RESUMEN

Ferroptosis, a recently identified non-apoptotic form of cell death, is strongly associated with neurological diseases and has emerged as a potential therapeutic target. Nevertheless, the fundamental mechanisms are still predominantly unidentified. In the current investigation, sulfiredoxin-1 (SRXN1) has been identified as a crucial regulator that enhances the susceptibility to ferroptosis in HT-22 mouse hippocampal cells treated with erastin. Utilizing TMT-based proteomics, a significant increase in SRXN1 expression was observed in erastin-exposed HT-22 cells. Efficient amelioration of erastin-induced ferroptosis was achieved via the knockdown of SRXN1, which resulted in the reduction of intracellular Fe2+ levels and reactive oxygen species (ROS) in HT-22 cells. Notably, the activation of Heme Oxygenase-1 (HO-1) was found to be crucial for inducing SRXN1 expression in HT-22 cells upon treatment with erastin. SRXN1 increased intracellular ROS and Fe2+ levels by activating HO-1 expression, which promoted erastin-induced ferroptosis in HT-22 cells. Inhibiting SRXN1 or HO-1 alleviated erastin-induced autophagy in HT-22 cells. Additionally, upregulation of SRXN1 or HO-1 increased the susceptibility of HT-22 cells to ferroptosis, a process that was counteracted by the autophagy inhibitor 3-Methyladenine (3-MA). These results indicate that SRXN1 is a key regulator of ferroptosis, activating the HO-1 protein through cellular redox regulation, ferrous iron accumulation, and autophagy in HT-22 cells. These findings elucidate a novel molecular mechanism of erastin-induced ferroptosis sensitivity and suggest that SRXN1-HO-1-autophagy-dependent ferroptosis serves as a promising treatment approach for neurodegenerative diseases.

Asunto(s)

Ferroptosis , Hemo-Oxigenasa 1 , Hipocampo , Neuronas , Oxidorreductasas actuantes sobre Donantes de Grupos Sulfuro , Piperazinas , Especies Reactivas de Oxígeno , Ferroptosis/efectos de los fármacos , Ferroptosis/genética , Animales , Ratones , Neuronas/metabolismo , Neuronas/efectos de los fármacos , Neuronas/patología , Especies Reactivas de Oxígeno/metabolismo , Piperazinas/farmacología , Hipocampo/metabolismo , Hipocampo/patología , Hipocampo/efectos de los fármacos , Oxidorreductasas actuantes sobre Donantes de Grupos Sulfuro/genética , Oxidorreductasas actuantes sobre Donantes de Grupos Sulfuro/metabolismo , Hemo-Oxigenasa 1/metabolismo , Hemo-Oxigenasa 1/genética , Línea Celular , Hierro/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Proteínas de la Membrana

RESUMEN

BACKGROUND: Doxorubicin (DOX) is limited in clinical use due to its cardiotoxic side effects. Oxidative stress and inflammation are pivotal mechanisms underlying doxorubicin-induced cardiotoxicity (DIC). Sulfiredoxin 1 (Srxn1) plays a central role in antioxidant effects. However, the role of Srxn1 in DIC has not yet been fully elucidated. This study aims to explore the effects and underlying mechanisms of Srxn1 on DIC. METHODS: We overexpressed Srxn1 in the myocardium using an adeno-associated virus 9 (AAV9) system, delivered through tail vein injection. C57BL/6 mice received intraperitoneal injections of DOX (4 mg/kg) weekly for four consecutive weeks to establish a mouse model of DIC. We used echocardiography, histopathological, and molecular techniques to elucidate the effects and mechanisms. RESULTS: Our findings demonstrate that overexpression of Srxn1 significantly enhanced cardiac function and mitigated myocardial injury in mice exposed to DOX. Overexpressing Srxn1 attenuated oxidative stress and inflammation induced by DOX. Furthermore, Srxn1 overexpression led to upregulation of sirtuin 1 (Sirt1) expression and inhibited the activation of the NOD-like receptor protein 3 (NLRP3) inflammasome. Notably, the protective effects of Srxn1 were significantly abrogated by the Sirt1 inhibitor EX527. CONCLUSION: The protective effects of Srxn1 against DOX-induced cardiac oxidative stress and inflammation operate by targeting the Sirt1/NLRP3 signaling pathway to alleviate DIC. Srxn1 could be a potential candidate for the treatment of DOX-induced myocardial injury.

Asunto(s)

Cardiotoxicidad , Doxorrubicina , Ratones Endogámicos C57BL , Proteína con Dominio Pirina 3 de la Familia NLR , Estrés Oxidativo , Oxidorreductasas actuantes sobre Donantes de Grupos Sulfuro , Transducción de Señal , Sirtuina 1 , Animales , Sirtuina 1/metabolismo , Sirtuina 1/genética , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Estrés Oxidativo/efectos de los fármacos , Oxidorreductasas actuantes sobre Donantes de Grupos Sulfuro/genética , Oxidorreductasas actuantes sobre Donantes de Grupos Sulfuro/metabolismo , Transducción de Señal/efectos de los fármacos , Ratones , Masculino , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Humanos , Miocardio/patología , Miocardio/metabolismo , Modelos Animales de Enfermedad , Antibióticos Antineoplásicos/toxicidad

RESUMEN

Advanced hepatocellular carcinoma (HCC) patients have poor prognosis. As an endogenous antioxidant enzyme involved in a variety of bioprocesses, sulfiredoxin-1 (SRXN1) plays an irreplaceable role in promoting the development of tumors. However, the role and working mechanism of SRXN1 in HCC remain unclear. In this study, we confirmed that SRXN1 promoted the cell proliferation of HCC at genetic and pharmacological level, respectively. Transcriptome sequencing analysis revealed SRXN1 knockdown had a significant effect on the expression of lysosome biogenesis related genes. Further experiments validated that lysosome biogenesis and autophagic flux were enhanced after SRXN1 inhibition and reduced as SRXN1 overexpression. Mechanism study revealed that ROS accumulation induced TFEB nuclear translocation, followed by increased autophagy. Following this rationale, the combination of SRXN1 inhibitor and sorafenib demonstrated noticeable synergistic antitumor effect through the boost of ROS both in vivo and in vitro. Taken together, SRXN1 could be a potential therapeutic target for HCC therapy.

Asunto(s)

Autofagia , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice , Carcinoma Hepatocelular , Proliferación Celular , Neoplasias Hepáticas , Lisosomas , Oxidorreductasas actuantes sobre Donantes de Grupos Sulfuro , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/tratamiento farmacológico , Humanos , Oxidorreductasas actuantes sobre Donantes de Grupos Sulfuro/genética , Oxidorreductasas actuantes sobre Donantes de Grupos Sulfuro/metabolismo , Autofagia/efectos de los fármacos , Autofagia/genética , Proliferación Celular/efectos de los fármacos , Lisosomas/metabolismo , Lisosomas/efectos de los fármacos , Animales , Ratones , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/metabolismo , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/genética , Ratones Desnudos , Especies Reactivas de Oxígeno/metabolismo , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Ratones Endogámicos BALB C , Masculino , Sorafenib/farmacología

RESUMEN

Biallelic variants in SUMF1 are associated with multiple sulfatase deficiency (MSD), a rare lysosomal storage disorder typically diagnosed in early infancy or childhood, marked by severe neurodegeneration and early mortality. We present clinical and molecular characterisation of three unrelated patients aged 13 to 58 years with milder clinical manifestations due to SUMF1 disease variants, including two adult patients presenting with apparent non-syndromic retinal dystrophy. Whole genome sequencing identified biallelic SUMF1 variants in all three patients; Patient 1 homozygous for a complex allele c.[290G>T;293T>A]; p.[(Gly97Val);(Val98Glu)], Patient 2 homozygous for c.866A>G; p.(Tyr289Cys), and Patient 3 compound heterozygous for c.726-1G>C and p.(Tyr289Cys). Electroretinography indicated a rod-cone dystrophy with additional possible inner retinal dysfunction in all three patients. Biochemical studies confirmed reduced, but not absent, sulfatase enzyme activity in the absence of extra-ocular disease (Patient 1) or only mild systemic disease (Patients 2, 3). These cases are suggestive that non-null SUMF1 genotypes can cause an attenuated clinical phenotype, including retinal dystrophy without systemic complications, in adulthood.

Asunto(s)

Alelos , Distrofias Retinianas , Sulfatasas , Humanos , Masculino , Femenino , Adulto , Adolescente , Distrofias Retinianas/genética , Distrofias Retinianas/patología , Persona de Mediana Edad , Sulfatasas/genética , Sulfatasas/deficiencia , Leucocitos/patología , Leucocitos/metabolismo , Oxidorreductasas actuantes sobre Donantes de Grupos Sulfuro/genética , Enfermedad por Deficiencia de Múltiples Sulfatasas/genética , Enfermedad por Deficiencia de Múltiples Sulfatasas/patología , Mutación , Fenotipo , Adulto Joven , Secuenciación Completa del Genoma , Genotipo

RESUMEN

BACKGROUND: IFI30 is a lysosomal thiol reductase involved in antigen presentation and immune regulation in various cancers, including breast cancer. Despite its known involvement, the precise mechanism, function, and relationship with the PD-L1 axis and immune response remain unclear. METHODS: We conducted an extensive investigation into IFI30 mRNA expression in breast cancer utilizing data from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases. Furthermore, we characterized IFI30 mRNA expression across various cell types using publicly available single-cell RNA sequencing datasets, and assessed protein expression through immunohistochemistry using an in-house breast cancer tissue microarray. Functional experiments were performed to elucidate the effects of IFI30 overexpression on PD-L1 expression and inhibitory efficacy in both macrophages and breast tumor cells. RESULTS: Our study unveiled a marked upregulation of IFI30 expression in breast cancer tissues compared to their normal counterparts, with notable associations identified with tumor stage and prognosis. Additionally, IFI30 expression demonstrated significant correlations with various immune-related signaling pathways, encompassing peptide antigen binding, cytokine binding, and MHC class II presentation. Notably, breast cancer samples exhibiting high IFI30 expression in tumor cells displayed high PD-L1 expression on corresponding cells, alongside a diminished ratio of CD8 + T cell infiltration within the tumor microenvironment. Furthermore, ectopic knockdown of IFI30 in both tumor cells and macrophages resulted in a reduction of PD-L1 expression, while conversely, overexpression of IFI30 led to an increase in PD-L1 expression. CONCLUSIONS: This study offers new insights into the involvement of IFI30 in breast cancer, elucidating its interplay with the PD-L1 axis and immune response dynamics. Our findings suggest that modulation of the IFI30-PD-L1 axis could serve as a promising strategy for regulating T cells infiltration in breast cancer thus treating breast cancer.

Asunto(s)

Antígeno B7-H1 , Neoplasias de la Mama , Inmunoterapia , Oxidorreductasas actuantes sobre Donantes de Grupos Sulfuro , Femenino , Humanos , Antígeno B7-H1/metabolismo , Antígeno B7-H1/genética , Neoplasias de la Mama/inmunología , Linfocitos T CD8-positivos/inmunología , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Macrófagos/inmunología , Macrófagos/metabolismo , Oxidorreductasas actuantes sobre Donantes de Grupos Sulfuro/genética , Oxidorreductasas actuantes sobre Donantes de Grupos Sulfuro/metabolismo , Pronóstico

RESUMEN

Pathological opening of the mitochondrial permeability transition pore (mPTP) is implicated in the pathogenesis of many disease processes such as myocardial ischemia, traumatic brain injury, Alzheimer's disease, and diabetes. While we have gained insight into mPTP biology over the last several decades, the lack of translation of this knowledge into successful clinical therapies underscores the need for continued investigation and use of different approaches to identify novel regulators of the mPTP with the hope of elucidating new therapeutic targets. Although the mPTP is known to be a voltage-gated channel, the identity of its voltage sensor remains unknown. Here we found decreased gating potential of the mPTP and increased expression and activity of sulfide quinone oxidoreductase (SQOR) in newborn Fragile X syndrome (FXS) mouse heart mitochondria, a model system of coenzyme Q excess and relatively decreased mPTP open probability. We further found that pharmacological inhibition and genetic silencing of SQOR increased mPTP open probability in vitro in adult murine cardiac mitochondria and in the isolated-perfused heart, likely by interfering with voltage sensing. Thus, SQOR is proposed to contribute to voltage sensing by the mPTP and may be a component of the voltage sensing apparatus that modulates the gating potential of the mPTP.

Asunto(s)

Mitocondrias Cardíacas , Poro de Transición de la Permeabilidad Mitocondrial , Oxidorreductasas actuantes sobre Donantes de Grupos Sulfuro , Animales , Ratones , Enfermedad de Alzheimer , Lesiones Traumáticas del Encéfalo , Sulfuros , Oxidorreductasas actuantes sobre Donantes de Grupos Sulfuro/genética

RESUMEN

Growing evidence suggests that dimethylarginine dimethylaminohydrolase 1 (DDAH1), a crucial enzyme for the degradation of asymmetric dimethylarginine (ADMA), is closely related to oxidative stress during the development of multiple diseases. However, the underlying mechanism by which DDAH1 regulates the intracellular redox state remains unclear. In the present study, DDAH1 was shown to interact with peroxiredoxin 1 (PRDX1) and sulfiredoxin 1 (SRXN1), and these interactions could be enhanced by oxidative stress. In HepG2 cells, H2O2-induced downregulation of DDAH1 and accumulation of ADMA were attenuated by overexpression of PRDX1 or SRXN1 but exacerbated by knockdown of PRDX1 or SRXN1. On the other hand, DDAH1 also maintained the expression of PRDX1 and SRXN1 in H2O2-treated cells. Furthermore, global knockout of Ddah1 (Ddah1-/-) or liver-specific knockout of Ddah1 (Ddah1HKO) exacerbated, while overexpression of DDAH1 alleviated liver dysfunction, hepatic oxidative stress and downregulation of PRDX1 and SRXN1 in CCl4-treated mice. Overexpression of liver PRDX1 improved liver function, attenuated hepatic oxidative stress and DDAH1 downregulation, and diminished the differences between wild type and Ddah1-/- mice after CCl4 treatment. Collectively, our results suggest that the regulatory effect of DDAH1 on cellular redox homeostasis under stress conditions is due, at least in part, to the interaction with PRDX1 and SRXN1.

Asunto(s)

Amidohidrolasas , Oxidación-Reducción , Oxidorreductasas actuantes sobre Donantes de Grupos Sulfuro , Peroxirredoxinas , Animales , Ratones , Homeostasis , Peróxido de Hidrógeno , Estrés Oxidativo , Oxidorreductasas actuantes sobre Donantes de Grupos Sulfuro/genética , Oxidorreductasas actuantes sobre Donantes de Grupos Sulfuro/metabolismo , Peroxirredoxinas/genética , Peroxirredoxinas/metabolismo , Amidohidrolasas/metabolismo

RESUMEN

Glioma remains one of the most challenging primary brain malignancies to treat. Long noncoding RNAs (lncRNAs) and mRNAs (mRNAs) are implicated in regulating the malignant phenotypes of cancers including glioma. This study aimed to elucidate the functions and mechanisms of lncRNA LINC00265 and mRNA IFI30 in the pathogenesis of glioma. Quantitative real-time polymerase chain reaction (RT-qPCR) analysis revealed the upregulated expression of LINC00265 and IFI30 in glioma cells compared to normal human astrocytes. Western blot (WB) quantified the associated proteins. Glioma stemness and epithelial-to-mesenchymal transition (EMT) were assessed by aldehyde dehydrogenase 1 (ALDH1) activity, sphere formation, and WB. Mechanistic and rescue assays evaluated the LINC00265/miR-let-7d-5p/IFI30/ZNF384/IGF2BP2 axis. The results demonstrated that LINC00265 and IFI30 were highly expressed in glioma cells, promoting stemness and EMT. ZNF384 was identified as a transcription factor that upregulates IFI30. Moreover, LINC00265 elevated ZNF384 by sponging miR-let-7d-5p and recruiting IGF2BP2. In conclusion, LINC00265 and IFI30 act as oncogenes in glioma by driving stemness and EMT, underscoring their potential as therapeutic targets.

Asunto(s)

Neoplasias Encefálicas , Glioma , MicroARNs , Humanos , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Glioma/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Oxidorreductasas actuantes sobre Donantes de Grupos Sulfuro/genética , Oxidorreductasas actuantes sobre Donantes de Grupos Sulfuro/metabolismo , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Transactivadores/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , ARN no Traducido/genética

RESUMEN

Microbial dissimilatory sulfur metabolism utilizing dissimilatory sulfite reductases (Dsr) influenced the biochemical sulfur cycle during Earth's history and the Dsr pathway is thought to be an ancient metabolic process. Here we performed comparative genomics, phylogenetic, and synteny analyses of several Dsr proteins involved in or associated with the Dsr pathway across over 195,000 prokaryotic metagenomes. The results point to an archaeal origin of the minimal DsrABCMK(N) protein set, having as primordial function sulfite reduction. The acquisition of additional Dsr proteins (DsrJOPT) increased the Dsr pathway complexity. Archaeoglobus would originally possess the archaeal-type Dsr pathway and the archaeal DsrAB proteins were replaced with the bacterial reductive-type version, possibly at the same time as the acquisition of the QmoABC and DsrD proteins. Further inventions of two Qmo complex types, which are more spread than previously thought, allowed microorganisms to use sulfate as electron acceptor. The ability to use the Dsr pathway for sulfur oxidation evolved at least twice, with Chlorobi and Proteobacteria being extant descendants of these two independent adaptations.

Asunto(s)

Hidrogenosulfito Reductasa , Proteínas , Filogenia , Oxidación-Reducción , Hidrogenosulfito Reductasa/genética , Hidrogenosulfito Reductasa/metabolismo , Proteínas/metabolismo , Sulfatos/metabolismo , Sulfitos , Azufre/metabolismo , Oxidorreductasas actuantes sobre Donantes de Grupos Sulfuro/genética

RESUMEN

BACKGROUND: Evidence shows that genetic factors play important roles in the severity of coronavirus disease 2019 (COVID-19). Sulfatase modifying factor 1 (SUMF1) gene is involved in alveolar damage and systemic inflammatory response. Therefore, we speculate that it may play a key role in COVID-19. RESULTS: We found that rs794185 was significantly associated with COVID-19 severity in Chinese population, under the additive model after adjusting for gender and age (for C allele = 0.62, 95% CI = 0.44-0.88, P = 0.0073, logistic regression). And this association was consistent with this in European population Genetics Of Mortality In Critical Care (GenOMICC: OR for C allele = 0.94, 95% CI = 0.90-0.98, P = 0.0037). Additionally, we also revealed a remarkable association between rs794185 and the prothrombin activity (PTA) in subjects (P = 0.015, Generalized Linear Model). CONCLUSIONS: In conclusion, our study for the first time identified that rs794185 in SUMF1 gene was associated with the severity of COVID-19.

Asunto(s)

COVID-19 , Sulfatasas , Humanos , Sulfatasas/genética , COVID-19/genética , Polimorfismo Genético , Oxidorreductasas actuantes sobre Donantes de Grupos Sulfuro/genética

RESUMEN

Circular RNAs (circRNAs) play a pivotal role in the tumorigenesis and progression of various cancers. However, the role and mechanisms of circABCA13 in esophageal squamous cell carcinoma (ESCC) are largely unknown. Here, we reported that circABCA13, a novel circular RNA generated by back-splicing of the intron of the ABCA13 gene, is highly expressed in ESCC tumor tissues and cell lines. Upregulation of circABCA13 correlated with TNM stage and a poor prognosis in ESCC patients. While knockdown of circABCA13 in ESCC cells significantly reduced cell proliferation, migration, invasion, and anchorage-independent growth, overexpression of circABCA13 facilitated tumor growth both in vitro and in vivo. In addition, circABCA13 directly binds to miR-4429 and sequesters miR-4429 from its endogenous target, SRXN1 mRNA, which subsequently upregulates SRXN1 and promotes ESCC progression. Consistently, overexpression of miR-4429 or knockdown of SRXN1 abolished malignant behavior promotion of ESCC results from circABCA13 overexpression in vitro and in vivo. Collectively, our study uncovered the oncogenic role of circABCA13 and its mechanism in ESCC, suggesting that circABCA13 could be a potential therapeutic target and a predictive biomarker for ESCC patients.

Asunto(s)

Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , MicroARNs , Humanos , Carcinoma de Células Escamosas de Esófago/patología , Neoplasias Esofágicas/patología , MicroARNs/genética , MicroARNs/metabolismo , Regulación hacia Arriba/genética , Biomarcadores , Proliferación Celular/genética , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica/genética , Movimiento Celular/genética , Oxidorreductasas actuantes sobre Donantes de Grupos Sulfuro/genética , Oxidorreductasas actuantes sobre Donantes de Grupos Sulfuro/metabolismo

RESUMEN

BACKGROUND: Multiple sulfatase deficiency (MSD) is a rare lysosomal storage disorder caused due to pathogenic variants in the SUMF1 gene. The SUMF1 gene encodes for formylglycine generating enzyme (FGE) that is involved in the catalytic activation of the family of sulfatases. The affected patients present with a wide spectrum of clinical features including multi-organ involvement. To date, almost 140 cases of MSD have been reported worldwide, with only four cases reported from India. The present study describes two cases of late infantile form of MSD from India and the identification of a novel missense variant in the SUMF1 gene. CASE PRESENTATION: In case 1, a male child presented to us at the age of 6 years. The remarkable presenting features included ichthyosis, presence of irritability, poor social response, thinning of corpus callosum on MRI and, speech regression. Clinical suspicion of MSD was confirmed by enzyme analysis of two sulfatase enzymes followed by gene sequencing. We identified a novel missense variant c.860A > T (p.Asn287Ile) in exon 7 of the SUMF1 gene. In case 2, a two and a half years male child presented with ichthyosis, leukodystrophy and facial dysmorphism. We performed an enzyme assay for two sulfatases, which showed significantly reduced activities thereby confirming MSD diagnosis. CONCLUSION: Overall, present study has added to the existing data on MSD from India. Based on the computational analysis, the novel variant c.860A > T identified in this study is likely to be associated with a milder phenotype and prolonged survival.

Asunto(s)

Ictiosis , Enfermedad por Deficiencia de Múltiples Sulfatasas , Masculino , Humanos , Enfermedad por Deficiencia de Múltiples Sulfatasas/diagnóstico , Enfermedad por Deficiencia de Múltiples Sulfatasas/genética , Oxidorreductasas actuantes sobre Donantes de Grupos Sulfuro/genética , Mutación Missense , Sulfatasas/genética

RESUMEN

OBJECTIVE: To explore the clinical features and genetic basis for a child with early-onset Isolated sulfite oxidase deficiency (ISOD). METHODS: A child with ISOD who was admitted to Weihai Hospital Affiliated to Qingdao University on May 10, 2020 was selected as the study subject. Clinical data of the child was analyzed. The child and her parents were subjected to trio-whole exome sequencing, and candidate variants were verified by Sanger sequencing. RESULTS: The female neonate was transferred to the intensive care unit due to "secondary pollution of amniotic fluid and laborious breathing for 11 minutes", and had developed frequent convulsions. Genetic testing revealed that she has harbored c.1200C>G and c.188G>A compound heterozygous variants of the SUOX gene, which were inherited from her mother and father, respectively. The c.1200C>G has been described previously and was rated as pathogenic based on guidelines from the American College of Medical Genetics and Genomics, whilst the c.188G>A variant was unreported previously and rated as variant of unknown significance. CONCLUSION: The compound heterozygous variants of the SUOX gene probably underlay the ISOD in this child. Above finding has enriched the spectrum of SUOX gene variants and provided a basis for the clinical diagnosis and genetic counseling.

Asunto(s)

Errores Innatos del Metabolismo de los Aminoácidos , Sulfito-Oxidasa , Femenino , Humanos , Recién Nacido , Errores Innatos del Metabolismo de los Aminoácidos/genética , Errores Innatos del Metabolismo de los Aminoácidos/diagnóstico , Asesoramiento Genético , Pruebas Genéticas , Mutación , Oxidorreductasas actuantes sobre Donantes de Grupos Sulfuro/genética , Sulfito-Oxidasa/genética

RESUMEN

Multiple sulfatase deficiency (MSD) is an ultrarare lysosomal storage disorder due to deficiency of all known sulfatases. MSD is caused by mutations in the Sulfatase Modifying Factor 1 (SUMF1) gene encoding the enzyme responsible for the post-translational modification and activation of all sulfatases. Most MSD patients carry hypomorph SUMF1 variants resulting in variable degrees of residual sulfatase activities. In contrast, Sumf1 null mice with complete deficiency in all sulfatase enzyme activities, have very short lifespan with significant pre-wean lethality, owing to a challenging preclinical model. To overcome this limitation, we genetically engineered and characterized in mice two commonly identified patient-based SUMF1 pathogenic variants, namely p.Ser153Pro and p.Ala277Val. These pathogenic missense variants correspond to variants detected in patients with attenuated MSD presenting with partial-enzyme deficiency and relatively less severe disease. These novel MSD mouse models have a longer lifespan and show biochemical and pathological abnormalities observed in humans. In conclusion, mice harboring the p.Ser153Pro or the p.Ala277Val variant mimic the attenuated MSD and are attractive preclinical models for investigation of pathogenesis and treatments for MSD.

Asunto(s)

Enfermedades por Almacenamiento Lisosomal , Enfermedad por Deficiencia de Múltiples Sulfatasas , Humanos , Animales , Ratones , Enfermedad por Deficiencia de Múltiples Sulfatasas/genética , Mutación , Sulfatasas , Mutación Missense , Oxidorreductasas actuantes sobre Donantes de Grupos Sulfuro/genética

RESUMEN

OBJECTIVE@#To explore the clinical features and genetic basis for a child with early-onset Isolated sulfite oxidase deficiency (ISOD).@*METHODS@#A child with ISOD who was admitted to Weihai Hospital Affiliated to Qingdao University on May 10, 2020 was selected as the study subject. Clinical data of the child was analyzed. The child and her parents were subjected to trio-whole exome sequencing, and candidate variants were verified by Sanger sequencing.@*RESULTS@#The female neonate was transferred to the intensive care unit due to "secondary pollution of amniotic fluid and laborious breathing for 11 minutes", and had developed frequent convulsions. Genetic testing revealed that she has harbored c.1200C>G and c.188G>A compound heterozygous variants of the SUOX gene, which were inherited from her mother and father, respectively. The c.1200C>G has been described previously and was rated as pathogenic based on guidelines from the American College of Medical Genetics and Genomics, whilst the c.188G>A variant was unreported previously and rated as variant of unknown significance.@*CONCLUSION@#The compound heterozygous variants of the SUOX gene probably underlay the ISOD in this child. Above finding has enriched the spectrum of SUOX gene variants and provided a basis for the clinical diagnosis and genetic counseling.

Asunto(s)

Femenino , Humanos , Recién Nacido , Errores Innatos del Metabolismo de los Aminoácidos/diagnóstico , Asesoramiento Genético , Pruebas Genéticas , Mutación , Oxidorreductasas actuantes sobre Donantes de Grupos Sulfuro/genética , Sulfito-Oxidasa/genética

RESUMEN

BACKGROUND: Multiple sulfatase deficiency (MSD) (MIM#272200) is an ultra-rare autosomal recessive lysosomal storage disorder caused by mutation of the Sulfatase Modifying Factor 1 (SUMF1) gene. METHODS: Herein, we report an eight-year-old boy with a late infantile form of multiple sulfatase deficiency. A combination of copy-number variation sequencing (CNV-seq) and whole-exome sequencing (WES) were used to analyze the genetic cause for the MSD patient. RESULTS: Our results, previously not seen in China, show a novel compound heterozygous mutation with one allele containing a 240.55 kb microdeletion on 3p26.1 encompassing the SETMAR gene and exons 4-9 of the SUMF1 gene, and the other allele containing a novel missense mutation of c.671G>A (p.Arg224Gln) in the SUMF1 gene. Both were inherited from the proband's unaffected parents, one from each. Bioinformatics analyses show the novel variation to be "likely pathogenic." SWISS-MODEL analysis shows that the missense mutation may alter the three-dimensional (3D) structure. CONCLUSIONS: In summary, this study reported a novel compound heterozygous with microdeletion in SUMF1 gene, which has not been reported in China. The complex clinical manifestations of MSD may delay diagnosis; however, molecular genetic analysis of the SUMF1 gene can be performed to help obtain an early diagnosis.

Asunto(s)

Enfermedad por Deficiencia de Múltiples Sulfatasas , Masculino , Humanos , Niño , Enfermedad por Deficiencia de Múltiples Sulfatasas/genética , Enfermedad por Deficiencia de Múltiples Sulfatasas/diagnóstico , Sulfatasas/genética , Mutación/genética , Mutación Missense , Biología Computacional , N-Metiltransferasa de Histona-Lisina/genética , Oxidorreductasas actuantes sobre Donantes de Grupos Sulfuro/genética

RESUMEN

BACKGROUND: Colorectal cancer (CRC) is the 3rd most common cancer worldwide. CircRNAs are promising novel biomarkers for CRC. T regulatory (Treg) cells express the immune checkpoint receptor of cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and promote tumor immunological tolerance. We therefore investigate the biological functions and mechanisms of circQSOX1 in CRC tumorigenesis; involvement of circQSOX1 in promoting Treg cell-mediated CRC immune escape in anti-CTLA-4 therapy. METHODS: Bioinformatics analyses were performed for circQSOX1expressions, specific binding sites, and N6-methyladenosine (m6A) motifs of circQSOX1, thatwere further validated with a series of experiments. Functions of circQSOX1 in promoting CRC development, Treg cells-based immune escape, and anti-CTLA-4 therapy response were investigated both in vitro and in vivo. RESULTS: High circQSOX1 expression was associated with carcinogenesis and poor clinical outcome of CRC patients. METTL3-mediated RNA m6A modification on circQSOX1 could be read by IGF2BP2 in CRC cells. CircQSOX1 promoted CRC development by regulating miR-326/miR-330-5p/PGAM1 axis. CircQSOX1 regulated glycolysis and promoted immune escape of CRC cells, and inhibits anti-CTLA-4 therapy response in CRC patients. CONCLUSION: m6A-modified circQSOX1 facilitated CRC tumorigenesis by sponging miR-326 and miR-330-5p to promotes PGAM1 expression, which further promoted CRC immune escape by activating glycolysis and inactivating the anti-CTLA-4 therapy response of CRC. Combined treatment with sh-circQSOX1 and anti-CTLA-4 could be a strategy to overcome Treg cell-mediated CRC immune therapy resistance.

Asunto(s)

Neoplasias Colorrectales , MicroARNs , Humanos , ARN Circular/genética , Linfocitos T Reguladores/metabolismo , Linfocitos T Reguladores/patología , Regulación Neoplásica de la Expresión Génica , MicroARNs/genética , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Línea Celular Tumoral , Carcinogénesis/genética , Adenosina , Proliferación Celular , Metiltransferasas/genética , Metiltransferasas/metabolismo , Oxidorreductasas actuantes sobre Donantes de Grupos Sulfuro/genética , Oxidorreductasas actuantes sobre Donantes de Grupos Sulfuro/metabolismo

RESUMEN

Oat is a food and forage crop species widely cultivated worldwide, and it is also an important forage grass in plateau regions of China, where there is a high level of ultraviolet radiation and sunlight. Screening suitable reference genes for oat under UV-B and high-light stresses is a prerequisite for ensuring the accuracy of real-time quantitative PCR (qRT-PCR) data used in plant adaptation research. In this study, eight candidate reference genes (sulfite oxidase, SUOX; victorin binding protein, VBP; actin-encoding, Actin1; protein PSK SIMULATOR 1-like, PSKS1; TATA-binding protein 2-like, TBP2; ubiquitin-conjugating enzyme E2, UBC2; elongation factor 1-alpha, EF1-α; glyceraldehyde-3-phosphate dehydrogenase 1, GAPDH1;) were selected based on previous studies and our oat transcriptome data. The expression stability of these reference genes in oat roots, stems, and leaves under UV-B and high-light stresses was first calculated using three frequently used statistical software (geNorm, NormFinder, and BestKeeper), and then the comprehensive stability of these genes was evaluated using RefFinder. The results showed that the most stably expressed reference genes in the roots, stems, and leaves of oat under UV-B stress were EF1-α, TBP2, and PSKS1, respectively; the most stably expressed reference genes in the roots, stems, and leaves under high-light stress were PSKS1, UBC2, and PSKS1, respectively. PSKS1 was the most stably expressed reference gene in all the samples. The reliability of the selected reference genes was further validated by analysis of the expression of the phenylalanine ammonia-lyase (PAL) gene. This study highlights reference genes for accurate quantitative analysis of gene expression in different tissues of oat under UV-B and high-light stresses.

Asunto(s)

Avena , Factor 1 de Elongación Peptídica , Actinas/genética , Avena/genética , Perfilación de la Expresión Génica , Regulación de la Expresión Génica de las Plantas , Gliceraldehído-3-Fosfato Deshidrogenasas/genética , Oxidorreductasas actuantes sobre Donantes de Grupos Sulfuro/genética , Factor 1 de Elongación Peptídica/genética , Fenilanina Amoníaco-Liasa/genética , Reacción en Cadena en Tiempo Real de la Polimerasa/métodos , Estándares de Referencia , Reproducibilidad de los Resultados , Proteína de Unión a TATA-Box/genética , Enzimas Ubiquitina-Conjugadoras/genética , Rayos Ultravioleta

RESUMEN

BACKGROUND: Isolated sulfite oxidase deficiency (ISOD) caused by sulfite oxidase gene (SUOX) mutations is a rare neurometabolic disease associated with ectopia lentis (EL). However, few genotype-phenotype correlations have been established yet. METHODS: Potentially pathogenic SUOX mutations were screened from a Chinese cohort of congenital EL using panel-based next-generation sequencing and analyzed with multiple bioinformatics tools. The genotype-phenotype correlations were evaluated via a systematic review of SUOX mutations within our data and from the literature. RESULTS: A novel paternal missense mutation, c.205G > C (p.A69P), and a recurrent maternal nonsense mutation, c.1200 C > G (p.Y400*), of SUOX were identified in a 4-year-old boy from 312 probands. The biochemical assays manifested elevated urine sulfite and S-sulfocysteine accompanied by decreased homocysteine in the blood. The patient had bilateral EL and normal fundus, yet minimal neurological involvement and normal brain structure. Molecular modeling simulation revealed the p.A69P mutant had an unstable structure but an unchanged affinity for sulfite, while the truncated p.Y400* mutant showed decreased binding capacity. Genotype-phenotype analysis demonstrated patients with biallelic missense mutations had milder symptoms (P = 0.023), later age of onset (P < 0.001), and a higher incidence of regression (P = 0.017) than other genotypes. No correlations were found regarding EL and other neurological symptoms. CONCLUSION: The data from this study not only enrich the known mutation spectrum of SUOX but also suggest that missense mutations are associated with mild and atypical symptoms.

Asunto(s)

Desplazamiento del Cristalino , Humanos , Mutación/genética , Estudios de Asociación Genética , Sulfitos , Oxidorreductasas actuantes sobre Donantes de Grupos Sulfuro/genética

RESUMEN

Mitochondrial dysfunction is a key contributor to necroptosis. We have investigated the contribution of p53, sulfiredoxin, and mitochondrial peroxiredoxin 3 to necroptosis in acute pancreatitis. Late during the course of pancreatitis, p53 was localized in mitochondria of pancreatic cells undergoing necroptosis. In mice lacking p53, necroptosis was absent, and levels of PGC-1α, peroxiredoxin 3 and sulfiredoxin were upregulated. During the early stage of pancreatitis, prior to necroptosis, sulfiredoxin was upregulated and localized into mitochondria. In mice lacking sulfiredoxin with pancreatitis, peroxiredoxin 3 was hyperoxidized, p53 localized in mitochondria, and necroptosis occurred faster; which was prevented by Mito-TEMPO. In obese mice, necroptosis occurred in pancreas and adipose tissue. The lack of p53 up-regulated sulfiredoxin and abrogated necroptosis in pancreas and adipose tissue from obese mice. We describe here a positive feedback between mitochondrial H2O2 and p53 that downregulates sulfiredoxin and peroxiredoxin 3 leading to necroptosis in inflammation and obesity.

Asunto(s)

Pancreatitis , Peroxiredoxina III , Enfermedad Aguda , Animales , Regulación hacia Abajo , Peróxido de Hidrógeno/metabolismo , Ratones , Ratones Obesos , Necroptosis , Oxidorreductasas actuantes sobre Donantes de Grupos Sulfuro/genética , Oxidorreductasas actuantes sobre Donantes de Grupos Sulfuro/metabolismo , Peroxiredoxina III/genética , Peroxiredoxina III/metabolismo , Proteína p53 Supresora de Tumor/genética