Identification of Dysregulated Complement Activation Pathways Driven by N-Glycosylation Alterations in T2D Patients

Zhao, Yang; Wang, Man; Meng, Bo; Gao, Ying; Xue, Zhichao; He, Minjun; You, Jane; Dai, Xinhua; Yan, Dan; Fang, Xiang

doi:10.3389/fchem.2021.677621

Cited by 9 publications

(8 citation statements)

References 53 publications

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“…Moreover, multiple serine proteases of the coagulation system have been shown to function as alternative activators of C5 and C3 of the complement cascade, 58 which was observed to be significantly elevated in other proteomic analyses of plasma from patients with T2D. 59 , 60 These pathways were strongly upregulated in PD of pancreatic islets, and the latter was also upregulated in liver of PD ( Figures 3 , 6 , and 7 ).…”

Section: Discussionmentioning

confidence: 95%

Organ-specific metabolic pathways distinguish prediabetes, type 2 diabetes, and normal tissues

Diamanti

Cavalli²,

Pereira³

et al. 2022

Cell Reports Medicine

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Section: Discussionmentioning

confidence: 95%

Organ-specific metabolic pathways distinguish prediabetes, type 2 diabetes, and normal tissues

Diamanti

Cavalli²,

Pereira³

et al. 2022

Cell Reports Medicine

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“…The AP can be triggered by the direct recognition of certain microbial surface structures [ 7 , 56 ], and AP-regulating proteins, including Bf [ 57 ], Df [ 58 ], and complement P factor [ 59 ], tightly control this pathway. Df, a member of the chymotrypsin family of serine proteases, plays a pivotal role in both initiation and amplification loops of complement system activation by continuously promoting C3 cleavage in the AP [ 60 , 61 ]. It has been reported in many human and mouse disease models that the deficiency or dysfunction of Df weakens the host immune killing ability to foreign pathogens, including viruses and bacteria [ 8 , 27 , 28 , 29 , 62 , 63 ].…”

Section: Discussionmentioning

confidence: 99%

“…Subsequently, activity of this C3 convertase leads to the cleavage of C3 and the activation of terminal complement components and to the formation of a membrane attack complex that eliminates invading microbes or host cells infected with viruses [ 10 , 74 ]. In addition, Df is a component absolutely required for the AP, since it is the only enzyme in mammalian blood able to catalyze C3bBb formation [ 61 , 62 , 75 ]. Therefore, Df plays an important role in the complement system against invading pathogens and is considered a vital target for the pharmaceutical control of complement activation.…”

Section: Discussionmentioning

confidence: 99%

Functional Identification of Complement Factor D and Analysis of Its Expression during GCRV Infection in Grass Carp (Ctenopharyngodon idella)

Ding

Xiao

Qin

et al. 2021

IJMS

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Complement factor D (Df) is a serine protease well known for activating the alternative pathway (AP) in mammals by promoting the cleavage of complement component 3 (C3), thus becoming involved in innate defense. In teleost fish, however, the functional mechanisms of Df in the AP and against pathogen infection are far from clear. In the present study, we cloned and characterized the Df gene, CiDf, from grass carp (Ctenopharyngodon idella) and analyzed its function in promoting C3 cleavage and expression changes after grass carp reovirus (GCRV) infection. The open reading frame of CiDf was found to be 753 bp, encoding 250 amino acids with a molecular mass of 27.06 kDa. CiDf harbors a conserved Tryp_SPc domain, with three conserved residues representing the catalytic triad and three conserved binding sites in the substrate specificity pocket. Pairwise alignment showed that CiDf shares the highest identity (96%) and similarity (98%) with Df from Anabarilius grahami. Phylogenetic analysis indicated that CiDf and other fish Dfs formed a distinct evolutionary branch. Similar to most Dfs from other vertebrates, the CiDf gene structure is characterized by four introns and five exons. The incubation of recombinant CiDf protein with grass carp serum significantly increased the C3b content, demonstrating the conserved function of CiDf in the AP in promoting C3 cleavage, similar to Dfs in mammals. CiDf mRNA expression was widely detected in various tissues and levels were relatively higher in the liver, spleen, and intestine of grass carp. During GCRV infection over a 168-hour period, a high level of CiDf mRNA expression in the liver, spleen, and intestine was maintained at 144 and 168 h, suggesting AP activity at the late stage of GCRV infection. Collectively, the above results reveal the conserved structure and function of CiDf and its distinct expression patterns after GCRV infection, which provide a key basis for studying the roles of Df and AP during GCRV infection in the grass carp C. idella.

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“…To maintain consistent data quality, each assay incorporated a 1 μg sample of the peptide mixture, undergoing a 78 min gradient separation. Specifics of the gradient and MS parameters can be found in our earlier publication [ 22 ]. Over a span of 8 months, our team successfully generated a total of 308 raw MS files for QC in HeLa proteomics analysis.…”

Section: Methodsmentioning

confidence: 99%

SEAOP: a statistical ensemble approach for outlier detection in quantitative proteomics data

Huang,

Zhao,

Meng

et al. 2024

Briefings in Bioinformatics

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Quality control in quantitative proteomics is a persistent challenge, particularly in identifying and managing outliers. Unsupervised learning models, which rely on data structure rather than predefined labels, offer potential solutions. However, without clear labels, their effectiveness might be compromised. Single models are susceptible to the randomness of parameters and initialization, which can result in a high rate of false positives. Ensemble models, on the other hand, have shown capabilities in effectively mitigating the impacts of such randomness and assisting in accurately detecting true outliers. Therefore, we introduced SEAOP, a Python toolbox that utilizes an ensemble mechanism by integrating multi-round data management and a statistics-based decision pipeline with multiple models. Specifically, SEAOP uses multi-round resampling to create diverse sub-data spaces and employs outlier detection methods to identify candidate outliers in each space. Candidates are then aggregated as confirmed outliers via a chi-square test, adhering to a 95% confidence level, to ensure the precision of the unsupervised approaches. Additionally, SEAOP introduces a visualization strategy, specifically designed to intuitively and effectively display the distribution of both outlier and non-outlier samples. Optimal hyperparameter models of SEAOP for outlier detection were identified by using a gradient-simulated standard dataset and Mann–Kendall trend test. The performance of the SEAOP toolbox was evaluated using three experimental datasets, confirming its reliability and accuracy in handling quantitative proteomics.

show abstract

Identification of Dysregulated Complement Activation Pathways Driven by N-Glycosylation Alterations in T2D Patients

Cited by 9 publications

References 53 publications

Organ-specific metabolic pathways distinguish prediabetes, type 2 diabetes, and normal tissues

Organ-specific metabolic pathways distinguish prediabetes, type 2 diabetes, and normal tissues

Functional Identification of Complement Factor D and Analysis of Its Expression during GCRV Infection in Grass Carp (Ctenopharyngodon idella)

SEAOP: a statistical ensemble approach for outlier detection in quantitative proteomics data

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