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1.
Biomed Environ Sci ; 37(4): 387-398, 2024 Apr 20.
Article in English | MEDLINE | ID: mdl-38727161

ABSTRACT

Objective: Recombinase-aided polymerase chain reaction (RAP) is a sensitive, single-tube, two-stage nucleic acid amplification method. This study aimed to develop an assay that can be used for the early diagnosis of three types of bacteremia caused by Staphylococcus aureus (SA), Pseudomonas aeruginosa (PA), and Acinetobacter baumannii (AB) in the bloodstream based on recombinant human mannan-binding lectin protein (M1 protein)-conjugated magnetic bead (M1 bead) enrichment of pathogens combined with RAP. Methods: Recombinant plasmids were used to evaluate the assay sensitivity. Common blood influenza bacteria were used for the specific detection. Simulated and clinical plasma samples were enriched with M1 beads and then subjected to multiple recombinase-aided PCR (M-RAP) and quantitative PCR (qPCR) assays. Kappa analysis was used to evaluate the consistency between the two assays. Results: The M-RAP method had sensitivity rates of 1, 10, and 1 copies/µL for the detection of SA, PA, and AB plasmids, respectively, without cross-reaction to other bacterial species. The M-RAP assay obtained results for < 10 CFU/mL pathogens in the blood within 4 h, with higher sensitivity than qPCR. M-RAP and qPCR for SA, PA, and AB yielded Kappa values of 0.839, 0.815, and 0.856, respectively ( P < 0.05). Conclusion: An M-RAP assay for SA, PA, and AB in blood samples utilizing M1 bead enrichment has been developed and can be potentially used for the early detection of bacteremia.


Subject(s)
Bacteremia , Mannose-Binding Lectin , Humans , Mannose-Binding Lectin/blood , Bacteremia/diagnosis , Bacteremia/microbiology , Bacteremia/blood , Recombinases/metabolism , Acinetobacter baumannii/genetics , Acinetobacter baumannii/isolation & purification , Staphylococcus aureus/isolation & purification , Staphylococcus aureus/genetics , Pseudomonas aeruginosa/isolation & purification , Pseudomonas aeruginosa/genetics , Polymerase Chain Reaction/methods , Sensitivity and Specificity , Bacteria/genetics , Bacteria/isolation & purification
2.
Blood ; 143(17): 1682-1684, 2024 Apr 25.
Article in English | MEDLINE | ID: mdl-38662386
3.
Sci Data ; 11(1): 435, 2024 Apr 30.
Article in English | MEDLINE | ID: mdl-38688916

ABSTRACT

The human mannose-binding lectin (MBL) gene encodes a polymorphic protein that plays a crucial role in the innate immune response. Human MBL deficiency is associated with immunodeficiencies, and its variants have been linked to autoimmune and infectious diseases. Despite this significance, gene studies concerning MBL sequencing are uncommon in Malaysia. Therefore, we aimed to preliminary described the human MBL sequencing dataset based on the Kelantan population. Blood samples were collected from 30 unrelated individuals and underwent DNA extraction, genotyping, and sequencing. The sequencing data generated 886 bp, which were deposited in GenBank (ON619541-ON619546). Allelic variants were identified and translated into six MBL haplotypes: HYPA, HYPB, LYPB, LXPB, HXPA, and LXPA. An evolutionary tree was constructed using the haplotype sequences. These findings contribute to the expansion of MBL information within the country, providing a valuable baseline for future research exploring the association between the gene and targeted diseases.


Subject(s)
Mannose-Binding Lectin , Humans , Haplotypes , Malaysia , Mannose-Binding Lectin/genetics , Base Sequence , Alleles
4.
Chemistry ; 30(30): e202400660, 2024 May 28.
Article in English | MEDLINE | ID: mdl-38527187

ABSTRACT

C-type lectins are a large superfamily of proteins involved in a multitude of biological processes. In particular, their involvement in immunity and homeostasis has rendered them attractive targets for diverse therapeutic interventions. They share a characteristic C-type lectin-like domain whose adaptability enables them to bind a broad spectrum of ligands beyond the originally defined canonical Ca2+-dependent carbohydrate binding. Together with variable domain architecture and high-level conformational plasticity, this enables C-type lectins to meet diverse functional demands. Secondary sites provide another layer of regulation and are often intricately linked to functional diversity. Located remote from the canonical primary binding site, secondary sites can accommodate ligands with other physicochemical properties and alter protein dynamics, thus enhancing selectivity and enabling fine-tuning of the biological response. In this review, we outline the structural determinants allowing C-type lectins to perform a large variety of tasks and to accommodate the ligands associated with it. Using the six well-characterized Ca2+-dependent and Ca2+-independent C-type lectin receptors DC-SIGN, langerin, MGL, dectin-1, CLEC-2 and NKG2D as examples, we focus on the characteristics of non-canonical interactions and secondary sites and their potential use in drug discovery endeavors.


Subject(s)
Lectins, C-Type , Lectins, C-Type/chemistry , Lectins, C-Type/metabolism , Humans , Ligands , Binding Sites , Calcium/metabolism , Calcium/chemistry , Receptors, Cell Surface/chemistry , Receptors, Cell Surface/metabolism , Cell Adhesion Molecules/chemistry , Cell Adhesion Molecules/metabolism , Protein Binding , Mannose-Binding Lectins/chemistry , Mannose-Binding Lectins/metabolism , Mannose-Binding Lectin/chemistry , Mannose-Binding Lectin/metabolism , NK Cell Lectin-Like Receptor Subfamily K/chemistry , NK Cell Lectin-Like Receptor Subfamily K/metabolism , Antigens, CD/chemistry , Antigens, CD/metabolism
5.
J Immunol ; 212(9): 1493-1503, 2024 May 01.
Article in English | MEDLINE | ID: mdl-38488502

ABSTRACT

Previous studies of pattern recognition molecules (PRMs) of the complement system have revealed difficulties in observing binding on pathogens such as Aspergillus fumigatus and Escherichia coli, despite complement deposition indicative of classical and lectin pathway activation. Thus, we investigated the binding dynamics of PRMs of the complement system, specifically C1q of the classical pathway and mannose-binding lectin (MBL) of the lectin pathway. We observed consistently increasing deposition of essential complement components such as C4b, C3b, and the terminal complement complex on A. fumigatus and E. coli. However, C1q and MBL binding to the surface rapidly declined during incubation after just 2-4 min in 10% plasma. The detachment of C1q and MBL can be linked to complement cascade activation, as the PRMs remain bound in the absence of plasma. The dissociation and the fate of C1q and MBL seem to have different mechanistic functions. Notably, C1q dynamics were associated with local C1 complex activation. When C1s was inhibited in plasma, C1q binding not only remained high but further increased over time. In contrast, MBL binding was inversely correlated with total and early complement activation due to MBL binding being partially retained by complement inhibition. Results indicate that detached MBL might be able to functionally rebind to A. fumigatus. In conclusion, these results reveal a (to our knowledge) novel "hit-and-run" complement-dependent PRM dynamic mechanism on pathogens. These dynamics may have profound implications for host defense and may help increase the functionality and longevity of complement-dependent PRMs in circulation.


Subject(s)
Complement C1q , Mannose-Binding Lectin , Escherichia coli/metabolism , Mannose-Binding Lectin/metabolism , Complement System Proteins , Complement Activation , Lectins/metabolism , Complement Pathway, Mannose-Binding Lectin
6.
Int J Biol Macromol ; 264(Pt 1): 130503, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38428783

ABSTRACT

Mannose-binding lectin plays an essential role in bacteria or virus-triggered immune response in mammals. Previous proteomic data revealed that in Eriocheir sinensis, the mannose-binding protein was differentially expressed after Spiroplasma eriocheiris infection. However, the function of mannose-binding protein against pathogen infection in invertebrates is poorly understood. In this study, a crab mannose-binding protein (EsMBP) was characterized and enhanced the host resistance to S. eriocheiris infection. The application of recombinant C-type carbohydrate recognition domain (CTLD) of EsMBP led to increased crab survival and decreased S. eriocheiris load in hemocytes. Meanwhile, the overexpression of CTLD of EsMBP in Raw264.7 cells inhibited S. eriocheiris intracellular replication. In contrast, depletion of EsMBP by RNA interference or antibody neutralization attenuated phenoloxidase activity and hemocyte phagocytosis, rendering host more susceptible to S. eriocheiris infection. Furthermore, miR-381-5p in hemocytes suppressed EsMBP expression and negatively regulated phenoloxidase activity to exacerbate S. eriocheiris invasion of hemocytes. Taken together, our findings revealed that crab mannose-binding protein was involved in host defense against S. eriocheiris infection and targeted by miR-381-5p, providing further insights into the control of S. eriocheiris spread in crabs.


Subject(s)
Brachyura , Catechol Oxidase , Enzyme Precursors , Mannose-Binding Lectin , MicroRNAs , Spiroplasma , Animals , Mannose-Binding Lectin/metabolism , Proteomics , Monophenol Monooxygenase/metabolism , Phagocytosis , MicroRNAs/genetics , MicroRNAs/metabolism , Hemocytes/metabolism , Mammals/genetics
7.
J Immunol ; 212(7): 1172-1177, 2024 Apr 01.
Article in English | MEDLINE | ID: mdl-38372634

ABSTRACT

The activation of the CP/LP C3 proconvertase complex is a key event in complement activation and involves cleavage of C4 and C2 by the C1s protease (classical pathway) or the mannose-binding lectin-associated serine protease (MASP)-2 (lectin pathway). Efficient cleavage of C4 by C1s and MASP-2 involves exosites on the complement control protein and serine protease (SP) domains of the proteases. The complement control protein domain exosite is not involved in cleavage of C2 by the proteases, but the role of an anion-binding exosite (ABE) on the SP domains of the proteases has (to our knowledge) never been investigated. In this study, we have shown that the ABE on the SP of both C1s and MASP-2 is crucial for efficient cleavage of C2, with mutant forms of the proteases greatly impaired in their rate of cleavage of C2. We have additionally shown that the site of binding for the ABE of the proteases is very likely to be located on the von Willebrand factor domain of C2, with the precise area differing between the enzymes: whereas C1s requires two anionic clusters on the von Willebrand factor domain to enact efficient cleavage of C2, MASP-2 apparently only requires one. These data provide (to our knowledge) new information about the molecular determinants for efficient activation of C2 by C1s and MASP-2. The enhanced view of the molecular events underlying the early stages of complement activation provides further possible intervention points for control of this activation that is involved in a number of inflammatory diseases.


Subject(s)
Complement Activation , Mannose-Binding Lectin , Mannose-Binding Protein-Associated Serine Proteases , Complement C1s , Complement C4/metabolism , Mannose-Binding Lectin/metabolism , Mannose-Binding Protein-Associated Serine Proteases/metabolism , Protein Domains , Serine Endopeptidases/metabolism , Serine Proteases/metabolism , von Willebrand Factor , Humans , HEK293 Cells
8.
Appl Microbiol Biotechnol ; 108(1): 193, 2024 Feb 03.
Article in English | MEDLINE | ID: mdl-38308716

ABSTRACT

The microbiological diagnosis of infection for hematological malignancy patients receiving chemotherapy or allogeneic hematopoietic stem cell transplantation (allo-HSCT) patients relies primarily on standard microbial culture, especially blood culture, which has many shortcomings, such as having low positive rates, being time-consuming and having a limited pathogenic spectrum. In this prospective observational self-controlled test accuracy study, blood, cerebrospinal fluid (CSF), and bronchoalveolar lavage fluid (BALF) samples were collected from chemotherapy or allo-HSCT patients with clinical symptoms of infections who were hospitalized at Peking University First Hospital. Possible pathogens were detected by the method based on recombinant mannan-binding lectin (MBL) magnetic bead enrichment (M1 method) and simultaneously by a standard method. The analytical sensitivity of M1 method was close to that of standard culture method. Besides, the turn-around time of M1-method was significantly shorter than that of standard culture method. Moreover, the M1 method also added diagnostic value through the detection of some clinically relevant microbes missed by the standard method. M1 method could significantly increase the detection efficiency of pathogens (including bacteria and fungi) in immunocompromised patients. KEY POINTS: • The detection results of M1-method had a high coincidence rate with that of standard method • M1 method detected many pathogens which had not been found by standard clinic method.


Subject(s)
Mannose-Binding Lectin , Humans , Bronchoalveolar Lavage Fluid , Bacteria , Immunocompromised Host , Magnetic Phenomena , High-Throughput Nucleotide Sequencing
9.
BMC Med Genomics ; 17(1): 11, 2024 01 02.
Article in English | MEDLINE | ID: mdl-38167099

ABSTRACT

BACKGROUND: It has been reported that Mannose-binding lectin 2 (MBL2) gene polymorphisms and expression levels are related to dilated cardiomyopathy (DCM). This study aimed to investigate the potential association between MBL2 gene polymorphisms and the pathogenesis of DCM. METHODS: Five single nucleotide polymorphisms (SNPs) of the MBL2 gene were genotyped in 440 DCM patients and 532 controls in Southwest China. A luciferase reporter assay was used to detect the transcriptional activity the different genotypes. MBL serum levels, left ventricle ejection fraction (LVEF) and lower left ventricular end-diastolic diameter (LVEDD) were measured. RESULTS: The rs11003125 C allele increased the transcriptional activity of the MBL2 promoter compared with the rs11003125 G allele. The rs11003125 CC carriers had higher MBL serum levels, LVEF and LVEDD than the rs11003125 CG and GG carriers. CONCLUSIONS: Our study first revealed that MBL2 polymorphisms and serum MBL levels were associated with DCM. Allele C in rs11003125 of MBL2 may upregulate the expression levels of MBL. High serum MBL levels may be a protective factor in DCM pathogenesis.


Subject(s)
Cardiomyopathy, Dilated , Mannose-Binding Lectin , Humans , Cardiomyopathy, Dilated/genetics , Gene Frequency , Genetic Predisposition to Disease , Genotype , Mannose-Binding Lectin/genetics , Polymorphism, Single Nucleotide
10.
Sci Rep ; 14(1): 638, 2024 01 05.
Article in English | MEDLINE | ID: mdl-38182717

ABSTRACT

Chiglitazar is a novel peroxisome proliferator-activated receptor (PPAR) pan-agonist, which passed phase III clinical trials and was newly approved in China for use as an adjunct to diet and exercise in glycemic control in adult patients with Type 2 Diabetes (T2D). To explore the circulating protein signatures associated with the administration of chiglitazar in T2D patients, we conducted a comparative longitudinal study using plasma proteome profiling. Of the 157 T2D patients included in the study, we administered chiglitazar to a specific group, while the controls were given either placebo or sitagliptin. The plasma proteomes were profiled at baseline and 12 and 24 weeks post-treatment using data-independent acquisition mass spectrometry (DIA-MS). Our study indicated that 13 proteins were associated with chiglitazar treatment in T2D patients, including 10 up-regulated proteins (SHBG, TF, APOA2, APOD, GSN, MBL2, CFD, PGLYRP2, A2M, and APOA1) and 3 down-regulated proteins (PRG4, FETUB, and C2) after treatment, which were implicated in the regulation of insulin sensitivity, lipid metabolism, and inflammation response. Our study provides insight into the response of chiglitazar treatment from a proteome perspective and demonstrates the multi-faceted effects of chiglitazar in T2D patients, which will help the clinical application of chiglitazar and further study of its action mechanism.


Subject(s)
Diabetes Mellitus, Type 2 , Insulin Resistance , Mannose-Binding Lectin , Adult , Humans , Diabetes Mellitus, Type 2/drug therapy , Proteome , Peroxisome Proliferator-Activated Receptors , Lipid Metabolism , Longitudinal Studies , Hypoglycemic Agents/pharmacology , Hypoglycemic Agents/therapeutic use , Inflammation/drug therapy
11.
Cell Death Differ ; 31(1): 90-105, 2024 01.
Article in English | MEDLINE | ID: mdl-38062244

ABSTRACT

Mesenchymal stromal cells (MSCs) are used to treat infectious and immune diseases and disorders; however, its mechanism(s) remain incompletely defined. Here we find that bone marrow stromal cells (BMSCs) lacking Pinch1/2 proteins display dramatically reduced ability to suppress lipopolysaccharide (LPS)-induced acute lung injury and dextran sulfate sodium (DSS)-induced inflammatory bowel disease in mice. Prx1-Cre; Pinch1f/f; Pinch2-/- transgenic mice have severe defects in both immune and hematopoietic functions, resulting in premature death, which can be restored by intravenous injection of wild-type BMSCs. Single cell sequencing analyses reveal dramatic alterations in subpopulations of the BMSCs in Pinch mutant mice. Pinch loss in Prx1+ cells blocks differentiation and maturation of hematopoietic cells in the bone marrow and increases production of pro-inflammatory cytokines TNF-α and IL-1ß in monocytes. We find that Pinch is critical for expression of Cxcl12 in BMSCs; reduced production of Cxcl12 protein from Pinch-deficient BMSCs reduces expression of the Mbl2 complement in hepatocytes, thus impairing the innate immunity and thereby contributing to infection and death. Administration of recombinant Mbl2 protein restores the lethality induced by Pinch loss in mice. Collectively, we demonstrate that the novel Pinch-Cxcl12-Mbl2 signaling pathway promotes the interactions between bone and liver to modulate immunity and hematopoiesis and may provide a useful therapeutic target for immune and infectious diseases.


Subject(s)
Bone and Bones , Cytokines , Liver , Animals , Mice , Bone and Bones/immunology , Bone and Bones/metabolism , Bone Marrow Cells , Cytokines/metabolism , Liver/immunology , Liver/metabolism , Mice, Transgenic , Signal Transduction , Chemokine CXCL12/metabolism , LIM Domain Proteins/metabolism , Mannose-Binding Lectin/metabolism , Hematopoiesis
12.
Chem Biol Drug Des ; 103(1): e14365, 2024 01.
Article in English | MEDLINE | ID: mdl-37749066

ABSTRACT

A mannose-binding protein from the mushroom Agaricus bisporus (Abmb) inhibits the growth of MDA-MB-231 cells, which is of an aggressive breast cancer subtype. This ability was observed in a monolayer cell (2D) culture setup, which often is unable to capture changes in cell morphology, polarity and division. That shortcoming may overestimate Abmb potency for its development as a pharmaceutical agent and its use in a therapy. Hence, Abmb's inhibition to the cell growth was performed in the 3D cell (spheroid) culture, which is more representative to the situation in vivo. The result showed that, although the presence of Abmb at ~14.7 µM already disrupted the MDA-MB-231 cell morphology in the 2D culture, its presence at ~16.5 µM only ceased the growth of the MDA-MB-231 spheroid. Further, Abmb is unique because structurally it belongs to the R-type lectin (RTL) family; most of mannose-binding protein is of the C-type lectin (CTL). As the natural ligand of Abmb is unknown thus the mechanism of action is unclear, Abmb effect on the cancer cells was assessed via observation of the altered expression of genes involved in the Wnt/ß-catenin signalling, which is one of the canonical pathways in the proliferation of cancer cells. The results suggested that Abmb did not alter the pathway upon exerting its anti-proliferative activity to the MDA-MB-231 cells.


Subject(s)
Agaricus , Breast Neoplasms , Mannose-Binding Lectin , Humans , Female , Mannose-Binding Lectin/pharmacology , Lectins/pharmacology , Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , Cell Proliferation , Cell Line, Tumor
13.
Biogerontology ; 25(1): 177-181, 2024 Feb.
Article in English | MEDLINE | ID: mdl-37707684

ABSTRACT

Plasma proteins serve as biomarkers of aging and various age-related diseases. While a number of plasma proteins have been identified that increase or decrease with age, the interpretation of each protein is challenging. This is due to the nature of plasma, which is a mixture of factors secreted by many different tissues and cells. Therefore, the catalog of age-related proteins secreted by a single cell type in a single tissue would be useful for understanding tissue-specific aging patterns. In this study, the author addressed this challenge by integrative data mining of the Human Protein Atlas and the recently published result of large-scale aging proteomics research. Finally, we identified the 17 age-related proteins produced by a single tissue and a single cell type: MBL2 and HP in the liver (hepatocytes), SFTPC in the lung (type II alveolar cells), PRL and POMC in the pituitary (anterior cells), GCG, CUZD1 and CPA2 in the pancreas (pancreatic cells), MYBPC1 in skeletal muscle (myocytes), PTH in the parathyroid gland (glandular cells), LPO and AMY1A in the salivary gland (glandular cells), INSL3 in the male testis (Leydig cells), KLK3 and KLK4 in the male prostate (glandular cells), MPO and ACP5 in immune cells. This list of proteins would be potentially useful for understanding age-related changes in the plasma proteome and inter-tissue networks.


Subject(s)
Mannose-Binding Lectin , Salivary alpha-Amylases , Male , Humans , Biomarkers/metabolism , Aging , Blood Proteins , Proteome/metabolism , Proteomics , Membrane Proteins
14.
Cancer Sci ; 115(1): 184-196, 2024 Jan.
Article in English | MEDLINE | ID: mdl-38050344

ABSTRACT

p53 is a key tumor suppressor mutated in half of human cancers. In recent years, p53 was shown to regulate a wide variety of functions. From the transcriptome analysis of 24 tissues of irradiated mice, we identified 553 genes markedly induced by p53. Gene Ontology (GO) enrichment analysis found that the most associated biological process was innate immunity. 16S rRNA-seq analysis revealed that Akkermansia, which has anti-inflammatory properties and is involved in the regulation of intestinal barrier integrity, was decreased in p53-knockout (p53-/- ) mice after radiation. p53-/- mice were susceptible to radiation-induced GI toxicity and had a significantly shorter survival time than p53-wild-type (p53+/+ ) mice following radiation. However, administration of antibiotics resulted in a significant improvement in survival and protection against GI toxicity. Mbl2 and Lcn2, which have antimicrobial activity, were identified to be directly transactivated by p53 and secreted by liver into the circulatory system. We also found the expression of MBL2 and LCN2 was decreased in liver cancer tissues with p53 mutations compared with those without p53 mutations. These results indicate that p53 is involved in shaping the gut microbiome through its downstream targets related to the innate immune system, thus protecting the intestinal barrier.


Subject(s)
Gastrointestinal Microbiome , Immunity, Innate , Tumor Suppressor Protein p53 , Animals , Humans , Mice , Liver Neoplasms/metabolism , Mannose-Binding Lectin/metabolism , Mice, Knockout , RNA, Ribosomal, 16S/genetics , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism
15.
Clin Exp Immunol ; 215(1): 58-64, 2024 01 09.
Article in English | MEDLINE | ID: mdl-37832142

ABSTRACT

Activation of the lectin pathway of the complement system, as demonstrated by elevated levels of mannan-binding lectin proteins (MBL), contributes to vascular pathology in type 1 diabetes (T1D). Vascular complications are greatest in T1D individuals with concomitant insulin resistance (IR), however, whether IR amplifies activiation of the lectin pathway in T1D is unknown. We pooled pretreatment data from two RCTs and performed a cross-sectional analysis on 46 T1D individuals. We employed estimated glucose disposal rate (eGDR), a validated IR surrogate with cut-points of: <5.1, 5.1-8.7, and > 8.7 mg/kg/min to determine IR status, with lower eGDR values conferring higher degrees of IR. Plasma levels of MBL-associated proteases (MASP-1, MASP-2, and MASP-3) and their regulatory protein MAp44 were compared among eGDR classifications. In a subset of 14 individuals, we assessed change in MASPs and MAp44 following improvement in IR. We found that MASP-1, MASP-2, MASP-3, and MAp44 levels increased in a stepwise fashion across eGDR thresholds with elevated MASPs and MAp44 levels conferring greater degrees of IR. In a subset of 14 patients, improvement in IR was associated with significant reductions in MASPs, but not MAp44, levels. In conclusion, IR in T1D amplifies levels of MASP-1/2/3 and their regulator MAp44, and improvement of IR normalizes MASP-1/2/3 levels. Given that elevated levels of these proteins contribute to vascular pathology, amplification of the lectin pathway of the complement system may offer mechanistic insight into the relationship between IR and vascular complications in T1D.


Subject(s)
Diabetes Mellitus, Type 1 , Insulin Resistance , Mannose-Binding Lectin , Humans , Mannose-Binding Protein-Associated Serine Proteases/metabolism , Cross-Sectional Studies , Lectins/metabolism , Complement System Proteins
16.
Cell Rep ; 43(1): 113611, 2024 01 23.
Article in English | MEDLINE | ID: mdl-38159276

ABSTRACT

Complement is a fundamental innate immune response component. Its alterations are associated with severe systemic diseases. To illuminate the complement's genetic underpinnings, we conduct genome-wide association studies of the functional activity of the classical (CP), lectin (LP), and alternative (AP) complement pathways in the Cooperative Health Research in South Tyrol study (n = 4,990). We identify seven loci, encompassing 13 independent, pathway-specific variants located in or near complement genes (CFHR4, C7, C2, MBL2) and non-complement genes (PDE3A, TNXB, ABO), explaining up to 74% of complement pathways' genetic heritability and implicating long-range haplotypes associated with LP at MBL2. Two-sample Mendelian randomization analyses, supported by transcriptome- and proteome-wide colocalization, confirm known causal pathways, establish within-complement feedback loops, and implicate causality of ABO on LP and of CFHR2 and C7 on AP. LP causally influences collectin-11 and KAAG1 levels and the risk of mouth ulcers. These results build a comprehensive resource to investigate the role of complement in human health.


Subject(s)
Genome-Wide Association Study , Mannose-Binding Lectin , Humans , Complement Activation , Complement System Proteins/metabolism , Lectins/metabolism , Haplotypes/genetics , Mannose-Binding Lectin/genetics
17.
Front Endocrinol (Lausanne) ; 14: 1230244, 2023.
Article in English | MEDLINE | ID: mdl-37941903

ABSTRACT

Aims: This study aimed to explore associations of mannan-binding lectin-associated serine protease (MASP) levels in early pregnancy with gestational diabetes mellitus (GDM). We also examined interactions of MASPs and deoxycholic acid (DCA)/glycoursodeoxycholic acid (GUDCA) for the GDM risk and whether the interactive effects if any on the GDM risk were mediated via lysophosphatidylcholine (LPC) 18:0. Materials and methods: A 1:1 case-control study (n = 414) nested in a prospective cohort of pregnant women was conducted in Tianjin, China. Binary conditional logistic regressions were performed to examine associations of MASPs with the GDM risk. Additive interaction measures were used to examine interactions between MASPs and DCA/GUDCA for the GDM risk. Mediation analyses and Sobel tests were used to examine mediation effects of LPC18:0 between the copresence of MASPs and DCA/GUDCA on the GDM risk. Results: High MASP-2 was independently associated with GDM [odds ratio (OR): 2.62, 95% confidence interval (CI): 1.44-4.77], while the effect of high MASP-1 on GDM was attributable to high MASP-2 (P for Sobel test: 0.003). Low DCA markedly increased the OR of high MASP-2 alone from 2.53 (1.10-5.85) up to 10.6 (4.22-26.4), with a significant additive interaction. In addition, high LPC18:0 played a significant mediating role in the links from low DCA to GDM and from the copresence of high MASP-2 and low DCA to GDM (P for Sobel test <0.001) but not in the link from high MASP-2 to GDM. Conclusions: High MASP-1 and MASP-2 in early pregnancy were associated with GDM in Chinese pregnant women. MASP-2 amplifies the risk of low DCA for GDM, which is mediated via LPC18:0.


Subject(s)
Diabetes, Gestational , Mannose-Binding Lectin , Humans , Female , Pregnancy , Mannose-Binding Protein-Associated Serine Proteases/analysis , Diabetes, Gestational/epidemiology , Pregnant Women , Case-Control Studies , East Asian People , Prospective Studies
18.
Exp Parasitol ; 255: 108630, 2023 Dec.
Article in English | MEDLINE | ID: mdl-37820893

ABSTRACT

INTRODUCTION: The free-living protozoan Acanthamoeba can cause severe keratitis known as Acanthamoeba Keratitis (AK) and granulomatous amoebic encephalitis (GAE). The pathogenesis of Acanthamoeba includes intricate interactions between the organism and the host's immune system. The downstream analysis of a well-annotated genome assembly along with proteomic analysis can unravel several biological processes and aid in the identification of potential genes involved in pathogenicity. METHODS: Based on the next-generation sequencing data analysis, genes including lysophospholipase, phospholipase, S8/S53 peptidase, carboxylesterase, and mannose-binding protein were selected as probable pathogenic targets that were validated by conventional PCR in a total of 30 Acanthamoeba isolates. This was followed by real-time PCR for the evaluation of relative gene expression in the keratitis and amoebic encephalitis animal model induced using keratitis (CHA5), encephalitis (CHA24) and non-pathogenic environmental isolate (CHA36). In addition, liquid chromatography-mass spectrometry (LC-MS/MS) was performed for keratitis, encephalitis, and non-pathogenic environmental isolate before and after treatment with polyhexamethylene biguanide (PHMB). RESULTS: The conventional PCR demonstrated the successful amplification of lysophospholipase, phospholipase, S8/S53 peptidase, carboxylesterase, and mannose-binding protein genes in clinical and environmental isolates. The expression analysis revealed phospholipase, lysophospholipase, and mannose-binding genes to be significantly upregulated in the keratitis isolate (CHA 5) during AK in the animal model. In the case of the amoebic encephalitis model, phospholipase, lysophospholipase, S8/S53 peptidase, and carboxylesterase were significantly upregulated in the encephalitis isolate compared to the keratitis isolate. The proteomic data revealed differential protein expression in pathogenic versus non-pathogenic isolates in the pre and post-treatment with PHMB. CONCLUSION: The gene expression data suggests that lysophospholipase, phospholipase, S8/S53 peptidase, carboxylesterase, and mannose-binding protein (MBP) could play a role in the contact-dependent and independent mechanisms of Acanthamoeba pathogenesis. In addition, the proteomic profiling of the 3 isolates revealed differential protein expression crucial for parasite growth, survival, and virulence. Our results provide baseline data for selecting possible pathogenic targets that could be utilized for designing knockout experiments in the future.


Subject(s)
Acanthamoeba Keratitis , Acanthamoeba , Amebiasis , Encephalitis , Mannose-Binding Lectin , Animals , Lysophospholipase/genetics , Chromatography, Liquid , Proteomics , Tandem Mass Spectrometry , Acanthamoeba Keratitis/parasitology , Amebiasis/parasitology , Real-Time Polymerase Chain Reaction , Gene Expression , Peptide Hydrolases
19.
Rev Med Inst Mex Seguro Soc ; 61(4): 502-508, 2023 07 31.
Article in Spanish | MEDLINE | ID: mdl-37540722

ABSTRACT

Single nucleotide polymorphisms (SNPs) have been reported to play an important role in the etiology of dental caries. The aim of this research was, through a systematic review, to identify SNPs recently associated with dental caries in pediatric populations. We included studies performed in humans up to 18 years of age that evaluated the relationship between SNPs and dental caries from 2017 to 2022. Articles that covered other study variables were excluded. PubMed, ScienceDirect and Web of Science were used to search for information and the included articles were evaluated with one of the Joanna Briggs Institute's tools. Twenty-five articles were selected, 60% of which were given high methodological quality. A total of 10,743 research subjects, ranging in age from 20 months to 17 years, participated in the study. The SNPs considered risk factors were identified in the genes miRNA202, VDR, AMELX, TUFT1, KLK4, MBL2, ENAM, DEFB1, HLA-DRB1, TAS1R1, DSPP, RUNX2 and MMP13; those considered protective factors were identified in the genes MMP20, AMBN, MMP9, TIMP2, TNF-α, VDR, IL1B, ENAM and HLA-DRB1. This systematic review presents the genetic polymorphisms that are associated with the etiology of caries in children and adolescents, some of which act as risk factors and others as protective factors against the disease.


Se ha reportado que los polimorfismos de nucleótido único (SNPs) juegan un papel importante en la etiología de la caries dental. El objetivo de esta investigación fue, a través de una revisión sistemática, identificar los SNPs asociados recientemente a la caries dental en poblaciones pediátricas. Se incluyeron estudios realizados en humanos de hasta 18 años de edad que evaluaron la relación entre los SNPs y la caries dental, publicados desde el 2017 hasta el 2022. Se excluyeron los artículos que abarcaron otras variables de estudio. PubMed, ScienceDirect y Web of Science se utilizaron para la búsqueda de información y los artículos incluidos fueron evaluados con una de las herramientas del Instituto Joanna Briggs. Fueron seleccionados 25 artículos, al 60% de ellos se le otorgó calidad metodológica alta. En total participaron 10,743 sujetos de invetigación, cuyas edades variaron de 20 meses a 17 años. Los SNPs considerados factores de riesgo fueron identificados en los genes miRNA202, VDR, AMELX, TUFT1, KLK4, MBL2, ENAM, DEFB1, HLA-DRB1, TAS1R1, DSPP, RUNX2 y MMP13, los considerados factores de protección se identificaron en los genes MMP20, AMBN, MMP9, TIMP2, TNF-α, VDR, IL1B, ENAM y HLA-DRB1. Esta revisión sistemática expone los polimorfismos genéticos que se encuentran asociados a la etiología de la caries en niños y adolescentes, algunos de los cuales actúan como factores de riesgo y otros como factores de protección ante la enfermedad.


Subject(s)
Dental Caries , Mannose-Binding Lectin , MicroRNAs , beta-Defensins , Adolescent , Humans , Child , Dental Caries/genetics , HLA-DRB1 Chains/genetics , Polymorphism, Single Nucleotide , Mannose-Binding Lectin/genetics , beta-Defensins/genetics
20.
Mol Biol Rep ; 50(10): 8145-8161, 2023 Oct.
Article in English | MEDLINE | ID: mdl-37558798

ABSTRACT

BACKGROUND: The physiological interactions of MBL suggest its contribution towards the pathogenesis of COPD. OBJECTIVE: The present case-control study was undertaken to elucidate the role of MBL with COPD risk and clinical outcomes in north Indian cohort. METHODS: Patients were enrolled as per GOLD criteria. MBL2 variants were selected based on the literature and their putative functional significance. Genotyping of six single nucleotide polymorphisms of MBL2 comprising of two coding (rs1800450, rs1800451) and four non-coding variants (rs11003125, rs7096206, rs11003123 and rs7095891) was done by using PCR-RFLP and ARMS-PCR. Serum MBL levels were analysed by sandwich ELISA. RESULTS: Overall findings of the molecular genetic analysis of MBL2 indicated significant difference in frequency of three of the six studied variants, between patients and controls or among different disease severity stages. Heterozygous genotype of rs7095891 showed significant protective association towards severity of disease. Linkage disequilibrium (LD) analysis indicated a strong LD between rs1800450 and rs7095891 while intermediate LD was observed for rs11003123/rs11003125 and rs7096206/rs11003125. Haplotype analysis revealed 17.14-fold risk of developing exacerbations conferred by GGGTGG haplotype. Significantly low serum MBL levels observed in COPD patients as compared to controls. Significant difference in MBL deficiency levels were also observed for homozygous wild and variant genotypes of rs11003125 and rs7096206 respectively, as well as for all genotypes of rs11003123 than respective controls. CONCLUSION: The present study reinforces the role played by MBL in the susceptibility, protection and clinical outcomes of COPD. Therefore, including the reported associations at diagnostic, prognostic and therapeutic interventions may prove helpful.


Subject(s)
Mannose-Binding Lectin , Pulmonary Disease, Chronic Obstructive , Humans , Genotype , Polymorphism, Single Nucleotide/genetics , Haplotypes/genetics , Pulmonary Disease, Chronic Obstructive/genetics , Mannose-Binding Lectin/genetics , Case-Control Studies , Genetic Predisposition to Disease
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