RESUMO
Bisphenol A (BPA) is an industrial pollutant that can cause immune impairment. Selenium acts as an antioxidant, as selenium deficiency often accompanies oxidative stress, resulting in organ damage. This study is the first to demonstrate that BPA and/or selenium deficiency induce pyroptosis and ferroptosis-mediated thymic injury in chicken and chicken lymphoma cell (MDCC-MSB-1) via oxidative stress-induced endoplasmic reticulum (ER) stress. We established a broiler chicken model of BPA and/or selenium deficiency exposure and collected thymus samples as research subjects after 42 days. The results demonstrated that BPA or selenium deficiency led to a decrease in antioxidant enzyme activities (T-AOC, CAT, and GSH-Px), accumulation of peroxides (H2O2 and MDA), significant upregulation of ER stress-related markers (GRP78, IER 1, PERK, EIF-2α, ATF4, and CHOP), a significant increase in iron ion levels, significant upregulation of pyroptosis-related gene (NLRP3, ASC, Caspase1, GSDMD, IL-18 and IL-1ß), significantly increase ferroptosis-related genes (TFRC, COX2) and downregulate GPX4, HO-1, FTH, NADPH. In vitro experiments conducted in MDCC-MSB-1 cells confirmed the results, demonstrating that the addition of antioxidant (NAC), ER stress inhibitor (TUDCA) and pyroptosis inhibitor (Vx765) alleviated oxidative stress, endoplasmic reticulum stress, pyroptosis, and ferroptosis. Overall, this study concludes that the combined effects of oxidative stress and ER stress mediate pyroptosis and ferroptosis in chicken thymus induced by BPA exposure and selenium deficiency.
Assuntos
Compostos Benzidrílicos , Galinhas , Estresse do Retículo Endoplasmático , Ferroptose , Fenóis , Piroptose , Espécies Reativas de Oxigênio , Selênio , Animais , Compostos Benzidrílicos/toxicidade , Ferroptose/efeitos dos fármacos , Piroptose/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Selênio/deficiência , Fenóis/toxicidade , Espécies Reativas de Oxigênio/metabolismo , Timo/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacosRESUMO
OBJECTIVE: To analyze the laboratory phenotype and genetic variants of two consanguineous Chinese pedigrees affected with Hereditary prokallikrein (PK) and High molecular weight kininogen (HMWK) deficiency and explore their molecular pathogenesis. METHODS: A PK deficiency pedigree (10 individuals from 4 generations) and a HMWK deficiency pedigree (6 individuals from 3 generations) which were admitted to the First Affiliated Hospital of Wenzhou Medical University on December 3, 2021 and June 16, 2022, respectively were selected as the study subjects. Clinical data of the two pedigrees were collected, and the related coagulation indexes of the probands and their family members were determined. Genomic DNA of the two pedigrees was extracted from peripheral blood samples. All of the exons and flanking sequences of the KLKB1 and KNG1 genes of the probands were analyzed by direct sequencing. And the corresponding sites were sequenced among other family members. Bioinformatic software was used to analyze the conservation of variation sites and the effect of variant on the protein function. RESULTS: The plasma PK activity of proband 1, a 29-year-old female, and her brother were extremely low (< 1.0%). Proband 2 was a 66-year-old male with extremely low plasma HMWK activity (< 1.0%). Genetic sequencing revealed that the proband 1 and her brother had both harbored a homozygous c.417_418insCATTCTTA (p.Arg140Hisfs*3) insertional variant in exon 5 of the KLKB1 gene. Proband 2 had harbored a homozygous c.460C>A (p.Pro154Thr) missense variant in exon 4 of the KNG1 gene. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variants were respectively rated as pathogenic (PVS1+PM2_Supporting+PM4) and likely pathogenic (PS4+PM2_Supporting+PP3+PP4). CONCLUSION: The c.417_418insCATTCTTA (p.Arg140Hisfs*3) variant of the KLKB1 gene and the c.460C>A (p.Pro154Thr) variant of the KNG1 gene probably underlay the decreased PK and HMWK activities in the two pedigrees, respectively.
Assuntos
Cininogênio de Alto Peso Molecular , Pré-Calicreína , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos da Coagulação Sanguínea , China , Consanguinidade , População do Leste Asiático/genética , Cininogênio de Alto Peso Molecular/deficiência , Cininogênio de Alto Peso Molecular/genética , Cininogênios , Linhagem , Pré-Calicreína/genética , Pré-Calicreína/deficiênciaRESUMO
BACKGROUND: Adequate levels of calcium, phosphate and Vitamin D are essential for bone physiology and growth, as well as preventing some common childhood illnesses. This study aimed to determine the prevalence of the deficiencies of these nutrients and factors affecting their serum levels in Nigerian children. METHODS: This was a cross-sectional study that involved 220 apparently healthy children aged 6-24 months in Ikenne Local Government Area of Ogun State, Nigeria. Serum calcium and phosphate were assayed using the calorimetric method, while Vitamin D (25-OH Vitamin D) was assayed with ELISA. RESULTS: The mean (±standard deviation [SD]) serum Vitamin D level was 55.07 ± 16.53 ng/ml, while the mean (±SD) serum calcium and phosphate were 2.27 ± 0.13 mmol/l and 1.28 ± 0.18 mmol/l, respectively. Eleven (5%) of the children had hypovitaminosis D, 23 (10.5%) had hypocalcaemia and 12 (5.5%) had hypophosphataemia. Factors found to be significantly associated with hypovitaminosis D included low consumption of milk and the use of a hijab veil, while malnutrition (both undernutrition and overnutrition) was significantly associated with hypocalcaemia. CONCLUSION: The prevalence levels of hypovitaminosis D and hypophosphataemia were low, while hypocalcaemia was more common. Low milk consumption and use of a hijab veil were risk factors for hypovitaminosis D, while malnutrition was a risk factor for hypocalcaemia. Malnourished children, especially overnourished ones, should be routinely screened for hypocalcaemia because of its high prevalence among them.
Assuntos
Cálcio , Fosfatos , Deficiência de Vitamina D , Vitamina D , Humanos , Nigéria/epidemiologia , Feminino , Prevalência , Masculino , Estudos Transversais , Deficiência de Vitamina D/epidemiologia , Fatores de Risco , Lactente , Cálcio/sangue , Cálcio/deficiência , Fosfatos/sangue , Vitamina D/sangue , Pré-EscolarRESUMO
Background: Zinc (Zn) content is of great importance in healthy human diet, crop productivity and stress tolerance in soils with zinc deficiency. The genes used to increase yield per unit area such as semi-dwarf 1 (sdw1) is commonly considered to reduce mineral content of grain. Methods: In the present study, influence of sdw1.d, a widely used allele for short plant height in barley breeding, on zinc accumulation and tolerance to zinc deficiency were investigated. A near isogenic line of sdw1.d allele, its recurrent parent Tokak 157/37 and donor parent Triumph were grown in zinc-deficient and-sufficient hydroponic cultures. Two experiments were conducted until heading stage and physiological maturity. Results: In zinc-deficient conditions, sdw1.d allele increased shoot dry weight by 112.4 mg plant-1, shoot Zn concentration by 0.9 ppm, but decreased root Zn concentration by 6.6 ppm. It did not affect grain characteristics, but increased grain Zn content. In zinc-sufficient conditions, sdw1.d allele increased shoot Zn content, and decreased root Zn content. sdw1.d did not affect grain weight but increased grain Zn concentration by about 30% under zinc-sufficient conditions. The results showed that sdw1.d allele has no negative effect on tolerance to zinc deficiency, and even promotes tolerance to zinc deficiency by more Zn translocation. It was revealed that sdw1.d allele improves Zn accumulation under both zinc-deficient and zinc-sufficient condition. The sdw1.d allele could contribute to solving the problems in plant growth and development caused by zinc-deficiency via improving tolerance to zinc-deficiency. It could also provide a better Zn biofortification.
Assuntos
Alelos , Hordeum , Zinco , Zinco/deficiência , Zinco/metabolismo , Hordeum/genética , Hordeum/metabolismo , Raízes de Plantas/metabolismo , Raízes de Plantas/genética , Melhoramento VegetalRESUMO
Atherosclerosis is a chronic inflammatory condition of the arteries and represents the primary cause of various cardiovascular diseases. Despite ongoing progress, finding effective anti-inflammatory therapeutic strategies for atherosclerosis remains a challenge. Here, we assessed the potential of molecular magnetic resonance imaging (MRI) to visualize the effects of 01BSUR, an anti-interleukin-1ß monoclonal antibody, for treating atherosclerosis in a murine model. Male apolipoprotein E-deficient mice were divided into a therapy group (01BSUR, 2 × 0.3 mg/kg subcutaneously, n = 10) and control group (no treatment, n = 10) and received a high-fat diet for eight weeks. The plaque burden was assessed using an elastin-targeted gadolinium-based contrast probe (0.2 mmol/kg intravenously) on a 3 T MRI scanner. T1-weighted imaging showed a significantly lower contrast-to-noise (CNR) ratio in the 01BSUR group (pre: 3.93042664; post: 8.4007067) compared to the control group (pre: 3.70679168; post: 13.2982156) following administration of the elastin-specific MRI probe (p < 0.05). Histological examinations demonstrated a significant reduction in plaque size (p < 0.05) and a significant decrease in plaque elastin content (p < 0.05) in the treatment group compared to control animals. This study demonstrated that 01BSUR hinders the progression of atherosclerosis in a mouse model. Using an elastin-targeted MRI probe, we could quantify these therapeutic effects in MRI.
Assuntos
Aterosclerose , Elastina , Interleucina-1beta , Imageamento por Ressonância Magnética , Animais , Elastina/metabolismo , Aterosclerose/diagnóstico por imagem , Aterosclerose/tratamento farmacológico , Aterosclerose/metabolismo , Camundongos , Interleucina-1beta/metabolismo , Imageamento por Ressonância Magnética/métodos , Masculino , Modelos Animais de Doenças , Meios de Contraste/química , Apolipoproteínas E/deficiência , Placa Aterosclerótica/diagnóstico por imagem , Placa Aterosclerótica/tratamento farmacológico , Gadolínio/química , Gadolínio/farmacologia , Anticorpos Monoclonais , Dieta HiperlipídicaRESUMO
BACKGROUND: Irritable bowel syndrome (IBS) is a common disease with unknown etiology. Poor dietary intake with nutritional deficiency and overweight have been described to increase the risk of IBS. The aim of the present study was to compare weight and circulating levels of micronutrients in IBS compared with healthy controls. DESIGN: Cross-sectional study. METHODS: Patients diagnosed with IBS and healthy volunteers were recruited. Participants had to complete a dietary diary book and the questionnaires Rome IV, IBS-severity scoring system (IBS-SSS), and visual analog scale for IBS (VAS-IBS). Weight and height were measured, and blood samples were drawn. C-reactive protein (CRP), cobalamin, folate, iron, total iron-binding capacity (TIBC), and 25-hydroxy (25-OH) vitamin D were analyzed. Differences were calculated between groups and generalized linear model for regressions was adjusted for false discovery rate (FDR). RESULTS: IBS patients (n = 260) were elder than controls (n = 50) (44.00 (33.25-56.00) vs. 37.85 (30.18-45.48) years; p = 0.012). After adjustment for age, both weight (ß: 5.880; 95% CI: 1.433-10.327; p = 0.010, FDR = 0.020) and body mass index (BMI) (ß: 2.02; 95% CI: 0.68-3.36; p = 0.003, FDR = 0.012) were higher in patients. Among IBS participants, 48.1% were overweight/obese compared with 26.0% in controls (p = 0.007). Diarrhea-predominated IBS had highest weight (p < 0.001) and BMI (p = 0.077). CRP and cobalamin were higher in patients than controls (p = 0.010 vs. p = 0.007), whereas folate was highest in controls (p = 0.001). IBS patients had lower intake of vegetables (p = 0.026), dairy products (p = 0.004), and cereals (p = 0.010) compared with controls. Despite 21.5% of IBS patients were taking vitamin D supplements, 23.65% of them had vitamin D levels below 50 nmol/L, compared with 26.0% observed in the control group (p = 0.720). Vitamin D levels were lower in overweight than in normal weight IBS patients (60 (48-73) nmol/L vs. 65 (53-78) nmol/L, p = 0.022). Vitamin D correlated with cobalamin and folate but correlated inversely with TIBC and BMI. IBS patients had a high degree of gastrointestinal and extraintestinal symptoms, which were inversely associated with iron levels. Extraintestinal symptoms were associated with increased BMI. CONCLUSION: IBS patients were often overweight or obese, with low vitamin D levels. High burden of extraintestinal symptoms were associated with overweight and lower iron levels. REGISTRATION: ClinicalTrials.gov, NCT05192603 (Date of registration 11/29/2021) and NCT03306381 (Date of registration 09/18/2017), respectively.
Assuntos
Síndrome do Intestino Irritável , Sobrepeso , Deficiência de Vitamina D , Humanos , Síndrome do Intestino Irritável/sangue , Síndrome do Intestino Irritável/etiologia , Estudos Transversais , Feminino , Masculino , Adulto , Pessoa de Meia-Idade , Sobrepeso/complicações , Sobrepeso/sangue , Deficiência de Vitamina D/complicações , Deficiência de Vitamina D/sangue , Deficiência de Vitamina D/epidemiologia , Estudos de Casos e Controles , Vitamina D/sangue , Vitamina D/análogos & derivados , Proteína C-Reativa/análise , Índice de Massa Corporal , Micronutrientes/deficiência , Micronutrientes/sangueRESUMO
Subretinal fibrosis permanently impairs the vision of patients with neovascular age-related macular degeneration. Despite emerging evidence revealing the association between disturbed metabolism in retinal pigment epithelium (RPE) and subretinal fibrosis, the underlying mechanism remains unclear. In the present study, single-cell RNA sequencing revealed, prior to subretinal fibrosis, genes in mitochondrial fatty acid oxidation are downregulated in the RPE lacking very low-density lipoprotein receptor (VLDLR), especially the rate-limiting enzyme carnitine palmitoyltransferase 1A (CPT1A). We found that overexpression of CPT1A in the RPE of Vldlr-/- mice suppresses epithelial-to-mesenchymal transition and fibrosis. Mechanistically, TGFß2 induces fibrosis by activating a Warburg-like effect, i.e. increased glycolysis and decreased mitochondrial respiration through ERK-dependent CPT1A degradation. Moreover, VLDLR blocks the formation of the TGFß receptor I/II complex by interacting with unglycosylated TGFß receptor II. In conclusion, VLDLR suppresses fibrosis by attenuating TGFß2-induced metabolic reprogramming, and CPT1A is a potential target for treating subretinal fibrosis.
Assuntos
Carnitina O-Palmitoiltransferase , Fibrose , Degeneração Macular , Mitocôndrias , Receptores de LDL , Epitélio Pigmentado da Retina , Fator de Crescimento Transformador beta2 , Epitélio Pigmentado da Retina/metabolismo , Epitélio Pigmentado da Retina/patologia , Animais , Degeneração Macular/metabolismo , Degeneração Macular/patologia , Degeneração Macular/genética , Camundongos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Carnitina O-Palmitoiltransferase/metabolismo , Carnitina O-Palmitoiltransferase/genética , Carnitina O-Palmitoiltransferase/deficiência , Fator de Crescimento Transformador beta2/metabolismo , Fator de Crescimento Transformador beta2/genética , Receptores de LDL/metabolismo , Receptores de LDL/genética , Receptores de LDL/deficiência , Humanos , Camundongos Knockout , Transição Epitelial-Mesenquimal , Metabolismo Energético , Camundongos Endogâmicos C57BLRESUMO
The liver is vulnerable to various hepatotoxins, including carbon tetrachloride (CCl4), which induces oxidative stress and apoptosis by producing reactive oxygen species (ROS) and activating the mitogen-activated protein kinase (MAPK) pathway. Cereblon (CRBN), a multifunctional protein implicated in various cellular processes, functions in the pathogenesis of various diseases; however, its function in liver injury remains unknown. We established a CRBN-knockout (KO) HepG2 cell line and examined its effect on CCl4-induced hepatocellular damage. CRBN-KO cells exhibited reduced sensitivity to CCl4-induced cytotoxicity, as evidenced by decreased levels of apoptosis markers, such as cleaved caspase-3, and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities. CRBN deficiency enhanced antioxidant defense, with increased superoxide dismutase activity and glutathione ratios (GSH/GSSG), as well as reduced pro-inflammatory cytokine expression. Mechanistically, the protective effects of CRBN deficiency appeared to involve the attenuation of the MAPK-mediated pathways, particularly through decreased phosphorylation of JNK and ERK. Overall, these results suggest the crucial role of CRBN in mediating the hepatocellular response to oxidative stress and inflammation triggered by CCl4 exposure, offering potential clinical implications for liver injury in a wide range of liver diseases.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Apoptose , Tetracloreto de Carbono , Doença Hepática Induzida por Substâncias e Drogas , Estresse Oxidativo , Humanos , Apoptose/efeitos dos fármacos , Células Hep G2 , Tetracloreto de Carbono/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Estresse Oxidativo/efeitos dos fármacos , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/deficiência , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Espécies Reativas de Oxigênio/metabolismoAssuntos
Deficiência de Magnésio , Magnésio , Humanos , Proteínas de Transporte de Cátions/deficiência , Proteínas de Transporte de Cátions/genética , Absorção Intestinal , Rim/metabolismo , Rim/fisiopatologia , Magnésio/sangue , Magnésio/metabolismo , Magnésio/uso terapêutico , Deficiência de Magnésio/sangue , Deficiência de Magnésio/tratamento farmacológico , Deficiência de Magnésio/genética , Deficiência de Magnésio/fisiopatologia , Síndrome do Intestino Curto/sangue , Síndrome do Intestino Curto/complicações , Síndrome do Intestino Curto/genética , Síndrome do Intestino Curto/metabolismoRESUMO
Zika virus, a mosquito-borne arbovirus, has repeatedly caused large pandemics with symptoms worsening from mild and self-limiting diseases to Guillain-Barré syndrome in adults and fetal microcephaly in newborns. In recent years, Zika virus diseases have posed a serious threat to human health. The shortage of susceptible small animal models makes it difficult to study pathogenic mechanisms and evaluate potential therapies for Zika virus infection. Therefore, we chose immunocompromised mice (AG129 mice) deficient in IFN-α/ß and IFN-γ receptors, which can abolish the innate immune system that prevents Zika virus infection early. AG129 mice were infected with the Zika virus, and this mouse model exhibited replication dynamics, tissue tropism, pathological lesion and immune activation of the Zika virus. Our results suggest that the inoculum dose of Zika virus can affect the viral replication dynamics, cytokine responses and survival rate in AG129 mice. By testing the potential antiviral drug favipiravir, several critical indicators, including replication dynamics and survival rates, were identified in AG129 mice after Zika virus infection. It is suggested that the model is reliable for drug evaluation. In brief, this model provides a potential platform for studies of the infectivity, virulence, and pathogenesis of the Zika virus. Moreover, the development of an accessible mouse model of Zika virus infection will expedite the research and deployment of therapeutics and vaccines.
Assuntos
Citocinas , Modelos Animais de Doenças , Hospedeiro Imunocomprometido , Replicação Viral , Infecção por Zika virus , Zika virus , Animais , Zika virus/imunologia , Zika virus/patogenicidade , Infecção por Zika virus/imunologia , Infecção por Zika virus/virologia , Replicação Viral/efeitos dos fármacos , Camundongos , Citocinas/metabolismo , Taxa de Sobrevida , Receptor de Interferon alfa e beta/genética , Antivirais/farmacologia , Antivirais/uso terapêutico , Receptores de Interferon/deficiência , Receptores de Interferon/genética , Receptores de Interferon/metabolismo , Receptor de Interferon gama , Células VeroRESUMO
Intestinal stem cells at the crypt divide and give rise to progenitor cells that proliferate and differentiate into various mature cell types in the transit-amplifying (TA) zone. Here, we showed that the transcription factor ARID3A regulates intestinal epithelial cell proliferation and differentiation at the TA progenitors. ARID3A forms an expression gradient from the villus tip to the upper crypt mediated by TGF-ß and WNT. Intestinal-specific deletion of Arid3a reduces crypt proliferation, predominantly in TA cells. Bulk and single-cell transcriptomic analysis shows increased enterocyte and reduced secretory differentiation in the Arid3a cKO intestine, accompanied by enriched upper-villus gene signatures of both cell lineages. We find that the enhanced epithelial differentiation in the Arid3a-deficient intestine is caused by increased binding and transcription of HNF1 and HNF4. Finally, we show that loss of Arid3a impairs irradiation-induced regeneration with sustained cell death and reprogramming. Our findings imply that Arid3a functions to fine-tune the proliferation-differentiation dynamics at the TA progenitors, which are essential for injury-induced regeneration.
Assuntos
Diferenciação Celular , Proliferação de Células , Proteínas de Ligação a DNA , Fator 1-alfa Nuclear de Hepatócito , Mucosa Intestinal , Camundongos Knockout , Regeneração , Fatores de Transcrição , Animais , Mucosa Intestinal/metabolismo , Mucosa Intestinal/citologia , Camundongos , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/deficiência , Fator 1-alfa Nuclear de Hepatócito/metabolismo , Fator 1-alfa Nuclear de Hepatócito/genética , Fator 4 Nuclear de Hepatócito/metabolismo , Fator 4 Nuclear de Hepatócito/genética , Células-Tronco/metabolismo , Células-Tronco/citologia , Camundongos Endogâmicos C57BL , Fator de Crescimento Transformador beta/metabolismo , Células Epiteliais/metabolismo , Enterócitos/metabolismo , Enterócitos/citologiaRESUMO
Pyruvate kinase (PK) deficiency, a rare, congenital haemolytic anaemia caused by mutations in the PKLR gene, is associated with many clinical manifestations, but the full disease burden has yet to be characterised. The Peak Registry (NCT03481738) is an observational, longitudinal registry of adult and paediatric patients with PK deficiency. Here, we described comorbidities and complications in these patients by age at most recent visit and PKLR genotype. As of 13 May 2022, 241 patients were included in the analysis. In total, 48.3% had undergone splenectomy and 50.5% had received chelation therapy. History of iron overload (before enrolment/during follow-up) was common (52.5%), even in never-transfused patients (20.7%). Neonatal complications and symptoms included jaundice, splenomegaly and hepatomegaly, with treatment interventions required in 41.5%. Among adults, osteopenia/osteoporosis occurred in 19.0% and pulmonary hypertension in 6.7%, with median onset ages of 37, 33 and 22 years, respectively. Biliary events and bone health problems were common across PKLR genotypes. Among 11 patients who had thromboembolic events, eight had undergone prior splenectomy. Patients with PK deficiency may have many complications, which can occur early in and throughout life. Awareness of their high disease burden may help clinicians better provide appropriate monitoring and management of these patients.
Assuntos
Anemia Hemolítica Congênita não Esferocítica , Piruvato Quinase , Erros Inatos do Metabolismo dos Piruvatos , Sistema de Registros , Humanos , Piruvato Quinase/deficiência , Piruvato Quinase/genética , Masculino , Feminino , Adulto , Criança , Anemia Hemolítica Congênita não Esferocítica/genética , Anemia Hemolítica Congênita não Esferocítica/epidemiologia , Erros Inatos do Metabolismo dos Piruvatos/genética , Erros Inatos do Metabolismo dos Piruvatos/epidemiologia , Adolescente , Pré-Escolar , Lactente , Comorbidade , Pessoa de Meia-Idade , Esplenectomia , Adulto Jovem , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/genética , Hipertensão Pulmonar/epidemiologia , Sobrecarga de Ferro/etiologia , Sobrecarga de Ferro/epidemiologia , Doenças Ósseas Metabólicas/etiologia , Doenças Ósseas Metabólicas/epidemiologia , Recém-NascidoRESUMO
The clinical penetrance of infectious diseases varies considerably among patients with inborn errors of immunity (IEI), even for identical genetic defects. This variability is influenced by pathogen exposure, healthcare access and host-environment interactions. We describe here a patient in his thirties who presented with epidermodysplasia verruciformis (EV) due to infection with a weakly virulent beta-papillomavirus (HPV38) and CD4+ T-cell lymphopenia. The patient was born to consanguineous parents living in the United States. Exome sequencing identified a previously unknown biallelic STK4 stop-gain mutation (p.Trp425X). The patient had no relevant history of infectious disease during childhood other than mild wart-like lesion on the skin, but he developed diffuse large B-cell lymphoma (DLBCL) and EBV viremia with a low viral load in his thirties. Despite his low CD4+ T-cell count, the patient had normal counts of CD3+ cells, predominantly double-negative T cells (67.4%), which turned out to be Vδ2+ γδ T cells. γδ T-cell expansion has frequently been observed in the 33 reported cases with STK4 deficiency. The Vδ2 γδ T cells of this STK4-deficient patient are mostly CD45RA-CD27+CCR7+ central memory γδT cells, and their ability to proliferate in response to T-cell activation was impaired, as was that of CD4+ T cells. In conclusion, γδ T-cell expansion may act as a compensatory mechanism to combat viral infection, providing immune protection in immunocompromised individuals.
Assuntos
Epidermodisplasia Verruciforme , Proteínas Serina-Treonina Quinases , Humanos , Epidermodisplasia Verruciforme/genética , Epidermodisplasia Verruciforme/diagnóstico , Masculino , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/deficiência , Adulto , Receptores de Antígenos de Linfócitos T gama-delta/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/deficiência , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/etiologia , Linfoma Difuso de Grandes Células B/imunologia , Linfoma Difuso de Grandes Células B/diagnóstico , Mutação/genética , Infecções por Vírus Epstein-Barr/imunologia , Infecções por Vírus Epstein-Barr/genética , Infecções por Vírus Epstein-Barr/complicações , Linfócitos Intraepiteliais/imunologia , ConsanguinidadeRESUMO
Adverse intrauterine conditions may cause fetal growth restriction (FGR), a pregnancy complication frequently linked to perinatal morbidity and mortality. Although many studies have focused on FGR, the pathophysiological processes underlying this disorder are complex and incompletely understood. We have recently determined that galectin-3 (gal-3), a ß-galactoside-binding protein, regulates pregnancy-associated processes, including uterine receptibility, maternal vascular adaptation and placentation. Because gal-3 is expressed at both sides of the maternal-fetal interface, we unraveled the contribution of maternal- and paternal-derived gal-3 on fetal-placental development in the prenatal window and its effects on the post-natal period. Deficiency of maternal gal-3 induced maternal gut microbiome dysbiosis, resulting in a sex-specific fetal growth restriction mainly observed in female fetuses and offspring. In addition, poor placental metabolic adaptions (characterized by decreased trophoblast glycogen content and insulin-like growth factor 2 (Igf2) gene hypomethylation) were only associated with a lack of maternal-derived gal-3. Paternal gal-3 deficiency caused compromised vascularization in the placental labyrinth without affecting fetal growth trajectory. Thus, maternal-derived gal-3 may play a key role in fetal-placental development through the gut-placenta axis.
Assuntos
Retardo do Crescimento Fetal , Galectina 3 , Placenta , Retardo do Crescimento Fetal/metabolismo , Retardo do Crescimento Fetal/genética , Gravidez , Feminino , Animais , Placenta/metabolismo , Camundongos , Galectina 3/metabolismo , Galectina 3/deficiência , Galectina 3/genética , Masculino , Microbioma Gastrointestinal , Camundongos Endogâmicos C57BL , Humanos , Desenvolvimento Fetal , Fator de Crescimento Insulin-Like II/metabolismo , Fator de Crescimento Insulin-Like II/genética , Fator de Crescimento Insulin-Like II/deficiência , Trofoblastos/metabolismoRESUMO
Histone lysine methyltransferase 2D (KMT2D) is the most frequently mutated epigenetic modifier in head and neck squamous cell carcinoma (HNSCC). However, the role of KMT2D in HNSCC tumorigenesis and whether its mutations confer any therapeutic vulnerabilities remain unknown. Here we show that KMT2D deficiency promotes HNSCC growth through increasing glycolysis. Additionally, KMT2D loss decreases the expression of Fanconi Anemia (FA)/BRCA pathway genes under glycolytic inhibition. Mechanistically, glycolytic inhibition facilitates the occupancy of KMT2D to the promoter/enhancer regions of FA genes. KMT2D loss reprograms the epigenomic landscapes of FA genes by transiting their promoter/enhancer states from active to inactive under glycolytic inhibition. Therefore, combining the glycolysis inhibitor 2-DG with DNA crosslinking agents or poly (ADP-ribose) polymerase (PARP) inhibitors preferentially inhibits tumor growth of KMT2D-deficient mouse HNSCC and patient-derived xenografts (PDXs) harboring KMT2D-inactivating mutations. These findings provide an epigenomic basis for developing targeted therapies for HNSCC patients with KMT2D-inactivating mutations.
Assuntos
Glicólise , Carcinoma de Células Escamosas de Cabeça e Pescoço , Animais , Humanos , Camundongos , Glicólise/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/genética , Proteína BRCA1/metabolismo , Proteína BRCA1/genética , Proteína BRCA1/deficiência , Proteína BRCA2/genética , Proteína BRCA2/metabolismo , Proteína BRCA2/deficiência , Histona-Lisina N-Metiltransferase/metabolismo , Histona-Lisina N-Metiltransferase/genética , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/patologia , Anemia de Fanconi/genética , Anemia de Fanconi/metabolismo , Regulação Neoplásica da Expressão Gênica , Ensaios Antitumorais Modelo de Xenoenxerto , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Feminino , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Transdução de Sinais , Regiões Promotoras Genéticas/genética , Proteína de Leucina Linfoide-MieloideRESUMO
Biallelic loss-of-function variants in the IYD gene cause hypothyroidism resulting from iodine wasting. We describe 8 patients (from 4 families in which the parents are first cousins) who are homozygous for a variant in IYD (including a novel missense deleterious variant, c.791C>T [P264L], in 1 family). Seven patients presented between 5 and 16 years of age with a large goiter, overt hypothyroidism, and a high serum thyroglobulin. The goiter subsided with levothyroxine therapy in most. Upon stopping levothyroxine in 5 patients, goiter and hypothyroidism reappeared in 3. In these 3 patients, a rising serum thyroglobulin concentration preceded hypothyroidism and goiter and urinary iodine excretion was low. In patients who remained euthyroid, urinary iodine was normal. In conclusion, these patients bearing biallelic pathogenic variants in IYD developed a large goiter, a high serum thyroglobulin, and overt hypothyroidism when their iodine intake was low.
Assuntos
Bócio , Hipotireoidismo , Linhagem , Tiroxina , Humanos , Feminino , Masculino , Adolescente , Hipotireoidismo/genética , Criança , Pré-Escolar , Tiroxina/uso terapêutico , Bócio/genética , Tireoglobulina/genética , Iodo/deficiência , Alelos , Mutação de Sentido Incorreto , SimportadoresRESUMO
BACKGROUND: Microglia and infiltrated macrophages (M/M) are integral components of the innate immune system that play a critical role in facilitating brain repair after ischemic stroke (IS) by clearing cell debris. Novel therapeutic strategies for IS therapy involve modulating M/M phenotype shifting. This study aims to elucidate the pivotal role of S100A9 in M/M and its downstream STAT6/PPARγ signaling pathway in neuroinflammation and phagocytosis after IS. METHODS: In the clinical study, we initially detected the expression pattern of S100A9 in monocytes from patients with acute IS and investigated its association with the long-term prognosis. In the in vivo study, we generated the S100A9 conditional knockout (CKO) mice and compared the stroke outcomes with the control group. We further tested the S100A9-specific inhibitor paqunimod (PQD), for its pharmaceutical effects on stroke outcomes. Transcriptomics and in vitro studies were adopted to explore the mechanism of S100A9 in modulating the M/M phenotype, which involves the regulation of the STAT6/PPARγ signaling pathway. RESULTS: S100A9 was predominantly expressed in classical monocytes and was correlated with unfavorable outcomes in patients of IS. S100A9 CKO mitigated infarction volume and white matter injury, enhanced cerebral blood flow and functional recovery, and prompted anti-inflammation phenotype and efferocytosis after tMCAO. The STAT6/PPARγ pathway, an essential signaling cascade involved in immune response and inflammation, might be the downstream target mediated by S100A9 deletion, as evidenced by the STAT6 phosphorylation inhibitor AS1517499 abolishing the beneficial effect of S100A9 inhibition in tMCAO mice and cell lines. Moreover, S100A9 inhibition by PQD treatment protected against neuronal death in vitro and brain injuries in vivo. CONCLUSION: This study provides evidence for the first time that S100A9 in classical monocytes could potentially be a biomarker for predicting IS prognosis and reveals a novel therapeutic strategy for IS. By demonstrating that S100A9-mediated M/M polarization and phagocytosis can be reversed by S100A9 inhibition in a STAT6/PPARγ pathway-dependent manner, this study opens up new avenues for drug development in the field.
Assuntos
Calgranulina B , AVC Isquêmico , Macrófagos , Camundongos Knockout , Microglia , PPAR gama , Fator de Transcrição STAT6 , Transdução de Sinais , Animais , Calgranulina B/genética , Calgranulina B/metabolismo , Fator de Transcrição STAT6/metabolismo , Fator de Transcrição STAT6/deficiência , Fator de Transcrição STAT6/genética , Microglia/metabolismo , Microglia/efeitos dos fármacos , Camundongos , Macrófagos/metabolismo , Macrófagos/efeitos dos fármacos , Masculino , PPAR gama/metabolismo , PPAR gama/genética , Humanos , AVC Isquêmico/metabolismo , AVC Isquêmico/genética , AVC Isquêmico/patologia , Transdução de Sinais/fisiologia , Transdução de Sinais/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Feminino , Pessoa de Meia-Idade , IdosoRESUMO
RATIONALE: SMARCA4-deficient undifferentiated tumor (SMARCA4-UT) is a recently reported rare malignancy that can rapidly metastasize to tissues and organs throughout the body. The tumor is characterized by a lower response to platinum-based chemotherapy. More regrettably, the mean survival time of patients with this disease after diagnosis is only 4 to 7 months. PATIENT CONCERNS: A 58-year-old man was admitted to a hospital for fatigue, sudden syncope, and a mass-like shadow of his left upper lobe demonstrated by a pulmonary computed tomographic. Based on his subsequent clinical and pathological features, he was highly suspected of SMARCA4-UT. DIAGNOSES: Combined with next-generation sequencing genetic testing and immunohistochemical examination results, the patient was diagnosed with SMARCA4-UT. INTERVENTIONS: The patient received a left upper lobectomy and lymph node dissection, four-course chemotherapy divided into 8 sessions with the use of paclitaxel simply, and a proper post-discharge self-care. OUTCOMES: The patient's operation and chemotherapy were all successful and he maintained a high quality of life after surgery that far exceeded his predicted survival. LESSONS: Early diagnosis, higher education level, attention to the disease and complications, reducing chemotherapy damage, adequate nutrient intake, relieving symptoms, controlling depression, and maintaining immunity and the ability to perform activities of daily living may all be the positive factors that can prolong the survival of patients with SMARCA4-UT.
Assuntos
DNA Helicases , Neoplasias Pulmonares , Qualidade de Vida , Fatores de Transcrição , Humanos , Masculino , Pessoa de Meia-Idade , DNA Helicases/genética , DNA Helicases/deficiência , Fatores de Transcrição/genética , Proteínas Nucleares/genética , Proteínas Nucleares/deficiência , PneumonectomiaRESUMO
BACKGROUND: Deoxyribonuclease 2 (DNase II) plays a key role in clearing cytoplasmic double-stranded DNA (dsDNA). Deficiency of DNase II leads to DNA accumulation in the cytoplasm. Persistent dsDNA in neurons is an early pathological hallmark of senescence and neurodegenerative diseases including Alzheimer's disease (AD). However, it is not clear how DNase II and neuronal cytoplasmic dsDNA influence neuropathogenesis. Tau hyperphosphorylation is a key factor for the pathogenesis of AD. The effect of DNase II and neuronal cytoplasmic dsDNA on neuronal tau hyperphosphorylation remains unclarified. METHODS: The levels of neuronal DNase II and dsDNA in WT and Tau-P301S mice of different ages were measured by immunohistochemistry and immunolabeling, and the levels of DNase II in the plasma of AD patients were measured by ELISA. To investigate the impact of DNase II on tauopathy, the levels of phosphorylated tau, phosphokinase, phosphatase, synaptic proteins, gliosis and proinflammatory cytokines in the brains of neuronal DNase II-deficient WT mice, neuronal DNase II-deficient Tau-P301S mice and neuronal DNase II-overexpressing Tau-P301S mice were evaluated by immunolabeling, immunoblotting or ELISA. Cognitive performance was determined using the Morris water maze test, Y-maze test, novel object recognition test and open field test. RESULTS: The levels of DNase II were significantly decreased in the brains and the plasma of AD patients. DNase II also decreased age-dependently in the neurons of WT and Tau-P301S mice, along with increased dsDNA accumulation in the cytoplasm. The DNA accumulation induced by neuronal DNase II deficiency drove tau phosphorylation by upregulating cyclin-dependent-like kinase-5 (CDK5) and calcium/calmodulin activated protein kinase II (CaMKII) and downregulating phosphatase protein phosphatase 2A (PP2A). Moreover, DNase II knockdown induced and significantly exacerbated neuron loss, neuroinflammation and cognitive deficits in WT and Tau-P301S mice, respectively, while overexpression of neuronal DNase II exhibited therapeutic benefits. CONCLUSIONS: DNase II deficiency and cytoplasmic dsDNA accumulation can initiate tau phosphorylation, suggesting DNase II as a potential therapeutic target for tau-associated disorders.