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Introduction: IgA nephropathy (IgAN), a prevalent form of glomerulonephritis globally, exhibits complex pathogenesis. Cathepsins, cysteine proteases within lysosomes, are implicated in various physiological and pathological processes, including renal conditions. Prior observational studies have suggested a potential link between cathepsins and IgAN, yet the precise causal relationship remains unclear. Methods: We conducted a comprehensive bidirectional and multivariable Mendelian randomization (MR) study using publicly available genetic data to explore the causal association between cathepsins and IgAN systematically. Additionally, immunohistochemical (IHC) staining and enzyme-linked immunosorbent assay (ELISA) were employed to evaluate cathepsin expression levels in renal tissues and serum of IgAN patients. We investigated the underlying mechanisms via gene set variation analysis (GSVA), gene set enrichment analysis (GSEA), and immune cell infiltration analysis. Molecular docking and virtual screening were also performed to identify potential drug candidates through drug repositioning. Results: Univariate MR analyses demonstrated a significant link between increased cathepsin S (CTSS) levels and a heightened risk of IgAN. This was evidenced by an odds ratio (OR) of 1.041 (95% CI=1.009-1.073, P=0.012) as estimated using the inverse variance weighting (IVW) method. In multivariable MR analysis, even after adjusting for other cathepsins, elevated CTSS levels continued to show a strong correlation with an increased risk of IgAN (IVW P=0.020, OR=1.037, 95% CI=1.006-1.069). However, reverse MR analyses did not establish a causal relationship between IgAN and various cathepsins. IHC and ELISA findings revealed significant overexpression of CTSS in both renal tissues and serum of IgAN patients compared to controls, and this high expression was unique to IgAN compared with several other primary kidney diseases such as membranous nephropathy, minimal change disease and focal segmental glomerulosclerosis. Investigations into immune cell infiltration, GSEA, and GSVA highlighted the role of CTSS expression in the immune dysregulation observed in IgAN. Molecular docking and virtual screening pinpointed Camostat mesylate, c-Kit-IN-1, and Mocetinostat as the top drug candidates for targeting CTSS. Conclusion: Elevated CTSS levels are associated with an increased risk of IgAN, and this enzyme is notably overexpressed in IgAN patients' serum and renal tissues. CTSS could potentially act as a diagnostic biomarker, providing new avenues for diagnosing and treating IgAN.
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Biomarcadores , Catepsinas , Glomerulonefritis por IGA , Humanos , Glomerulonefritis por IGA/diagnóstico , Catepsinas/metabolismo , Catepsinas/genética , Simulación del Acoplamiento Molecular , Masculino , FemeninoRESUMEN
Renal fibrosis, specifically tubulointerstitial fibrosis, represents the predominant pathological consequence observed in the context of progressive chronic kidney conditions. The pathogenesis of renal fibrosis encompasses a multifaceted interplay of mechanisms, including but not limited to interstitial fibroblast proliferation, activation, augmented production of extracellular matrix (ECM) components, and impaired ECM degradation. Notably, mitochondria, the intracellular organelles responsible for orchestrating biological oxidation processes in mammalian cells, assume a pivotal role within this intricate milieu. Mitochondrial dysfunction, when manifest, can incite a cascade of events, including inflammatory responses, perturbed mitochondrial autophagy, and associated processes, ultimately culminating in the genesis of renal fibrosis. This comprehensive review endeavors to furnish an exegesis of mitochondrial pathophysiology and biogenesis, elucidating the precise mechanisms through which mitochondrial aberrations contribute to the onset and progression of renal fibrosis. We explored how mitochondrial dysfunction, mitochondrial cytopathy and mitochondrial autophagy mediate ECM deposition and renal fibrosis from a multicellular perspective of mesangial cells, endothelial cells, podocytes, macrophages and fibroblasts. Furthermore, it succinctly encapsulates the most recent advancements in the realm of mitochondrial-targeted therapeutic strategies aimed at mitigating renal fibrosis.
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Fibrosis , Mitocondrias , Humanos , Mitocondrias/metabolismo , Mitocondrias/patología , Animales , Riñón/patología , Riñón/metabolismo , Enfermedades Renales/patología , Enfermedades Renales/metabolismo , Enfermedades Renales/etiología , Enfermedades Renales/terapia , Autofagia/fisiología , Matriz Extracelular/metabolismo , Matriz Extracelular/patologíaRESUMEN
Rationale: Monoclonal gammopathy of renal significance (MGRS) represents a group of disorders caused by monoclonal immunoglobulin (M protein) secreted by B cells or plasma cells. Proliferative glomerulonephritis with monoclonal immunoglobulin deposition (PGNMID) is a glomerular disease and a form of MGRS. Here, we presented a rare case of a patient with IgM kappa PGNMID complicated with nocardiosis dermatitis. Patient concerns and diagnoses: A 56-year-old man was admitted to the hospital because of cutaneous purpura and proteinuria. His initial pathological diagnosis indicated membranous proliferative glomerulonephritis, IgM(++), and subacute interstitial nephritis. Based on further examination, he was finally diagnosed to have IgM kappa PGNMID and subacute interstitial nephritis. After the initial diagnosis, the patient received hormonal therapy. During the treatment, nocardiosis dermatitis emerged as a complication, and the hormonal therapy was gradually reduced. The patient refused further treatment with rituximab, and his health is currently stable. Outcomes: IgM kappa PGNMID complicated with nocardiosis dermatitis is an extremely rare occurrence. Laboratory examination and pathological analysis are required to confirm the diagnosis of this disorder. Timely and accurate diagnosis is essential for the appropriate treatment of PGNMID.
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Microplastics (MPs) and polychlorinated biphenyls (PCBs) are pervasive pollutants in the marine environment, exerting adverse effects on marine organisms. While it is suggested that their exposure may compromise the immune responses of marine organisms, the cumulative immunotoxic effects remain uncertain. Additionally, the intricate mechanisms underlying the immunotoxicity of PCBs and MPs in marine organisms are not yet fully comprehended. To illuminate their combined biological impacts, Crassostrea gigas were exposed to 50 µg/L MPs (30-µm porous) alone, as well as 10 or 100 ng/L PCBs individually or in combination with 50 µg/L of MPs for 28 days. Our data demonstrated that oysters treated with the pollutants examined led to decreased total haemocyte count, inhibited phagocytosis of haemocytes, enhanced the intracellular contents of reactive oxygen species, lipid peroxidation and DNA damage, reduced lysozyme concentration and activity, gave rise to superoxide dismutase. Catalaseand glutathione S-transferaseactivity. The expression of three immune-related genes (NF-κB, TNF-α, TLR-6) was drastically suppressed by the PCBs and MPs treatment, while the apoptosis pathway-related genes (BAX and Caspase-3) showed a significant increase. In addition, compared to oysters treated with a single type of pollutant, coexposure to MPs and PCBs exerted more severe adverse impacts on all the parameters investigated, indicating a significant synergistic effect. Therefore, the risk of MPs and PCBs chemicals on marine organisms should be paid more attention.
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Crassostrea , Contaminantes Ambientales , Bifenilos Policlorados , Contaminantes Químicos del Agua , Animales , Microplásticos/toxicidad , Plásticos/metabolismo , Bifenilos Policlorados/toxicidad , Bifenilos Policlorados/metabolismo , Contaminantes Químicos del Agua/análisis , Contaminantes Ambientales/metabolismoRESUMEN
Chronic interstitial fibrosis presents a significant challenge to the long-term survival of transplanted kidneys. Our research has shown that reduced expression of acyl-coenzyme A oxidase 1 (ACOX1), which is the rate-limiting enzyme in the peroxisomal fatty acid ß-oxidation pathway, contributes to the development of fibrosis in renal allografts. ACOX1 deficiency leads to lipid accumulation and excessive oxidation of polyunsaturated fatty acids (PUFAs), which mediate epithelial-mesenchymal transition (EMT) and extracellular matrix (ECM) reorganization respectively, thus causing fibrosis in renal allografts. Furthermore, activation of Toll-like receptor 4 (TLR4)-nuclear factor kappa-B (NF-κB) signaling induced ACOX1 downregulation in a DNA methyltransferase 1 (DNMT1)-dependent manner. Overconsumption of PUFA resulted in endoplasmic reticulum (ER) stress, which played a vital role in facilitating ECM reorganization. Supplementation with PUFAs contributed to delayed fibrosis in a rat model of renal transplantation. The study provides a novel therapeutic approach that can delay chronic interstitial fibrosis in renal allografts by targeting the disorder of lipid metabolism.
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Acil-CoA Oxidasa , Trasplante de Riñón , Riñón , Enfermedades Metabólicas , Animales , Ratas , Acil-CoA Oxidasa/metabolismo , Aloinjertos , Fibrosis , Riñón/patología , LípidosRESUMEN
MOTIVATION: Proteins found in nature represent only a fraction of the vast space of possible proteins. Protein design presents an opportunity to explore and expand this protein landscape. Within protein design, protein sequence design plays a crucial role, and numerous successful methods have been developed. Notably, deep learning-based protein sequence design methods have experienced significant advancements in recent years. However, a comprehensive and systematic comparison and evaluation of these methods have been lacking, with indicators provided by different methods often inconsistent or lacking effectiveness. RESULTS: To address this gap, we have designed a diverse set of indicators that cover several important aspects, including sequence recovery, diversity, root-mean-square deviation of protein structure, secondary structure, and the distribution of polar and nonpolar amino acids. In our evaluation, we have employed an improved weighted inferiority-superiority distance method to comprehensively assess the performance of eight widely used deep learning-based protein sequence design methods. Our evaluation not only provides rankings of these methods but also offers optimization suggestions by analyzing the strengths and weaknesses of each method. Furthermore, we have developed a method to select the best temperature parameter and proposed solutions for the common issue of designing sequences with consecutive repetitive amino acids, which is often encountered in protein design methods. These findings can greatly assist users in selecting suitable protein sequence design methods. Overall, our work contributes to the field of protein sequence design by providing a comprehensive evaluation system and optimization suggestions for different methods.
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Aprendizaje Profundo , Secuencia de Aminoácidos , Proteínas/química , Aminoácidos/química , Estructura Secundaria de ProteínaRESUMEN
The Casparian strip (CS) is a ring-like lignin structure deposited between endodermal cells that forms an apoplastic barrier to control the selective uptake of nutrients in vascular plants. However, the molecular mechanism of CS formation in rice (Oryza sativa), which possesses one CS each in the endodermis and exodermis, is relatively unknown. Here, we functionally characterized CS INTEGRITY FACTOR1 (OsCIF1a, OsCIF1b), OsCIF2, and SCHENGEN3 (OsSGN3a, OsSGN3b) in rice. OsCIF1s and OsCIF2 were mainly expressed in the stele, while OsSGN3s localized around the CS at the endodermis. Knockout of all three OsCIFs or both OsSGN3s resulted in a discontinuous CS and a dramatic reduction in compensatory (less localized) lignification and suberization at the endodermis. By contrast, ectopic overexpression of OsCIF1 or OsCIF2 induced CS formation as well as overlignification and oversuberization at single or double cortical cell layers adjacent to the endodermis. Ectopic co-overexpression of OsCIF1 and SHORTROOT1 (OsSHR1) induced the formation of more CS-like structures at multiple cortical cell layers. Transcriptome analysis identified 112 downstream genes modulated by the OsCIF1/2-OsSGN3 signaling pathway, which is involved in CS formation and activation of the compensatory machinery in native endodermis and nonnative endodermis-like cell layers. Our results provide important insights into the molecular mechanism of CIF-mediated CS formation at the root endodermal and nonendodermal cell layers.
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Arabidopsis , Oryza , Arabidopsis/genética , Oryza/genética , Raíces de Plantas/metabolismo , Pared Celular/metabolismo , Péptidos/metabolismo , Transducción de Señal/genéticaRESUMEN
Rice (Oryza sativa) exhibits tremendous aluminum (Al)-tolerance. The C2H2-transcription factor (TF) ART1 critically regulates rice Al tolerance via modulation of specific gene expression. However, little is known about the posttranscriptional ART1 regulation. Here, we identified an ART1-interacted gene OsNAC016 via a yeast two-hybrid (Y2H) assay. OsNAC016 was primarily expressed in roots and weakly induced by Al. Immunostaining showed that OsNAC016 was a nuclear protein and localized in all root cells. Knockout of OsNAC016 did not alter Al sensitivity. Overexpression of OsNAC016 resulted in less Al aggregation within roots and enhanced Al tolerance in rice. Based on transcriptomic and qRT-PCR evaluations, certain cell-wall-related or ART-regulated gene expressions such as OsMYB30 and OsFRDL4 were altered in OsNAC016-overexpressing plants. These results indicated that OsNAC016 interacts with ART1 to cooperatively regulate some Al-tolerance genes and is a critical regulatory factor in rice Al tolerance.
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Oryza , Oryza/metabolismo , Aluminio/toxicidad , Aluminio/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Pared Celular/metabolismo , Plantas Modificadas Genéticamente/genética , Plantas Modificadas Genéticamente/metabolismo , Regulación de la Expresión Génica de las Plantas , Raíces de Plantas/metabolismoRESUMEN
BACKGROUND: Clinical significance of various subtypes of epidermal growth factor receptor (EGFR) exon 19 deletion (ex19del) mutation in non-small cell lung cancer (NSCLC) remains unclear. METHODS: We analyzed EGFR ex19del subtypes in NSCLC patients receiving first-line tyrosine kinase inhibitor (TKI) therapy at our center (January 2018-June 2022) and correlated them with median progression-free survival (mPFS) and median overall survival (mOS). RESULTS: We identified 17 different EGFR ex19del variants in 101 patients. Between the classic (E746_A750del, 64.4%) and nonclassic groups (the rest variants), no significant difference was observed in mPFS (13.5 vs. 19.3 months, p = 0.18) or mOS (44.1 vs. 77.0 months, p = 0.06). mPFS showed no significant difference between ex19del subgroups classified based on the presence of insertion (ex19delins), starting position or length of deletion. However, patients with ex19delins starting at E746 showed longer mPFS than the others (29.7 vs. 12.5 months, p = 0.04), and patients with ex19del of 15 nucleotides had shorter mOS than the others (44.1 vs. 77.0 months, p = 0.03). In multivariate analysis, ex19delins independently predicted a better PFS (HR = 0.311, p = 0.03); however, 15 nucleotide deletion was no longer associated with OS (HR = 0.181, p = 0.11). Secondary T790M mutation incidence was significantly higher in the ex19del subgroup starting at E746 than the others (64.7% vs. 30.8%, p = 0.04). CONCLUSIONS: Our study revealed potential differences in TKI efficacy, resistance mechanism, and prognosis of various EGFR ex19del subtypes in NSCLC, underscoring the need for precise selection of first-line therapy.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Estudios de Cohortes , Receptores ErbB , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Mutación , ExonesRESUMEN
BACKGROUND: Lupus nephritis (LN) is one of the most severe complications of systemic lupus erythematosus (SLE). However, the current management of LN remains unsatisfactory due to sneaky symptoms during early stages and lack of reliable predictors of disease progression. METHODS: Bioinformatics and machine learning algorithms were initially used to explore the potential biomarkers for LN development. Identified biomarker expression was evaluated by immunohistochemistry (IHC) and multiplex immunofluorescence (IF) in 104 LN patients, 12 diabetic kidney disease (DKD) patients, 12 minimal change disease (MCD) patients, 12 IgA nephropathy (IgAN) patients and 14 normal controls (NC). The association of biomarker expression with clinicopathologic indices and prognosis was analyzed. Gene Set Enrichment Analysis (GSEA) and Gene Set Variation Analysis (GSVA) were utilized to explore potential mechanisms. RESULTS: Interferon-inducible protein 16 (IFI16) was identified as a potential biomarker for LN. IFI16 was highly expressed in the kidneys of LN patients compared to those with MCD, DKD, IgAN or NC. IFI16 co-localized with certain renal and inflammatory cells. Glomerular IFI16 expression was correlated with pathological activity indices of LN, while tubulointerstitial IFI16 expression was correlated with pathological chronicity indices. Renal IFI16 expression was positively associated with systemic lupus erythematosus disease activity index (SLEDAI) and serum creatinine while negatively related to baseline eGFR and serum complement C3. Additionally, higher IFI16 expression was closely related to poorer prognosis of LN patients. GSEA and GSVA suggested that IFI16 expression was involved in adaptive immune-related processes of LN. CONCLUSION: Renal IFI16 expression is a potential biomarker for disease activity and clinical prognosis in LN patients. Renal IFI16 levels may be used to shed light on predicting the renal response and develop precise therapy for LN.
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Lupus Eritematoso Sistémico , Nefritis Lúpica , Humanos , Nefritis Lúpica/diagnóstico , Nefritis Lúpica/genética , Interferones , Riñón , PronósticoRESUMEN
Background: Systemic lupus erythematosus (SLE), a multisystemic autoimmune disease, is very aggressive in pediatric-onset patients as they are prone to develop lupus nephritis (LN). Although renal C4d positivity is correlated with the activity of renal disease and SLE in adult-onset LN patients, available information for pediatric-onset patients is limited. Methods: To evaluate the potential diagnostic significance of renal C4d staining in pediatric LN patients, we retrospectively detected C4d staining by immunohistochemistry on renal biopsy specimens from 58 pediatric LN patients. The clinical and laboratory data at the time of the kidney biopsy and the renal disease activity of histological injury were analyzed according to the C4d staining status. Results: Glomerular C4d (G-C4d)-positive staining was detected in all 58 cases of LN. Patients with a G-C4d score of 2 displayed more severe proteinuria than those with a G-C4d score of 1 (24-h urinary protein: 3.40 ± 3.55â g vs. 1.36 ± 1.24â g, P < 0.05). Peritubular capillary C4d (PTC-C4d) positivity was found in 34 of 58 LN patients (58.62%). The PTC-C4d-positive patient groups (patients with a PTC-C4d score of 1 or 2) had higher serum creatinine and blood urea nitrogen levels as well as renal pathological activity index (AI) and SLE disease activity index (SLEDAI) scores; however, they had lower serum complement C3 and C4 levels compared to PTC-C4d-negative patients (P < 0.05). In addition, there was positive tubular basement membrane C4d (TBM-C4d) staining in 11 of 58 LN patients (18.96%), and a higher proportion of TBM-C4d-positive patients than TBM-C4d-negative patients (63.63% vs. 21.27%) had hypertension. Conclusion: Our study revealed that G-C4d, PTC-C4d, and TMB-C4d were positively correlated with proteinuria, disease activity and severity, and hypertension, respectively, in pediatric LN patients. These data suggest that renal C4d is a potential biomarker for disease activity and severity in pediatric LN patients, providing insights into the development of novel identification and therapeutic approaches for pediatric-onset SLE with LN.
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Multiple primary cancers (MPCs) have an increasing incidence rate due to the detection of early stages of cancer and the development of effective therapeutic strategies. MPCs are less common compared with metachronous cancers. Therefore, distinguishing synchronous primary tumors from metastasis and developing an individualized treatment strategy can be challenging. In the present study, the case of a 70-year-old female who was referred to The First Hospital of Jilin University (Changchun, China) with an enlarged left cervical lymph node and no other clinical manifestations is reported. Radiography revealed distinct lesions in the left breast, left cervical lymph node and bilateral lungs. Subsequently, a biopsy was performed in all three lesions and then each specimen was subjected to immunohistochemistry, fluorescence in situ hybridization, amplification refractory mutation system-PCR and next-generation sequencing (NGS). Disease-related enrichment of lymph node mutant genes and Gene Ontology Biological Process enrichment of breast, as well as lung, mutant genes were performed using the Database for Annotation, Visualization and Integrated Discovery. Based on the molecular assessment, the patient was finally diagnosed with breast invasive ductal carcinoma, primary lung adenocarcinoma and cervical lymph node metastatic lung adenocarcinoma. Since primary synchronous breast and lung cancer (SBLC) is rare, a molecular assessment, particularly using NGS, could provide important information for both the diagnosis and treatment of SBLC.
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Myeloid-derived suppressor cells (MDSCs) are a group of immature myeloid cells that play an important role in diseases. MDSCs promote Th17 differentiation and aggravate systemic lupus erythematosus (SLE) progression by producing arginase-1 to metabolize arginine. However, the metabolic regulators remain unknown. Here, we report that MDSC derivative polyamines can promote Th17 differentiation via miR-542-5p in vitro. Th17 polarization was enhanced in response to polyamine treatment or upon miR-542-5p overexpression. The TGF-ß/SMAD3 pathway was shown to be involved in miR-542-5p-facilitated Th17 differentiation. Furthermore, miR-542-5p expression positively correlated with the levels of polyamine synthetases in peripheral blood mononuclear cells of patients with SLE as well as disease severity. In humanized SLE model mice, MDSC depletion decreased the levels of Th17 cells, accompanied by reduced expression of miR-542-5p and these polyamine synthetases. In addition, miR-542-5p expression positively correlated with the Th17 level and disease severity in both patients and humanized SLE mice. Together, our data reveal a novel molecular pathway by which MDSC-derived polyamine metabolism enhances Th17 differentiation and aggravates SLE.
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Lupus Eritematoso Sistémico , MicroARNs , Células Supresoras de Origen Mieloide , Animales , Ratones , Células Supresoras de Origen Mieloide/metabolismo , Células Th17/metabolismo , Leucocitos Mononucleares/metabolismo , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Progresión de la Enfermedad , Ligasas/metabolismoRESUMEN
Background: Immunoglobulin light chain amyloidosis is a clonal, non-proliferative plasma cell disorder, in which fragments of immunoglobulin light chain are deposited in tissues. Clinical features depend on organs involved but can include restrictive cardiomyopathy, nephrotic syndrome, hepatic failure, peripheral/autonomic neuropathy, and atypical multiple myeloma. Membranous nephropathy (MN) is a group of diseases characterized by deposition of immune complexes under the epithelial cells of glomerular basement and diffuse thickening of the basement membrane. Most patients with idiopathic MN (IMN) have been exposed to phospholipase A2 receptor (PLA2R) antigen, and anti-PLA2R antibodies that attack podocytes can be detected in their blood. IMN combined with amyloidosis nephropathy without secondary factors is rare. The present study describes a patient with IMN combined with immunoglobulin light chain amyloidosis nephropathy. Case report: A 39-year-old man was admitted to our hospital because of weight loss and edema. His clinical manifestation was nephrotic syndrome. Renal pathology revealed MN. A positive Congo red staining and the pathognomonic apple-green birefringence under cross-polarized light were considered to be associated with amyloid nephropathy. Immunofluorescence showed that λ light chain was positive. Heavy chain deposition disease and amyloid-associated protein amyloidosis were excluded by immunofluorescence and immunohistochemistry, respectively. Subsequent examinations showed that his serum was negative for antibodies against the PLA2R, but PLA2R was present in renal tissue. The final diagnosis was IMN with light chain amyloid nephropathy. Conclusion: Renal amyloidosis accompanied by IMN is uncommon. Attention should be paid to the subtype of the disease and the exclusion of secondary factors. Perfect clinical and pathological examination are helpful for the classification and staging of the disease. Congo red staining, light microscopy, immunofluorescence, immunohistochemistry, electron microscopic examination, pathological tissue staining for PLA2R antigen and testing for anti-PLA2R antibody in serum are helpful.
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Objective: Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease and end-stage renal disease worldwide. Early diagnosis is critical to prevent its progression. The aim of this study was to identify potential diagnostic biomarkers for DKD, illustrate the biological processes related to the biomarkers and investigate the relationship between them and immune cell infiltration. Materials and methods: Gene expression profiles (GSE30528, GSE96804, and GSE99339) for samples obtained from DKD and controls were downloaded from the Gene Expression Omnibus database as a training set, and the gene expression profiles (GSE47185 and GSE30122) were downloaded as a validation set. Differentially expressed genes (DEGs) were identified using the training set, and functional correlation analyses were performed. The least absolute shrinkage and selection operator (LASSO), support vector machine-recursive feature elimination (SVM-RFE), and random forests (RF) were performed to identify potential diagnostic biomarkers. To evaluate the diagnostic efficacy of these potential biomarkers, receiver operating characteristic (ROC) curves were plotted separately for the training and validation sets, and immunohistochemical (IHC) staining for biomarkers was performed in the DKD and control kidney tissues. In addition, the CIBERSORT, XCELL and TIMER algorithms were employed to assess the infiltration of immune cells in DKD, and the relationships between the biomarkers and infiltrating immune cells were also investigated. Results: A total of 95 DEGs were identified. Using three machine learning algorithms, DUSP1 and PRKAR2B were identified as potential biomarker genes for the diagnosis of DKD. The diagnostic efficacy of DUSP1 and PRKAR2B was assessed using the areas under the curves in the ROC analysis of the training set (0.945 and 0.932, respectively) and validation set (0.789 and 0.709, respectively). IHC staining suggested that the expression levels of DUSP1 and PRKAR2B were significantly lower in DKD patients compared to normal. Immune cell infiltration analysis showed that B memory cells, gamma delta T cells, macrophages, and neutrophils may be involved in the development of DKD. Furthermore, both of the candidate genes are associated with these immune cell subtypes to varying extents. Conclusion: DUSP1 and PRKAR2B are potential diagnostic markers of DKD, and they are closely associated with immune cell infiltration.
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The species of Camellia nitidissima Chi (CC) and C. euphlebia Merr. ex Sealy (CE) are two most important plant sources for commercialized herbal tea (Jinhuacha) worldwide. However, some other species of camellia genus are also sold as alternatives in market due to the great commercial value. In this study, the similarity and difference of CC and CE as well as C.insularis (CI) are comprehensively compared both in chemistry and pharmacology. Based on the ultraperformance liquid chromatography coupled with a hybrid quadrupole orthogonal time-of-flight mass spectrometer(UPLC-QTOF-MS) analysis, a sequential-optimization based new statistical model has been developed by combining the untargeted metabolomics and fingerprint analyses, and successfully applied for chemical pattern recognition and discrimination of three yellow camellias species. The results indicated that CC, CE and CI could be well discriminated with the optimized chemical combination including quercetin-3-O-rhamnoside (C2), okicamelliaside (C4), Kaempferol 7-O-rhamnoside (C6), Corymboside (C9), asiatic acid-glc-rha-xyl (C11) and 3'-methy-4'-glucoside-ellagic acid (C14). Moreover, the 30 % ethanolic extracts of yellow camellias species presented the optimal activities on anti-inflammation/anti-oxidation in LPS-stimulated Raw264.7 macrophages dose-dependently. The averaged 50 % inhibitory concentrations (IC50) on NO production were 754.68 ± 50.96, 1182.39 ± 22.10, 1527.83 ± 106.24 µg(herb)/mL, and ROS production were 311.70 ± 26.57, 332.64 ± 25.46, 917.60 ± 41.36 µg(herb)/mL for CC, CE and CI, respectively. The results indicated a certain similarity of CC and CE, as well as their significant difference from CI.
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Antioxidantes , Camellia , Antiinflamatorios/farmacología , Antioxidantes/análisis , Antioxidantes/farmacología , Cromatografía Liquida , Metabolómica/métodosRESUMEN
RATIONALE: Amyloidogenic leukocyte chemotactic factor 2 (ALECT2) was recently considered as a new clinicopathologic type of amyloid, which frequently affects kidney in adults and results in different degrees of renal insufficiency and failure with or without proteinuria. Here, we present a case of combining LECT2-associated renal amyloidosis with immunoglobulin (Ig)A nephropathy. PATIENT CONCERNS: A 71-year-old Chinese man presented with edema of both lower extremities. DIAGNOSES: There was pale eosinophilic material strongly positive for the Congo red stain in interstitium with demonstrated apple green birefringence under polarized light. Immunofluorescent stain was positive for IgA deposits (4+), IgG deposits (2+), C3 deposits (3+) within the mesangium and capillary wall. Immunohistochemistry was positive for κ (+), λ (2+) in mesangial area, and LECT2 (2+) in the interstitium. On electron microscopy, there were electron-dense deposits within mesangial area and subendothelial and randomly orientated and nonbranching fibrils 10 nm in size found in the interstitium areas. Liquid chromatography tandem mass spectrometry was performed on peptides extracted from Congo red-positive, microdissected areas of the paraffin-embedded kidney specimen. LECT 2-associated renal amyloidosis with IgA nephropathy was pathologically confirmed by renal biopsy. INTERVENTIONS: Steroids (60 mg/d) were used to treat IgA nephropathy daily. Antihypertensive treatment was switched to an angiotensin-converting enzyme inhibitor. OUTCOMES: One year after diagnosis, creatine remained stable in the normal range, and 24-hour proteinuria decreased to 2.9 g. LESSONS: To date, ALECT2 has still not been comprehensively investigated. The findings of this research provide insights for concurrent IgA nephropathy with ALECT2.
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Amiloidosis , Glomerulonefritis por IGA , Adulto , Anciano , Amiloidosis/complicaciones , Amiloidosis/diagnóstico , Amiloidosis/patología , Antígenos CD8 , Factores Quimiotácticos , Rojo Congo , Glomerulonefritis por IGA/complicaciones , Glomerulonefritis por IGA/diagnóstico , Glomerulonefritis por IGA/patología , Humanos , Péptidos y Proteínas de Señalización Intercelular , Riñón/patología , Leucocitos/patología , Masculino , Proteinuria/patologíaRESUMEN
BACKGROUND: It has been demonstrated that 12/15-lipoxygenase (LO) contributes to insulin resistance by promoting beta cells' exposure to inflammation. We investigate the mechanism by which 12/15-LO regulates the expression of inflammatory factors in obesity-related glomerular disease (ORG). METHODS: Glomerular mesangial cells were treated with metabolite of 12/15-LO, and the expression of inflammatory factors was measured. Cell histones methylation in 12/15-LO related metabolic memory process were evaluated by chromatin immunoprecipitation (ChIP) assays. Wild-type (WT) and 12/15-LO knockout mice were fed a high-fat diet (HFD) to induce ORG. RESULTS: 12(S)-HETE increased TNF-α, MCP-1, and IL-6 mRNA expression. Inhibition of 12/15-LO reduced the expression of inflammatory factors stimulated by PA or TNF-α. ChIP assays showed that 12(S)-HETE increased H3K4me modification in the TNF-α, IL-6, and MCP-1 gene promoters, and decreased H3K9me3 modification in the MCP-1 and IL-6 gene promoter. Urinary albumin excretion was greater in HFD-fed than in standard fat diet-fed mice, but both urinary protein and microalbumin amounts were lower in HFD-fed 12/15-LO knockout than in WT mice. The levels of TNF-α, IL-6, and MCP-1 in serum and renal cortex were higher in WT than in 12/15-LO knockout mice. CONCLUSIONS: 12/15-LO may regulate the expression of inflammatory factors in ORG by methylation of histones in the promoter regions of genes encoding inflammatory factors, sustaining the inflammatory phenotype of ORG.
Asunto(s)
Araquidonato 15-Lipooxigenasa , Histonas , Animales , Araquidonato 15-Lipooxigenasa/genética , Araquidonato 15-Lipooxigenasa/metabolismo , Dieta Alta en Grasa/efectos adversos , Histonas/metabolismo , Ácidos Hidroxieicosatetraenoicos/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Obesidad , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
BACKGROUND: The literature recommends that reduced dosage of CPT-11 should be applied in patients with UGT1A1 homozygous mutations, but the impact of UGT1A1 heterozygous mutations on the adverse reactions of CPT-11 is still not fully clear. METHODS: A total of 107 patients with UGT1A1 heterozygous mutation or wild-type, who were treated with CPT-11 from January 2018 to September 2021 in Peking University Third Hospital, were retrospectively enrolled. The adverse reaction spectra of patients with UGT1A1*6 and UGT1A1*28 mutations were analyzed. Adverse reactions were evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) 5.0. The efficacy was evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. The genotypes of UGT1A1*6 and UGT1A1*28 were detected by digital fluorescence molecular hybridization. RESULTS: There were 43 patients with UGT1A1*6 heterozygous mutation, 26 patients with UGT1A1*28 heterozygous mutation, 8 patients with UGT1A1*6 and UGT1A1*28 double heterozygous mutations, 61 patients with heterozygous mutation at any gene locus of UGT1A1*6 and UGT1A1*28. Logistic regression analysis showed that the presence or absence of vomiting (P=0.013) and mucositis (P=0.005) was significantly correlated with heterozygous mutation of UGT1A1*28, and the severity of vomiting (P<0.001) and neutropenia (P=0.021) were significantly correlated with heterozygous mutation of UGT1A1*6. In colorectal cancer, UGT1A1*6 was significantly correlated to diarrhea (P=0.005), and the other adverse reactions spectrum was similar to that of the whole patient cohort, and efficacy and prognosis were similar between patients with different genotypes and patients treated with reduced CPT-11 dosage or not. CONCLUSIONS: In clinical use, heterozygous mutations of UGT1A1*6 and UGT1A1*28 are related to the risk and severity of vomiting, diarrhea, neutropenia and mucositis in patients with Pan-tumor and colorectal cancer post CPT-11 therpy. In colorectal cancer, UGT1A1*6 is significantly related to diarrhea post CPT-11 use, efficacy and prognosis is not affected by various genotypes or CPT-11 dosage reduction.