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

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

• Papers retrieved: 20
• Snippets retrieved: 20

Relevant Papers

[1] Common immunopathogenesis of central nervous system diseases: the protein-homeostasis-system hypothesis

• Authors: Kyung-Yil Lee
• Year: 2022
• Venue: Cell & Bioscience
• URL: https://www.semanticscholar.org/paper/2984270ae67451b93007040848d9694d19714c9f
• DOI: 10.1186/s13578-022-00920-5
• PMID: 36384812
• PMCID: 9668226
• Citations: 9
• Influential citations: 1
• Summary: This article proposes a common immunopathogenesis of CNS diseases, including prion diseases, Alzheimer’s disease, and genetic diseases, through the PHS hypothesis, which proposes that the immune systems in the host control those substances according to the size and biochemical properties of the substances.
• Evidence snippets:
• Snippet 1 (score: 0.377) > There are hundreds of genetic diseases of the CNS. The defective proteins in genetic disorders include structural proteins for neurotransmitter receptors and other receptors or ion channels on CNS cells, and proteins involved in enzymatic process, metabolism (transport), or signal transduction pathways in various communication systems [98]. Because a discussion of each genetic disease is beyond the scope of this review, only crucial points about the pathogenesis of genetic diseases are discussed. Singlegene defect diseases of the CNS can be caused by a defective product from a gene, i.e., a protein deficiency or a malfunctioning protein. In general, autosomal dominant genetic diseases are caused by structural protein defects, and autosomal recessive diseases are caused by defects in enzymatic proteins. However, certain genetic diseases that involve an enzymatic or multifunctional protein defect can induce structural cell injury during the natural course of the illness. > Patients with genetic diseases, including HD, familial JCD, GSS, and the genetic forms of AD and PD, show different clinical manifestations from other affected people in their family, including the time of onset of neurological symptoms, speed of progression of the disease, and prognosis, suggesting that phenotypes can vary even when the genotypes are identical. Likewise, similar phenotypes of CNS symptoms can be found in different genetic diseases. In genetic animal models, the phenotypes of single gene knockout can vary by strain in mice, and the clinical manifestations of a gene defect can differ between mice and humans, and mice null for some genes have also no observable phenotypic abnormalities compared with controls [99]. These findings suggest that default of a protein might be at least partly controlled by individual's control systems and that there might exist a similar immune/repair system against cell injury in genetic diseases. > The pathophysiology of most genetic diseases in the CNS is complex because any affected gene is associated with numerous proteins and their corresponding activations of genes and epigenetic changes that occur during disease processes. Thus, the use of a genetic marker for diagnosing or predicting a prognosis remains impractical in clinical settings [100].

[2] Novel variants in KAT6B spectrum of disorders expand our knowledge of clinical manifestations and molecular mechanisms

• Authors: M. Yabumoto, Jessica Kianmahd, Meghna Singh, Maria F. Palafox, Angela Wei et al.
• Year: 2021
• Venue: Molecular Genetics & Genomic Medicine
• URL: https://www.semanticscholar.org/paper/3a47a1b1208ba7420900b090d3d7d712ed391719
• DOI: 10.1002/mgg3.1809
• PMID: 34519438
• PMCID: 8580094
• Citations: 12
• Influential citations: 2
• Summary: A range of features previously described for KAT6B‐related syndromes are identified, including concern for keratoconus, sensitivity to light or noise, recurring infections, and fractures in greater numbers than previously reported.
• Evidence snippets:
• Snippet 1 (score: 0.375) > Finally, as gene-centric models of disease have started to take hold, understanding the underlying functional mechanisms that are affected can help us elucidate the effect on molecular and cellular phenotypes that are regulated by KAT6B (Klein et al., 2019;Sheikh et al., 2012). We developed a model of KAT6B truncating variants in a human cell line to explore how these variants result in differential regulation of key transcripts. These types of approaches have been performed in a high throughput manner for tumor suppressor genes like BRCA1 (Findlay et al., 2018) and TP53 (Kotler et al., 2018) and can help identify key pathways that are dysregulated by KAT6B-related disorders and could be future targets for translational research. > Here, we analyze 20 clinical cases representing a KAT6B-related clinical spectrum across three domains: their genotype, phenotype, and experience with genetic counseling resources. Furthermore, we developed an in vitro model of KAT6B mutations using CRISPR technology to explore the effect of protein truncation on global transcriptional regulation. Here we demonstrate that the genes that drive core clinical phenotypes are enriched in our in vitro model system. Together, we show that our clinical observations parallel the transcriptional processes in our cell model systems which allow for a further understanding of the mechanisms underlying the KAT6Brelated clinical spectrum.

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

• Authors: R. Ragusa, Pasquale Bufano, A. Tognetti, M. Laurino, Chiara Caselli
• Year: 2025
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/2660cdbbe1f205c631fe890e5c6a3c8d9b81ce5f
• DOI: 10.3390/ijms26062571
• PMID: 40141213
• PMCID: 11942187
• Citations: 4
• Summary: A systematic review of the latest knowledge on epigenetic modifications that characterize COPD, summarizing epigenetic factors that could serve as potential novel biomarkers and therapeutic targets for the treatment of COPD patients.
• Evidence snippets:
• Snippet 1 (score: 0.373) > The papers included were clustered according to epigenetic mechanisms involved in COPD (molecular and cellular processes, as biomarker or therapeutic target). Tables 4-9 describe the extracted information, including the following: Study = name of first author et al., year; Country (Region) = where the study took place; Number of participants = sample size; Type of sample = biological sample employed; Gene affected = gene or group of genes whose expression can be "regulated" by epigenetic mechanisms; Epigenetic alteration = type of epigenetic alteration observed in the presence of disease; Activity in COPD = involvement of epigenetic elements in different molecular and cellular mechanisms associated with COPD; and Role of epigenetic mechanisms = epigenetic modifications that can be used to explain the pathophysiology of COPD or as biomarkers and therapeutic targets.

[4] 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: 0.369) > 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.

[5] 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: 0.368) > 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.

[6] 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: 0.365) > 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].

[7] The Diabetes Syndrome – A Collection of Conditions with Common, Interrelated Pathophysiologic Mechanisms

• Authors: A. W. Rachfal, S. Grant, S. Schwartz
• Year: 2021
• Venue: International Journal of General Medicine
• URL: https://www.semanticscholar.org/paper/4c088a6a8b613c15e817f7491d24022497b7f5c4
• DOI: 10.2147/IJGM.S305156
• PMID: 33776471
• PMCID: 7987256
• Citations: 6
• Summary: The “Diabetes Syndrome”, an overarching group of interrelated conditions linked by these overlapping mechanisms, can be viewed as a conceptual framework that can facilitate understanding of the inter-relationships of superficially disparate conditions.
• Evidence snippets:
• Snippet 1 (score: 0.363) > Although many pathways lead to hyperglycemia in diabetes -the so-called "Egregious Eleven" (Listed in Table 1) -β-cell dysfunction is the core defect. 1,2 Four basic pathophysiologic mechanisms damage the β-cell, namely, genes and epigenetic changes, inflammation, an abnormal environment [especially fuel excess], and insulin resistance (IR). 1,2 2][3] The interplay between these pathophysiologic mechanisms influences the specific risk of development and progression of complications in an individual patient. [6][7][8][9][10][11][12][13][14][15] In clinical practice we often encounter these common diseases, frequently within one individual patient and they are treated as independent conditions. However, we believe their epidemiologic associations is, in part, due to the same underlying pathophysiologies driving β-cell damage and diabetic complications. That is, the same pathophysiologic mechanisms that damage the β-cell and promote diabetesspecific complications also have key roles in the pathogenesis of these diseases. ][9][10][11][12][13][14][15] However, we propose these connections go beyond mere epidemiologic links due to overlapping pathophysiology. In fact, these conditions occur together in enough frequency and have common overlapping pathophysiologic drivers that we have created a conceptual framework called "The Diabetes Syndrome". The name is inspired by the Greek meaning of syndromē (sun-[together] + dramein [to run]) as the conditions, indeed, run together (Figure 1). This article will describe the shared pathophysiologic and etiologic factors across these prevalent and related diseases within the Diabetes Syndrome conceptual framework discussed within the context of the 4 basic pathophysiologic mechanisms -genes and epigenetic changes, abnormal environment, inflammation, and IR -with a focus on commonalities between these diseases and DM. In brief, genetics can mediate susceptibility to damage from abnormal external and internal environmental factors, including inflammation and IR. All these mechanisms can promote epigenetic changes.

[8] 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: 0.363) > 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.

[9] Chromatin modifiers in neurodevelopment

• Authors: Sarallah Rezazadeh, H. Ji, Cecilia Giulivi
• Year: 2025
• Venue: Frontiers in Molecular Neuroscience
• URL: https://www.semanticscholar.org/paper/7a4d8c063c2b3a908a65bcb637cd818edad8db92
• DOI: 10.3389/fnmol.2025.1551107
• PMID: 40469903
• PMCID: 12133960
• Citations: 2
• Summary: This mini review delves into key chromatin modifiers, including the histone methyl transferases NSD1 and ASH1L, the methyl-CpG-binding repressor MeCP2, and the enzymatic repressor EZH2, and spotlight their pivotal roles in early brain development and neurological disorders.
• Evidence snippets:
• Snippet 1 (score: 0.361) > Therefore, while epigenetic changes are essential for understanding specific aspects of neurodevelopmental disorders, it is crucial to view these mechanisms as part of a larger, more complex system that encompasses genetic, proteomic, and metabolic factors. Few examples underscore that while epigenetic mechanisms-such as DNA methylation and histone modificationsare essential in regulating gene expression and contribute to neurodevelopmental disorders, they do not fully explain the complex pathophysiology of these diseases. In many cases, the genetic mutations, absence of or dysfunction of protein, or toxic protein aggregation (e.g., Fragile X syndrome, HD) that occur in these disorders play a central role in the clinical phenotypes. Therefore, a comprehensive understanding of neurodevelopmental disorders must integrate epigenetic mechanisms and the broader genetic, proteomic, and cellular pathways that contribute to disease. An integrative approach that considers not only the regulation of gene expression but also the functional consequences of these changes at the protein, metabolic and cellular pathway levels will be essential for advancing our understanding of these intricate disorders and developing effective interventions and treatments. . B., Villate, O., Llano, I., Ocio, I., Martí, I., et al. (2020). Targeted next-generation sequencing in patients with suggestive X-linked intellectual disability. Genes 11:51. doi: 10.3390/genes11010051

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

• Authors: I. Condò
• Year: 2022
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/6aece75e6947f102b657851b74e8b96df5e654c1
• DOI: 10.3390/ijms23126525
• PMID: 35742964
• PMCID: 9223693
• Citations: 15
• Influential citations: 2
• Summary: A rare disease is defined by its low prevalence in the general population and its presence in a very small number of people.
• Evidence snippets:
• Snippet 1 (score: 0.361) > The selective expression or the particular role of specific genes in a single tissue explains the appearance of organ-specific inherited diseases. This is the case of genetic disorders of the kidney, which include dominant and recessive forms of cystic diseases, and renal tubulopathies. Mutations in polycystin-1 (PKD1) or -2 (PKD2) genes lead to autosomaldominant polycystic kidney disease (ADPKD), whose gender-dependent phenotype was analyzed in the study by Talbi et al. [9]. These results, obtained in mice lacking PKD1 expression, show the involvement of intracellular Ca2+ levels in the more severe phenotype affecting male ADPKD animals. Altogether, identification of the molecular mechanisms underlying enhanced Ca2+ signaling and proliferation in cells from male kidneys may contribute to develop novel therapeutics for ADPKD [9]. The autosomal-recessive form of polycystic kidney disease (ARPKD) mostly arises from defects in the gene named polycystic kidney and hepatic disease 1 (PKHD1), whereas a minority of cases is linked to a second causative gene DZIP1L. To examine the still unclear molecular pathophysiology of ARPKD, Cordido et al. recapitulate known molecular disease mechanisms and possible therapeutic approaches, from cellular and animal models to clinical trials [10]. The knowledge of ARPKD pathogenic pathways, involving the epidermal growth factor receptor (EGFR) axis, the production of adenylyl cyclase adenosine 3 ,5 -cyclic monophosphate (cAMP) and the activation of several protein kinases, begins to stimulate possible pharmacological interventions [10]. Inherited loss of function in various electrolyte transport proteins located along the nephron leads to two types of kidney tubulopathy with overlapping clinical symptoms: Gitelman and Bartter syndromes. The review by Nuñez-Gonzalez et al. aims to explain the different molecular basis of these difficult to diagnose monogenic syndromes. Moreover, the authors provide an overview of current therapeutic approaches and highlight the presence of common and specific options for Gitelman and Bartter patients [11].

[11] 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: 0.360) > 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

[12] The Use of Vitamin K2 in Patients With Parkinson's Disease and Mitochondrial Dysfunction (PD-K2): A Theranostic Pilot Study in a Placebo-Controlled Parallel Group Design

• Authors: Jannik Prasuhn, M. Kasten, Melissa Vos, I. König, S. Schmid et al.
• Year: 2021
• Venue: Frontiers in Neurology
• URL: https://www.semanticscholar.org/paper/e8e2d6c57929cb94c8bf02fc4db6c0e869226299
• DOI: 10.3389/fneur.2020.592104
• PMID: 33505346
• PMCID: 7829299
• Citations: 28
• Influential citations: 1
• Summary: The potential effects of vitamin K2 (long-chain menaquinone 7, MK-7) in genetically determined PD with mitochondrial dysfunction is investigated to investigate how neuroimaging and blood-derived biomarkers can predict individual treatment response in sporadic PD.
• Evidence snippets:
• Snippet 1 (score: 0.359) > The molecular basis of Parkinson's disease (PD) is complex, and many cellular components and metabolic processes are involved in the development and progression of the disease (1). Mitochondrial dyshomeostasis is a frequently postulated pathophysiological process that contributes to neurodegeneration in sporadic PD (sPD) (2). Although monogenic PD forms are rare, homozygous or compoundheterozygous mutations in Parkin and PINK1 (mitoPD) are described to lead to mitochondrial dyshomeostasis and consecutive bioenergetic deficits (3). However, when tailoring individualized treatment options for PD patients, it is desirable to target gene-specific pathways and pathophysiological hallmarks of the diseased individual (4). Monogenic PD might thus serve as an experimental model as we can pinpoint the genetic defect to specific molecular pathways. Even though the identification of the underlying disease mechanisms in monogenic PD for driving drug development tends to appear more viable, it is crucial to apply the findings from the selected group of mutation carriers to the much larger group of sPD patients. Deep phenotyping of monogenic PD patients, e.g., by neuroimaging of mitoPD patients, might, therefore, help to identify substantial subsets of sPD patients, who may specifically benefit from proposed treatment approaches (5). Besides, pathophysiologyoriented, accompanying diagnostics (i.e., theranostics, a portmanteau describing combined techniques to simultaneously or sequentially diagnose and treat medical conditions) may leverage clinical trial outcomes (6). Theranostics also provides a unique opportunity for adaptive clinical trial designs, where only the most promising study cohorts or participants will be enrolled, and potential medication-related harm will be warded off study participants (7). In this study, we will investigate the potential benefit of MK-7 (long-chain menaquinone 7, MK-7) in mitoPD patients, sPD patients, and healthy individuals. The PINK1-deficient biochemical and behavioral phenotype of Drosophila flies was rescued by administering MK-4. The observed effects also extended to Parkin-deficient flies (see supplementary data of the reference) (8)

[13] Identification of Molecular Markers Associated with Prostate Cancer Subtypes: An Integrative Bioinformatics Approach

• Authors: I. Granata, Paola Barboro
• Year: 2024
• Venue: Biomolecules
• URL: https://www.semanticscholar.org/paper/446fec3e04d2e55ae0de063190c0106d7448f05e
• DOI: 10.3390/biom14010087
• PMID: 38254687
• PMCID: 10813078
• Citations: 4
• Summary: This work provides a proof-of-concept for the use of an integrative approach to identify candidate biomarkers involved in PCa progression and CRPC pathogenesis within the goal of precision medicine.
• Evidence snippets:
• Snippet 1 (score: 0.357) > The significant efforts made to study the molecular mechanisms involved in PCa progression identified molecular alterations potentially relevant for improving the clinical management of patients [73,74]. Over the past decade, the use of new drugs inhibiting the AR axis improved the treatment of mPCa and some forms of CPRC, but these chemicals have led to increased CRPC with neuroendocrine features that are still incurable [3,51]. Hence, the hypothesis that PCa progression may depend not only on genetic alterations but also on epi-and/or non-genetic factors caused by drug-stress pressure. For this reason, researchers are currently focusing on identifying the key mechanisms and the master genes driving PCa cells' fate toward metastatic and resistant phenotypes to develop novel and more effective therapeutic approaches [7][8][9]11,75]. > Heterogeneity is an intrinsic characteristic of PCa that accentuates during neoplastic evolution, particularly in the advanced phases of disease and in the acquisition of Interestingly, using this approach, we observed that 17-AAG (Figure S3), a HSP90 inhibitor, exerts the inhibitory effect on its specific target and likely also on EZH2, PAX5, NOTCH4 and KHDRBS1. Indeed, the PPI network shows a strong physical and functional connection between the proteins coded by the upregulated genes of the PCa-gene set (Figure S7) and HSP90 (enrichment p-value 1.8 × 10 −4 ), mainly due to a co-involvement in transcription-related pathways (enrichment tables in Figure S7).

[14] 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: 0.356) > 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.

[15] Modeling psychiatric disorders: from genomic findings to cellular phenotypes

• Authors: Anna Falk, Vivi M. Heine, A. Harwood, Patrick F. Sullivan, M. Peitz et al.
• Year: 2016
• Venue: Molecular Psychiatry
• URL: https://www.semanticscholar.org/paper/235b41240d78140de7ab06a3ad8a7d0b1bdff1a5
• DOI: 10.1038/mp.2016.89
• PMID: 27240529
• PMCID: 4995546
• Citations: 77
• Influential citations: 2
• Summary: The challenges for modeling of psychiatric disorders, potential solutions and how iPSC technology can be used to develop an analytical framework for the evaluation and therapeutic manipulation of fundamental disease processes are critically reviewed.
• Evidence snippets:
• Snippet 1 (score: 0.354) > The key challenge for iPSC-based disease modeling is to identify one or more relevant cellular phenotypes that accurately represent the disease pathophysiology. Increasing numbers of reports have demonstrated that for many diseases specific pathophysiology can be captured in human iPSC-based disease models. These range from cardiovascular disease, 44,45 cancer, 46,47 ocular disease, 48,49 diabetes mellitus 50,51 and neurological disorders of the brain. 52,53 Can the same approach be applied to complex psychiatric disorders? > The problem is that almost all psychiatric disorders are characterized by clinical signs and symptoms, but lack independent verification from objective biomarkers. Thus, how might these clinical phenotypes manifest themselves in terms of cell behavior? The identity of robust cellular 'readouts', which typify any psychiatric disorder, is a crucial unsolved problem and an area of intense study 54 (Table 2). When satisfactorily answered, this will herald a new degree of biological objectivity and quantification for the study of psychiatric disorders. > The aim is to find a single or small number of cell phenotypes or parameters that strongly associate with psychiatric disorders, and establish a cellular profile characteristic of cells derived from the general patient population. Although a consensus set of cellular phenotypes for psychiatric disorder is yet to be established, we can define some of their desired characteristics. First, cellular phenotypes have to relate to the biological pathways identified by genetics. Second, although there are many risk genes in disparate biological pathways, at some level, phenotypes should converge onto a much smaller grouping. Third, phenotypes need to be quantifiable. Finally, to be useful for drug development cellular phenotypes should be reversed by pharmacological treatment, although not necessarily by drugs in current use. > Although human iPSC-based approaches underrepresent the complexity of the human central nervous system, cellular phenotypes are likely to lie more proximal to molecular disease mechanisms than phenotypes seen at the level of a tissue or organism, 55 and thus may bypass compensatory homeostatic (2) Gene expression profiles of SCZ human iPSC neurons identified altered expression of many components of the cyclic AMP and WNT signaling pathways. > (3

[16] Role of Transcriptomics in Precision Oncology

• Authors: Ruby Srivastava
• Year: 2024
• Venue: Reports of Radiotherapy and Oncology
• URL: https://www.semanticscholar.org/paper/0bd862558bbb7286336111d9dfd232b5f905d3d9
• DOI: 10.5812/rro-142195
• Citations: 4
• Summary: : Transcriptome profiling is one of the most widely used approaches in the field of multiomics research. It plays a crucial role in the prognostic, diagnostic, and predictive treatment of cancer patients. Novel next-generation sequencing (NGS) technologies permit the identification of cancer biomarkers, gene signatures, and their abnormal expression, affecting oncogenic and molecular targets and novel biomarkers for cancer therapies. Multiomics studies have changed the overall understanding o...
• Evidence snippets:
• Snippet 1 (score: 0.354) > : Transcriptome profiling is one of the most widely used approaches in the field of multiomics research. It plays a crucial role in the prognostic, diagnostic, and predictive treatment of cancer patients. Novel next-generation sequencing (NGS) technologies permit the identification of cancer biomarkers, gene signatures, and their abnormal expression, affecting oncogenic and molecular targets and novel biomarkers for cancer therapies. Multiomics studies have changed the overall understanding of cancer and opened a precise perspective for tumor diagnostics and therapy. The use of these approaches has strengthened our understanding of disease pathophysiology and classifications at the molecular level, including specific interference with drug mechanisms of action. Still, it has limited added value in the clinical setting. The omics data on precision medicine include the application of data from genes, transcripts, and proteins for diagnosis, monitoring of diseases, risk factor determination, counseling, and development of novel therapeutics. Bioinformatics applications have expanded statistics-based analysis toward deriving molecular pathways and process models for characterizing phenotypes and drug action mechanisms. In this review, we will discuss transcriptomics and interference analysis that allows the identification of predictive biomarkers at the molecular level to test drug response and analyze the molecular process interface of disease progression-relevant pathophysiology and mechanism of action to propose predictive biomarkers.

[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: 0.354) > 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] 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: 0.353) > 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.

[19] 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: 0.353) > 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.

[20] 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: 24
• 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: 0.351) > 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].

Notes

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