Asta Literature Retrieval: Pathophysiology and clinical mechanisms of FOXG1 Disorder. Core disease mechanisms, molecular and cellular pathways,...

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

• Papers retrieved: 18
• Snippets retrieved: 20

Relevant Papers

[1] 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: 0.497) > Rett syndrome (RTT, #312750) and Rett-like syndromes, e.g., CDKL5 deficiency disorder (CDD, #300672) and FOXG1-syndrome (or FOXG1-related encephalopathy, #613454) are rare monogenic neurodevelopmental disorders (NDDs). The relative recent recognition of their distinct clinical entities (1,2) has deepened our understanding of their underlying pathogenic mechanisms and clinical characteristics (Table 1). Although each disorder exhibits unique clinical features, they share common core symptoms and neurological traits (Table 1), suggesting that these disorders share critical molecular etiology. > Identifying shared pathways holds significant implications for targeted therapies development and drug repurposing (DR). DR, which involves using existing drugs for new therapeutic purposes, represents a promising approach in the treatment across multiple diseases especially for neurological disorders (3,4). The complex structure of the central nervous system (CNS), coupled with the challenge of penetrating the blood-brain barrier, poses significant hurdles in the development of new drugs for neuropathological conditions, making DR of particular interest for these disorders. Notable successes of DR in NDDs include e.g., repurposing of fenfluramine in Dravet syndrome (5) or bumetanide (6) and pregnenolone (7) for autism spectrum disorders. These studies validate DR as a valid treatment approach for multiple neuropathological conditions. > We here discuss the current state of art of DR efforts in RTT, CDD and FOXG1-syndrome, with particular emphasis on the shared molecular pathways and the identification of common drug targets across the three conditions. For a more detailed overview on the molecular and circuit mechanisms underlying each syndrome, please refer to (8)(9)(10) for RTT, (11,12) for CDD and (2, 13) for FOXG1-syndrome (2,13).
• Snippet 2 (score: 0.449) > 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.

[2] Conditional Deletion of Foxg1 Delayed Myelination during Early Postnatal Brain Development

• Authors: Guangliang Cao, Congli Sun, Hualin Shen, D-W Qu, Chuanlu Shen et al.
• Year: 2023
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/b05ba28c7ef5e5c4acf5dff2063fd35fbaa06535
• DOI: 10.3390/ijms241813921
• PMID: 37762220
• PMCID: 10530892
• Citations: 2
• Summary: It is found that Foxg1 deficiency resulted in a transient delay in myelination, evidenced by decreased myelin formation within the first two weeks after birth, but ultimately recovered to the control levels by P30.
• Evidence snippets:
• Snippet 1 (score: 0.480) > Fully mapping its diverse molecular interactions and cellular outputs remains an important and challenging goal for future studies. To gain more insights into the role of Foxg1 in OL development and myelination, future studies can employ more sophisticated and comprehensive techniques to explore novel targets. For example, transcriptomic and epigenetic analyses can be performed to identify the global gene expression and chromatin changes induced using Foxg1 deletion in OL lineage cells. Moreover, specific transgenic tools can be used to manipulate Foxg1 expression in a temporally and cell-type-specific manner. > It should be noted that there are still certain limitations in our study to be considered. While providing initial evidence for the role of Foxg1 in oligodendrocyte development and myelination, our study only examined the effects of Foxg1 deficiency in mice up to P30. Further long-term studies beyond this early developmental window will be important for fully understanding the consequences of Foxg1 deficiency on myelin integrity and disease progression. In addition, FOXG1 syndrome is a clinically heterogeneous disorder, and the diverse symptoms may arise not only from Foxg1 and OLs dysfunction but also from additional genetic, epigenetic, and environmental factors influencing neurodevelopment, suggesting that the underlying etiology of FOXG1 syndrome is likely multifactorial. Further research is needed to fully elucidate the complex pathophysiology underlying this disorder. > In conclusion, our study provides new insights into the role of Foxg1 in myelin development and uncovers potential pathological mechanisms of FOXG1 syndrome, which have important implications for the development of therapeutic strategies not only for FOXG1 syndrome but also for other neurodevelopmental disorders associated with abnormal myelination.

[3] FOXG1 Dose in Brain Development

• Authors: N. Hettige, C. Ernst
• Year: 2019
• Venue: Frontiers in Pediatrics
• URL: https://www.semanticscholar.org/paper/bd8fcfa4d63cbd7853030263d0d7c81237ecc83a
• DOI: 10.3389/fped.2019.00482
• PMID: 31824897
• PMCID: 6882862
• Citations: 59
• Influential citations: 3
• Summary: It is argued against a linear, symmetrical relationship between FoxG1 dosage states, although FOXG1 levels at the right time and place need to be carefully regulated, although neurodevelopmental disease states caused by mutations in FOXG 1 may therefore be regulated through different mechanisms.
• Evidence snippets:
• Snippet 1 (score: 0.427) > Clinical data on several FOXG1 deletion syndrome patients have been reviewed and discussed in this review; however, understanding why a loss or mutation in one copy of FOXG1 leads to microcephaly and severe intellectual disability in humans is unknown. Human-derived iPSCs now make it feasible to generate isogenic, patient-derived neurons to investigate neurodevelopment and to perform functional genetic studies (102). Patriarchi et al. generated iPSC-derived neurons from FOXG1 +/− patients and suggested that there is an imbalance in excitatory/inhibitory (E/I) synaptic protein expression in patient neurons compared to controls (103). However, these data do not explore the dynamics of FOXG1 dose as neurons develop. It seems reasonable to suspect that the molecular mechanism of disease will arise early on as cells differentiate and any overt cellular phenotype at a mature cell stage is a passenger effect to an earlier problem in cell differentiation. It is these early molecular mechanisms that need to be assessed to understand how FOXG1 dose leads to a reproducible, robust cellular phenotype. To this end, a recent study was able to generate human stem cells where FOXG1 dose could be fine-tuned (104). Studies such as these will become important in titrating specific doses at specific times for in vitro neurodevelopment.

[4] The patient-specific mouse model with Foxg1 frameshift mutation uncovers the pathophysiology of FOXG1 syndrome

• Authors: J. Park, J. Moon, Holly O’Shea, Dongjun Shin, S. Hwang et al.
• Year: 2023
• Venue: Research Square
• URL: https://www.semanticscholar.org/paper/7cbc15f07a50a30a5b3701eb7468e2b6cf1f8777
• DOI: 10.21203/rs.3.rs-2953760/v1
• PMID: 37398410
• PMCID: 10312924
• Citations: 1
• Summary: It is found that Q84Pfs-Het mice faithfully recapitulate human FS phenotypes at the cellular, brain structural, and behavioral levels and elucidated the essential pathophysiology mechanisms of FS.
• Evidence snippets:
• Snippet 1 (score: 0.413) > Importantly, these studies highlight that both copies of the Foxg1 gene are required for building the functional cortex. > In mice, neuronal migration and layer formation are largely completed by birth, and glial cells begin to emerge 3 . Oligodendrocyte precursor cells (OPCs) in the cortex proliferate and differentiate into myelinating oligodendrocytes (OLs) after birth, and the myelination continues to adulthood 17 . > In humans, the pathogenic variants in the FOXG1 gene lead to the debilitating neurodevelopmental disorder collectively termed FOXG1 syndrome (FS) 18,19,19−23 . Most FS is caused by de novo mutations in a single allele of the FOXG1 gene. FS patients exhibit structural brain abnormalities, such as microcephaly and corpus callosum agenesis, and a delay in oligodendrocyte differentiation and myelination. FS is also characterized by severe intellectual disability, hyperkinetic-dyskinetic movement disorder, irritability, and epilepsy. Many FS patients have autistic features, such as repetitive movements, poor social interaction skills, and a near absence of verbal speech and language development. Hence, FS belongs to the autism spectrum disorder (ASD). Currently, the molecular and cellular mechanisms leading to the pathology of FS remain elusive. > The crucial involvement of FOXG1 in forebrain development and human pathogenesis raises several questions. First, what are the cellular changes triggering FS symptoms? Second, what are the molecular changes leading to FS pathology? Third, what is the role of FOXG1 in myelination, and how does the disturbed myelination in FS contribute to FS clinical manifestation? Notably, a wide spectrum of symptoms of FS patients is associated with the type and location of the causative FOXG1 variants 19,24 . This highlights the need for patient-speci c FS mouse models, which carry FS-causing genetic variants, to understand FS pathophysiology and develop therapeutic interventions for FS patients. The existing Foxg1-null mouse lines 2,9,25,26 are inadequate as they have the complete deletion of the Foxg1 gene.
• Snippet 2 (score: 0.384) > A majority of FS patients possess mutations within the FOXG1 gene coding region, which are likely to produce faulty Foxg1 protein products that impact disease mechanisms and progression. Therefore, the currently available Foxg1-null mouse lines are inadequate to investigate FS pathophysiology because they delete the entire Foxg1 coding region 2,9,25,35,36 . Here, we established Q84Pfs-Het mice as the rst patient-speci c FS mouse model that accurately replicates human genetic conditions of FS. Remarkably, the heterozygous mice carrying only a single allele of Q84Pfs variant, without creating the homozygous conditions, recapitulated a wide range of human FS symptoms, such as brain structural de cits and ASDlike behaviors. Using this new FS mouse model, we uncovered molecular and cellular changes, such as oligodendrocyte lineage de ciency and dysregulation of synaptic genes, leading to the key hallmarks of FS, such as delayed myelination, movement de cits, and ASD-like behaviors. > A tight genetic and phenotypic resemblance between Q84Pfs-Het mice and human FS patients provides clear advantages in understanding the pathophysiology of neurodevelopmental disorders and developing therapeutics, compared to many ASD mouse models, in which the ASD genes are eliminated, unlike the corresponding human conditions in which ASD genes are often present as heterozygous conditions or are epigenetically silenced 37 . First, it allowed us to identify dysregulated genes in FS brains, which are likely to lead to cellular and structural de cits and further behavioral outcomes. Second, our studies uncovered new mouse phenotypes highly correlated with human FS symptoms, such as de ciency in oligodendrocyte development and myelination, increased repetitive behavior and anxiety levels, and extensive behavior arrest. Thus, Q84Pfs-Het mice will serve as an ideal mouse model to identify the pathogenic mechanism for these mouse phenotypes and human symptoms.

[5] New therapeutic targets in rare genetic skeletal diseases

• Authors: M. Briggs, Peter A. Bell, M. Wright, K. A. Pirog
• Year: 2015
• Venue: Expert Opinion on Orphan Drugs
• URL: https://www.semanticscholar.org/paper/1363107f71ae6d2d60abca471cddf3da5d13644b
• DOI: 10.1517/21678707.2015.1083853
• PMID: 26635999
• PMCID: 4643203
• Citations: 38
• Influential citations: 1
• Summary: An overview of disease mechanisms that are shared amongst groups of different GSDs and potential therapeutic approaches that are under investigation are described to generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.
• Evidence snippets:
• Snippet 1 (score: 0.400) > proteins of the cartilage ECM such as type II collagen [50]. However, emerging knowledge suggests that the primary genetic defect may be less important than the cells' response to the expression of the mutant gene product [107]. Moreover, the largely overlooked response of a cell (i.e. chondrocyte) to the abnormal extracellular environment is also important for disease progression as illustrated by several GSDs discussed in this review. > It is important that 'omics'-based approaches and technologies are systematically applied to the study of rare GSDs so that definitive reference profiles and disease signatures are generated for each phenotype. These can then be used in a Systems Biology approach to identify both common and dissimilar pathological signatures and disease mechanisms. This approach is entirely dependent upon relevant in vitro and in vivo models (and also novel 'disease-mechanism phenocopies' [107]) for testing new diagnostic and prognostic tools and for determining the molecular mechanisms that underpin the pathophysiology so that effective therapeutic treatments can be developed and validated. This approach will eventually lead to personalized treatments and care strategies centred on shared disease mechanisms with the use of relevant biomarkers to monitor the efficacy of treatment and disease progression. > It is vital that all relevant stakeholders are involved from the outset in defining the appropriate outcomes of any potential therapeutic regime. The perceptions of a successful therapy can differ widely between the clinical academic community and the relevant patient-support groups and it is vital that there is engagement on all these issues. > In summary, the identification of causative genes and mutations for GSDs over the last 20 years, coupled with the generation and in-depth analysis of a plethora of relevant cell and mouse models, has derived new knowledge on disease mechanisms and suggested potential therapeutic targets. The fast-evolving hypothesis that clinically disparate diseases can share common disease mechanisms is a powerful concept that will generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.

[6] 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: 0.395) > 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

[7] 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: 0.394) > 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].

[8] Conceptualizing Epigenetics and the Environmental Landscape of Autism Spectrum Disorders

• Authors: G. Torres, Mervat Mourad, Saba Iqbal, Emmanuel Moses-Fynn, Ashani Pandita et al.
• Year: 2023
• Venue: Genes
• URL: https://www.semanticscholar.org/paper/bf76f0682a8a1986ce889cee1fef818480abc83b
• DOI: 10.3390/genes14091734
• PMID: 37761876
• PMCID: 10531442
• Citations: 11
• Summary: The present work reviews recent evolutionary, molecular, and epigenetic mechanisms potentially linked to the etiology of autism, and presents a clinical vignette to describe clusters of maladaptive behaviors frequently diagnosed in autistic patients.
• Evidence snippets:
• Snippet 1 (score: 0.382) > Currently, there are hundreds of gene variants associated with the onset of ASD. Thus, the clinical presentation of the disease is highly variable, as one or more behavioral symptoms may be related to other comorbid conditions (e.g., anxiety disorder, seizure disorder) besides autism. In addition, antagonistic pleiotropy and dosage-sensitive genes further fragment the phenotypic characteristics of ASD. Regardless, here, we present a prototypical autism clinical vignette with five behavioral specifiers: cognitive disability; deficits in social-emotional reciprocity; repetitive or stereotyped motor behavior; improper coordinated language communication; and gastrointestinal distress. Underneath this clinical vignette, we microdissected and correlated a particular phenotype of the disease to functionally and anatomically related regions of the brain and bilateral body plan. The structural organization imposed here will not only identify a wide network of cells, but also specific clusters of genes targeting a particular symptom within behaviorally relevant regions. It is expected that such structural organization will help lay a solid foundation in psychiatry and point to more focused approaches to a deeper understanding of ASD and its individualized treatment (Table 2). Autism Spectrum Disorders can be managed with appropriate pharmacotherapy. Selective dopamine (DA) and serotonin (5HT) based drugs are the mainstay of pharmacological treatment [43,44]. Additional neurotransmitter systems (e.g., norepinephrine (NE) and histamine) are also drug targets. It is not known whether the listed drugs regulate epigenetic mechanisms to counteract autistic symptoms. What is broadly known is that atypical, typical and psychoactive drugs act on DA and 5HT signaling pathways within regions of the human brain (e.g., cortex and basal ganglia) that are behaviorally relevant to the pathophysiology of ASD. Attention Deficit Hyperactivity Disorder (ADHD) and Fragile X Syndrome are debilitating neuropsychiatric conditions commonly diagnosed in pediatric populations. Fragile X Syndrome is a monogenic inherited disease leading to cognitive disability and ASD.

[9] Personalized Medicine: The Future of Health Care

• Authors: A. Meiliana, Nurrani Mustika Dewi, A. Wijaya
• Year: 2016
• Venue: The Indonesian Biomedical Journal
• URL: https://www.semanticscholar.org/paper/02edaa39ecdab3dd64c077e71b14398b94beb742
• DOI: 10.18585/inabj.v8i3.271
• Citations: 8
• Summary: Personalized medicine seeks to use advances in knowledge about genetic factors and biological mechanisms of disease coupled with unique considerations of an individual’s patient care needs to make health care more safe and effective.
• Evidence snippets:
• Snippet 1 (score: 0.382) > (98,170,171) The genetic cardiomyopathies present a window to cardiac pathophysiology when discrete cellular pathways are disrupted. Over the past decades, the role of numerous proteins in triggering cardiomyopathy and hence HF has finally become clear. Despite the genetic complexity, direct application of genetic testing is now a mainstay in managing affected families, and scientifically and clinically useful themes are emerging that should lead to improved treatment.( 95) > Investigations of rare monogenic disorders of heart rhythm has elucidated the fundamental molecular and genetic mechanisms of sickle cell disease. After identification of more than 25 causal genes, there remain many subjects with inherited arrhythmia susceptibility but do not have mutations, this suggests that there is still other genes left unidentified. Newer strategies such as exome and WGS may be valuable to uncover additional molecular etiologies. Efforts to understand mechanisms responsible for incomplete penetrance, including identification of modifier genes, will also contribute to deciphering the complex relationships between genotype and phenotype. (97) In diabetes, personalized medicine refers to utilize the patients specific characters for most effective diagnostic or treatment strategies. These include individual behavioral and phenotypic features, standard clinical laboratory findings, and gene sequences and other molecular markers.( 172) Diabetes mellitus has long been recognized to be a complex, heterogeneous disorder, especially in type 2 diabetes patients with substantial variability in genetic risk factors, underlying pathogenic mechanisms, and clinical features. Therefore it represents a human disease that gains a substantial benefit from personalized approaches to treatment. Nevertheless, patients with type 2 diabetes often are treated similarly, with little consideration of individual characteristics that might affect clinical outcome and therapeutic response.(173) Both type 1 and type 2 diabetes are thought to be complex diseases, which means they need the interplay of numerous susceptibility and protective genes, acting in concert with negative and positive environmental factors to be developed. (174) Type 2 diabetes typically is characterized by a combination of abnormalities in both insulin secretion and responsiveness, plus a more gradual and less extensive loss of β-cell secretory capacity than occurs in type 1 diabetes.

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

• Authors: R. Ragusa, P. 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: 6
• 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: 0.374) > 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.

[11] 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: 0.373) > 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.

[12] Editorial: Impact of system biology and molecular medicine on the management of complex immune mediated respiratory diseases, volume II

• Authors: B. Cárdaba, G. Pelaia
• Year: 2023
• Venue: Frontiers in Medicine
• URL: https://www.semanticscholar.org/paper/89edb8e4f39ba41177cc4caa98150836f54e16f0
• DOI: 10.3389/fmed.2023.1187941
• PMID: 37351067
• PMCID: 10282990
• Summary: The impact of system biology and molecular medicine on the management of complex immune mediated respiratory diseases, volume II and the need for further research into this area is discussed.
• Evidence snippets:
• Snippet 1 (score: 0.372) > Complex Immune-Mediated Respiratory Diseases are highly complex and heterogeneous inflammatory disorders, sharing a common organ-disease target which is the lung, but including a broad clinical spectrum. The most frequent obstructive respiratory diseases include bronchial asthma and, chronic obstructive pulmonary disease (COPD). These disorders are characterized by airflow limitation, cough, dyspnea, chest tightness, shortness of breath, and mucus production that could be caused by numerous environmental agents, as well as, genetic, pharmacologic, physiologic, biological, or immunologic mechanisms, which give rise to distinct phenotypes, with underlying molecular mechanisms or endotypes that need to be understood. This great heterogeneity translate to a lack of good therapeutic options for an important percentage of patients that do not respond to standard treatments, who could receive relevant benefits by a precision or personalized strategy, which requires new diagnostic and therapeutic approaches. Our purpose in the second volume of this Research Topic was to collect the latest advances in the molecular and clinical characterization of these complex diseases, in order to better understand the underlying mechanisms and improve the overall management. > In this volume, five novelty works have been published: 4 original articles, 2 of them related to severe asthma, and the other 2 regarding COPD. The fifth is a mini review that summarizes the latest new advances about the T cell-mediated lung inflammation in COVID-19 infection. > In regard to bronchial asthma studies, the two published articles pursue a better understanding of underlying mechanisms of severe uncontrolled asthma, thus searching for cellular and molecular pathways involved in the pathobiology of asthmatic endotypes that do not respond to standard asthma treatments and remain uncontrolled, thereby being responsible for exacerbations and hospitalizations every year. > Asthma is a common, chronic respiratory disease, defined as "a heterogeneous disease, usually characterized by chronic airway inflammation" by the Global Initiative of Asthma (1). Despite its clinical heterogeneity, allergic mechanisms have been implicated in 50-80% of asthmatic patients and in ∼50% of severe asthma cases (2,3). Such considerations explain why there are several new biological treatments mainly directed against this subtype of inflammation (type 2 inflammation).

[13] Therapies for Mitochondrial Disease: Past, Present, and Future

• Authors: Megan Ball, Nicole J. Van Bergen, A. Compton, David R. Thorburn, S. Rahman et al.
• Year: 2025
• Venue: Journal of Inherited Metabolic Disease
• URL: https://www.semanticscholar.org/paper/196ee50a950f29bc4134cfb8fe6bdfa9a3a1468b
• DOI: 10.1002/jimd.70065
• PMID: 40714961
• PMCID: 12301291
• Citations: 4
• Summary: The latest developments in the pursuit to identify effective treatments for mitochondrial disease are examined and the barriers impeding their success in translation to clinical practice are discussed.
• Evidence snippets:
• Snippet 1 (score: 0.371) > Mitochondrial disease is a diverse group of clinically and genetically complex disorders caused by pathogenic variants in nuclear or mitochondrial DNA‐encoded genes that disrupt mitochondrial energy production or other important mitochondrial pathways. Mitochondrial disease can present with a wide spectrum of clinical features and can often be difficult to recognize. These conditions can be devastating; however, for the majority, there is no targeted treatment. In the last 60 years, mitochondrial medicine has experienced significant evolution, moving from the pre‐molecular era to the Age of Genomics in which considerable gene discovery and advancement in our understanding of the pathophysiology of mitochondrial disease have been made. In the last decade, in response to the urgent need for effective treatments, a wide range of emerging therapies have been developed, driven by innovative approaches addressing both the genetic and cellular mechanisms underpinning the diseases. Emerging therapies include dietary intervention, small molecule therapies aimed to restore mitochondrial function, stem cell or liver transplantation, and gene or RNA‐based therapies. However, despite these advances, translation to clinical practice is complicated by the sheer genetic and clinical complexity of mitochondrial disease, difficulty in efficient and precise delivery of therapies to affected tissues, rarity of individual genetic conditions, lack of reliable biomarkers and clinically relevant outcome measures, and the dearth of natural history data. This review examines the latest developments in the pursuit to identify effective treatments for mitochondrial disease and discusses the barriers impeding their success in translation to clinical practice. While treatment for mitochondrial disease may be on the horizon, many challenges must be addressed before it can become a reality.

[14] 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: 0.370) > 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.

[15] Immune Dysregulation in Autism Spectrum Disorder: What Do We Know about It?

• Authors: M. Robinson-Agramonte, Elena Noris García, Jarasca Fraga Guerra, Yamilé Vega Hurtado, Nicola Antonucci et al.
• Year: 2022
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/0d5e761dc4d912894a808ce3353286fc759f2ee5
• DOI: 10.3390/ijms23063033
• PMID: 35328471
• PMCID: 8955336
• Citations: 133
• Influential citations: 2
• Summary: Current insights into immune dysfunction in ASD are summarized, with particular reference to the impact of immunological factors related to the maternal influence of autism development; comorbidities influencing autism disease course and severity; and others factors with particular relevance, including obesity.
• Evidence snippets:
• Snippet 1 (score: 0.369) > Neuropsychiatric and neurodegenerative disorders display a biologically defined expression related to brain dysfunctions and age-related disease onset. The former, considered as a disturbed behavior and emotional state derived from the functional brain impairment, and the latter, viewed as an organic brain disease where the symptoms follow the damage of specific brain regions. Studies from different groups show biological evidence for the presence of common immune-mediated mechanisms overlapping both disease processes, although understandably with some distinctive characteristics. > Clinical and experimental evidence have argued similar mechanisms of innate immunity pathway signaling overlapping immune-pathological events in both neuropsychiatric and neurodegenerative disorders, characterized by the common influence of resident glial cells mediating inflammation via soluble molecules (mainly cytokines, chemokines, and complement proteins), which promote the recruitment of local immune cells and others coming from the peripheral compartment. To show this evidence, we refer to two pathologies occurring in the both extremes of the life: ASD, the main object of this review, and Parkinson disease (PD), following the main aspects of innate immunity relevant to both disorders and where the glial cells are the main cellular element. > In general, both disorders, ASD and PD, are related to brain dysfunctions, and in their particular context, genetic causes and risk factors play a central role in disease pathophysiology, severity, and disease progression besides the overlapping immunopathological mechanisms and molecular pathways. More than 100 candidate genes identified in ASD may converge as causal factors related to neuronal development, plasticity, synaptic structure, and performance [230,231]. Several genes and genomic regions, including alpha-synuclein (SNCA), parkinRBRE3 ubiquitin protein ligase (PARK2), chromosome 22q11deletion/DiGeorge region, and fragile X mental retardation 1 (FMR1) repeats, may be relevant to the development of both ASD and PD, with converging features related to synaptic function and neurogenesis. Both PD and ASD also show alterations and impairments at the synaptic level, representing early main disease phenotypes converging upon mechanisms active in the two diseases [232].

[16] 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: 14
• 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: 0.369) > 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

[17] Gastric Cancer: Molecular Pathology State

• Authors: Filomena Altieri, P. Arcari, E. Rippa
• Year: 2013
• Venue: Unknown venue
• URL: https://www.semanticscholar.org/paper/a085a501814bbf6e4a93494cce35bd87bd5803a7
• DOI: 10.5772/53757
• Citations: 3
• Summary: Despite the progressive decrease observed in the past fifty years, gastric cancer (GC) is the fourth of the world rankings incidence of various types of cancer and is the second as a cause of cancer-related death.
• Evidence snippets:
• Snippet 1 (score: 0.368) > In this review, we have summarized reports on genes, proteins and factors involved in gastric carcinogenesis based on currently available literature. Gastric carcinoma results from a complex interaction between bacterial, environmental, host-genetic and molecular mechanisms. It is evident that gastric cancer is the consequence of a multistep process involving different genetic and epigenetic changes in numerous genes. Host genetic background and environmental factors also play an important role in the pathogenesis of the disease. The majority of genetic alterations contributing to the malignant transformation were observed in growth regulatory genes, and in genes involved in cell cycle progression and arrest. In recent years, the analysis of molecular carcinogenesis gastric epithelial neoplasm has certainly provided information of great importance. It is understood that the molecular mechanisms involved in carcinogenesis of intestinal type are different from those prevailing in the development of diffuse one. The element of greater importance from a clinical point lies in the fact that the elucidation of these mechanisms is the prerequisite for exploring innovative therapeutic approaches. While the conventional forms of treatment seem to have reached the limit of effectiveness, it is possible that use of targeted therapies based on solid preclinical rational can translate into tangible clinical benefit. The reviewed signaling pathways are relevant contributors for gastric carcinogenesis and encompass a multitude of potential therapeutic targets. In addition to these signaling-related targets we included new data on GKN1 as being involved in gastric cancer susceptibility phenotype.

[18] Targeting Hepatic Stellate Cells for the Prevention and Treatment of Liver Cirrhosis and Hepatocellular Carcinoma: Strategies and Clinical Translation

• Authors: Hao Xiong, Jinsheng Guo
• Year: 2025
• Venue: Pharmaceuticals
• URL: https://www.semanticscholar.org/paper/76e92127053136900f7e3f10e2c9278251ced5d2
• DOI: 10.3390/ph18040507
• PMID: 40283943
• PMCID: 12030350
• Citations: 10
• Summary: HSC-targeted approaches using specific surface markers and receptors may enable the selective delivery of drugs, oligonucleotides, and therapeutic peptides that exert optimized anti-fibrotic and anti-HCC effects.
• Evidence snippets:
• Snippet 1 (score: 0.368) > Significant progress has been made in elucidating the cellular and molecular mechanisms of liver fibrosis; however, only a few findings have been successfully translated into clinical applications. Firstly, the high cost of drug development and target validation necessitates prolonged timelines and substantial financial investment. Secondly, as regulatory requirements become more stringent, there is an increasing demand for drugs with well-defined clinical efficacy and safety profiles. Moreover, the efficacy observed in animal models often fails to fully translate to clinical settings due to differences in pharmacokinetics, extracellular matrix (ECM) cross-linking, and disease pathophysiology. Despite advancements in anti-fibrotic drug development, accurately identifying ideal noninvasive biomarkers for fibrotic activity and establishing consensus on optimal clinical endpoints remain significant challenges [113,114]. > Currently, addressing the underlying cause remains the only proven strategy to halt or reverse liver fibrosis progression, while the development of effective anti-fibrotic therapies continues to pose a major challenge in liver disease management. Over the past few decades, substantial progress has been made in elucidating the cellular and molecular mechanisms underlying liver fibrosis. Liver fibrosis is a complex pathological change involving multiple cells, factors, and pathways, and the study of the cellular and molecular mechanisms of its occurrence and development provides an important theoretical basis and therapeutic target for clinical drug development. It is anticipated that improved animal models and well-designed clinical trials will facilitate the successful translation of anti-fibrotic research into effective clinical treatments in the near future.

Notes

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