Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Aland Islands Eye Disease. Core disease mechanisms, molecular and cellular...

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

• Papers retrieved: 20
• Snippets retrieved: 20

Relevant Papers

[1] From Pathophysiology to Innovative Therapies in Eye Diseases: A Brief Overview

• Authors: Karolina Kłodnicka, Jacek Januszewski, Hanna Tyc, Aleksandra Michalska, Alicja Forma et al.
• Year: 2025
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/cb2b096af151ee69c2d0503ef830842c3bffafeb
• DOI: 10.3390/ijms26178496
• PMID: 40943417
• PMCID: 12429432
• Citations: 1
• Summary: This review focuses on age-related macular degeneration, diabetic retinopathy, glaucoma, glaucoma, and uveitis, examining high-resolution imaging techniques such as optical coherence tomography (OCT), OCT angiography, MALDI-MSI, and spatial transcriptomics.
• Evidence snippets:
• Snippet 1 (score: 0.435) > Retinal neurons, glial cells, RPE, and vascular endothelial cells are among the many cell types whose proper function determines the integrity of the eye. The eye is a highly specialized and complex sensory organ [32]. When the homeostasis of any of these compartments is disrupted, disease processes can begin or progress, resulting in blindness or visual impairment [33]. Our knowledge of eye disorders has changed dramatically over the last 20 years due to developments in molecular biology and genomics [34]. Complex networks of oxidative, inflammatory, angiogenic, and genetic processes that contribute to their pathophysiology have been uncovered by these findings [35]. In many eye diseases, especially retinal diseases, a multitude of pathological factors have been discovered at the molecular level [36]. These include abnormal angiogenesis, oxidative stress, mitochondrial dysfunction, autophagy dysregulation, and chronic inflammation [37]. These mechanisms often work together to create a self-perpetuating cycle that results in cellular deterioration and tissue destruction [38]. For example, reactive oxygen species (ROS) generated by metabolic stress can induce apoptosis in retinal cells, activate pro-inflammatory signaling pathways (including NF-κB), and damage cellular proteins and DNA [39]. Additionally, genetic predisposition is a significant factor in the onset and progression of disease, particularly in age-related macular degeneration (AMD) and hereditary retinal dystrophies [40]. Variants in some genes can change how angiogenic factors, like VEGF, are controlled, alter inflammatory responses, or impact the structural integrity of photoreceptors [41]. The molecular causes of various retinal diseases will be discussed in this chapter.

[2] 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: 0.405) > 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.

[3] 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: 0.400) > 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.

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

• Authors: Hemalatha Sasidharakurup, Shyam Diwakar
• Year: 2020
• Venue: Applied Network Science
• URL: https://www.semanticscholar.org/paper/aea95bfe3c4303f1361a8ea72828d2926ea0d03e
• DOI: 10.1007/s41109-020-00307-w
• Citations: 9
• Summary: Simulations suggest insulin may be an important factor identifying neurodegeneration in AD and PD, through its action along with the neuroinflammation and oxidative stress.
• Evidence snippets:
• Snippet 1 (score: 0.394) > Modelling complex biological pathway networks including their cellular and molecular components, and interactions (Ji et al. 2017) can help connect critical factors statistically relevant as common signaling mechanisms or phentotypic functions to both disorders. Developing computational models can aid reproducing disease pathways and predicting dynamical behaviours essential for approprite protocol design and experimental testing and to map clinical symptoms to molecular processes going through cellular and circuit functions (Conradi et al. 2007;Bartocci and Lió 2016). Using biochemical systems theory (BST), sub-cellular reactions and biochemical pathways were modeled using ordinary differential equations (ODE) for reconstructing signalling dynamics in this study (Savageau et al. 1987). All biochemical reactions involved in disease-related signalling pathways were expressed mathematically using ODE and rate equations were computed using computational tools (Bartocci and Lió 2016). > The objective of this modeling exercise was to map major genes or proteins involved in disease mechanism, the reactions affected by the mutation of these genes and the difference in reactions when compared with healthy controls, action ofpotential drugs. In literature, BST models on oxidative stress and inflammation in insulin resistance were already available for PD condition (Braatz and Coleman 2015). These models explore some of the important pathways involved in PD and the treatment options. Most of the initial conditions for the model parameters were assigned as relative values rather than real data. With the need to model crosstalk and critical networks relevant to neurodegeneration identified by more recent studies, we have incorporated the crosstalk between insulin resistance, oxidative stress and neuroinflammation related to TNFα signalling in normal, AD and PD conditions (Fallahi-Sichani et al. 2011;Sasidharakurup et al. 2020;Su and Wu 2020). The parameteric values relating to biological states and initial conditions for this model were manually extracted from literature on disease models. In a previous study, we had modelled the role of TNFα mediated glutamate excitotoxicity and neuroinflammation (Sasidharakurup et al. 2020) and the variations in TNFα levels during both healthy and diseased conditions were analyzed.

[5] Advances in ocular aging: combining deep learning, imaging, and liquid biopsy biomarkers

• Authors: De-bao Zhang, Naiyang Li, Fan Li
• Year: 2025
• Venue: Frontiers in Medicine
• URL: https://www.semanticscholar.org/paper/57d8f72f0b5a07267654004074ca36f3461c8f4b
• DOI: 10.3389/fmed.2025.1591936
• PMID: 40771477
• PMCID: 12325013
• Citations: 3
• Summary: This review highlights how integrating deep learning with advanced imaging and liquid biopsy biomarkers has become a transformative approach to understanding ocular ageing and its implications for systemic health.
• Evidence snippets:
• Snippet 1 (score: 0.390) > Ocular aging at the molecular level is a complex process involving dynamic changes in various cellular and molecular pathways. Recent advancements in liquid biopsy techniques, combined with proteomics, have provided unprecedented insights into the molecular mechanisms underlying eye aging. By analyzing biomarkers in ocular fluids such as aqueous humor or vitreous humor, researchers can now identify specific proteins and cellular signatures associated with normal aging and age-related ocular diseases. This integration of liquid biopsy biomarkers with proteomics not only enhances our understanding of the molecular trajectory of ocular aging but also offers potential for early detection, diagnosis, and personalized treatment strategies for agerelated ocular conditions (51). > The relevant study has found that telomere shortening and declining NAD + levels are key molecular mechanisms of aging as we age. Telomere dysfunction activates the DNA damage response, leading to cell cycle arrest, apoptosis, and aging, which in turn leads to chronic inflammation and age-related diseases. In addition, the decrease in NAD + levels can affect cellular energy metabolism and accelerate the aging process. In the field of ophthalmology, the combination of liquid biopsy and proteomics provides new tools for early detection and intervention of age-related eye diseases. By detecting biomarkers in intraocular fluid, apoptosis of retinal ganglion cells, changes in retinal vascular density, and decreased optic nerve function can be identified earlier. Changes at these molecular levels may occur before clinical symptoms appear, so early intervention is essential to slow disease progression (52).

[6] Recent Advancements in Gene Therapy for Hereditary Retinal Dystrophies

• Authors: A. Öner
• Year: 2017
• Venue: Turkish Journal of Ophthalmology
• URL: https://www.semanticscholar.org/paper/406a0b7b7d2be5cb1b9cfd23f8746a9eb099128a
• DOI: 10.4274/tjo.41017
• PMID: 29326851
• PMCID: 5758769
• Citations: 17
• Influential citations: 1
• Summary: The results from the first clinical trials for a congenital form of blindness have generated great interest and have demonstrated the safety and efficacy of intraocular administrations of viral vectors in humans.
• Evidence snippets:
• Snippet 1 (score: 0.390) > Hereditary retinal dystrophies (HRDs) are degenerative diseases of the retina which have marked clinical and genetic heterogeneity. Common presentations among these disorders include night or colour blindness, tunnel vision, and subsequent progression to complete blindness. The known causative disease genes have a variety of developmental and functional roles, with mutations in more than 120 genes shown to be responsible for the phenotypes. In addition, mutations within the same gene have been shown to cause different disease phenotypes, even amongst affected individuals within the same family, highlighting further levels of complexity. The known disease genes encode proteins involved in retinal cellular structures, phototransduction, the visual cycle, and photoreceptor structure or gene regulation. Significant advancements have been made in understanding the genetic pathogenesis of ocular diseases, and gene replacement and gene silencing have been proposed as potentially efficacious therapies. Because of its favorable anatomical and immunological characteristics, the eye has been at the forefront of translational gene therapy. Recent improvements have been made in the safety and specificity of vector-based ocular gene transfer methods. Dozens of promising proofs of concept have been obtained in animal models of HRDs and some of them have been relayed to the clinic. The results from the first clinical trials for a congenital form of blindness have generated great interest and have demonstrated the safety and efficacy of intraocular administrations of viral vectors in humans. This review summarizes the clinical development of retinal gene therapy.

[7] Recent advances and prospects of nanoparticle-based drug delivery for diabetic ocular complications

• Authors: Siqi Wang, Hongyu Yang, Jiaying Zheng, Aiyang Tong, Sen Mu et al.
• Year: 2025
• Venue: Theranostics
• URL: https://www.semanticscholar.org/paper/163a5e270633cb64dc21b5f88a0122037d30841a
• DOI: 10.7150/thno.108691
• PMID: 40093887
• PMCID: 11905120
• Citations: 12
• Influential citations: 1
• Summary: This review highlights several common ocular complications associated with DM, focusing on their pathogenesis and treatment strategies, and emphasis is placed on the innovative applications and potential of nanotechnology in treating diabetic ocular complications.
• Evidence snippets:
• Snippet 1 (score: 0.389) > The eye is a vital organ in the human body. Diabetic eye complications primarily result from chronic hyperglycemia, which affects multiple ocular structures and contributes significantly to various eye diseases [1]. The increasing prevalence of diabetes mellitus (DM) has led to a rise in the incidence of ocular complications. Prominent among these complications are diabetic keratopathy, diabetic retinopathy (DR), cataracts, and glaucoma. These ocular manifestations cause considerable physical discomfort for affected individuals and impose a substantial economic burden on patients and healthcare systems (Figure 1). > Following extensive research over the years, significant progress has been made in understanding the pathogenesis of diabetic ocular diseases; however, the mechanisms underlying diabetic dry eye and other ocular lesions remain incompletely understood, which hampers the development of effective clinical treatment strategies. Several common pathogenic mechanisms of hyperglycemia have been proposed, such as increased polyol pathway flux, overactivation of the hexosamine pathway, accumulation of intracellular advanced glycation end products (AGEs), activation of the protein kinase C (PKC) pathway, inflammatory responses, and oxidative stress [2,3]. These mechanisms are summarized below. Since the proposal of a unified mechanism for diabetic complications, growing evidence indicates that reactive oxygen species (ROS) activate multiple signaling pathways, with oxidative stress induced by ROS being a key pathogenic factor in DM and its complications [4] (Figure 2). > The most commonly employed treatment approaches can be categorized into three types [5,6]: > (1) Topical administration, primarily for anterior segment diseases; (2) Intraocular administration, which provides superior efficacy compared to topical Ivyspring International Publisher treatments; and (3) Oral administration, notable for its high patient compliance. These traditional drug delivery systems are cost-effective, convenient, and generally safe. However, the eye's complex physiological barriers and anatomical structures hinder the entry and penetration of drugs into intraocular tissues, often resulting in suboptimal therapeutic outcomes for ocular drug delivery. Tear turnover, blinking, and nasolacrimal drainage rapidly eliminate many topical eye drops [7].

[8] 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: 0.388) > 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.

[9] Thyroid Eye Disease

• Authors: R. Rashad, Raquel Pinto, Emily Li, M. Sohrab, A. Distefano
• Year: 2022
• Venue: Life
• URL: https://www.semanticscholar.org/paper/15e5541072c3fb7e12d6d927454ea6b796c3a1a8
• DOI: 10.3390/life12122084
• PMID: 36556449
• PMCID: 9787503
• Citations: 24
• Influential citations: 2
• Summary: Thyroid eye disease (TED), an autoimmune inflammatory disorder of the orbit, presents with a potential array of clinical sequelae and diagnosis and evaluation include careful physical examination, targeted laboratory work up, appropriate imaging studies, and tailored treatment regimens.
• Evidence snippets:
• Snippet 1 (score: 0.387) > Thyroid eye disease (TED) is an inflammatory disease of orbital tissue characterized by infiltration of lymphocytic cells, orbital fat expansion, and extraocular muscle swelling [1].The gravity of thyroid eye disease lies in its sight-threatening, debilitating, and disfiguring potential.Despite extensive ongoing research about TED, the disorder remains elusive in its exact pathophysiology, prevention, and ideal treatment.The following discussion will present an evidence-based overview of what is currently known and clinically relevant to facilitate appropriate understanding, recognition, work up, monitoring, and management of TED.Clinicians can use this up-to-date and comprehensive review to guide treatment of patients with thyroid eye disease.Additionally, this discussion sheds light on recent advances in our understanding and treatment of the disease, a highly dynamic landscape with several ongoing promising clinical trials.As thyroid eye disease can profoundly affect quality of life, such a review is especially helpful and imperative for providing clinicians and patients with the most comprehensive and up-to-date care.

[10] A systems biology approach uncovers novel disease mechanisms in age-related macular degeneration

• Authors: Luz D. Orozco, Leah A. Owen, Jeffrey W. Hofmann, A. Stockwell, Jianhua Tao et al.
• Year: 2023
• Venue: Cell Genomics
• URL: https://www.semanticscholar.org/paper/71e90acd3f74f2163e658d934e4e35f993725a47
• DOI: 10.1016/j.xgen.2023.100302
• PMID: 37388919
• PMCID: 10300496
• Citations: 40
• Influential citations: 2
• Summary: A molecular atlas at different stages of age-related macular degeneration uncovered molecular mechanisms underlying AMD, including regulators of WNT signaling, FRZB and TLE2, as mechanistic players in disease.
• Evidence snippets:
• Snippet 1 (score: 0.382) > Deciphering mechanisms driving AMD onset and progression has been a major challenge. The diversity of risk factors and their interactions, the heterogeneous disease presentation and progression, and the lack of appropriate in vivo and in vitro models are obstacles to translational research in multifactorial ophthalmic diseases. For AMD, the nature of the disease and the inaccessibility of the affected tissues compounds these barriers to molecular characterization. The macula is a uniquely primate, intricate structure <6 mm in diameter. AMD phenotypes such as drusen and GA lesions are confined to this region and are only found in humans. To date, animal models do not recapitulate the full spectrum of phenotypes observed in the human condition. Furthermore, the patchiness of AMD lesions results in spatial variability of cellular dysfunction within the macula. Last but not least, the retina and RPE/choroid quickly undergo degradation postmortem, posing a logistical challenge for human sample banking. > To overcome these obstacles, here we used a multifaceted approach to investigate the epigenetic and transcriptional mechanisms underlying AMD. To address the issue of disease heterogeneity, tissues used for bulk analyses were carefully chosen from a collection of phenotyped human ocular tissue, where the controls showed little or no signs of drusen, and the disease tissues were delineated by clinical staging criteria. This is important, as we observed that at least 30% of presumed ''normal'' donors >60 years of age showed disease pathophysiology. 2 Lack of well-characterized phenotypes can introduce artifacts in downstream molecular experiments. The attention to postmortem interval (PMI) time, in tandem with rigorous phenotyping and dissecting procedures, is critical for data quality. As we and others have demonstrated, transcriptomic and epigenetic changes can be a reflection of long PMI rather than of underlying disease mechanisms. 2,49 To better understand the cellular complexity in AMD eyes, we employed single-cell genomics to complement and validate our bulk-tissue approach; our single-cell approach provides cell type information, and our bulk tissue provides a more complete molecular landscape. While many single-cell genomics studies of the human eye are publicly available, these

[11] 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: 0.382) > 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.

[12] 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: 0.381) > 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.

[13] 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: 0.378) > 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.

[14] 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: 0.375) > 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.

[15] Serum metabolite biomarkers for the early diagnosis and monitoring of age-related macular degeneration

• Authors: Shengjie Li, Yichao Qiu, Yingzhu Li, Jianing Wu, Ning Yin et al.
• Year: 2024
• Venue: Journal of Advanced Research
• URL: https://www.semanticscholar.org/paper/865fc67403e8dbb8a9c5b9efdeaef01dd3b5d7f8
• DOI: 10.1016/j.jare.2024.10.001
• PMID: 39369956
• PMCID: 12302346
• Citations: 10
• Summary: It is suggested that relevant blood biomarkers can be identified noninvasively, allowing patients with AMD to receive precision medicine.
• Evidence snippets:
• Snippet 1 (score: 0.375) > In addition to imaging and genetic markers, promising bloodbased biomarkers for early AMD detection have been proposed, particularly given the roles of systemic chronic inflammation, lipid accumulation, oxidative stress, and compromised extracellular matrix maintenance in AMD pathophysiology [1]. Proteomics [14,15] and metabolomics [16,17] provide intriguing opportunities for identifying specific protein and metabolite markers for AMD diagnosis. Despite their potential, these biomarkers have not yet been integrated into clinical practice for AMD screening, treatment guidance, or outcome determination. This gap stems from limitations in previous research, such as insufficient sample sizes, limited validation cohorts, poor control of disease variables, and nonspecific analyses. > Metabolomics offers a precise and detailed representation of biological phenotypes, providing distinct advantages over genomics and proteomics in certain contexts [18][19][20]. Additionally, some small metabolites, unlike larger macromolecules, can cross the blood-retina barrier and become detectable [21]. Considering that conditions such as systemic chronic inflammation, lipid accumulation, and oxidative stress trigger significant changes in metabolic pathways [22], blood has become recognized as a vital repository of human cellular components, underscoring its importance in clinical and biomedical research [23,24]. Therefore, metabolomics has emerged as a promising approach for identifying unique metabolite biomarkers for AMD diagnosis, distinguishing it from proteomic methods. > In this study, a multiphase, multicenter cohort approach was used to profile blood metabolites in AMD patients, controls with other eye diseases, and healthy controls via widely targeted metabolomics. This study aimed to identify metabolic signatures relevant to AMD, discover novel diagnostic biomarkers, and assess their specificity in AMD detection. Given that a single biomarker may not offer sufficient reliability, a panel of robust metabolite biomarkers was sought to increase diagnostic specificity and elucidate the underlying disease mechanisms.

[16] Inflammatory profiling and immune cell infiltration in dysthyroid optic neuropathy: insights from bulk RNA sequencing

• Authors: Qintao Ma, Yuanping Hai, Yongbo Duan, G-Q Yu, C. Song et al.
• Year: 2025
• Venue: Frontiers in Immunology
• URL: https://www.semanticscholar.org/paper/7a57f5efe0846133a8eda7ad3ba1c2a16ed16b6b
• DOI: 10.3389/fimmu.2025.1550694
• PMID: 40160813
• PMCID: 11951427
• Citations: 2
• Summary: This is the first study to identify the key molecular and immune drivers of DON through bulk transcriptomic analysis, emphasizing the central role of inflammation-related molecules and immune cell infiltration in its pathogenesis.
• Evidence snippets:
• Snippet 1 (score: 0.375) > Thyroid eye disease (TED) is a significant autoimmune condition observed in 25-30% of individuals with Graves' disease. This condition presents with a range of symptoms, including proptosis, tearing, photophobia, lid retraction, and diplopia (1,2). Among its complications, dysthyroid optic neuropathy (DON) is particularly concerning due to its potential to cause severe and rapid vision impairment. Approximately 4-8% of TED patients experience progression to DON, a condition that can drastically impact quality of life (3,4). However, the diagnostic criteria for DON are largely reliant on clinical signs and symptoms, lacking both sensitivity and specificity. Consequently, most patients recognize the risk only after substantial vision loss has already occurred (5). Current treatment options for DON remain limited, primarily involving high-dose glucocorticoids or orbital decompression. > Despite the pathogenesis of DON remains unclear, the prevailing hypothesis suggests direct compression of the optic nerve by enlarged extraocular muscles (EOMs) at the orbital apex-a mechanism supported by the European Group on Graves' Orbitopathy (EUGOGO), which found radiological evidence of apical optic nerve compression in 49 out of 56 DON-affected eyes (3). However, the contribution of immune-mediated mechanisms and inflammatory responses to DON pathogenesis has not been fully elucidated. Other contributing factors may include optic nerve stretching from proptosis, increased retrobulbar pressure, inflammation, and altered orbital blood flow, which together could exacerbate optic nerve injury and accelerate visual decline (6,7). > The core pathogenesis of DON is closely associated with the pathological mechanisms of TED. TED is primarily driven by the aberrant activation and proliferation of orbital fibroblasts, a process influenced by multiple factors. Among the numerous molecular pathways implicated in orbital fibroblast activation, immune and inflammatory dysregulation is recognized as a key driving force, playing a crucial role in both TED progression and the pathogenesis of DON (8,9). Patients with DON almost always present during the active phase of the disease, characterized by varying degrees of immune cell infiltration within the orbit, including T cells, B cells, monocytes, and mast cells (10,11).

[17] Differential metabolic markers associated with primary open-angle glaucoma and cataract in human aqueous humor

• Authors: C. Pan, Chaofu Ke, Qin Chen, Yijin Tao, Xu Zha et al.
• Year: 2020
• Venue: BMC Ophthalmology
• URL: https://www.semanticscholar.org/paper/a22a466f72ee8f8a5808f51c7000ff38b8b60b04
• DOI: 10.1186/s12886-020-01452-7
• PMID: 32375707
• PMCID: 7203853
• Citations: 26
• Influential citations: 1
• Summary: This study identified valuable metabolic biomarkers and pathways that may facilitate an improved understanding of the POAG pathogenesis and hold translational value in the development of new therapeutic measures for POAG.
• Evidence snippets:
• Snippet 1 (score: 0.374) > Primary open-angle glaucoma (POAG) is the most common subtype of glaucoma and the major cause of irreversible blindness throughout the world [1]. Although numerous studies have identified several important ocular risk factors for POAG such as increased intraocular pressure (IOP) [2,3], myopic refractive errors [4], larger optic disc size [5,6] and thinner central corneal thickness [7,8], these findings are limited in understanding the pathophysiology of POAG. Further knowledge regarding the pathophysiology might help to create new drug development research lines and expand current therapeutic targets for POAG. In current clinical practice, the treatment strategy of POAG mainly relies on IOP-lowering medications or surgeries. Although increased IOP is widely accepted to be the primary predictor for POAG, glaucomatous neuropathy is still observed in some patients with normal or even lower-than-normal IOPs, suggesting that other mechanisms exist in the pathophysiology of POAG. > Metabolomics is a widely used technology to assess biomarkers for diseases and provide molecular information regarding disease phenotype since metabolites are the ultimate product of gene, mRNA and protein activities [9]. Variations in the metabolome represent the interplay of genetic and environmental factors and are in relation to disease states, which may shed some lights in mechanism and pathophysiology of the disease [10]. With regard to eye diseases, metabolomics has been successfully used in identifying the metabolic signatures of diabetic retinopathy [11]. However, there were less studies focusing on POAG, especially in human participants. A previous analysis comparing plasma metabolic signatures as measured by mass spectrometry observed significant differences in some specific metabolic processes such as palmitoylcarnitine, sphingolipids, vitamin Drelated compounds, and steroid precursors between POAG patients and healthy controls [12]. These differences observed in metabolome might be linked to mitochondrial dysfunction and energy metabolism changes [12].

[18] Novel Approaches to Studying SLC13A5 Disease

• Authors: Adriana S. Beltran
• Year: 2024
• Venue: Metabolites
• URL: https://www.semanticscholar.org/paper/8469c534cd81d96f84b61e2d963dead12088feb7
• DOI: 10.3390/metabo14020084
• PMID: 38392976
• PMCID: 10890222
• Citations: 2
• Summary: Current technologies for generating patient-specific induced pluripotent stem cells (iPSCs) and their inherent advantages and limitations are discussed, followed by a summary of the methods for differentiating iPSCs into neurons, hepatocytes, and organoids.
• Evidence snippets:
• Snippet 1 (score: 0.372) > The precise pathophysiology underlying how SLC13A5 loss-of-function results in epilepsy refractory to treatment is a subject of open and ongoing research. Several hypotheses suggest SLC13A5 alters metabolic pathways, leading to neuronal dysfunction. Conversely, therapeutic inhibition of NaCT in the liver is a target to improve metabolic diseases, including non-alcoholic fatty liver disease, obesity, and insulin resistance. Thus, functionally accurate modeling and characterization of the mechanisms involved in citrate transport disruption are critical for understanding its role in human disease. > IPSC-derived cellular systems are a powerful tool for modeling rare human genetic diseases, such as SLC13A5 (Figure 5). IPSCs derived from patients containing the genetic information of the disease can overcome the limitations of animal models, providing access to relevant human cell types that recapitulate the disease phenotype. For instance, patient-derived iPSCs differentiated into neurons or hepatocytes can be used to investigate molecular and cellular mechanisms, including citrate transport and accumulation, energy metabolism, oxidative stress, and other cellular processes. They can also be used to define the spectrum of the disease and how different mutations might lead to various disease severities, screen for potential therapeutic compounds that can restore the transporter function or ameliorate the symptoms, and enable personalized medicine approaches that can tailor treatments to individual patients based on their genetic background and disease severity. > transport disruption are critical for understanding its role in human disease. > IPSC-derived cellular systems are a powerful tool for modeling rare human genetic diseases, such as SLC13A5 (Figure 5). IPSCs derived from patients containing the genetic information of the disease can overcome the limitations of animal models, providing access to relevant human cell types that recapitulate the disease phenotype. For instance, patient-derived iPSCs differentiated into neurons or hepatocytes can be used to investigate molecular and cellular mechanisms, including citrate transport and accumulation, energy metabolism, oxidative stress, and other cellular processes.

[19] Metabolomic analysis in ophthalmology.

• Authors: N. Nazifova-Tasinova, M. Radeva, B. Galunska, C. Grupcheva
• Year: 2020
• Venue: Biomedical papers of the Medical Faculty of the University Palacky, Olomouc, Czechoslovakia
• URL: https://www.semanticscholar.org/paper/5b76270f66d939fb483bcae3e1d29b3247430bfb
• DOI: 10.5507/bp.2020.028
• PMID: 32690974
• Citations: 16
• Influential citations: 1
• Summary: The current review highlights the major aspects of metabolomic analysis and its applications for the identification of relevant predictive, diagnostic and prognostic biomarkers for some ocular diseases including dry eye, keratoconus, retinal diseases, macular degeneration, and glaucoma.
• Evidence snippets:
• Snippet 1 (score: 0.371) > Modern science takes into account phenotype complexity and establishes approaches to track changes on every possible level. Many "omics" studies have been developed over the last decade. Metabolomic analysis enables dynamic measurement of the metabolic response of a living system to a variety of stimuli or genetic modifications. Important targets of metabolomics is biomarker development and translation to the clinic for personalized diagnosis and a greater understanding of disease pathogenesis. The current review highlights the major aspects of metabolomic analysis and its applications for the identification of relevant predictive, diagnostic and prognostic biomarkers for some ocular diseases including dry eye, keratoconus, retinal diseases, macular degeneration, and glaucoma. A Medline search of recent studies was made on metabolomic analysis for identification of biomarkers in ocular diseases, using keywords such as "biomarkers, "metabolomics", "ocular diseases", "macular degeneration", "dry eye", "keratoconus", "retinal diseases", inflammatory eye diseases", "glaucoma", and "diabetic retinopathy". To date, possible biomarker candidates for dry eye disease are lipid metabolites and androgens, for keratoconus cytokeratins, urea, citrate cycle, and oxidative stress metabolites. Palmitoylcarnitine, sphingolipids, vitamin D related metabolites, and steroid precursors may be used for distinguishing glaucoma patients from healthy controls. Dysregulation of amino acid and carnitine metabolism is critical in the development and progression of diabetic retinopathy. Further work is needed to discover and validate metabolic biomarkers as a powerful tool for understanding the molecular mechanisms of ocular diseases, to provide knowledge on their etiology and pathophysiology and opportunities for personalized clinical intervention at an early stage.

[20] Cerebral Small Vessel Disease (CSVD) – Lessons From the Animal Models

• Authors: M. Mustapha, Che Mohd Nasril Che Mohd Nassir, Niferiti Aminuddin, Amanina Ahmad Safri, M. Ghazali
• Year: 2019
• Venue: Frontiers in Physiology
• URL: https://www.semanticscholar.org/paper/e915013042141859a6afaed4430fe0abe000b060
• DOI: 10.3389/fphys.2019.01317
• PMID: 31708793
• PMCID: 6822570
• Citations: 73
• Influential citations: 2
• Summary: This chapter consolidates the contemporary insights from numerous experimental animal models of CSVD, to date: from the available experimentalAnimal models ofCSVD and its translational research value; the pathomechanical aspects of the disease; relevant aspects on systems biology; opportunities for early disease biomarkers; and finally, converging approaches for future therapeutic directions of CSV.
• Evidence snippets:
• Snippet 1 (score: 0.367) > Genetics might play a crucial role in elucidating the cellular and molecular mechanisms of CSVD, and thus the pathophysiology of its hereditary forms. CADASIL, CARASIL, and several other forms of CSVD have been discussed with regard to the genetic factors and their pathways. Therefore, cellular, molecular, and biochemical changes underlying CSVD can easily be assessed using animal models of these rare single-gene disorders. Increasing the number and variety of transgenic, induced mutants and naturally occurring animal models of genetic disease are vital to identifying new genes that are the root cause of the disease; then, allow better understanding of the cellular and molecular mechanisms of genetic diseases and elucidating the genes involved in such diseases with complex inheritance patterns. > Besides that, CADASIL is a neurological syndrome characterized by CSVD, stroke, and vascular cognitive impairment and dementia caused by mutations in the NOTCH3 gene (Joutel et al., 1996). A previous study showed that NOTCH3 signaling is linked to vSMC coverage in retinal vessels and demonstrated that restoring NOTCH3 signaling via genetic rescue and using a NOTCH3 agonist antibody (A13) prevents the CSVD phenotype in both mouse models of CADASIL and NOTCH3 knockout mice (Machuca-Parra et al., 2017). To date, four mutant mouse models express common CADASIL mutations: R90C, R169C, C428S, and R142C have been developed and studied in detail (Joutel et al., 1997). These models differ in their transgenic strategy and expression levels, endogenous NOTCH3 expression, and the predicted effects of mutations on Notch function. Overall, from the mutant mouse models, data suggest that one or all these mechanisms may contribute to or modulate the phenotype, possibly explaining some of the clinical heterogeneity in CADASIL (Ayata, 2010).

Notes

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