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

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

• Papers retrieved: 20
• Snippets retrieved: 20

Relevant Papers

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

• Authors: Hao Xiong, Jinsheng Guo
• Year: 2025
• Venue: Pharmaceuticals
• URL: https://www.semanticscholar.org/paper/76e92127053136900f7e3f10e2c9278251ced5d2
• DOI: 10.3390/ph18040507
• PMID: 40283943
• PMCID: 12030350
• Citations: 8
• Summary: HSC-targeted approaches using specific surface markers and receptors may enable the selective delivery of drugs, oligonucleotides, and therapeutic peptides that exert optimized anti-fibrotic and anti-HCC effects.
• Evidence snippets:
• Snippet 1 (score: 0.400) > 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.

[2] Early disease progression of Hurler syndrome

• Authors: B. Kiely, J. L. Kohler, H. Coletti, M. Poe, M. Escolar
• Year: 2017
• Venue: Orphanet Journal of Rare Diseases
• URL: https://www.semanticscholar.org/paper/a895995e4e765d9edf8bb31d016a93075f63c958
• DOI: 10.1186/s13023-017-0583-7
• PMID: 28193245
• PMCID: 5307824
• Citations: 73
• Influential citations: 4
• Summary: The aim of this study was to characterize the progression and timing of symptom onset in infants with Hurler syndrome and to determine the extent to which early clinical manifestations of MPS I can predict phenotype and treatment outcomes.
• Evidence snippets:
• Snippet 1 (score: 0.390) > BackgroundNewborn screening for mucopolysaccharidosis type I (MPS I) shows promise to improve outcomes by facilitating early diagnosis and treatment. However, diagnostic tests for MPS I are of limited value in predicting whether a child will develop severe central nervous system disease associated with Hurler syndrome, or minimal or no central nervous system involvement associated with the attenuated phenotypes (Hurler–Scheie and Scheie syndromes). Given that the optimal treatment differs between Hurler syndrome and the attenuated MPS I phenotypes, the absence of a reliable prognostic biomarker complicates clinical decision making for infants diagnosed through newborn screening. Information about the natural history of Hurler syndrome may aid in the management of affected infants, contribute to treatment decisions, and facilitate evaluation of treatment effectiveness and prognosis. Thus, the aim of this study was to characterize the progression and timing of symptom onset in infants with Hurler syndrome.ResultsClinical data from 55 patients evaluated at a single center were retrospectively reviewed. Information about each child’s medical history was obtained following a standardized protocol including a thorough parent interview and the review of previous medical records. All patients underwent systematic physical and neurodevelopmental evaluations by a multidisciplinary team. Nearly all patients (98%) showed signs of disease during the first 6 months of life. Common early disease manifestations included failed newborn hearing screen, respiratory symptoms, difficulty latching, and otitis media. Other symptoms such as kyphosis, corneal clouding, cardiac disease, joint restrictions, and enlarged head circumference typically appeared slightly later (median age, 8–10 months). During the first 12 months, gross motor development was the most severely affected area of functioning, and a significant number of patients also experienced language delays. Cognition was typically preserved during this period.ConclusionsIn this large cohort of patients with Hurler syndrome, the vast majority showed signs and symptoms of disease during the first months of life. More research is needed to determine the extent to which early clinical manifestations of MPS I can predict phenotype and treatment outcomes.

[3] 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: 0.388) > 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.

[4] Musculoskeletal manifestations in mucopolysaccharidosis type I (Hurler syndrome) following hematopoietic stem cell transplantation

• Authors: M. Schmidt, S. Breyer, U. Löbel, S. Yarar, R. Stücker et al.
• Year: 2016
• Venue: Orphanet Journal of Rare Diseases
• URL: https://www.semanticscholar.org/paper/0b2cdfb987e8047fca22d990fa1a1d468a32028c
• DOI: 10.1186/s13023-016-0470-7
• PMID: 27392569
• PMCID: 4938899
• Citations: 55
• Influential citations: 2
• Summary: Joint mobility, odontoid hypoplasia and craniocervical stenosis might stabilize or even improve in Hurler patients following HSCT, however, skeletal complications are frequently observed and the overall burden of orthopedic disease is significant.
• Evidence snippets:
• Snippet 1 (score: 0.385) > Mucopolysaccharidosis (MPS) type I is an autosomal recessive inherited metabolic disorder caused by a deficiency of lysosomal α-iduronidase (IDUA, EC 3.2.1.76). Consequently, the glycosaminoglycans (GAGs) heparanand dermatan-sulfate accumulate within the lysosomes causing cellular dysfunction [1,2]. The incidence of MPS I in Germany has been estimated as 0.69 cases per 100,000 births [3]. Clinical severity and progression of the disease vary significantly in affected patients. Based on the clinical appearance three different subtypes of MPS I are classified: the classical severe phenotype referred to as Hurler syndrome (MPS I-H), the less severe Hurler-Scheie syndrome (MPS I-H/S) and the attenuated form -Scheie syndrome (MPS I-S) [1,2,4]. Clinical symptoms of Hurler syndrome include the characteristically coarse facial features, corneal clouding, hearing impairment, cardiac involvement, obstructive and restrictive pulmonary disease and hepatosplenomegaly. With increasing age patients also show progressive neurological decline. Musculoskeletal involvement is common in all subtypes of MPS I. Skeletal abnormalities include: a short stature, degenerative joint disease and a skeletal dysplasia referred to as dysostosis multiplex [5,6]. > The pathophysiology of the bone disease is still not well understood. Disordered growth plate chondrocyte organization and trabecular architecture were observed in several animal models of different MPS subtypes [7]. As shown in studies in MPS I mice, accumulation of GAGs could lead to inactivation of the major osteoclastic protease cathepsin K, which in turn may result in reduction in cartilage degradation and contribute to the bone pathology observed in MPS [8]. The progressive arthropathy is assumed to be mediated by GAG accumulation, resulting in increased cytokine and chemokine recruitment (e.g.

[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: 0.382) > 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] New therapeutic targets in rare genetic skeletal diseases

• Authors: M. Briggs, Peter A. Bell, M. Wright, K. A. Pirog
• Year: 2015
• Venue: Expert Opinion on Orphan Drugs
• URL: https://www.semanticscholar.org/paper/1363107f71ae6d2d60abca471cddf3da5d13644b
• DOI: 10.1517/21678707.2015.1083853
• PMID: 26635999
• PMCID: 4643203
• Citations: 37
• Influential citations: 1
• Summary: An overview of disease mechanisms that are shared amongst groups of different GSDs and potential therapeutic approaches that are under investigation are described to generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.
• Evidence snippets:
• Snippet 1 (score: 0.381) > 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.

[7] 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: 2
• 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: 0.379) > 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.

[8] Building a knowledge graph to enable precision medicine

• Authors: P. Chandak, Kexin Huang, M. Zitnik
• Year: 2022
• Venue: Scientific Data
• URL: https://www.semanticscholar.org/paper/5cc58bcfb9bf39d4114eab88fca36eb0ce36afd9
• DOI: 10.1038/s41597-023-01960-3
• PMID: 36732524
• PMCID: 9893183
• Citations: 476
• Influential citations: 36
• Summary: PrimeKG is presented, a multimodal knowledge graph for precision medicine analyses that contains an abundance of ‘indications’, ‘contradictions’, and ‘off-label use’ drug-disease edges that lack in other knowledge graphs and can support AI analyses of how drugs affect disease-associated networks.
• Evidence snippets:
• Snippet 1 (score: 0.379) > gene/protein class. (c) Illustrated is the process of harmonizing these primary data records to extract relationships between node types. (d) The left side illustrates PrimeKG, and the right side shows all the textual sources of clinical information on drugs and diseases. The node type legend is consistent across the figure. Abbreviations -MF: molecular function, BP: biological process, CC: cellular component, PPI: protein-protein interactions, DO: disease ontology, MONDO: MONDO disease ontology, Entrez: Entrez gene, GO: gene ontology, UMLS: unified medical language system, HPO: human phenotype ontology, CTD: comparative toxicogenomics database, SIDER: side effect resource. > www.nature.com/scientificdata www.nature.com/scientificdata/ International Classification of Diseases (ICD), and Medical Dictionary for Regulatory Activities (MedDRA), it was our preferred ontology for defining diseases. We retrieved the ontology from http://purl.obolibrary.org/ obo/MONDO.obo on 31 May 2021. Processing involved parsing the ontology file to extract disease terms in the ontology, parent-child relationships, subsets of diseases, cross references to other ontologies, and definitions of disease terms. The processed data contains 64,388 disease-disease edges. > Orphanet. Orphanet 48 is a database that focuses on gathering knowledge about rare diseases. The Orphanet resource at https://www.orpha.net/consor/cgi-bin/Disease_Search_List.php?lng=EN has curated information about definitions, prevalence, management and treatment, epidemiology, and clinical description for 9,348 rare diseases. We retrieved the resource data and extracted disease features on 10 May 2021 using the orpha.py script available in the PrimeKG repository. > Let us illustrate features in PrimeKG for rare Hurler syndrome with the Orphanet ID 93473. Hurler syndrome is the most severe form of mucopolysaccharidosis type 1, a rare lysosomal storage disease characterized by skeletal abnormalities, cognitive impairment, heart disease, Four sources of physical protein-protein interactions. Protein-protein interactions (PP

[9] Human Dermal Fibroblast: A Promising Cellular Model to Study Biological Mechanisms of Major Depression and Antidepressant Drug Response

• Authors: P. Mesdom, R. Colle, É. Lebigot, S. Trabado, Eric Deflesselle et al.
• Year: 2020
• Venue: Current Neuropharmacology
• URL: https://www.semanticscholar.org/paper/79368e365458486de96794333613c12a6063bf54
• DOI: 10.2174/1570159X17666191021141057
• PMID: 31631822
• PMCID: 7327943
• Citations: 12
• Summary: This review highlights the great and still underused potential of HDF, which stands out as a very promising tool in the understanding of MDD and AD mechanisms of action.
• Evidence snippets:
• Snippet 1 (score: 0.366) > 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

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

• Authors: Giovanni Colonna
• Year: 2024
• Venue: Livers
• URL: https://www.semanticscholar.org/paper/2f31a9d4b1e7e8e8c18f5b714e724960c624f61d
• DOI: 10.3390/livers5010001
• Summary: The interactome tells us that genes involved in HCC and HVB-related pathways have the potential to activate disease processes and can be considered as a gold standard for personalized molecular medicine diagnoses.
• Evidence snippets:
• Snippet 1 (score: 0.365) > The interactions we studied derive from controlled in vivo studies in different cellular models without direct links to specific clinical phenotypes. Model cell systems mimic an organism but are not the organism [93][94][95][96]. This reinforces the idea that molecular interactions potentially reflect mechanistic processes rather than direct clinical outcomes. The multi-to-one or multi-multi correlations between molecular mechanisms and phenotypic expressions further complicate the assumption that molecular evidence can directly explain macroscopic disease processes like the progression from hepatitis to HCC. > In short, the SARS-CoV-2 S1 protein may induce microscopic conditions that develop differently based on individual phenotypic states, which is in line with the complexity of viral pathogenesis. This reflects the non-deterministic nature of interactome data-capturing potentialities rather than predicting phenotypic outcomes. We propose an approach to interpreting molecular data that avoids overgeneralization in linking it to clinical disease progression. We could use our molecular results as a gold standard against molecular data from specific patients to identify whether the metabolic system of the infected patient is implementing the mechanisms driving the progression of HBV infection. These processes should not be present in a healthy person. However, they could also be a clinically useful signal of the level of severity reached by the viral infection in a patient with previous morbidity. > We can now discuss in more detail some aspects of our results through our interpretation of the interactomics approach used by exploring the different levels at which molecular variability could influence the results. > 1. Phenotypic Heterogeneity in Liver Cells. Even without pre-existing liver diseases, subtle variations in liver cell signaling pathways or receptor expression could lead to diverse responses to the S1 protein. For instance, different tissues and even liver cell types variably express ACE2, a key receptor involved in SARS-CoV-2 entry [97]. If liver cells from two individuals express ACE2 at differing levels, the downstream signaling pathways activated by S1 binding will differ, leading to heterogeneity in the subsequent cellular response (e.g., stress, apoptosis, or immune modulation); > 2. S1's Influence on Liver-Specific Signaling Pathways. The S1 protein might activate or inhibit liver-specific pathways [98].

[11] 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: 0.361) > 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.

[12] Femoral Structure and Biomechanical Characteristics in Sanfilippo Syndrome Type-B Mice

• Authors: F. Ashby, Evelyn J. Castillo, Yan Ludwig, Natalia K Andraka, Cong Chen et al.
• Year: 2023
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/46054e66f1842cffe6d4cbc20c3a81c8abae7ad9
• DOI: 10.3390/ijms241813988
• PMID: 37762291
• PMCID: 10530914
• Citations: 2
• Summary: Bone mineral content (BMC), volumetric bone mineral density (vBMD), and biomechanical properties in femurs MPS IIIB C57BL/6 mice compared to phenotypic control C 57BL/ 6 mice are determined to suggest some skeletal features of the MPS IIB mouse model may be used as biomarkers of peripheral disease correction for preclinical treatment of MPSIIIB.
• Evidence snippets:
• Snippet 1 (score: 0.361) > Mucopolysaccharidosis (MPS) is a cluster of lysosomal storage diseases that affect the breakdown of glycosaminoglycans (GAGs), leading to each MPS type's molecular and clinical sequelae [1]. MPS diseases are categorized as Type-I, Type-II, Type-III, Type-IV, Type-VI, and Type-VII based on which enzyme in the respective GAG pathway is affected [2]. Type-V (Scheie syndrome) was later found to be a milder form of Type-I (Hurler syndrome), which affects the IDUA gene pathway. MPS I is known as Hurler's syndrome, and MPS II, known as Hunter's syndrome, are characterized by the accumulation of dermatan sulfate and heparan sulfate [3]. MPS Type-III, also known as Sanfilippo syndrome, is characterized by an inability to breakdown heparan sulfate alone. MPS VII, also known as Morquio syndrome, is characterized by the accumulation of dermatan sulfate, heparan sulfate, and chondroitin sulfate. It is worth noting that MPS Type-I, II, III, and VII all have heparan sulfate as a common GAG accumulation [2]. > All MPS types are afflicted with skeletal malformations, yet much remains to be elucidated about the mechanism of this. Heparan sulfate and other GAGs have been shown to stimulate Toll-like Receptor 4 (TLR-4) in human dendritic cells [4,5], resulting in the production of many cellular cytokines, such as TNF-α, that mediate neuroinflammation and abnormal bone ossification due to enhanced chondrocyte turnover [6][7][8][9]. In MPS I, II, and VI, a high TNF-α was shown to be associated with increased disability and pain [10]. It is also speculated that vitamin D deficiency plays a key role in osteological manifestations of MPS [11].

[13] Progress in the Management of Patients with Cholestatic Liver Disease: Where Are We and Where Are We Going?

• Authors: Xin Luo, Lungen Lu
• Year: 2024
• Venue: Journal of Clinical and Translational Hepatology
• URL: https://www.semanticscholar.org/paper/42239f0ce6e3997132a7eeccd6a9e6ff07f3d099
• DOI: 10.14218/JCTH.2023.00519
• PMID: 38974958
• PMCID: 11224908
• Citations: 8
• Influential citations: 1
• Summary: The recommended guidelines for the management of cholestatic disease and the progress of new drug research and development are summarized to provide an important reference for the clinical practice of cholestatic liver disease.
• Evidence snippets:
• Snippet 1 (score: 0.360) > The main reason for this unmet clinical need is the unclear mechanisms exploration of etiology in PBC and PSC. > The pathophysiology of PBC is largely elucidated and recent studies have focused on the initiating factors of the disease.It is generally accepted that PBC is a disease driven by both genetic and environmental factors, and is closely related to autoimmune dysfunction.For reasons that have not yet been elucidated, mitochondria in biliary epithelial cells (BECs) are attacked, leading to BEC dysfunction, bile duct injury, and cholestasis.A characteristic biochemical change in PBC patients is antimitochondrial antibody BEC seropositivity.One of the urgent questions to be answered is that although mitochondria are present in all nucleated cells, why are mitochondria in BECs but not other cells attacked in PBC patients. 58,59Study of this immunological mechanism is important for the development of new drugs that can target PBC and represents a new direction.The immune system may play an important role in the development of new drugs for PBC.Protection of BEC function is thought to be important.Because increased BEC apoptosis leads to bile duct dysfunction, the inhibition of BEC apoptosis is of great significance. 60It is also important to note that PBC is more common in women than in men. 61Does this suggest that sex hormones may be involved in the progression of PBC? Targeting the role of sex hormones in the progression of PBC is also an important direction for subsequent drug research and development. > Recent studies of the etiology of PSC have focused on the correlation of PSC and IBD.There is a controversy about whether PSC and IBD are two independent diseases or the same disease manifests in different organs.A lot of clinical evidence shows that the two diseases are similar, but further investigation is needed to determine a causal relationship between the two diseases.Although there is a strong correlation between the two diseases, a number of clinical trials have confirmed that drugs suitable for IBD have very limited benefits for the treatment of PSC, which suggests that pathophysiology of PSC differs from that of IBD. 62,63

[14] Current and Emerging Approaches for Nonalcoholic Steatohepatitis Treatment.

• Authors: Ming-Ming Chen, Jingjing Cai, Yao Yu, Zhi‐Gang She, Hongliang Li
• Year: 2019
• Venue: Gene expression
• URL: https://www.semanticscholar.org/paper/1f2b67b026eac95fc03f45146f25d55d11d6ca91
• DOI: 10.3727/105221619X15536120524171
• PMID: 30940296
• Citations: 22
• Influential citations: 1
• Summary: The potential strategies and challenges in therapeutic approaches to treating NASH are reviewed and some agents targeting various vital molecules and pathways, including those impacting metabolic perturbations, inflammatory cascades and oxidative stress, are in clinical trials.
• Evidence snippets:
• Snippet 1 (score: 0.357) > Drug development for NASH requires clear mechanisms, appropriate animal models, progressive clinical trials, convenient efficacy evaluation, and follow-up methods. Many challenges impeding the translation from bench to bedside remain in this drug discovery process. The pathogenesis of NASH has not been entirely elucidated and has been debated for a long time, which is one of the bottlenecks in drug development. The "multiple-parallel hit" hypothesis was recently proposed, providing a more adequate explanation of how fatty acids and their metabolites promote NASH through multiple sequential or parallel cytotoxic pathways 110 . The pathogenesis of human NASH involves varied molecular pathways and complex progression with a dynamic bidirectional nature, which is unlikely to be the same in all patients, raising concern about individual differences. > The perfect animal model that mimics the pathophysiology of NASH and displays the most clinical characteristics of human disease as closely as possible does not exist, further increasing the difficulty in identifying and validating potential drug targets for human NASH. Many species, including mice, rabbits, pigs, and monkeys, are used to develop models with a liver phenotype resembling human NASH, and each has its advantages and disadvantages 111 . Recently, monkeys have been recommended as models of NASH due to similarities in liver anatomy, physiology, metabolism, and genetics to humans 112,113 . Monkey breeding has specific disadvantages including sophisticated genetic methods, housing, cost, and logistics. Moreover, the ideal pharmacodynamics of drugs in animal models do not necessarily replicate in human NASH. > Because of the slow progression to clinically significant outcomes in NASH, drug development has been delayed, and the potential time to market for drugs has been extended. The use of optimal surrogate endpoints for clinical trials in NASH is imperative for evaluating pharmacologic agents 114 . For purposes of accelerated approval, the surrogate endpoints used by the FDA can be achieved in a reasonably short timeframe. Biomarkers of NASH are helpful for the diagnosis, monitoring, and prognosis of disease progression and evaluation of the effects of new regimens, which is urgent in the field of NASH. In addition, existing methods of pharmacodynamic evaluation and follow-up are still insufficient to assess NASH progression and regression for drug development.

[15] Changes in Serum Proteomic Profiles at Different Stages of Pregnancy Toxemia in Goats

• Authors: M. Uzti̇mür, C. N. Ünal, Gurler Akpinar
• Year: 2025
• Venue: Journal of Veterinary Internal Medicine
• URL: https://www.semanticscholar.org/paper/4b9c488b5dbd65d7b26fd2ad9aed70e8c4b59942
• DOI: 10.1111/jvim.70139
• PMID: 40492724
• PMCID: 12150350
• Summary: Understanding the serum proteome profiles of goats with pregnancy toxemia might help identify the proteomes and pathways responsible for the development of this disease and improve diagnosis and treatment.
• Evidence snippets:
• Snippet 1 (score: 0.356) > The pathophysiology and progression of this disease are not fully understood. > Traditional biomedical research has focused on the analysis of single genes, proteins, metabolites, or metabolic pathways in diseases. This molecular reductionist approach is based on the assumption that identifying genetic variations and molecular components will lead to new treatments for diseases [13][14][15][16]. However, many diseases are complex and multifactorial, and in order to determine the phenotype of such diseases, it is necessary to understand the changes that occur in more than one gene, pathway, protein, or metabolite at the cellular, tissue, and organismal levels [17][18][19]. Therefore, in recent years, proteomics, as one field of multi-omics technologies, has helped in evaluating the complex pathogenetic mechanisms of different diseases from a broad perspective and has made substantial contributions [20,21]. In veterinary medicine, proteomic analysis of metabolic diseases such as ketosis [16], hypocalcemia [22], and fatty liver [23] in dairy cows has contributed valuable insights for the definition of new pathophysiological pathways and new diagnosis and treatment protocols for these diseases. The proteomic approach can contribute importantly to a broad and detailed understanding of the changes that occur at the organismal level associated with the increase in BHBA concentration in goats with pregnancy toxemia. Our aim was to evaluate the serum protein profiles of goats with SPT or CPT using proteomic techniques to determine the proteomic profiles of these animals and to identify the relevant pathophysiological mechanisms.

[16] Exploring the molecular mechanisms of subarachnoid hemorrhage and potential therapeutic targets: insights from bioinformatics and drug prediction

• Authors: Yi Liu, Yang Zhang, Huan Wei, Li Wang, Lishang Liao
• Year: 2025
• Venue: Scientific Reports
• URL: https://www.semanticscholar.org/paper/19a91d9c8cabec6a5a186729d545077e252ecb67
• DOI: 10.1038/s41598-025-97642-8
• PMID: 40229542
• PMCID: 11997208
• Summary: The findings not only elucidate the molecular mechanisms underlying SAH but also provide robust bioinformatics and experimental evidence supporting IRN as a promising therapeutic candidate, offering novel insights for future intervention strategies in SAH.
• Evidence snippets:
• Snippet 1 (score: 0.352) > involved in SAH pathology. As a result, our understanding of the cellular composition and microenvironment in SAH remains incomplete 8 . > Advances in bioinformatics provide powerful tools to analyze large-scale gene expression data and understand complex biological processes. By integrating transcriptomic data with immune cell infiltration analysis, we can gain a deeper understanding of the molecular mechanisms underlying SAH and identify potential key genes as therapeutic targets 9,10 . Previous studies have indicated that inflammation, oxidative stress, and cell death play crucial roles in the development of SAH, processes that are often closely associated with changes in specific cell types and immune responses 11 . > The goal of this study is to explore the molecular mechanisms of SAH, with a focus on immune cell infiltration and its role in disease progression. We aim to identify key genes and signaling pathways associated with SAH and investigate potential therapeutic strategies. Specifically, we will examine Isorhynchophylline (IRN) as a potential treatment for SAH and analyze its effects on relevant targets and signaling pathways. Through a comprehensive understanding of the pathological features of SAH, this study aims to provide valuable insights into future clinical interventions and treatment strategies.

[17] Pulmonary fibrosis: pathogenesis and therapeutic strategies

• Authors: Jianhai Wang, Kuan Li, De Hao, Xue Li, Yu Zhu et al.
• Year: 2024
• Venue: MedComm
• URL: https://www.semanticscholar.org/paper/27d52cce107cbf87fe7b61df145de94a94bc4167
• DOI: 10.1002/mco2.744
• PMID: 39314887
• PMCID: 11417429
• Citations: 56
• Summary: This review thoroughly examines the diverse etiological factors, cellular and molecular mechanisms, and key signaling pathways involved in PF, such as TGF‐β, WNT/β‐catenin, and PI3K/Akt/mTOR and discusses current therapeutic strategies.
• Evidence snippets:
• Snippet 1 (score: 0.350) > This review highlights that PF involves multiple factors, including epithelial cells, mesenchymal cells, immune responses, and microorganisms. These elements interact with and modify various pathways simultaneously, necessitating a systematic and integrative research approach. Future research on the mechanisms, diagnostics, and therapies should incorporate advanced technologies, such as single-cell sequencing, organoid cultures, and metabolomics (Figure 3). Single-cell sequencing can be used to identify the unique contributions of specific cell types to the lung microenvironment. Organoid cultures replicate the three-dimensional structure and function of the lung tissue, providing a more physiologically relevant model for studying disease mechanisms and testing treatments. Metabolomics can reveal changes in metabolic pathways that contribute to disease progression, whereas microbiology can elucidate the role of microorganisms in PF. These studies should be integrated within a systems biology framework to capture the intricate interactions and regulatory networks involved in PF. > Early and accurate diagnosis is crucial for effective management of PF. Future efforts should focus on the discovery and clinical application of new biomarkers to detect this disease in its early stages. Advanced imaging techniques and molecular diagnostics can be used to monitor disease progression and evaluate treatment responses. Reliable biomarkers can facilitate personalized treatment strategies, allowing timely and targeted interventions to slow or halt disease progression. > Because of the multifactorial nature of PF, a single therapeutic approach is often inadequate. Therefore, a combination of treatments that target multiple pathways and cellular interactions should be considered. Combining antifibrotic drugs with cell and gene therapies, as well as leveraging nanoparticles and gene-editing technologies, can enhance treatment precision and efficacy. Exploring the synergistic effects of various therapies can improve therapeutic outcomes and reduce adverse effects. Supportive measures such as lifestyle modifications, pulmonary rehabilitation, and oxygen therapy should be incorporated to improve the overall quality of life of patients. > In summary, the pathogenic mechanisms underlying PF are complex and involve numerous cellular interactions and pathways. Future research should adopt a systematic and integrative approach to uncover the intricate details of PF pathogenesis. Early diagnosis using novel biomarkers and advanced imaging techniques coupled with multimodal treatment strategies holds promise for significantly improving patient outcomes.

[18] 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: 0.348) > 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].

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

• Authors: F. Iheagwam, A. J. Joseph, E. D. Adedoyin, Olawumi Toyin Iheagwam, Samuel Akpoyowvare Ejoh
• Year: 2025
• Venue: Pathophysiology
• URL: https://www.semanticscholar.org/paper/dbf8042761c1a5fc50f8cd894cc498505abac7cb
• DOI: 10.3390/pathophysiology32010009
• PMID: 39982365
• PMCID: 12077258
• Citations: 23
• Summary: This review aims to elucidate the complex link between mitochondrial dysfunction and diabetes, covering the spectrum of diabetes types, the role of mitochondria in insulin resistance, highlighting pathophysiological mechanisms, mitochondrial DNA damage, and altered mitochondrial biogenesis and dynamics.
• Evidence snippets:
• Snippet 1 (score: 0.345) > The landscape of DM research is continuously evolving, with emerging technologies and approaches offering new insights into the pathophysiology of the disease and potential therapeutic targets. Advancements in omics technologies, encompassing genomes, transcriptomics, proteomics, and metabolomics, have transformed the molecular mechanisms underlying DM [134]. High-throughput sequencing techniques enable comprehensive analysis of genetic variants, gene expression profiles, protein abundance, and metabolite levels associated with DM and its complications [135]. Single-cell omics approaches provide unprecedented resolution and granularity, allowing researchers to dissect cellular heterogeneity and identify novel cell types, subpopulations, and signalling pathways involved in DM pathogenesis. Integrating multi-omics data sets offers a systems-level perspective of DM, unravelling complex networks of molecular interactions and regulatory circuits underlying disease progression [136]. > In addition to omics technologies, advances in imaging modalities, such as MRI, PET, and optical imaging, enable non-invasive visualisation and quantification of metabolic, functional, and structural changes. Molecular imaging probes targeting specific biomarkers and metabolic pathways provide valuable insights into disease mechanisms and treatment responses in preclinical and clinical settings [85]. Despite significant progress in DM research, numerous unanswered questions and knowledge gaps persist, hindering the ability to develop effective prevention and treatment strategies. Key areas requiring further investigation include the role of epigenetics, environmental factors, and the microbiome in DM susceptibility and progression. Moreover, the interaction between environmental cues and genetic predisposition remains incompletely understood, highlighting the need for comprehensive multi-omics studies and large-scale epidemiological analyses to identify gene-environment interactions and modifiable risk factors for DM [137]. Furthermore, the heterogeneity of DM phenotypes and clinical outcomes poses a challenge for personalised medicine approaches, necessitating robust biomarkers and predictive models to stratify patients based on disease subtypes, prognosis, and treatment response [138].

[20] Increased Longevity and Metabolic Correction Following Syngeneic Bone Marrow Transplantation in a Murine Model of Mucopolysaccharidosis Type I

• Authors: D. Wolf, Andrew W. Lenander, Zhenhong Nan, E. Braunlin, Kelly M. Podetz-Pedersen et al.
• Year: 2011
• Venue: Bone marrow transplantation
• URL: https://www.semanticscholar.org/paper/51b7ce35bfb662994b1738c2c69bd35aa5aa54a7
• DOI: 10.1038/bmt.2011.239
• PMID: 22179554
• PMCID: 4465813
• Citations: 3
• Summary: This murine-transplantation model can be used to evaluate the effects of novel, more effective methods of delivering IDUA to the brain as an adjunct to BMT, and results are similar to those observed in Hurler patients following BMT.
• Evidence snippets:
• Snippet 1 (score: 0.345) > Mucopolysaccharidosis type I (MPS I) is an autosomal recessive inherited disease caused by deficiency of the glycosidase α-L-iduronidase (IDUA). IDUA is required for the degradation of the glycosaminoglycans (GAG) heparan and dermatan sulfate and deficiency of the enzyme leads to lysosomal accumulation of these substrates (1). MPS 1 affects approximately 1 in 125,000 live human births and homozygosity for specific mutations (e.g., W402X, Q70X) leads to the most severe phenotype, Hurler syndrome (2). Patients with Hurler syndrome develop progressively severe manifestations of the disease within the first year of life, including growth delay, hepatosplenomegaly, skeletal deformities, excess urinary GAG, corneal clouding, and severe neurological deficits. Untreated, these patients usually succumb to the disease in the first decade of life due to complications caused by respiratory infection, cardiac failure, and obstructive airway disease. > Early biochemical research led to discoveries that have provided the basis for treatment of Hurler patients by hematopoeitic stem cell transplantation (HSCT). After synthesis in the endoplasmic reticulum, IDUA is post-translationally modified by the addition of mannose-6 phosphate to Asn residues in the rough endoplasmic reticulum and Golgi apparatus (3). Most of the modified enzyme is sorted and translocated to the lysosomes, but a small proportion of IDUA escapes from the cell into the extracellular environment (4). Extracellular IDUA can then interact with mannose-6-phosphate receptors on the surface of neighboring cells, with subsequent endocytosis, and shuttling to the lysosomes (5-7). IDUA-deficient cells can thus be cleared of accumulated lysosomal GAG through the uptake of IDUA released by non-deficient cells. This cross-corrective mechanism constitutes the basis for development of cellular and molecular strategies to treat this disorder. > Currently, the standard of care for severe Hurler patients involves enzyme replacement therapy (ERT

Notes

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