, and afford further refinement of potential treatments.

[15] Molecular insights into the premature aging disease progeria

  • Authors: Sandra Vidak, R. Foisner
  • Year: 2016
  • Venue: Histochemistry and Cell Biology
  • URL: https://www.semanticscholar.org/paper/60fb3b46bb7e42d5d08cc3b7cbc783b118300c31
  • DOI: 10.1007/s00418-016-1411-1
  • PMID: 26847180
  • PMCID: 4796323
  • Citations: 105
  • Influential citations: 3
  • Summary: Changes in mechanosignaling, altered chromatin organization and impaired genome stability, and changes in signaling pathways, leading to impaired regulation of adult stem cells, defective extracellular matrix production and premature cell senescence are discussed.
  • Evidence snippets:
  • Snippet 1 (score: 0.370) > The number of molecular biological studies aiming at the identification of lamin-mediated molecular disease mechanisms involved in HGPS increased tremendously following the surprising discovery that LMNA is causally linked to the premature aging disease HGPS in 2003. Despite numerous cellular pathways that were identified to be affected by the expression of the mutant lamin A protein (Fig. 2), the mechanistic details behind these effects are still unclear in most cases. Knowledge based on what was already known on lamin biology before the protein was linked to HGPS and findings on novel roles of lamins in diverse pathways in recent years allowed the launch of translational studies and the efficient search for drug targets and therapeutic approaches within a short time period. The results of the first clinical trials taught us that some improvements of the disease phenotypes can be achieved by FTI treatment, but they also made clear that we need a much better understanding of the underlying disease mechanisms to be able to tackle specific aspects of the disease in a more focused approach. It will also be important to elucidate which of the numerous pathways found to be impaired in HGPS are most relevant for and causally involved in the pathologies, and which ones are just bystanders.

[16] Placing joint hypermobility in context: traits, disorders and syndromes

  • Authors: S. Morlino, M. Castori
  • Year: 2023
  • Venue: British Medical Bulletin
  • URL: https://www.semanticscholar.org/paper/dfc6a2564a6ebb5bf7b04e626232162747748a6b
  • DOI: 10.1093/bmb/ldad013
  • PMID: 37350130
  • PMCID: 10689077
  • Citations: 18
  • Influential citations: 1
  • Summary: In the clinical context, elucidation of the pathophysiology of pain related to JHM should develop in parallel with the analysis of pleiotropic manifestations of syndromes with JHM, and current limitations and disagreements concerning the ‘spectrum’, HSD and HEDS are discussed.
  • Evidence snippets:
  • Snippet 1 (score: 0.368) > Treating JHM-related MSK pain can be difficult because people are often referred to the 'expert' after years of evolving symptoms. Current understanding of the mechanisms which underlie JHMrelated MSK pain identifies a progression from soft tissue/joint traumas facilitated by JHM, to pain chronicity, to fluctuating disability (Fig. 3). Treatment follows an integrated, biopsychosocial approach 42 that considers pain as the summation of a multitude of intermingled mechanisms. Available strategies, such as physiotherapy, painkiller drugs and cognitive-behavioral therapy, are not always effective in the medium and long terms, and accessibility to tailored programs is not guaranteed in all healthcare systems. The availability of patient pathways emerging from the coordinated work of transnational initiatives, such as the European Reference Networks for rare and complex diseases and international foundations like the Ehlers-Danlos Society, facilitates standardization of treatment accessibility and delivery within the various healthcare systems. Similar needs are found for the syndromic patient who requests periodic follow-up for the early detection and treatment of late-onset complications related to the pleiotropic manifestations of the identified genetic mutation. > Cardiovascular and hollow organ involvement and, in particular, the risk of life-threatening events represent the most severe, though relatively rare manifestation of specific EDS subtypes. Spontaneous arterial ruptures are a major feature of vascular EDS but may occur at lower rates in other EDS clinical subtypes. 45 Preliminary genotype-phenotype correlations suggest a variable severity of cardiovascular involvement in vascular EDS according to the mutation type. 33 Much less information is available for the other EDS subtypes with a documented or presumed increased risk of vascular events. 46 Given the unpredictability of arterial and hollow organ ruptures in EDS, and the complexities generated by the tissue fragility in the emergency room, risk prediction according to patients' stratification and availability of risk reduction procedures are aims for the future. The identification of innovative drugs for treating pain and improving tissue fragility should become an emerging field of pre-clinical and clinical research in EDS and related disorders.

[17] A detailed review of pathophysiology, epidemiology, cellular and molecular pathways involved in the development and prognosis of Parkinson's disease with insights into screening models

  • Authors: Ayesha Sayyaed, Nikita Saraswat, N. Vyawahare, Ashish Kulkarni
  • Year: 2023
  • Venue: Bulletin of the National Research Centre
  • URL: https://www.semanticscholar.org/paper/d17a1728d60d692cfa41c0119128965a763a5ca2
  • DOI: 10.1186/s42269-023-01047-4
  • Citations: 26
  • Summary: This review paper discussed screening models, recent clinical trials, cellular and molecular pathways, and genetic variants (mutations) responsible for induction of Parkinson’s disease, a neurodegenerative disorder of the central nervous system that is one of the mental disorders that cause tremors, rigidity, and bradykinesia.
  • Evidence snippets:
  • Snippet 1 (score: 0.368) > Background Parkinson's disease is a neurodegenerative disorder of the central nervous system that is one of the mental disorders that cause tremors, rigidity, and bradykinesia. Many factors determine the development of disease. A comprehensive physical examination and medical history of the patient should be part of the differential diagnosis for Parkinson’s disease (PD). According to epidemiology, Parkinson’s disease majorly affects elderly persons and frequency of affecting men is more as compared to women where the worldwide burden of Parkinson’s disease (PD) increased more than twice in the past 20 years. Main body of the abstract In this review paper, we discussed screening models, recent clinical trials, cellular and molecular pathways, and genetic variants (mutations) responsible for induction of Parkinson’s disease. The paper also aims to study the pathophysiology, epidemiology, general mechanism of action, risk factors, neurotoxin models, cellular and molecular pathway, clinical trials genetic variants of Parkinson’s disease. These models correspond to our research into the pathogenesis of Parkinson’s disease. The collected data for the review have been obtained by studying the combination of research and review papers from different databases such as PubMed, Elsevier, Web of Science, Medline, Science Direct, Medica Database, Elton B. Stephens Company (EBSCO), and Google open-access publications from the years 2017–2023, using search keywords such as “Cellular and molecular pathways, Clinical trials, Genetic mutation, Genetic models, Neurotoxin, Parkinson’s disease, Pathophysiology.” Short Conclusion Microglia and astrocytes can cause neuroinflammation, which can speed the course of pathogenic damage to substantia nigra (SN). The mechanism of Parkinson’s disease (PD) that causes tremors, rigidity, and bradykinesia is a decrease in striatal dopamine. Genes prominently CYP1A2 (Cytochrome P450 A2), GRIN2A , and SNCA are Parkinson’s disease (PD) hazard factor modifiers. The most well-known neurotoxin is 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which

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

  • Authors: Megan Ball, Nicole J. Van Bergen, A. Compton, David R. Thorburn, S. Rahman et al.
  • Year: 2025
  • Venue: Journal of Inherited Metabolic Disease
  • URL: https://www.semanticscholar.org/paper/196ee50a950f29bc4134cfb8fe6bdfa9a3a1468b
  • DOI: 10.1002/jimd.70065
  • PMID: 40714961
  • PMCID: 12301291
  • Citations: 4
  • Summary: The latest developments in the pursuit to identify effective treatments for mitochondrial disease are examined and the barriers impeding their success in translation to clinical practice are discussed.
  • Evidence snippets:
  • Snippet 1 (score: 0.367) > Mitochondrial disease is a diverse group of clinically and genetically complex disorders caused by pathogenic variants in nuclear or mitochondrial DNA‐encoded genes that disrupt mitochondrial energy production or other important mitochondrial pathways. Mitochondrial disease can present with a wide spectrum of clinical features and can often be difficult to recognize. These conditions can be devastating; however, for the majority, there is no targeted treatment. In the last 60 years, mitochondrial medicine has experienced significant evolution, moving from the pre‐molecular era to the Age of Genomics in which considerable gene discovery and advancement in our understanding of the pathophysiology of mitochondrial disease have been made. In the last decade, in response to the urgent need for effective treatments, a wide range of emerging therapies have been developed, driven by innovative approaches addressing both the genetic and cellular mechanisms underpinning the diseases. Emerging therapies include dietary intervention, small molecule therapies aimed to restore mitochondrial function, stem cell or liver transplantation, and gene or RNA‐based therapies. However, despite these advances, translation to clinical practice is complicated by the sheer genetic and clinical complexity of mitochondrial disease, difficulty in efficient and precise delivery of therapies to affected tissues, rarity of individual genetic conditions, lack of reliable biomarkers and clinically relevant outcome measures, and the dearth of natural history data. This review examines the latest developments in the pursuit to identify effective treatments for mitochondrial disease and discusses the barriers impeding their success in translation to clinical practice. While treatment for mitochondrial disease may be on the horizon, many challenges must be addressed before it can become a reality.

[19] 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: 0.367) > 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].

[20] 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: 0.366) > : 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.

Notes

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