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1.
Emerg Med Clin North Am ; 40(1): 119-133, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34782083

RESUMO

Scombroid poisoning, systemic mastocytosis, and hereditary alpha tryptasemia all present with episodes that resemble allergic reactions. Knowledge regarding systemic mastocytosis and hereditary alpha tryptasemia is quickly evolving. Epidemiology, pathophysiology, and strategies to identify and diagnose are discussed. Evidence-based management in the emergency setting and beyond is also explored and summarized. Key differences are described between these events and allergic reactions.


Assuntos
Angioedema/diagnóstico , Hipersensibilidade/diagnóstico , Toxinas Marinhas/biossíntese , Angioedema/fisiopatologia , Mimetismo Biológico , Humanos , Hipersensibilidade/fisiopatologia , Toxinas Marinhas/metabolismo , Triptases/análise , Triptases/deficiência
2.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(11): 1051-1054, 2021 Nov 10.
Artigo em Chinês | MEDLINE | ID: mdl-34729741

RESUMO

OBJECTIVE: To analyze the metabolic profile and genetic variants for newborns with primary carnitine deficiency (PCD) from Guangxi, China. METHODS: From January 2014 to December 2019, 400 575 newborns from the jurisdiction of Guangxi Zhuang Autonomous Region Newborn Screening Center were subjected to tandem mass spectrometry (MS/MS) analysis. Newborns with positive results for PCD and their mothers were recalled for retesting. Those who were still positive were subjected to sequencing of the SLC22A5 gene. RESULTS: Twenty-two newborns and 9 mothers were diagnosed with PCD, which gave a prevalence rate of 1/18 208. Sequencing of 18 newborns and 4 mothers have identified 14 types of SLC22A5 gene variants, with the common ones including c.51C>G (10/44, 22.7%), c.1195C>T (9/44, 20.5%) and c.1400C>G (7/44, 15.9%), The c.517delC(p.L173Cfs*3) and c.1031C>T(p.T344I) were unreported previously and predicted to be pathogenic (PVS1+PM2_supporting+PM3+PP4) and likely pathogenic (PM1+PM2_supporting+PM3+PP3+PP4) based on the American College of Medical Genetics and Genomics standards and guidelines. CONCLUSION: c.51C>G, c.1195C>T and c.1400C>G are the most common variants underlying PCD in Guangxi.


Assuntos
Metaboloma , Espectrometria de Massas em Tandem , Cardiomiopatias , Carnitina/deficiência , China , Humanos , Hiperamonemia , Recém-Nascido , Doenças Musculares , Mutação , Membro 5 da Família 22 de Carreadores de Soluto/genética
3.
Molecules ; 26(21)2021 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-34771023

RESUMO

Zinc is the second most abundant trace element in the human body, and it plays a fundamental role in human physiology, being an integral component of hundreds of enzymes and transcription factors. The discovery that zinc atoms may compete with copper for their absorption in the gastrointestinal tract let to introduce zinc in the therapy of Wilson's disease, a congenital disorder of copper metabolism characterized by a systemic copper storage. Nowadays, zinc salts are considered one of the best therapeutic approach in patients affected by Wilson's disease. On the basis of the similarities, at histological level, between Wilson's disease and non-alcoholic liver disease, zinc has been successfully introduced in the therapy of non-alcoholic liver disease, with positive effects both on insulin resistance and oxidative stress. Recently, zinc deficiency has been indicated as a possible factor responsible for the susceptibility of elderly patients to undergo infection by SARS-CoV-2, the coronavirus responsible for the COVID-19 pandemic. Here, we present the data correlating zinc deficiency with the insurgence and progression of Covid-19 with low zinc levels associated with severe disease states. Finally, the relevance of zinc supplementation in aged people at risk for SARS-CoV-2 is underlined, with the aim that the zinc-based drug, classically used in the treatment of copper overload, might be recorded as one of the tools reducing the mortality of COVID-19, particularly in elderly people.


Assuntos
Fígado/efeitos dos fármacos , Fígado/lesões , Zinco/farmacologia , COVID-19/complicações , COVID-19/tratamento farmacológico , Quelantes/metabolismo , Cobre/metabolismo , Degeneração Hepatolenticular/complicações , Degeneração Hepatolenticular/tratamento farmacológico , Degeneração Hepatolenticular/metabolismo , Humanos , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , SARS-CoV-2/patogenicidade , Zinco/deficiência , Zinco/metabolismo
4.
Nutrients ; 13(10)2021 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-34684517

RESUMO

Preventive zinc supplementation provided as a stand-alone dispersible tablet, or via home fortification as multiple micronutrient powders (MNPs), has been considered a potential strategy to prevent zinc deficiency and improve health (including immune) outcomes among children in low- and middle-income countries. However, the impact of zinc supplementation on immune profiles has not been well characterized. We sought to define the effect of zinc supplementation on peripheral blood gene expression and cytokine levels among young children in Dhaka, Bangladesh. In a sub-study of a large randomized, controlled, community-based efficacy trial where children 9-11 months of age received one of the following interventions on a daily basis for 24 weeks: (1) MNPs containing 10 mg of zinc; (2) dispersible tablet containing 10 mg zinc; or (3) placebo powder, we used RNA sequencing to profile the peripheral blood gene expression, as well as highly sensitive multiplex assays to detect cytokine profiles. We profiled samples from 100 children enrolled in the parent trial (zinc MNPs 28, zinc tablets 39, placebo 33). We did not detect an effect from either zinc intervention on differential peripheral blood gene expression at the end of the intervention, or an effect from the intervention on changes in gene expression from baseline. We also did not detect an effect from either intervention on cytokine concentrations. Exploratory analysis did not identify an association between undernutrition (defined as stunting, underweight or wasting) and peripheral blood gene expression. Zinc interventions in children did not produce a gene expression or cytokine signature in the peripheral blood. However, this study demonstrates a proof of principle that sensitive multi-omic techniques can be applied to samples collected in field studies.


Assuntos
Citocinas/sangue , Suplementos Nutricionais , Expressão Gênica/efeitos dos fármacos , Micronutrientes/administração & dosagem , Zinco/administração & dosagem , Bangladesh , Feminino , Humanos , Lactente , Masculino , Pós , Comprimidos , Zinco/deficiência
5.
Hinyokika Kiyo ; 67(9): 419-421, 2021 Sep.
Artigo em Japonês | MEDLINE | ID: mdl-34610707

RESUMO

We report a case of 2,8-dihydroxyadenine (DHA) urolithiasis in a 65-year-old male. He initially visited another institution because right hydronephrosis was revealed in a medical checkup. Computed tomography demonstrated radiolucent right renal stones. We performed percutaneous nephrolithotripsy and flexible transurethral lithotripsy and removed the stones successfully. An analysis of the stone fragments revealed 2,8-DHA urolithiasis. 2,8-DHA stones are relatively rare and caused by adenine phosphoribosyltransferase deficiency.


Assuntos
Cálculos Renais , Litotripsia , Urolitíase , Adenina , Adenina Fosforribosiltransferase/deficiência , Idoso , Humanos , Cálculos Renais/terapia , Masculino , Erros Inatos do Metabolismo , Urolitíase/diagnóstico por imagem
6.
J Clin Invest ; 131(17)2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34623320

RESUMO

Genome-wide association studies revealed that loss-of-function mutations in protein tyrosine phosphatase non-receptor type 2 (PTPN2) increase the risk of developing chronic immune diseases, such as inflammatory bowel disease (IBD) and celiac disease. These conditions are associated with increased intestinal permeability as an early etiological event. The aim of this study was to examine the consequences of deficient activity of the PTPN2 gene product, T cell protein tyrosine phosphatase (TCPTP), on intestinal barrier function and tight junction organization in vivo and in vitro. Here, we demonstrate that TCPTP protected against intestinal barrier dysfunction induced by the inflammatory cytokine IFN-γ by 2 mechanisms: it maintained localization of zonula occludens 1 and occludin at apical tight junctions and restricted both expression and insertion of the cation pore-forming transmembrane protein, claudin-2, at tight junctions through upregulation of the inhibitory cysteine protease, matriptase. We also confirmed that the loss-of-function PTPN2 rs1893217 SNP was associated with increased intestinal claudin-2 expression in patients with IBD. Moreover, elevated claudin-2 levels and paracellular electrolyte flux in TCPTP-deficient intestinal epithelial cells were normalized by recombinant matriptase. Our findings uncover distinct and critical roles for epithelial TCPTP in preserving intestinal barrier integrity, thereby proposing a mechanism by which PTPN2 mutations contribute to IBD.


Assuntos
Mucosa Intestinal/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 2/metabolismo , Junções Íntimas/metabolismo , Adolescente , Adulto , Idoso , Animais , Claudinas/metabolismo , Modelos Animais de Doenças , Feminino , Estudo de Associação Genômica Ampla , Humanos , Técnicas In Vitro , Doenças Inflamatórias Intestinais/etiologia , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/metabolismo , Mucosa Intestinal/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Permeabilidade , Polimorfismo de Nucleotídeo Único , Proteína Tirosina Fosfatase não Receptora Tipo 2/deficiência , Proteína Tirosina Fosfatase não Receptora Tipo 2/genética , Junções Íntimas/patologia , Adulto Jovem
7.
J Clin Invest ; 131(17)2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34623322

RESUMO

Triggering receptor expressed on myeloid cells 2 (TREM-2) is a modulator of pattern recognition receptors on innate immune cells that regulates the inflammatory response. However, the role of TREM-2 in in vivo models of infection and inflammation remains controversial. Here, we demonstrated that TREM-2 expression on CD4+ T cells was induced by Mycobacterium tuberculosis infection in both humans and mice and positively associated with T cell activation and an effector memory phenotype. Activation of TREM-2 in CD4+ T cells was dependent on interaction with the putative TREM-2 ligand expressed on DCs. Unlike the observation in myeloid cells that TREM-2 signals through DAP12, in CD4+ T cells, TREM-2 interacted with the CD3ζ-ZAP70 complex as well as with the IFN-γ receptor, leading to STAT1/-4 activation and T-bet transcription. In addition, an infection model using reconstituted Rag2-/- mice (with TREM-2-KO vs. WT cells or TREM-2+ vs. TREM-2-CD4+ T cells) or CD4+ T cell-specific TREM-2 conditional KO mice demonstrated that TREM-2 promoted a Th1-mediated host defense against M. tuberculosis infection. Taken together, these findings reveal a critical role of TREM-2 in evoking proinflammatory Th1 responses that may provide potential therapeutic targets for infectious and inflammatory diseases.


Assuntos
Complexo CD3/imunologia , Glicoproteínas de Membrana/imunologia , Receptores Imunológicos/imunologia , Células Th1/imunologia , Tuberculose/imunologia , Proteína-Tirosina Quinase ZAP-70/imunologia , Adulto , Animais , Modelos Animais de Doenças , Feminino , Humanos , Imunidade Inata , Ativação Linfocitária , Masculino , Glicoproteínas de Membrana/deficiência , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Modelos Imunológicos , Mycobacterium tuberculosis/imunologia , Receptores Imunológicos/deficiência , Receptores Imunológicos/genética , Receptores de Reconhecimento de Padrão/imunologia , Fatores de Transcrição STAT/imunologia
8.
J Clin Invest ; 131(17)2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34623323

RESUMO

Hypoxia-induced pulmonary hypertension (PH) is one of the most common and deadliest forms of PH. Fibroblast growth factor receptors 1 and 2 (FGFR1/2) are elevated in patients with PH and in mice exposed to chronic hypoxia. Endothelial FGFR1/2 signaling is important for the adaptive response to several injury types and we hypothesized that endothelial FGFR1/2 signaling would protect against hypoxia-induced PH. Mice lacking endothelial FGFR1/2, mice with activated endothelial FGFR signaling, and human pulmonary artery endothelial cells (HPAECs) were challenged with hypoxia. We assessed the effect of FGFR activation and inhibition on right ventricular pressure, vascular remodeling, and endothelial-mesenchymal transition (EndMT), a known pathologic change seen in patients with PH. Hypoxia-exposed mice lacking endothelial FGFRs developed increased PH, while mice overexpressing a constitutively active FGFR in endothelial cells did not develop PH. Mechanistically, lack of endothelial FGFRs or inhibition of FGFRs in HPAECs led to increased TGF-ß signaling and increased EndMT in response to hypoxia. These phenotypes were reversed in mice with activated endothelial FGFR signaling, suggesting that FGFR signaling inhibits TGF-ß pathway-mediated EndMT during chronic hypoxia. Consistent with these observations, lung tissue from patients with PH showed activation of FGFR and TGF-ß signaling. Collectively, these data suggest that activation of endothelial FGFR signaling could be therapeutic for hypoxia-induced PH.


Assuntos
Fatores de Crescimento de Fibroblastos/metabolismo , Hipertensão Pulmonar/metabolismo , Hipóxia/metabolismo , Animais , Endotélio/metabolismo , Endotélio/patologia , Feminino , Humanos , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/prevenção & controle , Hipóxia/complicações , Masculino , Mesoderma/metabolismo , Mesoderma/patologia , Camundongos , Camundongos Knockout , Receptores de Fatores de Crescimento de Fibroblastos/deficiência , Receptores de Fatores de Crescimento de Fibroblastos/genética , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Transdução de Sinais , Remodelação Vascular
9.
J Clin Invest ; 131(17)2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34623328

RESUMO

Properly balancing microbial responses by the innate immune system through pattern recognition receptors (PRRs) is critical for intestinal immune homeostasis. Ring finger protein 186 (RNF186) genetic variants are associated with inflammatory bowel disease (IBD). However, functions for the E3 ubiquitin ligase RNF186 are incompletely defined. We found that upon stimulation of the PRR nucleotide-binding oligomerization domain containing 2 (NOD2) in human macrophages, RNF186 localized to the ER, formed a complex with ER stress sensors, ubiquitinated the ER stress sensor activating transcription factor 6 (ATF6), and promoted the unfolded protein response (UPR). These events, in turn, led to downstream signaling, cytokine secretion, and antimicrobial pathway induction. Importantly, RNF186-mediated ubiquitination of K152 on ATF6 was required for these outcomes, highlighting a key role for ATF6 ubiquitination in PRR-initiated functions. Human macrophages transfected with the rare RNF186-A64T IBD risk variant and macrophages from common rs6426833 RNF186 IBD risk carriers demonstrated reduced NOD2-induced outcomes, which were restored by rescuing UPR signaling. Mice deficient in RNF186 or ATF6 demonstrated a reduced UPR in colonic tissues, increased weight loss, and less effective clearance of bacteria with dextran sodium sulfate-induced injury and upon oral challenge with Salmonella Typhimurium. Therefore, we identified that RNF186 was required for PRR-induced, UPR-associated signaling leading to key macrophage functions; defined that RNF186-mediated ubiquitination of ATF6 was essential for these functions; and elucidated how RNF186 IBD risk variants modulated these outcomes.


Assuntos
Fator 6 Ativador da Transcrição/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Resposta a Proteínas não Dobradas/fisiologia , Fator 6 Ativador da Transcrição/química , Fator 6 Ativador da Transcrição/deficiência , Fator 6 Ativador da Transcrição/genética , Animais , Estresse do Retículo Endoplasmático , Variação Genética , Interações entre Hospedeiro e Microrganismos , Humanos , Imunidade Inata , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína Adaptadora de Sinalização NOD2/metabolismo , Receptores de Reconhecimento de Padrão/imunologia , Receptores de Reconhecimento de Padrão/metabolismo , Fatores de Risco , Transdução de Sinais , Ubiquitina-Proteína Ligases/deficiência , Ubiquitina-Proteína Ligases/genética , Ubiquitinação
10.
J Clin Invest ; 131(17)2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34623331

RESUMO

Pancreatic ß cell failure in type 2 diabetes mellitus (T2DM) is attributed to perturbations of the ß cell's transcriptional landscape resulting in impaired glucose-stimulated insulin secretion. Recent studies identified SLC4A4 (a gene encoding an electrogenic Na+-coupled HCO3- cotransporter and intracellular pH regulator, NBCe1) as one of the misexpressed genes in ß cells of patients with T2DM. Thus, in the current study, we set out to test the hypothesis that misexpression of SLC4A4/NBCe1 in T2DM ß cells contributes to ß cell dysfunction and impaired glucose homeostasis. To address this hypothesis, we first confirmed induction of SLC4A4/NBCe1 expression in ß cells of patients with T2DM and demonstrated that its expression was associated with loss of ß cell transcriptional identity, intracellular alkalinization, and ß cell dysfunction. In addition, we generated a ß cell-selective Slc4a4/NBCe1-KO mouse model and found that these mice were protected from diet-induced metabolic stress and ß cell dysfunction. Importantly, improved glucose tolerance and enhanced ß cell function in Slc4a4/NBCe1-deficient mice were due to augmented mitochondrial function and increased expression of genes regulating ß cell identity and function. These results suggest that increased ß cell expression of SLC4A4/NBCe1 in T2DM plays a contributory role in promotion of ß cell failure and should be considered as a potential therapeutic target.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Células Secretoras de Insulina/metabolismo , Simportadores de Sódio-Bicarbonato/metabolismo , Animais , Diabetes Mellitus Tipo 2/genética , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Expressão Gênica , Intolerância à Glucose/etiologia , Intolerância à Glucose/metabolismo , Intolerância à Glucose/prevenção & controle , Humanos , Camundongos , Camundongos Knockout , Mitocôndrias/metabolismo , Obesidade/genética , Obesidade/metabolismo , Simportadores de Sódio-Bicarbonato/deficiência , Simportadores de Sódio-Bicarbonato/genética , Estresse Fisiológico
11.
J Clin Invest ; 131(17)2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34623330

RESUMO

The heart forms early in development and delivers oxygenated blood to the rest of the embryo. After birth, the heart requires kilograms of ATP each day to support contractility for the circulation. Cardiac metabolism is omnivorous, utilizing multiple substrates and metabolic pathways to produce this energy. Cardiac development, metabolic tuning, and the response to ischemia are all regulated in part by the hypoxia-inducible factors (HIFs), central components of essential signaling pathways that respond to hypoxia. Here we review the actions of HIF1, HIF2, and HIF3 in the heart, from their roles in development and metabolism to their activity in regeneration and preconditioning strategies. We also discuss recent work on the role of HIFs in atherosclerosis, the precipitating cause of myocardial ischemia and the leading cause of death in the developed world.


Assuntos
Aterosclerose/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Coração/crescimento & desenvolvimento , Isquemia Miocárdica/metabolismo , Miocárdio/metabolismo , Animais , Aterosclerose/etiologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/deficiência , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Humanos , Fator 1 Induzível por Hipóxia/metabolismo , Precondicionamento Isquêmico Miocárdico , Redes e Vias Metabólicas , Camundongos , Camundongos Knockout , Modelos Cardiovasculares , Isquemia Miocárdica/etiologia , Neovascularização Patológica , Neovascularização Fisiológica
12.
Nat Commun ; 12(1): 5931, 2021 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-34635673

RESUMO

The chromatin remodeler RSF1 enriched at mitotic centromeres is essential for proper chromosome alignment and segregation and underlying mechanisms remain to be disclosed. We here show that PLK1 recruitment by RSF1 at centromeres creates an activating phosphorylation on Thr236 in the activation loop of Aurora B and this is indispensable for the Aurora B activation. In structural modeling the phosphorylated Thr236 enhances the base catalysis by Asp200 nearby, facilitating the Thr232 autophosphorylation. Accordingly, RSF1-PLK1 is central for Aurora B-mediated microtubule destabilization in error correction. However, under full microtubule-kinetochore attachment RSF1-PLK1 positions at kinetochores, halts activating Aurora B and phosphorylates BubR1, regardless of tension. Spatial movement of RSF1-PLK1 to kinetochores is triggered by Aurora B-mediated phosphorylation of centromeric histone H3 on Ser28. We propose a regulatory RSF1-PLK1 axis that spatiotemporally controls on/off switch on Aurora B. This feedback circuit among RSF1-PLK1-Aurora B may coordinate dynamic microtubule-kinetochore attachment in early mitosis when full tension yet to be generated.


Assuntos
Aurora Quinase B/genética , Proteínas de Ciclo Celular/genética , Segregação de Cromossomos , Mitose , Proteínas Nucleares/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Transdução de Sinais/genética , Transativadores/genética , Ácido Aspártico/metabolismo , Aurora Quinase B/metabolismo , Proteínas de Ciclo Celular/metabolismo , Cromatina/química , Cromatina/metabolismo , Retroalimentação Fisiológica , Regulação da Expressão Gênica , Células HeLa , Histonas/genética , Histonas/metabolismo , Humanos , Cinetocoros/metabolismo , Cinetocoros/ultraestrutura , Microtúbulos/metabolismo , Microtúbulos/ultraestrutura , Proteínas Nucleares/deficiência , Fosforilação , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Serina/metabolismo , Transativadores/deficiência
13.
N Engl J Med ; 385(17): 1581-1592, 2021 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-34614324

RESUMO

BACKGROUND: GNAS encodes the Gαs (stimulatory G-protein alpha subunit) protein, which mediates G protein-coupled receptor (GPCR) signaling. GNAS mutations cause developmental delay, short stature, and skeletal abnormalities in a syndrome called Albright's hereditary osteodystrophy. Because of imprinting, mutations on the maternal allele also cause obesity and hormone resistance (pseudohypoparathyroidism). METHODS: We performed exome sequencing and targeted resequencing in 2548 children who presented with severe obesity, and we unexpectedly identified 22 GNAS mutation carriers. We investigated whether the effect of GNAS mutations on melanocortin 4 receptor (MC4R) signaling explains the obesity and whether the variable clinical spectrum in patients might be explained by the results of molecular assays. RESULTS: Almost all GNAS mutations impaired MC4R signaling. A total of 6 of 11 patients who were 12 to 18 years of age had reduced growth. In these patients, mutations disrupted growth hormone-releasing hormone receptor signaling, but growth was unaffected in carriers of mutations that did not affect this signaling pathway (mean standard-deviation score for height, -0.90 vs. 0.75, respectively; P = 0.02). Only 1 of 10 patients who reached final height before or during the study had short stature. GNAS mutations that impaired thyrotropin receptor signaling were associated with developmental delay and with higher thyrotropin levels (mean [±SD], 8.4±4.7 mIU per liter) than those in 340 severely obese children who did not have GNAS mutations (3.9±2.6 mIU per liter; P = 0.004). CONCLUSIONS: Because pathogenic mutations may manifest with obesity alone, screening of children with severe obesity for GNAS deficiency may allow early diagnosis, improving clinical outcomes, and melanocortin agonists may aid in weight loss. GNAS mutations that are identified by means of unbiased genetic testing differentially affect GPCR signaling pathways that contribute to clinical heterogeneity. Monogenic diseases are clinically more variable than their classic descriptions suggest. (Funded by Wellcome and others.).


Assuntos
Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Mutação , Obesidade Pediátrica/genética , Receptor Tipo 4 de Melanocortina/metabolismo , Adolescente , Estatura , Criança , Cromograninas/genética , Feminino , Subunidades alfa Gs de Proteínas de Ligação ao GTP/deficiência , Humanos , Masculino , Mutação de Sentido Incorreto , Receptores da Tireotropina/metabolismo , Transdução de Sinais , Sequenciamento Completo do Exoma
14.
Nat Commun ; 12(1): 5857, 2021 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-34615877

RESUMO

The recently identified G-protein-coupled receptor GPR171 and its ligand BigLEN are thought to regulate food uptake and anxiety. Though GPR171 is commonly used as a T cell signature gene in transcriptomic studies, its potential role in T cell immunity has not been explored. Here we show that GPR171 is transcribed in T cells and its protein expression is induced upon antigen stimulation. The neuropeptide ligand BigLEN interacts with GPR171 to suppress T cell receptor-mediated signalling pathways and to inhibit T cell proliferation. Loss of GPR171 in T cells leads to hyperactivity to antigen stimulation and GPR171 knockout mice exhibit enhanced antitumor immunity. Blockade of GPR171 signalling by an antagonist promotes antitumor T cell immunity and improves immune checkpoint blockade therapies. Together, our study identifies the GPR171/BigLEN axis as a T cell checkpoint pathway that can be modulated for cancer immunotherapy.


Assuntos
Imunidade , Receptores Acoplados a Proteínas G/química , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Linfócitos T/metabolismo , Animais , Linhagem Celular Tumoral , Proliferação de Células , Células HEK293 , Humanos , Imunoterapia , Ligantes , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neoplasias/terapia , Neuropeptídeos/metabolismo , Receptores Acoplados a Proteínas G/deficiência , Transdução de Sinais
15.
Nat Commun ; 12(1): 5962, 2021 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-34645823

RESUMO

Pitt-Hopkins syndrome (PTHS) is a rare autism spectrum-like disorder characterized by intellectual disability, developmental delays, and breathing problems involving episodes of hyperventilation followed by apnea. PTHS is caused by functional haploinsufficiency of the gene encoding transcription factor 4 (Tcf4). Despite the severity of this disease, mechanisms contributing to PTHS behavioral abnormalities are not well understood. Here, we show that a Tcf4 truncation (Tcf4tr/+) mouse model of PTHS exhibits breathing problems similar to PTHS patients. This behavioral deficit is associated with selective loss of putative expiratory parafacial neurons and compromised function of neurons in the retrotrapezoid nucleus that regulate breathing in response to tissue CO2/H+. We also show that central Nav1.8 channels can be targeted pharmacologically to improve respiratory function at the cellular and behavioral levels in Tcf4tr/+ mice, thus establishing Nav1.8 as a high priority target with therapeutic potential in PTHS.


Assuntos
Haploinsuficiência , Proteínas de Homeodomínio/genética , Hiperventilação/genética , Deficiência Intelectual/genética , Canal de Sódio Disparado por Voltagem NAV1.8/genética , Neurônios/metabolismo , Fator de Transcrição 4/genética , Fatores de Transcrição/genética , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Benzimidazóis/farmacologia , Tronco Encefálico/efeitos dos fármacos , Tronco Encefálico/metabolismo , Tronco Encefálico/patologia , Dióxido de Carbono/metabolismo , Dióxido de Carbono/farmacologia , Modelos Animais de Doenças , Facies , Regulação da Expressão Gênica , Proteínas de Homeodomínio/metabolismo , Humanos , Hiperventilação/tratamento farmacológico , Hiperventilação/metabolismo , Hiperventilação/patologia , Deficiência Intelectual/tratamento farmacológico , Deficiência Intelectual/metabolismo , Deficiência Intelectual/patologia , Masculino , Camundongos , Camundongos Knockout , Canal de Sódio Disparado por Voltagem NAV1.8/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/patologia , Desempenho Psicomotor/efeitos dos fármacos , Desempenho Psicomotor/fisiologia , Pirazóis/farmacologia , Respiração/efeitos dos fármacos , Fator de Transcrição 4/deficiência , Fatores de Transcrição/metabolismo
16.
Biomolecules ; 11(10)2021 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-34680053

RESUMO

Analysis of liver biopsy specimens showed that SARS-CoV-2 might have led to liver damage. This study aimed to evaluate the role of selected hepatokines and myokines in the development and progression of COVID-19. Seventy patients with laboratory-confirmed COVID-19 and 20 healthy volunteers were enrolled in the study. Irisin, pentraxin 3, fetuin-A, and FGF-21 serum concentrations and biochemical parameters were assessed using an immunoenzymatic method with commercially available enzyme immunoassay (EIA) or enzyme-linked immunosorbent assay (ELISA) kits. Serum fetuin-A concentrations were significantly decreased in COVID-19 patients compared to healthy volunteers. The serum concentration of FGF-21 was significantly increased in obese COVID-19 patients compared to overweight ones. Moreover, the FGF-21 level was higher in COVID-19 patients diagnosed with metabolic syndrome than in patients without metabolic syndrome. PTX3 concentration was higher in COVID-19 patients with higher HOMA-IR values than those with lower HOMA-IR values. COVID-19 patients with HOMA-IR ≤ 3 and >3 had significantly lower fetuin-A levels than the control group. Irisin concentration was significantly decreased in the HOMA-IR ≤ 3 COVID-19 subgroup when comparing with the control group. Lower levels of fetuin-A observed in COVID-19 patients despite higher HOMA-IR, CRP, and ferritin levels, pneumonia, patients requiring ICU care suggests that fetuin-A deficiency predisposes to more severe COVID-19 course. Upregulated pentraxin 3 may be used as a potential predictor of COVID-19 severity.


Assuntos
COVID-19/metabolismo , alfa-2-Glicoproteína-HS/metabolismo , Animais , COVID-19/patologia , Masculino , Ratos , Ratos Wistar , alfa-2-Glicoproteína-HS/deficiência
17.
Med Clin North Am ; 105(6): 1017-1031, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34688412

RESUMO

Thyroid nodules may be discovered in a variety of settings. Familiarity with their management is important for medical specialists. Workup should start with history and physical examination, proceed to laboratory studies, and then to imaging. Nodules are selected for fine needle aspiration (FNA) biopsy based on imaging criteria. Most nodules can be accurately diagnosed on cytopathology, but some may require additional molecular testing to evaluate risk of malignancy. Patients with malignant lesions require additional investigation before referral to an experienced thyroid surgeon. Those who have benign lesions may require monitoring by periodic ultrasound to identify nodules requiring reevaluation.


Assuntos
Nódulo da Glândula Tireoide/patologia , Biópsia por Agulha Fina , Humanos , Iodo/deficiência , Anamnese , Exposição à Radiação , Fatores de Risco , Hormônios Tireóideos/sangue , Neoplasias da Glândula Tireoide/epidemiologia , Neoplasias da Glândula Tireoide/patologia , Nódulo da Glândula Tireoide/diagnóstico por imagem , Nódulo da Glândula Tireoide/epidemiologia
18.
Nat Commun ; 12(1): 5764, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34599187

RESUMO

Regulatory T (Treg) cells are one of the major immunosuppressive cell types in cancer and a potential target for immunotherapy, but targeting tumor-infiltrating (TI) Treg cells has been challenging. Here, using single-cell RNA sequencing of immune cells from renal clear cell carcinoma (ccRCC) patients, we identify two distinct transcriptional fates for TI Treg cells, Fate-1 and Fate-2. The Fate-1 signature is associated with a poorer prognosis in ccRCC and several other solid cancers. CD177, a cell surface protein normally expressed on neutrophil, is specifically expressed on Fate-1 TI Treg cells in several solid cancer types, but not on other TI or peripheral Treg cells. Mechanistically, blocking CD177 reduces the suppressive activity of Treg cells in vitro, while Treg-specific deletion of Cd177 leads to decreased tumor growth and reduced TI Treg frequency in mice. Our results thus uncover a functional CD177+ TI Treg population that may serve as a target for TI Treg-specific immunotherapy.


Assuntos
Proteínas Ligadas por GPI/metabolismo , Homeostase , Isoantígenos/metabolismo , Linfócitos do Interstício Tumoral/metabolismo , Receptores de Superfície Celular/metabolismo , Linfócitos T Reguladores/metabolismo , Animais , Sequência de Bases , Carcinogênese/genética , Carcinogênese/patologia , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/patologia , Proteínas Ligadas por GPI/deficiência , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Renais/genética , Neoplasias Renais/imunologia , Neoplasias Renais/patologia , Camundongos Knockout , Prognóstico , Receptores de Superfície Celular/deficiência , Análise de Célula Única , Transcrição Genética
19.
Int J Mol Sci ; 22(19)2021 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-34638902

RESUMO

Medium-chain fatty acids (mc-FAs) are currently applied in the treatment of long-chain fatty acid oxidation disorders (lc-FAOD) characterized by impaired ß-oxidation. Here, we performed lipidomic and proteomic analysis in fibroblasts from patients with very long-chain acyl-CoA dehydrogenase (VLCADD) and long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHADD) deficiencies after incubation with heptanoate (C7) and octanoate (C8). Defects of ß-oxidation induced striking proteomic alterations, whereas the effect of treatment with mc-FAs was minor. However, mc-FAs induced a remodeling of complex lipids. Especially C7 appeared to act protectively by restoring sphingolipid biosynthesis flux and improving the observed dysregulation of protein homeostasis in LCHADD under control conditions.


Assuntos
Caprilatos/farmacologia , Fibroblastos/efeitos dos fármacos , Heptanoatos/farmacologia , Erros Inatos do Metabolismo Lipídico/metabolismo , Lipidômica/métodos , Proteômica/métodos , Acil-CoA Desidrogenase de Cadeia Longa/deficiência , Acil-CoA Desidrogenase de Cadeia Longa/metabolismo , Cardiolipinas/metabolismo , Linhagem Celular , Feminino , Fibroblastos/metabolismo , Genótipo , Humanos , Erros Inatos do Metabolismo Lipídico/genética , Erros Inatos do Metabolismo Lipídico/patologia , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Fosfatidilcolinas/metabolismo , Fosfatidiletanolaminas/metabolismo , Proteoma/metabolismo , Esfingolipídeos/metabolismo
20.
Nutrients ; 13(10)2021 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-34684539

RESUMO

While rates of malnutrition have declined over the last decade in India due to successful government interventions, the prevalence of anemia remains high. Staple foods provide almost 70% of the daily iron intake. As staple foods are a rich source of phytate, this ingested iron is poorly absorbed. Currently, 59% of children below 3 years of age, 50% of expectant mothers and 53% of women aged 15-19 years are anemic. The most common intervention strategy has been through the use of iron supplements. While the compliance has been low and supplies irregular, such high rates of anemia cannot be explained by iron deficiency alone. This review attempts to fit dietary and cooking practices, field-level diagnostics, cultural beliefs and constraints in implementation of management strategies into a larger picture scenario to offer insights as to why anemia continues to plague India. Since the rural Indian diet is predominantly vegetarian, we also review dietary factors that influence non-heme iron absorption. As a reference point, we also contrast anemia-related trends in India to the U.S.A. Thus, this review is an effort to convey a holistic evaluation while providing approaches to address this public health crisis.


Assuntos
Anemia Ferropriva/epidemiologia , Dieta , Plantas/química , Fatores Socioeconômicos , Disponibilidade Biológica , Humanos , Índia/epidemiologia , Ferro/deficiência , Ferro/metabolismo
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