Asta Literature Retrieval: Pathophysiology and clinical mechanisms of MCM9-related gametogenic failure. Core disease mechanisms, molecular and c...

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

• Papers retrieved: 20
• Snippets retrieved: 20

Relevant Papers

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

• Authors: Sandra Vidak, Sohyoung Kim, Tom Misteli
• Year: 2026
• Venue: Nucleus
• URL: https://www.semanticscholar.org/paper/4bd99b0875508364d8672b6da5a50d024d485a53
• DOI: 10.1080/19491034.2025.2611484
• PMID: 41489464
• PMCID: 12773485
• Summary: To probe the clinical relevance of previously implicated cellular pathways and to address the extent of gene expression heterogeneity between patients, transcriptomic analysis of a comprehensive set of HGPS patients finds misexpression of several cellular pathways, including multiple signaling pathways, the UPR and mesodermal cell fate specification.
• Evidence snippets:
• Snippet 1 (score: 0.405) > Oxidative stress represents another key pathogenic mechanism in HGPS, as impaired NRF2 activity or increased reactive oxygen species (ROS) levels are sufficient to recapitulate HGPSassociated phenotypes [17,32,60]. Collectively, these findings underscore the multifactorial nature of HGPS pathogenesis, implicating interconnected signaling cascades involved in inflammation, oxidative stress, proteostasis, and vascular remodeling. Reassuringly, our findings indicate that many of the major pathways that have been described to contribute to HGPS phenotypes in mouse and cellular disease models are also misregulated in progeria patients, and targeting these pathways may provide therapeutic avenues to mitigate disease severity and improve outcomes in HGPS. > Although individuals with HGPS typically exhibit a characteristic set of clinical features, such as craniofacial abnormalities, growth retardation, and cardiovascular complications, there is notable variability in the age of onset, severity, and progression of symptoms between patients [7,9]. At the cellular level, HGPS is associated with several hallmark abnormalities, including nuclear envelope defects, decreased expression of several nuclear proteins and epigenetic marks, mitochondrial dysfunction, and increased cellular senescence [1,11,30,31,61]. These cellular phenotypes also exhibit considerable variation between patients, possibly contributing to differences in clinical outcomes. Our results indicate that even though some degree of transcriptional heterogeneity between the individual patients exists, the majority of patients exhibit misregulation of a set of shared pathways, suggesting that these pathways are universal driver mechanisms in HGPS. Further work is needed to understand the molecular and genetic factors that underlie inter-individual variability in disease expression and progression. > A limitation of pathway analysis of HGPS patient samples is to distinguish the pathways which are directly targeted by the disease-causing progerin protein and the emergence of adaptive secondary response pathways during progression of the disease in patients during their lifetime. The same caveat applies to the use of cell-based models used in the study of HGPS disease mechanisms.

[2] Molecular Therapies for Choroideremia

• Authors: Jasmina Cehajic Kapetanovic, A. Barnard, R. MacLaren
• Year: 2019
• Venue: Genes
• URL: https://www.semanticscholar.org/paper/87c56b44e88cddbc058a5e5361bd5da50656d576
• DOI: 10.3390/genes10100738
• PMID: 31548516
• PMCID: 6826983
• Citations: 23
• Summary: New insights into clinical phenotyping and molecular genetic testing in choroideremia are discussed with review of molecular mechanisms implicated in its pathogenesis and alternative molecular therapies are discussed including suitability of CRISPR gene editing, small molecule nonsense suppression therapy and vision restoration strategies in late stage choroidesremia.
• Evidence snippets:
• Snippet 1 (score: 0.403) > Molecular mechanisms in choroideremia are well established. Ultimately, the absence or reduced prenylation of REP1 activity disrupts intracellular trafficking pathways leading to accumulation of toxic products and premature degeneration of the retina and vision less. Logically then, replacement of REP1 to the retinal tissue, via gene-based therapy, could restore cellular function and slow down the degeneration. Multiple clinical trials are underway testing this hypothesis. The trials are using subretinal delivery of AAV2-REP1 to target surviving central islands of the retina with promising safety and early efficacy results. > Despite ubiquitous expression of REP1, a robust systemic association with choroideremia has not been identified, although the prenylation defect is visible in assays of the peripheral blood cells. This assay can be used to support the diagnosis of choroideremia. It is not known why the retina is the only part of the body that becomes clinically affected by the lack of REP1 activity. Moreover, the complex interactions between different retinal cell types during the pathogenesis of choroideremia mean that it is difficult to deconvolve the exact order in which RPE, photoreceptors and the choroid degenerate. It appears likely that the RPE is directly affected by the loss of REP1, and is a key driver of pathogenesis, but the importance of primary or secondary degeneration of photoreceptors is less clear. Elucidating these mechanisms may help us to understand what triggers the onset of clinically significant degeneration and how the rate of degeneration in each cell type might be affected following treatment. > Evidence to date has shown no apparent genotype-phenotype correlation within the spectrum of reported CHM mutations, with regard to the onset of symptoms and the rate of functional visual decline. Since variations in male phenotypes cannot be explained by mutations in CHM only, genetic modifiers or environmental factors must play a role in the onset and progression of degeneration in choroideremia. Ongoing natural history studies are adding insight into the progression of the disease and the characteristics of the clinical phenotype that will help to establish the optimal therapeutic window for choroideremia. Female carriers should be enrolled into natural history studies with aim to offer gene therapy (

[3] Molecular Mechanisms and Risk Factors for the Pathogenesis of Hydrocephalus

• Authors: Jing-wen Li, Xinjie Zhang, Jianfeng Guo, Chen Yu, Jun Yang
• Year: 2022
• Venue: Frontiers in Genetics
• URL: https://www.semanticscholar.org/paper/d53bdf5f73f54a6d5a8be8777d23c465a13e9185
• DOI: 10.3389/fgene.2021.777926
• PMID: 35047005
• PMCID: 8762052
• Citations: 15
• Influential citations: 2
• Summary: Some possible fundamental molecular mechanisms and facilitating risk factors involved in the pathogenesis of hydrocephalus are elicited, and knowledge could be used to improve patient care in different ways, such as early precise diagnosis and effective therapeutic regimens.
• Evidence snippets:
• Snippet 1 (score: 0.401) > Cwh43 modifies the glycosylphosphatidylinositol-anchored proteins on the ependymal cells, and the mutant Cwh43 is related to iNPH in both humans and mice. The clinical features manifest as late-onset communicating hydrocephalus with symptoms of gait and balance dysfunction (Yang et al., 2021a). > The clinical manifestation and progression, as well as experimental investigations, indicate that hydrocephalus is a complex disease with polygenic involvement, rather than a simple CSF accumulation disorder. Although the current studies have revealed that some genetic mutations are involved in the pathogenesis of hydrocephalus, how these mutations are associated with the disorder of CSF circulation and their pathogenic roles in the pathological progression of hydrocephalus still remain largely unknown. Previous studies indicated that a lot of genetic mutations were relevant to the disorders of ciliary and/or centrosome, resulting in the dysfunction of the glymphatic system. However, how these mutations and their interactions contribute to the pathogenesis of hydrocephalus needs to be further elucidated. Moreover, there is still a lack of basic knowledge on the mechanisms underlying the cognitive functional impairment of hydrocephalus. Therefore, further extensive studies should be conducted to explore the underlying molecular mechanisms of identified and/or unidentified genes in the pathophysiology of hydrocephalus. Based on our knowledge, we propose that the genetic mutations relevant to ciliary and centrosomal proteins and the interaction between glymphatic system and ciliary/ centrosomal structures/functions may be a critical molecular mechanism in the pathophysiology of hydrocephalus. In addition, based on these fundamental molecular mechanisms, it is noteworthy that environmental and other acquired risks or etiological factors are also involved in the facilitation of ventricular enlargement.

[4] 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: 0.400) > proteins of the cartilage ECM such as type II collagen [50]. However, emerging knowledge suggests that the primary genetic defect may be less important than the cells' response to the expression of the mutant gene product [107]. Moreover, the largely overlooked response of a cell (i.e. chondrocyte) to the abnormal extracellular environment is also important for disease progression as illustrated by several GSDs discussed in this review. > It is important that 'omics'-based approaches and technologies are systematically applied to the study of rare GSDs so that definitive reference profiles and disease signatures are generated for each phenotype. These can then be used in a Systems Biology approach to identify both common and dissimilar pathological signatures and disease mechanisms. This approach is entirely dependent upon relevant in vitro and in vivo models (and also novel 'disease-mechanism phenocopies' [107]) for testing new diagnostic and prognostic tools and for determining the molecular mechanisms that underpin the pathophysiology so that effective therapeutic treatments can be developed and validated. This approach will eventually lead to personalized treatments and care strategies centred on shared disease mechanisms with the use of relevant biomarkers to monitor the efficacy of treatment and disease progression. > It is vital that all relevant stakeholders are involved from the outset in defining the appropriate outcomes of any potential therapeutic regime. The perceptions of a successful therapy can differ widely between the clinical academic community and the relevant patient-support groups and it is vital that there is engagement on all these issues. > In summary, the identification of causative genes and mutations for GSDs over the last 20 years, coupled with the generation and in-depth analysis of a plethora of relevant cell and mouse models, has derived new knowledge on disease mechanisms and suggested potential therapeutic targets. The fast-evolving hypothesis that clinically disparate diseases can share common disease mechanisms is a powerful concept that will generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.

[5] 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: 0.399) > 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.

[6] 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: 0.397) > 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.

[7] Renal ciliopathies: promising drug targets and prospects for clinical trials

• Authors: L. Devlin, Praveen Dhondurao Sudhindar, J. Sayer
• Year: 2023
• Venue: Expert Opinion on Therapeutic Targets
• URL: https://www.semanticscholar.org/paper/ab2155b6e12caba53d57ac0e8ce28860d69ec9fd
• DOI: 10.1080/14728222.2023.2218616
• PMID: 37243567
• Citations: 10
• Summary: The advances in basic science and clinical research into renal ciliopathies which have yielded promising small compounds and drug targets are reviewed, within both preclinical studies and clinical trials.
• Evidence snippets:
• Snippet 1 (score: 0.396) > Although renal ciliopathies can be classified into distinct syndromes, causative mutations in genes encoding proteins involved in the primary cilium or centrosome mean they may share overlapping mechanisms of disease, which may be amenable for therapeutic intervention (Figure 2). Abnormal functioning of proteins involved in ciliogenesis, such as CEP164, can prevent proper cilia formation, which will effect a myriad of downstream ciliary signaling pathways. Additionally, mutations in genes encoding for proteins involved in cargo trafficking or regulation, such as CEP290, will have implications for signal pathway transduction, as well as mutations in components of signaling pathways themselves, such as PKD1. In regard to renal ciliopathies, abnormalities in signaling pathways such as cAMP, Shh, Wnt, mTOR, and AMPK, likely cause misoriented cellular divisions, increased proliferation, increased fluid secretion and subsequent cystogenesis, consequently leading to further kidney damage. Ciliary and centriolar proteins which have roles in DDR and cell cycle regulation may also be driving a renal cystogenesis phenotype alongside increased fibrosis and apoptosis. Increased inflammation and dysfunctional mitochondria are also byproducts of dysregulated signaling pathways have been shown to contribute to the progression of renal ciliopathies. Extensive reviews of mechanisms of renal ciliopathy diseases have recently been performed [23,24]. Importantly, due to the wide range of cellular processes that primary cilia regulate, it is likely that in each syndrome there are multiple pathogenic drivers of disease. In some ways, this is advantageous as it offers many points for potential therapeutic targets. However, the cross talk between pathways and feedback loops introduces complications of changing one pathway without negatively affecting another. Further challenges arise with core biological pathways, such as Shh signaling, in which modification in vitro may be beneficial, but systemic treatment is unrealistic due to the expected severe side effects [18,24,116].

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

• Authors: F. Iheagwam, A. J. Joseph, E. D. Adedoyin, Olawumi Toyin Iheagwam, Samuel Akpoyowvare Ejoh
• Year: 2025
• Venue: Pathophysiology
• URL: https://www.semanticscholar.org/paper/dbf8042761c1a5fc50f8cd894cc498505abac7cb
• DOI: 10.3390/pathophysiology32010009
• PMID: 39982365
• PMCID: 12077258
• Citations: 25
• Summary: This review aims to elucidate the complex link between mitochondrial dysfunction and diabetes, covering the spectrum of diabetes types, the role of mitochondria in insulin resistance, highlighting pathophysiological mechanisms, mitochondrial DNA damage, and altered mitochondrial biogenesis and dynamics.
• Evidence snippets:
• Snippet 1 (score: 0.396) > The landscape of DM research is continuously evolving, with emerging technologies and approaches offering new insights into the pathophysiology of the disease and potential therapeutic targets. Advancements in omics technologies, encompassing genomes, transcriptomics, proteomics, and metabolomics, have transformed the molecular mechanisms underlying DM [134]. High-throughput sequencing techniques enable comprehensive analysis of genetic variants, gene expression profiles, protein abundance, and metabolite levels associated with DM and its complications [135]. Single-cell omics approaches provide unprecedented resolution and granularity, allowing researchers to dissect cellular heterogeneity and identify novel cell types, subpopulations, and signalling pathways involved in DM pathogenesis. Integrating multi-omics data sets offers a systems-level perspective of DM, unravelling complex networks of molecular interactions and regulatory circuits underlying disease progression [136]. > In addition to omics technologies, advances in imaging modalities, such as MRI, PET, and optical imaging, enable non-invasive visualisation and quantification of metabolic, functional, and structural changes. Molecular imaging probes targeting specific biomarkers and metabolic pathways provide valuable insights into disease mechanisms and treatment responses in preclinical and clinical settings [85]. Despite significant progress in DM research, numerous unanswered questions and knowledge gaps persist, hindering the ability to develop effective prevention and treatment strategies. Key areas requiring further investigation include the role of epigenetics, environmental factors, and the microbiome in DM susceptibility and progression. Moreover, the interaction between environmental cues and genetic predisposition remains incompletely understood, highlighting the need for comprehensive multi-omics studies and large-scale epidemiological analyses to identify gene-environment interactions and modifiable risk factors for DM [137]. Furthermore, the heterogeneity of DM phenotypes and clinical outcomes poses a challenge for personalised medicine approaches, necessitating robust biomarkers and predictive models to stratify patients based on disease subtypes, prognosis, and treatment response [138].

[9] Cardiomyocytes Derived from Induced Pluripotent Stem Cells as a Disease Model for Propionic Acidemia

• Authors: Esmeralda Alonso-Barroso, B. Pérez, L. Desviat, E. Richard
• Year: 2021
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/da649a0f04477c53b448c5ac5f873f8762235290
• DOI: 10.3390/ijms22031161
• PMID: 33503868
• PMCID: 7865492
• Citations: 16
• Influential citations: 1
• Summary: The novel results show that PA iPSC-cardiomyocytes represent a promising model for investigating the pathological mechanisms underlying PA cardiomyopathies, also serving as an ex vivo platform for therapeutic evaluation.
• Evidence snippets:
• Snippet 1 (score: 0.394) > The study of the mechanisms involved in disease physiopathology has been mainly performed using the hypomorphic PA mouse model that mimics the biochemical and clinical phenotype [5]. Using this model, bioenergetic failure, oxidative damage and deregulation of miRNAs induced by accumulating propionyl-CoA have been described as potential mechanisms contributing to PA physiopathology [6][7][8]. The limitations of animal models for the study of cardiac energy metabolism [9] and of the commonly available cellular human models such as fibroblasts, underline the importance of generating new relevant cell models to provide deeper insight into the underlying mechanisms of disease. The use of in vitro models with human cellular context is highly recommended and, in this sense, induced pluripotent stem cells (iPSCs) have certain advantages since they provide the genetic background of the patient and represent an unlimited source of biological material for the study of pathophysiology and treatment effectiveness [10]. We have previously generated an iPSC line from a PA patient with defects in the PCCA gene that showed full pluripotency, differentiation capacity and genetic stability [11]. > In the present study, we aimed to establish a platform that served as a disease model to study the cellular and molecular alterations operating in cardiac tissue affected by PA disease. We described the characterization of cardiomyocytes derived from the PCCA iPSC line (PCCA iPSC-CMs) and the analysis of specific pathways potentially involved in cardiac PA physiopathology.

[10] Nasopharyngeal Carcinoma Signaling Pathway: An Update on Molecular Biomarkers

• Authors: W. Tulalamba, T. Janvilisri
• Year: 2012
• Venue: International Journal of Cell Biology
• URL: https://www.semanticscholar.org/paper/307cb9186444d9dad6e2e3b53763be0de76de186
• DOI: 10.1155/2012/594681
• PMID: 22500174
• PMCID: 3303613
• Citations: 93
• Influential citations: 5
• Summary: The molecular signaling pathways in the NPC are discussed for the holistic view of NPC development and progression and the important insights toward NPC pathogenesis may offer strategies for identification of novel biomarkers for diagnosis and prognosis.
• Evidence snippets:
• Snippet 1 (score: 0.390) > In the pregenomic eras, highly integrated and complex circuitry of molecular signaling in NPC pathogenesis was only partially understood. Over the past decade, the knowledge of the molecular mechanisms in NPC carcinogenesis has been rapidly accumulated. Dysregulation and abnormal protein expression of molecules in certain signaling pathways involved in cellular functions including proliferation, adhesion, survival, and apoptosis has been demonstrated in the NPC cells. Detailed information on the complex network in signaling pathway leading to a coordinated pattern of gene expression and regulation in NPC will undoubtedly provide important clues to develop novel prognostic and therapeutic strategies for this cancer. Refining molecular markers into clinically relevant assays may assist in the detection of NPC in asymptomatic patients, as well as stage classification and monitoring disease progression and treatments. Furthermore, selective regulation of particular proteins targeting cancer cell proliferation, invasion, and apoptosis is a hopeful prospect for future anticancer therapy that slow disease progression and improve survival.

[11] The Small RNA Landscape in Azoospermia: Implications for Male Infertility and Sperm Retrieval—A Preliminary Study

• Authors: Maria-Anna Kyrgiafini, Ares Kaltsas, Alexia Chatziparasidou, Z. Mamuris
• Year: 2025
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/05aad4dbca2759eef92858b645374ce23902f175
• DOI: 10.3390/ijms26083537
• PMID: 40331996
• PMCID: 12027063
• Citations: 6
• Summary: Highlights miRNA-mediated regulatory differences in azoospermic patients are highlighted, identifying potential biomarkers for sperm retrieval success and fertility outcomes and enhancing male infertility diagnostics.
• Evidence snippets:
• Snippet 1 (score: 0.387) > An additional key comparison in this study was made between individuals with rare spermatozoa who achieved pregnancy (RSPZP) and those who did not (RSPZNP). This analysis aimed to uncover the biological processes, cellular components, and molecular functions affected by differentially expressed miRNAs, providing insights into the molecular mechanisms that may contribute to reproductive success or failure. The most significantly enriched GO biological processes included cellular metabolic process, developmental process, nitrogen compound metabolic process, anatomical structure development, cellular component organization, primary metabolic process, multicellular organism development, regulation of biological quality, and metabolic process. The most enriched GO cellular component terms were intracellular, intracellular part, organelle, cytoplasm, membrane-enclosed lumen, nucleus, nucleoplasm, and non-membrane-bounded organelle. These results indicate that miRNA-regulated genes are primarily involved in intracellular structures, particularly within nuclear and cytoplasmic compartments, where they may influence gene expression. Finally, the most significantly enriched GO molecular function terms included protein binding, molecular function regulation, ion binding, catalytic activity, nucleoside phosphate binding, purine nucleotide binding, and transferase activity. These functions highlight the importance of protein interactions, enzymatic activity, and nucleotide metabolism (Figures 11-13). As in the previous analysis, we performed a pathway enrichment analysis to identify the biological pathways affected by the upregulated and downregulated miRNAs in the RSPZNP vs. RSPZP comparison. The enriched pathways associated with the gene targets of upregulated and downregulated miRNAs in RSPZNP are presented in Table 7. A KEGG pathway analysis also identified the major biological pathways in which the target genes of differentially expressed miRNAs are involved among all comparisons. The most significantly enriched pathways, ranked by corrected p-values, are presented in Table 8. These enriched pathways highlight the key molecular mechanisms that regulate cellular metabolism, survival, and signal transduction.

[12] Chemotherapy and Mechanisms of Resistance in Breast Cancer

• Authors: A. Oliveira, R. E. Santos, F. F. O. Rodrigues
• Year: 2012
• Venue: Unknown venue
• URL: https://www.semanticscholar.org/paper/502a86d8bcd7208be6f539fcceba631f82f25a7d
• DOI: 10.5772/24629
• Summary: The addition of adjuvant polychemotherapy in advanced breast cancer showed gain by controlling survival of micrometastases in patients with lymph nodes affected by cancer or not.
• Evidence snippets:
• Snippet 1 (score: 0.386) > The main reasons responsible for treatment failure in cancer patients are the mechanisms of drug resistance and emergence of disseminated disease (Terek et al, 2003). We identified two types of resistance most relevant to BC: primary resistance, which corresponds to the clinical situation where the patient showed no response to therapy, and secondary or acquired resistance in which, initially, there is an observed response and a subsequent failure of the treatment regimen (Kroger et al, 1999). Several mechanisms may cause the phenotype of multidrug resistance to chemotherapy drugs and are well characterized in in vitro experiments, including alterations in systemic pharmacology (pharmacokinetics and metabolism), extracellular mechanisms (tumor environment, multicellular drug resistance), and cellular mechanisms (cellular pharmacology, activation and inactivation of drugs, modification of specific targets and regulatory pathways of apoptosis) (Leonessa et al, 2003, Riddick et al, 2005. Identification of factors that affect cell metabolism, which are related to drug resistance, will enable the identification of which patients are at particular risk of treatment failure. Among the biochemical and molecular mechanisms of drug resistance, we stress: changes in the activity of topoisomerase II, alterations in the DNA repair mechanism, overexpression of P-glycoprotein; high intracellular concentrations of enzymes purification of cellular metabolism -among them enzymes the family of glutathione S-transferases (GSTs) and changes in the mechanisms of signaling via c-Jun N-terminal kinase 1 (JNK1) -and "apoptosis signal-regulating kinase (ASK1) required for activation of the" mitogenactivated protein (MAP kinases) in apoptosis and cellular restoration. These pathways are also mediated by proteins encoded by genes of GSTs (O'Brien, Tew, 1996;Burg, Mulder, 2002, L'Ecuyer et al, 2004). Different response rates to particular chemotherapy regimens, as observed in patient groups with the same biological characteristics and stage, suggest the existence of different mechanisms of drug resistance, probably induced by genetic alterations (Hayes, Pulford, 1995;O'Brien , Tew, 1996;Pakunlu et al, 2003). Among the mechanisms of purification of cellular metabolism involved in the

[13] Computational drug discovery approaches identify mebendazole as a candidate treatment for autosomal dominant polycystic kidney disease

• Authors: P. Brownjohn, A. Zoufir, Daniel J O’Donovan, Saatviga Sudhahar, A. Syme et al.
• Year: 2024
• Venue: Frontiers in Pharmacology
• URL: https://www.semanticscholar.org/paper/a595e78572ca02b8cb2897bfc4a989a2b021b279
• DOI: 10.3389/fphar.2024.1397864
• PMID: 38846086
• PMCID: 11154008
• Citations: 3
• Summary: It is determined that the anthelmintic mebendazole was a potent anti-cystic agent in human cellular and in vivo models of ADPKD, and is likely acting through the inhibition of microtubule polymerisation and protein kinase activity.
• Evidence snippets:
• Snippet 1 (score: 0.385) > Targets and molecules were ultimately filtered for validation based on biological and chemical insights, and the potential for clinical translation.Earlier this year, Wilk et al., 2023 applied a similar transcriptomic approach to us, in that case making use of publicly available transcriptomic datasets to create Pkd2-specific ADPKD disease signatures, from which signature reversion was sought from the Library of Integrated Network-based Cellular Signatures (LINCs) drug signature database in order to identify drug repurposing candidates.While one group has previously made use of a knowledge graph-based approach to prioritise preclinically active compounds with the highest chance of clinical translation (Malas et al., 2019), to our knowledge, the current study provides the first combined application of transcriptomic and machine-learning approaches to identify and prioritise putative treatments for ADPKD, and further deconvolute potential mechanisms of action for experimental validation. > In summary we report, using computational, in vitro and in vivo approaches, that the anthelmintic drug mebendazole ameliorates disease-relevant phenotypes in cellular and animal models of ADPKD.We further show that this effect is likely primarily due to the inhibitory effect of mebendazole on the polymerisation of microtubules, which underlie cellular processes important in ADPKD, including cell proliferation, transport, and cilia signalling, and extends previous work linking the importance of the microtubule network to ADPKD pathophysiology.We also describe the inhibitory profile of mebendazole on known and novel protein kinase targets, some of which have previously been implicated in ADPKD, suggesting mebendazole may be acting via polypharmacology to impact disease mechanisms.We acknowledge that further experimental efforts will be required to confirm the actions of mebendazole on these putative targets in relevant disease model systems.It would be particularly informative to investigate these mechanisms in dedicated in vivo studies, where the effects of mebendazole on a wider range of ADPKD-relevant cell types and phenotypes could be evaluated.

[14] Using Zebrafish Animal Model to Study the Genetic Underpinning and Mechanism of Arrhythmogenic Cardiomyopathy

• Authors: Yujuan Niu, Yuanchao Sun, Yuting Liu, Ke Du, Xiaolei Xu et al.
• Year: 2023
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/1ea7360cab3224c8bbe08bf376ceb2f4c216ca49
• DOI: 10.3390/ijms24044106
• PMID: 36835518
• PMCID: 9966228
• Citations: 5
• Summary: Arrhythmogenic cardiomyopathy (ACM) is largely an autosomal dominant genetic disorder manifesting fibrofatty infiltration and ventricular arrhythmia with predominantly right ventricular involvement. ACM is one of the major conditions associated with an increased risk of sudden cardiac death, most notably in young individuals and athletes. ACM has strong genetic determinants, and genetic variants in more than 25 genes have been identified to be associated with ACM, accounting for approximately...
• Evidence snippets:
• Snippet 1 (score: 0.384) > Currently, clinical management of ACM patients mainly focuses on the general control of heart failure and the prevention of arrhythmic sudden cardiac death (SCD) [12]. No specific genotype-tailored therapeutic approaches for ACM are currently available. > Classic human genetic studies, such as familial linkage analysis, are limited by exhaustible pedigree resources and difficulties in obtaining appropriate tissue samples, while next-generation genome-wide association studies (GWASs) lack the power to directly define the genotype-phenotype relationship. In addition, human genetic studies are also affected by other intrinsic limitations, including different lifestyles and environmental stimuli such as exercise, inflammation, viral infection, and drug usage, which hampered advances in our understanding of the ACM disease pathophysiology and the development of effective therapies. > As animal models can be housed under standardized and controlled conditions, the potential influences of many confounding variables such as environmental factors and genetic background can be circumvented to help define the causal roles of gene mutations in ACM. For variants with defined causal roles, genetic animal models allow for ready investigation of the molecular and cellular mechanisms underlying ACM disease progression at the whole organism level. Indeed, studies using the development of in vivo animal models combined with in vitro cell culture systems have led to the discovery of several major signaling pathways, such as the Wnt/β-catenin, Hippo/Yes associated protein (YAP), and transforming growth factor-β (TGF-β) signaling pathways, which are involved in the pathogenesis of ACM [8,9,13]. A deeper understanding of disease pathophysiology and mechanisms of action would help to identify new therapeutic targets and pave the way for the development of innovative disease therapies and cures. > Traditionally, owing to their well-conserved physiology to humans, mammals such as rodents have been the gold standard for animal models when studying disease pathophysiology and the underlying disease mechanisms of action. Due to the relatively long and costly experimental process and, thus, low throughput, rodent models are limited when functionally validating a vast number of gene variants and discovering new genetic disease associations on a large scale.

[15] 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: 0.382) > 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.

[16] Baseline urinary metabolites predict albuminuria response to spironolactone in type 2 diabetes.

• Authors: S. Mulder, P. Perco, C. Oxlund, Uzma F Mehdi, T. Hankemeier et al.
• Year: 2020
• Venue: Translational research : the journal of laboratory and clinical medicine
• URL: https://www.semanticscholar.org/paper/e5f7ffaa67fba1fe09d82c2d3787ad398d175bb6
• DOI: 10.1016/j.trsl.2020.04.010
• PMID: 32438071
• Citations: 9
• Summary: The data suggest that urinary metabolites may be used as a tool to tailor optimal therapy and move in the direction of personalized medicine.
• Evidence snippets:
• Snippet 1 (score: 0.377) > In-silico modeling of spironolactone mechanism of action and DKD pathophysiology. Network-based molecular models reflecting spironolactone mechanism of action as well as DKD pathophysiology were generated following previously described and successfully applied computational workflows. 8,9 In brief, molecular features associated with spironolactone were consolidated from 3 data sources, namely scientific literature, DrugBank, and a transcriptomics data set from DrugMatrix. Molecular features were defined as genes, transcripts, or proteins. Scientific articles annotated with spironolactone as major MeSH term were retrieved and genes were extracted using NCBI's gene2pubmed file. This set of genes was complemented by drug targets listed in DrugBank for spironolactone. 10 We further extracted transcripts being differentially expressed between spironolactone-treated and untreated kidney samples of animal models as stored in DrugMatrix. 11 The unique set of spironolactone associated molecular features was mapped onto a hybrid interaction network including protein-protein interaction data from IntAct, BioGrid, and Reactome together with computationally inferred relations. 12 Interactions between members of the spironolactone feature set were extracted and the MCODE algorithm was used to identify clusters of highly interconnected proteins. 13 A previously published DKD molecular model was used which was constructed following the same logic using data from scientific literature as well as from Omics datasets in the context of DKD. 7 Proteomics data of the published CKD273 proteomics classifier were used in order to identify DKD processes linked with DKD progression by mapping the set of proteins in the CKD273 classifier onto the DKD molecular network thus defining progression-associated process units. 14 Network interference analysis and identification of candidate metabolites. Network alignment method was used to identify DKD molecular processes linked to DKD prognosis affected by spironolactone treatment on the molecular level. Metabolites linked to proteins in affected DKD molecular processes were identified via enzyme-metabolite associations as stored in the Human Metabolome Database and forwarded to measurements in clinical samples. 15 A

[17] 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: 0.377) > 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.

[18] N6‐Methyladenosine Modification on the Function of Female Reproductive Development and Related Diseases

• Authors: Xiangrong Cui, Huihui Li, Xia Huang, Tingting Xue, Shu Wang et al.
• Year: 2024
• Venue: Immunity, Inflammation and Disease
• URL: https://www.semanticscholar.org/paper/a78388c3251253236f5a805675184c59f4af9f7f
• DOI: 10.1002/iid3.70089
• PMID: 39660878
• PMCID: 11632877
• Citations: 3
• Summary: N6‐methyladenosine (m6A) modification is a widespread and reversible epigenetic alteration in eukaryotic mRNA, playing a pivotal role in various biological functions. Its significance in female reproductive development and associated diseases has recently become a focal point of research.
• Evidence snippets:
• Snippet 1 (score: 0.377) > m 6 A modification plays a crucial role in facilitating the cellular sorting and management of RNA, contributing to the organized metabolism and functional regulation of cells, thereby enhancing the precise control of gene expression. The female reproductive process is a complex physiological phenomenon that necessitates the coordinated interplay of multiple mechanisms and meticulous regulation. Undoubtedly, m 6 A modification significantly impacts the development and early embryonic stages of oocytes, highlighting the extensive potential of m 6 A modification in the realm of reproduction. Current research suggests that m 6 A modification is involved in diverse mechanisms within female reproductive physiological processes, governing the orderly RNA metabolism. Furthermore, disruptions in m 6 A modification are closely linked to diseases, with various signaling pathways regulating the pathological progression of these conditions. Nevertheless, the molecular mechanisms governing the modification and regulation of m 6 A and its associated regulatory factors remain poorly understood, and there is a lack of in vivo experimental validation, significantly impeding its clinical translational potential. For example, the mechanisms through which m 6 A modulates early embryonic development and the functions of trophoblast cells and embryonic stem cells during the blastocyst stage are still unclear. Moreover, the influence of environmental factors on m 6 A regulation in embryonic development, such as exposure to the final metabolites of benzo(a) pyrene in cells or animals, and how it affects m 6 A levels, relevant methyltransferases, demethylases, and methyl-binding proteins, along with their subsequent effects, remains to be elucidated. Furthermore, which other female reproductive disorders are associated with m 6 A, and what are the specific molecular mechanisms involved? Additionally, considering that m 6 A formation is a complex and dynamic process regulated by methyltransferases and demethylases, there is currently a lack of real-time monitoring techniques for m 6 A, highlighting the need for advancements in existing detection technologies. A more profound comprehension of the regulatory mechanisms of m 6 A will enhance our understanding of the intrinsic processes of female reproductive system development and aging, offering more effective insights for disease treatment strategies and assisted reproduction.

[19] RNA N6-methyladenosine modification in female reproductive biology and pathophysiology

• Authors: Erqing Huang, Li-juan Chen
• Year: 2023
• Venue: Cell Communication and Signaling : CCS
• URL: https://www.semanticscholar.org/paper/05f09ccf0c74677cbc30c76f84f0eeef75766b94
• DOI: 10.1186/s12964-023-01078-4
• PMID: 36894952
• PMCID: 9996912
• Citations: 38
• Summary: A summary of the research results of m^6A on the female reproductive biology and pathophysiology in recent years is provided and future research directions and clinical applications of m*6A-related targets are discussed.
• Evidence snippets:
• Snippet 1 (score: 0.374) > Modification of pharmacogene mRNAs may alter their pharmacokinetics and pharmacodynamics, thus affecting drug efficacy. In future studies, not only do the pathophysiological mechanisms of female reproductive system diseases in which m 6 A is involved deserve attention but also the m 6 A modifications occurring in the pharmacodynamic gene targets corresponding to drugs need to be considered. For the successful design of tissue-or cell-specific RNA methylation agonists or inhibitors, more multicentre and large-scale studies are needed. Many essential issues must be addressed in a detailed manner. A very limited number of cell and animal models are used in all cited papers, and the results are hence subject to variation. First, although METTL4, FTO, and ALKBH5 are commonly known and well-studied m 6 A regulatory factors, the role of less studied m 6 A regulatory factors, such as RBM15/15B and ZC3H13, may only be the tip of the iceberg. Further research is needed on the interactions between RNA modification regulators and their downstream targets in the female reproductive system. Second, the reproductive-endocrine system plays a pivotal role in the progression of gynaecological diseases. Research currently focuses on the influence of m 6 A on cellular behaviour. The interplay between the hormonal milieu and endocrine system related to m 6 A modification remains a mystery and should be addressed in the future. Finally, the majority of published studies have concentrated only on the molecular mechanism of m 6 A modification. A greater focus should be placed on the diagnostic and therapeutic properties of m 6 A. According to a large body of evidence, m 6 A modifications are related to clinical phenotypes and prognoses. m 6 A is involved in the common pathological features shared by benign and malignant diseases of the female reproductive system, and different m 6 A phenotypes in these diseases may be involved in the transformation between benign and malignant diseases and between different pathological types in the same disease. > Compared with other reviews in this field, our article provides a more comprehensive overview of the relationship between m 6 A and the physiology and pathology of the female reproductive system.

[20] Clinical metabolomics in type 2 diabetes mellitus: from pathogenesis to biomarkers

• Authors: Chuanxin Liu, Hetao Chen, Yujin Ma, Lei Zhang, Lulu Chen et al.
• Year: 2025
• Venue: Frontiers in Endocrinology
• URL: https://www.semanticscholar.org/paper/36f8d26a208b7b96763df2e9aa3211e440031c0e
• DOI: 10.3389/fendo.2025.1501305
• PMID: 40070584
• PMCID: 11893406
• Citations: 11
• Summary: The results facilitate understanding the pathophysiology and mechanism of type 2 diabetes mellitus and supports research in accurate diagnosis, risk prediction, curative effect, distinct stages, and prognosis judgment of T2DM.
• Evidence snippets:
• Snippet 1 (score: 0.373) > The metabolome is sensitive to a variety of genetic and environmental stimuli and susceptible to genetic, environmental, and gut microbiome pressures, so subtle differences between individuals can lead to large perturbations in metabolite concentrations and fluxes (15, 24). At present, cystatin C has become an ideal endogenous marker for evaluating glomerular filtration function because it is not affected by sex, age or muscle mass (25). In addition, more and more evidence shows that serum CysC is involved in the pathological process of vascular remodeling and neovascularization, which is closely related to the occurrence and development of diabetic microangiopathy (26). > Eighty-four papers were included in this review and obtained through database searches, namely, PubMed, Cochrane Library, China national knowledge internet(CNKI), General Purpose, and VIP Database. The keywords for the searches were "metabolomics" and "type 2 diabetes mellitus" and its complications. The papers were incorporated by reading and summarizing the literature according to the classification standards (27). The profound analysis of clinical differential metabolites identified in type 2 diabetes and its complications were conducted concerning composition, frequency of category, sample type, and pathways to explore the pathological mechanism of type 2 diabetes and its complications to provide a systematic basis for clinical diagnosis, risk stratification, comprehending disease progression, prognosis assessment, and drug efficacy. Our goal is to apply metabolomics to clinical diagnostic biomarkers, metabolic mechanisms, and prognostic observations, and early diagnosis can be made through metabolites to avoid progression to more serious complications.

Notes

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