Asta Literature Retrieval: Pathophysiology and clinical mechanisms of ornithine aminotransferase deficiency. Core disease mechanisms, molecular...

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

• Papers retrieved: 20
• Snippets retrieved: 20

Relevant Papers

[1] The hyperornithinemia–hyperammonemia-homocitrullinuria syndrome

• Authors: D. Martinelli, D. Diodato, Emanuela Ponzi, M. Monné, S. Boenzi et al.
• Year: 2015
• Venue: Orphanet Journal of Rare Diseases
• URL: https://www.semanticscholar.org/paper/ed033868ee677da141e5c926bc7c93cac242ea06
• DOI: 10.1186/s13023-015-0242-9
• PMID: 25874378
• PMCID: 4358699
• Citations: 92
• Influential citations: 5
• Summary: The clinical phenotype of HHH syndrome is extremely variable and its severity does not correlate with the genotype or with recorded ammonium/ornithine plasma levels, suggesting the need for a better understanding of the still unsolved pathophysiology of the disease.
• Evidence snippets:
• Snippet 1 (score: 0.500) > Although the disease responds well to treatment with low risk of relapse of hyperammonemia [38], slowly progressive pyramidal signs characterize the chronic course, as also seen in argininemia [89]. However, the mechanism(s) of pyramidal dysfunction in HHH syndrome still remains to be elucidated. Creatine deficiency may contribute to the pathogenetic mechanism of the syndrome, as creatine is relevant for mitochondrial energy metabolism, regulation of glycolysis, proteins synthesis, membrane stabilization and neuromodulation [77,78,85]. This could be in line with the finding of abnormally shaped mitochondria at electron microscopy studies in skin fibroblasts, hepatocytes and muscle biopsy from HHH syndrome patients [11,23,82]. Furthermore, a mitochondrial dysfunction has been recently related to the effects of ornithine and homocitrulline in causing oxidative stress and disturbed mitochondrial homeostasis [79,80]. > A further mechanism that can be involved in the pathophysiology of HHH syndrome is related to polyamines metabolism. Shimizu and colleagues reported increased total and fractional (putrescine, cadaverine, spermine, spermidine) polyamines in one HHH syndrome patient [30]. Indeed, the clinical similarities between HHH syndrome and argininemia, which has been associated to an abnormal polyamine metabolism [91,92], may suggest a common pathogenetic mechanism causing pyramidal dysfunction. > Overall, the pathogenesis of HHH syndrome is complex and not completely understood. It is likely that different mechanisms, including the impact of low mitochondrial ornithine on UC flux, the presence of hyperammonemic crises and the disturbance of other pathways in major organs play a role in determining the heterogeneous clinical presentation of ORC1 deficiency. > In addition, as molecular studies failed to disclose a correlation between type of mutations or ornithine transport capacity and disease severity, an effect of genetic modifiers, such as ORC genes redundancy, seems to be likely, but further studies are certainly needed to clarify this point.

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

• Authors: M. Uzti̇mür, C. N. Ünal, Gurler Akpinar
• Year: 2025
• Venue: Journal of Veterinary Internal Medicine
• URL: https://www.semanticscholar.org/paper/4b9c488b5dbd65d7b26fd2ad9aed70e8c4b59942
• DOI: 10.1111/jvim.70139
• PMID: 40492724
• PMCID: 12150350
• Summary: Understanding the serum proteome profiles of goats with pregnancy toxemia might help identify the proteomes and pathways responsible for the development of this disease and improve diagnosis and treatment.
• Evidence snippets:
• Snippet 1 (score: 0.404) > The pathophysiology and progression of this disease are not fully understood. > Traditional biomedical research has focused on the analysis of single genes, proteins, metabolites, or metabolic pathways in diseases. This molecular reductionist approach is based on the assumption that identifying genetic variations and molecular components will lead to new treatments for diseases [13][14][15][16]. However, many diseases are complex and multifactorial, and in order to determine the phenotype of such diseases, it is necessary to understand the changes that occur in more than one gene, pathway, protein, or metabolite at the cellular, tissue, and organismal levels [17][18][19]. Therefore, in recent years, proteomics, as one field of multi-omics technologies, has helped in evaluating the complex pathogenetic mechanisms of different diseases from a broad perspective and has made substantial contributions [20,21]. In veterinary medicine, proteomic analysis of metabolic diseases such as ketosis [16], hypocalcemia [22], and fatty liver [23] in dairy cows has contributed valuable insights for the definition of new pathophysiological pathways and new diagnosis and treatment protocols for these diseases. The proteomic approach can contribute importantly to a broad and detailed understanding of the changes that occur at the organismal level associated with the increase in BHBA concentration in goats with pregnancy toxemia. Our aim was to evaluate the serum protein profiles of goats with SPT or CPT using proteomic techniques to determine the proteomic profiles of these animals and to identify the relevant pathophysiological mechanisms.

[3] L-Ornithine L-Aspartate Restores Mitochondrial Function and Modulates Intracellular Calcium Homeostasis in Parkinson’s Disease Models

• Authors: M. Sisalli, Salvatore Della Notte, A. Secondo, C. Ventra, L. Annunziato et al.
• Year: 2022
• Venue: Cells
• URL: https://www.semanticscholar.org/paper/520100d0482599c2dc27eed83d2aa026c35bc20e
• DOI: 10.3390/cells11182909
• PMID: 36139485
• PMCID: 9496730
• Citations: 8
• Summary: Results indicate that LOLA, by interfering with those mitochondrial mechanisms related to ROS and RNS production, promotes mitochondrial functional recovery, thus confirming the tight relationship existing between cytosolic ionic homeostasis and cellular metabolism depending on the type of insult applied.
• Evidence snippets:
• Snippet 1 (score: 0.397) > In this regard, ornithine, a non-essential amino acid, represents an interesting compound able to potentiate mitochondrial activity due to its ability to reach this cellular organelle so important for neuronal metabolism. Indeed, ornithine, once in the mitochondria, plays a key role in the urea cycle and creates an intermediate for arginine synthesis. Ornithine is produced by the enzymatic action of arginase on arginine, which results in the production of urea and generation of ornithine. Ornithine has been shown to reduce blood ammonia concentrations by increasing ammonia detoxification in the muscle and reducing the severity of hepatic encephalopathy in cirrhosis. Recent data have demonstrated the existence of the mitochondrial enzyme ornithine transcarbamylase (OTC) specifically in neurons positive for the nitric oxide synthesis enzyme (nNOS) [16], suggesting a potential role for ornithine in the modulation of brain functions. This hypothesis is supported by the observation that a defect in the ornithine translocase enzyme, responsible for the transport of ornithine at the mitochondrial level, determines a hyperornithinemia associated with hyperammonemia, homocitrullinemia, and neurological disorders accompanied, at the cellular level, by mitochondrial dysfunction and oxidative stress [17]. However, the molecular mechanisms through which ornithine at the mitochondrial level can perform actions to improve the redox and energy properties are not entirely understood. > On these premises, the present study has been undertaken to investigate the intracellular pathways affected by ornithine treatment in in vitro models of PD, with particular regards to cellular metabolism and mitochondrial function in order to identify new and selective therapeutic strategies to prevent the neuronal dysfunction occurring in PD, and consequently to slow down disease progression. This aspect is extremely relevant considering the key role played by mitochondria in regulating synaptic activity. Therefore, a therapeutic strategy able to promote mitochondrial function might be useful to counteract the early synaptic dysfunction and the functional and pathological changes occurring in the brain of PD-affected patients.

[4] Global and Targeted Metabolomics for Revealing Metabolomic Alteration in Niemann-Pick Disease Type C Model Cells

• Authors: Masahiro Watanabe, Masamitsu Maekawa, Keitaro Miyoshi, Toshihiro Sato, Yu Sato et al.
• Year: 2024
• Venue: Metabolites
• URL: https://www.semanticscholar.org/paper/27c7aa8f74e2997a59b92b38aec1fb9ff9cbb608
• DOI: 10.3390/metabo14100515
• PMID: 39452896
• PMCID: 11509386
• Citations: 2
• Summary: Several metabolite characteristics of Niemann-Pick disease type C that may fluctuate in a cellular model of the disease are identified using both global and targeted metabolomic analyses by liquid chromatography/tandem mass spectrometry.
• Evidence snippets:
• Snippet 1 (score: 0.396) > Background: Niemann-Pick disease type C (NPC) is an inherited disorder characterized by a functional deficiency of cholesterol transport proteins. However, the molecular mechanisms and pathophysiology of the disease remain unknown. Methods: In this study, we identified several metabolite characteristics of NPC that may fluctuate in a cellular model of the disease, using both global and targeted metabolomic analyses by liquid chromatography/tandem mass spectrometry (LC-MS/MS). Three cell lines, HepG2 cells (wild-type[WT]) and two NPC model HepG2 cell lines in which NPC1 was genetically ablated (knockout [KO]1 and KO2), were used for metabolomic analysis. Data were subjected to enrichment analysis using the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Results: The enrichment analysis of global metabolomics revealed that 8 pathways in KO1 and 16 pathways in KO2 cells were notably altered. In targeted metabolomics for 15 metabolites, 4 metabolites in KO1 and 10 metabolites in KO2 exhibited statistically significant quantitative changes in KO1 or KO2 relative to WT. Most of the altered metabolites were related to creatinine synthesis and cysteine metabolism pathways. Conclusions: In the future, our objective will be to elucidate the relationship between these metabolic alterations and pathophysiology.

[5] Rare biochemical & genetic conditions: clues for broader mechanistic insights

• Authors: A. Mentis, Maria Dalamaga
• Year: 2025
• Venue: Cellular and Molecular Life Sciences: CMLS
• URL: https://www.semanticscholar.org/paper/7093ca07773a0427930c301ef5c28ce909e4abf9
• DOI: 10.1007/s00018-025-05652-6
• PMID: 40210765
• PMCID: 11985829
• Summary: Evidence is synthesized demonstrating how valuable knowledge of biochemical pathways related to rare disorders can be for biomedicine, which highlights the continued value of biochemical pathways and studies in understanding human pathophysiology and drug discovery even in the genomics era.
• Evidence snippets:
• Snippet 1 (score: 0.384) > The discussion above highlights the importance of rare but distinct features (phenotypes, syndromes, or molecular responses) to human pathophysiology. However, distinct diseases like cancer and inborn errors of metabolism can share common and/or overlapping molecular pathways. For example, the rare biochemical disorder D-2-hydroxyglutaric aciduria type 2, which is caused by germline mutations in the isocitrate dehydrogenase 2 (IDH2) gene and which causes progressive brain damage, is treated with enasidenib, a drug that has been approved to treat a blood cancer, namely acute myeloid leukemia caused by somatic mutations in the IDH2 gene [28,29], Similarly, lonafarnib, a farnesyltransferase inhibitor with antineoplastic properties, also reduces Parkinson-related tau pathology through a lysosomeactivating mechanism involving the Rhes protein [30]. These approaches show how drugs can be repurposed based on shared mechanisms between apparently different disorders. > Additionally, biochemical substances previously considered byproducts of cellular metabolism, such as urea and lactate, have recently attracted considerable attention due to their mechanistic value. First, urea, a byproduct of nitrogen metabolism, has been reported as a cancer biomarker by increasing pyrimidine-to-purine conversion. The latter increases the number of DNA and RNA transversion mutations and, as such, increases the rates of hydrophobic tumor neoantigens responsive to immunotherapy [31]. Even if the precise impact of several variants remains unclear, enzymes that are part of the urea cycle (e.g., ornithine transcarbamylase) appear to provide metabolic clues about cancer survival and development, an area of potential future research interest [32,33]. Likewise, phenylalanine substitutions at the codon reassignment level enhance the repertoire of cell surface antigens under conditions of tryptophan depletion [34]. Third, lactate has recently been shown to be involved in DNA repair (namely, homologous recombination-mediated pathways) through lactylation of the Nijmegen breakage syndrome 1 (NBS1) protein.

[6] 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: 0.383) > 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].

[7] 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: 0.382) > 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.

[8] 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: 8
• 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: 0.379) > 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.

[9] The arginine metabolome in acute lymphoblastic leukemia can be targeted by the pegylated‐recombinant arginase I BCT‐100

• Authors: Carmela De Santo, S. Booth, A. Vardon, A. Cousins, Vanessa Tubb et al.
• Year: 2017
• Venue: International Journal of Cancer
• URL: https://www.semanticscholar.org/paper/ea9fca41e1911906bfea04bcb5dd83208aeaff86
• DOI: 10.1002/ijc.31170
• PMID: 29168171
• PMCID: 5849425
• Citations: 59
• Influential citations: 4
• Summary: It is shown that BCT‐100 is cytotoxic to ALL blasts from patients in vitro by necrosis, and is synergistic in combination with dexamethasone, and provides a new clinically relevant therapeutic approach to target arginine metabolism in ALL.
• Evidence snippets:
• Snippet 1 (score: 0.375) > Acute lymphoblastic leukemia (ALL) is the most common cancer of childhood. Significant progress has been made such that the majority of children will be cured of their disease through multi-drug chemotherapy regimens. However, major challenges remain. For children who are diagnosed with high-risk disease, or those who relapse the prognosis remains poor. 1 Fewer than 50% of adults will be cured despite successful induction of a complete remission with chemotherapy. 2 For those that are cured, the toxicities of treatment with chemotherapy over a 2-to 3-year period remain a lifelong burden. 3 Therefore, therapeutic strategies, which target ALL blasts through new mechanisms, but do not add to the cummulative toxicity, are urgently needed. > Arginine is a semi-essential amino acid required for protein synthesis, cell division and a number of intracellular pathways that maintain cell survival. 4,5 Although whole body arginine levels are maintained through dietary intake and resynthesis, under conditions of high demand such as inflammation, pregnancy and cancer, arginine availability is limiting for on-going cell growth and survival. Arginine is metabolized through the activity of Arginase I, II or iNOS enzymes. The enzymes ornithine transcarbamylase (OTC) and argininosuccinate synthase (ASS) provide the intracellular pathway in which normal cells can protect themselves by resynthesizing arginine from citrulline. However, cancer cells may be dependent on extracellular arginine for survivalarginine auxotrophism, due to the loss of ASS or OTC recycling enzyme expression; making them vulnerable to therapeutic arginine depletion. 6 BCT-100 is a clinical-grade, PEGylated (PEG) recombinant human arginase that catalyses the conversion of arginine to ornithine and urea, leading to arginine depletion. 7 BCT-100 has shown significant activity against solid tumors and acute myeloid leukemia both pre-clinically and in clinical trials. 8,9 Here, we investigate the role of arginine metabolism in ALL and the activity of BCT-100 as a clinically relevant therapeutic approach for ALL.

[10] New therapeutic targets in rare genetic skeletal diseases

• Authors: M. Briggs, Peter A. Bell, M. Wright, K. A. Pirog
• Year: 2015
• Venue: Expert Opinion on Orphan Drugs
• URL: https://www.semanticscholar.org/paper/1363107f71ae6d2d60abca471cddf3da5d13644b
• DOI: 10.1517/21678707.2015.1083853
• PMID: 26635999
• PMCID: 4643203
• Citations: 37
• Influential citations: 1
• Summary: An overview of disease mechanisms that are shared amongst groups of different GSDs and potential therapeutic approaches that are under investigation are described to generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.
• Evidence snippets:
• Snippet 1 (score: 0.374) > 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.

[11] Molecular and Cellular Studies Reveal Folding Defects of Human Ornithine Aminotransferase Variants Associated With Gyrate Atrophy of the Choroid and Retina

• Authors: R. Montioli, G. Sgaravizzi, M. A. Desbats, S. Grottelli, C. Voltattorni et al.
• Year: 2021
• Venue: Frontiers in Molecular Biosciences
• URL: https://www.semanticscholar.org/paper/75a15c9419b96982e9fe4d07c77244098e0dad96
• DOI: 10.3389/fmolb.2021.695205
• PMID: 34395527
• PMCID: 8360850
• Citations: 7
• Summary: Six representative missense mutations present in homozygous patients concerning residues spread over the hOAT structure are considered to represent a further effort toward a comprehensive analysis of GA pathogenesis at molecular and cellular level, with important relapses for the improvement of genotype/phenotype correlations and the development of novel treatments.
• Evidence snippets:
• Snippet 1 (score: 0.372) > The deficit of human ornithine aminotransferase (hOAT) is responsible for gyrate atrophy (GA), a rare recessive inherited disorder. Although more than 60 disease-associated mutations have been identified to date, the molecular mechanisms explaining how each mutation leads to the deficit of OAT are mostly unknown. To fill this gap, we considered six representative missense mutations present in homozygous patients concerning residues spread over the hOAT structure. E. coli expression, spectroscopic, kinetic and bioinformatic analyses, reveal that the R154L and G237D mutations induce a catalytic more than a folding defect, the Q90E and R271K mutations mainly impact folding efficiency, while the E318K and C394Y mutations give rise to both folding and catalytic defects. In a human cellular model of disease folding-defective variants, although at a different extent, display reduced protein levels and/or specific activity, due to increased aggregation and/or degradation propensity. The supplementation with Vitamin B6, to mimic a treatment strategy available for GA patients, does not significantly improve the expression/activity of folding-defective variants, in contrast with the clinical responsiveness of patients bearing the E318K mutation. Thus, we speculate that the action of vitamin B6 could be also independent of hOAT. Overall, these data represent a further effort toward a comprehensive analysis of GA pathogenesis at molecular and cellular level, with important relapses for the improvement of genotype/phenotype correlations and the development of novel treatments.

[12] Novel Approaches to Studying SLC13A5 Disease

• Authors: Adriana S. Beltran
• Year: 2024
• Venue: Metabolites
• URL: https://www.semanticscholar.org/paper/8469c534cd81d96f84b61e2d963dead12088feb7
• DOI: 10.3390/metabo14020084
• PMID: 38392976
• PMCID: 10890222
• Citations: 2
• Summary: Current technologies for generating patient-specific induced pluripotent stem cells (iPSCs) and their inherent advantages and limitations are discussed, followed by a summary of the methods for differentiating iPSCs into neurons, hepatocytes, and organoids.
• Evidence snippets:
• Snippet 1 (score: 0.372) > The precise pathophysiology underlying how SLC13A5 loss-of-function results in epilepsy refractory to treatment is a subject of open and ongoing research. Several hypotheses suggest SLC13A5 alters metabolic pathways, leading to neuronal dysfunction. Conversely, therapeutic inhibition of NaCT in the liver is a target to improve metabolic diseases, including non-alcoholic fatty liver disease, obesity, and insulin resistance. Thus, functionally accurate modeling and characterization of the mechanisms involved in citrate transport disruption are critical for understanding its role in human disease. > IPSC-derived cellular systems are a powerful tool for modeling rare human genetic diseases, such as SLC13A5 (Figure 5). IPSCs derived from patients containing the genetic information of the disease can overcome the limitations of animal models, providing access to relevant human cell types that recapitulate the disease phenotype. For instance, patient-derived iPSCs differentiated into neurons or hepatocytes can be used to investigate molecular and cellular mechanisms, including citrate transport and accumulation, energy metabolism, oxidative stress, and other cellular processes. They can also be used to define the spectrum of the disease and how different mutations might lead to various disease severities, screen for potential therapeutic compounds that can restore the transporter function or ameliorate the symptoms, and enable personalized medicine approaches that can tailor treatments to individual patients based on their genetic background and disease severity. > transport disruption are critical for understanding its role in human disease. > IPSC-derived cellular systems are a powerful tool for modeling rare human genetic diseases, such as SLC13A5 (Figure 5). IPSCs derived from patients containing the genetic information of the disease can overcome the limitations of animal models, providing access to relevant human cell types that recapitulate the disease phenotype. For instance, patient-derived iPSCs differentiated into neurons or hepatocytes can be used to investigate molecular and cellular mechanisms, including citrate transport and accumulation, energy metabolism, oxidative stress, and other cellular processes.

[13] Clinical and biochemical characteristics of patients with ornithine transcarbamylase deficiency and in silico analysis of OTC gene

• Authors: Yinchun Zhang, Xia Gu, C. Shi, Hui Xiong, Dongfan Xiao et al.
• Year: 2025
• Venue: Orphanet Journal of Rare Diseases
• URL: https://www.semanticscholar.org/paper/0f0c21efb1a97166692a0ceaba314bdbb2db8cd4
• DOI: 10.1186/s13023-025-03624-4
• PMID: 40102887
• PMCID: 11916849
• Citations: 1
• Summary: A retrospective analysis of the clinical and biochemical features of 12 patients with OTCD and examined their metabolite profiles broadened the genetic variation spectrum of OTCD and provided substantial evidence for genetic counselling to affected families.
• Evidence snippets:
• Snippet 1 (score: 0.372) > This study seeks to elucidate the clinical and biochemical features of Ornithine transcarbamylase deficiency (OTCD), a pleomorphic congenital hyperammonemia disorder with a non-specific clinical phenotype. Additionally, the research aims to analyze the mutation spectrum of the OTC gene and its potential association with phenotype, as well as to perform an in silico analysis of novel OTC variants to elucidate their structure-function relationship. In this study, we conducted a retrospective analysis of the clinical and biochemical features of 12 patients with OTCD and examined their metabolite profiles. Additionally, we reviewed existing literature to explore the range of mutations in the OTC gene and their possible associations with phenotypic outcomes. Furthermore, we employed the high ambiguity-driven protein-protein docking (HADDOCK) algorithm and protein-ligand interaction profiler (PLIP) to predict the pathogenicity of these mutations and elucidate the underlying mechanisms of pathogenesis in novel variants of the OTC gene. Nine cases, all of which were male, presented with early onset, while two cases, all of which were female, exhibited late onset. Additionally, one male case was asymptomatic. The ages of the patients at the time of diagnosis ranged from 1 day to 12 years. Peak plasma ammonia levels were found to be higher in patients with early onset compared to those with late onset. Molecular analyses identified a total of 12 different mutations, including two novel mutations (V323G and R320P). In silico analysis indicated a potential difference in affinity between wild-type and mutant OTCase, with V323G and R320P mutations leading to a decreased binding ability of OTCase to the substrate, potentially disrupting its function. This study broadened the genetic variation spectrum of OTCD and provided substantial evidence for genetic counselling to affected families. Additionally, we elucidated variant data of OTC in Chinese patients through comprehensive literature review. Given the ongoing uncertainty surrounding the genotype-phenotype correlation of OTCD, the results of our in silico analysis can contribute to a deeper understanding of this complex, rare, and severe genetic disorder.

[14] Lactate metabolism and lactylation in kidney diseases: insights into mechanisms and therapeutic opportunities

• Authors: Yuhua Cheng, Linjuan Guo
• Year: 2025
• Venue: Renal Failure
• URL: https://www.semanticscholar.org/paper/6208b88884af543f7c97d2e70ed6b727dcfb4f58
• DOI: 10.1080/0886022X.2025.2469746
• PMID: 40012230
• PMCID: 11869332
• Citations: 11
• Summary: A review examines the role of lactate esters, especially lactylation, in kidney diseases, with a focus on their regulatory mechanisms and potential as therapeutic targets.
• Evidence snippets:
• Snippet 1 (score: 0.371) > Lactate metabolism and its post-translational modifications, particularly lactylation, play critical roles in the pathophysiology of various kidney diseases, including AKI, DKD, and ccRCC (Figure 1). The kidney's ability to metabolize lactate is crucial for maintaining renal function under normal conditions. However, in pathological states, impaired lactate metabolism leads to its accumulation, exacerbating renal dysfunction and disease progression. For more details on lactate metabolism and kidney diseases, refer to previous reviews [2,3,25]. > Lactylation influences gene transcription, protein function, and cellular metabolism, contributing to inflammatory responses, mitochondrial dysfunction, and tumor progression. > Understanding the mechanisms of lactate metabolism and lactylation in kidney diseases opens new avenues for therapeutic interventions. Targeting these metabolic pathways could mitigate renal injury and improve patient outcomes. Future research should focus on elucidating the specific pathways and molecular targets affected by lactate and lactylation and developing inhibitors to modulate these processes. Clinical trials are necessary to validate the efficacy and safety of these therapies. Overall, the lactate-lactylation axis is a promising target for novel therapeutic strategies aimed at treating kidney diseases and improving renal health.

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

• Authors: H. Breiteneder, Z. Diamant, T. Eiwegger, W. Fokkens, C. Traidl‐Hoffmann et al.
• Year: 2019
• Venue: Allergy
• URL: https://www.semanticscholar.org/paper/e19b0755c4f4903f68377333676edebf9bd73c89
• DOI: 10.1111/all.13851
• PMID: 31056763
• PMCID: 6973012
• Citations: 90
• Influential citations: 3
• Summary: Recent developments in research and patient care and future trends in the discipline are reviewed and topics on food allergy, biologics, small molecules, and novel therapeutic concepts in allergen‐specific immunotherapy for airway disease are highlighted.
• Evidence snippets:
• Snippet 1 (score: 0.370) > The past decades have witnessed extensive progress in unraveling cellular and molecular mechanisms of immune regulation in asthma, allergic diseases, organ transplantation, autoimmune diseases, tumor biology, and chronic infections. 1,2 Consequently, a better understanding of the functions, the reciprocal regulation, and the counterbalance of subsets of immune and inflammatory cells but also structural cells-for example, epithelial and vascular cells, airway smooth muscle cells, neuroendocrine system-that interact via various intercellular messengers will indicate avenues for immune interventions and novel treatment modalities of allergic diseases and immunological disorders. It is generally expected that drug development in the next decades will show a significant shift from chemicals to biologicals. > After more than 20 years without any breakthrough drug becoming available for patients, several disciplines including allergology are now experiencing extraordinary times with the recent licensing of several major biological drugs and novel allergen-specific immunotherapy (AIT) vaccines. Several biological modifiers of the immune response targeting intracellular messengers or their receptors have been developed to date. [3][4][5][6][7][8] In addition, a number of promising small molecule drugs and vaccines are in the development pipeline. [9][10][11] This new era is now calling for the development of biomarkers and phenoand endotyping of diseases for customized patient care, which is termed stratified medicine, precision medicine, or personalized medicine. 4 Distinguishing phenotypes of a complex disease covers the observable clinically relevant properties of the disease but does not show a direct relationship to disease etiology and pathophysiology. In a complex condition, such as asthma, different pathogenetic mechanisms can induce similar clinical manifestations; however, they may require different treatment approaches. 12,13 These pathophysiological mechanisms underlying disease subgroups are addressed by the term "endotype." [12][13][14] Classification of complex diseases based on the concept of endotypes provides advantages for epidemiological, genetic, and drug-related studies. Accurate endotyping by using reliable biomarkers reflects the natural history of the disease and aims to predict the response to (targeted) treatments. 15 Recent studies have focused on better understanding

[16] The ties that bind: functional clusters in limb-girdle muscular dystrophy

• Authors: E. Barton, C. A. Pacak, Whitney L. Stoppel, P. Kang
• Year: 2020
• Venue: Skeletal Muscle
• URL: https://www.semanticscholar.org/paper/653422e1a9dc9cc7f16758b10f3f203155bc68c9
• DOI: 10.1186/s13395-020-00240-7
• PMID: 32727611
• PMCID: 7389686
• Citations: 24
• Summary: A deeper understanding of these disease pathways could yield a new generation of precision therapies that would each be expected to treat a broader range of LGMD patients than a single subtype, thus expanding the scope of the molecular medicines that may be developed for this complex array of muscular dystrophies.
• Evidence snippets:
• Snippet 1 (score: 0.364) > Pyridine nucleotide-disulfide reductase [55] Many of the protein functions listed require further confirmation or are disputed these methodologies. Those patients with moderate disease phenotypes regardless of the underlying causative gene mutation would likely fall into a category where there may be interest in testing a pharmacological treatment (that could be halted) but reduced interest in a more permanent experimental strategy. For all of the above-mentioned reasons, the identification of unifying therapeutic targets applicable to multiple subtypes of > LGMDs is highly desirable. > To identify such targets, we should first consider the question: What binds all of these LGMDs together? The two core phenotypic features are progressive proximal muscle weakness, along with characteristic signs of muscle fiber destruction on biopsy, referred to as "dystrophic" features. Nuances in clinical presentation have helped to distinguish some of the LGMDs, such as the frequent occurrence of difficulty walking on tiptoes in LGMD R2 (LGMD2B), caused by dysferlin deficiency. However, heterogeneity associated with variable ages of onset and ranges of severity makes it generally difficult to distinguish and diagnose LGMD subtypes based on clinical presentation alone. A change in perspective is in order to aid in understanding disease pathways responsible for clinical features even when the genetic mutation is unknown. Further, given the large number of genespecific LGMD subtypes, it could very well be that several major disease mechanisms may be shared across the family of diseases. Yet despite careful studies that have collectively determined the cellular localization of most proteins associated with LGMD (Fig. 1), there is limited knowledge of potentially unifying molecular disease mechanisms. We assert that the identification of functional clusters of these proteins, grouped by such common mechanisms, will streamline our understanding of the disease processes and identify therapeutic targets relevant to individuals in multiple disease subgroups, including individuals whose pathogenic mutations have not been found. By extension, this approach may serve as a tool to not only find common mechanisms, but may also help to distinguish LGMD subtypes that do not share similar functional patterns, and afford further refinement of potential treatments.

[17] The ties that bind: functional clusters in limb-girdle muscular dystrophy

• Authors: E. Barton, C. A. Pacak, Whitney L. Stoppel, Peter B. Kang
• Year: 2020
• Venue: Skeletal Muscle
• URL: https://www.semanticscholar.org/paper/3493c658bb8716d789a05ddf292162832e064e47
• DOI: 10.1186/s13395-020-00240-7
• Summary: A deeper understanding of these disease pathways could yield a new generation of precision therapies that would each be expected to treat a broader range of LGMD patients than a single subtype, thus expanding the scope of the molecular medicines that may be developed for this complex array of muscular dystrophies.
• Evidence snippets:
• Snippet 1 (score: 0.364) > Pyridine nucleotide-disulfide reductase [55] Many of the protein functions listed require further confirmation or are disputed these methodologies. Those patients with moderate disease phenotypes regardless of the underlying causative gene mutation would likely fall into a category where there may be interest in testing a pharmacological treatment (that could be halted) but reduced interest in a more permanent experimental strategy. For all of the above-mentioned reasons, the identification of unifying therapeutic targets applicable to multiple subtypes of > LGMDs is highly desirable. > To identify such targets, we should first consider the question: What binds all of these LGMDs together? The two core phenotypic features are progressive proximal muscle weakness, along with characteristic signs of muscle fiber destruction on biopsy, referred to as "dystrophic" features. Nuances in clinical presentation have helped to distinguish some of the LGMDs, such as the frequent occurrence of difficulty walking on tiptoes in LGMD R2 (LGMD2B), caused by dysferlin deficiency. However, heterogeneity associated with variable ages of onset and ranges of severity makes it generally difficult to distinguish and diagnose LGMD subtypes based on clinical presentation alone. A change in perspective is in order to aid in understanding disease pathways responsible for clinical features even when the genetic mutation is unknown. Further, given the large number of genespecific LGMD subtypes, it could very well be that several major disease mechanisms may be shared across the family of diseases. Yet despite careful studies that have collectively determined the cellular localization of most proteins associated with LGMD (Fig. 1), there is limited knowledge of potentially unifying molecular disease mechanisms. We assert that the identification of functional clusters of these proteins, grouped by such common mechanisms, will streamline our understanding of the disease processes and identify therapeutic targets relevant to individuals in multiple disease subgroups, including individuals whose pathogenic mutations have not been found. By extension, this approach may serve as a tool to not only find common mechanisms, but may also help to distinguish LGMD subtypes that do not share similar functional patterns, and afford further refinement of potential treatments.

[18] Aberrant NLRP3 Inflammasome Activation Ignites the Fire of Inflammation in Neuromuscular Diseases

• Authors: Christine Péladeau, J. Sandhu
• Year: 2021
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/763a36db080236fca8cde89b2afcdf056f3584d0
• DOI: 10.3390/ijms22116068
• PMID: 34199845
• PMCID: 8200055
• Citations: 18
• Influential citations: 1
• Summary: Whether therapeutic targeting of the NLRP3 inflammasome components is a viable approach to alleviating the detrimental phenotype of neuromuscular diseases and improving clinical outcomes is examined.
• Evidence snippets:
• Snippet 1 (score: 0.363) > Despite a large number of mechanisms that have been identified in muscle degeneration and nerve cell loss, none have proven to be the primary cause of the disease. There is much need for a deeper understanding of the biology of the pathogeneses and the molecular mechanisms that are activated early in the diseases in order to identify "druggable" targets and disease-modifying treatments for these devastating diseases. > Human iPSC technologies are emerging as useful platforms for disease modeling to study pathogenic mechanisms and discover novel therapeutics for neuromuscular diseases [211,237]. Indeed, patient-derived iPSCs are being used to create a "patient-in-adish" disease model to derive relevant cell types for testing potential therapeutics, paving the way towards personalized medicine. This approach allows drug screening in a dish prior to administration to patients and "bench-to-bedside" translation of potential therapies. Additionally, iPSCs may also be used to stratify patients with various phenotypes and guide future clinical trials for bringing improved therapies to patients. Since multiple cell types are involved in disease pathogenesis, future research efforts need to be focused on deciphering "disease-specific signatures" at single-cell resolution, and not only in neuronal cells but also in non-neuronal cells. The application of modern technologies, including single-cell RNA sequencing and spatial transcriptomics, to neuromuscular diseases, will allow to ascertain cellular vulnerability and cell-specific mechanisms during various stages of disease progression. > The vital roles of the NLRP3 inflammasome in neuromuscular diseases such as DMD, LGMD and ALS, reveal that targeting this pathway is indeed a promising therapeutic strategy. Dysregulation of the NLRP3 inflammasome in muscle tissues by muscle damage, membrane instability, extracellular ATP and Ca 2+ ions or signals from infiltrating immune cells, clearly impacts the progression of neuromuscular and neurodegenerative disorders. Thus, modulation of these pathways involved with activation and assembly of NLRP3 inflammasome could be truly beneficial.

[19] 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: 0.363) > : 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.

[20] Combined metabolomics and network pharmacology to elucidate the mechanisms of Dracorhodin Perchlorate in treating diabetic foot ulcer rats

• Authors: Pin Deng, Huan Liang, Shulong Wang, Rui-Lin Hao, Jin-Feng Han et al.
• Year: 2022
• Venue: Frontiers in Pharmacology
• URL: https://www.semanticscholar.org/paper/29251bcf9cf6d00e07f61c3ab592e54101f7857b
• DOI: 10.3389/fphar.2022.1038656
• PMID: 36532755
• PMCID: 9752146
• Citations: 15
• Summary: Research based on metabolomics and network pharmacology demonstrated that DP improves wound healing in DFU through multiple targets and pathways, and it can potentially be used for DFU treatment.
• Evidence snippets:
• Snippet 1 (score: 0.362) > Network pharmacology is a method based on bioinformatics and systems pharmacology (Zhong et al., 2018), which assess drug polypharmacological effects at the molecular level to investigate the interaction between natural products and targets and confirm major mechanisms (Sheng et al., 2014). Network pharmacology can help investigate reaction networks and key targets and metabolites (Yu et al., 2012). This integrated strategy discovers the crucial targets and important mechanisms of DP treating DFU rat by integrating network pharmacology and metabolomics. > Arginine is important in cellular physiology. Like other amino acids, it plays a role in the production of proteins. The conversion of arginine to nitric oxide and other polyamines has a role in cell signalling and cell proliferation. Arginine is an essential substrate for wound healing processes due to its multiple functions. In numerous studies, supplying arginine alleviates or improves healing (Witte, 2003). A previous study suggested that arginine metabolite-nitric oxide played a key role in wound healing. As a semi-essential amino acid, arginine is metabolised by arginase and nitric oxide synthase. Woundhealing emphasises the important role of strict reciprocal control among these enzymes (Stechmiller, 2008). > Arginase signalling plays a vital role in chronic wound pathophysiology and healing. As an evolutionarily conserved enzyme, arginase (ARG) can be expressed in a variety of cells. In the last stage of the urea cycle, arginine protects excess ammonia under homeostatic conditions by producing L-ornithine and urea. L-ornithine is located at the intersection of Arg dependent pathway and urea cycle, contributing to collagen production, cell proliferation and detoxification (Szondi et al., 2021). Collagen is an important component of connective tissue; thus, healing requires collagen formation and deposition (B. Behm, 2012). L-proline is an important collagen building block (Shih et al., 2010).

Notes

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