RESUMO

Alzheimer's disease (AD) affects the hippocampus during its progression, but the specific observable changes of hippocampal subfields during disease progression remain poorly understood. In this study, we employed an event-based model (EBM) to determine the sequence of occurrence of hippocampal subfield atrophy in mild cognitive impairment (MCI) and AD cohorts. Subjects (207) were included: 86 MCI, 53 AD, and 68 healthy controls from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Participants underwent structural magnetic resonance imaging (MRI) scans to analyse the hippocampal subfields. We assigned each patient to a specific EBM stage, based on the number of their abnormal subfields. A combination of 2-year follow-up MRI scans were applied to demonstrate the longitudinal consistency and utility of the model's staging system. The model estimated that the earliest atrophy occurs in the hippocampal fissure, then spreading to other subregions in both MCI and AD. We identified a marked divergence between the sequences of left and right hippocampal subfields atrophy, so inter-hemispheric asymmetry pattern was further analysed. The sequence of asymmetry index (AI) increases beginning in the molecular and granule cell layers of the dentate gyrus (GC-ML-DG), cornus ammonis (CA) 4, and the molecular layer (ML). Longitudinal analysis confirms the efficacy of the model. In addition, the model stages were significantly correlated with patients' memory scores (p < .05). Collectively, we used a data-driven method to provide new insight into AD hippocampal progression. The present model could aid in understanding of the disease stages, as well as tracking memory decline.

RESUMO

Cancer therapeutic resistance as a common hallmark of cancer is often responsible for treatment failure and poor patient survival. Cancer stem-like cells (CSCs) are one of the main contributors to therapeutic resistance, cancer relapse and metastasis. Through screening from our in-house library of natural products, we found polyphyllin II (PPII) as a potent anti-CSC compound for triple-negative breast cancer (TNBC). To enhance anti-CSC selectivity and improve druggability of PPII, we leverage the liposome-mediated delivery technique for increasing solubility of PPII, and more significantly, attaining broader therapeutic window. Liposomal PPII demonstrates its marked potency to inhibit tumor growth, post-surgical recurrence and metastasis compared to commercial liposomal chemotherapeutics in the mouse models of CSC-enriched TNBC tumor. We further identify PPII as an inhibitor of the Ras-related nuclear (RAN) protein whose upregulated expression is correlated with poor clinical outcomes. The direct binding of PPII to RAN reduces TNBC stemness, thereby suppressing tumor progression. Our work offers a significance from drug discovery to drug delivery benefiting from liposome technique for targeted treatment of high-stemness tumor.

RESUMO

Non-alcoholic fatty liver disease (NAFLD) poses a significant health threat due to its potential progression to liver fibrosis, cirrhosis, and even liver cancer. Without proper management, NAFLD can lead to severe complications and significantly impact overall health and longevity. This study explores the potential anti-steatosis effects of Nankun Mountain Mao tea (MT) on hepatic lipid accumulation using both in vitro and in vivo models. In vitro experiments reveal that MT reduces lipid accumulation in hepatocytes and counteracts hepatic steatosis induced by palmitic acid and oleic acid. In vivo investigations on high-fat diet (HFD)-fed and high-fat, fructose, and cholesterol (HFFC)-fed mice demonstrate that MT administration alleviates hepatic steatosis by reducing lipid accumulation, enhancing liver function, and mitigating inflammation. Transcriptomic analyses unveil the molecular mechanisms underlying the impact of MT on lipid metabolism and inflammation. It turns out that MT inhibits de novo lipid synthesis and NF-κB pathway against NAFLD. Furthermore, target prediction analysis identifies potential bioactive components group (BCG) within MT that may contribute to its anti-steatosis properties. Validation studies on primary hepatocytes confirm the effectiveness of these bioactive components in diminishing lipid accumulation and inflammation, suggesting their role in the therapeutic efficacy of MT against NAFLD.

Assuntos

Dieta Hiperlipídica , Hepatócitos , Metabolismo dos Lipídeos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica , Chá , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Animais , Camundongos , Masculino , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Chá/química , Humanos , Extratos Vegetais/farmacologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camellia sinensis/química , Modelos Animais de Doenças , NF-kappa B/metabolismo , NF-kappa B/genética

RESUMO

BACKGROUND: NUP98 rearrangements (NUP98-r) are rare but overrepresented mutations in pediatric acute myeloid leukemia (AML) patients. NUP98-r is often associated with chemotherapy resistance and a particularly poor prognosis. Therefore, characterizing pediatric AML with NUP98-r to identify aberrations is critically important. METHODS: Here, we retrospectively analyzed the clinicopathological features, genomic and transcriptomic landscapes, treatments, and outcomes of pediatric patients with AML. RESULTS: Nine patients with NUP98-r mutations were identified in our cohort of 142 patients. Ten mutated genes were detected in patients with NUP98-r. The frequency of FLT3-ITD mutations differed significantly between the groups harboring NUP98-r and those without NUP98-r (P = 0.035). Unsupervised hierarchical clustering via RNA sequencing data from 21 AML patients revealed that NUP98-r samples clustered together, strongly suggesting a distinct subtype. Compared with that in the non-NUP98-r fusion and no fusion groups, CMAHP expression was significantly upregulated in the NUP98-r samples (P < 0.001 and P = 0.001, respectively). Multivariate Cox regression analyses demonstrated that patients harboring NUP98-r (P < 0.001) and WT1 mutations (P = 0.030) had worse relapse-free survival, and patients harboring NUP98-r (P < 0.008) presented lower overall survival. CONCLUSIONS: These investigations contribute to the understanding of the molecular characteristics, risk stratification, and prognostic evaluation of pediatric AML patients.

Assuntos

Leucemia Mieloide Aguda , Complexo de Proteínas Formadoras de Poros Nucleares , Humanos , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Criança , Feminino , Masculino , Pré-Escolar , Adolescente , Lactente , Mutação , Estudos Retrospectivos , Transcriptoma/genética , Rearranjo Gênico , Prognóstico

RESUMO

To explore the cortical microstructural alterations in Parkinson's disease (PD) at different stages. 149 PD patients and 76 healthy controls were included. PD patients were divided into early stage PD (EPD) (Hoehn-Yahr stage ≤ 2) and moderate-to-late stage PD (MLPD) (Hoehn-Yahr stage ≥ 2.5) according to their Hoehn-Yahr stages. All participants underwent two-shell diffusion MRI and the images were fitted to Neurite Orientation Dispersion and Density Imaging (NODDI) model to obtain the neurite density index (NDI) and orientation dispersion index (ODI) to reflect the cortical microstructure. We used gray matter-based spatial statistics method to compare the voxel-wise cortical NODDI metrics between groups. Partial correlation was used to correlate the NODDI metrics and global composite outcome in PD patients. Compared with healthy controls, EPD patients showed lower ODI in widespread regions, covering bilateral frontal, temporal, parietal and occipital cortices, as well as regional lower NDI in bilateral cingulate and frontal lobes. Compared with healthy controls, MLPD patients showed lower ODI and NDI in more widespread regions. Compared with EPD patients, MLPD patients showed lower ODI in bilateral temporal, parietal and occipital cortices, where the ODI values were negatively correlated with global composite outcome in PD patients. PD patients showed widespread cortical microstructural degeneration, characterized by reduced neurite density and orientation dispersion, and the cortical neuritic microstructure exhibit progressive degeneration during the progression of PD.

RESUMO

Diabetic Nephropathy (DN) has become the leading cause of end-stage renal disease worldwide. Studies have indicated that Transforming Growth Factor beta1 (TGFß1) is the most potent factor contributing to renal fibrosis, and understanding the exact pathogenic mechanism of renal fibrosis is crucial for alleviating the condition. Previous research has identified Yin Yang 1 (YY1) as an effective inhibitor of TGF-ß1. Our study, through dual-luciferase reporter gene assays and Western blot experiments, screened and obtained the small molecule compound PdⅡ. Subsequently, validation in a high-glucose-induced renal mesangial cell injury model showed that PdⅡ treatment significantly increased the expression of YY1 protein and mRNA, while correspondingly reducing the expression of TGFß1 protein and mRNA. Dual-luciferase reporter gene assay results revealed that, compared to the control group, the luciferase transcription activity of YY1 molecules increased in the PdⅡ treatment group, and the luciferase transcription activity of TGFß1 decreased. By further designing mutations in the binding sites between TGFß1 and YY1 on the promoter, transfecting fluorescent enzyme reporter gene plasmids with TGFß1 mutant promoter into mesangial cells damaged by high glucose, and then treating the cells with PdⅡ, it was observed that the luciferase transcription activity of TGFß1 did not decrease. Therefore, these results suggest that PdⅡ may inhibit TGFß1 transcriptional activity by activating YY1, thereby slowing down the progression of diabetic nephropathy.

RESUMO

Epstein-Barr virus (EBV) related post-transplant lymphoproliferative disorder (EBV-PTLD) is a life-threatening complication after hematopoietic stem cell transplantation (HSCT) or solid organ transplantation (SOT), for which no standard therapeutic means have been developed. Significant increase expression of natural killer group 2 member D ligands (NKG2DLs) was observed on B-lymphoblastoid cells of EBV-PTLD, indicating NKG2DLs as potential therapeutic targets for treatment of EBV-PTLD. In this study, the recombinant constructs of NKG2D CAR and IL-15/IL-15Rα-NKG2D CAR were generated with a retroviral vector and then transduced to human T cells to produce NKG2D CAR-T and IL-15/IL-15Rα-NKG2D CAR-T cells, respectively. B-lymphoblastoid cell lines (B-LCLs) and the xenografted mouse models were established to evaluate the efficacy of these CAR-T cells. IL-15/IL-15Rα-NKG2D CAR-T cells exhibited superior proliferation and antigen-specific cytotoxic effect compared to NKG2D CAR-T, as IL-15/IL-15Rα signaling promoted the expansion of less differentiated central memory T cells (TCM) and increased expression of CD107a and IFN-γ. Moreover, EBV DNA load was dramatically reduced, and 80% B-LCL cells were eliminated by IL-15/IL-15Rα-NKG2D CAR-T cells after co-culturing. In-vivo study confirmed that IL-15/IL-15Rα-NKG2D CAR-T cell therapy significantly enhanced antiviral efficacy in mice, as the serum load of EBV after IL-15/IL-15Rα-NKG2D CAR-T cell infusion was 1500 times lower than the untreated control (P < 0.001). The enhanced efficacy of IL-15/IL-15Rα-NKG2D CAR T cells was probably due to the IL-15/IL-15Rα signaling improved homing and persistence of NKG2D CAR-T cells in vivo, and increased the production of IFN-γ, Perforin, and Granulysin. In conclusion, NKG2D CAR-T cells co-expressing IL-15/IL-15Rα promoted the central memory CAR T cell proliferation and improved the homing and persistence of CAR T cells in vivo, resulting in enhanced anti-tumor and anti-viral effects in treating EBV-PTLD.

RESUMO

ABSTRACT: Intestinal microecology (IM) is the largest and most important microecological system of the human body. Furthermore, it is the key factor for activating and maintaining the physiological functions of the intestine. Numerous studies have investigated the effects of the gut microbiota on the different tissues and organs of the human body as well as their association with various diseases, and the findings are gradually being translated into clinical practice. The gut microbiota affects the occurrence, progression, treatment response, and toxic side effects of tumors. The deepening of research related to IM and tumors has opened a new chapter in IM research driven by methods and technologies such as second-generation sequencing and bioinformatics. The IM maintains the function of the host immune system and plays a pivotal role in tumor-control drug therapy. Increasing evidence has proven that the efficacy of tumor-control drugs largely depends on the IM balance, and strategies based on the IM technology show promising application prospects in the diagnosis and treatment of tumor. The Tumor and Microecology Professional Committee of the Chinese Anti-cancer Association gathered relevant experts to discuss and propose the "Chinese guidelines for integrated diagnosis and treatment of IM technologies in tumor application (2024 Edition)," which was established based on the research progress of the application of the IM technology in tumor to provide a basis for the standardization of the diagnosis and treatment of the IM technology in the tumor.

Assuntos

Microbioma Gastrointestinal , Neoplasias , Humanos , China , Microbioma Gastrointestinal/efeitos dos fármacos , Neoplasias/diagnóstico , Neoplasias/terapia , Neoplasias/tratamento farmacológico , Neoplasias/patologia

RESUMO

BACKGROUND: The preservation of autophagosome formation presents a promising strategy for tackling neurological disorders, such as Parkinson's disease (PD). Mitochondria-associated endoplasmic reticulum (ER) membranes (MAM) serve not only as a focal point linked to various neurological disorders but also play a crucial role in supporting the biogenesis of autophagosomes. PURPOSE: This investigation aimed to elucidate the neuroprotective properties of phillyrin against PD and its underlying mechanisms in promoting autophagosome formation. METHODS: ER and mitochondria co-localization was assessed via fluorescent staining. Annexin V-fluorescein isothiocyanate (FITC) fluorescence was employed to quantify accessible cardiolipin (CL) on mitochondrial surfaces. The levels of CL within the MAM fraction of SH-SY5Y cells were evaluated using a CL probe assay kit. Monodansylcadaverine staining was utilized to detect autophagosome formation in SH-SY5Y cells. In an A53T-alpha-synuclein (αSyn)-induced PD mouse model, the anti-PD properties of phillyrin were assessed using open field, pole climbing, and rotarod tests, as well as immunohistochemistry staining of TH+ neurons in the brain sections. RESULTS: In A53T-αSyn-treated SH-SY5Y cells, phillyrin facilitated autophagosome formation by suppressing CL externalization and restoring MAM integrity. Phillyrin enhanced the localization of receptor expression-enhancing protein 1 (REEP1) within MAM and mitochondria, bolstering MAM formation. Increased REEP1 levels in mitochondria, attributed to phillyrin, enhanced the interaction between REEP1 and NDPK-D, thereby reducing CL externalization. Furthermore, phillyrin exhibited a dose-dependent enhancement of motor function in mice, accompanied by an increase in the abundance of dopaminergic neurons within the substantia nigra. CONCLUSIONS: These findings illuminate phillyrin's ability to enhance MAM formation through upregulation of REEP1 expression within MAM, while concurrently attenuating CL externalization via the REEP1-NDPK-D interaction. These mechanisms bolster autophagosome biogenesis, offering resilience against A53T-αSyn-induced PD. Thus, our study advances the understanding of phillyrin's complex mechanisms and underscores its potential as a therapeutic approach for PD, opening new avenues in natural product pharmacology.

Assuntos

Autofagossomos , Mitocôndrias , Doença de Parkinson , alfa-Sinucleína , Animais , alfa-Sinucleína/metabolismo , Humanos , Autofagossomos/efeitos dos fármacos , Autofagossomos/metabolismo , Camundongos , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Fármacos Neuroprotetores/farmacologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Retículo Endoplasmático/metabolismo , Retículo Endoplasmático/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Cardiolipinas/metabolismo

RESUMO

Parkinson's disease (PD) exhibits heterogeneity in terms of symptoms and prognosis, likely due to diverse neuroanatomical alterations. This study employs a contrastive deep learning approach to analyze Magnetic Resonance Imaging (MRI) data from 932 PD patients and 366 controls, aiming to disentangle PD-specific neuroanatomical alterations. The results reveal that these neuroanatomical alterations in PD are correlated with individual differences in dopamine transporter binding deficit, neurodegeneration biomarkers, and clinical severity and progression. The correlation with clinical severity is verified in an external cohort. Notably, certain proteins in the cerebrospinal fluid are strongly associated with PD-specific features, particularly those involved in the immune function. The most notable neuroanatomical alterations are observed in both subcortical and temporal regions. Our findings provide deeper insights into the patterns of brain atrophy in PD and potential underlying molecular mechanisms, paving the way for earlier patient stratification and the development of treatments to slow down neurodegeneration.

Assuntos

Progressão da Doença , Aprendizado de Máquina , Imageamento por Ressonância Magnética , Doença de Parkinson , Índice de Gravidade de Doença , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/patologia , Doença de Parkinson/metabolismo , Doença de Parkinson/líquido cefalorraquidiano , Humanos , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Encéfalo/metabolismo , Biomarcadores/líquido cefalorraquidiano , Aprendizado Profundo

RESUMO

Regulating cardiolipin to maintain mitochondrial homeostasis is a promising strategy for addressing Parkinson's disease (PD). Through a comprehensive screening and validation process involving multiple models, ginsenoside Rg3 (Rg3) as a compound capable of enhancing cardiolipin levels is identified. This augmentation in cardiolipin levels fosters mitochondrial homeostasis by bolstering mitochondrial unfolded protein response, promoting mitophagy, and enhancing mitochondrial oxidative phosphorylation. Consequently, this cascade enhances the survival of tyrosine hydroxylase positive (TH+) dopaminergic neurons, leading to an amelioration in motor performance within PD mouse models. Using limited proteolysis-small-molecule mapping combined with molecular docking analysis, it has confirmed Growth Factor Receptor-Bound Protein 2 (GRB2) as a molecular target for Rg3. Furthermore, these investigations reveal that Rg3 facilitates the interaction between GRB2 and TRKA (Neurotrophic Tyrosine Kinase, Receptor, Type 1), thus promotes EVI1 (Ecotropic Virus Integration Site 1 Protein Homolog) phosphorylation by ERK, subsequently increases CRLS1 (Cardiolipin Synthase 1) gene expression and boosts cardiolipin synthesis. The absence of GRB2 or CRLS1 significantly attenuates the beneficial effects of Rg3 on PD symptoms. Finally, Tenofovir Disoproxil Fumarate (TDF) that also promotes the binding between GRB2 and TRKA is further identified. The identified compounds, Rg3 and TDF, exhibit promising potential for the prevention of PD by bolstering cardiolipin expression and reinstating mitochondrial homeostasis.

RESUMO

Metagenomic next-generation sequencing (mNGS) has revolutionized the detection of pathogens, particularly in immunocompromised individuals such as pediatric patients undergoing intensive chemotherapy and hematopoietic stem cell transplantation. This study aims to explore the impact of neutrophil count on the diagnostic efficacy of mNGS in diagnosing infections in pediatric patients with febrile diseases. We conducted a retrospective analysis of pediatric patients with febrile diseases in the hematology/oncology department from January 2019 to September 2022. The study included 387 patients with 516 febrile episodes. Analyzing data from 516 pediatric cases, our study found that 70.7 % had febrile neutropenia (FN) and 29.3 % had febrile without neutropenia (FWN). mNGS demonstrated a high positive detection rate of 84.9 %, compared to 29.7 % for conventional microbiological tests (CMT). While the positive detection rates of mNGS were similar in both FN and FWN groups, bacterial pathogens were more frequently detected in FN patients. Furthermore, the rate of identifying a "probable" microbial etiology was lower in the FN group (46.8 %) compared to the FWN group (65.6 %, p＜0.001). When analyzing the types of organisms and specimens, the "probable" identification rates were particularly lower for viruses and fungi detected by mNGS, as well as in blood and nasopharyngeal swab samples. These findings underscore the significant influence of neutrophil counts on mNGS results in pediatric febrile patients and highlight the necessity for tailored diagnostic approaches in this population.

RESUMO

Background: Congenital fibrinogen disorders (CFDs) are rare bleeding disorders (RBDs) caused by mutations in 1 of the 3 fibrinogen genes (FGA, FGB, and FGG). Objectives: To investigate the clinical phenotype, laboratory features, diagnosis, treatment, and prognosis of CFDs. Methods: Clinical data of 93 subjects with CFDs identified from June 2018 to December 2023 were retrospectively analyzed. Results: Among the 93 patients, there were 46 males (49.5%) and 47 females (50.5%), with a median age of 23 years. Fifty-three of 93 (57%) subjects experienced bleeding, 3/93 (3.2%) experienced thrombosis, and 37/93 (39.8%) were asymptomatic. Females were more prone to experience bleeding (P < .0001). The 93 patients exhibited prolonged thrombin time, significantly decreased fibrinogen activity (Fg:C), and normal or decreased fibrinogen antigen. The 93 patients included 3 with hypofibrinogenemia, 16 with hypodysfibrinogenemia, and 74 with dysfibrinogenemia. Among the 53 patients with bleeding, bleeding episodes were identified in 3.8% (2/53), 20.8% (11/53), and 75.5% (40/53) patients with hypofibrinogenemia, hypodysfibrinogenemia, and dysfibrinogenemia, respectively. Genetic analysis was performed on 22 cases from 8 pedigrees, revealing 10 mutations, including 1 novel splice mutation. Twenty-eight (30.1%) subjects received replacement therapy to treat or prevent bleeding, consisting of 8 fresh frozen plasma transfusions, 3 packing and suture treatment, and 61 fibrinogen infusions. Conclusion: Most patients with CFDs have mild or no bleeding symptoms. Fg:C combined with fibrinogen antigen and pedigree investigation can improve the feasibility and accuracy of diagnosis of CFDs. The severity of bleeding symptoms was negatively correlated with Fg:C.

RESUMO

Background: Few studies have compared the associations between long-term exposures to particulate matters (aerodynamic diameter ≤1, ≤2.5 and ≤10 µm: PM1, PM2.5 and PM10, respectively) and asthma and asthma-related respiratory symptoms. The objective of the present study was to compare the strength of the aforementioned associations in middle-aged and elderly adults. Methods: We calculated the mean 722-day personal exposure estimates of PM1, PM2.5 and PM10 at 1 km×1 km spatial resolution between 2013 and 2019 at individual levels from China High Air Pollutants (CHAP) datasets. Using logistic regression models, we presented the associations as odds ratios and 95% confidence intervals, for each interquartile range (IQR) increase in PM1/PM2.5/PM10 concentration. Asthma denoted a self-reported history of physician-diagnosed asthma or wheezing in the preceding 12 months. Results: We included 7371 participants in COPD surveillance from Guangdong, China. Each IQR increase in PM1, PM2.5 and PM10 was associated with a greater odds (OR (95% CI)) of asthma (PM1: 1.22 (1.02-1.45); PM2.5: 1.24 (1.04-1.48); PM10: 1.30 (1.07-1.57)), wheeze (PM1: 1.27 (1.11-1.44); PM2.5: 1.30 (1.14-1.48); PM10: 1.34 (1.17-1.55)), persistent cough (PM1: 1.33 (1.06-1.66); PM2.5: 1.36 (1.09-1.71); PM10: 1.31 (1.02-1.68)) and dyspnoea (PM1: 2.10 (1.84-2.41); PM2.5: 2.17 (1.90-2.48); PM10: 2.29 (1.96-2.66)). Sensitivity analysis results were robust after excluding individuals with a family history of allergy. Associations of PM1, PM2.5 and PM10 with asthma and asthma-related respiratory symptoms were slightly stronger in males. Conclusion: Long-term exposure to PM is associated with increased risks of asthma and asthma-related respiratory symptoms.

RESUMO

Immunoglobulin (Ig) has been widely acknowledged to be produced solely by B-lineage cells. However, growing evidence has demonstrated the expression of Ig in an array of cancer cells, as well as normal cells including epithelial cells, epidermal cells, mesangial cells, monocytes, and neutrophils. Ig has even been found to be expressed in non-B cells at immune-privileged sites such as neurons and spermatogenic cells. Despite these non-B cell-derived Igs (non-B-Igs) sharing the same symmetric structures with conventional Igs (B-Igs), further studies have revealed unique characteristics of non-B-Ig, such as restricted variable region and aberrant glycosylation. Moreover, non-B-Ig exhibits properties of promoting malignant behaviours of cancer cells, therefore it could be utilised in the clinic as a potential therapeutic biomarker or target. The elucidation of the generation and regulation of non-B-Ig will certainly broaden our understanding of immunology.

Assuntos

Imunoglobulinas , Humanos , Animais , Imunoglobulinas/genética , Imunoglobulinas/metabolismo , Imunoglobulinas/imunologia , Glicosilação , Linfócitos B/imunologia , Linfócitos B/metabolismo , Neoplasias/imunologia , Neoplasias/genética , Neoplasias/patologia , Neoplasias/metabolismo

RESUMO

Although V(D)J recombination and immunoglobulin (Ig) production are traditionally recognised to occur only in B lymphocytes and plasma cells, the expression of Igs in non-lymphoid cells, which we call non B cell-derived Igs (non B Igs), has been documented by growing studies. It has been demonstrated that non B-Igs can be widely expressed in most cell types, including, but not limited to, epithelial cells, cardiomyocytes, hematopoietic stem/progenitor cells, myeloid cells, and cells from immune-privileged sites, such as neurons and spermatogenic cells. In particular, malignant tumour cells express high level of IgG. Moreover, different from B-Igs that mainly localised on the B cell membrane and in the serum and perform immune defence function mainly, non B-Igs have been found to distribute more widely and play critical roles in immune defence, maintaining cell proliferation and survival, and promoting progression. The findings of non B-Igs may provide a wealthier breakthrough point for more therapeutic strategies for a wide range of immune-related diseases.

Assuntos

Imunoglobulinas , Humanos , Animais , Imunoglobulinas/genética , Imunoglobulinas/metabolismo , Imunoglobulinas/imunologia , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Hematopoéticas/imunologia , Células-Tronco Hematopoéticas/citologia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Células Epiteliais/metabolismo , Células Epiteliais/imunologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/imunologia , Células Mieloides/imunologia , Células Mieloides/metabolismo

RESUMO

The development of simplified synthetic strategy to create structurally and functionally diverse pseudo-natural macrocyclic molecules is highly appealing but poses a marked challenge. Inspired by natural scaffolds, herein, we describe a practical and concise ligand-enabled Pd(II)-catalysed sp3 C‒H alkylation, olefination and arylation macrocyclization, which could offer a novel set of pseudo-natural macrocyclic sulfonamides. Interestingly, the potential of ligand acceleration in C‒H activation is also demonstrated by an unprecedented enantioselective sp3 C‒H alkylation macrocyclization. Moreover, a combination of in silico screening and biological evaluation led to the identification of a novel spiro-grafted macrocyclic sulfonamide 2a, which showed a promising efficacy for the treatment of Parkinson's disease (PD) in a mouse model through the activation of silent information regulator sirtuin 3 (SIRT3).

RESUMO

Heavy metals and pesticides are significant pollutants in aquatic environments, often leading to combined pollution and exerting toxic effects on aquatic organisms. With the rapid growth of modern industry and agriculture, heavy metal cadmium (Cd) and pesticide triazophos (TRI) are frequently detected together in various water bodies, particularly in agricultural watersheds. However, the combined toxic mechanisms of these pollutants on fish remain poorly understood. This experiment involved a 21-day co-exposure of Cd and TRI to the hook snout carp Opsariichthys bidens to investigate the toxic effects on liver tissues at both enzymatic and transcriptional levels. Biochemical analysis revealed that both individual and combined exposures significantly increased the content or activity of caspase-3 (CASP-3) and malondialdehyde (MDA). Moreover, the impact on these parameters was greater in the combined exposure groups compared to the corresponding individual exposure groups. These findings suggested that both individual and combined exposures could induce mitochondrial dysfunction and lipid peroxidation damage, with combined exposure exacerbating the toxicological effects of each individual pollutant. Furthermore, at the molecular level, both individual and combined exposures upregulated the expression levels of cu-sod, cat, and erß, while downregulating the expression of il-1. Similar to the patterns observed in the biochemical parameters, the combined exposure group exhibited a greater impact on the expression of these genes compared to the individual exposure groups. These results indicated that exposure to Cd, TRI, and their combination induced oxidative stress, endocrine disruption, and immunosuppression in fish livers, with more severe effects observed in the combined exposure group. Overall, the interaction between Cd and TRI appeared to be synergistic, shedding light on the toxic mechanisms by which fish livers responded to these pollutants. These findings contributed to the understanding of mixture risk assessment of pollutants and were valuable for the conservation of aquatic resources.

Assuntos

Cádmio , Fígado , Organotiofosfatos , Triazóis , Poluentes Químicos da Água , Animais , Cádmio/toxicidade , Poluentes Químicos da Água/toxicidade , Organotiofosfatos/toxicidade , Triazóis/toxicidade , Fígado/efeitos dos fármacos , Fígado/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Malondialdeído/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Caspase 3/metabolismo , Caspase 3/genética , Carpas/metabolismo , Carpas/genética , Superóxido Dismutase/metabolismo , Praguicidas/toxicidade

RESUMO

Background: Metagenomic next-generation sequencing (mNGS) of plasma DNA has become an attractive diagnostic method for infectious diseases; however, the rate of false-positive results is high. This study aims to evaluate the diagnostic accuracy of mNGS in plasma versus blood cell samples for immunocompromised children with febrile diseases. Methods: The results of conventional microbiological test (CMT) and mNGS using plasma and blood cells in 106 patients with 128 episodes of febrile diseases from the Department of Hematology/Oncology were analyzed and described. Results: The positivity rates for CMT and mNGS of plasma and blood cells were 35.9 %, 84.4 % and 46.9 %, respectively (P < 0.001). Notably, mNGS identified multiple pathogens in a single specimen in 68.5 % of plasma samples and 38.3 % of blood cell samples (P < 0.001). Furthermore, plasma and blood cell mNGS identified causative pathogens in 58 and 46 cases, accounting for 53.7 % and 76.7 % of the mNGS-positive cases for each sample type, respectively (P = 0.002). By integrating results from both plasma and blood cell samples, causative pathogens were identified in 77 cases (60.2 %), enhancing sensitivity to 87.5 % but reducing specificity to 15.0 %, compared to plasma (65.9 % sensitivity and 20.0 % specificity) and blood cell samples (52.3 % sensitivity and 80.0 % specificity). Conclusions: mNGS of plasma is sensitive but has a high false-positive rate, while mNGS of blood cells has low sensitivity but higher specificity.