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Increasing evidence shows the oncogenic function of FAM83D in human cancer, but how FAM83D exerts its oncogenic function remains largely unclear. Here, we investigated the importance of FAM83D/FBXW7 interaction in breast cancer (BC). We systematically mapped the FBXW7-binding sites on FAM83D through a comprehensive mutational analysis together with co-immunoprecipitation assay. Mutations at the FBXW7-binding sites on FAM83D led to that FAM83D lost its capability to promote the ubiquitination and proteasomal degradation of FBXW7; cell proliferation, migration, and invasion in vitro; and tumor growth and metastasis in vivo, indicating that the FBXW7-binding sites on FAM83D are essential for its oncogenic functions. A meta-evaluation of FAM83D revealed that the prognostic impact of FAM83D was independent on molecular subtypes. The higher expression of FAM83D has poorer prognosis. Moreover, high expression of FAM83D confers resistance to chemotherapy in BCs, which is experimentally validated in vitro. We conclude that identification of FBXW7-binding sites on FAM83D not only reveals the importance for FAM83D oncogenic function, but also provides valuable insights for drug target.
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Neoplasias da Mama , Proteínas de Ciclo Celular , Humanos , Feminino , Proteína 7 com Repetições F-Box-WD/genética , Proteína 7 com Repetições F-Box-WD/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Prognóstico , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismoRESUMO
BACKGROUND: Hutchinson-Gilford progeria syndrome (HGPS) and progeroid laminopathies (PL) are extremely rare genetic diseases with extremely poor prognoses. This study aims to investigate the epidemiological and genotypic characteristics of patients with HGPS/PL in China. METHODS: Using a cross-sectional study design, general characteristics and genotypic data of 46 patients with HGPS/PL from 17 provinces in China were analyzed. RESULTS: Among the 46 patients with HGPS/PL, 20 patients are HGPS, and the rest are PL; the identified total prevalence of HGPS/PL is 1/23 million. Among 42 patients with gene reports, 3 carried compound heterozygous mutations in the ZMPSTE24 while the other 39 carried LMNA mutations. Among PL, LMNA c.1579 C > T homozygous mutation was the most common. The onset of classic genotype HGPS is skin sclerosis in the first month after birth. The primary clinical manifestations of PL patients include skin abnormalities, growth retardation, and joint stiffness. The median age of onset for PL was 12 (6,12) months. CONCLUSIONS: In China, the identified total prevalence of HGPS/PL is 1/23 million. 92.8% of the genetic mutations of HGPS/PL were located in LMNA, and the rest in ZMPSTE24. Most patients of HGPS/PL have skin abnormalities as the earliest manifestation. Compared to PL, the classic genotype HGPS starts earlier. IMPACT STATEMENT: Hutchinson-Gilford progeria syndrome (HGPS) and progeroid laminopathies (PL) are extremely rare genetic diseases with extremely poor prognoses. To date, there is a paucity of epidemiological data related to HGPS/PL in China. This study first examined the genotypic, phenotypic, and prevalence characteristics of 40-50% of the cases of HGPS/PL in mainland China through a collaborative international registry effort. In China, the identified total prevalence of HGPS/PL is 1/23 million. 92.8% of the genetic mutations of HGPS/PL are located in LMNA. LMNA c.1579 C > T homozygous mutations are the most common form of gene mutations among the Chinese PL population.
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Lamina Tipo A , Proteínas de Membrana , Mutação , Progéria , Humanos , Progéria/genética , Progéria/epidemiologia , China/epidemiologia , Masculino , Feminino , Lamina Tipo A/genética , Estudos Transversais , Pré-Escolar , Lactente , Prevalência , Criança , Proteínas de Membrana/genética , Metaloendopeptidases/genética , Genótipo , Adolescente , Laminopatias/genética , Laminopatias/epidemiologia , FenótipoRESUMO
BACKGROUND: Calcification is common in advanced atheromatous plaque, but its clinical significance remains unclear. This study aimed to assess the prevalence of plaque calcification in the moderate-to-severe internal carotid artery stenosis and investigate its relationship with ipsilateral ischemia. METHODS: The retrospective study included 178 patients detected with proximal internal carotid artery (pICA) stenosis of ≥ 50% on multidetector computed tomography at Zhejiang Hospital from January 2019 to March 2023. Association between plaque calcification characteristics (calcification thickness, position, type, circumferential extent, calcium volume and calcium score) and ipsilateral cerebrovascular events was analyzed. RESULTS: The 178 patients (mean age 71.24 ± 10.02 years, 79.78% males) had 224 stenosed pICAs overall. Plaque calcification was noted in 200/224 (89.29%) arteries. Calcification rates were higher in older age-groups. Calcification volume (r = 0.219, p < 0.001) and calcification score (r = 0.230, p < 0.001) were correlated with age. Ipsilateral ischemic events were significantly more common in the noncalcification group than in the calcification group (χ2 = 4.160, p = 0.041). The most common calcification type was positive rim sign calcification (87/200, 43.50%), followed by bulky calcification (66/200, 33.00%); both were significantly associated with ischemic events (χ2 = 10.448, p = 0.001 and χ2 = 4.552, p = 0.033, respectively). Calcification position, thickness, and circumferential extent, and calcification volume and score, were not associated with ischemic events. In multivariate analysis, positive rim signs (OR = 2.795, 95%CI 1.182-6.608, p = 0.019) was an independent predictor of ischemic events. CONCLUSIONS: Plaque calcification in proximal internal carotid artery is common, and prevalence increases with age. Calcification characteristics could be predictive of ipsilateral ischemic events. The positive rim sign within plaque is a high-risk factor for a future ischemic event.
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Artéria Carótida Interna , Estenose das Carótidas , Humanos , Estenose das Carótidas/epidemiologia , Estenose das Carótidas/diagnóstico por imagem , Estudos Retrospectivos , Masculino , Feminino , Idoso , Prevalência , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Artéria Carótida Interna/diagnóstico por imagem , Artéria Carótida Interna/patologia , Calcificação Vascular/epidemiologia , Calcificação Vascular/diagnóstico por imagem , Calcificação Vascular/patologia , Placa Aterosclerótica/epidemiologia , Placa Aterosclerótica/diagnóstico por imagem , Placa Aterosclerótica/patologia , Calcinose/epidemiologia , Calcinose/diagnóstico por imagem , Calcinose/patologia , Tomografia Computadorizada Multidetectores/métodosRESUMO
BACKGROUND: Children with IgA Vasculitis (IgAV) may develop renal complications, which can impact their long-term prognosis. This study aimed to build a machine learning model to predict renal damage in children with IgAV and analyze risk factors for IgA Vasculitis with Nephritis (IgAVN). METHODS: 50 clinical indicators were collected from 217 inpatients at our hospital. Six machine learning algorithms-Logistic Regression, Linear Discriminant Analysis, K-Nearest Neighbor, Support Vector Machine, Decision Trees, and Random Forest-were utilized to select the model with the highest predictive performance. A simplified model was developed through feature importance ranking and validated by an additional cohort with 46 patients. RESULTS: The random forest model had the highest accuracy, precision, recall, F1 score, and area under the curve, with values of 0.91, 0.98, 0.70, 0.79 and 0.94, respectively. The top 11 features according to the importance ranking were anti-streptolysin O, corticosteroids therapy, antihistamine therapy, absolute eosinophil count, immunoglobulin E, anticoagulant therapy, C-reactive protein, prothrombin time, age at onset, D-dimer, recurrence of rash ≥ 3 times. A simplified model using these features demonstrated optimal performance with an accuracy of 84.2%, a sensitivity of 89.4%, and a specificity of 82.5% in external validation. Finally, we provided a web tool based on the simplified model, whose code was published on https://github.com/mulanruo/IgAVN_Prediction . CONCLUSION: The model based on the random forest algorithm demonstrates good performance in predicting renal damage in children with IgAV, providing a basis for early clinical diagnosis and decision-making.
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BACKGROUND: Previously, several studies have indicated that pediatric IgA nephropathy (IgAN) might be different from adult IgAN, and treatment strategies might be also different between pediatric IgAN and adult IgAN. METHODS: We analyzed two prospective cohorts established by pediatric and adult nephrologists, respectively. A comprehensive analysis was performed investigating the difference in clinical and pathological characteristics, treatment, and prognosis between children and adults with IgAN. RESULTS: A total of 1015 children and 1911 adults with IgAN were eligible for analysis. More frequent gross hematuria (88% vs. 20%, p < 0.0001) and higher proteinuria (1.8 vs. 1.3 g/d, p < 0.0001) were seen in children compared to adults. In comparison, the estimated glomerular filtration rate (eGFR) was lower in adults (80.4 vs. 163 ml/min/1.73 m2, p < 0.0001). Hypertension was more prevalent in adult patients. Pathologically, a higher proportion of M1 was revealed (62% vs. 39%, p < 0.0001) in children than in adults. S1 (62% vs. 28%, p < 0.0001) and T1-2 (34% vs. 8%, p < 0.0001) were more frequent in adults. Adjusted by proteinuria, eGFR, and hypertension, children were more likely to be treated with glucocorticoids than adults (87% vs. 45%, p < 0.0001). After propensity score matching, in IgAN with proteinuria > 1 g/d, children treated with steroids were 1.87 (95% CI 1.16-3.02, p = 0.01) times more likely to reach complete remission of proteinuria compared with adults treated with steroids. CONCLUSIONS: Children present significantly differently from adults with IgAN in clinical and pathological manifestations and disease progression. Steroid response might be better in children.
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Taxa de Filtração Glomerular , Glomerulonefrite por IGA , Proteinúria , Humanos , Glomerulonefrite por IGA/tratamento farmacológico , Glomerulonefrite por IGA/fisiopatologia , Glomerulonefrite por IGA/diagnóstico , Glomerulonefrite por IGA/patologia , Glomerulonefrite por IGA/complicações , Glomerulonefrite por IGA/terapia , Masculino , Feminino , Criança , Adulto , Proteinúria/etiologia , Proteinúria/diagnóstico , Adolescente , Estudos Prospectivos , Adulto Jovem , Prognóstico , Pessoa de Meia-Idade , Fatores Etários , Hematúria/etiologia , Hematúria/diagnóstico , Hipertensão/tratamento farmacológico , Hipertensão/epidemiologia , Hipertensão/diagnóstico , Rim/patologia , Rim/fisiopatologia , Progressão da Doença , Glucocorticoides/uso terapêuticoRESUMO
AIM: Saliva can reflect an individual's physiological status or susceptibility to systemic disease. However, little attention has been given to salivary analysis in children with idiopathic nephrotic syndrome (INS). We aimed to perform a comprehensive analysis of saliva from INS children. METHODS: A total of 18 children (9 children with INS and 9 normal controls) were recruited. Saliva was collected from each INS patient in the acute and remission phases. 16S rRNA gene sequencing, widely targeted metabolomics, and 4D-DIA proteomics were performed. RESULTS: Actinobacteria and Firmicutes were significantly enriched in the pretreatment group compared with the normal control group, while Bacteroidota and Proteobacteria were significantly decreased. A total of 146 metabolites were identified as significantly different between INS children before treatment and normal controls, which covers 17 of 23 categories. KEGG enrichment analysis revealed three significantly enriched pathways, including ascorbate and aldarate metabolism, pentose and glucuronate interconversions, and terpenoid backbone biosynthesis (P < 0.05). A total of 389 differentially expressed proteins were selected between INS children before treatment and normal controls. According to the KEGG and GO enrichment analyses of the KOGs, abnormal ribosome structure and function and humoral immune disorders were the most prominent differences between INS patients and normal controls in the proteomic analysis. CONCLUSION: Oral microbiota dysbiosis may modulate the metabolic profile of saliva in children with INS. It is hypothesized that children with INS might have "abnormal ribosome structure and function" and "humoral immune disorders".
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Disbiose , Multiômica , Síndrome Nefrótica , Saliva , Criança , Feminino , Humanos , Masculino , Estudos de Casos e Controles , Disbiose/diagnóstico , Disbiose/metabolismo , Disbiose/microbiologia , Metabolômica/métodos , Multiômica/métodos , Síndrome Nefrótica/microbiologia , Síndrome Nefrótica/metabolismo , Proteômica/métodos , RNA Ribossômico 16S/genética , Saliva/microbiologia , Saliva/metabolismoRESUMO
The transient receptor potential canonical 6 (TRPC6) channel, a nonselective cation channel that allows the passage of Ca2+, plays an important role in renal diseases. TRPC6 is activated by Ca2+ influx, oxidative stress, and mechanical stress. Studies have shown that in addition to glomerular diseases, TRPC6 can contribute to renal tubular disorders, such as acute kidney injury, renal interstitial fibrosis, and renal cell carcinoma (RCC). However, the tubule-specific physiological functions of TRPC6 have not yet been elucidated. Its pathophysiological role in ischemia/reperfusion (I/R) injury is debatable. Thus, TRPC6 may have dual roles in I/R injury. TRPC6 induces renal fibrosis and immune cell infiltration in a unilateral ureteral obstruction (UUO) mouse model. Additionally, TRPC6 overexpression may modify G2 phase transition, thus altering the DNA damage checkpoint, which can cause genomic instability and RCC tumorigenesis and can control the proliferation of RCC cells. This review highlights the importance of TRPC6 in various conditions of the renal tubular system. To better understand certain renal disorders and ultimately identify new therapeutic targets to improve patient care, the pathophysiology of TRPC6 must be clarified.
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Canal de Cátion TRPC6 , Humanos , Canal de Cátion TRPC6/metabolismo , Canal de Cátion TRPC6/genética , Animais , Túbulos Renais/patologia , Túbulos Renais/metabolismo , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/etiologia , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Traumatismo por Reperfusão/metabolismo , Fibrose , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Neoplasias Renais/genética , Camundongos , Canais de Cátion TRPC/metabolismo , Canais de Cátion TRPC/genética , Estresse Oxidativo , Nefropatias/metabolismo , Nefropatias/etiologiaAssuntos
Proteína Proto-Oncogênica N-Myc , Neuroblastoma , Proteínas Nucleares , Proteínas Oncogênicas , Humanos , Proteína Proto-Oncogênica N-Myc/genética , Neuroblastoma/genética , Neuroblastoma/patologia , Neuroblastoma/diagnóstico , Proteínas Oncogênicas/genética , Proteínas Oncogênicas/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Prognóstico , Amplificação de Genes , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismoRESUMO
Background: Hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHIs) are novel oral agents used for renal anemia treatment. Roxadustat, a first-in-class HIF-PHI used for treating anemia in chronic kidney disease patients, has been approved in China, Japan, South Korea, Chile, and Europe. Roxadustat is involved in HIF degradation, which can stimulate endogenous erythropoietin (EPO) production and improve iron utilization. Besides, roxadustat can promote dietary iron uptake and transport. In comparison with traditional erythropoiesis-stimulating agent treatment, it might reduce cardiovascular risk and mortality as it causes only a slight increase in the plasma EPO level. Phase II and III clinical trial reports have shown that roxadustat is effective for treating chronic kidney disease patients. The role of roxadustat in kidney transplant recipients (KTRs) needs to be examined as patients with chronic kidney disease are different from those receiving renal transplants. Summary: Clinical trials have demonstrated that roxadustat effectively increases and maintains hemoglobin levels in patients with dialysis-dependent and non-dialysis-dependent chronic kidney disease by stimulating endogenous EPO production and optimizing iron utilization. Roxadustat has recently been used effectively to treat patients with EPO-resistant anemia. It has also been used for treating patients with posttransplant anemia (PTA), which is a prognostic factor for mortality in KTRs with an iron deficiency and impaired glomerular filtration rate. Here, we examined the findings of four studies in a narrative review and discussed our perspectives regarding this field of study. Key Messages: Roxadustat significantly improves hemoglobin levels without affecting renal function in KTRs with PTA. It also enhances iron utilization by decreasing ferritin and hepcidin levels and increasing total iron binding capacity, transferrin, and serum iron levels. Roxadustat ameliorates anemia and inflammation, and might have reno-protective effects in KTRs.
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Although immunotherapy is expanding treatment options for cancer patients, the prognosis of advanced cancer remains poor, and these patients must contend with both cancers and cancer-related thrombotic events. In particular, immune checkpoint inhibitors are associated with an increased risk of atherosclerotic thrombotic events. Given the fundamental role of platelets in atherothrombosis, co-administration of antiplatelet agents is always indicated. Platelets are also involved in all steps of cancer progression. Classical antithrombotic drugs can cause inevitable hemorrhagic side effects due to blocking integrin ß3 bidirectional signaling, which regulates simultaneously thrombosis and hemostasis. Meanwhile, many promising new targets are emerging with minimal bleeding risk and desirable anti-tumor effects. This review will focus on the issue of thrombosis during immune checkpoint inhibitor treatment and the role of platelet activation in cancer progression as well as explore the mechanisms by which novel antiplatelet therapies may exert both antithrombotic and antitumor effects without excessive bleeding risk.
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ABSTRACT: Over the past decade, mitochondrial dysfunction has been investigated as a key contributor to acute and chronic kidney disease. However, the precise molecular mechanisms linking mitochondrial damage to kidney disease remain elusive. The recent insights into the cyclic guanosine monophosphate-adenosine monophosphate (GMP-AMP) synthetase (cGAS)-stimulator of interferon gene (STING) signaling pathway have revealed its involvement in many renal diseases. One of these findings is that mitochondrial DNA (mtDNA) induces inflammatory responses via the cGAS-STING pathway. Herein, we provide an overview of the mechanisms underlying mtDNA release following mitochondrial damage, focusing specifically on the association between mtDNA release-activated cGAS-STING signaling and the development of kidney diseases. Furthermore, we summarize the latest findings of cGAS-STING signaling pathway in cell, with a particular emphasis on its downstream signaling related to kidney diseases. This review intends to enhance our understanding of the intricate relationship among the cGAS-STING pathway, kidney diseases, and mitochondrial dysfunction.
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DNA Mitocondrial , Nefropatias , Proteínas de Membrana , Mitocôndrias , Nucleotidiltransferases , Transdução de Sinais , Humanos , Transdução de Sinais/fisiologia , Nucleotidiltransferases/metabolismo , Mitocôndrias/metabolismo , Nefropatias/metabolismo , DNA Mitocondrial/metabolismo , DNA Mitocondrial/genética , Proteínas de Membrana/metabolismo , Proteínas de Membrana/fisiologia , AnimaisRESUMO
BACKGROUND: Fabry disease (FD) is a rare X-linked inherited disease caused by mutations in the GLA gene. We established a cohort of FD patients and performed whole-exome sequencing (WES) to identify some novel mutations. AIM: The aim of this study is to investigate the etiology of the novel mutation (c.72G > A, p.Trp24*ï¼in the GLA gene in affected patients by using induced pluripotent stem cells (iPSCs) as a valuable tool. METHODS: We explored the clinical implications of this proband and examined the deleteriousness and conservation of the mutation site through bioinformatics analysis. Simultaneously, we collected the peripheral blood mononuclear cells (PBMCs) of the affected patient, then reprogrammed them into iPSCs and assessed their enzymatic activity to confirm the function of lysosomal enzyme α-galactosidase A (α-Gal A). RESULTS: Clinical examination of the patient demonstrated a classical FD, such as neuropathic pain, gastrointestinal disorders, deficiency of α-Gal A activity, and accumulation of Lyso-Gb-3. The novel mutation located on the N-terminal region, leading to a truncation of the protein and remaining only 24 amino acids. The α-Gal A activity of the patient-specific iPSC (iPS-FD) was significantly lower (60%) than that of normal iPSCs derived from healthy donors (iPS-B1). CONCLUSION: This work not only elucidated the etiology of novel mutations in affected patients but also highlighted the utility of iPSCs as a valuable tool for clarifying the molecular mechanisms and providing new insights into the therapy of FD.
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Concurrent malignancy and IgA nephropathy are rare. Despite the lack of solid experimental evidence, there are theoretical hypotheses of pathophysiology for the development of glomerular damage in cancer patients, like aberrant immune activities. Here, we describe a nine-year-old child who was admitted due to nephrotic syndrome. Abdominal imaging examination accidentally revealed a retroperitoneal tumor, and surgical resection was performed with a pathological diagnosis of neuroblastoma. However, complete removal of the tumor had no impact on the clinical manifestation of nephrotic syndrome, like proteinuria. The use of corticosteroids alone only led to a partial resolution of proteinuria, and resistance developed after one month of treatment. A further kidney biopsy was performed, which suggested IgA nephropathy. Clinical remission of IgA nephropathy was achieved after standard combination treatment of corticosteroids and mycophenolate mofetil for 10 months. This study represented the first case report of neuroblastoma associated with IgA nephropathy. We postulated that IgA nephropathy pathogenesis might be associated with neuroblastoma, though a coincidence of these two conditions cannot be fully excluded. Standard treatment for IgA nephropathy is applicable for patients with concomitant cancer.
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Background: Arterial remodeling is a compensatory mechanism of the vessel wall in response to atherosclerotic plaque growth. However, the clinical significance of vascular remodeling of carotid lesions remains unclear. Through this study, we aimed to evaluate the association between vascular remodeling and ischemic symptoms in patients with an internal carotid artery (ICA) stenosis degree ≥50%, considering the differences in plaque calcification patterns. Methods: This retrospective cross-sectional study included adult patients with moderate-to-severe proximal ICA stenosis associated with atherosclerotic plaques admitted to the Zhejiang Hospital between September 2018 and March 2023. Parameters such as lumen diameter, plaque calcification types, calcium scores, and calcification thickness were assessed using non-contrast and contrast-enhanced computed tomography angiography (CTA). The remodeling ratio (RR) was calculated by dividing the maximum distance of the proximal ICA between the inner border of the arterial lumen at the plaque site and the outer borders of the plaque by the luminal diameter. Atherosclerosis risk factors and medications were recorded. The Mann-Whitney U test or chi-square test was used to compare the differences between groups. Correlations were measured using Pearson's correlation coefficient. Predictors of ischemic symptoms were assessed using multivariable logistic regression analysis, with results expressed as odds ratio (ORs) with 95% confidence intervals (CIs). A P value less than 0.05 (two-sided) was considered to indicate statistical significance The differences in RR among plaque calcification types and the association between vascular remodeling and clinical symptoms were analyzed. Results: A total of 242 ICAs in 196 patients were included in this study, and 84 were symptomatic and 158 were asymptomatic. The RR in symptomatic ICA [median, 1.31 (interquartile range, 1.17-1.68)] was significantly greater than that in asymptomatic group [median, 1.20 (interquartile range, 1.05-1.45)], P=0.006). Significant differences in RR existed among plaque calcification types, among which type 5 and 6 plaques had the highest RR. About 71.5% (173/242) of all ICAs showed positive remodeling. Significant correlations were observed between RR and ischemic symptoms and between positive remodeling and calcification thickness (P<0.05 for all variables). On multivariable logistic regression analysis, calcification thickness remained significantly associated with positive remodeling of carotid arteries (OR 2.30; 95% CI: 1.06-5.01; P=0.036). Conclusions: Arterial remodeling exists in the ICA. A significant association between arterial positive remodeling and plaque calcification thickness was established. RR helps predict ischemic symptoms. The results of our study suggest that arterial remodeling serves as a novel measure to help ascertain the risk stratification of ischemic events in carotid atherosclerotic disease.
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Proteinuria is a common and important clinical manifestation of chronic kidney disease (CKD) and an independent risk factor for the progression of kidney disease. As a component of the glomerular filtration barrier (GFB), podocyte plays a key role in the pathogenesis of glomerular diseases and proteinuria. However, the pathophysiology of glomerular diseases associated with mitochondrial function is incompletely understood. Here, we identified three novel mutations in MTX2, encoding a membrane protein in mitochondria, associated with multisystem manifestations including nephrotic proteinuria and kidney injury in two Chinese patients. Conditional podocyte-specific Mtx2 knockout (Pod-Mtx2-KO) mice present a series of podocyte and glomerular abnormalities from 8 weeks to old age, including microalbuminuria, glomerular mesangial hyperplasia, fusion and effacement of foot process. MTX2 deficiency impaired podocyte functions in vitro, manifested by reductions of adhesion, migration and endocytosis, which were further restored by overexpression of MTX2. Moreover, MTX2 defects led to abnormal mitochondrial structure and dysfunction, evidenced with defects of complex I and III, increased production of reactive oxygen species (ROS), and decreased protein levels of Sam50-CHCHD3-Mitofilin axis in the mitochondrial intermembrane space bridging (MIB) complex which is responsible for maintaining mitochondrial cristae morphology. Collectively, these findings reveal that the normal expression of MTX2 in glomerulus plays an important role in the adhesion, migration, endocytosis, proliferation and other physiological functions of podocytes, which may be realized by maintaining the morphological structure and function of mitochondria. Abnormal expression of MTX2 can lead to mitochondrial dysfunction and structural abnormalities by Sam50-CHCHD3-Mitofilin axis in podocyte, which further induces podocyte injury, glomerular lesions and proteinuria.
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Doenças Mitocondriais , Proteínas Mitocondriais , Podócitos , Insuficiência Renal Crônica , Animais , Humanos , Camundongos , Glomérulos Renais , Proteínas Mitocondriais/genética , Proteinúria/genéticaRESUMO
BACKGROUND: Steroid-sensitive nephrotic syndrome (SSNS) accounts for approximately 80% of cases of nephrotic syndrome. The involvement of aberrant lipid metabolism in early SSNS is poorly understood, warranting further investigation. This study aimed to explore alterations in lipid metabolism associated with SSNS pathogenesis. METHODS: A screening cohort containing serum (50 SSNS, 37 controls) and urine samples (27 SSNS, 26 controls) was analyzed by untargeted lipidomic profiling using UHPLC-QTOF-MS. Then, a validation cohort (20 SSNS, 56 controls) underwent further analysis to check the potential clinical application by ROC curve analysis. RESULTS: Lipidomic profiling of serum and urine samples revealed significant lipid alterations in SSNS patients, with the alterations in the serum samples being more significant. An elevated concentration of PE and PG and downregulated concentration of FA were observed in SSNS serum. A total of 38 dysregulated lipids and 5 lipid metabolic pathways were identified in the serum samples in SSNS patients. Validation in the second cohort confirmed differential regulation of nine kinds of lipids, including 5 up-regulated substances [SM d33:2 (m/z = 686.5361), SHexCer d34:1 (m/z = 779.521), PI 20:4_22:4 (m/z = 934.5558), Cer_NS d18:1_23:0 (m/z = 635.6216), and GM3 d36:1 (m/z = 1180.7431)], as well as 4 down-regulated substances: [CE 18:1 (m/z = 650.601), PE 38:6 (m/z = 763.5205), PC 17:0_20:4 (m/z = 795.5868) and EtherPC 16:2e_20:4 (m/z = 763.5498)]. CONCLUSIONS: Untargeted lipidomic analysis successfully identified specific lipid class changes in patients with SSNS, providing a deeper understanding of lipid alterations and underlying mechanisms associated with SSNS.
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Líquidos Corporais , Síndrome Nefrótica , Criança , Humanos , Síndrome Nefrótica/tratamento farmacológico , Lipidômica , Metabolismo dos Lipídeos , LipídeosRESUMO
BACKGROUND: The understanding of bile acid (BA) and unsaturated fatty acid (UFA) profiles, as well as their dysregulation, remains elusive in individuals with type 2 diabetes mellitus (T2DM) coexisting with non-alcoholic fatty liver disease (NAFLD). Investigating these metabolites could offer valuable insights into the pathophy-siology of NAFLD in T2DM. AIM: To identify potential metabolite biomarkers capable of distinguishing between NAFLD and T2DM. METHODS: A training model was developed involving 399 participants, comprising 113 healthy controls (HCs), 134 individuals with T2DM without NAFLD, and 152 individuals with T2DM and NAFLD. External validation encompassed 172 participants. NAFLD patients were divided based on liver fibrosis scores. The analytical approach employed univariate testing, orthogonal partial least squares-discriminant analysis, logistic regression, receiver operating characteristic curve analysis, and decision curve analysis to pinpoint and assess the diagnostic value of serum biomarkers. RESULTS: Compared to HCs, both T2DM and NAFLD groups exhibited diminished levels of specific BAs. In UFAs, particular acids exhibited a positive correlation with NAFLD risk in T2DM, while the ω-6:ω-3 UFA ratio demonstrated a negative correlation. Levels of α-linolenic acid and γ-linolenic acid were linked to significant liver fibrosis in NAFLD. The validation cohort substantiated the predictive efficacy of these biomarkers for assessing NAFLD risk in T2DM patients. CONCLUSION: This study underscores the connection between altered BA and UFA profiles and the presence of NAFLD in individuals with T2DM, proposing their potential as biomarkers in the pathogenesis of NAFLD.
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N6, 2'-O-dimethyladenosine (m6Am) is a widespread RNA modification catalyzed by the methyltransferase PCIF1 (phosphorylated CTD interacting factor 1). Despite its prevalence, the biological functions of m6Am in RNA remain largely elusive. Here, we report a critical role of PCIF1-dependent m6Am RNA modification in ciliogenesis in RPE-1 cells. Our findings demonstrate that PCIF1 acts as a negative regulator of ciliation through its m6Am methyltransferase activity. A quantitative proteomic analysis identifies BICD2 as a downstream target of PCIF1, with PCIF1 depletion resulting in a significant increase in BICD2 levels. BICD2 depletion leads to a significant reduction in ciliation. Crucially, the ciliary phenotype in PCIF1-depleted cells is reversed upon BICD2 knockdown. Further investigations reveal that PCIF1 regulates BICD2 protein levels through its m6Am catalytic activity, which reduces the stability and translation efficiency of BICD2 mRNA. Single-base resolution LC-MS analysis identifies the m6Am site on BICD2 mRNA modified by PCIF1. These findings establish the essential involvement of PCIF1-dependent m6Am modification in ciliogenesis.
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Proteínas Adaptadoras de Transdução de Sinal , Espectrometria de Massa com Cromatografia Líquida , Proteínas Associadas aos Microtúbulos , Proteínas Nucleares , Proteômica , Metiltransferases/genética , RNA , RNA Mensageiro/genética , Humanos , Linhagem Celular , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismoRESUMO
The insights into interactions between host genetics and gut microbiome (GM) in colorectal tumor susceptibility (CTS) remains lacking. We used Collaborative Cross mouse population model to identify genetic and microbial determinants of Azoxymethane-induced CTS. We identified 4417 CTS-associated single nucleotide polymorphisms (SNPs) containing 334 genes that were transcriptionally altered in human colorectal cancers (CRCs) and consistently clustered independent human CRC cohorts into two subgroups with different prognosis. We discovered a set of genera in early-life associated with CTS and defined a 16-genus signature that accurately predicted CTS, the majority of which were correlated with human CRCs. We identified 547 SNPs associated with abundances of these genera. Mediation analysis revealed GM as mediators partially exerting the effect of SNP UNC3869242 within Duox2 on CTS. Intestine cell-specific depletion of Duox2 altered GM composition and contribution of Duox2 depletion to CTS was significantly influenced by GM. Our findings provide potential novel targets for personalized CRC prevention and treatment.
Assuntos
Azoximetano , Camundongos de Cruzamento Colaborativo , Neoplasias Colorretais , Microbioma Gastrointestinal , Polimorfismo de Nucleotídeo Único , Animais , Neoplasias Colorretais/microbiologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/induzido quimicamente , Humanos , Camundongos , Camundongos de Cruzamento Colaborativo/genética , Oxidases Duais/genética , Oxidases Duais/metabolismo , Predisposição Genética para Doença , Masculino , Bactérias/genética , Bactérias/classificação , Bactérias/metabolismo , Bactérias/isolamento & purificação , Modelos Animais de Doenças , FemininoRESUMO
AIMS: A myokine secreted by skeletal muscles during exercise called irisin mitigates ischemia-reperfusion (I/R) injury in epithelial cells of various organs by limiting damage to mitochondria. We test whether irisin may preserve the mitochondrial integrity and function in renal tubular epithelial cells and protect against ischemia-reperfusion-induced acute kidney injury (AKI). METHODS: We correlated serum irisin levels with serum creatinine and BUN levels from both AKI patients and healthy individuals. In mice with irisin administration, various renal injury markers such as serum creatinine, BUN, kidney injury molecule-1 (Kim-1), and neutrophil gelatinase-associated lipocalin (NGAL), and renal histopathology were assessed after I/R. To identify the potential mechanisms of the protective of irisin's protective effect, we perfused proximal tubules under confocal microscopy and analyzed kidney tissues by qPCR, western blot, and immunohistochemistry. RESULTS: Serum irisin correlated inversely with serum creatinine and BUN levels were significantly lower in AKI patients than in healthy subjects. Administering irisin to mice after I/R decreased biomarker levels for AKI including serum creatinine, BUN, Kim-1, NAGL and lessened histological changes. In kidney tissues of mice, irisin upregulated the mitochondrial autophagy marker protein microtubule-associated protein 1 light chain 3 (LC3), the mitochondrial autophagy pathway-related proteins PTEN-induced putative kinase 1 (PINK1) and Parkinson's disease 2 parkin (PARK2) and downregulated the reactive substrate protein sequestosome 1 (P62) and mitochondrial membrane proteins translocase of outer mitochondrial membrane 20 (TOM20) and translocase of inner mitochondrial membrane 23 (TIM23). CONCLUSION: Irisin protects against renal I/R injury, which may involve the preservation of mitochondrial integrity and function.