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

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

• Papers retrieved: 20
• Snippets retrieved: 20

Relevant Papers

[1] Knockdown of Son, a mouse homologue of the ZTTK syndrome gene, causes neuronal migration defects and dendritic spine dysgenesis

• Authors: M. Ueda, Tohru Matsuki, M. Fukada, S. Eda, Akie Toya et al.
• Year: 2020
• Venue: Unknown venue
• URL: https://www.semanticscholar.org/paper/609f724952969a82fed78d27881321d1c78c4799
• DOI: 10.21203/rs.3.rs-17672/v1
• Summary: The results strongly suggest that the neural abnormalities in ZTTK syndrome are caused by SON haploinsufficiency independent of the types of mutation that results in functional or dysfunctional proteins.
• Evidence snippets:
• Snippet 1 (score: 0.430) > Recent genetic studies identi ed 31 individuals exhibiting intellectual disability (ID) and/or developmental delay with de novo heterozygous mutations in SON, which was established as Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome [1][2][3][4][5][6]. ZTTK syndrome was further characterized as a congenital anomaly syndrome of ID, brain malformation, facial dysmorphism, musculoskeletal abnormalities, and less common visceral malformations [1,2,4]. The mutations found to be associated with ZTTK syndrome are mostly frameshift mutations and nonsense substitutions generating a premature termination codon [1][2][3][4][5][6], and transcripts of the mutant gene seem to be degraded due to nonsense-mediated mRNA decay (NMD) [1]; this has made ZTTK syndrome to be regarded as an entity caused by SON haploinsu ciency. > SON is a ubiquitously expressed and evolutionarily conserved gene in vertebrates and is located on the human chromosome region 21q22.11 [4]. It encodes the DNA-and RNA-binding protein SON, which functions in RNA splicing as well as gene repression [7][8][9][10][11][12]. A wide variety of genes are, thus, under the control of SON, and SON has been reported to be involved in cell cycle regulation and stem cell maintenance [7][8][9][10][11]. However, the functional signi cance of SON in neural development is largely unknown, and the pathological consequence of SON haploinsu ciency underlying the neural phenotypes of ZTTK syndrome, such as ID and brain malformation, remains undetermined. In this report, we revealed through knockdown experiments in the developing mouse brain that Son insu ciency caused neuronal migration abnormalities and dendritic spine dysgenesis. Rescue experiments that induced the expression of human wild-type SON protein and truncated SON proteins encoded by disease-associated mutant SON genes provided further information relevant to the pathophysiology of ZTTK syndrome.

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

• Authors: M. Uzti̇mür, C. N. Ünal, Gurler Akpinar
• Year: 2025
• Venue: Journal of Veterinary Internal Medicine
• URL: https://www.semanticscholar.org/paper/4b9c488b5dbd65d7b26fd2ad9aed70e8c4b59942
• DOI: 10.1111/jvim.70139
• PMID: 40492724
• PMCID: 12150350
• Summary: Understanding the serum proteome profiles of goats with pregnancy toxemia might help identify the proteomes and pathways responsible for the development of this disease and improve diagnosis and treatment.
• Evidence snippets:
• Snippet 1 (score: 0.423) > The pathophysiology and progression of this disease are not fully understood. > Traditional biomedical research has focused on the analysis of single genes, proteins, metabolites, or metabolic pathways in diseases. This molecular reductionist approach is based on the assumption that identifying genetic variations and molecular components will lead to new treatments for diseases [13][14][15][16]. However, many diseases are complex and multifactorial, and in order to determine the phenotype of such diseases, it is necessary to understand the changes that occur in more than one gene, pathway, protein, or metabolite at the cellular, tissue, and organismal levels [17][18][19]. Therefore, in recent years, proteomics, as one field of multi-omics technologies, has helped in evaluating the complex pathogenetic mechanisms of different diseases from a broad perspective and has made substantial contributions [20,21]. In veterinary medicine, proteomic analysis of metabolic diseases such as ketosis [16], hypocalcemia [22], and fatty liver [23] in dairy cows has contributed valuable insights for the definition of new pathophysiological pathways and new diagnosis and treatment protocols for these diseases. The proteomic approach can contribute importantly to a broad and detailed understanding of the changes that occur at the organismal level associated with the increase in BHBA concentration in goats with pregnancy toxemia. Our aim was to evaluate the serum protein profiles of goats with SPT or CPT using proteomic techniques to determine the proteomic profiles of these animals and to identify the relevant pathophysiological mechanisms.

[3] 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: 0.412) > 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.

[4] 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: 0.410) > 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.

[5] 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: 0.404) > 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

[6] Knockdown of Son, a mouse homologue of the ZTTK syndrome gene, causes neuronal migration defects and dendritic spine abnormalities

• Authors: M. Ueda, Tohru Matsuki, M. Fukada, S. Eda, Akie Toya et al.
• Year: 2020
• Venue: Molecular Brain
• URL: https://www.semanticscholar.org/paper/976a2685a1dc9775c2b442d6106ba2240ee3558c
• DOI: 10.1186/s13041-020-00622-4
• PMID: 32448361
• PMCID: 7245844
• Citations: 18
• Influential citations: 1
• Summary: The results support that the neural abnormalities in ZTTK syndrome are caused by SON haploinsufficiency independent of the types of mutation that results in functional or dysfunctional proteins.
• Evidence snippets:
• Snippet 1 (score: 0.400) > Recent genetic studies identified 31 individuals exhibiting intellectual disability (ID) and/or developmental delay with de novo heterozygous mutations in SON, which was established as Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome [1][2][3][4][5][6]. ZTTK syndrome was further characterized as a congenital anomaly syndrome of ID, brain malformation, facial dysmorphism, musculoskeletal abnormalities, and less common visceral malformations [1,2,4]. The mutations found to be associated with ZTTK syndrome are mostly frameshift mutations and nonsense substitutions generating a premature termination codon [1][2][3][4][5][6], and transcripts of the mutant gene seem to be degraded due to nonsensemediated mRNA decay (NMD) [1]; this has made ZTTK syndrome to be regarded as an entity caused by SON haploinsufficiency. > SON is a ubiquitously expressed and evolutionarily conserved gene in vertebrates and is located on the human chromosome region 21q22.11 [4]. It encodes the DNA-and RNA-binding protein SON, which functions in RNA splicing as well as gene repression [7][8][9][10][11][12][13]. A wide variety of genes are, thus, under the control of SON, and SON has been reported to be involved in cell cycle regulation and stem cell maintenance [7][8][9][10][11][12]. However, the functional significance of SON in neural development is largely unknown, and the pathological consequence of SON haploinsufficiency underlying the neural phenotypes of ZTTK syndrome, such as ID and brain malformation, remains undetermined. In this report, we revealed through knockdown experiments in the developing mouse brain that Son insufficiency caused neuronal migration abnormalities and reduced spine density. Rescue experiments that induced the expression of human wild-type SON protein and truncated SON proteins encoded by disease-associated mutant SON genes provided further information relevant to the pathophysiology of ZTTK syndrome.

[7] Mitochondrial transplantation as a promising therapy for mitochondrial diseases

• Authors: Tian-Guang Zhang, Chaoyu Miao
• Year: 2022
• Venue: Acta Pharmaceutica Sinica. B
• URL: https://www.semanticscholar.org/paper/72802097939b0bffc319c93d05128d7e3160e0eb
• DOI: 10.1016/j.apsb.2022.10.008
• PMID: 36970208
• PMCID: 10031255
• Citations: 84
• Influential citations: 1
• Summary: Different techniques used in mitochondrial isolation and delivery, mechanisms of mitochondrial internalization and consequences of mitochondrial transplantation, along with challenges for clinical application are presented.
• Evidence snippets:
• Snippet 1 (score: 0.400) > Mitochondria, the vital organelles of eukaryotic cells, are integrators of various cellular metabolic pathways, including oxidative phosphorylation, fatty acid oxidation, urea cycle, Krebs cycle, ketogenesis and gluconeogenesis 1 . Mitochondria are also important in many other essential cellular processes such as calcium homeostasis, lipid metabolism, amino acid metabolism, biosynthesis of heme, and thermogenesis 2 . However, they also have important roles in many pathways which can cause both apoptosis and necrosis 3 . Therefore, the importance of the mitochondrion in the maintenance of cellular homeostasis is well established, meanwhile a large amount of evidence shows that mitochondrial dysfunction is deleterious 4 . > Due to the essential function of mitochondria in the human body, mitochondrial dysfunction causes a great variety of mitochondrial diseases, which can affect almost all the organs in the body and present at any age 4,5 . Mitochondrial diseases are a group of metabolic disorders characterized by energy metabolism dysfunction. The pathophysiology is further complicated by the involvement of genetic mutations in nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) which encode mitochondrial proteins. This means that mitochondrial diseases may result from inheritance for nDNA mutations and maternal inheritance for mtDNA mutations. The estimated minimum prevalence of mitochondrial diseases is 1 in 5000, whereas it could be higher 6 . > As advances in molecular and biochemical methodologies led to a better understanding of the mechanisms of mitochondrial disorders for various diseases, mitochondria have become a major target for research institutions and pharma companies. Pharmacological approaches include dietary supplements such as agents increasing respiratory chain function (coenzyme Q10 and riboflavin), agents inducing mitochondrial biogenesis (AICAR and bezafibrate), antioxidants (vitamin C and vitamin E), mitochondrial substrates (L-carnitine) and so on 7,8 . However, these agents fail to significantly alleviate disease symptoms or effectively slow disease progressions, there has therefore been no satisfactory therapeutic strategy available for mitochondrial diseases so far 9 . In addition, all new drugs under clinical trials for treatment of mitochondrial diseases are unable to cure these diseases permanently 9 .

[8] Future research trends in understanding the mechanisms underlying allergic diseases for improved patient care

• Authors: H. Breiteneder, Z. Diamant, T. Eiwegger, W. Fokkens, C. Traidl‐Hoffmann et al.
• Year: 2019
• Venue: Allergy
• URL: https://www.semanticscholar.org/paper/e19b0755c4f4903f68377333676edebf9bd73c89
• DOI: 10.1111/all.13851
• PMID: 31056763
• PMCID: 6973012
• Citations: 90
• Influential citations: 3
• Summary: Recent developments in research and patient care and future trends in the discipline are reviewed and topics on food allergy, biologics, small molecules, and novel therapeutic concepts in allergen‐specific immunotherapy for airway disease are highlighted.
• Evidence snippets:
• Snippet 1 (score: 0.394) > The past decades have witnessed extensive progress in unraveling cellular and molecular mechanisms of immune regulation in asthma, allergic diseases, organ transplantation, autoimmune diseases, tumor biology, and chronic infections. 1,2 Consequently, a better understanding of the functions, the reciprocal regulation, and the counterbalance of subsets of immune and inflammatory cells but also structural cells-for example, epithelial and vascular cells, airway smooth muscle cells, neuroendocrine system-that interact via various intercellular messengers will indicate avenues for immune interventions and novel treatment modalities of allergic diseases and immunological disorders. It is generally expected that drug development in the next decades will show a significant shift from chemicals to biologicals. > After more than 20 years without any breakthrough drug becoming available for patients, several disciplines including allergology are now experiencing extraordinary times with the recent licensing of several major biological drugs and novel allergen-specific immunotherapy (AIT) vaccines. Several biological modifiers of the immune response targeting intracellular messengers or their receptors have been developed to date. [3][4][5][6][7][8] In addition, a number of promising small molecule drugs and vaccines are in the development pipeline. [9][10][11] This new era is now calling for the development of biomarkers and phenoand endotyping of diseases for customized patient care, which is termed stratified medicine, precision medicine, or personalized medicine. 4 Distinguishing phenotypes of a complex disease covers the observable clinically relevant properties of the disease but does not show a direct relationship to disease etiology and pathophysiology. In a complex condition, such as asthma, different pathogenetic mechanisms can induce similar clinical manifestations; however, they may require different treatment approaches. 12,13 These pathophysiological mechanisms underlying disease subgroups are addressed by the term "endotype." [12][13][14] Classification of complex diseases based on the concept of endotypes provides advantages for epidemiological, genetic, and drug-related studies. Accurate endotyping by using reliable biomarkers reflects the natural history of the disease and aims to predict the response to (targeted) treatments. 15 Recent studies have focused on better understanding

[9] 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: 0.392) > 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.

[10] The Expanding Phenotype of ZTTK Syndrome Due to the Heterozygous Variant of SON Gene Focusing on Liver Involvement: Patient Report and Literature Review

• Authors: A. Pietrobattista, Luca Della Volpe, P. Francalanci, L. Figá Talamanca, L. Monti et al.
• Year: 2023
• Venue: Genes
• URL: https://www.semanticscholar.org/paper/d2a98c42645c17d3239e8b519ea2384456da8af9
• DOI: 10.3390/genes14030739
• PMID: 36981010
• PMCID: 10048019
• Citations: 1
• Summary: The report provides new information on this rare condition and suggests the expansion of the ZTTK syndrome phenotype, including possible liver involvement, and recommends screening patients with SON variants specifically for liver involvement from the first years of life.
• Evidence snippets:
• Snippet 1 (score: 0.391) > Therefore, the normal LFTs reported in all previously published single cases and series of ZTTK syndrome may not be completely reassuring. Moreover, a pattern of normal biochemical tests in CLDs is not completely unexpected because there are other known disease models which can progress toward PH maintaining normal LFTs. In our case, liver involvement was accidentally detected at age 16 during a follow-up ultrasound that monitored the surgical vesicoureteral reflux correction. A proper ecographic evaluation of the liver requires dedicated pediatric radiological skills as well as a doppler study of the hepatic vascular flows which could be missed during routine studies. > The role of SON as a master regulator of genes that are essential for human neurodevelopmental processes, kidney development, and metabolism has already been revealed through a description of various essential genes that are significantly downregulated upon SON haploinsufficiency, thus potentially impairing normal development and/or functions of multiple organs [3,4]. As such, it is important to identify direct SON targets in cells that are relevant to the observed clinical phenotypes. > Overall, it is still not clear whether hepatic involvement is a possible phenotypic manifestation associated with a mutation of the SON gene or if it is an epiphenomenon in the context of patients with ZTTK syndrome. However, in the absence of other definitive causes, it seems reasonable to include liver disease in a proposal of expanding phenotypes. > Unfortunately, in our case, even if we excluded variants in all genes known to be associated with CLD pathogenesis, we would not be able to investigate whether there was a downregulation of those genes due to SON haploinsufficiency. In this view, the absence of functional studies is the major limitation of our study that prevents us from establishing a direct link between the SON variant and the CLD. At this stage, we can only surmise that this hypothesis is worthy of further consideration as a field of future research mainly focusing on SON and mechanisms of hepatic fibrogenesis.

[11] New Insights into Mitochondria in Health and Diseases

• Authors: Ya Li, Huhu Zhang, Chunjuan Yu, Xiaolei Dong, Fanghao Yang et al.
• Year: 2024
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/23002a4ffabfd043f52c664f4d5acab85b8dcac0
• DOI: 10.3390/ijms25189975
• PMID: 39337461
• PMCID: 11432609
• Citations: 38
• Summary: This overview outlines the various mechanisms by which mitochondria are involved in numerous illnesses and cellular physiological activities and provides new discoveries regarding the involvement of mitochondria in both disorders and the maintenance of good health.
• Evidence snippets:
• Snippet 1 (score: 0.391) > Mitochondria are essential organelles within cells, playing critical roles not only in energy metabolism but also in various cellular activities, such as cell differentiation, signal transduction, and apoptosis. Mitochondrial dysfunction is implicated in a range of diseases, including but not limited to diabetes and its complications, neurodegenerative disorders, myocardial ischemia-reperfusion injury, and heart failure. Therefore, investigating the structure and function of mitochondria as well as the mechanisms underlying mitochondrial dysfunction in disease contexts holds significant scientific and clinical importance. > Basic scientific research: Diseases manifest systemically and exhibit complexity; thus, it is imperative to understand mitochondrial structure at the molecular level along with known pathways while characterizing novel pathways that influence mitochondrial behavior and functionality. For instance, mapping genetic interactions among genes encoding mitochondrial proteins can elucidate interrelations between different aspects of mitochondrial function. The first focused map of mitochondria has been constructed in yeast models, revealing dense and significant connections among localization pathways distributed across various mitochondrial compartments [126]. > Disease diagnosis: A comprehensive understanding of the mechanisms governing mitochondrial dysfunction can facilitate the development of innovative diagnostic tools. By monitoring specific indicators related to mitochondrial function, earlier diagnosis of diseases associated with mitochondrial impairment becomes feasible. Employing nextgeneration sequencing technologies for analyzing the mitochondrial proteome aids in identifying novel proteins and pathways linked to mitochondria while enabling streamlined diagnostics alongside genetic counseling opportunities for patients with mitochondrial diseases [127]. > Drug development: Advancements in our comprehension of how mitochondria contribute to disease processes may promote targeted therapeutic strategies. For example, metformin-a widely used antidiabetic agent-has recently been repurposed as an anticancer drug; its combination with standard epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) significantly improves progression-free survival rates and overall survival outcomes for patients with advanced lung adenocarcinoma [125]. > Personalized medicine: Given that manifestations of mitochondrial dysfunction may vary among individuals, research into mitochondria provides a theoretical foundation for personalized medicine by allowing tailored treatment plans based on individual states of mitochondrial functionality [127].

[12] 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: 0.387) > 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

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

• Authors: Claudia Fuchs, P. A. ‛. ’t Hoen, A. Müller, Friederike Ehrhart, C. V. van Karnebeek
• Year: 2024
• Venue: Frontiers in Medicine
• URL: https://www.semanticscholar.org/paper/b00d0859458647edeebf3cf53f9b39c79311d5ed
• DOI: 10.3389/fmed.2024.1425038
• PMID: 39135718
• PMCID: 11317438
• Citations: 1
• Summary: The potential of drug repurposing (DR) as a promising avenue for addressing the unmet medical needs of individuals with RTT and related disorders is explored and Leveraging existing drugs for new therapeutic purposes presents an attractive strategy.
• Evidence snippets:
• Snippet 1 (score: 0.386) > Rigorous preclinical and clinical studies are also crucial for better understanding the complex pathophysiology of these syndromes. To date, the precise molecular mechanisms underlying these complex disorders are still not fully understood; hindering the identification and validation of potential drug targets. This specifically applies to CDD and FOXG1-syndrome: both conditions were identified as distinct clinical entities only recently and it is understandable that research efforts initially focused primarily on "classical" RTT. This discrepancy is reflected also in the very different numbers of repurposing studies highlighted in Figure 1. Continued efforts in pre-clinical (identification of valuable cell and animal models etc.) and clinical research (better understanding of the natural history, clinical manifestations, disease progression, biomarkers etc.) will be essential for advancing our understanding and improving outcomes for individuals affected by these syndromes. In particular, better characterizing the shared symptoms and pathways across these entities, will provide valuable insights into the underlying biology and potentially uncover new common mechanisms and targeted therapies. If the disorders demonstrate convergence in their underlying molecular pathways, this provides an opportunity for designing joint DR 10.3389/fmed.2024.1425038 strategies across RTT and RTT-like disorders. This could reduce the time needed for the development of DR and increase the number of patients benefiting from the treatments, resulting in more attractive business models. > Despite promising DR results in preclinical or early-phase clinical trials for RTT and related disorders in our opinion DR is still underrated and underutilized in this kind of disorders. DR holds immense potential for addressing the unmet medical needs and therapeutic challenges posed by such complex NDDs, and recent advancements screening and computational techniques, offer the unique opportunity to predict drug-disease interactions and prioritize candidate compounds for further investigation. By leveraging existing drugs and repurposing them for new indications, this approach offers a pragmatic and efficient strategy to accelerate the development of treatments for individuals affected by these debilitating conditions.

[14] 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: 0.386) > T2DM is a chronic disease characterized by two primary pathophysiological mechanisms: ① a reduction in the mass and function of pancreatic b cells, ranging from 20% to 65%, which leads to impaired insulin secretion; ② insulin resistance, where cells in muscles, fat, and liver tissues fail to respond adequately to insulin (9). Consequently, higher levels of insulin are required to maintain normal blood glucose concentrations by inhibiting hepatic glucose production and promoting glucose uptake in muscle and adipose tissues. Prolonged exposure to elevated levels of circulating insulin leads to the development of insulin resistance in peripheral tissues, and over time, the pancreas fails to produce sufficient insulin to overcome this cellular resistance (10). However, due to the long latent period and absence of obvious symptoms initially, reversing T2DM with drug intervention is difficult after the symptoms are exposed or clinically confirmed in light of clear diagnostic criteria. According to the literature, the pathogenesis and process of metabolic syndromes such as diabetes and its complications are mainly reflected in the metabolite network, and the mechanism changes at the gene level are also found in the network. Studies have shown that some related metabolites in patients with diabetes have changed before the occurrence of obvious organic damage (11). Therefore, it is necessary to scientifically prevent T2DM in the early stages of disease onset. Fortunately, clinical metabolomics were employed to understand the progression pathologies of T2DM and its corresponding complications in detail (12). Studies have demonstrated that metabolomic analysis enables the exploration of metabolic disorders associated with T2DM, thereby deepening our understanding of disease progression (13,14). This approach has the potential to facilitate novel clinical diagnoses and the development of effective treatment strategies. Moreover, identifying specific metabolites may provide promising biomarkers for the early prediction, prevention, and management of hyperglycemia and its complications (15). In recent years, excellent progress has been made in the study of T2DM and its complications through High throughput sequencing method, i.e., a discipline specifically focused on metabolic small molecules. > Clinical metabolomics is a type of systems biology research closely linked to phenotype.

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

• Authors: Debopam Samanta
• Year: 2025
• Venue: Children
• URL: https://www.semanticscholar.org/paper/455479c1bfbea7b90b73c109228f67c813d13888
• DOI: 10.3390/children12040481
• PMID: 40310132
• PMCID: 12025602
• Citations: 19
• Influential citations: 1
• Summary: A narrative review explores precision therapeutic strategies for LGS based on molecular pathophysiology, including channelopathies, receptor and ligand dysfunction, receptor and ligand dysfunction, cell signaling abnormalities, cell signaling abnormalities, synaptopathies, and the repurposing of existing medications with mechanism-specific effects.
• Evidence snippets:
• Snippet 1 (score: 0.385) > Lennox–Gastaut syndrome (LGS) is a severe childhood-onset developmental and epileptic encephalopathy characterized by multiple drug-resistant seizure types, cognitive impairment, and distinctive electroencephalographic patterns. Current treatments primarily focus on symptom management through antiseizure medications (ASMs), dietary therapy, epilepsy surgery, and neuromodulation, but often fail to address the underlying pathophysiology or improve cognitive outcomes. As genetic causes are identified in 30–40% of LGS cases, precision therapeutics targeting specific molecular mechanisms are emerging as promising disease-modifying approaches. This narrative review explores precision therapeutic strategies for LGS based on molecular pathophysiology, including channelopathies (SCN2A, SCN8A, KCNQ2, KCNA2, KCNT1, CACNA1A), receptor and ligand dysfunction (GABA/glutamate systems), cell signaling abnormalities (mTOR pathway), synaptopathies (STXBP1, IQSEC2, DNM1), epigenetic dysregulation (CHD2), and CDKL5 deficiency disorder. Treatment modalities discussed include traditional ASMs, dietary therapy, targeted pharmacotherapy, antisense oligonucleotides, gene therapy, and the repurposing of existing medications with mechanism-specific effects. Early intervention with precision therapeutics may not only improve seizure control but could also potentially prevent progression to LGS in susceptible populations. Future directions include developing computable phenotypes for accurate diagnosis, refining molecular subgrouping, enhancing drug development, advancing gene-based therapies, personalizing neuromodulation, implementing adaptive clinical trial designs, and ensuring equitable access to precision therapeutic approaches. While significant challenges remain, integrating biological insights with innovative clinical strategies offers new hope for transforming LGS treatment from symptomatic management to targeted disease modification.

[16] 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: 0.385) > 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].

[17] Recent advances in modelling of cerebellar ataxia using induced pluripotent stem cells

• Authors: M. M. Wong, L. Watson, Esther B. E. Becker
• Year: 2017
• Venue: Journal of neurology & neuromedicine
• URL: https://www.semanticscholar.org/paper/0d962652305116e383ab260b9e82d3a5ffe1722f
• DOI: 10.29245/2572.942X/2017/7.1134
• PMID: 28825058
• PMCID: 5558869
• Citations: 9
• Summary: This review focuses on recent breakthroughs in generating human iPSC-derived Purkinje cells and highlights the future challenges that will need to be addressed in order to fully exploit these models for the modelling of the molecular mechanisms underlying cerebellar ataxias and the development of effective therapeutics.
• Evidence snippets:
• Snippet 1 (score: 0.384) > dominant polyglutamine spinocerebellar ataxias (SCAs) are the most studied forms of ataxias. Despite significant clinical and genetic heterogeneity, emerging evidence points to the existence of common pathogenic mechanisms that may be shared by several genetically distinct forms of cerebellar ataxias (reviewed in5-8). However, it is still unclear how the proposed pathological pathways ultimately result in cerebellar dysfunction and degeneration, predominantly affecting Purkinje cells. > Understanding disease mechanisms is key to treating neurodegenerative disorders. The heterogeneous nature of the cerebellar ataxias combined with the unavailability of human brain tissue and the lack of reliable disease models have, however, hampered our understanding of the molecular disease mechanisms underlying cerebellar ataxias and thus, the development of effective therapies. Although mouse models of several cerebellar ataxias, including FRDA and SCAs, have provided valuable insights into the pathophysiology of these disorders (reviewed in9), many questions remain about the observed species differences in disease phenotypes and the effectiveness of potential drugs in clinical trials. > To help translate research from animal models into novel treatments for ataxia patients, it is essential to validate findings in the relevant affected human cell types, particularly in cerebellar Purkinje cells. The current obstacles might be overcome by exploiting recently developed human induced pluripotent stem cell (iPSC) technology and neuronal differentiation protocols.

[18] Insights in biomarkers complexity and routine clinical practice for the diagnosis of thyroid nodules and cancer

• Authors: M. G. de Matos, Mafalda Pinto, A. Gonçalves, Sule Canberk, M. J. Bugalho et al.
• Year: 2025
• Venue: PeerJ
• URL: https://www.semanticscholar.org/paper/655de68f1a7e8137dcba8a2046f14dee4f07594d
• DOI: 10.7717/peerj.18801
• PMID: 39850836
• PMCID: 11756370
• Citations: 4
• Summary: The knowledge of genetic and molecular biomarkers has achieved a high level of complexity, and the difficulties related to its applicability determine that their implementation in clinical practice is not yet a reality.
• Evidence snippets:
• Snippet 1 (score: 0.381) > Knowledge of molecular mechanisms implicated in thyroid carcinogenesis has been attained in recent years. Thyroid neoplasm result from alterations in gene expression patterns, which occur due to a gradual accumulation of genetic and epigenetic events. These changes are associated with specific tumor phenotypes and are implicated in disease etiology. Molecular alterations induce the activation of different signaling pathways, such as the mitogen-activated protein kinase (MAPK), and phosphatidylinositol 3-kinase (PI3K/AKT/mTOR), which are involved in and promote carcinogenesis (Hsiao & Nikiforov, 2014). In a few years, the knowledge of molecular mechanisms implicated in thyroid carcinogenesis changed from understanding signaling pathways and identification of a few genes mutations to the knowledge of the main genes implicated in thyroid carcinogenesis, reviewed by De Leo et al. (2024). Genetic changes in thyroid neoplasms were divided in early/driver molecular alterations and late/progression events. Late/ progression events may be associated with early/driver molecular alterations and represent the evolution from well-differentiated to high-grade and undifferentiated carcinoma, being (Pozdeyev et al., 2018). Most frequent gene mutations present in follicular-cell derived thyroid tumors are BRAF, RAS, and TERTp mutations, associate with clinically relevant clinicopathologic features, as shown in Table 3.

[19] From Data to Cure: A Comprehensive Exploration of Multi-omics Data Analysis for Targeted Therapies

• Authors: Arnab Mukherjee, S. Abraham, Akshita Singh, S. Balaji, K. Mukunthan
• Year: 2024
• Venue: Molecular Biotechnology
• URL: https://www.semanticscholar.org/paper/04593d2268ccd7c26b5296d8342b468ca84ae7b1
• DOI: 10.1007/s12033-024-01133-6
• PMID: 38565775
• PMCID: 11928429
• Citations: 69
• Influential citations: 2
• Summary: This review navigates the expansive omics landscape, showcasing tailored assays for each molecular layer through genomes to metabolomes, and aims to illuminate the transformative impact of multi-omics in the big data era, shaping the future of biological research.
• Evidence snippets:
• Snippet 1 (score: 0.379) > Biological processes and molecular functions arise from intricate interactions among thousands of molecules, constituting inherent complexity. Integration of metabolomics data with other omics data holds significant promise for achieving a holistic understanding of disease mechanisms. Metabolomics, which focuses on the comprehensive analysis of small molecule metabolites within biological systems, provides unique insights into the functional status and metabolic phenotypes associated with various physiological and pathological conditions [160,161]. The integration of omics datasets with computational models and network analysis tools elucidates the complex interplay between genes, proteins, metabolites, and cellular processes underlying disease phenotypes. > Despite recent progress in omics technologies, the underlying genetic factors contributing to numerous metabolic phenotypes remain elusive. Metabolite biomarkers can be integrated with genomics and clinical parameters to enhance diagnostic accuracy or refine disease risk prediction models. Metabolites can also serve as intermediate phenotypes for genetic investigations, offering insights into underlying genetic mechanisms [162]. The integration of metabolomics data with either whole-exome sequencing or WGS-data presents a promising systematic strategy for pinpointing disease-causing variants and holds potential utility within the framework of a specific pathway under investigation [163]. Furthermore, at a more intricate biological and analytical level, metabolomics can be combined with various omic platforms, facilitating a comprehensive understanding of complex biological systems and interactions (Fig. 4). > The alterations in metabolite levels, perturbations in metabolic pathways, and the onset of disease states can be elucidated by assessing the epigenetic alterations. This approach offers molecular insights into the intricate interplay among genetic, epigenetic, and metabolic factors during the disease progression. Through the integration of epigenomic Fig. 4 The workflow for integration of metabolomics with other omics for a holistic understanding of disease progression and metabolomic data, the intricate relationships between epigenetic alterations and metabolic pathways in disease pathogenesis can be uncovered. In recent years, metabolomics and epigenomics have experienced notable advancement as prominent molecular and analytical methodologies for biomarker identification [164,165].

[20] 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: 0.379) > 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.

Notes

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