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1.
J Exp Med ; 220(1)2023 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-36342455

RESUMO

Inborn and acquired deficits of type I interferon (IFN) immunity predispose to life-threatening COVID-19 pneumonia. We longitudinally profiled the B cell response to mRNA vaccination in SARS-CoV-2 naive patients with inherited TLR7, IRF7, or IFNAR1 deficiency, as well as young patients with autoantibodies neutralizing type I IFNs due to autoimmune polyendocrine syndrome type-1 (APS-1) and older individuals with age-associated autoantibodies to type I IFNs. The receptor-binding domain spike protein (RBD)-specific memory B cell response in all patients was quantitatively and qualitatively similar to healthy donors. Sustained germinal center responses led to accumulation of somatic hypermutations in immunoglobulin heavy chain genes. The amplitude and duration of, and viral neutralization by, RBD-specific IgG serological response were also largely unaffected by TLR7, IRF7, or IFNAR1 deficiencies up to 7 mo after vaccination in all patients. These results suggest that induction of type I IFN is not required for efficient generation of a humoral response against SARS-CoV-2 by mRNA vaccines.


Assuntos
Linfócitos B , Vacinas contra COVID-19 , COVID-19 , Interferon Tipo I , Humanos , Anticorpos Neutralizantes , Anticorpos Antivirais , Autoanticorpos , COVID-19/imunologia , COVID-19/prevenção & controle , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus/genética , Receptor 7 Toll-Like/genética , Vacinação , Vacinas de mRNA , Vacinas contra COVID-19/imunologia , Linfócitos B/imunologia , Interferon Tipo I/deficiência
2.
Dis Model Mech ; 16(5)2023 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-36374036

RESUMO

Nicotinamide adenine dinucleotide (NAD) is a key metabolite synthesised from vitamin B3 or tryptophan. Disruption of genes encoding NAD synthesis enzymes reduces NAD levels and causes congenital NAD deficiency disorder (CNDD), characterised by multiple congenital malformations. SLC6A19 (encoding B0AT1, a neutral amino acid transporter), represents the main transporter for free tryptophan in the intestine and kidney. Here, we tested whether Slc6a19 heterozygosity in mice limits the tryptophan available for NAD synthesis during pregnancy and causes adverse pregnancy outcomes. Pregnant Slc6a19+/- mice were fed diets depleted of vitamin B3, so that tryptophan was the source of NAD during gestation. This perturbed the NAD metabolome in pregnant Slc6a19+/- females, resulting in reduced NAD levels and increased rates of embryo loss. Surviving embryos were small and exhibited specific combinations of CNDD-associated malformations. Our results show that genes not directly involved in NAD synthesis can affect NAD metabolism and cause CNDD. They also suggest that human female carriers of a SLC6A19 loss-of-function allele might be susceptible to adverse pregnancy outcomes unless sufficient NAD precursor amounts are available during gestation. This article has an associated First Person interview with the first author of the paper.


Assuntos
Sistemas de Transporte de Aminoácidos Neutros , Anormalidades Congênitas , NAD , Animais , Feminino , Camundongos , Gravidez , Sistemas de Transporte de Aminoácidos Neutros/genética , Sistemas de Transporte de Aminoácidos Neutros/metabolismo , Heterozigoto , Rim/metabolismo , NAD/deficiência , Niacinamida , Triptofano/genética , Triptofano/metabolismo , Anormalidades Congênitas/genética
3.
Nature ; 611(7937): 818-826, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36385524

RESUMO

Immune-related adverse events, particularly severe toxicities such as myocarditis, are major challenges to the utility of immune checkpoint inhibitors (ICIs) in anticancer therapy1. The pathogenesis of ICI-associated myocarditis (ICI-MC) is poorly understood. Pdcd1-/-Ctla4+/- mice recapitulate clinicopathological features of ICI-MC, including myocardial T cell infiltration2. Here, using single-cell RNA and T cell receptor (TCR) sequencing of cardiac immune infiltrates from Pdcd1-/-Ctla4+/- mice, we identify clonal effector CD8+ T cells as the dominant cell population. Treatment with anti-CD8-depleting, but not anti-CD4-depleting, antibodies improved the survival of Pdcd1-/-Ctla4+/- mice. Adoptive transfer of immune cells from mice with myocarditis induced fatal myocarditis in recipients, which required CD8+ T cells. The cardiac-specific protein α-myosin, which is absent from the thymus3,4, was identified as the cognate antigen source for three major histocompatibility complex class I-restricted TCRs derived from mice with fulminant myocarditis. Peripheral blood T cells from three patients with ICI-MC were expanded by α-myosin peptides. Moreover, these α-myosin-expanded T cells shared TCR clonotypes with diseased heart and skeletal muscle, which indicates that α-myosin may be a clinically important autoantigen in ICI-MC. These studies underscore the crucial role for cytotoxic CD8+ T cells, identify a candidate autoantigen in ICI-MC and yield new insights into the pathogenesis of ICI toxicity.


Assuntos
Linfócitos T CD8-Positivos , Imunoterapia , Miocardite , Miosinas Ventriculares , Animais , Camundongos , Autoantígenos/imunologia , Linfócitos T CD8-Positivos/imunologia , Antígeno CTLA-4/deficiência , Antígeno CTLA-4/genética , Imunoterapia/efeitos adversos , Miocardite/induzido quimicamente , Miocardite/etiologia , Miocardite/mortalidade , Miocardite/patologia , Miosinas Ventriculares/imunologia
4.
Physiol Rep ; 10(22): e15509, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36426716

RESUMO

Methamphetamine is a commonly abused illicit stimulant that has prevalent use among women of child-bearing age. While there are extensive studies on the neurological effects of prenatal methamphetamine exposure, relatively little is known about the effect of prenatal methamphetamine on the adult cardiovascular system. Earlier work demonstrated that prenatal methamphetamine exposure sex dependently (females only) sensitizes the adult heart to ischemic injury. These data suggest that prenatal exposure to methamphetamine may induce sex-dependent changes in cardiac gene expression that persist in adult offspring. The goal of this study was to test the hypothesis that prenatal methamphetamine exposure induces changes in cardiac gene expression that persist in the adult heart. Hearts of prenatally exposed female offspring exhibited a greater number of changes in gene expression compared to male offspring (184 changes compared with 74 in male offspring and 89 changes common between both sexes). Dimethylarginine dimethylaminohydrolase 2 and 3-hydroxybutyrate dehydrogenase 1 (genes implicated in heart failure) were shown by Western Blot to be under expressed in adult females that were prenatally exposed to methamphetamine, while males were deficient in 3-Hydroxybutyrate Dehydrogenase 1 only. These data indicate that prenatal methamphetamine exposure induces changes in gene expression that persist into adulthood. This is consistent with previous findings that prenatal methamphetamine sex dependently sensitizes the adult heart to ischemic injury and may increase the risk of developing cardiac disorders during adulthood.


Assuntos
Crianças Adultas , Cardiopatias , Hidroxibutirato Desidrogenase , Metanfetamina , Efeitos Tardios da Exposição Pré-Natal , Adulto , Criança , Feminino , Humanos , Masculino , Gravidez , Expressão Gênica , Hidroxibutirato Desidrogenase/deficiência , Metanfetamina/efeitos adversos , Miocárdio , Fatores Sexuais , Efeitos Tardios da Exposição Pré-Natal/genética , Cardiopatias/genética
5.
Science ; 378(6620): eadd9959, 2022 11 11.
Artigo em Inglês | MEDLINE | ID: mdl-36356131

RESUMO

Hellweger et al. (Reports, 27 May 2022, pp. 1001) predict that phosphorus limitation will increase concentrations of cyanobacterial toxins in lakes. However, several molecular, physiological, and ecological mechanisms assumed in their models are poorly supported or contradicted by other studies. We conclude that their take-home message that phosphorus load reduction will make Lake Erie more toxic is seriously flawed.


Assuntos
Toxinas Bacterianas , Lagos , Microcystis , Fósforo , Monitoramento Ambiental , Lagos/química , Lagos/microbiologia , Fósforo/deficiência , Microcystis/metabolismo , Toxinas Bacterianas/metabolismo , Toxinas Bacterianas/toxicidade
6.
Science ; 378(6620): eade2277, 2022 11 11.
Artigo em Inglês | MEDLINE | ID: mdl-36356147

RESUMO

Huisman et al. claim that our model is poorly supported or contradicted by other studies and the predictions are "seriously flawed." We show their criticism is based on an incomplete selection of evidence, misinterpretation of data, or does not actually refute the model. Like all ecosystem models, our model has simplifications and uncertainties, but it is better than existing approaches hat ignore biology and do not predict toxin concentration.


Assuntos
Toxinas Bacterianas , Lagos , Microcystis , Fósforo , Ecossistema , Lagos/química , Lagos/microbiologia , Fósforo/deficiência , Toxinas Bacterianas/metabolismo , Toxinas Bacterianas/toxicidade , Microcystis/metabolismo
7.
FASEB J ; 36(12): e22661, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36398584

RESUMO

The process of spermatogenesis is a complex and delicate process that is still not fully understood. In this study, we examined the role of fatty acid oxidase 3-hydroxy acyl CoA dehydrogenase (HADH) in maintaining normal spermatogenesis in mice. In male mice, ablation of the Hadh gene using CRISPR/Cas9 technology arrested spermatocyte meiosis, increased multinucleated giant germ cells and vacuoles in seminiferous tubules, and accompanied with acrosomal dysplasia. Hadh-/- male mice showed the typical features of oligoasthenoteratozoospermia (OAT), including decreased sperm concentration and motility and increased sperm abnormalities. Next, we explored the molecular events in the testes of the mutant mice. We found fatty acids accumulated in the testis of Hadh-/- mice. And also, inflammatory factors TNF-α, IL-1ß, and IL-6 were significantly increased, apoptosis-related protein Bcl-2 was decreased, and Bax and cleaved-Caspase3 were increased in Hadh-/- male mice testis. After using etanercept, a specific inhibitor of TNF-α, testis injury caused by Hadh knockout was significantly alleviated, the sperm quality and motility were improved, and germ cell apoptosis was reduced. So our study demonstrated that Hadh deletion caused an increase in fatty acids. The accumulated fatty acids further induced testicular inflammation and germ cell apoptosis through the TNF-α/Bcl-2 signaling pathway, finally resulting in OAT in the Hadh-/- mice. Inhibiting TNF-α may be used as a new treatment approach for testicular inflammation and OAT.


Assuntos
3-Hidroxiacil-CoA Desidrogenase , Astenozoospermia , Infertilidade Masculina , Oligospermia , Animais , Masculino , Camundongos , Astenozoospermia/genética , Astenozoospermia/metabolismo , Ácidos Graxos , Infertilidade Masculina/genética , Infertilidade Masculina/metabolismo , Inflamação/genética , Inflamação/metabolismo , Oligospermia/genética , Oligospermia/metabolismo , Sêmen/metabolismo , Espermatócitos/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , 3-Hidroxiacil-CoA Desidrogenase/deficiência , 3-Hidroxiacil-CoA Desidrogenase/genética , 3-Hidroxiacil-CoA Desidrogenase/metabolismo , Genes bcl-2/genética , Genes bcl-2/fisiologia
8.
Nature ; 611(7937): 780-786, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36385534

RESUMO

Enteric pathogens are exposed to a dynamic polymicrobial environment in the gastrointestinal tract1. This microbial community has been shown to be important during infection, but there are few examples illustrating how microbial interactions can influence the virulence of invading pathogens2. Here we show that expansion of a group of antibiotic-resistant, opportunistic pathogens in the gut-the enterococci-enhances the fitness and pathogenesis of Clostridioides difficile. Through a parallel process of nutrient restriction and cross-feeding, enterococci shape the metabolic environment in the gut and reprogramme C. difficile metabolism. Enterococci provide fermentable amino acids, including leucine and ornithine, which increase C. difficile fitness in the antibiotic-perturbed gut. Parallel depletion of arginine by enterococci through arginine catabolism provides a metabolic cue for C. difficile that facilitates increased virulence. We find evidence of microbial interaction between these two pathogenic organisms in multiple mouse models of infection and patients infected with C. difficile. These findings provide mechanistic insights into the role of pathogenic microbiota in the susceptibility to and the severity of C. difficile infection.


Assuntos
Clostridioides difficile , Enterococcus , Interações Microbianas , Animais , Humanos , Camundongos , Antibacterianos/farmacologia , Arginina/deficiência , Arginina/metabolismo , Clostridioides difficile/metabolismo , Clostridioides difficile/patogenicidade , Clostridioides difficile/fisiologia , Modelos Animais de Doenças , Farmacorresistência Bacteriana , Enterococcus/efeitos dos fármacos , Enterococcus/metabolismo , Enterococcus/patogenicidade , Enterococcus/fisiologia , Microbioma Gastrointestinal/efeitos dos fármacos , Intestinos/efeitos dos fármacos , Intestinos/metabolismo , Intestinos/microbiologia , Leucina/metabolismo , Ornitina/metabolismo , Virulência , Suscetibilidade a Doenças
9.
Nature ; 611(7936): 603-613, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36352230

RESUMO

Around 30-40% of patients with colorectal cancer (CRC) undergoing curative resection of the primary tumour will develop metastases in the subsequent years1. Therapies to prevent disease relapse remain an unmet medical need. Here we uncover the identity and features of the residual tumour cells responsible for CRC relapse. An analysis of single-cell transcriptomes of samples from patients with CRC revealed that the majority of genes associated with a poor prognosis are expressed by a unique tumour cell population that we named high-relapse cells (HRCs). We established a human-like mouse model of microsatellite-stable CRC that undergoes metastatic relapse after surgical resection of the primary tumour. Residual HRCs occult in mouse livers after primary CRC surgery gave rise to multiple cell types over time, including LGR5+ stem-like tumour cells2-4, and caused overt metastatic disease. Using Emp1 (encoding epithelial membrane protein 1) as a marker gene for HRCs, we tracked and selectively eliminated this cell population. Genetic ablation of EMP1high cells prevented metastatic recurrence and mice remained disease-free after surgery. We also found that HRC-rich micrometastases were infiltrated with T cells, yet became progressively immune-excluded during outgrowth. Treatment with neoadjuvant immunotherapy eliminated residual metastatic cells and prevented mice from relapsing after surgery. Together, our findings reveal the cell-state dynamics of residual disease in CRC and anticipate that therapies targeting HRCs may help to avoid metastatic relapse.


Assuntos
Neoplasias Colorretais , Metástase Neoplásica , Proteínas de Neoplasias , Recidiva Local de Neoplasia , Neoplasia Residual , Receptores de Superfície Celular , Animais , Humanos , Camundongos , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Neoplasias Colorretais/terapia , Progressão da Doença , Proteínas de Neoplasias/deficiência , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/prevenção & controle , Recidiva Local de Neoplasia/terapia , Neoplasia Residual/genética , Neoplasia Residual/patologia , Receptores de Superfície Celular/deficiência , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Metástase Neoplásica/genética , Metástase Neoplásica/patologia , Metástase Neoplásica/prevenção & controle , Metástase Neoplásica/terapia , Modelos Animais de Doenças , Linfócitos T/citologia , Linfócitos T/imunologia , Linfócitos do Interstício Tumoral/citologia , Linfócitos do Interstício Tumoral/imunologia , Terapia Neoadjuvante , Imunoterapia
10.
Front Endocrinol (Lausanne) ; 13: 1023194, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36387896

RESUMO

Dysregulation of decidual macrophages leads to the occurrence of recurrent spontaneous abortion (RSA). However, the role of macrophages in RSA occurrence remains unclear. In this study, we found that the expression of Grim-19 was decreased, and the expression of autophagy related proteins Beclin1, LC3B II/I and BNIP3 was markedly upregulated in decidual macrophages of RSA patients compared with the normal pregnancy group. Furthermore, we demonstrated that downregulation of GRIM-19 increased the expression of autophagy related proteins Beclin1, LC3B II/I, BNIP3 and the proinflammatory cytokines IL1B, IL6 and TNFa in uterine mononuclear cells of GRIM-19+/- mice. The proportion of CD45+CD11b+F4/80+LC3B+ cells in GRIM-19+/- mouse uteri was significantly higher than that in WT mouse uteri. In addition, we confirmed that inhibition of Grim-19 by siRNA enhanced the expression of autophagy related proteins in RAW264.7 cells and THP-1 cells. More importantly, downregulation of Grim-19 in RAW264.7 cells promoted the release of proinflammatory cytokines and promoted phagocytic activity, which could be reversed by autophagy blockade. For THP-1-derived macrophages, the results of RNA-seq suggested that Grim-19 mainly modulates immune and inflammatory-related pathways, leading to cytokine production, and thus contributing to inflammation. Therefore, our data reveal that Grim-19 deficiency influences macrophage function, characterized by enhanced proinflammatory cytokines and phagocytic activity, and this might be regulated by autophagy. This may represent a novel mechanism for the occurrence of RSA.


Assuntos
Aborto Espontâneo , Proteínas Reguladoras de Apoptose , Autofagia , Macrófagos , NADH NADPH Oxirredutases , Animais , Feminino , Humanos , Camundongos , Gravidez , Aborto Espontâneo/genética , Proteína Beclina-1/metabolismo , Citocinas/metabolismo , Células RAW 264.7 , NADH NADPH Oxirredutases/deficiência , NADH NADPH Oxirredutases/genética , Proteínas Reguladoras de Apoptose/deficiência , Proteínas Reguladoras de Apoptose/genética
11.
Arch. argent. pediatr ; 120(5): e207-e209, oct. 2022.
Artigo em Espanhol | LILACS, BINACIS | ID: biblio-1395677

RESUMO

El síndrome de deficiencia del transportador de glucosa cerebral de tipo 1 es una enfermedad neurometabólica rara en pediatría. Existe un fenotípico clásico (85 %) y otro no clásico (15 %). Ambos fenotipos se asocian con hipoglucorraquia. Se identifican múltiples mutaciones en el gen SLC2A1. El tratamiento es la terapia cetogénica. Se presenta un varón que comenzó a los cuatro años con hemicorea y hemidistonía medicado con anticonvulsivantes sin respuesta clínica, por lo que consultó nuevamente a los seis años. Con sospecha diagnóstica de síndrome de déficit de glut-1 atípico se realizó punción lumbar; el diagnóstico se confirmó por la presencia de hipoglucorraquia. Inmediatamente después de iniciar la dieta cetogénica, el paciente no presentó más movimientos anormales durante los siguientes 8 años hasta la actualidad, ya cumplidos los 14 años.


Glucose transporter type 1 deficiency syndrome is a rare pediatric neurometabolic disorder. There are two phenotypes: the classical phenotype (85%) and the non-classic (15%). Both phenotypes are associated with hypoglycorrhachia. Multiple mutations are described in the SCL2A1 gene. The treatment is the ketogenic diet. We report a case of a four-year-old male patient who started with hemichorea and hemidystonia and was medicated with drugs for seizures without clinical response, that's why his parents made another pediatric consultation at his six-year-old. With the suggestive clinical findings of glucose transporter type 1 deficiency syndrome the lumbar puncture was made confirming the diagnosis. Immediately after starting the ketogenic diet the patient stopped making abnormal movements up to the moment when he is fourteen years old, eight years after.


Assuntos
Humanos , Masculino , Adolescente , Erros Inatos do Metabolismo dos Carboidratos/complicações , Erros Inatos do Metabolismo dos Carboidratos/diagnóstico , Erros Inatos do Metabolismo dos Carboidratos/genética , Dieta Cetogênica , Proteínas de Transporte de Monossacarídeos/deficiência , Proteínas de Transporte de Monossacarídeos/genética , Transportador de Glucose Tipo 1
12.
Endocr J ; 69(11): 1281-1284, 2022 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-36244744

RESUMO

"What's in a name? That which we call a rose/By any other name would smell as sweet." (Juliet, from Romeo and Juliet by William Shakespeare). Shakespeare's implication is that a name is nothing but a word and it therefore represents a convention with no intrinsic meaning. Whilst this may be relevant to romantic literature, disease names do have real meanings, and consequences, in medicine. Hence, there must be a very good rational for changing the name of a disease that has a centuries-old historical context. A working group of representatives from national and international endocrinology and pediatric endocrine societies now proposes changing the name of "diabetes insipidus" to "Arginine Vasopressin Deficiency (AVP-D)" for central etiologies, and "Arginine Vasopressin Resistance (AVP-R)" for nephrogenic etiologies. This editorial provides both the historical context and the rational for this proposed name change.


Assuntos
Arginina Vasopressina , Diabetes Insípido , Humanos , Arginina Vasopressina/deficiência , Diabetes Insípido/classificação , Diabetes Mellitus , Sociedades Médicas
13.
Ital J Pediatr ; 48(1): 178, 2022 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-36221102

RESUMO

BACKGROUND: Congenital Disorders of Glycosylation (CDG) are a large group of inborn errors of metabolism with more than 140 different CDG types reported to date (1). The first characterized, PMM2-CDG, with an autosomal recessive transmission, is also the most frequent. The PMM2 gene encodes a phosphomannomutase. Here, a novel genetic variation causing PMM2-CDG is reported.  CASE PRESENTATION: We report the case of a French child, from healthy and unrelated parents, presenting congenital ataxia with hypotonia, hyperlaxity, inverted nipples, as well as altered coagulation parameters and liver function. Transferrin isoelectrofocusing revealed a typical type I CDG profile. Direct Sanger sequencing and quantitative PCR of PMM2 revealed a unique and novel genotype. On one allele, the patient was heterozygote with a known missense variant NM_000303.3(PMM2):c.323C > T, p.Ala108Val in exon 4. On the second allele, whole genome sequencing (WGS) indicated the presence of a novel heterozygous 70 kb deletion. CONCLUSION: We report in the present paper the largest known heterozygous deletion of a PMM2 gene. The observation reveals the impact of a precise diagnostic on genetic counselling: by using WGS, an erroneous conclusion of homozygosity in the case of a relatively rare variant could be avoided, and an index patient with healthy and unrelated parents correctly identified.


Assuntos
Defeitos Congênitos da Glicosilação , Criança , Defeitos Congênitos da Glicosilação/diagnóstico , Defeitos Congênitos da Glicosilação/genética , Heterozigoto , Humanos , Mutação , Fosfotransferases (Fosfomutases)/deficiência , Transferrinas/genética
14.
Nat Commun ; 13(1): 6061, 2022 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-36229432

RESUMO

Overexposure to manganese disrupts cellular energy metabolism across species, but the molecular mechanism underlying manganese toxicity remains enigmatic. Here, we report that excess cellular manganese selectively disrupts coenzyme Q (CoQ) biosynthesis, resulting in failure of mitochondrial bioenergetics. While respiratory chain complexes remain intact, the lack of CoQ as lipophilic electron carrier precludes oxidative phosphorylation and leads to premature cell and organismal death. At a molecular level, manganese overload causes mismetallation and proteolytic degradation of Coq7, a diiron hydroxylase that catalyzes the penultimate step in CoQ biosynthesis. Coq7 overexpression or supplementation with a CoQ headgroup analog that bypasses Coq7 function fully corrects electron transport, thus restoring respiration and viability. We uncover a unique sensitivity of a diiron enzyme to mismetallation and define the molecular mechanism for manganese-induced bioenergetic failure that is conserved across species.


Assuntos
Doenças Mitocondriais , Ubiquinona , Ataxia , Humanos , Manganês/toxicidade , Doenças Mitocondriais/metabolismo , Oxigenases de Função Mista , Debilidade Muscular , Ubiquinona/deficiência , Ubiquinona/metabolismo
15.
J Biosci ; 472022.
Artigo em Inglês | MEDLINE | ID: mdl-36222131

RESUMO

Gallbladder cancer (GBC) is one of the most fatal malignancies of the biliary tract system and is ranked sixth among the neoplasms of the gastrointestinal tract. Gallstone disease (GSD) is considered the major risk factor for GBC. However, the underlying molecular mechanism of GBC pathogenesis from different stages of GSD is not yet clearly understood. We analyzed transcriptomic datasets of GBC with reference to GSD of three different follow-up periods, i.e.,GBC vs. GSD3 (1-3 years), GBCvs. GSD5 (5-10 years), andGBC vs. GSD10 (more than 10 years). We identified overlapping and specific molecular signatures in GBC compared with GSD at three different follow-up periods. Using integrative network biology approaches, such as protein-protein interaction network analysis, transcriptional regulatory network analysis, and miRNA-target gene network analysis, we have identified a few hub genes. The hub genes identified from GBC vs. GSD3, GBC vs. GSD5, and GBC vs. GSD10 were directly or indirectly associated with cancer progression and initiation from GSD. Functional enrichment analysis indicated significant correlation between GSD and GBC pathogenesis. The identified hub genes can be used for future targeted validation to develop potential diagnostic, prognostic, or therapeutic biomarkers in GBC.


Assuntos
Colelitíase , Neoplasias da Vesícula Biliar , MicroRNAs , Neoplasias da Vesícula Biliar/genética , Neoplasias da Vesícula Biliar/patologia , Humanos , Nefropatias , MicroRNAs/genética , Doenças Musculares , Fosfoglicerato Mutase/deficiência
17.
Int J Mol Sci ; 23(19)2022 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-36232540

RESUMO

Aromatic amino acid decarboxylase (AADC) deficiency is a rare monogenic disease due to mutations in the ddc gene producing AADC, a homodimeric pyridoxal 5'-phosphate-dependent enzyme. The disorder is often fatal in the first decade and is characterized by profound motor impairments and developmental delay. In the last two years, there has been a net rise in the number of patients and variants identified, maybe also pushed by the ongoing gene therapy trials. The majority of the identified genotypes are compound heterozygous (about 70%). Efforts are underway to reach early diagnosis, find possible new markers/new fast methods, and predict clinical outcome. However, no clear correlation of genotype-to-phenotype exists to date. Nevertheless, for homozygous patients, reliable results have been obtained using genetic methods combined with available computational tools on crystal structures corroborated by biochemical investigations on recombinant homodimeric AADC variants that have been obtained and characterized in solution. For these variants, the molecular basis for the defect has been suggested and validated, since it correlates quite well with mildness/severity of the homozygous phenotype. Instead, prediction for compound heterozygous patients is more difficult since complementation effects could happen. Here, by analyzing the existing literature on compound heterozygosity in AADC deficiency and other genetic disorders, we highlight that, in order to assess pathogenicity, the measurement of activity of the AADC heterodimeric variant should be integrated by bioinformatic, structural, and functional data on the whole protein constellation theoretically present in such patients. A wider discussion on symptomatic heterozygosity in AADC deficiency is also presented.


Assuntos
Carboxiliases , Erros Inatos do Metabolismo dos Aminoácidos , Descarboxilases de Aminoácido-L-Aromático/deficiência , Descarboxilases de Aminoácido-L-Aromático/genética , Carboxiliases/genética , Fenótipo , Fosfatos , Piridoxal
18.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 51(3): 278-283, 2022 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-36207829

RESUMO

OBJECTIVE: To investigate the clinical characteristics of infants with short-chain acyl-CoA dehydrogenase deficiency (SCADD) and related gene mutations in Beijing. METHODS: The acylcarnitine levels in the blood samples of 100 603 neonates in Beijing during August 2014 and March 2022 were measured by tandem mass spectrometry (MS/MS). The suspected SCADD neonates were rechecked by MS/MS, urine gas chromatography-mass spectrometry (GC/MS) and next-generation sequencing (NGS) for diagnosis. The clinical, biochemical and gene mutation characteristics of infants with SCADD were analyzed; the growth and intellectual development of these patients were observed regularly. RESULTS: Among 100 603 live births, the elevated C4 concentration or elevated C4/C3 ratio were detected in the initial screening from 196 neonates, and 131 were recalled. Five cases of SCADD were diagnosed with an incidence rate of 4.97/100 000 (1/20 121). There was no significant abnormality in clinical manifestations, however, the blood butyrylcarnitine (C4) level and the ratio of C4 to propionylcarnitine (C3) were raised in all diagnosed cases. Urinary organic acids were analyzed in 4 cases, all of whom had increased ethyl malonate acid levels. Seven mutations were detected in the ACADS gene, all of which were known missense mutations. One patient had homozygous mutation, and the others showed compound heterozygous mutations. No clinical symptoms were observed, and the physical and intellectual development was normal in all patients at a median age of 33 (4-40) months during follow-up. CONCLUSIONS: The incidence rate of SCADD was 1/20 121 in Beijing. Neonates with early diagnosis and without clinical symptoms usually have good prognosis.


Assuntos
Triagem Neonatal , Espectrometria de Massas em Tandem , Acil-CoA Desidrogenase/deficiência , Pequim/epidemiologia , Pré-Escolar , Humanos , Lactente , Recém-Nascido , Erros Inatos do Metabolismo Lipídico , Malonatos , Mutação
19.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 51(3): 284-289, 2022 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-36207830

RESUMO

OBJECTIVE: To analyze the incidence, phenotype, genotype and prognosis of neonatal medium-chain acyl-CoA dehydrogenase deficiency (MCADD) in Zibo city of Shandong province. METHODS: A total of 241 297 neonates were screened for MCADD in Zibo city of Shandong province from November 2013 to January 2022. Non-derivatized tandem mass spectrometry was used to detect blood free carnitine and acylcarnitine profiles in neonatal screening. Neonates with octanoylcarnitine (C8)≥0.25 µmol/L, or combined with C8/decanoylcarnitine (C10)≥1.5 were recalled, and second-generation high-throughput sequencing was performed for genetic diagnosis. RESULTS: Among 241 297 neonates, 6 cases of MCADD were screened, including 2 boys and 4 girls, with an incidence of 1/40 216. Two mutation sites of ACADM gene were identified in all MCADD infants, and 12 mutation with 8 types were detected in total. The hot spot mutations were c.449_452del (p.T150Rfs*4) and c.387+1delG, and exon 11 c.1076C>T (p.A359V) was a newly detected mutation. No phenotype-genotype correlation was found. One case died on day 4 after birth; 5 cases were followed up for 2 to 60 months, none of them received special diet treatment. The growth and intellectual development of the surviving cases were normal, and no abnormality was found in routine biochemical indicators. CONCLUSIONS: The incidence of MCADD in Zibo city seems to be higher than that in other areas in China. The ACADM gene mutations c.449_452del (p.T150Rfs*4) and c.387+1delG are common, and a new mutation c.1076C>T (p.A359V) has been detected. No phenotype-genotype correlation has been found. Early diagonsis and treatment are effective measures to reduce poor prognosis.


Assuntos
Erros Inatos do Metabolismo Lipídico , Acil-CoA Desidrogenase/deficiência , Acil-CoA Desidrogenase/genética , Carnitina , Seguimentos , Humanos , Erros Inatos do Metabolismo Lipídico/diagnóstico , Erros Inatos do Metabolismo Lipídico/genética , Mutação
20.
Am J Physiol Endocrinol Metab ; 323(5): E428-E434, 2022 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-36198111

RESUMO

In people with type 1 diabetes, hypoglycemia can induce cardiac arrhythmias. In rodent experiments, severe hypoglycemia can induce fatal cardiac arrhythmias, especially so in diabetic models. Increased oxidative stress associated with insulin-deficient diabetes was hypothesized to increase susceptibility to severe hypoglycemia-induced fatal cardiac arrhythmias. To test this hypothesis, Sprague-Dawley rats were made insulin deficient with streptozotocin and randomized into two groups: 1) control (n = 22) or 2) vitamin E treated (four doses of α-tocopherol, 400 mg/kg, n = 20). Following 1 week of treatment, rats were either tested for cardiac oxidative stress or underwent a hyperinsulinemic-severe hypoglycemic (10-15 mg/dL) clamp with electrocardiogram recording. As compared with controls, vitamin E-treated rats had threefold less cardiac oxidative stress, sixfold less mortality due to severe hypoglycemia, and sevenfold less incidence of heart block. In summary, vitamin E treatment and the associated reduction of cardiac oxidative stress in diabetic rats reduced severe hypoglycemia-induced fatal cardiac arrhythmias. These results indicate that in the setting of diabetes, pharmacological treatments that reduce oxidative stress may be an effective strategy to reduce the risk of severe hypoglycemia-induced fatal cardiac arrhythmias.NEW & NOTEWORTHY For people with type 1 diabetes, severe hypoglycemia can be fatal. We show in our animal model that insulin-deficient diabetic rats have fatal cardiac arrhythmias during severe hypoglycemia that are associated with increased cardiac oxidative stress. Importantly, treatment with vitamin E, to reduce oxidative stress, decreased fatal cardiac arrhythmias during severe hypoglycemia.


Assuntos
Diabetes Mellitus Experimental , Hipoglicemia , Vitamina E , Animais , Ratos , Arritmias Cardíacas/etiologia , Arritmias Cardíacas/prevenção & controle , Glicemia , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/tratamento farmacológico , Hipoglicemia/complicações , Hipoglicemia/tratamento farmacológico , Insulina/deficiência , Ratos Sprague-Dawley , Vitamina E/uso terapêutico
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