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Molecular Genetics & Genomic Medicine Apr 2024The ASNS (ASNS, MIM 108370) gene variations are responsible for asparagine synthetase deficiency (ASNSD, MIM 615574), a very rare autosomal recessive disease... (Review)
Review
BACKGROUND
The ASNS (ASNS, MIM 108370) gene variations are responsible for asparagine synthetase deficiency (ASNSD, MIM 615574), a very rare autosomal recessive disease characterized by cerebral anomalies. These patients have congenital microcephaly, progressive encephalopathy, severe intellectual disability, and intractable seizures.
METHOD
Clinical characteristics of the patient were collected. Exome sequencing was used for the identification of variants. Sanger sequencing was used to confirm the variant in the target region. The structure of the protein was checked using the DynaMut2 web server.
RESULTS
The proband is an 11-year-old Iranian-Azeri girl with primary microcephaly and severe intellectual disability in a family with a consanguineous marriage. Symptoms emerged around the 10-20th days of life, when refractory epileptic gaze and unilateral tonic-clonic seizures initiated without any provoking factor such as fever. A brain MRI revealed no abnormalities except for brain atrophy. The karyotype was normal. Using exome sequencing, we identified a novel homozygous variant of thymine to adenine (NM_001673.5:c.538T>A) in the ASNS gene. Both parents had a heterozygous variant in this location. Subsequently, Sanger sequencing confirmed this variant. We also reviewed the clinical manifestations and MRI findings of the previously reported patients.
CONCLUSION
In the present study, a novel homozygous variant was recognized in the ASNS gene in an Iranian-Azeri girl manifesting typical ASNSD symptoms, particularly intellectual disability and microcephaly. This study expands the mutation spectrum of ASNSD and reviews previously reported patients.
Topics: Female; Humans; Child; Microcephaly; Intellectual Disability; Iran; Brain Diseases; Nervous System Malformations; Atrophy
PubMed: 38546112
DOI: 10.1002/mgg3.2424 -
Microorganisms Feb 2024Evidence shows that the gut microbiome in early life is an essential modulator of physiological processes related to healthy brain development, as well as mental and... (Review)
Review
Evidence shows that the gut microbiome in early life is an essential modulator of physiological processes related to healthy brain development, as well as mental and neurodegenerative disorders. Here, we conduct a systematic review of gut microbiome assessments on infants (both healthy and with conditions that affect brain development) during the first thousand days of life, associated with neurodevelopmental outcomes, with the aim of investigating key microbiome players and mechanisms through which the gut microbiome affects the brain. and were associated with non-social fear behavior, duration of orientation, cognitive and motricity development, and neurotypical brain development. Lachnospiraceae, , and showed variable levels of influence on behavior and brain development. Few studies described mechanistic insights related to NAD salvage, aspartate and asparagine biosynthesis, methanogenesis, pathways involved in bile acid transformation, short-chain fatty acids production, and microbial virulence genes. Further studies associating species to gene pathways and robustness in data analysis and integration are required to elucidate the functional mechanisms underlying the role of microbiome-gut-brain axis in early brain development.
PubMed: 38543475
DOI: 10.3390/microorganisms12030424 -
Foods (Basel, Switzerland) Mar 2024Asparagus production generates significant amounts of by-products during the summer and post-harvest growth period. By-products can be good sources of nutrients and...
Asparagus production generates significant amounts of by-products during the summer and post-harvest growth period. By-products can be good sources of nutrients and phytochemicals. The interest in increasing the availability of proteins for human consumption has led to the use of new plant sources rich in proteins. The objective of this study was to use response surface methodology (RSM) to optimize the aqueous extraction process of proteins from asparagus leafy by-products, for the production of new protein ingredients. The optimum extraction condition was at pH 9, with 40 min of extraction at 50 °C, and the concentration was fixed at 5 g·L. The isolate obtained presented 90.48% protein with 43.47% protein yield. Amino acids such as alanine, proline, valine, leucine/isoleucine, asparagine, and phenylalanine were identified, and the antioxidant activity for 2,2 AZINO BIS (3-ethylbenzo thiazoline 6 sulfonic acid diammonium salt) was 145.76 equivalent to Trolox μmol.100g and for DPPH 65.21 equivalent to Trolox μmol.100g. The product presented favorable technological properties (water absorption capacity 4.49 g·g and oil absorption capacity 3.47 g·g) and the color tended towards dark green (L* 31.91, a* -1.01, b* -2.11). The protein isolate obtained through the extraction optimization process showed high potential to be used as a protein ingredient.
PubMed: 38540884
DOI: 10.3390/foods13060894 -
Cancers Mar 2024Cancer cells demand amino acids beyond their usage as "building blocks" for protein synthesis. As a result, targeting amino acid acquisition and utilization has emerged... (Review)
Review
Cancer cells demand amino acids beyond their usage as "building blocks" for protein synthesis. As a result, targeting amino acid acquisition and utilization has emerged as a pivotal strategy in cancer treatment. In the setting of leukemia therapy, compelling examples of targeting amino acid metabolism exist at both pre-clinical and clinical stages. This review focuses on summarizing novel insights into the metabolism of glutamine, asparagine, arginine, and tryptophan in leukemias, and providing a comprehensive discussion of perturbing their metabolism to improve the therapeutic outcomes. Certain amino acids, such as glutamine, play a vital role in the energy metabolism of cancer cells and the maintenance of redox balance, while others, such as arginine and tryptophan, contribute significantly to the immune microenvironment. Therefore, assessing the efficacy of targeting amino acid metabolism requires comprehensive strategies. Combining traditional chemotherapeutics with novel strategies to perturb amino acid metabolism is another way to improve the outcome in leukemia patients via overcoming chemo-resistance or promoting immunotherapy. In this review, we also discuss several ongoing or complete clinical trials, in which targeting amino acid metabolism is combined with other chemotherapeutics in treating leukemia.
PubMed: 38539506
DOI: 10.3390/cancers16061171 -
Scientific Reports Mar 2024Malaria is the leading parasitic disease worldwide, with P. vivax being a major challenge for its control. Several studies have indicated metabolomics as a promising...
Malaria is the leading parasitic disease worldwide, with P. vivax being a major challenge for its control. Several studies have indicated metabolomics as a promising tool for combating the disease. The study evaluated plasma metabolomic profiles of patients with recurrent and non-recurrent P. vivax malaria in the Brazilian Amazon. Metabolites extracted from the plasma of P. vivax-infected patients were subjected to LC-MS analysis. Untargeted metabolomics was applied to investigate the metabolic profile of the plasma in the two groups. Overall, 51 recurrent and 59 non-recurrent patients were included in the study. Longitudinal metabolomic analysis revealed 52 and 37 significant metabolite features from the recurrent and non-recurrent participants, respectively. Recurrence was associated with disturbances in eicosanoid metabolism. Comparison between groups suggest alterations in vitamin B6 (pyridoxine) metabolism, tyrosine metabolism, 3-oxo-10-octadecatrienoate β-oxidation, and alkaloid biosynthesis II. Integrative network analysis revealed enrichment of other metabolic pathways for the recurrent phenotype, including the butanoate metabolism, aspartate and asparagine metabolism, and N-glycan biosynthesis. The metabolites and metabolic pathways predicted in our study suggest potential biomarkers of recurrence and provide insights into targets for antimalarial development against P. vivax.
Topics: Humans; Malaria, Vivax; Metabolomics; Malaria; Metabolome; Antimalarials
PubMed: 38538661
DOI: 10.1038/s41598-024-54231-5 -
Ecotoxicology and Environmental Safety Apr 2024Pregnancy is a sensitive window period for bisphenol A (BPA) exposure. BPA can pass through the placenta and cause reproductive damage in offspring female mice. Even BPA...
Cuscuta chinensis flavonoids alleviate ovarian damage in offspring female mice induced by BPA exposure during pregnancy by regulating the central carbon metabolism pathway.
Pregnancy is a sensitive window period for bisphenol A (BPA) exposure. BPA can pass through the placenta and cause reproductive damage in offspring female mice. Even BPA that is not metabolized during lactation can be passed through milk. Cuscuta chinensis flavonoids (CCFs) can alleviate reproductive damage caused by BPA, but the mechanism of action is unclear. To investigate the potential mitigating impact of CCFs on ovarian damage resulting from BPA exposure during pregnancy, we administered BPA and CCFs to pregnant mice during the gestational period spanning from 0.5 to 17.5 days. Aseptic collection of serum and ovaries from female mice was conducted on postnatal day 21 (PND21). Serum hormone levels and tissue receptor levels were quantified utilizing ELISA and PCR, while ovaries underwent sequencing and analysis through transcriptomics and metabolomics techniques. Additionally, the assessment of ovarian oxidative stress levels was carried out as part of the comprehensive analysis. The results showed that CCFs administration mitigated the adverse effects induced by BPA exposure on ovarian index, hormone levels, receptor expression, and mRNA expression levels in female offspring mice. The joint analysis of transcriptome and metabolome revealed 48 enriched pathways in positive ion mode and 44 enriched pathways in negative ion mode. Among them, the central carbon metabolism pathway is significantly regulated by BPA and CCFs. The screened sequencing results were verified through qPCR and biochemical kits. In this study, CCFs may participate in the central carbon metabolism pathway by reducing the expression of Kit proto-oncogene (Kit), hexokinase 1 gene (Hk1) and pyruvate kinase M (Pkm) mRNA and increasing the expression of h-ras proto-oncogene (Hras), sirtuin 3 (Sirt3), sirtuin 6 (Sirt6) and TP53 induced glycolysis regulatory phosphatase gene (Tigar) mRNA, thereby resisting the effects of BPA on the body. At the same time, the metabolic levels of D-Fructose 1,6-bisphosphate and L-Asparagine tend to be stable. Moreover, CCFs demonstrated a capacity to diminish the BPA-induced escalation in reactive oxygen species (ROS) and malondialdehyde (MDA). Simultaneously, it exhibited the ability to elevate levels of glutathione (GSH) and catalase (CAT), thereby effectively preventing peroxidation. In summary, CCFs alleviate BPA-induced ovarian damage in offspring female mice by regulating the central carbon metabolism pathway. This study will improve the information on BPA reproductive damage antagonist drugs and provide a theoretical basis for protecting animal reproductive health.
Topics: Pregnancy; Mice; Animals; Female; Ovary; Cuscuta; Flavonoids; Benzhydryl Compounds; Hormones; RNA, Messenger; Endocrine Disruptors; Sirtuins; Phenols
PubMed: 38537475
DOI: 10.1016/j.ecoenv.2024.116253 -
Pathogens (Basel, Switzerland) Feb 2024In this study, we investigated the spore germination phenotype of strains isolated from diarrheic animals (animal strains). The transcripts of germination-specific...
In this study, we investigated the spore germination phenotype of strains isolated from diarrheic animals (animal strains). The transcripts of germination-specific genes and their protein products were also measured. Our study found the following results: (i) animal strains spores germinated at a slower rate with AK (mixture of L-asparagine and KCl), L-cysteine, or L-lysine, but the extent of germination varied based on strains and germinants used; (ii) none of the amino acids (excluding L-cysteine and L-lysine) were identified as a universal germinant for spores of animal strains; (iii) animal strain spores germinated better at a pH range of 6.0-7.0; (iv) all tested germination-specific genes were expressed in animal strains; the levels of expression of major germinant receptor gene () were higher and the cortex hydrolysis machinery genes ( and ) were lower in animal strains, compared to the food poisoning strain SM101; and (v) the levels of CspB and SleC were significantly lower in spores of animal strains compared to strain SM101, suggesting that these animal strains lack an efficient spore cortex hydrolysis machinery. In summary, our findings suggest that the poor or slow spore germination in animal strains might be due to incomplete spore cortex hydrolysis.
PubMed: 38535537
DOI: 10.3390/pathogens13030194 -
Data in Brief Apr 2024The Unfolded Protein Response (UPR) is a retrograde, ER-to-nucleus, signalling pathway which is conserved across kingdoms. In plants, it contributes to development,...
The Unfolded Protein Response (UPR) is a retrograde, ER-to-nucleus, signalling pathway which is conserved across kingdoms. In plants, it contributes to development, reproduction, immunity and tolerance to abiotic stress. This RNA sequencing (RNA-seq) dataset was produced from 14-day-old seedlings challenged by tunicamycin (Tm), an antibiotic inhibiting Asn-linked glycosylation in the endoplasmic reticulum (ER), causing an ER stress and eventually activating the UPR. Wild-type (WT) and a double mutant deficient for two main actors of the UPR ( and ) were used as genetic backgrounds in our experimental setup, allowing to distinguish among differentially-expressed genes (DEGs) which ones are dependent on or independent on IRE1s. Also, shoots and roots were harvested separately to determine organ-specific transcriptomic responses to Tm. Library and sequencing were performed using DNBseq™ technology by the Beijing Genomics Institute. Reads were mapped and quantified against the Arabidopsis genome. Differentially-expressed genes were identified using Rflomics upon filtering and normalization by the Trimmed Mean of M-value (TMM) method. While the genotype effect was weak under mock conditions (with a total of 182 DEGs in shoots and 195 DEGs in roots), the tunicamycin effect on each genotype was characterized by several hundred of DEGs in both shoots and roots. Among these genes, 872 and 563 genes were statistically up- and down-regulated in the shoot tissues of the double mutant when compared to those of WT, respectively. In roots of Tm-challenged seedlings, 425 and 439 genes were significantly up- and down-regulated in mutants with respect to WT. We believe that our dataset could be reused for investigating any biological questions linked to ER homeostasis and its role in plant physiology.
PubMed: 38533111
DOI: 10.1016/j.dib.2024.110243 -
Cell Death & Disease Mar 2024AURKA is an established target for cancer therapy; however, the efficacy of its inhibitors in clinical trials is hindered by differential response rates across different...
AURKA is an established target for cancer therapy; however, the efficacy of its inhibitors in clinical trials is hindered by differential response rates across different tumor subtypes. In this study, we demonstrate AURKA regulates amino acid synthesis, rendering it a vulnerable target in KEAP1-deficient non-small cell lung cancer (NSCLC). Through CRISPR metabolic screens, we identified that KEAP1-knockdown cells showed the highest sensitivity to the AURKA inhibitor MLN8237. Subsequent investigations confirmed that KEAP1 deficiency heightens the susceptibility of NSCLC cells to AURKA inhibition both in vitro and in vivo, with the response depending on NRF2 activation. Mechanistically, AURKA interacts with the eIF2α kinase GCN2 and maintains its phosphorylation to regulate eIF2α-ATF4-mediated amino acid biosynthesis. AURKA inhibition restrains the expression of asparagine synthetase (ASNS), making KEAP1-deficient NSCLC cells vulnerable to AURKA inhibitors, in which ASNS is highly expressed. Our study unveils the pivotal role of AURKA in amino acid metabolism and identifies a specific metabolic indication for AURKA inhibitors. These findings also provide a novel clinical therapeutic target for KEAP1-mutant/deficient NSCLC, which is characterized by resistance to radiotherapy, chemotherapy, and targeted therapy.
Topics: Humans; Asparagine; Aurora Kinase A; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Kelch-Like ECH-Associated Protein 1; Lung Neoplasms; NF-E2-Related Factor 2
PubMed: 38521813
DOI: 10.1038/s41419-024-06577-x -
MSystems Apr 2024The gut microbiota plays a crucial role in health and is significantly modulated by human diets. In addition to Western diets which are rich in proteins, high-protein...
The gut microbiota plays a crucial role in health and is significantly modulated by human diets. In addition to Western diets which are rich in proteins, high-protein diets are used for specific populations or indications, mainly weight loss. In this study, we investigated the effect of protein supplementation on , a Gram-negative gut symbiont. The supplementation with whey proteins led to a significant increase in growth rate, final biomass, and short-chain fatty acids production. A comprehensive genomic analysis revealed that possesses a set of 156 proteases with putative intracellular and extracellular localization and allowed to identify amino acid transporters and metabolic pathways. We developed a fully curated genome-scale metabolic model of that incorporated its proteolytic activity and simulated its growth and production of fermentation-related metabolites in response to the different growth media. We validated the model by comparing the predicted phenotype to experimental data. The model accurately predicted 's growth and metabolite production ( = 0.92 for the training set and = 0.89 for the validation set). We found that accounting for both ATP consumption related to proteolysis, and whey protein accessibility is necessary for accurate predictions of metabolites production. These results provide insights into 's adaptation to a high-protein diet and its ability to utilize proteins as a source of nutrition. The proposed model provides a useful tool for understanding the feeding mechanism of in the gut microbiome.IMPORTANCEMicrobial proteolysis is understudied despite the availability of dietary proteins for the gut microbiota. Here, the proteolytic potential of the gut symbiont was analyzed for the first time using pan-genomics. This sketches a well-equipped bacteria for protein breakdown, capable of producing 156 different proteases with a broad spectrum of cleavage targets. This functional potential was confirmed by the enhancement of growth and metabolic activities at high protein levels. Proteolysis was included in a metabolic model which was fitted with the experiments and validated on external data. This model pinpoints the links between protein availability and short-chain fatty acids production, and the importance for to gain access to glutamate and asparagine to promote growth. This integrated approach can be generalized to other symbionts and upscaled to complex microbiota to get insights into the ecological impact of proteins on the gut microbiota.
Topics: Humans; Proteolysis; Bacteria; Fatty Acids, Volatile; Peptide Hydrolases; Bacteroides
PubMed: 38517169
DOI: 10.1128/msystems.00153-24