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Toxoplasma gondii is a protozoan parasite, occurring worldwide, endangers human health and causes enormous economic losses to the Ministry of Agriculture. A safe and effective vaccination is needed to handle these problems. In addition, ideal vaccine production is a challenge in the future. In this study, we knocked out the adenylosuccinate lyase (ADSL) gene and found that the gene reduces the growth rate of T. gondii tachyzoites in vitro under standard growth conditions by plaque or replication experiments. Furthermore, mice that were immunized with tachyzoites of the ME49ΔADSL strain induced 100% protection efficacy against challenge with the type 1 strain RH, type 2 strain ME49 and type 3 strain VEG. All mice that were immunized with ME49ΔADSL had a survival rate of 100% when they were reinfected with wild-type strains, either 30 days or 70 days after immunization, and immunization was also protective against homologous infection with 50 T. gondii ME49 tissue cysts. In addition, the level of Toxoplasma-specific IgG was significantly elevated at 30 and 70 days after immunization. ME49ΔADSL induced high levels of Th1 cytokines (interferon gamma (IFN-γ), interleukin (IL)-12) at 4 weeks after immunization and spleen cell cultures from mice vaccinated for 150 days were able to produce robust INF-γ and IL-12 levels in the supernatant. The results of the present study showed that ΔADSL vaccination induced a T. gondii-specific cellular immune response against further infections. These results suggest that the ADSL-deficient vaccine can induce anti-Toxoplasma gondii humoral and cellular immune responses and has 100% immune protection against post-challenge by the type 1 strain RH, type 2 strain ME49 and type 3 strain VEG. It will be used as an excellent candidate for live vaccines and may contribute in a positive meaning to control human toxoplasmosis.

Adenylosuccinate lyase (ADSL) is an essential enzyme for purine biosynthesis. Here we sought to investigate the putative role of ADSL in colorectal carcinoma (CRC) carcinogenesis and response to antimetabolites. ADSL expression levels were assessed by immunohistochemistry or retrieved from The Cancer Genome Atlas (TCGA) dataset. The effects of ADSL silencing or overexpression were evaluated on CRC cell proliferation, cell migration and cell-cycle. tumor growth was assessed by the chicken chorioallantoic membrane (CAM). Transfected cell lines or patient-derived organoids (PDO) were treated with 5-fluorouracil (5-FU) and 6-mercaptopurine (6-MP) and drug response was correlated with ADSL expression levels. Metabolomic and transcriptomic profiling were performed to identify dysregulated pathways and ADSL downstream effectors. Mitochondrial respiration and glycolytic capacity were measured using Seahorse; mitochondrial membrane potential and the accumulation of ROS were measured by FACS using MitoTracker Red and MitoSOX staining, respectively. Activation of canonical pathways was assessed by immunohistochemistry and immunoblotting. ADSL expression is significantly increased in CRC tumors compared to non-tumor tissue. ADSL-high CRCs show upregulation of genes involved in DNA synthesis, DNA repair and cell cycle. Accordingly, ADSL overexpression accelerated progression through the cell cycle and significantly increased proliferation and migration in CRC cell lines. Additionally, ADSL expression increased tumor growth and sensitized CRCs to 6-MP , (PDOs) and (CAM model). ADSL exerts its oncogenic function by affecting mitochondrial function via alteration of the TCA cycle and impairment of mitochondrial respiration. The KEAP1-NRF2 and mTORC1-cMyc axis are independently activated upon ADSL overexpression and may favor the survival and proliferation of ROS-accumulating cells, favoring DNA damage and tumorigenesis. Our results suggest that ADSL is a novel oncogene in CRC, modulating mitochondrial function, metabolism and oxidative stress, thus promoting cell cycle progression, proliferation and migration. Our results also suggest that ADSL is a predictive biomarker of response to 6-mercaptopurine in the pre-clinical setting.

Purine homeostasis is ensured through a metabolic network widely conserved from prokaryotes to humans. Purines can either be synthesized de novo, reused, or produced by interconversion of extant metabolites using the so-called recycling pathway. Although thoroughly characterized in microorganisms, such as yeast or bacteria, little is known about regulation of the purine biosynthesis network in metazoans. In humans, several diseases are linked to purine metabolism through as yet poorly understood etiologies. Particularly, the deficiency in adenylosuccinate lyase (ADSL)—an enzyme involved both in the purine de novo and recycling pathways—causes severe muscular and neuronal symptoms. In order to address the mechanisms underlying this deficiency, we established Caenorhabditis elegans as a metazoan model organism to study purine metabolism, while focusing on ADSL. We show that the purine biosynthesis network is functionally conserved in C. elegans. Moreover, adsl-1 (the gene encoding ADSL in C. elegans) is required for developmental timing, germline stem cell maintenance and muscle integrity. Importantly, these traits are not affected when solely the de novo pathway is abolished, and we present evidence that germline maintenance is linked specifically to ADSL activity in the recycling pathway. Hence, our results allow developmental and tissue specific phenotypes to be ascribed to separable steps of the purine metabolic network in an animal model.

Adenylosuccinate lyase (ADSL) functions in de novo purine synthesis (DNPS) and the purine nucleotide cycle. ADSL deficiency (ADSLD) causes numerous neurodevelopmental pathologies, including microcephaly and autism spectrum disorder. ADSLD patients have normal serum purine nucleotide levels but exhibit accumulation of dephosphorylated ADSL substrates, S-Ado, and SAICAr, the latter being implicated in neurotoxic effects through unknown mechanisms. We examined the phenotypic effects of ADSL depletion in human cells and their relation to phenotypic outcomes. Using specific interventions to compensate for reduced purine levels or modulate SAICAr accumulation, we found that diminished AMP levels resulted in increased DNA damage signaling and cell cycle delays, while primary ciliogenesis was impaired specifically by loss of ADSL or administration of SAICAr. ADSL-deficient chicken and zebrafish embryos displayed impaired neurogenesis and microcephaly. Neuroprogenitor attrition in zebrafish embryos was rescued by pharmacological inhibition of DNPS, but not increased nucleotide concentration. Zebrafish also displayed phenotypes commonly linked to ciliopathies. Our results suggest that both reduced purine levels and impaired DNPS contribute to neurodevelopmental pathology in ADSLD and that defective ciliogenesis may influence the ADSLD phenotypic spectrum.

In recent years, strategic plans for poultry production have emphasized quantitative traits, particularly body weight and carcass traits (meat yield), in response to overpopulation challenges. Candidate genes such as adenylosuccinate lyase (ADSL), melanocortin-4-receptor (MC4R), and calpain 1 (CAPN1) have played vital roles in this context due to their associations with muscle growth and body composition. This study aims to investigate the influence of polymorphisms and gene expressions of the aforementioned genes on body weight (BW), growth rate (GR), breast weight (BrW), and thigh weight (TW) across four distinct chicken breeds: Fayoumi, Matrouh, Mamourah, and Leghorn. The use of PCR-SSCP analysis revealed genetic polymorphisms through the identification of various patterns (genotypes) within the three examined genes. The ADSL, MC4R, and CAPN1 genes exhibited five, three, and two different genotypes, respectively. These polymorphisms displayed promising connections with enhancing economically significant production traits, particularly BW, BrW and TW. Furthermore, gene expression analyses were conducted on breast and thigh tissues obtained from the chicken breeds at 60 days of age, where ADSL and MC4R exhibited a noteworthy up-regulation in Fayoumi and Matrouh breeds, and down-regulation in Mamourah and Leghorn. In contrast, CAPN1 expression decreased across most breeds with a slight increase noted in Fayoumi breed. In conclusion, this investigation underscores the substantial impact of ADSL, MC4R, and CAPN1 genes on economically important production traits within Egyptian domestic chicken breeds. Consequently, these genes emerge as significant molecular markers, holding potential utility in avian selection and breeding programs aimed at enhancing productive performance.

Background The role of ADSL in various types of cancer remains inadequately understood. We encompassed a comprehensive examination of the mechanistic features of ADSL and explored its viability as a broad-spectrum predictor for malignancies. Methods Through a comprehensive pan-cancer examination, methylation assessment, immune infiltration evaluation, and further integration of single-cell transcriptome analysis, cellular communication, nomogram modeling, and prospective drug prediction in hepatocellular carcinoma (HCC), we have undertaken a thorough investigation of the biological roles of ADSL in neoplasms, especially in HCC. Results ADSL is markedly overexpressed in neoplastic tissues. ADSL downregulation is significantly correlated with improved overall survival (OS) across diverse cancer types, particularly in HCC. Moreover, in a broad spectrum of cancer subtypes, there is a reduction in the promoter methylation levels of ADSL. In single-cell transcriptome analysis, compared to the ADSL low expression group, the interactions between HCC cells and other cells in the ADSL high expression group were significantly enhanced in both quantity and intensity, suggesting that the ADSL high expression group may have a more complex cell communication network, with key pathways related to tumor progression possibly being significantly activated. Subsequent drug prediction assessments revealed that ADSL is linked to multiple pharmaceuticals, including Thapsigargin, Doramapimod, Elesclomol, and PF − 562271. Conclusions ADSL holds potential as a promising prognostic marker for OS in various cancer types, particularly in HCC. Additional research is needed to confirm these findings and to understand how ADSL affects cancer development.

Background Prostate cancer (PCa) is still a serious male malignant disease across the world. However, no exact pathogenesis had been explained. Although adenylosuccinate lyase (ADSL) gene was identified to be important in PCa early in 1987, its comprehensive functions for PCa have not been presented. Methods The cBioPortal for Cancer Genomics, Oncomine and GEO database were retrieved to investigate the associations between of the ADSL gene and PCa. Then, the PC-3, DU145 and C4-2B cell lines were applied in vitro experiments. RNA sequencing and further western blot (WB) were applied to explore the potential mechanisms of ADSL gene in PCa. Results Based on PCa clinical datasets, we firstly found ADSL gene highly expressed in PCa tissues. Moreover, its transcript level increased in the metastatic PCa further. Elevated ADSL gene expression indicated a poor prognosis of PCa. While inhibiting the expression of ADSL with siRNA, the ability of cell proliferation and migration all declined markedly, with increased cell apoptosis inversely. Most of cells were blocked in the G0/G1 phase. Additionally, RNA sequencing also discovered the inactivity of cell cycle pathway after ADSL knockdown, which had also confirmed on the proteins levels. Conclusions Our study identified the ADSL as an oncogene of PCa through regulating the cell cycle pathway firstly, with explicit cell and clinical phenotypes. Further mechanisms were needed to confirm its carcinogenic effect.

Purine nucleotides are involved in a multitude of cellular processes, and the dysfunction of purine metabolism has drastic physiological and pathological consequences. Accordingly, several genetic disorders associated with defective purine metabolism have been reported. The etiology of these diseases is poorly understood and simple model organisms, such as yeast, have proved valuable to provide a more comprehensive view of the metabolic consequences caused by the identified mutations. In this review, we present results obtained with the yeast Saccharomyces cerevisiae to exemplify how a eukaryotic unicellular organism can offer highly relevant information for identifying the molecular basis of complex human diseases. Overall, purine metabolism illustrates a remarkable conservation of genes, functions and phenotypes between humans and yeast.

Adenylosuccinate lyase (ADSL) deficiency is a rare inherited metabolic disorder with a wide phenotypic presentation, classically grouped into three types (neonatal, type I, and type II). We aim to better delineate the pathological spectrum, focusing on the electroclinical characteristics and phenotypic differences of patients with ADSL deficiency. Seven patients, from four different families, underwent serial electroencephalogram (EEG), clinical assessment, and neuroimaging. We also performed a systematic review of the cases published in the literature, summarizing the available clinical, neurophysiological, and genetic data. We report seven previously unreported ADSL deficiency patients with long-term follow-up (10-34 years). From the literature review, we collected 81 previously reported cases. Of the included patient population, 58 % (51/88) were classified as having ADSL deficiency type I, 28% (25/88) as having type II, and 14% (12/88) as having neonatal. The most frequently reported pathogenic variants are p.R426H homozygous (19 patients), p.Y114H in compound heterozygosity (13 patients), and p.D430N homozygous (6 patients). In the majority (89.2%), disease onset was within the first year of life. Epilepsy is present in 81.8% of the patients, with polymorphic and often intractable seizures. EEG features seem to display common patterns and developmental trajectories: (i) poor general background organization with theta-delta activity; (ii) hypsarrhythmia with spasms, usually adrenocorticotropic hormone-responsive; (iii) generalized epileptic discharges with frontal or frontal temporal predominance; and (iv) epileptic discharge activation in sleep with an altered sleep structure. Imaging features present consistent findings of cerebral atrophy with frontal predominance, cerebellar atrophy, and white matter abnormalities among the three types. ADSL deficiency presents variable phenotypic expression, whose severity could be partially attributed to residual activity of the mutant protein. Although a precise phenotype-genotype correlation was not yet feasible, we delineated a common pattern of clinical, neuroradiological, and neurophysiological features.

Introduction Breast cancer is a prevalent and significant contributor to cancer-related mortality among women worldwide. Its increasing incidence, especially in regions like North-West Iran, necessitates a deeper understanding of genetic factors contributing to its development. Genetic alterations, particularly single nucleotide polymorphisms (SNPs), are implicated in breast cancer susceptibility, making investigation in this context crucial. This study explores the role of CYP1A2-rs17861162 and ADSL-rs3788579 SNPs in breast cancer risk among Iranian women. Methods This study involved 200 female breast cancer patients and 200 healthy controls in North-West Iran. DNA was extracted from blood samples, and PCR–RFLP was used for genotyping the CYP1A2 and ADSL genes. Results The CYP1A2-rs17861162 SNP exhibited a shift from the C allele to the G allele in breast cancer patients, resulting in a 21.7% decrease in CC genotype frequency and a 21.6% and 77.8% increase in CG and GG genotypes, respectively, compared to controls. In ADSL-rs3788579 SNP, breast cancer patients had a significantly higher prevalence of the T allele, with a 28.5% increase compared to controls. In healthy participants, CC was most common, while in the breast cancer group, TT was most common. Conclusion This study highlights significant genetic alterations in CYP1A2-rs17861162 and ADSL-rs3788579 SNPs among breast cancer patients in North-West Iran, suggesting their potential as diagnostic and prognostic biomarkers. Further research is warranted to elucidate the precise mechanisms underlying their contributions to breast cancer susceptibility in this population.