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

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

• Papers retrieved: 20
• Snippets retrieved: 20

Relevant Papers

[1] 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: 3
• 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: 0.394) > 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.

[2] 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: 0.394) > 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].

[3] 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: 0.384) > 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.

[4] 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: 0.383) > 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.

[5] 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: 0.377) > 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.

[6] 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: 58
• 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: 0.367) > 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.

[7] Heat Shock Proteins in Oxidative Stress and Ischemia/Reperfusion Injury and Benefits from Physical Exercises: A Review to the Current Knowledge

• Authors: Jakub Szyller, I. Bil-Lula
• Year: 2021
• Venue: Oxidative Medicine and Cellular Longevity
• URL: https://www.semanticscholar.org/paper/4ec4bee9f1b89cdf5a3c513d847990f3cfc18bb8
• DOI: 10.1155/2021/6678457
• PMID: 33603951
• PMCID: 7868165
• Citations: 112
• Influential citations: 2
• Summary: The latest research focuses on determining the role of H SPs in OS, their antioxidant activity, and the possibility of using HSPs in the treatment of I/R consequences, where reactive oxygen species play a major role.
• Evidence snippets:
• Snippet 1 (score: 0.366) > Heat shock proteins play a cytoprotective role under pathological conditions such as cardiovascular diseases. The knowledge about cellular and molecular mechanisms underlying ROS-mediated modulation of HSP expression can help to better understand the pathophysiology of OS, which is associated with the development of many diseases (cardiovascular, neurodegenerative, etc.). I/R injury is considered a major contributor to tissue damage in multiple clinical situations such as myocardial infarction, stroke, and organ transplantation. Oxidative damage is a key factor in the initiation of I/R. HSP expression is highly sensitive to I/R injury. > Understanding the exact mechanisms of HSP and the structure of the protein interaction network can help to better understand the pathophysiology and treatment of many diseases, as well as to develop new drugs. There is a need to understand the relationship between cell pathways-signaling, metabolism, etc. The relationships between HSP and OS discussed in this work seem to be very complicated and not yet fully understood. Data showed that modulation of HSP expression in reperfusion injuries may result in better treatment of myocardial infarction. This can also help to prepare organs for the transplantation.

[8] 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: 0.362) > 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.

[9] Precision Therapeutics in Lennox–Gastaut Syndrome: Targeting Molecular Pathophysiology in a Developmental and Epileptic Encephalopathy

• Authors: Debopam Samanta
• Year: 2025
• Venue: Children
• URL: https://www.semanticscholar.org/paper/455479c1bfbea7b90b73c109228f67c813d13888
• DOI: 10.3390/children12040481
• PMID: 40310132
• PMCID: 12025602
• Citations: 19
• Influential citations: 1
• Summary: A narrative review explores precision therapeutic strategies for LGS based on molecular pathophysiology, including channelopathies, receptor and ligand dysfunction, receptor and ligand dysfunction, cell signaling abnormalities, cell signaling abnormalities, synaptopathies, and the repurposing of existing medications with mechanism-specific effects.
• Evidence snippets:
• Snippet 1 (score: 0.361) > Lennox–Gastaut syndrome (LGS) is a severe childhood-onset developmental and epileptic encephalopathy characterized by multiple drug-resistant seizure types, cognitive impairment, and distinctive electroencephalographic patterns. Current treatments primarily focus on symptom management through antiseizure medications (ASMs), dietary therapy, epilepsy surgery, and neuromodulation, but often fail to address the underlying pathophysiology or improve cognitive outcomes. As genetic causes are identified in 30–40% of LGS cases, precision therapeutics targeting specific molecular mechanisms are emerging as promising disease-modifying approaches. This narrative review explores precision therapeutic strategies for LGS based on molecular pathophysiology, including channelopathies (SCN2A, SCN8A, KCNQ2, KCNA2, KCNT1, CACNA1A), receptor and ligand dysfunction (GABA/glutamate systems), cell signaling abnormalities (mTOR pathway), synaptopathies (STXBP1, IQSEC2, DNM1), epigenetic dysregulation (CHD2), and CDKL5 deficiency disorder. Treatment modalities discussed include traditional ASMs, dietary therapy, targeted pharmacotherapy, antisense oligonucleotides, gene therapy, and the repurposing of existing medications with mechanism-specific effects. Early intervention with precision therapeutics may not only improve seizure control but could also potentially prevent progression to LGS in susceptible populations. Future directions include developing computable phenotypes for accurate diagnosis, refining molecular subgrouping, enhancing drug development, advancing gene-based therapies, personalizing neuromodulation, implementing adaptive clinical trial designs, and ensuring equitable access to precision therapeutic approaches. While significant challenges remain, integrating biological insights with innovative clinical strategies offers new hope for transforming LGS treatment from symptomatic management to targeted disease modification.

[10] Drug repurposing in Rett and Rett-like syndromes: a promising yet underrated opportunity?

• Authors: Claudia Fuchs, P. A. ‛. ’t Hoen, A. Müller, Friederike Ehrhart, C. V. van Karnebeek
• Year: 2024
• Venue: Frontiers in Medicine
• URL: https://www.semanticscholar.org/paper/b00d0859458647edeebf3cf53f9b39c79311d5ed
• DOI: 10.3389/fmed.2024.1425038
• PMID: 39135718
• PMCID: 11317438
• Citations: 1
• Summary: The potential of drug repurposing (DR) as a promising avenue for addressing the unmet medical needs of individuals with RTT and related disorders is explored and Leveraging existing drugs for new therapeutic purposes presents an attractive strategy.
• Evidence snippets:
• Snippet 1 (score: 0.360) > Rigorous preclinical and clinical studies are also crucial for better understanding the complex pathophysiology of these syndromes. To date, the precise molecular mechanisms underlying these complex disorders are still not fully understood; hindering the identification and validation of potential drug targets. This specifically applies to CDD and FOXG1-syndrome: both conditions were identified as distinct clinical entities only recently and it is understandable that research efforts initially focused primarily on "classical" RTT. This discrepancy is reflected also in the very different numbers of repurposing studies highlighted in Figure 1. Continued efforts in pre-clinical (identification of valuable cell and animal models etc.) and clinical research (better understanding of the natural history, clinical manifestations, disease progression, biomarkers etc.) will be essential for advancing our understanding and improving outcomes for individuals affected by these syndromes. In particular, better characterizing the shared symptoms and pathways across these entities, will provide valuable insights into the underlying biology and potentially uncover new common mechanisms and targeted therapies. If the disorders demonstrate convergence in their underlying molecular pathways, this provides an opportunity for designing joint DR 10.3389/fmed.2024.1425038 strategies across RTT and RTT-like disorders. This could reduce the time needed for the development of DR and increase the number of patients benefiting from the treatments, resulting in more attractive business models. > Despite promising DR results in preclinical or early-phase clinical trials for RTT and related disorders in our opinion DR is still underrated and underutilized in this kind of disorders. DR holds immense potential for addressing the unmet medical needs and therapeutic challenges posed by such complex NDDs, and recent advancements screening and computational techniques, offer the unique opportunity to predict drug-disease interactions and prioritize candidate compounds for further investigation. By leveraging existing drugs and repurposing them for new indications, this approach offers a pragmatic and efficient strategy to accelerate the development of treatments for individuals affected by these debilitating conditions.

[11] Systems pharmacology-based integration of human and mouse data for drug repurposing to treat thoracic aneurysms.

• Authors: J. Hansen, J. Galatioto, Cristina I. Caescu, P. Arnaud, R. C. Calizo et al.
• Year: 2019
• Venue: JCI insight
• URL: https://www.semanticscholar.org/paper/261628418de4c8b21daeb694301dc1b8759b622d
• DOI: 10.1172/jci.insight.127652
• PMID: 31167969
• Citations: 20
• Summary: System pharmacology approaches that compare patient- and mouse-derived transcriptomic data for subcellular pathway-based drug repurposing represent an effective strategy to identify potential new treatments of human diseases.
• Evidence snippets:
• Snippet 1 (score: 0.359) > TAA with ensuing dissection and rupture of the vessel wall is the clinical hallmark of Marfan syndrome (MFS), a relatively common connective tissue disease associated with mutations in the gene that codes for the multifunctional ECM glycoprotein fibrillin-1 (4,5). Fibrillin-1 assemblies (microfibrils and elastic fibers) impart specific physical properties to tissues, distribute mechanical forces within and across them, communicate to multiple types of vessel wall cells through integrin receptors, and modulate local bioavailability of ECM-bound latent TGF-β complexes (5). In spite of significant research effort, the molecular pathogenesis of arterial disease in MFS remains unresolved, therefore hindering advances in drug therapy. Earlier studies of MFS mice with nondissecting TAA (Fbn1 C1039G/+ mice) have correlated aneurysm onset and progression with increased TGF-β signaling in the media stimulated by improper angiotensin II (AngII) type I receptor (AT1r) activity (6,7). More recent findings indicate a more complex disease mechanism involving the gradual stratification of stress-stimulated interactions among different cell types and multiple regulatory pathways, of which the AT1r and TGF-β signaling pathways are a critical subset (8)(9)(10)(11)(12)(13)(14). > An overview of regulatory pathways and networks associated with a given pathology can often be obtained by examining changes in gene expression during disease progression. Systems pharmacology approaches that consider drug targets as nodes within cellular regulatory networks can use differentially expressed genes (DEGs) to predict dysregulated SCPs that underlie cell-level mechanisms (1,3). Further, computational analyses of the pharmacologically induced perturbations of gene expression listed in the Connectivity Map (CMap) database can predict drugs to be repurposed to normalize dysregulated SCPs (15).

[12] 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: 0.358) > 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.

[13] Perspectives in Amyotrophic Lateral Sclerosis: Biomarkers, Omics, and Gene Therapy Informing Disease and Treatment

• Authors: Nina Bono, Flaminia Fruzzetti, Giorgia Farinazzo, Gabriele Candiani, S. Marcuzzo
• Year: 2025
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/37fa957837679879485794fb4292e8a730519f55
• DOI: 10.3390/ijms26125671
• PMID: 40565135
• PMCID: 12193257
• Citations: 8
• Summary: This review examines innovative approaches transforming ALS research and clinical management, and highlights current gene therapy strategies, including antisense oligonucleotides (ASOs), RNA interference (RNAi), and CRISPR/Cas9 gene editing systems, alongside advanced delivery methods for crossing the blood–brain barrier.
• Evidence snippets:
• Snippet 1 (score: 0.357) > The recently approved AMX0035 (Relyvrio; 2022) targets endoplasmic reticulum stress and mitochondrial dysfunction with encouraging but still incremental survival benefits [90]. > These approved treatments share fundamental limitations: they address single pathways in a disease characterized by multiple interacting mechanisms, fail to target specific genetic causes, cannot restore lost motor neurons, and face significant challenges in crossing the BBB to achieve adequate therapeutic concentrations in the CNS. Perhaps most significantly, they provide symptomatic relief rather than disease modification, highlighting the urgent need for transformative approaches toward a true disease-modifying treatment for this devastating illness. > The limited success of ALS clinical trials can be ascribed to multiple factors, with a poor understanding of disease mechanisms being paramount. Additional challenges include limited bioavailability of therapeutic agents, inefficient therapeutic delivery to the CNS, difficulties in administration, lack of effective biomarkers for patient stratification and treatment response monitoring, late diagnosis reducing the therapeutic window, and lack of clinically relevant disease models that fully recapitulate human pathophysiology. The multifactorial nature of ALS and the complexity of its pathogenic mechanisms have made it exceptionally difficult to develop interventions that effectively address the disease progression. > Recent advances in the understanding of ALS pathophysiology, including the discovery of many of its genetic underpinnings, have enabled the development of targeted therapies, with today's clinical trials holding growing promise for more efficacious treatments that address the fundamental limitations of current therapeutic approaches. > Numerous clinical trials are currently investigating various therapeutic approaches targeting different pathological mechanisms of ALS. These range from ASOs, designed to silence mutated genes, to AAV-delivered gene therapies, stem cell treatments, and small molecule interventions. The diversity of approaches reflects both the complex multifactorial nature of ALS and the rapidly evolving landscape of therapeutic technologies [3].

[14] 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: 0.356) > 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

[15] Recent Evidences of Epigenetic Alterations in Chronic Obstructive Pulmonary Disease (COPD): A Systematic Review

• Authors: R. Ragusa, Pasquale Bufano, A. Tognetti, M. Laurino, Chiara Caselli
• Year: 2025
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/2660cdbbe1f205c631fe890e5c6a3c8d9b81ce5f
• DOI: 10.3390/ijms26062571
• PMID: 40141213
• PMCID: 11942187
• Citations: 4
• Summary: A systematic review of the latest knowledge on epigenetic modifications that characterize COPD, summarizing epigenetic factors that could serve as potential novel biomarkers and therapeutic targets for the treatment of COPD patients.
• Evidence snippets:
• Snippet 1 (score: 0.352) > The papers included were clustered according to epigenetic mechanisms involved in COPD (molecular and cellular processes, as biomarker or therapeutic target). Tables 4-9 describe the extracted information, including the following: Study = name of first author et al., year; Country (Region) = where the study took place; Number of participants = sample size; Type of sample = biological sample employed; Gene affected = gene or group of genes whose expression can be "regulated" by epigenetic mechanisms; Epigenetic alteration = type of epigenetic alteration observed in the presence of disease; Activity in COPD = involvement of epigenetic elements in different molecular and cellular mechanisms associated with COPD; and Role of epigenetic mechanisms = epigenetic modifications that can be used to explain the pathophysiology of COPD or as biomarkers and therapeutic targets.

[16] Pathophysiology, Clinical Heterogeneity, and Therapeutic Advances in Amyotrophic Lateral Sclerosis: A Comprehensive Review of Molecular Mechanisms, Diagnostic Challenges, and Multidisciplinary Management Strategies

• Authors: M. González-Sánchez, M. J. Ramírez-Expósito, J. M. Martínez-Martos
• Year: 2025
• Venue: Life
• URL: https://www.semanticscholar.org/paper/068cd6b38871f5b807d15db5e20bb35d9d2610f5
• DOI: 10.3390/life15040647
• PMID: 40283201
• PMCID: 12029092
• Citations: 17
• Influential citations: 1
• Summary: This comprehensive review synthesizes the current knowledge on ALS pathophysiology, clinical heterogeneity, diagnostic frameworks, and evolving therapeutic strategies to highlight the need for patient-centered communication and palliative strategies.
• Evidence snippets:
• Snippet 1 (score: 0.350) > This review on ALS underscores the inherent complexity of this neurodegenerative disease, from its phenotypic heterogeneity to the intricate network of pathophysiological mechanisms that contribute to its progression. ALS manifests as a diagnostic challenge due to its clinical variability, requiring a comprehensive approach that combines a detailed neurological evaluation with complementary tests to confirm upper and lower motor neuron involvement. The application of standardized diagnostic criteria, such as the revised El Escorial criteria, facilitates a more accurate classification of the disease, which in turn allows for better patient stratification and more informed therapeutic decision-making. > Pathophysiology research has revealed the involvement of multiple molecular and cellular pathways in ALS, including alterations in autophagy, RNA metabolism, nucleocytoplasmic transport, and protein aggregate formation. Genes such as C9orf72, SOD1, TDP-43, and FUS play a crucial role in these pathological processes, and their dysfunction contributes to motor neuron degeneration and disease progression. Understanding these underlying mechanisms is critical for the development of targeted therapies that can modify the course of ALS and improve the clinical outcomes. > Treatment of ALS remains a challenge, but advances in multidisciplinary care and the development of new drugs offer hope for patients and their families. Riluzole, edavarone, and tofersen are approved treatments that have been shown to modestly prolong survival in some ALS patients. However, their efficacy is limited, and more effective therapies are urgently needed. A multidisciplinary approach, including physiotherapy, occupational therapy, speech therapy, and psychosocial support, is essential to optimize patients' quality of life and address the multiple symptoms and complications of the disease. > The management of specific symptoms, such as dysphagia, dysarthria, cramping, and sleep disturbances, requires an individualized approach and the application of specific strategies, such as airway clearance techniques, noninvasive ventilation, and neuropathic pain management. The prognosis for ALS remains variable, but ongoing research and advances in clinical care offer promise for improving the quality of life and prolonging the survival of patients affected by this devastating disease.

[17] Psychobiotics at the Frontiers of Neurodegenerative and Neuropsychiatric Research

• Authors: Guillermo Roberto Jiménez-Pareyón, J. Cristóbal-Luna, Y. García-Martínez, Cynthia Garfias-Noguez, Morayma Ramírez-Damián et al.
• Year: 2025
• Venue: Microorganisms
• URL: https://www.semanticscholar.org/paper/6c92b8101905064ff4e4e8585f4fa86ebfac0826
• DOI: 10.3390/microorganisms13122718
• PMID: 41471921
• PMCID: 12735313
• Summary: A review of current evidence on the GBA’s involvement in conditions such as Alzheimer’s disease, Parkinson’s disease, depression, and anxiety examines how psychobiotics may modulate neuroinflammation, oxidative stress, and neurotransmitter signaling, thereby contributing to cognitive and emotional regulation.
• Evidence snippets:
• Snippet 1 (score: 0.350) > Neurodegenerative diseases (NDs) are a group of disorders characterized by the progressive deterioration of the central or peripheral nervous system. These diseases cause morphological changes in the brain, leading to significant cognitive or motor impairments, debilitating symptoms, and a reduced quality of life [16]. NDs involve complex cellular responses triggered by the accumulation of pathologically altered brain substances, ultimately resulting in irreversible loss of neuronal populations [17]. > The pathophysiology of NDs is multifactorial and intricate, involving cellular, molecular, and genetic mechanisms. These include protein misfolding and aggregation, oxidative stress, mitochondrial dysfunction, cytoskeletal abnormalities, disrupted synaptic networks, neuronal death, aberrant cell proliferation, neuroinflammation, demyelination, altered axonal transport, dysregulated energy metabolism, and abnormal modifications of DNA or RNA [16,[18][19][20][21][22]. > NDs can be classified according to several criteria, such as their etiology, the molecular mechanisms involved, and the anatomical regions affected [23]. Although multiple classification systems exist, these disorders often share overlapping cellular and molecular mechanisms [24], which complicates efforts to categorize them into a single scheme. From a mechanistic perspective, NDs commonly exhibit recurring pathological events such as neuroinflammation, oxidative stress, mitochondrial dysfunction, and the accumulation of misfolded proteins [16]. Recent classification systems increasingly emphasize the type of protein aggregates for diagnostic accuracy [25]. Clinically, NDs can also be classified clinically based on predominant symptoms, such as movement disorders in PD and Huntington's disease, cognitive deficits in AD, or a combination of both [12,26,27]. This approach allows for a better understanding of their heterogeneity and facilitates the development of more specific therapeutic strategies. Among the spectrum of neurodegenerative conditions, AD and PD are the most prevalent and extensively studied (Figure 1).

[18] Crosstalk of organelles in Parkinson’s disease – MiT family transcription factors as central players in signaling pathways connecting mitochondria and lysosomes

• Authors: M. Lang, P. Pramstaller, I. Pichler
• Year: 2022
• Venue: Molecular Neurodegeneration
• URL: https://www.semanticscholar.org/paper/61554668ad754c9cf8ea032cfb48773e91592041
• DOI: 10.1186/s13024-022-00555-7
• PMID: 35842725
• PMCID: 9288732
• Citations: 20
• Summary: The activation of MiT transcription factors through genetic and pharmacological approaches have shown encouraging results at ameliorating PD-related phenotypes in in vitro and in vivo models and focus on the role of the MiT pathway and its potential as pharmacological target against PD.
• Evidence snippets:
• Snippet 1 (score: 0.349) > PD is a NDD that is characterized by pathological protein misfolding and aggregation as well as organellar dysfunction leading to neuronal cell death, which causes motor-and non-motor symptoms. Mitochondrial homeostasis and quality control have historically been recognized as crucial contributors to PD pathogenesis, and several aspects of mitochondrial biology are impaired in PD patients and models. In addition, defects of macroautophagy and the ALP have been observed in cell and animal models of PD as well as PD patients' brains, where constitutive autophagy is indispensable for adaptation to stress and energy deficiency. Various mechanisms are involved in the interplay between PD-related mitochondrial defects, lysosomal dysfunctions, and protein aggregate formations. The specific disease cascade in PD patients may differ based on which genetic and environmental factors act as main triggers. As outlined in this review, the functions of various organellar compartments are tightly linked and influence each other. Connections between these organelles are constituted among others by mitophagy, metabolite homeostasis, organellar dynamics, including exo-and endocytosis, and cellular signaling cascades, including Ca 2+ signaling, This may lead to the recognition of druggable proteins that can influence MiT activation and help to develop pharmacologically relevant molecules that would increase lysosomal biogenesis and boost degradation pathways in the brain of affected individuals. Such treatment strategies would best be applied before debilitating effects of the disease are being experienced. This, however, will require parallel efforts for the development of early diagnostic methods that would help to recognize biological malfunctions before the damage to cells is too extensive and clinical symptoms appear. Only if diseasealtering treatment options are applied before significant brain regions are impacted by the disease, it will be possible to achieve truly meaningful effects. Overall, more work will be needed to bridge basic knowledge of the main pathways affecting PD with their potential clinical applications, but recent developments in the field have uncovered promising pathways, including the here described approaches, that may provide disease-altering therapies against PD.

[19] Integration of Immunome With Disease-Gene Network Reveals Common Cellular Mechanisms Between IMIDs and Drug Repurposing Strategies

• Authors: Abhinandan Devaprasad, T. Radstake, A. Pandit
• Year: 2019
• Venue: Frontiers in Immunology
• URL: https://www.semanticscholar.org/paper/da3d168a672593e5da82bb4178e49118bc4b3170
• DOI: 10.3389/fimmu.2021.669400
• PMID: 34108969
• PMCID: 8181425
• Citations: 13
• Summary: The method identified top DACs, DAGs, common pathways, and proposed potential drug repurposing targets between IMIDs and built the DIME tool, paving way for future (pre-)clinical research.
• Evidence snippets:
• Snippet 1 (score: 0.349) > Objective Development and progression of immune-mediated inflammatory diseases (IMIDs) involve intricate dysregulation of the disease associated genes (DAGs) and their expressing immune cells. Due to the complex molecular mechanism, identifying the top disease associated cells (DACs) in IMIDs has been challenging. Here, we aim to identify the top DACs and DAGs to help understand the cellular mechanism involved in IMIDs and further explore therapeutic strategies. Method Using transcriptome profiles of 40 different immune cells, unsupervised machine learning, and disease-gene networks, we constructed the Disease-gene IMmune cell Expression (DIME) network, and identified top DACs and DAGs of 12 phenotypically different IMIDs. We compared the DIME networks of IMIDs to identify common pathways between them. We used the common pathways and publicly available drug-gene network to identify promising drug repurposing targets. Result We found CD4+Treg, CD4+Th1, and NK cells as top DACs in the inflammatory arthritis such as ankylosing spondylitis (AS), psoriatic arthritis, and rheumatoid arthritis (RA); neutrophils, granulocytes and BDCA1+CD14+ cells in systemic lupus erythematosus and systemic scleroderma; ILC2, CD4+Th1, CD4+Treg, and NK cells in the inflammatory bowel diseases (IBDs). We identified lymphoid cells (CD4+Th1, CD4+Treg, and NK) and their associated pathways to be important in HLA-B27 type diseases (psoriasis, AS, and IBDs) and in primary-joint-inflammation-based inflammatory arthritis (AS and RA). Based on the common cellular mechanisms, we identified lifitegrast as potential drug repurposing candidate for Crohn’s disease, and other IMIDs. Conclusion Our method identified top DACs, DAGs, common pathways, and proposed potential drug repurposing targets between IMIDs. To extend our method to other diseases, we built the DIME tool. Thus paving way for future (pre-)clinical research.

[20] Patient-Derived Induced Pluripotent Stem Cell Models for Phenotypic Screening in the Neuronal Ceroid Lipofuscinoses

• Authors: A. Morsy, Angelica V Carmona, P. Trippier
• Year: 2021
• Venue: Molecules
• URL: https://www.semanticscholar.org/paper/d510bd31c2c0312641423e0a06892605943439bc
• DOI: 10.3390/molecules26206235
• PMID: 34684815
• PMCID: 8538546
• Citations: 10
• Influential citations: 2
• Summary: An overview of available iPSC models for a number of different NCLs is provided and findings in these models that may spur target identification and drug development are highlighted.
• Evidence snippets:
• Snippet 1 (score: 0.346) > The NCLs encompasses a group of rare, fatal, pediatric neurodegenerative lysosomal storage disorders.Several gene mutations (CLN1-CLN8, CLN10-CLN14) can lead to NCL; however, a partial understanding of the function of the disease-associated proteins has hindered therapy development.Current treatment options are only symptomatic and focus on delaying progression.To date, there are only two clinically approved drugs, Brineuria, for the treatment of CLN2 disease, and Neurogene's recently approved gene therapy to treat CLN5 disease.Different organism models have become available for NCL disease research which have provided a myriad of important information about the protein function or dysfunction for each of the associated genes, possible disease mechanisms, and have enabled detailed preclinical studies and in a small number of cases, clinical trials. > Herein, we have highlighted the contributions of different disease models to NCL research, focusing on the established patient-derived iPSC phenotypic screening models.The ability of iPSCs to encompass the precise pattern of genetic variants, along with acquiring disease pathogenesis and phenotype makes them a more translational model compared to mice and eliminates the problem of species difference.However, compared to animal models, fewer iPSC models currently exist. > The brain is a complex network of many different cellular phenotypes and screening compounds in just one phenotype, i.e., neurons, is not a complete representation of the environment in the brain.While most studies in NCL patient-derived iPSCs employ either NPCs or neurons there are emerging studies looking at biochemical and pathophysiology effects of NCL on other cell phenotypes, one such example is the use of BMECs to model the blood-brain barrier that identified an impaired barrier phenotype in CLN3.Differentiation of iPSCs into other phenotypes including oligodendrocytes, astrocytes, microglia etc. is ongoing and results are expected in due course.These cell types will allow the construction of increasingly complex co-culture models that more readily represent the human brain and thus allow a greater understanding of the disease.

Notes

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