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

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• Papers retrieved: 20
• Snippets retrieved: 20

Relevant Papers

[1] Role of the DDX11 DNA Helicase in Warsaw Breakage Syndrome Etiology

• Authors: Diana Santos, M. Mahtab, A. Boavida, F. M. Pisani
• Year: 2021
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/92bfe4899d538bf996264146a3bbf5e61bf512de
• DOI: 10.3390/ijms22052308
• PMID: 33669056
• PMCID: 7956524
• Citations: 8
• Summary: What is known about the molecular and cellular functions of human DDX11 and its role in WABS etiopathogenesis is reviewed, even in light of recent findings on the role of cohesin and its regulator network in promoting chromatin loop formation and regulating chromatin spatial organization.
• Evidence snippets:
• Snippet 1 (score: 0.421) > Warsaw breakage syndrome (WABS) is a very rare autosomal recessive disease, due to biallelic mutations of the gene coding for the DDX11 DNA helicase [66,67]. The clinical spectrum of WABS is heterogeneous with some cardinal symptoms observed in all patients including: (1) severe pre-and post-natal growth retardation, (2) microcephaly, (3) sensorineural hearing loss, (4) cochlear anomalies, (5) facial dysmorphia and ( 6) sister chromatid cohesion defects. This latter clinical manifestation led to the notion that WABS is a cohesinopathy, even if not all the cohesinopathies are characterized by a precocious chromatid separation cellular phenotype [68]. Cohesinopathies are genetic diseases caused by mutations in genes involved in the sister chromatid cohesion process, including: Cornelia de Lange syndrome (CdLS), caused by mutations in genes encoding the cohesin structural components (SMC1A, SMC3 and RAD21) and regulators (NIPBL and HDAC8); Roberts syndrome (RBS), due to mutations of the cohesin acetyl-transferase gene (ESCO2) and chronic atrial and intestinal dysrhythmia (CAID) syndrome, linked to mutations of the SGOL1 gene encoding Shugoshin [68,69]. It should be pointed out that sister chromatid cohesion defects are observed in WABS and RBS patient cells, but not in those taken from CdLS or CAID probands. This can be due to the multiple functions played by the cohesin complex that are differentially affected in the various "cohesinopathies" [68][69][70]. The cohesion defects observed in metaphase chromosome spreads of WABS (and also RBS) immortalized fibroblasts mainly consist in a characteristic "railroad" configuration of the paired sisters with the centromere constriction that seems to be loosened (premature centromere division, PCD).

[2] Molecular and Cellular Functions of the Warsaw Breakage Syndrome DNA Helicase DDX11

• Authors: F. M. Pisani, Ettore Napolitano, L. M. Napolitano, S. Onesti
• Year: 2018
• Venue: Genes
• URL: https://www.semanticscholar.org/paper/04d885429b8d231e30c34cfd78ad49b67fea2c64
• DOI: 10.3390/genes9110564
• PMID: 30469382
• PMCID: 6266566
• Citations: 30
• Influential citations: 1
• Summary: The biochemical and structural features of DDX11 are illustrated and how it cooperates with multiple protein partners in the cell, acting at the interface of DNA replication/repair/recombination and sister chromatid cohesion to preserve genome stability.
• Evidence snippets:
• Snippet 1 (score: 0.406) > While sister chromatid cohesion defects were observed in all the patients described so far, two of these novel WABS patients do not display drug-induced elevated chromosomal breakage. Thus, while diagnostic clinical symptoms of WABS (microcephaly, growth retardation, cochlear anomalies and chromosomal cohesion defects) are observed in all cases reported in the literature, the chromosomal breakage phenotype is not universally present. In view of these findings, it was proposed to rename this disease "Warsaw syndrome", eliminating reference to the chromosomal breakage phenotype [84]. > The observed phenotypic differences among WABS patients may be due to the different effects of the DDX11 gene mutations and/or to different genetic background of the affected individuals. The ethiopathogenesis of WABS has not yet been deciphered as the cellular functions of DDX11 are not fully understood. However, the partial overlap of clinical manifestations (growth retardation, microcephaly, intellectual disability) with other cohesinopathies (CdLS and RBS) suggests that all these diseases share common developmental defects due to altered transcription profiles during embryonic development. This is consistent with the evidence that cohesin and its regulators play a role in stabilizing chromatin loops, through which developmental gene transcription programs are executed. In this context, it is interesting to point out that either DDX11 or Esco2 were reported to play an important function in chromosome architecture maintenance and their depletion in mammalian cells causes chromosome condensation defects in addition to sister chromatid cohesion anomalies, as described in Section 8. It was proposed that Esco2 could be responsible for recruiting chromatin modifiers (such as histone H3 methyltransferases and demethylases) affecting gene expression [92]. Moreover, DDX11 was believed to contribute to heterochromatin formation by targeting HP1α factor to proper sites in pericentric regions and at telomeres in DDX11-depleted HeLa and in DDX11 knockout mouse embryo-derived cells [67].

[3] Towards Mutation-Specific Precision Medicine in Atypical Clinical Phenotypes of Inherited Arrhythmia Syndromes

• Authors: T. Nakajima, S. Tamura, M. Kurabayashi, Y. Kaneko
• Year: 2021
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/3d299f57f344d42eff9d3565d1581dae7fb87a54
• DOI: 10.3390/ijms22083930
• PMID: 33920294
• PMCID: 8069124
• Citations: 6
• Influential citations: 1
• Summary: Since the epileptic phenotype appears to manifest prior to cardiac events in this mutation carrier, identifying KCND3 mutations in patients with epilepsy and providing optimal therapy will help prevent sudden unexpected death in epilepsy.
• Evidence snippets:
• Snippet 1 (score: 0.394) > Recent advances in molecular genetics have identified many causal genes for inherited arrhythmia syndromes (IASs) such as long QT syndrome (LQTS) [1], short QT syndrome (SQTS) [2], Brugada syndrome (BrS) [3,4] and early repolarization (ER) syndrome (ERS) [3,5]. Most causal genes for IASs encode cardiac ion channels or their related proteins. Genotype-phenotype studies and functional analyses of mutant genes, using heterologous expression systems and experimental animal models, have revealed the pathophysiology of IASs and enabled the establishment of causal gene-specific precision medicine [6][7][8]. Furthermore, analyses of patient-specific and/or genome-edited induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) have provided further insights into the pathophysiology of IASs and novel promising therapeutic strategies for IASs, although there are still some limitations of using iPSC-CMs, such as immature structure and function and mixed population of atrial, ventricular, and nodal cells, as a standard technology [9]. > The altered function of causal genes that encode cardiac ion channels is caused by multiple mechanisms, including trafficking defects, producing non-functional channels, altered channel gating properties, and a combination thereof. These altered functions of mutant channels underly the clinical phenotypes of IASs [10][11][12]. Particularly, unique electrophysiological properties of mutant channels have been shown to be associated with the atypical clinical phenotypes of IASs [10,13]. Furthermore, the elucidation of the mechanisms underlying the atypical clinical phenotypes of IASs has raised the possibility of mutation-specific precision medicine. > We herein review the current knowledge of genotype-phenotype relationships, underlying molecular and cellular mechanisms, and established pharmacological therapies of IASs, including LQTS, SQTS, and J wave syndrome (BrS and ERS).

[4] 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: 0.383) > 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].

[5] CHCHD2 up-regulation in Huntington disease mediates a compensatory protective response against oxidative stress

• Authors: Xuanzhuo Liu, Fang Wang, Xinman Fan, Mingyi Chen, Xiaoxin Xu et al.
• Year: 2024
• Venue: Cell Death & Disease
• URL: https://www.semanticscholar.org/paper/50ed416a063a1a7d3435fa600233ce0d7500986b
• DOI: 10.1038/s41419-024-06523-x
• PMID: 38341417
• PMCID: 10858906
• Citations: 18
• Influential citations: 1
• Summary: It is demonstrated that CHCHD2 up-regulation in HD serves as a compensatory protective response against oxidative stress, suggesting a potential anti-oxidative strategy for the treatment of HD.
• Evidence snippets:
• Snippet 1 (score: 0.378) > Huntington disease (HD) is a genetic neurodegenerative disease caused by the abnormal expansion of the CAG repeats encoding polyglutamine in the HTT gene resulting in the mutant huntingtin protein [1]. Currently, treatment options for HD are limited to symptom management, with no effective method to halt or delay disease progression. Research on HD pathogenesis holds great significance: the clear genetic basis of HD facilitates the establishment of animal and cellular models, providing a solid foundation for exploring underlying disease mechanisms and an opportunity to evaluate promising therapies in a well-defined patient population. Furthermore, HD shares clinical manifestations and molecular signaling pathway abnormalities with other neurodegenerative diseases like Alzheimer's disease (AD) and Parkinson's disease (PD), including specific subtypes of neuronal death and protein misfolding and deposition [2]. Therefore, investigating HD pathogenesis can offer important insights and ideas for the study and treatment of other neurodegenerative diseases. > The specific molecular mechanisms underlying HD pathogenesis remain incompletely understood, but previous studies have highlighted the involvement of oxidative stress in HD pathophysiology. For instance, increased oxidative stress has been observed in the peripheral blood of HD patients [3] and HD animal models [4]. Factors contributing to oxidative stress in HD include the aggregation of mutant huntingtin proteins, impaired antioxidant systems, elevated brain lipid content, high neuronal energy demands, mitochondrial electron transport chain damage, and mitochondrial dysfunction. HD cell mitochondria demonstrate significant alterations in morphology, structure, and Ca2 + homeostasis. These changes lead to reduced oxidative phosphorylation levels, inadequate ATP production, elevated levels of reactive oxygen species (ROS), and subsequent onset of oxidative stress. Excessive ROS levels are considered pathological markers of HD, inducing toxicity, contributing to further mitochondrial damage and protein misfolding, and ultimately resulting in neuronal death [5]. The nuclear factor NFE2-related factor 2-antioxidant response element (Nrf2-ARE) signaling pathway represents one of the most critical anti-oxidative stress pathways [6].

[6] A Journey through Huntington's Disease: Exploring Genetics, Neurobiology, and Therapeutic Advances

• Authors: Sandeep Dey, Shreyas Katta, S. Suresh, Janhvi Mishra
• Year: 2024
• Venue: International Journal For Multidisciplinary Research
• URL: https://www.semanticscholar.org/paper/735574648bec278cf15dc25fd5f1d735afaf6ae6
• DOI: 10.36948/ijfmr.2024.v06i03.19194
• Summary: The clinical features, ethics, and neurobiology of HD are discussed and the exciting approaches being employed today to advance understanding of underlying mechanisms in an effort to develop therapies that would delay the onset and slow progression of this disease are reviewed.
• Evidence snippets:
• Snippet 1 (score: 0.373) > Also, we present a modern view on the molecular biology of HD as a representative of the group of polyglutamine diseases, with an emphasis on conformational changes of mutant huntingtin, disturbances in its cellular processing, and proteolytic stress in degenerating neurons. > The main pathogenetic mechanisms of neurodegeneration in HD are discussed in detail, such as autophagy, impaired mitochondrial biogenesis, lysosomal dysfunction, organelle and protein transport, inflammation, oxidative stress, and transcription factor modulation. However, other unravelling mechanisms are still unknown. This practical and brief review summarises some of the currently known functions of the wild-type huntingtin protein and the recent findings related to the mechanisms involved in HD pathogenesis. Cellular mechanisms implicated in HD pathogenesis: The major mechanisms associated with HD pathogenesis are depicted here. The schematic shows a presynaptic neuron and a postsynaptic neuron flanked by two astrocytes. Huntingtin gene(HTT) itself is depicted as a "solenoid," based on the presumed folding due to its HEAT repeats. The mechanisms depicted are multimerization of mHtt-containing complexes, transcriptional modulation, ER-Golgi stress pathways, mitochondria and energy homeostasis, microtubular dynamics, endocytic and vesicular trafficking dynamics, autophagy, and synaptic signalling mechanisms. mHTT(mutant HTT protein). Traditionally, therapeutic approaches to HD have included compounds developed for psychiatric indications based on the affected neuronal circuitry: the frontal and motor corticostriatal circuits. None of these were initially developed for the treatment of HD. In this review we focus on the cellular and biological pathways affected by mutant HTT (mHTT) and the current status of associated drug discovery efforts. We also emphasise the need for further clinical research to validate existing hypotheses, which are mostly derived from animal studies and postmortem human tissues. It is generally accepted that most candidate therapeutics fail due to lack of efficacy in pivotal clinical studies.

[7] 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: 0.368) > 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.

[8] Molecular insights into the premature aging disease progeria

• Authors: Sandra Vidak, R. Foisner
• Year: 2016
• Venue: Histochemistry and Cell Biology
• URL: https://www.semanticscholar.org/paper/60fb3b46bb7e42d5d08cc3b7cbc783b118300c31
• DOI: 10.1007/s00418-016-1411-1
• PMID: 26847180
• PMCID: 4796323
• Citations: 105
• Influential citations: 3
• Summary: Changes in mechanosignaling, altered chromatin organization and impaired genome stability, and changes in signaling pathways, leading to impaired regulation of adult stem cells, defective extracellular matrix production and premature cell senescence are discussed.
• Evidence snippets:
• Snippet 1 (score: 0.367) > The number of molecular biological studies aiming at the identification of lamin-mediated molecular disease mechanisms involved in HGPS increased tremendously following the surprising discovery that LMNA is causally linked to the premature aging disease HGPS in 2003. Despite numerous cellular pathways that were identified to be affected by the expression of the mutant lamin A protein (Fig. 2), the mechanistic details behind these effects are still unclear in most cases. Knowledge based on what was already known on lamin biology before the protein was linked to HGPS and findings on novel roles of lamins in diverse pathways in recent years allowed the launch of translational studies and the efficient search for drug targets and therapeutic approaches within a short time period. The results of the first clinical trials taught us that some improvements of the disease phenotypes can be achieved by FTI treatment, but they also made clear that we need a much better understanding of the underlying disease mechanisms to be able to tackle specific aspects of the disease in a more focused approach. It will also be important to elucidate which of the numerous pathways found to be impaired in HGPS are most relevant for and causally involved in the pathologies, and which ones are just bystanders.

[9] Hyper-IgD syndrome/mevalonate kinase deficiency: what is new?

• Authors: C. Mulders-Manders, A. Simon
• Year: 2015
• Venue: Seminars in Immunopathology
• URL: https://www.semanticscholar.org/paper/b0c6a9943fcdf22c8aece6bd26c62c9c7e9d31f7
• DOI: 10.1007/s00281-015-0492-6
• PMID: 25990874
• PMCID: 4491100
• Citations: 57
• Influential citations: 2
• Summary: New findings in this disorder that have been published in the last 2 years are discussed, including new insights into pathophysiology, treatment, and the clinical phenotype linked to the genetic defect.
• Evidence snippets:
• Snippet 1 (score: 0.363) > valonate aciduria, a severe disease characterized by neurologic involvement with psychomotor retardation, cerebellar ataxia, and facial dysmorphy besides the inflammatory symptoms, leading to early death. MKD forms a continuous spectrum of disease between these two clinical entities. Overlapping clinical syndromes are seen with increasing frequency. As there is no clear border between phenotypes, we will use the term mevalonate kinase deficiency, which encompasses both HIDS and mevalonate aciduria, to describe the disease in this paper. > In this review, we will discuss new findings in MKD that have been published between January 1, 2012 and December 31, 2014. > What is new on the pathophysiological mechanism of MKD? > In the past 30 years, MKD has been proven to be a typical monogenetic autoinflammatory disease with overproduction This article is a contribution to the Special Issue on The Inflammasome and Autoinflammatory Diseases -Guest Editors: Seth L. Masters, Tilmann Kallinich and Seza Ozen of the inflammatory cytokine interleukin-1 beta (IL-1β) as prominent pathophysiological mechanism [3][4][5][6][7]. The importance of this cytokine in MKD is backed up by the beneficial effects of IL-1β-targeting drugs such as anakinra in patients with this disease [8][9][10][11]. > Most studies on the pathophysiology of MKD are based on in vitro cellular models with murine [12][13][14] or human cells with drug-induced block of the mevalonate kinase pathway w i t h e i t h e r H M G -C o A r e d u c t a s e i n h i b i t o r s o r bisphosphonates (Fig. 1). In these models, LPS or other bacterial components are used to mimic the inflammatory stimulus needed for the production of IL-1β. Stimulation of monocytes with LPS leads to increased pro-IL-1β transcription via activation of transcription factor NF-kB [5]. The effects of bisphosphonates

[10] Transcriptional profiling of Hutchinson-Gilford progeria patients identifies primary target pathways of progerin

• Authors: Sandra Vidak, Sohyoung Kim, Tom Misteli
• Year: 2026
• Venue: Nucleus
• URL: https://www.semanticscholar.org/paper/4bd99b0875508364d8672b6da5a50d024d485a53
• DOI: 10.1080/19491034.2025.2611484
• PMID: 41489464
• PMCID: 12773485
• Summary: To probe the clinical relevance of previously implicated cellular pathways and to address the extent of gene expression heterogeneity between patients, transcriptomic analysis of a comprehensive set of HGPS patients finds misexpression of several cellular pathways, including multiple signaling pathways, the UPR and mesodermal cell fate specification.
• Evidence snippets:
• Snippet 1 (score: 0.362) > Oxidative stress represents another key pathogenic mechanism in HGPS, as impaired NRF2 activity or increased reactive oxygen species (ROS) levels are sufficient to recapitulate HGPSassociated phenotypes [17,32,60]. Collectively, these findings underscore the multifactorial nature of HGPS pathogenesis, implicating interconnected signaling cascades involved in inflammation, oxidative stress, proteostasis, and vascular remodeling. Reassuringly, our findings indicate that many of the major pathways that have been described to contribute to HGPS phenotypes in mouse and cellular disease models are also misregulated in progeria patients, and targeting these pathways may provide therapeutic avenues to mitigate disease severity and improve outcomes in HGPS. > Although individuals with HGPS typically exhibit a characteristic set of clinical features, such as craniofacial abnormalities, growth retardation, and cardiovascular complications, there is notable variability in the age of onset, severity, and progression of symptoms between patients [7,9]. At the cellular level, HGPS is associated with several hallmark abnormalities, including nuclear envelope defects, decreased expression of several nuclear proteins and epigenetic marks, mitochondrial dysfunction, and increased cellular senescence [1,11,30,31,61]. These cellular phenotypes also exhibit considerable variation between patients, possibly contributing to differences in clinical outcomes. Our results indicate that even though some degree of transcriptional heterogeneity between the individual patients exists, the majority of patients exhibit misregulation of a set of shared pathways, suggesting that these pathways are universal driver mechanisms in HGPS. Further work is needed to understand the molecular and genetic factors that underlie inter-individual variability in disease expression and progression. > A limitation of pathway analysis of HGPS patient samples is to distinguish the pathways which are directly targeted by the disease-causing progerin protein and the emergence of adaptive secondary response pathways during progression of the disease in patients during their lifetime. The same caveat applies to the use of cell-based models used in the study of HGPS disease mechanisms.

[11] 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: 0.359) > 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.

[12] Replication stress as a driver of cellular senescence and aging

• Authors: Lauren M. Herr, Ethan Schaffer, Kathleen F Fuchs, A. Datta, Robert Michael Brosh
• Year: 2024
• Venue: Communications Biology
• URL: https://www.semanticscholar.org/paper/698be046efd479e99bba82c812613e880f855d44
• DOI: 10.1038/s42003-024-06263-w
• PMID: 38777831
• PMCID: 11111458
• Citations: 42
• Summary: Recent advances demonstrating the role of replication stress as an ultimate driver of cellular senescence and aging are reviewed, highlighting connections to hallmarks of aging, hereditary accelerated aging disorders, and senotherapeutics.
• Evidence snippets:
• Snippet 1 (score: 0.358) > Warsaw Breakage Syndrome (WABS) is classified as a cohesinopathy disorder characterized by developmental abnormalities 58 .Although WABS does not fully resemble a classic premature aging disorder, the pre-and postnatal growth inhibition is accompanied by chromosomal instability, a hallmark of many more traditional hereditary accelerated aging diseases.The mutated DDX11 gene encodes a DNA helicase that interacts with proteins involved in replication fork protection and stability 59 (Table 2).Cells from WABS patients display reduced replication fork progression 59 .Moreover, cancer cell lines depleted of DDX11 by RNA interference or in which DDX11 was deleted by CRISPR were found to be hypersensitive to chemotherapy drugs that induce replication stress 60 .DDX11 is believed to resolve G-quadruplex (G4) DNA to enable smooth replication [61][62][63] .However, the precise relationship of G4 DNA metabolism to aging and the mechanistic function(s) of DDX11 in G4-induced replication stress have not yet been fully elucidated.

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

• Authors: Yaomeng Huang, Tongxin Li, Shichao Gao, Shuyu Li, Xiaoran Zhu et al.
• Year: 2023
• Venue: Frontiers in Pharmacology
• URL: https://www.semanticscholar.org/paper/be229f6f2059faab4c97ec0a04bd055adab9dfe1
• DOI: 10.3389/fphar.2023.1290253
• PMID: 38026943
• PMCID: 10662320
• Citations: 3
• Summary: Natriuretic peptide receptor 1 (NPR1) was identified as a core gene associated with DCM through bioinformatics analysis and led to substantial improvements in cardiac and renal function, accompanied by an upregulation of NPR1 expression.
• Evidence snippets:
• Snippet 1 (score: 0.357) > Multiple pathways and molecules are involved in this process; however, the detailed underlying mechanisms remain unclear. In recent years, with the development of high-throughput sequencing and gene chip technologies, the use of bioinformatics technology to explore the occurrence, development, and prognosis of diseases has become a hot topic for scholars worldwide (Hwang et al., 2018;Nayor et al., 2019;Rinschen et al., 2019;Sturm et al., 2019;Montaner et al., 2020). > The present study aimed to use bioinformatics technology to screen for DCM-related genes and investigate their mechanisms, with the purpose of revealing the pathogenesis of DCM and seeking treatment methods. The GSE3586 dataset, containing expression profiles related to DCM, was selected from the Gene Expression Omnibus (GEO) database. This study aimed to predict the core genes that may play crucial roles in disease progression at the molecular level through the enrichment of relevant molecular pathways associated with DCM. Furthermore, the phenotype of the core genes was validated to further support the results of the bioinformatics analysis through basic and clinical experiments. Additionally, the role of glucocorticoids in DCM treatment is discussed in this article with the purpose of providing a theoretical and experimental basis for exploring the pathogenesis of DCM and elucidating therapeutic methods. This study also provides a theoretical reference for the interpretation, early diagnosis, and treatment of DCM.

[14] Rare Monogenic Diseases: Molecular Pathophysiology and Novel Therapies

• Authors: I. Condò
• Year: 2022
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/6aece75e6947f102b657851b74e8b96df5e654c1
• DOI: 10.3390/ijms23126525
• PMID: 35742964
• PMCID: 9223693
• Citations: 16
• Influential citations: 2
• Summary: A rare disease is defined by its low prevalence in the general population and its presence in a very small number of people.
• Evidence snippets:
• Snippet 1 (score: 0.355) > The selective expression or the particular role of specific genes in a single tissue explains the appearance of organ-specific inherited diseases. This is the case of genetic disorders of the kidney, which include dominant and recessive forms of cystic diseases, and renal tubulopathies. Mutations in polycystin-1 (PKD1) or -2 (PKD2) genes lead to autosomaldominant polycystic kidney disease (ADPKD), whose gender-dependent phenotype was analyzed in the study by Talbi et al. [9]. These results, obtained in mice lacking PKD1 expression, show the involvement of intracellular Ca2+ levels in the more severe phenotype affecting male ADPKD animals. Altogether, identification of the molecular mechanisms underlying enhanced Ca2+ signaling and proliferation in cells from male kidneys may contribute to develop novel therapeutics for ADPKD [9]. The autosomal-recessive form of polycystic kidney disease (ARPKD) mostly arises from defects in the gene named polycystic kidney and hepatic disease 1 (PKHD1), whereas a minority of cases is linked to a second causative gene DZIP1L. To examine the still unclear molecular pathophysiology of ARPKD, Cordido et al. recapitulate known molecular disease mechanisms and possible therapeutic approaches, from cellular and animal models to clinical trials [10]. The knowledge of ARPKD pathogenic pathways, involving the epidermal growth factor receptor (EGFR) axis, the production of adenylyl cyclase adenosine 3 ,5 -cyclic monophosphate (cAMP) and the activation of several protein kinases, begins to stimulate possible pharmacological interventions [10]. Inherited loss of function in various electrolyte transport proteins located along the nephron leads to two types of kidney tubulopathy with overlapping clinical symptoms: Gitelman and Bartter syndromes. The review by Nuñez-Gonzalez et al. aims to explain the different molecular basis of these difficult to diagnose monogenic syndromes. Moreover, the authors provide an overview of current therapeutic approaches and highlight the presence of common and specific options for Gitelman and Bartter patients [11].

[15] 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: 0.354) > 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

[16] 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: 0.353) > 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.

[17] The Classification of Autosomal Recessive Cerebellar Ataxias: a Consensus Statement from the Society for Research on the Cerebellum and Ataxias Task Force

• Authors: M. Beaudin, A. Matilla-Dueñas, B. Soong, J. Pedroso, O. Barsottini et al.
• Year: 2019
• Venue: Cerebellum (London, England)
• URL: https://www.semanticscholar.org/paper/8be333265c4faffaeb605213aa48cb23b33981c1
• DOI: 10.1007/s12311-019-01052-2
• PMID: 31267374
• PMCID: 6867988
• Citations: 49
• Summary: A consensus is built on the classification of autosomal recessive ataxias in order to develop a general approach to a patient presenting with ataxia, organize disorders according to clinical presentation, and define this field of research by identifying common pathogenic molecular mechanisms in these disorders.
• Evidence snippets:
• Snippet 1 (score: 0.352) > The importance of a proper recessive ataxia classification goes beyond the clinical diagnosis perspective. Autosomal recessive ataxias can be regrouped according to the deficient cellular and metabolic pathways involved, which provide a better understanding of cerebellar physiology and of its selective vulnerability to certain metabolic defects. This is also essential from a therapeutic perspective, as disorders that belong to the same metabolic pathway may to the same treatment options, indicating potential for drug repurposing. Figure 3 presents a pathophysiological classification of autosomal recessive ataxias. Certain genes are presented more than once since some proteins are involved in several metabolic pathways or may interfere with other cellular processes as they accumulate in neurons or glial cells. Table 3 presents a more detailed listing of the pathogenic pathways involved along with relevant references. Certain pathways are predominantly involved, notably mitochondrial dysfunction, which may result from abnormal mitochondrial DNA maintenance with progressive mutagenesis, defective mitochondrial protein synthesis and quality control, increased levels of reactive oxygen species and oxidative stress, deficient coenzyme Q10 metabolism, altered mitochondrial dynamics, defective mitochondrial chain assembly, or abnormal mitochondrial RNA maturation and processing (Table 3). Interestingly, many of the disorders caused by mitochondrial dysfunction also present with a mitochondrial clinical syndrome as shown in Fig. 1. Disorders of DNA repair mechanisms are also common, with double-strand break repair pathway or single-strand break repair complexes predominantly involved. Pathogenic mutations in these genes are also associated with a susceptibility to ionizing radiations and predisposition for cancers, but the neurological syndrome is characterized by cerebellar involvement and extrapyramidal movement disorders. It remains debated whether defective DNA repair is the main pathogenic mechanism causing the neurological phenotype [230], but the fact that several interacting genes in this pathway are involved in degenerative cerebellar ataxias suggests that the cerebellum has a peculiar susceptibility to DNA damage for which the underlying mechanism is not understood. Finally, altered synaptic morphology or synaptic dysfunction of Purkinje cells (PC) is frequently involved in recessive ataxias and is associated with aberrant Fig. 1 Clinical classification of autosomal recessive ataxias.

[18] The hyperornithinemia–hyperammonemia-homocitrullinuria syndrome

• Authors: D. Martinelli, D. Diodato, Emanuela Ponzi, M. Monné, S. Boenzi et al.
• Year: 2015
• Venue: Orphanet Journal of Rare Diseases
• URL: https://www.semanticscholar.org/paper/ed033868ee677da141e5c926bc7c93cac242ea06
• DOI: 10.1186/s13023-015-0242-9
• PMID: 25874378
• PMCID: 4358699
• Citations: 93
• Influential citations: 5
• Summary: The clinical phenotype of HHH syndrome is extremely variable and its severity does not correlate with the genotype or with recorded ammonium/ornithine plasma levels, suggesting the need for a better understanding of the still unsolved pathophysiology of the disease.
• Evidence snippets:
• Snippet 1 (score: 0.349) > Although the disease responds well to treatment with low risk of relapse of hyperammonemia [38], slowly progressive pyramidal signs characterize the chronic course, as also seen in argininemia [89]. However, the mechanism(s) of pyramidal dysfunction in HHH syndrome still remains to be elucidated. Creatine deficiency may contribute to the pathogenetic mechanism of the syndrome, as creatine is relevant for mitochondrial energy metabolism, regulation of glycolysis, proteins synthesis, membrane stabilization and neuromodulation [77,78,85]. This could be in line with the finding of abnormally shaped mitochondria at electron microscopy studies in skin fibroblasts, hepatocytes and muscle biopsy from HHH syndrome patients [11,23,82]. Furthermore, a mitochondrial dysfunction has been recently related to the effects of ornithine and homocitrulline in causing oxidative stress and disturbed mitochondrial homeostasis [79,80]. > A further mechanism that can be involved in the pathophysiology of HHH syndrome is related to polyamines metabolism. Shimizu and colleagues reported increased total and fractional (putrescine, cadaverine, spermine, spermidine) polyamines in one HHH syndrome patient [30]. Indeed, the clinical similarities between HHH syndrome and argininemia, which has been associated to an abnormal polyamine metabolism [91,92], may suggest a common pathogenetic mechanism causing pyramidal dysfunction. > Overall, the pathogenesis of HHH syndrome is complex and not completely understood. It is likely that different mechanisms, including the impact of low mitochondrial ornithine on UC flux, the presence of hyperammonemic crises and the disturbance of other pathways in major organs play a role in determining the heterogeneous clinical presentation of ORC1 deficiency. > In addition, as molecular studies failed to disclose a correlation between type of mutations or ornithine transport capacity and disease severity, an effect of genetic modifiers, such as ORC genes redundancy, seems to be likely, but further studies are certainly needed to clarify this point.

[19] Molecular Pathogenesis in Myeloid Neoplasms with Germline Predisposition

• Authors: Juehua Gao, Yihua Chen, M. Sukhanova
• Year: 2021
• Venue: Life
• URL: https://www.semanticscholar.org/paper/e92b2ee66272a4073ff4b6dfa5993cb9e23c577c
• DOI: 10.3390/life12010046
• PMID: 35054439
• PMCID: 8779845
• Citations: 5
• Summary: This review uses examples of these disorders to illustrate the key molecular pathways of myeloid neoplasms and models and tools that can further understand the biology and molecular mechanisms of this disease.
• Evidence snippets:
• Snippet 1 (score: 0.349) > The risk of developing a myeloid neoplasm is increased in patients with bone marrow failure syndromes, including Fanconi anemia (FA), severe congenital neutropenia, dyskeratosis congenita, Shwachman-Diamond syndrome, and Diamond-Blackfan anemia. Although the molecular mechanisms of these disorders have not entirely been elucidated, the concept of dysfunctional DNA repair being responsible for the main pathophysiology of FA is well accepted. As a result, cells from patients with FA display hypersensitivity to DNA cross-linking agents, such as mitomycin C (MMC) and diepoxybutane (DEB), revealing an increased rate of chromosome breakage upon exposure to one of these two agents. The chromosome breakage test has been developed as a clinical diagnostic test for patients with clinical suspicion of having FA. If positive, next-generation sequencing testing with a panel of FA genes is recommended to detect mutations and affected genes associated with FA for further family studies in order to identify mutation carriers. Many FA genes have been identified and grouped into broad categories: the FA core complex, ID2 complex proteins (FANCD2 (FA Complementation Group D2), FANCI (FA Complementation Group I)), and a group of proteins in the downstream functional units. Proteins in the FA core complex work together to activate the ID2 complex and downstream proteins to bring in DNA repair proteins. Mutations in any of the genes involved in the FA pathway impair DNA repair, especially the homologous recombination repair of double-strand DNA damage. Hematopoietic elements are particularly sensitive to this defect. According to the International Fanconi Anemia Registry Study, the risk of developing either MDS or AML before the age of 20 is 27%, and it rapidly increases to 52% by the age of 40 [42]. The mechanism of leukemogenesis in FA is thought to be due to emerged malignant clones harboring mutations that allow them to evade cell cycle regulation and apoptosis, leading to MDS and AML [43].

[20] 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: 0.348) > 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.

Notes

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